Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:23])[C:17]=4[C:16]=3[CH:41]=[CH:42][CH2:43][CH2:44][CH3:45])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.[H][H]>[Pt]=O.C(O)C>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])[C:22](=[O:23])[C:17]=4[C:16]=3[CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:13])[F:14])[CH2:3][CH2:2]1
Reactant: CCCC=Cc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CCCCCc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Yield: 62.1 %

Procedure:
To 26 ml of ethanol solution containing 1.08 g (1.60 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-(1-pentenyl)-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in the same manner as in Example 68-(a) was added 43.8 mg of platinum oxide, and the mixture was stirred under 1 atm hydrogen atmosphere at room temperature for 3 hours. After completion of the reaction, the insoluble material was filtered off from the reaction mixture, and the filtrate was concentrated under reduced pressure. The residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=1:3 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 0.66 g of the title compound as a colorless oil. (Yield: 626).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]([CH3:12])=[O:11].[OH-].[Na+].O>C(O)C>[C:2]1([CH:1]=[CH:9][C:10](=[O:11])[CH:12]=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.2 %

Procedure:
Benzaldehyde (1b, 2.54 ml, 25.0 mmol) and acetone (19, 0.90 ml, 12.2 mmol) were combined in ethanol (20 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (2.50 g, 62.5 mmol) and water (25 ml) was added and the solution stirred for 3 hr at room temperature. The resulting precipitate was filtered and recrystallized from ethanol to afford 2.35 g (82%) of yellow crystals: mp 110-112° C. [expected mp 112-114° C.]; 1H NMR: δ 7.07 (d, 2H, J=15.9 Hz), 7.40 (m, 8H), 7.61 (m, 2H), 7.73 (d, 2H, J=15.9 Hz); 13C NMR: δ 125.4, 128.3, 12.9, 130.4, 134.7, 143.2, 188.7.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:7]=1[NH2:26].Cl.[N:28]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.O>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:7]=1[NH:26][N:28]=[C:12]2[S:13]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: O=N[O-]
Reactant: Nc1c(CS(=O)(=O)c2cccc3ccccc23)cccc1OCCCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2c(OCCCCl)cccc12
Temperature: 3 °C

Procedure:
A mixture of 2-(3-chloro-propoxy)-6-(naphthalene-1-sulfonylmethyl)-phenyl amine (1.66 g, 4.25 mmoles) in THF (7 mL), and 4M HCl (15 mL) was stirred in a round bottom flask, under nitrogen, at 3° C. A solution of sodium nitrite (0.3 g, 4.4 mmoles) in H2O (1 mL) was added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 mL) and extracted with EtOAc. Compound was dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (1.6 g, 4 mmoles).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.[CH2:14]([NH2:24])[C:15]1[CH:23]=[CH:22][C:21]2[O:20][CH2:19][O:18][C:17]=2[CH:16]=1>C(O)C>[O:20]1[C:21]2[CH:22]=[CH:23][C:15]([CH2:14][NH:24][C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=4)[N:3]=[C:2]([Cl:1])[N:11]=3)=[CH:16][C:17]=2[O:18][CH2:19]1
Reactant: Clc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: NCc1ccc2c(c1)OCO2
Solvent: CCO
Product: Clc1ccc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c2c1
Temperature: 55 °C
Yield: 96.2 %

Procedure:
A solution of 2,4,6-trichloroquinazoline (0.186 g, 0.80 mmol) in ethanol (20 ml) was heated to 55° C. and piperonylamine (0.145 g, 0.96 mmol) was added. The resulting mixture was stirred at 55° C. over night. Volatiles were evaporated and the residue was partitioned between methylene chloride and saturated solution of ammonium hydroxide. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to yield 0.268 g (96% yield) of the title compound as a white solid. 1H NMR (300 MHz, DMSO) δ 4.59-4.63 (d, 2H), 5.98 (s, 2H), 6.86 (s, 2H), 6.96 (s, 1H), 7.62-7.66 (d, 1H), 7.79-7.84 (d, 1H), 8.46 (s, 1H), 9.24-9.28 (t,1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[NH:13][N:12]=[N:11][N:10]=1.IC.[C:16](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:10]=[N:11][N:12]([CH3:16])[N:13]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc(Br)c(-c2nnn[nH]2)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nnc(-c2cc(F)ccc2Br)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.4 %

Procedure:
A mixture of 5-(2-bromo-5-fluoro-phenyl)-1H-tetrazole (1.0 g, 4.12 mmol), iodomethane (1.12 g, 10 mmol) and potassium carbonate (1.5 g) in dimethylformamide (5 mL) was stirred at room temperature for 16 hrs, then concentrated in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2) to provide 650 mg (Yield 61%) of the title compound as a white powder. 1H NMR (500 MHz, CDCl3) δ ppm: 4.45 (3 H, s) 7.03-7.11 (1 H, m) 7.63 (1 H, dd, J=8.9, 3.1 Hz) 7.69 (1 H, dd, J=8.9, 5.5 Hz); 13C NMR(126 MHz, CDCl3) δ ppm: 39.86, 116.28, 118.66, 118.76, 130.13, 135.73, 161.74, 163.53; LC/MS m/z 257/259.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([C:15]([OH:17])=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.[NH2:29][C:30]1[CH:49]=[CH:48][C:33]([O:34][CH:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]2)=[CH:32][CH:31]=1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH:13]([C:15]([NH:29][C:30]2[CH:31]=[CH:32][C:33]([O:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])[CH2:37][CH2:36]3)=[CH:48][CH:49]=2)=[O:17])[CH2:14]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)C3CN(C(=O)OCc4ccccc4)C3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(Benzyloxycarbonyl)azetidine-3-carboxylic acid (5.10 g, 21.67 mmol), 1-hydroxybenzotriazole hydrate (4.15 g, 27.1 mmol) and tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate (5.28 g, 18.06 mmol) were suspended in dimethylformamide (25 ml) followed by addition of diisopropylethylamine (9.64 ml, 54.2 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (5.19 g, 27.1 mmol). The mixture was stirred at room temperature overnight and the solution was diluted with water. The resulting turbid mixture was extracted with ethyl acetate and then ethyl acetate/tetrahydrofuran. The organics were combined and dried over magnesium sulfate, filtered and concentrated to give a solid which was triturated with ether and filtered to give the title compound.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([F:11])=[CH:7][CH:8]=2)[C:3]1=O.Cl.[NH:14]1[CH:18]=[C:17]([CH2:19][C:20]([NH2:22])=[S:21])[N:16]=[CH:15]1>>[F:11][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][C:2]3[S:21][C:20]([CH2:19][C:17]4[N:16]=[CH:15][NH:14][CH:18]=4)=[N:22][C:3]=3[C:4]=2[CH:5]=1
Reactant: NC(=S)Cc1c[nH]cn1
Reactant: O=C1c2cc(F)ccc2CC1Br
Agent: Cl
Product: Fc1ccc2c(c1)-c1nc(Cc3c[nH]cn3)sc1C2

Procedure:
Starting compounds: 2-bromo-6-fluoro-1-indanone, 4-imidazolylthioacetamide hydrochloride
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=1)Br.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH2:25])=[S:24].CO>C(O)C>[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]1[S:24][C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:25]=1
Reactant: NC(=S)c1ccccc1Cl
Reactant: CSc1ccc(C(Br)C(=O)c2ccccc2F)cc1
Solvent: CO
Solvent: CCO
Product: CSc1ccc(-c2sc(-c3ccccc3Cl)nc2-c2ccccc2F)cc1
Temperature: 25 °C
Yield: 79.3 %

Procedure:
A solution of 1-(2-fluorophenyl)-2-(4-methylthiophenyl)-2-bromo-ethanone from Step 3 (1.39 g, 4.1 mmol) and 2-chlorothiobenzamide (0.71 g, 4.1 mmol) in 10 mL of ethanol was heated to reflux for 4.4 hours. The solution was cooled to room temperature and poured into 25 mL of methanol, chilled with an ice bath whereupon crystals of pure product formed which were isolated by filtration and air dried to afford the thiazole (1.34 g, 79%): mp 117°-119° C. 1H NMR (CDCl3) 300 MHz 8.37 (m, 1H), 7.62 (m, 2H), 7.49 (d, J=7.7Hz,1H), 7.32 (m, 7H), 7.22 (d, J=8.5Hz, 2H), 2.51 (s, 3H). Mass spectrum M+ +H=412.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9]([CH3:19])=[CH:10][C:11](=[O:18])[N:12]3[CH2:15][CH:16]=O)=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.[O:20]1[C:25]2[CH:26]=[CH:27][C:28]([CH2:30][N:31]([CH:39]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:29][C:24]=2[O:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[CH:1]1([O:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9]([CH3:19])=[CH:10][C:11](=[O:18])[N:12]3[CH2:15][CH2:16][N:42]3[CH2:43][CH2:44][CH:39]([N:31]([CH2:30][C:28]4[CH:27]=[CH:26][C:25]5[O:20][CH2:21][CH2:22][O:23][C:24]=5[CH:29]=4)[C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:40][CH2:41]3)=[CH:7][CH:6]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(=O)n(CC=O)c2cc(OC3CC3)ccc12
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(OC3CC3)ccc12
Reaction time: 0.25 h
Yield: 72.9 %

Procedure:
To 2 mL of dichloromethane solution containing 60 mg of (7-cyclopropoxy-4-methyl-2-oxo-1,2-dihydroquinolin-1-yl)acetaldehyde, 81 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 20 μL of acetic acid were added, and stirred for 15 min. To the reaction mixture, 74 mg of sodium triacetoxyborohydride was added, and stirred for 40 min. Chloroform and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=1:4], to give 0.10 g of tert-butyl (1-(2-(7-cyclopropoxy-4-methyl-2-oxo-1,2-dihydroquinolin-1-yl)ethyl)piperidin-4-yl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)carbamate as a colorless oil.
Reaction SMILES: [Cl-].[NH4+].[Cl:3][C:4]1[C:5]([O:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:6]([C:8]([N+:18]([O-])=O)=[CH:9][C:10]=1[O:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[NH2:7]>CO.O.[Fe]>[Cl:3][C:4]1[C:5]([O:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:6]([NH2:7])[C:8]([NH2:18])=[CH:9][C:10]=1[O:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: Nc1c([N+](=O)[O-])cc(Oc2cccnc2)c(Cl)c1Oc1cccnc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1cc(Oc2cccnc2)c(Cl)c(Oc2cccnc2)c1N

Procedure:
128 mg of ammonium chloride and 67 mg of iron powder were added to a suspension of 143 mg of 3-chloro-2,4-bis(pyridin-3-yloxy)-6-nitroaniline in 8 ml of methanol and 4 ml of water, and the reaction liquid was heated under reflux for 2 hours. The reaction liquid was filtered, and the solvent was evaporated away under reduced pressure. The residue was diluted with ethyl acetate, washed with water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away to obtain the entitled compound as a pale brown solid.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:35])=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:43][N:44]([CH3:48])[CH2:45][CH2:46]Cl>CN(C)C=O>[CH3:43][N:44]([CH3:48])[CH2:45][CH2:46][O:35][C:3]1[C:2]([F:1])=[C:26]([NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[C:6]2[C:7](=[O:25])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)[O:10][C:5]=2[C:4]=1[F:34]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(O)c(F)c3o2)cc1F
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1c(F)c(NC(=O)C(C)(C)C)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Temperature: 50 °C
Reaction time: 12 h
Yield: 41 %

Procedure:
490 mg (1.00mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-hydroxy-5-pivaloylamino-4H-1-benzopyran-4-one obtained in Example 86 (3) was dissolved in 40 mL of dimethylformamide, 3.60 mg (26.0 mmol) of potassium carbonate and 2.88 g (20.0 mmol) of 2-dimethylaminoethyl chloride hydrochloride were added and the mixture was stirred at 50° C. for 12 hours. The reaction solution was filtered, the filtrate was concentrated, water was added to the residue and the mixture was extracted once with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=30:1) to give 230 mg of 7-(2-dimethylaminoethoxy)-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-pivaloylamino-4H-1-benzopyran-4-one (yield: 41%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C@@H:6]([N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:7]([CH3:11])[CH2:8][CH2:9][OH:10].N1C=CN=C1.[CH3:26][C:27]([Si:30](Cl)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([CH3:29])[CH3:28]>CN(C=O)C.CCOC(C)=O>[Si:30]([O:10][CH2:9][CH2:8][C@@H:7]([CH3:11])[C@H:6]([N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)([C:27]([CH3:29])([CH3:28])[CH3:26])([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: C[C@H](CCO)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a solution of 2.18.1d (1.87 g, 6.60 mmol) in DMF (9.7 mL) at 0° C. was added imidazole (988 mg, 14.52 mmol, 2.2 equiv) and TBDPSCl (2.18 g, 7.92 mmol, 1.2 equiv). After stirring at room temperature for 12 hours, the reaction mixture was diluted with EtOAc (20 mL) and washed sequentially with water (5 mL), aqueous 1.0 M HCl solution, saturated aqueous NaHCO3 solution and brine. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (EtOAc/heptane) to give product 2.18.1e (3.55 g, yield 100%).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([CH3:6])=[O:5].[Cl:7][C:8]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:9]=1[CH:10]=O>O>[Cl:7][C:8]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:9]=1[CH:10]=[CH:3][C:4](=[O:5])[CH3:6]
Reactant: CC(C)=O
Reactant: O=Cc1cc(Cl)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In water (500 ml) was dissolved sodium hydroxide (4.0 g), and to the mixture was added acetone (100 ml), and then 2,5-dichlorobenzaldehyde (15.9 g). The mixture was stirred at room temperature for 1 hour, and acetone was evaporated under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and concentrated under reduced pressure to give 4-(2,5-dichlorophenyl)-3-buten-2-one (19.0 g).
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9]CC)=[O:8])=[CH:5][CH:4]=1)#[N:2].CO.[OH-].[Na+]>O>[C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)c1ccc(C#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1ccc(C(=O)O)cc1
Temperature: 80 °C
Yield: 87.9 %

Procedure:
A mixture containing ethyl p-cyanobenzoate (87.5 g, 0.5 mol), methanol (192.5 g), water (449.2 g) was placed in a 1 l-flask. The mixture was heated to 80° C. with stirring. A 20% aqueous solution of sodium hydroxide was added to the mixture so as to adjust the pH of the mixture at 8.0-8.3. Eighteen hours after the reaction started, liquid chromatographic analysis revealed that the reaction mixture contained 64.7 g of p-cyanobenzoic acid (yield 88%). The reaction mixture was cooled to 30° C., and hydrochloric acid was added thereto to lower the pH to 3.1. The mixture was heated again to 82° C., and methanol was added thereto until the mixture dissolves. The resultant mixture was cooled for crystallization, to thereby obtain 64.6 g of p-cyanobenzoic acid crystal (purity 96.7%, yield 85%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]=[N:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: BrCCCCCCBr
Reactant: N#Cc1ccc(N=Nc2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(N=Nc2ccc(OCCCCCCBr)cc2)cc1
Temperature: 25 °C
Yield: 47 %

Procedure:
0.2 mol (44.6 g) of 4-hydroxy-4′-cyanoazobenzene, 2 mol (488.1 g) of 1,6-dibromohexane, 1.45 mol (220.4 g) of K2CO3 and 800 ml of acetone were charged in a 2-liter three-necked flask and reacted under reflux for 20 hours by using a water bath. After cooling to a room temperature, by-products and excess K2CO3 were removed by filtration. After concentrating to about 1/2 by using a rotary evaporator, the product was left in a refrigeration box to be crystallized. After filtration under suction, crystals were washed with n-hexane and dried under a reduced pressure (0.117 mol (45.3 g, yield; 58.6%)). Further, they were recrystallized in ethanol to obtain 0.094 mol of 4-(6-bromohexyloxy)-4′-cyanoazobenzene (36.3 g, yield: 47.0%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:11])=[N:6][CH:5]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:25])(=O)=O.[Br:27][C:28]1[O:32][C:31]([CH:33]=O)=[CH:30][CH:29]=1>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([NH2:10])[C:7]2[N:6]([N:25]=[C:33]([C:31]3[O:32][C:28]([Br:27])=[CH:29][CH:30]=3)[N:11]=2)[CH:5]=1)=[O:12]
Reactant: COC(=O)c1cnc(N)c(N)c1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: O=Cc1ccc(Br)o1
Product: COC(=O)c1cc(N)c2nc(-c3ccc(Br)o3)nn2c1

Procedure:
The title compound, MS m/e (%): 338.2 (M+, 100), was prepared in accordance with the general method of example 1 from 5,6-diamino-nicotinic acid methyl ester, O-mesitylene-sulfonylhydroxylamine, and 5-bromofuran-2-carboxaldehyde. The purification was performed by flash column chromatography on silica eluting with a mixture of ethyl acetate and n-hexane.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.CN(C)/[CH:17]=[C:18](/[C:24](=[O:33])[C:25]1[CH:30]=[C:29]([I:31])[CH:28]=[CH:27][C:26]=1F)\[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>O>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][CH:3]([CH2:2][N:1]2[C:26]3[C:25](=[CH:30][C:29]([I:31])=[CH:28][CH:27]=3)[C:24](=[O:33])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17]2)[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1cc(I)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCC(CN)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cn(CC2CCN(C(=O)OC(C)(C)C)C2)c2ccc(I)cc2c1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
3-(Aminomethyl)-1-N-Boc-pyrrolidine (2.5 g, 12.5 mmol) was added to the stock solution of (Z)-ethyl 3-(dimethylamino)-2-(3-iodobenzoyl)acrylate (Intermediate 24, 0.34M, 34 mL, 11.3 mmol). The reaction mixture was heated at 50° C. for 3 h. The solvent was removed in vacuo and the resulting residue was dried in a vacuum oven for 1.5 h. The residue was then dissolved in dimethylformamide (20 mL) and potassium carbonate powder (2.2 g, 15.8 mmol) was added. The reaction mixture was heated at 70° C. for 3 h then cooled to room temperature. Water (100 mL) was added and the suspension was extracted with 1:1 ethyl acetate: methyl tert-butyl ether (3×50 mL). The organic layers were dried over sodium sulfate, and the solvent was removed in vacuo. The residue was suspended in methyl tert-butyl ether (20 mL) and stirred at 40° C. for 1 h. The suspension was filtered and the solid dried to give 4.15 g (70% yield) of ethyl 1-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methyl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate as a yellowish powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:11][OH:12])=[CH:8][C:9]=1[Br:10])=[O:4].I(O)(=O)(=O)=[O:14]>CC#N.CCOC(C)=O.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([OH:14])=[O:12])=[CH:8][C:9]=1[Br:10])=[O:4]
Reactant: [O-][I+3]([O-])([O-])O
Reactant: COC(=O)c1sc(CO)cc1Br
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1sc(C(=O)O)cc1Br
Reaction time: 2 h
Yield: 101.3 %

Procedure:
A mixture of 3-Bromo-5-hydroxymethyl-thiophene-2-carboxylic acid methyl ester (0.19 g, 0.76 mmol) and Periodic Acid (0.38 g, 1.66 mmol) in MeCN (10 ml) was stirred for 30 min A solution of PCC (0.010 g, 0.015 mmol) in MeCN (0.2 ml) was added. After 2 h, the reaction mixture was diluted with EtOAc (50 ml), washed with sodium sulfite, brine, dried over sodium sulfate, filtered and evaporated. Isolate 0.204 g (100%) of yellow solid product.