Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:35]=[CH:34][C:8]([CH2:9][N:10]2[C:14]([C:15]([O:17]CC)=[O:16])=[C:13]([C:20](=[O:33])[C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([CH3:29])=[CH:23][C:22]=3[N+:30]([O-:32])=[O:31])[N:12]=[N:11]2)=[CH:7][CH:6]=1.Cl>O1CCCC1.CCOCC.O>[CH3:3][O:4][C:5]1[CH:35]=[CH:34][C:8]([CH2:9][N:10]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([C:20](=[O:33])[C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([CH3:29])=[CH:23][C:22]=3[N+:30]([O-:32])=[O:31])[N:12]=[N:11]2)=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1c(C(=O)c2cc(OC)c(C)cc2[N+](=O)[O-])nnn1Cc1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(Cn2nnc(C(=O)c3cc(OC)c(C)cc3[N+](=O)[O-])c2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 1N aqueous sodium hydroxide solution (1.1 ml) was added to a solution of ethyl 1-(4-methoxybenzyl)-4-(5-methoxy-4-methyl-2-nitrobenzoyl )-1,2,3-triazole-5-carboxylate (b-1) (243 mg, 0.535 mmole) obtained in the preceding step (b) in tetrahydrofuran (6 ml), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with ether, and water was added. The aqueous layer was acidified with hydrochloric acid, it was extracted with ethyl acetate, and washed with water and a saturated aqueous saline. After the organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 1-(4-methoxybenzyl)-4-(5-methoxy-4-methyl-2-nitrobenzoyl)-1,2, 3-triazole-5-carboxylic acid (c-1': LP) as a pale yellow crystalline powder (204 mg, 89%). Next, 1-(4-methoxybenzyl)-4-(5-methoxy-4-methyl-2-nitrobenzoyl)-1,2,3-triazole-5-carboxylic acid (c-1': LP) (200 mg, 0.469 mmole) thus obtained was dissolved in a mixed solvent of ethanol (12 ml) and ethyl acetate (12 ml), 10% palladium on carbon (25 mg) was added, and the mixture was stirred under the hydrogen atmosphere at room temperature for 6.5 hours. After the reaction mixture was filtered through celite, the filtrate was concentrated under reduced pressure, and precipitates were collected by filtration to give 4-(2-amino-5-methoxy-4-methylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylic acid (c-1 LP) as a red crystalline powder (178 mg, 96%).
Reaction SMILES: N1[CH:6]=[CH:5][N:4]=[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])N=1.[C:12]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13]1.N1CCCC1>C1(C)C=CC=CC=1>[C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:13]2[CH2:14][CH2:15][CH2:16][C:12]=2[CH:6]=[CH:5][N:4]=1
Reactant: O=C1CCCC1
Reactant: CCOC(=O)c1nccnn1
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: CCOC(=O)c1nccc2c1CCC2
Yield: 23.1 %

Procedure:
Ethyl 1,2,4-triazine-3-carboxylate (7 g, 45.8 mmol), cyclopentanone (4.9 mL, 55.0 mmol), and pyrrolidine (4.6 mL, 55.0 mmol) in toluene (100 mL) were heated to reflux for 12 h. The mixture was purified by column on silica gel chromatography (PE/EtOAc=5:1) to give the title compound (2.02 g, 25%) as a brown oil. LCMS: 192 (M+1)+
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:16](O)=[O:17].CCN=C=NCCCN(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:16]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[O:17]
Reactant: COc1ccc(C(=O)O)cc1Cl
Reactant: COC(=O)c1ccccc1N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1NC(=O)c1ccc(OC)c(Cl)c1
Reaction time: 24 h
Yield: 33.2 %

Procedure:
A solution of methyl 2-aminobenzoate (500 mg, 3.3 mmol) (Aldrich Chemical Co., Milwaukee, Wis.) and 3-chloro-4-methoxybenzoic acid (645 mg, 3.3 mmol) (Lancaster Synthesis Ltd., Windham, N.H.) in DMF (20 mL) was treated with EDCI (1.3 g, 6.6 mmol) and DMAP (800 mg, 6.6 mmol) at room temperature. The reaction mixture was stirred for 24 hours, and then concentrated. The crude residue was dissolved in EtOAc (50 mL) and washed with 0.1 N HCl (2×20 mL), saturated aqueous NaHCO3 (2×20 mL). The organic layer was dried (Na2SO4), filtered, and concentrated. The crude product was purified by chromatography (SiO2, 15% EtOAc in hexanes) to afford 42A as a white solid (350 mg, 33%).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:20]1([C:26]2[O:30][N:29]=[C:28]([C:31]([OH:33])=O)[CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.Cl.[NH2:46][CH2:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:56](=[O:68])[C:57]2[CH:62]=[C:61]([F:63])[CH:60]=[CH:59][C:58]=2[C:64]([F:67])([F:66])[F:65])[CH2:52][CH2:51]1)=[O:49]>CN(C=O)C.O>[F:63][C:61]1[CH:60]=[CH:59][C:58]([C:64]([F:66])([F:65])[F:67])=[C:57]([CH:62]=1)[C:56]([N:53]1[CH2:54][CH2:55][N:50]([C:48](=[O:49])[CH2:47][NH:46][C:31]([C:28]2[CH:27]=[C:26]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:30][N:29]=2)=[O:33])[CH2:51][CH2:52]1)=[O:68]
Reactant: O=C(O)c1cc(-c2ccccc2)on1
Reactant: NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1)c1cc(-c2ccccc2)on1
Temperature: 10 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
HOBt (38 mg, 0.28 mmol) and DIPEA (145 mg, 1.12 mmol) were added to a stirred solution of 5-phenyl-isoxazole-3-carboxylic acid (43 mg, 0.22 mmol) in DMF (1.0 mL). Then reaction mass was cooled to 10° C. and EDCI.HCl (54 mg, 0.28 mmol) and 2-amino-1-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone (as TFA salt) (100 mg, 0.22 mmol) were added. Then resulting mixture was stirred at the room temperature overnight. The mixture was then diluted with water and the product extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4, evaporated and purified by column chromatography using silica gel (60-120 mesh) and 50% ethyl acetate in hexane as the eluant to afford 5-phenyl-isoxazole-3-carboxylic acid {2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide as a solid in 49.1% yield. LC-MS purity: 95.66%, 1H NMR (DMSO-D6): δ 8.7 (t, 1H), 7.94 (m, 3H), 7.56 (m, 5H), 7.4 (s, 1H), 4.15 (m, 2H), 3.75 (m, 1H), 3.6 (m, 3H), 3.45 (m, 2H), 3.2 (m, 2H), 3.1 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:10]([CH2:11][C@@H:12]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[NH:13]C(OC(C)(C)C)=O)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:37].O1CCOCC1>C(Cl)Cl>[ClH:37].[CH2:1]([N:8]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:10]([CH2:11][C@@H:12]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[NH2:13])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cn(Cc2ccccc2)c2ccccc12)C(=O)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N[C@@H](Cc1cn(Cc2ccccc2)c2ccccc12)C(=O)OCc1ccccc1
Yield: 81 %

Procedure:
The same procedures as in Example 143 were carried out from the compound obtained in Example 152 (12.2 g), 4 mol/L of hydrogen chloride-dioxane solution (31 mL), and methylene chloride (300 mL), to give the captioned compound (8.6 g, 81%) as crystals.
Reaction SMILES: N1CCC[C@H]1C(O)=O.[H-].[Na+].[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]=[C:20](I)[CH:21]=1)[C:15]([O:17][CH3:18])=[O:16].[CH3:23][S:24]([O-:26])=[O:25].[Na+].C([O-])(O)=O.[Na+]>CS(C)=O.[Cu]I.CCOC(C)=O>[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]=[C:20]([S:24]([CH3:23])(=[O:26])=[O:25])[CH:21]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: CS(=O)[O-]
Reactant: COC(=O)c1cc(Cl)cc(I)c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1cc(Cl)cc(S(C)(=O)=O)c1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a solution of L-proline (77.7 mg, 675 μmol) in DMSO (4 mL) was added sodium hydride (27.0 mg, 675 μmol, 60% dispersion in mineral oil) and the mixture was stirred at room temperature for 30 minutes before copper(I)iodide (128 mg, 675 μmol), methyl 3-chloro-5-iodobenzoate (0.25 g, 843 μmol) and sodium methanesulfinate (689 mg, 6.75 mmol) were added. The reaction mixture was heated to 120° C. in a sealed tube to give a turbid blue solution. After 2 hours the reaction mixture was allowed to cool down and was poured on saturated aqueous NaHCO3 solution and EtOAc and filtered. The filtrate layers were separated and the aqueous layer was extracted twice with EtOAc. The organic layers were washed once with brine, dried over MgSO4, filtered and evaporated. Light brown solid (0.135 g; 64%). MS (EI): m/z=248 [M].
Reaction SMILES: [O-][CH2:2][CH3:3].[Na+].[C:5]1(=[O:22])[N:20]2[C:21]3[C:12](=[CH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=42)[CH2:11][CH:10]=[CH:9][C:8]=3[CH2:7][CH2:6]1.C(=O)(OCC)OCC.Cl>C(O)C>[CH2:2]([CH:6]1[C:5](=[O:22])[N:20]2[C:21]3[C:12](=[CH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=42)[CH2:11][CH:10]=[CH:9][C:8]=3[CH2:7]1)[CH3:3]
Reactant: O=C1CCC2=C3C(=Cc4ccccc4N13)CC=C2
Reactant: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(=O)OCC
Product: CCC1CC2=C3C(=Cc4ccccc4N3C1=O)CC=C2

Procedure:
To a freshly prepared solution of sodium ethoxide in ethanol (from 0.35 g sodium metal and 10 ml ethanol) was added 6H-pyrido[3,2,1-de]acridin-1 (2H)-one (1.2 g) portionwise over a period of 10 minutes. To the resulting dark red solution was slowly added diethyl carbonate (1.77 g) and the solution was then refluxed for 3 hours. The reaction mixture was cooled, acidified to pH 2 with concentrated HCl and then extracted with methylene chloride. The organic extract was washed with water and was then collected, dried and evaporated to dryness to obtain a light amber solid (1.8 g; m.p. 113°-118° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[OH:13])([O-])=O.[OH-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:1][C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[OH:13]
Reactant: CC(=O)c1ccc(O)c([N+](=O)[O-])c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1ccc(O)c(N)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 39.1 %

Procedure:
In a 300 ml three-neck flask, 5.00 g (27.6 m mole) of 2-nitro-4-acetylphenol and 75 ml of 2N-sodium hydroxide solution were placed. To the mixture solution, a solution, which 25.00 g of sodium hydrosulfite was dissolved in 75 ml to water, was added dropwise in 10 minutes. Then the mixture solution was stirred for 20 minutes at room temperature to precipitate a crystal. The crystal was filtered and recrystallized from a mixture solvent of methanol-water to obtain 1.63 g of 2-amino-4-acetylphenol (Yield: 39.1%).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][C:14]1[CH:19]=[C:18]([C:20]([OH:22])=O)[CH:17]=[CH:16][N:15]=1.[CH3:23][O:24][C:25](=[O:36])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1[Cl:35].[H-].[Na+].[NH4+].[Cl-]>CN(C=O)C>[CH3:23][O:24][C:25](=[O:36])[CH:26]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1[Cl:35])[C:20]([C:18]1[CH:17]=[CH:16][N:15]=[C:14]([CH3:13])[CH:19]=1)=[O:22]
Reactant: COC(=O)Cc1ccc(OC)cc1Cl
Reactant: Cc1cc(C(=O)O)ccn1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)c1ccnc(C)c1)c1ccc(OC)cc1Cl
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 43 %

Procedure:
1,1′-Carbonyldiimidazole (12.35 g) was added to a solution of 2-methylpyridine-4-carboxylic acid (9.95 g, [CAS Reg. No. 4021-11-8]) in DMF (500 mL). The mixture was stirred for 1.5 hours at 50° C. The reaction mixture was cooled to −10° C. in an ice/methanol bath and (2-chloro-4-methoxy-phenyl)-acetic acid methyl ester (15.57 g) (obtained in Example 93, step 1) was added to the light brown solution followed by addition of sodium hydride (50% in mineral oil, 11.59 g) in small portions over 30 minutes. The viscous reaction mixture was stirred at 0° C. for 1.5 hours, until the reaction was complete. The reaction mixture was poured into a sat. NH4Cl solution and extracted two times with ethyl acetate. The organic layers were washed with H2O and brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a yellow oil (13.95 g, 43%). MS (m/e)=334.2 [MH+].
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=1)=[O:8].[NH:24]1[CH2:28][CH2:27][C@H:26]([CH2:29][OH:30])[CH2:25]1>>[Br:1][C:2]1[C:3]([N:24]2[CH2:28][CH2:27][C@H:26]([CH2:29][OH:30])[CH2:25]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(Cl)c(Br)c1
Reactant: OC[C@H]1CCNC1
Product: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 33.1 using 5-bromo-6-chloro-N-(3-fluoro-4-(trifluoromethoxy)phenyl)nicotinamide (Stage 198.2) and (S)-1-pyrrolidin-3-yl-methanol to afford an off-white crystalline solid. HPLC (Condition 4) tR=5.99 min, UPLC-MS (Condition 3) tR=1.18 min, m/z=478.1/480.1 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:29])[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2[NH:19][C:20]2[CH:28]=[C:27]3[C:23]([CH:24]=[N:25][NH:26]3)=[CH:22][CH:21]=2)=[CH:7][C:6]=1[NH:30][CH2:31][CH2:32]O)([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:35].C1(P(C(P(C2C=CC=CC=2)C2C=CC=CC=2)(C)C)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:35][CH2:32][CH2:31][NH:30][C:6]1[CH:7]=[C:8]([NH:11][C:12](=[O:29])[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2[NH:19][C:20]2[CH:28]=[C:27]3[C:23]([CH:24]=[N:25][NH:26]3)=[CH:22][CH:21]=2)[CH:9]=[CH:10][C:5]=1[C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)c1ccc(NC(=O)c2cccnc2Nc2ccc3cn[nH]c3c2)cc1NCCO
Agent: CC(C)(P(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(NC(=O)c2cccnc2Nc2ccc3cn[nH]c3c2)cc1NCCBr
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The title compound was prepared from N-[4-tert-butyl-3-(2-hydroxy-ethylamino)-phenyl]-2-(1H-indazol-6-ylamino)-nicotinamide by dissolving in CH2Cl2 (5 ml) and adding CBr4 (215 mg) and bis(diphenylphosphino)-propane (270 mg). The reaction was stirred at RT for 3 h then worked up with partitioning between H2O and CH2Cl2. The aqueous layer was extracted with CH2Cl2 (3×) and the combined organic fractions were washed with H2O, brine and dried (MgSO4). The crude material was purified by flash chromatography to yield a yellow foamed solid. M+H 508.
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[C:20]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=3[F:29])=[C:19]([F:30])[C:15]3[N:16]=[CH:17][S:18][C:14]=3[CH:13]=2)=[O:11])[CH2:4][O:3]1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10]([C:12]1[C:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])=[C:19]([F:30])[C:15]2[N:16]=[CH:17][S:18][C:14]=2[CH:13]=1)=[O:11]
Reactant: CC1(C)OCC(CONC(=O)c2cc3scnc3c(F)c2Nc2ccc(I)cc2F)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NOCC(O)CO)c1cc2scnc2c(F)c1Nc1ccc(I)cc1F
Yield: 70 %

Procedure:
To a solution of N-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxamide (475 mg, 0.85 mmol) in CH2Cl2 (10 mL) was added trifluoroacetic acid (0.2 mL, 2.69 mmol). The mixture was stirred for 1 h and neutralized with saturated sodium bicarbonate (aq.). The aqueous layer was extracted by CH2Cl2 (10 mL×2). The combined organic layers were washed by water (10 mL) and brine (10 mL) sequentially, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH2Cl2/MeOH, 20:1, v/v) to afford the desired product (white solid, 310 mg, 45.4% yield for two steps). 1H NMR (400 MHz, DMSO-d6): δ 11.82 (s, 1H), 9.56 (s, 1H), 8.23 (s, 1H), 8.15 (s, 1H), 7.57 (d, 1H), 7.32 (d, 1H), 6.47 (m, 1H), 4.85 (d, 1H), 4.62 (m, 1H), 3.86 (m, 1H), 3.71 (m, 2H), 3.35 (m, 2H). MS APCI (+) m/z: 522.5 [M+H].
Reaction SMILES: [CH3:1][C@:2]1([C:19]([O-])=[O:20])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1.[Li+].Cl.[NH2:24][C@H:25]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)[CH3:26]>>[CH3:1][C@:2]1([C:19]([NH:24][C@H:25]([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)[CH3:26])=[O:20])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:11][CH:10]=1
Reactant: C[C@]1(C(=O)[O-])CCCCN1Cc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Agent: [Li+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@@]2(C)CCCCN2Cc2ccc(C(F)(F)F)cc2)cc1
Yield: 33.2 %

Procedure:
The title compound (D158) (10 mg) was prepared according to the general procedure for amides preparation (Method B) starting from lithium (R)-2-methyl-1-(4-(trifluoromethyl)benzyl)piperidine-2-carboxylate (D112) (20 mg) and (S)-methyl 4-(1-aminoethyl)benzoate hydrochloride (16.32 mg).
Reaction SMILES: [F:1][C:2]1([F:49])[CH2:7][C@H:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([S:16]([N:19](CC3C=CC(OC)=CC=3OC)[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:18])=[O:17])=[C:11]([F:37])[CH:10]=2)[C@@H:5]([C:38]2[CH:39]=[N:40][N:41](C3CCCCO3)[CH:42]=2)[CH2:4][CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.ClCCl>CO>[F:49][C:2]1([F:1])[CH2:7][C@H:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([S:16]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:17])=[O:18])=[C:11]([F:37])[CH:10]=2)[C@@H:5]([C:38]2[CH:42]=[N:41][NH:40][CH:39]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CC(F)(F)CC[C@@H]3c3cnn(C4CCCCO4)c3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: O=S(=O)(Nc1ccncn1)c1cc(F)c(O[C@H]2CC(F)(F)CC[C@@H]2c2cn[nH]c2)cc1F
Yield: 70.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 22c by using the 4-({(1S*,2R*)-5,5-difluoro-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (170 mg, 0.24 mmol) prepared in Example 103d, triethylsilane (0.20 mL), trifluoroacetic acid (2.0 mL), dichloromethane (2.0 mL) and methanol (2.0 mL), to yield the title compound (80 mg, 72%) as a colorless solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][O:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[NH:8]1[CH2:13][CH2:12][C:11]2([C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][O:14]2)[CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: c1ccc(CN2CCC3(CC2)OCCc2ccccc23)cc1
Agent: [Pd]
Solvent: CCO
Product: c1ccc2c(c1)CCOC21CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
A solution of 1′-benzyl-3,4-dihydrospiro[isochromene-1,4′-piperidine] (0.40 g, 1.3 mmol) in ethanol (15 ml) was purged with argon. After addition of the palladium catalyst (10% Pd on activated charcoal, 0.14 g) the reaction vessel was filled with hydrogen gas. The mixture was stirred for 18 h at room temperature. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give the title compound (0.23 g) as white solid with a purity of approx. 88% as assessed by 1H-NMR (contaminated with 1′-ethyl-3,4-dihydrospiro[isochromene-1,4′-piperidine]). MS m/e: 204 (M+H+).
Reaction SMILES: C([O:8][C:9]([C:11]1[S:12][C:13]([CH:16]=[CH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:14][CH:15]=1)=[O:10])C1C=CC=CC=1>CO.C(Cl)(Cl)Cl.[OH-].[Pd+2].[OH-]>[C:21]([O:20][C:18]([CH2:17][CH2:16][C:13]1[S:12][C:11]([C:9]([OH:10])=[O:8])=[CH:15][CH:14]=1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(C(=O)OCc2ccccc2)s1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)CCc1ccc(C(=O)O)s1

Procedure:
The compound (0.5 g, 1.45 mmol) obtained in step 1 was dissolved in methanol (5 mL) and chloroform (0.5 mL), palladium hydroxide (0.1 g) was added, and the mixture was dried at room temperature under a hydrogen atmosphere overnight. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure to give the title compound.
Reaction SMILES: [N:1]1([C:7]2[C:8]([N:13]3[CH2:18][CH2:17][CH:16]([CH2:19][OH:20])[CH2:15][CH2:14]3)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:21]([N:23]1[CH:27]=[C:26]([CH:28]=O)[CH:25]=[N:24]1)[CH3:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].[ClH:46]>ClCCCl.C(#N)C.C(Cl)Cl>[ClH:46].[CH2:21]([N:23]1[CH:27]=[C:26]([CH2:28][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[C:8]([N:13]4[CH2:14][CH2:15][CH:16]([CH2:19][OH:20])[CH2:17][CH2:18]4)=[N:9][CH:10]=[CH:11][CH:12]=3)[CH2:6][CH2:5]2)[CH:25]=[N:24]1)[CH3:22]
Reactant: CCn1cc(C=O)cn1
Reactant: OCC1CCN(c2ncccc2N2CCNCC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: ClCCCl
Product: CCn1cc(CN2CCN(c3cccnc3N3CCC(CO)CC3)CC2)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.3 %

Procedure:
To a solution of (3′-piperazin-1-yl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methanol (0.145 g, 0.524 mmol, 1 eq) and 1-ethyl-1H-pyrazole-4-carbaldehyde (97.69 mg, 0.787 mmol, 1.5 eq) in 1,2-dichloroethane (10 mL) add sodium triacetoxyborohydride (166.79 mg, 0.787 mmol, 1.5 eq) in one portion as a solid. Stir the mixture at room temperature under nitrogen for 20 hr. Add 2 M aqueous sodium hydroxide solution (20 ml) and DCM (20 ml). Separate using a phase separator and extract the aqueous layer with DCM (10 ml). Concentrate the combined organic extracts and purify by high pH reverse phase HPLC. Dissolve this material (120 mg, 0.31 mmol) in the minimum quantity of 50% aqueous acetonitrile. Add 2 M aqueous hydrogen chloride (155 μL, 0.31 mmol) and lyophilize to give the title compound (127 mg, 58%). MS (m/z): 385.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Li]CCCC.[CH:15](N1CCCCC1)=[O:16]>C1COCC1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([CH3:9])=[C:2]([CH:7]=1)[CH:15]=[O:16]
Reactant: O=CN1CCCCC1
Reactant: Cc1ccc(Cl)cc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(Cl)cc1C=O
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-4-chlorotoluene (20.0 g; 97.3 mmol) in 300 mL of THF at −78° C. was added dropwise a 2.5 M solution of n-BuLi (102.2 mmol). After 30 min of stirring at that temperature, 1-formylpiperidine (11.4 mL) in 10 mL of THF was added and the solution left for 1 h. It was brought to 0° C. , quenched with NH4OAc (25%) and diluted with EtOAc. The organic phase was dried over Na2SO4, filtered and the solvent removed to yield 13.3 g of the title compound.