Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C@H:21]([C:24]2[CH:25]=[C:26]3[C:35](=[CH:36][C:37]=2Br)[O:34][CH2:33][C:32]2[N:27]3[C@H:28]([CH3:40])[C:29](=[O:39])[NH:30][N:31]=2)[C@H:20]([CH3:41])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C@H:21]([C:24]2[CH:25]=[C:26]3[C:35](=[CH:36][C:37]=2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[O:34][CH2:33][C:32]2[N:27]3[C@H:28]([CH3:40])[C:29](=[O:39])[NH:30][N:31]=2)[C@H:20]([CH3:41])[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1cc2c(cc1Br)OCC1=NNC(=O)[C@@H](C)N12
Reactant: OB(O)c1ccccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1cc2c(cc1-c1ccccc1F)OCC1=NNC(=O)[C@@H](C)N12
Temperature: 90 °C
Yield: 77.8 %

Procedure:
To a mixture of (2-fluorophenyl)boronic acid (0.019 g, 0.137 mmol), (3S,4S)-4-((R)-7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (0.045 g, 0.091 mmol) and K2CO3 (0.025 g, 0.182 mmol) in dioxane (12 mL) and water (2 mL) was added PdCl2(dppf)-CH2Cl2 adduct (7.45 mg, 9.12 μmol) and the reaction mixture was heated at 90° C. overnight. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by prep-TLC (eluting with 55% EtOAc in petroleum ether) to give (3S,4S)-4-[(R)-7-(2-fluoro-phenyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (0.036 g, 78%) as a white solid. 1H NMR (400 MHz, MeOD) δ 7.48-7.37 (m, 1H), 7.29-7.14 (m, 3H), 6.91 (s, 1H), 6.81 (s, 1H), 4.93 (m, 1H), 4.63-4.58 (m, 2H), 4.23 (m, 1H), 3.81 (m, 1H), 3.03-2.86 (m, 1H), 2.79-2.42 (m, 3H), 2.34-2.11 (m, 2H), 1.50-1.41 (m, 14H), 0.75 (m, 3H). LC/MS (Table 1, Method 4) Rt=2.830 min.; MS m/z: 531 [M+Na]+& 453 [M+H−56]+. SFC (Table 1, Method 46), Rt=6.84 min.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[O:6][CH:7]=[CH:8][C:9]=1[SH:10].Cl[CH2:12][CH:13]=[CH:14][CH3:15].ClC(C)C=C>CO>[CH2:12]([S:10][C:9]1[CH:8]=[CH:7][O:6][C:5]=1[CH3:4])[CH:13]=[CH:14][CH3:15]
Reactant: Cc1occc1S
Reactant: CC=CCCl
Agent: C=CC(C)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC=CCSc1ccoc1C
Temperature: 33 °C
Reaction time: 0.17 h

Procedure:
Into a 50 ml round bottom 1 neck flask equipped with nitrogen inlet tube, Y tube, reflux condenser, magnetic stirrer, and cold water bath is placed a solution containing 0.54 g of sodium methylate (0.01 moles) in 6 ml of anhydrous methanol. 1.14 g (0.01 moles) of 2-methyl-3-furan thiol in 6 ml of anhydrous methanol is then added to the sodium methylate solution. The reaction mass is stirred for a period of 10 minutes, with cooling, maintaining the temperature thereof between 24° and 30° C. 0.91 g (0.01 moles) of a mixture of 80% 1-chloro-2-butene and 20% 3-chloro-1-butene dissolved in 2 ml of anhydrous methanol is then added over a 4 minute period warming to 33° C. The reaction mass is allowed to cool to 23° C and remains at that temperature, with stirring, for a period of 2.5 hours, at which time it is concentrated to 7 ml on a rotary evaporator using water aspirator vacuum. 20 ml water is then added and the reaction mass is neutralized to a pH of 5 - 6 using 4% hydrochloric acid. The reaction mass is extracted with three 10 ml portions of n-hexane. The hexane extracts are combined, washed with 2 ml saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated using a rotary evaporator to yield 1.24 g of a yellow oil.
Reaction SMILES: [OH-].[K+].[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:47]([O:49]C)=[O:48])=[CH:14][C:15]=3[N:16]3[C:22]=2[C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[O:19][CH:18]([CH2:27][N:28]([CH3:46])[CH2:29][CH2:30][N:31]([CH3:45])[CH2:32][CH2:33][S:34](=[O:44])(=[O:43])[NH:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:17]3)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl>C1COCC1.CCOCC>[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:47]([OH:49])=[O:48])=[CH:14][C:15]=3[N:16]3[C:22]=2[C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[O:19][CH:18]([CH2:27][N:28]([CH3:46])[CH2:29][CH2:30][N:31]([CH3:45])[CH2:32][CH2:33][S:34](=[O:44])(=[O:43])[NH:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:17]3)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CN(C)CCN(C)CCS(=O)(=O)NCc1ccccc1)Oc1ccccc1-3
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(CCN(C)CC1Cn2c(c(C3CCCCC3)c3ccc(C(=O)O)cc32)-c2ccccc2O1)CCS(=O)(=O)NCc1ccccc1
Temperature: 60 °C

Procedure:
KOH (5.0 eq.) was added to a solution of methyl 13-cyclohexyl-6-(2,5-dimethyl-8,8-dioxido-10-phenyl-8-thia-2,5,9-triazadec-1-yl)-6,7-dihydroindolo[1,2-d][1,4]benzoxazepine-10-carboxylate (0.02 M) in dioxane/H2O (1/1). The reaction was heated at 60° C. for 4.5 h. The reaction was allowed to cool to RT and acidified with 1N HCl (aq), the mixture was extracted two times with DCM. The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford the product (quant.). (ES+) m/z 659 (M+H)+.
Reaction SMILES: [CH2:1]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(N(CC)CC)C.[CH3:24][C:25]([CH3:32])([CH2:29][CH2:30][CH3:31])[C:26](Cl)=[O:27].Cl>C(OCC)C>[F:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[CH2:8][N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:26](=[O:27])[C:25]([CH3:32])([CH3:24])[CH2:29][CH2:30][CH3:31]
Reactant: CCCC(C)(C)C(=O)Cl
Reactant: CCCCCCNCc1ccc(F)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCCN(Cc1ccc(F)cc1F)C(=O)C(C)(C)CCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
22.7 g (0.10 mol) of N-hexyl-2,4-difluorobenzylamine and 24.3 g (0.24 mol) of triethylamine are dissolved in 150 ml of diethyl ether. A solution of 17.8 g (0.12 mol) of 2,2-dimethylpentanoyl chloride in 50 ml of diethyl ether is added dropwise at room temperature over the course of 30 minutes. The mixture is stirred for a further 18 hours at room temperature until the reaction is complete (GC check). For work-up, the resultant suspension is adjusted to pH 7 using 70 ml of 2N hydrochloric acid. Everything dissolves, and two phases form, which are separated. The organic phase is washed with 50 ml of water, dried using magnesium sulfate, filtered and evaporated on a vacuum rotary evaporator. 37.8 g of a pale yellow liquid, which is subjected to fractional distillation, are obtained. 21.4 g (63% of theory) of a colourless oil which boils at 126°-127° C. and 0.4 mbar are obtained.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15](F)[CH:14]=1.C(N(CC)C(C)C)(C)C>>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([NH:1][CH:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:3][CH2:4][OH:5])[CH:14]=1
Reactant: NC(CCO)c1ccccc1
Reactant: N#Cc1ccc(Cl)cc1F
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(Cl)cc1NC(CCO)c1ccccc1
Temperature: 140 °C
Yield: 59.9 %

Procedure:
A mixture of 3-amino-3-phenyl-1-propanol (1 g, 6.6 mmol), 4-chloro-2-fluorobenzonitrile (1 g, 6.4 mmol) and N,N-diisopropylethylamine (1.2 ml, 6.9 mmol) was stirred and heated at 140° C. for 5 h. The crude reaction mixture was cooled and purified on silica gel (ether/isohexane 1:4). The product was isolated as a colourless solid (1.1 g, 58%), m.p. 88-90° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[CH:8][N:7]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]=2[CH:5]=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[C:18]1([CH:11]([N:7]2[C:6]3[CH:5]=[C:4]([C:24]([F:26])([F:27])[F:25])[CH:3]=[CH:2][C:10]=3[N:9]=[CH:8]2)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C=C(c1ccccc1)n1cnc2c(Br)cc(C(F)(F)F)cc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(C(F)(F)F)cc21
Temperature: 25 °C

Procedure:
To a solution of ethyl 3-[4-bromo-6-(trifluoromethyl)-1H-benzimidazol-1-yl]-3-phenyl-2-propenoate (111 mg, 253 μmol) in ethanol (4 mL) was added palladium on carbon (23 mg, 10% w/w Pd) and ammonium formate (159 mg, 2.52 mmol). The suspension was heated to reflux for 3 hours, then cooled to room temperature, and filtered through a pad of Celite®. The filtrate was evaporated in vacuo to afford the title compound, 1H NMR: (CDCl3), 8.10 (s, 1H), 7.79 (d, J=8.79, 1H), 7.49 (s, 1H), 7.42 (d, H=8.79, 1H), 7.31-7.23 (m, 3H), 7.18-7.14 (m, 2H), 6.00 (dd, J=6.96, 6.96, 1H), 3.98 (q, J=7.32, 2H), 3.36-3.25 (m, 2H), 1.03 (t, J=7.32, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:12])[O:10][CH3:11])=[C:6]([NH2:13])[N:5]=[C:4]([C:14]2[N:18]=[C:17]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)[N:16]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[N:15]=2)[N:3]=1.[H-].[Na+].I[CH3:35].O>CN(C=O)C.CC#N.CO.C(Cl)Cl>[NH2:1][C:2]1[C:7]([N:8]([CH3:35])[C:9](=[O:12])[O:10][CH3:11])=[C:6]([NH2:13])[N:5]=[C:4]([C:14]2[N:18]=[C:17]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)[N:16]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[N:15]=2)[N:3]=1
Reactant: COC(=O)Nc1c(N)nc(-c2nc(-c3nccs3)n(Cc3ccccc3F)n2)nc1N
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: COC(=O)N(C)c1c(N)nc(-c2nc(-c3nccs3)n(Cc3ccccc3F)n2)nc1N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
A suspension of methyl 4,6-diamino-2-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)pyrimidin-5-ylcarbamate (I-60, 0.16 mmol) in DMF (3.0 mL) at 0° C. was treated with sodium hydride (1.1 equiv). After 15 min, the reaction mixture was warmed to ambient temperature and stirred for 15 min. The reaction was cooled to 0° C. and iodomethane (1.1 equiv) was added. The resultant mixture was brought to ambient temperature and stirred for 20 min. Water was added and the aqueous mixture was extracted with EtOAc and iPrOH/CH2Cl2 (1:4). The organic phases were dried over Na2SO4, filtered, conc. and purified using SiO2 chromatography and an appropriate gradient (CH3CN/MeOH/CH2Cl2) to afford methyl 4,6-diamino-2-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)pyrimidin-5-yl(methyl)carbamate as an off-white solid (81% yield).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([OH:20])[C:9]2[C:17]3[C:16]([O:18][CH3:19])=[N:15][CH:14]=[N:13][C:12]=3[NH:11][CH:10]=2)=[C:6]([F:21])[CH:5]=[CH:4][C:3]=1[NH:22][S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24].C(=O)(O)[O-].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C.O.O1CCCC1>[F:1][C:2]1[C:7]([C:8]([C:9]2[C:17]3[C:16]([O:18][CH3:19])=[N:15][CH:14]=[N:13][C:12]=3[NH:11][CH:10]=2)=[O:20])=[C:6]([F:21])[CH:5]=[CH:4][C:3]=1[NH:22][S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncnc(OC)c23)c1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncnc(OC)c23)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
To propane-1-sulfonic acid {2,4-difluoro-3-[hydroxy-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methyl]-phenyl}-amide (P-0057, 0.176 g, 0.427 mmol), 9.2 mL of tetrahydrofuran was added followed by sodium bicarbonate (0.358 g, 4.27 mmol) and Dess-Martin periodinane (0.181 g, 0.427 mmol). The reaction was allowed to stir at room temperature for 30 minutes, then 25 mL of saturated sodium thiosulfate and 30 mL of water were added followed by 50 mL of ethyl acetate. The organic layer was dried with magnesium sulfate, filtered, and the filtrate concentrated under vacuum. The resulting residue was purified by silica gel column chromatography eluting with a gradient of 20-60% ethyl acetate in hexanes. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (P-0058, 146 mg). 1H NMR was consistent with the compound structure. MS(ESI) [M+H+]−=411.1.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C1C[O:23][CH2:22][CH2:21]1>>[F:13][C:14]1[C:19]([C:22](=[O:23])[CH3:21])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: C1CCOC1
Reactant: Fc1ccccn1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: CC(=O)c1cccnc1F
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of 3.13 mL (30.90 mmol) of freshly distilled diisopropylamine in 10 mL of anhydrous THF under nitrogen cooled to −78° C. was treated dropwise with 19.31 mL (30.90 mmol) of a 1.6 M solution of n-BuLi in hexanes. The resulting solution was stirred at −78° C. for approximately 20 minutes, and was briefly (5-10 minutes) warmed to −40° C., then recooled to −78° C. At 30 minutes post addition, 3.00 g (30.90 mmol) of 2-fluoropyridine was added dropwise to the reaction. The resulting solution was stirred at −78° C. for 30 minutes. The reaction was treated dropwise with a solution of 3.16 mL (30.90 mmol) of the Weinreb amide (i.e., N-methoxy-n-methylacetamide) in 30 mL of THF. The resulting solution was stirred 18 hours, allowing the bath to slowly evaporate and the reaction temperature to rise to room temperature. The reaction was treated with 5 mL of 1N HCl, and was concentrated to remove most of the THF. The residue was extracted twice with EtOAc, and the combined extracts were washed with 1N HCl, saturated aqueous NaHCO3 solution, and brine, and were dried over anhydrous MgSO4. Filtration and concentration of the filtrate provided a crude orange oil, which was purified by flash chromatography over silica gel with 3:1 hexanes/EtOAc to provide 1.10 g of the title product as an orange oil. 1H NMR (CDCl3): δ 2.72 (s, 3H), 7.33 (m, 1H), 8.34 (m, 1H), 8.41 (m, 1H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[F:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([F:18])[CH:11]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([F:18])[C:11]=1[C:5](=[O:7])[CH3:6]
Reactant: COc1cc(F)cc(F)c1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(F)c(C(C)=O)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
A mixture of aluminium chloride (10.0 g, 69.4 mmol, 5.0 equiv) and acetyl chloride (2.0 mL, 28 mmol, 2.0 equiv) in CH2Cl2 (50.0 mL) was stirred at 0° C. for 30 min. The reaction mixture was slowly added with 1,3-difluoro-5-methoxy-benzene (2.0 g, 13.9 mmol, 1.0 equiv) in CH2Cl2 (10.0 mL), and the resultant solution was stirred at room temperature for additional 2.0 h. The solution was basified with saturated aqueous NaHCO3 (20 mL) to pH 8-9. The organic layer was separated, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (15% EtOAc in hexanes as eluant) at give 1-(2,6-difluoro-4-methoxyphenyl)ethanone (1.5 g, 8.1 mmol) as yellow oil in 58% yield: 1H NMR (CDCl3, 500 MHz) δ 6.46-6.48 (m, 2H), 3.83 (s, 3H), 2.56 (s, 3H); ESI-MS: m/z 187.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:37])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].F[C:40]1[CH:47]=[CH:46][C:43]([C:44]#[N:45])=[CH:42][CH:41]=1>>[C:1]([O:5][C:6](=[O:38])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:37])[C:16]2[CH:17]=[C:18]([O:23][C:24]3[CH:25]=[CH:26][C:27]([CH2:30][NH:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:28][CH:29]=3)[CH:19]=[C:20]([O:22][C:40]3[CH:47]=[CH:46][C:43]([C:44]#[N:45])=[CH:42][CH:41]=3)[CH:21]=2)[CH2:10][CH2:9]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: N#Cc1ccc(F)cc1
Reactant: CCOC(=O)NCc1ccc(Oc2cc(O)cc(C(=O)NC3CCC(NC(=O)OC(C)(C)C)CC3)c2)cc1
Product: CCOC(=O)NCc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)NC3CCC(NC(=O)OC(C)(C)C)CC3)c2)cc1
Yield: 91.5 %

Procedure:
Using 0.56 g (1.06 mmol) of (4-{3-[4-(Ethoxycarbonylamino-methyl)-phenoxy]-5-hydroxy-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester and 4-fluoro-benzonitrile (0.32 g, 2.65 mmol) and following the procedure of Example 42(b) afforded 0.61 g of the required product. Percentage purity (LCMS): 45.2%, (M+1)=628.3+1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])=[O:10])[CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:21][O:22][C:23]([N:25]=[C:26]=S)=[O:24].C1CCC(N=C=NC2CCCCC2)CC1>C(#N)C.C1C=CC=CC=1>[CH3:21][O:22][C:23]([NH:25][C:26]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([C:9]([C:11]3[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=3[C:13]([O:15][CH3:16])=[O:14])=[O:10])=[CH:3][C:2]=2[N:1]=1)=[O:24]
Reactant: COC(=O)c1ccccc1C(=O)c1ccc(N)c(N)c1
Reactant: COC(=O)N=C=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Solvent: c1ccccc1
Product: COC(=O)Nc1nc2cc(C(=O)c3ccccc3C(=O)OC)ccc2[nH]1
Temperature: 25 °C
Yield: 70.8 %

Procedure:
To a solution of methyl 2-[(3,4-diaminophenyl)carbonyl]benzoate (134 mg, 0.50 mmol) in a mixture of acetonitrile-benzene (1:1, 5 mL) methyl isothiocyanatidocarbonate (70 mg, 0.60 mmol) was added followed by the addition of DCC (153 mg, 0.75 mmol) and the reaction mixture was heated to reflux for 18 h. After cooling to room temperature the reaction mixture was concentrated. The residue was triturated with diethyl ether (2×, 10 mL) and the pale orange solid was collected by filtration to give methyl 2-[(2-{[(methoxy)carbonyl]amino}-1H-benzimidazol-5-yl)carbonyl]benzoate (125 mg, 71%). MS (EI) for C18H15N3O5: 354 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:52])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C@@H:16]([CH2:47][C:48]([NH:50][NH2:51])=[O:49])[CH2:15]2)=[CH:10][CH:9]=1.CO[CH:55](OC)[N:56]([CH3:58])[CH3:57]>C(Cl)Cl>[CH3:55][N:56]([CH3:58])/[CH:57]=[N:51]/[NH:50][C:48](=[O:49])[CH2:47][C@H:16]1[CH2:15][C@H:14]([C:11]2[CH:10]=[CH:9][C:8]([CH2:7][O:6][CH2:5][C@@H:4]([CH3:52])[CH2:3][O:2][CH3:1])=[CH:13][CH:12]=2)[C@@H:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=3[CH:36]=2)[CH2:18][N:17]1[S:37]([C:40]1[CH:41]=[CH:42][C:43]([CH3:46])=[CH:44][CH:45]=1)(=[O:38])=[O:39]
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)NN)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Reactant: COC(OC)N(C)C
Solvent: ClCCl
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)N/N=C/N(C)C)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Temperature: 25 °C

Procedure:
A solution of 1 mmol of [(2R,4R,5R)-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-acetic acid hydrazide in 5 ml of CH2Cl2 is treated at RT with 1.1 mmol of N,N-dimethylformamide dimethylacetal and refluxed for 1 h. The mixture is cooled to RT, and concentrated under reduced pressure to afford the title compound as a viscous brown-orange oil. Rt=4.75 (gradient I).
Reaction SMILES: Cl.[CH3:2][NH2:3].C[Al](C)C.[NH2:8][C:9]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[S:11][C:10]=1[C:18]([O:20]C)=O.Cl.[OH-].[K+]>C1(C)C=CC=CC=1>[CH3:2][NH:3][C:18]([C:10]1[S:11][C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:13][C:9]=1[NH2:8])=[O:20]
Reactant: COC(=O)c1sc(C(C)(C)C)cc1N
Reactant: CN
Agent: C[Al](C)C
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: CNC(=O)c1sc(C(C)(C)C)cc1N
Temperature: 0 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A slurry of methylamine hydrochloride (9.51 g, 141 mmol, 3.1 equiv) in anh. toluene (600 mL) at 0° C. was treated with AlMe3 (2M in toluene, 70 mL, 141 mmol, 3.1 equiv) over 10 min. The resulting solution was stirred at 0° C. for 1 h then allowed to warm to room temp. and stirred for 40 min. Methyl 3-amino-5-tert-butylthiophene-2-carboxylate (9.87 g, 46 mmol) was added to the aluminum amide solution. The resulting mixture was heated at the reflux temp. for 3 d, cooled to 0° C., and a 6N HCl solution was added dropwise. The quenched mixture was made basic with a 20% KOH solution (95 mL). The resulting slurry was partitioned between H2O (300 mL) and EtOAc (300 mL) and the aqueous layer was extracted with EtOAc (3×300 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to afford N-methyl-3-amino-5-tert-butylthiophene-2-carboxamide as a green-yellow solid (9.47 g, 97%): mp 230-1° C.; TLC (20% EtOAc/CH2Cl2) Rf0.23; 1H NMR (d6-DMSO) δ1.28 (s, 9H), 2.63 (d, J=4.8 Hz, 3H), 6.29 (br s, 2H), 6.37 (d, J=1.1 Hz, 1H), 7.22 (q, J=4.0 Hz, 1H).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]3[C:21](=[O:22])[CH2:20][S:19][C:18]3=[O:23])(=[O:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:24](=O)[CH2:25][CH2:26][CH3:27].N1CCCCC1>C(O)C>[CH:24](=[C:20]1[S:19][C:18](=[O:23])[N:17]([CH2:16][CH2:15][CH2:14][CH2:13][S:10]([C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)(=[O:12])=[O:11])[C:21]1=[O:22])[CH2:25][CH2:26][CH3:27]
Reactant: O=C1CSC(=O)N1CCCCS(=O)(=O)c1cccc2nccn12
Reactant: CCCC=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCC=C1SC(=O)N(CCCCS(=O)(=O)c2cccc3nccn23)C1=O

Procedure:
To a solution of 0.22 g (0.62 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylsulfonyl)butyl]thiazolidine-2,4-dione and 0.10 ml (1.1 mmol) of n-butyraldehyde in 5 ml of ethanol, 0.01 ml (0.1 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4) to yield 0.269 g (quant., yellow oily substance) of the desired product.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[N:12][C@@H](C)CSC)[O:5][C:6]2=[O:11].FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)CC1[N:29]=C(C)C(N)=CC=1>C(#N)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:6]([NH2:29])(=[O:11])[C:7]1[C:3](=[CH:2][CH:10]=[CH:9][CH:8]=1)[C:4]([NH2:12])=[O:5]
Reactant: CSC[C@H](C)N=C1OC(=O)c2cccc(Cl)c21
Reactant: Cc1nc(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: NC(=O)c1ccccc1C(N)=O
Temperature: 60 °C
Reaction time: 20 h
Yield: 194.4 %

Procedure:
4-Chloro-3-[(S)-1-methyl-2-methylthioethylimino]-3-H-isobenzofuran-1-one (0.2 g) and 6-(3,5-bis-trifluoromethyl-benzyl)-2-methyl-pyridin-3-ylamine (0.22 g) were dissolved in acetonitrile (10 ml), to which p-toluenesulfonic acid hydrate (0.01 g) was added, and stirred at 60° C. for 20 hours. After the reaction, the solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography to obtain N1-[6-3,5-bis-trifluoromethyl-benzyl)-2-methyl-pyridin-3-yl]-3-chloro-N2-(S)-1-methyl-2-methylhioethyl)phthalamide (0.21 g).