Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([O:5]C)=[O:4].C(=O)([O-])[O-].[K+].[K+].[Br:13][C:14]1([N+:37]([O-:39])=[O:38])[CH:19]=[C:18]([C:20]2[C:32]3[C:31]([CH3:33])=[C:30]([CH3:34])[S:29][C:28]=3[C:27]([Br:35])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)[CH:17]=[CH:16][CH:15]1[OH:36].O>CN(C=O)C>[Br:13][C:14]1([N+:37]([O-:39])=[O:38])[CH:19]=[C:18]([C:20]2[C:32]3[C:31]([CH3:33])=[C:30]([CH3:34])[S:29][C:28]=3[C:27]([Br:35])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)[CH:17]=[CH:16][CH:15]1[O:36][CH2:2][C:3]([OH:5])=[O:4]
Reactant: Cc1sc2c(Br)c3ccccc3c(C3=CC(Br)([N+](=O)[O-])C(O)C=C3)c2c1C
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1sc2c(Br)c3ccccc3c(C3=CC(Br)([N+](=O)[O-])C(OCC(=O)O)C=C3)c2c1C
Reaction time: 15 h
Yield: 68.1 %

Procedure:
Methyl bromoacetate (0.150 mL, 1.58 mmol) was added to a stirred suspension of potassium carbonate (0.223 g, 1.61 mmol), 2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenol (0.400 g, 0.789 mmol) in DMF (2.8 mL). After 15 h, the reaction mixture was added to water and extracted with ethyl acetate. Silica gel was added to the ethyl acetate and the solvent was removed. The adsorbate was flashed (9:1 petroleum ether: ethyl actetate) to provide the title compound as a yellow solid (0.305 g, 67%). This solid (0.050 g, 0.086 mmol) was dissolved in 1:1 THF:methanol (2 mL) and treated with aqueous potassium hydroxide (1.0 N, 0.30 mL, 0.30 mmol). After 25 min the reaction mixture was diluted with water, acidified with 10% aqeous HCl and extracted with ether. The ether phase was dried (sodium sulfate), concentrated and recrystallized from petroleum ether:ether to provide the title compound as a white solid (0.025 g, 51%): mp 228-229° C.: NMR (DMSO-d6); δ 8.23 (d, J=9 Hz, 1H), 8.14 (d, J=2 Hz, 1H), 8.04 (d, J=2 Hz, 1H), 7.69 (ddd, J=8, 7, 1, 1H), 7.54 (ddd, J=8, 7, 1 Hz, 1H), 7.48 (d, J=8 Hz, 1H), 4.87 (d, J=6 Hz, 1H), 4.82 (d, J=6 Hz, 1H), 2.46 (s, 3H), 1.62 (s, 3H); MS (+FAB): 2 bromine isotope pattern 563 (40%), 565 (100%), 567 (50%); Anal. Calc. for C22H15Br2NO5S: C, 46.75, H, 2.68, N, 2.48. Found: C, 45.18, H, 2.66, N, 2.38.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[C:5]([Cl:15])=[CH:4][N:3]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:26]=[C:25]([CH:27]2[CH2:31][CH2:30][CH2:29][NH:28]2)[O:24][N:23]=1.C(N(C(C)C)CC)(C)C>C(O)CCCCC>[Cl:15][C:5]1[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)=[N:7][C:2]([N:28]2[CH2:29][CH2:30][CH2:31][CH:27]2[C:25]2[O:24][N:23]=[C:22]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=3)[CH:26]=2)=[N:3][CH:4]=1
Reactant: c1ccc(-c2cc(C3CCCN3)on2)nc1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Solvent: CCCCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(N3CCCC3c3cc(-c4ccccn4)no3)ncc2Cl)n[nH]1
Yield: 109.5 %

Procedure:
A mixture of 2,5-dichloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Method 10 of WO 03/048133) (158 mg, 0.648 mmol), 2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidine (Method 12) (212 mg, 0.972 mmol) and di-isopropylethylamine (282 μL, 1.62 mmol) was stirred and heated at 140° C. in n-hexanol (7.0 ml) under nitrogen for 9 hours. The bulk of the hexanol was then removed by evaporation and the residue partitioned between ethyl acetate and water. The ethyl acetate layer was separated, washed with 1.0 molar phosphate buffer pH 4 (×2), then water and finally brine. The organic layer was dried (Na2SO4), filtered and evaporated and the crude product was absorbed onto a 10 g isolute SCX2 ion exchange column. The column was eluted with DCM/methanol (4:1) to remove neutrals and then with dichloromethane/2M methanolic ammonia (4:1) to elute the product. The purified product was dissolved in the minimum volume of DCM and to the stirred solution a slight excess of 1.0 M ethereal hydrogen chloride was added. Further diethyl ether was added and the solid product collected by filtration, washed with diethyl ether and dried to give the hydrochloride salt of the title compound (300 mg, 100%).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1.[F:22][C:23]([F:32])([F:31])[C:24]1[N:25]=[C:26]([CH2:29]O)[S:27][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCCOC)=O)=NC(OCCOC)=O>C1COCC1.O>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([O:18][CH2:29][C:26]5[S:27][CH:28]=[C:24]([C:23]([F:32])([F:31])[F:22])[N:25]=5)=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1
Reactant: OCc1nc(C(F)(F)F)cs1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4nc(C(F)(F)F)cs4)cc3=O)cn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.6 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (49 mg), (4-(trifluoromethyl)-1,3-thiazol-2-yl)methanol (68.3 mg) and triphenylphosphine (137 mg) in THF (5 ml) was added bis(2-methoxyethyl) azodicarboxylate (122 mg), and the mixture was stirred at room temperature for 3 h. The reaction mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from EtOH-hexane to give the title compound (21.5 mg) as a white solid.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:31][C:32](=[O:42])[CH:33]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)O>>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH:33]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:32]([OH:42])=[O:31])=[CH:27][CH:28]=2)=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1
Reactant: COC(=O)C(O)Cc1ccccc1
Product: O=C(O)C(Cc1ccccc1)Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzo[b]-thiophen-3-yl)-biphenyl-4-ol, and 3-phenyllactic acid methyl ester, in substantially the same manner, as described in Example 1, steps g-h, and was obtained as a white solid, mp 165-167° C.; MS m/e 540 (M+);
Reaction SMILES: [CH3:1][CH:2]1[C:10](=O)[C:9]2[CH:8]=[C:7]3[C:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][C:15]([CH3:17])([CH3:16])[C:6]3=[CH:5][C:4]=2[CH2:3]1.[BH4-].[Na+].C(O)C.Cl>C(OCC)C>[CH3:1][C:2]1[CH2:10][C:9]2[CH:8]=[C:7]3[C:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][C:15]([CH3:17])([CH3:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1
Reactant: CC1Cc2cc3c(cc2C1=O)C(C)(C)CCC3(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CC1=Cc2cc3c(cc2C1)C(C)(C)CCC3(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
(2,3,5,7-Tetrahydro-2,5,5,8,8-pentamethyl-1H-Benz(f)inden-1-one (14.89 g, 58.08 mmol) and NaBH4 (2.21 g, 58.5 mmol) were stirred in diethylether (200 mL) at 0° C. as ethanol (100 mL) was added slowly. This mixture was allowed to warm slowly to room temperature and then stirred at room temperature overnight. After the reaction period the mixture was poured onto crushed ice and made acidic with HCl. The organic layer was then separated and washed with 1M HCl (1×100 mL). The volatiles were then removed from the organic layer and the residue refluxed in benzene (300 mL) with ptoluenesulfonic acid (0.12 g) using a Dean-Stark apparatus until no more H2O was evolved. The mixture was then washed with 1 M NaHCO3 (2×100 mL) and the volatiles were removed from the organic layer resulting in the isolation of a yellow oil. Recrystallization from MeOH (0° C.) gave the desired product as off-white crystals (10.37 g, 74.3 percent yield).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7](Cl)(=[O:11])/[CH:8]=[CH:9]/[CH3:10].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:11])/[CH:8]=[CH:9]/[CH3:10]
Reactant: c1ccccc1
Reactant: C/C=C/C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C/C=C/C(=O)c1ccccc1

Procedure:
Benzene (1 mL), crotonoyl chloride (236 mg), and aluminium chloride (280 mg) were reacted in dichloromethane (1.5 mL) at from −30° C. to room temperature for 16 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (66 mg).
Reaction SMILES: [H][H].C([O:8][CH:9]([CH2:17][CH3:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=O)C(C)=C.C(OC(CC)CCCCCCC)(=O)C=C.C1C2C3C=CC(C2C=C1)C3>O>[CH2:13]1[CH:12]2[CH:11]3[CH2:10][CH:9]([OH:8])[CH:17]([CH:16]2[CH:15]=[CH:14]1)[CH2:18]3
Reactant: C=C(C)C(=O)OC(CC)CCCCCCC
Reactant: [H][H]
Agent: C=CC(=O)OC(CC)CCCCCCC
Solvent: C1=CC2C3C=CC(C3)C2C1
Solvent: O
Product: OC1CC2CC1C1C=CCC21

Procedure:
The compound of the formula: ##STR3## wherein Rl is hydrogen or a methyl group, that is, tricyclo-[5.2.1.02,6 ]deca-8-yl methacrylate or tricyclo[5.2.1.02,6 ]-deca-8-yl acrylate, can be prepared by a conventional process for synthesizing a methacrylic or acrylic acid ester. For example, the compound of the formula (I) can be prepared by adding H2O to dicyclopentadiene to give dicyclopentenyl alcohol, which is changed to tricyclo[5.2.1.02,6 ]deca-8-ol by catalytic hydrogenation reaction, followed by ester exchange reaction with methyl methacrylate or methyl acrylate, or condensation reaction with methacrylic acid, acrylic acid, methacrylic acid chloride or acrylic acid chloride.
Reaction SMILES: [Br:1]Br.[CH3:3][CH2:4][C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)=[O:6]>C(O)C>[Br:1][CH:4]([CH3:3])[C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)=[O:6]
Reactant: CCC(=O)c1cccc2ccccc12
Reactant: BrBr
Solvent: CCO
Product: CC(Br)C(=O)c1cccc2ccccc12

Procedure:
53.3 g (0.334 mol) of bromine was added dropwise to a solution consisting of 61.1 g (0.332 mol) of 1-propionaphthone and 180 mL of ethanol at 50 to 55° C. After completion of addition, the ethanol was distilled off in vacuo, and the resulting concentrate was dissolved in 130 mL of toluene, washed with a mixed aqueous solution of sodium bicarbonate and sodium chloride (150 mL×two times), and then dried over sodium sulfate to obtain a toluene solution of 2-bromo-1′-propionaphthone.
Reaction SMILES: Cl[C:2]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)([CH3:19])[CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=2[C:6]2[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:5]1=2.[N-:26]=[N+:27]=[N-:28].[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C.O>[N:26]([C:2]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)([CH3:19])[CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=2[C:6]2[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:5]1=2)=[N+:27]=[N-:28]
Reactant: Cc1ccc2c(c1)c1c(n2CC(C)(Cl)c2cccnc2)CCN(C)C1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(N=[N+]=[N-])c2cccnc2)CCN(C)C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
5-(2-Chloro-2-(pyridin-3-yl)propyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (crude) (700 mg) was dissolved in DMF (4 mL). Sodium azide (975 mg, 15 mmol) was added and reaction mixture was stirred at 80° C. for 1 h. The reaction mixture was diluted with water, basified with aqueous NaHCO3 solution and was extracted with EtOAc (200 mL). The organic layer was washed with water (6×50 mL), dried over anhydrous sodium sulfate and evaporated in vacuo to obtain the crude product that was purified by reverse phase HPLC to obtain 1 mg of 5-(2-azido-2-(pyridin-3-yl)propyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.56 (m, 2H), 8.11 (dd, 1H), 7.6 (t, 1H), 7.2 (s, 1H), 6.85 (m, 2H), 4.67 (d, 1H), 4.47 (d, 1H), 4.39 (s, 2H), 3.84 (m, 1H), 3.48 (m, 1H), 3.34 (m, 1H), 3.12 (s, 3H), 3.12 (m, 1H), 2.36 (s, 3H), 2.03 (s, 3H). Separation by chiral HPLC provides enantiomers V-3a-b.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[CH2:16]1[CH2:26][C:24](=O)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21]C=2)[CH2:17]1>CCCCCC.O1CCCC1>[OH:4][C:3]1[CH2:5][C:8]2([C:23]3[C:18](=[CH:17][CH:16]=[CH:26][CH:24]=3)[CH2:19][CH2:20][CH2:21]2)[O:7][C:1](=[O:6])[CH:2]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=C1CCCc2ccccc21
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=C(O)CC2(CCCc3ccccc32)O1

Procedure:
The title compound was prepared as described in General Method 1 using 25 mmol of methyl acetoacetate, 27.5 mmol of NaH 60% dispersion in oil, 26.25 mmol of 1.6M n-butyl lithium in hexane, 25 mmol of α-tetralone and 70 mL of tetrahydrofuran. The product was recrystallized from ethyl acetate/diethyl ether (m.p. 117°-119° C.). 1H NMR (CDCl3) δ 1.7-1.9 (m, 1 H), 1.9-2.1 (m, 2 H), 2.1-2.3 (m, 1 H), 2.7-3.0 (m, 2 H), 2.95 (d, 1 H), 3.1 (d, 1 H), 3.5 (s, 2 H), 7.1-7.2 (m, 1 H), 7.2-7.3 (m, 2 H), 7.4-7.5 (m, 1 H).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]([OH:7])=[O:6].[CH2:8]([O:24][CH2:25][CH:26]([OH:50])[CH2:27][O:28]C(C1C=CC(OC)=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].O>C1(C)C=CC=CC=1>[CH2:8]([O:24][CH2:25][CH:26]([CH2:27][OH:28])[O:50][CH2:4][C:5]([OH:7])=[O:6])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=C(O)CCl
Reactant: CCCCCCCCCCCCCCCCOCC(O)COC(c1ccccc1)(c1ccccc1)c1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCOCC(CO)OCC(=O)O
Yield: 53.5 %

Procedure:
To a suspension of 13.1 g of 50% sodium hydride in 200 ml of toluene was add a solution of 12.6 g of chloroacetic acid in 50 ml of toluene over a 45 minute period. A solution of 65.5 g of 1-(hexadecyloxy)-3-[(4-methoxyphenyl)diphenylmethoxy]-2-propanol in 100 ml of toluene was added over 30 minutes. The mixture was refluxed for 65 hours, poured into water and acidified to pH 4. The mixture was extracted with ether. The ether solution was dried and evaporated. The residue was purified by chromatography giving 22.3 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[S:6][C:7]=1[C:8]([OH:10])=O.[C:17]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]([N:28]2[CH2:33][CH2:32][C@@H:31]([NH:34][CH3:35])[C@H:30]([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=3)[CH2:29]2)=[O:27])[CH2:22][CH2:21]1)(=[O:19])[CH3:18]>>[C:17]([N:20]1[CH2:21][CH2:22][CH:23]([C:26]([N:28]2[CH2:33][CH2:32][C@@H:31]([N:34]([CH3:35])[C:8]([C:7]3[S:6][C:5]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:4][C:3]=3[O:2][CH3:1])=[O:10])[C@H:30]([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=3)[CH2:29]2)=[O:27])[CH2:24][CH2:25]1)(=[O:19])[CH3:18]
Reactant: CN[C@@H]1CCN(C(=O)C2CCN(C(C)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: COc1nc(-c2ccccc2)sc1C(=O)O
Product: COc1nc(-c2ccccc2)sc1C(=O)N(C)[C@@H]1CCN(C(=O)C2CCN(C(C)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
Using the compound obtained in step 1 and the compound obtained in Example 78, and by the reaction and purification in the same manner as in Example 3, the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1.O[CH:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:32][CH2:31]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:13]=[CH:14][C:15]([O:18][CH:30]4[CH2:31][CH2:32][N:33]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35]4)=[CH:16][CH:17]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1
Reactant: CCCCCCN1CCC(O)CC1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCCCCN1CCC(Oc2ccc(C(=O)c3c(-c4ccc(OC)cc4)sc4cc(OC)ccc34)cc2)CC1
Yield: 50.9 %

Procedure:
6-Methoxy-2-(4-methoxyphenyl)-3-(4-hydroxybenzoyl)benzo[b]thiophene (895 mg, 2.30 mmol), 4-hydroxy-1-hexylpiperidine (850 mg, 4.59 mmol), triphenylphosphine (1.20 g, 4.59 mmol), and DEAD (4.59 mmol) were converted to product by the procedure of Example 1 to give 653 mg of the title compound. Yield: 51%. MS(FD) 557(M+). EA calculated for C34H39NO4S: C, 73.21; H, 7.05; N, 2.51. Found: C, 73.46; H, 7.26; N, 2.57.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:3].Cl.[CH3:16][N:17]1[C:26]2[NH:25][C:24]3[CH:27]=[C:28]([CH3:31])[CH:29]=[CH:30][C:23]=3[N:22]([C:32]([CH:34]3[CH2:39][CH2:38][CH:37]([CH2:40][NH:41][C:42](=[O:50])[CH2:43][CH:44]4[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]4)[CH2:36][CH2:35]3)=[O:33])[CH2:21][C:20]=2[CH:19]=[N:18]1>ClCCl.C(N(CC)CC)C>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][O:4][C:2]([N:47]2[CH2:48][CH2:49][CH:44]([CH2:43][C:42](=[O:50])[NH:41][CH2:40][CH:37]3[CH2:36][CH2:35][CH:34]([C:32]([N:22]4[CH2:21][C:20]5[CH:19]=[N:18][N:17]([CH3:16])[C:26]=5[NH:25][C:24]5[CH:27]=[C:28]([CH3:31])[CH:29]=[CH:30][C:23]4=5)=[O:33])[CH2:39][CH2:38]3)[CH2:45][CH2:46]2)=[O:3])=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)C1CCC(CNC(=O)CC2CCNCC2)CC1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)C1CCC(CNC(=O)CC2CCN(C(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-nitrobenzyl chloroformate (1.08 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of N-[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-cyclohexylmethyl]-2-piperidin-4-yl-acetamide hydrochloride from Example E17 (2.58 mg, 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (0.0035 ml). The mixture was stirred at room temperature for 1 h then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=658.5
Reaction SMILES: [O:1]=[CH:2][C:3]([Cl:6])([Cl:5])[Cl:4].[N:7]1([CH2:12][C:13]([C:15]2([CH2:20][CH3:21])[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])[CH:11]=[N:10][CH:9]=[N:8]1.C(=O)([O-])[O-].[K+].[K+].O>O1CCCC1>[Cl:4][C:3]([Cl:6])([Cl:5])[CH:2]([OH:1])[CH:12]([N:7]1[CH:11]=[N:10][CH:9]=[N:8]1)[C:13]([C:15]1([CH2:20][CH3:21])[CH2:16][CH2:17][CH2:18][CH2:19]1)=[O:14]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: CCC1(C(=O)Cn2cncn2)CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCC1(C(=O)C(C(O)C(Cl)(Cl)Cl)n2cncn2)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
9.3 g (0.064 mol) of chloral were added dropwise to 10.4 g (0.05 mol) of 1-ethylcyclopentyl (1,2,4-triazol-1-yl)methyl ketone (prepared as described in Example 1) and 13.8 g (0.1 mol) of ground potassium carbonate in 100 ml of tetrahydrofuran. The reaction mixture was stirred overnight at room temperature and was then stirred with water. The solid formed was filtered off under suction and recrystallized from ethyl acetate. 7 g (39.5% of theory) of 1,1,1-trichloro-2-hydroxy-3-(1,2,4-triazol-1-yl)-4-(1-ethylcyclopentan-1-yl)-butan-4-one of melting point 194° to 196° C. were obtained.
Reaction SMILES: [NH:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[OH:12][CH:13]([C:15](=[CH2:19])[C:16]([O-:18])=[O:17])[CH3:14]>O>[C:16]([CH:15]([CH:13]([OH:12])[CH3:14])[CH2:19][N:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4])([OH:18])=[O:17]
Reactant: C=C(C(=O)[O-])C(C)O
Reactant: O=C(O)CNCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(O)C(CN(CC(=O)O)CC(=O)O)C(=O)O
Temperature: 80 °C
Reaction time: 20 h
Yield: 49 %

Procedure:
(0.1 mole) of iminodiacetic acid were suspended in 100 ml. of water and neutralized with sodium hydroxide to pH=10-12. 14.4 g (0.1 mole) ethyl----2--(1--hydroxyethyl)propenoate was added and the pH was maintained at 10-12 by further addition of sodium hydroxide. The reaction mixture was stirred at 80°C for 20 hours and then cooled at room temperature and acidified to pH=2. The solvent was distilled under reduced pressure to one-third of the weight of the solution and sodium chloride was filtered off. The filtrate was poured in 400 ml. of methanol/acetone (50/50) and the precipitate was washed with acetone and dried in vacuum to 12.3 g of a white powder. The yield was 49% of theoretical.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][C:10]2([O:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O-:16].[Na+]>CO>[CH2:1]([N:8]1[CH2:14][CH2:13][C:10]([OH:12])([CH2:11][O:16][CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: c1ccc(CN2CCC3(CO3)C2)cc1
Agent: [Na+]
Solvent: CO
Product: COCC1(O)CCN(Cc2ccccc2)C1

Procedure:
26.8 g (0.14 mol) of 5-benzyl-1-oxa-5-azaspiro[2,4]heptane are heated overnight under reflux with 2.6 ml (14 mmol) of 30% strength sodium methoxide solution in 200 ml of absolute methanol. The product is concentrated and distilled.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9]N.CO[CH:15](OC)[CH2:16][CH2:17][CH2:18][NH2:19].[OH-].[NH4+]>Cl>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[NH:9][CH:15]=[C:16]2[CH2:17][CH2:18][NH2:19]
Reactant: COC(CCCN)OC
Reactant: NNc1ccccc1C(F)(F)F
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: NCCc1c[nH]c2c(C(F)(F)F)cccc12
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
Combine in a 500 mL round bottom flask equipped with magnetic stirring, (2-trifluoromethyl-phenyl)-hydrazine (5.0 g, 28.4 mmol) and 4-aminobutyraldehyde dimethyl acetal (4.54 g, 34.1 mmol) and stir. After 5 minutes, slowly add 1N HCl (200 mL) and heat the reaction to 85° C. for 2 hours forming an orange-red colored solution. Increase the temperature to 100° C. for 10 minutes and cool to room temperature. Pour the reaction mixture over ice and stir for 10 minutes followed by adjustment to pH ˜10 with ammonium hydroxide. Extract the mixture with methylene chloride, pool the organic phases, dry over sodium sulfate, and concentrate in vacuo to give a dark orange-brown oil. Purification on a pre-packed, HMDS treated silica column using a step gradient of 9% to 17% methanol in methylene chloride gives the pure title compound as an orange oil: 1H NMR (400 MHz, dmso-d6): 11.18 (br s, 1H), 7.82 (d, 1H, J=7.6 Hz), 7.40 (d, 1H, J=7.2 Hz), 7.24 (d, 1H, J=2.0 Hz), 7.13 (t, 1H, J=7.6 Hz) 2.76–2.83 (m, 4H). MS (APCI): m/e 229.0 (M+1), 212.0 (M-NH2).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[N:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)(=O)=O)=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+].O>O1CCOCC1>[N:30]([CH2:12][CH2:13][C@@H:14]1[CH2:16][C@@H:15]1[CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[N:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=2)[CH2:19][CH2:18]1)=[N+:31]=[N-:32]
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: [N-]=[N+]=NCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Temperature: 100 °C

Procedure:
2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethyl 4-methylbenzenesulfonate (65 mg, 0.15 mmol) from step 1 of this example was dissolved in dioxane (1.2mL). Sodium azide (22.3 mg, 0.34 mmol) was added, then water (0.3 mL). The reaction was heated to 100° C. to reflux for 2 hours. The reaction was cooled to room temperature, water (10 mL) was added and extracted with EtOAc (10 mL×2). The combined organic phase was dried by magnesium sulfate, filter, concentrated and purified by column chromatography through a 12 gram RediSep Rf™ silica gel cartridge eluting with 5% ethyl acetate/hexanes to give the title compound as a white solid.