Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]#[C:22][CH2:23][F:24])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(OCC)(=O)C.ClCCl>[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21]/[CH:22]=[CH:23]\[F:24])=[CH:17][CH:16]=1)(=[O:14])=[O:13]
Reactant: CS(=O)(=O)c1ccc(C#CCF)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C/C=C\F)cc1
Yield: 98.9 %

Procedure:
cis-hydrogenation using Lindlar catalyst and quinoline. Shake a mixture of recrystallized title compound of Example 1 (1 g, 4.72 mmoles), quinoline (60 mg, 99% pure Aldrich) and Lindlar catalyst of procedure A of Example 2 (200 mg) in ethyl acetate (50 mL) in a Parr apparatus under hydrogen at atmospheric pressure at 30 for 20 min. or until theoretical amount of hydrogen (118 mL) is taken up. Remove catalyst by filtration and wash it with ethyl acetate. Evaporate the solvent under vacuum at 35° to give an oil. Dissolve the oil in dichlormethane (40 mL) and wash the dichloromethane solution successively with ice-cold 1M HCl solution, saturated NaHCO3 solution and water, and then dry over anhydrous MgSO4. Evaporate the under vacuum to give the title compound as an oil (1 g). Purify a portion of the oil (220 mg) by column chromatography. Elute the column with ethyl acetate-hexane (1:1, v/v) to give the title compound as an oil (213 mg). The oil was 95% pure and contained 5% of the over-reduced compound 3-(4-methylsulfonylphenyl)-1-fluoropropane and had the following physical and spectral properties:
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.O.O=[C:13]([CH3:16])[CH:14]=[O:15]>C(O)(=O)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]/[N:10]=[C:13](\[CH3:16])/[CH:14]=[O:15])=[CH:5][CH:4]=1
Reactant: NNc1ccc(F)cc1
Reactant: CC(=O)C=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: C/C(C=O)=N\Nc1ccc(F)cc1
Reaction time: 4 h

Procedure:
A mixture of (4-fluorophenyl)hydrazine HCl salt (2.0 g, 12.30 mmol), water (10 mL), and acetic acid (10 mL) was added with stirring to a 40% aqueous solution of 2-oxopropanal (9.41 mL, 61.5 mmol) for 20 minutes. Stirring was continued for 4 hours and the mixture was then filtered. The precipitate was washed with water and dried to afford the desired products. The crude was purified by silica gel flash column chromatography (1:50 to 1:10=EtOAc:CH2Cl2) to afford 2.05 g (93%) along with byproduct. 1H-NMR (400 MHz, CDCl3) δ 9.47 (s, 1H), 8.09 (br. s, 1H), 7.24 (m, 2H), 7.06 (t, 2H), 1.98 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −121.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]([F:25])([F:24])[C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1.[H-].[Na+]>>[C:1]([O:5][C:6](=[O:13])[N:7]([CH2:20][C:19]1[CH:18]=[CH:17][C:16]([C:15]([F:14])([F:24])[F:25])=[CH:23][CH:22]=1)[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)Nn1cccc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(Cc1ccc(C(F)(F)F)cc1)n1cccc1

Procedure:
Prepared according to the benzylation condition used in Example 1 step b) from pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.), 4-trifluoromethylbenzyl chloride (1.0 eq.) and sodium hydride (1.3 eq.). ESI (m/z): 341 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]([CH3:18])=[CH:6]2.[C:19]([O-:22])(=[O:21])[CH3:20].[Na+].O>CN(C)C=O>[C:19]([O:22][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]([CH3:18])=[CH:6]2)(=[O:21])[CH3:20]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)c1nc2ccc(CBr)cc2cc1C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2ccc(COC(C)=O)cc2cc1C
Reaction time: 24 h
Yield: 69.3 %

Procedure:
To a solution of ethyl 6-bromomethyl-3-methylquinoline-2-carboxylate (700 mg) in dimethylformamide (7 ml) was added sodium acetate (373 mg) at ambient temperature, and the mixture was stirred for 24 hours at the same temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (n-hexane:ethyl acetate=1:2, V/V) to give ethyl 6-acetoxymethyl-3-methylquinoline-2-carboxylate (452 mg) as an oil.
Reaction SMILES: [NH2:1][C@H:2]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:3]([NH:5][CH:6]1[CH2:15][C:14]2[C:9](=[C:10]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])[CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:22][C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[C:7]1=[O:28])=[O:4].[C:33]([O:37][C:38]([NH:40][C:41]([CH3:46])([CH3:45])[C:42](O)=[O:43])=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[CH3:46][C:41]([NH:40][C:38](=[O:39])[O:37][C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:45])[C:42]([NH:1][C@H:2]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:3](=[O:4])[NH:5][CH:6]1[CH2:15][C:14]2[C:9](=[C:10]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])[CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:22][C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[C:7]1=[O:28])=[O:43]
Reactant: CC(C)C[C@@H](N)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Product: CC(C)C[C@@H](NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Yield: 90.6 %

Procedure:
The procedure of Example 14(a) was repeated, except that (2R)-2-amino-4-methyl-N-[2-oxo-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-yl]pentanamide (400 mg) and 2-(tert-butoxycarbonylamino)-2-methylpropanoic acid (215 mg) were used, whereby the title compound (510 mg) was yielded.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]1[CH:17]=[C:18]([S:23](Cl)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1.[CH3:27][O:28][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:38]=1[CH:37]([NH2:39])[CH2:36][CH2:35][CH2:34]2>>[F:15][C:16]1[CH:17]=[C:18]([S:23]([NH:1][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][C:8]([NH:39][CH:37]2[C:38]4[C:33](=[CH:32][CH:31]=[CH:30][C:29]=4[O:28][CH3:27])[CH2:34][CH2:35][CH2:36]2)=[N:9]3)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Reactant: COc1cccc2c1C(N)CCC2
Product: COc1cccc2c1C(Nc1ccc3c(NS(=O)(=O)c4cc(F)cc(F)c4)cccc3n1)CCC2

Procedure:
The title compound, MS: m/e=496.3 (M+H+), was prepared in accordance with the general method of example 13 from 5-nitro-2-chloroquinoline, 3,5-difluorobenzenesulfonyl chloride and 8-methoxy-1,2,3,4-tetrahydronaphthalen-1-amine (CAS 535935-61-6).
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)C(O)=O)[CH:2]=1.Cl.[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][CH2:30][NH2:31].CN([C:35]([O:39]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][CH2:30][NH:31][C:35](=[O:39])[C:14]1[CH:15]=[CH:16][C:8]([O:7][C:3]2[CH:2]=[C:1]([CH3:17])[CH:6]=[CH:5][CH:4]=2)=[CH:9][CH:10]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1cccc(Oc2cccc(C(=O)O)c2)c1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(Oc2ccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)cc2)c1
Yield: 35.1 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(m-tolyloxy)benzamide was prepared according to method A with 3-(m-tolyloxy)benzoic acid (0.080 g, 0.35 mmol), 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.077 g; 0.331 mmol), HATU (0.190 g; 0.365 mmol) and N,N-diisopropylethylamine (0.142 mL; 0.829 mmol) in DMF (3 mL). Flash chromatography on silica gel (eluent 20 to 100% ethyl acetate in heptane) furnished 0.047 g (33%) of the title compound as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH:4]([CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)[N:5]([CH2:19][O:20][CH:21]([Si:23]([CH3:26])([CH3:25])[CH3:24])[CH3:22])[C:6]([O:8][CH:9]1[CH:16]2[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:18][CH:10]1[CH2:11]3)[CH2:15]2)=[O:7].[Li+].[OH-].O1CCOCC1.Cl>O>[CH:10]12[CH2:11][CH:12]3[CH2:13][CH:14]([CH2:15][CH:16]([CH2:17]3)[CH:9]1[O:8][C:6]([N:5]([CH2:19][O:20][CH:21]([Si:23]([CH3:25])([CH3:24])[CH3:26])[CH3:22])[CH:4]([C:3]([OH:37])=[O:2])[CH2:27][C:28]1[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][CH:29]=1)=[O:7])[CH2:18]2
Reactant: COC(=O)C(Cc1c[nH]c2ccccc12)N(COC(C)[Si](C)(C)C)C(=O)OC1C2CC3CC(C2)CC1C3
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(OCN(C(=O)OC1C2CC3CC(C2)CC1C3)C(Cc1c[nH]c2ccccc12)C(=O)O)[Si](C)(C)C
Temperature: 60 °C
Reaction time: 16 h
Yield: 91.8 %

Procedure:
A mixture of N-[(2-adamantyloxy)carbonyl]-α-trimethylsilylethoxymethyl-DL-tryptophan methyl ester (4.5 g, 8.5 mmol), LiOH (0.22 g, 9.1 mmol), dioxane (90 mL), and water (30 mL) was stirred at 60° C. for 16 hours. After cooling, the reaction mixture was acidified to pH 4 with 1N hydrochloric acid and extracted with ethyl acetate. The organic extract was dried over Na2SO4 and then concentrated in vacuo. Trituration of the oily residue with diethyl ether gave the title compound as a white solid (4.0 g, 91.7%), mp 203° C. (dec.).
Reaction SMILES: [C:1]1([O:7][C:8](=[O:25])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15]CC3C=CC=CC=3)[C:11]=2[C:23]#[N:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([OH:32])C=CC=CC=1>S(=O)(=O)(O)O>[C:1]1([O:7][C:8](=[O:25])[NH:9][C:10]2[S:14][N:13]=[C:12]([OH:15])[C:11]=2[C:23](=[O:32])[NH2:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1c(OCc2ccccc2)nsc1NC(=O)Oc1ccccc1
Reactant: Oc1ccccc1
Agent: O=S(=O)(O)O
Product: NC(=O)c1c(O)nsc1NC(=O)Oc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
The wet solid, (3-Benzyloxy-4-cyano-isothiazol-5-yl)-carbamic acid phenyl ester, (320 g) was added slowly to concentrated sulfuric acid (650 mL) over 1.5 hours. Additional concentrated sulfuric acid (100 mL) was added and the mixture stirred a further 3 hours. The viscous solution was diluted by slow addition of ice (2000 g) followed by vigorous stirring for an additional 2 hours. The acid was partially removed by dividing the suspension into eight containers that were placed in a centrifuge, spun at 3000 rpm for 45 minutes at 21° C. The aqueous layer was discarded, additional pure water was added, the pellet resuspended, and the process repeated. After seven dilution/centrifugation/redilution cycles, the pH of the aqueous layer had increased to −4 and the solid was collected and dried by drawing air through a cake in a funnel for 2 days. The less-wet solid was crushed, placed again in the filter, and air was again drawn through the solid for another day. This process was repeated until the solid was dry to afford a tan solid (234 g, 105% over two steps, minor impurities present—did not interfere appreciably with the subsequent steps). 1H NMR (400 MHz, DMSO) δ 7.00 (broad s, 1H), 7.27-7.31 (m, 3H), 7.40-7.45 (m, 2H), 7.59 (s, 1H), 5.05 (s, 1H), 11.22 (s, 1H); MS (APCI, m/z): 184 [M−(H and PhOH)]−.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[C:7]#[N:8])[CH:2]=[CH2:3].C(N(CC)CC)C.[Cl:20][C:21]([Cl:26])([Cl:25])[C:22](Cl)=[O:23]>ClCCl>[Cl:20][C:21]([Cl:26])([Cl:25])[C:22]([O:12][C:11]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[CH2:1][CH:2]=[CH2:3])=[O:23]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C=CCc1cc(C#N)ccc1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCc1cc(C#N)ccc1OC(=O)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of INT 25 (10.0 g, 62.8 mmol) in dichoromethane (450 mL) was added triethylamine (7.98 g, 79 mmol), followed by dropwise addition of trichloroacetyl chloride (14.42 g, 79 mmol) and the resulting mixture was stirred at room temperature overnight. The mixture was washed with saturated aqueous ammonium chloride and saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and concentrated to give INT 26 which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:18][C:6]2=[C:7]([C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)[S:8][C:9](S(C)=O)=[C:5]2[C:4](=[O:19])[CH2:3]1.[CH3:21][O-:22].[Na+]>CO>[CH3:1][C:2]1([CH3:20])[CH2:18][C:6]2=[C:7]([C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)[S:8][C:9]([O:22][CH3:21])=[C:5]2[C:4](=[O:19])[CH2:3]1
Reactant: C[O-]
Reactant: CS(=O)c1sc(-c2cc[nH]n2)c2c1C(=O)CC(C)(C)C2
Agent: [Na+]
Solvent: CO
Product: COc1sc(-c2cc[nH]n2)c2c1C(=O)CC(C)(C)C2
Temperature: 70 °C
Yield: 15 %

Procedure:
To a stirred solution of 6,6-dimethyl-3-methanesulphinyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (80 mg, 0.26 mmol) in methanol (3 mL) was added a solution of sodium methoxide in methanol (1.0 mL of a 0.5M solution, 0.5 mmol). The solution was heated at 70° C. for 24 h. after which time the mixture was cooled to room temperature and partitioned between EtOAc (2×20 mL) and water (20 mL). The combined organic layers were dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel, eluting with CH2Cl2:MeOH (95:5), to give the title compound (11 mg, 15%) as a pale yellow solid. mp 202-204° C. Found: C, 60.24; H, 5.66; N, 10.06%. C14H16N2O2S.0.1 (H2O) requires: C, 60.45; H, 5.87; N, 10.07%. 1HNMR (360 MHz, d6-DMSO)δ 0.98 (6H, s), 2.27 (2H, s), 2.79 (2H, s), 4.03 (3H, s), 6.54 (1H, br s), 7.81 (1H, br s), 12.92 (1H, br s). MS (ES+) 277 (M+1).
Reaction SMILES: O1C=C(CN)N=C1.[CH3:8][N:9]1[C:13]([CH3:14])=[C:12]([CH2:15][NH2:16])[C:11]([CH3:17])=[N:10]1.[F:18][C:19]1[CH:40]=[CH:39][C:22]([CH2:23][N:24]2[CH2:28][CH2:27][N:26]([C:29]3[CH:30]=[C:31]([CH:35]=[CH:36][N:37]=3)[C:32](O)=[O:33])[C:25]2=[O:38])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][N:24]2[CH2:28][CH2:27][N:26]([C:29]3[CH:30]=[C:31]([CH:35]=[CH:36][N:37]=3)[C:32]([NH:16][CH2:15][C:12]3[C:11]([CH3:17])=[N:10][N:9]([CH3:8])[C:13]=3[CH3:14])=[O:33])[C:25]2=[O:38])=[CH:39][CH:40]=1
Reactant: O=C(O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Reactant: Cc1nn(C)c(C)c1CN
Agent: NCc1cocn1
Product: Cc1nn(C)c(C)c1CNC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Yield: 67 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace oxazol-4-ylmethanamine with (1,3,5-trimethyl-1H-pyrazol-4-yl)methanamine to react with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinic acid, 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-((1,3,5-trimethyl-1H-pyrazol-4-yl)methyl)isonicotinamide was obtained as a colorless solid in 67% yield: mp 179-181° C.; 1H NMR (300 MHz, CDCl3) δ 8.48 (s, 1H), 8.33 (d, J=5.1 Hz, 1H), 7.37 (dd, J=5.1 Hz, 1.2 Hz, 1H), 7.25-7.21 (m, 2H), 7.03-6.97 (m, 2H), 6.35 (br s, 1H), 4.40-4.36 (m, 4H), 4.01 (t, J=8.1 Hz, 2H), 3.68 (s, 3H), 3.34 (t, J=8.1 Hz, 2H), 2.21 (s, 3H), 2.19 (s, 3H); MS (ES+) m/z 436.8 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.N1C=CC=CC=1.[CH3:23][N:24]1[C:28]([C:29](Cl)=[O:30])=[CH:27][C:26]([CH3:32])=[N:25]1>O1CCCC1>[NH2:12][C:9]1[N:10]=[CH:11][C:6]([O:5][C:4]2[CH:13]=[CH:14][C:15]([Cl:16])=[C:2]([NH:1][C:29]([C:28]3[N:24]([CH3:23])[N:25]=[C:26]([CH3:32])[CH:27]=3)=[O:30])[CH:3]=2)=[CH:7][CH:8]=1
Reactant: Nc1ccc(Oc2ccc(Cl)c(N)c2)cn1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc(N)nc3)ccc2Cl)n(C)n1
Yield: 10 %

Procedure:
In the same manner as in Reference Example 3 and using 5-(3-amino-4-chlorophenoxy)pyridin-2-amine (2.01 g, 8.55 mmol), pyridine (725 μL, 8.98 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (1.42 g, 8.98 mmol) and tetrahydrofuran (50 mL) as starting materials, the title compound (306 mg, 10%) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:41]=[CH:40][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]4[C:22](=[O:23])[N:21]5[CH2:24][CH2:25][CH2:26][CH:27]([O:28][CH2:29][CH2:30][CH2:31][NH:32]C(=O)C(C)(C)C)[C:20]5=[N:19][C:18]=4[CH3:39])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:32][CH2:31][CH2:30][CH2:29][O:28][CH:27]1[C:20]2=[N:19][C:18]([CH3:39])=[C:17]([CH2:16][CH2:15][N:12]3[CH2:11][CH2:10][CH:9]([C:6]4[C:5]5[CH:40]=[CH:41][C:2]([F:1])=[CH:3][C:4]=5[O:8][N:7]=4)[CH2:14][CH2:13]3)[C:22](=[O:23])[N:21]2[CH2:24][CH2:25][CH2:26]1
Reactant: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2OCCCNC(=O)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2OCCCN

Procedure:
A solution of N-(3-((3-(2-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)ethyl)-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)oxy)propyl)pivalamide, prepared as described in Step A, (1.482 g, 2.54 mmol) in dichloromethane (10 mL) and trifluoroacetic acid (5 mL) was stirred for 1 h at room temperature. The reaction mixture was purified on a Porapak CX column to give the title compound which was used without further purification in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[F:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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:8][C:5]1[N:4]=[CH:3][C:2]([C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([F:9])[C:15]=2[F:16])=[CH:7][N:6]=1
Reactant: OB(O)c1cccc(F)c1F
Reactant: Clc1ncc(Br)cn1
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: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1cccc(-c2cnc(Cl)nc2)c1F
Yield: 57.8 %

Procedure:
A reaction of 288 mmol of 5-bromo-2-chloropyrimidine, 288 mmol of 2,3-difluorophenylboronic acid, 576 mmol of sodium carbonate and 5.8 mmol of tetrakis(triphenylphosphine)palladium(0) in 560 ml of toluene, 280 ml of ethanol and 280 ml of water is carried out analogously to the procedure indicated for precursor 3. Corresponding purification gives 37.7 g (58%) of a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2C=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:31])C=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[OH:31])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)cc2C=O)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)cc2O)C1
Reaction time: 18 h

Procedure:
To a CH2Cl2 (25 mL) solution of the title compound of Step A (1.4 g, 4.3 mmol) was added 77% m-CPBA (1.4 g, 6.2 mmol). After 18 h, additional CH2Cl2 was added and the reaction washed with saturated NaHCO3 (aq.) and 10% Na2S2O5 until KI paper negative. The combined organic layers were dried then treated with MeOH (25 mL) and 1N NaOH (25 mL). After 15 h, the reaction was acidified with 1M KHSO4 then extracted with EtOAc (2×). The combined organic layers were washed with brine and dried to give the title compound as a white solid. 1H NMR (CDCl3): 6.96 (s, 1H), 6.82-6.80 (m, 1H), 6.73 (d, J=8.6 Hz, 1H), 5.62 (s, 1H), 4.91 (s, 1H), 3.66-3.46 (m, 4H), 2.20-2.11 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](O)=[O:6].C(Cl)(=O)C([Cl:15])=O.CN(C=O)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([Cl:15])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(F)c(Br)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94.4 %

Procedure:
A solution of 3-bromo-4-fluorobenzoic acid (976 mg, 4.46 mmol) in DCM (25 mL) was stirred at rt and treated with oxalyl chloride (1.950 mL, 22.28 mmol), followed by a drop of DMF, causing gas evolution to commence. After 2.5 h, the solution was heated to boiling for 1-2 min and allowed to cool to rt. After 3 h total, the solution was concentrated to provide 3-bromo-4-fluorobenzoyl chloride as a white solid (1.00 g, 94%). A portion of this material (200 mg, 0.842 mmol) was added to an ice-cold solution of 4-fluoroaniline (0.081 mL, 0.842 mmol) in pyridine (4 mL), and the solution was stirred at rt for 65 h The solution was concentrated and the residue was stirred in 1 M hydrochloric acid, forming a precipitate which was collected by filtration, washed with water and dried to provide 3-bromo-4-fluoro-N-(4-fluorophenyl)benzamide as an off-white solid (227.5 mg, 80%). 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H) 8.29 (dd, J=6.7, 2.1 Hz, 1H) 8.01 (ddd, J=8.6, 4.8, 2.2 Hz, 1H) 7.75 (dd, J=9.0, 5.1 Hz, 2H) 7.55 (t, J=8.6 Hz, 1H) 7.20 (t, J=8.9 Hz, 2H). Mass spectrum m/z 312, 314 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[C:7]([CH3:21])[C:6]=2[C:5]([C:22]#[N:23])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C[Si]([N:35]=[N+:36]=[N-:37])(C)C.C([Sn](=O)CCCC)CCC>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:22]2[NH:37][N:36]=[N:35][N:23]=2)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[C:7]2[CH3:21]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: Cc1nc2c(Cl)ccc(C#N)c2c(C)c1Cc1ccc(Cl)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1nc2c(Cl)ccc(-c3nnn[nH]3)c2c(C)c1Cc1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A mixture of 8-chloro-3-(4-chlorobenzyl)-2,4-dimethylquinoline-5-carbonitrile (0.048 g), toluene (1.5 mL), trimethylsilyl azide (0.081 g) and dibutyltin oxide (0.007 g) were sealed in a flask and heated at 100° C. for 66 hours. The mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with saturated aqueous sodium hydrogen carbonate solution and the pH of the aqueous phase was adjusted to 5 by the addition of glacial acetic acid. The resulting precipitate was collected by filtration, washed with diluted aqueous acetic acid solution and dried to afford title compound as a white solid, 0.017 g.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[CH:8]=2)[N:3]=1.[N:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[N:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.CCO.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>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([C:26]2[CH:27]=[N:22][CH:23]=[N:24][CH:25]=2)[N:11]=[C:10]3[NH:12][CH3:13])[CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1cncnc1
Reactant: CNc1nc(Cl)nc2ccc(-c3cccc(OC)c3)cc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: CNc1nc(-c2cncnc2)nc2ccc(-c3cccc(OC)c3)cc12
Yield: 38.2 %

Procedure:
In a 10 mL microwave vial was added 2-chloro-6-(3-methoxyphenyl)-N-methylquinazolin-4-amine (0.080 g, 0.267 mmol), pyrimidine-5-boronic acid (0.099 g, 0.801 mmol), dichlorobis(triphenylphosphine)palladium (II) (Pd(PPh3)2Cl2) (9.37 mg, 0.013 mmol), and potassium carbonate (0.111 g, 0.801 mmol) in DME (3 mL), EtOH (1.286 mL), and water (0.857 mL) to give a yellow suspension. The vial was irradiated at 120° C. for 15 min under argon. Water (10 rill) was added to the mixture and extracted with ethyl acetate (2×10 mL). The organic layers were combined and washed with brine (1×20 mL) and then dried over MgSO4, filtered and concentrated. The residue was washed with MeOH-CH2Cl2 and dried to give 35 mg of 6-(3-methoxyphenyl)-N-methyl-2-(pyrimidin-5-yl)quinazolin-4-amine as a white solid (38%). LCMS m/z=344 (M+1) (Method D) (retention time=1.78 min) 1H NMR (300 MHz, DMSO) δ 9.79-9.59 (m, 2H), 9.30 (s, 1H), 8.72 (d, J=4.6 Hz, 1H), 8.59 (s, 1H), 8.16 (d, J=8.6 Hz, 1H), 7.85 (d, J=8.7 Hz, 1H), 7.53-7.28 (m, 3H), 7.00 (d, J=6.8 Hz, 1H), 3.86 (s, 3H), 3.18 (d, J=3.9 Hz, 3H).