Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:21][O:22][CH2:23][C:24]3[C:29]4[N:30]([CH3:33])[N:31]=[N:32][C:28]=4[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=3)[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].C=O>FC(F)(F)C(O)=O.C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:21][O:22][CH2:23][C:24]3[C:29]4[N:30]([CH3:33])[N:31]=[N:32][C:28]=4[CH:27]=[C:26]([C:34]([F:37])([F:35])[F:36])[CH:25]=3)[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cn1nnc2cc(C(F)(F)F)cc(COCC3(c4ccc(F)cc4)CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CN1CCC(COCc2cc(C(F)(F)F)cc3nnn(C)c23)(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 4-(4-fluorophenyl)-4-(((1-methyl-5-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-7-yl)methoxy)methyl)piperidine-1-carboxylate (17 mg, 0.033 mmol) was dissolved in trifluoroacetic acid (25% in dichloromethane, 1 mL) and stirred at room temperature for 30 min. The reaction was concentrated, loaded onto a strong cation exchange cartridge in methanol, and flushed with several volumes of methanol which were discarded. The crude secondary amine was eluted in 2M ammonia and concentrated. The resulting residue was dissolved in acetonitrile (1 mL), cooled to 0° C., treated with sodium cyanoborohydride (4.1 mg, 0.065 mmol) and formalin (75 μl). After 5 min, the reaction was treated with 1 drop of acetic acid. The ice bath was removed and stirring continued for 1 h. The reaction was diluted with ether and washed with 1M sodium hydroxide. The ethereal was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which was discarded. The product was eluted with 2 M ammonia and concentrated to give 10.4 mg (73%) as a colorless film. 1H-NMR (CDCl3, 500 MHz) δ 8.28 (s, 1H), 7.42 (s, 1H), 7.12 (m, 2H), 6.89 (m, 2H), 4.69 (s, 2H), 4.08 (s, 3H), 3.44 (s, 2H), 2.51 (m, 2H), 2.19 (s, 3H), 2.12 (m, 4H), 1.89 (m, 2H). Mass spec.: 437.14 (MH)+.
Reaction SMILES: [Cl:1][C:2]([Cl:30])([Cl:29])[CH2:3][O:4][C:5](=[O:28])[C:6]([N:10]1[C@H:13]([S:14]SC2SC3C=CC=CC=3N=2)[C@@H:12]([O:25][CH3:26])[C:11]1=[O:27])=[C:7]([CH3:9])[CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.[C:56](OC(=O)C)(=[O:58])[CH3:57]>C(O)(=O)C>[Cl:30][C:2]([Cl:1])([Cl:29])[CH2:3][O:4][C:5](=[O:28])[C:6]([N:10]1[C@H:13]([S:14][C:56](=[O:58])[CH3:57])[C@@H:12]([O:25][CH3:26])[C:11]1=[O:27])=[C:7]([CH3:8])[CH3:9]
Reactant: CO[C@H]1C(=O)N(C(C(=O)OCC(Cl)(Cl)Cl)=C(C)C)[C@@H]1SSc1nc2ccccc2s1
Reactant: CC(=O)OC(C)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CO[C@H]1C(=O)N(C(C(=O)OCC(Cl)(Cl)Cl)=C(C)C)[C@@H]1SC(C)=O
Reaction time: 1.25 h

Procedure:
A solution of 3.26 g of 2-[(3S,4R)-4-(benzthiazol-2-yldithio)-3-methoxy-2-oxoazetidin-1-yl]-3-methylcrotonic acid 2,2,2-trichloroethyl ester in 36.3 ml of acetic anhydride and 12.4 ml of acetic acid is cooled to -15° and 1.7 g of triphenylphosphine are added. After stirring under nitrogen at the same temperature for 75 minutes, 24.8 ml of pyridine are added to the mixture. After stirring for a further 3 hours at 0°, the reaction mixture is concentrated by evaporation under reduced pressure and the resulting residue is purified by chromatography over silica gel with toluene and toluene/ethyl acetate (19:1). IR spectrum (in methylene chloride): characteristic absorption bands at 3.40, 5.63, 5.77, 5.80, 6.13, 7.25, 7.35, 8.26, 9.0, 9.52 and 11.90μ.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:11])[C:8]=1[O:9][CH3:10])[NH2:5].C(N(CC)CC)C.[CH3:19][O:20][CH2:21][C:22](Cl)=[O:23]>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([NH:5][C:22](=[O:23])[CH2:21][O:20][CH3:19])[CH:6]=[C:7]([CH3:11])[C:8]=1[O:9][CH3:10]
Reactant: COCC(=O)Cl
Reactant: COc1c(C)cc(N)cc1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)Nc1cc(C)c(OC)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
To a solution of 5.00 g (33 mmol) of 3,5-dimethyl-4-methoxyaniline and 7.1 ml of triethylamine in 50 ml of dichloromethane was dropwise added a solution of 4.31 g (40 mmol) of methoxyacetylchloride in 20 ml of dichloromethane under chilling with ice for a period of 30 min. The resulting mixture was stirred for 30 min. at room temperature. The reaction mixture was washed sequentially with 5 aqueous sodium carbonate and 3 N hydrochloric acid, and then dried over anhydrous sodium sulfate. Dichloromethane was distilled off. The residue was crystallized from ether hexane to obtain 6.70 g of the desired compound as a white crystal. (Yield: 90.7 %)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@:11]([F:14])([CH3:13])[CH2:10][C@H:9]1[C:15](=[O:28])[NH:16][C@@H:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[F:27])[CH2:18][OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29]COC(C)=O>>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@:11]([F:14])([CH3:13])[CH2:10][C@H:9]1[C:15](=[O:28])[NH:16][C@@H:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[F:27])[CH2:18][O:19][CH3:29])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1C[C@](C)(F)C[C@H]1C(=O)N[C@H](CO)c1cccc(Cl)c1F
Product: COC[C@@H](NC(=O)[C@@H]1C[C@@](C)(F)CN1C(=O)OC(C)(C)C)c1cccc(Cl)c1F

Procedure:
was prepared according to Scheme B9 (Step B) from (2S,4R)-2-[(S)-1-(3-chloro-2-fluoro-phenyl)-2-hydroxy-ethylcarbamoyl]-4-fluoro-4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester. TLC, Rf (EtOAc)=0.90; MS (UPLC-MS): 433.4/435.4 [M+H]+, 477.4 [M+HCOO]−; tR (HPLC conditions a): 3.73 min.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([CH2:7][CH2:8][CH2:9][S:10]([CH2:13][CH2:14]Cl)(=[O:12])=[O:11])(=[O:6])=[O:5].C1(C=CC(O)=CC=1)O.C(N(CC)CC)C>C(OCC)(=O)C>[CH:13]([S:10]([CH2:9][CH2:8][CH2:7][S:4]([CH:3]=[CH2:2])(=[O:6])=[O:5])(=[O:12])=[O:11])=[CH2:14]
Reactant: O=S(=O)(CCCl)CCCS(=O)(=O)CCCl
Agent: Oc1ccc(O)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)CCCS(=O)(=O)C=C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1,3-Bis(2-chloroethylsulfonyl)propane (74.5 g., 0.249 mole) was suspended in 2,300 ml. of ethyl acetate containing 0.12 g. hydroquinone. Triethylamine (50.7 g., 0.50 mole) was dropped in with stirring, within 10 minutes at 25° C. The resulting mixture was stirred at 25° C. for 20 hours. The amine salt was filtered off and the ethyl acetate solution evaporated at 30° C. The tan-colored solid was washed with water, then recrystallized from ethanol; yield 32.8 g. (59 percent); m.p. 60°-63° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:10][CH3:11])=[CH:4][N:3]=1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]2[N:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:28](=[O:29])[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:9]([CH2:10][CH3:11])[C:5]2=[CH:4][N:3]=1
Reactant: CCC(Nc1ccc(OC)cc1)c1cnc(Cl)nc1Cl
Reactant: O=C=Nc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCC1c2cnc(Cl)nc2N(c2ccccc2)C(=O)N1c1ccc(OC)cc1
Temperature: 110 °C

Procedure:
To a solution of (±)-[1-(2,4-dichloro-pyrimidin-5-yl)-propyl]-(4-methoxy-phenyl)-amine (0.19 g; 0.59 mmol) (from Example 7c supra) in toluene (2 mL) was added phenyl isocyanate (83 μL; 0.76 mmol) (Aldrich). The solution was heated in an oil bath at 110° C. for 1 hour. Upon cooling to room temperature, the reaction was concentrated. The residue was triturated with hexanes and then dried briefly under high vacuum. The solid residue (intermediate urea) was dissolved in freshly distilled tetrahydrofuran (2 mL), cooled to −3° C. and treated with potassium tert-butoxide (1.0 M in tetrahydrofuran; 0.65 mL; 0.65 mmol) (Aldrich). After 15 minutes in the cold, the reaction mixture was filtered through a silica gel pad (1 g) and washed with ethyl acetate. The filtrate was concentrated and purified by flash chromatography (Biotage, 40S, 20:80 to 40:60 ethyl acetate-hexanes gradient) to give (±)-7-chloro-4-ethyl-3-(4-methoxy-phenyl)-1-phenyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a solid. (Yield 0.14 g; 60.2%). The NMR of this material showed only two singlets for the pyrimidine proton indicating a mixture of the desired product and the corresponding 7-bromo compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1>CCO.[Pd]>[NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(N)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccnc(N)c1N
Reaction time: 36 h

Procedure:
To a slurry of 2-amino-4-methyl-3-nitropyridine (10.0 g, 65.3 mmol) in 350 ml of 95% EtOH was added 500 mg of a 10% Pd/C catalyst. The mixture was stirred under a H2 atmosphere (1 atm) for 36 hours. Filtration and evaporation gave a black solid which was used directly in the next step.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[N:4]=[N:5][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]([CH3:17])[CH3:16])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1.[CH3:18][C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][NH:20]1>>[ClH:2].[ClH:1].[ClH:2].[CH:15]([N:12]1[CH2:13][CH2:14][CH:9]([C:6]2[N:5]=[N:4][C:3]([C:23]3[CH:22]=[CH:21][N:20]=[C:19]([CH3:18])[CH:24]=3)=[CH:8][CH:7]=2)[CH2:10][CH2:11]1)([CH3:17])[CH3:16]
Reactant: CC1(B(O)O)C=CC=CN1
Reactant: CC(C)N1CCC(c2ccc(Cl)nn2)CC1
Agent: Cl
Product: Cc1cc(-c2ccc(C3CCN(C(C)C)CC3)nn2)ccn1

Procedure:
3-Chloro-6-(1-isopropylpiperidin-4-yl)pyridazine, hydrochloride (0.5 g, 1.6 mmol) and 2-methylpyridin boronic acid (0.241 g, 1.76 mmol) were mixed with catalyst and reacted in the same manner as in example 18. The title compound was isolated as white crystals of the trihydrochloride. Yield: 164 mg (25%).
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=1.C(=O)([O-])O.[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:28][C:25]1[CH:26]=[CH:27][C:22]([F:21])=[CH:23][C:24]=1[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2
Reactant: CC1(C)OB(c2cc(F)ccc2N)OC1(C)C
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cc(F)ccc3N)[nH]c2c1
Temperature: 25 °C
Yield: 95.4 %

Procedure:
To a suspension of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (2.35 g, 6.98 mmol) obtained in the same manner as in the method described in WO03/010140 and 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine (1.99 g, 8.38 mmol) in 1,2-dimethoxyethane (24 ml) and water (12 ml) were added sodium hydrogen carbonate (2.00 g, 24.0 mmol) and tetrakis(triphenylphosphine)palladium (400 mg, 0.34 mmol), and the mixture was heated under reflux for 14 hr. The mixture was allowed to cool to room temperature, and water was added to the reaction mixture. The mixture was extracted with ethyl acetate and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1-3:1) to give methyl 2-(2-amino-5-fluorophenyl)-3-cyclohexyl-1H-indole-6-carboxylate (2.44 g, yield 95.7%).
Reaction SMILES: [CH3:1][S-:2].[Na+].Br[C:5]1[C:13]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[N:8][N:9]2[CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1.O>CN(C)C=O>[CH3:1][S:2][C:5]1[C:13]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[N:8][N:9]2[CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1
Reactant: C[S-]
Reactant: Brc1c(OC2CCCCO2)ccc2c1cnn2C1CCCCO1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1c(OC2CCCCO2)ccc2c1cnn2C1CCCCO1
Temperature: 70 °C
Reaction time: 11 h
Yield: 81.3 %

Procedure:
Sodium thiomethoxide (0.0265 g, 0.38 mmol) was added to a solution of 4-bromo-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole (0.100 g, 0.26 mmol) in N,N-dimethylformamide (1 ml), and the resulting mixture was heated at 70° C. and stirred for 11 hours. The reaction solution was added to water and extracted three times with toluene/ethyl acetate=1/1, and the extract solution was dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by a silica gel chromatography (hexane/ethyl acetate=10/1) to obtain 4-(methylthio)-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole (0.0737 g, 80%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][S:17]2(=[O:22])=[O:21])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>ClCCl>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[O:22]=[S:17]1(=[O:21])[CH2:18][CH2:19][CH2:20][N:16]1[CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCN2CCCS2(=O)=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S1(=O)CCCN1CCN1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-[2-(1,1-Dioxo-isothiazolidine-2-yl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (2.01 g) was treated with 30% trifluoroacetic acid in dichloromethane (10 mL), and the mixture was stirred at room temperature for 30 min. The mixture was concentrated in vacuo to give 2.46 g of 1-[2-(1,1-dioxo-isothiazolidine-2-yl)-ethyl]-piperazine trifluoroacetate as a solid. LR-MS: 234 [(M+H)+]
Reaction SMILES: [C:1]([Si:5]([CH3:23])([CH3:22])[O:6][C@H:7]1[CH2:16][CH2:15][CH2:14][C@@:13]2([CH3:17])[C@H:8]1[CH2:9][CH2:10][CH2:11][C@@H:12]2[C@H:18]([CH3:21])[CH2:19][NH2:20])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]([F:34])([F:33])[C:26](O)([CH3:31])[CH2:27][C:28](O)=[O:29].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:1]([Si:5]([CH3:23])([CH3:22])[O:6][CH:7]1[CH2:16][CH2:15][CH2:14][C:13]2([CH3:17])[CH:8]1[CH2:9][CH2:10][CH2:11][CH:12]2[CH:18]([CH3:21])[CH2:19][NH:20][C:28](=[O:29])[CH:27]=[C:26]([CH3:31])[C:25]([F:34])([F:33])[F:24])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(O)(CC(=O)O)C(F)(F)F
Reactant: C[C@H](CN)[C@H]1CCC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(=CC(=O)NCC(C)C1CCCC2C(O[Si](C)(C)C(C)(C)C)CCCC12C)C(F)(F)F
Yield: 15.2 %

Procedure:
701 mg (2.06 mmol) of (S)-2-[(1R,4aR,5S,8aR)-5-(tert-Butyl-dimethyl-silanyloxy)-8a-methyl-decahydro-naphthalen-1-yl]-propylamine, 532 mg (1.5 eq.) of rac-3-trifluoromethyl-3-hydroxy-butyric acid, and 50 mg (0.2 eq.) of DMAP (N,N-dimethylaminopyridine) were dissolved in 20 ml of CH2Cl2. At 0° 680 mg (1.6 eq.) of DCC (dicyclohexylcarbodiimide) was added and the mixture allowed to react for 4 h at ambient temperature. The precipitated urea was filtered off and the filtrate evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=85/15) yielded in the less polar fractions 149 mg of unwanted 4,4,4-trifluoro-3-methyl-but-2-enoic acid {2-[5-(tert-butyl-dimethyl-silanyloxy)-8a-methyl-decahydro-naphthalen-1-yl]-propyl}-amide and in the more polar ones 811 mg of the title compound as colorless oil. Medium pressure chromatography of the latter (SiO2, hexane/AcOEt=90/10) gave in the less polar fractions 367 mg of the (R)-butyramide and in the more polar ones 314 mg of the (S)-isomer, both as white foam. For determination of abs. configuration see d] below.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:10][O:11][C:12]=1[CH3:13])=[O:7].Br.Br.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([OH:35])=[C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([OH:35])=[C:27]([N:29]2[CH2:30][CH2:31][N:32]([CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]3[C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[N:10][O:11][C:12]=3[CH3:13])=[O:7])[CH2:33][CH2:34]2)[CH:28]=1
Reactant: Oc1ccc(Cl)cc1N1CCNCC1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NCCCCl
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Cc1onc(-c2ccccc2)c1C(=O)NCCCN1CCN(c2cc(Cl)ccc2O)CC1
Temperature: 160 °C
Yield: 125.4 %

Procedure:
A mixture of 0.28 g of Compound 2B, 0.21 g of Compound 2A and 0.14 g of potassium carbonate was heated at 160° C. for 20 minutes. After cooling to room temperature, the mixture was taken up with 8 mL of chloroform, and inorganic matter was filtered off. The filtrate was evaporated to dryness and purified by flash chromatography (chloroform:methanol 97.5:2.5) to yield 0.32 g (71%) of the title compound. M.p. 92-98° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH:16]([F:18])[F:17])[C:12]([CH3:19])=[N:11]1.Br[CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O.C(OCC)C>[Br:8][C:6]1[CH:7]=[C:2]([Br:1])[C:3]([N:10]2[C:14](=[O:15])[N:13]([CH:16]([F:17])[F:18])[C:12]([CH3:19])=[N:11]2)=[CH:4][C:5]=1[O:9][CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: Cc1nn(-c2cc(O)c(Br)cc2Br)c(=O)n1C(F)F
Reactant: CCOC(=O)C(C)Br
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1cc(-n2nc(C)n(C(F)F)c2=O)c(Br)cc1Br
Reaction time: 2 h
Yield: 64.6 %

Procedure:
To a stirred solution of 1.25 g (0.0031 mole) of 1-(2,4-dibromo-5-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one in 60 mL of N,N-dimethylformamide was added 0.57 g (0.0033 mole) of ethyl 2-bromopropionate. The resultant mixture was heated at 130° . for two hours, then was cooled. The solvent was evaporated from the mixture under reduced pressure, leaving a solid. This solid was dissolved in diethyl ether, and the solution was washed first with water, then with an aqueous 10% sodium hydroxide solution. The organic solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 1.0 g of ethyl 2-[2,4-dibromo-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]propionate as an oil, Compound 8.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23](OC)=[O:24])[N:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[CH:28]1([CH2:31][NH2:32])[CH2:30][CH2:29]1>>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23]([NH:32][CH2:31][CH:28]3[CH2:30][CH2:29]3)=[O:24])[N:17]=[CH:16]4)[CH:12]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)Cn1ncc2cc(-c3cc(C(=O)NC4CC4)ccc3C)ccc21
Reactant: NCC1CC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(cnn2CC(=O)NCC2CC2)c1

Procedure:
Example 129 was prepared by General Method D using methyl (5-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-1H-indazol-1-yl)acetate (Example 117) and 1-cyclopropylmethanamine to give the title compound (0.015 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1F)[N:8]([CH:14]1[CH2:16][CH2:15]1)[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20].[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CN1CCCC1=O>[N:21]1([C:11]2[C:10]([CH3:13])=[C:9]3[C:4]([C:5](=[O:20])[C:6]([C:17]([OH:19])=[O:18])=[CH:7][N:8]3[CH:14]3[CH2:16][CH2:15]3)=[CH:3][C:2]=2[F:1])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: C1CNCCN1
Reactant: Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: CN1CCCC1=O
Product: Cc1c(N2CCNCC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 150 °C
Reaction time: 3 h
Yield: 2.7 %

Procedure:
6,7-Difluoro-1-cyclopropyl-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.8 g) is suspended in N-methylpyrrolidone (5 ml) and thereto is added piperazine (1.8 g), and the mixture is stirred at 150° C. for 3 hours. After the reaction, the reaction mixture is concentrated, and the resulting residue is purified by silica gel column chromatography (solvent, dichloromethane:methanol=3:1) to give 7-(1-piperazinyl)-1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.06 g), as white crystals, m.p. 291°-295° C. (decomp.).
Reaction SMILES: [CH2:1]([C@:3]1([OH:11])[CH2:7][CH2:6][NH:5][C@H:4]1[CH:8]([CH3:10])[CH3:9])[CH3:2].[F:12][C:13]1[CH:20]=[C:19](F)[CH:18]=[CH:17][C:14]=1[C:15]#[N:16].C(=O)([O-])[O-].[Li+].[Li+]>>[CH2:1]([C@:3]1([OH:11])[CH2:7][CH2:6][N:5]([C:19]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([F:12])[CH:20]=2)[C@H:4]1[CH:8]([CH3:10])[CH3:9])[CH3:2]
Reactant: N#Cc1ccc(F)cc1F
Reactant: CC[C@]1(O)CCN[C@H]1C(C)C
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@]1(O)CCN(c2ccc(C#N)c(F)c2)[C@H]1C(C)C

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-3-ethyl-2-isopropylpyrrolidin-3-ol 0.5 oxalate (162 mg), 2,4-difluorobenzonitrile (112 mg) and lithium carbonate (126 mg), the title compound was obtained as colorless oil (yield: 136 mg, yield: 62%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([O:15][CH2:16][C:17](O)=[O:18])=[CH:9][C:10]([C:11]([F:14])([F:13])[F:12])=[C:5]2[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:3]1.CC(C)N=C=NC(C)C.C1C=CC2N(O)N=NC=2C=1.[C:45]1([C@H:51]([CH3:54])[CH2:52][NH2:53])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CN(C=O)C>[CH3:1][N:2]1[C:6]2=[N:7][C:8]([O:15][CH2:16][C:17]([NH:53][CH2:52][C@H:51]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH3:54])=[O:18])=[CH:9][C:10]([C:11]([F:14])([F:12])[F:13])=[C:5]2[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:3]1
Reactant: Cn1nc(-c2ccccc2)c2c(C(F)(F)F)cc(OCC(=O)O)nc21
Reactant: C[C@H](CN)c1ccccc1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C[C@H](CNC(=O)COc1cc(C(F)(F)F)c2c(-c3ccccc3)nn(C)c2n1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of (1-Methyl-3-phenyl-4-trifluoromethyl-1H-pyrazolo[3,4-b]pyridin-6-yloxy)-acetic acid (100 mg, 0.28 mmol), DIC (53 mg, 0.42 mmol) and HOBt (49 mg, 0.36 mmol) in DMF (5 ml) was stirred at rt for 10 min. (S)-(+)-2-Phenyl-propylamine (42 mg, 0.31 mmol) was added to the reaction mixture at rt and stirring was continued overnight at rt. After completion of the reaction, ice-cold water (10 mL) was added to the reaction mixture and the mixture was stirred for 20 min. The reaction mixture was extracted with diethyl ether, dried over sodium sulfate and concentrated under reduced pressure. The solid was triturated with pentane (20 ml×3) followed by hexane (15 ml) to yield the title compound as white solid. (100 mg, 75%). Mp=91-93° C. [1H-NMR (CDCl3, 300 MHz) δ 7.63-7.42 (m, 5H), 7.20-6.92 (m, 5H), 6.80 (s, 1H), 6.18-6.12 (m, 1H), 4.92 (dd, 2H), 4.1 (s, 3H), 3.81-3.68 (m, 1H), 3.40-3.33 (m, 1H), 2.98-2.90 (m, 1H), 1.41 (d, 3H); HPLC RtA=6.325 min. (98%); LCMS RtA=1.835, [M+H]+=469.1]
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO>[C:1]1([CH:7]2[CH2:8][CH2:9][CH:10]([OH:13])[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(c2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCC(c2ccccc2)CC1
Yield: 66.2 %

Procedure:
To a solution of 31.4 g (0.18 mol) of 4-phenylcyclohexanone in 500 ml of absolute methanol, which is cooled to -10° C., are added 6.8 g (0.18 mol) of sodium borohydride in batches with stirring. The reaction mixture is allowed to react for 0.5 hours at -10° C. and for 3 hours at ambient temperature and then evaporated down in vacuo. The residue remaining is mixed with water and acidified with 2N hydrochloric acid. The suspension formed is stirred for 1 hour and the crystalline product is suction filtered, dried and recrystallised from diisopropylether. 21 g (66% of theory) of 4-phenylcyclohexanol are obtained, melting point: 112°-114° C.