Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH2:10][CH3:11])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21]>CN(C)C(=O)C>[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:20](=[O:21])[O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[CH:7][CH:6]=1)(=[O:12])[CH2:10][CH3:11]
Reactant: CCC(=O)Nc1ccc(N)cc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: CCC(=O)Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Temperature: 0 °C
Yield: 97.5 %

Procedure:
To a solution of N-(4-aminophenyl)propanamide (2.00 g, 10.3 mmol) and pyridine (2.50 ml, 30.9 mmol) in N,N-dimethylacetamide (40 ml) was added 2,2,2-trichloroethyl chloroformate (2.13 ml, 15.5 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 2 hours. The reaction mixture was poured into ice-water, and 3.41 g (97.4%) of the desired product was collected by filtration as a solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20]([C:22]2[C:23]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:21])[CH2:15][CH2:14]1)[CH2:5][C:6]([O:8][CH3:9])=[O:7].[CH3:44]I>CN(C)C=O>[CH3:3][C:4]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([CH2:10][CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][CH:16]([N:19]([C:20]([C:22]2[C:23]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:30][CH:29]=3)=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:21])[CH3:44])[CH2:17][CH2:18]1)[CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: CI
Reactant: COC(=O)CC(C)(CCCN1CCC(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)CC1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CC(C)(CCCN1CCC(N(C)C(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)CC1)c1ccccc1
Reaction time: 1 h

Procedure:
0.095 g (0.803 mmol) of sodium hydride (55 to 65% in oil) are added to a solution of 0.4 g (0.724 mmol) of methyl 2-methyl-2-phenyl-5-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-piperidin-1-yl}-pentanecarboxylate in 5 ml of dimethylformamide at ambient temperature and stirred for one hour. Then 0.05 ml (0.803 mmol) of methyl iodide are added and the mixture is stirred for 14 hours. The reaction solution is poured onto water, extracted with ethyl acetate, and the organic phase is dried over sodium sulphate. The product is purified by column chromatography on silica gel (eluant: dichloromethane/methanol=5:1).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([O-:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].C([N+](CCCC)(CCCC)CCCC)CCC.I[CH2:31]/[CH:32]=[CH:33]/[B:34]1[O:38][C:37]([CH3:40])([CH3:39])[C:36]([CH3:42])([CH3:41])[O:35]1>ClCCl>[CH3:39][C:37]1([CH3:40])[C:36]([CH3:41])([CH3:42])[O:35][B:34](/[CH:33]=[CH:32]/[CH2:31][O:12][C:10]2[CH:9]=[CH:8][C:6]3[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]=3[CH:11]=2)[O:38]1
Reactant: CC1(C)OB(/C=C/CI)OC1(C)C
Reactant: N#Cc1nc2ccc([O-])cc2s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: CC1(C)OB(/C=C/COc2ccc3nc(C#N)sc3c2)OC1(C)C
Temperature: 80 °C

Procedure:
A reaction vial was charged with tetrabutylammonium 2-cyanobenzo[d]thiazol-6-olate (209 mg, 1.19 mmol), (E)-2-(3-iodoprop-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (386 mg, 1.31 mmol) and 15 mL of dry dichloromethane. The vial was sealed, and the solution was heated in an oil bath at 80° C. overnight (˜16 hours). The crude reaction mixture was added to 1 gram of celite, and the solvent was evaporated under vacuum. The product was purified by silica gel chromatography using an increasing gradient of ethyl acetate in dichloromethane as eluent. This gave 166 mg of (E)-6-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)benzo[d]thiazole-2-carbonitrile as a colorless oil that crystallized to a white solid upon standing at ambient temperature.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7](O)=O)[CH:3]=1.[NH2:10][C:11]1[C:23]([NH2:24])=[CH:22][C:14]2[N:15]([CH:19]([CH3:21])[CH3:20])[C:16](=[O:18])[NH:17][C:13]=2[CH:12]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[CH:19]([N:15]1[C:14]2[CH:22]=[C:23]3[C:11](=[CH:12][C:13]=2[NH:17][C:16]1=[O:18])[NH:10][C:7]([C:4]1[CH:3]=[C:2]([CH3:1])[NH:6][N:5]=1)=[N:24]3)([CH3:21])[CH3:20]
Reactant: CC(C)n1c(=O)[nH]c2cc(N)c(N)cc21
Reactant: Cc1cc(C(=O)O)n[nH]1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: Cc1cc(-c2nc3cc4c(cc3[nH]2)[nH]c(=O)n4C(C)C)n[nH]1

Procedure:
5-Methyl-1H-pyrazole-3-carboxylic acid (126 mg, 1 mmol) and 5,6-diamino-1-isopropyl-1,3-dihydro-benzoimidazol-2-one (206 mg, 1 mmol) were heated to 160° C. in a mixture of polyphosphoric acid (5 g) and phosphorus pentoxide (500 mg, 3.5 mmol) for 6 h. This mixture was poured on water (20 ml) and stirring continued until a precipitate formed. After filtration the crude product was suspended in water and neutralized by the addition of aqueous ammonia (25%). The precipitate was collected, washed with water and dried in vacuo. Purification was achieved by chromatography on silica (dichloromethane/methanol 95:5) yielding 1-isopropyl-6-(5-methyl-1H-pyrazol-3-yl)-3,5-dihydro-1H-benzo[1,2-d;4,5-d′]diimidazol-2-one as slightly yellow solid. Yield 36 mg (12%)
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2]>S(Cl)(Cl)=O>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([O:8][C:5]([CH3:9])([CH3:6])[CH3:4])=[O:7])([O-:3])=[O:2]
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)c1ccccc1[N+](=O)[O-]
Yield: 141.3 %

Procedure:
A mixture of 2-nitrobenzoic acid (25.0 g.) and thionyl chloride (50 ml.) was refluxed for an hour and then evaporated. To the residue was added benzene (125 ml.) followed by removal of benzene. To the residue were added benzene (125 ml.), pyridine (23.7 g.) tert-butyl alcohol (22.2 g.) under ice-cooling and then the resulting solution was refluxed under heating for 2 hours. The reaction mixture was poured into ice water. The benzene layer was separated, washed successively with water, 1N aqueous solution of sodium hydroxide (twice), water 1M aqueous solution of citric acid (twice), water and an aqueous solution of sodium chloride, dried over magnesium sulfate and then teated with activated charcoal. Thus obtained organic layer was chromatographed on silica gel (150 g.) eluting with a mixture of benzene and n-hexane (1:1) to give a yellowish oil of the title compound (23.6 g.)
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[CH:17]1[C:29]2[C:28](=[CH:30][C:31](O)=[O:32])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1>>[C:12]([C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([CH3:14])([CH3:15])[C@@H:3]([OH:16])[C@H:2]([NH:1][C:31](=[O:32])[CH:30]=[C:28]3[C:29]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:22]4[C:27]3=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:7]=2[CH:8]=1)#[N:13]
Reactant: O=C(O)C=C1c2ccccc2-c2ccccc21
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=O)C=C2c3ccccc3-c3ccccc32)[C@@H]1O

Procedure:
The title compound was prepared from (3S-trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (the title B compound of Example 1) and 2-(9H-fluoren-9-ylidene)acetic acid by the same method as described for the title compound of Example 2. The product was obtained as a light yellow solid, m.p. >300° C.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[C:13]([O:17][C:18](=[O:29])[NH:19][C@H:20]([CH2:27]O)[CH2:21][C:22]([CH3:26])([CH3:25])[CH:23]=[CH2:24])([CH3:16])([CH3:15])[CH3:14].[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:13]([O:17][C:18](=[O:29])[NH:19][C@H:20]([CH2:27][N:34]1[C:30](=[O:40])[C:31]2[C:32](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:33]1=[O:35])[CH2:21][C:22]([CH3:26])([CH3:25])[CH:23]=[CH2:24])([CH3:16])([CH3:15])[CH3:14]
Reactant: C=CC(C)(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CC(C)(C)C[C@@H](CN1C(=O)c2ccccc2C1=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DEAD (0.63 ml, 4 mmol) is added to a suspension of ((S)-1-Hydroxymethyl-3,3-dimethyl-pent-4-enyl)-carbamic acid tert-butyl ester (1 g, 4 mmol), phthalimide (588 mg, 4 mmol) and PS-triphenylphosphine (3.72 g, 8 mmol) in THF (50 ml) and the resulting solution is stirred at room temperature overnight. The resin is removed by filtration, and the filtrate concentrated in vacuo. Purification by flash chromatography (SiO2, EtOAc/iso-hexane) yields [(S)-1-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3,3-dimethyl-pent-4-enyl]-carbamic acid tert-butyl ester as a white solid; [M+H-BOC]+ 273.
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:11]=[C:12]([CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=2[OH:22])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH2:27](O)[CH2:28][CH2:29][CH2:30][CH2:31][CH:32](C)[CH3:33].C([Sn](=O)CCCC)CCC>>[N:1]1[N:2]([C:10]2[CH:11]=[C:12]([CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=2[OH:22])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:16])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: COC(=O)CCc1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)C)c1
Reactant: CC(C)CCCCCO
Agent: CCCC[Sn](=O)CCCC
Product: CCCCCCCCOC(=O)CCc1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)C)c1
Temperature: 175 °C
Reaction time: 0.5 h

Procedure:
Methyl 3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyhydrocinnamate (353 g, 1 mol), isooctanol (260 g, 2 mol, from Exxon) and dibutyltin oxide (0.5 g, 0.002 mol) are charged to a reaction flask and heated to 175° C. While heating to 175° C., a 300 mm Hg vacuum is applied. After holding at 175° C. for 30 minutes, the excess isooctanol is distilled by slowly reducing the pressure to <5 mm Hg. The desired product is cooled and discharged. The title compound is obtained in a yield of 451 g (100%) as a light yellow oil whose structure is verified by 1Hnmr and mass spectroscopy. The non-distilled product is analyzed by ICP (Inductively Coupled Plasma) for tin and is found to contain 170 ppm of tin.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:12][CH2:13]Cl)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]#[N:24].[H-].[Na+]>C1COCC1.CN(C=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1([C:23]#[N:24])[CH2:2][CH2:3][N:4]([C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])[CH2:12][CH2:13]1
Reactant: N#CCc1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccccc2Cl)CC1

Procedure:
A solution of bis(2-chloroethyl)-N-(1,1-dimethylethoxy)carbonyl amine (9.298 g, 38.4 mmol) and 2-chlorophenylacetonitrile (5.0 g, 32.0 mmol) in a 4:1 mixture of THF/DMF (15 mL) was treated with NaH (2.82 g, 70.4 mmol) at 60 OC (7 d). The solvent was removed in vacuo, the residue dissolved in EtOAc (200 ml) and washed with saturated NaHCO3 (50 ml), H2O (2×50ml), and saturated aqueous NaCl (50 ml), dried Na2SO4) and concentrated in vacuo. Trituration of the residue with 100% MeOH afforded 4-(2-chlorophenyl)4-cyano-N-(1,1-dimethylethoxy) carbonyl piperidine as a white solid.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([C:22]3[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=3[F:29])[C:4]=2[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[N:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[CH2:13]([N:12]([CH2:15][CH3:16])[CH2:11][CH2:10][CH2:9][NH:8][C:6]1[N:7]=[C:2]([C:38]2[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=2)[C:3]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([C:22]3[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=3[F:29])[C:4]=2[N:5]=1)[CH3:14]
Reactant: CCN(CC)CCCNc1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCN(CC)CCCNc1nc(-c2ccc(C(=O)O)cc2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 150 °C
Yield: 72.4 %

Procedure:
To the compound 4-chloro-2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)pyrido[2,3-d]pyrimidin-7(8H)-one (168.75 mg, 0.40 mmol) in dioxane (12 mL) and water (4 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (148.85 mg, 0.60 mol), potassium carbonate (208 mg, 1.20 mmol) and tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol). The mixture was heated with microwave at 150° C. for 15 min. The mixture was concentrated. It was mixed with DMSO (0.75 mL) and water (0.25 mL). Separation by HPLC afforded the title compound (147 mg, 72%). LC-MS m/z 508 (M+H)+.
Reaction SMILES: [C:1]1(=[O:11])[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][NH:2]1.C(N(CC)CC)C.Br[C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH3:26][C:20]([N:8]1[CH2:9][CH2:10][C:5]2([C:1](=[O:11])[NH:2][CH2:3][CH2:4]2)[CH2:6][CH2:7]1)([CH3:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=C1NCCC12CCNCC2
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(C)N1CCC2(CCNC2=O)CC1
Temperature: 80 °C

Procedure:
A mixture of 2,8-diazaspiro[4.5]decan-1-one (3.03 g, 19.65 mmol), triethylamine (5.48 ml, 39.3 mmol) and ethyl 2-bromo-2-methylpropanoate (5.77 ml, 39.3 mmol) was heated at 80° C. overnight. The reaction mixture was partitioned between methylene chloride (200 mL) and saturated sodium bicarbonate, the alkaline phase was extracted with methylene chloride (3×100 mL). The combined organic phase was dried over magnesium sulfate, concentrated and the residue was purified on silica gel using methanol/methylene chloride to give the title compound. LC/MS (M+1)+: 269.4
Reaction SMILES: Cl.[CH:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:5]=[CH:4][N:3]=1.C1C=C[NH+]=CC=1.[Br:19][Br-]Br>C(O)(=O)C>[BrH:19].[Br:19][CH:8]1[CH2:9][CH2:10][C:11]2[CH:2]=[N:3][CH:4]=[CH:5][C:6]=2[C:7]1=[O:12]
Reactant: O=C1CCCc2cnccc21
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: Br
Product: O=C1c2ccncc2CCC1Br
Temperature: 100 °C
Yield: 83 %

Procedure:
A suspension of 7,8-dihydro-6H-isoquinolin-5-one 8A (13.3 mmol) and pyridinium bromide perbromide (13.3 mmol) were suspended in glacial acetic acid (15 mL), and heated to 100° C. with microwave irradiation for 15 min. The solid formed was filtered to give the title compound as a yellow solid in 83% yield. ESI (+) MS: m/z 227 (MH+). 1H NMR: 2.39-2.62 (m, 2H), 3.00-3.15 (m, 2H), 4.43 (dd, J=12.50, 4.94, 1H), 7.72-7.83 (m, 1H), 8.61-8.74 (m, 1H), 8.75-8.85 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[CH:3]([C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1)[O:4][C:5]1[C:6]([NH:15][S:16]([C:19]2[CH:34]=[CH:33][C:22]([CH2:23][CH2:24][NH:25]C(=O)OC(C)(C)C)=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2.FC(F)(F)C(O)=O>ClCCl>[NH2:25][CH2:24][CH2:23][C:22]1[CH:21]=[CH:20][C:19]([S:16]([NH:15][C:6]2[C:5]([O:4][CH:3]([C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)[C:2]([F:41])([F:1])[F:42])=[N:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)(=[O:17])=[O:18])=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(S(=O)(=O)Nc2nc3ccccc3nc2OC(c2cccnc2)C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCc1ccc(S(=O)(=O)Nc2nc3ccccc3nc2OC(c2cccnc2)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
4-(N-{3-[2,2,2-trifluoro-1-(pyridin-3-yl)ethoxy]quinoxalin-2-yl}sulfamoyl)phenethylcarbamate (Compound 208) was dissolved in dichloromethane (2 mL). To this, trifluoroacetic acid (2 mL) was added at room temperature and the mixture was stirred at room temperature for 24 hours. The solvent in the reaction mixture was evaporated off under reduced pressure, and purification by silica gel column chromatography (ethyl acetate/methanol=1/0 to 5/1) was performed to give 4-(2-aminoethyl)-N-{3-[2,2,2-trifluoro-1-(pyridin-3-yl)-ethoxy]quinoxalin-2-yl}benzenesulfonamide (Compound 209) (48 mg, 90%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([CH2:22][CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)C(OCC)=O)[CH3:2].O.[Cl-].[Li+]>CS(C)=O>[CH2:1]([O:3][C:4](=[O:31])[CH:5]([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[CH2:22][CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:2]
Reactant: CCOC(=O)C(CC=Cc1ccccc1)(Cc1cccc2ccccc12)C(=O)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C(CC=Cc1ccccc1)Cc1cccc2ccccc12
Yield: 68.5 %

Procedure:
To a solution of 1.5 g of the malonic acid diethyl ester obtained in 10 ml of dimethyl sulfoxide and 0.3 ml of water was added 0.92 g of lithium chloride, and the mixture was heated for 4.5 hours at from 180° to 190° C. After cooling, water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The ethereal layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 0.85 g of 2-(1-naphthylmethyl)-5-phenyl-4-pentenoic acid ethyl ester as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[O:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.C(O)(=O)C.C([BH3-])#N.[Na+].[OH-].[Na+]>CO>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:12]2[CH2:13][CH2:14][O:9][CH2:10][CH2:11]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: Fc1ccc(NC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 739.9 %

Procedure:
A mixture of 4-fluoroaniline (1 g; 0.9 mmol) and tetrahydro-4H-pyran-4-one (0.98 g; 1.1 equiv.) in methanol (20 ml) was treated with acetic acid (0.67 ml; 1.3 equiv.) and sodium cyanoborohydride (0.73 g; 1.3 equiv.) then stirred at room temperature overnight. The reaction was cooled to 0° C., basified with 2M sodium hydroxide solution and the resultant solid collected by filtration, washed with water and dried under vacuum to give 1.3 g of the title compound. 1H NMR (DMSO-d6) 6.80 (2H, t), 6.48 (2H, dd), 5.25 (1H, d), 3.75 (2H, dt), 3.33-3.23 (3H, m), 1.78-1.71 (2H, m), 1.28-1.18 (2H, m).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([F:15])([F:14])[C:4]([F:13])([F:12])[C:5]([F:11])([F:10])[S:6]([O-:9])(=[O:8])=[O:7].[OH:18][C:19]1[CH:24]=[CH:23][C:22]([S+:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][CH:20]=1.[CH2:38]([S:42](Cl)(=[O:44])=[O:43])[CH2:39][CH2:40][CH3:41].C(N(CC)CC)C.O>ClCCl>[F:17][C:2]([F:1])([F:16])[C:3]([F:14])([F:15])[C:4]([F:12])([F:13])[C:5]([F:10])([F:11])[S:6]([O-:9])(=[O:8])=[O:7].[CH2:38]([S:42]([O:18][C:19]1[CH:24]=[CH:23][C:22]([S+:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)(=[O:44])=[O:43])[CH2:39][CH2:40][CH3:41]
Reactant: Oc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Reactant: CCCCS(=O)(=O)Cl
Agent: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCS(=O)(=O)Oc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 73.7 %

Procedure:
30 g of 4-hydroxyphenyl diphenylsulfonium nonafluoro-n-butanesulfonate was dissolved in 300 g of dichloromethane in a reaction flask, in which the atmosphere was replaced with nitrogen. 17.9 g of n-butanesulfonyl chloride and 10.5 g of triethylamine were added in this order. The mixture was stirred for 20 minutes at room temperature. After the addition of 100 g of ion-exchanged water, the mixture was transferred to a separatory funnel, shaken, and allowed to stand still. The water layer was removed. After the addition of 300 ml of distilled water, the solution was shaken and allowed to stand still. The water layer was removed. The resulting dichloromethane solution was dried using anhydrous magnesium sulfate and filtered. After evaporating dichloromethane from the dichloromethane solution, the residual liquid was dried under reduced pressure to obtain 26.7 g of 4-n-butanesulfonyloxyphenyl diphenylsulfonium nonafluoro-n-butanesulfonate. This compound is indicated as “acid generator (A-1)”.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])=[O:4].FC1C([O:21][C:22](=O)[CH2:23][S:24][C:25](=[O:27])[CH3:26])=C(F)C(F)=C(F)C=1F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:25]([S:24][CH2:23][C:22]([NH:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])=[O:4])=[O:21])(=[O:27])[CH3:26]
Reactant: CC(=O)SCC(=O)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: NCC(=O)NCC(=O)NCC(=O)O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)SCC(=O)NCC(=O)NCC(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of H-Gly-Gly-Gly-OH (1.28 g, 6.76 mmol), S-acetyl-thioglycolic acid pentafluorophenyl ester (Novabiochem, 2 g, 6.76 mmol) and DIPEA (1.14 ml, 6.76 mmol) in a mixture of DMF (25 ml) and water (12 ml), was stirred overnight at room temperature. The reaction mixture was filtered to remove some remaining H-Gly-Gly-Gly-OH, brought to pH2 with 1M aqueous HCl and evaporated to dryness. The residue was triturated with acetone to afford the title compound.
Reaction SMILES: N1C=CC=CC=1.[CH2:7](O)[C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].P(Br)(Br)[Br:17]>CCOCC.[Cl-].[Na+].O>[Br:17][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCC#CCO
Reactant: BrP(Br)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: c1ccncc1
Product: CCCCCC#CCBr
Reaction time: 1 h
Yield: 193.5 %

Procedure:
Under argon atmosphere, anhydrous pyridine (0.4 ml, 4.9 mmol) was added to a solution of 2-octyne-1-ol (9.4658 g, 75.0 mmol) in anhydrous ether (50 ml). To the mixture was added dropwise phosphorus tribromide (2.35 ml, 25.0 mmol) at -30° to -35° C. and the mixture was stirred at the same temperature for one hour and then stirred for one hour at room temperature under argon atmosphere. To the resulting mixture was added brine (100 ml), and the mixture was then extracted with ether (50 ml×4). The combined ether layers were washed with an aqueous saturated solution of sodium bicarbonate (150 ml), with water (150 ml) and with brine (150 ml), dried over anhydrous sodium sulfate (40 g), and concentrated. Distillation of the residue gave a colorless oily product of 1-bromo-2-octyne (9.1493 g, 65%, B.p.: 53°-58° C./0.39 mmHg). The product was assigned the structure by the following data.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([S:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:11].[C:31](=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:29]=[CH:30][C:21]=1[S:18]([N:15]1[CH2:16][CH2:17][N:12]([C:10](=[O:11])[CH2:9][S:7][C:1]2[CH:6]=[CH:5][C:4]([CH3:31])=[CH:3][CH:2]=2)[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: O=C(CCl)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Reactant: Sc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(SCC(=O)N2CCN(S(=O)(=O)c3ccc4ccccc4c3)CC2)cc1

Procedure:
Thio phenol (100 mg, 0.85 mmol), 2-chloro-1-(4-(naphthalen-2-ylsulfonyl)piperazin-1-yl)ethanone (compound 5, 0.3 g, 0.85 mmol) and anhydrous potassium carbonate (0.293 g, 2.125 mmol) were stirred for over night in dry acetonitrile (20 mL). The mixture was then stirred into a large volume of water and the solution extracted with ether. Unreacted phenol was removed with cold 1N NaOH solution. The ether extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield the title compound in quantitative yield.