Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.[NH2:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>S(Cl)(Cl)=O>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:14]=1)=[O:7]
Reactant: Nc1cccc(-c2ccccn2)c1
Reactant: Cc1ccc(C(=O)O)cc1I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: Cc1ccc(C(=O)Nc2cccc(-c3ccccn3)c2)cc1I
Temperature: 25 °C
Reaction time: 264 h

Procedure:
3-Iodo-4-methylbenzoic acid (154 mg, 0.59 mmol) was heated at 80° C. in thionyl chloride (2 ml) for 3 hrs. The reaction was allowed to cool to room temperature and the excess thionyl chloride evaporated under vacuum. The residue was dissolved in acetone (3 ml), 2-(3-aminophenyl)pyridine (100 mg, 0.59 mmol) and sodium carbonate (400 mg) were added to the solution. The reaction was stirred at room temperature for 11 days, filtered and the filtrate reduced to dryness under vacuum. The residue was dissolved in ether and filtered through a bond-elut (1 g, silica), washing with ether. The solvent was evaporated from the combined filtrate and washings to give 3-iodo-4-methyl-N-(3-pyridin-2-yl-phenyl)benzamide as a cream foam. NMR: δH CDCl3 8.70,(1H, dt), 8.33,(1H, d), 8.18,(1H, t), 7.93-7.89,(2H, m), 7.79-7.75,(4H, m), 7.50,(1H, t), 7.35,(1H, d), 7.26,(1H, m), 2.51,(3H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][N:37]([CH:40]2[CH2:42][CH2:41]2)[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[CH:40]1([N:37]2[CH2:36][CH2:35][N:34]([S:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[C:6]3[CH:5]=[CH:4][C:3]([C:17]4[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=4)=[C:2]([F:1])[CH:7]=3)(=[O:33])=[O:32])[CH2:39][CH2:38]2)[CH2:42][CH2:41]1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(c1ccccc1Br)N1CCN(C2CC2)CC1
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCN(C4CC4)CC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 1-((2-bromophenyl)sulfonyl)-4-cyclopropylpiperazine. MS (ESI): mass calcd. for C23H24FN5O2S, 453.16; m/z found, 454.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.40 (s, 1H), 8.18-8.12 (m, 2H), 7.97 (m, 1H), 7.79-7.74 (m, 1H), 7.68-7.63 (m, 1H), 7.49-7.46 (m, 1H), 7.34-7.30 (m, 2H), 3.28-2.98 (d, J=1.6, 8H), 2.82-2.75 (m, 1H), 0.96-0.85 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[N:6]=[CH:5]2.C([Li])CCC.[C:17](OCC)(=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1>[CH3:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cn1ncc2cc(Br)ccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1ccc2c(cnn2C)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 5-bromo-1-methyl-1H-indazole (Aldrich, 1.06 g, 5 mmol) in THF (22 mL) at −78° C. was added n-butyllithium (2.2 mL, 2.5 M, 5.5 mmol) slowly. The mixture was stirred for 20 minutes, and the solution of diethyl oxalate (0.68 mL, 5.0 mmol) in THF (5 mL) was added over one minute period. The reaction was kept at −78° C. for 40 minutes, and was quenched with saturated ammonium chloride solution and warmed to 25° C. The mixture was extracted with ethyl acetate, and the organic phase was washed with water, brine, and dried over sodium sulfate. Concentration and purification with flash column chromatography (hexanes/EtOAc) gave ethyl 2-(1-methyl-1H-indazol-5-yl)-2-oxoacetate. LCMS-ESI+: calc'd for C12H13N2O3: 233.2 (M+H+); Found: 233.0 (M+H+).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[N-]=C=O.[CH2:22]([O:29][C:30]1[CH:31]=[C:32](/[CH:50]=[CH:51]/[CH2:52][CH2:53][N:54]2[C:62](=[O:63])[C:61]3[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=3)[C:55]2=[O:64])[CH:33]=[CH:34][C:35]=1[N:36]1[CH2:40][C:39](=[O:41])[N:38](CC[Si](C)(C)C)[S:37]1(=[O:49])=[O:48])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH2:22]([O:29][C:30]1[CH:31]=[C:32](/[CH:50]=[CH:51]/[CH2:52][CH2:53][N:54]2[C:55](=[O:64])[C:56]3[C:61](=[CH:60][CH:59]=[CH:58][CH:57]=3)[C:62]2=[O:63])[CH:33]=[CH:34][C:35]=1[N:36]1[CH2:40][C:39](=[O:41])[NH:38][S:37]1(=[O:48])=[O:49])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/CCN3C(=O)c4ccccc4C3=O)cc2OCc2ccccc2)S1(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [N-]=C=O
Solvent: C1CCOC1
Product: O=C1CN(c2ccc(/C=C/CCN3C(=O)c4ccccc4C3=O)cc2OCc2ccccc2)S(=O)(=O)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tetrabutylammonium fluoride (1.0M in THF, 1.5 mL) is added to a suspension of PS-isocyanate resin (0.4 g) in THF (1.5 mL) and the mixture is stirred at RT for 2 h. The resin is filtered off and the filtrate is added to a solution of 2-((E)-4-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-phenyl}-but-3-enyl)-isoindole-1,3-dione (90 mg, 0.146 mmol) in THF (1 mL). The reaction is stirred at 65° C. for 1 h and at RT for 18 h. The mixture is cooled and concentrated. The residue is partitioned between EtOAc and water and the organic layer is washed with 2N HCl (3×) and saturated aqueous sodium chloride. The organic layer is dried over Na2SO4 and the solvent removed under reduced pressure to give the title compound: (M−1)−=516.
Reaction SMILES: Br[CH:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14]([OH:16])=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.CS(C)=[O:24]>O>[CH:12]1[C:7]2[CH:6]=[CH:5][C:4]3[CH:18]=[CH:19][CH:20]=[CH:21][C:3]=3[C:2](=[O:24])[C:8]=2[CH:9]=[CH:10][C:11]=1[CH:13]([CH3:17])[C:14]([OH:16])=[O:15]
Reactant: CS(C)=O
Reactant: CC(C(=O)O)c1ccc2c(c1)C=Cc1ccccc1C2Br
Solvent: O
Product: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
0.5 G. of 2-(5-bromo-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid is dissolved in 10 ml. of dimethylsulfoxide and heated at 150°-180° C. under nitrogen for 2 hours, then cooled, poured into water and worked up as in part A to afford 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionic acid.
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[NH2:15][CH2:16][C:17]([CH:19]1[CH:24]2[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]2)[CH2:20]1)=[O:18].[C:27](Cl)(=[O:29])[CH3:28].N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:27]([NH:15][CH2:16][C:17]([CH:19]1[CH:24]2[CH2:23][CH2:22][N:21]([CH2:26][CH2:25]2)[CH2:20]1)=[O:18])(=[O:29])[CH3:28]
Reactant: NCC(=O)C1CN2CCC1CC2
Reactant: CC(=O)Cl
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)NCC(=O)C1CN2CCC1CC2
Temperature: 25 °C
Yield: 57.6 %

Procedure:
A suspension of the dihydrochloride salt of (±) 3-(α-aminoacetyl)-1-azabicyclo[2.2.2]octane (D14) (0.8 g; 0.0033 mole) in absolute chloroform (30 ml) was treated with acetyl chloride (0.76 g, 0.01 mole) and pyridine (4.58 g, 0.058 mole) at 0° C. for 1/2 h. The reaction was allowed to warm to room temperature for 15 h and then concentrated in vacuo. The residue was partitioned between chloroform and saturated aqueous potassium carbonate solution. The organic phase was separated, dried over sodium sulphate and concentrated in vacuo to a gum, which was chromatographed on neutral alumina in 10% methanol in ethyl acetate. This afforded the title compound as an oil (0.4 g, 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][OH:16])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[C:24]([O:31]C(=O)CCCCC)(=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>O>[C:24]([OH:31])(=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][OH:16])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1
Reactant: CCCCCC(=O)OC(=O)CCCCC
Agent: OCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Solvent: O
Product: CCCCCC(=O)O

Procedure:
In a manner similar to Example 12, a mixture of 8-chloro-1-(hydroxymethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine and hexanoic anhydride was heated on the water bath to give 8-chloro-1-(hydroxymethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine hexanoate (ester).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:14][CH:15]=[CH:16][C:17]=1[O:18][CH3:19].[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH2:31][C:32](Cl)=[O:33]>C([O-])(O)=O.[Na+].C1COCC1>[CH3:19][O:18][C:17]1[CH:16]=[CH:15][NH:14][C:13]=1/[CH:12]=[C:5]1\[C:6](=[O:11])[NH:7][C:8]2[C:4]\1=[C:3]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:2]([NH:1][C:32](=[O:33])[CH2:31][C:27]1[S:26][CH:30]=[CH:29][CH:28]=1)=[CH:10][CH:9]=2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(N)c(-c3ccccc3)c21
Reactant: O=C(Cl)Cc1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(NC(=O)Cc3cccs3)c(-c3ccccc3)c21
Yield: 65.9 %

Procedure:
Using Method M above, (Z)-5-amino-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-4-phenyl-2H-indol-2-one (26.5 mg, 0.08 mmol) (from Example 43 infra) was acylated with 2-thiopheneacetyl chloride (25.7 mg, 0.16 mmol) (Aldrich) in saturated aqueous NaHCO3 (0.16 mL) and THF (2 mL) at room temperature for 3 h to give (Z)-N-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-4-phenyl-1H-indol-5-yl]-2-thiopheneacetamide (yield: 24 mg, 67%).
Reaction SMILES: [F:1][CH:2]([F:30])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]([O:27]CC)=[O:26])[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.Cl>O1CCCC1.O>[F:30][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([CH:8]([F:9])[F:10])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]([OH:27])=[O:26])[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1
Reactant: CCOC(=O)c1csc(C2CCN(C(=O)Cn3nc(C(F)F)cc3C(F)F)CC2)n1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1csc(C2CCN(C(=O)Cn3nc(C(F)F)cc3C(F)F)CC2)n1
Reaction time: 3 h

Procedure:
Ethyl 2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (IV-1, 13.3 g) is dissolved in tetrahydrofuran (80 ml). LiOH monohydrate (1.86 g) dissolved in water (20 ml) is then added. After 3 hours, water is added, the pH is adjusted to 2-3 with dilute hydrochloric acid (1M), the mixture is then extracted with ethyl acetate and the combined organic phases are dried with sodium sulfate. The solid is filtered off and the solvent is removed by distillation. This gives 2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (11.7 g, 94%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([O:19][CH2:20][C:21]2[O:25][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:23][C:22]=2[CH:32]=O)=[CH:17][CH:16]=1.C(OP([CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])(OCC)=O)C.CN(C)C=O.[H-].[Na+]>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([O:19][CH2:20][C:21]2[O:25][C:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[N:23][C:22]=2/[CH:32]=[CH:44]/[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:17][CH:16]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(OCc2oc(-c3ccccc3)nc2C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1nc(-c2ccccc2)oc1COc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Reaction time: 3 h
Yield: 47.8 %

Procedure:
To a mixture of 5-({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenoxy}methyl)-2-phenyl-1,3-oxazole-4-carbaldehyde (1.0 g), ethyl diethylphosphonoacetate (0.52 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.10 g) at room temperature, and the mixture was stirred at the same temperature for 3 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl (2E)-3-[5-({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenoxy}methyl)-2-phenyl-1,3-oxazol-4-yl]-2-propenoate as colorless crystals (0.55 g, yield 49%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 107-108° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:29])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:33].O>CN(C)C=O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:29][CH3:33])[C:25]([F:27])([F:28])[F:26])=[CH:4][CH:3]=1
Reactant: CI
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(O)C(F)(F)F)c23)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(OC)C(F)(F)F)c23)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a solution of 1-[9-chloro-1-(2-chloro-4-methoxyphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanol (100 mg, 0.224 mmol) in N,N-dimethylformamide (2.0 mL) was added sodium hydride (60% dispersion in mineral oil, 14 mg, 0.35 mmol) at 0° C. After the mixture was stirred at 0° C. for 0.5 hr, iodomethane (0.0697 mL, 1.12 mmol) was added to the reaction mixture at 0° C. The mixture was stirred at room temperature for 8 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture and recrystallization from ethyl acetate/n-hexane to give the title compound (79.1 mg, 0.172 mmol, 77%) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[C:19]([CH3:21])[C:18](Cl)=[CH:17][C:16]=2[N+:23]([O-:25])=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[C:19]([CH3:21])[C:18]([C:30]3[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=3)=[CH:17][C:16]=2[N+:23]([O-:25])=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])cc1Cl
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])cc1-c1cnn(C)c1
Temperature: 150 °C

Procedure:
A mixture of 4-(4-Chloro-5-methyl-2-nitro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester from the previous step (375.8 mg, 1.01 mmol), 1-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (Boron Molecular, 224.4 mg 1.08 mmol), potassium phosphate tribasic monohydrate (392 mg), Pd2(dba)3 (45 mg), and dicyclophosphinobiphenyl (43 mg) in 4 mL of 1,4-dioxane/H2O (3/1) is heated in a sealed tube at 150° C. for 20 min under microwave radiation. The reaction mixture is filtered through a small plug of Celite, dried over Na2SO4 and concentrated. The residue is purified using a SiO2 column (ISCO), affording 4-[5-Methyl-4-(1-methyl-1H-pyrazol-4-yl)-2-nitro-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester. MS (ES+); 417.3 (MH+), 439.2 (MNa+).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH2:10][C:11](=O)[CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.C(O)(=O)C>[CH2:16]([NH:23][CH:11]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:14]=[CH:15][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[CH2:12]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=[N+]([O-])c1ccc2c(c1)CC(NCc1ccccc1)CCC2
Reaction time: 5 h

Procedure:
Under nitrogen, to a solution of 3-nitro-5,7,8,9-tetrahydrobenzocyclohepten-6-one (300 mg) in 1,2-dichloroethane (10 ml) were added benzylamine (0.24 ml), sodium triacetoxyborohydride (460 mg) and acetic acid (0.17 ml) at room temperature, and the mixture was stirred at the same temperature for 5 hours. The resulting mixture was poured into aqueous 1N sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1 to 1:5) to give N-benzyl-(3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (342 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:27][CH3:28])(=[N:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])[CH:14]=2)=[CH:5][C:4]=1[N:29]=[CH:30]N(C)C)#[N:2].[NH2:34][C:35]1[S:36][CH:37]=[CH:38][N:39]=1.ClCCl.CO>CO>[CH2:25]([O:24][C:22]([N:21]=[S:19]([CH2:27][CH3:28])([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][O:11][C:6]2[CH:5]=[C:4]3[C:3]([C:1]([NH:34][C:35]4[S:36][CH:37]=[CH:38][N:39]=4)=[N:2][CH:30]=[N:29]3)=[CH:8][C:7]=2[O:9][CH3:10])[CH:14]=1)=[O:20])=[O:23])[CH3:26]
Reactant: CCOC(=O)N=S(=O)(CC)c1cccc(COc2cc(N=CN(C)C)c(C#N)cc2OC)c1
Reactant: Nc1nccs1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)N=S(=O)(CC)c1cccc(COc2cc3ncnc(Nc4nccs4)c3cc2OC)c1
Yield: 72 %

Procedure:
According to GWP 5, the reaction of N′-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-ethylsulphonimidoyl]benzyloxy}-4-methoxyphenyl)-N,N-dimethylformimidamide (50 mg, 0.11 mmol) with 2-aminothiazole (12.8 mg, 0.13 mmol) and chromatographic purification (silica gel, dichloromethane/methanol: 0→30% methanol) gives the desired product in 72% yield (40 mg).
Reaction SMILES: C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1.[CH3:49][O:50][C:51]1[CH:52]=[C:53]([CH2:59][C:60](=[O:62])[CH3:61])[CH:54]=[CH:55][C:56]=1[O:57][CH3:58]>>[CH3:49][O:50][C:51]1[CH:52]=[C:53]([CH2:59][C@@H:60]([OH:62])[CH3:61])[CH:54]=[CH:55][C:56]=1[O:57][CH3:58]
Reactant: COc1ccc(CC(C)=O)cc1OC
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: COc1ccc(C[C@H](C)O)cc1OC

Procedure:
The carbonyl reductases of the present invention can utilize NADPH as a coenzyme, have no alcohol dehydrogenating activity, and reduce 3,4-dimethoxyphenylacetone by utilizing NADPH as a coenzyme to produce 90% ee or more (S)-1-(3,4-dimethoxyphenyl)-2-propanol.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][CH:15]=O)[C:6](=[O:17])[CH2:5]1)(=[O:3])[CH3:2].[C:18]([O:22][C:23](=[O:42])[N:24]([CH2:31][C:32]1[CH:41]=[CH:40][C:35]2[O:36][CH2:37][CH2:38][O:39][C:34]=2[CH:33]=1)[CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([CH3:21])([CH3:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[C:18]([O:22][C:23](=[O:42])[N:24]([CH2:31][C:32]1[CH:41]=[CH:40][C:35]2[O:36][CH2:37][CH2:38][O:39][C:34]=2[CH:33]=1)[CH:25]1[CH2:30][CH2:29][N:28]([CH2:15][CH2:14][N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:4]([C:1](=[O:3])[CH3:2])[CH2:5][C:6]2=[O:17])[CH2:27][CH2:26]1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: CC(=O)N1CC(=O)N(CC=O)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CC(=O)N(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To 15 mL of a chloroform solution containing 337 mg of (4-acetyl-2-oxo-3,4-dihydroquinoxalin-1(2H)-yl)acetaldehyde and 504 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 83 μL of acetic acid was added, and stirred at room temperature for 1 hour. To the reaction mixture, 477 mg of sodium triacetoxyborohydride was added, and stirred for 1.5 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform:methanol=20:1] to give 691 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4-acetyl-2-oxo-3,4-dihydroquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a pale yellow foam.
Reaction SMILES: [C:1]([O:10]CC)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Br[CH2:14][CH2:15][CH:16]=[CH2:17].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:17]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9])[CH2:16][CH:15]=[CH2:14]
Reactant: CCOC(=O)c1ccccc1O
Reactant: C=CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCCOc1ccccc1C(=O)O

Procedure:
The reaction of ethyl salicylate and 4-bromo-1-butene in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 2-But-3-enyloxy-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.57 (s, —CO2H); 7.63 (m, 1 arom. H); 7.46 (m, 1 arom. H); 7.12 (m, 1 arom. H); 6.99 (m, 1 arom. H); 5.92 (m, —CH═CH2); 5.18, 5.08 (2 d-like, —CH═CH2); 4.07 (t, J=6.4, OCH2—CH2—CH═CH2); 2.49 (m, OCH2—CH2—CH═CH2). 13C-NMR (100 MHz, d6-DMSO): 167.33 (—C═O); 157.18; 134.77; 132.85; 130.52; 121.75; 120.16; 117.01; 113.60; 67.70; 33.20.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([CH3:27])[C:24]([OH:26])=[O:25])=[CH:18][C:17]=2[F:28])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[C:7](=[O:12])[C:6]=2[CH:13]=1.[BH4-].[Na+].O>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([CH3:27])[C:24]([OH:26])=[O:25])=[CH:18][C:17]=2[F:28])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH:7]([OH:12])[C:6]=2[CH:13]=1
Reactant: CC(Cc1ccc(OCc2cc(Cl)cc3c2OC(C)(C)C3=O)c(F)c1)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(Cc1ccc(OCc2cc(Cl)cc3c2OC(C)(C)C3O)c(F)c1)C(=O)O

Procedure:
To a solution of 3-(4-((5-chloro-2,2-dimethyl-3-oxo-2,3-dihydrobenzofuran-7-yl)methoxy)-3-fluorophenyl)-2-methylpropanoic acid (106) (80 mg, 0.197 mmol) in tetrahydrofuran/methanol (2:1, 2 mL) was added sodium borohydride (15 mg, 0.393 mmol). After the reaction was stirred at room temperature for 1.5 hours water was added and the solution was extracted with ethyl acetate, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to yield 3-(4-((5-chloro-3-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)-3-fluorophenyl)-2-methylpropanoic acid (109). 1H NMR (400 MHz, CDCl3) δ 7.40 (s, 1H), 7.31 (s, 1H), 6.92 (m, 2H), 6.82 (d, J=12.0 Hz, 1H), 5.04 (s, 2H), 4.75 (s, 1H), 2.93 (m, 1H), 2.71 (m, 1H), 2.64 (m, 1H), 1.49 (s, 3H), 1.34 (s, 3H), 1.18 (d, J=6.9 Hz, 3H). LC-MS ESI m/z: found 407.3 [M−H]−.