Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=[C:7]([C:9]([CH3:11])=[CH2:10])[CH:8]=1.[BH4-].[Na+].Cl>CCO.C1COCC1>[NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:8]=1
Reactant: C=C(C)c1cc(CN)cc(N(C)S(C)(=O)=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)c1cc(CN)cc(N(C)S(C)(=O)=O)c1
Reaction time: 3.5 h

Procedure:
To a stirring solution of crude N-(3-(aminomethyl)-5-(prop-1-en-2-yl)phenyl)-N-methylmethanesulfonamide and 68.3 mg (0.2871 mmol) of CoCl2.6H2O in 3 mL of EtOH and 1 mL of THF at 50° C. was added 0.169 g of NaBH4 in 2 portions. After the mixture was stirred for about 3.5 h, 5 N HCl was added to a pH=1. The mixture was concentrated and (28-30) % NH4OH solution was added to pH=8. The aqueous layer was extracted with the extract of (40 mL of CHCl3: 5 mL of H2O: 5 mL of MeOH) (3×). The combined extracts were dried over Na2SO4, filtered, and concentrated. N-(3-(aminomethyl)-5-isopropylphenyl)-N-methylmethanesulfonamide was used in the next reaction without further purification.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:11])=O)(C)(C)C.[ClH:20].CO>>[ClH:20].[NH2:8][CH2:9][C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:11]
Reactant: CCOC(=O)CCNC(=O)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CCOC(=O)CCNC(=O)CN
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2.0 Grams of ethyl 3-(2-{(tert-butoxycarbonyl)amino}-acetylamino)propionate were dissolved in 30 ml of 10% hydrochloric acid-methanol and stirred for 15 hours at room temperature. Upon distilling the reaction liquid off under reduced pressure, 1.52 g of the title compound was obtained.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH:24]=[CH:23][CH:22]([C:26]([OH:28])=[O:27])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH:24]=[CH:23][CH:22]([C:26]([O:28][CH3:1])=[O:27])[CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CC=CC(C(=O)O)C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1C=CCN(C(=O)OC(C)(C)C)C1
Reaction time: 1 h

Procedure:
1,1'-Carbonyldiimidazole (4 g, 24.7 mmol) in methylene chloride (100 ml) was added dropwise to a solution of 1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine-3-carboxylic acid (5 g, 22 mmol) in methylene chloride (200 ml) under a nitrogen atmosphere. Stirring was continued for 1 h followed by addition of methanol (300 ml), and reflux for 26 h. 10% aqueous citric acid (100 ml) was added and the mixture extracted with methylene chloride. The organic layer was dried over magnesium sulphate, evaporated to dryness in vacuo and purified on a silica gel column (Eluent: methylene chloride/methanol (90/1)) to give methyl 1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine-3-carboxylate as yellow oil. (Yield: 3.9 g, 73%)
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[F:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([F:30])[CH:29]=1)[CH2:24][CH2:25][NH-:26]>>[F:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([F:30])[CH:29]=1)[CH2:24][CH2:25][NH:26][S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: [NH-]CCc1cc(F)cc(F)c1
Product: CCc1cc(-c2ccc(S(=O)(=O)NCCc3cc(F)cc(F)c3)s2)c(C)[nH]c1=O
Yield: 15 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with (3,5-difluorobenzyl)methylamide as described in Step 5, Example 24 to give the title compound as a solid (15% yield). LC/MS: RT 3.30 min; m/e 439 (M+H); 1H NMR (δ, ppm): 11.82 (1H, s), 7.72 (1H, d), 7.37 (1H, s); 7.28 (1H, d); 7.03 (3H, m), 4.26 (2H, s), 2.71 (3H, s), 2.37 (2H, q), 2.34 (3H, s), 1.11 (3H, t); 19F NMR −109.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][C:9]2[CH:25]=[CH:24][C:12]([C:13]([NH:15][C@H:16]([C:21](O)=[O:22])[CH2:17][CH2:18][S:19][CH3:20])=[O:14])=[C:11]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:10]=2)[CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:44][S:45]([NH2:48])(=[O:47])=[O:46].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH3:44][S:45]([NH:48][C:21](=[O:22])[C@H:16]([CH2:17][CH2:18][S:19][CH3:20])[NH:15][C:13](=[O:14])[C:12]1[CH:24]=[CH:25][C:9]([CH2:8][O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:10][C:11]=1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:47])=[O:46]
Reactant: CSCC[C@H](NC(=O)c1ccc(COc2cccnc2)cc1-c1ccccc1)C(=O)O
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CSCC[C@H](NC(=O)c1ccc(COc2cccnc2)cc1-c1ccccc1)C(=O)NS(C)(=O)=O
Temperature: 47.5 °C
Reaction time: 8 h

Procedure:
A solution in THF (5 mL) of [4-(3-pyridyloxymethyl)-2-phenylbenzoyl]methionine (143 mg, 0.32 mmol), prepared as in Example 235, and carbonyldiimidazole (136 mg, 0.84 mmol) was stirred overnight at 45-50° C. A 1.6 mL aliquot of the reaction mixture was removed and to it was added methanesulfonamide (78 mg, 0.82 mmol) and DBU (0.12 mL, 0.80 mmol) and the mixture was stirred overnight at ambient temperature. The reaction mixture was partitioned between ethty acetate and pH 4 water. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. Chromatographyl on silica gel (98.5:1.5:0.5 chloroform-methanol-acetic acid) gave [4-(3-pyridyloxymethyl)-2-phenylbenzoyl]methionine methylsulfonyl amide. (31 mg after azeotroping and lyophilization). 1H NMR (300 MHz, DMSO-d6) δ 8.62 (d, 1H), 8.39 (d, 1H), 8.18 (d, 1H), 7.50 (m, 4H), 7.36 (m, 6H), 5.28 (s, 2H), 4.27 (m, 1H), 3.21 (s, 3H), 2.20 (t, 2H), 2.02 (s, 3H), 1.81 (m, 2H). MS (APCI) m/e 514 (M+H)+. Anal calcd for C25H27N3O3S2.1.25H2O: C, 56.01; H, 5.55; N, 7.84. Found: C, 55.72; H, 5.08; N, 8.18.
Reaction SMILES: [Br-].Cl[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH2:13][N+:14]([CH2:19][CH3:20])([CH2:17][CH3:18])CC)[N:6]=[CH:5][N:4]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26].CC(O[C:35]([NH:37]C1CCNCC1)=O)(C)C>CC#N>[NH2:37][CH:35]1[CH2:18][CH2:17][N:14]([CH2:13][C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:12]=2[C:3]([NH:26][C:25]2[CH:27]=[CH:28][CH:29]=[C:23]([O:22][CH3:21])[CH:24]=2)=[N:4][CH:5]=[N:6]3)[CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COc1cccc(N)c1
Reactant: CC[N+](CC)(CC)Cc1cccc2ncnc(Cl)c12
Agent: [Br-]
Solvent: CC#N
Product: COc1cccc(Nc2ncnc3cccc(CN4CCC(N)CC4)c23)c1
Temperature: 55 °C
Reaction time: 1 h
Yield: 17.3 %

Procedure:
A mixture of 14A (80 mg, 0.223 mmol) and 3-methoxyaniline (18.6 mg, 0.151 mmol) in CH3CN (1.5 ml) was heated at 55° C. for 2 h. After cooling to room temperature, 4-N-Boc-aminopiperidine (300 mg, 1.5 mmol) was added and the mixture was heated at 60° C. overnight. The reaction mixture was concentrated in vacuo and the residue was purified by prep HPLC. The desired fraction was concentrated and the resulting residue was dissolved in a mixture of TFA/DCM (1 ml/1 ml) and stirred at room temperature for 1 h, then concentrated. The residue was purified by SCX column, followed by silica gel flash column (DCM/MeOH/NH4OH=90/10/1) to give 14B (9.5 mg, 17%). The compound has an analytical HPLC retention time=1.288 min (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 254 nm) and a LC/MS M++H=364+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[C:19]([C:26]2[N:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[N:18]1)[CH3:16].[H-].[Na+].O>CN(C=O)C>[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[C:19]([C:26]2[CH:27]=[CH:28][C:29]([O:32][C:3]3[N:2]([CH3:1])[C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:5]4[N:4]=3)=[CH:30][N:31]=2)=[N:18]1)[CH3:16]
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: CCn1nc(-c2ccc(O)cn2)c2ncccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc(-c2ccc(Oc3nc4cccnc4n3C)cn2)c2ncccc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 36.2 %

Procedure:
To a mixture of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (90 mg) and 6-(1-ethyl-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-3-ol (68 mg) in DMF (1 mL) was added NaH (60% in oil, 18.11 mg), and the mixture was stirred at 100° C. for 1 h. The mixture was heated at 180° C. for 30 min under microwave irradiation. The mixture was poured into water and extracted with AcOEt. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (AcOEt/hexane). The eluent was evaporated and the residue was crystallized from EtOH/hexane to give the title compound (38.1 mg).
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:12])[O:9][CH2:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)(O)[C:15]#[N:16].CN(C)C(=N)N(C)C.Cl>CC#N>[O:12]=[C:8]1[O:9][CH2:10][CH:11]([C:15]#[N:16])[CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1OCC=C1c1ccccc1
Reactant: CC(C)(O)C#N
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CC#N
Product: N#CC1COC(=O)C1c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 56 %

Procedure:
3-Phenyl-5H-furan-2-one (Description 2; 4.5 g, 0.028 mol), and acetone cyanohydrin (3.06 ml) were dissolved in CH3CN (80 ml) and cooled to −0° C. Tetramethylguanidine (3.5 ml) was added dropwise over 15 minutes and the reaction left to stand for a further 15 minutes. 0.5M HCl (100 ml) was added and the reaction mixture de-colourised and the product extracted with ethyl acetate (2×40 ml), washed with brine (2×30 ml) and dried over MgSO4. The solvent was removed in vacuo to afford a brown oil which was a mixture of the cis and trans isomers. Purification was carried out using flash column chromatography on silica gel eluting in increasing concentrations of ethyl acetate in hexane (0-60%) to yield the title compound (2.93 g, 56%). The only isolated product from the column was the more thermodynamically stable trans isomer.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:20]=[C:21]([CH:28]=[CH:29][C:30](OCC)=[O:31])[C:22]([N+:25]([O-])=O)=[CH:23][CH:24]=4)[CH2:15][CH2:14]3)=[O:12])[N:10]=[C:4]2[CH:3]=1.ClCCl.[H][H]>[C].[Pd].CO>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:20]=[C:21]5[C:22](=[CH:23][CH:24]=4)[NH:25][C:30](=[O:31])[CH2:29][CH2:28]5)[CH2:15][CH2:14]3)=[O:12])[N:10]=[C:4]2[CH:3]=1
Reactant: CCOC(=O)C=Cc1cc(N2CCN(C(=O)c3cn4ccc(C)cc4n3)CC2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccn2cc(C(=O)N3CCN(c4ccc5c(c4)CCC(=O)N5)CC3)nc2c1
Yield: 78.7 %

Procedure:
A mixture of ethyl 3-[3-[4-(7-methylimidazo[1,2-a]-pyridine-2-carbonyl)-1-piperazinyl]-6-nitrophenyl]acrylate (926 mg), 10% palladium carbon (139 mg), dichloromethane (50 ml) and methanol (50 ml) was hydrogenated under one atmospheric pressure of hydrogen at ambient temperature for 2.5 hours. After filtration, acetic acid (1 ml) was added to the filtrate containing ethyl 3-[3-[4-(7-methylimidazo[1,2-a]pyridine-2-carbonyl-1-piperazinyl]-6-aminophenyl]propionate and 6-[4-(7-methylimidazo[1,2-a]-pyridine-2-carbonyl)-1-piperazinyl]-3,4-dihydro-2(1H)-quinolinone and evaporated in vacuo. The residue was dissolved in chloroform (30 ml) and washed with saturated aqueous solution of sodium hydrogene carbonate. The extract was dried over magnesium sulfate and concentrated. The residue was crystallized from ethanol to give 6-[4-(7-methylimidazo[1,2-a]pyridine-2-carbonyl)-1-piperazinyl]-3,4-dihydro-2(lH)-quinolinone (612 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11].[CH3:29][CH2:30][N:31](C(C)C)C(C)C.CN(C=O)C.BrCC#N.N>CO>[NH2:19][C:18]1[N:17]=[CH:16][C:15]2[C:20]([C:23]3[CH2:24][CH2:25][N:26]([CH2:29][C:30]#[N:31])[CH2:27][CH:28]=3)=[CH:21][O:22][C:14]=2[C:13]=1[O:12][C@@H:10]([C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1])[CH3:11]
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: CCN(C(C)C)C(C)C
Agent: N
Agent: N#CCBr
Solvent: CN(C)C=O
Solvent: CO
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCN(CC#N)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
7-[(R)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-3-(1,2,3,6-tetrahydropyridin-4-yl)furo[3,2-c]pyridin-6-ylamine (10.0 mg, 0.0237 mmol), DIPEA (16.5 μL, 0.0947 mmol) and DMF (1.00 mL, 12.9 mmol) were mixed. Bromoacetonitrile (1.7 μL, 0.026 mmol) was added at last at 0° C. The mixture was stirred at 0° C. for 2 hours. Crude was passed through SCX-2 SPE, and the product was released by 2 M NH3 in methanol and purified on the MDPS. MS (ES+): m/z 461.03/463.05 (100/81) [MH+]. HPLC: tR=0.83 min (HPLC-ACQUITY, Analytical). 1H NMR (400 MHz, DMSO-d6): δ=1.82 (d, J=6.8 Hz, 3H), 2.46 (br. s., 2H), 2.65-2.74 (m, 2H), 3.19-3.22 (m, 2H), 3.85 (s, 2H), 5.60 (s, 2H), 6.21 (q, J=6.6 Hz, 1H), 6.31 (br. s., 1H), 7.45 (t, J=8.7 Hz, 1H), 7.52 (dd, J=9.0, 5.2 Hz, 1H), 7.78 (s, 1H), 8.30 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[NH:11][CH:10]=[N:9][N:8]=1.O1CCCC1.[Li]CCCC.[Cl:22][C:23]1[CH:34]=[CH:33][C:26]([C:27](N(OC)C)=[O:28])=[CH:25][CH:24]=1.[Cl-].[NH4+].O>>[Cl:22][C:23]1[CH:34]=[CH:33][C:26]([C:27]([C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]2[NH:11][CH:10]=[N:9][N:8]=2)=[O:28])=[CH:25][CH:24]=1
Reactant: CON(C)C(=O)c1ccc(Cl)cc1
Reactant: Brc1ccsc1-c1nnc[nH]1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)cc1)c1ccsc1-c1nnc[nH]1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
To a solution of 3-(3-bromo-2-thienyl)-4H-1,2,4-triazole (15.05 g, 65.41 mmol) in Tetrahydrofuran (500 mL, 6000 mmol) was added dropwise 2.5M BuLi in hexanes (104 mL, 262 mmol) at −70° C. (internal temperature) and the solution was stirred for 30 min at −78° C. A solution of 4-chloro-N-methoxy-N-methylbenzamide (41.24 g, 206.6 mmol) in tetrahydrofuran (80 mL, 1000 mmol) was then added dropwise into the suspension. The resulting mixture was stirred for 60 min at −78° C. Ammonium chloride (17.49 g, 327.0 mmol) in water (100 mL, 6000 mmol) was added to the mixture at −78° C. and the mixture was stirred for 15 min before being warmed to rt. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, and then filtered to remove drying agent. The solvent was evaporated and the residue was purified by chromatography to afford (4-chlorophenyl)[2-(4H-1,2,4-triazol-3-yl)-3-thienyl]methanone as white solid (16.8 g, 88.5%). LCMS: (FA) ES+ 289.9, 291.8
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=O.NO.[N:8]([O-:10])=O.[Na+:11].[S:12](=[O:15])([OH:14])[O-:13].[Na+].S(=O)=O>>[N:8]([S:12]([O-:15])(=[O:14])=[O:13])([S:1]([O-:5])(=[O:4])=[O:3])[OH:10].[Na+:11].[Na+:11]
Reactant: O=N[O-]
Reactant: O=S(=O)(O)O
Reactant: O=S([O-])O
Agent: NO
Agent: O=S=O
Agent: [Na+]
Product: O=S(=O)([O-])N(O)S(=O)(=O)[O-]

Procedure:
One suitable technique for preparing hydroxylamine sulfate is the classical Raschig process, described in Kirk-Othmer, Vol. 7 (1951), page 766, paragraph 4, Briefly, the classical Raschig process involves the reduction of sodium nitrite with sodium bisulfite and sulfur dioxide to give sodium hydroxylamine -N, N-disulfonate, followed by hydrolysis of the hot solution to give hydroxylammonium acid sulfate.
Reaction SMILES: C[O:2][C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]=2[CH:4]=1.Cl.N1C=CC=CC=1.[OH2:24]>>[OH:2][C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:24])[C:5]=2[CH:4]=1
Reactant: O
Reactant: COc1ccc2c(c1)Cc1ccccc1O2
Agent: Cl
Solvent: c1ccncc1
Product: O=c1c2ccccc2oc2ccc(O)cc12
Temperature: 25 °C

Procedure:
A solid mixture of 2-methoxy-9H-xanthene 2 (3.09 g, 14.6 mmole) and pyridine hydrochloride (23.85 g, 206.4 mmole) was heated at 200-210° for 1.5 hrs. The resulting reaction mixture was cooled to about 80° and treated with water, while a white powder dropped out of solution. The suspended mixture was stirred at ambient temperature and then cooled to 0°. The solid was filtered on a Buchner funnel and washed with cold water. A large quantity of CH2Cl2 was needed to redissolve the crude product. The CH2Cl2 solution was washed with dilute HCl solution. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4. TLC showed a small by-product at the origin, but neither of the starting material nor the oxidation product, 2-hydroxy-9H-xanthene-9-one, was formed. The CH2Cl2 solution was filtered through a silica gel plug, the silica gel was flushed with 20% EtOAc-hexanes (100 ml). After concentration of the filtrate, the crude 2-hydroxy-9H-xanthene 3 (2.68 g, 93%) was collected as a slightly yellow powder: mp 137-139° C. 1H NMR (DMSO-d6): delta 9.18 (1H, s), 7.14-7.22 (2H, m), 6.97-7.03 (2H, m), 6.87 (1H, dd, J=7.3, 1.8 Hz), 6.57-6.62 (2H, m) and 3.94 (2H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]([Cl:18])([CH2:15][CH2:16][CH3:17])[CH:13]=O.[NH:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[N:20]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:19]1([CH:13]([NH:8][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:12]([Cl:18])([Cl:11])[CH2:15][CH2:16][CH3:17])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[N:20]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: CCCC(Cl)(Cl)C=O
Reactant: NC(=O)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCC(Cl)(Cl)C(NC(=O)c1ccc(Cl)cc1)n1nnc2ccccc21

Procedure:
A suspension of 4-chlorobenzamide, 2,2-dichloropentanal, benzotriazole, and p-toluenesulfonic acid was processed as in Example 1C to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.CC1C([C:26](O)=[O:27])=CC=CC=1.C[O-].[Na+].C(OCC)(=O)C.C(O)(=O)C>CO>[Cl:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:26][OH:27])[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: Cc1ccccc1C(=O)O
Reactant: CC(C)Cn1cnc2c(Cl)nc3ccccc3c21
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)Cn1c(CO)nc2c(Cl)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 5 h
Yield: 7.2 %

Procedure:
4-Chloro-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methyl benzoate (14.3 g; 0.36 mol, Example 7) was suspended in dry methanol (350 mL). The mixture was made basic (pH 10) with 25% sodium methoxide. The mixture was stirred at room temperature for 5 hr after which time only a trace of starting material was detected by silica gel TLC (ethyl acetate eluent). The mixture was made acidic with acetic acid and then concentrated to dryness. The residue was slurried in ether. The solid was filtered from the mixture and then suspended in aqueous sodium hydroxide. The product was filtered from the mixture, washed with water, and dried to yield 7.5 g (71.4%) of tan solid. The product was recrystallized from ethanol to yield 4.8 g of pure product m.p. 162°-166° C.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([NH2:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=1.[OH-].[Na+]>CO>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([NH:16][CH2:1][CH:3]2[O:5][CH2:4]2)([CH3:14])[CH3:15])=[CH:11][CH:12]=1
Reactant: CC(C)(N)c1ccc(Cl)cc1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(NCC1CO1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
Epichlorohydrin (8.05 ml) was added dropwise to a solution of 1-(4-chlorophenyl)-1-methylethylamine (17.38 g) in methanol (17.5 ml) at 0° C. with stirring. The solution was warmed to ambient temperature and stirred for 48 hours. Sodium hydroxide solution (50%) (17.5 ml) was added and the mixture stirred for 15 minutes. The product was extracted with ether to give an oil which was purified by flash column chromatography on silica using petroleum ether, b.p. 40-60° C./ethyl acetate/triethylamine (8:2:1) as the mobile phase with gradually increasing amounts of ethyl acetate to give N-[1-(4-chlorophenyl)-1-methylethyl]-2,3-epoxypropylamine as an oil.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.Cl.Cl.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[C:29]1[NH:33][C:32](=[O:34])[C:31]2([CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[N:30]=1>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:37]2[CH2:36][CH2:35][C:31]3([N:30]=[C:29]([C:23]4[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:22]=4[Cl:21])[NH:33][C:32]3=[O:34])[CH2:39][CH2:38]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: O=C1NC(c2ccc(Cl)cc2Cl)=NC12CCNCC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1NC(c2ccc(Cl)cc2Cl)=NC12CCN(S(=O)(=O)c1ccc(Cl)cc1)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.1 %

Procedure:
Triethylamine (88 μl, 0.632 mmol) and 4-chlorobenzenesulfonyl chloride (70 mg, 0.332 mmol) were added to a mixed solution of 2-(2,4-dichloro-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one dihydrochloride (100 mg, 0.299 mmol) in dichloromethane (3 ml). The reaction solution was stirred at room temperature for 16 hours and then diluted with dichloromethane, and the organic layer was washed with water. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane) to give 8-(4-chloro-benzenesulfonyl)-2-(2,4-dichloro-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (70.8 mg, 96%).
Reaction SMILES: [CH2:1]([OH:6])[C:2]([F:5])([F:4])[F:3].[H-].[Na+].[Cl:9][C:10]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:13](F)=[CH:12][CH:11]=1>CS(C)=O>[Cl:9][C:10]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:13]([O:6][CH2:1][C:2]([F:5])([F:4])[F:3])=[CH:12][CH:11]=1
Reactant: OCC(F)(F)F
Reactant: Fc1ccc(Cl)nc1-c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: FC(F)(F)COc1ccc(Cl)nc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.5 %

Procedure:
To a solution of 1.273 g trifluoroethanol in 20 ml dimethylsulfoxide was added 0.463 g sodiumhydride 55% in oil and the mixture was stirred at room temperature for 15 min. To the resulting solution was added a solution of 3.2 g 6-chloro-2-(4-chloro-phenyl)-3-fluoro-pyridine in 10 ml dimethylsulfoxide and the mixture was stirred at room temperature for 3 h. The reaction mixture was partitioned between water and ethyl acetate. The phases were separated and the organic phase was purified by chromatography on silica gel with a gradient of heptane to dichloromethane to yield 3.30 g of the title compound as slightly yellow solid. MS (EI): 322.1 and 324.2 (M+H). The product was obtained as 85:15 mixture of F vs Cl substitution products (6-chloro-2-(4-chloro-phenyl)-3-(2,2,2-trifluoro-ethoxy)-pyridine vs. 2-(4-chloro-phenyl)-3-fluoro-6-(2,2,2-trifluoro-ethoxy)-pyridine) that were better separable at the next step.