Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)[C:3]([OH:5])=[O:4].C([O-])(O)=O.[Na+].O.Cl[C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1COCC1>[Br:13][C:9]1[CH:8]=[C:7]([CH2:6][CH:2]([NH:1][C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:3]([OH:5])=[O:4])[CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: NC(Cc1cccc(Br)c1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)NC(Cc1cccc(Br)c1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.2 %

Procedure:
To a suspension of 2-amino-3-(3-bromophenyl)propanoic acid (11.0 g, 45.5 mmol) and NaHCO3 (11.5 g, 136.5 mmol) in THF (100 mL)/H2O (100 mL), ethyl 2-chloro-2-oxoacetate (18.4 g, 135.2 mmol) was added dropwise at 0° C. The mixture was stirred at RT overnight, acidified with aqueous critic acid (10%), and then extracted with EtOAc (3×100 mL). The combined organic layers were washed with H2O (100 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated to afford the crude product, which was purified by Combiflash reverse phase chromatography (50%˜60% MeCN/H2O containing 0.01% TFA) to afford 3-(3-bromophenyl)-2-(2-ethoxy-2-oxoacetamido)propanoic acid as a colorless oil (5.2 g, 33%). MS (ES+) C13H14BrNO5 requires: 343, 345 found: 344 [M+H]+, 346 [M+2+H]+(1:1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH2:13][C:14]([OH:17])([CH3:16])[CH3:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[C:19](Cl)(=[O:21])[CH3:20]>C(Cl)Cl>[C:19]([O:17][C:14]([CH3:15])([CH2:13][CH2:12][O:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH3:16])(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)(C)O)cc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)OC(C)(C)CCOS(=O)(=O)c1ccc(C)cc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
To a mixture of the alcohol 2 (0.500 g, 1.937 mmol), ZrOCl28.H2O (0.0031 g, 0.5 mol %) in methylene chloride (5 mL), acetyl chloride (0.304 g, 3.87 mmol) is added and the reaction is stirred for overnight at 20° C. The reaction on completion, is diluted with methylene chloride (5 mL) and washed with saturated sodium bicarbonate (2×10 mL), brine (1×10 mL) and dried. The solvent is evaporated to get the crude product. 1H NMR (400 MHz, CDCl3): δ 1.54 (s, 6H), 1.59 (s, 3H), 2.14-2.07 (m, 2H), 2.43 (s, 3H), 4.26 (dt, J=6.9, 13.5, 3H), 7.33 (d, J=7.9, 2H), 7.77 (d, J=8.2, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][C:13]2([OH:16])[CH2:15][CH2:14]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.CN(C)CCN(C)C.C([Li])CCC.CCCCCC.ClCC[I:45]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([I:45])[N:8]2[CH2:11][CH2:12][C:13]2([OH:16])[CH2:15][CH2:14]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: ClCCI
Reactant: OC1(CCn2cnc3c(N4CCOCC4)nc(Cl)nc32)CC1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC1(CCn2c(I)nc3c(N4CCOCC4)nc(Cl)nc32)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
A solution of 1-(2-(2-chloro-6-morpholino-9H-purin-9-yl)ethyl)cyclopropanol (220 mg, 0.68 mmol) and N,N,N′,N′-tetramethylethylene-diamine (0.15 mL, 1.0 mmol) in THF (4.9 mL) was cooled to −42° C. and treated with a solution of 2.5M n-butyllithium in hexane (1.5 mL, 3.7 mmol) dropwise over 5 minutes. After 30 minutes at −42° C., 1-chloro-2-iodoethane (0.31 mL, 3.3 mmol) was added and the reaction mixture was slowly warmed to 0° C. over 1 hr. The mixture was quenched with a saturated solution of NH4Cl, and diluted with ethyl acetate. The aqueous layer was extracted into ethyl acetate (3×), and the combined organics were dried over sodium sulfate, filtered, and absorbed onto celite for purification by flash chromatography to afford 1-(2-(2-chloro-8-iodo-6-morpholino-9H-purin-9-yl)ethyl)cyclopropanol as a colorless oil (220 mg, 71%). LC/MS (ESI+): m/z 450 (M+H)
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1([CH3:10])[CH3:9].Cl.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19]N)=[CH:15][CH:14]=1.[CH3:21][N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1>C(N(CC)CC)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]2[N:19]([CH2:2][CH2:3][N:4]3[CH2:8][CH2:7][CH2:6][C:5]3([CH3:10])[CH3:9])[C:25]3[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][C:24]=3[C:15]=2[CH:14]=1
Reactant: CC1(C)CCCN1CCBr
Reactant: NNc1ccc(Cl)cc1
Reactant: CN1CCC(=O)CC1
Agent: Cl
Solvent: CCN(CC)CC
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCN2CCCC2(C)C)C1

Procedure:
The title compound is prepared by following Method 8 by using 1-(2-bromoethyl)-2,2-dimethylpyrrolidine, 4-chlorophenylhydrazine hydrochloride, triethylamine and N-methyl-4-piperidone
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:5]2=[N:6][CH:7]=1.CN(C(ON1N=[N:37][C:32]2[CH:33]=CC=N[C:31]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.CC(N)C>O>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:37][CH:32]([CH3:33])[CH3:31])=[O:13])=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:5]2=[N:6][CH:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(Br)cnc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)N
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 94 %

Procedure:
2-Bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1.12 g, 3.01 mmol) and HATU (1.37 g, 3.61 mmol) were combined with DMF (5.2 mL) then propan-2-amine (711 mg, 1.03 mL, 12.0 mmol) was added via syringe. The reaction mixture was stirred at 25° C. After 14 h, water (50 mL) was added and the mixture extracted with EtOAc (4×50 mL). The combined organics were washed with water (30 mL), saturated sodium chloride solution (3×20 mL) and dried with MgSO4. Solvents were evaporated and the residue purified by chromatography (silica, 0 to 30% EtOAc in hexanes over 15 min) to yield 2-bromo-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (1.17 g, 2.83 mmol, 94%) as a white solid. MS (M+Na)+=435; 1H NMR (CDCl3) δ: 8.41 (s, 1H), 8.35 (s, 1H), 7.72 (d, J=4.9 Hz, 1H), 5.65 (s, 2H), 4.19-4.45 (m, 1H), 3.41-3.69 (m, 2H), 1.34 (d, J=6.8 Hz, 6H), 0.82-0.97 (m, 2H), −0.13-0.09 (m, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[N:7]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=2)[C:6]=1[C:25]1[CH:30]=[CH:29][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=1)=[O:4].[Cl:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][C:39]3[CH:40]=[CH:41][C:36]([Cl:35])=[CH:37][CH:38]=3)[CH:12]=2)[N:7]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:19][CH:20]=2)[C:6]=1[C:25]1[CH:26]=[CH:27][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:30]=1)=[O:4]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(-c2c(C(=O)OC)c3cc(O)ccc3n2-c2ccc(OC(C)C)cc2)cc1
Product: COC(=O)c1ccc(-c2c(C(=O)OC)c3cc(Oc4ccc(Cl)cc4)ccc3n2-c2ccc(OC(C)C)cc2)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 5-hydroxy-1-(4-isopropoxyphenyl)-2-(4-methoxycarbonylphenyl)indole-3-carboxylic acid methyl ester (150 mg, 0.32 mmol, see step (b) Example 43) and 4-chlorophenylboronic acid (100 mg, 0.64 mmol). Yield 97 mg (54%).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([CH3:7])(=[O:6])=[O:5].CS(C)=O.[CH3:12][N:13]([C:17]1[CH:18]=[C:19]([CH:24]=[C:25]([N:27](C)[C:28](=O)C)[CH:26]=1)[C:20](OC)=[O:21])C(=O)C>O.C(O)(=O)C>[CH3:28][NH:27][C:25]1[CH:24]=[C:19]([C:20](=[O:21])[CH2:3][S:4]([CH3:7])(=[O:6])=[O:5])[CH:18]=[C:17]([NH:13][CH3:12])[CH:26]=1
Reactant: COC(=O)c1cc(N(C)C(C)=O)cc(N(C)C(C)=O)c1
Reactant: CS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CNc1cc(NC)cc(C(=O)CS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of 19.2 g. of sodium hydride (50% dispersion in oil) and 56.1 g. of dimethylsulfone in 200 ml. of absolute dimethylsulfoxide was stirred with the exclusion of moisture for 3 hours at 50° C. and then treated at 25° C. with 41.8 g. of methyl 3,5-bis-(N-methylacetamido)benzoate. The mixture was stirred for 18 hours at 25° C., diluted with 2 liters of water, adjusted to pH 7 with glacial acetic acid and extracted with 9 liters of ethyl acetate. The ethyl acetate solution was washed with 3 liters of water, dried over magnesium sulfate and evaporated in vacuo. Recrystallization of the residue from ethanol yielded 3',5'-bis(methylamino)-2-methylsulfonylacetophenone, having a melting point of 144°-146° C.
Reaction SMILES: N1CCOCC1.[OH:7][CH2:8][C:9](=O)[C:10]([CH3:13])([CH3:12])[CH3:11].[CH2:15]([C:18]#[N:19])[C:16]#[N:17]>CN(C)C=O>[NH2:19][C:18]1[O:7][CH:8]=[C:9]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:15]=1[C:16]#[N:17]
Reactant: CC(C)(C)C(=O)CO
Reactant: N#CCC#N
Solvent: C1COCCN1
Solvent: CN(C)C=O
Product: CC(C)(C)c1coc(N)c1C#N
Temperature: 0 °C
Yield: 51.8 %

Procedure:
174 g (2 moles) of morpholine were added dropwise to a solution of 232 g (2 moles) of hydroxy-pinacolone and 132 g (2 moles) of malonic acid dinitrile in 500 ml of dimethylformamide, while cooling, in a manner such that the internal temperature did not rise above 40° C. After the reaction had ended, the reaction mixture was stirred into 5 liters of ice-water. The solid product which thereby precipitated was filtered off, washed with water and dried. 170 g of 2-amino-3-cyano-4-tert.-butyl-furan of melting point 86° C. were obtained in this manner.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[N:5][N:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12.[NH2:12][C:13]1[C:14](=[O:33])[N:15]([CH3:32])[N:16]=[C:17]([O:19][CH2:20][C@H:21]2[CH2:23][C@@H:22]2[C:24]2[CH:29]=[CH:28][C:27](OC)=[CH:26][N:25]=2)[CH:18]=1.[NH4+].[Cl-].[CH3:36]O.O>C(Cl)Cl.C(#N)C.O>[CH3:32][N:15]1[C:14](=[O:33])[C:13]([NH:12][CH2:2][C:3]2[CH:4]=[N:5][N:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=23)=[CH:18][C:17]([O:19][CH2:20][C@H:21]2[CH2:23][C@@H:22]2[C:24]2[CH:29]=[CH:28][C:27]([CH3:36])=[CH:26][N:25]=2)=[N:16]1
Reactant: CO
Reactant: COc1ccc([C@H]2C[C@@H]2COc2cc(N)c(=O)n(C)n2)nc1
Reactant: BrCc1cnn2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: Cc1ccc([C@H]2C[C@@H]2COc2cc(NCc3cnn4ccccc34)c(=O)n(C)n2)nc1
Reaction time: 1 h

Procedure:
To the solution of 3-(bromomethyl)pyrazolo[1,5-a]pyridine (3) (4 mL, 0.27 mmol, 0.0675 mmol/ml) in DCM (4 mL) was added TEA (33 mg, 0.33 mmol) and 4-amino-6-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyridazin-3(2H)-one (50 mg, 0.165 mmol) at room temperature and stirred for 1 h, then 10 mL sat. NH4Cl was added, extracted with EtOAc (3×10 mL). The combined organic phase were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by reverse phase chromatography (X bridge Prep C18OBD, 40-60% acetonitrile in water with 10 mmol NH4HCO3 modifier) to afford the compound as an oil. 1H NMR (400 MHz, MeOD) δ 8.47 (d, 1H), 8.03 (d, 1H), 7.96 (s, 1H), 7.67 (d, 1H), 7.26-7.11 (m, 3H), 6.87-6.84 (m, 1H), 5.85 (s, 1H), 4.50 (s, 2H), 4.17-4.13 (m, 1H), 4.02-3.97 (m, 1H), 3.82 (s, 3H), 3.59 (s, 3H), 2.06-2.02 (m, 1H), 1.75-1.71 (m, 1H), 1.17-1.13 (m, 1H) 1.02-0.99 (m, 1H); LRMS m/z (M+H) 433.1 found, 433.15 required.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[NH:11]1[CH2:15][CH:14]([CH:16]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=2)[CH3:17])[N:13]=[CH:12]1.C(N(CC)CC)C>ClCCl>[NH:11]1[CH:15]=[C:14]([CH:16]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=2)[CH3:17])[N:13]=[CH:12]1
Reactant: CC(c1ccnc2ccccc12)C1CNC=N1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(c1c[nH]cn1)c1ccnc2ccccc12
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 50.4 %

Procedure:
To oxalyl chloride (0.85 μl, 0.976 mmol) in 5 ml of anhydrous dichloromethane at −78° C., dimethylsulfoxide (0.14 ml, 1.95 mmol) was added over a five minute period. After stirring for 5 minutes at the same temperature, 4-[1-(4,5-Dihydro-1H-imidazol-4-yl)-ethyl]quinoline (0.200 g, 0.888 mmol) was added slowly and the reaction mixture was stirred for a further 20 minutes at −78° C. Triethylamine (0.62 ml, 4.44 mmol) was added and the reaction mixture was stirred for 5 minutes at −78° C. and then 20 minutes at room temperature. The reaction mixture was concentrated under reduced pressure and partitioned between EtOAc (10 ml) and water (5 ml). The organic layer was dried over sodium sulfate, filtered, concentrated and column purified [EtOAc:MeOH:Methanol NH3 (1.0 M); 3.5:1:0.5) to give 0.100 g (51%) of the product as a syrup.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:13]=[C:12]([O:27][CH3:28])[N:11]=2)=[CH:6][C:3]=1[CH:4]=O.[CH3:29][O:30][CH2:31][CH2:32][NH2:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:48]>C(Cl)Cl.CCOC(C)=O>[ClH:48].[F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([O:27][CH3:28])[N:13]=[C:14]([NH:16][CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[CH:15]=2)=[CH:6][C:3]=1[CH2:4][NH:33][CH2:32][CH2:31][O:30][CH3:29]
Reactant: COCCN
Reactant: COc1ccc(CCNc2cc(-c3ccc(F)c(C=O)c3)nc(OC)n2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COCCNCc1cc(-c2cc(NCCc3ccc(OC)cc3)nc(OC)n2)ccc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
A mixture of 2-fluoro-5-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzaldehyde [300 mg, 0.787 mmol, Example 35(j)], 2-methoxyethylamine (170 μL, 1.97 mmol), sodium triacetoxyborohydride (500 mg, 2.36 mmol) and 3 Å sieves (500 mg) in DCM (7 mL) is stirred at room temperature under a nitrogen atmosphere for 5 hours. The reaction mixture is filtered and the filter cake is washed with DCM (50 mL). The combined filtrate and washings are extracted with water (50 mL). The aqueous extract is extracted with DCM (50 mL). The new organic extract is washed with water (30 mL), with brine (30 mL), dried over sodium sulfate, filtered and concentrated by rotary evaporator. The resulting solid is subjected to flash column chromatography on silica (4.5 g) eluting with 0 to 8% MeOH in DCM gradient to afford a solid. This material is treated with hydrogen chloride in EtOAc and concentrated to afford (6-{4-fluoro-3-[(2-methoxy-ethylamino)-methyl]-phenyl}-2-methoxy-pyrimidin-4-yl)-[2-(4-methoxy-phenyl)-ethyl]-amine hydrochloride [260 mg, 75%, Example 13(b)] as a solid. LCMS: RT=1.98 minutes, MS: 441 (M+H). 1H NMR (300 MHz, CDCl3): δ 9.65 (1H, s), 8.27 (1H, s), 7.91 (1H, s), 7.47 (1H, t, J=0.03 Hz), 7.21 (2H, d, J=0.027 Hz), 6.85 (2H, d, J=0.027 Hz), 4.26 (2H, s), 4.03 (2H, s), 3.72 (6H, s), 3.31 (3H, s), 3.17 (2H, m), 2 (2H, t, J=0.024), 2.5 (2H, s).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])=[N:5][N:4]=[C:3]1[C:14]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])=[N:5][N:4]=[C:3]1[C:14]1([NH:19][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: Cc1ccccc1-c1nnc(C2(N)CCCC2)n1C
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1ccccc1-c1nnc(C2(NC(=O)c3ccccc3)CCCC2)n1C
Temperature: 25 °C
Reaction time: 19 h

Procedure:
1-[4-Methyl-5-(2-methylphenyl)-1,2,4-triazol-3-yl]cyclopentanamine (270 mg) was dissolved in chloroform (5 ml) and then diisopropylethylamine (1.7 ml) and benzoyl chloride (0.48 ml) were added thereto, followed by stirring at room temperature for 19 hours. The reaction solution was diluted with a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform (10 ml×2). The organic layer was dried over anhydrous sodium sulfate and filtered and then the solvent was removed by evaporation under reduced pressure. The resulting residue was purified by column chromatography (methanol:chloroform=1:19) and the resulting solid was dissolved in ethanol (1 ml) and then a 1M aqueous sodium hydroxide solution (2 ml) was added thereto, followed by stirring at room temperature for 6 days. The resulting solid was collected by filtration and washed with water to obtain 51 mg of N-{1-[4-methyl-5-(2-methylphenyl)-1,2,4-triazol-3-yl]cyclopentyl}benzamide (white solid).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]([O:16][C:17]([CH3:20])(C)C)=[O:15])[C:3]1=[O:21].O.[C:23]1(C)[CH:28]=[CH:27]C(S(O)(=O)=O)=[CH:25][CH:24]=1.C(O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]([O:16][CH2:17][C:20]2[CH:27]=[CH:28][CH:23]=[CH:24][CH:25]=2)=[O:15])[C:3]1=[O:21]
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(N)CCc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: OCc1ccccc1
Product: NC1CCc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Reaction time: 4 h
Yield: 69.9 %

Procedure:
10.5 g of tert-butyl 3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetate (see Example 1I) for preparation), 8.25 g of p-toluenesulfonic acid hydrate and 20.1 ml of benzyl alcohol were added to 174 ml of toluene. The reaction mixture was boiled with a water trap for 4 hours, during which a precipitate which originally separated out slowly dissolved. The toluene was then stripped off under reduced pressure, and the remaining residue was stirred with methyl tert-butyl ether and then filtered out. The resulting solid residue was dissolved in dichloromethane, and the solution was made alkaline by adding aqueous sodium carbonate solution while cooling in ice. The dichloromethane phase was then separated, washed with water, dried over sodium sulfate and evaporated. The resulting crude product was recrystallized from methyl tert-butyl ether for purification. 8.2 g of benzyl 3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetate were obtained with a melting point of 105° to 107° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([S:12][CH2:13][CH2:14][CH3:15])[N:3]=1.C(N(CC)CC)C.[NH2:23][C@@H:24]1[CH2:28][C@H:27]([OH:29])[CH:26]=[CH:25]1>O1CCCC1.O1CCCC1.O1CCOCC1>[Cl:11][C:6]1[N:5]=[C:4]([S:12][CH2:13][CH2:14][CH3:15])[N:3]=[C:2]([NH:23][C@@H:24]2[CH2:28][C@H:27]([OH:29])[CH:26]=[CH:25]2)[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: N[C@H]1C=C[C@@H](O)C1
Reactant: CCCSc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCSc1nc(Cl)c([N+](=O)[O-])c(N[C@H]2C=C[C@@H](O)C2)n1
Yield: 64.4 %

Procedure:
To a solution of 4,6-dichloro-5-nitro-2-propylthiopyrimidine (prepared as described in WO 9703084) (4.00 g) and triethylamine (2.00 ml) in dry tetrahydrofuran (THF) (100 ml) was added a solution of [1S-cis]-4-amino-2-cyclopenten-1-ol (prepared as described by S. F. Martin et al., Tetrahedron Lett., 1992, 33, 3583) (1.48 g) in THF/1,4-dioxane 2:1 (150 ml) dropwise over 1 hour. The reaction mixture was filtered, concentrated and purified (SiO2, ethyl acetate:isohexane 1:4 to 1:1 as eluant) to afford the subtitle compound (3.18 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([C:8]#[C:9][Si](C)(C)C)[CH:7]=1.C([O-])([O-])=O.[K+].[K+].O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([C:8]#[CH:9])[CH:7]=1
Reactant: COc1ccc(Cl)cc1C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#Cc1cc(Cl)ccc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
((5-chloro-2-methoxyphenyl)ethynyl)trimethylsilane (0.4 g, 1.7 mmol) was dissolved in MeOH (1 mL), K2CO3 (0.69 g, 5 mol) was added to it. Then the mixture was stirred at 25° C. for 1 hour, and added to H2O (50 mL). The mixture was extracted with ethyl acetate and washed with brine, dried over Na2SO4. After the combined organic layers were concentrated, the resulting residue was purified using prep-TLC (petroleum ether:EtOAc=10:1) to provide the product of 4-chloro-2-ethynyl-1-methoxybenzene (0.25 g, yield: 80%). 1H-NMR (CDCl3, 400 MHz) δ 7.43 (s, 1H), 7.28˜7.29 (m, 1H), 6.81˜6.85 (m, 1H), 3.89 (s, 3H), 3.34 (s, 1H). MS (M+H)+: 167/169.
Reaction SMILES: Cl.[C:2]1([CH:8]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]([NH:11][C@@H:12]([C:17]([NH:19][C@@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:21])=[O:18])[CH2:13][CH2:14][CH2:15][NH2:16])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([NH:44][C:45](=[N:48][C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50])SC)([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35].CCN(C(C)C)C(C)C>>[C:49]([NH:48][C:45](=[N:44][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[NH:16][CH2:15][CH2:14][CH2:13][C@H:12]([C:17]([NH:19][C@@H:20]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH3:21])=[O:18])[NH:11][C:9](=[O:10])[CH:8]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)([O:51][CH2:52][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)=[O:50]
Reactant: C[C@@H](NC(=O)[C@@H](CCCN)NC(=O)C(c1ccccc1)c1ccccc1)c1ccccc1
Reactant: CSC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)[C@@H](CCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)NC(=O)C(c1ccccc1)c1ccccc1)c1ccccc1
Yield: 78.4 %

Procedure:
Prepared according to the method described in Example 4(f) above from (R)-N2 -(diphenylacetyl)-(R)-N-(1-phenylethyl)ornithine amide (0.50 g; 1.0 mmol; from step (c) above), N,N'-bis(Cbz)-S-methylisothiourea (0.40 g; 1.1 mmol) and DiPEA (0.3 mL; 1.6 mmol) yielding 0.58 g (73%) of the sub-title compound as a solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[C:24]1([NH2:31])[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1>C(OCCO)C.C(OCC)(=O)C>[C:9]1([S:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:30][C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([NH2:31])[CH:25]=3)[N:7]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Clc1nccc(Sc2ccccc2)n1
Reactant: Nc1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCCO
Solvent: CCOC(C)=O
Product: Nc1cccc(Nc2nccc(Sc3ccccc3)n2)c1
Temperature: 25 °C
Yield: 42 %

Procedure:
To a stirred mixture of 2-chloro-4-(phenylthio)pyrimidine (300 mg, 1.35 mmol) and diisopropylethylamine (0.35 mL, 2.02 mmol) in 2-ethoxyethanol (2 mL), was added 1,3-phenylenediamine (291 mg, 2.70 mmol) in one portion. The whole was heated under reflux for 20 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (20 mL), washed with water and brine. The organic solution was dried (Na2SO4), concentrated in vacuo. The residue was flash chromatographed on silica gel using ethyl acetate:petroleum ether (20:80→50:50) as eluant to give the product (167 mg, 42%).