Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7]([C@H:11]([C:19]2[CH:31]=[CH:30][C:22]([C:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[C@@H:6]([CH3:32])[CH2:5]1)[CH:2]=[CH2:3].[C:33](OC(=O)C)(=[O:35])[CH3:34].C(N(CC)CC)C>ClCCl>[C:33]([O:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[C@@H:11]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([N:25]([CH2:26][CH3:27])[CH2:28][CH3:29])=[O:24])=[CH:30][CH:31]=1)[N:7]1[CH2:8][C@@H:9]([CH3:10])[N:4]([CH2:1][CH:2]=[CH2:3])[CH2:5][C@@H:6]1[CH3:32])(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCN1C[C@H](C)N([C@H](c2ccc(C(=O)N(CC)CC)cc2)c2cccc(O)c2)C[C@H]1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCN1C[C@H](C)N([C@H](c2ccc(C(=O)N(CC)CC)cc2)c2cccc(OC(C)=O)c2)C[C@H]1C
Yield: 70.3 %

Procedure:
A solution of (±)-4-((αR*)-α((2S*,5R*)-4-allyi-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide (1.2 g, 2.8 mmol, Example 6), acetic anhydride (0.40 mL, 4.2 mmol), and triethylamine (0.80 mL, 5.6 mmol) in 30 mL of dichloromethane was stirred overnight under nitrogen. The solution was washed twice with 15 mL of 5% sodium bicarbonate, dried over sodium sulfate and the solvent removed. The product was purified by chromotography on silica gel with ethyl acetate (30-100%) in dichloromethane to give 0.94 g (71%) of (±)-4-((αR*)-3-acetoxy-α-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide as a white foam. NMR (200 MHz, DMSO-d6): δ0.9 (d, J=6 Hz, 3H); 1.1 (d, J=6 Hz, 3H); 1.0-1.2 (br m, 6H); 1.75 (dd, J1 =7.5 Hz, J2 =12 Hz, 1H); 2.1 (dd, J1 =8.5 Hz, J2 =12.5 Hz, 1H); 2.2 (s, 3H); 2.4-2.6 (m, 3H); 2.7 (m, 1H; 2.8 (dd, J1 =7.5 Hz, J2 =15 Hz, 1H); 3.1 (dd, J1 =6 Hz, J2 =14 Hz, 1H); 3.1 -3.4 (br m, 4H); 5.05 (d, J=15 Hz, 1H); 5.1 (s, 1H); 5.15 (d, 10 Hz, 1H); 5.8 (m, 1H) 1H); 7.0 (d, J=8 Hz, 1H); 7.15 (d, J=8 Hz, 1H); 7.25 and 7.4 (ABq, J=8 Hz, 4H); 7.4(t, J=8 Hz, 1H). The amine was dissolved in ethanol and convened to the monohydrochloride salt by titration with ethanolic hydrogen chloride. After the solvent was removed, the salt was dissolved in a minimal amount of dichloromethane and precipitated with diethyl ether. Filtration gave 0.50 g of the hygroscopic salt. Calc for C29H39N3O3HCl H2O: C, 65.46; H, 7.97; N, 7.90; Cl, 6.66. Found: C, 65.43; H, 7.97; N, 8.00; Cl, 6.79.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH2:19][CH:18]4[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:15]([CH2:16][CH2:17]4)[CH:14]=3)=[CH:10][CH:11]=2)[N:6]([CH3:28])[C:5]1=[O:29].[O:32]1CCCC1.B.OO.[OH-].[Na+]>CCOC(C)=O.C1COCC1>[CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([CH:13]3[CH2:19][CH:18]4[N:20]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH:15]([CH2:16][CH2:17]4)[CH:14]3[OH:32])=[CH:10][CH:11]=2)[N:6]([CH3:28])[C:5]1=[O:29]
Reactant: C1CCOC1
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CCC(C3)N4C(=O)OC(C)(C)C)nc21
Agent: B
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3CC4CCC(C3O)N4C(=O)OC(C)(C)C)nc21
Temperature: 0 °C

Procedure:
To a round bottom flask was added tert-butyl 3-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (17-31) (1.5 g, 3.52 mmol), and anhydrous THF (15 mL). The reaction mixture was then cooled to 0° C. under an atmosphere of nitrogen, and added borane tetrahydrofuran COMPLEX (1M in THF) (3.87 ml, 3.87 mmol) dropwise over 10 minutes while stirring. Stirred for ˜10 minutes, then permitted to warm to room temperature for 30 minutes. Next cooled back to 0° C. and uncapped, and when open to atmosphere added hydrogen peroxide(35% by wt in H2O) (1.539 ml, 17.58 mmol) & sodium hydroxide (1M in H2O) (8.79 mL, 8.79 mmol) slowly over 20 minutes, then warmed to room temperature. The reaction was then permitted to stir overnight at room temperature (16 hours), then suspended in EtOAc, washed with a saturated solution of Na2S2O3, then saturated NaHCO3, followed by water and brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel chromatography (0-100% EtOAc/Hex) to yield tert-Butyl 3-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo-[4,5-b]pyridin-5-yl]-2-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (20-1). HRMS (M+H)+: observed=429.2865, calculated=429.2860.
Reaction SMILES: C([O:5][C:6]([C:8]1[N:9]([CH2:22][C:23]2[CH:27]=[C:26]([C:28]3[S:29][C:30]([Cl:33])=[CH:31][CH:32]=3)[O:25][N:24]=2)[C:10]([C:13]([N:15]2[CH2:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])=[N:11][CH:12]=1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[Cl:33][C:30]1[S:29][C:28]([C:26]2[O:25][N:24]=[C:23]([CH2:22][N:9]3[C:8]([C:6]([OH:7])=[O:5])=[CH:12][N:11]=[C:10]3[C:13]([N:15]3[CH2:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:14])[CH:27]=2)=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)c1cnc(C(=O)N2CCCOCC2)n1Cc1cc(-c2ccc(Cl)s2)on1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cnc(C(=O)N2CCCOCC2)n1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To the resulting solution containing 3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-([1,4]oxazepane-4-carbonyl)-3H-imidazole-4-carboxylic acid tert-butyl ester was added TFA (216 μL). The mixture was stirred for 3 h at RT and for 3 h at 40° C. More TFA (1 mL) was added and stirring was continued at 50° C. for 2 h. The mixture was concentrated under reduced pressure. The residue was evaporated three times from toluene to provide crude 3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-([1,4]oxazepane-4-carbonyl)-3H-imidazole-4-carboxylic acid (311 mg) which was directly used in the next step.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6](/[CH:18]=[CH:19]/[C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][N:21]=2)=[C:7]([NH:9][C:10]([C:12]2[S:13][CH:14]=[CH:15][C:16]=2[CH3:17])=[O:11])[CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:49].C(OCC)(=O)C>CN(C=O)C>[NH:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20](/[CH:19]=[CH:18]/[C:6]2[CH:5]=[CH:4][C:3]([CH2:2][Br:49])=[CH:8][C:7]=2[NH:9][C:10]([C:12]2[S:13][CH:14]=[CH:15][C:16]=2[CH3:17])=[O:11])=[N:21]1
Reactant: Cc1ccsc1C(=O)Nc1cc(CO)ccc1/C=C/c1n[nH]c2ccccc12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccsc1C(=O)Nc1cc(CBr)ccc1/C=C/c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 108 (0.30 g, 0.77 mmol) was dissolved in DMF (12 mL) and the solution was added with triphenylphosphine (0.45 g, 1.5 mmol) and carbon tetrabromide (0.51 g, 1.5 mmol), followed by stirring at room temperature for 1 hour. After the reaction, the mixture was added with ethyl acetate and washed with saturated aqueous sodium hydrogencarbonate solution. The organic layer was concentrated under reduced pressure to obtain (E)-N-{2-[2-(1H-indazol-3-yl)vinyl]-5-(bromomethyl)phenyl}-3-methylthiophene-2-carboxamide.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[Cl:15][C:16]1[C:24]2[CH:23]=[C:22]([C:25]3[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=3)[S:21][C:20]=2[CH:19]=[CH:18][CH:17]=1.C(O)C.[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36]>C(OCC)(=O)C>[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36].[Cl:15][C:16]1[C:24]2[CH:23]=[C:22]([C:25]3[CH2:26][CH2:27][N:28]([CH2:3][C@H:2]([OH:1])[CH2:4][O:5][C:6]4[CH:14]=[CH:13][CH:12]=[C:11]5[C:7]=4[CH:8]=[CH:9][NH:10]5)[CH2:29][CH:30]=3)[S:21][C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Clc1cccc2sc(C3=CCNCC3)cc12
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CC=C(c2cc3c(Cl)cccc3s2)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 1 using (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.129 g, 0.068 mmol) and 4-chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)benzo[b]thiophene (0.170 g, 0.068 mmol) using ethanol as reaction solvent. Yield 0.105 g (34%) of a tan powder. FDMS m/e=438 (M+ of free base). A sample was dissolved in ethyl acetate and treated with 1.0 equivalent of oxalic acid and evaporated to an orange powder. mp 138°-142° C. (dec) α[D]589 =-5.3 (c=1.13, dimethylsufoxide).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([NH:7][NH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1)=[O:10])=O>O=P(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)=[N:8][N:7]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(NNC(=O)c1cccc([N+](=O)[O-])c1)c1cccc(Cl)c1
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc(-c2nnc(-c3cccc(Cl)c3)o2)c1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
A suspension of N′1-(3-chlorobenzoyl)-3-nitrobenzene-1-carbohydrazide (0.321 g) in POCl3 (3 mL) was stirred at 90° C. for 24 h. The resulting clear solution was quenched with ice-water, solid obtained was filtered washed with water, dried and analyzed to give [2-(3-chlorophenyl)-1,3,4-oxadiazol-5-yl]-3-nitrobenzene. 1H NMR (DMSO-d6): δ 8.86 (t, 1H, J=1.8 Hz), 8.59 (dt, 1H, J=1.8 and 8.4 Hz), 8.48 (m, 1H), 8.25 (t, 1H, J=1.8 Hz), 8.16 (dt, 1H, J=1.2 and 7.5 Hz), 7.93 (t, 1H, J=8.1 Hz), 7.75 (m, 1H), 7.66 (t, 1H, J=7.5 Hz), LCMS: purity: 86%; MS (m/e): 302 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:28])=[C:7]([N:9]([CH2:14][C:15]([N:17]([N:19]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)[CH3:18])=[O:16])[CH2:10][C:11]([OH:13])=[O:12])[CH:8]=1)#[N:2].CCN=C=NCCCN(C)C.[C:40](O)([CH3:43])([CH3:42])[CH3:41]>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C.CCCCCC>[C:40]([O:12][C:11](=[O:13])[CH2:10][N:9]([C:7]1[CH:8]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=1[CH3:28])[CH2:14][C:15]([N:17]([N:19]1[CH2:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:27]1)[CH3:18])=[O:16])([CH3:43])([CH3:42])[CH3:41]
Reactant: Cc1ccc(C#N)cc1N(CC(=O)O)CC(=O)N(C)N1Cc2ccccc2C1
Reactant: CC(C)(C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: Cc1ccc(C#N)cc1N(CC(=O)OC(C)(C)C)CC(=O)N(C)N1Cc2ccccc2C1
Reaction time: 8 h
Yield: 74.5 %

Procedure:
The compound (2.06 g, 5.44 mmol) of Example 1, step A, 4-dimethylaminopyridine (1.40 g, 11.5 mmol) and WSC (1.46 g, 7.62 mmol) were dissolved in dichloromethane (22 ml), tert-butanol (1.0 ml, 10 mmol) was added at room temperature, and the mixture was stirred at the same temperature overnight. The reaction mixture was diluted with an ethyl acetate-hexane=1:1 mixed solvent, and the organic layer was washed with 10% aqueous citric acid solution, water, diluted aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (1.76 g, yield 74%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@@H:13]([OH:18])[C:14]([O:16][CH3:17])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35].O>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C@@H:13]([O:18][S:34]([CH3:33])(=[O:36])=[O:35])[C:14]([O:16][CH3:17])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@H](OS(C)(=O)=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
206 g of methyl N-benzyloxycarbonyl-3(S)-amino-2(R)-hydroxy-4-phenylbutyrate was dissolved in 1,000 ml of methylene chloride and cooled to -10° C. After adding 79 g of triethylamine, 82.5 g of methanesulfonyl chloride was slowly added thereto under cooling at the same temperature. The obtained mixture was stirred at 15° to 0° C. for 1 hour and then 500 ml of water was added thereto to effect liquid/liquid separation. The organic layer was separated and washed successively with 1N hydrochloric acid, a 5% aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. Thus 253 g of methyl N-benzyloxycarbonyl-3(S)-amino-2(R)-methanesulfonyloxy-4-phenylbutyrate was obtained as a pale yellow, oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][C@@H:13]2[CH2:18][N:17]([CH3:19])[C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[O:14]2)[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:24][C:25]1[CH:26]=[C:27]([C:32]([CH3:38])([CH3:37])[C:33]([O:35][CH3:36])=[O:34])[CH:28]=[CH:29][C:30]=1[Cl:31].N1C=CC=CC=1.O>ClCCl>[Cl:31][C:30]1[CH:29]=[CH:28][C:27]([C:32]([CH3:37])([CH3:38])[C:33]([O:35][CH3:36])=[O:34])=[CH:26][C:25]=1[NH:24][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([O:11][CH2:12][C@@H:13]2[CH2:18][N:17]([CH3:19])[C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[O:14]2)=[CH:10][C:2]=1[Cl:1]
Reactant: CN1C[C@@H](COc2ccc(C(=O)Cl)c(Cl)c2)Oc2ccccc21
Reactant: COC(=O)C(C)(C)c1ccc(Cl)c(N)c1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(C)(C)c1ccc(Cl)c(NC(=O)c2ccc(OC[C@@H]3CN(C)c4ccccc4O3)cc2Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the compound prepared in Example 17 in dichloromethane (1.8 mL) was dropped to a solution of the compound (100 mg) prepared in Example 16 in dichloromethane (1.8 mL). Pyridine (0.057 mL) was added to the reaction mixture, which was stirred for 1 hour at room temperature. The reaction mixture dissolved to water was extracted with ethyl acetate. The organic layer was sequentially washed with diluted hydrochloric acid, saturated sodium hydrogencarbonate solution, and saturated brine solution and was dried by anhydrous magnesium sulphate. The title compound (164 mg) having the following physical data was obtained by purifying the residue obtained by removing the solvent by silica gel column chromatography (n-hexane:ethyl acetate=4:1). TLC: Rf 0.41 (n-hexane:ethyl acetate=2:1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][N:3]=[C:2]1[C:7]1[CH:27]=[CH:26][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18](C(OCC)=O)[CH2:17][CH2:16]2)=[CH:9][CH:8]=1.[OH-].[K+]>CC(O)C>[NH:18]1[CH2:19][CH2:20][CH:15]([CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:26]=[CH:27][C:7]([C:2]3[O:1][CH2:6][CH2:5][CH2:4][N:3]=3)=[CH:8][CH:9]=2)[CH2:16][CH2:17]1
Reactant: CCOC(=O)N1CCC(CCCOc2ccc(C3=NCCCO3)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: c1cc(C2=NCCCO2)ccc1OCCCC1CCNCC1
Yield: 100 %

Procedure:
A mixture of ethyl 4-[3-[4-(5,6-dihydro-4H-1,3-oxazin-2-yl)phenoxy]propyl]-1-piperidinecarboxylate, 26.3 parts of potassium hydroxide and 200 parts of 2-propanol was stirred and refluxed for 3 hours. After evaporation, water was added and the solvent was distilled off till all traces of 2-propanol were removed. After cooling, ice water was added and the product was extracted with dichloromethane. The organic layer was dried, filtered and evaporated, yielding 14.5 parts (100%) of 5,6-dihydro-2-[4-[3-(4-piperidinyl)propoxy]phenyl]-4H-1,3-oxazine as a residue (int. 60).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])=[CH:4][CH2:3]1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[C:11]([C:10]1[CH:9]=[C:8]([CH:5]2[CH2:6][CH2:7][CH:2]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:3][CH2:4]2)[CH:15]=[CH:14][CH:13]=1)#[N:12]
Reactant: N#Cc1cccc(C2=CCC(=O)CC2)c1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: N#Cc1cccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1

Procedure:
The title compounds were prepared as white solids from hydrogenation of 3-(4-oxo-cyclohex-1-enyl)-benzonitrile (as prepared in the previous step) followed by reductive amination of the corresponding ketone with N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedures described in Step C of Example 5 and Step C of Example 4.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(C(F)(F)F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(pyridin-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 470 [M+1]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH2:19][OH:20])[CH:12]=1.C(N(CC)CC)C>ClCCl.O>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH:19]=[O:20])[CH:12]=1
Reactant: OCCCc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CCCc1cccnc1
Temperature: -10 °C
Reaction time: 0.03 h

Procedure:
A stirred solution of oxalyl chloride (1 ml) in dichloromethane (25 ml) under argon was cooled to -60° C. A solution of dimethylsulphoxide (1.7 ml) in dichloromethane (5 ml) was then added dropwise and the temperature maintained at <-50° C. After 2 minutes, a solution of 3-(3-pyridyl)propanol (1.37 g) in dichloromethane (10 ml) was added dropwise during 5 minutes. Stirring was continued for a further 15 minutes and then triethylamine (7.0 ml) was added dropwise. The mixture was allowed to warm to -10° C. and water (50 ml) was then added. The aqueous mixture was extracted with ether (1×100, 2×25 ml) and the combined extracts washed with saturated brine (2×25 ml), then dried (MgSO4) and evaporated. Flash chromatography of the residue, eluting with ethyl acetate, gave 3-(3-pyridyl)propionaldehyde, as a pale yellow oil (630 mg); NMR (90 MHz; CDCl3): 2.85 (4H, m), 7.16 (1H, m), 7.48 (1H, m), 8.40 (2H, m), 9.76 (1H, s).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH2:7][S:8][C:9]23[CH:18]=[CH:17][CH:16]=[CH:15][C:10]2=[N:11][CH:12]=[CH:13][C:14]=13)=O)C.[NH2:19][NH2:20].C(N(CC)CC)C>CO>[S:8]1[C:9]23[CH:18]=[CH:17][CH:16]=[CH:15][C:10]2=[N:11][CH:12]=[CH:13][C:14]3=[C:6]([C:4]([NH:19][NH2:20])=[O:3])[CH2:7]1
Reactant: NN
Reactant: CCOC(=O)C1=C2C=CN=C3C=CC=CC32SC1
Solvent: CO
Solvent: CCN(CC)CC
Product: NNC(=O)C1=C2C=CN=C3C=CC=CC32SC1
Yield: 34.7 %

Procedure:
In 20 ml of desiccated methanol was dissolved 515 mg of benzo[b]thieno[2,3-c]pyridine-3-carboxylic acid ethyl ester and after adding thereto 252 mg of hydrazine.di-chloride and 700 μl of triethylamine, the mixture was stirred for 2 days. Then, after refluxing the mixture for 2 hours, the temperature was allowed to lower to room temperature and crystals thus deposited were collected by filtration to provide 169 mg (yield of 0%) of benzo[b]thieno[2,3-c]pyridine-3-carbohydrazide.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1C#N.C[Mg]Cl.Cl.CC[O:17][CH2:18][CH3:19]>>[NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[C:18](=[O:17])[CH3:19]
Reactant: CCOCC
Reactant: N#Cc1ccc(Cl)cc1N
Agent: C[Mg]Cl
Agent: Cl
Product: CC(=O)c1ccc(Cl)cc1N
Temperature: -60 °C
Reaction time: 1 h

Procedure:
To a vigorously stirred, Et2O (100 mL) solution of 2-amino-4-chloroberizonitrile (1.00 g, 6.55 mmol) cooled in an ice-H2O bath was added MeMgCl (3.0 M in THF, 6.5 mL, 19.7 mmol) dropwise over 5 min. During that time the reaction became a thick yellow suspension. Stirring was continued at the temperature for 1 h before the cooling bath was removed and the reaction stirred for 21 h at rt. The resultant light yellow suspension cooled to −60° C. and treated with aq HCl (5 M, 8 mL, 40 mmol) dropwise over ˜3 min. The mixture was allowed to warm slowly to it within the cooling bath. Later more aq HCl (5 M, 6.5 mL, 33 mmol) was added. The Et2O layer was separated, the aq phase was basicified (pH 4-5) by addition of solid KOH and later extracted with EtOAc (3×). The Et2O and EtOAc layers were combined, dried (Na2SO4) and concentrated under reduced pressure to afford the title material which was used without further purification; 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J=8.4 Hz, 1H), 6.65 (d, J=2.0 Hz, 1H), 6.60 (dd, J=2.0 Hz, 8.0 Hz, 1H), 6.40 (br, 2H), 2.55 (s, 3H); MS (ES+): m/z 170.07 (100) [MH+]; HPLC: tR=3.12 min (OpenLynx, polar—5 min).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].OC1C2N=NNC=2C=CC=1.[F:27][C:28]([F:46])([F:45])[C:29]1[CH:30]=[C:31]([CH:42]=[CH:43][CH:44]=1)[CH2:32][N:33]1[CH2:37][C@H:36]2[C@H:38]([NH2:41])[CH2:39][CH2:40][C@H:35]2[CH2:34]1.CN(C)CCCN=C=NCC>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([NH:41][C@H:38]1[C@H:36]2[C@H:35]([CH2:34][N:33]([CH2:32][C:31]3[CH:42]=[CH:43][CH:44]=[C:29]([C:28]([F:46])([F:27])[F:45])[CH:30]=3)[CH2:37]2)[CH2:40][CH2:39]1)=[O:16])[CH2:10][CH:11]([CH3:12])[CH3:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: N[C@@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
N-(tert-Butoxycarbonyl)-L-leucine (180 mg, 0.778 mmol), hydroxybenzotriazole (119 mg, 0.778 mmol), and (3aS,4R,6aR)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine (201 mg, 0.707 mmol) from Example 154 Step A were combined in dichloromethane (1 mL). After 20 minutes, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (0.138 mL, 0.778 mmol) was added and the reaction stirred at room temperature for 24 hours. The reaction was quenched with water, and the layers were separated. The aqueous layer extracted with 1 mL of dichloromethane. The combined organic layers were applied to a silica gel cartridge (Analogix®, Burlington, Wis., RS15-24) and eluted with 1-10% methanol (2 N ammonia)/dichloromethane to give N2-(tert-butyloxycarbonyl)-N1-{(3aS,4R,6aR)-2-[3-(trifluoromethyl)benzyl]octahydrocyclopenta[c]pyrrol-4-yl}-L-leucinamide: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.66 (d, J=7.1, 1H), 7.97 (d, J=8.5, 1H), 7.73 (s, 1H), 7.56 (s, 2H), 7.44 (t, J=7.7, 1H), 4.70 (dd, J=5.9, 11.0, 1H), 4.40 (br s, 1H), 3.56 (d, J=13.5, 1H), 3.41 (d, J=13.5, 1H), 2.74 (d, J=8.9, 1H), 2.48 (s, 2H), 2.37-2.31 (m, 1H), 2.27 (d, J=8.4, 1H), 2.24-2.19 (m, 1H), 2.12 (dq, J=6.0, 12.0, 1H), 1.91-1.81 (m, 4H), 1.66 (td, J=7.4, 14.7, 1H), 1.50 (s, 9H), 1.43-1.35 (m, 1H), 0.87 (d, J=5.9, 3H), 0.84 (d, J=5.6, 3H); MS (ESI+) m/z 498 (M+H)+.