Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH2:15]O)[O:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)[Cl:20]>CCOCC>[CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH2:15][Cl:20])[O:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1cc(CO)occ1OCc1ccccc1
Solvent: CCOCC
Product: O=c1cc(CCl)occ1OCc1ccccc1
Reaction time: 1 h

Procedure:
To a suspension of 5-(benzyloxy)-2-(hydroxymethyl)-4H-pyran-4-one (18.5 g, 80 mmol) in Et2O (130 mL) was added SOCl2 (18 mL, 110 mmol) at r.t. and the mixture was stirred for 1 h. The reaction mixture was poured onto ice-water and more Et2O was added. Then the Et2O phase was collected and water phase was extracted by Et2O twice, the combined Et2O layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography to give 5-(benzyloxy)-2-(chloromethyl)-4H-pyran-4-one 1HNMR (DMSO, 400 MHZ) δ 8.27 (s, 1H), 7.32-7.41 (m, 5H), 6.55 (s, 1H), 4.92 (s, 2H), 4.65 (s, 2H). MS (M+H)+ 250.1/252.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[C:14]([F:17])([F:16])[F:15])[N:10]=[C:9]([C:18]([O:20]CC)=[O:19])[C:8](=[O:23])[NH:7]2)([O-:3])=[O:2].[OH-].[K+].O.Cl>C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[C:14]([F:17])([F:16])[F:15])[N:10]=[C:9]([C:18]([OH:20])=[O:19])[C:8](=[O:23])[NH:7]2)([O-:3])=[O:2]
Reactant: CCOC(=O)c1nc2cc(C(F)(F)F)c([N+](=O)[O-])cc2[nH]c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1nc2cc(C(F)(F)F)c([N+](=O)[O-])cc2[nH]c1=O
Yield: 92.9 %

Procedure:
To a solution of ethyl 3,4-dihydro-6-nitro-3-oxo-7-trifluoromethylquinoxaline-2-carboxylate (120 mg, 362 μmol) in ethanol (5 ml) was added 1N aqueous solution of potassium hydroxide (724 μl, 724 μmol), and the mixture was refluxed for 1 hour. After cooling, water was added and the pH value was brought to 2 with concentrated hydrochloric acid. The precipitate was collected by filtration, washed with water and then air-dried to obtain 102 mg of the title compound as colorless powder. Yield 88%.
Reaction SMILES: [CH2:1]([C:3]1[CH:32]=[CH:31][C:6]([C:7]([C:9]2[CH:17]=[C:16]([C:18](=O)[C:19]3[CH:24]=[CH:23][C:22]([CH2:25]C)=[CH:21][CH:20]=3)[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=2[C:28]([OH:30])=[O:29])=O)=[CH:5][CH:4]=1)C.[H][H]>[Pd].C(O)(=O)C>[CH3:1][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:9]2[CH:17]=[C:16]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=2[C:28]([OH:30])=[O:29])=[CH:31][CH:32]=1
Reactant: CCc1ccc(C(=O)c2cc(C(=O)c3ccc(CC)cc3)c(C(=O)O)cc2C(=O)O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1ccc(Cc2cc(Cc3ccc(C)cc3)c(C(=O)O)cc2C(=O)O)cc1

Procedure:
A mixture of 21.1 grams of 4,6-bis(4 ethylbenzoyl)isophthalic acid, 350 mL of acetic acid, and 2.10 grams of 5% palladium on carbon (as a catalyst) was heated to 65° C. for 17 hours in an atmosphere of hydrogen at 270 kPa. The mixture was filtered through Celite™ diatomaceous earth filter agent to remove the catalyst. The resulting filtrate was concentrated in vacuo to give 4,6-bis(4-methylbenzyl)isophthalic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:22]=[N:21][C:14]3[O:15][CH2:16][C:17](=[O:20])[N:18]([CH3:19])[C:13]=3[CH:12]=2)=[O:10])=[C:4]([Cl:23])[CH:3]=1.[H-].[Na+].[CH3:26]I>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([C:11]2[CH:22]=[N:21][C:14]3[O:15][CH2:16][C:17](=[O:20])[N:18]([CH3:19])[C:13]=3[CH:12]=2)=[O:10])=[C:4]([Cl:23])[CH:3]=1
Reactant: CN1C(=O)COc2ncc(C(=O)Cc3ccc(Br)cc3Cl)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CC(C(=O)c1cnc2c(c1)N(C)C(=O)CO2)c1ccc(Br)cc1Cl

Procedure:
In analogy to Example 1, step 2, 7-[2-(4-bromo-2-chloro-phenyl)-acetyl]-1-methyl-1H-pyrido[2,3-b][1,4]oxazin-2-one was reacted with sodium hydride and methyl iodide to give the title compound as a light yellow oil. MS (m/e, ISP neg. ion)=407.2 [M−H+].
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=O)[NH:4]1)(=[O:3])=[O:2].[C:13]1([Mg]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[C:13]1([C:5]2([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[S:1](=[O:3])(=[O:2])[NH:4]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: O=S1(=O)NC(c2ccccc2)(c2ccccc2)c2ccccc21

Procedure:
Various procedures have been reported for synthesizing 3-substituted-benz[d]isothiazole-1,1-dioxides and 3,3-disubstituted-2,3-dihydrobenz[d]isothiazole-1,1-dioxides from saccharin (3-oxo-2,3-dihydrobenz[d]isothiazole-1,1-dioxide) and from saccharin pseudo-chloride (3-chlorobenz[d]isothiazole-1,1-dioxide). As reported by A. Mustafa et al, J. Chem. Soc., 1952, p. 1339, the treatment of saccharin pseudo-chloride with excess phenylmagnesium bromide gave the corresponding 3,3-diphenyl-2,3-dihydrobenz[d]isothiazole-1,1-dioxide in almost quantitative yield. Methyl-, ethyl-, n-propyl- and n-butylmagnesium halides were reported by these authors to react analogously. R. A. Abramovitch et al, J. Chem. Soc., Perkin Trans I, 1974 (22), p. 2589, reviewed and reinvestigated the reactions of saccharins with alkyl and aryl Grignard reagents and found that either the 3-alkyl (or 3-aryl)-benz[d]-isothiazole-1,1-dioxide and/or the open-chain tertiary alcohol, o--CH2OH benzenesulfonamide wherein R is alkyl (or aryl) were obtained with one exception. When saccharin was treated with an excess of phenylmagnesium bromide in boiling tetrahydrofuran, 3,3-diphenyl-2,3-dihyrobenz[d]isothiazole-1,1-dioxide was obtained as the minor product together with the open-chain tertiary alcohol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH3:8].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[N+](C1C=CC([O:28][C:29]([C:31]2[C:32]3[CH:41]=[C:40]([C:42]([O:46][CH3:47])([O:44][CH3:45])[CH3:43])[O:39][C:33]=3[C:34]([O:37][CH3:38])=[N:35][CH:36]=2)=O)=CC=1)([O-])=O>CN(C)C=O>[CH3:8][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[NH:1][C:29]([C:31]1[C:32]2[CH:41]=[C:40]([C:42]([O:44][CH3:45])([O:46][CH3:47])[CH3:43])[O:39][C:33]=2[C:34]([O:37][CH3:38])=[N:35][CH:36]=1)=[O:28]
Reactant: Cc1cnccc1N
Reactant: COc1ncc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cc(C(C)(OC)OC)oc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ncc(C(=O)Nc2ccncc2C)c2cc(C(C)(OC)OC)oc12
Reaction time: 0.17 h
Yield: 81.3 %

Procedure:
A solution of 4-amino-3-methylpyridine (0.11 g) in dry N,N-dimethylformamide (20 ml) was stirred at 0° C. under an atmosphere of dry nitrogen. Sodium bis(trimethylsilyl)amide (1.0M solution in tetrahydrofuran, 1.0 ml) was added and stirring continued at 0° C. for 10 minutes. 2-(1,1-Dimethoxyethyl)-7-methoxyfuro[2,3-c]pyridine-4-carboxylic acid 4-nitrophenyl ester (0.20 g) was added and stirring continued at room temperature for 90 minutes. The solvent was then removed in vacuo, the residue taken up in water (100 ml) and extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with water (100 ml), then brine (50 ml), dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification by column chromatography on silica eluting with ethyl acetate gave the title compound (0.15 g) as a white solid.
Reaction SMILES: Cl.C(O[C:7]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[C@@H:11]([NH:18][C@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:20])[CH2:10]1)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+].ClC1[N:39]=[CH:38][N:37]=[C:36]([NH2:40])[C:35]=1[F:41]>O1CCOCC1>[NH2:40][C:36]1[N:37]=[CH:38][N:39]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[C@@H:11]([NH:18][C@H:19]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH3:20])[CH2:10]2)[C:35]=1[F:41]
Reactant: Nc1ncnc(Cl)c1F
Reactant: C[C@H](N[C@H]1CN(C(=O)OC(C)(C)C)CCC1C(=O)O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@H](N[C@H]1CN(c2ncnc(N)c2F)CCC1C(=O)O)c1ccccc1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a 50 L reactor was charged with 10 L of 2N HCl and 3-5 (850 g, 2.44 mol, 1.0 equiv). The mixture was warmed to 30° C. and stirred for 2 hours, at which time HPLC indicted complete consumption of starting 3-5. The solution was diluted with MTBE (4 L) and stirred for 20 min, layers were separated and to the aqueous layer was added solid K2CO3 (660 g) over 1 hour to pH ˜7. Additional K2CO3 (660 g, 4.8 mol, 2.0 equiv) was added following by 6-chloro-5-fluoropyrimidine-4-ylamine (360 g, 2.44 mole 1.0 equiv) and 1,4-dioxane (5 L). The mixture was heated to gentle reflux at 100° C. and stirred at this temperature for 16 hours. HPLC indicated <2% of compound 3-6 remained. The mixture was washed with DCM (2×5 L) and the organic wash solutions were discarded. The aqueous layer was treated with active carbon (425 g) by stirring the slurry for 1 hour at 30° C. followed by filtration through diatomite. This active carbon treatment was repeated. The resulting aqueous solution was neutralized to pH ˜7 with concentrated HCl, and stirred at 22° C. for 3 hours, the resulting slurry was filtered and the wet cake was washed with washed with 1,4-dioxane/water (1:1, 1.2 L), dried under vacuum at 50° C. for 18 hr until KF ˜0.5%. of product 3-7 was obtained as a pale white solid (690 g, 81% yield) with purity of 98.6%. The product contains a mixture of 1:9 cis/trans isomers at the C3 and C4 positions. ESI-MS (M+H-1)+: 460.2. 1H NMR (400 MHz, CD3OD) δ: 8.49 (d, J=2.01 Hz, 1H), 8.21-8.14 (m, 5H) 4.94-4.90 (m, 1H), 4.63 (d, J=11.55 Hz, 1H), 4.42 (m, 1H), 4.03 (m, 2H), 3.59-3.72 (m, 3H), 2.84-2.93 (m, 1H), 2.20-2.31 (m, 1H), 2.15 (d, J=6.78 Hz, 3H).
Reaction SMILES: Cl.[CH2:2]([NH2:6])[CH2:3][C:4]#[CH:5].C(N(CC)CC)C.S=[C:15]1[CH2:19][S:18][C:17](=[O:20])[NH:16]1>C(O)C>[CH2:2]([NH:6][C:15]1[CH2:19][S:18][C:17](=[O:20])[N:16]=1)[CH2:3][C:4]#[CH:5]
Reactant: O=C1NC(=S)CS1
Reactant: C#CCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: C#CCCNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 50.1 %

Procedure:
To a solution of but-3-yn-1-amine hydrochloride (4.88 g) and triethylamine (6.44 mL) in ethanol (60 mL) was added 4-thioxo-1,3-thiazolidin-2-one (3.08 g), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate to give the title compound (1.95 g).
Reaction SMILES: CSC.B.[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][C:14](O)=[O:15].S(C)C>C1COCC1>[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][CH2:14][OH:15]
Reactant: O=C(O)CCc1ccccc1Br
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: OCCCc1ccccc1Br
Temperature: 0 °C

Procedure:
Borane-dimethyl sulfide complexe (2.2 eq.) was added to a stirred solution of commercially available 3-(2-bromophenyl)propanoic acid (1 eq.) in THF (0.15M). The mixture was reflux for 3 h. without a condensor allowing the SMe2 to escape. The final reaction concentration was 0.3M. The mixture was cooled to 0° C. and quenched with a slow addition of HCl 1N. The resulting mixture was extracted with Et2O. The organic extract was washed with water, brine, dried over MgSO4 filtered and concentrated to afford the desired material as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[NH:6][CH:5]=[N:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.ClCCl>CN(C=O)C>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:4]2[CH:3]=[C:2]([Br:1])[N:6]=[CH:5]2)=[CH:16][CH:17]=1
Reactant: Brc1cnc[nH]1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cnc(Br)c2)cc1
Reaction time: 16 h
Yield: 67.2 %

Procedure:
To a suspension of 5-bromo-1H-imidazole (10 g, 68.5 mmol) and K2CO3 (37.8 g, 274 mmol) in DMF (100 mL) was added 1-(chloromethyl)-4-methoxybenzene (11.8 g, 75.4 mmol) dropwise at room temperature. The resulting mixture was stirred for 16 hours, and then dichloromethane (DCM) was added. The mixture was successively washed with water and brine, dried and concentrated to give a residue that was purified by column chromatography to afford 12.3 g of the desired compound as a solid. LC-MS: m/z 267 (M+H+).
Reaction SMILES: [C:1](=[S:14])([S:9][CH2:10][C:11](Cl)=[CH2:12])[NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:3]1([N:2]=[C:1]2[S:14][C:11]([CH3:12])=[CH:10][S:9]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=C(Cl)CSC(=S)Nc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1csc(=Nc2ccccc2)s1
Temperature: 25 °C
Yield: 50.9 %

Procedure:
In a suitable reaction vessel, 2-chloroallyl dithiocarbanilate (20.3 g, 0.0834 mol) and concentrated hydrochloric acid (26.2 ml, ca. 0.326 mol) are mixed and heated at reflux temperatures for 5 hours. The resulting solution is cooled to room temperature and is diluted with water. Solid sodium carbonate is added to the solution to raise the pH to 6 and the reaction mixture is then extracted with ether. The ether layer is separated and washed with 6N hydrochloric acid. The resulting aqueous acidic layer is neutralized with sodium carbonate and the separated product is extracted with ether. The ether layer is washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness in vacuo to leave crude 2-phenylimino-4-methyl-1,3-dithiole which crystallizes on standing. The crude product is recrystallized from petroleum ether to yield 8.8 g of the purified product, a tan solid melting at from 44.5° C. to 49.5° C.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][C@@H:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=2[S:4][CH:3]=1.[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:20][C:21]1[CH:26]=[C:25]([C:2]2[C:11]3[O:10][C@@H:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=3[S:4][CH:3]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)Cc2scc(Br)c2O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: C[C@H]1CN(C(=O)OC(C)(C)C)Cc2scc(-c3cccc(F)c3)c2O1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
A mixed solution of tert-butyl (2S)-8-bromo-2-methyl-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (434 mg), (3-fluorophenyl)boronic acid (227 mg), dichlorobis(triphenylphosphine)palladium (44 mg) and potassium carbonate (518 mg) in DME-water (1:1, 12 mL) was stirred at 85° C. for 2 hr under a nitrogen stream. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 5→15% ethyl acetate/hexane) to give the title compound (430 mg, 95%) as a colorless oil.
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[S:2].[CH2:13]1[O:21][C:20]2[CH:19]=[CH:18][C:17]([CH:22]3[C:26]4[NH:27][C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=5[C:34](=[O:35])[C:25]=4[CH2:24][NH:23]3)=[CH:16][C:15]=2[O:14]1>CN(C=O)C.O>[N:3]1([C:1]([N:23]2[CH2:24][C:25]3[C:34](=[O:35])[C:33]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[NH:27][C:26]=3[CH:22]2[C:17]2[CH:18]=[CH:19][C:20]3[O:21][CH2:13][O:14][C:15]=3[CH:16]=2)=[S:2])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)OCO3)NC2
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)OCO3)N(C(=S)n1ccnc1)C2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of 1,1′-thiocarbonyldiimidazole (0.192 g, 1.08 mmol) in DMF (5 mL, anhydrous) at 0° C. was added 1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one (0.30 g, 0.98 mmol) (prepared as in Example 5). The mixture warmed to room temperature and stirred for 20 h. The solution was diluted with water and extracted into ethyl acetate. The organic layers were combined and washed with aq. NaHCO3 and brine, dried with MgSO4 and concentrated in vacuo, to yield the product as a light tan solid.
Reaction SMILES: [F:1][C:2]1[CH:42]=[C:41]([NH:43][C:44]([NH:46][C:47]2[CH:51]=[C:50]([CH3:52])[O:49][N:48]=2)=[O:45])[CH:40]=[CH:39][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:38]=[CH:37][C:17]([CH2:18][N:19]([CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])C(=O)OC(C)(C)C)=[CH:16][CH:15]=3)[S:13][C:6]=12.FC(F)(F)C(O)=O>ClCCl>[CH2:18]([C:17]1[CH:37]=[CH:38][C:14]([C:12]2[S:13][C:6]3[C:7](=[N:8][CH:9]=[CH:10][C:5]=3[O:4][C:3]3[CH:39]=[CH:40][C:41]([NH:43][C:44]([NH:46][C:47]4[CH:51]=[C:50]([CH3:52])[O:49][N:48]=4)=[O:45])=[CH:42][C:2]=3[F:1])[CH:11]=2)=[CH:15][CH:16]=1)[NH:19][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36]
Reactant: COCCOCCOCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)Nc5cc(C)on5)cc4F)c3s2)cc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCOCCOCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)Nc5cc(C)on5)cc4F)c3s2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
To a solution of 367 (0.074 g, 0.10 mmol) in dichloromethane (50 mL) was added trifluoroacetic acid (1.0 mL). The reaction mixture was stirred for 3 h at r.t. then concentrated and the residue was partitioned between dichloromethane and sat. NaHCO3. The organic phase was collected, washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by Gilson reverse phase HPLC (35-75% MeOH/H2O, Aquasil C18, 30 min) and lyophilized. The purified product (containing some formic acid from the HPLC) was partitioned between dichloromethane and 1M NaOH). The organic phase was collected, dried (MgSO4), filtered and concentrated to give compound 368 (0.033 g, 0.052 mmol, 52% yield).
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[C:7]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:6]=1>O1CCCC1.C(N(CC)C(C)C)(C)C>[Cl:11][C:9]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]([NH2:8])[N:6]=[C:5]([N:2]([CH3:3])[CH3:1])[CH:10]=1
Reactant: Clc1cc(Cl)nc(Nc2ccccc2)n1
Reactant: CNC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)C1=NC(N)N(c2ccccc2)C(Cl)=C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Dimethylamine in tetrahydrofuran (2M, 15 mL) was added to a solution of 4,6-dichloro-N-phenyl-2-pyrimidinamine (0.715 g, 2.97 mmol) in tetrahydrofuran (30 mL) and N,N-diisopropylethylamine (0.52 mL). The resulting mixture was stirred at room temperature overnight. The solvent was removed and the crude material was purified by flash chromatography on silica gel, eluting with ethyl acetate/hexane (1:9). The eluent was removed, giving 6-chloro-N4, N4-dimethyl-1-phenyl-2,4-pyrimidinediamine (0.592 g, 2.39 mmol, 80%, Rf=0.3).
Reaction SMILES: [N:1]1([C:6]2[CH:24]=[CH:23][C:9]([O:10][CH2:11][C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[S:15][CH:16]=3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.Cl.[N:26]1([C:31](N)=[NH:32])C=CC=N1.C(N(CC)CC)C>CN(C=O)C>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]3[N:13]=[C:14]([CH:17]4[CH2:18][CH2:19][N:20]([C:31]([NH2:32])=[NH:26])[CH2:21][CH2:22]4)[S:15][CH:16]=3)=[CH:23][CH:24]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: N=C(N)n1cccn1
Reactant: c1cc(-n2cnnn2)ccc1OCc1csc(C2CCNCC2)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N=C(N)N1CCC(c2nc(COc3ccc(-n4cnnn4)cc3)cs2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine (300 mg, 0.876 mmol), pyrazole-1-carboxamidine hydrochloride (0.128 g, 0.876 mmol.) and triethylamine (0.122 mL, 0.876 mmol) in DMF (2 mL) was stirred at rt for 3 hours. The precipitate was collected by filtration and washed with ether to afford the expected product. 1H NMR (DMSO-d6): δ 10.02 (1H, s), 7.93 (1H, s), 7.82 (2H, m), 7.70 (1H, s), 7.60(2H, br), 7.28 (2H, m), 5.20 (2H, s), 3.95 (2H, m), 3.38 (1H, m), 3.15 (2H, m), 2.09 (2H, m), 1.66 (2H, m).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:24]1[CH2:28][CH2:27][NH:26][C:25]1=[O:29]>>[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:26]3[CH2:27][CH2:28][O:24][C:25]3=[O:29])=[CH:3][CH:4]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: O=C(c1ccc(Br)cc1)N1CCN(c2ccc(Cl)cc2Cl)CC1
Reactant: O=C1NCCO1
Product: O=C(c1ccc(N2CCOC2=O)cc1)N1CCN(c2ccc(Cl)cc2Cl)CC1
Yield: 58.6 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromophenyl)[4-(2,4-dichlorophenyl)piperazin-1-yl]methanone (828 mg) described in Preparation Example 19 and oxazolidin-2-one (174 mg), the title compound (492 mg) was obtained.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][N:5]=[C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=1)[C:7]([O:9]C)=[O:8]>CO>[CH3:3][O:4][N:5]=[C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: CON=C(C(=O)OC)c1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CON=C(C(=O)O)c1cccc(O)c1
Yield: 73.5 %

Procedure:
An aqueous solution of 2 N sodium hydroxide (8 ml.) was added with stirring at ambient temperature to a solution of methyl 2-methoxyimino-2-(3-hydroxyphenyl)acetate (anti isomer) (1.56 g.) in methanol (30 ml.). After stirring for 3 hours at the same temperature, methanol was distilled off. To the residue was added water and the mixture was washed with ether. The aqueous layer was adjusted to pH 1 with 10% hydrochloric acid, subjected to salting-out and extracted with ether. The extract was washed with a sodium chloride aqueous solution and dried over magnesium sulfate. Ether was distilled off to give crystals of 2-methoxyimino-2-(3-hydroxyphenyl)acetic acid (anti isomer) (1.07 g.). The crystals were recrystallized from a mixture of petroleum ether and ether to give crystals (0.7 g.), mp 99° to 101° C. (dec.).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[CH:12]=[C:11]([NH:14][C:15](=[O:21])OC(C)(C)C)[N:10]=[CH:9][C:8]=3[CH:7]=[CH:6]2)[CH2:3][CH2:2]1.N1C=CC=CC=1.ClC([C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1)=O>Cl.O1CCOCC1>[CH:1]1([CH2:4][N:5]2[C:13]3[CH:12]=[C:11]([NH:14][C:15]([C:31]4[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=4)=[O:21])[N:10]=[CH:9][C:8]=3[CH:7]=[CH:6]2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)Nc1cc2c(ccn2CC2CC2)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(=O)Nc2cc3c(ccn3CC3CC3)cn2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.6 %

Procedure:
A mixture of tert-butyl 1-(cyclopropylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-ylcarbamate (2C, 260 mg, 0.91 mmol) in 4M HCl in dioxane (3 ml) was stirred at room temperature for 15 h. The mixture was concentrated in vacuo and dissolved in pyridine (3 ml, 37 mmol). To the mixture, methyl 4-(chlorocarbonyl)benzoate (270 mg, 1.4 mmol) was added and stirred at room temperature for 3 hours. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude mixture was purified by chromatography (NH—SiO2, EtOAc) to give methyl 4-(1-(cyclopropylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-ylcarbamoyl)benzoate (2D, 270 mg, 0.77 mmol, 85% yield) as a white powder. 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.39-0.47 (m, 2 H) 0.50-0.59 (m, 2 H) 1.17-1.33 (m, 1 H) 3.89 (s, 3 H) 4.06 (d, J=7.07 Hz, 2 H) 6.57-6.59 (m, 1 H) 7.52 (d, J=3.28 Hz, 1 H) 8.03-8.09 (m, 2 H) 8.14-8.19 (m, 2 H) 8.34 (s, 1 H) 8.65 (s, 1 H) 10.86 (s, 1 H). ESI-MS: m/z 350.0 (M+H)+.