Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:12]1(O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[O:11]([CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(OC2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 52.1 %

Procedure:
To a solution of 1,4-dioxa-spiro[4.5]decan-8-ol (1.85 mg, 11.70 mmol), phenol (1.0 g, 10.64 mmol), PPh3 (3.07 g, 11.70 mmol) in 15 mL of THF at 0° C. was added diisopropyl azodicarboxylate (6 mL, 11.70 mmol, 40% in toluene). The reaction mixture was stirred at room temperature for 48 h. Excess THF was removed in rotary evaporator and the residue was purified by silica gel column chromatography using ethyl acetate and hexane (1:19) to obtain 8-phenoxy-1,4-dioxa-spiro[4.5]decane (1.3 g, 52%) as a solid.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[C:15]([OH:17])=O>C1(C)C=CC=CC=1>[CH3:5][C:6]1[CH:14]=[CH:13][C:12]2=[N:11][N:10]3[C:9]([C:15](=[O:17])[N:10]4[N:11]=[C:12]5[C:8]([CH:7]=[C:6]([CH3:5])[CH:14]=[CH:13]5)=[C:9]4[C:15]3=[O:17])=[C:8]2[CH:7]=1
Reactant: Cc1ccc2[nH]nc(C(=O)O)c2c1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc2nn3c(=O)c4c5cc(C)ccc5nn4c(=O)c3c2c1
Yield: 135.5 %

Procedure:
Thionyl chloride (11 ml; 0.151 mol) was added to a suspension of 5-methyl-1H-indazole-3-carboxylic acid (12.2 g; 0.056 mol), prepared as described in J. Heterocyclic Chem. 1964, Vol. 1 (5) 239-241, in toluene (130 ml), and the reaction mixture was refluxed for 4 hours. The solvent was removed by evaporation under reduced pressure and the residue was taken up twice in toluene to give 12 g of the desired product.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:8]([Cl:9])=[C:7]([C:10](Cl)=[O:11])[S:6][N:5]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C1COCC1>[Cl:3][C:4]1[C:8]([Cl:9])=[C:7]([CH2:10][OH:11])[S:6][N:5]=1
Reactant: O=C(Cl)c1snc(Cl)c1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1snc(Cl)c1Cl
Reaction time: 0.5 h
Yield: 81 %

Procedure:
1.9 g (50.5 mmol) of sodium borohydride was suspended in 40 ml of water. To the resulting suspension was dropwise added, at 10 to 15° C., a solution of the 3,4-dichloroisothiazole-5-carbonyl chloride dissolved in THF (4 ml). Stirring was conducted at 15° C. for 30 minutes. Then, an aqueous citric acid solution was added to make the mixture weakly acidic and extraction with ethyl acetate was conducted. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The resulting crystals were washed with hexane to obtain 3.0 g (yield: 81%) of (3,4-dichloroisothiazol-5-yl)methanol as colorless crystals (melting point: 94 to 95° C.).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[Cl:22])[C:4]([C:7]2[CH:8]=[C:9]([C:12](O)=[O:13])[NH:10][CH:11]=2)=[N:5][N:6]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:35]1[CH2:39][CH:38]=[CH:37][CH2:36]1>CC(N(C)C)=O>[NH2:1][C:2]1[N:3]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[Cl:22])[C:4]([C:7]2[CH:8]=[C:9]([C:12]([N:35]3[CH2:39][CH:38]=[CH:37][CH2:36]3)=[O:13])[NH:10][CH:11]=2)=[N:5][N:6]=1
Reactant: Nc1nnc(-c2c[nH]c(C(=O)O)c2)n1-c1cccc(Cl)c1Cl
Reactant: C1=CCNC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)N(C)C
Product: Nc1nnc(-c2c[nH]c(C(=O)N3CC=CC3)c2)n1-c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
To a solution of 4-[5-amino-4-(2,3-dichloro-phenyl)-4H-[1,2,4]triazol-3-yl]-1H-pyrrole-2-carboxylic acid (10 mg, 0.03 mmol) in DMA (1 mL) was added CDI (6 mg, 0.04 mmol). The solution was stirred at RT for 30 min before the addition of 2,5-dihydro-1H-pyrrole (6 mg, 0.09 mmol). The reaction mixture was stirred at RT for another 60 min and purified by Gilson HPLC directly to afford a white solid (7.5 mg, 64%). MS (ES+): m/e=389.2 (M+H); LC: 2.65 min.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]2[NH:20][CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:23]=2)=[CH:13][CH:12]=1>CC#N>[Br:1][C:21]1[N:20]=[C:19]([CH2:18][CH2:17][C:14]2[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[NH:23][C:22]=1[C:24]([F:25])([F:26])[F:27]
Reactant: COc1ccc(CCc2nc(C(F)(F)F)c[nH]2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COc1ccc(CCc2nc(Br)c(C(F)(F)F)[nH]2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-Bromosuccinimide (5.4 g, 0.03 mole) was added to a solution of VI (8.1 g, 0.03 mole) in CH3CN (150 mL) and the mixture stirred at room temperature. After 18 hours, the solution was evaporated to dryness in vacuo. The residue was partitioned between CHCl3 and H2O. Evaporation of the washed and dried CHCl3 extract under reduced pressure left 10.5 g (quant.) of VII; m.p. 104°-106° C. (CHCl3 --C6H14).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:10]=[C:11]([C:27]#[N:28])[N:12]3[C:17]([NH:18][CH:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])=[CH:16][C:15]([CH3:26])=[N:14][C:13]=23)=[C:4]([CH3:29])[CH:3]=1.C(=O)([O-])[OH:31].[Na+]>OS(O)(=O)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:29])[C:5]([C:9]2[CH:10]=[C:11]([C:27]([NH2:28])=[O:31])[N:12]3[C:17]([NH:18][CH:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])=[CH:16][C:15]([CH3:26])=[N:14][C:13]=23)=[C:6]([CH3:8])[CH:7]=1
Reactant: CCCC(CCC)Nc1cc(C)nc2c(-c3c(C)cc(Br)cc3C)cc(C#N)n12
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCCC(CCC)Nc1cc(C)nc2c(-c3c(C)cc(Br)cc3C)cc(C(N)=O)n12
Temperature: 55 °C

Procedure:
8-(4-Bromo-2,6-dimethyl-phenyl)-2-methyl-4-(1-propyl-butylamino)-pyrrolo[1,2-a]pyrimidine-6-carbonitrile (10.0 g) was added into conc. H2SO4 (50 mL) and heated for 55° C. for 5 hours. The reaction mixture was cooled to room temperature, poured into ice-water and then a saturated aqueous sodium hydrogencarbonate was added to make the aqueous mixture alkaline (pH=8) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: hexane/ethyl acetate/chloroform=10:3:1) to give a solid. The solid was recrystallized from ethyl acetate to provide 8-(4-bromo-2,6-dimethyl-phenyl)-2-methyl-4-(1-propyl-butylamino)-pyrrolo[1,2-a]pyrimidine-6-carboxylic acid amide (5.8 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:43])[N:14]([CH2:29][C:30]([NH:32][CH:33]([CH:40]([CH3:42])[CH3:41])[C:34](=[O:39])[C:35]([F:38])([F:37])[F:36])=[O:31])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24]C(C)(C)C)[CH:19]=2)=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:43])[N:14]([CH2:29][C:30]([NH:32][CH:33]([CH:40]([CH3:41])[CH3:42])[C:34](=[O:39])[C:35]([F:38])([F:36])[F:37])=[O:31])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=2)=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2cccc(OC(C)(C)C)c2)ccc(NC(=O)OCc2ccccc2)c1=O)C(=O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(NC(=O)Cn1c(-c2cccc(O)c2)ccc(NC(=O)OCc2ccccc2)c1=O)C(=O)C(F)(F)F
Reaction time: 5 h
Yield: 84.8 %

Procedure:
To a solution of 2-[3-benzyloxycarbonylamino-6-(3-tert-butoxyphenyl)-2-oxo-1,2-dihydro-1-pyridyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (78 mg) in dry dichloromethane (3 mL) was added trifluoroacetic acid (57 mg). After 5 h the reaction was incomplete, and additional trifluoroacetic acid (57 mg) was added. After 18 h the reaction mixture was diluted with dichloromethane (50 mL), washed with water and brine, dried, and evaporated to a crude oil which was purified by chromatography, eluting with ethanol:ethyl acetate:dichloromethane (0.5:5:94.5), to give the title compound as a white solid (60 mg); TLC: Rf =0.15, ethanol:ethyl acetate:dichloromethane (0.5:5:94.5); HPLC: tR =6.04, FR=2.0, column A, water:acetonitrile (55:45); MS: m/z=546(M+1).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[CH:22][S:23][C:16]=34)[CH:11]=[CH:10][C:5]=2[C:6]=1[C:7]([OH:9])=O.[C:24]1([C:30]2[S:34][C:33]([NH2:35])=[N:32][N:31]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([C:30]2[S:34][C:33]([NH:35][C:7]([C:6]3[C:5]4[CH:10]=[CH:11][C:12]([O:14][C:15]5[CH:20]=[CH:19][N:18]=[C:17]6[CH:21]=[CH:22][S:23][C:16]=56)=[CH:13][C:4]=4[O:3][C:2]=3[CH3:1])=[O:9])=[N:32][N:31]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1nnc(-c2ccccc2)s1
Reactant: Cc1oc2cc(Oc3ccnc4ccsc34)ccc2c1C(=O)O
Product: Cc1oc2cc(Oc3ccnc4ccsc34)ccc2c1C(=O)Nc1nnc(-c2ccccc2)s1

Procedure:
This material was prepared from 2-methyl-6-[thieno[3,2-b]pyridin-7-yloxy]benzofuran-3-carboxylic acid 100 and 5-phenyl-[1,3,4]thiadiazol-2-ylamine in a similar manner as that described for example 102. 1H NMR (CD3CN/CD3OD) δ 8.45 (1H, d, J=5.6 Hz), 8.00–7.95 (4H, m), 7.52–7.50 (4H, m), 7.48 (1H, d, J=2.3 Hz), 7.25 (1H, dd, J=8.6, 2.3 Hz), 6.66 (1H, d, J=5.3 Hz), 2.76 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O1CCCC1>CO.[C].[Pd]>[NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cccc(C(=O)O)c1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 107 %

Procedure:
10% Palladium carbon (water content 51.7%, 250 mg) was added to a solution of methyl ester of 2-amino-3-nitrobenzoic acid (980 mg, 5.00 mmol) in methanol (20 ml)-tetrahydrofuran (10 ml) and the mixture was stirred under hydrogen atmosphere at room temperature for 3 hrs. The catalyst was removed by filtration and washed with tetrahydrofuran. The filtrate and washings were combined and the solvent was distilled off under reduced pressure to give methyl ester of 2,3-diaminobenzoic acid (814 mg, 98%) as a yellowish green solid.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:18]=[C:19]([CH:39]=[CH:40][CH:41]=1)[CH2:20][O:21]/[N:22]=[C:23](/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)\[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30]CC)=[O:29].CO.Cl>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:18]=[C:19]([CH:39]=[CH:40][CH:41]=1)[CH2:20][O:21]/[N:22]=[C:23](/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)\[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29]
Reactant: CCOC(=O)CCCC/C(=N\OCc1cccc(OCc2nc(-c3ccccc3)oc2C)c1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(CO/N=C(\CCCCC(=O)O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added to a solution of ethyl E-6-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanoate (520 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at room temperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-6-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanoic acid (432 mg, yield 88%) as colorless crystals. m.p. 114-115° C.
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][CH3:3].[H-].[Na+].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[C:22]1[CH:23]=[N:24][C:25](Cl)=[N:26][CH:27]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C=O)C>[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[C:22]1[CH:27]=[N:26][C:25]([S:4][CH2:1][CH2:2][CH3:3])=[N:24][CH:23]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Clc1ccc(OCc2ccccc2)c(-c2cnc(Cl)nc2)c1
Reactant: CCCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCSc1ncc(-c2cc(Cl)ccc2OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Propanethiol (3.1 ml) was added to a stirred suspension of sodium hydride (1.4 g, 60% in oil) in DMF (30 ml). After 1 hour a solution of the product from step (i) (2.4 g) in DMF (10 ml) was added. The reaction mixture was stirred at RT for 1 hour then partitioned between EtOAc and water. The organics were washed with water, brine, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 5% EtOAc/isohexane. Yield 1.87 g
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[CH:12]=2)[CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][OH:23].C([BH3-])#N.[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(O)(=O)C.CO>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:19][CH2:20][CH2:21][CH2:22][OH:23])[CH:12]=2)[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1
Reactant: NCCCO
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: N#Cc1ccc(Cl)cc1Oc1cccc(CNCCCO)c1
Yield: 100.4 %

Procedure:
4-Chloro-2-(3-formylphenoxy)benzonitrile (0.21 g, 0.81 mmol), 3-aminopropan-1-ol (65 μL, 64 mg, 0.85 mmol) and sodium cyanoborohydride (60 mg, 0.96 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (20 mL) for 5 days. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.10 g, 0.86 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-chloro-2-{3-[(3-hydroxypropylamino)methyl]phenoxy}benzonitrile fumarate (352 mg, 99%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:11][C:10]([C:20]([F:23])([F:22])[F:21])=[N:9]1.[CH3:24][S:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)(=[O:27])=[O:26].CCN(CC)CC>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]([O:19][C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH:33]=3)=[CH:17][CH:18]=2)=[CH:11][C:10]([C:20]([F:23])([F:21])[F:22])=[N:9]1
Reactant: Oc1ccc(-c2cc(C(F)(F)F)nn2-c2ccccc2Cl)cc1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1cccc(Oc2ccc(-c3cc(C(F)(F)F)nn3-c3ccccc3Cl)cc2)c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 35.7 %

Procedure:
A mixture of 4-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenol (169 mg, 0.5 mmol), 3-methylsulfonylphenylboronic acid (200 mg, 1 mmol), Cu(OAc)2 (181 mg, 1 mmol), and NEt3 (35 μL, 2.5 mmol) and molecule sieves (4A) in DCM was shaken overnight at 20° C. Solid was removed by filtration and filtrate was evaporated to give a crude, which was purified by column chromatography on silica gel eluting with EtOAc-hexane (1:4 to 1:2) to afford 1-(2-chlorophenyl)-5-(4-{[3-(methylsulfonyl)phenyl]oxy}phenyl)-3-(trifluoromethyl)-1H-pyrazole (88 mg). 1H-NMR: CDCl3: 7.68 (m, 1H), 7.55 (m, 2H), 7.48 (m, 1H), 7.62-7.40 (m, 2H), 7.27 (m, 2H), 7.21 (m, 1H), 6.93 (m, 1H), 6.80 (s, 1H), 3.04 (s, 3H), MS(ES): 493 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([C@H:15]2[C@H:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=3[F:27])[C@:18]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[F:37])([C:28]#[N:29])[C@H:17]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[NH:16]2)=[O:14])=[CH:7][N:6]=1)=[O:4].O.[OH-].[Li+]>C1COCC1.O>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([C@@:18]2([C:28]#[N:29])[C@H:17]([CH2:38][C:39]([CH3:41])([CH3:40])[CH3:42])[NH:16][C@@H:15]([C:13]([NH:12][CH2:11][C:8]3[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=3)=[O:14])[C@@H:19]2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=2[F:27])=[C:31]([F:37])[CH:32]=1
Reactant: COC(=O)c1ccc(CNC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NCc2ccc(C(=O)O)nc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C

Procedure:
In a manner similar to the method described in Example 380, chiral 5-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-pyridine-2-carboxylic acid methyl ester (24.9 mg, 0.0405 mmol) in THF (3 ml) was treated with lithium hydroxide hydrate (12.0 mg, 0.286 mmol) in water (1.5 mL). It was stirred at room temperature to give chiral 5-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-pyridine-2-carboxylic acid as a white lyophilized solid (25.4 mg, 100). RMS (ES+) m/z Calcd C30H28Cl2F2N4O3+H [(M+H):601.1580. Found: 601.1579.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:10]([O:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)[CH2:28][CH2:27]1)[C:9]2=[O:43])=[O:5])C.C(=O)([O-])O.[Na+].C(O)(=O)C>C(O)C>[C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[C:10]([O:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:27][CH2:28][N:29]([CH2:32][C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)[CH2:30][CH2:31]1)[C:9]2=[O:43])([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc2oc(-c3ccccc3)c(OCCCN3CCN(Cc4ccc5ccccc5n4)CC3)c(=O)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)c1ccc2oc(-c3ccccc3)c(OCCCN3CCN(Cc4ccc5ccccc5n4)CC3)c(=O)c2c1
Yield: 74 %

Procedure:
6-Ethoxycarbonyl-3-[3-{4-(2-quinolinylmethyl)piperazin-1-yl}propoxy]flavone (0.8 mmol) was dissolved in 20 ml of ethanol, followed by the addition of 2 ml of a saturated aqueous solution of sodium hydrogencarbonate. The reaction mixture was refluxed for 2 hours and was then allowed to cool down. The solvent was driven off under reduced pressure. Acetic acid was added to the residue to neutralize the same, followed by extraction with chloroform. After the organic layer was concentrated under reduced pressure, the residue was recrystallized from EtOH-ether, whereby the title compound represented by the following formula was obtained (yield: 74%). ##STR67##
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[C:4]([CH3:10])[N:3]=1.[OH-].[K+].[Cl:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[C:18](Cl)[C:17]([N+:24]([O-:26])=[O:25])=[CH:16][C:15]=1[C:27]([F:30])([F:29])[F:28].Cl>O.CN(C)C=O>[Cl:8][C:7]1[C:2]([NH:1][C:18]2[C:17]([N+:24]([O-:26])=[O:25])=[CH:16][C:15]([C:27]([F:28])([F:29])[F:30])=[C:14]([Cl:13])[C:19]=2[N+:20]([O-:22])=[O:21])=[N:3][C:4]([CH3:10])=[C:5]([Cl:9])[CH:6]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Reactant: Cc1nc(N)c(Cl)cc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(Nc2c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c2[N+](=O)[O-])c(Cl)cc1Cl
Reaction time: 3 h

Procedure:
In 30 ml. of dimethylformamide, 1.8 g. of 2-amino-3,5-dichloro-6-methylpyridine was dissolved in 0.67 g. of powdery potassium hydroxide was gradually added with stirring. After the addition, a solution of 3.07 g. of 2,4-dichloro-3,5-dinitrobenzotrifluoride in 10 ml. of dimethylformamide was added dropwise at room temperature and the reaction was continued for about 3 hours. The reaction mixture was acidified with conc. HCl and was poured into water. The precipitate was filtered and recrystallized from methanol to obtain 2.96 g. of the object compound having a melting point of 128° to 130° C.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([CH:15]3[CH2:20][NH:19][CH2:18][CH2:17][N:16]3[CH3:21])[O:12][N:11]=2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1.[OH-].[Na+]>ClCCl>[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([N:19]2[CH2:18][CH2:17][N:16]([CH3:21])[CH:15]([C:13]3[O:12][N:11]=[C:10]([C:7]4[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=4)[N:14]=3)[CH2:20]2)=[O:35])=[CH:32][CH:31]=1
Reactant: CN1CCNCC1c1nc(-c2ccc(F)cc2)no1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)c2ccc(F)cc2)CC1c1nc(-c2ccc(F)cc2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.3 %

Procedure:
To a suspension of 2-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-methyl-piperazine dihydrochloride (0.285 g, 0.86 mmol) in anhydrous dichloromethane (6 mL), under nitrogen atmosphere, triethylamine (374 mL, 2.7 mmol) and 4-fluorobenzoyl chloride (102 mL, 0.86 mmol) were subsequently added at 0° C. The reaction mixture was allowed to warm at room temperature and stirred for 2 h. NaOH 1N (6 mL) was added and the phases were separated. The organic layer was washed sequentially with NaOH 1N (6 mL) and with water, then was dried over sodium sulphate and evaporated under reduced pressure. Purification of the crude by flash chromatography (silica gel, eluent: DCM/MeOH/NH4OH 99/1/0.1) afforded (4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-methyl-piperazin-1-yl}-methanone (0.12 g).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:9]([C:11]1[CH:33]=[CH:32][C:14]2[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][C:21]=3[O:29][CH3:30])=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:42]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:43]>ClCCl.C(O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:9]([C:11]1[CH:33]=[CH:32][C:14]2[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:42]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:43])=[CH:22][C:21]=3[O:29][CH3:30])=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCCCCCCOC(=O)Cl
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1OC)n2C)c1ccccn1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)c(OC)c1
Yield: 55 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-heptyl chloroformate. Yield: 55% of theory, C36H45N7O6 (671.8) Rf value: 0.54 (silica gel; dichloromethane/ethanol=9:1) ##EQU144##
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[CH3:11][S-:12].[Na+].C(OCC)(=O)C>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:12][CH3:11])[CH:5]=[O:6]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CSc1ccc(C=O)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.1 %

Procedure:
The 3,4-diflourobenzaldehyde (52.1 g, 0.36 mol) was dissolved in acetonitrile (500 mL). Sodium thiomethoxide (25.6 g, 0.36 mol) was added in four equal portions at 15 minute intervals. The slightly exothermic reaction was stirred at room temperature for 4 hours. The reaction mixture was poured into ethyl acetate (500 mL) and extracted with saturated sodium bicarbonate (2×200 mL) followed by saturated ammounium chloride (2×100 mL). The solution was dried over sodium sulfate and solvent removed at reduced pressure. The 3-flouro-4-(methylthio)-benzaldehyde (38.5 g, 0.22 mol) was isolated by vacuum distillation (135-145° C. at 25 mm Hg) as clear liquid. (61% yield) ESHRMS m/z 171.0302 (calcd for M+H, 171.0280).