Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[OH:11].BrC[O:14][C:15](=[O:17])[CH3:16].O>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[O:11][CH2:16][C:15]([OH:17])=[O:14]
Reactant: CC(=O)OCBr
Reactant: Oc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)COc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.3 %

Procedure:
Sodium hydride (60 mg) was dissolved in dimethylformamide (3 ml) to prepare a solution. A dimethylformamide solution (5 ml) of 2,4-dichlorophenol (245 mg) was then added to the solution, and the mixture was stirred at room temperature for 10 min. Subsequently, a dimethylformamide solution (5 ml) of bromomethylacetate (344 mg) was added thereto, and the mixture was further stirred at room temperature for 90 min. Water was added to stop the reaction, and the reaction solution was extracted with ethyl acetate, followed by washing with water and saturated brine. The extract was then dried over sodium sulfate. After the concentration of the extract, a 5% aqueous sodium hydroxide solution (10 ml) was added thereto, and the mixture was stirred at 80° C. for 10 hr. Subsequently, the solution was acidified by the addition of 1 N hydrochloric acid. The resultant white precipitate was collected by filtration and was dried to give 2-(2,4-dichlorophenoxy)acetic acid (310 mg, yield 94%).
Reaction SMILES: CN1CCCN(C)C1=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:20]=[C:21]1[CH2:27][CH:26]([S:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:30])=[O:29])[C:25]2[CH:37]=[C:38]([C:41]([O:43][CH3:44])=[O:42])[CH:39]=[CH:40][C:24]=2[O:23][CH2:22]1.[CH2:45](Br)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.Cl>O1CCCC1.ClCCl.O>[CH2:45]([C:26]1([S:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:30])=[O:29])[C:25]2[CH:37]=[C:38]([C:41]([O:43][CH3:44])=[O:42])[CH:39]=[CH:40][C:24]=2[O:23][CH2:22][C:21](=[CH2:20])[CH2:27]1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: BrCc1ccccc1
Reactant: C=C1COc2ccc(C(=O)OC)cc2C(S(=O)(=O)c2ccccc2)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: C=C1COc2ccc(C(=O)OC)cc2C(Cc2ccccc2)(S(=O)(=O)c2ccccc2)C1
Reaction time: 0.25 h
Yield: 86 %

Procedure:
0.072 ml (1.1 equivalents) of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and then 0.6 ml (1.1 equivalents) of 1.06M lithium bis(trimethylsilyl)amide in tetrahydrofuran are added at ambient temperature to 195 mg (0.55 mmol) of methyl 3-methylene-5-(phenylsulfonyl)-2,3,4,5-tetrahydro-1-benzoxepin-7-carboxylate, prepared according to example 1, in solution in 5 ml of tetrahydrofuran. The reaction medium then assumes a dark yellow color. After stirring for 15 minutes, 0.073 ml (1.1 equivalents) of benzyl bromide is added. After stirring for 5 minutes, water, 1N hydrochloric acid and dichloromethane are added. After separating the organic and aqueous phases, the aqueous phase is extracted three times with dichloromethane. The combined organic phases are washed with brine, are dried and are finally concentrated under vacuum. The crude reaction product is then purified by chromatography on silica gel (ethyl acetate/heptane 25/75) to provide 211 mg (86%) of methyl 5-benzyl-3-methylene-5-(phenylsulfonyl)-2,3,4,5-tetrahydro-1-benzoxepin-7-carboxylate in the form of a white solid; M.p.=164–165° C.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][C:4](=[N:7][OH:8])[CH2:3][CH2:2]1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][C:25](OCC)=O)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH2:24][C:25]3[O:8][N:7]=[C:4]4[CH2:3][CH2:2][S:1][CH2:6][C:5]=34)[CH2:20][CH2:21]2)=[CH:14][CH:15]=1
Reactant: ON=C1CCSCC1
Reactant: CCOC(=O)CCCN1CCN(c2ccc(Cl)cc2)CC1
Product: Clc1ccc(N2CCN(CCCc3onc4c3CSCC4)CC2)cc1

Procedure:
By the same reaction and treatment as in Example 48 using tetrahydro-4H-thiopyran-4-one oxime and ethyl 4-(4-(4-chlorophenyl)piperazin-1-yl)-n-butyrate, 3-(3-(4-(4chlorophenyl)piperazin-1-yl)propyl)-6,7-dihydro-4H-thiopyrano[4,3-c]isoxazole is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:20][C:21]4[N:26]([CH2:27][CH2:28][C:29]#N)[C:25](=[O:31])[CH2:24][O:23][C:22]=4[N:32]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].O=C1COC2N=C(C3C=CC(C4(NC(=O)OC(C)(C)C)CCC4)=CC=3)C(C3C=CC=CC=3)=CC=2N1.ICCC>>[C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:20][C:21]4[N:26]([CH2:27][CH2:28][CH3:29])[C:25](=[O:31])[CH2:24][O:23][C:22]=4[N:32]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CCC#N)C(=O)CO4)cc2)CCC1
Agent: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Solvent: CCCI
Product: CCCN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21

Procedure:
Following the procedure for tert-butyl(1-(4-(1-(2-cyanoethyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate, tert-butyl 1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (60 mg, 0.127 mmol) was reacted with 1-iodopropane (32.4 mg, 0.191 mmol) to afford the title compound (43 mg. 1H NMR (500 MHz, CD3OD): 7.53 (1H, s), 7.21-7.32 (9H, m), 4.94 (2H, s), 4.02 (2H, t), 2.44-2.47 (4H, m), 2.05-2.10 (1H, m), 1.85-1.87 (1H, m), 1.73-1.77 (2H, m), 1.02-1.48 (9H, br), 1.01 (3H, t).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:16]O)[C:11]=1[CH3:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][Cl:21])[C:11]=1[CH3:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCOc1ccnc(CO)c1C
Solvent: ClC(Cl)Cl
Product: CCCCCCCCOc1ccnc(CCl)c1C
Yield: 187.7 %

Procedure:
11.8 g (0.047 mol, 1.0 eq.) of 4-octyloxy-2-hydroxymethyl-3-methylpyridine was dissolved in 600 mL of chloroform, and 28.6 g (0.240 mol, 5.1 eq.) of thionyl chloride was added dropwise at 19 to 27° C. Subsequently, the mixture was heated to reflux for one hour and then concentrated, to obtain 23.8 g of 4-octyloxy-2-chloromethyl-3-methylpyridine as a black oily matter.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.[CH2:17]([O:19][C:20](=[O:36])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:28]1[C:33]([Cl:34])=[CH:32][N:31]=[C:30](Cl)[N:29]=1)[CH3:18].C(O)C.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>>[CH2:17]([O:19][C:20](=[O:36])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:28]1[C:33]([Cl:34])=[CH:32][N:31]=[C:30]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)[N:29]=1)[CH3:18]
Reactant: CCOC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Product: CCOC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl
Yield: 59.6 %

Procedure:
3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (1.00 g, 4.54 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-benzoic acid ethyl ester (1.29 g, 4.13 mmol) were dissolved in ethanol (40.00 mL, 685 mmol) and 10-camphorsulfonic acid (1.15 g, 4.95 mmol) was added. The reaction was microwaved on 300 watts, 120° C. for 40 minutes and then concentrated under reduced pressure. The residue was taken up in DCM (100 mL) and washed with sat. NaHCO3 (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by amine capped silica gel chromatography using a gradient of 0-40% EtOAc/hex as the eluting solvent to obtain 2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-benzoic acid ethyl ester as a yellow solid (1.22 g, 60%). m.p.=78-80° C.; LCMS (m/e) 496 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 11.16 (s, 1H), 8.85 (d, 1H, J=8.5 Hz), 8.14 (s, 1H), 8.11 (d, 1H, J=8.0 Hz), 7.56-7.45 (m, 1H), 7.35 (s, 1H), 7.30-7.20 (m, 1H), 7.13-7.01 (m, 2H), 6.93 (s, 1H), 4.45 (q, 2H, J=7.1 Hz), 3.60-3.50 (m, 2H), 3.39 (s, 3H), 3.0-2.88 (m, 4H), 2.80-2.67 (m, 6H), 1.45 (t, 3H, J=7.1 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.ClCCl.[C:12]([NH:19][C:20](=[N:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])SC)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>C(N(CC)CC)C.[Hg](Cl)Cl>[C:27]([O:26][C:24](=[O:25])[NH:23]/[C:20](/[NH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1)=[N:19]\[C:12](=[O:13])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:30])([CH3:28])[CH3:29]
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: Nc1ccnc(Cl)c1
Agent: Cl[Hg]Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)/N=C(\NC(=O)OC(C)(C)C)Nc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 75 %

Procedure:
20.22 g (0.157 mol) of 4-amino-2-chloropyridine were diluted in triethylamine (67 ml) and dichloromethane (600 ml) at 0-5° C. 47 g of Mercury(II) chloride (0.173 mol) and 50.24 g (0.173 mol) of N,N′-bis(boc)-S-methyl-isothiourea were added to the reaction mixture, which was then stirred at room temperature for 4 days, filtered on a fritted funnel, concentrated in vacuo and chromatographed on silica (Heptane90/AcOEt10) to yield 43.67 g of di-tert-butyl{(Z)-[(2-chloropyridin-4-yl)amino]methylylidene}biscarbamate (yield=71%).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][CH2:10][CH2:11][Cl:12].[OH-].[Na+]>O>[Cl:12][CH2:11][CH2:10][CH2:9][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: ClCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: ClCCCSc1ccccc1
Temperature: 0 °C
Yield: 70.3 %

Procedure:
6.0 g of thiophenol and 7.8 g of 3-bromo-1-chloropropane were placed in 40 ml of water, and the resultant solution was subjected to reflux for 1 hour under heating. Then, 40 ml of an aqueous solution containing 2.4 g of sodium hydroxide were fed dropwise to the solution. The solution was then further subjected to reflux for another 2 hours under heating. The solution reacted was then poured into ice-water and extracted with ethyl acetate. The ethyl acetate layer resulted was then washed with dilute aqueous alkaline solution and saturated saline solution in series, and the organic layer resulted was dried with anhydrous magnesium sulfate. The solvent used was removed by distillation under reduced pressure, and the residue obtained was then purified by using silica gel column chromatography, for which hexane was used for the developer, thereby affording 6.5 g of 1-chloro-3-phenylthio propane.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:14]([CH2:24][O:25][Si:26]([C:39]([CH3:42])([CH3:41])[CH3:40])([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[C:43]([C:45]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[C:47]([O:53][CH3:54])[CH:46]=1)#[CH:44].C(N(CC)CC)C.C(OCC)(=O)C>C1COCC1.[Cu]I.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:14]([CH2:24][O:25][Si:26]([C:39]([CH3:42])([CH3:41])[CH3:40])([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:13]3)[N:9]=[C:10]([C:44]#[C:43][C:45]3[CH:46]=[C:47]([O:53][CH3:54])[CH:48]=[C:49]([O:51][CH3:52])[CH:50]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1C[C@@H](n2nc(I)c3c(N)ncnc32)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: C#Cc1cc(OC)cc(OC)c1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C#Cc2nn([C@H]3C[C@@H](CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)N(C(=O)OC(C)(C)C)C3)c3ncnc(N)c23)cc(OC)c1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
PdCl2(dppf)CH2Cl2 (13 mg) was added to a mixture of (2S,4S)-tert-butyl 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-((tert-butyldiphenylsilyloxy)methyl)pyrrolidine-1-carboxylate (113 mg) obtained in Step 3 above, 1-ethynyl-3,5-dimethoxybenzene (52 mg), copper (I) iodide (6 mg), and triethylamine (0.4 ml) in THF (4 ml). After nitrogen purging, the mixture was stirred at 85° C. for 3 hours. Ethyl acetate and water were added to the reaction mixture to separate the organic layer. After washing with a saturated sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a colorless, amorphous substance (100 mg). Physical properties: m/z [M+H]+ 733.3
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].O.[O:7]=[C:8]1[C:17](=[O:18])[NH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([S:19](Cl)(=[O:21])=[O:20])[CH:14]=2)[NH:9]1>>[CH2:1]([NH:5][S:19]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:7])[C:17](=[O:18])[NH:16]2)(=[O:20])=[O:21])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: O=c1[nH]c2ccc(S(=O)(=O)Cl)cc2[nH]c1=O
Solvent: O
Product: CCCCNS(=O)(=O)c1ccc2[nH]c(=O)c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
To a solution of 7.31 g (0.1 mole) of n-butylamine in 20 ml of water 5.21 g (0.02 mole) of 1,2,3,4-tetrahydro-2,3-dioxo-6-quinoxalinesulfonyl chloride are added, and the mixture is stirred at room temperature for 5 hours. Then it is allowed to stand for 16 hours, the separated crystals are filtered off, washed with water, dried and recrystallized from acetone. Thus 4.50 g (76%) of N-(n-butyl)-1,2,3,4-tetrahydro-2,3-dioxo-6-quinoxaline sulfonamide are obtained, m.p.: 257-262° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][CH2:7][C:6]=2[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26]Br)(=[O:21])[CH3:20]>CS(C)=O>[C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][CH2:7][C:6]=2[CH:12]=1)(=[O:21])[CH3:20]
Reactant: O=C1Nc2ccc(O)cc2CO1
Reactant: CC(=O)OCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)OCCCCOc1ccc2c(c1)COC(=O)N2
Temperature: 50 °C
Reaction time: 6 h

Procedure:
One hundred two grams (0.62 mol) of 6-hydroxy-4H-3,1-benzoxazin-2-one are dissolved in 1 liter of dimethylsulfoxide and mixed with 227 gm (1.64 mol) of potassium carbonate and 166 gm (0.73 mol) of 4-acetoxy-butylbromide. The reaction mixture is stirred for six hours at 50° C., and then ice water is added. The precipitate is subjected to suction filtration, washed with water, and dried.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([NH:9][CH2:10][CH2:11][N:12]2[C:17](=[O:18])[CH:16]=[CH:15][C:14]([C:19]([OH:21])=[O:20])=[CH:13]2)=[O:8])[CH:2]=1.S(Cl)(Cl)=O.N1C=CC=[CH:28][CH:27]=1>>[CH2:27]([O:20][C:19]([C:14]1[CH:15]=[CH:16][C:17](=[O:18])[N:12]([CH2:11][CH2:10][NH:9][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:8])[CH:13]=1)=[O:21])[CH3:28]
Reactant: c1ccncc1
Reactant: O=C(O)c1ccc(=O)n(CCNC(=O)c2cccnc2)c1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(=O)n(CCNC(=O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 10 ml round bottomed flask fitted with a magnetic stirrer bar, reflux condensor, and nitrogen inlet was added 1,6-dihydro-1-[2-(3-pyridinylcarbonylamino)ethyl]-6-oxo-3-pyridinecarboxylicacid (0.14 g, 0.49 mmol) and thionyl chloride (3.0 ml). The mixture was heated for 1 hour at reflux, cooled to room temperature, and concentrated. The residue was suspended in absolute ethanol (7.0 ml) and 4-dimethylaminopyridine (1 mg). Pyridine (0.12 ml, 1.47 mmol) was added with stirring at room temperature. After 16 hours, the mixture was concentrated. Purification via medium liquid chromotography (silica gel, 5-10% methanol/dichloromethane) gave the desired ester, MP: 240°-242° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][NH:27][CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:30][CH2:31][C:32](Cl)=[O:33]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][N:27]([C:32](=[O:33])[CH2:31][Cl:30])[CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CNCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CN(C(=O)CCl)CC2
Reaction time: 1 h
Yield: 100.1 %

Procedure:
4-(Benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (75 mg, 0.16 mmol) was dissolved in a mixture of CH2Cl2 (1 mL) and sat. NaHCO3 solution (1 mL) and chloroacetyl chloride (28 mg, 0.25 mmol) was added. The reaction mixture was vigorously stirred for 1 h then the phases were separated. The aqueous phase was extracted with CH2Cl2 and the combined organic extracts were dried over Na2SO4, filtered and concentrated to dryness providing the title compound (74 mg, 97%) as a beige solid which was a mixture of rotamers: ESI MS m/z 462 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>ClCCl>[Si:23]([O:13][C@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([C:14]([O:16][CH3:17])=[O:15])[CH2:10]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 102.7 %

Procedure:
To a solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-2-methoxycarbonylpyrrolidine (21.46 g) and imidazole (7.74 g) in dichloromethane (150 ml) was added dropwise a solution of tert-butyldimethylsilyl chloride (14.67 g) in dichloromethane (30 ml) at room temperature. After two hours, resultant precipitate was filtered off, and the filtrate was washed in turn with water and brine. Evaporation of the solvent gave an oil, which was chromatographed on silica gel (500 ml) eluting with a mixture of hexane and ethyl acetate (2:1, V/V) to give (2S,4R)-4-(tert-butyldimethylsilyloxy)-1-(tert-butoxycarbonyl)-2-methoxycarbonylpyrrolidine (32.3 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([O:9][CH2:10][CH3:11])[N:3]=1.C(N(CC)CC)C.[Cl:19][CH2:20][C:21](Cl)=[O:22]>CCOCC>[Cl:1][C:2]1[C:7]([NH:8][C:21](=[O:22])[CH2:20][Cl:19])=[CH:6][CH:5]=[C:4]([O:9][CH2:10][CH3:11])[N:3]=1
Reactant: CCOc1ccc(N)c(Cl)n1
Reactant: O=C(Cl)CCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOc1ccc(NC(=O)CCl)c(Cl)n1

Procedure:
A solution of 2-chloro-3-amino-6-ethoxypyridine (17 grams) in ether (200 ml), and triethylamine (10 grams) are placed in a glass reaction flask equipped with stirrer, thermometer and addition funnel. The mixture is cooled to about 0° to 10° C and a solution of chloroacetyl chloride (11.3 grams) in ether (40 ml) is slowly added thereto over a period of about 30 minutes resulting in the formation of a precipitate. The precipitate is recovered by filtration and is washed first with aqueous sodium bicarbonate and then with water. The washed product is then dried to yield the desired product N-(2-chloro-6-ethoxy-3-pyridyl)-α-chloroacetamide.
Reaction SMILES: Cl[CH:2]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[N:4]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([NH:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])=[O:32])=[CH:27][CH:26]=1>>[CH:18]1([CH:2]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([NH:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:32])=[CH:29][CH:30]=2)[C:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[N:4]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: ClC(c1nn(C2CCCCC2)c2ccccc12)C1CCCCC1
Product: O=C(O)CCNC(=O)c1ccc(NC(c2nn(C3CCCCC3)c3ccccc23)C2CCCCC2)cc1
Yield: 72.6 %

Procedure:
Using 3-[chloro(cyclohexyl)methyl]-1-cyclohexyl-1H-indazole (400 mg) synthesized in Example A18(4) and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (286 mg) synthesized in Example 1(2) and in the same manner as in Example A7(3), the title object compound (441 mg, 72%) was obtained as a white solid.
Reaction SMILES: [NH:1]1[CH:5]([C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])[CH2:4][CH2:3][C:2]1=[O:14].C(=O)([O-])[O-].[K+].[K+].[Cl:21][CH2:22][C:23](Cl)=[O:24]>C(Cl)Cl>[NH:1]1[CH:5]([C:6]([N:8]2[CH2:9][CH2:10][N:11]([C:23](=[O:24])[CH2:22][Cl:21])[CH2:12][CH2:13]2)=[O:7])[CH2:4][CH2:3][C:2]1=[O:14]
Reactant: O=C(Cl)CCl
Reactant: O=C1CCC(C(=O)N2CCNCC2)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C1CCC(C(=O)N2CCN(C(=O)CCl)CC2)N1
Temperature: 0 °C
Yield: 73 %

Procedure:
A mixed solution of 2.3 g of N-(2-pyrrolidone-5-carbonyl)piperazine, 50 ml of methylene chloride, and 2.8 g of anhydrous potassium carbonate was cooled with ice water and 1.3 g of chloro acetyl chloride was dropped therein with stirring. After the dropping, the mixture was stirred for another 1 hour at room temperature. The insoluble matter was removed by filtration and the solvent was evaporated in vacuo from the filtrate to give 2.3 g of oily N-(2-pyrrolidone-5-carbonyl)-N'-chloroacetylpiperazine. This was dissolved in 15 ml of N,N-dimethylformamide and 0.8 g of morpholine and 2.2 g of anhydrous potassium carbonate were added thereto, and the mixture was heated at 80° C. for 3 hours with stirring. The insoluble matter was filtered off therefrom and the solvent was evaporated in vacuo from the filtrate. The residue was purified by a silica gel column chromatography to give 2.5 g of the product. This was recrystallized from a mixture of methanol and ethyl ether to give 2.1 g of desired product, m.p. 204°-205° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12](OC)=[O:13])[C:5](=[CH:10][CH:11]=1)[C:6](OC)=[O:7].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][OH:7])=[C:4]([CH2:12][OH:13])[CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(Br)cc1CO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The compound of example 668 (2 g, 7.326 mmol) was taken in dry THF and was added to a slurry of LiAlH4 (1.67 g, 43.95 mmol) in THF cooled to 0° C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with aqueous NaOH solution followed by extraction with ethyl acetate. The solvent was removed by distillation to afford the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=2[CH:10]=[C:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])[CH2:4][CH2:3]1.[H][H]>[Pd].CO>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=2[CH2:10][CH:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: CN1CC=C(c2ccccc2C=C2CCNC2=O)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCC(c2ccccc2CC2CCNC2=O)CC1
Temperature: 50 °C
Yield: 99 %

Procedure:
A mixture of 3-[2-(1-Methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-benzylidene]-pyrrolidin-2-one (Example 78), 308 mg, 1.15 mmol) and 10% palladium on carbon (300 mg) in methanol (20 mL) was placed under 50 psi hydrogen and was heated at 50° C. for 8 hours. The mixture was cooled to room temperature, was filtered through Celite™, and the solvent was removed in vacuo to afford 310 mg (99% yield) of the title compound. 13C NMR (100 MHz, CDCl3) d 180.1, 144.5, 136.8, 129.9, 127.1, 126.6, 126.2, 56.7, 46.7, 42.7, 40.6, 37.2, 33.9, 33.6, 33.5, 27.7; MS (AP/Cl) 273.2 (M+H)+.