Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([OH:12])(=[O:11])=[O:10].Cl[C:14]([O:16][CH2:17][CH:18]1[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15]>>[CH:29]1[C:30]2[CH:18]([CH2:17][O:16][C:14]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=3[S:9]([OH:12])(=[O:11])=[O:10])=[O:15])[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]=2[CH:26]=[CH:27][CH:28]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: Nc1ccc(F)cc1S(=O)(=O)O
Product: O=C(Nc1ccc(F)cc1S(=O)(=O)O)OCC1c2ccccc2-c2ccccc21

Procedure:
2-(9H-Fluoren-9-ylmethoxycarbonylamino)-5-fluoro-benzenesulfonic acid was prepared from 2-Amino-5-fluoro-benzenesulfonic acid (5.0 g, 0.026 mol) (Suter, C. M.; Weston, A. W., J. Amer. Chem. Soc., 1940, 62, 604-606) and 9-Fluorenylmethyl chloroformate (7.4 g, 0.029 mol) in an analogous manner to Example 820a. Product isolated as a white solid (8.08 g, 74%). 1HNMR (400 MHz, DMF-d7, δ, ppm): 10.25 (br s, 1H), 8.20-8.00 (m, 1H), 7.95 (d, 2H, J=7.3 Hz), 7.77 (d, 2H, J=7.3 Hz), 7.54 (dd, 1H, J=8.8 and 3.0 Hz), 7.45 (t, 2H, J=7.3 Hz), 7.38 (t, 2H, J=7.3 Hz), 7.21-7.12 (m, 1H), 4.70-4.10 (m, 4H).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:8]([C:9]([NH2:11])=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:14][N:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16](Cl)=[O:17]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][C:16](=[O:17])[N:15]([CH3:14])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:8]([C:9](=[O:10])[NH2:11])[CH:12]=1)(=[O:3])[CH3:2]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CC(=O)c1ccc(O)c(C(N)=O)c1
Product: CC(=O)c1ccc(OC(=O)N(C)c2ccccc2)c(C(N)=O)c1

Procedure:
The title product was prepared from 5-acetylsalicylamide and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (87%, white solid). HPLC-MS: m/z=313.1 (M+1); Rt: 2.51 min.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[O:24][C:25]4[C:30]([C:31](=[O:33])[CH:32]=3)=[CH:29][CH:28]=[CH:27][C:26]=4[N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)=[O:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(OCC)(=O)C>[N:11]1([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[O:24][C:25]4[C:30]([C:31](=[O:33])[CH:32]=3)=[CH:29][CH:28]=[CH:27][C:26]=4[N:34]3[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]3)=[O:22])=[CH:16][CH:15]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CN1CCN(c2cccc3c(=O)cc(C(=O)Nc4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)oc23)CC1
Solvent: CCOC(C)=O
Product: CN1CCN(c2cccc3c(=O)cc(C(=O)Nc4ccc(N5CCNCC5)cc4)oc23)CC1
Temperature: 0 °C
Yield: 74.5 %

Procedure:
4-[4-({1-[8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromen-2-yl]-methanoyl}-amino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (Example 29) (160 mg, 0.3 mmol) was dissolved ethyl acetate (20 mL) and cooled to 0° C. HCl gas was bubbled in slowly for 2 minutes. A solid began to precipitate. Methanol (3-4 mL) was added to dissolve this solid and HCl gas was bubbled in for another 2 minutes. The mixture was concentrated under reduced pressure and triturated with ether and dried under vacuum to yield a tan solid (100 mg, 76%). LCMS/m/z=448.6.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[F:26][C:27]1([F:33])[CH2:29][CH:28]1[C:30](O)=[O:31]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:30]([CH:28]5[CH2:29][C:27]5([F:33])[F:26])=[O:31])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: O=C(O)C1CC1(F)F
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)C1CC1(F)F

Procedure:
The title compound, white solid (9.7 mg, 31.9%), MS (ISP) m/z=435.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25.7 mg, 0.070 mmol) and 2,2-difluorocyclopropanecarboxylic acid
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][P:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])=[CH:14][CH:15]=2)[C:10]([CH:32]2[CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]2C(OC(C)(C)C)=O)=[N:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[NH:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:40][CH:32]1[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:17][P:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:19])[CH:12]=2)[NH:8][N:9]=1
Reactant: CC(C)(C)OC(=O)N1c2ccccc2CC1c1nn(C(=O)OC(C)(C)C)c2ccc(OP(=O)(c3ccccc3)c3ccccc3)cc12
Agent: Cl
Solvent: C1COCCO1
Product: O=P(Oc1ccc2[nH]nc(C3Cc4ccccc4N3)c2c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
A solution of 200 mg of 3-(1-tert-butoxycarbonyl-2,3-dihydro-1H-indol-2-yl)-5-(diphenylphosphinoyloxy)indazole-1-carboxylic acid tert-butyl ester in 4 ml of dioxane and 1 ml of a 4M hydrochloric acid solution in dioxane is stirred at ambient temperature. After 1 hour, 1 ml of a 4M hydrochloric acid solution in dioxane is added. The reaction medium is stirred overnight at ambient temperature. The suspension is filtered through sintered glass. The solid is rinsed with ethyl ether. The solid is taken up in 200 ml of dichloromethane and 8 ml of a 2N aqueous sodium hydroxide solution. The solution is stirred for a few minutes and is then separated by settling out. The organic phase is dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 114 mg of diphenylphosphinic acid 3-(2,3-dihydro-1H-indol-2-yl)-1H-indazol-5-yl ester.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.CCCCCC.C([Li])CCC.[CH2:21]([N:28]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:31](=[O:32])[C:29]1=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[C:39]([O:42][CH2:43][CH3:44])(=[O:41])[CH3:40]>O1CCCC1.O>[CH2:21]([N:28]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:31]([CH2:40][C:39]([O:42][CH2:43][CH3:44])=[O:41])([OH:32])[C:29]1=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(C)=O
Reactant: O=C1C(=O)N(Cc2ccccc2)c2ccccc21
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCOC(=O)CC1(O)C(=O)N(Cc2ccccc2)c2ccccc21
Reaction time: 0.17 h
Yield: 81 %

Procedure:
To a solution of 2.4 ml of 1,1,1,3,3,3-hexamethyldisilazane in 10 ml of dry tetrahydrofuran was added dropwise 6.4 ml of a 1.59M hexane solution of n-butyl lithium at -78° C. under a nitrogen atmosphere, followed by stirring at that temperature for 10 minutes. To the mixture was slowly added 0.976 ml of ethyl acetate, followed by stirring at -78° C. for 30 minutes. To the mixture was further added a solution of 2.00 g of 1-benzylisatin in 10 ml of dry tetrahydrofuran, followed by stirring at that temperature for 1 hour. Water was added to the reaction mixture, and the product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate to give 2.23 g (81%) of the title compound.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:22])[N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[C:23]([O:27][CH3:28])(=[O:26])[CH2:24][SH:25]>>[CH3:28][O:27][C:23](=[O:26])[CH2:24][S:25][C:2]1[S:6][C:5]([NH:7][C:8]([N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:22])=[N:4][CH:3]=1
Reactant: COC(=O)CS
Reactant: O=C(Nc1ncc(Br)s1)N(C1CCCCC1)C1CCCCC1
Product: COC(=O)CSc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1

Procedure:
Prepared as described in general procedure (D) using 3-(5-bromo-thiazol-2-yl)-1,1-dicyclohexyl-urea and methyl thioglycolate
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][N:12]3[CH2:16][CH2:15][CH:14]([C:17]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:18]([NH2:20])=[O:19])[CH2:13]3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.C(O)CCC.Br>C(O)(=O)C.[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][N:12]3[CH2:16][CH2:15][C@@H:14]([C:17]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:18]([NH2:20])=[O:19])[CH2:13]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCN(CCc2ccc3occc3c2)C1
Agent: [Pd]
Agent: Br
Solvent: CCCCO
Solvent: CC(=O)O
Product: NC(=O)C(c1ccccc1)(c1ccccc1)[C@@H]1CCN(CCc2ccc3c(c2)CCO3)C1
Reaction time: 6.5 h
Yield: 85 %

Procedure:
Pd/C 10% (0.8 g) was added to a solution of S)-2-{1-[2-(benzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide (8 g) in acetic acid (160 ml). The mixture was hydrogenated at 45-50° C. and at atmospheric pressure for about 6-7 hrs. Catalyst was filtered off and solution was concentrated under vacuum obtaining an oily residue. n-Butanol (40 ml) was added and stirred to obtain a solution. 48% HBr (3.5 g) was added and a mixture n-Butanol/water was eliminated by distillation to reduce water content to less then 1%. Darifenacin .HBr crystallizes and after 2 hrs at 15-20° C. was filtered and washed with n-Butanol (3×5 ml). After drying at 55-60° C. under vacuum 8.1 g of Darifenacin hydrobromide were obtained. (Yield 85%).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[C:4]([CH3:8])[NH:3]1.C(N(CC)CC)C.[C:16]1([N:22]=[C:23]=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1C=CC=CC=1>[CH3:1][N:2]1[C:6](=[O:7])[CH:5]([C:23]([NH:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:24])[C:4]([CH3:8])=[N:3]1
Reactant: Cc1cc(=O)n(C)[nH]1
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC1=NN(C)C(=O)C1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 76 %

Procedure:
1,3-Dimethylpyrazole-5-one above (11.2 g) and triethylamine (10.2 g) were dissolved in dry benzene and phenyl isocyanate (12 g) added. The mixture was stirred 16-18 hrs at room temperature, whereupon it was extracted with water (4 × 50 ml). The combined aqueous extracts were acidified with dilute hydrochloric acid and the mixture refrigerated for several hours. The product was then recovered by filtration and dried. 4,5-dihydro-1,3-dimethyl-5-oxo-N-phenyl-4-pyrazolecarboxamide (17.5 g, 76%) was obtained as a colourless powder, m.p. 231-233° C.
Reaction SMILES: [C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([N:16](C)[C:17](=O)OC(C)(C)C)[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][C:29]=2[CH3:38])[C:6]2[CH:39]=[CH:40][CH:41]=[CH:42][C:5]1=2)(=[O:3])[CH3:2].[ClH:43]>O1CCOCC1.CCOCC>[ClH:43].[C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([NH:16][CH3:17])[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][C:29]=2[CH3:38])[C:6]2[CH:39]=[CH:40][CH:41]=[CH:42][C:5]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2N(Cc2c(C)ccc3ccccc23)C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@@H]1C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(C)ccc3ccccc23)c2ccccc2N(C(C)=O)[C@H]1C
Reaction time: 2 h
Yield: 84 %

Procedure:
A rt suspension of tert-butyl(S)-1-((2S,3S)-1-acetyl-2-methyl-5-((2-methylnaphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (73.1 mg, 128 μmol) in 4 M HCl in dioxane (638 μl) was stirred for 2 h. The reaction was diluted with Et2O and the solids were collected by vacuum filtration, taken up in MeCN—H2O, and lyophilized to provide (S)-N-((2S,3S)-1-acetyl-2-methyl-5-((2-methylnaphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride (54.3 mg, 84%) as a white solid. MS m/z 473 (MH)+.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:6]=2[C:5]([C:17](=[O:19])[CH3:18])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].COC1C=CC(C[NH2:33])=CC=1.ClCCl>CN(C=O)C.CO>[NH2:33][C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:6]=2[C:5]([C:17](=[O:19])[CH3:18])=[CH:4][N:3]=1
Reactant: CC(=O)c1cnc(Cl)c2cc(-c3ccccc3)sc12
Reactant: COc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1cnc(N)c2cc(-c3ccccc3)sc12
Temperature: 55 °C

Procedure:
To a suspension of 1-(4-chloro-2-phenyl-thieno[3,2-c]pyridin-7-yl)-ethanone 97 (61 mg, 0.21 mmol) and potassium carbonate (174 mg, 1.26 mmol) in DMF (1.8 mL) was added 4-methoxybenzylamine (85 μl, 0.64 mmol). The resultant mixture was heated at 50° C. for 6.75 h. After this time, 20 mL of a 1:1 mixture of dichloromethane and methanol was added and the resultant slurry was filtered. The filtrate was concentrated and the residue was dissolved in trifluoroacetic acid (7 mL). The resultant mixture was heated at 55° C. for 2.75 h. After this time, the reaction mixture was concentrated and the residue was purified by silica gel column chromatography (eluent: dichloromethane:MeOH:Et3N, 98.5:1.5:0.5) to give 98.
Reaction SMILES: [BH4-].[Na+].[Cl-].[Cl-].[Ca+2].C([O:8][C:9]([C:11]1[CH:16]=[N:15][CH:14]=[C:13]2[S:17][C:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:19][C:12]=12)=O)C>CO.C1COCC1>[OH:8][CH2:9][C:11]1[CH:16]=[N:15][CH:14]=[C:13]2[S:17][C:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:19][C:12]=12
Reactant: CCOC(=O)c1cncc2sc(C(=O)OC(C)(C)C)cc12
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc2c(CO)cncc2s1
Reaction time: 0.33 h
Yield: 32.4 %

Procedure:
To a stirred solution of NaBH4 (0.18 g, 4.89 mmol) in anhydrous 50% MeOH/THF at 0° C. was added powdered CaCl2 (0.54 g, 4.89 mmol). The suspension was stirred 20 minutes and a solution of Example 237D (0.50 g, 1.63 mmol) in anhydrous 50% MeOH/THF was slowly added over a period of 10 minutes. The reaction stirred 1 hour at 0° C. followed by 16 hours at room temperature. Reaction was quenched into a slurry of dilute AcOH (aq)/ice. After all gas evolution ceased with occasional stirring, aqueous was made basic with sat. NaHCO3. Aqueous was extracted with dichloromethane (3×40 mL) and extracts combined. The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel using EtOAc/hexane as eluent to provide dimethylethyl 4-(hydroxymethyl)-thieno[2,3-c]pyridine-2-carboxylate compound as a solid (0.14 g, 32%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])=[CH:5][C:4]=1[F:20]>CO.[Pt](=O)=O>[ClH:2].[Cl:2][C:3]1[C:4]([F:20])=[CH:5][C:6]([CH:10]2[CH2:11][CH:12]([C:13]([O:15][CH3:16])=[O:14])[CH2:17][CH2:18][NH:19]2)=[CH:7][C:8]=1[F:9]
Reactant: COC(=O)c1ccnc(-c2cc(F)c(Cl)c(F)c2)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: COC(=O)C1CCNC(c2cc(F)c(Cl)c(F)c2)C1
Reaction time: 7 h
Yield: 184.2 %

Procedure:
Methyl 2-(4-chloro-3,5-difluorophenyl)isonicotinate hydrochloride (1.94 g, 6.06 mmol) was dissolved in methanol. Platinum(IV) oxide (0.138 g, 0.61 mmol) was added and the mixture was hydrogenated at 5 bar at room temperature in a Büchi hydrogenator for 7 h. The catalyst was removed by filtration and the solvent evaporated. Methyl 2-(4-chloro-3,5-difluoro-phenyl)piperidine-4-carboxylate hydrochloride (1.820 g, 92%) was yielded as a colorless oil. MS m/z 290 (M+H)+
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:17]([N:2]1[CH2:3][CH2:4][CH:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N#Cc1ccc(OC2CCNCC2)cc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc(OC2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
Combine 4-(piperidin-4-yloxy)-benzonitrile hydrochloride (64 mg, 0.268 mmol), benzaldehyde (55 μL, 0.536 mmol) and sodium triacetoxy borohydride (85 mg, 0.402 mmol) in CH2Cl2 (3 mL). Stir at room temperature overnight. Dilute the reaction mixture with CH2Cl2 (3 mL) and wash with NaOH (1M aq. 5 mL). Separate the organic layer and place it in an SCX column, eluting with ammonia (2.0M in methanol) to provide the title compound (74 mg, 95%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C@@H:5](/[CH:18]=[CH:19]/[C:20](=[O:28])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:4][S:3]1.CO.C([BH3-])#N.[Na+]>C(O)(=O)C>[OH:28][CH:20]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)/[CH:19]=[CH:18]/[C@H:5]1[CH2:4][S:3][C:2](=[O:1])[N:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CCCCCCN1C(=O)SC[C@@H]1/C=C/C(=O)Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)CCCCCCN1C(=O)SC[C@@H]1/C=C/C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
To a solution of 3-7 (0.4 g, 1.0 mmol) in 12 mL 5:1 MeOH:acetic acid was added sodium cyanoborohydride (100 mg, 1.4 mmol) and the resulting solution was stirred overnight at room temperature. The solution was quenched with water and was concentrated in vacuo. The concentrate was extracted with ethyl acetate and washed with 2M Na2CO3 and then brine, after which it was dried over Na2SO4, filtered and concentrated in vacuo. The compound was purified by flash chromatography using 60% ethyl acetate/hexanes to yield 400 mg of 3-8 as a colorless oil. Data shown is for the major diastereomer. 1H NMR (400 MHz, CDCl3): δ 7.35–7.21 (m, 5H), 5.84 (dd, 1H), 5.66 (dd, 1H), 4.46 (q, 1H), 4.23 (q, 1H), 4.14 (q, 2H), 3.68–3.37 (m, 2H), 2.97 (dd, 1H), 2.88 (m, 2H), 2.78 (m, 1H), 2.30 (t, 2H), 1.64–1.30 (m, 8H), 1.27 (t, 3H); MS (+ESI): m/z 406.2 (M+1)+.
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH:6]=1.[OH-].[Na+]>CO>[C:35]1([CH:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:27][N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[CH:18]=2)[CH2:14][CH2:13][CH2:12][O:11][C:7]2[CH:6]=[C:5]([CH2:4][C:3]([OH:41])=[O:2])[CH:10]=[CH:9][CH:8]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2)CC(c2ccccc2)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2)CC(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A solution of (3-{3-[(2,2-Diphenyl-ethyl)-(3-trifluoromethyl-benzyl)-amino]-propoxy}-phenyl)-acetic acid methyl ester (4g). (0.37 g, 0.0007 mol) in methanol (7.5 mL) was treated with 2N NaOH (5 mL) and the mixture stirred overnight at ambient temperature. After concentration to dryness, the residue was dissolved in EtOAc (25 mL) and water was added (10 mL), the solution acidified to pH 3 with concentrated hydrochloric acid, then extracted into EtOAc (3×20 mL). The combined organic extracts were dried over Na2SO4, and then concentrated in vacuo to provide the carboxylic acid as waxy oil, which was purified by flash chromatography (9:1 CH2Cl2/MeOH) to give the desired product as oil 0.33 g in 87% yield. 1H NMR (CD3OD) δ 7.38 (d, 2H), 7.26 (t, 1H), 7.21 (m, 8H), 7.13 (t, 4H), 6.82 (d, 1H), 6.59 (s, 1H), 6.53 (d, 1H), 4.21 (t, 1H), 3.68 (s, 2H), 3.55 (t, 2H), 3.52 (s, 2H), 3.10 (d, 2H), 2.61 (t, 2H), 1.79 (t, 2H); 13C NMR (CD3OD) δ 173.7, 160.4, 145.1, 142.7, 139.3, 133.7, 130.2, 129.8, 127.3, 126.5, 124.6, 122.4, 116.5, 113.9, 66.3, 60.9, 59.7, 51.5, 51.2, 42.6, 27.9. Anal. Calcd for C33H32F3NO3: C, 72.38; H, 5.89; N, 2.56; F, 10.41. Found: C, 72.29; H, 6.09; N, 2.96; F, 10.08.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[C:9]=1[C:21]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)=[O:22].[BH4-].[Na+]>C(O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[C:9]=1[CH:21]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[OH:22]
Reactant: O=C(c1cccnc1)c1c(-c2ccc(Cl)cc2Cl)noc1-c1ccccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: OC(c1cccnc1)c1c(-c2ccc(Cl)cc2Cl)noc1-c1ccccc1Cl
Reaction time: 2 h
Yield: 78.9 %

Procedure:
To a solution of 80 mg (0.19 mmol) of 5-(2-chlorophenyl)-3-(2,4-dichlorophenyl)-4-[(3-pyridyl)carbonyl]isoxazole in 3 mL of ethanol at 0° C. was added 40 mg (1.06 mmol) of sodium borohydride. The mixture was stirred for 2 hrs and then diluted with ethyl acetate. The ethyl acetate solution was washed with saturated sodium chloride solution and dried over magnesium sulfate. The drying agent was filtered off, and the ethyl acetate was removed by rotoevaporation. The crude product was purified by prep TLC to give 65 mg (0.15 mmol) of 5-(2-chlorophenyl)-3-(2,4-dichlorophenyl)-4-[(3-pyridyl)hydroxymethyl]-isoxazole. 1H NMR (CDCl3): δ 5.80 (br s, 1), 6.97 (m, 1), 8.23 (br s, 1), and 8.28 ppm (br s, 1). MS m/z: 431.0 (M+H).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[N:20]1([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1>CC#N.CN(C=O)C>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:31][C:28]2[CH:27]=[CH:26][C:25]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:30][CH:29]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(N2CCCC2)cc1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(C)(C)N1C(=O)C(Nc2ccc(N3CCCC3)cc2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 68.6 %

Procedure:
A mixture of 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.150 g, 0.500 mmol), (4-pyrrolidin-1-ylphenyl)amine (0.081 g, 0.500 mmol) and TEA (0.070 ml, 0.500 mmol) in MeCN (2 ml) and DMF (1 ml) was heated in a microwave reactor at 120° C. for 45 mins. TEA (0.070 ml, 0.500 mmol) was added and the mixture was heated at 120° C. for 15 mins. The precipitate from the reaction mixture was isolated by filtration and washed with MeCN. The crude product was dissolved in MeOH and purified by silica gel column chromatography using 15-100% EtOAc in petroleum ether 40-60° C. as eluent, to give the title compound (0.146 g, 69%). 1H NMR (500 MHz, CDCl3): δ 7.22-7.02 (m, 5H), 6.55 (d, 2H), 6.14 (d, 2H), 3.15-3.10 (m, 4H), 1.99-1.92 (m, 4H), 1.77 (s, 9H); 13C NMR (125 MHz CDCl3): δ 160.8, 149.9, 131.6, 129.7, 128.5, 127.9, 125.5, 124.7, 123.9, 111.2, 108.8, 61.8, 47.9, 27.9, 25.6; Mass Spectrum: M+H+ 426.