Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O.[CH2:20]([CH:22]([CH2:28][CH3:29])[C:23](=O)[CH2:24][C:25]#[N:26])[CH3:21]>>[CH2:20]([CH:22]([C:23]1[C:24]([C:25]#[N:26])=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]2[C:2](=[CH:7][CH:6]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:4]=2)[N:1]=1)[CH2:28][CH3:29])[CH3:21]
Reactant: CCC(CC)C(=O)CC#N
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)c1ccccc1
Product: CCC(CC)c1nc2ccc(C(F)(F)F)cc2c(-c2ccccc2)c1C#N

Procedure:
The title compound was prepared in analogy to example 101 step B from (2-amino-5-trifluoromethyl-phenyl)-phenyl-methanone and 4-ethyl-3-oxo-hexanenitrile (prepared as described in example 101 step A). Off-white solid. MS (ESI): 369.4 (M+H)+.
Reaction SMILES: C(OC(N1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.NCCC1[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=1>>[S:40]([C:37]1[CH:38]=[CH:39][C:12]([CH2:11][CH2:10][NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])=[CH:35][CH:36]=1)(=[O:42])(=[O:41])[NH2:43]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Product: NS(=O)(=O)c1ccc(CCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 4-(2-aminoethyl)benzenesulfonamide instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 422 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (1H, br. s.) 10.31 (1H, s) 8.23 (1H, t, J=5.86 Hz) 8.02 (1H, d, J=5.37 Hz) 7.68-7.83 (3H, m) 7.48 (1H, d, J=5.47 Hz) 7.42 (2H, d, J=8.30 Hz) 7.32 (1H, d, J=2.93 Hz) 7.28 (2H, s) 6.83 (1H, d, J=5.37 Hz) 6.44 (1H, dd, J=3.51, 1.95 Hz) 3.50 (2H, q, J=7.13 Hz) 2.91 (2H, t, J=7.27 Hz)
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:11]=[CH:10][CH:9]=[CH:8][N:7]=1)CCC.Br[C:21]1[N:29]2[C:24]([CH:25]=[N:26][C:27]([S:30][CH3:31])=[N:28]2)=[CH:23][CH:22]=1>>[CH3:31][S:30][C:27]1[N:26]=[CH:25][C:24]2=[CH:23][CH:22]=[C:21]([C:6]3[N:7]=[CH:8][CH:9]=[CH:10][N:11]=3)[N:29]2[N:28]=1
Reactant: CSc1ncc2ccc(Br)n2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Product: CSc1ncc2ccc(-c3ncccn3)n2n1
Yield: 20.6 %

Procedure:
Analogous to Example 1562a, 2-Tributylstannanyl-pyrimidine (0.761 g, 2.06 mmol) and 7-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.224 g, 0.916 mmol) were reacted to afford 2-Methylsulfanyl-7-pyrimidin-2-yl-pyrrolo[2,1-f][1,2,4]triazine (46 mg, 20%). 1H-NMR (DMSO-d6): 9.14 (s, 1H), 8.95 (d, 2H, J=4.94 Hz), 7.58 (m, 1H), 7.44 (t, 1H, J=4.83 Hz), 7.10 (d, 1H, J=4.83 Hz), 2.59 (s, 3H).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:9]=[CH:8][C:7]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][C:5]=1[C:15]([F:18])([F:17])[F:16].CCOCC.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([NH:31][CH2:3][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][C:5]=1[C:15]([F:18])([F:17])[F:16])[OH:1])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: CS(=O)(=O)Oc1ccc(C2CO2)c(C(F)(F)F)c1
Solvent: CCOCC
Product: CS(=O)(=O)Oc1ccc(C(O)CNCc2ccccc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Methanesulfonic acid 4-oxiranyl-3-trifluoromethyl-phenyl ester (23.54 g; 79.2 mmol) was dissolved in benzylamine (26 mL). The resulting mixture was stirrred at 80° C. for 4 h. After cooling to RT, Et2O was added and the mixture cooled to 0° C. The formed precipitate was collected by filtration, washed with Et2O, and dried under vacuum, at 40° C., to afford methanesulfonic acid 4-(2-benzylamino-1-hydroxy-ethyl)-3-trifluoromethyl-phenyl ester as a white solid (26.87 g) which was used as such.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=5)=[C:21]([F:33])[CH:20]=4)=[C:14]([CH2:34][CH2:35][CH3:36])[N:13]4[N:37]=[CH:38][N:39]=[C:12]34)[CH2:7][CH2:6]2)[O:4]CC1.Cl.O1CCCC1>C(OCC)(=O)C>[F:33][C:21]1[CH:20]=[C:19]([CH2:18][C:15]2[C:16](=[O:17])[N:11]([CH:8]3[CH2:7][CH2:6][CH:5]([OH:4])[CH2:10][CH2:9]3)[C:12]3[N:13]([N:37]=[CH:38][N:39]=3)[C:14]=2[CH2:34][CH2:35][CH3:36])[CH:24]=[CH:23][C:22]=1[C:25]1[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(F)c2)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(F)c2)c(=O)n(C2CCC(O)CC2)c2ncnn12
Temperature: 80 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
A mixture of 4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-2′-fluorobiphenyl-2-carbonitrile (1.2 g), 3N hydrochloric acid (50 mL) and tetrahydrofuran (50 mL) was stirred at 80° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (10 mL) and methanol (10 mL), sodium borohydride (0.17 g) was added, and the mixture was stirred at room temperature for 1 hr. After evaporation of the solvent under reduced pressure, the residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.95 g, 88%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH:8]3[CH2:17][CH2:16][CH2:15][CH:9]3[C:10](=O)[NH:11][C:12]=2[CH:13]=1)([O-:3])=[O:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH:8]3[CH2:17][CH2:16][CH2:15][CH:9]3[C:10](=[S:27])[NH:11][C:12]=2[CH:13]=1)([O-:3])=[O:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1Nc2cc([N+](=O)[O-])ccc2C2CCCC12
Product: O=[N+]([O-])c1ccc2c(c1)NC(=S)C1CCCC21

Procedure:
7-Nitro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one (91 mg, 0.30 mmol) is stirred with Lawesson's reagent (170 mg, 0.43 mmol) for 6 hours at room temperature. The batch is concentrated by evaporation in a vacuum, and the residue is purified on silica gel with toluene: 52 mg (54%) of product.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:20][CH3:21])[CH2:16][CH2:15]2)=[C:10]([CH2:22][NH:23][CH3:24])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25](Cl)(=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:15][CH2:16][C@H:17]([N:20]([C:25](=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH3:21])[CH2:18][CH2:19]2)=[C:10]([CH2:22][NH:23][CH3:24])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCC(=O)Cl
Reactant: CNCc1cc(C(=O)OC(C)(C)C)ccc1[C@H]1CC[C@H](NC)CC1
Product: CCCCCC(=O)N(C)[C@H]1CC[C@H](c2ccc(C(=O)OC(C)(C)C)cc2CNC)CC1

Procedure:
from trans-4-(4-tert.butoxycarbonyl-methylaminomethylphenyl)-N-methylcyclohexylamine and hexanoic acid chloride. Melting point: 83°-85° C.
Reaction SMILES: Cl[C:2]1[C:15]([F:16])=[CH:14][C:5]([C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])[N:3]=1.Cl.Cl.[NH2:28][CH:29]1[CH2:33][CH2:32][NH:31][CH2:30]1.C(N(CC)CC)C.C(OC(C)C)(C)C>C(Cl)(Cl)Cl.O>[NH2:28][CH:29]1[CH2:33][CH2:32][N:31]([C:2]2[C:15]([F:16])=[CH:14][C:5]([C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[C:4]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[N:3]=2)[CH2:30]1
Reactant: CCOC(=O)CC(=O)c1cc(F)c(Cl)nc1Nc1ccc(F)cc1F
Reactant: NC1CCNC1
Agent: Cl
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)c1cc(F)c(N2CCC(N)C2)nc1Nc1ccc(F)cc1F
Yield: 84.7 %

Procedure:
In 5 ml of chloroform was dissolved 500 mg of ethyl 2-[6-chloro-2-(2,4-difluorophenylamino)-5-fluoronicotinoyl]acetate, and 260 mg of 3-aminopyrrolidine dihydrochloride and 500 mg of triethylamine were added thereto, after which the resulting mixture was subjected to reaction under reflux for 1.5 hours. Subsequently, the reaction mixture was added to a mixture of 5 ml of chloroform and 5 ml of water, and the organic layer was separated, washed successively with 5 ml of water and 5 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the crystalline material thus obtained was added 2 ml of diisopropyl ether, after which crystals were collected by filtration to obtain 480 mg (yield 84.7%) of ethyl 2-[6-(3-amino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinoyl]acetate having a melting point of 140°-142° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F-].[K+].[CH2:14](B(O)O)[CH2:15][CH2:16][CH3:17]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:14][CH2:15][CH2:16][CH3:17])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: CCCCB(O)O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [F-]
Solvent: C1CCOC1
Product: CCCCc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 115.6 %

Procedure:
A 4 ml vial was charged with 4-tert-butylbromobenzene (1.00 mmol), Pd(dba)2 (0.01 mmol, 1 mol %), Ph5FcP(t-Bu)2 (0.02 mmol, 2 mol %), KF (2.02 mmol, powdered) and n-butylboronic acid (1.21 mmol). Anhydrous THF (2 ml) and a stirring bar were added, and the vial was sealed with a cap containing a PTFE septum and removed from the drybox. The reaction mixture was stirred at room temperature for 18 h. After a starting aryl halide was consumed as determined by GC, the reaction solution was cooled to room temperature. Then the reaction solution was adsorbed onto silica gel directly, and the product was isolated by eluting with ethyl acetate/hexanes to give 220 mg (98%) of 4-tert-butyl-1-n-butylbenzene as a colorless oil. Kugelrohl distillation was used for further purification.
Reaction SMILES: CO[C:3]([CH:5]1[CH2:9][CH:8]([NH:10][C:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[O:12])[CH:7]([OH:18])[CH2:6]1)=[O:4].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]2=[O:32])=[CH:22][C:21]=1[F:33]>>[F:33][C:21]1[CH:22]=[C:23]([N:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]2=[O:32])[CH:24]=[CH:25][C:20]=1[NH:19][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[O:12])[C@@H:7]([OH:18])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CC(O)C(NC(=O)c2cccs2)C1
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Product: O=C(N[C@H]1C[C@@H](C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@@H]1O)c1cccs1

Procedure:
In analogy to example 1C, 1R,3S,4S)-3-hydroxy-4-[(thiophene-2-carbonyl)-amino]-cyclo-pentanecarboxylic acid methyl ester was reacted with 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (CAS 536747-52-1, prepared according to C. F. Bigge et al., patent application WO 2003045912) to give thiophene-2-carboxylic acid {(1S,2S,4R)-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-hydroxy-cyclopentyl}-amide. Light yellow solid. MS: 442.1 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[C:12]=2[CH2:18][CH2:19][CH3:20])=[CH:8][CH:7]=[CH:6][C:5]=1[F:21].[CH2:23]([O:30][C:31]1[CH:36]=[C:35]([O:37][CH2:38][CH2:39][CH2:40]Cl)[C:34]([CH2:42][CH3:43])=[CH:33][C:32]=1[Br:44])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:40][CH2:39][CH2:38][O:37][C:35]3[CH:36]=[C:31]([O:30][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:32]([Br:44])=[CH:33][C:34]=3[CH2:42][CH3:43])[C:12]=2[CH2:18][CH2:19][CH3:20])=[CH:8][CH:7]=[CH:6][C:5]=1[F:21]
Reactant: CCc1cc(Br)c(OCc2ccccc2)cc1OCCCCl
Reactant: CCCc1c(O)cccc1Oc1cccc(F)c1C(=O)OC
Product: CCCc1c(OCCCOc2cc(OCc3ccccc3)c(Br)cc2CC)cccc1Oc1cccc(F)c1C(=O)OC

Procedure:
2-Fluoro-6-(3-hydroxy-2-propylphenoxy)benzoic acid methyl ester (1.84 g, 4.80 mmol) was alkylated with 2-benzyloxy-1-bromo-5-ethyl-4-(3-chloro-1-propyloxy)benzene to provide crude product as an oil. Silica gel chromatography provided 2.05 g (66%) of the purified title intermediate as a colorless oil: NMR (CDCl3) 7.49 (d, J=7.1 Hz, 2H), 7.20-7.45 (m, 5H), 7.14 (t, J=8.2 Hz, 1H), 6.82 (t, J=8.5 Hz, 1H), 6.73 (d, J=8.3 Hz, 1H), 6.60 (d, J=8.4 Hz, 1H), 6.53 (s, 1H), 6.52 (d, J=8.5 Hz, 1H), 5.13 (s, 2H), 4.20 (t, J=6.0 Hz, 2H), 4.13 (t, J=6.0 Hz, 2H), 3.92 (s, 3H), 2.58 (m, 4H), 2.30 (quintet, J=6.0 Hz, 2H), 1.51 (hextet, J=7.6 Hz, 2H), 1.16 (t, J=7.9 Hz, 3H), 0.90 (t, J=7.3 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:26][CH3:27])=[CH:4][C:5]2[CH2:11][N:10]([CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH2:9][C:8](=[O:18])[N:7]([CH2:19][C:20](=[O:24])[N:21]([CH3:23])[CH3:22])[C:6]=2[CH:25]=1.Cl[C:29]1[N:34]=[C:33]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[S:42]([N:45]([CH3:47])[CH3:46])(=[O:44])=[O:43])[C:32]([Cl:48])=[CH:31][N:30]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C>[Cl:48][C:32]1[C:33]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[S:42](=[O:44])(=[O:43])[N:45]([CH3:46])[CH3:47])=[N:34][C:29]([NH:1][C:2]2[C:3]([O:26][CH3:27])=[CH:4][C:5]3[CH2:11][N:10]([CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH2:9][C:8](=[O:18])[N:7]([CH2:19][C:20](=[O:24])[N:21]([CH3:22])[CH3:23])[C:6]=3[CH:25]=2)=[N:30][CH:31]=1
Reactant: COc1cc2c(cc1N)N(CC(=O)N(C)C)C(=O)CN(CC(=O)N(C)C)C2
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)N(CC(=O)N(C)C)C(=O)CN(CC(=O)N(C)C)C2
Temperature: 90 °C
Yield: 29.1 %

Procedure:
To a mixture of 2-(8-amino-1-dimethylcarbamoylmethyl-7-methoxy-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-N,N-dimethyl-acetamide (80 mg, 0.21 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide (69 mg, 0.20 mmol) in isopropanol (5 mL) was added 10-camphorsulfonic acid (123 mg, 0.53 mmol). The mixture was heated to 90° C. for 20 minutes under microwave irradiation, cooled to room temperature, and concentrated on a rotary evaporator. The residue was dissolved in dichloromethane and stirred with saturated aqueous sodium bicarbonate to neutral pH. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography over silica gel (MeOH/DCM) to give 40 mg (29%) of 2-{8-[5-chloro-4-(2-dimethylsulfamoyl-phenylamino)-pyrimidin-2-ylamino]-1-dimethylcarbamoylmethyl-7-methoxy-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl}-N,N-dimethyl-acetamide as a pale yellow solid; NMR (400 MHz, CDCl3) δ 9.39 (s, 1H), 8.51 (d, J=8 Hz, 1H), 8.34 (s, 1H), 8.19 (s, 1H), 7.90 (d, J=8 Hz, 1H), 7.61 (s, 1H), 7.56 (m, 1H), 7.28 (m, 1H), 6.94 (s, 1H), 4.45 (br s, 2H), 4.08 (s, 2H), 3.93 (s, 3H), 3.54 (s, 2H), 3.35 (s, 2H), 3.10 (s, 3H), 3.00 (s, 3H), 2.96 (s, 2H), 2.91 (s, 3H), 2.79 (s, 6H); MS (m/e) 689 (M+1); mp 154° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[NH:7][C@H:8]1[CH2:12][C@@H:11]([N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][C:16]([C:37](=[O:42])[NH:38][CH2:39][CH2:40][NH2:41])=[N:17][C:18]=3[NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:10]([OH:43])[C@@H:9]1[OH:44])([CH3:4])([CH3:3])[CH3:2].[N:46]1([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][N:61]=2)[CH2:51][CH2:50][CH:49]([NH:52][C:53](N2C=CN=C2)=[O:54])[CH2:48][CH2:47]1>CC(O)C.C(Cl)Cl>[C:1]([O:5][C:6](=[O:45])[NH:7][C@H:8]1[CH2:12][C@@H:11]([N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][C:16]([C:37](=[O:42])[NH:38][CH2:39][CH2:40][NH:41][C:53]([NH:52][CH:49]2[CH2:48][CH2:47][N:46]([C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][N:61]=4)[CH2:51][CH2:50]2)=[O:54])=[N:17][C:18]=3[NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:10]([OH:43])[C@@H:9]1[OH:44])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(NC1CCN(c2ccccn2)CC1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCN)nc32)[C@H](O)[C@@H]1O
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NC4CCN(c5ccccn5)CC4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of {(1S,2R,3S,4R)-4-[2-(2-amino-ethylcarbamoyl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-carbamic acid tert-butyl ester (2.5 g, 4.05 mmol) in IPA (10 ml) is added imidazole-1-carboxylic acid (3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-4-yl)-amide (Intermediate C) (151 ml of a 10 mg/ml solution in DCM, 5.56 mmol) and the reaction mixture is stirred at room temperature overnight. The solvent is removed in vacuo and the crude product is purified by chromatography on silica eluting with DCM/MeOH (25:1 increasing to 15:1). The resulting solid is further purified by dissolving in DCM and washing the solution with water, drying (MgSO4) and concentrating in vacuo to afford the title product. (MH+ 820.7)
Reaction SMILES: [C:1]1([CH2:7][C:8]2[O:12][N:11]=[C:10]([CH2:13][CH2:14][CH:15]=[O:16])[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO>[C:1]1([CH2:7][C:8]2[O:12][N:11]=[C:10]([CH2:13][CH2:14][CH2:15][OH:16])[N:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CCCc1noc(Cc2ccccc2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCCCc1noc(Cc2ccccc2)n1
Reaction time: 1 h
Yield: 59 %

Procedure:
A solution of crude 3-[5-(phenylmethyl)-1,2,4-oxadiazol-3-yl]propanal (3.76 g, 17.4 mmol) in MeOH (60 ml) was cooled to 0° C. and sodium borohydride (0.724 g, 19.1 mmol) added portionwise over 30 min. The cooling bath was removed and the solution stirred for a further 1 h then partitioned between 1M HCl and EtOAc. The organic layer was separated and the aqueous extracted with EtOAc. The combined extracts were washed with brine, dried and concentrated to an orange liquid. This was purified on a 50 g silica SPE eluting with cyclohexane/EtOAc (20% to 80% gradient elution) to provide the title compound as a yellow oil (2.24 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH3:25][O:26][C:27]1[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=1[NH2:29]>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14]([NH:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[O:26][CH3:25])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Reactant: COc1ccccc1N
Solvent: CCOCC
Product: COc1ccccc1Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Temperature: 175 °C

Procedure:
A mixture of 0.113 g (0.29 mmol) of 6-(2,6-dichlorophenyl)-2-methanesulfonyl-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 39 and 0.50 g (4.10 mmol) of 2-methoxyaniline was heated, with stirring, in a 175° C. oil bath. The resulting solution was heated for 5 minutes and cooled to room temperature. Ether (2 mL) was added. The crystals that developed were filtered and washed with 1 mL of ether; wt 0.070 g. The solid was purified to remove dark colors by silica gel chromatography, eluting with chloroform. Recrystallization from ether gave pure product; wt 0.029 g; mp 200°-201° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].[N+:15]([CH:18]=[C:19]1[NH:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:20]1)([O-:17])=[O:16]>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:19]([NH:23][CH2:22][CH:21]([OH:20])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:18][N+:15]([O-:17])=[O:16])[N:9]=1)[CH3:1]
Reactant: CN(C)Cc1nc(CSCCN)cs1
Reactant: O=[N+]([O-])C=C1NCC(c2ccccc2)O1
Solvent: CCO
Product: CN(C)Cc1nc(CSCCNC(=C[N+](=O)[O-])NCC(O)c2ccccc2)cs1
Yield: 68.7 %

Procedure:
With 2 ml of ethanol was mixed 1 g of 2-{[2-(dimethylamino)methyl-4-thiazolyl]methylthio}ethylamine and 1.1 g of 2-nitromethylene-5-phenyl-oxazolidine, and the resulting mixture was subjected to reaction under reflux for 1 hour. After completion of the reaction, the reaction mixture was filtered with cooling, and the solvent was removed by distillation under reduced pressure, after which the resulting residue was purified by a column chromatography (Wako Silica Gel C-200, eluent; chloroform:ethanol=20:1 by volume) to obtain 1.3 g (yield 68%) of N-{2-[[2-(dimethylamino)methyl-4-thiazolyl]methylthio]ethyl}-N'-(β-hydroxyphenethyl)-2-nitro-1,1-ethenediamine having a melting point of 100°-101° C.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:42])([C:18]3[N:19]=[CH:20][N:21](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:22]=3)[CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)=[CH:6][C:5]([NH:43][C:44](=[O:46])[CH3:45])=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1>>[F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:42])([C:18]3[N:19]=[CH:20][NH:21][CH:22]=3)[CH:15]([CH3:16])[CH3:17])=[CH:10][CH:9]=2)=[CH:6][C:5]([NH:43][C:44](=[O:46])[CH3:45])=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1ccc(F)c(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(F)c(-c2ccc(C(O)(c3c[nH]cn3)C(C)C)cc2)c1
Yield: 50.6 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using N-{6-fluoro-4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-yl}acetamide (820 mg) and pyridine hydrochloride (230 mg), the title compound (250 mg) was obtained as a colorless amorphous powder.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]([N+:15]([O-:17])=[O:16])=[C:11]([CH3:18])[N:10]([CH3:19])[C:9]1=[O:20])(=[O:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O.C([O-])(=O)C.[Na+]>CC(O)=O.CC(=O)OCC.O>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]([N+:15]([O-:17])=[O:16])=[C:11](/[CH:18]=[CH:25]/[C:24]2[CH:27]=[CH:28][CH:29]=[C:22]([Cl:21])[CH:23]=2)[N:10]([CH3:19])[C:9]1=[O:20])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCn1c(=O)c([N+](=O)[O-])c(C)n(C)c1=O
Reactant: O=Cc1cccc(Cl)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OCCCn1c(=O)c([N+](=O)[O-])c(/C=C/c2cccc(Cl)c2)n(C)c1=O
Temperature: 150 °C
Yield: 16.3 %

Procedure:
To a solution of 3-(3,4-dimethyl-5-nitro-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)propyl acetate (300 mg, 1.05 mmol) in HOAc (0.7 mL) was added 3-chlorobenzaldehyde (221 mg, 1.58 mmol) and sodium acetate (431 mg, 5.26 mmol). The reaction was heated at 150° C. for 7 h, cooled to RT then diluted with EA (20 mL) and water (20 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography PE/EA (5:1 to 2:1) to give (E)-3-(4-(3-chlorostyryl)-3-methyl-5-nitro-2,6-dioxo-2,3-dihydropyrimidin-1 (6H)-yl)propyl acetate (70 mg, 16.4% yield) as a brown oil. LCMS: MH+ 408 and TR=1.560 min.
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][C:8](=[O:10])[CH2:7][C:6](=[O:11])[CH2:5]1)([CH3:3])[CH3:2].[C:12]1([CH3:24])[CH:17]=[CH:16][C:15]([S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19])=[CH:14][CH:13]=1>C1C=CC=CC=1>[CH:1]([CH:4]1[CH2:5][C:6](=[O:11])[CH:7]([C:22](=[O:23])[NH:21][S:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:24])=[CH:13][CH:14]=2)(=[O:19])=[O:20])[C:8](=[O:10])[CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)C1CC(=O)CC(=O)C1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)NC(=O)C2C(=O)CC(C(C)C)CC2=O)cc1

Procedure:
Reaction of 5-isopropyl-1,3-cyclohexanedione with p-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5-ISOPROPYL-2-(N-p-TOLUENESULFONYLCARBAMOYL)-1,3-CYCLOHEXANEDIONE, m.p. 106.5°-107.5° C. (corr.).