Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5]([O:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)([CH3:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][NH:19][C:18](=[O:21])[N:17]2[CH3:22])=[CH:9][CH:8]=1)C.[H-].[Na+].[CH3:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][C:43]=1[CH3:44])[CH2:39]Cl>CN(C=O)C.CCOCC.Cl>[CH3:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][C:43]=1[CH3:44])[CH2:39][N:19]1[CH2:20][CH:16]([CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C:5]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)([CH3:23])[C:4]([OH:3])=[O:32])=[CH:12][CH:11]=2)[N:17]([CH3:22])[C:18]1=[O:21]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccc(F)cc1
Reactant: Cc1ccc(CCl)cc1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1ccc(CN2CC(CCOc3ccc(CC(C)(Oc4ccc(F)cc4)C(=O)O)cc3)N(C)C2=O)cc1C
Reaction time: 0.33 h
Yield: 56 %

Procedure:
To a mixture of 80 mg of 2-(4-Fluoro-phenoxy)-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester in 5 mL of dry DMF at 0° C. under an atmosphere of nitrogen, 18 mg of NaH (0.45 mmol) is added. The resulting solution is allowed to stand at r.t. for 20 min. Then 0.07 mL of 3,4-dimethylbenzyl chloride is added and resulting mixture is allowed to stand at r.t. for overnight. Reaction mixture is diluted with Et2O and 1N HCl. Organic layer is then washed with 1N HCl (2×10 mL), brine (2×10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The crude material is in 5 mL of EtOH and 0.4 mL of 5N NaOH. The mixture is heated to reflux for 1 h. The organic solvent is then removed under vacuum and residue is dissolved in CH2Cl2 and 1N HCl. Aqueous layer is washed with CH2Cl2 (2×10 mL). Combined organic layer is dried over Na2SO4, filtered and concentrated under vacuum. The crude material is purified by MS/LC to give 54 mg (56%) of the title product. 1H NMR (400 MHz, CDCl3): δ 7.18 (d, 2H, J=8.4 Hz), 7.06 (d, 1H, J=7.6 Hz), 7.00 (s, 1H), 6.97-6.85 (m, 5H), 6.75 (d, 2H, J=8.4 Hz), 4.34, 4.25 (ABq, 2H, J=15.0 Hz), 4.31 (bs, 1H), 3.98-3.90 (m, 2H), 3.69-3.61 (m, 1H), 3.39 (t, 1H, J=8.7 Hz), 3.25, 3.11 (ABq, 2H, J=14.0 Hz), 3.00 (t, 1H, J=8.7 Hz), 2.84 (s, 3H), 2.29-2.17 (m, 1H), 2.22 (s, 6H), 1.94-1.87 (m, 1H), 1.37 (s, 3H). HRMS (ES+) m/z exact mass calcd for C31H36N2O5F (m+1) 535.2608, found 535.2614.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[C:10]([CH3:29])([CH3:28])[CH2:9]1)=O)(C)(C)C.[F:30][C:31]1[CH:32]=[C:33]([CH2:38][CH2:39][NH2:40])[CH:34]=[C:35]([F:37])[CH:36]=1>>[F:30][C:31]1[CH:32]=[C:33]([CH2:38][CH2:39][NH:40][C:23]2[N:22]=[C:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][N:11]4[CH2:12][CH2:13][NH:8][CH2:9][C:10]4([CH3:29])[CH3:28])[CH:16]=3)[CH:26]=[CH:25][N:24]=2)[CH:34]=[C:35]([F:37])[CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3ccnc(Cl)n3)c2)C(C)(C)C1
Reactant: NCCc1cc(F)cc(F)c1
Product: CC1(C)CNCCN1Cc1cccc(-c2ccnc(NCCc3cc(F)cc(F)c3)n2)c1

Procedure:
Intermediate 141 was coupled with 2-(3,5-difluoro-phenyl)-ethylamine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H3O+of 456. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.76 (s, 1H) 8.36 (d, 1H) 8.33 (d, 1H) 7.97 (d, 1H) 7.70 (t, 2H) 7.03 (d, 2H) 6.76 (m, 1H) 4.54 (s, 2H) 3.98 (t, 2H) 3.72 (s, 2H) 3.35 (m, 4H) 3.10 (t, 2H) 1.74 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[C:35](Cl)[N:34]=[N:33][C:32]=2[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:27][C:26]=1[O:42][CH3:43])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:35]2[N:34]=[N:33][C:32]([CH2:38][CH2:39][CH2:40][CH3:41])=[C:31]([C:28]3[CH:29]=[CH:30][C:25]([O:24][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[C:26]([O:42][CH3:43])[CH:27]=3)[CH:36]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OCc2ccccc2)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OCc2ccccc2)c(OC)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (3.0 mmol, 604 mg) in THF (10 mL) at 0° C., NaH (60% dispersion in mineral oil, 4.0 mmol, 160 mg) was added and stirring continued for 10 min at room temperature, then 4-(4-benzyloxy-3-methoxy-phenyl)-3-butyl-6-chloro-pyridazine (2.0 mmol, 766 mg) was added. The resulting mixture was stirred at 50° C. for 1 hour, poured into ice-water and extracted with ethyl acetate. The organic layers were combined and concentrated under reduced pressure. The product was purified by column chromatography using 50% ethyl acetate in hexanes to give 4-[5-(4-benzyloxy-3-methoxy-phenyl)-6-butyl-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester, which was dissolved in dichloromethane (2.0 mL), added 4.0 M HCl in dioxane (2.0 mL) and stirred at room temperature for 1 hour. Solvents were evaporated in vacuo to give 4-(4-benzyloxy-3-methoxy-phenyl)-3-butyl-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (635 mg).
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]([CH2:6][O:7][CH2:8][C@@H:9]2[CH2:11][C@@H:10]2[CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:27].C([Li])CCC.CCCCCC.[CH3:39][S:40]SC>C(OCC)C>[F:27][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:2]=1[S:40][CH3:39])[CH2:6][O:7][CH2:8][C@@H:9]1[CH2:11][C@@H:10]1[CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2COCc2ccc(Br)c(F)c2)CC1
Reactant: CSSC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CSc1ccc(COC[C@@H]2C[C@@H]2C2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 100.1 %

Procedure:
tert-butyl 4-((1R,2R)-2-(((4-bromo-3-fluorobenzyl)oxy)methyl)cyclopropyl)piperidine-1-carboxylate (Step A product, 7.7 g, 17.4 mmol) was dissolved in Diethyl ether (70 ml) and cooled to −78° C. The mixture was stirred for 5 min, then n-Butyllithium in hexane (2.5 M, 7.66 ml, 19.15 mmol) was added dropwise. The mixture was stirred at −78° C. for 10 min and dimethyl disulfide (1.85 ml, 20.9 mmol) was added dropwise. The mixture was stirred at −78° C. for 30 min and TLC showed the SM was almost consumed. The mixture was quenched with sat. NH4Cl at −78° C., extracted with EtOAc (2×). The EtOAc phase was washed with brine, dried over MgSO4, and concentrated to afford 7.13 g (100%) of the designed product. This crude product was used for the next step without further purification.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f13) and commercially methoxyacetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=[C:15]([NH:17][CH3:18])[N:14]=[CH:13][N:12]=2)=[CH:6][CH:5]=1)[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[N:29]=[C:30]=[O:31]>>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[NH:29][C:30](=[O:31])[N:17]([C:15]1[CH:16]=[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([N:3]([CH2:1][CH3:2])[CH2:19][CH3:20])=[CH:5][CH:6]=2)[N:12]=[CH:13][N:14]=1)[CH3:18]
Reactant: CCN(CC)c1ccc(Nc2cc(NC)ncn2)cc1
Reactant: O=C=Nc1c(Cl)cccc1Cl
Product: CCN(CC)c1ccc(Nc2cc(N(C)C(=O)Nc3c(Cl)cccc3Cl)ncn2)cc1

Procedure:
The title compound is prepared analogously as described in Example 105B from N-(4-diethylamino-phenyl)-N′-methyl-pyrimidine-4,6-diamine and 2,6-dichlorophenyl isocyanate.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH2:15][C:14]([CH:17]=O)=[CH:13][C:12]=2[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22]>N1C=CC=CC=1.C(O)C>[O:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH2:15][C:14]([CH:17]=[N:21][OH:22])=[CH:13][C:12]=2[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC1=Cc2cc(Oc3ccccc3)ccc2OC1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: ON=CC1=Cc2cc(Oc3ccccc3)ccc2OC1
Reaction time: 1 h

Procedure:
6-Phenoxy-2H-1-benzopyran-3-carboxaldehyde (5.00 g, 19.9 mmol) is dissolved in 175 ml of pyridine/ethanol (1:1) and treated with hydroxylamine hydrochloride (2.07 g, 29.7 mmol). The mixture is stirred for 1 hour and partitioned between ether and water. The aqueous layer is extracted with ether, and the ether layer is washed with 2N HCl, dried (MgSO4) and evaporated to give 6-phenoxy-2H-1-benzopyran-3-carboxaldehyde oxime as a pale yellow solid.
Reaction SMILES: [N:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9]CN2CCCC2)=[CH:6][CH:5]=1)=[C:2]=[S:3].[CH3:18]OC1C=CC(N)=C(C)C=1>>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[CH:16][C:17]=1[CH3:18])=[C:2]=[S:3]
Reactant: S=C=Nc1ccc(OCCN2CCCC2)cc1
Reactant: COc1ccc(N)c(C)c1
Product: COc1ccc(N=C=S)c(C)c1

Procedure:
The title compound is prepared as described in Example 1 for 1-[2-(4 isothiocyanato-phenoxy)-ethyl]-pyrrolidine but using 4-methoxy-2-methylaniline. Title compound: ES-MS: 180.9 [M+H]+; single peak at tR=5.56 min (System 2).
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C1(C)C=CC(S(O[CH2:21][C@H:22]2[CH2:27][CH2:26][C@H:25]([C@H:28]3[CH2:33][CH2:32][C@H:31]([CH2:34][CH2:35][CH:36]4[O:40][CH2:39][CH2:38][O:37]4)[CH2:30][CH2:29]3)[CH2:24][CH2:23]2)(=O)=O)=CC=1>C(O)C>[O:37]1[CH2:38][CH2:39][O:40][CH:36]1[CH2:35][CH2:34][C@H:31]1[CH2:32][CH2:33][C@H:28]([C@H:25]2[CH2:26][CH2:27][C@H:22]([CH2:21][O:10][C:7]3[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=3)[CH2:23][CH2:24]2)[CH2:29][CH2:30]1
Reactant: Oc1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H]([C@H]3CC[C@H](CCC4OCCO4)CC3)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Fc1ccc(OC[C@H]2CC[C@H]([C@H]3CC[C@H](CCC4OCCO4)CC3)CC2)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A solution of 0.33 g of potassium hydroxide in 7 ml of 95 percent ethanol is treated with 1.12 g of p-fluorophenol. Thereafter, the mixture is treated with a solution of 2.26 g of [trans-4-[trans-4-(2-(1,3-dioxolan-2-yl)ethyl)cyclohexyl]cyclohexyl]methyl p-toluenesulfonate in 23 ml of ethanol and stirred at 80° C. (bath temperature) for 24 hours. Subsequently, the reaction mixture is partitioned in 1N hydrochloric acid and methylene chloride. The organic phase is washed several times with water, dried over magnesium sulfate, filtered and evaporated. Chromatographic purification of the resulting crude product on silica gel with ethyl acetate/petroleum ether gives 1-[[trans-4-(trans-4-(2-(1,3-dioxolan-2-yl)ethyl)cyclohexyl]cyclohexyl]methoxy]-4-fluorobenzene.
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[N:5]=[CH:6][C:7]([O:10][C@H:11]2[CH2:32][N:14]3[CH2:15][CH2:16][N:17]([S:19]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)(=[O:21])=[O:20])[CH2:18][C@@H:13]3[CH2:12]2)=[N:8][CH:9]=1)[CH3:3].[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[CH:2]([C:4]1[N:5]=[CH:6][C:7]([O:10][C@H:11]2[CH2:32][N:14]3[CH2:15][CH2:16][N:17]([S:19]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=4)(=[O:20])=[O:21])[CH2:18][C@@H:13]3[CH2:12]2)=[N:8][CH:9]=1)([CH3:3])[CH3:1]
Reactant: C=C(C)c1cnc(O[C@@H]2C[C@H]3CN(S(=O)(=O)c4cccc(C(F)(F)F)c4)CCN3C2)cn1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1cnc(O[C@@H]2C[C@H]3CN(S(=O)(=O)c4cccc(C(F)(F)F)c4)CCN3C2)cn1
Yield: 86.4 %

Procedure:
(7R,8aS)-7-{[5-(Prop-1-en-2-yl)pyrazin-2-yl]oxy}-2-{[3-(trifluoromethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine (196 mg, 0.418 mmol, Example 115) in ethanol (10 mL) was added to 20% palladium hydroxide on carbon (12 mg, 0.084 mmol). The mixture was stirred at room temperature for 16 hours under 30 psi of hydrogen. The mixture was filtered through a nylon membrane and concentrated. The residue was purified by chromatography on silica gel (hexane/ethyl acetate=1:1) to give the title compound (170 mg, 86%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21 (s, 6H), 1.77 (m, 1H), 1.91 (m, 1H), 2.09 (m, 1H), 2.20-2.30 (m, 2H), 2.39 (m, 2H), 3.01 (m, 2H), 3.56 (m, 1H), 3.66 (m, 1H), 3.84 (m, 1H), 5.21 (m, 1H), 7.95 (m, 2H), 8.10 (m, 2H), 8.26 (m, 1H), 8.38 (m, 1H); MS (ESI) m/z 471 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2([NH2:11])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH3:21])[C:15]=1[N:22]=[C:23]=[O:24])[CH3:13]>C(OC(=O)C)C>[CH2:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH3:21])[C:15]=1[NH:22][C:23]([NH:11][C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:10][CH2:9][CH2:8]1)=[O:24])[CH3:13]
Reactant: NC1(c2ccccc2)CCC1
Reactant: CCc1cccc(CC)c1N=C=O
Solvent: CCOC(C)=O
Product: CCc1cccc(CC)c1NC(=O)NC1(c2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 79.4 %

Procedure:
To a solution of 1-phenylcyclobutyl amine (1.0, 0.0057 mole) in 30 ml of ethylacetate, 2,6-diethylphenylisocyanate (0.84 g, 0.0057 mole) is added and the reaction mixture is stirred at room temperature for 20 hours. Precipitated solid is filtered, washed with ethylacetate and dried yielding 1.46 gm of N-(2, 6-diethylphenyl)-N'-(1-phenylcyclobutyl)urea having a melting point of 227°-230° C.
Reaction SMILES: [BH4-].[Li+].Cl[Si](C)(C)C.[CH3:8][O:9][C:10]1[C:15]([CH:16]=[CH:17][N+:18]([O-])=O)=[CH:14][CH:13]=[C:12]([C:21]([F:24])([F:23])[F:22])[N:11]=1>O1CCCC1>[CH3:8][O:9][C:10]1[C:15]([CH2:16][CH2:17][NH2:18])=[CH:14][CH:13]=[C:12]([C:21]([F:24])([F:23])[F:22])[N:11]=1
Reactant: COc1nc(C(F)(F)F)ccc1C=C[N+](=O)[O-]
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1nc(C(F)(F)F)ccc1CCN
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
To a suspension of lithium borohydride (71.2 mg, 3.27 mmol) in tetrahydrofuran (5 ml) was added chlorotrimethylsilane (826 μl, 6.53 mmol) at ambient temperature (exothermic reaction) and the reaction was allowed to stir for 30 minutes. 2-Methoxy-3-(2-nitrovinyl)-6-(trifluoromethyl)pyridine (193 mg, 0.778 mmol) was added, and the reaction was heated to reflux for 6 hours. The reaction was cooled to ambient temperature and quenched by the addition of 1M HCl (9 ml). After 15 minutes, the reaction was diluted with water and washed with ether and hexanes. The aqueous layer was adjust to pH 13 with 5 N aqueous sodium hydroxide and extracted with ethyl acetate (2×25 ml). The combined ethyl acetate extractions were dried over Na2SO4, filtered, and concentrated to yield the desired compound (143 mg, 0.649 mmol, 83.5% yield).
Reaction SMILES: [Na].[C:2]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:11])[CH2:3][C:4]([O:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:5].[C:17]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:27])/[CH:18]=[CH:19]\[C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21]>C(O)CCC.Cl>[CH:3]([C:4]([O:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:5])([C:2]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:11])[CH:18]([C:17]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27])[CH2:19][C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21]
Reactant: CCCCOC(=O)CC(=O)OCCCC
Reactant: CCCCOC(=O)/C=C\C(=O)OCCCC
Agent: Cl
Agent: [Na]
Solvent: CCCCO
Product: CCCCOC(=O)CC(C(=O)OCCCC)C(C(=O)OCCCC)C(=O)OCCCC
Reaction time: 0.08 h
Yield: 95.8 %

Procedure:
One half gram of sodium metal is dissolved in 200 mls n-butanol and to this solution is added 108 g (0.5 mol) of dibutyl malonate. After reacting for five minutes, 114 grams (0.5 mole) of dibutyl maleate is added and the reaction mixture is refluxed for 6 hours. The solution is neutralized with a few drops of conc. hydrochloric acid and then filtered. The excess n-butanol is distilled off in vacuo to give 213 grams of a tetrabutyl propane-1,1,2,3-tetracarboxylate. The structure is confirmed by NMR analysis (CDCl3) ##STR14## CH3 (a) multiplet at 0.84-1.12δ CH2 (b) multiplet at 1.12-2.00δ
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[N+:27]([C:30]1[O:34][C:33]([CH:35]=O)=[CH:32][CH:31]=1)([O-:29])=[O:28]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:35][C:33]4[O:34][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=4)[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(Cc3ccc([N+](=O)[O-])o3)CC2)cc1

Procedure:
Using the general procedure described in Example 3, N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (0.14 mmol) was reacted with 5-nitro-2-furaldehyde to provide 30 mg of the title product as the free base. Treatment with hydrochloric acid and concentration in vacuo yielded the salt of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([CH:15]=1)[CH:7]=[N:8][CH2:9][CH:10](OC)OC.S(=O)(=O)(O)O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]2[C:15]=1[CH:10]=[CH:9][N:8]=[CH:7]2
Reactant: COC(CN=Cc1cc(Br)ccc1F)OC
Agent: O=S(=O)(O)O
Product: Fc1ccc(Br)c2ccncc12
Temperature: 135 °C
Reaction time: 0.5 h
Yield: 2 %

Procedure:
A mixture of 5-bromo-2-fluorobenzaldehyde (15 g, 74 mmol) and 2,2-dimethoxy-ethylamine (7.77 g, 74 mmol) in toluene (142 mL) was heated to reflux for 30 minutes using a Dean-Stark trap to remove water. The solution was then concentrated under vacuum to provide 5-bromo-2-fluorobenzylidene-2,2-dimethoxyethylamine. 5-Bromo-2-fluorobenzylidene-2,2-dimethoxyethylamine and cold concentrated sulfuric acid (28 mL) were added separately, dropwise, over a period of 20 minutes to concentrated sulfuric acid (83 mL) at 140° C. The mixture was stirred at 135° C. for 30 minutes, allowed to cool, and carefully poured onto ice. Filtered to remove solids and the mixture was washed with dichloromethane. The aqueous layer was made basic by cautious addition of 50% sodium hydroxide solution, and extracted with diethyl ether. Combined ether layers were dried (MgSO4), filtered and concentrated under vacuum to provide 310 mg (2%) of the desired product. MS (ESI) m/e 226 (M+H)+.
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][C:21]1[C:22](=[O:51])[N:23]([C:27]2[C:32]([CH3:33])=[CH:31][C:30]([N:34]3[CH2:38][C@H:37]([CH2:39][NH:40][C:41]([C:43]4[S:44][C:45]([Cl:48])=[CH:46][CH:47]=4)=[O:42])[O:36][C:35]3=[O:49])=[CH:29][C:28]=2[CH3:50])[CH:24]=[CH:25][CH:26]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.Cl>ClCCl>[Cl:48][C:45]1[S:44][C:43]([C:41]([NH:40][CH2:39][C@@H:37]2[O:36][C:35](=[O:49])[N:34]([C:30]3[CH:29]=[C:28]([CH3:50])[C:27]([N:23]4[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][CH2:19][OH:18])[C:22]4=[O:51])=[C:32]([CH3:33])[CH:31]=3)[CH2:38]2)=[O:42])=[CH:47][CH:46]=1
Reactant: Cc1cc(N2C[C@H](CNC(=O)c3ccc(Cl)s3)OC2=O)cc(C)c1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(N2C[C@H](CNC(=O)c3ccc(Cl)s3)OC2=O)cc(C)c1-n1cccc(CCO)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
157 g (174 mmol) of the compound from Example 64A (alternative synthesis) are dissolved in 1.44 l of dichloromethane. At 15-20° C., 453 ml (5.32 mol) of concentrated hydrochloric acid are added dropwise, and the mixture is stirred at room temperature for 1 h. The phases are separated, the organic phase is discarded. The aqueous phase is washed twice with dichloromethane. Dichloromethane is then added to the aqueous phase, and the mixture is adjusted with cooling to pH=10 using 1:1 dilute aqueous sodium hydroxide solution. The phases are separated, and the organic phase is washed twice with water and then dried over sodium sulphate. After filtration, the filtrate is concentrated to dryness under reduced pressure. The residue is triturated with acetone, cooled to 10° C., filtered off at this temperature and washed with cold acetone. Drying gives 75 g (85% of theory) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:24](=[O:25])[N:23]([CH3:26])[C:12]2[NH:13][C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20](=[S:22])[NH2:21])=[CH:16][CH:15]=3.[Cl:27][CH2:28][C:29]([CH2:31]Cl)=O>>[Cl:27][CH2:28][C:29]1[N:21]=[C:20]([C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12]2[N:23]([CH3:26])[C:24](=[O:25])[C:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])=[CH:10][C:11]3=2)[S:22][CH:31]=1
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(C(N)=S)ccc3[nH]c21
Reactant: O=C(CCl)CCl
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4nc(CCl)cs4)ccc3[nH]c21

Procedure:
The process is carried out as in Example 75, with compound A: 3-(2,4-dichlorophenyl)-1-methyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indole-6-carbothioic acid amide and 1,3-dichloroacetone.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C:5](=[NH:7])[NH2:6].C[O-].[Na+].[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([C:32](=O)[CH2:33][CH2:34][CH2:35][CH3:36])[C:27](OCC)=[O:28])=[CH:21][CH:20]=1)#[N:12]>CO.O1CCOCC1>[CH2:33]([C:32]1[N:7]=[C:5]([CH2:4][O:3][CH3:2])[NH:6][C:27](=[O:28])[C:26]=1[CH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:14]2[C:13]([C:11]#[N:12])=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:24][CH:23]=1)[CH2:34][CH2:35][CH3:36]
Reactant: COCC(=N)N
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CCCCc1nc(COC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 75 %

Procedure:
To a mixture of 2-methoxyethanimidamide hydrochloride (2.1 g) and methanol (15 mL) were added sodium methoxide (28% methanol solution, 4.8 g), and then a solution of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (3.0 g) in methanol (25 mL) and 1,4-dioxane (10 mL) at 0° C., and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated, and the residue was adjusted to pH 5 with water (50 mL) and 50% aqueous acetic acid solution, and extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (2.4 g, 75%).