Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:5]=[C:6]([O:8]C)[CH:7]=1.[I-].[Na+].C[Si](Cl)(C)C>C(#N)C.O>[I:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([S:10]([CH3:13])(=[O:11])=[O:12])[CH:3]=1
Reactant: COc1cc(I)cc(S(C)(=O)=O)c1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CS(=O)(=O)c1cc(O)cc(I)c1
Temperature: 25 °C
Yield: 63.6 %

Procedure:
To a suspension of 3-iodo-1-methanesulfonyl-5-methoxy-benzene (1.03 g, 3.31 mmol) and sodium iodide (4.97 g, 33.15 mmol) in acetonitrile (30 mL) was added trimethylsilyl chloride (2.09 mL, 16.58 mmol) at room temperature. Then, the resulting light yellow suspension was heated to reflux for 48 h. Then, it was cooled to room temperature and diluted with water (50 mL). The organic compound was extracted into ethyl acetate (2×50 mL) and the combined ethyl acetate extracts were washed with saturated sodium thiosulfate solution (100 mL) to remove the iodine color and was also washed with brine solution (100 mL). Then, the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by using an ISCO 40 g column, eluting with 0-25% ethyl acetate in hexanes to obtain 3-iodo-5-methanesulfonyl-phenol (628 mg, 63.5%) as a light brown solid: ES(+)-HRMS m/e calcd for C7H7IO3S (M+H)+ 298.9234, found 298.9234.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)#[N:21]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:31]1[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[C:20]#[N:21])[CH2:33][CH2:32]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Product: COc1nc2cc(Cl)ccc2nc1NC(=O)N1CCN(c2ccccc2C#N)CC1
Yield: 89 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate and 1-(2-cyanophenyl)piperazine were reacted by the same way with the example 106 to obtain the titled compound (yield, 89%). 1H NMR (300 MHz, CDCl3): δ 3.30 (s, 4H), 3.84 (s, 3H), 4.14 (s, 3H), 7.02-7.10 (m, 2H), 7.35-7.89 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[I:44][C:45]1[CH:46]=[C:47]([CH:49]=[CH:50][C:51]=1[CH3:52])[NH2:48]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:48][C:47]1[CH:49]=[CH:50][C:51]([CH3:52])=[C:45]([I:44])[CH:46]=1)=[O:7]
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: Cc1ccc(N)cc1I
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1I
Yield: 89.5 %

Procedure:
2-Chloroisonicotinic acid (3.3 g, 21 mmol), HATU (8.75 g, 23 mmol), diisopropylethyl amine (10.9 ml, 63 mmol) and 3-iodo-4-methylaniline (5.00 g, 21 mmol) in dimethylformamide (50 ml) were heated under nitrogen for 16 hours. The reaction was cooled, solvent removed in vacuo and the residue taken up in dichloromethane (150 ml). The organic solution was washed with water (3×100 ml) and brine (100 ml), dried over magnesium sulfate, filtered and solvent removed in vacuo. The residue was purified by column chromatography (40:60 ethyl acetate:cyclohexane) to give 2-chloro-N-(3-iodo-4-methylphenyl)-isonicotinamide as a white solid (7.00 g, 18.8 mmol).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[N:5]=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:3]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)CC)C>CCO>[Cl:9][C:6]1[N:5]=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:3]=[C:2]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:7]=1[CH3:8]
Reactant: C1COCCN1
Reactant: Cc1c(Cl)nc(N2CCOCC2)nc1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1c(Cl)nc(N2CCOCC2)nc1N1CCOCC1
Temperature: 125 °C
Yield: 96 %

Procedure:
To a solution of 4-(4,6-dichloro-5-methylpyrimidin-2-yl)morpholine in EtOH (0.15 M) was added morpholine (2.0 equiv.) followed by triethylamine (4.00 equiv.). The resulting mixture was heated under microwave irradiation at 125° C. for 50 min (2×25 min). The reaction mixture was then concentrated in vacuo to yield 4,4′-(6-chloro-5-methylpyrimidine-2,4-diyl)dimorpholine as a white solid in 96% yield which was utilized without further purification in the subsequent reaction. LCMS (m/z) (M+H)=299.1, Rt=0.85 min.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26]([C@H:29]([NH2:31])[CH3:30])=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:21][O:22][C:23]1[N:24]=[CH:25][C:26]([C@H:29]([NH:31][C:2]2[C:3]3[CH2:11][N:10]([C:12]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=4[C:14]#[N:15])[CH2:9][CH2:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH3:30])=[CH:27][N:28]=1
Reactant: COc1ncc([C@@H](C)N)cn1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc([C@@H](C)Nc2ncnc3c2CN(c2ccc(C)cc2C#N)CC3)cn1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (430 mg, 1.51 mmol) and (R)-1-(2-methoxypyrimidin-5-yl)ethanamine (238 mg, 1.56 mmol) (prepared similarly according to the method for Intermediate 16) in acetonitrile (6 mL) and N,N-diisopropylethylamine (2 mL, 9 mmol) was subjected to microwave irradiation at 185° C. for 3.5 h. The reaction mixture was concentrated and the residue was purified by semi-preparative HPLC (100×20.2 mm, C18 column; 30-60% acetonitrile-water [10 mM Et2NH]) to yield a light yellow solid.
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[N:11]([CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:10]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:31][CH2:30][CH2:29][C@H:28]([C:32]([O:34]CC)=[O:33])[CH2:27]3)(=[O:25])=[O:24])=[CH:22][C:9]=2[N:8]=1)([CH3:6])([CH3:5])[CH3:4].CO>O>[C:3]([C:7]1[N:11]([CH2:12][CH:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[C:10]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:31][CH2:30][CH2:29][C@H:28]([C:32]([OH:34])=[O:33])[CH2:27]3)(=[O:25])=[O:24])=[CH:22][C:9]=2[N:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)[C@H]1CCCN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CCC[C@H](C(=O)O)C3)ccc2n1CC1CCOCC1
Reaction time: 8 h

Procedure:
NaOH (0.15 mL, 2M, 0.3 mmol) was added to a solution of ethyl (3S)-1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}piperidine-3-carboxylate (265 mg, 0.54 mmol) in a 1:1 mixture of MeOH:H2O (10 mL) at ambient temperature. The reaction mixture was stirred overnight and diluted with water (50 mL). The solvent was concentrated to 50 mL. The resulting solution was neutralized with HCl solution, the product was extracted with EtOAc and dried over anhydrous Na2SO4. The solvent was concentrated to provide the title compound as white solid. Yield: 220 mg (88%); MS (ESI) (M+H)+=464.1.
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.[N+:11]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)([O-:13])=[O:12].C(O)(=O)C.[BH4-].[Na+]>CO>[N+:11]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:6][C:5]2[CH:7]=[CH:8][C:9]3[O:10][CH2:1][O:2][C:3]=3[CH:4]=2)=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc2c(c1)OCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=[N+]([O-])c1ccc(CNc2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3,4-methylenedioxyaniline (10 mmol) and 4-nitrobenzaldehyde (10 mmol) in methanol is stirred at ambient temperature for 18 hours. The precipitate obtained is filtered off and washed and then dissolved in tetrahydrofuran. After the addition of acetic acid and sodium borohydride (25 mmol), the reaction mixture is stirred at ambient temperature for 1 hour, then the solvent is evaporated off and the crude residue is purified by chromatography on silica using dichloromethane as eluant.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1.Cl.[CH3:17][N:18]([CH2:20][CH:21]1[CH2:26][CH:25]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23][C:22]1=[O:35])[CH3:19]>CCOCC.CCCCCC>[CH2:9]([O:8][C:4]1[CH:3]=[C:2]([C:22]2([OH:35])[CH2:23][CH2:24][CH:25]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=3)[CH2:26][CH:21]2[CH2:20][N:18]([CH3:17])[CH3:19])[CH:7]=[CH:6][CH:5]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccc(CC2CCC(=O)C(CN(C)C)C2)cc1
Reactant: Brc1cccc(OCc2ccccc2)c1
Agent: Cl
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1ccc(CC2CCC(O)(c3cccc(OCc4ccccc4)c3)C(CN(C)C)C2)cc1
Yield: 65 %

Procedure:
1-bromo-3-benzyloxy-benzene and the base of compound (42) were reacted corresponding to the conditions described in Example 1. The product obtained was dissolved in ether/hexane and the base was extracted with 10% acetic acid. After adjusting to an alkaline pH, compound (43) was extracted with ether and dried over sodium sulphate. After removing the solvent by distillation the product was purified with 1:1 ether/diisopropyl ether via an alumina column (3.6% water). Compound (43) was obtained in a yield of 65% theoretical.
Reaction SMILES: CS(Cl)(=O)=O.[Br:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[CH:14](O)[CH3:15].CCN(CC)CC.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)=[CH:27][CH:26]=1>C(Cl)Cl>[Br:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[CH:14]([NH:37][C:34]1[CH:33]=[CH:32][C:31]([C:28]2[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=2)=[CH:36][CH:35]=1)[CH3:15]
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CC(O)c1ccc(Cl)cc1Br
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Nc1ccc(-c2ccc(Cl)cc2)cc1)c1ccc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Neat methanesulfonyl chloride (0.40 mL, 5.1 mmol) was added to a 0° C., DCM solution (20 mL) of 1-(2-bromo-4-chlorophenyl)ethanol (1.2 g, 5.1 mmol) and Et3N (0.78 mL, 5.6 mmol) and the resulting mixture was allowed to warm to room temperature gradually. After 30 min, Et3N (0.78 mL, 5.6 mmol) and 4′-chloro-[1,1′-biphenyl]-4-amine (1.0 g, 5.1 mmol) were added sequentially and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture was concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=O.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].N1CCCCC1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:7]=[CH:12][C:13]([OH:15])=[O:14])[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cc(Br)ccc1F
Temperature: 100 °C
Reaction time: 3 h
Yield: 21.6 %

Procedure:
5-Bromo-2-fluoro-benzaldehyde (5.0 g, 24.6 mmol), malonic acid (5.6 g, 53.7 mmol), and piperidine (0.5 mL, 4.9 mmol) were added to pyridine (11.4 mL). The reaction mixture was stirred at 100° C. for 3 hours and then concentrated under reduced pressure. Distilled water was added to the reaction mixture, which was then filtered. The resulting solid was recrystallized from ethanol to give 1.3 g of the titled compound as a white solid.
Reaction SMILES: C[O:2][C:3]1[C:4]([N+:21]([O-:23])=[O:22])=[CH:5][C:6]2[CH:12]([CH3:13])[CH2:11][N:10]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:9][CH2:8][C:7]=2[N:20]=1.Br.CC(O)=O.C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH3:13][CH:12]1[CH2:11][N:10]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:9][CH2:8][C:7]2[N:20]=[C:3]([OH:2])[C:4]([N+:21]([O-:23])=[O:22])=[CH:5][C:6]1=2
Reactant: COc1nc2c(cc1[N+](=O)[O-])C(C)CN(C(=O)C(F)(F)F)CC2
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC1CN(C(=O)C(F)(F)F)CCc2nc(O)c([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.7 %

Procedure:
A mixture of 2-methoxy-5-methyl-3-nitro-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (2.00 g, 6.00 mmol), HBr/AcOH (33 wt %, 20 ml) and H20 (5 ml) was stirred for 10 min at room temperature. The reaction was parted between sat. aq. NaHCO3 and EtOAc. The organic phased was dried and concentrated in vacuo to give 1.68 g (88%) of pure 5-methyl-3-nitro-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol. 1H-NMR (CDCl3) δ 8.42 (s, 1H), 4.20-3.20 (m, 8H), 1.45 (d, 1.2H), 1.39 (d, 1.8H) ppm. A mixture of 5-methyl-3-nitro-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol (1.63 g, 5.10 mmol), Bu4NBr (4.94 g, 15.3 mmol), P2O5 (3.62 g, 12.8 mmol) and toluene (100 ml) was heated to 110° C. for 5 h. The reaction was cooled to room temperature and the liquid part was decanted and concentrated in vacuo to give 1.25 g (64%) of pure 2-bromo-5-methyl-3-nitro-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (CDCl3) δ 8.05 (s, 1H), 3.80 (m, 3H), 3.60-3.25 (m, 4H), 1.41 (d, 1.2H), 1.35 (d, 1.8H) ppm. Concurent reduction of the nitro group and halogene on was carried out with 5% Pd/C in MeOH under H2 (1 atm) to give 1.20 g (97%) of pure 5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine. 1H-NMR of rotamers (MeOH-d4) δ 7.77 (2× d, 1H), 7.62 (d, 0.4H), 7.58 (d, 0.6H), 4.10-3.35 (m, 7H), 1.42 (d, 1.3H), 1.35 (d, 1.7H) ppm. A mixture of 5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine (130 mg, 476 μmol), K2CO3 (100 mg), MeOH (6 ml) and H2O (1 ml) was stirred for 16 h at room temprature. The reaction mixture was parted between aq. NaHCO3 and DCM, the organic layer was dried and then concentrated in vacuo. The resulting residue was purified by column chromatography to yield 20.0 mg (24%) of 5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine. 1H-NNMR (MeOH-d4) δ 7.68 (s, 1H), 7.24 (s, 1H), 3.45-2.95 (m, 7H), 1.37 (d, 3H) ppm.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[OH-:11].[Na+]>>[C:3]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[NH:1][C:2](=[O:10])[CH2:3]2)(=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: [OH-]
Agent: [Na+]
Product: O=C1Cc2cccc(C(=O)c3ccccc3)c2N1

Procedure:
The hydrolysis of an indolin-2-one (II) is carried out in dilute aqueous base as, for example, 3N sodium hydroxide solution, for a period of from about 0.5 hour to about 1.0 hour. The hydrolysis may be run in an inert atmosphere using nitrogen. The hydrolysis mixture may be filtered to remove base-insoluble materials and the pH of the basic solution is adjusted to pH 6-pH 7 by the addition of a weak organic acid such as glacial acetic acid or a dilute mineral acid such as hydrochloric acid. When (I) is a 2-amino-5-benzoylphenylacetic acid or a 2-amino-6-benzoylphenylacetic acid the product can be readily recrystallized from a suitable solvent. When (I) is a 2-amino-3-benzoylphenylacetic acid, recrystallization may result in partial cyclization to the precursor 7-benzoylindolin-2-one (II). Therefore, in the preparation of a 2-amino-3-benzoylphenylacetic acid (I) the product is preferably not recrystallized and is isolated by careful acidification of the filtered basic hydrolysis mixture.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([NH:36][C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCc1ccccc1
Reactant: CS(=O)(=O)c1nccc(-c2cnc3c(NCCN4CCOCC4)nccn23)n1
Product: c1ccc(CNc2nccc(-c3cnc4c(NCCN5CCOCC5)nccn34)n2)cc1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
The mixture of [3-(2-methanesulfonyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-morpholin-4-yl-ethyl)-amine (from Example 50 supra) (120 mg, 0.30 mmol) and benzylamine (128 mg, 1.19 mmol) was heated at 140° C. with stirring for 2 hours. The oil was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 30:1 to 10:1) to afford the crude product (100 mg). The crude product was purified by prep-HPLC. Several drops of concentrated HCl were added to the fractions with product. After sonicating for several minutes, solution was concentrated under reduced pressure to afford [3-(2-benzylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-morpholin-4-yl-ethyl)-amine; hydrochloride. (Yield 25 mg, 19.5%). 1H NMR (300 MHz, CD3OD): δ 8.77 (s, 1H), 8.57-8.38 (m, 2H), 7.62 (d, 1H, J=6.6 Hz), 7.48-7.34 (m, 6H), 4.82 (brs, 2H), 4.21 (brs, 2H), 3.99 (brs, 4H), 3.63-3.47 (m, 6H). LC-MS: [M+H]+ 431.
Reaction SMILES: [OH:1][CH:2]([CH2:15][N:16](CC1C=CC=CC=1)CC1C=CC=CC=1)[CH2:3][O:4][C:5]1[C:13]2[NH:12][C:11](=[O:14])[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.C([O-])=O.[NH4+]>CO.[Pd]>[OH:1][C@@H:2]([CH2:15][NH2:16])[CH2:3][O:4][C:5]1[C:13]2[NH:12][C:11](=[O:14])[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: O=c1[nH]c2cccc(OCC(O)CN(Cc3ccccc3)Cc3ccccc3)c2[nH]1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12

Procedure:
4-[2-Hydroxy-3-(N,N dibenzylamino)propoxy]-1,3-dihydro-2H-benzimidazol-2-one (4.35 g, 10.8 mmol) was dissolved in methanol (200 mL) and treated with a vast excess of ammonium formate (13.0 g, 0.21 mol), followed by 10% palladium on carbon (1.5 g). The suspension was stirred at reflux for 3 hours. After cooling the suspension, the reaction mixture was filtered through Celite. The filtrate concentrated in vacuo to a pale brown oil which slowly crystallized upon standing. The resulting solid was triturated using chloroform containing methanol and filtered to give 1.56 g (65%) as the desired product of a pale grey solid. NMR. MS.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:5]([C:6]([NH2:8])=O)=[CH:4][N:3]=1.O=P(Cl)(Cl)Cl>>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[C:5]([C:6]#[N:8])=[CH:4][N:3]=1
Reactant: NC(=O)c1cnc(Cl)cc1C(F)(F)F
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cnc(Cl)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A mixture of 6-chloro-4-(trifluoromethyl)nicotinamide (0.847 g, 3.77 mmol, Preparation #27) and POCl3 (7.03 mL, 75.0 mmol) was heated at about 60° C. with stirring for about 1 h. The reaction mixture was cooled to ambient temperature and concentrated to dryness under reduced pressure and the resulting material was partitioned between chilled saturated aqueous NaHCO3 (30 mL) and EtOAc (30 mL). The layers were separated and the organic solution was washed with saturated aqueous NaHCO3 solution (30 mL) and brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give 6-chloro-4-(trifluoromethyl)nicotinonitrile (0.67 g, 86%) as a brown liquid: LC/MS (Table 2, Method a) Rt=2.31 min: 1H NMR (CDCl3) δ 8.87 (s, 1H), 7.75 (s, 1H).
Reaction SMILES: BrBr.Br[CH:4]([C:16]([C:18]1[N:19]([CH3:23])[CH:20]=[CH:21][CH:22]=1)=[O:17])[CH2:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7].[C:24]([O-:32])(=[S:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Na+]>C(O)(=O)C>[C:24]([S:31][CH:4]([C:16]([C:18]1[N:19]([CH3:23])[CH:20]=[CH:21][CH:22]=1)=[O:17])[CH2:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])(=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cn1cccc1C(=O)C(Br)CC(=O)N1CCC[C@H]1C(=O)O
Reactant: [O-]C(=S)c1ccccc1
Agent: BrBr
Agent: [Na+]
Solvent: CC(=O)O
Product: Cn1cccc1C(=O)C(CC(=O)N1CCC[C@H]1C(=O)O)SC(=O)c1ccccc1

Procedure:
As for Example 1, the preceding compound is coupled to L-proline to give 1-[3-(1-methyl-2-pyrrolylcarbonyl)propionyl]-L-proline. The preceding compound (0.01 mole) is brominated with bromine (0.011 mole) in acetic acid and the resulting 1-[3-bromo-(1-methyl-2-pyrrolylcarbonyl)propionyl]-L-proline (0.01 mole) is reacted with sodium thiobenzoate as for Example 21 to give the product of the Example as a glass.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=[O:19].[Na].O.[CH2:23](I)[CH3:24]>CN(C)C=O>[NH2:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([O:20][CH2:23][CH3:24])=[O:19]
Reactant: Nc1c(CC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Reactant: CCI
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1cccc(C(=O)c2ccc(Cl)cc2)c1N
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Fourteen g of 2-amino-3-(4-chlorobenzoyl)benzene acetic acid, sodium salt.H2O was dissolved in 150 ml of dimethylformamide and then treated with 30 g of ethyl iodide. The resulting solution was stirred at room temperature for 2.5 hours. The solution was then added to water and the mixture was extracted several times with benzene. The benzene layer obtained was washed with dilute base and water, dried over sodium sulfate and stripped to leave an oil which crystallized on trituration with pet. ether. Recrystallization from ethyl alcohol gave 11.6 g of the titled compound as yellow flakes, m.p. 101°-102° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([CH3:38])([CH3:37])[CH2:34][CH:35]=[O:36])=[CH:29][CH:28]=1>O1CCCC1>[F:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]([CH3:38])([CH3:37])[CH2:34][CH:35]([Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][CH2:14][CH2:15][CH3:16])[OH:36])=[CH:31][CH:32]=1
Reactant: CC(C)(CC=O)c1ccc(F)cc1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)C(O)CC(C)(C)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
A stirring solution of 10.8 mL (0.077 mole) of diisopropylamine in 100 mL of tetrahydrofuran is cooled to 0° C., and 30.8 mL (0.077 mole) of n-butyllithium (2.5M in hexanes) is added dropwise. Upon completion of the addition, the reaction mixture is stirred for about 10 minutes, then 22.3 grams (0.077 mole) of tributyltin hydride is added dropwise at a rate to maintain the reaction mixture temperature at about 0° C. The reaction mixture is then stirred for about 15 minutes. After this time the reaction mixture is cooled to -78° C., and a solution of 13.8 grams (0.077 mole) of 3-(4-fluorophenyl)-3-methylbutyraldehyde in about 15 mL of tetrahydrofuran is added dropwise during a 30 minute period. Upon completion of addition, the reaction mixture is stirred at -78° C. for ten minutes. After this time the reaction mixture is quenched by the dropwise addition of 300 mL of aqueous 10% ammonium chloride. The mixture is then extracted with two 200 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, at a temperature of less than 30° C., yielding 36.3 grams of 3-(4-fluorophenyl)-3-methyl-1-tributylstannylbutanol. The NMR spectrum is consistent with the proposed structure.