Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13].[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1.C(N(C(C)C)C(C)C)C>CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+]>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[O:8])=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13]
Reactant: CN1CCC(N)CC1
Reactant: Nc1ccc(C(=O)O)cc1OC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)c2ccc(N)c(OC(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
To a solution of 0.5 g (2.3 mmole) of 4-amino-3-trifluoromethoxy-benzoic acid, 0.31 g (2.8 mmole) of 4-amino-1-methyl-piperidine, 1.2 mL (69 mmole) of ethyldiisopropyl amine and 4 mL of dimethylformamide was added the solution of 1.2 g (2.8 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate in 2 mL of dimethylformamide. The mixture was stirred at room temperature for 2 hour, then diluted with ice water and saturated sodium carbonate. The mixture was extracted with dichloromethane twice. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-60:40) gave 0.7 g of 4-amino-N-(1-methyl-piperidin-4-yl)-3-trifluoromethoxy-benzamide as a white solid.
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:19]O>>[F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1F
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc([N+](=O)[O-])c1F
Temperature: 70 °C
Reaction time: 8 h

Procedure:
2-Fluoro-3-nitrobenzoic acid (75 g) was dissolved in 300 ml of methanol, and then 20 ml of concentrated H2SO4 was added. The mixture was stirred at 70° C. overnight and cooled to rt, the resulting solid was filtered and washed with water (3×200 ml), to the filtered was added water (400 ml), the resulting precipitate was filtered and washed with water (2×100 ml) to afford another batch of product. The solid were combined and dried under vacuum to afford the title compound was obtained as a light yellow solid (78 g, 96%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=C(C2C=CN=CC=2)C(C2C=CC(OCC3C=CC4C(=CC=CC=4)N=3)=CC=2)=[N:3]1.[F:31][C:32]1[C:37]([F:38])=[C:36]([O:39][CH2:40][C:41]2[CH:50]=[CH:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[N:42]=2)[CH:35]=[CH:34][C:33]=1[C:51](=O)[CH2:52][C:53]1[CH:58]=[CH:57][N:56]=[CH:55][CH:54]=1>>[F:38][C:37]1[C:32]([F:31])=[C:33]([C:51]2[C:52]([C:53]3[CH:58]=[CH:57][N:56]=[CH:55][CH:54]=3)=[CH:1][N:2]([CH3:6])[N:3]=2)[CH:34]=[CH:35][C:36]=1[O:39][CH2:40][C:41]1[CH:50]=[CH:49][C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[N:42]=1
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ccccc3n2)c(F)c1F
Product: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)c(F)c2F)n1

Procedure:
Following the procedure for the preparation of 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting 1-[2,3-Difluoro-4-(quinolin-2-ylmethoxy)-phenyl]-2-pyridin-4-yl-ethanone provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.44 (bs, 2H), 8.22 (d, J=8.7 Hz, 1H), 8.06 (d, J=8.7 Hz, 1H), 7.84 (d, J=7.9 Hz, 1H), 7.70 (m, 2H), 7.66 (s, 1H), 7.56 (t, J=7.9 Hz, 1H), 7.08 (m, 3H), 6.88 (m, 1H), 5.48 (s, 2H); MS: (M+H m/z=429.1).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.[Br:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.CCOCC>[Br:29][C:30]1[CH:35]=[CH:34][C:33]([O:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[CH:32][CH:31]=1
Reactant: CC(C)OC(=O)N1CCC(CO)CC1
Reactant: Oc1ccc(Br)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
Diisopropyl azodicarboxylate (9.1 mL, 46.27 mmol) in THF (15 mL) was added dropwise to a solution of 1-methylethyl 4-(hydroxymethyl)-1-piperidinecarboxylate (7.76 g, 38.56 mmol), 4-bromophenol (6.67 g, 38.56 mmol) and Ph3P (13.15 g, 50.12 mmol) in THF (85 mL) at −20° C. The reaction mixture was allowed to warm to ambient temperature and stirred at ambient temperature overnight. The mixture was concentrated, and the residue was purified by chromatography on a silica gel column using 0 to 25% EtOAc/hexane to give the crude product. The crude product was taken up in Et2O (250 mL) and washed with 1N NaOH (aq). The organic extracts were dried over MgSO4, filtered, and the filtrate was concentrated to give 7.5 g (55%) of 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate as a white solid. 1H NMR (400 MHz, CDCl3): δ7.35 (d, 2H, J=8.9 Hz), 6.75 (d, 2H, J=8.9 Hz), 4.96-4.83 (m, 1H), 4.24-4.14 (m, 2H), 3.75 (d, 2H, J=6.4 Hz), 2.81-2.71 (m, 2H), 2.02-1.87 (m, 1H), 1.85-1.75 (m, 2H), 1.33-1.13 (m, 8H); LRMS (ESI), m/z 356/358 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][O:14][C:15]([NH:17][C:18]3[C:19]([NH2:24])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:16])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.N1C=CC=CC=1.[Br:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1>C(Cl)(Cl)Cl>[Br:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH:24][C:19]2[C:18]([NH:17][C:15]([O:14][CH2:13][CH:10]3[CH2:9][CH2:8][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH2:12][CH2:11]3)=[O:16])=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:37])=[CH:34][CH:33]=1
Reactant: Nc1ccccc1NC(=O)OCC1CCN(c2ccncc2)CC1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccccc1NC(=O)c1ccc(Br)cc1)OCC1CCN(c2ccncc2)CC1
Reaction time: 20 h
Yield: 42.7 %

Procedure:
A solution of N1-[1-(4-pyridyl)piperidin-4-yl-methoxycarbonyl)-1,2-benzenediamine (300 mg, 0.920 mmol) and pyridine (0.74 mL) in chloroform (5 mL) was treated with 4-bromobenzoyl chloride (405 mg, 1.84 mmol). After 20 h, the mixture was concentrated and the residue partitioned between water and ethyl acetate. The aqueous layer was extracted three times with ethyl acetate and the combined organics were washed with 1 N aqueous sodium hydroxide, water, saturated sodium chloride solution. The solution was dried (potassium carbonate), filtered, and concentrated in vacuo. Recrystallization (methanol/chloroform and hexanes) yielded 200 mg (43%) of the title compound.
Reaction SMILES: CC1C(N=C=O)=CC(N=C=[O:10])=CC=1.[CH2:14]([C:16]([CH2:21][OH:22])([CH2:19][OH:20])[CH2:17][CH3:18])[OH:15]>>[C:21]([OH:22])(=[O:10])[CH:16]=[CH2:19].[C:21]([OH:22])(=[O:10])[CH:16]=[CH2:19].[C:21]([OH:22])(=[O:10])[CH:16]=[CH2:19].[CH2:14]([C:16]([CH2:21][OH:22])([CH2:19][OH:20])[CH2:17][CH3:18])[OH:15]
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Agent: CCC(CO)(CO)CO
Product: C=CC(=O)O

Procedure:
First, 4.24 g of an adduct (trade name: Colonate L, a substance containing 25% by mass of ethyl acetate, produced by Nippon Polyurethane Industry Co., Ltd.) in which tolylenediisocyanate and trimethylolpropane are added in a ratio of 3:1 (molar ratio) as a material for forming micro-capsule walls, 1.12 g of trimethylolpropane triacrylate (produced by Kyoeisha Chemical Co., Ltd.), and 0.93 g of a near-infrared absorbing dye (“KayasorbIR-820B” produced by Nippon Kayaku Co., Ltd.) were dissolved uniformly in 21.7 g of glycidyl methacrylate to prepare an oil component.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:9][C@H:8]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([NH:19][C@@H:20]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH2:22][CH2:21]4)[C:13]=3[CH:12]=[CH:11]2)[CH2:7][C@H:6]1[CH2:29][O:30][Si](C(C)(C)C)(C)C)(=[O:3])[CH3:2].N1C=CC=CC=1.F.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C1COCC1>[C:1]([O:4][C@H:5]1[CH2:9][C@H:8]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([NH:19][C@@H:20]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH2:22][CH2:21]4)[C:13]=3[CH:12]=[CH:11]2)[CH2:7][C@H:6]1[CH2:29][OH:30])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1C[C@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: *CC(*)C
Agent: F
Agent: O=C([O-])O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1C[C@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@H]1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
(1S,2S,4R)-2-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl acetate (3.66 g, 7.03 mmol) was dissolved in THF (31.3 mL) and pyridine (31.3 mL, 387 mmol) in a polypropylene vial and the solution was cooled to 0° C. Pyridine hydrofluoride (8.61 mL, 95.6 mmol) was added dropwise and the mixture was stirred at rt for 1 hour. The resulting solution was added dropwise into a solution of saturated aqueous sodium bicarbonate (150 mL), extracted with EtOAc (3×50 mL), dried with MgSO4, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM to afford the title compound (2.30 g, 80%). LC/MS: Rt=1.64 min, ES+ 407 (AA standard).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:5]=1[O:11][CH3:12].C([Li])CCC.[CH2:20]([N:27]1[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CCOCC.CCCCCC>[CH3:1][O:2][CH:3]([O:13][CH3:14])[C:4]1[CH:9]=[CH:8][C:7]([C:30]2([OH:33])[CH2:31][CH2:32][N:27]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29]2)=[CH:6][C:5]=1[O:11][CH3:12]
Reactant: COc1cc(Br)ccc1C(OC)OC
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: COc1cc(C2(O)CCN(Cc3ccccc3)CC2)ccc1C(OC)OC
Temperature: -50 °C
Reaction time: 0.83 h

Procedure:
15.0 g of 4-bromo-2-methoxybenzaldehyde dimethyl acetal was dissolved in 150 ml of ether and the obtained solution was cooled to −50° C. Then 25.3 ml of a 1.6 M solution of n-butyllithium in hexane was dropped thereinto. 1 hour thereafter, 30 ml of a solution of 11.7 ml of 1-benzyl-4-piperidone in diethyl ether was dropped thereinto in such a manner that the bulk temperature did not exceed −35° C. After stirring at room temperature for 50 minutes, water was added thereto followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, 23.82 g of a pale yellow oily substance was obtained. 13.82 g of this oily substance was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 6.31 g of the title compound as a pale yellow solid.
Reaction SMILES: [I-].[F:2][CH2:3][CH2:4][N:5]([N:21]=[O:22])[C:6]([NH:8][CH2:9][CH2:10][O:11][C:12](C1[CH2+]=CC=CN1C)=[O:13])=[O:7].[CH2:23]([N:30]1[CH:38]=[CH:37][C:33](C(N)=O)=[CH:32][CH2:31]1)C1C=CC=CC=1>CO>[F:2][CH2:3][CH2:4][N:5]([N:21]=[O:22])[C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]([C:37]1[CH2:33][CH:32]=[CH:31][N:30]([CH3:23])[CH:38]=1)=[O:13])=[O:7]
Reactant: NC(=O)C1=CCN(Cc2ccccc2)C=C1
Reactant: CN1C=CC=[CH2+]C1C(=O)OCCNC(=O)N(CCF)N=O
Agent: [I-]
Solvent: CO
Product: CN1C=CCC(C(=O)OCCNC(=O)N(CCF)N=O)=C1
Yield: 55 %

Procedure:
A solution of the quaternary nitrosourea prepared in Example 126 (0.426 g, 1 mmol) and 1-benzyl-1,2-dihydroisonicotinamide (0.21 g, 1 mmol) in 25 mL of anhydrous methanol was stirred at 0° C. for 4 hours under nitrogen. The solvent was evaporated in vacuo at about 30° C. and the residue was suspended in chloroform, filtered and flash chromatographed on a short column of neutral alumina. The title compound was obtained in 55% yield after elution with chloroform and was assigned the structure ##STR156## consistent with UV analysis.
Reaction SMILES: [OH:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].C(N(CC)CC)C.Cl[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1[N+:30]([O-:32])=[O:31]>CC(C)=O>[N+:27]([C:24]1[CH:23]=[C:22]([N+:30]([O-:32])=[O:31])[CH:21]=[CH:26][C:25]=1[O:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12])([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1Oc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 1 L four-necked flask equipped with an overhead stirrer, thermocouple and a condenser was charged with 2-hydroxyisoindoline-1,3-dione (25 g, 153 mmol) and acetone (500 mL). To this stirred suspension was added triethylamine (15.7 g, 154 mmol). The reaction mixture turned dark red and 2-hydroxyisoindoline-1,3-dione slowly dissolved and became a homogeneous solution after 10 minutes. 1-Chloro-2,4-dinitrobenzene (31 g, 153 mmol) was added and the reaction was stirred at room temperature for 2 hours. After this time, a bright yellow suspension formed, and the reaction mixture was poured into 500 mL of ice-water. The precipitate was filtered and washed three times with cold MeOH (100 mL). The solid was compressed and washed with heptanes (3×100 mL) and dried under vacuum to give 2-(2,4-dinitrophenoxy)isoindoline-1,3-dione (I-33). 1H NMR (400 MHz, CDCl3) δ 8.99 (d, 1 H), 8.44 (dd, 1 H), 8.03-7.97 (m, 2 H), 7.95-7.90 (m, 2 H), 7.46 (d, 1 H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([C:10]([NH2:12])=[O:11])[CH:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:26]=[CH:25][C:24]([C:27]3([OH:31])[CH2:30][O:29][CH2:28]3)=[CH:23][CH:22]=2)O1.C([O-])([O-])=O.[Na+].[Na+].[NH4+].[Cl-]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[OH:31][C:27]1([C:24]2[CH:25]=[CH:26][C:21]([C:2]3[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([C:10]([NH2:12])=[O:11])[CH:3]=3)=[CH:22][CH:23]=2)[CH2:30][O:29][CH2:28]1
Reactant: NC(=O)c1cc(Br)sc1[N+](=O)[O-]
Reactant: CC1(C)OB(c2ccc(C3(O)COC3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1cc(-c2ccc(C3(O)COC3)cc2)sc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 8 h

Procedure:
5-Bromo-2-nitrothiophene-3-carboxamide (Intermediate 10, Step 4) (1.44 g, 5.74 mmol), 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]oxetan-3-ol (1.821 g, 6.60 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.331 g, 0.287 mmol) were taken up in THF (25 mL)/2 N Na2CO3 (10 mL) and the reaction mixture was stirred at 80° C. overnight. After cooling to room temperature, saturated NH4Cl and EtOAc were added. The resulting precipitate was collected by filtration, washed with water and dried to give 5-[4-(3-hydroxyoxetan-3-yl)phenyl]-2-nitrothiophene-3-carboxamide as a brown solid (batch 1). The organic phase from the filtrate was separated, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo while loading onto silica. Purification of the residue by flash silica gel column chromatography (12-100% EtOAc-hexanes followed by 0-10% MeOH-EtOAc) gave the title compound as an orange solid after recrystallising from EtOH (batch 2).
Reaction SMILES: COC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC(OC)=O)C=CC=1OC.[CH2:27]([C:29]1[CH:30]=[C:31]([C:37](=O)[C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([O:46][CH3:47])[CH:39]=2)[CH:32]=[CH:33][C:34]=1[CH2:35][CH3:36])[CH3:28].C(OP([CH2:57][C:58]#[N:59])(=O)OCC)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>CCCCCC>[CH2:27]([C:29]1[CH:30]=[C:31]([C:37]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([O:46][CH3:47])[CH:39]=2)=[CH:57][C:58]#[N:59])[CH:32]=[CH:33][C:34]=1[CH2:35][CH3:36])[CH3:28]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CCc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1CC
Agent: COC(=O)C=C(c1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Product: CCc1ccc(C(=CC#N)c2ccc(OC)c(OC)c2)cc1CC

Procedure:
3-(3,4-Diethylphenyl)-3-(3,4-dimethoxyphenyl)acrylonitrile was prepared analogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylate using 3′,4′-diethyl-3,4-dimethoxybenzophenone (0.51 g, 1.7 mmol), diethylcyanomethylphosphonate (0.31 mL, 1.9 mmol) and lithium hexamethyldisilazide (1.4 mL, 1.9 mmol, 1.3M) with a reaction time of 60 hours at room temperature. The crude product was purified by chromatography (silica gel, 1% ethyl acetate/methylene chloride) to afford an oil which was stirred in hexane until it solidified. The resulting slurry was filtered, the solid washed with hexane, air dried, and dried in vacuo to afford 0.31 g (57%) of a mixture of the E and Z isomers as an off white solid: mp 78–82° C.; 1H NMR (CDCl3) δ 7.30–6.75 (m, 12H), 5.61 (s, 1H), 5.60 (s, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 3.87 (s, 3H), 3.83 (s, 3H), 2.80–2.59 (m, 8H), 1.35–1.14 (m, 12H); 13C NMR (CDCl3) δ 163.0, 163.0, 151.0, 150.5, 148.8, 148.6, 144.6, 143.9, 142.1, 141.8, 136.8, 134.5, 131.9, 129.7, 128.6, 128.5, 128.2, 127.3, 126.3, 123.2, 122.2, 118.7, 118.6, 112.8, 111.3, 110.7, 92.5, 92.2, 56.1, 56.0, 25.5, 25.4, 25.4, 25.3, 15.3, 15.2, 15.0, 14.9; Anal. Calcd for C21H23NO2. Theoretical: C, 78.47; H, 7.21; N, 4.36. Found: C, 77.80; H, 7.25; N, 4.68.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([NH:14][N:15]=[C:16]([C:19]#[N:20])[C:17]#[N:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O(C1C=C(C=CC=1)N)C1C=CC=CC=1.C(#N)CC#N.O.NN>>[O:1]([C:8]1[CH:9]=[C:10]([NH:14][N:15]=[C:16]2[CH:17]=[N:18][N:20]=[CH:19]2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC(C#N)=NNc1cccc(Oc2ccccc2)c1
Agent: NN
Agent: Nc1cccc(Oc2ccccc2)c1
Solvent: N#CCC#N
Solvent: O
Product: C1=NN=CC1=NNc1cccc(Oc2ccccc2)c1
Yield: 65.8 %

Procedure:
The title compound was prepared using 131 mg (0.5 mmol) of 2-[(3-phenoxyphenyl)-hydrazono]malononitrile, which was derived from 3-phenoxyaniline (185 mg, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. Precipitate formed in the reaction tube approximately 5 min after the addition of hydrazine hydrate. The resulting solid was isolated by filtration, recrystallized from ethanol, and dried to yield 87 mg (59%) of the title compound as a mustard coloured solid.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11](=[O:23])[C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=O)[CH3:20])=[C:14]([NH2:22])[CH:13]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CO.C(=O)([O-])O.[K+]>O>[C:1]1([S:7]([NH:10][C:11]([C:12]2[CH:17]=[CH:16][C:15]3[N:18]=[C:19]([CH3:20])[NH:22][C:14]=3[CH:13]=2)=[O:23])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1nc2ccc(C(=O)NS(=O)(=O)c3ccccc3)cc2[nH]1
Temperature: 60 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
A mixture of 0.500 g of N-benzenesulfonyl-4-acetylamino-3-aminobenzamide, 3.9 g of 35% hydrochloric acid, 15 ml of methanol and 12 ml of water was stirred at 60° C. for 1 hour. The reaction mixture was neutralized with a potassium hydrogencarbonate aqueous solution. The crystals precipitated were separated through filtration, and were dried to give 0.404 g of 5-benzenesulfonylcarbamoyl-2-methylbenzimidazole (272).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.[NH2:16][C@H:17]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C@@H:18]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([Cl:31])[CH:25]=1)[CH2:19][CH2:20][C:21]([OH:23])=O.[CH3:39][C:40]([CH3:42])=O.ClC(Cl)C>CN(C=O)C>[Cl:31][C:26]1[CH:25]=[C:24]([C@@H:18]2[C@@H:17]([C:32]3[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=3)[N:16]([CH:40]([CH3:42])[CH3:39])[C:21](=[O:23])[CH2:20][CH2:19]2)[CH:29]=[CH:28][C:27]=1[F:30]
Reactant: CC(C)=O
Reactant: N[C@H](c1ccc(Cl)cc1)[C@H](CCC(=O)O)c1ccc(F)c(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)CC[C@H](c2ccc(F)c(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium triacetoxyborohydride (1.796 g, 8.48 mmol) was added to a solution of (4R,5S)-5-amino-4-(3-chloro-4-fluorophenyl)-5-(4-chlorophenyl)pentanoic acid hydrochloride (2.56 g, 6.52 mmol; Example 390, Step B) and acetone (0.491 mL, 6.68 mmol) in anhydrous DMF (6.52 mL) at rt. The reaction mixture was stirred at rt for 16 hours. Dichloroethane (25 mL) was added followed by 3 Å molecular sieves. The reaction mixture was heated to 70° C. for 22 hours, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using a 220 g column and eluting with 30 to 100% EtOAc/hexanes provided the desired product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:12][CH:11]=2)[C:5]([C:21]#[N:22])=[C:4]([SH:23])[N:3]=1.C(=O)(O)[O-].[Na+].Cl[CH2:30][C:31]1[N:32]=[C:33]([CH3:36])[S:34][CH:35]=1.O>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)[C:5]([C:21]#[N:22])=[C:4]([S:23][CH2:30][C:31]2[N:32]=[C:33]([CH3:36])[S:34][CH:35]=2)[N:3]=1
Reactant: Cc1nc(CCl)cs1
Reactant: COCCOc1ccc(-c2c(C#N)c(N)nc(S)c2C#N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc(-c2c(C#N)c(N)nc(SCc3csc(C)n3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.31 mmol) of 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-sulphanyl-pyridine-3,5-dicarbonitrile are dissolved in 1 ml of DMF. 103 mg (1.23 mmol) of sodium bicarbonate and 90.5 mg (0.61 mmol) of 4-chloromethyl-2-methyl-1,3-thiazole are then added. The suspension is shaken at RT overnight, and water is added. The precipitate is filtered off with suction and dried at 40° C. under reduced pressure. This gives 88.8 mg (66.2% of theory) of product.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:19][C:18]2[C:13](=[N:14][C:15]([NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:23][CH2:22]3)=[N:16][CH:17]=2)[NH:12][C:11]1=[O:35].[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.O>CN1CCCC1=O>[CH2:36]([N:12]1[C:13]2=[N:14][C:15]([NH:20][C@H:21]3[CH2:22][CH2:23][C@H:24]([O:27][Si:28]([C:31]([CH3:32])([CH3:34])[CH3:33])([CH3:29])[CH3:30])[CH2:25][CH2:26]3)=[N:16][CH:17]=[C:18]2[CH2:19][N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[Cl:3])[C:11]1=[O:35])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](Nc2ncc3c(n2)NC(=O)N(c2ccccc2Cl)C3)CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](Nc2ncc3c(n2)N(Cc2ccccc2)C(=O)N(c2ccccc2Cl)C3)CC1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Sodium hydride (44 mg, 1.1 mmol (60% oil dispersion)) was added to a suspension of 3-(2-chlorophenyl)-7-(trans-4-tert-butyldimethylsilyloxycyclohexyl-amino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (486 mg, 1 mmol) in 1-methyl-2-pyrrolidinone, and was stirred at room temperature for 25 minutes. To this solution was added benzyl bromide (0.12 mL 1 mmol) and stirred at room temperature for 4 hours. The reaction mixture was added to water and extracted with ethyl acetate. The layers were separated, and the organic layer was washed with water, dried with magnesium sulfate, concentrated in vacuo. The residue was purified by column chromatography using 25:75 acetone/hexane as eluant to give 1-benzyl-3-(2-chlorophenyl)-7-(trans4-tert-butyldimethylsilyloxycyclohexylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as an oil.