Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([OH:16])[C:6]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=3[S:9][C:7]=2[N:8]=1.C(N([CH2:22][CH3:23])CC)C.[OH2:24]>C(OC(=O)C)(=O)C>[OH:16][C:5]1[C:6]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=3[S:9][C:7]=2[N:8]=[C:3]([CH2:2][O:1][C:22](=[O:24])[CH3:23])[N:4]=1
Reactant: O
Reactant: OCc1nc(O)c2c3c(sc2n1)CCCC3
Reactant: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCc1nc(O)c2c3c(sc2n1)CCCC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
The 2-hydroxymethyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-ol (4.5 g, 0.019 mol) in 10 ml of acetic anhydride was treated with triethylamine (3.8 g, 0.038 mol) at 0° C., and the mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water and the resulting solid was filtered, washed with water & hexanes, and dried to provide acetic acid 4-hydroxy-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-ylmethyl ester (4 g, 75%) as yellow solid. 1H NMR (400 MHz, CDCl3): δ 1.74-1.90 (m, 4H), 2.21 (s, 3H), 2.70-2.80 (m, 2H), 2.95-3.02 (m, 2H), 5.07 (s, 2H), 10.52 (brs, 1H); LC-MS: [M+H]=279.1 m/z.
Reaction SMILES: [CH3:1][C:2]1([CH3:47])[C@@H:5]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])[CH2:4][C@H:3]1[NH:14][C:15]([C@:17]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:18]1[C@@H:19]1[C@@:32]([CH3:35])([CH2:33][CH2:34]2)[C@@:31]2([CH3:36])[C@@H:22]([C@:23]3([CH3:40])[C@@H:28]([CH2:29][CH2:30]2)[C:27]([CH3:38])([CH3:37])[C@@H:26]([OH:39])[CH2:25][CH2:24]3)[CH2:21][CH2:20]1)=[O:16].[CH3:48][C:49]1([CH3:56])[CH2:54][C:53](=[O:55])[O:52][C:50]1=[O:51]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1.CCOC(C)=O>[CH3:1][C:2]1([CH3:47])[C@@H:5]([C:6]([N:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[O:7])[CH2:4][C@H:3]1[NH:14][C:15]([C@:17]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:18]1[C@@H:19]1[C@@:32]([CH3:35])([CH2:33][CH2:34]2)[C@@:31]2([CH3:36])[C@@H:22]([C@:23]3([CH3:40])[C@@H:28]([CH2:29][CH2:30]2)[C:27]([CH3:37])([CH3:38])[C@@H:26]([O:39][C:53](=[O:55])[CH2:54][C:49]([CH3:56])([CH3:48])[C:50]([OH:52])=[O:51])[CH2:25][CH2:24]3)[CH2:21][CH2:20]1)=[O:16]
Reactant: CC1(C)CC(=O)OC1=O
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C[C@H](C(=O)N4CCCCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C[C@H](C(=O)N4CCCCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 39.6 %

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-N-((1R,3S)-2,2-dimethyl-3-(piperidine-1-carbonyl)cyclobutyl)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxamide (Example 47, 0.190 g, 0.293 mmol) 2,2-Dimethylsuccinic anhydride (0.375 g, 2.932 mmol) and DMAP (0.071 g, 0.586 mmol) in pyridine (10 ml) were added at room temperature and refluxed for about 24 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc, washed with aqueous 1N HCl, then water and brine, and dried over Na2SO4 then the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 20% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.090 g; Yield: 39.6%; 1H NMR (300 MHz, CDCl3): δ 5.96 (d, 111, J=8.1 Hz), 4.72 (s, 1H), 4.58 (s, 1H), 4.52-4.44 (m, 1H), 4.16-4.07 (m, 1H), 3.79-3.58 (m, 1H), 3.50-3.31 (m, 3H), 3.18-3.07 (m, 1H), 2.91-2.87 (m, 1H), 2.71-2.56 (m, 2H), 2.56-2.37 (m, 2H), 2.30-2.19 (m, 1H), 2.01-1.81 (m, 3H), 1.80-1.10 (m, 35H), 0.95, 0.93, 0.88, 0.87 (s, 21H); Mass: [M+1]+ 777 (30%), [M+Na]+ 799 (100%); IR (KBr, cm−1): 3400, 2947, 2868, 1733, 1622, 1456, 1390, 1369, 1320, 1252, 1231, 1192, 1150, 1021, 978, 881; HPLC: 97.37%; M.R: 168.5° C.-176.9° C.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8](/[CH:10]=[CH:11]/[C:12]2[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][CH:13]=2)=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([C:5]1[O:9][C:8]([CH2:10][CH2:11][C:12]2[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][CH:13]=2)=[N:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Nc1ncc(/C=C/c2ncc(C(C)(C)C)o2)s1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ncc(CCc2ncc(C(C)(C)C)o2)s1
Reaction time: 24 h

Procedure:
A solution N-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]acetamide (67 mg, 0.23 mmol) in ethyl acetate (10 mL) was added to a suspension of pre-reduced Pd/C (10%) in ethyl acetate (5 mL). The reaction flask was fitted with a hydrogen balloon and stirred for 24 hours. The reaction was filtered, and the mixture was resubmitted to hydrogenation using the same conditions as above. After an additional 24 hours, the reaction was filtered through a plug of celite, concentrated, and purified by chromatography (SiO2, 5% MeOH/CHCl3) to give N-[5-(2-(5-t-butyl-oxazol-2-yl)-ethyl)-thiazol-2-yl]-acetamide as a white solid (3.5 mg, 5%, C14H19N3O2S, MS m/e 294 (M+H)+). HPLC-HI 91% at 6.75 min (Zorbax SB C18 column 4.6×75 mm, 10-90% aqueous methanol over 8 minutes containing 0.1% TFA, 2.5 mL/min, monitoring at 220 nm).
Reaction SMILES: [C:1]([O:4][C:5](=O)C)(=O)C.[C:8]([NH:16][C@H:17]([C:22]([OH:24])=[O:23])[CH2:18][CH2:19][S:20][CH3:21])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:8]([NH:16][C:17]1([CH2:18][CH2:19][S:20][CH3:21])[CH2:5][O:4][CH2:1][O:23][C:22]1=[O:24])(=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CSCC[C@H](NC(=O)c1ccccc1)C(=O)O
Reactant: CC(=O)OC(C)=O
Product: CSCCC1(NC(=O)c2ccccc2)COCOC1=O
Temperature: 100 °C
Reaction time: 17 h

Procedure:
In accordance with the literature (J. Peptide Sci., 2001, 7, 619-625), 10 g of DL-methionine was added to 20 ml of water and 11.5 ml of 6 N NaOH, and dissolved therein. While keeping pH at 10.5 to 11.5, 8.6 ml of benzoyl chloride was added thereto, and the mixture was stirred at room temperature for two hours. The resulting reaction mixture was filtrated and then washed with diethyl ether. Concentrated hydrochloric acid was gradually added to adjust the pH to 1 to precipitate a crystal. The crystal was filtrated, washed with water, and dried under reduced pressure to obtain 16.2 g of N-benzoylmethionine. 24 ml of acetic anhydride was added to 4.9 g of obtained N-benzoylmethionine, the solution was heated at 100° C. for 4 hours, then cooled to room temperature, and the solvent was evaporated. The steps of adding 24 ml of toluene to the residue and evaporating the solvent were repeated twice. The, the residue was dissolved in 2.5 ml of pyridine, 10 ml of 35% formaldehyde solution was added, and the solution was stirred at room temperature for 17 hours. 40 ml of water was added to the resulting reaction solution, which was then extracted with 40 ml of ethyl acetate. The extract was washed with water and saturated brine, and dried on magnesium sulfate. Magnesium sulfate was removed and the solvent was evaporated. The residue was purified by silica gel chromatography (hexane/ethyl acetate 4/1 to 1/1). After evaporating the solvent, 2.56 g of 5-benzoylamino-5-methylthioethyl-4-oxo-1,3-dioxane was obtained. 7.5 ml of 6 N hydrochloric acid was added to 1.06 g of the obtained 5-benzoylamino-5-methylthioethyl-4-oxo-1,3-dioxane, which was then heated and refluxed for 7 hours. The reaction solution was filtrated, and then the solvent was evaporated. 5 ml of water was added to the residue, which was then purified using an ion exchange resin (Amberlite 120). After evaporating the solvent, the resulting crystal was recrystallized from water/ethanol, and dried under reduced pressure to obtain 129 mg of α-methylthioethyl-serine. NMR of this compound was measured, and almost agreed with the values described in the literature.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][C:3]([OH:5])=[O:4].[CH2:8]([K])[CH3:9].[Mg+2].[Cl-].[Cl-].[CH3:14][O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21](C(O)=O)[CH2:20][CH:19]1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=1)=[O:17].C(N1C=CN=C1)(N1C=CN=C1)=O>C(OCC)C.O.C1COCC1>[CH2:8]([O:5][C:3](=[O:4])[CH2:2][C:1]([CH:21]1[CH2:22][CH2:23][N:18]([C:16]([O:15][CH3:14])=[O:17])[CH:19]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([S:34]([CH3:37])(=[O:35])=[O:36])=[CH:32][CH:33]=2)[CH2:20]1)=[O:7])[CH3:9]
Reactant: O=C(O)CC(=O)O
Reactant: CC[K]
Reactant: COC(=O)N1CCC(C(=O)O)CC1Cc1ccc(S(C)(=O)=O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(=O)C1CCN(C(=O)OC)C(Cc2ccc(S(C)(=O)=O)cc2)C1
Temperature: 50 °C
Reaction time: 4 h
Yield: 79.3 %

Procedure:
Ethyl potassium malonate (2.414 g, 14.18 mmol) and MgCl2 (1.125 g, 11.82 mmol) were added to dry THF (75 mL). The reaction flask was stirred vigorously for 4 h at 50° C. (flask 1). 1-(Methoxycarbonyl)-2-(4-(methylsulfonyl)benzyl)piperidine-4-carboxylic acid (4.2 g, 11.82 mmol) (reference compound 51) and carbonyldiimidazole (2.87 g, 17.73 mmol) were added to dry THF (75 mL) at room temperature (flask 2). More di(1H-imidazol-1-yl)methanone (0.5 g) was added and after 2 h the contents of flask 2 was added to flask 1 at room temperature and stirred overnight. The reaction mixture was dissolved between water and diethyl ether. The organic phase was isolated, dried with Na2SO4, filtered through celite and the solvent was evaporated. Chromatography using the Biotage equipment. Gradient eluation using ethylacetate-heptane, started 10-90 and ended 100-0. Methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(methylsulfonyl)benzyl)piperidine-1-carboxylate (3.99 g, 79%) was isolated.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:13][C:14]1C=C(C)C=CC=1S([O-])(=O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-]#[N:32].[K+].C1OCCOCCOCCOCCOCCOC1.[I-].[K+]>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:13][C:14]#[N:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)[O-])c(C[C@@H](NC(=O)OCc2ccccc2)c2ccccc2)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC[C@H](NC(=O)OCc1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
60.5 g of ((R)-2-benzyloxycarbonylamino-2-phenylethyl)-4-methylphenylsulphonate (142.2 mmol) are dissolved in 675 ml of dimethylformamide. 13.9 g of potassium cyanide (213.3 mmol), 5.64 g of 18-crown-6 (21.33 mmol) and 520 mg of potassium iodide (3.13 mmol) are added and the mixture is stirred at 50° C. for 20 hours. The reaction solution is poured into 500 ml of ice water and this mixture is subsequently stirred at 0° C. for 5 hours. The mixture is filtered with suction and the precipitate is dissolved in ethyl acetate. The organic phase is washed three times with water, dried over magnesium sulphate and concentrated in vacuo. The residue is triturated with diethyl ether, filtered off with suction, washed with diethyl ether and dried over phosphorus pentoxide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](Cl)=[O:14])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([NH2:36])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:19][CH:18]=1.C(N(CC)CC)C.O>C(Cl)(Cl)Cl>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([NH:36][C:13]([CH2:12][C:9]2[CH:10]=[CH:11][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)=[O:14])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N:30]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)=[CH:19][CH:18]=1
Reactant: NC(c1ccc(Cl)cc1)c1ccccc1N1CCCCC1
Reactant: CCOC(=O)c1ccc(CC(=O)Cl)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(CC(=O)NC(c2ccc(Cl)cc2)c2ccccc2N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5 gm (22.1 m mol) of 4-ethoxycarbonylphenylacetyl chloride in 20 ml of chloroform was added dropwise, under cooling with ice, to a solution of 6.02 gm (20 m mol) of α-(4-chloro-phenyl)-2-piperidino-benzylamine and 3.5 ml (25 m mol) of triethylamine in 50 ml of chloroform. The mixture was stirred for two hours at ambient temperature, added to water, and extracted with chloroform. The extracts were dried and concentrated by evaporation. The evaporation residue was chromatographed on silica gel by use of toluene/ethyl acetate (5:1) as eluant.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1Cl)=[O:13])[CH2:8]2.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:13])[CH2:8]2
Reactant: CC(C)(C)n1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Reactant: C1CCNCC1
Product: CC(C)(C)n1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1N1CCCCC1

Procedure:
Heating a mixture of 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 36, 101 mg; 0.30 mmol) and piperidine (0.30 mL; 3.0 mmol) under microwave irradiation according to the procedure described in Example 37, Step 5 provided after purification by reverse phase HPLC, 1-tert-butyl-5-piperidin-1-yl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (19 mg, 16%) as an off-white powder. ES-HRMS m/e calcd for C23H37N4O (M+H+) 385.2962, found 385.2958.
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:25][CH3:26])[C:8](=[O:24])[CH2:9][CH2:10][CH:11]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[C:12]2=[O:23])=[CH:5][N:4]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[N:3]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[C:6]([N:7]([CH2:25][CH3:26])[C:8](=[O:24])[CH2:9][CH2:10][CH:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:23])=[CH:5][N:4]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[N:3]=1
Reactant: CCN(C(=O)CCC1CCN(C(=O)OC(C)(C)C)C1=O)c1cn(-c2cccnc2)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(C(=O)CCC1CCNC1=O)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 3-(3-((3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(ethyl)amino)-3-oxopropyl)-2-oxopyrrolidine-1-carboxylate (0.076 g, 0.17 mmol) in dry CH2Cl2 (0.33 mL), TFA (0.33 mL) was added at room temperature under N2. The reaction was stirred at room temperature for about 90 minutes. Saturated aqueous NaHCO3 (about 10 mL) was carefully added until reaction mixture became basic. The product was extracted with CH2Cl2 (3×10 mL), dried and concentrated. The residue was purified by silica gel chromatography by eluting with 0%-15% MeOH/CH2Cl2 to afford the title compound F131 as a white foam (0.041 g, 66%).
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]4)=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:29])[CH2:3][CH2:4]2)=[O:9])=[CH:33][CH:32]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccc(Cl)cc2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 4-chlorophenylboronic acid. The title compound was obtained in 93% yield as light yellow foam. MS (m/e): 516.2 (MH+, 100%).
Reaction SMILES: [CH:1]([NH:14][C:15](=[O:30])[O:16][CH:17]1[CH2:22][CH2:21][N:20](CC2C=CC=CC=2)[CH2:19][CH2:18]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=O>CO>[CH:1]([NH:14][C:15](=[O:30])[O:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(NC(c1ccccc1)c1ccccc1)OC1CCN(Cc2ccccc2)CC1
Solvent: CO
Solvent: O=CO
Product: O=C(NC(c1ccccc1)c1ccccc1)OC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-benzylpiperidin-4-yl benzhydrylcarbamate (46.3 g, 119 mmol) and formic acid (100 mL) in methanol (600 mL) was stirred at room temperature and nitrogen was bubbled through the reaction mixture for about 20 min. The reaction mixture was then transferred to a slurry of 10% palladium on carbon in water (75 mL.) via a thick needle and stirring was continued overnight. The reaction mixture was filtered, concentrated under reduced pressure, and dried under high vacuum overnight. The residue was then diluted with ethyl acetate and washed with satd. NaHCO3 (aq.). The organic layer was separated, concentrated under reduced pressure, diluted with 0.1 N HCl (pH3) and ether. The ether layer was separated and the aqueous layer was basified with 1N NaOH (aq) to pH13-14. to give a solid which was filtered to yield piperidin-4-yl benzhydrylcarbamate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][CH:8]=[CH:7][C:6]2=O.S(Cl)([Cl:18])=O>CN(C=O)C>[ClH:18].[Cl:18][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2[nH]ccc(=O)c2cc1OC
Solvent: CN(C)C=O
Product: COc1cc2nccc(Cl)c2cc1OC
Product: Cl

Procedure:
A suspension of 6,7-dimethoxy-1,4-dihydroquinolin-4-one (3 g, 14 mmol), (J. Chem. Soc. 1940, 1209), in thionyl chloride (60 ml) and DMF (0.3 ml) was heated at reflux for 3 hours. Excess thionyl chloride was removed by evaporation and the residue azeotroped with toluene and washed with ether to give 4-chloro-6,7-dimethoxyquinoline hydrochloride.
Reaction SMILES: [C:1]([C:5]1[NH:9][N:8]=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]([C:10]([F:12])([F:13])[F:11])[N:8]([CH2:21][C:22]([N:24]2[CH2:25][CH2:26][N:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:28][CH2:29]2)=[O:23])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: CC(C)(C)c1cc(C(F)(F)F)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)c1cc(C(F)(F)F)n(CC(=O)N2CCN(c3ccc(F)cc3)CC2)n1

Procedure:
Protocol T was followed using 5-tert-Butyl-3-trifluoromethyl-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1) afforded the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3); 6.92–7.08 (t, 2H), 6.82–6.88 (dd, 2H), 6.52 (s, 1H), 5.08 (s, 2H), 3.70–3.80 (m, 2H), 3.58–3.68 (m, 2H), 3.05–3.15 (m, 4H), 1.3 (s, 9H). 13C NMR (400 MHz, CDCl3): 164, 161.2, 158.2, 156.4, 147.2, 118.4, 118.2, 115.8, 115.4, 108.2, 54, 50.6, 50.2, 45, 44, 30.
Reaction SMILES: [CH:1]1([CH:7]([O:20][CH3:21])[C:8]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:9]=2[CH:10]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][N:23]1[N:27]=[N:26][C:25]([NH2:28])=[N:24]1.[BH4-].[Na+]>C1(C)C=CC=CC=1>[CH:1]1([CH:7]([O:20][CH3:21])[C:8]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:9]=2[CH2:10][NH:28][C:25]2[N:26]=[N:27][N:23]([CH3:22])[N:24]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1nnc(N)n1
Reactant: COC(c1ccc(C(F)(F)F)cc1C=O)C1CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(c1ccc(C(F)(F)F)cc1CNc1nnn(C)n1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
A solution of 2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzaldehyde (90 mg, 0.30 mmol) and 2-methyl-2H-tetrazol-5-amine (35.6 mg, 0.36 mol) in toluene (1.5 ml) was heated at 50° C. for overnight. Solvent was removed in vacuo and reaction mixture was diluted with ethanol (2 ml) and treated with sodium borohydride (21.8 mg, 0.577 mmol) and stirred at room temperature for overnight. Reaction mixture was concentrated in vacuo and diluted with ethyl acetate (100 ml) and washed with water (30 ml). Organic layer was dried over anhydrous magnesium sulphate and concentrated in vacuo. The crude product was purified on Biotage column (12+M), eluting with 7% ethyl acetate in heptane (1 CV), 7-60% (10CV), 60% (2CV) to yield the title compound (65 mg, 58%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.1 (m, 4H) 1.25 (s, 2H) 1.62 (m, 3H) 1.76 (m, 1H) 1.99 (d, J=14.1 Hz, 1H) 3.16 (s, 3H) 4.13 (s, 3H) 4.2 (d, J=7.5 Hz, 1H) 4.48 (dd, J=5.4 Hz, 1H) 4.65 (dd, J=6.6 Hz, 1H) 4.93 (m, 1H) 7.47 (d, J=7.8 Hz, 1H) 7.54 (d, J=8.3 Hz, 1H) 7.67 (s, 1H). MS (ES+) Calc: 383.4, Found: 349.3 (M−34).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]([C:13]2[C:14]([CH2:27][CH2:28][CH3:29])=[N:15][CH:16]=[CH:17][C:18]=2[O:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[N:11][OH:12])=[C:4](F)[C:3]=1[Si](C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]2[C:10]([C:13]3[C:14]([CH2:27][CH2:28][CH3:29])=[N:15][CH:16]=[CH:17][C:18]=3[O:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[N:11][O:12][C:4]=2[CH:3]=1
Reactant: CCCc1nccc(Oc2ccc(Cl)cc2)c1C(=NO)c1cc(OC)c(Cl)c([Si](C)(C)C)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1nccc(Oc2ccc(Cl)cc2)c1-c1noc2cc(Cl)c(OC)cc12
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of the oxime from Step 8 (12.0 g, 27 mmol) and cesium carbonate (17 g, 54 mmol) in DMF (200 mL) was stirred at 80° C. for 18 h. The reaction was diluted with ethyl acetate and washed with water. The crude product was purified by chromatography on silica gel to give the title product.