Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:14]([N:15]2[N:24]=[C:23]3[C:17]([CH2:18][CH2:19][O:20][C:21]4[CH:28]=[CH:27][C:26]([CH:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[CH:25][C:22]=43)=[CH:16]2)=[N:13][CH:12]=[N:11]1.Br[CH2:36][CH2:37][O:38]C1CCCCO1>>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:14]([N:15]2[N:24]=[C:23]3[C:17]([CH2:18][CH2:19][O:20][C:21]4[CH:28]=[CH:27][C:26]([CH:29]5[CH2:34][CH2:33][N:32]([CH2:36][CH2:37][OH:38])[CH2:31][CH2:30]5)=[CH:25][C:22]=43)=[CH:16]2)=[N:13][CH:12]=[N:11]1
Reactant: BrCCOC1CCCCO1
Reactant: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2cc(C4CCNCC4)ccc2OCC3)c(F)c1
Agent: Cl
Product: OCCN1CCC(c2ccc3c(c2)-c2nn(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)CC1

Procedure:
Following the procedure for 142, 2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-piperidin-4-yl-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene hydrochloride was reacted with 2-(2-bromo-ethoxy)-tetrahydro-pyran to give 179 as a white solid. 1H NMR (400 MHz, DMSO-d): δ 9.86 (s, 1H); 8.44 (s, 1H); 8.29 (s, 1H); 7.84 (td, J=8.75, 5.94 Hz, 1H); 7.72 (td, J=9.64, 2.83 Hz, 1H); 7.43-7.37 (m, 1H); 7.21 (d, J=2.28 Hz, 1H); 7.09 (dd, J=8.45, 2.36 Hz, 1H); 6.96 (d, J=8.40 Hz, 1H); 5.37 (t, J=4.89 Hz, 1H); 4.21 (t, J=5.01 Hz, 2H); 3.83 (d, J=5.48 Hz, 2H); 3.65 (d, J=12.04 Hz, 2H); 3.23 (m, 2H); 3.10 (m, 4H); 2.69-2.60 (m, 1H); 2.01-1.80 (m, 4H). LCMS: RT=7.55 min, M+H+=493
Reaction SMILES: [C:1]([CH2:3][C:4](=S)[NH2:5])#[N:2].BrCC.[O-]CC.[Na+].[NH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17]([OH:19])=O>>[Cl:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:15]2[C:16]=1[C:17](=[O:19])[N:5]=[C:4]([CH2:3][C:1]#[N:2])[NH:14]2
Reactant: N#CCC(N)=S
Reactant: Nc1cccc(Cl)c1C(=O)O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCBr
Product: N#CCc1nc(=O)c2c(Cl)cccc2[nH]1
Reaction time: 6 h
Yield: 23.2 %

Procedure:
2-cyanoethanethioamide (300 mg, 3.00 mmol) and bromoethane (261 μL, 3.50 mmol) were added to an ethanolic solution of sodium ethoxide (3.50 mmol, 2.5 mL). The resulting mixture was stirred for 6 hours, 2-amino-6-chlorobenzoic acid (500 mg, 2.91 mmol) was added, and the reaction was refluxed overnight with stirring. A solid precipitate formed upon cooling of the reaction mixture, which was recovered by vacuum filtration and washed sequentially with ethanol, water, ethanol, and diethyl ether. The solid was then dried to yield 2-(5-chloro-4-oxo-1,4-dihydroquinazolin-2-yl)acetonitrile (148 mg, 22%). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.15 (s, 2H), 7.54 (dd, J1=7.8 Hz, J2=1.1 Hz, 1H), 7.61 (dd, J1=8.2 Hz, J2=1.1 Hz, 1H), 7.74 (t, J=8.0 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[C:28]1[NH:32][C:31](=[O:33])[O:30][N:29]=1)[O:6][CH2:7][C:8]1[S:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH:23]=O.C(N(CC)CC)C.Cl.[F:42][C:43]([F:48])([F:47])[CH2:44][CH2:45][NH2:46].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:6][CH2:7][C:8]2[S:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=3)=[N:10][C:9]=2[CH2:23][NH:46][CH2:45][CH2:44][C:43]([F:48])([F:47])[F:42])[CH:25]=[CH:26][C:27]=1[C:28]1[NH:32][C:31](=[O:33])[O:30][N:29]=1
Reactant: NCCC(F)(F)F
Reactant: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C=O)ccc1-c1noc(=O)[nH]1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CNCCC(F)(F)F)ccc1-c1noc(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
To a suspension of 30 mg of 5-[3-methoxy-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxymethyl]-2-(4-trifluoromethyl-phenyl)-thiazole-4-carbaldehyde in 1.5 mL of methanol were added 0.018 mL of triethylamine, 10 mg of 3,3,3-trifluoro-propylamine hydrochloride and 0.5 g of 4 Å powdered molecular sieves. The resulting mixture was stirred at room temperature for 1 h then 2.4 mg of sodium borohydride was added. After stirring at room temperature for 45 minutes, the reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography on silica gel (dichloromethane 90/methanol 10/water 1/acetic acid 1) followed by azeotropal removal of traces of acetic acid with cyclohexane to give 6.5 mg of 3-(2-methoxy-4-{2-(4-trifluoromethyl-phenyl)-4-[(3,3,3-trifluoro-propylamino)-methyl]-thiazol-5-ylmethoxy}-phenyl)-4H-[1,2,4]oxadiazol-5-one as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10].[C:25]([N:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33])(=[O:27])[CH3:26]>>[C:25]([N:28]1[CH2:32][CH2:31][N:30]([C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=2[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])[C:29]1=[O:33])(=[O:27])[CH3:26]
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3Br)CC2)c(C)c1
Reactant: CC(=O)N1CCNC1=O
Product: CC(=O)N1CCN(c2cc(Cl)ccc2C(=O)N2CCN(c3ncc(C)cc3C)CC2)C1=O
Yield: 48.6 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 12 and using (2-bromo-4-chlorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (408.7 mg) described in Preparation Example 119 and 1-acetyl-2-imidazolidinone (128 mg), the title compound (221.5 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[CH2:9][CH2:10]Cl)=[CH:4][CH:3]=1.[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[CH2:9][CH2:10][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[CH:4][CH:3]=1
Reactant: OC(CCCl)c1ccc(Br)cc1
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: OC(CCn1ccnc1)c1ccc(Br)cc1
Yield: 44 %

Procedure:
A solution of 1-(4-Bromo-phenyl)-3-chloro-propan-1-ol* (1.5 g, 6.01 mmol) and imidazole (1.23 g, 18.03 mmol) in dimethylformamide (18 ml) was heated at 100° C. for 18 hrs then partitioned between water and ethyl acetate. The organic extracts were combined, dried (MgSO4), filtered, concentrated and purified by column chromatography (SiO2), eluting with methanol:dichloromethane (2:98) to methanol:dichloromethane (6:94) to afford the title compound (0.75 g, 44% yield). LC/MS: (PS-B3) Rt 2.48 [M+H]+281.14, 283.11. *This starting material can be made by the method described in Example 43A.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][NH:4]1.S(O[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]2[O:22][CH2:23][O:24][C:18]=2[CH:17]=1)(=O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(#N)C>[OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]2[O:22][CH2:23][O:24][C:18]=2[CH:17]=1
Reactant: OC[C@H]1CCCCN1
Reactant: CS(=O)(=O)OCCc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: OC[C@H]1CCCCN1CCc1ccc2c(c1)OCO2
Temperature: 90 °C

Procedure:
(R)-2-hydroxymethylpiperidine (288 mg, 2.50 mmol), 3,4-methylenedioxyphenethyl mesylate (732 mg, 3.00 mmol), sodium carbonate (320 mg, 3.00 mmol) and sodium iodide (30 mg, 0.20 mmol) were added to acetonitrile (25 ml), and they were heated under reflux at 90° C. for 10 hours. The solvent was evaporated under reduced pressure. The residue was distributed in ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with water and dried over magnesium sulfate. Then the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with dichloromethane as the eluent and then with dichloromethane and methanol (20:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (R)-2-hydroxymethyl-1-(3,4-methylenedioxyphenethyl)piperidine in the form of a light yellow oil (370 mg, 56%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH2:8].CN(C)/[CH:11]=[C:12](/[C:18](=[O:27])[C:19]1[CH:24]=[C:23]([I:25])[CH:22]=[CH:21][C:20]=1F)\[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>O>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:20]2[C:19](=[CH:24][C:23]([I:25])=[CH:22][CH:21]=2)[C:18](=[O:27])[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11]1
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1cc(I)ccc1F
Reactant: N[C@H]1CCCC[C@@H]1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cn([C@H]2CCCC[C@@H]2N)c2ccc(I)cc2c1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 42.2 %

Procedure:
(1S,2S)-(+)-1,2-Diaminocyclohexane (500 mg, 4.3 mmol) was added to the solution of (Z)-ethyl-3-(dimethylamino)-2-(3-iodobenzoyl)acrylate (Intermediate 24, 0.34M, 11.7 mL, 3.9 mmol) and the mixture was heated at 50° C. for 3 h. The solvent was removed in vacuo and the residue was dried in a vacuum oven for 1.5 h. The residue was then dissolved in dimethyl formamide (7 mL) and potassium carbonate powder (753 mg, 5.5 mmol) was added. The reaction was heated at 70° C. for 3 h then cooled to room temperature. Water (30 mL) was added and the suspension was extracted with 1:1 ethyl acetate:methyl tert-butyl ether (3×50 mL). The organic layers were dried over sodium sulfate, and the solvent was removed in vacuo. The residue was suspended in methyl tert-butyl ether (20 mL) and stirred at 40° C. for 1 h. The suspension was filtered and the solid dried to give 724 mg (42% yield) of ethyl 1-((1S ,2S)-2-aminocyclohexyl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate as a yellowish powder that was contaminated with about 40% bis dihydroquinoline. This material was used as is in the coupling step.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:8].Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25])=[O:18].O>CC(C)=O.C(OCC)(=O)C>[C:7]([CH:9]([CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25])=[O:18])[C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:8]
Reactant: CCOC(=O)CC#N
Reactant: O=C(CBr)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)C(C#N)CC(=O)c1ccccc1F
Temperature: 45 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
To a solution of 2′-fluoroacetophenone (28.6 g) in ethyl acetate (400 mL) was added copper (II) bromide (92.6 g), and the mixture was heated under reflux for 4 hr. The reaction mixture was allowed to cool to room temperature and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give crude 2-bromo-1-(2-fluorophenyl)ethanone (yield 90.5 g) as an oil. Potassium carbonate (88 g) was added to ethyl cyanoacetate (168 g), and the mixture was stirred at 45° C. for 1 hr. A solution (360 mL) of crude 2-bromo-1-(2-fluorophenyl)ethanone (90.5 g) in acetone was added dropwise over 20 min. After completion of the dropwise addition, the mixture was stirred at the same temperature for 1 hr. Water (300 mL) and ethyl acetate (300 mL) were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with 10% aqueous sodium dihydrogen phosphate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Excess ethyl cyanoacetate contained in the obtained oil was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=20:1→4:1) to give the title compound as an oil (yield 64.0 g, yield about 100%).
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:6][C:5]=1[N+:19]([O-:21])=[O:20].[OH-].[Li+].CCOCC>CO.O>[C:15]([O:14][C:12]([NH:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:22])=[O:2])=[C:5]([N+:19]([O-:21])=[O:20])[CH:6]=1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
A mixture of 4-(tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid methyl ester (64.36 g, 207.4 mmol), lithium hydroxide (5.96 g, 248.9 mmol) in methanol (500 mL) and water (250 mL) was stirred with a mechanical stirrer at room temperature overnight. The methanol was evaporated, and to the aqueous solution, was added 1 N HCl (300 mL) to form the precipitate. Ether (350 mL) was added, and the mixture was stirred at 0° C. for 2 hours. No desired precipitation was formed. The mixture was evaporated. To the mixture, was added water (500 mL). The aqueous layer was extracted with ethyl acetate (5×120 mL). The combined organic layers were separated, dried over magnesium sulfate, and concentrated to give 4-(tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid as a brown oil (56.69 g, 92% yield). The product was used in the next step without further purification.
Reaction SMILES: [C:1](#[N:6])[CH2:2][CH2:3][C:4]#[CH:5].Br[C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([OH:26])[C:14]([N:18]3[S:22](=[O:24])(=[O:23])[NH:21][C:20](=[O:25])[CH2:19]3)=[CH:15]2)=[CH:10][CH:9]=1>>[OH:26][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][C:14]=1[N:18]1[CH2:19][C:20](=[O:25])[NH:21][S:22]1(=[O:24])=[O:23])[CH:17]=[C:8](/[CH:5]=[CH:4]/[CH2:3][CH2:2][C:1]#[N:6])[CH:9]=[CH:10]2
Reactant: C#CCCC#N
Reactant: O=C1CN(c2cc3cc(Br)ccc3cc2O)S(=O)(=O)N1
Product: N#CCC/C=C/c1ccc2cc(O)c(N3CC(=O)NS3(=O)=O)cc2c1

Procedure:
The title compound is prepared analogously to Example 8, step A, beginning with pent-4-ynenitrile and 5-(7-bromo-3-hydroxynaphthalen-2-yl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (Example 3, step E): Retention time=0.91 min (Method A); (M−H)−=356.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:32])[C@@H:19]([C:20]#[C:21][C:22]([OH:24])=[O:23])[C@H:18]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].[Cl:33][C:34]([Cl:38])([Cl:37])[CH2:35]O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:16][C:17]1([CH3:32])[C@@H:19]([C:20]#[C:21][C:22]([O:24][CH2:35][C:34]([Cl:38])([Cl:37])[Cl:33])=[O:23])[C@H:18]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]
Reactant: OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](C#CC(=O)O)C1(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1[C@H](C#CC(=O)OCC(Cl)(Cl)Cl)C1(C)C
Reaction time: 1 h

Procedure:
6.2 g of dicyclohexylcarbodiimide were introduced into a solution of 7.15 g of tert.-butyl (1R,cis) 2,2-dimethyl-3-(2-carboxyethynyl)-cyclopropane-carboxylate and 80 mg of 4-dimethylamino-pyridine in 35 ml of methylene chloride and the reaction mixture was stirred for 10 minutes after which 4.5 of 2,2,2-trichloroethanol were added. The mixture was stirred for 1 hour and was filtered. The filtrate was washed with N hydrochloric acid, then with water until neutral, dried and evaporated to dryness. The 14 g of oil residue were chromatographed over silica gel and eluted with a 97-3 mixture of benzene-ethyl acetate to obtain 9 g of tert.butyl (1R,cis) 2,2-dimethyl-3-(2,2,2-trichloroethoxycarbonylethynyl)-cyclopropane-carboxylate melting at 70-71° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:14])=[C:4]([C:12]#[N:13])[C:5]([Cl:11])=[N:6][C:7]=1[N:8]([CH3:10])[CH3:9].C(=O)([O-])[O-:16].[Na+].[Na+]>S(=O)(=O)(O)O.O>[Br:1][C:2]1[C:3]([CH3:14])=[C:4]([C:12]([NH2:13])=[O:16])[C:5]([Cl:11])=[N:6][C:7]=1[N:8]([CH3:9])[CH3:10]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(Br)c(N(C)C)nc(Cl)c1C#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1c(Br)c(N(C)C)nc(Cl)c1C(N)=O

Procedure:
A solution of 5-bromo-2-chloro-3-cyano-6-(N,N-dimethylamino)-4-methylpyridine (1.3 g) in concentrated sulfuric acid (3 mL) was heated at 120° C. for 10 minutes. The mixture was cooled, diluted with water (50 mL), and neutralized with saturated sodium carbonate. After extraction with methylene chloride, evaporation of the organic phase gave 1.37 g of the title compound, suitable for use in the next reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:12])[CH2:9][C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.[C:13]1([CH2:19][CH:20]=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH4-].[Na+]>CO>[OH:12][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH2:20][CH2:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1)[CH2:9][C:10]#[N:11]
Reactant: N#CCC(O)c1cccc(N)c1
Reactant: O=CCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#CCC(O)c1cccc(NCCc2ccccc2)c1
Reaction time: 18 h

Procedure:
Hydrogenation of aniline 12 and 2-phenylacetaldehyde gives 3-hydroxy-3-(3-(phenethylamino)phenyl)propanenitrile. A mixture of aniline 12 (1.00 g, 6.17 mmol), 2-phenylacetaldehyde (0.66 g, 5.55 mmol) and Å-3 molecular sieves in MeOH was stirred for 18 h and then NaBH4 (1.16 g, 30.8 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was filtered through Celite, concentrated under reduced pressure. Purification by column chromatography (100-200 silica mesh, 20% EtOAc—hexane) gave 3-hydroxy-3-(3-(phenethylamino)phenyl)propanenitrile as a yellow liquid. Yield (0.432 g, 27%); 1H NMR (400 MHz, DMSO-d6) δ 7.32-7.26 (m, 4H), 7.20 (t, J=6.4 Hz, 1H), 7.04 (t, J=7.6 Hz, 1H), 6.64 (s, 1H), 6.55 (d, J=7.2 Hz, 1H), 6.50 (d, J=8.4 Hz, 1H), 5.77 (d, J=4.4 Hz, 1H), 5.68 (t, J=5.6 Hz, 1H), 4.76-4.72 (m, 1H), 3.26-3.21 (m, 2H), 2.85-2.81 (m, 3H), 2.79-2.72 (m, 1H).
Reaction SMILES: [ClH:1].[CH2:2]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[C:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[CH2:22][C:21]([CH3:28])([CH3:27])[CH:20]=2)[CH2:8][CH2:7]1)[CH2:3][CH2:4][CH3:5]>CO.[Pd]>[ClH:1].[CH2:2]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[CH:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[CH2:22][C:21]([CH3:27])([CH3:28])[CH2:20]2)[CH2:10][CH2:11]1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCN1CCC(c2cc(F)ccc2C2=CC(C)(C)CC(C)(C)C2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCCN1CCC(c2cc(F)ccc2C2CC(C)(C)CC(C)(C)C2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.6 %

Procedure:
To a solution of 1-butyl-4-[5-fluoro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperidine hydrochloride (47 mg, 0.12 mmol) produced in Example (106h) in methanol (3 mL) was added 10% palladium on carbon (100 mg, wet), followed by stirring for 4 hours at atmospheric pressure and room temperature under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Hexane was added to the residue to produce a solid, which was then triturated by sonication. The solid was filtered and dried under reduced pressure to give 19 mg of the title compound as a light yellow solid.
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)=[O:14])=[CH:8][CH:7]=1.[CH:27]1([CH:30]=O)[CH2:29][CH2:28]1.C(=O)([O-])O.[Na+].[BH4-].[Na+]>CO.C1COCC1>[ClH:1].[CH:27]1([CH2:30][NH:2][C@@H:3]2[CH2:5][C@H:4]2[C:6]2[CH:7]=[CH:8][C:9]([NH:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:17][CH:16]=3)=[O:14])=[CH:10][CH:11]=2)[CH2:29][CH2:28]1
Reactant: O=CC1CC1
Reactant: N[C@@H]1C[C@H]1c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccc([C@@H]2C[C@H]2NCC2CC2)cc1)c1ccc(-c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
A solution of N-[4-(trans-2-aminocyclopropyl)phenyl]biphenyl-4-carboxamide hydrochloride (2.2 g) in methanol (75 mL)/THF (75 mL) was ice-cooled, and cyclopropanecarbaldehyde (549 mg) and sodium hydrogen carbonate (1.01 g) were added. The mixture was stirred at 60° C. for 1 hr, and ice-cooled to 0° C. and sodium borohydride (456 mg) was added. The mixture was stirred for 1 hr, and saturated aqueous sodium hydrogen carbonate solution was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate, ethyl acetate/methanol). 10% Hydrochloric acid methanol solution was added and the solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/diisopropyl ether to give the title compound (1.62 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:16])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Br:15])[CH:9]=1)[NH2:6].[N:17]1[S:21][N:20]=[C:19]2[C:22]([S:26]([NH:29][C:30]3[CH:38]=[C:37]([Cl:39])[C:36]([Cl:40])=[CH:35][C:31]=3[C:32](O)=[O:33])(=[O:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=12>>[CH3:2][O:3][C:4](=[O:16])[C@@H:5]([NH:6][C:32](=[O:33])[C:31]1[CH:35]=[C:36]([Cl:40])[C:37]([Cl:39])=[CH:38][C:30]=1[NH:29][S:26]([C:22]1[C:19]2=[N:20][S:21][N:17]=[C:18]2[CH:25]=[CH:24][CH:23]=1)(=[O:28])=[O:27])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Br:15])[CH:9]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(F)c(Br)c1
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(F)c(Br)c1)NC(=O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
The title compound was prepared from 3-bromo-4-fluoro-L-phenylalanine methyl ester hydrochloride and 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoic acid as in Example 1, Part C. HPLC: RT=10.74 min. MS (ESI−): mass calcd. for C23H16BrCl2FN4O5S2, 662.34; m/z found, 659/661 [M−H]−. 1H NMR (500 MHz, CDCl3): 11.16 (s, 1H), 8.36 (dd, J=7.1, 0.8, 1H), 8.24 (dd, J=8.8, 0.8, 1H), 7.86 (s, 1H), 7.74 (dd, J=8.8, 7.1, 1H), 7.33 (s, 1H), 7.30-7.27 (m, 1H), 7.06 (t, J=8.3, 1H), 7.03-6.98 (m, 1H), 6.53 (d, J=7.1, 1H), 4.93 (q, J=5.8, 1H), 3.22 (s, 3H), 3.24-3.11 (m, 2H).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([CH3:24])[N:18]=2)[CH2:13][CH2:12]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH3:24][C:19]1[N:18]=[C:17]([N:14]2[CH2:13][CH2:12][CH:11]([CH2:10][CH2:9][NH2:8])[CH2:16][CH2:15]2)[CH:22]=[C:21]([CH3:23])[N:20]=1
Reactant: Cc1cc(N2CCC(CCN(Cc3ccccc3)Cc3ccccc3)CC2)nc(C)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(N2CCC(CCN)CC2)nc(C)n1
Reaction time: 12 h
Yield: 66 %

Procedure:
A solution of N,N-dibenzyl-2-(1-(2,6-dimethylpyrimidin-4-yl)piperidin-4-yl)ethanamine (700 mg, 1.691 mmol, 1.0 eq) in MeOH (10 ml) was degassed for 30 minutes with nitrogen; 10% Pd(OH)2 (420 mg) was added and hydrogenation was carried out for 12 hours at RT. After monitoring by TLC, the reaction mixture was filtered off over Celite and washed with MeOH (100 ml). The filtrate was concentrated under reduced pressure and dried. Yield: 66% (260 mg, 1.11 mmol)
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]>[Pd]>[C:1]([C:4]1[CH2:9][CH2:8][CH2:7][NH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccnc1
Agent: [Pd]
Product: CC(=O)C1=CNCCC1

Procedure:
3-acetyl-1,4,5,6-tetrahydropyridine was prepared by hydrogenation of 3-acetylpyridine in the presence of palladium on carbon according to the method of Freifelder, J.Orq.Chem. 29, 2895 (1964).