Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[O:19][CH3:20].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[Cl:18][C:17]1[C:12]([Cl:11])=[C:13]([O:19][CH3:20])[CH:14]=[CH:15][C:16]=1[C:6]([C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=1)=[O:7]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1cccc(Cl)c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(C(=O)c2ccc(F)cc2)c(Cl)c1Cl

Procedure:
The Friedel-Crafts procedure of Example 24a is repeated with 31.55 g of p-fluorobenzoyl chloride, 32 g of 2,3-dichloroanisole and 35.22 g of AlCl3 combined in 1,2-dichloroethane and reacted. The resultant crude product is triturated with warm hexane, cooled and filtered to yield 2,3-dichloro-4-methoxy-4'-fluorobenzophenone.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](Cl)=[O:5].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([NH2:18])[CH3:17])=[CH:12][CH:11]=1.C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([NH:18][CH:16]([C:13]1[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=1)[CH3:17])=[O:5]
Reactant: CC(C)(CCl)C(=O)Cl
Reactant: CC(N)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(NC(=O)C(C)(C)CCl)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-chloro-2,2-dimethylpropionyl chloride (7.0 g) in dichloromethane (50 ml) was added dropwise to a stirred solution of 1-(4-chlorophenyl)ethylamine (7.0 g) and triethylamine (6.3 ml) in dichloromethane (100 ml) at 0°-5° C. under nitrogen. After the addition, the mixture was stirred at 0° C. for 0.5 hours and then stirred at ambient temperature for 2 hours. The mixture was washed with 5M hydrochloric acid and then with water. The mixture was dried and evaporated. The residue was recrystallised from petroleum ether (b.p. 60°-80° C.) to give 3-chloro-N-[1-(4-chlorophenyl)ethyl]-2,2-dimethylpropionamide, m.p. 95°-96° C.
Reaction SMILES: C(O[C:4](=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([O:14]CC)=O)C.[NH2:18][CH2:19][CH2:20][OH:21]>>[OH:21][CH2:20][CH2:19][N:18]1[C:4](=[O:17])[C:5]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:11][C:12]1=[O:14]
Reactant: CCOC(=O)Nc1ccccc1C(=O)OCC
Reactant: NCCO
Product: O=c1[nH]c2ccccc2c(=O)n1CCO
Temperature: 25 °C
Yield: 71.3 %

Procedure:
A mixture of 2-[(ethoxycarbonyl)amino]benzoic acid ethyl ester (65.75 g, 0.277 mol) and 2-aminoethanol (16.9 g, 0.277 mol) was refluxed for 2.5 days in 350 mL of xylenes. The reaction was cooled to room temperature and xylene was removed. Chloroform was added to the residue and a brown solid crystallized. The brown solid was filtered from the solution. The chloroform layer was extracted with water, dried (Na2SO4), filtered and the solvent was removed. The residue was placed in the freezer in isopropyl alcohol. The brown solid was triturated with isopropyl alcohol. Both produced a crystalline white solid which was dried in vacuo overnight at 80° C. This gave a total of 40.70 g (71.3% yield) of white crystalline solid, mp 250°-252° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-])=O.[CH2:15]([O:17][C:18](/[CH:20]=[CH:21]/[C:22]1[NH:26][C:25]([C:27](OCC)=[O:28])=[CH:24][CH:23]=1)=[O:19])[CH3:16].C(=O)([O-])[O-].[K+].[K+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(O)(=O)C.O.C(OCC)C.CS(C)=O>[O:28]=[C:27]1[NH:12][C:3]2[C:2](=[CH:7][CH:6]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:4]=2)[N:26]2[C:22](/[CH:21]=[CH:20]/[C:18]([O:17][CH2:15][CH3:16])=[O:19])=[CH:23][CH:24]=[C:25]12
Reactant: CCOC(=O)/C=C/c1ccc(C(=O)OCC)[nH]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)/C=C/c1ccc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n12
Temperature: 100 °C
Yield: 68.5 %

Procedure:
A mixture of 1-fluoro-2-nitro-4-trifluoromethylbenzene 523 mg, ethyl 5-[(E)-2-ethoxycarbonylvinyl]-1H-pyrrole-2-carboxyate 593 mg, potassium carbonate 864 mg and dimethylsulfoxide 10 mL was heated at 100° C. for 3.5 hours. After cooling off the reaction liquid, 100 mL of diethyl ether was added, followed by filtration. To the filtrate 100 mL of water was added to separate the organic layer. The aqueous layer was extracted twice with 50 mL of diethyl ether, and the extract was combined with the organic layer, followed by washing three times with 20 mL of water and once with 20 mL of saturated brine by the order stated. After drying the same over magnesium sulfate, the solvent was distilled off under reduced pressure, leaving 965 mg of a brown, viscous substance. This was dissolved in a liquid mixture of 12 mL of acetic acid and 5 mL of water, and to the solution 1.31 g of sodium hyposulfite was added, followed by heating under reflux for 30 minutes. After cooling off the reaction liquid, 50 mL of water was added and the precipitated crystals were recovered by filtration. The crystals were washed with water and diethyl ether, and dried under heating to provide 600 mg of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([OH:13])=[C:9]([CH:12]=1)[C:10]#[N:11])([CH3:4])([CH3:3])[CH3:2].[Na].[CH3:15]I>C(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:13][CH3:15])=[C:9]([CH:12]=1)[C:10]#[N:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(O)c(C#N)c1
Reactant: CI
Agent: [Na]
Solvent: CCO
Product: COc1ccc(C(C)(C)C)cc1C#N

Procedure:
5-tert-Butyl-2-hydroxybenzonitrile (50 g; prepared as described by F. B. Dains and I. R. Rothrock, J. Amer. Chem., 1894 16, 635) was added to a solution of sodium (7.43 g.) in anhydrous ethanol (150 ml.), followed by methyl iodide (50 ml.). The mixture was refluxed for 3 hours, during which time a further quantity of methyl iodide (20 ml.) was added in portions. The mixture was evaporated in vacuo, and the residue treated with water (500 ml.). The oil obtained was extracted with diethyl ether, and the aqueous layer further extracted twice with diethyl ether. The combined extracts were dried and evaporated, and the residual oil was distilled in vacuo to give 5-tert-butyl-2-methoxybenzonitrile (50.3 g.), b.p. 138°-140° C./0.2 mm.Hg.
Reaction SMILES: [CH2:1]([C:4]1[CH:21]=[CH:20][C:7]([NH:8][C:9]2[C:17]([F:18])=[C:16]([F:19])[CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)=[C:6]([F:22])[CH:5]=1)[CH:2]=[CH2:3].[NH2:23][O:24][CH2:25][CH2:26][OH:27].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CO>[CH2:1]([C:4]1[CH:21]=[CH:20][C:7]([NH:8][C:9]2[C:17]([F:18])=[C:16]([F:19])[CH:15]=[CH:14][C:10]=2[C:11]([NH:23][O:24][CH2:25][CH2:26][OH:27])=[O:13])=[C:6]([F:22])[CH:5]=1)[CH:2]=[CH2:3]
Reactant: NOCCO
Reactant: C=CCc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: C=CCc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.9 %

Procedure:
2-(4-Allyl-2-fluoroanilino)-3,4-difluorobenzoic acid (700 mg, 2.28 mmol) was dissolved in MeOH (20 mL) to which was added 2-(aminooxy)ethanol (263 mg, 3.42 mmol), followed by 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methymorpholinium chloride [DMT-MM, prepared according to the procedure of Kunishima et al [Tetrahedron, 55, 13159–13170 (1999)]] (946 mg, 3.42 mmol). This mixture was stirred 15 h. at room temperature. The MeOH was removed under reduced pressure and the resulting oil dissolved in EtOAc (100 mL), which was washed with water (2×100 mL), brine (100 mL) and dried (Na2SO4). The solvent was removed under reduced pressure to afford a crude yellow oil which was purified by filtration through a plug of silica gel (50% EtOAc/PE as eluant) to give 2-(4-allyl-2-fluoroanilino)-3,4-difluoro-N-(2-hydroxyethoxy)benzamide as a white solid (734 mg, 88%); m.p. (EtOAc/hexane) 173–177° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.85 (br s, 1 H), 8.75 (br s, 1 H), 7.43–7.37 (m, 1 H), 7.14–7.07 (m, 1 H), 7.05–6.99 (m, 1 H), 6.90–6.81 (m, 2 H), 5.99–5.87 (m, 1 H), 5.02–5.11 (m, 2 H), 4.70 (br s, 1 H), 3.85 (t, J=4.9 Hz, 1H), 3.57 (t, J=4.9 Hz, 1 H), 3.51–3.40 (m, 2H, obscured by H2O). Anal. calcd. for C18H17F3N2O3: C, 59.0; H, 4.7; N, 7.7. Found C, 59.1; H, 4.5; N, 7.4.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][CH2:5][N:4]([C:7]2[CH:11]=[CH:10][N:9]([CH3:12])[N:8]=2)[C:3]1=[O:13].[N+:15]([O-])([OH:17])=[O:16].C(=O)([O-])O.[Na+]>C(OC(=O)C)(=O)C>[CH3:1][C:2]1([CH3:14])[CH2:6][CH2:5][N:4]([C:7]2[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][N:9]([CH3:12])[N:8]=2)[C:3]1=[O:13]
Reactant: Cn1ccc(N2CCC(C)(C)C2=O)n1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cn1cc([N+](=O)[O-])c(N2CCC(C)(C)C2=O)n1
Temperature: 0 °C

Procedure:
To a solution of 3,3-dimethyl-1-(1-methyl-1H-pyrazol-3-yl)pyrrolidin-2-one (170 mg) in acetic anhydride (2.1 mL) was added fuming nitric acid (0.073 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 1.5 hr. The reaction mixture was poured into ice water, and the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (170 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.Cl.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][NH2:19])=[CH:14][CH:13]=1.CO>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].O.C(Cl)(Cl)Cl>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]([CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[NH2:19])=[CH:14][CH:13]=1
Reactant: ClCCN1CCCCC1
Reactant: NNc1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Cl-]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: NN(CCN1CCCCC1)c1ccc(Cl)cc1
Temperature: 80 °C
Yield: 42.4 %

Procedure:
1-(2-Chloro-ethyl)piperidine (5 g, 27.9 mmol) was added to a vigorously stirred mixture of 4-chlorophenyl hydrazine hydrochloride (5 g, 27.9 mmol) and tetra-n-butylammonium chloride (0.40 g) in 50% aqueous sodium hydroxide (30 mL). The reaction was heated to 80° C. (oil bath temperature) for 3.5 h. The reaction was cooled, diluted with water and extracted with chloroform. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure to give a red oil. The oil was subjected to column chromatography (silica gel, eluent: 10% methanol in chloroform) to give a red oil (˜3 g). This was purified again by column chromatography (silica gel, eluent: {tilde over (5)}10% methanol in chloroform) to give a red oil (1.77 g, 25%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.OS(O)(=O)=O.[N+:24]([O-])([OH:26])=[O:25]>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[O:9])=[CH:6][C:7]=1[N+:24]([O-:26])=[O:25]
Reactant: O=[N+]([O-])O
Reactant: O=C(c1ccc(Br)cc1)c1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)O
Solvent: CC(Cl)Cl
Product: O=C(c1ccc([N+](=O)[O-])cc1)c1ccc(Br)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
The crude (4-Bromo-phenyl)-(4-nitro-phenyl)-methanone (15 g, 49 mmol) was dissolved in 45 mL of dichloroethane and added dropwise via addition funnel to a mixture of concentrated H2SO4(aq) (2 mL, 392 mmol) and fuming HNO3(aq) (15.7 mL, 392 mmol). The mixture was stirred at 60° C. overnight. Subsequently the mixture was poured over ice water and allowed to stir resulting in precipitation of the product. The product was filtered and dried affording 78% yield of the desired (4-Bromo-3-nitro-phenyl)-(−4-nitro-phenyl)-methanone (13.1 g, 38 mmol).
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O.Cl.[CH3:21][S:22]([C:25]1[S:29][C:28]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:27][CH:26]=1)(=[O:24])=[O:23]>>[CH3:18][C:2]([CH3:1])([CH3:19])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:33]1[CH2:34][CH2:35][N:30]([C:28]2[S:29][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:26][N:27]=2)[CH2:31][CH2:32]1)=[O:9]
Reactant: CC(C)(C)COc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: CS(=O)(=O)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CC(C)(C)COc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(S(C)(=O)=O)s2)CC1
Yield: 36 %

Procedure:
Prepared in analogy to example 1 (b) from 2-(2,2-dimethyl-propoxy)-5-methanesulfonyl-benzoic acid (Example A11) and 1-(5-methanesulfonyl-thiazol-2-yl)-piperazine hydrochloride (Example 21(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 36%). MS (m/e): 516.2 (M+H+, 100%).
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:2]CC.[I:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]Cl>C1(C)C(C)=CC=CC=1>[CH2:9]([O:8][P:1]([CH2:14][C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=1[I:11])(=[O:2])[O:5][CH2:6][CH3:7])[CH3:10]
Reactant: ClCc1ccccc1I
Reactant: CCOP(OCC)OCC
Solvent: Cc1ccccc1C
Product: CCOP(=O)(Cc1ccccc1I)OCC
Reaction time: 24 h

Procedure:
Triethyl phosphite (ca 66.6 ml; 94% pure; ca. 396.8 mmol) and 2-iodobenzyl chloride 1 (100 g, 400 mmol; melted prior to use) were mixed with xylene (65 ml) in a 250 ml roundbottomed flask. The clear solution was heated to reflux while stirring for 24 hours. The reaction was followed by GC and 1H-NMR (CDCl3). The disappearing proton resonance of 2H, s, CH2I at 4.73 ppm and the new 2H, d, CH2PO(OEt)2 at 3.47 ppm were indicative for the progress of the reaction.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[C:16](Cl)([CH3:18])=[O:17]>C(Cl)Cl.O>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:16](=[O:17])[CH3:18])[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(Br)n1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(Br)n1
Reaction time: 8 h
Yield: 85.3 %

Procedure:
To a solution of 6-bromopyridin-2-amine (10 g, 0.060 mol) and Et3N (25 g, 0.27 mol) in CH2Cl2 (300 mL) was added AcCl (13 g, 0.17 mol) at 0° C. The mixture was stirred overnight. The reaction mixture was diluted with water and extracted with EtOAc (200 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give N-(6-bromopyridin-2-yl)acetamide (11 g, 88%). 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J=8.0 Hz, 1H), 7.97 (brs, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 2.19 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@:4]12[CH2:16][CH2:15][CH2:14][N:5]1[C@@H](C(Cl)(Cl)Cl)[O:7][C:8]2=O.[NH3:17]>CO>[CH3:1][O:2][CH2:3][C@@:4]1([C:8]([NH2:17])=[O:7])[CH2:16][CH2:15][CH2:14][NH:5]1
Reactant: N
Reactant: COC[C@@]12CCCN1[C@@H](C(Cl)(Cl)Cl)OC2=O
Solvent: CO
Product: COC[C@@]1(C(N)=O)CCCN1
Reaction time: 48 h

Procedure:
A mixture of (3R,7aR)-7a-methoxymethyl-3-trichloromethyl-tetrahydro-pyrrolo[1,2-c]oxazol-1-one (Stage G.1, 0.6 g) and 7 M ammonia in MeOH (6 mL) was stood at rt for 2 days in a sealed vessel. The RM was then evaporated to give the title compound as a pale yellow oil which was used without further purification.
Reaction SMILES: [CH2:1]([N:3](CC)CC)[CH3:2].[Cl:8][C:9]1[C:18]([C:19](Cl)=[O:20])=[C:17]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:8][C:9]1[C:18]([C:19]2[O:20][CH2:2][CH2:1][N:3]=2)=[C:17]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C(=O)Cl)c1Cl
Reactant: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C2=NCCO2)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 45.6 %

Procedure:
At room temperature, 41.8 g (0.41 mol) of triethylamine and then 31.1 g (0.10 mol) of methyl 2-chloro-3-chlorocarbonyl-4-methylsulfonylbenzoate in 150 ml of toluene were added dropwise to 26.6 g (0.13 mol) of I-amino-2-bromoethane hydrobromide in 500 ml of toluene. The mixture was heated under reflux for 5 hours and then stirred at room temperature for 12 hours, another 5.0 g (0.02 mol) of I-amino-2-bromoethane hydrobromide were added and the mixture was heated under reflux for 7.5 hours. The reaction mixture was allowed to cool, diluted with ethyl acetate, washed with water, dried and concentrated. The residue was then recrystallized from methyl tert-butyl ether/ethyl acetate. 14.5 g (46% of theory) of methyl 2-chloro-4-methylsulfonyl-3-(4,5-dihydrooxazol-2-yl)benzoate were obtained.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Br.[Cl:16][C:17]1[CH:18]=[C:19]([CH:29]=[C:30]([Cl:32])[CH:31]=1)[O:20][C:21]1[C:22]([CH3:28])=[N:23][NH:24][C:25]=1[CH2:26][NH2:27].[C:33]([C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1)#[N:34]>C(O)(=O)C.ClCCl>[Cl:16][C:17]1[CH:18]=[C:19]([CH:29]=[C:30]([Cl:32])[CH:31]=1)[O:20][C:21]1[C:22]([CH3:28])=[N:23][NH:24][C:25]=1[CH2:26][NH:27][CH2:39][C:38]1[CH:41]=[CH:42][C:35]([C:33]#[N:34])=[CH:36][CH:37]=1
Reactant: Cc1n[nH]c(CN)c1Oc1cc(Cl)cc(Cl)c1
Reactant: N#Cc1ccc(C=O)cc1
Agent: Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1n[nH]c(CNCc2ccc(C#N)cc2)c1Oc1cc(Cl)cc(Cl)c1
Reaction time: 14 h
Yield: 3 %

Procedure:
Sodium triacetoxyborohydride (216 mg, 1.09 mmol) was added in one portion to a stirred solution of the pyrazole of Example 109 (300 mg, 0.850 mmol), 4-cyanobenzaldehyde (111 mg, 0.850 mmol) and acetic acid (3 drops) in dichloromethane (25 ml) at room temperature tinder nitrogen. The reaction was stirred for 14 hours and then washed with 1M aqueous sodium carbonate solution (2×10 ml) and brine (10 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:4:1, by volume) to provide the title compound (10 mg) as a colourless oil.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@H:8]1[CH2:32][C:33](=O)[NH2:34])=[O:6])[CH:2]=[CH2:3].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:45])=CC=1.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>COCCOC.O>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:9][C@@H:8]1[CH2:32][C:33](=[S:45])[NH2:34])=[O:6])[CH:2]=[CH2:3]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@@H]1CC(N)=S
Temperature: 50 °C
Reaction time: 4 h
Yield: 98.7 %

Procedure:
To a solution of (2R,4S)-1-allyloxycarbonyl-2-carbamoylmethyl-4-(triphenylmethylthio) pyrrolidine (255 mg) in ethylene glycol dimethyl ether (5 ml) was added Lawesson's reagent (106 mg). After stirring at 50° C. for 4 hours, the solution was poured into a mixture of ethyl acetate and water, and adjusted to pH 7.0 with aqueous sodium hydrogen carbonate solution. The separated organic layer was washed with aqueous sodium chloride solution, dried over magnesium sulfate and evaporated. The residue was subjected to column chromatography on silica gel (eluent; n-hexane:ethyl acetate=2:1) to give (2R,4S)-1-allyloxycarbonyl-2-thiocarbamoylmethyl-4-(triphenyl-methylthio) pyrrolidine (130 mg).
Reaction SMILES: C([N:3]([CH2:15][CH3:16])[C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[CH3:13])C.C([Li])(C)(C)C.CCCCC.[F:27][C:28]1[CH:29]=C([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])C#N>C1COCC1>[F:27][C:28]1[CH:29]=[C:16]([C:15]2[N:3]=[C:4]([OH:14])[C:5]3[C:6]([CH:13]=2)=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=3)[CH:33]=[CH:34][C:35]=1[O:36][CH3:37]
Reactant: COc1ccc(C#N)cc1F
Reactant: CCN(CC)C(=O)c1ccc(OC)cc1C
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: COc1ccc2c(O)nc(-c3ccc(OC)c(F)c3)cc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.4 %

Procedure:
To a solution of N,N-diethyl-4-methoxy-2-methylbenzamide (1.00 g, 4.52 mmol) in THF (9 ml) at −78° C. was added dropwise tert-butyllithium 1.7 M in pentane (3.19 ml, 5.42 mmol) and the solution was stirred for 0.5 h before addition of 3-fluoro-4-methoxybenzonitrile (0.683 g, 4.52 mmol) in THF (9 ml). The resulting solution was warmed to rt and stirred for 16 h. The reaction mixture was quenched with water, neutralized with 1 N HCl. The precipitated solid was collected and washed with water to give 3-(3-fluoro-4-methoxyphenyl)-6-methoxyisoquinolin-1-ol (926 mg, 69% yield) as a solid after drying. MS: MS m/z 300.1 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]1[CH3:18].Br[CH2:20][CH2:21][CH3:22].[H-].[Na+]>>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]([CH2:20][CH2:21][CH3:22])[N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]1[CH3:18]
Reactant: CCCBr
Reactant: Cc1cc2ccccc2n1Nc1ccncc1F
Agent: [H-]
Agent: [Na+]
Product: CCCN(c1ccncc1F)n1c(C)cc2ccccc21

Procedure:
The title compound was prepared from N-(3-fluoro-4-pyridinyl)-2-methyl-1H-indol-1-amine and 1-bromopropane with the aid of NaH in substantially the same manner as in Example 4, m.p. 5° C.
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:23][F:24])[CH:8]=[CH:7][C:6]2[CH:9]=[C:10]([C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])[CH:11]=[CH:12][C:5]=2[O:4]1.ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)Cl>[O:33]1[CH:7]2[CH:8]1[C:3]([CH2:2][F:1])([CH2:23][F:24])[O:4][C:5]1[CH:12]=[CH:11][C:10]([C:13]([F:22])([F:21])[C:14]([F:19])([F:20])[C:15]([F:16])([F:17])[F:18])=[CH:9][C:6]=12
Reactant: FCC1(CF)C=Cc2cc(C(F)(F)C(F)(F)C(F)(F)F)ccc2O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: FCC1(CF)Oc2ccc(C(F)(F)C(F)(F)C(F)(F)F)cc2C2OC21
Temperature: 25 °C
Reaction time: 27 h
Yield: 44.5 %

Procedure:
A mixture of 3.1 g of 2,2-bisfluoromethyl-6-heptafluoropropyl-2H-1-benzopyran, 4.20 g of m-chloroperbenzoic acid (70%) and 50 ml of methylene chloride was stirred at room temperature for 27 hours. After removal of the separated crystal by filtration, the filtrate was washed with saturated sodium hydrogen carbonate solution and saturated saline'solution, and dried with sodium sulfate. The solvent was distilled off and the resultant residue was purified using silica gel column chromatography (developing solution, hexane:CH2Cl2 =5:1) to obtain 1.44 g of oily 3,4-epoxy-2,2-bisfluoromethyl-6-heptafluoropropyl-3,4-dihydro-2H-1-benzopyran represented by the following formula.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Cl.C(OCN1C2N=CN=C(C3C=NN([CH:30]([O:32][CH2:33][CH3:34])[CH3:31])C=3)C=2C=C1)(=O)C(C)(C)C>C(Cl)Cl.O1CCOCC1>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:31][CH2:30][O:32][CH2:33][CH3:34])[CH:6]=1
Reactant: CCOC(C)n1cc(-c2ncnc3c2ccn3COC(=O)C(C)(C)C)cn1
Reactant: Brc1cn[nH]c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOCCn1cc(Br)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 108.4 %

Procedure:
To a solution of 4-bromopyrazole (21, 70.0 g, 0.476 mol) in CH2Cl2 (600 mL) was added a solution of 3.1 M HCl in dioxane (4 mL) and ethyl vinyl ether (18, 41 g, 0.569 mol, 1.2 equiv). The resulting reaction mixture was stirred at room temperature for 3 hrs. The reaction was quenched with aqueous NaHCO3 and the two layers were separated. The organic layer was washed with water, dried over Na2SO4, and concentrated under reduced pressure to dryness to afford 4-bromo-1-(ethoxyethyl)-1H-pyrazole (22, 113 g, 104.3 g theoretical, 97% yield) as an oily (GC purity: 89%), which was directly used in the subsequent reaction without further purification.