Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][C:7]=1[F:14].[H-].[Na+].Cl[C:22]1[CH:23]=[C:24]2[N:31]([CH3:32])[CH2:30][CH2:29][N:25]2[C:26](=[O:28])[N:27]=1>O1CCCC1.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][O:13][C:22]2[CH:23]=[C:24]3[N:31]([CH3:32])[CH2:30][CH2:29][N:25]3[C:26](=[O:28])[N:27]=2)=[CH:8][C:7]=1[F:14]
Reactant: OCc1ccc(Oc2ccc(Cl)c(Cl)c2)c(F)c1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1ccc(Oc3ccc(Cl)c(Cl)c3)c(F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using (4-(3,4-dichlorophenoxy)-3-fluorophenyl)methanol (0.101 g, 0.350 mmol) in tetrahydrofuran (THF) (8 mL), sodium hydride (0.021 g, 0.525 mmol) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (0.065 g, 0.350 mmol) in DMF (1 mL).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[S:9][C:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[C:6]2=[C:5]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:4]=1[CH2:23][C:24]([O:26][CH3:27])=[O:25].I[CH2:29][CH2:30][CH3:31]>>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[S:9][C:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[C:6]2=[C:5]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[C:4]=1[CH:23]([CH2:29][CH2:30][CH3:31])[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)Cc1c(OC)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Reactant: CCCI
Product: CCCC(C(=O)OC)c1c(OC)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3

Procedure:
The compound is prepared from the methyl [2-methoxy-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate and 1-iodopropane as described in the general method C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15].[O:34]1[CH:38]=[CH:37][C:36]2[CH:39]=[C:40]([C:43](Cl)=[O:44])[CH:41]=[CH:42][C:35]1=2>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:43]([C:40]1[CH:41]=[CH:42][C:35]3[O:34][CH:38]=[CH:37][C:36]=3[CH:39]=1)=[O:44])=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15]
Reactant: O=C(Cl)c1ccc2occc2c1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C(=O)c3ccc4occc4c3)c3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
4-Chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indole obtained in Example 1-(3) and benzo[b]furan-5-carbonyl chloride were treated in a manner similar to Example 2-(4) to give benzo[b]furan-5-yl 4-chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indol-3-yl ketone as a colorless powder. APCI-Mass m/Z 626/628 (M+H). 1H-NMR (DMSO-d6) δ 1.74 (s, 3H), 1.97 (s, 3H), 1.98 (s, 3H), 2.03 (s, 3H), 4.10-4.11 (m, 2H), 4.30 (dt, J=9.9, 4.2 Hz, 1H), 5.27 (t, J=9.9 Hz, 1H), 5.54 (t, J=9.6 Hz, 1H), 5.74 (t, J=9.3 Hz, 1H), 6.34 (d, J=9.0 Hz, 1H), 7.06 (d, J=1.3 Hz, 1H), 7.28 (d, J=7.5 Hz, 1H), 7.37 (t, J=8.0 Hz, 1H), 7.75 (d, J=8.7 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.85 (dd, J=8.6, 1.7 Hz, 1H), 8.12 (d, J=1.4 Hz, 1H), 8.13 (s, 2H).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: c1ccc(CC2CCN(CCOc3ccccc3)CC2)cc1

Procedure:
4-Benzylpiperidine was treated with 1-bromo-2-phenoxyethane and excess potassium carbonate as a solution in methylethylketone and heated at reflux for 12 hours. Standard workup and chromatography gave the title compound.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH2:10]([O:17][C:18]1[C:22]([OH:23])=[C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:20]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:19]=1[C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:10]([O:17][C:18]1[C:22]([O:23][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:20]([C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)[C:19]=1[C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1c(O)c(OCc2ccccc2)c(C(=O)OCC)n1-c1ccc(OC)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(OCC(=O)OC(C)(C)C)c(OCc2ccccc2)c(C(=O)OCC)n1-c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.3 %

Procedure:
tert-Butyl 2-bromoacetate (0.55 ml, 3.41 mmol) was added dropwise to a stirred solution of diethyl 3-(benzyloxy)-4-hydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2,5-dicarboxylate (23) (1.0 g, 2.28 mmol) and K2CO3 (0.63 g, 4.55 mmol) in DMF (20 mL). The reaction mixture was stirred at RT for 18 h, and partitioned between EtOAc (200 mL) and sat. NaHCO3 (aq.) (200 mL), the organic layer was separated and washed with sat. NaHCO3 (aq.) (2×200 mL), dried (MgSO4), filtered and solvents removed in vacuo to give a yellow oil. The residue was purified by silica gel chromatography (120 g, 0-20% EtOAc in isohexane) to afford diethyl 3-(benzyloxy)-4-(2-(tert-butoxy)-2-oxoethoxy)-1-(4-methoxyphenyl)-1H-pyrrole-2,5-dicarboxylate (UL2-028) (912 mg, 72%) as a pale yellow oil: m/z 554 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 7.49-7.44 (m, 2H), 7.43-7.31 (m, 3H), 7.15-7.08 (m, 2H), 6.94-6.88 (m, 2H), 5.12 (s, 2H), 4.59 (s, 2H), 4.02-3.94 (m, 4H), 3.79 (s, 3H), 1.40 (s, 9H), 1.02 (t, J=7.1 Hz, 3H), 0.97 (t, J=7.1 Hz, 3H).
Reaction SMILES: OC(C(F)(F)F)=O.[C:8]([NH:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=2)[C:17]([NH:28][CH2:29][C:30](=[O:36])[NH:31][CH:32]2[CH2:35][NH:34][CH2:33]2)=[N:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[C:37]([Si:41]([CH3:51])([CH3:50])[O:42][CH:43]1[CH2:48][CH2:47][C:46](=O)[CH2:45][CH2:44]1)([CH3:40])([CH3:39])[CH3:38]>>[C:8]([NH:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([F:26])([F:25])[F:27])=[CH:21][CH:22]=2)[C:17]([NH:28][CH2:29][C:30](=[O:36])[NH:31][CH:32]2[CH2:33][N:34]([CH:46]3[CH2:47][CH2:48][CH:43]([O:42][Si:41]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:50])[CH3:51])[CH2:44][CH2:45]3)[CH2:35]2)=[N:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(=O)CC1
Reactant: CC(C)(C)NC(=O)n1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)n1nc(NCC(=O)NC2CN(C3CCC(O[Si](C)(C)C(C)(C)C)CC3)C2)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of 3-[(azetidin-3-ylcarbamoylmethyl)-amino]-5-trifluoromethyl-indazole-1-carboxylic acid tert-butyl amide TFA salt (as prepared in Example 81, Step D) and 4-(tert-butyl-dimethyl-silanyloxy)-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [C:1](/[C:3](=[N:10]\[O:11][CH2:12][C:13]1[N:18]=[C:17]([NH:19]C(=O)OC(C)(C)C)[CH:16]=[CH:15][CH:14]=1)/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:19][C:17]1[N:18]=[C:13]([CH2:12][O:11]/[N:10]=[C:3](/[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)\[C:1]#[N:2])[CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CO/N=C(\C#N)c2ccccc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#C/C(=N\OCc1cccc(N)n1)c1ccccc1
Yield: 99.9 %

Procedure:
To a solution of tert-butyl {6-[({[(Z)-cyano(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}carbamate (5.4 g, 15.32 mmol, 1 eq.) in DCM (200 ml) was added TFA (17.47 g, 153 mmol, 10 eq.). The solution was refluxed for 12 h. The reaction was quenched by addition of aq. sat. NaHCO3 and extracted with EtOAc (3×50 ml). The organics were combined, dried over MgSO4 and concentrated to give (2Z)-{[(6-aminopyridin-2-yl)methoxy]imino}(phenyl)acetonitrile (3.86g, 89% yield).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH2:32]([O:39][NH:40][C:41](=[O:54])[CH2:42][C@H:43](O)[CH2:44][O:45][C:46]1[CH:51]=[CH:50][C:49]([Br:52])=[CH:48][CH:47]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1.CN(C=O)C>[CH2:32]([O:39][N:40]1[C@@H:43]([CH2:44][O:45][C:46]2[CH:51]=[CH:50][C:49]([Br:52])=[CH:48][CH:47]=2)[CH2:42][C:41]1=[O:54])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(C[C@H](O)COc1ccc(Br)cc1)NOCc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1C[C@H](COc2ccc(Br)cc2)N1OCc1ccccc1

Procedure:
A solution of triphenylphosphine (121 g) in THF (1.9 L) was treated with DEAD (80.1 g) over 30 minutes, treated with a solution of Example 3D in DMF (600 mL) at 40° C. by cannula over 90 minutes and a solution of triphenylphosphine (6.2 g) and DEAD (3.8 mL) in THF (20 mL), concentrated, treated with toluene (350 mL), and concentrated. The concentrate was treated with toluene (1.9 L), washed with water, and concentrated to half of its original volume, to provide a solution of (4R)-1-(benzyloxy)-4-((4-bromophenoxy)-methyl)-2-azetidinone. 1H NMR (300 MHz, CDCl3) δ7.4 (m, 7H), 6.70 (m, 2H), 5.00 (d, 1H, J=10), 4.92 (d, 1H, J=12 Hz), 3.86 (m, 1H), 3.82 (dd, 1H, J=1, 4 Hz), 2.81 (dd, 1H, J=6, 15 Hz), 2.66 (dd, 1H, J=2, 15 Hz).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:23]4[CH2:24][CH:20]([CH2:21][CH2:22]4)[C:19]=3[CH2:25][C:26]3[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=3)[C:29]([O:31]C)=[O:30])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.C1COCC1>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:23]4[CH2:24][CH:20]([CH2:21][CH2:22]4)[C:19]=3[CH2:25][C:26]3[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=3)[C:29]([OH:31])=[O:30])[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc(CC2=C(c3nc(-c4ccccc4)c(-c4ccccc4)o3)C3CCC2C3)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cccc(CC2=C(c3nc(-c4ccccc4)c(-c4ccccc4)o3)C3CCC2C3)c1
Reaction time: 0.08 h
Yield: 103.1 %

Procedure:
To a solution of methyl 3-{[3-(4,5-diphenyloxazol-2-yl)bicyclo[2.2.1]hept-2-en-2-yl]methyl}benzoate (1.0 g) in a mixture of methanol (10 ml) and THF (10 ml) was added 1N-NaOH solution (11 ml). After being stirred for 5 minutes, the solvent was removed in vacuo. The residue was dissolved in a mixture of ethyl acetate and 1N-HCl solution. The organic layer was washed with brine and dried over MgSO4. The solution was evaporated in vacuo to give 3-{[3-(4,5-diphenyloxazol-2-yl)bicyclo[2.2.1]hept-2-en-2-yl]methyl}-benzoic acid (1.0 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[O:13][CH3:14].C(N(CC)CC)C.[C:22]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])([CH3:24])[CH3:23]>C(Cl)Cl>[Si:26]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[O:13][CH3:14])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc(C=CC(C)=O)ccc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C=CC(C)=O)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.3 %

Procedure:
To a methylene chloride (100 mL) solution of 1-(4'-hydroxy-3'-methoxyphenyl)-1-butene-3-one (10.0 g, 52 mmol) is added triethyl amine (5.8 g, 57.2 mmol) and t-butylchlorodimethyl silane (15.7 g, 104 mmol). The reaction is stirred at room temperature for 12 hours under an argon atmosphere. The mixture is washed with water (3×100 mL) and brine (100 mL). The organic layer is dried over MgSO4 and evaporated. Flash chromatography (ethyl ether/hexane 1:1) affords 12.8 g (80%) of the desired 1-(4'-t-butyldimethylsilyloxy-3'-methoxyphenyl)-1-butene-3-one, mp=65°-68° C.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1([OH:16])[CH2:15][CH2:14]1)C1C=CC=CC=1.CCOC(C)=O.CO.N>>[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1([OH:16])[CH2:15][CH2:14]1
Reactant: OC1([C@@H]2CCCN2Cc2ccccc2)CC1
Agent: N
Solvent: CCOC(C)=O
Solvent: CO
Product: OC1([C@@H]2CCCN2)CC1

Procedure:
The product was obtained analogously to IP 5d starting from 745 mg (3.43 mmol) 1-((S)-1-benzylpyrrolidin-2-yl)cyclopropanol. Yield: 350 mg (80% of theoretical); C7H13NO (M=127.184); calc.: molpeak (M+H)+: 128; found: molpeak (M+H)+: 128; Rf value: 0.10 (silica gel, EtOAc/MeOH/NH3 5:5:0.5).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[C:11]([CH:17]=[C:18]2[C:22]([CH3:24])([CH3:23])[O:21][C:20]([CH3:26])([CH3:25])[C:19]2=[O:27])[CH:10]=1.[OH:28]O.[OH-].[Li+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[C:11]([CH:17]2[C:18]3([C:19](=[O:27])[C:20]([CH3:26])([CH3:25])[O:21][C:22]3([CH3:24])[CH3:23])[O:28]2)[CH:10]=1
Reactant: OO
Reactant: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C=C1C(=O)C(C)(C)OC1(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C1OC12C(=O)C(C)(C)OC2(C)C
Temperature: 25 °C

Procedure:
To a solution of 4-[1-(2′,4′-dichloro-4-ethylbiphenyl-3-yl)-methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (2.04 g, 0.0051 mol) in methanol (24 ml) at 55° C. is added hydrogen peroxide solution (0.43 ml, 0.0076 mmol, 50% wt solution), followed immediately by aqueous lithium hydroxide (0.25 ml, 0.0005 mol). The reaction mixture is heated at this temperature for 30 minutes, then is rapidly cooled to room temperature and quenched with saturated sodium thiosulphate. The crude product is extracted with diethyl ether (×3), washed with saturated sodium bicarbonate, then dried over magnesium sulfate. The residue is purified by flash column chromatography (5% ethyl acetate in isohexane to 25% ethyl acetate in isohexane) to afford 2-(2′,4′-dichloro-4-ethylbiphenyl-3-yl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one as a yellow gum.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:5]=[C:4]([CH3:20])[C:3]=1[NH:21][C:22](=[O:24])[CH3:23].C=O.[C:27]([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]([CH3:27])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:19])[F:17])=[CH:12][CH:11]=2)[CH:5]=[C:4]([CH3:20])[C:3]=1[NH:21][C:22](=[O:24])[CH3:23]
Reactant: CC(=O)Nc1c(C)cc(NCc2ccc(C(F)(F)F)cc2)cc1C
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)Nc1c(C)cc(N(C)Cc2ccc(C(F)(F)F)cc2)cc1C
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 60.5 %

Procedure:
To a stirred solution of N-[2,6-dimethyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-acetamide (4a, 1.0 g) and formaldehyde (1 mL) in methanol (20 mL) and acetic acid (1 mL) was slowly added sodium cyanoborohydride (0.30 g). After 15 minutes, the reaction mixture was cooled to 5° C. for 16 hours to precipitate the product, which was collected by filtration and washed with water (100 mL) to furnish 0.63 g (60% yield) of the title compound as a pale yellow solid. LC-MS-TOF (m/z) 351 (MH+); tR=2.58, (UV, ELSD) 99%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.97 (s, 3H), 2.02 (s, 6H), 2.97 (s, 3H), 4.63 (s, 2H), 7.41 (d, 2H), 7.68 (d, 2H), 8.88 (s, 1H).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5]C=C[CH:2]=1.[S:21]1C=CC(B(O)O)=C1>>[S:21]1[CH:5]=[CH:6][C:1]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)=[CH:2]1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: OB(O)c1ccsc1
Product: O=C1NCCc2c(-c3ccsc3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (300 mg, 1.13 mmol) and thiophene-3-boronic acid (159 mg, 1.24 mmol) were coupled to yield 2-thiophen-3-yl-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 249 mg (82%) as a beige solid: m.p. 255-256° C.; 1H NMR (300 MHz, d6-DMSO) δ 3.08 (m, 2H), 3.43 (m, 2H), 7.19 (t, J=7.8 Hz, 1H), 7.54 (m, 2H), 7.67 (dd, J=7.5, 0.9 Hz, 1H), 7.74 (m, 1H), 7.78 (m, 1H), 8.03 (br t, 1H), 11.49 (br s, 1H). MS (electrospray, MH+) 269. Anal. (C15H12N2OS.0.35 H2O) C, H, N, S.
Reaction SMILES: [H-].[K+].C1(S)C=CC=CC=1.[CH3:10][N:11]([CH2:13][C@H:14]1[C@:19]([OH:28])([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26]C)[CH:21]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH3:12]>C(O)COCCO>[CH3:12][N:11]([CH2:13][C@@H:14]1[C@@:19]([OH:28])([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH3:10]
Reactant: COc1cccc([C@]2(O)CCCC[C@H]2CN(C)C)c1
Agent: Sc1ccccc1
Agent: [H-]
Agent: [K+]
Solvent: OCCOCCO
Product: CN(C)C[C@H]1CCCC[C@]1(O)c1cccc(O)c1

Procedure:
First, O-desmethyl tramadol was prepared as set forth hereinafter. Diethylene glycol (125 mL) was added with cooling to potassium hydride (9.5 g) with the temperature being maintained at <50° C. To the solution was added thiophenol (10 mL) dissolved in diethylene glycol (25 mL), and then (−)-tramadol as the free base (9.3 g) in diethylene glycol (50 mL) was added. The final reaction mixture was heated slowly to reflux for 45 minutes. The mixture was cooled and then quenched into water. The pH was adjusted to about 3, and the mixture was extracted with ethyl ether. The pH was readjusted to about 8 and the resulting mixture was extracted 5 more times with methylene chloride. The extract was dried and the methylene chloride was evaporated to yield 4.6 g of the title compound as an oil. The oil was distilled (Kugelrohr), dissolved in tetrahydrofuran, treated with an ethanol/HCl solution to give 2.3 g of the salt. The salt was recrystallized from ethanol/ethyl ether and dried to yield 1.80 g of the salt of the (−) enantiomer of O-desmethyl tramadol (mp. 242°-3° C.), [α]D25=−32.9 (C=1, EtOH).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:18]3[CH2:19][C@H:20]4[CH2:33][C@H:21]4[C:22]=3[N:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])[N:24]=2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:18]3[CH2:19][C@H:20]4[CH2:33][C@H:21]4[C:22]=3[N:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])[N:24]=2)=[O:16])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2nn(-c3ccc(F)cc3F)c3c2C[C@H]2C[C@@H]32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CCNCC1)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
4-{[(1aR,5aR)-2-(2,4-Difluoro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.218 mmol) was dissolved in 20% TFA/DCM (3 mL). The reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated, and the residue was purified by cation exchange resin to give the title compound (66 mg). LCMS m/z=359.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.48 (td, J=4.2 and 3.6 Hz, 1H), 1.10-1.17 (m, 1H), 1.49-1.55 (m, 2H), 1.97-2.05 (m, 2H), 2.06-2.12 (m, 1H), 2.22-2.29 (m, 1H), 2.78 (t, J=11.1 Hz, 2H), 2.95 (d, J=16.5 Hz, 1H), 3.03 (dd, J=16.4 and 6.2 Hz, 1H), 3.11-3.19 (d, J=11.9 Hz, 2H), 3.97-4.05 (m, 1H), 6.85 (d, J=8.1 Hz, 1H), 6.98-6.74 (m, 2H), 7.61-7.67 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[N:7]=[C:8]([OH:10])[CH:9]=1)=[O:4].[CH3:12][C:13]1[O:17][N:16]=[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:14]=1[CH2:24]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[N:7]=[C:8]([O:10][CH2:24][C:14]2[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:16][O:17][C:13]=2[CH3:12])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(O)nn1C
Reactant: Cc1onc(-c2ccccn2)c1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)nn1C
Temperature: 25 °C
Yield: 29.4 %

Procedure:
To a stirred solution of 5-hydroxy-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (355 mg, 2.28 mmol) and (5-methyl-3-pyridin-2-yl-isoxazol-4-yl)-methanol (432 mg, 2.28 mmol) in THF (10 mL) at 5° C. under argon was added triphenylphosphine (775 mg, 2.95 mmol), then diethyl azodicarboxylate (515 mg, 2.95 mmol) was added dropwise. The reaction mixture was warmed to room temperature overnight. Then the reaction mixture was evaporated and purified by chromatography (silica, heptane:ethyl acetate=1:1 to 7.5:2.5) to afford the title compound (220 mg, 30%) as a white solid. MS: m/e=329.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([N:9]([CH3:11])[NH2:10])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:12]([N:19]=[C:20]=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:20]([NH:10][N:9]([C:2]([CH3:1])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C=NCc1ccccc1
Reactant: CCOC(=O)C(C)(C)N(C)N
Product: CCOC(=O)C(C)(C)N(C)NC(=O)NCc1ccccc1
Yield: 56.8 %

Procedure:
According to the procedure described in the synthesis method of Compound V-1, ethyl 2-methyl-2-(1-methylhydrazinyl)propanoate (10.27 g, 77.8 mmol) was reacted with benzyl isocyanate (15.53 g, 116.7 mmol) to obtain the title compound (12.97 g, 57%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:13])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:14]N1C(=O)CCC1=O>C(#N)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:13])=[CH:10][C:11]=2[Cl:14])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(Br)ccc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CC(=O)N1CCc2cc(Br)cc(Cl)c21
Temperature: 25 °C
Yield: 39.9 %

Procedure:
A mixture of 1-acetyl-5-bromo-indoline (1.20 g, 5 mmol) and N-chlorosucinimide (0.734 g, 5.5 mmol) in acetonitrile (80 mL) was heated to reflux for 12 hours, cooled to room temperature, and concentrated. The concentrate was purified by flash column chromatography on silica gel to provide 0.548 g of the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[O:12]CCO2)[S:5][C:6]=1[CH3:7].C([Li])CCC.[C:18](=[O:20])=[O:19].C(=O)([O-])O.[Na+]>O1CCCC1>[CH:8]([C:4]1[S:5][C:6]([CH3:7])=[C:2]([C:18]([OH:20])=[O:19])[CH:3]=1)=[O:12]
Reactant: Cc1sc(C2OCCO2)cc1Br
Reactant: O=C=O
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1sc(C=O)cc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
To a solution of 2-(4-bromo-5-methyl-2-thienyl)-1,3-dioxolane (5.0 g) in tetrahydrofuran (50 mL) was added dropwise n-butyl lithium (1.6M hexane solution, 12.5 mL) at −78° C. and, after the dropwise addition, the mixture was stirred for 1 hr. Carbon dioxide was blown into the reaction solution for 30 min. The reaction mixture was warmed to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The aqueous layer was acidified with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was dissolved in tetrahydrofuran (50 mL), 1N hydrochloric acid (50 mL) was added, and the mixture was stirred at 50° C. for 1 hr. The reaction mixture was concentrated and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to give 5-formyl-2-methylthiophene-3-carboxylic acid (1.2 g, yield 36%) as yellow crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). melting point 173° C.