Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1C2C(=CC(S(N3CCC[C@H]3COC3C=CC=CC=3)(=O)=O)=CC=2)C(=O)C1=O.[O:29]([CH2:36][C@@H:37]1[CH2:40][CH2:39][N:38]1[S:41]([C:44]1[CH:45]=[C:46]2[C:50](=[CH:51][CH:52]=1)[NH:49][C:48](=[O:53])[C:47]2=[O:54])(=[O:43])=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[CH3:55][O:56][C:57]1[CH:64]=[CH:63][C:60]([CH2:61]Cl)=[CH:59][CH:58]=1>>[CH3:55][O:56][C:57]1[CH:64]=[CH:63][C:60]([CH2:61][N:49]2[C:50]3[C:46](=[CH:45][C:44]([S:41]([N:38]4[CH2:39][CH2:40][C@H:37]4[CH2:36][O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)(=[O:43])=[O:42])=[CH:52][CH:51]=3)[C:47](=[O:54])[C:48]2=[O:53])=[CH:59][CH:58]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CC[C@H]3COc3ccccc3)cc2C1=O
Agent: CN1C(=O)C(=O)c2cc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)ccc21
Product: COc1ccc(CN2C(=O)C(=O)c3cc(S(=O)(=O)N4CC[C@H]4COc4ccccc4)ccc32)cc1
Yield: 50 %

Procedure:
(S)-1-(4-Methoxybenzyl)-5-(2-phenoxymethyl-azetidine-1-sulfonyl)-1H-indole-2,3-dione (18c) was prepared according to the same procedure for compound 11a, except using compound 17 and 4-methoxybenzyl chloride, and purified with hexanes-ether (1:2) to afford 62 mg (50%) of 18c as an orange solid, mp 159.8-161.5° C. 1H NMR (300 MHz, CDCl3) δ 8.04 (s, 1H), 7.96 (dd, J=8.25 Hz, J=2.1 Hz, 1H), 7.25 (m, 4H), 6.97-6.87 (m, 4H), 6.80 (d, J=7.8 Hz, 2H), 4.87 (s, 2H), 4.45 (m, 2H), 4.11 (m, 2H), 3.84 (m, 2H), 3.81 (s, 3H), 2.32 (m, 2H). Anal. Calcd for C26H24N2O6S: C, 63.40, H, 4.91; N, 5.69. Found: C, 63.65, H, 4.93; N, 5.59.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[CH:6]2.[OH-].[K+].CCO[C:22]([CH3:24])=O>C1(C)C=CC=CC=1.O>[CH:9]1[C:10]2[C:5](=[C:22]([CH2:24][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[C:9]([CH3:15])=[N:8][C:7]=3[OH:16])[CH:3]=[CH:12][CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Reactant: CCOC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc2c(C)nc(O)c(Cc3cccc4cnccc34)c2cc1OC
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (158 mg, 721 μmol) in toluene (15 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.86 mL, 1.72 mmol) at RT followed by MDE 32016 (185 mg, 864 μmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with H2O (10 mL) before extraction with EtOAc (50 mL). The organic phase was isolated and the aqueous phase was further extracted with CH2Cl2 (50 mL). Both organic phases were washed with brine (10 mL), combined, dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 94:6) gave 48 mg of 4-(isoquinolin-5-ylmethyl)-6,7-dimethoxy-1-methylisoquinolin-3-ol. The free base was dissolved in MeOH (3 mL) in a 25 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.09 M HCl solution in MeOH (4.5 mL). The reaction mixture solution was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 4-(isoquinolin-5-ylmethyl)-6,7-dimethoxy-1-methylisoquinolin-3-ol dihydrochloride 22 as a brown solid (58 mg, 19% yield).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16]([C:20]5[CH:21]=[C:22]6[CH:28]=[CH:27][NH:26][C:23]6=[N:24][CH:25]=5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:29])[C:8]2=[O:30])[C:4]([CH3:31])=[N:3]1.[H-].[Na+].I[CH3:35]>CN(C=O)C.CO>[CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16]([C:20]5[CH:21]=[C:22]6[CH:28]=[CH:27][N:26]([CH3:35])[C:23]6=[N:24][CH:25]=5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:29])[C:8]2=[O:30])[C:4]([CH3:31])=[N:3]1
Reactant: CI
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc5[nH]ccc5c4)cc3c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc5c(ccn5C)c4)cc3c21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of a new batch of 1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 36, 45.4 mg, 0.111 mmol) in 1.5 ml anhydrous DMF was treated with 55% NaH in oil (6.0 mg, 0.138 mmol). The reaction mixture was stirred for 20 min at rt, then was added iodomethane (0.009 ml, 138 mmol). The reaction mixture was stirred for 1.5 h at rt. The RM was diluted with MeOH+3 drops TFA and purified directly by Prep.HPLC (H2O (0.1% TFA)/CH3CN 95:5 to 60:40). The fractions containing products were collected together and basified with NaHCO3 (0.3 g), before being concentrated. The resulting suspension was filtered and the cake was washed with water, before being dried under high vacuum to give the title compound as a white solid. (HPLC: tR 2.62 min (Method A); M+H=424 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.96 (s, 1H), 8.38-8.36 (m, 1H), 8.18-8.16 (m, 1H), 8.13-8.09 (m, 1H), 8.06-8.04 (m, 1H), 7.99-7.95 (m, 1H), 7.60-7.58 (m, 1H), 7.57-7.55 (m, 1H), 6.54-6.51 (m, 1H), 3.93 (s, 3H), 3.85 (s, 3H), 3.58 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)=[CH:5][CH:4]=1.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(C)C(S(O)(=O)=O)=CC=CC=1.[ClH:33]>C(O)(C)C.C1(C)C=CC=CC=1>[ClH:33].[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:21][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc2c(c1)CC(=O)CC2
Agent: Cc1ccccc1S(=O)(=O)O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: COc1ccc2c(c1)CC(NCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 8 g of 7-methoxy-2-tetralone, 4.8 g of benzylamine, 150 ml of anhydrous toluene and 100 mg of p.toluenesulfonic acid is heated with reflux. The residual oil is evaporated to dryness, taken up with 100 ml of methanol then 8.5 g of sodium borohydride are carefully added to the solution at 0°-5° C. The mixture is left under stirring at room temperature overnight, then 50 ml of water are added thereto. The solution is left under stirring for 30 minutes, the solvent is evaporated, the residue is taken up with 30 ml of water and 10 ml of a concentrated ammonium hydroxide solution. The product is extracted with 200 ml of ethyl acetate, the organic phase is dried over sodium sulfate, filtered and evaporated to dryness. A dark oil is obtained that is purified by flash chromatography (elution with a 95/5 mixture of ethyl acetate/methanol). The base thus obtained is transformed into its hydrochloride by dissolving it in 40 ml of isopropanol and by adding isopropanol saturated with hydrogen chloride. Thus, there is obtained 11.4 g of 7-methoxy-2-benzylamino-1,2,3,4-tetrahydronaphtalene hydrochloride; m.p. 265°-267° C. (dec.).
Reaction SMILES: [O:1]=[C:2]1[C:10](=[O:11])[C:9]2[N:8]([CH2:12][CH2:13][P:14](=[O:17])([OH:16])[OH:15])[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=2.C(N(CC)[CH:22]([CH3:24])[CH3:23])(C)C.Cl[CH2:28][O:29][C:30](=[O:38])[CH:31]([CH2:35][CH2:36][CH3:37])[CH2:32][CH2:33][CH3:34]>CN(C=O)C>[CH2:32]([CH:31]([CH2:24][CH2:22][CH3:23])[C:30]([O:29][CH2:28][O:17][P:14]([CH2:13][CH2:12][N:8]1[CH2:7][CH2:6][CH2:5][NH:4][C:3]2[C:2](=[O:1])[C:10](=[O:11])[C:9]1=2)(=[O:15])[O:16][CH2:28][O:29][C:30](=[O:38])[CH:31]([CH2:35][CH2:36][CH3:37])[CH2:32][CH2:33][CH3:34])=[O:38])[CH2:33][CH3:34]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=c1c2c(c1=O)N(CCP(=O)(O)O)CCCN2
Reactant: CCCC(CCC)C(=O)OCCl
Solvent: CN(C)C=O
Product: CCCC(CCC)C(=O)OCOP(=O)(CCN1CCCNc2c1c(=O)c2=O)OCOC(=O)C(CCC)CCC
Temperature: 65 °C
Reaction time: 16 h
Yield: 56.4 %

Procedure:
A solution of the starting [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid (26 mmol, 6.765 g) in dry DMF (250 mL) was treated with N,N-diisopropylethylamine (104 mmol, 13.442 g) followed by 2-propyl-pentanoic acid chloromethyl ester (88 mmol, 17 g, synthesis described below) at ambient temperature and under exclusion of moisture. The reaction mixture was heated to 65° C. and held, with stirring, at 65° C. for over 16 hours. The solvent was removed by vacuum distillation and the residue was partitioned (2×) between water and ether. The organic phase was separated, dried over magnesium sulfate, filtered, and evaporated to dryness affording about 16 g of crude product as a dense yellow oil. This oil was flash chromatographed on 350 g silica gel. Elution with 8% methanol/ethyl acetate afforded 8.4 g (56%) of the desired product as a colorless solidified wax. MS (ES+): m/e 573 (M+H).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)[CH2:2][C:3]#[CH:4].I[C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>CCN(CC)CC.[Cu]I.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>[NH2:23][C:22]1[CH:24]=[CH:25][C:19]([C:4]#[C:3][CH2:2][CH2:1][N:5]2[CH2:6][CH2:7][CH:8]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:9][CH2:10]2)=[CH:20][CH:21]=1
Reactant: Nc1ccc(I)cc1
Reactant: C#CCCN1CCC(Cc2ccccc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Nc1ccc(C#CCCN2CCC(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 15.7 %

Procedure:
A mixture of 1-(but-3-yn-1-yl)-4-benzylpiperidine (227 mg, 1.00 mmol), 4-iodoaniline (263 mg, 1.20 mmol), copper (I) iodide (15 mg), PdCl2(PPh3)2 (28 mg) in 10 mL of Et3N is stirred at room temperature under N2 for 20 hr. The mixture is filtered and washed with Et3N (3×15 mL). The filtrate is evaporated in vacuo and is purified by flash chromatography to give the product as a pale yellow oil (50 mg, 16%): 1H NMR (CDCl3) 1.29 (m, 2 H) , 1.51 (m, 1 H), 1.66 (m, 2 H), 1.99 (m, 2 H), 2.58 (m, 6 H), 2.91 (m, 2 H), 3.73 (m, 2 H), 6.55 (d, J=7.8 Hz, 2 H), 7.13-7.28 (m, 7 H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:5][C:3]=1[NH2:4].[C:16]1(=O)[O:21][C:19](=[O:20])[C:18]2[CH2:22][CH2:23][CH2:24][CH2:25][C:17]1=2.O>C(O)(=O)C>[F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:5][C:3]=1[N:4]1[C:19](=[O:20])[C:18]2[CH2:22][CH2:23][CH2:24][CH2:25][C:17]=2[C:16]1=[O:21]
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: Nc1cc(OC2CCCC2)c(Cl)cc1F
Solvent: O
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Yield: 65 %

Procedure:
A solution of 2-fluoro-4-chloro-5-cyclopentyloxyaniline (0.50 g, 2.18 mmol) and 3,4,5,6-tetrahydrophthalic anhydride (0.398 g, 2.61 mmol) in acetic acid (3.0 ml) was stirred for 3 hours under refluxing. Water (20 ml) was added to the resulting reaction mixture, and the mixture was extracted with ethyl acetate (20 ml×3 times). The organic layer was dried, and the solvent was distilled off under reduced pressure. The resulting pale yellow oily substance was purified by silica gel column chromatography (development solvent: hexane/ethyl acetate=8/1) to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide as a colorless transparent oily substance (0.513 g, 1.41 mmol, 65% yield). Ethanol (1.0 ml) was added thereto for recrystallization to obtain the product as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([S:8][CH2:9][CH2:10][C:11]([F:15])=[C:12]([F:14])[F:13])[O:6][CH:7]=1.[CH3:16][S-:17].[Na+].[I-].[Na+].CN(C)C=O>O>[CH3:16][S:17][CH2:2][C:3]1[N:4]=[C:5]([S:8][CH2:9][CH2:10][C:11]([F:15])=[C:12]([F:14])[F:13])[O:6][CH:7]=1
Reactant: C[S-]
Reactant: FC(F)=C(F)CCSc1nc(CCl)co1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCc1coc(SCCC(F)=C(F)F)n1
Temperature: 80 °C
Reaction time: 10 h
Yield: 23.9 %

Procedure:
1.2 g of 4-chloromethyl-2-(3,4,4-trifluoro-3-butenylthio)oxazole, 0.5 g of sodium thiomethoxide and 0.1 g of sodium iodide were added to 20 ml of dimethylformamide (hehydrated) and stirred at 80° C. for 10 hours. After cooling, 200 ml of water were added to the reaction mixture and extracted with 100 ml of diethyl ether twice. The extracted diethyl ether layers were put together, washed with 200 ml of water, dried with magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (eluent: hexane:dichloromethane=2:1) to obtain 0.3 g of 4-methylthiomethyl-2-(3,4,4-trifluoro-3-butenylthio)oxazole as colorless oil (yield 23.9%). n20D=1.5099.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[C:13]([O-:16])([O-])=O.[K+].[K+].Cl[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1>CN(C=O)C>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][O:1][C:2]2[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]\[C:10]([O:12][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([O:16][CH3:13])=[CH:3][CH:4]=3)=[O:11])=[CH:6][CH:7]=2)=[CH:22][CH:23]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(CCl)cc1
Reactant: O=C(O)/C=C\c1ccc(O)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)/C=C\c2ccc(OCc3ccc(OC)cc3)cc2)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 182.7 %

Procedure:
To a 250 mL RB flask fitted with magnetic stirrer was charged with 25 mL of DMF. To the stirred solvent were added (2Z)-3-(4-hydroxyphenyl)prop-2-enoic acid (2 g, 12.18 mmol), K2CO3 (6.67 g, 48.73 mmol) and 1-(chloro methyl)-4-methoxybenzene (3.81 g, 24.36 mmol), stirred at 85° C. for 8 h under nitrogen atmosphere. The RM was concentrated by removal of solvent. The crude was dissolved in ethyl acetate (100 mL). The organic layer was washed with water (50 mL) and saturated brine solution (50 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as white color solid (4.5 g, yield: 91.83%). MS (ESI, 120 eV): m/z=403 (M−H)+; 1H NMR (300 MHz, CDCl3): δ 7.55-7.60 (d, 1H), 7.35-7.38 (d, 2H), 7.25-7.28 (dd, 4H), 6.81-6.88 (m, 5H), 5.09 (s, 2H), 4.92 (s, 2H), 3.73 (s, 6H).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]([OH:13])=O>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]([Cl:3])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1sccc1Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1sccc1Cl
Temperature: 25 °C

Procedure:
Excess thionyl chloride (3.5 ml, 48.0 mmoles) was added to 0.85 g (5.2 mmoles) of 3-chloro-2-thiophenecarboxylic acid (prepared according to Corral, C., et al., Heterocycles 23:1431 (1985)) dissolved in 50 ml of toluene and stirring at room temperature. After addition the solution was refluxed for 3 hours to form 3-chloro-2-thiophenecarbonyl chloride. Concentration of the reaction solution gave the acid chloride as a white solid. The acid chloride was then dissolved in 4 ml of N,N-dimethylformamide and slowly added to a cooled (ice/water bath) stirring solution of 5-chloro-2-oxindole-1-carboxamide (1.0 g, 4.71 mmoles) and 4-(N,N-dimethylamino)pyridine (1.3 g, 10.5 mmoles) in 10 ml of N,N-dimethylformamide. After 45 minutes the solution was allowed to warm to room temperature and after 2 hours was worked-up by pouring into a mixed ice/6N hydrochloric acid solution. A yellow precipitate formed. The precipitate was filtered, washed with water and dried to give 1.3 g of impure product as a yellow solid. Recrystallization with acetic acid/heptane (2:1) gave 0.77 g (2.2 mmoles) of pure title compound as yellow needles, m.p. 222°-224° C. Total yield of product was 42%.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([O:17][CH2:18][CH2:19]Cl)[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([O:17][CH2:18][CH2:19][N:32]3[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]3)[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: Cc1cccc(-c2nc3ccc(OCCCl)cc3n2Cc2ccccc2)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(-c2nc3ccc(OCCN4CCN(C)CC4)cc3n2Cc2ccccc2)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
The title compound was prepared by reacting the compound of Example 98, supra, (1.89 g, 5.01 mmol) with 1-methyl-piperazine (65 ml) in the presence of N,N-diisopropylethyl amine (4 ml) and N,N-dimethylformamide (100 ml) under nitrogen atmosphere. This reaction mixture was heated to 50° C. and stirred overnight at that temperature. The compound was purified essentially as described in Example 99, supra. NMR, IR, MS 440, 441, mp 91° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[Cl:7][CH2:8][C:9]([NH:11][C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([CH3:19])=[C:14]([Cl:20])[C:13]=1[OH:21])=[O:10]>C(OCC)(=O)C>[Cl-:7].[Cl:20][C:14]1[C:13]([OH:21])=[C:12]([NH:11][C:9]([CH2:8][N:4]2[CH:5]=[CH:6][N+:2]([CH3:1])=[CH:3]2)=[O:10])[CH:17]=[C:16]([Cl:18])[C:15]=1[CH3:19]
Reactant: Cn1ccnc1
Reactant: Cc1c(Cl)cc(NC(=O)CCl)c(O)c1Cl
Solvent: CCOC(C)=O
Product: Cc1c(Cl)cc(NC(=O)Cn2cc[n+](C)c2)c(O)c1Cl
Product: [Cl-]
Reaction time: 3 h
Yield: 76.7 %

Procedure:
4.45 ml of N-methylimidazole (56 mmol) were added to a suspension of 5 g of 2-chloro-N-(3,5-dichloro-2-hydroxy-4-methylphenyl)acetamide (18.6 mmol), obtained above in the preceding step, in 5 ml of ethyl acetate, leading to a clear solution. After 3 hours and 30 minutes, the insoluble product which formed was drained and abundantly washed with ethyl acetate. The new precipitate which formed in the filtrates was drained and abundantly washed with ethyl acetate. The white powders thus obtained were combined and dried to give 5 g of 3-[(3,5-dichloro-2-hydroxy-4-methylphenylcarbamoyl)methyl]-1-methyl-3H-imidazol-1-ium chloride whose melting point was 251° C., (yield 77%).
Reaction SMILES: [NH2:1]/[C:2](/OCC)=[CH:3]\[C:4](=O)[C:5]([F:8])([F:7])[F:6].Cl.[F:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1.C(N(CC)CC)C>>[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:2]([NH2:1])=[CH:3][C:4]([C:5]([F:6])([F:7])[F:8])=[N:22]2)=[CH:17][CH:16]=1
Reactant: NNc1ccc(F)cc1
Reactant: CCO/C(N)=C/C(=O)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Product: Nc1cc(C(F)(F)F)nn1-c1ccc(F)cc1
Yield: 63.8 %

Procedure:
According to the procedure described in Example 161A Step 3, using (E)-4-amino-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (2.747 g, 15 mmol), (4-fluorophenyl)hydrazine hydrochloride (2.439 g, 15 mmol), and triethylamine (2.03 g, 20 mmol) at 95° C. for 8 hours, which was purified by silica gel chromatography with 5-25% EtOAc/hexane as eluants to afford 1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-amine as solid (2.346 g, 64%). 1H NMR (300 MHz, CDCl3) 67.55 (m, 2H), 7.20 (m, 2H), 5.87 (s, 1H), 3.87 (br, 2H); LC-MS (ESI) m/z 246 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH2:11][OH:12]>>[C:1]([N:4]1[CH2:9][CH2:8][C:7](=[N:11][OH:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: NO
Reactant: CC(=O)N1CCC(=O)CC1
Product: CC(=O)N1CCC(=NO)CC1

Procedure:
1-Acetyl-piperidin-4-one oxime was prepared from 1-acetyl-piperidin-4-one and hydroxylamine using conditions of General Method 1. 1H NMR (400 MHz, DMSO-d6) δ 10.48 (1H, d, 3.2 Hz), 3.43-3.56 (4H, m), 2.48-2.56 (1H, m), 2.42 (1H, t, 6.2 Hz), 2.29-2.34 (1H, m), 2.17-2.26 (1H, m), 2.03 (3H, d, 4.2 Hz).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:15])[C@H:6]([CH2:8][C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[OH:7])([CH3:3])[CH3:2].I[CH2:17][CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH:18]1([CH2:17][C@H:8]([C@H:6]([OH:7])[C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[O:15])[C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: ICC1CCCC1
Reactant: CC(C)OC(=O)C[C@H](O)C(=O)OC(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)OC(=O)[C@@H](O)[C@@H](CC1CCCC1)C(=O)OC(C)C
Temperature: 20 °C

Procedure:
To a cold (5° C.) solution of diisopropyl-(S)-(−)-malate (50.0 g, 229.1 mmol, 1.0 eq.) and (iodomethyl)cyclopentane (55.6 g, 264.6 mmol, 1.15 eq.) in anhydrous THF (250 mL) under N2 was added over a period of 90 min. a solution (1M) of lithium bis(trimethylsilyl)amide (481 mL; 1.0 M, 481.1 mmol, 2.1 eq.) in THF. The temperature was allowed to warm to 20° C. and the mixture was stirred for 15 hours until completion (monitoring by TLC (SiO2); cyclohexane 8-ethyl acetate 2; treated with molibdic acid).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11]([C:23]2[S:24][C:25]([Cl:28])=[CH:26][N:27]=2)CC2C=CC(OC)=CC=2OC)(=[O:10])=[O:9])[CH:7]=1.[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([OH:49])=[C:36]([CH:38]2[CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39]2)[CH:37]=1.FC(F)(F)C(O)=O>ClCCl>[NH:40]1[CH2:41][CH:38]([C:36]2[CH:37]=[C:32]([Cl:31])[CH:33]=[CH:34][C:35]=2[O:49][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([S:8]([NH:11][C:23]3[S:24][C:25]([Cl:28])=[CH:26][N:27]=3)(=[O:9])=[O:10])=[C:5]([F:29])[CH:4]=2)[CH2:39]1
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(Cl)ccc2O)C1
Reactant: COc1ccc(CN(c2ncc(Cl)s2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ncc(Cl)s1)c1cc(Cl)c(Oc2ccc(Cl)cc2C2CNC2)cc1F

Procedure:
5-Chloro-N-(5-chloro-1,3-thiazol-2-yl)-N-(2,4-dimethoxybenzyl)-2,4-difluorobenzenesulfonamide (Preparation 655) and tert-butyl 3-(5-chloro-2-hydroxyphenyl)azetidine-1-carboxylate (Preparation 237) were stirred in dichloromethane (2 ml) and trifluoroacetic acid (1 ml) to prepare the title compound using Method F above but where the N,N-dimethylformamide was replaced with dimethyl sulphoxide. The crude product was concentrated in vacuo and purified by preparative HPLC to afford the title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24]CC5C=CC=CC=5)=[CH:20][CH:19]=4)=[N:14][C:13]=3[CH:32]=2)[S:3]1.Br.C(OCC)(=O)C.O>C(O)(=O)C>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)=[N:14][C:13]=3[CH:32]=2)[S:3]1
Reactant: O=C1NC(=O)C(Cc2ccc3oc(Cc4ccc(OCc5ccccc5)cc4)nc3c2)S1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1NC(=O)C(Cc2ccc3oc(Cc4ccc(O)cc4)nc3c2)S1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
A mixture of 0.95 g of 5-[(2,4-dioxothiazolidin-5-yl)methyl)-2-(4-benzyloxybenzyl)benzoxazole, 10 ml of a 25% hydrogen bromide solution in acetic acid and 10 ml of acetic acid is stirred at room temperature overnight. Ethyl acetate and water are added to the reaction mixture. The ethyl acetate layer is washed with water, dried and evaporated to remove the solvent. The residue is crystallized with n-hexane, and recrystallized from a mixture of ethyl acetate and n-hexane, whereby 0.42 g of 5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-(4-hydroxybenzyl)benzoxazole is obtained as colorless needles.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[O:9])=[CH:6][C:5]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[CH:4][N:3]=1.O.[NH3:28]>C(O)(C)C>[NH2:28][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[O:9])=[CH:6][C:5]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[CH:4][N:3]=1
Reactant: N
Reactant: COc1cc(C(=O)c2cc(-c3nccs3)cnc2Cl)cc(OC)c1OC
Solvent: CC(C)O
Solvent: O
Product: COc1cc(C(=O)c2cc(-c3nccs3)cnc2N)cc(OC)c1OC
Yield: 38.84 %

Procedure:
(2-Chloro-5-(thiazol-2-yl)pyridin-3-yl)(3,4,5-trimethoxyphenyl)methanone (65 mg, 0.16 mmol) as a starting material was dissolved in isopropyl alcohol (3 ml), and ammonia water (10 ml) was added thereto. The mixture was heated for 3 hours in a Steel Bomb. After completion of the reaction, the reaction mixture was vacuum concentrated, and extracted with dichloromethane (30 ml) and water (10 ml). The organic layer was washed with brine, and dried over anhydrous MgSO4. The solid substance filtered off, and the filtrate was vacuum concentrated. The resulting residue was purified by column chromatography (SiO2, n-Hex/EA=1/1) to obtain a desired yellow solid compound (24.0 mg, 38.84%).