Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@H:4]([CH2:16][OH:17])[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].ClC(Cl)(Cl)C(=N)O[CH2:23][CH:24]=[CH2:25]>C(Cl)Cl.C1CCCCC1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:18])[C@H:4]([CH2:16][O:17][CH2:25][CH:24]=[CH2:23])[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: COC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Solvent: C1CCCCC1
Solvent: ClCCl
Product: C=CCOC[C@H](NC(=O)OCc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dissolve N-(benzyloxycarbonyl)-L-serine methyl ester (63 mmol) in methylene chloride/cyclohexane (1:1, 600 mL). Add allyl trichloroacetimidate (26 g, 128 mmol) and trifluroromethanesulfonic acid (5 mL, 56.6 mmol). Stir at room temperature under a nitrogen atmosphere for 5 hours and dilute with methylene chloride. Wash with saturated aqueous sodium hydrogen carbonate, water, dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography to give N-(benzyloxycarbonyl)-O-2-propenyl-L-serine methyl ester.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][C:6]2([CH3:15])[CH3:14])#[CH:2].I[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:14][C:6]1([CH3:15])[C:5]2[CH:4]=[C:3]([C:1]#[C:2][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=3)[CH:12]=[CH:11][C:10]=2[C:9](=[O:13])[CH2:8][CH2:7]1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 8.8 g (47.8 mmol) of 6-ethynyl-1,2,3,4-tetrahydro-4,4-dimethylnaphthalen-1-one (Compound K) flushed for 15 minutes with a stream of argon, and 13.2 g (47.8 mmol) of ethyl 4-iodobenzoate in 200 ml of triethylamine was added 1.1 g (1.6 mmol) of bis(triphenylphosphine)palladium(II) chloride and 0.30 g (1.6 mmol) of cuprous iodide. The solution mixture was flushed with argon for 5 minutes and then stirred at ambient temperature for 18 hours. The reaction mixture was filtered through celite and the filtrate concentrated in vacuo. Purification by flash chromatography (silica, 10% EtOAc-hexane) yielded the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[N:5][N:6]=1.C([O:17][CH:18]=[CH:19][C:20](OCC)=O)C>>[CH2:8]([S:7][C:4]1[S:3][C:2]2=[N:1][CH:20]=[CH:19][C:18](=[O:17])[N:6]2[N:5]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCOC=CC(=O)OCC
Reactant: CCCCCCCSc1nnc(N)s1
Product: CCCCCCCSc1nn2c(=O)ccnc2s1
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
A mixture of 20.1 g of 2-amino-5-heptylthio-1,3,4-thiadiazole, 20.0 g of ethyl 3-ethoxypropenoate and 23 g of polyphosphoric acid was heated to 130°~140° C. and stirred for 30 minutes. The residue obtained by the same procedure as in Preparation Example 13 was purified by silica gel column chromatography using an ethyl acetate/toluene mixture as an eluent. Thus 12.6 g of 2-heptylthio-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][NH:20][CH3:21])[C:12]3[CH:22]=[CH:23][CH:24]=[CH:25][C:11]=3[S:10]2)=[CH:5][CH:4]=1.C(Cl)Cl.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[CH2:34][CH2:35]Cl.[I-].[Na+]>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:21])[CH2:35][CH2:34][C:33]3[CH:37]=[CH:38][CH:39]=[C:31]([O:30][CH3:29])[CH:32]=3)[C:12]3[CH:22]=[CH:23][CH:24]=[CH:25][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1cccc(CCCl)c1
Reactant: CNCCN1C(=O)[C@H](O)[C@H](c2ccc(OC)cc2)Sc2ccccc21
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)CCc3cccc(OC)c3)C(=O)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 43.3 %

Procedure:
A mixture of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(methylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (1.07 g), methylene chloride (20 ml), 3-methoxyphenethyl chloride (500 mg), triethylamine (313 mg) and sodium iodide (30 mg) is stirred at room temperature for 48 hours. After the completion of the reaction, the solvent is distilled off, and the resulting residue is purified by silica gel column chromatography (eluent; chloroform: ethanol=15:1) to give (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-{2-[N-methyl-N-(3-methoxyphenethyl)amino]ethyl}-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (625 mg) as oily product.
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[CH2:24]([O:26][C:27]([CH2:29][CH2:30][NH:31][CH2:32][C:33]1[CH:34]=[C:35]([CH:37]=[CH:38][CH:39]=1)[NH2:36])=[O:28])[CH3:25]>CN(C=O)C>[CH2:24]([O:26][C:27]([CH2:29][CH2:30][NH:31][CH2:32][C:33]1[CH:34]=[C:35]([NH:36]/[C:4](=[C:11]2\[C:12](=[O:23])[NH:13][C:14]3[C:19]\2=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)/[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:37]=[CH:38][CH:39]=1)=[O:28])[CH3:25]
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CCOC(=O)CCNCc1cccc(N)c1
Solvent: CN(C)C=O
Product: CCOC(=O)CCNCc1cccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 89 from 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 3-(2-ethoxycarbonyl-ethylaminomethyl)-aniline in DMF.
Reaction SMILES: Br[C:2]1[C:3]([Cl:18])=[C:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[CH3:19][N:20]([CH3:24])[C:21](=[O:23])C>[Cu]I>[C:13]([O:12][C:11]([NH:10][C:4]1[C:3]([Cl:18])=[C:2]([CH:2]2[CH2:3][CH2:24][N:20]([C:21]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:23])[CH2:19][CH2:7]2)[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=1)=[O:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(Br)c1Cl
Reactant: CC(=O)N(C)C
Agent: [Cu]I
Product: CC(C)(C)OC(=O)Nc1cc(C#N)cc(C2CCN(C(=O)OC(C)(C)C)CC2)c1Cl
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of tert-butyl (3-bromo-2-chloro-5-cyanophenyl)carbamate (1.0 g, 3.02 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(I) (0.206 g, 0.302 mmol), and copper(I) iodide (0.115 g, 0.603 mmol) in a dry microwave vial was flushed with nitrogen. N,N-dimethylacetamide (3 mL) was added followed by (1-(tert-butoxycarbonyl)piperidin-4-yl)zinc(II) iodide (9.52 mL, 9.05 mmol, approximately 1 M solution in N,N-dimethylacetamide prepared as described in the Journal of Organic Chemistry, 2004, 69, 5120). The vial was sealed and heated at 80° C. overnight. After cooling to room temperature, the reaction was partitioned between EtOAc and sat. aq. NH4Cl solution. This was left stirring for 30 min. The aqueous phase was washed with EtOAc and the combined organic phases were washed with brine and dried with sodium sulfate. Removal of the solvents followed by radial silica gel chromatography eluting with hexane containing 5 to 30% EtOAc afforded tert-butyl 4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)piperidine-1-carboxylate (0.376 g) as a white solid.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH:19]=[CH2:20])=[C:6]([CH:21]([CH3:23])[CH3:22])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:7]([CH2:19][CH3:20])=[C:6]([CH:21]([CH3:22])[CH3:23])[N:5]=1)([CH3:3])[CH3:2]
Reactant: C=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 2,6dusopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5ethenylpyridine (Example 22) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCl3): δ7.15 (m, 4 H), 4.33 (d, J=3.6 Hz, 2 H), 3.41 (sept, J=6.6 Hz, 1 H), 3.26 (sept, J=6.6 Hz, 1 H), 2.34 (q, J=7.35 Hz, 2 H), 1.33 (d, J=6.6 Hz, 6 H), 1.31 (d, J=6.6 Hz, 6 H), 1.19 (m, 1 H), 0.93 (t, J=7.35 Hz, 3 H). FAB-MS: calculated for (C20H26FNO) 315, found 316 (M+H). Anal. Caled for C20H26FNO: C, 76.16; H, 8.31; N, 4.44. Found: C, 75.74; H, 8.50; N, 4.27. mp 126-129° C. Rf=0.4 (20% ethyl acetate/hexane).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][NH:20]CC3C=CC=CC=3)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[H][H]>C1COCC1.[OH-].[OH-].[Pd+2]>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][NH2:20])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1oc2cccc(OCCCNCc3ccccc3)c2c1C
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)c1oc2cccc(OCCCN)c2c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(3-benzylamino-propoxy)-3-methyl-benzofuran-2-carboxylic acid ethyl ester (the compound in Example 98: 180 mg) in THF (10 ml) was added 20% Pd(OH)2 on charcoal catalyst (40 mg) under N2. The nitrogen atmosphere was replaced by hydrogen (1 atom) and the resulting mixture was stirred overnight at room temperature. The reaction mixture was filtered through a pad of celite and the pad of celite was rinsed with methanol and dichloromethane. The filtrate combined was concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane-MeOH) to give 4-(3-amino-propoxy)-3-methyl-benzofuran-2-carboxylic acid ethyl ester (125 mg) as a colorless oil. FAB-MS: m/z 278 (MH+).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][N:4]=[C:5]([NH2:25])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][NH:16][C:17](=[N:20][S:21]([CH3:24])(=[O:23])=[O:22])SC)[N:11]=1.[CH3:28][NH2:29]>>[F:27][C:2]([F:1])([F:26])[CH2:3][N:4]=[C:5]([NH2:25])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][NH:16][C:17]([NH:29][CH3:28])=[N:20][S:21]([CH3:24])(=[O:22])=[O:23])[N:11]=1
Reactant: CSC(=NS(C)(=O)=O)NCCSCc1csc(NC(N)=NCC(F)(F)F)n1
Reactant: CN
Product: CNC(=NS(C)(=O)=O)NCCSCc1csc(NC(N)=NCC(F)(F)F)n1
Reaction time: 64 h

Procedure:
2-[2-(2,2,2-Trifluoroethyl)guanidino]-4-[2-(3-methylsulphonyl-2-methylisothioureido)ethylthiomethyl]thiazole (0.4 g.) was dissolved in ethanolic methylamine (33% w/v 15 ml.) and allowed to stand at room temperature for 64 hours. The solvent was evaporated and the residual gum was purified by preparative thin layer chromatography using chloroform/methanol/ammonia 8:2:0.2 v/v/v as developing solvent. The appropriate zone of the chromatogram was isolated and extracted with methanol/ammonia 10:1 v/v (50 ml.). The solvent was evaporated and the residual gum was dissolved in acetonitrile, filtered and the filtrate evaporated. The residual gum was dissolved in methanol and treated with a solution of excess fumaric acid in methanol. The solvent was evaporated and the residue triturated with acetonitrile to give 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[2-(2-methylsulphonyl-3-methylguanidino)ethylthiomethyl]thiazole as a cream solid (0.29 g.), m.p. 118°-123° (decomp.), containing 1.5 molar equivalents of fumaric acid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([CH:31]=[CH:32][CH:33]=1)[CH2:15][N:16]1[C:22](=[O:23])[C@H:21]2[CH2:24][CH2:25][CH2:26][C@H:20]2[NH:19][C:18]2[CH:27]=[CH:28][CH:29]=[CH:30][C:17]1=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]1(=[O:48])[N:38]([CH2:39][C:40](Cl)=[O:41])[C:37](=[O:43])[C:36]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:35]12.C([O-])(O)=O.[Na+]>ClCCCl.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([CH:31]=[CH:32][CH:33]=1)[CH2:15][N:16]1[C:22](=[O:23])[C@H:21]2[CH2:24][CH2:25][CH2:26][C@H:20]2[N:19]([C:40](=[O:41])[CH2:39][N:38]2[C:37](=[O:43])[C:36]3=[CH:44][CH:45]=[CH:46][CH:47]=[C:35]3[C:34]2=[O:48])[C:18]2[CH:27]=[CH:28][CH:29]=[CH:30][C:17]1=2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1cccc(CN2C(=O)[C@H]3CCC[C@H]3Nc3ccccc32)c1)OCc1ccccc1
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: O=C(Nc1cccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)c1)OCc1ccccc1
Yield: 55.5 %

Procedure:
To a solution of (3aR*,10aS*)-9-[3-(benzyloxycarbonylamino)benzyl]-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (1.9 g, 4.3 mmol) in 1,2-dichloroethane (50 mL) was added phthalimidoacetyl chloride (1.1 g, 4.7 mmol) at room temperature and the mixture was refluxed for 17 hours. After cooling, saturated aqueous NaHCO3 solution (30 mL) was added and the mixture was diluted with water and extracted with 2 portions of chloroform. The pooled organic layer was washed with saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was crystallized from diethyl ether to provide 1.5 g (yield 55%) of the title compound. m.p. 224°-225° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([N:22]=[C:23]=[O:24])(=[O:21])=[O:20]>C(Cl)Cl>[CH3:11][O:10][C:4]1[N:3]=[C:2]([NH:1][C:23]([NH:22][S:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[Cl:12])(=[O:20])=[O:21])=[O:24])[CH:7]=[C:6]([O:8][CH3:9])[N:5]=1
Reactant: COc1cc(N)nc(OC)n1
Reactant: O=C=NS(=O)(=O)c1ccccc1Cl
Solvent: ClCCl
Product: COc1cc(NC(=O)NS(=O)(=O)c2ccccc2Cl)nc(OC)n1
Reaction time: 0.5 h

Procedure:
To a mixture of 1.10 g of 4-amino-2,6-dimethoxypyrimidin in 40 ml methylene chloride at ambient temperature and pressure was added 1.60 g of 2-chlorobenzenesulfonylisocyanate. The reaction was stirred 30 minutes and then refluxed an additional 15 minutes. Volatiles were removed under reduced pressure and the solid thereby obtained was washed with a little diethyl ether; yield 2.30 g, m.p. 193°-196°.
Reaction SMILES: [C:1]([C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[N:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1([Mg]Br)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[Cl-].[NH4+]>C1COCC1>[C:2]1([C:1]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([OH:8])[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[C:16]3[N:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)=[CH:11][CH:10]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CN1CCN(c2cccc3ccc(C(=O)c4ccccc4)cc23)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1CCN(c2cccc3ccc(C(O)(c4ccccc4)c4ccccc4)cc23)CC1
Temperature: 0 °C
Yield: 92.1 %

Procedure:
The title product of example 43 (0.072 g, 0.218 mmol) was dissolved in dry THF (10 mL) and chilled to 0° C. Phenyl magnesium bromide (3 M in ether, 0.08 mL, 0.24 mmol) was added dropwise. The mixture turned greenish and then returned to a yellow color. The reaction was allowed to warm to room temperature for 30 minutes and then refluxed for 45 minutes. Additional phenyl magnesium bromide (0.1 mL, 0.26 mmol) was added and the mixture was refluxed 1 hour more. Saturated aqueous ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated to a light yellow oil. The product was purified by silica gel flash chromatography (1×6 inches). Elution with 50% ethyl acetate/hexane followed by ethyl acetate gave 0.082 g (92%) of the title product. A sample was recrystallized from chloroform/ether for analysis: mp 217.5°-218.5° C. Analysis calculated for C28H28N2O·0.5 H2P: C, 80.54; H, 7.00; N, 6.71. Found: C, 80.47; H, 6.63; N, 6.78.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.[CH:27]1[C:32]([OH:33])=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:34]>>[Cl:26][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:33][C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:34])[CH:27]=2)=[N:3][CH:4]=1
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: Cc1cccc(O)c1
Product: Cc1cccc(Oc2ncc(Cl)cc2C(=O)N[C@@H](C)c2ccc(C(=O)OC(C)(C)C)cc2)c1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from tert-butyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 45) and m-cresol: MS (ESI) m/z 467 (M+H)+, 465 (M−H)−.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:8]1[C:12]([CH:13]2[CH2:15][CH2:14]2)=[CH:11][N:10]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[CH:9]=1)(O)=[O:6]>C(Cl)(Cl)Cl>[Cl:3][C:5]([C:8]1[C:12]([CH:13]2[CH2:15][CH2:14]2)=[CH:11][N:10]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[CH:9]=1)=[O:6]
Reactant: O=C(O)c1cn(-c2ccnc3ccccc23)cc1C1CC1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1cn(-c2ccnc3ccccc23)cc1C1CC1
Reaction time: 1 h
Yield: 100 %

Procedure:
10 mL (137 mmol) of sulphinyl chloride are added to 1.05 g (3.78 mmol) of 3-carboxy-4-cyclopropyl-1-(quinolin-4-yl)-1H-pyrrole dissolved in 20 mL of chloroform at a temperature in the region of 20° C. under an argon atmosphere. After stirring for one hour at the reflux temperature of the solvent, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is dissolved in 20 mL of chloroform and then concentrated to dryness again, giving 1.12 g (3.78 mmol) of 3-chlorocarbonyl-4-cyclopropyl-1-(quinolin-4-yl)-1H-pyrrole in the form of a yellow solid, which is used directly in the following step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:22][CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Cl)(=[O:29])=[O:28]>C(N(C(C)C)C(C)C)C>[OH:22][CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:14][CH2:13]1)(=[O:29])=[O:28]
Reactant: O=S(=O)(CCCCCCCl)NCCCO
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCCN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)NCCCO
Yield: 95.8 %

Procedure:
1-[Bis(4-fluorophenyl)methyl]piperazine (576.7 mg, 2.00 mmol) and N-(3-hydroxypropyl)-6-chlorohexanesulfonamide (515.6 mg, 2.00 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was concentrated in vacuc, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-(3-hydroxypropyl)-6-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]hexanesulfonamide (976.6 mg) as a pale yellow oil (95.8%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH2:11]([O:18][CH2:19][C:20](Cl)=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C1COCC1>[CH2:11]([O:18][CH2:19][C:20]([NH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5])=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC(=O)c1cccnc1N
Reactant: O=C(Cl)COCc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1cccnc1NC(=O)COCc1ccccc1
Yield: 38.1 %

Procedure:
To a slurry of 2-amino-nicotinamide (100 mg, 0.7 mmol) in THF (5 ml) was added dropwise benzyloxyacetyl chloride [19810-31-2] (127 μL, 0.8 mmol) in THF (2 ml) at 5° C. The reaction mixture was heated to reflux for 2 hours. Water was added, the phases were separated and the inorganic layer was extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over Na2SO4, filtrated and concentrated in vacuo. Column chromatography on silica gel with CH2Cl2:MeOH 9:1 as eluent yielded 2-(2-benzyloxy-acetylamino)-nicotinamide (76 mg, 36%), MS(m/e): 286.1 [M+H+].
Reaction SMILES: C[N:2]([CH3:12])[CH:3]=[C:4]([N+:10]#[C-:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].N[CH:14]1[CH:21]2[CH2:22][CH:17]3C[CH:19]([CH2:23][CH:15]1[CH2:16]3)[CH2:20]2.C(O)CCC>O>[CH:19]12[CH2:23][CH:15]3[CH2:14][CH:21]([CH2:22][CH:17]([CH2:16]3)[CH:12]1[N:2]1[CH:3]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:10]=[CH:11]1)[CH2:20]2
Reactant: [C-]#[N+]C(=CN(C)C)C(=O)OCC
Reactant: NC1C2CC3CC(C2)CC1C3
Solvent: O
Solvent: CCCCO
Product: CCOC(=O)c1cn(C2C3CC4CC(C3)CC2C4)cn1
Temperature: 150 °C
Reaction time: 13 h
Yield: 29.4 %

Procedure:
Ethyl 3-(dimethylamino)-2-isocyanoacrylate (0.50 g), 2-aminoadamantane (0.54 g), and n-butanol (2.5 mL) were added and stirred at 150° C. for 13 hours. To the reaction solution, water was added, and organic matter was extracted with ethyl acetate. The organic layer was concentrated and then purified by silica gel column chromatography (eluting solvent: methylene chloride-methylene chloride/methanol=95/5 and ethyl acetate) to obtain the title compound (0.24 g).
Reaction SMILES: [CH3:1][Mg]I.[Cl:4][C:5]1[CH:16]=[C:15]([C:17]([C:19]2[N:20]=[CH:21][N:22]([C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:23]=2)=[O:18])[C:8]2[O:9][C:10]([CH3:14])([CH3:13])[O:11][CH2:12][C:7]=2[CH:6]=1>>[Cl:4][C:5]1[CH:16]=[C:15]([C:17]([CH3:1])([C:19]2[N:20]=[CH:21][N:22]([C:24]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:23]=2)[OH:18])[C:8]2[O:9][C:10]([CH3:13])([CH3:14])[O:11][CH2:12][C:7]=2[CH:6]=1
Reactant: C[Mg]I
Reactant: CC1(C)OCc2cc(Cl)cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)c2O1
Product: CC1(C)OCc2cc(Cl)cc(C(C)(O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)c2O1
Yield: 80 %

Procedure:
This compound is prepared like the preceding compound starting from methyl magnesium iodide and (6-chloro-2,2-dimethyl-4H-1,3-benzodioxin-8-yl)(1-triphenylmethyl-1H-imidazol-4-yl)ketone. The residue obtained after evaporation of the dichloromethane crystallizes when stirred in diethyl ether. Yield: 80% of theory; M.P.: 182°-184° C. (recrystallized from ethyl acetate).