Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:32])/[C:3](=[N:9]\[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:14][CH:13]=1)/[C:4]([O:6]CC)=[O:5].Cl>O1CCCC1.CO.[OH-].[Na+]>[CH3:1][CH:2]([CH3:32])/[C:3](=[N:9]\[O:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[O:23][C:24]=2[CH3:25])=[CH:16][CH:17]=1)/[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)/C(=N/OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(/C(=O)O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
Ethyl E-3-methyl-2-[4(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyrate (1.27 g) was dissolved in tetrahydrofuran (10 ml)-methanol (5 ml), and 1N aqueous solution of sodium hydroxide (5 ml) was added and the mixture was stirred for 2 hours at room temperature. 1N HCl (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residual crystal was recrystallized from ethyl acetate-hexane to obtain E-3-methyl-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyric acid (1.02 g, yield: 85%) as colorless crystals. m.p. 128-129° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:3]=1[NH2:13].Br[CH2:15][CH2:16][O:17][CH2:18][CH2:19]Br.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:3]=1[NH2:13]
Reactant: Nc1cc(Br)c(N)c(C(F)(F)F)c1
Reactant: BrCCOCCBr
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1c(Br)cc(N2CCOCC2)cc1C(F)(F)F
Reaction time: 0.5 h
Yield: 63 %

Procedure:
2-Bromo-6-trifluoromethyl-benzene-1,4-diamine (2.21 g), bis-(2-bromoethyl)ether (1.30 mL) and N,N-diisopropyl-ethylamine (4.64 mL) were mixed in N,N-dimethylformamide (19 mL) and healed to 180° C. for 30 minutes in a sealed microwave process vial. Saturated aqueous bicarbonate (100 mL) was added and the crude mixture was extracted with ethyl acetate (100 mL). The organic phase was washed with water (100 mL) and brine (100 mL), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to furnish 1.78 g (63%) of the title compound as a yellow solid. LC-MS (m/z) 326 (MH+); tR=2.54, (UV, ELSD) 83%, 75%. 1H NMR (500 MHz, DMSO-d6): 2.99 (m, 4H), 3.70 (m, 4H), 5.00 (s, 2H), 7.00 (d, 1H), 7.38 (d, 1H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:19][NH:18][C:17](=[O:20])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][C:29]([Cl:35])=[CH:30][CH:31]=2)[N:26]=1>CN(C=O)C.O>[Cl:35][C:29]1[CH:28]=[C:27]2[C:32]([CH:33]=[CH:34][C:25]([CH2:24][N:18]3[CH2:19][CH:15]([C:9]4[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[CH:8]=4)[CH2:16][C:17]3=[O:20])=[N:26]2)=[CH:31][CH:30]=1
Reactant: COc1ccc(C2CNC(=O)C2)cc1OC1CCCC1
Reactant: ClCc1ccc2ccc(Cl)cc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C2CC(=O)N(Cc3ccc4ccc(Cl)cc4n3)C2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-[3-Cyclopentyloxy-4-methoxyphenyl]-2-pyrrolidinone (1.00 g, 3.63 mmol, 1.0 eq) was added to a room temperature suspension of (145 mg, 3.63 mmol, 1.0 eq) NaH (60% oil dispersion) in 30 ml of anhydrous DMF. After stirring at room temperature for 1 hour, (0.77 g, 3.63 mmol, 1.0 eq) 2-chloromethyl-7-chloroquinoline was added, and the reaction mixture was allowed to stir at room temperature for 60 hours. The reaction mixture was then diluted with 250 mL H2O and extracted with ethyl acetate. The ethyl acetate extract was washed twice with H2O, once with brine, dried over Na2SO4 and concentrated to yield a yellow oil. Silica gel chromatography eluting with 5% CH3OH/CH2Cl2 followed by recrystallization from ethyl acetate-hexane yielded 0.61 g, 37%, of white crystals. M.P.: 106°-107° C. Elemental Analysis Calc'd for C26H27N2O3Cl: Calc'd: C, 69.15; H, 6.03; N, 6.21. Found: C, 69.22; H, 5.75; N, 615.
Reaction SMILES: [OH-].[K+].C[Si]([C:7]#[C:8][C:9]1[CH:23]=[CH:22][C:12]([N:13]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=1)(C)C.O>CO>[C:8]([C:9]1[CH:23]=[CH:22][C:12]([N:13]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=1)#[CH:7]
Reactant: CCCCN(CCCC)c1ccc(C#C[Si](C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C#Cc1ccc(N(CCCC)CCCC)cc1
Yield: 112.6 %

Procedure:
Potassium hydroxide (5 mL, 2 M) was added to a solution of 4-trimethysilylethynyl-N,N-dibutylaniline (3 g, 9.1 mmol) in MeOH (100 mL) with stirring. The solution was stirred at 40° C. for 0.5 h, poured into water (200 mL), extracted with Et2O (3×50 mL), washed with water (50 mL), dried (MgSO4) and the solvent removed under reduced pressure to give the title compound (2.35 g, 100%) as a brown oil.
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[CH3:24][NH:25][CH2:26][CH2:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1>>[CH3:24][NH:25][CH2:26][CH2:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32]/[C:4](=[C:11]2\[C:12](=[O:23])[NH:13][C:14]3[C:19]\2=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)/[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:30][CH:29]=1
Reactant: CNCCc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Product: CNCCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 89 by reacting 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(2-methylamino-ethyl)-aniline.
Reaction SMILES: [H-].[Na+].C(O)C.[CH3:6][C:7](=[O:10])[CH2:8][CH3:9].[C:11]([O:18][CH2:19][CH3:20])(=[O:17])[C:12]([O:14]CC)=O.S(=O)(=O)(O)O>>[O:14]=[C:12]([CH2:6][C:7](=[O:10])[CH2:8][CH3:9])[C:11]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCC(C)=O
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)CC
Temperature: 25 °C
Yield: 39.7 %

Procedure:
To a suspension of sodium hydride (44 g, 1.10 mol, 60% in mineral oil) dry ethanol (318 mL, 5.44 mol) was added dropwise at a temperature of 0° C. Ten minutes after the addition was completed and still at 0° C., a mixture of 2-butanone (90 mL, 1.0 mol) and diethyl oxalate (136 mL, 1.0 mol) was added dropwise. The reaction mixture was stirred at rt over night. Then, sulfuric acid was added (4N aq., 550 mL, 1.1 mol). The crude product was extracted into diethyl ether. After washing with water and brine, the organic extract was dried over anhydrous magnesium sulfate, followed by filtration and evaporation of the solvent. The residue was subjected to distillation in vacuo. At a boiling point of 68-78° C. (2.2-2.6 mbar) the product was obtained as a colorless liquid (68.4 g, 40%): 1H NMR (400 MHz, CDCl3) δ 14.40 (broad, 1H), 6.38 (s, 1H), 4.36 (quart, 2H), 2.53 (quart, 2H), 1.38 (t, 3H), 1.17 (t, 3H); DCI(NH3)-MS m/z 173 (MH)+, 190 (M+NH4)+; HPLC RT (Method I) 4.02 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[O:24])=[CH:19][CH:18]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:31][C:28]1[CH:27]=[CH:26][C:25]([C:23]([C:20]2[CH:19]=[CH:18][C:17]([CH3:16])=[CH:22][CH:21]=2)=[O:24])=[CH:30][CH:29]=1
Reactant: Cc1ccc(C(=O)c2ccc(O)cc2)cc1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Product: COc1cc2nccc(Oc3ccc(C(=O)c4ccc(C)cc4)cc3)c2cc1OC
Temperature: 180 °C
Reaction time: 0.17 h
Yield: 74.2 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (89 mg) and 4-hydroxyphenyl 4-methylphenyl ketone (248 mg) obtained in Example 25 were mixed and stirred at 180° C. for 10 minutes, and the reaction mixture was then purified in the same manner as described in Example 24 to obtain 118 mg of the title compound (yield: 74%).
Reaction SMILES: [OH:1][N:2]1[CH:6]=[C:5]([CH:7]=[O:8])[CH:4]=[N:3]1.[CH3:9][N:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11](Cl)=[O:12]>>[CH:7]([C:5]1[CH:4]=[N:3][N:2]([O:1][C:11](=[O:12])[N:10]([CH3:9])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=1)=[O:8]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=Cc1cnn(O)c1
Product: CN(C(=O)On1cc(C=O)cn1)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-4-formylpyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (73%, oil).
Reaction SMILES: [CH:1]([NH:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19]([OH:21])=O)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[NH2:25][CH:26]1[CH:33]2[CH2:34][C:29]3([OH:36])[CH2:30][CH:31]([CH2:35][CH:27]1[CH2:28]3)[CH2:32]2>>[CH:1]([NH:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([CH2:13][CH2:14][O:15][C:16]2[CH:24]=[CH:23][CH:22]=[C:18]([C:19](=[O:21])[NH:25][CH:26]3[CH:27]4[CH2:35][CH:31]5[CH2:30][C:29]([OH:36])([CH2:34][CH:33]3[CH2:32]5)[CH2:28]4)[CH:17]=2)[CH2:11][CH2:12]1)=[O:6])([CH3:2])[CH3:3]
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Reactant: CC(C)NC(=O)N1CCC(CCOc2cccc(C(=O)O)c2)CC1
Product: CC(C)NC(=O)N1CCC(CCOc2cccc(C(=O)NC3C4CC5CC3CC(O)(C5)C4)c2)CC1

Procedure:
Prepared from 3-[2-(1-isopropylcarbamoyl-piperidin-4-yl)-ethoxy]-benzoic acid and 4-amino-1-hydroxyadamantane. 1H NMR (400 MHz, CDCl3): δ 7.31-7.37 (m, 2H), 7.23-7.26 (m, 1H), 7.04 (dd, 1H), 6.37 (d, 1H), 4.18-4.24 (m, 1H), 4.06 (t, 2H), 3.98 (septet, 1H), 3.90 (d, 2H), 2.82 (t, 2H), 2.17-2.29 (m, 3H), 1.92-1.99 (m, 2H), 1.73-1.86 (m, 11H), 1.59 (d, 2H), 1.19-1.30 (m, 2H), 1.16 (d, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9](=[O:12])[NH:8][C:7]=1[C:13]([F:16])([F:15])[F:14])=[O:5])[CH3:2].[Br:17]N1C(=O)CCC1=O>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([Br:17])[C:9](=[O:12])[NH:8][C:7]=1[C:13]([F:16])([F:14])[F:15])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc(=O)[nH]c1C(F)(F)F
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(Br)c(=O)[nH]c1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
To a solution of 1,6-dihydro-6-oxo-2-(trifluoromethyl)-3-pyridinecarboxylic acid ethyl ester (157.6 g, 0.60 mol) in tetrahydrofuran (1500 mL) was added with stirring N-bromosuccinimide (124.3 g, 0.66 mol). The mixture was stirred for 1 h at room temperature. Two thirds of the solvent were removed in vacuo and the remaining material was poured portionwise (15 min) with stirring into cold water (20 L). The product precipitated and the suspension was stirred for 1 h at room temperature, filtered and the filter cake was washed extensively with water (6×200 mL). The filter cake was redissolved in ethyl acetate (2000 mL), dried with MgSO4 and concentrated to a volume of ˜300 mL. This solution was added dropwise into n-heptane (800 mL) to precipitate the product. Filtration and washing with n-heptane/ethyl acetate (4:1, 4×50 mL) and drying (in vacuo, 40° C.) yielded the title compound (93 g) as a white solid. Concentration of the mother liquor and addition of n-heptane/ethyl acetate (3:1, 150 mL) yielded a second crop of 16.4 g.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[N:20]([CH2:21][C:22]3[O:23][CH:24]=[CH:25][CH:26]=3)[C:19]3[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=3[N:17]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[O:23]1[CH:24]=[CH:25][CH:26]=[C:22]1[CH2:21][N:20]1[C:19]2[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=2[N:17]=[C:16]1[C:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3n2Cc2ccco2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1nc2ccccc2n1Cc1ccco1)C1CCNCC1
Reaction time: 0.25 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazole-2-carbonyl)piperidine (1.16 mmol), furfuryl alcohol (0.10 mL, 1.16 mmol), and triphenylphosphine (0.33 g, 1.28 mmol) in tetrahydrofuran (5 mL). Add diethyl azodicarboxylate (0.20 mL, 1.28 mmol). After 18 hours, evaporate the reaction mixture in vacuo to give a residue. Partition the residue between ethyl acetate and water. Separate the organic layer and extract with water and saturated aqueous sodium chloride solution. Dry the organic layer over Na2SO4, filter, and evaporate invacuo to give the title compound. Chromatograph the residue on silica gel eluting with 5% acetone/dichloromethane to give 1-(t-butoxycarbonyl)-4-(1-(fur-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine. Cool 1-(t-butoxycarbonyl)-4-(1-(fur-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine (1.0 mmol), and dichloromethane (5 mL). Slowly add a cold solution of trifluoroacetic acid (1 mmol) in dichloromethane (2 mL). After 15 minutes, partition the reaction mixture between dichloromethane and saturated aqueous sodium bicarbonate solution. Separate the organic layer and extract with brine. Dry the organic layer over Na2SO4, filter, and evaporate invacuo to give the title compound.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22](O)=[O:23])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[N:7][C:6]([CH3:26])=[N:5]1)([CH3:3])[CH3:2].Cl.[CH3:28][O:29][NH:30][CH3:31].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]([N:30]([O:29][CH3:28])[CH3:31])=[O:23])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[N:7][C:6]([CH3:26])=[N:5]1)([CH3:2])[CH3:3]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(C(=O)O)cc2OCC3)n(C(C)C)n1
Reactant: CNOC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylic acid (4.00 g, 11.3 mmol) and N-methoxymethanamine hydrochloride (1.32 g, 13.6 mmol) in N,N-Dimethylformamide (100 mL) was added N-Ethyldiisopropylamine 7.9 mL, 45.3 mmol) followed by HBTU (4.72 g, 12.5 mmol). The reaction mixture was stirred at room temperature for 1 hour. LC-MS analysis of the reaction mixture showed no more starting material. The solvent was removed and the residue was diluted with DCM, washed with NaHCO3 sat. aq., dried over Na2SO4, filtered and concentrated. The resulting oil was purified on silica gel (0→10% MeOH/DCM) to give 2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-N-methoxy-N-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxamide
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]([F:26])([F:25])[F:24])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[NH2:8].[C:27](O)(=O)[CH2:28][CH2:29][CH3:30]>O=P(Cl)(Cl)Cl>[CH2:28]([C:27]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([N:9]3[CH2:10][CH2:11][N:12]([C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:23]([F:26])([F:25])[F:24])=[O:16])[CH2:13][CH2:14]3)=[CH:3][C:2]=2[N:1]=1)[CH2:29][CH3:30]
Reactant: CCCC(=O)O
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cc1N
Solvent: O=P(Cl)(Cl)Cl
Product: CCCc1nc2cc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)ccc2[nH]1
Temperature: 25 °C
Yield: 52 %

Procedure:
A mixture of [4-(3,4-diaminophenyl)piperazin-1-yl](2-trifluoromethylphenyl)-methanone (0.500 g, 1.370 mmol) and butyric acid (0.180 g, 2.040 mmol) was heated to reflux in POCl3 for 12 h. The mixture was cooled to room temperature and then concentrated. The black syrup was poured over 10% Na2CO3 solution, then extracted with ethyl acetate, washed with water and brine. The solvent was removed in vacuo and the residue was purified by column chromatography to yield the title compound as a yellow syrup in 52% yield (0.115 g). 1H NMR (300 MHz, CDCl3) δ 8.90 (br., s, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.62-7.42 (m, 2H), 7.36 (d, J=9.2 Hz, 2H), 6.98 (s, 1H), 6.87 (dd, J=2.0, 8.7 Hz, 1H), 4.01-3.91 (m, 2H), 3.33 (t, J=4.8 Hz, 2H), 3.15 (t, J=4.8 Hz, 2H), 3.05-2.95 (m, 2H), 2.79 (t, J=7.4 Hz, 2H), 1.85-1.70 (m, 2H), 0.90 (t, J=7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 167.5, 155.4, 147.2, 134.5, 134.5, 132.3, 129.3, 127.2, 127.0, 126.8, 126.8, 126.7, 126.7, 126.6, 126.2, 125.4, 121.8, 114.7, 102.5, 102.4, 102.3, 51.4, 51.2, 47.3, 41.9, 31.1, 21.6, 13.8. MS (ES+) m/z 417.1 (M+1).
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:22])=[CH:6][C:7]([O:20][CH3:21])=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[CH:9]=1)(=[O:3])[CH3:2].[Cl:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([Cl:30])[CH:29]=1>>[C:1]([C:4]1[C:5]([CH3:22])=[CH:6][C:7]([O:20][CH3:21])=[C:8]([NH:10][C:11]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:25]=[C:24]([Cl:23])[CH:29]=[C:28]([Cl:30])[CH:27]=3)[CH2:36][CH2:35]2)=[O:19])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: Clc1cc(Cl)cc(N2CCNCC2)c1
Reactant: COc1cc(C)c(C(C)=O)cc1NC(=O)Oc1ccccc1
Product: COc1cc(C)c(C(C)=O)cc1NC(=O)N1CCN(c2cc(Cl)cc(Cl)c2)CC1
Yield: 78 %

Procedure:
Phenyl N-(5-acetyl-2-methoxy-4-methylphenyl)carbamate and 1-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 170 to obtain the titled compound.
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:29]=[CH:28][C:27]([CH2:30][OH:31])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:39][O:40][CH2:41][C:42](Cl)=[O:43]>C(Cl)Cl>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:29]=[CH:28][C:27]([CH2:30][O:31][C:42](=[O:43])[CH2:41][O:40][CH3:39])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCC(=O)Cl
Reactant: OCc1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)OCc1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Reaction time: 1 h
Yield: 40.5 %

Procedure:
{6-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-pyridin-3-yl}-methanol (80 mg, 0.194 mmol), CH2Cl2 (1 mL), and triethylamine (40 μL, 2.916 mmol) are added to a flask. Add methoxyacetyl chloride (23.2 mg, 0.214 mmol) dropwise at room temperature. Stir 1 h. The crude mixture is purified by flash chromatography on silica gel (MeOH/CH2Cl2) to afford the title compound (38 mg, 40%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[CH3:19][NH:20][CH:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:20]([CH3:19])[CH:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[S:8][C:6]=2[N:7]=1
Reactant: CNC1CCN(C)CC1
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN1CCC(N(C)Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.5 %

Procedure:
To a solution of 2-chloro-4-morpholinothieno[2,3-d]pyrimidine-6-carbaldehyde (0.3 g, 1.0 mmol) in 1,2-dichloroethane (3.6 mL) was added N,1-dimethylpiperidin-4-amine (1.4 mmol), and AcOH (1.0 mmol). After the reaction mixture stirred 10 min at room temperature, Na(OAc)3BH (1.1 mmol) was added then the mixture stirred 72 h at room temperature. The reaction was quenched by the addition of saturated aqueous NaHCO3. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organics were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-20% MeOH in CH2Cl2) to afford pure N-((2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)-N,1-dimethylpiperidin-4-amine (0.2 g). MS (Q1) 410 (M)+
Reaction SMILES: [OH:1]S(O)(=O)=O.[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]#[C:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]>O>[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=[O:1])[CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C(O)CCC#Cc1ccccc1Br
Reactant: O=S(=O)(O)O
Solvent: O
Product: O=C(O)CCCC(=O)c1ccccc1Br
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Into 20cc of concentrated H2SO4 was dissolved 0.1g (0.4 mmol) of the product of Example 1 to give a brown solution. The solution was allowed to stand at room temperature for 10 minutes. Thereafter, the solution was cooled to 0°C. in an ice bath and ice was then added to it. The solution was then diluted with water and extracted twice with ethyl acetate. The combined extracts were sequentially washed once each with water and brine and then dried (MgSO4). Removal of the solvent under reduced pressure produced a yellow oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:26])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:25])[C:9]([OH:24])([C:14]1[CH:15]=[N:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([F:13])([F:12])[F:11].C(=O)([O-])[O-].[Cs+].[Cs+].[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>CN(C)C(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:26][S:39]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)(=[O:41])=[O:40])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:25])[C:9]([OH:24])([C:14]1[CH:15]=[N:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([F:11])([F:13])[F:12]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1cnc2ccccc2c1)C(F)(F)F
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(c1ccc(OS(=O)(=O)c2ccccc2)cc1Cl)C(O)(c1cnc2ccccc2c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 39.3 %

Procedure:
To a suspension of 3-chloro-4-(3,3,3-trifluoro-2-hydroxy-1-methyl-2-quinolin-3-yl-propyl)-phenol (Example 179, 55 mg) and cesium carbonate (52 mg) in N,N-dimethylacetamide (1 ml) was added benzenesulfonyl chloride (25 mg). After being stirred at room temperature for 2 days, more benzenesulfonyl chloride (14 mg) was added and the mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with EtOAc. The organic phase was washed with brine and with water and dried (MgSO4). The product was purified by chromatography (SiO2, cyclohexane=>cyclohexane/EtOAc 1:1) to give the title compound (29 mg) as an off-white solid. MS (m/e)=522.2 [M+H+].
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].O=[C:9]([CH3:25])[CH:10]=[CH:11][C:12]1[CH:24]=[CH:23][CH:22]=[CH:21][C:13]=1[O:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C([O-])(=O)C.[NH4+].C1(C)C=CC=CC=1>O>[O:6]=[C:5]1[CH:7]=[SH:1](=[C:9]([CH3:25])[CH:10]=[CH:11][C:12]2[CH:24]=[CH:23][CH:22]=[CH:21][C:13]=2[O:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:2](=[S:3])[NH:4]1
Reactant: CCOC(=O)COc1ccccc1C=CC(C)=O
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)COc1ccccc1C=CC(C)=[SH]1=CC(=O)NC1=S
Yield: 35.8 %

Procedure:
A mixture of 1.33 g (0.01 mol) of rhodanine, 2.48 g (0.01 mol) of ethyl 2-(3-oxo-1-butenyl]phenoxyacetate, 0.77 g (0.01 mol) of ammonium acetate and 20 ml of toluene was heated under reflux for 3 hours. After cooling, 100 ml of water were added to the reaction mixture which was extracted with ethyl acetate (3×100 ml). The ethyl acetate layer was washed twice with water and once with a saturated saline solution, dried and concentrated under reduced pressure to give orange crystals. The crystals were purified by silica gel column chromatography (eluent, chloroform : ethyl acetate) to obtain ethyl 2-[3-(4-oxo-2-thioxo-5-thiazolinylidene)-1-butenyl]phenoxyacetate (35.8% yield) from the first eluate.