Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Si:12]([O:19][CH2:20][C:21]([CH3:63])([CH3:62])[CH2:22][N:23]1[CH:32]=[C:31]([S:33][CH:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]2)[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:47]3[CH:52]=[C:51]([C:53](=[O:58])[NH:54][CH:55]4[CH2:57][CH2:56]4)[CH:50]=[C:49]([F:59])[C:48]=3[CH3:60])[CH:29]=2)[C:24]1=[O:61])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>C(Cl)Cl>[Si:12]([O:19][CH2:20][C:21]([CH3:63])([CH3:62])[CH2:22][N:23]1[CH:32]=[C:31]([S:33]([CH:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]2)=[O:9])[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:47]3[CH:52]=[C:51]([C:53](=[O:58])[NH:54][CH:55]4[CH2:56][CH2:57]4)[CH:50]=[C:49]([F:59])[C:48]=3[CH3:60])[CH:29]=2)[C:24]1=[O:61])([C:15]([CH3:16])([CH3:17])[CH3:18])([CH3:13])[CH3:14]
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)cc(SC3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)cc(S(=O)C3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
mCPBA (0.025 g of 77% Max) was added to a solution of tert-butyl 4-({2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-1-oxo-1,2-dihydroisoquinolin-4-yl}sulfanyl)piperidine-1-carboxylate (Example 58d, 0.1 g) in DCM (2 mL). The reaction was stirred at room temperature for 1 h. The reaction was washed with saturated NaHCO3 solution (3×5 mL), then brine (3×5 mL). The organic layer was concentrated under reduced pressure to give the subtitle compound (0.060 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([CH3:17])[C:11]=2[N+:18]([O-])=O)=[CH:5][CH:4]=1)#[N:2]>ClCCl.C(O)C.[Pd]>[NH2:18][C:11]1[C:12]([CH3:17])=[N:13][C:14]([CH3:16])=[CH:15][C:10]=1[NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: Cc1cc(Nc2ccc(C#N)cc2)c([N+](=O)[O-])c(C)n1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(Nc2ccc(C#N)cc2)c(N)c(C)n1
Yield: 94.8 %

Procedure:
A solution of 4-(4-cyanophenyl)amino-2,6-dimethyl-3-nitropyridine (5.00 g, 18.6 mmol) in a mixture of dichloromethane (20 ml) and ethanol (100 ml) was hydrogenated at 20° C. over 10% palladium on charcoal (500 mg) at 138 kPa (20 p.s.i) for 3 hours. The catalyst was filtered off and the solvents were removed under reduced pressure to give the title compound as a brown solid (4.20 g, 94%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][C:12]1[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:36])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccncc3)c1)=N2

Procedure:
The title compound was prepared from {5-methyl-2-[3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M60) (0.33 g, 0.64 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (206 mg, 81%).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)Cl.Cl.[CH3:21][NH:22][C:23](=[O:31])[C@H:24]([C:27](=[O:30])[O:28][CH3:29])[NH:25][CH3:26].C(N(CC)CC)C>O>[CH3:29][O:28][C:27](=[O:30])[CH:24]([N:25]([CH3:26])[C:11]([C:10]1[CH:14]=[CH:15][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][CH:9]=1)=[O:12])[C:23]([NH:22][CH3:21])=[O:31]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CNC(=O)[C@@H](NC)C(=O)OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
4-Phenylbenzoyl chloride (2.23 g) was added little by little to a chloroform (20 mL) solution of N,N2,O-trimethyl-3-oxoserinamide hydrochloride (Intermediate 5-2, 2.02 g) and triethylamine (2.18 g) under ice cooling, and the mixture was stirred for 30 minutes at the same temperature and for 1 hour, with the temperature raised to room temperature. Water was added to the reaction mixture, and the system was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and the desiccant was filtered out, whereafter the solvent was distilled off under reduced pressure. The resulting residue was purified by OH type silica gel column chromatography (gradient elution with chloroform/methanol=98/2→90/10) to obtain 4-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}biphenyl (yellow solid) (3.0 g, 86%).
Reaction SMILES: C(OC1C=CN(CC(C2C=CC(CO)=CC=2)=O)C(=O)C=1)C1C=CC=CC=1.[CH2:27]([O:34][C:35]1[CH:40]=[N:39][NH:38][C:37](=[O:41])[CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Br[CH2:43][C:44]([C:46]1[CH:51]=[CH:50][C:49]([CH:52]([OH:54])[CH3:53])=[CH:48][CH:47]=1)=[O:45]>>[CH2:27]([O:34][C:35]1[CH:40]=[N:39][N:38]([CH2:43][C:44]([C:46]2[CH:51]=[CH:50][C:49]([CH:52]([OH:54])[CH3:53])=[CH:48][CH:47]=2)=[O:45])[C:37](=[O:41])[CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(O)c1ccc(C(=O)CBr)cc1
Reactant: O=c1cc(OCc2ccccc2)cn[nH]1
Agent: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Product: CC(O)c1ccc(C(=O)Cn2ncc(OCc3ccccc3)cc2=O)cc1

Procedure:
5-Benzyloxy-2-{2-[4-(1-hydroxy-ethyl)-phenyl]-2-oxo-ethyl}-2H-pyridazin-3-one is prepared following preparation 15b (DMSO as solvent) from 624 mg (3.09 mmol) 5-benzyloxy-2H-pyridazin-3-one (preparation 5c) and 750 mg (3.09 mmol) 2-bromo-1-[4-(1-hydroxy-ethyl)phenyl]-ethanone (preparation 30a).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:7])/[CH:4]=[CH:5]/[CH3:6].C(N(C(C)C)CC)(C)C.[CH3:17][O:18][C:19](Cl)=[O:20].O>ClCCl>[CH3:17][O:18][C:19](=[O:20])[NH:1][CH2:2][CH:3]([OH:7])/[CH:4]=[CH:5]/[CH3:6]
Reactant: C/C=C/C(O)CN
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: C/C=C/C(O)CNC(=O)OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 102.3 %

Procedure:
(E)-1-Amino-3-penten-2-ol (1.3 g, 12.9 mmol) (Overman, L. E. in J. Am. Chem. Soc. 55, 22, 1983, 6622-6629) and diisopropylethylamine (2.7 mL, 15.4 mmol) were dissolved in dichloromethane (20 mL). Methylchloroformate (1 mL, 12.9 mmol) was added slowly and the mixture was stirred a 0° C. for 2 h. Water (25 mL) was added and the phases separated. Extraction with dichloromethane (3×25 mL), drying, filtration and evaporation gave the crude product ((E)-2-hydroxy-pent-3-enyl)carbamic acid methyl ester (2.1 g, 100%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[N:3]=1.[NH:21]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[N:22]1.O>C(Cl)Cl>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:24]3[CH:25]=[N:21][NH:22][CH:23]=3)[N:7]=[C:6]3[N:8]([CH3:11])[N:9]=[CH:10][C:5]=23)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc(Nc2nc(Cl)nc3c2cnn3C)c1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Solvent: ClCCl
Solvent: O
Product: COc1cccc(Nc2nc(-c3cn[nH]c3)nc3c2cnn3C)c1

Procedure:
6-Chloro-N-(3-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 6 was reacted with pyrazole-4-boronic acid pinacol ester using General Procedure A. Addition of water and CH2Cl2 to the reaction, followed by sonication and filtration yielded 101. NMR: (CDCl3): 3.87 (s, 3H, CH3), 4.07 (s, 3H, CH3), 6.87 (dd, H, ArH, J=2.4, 8.37), 7.13 (d, H, ArH, J=7.85), 7.29 (m, H, ArH), 7.37 (t, H, ArH, J=8.13), 7.43 (s, H, ArH), 8.37 (s, 2H, 2×ArH). MS: (ESI+) MH+==322.23
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClOC(C)(C)C.[S:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C[O-].[Na+]>CO.C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: C1CCSC1
Agent: CC(C)(C)OCl
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: Nc1ccccc1
Product: Nc1ccccc1C1CCCS1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a vigorously stirred solution of 10.0 grams (0.11 mole) of aniline in 200 ml. of methylene chloride cooled to -78° C. under nitrogen were added by means of a jacketed constant pressure additional funnel 11.7 grams (0.11 mole) of tert.-butyl hypochlorite also cooled to -78° C. This solution was stirred for 10 minutes. The funnel was rinsed with a few ml. of cold methylene chloride and 44 ml. (ca. 5 equivalents) of tetrahydrothiophene was cooled to -78° C., added dropwise to the reaction mixture, and stirred for three hours. In 50 ml. of methanol, 7.0 grams (0.13 mole, 1.2 equivalents) of sodium methoxide were placed in the funnel, cooled, and added quickly to the reaction mixture. The dry-ice/acetone cooling bath was removed and the solution stirred for 2 hours. The reaction was quenched by the addition of 100 ml. of water, the heterogeneous mixture separated, the aqueous layer was extracted two times with 100-ml. portions of methylene chloride. The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The solvent was removed in vacuo to produce a dark red oil. Fractional distillation of the oil gave 5.03 grams (0.054 mole) of aniline and 6.11 grams (0.034 mole) of 2-(2-tetrahydrothienyl)aniline for a 31% yield based on starting material and a 64% yield based on unrecovered starting material: b.p. 130°-134° C. (0.19 mm), ND26.8 1.6258, IR (neat) 2.92, 3.36, 6.12, 6.70, and 13.40μ, NMR (CCl4)T 7.82 (4H, m), 6.99 (2H, m) 6.06 (2H, s), 5.52 (2H, t), 3.20 (4H, m).
Reaction SMILES: N[C:2]1C=CC=C2[C:3]=1[CH:4]=[CH:5][CH:6]=N2.C([N:14]([CH2:17][CH3:18])CC)C.C1C[O:22]CC1>C(Cl)(Cl)Cl>[C:17]([NH2:14])(=[O:22])[C:18]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cccc2ncccc12
Reactant: CCN(CC)CC
Reactant: C1CCOC1
Solvent: ClC(Cl)Cl
Product: NC(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
As shown in reaction scheme 2 above, after cooling a solution of 5-aminoquinoline represented by Formula 84 (439.93 mg, 3.05 mmol, purchased from TCI Co.) and triethylamine (0.95 mL, 6.78 mmol) in THF (10 mL) at 0° C. under a nitrogen atmosphere, a solution of 4-n-benzyloxy-3,5-dimethoxybenzoic acid chloride represented by Formula 85 (1.04 g, 3.39 mmol) in THF (15 mL) was slowly added to the above cold solution. After agitating the prepared solution at the same temperature for 30 minutes, this solution was left at room temperature for 18 hours. After filtering and removing a precipitate generated during the reaction, the remaining solution was diluted with chloroform and washed with a potassium carbonate solution, followed by separation and drying with (anhydrous) sodium sulfate. A concentrate remaining after removing the solvent under reduced pressure was recrystallized using ethyl acetate and hexane, resulting in a benzamide compound represented by Formula 2 as a desired product (VVZ-001; 1.08 g, 77% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:13]([NH:16][S@@](C(C)(C)C)=O)[CH2:14][CH3:15])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].C(Cl)Cl.Cl.O1CCOCC1>CCOCC>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@H:13]([NH2:16])[CH2:14][CH3:15])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:11])([F:12])[F:10]
Reactant: CC[C@@H](N[S@](=O)C(C)(C)C)c1ccc(OC(F)(F)F)c(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC[C@@H](N)c1ccc(OC(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 175.9 %

Procedure:
To a solution of 220 (3.5 g, 9.8 mmol) and DCM (10 mL) was added 4N HCl in dioxane (17 mL, 68 mmol) and the reaction stirred for 30 min at RT. Et2O was added, and the reaction stirred for 10 min and filtered, washed with ether and dried to afford 2.5 g (88%) of (R)-1-(3-chloro-4-(trifluoromethoxy)phenyl)propan-1-amine hydrochloride (222) as a white solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH3:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17]>>[CH3:1][N:2]([CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:16](=[O:17])[C:15]1[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=1[CH3:13]
Reactant: CNCCC#Cc1ccccn1
Reactant: Cc1ccccc1C(=O)Cl
Product: Cc1ccccc1C(=O)N(C)CCC#Cc1ccccn1
Yield: 37.7 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) and 2-methylbenzoyl chloride (58 mg, 0.37 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH from 100/0 to 98/2 as eluent) to afford 32.5 mg of N,2-dimethyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide as a brown oil (Yield: 37%).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[OH-].[Na+].[Cl:11][C:12]([Cl:17])([CH3:16])[C:13](Cl)=[O:14]>C(Cl)Cl>[Cl:11][C:12]([Cl:17])([CH3:16])[C:13]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])=[O:14]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC(Cl)(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(Cl)(Cl)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
To a dry reaction vessel were added L-proline (115 g., 1.0 moles, 1.0 eq.), 144 mL of 6 N sodium hydroxide and 20 g. solid sodium hydroxide. The clear, colorless solution (pH=11.5) was cooled to +10° C. in an ice bath with stirring. All of the above 2,2-dichloropropionyl chloride was diluted with 50 mL methylene chloride and added to the L-proline solution over 2 hours, keeping the solution temperature below +10 ° C. and the pH at 11.5 by simultaneous addition of 290 mL of 6N sodium hydroxide to yield 2,2-dichloropropionyl-L-proline. The pH was adjusted to 3 by the addition of 216 mL of 6N hydrochloric acid. The solid which formed was collected by filtration using 300 mL of 6N hydrochloric acid as a wash to yield white crystalline 2,2-dichloropropionyl-L-proline which was dried under vacuum (30 Torr) for 18 hours to give 216 g. (90% yield based on L-proline). HPLC at 23 minutes showed ≥96% purity. The recrystallization from ethyl acetate or ethyl acetate-hexane removes 0.5 mole of water but does not significantly improve purity. m.p. 61°-62° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[BrH:18].[NH+]1C=CC=CC=1>O1CCCC1>[CH3:1][O:2][N:3]=[C:4]([C:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])[CH2:11][Br:18])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(=NOC)C(C)(OCC)OCC
Reactant: Br
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(=NOC)C(CBr)(OCC)OCC

Procedure:
Ethyl 2-methoxyimino-3,3-diethoxybutyrate (syn isomer, 10.0 g), pyridinium hydrobromide perbromide (15.5 g) and tetrahydrofuran (100 ml) were treated in a similar manner to that of Example 8 (2) to give ethyl 2-methoxyimino-3,3-diethoxy-4-bromobutyrate (syn isomer, 16.20 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:6][NH:7][C:8]([C:10]1[O:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-])=O)=[CH:13][CH:14]=1)=[NH:9].C(O)C.C>[Pd].CO>[CH3:10][O-:11].[ClH:2].[NH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:12]1[O:11][C:10]([C:8](=[NH:9])[NH:7][CH2:6][C:5]2[CH:24]=[CH:25][C:26]([Cl:27])=[C:3]([Cl:2])[CH:4]=2)=[CH:14][CH:13]=1
Reactant: N=C(NCc1ccc(Cl)c(Cl)c1)c1ccc(-c2ccccc2[N+](=O)[O-])o1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: C[O-]
Product: N=C(NCc1ccc(Cl)c(Cl)c1)c1ccc(-c2ccccc2N)o1
Reaction time: 5 h

Procedure:
The mixture of the compound of Example I (31 g, 0.073 mole), ethanol (350 ml) and 5% Pd/C-50% H2O (1.5 g) was subjected to hydrogenation for 5 hours at room temperature, using 14.0 psia H2 (theory: 14.7 psia). Methanol (1000 ml) was added to the reaction mixture. The mixture was heated, treated with Darco, filtered, and the filtrate was reduced in volume to 400 ml under reduced pressure. The mixture was cooled and the product was collected by filtration. The product was recrystallized from methanol: m.p. 225°-257°, yield: 10 g (34%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[NH2:12][C:13]1[N:18]=[C:17]([C:19]2[C:24]3[CH:25]=[C:26]([C:29]#[N:30])[CH:27]=[CH:28][C:23]=3[O:22][C:21]([CH3:32])([CH3:31])[CH:20]=2)[CH:16]=[CH:15][CH:14]=1>ClCCl>[NH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([C:19]2[C:24]3[CH:25]=[C:26]([C:29]#[N:30])[CH:27]=[CH:28][C:23]=3[O:22][C:21]([CH3:32])([CH3:31])[CH:20]=2)[N+:18]=1[O-:9]
Reactant: CC1(C)C=C(c2cccc(N)n2)c2cc(C#N)ccc2O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(C)C=C(c2cccc(N)[n+]2[O-])c2cc(C#N)ccc2O1
Reaction time: 3 h
Yield: 22.2 %

Procedure:
406 mg of m-chloroperbenzoic acid were added to a solution of 554 mg of 4-(6-amino-2-pyridyl)-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile in 10 ml of dichloromethane and the mixture was stirred for 3 hours. The mixture was then washed with sodium bicarbonate solution, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using methanol/ethyl acetate (1:4) for the elution to give a solid which was triturated with dichloromethane and recrystallized from isopropanol. There were obtained 130 mg of 2-amino-6-(6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide of melting point 241°-242° C.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C:3]([N:5]([CH3:7])[CH3:6])=[NH:4].[ClH:9]>O>[Cl-:9].[CH3:1][N:2]([CH3:8])[C:3]([N:5]([CH3:7])[CH3:6])=[NH2+:4]
Reactant: CN(C)C(=N)N(C)C
Reactant: Cl
Solvent: O
Product: CN(C)C(=[NH2+])N(C)C
Product: [Cl-]

Procedure:
1,1,3,-tetramethylguanidinium chloride ([TMGH]Cl) is a hygroscopic salt that melts around 200° C. in the absence of water. In the presence of water it forms a melt at room temperature. The salt was prepared by neutralization of 1,1,3,3-tetramethylguanidine with aqueous HCl. The solvent was removed and the product was recrystallized in ethanol. The sample used was in equilibrium with the atmosphere when it was loaded into the instrument analogous to previous examples. Before adding NO to the gas flow, the sample was given further time to equilibrate with the moisture from the air/water mixture. When NO was added to the flow it was observed, that water was consumed while the intensity of the bands in the areas around 1650 and 940 cm−1 started to increase. Due to overlap with N—H bending of the NH2 group on the [TMGH]+ ion it was not possible to follow the reaction.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:16][NH:17][CH3:18].C(O)C>CN(C)C=O.C(OCC)(=O)C>[CH3:16][N:17]([CH3:18])[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccccc1F
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)c1ccccc1C=O
Temperature: 110 °C
Reaction time: 12 h
Yield: 84.6 %

Procedure:
To a suspension of 2-fluorobenzaldehyde (250 μL, 2.37 mmol) and potassium carbonate (328 mg, 2.37 mmol) in 5 mL of dry N,N-dimethylformamide was added dimethylamine/ethanol solution (0.65 mL, 5.6 M, 3.6 mmol) at room temperature. After being stirred at 110° C. for 12 h, the reaction mixture was diluted with ethyl acetate. The solution was washed with water, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 80/20) to obtain the title compound as a yellow oil (299 mg, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][CH3:10])=[CH:4][N:3]=1.Cl.[C:12](=[NH:17])(OCC)[CH3:13]>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:10])[C:12](=[NH:17])[CH3:13])=[CH:4][N:3]=1
Reactant: CCOC(C)=N
Reactant: CNCc1ccc(Cl)nc1
Agent: Cl
Solvent: CCO
Product: CC(=N)N(C)Cc1ccc(Cl)nc1
Temperature: 25 °C
Yield: 191.5 %

Procedure:
To 40 ml of ethanol was added 5.1 g of N-(2-chloro-5-pyridylmethyl)-N-Methylamine and then 4 g of ethyl acetimidate hydrochloride at 0° C. After stirring for an hour, the reaction mixture was allowed to warm to room temperature and stirred over night. The solvent was then distilled off. The obtained white residue was washed with diethyl ether to afford 7.3 g of the title compound m.p. 192°-197° C.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:13]([O:17][CH3:18])(=[O:16])[CH2:14][SH:15].[F:19][C:20]1[CH:34]=[CH:33][C:23]([CH:24](O)[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:22][CH:21]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH:24]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[S:15][CH2:14][C:13]([O:17][CH3:18])=[O:16])=[CH:33][CH:34]=1
Reactant: COC(=O)CS
Reactant: OC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)CSC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 50 %

Procedure:
A slurry of ρ-toluenesulfonic acid monohydrate (108 mg, 0.57 mmol) and activated 3 Å molecular sieves (300-500 mg) in 4 mL of toluene is stirred for 15 minutes. Methyl thioglycolate (265 mg, 2.50 mmol ) is then added followed by 4,4'-difluoro-benzhydrol (Aldrich) (500 mg, 2.27 mmol). The reaction is stirred for 2.5 hours at room temperature followed by heating at 50°-60° C. for 45 minutes. The mixture is diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, brine and dried over magnesium sulfate. Chromatography on silica gel, eluting with a gradient of 10% ethyl acetate in hexane to 20% ethyl acetate in hexane, provides methyl [[bis-(4-fluorophenyl)methyl]thio]acetate as a yellow oil in 50% yield.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:26])[C:4](=[O:25])[C:5]([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[CH:9][CH:8]=2)[N:6]=1.[CH2:27]([NH2:33])[C:28]1[O:32][CH:31]=[CH:30][CH:29]=1.[BH4-].[Na+].[OH-].[Na+]>CO>[NH2:1][C:2]1[N:3]([CH3:26])[C:4](=[O:25])[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[CH:9][CH:8]=2)([C:17]2[CH:24]=[CH:23][CH:22]=[C:19]([CH2:20][NH:33][CH2:27][C:28]3[O:32][CH:31]=[CH:30][CH:29]=3)[CH:18]=2)[N:6]=1
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(C=O)c2)N=C1N
Reactant: NCc1ccco1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(CNCc3ccco3)c2)N=C1N
Yield: 71.2 %

Procedure:
A small vial (2 ml) was charged with 3-[2-amino-4-(4-difluoromethoxy-phenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-benzaldehyde (110 mg, 306 μmol). To this was added furfurylamine (30 mg, 308 μmol) in methanol (1 ml). After stirring overnight at room temperature sodium borohydride (29 mg) was added, then after another 90 minutes 1N sodium hydroxide (1 ml) was added and the mixture extracted with diethyl ether. The ethereal layer was concentrated by rotary evaporation, diluted with methanol and re-concentrated (repeated three times). Finally the oily residue was redissolved in diethylether/hexanes and concentrated, twice then placed under vacuum to give a white foam 96 mg (71%) 1H NMR (400 MHz, DMSO-d6) δ ppm 2.94 (s, 3H) 3.56 (br. s., 4H) 6.15 (d, J=3.2 Hz, 1H) 6.68 (br. s., 1H) 6.34 (t, J=2.4 Hz, 1H) 6.64 (s, 2H) 7.06 (d, J=8.8 Hz, 2H) 7.13 (t, J=74.18 Hz, 1H) 7.15-7.28 (m, 3H) 7.37 (s, 1H) 7.43 (d, J=8.8 Hz 2H) 7.51 (t, J=1.4 Hz, 1H); MS (ES) m/z 439.2 [M−H]−