Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10](=[CH2:24])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=1)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClC1C=CC(NC(=O)CC[C:36]2[CH:41]=[CH:40][C:39]([O:42][C:43]3[CH:48]=[CH:47][N:46]=[C:45]([C:49]#[N:50])[CH:44]=3)=[CH:38][CH:37]=2)=CC=1>>[Si:1]([O:8][CH2:9]/[C:10](=[CH:24]\[C:37]1[CH:36]=[CH:41][CH:40]=[C:39]([O:42][C:43]2[CH:48]=[CH:47][N:46]=[C:45]([C:49]#[N:50])[CH:44]=2)[CH:38]=1)/[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=1)=[O:12])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: N#Cc1cc(Oc2ccc(CCC(=O)Nc3ccc(Cl)cc3)cc2)ccn1
Reactant: C=C(CO[Si](C)(C)C(C)(C)C)C(=O)Nc1cccc(C(C)(C)C)c1
Product: CC(C)(C)c1cccc(NC(=O)/C(=C/c2cccc(Oc3ccnc(C#N)c3)c2)CO[Si](C)(C)C(C)(C)C)c1

Procedure:
The title compound was prepared as described in Example 36, Step 2, using 2-((tert-butyldimethylsilyloxy)methyl)-N-(3-tert-butylphenyl)acrylamide and 4-(3-iodophenoxy)picolinonitrile (prepared as described in Example 11, Step 1 using 3-iodophenol and 4-chloropicolinonitrile). LCMS, FA: Rt=2.61 min, [MH+542.0].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[CH:22]1([N:25]2[C:29]([C:30]([F:33])([F:32])[F:31])=[C:28]([CH2:34][C:35](O)=[O:36])[CH:27]=[N:26]2)[CH2:24][CH2:23]1.CCCP(O)(O)=O>C1COCC1>[CH:22]1([N:25]2[C:29]([C:30]([F:32])([F:31])[F:33])=[C:28]([CH2:34][C:35]([NH:1][C:2]3[CH:7]=[N:6][CH:5]=[C:4]([C:8]([C:10]4[C:18]5[CH:17]=[N:16][CH:15]=[N:14][C:13]=5[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=4)=[O:9])[CH:3]=3)=[O:36])[CH:27]=[N:26]2)[CH2:23][CH2:24]1
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Reactant: O=C(O)Cc1cnn(C2CC2)c1C(F)(F)F
Agent: CCCP(=O)(O)O
Solvent: C1CCOC1
Product: CC(C)n1cc(C(=O)c2cncc(NC(=O)Cc3cnn(C4CC4)c3C(F)(F)F)c2)c2cncnc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 76 %

Procedure:
To a solution of (5-Amino-pyridin-3-yl)-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (Preparation 95, 50 mg, 0.17 mmol), (1-Cyclopropyl-5-trifluoromethyl-1H-pyrazol-4-yl)-acetic acid (Preparation 141, 47.1 mg, 0.21 mmol) and TEA (0.08 mL, 0.62 mmol) in THF (1 mL), 1-propylphosphonic acid cyclic anhydride (50% solution in EtOAc, 0.26 mL, 0.44 mmol) was added and the mixture was stirred at room temperature for 14 hours. The reaction mixture was evaporated under reduced pressure and the residue partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and dried (Na2SO4) and evaporated in vacuo. Purification by column chromatography on silica gel (gradient of EtOAc:Hexane 0:100 to 80:20) gave the title compound as a white solid in 76% yield, 67 mg. 1H NMR (400 MHz, DMSO-D6) δ: 1.05-1.07 (m, 2H), 1.08-1.15 (m, 2H), 1.54 (d, 6H), 3.73-3.76 (m, 3H), 5.06-5.13 (m, 1H), 7.55 (s, 1H), 8.44 (s, 1H), 8.51 (s, 1H), 8.73 (s, 1H), 8.94 (d, 1H), 8.99 (s, 1H), 9.44 (s, 1H), 10.61 (s, 1H). LCMS (System 10): Rt=3.03 min m/z 498 [M+H]+
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:22])[CH2:11][CH2:12][CH2:13][CH:14]([OH:21])[N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:6][CH:5]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(C)C=CC=CC=1>O1CCCC1.CCCCCC>[CH2:23]([O:22][CH:10]([C:7]1[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=1)[CH2:11][CH2:12][CH2:13][C:14]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(CCCC(O)N1CCOCC1)c1ccc(F)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(CCCC(OCc1ccccc1)c1ccc(F)cc1)N1CCOCC1
Reaction time: 6 h
Yield: 84.8 %

Procedure:
1.8 gms of Sodium hydride was taken in 50 ml of tetrahydrofuran at 0° C., to this 5 gms of 1-(4-Fluoro-phenyl)-5-hydroxy-5-morpholin-4-yl-pentan-1-one was added under nitrogen atmosphere and maintained for about 30 minutes. To the reaction mass 3.4 gms of benzyl bromide was added at 20-25° C. and stirred for about 6 hours. Quenched the reaction mass with hydrochloric acid and stirred for about 15 minutes. Separated the layers and extracted the reaction mass with ethyl acetate. Organic layer was separated and dried over sodium sulphate. Distilled off the solvent completely and isolated the compound by adding 7 ml of toluene and 35 ml of hexane. Filtered the compound, washed with hexane and dried at 35-40° C. to get 5.6 gms of 5-Benzyloxy-5-(4-fluoro-phenyl)-1-morpholin-4-yl-pentan-1-one.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([C:28]([CH2:31][CH3:32])=[CH:29][CH:30]=3)[N:12]=[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:14]=2[CH2:15][CH2:16][CH2:17][CH2:18][C:19](O)=[O:20])[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.CN(C)CCCN=C=NCC.[NH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1>ClCCl.CN(C)C1C=CN=CC=1.O>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([C:28]([CH2:31][CH3:32])=[CH:29][CH:30]=3)[N:12]=[C:13]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:14]=2[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([NH:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=2)=[O:20])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCc1ccc2c(-c3cccc(C#N)c3)c(CCCCC(=O)O)c(-c3ccccc3)nn12
Reactant: Nc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCc1ccc2c(-c3cccc(C#N)c3)c(CCCCC(=O)Nc3ccccn3)c(-c3ccccc3)nn12
Reaction time: 0.17 h
Yield: 78.7 %

Procedure:
To a stirred solution of 5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid (60 mg) in dichloromethane (2 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (35.3 mg) and 2-aminopyridine (20 mg) and the reaction mixture was stirred for 10 minutes. 4-Dimethylaminopyridine (2 mg) was added and the reaction mixture was stirred at room temperature for 15 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a mixture of ethyl acetate and n-hexane (1:2) to give 5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-N-(2-pyridinyl)pentanamide (55.7 mg) as an yellow amorphous.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])=[C:6]([Cl:16])[CH:5]=1.CO.[OH-].[Na+]>C1COCC1>[Cl:16][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])[C:3]([OH:17])=[O:2]
Reactant: COC(=O)c1ccc(OCCCC#N)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: N#CCCCOc1ccc(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A solution of 3-Chloro-4-(4-nitrilo-butoxy)-benzoic acid methyl ester (6.24 g, 24.6 mmol in THF (100 ml) and methanol (100 ml) was treated with 5 N sodium hydroxide solution (35 ml) with stirring at room temperature for 1 h. The reaction mixture was concentrated in vacuo, diluted with water, and acidified to pH 1 with 5 N hydrochloric acid. The resulting suspension was extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The resulting off white solid was triturated with hot petroleum ether, cooled and filtered to give 5.58 g (95%) of the title compound as a white solid mp 150° C.; 1H NMR (CDCl3) δ2.22-2.28 (m, 2H), 2.69 (t, J=7.0 Hz, 2H), 3.90 (s, 3H), 4.23 (t, J=5.5 Hz, 2H), 6.97 (d, J=8.6 Hz, 1H), 8.01 (dd, J=8.6, 2.2 Hz, 1H), 8.14 (d, J=2.0 Hz, 1H). IR (KBr) 3400, 2200, 1700, 1600, 1450, 1275 and 1050 cm−1, mass spectrum (EI), m/z 239/241. Anal. Calcd. for C11H10ClNO3: C, 55.13; H, 4.21; N, 5.85. Found: C, 54.84; H, 4.01; N, 5.69.
Reaction SMILES: [C:1]([C:3]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][S:5][C:4]=1[N:12]=[C:13]=[O:14])#[N:2].[CH3:15][NH:16][CH3:17]>C1(C)C=CC=CC=1>[C:1]([C:3]1[C:7]([C:8]([CH3:10])([CH3:11])[CH3:9])=[CH:6][S:5][C:4]=1[NH:12][C:13]([N:16]([CH3:17])[CH3:15])=[O:14])#[N:2]
Reactant: CC(C)(C)c1csc(N=C=O)c1C#N
Reactant: CNC
Solvent: Cc1ccccc1
Product: CN(C)C(=O)Nc1scc(C(C)(C)C)c1C#N
Yield: 80 %

Procedure:
20.6 g (0.1 mole) of 3-cyano-4-tert.-butyl-thien-2-yl isocyanate were added dropwise to a solution of 6.5 g (0.145 mole) of dimethylamine in 200 ml of toluene at room temperature. After the exothermic reaction had subsided, the mixture was concentrated and the residue was recrystallized from a little toluene. 20.1 g of 1-(3-cyano-4-tert.-butyl-thien-2-yl)-3,3-dimethyl-urea of melting point 140° C. were obtained in this manner.
Reaction SMILES: C(OC([C:7]1([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25]([F:32])[CH:24]=2)[C:12](=[O:13])[CH:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][S:9][CH2:8]1)=O)C=C.N1CCOCC1.C([O-])(O)=O.[Na+]>C1COCC1>[C:18]([O:17][C:15](=[O:16])[NH:14][C@@H:11]1[C:12](=[O:13])[C@H:7]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25]([F:32])[CH:24]=2)[CH2:8][S:9][CH2:10]1)([CH3:21])([CH3:19])[CH3:20]
Reactant: C=CCOC(=O)C1(Cc2ccc([N+](=O)[O-])c(F)c2)CSCC(NC(=O)OC(C)(C)C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CC(C)(C)OC(=O)N[C@H]1CSC[C@@H](Cc2ccc([N+](=O)[O-])c(F)c2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a degassed solution of 5-tert-butoxycarbonylamino-3-(3-fluoro-4-nitro-benzyl)-4-oxo-tetra-hydro-thiopyran-3-carboxylic acid allyl ester (3.56 g, 7.6 mmol) and morpholine (1.4 mL, 15.2 mmol) in THF (50 mL) was added under argon Pd(PPh3)4 (0.092 g, 0.076 mmol) and the reaction mixture was stirred at 25° C. for 3 h. The reaction mixture was poured onto cold saturated NaHCO3 solution and extracted with EtOAc. Combined extracts were washed with brine, dried over MgSO4 and evaporated. The residue was re-dissolved in THF (10 mL) and kept at 25° C. for 3 h after addition of a catalytic amount of DBU. The title compound was obtained after evaporation and crystallization from diisopropylether as single diastereoisomer: TLC (hexane-EtOAc 1:2) Rf=0.38; HPLC RtA=2.17 min; ESIMS [M+NH4]+=402; 1H NMR (400 MHz, CDCl3): δ 8.0 (dd, 1H), 7.14 (m, 2H), 5.68 (m, 1H), 4.54 (m, 1H), 3.41 (m, 1H), 3.28 (dd, 1H), 3.14 (m, 1H), 2.84 (ddd, 1H), 2.69 (dd, 1H), 2.65 (m, 2H), 1.42 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C@@H:11]3[CH2:28][CH2:29][CH2:30][N:10]3[CH2:9]2)=[CH:4][CH:3]=1.[C:31]([Cu])#[N:32]>CN(C=O)C>[N:22]1([CH2:21][CH2:20][CH2:19][O:18][C:14]2[CH:13]=[C:12]3[C:17]([C@H:8]([C:5]4[CH:6]=[CH:7][C:2]([C:31]#[N:32])=[CH:3][CH:4]=4)[CH2:9][N:10]4[CH2:30][CH2:29][CH2:28][C@@H:11]43)=[CH:16][CH:15]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: N#C[Cu]
Reactant: Brc1ccc([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCCCC4)ccc32)cc1
Solvent: CN(C)C=O
Product: N#Cc1ccc([C@@H]2CN3CCC[C@@H]3c3cc(OCCCN4CCCCC4)ccc32)cc1
Temperature: 150 °C

Procedure:
To a sealed tube reaction vessel were added cis-6-(4-bromo-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline (0.21 mmol), CuCN (5.2 equiv.), and DMF (1.7 M). The tube was purged with nitrogen, sealed, and heated at 150° C. overnight. The reaction mixture was cooled to rt, diluted with aqueous NaCN, and extracted with diethyl ether. The organic layer was washed with water, satd. aq. NaHCO3, and brine, dried (Na2CO3), and concentrated to give the crude product. Chromatographic purification (NH3 in MeOH/CH2Cl2) followed by reverse-phase HPLC gave the desired product as a mixture with the 6-trans isomer (7% combined yield).
Reaction SMILES: [Li][CH2:2]CCC.[F:6][C:7]1[CH:33]=[CH:32][C:10]([C:11]([C:13]2[CH:14]=[N:15][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[N:17][CH:18]=2)=O)=[CH:9][CH:8]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[F:6][C:7]1[CH:33]=[CH:32][C:10]([C:11]([C:13]2[CH:14]=[N:15][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[N:17][CH:18]=2)=[CH2:2])=[CH:9][CH:8]=1
Reactant: [Li]CCCC
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C(=O)c3ccc(F)cc3)cn2)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C(c1ccc(F)cc1)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a solution of methyltriphenylphosphonium bromide (6.0 g, 16.84 mmol) in THF (40 mL) at −78° C. was dropwise added n-BuLi (2.4 M, 7.2 mL, 17.19 mmol). After stirred at −78° C. for 1 h, tert-butyl 4-(5-(4-fluorobenzoyl)pyrimidin-2-yl)piperazine-1-carboxylate (1.3 g, 3.37 mmol) was added. The reaction mixture was stirred at RT overnight. LCMS showed the reaction was completed. The reaction was quenched with aqueous NH4Cl solution and extracted with EA (2×50 mL). The organic phases were washed with H2O (3×30 mL) and brine (50 mL), dried over sodium sulfate, filtered, concentrated and purified by silica gel chromatography (PE:EA=10:1) to get the title compound as a white solid (1.2 g, 93%). MS (ES+) C21H25FN4O2 requires: 384. found: 329 [M−56+1]+.
Reaction SMILES: [CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([S:13][C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[CH2:16][NH2:17])[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2].N1C=CC=CC=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>ClCCl>[CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([S:13][C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[CH2:16][NH:17][C:28](=[O:30])[CH3:29])[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nnc2ccc(Sc3ccccc3CN)cn12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCc1ccccc1Sc1ccc2nnc(C(C)C)n2c1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 67.6 %

Procedure:
To a solution of 2-(3-Isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-ylsulfanyl)-benzylamine (30 mg, 0.1 mmol) in dichloromethane (400 μL) was added pyridine (16 μL, 0.2 mmol) and acetic anhydride (9 μL, 0.1 mmol) and the reaction stirred for 25 minutes at ambient temperature. The reaction was concentrated in vacuo to an oily residue. The residue was purified by flash chromatography (eluting with 10% methanol/ethyl acetate), followed by trituration with diethyl ether to yield the title compound as a white solid (23 mg, 68%). MS (M+1)=341.4.
Reaction SMILES: [N:1]([C@H:4]1[CH2:8][C@@H:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5]1)=[N+]=[N-].CC1CCCO1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC(OC)(C)C>[C:9]1([C@@H:7]2[CH2:8][C@H:4]([NH2:1])[CH:5]=[CH:6]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: [N-]=[N+]=N[C@@H]1C=C[C@H](c2ccccc2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC1CCCO1
Solvent: O
Solvent: COC(C)(C)C
Product: N[C@@H]1C=C[C@H](c2ccccc2)C1
Reaction time: 0.83 h

Procedure:
A solution of Example 48B (530 mg, 2.86 mmol), 2-methyl tetrahydrofuran (9.5 mL), water (1.056 mL), and triphenylphosphine (900 mg, 3.43 mmol) was heated to 70° C. After 50 minutes, LCMS showed complete reaction. The mixture was diluted with MTBE (50 mL) and extracted with 2N HCl (25 mL) and water (25 mL). Aqueous 2N NaOH (30 mL) was added to the aqueous layer, followed by extraction with MTBE (50 mL×3). The final organic layers were dried (Na2SO4), filtered, and concentrated to provide the title compound, which was used crude in the next step. MS (DCI) m/z 160 (M+H)+.
Reaction SMILES: C1(S([N:10]([CH2:20][CH2:21][CH2:22][N:23]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:24][CH2:25][SH:26])[CH2:11][CH2:12][C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])=O)(=O)=O)C=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>COCCOC.C(Cl)Cl>[CH2:27]([N:23]([CH2:22][CH2:21][CH2:20][NH:10][CH2:11][CH2:12][CH2:13][NH:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:24][CH2:25][SH:26])[CH2:28][CH2:29][CH3:30]
Reactant: CCCCNC(=O)CCN(CCCN(CCS)CCCC)S(=O)(=O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: CCCCNCCCNCCCN(CCS)CCCC

Procedure:
Dissolve 3-(benzenesulfonyl-{3-[butyl-(2-mercapto-ethyl)-amino]-propyl}-amino)-N-butyl-proponamide (10 mmol) prepared in Scheme VII, step B in 1,2-dimethoxyethane (50 mL) and treat with lithium aluminum hydride (20 mmol). Heat the re action to reflux for 18 hours. After cooling the react ion is worked up by consecutive addition of water (0.8 mL), 10% sodium hydroxide (1.2 mL) and water (2 .2 mL). Then dilute with methylene chloride (200 mL), rinse with water (100 mL), brine (100 mL), dry over anhydrous sodium sulfate, filter and concentrate under vacuum. Purify the residue by flash chromatography (silica gel, methanol/methylene chloride) to provide the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)([O-])=O>C(O)C.[Pd]>[F:25][C:22]([F:23])([F:24])[C:18]1[CH:17]=[C:16]([CH:13]2[CH2:12][CH2:11][N:10]([C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][N:8]=3)[CH2:15][CH2:14]2)[CH:21]=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(N2CCC(c3cccc(C(F)(F)F)c3)CC2)nc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCC(c3cccc(C(F)(F)F)c3)CC2)nc1
Reaction time: 2 h

Procedure:
To a solution of 5′-nitro-4-(3-trifluoromethyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl (500 mg, 1.42 mmol) from above in ethanol (15 mL) was added 10% palladium on carbon (100 mg). The mixture was hydrogenated at 50 psi for 2 hr. The mixture was filtered over celite and the solvents were evaporated to give 4-(3-trifluoromethyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-ylamine that was used in the next step with further purification. LCMS calcd for C17H18F3N3 (m/e) 321, obsd 322 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C@H:12]([OH:14])[CH3:13])[CH2:11][O:10]1.[N+:15]([C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[C:21](Cl)=[O:22])([O-:17])=[O:16]>C(Cl)Cl.C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([O:14][C:21](=[O:22])[C:20]2[CH:19]=[C:18]([N+:15]([O-:17])=[O:16])[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=2)[CH3:13])[CH2:11][O:10]1
Reactant: C[C@@H](O)C1(c2ccc(F)cc2F)CO1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](OC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)[C@@]1(c2ccc(F)cc2F)CO1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 46.3 %

Procedure:
(1R)-1-[2-(2,4-Difluorophenyl)-2-oxiranyl]ethanol (31.5 g) and 40 g of 3,5-dinitrobenzoyl chloride were dissolved in 500 ml of methylene chloride and, with ice cooling, 24.1 ml of triethylamine was added dropwise thereinto. The reaction solution was stirred at room temperature for 3.5 hours, washed with 150 ml of water and then with 150 ml of 5% aqueous solution of sodium bicarbonate, dried over magnesium sulfate and concentrated under reduced pressure. The crystals separated out were collected by filtration and washed with methylene chloride. The mother liquor and the washing were combined and distilled off under reduced pressure, then 25 ml of ethyl acetate and 300 ml of methanol were added to the residue and the mixture was cooled with ice. The crystals separated out were collected by filtration and recrystallized from a mixture of 25 ml of ethyl acetate and 250 ml of methanol to give 28.7 g of [(1R)-1-[(2R)-2-(2,4-difluorophenyl)- 2-oxiranyl]ethyl]3,5-dinitrobenzoate as colorless needles.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.[Cl:13][CH2:14][CH2:15][N:16]=[C:17]=[O:18]>>[Cl:13][CH2:14][CH2:15][NH:16][C:17](=[O:18])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:6][CH:7]=1
Reactant: Nc1ccc(CCCCO)cc1
Reactant: O=C=NCCCl
Product: O=C(NCCCl)Nc1ccc(CCCCO)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To a solution of 4-(p-amino phenyl) butanol (2 g in 125 mL of ethyl ether) is added dropwise 1.25 g of 2-chloroethyl isocyanate. This solution is stirred for 3 h at room temperature, cooled at -20° C., and faltered. A white solid of 4-{p-[3-(2-chloroethyl)ureido]phenyl}butanol is separated and recrystallized from ethanol (white flakes), yield 55%, mp 123°-124° C., IR (KBr pellet): 3300 (NH), 1730 (C=O, ester), and 1640 cm-1 (C=O, ureido); 1H NMR (DMSO-d6): 8.65 (s, 1p, ArNH), 7.4-7.0 (dd, 4p, p-substituted Ar), 6.4 (broad t, 1p, NHCH2), 3.7-3.4 (m, 6p, ArCH2 and NHCH2CH2Cl), 2.85 (t, 2p, CH2OH), 2.3 (s, 1p, CH2OH), 1.85 (q, 2p, CH2CH2CH2), 1.45 (q, 2p, CH2CH2OH)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([C@@H:27]4[C@@H:32]([CH3:33])[O:31][CH2:30][C:29](=O)[NH:28]4)=O)[CH2:21][CH2:20]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][C@H:27]4[C@@H:32]([CH3:33])[O:31][CH2:30][CH2:29][NH:28]4)[CH2:21][CH2:20]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: C[C@H]1OCC(=O)N[C@@H]1C(=O)N1CCC(c2cc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H]1OCCN[C@H]1CN1CCC(c2cc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Yield: 40.3 %

Procedure:
To a stirred suspension of the product of Step B (54 mg, 0.12 mmol) in 2 mL tetrahydrofuran at 0° C. was added lithium aluminum hydride (1.0M in tetrahydrofuran, 0.20 mL, 0.20 mmol). After refluxing for 2 hours, the reaction mixture was quenched with few drops of saturated sodium sulfate, and then solvent was removed in vacuo. Purification by prep-TLC afforded the title reduction product (21 mg, 41%).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[CH2:25][CH2:24][C@@:18]3([NH:22]C(=O)[O:20][CH2:19]3)[CH2:17]2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O.[OH-].[Li+].O>O1CCOCC1>[NH2:22][C@:18]1([CH2:19][OH:20])[CH2:24][CH2:25][C@@H:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:11][CH:12]=2)[CH2:17]1
Reactant: CCCCCCCCOc1ccc([C@@H]2CC[C@]3(COC(=O)N3)C2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCCCCCCOc1ccc([C@@H]2CC[C@](N)(CO)C2)cc1
Yield: 58.4 %

Procedure:
A solution of (5R,7R)-7-(4-octyloxy-phenyl)-3-oxa-1-aza-spiro[4.4]nonan-2-one (61.0 mg, 0.177 mmol) in dioxane (3.0 mL) was treated with lithium hydroxide, hydrate (100 mg, 2.38 mmol) and water (1.0 mL). The mixture was heated to reflux for about 10 hours. The reaction was concentrated, treated with water (10 mL) and extracted twice with ether (10 mL). The ether extracts were dried over Na2SO4, filtered and concentrated. The residue was treated with 2 M HCl (2.0 mL) to yield a white solid which was collected and dried to yield 33.0 mg (52%) of [(1R,3R)-1-Amino-3-(4-octyloxy-phenyl)-cyclopentyl]-methanol; hydrochloride.
Reaction SMILES: C([Li])CCC.[N:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.[C:19](C1NC=CN=1)(=[O:21])[CH3:20]>O1CCCC1.C(NC(C)C)(C)C.CCCCCC>[C:19]([CH:14]1[CH2:13][CH:12]([C:9]2[CH:10]=[CH:11][N:6]=[CH:7][CH:8]=2)[CH2:17][CH2:16][C:15]1=[O:18])(=[O:21])[CH3:20]
Reactant: O=C1CCC(c2ccncc2)CC1
Reactant: CC(=O)c1ncc[nH]1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=O)C1CC(c2ccncc2)CCC1=O
Temperature: 25 °C
Yield: 66.5 %

Procedure:
In 40 ml of tetrahydrofuran was dissolved 3.2 ml of diisopropylamine and, 14.2 ml of 1.6 mol n-butyl lithium solution in hexane was added to the solution at -20° C. Next, a solution of 2 g of 4-(4-pyridyl)cyclohexanone obtained in Example 1 in 40 ml of tetrahydrofuran was added to the mixture at -40° C. The reaction solution was cooled to -78° C., to which a solution of 2.5 g of acetylimidazole in 40 ml of tetrahydrofuran was added. After stirring at room temperature, the reaction solution was poured onto ice. After washing with ether, the aqueous phase was saturated with ammonium chloride and extracted with methylene chloride to give 1.65 g of 2-acetyl-4-(4-pyridyl)cyclohexanone.