Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O)(=O)=O.[N:6]1([C:12]2[C:13](=[O:19])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=1)=[O:29]>C(#N)C>[CH3:39][O:38][C:32]1[CH:31]=[C:30]([C:28](=[O:29])[CH2:27][N:9]2[CH2:8][CH2:7][N:6]([C:12]3[C:13](=[O:19])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:11][CH2:10]2)[CH:35]=[CH:34][C:33]=1[O:36][CH3:37]
Reactant: COc1ccc(C(=O)CBr)cc1OC
Reactant: O=c1cccccc1N1CCNCC1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C(=O)CN2CCN(c3cccccc3=O)CC2)cc1OC
Temperature: 85 °C
Reaction time: 1.25 h
Yield: 32.5 %

Procedure:
To a suspension of 2-(1-piperazinyl)-2,4,6-cycloheptatrien-1-one methane sulfonate (19.64 g, described in Example 2) in acetonitrile, (150 ml) was added potassium carbonate (20.8 g). The resulting suspension was refluxed for about 20 min. A solution of 2-bromo-1-(3,4-dimethoxyphenyl)-1-ethanone (17.8 g) in acetonitrile (100 ml) was added dropwise. The mixture was stirred at 85° C. for 1.25 hr. The mixture was filtered and the filtrate was evaporated. The filtered solid and oily residue was taken up in chloroform-water, and the chloroform layer was dried and evaporated to yield crude product (24.17 g). Chromatographic purification on silica gel (1000 gel) using ethyl acetate gave 2-[4-[2-(3,4-dimethoxyphenyl)-2-oxoethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one (8.2 g), mp 132°-135° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:27][C@@H:28]([C:30]1[CH:31]=[N:32][C:33](Cl)=[CH:34][CH:35]=1)[OH:29])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>[Pd].CO.O>[C:1]([O:5][C:6]([N:8]([CH2:27][C@H:28]([OH:29])[C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)[CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCCc1ccc(-c2ccc(C(=O)O)cc2)cc1)C[C@H](O)c1ccc(Cl)nc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N(CCCc1ccc(-c2ccc(C(=O)O)cc2)cc1)C[C@H](O)c1cccnc1
Yield: 96.5 %

Procedure:
4′-[3-[(tert-Butoxycarbonyl)[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]amino]propyl]-1,1′-biphenyl-4-carboxylic acid (100 mg), ammonium formate (50 mg) and palladium on carbon powder (30 mg) in methanol (5 ml) and water (1.0 ml) was refluxed for 30 minutes. The reaction mixture was filtrated and poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. A mixture of the residue was chromatographed (chloroform-methanol) over silica gel to give 4′-[3-[(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]-propyl]-1,1′-biphenyl-4-carboxylic acid (90 mg) as a colorless foam.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20][S:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[N:29]=[C:30]([NH:33][CH2:34][CH:35]5[CH2:37][CH2:36]5)[S:31][CH:32]=4)=[CH:24][CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[CH2:20][S:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[N:29]=[C:30]([NH:33][CH2:34][CH:35]3[CH2:37][CH2:36]3)[S:31][CH:32]=2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSc3ccc(-c4csc(NCC5CC5)n4)cc3)c2CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc2c(c1CSc1ccc(-c3csc(NCC4CC4)n3)cc1)CCNCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of 3-tert-butoxycarbonyl-7-chloro-6-{4-[2-(cyclopropylmethyl-amino)-thiazol-4-yl]-phenylthiomethyl}-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.305 g, 0.548 mmol) in dry DCM (12.6 mL) at room temperature add trifluoroacetic acid (12.6 mL) and stir the solution at room temperature overnight. Concentrate in vacuo and elute the residue through a SCX column (20 g). Dissolve the residue in DCM, load the solution on to a RediSep® column (40 g) and purify the crude mixture by preparative liquid chromatography (100:0 to 95:5 DCM/2M ammonia in methanol over 33 min; 95:5 to 90:10 DCM/2M ammonia in methanol over 33 min; 35 mL/min) to afford 7-chloro-6-{4-[2-(cyclopropylmethyl-amino)-thiazol-4-yl]-phenylthiomethyl}-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.215 g, 86%) as an off-white foam.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+].O>C(O)(C)C>[F:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1cc(I)ccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: OCc1cc(I)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.4 %

Procedure:
A solution of 2-fluoro-5-iodobenzaldehyde (1.173 g, 4.692 mmol) in isopropanol (25 mL) was treated with sodium borohydride (0.379 g, 10.02 mmol), stirred at room temperature for 18 h, poured into water (125 mL), and extracted with isopropyl ether (2×25 mL). The combined organic phase was dried (Na2SO4), and concentrated in vacuo to give the title compound (1.187 g, 99%) as a pale yellow solid; NMR δH (400 MHz, CDCl3) 7.77 (1H, m), 7.57 (1H, m), 6.82 (1H, t, J 8.8 Hz), 4.73 (2H, d, J 6.1 Hz), and 1.79 (1H, t, J 6.1 Hz).
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[C:12]([CH:17]=[CH:18][C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:11]([CH3:26])[CH2:10]1)(C(C)(C)C)(C)C.[OH:27]C1(C)CC(O)CC(C)(C)C1C=CC(O)C>>[OH:27][C:11]1([CH3:26])[CH2:10][CH:9]([OH:8])[CH2:14][C:13]([CH3:16])([CH3:15])[CH:12]1[CH:17]=[CH:18][CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CC(O)C=CC1C(C)(C)CC(O)CC1(C)O
Reactant: CCCCCC(=O)C=CC1=C(C)CC(O[Si](C)(C)C(C)(C)C)CC1(C)C
Product: CCCCCC(O)C=CC1C(C)(C)CC(O)CC1(C)O

Procedure:
The entitled compound was prepared from 1-[4-(t-butyldimethylsilyl)oxy-2,6,6-trimethylcyclohex-1enyl]oct-1-en-3-one in the same manner as described in Example 1-(4), (5), and (6).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1([NH2:16])[CH2:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>CC#N>[CH:12]1([NH:16][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: NC1CCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(F)cc1NC1CCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,4-difluoro-1-nitrobenzene (0.7 mL, 6.3 mmol) in CH3CN (10 mL) were added cyclobutylamine (0.54 mL, 6.3 mmol) and DIPEA (1.1 mL, 6.3 mmol). The reaction mixture was stirred at RT for 18 h then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% EtOAc in cyclohexane) to afford cyclobutyl-(5-fluoro-2-nitrophenyl)amine as a yellow oil (1.38 g, quantitative). To a solution of the product thus obtained (6.3 mmol) in EtOAc (60 mL) was added 10% Pd/C (150 mg) and the reaction mixture stirred at RT for 18 h under a hydrogen atmosphere. The suspension was filtered through a pad of Celite® and the filtrate concentrated in vacuo to afford the title compound as an orange oil (1.1 g, quantitative). 1H NMR (CDCl3, 300 MHz): δ 6.63-6.56 (1H, m), 6.35-6.19 (2H, m), 3.92-3.78 (1H, m), 3.66-2.91 (2H, m), 2.53-2.36 (2H, m), 1.94-1.73 (4H, m).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH:14]([CH2:18][CH2:19][OH:20])[CH2:13]1.[H-].[Na+].I[CH3:24].O>C1COCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH:14]([CH2:18][CH2:19][O:20][CH3:24])[CH2:13]1
Reactant: CI
Reactant: OCCC1CCCN(CC2COc3ccccc3O2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCC1CCCN(CC2COc3ccccc3O2)C1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A solution of 2-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]ethanol (0.1 g, 0.36 mmol) in THF (5 ml) was added NaH (79.0 mg, 1.79 mmol), which was previously washed with heptane. The reaction mixture was stirred at 70° C. for 1 h followed by a dropwise addition of a solution of iodomethane (0.034 ml, 0.54 mmol) in THF (1 ml). Stirring was continued for 1 h. Water was slowly added and the reaction mixture was extracted with DCM (3×20 ml). The combined organic phases were dried (Na2SO4), filtered and the filtrate was evaporated to give the title compound, which was purified by column chromatography (DCM/MeOH, 90:10).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=O.[C:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])#[N:15]>>[C:14](/[C:16](=[C:6]1/[C:7](=[O:12])[NH:8][C:9]2[C:5]/1=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)/[C:17]([O:19][CH3:20])=[O:18])#[N:15]
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2
Reactant: COC(=O)CC#N
Product: COC(=O)/C(C#N)=C1\C(=O)Nc2ccc(OC)cc21
Yield: 88 %

Procedure:
Following the general method as outlined for Intermediate 1, starting from 5-methoxy-1H-indole-2,3-dione and methyl cyanoacetate, the title compound was isolated, after evaporation, as a dark purple solid in 88% yield. This was a 4.5:1 mixture of geometric isomers (99% purity by HPLC).
Reaction SMILES: [OH:1][C:2]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:7][CH2:6][N:5]([C:8]2[CH:20]=[CH:19][C:11]([C:12]([O:14]C(C)(C)C)=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1>C(O)(C(F)(F)F)=O>[OH:1][C:2]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:3][CH2:4][N:5]([C:8]2[CH:20]=[CH:19][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)c1ccc(N2CCC(O)(c3ccccc3)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(N2CCC(O)(c3ccccc3)CC2)cc1

Procedure:
A solution of Example 493A (0.32 g, 0.91 mmol) in TFA (2 mL) at room temperature was stirred for 1 hour, and concentrated. The concentrate was azeotropically distilled with toluene three times and dried to provide the desired product. MS (ESI(+)) m/e 298 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:22][CH:23]1[CH2:25][CH2:24]1>CN(C=O)C>[CH:25]1([CH2:24][O:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:22][CH:23]3[CH2:25][CH2:24]3)=[O:7])=[CH:4][C:3]=2[C:11]([F:12])([F:13])[F:14])[CH2:23][CH2:22]1
Reactant: BrCC1CC1
Reactant: O=C(O)c1ccc(O)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(OCC1CC1)c1ccc(OCC2CC2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 87.3 %

Procedure:
To a solution of 4-hydroxy-3-(trifluoromethyl)benzoic acid (0.483 g, 2.343 mmol) in DMF (10 mL) was added Cs2CO3 (2.29 g, 7.03 mmol), followed by (bromomethyl)cyclopropane (0.568 mL, 5.86 mmol). The reaction was stirred at 80° C. for 16 h. The mixture was filtered. The filtrate was concentrated under vacuum and taken up in EtOAc. The organic solution was washed with water (thrice), dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography to give the title compound as an oil (0.643 g). LCMS m/z=315.3 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 0.33-0.44 (m, 4H), 0.59-0.69 (m, 4H), 1.21-1.34 (m, 2H), 4.01 (d, J=6.57 Hz, 2H), 4.15 (d, J=7.20 Hz, 2H), 6.99 (d, J=8.84 Hz, 1H), 8.18 (dd, J=8.72, 2.15 Hz, 1H), 8.28 (d, J=2.02 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=[C:11](N3CCCCC3)[C:10]3[CH:25]=[CH:26][CH:27]=[CH:28][C:9]2=3)[CH2:4][CH2:3]1.Cl.C[OH:31]>O>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][C:11](=[O:31])[C:10]3[CH:25]=[CH:26][CH:27]=[CH:28][C:9]2=3)[CH2:4][CH2:3]1
Reactant: CN1CCC(=C2c3ccccc3C=C(N3CCCCC3)c3ccccc32)CC1
Reactant: CO
Agent: Cl
Solvent: O
Product: CN1CCC(=C2c3ccccc3CC(=O)c3ccccc32)CC1

Procedure:
1-Methyl-4-(10-[1-piperidyl]-5H-dibenzo[a,d]cyclohepten-5-ylidene)-piperidine, 2.4 g., is refluxed for 4 hours with 100 ml. of 10% HCl in water and 50 ml. of methanol. The methanol is evaporated and the remaining oil and water is made basic with solid NaHCO3 until no more CO2 is evolved. It is then extracted three times with 50 ml. each of toluene, combined extracts dried over MgSO4, filtered and the toluene evaporated on a rotary evaporator leaving a residual product which crystallizes on standing. Three recrystallizations of this product from hexane give 1-methyl-4-(10,11-dihydro-10-oxo-dibenzo[a,d]cyclohepten-5-ylidene)-piperidine, m.p. 142°-143°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([CH2:7][NH:8][C:9]2[N:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH:19](O)[CH:20]=[CH:21][C:22]3[CH:31]=[N:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(O)(=O)CC.Cl.[Cl-].[Na+].O.[C:44]([CH3:54])(OCC)([O:48]CC)[O:45][CH2:46][CH3:47]>>[CH2:46]([O:45][C:44](=[O:48])[CH2:54][CH:21]([C:22]1[CH:31]=[N:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1)[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16][CH2:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:8][CH2:7][C:6]2[CH:33]=[CH:34][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:14]=1)[CH3:47]
Reactant: COc1ccc(CNc2cccc(CCCCC(O)C=Cc3cnc4ccccc4n3)n2)cc1
Reactant: CCOC(C)(OCC)OCC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCC(=O)O
Product: CCOC(=O)CC(C=CCCCCc1cccc(NCc2ccc(OC)cc2)n1)c1cnc2ccccc2n1
Temperature: 150 °C
Yield: 48 %

Procedure:
A solution of the allylic alcohol 22-3 (0.26 g, 0.57 mmol) in (EtO)3CMe (10 mL) was treated with 100 μL of a 1 mL solution of (EtO)3CMe containing 10 μL of propionic acid. The yellow solution was heated at 150° C. for 90 minutes. The solution was cooled to room temperature and poured into 1N HCl/brine. The mixture was extracted with CHCl3, dried, concentrated, and purified on silica gel (90:5:5 CHCl3:EtOAc:MeOH) to give 0.143 g (48%)of 22-4.
Reaction SMILES: Cl.O1CCOCC1.C(OC([NH:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[C@H:22]1[CH2:27][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C@@H:25]([N:36]=[N+:37]=[N-:38])[C@@H:24]([CH3:39])[CH2:23]1)=O)(C)(C)C.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>C(Cl)Cl>[NH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[C@H:22]1[CH2:27][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C@@H:25]([N:36]=[N+:37]=[N-:38])[C@@H:24]([CH3:39])[CH2:23]1
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N=[N+]=[N-]
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@H]1C[C@@H](c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
A solution of 4 M HCl in dioxane (30.0 equiv.) was added to tert-butyl ((1R,2S,3S,5R)-5-(3-((tert-butoxycarbonyl)amino)pyridin-4-yl)-2-azido-3-methylcyclohexyl)carbamate (1.0 equiv.). The solution started to go homogeneous for a few minutes, but then a ppt formed and the solution went very thick. After sitting at rt for 1 hour, the volatiles were removed in vacuo and the solid was pumped on for 5 minutes on the high vac. To the residue was added CH2Cl2 (0.15 M), TEA (5.0 equiv.) and Boc2O (1.0 equiv.). The solution was left stirring at rt for 1 hr. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and H2O. The organic layer was washed with Na2CO3(sat), NaCl(sat), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography to yield tert-butyl (1R,2S,3S,5R)-5-(3-aminopyridin-4-yl)-2-azido-3-methylcyclohexylcarbamate in 57% yield. LC/MS (m/z)=347.3 (MH+), Rt=0.70 min. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J=6.65 Hz, 3 H), 1.43-1.58 (m, 11 H), 1.79 (d, J=12.52 Hz, 1 H), 1.95 (d, J=6.26 Hz, 1 H), 2.60 (br. s., 1 H), 3.61 (br. s., 2 H), 3.77-3.91 (m, 2 H), 4.78 (d, J=7.43 Hz, 1 H), 6.96 (d, J=4.70 Hz, 1 H), 7.97-8.07 (m, 2 H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.O=[C:12]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:19](=[O:21])[CH3:20])[CH2:13]1>CC(O)=O>[F:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:12]1[CH2:13][CH:14]([NH:18][C:19](=[O:21])[CH3:20])[CH2:15][CH2:16][C:17]2=1
Reactant: CC(=O)NC1CCCC(=O)C1
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)NC1CCc2c([nH]c3ccc(F)cc23)C1
Reaction time: 4.5 h

Procedure:
A mixture of 0.05 mol of 4-fluorophenylhydrazine hydrochloride and 0.05 mol of N-(3-oxocyclohexyl)acetamide in 75 ml of glacial HOAc was stirred and heated on the steam bath. At 80°-90° an exothermic reaction occurred and the source of heat was removed until the temperature had fallen to 85°. After an additional 4-5 hr at 85°-90°, the warm mixture was poured into H2O and the gummy insolubles triturated until solid. The filtered solid was washed thoroughly with H2O and then with Et2O until the washings were essentially colorless. The crude product was recrystallized from ethanol to give the title compound, mp 209°-210°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[N:10][C:11]([O:13][Si](C)(C)C)=[CH2:12].C(OC([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([Cl:34])[CH:32]=2)/[C:27](=[CH:35]/[C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)/[C:26]1=[O:43])=O)(C)(C)C.CO>C1(C)C=CC=CC=1>[Cl:34][C:31]1[CH:32]=[C:33]2[NH:25][C:26](=[O:43])[C:27]3([CH:35]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=4)[CH2:13][C:11](=[O:12])[NH:10][CH:9]3[C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[C:28]2=[CH:29][CH:30]=1
Reactant: C=C(N=Cc1ccc(F)cc1F)O[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2ccc(F)cc2F)N1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
To a solution of 1-(2,4-difluorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 41a (2.4 g, 9.40 mmol) in toluene (30 mL) was added E/Z-6-chloro-3-(3-chlorobenzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 24a (0.3 g, 0.77 mmol). The reaction mixture was stirred under nitrogen in a sealed tube at 140° C. for 0.5 h. After the solution was cooled to room temperature, methanol (10 mL) was added. The reaction mixture was filtered through a short pad of celite gel and washed with ethyl acetate. The filtrate was concentrated. The residue was dissolved in dichloromethane (20 mL) and trifluoroactic acid (15 mL) was added. After the reaction mixture was stirred at room temperature for 1 h, the mixture was concentrated. The residue was partitioned between saturated NaHCO3 solution and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by chromatography (EtOAc:hexanes=2:1) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,4-difluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (Yield 0.23 g, 63.9%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[CH2:4][C:5]1[C:13]2[NH:12][C:11](=[O:14])[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC(C)([O-])C.[K+]>CN(C=O)C>[CH2:17]([N:10]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH2:4][CH:3]([O:2][CH3:1])[O:15][CH3:16])[C:13]=2[NH:12][C:11]1=[O:14])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(Cc1cccc2[nH]c(=O)[nH]c12)OC
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(Cc1cccc2c1[nH]c(=O)n2Cc1ccccc1)OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 16.3 %

Procedure:
4-(2,2-Dimethoxy-ethyl)-1,3-dihydro-benzoimidazol-2-one (435 mg, 1.96 mmol) was dissolved along with benzyl bromide (335 mg, 1.96 mmol) in 10 mL of anhydrous DMF. Potassium tert-butoxide (1.0 M in THF, 2.2 mL, 2.2 mmol) was added. The reaction mixture was stirred at room temperature for 90 minutes and then partitioned between ether and water. The organic phase was washed with brine and dried over Na2SO4. After filtration and removal of solvent under reduced pressure, the crude material was chromatographed to afford 1-benzyl-4-(2,2-dimethoxy-ethyl)-1,3-dihydro-benzoimidazol-2-one (100 mg, 16%). 1H NMR (CDCl3) δ 3.00 (2H, d, J=5.0 Hz), 3.40 (6H, s), 4.55 (1H, t, J=5.0 Hz), 6.75 (d, 1H, J=7.5 Hz), 6.84-6.95 (m, 2H), 7.23-7.35 (m, 5H), 8.95 (br s, 1H). 13C(CDCl3) δ 36.9, 44.9, 54.4, 105.6, 107.5, 118.8, 121.7, 124.0, 127.9, 128.0, 129.1, 129.2, 130.8, 136.7.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([OH:5])[CH2:2]1.N1C=CC=CC=1.Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:14]>C1COCC1>[O:1]1[CH2:4][CH:3]([O:5][C:13](=[O:14])[O:15][C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)[CH2:2]1
Reactant: OC1COC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1COC1
Temperature: 25 °C

Procedure:
A solution of Oxetan-3-ol (0.100 g, 1.35 mmol) and pyridine (0.13 mL, 1.62 mmol) in THF (2.5 mL) was cooled to 0° C. with an external ice bath, stirring. A solution of 4-Nitrophenyl chloroformate (0.299 g, 1.485 mmol) in THF (2 mL) was added at 0° C. and the solution was allowed to warm to room temperature. The crude reaction was purified by normal phase silica gel (0-100% ethyl acetate:hexanes) chromatography to give Carbonic acid 4-nitro-phenyl ester oxetan-3-yl ester. LCMS-ESI+: calc'd for C10H9NO6: 239.04 (M+); Found: 239.97 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH2:4][CH2:5][CH2:6]Cl.C[O-].[Na+].[CH2:12]([SH:15])[CH:13]=[CH2:14]>O>[CH3:1][O:2][C:3](=[O:8])[CH2:4][CH2:5][CH2:6][S:15][CH2:12][CH:13]=[CH2:14]
Reactant: COC(=O)CCCCl
Reactant: C=CCS
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: C=CCSCCCC(=O)OC

Procedure:
Into a 1 liter flask equipped with cooling bath, thermometer, reflux condenser and additional funnel as well as electric stirrer is placed 68.2 grams of methyl-4-chlorobutyrate. The methyl-4-chlorobutyrate is cooled to 20° C. The mixture of sodium methoxide and allyl mercaptan is added to the addition funnel. Over a period of 0.5 hours while maintaining the pot temperature at 20°-30° C., the mixture of allyl mercaptan and sodium methoxide is added slowly to the methyl-4-chlorobutyrate with stirring. The reaction is exothermic and requires slight cooling. At the end of the addition of the mixture of allyl mercaptan and sodium methoxide, the reaction mass is stirred for 1 hour and the temperature of the reaction mass is permitted to rise to 38° C. 500 ml water are then added to the reaction mass and the reaction mass is transferred to a separatory funnel. The reaction mass is then extracted with three 50 ml portions of methylene dichloride and dried over anhydrous sodium sulfate and filtered. The reaction mass is then distilled on a micro Vigreux column yielding the following fractions:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][CH3:10])[CH:4]=1)#[N:2].Cl.CCOCC>CO.[Pd]>[CH3:10][O:9][C:5]1[CH:4]=[C:3]([CH2:1][NH2:2])[CH:8]=[CH:7][N:6]=1
Reactant: COc1cc(C#N)ccn1
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COc1cc(CN)ccn1
Reaction time: 8 h

Procedure:
4-Cyano-2-methoxypyridine (1.7 g) was dissolved in MeOH (50 ml) and conc. HCl (4.96 ml) was added. Pd/C (10%) was added and H2 was added and let stand overnight. The solids were filtered through Celite® and the cake was washed with MeOH (˜250 ml). Concentration in vacuo produced an oil which was dissolved in MeOH (˜20 ml). Et2O (200 ml) was added and stirred for 1 h. The resulting precipitate was filtered and washed with Et2O to afford (2-methoxypyridin-4-yl)methylamine (HCl salt) as an off-white solid.