Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:23]([F:26])([F:25])[F:24])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([NH2:22])[CH2:17][CH2:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[F:27][C:28]([F:34])([F:33])[CH2:29][C:30](O)=[O:31].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:23]([F:24])([F:25])[F:26])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([NH:22][C:30](=[O:31])[CH2:29][C:28]([F:34])([F:33])[F:27])[CH2:17][CH2:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: O=C(O)CC(F)(F)F
Reactant: NN1CCc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CC(F)(F)F)NN1CCc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)indoline-1-amine (0.1 g, 0.247 mmol) in CH2Cl2 (10.0 ml) was added 3,3,3-trifluoropropanoic acid (0.038 g, 0.297 mmol), PyBOP (0.192 g, 0.370 mmol) and DIPEA (0.047 g, 0.370 mmol) and the reaction was stirred at ambient temperature for 18 h. The reaction mixture was diluted with CH2Cl2, and the separated CH2Cl2 layer dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 20-25% EtOAc/petroleum ether) to afford the title compound as a light brown gummy material (0.12 g, 33%): 1H NMR (400 MHz, CDCl3) δ 7.32, (d, J=6.0 Hz, 2H) 7.28 (m, 1H), 7.20 (d, J=8.0, 1H), 7.14 (d, J=8.8, 1H), 6.70 (d, J=8.0 Hz, 1H), 6.60 (m, 2H), 4.15 (m, 1H), 3.85 (m, 1H), 3.65 (m, 1H), 3.46 (m, 2H), 3.19 (m, 2H); ESIMS m/z 514.86 ([M+H]+); IR (thin film) 3428, 1112, 857 cm−1.
Reaction SMILES: [H-].[Na+].[CH:3]1([N:9]2[C:13]3[CH:14]=[C:15]([O:18][CH:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[CH:16]=[CH:17][C:12]=3[NH:11][C:10]2=[O:24])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CN(C=O)C.[CH3:30][O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[C:36]([O:44][CH3:45])[CH:35]=1)=[O:33]>O.C1COCC1>[CH:3]1([N:9]2[C:13]3[CH:14]=[C:15]([O:18][CH:19]4[CH2:20][CH2:21][CH2:22][CH2:23]4)[CH:16]=[CH:17][C:12]=3[N:11]([S:40]([C:37]3[CH:38]=[CH:39][C:34]([C:32]([O:31][CH3:30])=[O:33])=[CH:35][C:36]=3[O:44][CH3:45])(=[O:42])=[O:41])[C:10]2=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)c(OC)c1
Reactant: O=c1[nH]c2ccc(OC3CCCC3)cc2n1C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(S(=O)(=O)n2c(=O)n(C3CCCCC3)c3cc(OC4CCCC4)ccc32)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
0.095 g of sodium hydride as a 60% dispersion in oil is added in portions to a mixture of 0.7 g of 3- cyclohexyl-5-cyclopentoxy-1,3-dihydro-2H-benzimidazol-2-one, 50 ml of DMF and 50 ml of THF and the mixture is stirred for 30 minutes at RT. 0.6 g of 4-methoxycarbonyl-2-methoxybenzenesulfonyl chloride is then added and the mixture is stirred for 18 hours at RT. The reaction mixture is poured into a mixture of water and ice and the precipitate formed is filtered off and washed with water and then with heptane to give 1 g of the expected product, which is used as such in the next step.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[C:4]([Cl:17])=[C:5]([C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)[C:6](=[N:8][OH:9])[NH2:7].[CH:20]1([CH2:23]Br)[CH2:22][CH2:21]1>C(Cl)(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:20]1([CH2:23][O:9][N:8]=[C:6]([NH2:7])[C:5]2[C:10]([C:13]([F:15])([F:14])[F:16])=[CH:11][CH:12]=[C:3]([C:2]([F:18])([F:1])[F:19])[C:4]=2[Cl:17])[CH2:22][CH2:21]1
Reactant: NC(=NO)c1c(C(F)(F)F)ccc(C(F)(F)F)c1Cl
Reactant: BrCC1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: ClC(Cl)Cl
Product: NC(=NOCC1CC1)c1c(C(F)(F)F)ccc(C(F)(F)F)c1Cl
Yield: 56.7 %

Procedure:
In 10 ml of chloroform was dissolved 0.60 g of 3,6-bistrifluoromethyl-2-chlorobenzamidoxime and 0.50 g of cyclopropylmethylbromide, and to the solution was added 0.1 g of tetrabutylammonium bromide at room temperature with stirring, and then 1.2 ml of 10% aqueous solution of sodiunhydroxide, then stirred for 3 hours at 30°-40° C. The solution was washed with water, washed with saturated saline solution and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography to obtain 0.40 g of the objective compound.m.p. 75°-80° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[C:3]=1[F:10].CC([O-])(C)C.[K+].[Cl:17][C:18]1[CH:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1>CC(N(C)C)=O>[Cl:9][C:4]1[C:3]([F:10])=[C:2]([CH:7]=[CH:6][C:5]=1[O:8][C:22]1[CH:21]=[CH:20][N:19]=[C:18]([Cl:17])[CH:23]=1)[NH2:1]
Reactant: Nc1ccc(O)c(Cl)c1F
Reactant: Clc1ccnc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Nc1ccc(Oc2ccnc(Cl)c2)c(Cl)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
A mixture of 4-amino-2-chloro-3-fluorophenol (11 g, 68.3 mmol) and potassium 2-methylpropan-2-olate (8.4 g, 75.2 mmol) in DMA (120 mL) was stirred at RT under N2 for 0.5 h, treated with 2,4-dichloropyridine (9.1 g, 62.1 mmol), and heated at 80° C. for 8 h. The mixture was concentrated to dryness, the residue treated with water, extracted with EtOAc (3×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography to afford 3-chloro-4-(2-chloropyridin-4-yloxy)-2-fluoroaniline (10 g, 59%). 1H NMR (400 MHz, DMSO-d6): δ 8.26 (d, J=5.6 Hz, 1H), 6.98-6.96 (m, 2 H), 6.88 (dd, J=5.6 Hz, 2.0 Hz, 1 H), 6.80 (t, J=9.2 Hz, 1 H), 5.57 (s, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:22]([O:24]C)=O)[CH:2]=1.[NH3:26]>C1COCC1.[OH-].[NH4+]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:22](=[O:24])[NH2:26])[CH:2]=1
Reactant: N
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccnc1
Temperature: 35 °C
Yield: 74 %

Procedure:
A solution of the 9-[(3-pyridyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (362 mg, 1.09 mmol) in 15 mL THF and 60 mL concentrated aqueous ammonium hydroxide was treated with a stream of NH3 gas to ensure saturation. The reaction vessel was capped and the mixture heated to 35° C. with stirring until tlc indicated complete consumption of starting material (48 hours). The mixture was neutralized to pH 8 with 5 N aqueous HCl, saturated with solid sodium chloride, and extracted twice with THF. The combined organic layers were concentrated. The resulting foam was taken up in a minimal amount of THF and loaded onto a silica gel column which had been pre equilibrated with EtOAc. Elution with EtOAc afforded 255 mg (74%) of the 9-[(3-pyridyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a yellow solid. 1H NMR (DMSO-d6) δ 10.46 (s, 1H), 8.79 (br s, 1H), 8.43 (d, 1H, J=1.5 Hz), 8.39 (dd, 1H, J=1.4 and 4.9 Hz), 8.35 (br s, 1H), 7.84 (d, 1H, J=7.8 Hz), 7.48-7.22 (m, 6H), 7.13 (d, 1H, J=8.3 Hz), 6.58 (d, 1H, J=7.8 Hz), and 5.73 (s, 2H). IR (KBr, cm−1) 3436, 3198 (br), 1629, 1619, 1599, 1580, 1564, 1547, 1444, 1433, 1329, 1263, and 776. MS (ES) m/e 318 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[OH:21])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[C:39](Cl)=[O:40]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH:9]2[O:21][C:39]([C:30]2[CH:31]=[CH:32][C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:29]=2)=[O:40])=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(O)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(OC(=O)c2ccc3ccccc3c2)C1
Temperature: 0 °C
Reaction time: 18 h
Yield: 97.4 %

Procedure:
A solution of 5.0 g (16.9 mmol) of tert-butyl (3RS,4RS)-4-(4-fluoro-phenyl)-3-hydroxy-piperidine-1-carboxylate in 50 ml of methylene chloride was treated with 240 mg (1.96 mmol) of 4-dimethylamino-pyridine and 4.2 ml (29 mmol) of triethylamine and cooled to 0° C. Subsequently, 4.65 g (24.4 mmol) of 2-naphthoyl chloride were added portionwise and the reaction mixture was stirred at room temperature for 18 hours. Thereupon, the reaction mixture was treated with ice-water and extracted with methylene chloride. The combined methylene chloride phases were dried over magnesium sulphate, filtered and the solvent was distilled off in a water-jet vacuum. The crude product was chromatographed on silica gel with methylene chloride as the eluent. The thus-obtained product fractions were recrystallized from ether and n-hexane. There were obtained 7.4 g (97% of theory) of tert-butyl (3RS,4RS)-4-(4-fluoro-phenyl)-3-(naphthalen-2-ylcarbonyloxy)-piperidine-1-carboxylate as a colourless solid; MS: 450 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH3:13])=[CH:8][CH:7]=1)=[O:4].[F:16][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])([F:19])[F:18].[O-2].[Mg+2].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2].ClCCl>[CH3:13][S:12]([C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C:2]([F:1])([F:14])[F:15])=[CH:7][CH:8]=1)=[N:23][S:20]([C:17]([F:19])([F:18])[F:16])(=[O:22])=[O:21]
Reactant: NS(=O)(=O)C(F)(F)F
Reactant: CSc1ccc(NC(=O)C(F)(F)F)cc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Agent: [Mg+2]
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CS(=NS(=O)(=O)C(F)(F)F)c1ccc(NC(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
2.44 g (10.4 mmol) of 2,2,2-trifluoro-N-(4-methylsulphanylphenyl)acetamide and 2.80 g (18.8 mmol) of trifluoromethylsulphonamide are mixed with 145 ml of dichloromethane. 2.09 g (51.9 mmol) of magnesium oxide, 460 mg (1.04 mmol) of rhodium(II) acetate dimer and 6.68 g (20.75 mmol) of iodobenzene diacetate are added to the mixture. The mixture is stirred at room temperature for 1 hour and then filtered, and the filter cake is washed with dichloromethane. On concentration of the filtrate, crystals separate out and are filtered off with suction and washed with a little dichloromethane. Drying results in 3.60 g (9.42 mmol; yield: 91%) of the product.
Reaction SMILES: [CH2:1]([N:6]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:14])[CH2:2][CH2:3][CH:4]=C.I([O-])(=O)(=O)=[O:16].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[O:14]=[C:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:6]1[CH2:1][CH2:2][CH2:3][CH:4]=[O:16]
Reactant: C=CCCCN1CCCCCCC1=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=CCCCN1CCCCCCC1=O
Reaction time: 0.08 h
Yield: 84.5 %

Procedure:
Osmium tetroxide (17 mg, 0.07 mmole) was added to 1-pent-4-enyl-azocan-2-one (5.52 g, 28.3 mmole) in a mixture of tetrahydrofuran (100 mL) and water (50 mL) under ambient water bath cooling. The mixture was stirred for 5 minutes and solid sodium periodate (15.11 g, 70.65 mmole) was added in portions over 15 minutes. The reaction mixture was stirred for 3 hours and filtered. The filtrate was concentrated, saturated with solid sodium chloride, and extracted with methylene chloride. The organic phase was dried (magnesium sulfate) and concentrated. Purification by silica gel chromatography, eluting with chloroform, gave 4-(2-oxo-azocan-1-yl)-butyraldehyde (4.72 g).
Reaction SMILES: [CH:1]1([CH:7]([NH:23][C:24]([C:26]2[CH:31]=[N:30][CH:29]=[CH:28][N:27]=2)=[O:25])[CH:8]([NH:13][CH:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:15]([O:17]C)=[O:16])[C:9]([F:12])([F:11])[F:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si](C)(C)[O-].[K+]>O1CCCC1.C(OCC)(=O)C>[CH:1]1([CH:7]([NH:23][C:24]([C:26]2[CH:31]=[N:30][CH:29]=[CH:28][N:27]=2)=[O:25])[CH:8]([NH:13][CH:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:15]([OH:17])=[O:16])[C:9]([F:11])([F:12])[F:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C(NC(C(NC(=O)c1cnccn1)C1CCCCC1)C(F)(F)F)C(C)(C)C
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)C(NC(C(NC(=O)c1cnccn1)C1CCCCC1)C(F)(F)F)C(=O)O
Temperature: 140 °C

Procedure:
The stereoisomer of methyl 2-(3-cyclohexyl-1,1,1-trifluoro-3-(pyrazine-2-carboxamido)propan-2-ylamino)-3,3-dimethylbutanoate designated as 7A1-isomer A (107 mgm), and potassium trimethylsilanolate (124 mgm, 4 eq) in tetrahydrofuran (2.5 mL) were heated to 140° C. in a microwave apparatus for 10 minutes. The reaction mixture was diluted with ethyl acetate, and washed successively with 1N hydrochloric acid, water, brine, and then dried over anhydrous sodium sulfate. Evaporation to dryness under reduced pressure gave crude 2-(3-cyclohexyl-1,1,1-trifluoro-3-(pyrazine-2-carboxamido)propan-2-ylamino)-3,3-dimethylbutanoic acid (8), designated as 8A1-isomer A.
Reaction SMILES: B(Br)(Br)Br.C([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[S:25][C:26]3[CH:32]=[C:31]([C:33]4[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[CH:35][CH:34]=4)[CH:30]=[CH:29][C:27]=3[N:28]=2)=[CH:20][CH:19]=1)CCCCCCCCCCC>ClCCl>[OH:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[S:25][C:26]3[CH:32]=[C:31]([C:33]4[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[CH:35][CH:34]=4)[CH:30]=[CH:29][C:27]=3[N:28]=2)=[CH:22][CH:23]=1
Reactant: CCCCCCCCCCCCOc1ccc(-c2nc3ccc(-c4ccc(CCCCCCCCC)cc4)cc3s2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCCCCCCc1ccc(-c2ccc3nc(-c4ccc(O)cc4)sc3c2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
Boron tribromide (0.53 cm3, 5.65×10−3 mol) was added dropwise to a cooled (0° C.) stirred solution of 2-(4-dodecyloxyphenyl)-6-(4-nonylphenyl)benzothiazole (2.25 g, 3.76×10−3 mol) in dichloromethane (100 cm3). The reaction mixture was stirred at room temperature overnight, then poured onto an ice/water mixture (200 g) and stirred (30 min). The reaction mixture was extracted with dichloromethane (2×75 cm3) and the combined organic layers were washed with brine (2×100 cm3) and dried (MgSO4). After filtration the solvent was removed under reduced pressure and the residue was purified by column chromatography [silica gel, ethyl acetate:hexane 1:1] followed by recrystallisation from ethyl acetate to yield 1.25 g (77.3%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][C:28]([CH3:41])([CH3:40])[C:29]([NH:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1)=[O:30]>C1(C)C=CC=CC=1.O1CCOCC1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:37][CH2:36][C:35]1[CH:34]=[CH:33][C:32]([NH:31][C:29](=[O:30])[C:28]([CH3:40])([CH3:27])[CH3:41])=[CH:39][CH:38]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(CN)cc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)Nc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 70.8 %

Procedure:
Use a method similar to the General Procedure 1-3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.33 g, 0.78 mmol) with a solution of 4-(2,2-dimethyl-propionylamino)-benzylamine (0.32 g, 1.6 mmol) in anhydrous toluene/dioxane (4:1, 10 mL). Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (1:0 to 7:3 gradient over 30 min; 35 mL/min) and then by SCX chromatography to obtain 7-chloro-6-[4-(2,2-dimethyl-propionylamino)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil (0.266 g, 70%). MS (ES+) m/z: 482 (M+H)+.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.[CH3:6][C:7]1[O:11][N:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[C:18]1[N:19]=[CH:20][N:21]([C:23]2[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=2[C:25](O)=[O:26])[CH:22]=1>>[CH:1]1([NH:5][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=2[N:21]2[CH:22]=[C:18]([C:8]3[C:9]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:10][O:11][C:7]=3[CH3:6])[N:19]=[CH:20]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccccc2C(=O)O)cn1
Reactant: NC1CCC1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccccc2C(=O)NC2CCC2)cn1
Yield: 46 %

Procedure:
As described for Example 71, cyclobutylamine was converted, using 2-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid (100 mg, 0.29 mmol) instead of 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid, to the title compound (53 mg, 46%) which was obtained as an off-white solid. MS: m/e=399.1 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]2[C:19]3[NH:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]=3[CH2:10][CH2:9][N:8]2[C:20](=[O:31])/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][C:26]([CH:29]=[O:30])=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-]#N.[Na+].[C:35](O)(=[O:37])C.C(Cl)Cl.CO>CO.O=[Mn]=O>[O:31]=[C:20]([N:8]1[CH2:9][CH2:10][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:18][C:19]=2[CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)/[CH:21]=[CH:22]/[C:23]1[CH:28]=[CH:27][C:26]([C:29]([O:37][CH3:35])=[O:30])=[CH:25][CH:24]=1
Reactant: CC(=O)O
Reactant: O=Cc1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccccc2)cc1
Agent: O=[Mn]=O
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccccc2)cc1
Reaction time: 5 h
Yield: 70.1 %

Procedure:
To a solution of Example 9 (0.2 g, 0.49 mmol) in 20 mL of MeOH was added activated MnO2 (0.59 g, 14 equiv.), sodium cyanide (0.05 g, 2 equiv.) and acetic acid (0.05 g, 1.7 equiv.). The resulting mixture was stirred for 5 hours. Tlc monitoring showed a new compound (SiO2, DCM:MeOH (95:5), Rf=0.82). The mixture was filtered through a short column of celite using 150 mL of a mixture of MeOH:EtOAc:CHCl3 (1:25:25). After evaporation in vacuo the residue was purified via flash chromatography on a 2×20 cm2 column using DCM as eluting solvent. Evaporation and recrystallization from EtOH gave the title compound (0.15 g, 70%) as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=O)[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.[NH2:13]C(N)=O>C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:8])[NH:13][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1
Reactant: NC(N)=O
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Solvent: Cc1ccccc1C
Product: Cc1ccc2c(c1)C(=O)NC2=O
Temperature: 150 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
Xylene (15 ml) was added to 4-methylphthalic anhydride (3.0 g) and urea (1.2 g), and the mixture was stirred overnight at 150° C. The reaction mixture was cooled to room temperature, and precipitated crystals were collected by filtration and washed with ethanol and water. The crystals were dried under reduced pressure to give 4-methylphthalimide (2.4 g, Y.:82%) as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:20][OH:21])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[O:16][CH2:17][O:18][CH3:19].I[CH2:23][CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[OH:21][CH2:20][C:6]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[O:16][CH2:17][O:18][CH3:19])=[C:2]([O:1][CH2:23][CH2:24][CH3:25])[CH:3]=[N:4][CH:5]=1
Reactant: CCCI
Reactant: COCOc1cc(OC)ccc1-c1c(O)cncc1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1cncc(CO)c1-c1ccc(OC)cc1OCOC

Procedure:
A mirxture of 3-hydroxy-5-hydroxymethyl-4-(2-methoxymethoxy-4-methoxy-phenyl)-pyridine (550 mg, 1.89 mmol), iodopropane (0.210 ml, 2.15 mmol), potassium carbonate (3 g) in dry DMF (70 ml) was stirred overnight at rt. The mixture was dissolved in water and extracted with a 1:1 hexane:t-butyl methyl ether solution (×3) and washed with brine, dried (Na2SO4), and concentrated to afford the title compound as a greenish oil. (527 mg, 84%)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH2:21])[C:5]([NH:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)=[O:6].[CH3:22][O:23][C:24](=[O:37])[CH2:25][O:26][C:27]1[CH:32]=[C:31]([Cl:33])[C:30]([CH:34]=O)=[C:29]([Cl:36])[CH:28]=1>>[CH3:22][O:23][C:24](=[O:37])[CH2:25][O:26][C:27]1[CH:28]=[C:29]([Cl:36])[C:30]([C:34]2[NH:1][C:2]3[CH:3]=[C:4]([C:5](=[O:6])[NH:7][C:8]4[CH:17]=[CH:16][C:15]5[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=5)[N:9]=4)[CH:18]=[CH:19][C:20]=3[N:21]=2)=[C:31]([Cl:33])[CH:32]=1
Reactant: COC(=O)COc1cc(Cl)c(C=O)c(Cl)c1
Reactant: Nc1ccc(C(=O)Nc2ccc3ccccc3n2)cc1N
Product: COC(=O)COc1cc(Cl)c(-c2nc3ccc(C(=O)Nc4ccc5ccccc5n4)cc3[nH]2)c(Cl)c1

Procedure:
The title compound was prepared from 3,4-diamino-N-quinolin-2-yl-benzamide (from Example 6-17) and (3,5-dichloro-4-formylphenoxy)-acetic acid methyl ester (from Example 6-5) analogous to Example 6-17. 1H NMR (Methanol-d4, 400 MHz): δ 8.44 (m, 3H), 8.06 (d, 1H), 7.92 (d, 2H), 7.74 (m, 2H), 7.54 (m, 1H), 7.23 (s, 2H), 4.89 (s, 2H), 3.82 (s, 3H). MS (m/z) 521.2 (M+1); Retention time: 1.42 min (Method 10).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.CC(=CC)C.[O-:20]Cl=O.[Na+]>C(O)(C)(C)C.O>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]([OH:20])=[O:12])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1ccc(-c2ccncc2)cc1
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)c1ccc(-c2ccncc2)cc1
Reaction time: 0.33 h
Yield: 78.3 %

Procedure:
To a suspension of 4-[pyridin-4-yl]-benzaldehyde (approx. 2.8 g, 15 mmol) (reference example 8a) in t-butanol (100 mL) was added 2-methy-but-2-ene (15 mL) followed by a solution comprised of NaClO2 (14.7 g, tech. grade) and NaH2PO4.H2O (14.7 g, 105 mmol) in H2O (100 mL). This mixture was stirred for 20 min then the precipitated solid filtered off. This solid was washed with water then set aside. The organic phase of the mother liquor was separated then washed with brine, dried over MgSO4 and concentrated to give a solid. This material was combined with the solid obtained by filtration and dried under vacuum to give 2.34 g of the title compound. 1H NMR (DMSO) d 7.77 (d, J=6 Hz, 2H), 7.93 (d, J=8 Hz, 2H), 8.06 (d, J=8 Hz, 2H), 8.70 (d, J=6 Hz, 2H). MS (EI) m/z 199 (M)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[C:4]([O:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:3]=1.[C:20]([CH2:22][C:23](O)=[O:24])#[N:21].C(Cl)CCl.C(N(CC)CC)C>C1COCC1>[NH2:1][C:2]1[C:7]([NH:8][C:23](=[O:24])[CH2:22][C:20]#[N:21])=[CH:6][N:5]=[C:4]([O:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:3]=1
Reactant: N#CCC(=O)O
Reactant: COC(=O)c1cccc(Oc2cc(N)c(N)cn2)c1
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(Oc2cc(N)c(NC(=O)CC#N)cn2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product of Step 3 in THF (150 mL), was added cyanoacetic acid (870 mg, 10.2 mmol), EDC (4.32 g, 22.5 mmol) and triethylamine (8 ml, 51 mmol). This mixture was then stirred at rt for overnight. The reaction mixture was concentrated, taken up in EtOAC (300 mL), washed with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated. The residue was dissolved in AcOH (100 ml), and then heated to 115° C. for 24 h. The reaction mixture was concentrated to afford the title compound, which was used directly to next step without further purification. MS (ES+) m/e 309 [M+H]+.