Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.[C:12]1([NH2:22])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>O>[CH:7]1[CH:6]=[C:5]2[C:10]([CH:1]=[C:2]([NH:22][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)[CH:3]=[CH:4]2)=[CH:9][CH:8]=1
Reactant: Nc1cccc2ccccc12
Reactant: Oc1ccc2ccccc2c1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Product: c1ccc2cc(Nc3cccc4ccccc34)ccc2c1
Reaction time: 3 h
Yield: 96 %

Procedure:
144 parts of β-naphthol, 143 parts of α-naphthylamine and 10 parts of triphenyl phosphite are mixed. A homogeneous melt is formed at 120° C internal temperature. The elimination of water commences when the internal temperature reaches 230° C and has ended after 3 hours, at an internal temperature of 250° C. 18 parts of water have distilled off. 258 parts of 1,2'-dinaphthylamine, of melting point 106° - 108° C, are obtained by distillation at 239° C/0.1 mm Hg. This corresponds to a yield of 96% of theory.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:21]=[CH:22][C:23]5[O:27][C:26]([C:28]([O:30]C)=O)=[CH:25][C:24]=5[CH:32]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.Cl.[CH3:34][NH2:35]>>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:21]=[CH:22][C:23]5[O:27][C:26]([C:28]([NH:35][CH3:34])=[O:30])=[CH:25][C:24]=5[CH:32]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4ccc5c(c4)OCCO5)n3)ccc2o1
Reactant: CN
Agent: Cl
Product: CNC(=O)c1cc2cc(Nc3ncc(F)c(Nc4ccc5c(c4)OCCO5)n3)ccc2o1

Procedure:
In like manner to preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine, the reaction of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine and methylamine hydrochloride gave N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 8.06 (s, 1H), 7.85 (d, 1H, J=3.3 Hz), 7.42 (d, 2H, J=1.2 Hz), 7.35 (s, 1H), 7.29 (d, 1H, J=2.4 Hz). 6.99 (dd, 1H, J=3.3 and 8.7 Hz), 6.78 (d, 1H, J=8.7 Hz), 4.24 (s, 4H), 2.94 (s, 3H); LCMS: ret. time: 18.05 min.; purity: 99%; MS (m/e): 436 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:15]=1[O:23][CH3:24])(=[O:13])=[O:12])[C:6](=[O:25])[C:5]2([CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[NH:26][CH3:27].CO>[Ni].C1COCC1>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([S:11]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)[C:5]([CH2:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)([NH:26][CH3:27])[C:6]2=[O:25])(=[O:12])=[O:13])=[C:15]([O:23][CH3:24])[CH:16]=1
Reactant: CNC1(CC2CCCCC2)C(=O)N(S(=O)(=O)c2ccc([N+](=O)[O-])cc2OC)c2ccc(Cl)cc21
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: CNC1(CC2CCCCC2)C(=O)N(S(=O)(=O)c2ccc(N)cc2OC)c2ccc(Cl)cc21
Reaction time: 0.67 h
Yield: 53.1 %

Procedure:
A mixture of 1.2 g of the compound obtained in EXAMPLE 102, 3 g of Raney® nickel, 30 ml of MeOH and 40 ml of THF is hydrogenated at atmospheric pressure and at RT. After 40 minutes, the catalyst is filtered off on Celite® and the filtrate is evaporated under vacuum. The residue is chromatographed on silica using DCM and then a DCM/AcOEt mixture (75/25; v/v) as the eluent to give 0.6 g of the expected product, which is used as such in the next step.
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:10]=[N:9][N:8]([CH2:11][C:12]2[O:16][C:15]([CH:17]([OH:19])[CH3:18])=[CH:14][CH:13]=2)[N:7]=1)([O-:5])=[O:4]>C(C#N)(C)=O.O=[Mn]=O>[N+:3]([C:6]1[CH:10]=[N:9][N:8]([CH2:11][C:12]2[O:16][C:15]([C:17](=[O:19])[CH3:18])=[CH:14][CH:13]=2)[N:7]=1)([O-:5])=[O:4]
Reactant: CC(O)c1ccc(Cn2ncc([N+](=O)[O-])n2)o1
Agent: O=[Mn]=O
Agent: CC(=O)C#N
Agent: N#N
Product: CC(=O)c1ccc(Cn2ncc([N+](=O)[O-])n2)o1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-[5-(4-nitro-[1,2,3]triazol-2-ylmethyl)-furan-2-yl]-ethanol (98 mg, 0.41 mmol) in AcCN (4.0 mL) was treated at rt with MnO2 (238 mg, 2.47 mmol) and the reaction mixture was stirred for 2 days at rt before being filtered though Celite. The solvent was removed under reduced pressure to give the title compound as a white solid. LC-MS-conditions 02: tR=0.86 min.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C.Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O.C(OCC)C.O1CCOCC1>[ClH:12].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[NH2:11])=[CH:15][CH:14]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: COc1ccc(NN)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-Methoxyphenylhydrazine hydrochloride (10.0 g, 57.3 mmol), 4-chlorobenzylchloride (9.2 g, 57.2 mmol), tetrabutylammonium bromide (3.7 g, 11.5 mmol), and diisopropylethylamine (2 mL, 115 mmol) in CH2Cl2 (250 mL) was stirred at room temperature for several days. The reaction mixture was diluted with water and the organic layer was dried over MgSO4, filtered, and concentrated. The residue was taken up in toluene (200 mL) and diethyl ether (100 mL), and 1 equivalent of 4N HCl in dioxane was added at 0° C. The mixture was stirred at room temperature for 2 hours, and then evaporated to dryness to give the desired product (C-1; X═Cl) as a purple solid.
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:33]1([CH2:39][CH2:40][S:41][CH:42]([C:46](O)=[O:47])[C:43](O)=[O:44])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[OH:47][C:46]1[CH:16]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:8])=[CH:10][CH:11]=2)[O:17][C:43](=[O:44])[C:42]=1[S:41][CH2:40][CH2:39][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Reactant: CC(=O)c1ccc(S(=O)c2ccccc2)cc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc(S(=O)c3ccccc3)cc2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-(phenylsulfinyl)acetophenone (2.50 g, 10.24 mmol), lithium bis(trimethylsilyl)amide (2.57 g, 15.36 mmol), chlorotrimethylsilane (1.94 mL, 15.36 mmol), THF (100 mL), and diethyl ester of [(2-phenylethyl)thio]-propanedioic acid (1.00 g, 3.37 mmol). m.p. 171°-173° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.76 (t, 2 H), 3.01 (t, 2 H), 6.83 (s, 1 H), 7.19 (m, 5 H), 7.54 (m, 3 H), 7.75 (d, 2 H), 7.86 (d, 2 H), 7.95 (d, 2 H), 12.05 (bs, 1 H).
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])[CH3:14].[OH-].[Na+]>C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1>[C:16]1([C@@H:13]([OH:15])[CH3:14])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)c1ccccc1
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Product: C[C@H](O)c1ccccc1
Temperature: 30 °C
Reaction time: 20 h
Yield: 97.4 %

Procedure:
Culture fluid was obtained by cultivating E. coli HB101 (pNCMG) in a similar manner to Example 9. In a 100-mL portion of the culture fluid, 17 g of glucose, 3 mg of NAD+, and 10 g of acetophenone were added and the mixture was stirred at 30° C. for 20 hours while controlling the pH of the reaction mixture to 6.5 with 5 N aqueous sodium hydroxide, which was added dropwise to the mixture. After the reaction, the reaction mixture was extracted with toluene, and combined organic layer was dried over anhydrous sodium sulfate. Removal of sodium sulfate, and evaporation of organic solvents from the organic layer under reduced pressure yielded 9.9 g of (S)-phenylethanol. The product (S)-phenylethanol was analyzed in accordance with the [Analysis condition (1) for gas chromatography] as described above, and found that the optical purity of the product was 99.9% e.e. or higher.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([F:23])=[CH:20][CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[NH:24]1[CH2:29][CH:28]=[C:27]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][CH:31]=2)[CH2:26][CH2:25]1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O1CCCC1>[F:23][C:19]1[C:17]2[O:18][CH:13]([CH2:12][N:24]3[CH2:25][CH:26]=[C:27]([C:30]4[C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[NH:32][CH:31]=4)[CH2:28][CH2:29]3)[CH2:14][O:15][C:16]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3cccc(F)c3O2)cc1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Fc1cccc2c1OC(CN1CC=C(c3c[nH]c4ccccc34)CC1)CO2

Procedure:
[(2R)-8-Fluoro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl 4-methylbenzenesulfonate (1.2 g, 3.5 mmole) was dissolved in a mixture of dimethylformamide/tetrahydrofuran (1:1 v/v, 30 mL) and 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.60 g, 3.0 mmole) added, followed by the addition of sodium bicarbonate (0.60 g, 7.1 mmole) and the mixture refluxed under nitrogen for 18 hours. The solvent was evaporated in vacuum, and the residue partitioned between 400 mL each of methylene chloride and water. The organic phase was dried over magnesium sulfate and filtered. The filtrate was evaporated and the residue chromatographed on silica gel using 4% methanol in chloroform as eluant. The product fractions were combined and concentrated in vacuum to give 0.20 g (16%) of the (S)-enantiomer of the title compound as a yellow solid, m.p. 174–177° C.
Reaction SMILES: C[N:2]([CH:4]=[O:5])C.[CH3:6][C:7]([C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1C(O)=O)([CH3:16])[CH2:8][C@:9]1([C:12]([F:15])([F:14])[F:13])[CH2:11][O:10]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[OH-].[NH4+]>C(=O)(O)[O-].[Na+]>[CH3:16][C:7]([C:17]1[CH:18]=[CH:22][CH:23]=[CH:24][C:25]=1[C:4]([NH2:2])=[O:5])([CH3:6])[CH2:8][C@:9]1([C:12]([F:13])([F:14])[F:15])[CH2:11][O:10]1
Reactant: CC(C)(C[C@]1(C(F)(F)F)CO1)c1ccccc1C(=O)O
Reactant: CN(C)C=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Product: CC(C)(C[C@]1(C(F)(F)F)CO1)c1ccccc1C(N)=O
Reaction time: 0.5 h

Procedure:
A stirred, ice-cooled, DMF (60 mL) solution of the 2-[1,1-dimethyl-2-((R)-2-trifluoromethyloxiranyl)ethyl]benzoic acid (8.5 g, ˜80%, 23.6 mmol) triethylamine (6.6 mL, 47.2 mmol) was added and after 2-3 minutes TBTU (8.3 g, 26 mmol) was added. After stirring for 30 minutes, ammonium hydroxide solution (7 mL, 98 mmol) was added and stirred for 40 minutes. The reaction mixture was diluted with 500 mL of saturated aqueous sodium bicarbonate solution and extracted with three 200 mL portions of dichloromethane. The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and the solvent evaporated in vacuo to give 2-[1,1-dimethyl-2-((R)-2-trifluoromethyloxiranyl)ethyl]benzamide as a colorless thick oil which solidified on standing (6.0 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([CH2:13][NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>C1COCC1.CO.O>[Cl:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([CH2:13][NH:14][C:15](=[O:20])[C:16]([CH3:18])([CH3:17])[CH3:19])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(CNC(=O)C(C)(C)C)c(F)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)C(=O)NCc1cc(C(=O)O)c(Cl)cc1F
Yield: 83.8 %

Procedure:
The title compound was prepared following the procedure described in step-3 of Intermediate-2 using methyl 2-chloro-4-fluoro-5-(pivalamidomethyl)benzoate (250 mg, 0.83 mmol) in THF:MeOH:H2O (3:2:1; 6 mL) and NaOH (66 mg, 1.66 mmol) to afford 200 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.17-8.14 (t, J=6.0 Hz, 1H), 7.76-7.73 (d, J=8.4 Hz, 1H), 7.53-7.50 (d, J=9.9 Hz, 1H), 4.26 (d, J=5.7 Hz, 2H), 1.12 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[Cl:16][C:17]1[CH:18]=[C:19]([N:25]=[C:26]=[O:27])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:26]([NH:25][C:19]3[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([Cl:16])[CH:18]=3)=[O:27])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: COc1ccc(N=C=O)cc1Cl
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Product: COc1ccc(NC(=O)NC2CCCc3c2[nH]c2ccc(Br)cc32)cc1Cl

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-(3-chloro-4-methoxyphenyl)urea was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and 3-chloro-4-methoxyphenyl isocyanate in a similar manner as described above to give a tan solid (42% yield). 1H-NMR (DMSO-d6): δ 10.98 (s, 1H), 8.33 (s, 1H), 7.73 (d, 1H), 7.60 (d, 1H), 7.30 (d, 1H), 7.25-7.14 (m, 2H), 7.08 (d, 1H), 6.63 (d, 1H), 5.01 (m, 1H), 3.82 (s, 3H), 2.65 (m, 2H), 2.04 (m, 1H), 1.94-1.76 (m, 3H); MS m/z 448 (M−1).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[C:5]([CH2:7][CH2:8][CH3:9])[N:6]=1.[Cl:18][C:19]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:21]2[C:22]([O:24][C:25](=[O:26])[C:20]=12)=[O:23]>>[NH2:1][C:2]1[S:3][C:4]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:22]([C:21]3[C:27]([Cl:30])=[CH:28][CH:29]=[C:19]([Cl:18])[C:20]=3[C:25]([OH:26])=[O:24])=[O:23])=[CH:15][CH:16]=2)=[C:5]([CH2:7][CH2:8][CH3:9])[N:6]=1
Reactant: O=C1OC(=O)c2c(Cl)ccc(Cl)c21
Reactant: CCCc1nc(N)sc1Cc1ccc(N)cc1
Product: CCCc1nc(N)sc1Cc1ccc(NC(=O)c2c(Cl)ccc(Cl)c2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.9 %

Procedure:
1.9 g of 2-amino-5-(4-aminobenzyl)-4-propylthiazole (7.65 mmol) and 1.7 g of 3,6-dichlorophthalic anhydride are reacted under the conditions of Example 26. The reaction mixture is stirred for one day at room temperature. After concentration, a beige solid is obtained which is triturated in ether to give 2.2 g of 2-[4-(2-amino-4-propylthiazol-5-ylmethyl)phenylaminocarbonyl]-3,6-dichlorobenzoic acid in the form of a beige powder melting at 153° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:15]=[CH:14][C:7]([C:8](N(OC)C)=[O:9])=[CH:6][CH:5]=1.[CH2:17]([Mg]Cl)[CH2:18][CH3:19]>C1COCC1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:5]=[CH:6][C:7]([C:8](=[O:9])[CH2:17][CH2:18][CH3:19])=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(C(=O)N(C)OC)cc1
Reactant: CCC[Mg]Cl
Solvent: C1CCOC1
Product: CCCC(=O)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
To a solution of N-methoxy-N-methyl-terephthalamic acid methyl ester (4.56 g, 20.4 mmol) in THF (100 mL) is added PrMgCl (2.0M, 30.6 mmol) at 0° C., the reaction is warmed to room temperature, stirred overnight, quenched by NH4Cl aqueous solution, extracted with ethyl acetate. The combined organic layers are washed with brine, dried over sodium sulfate, concentrate. Column chromatography on silica gel gives the title compound (1 g, 23.7%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH2:12][CH3:13])[N:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[N:7]=1)=[O:5])C.C1COCC1.O>>[CH2:11]([C:9]1[N:8]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31]([C:32]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]=[N:29][N:28]=3)=[CH:19][CH:20]=2)[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=1)[CH2:12][CH3:13]
Reactant: CCCc1cc(C(=O)OCC)nn1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCc1cc(C(=O)O)nn1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 88.8 %

Procedure:
5-Propyl-1-[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1H-pyrazole-3-carboxylic acid ethyl ester (400 mg, 607 μmol) was dissolved in THF (12.0 mL, 148 mmol). A solution of LiOH monohydrate (127 mg, 3.04 mmol) in water (4.0 mL, 222 mmol) was then added and the mixture was stirred at room temperature for about 19 hours. The mixture was then heated to 60° C. overnight. LCMS showed that the reaction was complete, but that two additional side products had also formed. The mixture was partitioned between EtOAc and a saturated ammonium chloride solution. The EtOAc layer was dried over Na2SO4 and concentrated to yield the title compound (340 mg). LCMS showed that the side products were no longer present.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([N:10]1[CH:14]=[CH:13][N:12]=[N:11]1)=[CH:6]N(C)C)C.C([O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[N:22][CH:21]=1)C.C[O-].[Na+].Cl>C(O)(=O)C.C(O)C.CO>[O:3]=[C:4]1[N:26]([C:23]2[N:22]=[CH:21][C:20]([C:19]([OH:18])=[O:28])=[CH:25][CH:24]=2)[NH:27][CH:6]=[C:5]1[N:10]1[CH:14]=[CH:13][N:12]=[N:11]1
Reactant: CCOC(=O)c1ccc(NN)nc1
Reactant: CCOC(=O)C(=CN(C)C)n1ccnn1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)c1ccc(-n2[nH]cc(-n3ccnn3)c2=O)nc1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
491 mg (1.8 mmol, 80% purity) of the compound from Example 3A and 289 mg (1.6 mmol) 6-hydrazinonicotinic acid ethyl ester [for the preparation see WO 2006/114213] are stirred in 10 ml acetic acid at RT for 12 h. Thereafter, 120 mg (0.7 mmol) 6-hydrazinonicotinic acid ethyl ester are again added to the reaction mixture and the mixture is stirred again at RT for 13 h. After standing at RT for a further two days, the reaction solution is concentrated in vacuo, the residue is taken up in ethyl acetate, the mixture is washed neutral with saturated sodium bicarbonate solution and the organic phase is dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The intermediate product obtained in this way is dissolved in 10 ml ethanol, 0.3 ml (1.8 mmol) of a 30% strength sodium methylate solution in methanol are added and the mixture is stirred at RT for 17 h. The reaction solution is adjusted to pH 5 with 1 N hydrochloric acid and is subsequently stirred at RT for a further 2 h. It is concentrated in vacuo, acetonitrile is added to the residue, the precipitate which has separated out is filtered off and the residue on the filter is washed with diethyl ether and dried in vacuo. 9.4 ml 0.1 M ethanolic potassium hydroxide solution are added to the ester obtained in this way and the mixture is stirred at RT for 16 h. The reaction solution is adjusted to pH 2 with 1 N hydrochloric acid, the solvent is removed on a rotary evaporator, the residue is taken up in water and the mixture is extracted with ethyl acetate. The crystals which have precipitated out from the aqueous phase are filtered off, the residue on the filter is washed with diethyl ether and the product is dried in vacuo.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.Cl[CH:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13](Cl)=[O:14]>>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:7][C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:13]([OH:14])[N:8]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(N)=S)cc1
Reactant: O=C(Cl)C(Cl)c1ccccc1
Product: Cc1ccc(-c2nc(O)c(-c3ccccc3)s2)cc1

Procedure:
The title compound was prepared according to the method of Scheme II in a manner analogous to Example 31 except 4-methylthiobenzamide was used instead of thiobenzamide and 2-chloro-2-phenylacetyl chloride was used instead of 2-bromopropionate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:13])([CH3:12])[C:10]#N)[CH:6]=[CH:7][CH:8]=1.[H-].C([Al+]CC(C)C)C(C)C.[OH:24]S(O)(=O)=O>C1COCC1.CCCCCCC.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:13])([CH3:12])[CH:10]=[O:24])[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(O)O
Reactant: COc1cccc(C(C)(C)C#N)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C(C)(C)C=O)c1
Temperature: 25 °C

Procedure:
To a ice cold stirred solution of 2-(3-methoxyphenyl)-2-methylpropanenitrile (27.7 g, 158 mmoles) in 250 mL of THF was added dropwise diisobutylaluminum hydride in heptane (202 mL, 1.0M solution). The mixture was allowed to warm to room temperature overnight. After cooling, a solution of concentrated H2SO4 (21.5 mL) in 85 mL of water was cautiously added in small portions. The resulting mixture was partitioned between Et2O and water, the aqueous layer further extracted, and the combined organic extracts dried over Na2SO4, filtered, and evaporated to give 2-(3-methoxyphenyl)-2-methylpropanal, 21.7 g, as an oil.
Reaction SMILES: [O:1]=[S:2]1(=[O:34])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C:11](=[O:33])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:15]([O:22]C)=[C:14]([C:24]([N:26]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27]3)=[O:25])[CH:13]=2)[CH2:3]1.[Cl-].[Li+].Cl>CN(C)C=O>[O:34]=[S:2]1(=[O:1])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C:11](=[O:33])[C:12]2[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[C:15]([OH:22])=[C:14]([C:24]([N:26]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27]3)=[O:25])[CH:13]=2)[CH2:3]1
Reactant: COc1c(C(=O)N2CCS(=O)(=O)C2)cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc1C(F)(F)F
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C(c1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(C(F)(F)F)c1O)N1CCS(=O)(=O)C1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 47.4 %

Procedure:
1,1-dioxo-3-[3-(1,1-dioxo-1,3-thiazolidine-3-carbonyl)-4-methoxy-5-trifluoromethylbenzoyl]-2,3-dihydro-1,3-benzothiazole (260 mg) was dissolved in N,N-dimethylformamide (2.5 mL), and lithium chloride (200 mg) was added to the solution, and then the mixture was stirred at 120° C. for 1.5 hours. To the reaction solution, 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was crystallized from n-hexane-chloroform to obtain the title compound (120 mg) as a pale yellow crystal.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17]1.B.N1C=CC=CC=1C>CO.CC(O)=O>[CH:16]1([NH:15][C:12]2[CH:11]=[CH:10][C:9]([C:8]#[C:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:14][N:13]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C1CCCC1
Reactant: Nc1ccc(C#Cc2ccccc2)cn1
Agent: B
Solvent: Cc1ccccn1
Solvent: CO
Solvent: CC(=O)O
Product: C(#Cc1ccc(NC2CCCC2)nc1)c1ccccc1
Temperature: 40 °C
Reaction time: 48 h

Procedure:
5-Phenylethynyl-pyridin-2-ylamine (100 mg, 0.515 mmol), cyclopentanone (77 mg, 0.927 mmol) and 2-picoline borane (85 mg, 0.927 mmol) were dissolved in 5.5 ml MeOH:AcOH (10:1 v/v) and stirred for 48 hours at 40° C. MeOH was then evaporated and the residue was acidified to pH 1 with 6 ml 10% HCl. The resulting white suspension was stirred for 2 hours. The mixture was extracted with dichloromethane and brine. The pH of the aqueous layer was adjusted to 12 by addition of conc. NaOH and the mixture was extracted twice with dichloromethane. The organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silicagel (heptane/ethyl acetate 100:0→50:50 gradient). The desired compound was obtained as a light yellow solid (70 mg, 53%), MS: m/e=263.3 (M+H+).