Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1>C(#N)C.CN(C)C=O>[OH:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3]([NH:2][CH3:1])=[O:4])=[CH:7][CH:8]=1
Reactant: Nc1ccc(O)cc1
Reactant: CN=C=O
Solvent: CC#N
Solvent: CN(C)C=O
Product: CNC(=O)Nc1ccc(O)cc1
Reaction time: 12 h
Yield: 51.8 %

Procedure:
A solution of methyl isocyanate (6 g) in acetonitrile (10 ml) was added dropwise to a solution of 4-aminophenol (10.9 g) in N,N-dimethylformamide (50 ml) at 10° C. to 20° C. The mixture was stirred at 25° C. to 35° C. for 12 hours and evaporated under reduced pressure. Water (100 ml) was added to the resulting syrup and the mixture was stirred for 30 minutes. The mixture became thick in the course of stirring. The solid substance was collected by filtration, washed with cold water and recrystallized from aqueous alcohol to give 8.6 g of N-(4-hydroxyphenyl)-N'-methylurea of melting point 169°-171° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:20](Cl)=[O:21])[C:5]2[O:10][CH:9]([C:11]([Cl:14])([Cl:13])[Cl:12])[O:8][CH:7]([C:15]([Cl:18])([Cl:17])[Cl:16])[C:6]=2[CH:19]=1.[NH3:23]>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:20]([NH2:23])=[O:21])[C:5]2[O:10][CH:9]([C:11]([Cl:14])([Cl:13])[Cl:12])[O:8][CH:7]([C:15]([Cl:18])([Cl:17])[Cl:16])[C:6]=2[CH:19]=1
Reactant: N
Reactant: Cc1cc(C(=O)Cl)c2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Solvent: CCO
Product: Cc1cc(C(N)=O)c2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2

Procedure:
A mixture of 6-methyl-2,4-bis(trichloromethyl)benzo[1,3]dioxin-8-carbonyl chloride (2.0 g.) concentrated ammonia (10 ml.) and ethanol (10 ml.) was heated under reflux for 2 hours. A complete solution was not obtained, but the reaction mixture was cooled and filtered, and the solid product was washed with ethanol and dried, to give 6-methyl-2,4-bis(trichloromethyl)benzo[1,3]dioxin-8-carboxamide, m.p. 281°-283° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([CH3:23])[CH2:11][N:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH2:14][C:13]1=[O:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C[O:46][CH2:45]C1>>[Si:1]([O:8][CH2:9][C@@H:10]([CH3:23])[CH2:11][N:12]1[C:17]2[CH:18]=[C:19]([O:46][CH3:45])[CH:20]=[CH:21][C:16]=2[O:15][CH2:14][C:13]1=[O:22])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(CO[Si](C)(C)C(C)(C)C)CN1C(=O)COc2ccccc21
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: COc1ccc2c(c1)N(C[C@H](C)CO[Si](C)(C)C(C)(C)C)C(=O)CO2
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a 100 mL flask was charged 4-[3-(tert-Butyldimethylsilanyloxy)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one (1.0 equiv) and Tetrabutylammonium flouride monohydrate (1.3 equiv) and dissolved in 40 mL dry THF. The reaction was stirred in rt under an inert atmosphere for 20-24 hours. The reaction mixture was concentrated and purified by CC (Heptane/EtOAc).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:20][CH2:19][NH:18][CH2:17][C@H:16]2[F:21])=[CH:11][CH:10]=1)C1C=CC=CC=1>CC(O)C.[Pd]>[F:21][C@H:16]1[C@@H:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[CH2:20][CH2:19][NH:18][CH2:17]1
Reactant: F[C@@H]1CNCC[C@@H]1c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CC(C)O
Product: Oc1ccc([C@H]2CCNC[C@H]2F)cc1
Yield: 93.9 %

Procedure:
To 10% Pd/C (40 mg) under nitrogen was added a solution of cis-4-(4-(benzyloxy)phenyl)-3-fluoropiperidine (140 mg, 0.49 mmol) in IPA (4 mL). The mixture was stirred under a hydrogen atmosphere using balloon pressure at rt for 2 h. The Pd/C was removed by filtration through a glass fiber filter. The filtrate was concentrated to give cis-4-(3-fluoropiperidin-4-yl)phenol (90 mg, 0.46 mmol, 94% yield). LC/MS (Method J, M+H)+=196.25, RT=0.706 min; 1H NMR (500 MHz, methanol-d4) δ 7.14 (d, J=8.4 Hz, 2H), 6.74 (d, J=8.7 Hz, 2H), 4.63 (d, J=48.4 Hz, 1H), 3.30-3.22 (m, 1H), 3.15 (dt, J=13.1, 2.0 Hz, 1H), 2.95-2.66 (m, 3H), 2.12 (qd, J=13.0, 4.2 Hz, 1H), 1.64 (dd, J=13.4, 3.0 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].F[C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21]>CCO>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][O:8][CH3:9])[C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21]
Reactant: COCCNCCOC
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CCO
Product: COCCN(CCOC)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
Bis(2-methoxyethyl)amine (Aldrich B4,820-7; 1.6 g; 12 mmol; 3 eq.) was added to a solution of 4-fluoro-3-nitrobenzoic acid (740 mg; 4 mmol; 1 eq.) in EtOH (20 mL) and the resulting mixture was stirred at room temperature for 2 hours then at 70° C. for 20 hours. The solution was concentrated in vacuo and the residue was partitioned between NaOH 0.5M and Et2O. The aqueous layer was acidified to pH 2 with HCl 5M, extracted with ethyl acetate (3×) and the combined organic phase was dried over magnesium sulfate. After evaporation of the solvent, the residue was crystallised from ethyl acetate/n-pentane to afford the title compound (1.12 g, 94%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([C:11]1[S:12][C:13]([C:16]2[CH:21]=[C:20]([NH:22][C:23]3[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=3)[CH:19]=[C:18]([CH3:33])[CH:17]=2)=[CH:14][N:15]=1)([CH3:10])[C:3]([O:5]C(C)(C)C)=[O:4].Cl>O1CCOCC1.CCOCC>[CH3:10][C:2]([C:11]1[S:12][C:13]([C:16]2[CH:21]=[C:20]([NH:22][C:23]3[N:28]=[C:27]([C:29]([F:31])([F:32])[F:30])[CH:26]=[CH:25][N:24]=3)[CH:19]=[C:18]([CH3:33])[CH:17]=2)=[CH:14][N:15]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(C)(C)C(=O)OC(C)(C)C)s2)c1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(C)(C)C(=O)O)s2)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 106.2 %

Procedure:
tert-Butyl 2-methyl-2-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol-2-yl]propanoate (400 mg, 0.836 mmol) was taken up in dioxane (8 mL) before adding HCl (4 M in dioxane, 16 mL, 64.0 mmol). The reaction was stirred at room temperature for 4 d (became yellow suspension over time). The yellow suspension was diluted with Et2O and filtered to isolate 2-methyl-2-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]propanoic acid (HCl salt, 375 mg, 98%) as a yellow solid. MS ESI: [M+H]+ m/z 423.0.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=[O:10])[CH2:5][CH2:4]1.[Br:18]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:18][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=[O:10])[CH2:5][CH2:4]1
Reactant: BrC(Br)(Br)Br
Reactant: C[Si](C)(C)CCOC(=O)N1CCC(CO)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOC(=O)N1CCC(CBr)CC1
Temperature: 0 °C
Reaction time: 14 h

Procedure:
19.9 g of 2-trimethylsilanylethyl 4-hydroxymethylpiperidine-1-carboxylate were dissolved in 600 ml of THF. After cooling to 0° C., 50.7 g of tetrabromomethane were added. Then 42.1 g of triphenylphosphine were added in 4 portions at intervals each of 20 min. The mixture was allowed to reach room temperature and was stirred for 14 h. The solvent was then removed in vacuo, and the residue was chromatographed on silica gel.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH:9]=[O:10])=[C:4]([Cl:11])[N:3]=1.[CH:12]([S:15]([C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20])(=[O:17])=[O:16])([CH3:14])[CH3:13]>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]([CH:9]=[O:10])=[C:6]([NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[S:15]([CH:12]([CH3:14])[CH3:13])(=[O:17])=[O:16])[N:7]=1
Reactant: O=Cc1c(Cl)nc(Cl)nc1Cl
Reactant: CC(C)S(=O)(=O)c1ccccc1N
Solvent: ClCCl
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nc(Cl)c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2,4,6-trichloropyrimidine-5-carbaldehyde (5.0 g, 23.8 mmol) in DCM (50 mL) was added 2-(isopropylsulfonyl)aniline (9.5 g, 47.6 mmol) at 0° C. under nitrogen atmosphere. The reaction mixture was warmed to room temperature gradually and stirred overnight. The solid was filtered off, and the filtrate was concentrated in vacuo and purified by silica gel chromatography (DCM/EtOAC/Hexanes: 15/15/70) to afford 2,4-dichloro-6-(2-(isopropylsulfonyl)phenylamino)pyrimidine-5-carbaldehyde. MS (ES+): 374.0 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.C(O)(=O)C.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[N:22]1[CH:26]=[CH:25][CH:24]=[CH:23]1>C(O)C>[CH3:21][O:20][C:18]1[CH:19]=[C:14]2[C:15](=[CH:16][CH:17]=1)[N:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:5]1([CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)[NH:13]2
Reactant: CN1CCC(=O)CC1
Reactant: COc1ccc(-n2cccc2)c(N)c1
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc2c(c1)NC1(CCN(C)CC1)c1cccn1-2

Procedure:
3.48 g (0.03 mole) of 1-methyl-4-piperidone and 3 ml. of glacial acetic acid are added to a solution of 5.65 g (0.03 mole) of 1-(2-amino-4-methoxy-phenyl) pyrrole in 100 ml. of absolute ethanol. The solution is refluxed for 15 hours and concentrated, and the residue is dissolved in water. The solution is filtered and basified. A solid precipitates and is filtered, dried and recrystallized from ethanol to give 4,5-dihydro-7-methoxy-1'-methylspiro[pyrrolo(1,2-a)quinoxaline-4,4'-piperidine], m.p. 124°-125° C.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH2:6]([OH:10])[CH2:7][CH2:8][CH3:9].C=CC1OC1>CCCCCC>[CH2:6]([OH:10])[CH:7]=[CH:8][CH2:9][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Reactant: [Li]CCCC
Agent: C=CC1CO1
Solvent: CCCCCC
Product: CCCCCC=CCO
Temperature: 0 °C
Yield: 49.1 %

Procedure:
A hexane solution of n-butyllithium (2.1 mmol) was cooled at 0° C. under the argon atmosphere. A hexane solution of n-butanol (75.9 mg; 1.0 mmol) was added dropwise thereto and stirred. To the resulting solution, there was further added dropwise a hexane solution of 3,4-epoxy-butene-1 (70.0 mg; 1 mmol), and after the addition was completed, the resulting mixture was cooled at 0° C. for 1 hour and at room temperature for 30 minutes, followed by the usual work up. Removal of the solvent and distillation of the residue gave 63 mg of 2-octen-1-ol (yield, 49%). After acetylation of the thus obtained product, gas chromatographic analysis (PEG 20M, 4 m) was effected at a temperature of 130° C. The retention times of Z-isomer and E-isomer were respectively 13.7 minutes and 14.7 minutes, and the Z/E ratio was 89.1/10.9.
Reaction SMILES: [NH2:1][C:2]1[C:32]([C:33]([F:36])([F:35])[F:34])=[CH:31][C:5]([CH2:6][CH:7]([CH2:10][C:11](=[O:30])[N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:24][CH2:23][C:22]4[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=4[NH:20][C:19]3=[O:29])[CH2:14][CH2:13]2)[CH:8]=O)=[CH:4][C:3]=1[Cl:37].Cl.Cl.Cl.[CH3:41][N:42]([CH3:56])[CH2:43][C:44]([CH3:55])([CH3:54])[CH2:45][NH:46][C:47]1[C:48]([NH2:53])=[CH:49][CH:50]=[CH:51][CH:52]=1>CN(C=O)C>[NH2:1][C:2]1[C:32]([C:33]([F:36])([F:35])[F:34])=[CH:31][C:5]([CH2:6][CH:7]([C:8]2[N:46]([CH2:45][C:44]([CH3:55])([CH3:54])[CH2:43][N:42]([CH3:41])[CH3:56])[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[N:53]=2)[CH2:10][C:11]([N:12]2[CH2:13][CH2:14][CH:15]([N:18]3[CH2:24][CH2:23][C:22]4[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=4[NH:20][C:19]3=[O:29])[CH2:16][CH2:17]2)=[O:30])=[CH:4][C:3]=1[Cl:37]
Reactant: CN(C)CC(C)(C)CNc1ccccc1N
Reactant: Nc1c(Cl)cc(CC(C=O)CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)cc1C(F)(F)F
Agent: Cl
Solvent: CN(C)C=O
Product: CN(C)CC(C)(C)Cn1c(C(CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)Cc2cc(Cl)c(N)c(C(F)(F)F)c2)nc2ccccc21
Reaction time: 16 h

Procedure:
To a solution of 320 mg (0.596 mmol) 2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butyraldehyde (Intermediate product 36) in 7 mL DMF was added 230 mg (0.695 mmol) N-(3-dimethylamino-2,2-dimethyl-propyl)-benzene-1,2-diamine-trihydrochloride (Intermediate product 37) and the mixture was stirred for 16 hours in an atmosphere of air. The reaction mixture was evaporated down i. vac. and the residue combined with EtOAc. The org. phase was washed with sat. aqueous sodium bicarbonate solution, dried over sodium sulphate and evaporated i. vac. The crude product was purified by column chromatography (silica gel, gradient dichloromethane/MeOH 20/1→10/1 v/v) then (Alox, neutral, activity III-III, gradient EtOAc/MeOH 100/0→40/ 1) and HPLC-MS (Zorbax Bonus C18 amide-phase 5 μm, gradient 0.15% formic acid in water/acetonitrile 10/90→90/10 v/v).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[N:25]([C:26]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]([CH2:45][CH2:46][CH3:47])=[N:5][C:4]=1[CH:48]=[CH2:49].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH2:45]([C:6]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[N:25]([C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:24]=[N:23][N:22]=3)=[CH:13][CH:14]=2)[C:3]([CH:2]=[O:1])=[C:4]([CH:48]=[CH2:49])[N:5]=1)[CH2:46][CH3:47]
Reactant: C=Cc1nc(CCC)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: C=Cc1nc(CCC)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1C=O
Reaction time: 8 h
Yield: 66.3 %

Procedure:
5-hydroxymethyl-2-n-propyl-1-[(2'-(N-triphenylmethyl-(1H-tetrazol-5-yl))biphenyl-4-yl)methyl]-4-vinylimidazole (470 mg, 0.73 mmol, 1 eq), Dess-Martin periodinane (J. Org. Chem. (1983) 48, 4155) (341 mg, 0.80 mmol, 1.1 eq) and methylene chloride (10mL) were mixed and stirred under nitrogen overnight. The solvent was removed in vacuo and the residue flash chromatographed in 3:2 hexane ethyl acetate over silica gel to yield 310 mg (66%) of a white glass. NMR (DMSO-d6) δ 9.91 (s,1H); 7.80 (d,1H,J=7Hz); 7.61 (t,1H, J=7Hz); 7.54 (t,1H,J=7Hz); 7.48-7.22(m,10H); 7.20 (d,1H,J=9Hz); 7.06 (d,2H,J=9Hz); 7.00-6.75 (m,8H); 6.15 (d of d,1H,J=17,3 Hz); 5.52 (s,2H); 5.47 (d of d,1H,J=12,3 Hz); 2.49 (t,2H,J=7Hz); 1.57 (t of q,2H,J=7,7Hz); 0.79 (t,3H,J=7Hz). IR (neat) 1658 cm-1. Anal. calcd. for C42H36N6O.(H2O)0.5 : C, 77.63; H, 5.74; N, 12.93. Found: C, 77.53; H, 5.73; N, 12.64. ##STR81##
Reaction SMILES: CC1C(=O)[C:5]2=[CH:6][C:7]3[C:8]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:9]4[C:14]([C:15]=3[CH:16]=[C:4]2C1)=[CH:13][CH:12]=[CH:11][CH:10]=4.[BH4-].[Na+].[CH2:49]1[CH2:53]O[CH2:51][CH2:50]1>C(O)C>[CH3:51][C:50]1[C:5]2=[CH:6][C:7]3[C:8]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:9]4[C:14]([C:15]=3[CH:16]=[C:4]2[CH2:53][CH:49]=1)=[CH:13][CH:12]=[CH:11][CH:10]=4
Reactant: C1CCOC1
Reactant: CCCCCCCCCCCCCCC1(CCCCCCCCCCCCCC)c2ccccc2-c2cc3c(cc21)C(=O)C(C)C3
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCCCCC1(CCCCCCCCCCCCCC)c2ccccc2-c2cc3c(cc21)C(C)=CC3
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.5 %

Procedure:
In a 500 mL round flask, 2 methyl-9,9-ditetradecyl-2,3-dihydrocyclopenta[b]fluoren-1(9H)-one (20 g, 31.9 mmol) was dissolved in 150 mL of THF and 150 mL of ethanol, and then stirred. Sodium borohydride (NaBH4) (1.8 g, 47.8 mmol) was added to the reactant in five lots, and then stirred for 12 hours. The resultant mixture, after removal of solvent, was dissolved in ethylacetate, and then washed with water three times. The organic layer was dried over magnesium sulfate, followed by removal of volatile materials. The dried reactant was dissolved in 150 mL of toluene, and then inputted to a round flask. After that, p-toluene sulfonic acid (0.08 g) was inputted thereto, and then water was completely removed under reflux with Dean-Stark. The resultant material was cooled to room temperature, and then an aqueous ammonium chloride solution (100 mL) and 200 mL of diethyl ether were injected thereto, followed by separation of the organic layer. The organic layer collected by extracting the residue with diethyl ether was dried over magnesium sulfate, followed by removal of volatile materials, and then purified by using silica gel column chromatography, to thereby obtain 15.3 g of 2 methyl-9,9-ditetradecyl-3,9-dihydrocyclopenta[b]fluorene (yield: 78.5%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[CH:24][C:23]([CH2:26][O:27][CH3:28])=[CH:22][N:21]=3)[CH2:16][CH2:15]2)[CH:5]=[C:4]([F:29])[C:3]=1[CH2:30][C:31]([O:33]C)=[O:32].CO.[OH-].[Na+].Cl>O1CCCC1.O>[F:29][C:4]1[CH:5]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:21]=[CH:22][C:23]([CH2:26][O:27][CH3:28])=[CH:24][N:25]=3)[CH2:16][CH2:15]2)[CH:7]=[C:2]([F:1])[C:3]=1[CH2:30][C:31]([OH:33])=[O:32]
Reactant: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)OC)c(F)c3)CC2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)O)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl {2,6-difluoro-4-[2-((1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl)ethoxy]phenyl}acetate (3.15 g, 6.62 mmol) in 21 ml of tetrahydrofuran was added 14 ml of methanol and 14 ml of water. 5 M sodium hydroxide (4.50 ml, 22.5 mmol) was added and the mixture stirred at RT overnight. 2 M hydrochloric acid (11.3 ml, 22.5 mmol) was added to adjust the pH of the solution to 4. The volatiles were removed under vacuum, and the aqueous phase extracted with dichloromethane (3×30 ml). The organic layers were combined, dried over magnesium sulphate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (Biotage column, 50 g) using a gradient eluent of 0-60% EtOAc:hexanes (700 ml) to afford the title compound. 1H NMR (CDCl3): δ 8.29 (s, 2H), 6.48 (d, J=9.1 Hz, 2H), 4.67-4.74 (m, 2H), 4.26 (s, 2H), 4.00-4.04 (m, 2H), 3.67 (s, 2H), 3.34 (s, 3H), 2.84-2.91 (m, 2H), 2.12-2.18 (m, 1H), 1.83 (d, J=12.4 Hz, 2H), 1.48-1.55 (m, 1H), 1.33-1.41 (m, 2H), 1.05-1.12 (m, 1H), 0.87-0.94 (m, 1H), 0.64-0.71 (m, 1H), 0.58-0.64 (m, 1H), −0.10 (m, 1H). LC/MS (m/z) 463.4 (M+H)+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][C:14]#[N:15])[CH:8]=1.O.[OH-].[Na+]>C(OCC)C>[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][NH2:15])[CH:8]=1
Reactant: N#CCc1cccnc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: NCCc1cccnc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 39.1 %

Procedure:
LAH (1.90 g, 50 mmol) was suspended in diethyl ether (150 ml), and a solution of 3-pyridylacetonitrile (5.91 g, 50 mmol, 1.0 eq) in diethyl ether (150 ml) was added at room temperature. The mixure was stirred at room temperature for 14 hours. To this reaction mixture were successively added water (1.9 ml), a 15% aqueous sodium hydroxide solution (1.9 ml) and water (5.7 ml). The resulting precipitate was filtered through Celite and washed with diethyl ether, which was followed by concentration under reduced pressure. The obtained residue was subjected to column chromatography (chloroform/methanol=30/1-chloroform/methanol/triethylamine=8/2/0.1) to give 2-(3-pyridyl)ethylamine (2.39 g, 39%) as a colorless oil.
Reaction SMILES: [C:1]([C:4]1[CH:20]=[CH:19][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[NH:18][N:17]=[N:16][N:15]=2)=[C:6]([CH2:21][CH2:22][CH3:23])[C:5]=1[OH:24])(=[O:3])[CH3:2].[C:25](=O)([O-])[O-].[K+].[K+].CI.Cl>C(C(C)=O)C>[CH3:25][N:18]1[C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:7]2[CH:19]=[CH:20][C:4]([C:1](=[O:3])[CH3:2])=[C:5]([OH:24])[C:6]=2[CH2:21][CH2:22][CH3:23])=[N:15][N:16]=[N:17]1
Reactant: CCCc1c(OCCCCCc2nnn[nH]2)ccc(C(C)=O)c1O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CCC(C)=O
Product: CCCc1c(OCCCCCc2nnnn2C)ccc(C(C)=O)c1O

Procedure:
A solution of 5 g. of 5-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyl]-tetrazole, 3 g. of potassium carbonate, and 2.4 g. of methyl iodide in 250 ml. of methyl ethyl ketone was allowed to reflux overnight. The reaction mixture was treated with dilute hydrochloric acid and the layers were separated. The organic layer was dried over sodium sulfate and evaporated to dryness. The residue was purified by chromatography over silica gel (2% ethanol in methylene chloride). The appropriate fractions were pooled and evaporated to an oil. Crystallization from ethyl acetate/hexane afforded 1.5 g. of the title product, m.p. about 72°-75° C.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[C:4]([OH:13])(=[O:12])[C@@H:5]([C@H:7]([C:9]([OH:11])=[O:10])[OH:8])[OH:6]>C(O)(=O)C>[C:9]([CH:7]([CH:5]([C:4]([O-:13])=[O:12])[OH:6])[OH:8])([O-:11])=[O:10].[C:1](#[N:3])[CH3:2]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CC(=O)O
Solvent: CC#N
Product: O=C([O-])C(O)C(O)C(=O)[O-]
Temperature: 50 °C
Reaction time: 8 h

Procedure:
In 80 volume parts of acetic acid are dissolved 19 parts of TRH monohydrate and 7.5 parts of L-tartaric acid, and while the solution is warmed to 50°C, 240 volume parts of acetonitrile is added in installments. The temperature is gradually brought down to room temperature, at which temperature the solution is allowed to stand overnight. The resultant crystals are harvested by filtration, washed with acetonitrile and dried under reduced pressure. The procedure yields 25.7 parts of TRH tartrate-acetonitrile as crystals melting at 145°C-148°C. [α]D22 =-47.1° (c=1.0 in water)
Reaction SMILES: C([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:11][C:10]=1[S:21]([CH3:24])(=[O:23])=[O:22])C1C=CC=CC=1.Cl>O1CCOCC1.CO.[Pd]>[CH3:24][S:21]([C:10]1[CH:11]=[C:12]([C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)[CH:13]=[CH:14][C:9]=1[NH2:8])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)c1cc(-c2ccncc2)ccc1NCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CS(=O)(=O)c1cc(-c2ccncc2)ccc1N
Reaction time: 18 h
Yield: 98.8 %

Procedure:
To a solution of benzyl-(2-methanesulfonyl-4-pyridin-4-yl-phenyl)-amine (2.0 g) in dioxane/methanol 1:1 (100 ml) was added 2N HCl (5 ml) and palladium black (1.0 g). The reaction mixture was hydrogenated at 1.1 bar and rt for 18 h. The catalyst was filtered off over a microfilter and washed with methanol. The filtrate was evaporated to dryness to obtain the desired compound (1.45 g) as a yellowish solid. MS (ISP): 249.1 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)[CH3:2].[NH:13]1[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:13]2[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: OC1CCNCC1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2CCC(O)CC2)cc1
Temperature: 120 °C
Yield: 64.2 %

Procedure:
A mixture of 4-fluoro-benzoic acid ethyl ester (1.68 g, 10 mmoles), piperidin-4-ol (1.12 g, 11 mmoles) and anhydrous potassium carbonate (1.38 g, 10 mmoles) in DMSO (10 ml) was heated at 120° C. for 6 hours. After cooling, the mixture was poured into water and ice (500 ml) and extracted with ethyl acetate. The organic layer was washed with water and brine, dried and evaporated. The residue was purified by flash chromatography on silica gel using hexane/EtOAc (10/30) as eluent to give the title compound as a white solid (1.6 g, 64%).