Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2([OH:28])[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25](Cl)[N:24]=[CH:23][N:22]=3)[CH2:17][CH2:16]2)[C:10](=[O:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2([OH:28])[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][N:22]=3)[CH2:17][CH2:16]2)[C:10](=[O:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(CC2(O)CCN(c3cc(Cl)ncn3)CC2)C(=O)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(CC2(O)CCN(c3ccncn3)CC2)C(=O)C1
Reaction time: 8 h
Yield: 71 %

Procedure:
In ethanol (30 ml) was dissolved 4-(tert-butoxycarbonyl)-1-[1-(6-chloro-4-pyrimidinyl)-4-hydroxypiperidin-4-ylmethyl]piperazin-2-one (808 mg), and to the solution was added 10% palladium on carbon (containing 50% water, 242 mg). Under hydrogen atmosphere, the mixture was vigorously stirred overnight, and the catalyst was removed. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (eluent:methanol/ethyl acetate=1/10) to give colorless amorphous of 4-(tert-butoxycarbonyl)-1-[4-hydroxy-1-(4-pyrimidinyl)piperidin-4-ylmethyl]piperazin-2-one (527 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][CH2:27][C:28]1([NH2:32])[CH2:31][CH2:30][CH2:29]1>>[NH2:32][C:28]1([CH2:27][NH:26][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=[C:4]([N:13]3[CH2:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]3)[CH:3]=2)[CH2:31][CH2:30][CH2:29]1
Reactant: NCC1(N)CCC1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(N)CCC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 1-(aminomethyl)cyclobutanamine. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (m, J=2.0 Hz, 1 H), 7.86 (d, J=1.8 Hz, 1 H), 7.70 (s, 1 H), 7.61 (t, J=3.6 Hz, 1 H), 7.45 (m, J=3.0 Hz, 2 H), 7.30 (m, J=2.5 Hz, 1 H), 6.13 (s, 1 H), 5.18 (s, 2 H), 4.53 (br. s., 2 H), 3.59 (t, J=2.3 Hz, 2 H), 3.46 (s, 2 H), 2.43 (s, 3 H), 2.28-2.22 (m, J=6.3 Hz, 2 H), 2.12-2.03 (m, J=9.2 Hz, 2 H), 1.97-1.82 (m, J=14.7 Hz, 2 H).
Reaction SMILES: [F:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[CH:15]([CH3:16])[C:14](=[O:17])[C:13]([CH3:19])([CH3:18])[C:12]2=[O:20])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].C1COCC1>>[F:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[C@H:15]([CH3:16])[C@H:14]([OH:17])[C:13]([CH3:19])([CH3:18])[C:12]2=[O:20])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1c(N2C(=O)C(C)(C)C(=O)C2C)ccc(C#N)c1F
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(N2C(=O)C(C)(C)[C@@H](O)[C@H]2C)ccc(C#N)c1F

Procedure:
Using 2-fluoro-3-methyl-4-(3,3,5-trimethyl-2,4-dioxopyrrolidin-1-yl)benzonitrile (60 mg) and lithium tri(sec-butyl)borohydride-THF solution (0.33 mL, 1 mol/L), and in the same manner as in Example 5, the title compound was obtained as colorless crystals (yield: 41.4 mg, 69%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([C:37]1([O:40]C(=O)C)[CH2:39][CH2:38]1)=[O:36]>>[OH:40][C:37]1([C:35]([NH:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=5[O:29][CH2:30][CH:31]5[CH2:33][CH2:32]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:36])[CH2:39][CH2:38]1
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)cc1F
Reactant: CC(=O)OC1(C(=O)Cl)CC1
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)C5(O)CC5)CC4)c[nH]c23)cc1F

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A139) and acetic acid 1-chlorocarbonyl-cyclopropyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:18][C:19]#[N:20])[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B#B.[ClH:23]>>[ClH:23].[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:18][CH2:19][NH2:20])[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Agent: B#B
Agent: Cl
Product: NCCc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1

Procedure:
2.7 g of (3-benzyloxy-4-nitrophenyl)acetonitrile is reduced with diborane, as described in the preparation of 2-benzyloxy-5-(2-dipropylamino)aniline, and converted into the hydrochloride, thus obtaining 3.2 g of 2-(3-benzyloxy-4-nitrophenyl)ethylamine, hydrochloride.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:19])=[C:4]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH:6]([CH3:17])[C:5]2=[O:18].ClC=C1C2(CCC2)OC2C(=C(C)C(O)=C(C)C=2C)C1=O.[BH4-].[Na+]>CO>[CH3:17][CH:6]1[C:7]2([CH2:10][CH2:9][CH2:8]2)[O:11][C:12]2[C:4](=[C:3]([CH3:19])[C:2]([OH:1])=[C:14]([CH3:15])[C:13]=2[CH3:16])[CH:5]1[OH:18]
Reactant: Cc1c(C)c2c(c(C)c1O)C(=O)C(C)C1(CCC1)O2
Agent: Cc1c(C)c2c(c(C)c1O)C(=O)C(=CCl)C1(CCC1)O2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1O)C(O)C(C)C1(CCC1)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-hydroxy-3,5,7,8-tetramethylspiro[chromene-2,1′-cyclobutan]-4(3H)-one, prepared by reduction of 3-(chloromethylene)-6-hydroxy-5,7,8-trimethylspiro[chromene-2,1′-cyclobutan]-4(3H)-one (see Example 19) (168 mg) in 10 mL of MeOH was added NaBH4 (250 mg). The reaction mixture was allowed to stir at room temperature for 1 hour to give 3,5,7,8-tetramethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutane]-4,6-diol. Subsequently 20 mL of MeOH was added to the reaction mixture, followed by 2 mL of conc. HCl. After 30 min, the reaction mixture was neutralized by adding saturated NaHCO3 and extracted with ethyl acetate. After drying it over anhydrous Na2SO4 and concentrating in vacuo, the residue was purified by flash chromatography eluted with 20% ethyl acetate in hexane to give 113.2 mg of 4-methoxy-3,5,7,8-tetramethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-ol as a yellow solid. 1H-NMR (300 MHz, CDCl3) δ=4.83 (s, 1H), 3.08 (s, 2H), 2.46 (s, 3H), 2.28 (s, 3H), 2.26 (s, 3H), 2.28-1.90 (m, 6H) ppm. 13C-NMR (75 MHz, CDCl3) δ=198.6, 149.9, 132.3, 131.8, 129.1, 128.8, 122.7, 57.9, 46.3, 35.1, 16.6, 15.7, 13.7, 13.3 ppm. MS: (m/z)=245.1 (M−OMe+).
Reaction SMILES: C([O:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=O)(=O)C.[C:17]([NH:19][C:20]([NH2:22])=[NH:21])#[N:18].[ClH:23]>O1CCOCC1>[ClH:23].[NH:19]([C:17]1[O:4][CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[N:18]=1)[C:20]([NH2:22])=[NH:21]
Reactant: N#CNC(=N)N
Reactant: CC(=O)OCC(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: C1COCCO1
Product: N=C(N)Nc1nc(-c2ccc([N+](=O)[O-])cc2)co1
Reaction time: 72 h

Procedure:
A solution of 90 gm of 4-nitro-phenacyl acetate and 33.9 gm of 1-cyano-guanidine in 200 ml of dioxane and 20 ml of 5N hydrochloric acid was stirred for 2 days at room temperature. A first crop of the product was filtered off; the solution, after the addition of another 40 ml of 5N hydrochloric acid, was stirred for 3 days and furnished a second crop of the product. The total yield of the title compound was 46 gm, m.p. >285° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]2[C:19](=[O:20])[NH:18]/[C:17](=[N:21]\[S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])/[C:4]2=[C:5]([S:9]CCC(OCC)=O)[S:6][C:7]=1[CH3:8].[OH-].[K+].Cl>C1COCC1.CO>[SH:9][C:5]1[S:6][C:7]([CH3:8])=[C:2]([CH3:1])[N:3]2[C:19](=[O:20])[NH:18]/[C:17](=[N:21]\[S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])/[C:4]=12
Reactant: CCOC(=O)CCSc1sc(C)c(C)n2c(=O)[nH]/c(=N\S(=O)(=O)c3ccc(C)cc3)c1-2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)/N=c2\[nH]c(=O)n3c(C)c(C)sc(S)c2-3)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
After ethyl 3-[[(1Z)-5,6-dimethyl-1-[[(4-methylphenyl)sulfonyl]imino]-3-oxo-2,3-dihydro-1H-imidazo[5,1-c][1,4]thiazin-8-yl]sulfanyl]propanoate (5.00 g, 10.4 mmol) synthesized in (iii) described above was dissolved in THF (50 ml) and methanol (50 ml), potassium hydroxide (2.74 g, 41.5 mmol) was added to the solution. The mixture was stirred at room temperature for 45 minutes. 1N Hydrochloric acid (42 ml) was added to and mixed with the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The formed precipitate was filtrated, washed with 50% methanol-water and dried to give red powders of the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>[N+](C1C=CC=CC=1)([O-])=O>[C:13]([C:4]1[CH:5]=[CH:6][C:1]([CH2:7][CH2:8][NH:9][C:10](=[O:12])[CH3:11])=[CH:2][CH:3]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)NCCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)NCCc1ccc(C(=O)c2ccccc2)cc1
Temperature: 50 °C
Yield: 34.3 %

Procedure:
N-(2-Phenylethyl)acetamide (49.01 mmol, 8.00 g) was introduced into nitrobenzene (40 ml). Benzoyl chloride (54.07 mmol, 7.60 g) was added thereto and then, at room temperature, aluminum tri-chloride (73.52 mmol, 9.80 g) was introduced in portions. The mixture was then heated at 50° C. for 8 h. The reaction mixture was poured into a mixture of ice and concentrated hydrochloric acid, and nitrobenzene was removed by steam distillation. The aqueous residue was extracted with ethyl acetate. The residue after concentration of the organic phase was chromatographed on silica gel (mobile phase dichloromethane/methanol (3% by volume)), resulting in 4.5 g of the title compound as orange oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])/[C:4](/[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]([CH3:23])=[N:21][N:20]=[N:19]2)=[C:14]([Cl:24])[CH:13]=1)=[CH:5]/[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3](=[O:25])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]([CH3:23])=[N:21][N:20]=[N:19]2)=[C:14]([Cl:24])[CH:13]=1)[CH2:5][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: COC(=O)/C(=C/C1CCCCC1)c1ccc(-n2nnnc2C)c(Cl)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C(CC1CCCCC1)c1ccc(-n2nnnc2C)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95.8 %

Procedure:
A solution of nickel (II) chloride hexahydrate (78 mg, 0.328 mmol) and (E)-2-[3-chloro4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-acrylic acid methyl ester (295 mg, 0.82 mmol) in methanol (8 mL) was cooled to 0° C. and lien treated with sodium borohydride (186 mg, 4.92 mmol) in four portions. After the addition, the black reaction mixture was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 24 h. The reaction mixture was then concentrated in vacuo, and the residue was diluted with water (30 mL) and ethyl acetate (50 mL). The two layers were separated. The organic layer was washed successively with a 3N aqueous hydrochloric acid solution (1×50 mL), a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford racemic 2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-propionic acid methyl ester (285 mg, 96%) as a viscous oil: EI-HRMS m/e calcd for C18H23ClN4O2 (M+) 362.1509, found 362.1516.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[CH3:23])[C:5](O)=[O:6].CN(C)C=O.C(Cl)([Cl:31])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[CH3:23])[C:5]([Cl:31])=[O:6]
Reactant: O=C(Cl)Cl
Reactant: CON=C(C(=O)O)c1ccccc1COc1cc(C)ccc1C
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CON=C(C(=O)Cl)c1ccccc1COc1cc(C)ccc1C
Reaction time: 5 h

Procedure:
To 232 g of a toluene solution containing 50.1 g (0.160 mol, E/Z=23/77) of α-methoxyimino-2-(2,5-dimethylphenoxymethyl)phenylacetic acid produced in accordance with Example 5-(1) and 0.117 g (0.0016 mol) of dimethylformamide was added dropwise a mixed solution of 23.8 g (0.240 mol) of phosgene and 45.1 g of toluene over 5 hours while keeping at 60°-65° C., and the reaction was subsequently allowed to proceed at the same temperature for 5 hours, which afforded 239.0 g of a toluene solution of α-methoxyimino-2-(2,5-dimethylphenoxymethyl)phenylacetyl chloride.
Reaction SMILES: CS[CH:3]1[CH2:12][CH:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH2:10]2)[C:5](=O)[C:4]1=[CH:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.[CH3:28][NH:29][NH2:30].O>C(O)C>[C:24]([O:23][C:21]([N:18]1[CH2:17][CH2:16][N:15]([C:14]2[C:4]3[CH2:3][CH2:12][C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[C:5]=3[N:29]([CH3:28])[N:30]=2)[CH2:20][CH2:19]1)=[O:22])([CH3:25])([CH3:27])[CH3:26]
Reactant: CSC1CC2CC=CC=C2C(=O)C1=CN1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CNN
Solvent: CCO
Solvent: O
Product: Cn1nc(N2CCN(C(=O)OC(C)(C)C)CC2)c2c1-c1ccccc1CC2
Yield: 11 %

Procedure:
2-(Methylthio(4-(tert-butyloxycarbonyl)piperazin 1-yl)methylene-4,5-dihydro-2H-naphthalen-1-one (3.2 g, 8.2 mmol) and methylhydrazine (5 ml) were kept in ethanol (30 ml) for four days. Water (150 ml) was added, and the mixture extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine, dried (MgSO4), evaporated in vacuo, and purified by flash chromatography, eluting with hexane:ethyl acetate (4:1 v/v) to give 3-(4-(tert-butyloxycarbonyl)piperazin-1-yl)-4,5-dihydro-1-methyl-1H-benzo[g]indazole (342 mg, 11%) as a colourless oil; 1H NMR (360 MHz, CDCl3) δ 1.52 (9H, s, tBu), 2.67 (2H, t, J=7.3 Hz, CCH2CH2C), 2.94 (2H, t, J=7.3 Hz, CCH2CH2C), 3.15 (4H, t, J=5.1 Hz, NCH2), 3.61 (4H, t, J=5.1 Hz, NCH2), 4.15 (3H, s, Me), 7.22-7.34 (3H, m, ArH), 7.55 (1H, d, J=7.7 Hz, H-9). Iradiation at δ 4.15 gave a positive nOe to the doublet at δ 7.55, and the reverse; and 3-(4-(tert-butyloxycarbonyl)piperazin-1-yl)-4,5-dihydro-2-methyl-2H-benzo[g]indazole (561 mg, 19%) as a white solid δ (360 MHz, CDCl3) 1.54 (9H, s, tBu), 2.86 (2H, t, J=7.8 Hz, CCH2CH2C), 2.95 (2H, t, J=7.8 Hz, CCH2CH2C), 3.08 (4H, t, J=4.9 Hz, NCH2), 3.60 (4H, t, J=4.9 Hz, NCH2), 7.20-7.30 (3H, m, ArH), 7.83 (1H, d, J=7.5 Hz, H-9).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=3[O:26][CH3:27])=[CH:14][CH:13]=2)[CH:5]=1.[OH-].[K+]>CO>[F:25][C:21]1[C:22]([F:24])=[CH:23][C:18]([C:15]2[CH:14]=[CH:13][C:12]([O:11][CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:28])=[O:2])=[CH:17][CH:16]=2)=[C:19]([O:26][CH3:27])[CH:20]=1
Reactant: COC(=O)c1cccc(COc2ccc(-c3cc(F)c(F)cc3OC)cc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc(C(=O)O)c2)cc1
Yield: 97.3 %

Procedure:
3-(4′,5′-Difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-benzoic acid methyl ester (6.5 g, 16.92 mmol) and 2N KOH (33.84 mL, 67.68 mmol) in 100 mL MeOH were reacted as above to yield 6.1 g (97.4) of 3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-benzoic acid. LC-MS (ES) calculated for C21H16F2O4, 370.36; found m/z 369 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([O:17][CH2:18][C:19]([OH:21])=O)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([O:17][CH2:18][C:19]([Cl:24])=[O:21])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)COS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Product: O=C(Cl)COS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
A mixture of acid 13 (100 mg, 0.306 mmol) and thionyl chloride (1 ml) was heated at reflux for 1.5 h. The excess thionyl chloride was removed in vacuo and the resulting pale yellow/white solid dried under high vacuum at 50° C. for 1.5 h. The product acid chloride 14 was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:18])=[C:6]([S:8](NC2C=CC=CC=2)(=[O:10])=[O:9])[CH:7]=1.NC1C=CC=CC=1.[F:26][C:27]([F:36])([F:35])[C:28]1[CH:29]=[CH:30][C:31]([NH2:34])=[N:32][CH:33]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:18])=[C:6]([S:8]([NH:34][C:31]2[CH:30]=[CH:29][C:28]([C:27]([F:26])([F:35])[F:36])=[CH:33][N:32]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: O=S(=O)(Nc1ccccc1)c1cc(Br)ccc1Cl
Solvent: Nc1ccccc1
Product: O=S(=O)(Nc1ccc(C(F)(F)F)cn1)c1cc(Br)ccc1Cl

Procedure:
The titled compound is prepared as described for 5-Bromo-2-chloro-N-phenyl-benzenesulfonamide (Intermediate F, step 2), by replacing aniline in this procedure with 5-trifluoromethyl-pyridin-2-ylamine
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[CH:23][CH:24]=[O:25])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1ccc(-c2ccncc2)cc1
Product: O=CC=Cc1ccc(-c2ccncc2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(4-pyridinyl)-benzaldehyde (prepared as described in WO 9828264) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 210 (M+H)+.
Reaction SMILES: CS(C)=O.[C:5]([C:7]1[CH:8]=[CH:9][C:10]2[O:15][C:14]([CH3:17])([CH3:16])[CH2:13][N:12]([CH:18]3[CH2:22][CH2:21][CH2:20][CH:19]3[OH:23])[C:11]=2[CH:24]=1)#[N:6].C(N(CC)CC)C>C(Cl)Cl.C(Cl)(=O)C(Cl)=O.O>[C:5]([C:7]1[CH:8]=[CH:9][C:10]2[O:15][C:14]([CH3:17])([CH3:16])[CH2:13][N:12]([CH:18]3[CH2:22][CH2:21][CH2:20][C:19]3=[O:23])[C:11]=2[CH:24]=1)#[N:6]
Reactant: CC1(C)CN(C2CCCC2O)c2cc(C#N)ccc2O1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)CN(C2CCCC2=O)c2cc(C#N)ccc2O1
Reaction time: 0.03 h
Yield: 52.2 %

Procedure:
In 5 ml of methylene chloride was dissolved 0.2 ml of oxalyl chloride and at a constant temperature between -50° C. and -60° C., a solution prepared by dissolving 0.34 ml of dimethyl sulfoxide in 1 ml of methylene chloride was added dropwise. The mixture was stirred for 2 minutes, after which a solution of 0.54 g of 6-cyano-3,4-dihydro-2,2-dimethyl-4-(2-hydroxycyclopentan-1-yl)-2H-1,4-benzoxazine in 2 ml of methylene chloride was added dropwise. The mixture was further stirred for 15 minutes and 0.7 ml of triethylamine was added. The mixture was stirred for an additional 5 minutes, after which it was allowed to return to room temperature. The reaction mixture was diluted with 10 ml of water and extracted with methylene chloride. The extract was washed with aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recovered by filtration, washed with ethanol and recrystallized from ethyl acetate to give 0.28 g of 6-cyano-3,4-dihydro-2,2-dimethyl-4(2-oxocyclopentyl)-2H-1,4-benzoxazine.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:6].S(OC)(O[CH3:27])(=O)=O>CN(C)C=O>[CH3:3][O:4][C:5]([C:7]1[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[C:14]([C:15]=1[O:16][CH3:27])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:6]
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)c1c(O)c2ccccc2n1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(OC)c2ccccc2n1-c1ccccc1
Reaction time: 1 h

Procedure:
A suspension of 3.9 g (0.081 mole) of 50% sodium hydride/mineral oil in 85 ml of N,N-dimethylformamide under a nitrogen atmosphere was cooled in ice and treated portionwise over 90 minutes with 17.1 g (0.064 mole) of 3-hydroxy-1-phenyl-1H-indole-2-carboxylic acid methyl ester [P. Friedlander and K. Kunz, Chem. Ber., 55, 1597 (1922)]. The mixture was stirred in ice an additional one hour, 7.9 ml (10.5 g; 0.083 mole) of dimethyl sulfate was added dropwise over 15 minutes, the ice bath was removed, and stirring was continued for a total of 65 hours. The reaction mixture was added to 600 g of ice/water, acidified with 4.0N hydrochloric acid, and extracted with dichloromethane (4×250 ml). The combined organic layers were washed with water (3×500 ml), dried (anhydrous sodium sulfate), and evaporated to yield a crude residue of 3-methoxy-1-phenyl-1H-indole-2-carboxylic acid methyl ester, plus a small amount of N,N-dimethylformamide.
Reaction SMILES: [CH:1]([NH2:5])([CH2:3][CH3:4])[CH3:2].Br[CH:7]([CH2:9][CH2:10][CH3:11])[CH3:8].OS(O)(=O)=O.[OH-].[Na+]>C(O)C>[CH:1]([NH:5][CH:7]([CH2:9][CH2:10][CH3:11])[CH3:8])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)N
Reactant: CCCC(C)Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCC(C)NC(C)CC
Yield: 55.3 %

Procedure:
Into a 150 ml flask, provided with a reflux condenser, were placed 14.6 g of monosec.butylamine dissolved in 15.5 ml of C2H5OH. Added thereto was 30 g of 2-bromo-pentane. This mass was then boiled to reflux temperature for 10-12 hours and thereafter cooled down and neutralized with dilute H2SO4. The whole was then evaporated to dryness. The residue thus obtained was treated with an excess of a 15% NaOH solution and extracted with 3 successive portions of ethyl ether. The ether extracts were then combined and washed with H2O, dried or anhydrous Na2SO4, filtered and the ether removed by evaporation. The residue was distilled under atmospheric pressure and the fraction was gathered which passed over at 160° - 161°C. 15.75 g of N-sec.butyl,N-sec.amylamine were obtained thereby. The picrate shows a melting point of from 61°-63°C (crystals from petroleum ether). The analysis of the picrate gave: calculated C = 48.58%, found C = 48.22%; calculated H = 6.50%, found H = 6.4%.
Reaction SMILES: [N:1]([CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[F:15])=[O:6])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[NH2:1][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[F:15])=[O:6]
Reactant: COc1ccc(C(=O)CN=[N+]=[N-])c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CN)c(F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-azido-1-(2-fluoro-4-methoxyphenyl)ethanone (4.80 g, 25.36 mmol) in 100 mL of tetrahydrofuran were added triphenylphosphine (6.65 g, 25.36 mmol) and p-toluenesulfonic acid (14.5 g, 76.11 mmol), followed by stirring at room temperature for 16 hrs.