Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=3)[S:10][C:11]=2[C:12](O)=[O:13])=[CH:4][CH:3]=1.CC[N:26]=C=NCCCN(C)C.O.ON1C2C=CC=CC=2N=N1.[OH-].[NH4+]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=3)[S:10][C:11]=2[C:12]([NH2:26])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)c1sc(-c2ccnc(Cl)c2)nc1Cc1ccc(Cl)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: NC(=O)c1sc(-c2ccnc(Cl)c2)nc1Cc1ccc(Cl)cc1
Reaction time: 0.17 h
Yield: 67.8 %

Procedure:
To a mixture of 4-(4-chlorobenzyl)-2-(2-chloropyridin-4-yl)thiazole-5-carboxylic acid (179 mg, 0.490 mmol) in DCM (27.5 mL) was added EDCI (282 mg, 1.47 mmol) and 1-hydroxybenzotriazole hydrate (150 mg, 0.980 mmol) and the solution was stirred for 10 minutes. 28% ammonium hydroxide (2.12 mL, 24.5 mmol) was added and the resulting mixture was stirred at room temperature overnight. Water (20 mL) was added and the mixture was extracted with DCM (2×25 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (methanol/DCM=0/100→15/85) to give 121 mg of the title compound as a white solid (67% yield). LC/MS (FA) ES+ 364, 366. 1H NMR (400 MHz, d6-DMSO) δ: 8.54 (dd, 1H, J=5.2, 0.7 Hz), 8.02 (bs, 1H), 7.91 (dd, 1H, J=1.5, 0.7 Hz), 7.84 (dd, 1H, J=5.2, 1.5 Hz), 7.79 (bs, 1H), 7.36-7.29 (m, 4H), 4.43 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:7][C:6]=12.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:7][C:6]=12
Reactant: COc1ccccc1B(O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ccn2ncc(Br)c2n1
Product: COc1ccccc1-c1cnn2ccc(NC[C@@H]3CCCN3C(=O)OC(C)(C)C)nc12
Yield: 68 %

Procedure:
The Suzuki coupling of (5)-tert-butyl 2-(((3-bromopyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)pyrrolidine-1-carboxylate with (2-methoxyphenyl)boronic acid under the same conditions as described in example 5.6.5 to give 68% of the titled compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.50 (s, 9 H) 1.85-2.12 (m, 4 H) 3.40 (dd, J=7.58, 4.04 Hz, 2 H) 3.46-3.59 (m, 1 H) 3.59-3.67 (m, 1 H) 3.94 (s, 3 H) 4.19 (br. s., 1 H) 6.07 (d, J=7.07 Hz, 1 H) 6.99 (d, J=7.58 Hz, 1 H) 7.06 (td, J=7.45, 1.01 Hz, 1 H) 7.15-7.22 (m, 1 H) 8.14-8.28 (m, 1 H) 8.45 (d, J=6.82 Hz, 1 H) 8.51 (s, 1 H); LRMS (ESI) m/e 424.0 [(M+H)+, calcd for C23H29N5O3 423.0].
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:14])[O:4][C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][CH:8]=[C:7]([OH:13])[CH:6]=2.C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C.[C:28](Cl)(=O)[CH2:29][CH2:30]CCCCCCCCC>O1CCCC1.C(OCC)(=O)C.O>[C:3]([OH:4])(=[O:14])[CH2:2][CH2:11][CH2:10][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:28][CH2:29][CH3:30].[Cl:1][C:2]1[C:3](=[O:14])[O:4][C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][CH:8]=[C:7]([OH:13])[CH:6]=2
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: Cc1c(Cl)c(=O)oc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.5 g of 3-chloro-4-methyl-7-hydroxy coumarin was dissolved in 60 ml of tetrahydrofuran in a 250 ml flask, followed by the addition of 3.6 g of potassium carbonate and 3.6 ml of triethylamine. After 30 minutes, 8.0 ml of lauroyl chloride was added thereto and the mixture was stirred for 2 hours at room temperature. Thereafter, 50 ml of distilled water and 250 ml of ethyl acetate were added to extract the title compound into the ethyl acetate phase. The ethyl acetate phase was washed with 200 ml of salt water, and then dried with anhydrous manganese. Following the distillation and evaporation of the solvent, the residue was recrystalized with hexane and ethyl acetate to obtain white 3-chloro-4-methyl-7-hydroxy coumarin laurate.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:17]=[N:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]C)=[CH:24][CH:23]=2)=[N:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(OC1C=NC(C2C=CC(CCCCCCCCCC)=CC=2)=NC=1)CCCCCCCCCCCCC.C(OC1C=NC(C2C=CC(CCCCCCCCC)=CC=2)=NC=1)CCCCCCCCCCCCC>>[CH2:1]([O:15][C:16]1[CH:21]=[N:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:24][CH:23]=2)=[N:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1cnc(-c2ccc(CCCCCC)cc2)nc1
Agent: CCCCCCCCCCCCCCOc1cnc(-c2ccc(CCCCCCCCC)cc2)nc1
Agent: CCCCCCCCCCCCCCOc1cnc(-c2ccc(CCCCCCCCCC)cc2)nc1
Product: CCCCCCCCCCCCCCOc1cnc(-c2ccc(CCCCC)cc2)nc1

Procedure:
5-tetradecyloxy-2-(4-hexylphenyl)pyrimidine ##STR38## 5-tetradecyloxy-2-(4-heptylphenyl)pyrimidine 5-tetradecyloxy-2-(4-octylphenyl)pyrimidine ##STR39## 5-tetradecyloxy-2-(4-nonylphenyl)pyrimidine 5-tetradecyloxy-2-(4-decylphenyl)pyrimidine
Reaction SMILES: O[C:2]1[C:7]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:6](O)[N:5]=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.O=P(Cl)(Cl)[Cl:30]>>[Cl:30][C:6]1[C:7]2[N:8]=[C:9]([C:10]3[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=3)[O:17][C:2]=2[N:3]=[CH:4][N:5]=1
Reactant: O=C(Nc1c(O)ncnc1O)c1ccc(F)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(-c2nc3c(Cl)ncnc3o2)cc1
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 30 %

Procedure:
To a solution of N-(4,6-dihydroxypyrimidin-5-yl)-4-fluorobenzamide (0.30 g, 1.20 mmol) in POCl3 (6 ml) was added diisopropylethylamine (0.42 ml, 2.41 mmol). The reaction mixture was stirred under N2 at 90° C. for 3.5 hours. The reaction mixture was allowed to cool down to room temperature and the volatiles were evaporated to dryness. The residue was diluted with water and the aqueous phase was extracted with diethyl ether. The combined organic layers were washed with a saturated NaHCO3 solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (CH2Cl2/MeOH 100:1) to yield the title compound as a white solid (0.13 g, 30%).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][C:21](=[O:32])[CH2:22][N:23]([C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][N:26]=1)[CH3:24]>>[CH3:19][O:20][C:21](=[O:32])[CH2:22][N:23]([CH3:24])[C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:27][N:26]=1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: COC(=O)CN(C)c1ccc(N)cn1
Product: COC(=O)CN(C)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 1 above, (methyl-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-amino)-acetic acid methyl ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and [(5-amino-pyridin-2-yl)-methyl-amino]-acetic acid methyl ester. LCMS calcd for C20H17F3N4O4 (m/e) 434, obsd 435 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:13](=[C:15]2\[C:16](=[C:22]([CH3:24])[CH3:23])[C:17](O[C:20]\2=[O:21])=[O:18])/[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[CH3:12][O:11][C:7]1[CH:6]=[C:5](/[C:13](=[C:15]2\[C:16](=[C:22]([CH3:23])[CH3:24])[C:17]([N:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]\2=[O:21])=[O:18])/[CH3:14])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: Nc1ccccc1
Reactant: COc1cc(/C(C)=C2/C(=O)OC(=O)C2=C(C)C)cc(OC)c1OC
Solvent: Cc1ccccc1
Product: COc1cc(/C(C)=C2/C(=O)N(c3ccccc3)C(=O)C2=C(C)C)cc(OC)c1OC
Reaction time: 2 h

Procedure:
(E)-α-(3,4,5-trimethoxyphenyl) ethylideneisopropylidene succinic anhydride (4 parts), prepared as in Example 3, in toluene (40 parts by volume), and aniline (1 part) were heated (12 hours) at 70°. Petrol was added and the liberated succinamic acid separated. The dry acid (1.8 parts) was dissolved in acetyl chloride (40 parts by volume) boiled for 2 hours and the solvent removed. Crystallisation of the product from a toluene/petrol mixture gave (E)-α-(3,4,5-trimethoxyphenyl) ethylideneisopropylidene-N-phenylsuccinimide as pale yellow needles, melting point 169.5°. The compound shows similar photochromic properties to the corresponding (E)-anhydride.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][CH3:23])[CH:21]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:30]1[CH2:35][CH2:34][CH2:33][C@@H:32]([NH:36]C(=O)OC(C)(C)C)[CH2:31]1>>[CH2:22]([N:20]1[CH:21]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([N:30]5[CH2:35][CH2:34][CH2:33][C@@H:32]([NH2:36])[CH2:31]5)[CH:3]=[CH:4][CH:5]=4)=[N:9][NH:10][C:11]3=[CH:12][N:13]=2)[CH:18]=[N:19]1)[CH3:23]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: CCn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Product: CCn1cc(-c2cc3c(-c4cccc(N5CCC[C@@H](N)C5)n4)n[nH]c3cn2)cn1
Yield: 41.6 %

Procedure:
Following the procedures as described in Example 189, 3-(6-fluoropyridin-2-yl)-5-(1-ethyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and (R)-tert-butyl piperidin-3-ylcarbamate were reacted. The product was deprotected and purified to give 285 as a white solid (41.6% over two steps). 1H NMR (400 MHz, DMSO) δ 9.02 (s, 1H), 8.60 (s, 1H), 8.34 (s, 1H), 7.97 (s, 1H), 7.62 (t, J=8.0 Hz, 1H), 7.42 (d, J=7.4 Hz, 1H), 6.83 (d, J=8.5 Hz, 1H), 4.45 (d, J=8.7 Hz, 1H), 4.28-4.12 (m, 3H), 2.98 (t, J=10.9 Hz, 1H), 2.82-2.72 (m, 2H), 2.03-1.93 (m, 1H), 1.86-1.77 (m, 1H), 1.67-1.51 (m, 1H), 1.42 (t, J=7.3 Hz, 3H), 1.38-1.26 (m, 1H); 3 protons not seen. LC/MS: m/z 389.2 [M+1]
Reaction SMILES: CN1CCNCC1.[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]2[CH:38]=[CH:37][C:24]3[NH:25][C:26]([C:28]4[N:29]=[N:30][C:31]5[C:36]=4[CH2:35][CH:34]=[CH:33][CH:32]=5)=[N:27][C:23]=3[CH:22]=2)=[O:20])[CH2:11][CH2:10]1>>[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]2[CH:38]=[CH:37][C:24]3[NH:25][C:26]([C:28]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[NH:30][N:29]=4)=[N:27][C:23]=3[CH:22]=2)=[O:20])[CH2:11][CH2:10]1
Reactant: CN1CCN(CCCNC(=O)c2ccc3[nH]c(C4=C5CC=CC=C5N=N4)nc3c2)CC1
Agent: CN1CCNCC1
Product: CN1CCN(CCCNC(=O)c2ccc3[nH]c(-c4n[nH]c5ccccc45)nc3c2)CC1

Procedure:
By proceeding in a manner similar to Example 246(ab) above but using 443-(aminopropyl))-1-methyl piperazine there was prepared 2-(4H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid [3-(4-methyl-piperazin-1-yl)-propyl]-amide as an oil. MS: 416.21 (M+H)+. HPLC (Method L): RT=4.46 minutes.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:22][CH:21]=2)[CH2:15][CH2:14]1.C(N(CC)CC)C>ClCCl.O>[CH:12]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])=[CH:31][CH:32]=2)[CH2:15][CH2:14]1)=[O:11]
Reactant: CC(C)(C)OC(=O)c1ccc(CN2CCC(CO)CC2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1ccc(CN2CCC(C=O)CC2)cc1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
To a solution of oxalyl chloride (0.408 mL, 4.67 mmol) in dichloromethane (5 mL) at −60° C. was added a solution of DMSO (0.508 mL, 7.15 mmol) in 15 mL of dichloromethane over 30 minutes. The reaction was stirred for 30 minutes at −60° C. A solution of tert-butyl 4((4-(hydroxymethyl)piperidin-1-yl)methyl)benzoate (950 mg, 3.11 mmol) in 5 mL of dichloromethane was added over 10 minutes at −60° C. The reaction mixture was stirred for 3 hours at −60° C., then triethylamine (2.168 mL, 15.55 mmol) was added and after 10 minutes 10 mL of water was added. The reaction mixture was allowed to warm up to the room temperature. The layers were separated. The pH of the water layer was adjusted to ˜7 with 1 M HCl and then extracted with 20 mL of dichloromethane. The combined organic layers were washed with water and brine, then dried over MgSO, filtered and evaporated. The resulting oil was purified on a silica column eluting with EtOAc to yield tert-butyl 4-((4-formylpiperidin-1-yl)methyl)benzoate (550 mg, 1.722 mmol, 55.4% yield) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 9.67 (d, J=1.26 Hz, 1H), 7.96 (d, J=8.34 Hz, 2H), 7.38 (d, J=8.34 Hz, 2H), 3.56 (s, 2H), 2.75-2.92 (m, 2H), 2.21-2.35 (m, 1H), 2.14 (t, J=10.48 Hz, 2H), 1.91 (dd, J=2.78, 13.14 Hz, 2H), 1.65-1.81 (m, 2H), 1.58-1.64 (m, 9H); LC-MS Rt=0.69 min; MS (ESI): 304.2 [M+H]+, 322.2 [M+H2O]+, 336.6 [M+Na]+
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[C:11]([NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][N:17]=2)[CH3:15])=[O:12])=[CH:4][CH:3]=1.Br.Br[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][O:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:10][C@@H:9]2[C:11]([NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:25])[F:26])=[CH:18][N:17]=2)[CH3:15])=[O:12])=[CH:6][CH:7]=1
Reactant: C[C@@H](NC(=O)[C@H]1C[C@@H]1c1ccc(O)cc1)c1ccc(OCC(F)(F)F)cn1
Reactant: BrCc1ccccn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)[C@H]1C[C@@H]1c1ccc(OCc2ccccn2)cc1)c1ccc(OCC(F)(F)F)cn1
Reaction time: 48 h
Yield: 27.2 %

Procedure:
A mixture of (1S*,2S*)-2-(4-hydroxyphenyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide (15 mg, 0.039 mmol), 2-(Bromomethyl)pyridine hydrobromide (100 mg, 0.394 mmol) and potassium carbonate (27 mg, 0.197 mmol) in DMF (2 mL) was heated at 70 oC with stirring for 2 days. The mixture was poured into water, and the aqueous layer was extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative LC-MS to give 5 mg (27% yield) of the title compound.
Reaction SMILES: [CH:1]1([NH:4][CH:5]([C:7]2[CH:8]=[CH:9][C:10]([O:27][CH3:28])=[C:11]([C:13]#[C:14][CH2:15][NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:12]=2)[CH3:6])[CH2:3][CH2:2]1.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][O:39][C@@H:38]([C:42](O)=[O:43])[CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[CH2:19]([O:18][C:17]([NH:16][CH2:15][C:14]#[C:13][C:11]1[CH:12]=[C:7]([CH:5]([N:4]([CH:1]2[CH2:2][CH2:3]2)[C:42]([C@@H:38]2[O:39][CH2:40][CH2:41][N:36]([C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH2:37]2)=[O:43])[CH3:6])[CH:8]=[CH:9][C:10]=1[O:27][CH3:28])=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](C(=O)O)C1
Reactant: COc1ccc(C(C)NC2CC2)cc1C#CCNC(=O)OCc1ccccc1
Product: COc1ccc(C(C)N(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)C2CC2)cc1C#CCNC(=O)OCc1ccccc1

Procedure:
Benzyl (3-{5-[1-(cyclopropylamino)ethyl]-2-methoxyphenyl}prop-2-yn-1-yl)carbamate and (2R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid were treated in the similar manner to Example 162 to give tert butyl (2R)-2-{[{1-[3-(3-{[(benzyloxy)carbonyl]amino}prop-1-yn-1-yl)-4-methoxyphenyl]ethyl}(cyclopropyl)amino]carbonyl}morpholine-4-carboxylate [Ex(295-3)] as a colorless solid.
Reaction SMILES: FC(F)(F)C1C=C(C=O)C2N([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])N=NC=2C=1.[F:24][C:25]([F:46])([F:45])[C:26]1[CH:27]=[C:28]([CH:43]=[O:44])[C:29]2[C:30]([CH:42]=1)=[N:31][N:32](COCC[Si](C)(C)C)[N:33]=2>>[F:46][C:25]([F:24])([F:45])[C:26]1[CH:27]=[C:28]([CH:43]=[O:44])[C:29]2[N:33]=[N:32][N:31]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:30]=2[CH:42]=1
Reactant: C[Si](C)(C)CCOCn1nc2cc(C(F)(F)F)cc(C=O)c2n1
Reactant: C[Si](C)(C)CCOCn1nnc2cc(C(F)(F)F)cc(C=O)c21
Product: C[Si](C)(C)CCOCn1nnc2c(C=O)cc(C(F)(F)F)cc21

Procedure:
5-(Trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazole-7-carbaldehyde and 6-(Trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-benzo[d][1,2,3]triazole-4-carbaldehyde and 6-(Trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazole-4-carbaldehyde. To a solution of 5-(trifluoromethyl)-1H-benzo[d][1,2,3]triazole-7-carbaldehyde (700 mg, 2.027 mmol) and N-methyldicyclohexylamine (0.59 mL, 2.74 mmol) in tetrahydrofuran (6 mL) at 0° C. was added (2-(chloromethoxy)ethyl)trimethylsilane (0.45 mL, 2.53 mmol). After 30 min, the ice bath was removed and stirring continued for an additional 30 min. The reaction was poured into ether, washed with water (2×), then 1M potassium bisulfate, then water, then brine, dried over magnesium sulfate, and concentrated. Column chromatography (5%→25% ethyl acetate/hexanes) gave two fractions. Concentration of the first fraction gave a mixture of 5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazole-7-carbaldehyde and 6-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-benzo[d][1,2,3]triazole-4-carbaldehyde (600 mg) as an oil. Concentration of the second fraction gave 6-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazole-4-carbaldehyde (165 mg) as a tan solid. 6-(Trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazole-4-carbaldehyde: 1H-NMR (CDCl3, 500 MHz) δ 10.92 (s, 1H), 8.29 (s, 1H), 8.21 (s, 1H), 6.12 (s, 2H), 3.59 (m, 2H), 0.91 (m, 2H), −0.07 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 187.9, 146.2, 133.3, 130.4 (q, J=34 Hz), 127.4, 123.4 (q, J=274 Hz), 121.5 (q, J=2.9 Hz), 113.8 (q, J=4.8 Hz), 68.0, 17.7, −1.4.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[CH3:15][C:16]([CH3:20])([CH3:19])[C:17]#[CH:18]>CN(C)C=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:15][C:16]([CH3:20])([CH3:19])[C:17]#[C:18][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: C#CC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)C#Cc1ccccc1
Temperature: 75 °C
Yield: 95.4 %

Procedure:
A degassed solution of iodobenzene (0.549 mL, 4.90 mmol), dichlorobis(triphenylphosphine)-palladium(II) (0.206 g, 0.294 mmol), copper(I) iodide (0.047 g, 0.245 mmol), and diisopropylamine (3.49 mL, 24.5 mmol) in N,N-dimethylformamide (20 mL) was added 3,3-dimethylbut-1-yne (0.896 mL, 7.35 mmol). The reaction mixture was and heated to 75° C. for 45 minutes. The reaction mixture was then diluted with ethyl acetate (150 mL), washed with 10% aqueous solution of lithium chloride (2×100 mL), washed with a 2M aqueous solution of ammonium hydroxide, washed with brine (100 mL), and dried over anhydrous sodium sulfate. Concentration followed by purification on silica gel chromatography with hexanes/dichloromethane (10/1) afforded (3,3-Dimethylbut-1-ynyl)benzene (740 mg). The compound had an HPLC ret. time=3.78 min.−Column: YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH−90% Water−0.2% H3PO4; Solvent B=90% MeOH−10% water−0.2% H3PO4; Start % B=0; Final % B=100.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@H:15]1[CH2:17][O:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH3:28].[NH2:29][CH2:30][CH2:31][CH2:32][N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>CN(C=O)C>[OH:16][C@H:15]([CH2:17][NH:29][CH2:30][CH2:31][CH2:32][N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]=[C:22]4[CH3:28])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H]1CO1
Reactant: NCCCN1CCCC1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H](O)CNCCCN1CCCC1
Temperature: 60 °C
Yield: 66.6 %

Procedure:
A mixture of (2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline (70 mg, 0.19 mmol), (prepared as described in Example 278), and 1-(3-aminopropyl)pyrrolidine (74 mg, 0.58 mmol) in DMF (5 ml) was heated to 60° C. overnight. The solvents were removed in vacuo and the residue purified by column chromatography using gradient elution (dichloromethane, 5% methanol/95% dichloromethane, 20% methanolic ammonia (7M)/80% dichloromethane) to give (2R)-7-(2-hydroxy-3-(3-(pyrrolidin-1-yl)propylamino)propoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (64 mg, 68%).
Reaction SMILES: [CH3:1][N:2]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]([C:25]2[NH:29][C:28](=[O:30])[NH:27][N:26]=2)[N:16]=1)[C@H:3]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]([C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1)[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]([C:25]2[NH:29][C:28](=[O:30])[NH:27][N:26]=2)[N:16]=1
Reactant: CN(c1nc(-c2n[nH]c(=O)[nH]2)cc2ccccc12)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(c1nc(-c2n[nH]c(=O)[nH]2)cc2ccccc12)[C@H]1CCNC1

Procedure:
To (S)-tert-butyl 3-(methyl(3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)amino)pyrrolidine-1-carboxylate (91 mg, 0.222 mmol) in DCM was added TFA (1.5 mL). After 2 hours the solvent was removed in vacuo to give the title compound, which was used without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[CH2:5].C(N(C(C)C)CC)(C)C.[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20]>C(Cl)Cl>[CH2:2]([NH:20][CH2:19][C:18]1[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:17]=1[O:16][CH3:15])[CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCBr
Reactant: COc1ccc(CN)c(OC)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCNCc1ccc(OC)cc1OC
Yield: 40 %

Procedure:
0.5 ml of 1-Bromo-3-butene (4.93 mmol) and 0.94 ml of diisopropyl ethylamine (5.40 mmol) were added to the reaction solution containing 0.74 ml of 2,4-dimethoxybenzylamine (a) (4.93 mmol) dissolved in methylene chloride with stirring and the mixture was stirred at room temperature for overnight. The reaction mixture was washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated in vacuo. The resulting compound was purified with Silica gel column chromatography with EtOAc solvent as an eluant to give 436 mg of the pure title compound (b) (yield: 40%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[Cl:18][C:19]1[C:20]([C:29](Cl)=[O:30])=[N:21][C:22]2[C:27]([N:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2.O>ClCCl>[Cl:18][C:19]1[C:20]([C:29]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([S:8](=[O:9])(=[O:10])[NH2:11])[CH:3]=2)=[O:30])=[N:21][C:22]2[C:27]([N:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2
Reactant: O=C(Cl)c1nc2ccccc2nc1Cl
Reactant: Nc1cccc(S(N)(=O)=O)c1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: NS(=O)(=O)c1cccc(NC(=O)c2nc3ccccc3nc2Cl)c1
Temperature: 25 °C
Yield: 74 %

Procedure:
To a solution of 3-aminobenzenesulfonamide (4.5 g, 26.43 mmol) and pyridine (12.83 mL, 158.6 mmol) in dichloromethane (48 mL) at 0° C. was added 3-chloroquinoxaline-2-carbonyl chloride (6.0 g, 26.43 mmol) in dichloromethane (60 mL) and the mixture was stirred and allowed to warm up to room temperature overnight. To the reaction slurry, water (60 mL) was added. The solid was isolated by filtration, washed with water (3×50 mL), hexane (50 mL) and a small amount of dichloromethane. The solid was dried under vacuum to yield 3-chloro-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide (7.1 g, 74%) as a salmon colored solid. ESI-MS m/z calc. 362.02, found 363.3 (M+1)+; Retention time: 1.43 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 8.40-8.33 (m, 1H), 8.31-8.24 (m, 1H), 8.24-8.14 (m, 1H), 8.12-7.98 (m, 2H), 7.90-7.81 (m, 1H), 7.69-7.58 (m, 2H), 7.47 (s, 2H) ppm.