Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21]CC2CC2)[CH:12]=1)[OH:10].Cl.[OH-].[Na+]>O>[Cl:26][C:6]1[CH:5]=[N+:4]([O-:27])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([OH:21])[CH:12]=1)[OH:10]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(O)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
(S)-3,5-Dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (5 g, 11.90 mmol) was added to 100 mL of 37% HCl and stirred at room temperature for about 3 min., obtaining a yellow solution. After stirring for further 3 min. the solution was poured into a solution of NaOH (48 g) in water (500 mL). The red solution was added with 1 M HCl to pH 1. The brown solid was filtered, washed with water and triturated with hot EtOH (50 mL). After stirring at r.t. for 1 h the solid was filtered, washed with EtOH and dried under vacuum at 40 C yielding 2.4 of the title compound.
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:17])=[C:7]([CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[H][H].O>CN(C)C=O>[C:1]([C:5]1[C:6]([O:17][CH2:2][CH2:1][CH2:5][CH3:12])=[C:7]([CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C=O)c(O)c(C(C)(C)C)c1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1c(C=O)cc(C(C)(C)C)cc1C(C)(C)C
Temperature: 85 °C
Yield: 217.8 %

Procedure:
4.0 g of 3,5-di-tert.-butyl-2-hydroxybenzaldehyde (CAS # 37942-07-7) was dissolved in dimethylformamide (DMF). This was treated with 0.89 g of sodium hydride (50% in oil suspension) and stirred at 25° C. until hydrogen was no longer evolved. To this was added 2.01 ml n-bromobutane and the mixture was heated to 85° C. for 14 hr. This was cooled and poured into water. The aqueous was extracted with ether. The ether layer was washed with water, dried (MgSO4), and solvent was removed. Purification was accomplished by florsil column chromatography (15% ether/hexane) to give 5.4 g of 3,5-di-tert.-butyl-2-butyloxybenzaldehyde; 1H NMR (CDCl3) δ 10.31 (s, 1H,aldehyde), 7.70 (dd,4H,aromatics), 3.94 (t,2H,—OCH2—).
Reaction SMILES: [C:1]1([N:7]2[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:10](=[O:17])[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>ClCCl>[O:17]=[C:10]1[C:11]2([CH2:12][CH2:13][N:14]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[CH2:15][CH2:16]2)[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][NH:9]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OCc1ccccc1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.1 %

Procedure:
A solution of 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (10 g, 43.23 mmol, 1 equiv) in dichloromethane was treated with pyridine (6.99 ml, 86.46 mmol, 2 equiv) at 0° C. This was followed by the slow addition of benzyl chloroformate (6.39 ml, 45.4 mmol, 1.05 equiv). The reaction was stirred at ambient temperature for 16 h. The mixture was partitioned between dichloromethane and 10% citric acid followed by washes with water and brine. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to afford benzyl 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate as an off-white powder (12.5 g, 79%); MS for C21H23N3O3 m/z 366.18 (M+H)+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:14]([NH:16][CH2:17][CH2:18][O:19][CH3:20])[CH3:15].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:14]([N:16]([CH2:17][CH2:18][O:19][CH3:20])[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:15]
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Reactant: CCNCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCN(CCOC)c1ccc(C(F)(F)F)cc1C=O
Temperature: 120 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
2-Fluoro-5-trifluoromethyl-benzaldehyde (2.7 g) and ethyl-(2-methoxy-ethyl)-amine (2.18 g) are dissolved in toluene (20 ml), and thereto is added potassium carbonate (5.83 g) and the mixture is stirred at 120° C. overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and a saturated brine and the mixture is separated, and the organic layer is washed with a saturated brine, and the mixture is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give 2-[ethyl-(2-methoxy-ethyl)-amino]-5-trifluoromethyl-benzaldehyde (3.75 g). MS (m/z): 276 [M+H]+
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([CH2:15]Br)=[CH:10][CH:11]=2)[N:6]=1)(=[O:3])[CH3:2].[C-:17]#[N:18].[Na+]>CN(C=O)C>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([CH2:15][C:17]#[N:18])=[CH:10][CH:11]=2)[N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2ccc(CBr)cc2n1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc2ccc(CC#N)cc2n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 62.6 %

Procedure:
Compound 21 (0.216 g, 0.773 mmol) was diluted with anhydrous DMF (10 mL), and NaCN (0.190 g, 3.87 mmol) was added. The orange mixture was stirred at room temperature for 17 h. The mixture was concentrated and partitioned between EtOAc and H2O (50 mL each), and the layers were separated. The aqueous phase was extracted with EtOAc (2×50 mL), the combined organic layers were washed with H2O (2×80 mL) and sat aq. NaCl (50 mL) and dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography (SiO2), eluting with a gradient of 15% EtOAc in CH2Cl2 to 25% EtOAc in CH2Cl2 to yield the title compound as a white solid (0.109 g, 63%): mp 180-182° C. 1H-NMR (500 MHz; CDCl3): δ 8.44 (dd, J=8.3, 0.4 Hz, 1 H), 8.27-8.22 (m, 1 H), 8.18 (d, J=9.0 Hz, 1 H), 7.81 (d, J=8.4 Hz, 1 H), 7.79 (s, 1 H), 7.40 (dd, J=8.3, 1.7 Hz, 1 H), 3.94 (s, 2 H), 2.28 (s, 3 H); 13C-NMR (126 MHz; CDCl3): δ 169.2 (1 C), 151.5 (1 C), 138.8 (1 C), 132.1 (1 C), 128.7 (1 C), 126.2 (1 C), 125.6 (1 C), 124.9 (1 C), 117.3 (1 C), 114.7 (1 C), 25.1 (1 C), 24.0 (1 C); ESIMS m/z (rel. intensity) 473 (2M+Na+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].[Cl:24][CH2:25][C:26](Cl)=[O:27].Cl>CC(C)=O>[Cl:24][CH2:25][C:26]([NH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]#[N:6])=[O:27]
Reactant: N#Cc1ccc(OCc2ccccc2)c(N)c1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(OCc2ccccc2)c(NC(=O)CCl)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
A slurry of 3-amino-4-(benzyloxy)benzonitrile (7 g, 31.2 mmol) and anhydrous potassium carbonate (8.6 g, 62.4 mmol) in 50 mL of acetone was stirred under nitrogen as chloroacetylchloride (2.6 mL, 33 mmol) was added portion-wise. The reaction was stirred overnight. The reaction was poured into ice water and the liquid was neutralized with 6 N hydrochloric acid. The resulting solid was isolated by filtration, washed with water, and dried under reduced pressure to give 3-((chloromethyl)carbonylamino)-4-(benzyloxy)benzonitrile (8.3 g) as a white solid; NMR (CDCl3, TMS) δ4.22 (s, 2), 5.23 (s, 2), 7.03 (d, 1), 7.43 (m, 7), 8.73 (d, 1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4](O)([C:19]([F:22])([F:21])[F:20])[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[NH:7][C:6]=1[CH3:18].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:24])[C:4](=[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[N:7]=[C:6]1[CH3:18])[C:19]([F:21])([F:20])[F:22]
Reactant: COC(=O)C(O)(c1c(C)[nH]n(-c2ccc(Cl)cc2)c1=O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)C(=C1C(=O)N(c2ccc(Cl)cc2)N=C1C)C(F)(F)F

Procedure:
To a toluene solution (5 ml) of 1-(4-chlorophenyl)-2,5-dihydro-α-hydroxy-3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester (182 mg, 0.5 mmol), thionyl chloride (0.365 ml, 5.0 mmol) was added and the mixture was stirred under reflux for 3 hours. After concentrating the liquid reaction mixture under reduced pressure, the title compound was obtained as a reddish brown solid (173 mg).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:22])[NH:9]2)(=[O:3])[CH3:2].[Cl:23]CCCl>C(O)(=O)C.O.C(=O)(O)[O-].[Na+].S(=O)(O)[O-].[Na+]>[CH2:15]([O:14][C:12]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:22])[NH:9]2)=[C:4]([C:1](=[O:3])[CH2:2][Cl:23])[CH:13]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCCCl
Reactant: CC(=O)c1cc(OCc2ccccc2)cc2[nH]c(=O)ccc12
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(CCl)c1cc(OCc2ccccc2)cc2[nH]c(=O)ccc12
Temperature: 65 °C
Reaction time: 4.5 h

Procedure:
5-acetyl-7-benzyloxy-1H-quinolin-2-one (7.0 g, 23.86 mmol) is dissolved in a mixture of 1,2-dichloroethane (147 mL), glacial acetic acid (43 mL), and water (7 mL) and combined with N-benzyltrimethylammonium-dichloriodate (19.0 g, 54.58 mmol). The mixture is stirred for 4.5 hours at 65° C., then diluted with sodium bicarbonate solution and 5% sodium bisulfite solution and stirred for 5 minutes. The precipitate formed is filtered off, washed with water (2×20 mL) and dried in the oven. Yield: 6.0 g (77%); mass spectroscopy:
Reaction SMILES: O[CH2:2][C@@H:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:4][C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].C(P(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:13][N:10]1[CH:11]=[CH:12][C:8]([N:7]2[C:5](=[O:6])[CH2:4][C@H:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:2]2)=[N:9]1
Reactant: Cn1ccc(NC(=O)C[C@@H](CO)NC(=O)OC(C)(C)C)n1
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cn1ccc(N2C[C@@H](NC(=O)OC(C)(C)C)CC2=O)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
To a solution of tert-butyl ((2S)-1-hydroxy-4-((1-methyl-1H-pyrazol-3-yl)amino)-4-oxobutan-2-yl)carbamate (553.0 mg) and tri-n-butylphosphine (0.924 mL) in a mixed solvent of toluene (9 mL)/THF (3 mL) was added 40% diethyl azodicarboxylate toluene solution (0.954 mL) under ice-cooling, and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (358 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6][OH:7].[Si:13](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CN=C1>>[CH3:12][O:11][C:9]1[CH:8]=[C:5]([CH2:6][O:7][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:10]=1
Reactant: COc1cc(CO)cc(OC)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Product: COc1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc(OC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.9 %

Procedure:
A mixture of 3,5-dimethoxybenzyl alcohol (4.0 g), t-butyl-diphenylsilyl chloride (6.54 g) and imidazole (3.28 g) in DML (60 mL) was stirred at room temperature for 24 h. DMF was evaporated and the residue was purified by column chromatography (silica gel; eluent: hexane to hexane/EtOAc 20%) to yield 8.5 g of 3,5-dimethoxy-1-[(t-butyldiphenylsilyloxy)methyl]benzene. ESMS: m/z 407 (MH+).
Reaction SMILES: [CH3:1][C:2]1([N:14]2[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[CH2:21]1[CH2:26][C@@H:25]([NH2:27])[C@H:24]([NH2:28])[CH2:23][CH2:22]1>>[NH2:27][C@@H:25]1[CH2:26][CH2:21][CH2:22][CH2:23][C@H:24]1[NH:28][CH:17]1[CH2:18][CH2:19][N:14]([C:2]2([CH3:1])[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(=O)CC2)C1
Reactant: N[C@@H]1CCCC[C@H]1N
Product: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(N[C@@H]3CCCC[C@H]3N)CC2)C1

Procedure:
Following the procedure used in step D of the example 7 and starting with tert-butyl 3-methyl-3-(4-oxo-1-piperidyl)pyrrolidine-1-carboxylate (300 mg, 1.06 mmol) and 1R,2R-diaminocyclohexane (244.2 mg, 2.12 mmol), the title compound was obtained (300 mg). MS (M+1): 381.30
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:21]=[CH:20][C:14]([C:15](=[NH:19])OCC)=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[C:11]2[CH:12]=[CH:13][C:14]([C:15](=[NH:19])[N:32]3[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]3)=[CH:20][CH:21]=2)=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: CCOC(=N)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Reactant: CN1CCNCC1
Solvent: CO
Product: CN1CCN(C(=N)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cc2)CC1

Procedure:
Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate (2.0 ml of a 0.075 M methanol solution, 0.15 mmol) was treated with 1-methylpiperazine (23 mg, 0.23 mmol) via procedure W to afford 35 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(imino(4-methylpiperazin-1-yl)methyl)benzamide. MS (Q1) 434 (M)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[C:29]([O:33][C:34](=[O:39])[NH:35][CH2:36][CH2:37][NH2:38])([CH3:32])([CH3:31])[CH3:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:29]([O:33][C:34](=[O:39])[NH:35][CH2:36][CH2:37][NH:38][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCNC(=O)OC(C)(C)C)ccc21
Yield: 83.2 %

Procedure:
(2-{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-ethyl)-carbamic acid tert-butyl ester (92 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (82 mg), (2-amino-ethyl)-carbamic acid tert-butyl ester (64 mg), HBTU (76 mg), and DIEA (0.2 ml). LC/MS: m/z 552. 1H NMR (DMSO-d6, 400 MHz): δ 8.40 (br, 1H), 8.06 (s, 1H), 7.91 (s, 1H), 7.73 (m, 2H), 7.46 (d, 1H), 7.34 (d, 1H), 6.91 (t, 1H), 4.24 (t, 2H), 3.64 (s, 3H), 3.14-3.09 (q, 2H), and 1.36 (s, 9H), —NH proton signal was not observed.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[CH3:14][C:15]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:19][N:18]=[C:17]([NH2:27])[CH:16]=1>ClCCl>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([NH:6][C:7]([NH:27][C:17]1[CH:16]=[C:15]([CH3:14])[C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:19][N:18]=1)=[O:8])=[O:5]
Reactant: Cc1cc(N)ncc1-c1ccccc1
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Solvent: ClCCl
Product: Cc1cc(NC(=O)NC(=O)c2c(Cl)cccc2Cl)ncc1-c1ccccc1
Temperature: 25 °C

Procedure:
2,6-Dichlorobenzoyl isocyanate (1.4 grams) was reacted with 4-methyl-5-phenyl-2-pyridylamine (0.9 gram) in dichloromethane. There was an immediate exotherm and spontaneous reflux. The reaction mixture was then stirred at ambient temperature but no precipitate formed. After the mixture was stripped, the residue was recrystallized from ethanol yielding 1.0 gram of tan crystals, m.p. 210°-214° C. The identity of the desired product was confirmed by NMR.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([NH:20][CH2:21][C:22]([OH:24])=O)[S:18][CH:19]=2)=[CH:11][CH:10]=1.[NH:25]1[CH2:28][CH2:27][CH2:26]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:25]1([C:22](=[O:24])[CH2:21][NH:20][C:17]2[S:18][CH:19]=[C:15]([C:12]3[CH:11]=[CH:10][C:9]([F:8])=[CH:14][CH:13]=3)[N:16]=2)[CH2:28][CH2:27][CH2:26]1
Reactant: C1CNC1
Reactant: O=C(O)CNc1nc(-c2ccc(F)cc2)cs1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNc1nc(-c2ccc(F)cc2)cs1)N1CCC1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.27 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-ylamino]-acetic acid trifluoroacetic acid salt and 31.2 mg (0.54 mmol) of azetidine. Yield: 27 mg.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][CH:14]1[C:21](=[O:22])[N:20]2[CH:23]([C:26]([OH:28])=O)[CH2:24][CH2:25][CH:19]2[CH2:18][CH:17]=[CH:16][CH2:15]1)=[O:12].CCN=C=NCCCN(C)C.[NH2:40][CH:41]([CH2:56][C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C:42](=[O:55])[CH2:43][O:44][C:45](=[O:54])[C:46]1[C:51]([CH3:52])=[CH:50][CH:49]=[CH:48][C:47]=1[CH3:53].C(N(CC)CC)C>ClCCl>[C:60]([O:59][C:57]([CH2:56][CH:41]([NH:40][C:26]([CH:23]1[N:20]2[C:21](=[O:22])[CH:14]([NH:13][C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[O:12])[CH2:15][CH:16]=[CH:17][CH2:18][CH:19]2[CH2:25][CH2:24]1)=[O:28])[C:42](=[O:55])[CH2:43][O:44][C:45](=[O:54])[C:46]1[C:47]([CH3:53])=[CH:48][CH:49]=[CH:50][C:51]=1[CH3:52])=[O:58])([CH3:63])([CH3:61])[CH3:62]
Reactant: O=C(NC1CC=CCC2CCC(C(=O)O)N2C1=O)c1ccc2ccccc2c1
Reactant: Cc1cccc(C)c1C(=O)OCC(=O)C(N)CC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1C(=O)OCC(=O)C(CC(=O)OC(C)(C)C)NC(=O)C1CCC2CC=CCC(NC(=O)c3ccc4ccccc4c3)C(=O)N21

Procedure:
To a solution of 6-[(naphthalene-2-carbonyl)-amino]-5-oxo-1,2,3,5,6,7,10,10a-octahydro-pyrrolo[1,2-a]azocine-3-carboxylic acid, (124 mg, 0.33 mmol)in dichloromethane is added EDCI (191 mg, 1 mmol), 2,6-dimethyl-benzoic acid 3-amino-4-tert-butoxycarbonyl-2-oxo-butyl ester, 111, (200 mg, 0.62 mmol), and triethylamine (150 ul). After consumption of the starting material, the reaction is washed with 1N HCl (1×50 ml), water (1×50 ml), and brine (1×50 ml). The CHCl2 is reduced in vacuo. The residue is used directly in the next step without purification. ESI MS 696.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:12]([CH3:15])=[N:13][N:14]=2)[C:5]2[CH:10]=[C:9]([CH3:11])[NH:8][C:6]=2[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>CN(C=O)C.O>[Cl:1][C:2]1[C:3]2[N:4]([C:12]([CH3:15])=[N:13][N:14]=2)[C:5]2[CH:10]=[C:9]([CH3:11])[N:8]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[C:6]=2[CH:7]=1
Reactant: Cc1cc2c(cc(Cl)c3nnc(C)n32)[nH]1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(cc(Cl)c3nnc(C)n32)n1Cc1ccccn1
Reaction time: 8 h

Procedure:
To 4-chloro-1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (0.150 g, 0.680 mmol, from Example 228, Step 6) and Cs2CO3 (0.88 g, 2.7 mmol) in DMF (2.10 mL) was added 2-(chloromethyl)pyridine hydrochloride (0.139 g, 0.850 mmol, Aldrich). The reaction was stirred overnight, then diluted with water and extracted with three portions of 5% iPrOH in DCM. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The product was purified by flash chromatography, eluting with a gradient from 0-10% MeOH in DCM. Yield: (206 mg, 97%).
Reaction SMILES: [N:1]([C:4]1[CH:20]=[CH:19][CH:18]=[CH:17][C:5]=1[O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)=[C:2]=[O:3].[CH3:21][N:22]([CH3:24])[NH2:23]>O1CCCC1>[CH3:21][N:22]([CH3:24])[NH:23][C:2]([NH:1][C:4]1[CH:20]=[CH:19][CH:18]=[CH:17][C:5]=1[O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)=[O:3]
Reactant: O=C=Nc1ccccc1Oc1ccc2ccccc2c1
Reactant: CN(C)N
Solvent: C1CCOC1
Product: CN(C)NC(=O)Nc1ccccc1Oc1ccc2ccccc2c1
Temperature: 0 °C

Procedure:
The title compound of Step C was dissolved in 100 mL of dry tetrahydrofuran and cooled to 0° C. Then 1,1-dimethylhydrazine (2.3 g, 38.2 mmol) was added at 0° C. The resultant mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, diluted with water, extracted twice with methylene chloride and the combined extracts were dried (MgSO4). The organic solution was then concentrated under reduced pressure to yield the title compound of Step D as a brown solid which was carried on entirely in Step E.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:11](=[O:19])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:20])[N:4]=1.[C:21](=N)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCCl>[C:21](=[N:1][CH2:2][C:3]1[N:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:11](=[O:19])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:20])[N:4]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Cc1cccc2nc(CN)n(-c3ccccc3)c(=O)c12
Solvent: ClCCCl
Product: Cc1cccc2nc(CN=C(c3ccccc3)c3ccccc3)n(-c3ccccc3)c(=O)c12
Temperature: 25 °C

Procedure:
A 100-mL, one-neck, round bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 2-aminomethyl-5-methyl-3-phenyl-3H-quinazolin-4-one (2.91 g, 11.0 mmol), benzhydrylideneamine (2.39 g, 13.2 mmol), and 1,2-dichloroethane (15 mL). The reaction mixture was heated at reflux for 4 h under nitrogen atmosphere and then cooled to ambient temperature. Concentration under reduced pressure followed by purification by column chromatography afforded the compound 162 as an orange solid. m.p. 49° C. (dec); 1H NMR (DMSO-d6) δ (ppm) 7.22-7.78 (m, 17H), 6.74 (m, 1H), 4.17 (S, 2H), 2.74 (s, 3H); m/z=430 (M+H). The reaction described above and compound 162 are shown below.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[C:10][CH:11]([O:17][C:18](=[O:20])[CH3:19])[CH2:12][O:13][CH2:14][CH2:15][CH3:16].[H][H]>C(OCC)(=O)C.[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH:11]([O:17][C:18](=[O:20])[CH3:19])[CH2:12][O:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCOCC(C#CCOC1CCCCO1)OC(C)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCOCC(CCCOC1CCCCO1)OC(C)=O

Procedure:
1-(2-Tetrahydropyranyloxy)-4-acetoxy-5-propoxy-2-pentyne (10.8 g., 0.04 mole) is dissolved in ethyl acetate (100 ml.). 5% Palladium on carbon is added and the mixture is hydrogenated on the Parr apparatus at an initial pressure of 41 lbs./in2 and 25° C. When 0.08 mole of hydrogen is absorbed, the catalyst is removed by filtration and the solvent is evaporated under vacuum to give the title compound as a light orange residual oil.