Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[NH:5]1[CH2:10][CH2:9][CH:8]([CH:11]([NH:13][CH:14]=[O:15])[CH3:12])[CH2:7][CH2:6]1.ClC1N=C(Cl)C=CN=1.C(N(C(C)C)C(C)C)C>C(O)C>[N:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:13][CH:14]=[O:15])[CH3:12])=[CH:7][CH:6]=1
Reactant: CC(NC=O)C1CCNCC1
Agent: Clc1ccnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CC(=O)O
Product: CC(NC=O)c1ccncc1

Procedure:
N-(1-Piperidin-4-yl-ethyl)-formamide; compound with acetic acid (350 mg, 1.61 mmol), 2,4-dichloro-pyrimidine (265 mg, 1.78 mmol) and ethyl-diisopropyl-amine (848 mg, 6.56 mmol) in 20 ml of ethanol were heated under reflux for 5 hours. The mixture was evaporated and the residue dissolved in water and extracted with ethyl acetate. The organic layer was dried with MgSO4 and evaporated.
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][N:13]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15]1.C(=O)([O-])O.[Na+]>C(O)(=O)C.O>[NH2:3][C:2]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][N:13]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:18][CH2:19]1)=[O:1]
Reactant: N#C[O-]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1N)C1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1ccccc1NC(N)=O)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.0 g (0.03 mol) of sodium cyanate were added to a solution of 7.91 g (0.02 mol) of N-[(2-aminophenyl)methyl]-N-(1,1-dimethylethoxycarbonyl)-1-(phenylmethyl)-4-piperidineamine in a mixture of 5.5 ml glacial acetic acid and 80 ml of water and the mixture was stirred overnight at ambient temperature. The mixture was made slightly alkaline by the addition of saturated sodium hydrogen carbonate solution, then extracted exhaustively with EE. The combined ethyl acetate extracts were washed with water, dried over sodium sulphate and concentrated by evaporation in vacuo. 8.7 g (99% of theoretical) of colourless crystals were obtained, Rf 0.71 (El D), which were further processed without any additional purification.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([O:13]CC)=O.[CH2:16]([NH:23][C:24](=O)[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O=P(Cl)(Cl)Cl>ClCCCl>[CH2:16]([N:23]1[C:11](=[O:13])[C:3]2[C:4]3[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]=2[N:1]=[C:24]1[C:25]1[CH:26]=[C:27]([O:35][CH3:36])[C:28]([O:33][CH3:34])=[C:29]([O:31][CH3:32])[CH:30]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc(C(=O)NCc2ccccc2)cc(OC)c1OC
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(-c2nc3sc4c(c3c(=O)n2Cc2ccccc2)CCCC4)cc(OC)c1OC
Temperature: 0 °C
Yield: 68 %

Procedure:
Commercially available ethyl 2-amino-4,5,6,7-tetrahydrobenzo(b)-thiophene-3-carboxylate (6.0 g, 26.6 mmol, 100 mol-%) and N-benzyl-3,4,5-trimethoxybenzamide (10.4 g, 34.6 mmol, 130 mol-%) were dissolved in dry 1,2-dichloroethane. The reaction mixture was cooled with an ice-salt-bath and POCl3 (1.7 ml, 24.6 mmol, 130 mol-%) was added. The reaction mixture was refluxed for 24 hours. During refluxing POCl3 (340 μl) was added twice. The reaction mixture was poured into ice-water and after neutralization with sodium acetate the product was extracted into dichloromethane. The organic phases combined were washed with sodium bicarbonate sat. (3×50 ml) and dried with MgSO4. The yield after recrystallization from i-propanol was 8.3 g (yield 68%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[O:27])=[C:24](Br)[N:23]=[C:22]3[O:29][CH2:30][CH2:31][CH3:32])=[C:16]([F:33])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][CH2:35]OC(C)=O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[O:27])=[C:24]([CH:34]=[CH2:35])[N:23]=[C:22]3[O:29][CH2:30][CH2:31][CH3:32])=[C:16]([F:33])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCOc1nc(Br)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Reactant: CCOC(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1nc(OCCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2F)c1C=O
Temperature: 110 °C
Reaction time: 1 h

Procedure:
Intermediate (18a) (10.0 g, 19.3 mmol) was dissolved in DMF (100 mL). Tetrakis(triphenylphosphine)palladium(0) (400 mg, 0.4 mmol) was added, followed by (2-ethenyl)tri-n-butyltin (8.5 mL, 29.0 mmol). The reaction vessel was fitted with a reflux condenser and was heated to 110° C. with stirring for 1 hour, under nitrogen. The mixture was cooled and 200 mL EtOAc was added. The organic layer was washed with a 20% solution of potassium fluoride (2×50 mL) followed by saturated aqueous NaCl (100 mL), then dried over MgSO4, filtered and concentrated in vacuo. The resulting material was purified by silica gel chromatography (0-80% EtOAc:hexanes) to yield intermediate (18b) as a colorless oil (7.2 g). Anal. HPLC retention time=4.9 minutes. Gradient conditions: 25% solvent B/75% solvent A to 95% solvent B/5% solvent A over 6 minutes. MS m/z: [M+H+] calcd for C27H29FN2O4, 465.22; found 465.6. 4′-[2-Propoxy-5-(hydroxyiminomethyl)-4-vinylimidazol-1-ylmethyl]-3′-fluorobiphenyl-2-carboxylic acid t-butyl ester (18c): Intermediate (18b) (7.2 g, 15.5 mmol) was dissolved in pyridine (30 mL). Hydroxylamine hydrochloride (4.0 g, 57.9 mmol) was added followed by water (20 mL) and the mixture was stirred at 40° C. for 2 hours. The reaction was quenched with water, extracted with 200 mL EtOAc, washed with 3×100 mL 1M phosphoric acid, 1×100 mL saturated sodium bicarbonate solution, and 2×100 mL saturated aqueous NaCl, then dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-80% EtOAc:hexanes) to yield intermediate (18c) as a white solid (7.4 g). Anal. HPLC retention time=4.9 minutes. Gradient conditions: 25% solvent B/75% solvent A to 95% solvent B/5% solvent A over 6 minutes. MS m/z: [M+H+] calcd for C27H30FN3O4, 480.23; found 480.4. 1H-NMR (DMSO-d6) 10.99 (1H, s), 8.21 (1H, s), 7.67 (1H, d), 7.54 (1H, m), 7.44 (1H, s), 7.34 (1H, m), 7.11 (2H, m), 6.81 (2H, m), 5.73 (1H, d), 5.36 (2H, s), 5.10 (1H, d), 1.66 (2H, m), 1.13 (9H, s), 0.85 (4H, m).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])O[C:5]2=[O:12].Cl.[NH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17]>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:14]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:5]2=[O:12]
Reactant: O=C1OC(=O)c2cc(O)ccc21
Reactant: COC(=O)CN
Agent: Cl
Solvent: Cc1ccccc1
Product: COC(=O)CN1C(=O)c2ccc(O)cc2C1=O
Temperature: 200 °C

Procedure:
In a MW vial 5-hydroxyisobenzofuran-1,3-dione (561 mg, 3.42 mmol) and methyl 2-aminoacetate hydrochloride (386 mg, 3.08 mmol) were suspended in toluene (15 ml). The obtained mixture was heated under microwave irradiation at 200° C. for 5 hours. A mixture of the desired compound with an undesired byproduct (about 1:2 ratio) was obtained. After filtration, the obtained beige solid was purified by silica gel flash chromatography (petroleum ether/EtOAc 1/1 to EtOAc) to give 7 methyl 2-(5-hydroxy-1,3-dioxoisoindolin-2-yl)acetate (78 mg, 0.332 mmol, 9.70% yield, MS/ESI+ 235.9 [MH]+).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][S:15][CH2:16][CH2:17]Cl)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][S:15][CH:16]=[CH2:17])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CSCCCl)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: C=CSCc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 98.8 %

Procedure:
A mixture of 4-chloro-4'-(2-chloroethylmercaptomethyl)benzophenone (4.9 g) and 1,8-diaza-bicyclo[5.4.0]undec-7-ene (4.3 g) in 100 ml of toluene was stirred for 3 hours at 80° C. After that, the mixture was washed with aqueous 2N hydrochloric acid solution and water, followed by drying over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 4-chloro-4'-vinylmercaptomethylbenzophenone (4.3 g).
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][N:11]([C:16]1[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=3)[N:17]=1)[CH2:12]2)=O)(C)(C)C.FC(F)(F)C(O)=O.N>ClCCl>[CH:13]12[NH:8][CH:9]([CH2:15][CH2:14]1)[CH2:10][N:11]([C:16]1[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=3)[N:17]=1)[CH2:12]2
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(c1ccc3cc([N+](=O)[O-])ccc3n1)C2
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2nc(N3CC4CCC(C3)N4)ccc2c1
Reaction time: 15 h

Procedure:
A mixture of 3-(6-nitro-quinolin-2-yl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.0 g, 2.6 mmol), trifluoroacetic acid (2.97 g, 26.0 mmol) and dichloromethane (10 ml) was stirred for 15 h. The mixture was made alkaline by adding concentrated ammonia. The mixture was extracted with dichloromethane, dried and evaporated. Yield 0.50 g (90%) Mp 185° C. decomp.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH:20]=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C([BH3-])#N.[Na+]>CO.C(OCC)(=O)C>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2C=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2CN2CCOCC2)CC1
Reaction time: 24 h
Yield: 29.6 %

Procedure:
To a solution of 1-Boc-4-(2-formyl-phenyl)-piperazine (500 mg, 1.7 mmol) in methanol (10 mL) was added morpholine (348 mg, 4.0 mmol) and sodium cyanoborohydride (315 mg, 5 mmol) and the mixture was stirred for about 24 hours. The mixture was diluted with ethyl acetate (100 mL), washed with saturated NaHCO3 solution (10 ml), water (10 mL) and brine (10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. Silica gel chromatography (1:1 hexanes/ethyl acetate) afforded the title compound as a colorless oil (182 mg, 30%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[N:22]3[C:17]([C:18]([O:23][CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])=[CH:19][CH:20]=[CH:21]3)=[C:16]([O:32][CH3:33])[C:15]=2[CH3:34])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]>FC(F)(F)C(O)=O.ClCCl.C(OCC)C>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[N:22]3[C:17]([C:18]([O:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:19][CH:20]=[CH:21]3)=[C:16]([O:32][CH3:33])[C:15]=2[CH3:34])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C(=O)c2c(C)c(OC)c3c(OCC(=O)OC(C)(C)C)cccn23)ccc1N
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(C(=O)c2c(C)c(OC)c3c(OCC(=O)O)cccn23)ccc1N
Temperature: 25 °C
Reaction time: 48 h
Yield: 97 %

Procedure:
The solution of 0.68 g (1.45 mmol) of methyl 2-amino-5-{[8-(2-tert-butoxy-2-oxoethoxy)-1-methoxy-2-methylindolizin-3-yl]carbonyl}benzoate in 4.44 ml of trifluoroacetic acid and 7 ml of dichloromethane is stirred. After stirring at ambient temperature for 48 hours, the reaction medium is concentrated to dryness and the red solid obtained is taken up in ethyl ether. The solid in suspension is filtered and is dried at 50° C. under vacuum so as to obtain 0.58 g (95%) of an orange powder.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([NH2:12])=[O:11])=[CH:9][C:4]=2[CH2:3]1.[C:13]1([C:19]2[C:23]([CH:24]=O)=[CH:22][NH:21][N:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1CCCCC1.CC(O)C>[O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([NH2:12])=[O:11])=[CH:9][C:4]=2/[C:3]/1=[CH:24]/[C:23]1[C:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[N:20][NH:21][CH:22]=1
Reactant: O=Cc1c[nH]nc1-c1ccccc1
Reactant: NC(=O)c1cc2c(s1)NC(=O)C2
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: NC(=O)c1cc2c(s1)NC(=O)/C2=C\c1c[nH]nc1-c1ccccc1
Temperature: 75 °C
Yield: 45.5 %

Procedure:
5,6-Dihydro-5-oxo-4H-thieno[2,3-b]pyrrole-2-carboxamide (30 mg, 0.17 mmol) was dissolved in a solution of 1% piperidine in 2-propanol (2 ml). 3-Phenyl-1H-pyrazole-4-carboxaldehyde (0.18 mmol, 31 mg) was added in one portion and the mixture heated at 75° C. for 1 hour. The reaction mixture was poured into an ice/water mixture (2 ml) and the precipitated solid was collected by filtration and washed with water to give 26 mg of (Z)-5,6-dihydro-5-oxo-4-[(3-phenyl-1H-pyrazol-4-yl)methylene]-4H-thieno[2,3-b]pyrrole-2-carboxamide as a yellow/brown solid. MS(ES): m/e 337 [M+H].
Reaction SMILES: C(N1[CH2:13][CH2:12][NH:11][CH2:10]C1)(OC(C)(C)C)=O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:31]=[N:32][NH:33][CH:34]=3)=[CH:26][CH:25]=2)[CH:22]=O)=[CH:17][CH:16]=1.N1CCC1>>[N:11]1([CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:31]=[N:32][NH:33][CH:34]=3)=[CH:26][CH:25]=2)[C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)[CH2:10][CH2:13][CH2:12]1
Reactant: O=CC(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: C1CNC1
Product: Clc1ccc(C(CN2CCC2)c2ccc(-c3cn[nH]c3)cc2)cc1

Procedure:
By following the procedure described in Example 33B but replacing bis-(4-chloro-phenyl)-acetaldehyde and N—BOC-piperazine with (4-Chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-acetaldehyde and azetidine, the title compound was obtained. LC/MS: (PS-B3) Rt 2.99 [M+H]+ 338.09. 1H NMR (Me-d3-OD) δ 3.57-3.60 (1H, m), 3.63-3.70 (2H, m), 3.71-3.77 (1H, m), 4.01 (2H, m), 4.14 (2H, m), 4.40 (1H, t), 7.40 (4H, br s), 7.49 (2H, d), 7.73 (2H, d), 8.69 (2H, br s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([NH2:18])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=C2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[CH:30]2)C1C=CC=CC=1.NOS(O)(=O)=O.Cl.ClC1C=CN=CC=1>CN1CCCC1=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([NH:18][C:35]1[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=1)[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nn1ccc2cc(OCc3ccccc3)ccc21
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Agent: Cl
Agent: Clc1ccncc1
Agent: NOS(=O)(=O)O
Solvent: CN1CCCC1=O
Product: c1ccc(COc2ccc3c(ccn3Nc3ccncc3)c2)cc1

Procedure:
The title compound was prepared from 5-benzyloxy-1H-indol-1-amine (which had been prepared from 5-benzyloxy-1H-indole and hydroxylamine-O-sulfonic acid in substantially the same manner as in Example 25) and 4-chloropyridine hydrochloride in N-methyl-2-pyrrolidinone at 70° C. for 1.5 hours in substantially the same manner as in Example 1, m.p. 143°-145° C.
Reaction SMILES: Cl[C:2]([C:4]1[C:17]2[O:16][C:15]([CH3:19])([CH3:18])[S:14][C:13]=2[C:12]([C:20]([C:41]2[C:49]3[S:50][C:51]([CH3:54])([CH3:53])[O:52][C:48]=3[C:47]([C:55](Cl)=[O:56])=[C:46]3[C:42]=2[S:43][C:44]([CH3:59])([CH3:58])[O:45]3)([C:22]2[C:30]3[S:31][C:32]([CH3:35])([CH3:34])[O:33][C:29]=3[C:28]([C:36](Cl)=[O:37])=[C:27]3[C:23]=2[S:24][C:25]([CH3:40])([CH3:39])[O:26]3)[OH:21])=[C:6]2[S:7][C:8]([CH3:11])([CH3:10])[O:9][C:5]=12)=[O:3].[OH:60][CH2:61][CH2:62][NH:63][CH2:64][CH2:65][OH:66]>C1C=CC=CC=1.O>[OH:60][CH2:61][CH2:62][N:63]([CH2:64][CH2:65][OH:66])[C:2]([C:4]1[C:17]2[O:16][C:15]([CH3:19])([CH3:18])[S:14][C:13]=2[C:12]([C:20]([C:41]2[C:49]3[S:50][C:51]([CH3:54])([CH3:53])[O:52][C:48]=3[C:47]([C:55]([N:63]([CH2:64][CH2:65][OH:66])[CH2:62][CH2:61][OH:60])=[O:56])=[C:46]3[C:42]=2[S:43][C:44]([CH3:59])([CH3:58])[O:45]3)([C:22]2[C:30]3[S:31][C:32]([CH3:35])([CH3:34])[O:33][C:29]=3[C:28]([C:36]([N:63]([CH2:64][CH2:65][OH:66])[CH2:62][CH2:61][OH:60])=[O:37])=[C:27]3[C:23]=2[S:24][C:25]([CH3:40])([CH3:39])[O:26]3)[OH:21])=[C:6]2[S:7][C:8]([CH3:11])([CH3:10])[O:9][C:5]=12)=[O:3]
Reactant: OCCNCCO
Reactant: CC1(C)Oc2c(c(C(O)(c3c4c(c(C(=O)Cl)c5c3SC(C)(C)O5)OC(C)(C)S4)c3c4c(c(C(=O)Cl)c5c3SC(C)(C)O5)OC(C)(C)S4)c3c(c2C(=O)Cl)OC(C)(C)S3)S1
Solvent: O
Solvent: c1ccccc1
Product: CC1(C)Oc2c(c(C(O)(c3c4c(c(C(=O)N(CCO)CCO)c5c3SC(C)(C)O5)OC(C)(C)S4)c3c4c(c(C(=O)N(CCO)CCO)c5c3SC(C)(C)O5)OC(C)(C)S4)c3c(c2C(=O)N(CCO)CCO)OC(C)(C)S3)S1
Reaction time: 8 h
Yield: 63.4 %

Procedure:
Tris-(8-chlorocarbonyl-2,2,6,6-tetramethyl-benzo[1,2-d:5,4-d']-bis(1,3)oxathiol-4-yl)methanol (0.80 g, 0.80 mmol) was dissolved in benzene (200 mL). A solution of of bis(2-hydroxyethyl)amine (8.0 g, 48 mmol) in water (200 mL) was added and after vigorous stirring overnight, the mixture was transferred to a separatory funnel. The aqueous layer was removed and the remaining solid plus the benzene layer was evaporated, dissolved in methanol and passed through a short column (neutral alumina). After elution of unwanted materials with acetonitrile, the amide was eluted with methanol. After evaporation, the product was stirred with water (50 mL) at 40° C. for 2 h and then isolated by filtration. After drying, 0.60 g (60%) of the pure amide was obtained.
Reaction SMILES: C(O[K:6])(C)(C)C.[C:7]([OH:16])(=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]>CO>[C:7]([O-:16])(=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O-:14])=[O:13].[K+:6].[K+:6]
Reactant: O=C(O)CCCCC(=O)O
Reactant: CC(C)(C)O[K]
Solvent: CO
Product: O=C([O-])CCCCC(=O)[O-]
Product: [K+]
Temperature: 25 °C

Procedure:
tert-Butoxypotassium (7.68 g, 68.4 mmol) was dissolved in methanol (100 mL) and then adipic acid (5.0 g, 34.2 mmol) was added to the solution. After stirring the reaction mixture at room temperature for a while, the mixture was concentrated and the residue dried to give dipotassium adipate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH:3]=1.S(=O)(=O)(O)O.[CH3:27]O>>[CH3:27][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=1
Reactant: O=C(O)c1ccc(Cl)cc1Oc1cccc(C(F)(F)F)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Cl)cc1Oc1cccc(C(F)(F)F)c1

Procedure:
136 G. of 4-chloro-2-(3-trifluoromethyl-phenoxy)-benzoic acid are boiled at reflux for 2.5 hours in a mixture of 1000 ml. of methanol and 100 ml. of concentrated sulfuric acid. After concentration of the mixture under vacuum, the residue is poured on to ice and extracted with benzene. The benzene extracts are washed with water, aqueous sodium bicarbonate solution and again with water. After evaporation of the benzene, there is obtained 4-chloro-2-(3-trifluoromethyl-phenoxy)-benzoic acid methyl ester in the form of an oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br.CO[CH:31](OC)[C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[C:35](O)=[O:36].C[O-].[Na+].C[N:49](C)C=O>CO>[F:20][C:21]1[CH:22]=[C:23](/[CH:24]=[CH:31]/[C:32]2[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=2[O:41][CH3:42])[C:35]([NH2:49])=[O:36])[CH:26]=[CH:27][CH:28]=1
Reactant: CN(C)C=O
Reactant: Fc1cccc(CBr)c1
Reactant: COc1ccc(C(=O)O)cc1C(OC)OC
Agent: C[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: COc1ccc(C(N)=O)cc1/C=C/c1cccc(F)c1
Temperature: 80 °C
Reaction time: 10 h
Yield: 13 %

Procedure:
N,N-Dimethylformamide (5 mL) was added to 1.0 g of polymer-supported triphenylphosphine (produced by Fluka, CAS registry number 39319-11-4) and 1.1 g of 3-fluorobenzyl bromide, and the mixture was stirred for 10 hours at 80° C. The reaction mixture was filtered, and then washed with N,N-dimethylformamide, dichloromethane, and methanol. The residue was dried under reduced pressure to prepare polymer-supported (3-fluorobenzyl)triphenylphosphonium bromide. This product (111 mg) was added to a methanol solution (2 mL) of 20 mg of 3-formyl-4-methoxybenzamide obtained in step B. After 62 μL of 28% sodium methoxide was added, the reactor was sealed, and the mixture was stirred for 4 hours at 70° C. The reaction mixture was purified by thin-layer chromatography to obtain 4 mg (13%) of 3-[(E)-2-(3-fluorophenyl)-vinyl]-4-methoxybenzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:9]1([CH:15]=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[OH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26](=[O:35])[CH2:27][C:28](=[O:34])[C:29]([O:31]CC)=O)=[CH:20][CH:19]=1>C(O)(=O)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH:15]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[C:27]([C:26](=[O:35])[CH2:25][CH2:24][C:21]3[CH:20]=[CH:19][C:18]([OH:17])=[CH:23][CH:22]=3)=[C:28]([OH:34])[C:29]2=[O:31])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=CC1CCCCC1
Reactant: CCOC(=O)C(=O)CC(=O)CCc1ccc(O)cc1
Solvent: CC(=O)O
Product: O=C(CCc1ccc(O)cc1)C1=C(O)C(=O)N(c2ccc(Cl)cc2)C1C1CCCCC1
Temperature: 25 °C

Procedure:
To a stirring solution of p-chloraniline (320 mg, 2.5 mmol) in 2.5 mL of acetic acid at room temperature, are added cyclohexane carboxaldehyde (0.30 mL, 2.5 mmol) and ethyl 6-(4-hydroxyphenyl)-2,4-dioxohexanoate (618 mg, 2.5 mmol). The reaction mixture is stirred at room temperature. After 30 minutes a white precipitate is formed. The solvent is removed under reduced pressure and the crude material recrystallized from a mixture of ether/methanol. The final compound is collected after filtration as a white crystalline solid m.p. 259° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:11])([C:7]([F:10])([F:9])[F:8])[CH2:5][OH:6].Cl[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=1.[OH-].[Na+]>CN(C)C(=O)C>[F:3][C:4]([F:11])([C:7]([F:10])([F:9])[F:8])[CH2:5][O:6][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: OCC(F)(F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(OCC(F)(F)C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.8 %

Procedure:
To a stirred suspension of sodium hydride (4.9 g, 120 mmol, 60% in oil) in N,N-dimethylacetamide (100 mL) is added dropwise 2,2,3,3,3-pentafluoropropan-1-ol (8.1 mL, 82 mmol) at 0° C. After stirring for 10 minutes, a solution of methyl 6-chloronicotinate (7.0 g, 41 mmol) in N,N-dimethylacetamide (120 mL) is added dropwise at 0° C., and the mixture is stirred for 30 minutes at room temperature. Then, the mixture is stirred at 90° C. for 2 hours. After cooled to room temperature, 2M aqueous sodium hydroxide is added (pH is around 6). The mixture is extracted with n-hexane/ethyl acetate (1:2, 200 mL). The organic layer is washed with water, brine, and dried over sodium sulfate. The organic solvent is concentrated under reduced pressure to give 8.4 g of the title compound as a crude product (include 2,2,3,3,3-pentafluoropropyl 6-(2,2,3,3,3-pentafluoropropoxy)nicotinate as a byproduct). The residue is used for the next reaction (Step-2) without further purification.