Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](/[C:3](=[CH:9]\[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)/[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[N+]([CH:19]([CH3:21])[CH3:20])([O-])=O.[O-]CC.[Na+]>C(O)C>[C:1]([C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:19]1([CH3:21])[CH3:20])#[N:2]
Reactant: CCOC(=O)/C(C#N)=C/c1ccccc1
Reactant: CC(C)[N+](=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1(C#N)C(c2ccccc2)C1(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.2 %

Procedure:
A mixture of 534 mg (2.65 mmoles) of cyanoester 1 (produced in accordance with Example I), 0.25 mL (2.78 mmoles) of 2-nitropropane, and 4.0 mL (2.60 mmoles of sodium ethoxide) of an 0.65M solution of sodium ethoxide (prepared from sodium metal and ethyl alcohol) in ethyl alcohol was stirred at room temperature for 10 minutes and subsequently heated at gentle reflux, protected from atmospheric moisture, for 3 hours. The product was isolated by cooling the mixture to room temperature, diluting it with 30 mL of 10% aqueous sodium chloride, and extraction with dichloromethane. The dichloromethane extracts were washed with 10% aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. Removal of the dichloromethane at reduced pressure, followed by evaporative distillation, [bath temperature: 125°-135° C. (0.05 mm)], afforded 620 mg (96% yield) of cyclopropanoid cyanoester 10. The presence of a single sharp peak (δ3.30) for the cyclopropyl H in 10 suggested the presence of only one stereoisomer (neglecting optical isomerism)--the phenyl and cyano substituents being cis, as shown by subsequent decarbalkoxylation results).
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10](Br)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br-].[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[Zn+].[NH4+].[Cl-]>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:2]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: [Zn+]c1cccs1
Reactant: CCOC(=O)c1cc(Br)c(C(=O)OCC)cc1Br
Agent: [Pd]
Agent: [Br-]
Agent: [Cl-]
Product: CCOC(=O)c1cc(-c2cccs2)c(C(=O)OCC)cc1-c1cccs1
Temperature: 70 °C
Yield: 80.6 %

Procedure:
Diethyl 2,5-dibromoterephthalate (4.27 g, 11.24 mmol) and 2-thienylzinc bromide (0.5 M in THF, 50 ml, 25 mmol) are introduced into a two necked flask. The catalyst palladium tetrakis(triphenylphosphine) (Pd(PPh3)4) is then introduced into the two necked flask. The mixture thereby obtained is heated to reflux (70° C.) for 3 h. After a return to ambient temperature, the reaction mixture is poured into a saturated solution of NH4Cl. The product is extracted with ethyl acetate (3×100 ml). The extracts are combined and washed with water then dried on Na2SO4. After filtration, the solvent is removed under reduced pressure. The crude product is purified on chromatography column (silica gel, hexane/dichloromethane, 10:1, v/v)) to provide a white solid (3.5 g, 80%).
Reaction SMILES: [C:1]([OH:32])(=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].CO.[CH2:35](O)[CH3:36]>>[CH2:35]([O:31][C:1](=[O:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH3:36]
Reactant: CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: CCO
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)OCC
Reaction time: 0.75 h

Procedure:
The acid chloride of 1-triacontanoic acid is converted to the ester by adding methanol or ethanol and stirring for 1/2 to 1 hour. The alcohol was evaporated on a rotary evaporator leaving ethyl-1-triacontanoate. The ester is then reacted in a pressure vessel under about 250 atmospheres of hydrogen in the presence of a powdered copper chromite catalyst for about 12 hours at 250° C. to produce 1-triacontanol. One part of catalyst is present for every 5 to 10 parts of ester.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[N:9]1([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][CH:18]=[CH:17]3)[CH2:13][CH2:12][CH2:11][CH2:10]1.[OH-].[K+]>CO>[CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:17]2[C:16]3[C:20](=[CH:21][CH:22]=[C:14]([N:9]4[CH2:13][CH2:12][CH2:11][CH2:10]4)[CH:15]=3)[NH:19][CH:18]=2)[CH2:4][CH2:3]1
Reactant: c1cc2cc(N3CCCC3)ccc2[nH]1
Reactant: CN1CCC(=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1CC=C(c2c[nH]c3ccc(N4CCCC4)cc23)CC1
Yield: 39.5 %

Procedure:
1-methylpiperidin-4-one (1.2 g, 10.62 mmol) was added to a solution of 5-(pyrrolidin-1-yl)-1H-indole (200 mg, 1.08 mmol) in methanol (20 mL). KOH (600 mg, 10.71 mmol) was then added, and the resulting solution was stirred at reflux temperature overnight. The mixture was concentrated, quenched by the addition of water and filtered. The filter cake was washed with water and ether to afford 120 mg (37%) of 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(pyrro-lidin-1-yl)-1H-indole as a yellow solid. 1H NMR (CDCl3) δ 7.85 (s, 1H), 7.09 (d, 1H), 6.98 (s, 1H), 6.69 (d, 1H), 6.12 (s, 1H), 3.32 (t, 4H), 3.25 (s, 2H), 2.75 (t, 2H), 2.66 (t, 2H), 2.47 (s, 3H), 1.71 (t, 4H).
Reaction SMILES: [Na].[CH2:2]([SH:5])[CH:3]=[CH2:4].[C:6]([O:10][C:11]1[N:12]=[N:13][C:14](Cl)=[CH:15][CH:16]=1)([CH3:9])([CH3:8])[CH3:7]>CO>[C:6]([O:10][C:11]1[N:12]=[N:13][C:14]([S:5][CH2:2][CH:3]=[CH2:4])=[CH:15][CH:16]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)Oc1ccc(Cl)nn1
Reactant: C=CCS
Agent: [Na]
Solvent: CO
Product: C=CCSc1ccc(OC(C)(C)C)nn1

Procedure:
0.46 g(0.02 mol) of metallic sodium was dissolved in 30 ml of absolute methanol and then mixed with 1.99 ml(0.02 mol) of allylmercaptan. To this mixture was added 3.75 g(0.02 mol) of 3-(t-butoxy)-6-chloropyridazine. The reaction solution was refluxed for 24 hours and then treated according to the same manner as Example 1 to obtain the title compound as a pale yellow oil.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[N:25][CH:26]=1.O>CN(C)C=O>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=4)=[N:25][CH:26]=3)=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: FC(F)(F)c1cccc(-c2ccc(CCl)cn2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(-c2ccc(COc3ccc(CCCCn4ccnn4)cc3)cn2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
A solution of 100 mg (0.46 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 4.0 ml N,N-dimethylformamide was treated at 0° C. with 19 mg (0.48 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 125 mg (0.46 mmol) 5-Chloromethyl-2-(3-trifluoromethyl-phenyl)-pyridine were added and stirred continued at r.t. over night. After addition of 8 ml water, the precipitate was isolated, washed thoroughly with water, methanol/water 1:1 and diisopropylether. The residue was dried at 40° C. to give 170 mg (82%) of the title compound as white powder.
Reaction SMILES: CS(O)(=O)=O.C(C1C(OC)=NC2C(C=1)=CC=C(SCCC[C:24]1[C:40](OCC3C=CC=CC=3)=[CH:39][C:27]3[CH2:28][CH:29]([CH2:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:30][C:26]=3[CH:25]=1)C=2)(OC)=O.FC(F)(F)C(O)=O.C1(SC)C=CC=CC=1.C(=O)(O)[O-].[Na+]>[Cl-].[Na+].O.C(OCC)C.O1CCCC1>[C:33]1([CH2:32][CH2:31][CH:29]2[CH2:28][C:27]3[CH:39]=[CH:40][CH:24]=[CH:25][C:26]=3[O:30]2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COC(=O)c1cc2ccc(SCCCc3cc4c(cc3OCc3ccccc3)CC(CCc3ccccc3)O4)cc2nc1OC
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: c1ccc(CCC2Cc3ccccc3O2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methanesulfonic acid (0.5 mL) was added dropwise to a solution of 6-[3-(carbomethoxy-2-methoxyquinolin-7-yl)thiopropyl]-5-benzyloxy-2-(2-phenylethyl)-2,3-dihydrobenzofuran, E25, (1.1 gm; 1.7 mmoles), trifluoroacetic acid (11 mL) and thioanisole (3 mL) at 5° C. The mixture was stirred for 30 minutes and then added in portions to an ice cold stirring biphasic mixture of saturated sodium bicarbonate solution (150 mL), brine (25 mL), tetrahydrofurane (125 mL) and diethyl ether (25 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed on silica gel using 30% ethyl acetate in hexane as eluent to yield 900 mgs (95%) of 6-[3-(3-carbomethoxy-2-methoxyquinolin-7-yl)thiopropyl]-5-hydroxy-2-(2-phenylethyl-2,3-dihydrobenzofuran, E26, that had crystallized from diethyl ether, m.p. 112°-114° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][OH:10])=[CH:7][CH:8]=1.[H-].[Na+].[Br:13][C:14]1[CH:19]=[C:18](F)[CH:17]=[C:16]([Cl:21])[CH:15]=1>CN1CCCC1=O>[Br:13][C:14]1[CH:19]=[C:18]([O:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:17]=[C:16]([Cl:21])[CH:15]=1
Reactant: Fc1cc(Cl)cc(Br)c1
Reactant: COc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COc1ccc(COc2cc(Cl)cc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a mixture of 5.8 ml of p-methoxybenzyl alcohol and 90 ml of N-methylpyrrolidone was added 2.13 g of sodium hydride (60% oil dispersion), and the resulting mixture was stirred at room temperature for 45 minutes in a nitrogen atmosphere. To the reaction mixture was added 9.3 g of 1-bromo-3-chloro-5-fluorobenzene, followed by stirring at 50° C. for 3 hours. The reaction mixture was poured into 50 ml of ice-diluted hydrochloric acid and extracted three times with diethyl ether-hexane (1:1 by volume). The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography using a hexane-ethyl acetate (19:1 by volume) mixed solvent. The fraction containing the desired compound was concentrated to furnish 13.2 g of the title compound.
Reaction SMILES: O[C:2]1[CH:15]=[CH:14][C:13](OC)=[C:12]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]12O[CH2:10][CH2:9][O:8]1.I[C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1C(OC)=C[CH:25]=[CH:24]2.C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1>[C:9]1([O:8][C:7]2[C:12]3[C:3](=[CH:2][CH:15]=[CH:14][CH:13]=3)[CH:4]=[CH:5][CH:6]=2)[C:28]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][CH:10]=1
Reactant: COc1ccc(O)c2c1C1(CCC2)OCCO1
Reactant: COc1cccc2cccc(I)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: c1ccc2c(Oc3cccc4ccccc34)cccc2c1
Reaction time: 12 h
Yield: 113.6 %

Procedure:
To a solution of compound 6 (4.72 g, 0.02 mol) and 7 (8.52 g, 0.03 mol) in degassed pyridine (150 mL) were added K2CO3 (2.76 g, 0.02 mol) and Cu20 (286 mg, 0.002 mol). This reaction mixture was heated at reflux for 12 hours under a nitrogen atmosphere. After addition of additional Cu2O (286 mg, 0.002 mol) to the solution, heating was continued for 12 h. Pyridine was removed under reduced pressure and the residue was redissolved in EtOAc (300 mL). It was washed with water (100 mL) and brine (100 mL), dried (Na2SO4), and concentrated in vacuo. Chromatography on SiO2 (hexanes/EtOAc, 2: 1) gave 6.14 g (78%) of compound 9 as an oil. This oil was treated with TsOH (100 mg) in a mixture of acetone/water (7: 1, 50 mL) for 7 hours at room temperature. The reaction mixture was concentrated in vacuo and the residue was diluted with EtOAc (300 mL), washed with water (2×100 mL) and brine (100 mL), dried (Na2SO4), and concentrated in vacuo. Chromatography on SiO2 (hexanes/EtOAc, 1: 1) gave 5.44 g (100%) of compound 10 as a colorless solid: Mp 152-153 ° C; IR(neat) 2952, 1696, 1581, 1484, 1387, 1272, 1245, 1183, 1095, 980, 838, 821, 759 cm−1; 1H NMR δ7.59 (dd, 1 H, J =8.2, 0.8 Hz), 7.45 (dd, 1 H, J =8.2, 1.0Hz), 7.37 (q, 2 H, J =7.9Hz), 6.87 (dd, 1 H, J =7.6, 0.8 Hz), 6.81 (dd, 1 H, J =7.6, 0.8 Hz), 6.72 (d, 1 H, J=8.9 Hz), 6.67 (d, 1 H, J =9.1 Hz), 3.84 (s, 3 H),3.74 (s, 3 H), 3.05 (t, 2 H, J=6.2 Hz), 2.67 (t, 2 H, J =6.3 Hz), 2.11 (p, 2 H, J =6.4 Hz); 13C NMR δ197.9, 156.2, 155.4, 152.7, 149.3, 137.6,136.4, 126.7, 126.4, 124.1, 123.1, 121.7, 120.7, 118.8, 115.9, 110.1, 106.1, 56.3, 56.0, 40.9, 24.1, 22.5; MS (EI) m/z (rel intensity) 348 (M+, 100), 319 (7), 305 (10), 291 (14), 261 (8), 218 (7), 189 (12), 174 (24), 158 (45), 127 (34), 115 (29), 101 (10), 77 (15), 63 (8); HRMS (EI) Calcd for C22H20O4 348.1361, found 348.1361.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.[Cl:25][C:26]1[CH:27]=[C:28]([NH:32]N)[CH:29]=[CH:30][CH:31]=1.Cl>>[Cl:25][C:26]1[CH:27]=[C:28]([N:32]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:29]=[CH:30][CH:31]=1
Reactant: NNc1cccc(Cl)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Agent: Cl
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1cccc(Cl)c1
Yield: 51 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethyl-phenyl)-1H-pyridazin-4-one (A-3) and 3-chloro-phenylhydrazine×HCl according to the method described for Example 1 in 51% yield. MS: M=417.4 (M+H)+
Reaction SMILES: Br[C:2]1[C:3]([CH3:22])=[C:4]([CH3:21])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH:7]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[C:6]=2[C:19]=1[CH3:20].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O[Na])(C)(C)C.Cl>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH2:23]([NH:30][C:2]1[C:3]([CH3:22])=[C:4]([CH3:21])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH:7]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[C:6]=2[C:19]=1[CH3:20])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(C2c3c(C)c(Br)c(C)c(C)c3OC2(C)C)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[Na]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C2c3c(C)c(NCc4ccccc4)c(C)c(C)c3OC2(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.3 %

Procedure:
Under a nitrogen atmosphere, to toluene (500 mL) were added 5-bromo-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran (100 g) and benzylamine (36.5 mL), then palladium acetate (62.5 mg) and 2,2′-bis(diphenylphosphinino)-1,1′-binaphthyl [(BINAP, 0.52 g)], and further t-BuONa (37.45 g). The mixture was stirred at 25° C. for 20 minutes and then at 107° C. for 24 hours. To the mixture were added dropwise 1N HCl (167 mL) and water (113 mL) at 70° C. or below, and the mixture was stirred for 10 minutes. The organic layer was separated and washed with a 10% aqueous sodium chloride solution, and the solvent was distilled off. The residue was crystallized from isopropanol-water to obtain the title compound (99 g, 92.3%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH:38]=O)=[N:30]1>CO.N1CCCCC1>[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](/[CH:38]=[C:8]2\[O:9][C:5]3[C:4]([CH2:13][CH2:14][CH2:15][CH:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:30]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: COc1ccc2c(c1CCCC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1CCCC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
A solution of tert-butyl 4-[3-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)propyl]piperidine-1-carboxylate (0.0330 g, 0.0847 mmol) in methanol (3 mL) was added with 1H-indazole-3-carboxaldehyde (0.0124 g, 0.0847 mmol) and piperidine (5 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was subjected to silica gel column chromatography (chloroform/methanol). The resulting crude product was further purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl (Z)-4-(3-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}propyl)piperidine-1-carboxylate (0.0313 g, 71%).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=[C:9]([CH3:12])[C:10]=1F)(=[O:4])=[O:3].[CH3:16][O-:17].[Na+]>>[NH2:1][S:2]([C:5]1[CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=[C:9]([CH3:12])[C:10]=1[O:17][CH3:16])(=[O:4])=[O:3]
Reactant: C[O-]
Reactant: Cc1cc([N+](=O)[O-])cc(S(N)(=O)=O)c1F
Agent: [Na+]
Product: COc1c(C)cc([N+](=O)[O-])cc1S(N)(=O)=O

Procedure:
The resulting 3-aminosulfonyl-4-fluoro-5-methylnitrobenzene (0.940 g, 4 mmol) was stirred with 25% methanolic NaOMe (1.00 mL) at 60° C. for overnight. The resulting solution was then filtered through a pad of Celite, washed with methanol and the methanolic solution was concentrated to give 3-aminosulfonyl-4-methoxy-5-methylnitrobenzene. LCMS: purity: 100%, MS (m/e): 247 (MH+).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]([C:12](=[S:14])[NH2:13])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.Cl[CH:16]([C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31])=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CC(O)C>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:22]1[N:13]=[C:12]([C:11]2[C:3]([CH3:2])=[N:4][N:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=23)[S:14][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)C(Cl)C(=O)c1ccccc1OC
Reactant: Cc1nn2ccccc2c1C(N)=S
Agent: Cl
Solvent: CC(C)O
Product: CCOC(=O)c1sc(-c2c(C)nn3ccccc23)nc1-c1ccccc1OC
Yield: 351.9 %

Procedure:
Using 2-methylpyrazolo[1,5-a]pyridine-3-carbothioamide hydrochloride (300 mg, 1.3 mmol) produced in Example 11-B(v), ethyl 2-chloro-3-(2-methoxyphenyl)-3-oxopropanoate (600 mg, 2.3 mmol) produced above and 2-propanol (40 mL) as starting materials and in the same manner as in Example 11-B(vi), the title compound (1.8 g, 71%) was obtained as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:24][NH:25][O:26][CH3:27].C(N(CC)CC)C>CCOC(C)=O.CN(C=O)C.C(Cl)Cl>[CH3:27][O:26][N:25]([CH3:24])[C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]=1[OH:1]
Reactant: O=C(O)c1cccc(-c2ccccc2)c1O
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cccc(-c2ccccc2)c1O
Reaction time: 1 h
Yield: 30.3 %

Procedure:
2-hydroxy-3-phenylbenzoic acid (218, 3.0 g, 14 mmol) is dissolved in EtOAc (50 ml) and a few drops of DMF are added. Oxalyl chloride (2.5 ml, 1.5 eq) is added and the reaction is stirred under a dry atmosphere for 1 h. The reaction mixture is then concentrated in vacuo to yield a mixture of clear oil and white solid. This mixture is diluted with CH2Cl2 (50 ml) followed by the addition of N,O-dimethyl hydroxylamine hydrochloride (1.5 g, 1.1 eq) and triethylamine (3.9 ml, 2 eq). This mixture is stirred for 12-18 h under a dry atmosphere. Dilution of the reaction mixture with EtOAc and subsequent washing with dilute HCl and brine, followed by drying (MgSO4) and concentration in vacuo yields a mixture of reaction products. Flash chromatography (20/80 EtOAc/Hexanes) afforded N-methoxy-N-methyl-2-hydroxy-3-phenylbenzamide (219, 1.09 g) as a white solid.
Reaction SMILES: O1CCCC1.[CH3:6][N:7]1[C@@H:11]([CH3:12])[C@@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]([C:19](=[O:36])[CH2:20][CH2:21][CH2:22][C:23]([F:35])([F:34])[C:24]([F:33])([F:32])[C:25]([F:31])([F:30])[C:26]([F:29])([F:28])[F:27])[C:8]1=[O:37].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH:55]=[CH2:56]>CN(P(N(C)C)(N(C)C)=O)C>[CH3:6][N:7]1[C@@H:11]([CH3:12])[C@@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]([C:19](=[O:36])[C@@H:20]([CH2:21][CH2:22][C:23]([F:35])([F:34])[C:24]([F:33])([F:32])[C:25]([F:30])([F:31])[C:26]([F:27])([F:28])[F:29])[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH:50]=[CH2:49])[C:8]1=[O:37]
Reactant: C[C@H]1[C@@H](c2ccccc2)N(C(=O)CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)N1C
Reactant: C=CCCCCCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCCCCCC[C@H](CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)N1C(=O)N(C)[C@@H](C)[C@H]1c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
Anhydrous tetrahydrofuran (10 ml) was added to (4S, 5R)-3,4-dimethyl-1-(5,5,6,6,7,7,8,8,8-nonafluoro-octanoyl)-5-phenylimidazolidin-2-one (1.20 g, 2.5 mmol) under nitrogen atmosphere, and the resulting mixture was cooled to −78° C. Lithium bis(trimethylsilyl)amide (2.75 ml, 1.0 M in tetrahydrofuran, 2.75 mmol) was added to the mixture, which was then stirred for 1 hour. After addition of 8-bromo-1-octene (714 mg, 3.0 mmol) and HMPA (1.25 ml) at −78° C., the reaction mixture was warmed with stirring up to −50° C. over 2 hours and up to 0° C. over 30 minutes, and then stirred for 12 hours at 0° C. The reaction mixture was quenched with saturated aqueous ammonium chloride at 0° C., and then extracted with a mixed solvent of ethyl acetate and n-hexane (3:7). The organic layer was washed sequentially with saturated aqueous potassium bisulfate, saturated aqueous sodium chloride, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure using an evaporator and the resulting residue was purified by silica gel column chromatography (Kanto Kagaku, silica gel 60 (spherical, neutral), 40-100 μm, eluent: ethyl acetate/n-hexane=1/5 3/7) to give (4S, 5R)-3,4-dimethyl-1-[(2R)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-decenoyl]-5-phenylimidazolidin-2-one (1.37 g, Yield 93%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=O.[Cs+].[Cs+].[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27]Br.CCOCC>CC(C)=O>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[CH:9][C:2]=1[O:1][CH2:27][C:23]1[O:22][CH:26]=[CH:25][CH:24]=1)#[N:5]
Reactant: N#Cc1ccc(Nc2nccs2)cc1O
Reactant: BrCc1ccco1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: N#Cc1ccc(Nc2nccs2)cc1OCc1ccco1
Yield: 57 %

Procedure:
Following the general procedure for O-alkylation, Method B, a mixture of 2-hydroxy-4-(thiazol-2-ylamino)benzonitrile (70 mg, 0.32 mmol) and Cs2CO3 (105, 0.32 mmol) in acetone (4.4 mL) was treated with a freshly prepeared solution of 2-furylbromomethane in ether (0.60 mL, 0.32 mmol) at room temperature. Reaction control by TLC showed full conversion after 7.5 hrs. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 3/1) in 57% yield (54 mg).