Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.[OH-].[Na+].OO.CC(O)=[O:38]>CCO.CS(C)=O>[NH2:1][C@H:2]1[C:7]([F:8])([F:9])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=3)=[CH:22][CH:21]=2)[C:14]([C:17]([NH2:18])=[O:38])=[N:15][CH:16]=1
Reactant: N#Cc1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1ccc(-c2ccncc2)cc1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)c1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The compound 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(4-(pyridin-4-yl)phenylamino)pyrazine-2-carbonitrile (41 mg, 0.097 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 15 min. HOAc (0.1 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (32 mg). MS 440.3 (M+H); UV 201.7, 242.5, 278.7 nm; t 0.384 min.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH2:35])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:38]1([CH:44]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:45](Cl)=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CO>C(Cl)Cl>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH:35][C:45](=[O:46])[CH:44]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Solvent: CO
Solvent: ClCCl
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Yield: 73 %

Procedure:
By the procedure of Example 13, Step C, 5-n-butyl-2,4-dihydro-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Example 16, Step C) was reacted with diphenylacetyl chloride. The crude product was evaporated twice from toluene and flash chromatographed twice on silica gel (gradient elution with 0.1-1% MeOH in CH2Cl2 and then approx. 0.01-1% MeOH in CH2Cl2) to give a 73% yield of the title compound as off-white crystals, mp 144°-146° C.; homogeneous by TLC in 19:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 725 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15]/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])[N:10]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:5]=[CH:6][C:7]=1[F:8].[H][H]>C(OCC)(=O)C.[C].[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[N:10]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)/C=C/CC[C@H]1CC[C@@H](c2ccc(F)c(F)c2)N1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCCC[C@H]1CC[C@@H](c2ccc(F)c(F)c2)N1C(=O)OC(C)(C)C
Yield: 99.5 %

Procedure:
Palladium-carbon (containing 50% water, 0.492 g) was added to a solution of tert-butyl (2S,5S)-2-(3,4-difluorophenyl)-5-[(E)-4-methoxycarbonyl-3-butenyl]pyrrolidine-1-carboxylate (1.7 g) in ethyl acetate (60 mL), and the reaction solution was stirred in a hydrogen atmosphere at room temperature for two hours. Palladium-carbon in the reaction solution was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 1.7 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[CH3:11][Si:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][O:15][CH2:16]Cl.CN(C=O)C.[H-].[Na+]>C(OC)(C)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:16][O:15][CH2:14][CH2:13][Si:12]([CH3:19])([CH3:18])[CH3:11])[CH:9]=[CH:10][C:3]=12
Reactant: Brc1ccnc2[nH]ccc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: C[Si](C)(C)CCOCn1ccc2c(Br)ccnc21
Reaction time: 4 h
Yield: 139 %

Procedure:
To a solution of 4-bromo-1H-pyrrolo[2,3-b]pyridine (6.2 g, 0.031 mol) and [β-(trimethylsilyl)ethoxy]methyl chloride (6.7 mL, 0.038 mol) in DMF (62 mL, 0.80 mol) was added sodium hydride (1.5 g, 0.038 mol) at 0° C., and the resulting solution turned opaque. The mixture was stirred for additional 4 h, then diluted with methyl tert-butyl ether (MTBE). The organic layer was separated and washed with water (×2) and brine aqueous solution successively. The organic phase was dried and concentrated in vacuo to give 14.1 g of a product as a pale orange oil. The oil was purified by column chromatography eluting with 5-20% ethyl acetate/hexanes to give the purified product as a colorless oil (9.66 g, 94% yield).
Reaction SMILES: Cl.[C:2]([C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1C(OC(C)(C)C)=O)#[CH:3].[CH2:16](Cl)[Cl:17].CO>C(OCC)(=O)C>[Cl-:17].[C:2]([CH:4]1[CH2:8][CH2:7][CH2:6][NH2+:5]1)#[C:3][CH3:16]
Reactant: C#C[C@H]1CCCN1C(=O)OC(C)(C)C
Reactant: ClCCl
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC#CC1CCC[NH2+]1
Product: [Cl-]

Procedure:
Anhydrous HCl was bubbled into a stirred solution of tert-butyl (2R)-2-ethynylpyrrolidine-1-carboxylate (0.71 g, 3.4 mmol) in ethyl acetate (15 mL) at 0° C. and allowed to mix for 45 min. Upon completion of the reaction as visualized by TLC (99:1 CH2Cl2 to MeOH), the solution was dried in vacuo to yield 2-prop-1-ynylpyrrolidinium chloride. LC-MS m/z=111. 1H NMR (CD3OD, 400 Mhz) 4.33-4.31 ppm (m, 1H), 3.42-3.24 (m, 2H), 2.36-1.99 (m, 4H), 1.88 (s, 3H).
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:15]([OH:17])=O)[N:12]([CH3:14])[CH:13]=2)=[CH:5][CH:4]=1.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH3:34][NH:35][O:36][CH3:37]>C(Cl)Cl>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([C:15]([N:35]([CH3:34])[O:36][CH3:37])=[O:17])[N:12]([CH3:14])[CH:13]=2)=[CH:7][CH:8]=1
Reactant: Cn1cc(-c2ccc(Br)cc2)nc1C(=O)O
Reactant: CNOC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: [Na]
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)c1nc(-c2ccc(Br)cc2)cn1C
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 32 %

Procedure:
To a solution of ethyl 4-(4-bromophenyl)-1-methyl-1H-imidazole-2-carboxylate (1.66 g, 5.37 mmol) in MeOH (38 mL) was added 1N NaOH solution (19 mL). The reaction turned cloudy white and was stirred at room temperature for 30 minutes. The reaction mixture was concentrated in vacuo and pumped under high vacuum overnight to give the sodium salt of 4-(4-bromophenyl)-1-methyl-1H-imidazole-2-carboxylic acid as a white solid. The sodium salt of 4-(4-bromophenyl)-1-methyl-1H-imidazole-2-carboxylic acid was dissolved in anhydrous CH2Cl2 (40 mL) under nitrogen at −15° C. (ice/methanol bath) and N-methylmorpholine (1.1 equiv, 5.91 mmol) was added followed by isobutyl chloroformate (1.1 equiv, 5.91 mmol). The reaction mixture was stirred at −15° C. for 15 minutes and then N,O-dimethylhydroxylamine hydrochloride (1.0 equiv, 5.37 mmol) was added. The reaction was allowed to warm to room temperature and was stirred for 17 hours. The reaction was quenched with H2O (10 mL). The product was extracted using EtOAc (3×30 mL) and the combined organic layers were washed with brine (20 mL), dried over MgSO4, and concentrated in vacuo. Purification by silica gel chromatography (Analogix IF280, 20-100% EtOAc/hexanes) afforded the title compound as a tan solid (32%). ESMS [M+H]+: 324.2.
Reaction SMILES: [N+](C1C=CC=CC=1)([O-])=O.C(Cl)(Cl)C(Cl)Cl.[C:16]1(=[O:22])[O:21][C:19](=[O:20])[CH2:18][CH2:17]1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([O:30]C)=[CH:26][CH:25]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([OH:30])=[C:28]([CH:29]=1)[C:19]([CH2:18][CH2:17][C:16]([OH:21])=[O:22])=[O:20]
Reactant: COc1ccc(Cl)cc1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: ClC(Cl)C(Cl)Cl
Product: O=C(O)CCC(=O)c1cc(Cl)ccc1O
Temperature: 5 °C

Procedure:
A dry flask was charged with 650 ml. each of nitrobenzene and sym-tetrachloroethane, 104 g. (1.04 moles) succinic anhydride and 130 g. (0.913 mole) p-chloroanisole. The mixture was stirred at 5° C and 276 g. (2.07 moles) of anhydrous AlCl3 was added portionwise over a 90 minute period such that the temperature did not exceed 10° C. The resulting mixture was stirred under nitrogen for 5 days at 7° C and then poured into a mixture of 1 kg. of ice and 176 ml. concentrated hydrochloric acid. The thus quenched mixture was steam distilled until all organic solvents were removed. The residual aqueous-oil combination was cooled to 20° C whereupon the oil phase crystallized. The aqueous supernate was then drawn off and one liter of methylene chloride was added to the remaining crystallized solid mass. The resulting slurry was warmed at 25° C with stirring, and then filtered, and the filtered-off solids washed with CH2Cl2. Upon drying of the washed solids, 84.4 g. of 3-(5-chloro-2-hydroxybenzoyl) propionic acid, m.p. 178°-182° C., was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH:11]([CH2:14][CH2:15][C@H:16]3[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:17]3)[CH2:10][O:9]2)=[CH:4][C:3]=1[F:26].[C:27]([Cu])#[N:28]>CN1C(=O)CCC1>[C:27]([C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:13][CH2:12][C@H:11]([CH2:14][CH2:15][C@H:16]3[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:17]3)[CH2:10][O:9]2)=[CH:4][C:3]=1[F:26])#[N:28]
Reactant: CCCC[C@H]1CC[C@H](CCC2COC(c3ccc(Br)c(F)c3)OC2)CC1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: CCCC[C@H]1CC[C@H](CC[C@H]2CO[C@H](c3ccc(C#N)c(F)c3)OC2)CC1
Temperature: 25 °C

Procedure:
8.4 g (0.02 mol) of 2-(4'-bromo-3'-fluorophenyl)-5-[2'-(trans-4"-butylcyclohexyl)ethyl]-1,3-dioxane and 2.7 g (0.03 mol) of CuCN were refluxed in 100 cm3 of NMP for 2 hours. The product was cooled to room temperature and 4 cm3 of EDA was added. The solution was poured into 100 cm3 of ice water, extracted with hexane, and washed with an aqueous solution of EDA and water. The hexane was distilled off. The residue was treated through a silica gel column with chloroform as the solvent and the chloroform was distilled off. The residue was recrystallized from a solvent mixture of acetone and methanol to yield 3.1 g (0.008 mol) of trans-2-(4'-cyano-3'fluorophenyl)-5-[2'-(trans-4"-butylcyclohexyl)ethyl]-1,3-dioxane. The phase transition points of this compound, measured by DSC, were: ##STR49## wherein C is the crystal phase, N is the nematic phase, and I is the isotropic liquid phase.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[CH:3]1[OH:9].[H-].[Na+].[CH2:13]1OCCOCCOCCOCCOCCOC1.[N+:31]([C:34]([CH3:36])=[CH2:35])([O-:33])=[O:32]>C(#N)C.O1CCCC1>[N+:31]([C:34]([CH3:13])([CH3:36])[CH2:35][O:9][CH:3]1[C:4]([CH3:8])([CH3:7])[CH2:5][CH2:6][C:2]1([CH3:10])[CH3:1])([O-:33])=[O:32]
Reactant: C=C(C)[N+](=O)[O-]
Reactant: CC1(C)CCC(C)(C)C1O
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CC1(C)CCC(C)(C)C1OCC(C)(C)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,2,5,5-Tetramethyl-1-cyclopentanol is added to a dry flask under argon at 0° C. Dry tetrahydrofuran was added with a syringe. Sodium hydride (60% dispersion in oil) is added quickly in one portion and the contents of the flask are stirred for one hour at room temperature. A 10 mM solution of 18-crown-6-ether in acetonitrile is added with a syringe and the flask cooled to 0° C. A tetrahydrofuran solution of 2-nitropropene is added with vigorous stirring over a 10 minute period. After completion of the reaction, as judged by thin layer chromatography, it is quenched with dimethyl sulfate, poured into saturated ammonium chloride and extracted with ethyl acetate. The organic layer is dried over MgSO4 and evaporated to yield 1-(2-nitro-2-methylpropoxy)-2,2,5,5-tetramethylcyclopentane.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.CC(OC([N:30]1[CH2:35][CH2:34][N:33]([CH2:36][C:37]2[CH:38]=[C:39]([C:43]3[C:48]([F:49])=[CH:47][CH:46]=[C:45]([CH2:50][NH:51][S:52]([C:55]4[CH:56]=[C:57]([CH:61]=[CH:62][CH:63]=4)[C:58](O)=[O:59])(=[O:54])=[O:53])[CH:44]=3)[CH:40]=[CH:41][CH:42]=2)[CH2:32][CH2:31]1)=O)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:58](=[O:59])[C:57]3[CH:61]=[CH:62][CH:63]=[C:55]([S:52]([NH:51][CH2:50][C:45]4[CH:44]=[C:43]([C:39]5[CH:40]=[CH:41][CH:42]=[C:37]([CH2:36][N:33]6[CH2:34][CH2:35][NH:30][CH2:31][CH2:32]6)[CH:38]=5)[C:48]([F:49])=[CH:47][CH:46]=4)(=[O:54])=[O:53])[CH:56]=3)[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3cc(CNS(=O)(=O)c4cccc(C(=O)O)c4)ccc3F)c2)CC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(S(=O)(=O)NCc2ccc(F)c(-c3cccc(CN4CCNCC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 32.7 %

Procedure:
To a solution of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-amine (0.0195 g, 0.0641 mmol) in DCM (0.64 mL) was added 3-{[({3′-[(4-{[(1,1-dimethyl ethyl)oxy]carbonyl}-1-piperazinyl)methyl]-6-fluoro-3-biphenylyl}methyl)amino]sulfonyl}benzoic acid (0.0374 g, 0.0641 mmol), HBTU (0.0365 g, 0.0962 mmol), Et3N (0.018 mL, 0.128 mmol). The result mixture was stirred at room temperature for 21 h before it was concentrated and purified using a Gilson HPLC (w/TFA). The HPLC fraction was concentrated on a GeneVac EZ-2 evaporator at 45° C. (de-Boc completed during evaporation), basified with an amine cartridge to afford 0.0161 g (33%) of the title compound. LC-MS m/z 769 (M+H)+; 1H-NMR (400 MHz, MeOD) δ ppm 1.41 (t, J=7.30 Hz, 3 H) 1.49 (t, J=7.05 Hz, 3 H) 1.86 (q, J=9.90 Hz, 2 H) 2.09 (d, J=12.34 Hz, 2 H) 3.17 (q, J=7.39 Hz, 2 H) 3.46-3.59 (m, J=12.59 Hz, 8 H) 3.67 (t, J=11.33 Hz, 2 H) 4.04 (d, J=11.83 Hz, 2 H) 4.16 (s, 2 H) 4.30-4.39 (m, 1 H) 4.41 (s, 2 H) 4.48 (q, J=6.88 Hz, 2 H) 4.70 (s, 2 H) 7.04 (t, J=9.44 Hz, 1 H) 7.18-7.27 (m, 1 H) 7.34 (d, J=7.05 Hz, 1 H) 7.50-7.58 (m, 3 H) 7.60-7.68 (m, 2 H) 7.98 (d, J=7.55 Hz, 1 H) 8.08 (d, J=7.81 Hz, 1 H) 8.30 (d, J=13.60 Hz, 2 H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[C:22]=3[Cl:31])[CH:15]=[CH:16][C:17]=1[CH3:18])[N:5]=2.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:31][C:22]1[C:23]([C:27]([F:29])([F:28])[F:30])=[CH:24][CH:25]=[CH:26][C:21]=1[C:20]([NH:19][C:14]1[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:36]([CH:33]4[CH2:35][CH2:34]4)=[O:37])=[N:10][C:9]3=[CH:8][CH:7]=2)[CH:13]=1)=[O:32]
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2Cl)cc1Oc1ccc2nc(N)sc2n1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2Cl)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.4 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-methylphenyl}-2-chloro-3-(trifluoromethyl)benzamide (200 mg, 0.417 mmol) in pyridine (5 mL) was added cyclopropanecarbonyl chloride (57.4 μL, 0.835 mmol), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The residue was filtered through a pad filled with silica gel, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→70/30), and recrystallized from tetrahydrofuran to give the title compound (115 mg, 50%) as white crystals.
Reaction SMILES: [CH3:1][O:2]/[CH:3]=[CH:4]/[C:5]([OH:7])=O.O1CCCC1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:20][C:21]1[N:22]=[C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([CH3:46])=[C:34]([NH:36][C:37]([C:39]4[N:43]([CH3:44])[N:42]=[C:41]([CH3:45])[CH:40]=4)=[O:38])[CH:35]=3)=[N:25][N:24]2[CH:47]=1>CN(C)C=O.CN(C)C(=O)C>[CH3:1][O:2]/[CH:3]=[CH:4]/[C:5]([NH:20][C:21]1[N:22]=[C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([CH3:46])=[C:34]([NH:36][C:37]([C:39]4[N:43]([CH3:44])[N:42]=[C:41]([CH3:45])[CH:40]=4)=[O:38])[CH:35]=3)=[N:25][N:24]2[CH:47]=1)=[O:7]
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2C)n(C)n1
Reactant: CO/C=C/C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CO/C=C/C(=O)Nc1cn2nc(Oc3ccc(C)c(NC(=O)c4cc(C)nn4C)c3)ccc2n1
Yield: 28.4 %

Procedure:
In the same manner as in Example 279 and using (2E)-3-methoxyacrylic acid (99 mg, 0.97 mmol), tetrahydrofuran (1.5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (83 μL, 0.97 mmol), N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide hydrochloride (200 mg, 0.48 mmol) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (63 mg, 28%) was obtained as a white solid.
Reaction SMILES: [NH:1]([C:8]([NH:10][CH2:11][CH2:12][N:13]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[CH2:22][CH2:23][N:24](C(OC(C)(C)C)=O)[CH2:25][CH2:26][C:14]1=2)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C(O)=O)(F)(F)F.C(Cl)[Cl:42]>>[ClH:42].[C:2]1([NH:1][C:8]([NH:10][CH2:11][CH2:12][N:13]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]3[CH2:22][CH2:23][NH:24][CH2:25][CH2:26][C:14]2=3)=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCNC(=O)Nc3ccccc3)c3ccccc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=C(NCCn1c2c(c3ccccc31)CCNCC2)Nc1ccccc1
Reaction time: 0.75 h
Yield: 88 %

Procedure:
tert-Butyl 6-{2-[(anilinocarbonyl)amino]ethyl}-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.0390 g, 0.0869 mmol) was dissolved in CH2Cl2 (2 mL) at rt. CF3CO2H (1 mL) was added, then the reaction mixture was stirred for 45 min. The reaction mixture was concentrated and the residue was taken up in EtOAc (2 mL). 1 N HCl in Et2O (2 mL) was added and the precipitated salt was collected by filtration. N-Phenyl-N′-[2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethyl]urea hydrochloride (0.0296 g) was obtained in 88% yield. 1H NMR (300 MHz, CD3OD) δ 3.19-3.22, 3.35-3.38, 3.43-3.53, 4.35, 6.97-7.03, 7.07, 7.17, 7.25-7.27, 7.44, 7.48; MS (ESI+) for C21H24N4O m/z 349.2 (M+H)+.
Reaction SMILES: C(Cl)(Cl)Cl.[Cl:5][C:6]1([CH:20]=[CH:19]N=[C:17]([CH:21]([OH:29])[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:16]1)C(NC1C=CC=CC=1)=O.C([N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])C.P(Br)(Br)Br>O>[Cl:5][C:6]1[CH:20]=[CH:19][C:35]2[N:32]=[C:33]([C:34]3[CH:34]=[CH:33][N:32]=[CH:35][CH:36]=3)[O:29][CH:21]([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)[C:17]=2[CH:16]=1
Reactant: O=C(Nc1ccccc1)C1(Cl)C=CN=C(C(O)c2ccc(Cl)cc2)C1
Reactant: CCN(CC)CC
Agent: BrP(Br)Br
Solvent: O
Solvent: ClC(Cl)Cl
Product: Clc1ccc(C2OC(c3ccncc3)=Nc3ccc(Cl)cc32)cc1
Reaction time: 1 h
Yield: 85 %

Procedure:
To chloroform (300 ml), 4-chloro-2-(4-chloro-α-hydroxybenzyl)-isonicotinanilide (12.4 g) and triethylamine (5.0 ml) were added. With stirring and under cooling with ice, phosphorus tribromide (9.1 g) was added slowly, and the stirring was continued for 1 hour. Following another 3-hour stirring at room temperature, the reaction mixture was poured into water. The chloroform layer was thoroughly washed with water and subsequently dried. The chloroform was completely distilled off under vacuum. Upon recrystallization from a mixed solvent of ethyl acetate and n-hexane, the titled compound was obtained in an amount of 10.1 g (yield: 85%). m.p. 140°-141° C.
Reaction SMILES: C([O:3][P:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])C.[NH2:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14].[CH:19](=O)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)(=O)C>[CH2:9]([O:8][P:4]([O:5][CH2:6][CH3:7])([CH:19]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:3])[CH3:10]
Reactant: CCOP(OCC)OCC
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: O=CCCc1ccccc1
Solvent: CC(=O)O
Product: CCOP(=O)(OCC)C(CCc1ccccc1)N[C@H](C(=O)O)C(C)C

Procedure:
Triethylphosphite (7.09 g, 42.7 mmol), L-valine (5 g, 42.7 mmol) and hydrocinnamaldehyde (5.73 g, 42.7 mmol) are heated in acetic acid (15 mL) at 80° C. for 4 h. After evaporating the solvent, the solid is dissolved in 5% sodium bicarbonate solution, washed with ether and acidified to pH =4. The aqueous mixture is extracted with ethyl acetate, dried and evaporated to afford the title compound.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]1([N:8]([CH3:10])[CH3:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.[Cl:17][C:18]1[CH:26]=[C:25]([S:27][CH3:28])[C:21]([C:22](O)=[O:23])=[C:20]([CH3:29])[CH:19]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[Cl:17][C:18]1[CH:26]=[C:25]([S:27][CH3:28])[C:21]([C:22]([NH:1][CH:2]([C:3]2([N:8]([CH3:10])[CH3:9])[CH2:7][CH2:6][CH2:5][CH2:4]2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:23])=[C:20]([CH3:29])[CH:19]=1
Reactant: CN(C)C1(C(N)c2ccccc2)CCCC1
Reactant: CSc1cc(Cl)cc(C)c1C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CSc1cc(Cl)cc(C)c1C(=O)NC(c1ccccc1)C1(N(C)C)CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
A mixture of {1-[amino(phenyl)methyl]cyclopentyl}dimethylamine D3 enantiomer 2 (203 mg; 0.93 mmol), 4-chloro-2-methyl-6-(methylthio)benzoic acid (obtainable as described in F. P. Doyle, J. H. C. Nayler, H. R. J. Waddington, J. C. Hanson and G. R. Thomas. J. Chem. Soc. 1963, 497) (202 mg; 0.93 mmol), EDC (178 mg; 0.93 mmol) and HOBt (143 mg; 0.93 mmol) in DCM (20 ml) was stirred at room temperature for 4 h and then stood at room temperature for 90 h. The resulting reaction mixture was washed with saturated aqueous sodium bicarbonate (50 ml) and the organic layer separated by passage through a phase separation cartridge. The organic layer was evaporated, the residue dissolved in a minimum of DCM and chromatographed on silica gel, eluting with 0-100% ethyl acetate-pentane. The fractions were combined and evaporated under reduced pressure to afford the title compound (200 mg; 52%). 1H NMR (CDCl3) δ: 0.90-1.10 (1H, m), 1.38-1.55 (3H, m), 1.60-1.76 (2H, m), 1.80-1.90 (2H, m), 2.21 (6H, s), 2.26 (3H, s), 2.47 (3H, s), 5.11 (1H, d, J=6 Hz), 6.94 (1H, d, J=5.2 Hz), 7.00 (1H, m), 7.09 (1H, m), 7.20-7.35 (3H, m), 7.40-7.50 (2H, m). Mass spectrum (Electrospray LC/MS), ES+: Found 417 (MH+). C23H2935ClN2OS requires 416. Ret. time 2.03 min. The title product was converted to its corresponding hydrochloride salt (210 mg).