Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH2:16][C:17]1[S:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[C:18]=1[S:26](Cl)(=[O:28])=[O:27]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:26]([C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:17]=1[CH2:16][C:15]1[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:13]([O:12][CH3:11])[CH:14]=1)(=[O:27])=[O:28]
Reactant: COc1ccc(Cc2sc3ccccc3c2S(=O)(=O)Cl)cc1OC
Reactant: Cc1noc(N)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(Cc2sc3ccccc3c2S(=O)(=O)Nc2onc(C)c2Br)cc1OC

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-(3,4-dimethoxy-benzyl)-benzo[b]thiophene-3-sulfonamide was prepared in the same manner as described in Example 41. Reaction of 4-bromo-3-methyl-5-aminoisoxazole (1.0 mmoles, 0.18 g), NaH (2.5 mmoles, 60 mg), and 2-(3,4-dimethoxybenzyl)benzo[b]thiophene-3-sulfonylchloride (1.2 mmoles, 0.44 g) in THF (6 ml), after recrystallization from chloroform and hexanes, yielded 0.42 g (80%) of a brown solid, m.p. 151-153° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:17][CH:18]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:22]2[CH2:23][CH2:24][N:19]([C:16]3[CH:15]=[CH:14][C:13]([CH3:12])=[CH:18][N:17]=3)[CH2:20][CH2:21]2)=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: Cc1ccc(N2CCNCC2)nc1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)nc1
Yield: 88.9 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 90 and using 4-bromo-2-fluorobenzoic acid (1.45 g) and 1-(5-methylpyridin-2-yl)piperazine (1.06 g) described in Preparation Example 183, the title compound (2.01 g) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH:9]=1)[CH3:2].[CH3:11][N:12]([CH3:15])[CH:13]=O>>[CH3:11][N:12]([CH:15]=[C:6]1[C:5](=[O:10])[C:4]([O:3][CH2:1][CH3:2])=[CH:9][CH2:8][CH2:7]1)[CH3:13]
Reactant: CCOC1=CCCCC1=O
Reactant: CN(C)C=O
Product: CCOC1=CCCC(=CN(C)C)C1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
3.4 g (0.02 mmol) of 2-ethoxycyclohex-2-en-1-one were dissolved in 30 mL of dry dimethylformamide and 30 mL (0.05 mmol) of dimethylformamide dimethyl acetale were added. The solution was stirred at 60° C. for 2 hours. The solvent was then evaporated under vacuum, the residue triturated with diethyl ether and collected by filtration to give 6.6 g of the title compound (80% yield).
Reaction SMILES: C([N:11]1[CH2:18][C:17]([OH:26])([CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])(OCC1C=CC=CC=1)=O.C(SC1(C(O)=O)C(C(=O)C)=CCN1CC1OC=CC=1)(=O)C>>[OH:26][C:17]1([CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:18][NH:11][C@H:12]([C:13]([OH:15])=[O:14])[CH2:16]1
Reactant: O=C(O)[C@@H]1CC(O)(Cc2ccncc2)CN1C(=O)OCc1ccccc1
Agent: CC(=O)SC1(C(=O)O)C(C(C)=O)=CCN1Cc1ccco1
Product: O=C(O)[C@@H]1CC(O)(Cc2ccncc2)CN1

Procedure:
The N-carbobenzyloxy-4-hydroxy-4-[(4-pyridyl)methyl]-L-proline from part (a) is hydrogenated according to the procedure of Example 1 (b) to yield 4-hydroxy-4-[(4-pyridyl)methyl]-L-proline. This amino acid is reacted with D-3-acetylthio-2-methylpropionyl chloride according to the procedure of Example 1 (c) to yield [1(S)]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-4-hydroxy-4-[(4-pyridyl)methyl]-L-proline.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].[S:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.C1([SiH3])C=CC=CC=1>C1COCC1.[Sn](CCCC)(CCCC)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH:10][CH:20]1[CH2:21][CH2:22][S:17][CH2:18][CH2:19]1)=[O:4]
Reactant: O=C1CCSCC1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1sc(-c2ccccc2)cc1NC1CCSCC1
Yield: 56.5 %

Procedure:
Reductive amination of 3-amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (0.933 g, 4.0 mmol) and tetrahydro-thiopyran-4-one (0.464 g, 4.0 mmol)in THF (1.0 mL) employing Bu2SnCl2 (60.5 mg, 0.2 mmol) and PhSiH3 (0.476 g, 0.542 mL) was carried out as described for example 13, step 1 gave 5-phenyl-3-(tetrahydro-thiopyran-4-ylamino)-thiophene-2-carboxylic acid methyl ester (0.753 g, 56.3%). NMR 1H (CDCl3, 400 MHz): 7.64-7.6 (m, 2H), 7.44-7.34 (m, 3H), 6.9 (brm, 1H), 6.81 (brs, 1H), 3.84 (s, 3H), 3.5-3.4 (m, 1H), 2.85-2.7 (m, 4H), 2.4-2.25 (m, 2H), 1.85-1.7 (m, 2H).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:20])[NH:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)=[N:9][N:10]=1)[CH2:3][CH3:4].[CH:21]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]1>>[N+:17]([C:13]1[CH:12]=[C:11]([C:8]2[NH:7][C:6](=[O:20])[C:5]([CH:2]([NH:1][C:26]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:27])[CH2:3][CH3:4])=[N:10][N:9]=2)[CH:16]=[CH:15][CH:14]=1)([O-:19])=[O:18]
Reactant: O=C(Cl)C1CCCC1
Reactant: CCC(N)c1nnc(-c2cccc([N+](=O)[O-])c2)[nH]c1=O
Product: CCC(NC(=O)C1CCCC1)c1nnc(-c2cccc([N+](=O)[O-])c2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 3.0 g (10.9 mmol) 6-(1-aminopropyl)-3-(3-nitrophenyl)-1,2,4-triazin-5(4H)-one, 2.2 g (16.3 mmol) cyclopentanecarbonyl chloride and proportionate amounts of the other reagents are used.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([Cl:23])=[CH:11][C:10]=1[C:24]1[C:28]([I:29])=[CH:27][NH:26][N:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:36][Si:37]([CH3:44])([CH3:43])[CH2:38][CH2:39][O:40][CH2:41]Cl>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([Cl:23])=[CH:11][C:10]=1[C:24]1[C:28]([I:29])=[CH:27][N:26]([CH2:41][O:40][CH2:39][CH2:38][Si:37]([CH3:44])([CH3:43])[CH3:36])[N:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1cc(-c2n[nH]cc2I)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(I)c(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
To a mixture of 3-(2,4-bis-benzyloxy-5-chloro-phenyl)-4-iodo-1H-pyrazole (4.46 g, 8.63 mmol) and caesium carbonate (8.43 g, 25.88 mmol) in DMF (50 ml) was added 2-(trimethylsilyl)ethoxymethyl chloride (2.29 ml, 12.94 mmol). The mixture was stirred at room temperature overnight before being partitioned between water and DCM. The organics were then washed with brine and water and concentrated in vacuo to give a yellow oil which was purified by column chromatography using hexanes and ethyl acetate as eluent, yielding 3-(2,4-bis-benzyloxy-5-chloro-phenyl)-4-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazole as a clear colourless oil (4.44 g, 80%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([CH:28]4[CH2:33][CH2:32][CH:31]([C:34](O)=[O:35])[CH2:30][CH2:29]4)=[O:27])[CH2:22][CH2:21]3)=[N:18][CH:19]=2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:37]([S:39]([NH2:42])(=[O:41])=[O:40])[CH3:38].IC1C=CC(NC(C2C=CC(N3CCC(C(NS(C(C)(C)C)(=O)=O)=O)CC3)=NC=2)=O)=CC=1C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:13])[C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([CH:28]4[CH2:33][CH2:32][CH:31]([C:34]([NH:42][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])=[O:35])[CH2:30][CH2:29]4)=[O:27])[CH2:22][CH2:21]3)=[N:18][CH:19]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(C(=O)C4CCC(C(=O)O)CC4)CC3)nc2)c1
Reactant: CCS(N)(=O)=O
Agent: Cc1cc(NC(=O)c2ccc(N3CCC(C(=O)NS(=O)(=O)C(C)(C)C)CC3)nc2)ccc1I
Product: CCS(=O)(=O)NC(=O)C1CCC(C(=O)N2CCN(c3ccc(C(=O)Nc4cccc(C(C)(C)C)c4)cn3)CC2)CC1

Procedure:
N-(3-tert-Butyl-phenyl)-6-[4-(4-ethanesulfonylaminocarbonyl-cyclohexanecarbonyl)-piperazin-1-yl]-nicotinamide was prepared from 4-{4-[5-(3-tert-butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carbonyl}-cyclohexanecarboxylic acid and ethyl sulfonamide in a manner similar to the one described in the synthesis of 4-(2-methyl-propane-2-sulfonylaminocarbonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (4-iodo-3-methyl-phenyl)-amide above. The product was isolated after silica gel purification with 0-3% MeOH in CH2Cl2 gradient. HRMS m/z calcd for C30H41N5O5S [M+H]+: 584.2901. Found: 584.2902.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].[C:15]([C:18](=[CH:24]N(C)C)[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=O)[CH3:16]>C(O)C>[CH2:22]([O:21][C:19]([C:18]1[CH:24]=[N:14][N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][C:4]=2[Cl:12])[C:15]=1[CH3:16])=[O:20])[CH3:23]
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CCOC(=O)C(=CN(C)C)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C
Yield: 91.8 %

Procedure:
By the method of Example 5, Step A, 101.3 g (0.4134 mole) of 2,6-dichloro-4-trifluoromethylphenylhydrazine and 76.8 g (0.415 mole) of ethyl 2-acetyl-3-dimethylaminoacrylate were reacted in 1944 mL of ethanol, yielding 139.4 g of 4-ethoxycarbonyl-5-methyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazole as a viscous oil. A 4 g sample of this oil was removed and allowed to crystallize. The nmr spectrum of this waxy solid was consistent with the proposed structure.
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=O)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].[CH3:34][N:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)N>>[CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[N:35]([CH3:34])[C:22]=3[C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CN(N)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc([N+](=O)[O-])cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc([N+](=O)[O-])cc4)n(C)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-(3-{1-[5-(4-nitrophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)propanamide and 1-methyl-1-phenylhydrazine: ESMS m/e: 539.6 (M+H)+.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1)[C:9]([OH:11])=[O:10].[C:18]1(C)C=CC=C[CH:19]=1>>[Br:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1)[C:9]([O:11][CH2:18][CH3:19])=[O:10]
Reactant: Cc1ccccc1
Reactant: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
Thionyl chloride (15.7 g, 120 mmol) was added to a solution of 3-bromo-5-nitrobenzoic acid in toluene (100 ml). The mixture was refluxed for 6 hours. The solvent was evaporated and the residue dissolved in dry tetrahydrofuran (50 ml), ethanol (10 ml) was added and the mixture stirred at room temperature for 30 mins. The solvent was evaporated and the residue chromatographed in dichloromethane to give the title compound as an off-white solid (13 g, 79%)
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]2[C:9]3[C:14]([NH:15][C:16]4[CH:25]=[CH:24][C:19]5[NH:20][C:21](=[O:23])[S:22][C:18]=5[CH:17]=4)=[N:13][CH:12]=[N:11][C:10]=3[S:26][C:5]=2[CH2:4]1.[N:27]([CH:30]([CH3:32])[CH3:31])=[C:28]=[O:29]>CN(C)C=O>[O:23]=[C:21]1[NH:20][C:19]2[CH:24]=[CH:25][C:16]([NH:15][C:14]3[C:9]4[C:6]5[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:28]([NH:27][CH:30]([CH3:32])[CH3:31])=[O:29])[CH2:4][C:5]=5[S:26][C:10]=4[N:11]=[CH:12][N:13]=3)=[CH:17][C:18]=2[S:22]1
Reactant: NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1
Reactant: CC(C)N=C=O
Solvent: CN(C)C=O
Product: CC(C)NC(=O)NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1
Yield: 56 %

Procedure:
A mixture comprising 75 mg (196 μmol) (RS)-6-{[7-(aminomethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-yl]amino}-1,3-benzothiazol-2(3H)-one (prepared according to example 20), 6 mL N,N-dimethylforamide and 19.2 μL 2-isocyanatopropane was stirred at 23° C. overnight. The solvent was removed and the residue purified by chromatography to give 54 mg (56%) of the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[O:12])[N:10]=2)[CH2:3]1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[CH3:20][S:21]([O:1][CH:2]1[CH2:3][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[O:12])[N:10]=2)[CH2:5]1)(=[O:23])=[O:22]
Reactant: CN1CCN(C(=O)c2csc(N3CC(O)C3)n2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)c2csc(N3CC(OS(C)(=O)=O)C3)n2)CC1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 3-hydroxy-1-[4-(4-methylpiperazine-1-carbonyl)-1,3-thiazol-2-yl]azetidine (422 mg, 1.49 mmol) (obtained as described in Reference Example 30(2)) in methylene chloride (21 ml) were added methanesulfonyl chloride (0.14 ml, 1.79 mmol) and triethylamine (0.25 ml, 1.79 mmol) in an ice bath, and then the mixture was stirred for 1 hour. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:methanol (3:1) as the eluant to afford 3-methanesulfonyloxy-1-[4-(4-methylpiperazine-1-carbonyl)-1,3-thiazol-2-yl]azetidine (537 mg, yield 100%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[S:12][CH3:13])[N:8]=[CH:7][NH:6][C:5]2=[O:14].Br[CH2:16][C:17](=[O:33])[CH2:18][C@H:19]1[C@H:24]([O:25][CH3:26])[CH2:23][CH2:22][CH2:21][N:20]1[C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[S:12][CH3:13])[N:8]=[CH:7][N:6]([CH2:16][C:17](=[O:33])[CH2:18][C@H:19]1[C@H:24]([O:25][CH3:26])[CH2:23][CH2:22][CH2:21][N:20]1[C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])[C:5]2=[O:14]
Reactant: CSc1cc2nc[nH]c(=O)c2cc1Cl
Reactant: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)CBr
Product: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)Cn1cnc2cc(SC)c(Cl)cc2c1=O

Procedure:
In the manner of Example 4, 0.679 g (0.003 mol) of 6-chloro-7-methylthioquinazolin-4(3H)-one and 1.0 g (0.003 mol) of allyl trans-2-(3-bromo-2-oxopropyl)-3-methoxy-1-piperidinecarboxylate were converted into the title compound: yield 0.56 g (39%). 1H-NMR(CDCl3) 1.4-2.2 ppm (multiplet, 4H, OCHCH2CH2CH2N), 2.6 (singlet, 3H, SCH3), 2.8-3.4 (multiplet, 4H, NCH2, COCH2CH), 3.4 (singlet, 3H, OCH3), 4.0 (broad singlet, 1H, CHNCO), 4.6 (doublet, 2H, CH2CH=CH2), 5.0 (singlet, 2H, NCH2CO), 5.0-5.5 (multiplet, 2H, CH=CH2), 5.6-6.1 (octet, 1H, CH2 =CH), 7.4 (singlet, 1H, aromatic H), 7.9 (singlet, 1H, N=CH-N), 8.2 (singlet, 1H, aromatic H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([CH:7]=[N:8]O)=[CH:5][CH:4]=1.Cl.[H][H].[OH-].[Na+]>CO.CCOCC>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:11]=[CH:10][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: ON=Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: NCc1ccc(C(F)(F)F)cc1
Yield: 93.6 %

Procedure:
The first and second steps of the process of the present invention were conducted as follows. At first, 8.79 g (50.5 mmol) of 4-trifluoromethylbenzaldehyde and 3.83 g (55.1 mmol) of hydroxylamine hydrochloride were dissolved in 12.5 ml of ethanol and 34 ml of water followed by the addition of 2,5 g of sodium hydroxide and stirring for 1 hour at room temperature. After adding ether and washing with dilute hydrochloric acid, the reaction liquid was further washed with saturated brine followed by drying with mirabilite and concentrating to obtain 9.25 g (48.2 mmol) of 4-trifluoromethylbenzylaldehyde oxime (yield: 95.5%). 5.00 g (26.4 mmol) of this 4-trifluoromethylbenzaldehyde oxime were dissolved in methanol followed by the addition of 4.0 g (109.7 mmol) of hydrogen chloride gas and 252 mg of the same catalyst as that of Example 1 and stirring for 3 hours in a hydrogen atmosphere at 10 atm and room temperature (approx. 250° C.). After removing the catalyst, ether was added to the reaction liquid, and the reaction liquid was neutralized with aqueous sodium hydroxide solution. As a result of analyzing the separated ether layer by gas chromatography, 4-trifluoromethylbenzylamine was formed at a yield of 93.6%.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3].[Cl:23]N1C(=O)CCC1=O.O>CN(C)C=O>[NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=[C:8]([Cl:23])[C:9]=1[C:10]([NH2:12])=[O:11])=[O:3]
Reactant: NC(=O)Nc1[nH]c(-c2ccc3ccccc3c2)cc1C(N)=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)Nc1[nH]c(-c2ccc3ccccc3c2)c(Cl)c1C(N)=O
Yield: 45 %

Procedure:
A solution of 2-aminocarbonylamino-5-(2-naphthyl)pyrrole-3-carboxamide (Compound No. 1-1, 92 mg, 0.31 mmol) and N-chlorosuccinimide (46 mg, 0.34 mmol) in anhydrous N,N-dimethylformamide (2 mL) was stirred at 60° C. for 2 hours. After cooling, water (10 mL) was added thereto, the precipitated solid was filtered off, and washed with water (10 mL) and acetone (10 mL). The obtained solid was dried at 50° C. under reduced pressure to give the target compound (46 mg) as a pale brown solid (Yield 45%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[N:4]([CH:9]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[Cl:18][C:19]1[CH:20]=[C:21]([O:28][CH3:29])[CH:22]=[C:23]2[C:27]=1[NH:26][CH2:25][CH2:24]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:26]2[C:27]3[C:23](=[CH:22][C:21]([O:28][CH3:29])=[CH:20][C:19]=3[Cl:18])[CH2:24][CH2:25]2)[C:3](=[O:16])[N:4]([CH:9]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=1
Reactant: CCC(C1CCC1)n1cc(Cl)nc(Cl)c1=O
Reactant: COc1cc(Cl)c2c(c1)CCN2
Agent: Cl
Product: CCC(C1CCC1)n1cc(Cl)nc(N2CCc3cc(OC)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-(1-cyclobutylpropyl)-2(1H)-pyrazinone and 7-chloro-5-methoxyindoline hydrochloride as the starting materials to give a yellow oil. 1H NMR (300 MHz, CDCl3): δ 6.74 (s, 2H), 6.67 (s, 1H), 4.90–4.80 (m, 1H), 4.34 (t, J=7.9 Hz, 2H), 3.78 (s, 3H), 3.10 (t, J=7.7 Hz, 2H), 2.60–2.50 (m, 1H), 2.18–2.12 (m, 1H), 1.90–1.70 (m, 6H), 1.55–1.43 (m, 1H), 0.84 (t, J=7.5 Hz, 3H); HRMS (ESI) m/z 408.1270 [(M+H)+, calcd for C20H24N3O2Cl2 408.1246].
Reaction SMILES: CS([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][N:6]=1)(=O)=O.[CH3:15][O-:16].[Na+].CO>CO>[CH3:15][O:16][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][N:6]=1
Reactant: CS(=O)(=O)c1ccc(S(C)(=O)=O)nc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(S(C)(=O)=O)cn1
Temperature: 50 °C

Procedure:
A suspension was prepared from 23.5 g of 2,5-bis(methylsulfonyl)pyridine and 200 ml of methanol and this was stirred rapidly under nitrogen while 24 ml of 25% sodium methoxide/methanol was added. This mixture was warmed to 50° C. for 20 minutes to give a homogeneous black solution. The solvent was removed by evaporation under reduced pressure and the resulting slurry was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with aqueous saturated sodium chloride solution and dried over magnesium sulfate. The mixture was treated with carbon and filtered through Celite to give a pale yellow filtrate. Concentration of the filtrate under reduced pressure gave a pale yellow oil which solidified on cooling. This was recrystallized from 2-propanol to give 2-methoxy-5-(methylsulfonyl)pyridine as colorless crystals melting at about 85°-86.5° C. Bromination of this compound according to the procedure described in Example 2 gave 3-bromo-2-methoxy-5-(methylsulfonyl)pyridine melting at about 148.5°-150.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:18]I.O>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:14][CH2:13][N:12]([CH3:18])[C:11]2=[O:15])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CI
Reactant: O=C1NCCN1c1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-(p-nitrophenyl)-2-imidazolidinone (25 g) in 450 ml of dimethylformamide is stirred under nitrogen and sodium hydride (50%, 6.4 g) added in small portions. The mixture is stirred at 50° for 11/2 hours, cooled to room temperature, and then methyl iodide (25 g) is added. After stirring 2 hours, the pH of the reaction mixture is 9. Another batch of methyl iodide (4 g) is added over 6 hours until the pH of the mixture is about 8. Water (150 ml) is added, the precipitated solid is filtered off, washed with dimethylformamide/water (1:1), then with water (2×150 ml). The solid is dried to give 1-(p-nitrophenyl)-3-methyl-2-imidazolidinone, m.p. 207°-208°.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH:6]1([N:9]2[C:17]3[C:12](=[C:13]([O:23][CH3:24])[CH:14]=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:16]=3)[CH:11]=[CH:10]2)[CH2:8][CH2:7]1.CN([CH:28]=[O:29])C>CCOC(C)=O.[OH-].[Na+]>[CH:6]1([N:9]2[C:17]3[C:12](=[C:13]([O:23][CH3:24])[CH:14]=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:16]=3)[C:11]([CH:28]=[O:29])=[CH:10]2)[CH2:7][CH2:8]1
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cc(OC)c2ccn(C3CC3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(OC)c2c(C=O)cn(C3CC3)c2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.28 ml of POCl3 was added dropwise to a solution of 3.24 g of ethyl 1-cyclopropyl-4-methoxy-1H-indole-6-carboxylate in 30 ml of DMF and the mixture was stirred at 0° C. for 2 hrs. The mixture was diluted with EtOAc and 25 ml of 1N NaOH was added. Then the mixture was made basic using saturated NaHCO3aq. The mixture was extracted with EtOAc and the extract was washed with water and saturated brine, dried over Na2SO4, then concentrated. The residue was purified on SiO2 column chromatography (EtOAc-n-Hexane system) to give 2.4 g of ethyl 1-cyclopropyl-3-formyl-4-methoxy-1H-indole-6-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[C:8]=2[Cl:15])[N:5]=[CH:4][C:3]=1[C:16]([OH:18])=O.S(Cl)([Cl:21])=O>>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[C:8]=2[Cl:15])[N:5]=[CH:4][C:3]=1[C:16]([Cl:21])=[O:18]
Reactant: Nc1c(C(=O)O)cnn1-c1ccc(Cl)c(Cl)c1Cl
Reactant: O=S(Cl)Cl
Product: Nc1c(C(=O)Cl)cnn1-c1ccc(Cl)c(Cl)c1Cl

Procedure:
5-Amino-1-(2,3,4-trichlorophenyl)pyrazol-4-yl carboxylic acid (54 g) and thionyl chloride (75 ml) were heated together under reflux for one hour. The reaction mixture was then evaporated to dryness and residual thionyl chloride was removed by evaporation in the presence of toluene (3×200 ml) to give 5-amino-1-(2,3,4-trichlorophenyl)pyrazol-4-yl carbonyl chloride, in the form of a dark coloured oil which was used in the preparation described in Example 11 without further purification.