Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[CH:24][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:12]=1)=[O:9]>N1C=CC=CC=1>[C:1]([NH:5][C:6]1[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[CH:24][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:12]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(N)c1
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(S(C)(=O)=O)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
20 μL of acetyl chloride was added to a solution of 90 mg of 2-amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide in 2 mL of pyridine at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched with MeOH and evaporated. The product was purified on reverse phase HPLC to yield 2-acetamido-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide. MS (Q1) 444.0 (M)+.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:15][CH2:14][C@@H:13]([O:16][Si](C(C)(C)C)(C)C)[CH2:12][C@@H:11]1[C:24]1[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([O:9][C@H:10]1[CH2:15][CH2:14][C@@H:13]([OH:16])[CH2:12][C@@H:11]1[C:24]1[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1nccc1[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1OC(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cn1nccc1[C@H]1C[C@H](O)CC[C@@H]1OC(=O)c1ccccc1
Yield: 91.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 120c by using the (1S*,2R*,4R*)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl benzoate (1.30 g, 3.14 mmol) prepared in Example 162a, tetrabutyl ammonium fluoride (1.0 M solution in THF; 9.42 mL, 9.42 mmol) and THF (5.0 mL), to yield the title compound (867 mg, 92%) as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([C:22](OC)=[O:23])=[CH:20][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([CH2:22][OH:23])=[CH:20][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Solvent: C1CCOC1
Product: OCc1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Yield: 86 %

Procedure:
A solution of 1-benzyl-3-(5-methoxycarbonyl-2-furyl)-1H-indazole in THF (150 mL) was added dropwise to a suspension of CaBH4.2THF (3.9 g, 18.23 mmol) in THF (150 mL) at room temperature. The resultant mixture was heated to reflux for 15 h. The reaction mixture was allowed to cool, then poured slowly onto brine. The layers were separated and the aqueous layer was extracted three times with ether. The combined organic material was dried (MgSO4) and concentrated under reduced pressure. The crude product was chromatographed on silica (30–40% EtOAc/cyclohexane) and then recrystallised (ethanol/H2O) to give the product as fine cream needles (1.56 g, 86%): mp 112–112.5° C. (lit. mp 108–109° C.); MS (EI) M+ 304; 1H-NMR (CDCl3) 4.76 (s, 2H), 5.68 (s, 2H), 6.50 (d, 1H, J=3.3 Hz), 6.90 (d, 1H, J=3.3 Hz), 7.21–7.40 (m, 8H), 8.08 (d, 1H, J=8.5 Hz); 13C-NMR (CDCl3) 54.12, 58.53, 108.87, 110.57, 110.59, 122.25, 122.38,122.50, 127.83, 128.00(2C), 128.72, 129.68(2C), 137.14, 137.53, 141.45, 149.52, 154.88; Anal. (C19H16N2O2) C, calcd 74.98; found 74.80, H, calcd 5.30; found 5.28, N, calcd 9.20; found 9.15.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([O:14][CH3:15])=[CH:13][C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1.S(Cl)([Cl:19])(=O)=O>C(O)(=O)C.C(OCC)(=O)C>[Cl:19][C:13]1[C:8]2[N:7]=[N:6][N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[C:9]=2[CH:10]=[CH:11][C:12]=1[O:14][CH3:15]
Reactant: COc1ccc2c(c1)nnn2CC1CC1
Reactant: O=S(=O)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc2c(nnn2CC2CC2)c1Cl
Temperature: 0 °C
Reaction time: 14 h

Procedure:
1-(Cyclopropylmethyl)-5-methoxy-1H-benzotriazole (10 g, 49 mmol) was dissolved in acetic acid (100 mL), cooled to 0° C. and treated with sulfuryl dichloride (4.8 mL, 59 mmol, 1.2 equiv) over three minutes. The mixture was warmed to ambient temperature over three hours and stirred for an additional 14 hours. The mixture was diluted with ethyl acetate and washed with aqueous saturated sodium bicarbonate. The organic layer was dried with magnesium sulfate, filtered and partially concentrated in vacuo to ˜30 mL, which was then treated with water. The resulting precipitate was filtered, collected and dried in vacuo, providing the titled compound.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].[CH2:9]([OH:13])[CH2:10][CH2:11]O>[Pd]>[OH:5][CH2:4][CH2:3][CH2:2][O:5][CH:4]([CH3:6])[CH2:3][CH2:2][C:1]([O:8][CH2:11][CH2:10][CH2:9][OH:13])=[O:7]
Reactant: OCCCO
Reactant: CC(=O)CCC(=O)O
Agent: [Pd]
Product: CC(CCC(=O)OCCCO)OCCCO
Temperature: 200 °C
Yield: 5.3 %

Procedure:
Levulinic acid (11.6 g; 0.1 mol), 1,3-propanediol (67.6 g; 0.89 mol), and 2.32 g of 10% Pd/C from Aldrich (20 wt % relative to levulinic acid) are charged to a Parr reactor, purged with nitrogen three times, heated to 200° C. with stirring, and reacted with 1000 psi of hydrogen for 20 hrs. GC analysis reveals that the reaction is complete. 1,3-Propylene glycol is distilled off at 58-59° C./0.1 mm to give 14.7 g of the crude product containing 79% of the desired monomer. The crude product (1.0 g) is chromatographed on silica gel using hexane-ethyl acetate from 3:1 to 1:1 to isolate about 0.62 g of 3-hydroxypropyl 4-(3-hydroxypropoxy)pentanoate. 1H NMR (δ, ppm, CDCl3): 1.07 d (3H, CH3), 1.66-1.80 m (6H, CH2), 2.31 m (2H, CH2CO), 3.1 (broad, 2H, OH), 3.39 m (2H, CH2O), 3.57 m (5H, 2×CH2OH, CH), 4.11 m (2H, COOCH2). 13C NMR (δ, ppm, CDCl3): 19.69 (CH3); 30.67, 31.85, 31.88; 32.68 (CH2 groups); 59.02, 61.21, 61.70, 67.06 (CH2O groups), 74.97 (CH), 174.15 (COO). Mass spectrum: m/e 234 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](/[CH:10]=[CH:11]/[C:12]([NH:14][CH:15]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[C:16]([F:19])([F:18])[F:17])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O.O.[OH-].[Na+]>C(O)C>[NH2:1][C:4]1[CH:5]=[C:6](/[CH:10]=[CH:11]/[C:12]([NH:14][CH:15]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=2)[C:16]([F:17])([F:18])[F:19])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(/C=C/c1cccc([N+](=O)[O-])c1)NC(c1cccc(C(F)(F)F)c1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cccc(/C=C/C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)c1

Procedure:
626 mg (3.30 mmol) of Sn(II)Cl2 were initially charged in 5 ml of ethanol, and 350 mg (0.83 mmol) of (2E)-3-(3-nitrophenyl)-N-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-acrylamide from Example 3, Stage 1 were added. The reaction solution was stirred at reflux temperature for 1 hour, cooled and admixed with 50 ml of water. While cooling with ice, the pH was adjusted to 9 with concentrated sodium hydroxide solution and the mixture was then extracted with dichloromethane. The organic phase was dried with sodium sulphate, the solvent distilled off under reduced pressure and the residue stirred with diisopropyl ether.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[CH:36]=[C:35]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH3:46])=[CH:40][CH:39]=3)[C:34](Cl)=[C:33](Br)[C:32]=2[O:49][CH2:50][CH2:51][CH2:52]Cl)[O:11][C@@H:10]1[CH2:54][O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[NH4+].[Cl-:69]>C1COCC1>[Cl:69][C:34]1[C:35]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH3:46])=[CH:40][CH:39]=2)=[CH:36][C:31]([C@H:12]2[C@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@@H:10]([CH2:54][O:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[O:11]2)=[C:32]2[C:33]=1[CH2:52][CH2:51][CH2:50][O:49]2
Reactant: [Cl-]
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(OCCCCl)c(Br)c2Cl)cc1
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)CCCO3)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 28 %

Procedure:
To a solution of chloride 29-1 (1.03 g, 1.09 mmol) in THF (30 mL) was added n-BuLi (2.5M in hexane, 0.87 mL, 2.18 mmol) at −78° C. The mixture was allowed to slowly warm to r.t. and stirred at r.t. for 12 hours. To the mixtures was added aqueous saturated NH4Cl solution (50 mL). The mixture was extracted with EtOAc (100 mL). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified using normal phase column chromatography to provide the title product 30 (255 mg, 28%).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[N:6]=[N:7][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][C:10]=1[CH3:11].O>CO>[CH3:11][C:10]1[CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=[N:6][C:5]=1[O:2][CH3:1]
Reactant: Cc1cc(-c2ccccc2)nnc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nnc(-c2ccccc2)cc1C
Yield: 89.9 %

Procedure:
Sodium methoxide (243 g) is cautiously added to a solution of 3-chloro-4-methyl-6-phenylpyridazine (307 g, 1.5 mol) in 3.4 L of methanol. The mixture is heated to refluxing temperature for approximately eight hours under an atmosphere of nitrogen and then poured into water (4.5 L). The resulting precipitate is collected, washed with water, and dried to give 270 g (90%) of product with a melting point of 62°-64° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14](=O)[CH:15]([F:17])[F:16])[CH2:9]2)=[N:6][CH:7]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][CH2:14][CH:15]([F:17])[F:16])[CH2:9]2)=[N:6][CH:7]=1
Reactant: O=C(N[C@@H]1CCN(c2ccc(Br)cn2)C1)C(F)F
Solvent: C1CCOC1
Product: FC(F)CN[C@@H]1CCN(c2ccc(Br)cn2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 53.3 %

Procedure:
Dissolve N—[(R)-1-(5-bromo-pyridin-2-yl)-pyrrolidin-3-yl]-2,2-difluoro-acetamide (1.98 g, 6.19 mmol) in THF (50 mL) and cool to 0° C. Add 1.0 M BH3 THF complex in THF (18.6 mL, 18.6 mmol) dropwise. Stir the mixture at 0° C. for 10 min and then reflux for 4 h. Cool the mixture to 0° C. and quench with CH3OH (5 mL) and saturated NH4Cl (20 mL). Stir the mixture at 0° C. for 5 min and at RT for 30 min. Dilute with H2O (50 mL) and extract with EtOAc (2×80 mL). Dry the organic portion with Na2SO4, filter, and concentrate. Purify the crude material by chromatography, eluting with 50-70% EtOAc/hexane to give 1.01 g (50%) of the title compound. MS/ES m/z (79Br) 306.0 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[I-:13].[Na+]>CC(C)=O>[I:13][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: BrCCCCCC1CCCCC1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCCCCC1CCCCC1
Temperature: 60 °C
Yield: 56.6 %

Procedure:
A mixture of (5-bromo-pentyl)-cyclohexane (2 gm, 8.58 mmol) in acetone (20 ml), and sodium iodide (2.57 g, 17.15 mmol) was heated at 60° C. for 12 hrs and then cooled to room temperature. The solvent was evaporated, the residue was taken up in EtOAc (30 ml), washed with water (20 ml) and then brine (30 ml). The organic layer was separated, dried over anhydrous sodium sulfate and solvent was removed under reduced pressure. The crude product was purified by column chromatography using hexane as an eluent to yield an oily liquid (1.36 gm). 1H NMR (CDCl3): δ 0.8 (t, 2H, J=10.2 Hz), 1.00-1.38 (m, 9H), 1.52-168 (m, 6H), 1.70-1.80 (m, 2H), 3.10 (t, 2H, J=6.9 Hz).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Cl[C:9]1[C:14]2[N:15]=[C:16]([O:32][CH2:33][CH3:34])[N:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[CH:22][CH:21]=3)[C:18](=[O:19])[C:13]=2[CH:12]=[CH:11][N:10]=1.O>CN(C)C=O>[CH2:33]([O:32][C:16]1[N:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[CH:22][CH:21]=2)[C:18](=[O:19])[C:13]2[CH:12]=[CH:11][N:10]=[C:9]([O:5][CH2:4][CH2:3][O:2][CH3:1])[C:14]=2[N:15]=1)[CH3:34]
Reactant: CCOc1nc2c(Cl)nccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1nc2c(OCCOC)nccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-methoxyethanol (0.019 ml) in N,N-dimethylformamide (3 ml) was added sodium hydride (60% in oil, 9 mg) at room temperature, and the mixture was stirred for 30 min. 8-Chloro-2-ethoxy-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[3,4-d]pyrimidin-4(3H)-one (80 mg) was added to reaction mixture, and the mixture was stirred at 60° C., for 5 hr, and allowed to be cooled to room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane). The obtained residue was suspended in a mixed solvent of ethyl acetate/hexane, and the resulting solid was collected by filtration to give the title compound (21 mg).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([NH2:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:20])=CC=1>C(Cl)CCl.CCOC(C)=O>[OH:1][C:2]1[C:3]([C:8](=[S:20])[NH2:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1ncccc1O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: NC(=S)c1ncccc1O
Yield: 69.1 %

Procedure:
A stirred solution of 3-hydroxypicolinamide (1.35 g, 9.75 mmol) and Lawesson's reagent (2.37 g, 5.85 mmol) in dry ClCH2CH2Cl (12 mL) was heated to reflux under nitrogen for 5 hr. At ambient temperature, the mixture was diluted with EtOAc (50 mL), washed with half-saturated aq. NaCl (30 o5 mL) containing NaHCO3 (840 mg) and with brine (20 mL). After drying over MgSO4 and filtration, the filtrate was concentrated in vacuo to give a brown solid, which was subject to flash chromatography on silica gel CH2Cl2 as eluent) to provide 3c (623 mg, 42%) as a greenish yellow solid after crystallization from EtOAc/hexane. mp 152.0°-153.0° C.; IR (KBr) 3372, 3259, 2464, 1626, 1458, 1317 cm-1 ; 1H NMR (DMSO-d6) δ 7.33 (1H, dd, J=8.6 and 1.0 Hz, Ar), 7.46 (1H, dd, J=8.6 and 4.3 Hz, Ar), 8.07-8.10 (1H, m, Ar), 8.15(1H, s, NH), 8.49 (1H, s, NH), 12.76 (1H, s, OH); FABMS m/z 154 (M+); Anal. Calcd for C6H6N2OS: C, 46.74; H, 3.92; N, 18.17. Found: C, 46.83; H, 3.89; N, 17.90.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][C:11]([C:20](O)=[O:21])=[N:10]2)=[CH:5][CH:4]=1.O.C(OCC)(=O)C>O1CCCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][C:11]([CH2:20][OH:21])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2nc(C(=O)O)cc2-c2ccccc2)cn1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(CO)cc2-c2ccccc2)cn1
Reaction time: 0.17 h

Procedure:
In an argon atmosphere while cooling with ice, 1.08M borane-tetrahydrofuran complex in tetrahydrofuran (9.2 mL) was added dropwise to 1-(6-methoxy-3-pyridyl)-5-phenylpyrazole-3-carboxylic acid (1.181 g) in tetrahydrofuran (20 mL) obtained from Referential Example 41 over a period of 10 minutes, and the resultant mixture was stirred at room temperature for 7 hours. Water and ethyl acetate were added to the reaction mixture, followed by stirring, and precipitated insoluble matter was removed by filtration, and then an organic layer was separated. The organic layer was sequentially washed with water and saturated brine, and then dried over sodium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure, and the residue was purified through silica gel column chromatography (hexane-ethyl acetate), to thereby give the title compound as an oily product (682 mg, 60%).
Reaction SMILES: [I-].BrC1C=CC=C[N+]=1C.[CH2:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:18]1([CH2:24][C:25](O)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CCCC)CCCC)CCC>C(Cl)Cl>[C:18]1([CH2:24][C:25]([O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)Cc1ccccc1
Agent: C[n+]1ccccc1Br
Agent: [I-]
Solvent: ClCCl
Solvent: CCCCN(CCCC)CCCC
Product: O=C(Cc1ccccc1)OCc1ccccc1
Yield: 97 %

Procedure:
To a suspended CH2Cl2 (2 ml) solution of 2-bromo-1-methylpyridinium iodide (720 mg, 2.4 mmol) was added a mixture of benzyl alcohol (216 mg, 2.0 mmol), phenylacetic acid (272 mg, 2.0 mmol) and tri-n-butylamine (888 mg, 4.8 mmol) in CH2Cl2 (2 ml), and the resulting mixture was refluxed for 3 hours. After evaporation of the solvent, the residue was separated by silica gel column chromatography, and benzyl phenylacetate was isolated in 97% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:33])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=O)[NH:12][CH:11]3[C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[C:26]([F:31])[C:25]=3[F:32])[C:5]2=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:43]2)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:33])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[S:43])[NH:12][CH:11]3[C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[C:26]([F:31])[C:25]=3[F:32])[C:5]2=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccc(F)c(F)c1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Solvent: Cc1ccccc1
Product: Cc1ccc(F)c(F)c1C1NC(=S)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 69.8 %

Procedure:
In a manner similar to the method described in example 30, racemic (2′S,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.18 g, 0.37 mmol) prepared in example 52c was reacted with 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (0.32 g, 0.96 mmol) in toluene to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-methylphenyl)-6′-thioxospiro[3H-indole-3,3′-piperidine]-2(1H)-one (Yield 0.13 g, 69.8%).
Reaction SMILES: C([SiH](CC)CC)C.[F:8][C:9]1[CH:25]=[CH:24][C:12]2[C:13]3([CH3:23])[C:18](=[CH:19][CH2:20][C:11]=2[CH:10]=1)[N:17]([CH3:21])[C:16](=[O:22])[CH2:15][CH2:14]3.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:8][C:9]1[CH:25]=[CH:24][C:12]2[C:13]3([CH3:23])[CH:18]([CH2:19][CH2:20][C:11]=2[CH:10]=1)[N:17]([CH3:21])[C:16](=[O:22])[CH2:15][CH2:14]3
Reactant: CN1C(=O)CCC2(C)C1=CCc1cc(F)ccc12
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)CCC2(C)c3ccc(F)cc3CCC12
Temperature: 0 °C
Reaction time: 96 h

Procedure:
Triethylsilane (1 ml; 6.12 mmol) was added to 8-fluoro-4,10b-dimethyl-1,2,3,4,6,10b-hexahydrobenzo[f]quinolin-3-one (500 mg; 2.04 mmol) in CH2Cl2 (15 ml) at room temperature. The reaction mixture was cooled to 0° C. and trifluoroacetic acid (2.6 ml) was added. After stirring at room temperature for four days, the reaction mixture was diluted with CH2Cl2 and treated with saturated NaHCO3. The resulting layers were separated and the organic layer was washed with saturated NaHCO3, dried over MgSO4 and concentrated under vacuum to a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([CH:14]([F:16])[F:15])=[CH:12][N:11]([CH:17]([CH3:21])[C:18]([OH:20])=O)[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[NH2:25][C:26]1[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([CH:14]([F:15])[F:16])=[CH:12][N:11]([CH:17]([CH3:21])[C:18]([NH:25][C:26]3[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])=[CH:28][CH:27]=3)=[O:20])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CC(C(=O)O)n1cc(C(F)F)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(C(F)F)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
65 mg (purity 88%, 0.16 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-(difluoromethyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) and 1.2 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 65 mg (76% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([N:12]2[CH2:16][CH2:15][CH2:14][S:13]2(=[O:18])=[O:17])[CH:3]=1.[OH-].[Na+]>C(O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N:12]2[CH2:16][CH2:15][CH2:14][S:13]2(=[O:17])=[O:18])[CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1N1CCCS1(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(Br)cc1N1CCCS1(=O)=O
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 98.4 %

Procedure:
To methyl 4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)benzoate (5.57 g) described in Preparation Example 116 were added ethanol (43 mL) and 1N aqueous sodium hydroxide solution (21.7 mL) and the mixture was stirred at 60° C. for 40 min. Ethanol was evaporated and the mixture was neutralized with water and 1N hydrochloric acid under ice-cooling and the mixture was stirred. The precipitated crystal were collected by filtration to give the title compound (5.25 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[CH2:20]([O:23][CH:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1)[CH3:25])[CH2:21][CH3:22]>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:26]([CH:24]([O:23][CH2:20][CH2:21][CH3:22])[CH3:25])=[CH:27][CH:28]=1
Reactant: CCCOC(C)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: CCCOC(C)c1ccc(C(=O)Nc2ccc(N3CCC(N4CCCC4C)C3)cc2C)cc1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 4-(1-propoxy-ethyl)-benzoic acid. MS: 463.3 (M+H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)C1C=CC=CC=1.[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16]>C1(C)C=CC=CC=1.Cl[Ti](Cl)(Cl)Cl>[C:15]([NH:19][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)N
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)NC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere a solution of 8.6 mL (78 mmol) TiCl4 in 100 mL toluene was added dropwise to a solution, cooled to 0° C., of 24.1 mL (130 mmol) 1-benzyl-piperidin-4-one and 55 mL (519 mmol) of tert-butylamine in 200 mL toluene in such a way that the internal temperature did not exceed 15° C. The reaction mixture was stirred overnight at RT, the precipitate formed was suction filtered and the solution remaining after the addition of 65 mg of platinum oxide was hydrogenated until the theoretical uptake of H2 had been achieved. After hydrogenation had ended, 160 mL of 2 N NaOH solution were added to the suspension, it was filtered, the organic phase was separated off, the aqueous solution was extracted three times with toluene and the combined organic phases were dried over Na2SO4. After the desiccant and solvent had been eliminated the product was further reacted without being purified.