Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][CH:11]([CH3:22])[NH:10][N:9]=2)=[CH:4][CH:3]=1.C(O[C:27](=[O:29])[CH3:28])(=O)C>>[C:17]([N:1]([C:27](=[O:29])[CH3:28])[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][CH:11]([CH3:22])[N:10]([C:16](=[O:21])[CH3:15])[N:9]=2)=[CH:4][CH:3]=1)(=[O:19])[CH3:18]
Reactant: CC1Cc2cc3c(cc2C(c2ccc(N)cc2)=NN1)OCO3
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N(C(C)=O)c1ccc(C2=NN(C(C)=O)C(C)Cc3cc4c(cc32)OCO4)cc1
Yield: 84.6 %

Procedure:
2.0 g (6.7 mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine were refluxed with 40 ml of acetic anhydride for 3 hours, then it was evaporated to dryness under reduced pressure. The crystalline residue was transferred with 25 ml of water to a filter and washed with 5×3 ml of water. After drying 2.79 g of the raw triacetyl derivative were obtained. After washing with 20 ml of isopropanol and drying at 100° C. 2.39 g (84.6%) of the pure aimed product were obtained, m.p. 224°-227° C.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH2:9])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[C:13]=1[S:20](Cl)(=[O:22])=[O:21]>>[C:1]([C:4]1[S:8][C:7]([NH:9][S:20]([C:13]2[C:14]([Cl:19])=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=2[Cl:11])(=[O:22])=[O:21])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)c1sc(N)nc1C
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Product: CC(=O)c1sc(NS(=O)(=O)c2c(Cl)cc(Cl)cc2Cl)nc1C

Procedure:
The title compound was prepared from 5-acetyl-2-amino-4-methylthiazole and 2,4,6-trichlorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white-yellow solid (15.5 mg) with purity >90%. MS (pos) m/z 399.1, 401.1, 403.1.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[S:18]1[CH2:22][C:21](=[O:23])[NH:20][C:19]1=[O:24].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:16][C:14]([C:11]1[CH:10]=[C:7]([CH:8]=[C:22]2[S:18][C:19](=[O:24])[NH:20][C:21]2=[O:23])[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:12]=1[OH:13])([CH3:15])[CH3:17]
Reactant: O=C1CSC(=O)N1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(C=C2SC(=O)NC2=O)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.5 %

Procedure:
To a flask containing 41.7 g (0.18 moles) of 3,5-di-tert-butyl-4-hydroxybenzaldehyde, 25 g (0.21 moles) of 2,4-thiazolidinedione and 29.5 g (0.36 moles) of anhydrous sodium acetate were added. To these solids 175 ml of glacial acetic acid was added and the mixture was stirred and refluxed for 18 hours. The mixture was allowed to cool to room temperature and the precipitated solid was collected by filtration. The precipitate was rinsed with 1:1 water/ethanol then dried. The dried solid was slurried in 300 ml of methylene chloride for five hours, then collected and dried to yield 38.7 g of the sub-titled intermediate.
Reaction SMILES: C([Li])(CC)C.[F:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([CH3:17])=[CH2:16])=[CH:9][C:8]=1[F:18].[C:19](=[O:21])=[O:20].Cl>C1CCCCC1.O1CCCC1.O>[F:18][C:8]1[C:7]([F:6])=[CH:12][CH:11]=[C:10]([O:13][CH2:14][C:15]([CH3:17])=[CH2:16])[C:9]=1[C:19]([OH:21])=[O:20]
Reactant: C=C(C)COc1ccc(F)c(F)c1
Reactant: O=C=O
Agent: Cl
Agent: [Li]C(C)CC
Solvent: O
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: C=C(C)COc1ccc(F)c(F)c1C(=O)O
Temperature: -75 °C
Reaction time: 2.5 h

Procedure:
To a 1.4 M solution of sec-butyllithium in cyclohexane (6.7 mL) and anhydrous tetrahydrofuran (15 mL) at −75° C. was added 1,2-difluoro-4-(2-methylallyloxy)benzene (731) (1.6 g, 8.68 mmol). The resulting mixture was stirred at −75° C. for 2.5 hours and was then transferred to a round bottom flask containing dry ice. The resulting mixture was shaken for 5 min, and water (10 mL) was added dropwise. The mixture was acidified to pH 1 with concentrated hydrochloric acid and extracted with EtOAc (80 mL×3). The organic phase was washed with brine (60 mL×2), water (60 mL), and dried over anhydrous sodium sulfate, and the solvent removed in vacuo to give an oil 2,3-difluoro-6-(2-methylallyloxy)benzoic acid (732) (1.9 g), The product was used directly in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18][NH2:19]>CO>[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18][N:19]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[C:9]1=[O:14]
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Reactant: CN(C)CCN
Solvent: CO
Product: CN(C)CCn1ccc2c([N+](=O)[O-])cccc2c1=O
Yield: 46.2 %

Procedure:
5-Nitro-isochromen-1-one (1.0 g, 5.2 mmol) and N,N-dimethyl-1,2-ethanediamine (4 g, 40 mmol) were refluxed in methanol (40 mL) for 1.5 hours. The volatiles were removed via rotovapor and the residue was purified via flash chromatography (12 of silica gel, 0-70% EtOAc/CH2Cl2 gradient) gave 2-(2-Dimethylamino-ethyl)-5-nitro-2H-isoquinolin-1-one as a yellow solid (1.4 g, 2.4 mmol, 46%).
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([CH3:23])[NH:16][C:15]([CH2:24][O:25][CH2:26][C:27](=O)[CH2:28][C:29](OCC)=[O:30])=[C:14]1[C:35]([O:37][CH2:38][CH3:39])=[O:36].N12CCCC1=NCCC2>C(O)C>[NH2:4][C:3]1[NH:5][C:29](=[O:30])[CH:28]=[C:27]([CH2:26][O:25][CH2:24][C:15]2[NH:16][C:17]([CH3:23])=[C:18]([C:19]([O:21][CH3:22])=[O:20])[CH:13]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[Cl:6])[C:14]=2[C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:2]=1
Reactant: CCOC(=O)CC(=O)COCC1=C(C(=O)OCC)C(c2ccccc2Cl)C(C(=O)OC)=C(C)N1
Reactant: N=C(N)N
Agent: C1CN=C2CCCN2C1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1=C(COCc2cc(=O)[nH]c(N)n2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Yield: 23.5 %

Procedure:
A solution of guanidine hydrochloride (0.20 g), ethyl 4-{[4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxy}acetoacetate (0.99 g), and 1,5-diazabicyclo[4.3.0]non-5-ene (0.30 g) in ethanol (50 ml) was stirred at room temperature for 5 days and then evaporated. The residue was dissolved in chloroform and washed with 2M hydrochloric acid, 10% aqueous sodium carbonate, and water, dried (MgSO4), and evaporated. The residual solid was recrystallised from ethyl acetate to give the title compound (0.23 g), m.p. 185°-187° C. Found: C,56.08; H,5.14; N,11.33. C23H25ClN4O6 requires C,56.50; H,5.15; N,11.46%.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[C:4]=2[N:5]=[C:6]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[N:7]=1.[CH3:27][S:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:27][S:28][C:29]1[CH:34]=[C:33]([C:2]2[C:3]3[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[C:4]=3[N:5]=[C:6]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[N:7]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: CSc1cccc(B(O)O)c1
Reactant: O=c1ccc2c(Cl)nc(NC(CO)CO)nc2n1-c1ccc(F)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CSc1cccc(-c2nc(NC(CO)CO)nc3c2ccc(=O)n3-c2ccc(F)cc2F)c1
Temperature: 150 °C
Yield: 90 %

Procedure:
A solution of 4-Chloro-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2, 4-difluoro-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one (50 mg, 0.13 mmol) in dioxane/H2O (3:1, 4.8 mL) was mixed with 3-methylthiophenyl boronic acid (33.8 mg, 0.20 mmol) and K2CO3 (54.3 mg, 0.39 mmol). The resultant mixture was bubbled with argon for 5 minutes follwoed by the addition of Pd(PPh3)4 (3.0 mg, 0.0026 mmol). The reaction tube was sealed and heated with “Smith Creator” (microwave, 150° C.) for 15 minutes. The mixture was concentrated under vaco. Flash chromatography (EtOAc/Hexane, 3:1) then provided the title compound (90%): MS (ES) m/z 471 (M+H)+; 1H-NMR(CDCl3) δ 2.40 (s, br, 2H), 2.40 (s, 3H), 3.90 (m, br, 5H), 6.00 (m, br, 1H), 6.45 (m, 1H), 7.15 (m, 2H), 7.40 (m, 5H), 7.85 (m, 1H).
Reaction SMILES: [Br:1]C1C=CC([N+]([O-])=O)=CC=1.C(OCC)=C.C(N(CC)CC)C.C([O:25][CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)C.BrBr.C(=O)(O)[O-].[Na+]>C(OCC)C.C([O-])(=O)C.[Pb+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.O>[Br:1][CH:27]([C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)[CH:26]=[O:25]
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: CCOC=Cc1ccc([N+](=O)[O-])cc1
Agent: BrBr
Agent: C=COCC
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: O
Product: O=CC(Br)c1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 106.5 %

Procedure:
A mixture of 16.0 g (80 mmole) of 1-bromo-4-nitrobenzene, 11.2 ml (ca. 120 mmole) of ethyl vinyl ether, 179.2 mg of lead(II) acetate, 484 mg of tri-o-tolylphosphine, and 22 ml (ca. 160 mmole) of triethylamine was placed in a bomb, purged with nitrogen, and heated at 100° for eight hours. The reaction mixture was partitioned between diethyl ether and water and clarified by filtration. The organic layer was washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography of the residue on silica gel (using toluene-hexane as eluant) yielded three principle components (in order of elution): 2.1 g of 4-(1-ethoxyvinyl)nitrobenzene, 3.0 g of the cis isomer of 4-(2-ethoxyviny)nitrobenzene, and 7.2 g of the trans isomer of 4-(2-ethoxyvinyl)nitrobenzene. A solution of 3.0 g (15 mmole) of 4-(2-ethoxyvinyl)nitrobenzene (as a mixture of cis and trans isomers) in 30 ml of diethyl ether was cooled to - 15°. Bromine (2.48 ml, ca. 15 mmole) was added dropwise as the temperature was maintained at or below -10°. The reaction mixture was poured into 50 ml of water containing 5 g of sodium bicarbonate. After two hours of stirring, the mixture was allowed to separate into layers. The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo to yield 3.9 g of 2-bromo-2-(4-nitrophenyl)acetaldehyde as an oil. A mixture of 1.98 g (15 mmole) of 3-hydroxymethyl-2-pyridinamine and 3.9 g (15 mmole) of 2-bromo-2-(4-nitrophenyl)acetaldehyde was warmed to initiate an exothermic reactiion. After cooling, the mixture was shaken with aqueous potassium carbonate and dichloromethane. The solid was collected, washed with water and dichloromethane, and air dried to yield 2.84 g of 8-hydroxymethyl-2-(4-nitrophenyl)imidazo[1,2-a]pyridine, as confirmed by the nmr and infrared spectra. The title compound (100 mg) was prepared by the method described in Example 6 using 1.4 g (5.2 mmole) of 8-hydroxymethyl-2-(4-nitrophenyl)imidazo[1,2-a]pyridine instead of 8-hydroxymethylimidazo[1,2-a]pyridine. Structure assignment was supported by the nmr and infrared spectra and by elemental analysis.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH:12]([CH3:22])[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:8][C:7]([CH3:24])([CH3:23])[C:6]1[CH2:25][CH2:26][CH2:27][C:28](=[O:29])[C:5]2=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1>[C:30]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH:12]([CH3:22])[CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[NH:8][C:7]([CH3:23])([CH3:24])[C:6]1[CH2:25][CH2:26][CH2:27][C:28](=[O:29])[C:5]2=1)(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: CC(CCCc1ccccc1)c1cc2c(cc1O)C1=C(CCCC1=O)C(C)(C)N2
Solvent: c1ccncc1
Product: CC(=O)Oc1cc2c(cc1C(C)CCCc1ccccc1)NC(C)(C)C1=C2C(=O)CCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Pyridine (2.2 ml.) is added to a suspension of 5,6,7,8,9,10-hexahydro-2-hydroxy-3-(1-methyl-4-phenylbutyl)-6,6-dimethyl-10-oxobenzo[c]quinoline (250 mg., 0.642 mmole) in 2.2 ml. of acetic anhydride under a nitrogen atmosphere. The mixture is stirred for 1.5 hours at room temperature and then poured onto ice (50 ml.). The mixture is extracted with ether, the extracts washed with water (4×50 ml.) and brine (1×60 ml.), dried (MgSO4) and evaporated under reduced pressure.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:28][CH:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:15]([O:26]C)[CH:14]=1)[CH2:4][CH2:5][CH3:6].C[S-].[Na+].O.Cl>CN(C=O)C.C(Cl)Cl.CCOCC>[ClH:1].[ClH:1].[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:28][CH:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:15]([OH:26])[CH:14]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(OC)c1
Agent: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(O)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 142.4 %

Procedure:
To a stirred solution of 3-butyl-4-(4-cyclohexyloxy-3-methoxy-phenyl)-6-(1-methyl-piperidin-4-yloxy)-pyridazine dihydrochloride (Example 73, 0.2 mmol, 104 mg) in dry DMF (2.0 mL), sodium thiomethoxide (1.0 mmol, 70 mg) was added and the resulting mixture was stirred at 100° C. for 2 hours. At completion, it was poured into water and extracted with ethyl acetate. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (DCM to DCM+10% 2N NH3 in MeOH) to give a colorless sticky solid, which was dissolved in DCM (1.0 mL), 2N HCl in ether (1.0 mL) was added, kept at room temperature for 10 min, condensed, triturated with hexanes to provide the title compound (73 mg). LCMS: m/z 441 [M+1]. 1H NMR (400 MHz, CD3OD): δ 7.10 (1H, d), 6.98-7.03 (2H, m), 6.90-6.93 (1H, m), 5.46 (1H, bs), 4.31-4.38 (1H, m), 3.11-3.37 (4H, m), 2.91-2.96 (2H, m), 2.79 (3H, s), 2.11-2.36 (4H, m), 1.97-2.03 (2H, m), 1.80-1.86 (2H, m), 1.32-1.63 (8H, m), 1.20-1.29 (2H, m), 0.80 (3H, t).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([F:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([F:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCCNC4)c[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCCN(C(C)=O)C4)c[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-piperidin-3-ylamide hydrochloride (example A164) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(O)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:7][CH:8]=1>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CC(O)(Cc1cccc(OC)c1)c1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)CC(Cc1cccc(OC)c1)c1ccccc1
Reaction time: 24 h
Yield: 45.3 %

Procedure:
A mixture of ethyl 4-(m-methoxyphenyl)-3-phenyl-3-hydroxybutyrate (4.39 g, 13.98 mmol), palladium/carbon (10%, 2.5 g) hydrochloric acid (1.2 mL) in acetic acid (150 mL) was subjected to hydrogenation (50 psi) for 24 h. The catalyst was filtered, and the filtrate was concentrated to afford 1.89 g (45%) of the desired product. 1H NMR (CDCl3) □ 7.10-7.27 (m, 6H), 6.63-6.70 (m, 2H), 6.55 (s, 1H), 3.95—4.05 (m, 2H), 3.70 (s, 3H), 3.39 (m, 1H), 2.83-2.89 (m, 2H), 2.56-2.68 (m, 2H), 1.10 (m, 3H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11](=[O:19])OC3C=CC=CC=3)=[CH:9][C:4]=2[N:3]=[N:2]1.Cl.[NH:21]1[CH2:26][CH2:25][C:24](=[CH:27][C:28]2[CH:29]=[C:30]([CH:42]=[CH:43][CH:44]=2)[O:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][N:33]=2)[CH2:23][CH2:22]1.C(N(CC)CC)C.CCOC(C)=O>CS(C)=O>[NH:3]1[C:4]2[CH:9]=[C:8]([NH:10][C:11]([N:21]3[CH2:26][CH2:25][C:24](=[CH:27][C:28]4[CH:44]=[CH:43][CH:42]=[C:30]([O:31][C:32]5[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:34][N:33]=5)[CH:29]=4)[CH2:23][CH2:22]3)=[O:19])[CH:7]=[CH:6][C:5]=2[N:1]=[N:2]1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: O=C(Nc1ccc2[nH]nnc2c1)Oc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(Nc1ccc2nn[nH]c2c1)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
To a solution of phenyl 1H-benzo[d][1,2,3]triazol-5-ylcarbamate (0.15 g, 0.62 mmol, from Step 1) in DMSO (5 mL) was added 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride (0.23 g, 0.62 mmol) (from Example 1, Step 5), followed by triethylamine (0.16 mL, 1.2 mmol). The reaction was stirred at 60° C. overnight. The reaction was cooled down and EtOAc (30 mL) was added. The organic layer was washed with water, saturated NH4Cl, and brine, dried over anhydrous Na2SO4, filtered and concentrated. Purification by column chromatography (0-5% MeOH/CH2Cl2) gave the desired compound as a foam (144 mg). MS (M+1): 495.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.76-8.80 (m, 1H) 8.54-8.56 (m, 1H) 8.20 (dd, 1H) 8.01-8.04 (m, 1H) 7.76-7.82 (m, 1H) 7.37-7.42 (m, 2H) 7.21 (d, 1H) 7.13 (d, 1H) 7.02-7.05 (m, 2H) 6.37-6.40 (m, 1H) 3.56 (t, 2H) 3.48 (t, 2H) 3.28-3.30 (m, 1H) 2.50-2.51 (m, 1H) 2.33-2.38 (m, 2H).
Reaction SMILES: C(C1C=CC(C2C=CC=CC=2C(O)=O)=CC=1)(C)(C)C.S(Cl)(Cl)=O.NC1C=CC([N:31]2[CH2:36][CH2:35][CH:34]([CH:37](C3C=CC=CC=3)[C:38]([O:40]C)=[O:39])[CH2:33][CH2:32]2)=CC=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[NH:31]1[CH2:36][CH2:35][CH:34]([CH2:37][C:38]([OH:40])=[O:39])[CH2:33][CH2:32]1
Reactant: COC(=O)C(c1ccccc1)C1CCN(c2ccc(N)cc2)CC1
Agent: CC(C)(C)c1ccc(-c2ccccc2C(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: O=C(O)CC1CCNCC1
Yield: 303.8 %

Procedure:
A mixture of 2-(4-tert-butylphenyl)benzoic acid (0.02 mol) and thionyl chloride (0.04 mol) and DMF (5 drops) in DCM (50 ml) was stirred and refluxed for 1 hour. The solvent was evaporated and DCM (2×50 ml) was added and again the solvent was evaporated. The residue was dissolved in DCM (50 ml) and added to a solution of intermediate (18) (0.02 mol) and DIPEA (0.04 mol) in DCM (50 ml). The reaction mixture was stirred at room temperature for 4 hours. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 99.5/0.5). The product fractions were collected and the solvent was evaporated. The residue was dissolved in 2-propanol and DIPE and converted into the hydrochloric acid salt (1:1) with HCl/2-propanol. The residue was filtered off and dried, yielding 8.7 g of 4-piperidineacetic acid, 1-[4-[[[4′-(1,1-dimethylethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]phenyl]-α-phenyl-, methyl ester hydrochloride (1:1) 2-propanolate (1:1) (intermediate 19).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:7][N:8]([CH3:10])[CH3:9])[S:5][CH:6]=1.[CH:11]([O:14][B:15](OC(C)C)[O:16][CH:17]([CH3:19])[CH3:18])([CH3:13])[CH3:12].[Li]CCCC.CCCCCC>C1COCC1>[CH3:9][N:8]([CH2:7][C:4]1[S:5][CH:6]=[C:2]([B:15]([O:16][CH:17]([CH3:19])[CH3:18])[O:14][CH:11]([CH3:13])[CH3:12])[CH:3]=1)[CH3:10]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CN(C)Cc1cc(Br)cs1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)OB(OC(C)C)c1csc(CN(C)C)c1
Temperature: -78 °C
Reaction time: 6.5 h

Procedure:
To a solution of 1-(4-bromo-2-thienyl)-N,N-dimethylmethanamine (2.8 g, 12.8 mmol) in THF (130 mL) at −78° C. under N2 was added tri-isopropylborate (4.4 mL, 19.2 mmol). The reaction mixture was stirred briefly before nBuLi (12 mL of a 1.6 M hexane solution) was added dropwise via syringe. The reaction mixture then stirred for 6.5 h at −78° C. before being concentrated by rotary evaporation. The resulting white solid was used without further purification.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][N:2]=1.[H][H]>[Pd].[Ni].CO>[C:5]1([CH2:4][NH2:3])[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[CH2:1][NH2:2]
Reactant: c1ccc2cnncc2c1
Reactant: [H][H]
Agent: [Ni]
Agent: [Pd]
Solvent: CO
Product: NCc1ccccc1CN

Procedure:
Phthalazine (21.5 g, 0.165 mol), 10% palladium on carbon (2 g), and methanol (125 mL) were combined in a pressure bottle and shaken at room temperature under 60 psi of hydrogen for 5 days. Raney-nickel® slurry (6.42 g) and 10% palladium on carbon (0.50 g) were added, and the mixture was shaken at 50° C. under 60 psi of hydrogen for 16 hours. The mixture was filtered through a nylon membrane and concentrated to give the titled compound: 1H NMR (300 MHz, DMSO-d6) δ ppm 7.32 (dd, J=5.4, 3.5 Hz, 2H), 7.17 (dd, J=5.6, 3.4 Hz, 2H), 3.74 (s, 4H); MS (DCI/NH3) m/z 137 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12]([CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[O:23])[CH2:16][CH2:15]1)=[O:13])=[CH:9][CH:8]=[CH:7]2.ClC1C=C2C(=CC=1)C=C(C(C1CCN(CCCC(C3C=CC(F)=CC=3)=O)CC1)=O)C=C2>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH:22]([OH:23])[CH2:21][CH2:20][N:17]2[CH2:16][CH2:15][CH:14]([CH:12]([C:10]3[C:11]4[C:6](=[CH:5][CH:4]=[CH:3][C:2]=4[CH3:1])[CH:7]=[CH:8][CH:9]=3)[OH:13])[CH2:19][CH2:18]2)=[CH:25][CH:26]=1
Reactant: Cc1cccc2cccc(C(=O)C3CCN(CCC(=O)c4ccc(F)cc4)CC3)c12
Agent: O=C(CCCN1CCC(C(=O)c2ccc3cc(Cl)ccc3c2)CC1)c1ccc(F)cc1
Product: Cc1cccc2cccc(C(O)C3CCN(CCC(O)c4ccc(F)cc4)CC3)c12

Procedure:
When in the procedure of Example 39, 3-[4-(8-methyl-1-naphthoyl)-1-piperidyl]-1-(4-fluorophenyl)-1-propanone is substituted for 4-[4-(6-chloro-2-naphthoyl)-1-piperidyl]-1-(4-fluorophenyl)-1-butanone, α-(4-fluorophenyl)-4-[(8-methyl-1-naphthyl)hydroxymethyl]-1-piperidinepropanol is obtained.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:9]1[CH2:19][OH:20])=O)(C)(C)C.C1COCC1.Cl.[OH-].[Na+]>CO>[C:13]1([C@H:10]2[CH2:11][CH2:12][NH:8][C@H:9]2[CH2:19][OH:20])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccccc2)[C@@H]1CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: OC[C@@H]1NCC[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
rac-(cis)-3-Phenylpyrrolidin-2-yl)methanol. To a stirred solution of rac-(cis)-tert-butyl-2-(hydroxymethyl)-3-phenylpyrrolidine-1-carboxylate, racemic (0.2133 g, 769 μmol) in THF (2.0 mL, 24409 μmol) was added hydrogen chloride (4.0 N solution in 1,4-dioxane) (1.9 mL, 7690 μmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The entire mixture was neutralized with SN NaOH and concentrated to give rac-(cis)-3-phenylpyrrolidin-2-ylmethanol (76 mg, 56% yield) as a white solid, which was pure enough to be used without further purification.