Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:26][CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[CH:19][C:20]=3[O:22][CH:23]([CH3:25])[CH3:24])[N:15]=[CH:14][N:13]=2)=[C:4]2[O:10][CH2:9][O:8][C:5]2=[N:6][CH:7]=1.Cl.[CH3:36][N:37]([CH3:42])[CH2:38][C:39](Cl)=[O:40].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:26][CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][N:32]([C:39](=[O:40])[CH2:38][N:37]([CH3:42])[CH3:36])[CH2:31][CH2:30]4)=[CH:19][C:20]=3[O:22][CH:23]([CH3:25])[CH3:24])[N:15]=[CH:14][N:13]=2)=[C:4]2[O:10][CH2:9][O:8][C:5]2=[N:6][CH:7]=1
Reactant: CN(C)CC(=O)Cl
Reactant: CC(C)Oc1cc(OCCN2CCNCC2)cc2ncnc(Nc3c(Cl)cnc4c3OCO4)c12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Oc1cc(OCCN2CCN(C(=O)CN(C)C)CC2)cc2ncnc(Nc3c(Cl)cnc4c3OCO4)c12
Temperature: 0 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
4-(5-Chloro-2,3-methylenedioxypyrid-4-ylamino)-5-isopropoxy-7-(2-piperazin-1-ylethoxy)quinazoline (0.2 g) was added to a stirred mixture of 2-dimethylaminoacetyl chloride hydrochloride (0.097 g), triethylamine (0.15 ml) and methylene chloride (5 ml) that had been cooled to 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 2 hours. A second portion of each of 2-dimethylaminoacetyl chloride hydrochloride (0.097 g) and triethylamine (0.057 ml) were added and the reaction was stirred at ambient temperature for 16 hours overnight. Methylene chloride (50 ml) was added and the reaction mixture was extracted twice with a saturated aqueous sodium bicarbonate solution. The organic phase was dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using increasingly polar solvent mixtures, starting with a 9:1 mixture of methylene chloride and methanol and ending with a 90:8:2 mixture of methylene chloride, methanol and a saturated methanolic ammonia solution. There was thus obtained the title compound as a foam (0.155 g); NMR Spectrum: (CDCl3) 1.55 (d, 6H), 2.3 (s, 6H), 2.6 (m, 4H), 2.9 (t, 2H), 3.1 (s, 2H), 3.65 (m, 4H), 4.25 (t, 2H), 4.85 (s, 1H), 6.15 (s, 2H), 6.55 (s, 1H), 6.85 (s, 1H), 7.75 (s, 1H), 8.6 (s, 1H), 9.6 (s, 1H); Mass Spectrum: M+H+ 572 and 574; Elemental Analysis: Found C, 55.1; H, 6.1; N, 16.8; C27H34ClN7O5 0.75H2O requires C, 55.4; H, 6.1; N, 16.7%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](N)=[C:10]3[CH:24]=[N:23][N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.[ClH:32].N([O-])=O.[Na+].C([O-])(O)=O.[Na+]>CC#N>[Cl:32][C:9]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[C:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[N:12]=[C:11]2[N:22]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:23]=[CH:24][C:10]=12
Reactant: Nc1c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc2c1cnn2-c1ccccc1
Reactant: Cl
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Product: Clc1ccc(-c2c(-c3ccc(Cl)cc3Cl)nc3c(cnn3-c3ccccc3)c2Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 24 %

Procedure:
To a solution of 5-(4-chloro-phenyl)-6-(2,4-dichlorophenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-ylamine (16 mg, 0.034 mmol) in CH3CN (0.4 mL) is added cone. HCl (0.8 mL). NaNO2 (20 mg, 0.29 mmol) is added into the mixture at 0° C. After the addition, the mixture is warmed up to room temperature and stirred for 24 h. The mixture is then neutralized to pH˜7 by adding saturated aqueous NaHCO3 and extracted with EtOAc (3×3 mL). The combined organic layers are concentrated and purified by preparative thin layer chromatography to provide the titled compound as a white solid (4 mg, 24%). 1H NMR (CDCl3) δ(ppm) 8.35(s, 1H), 8.28 (d, 2H), 7.50 (t, 2H), 7.27-7.37(m, 2H), 7.24-7.26 (m, 2H), 7.07-7.16 (m, 4H); HPLC-MS calculated for C24H13Cl4N3 (M+1+): 484.0. Found: 484.1.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[CH:17]12[O:22][CH:21]1[CH2:20][O:19][CH2:18]2>>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][C@@H:21]2[CH2:20][O:19][CH2:18][C@H:17]2[OH:22])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: C1OCC2OC12
Product: CC(C)(C)c1cc(S[C@@H]2COC[C@H]2O)cc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
2,6-bis(1,1-Dimethylethyl)-4-mercaptophenol (1.85 g, 0.0078 mole) and the compound of Example 1 (0.64 g, 0.0074 mole) were added to a degassed (Argon) solution of 50% sodium hydroxide (5 ml) and isopropyl alcohol (50 ml). The reaction was heated to reflux for 24 hours. The reaction was cooled to room temperature and poured into water (125 ml). The solution was made acidic with 1N hydrochloric acid and extracted 3 times with 100 ml of diethyl ether. The combined diethyl ether extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to an oily solid in a rotary evaporator. The product was purified by silica gel chromatography and recrystallized from hexane (m.p. ca. 104° C.). The structure was supported by NMR and infrared spectroscopy and elemental analysis.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:22]([O:42][CH3:43])[C:23]2[N:27](COCC[Si](C)(C)C)[C:26]3[CH:36]=[CH:37][C:38]([C:40]#[N:41])=[CH:39][C:25]=3[N:24]=2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7](S(C1C=CC(C)=CC=1)(=O)=O)[CH:6]=[CH:5]2.CC1C(C(OC)C2N(COCC[Si](C)(C)C)C3C=C(C#N)C=CC=3N=2)=C2C(=C(C)C=1)N(S(C1C=CC(C)=CC=1)(=O)=O)C=C2>>[CH3:1][C:2]1[C:3]([CH:22]([O:42][CH3:43])[C:23]2[NH:27][C:26]3[CH:36]=[CH:37][C:38]([C:40]#[N:41])=[CH:39][C:25]=3[N:24]=2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: COC(c1c(C)cc(C)c2c1ccn2S(=O)(=O)c1ccc(C)cc1)c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Agent: COC(c1c(C)cc(C)c2c1ccn2S(=O)(=O)c1ccc(C)cc1)c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Product: COC(c1nc2cc(C#N)ccc2[nH]1)c1c(C)cc(C)c2[nH]ccc12

Procedure:
The title compound was synthesized from a mixture of (±)-2-((5,7-dimethyl-1-tosyl-1H-indol-4-yl)(methoxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-((5,7-dimethyl-1-tosyl-1H-indol-4-yl)(methoxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile as described in Example 64-B and 64-C. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.96 (s, 1H) 7.96 (s, 1H) 7.63 (d, J=8.34 Hz, 1H) 7.53 (d, J=8.34 Hz, 1H) 7.20 (t, J=2.65 Hz, 1H) 6.75 (s, 1H) 6.49 (br.s, 1H) 6.21 (s, 1H) 3.35 (s, 3H) 2.43 (s, 3H) 2.42 (s, 3H). HRMS calcd. for C20H18N4O (M+H)+ 331.1553. found 331.1559.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[NH2:16][CH:17]([C:19]1[CH:20]=[C:21]([CH3:31])[C:22]([NH:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[N:23][CH:24]=1)[CH3:18]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:16]([CH:17]([C:19]3[CH:24]=[N:23][C:22]([NH:25][CH2:26][C:27]([F:30])([F:28])[F:29])=[C:21]([CH3:31])[CH:20]=3)[CH3:18])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(C(C)N)cnc1NCC(F)(F)F
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1NCC(F)(F)F
Yield: 62 %

Procedure:
The title compound is prepared in 62% yield (220 mg, pale yellow solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (260 mg, 0.93 mmol, Step-1 of Intermediate-1) and 5-(1-aminoethyl)-3-methyl-N-(2,2,2-trifluoroethyl)pyridin-2-amine hydrochloride (250 mg, 0.93 mmol, Amine-46, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [CH:1]1([C:4]2[N:5]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:6]3[C:11]([C:12]=2[CH2:13][C:14]([NH2:16])=[O:15])=[CH:10][C:9]([O:17]C)=[CH:8][CH:7]=3)[CH2:3][CH2:2]1.B(Br)(Br)Br.C(Cl)Cl.O.C(OCC)(=O)C>C(Cl)Cl>[CH:1]1([C:4]2[N:5]([CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:6]3[C:11]([C:12]=2[CH2:13][C:14]([NH2:16])=[O:15])=[CH:10][C:9]([OH:17])=[CH:8][CH:7]=3)[CH2:2][CH2:3]1
Reactant: COc1ccc2c(c1)c(CC(N)=O)c(C1CC1)n2Cc1ccccc1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: NC(=O)Cc1c(C2CC2)n(Cc2ccccc2)c2ccc(O)cc12
Yield: 78 %

Procedure:
A solution of 400 mg (1.2 mmol) of 2-cyclopropyl-5-methoxy-1-(phenylmethyl)-1H-indole-3-acetamide and 2 mL of 1M BBr3 /methylene chloride in 130 mL of methylene chloride was stirred for 1 hour with an ice-water bath and 3 hours at room temperature. The mixture was poured into water, 200 mL of ethyl acetate added, the organic layer separated, washed with brine and dried (Na2SO4). After concentrating at reduced pressure, the residue was crystallized from ethyl acetate to give 300 mg (79% yield) of 2-cyclopropyl-5-hydroxy-1-(phenylmethyl)-1H-indole-3-acetamide, mp, 174°-175° C.
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:23][C:24]1[C:29]2[N:30]=[C:31]([NH2:33])[S:32][C:28]=2[CH:27]=[CH:26][CH:25]=1>>[N:1]1([S:11]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:33][C:31]3[S:32][C:28]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:23])[C:29]=4[N:30]=3)=[O:20])=[CH:21][CH:22]=2)(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Reactant: Cc1cccc2sc(N)nc12
Product: Cc1cccc2sc(NC(=O)c3ccc(S(=O)(=O)N4CCCc5ccccc54)cc3)nc12

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with 4-methylbenzo[d]thiazol-2-amine (44 mg, 0.24 mmol) using method B. The residue was purified using flash chromatography eluting with 0-30% EtOAc in hexanes to give 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(4-methylbenzo[d]thiazol-2-yl)benzamide as a white solid. Yield: 24 mg (21%). 1H-NMR: 8.22 (d, J=8.5 Hz, 2H), 7.84 (d, J=8.0 Hz, 1H), 7.76 (d, J=8.5 Hz, 2H), 7.62 (d, J=8.5 h, 1H), 7.31-7.08 (m, 5H), 3.85-3.79 (m, 2H), 2.62 (s, 3H), 2.45 (t, J=7.0 Hz, 2H), 1.66-1.58 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18]C)=[CH:15][CH:16]=3)[C:11]([CH2:20][C:21]([NH2:23])=[O:22])=[C:10]2[CH3:24])[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)Br.C(Cl)Cl.O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11]([CH2:20][C:21]([NH2:23])=[O:22])=[C:10]2[CH3:24])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)c(CC(N)=O)c(C)n2Cc1cccc(Cl)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cc1c(CC(N)=O)c2cc(O)ccc2n1Cc1cccc(Cl)c1
Reaction time: 16 h
Yield: 47.8 %

Procedure:
A solution of 483 mg (1.4 mmol) of 1-[(3-chlorophenyl) methyl]-5-methoxy-2-methyl-1H-indole-3-acetamide and 5.6 mL of 1M BBr3/methylene chloride in 20 mL of methylene chloride was stirred for 5 hours, 2 mL of 1M BBr3/methylene chloride added and stirred 16 hours. The mixture was poured into water, extracted with ethyl acetate, the ethyl acetate solution washed with brine, dried (MgSO4) and concentrated at reduced pressure. The residue was chromatographed on silica gel and eluted using a gradient, 50% EtOAc/hexane→4EtOAc, to give 155 mg of starting material, 1-[(3-chlorophenyl)methyl]-5-methoxy-2-methyl-1H-indole-3-acetamide, and 220 mg (48% yield) of 1-[(3-chlorophenyl)methyl]-5-hydroxy-2-methyl-1H-indole-3-acetamide, mp, 173-177° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2OC2C=CC=CC=2)=[CH:4][CH:3]=1.[NH2:19]C1C2C(=CC(Br)=CC=2)C=CN=1>>[NH2:19][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: Brc1ccc2ccnc(Oc3ccccc3)c2c1
Reactant: Nc1nccc2cc(Br)ccc12
Product: Nc1nccc2ccc(Br)cc12

Procedure:
Compound 37d was prepared from 37c using the procedure described for 1d. 1H-NMR 200 MHz (CDCl3) δ: 5.1 (2H, br. s), 7.03 (1H, dd, J=6 Hz and J=1 Hz), 7.59 (1H, d, J=9 Hz), 7.70 (1H, dd, J=9 Hz and J=2 Hz), 7.95-8.00 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3Br)[C:18]2=[O:27])=[CH:12][CH:11]=1.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([F:36])[CH:35]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[C:32]3[CH:31]=[C:30]([F:29])[CH:35]=[C:34]([F:36])[CH:33]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(Br)cccc3C2=O)cc1
Product: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(cccc3-c3cc(F)cc(F)c3)C2=O)cc1
Yield: 82 %

Procedure:
The procedure of Example 2 was repeated except for using N-(2-aminophenyl)-4-((4-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 9 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and 3,5-difluorophenyl boronic acid instead of phenyl boronic acid to obtain the title compound (82%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15]C)[CH:13]=2)[CH2:8][CH2:7][NH:6]1)[CH3:3].[BrH:17]>>[BrH:17].[BrH:17].[CH3:3][N:2]([CH2:4][CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH2:8][CH2:7][NH:6]1)[CH3:1]
Reactant: COc1ccc2c(c1)C(CN(C)C)NCC2
Agent: Br
Product: CN(C)CC1NCCc2ccc(O)cc21

Procedure:
1.0 g (4.55 mmoles) of 1-dimethylaminomethyl-7-methoxy-1,2,3,4-tetrahydroisoquinoline was heated two hours at 130° C. with 30 ml of 48% HBr.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]([CH3:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][N:22]([CH2:25][CH2:26][OH:27])[N:21]=1)=[CH:16][CH:15]=3.Cl[CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]([CH3:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][N:22]([CH2:25][CH2:26][O:27][CH2:34][CH2:35][N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[N:21]=1)=[CH:16][CH:15]=3
Reactant: ClCCN1CCCC1
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn(CCO)n4)ccc3n(C)c21
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn(CCOCCN5CCCC5)n4)ccc3n(C)c21

Procedure:
The process is carried out as indicated in Example 101 above, with the compound from Example 51 above, 3-(2,4-dichlorophenyl)-6-[1-(2-hydroxyethyl)-1H-pyrazol-3-yl]-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one, and 1-(2-chloroethyl)-pyrrolidine.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].O.C(=O)([O-])O.[Na+].[C:19](Cl)(Cl)=[S:20]>C(Cl)(Cl)Cl>[F:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([N:1]=[C:19]=[S:20])[CH:11]=1
Reactant: S=C(Cl)Cl
Reactant: COC(=O)c1ccc(F)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(F)cc1N=C=S
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
Methyl 2-amino-4-fluorobenzoate (7.3 g, 43.2 mmol) was dissolved in chloro-form, followed by addition of water (150 mL) and sodium hydrogencarbonate (36.3 g, 432 mmol). Thiophosgene (3.73 mL, 47.5 mmol) was added and the mixture was stirred at RT for 2 h. Water (250 mL) was added and the mixture was extracted with DCM. The combined organics were dried (MgSO4) and evaporated to give the title compound (8.90 g, 98%).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:8]=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.CN([CH:26]=[O:27])C>>[C:1]([C:5]1[N:9]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:8]([CH:26]=[O:27])=[N:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cncn1COCC[Si](C)(C)C
Reactant: CN(C)C=O
Agent: [Li]CCCC
Product: CC(C)(C)c1cnc(C=O)n1COCC[Si](C)(C)C
Yield: 98.7 %

Procedure:
Reaction 5-tert-butyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (276 mg, 1.09 mmol), 2.5 M n-BuLi (567 uL, 1.42 mmol), and DMF (253 uL, 3.27 mmol) for 2 h at −40° C. gave the title compound (304 mg, 99%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 0.91 (t, 2H, J=9.0 Hz), 1.33 (s, 9H), 3.57 (t, 2H, J=7.5 Hz), 5.72 (s, 2H), 7.10 (s, 1H), 9.80 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:12](=[O:21])[NH:13][CH:14]=[CH:15][C:16]=2[C:17]([F:20])([F:19])[F:18])[CH:9]=1)[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].[NH2:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:42])[CH2:40]Br)=[C:34]([Cl:43])[CH:33]=1)(=[O:31])=[O:30]>CN(C)C=O.C(OCC)(=O)C>[NH2:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:42])[CH2:40][N:13]2[CH:14]=[CH:15][C:16]([C:17]([F:18])([F:19])[F:20])=[C:11]([O:10][C:8]3[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=[C:2]([Cl:1])[CH:9]=3)[C:12]2=[O:21])=[C:34]([Cl:43])[CH:33]=1)(=[O:31])=[O:30]
Reactant: NS(=O)(=O)c1ccc(NC(=O)CBr)c(Cl)c1
Reactant: N#Cc1cc(Cl)cc(Oc2c(C(F)(F)F)cc[nH]c2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(Cl)cc(Oc2c(C(F)(F)F)ccn(CC(=O)Nc3ccc(S(N)(=O)=O)cc3Cl)c2=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 3-chloro-5-{[2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl]oxy}benzonitrile (3C, 0.050 g, 0.159 mmol) and potassium carbonate (0.022 g, 0.159 mmol) suspended in dimethylformamide (1 mL) was added N-[4-(aminosulfonyl)-2-chlorophenyl]-2-bromoacetamide (0.052 g, 0.149 mmol) as a solution in dimethylformamide (1 mL). The reaction mixture was allowed to stir at room temperature. After 16 hours, the reaction mixture was diluted with ethyl acetate (20 mL), washed with water (3×10 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography on a pre-packed silica gel Redi Sep 12 gram column, eluting with 0-5% methanol in CH2Cl2 to yield the title compound. 1H NMR (DMSO-d6) δ 10.23 (s, 1H), 8.05-7.96 (m, 2H), 7.89 (d, J=2.1 Hz, 1H), 7.76-7.72 (m, 2H), 7.55-7.53 (m, 1H), 7.52-7.50 (m, 1H), 7.45 (s, 2H), 6.68 (d, 0.1=7.1 Hz, 1H), 5.02 (s, 2H). HRMS (M+1)=560.998.
Reaction SMILES: [Cl:1][C:2]1([Cl:14])[CH:12]2[CH:3]1[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([OH:13])[C:10]=1[CH2:11]2.C(O)C.[H-].[Na+].[H][H].[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25]Br>>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][O:13][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH2:11][CH:12]1[C:2]([Cl:14])([Cl:1])[CH:3]1[CH2:4]2
Reactant: CN(C)CCBr
Reactant: Oc1cccc2c1CC1C(C2)C1(Cl)Cl
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)CCOc1cccc2c1CC1C(C2)C1(Cl)Cl
Reaction time: 3 h

Procedure:
To a cooled solution of 2.3g (0.01 mole) of product of Example 2 in 50 ml of anhydrous ethanol 0.48g (0.01 mole) of 50% sodium hydride is added in portions. After the evolution of hydrogen has ceased, 1.5g (0.01 mole) of 2-(dimethylamino) ethyl bromide is added dropwise, and the mixture is refluxed with stirring for 3 hours. The solvent is removed in vacuo, the residue is mixed with 25 ml of water and the mixture extracted with chloroform. The chloroform extract is washed with water, dried (MgSO4), and concd. to give 3-[2-(dimethylamino)ethoxy]-1,1-dichloro-1a, 2,7,7a-tetrahydro[1H]-cyclopropa[b]naphthalene.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[C:10]=1[Cl:11])=[O:5])C.[Li+].[OH-]>CO.O>[Cl:11][C:10]1[N:9]([CH:12]2[CH2:13][CH2:14][CH2:15]2)[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnn(C2CCC2)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cnn(C2CCC2)c1Cl
Yield: 93.4 %

Procedure:
To a solution of 5-chloro-1-cyclobutyl-1H-pyrazole-4-carboxylic acid ethyl ester (182 mg, 0.79 mmol) in methanol (8 mL) and water (8 mL) was added LiOH (23 mg, 0.96 mmol). The reaction mixture was stirred at reflux for 4 hours and then concentrated under reduced pressure to remove the methanol. The residue was diluted with water, acidified to pH 2 with concentrated HCl and extracted with ethyl acetate. The organic layer was evaporated in vacuo to give 5-chloro-1-cyclobutyl-1H-pyrazole-4-carboxylic acid (148 mg, 94%) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][NH:20][C@@H:21]([CH3:29])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=1.Cl[C:32]([O:34][CH3:35])=[O:33]>>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][N:20]([C:32]([O:34][CH3:35])=[O:33])[C@@H:21]([CH3:29])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=1
Reactant: COC(=O)Cl
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN[C@@H](C)Cc2ccccc2)c1
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN(C(=O)OC)[C@@H](C)Cc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 2, Step 4, using the following starting materials: (3-{4-bromo-2-[((S)-1-methyl-2-phenyl-ethylamino)-methyl]-phenoxy}-phenyl)-acetic acid methyl ester and methyl chloroformate.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:13][C:10]1[CH:11]=[CH:12][C:3]([CH2:2][C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([F:14])[CH:20]=2)=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)c1cc(Cl)ccc1CBr
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)ccc1Cc1cccc(F)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 33.7 %

Procedure:
A mixture of methyl 2-(bromomethyl)-5-chlorobenzoate (step 1, 300 mg, 1.14 mmol) and tetrakis(triphenylphosphine)palladium (0) (132 mg, 0.11 mmol) in 1,2-dimethoxyethane (6 mL) was stirred at 50° C. under nitrogen for 30 min. Then 3-fluorophenylboronic acid (191 mg, 1.37 mmol) and 2 M sodium carbonate solution (2.28 mL, 4.55 mmol) was added, and the resulting mixture was heated at 90° C. under nitrogen for 16 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (50 mL) and washed with 1 M hydrochloric acid (30 mL), saturated sodium hydrogen carbonate aqueous (30 mL), and brine (30 mL). The organic layer was dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by TLC [hexane/ethyl acetate (8:1)] to give 107 mg (34%) of the title compound as colorless oil: 1H-NMR (CDCl3) δ 7.91 (1H, d, J=2.4 Hz), 7.41 (1H, dd, J=8.4, 2.4 Hz), 7.26–7.14 (2H, m), 6.91–6.79 (3H, m), 4.34 (2H, s), 3.84 (3H, s).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:27]>>[CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10]([NH:27][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: Nc1ccccn1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccccn3)nc2n1C1CCCC1
Yield: 293.8 %

Procedure:
Following Buchwald Method B, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.34 mmol) and pyridine-2-ylamine (64 mg, 0.68 mmol) gave 7-cyclopentyl-2-(pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (350 mg, 84%).