Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][S:16](Cl)(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25]>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][S:16]([NH:25][CH2:24][C:23]2[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:22]=2[O:21][CH3:20])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)Cc1cccc(OCc2ccccc2)c1
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CNS(=O)(=O)Cc2cccc(OCc3ccccc3)c2)c(OC)c1
Reaction time: 0.5 h

Procedure:
Under inert gas, 4.89 g of (3-benzyloxyphenyl)methanesulfonyl chloride were initially charged in 50 ml of THF, then, at a temperature of −20° C., 3.00 ml of 2,4-dimethoxybenzylamine were added dropwise and the reaction solution was allowed to come to 0° C. within 30 minutes. The reaction solution was diluted with 80 ml of ethyl acetate and washed with water, with 10% aqueous potassium hydrogensulfate solution, saturated aqueous sodium hydrogencarbonate solution and saturated sodium chloride solution. The organic phase was dried over MgSO4 and concentrated by rotary evaporation. The crude product was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined, concentrated by rotary evaporation and dried under high vacuum. This gave the product (3.12 g) with a molecular weight of 427.5 g/mol (C23H25NO5S).
Reaction SMILES: [N:1]([CH2:4][CH2:5][S:6][C:7]1[N:8]=[CH:9][N:10]2[CH:14]=[CH:13][S:12][C:11]=12)=[N+]=[N-].C1C[O:18][CH2:17]C1.Cl.[H][H]>[Pd].O>[CH:17]([NH:1][CH2:4][CH2:5][S:6][C:7]1[N:8]=[CH:9][N:10]2[CH:14]=[CH:13][S:12][C:11]=12)=[O:18]
Reactant: [H][H]
Reactant: C1CCOC1
Reactant: [N-]=[N+]=NCCSc1ncn2ccsc12
Agent: [Pd]
Agent: Cl
Solvent: O
Product: O=CNCCSc1ncn2ccsc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
7-(2-Azidoethyl)thioimidazo[5,1-b]thiazole (397 mg) was dissolved in a mixed solvent composed of 10 ml of THF and 10 ml of water. A 1 N aqueous hydrochloric acid solution (5.3 ml) and 200 mg of 10% Pd-C were added to the solution. The air in the reaction vessel was replaced by hydrogen, and the contents of the reaction vessel were stirred at room temperature for 6 hr. The catalyst was removed by filtration on Celite, and was then washed with water. The filtrate was concentrated under the reduced pressure until the volume was substantially halved. Dichloromethane (20 ml) was added, and the mixture was adjusted to pH 7.0 by the addition of an aqueous sodium hydrogencarbonate solution. Formic acid (0.90 ml) and 0.50 ml of acetic anhydride, which had been stirred at 50° C. for 5 min, were added thereto under ice cooling. The mixture was stirred at that temperature for 20 min while maintaining the pH value at about 7.0. The reaction solution was adjusted to pH 8.3 by the addition of an aqueous sodium hydrogencarbonate solution, and was then extracted with dichloromethane three times. The organic layer was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation, and the residue was purified by column chromatography on silica gel (dichloromethane:methanol=20:1) to prepare 250 mg of 7-(2-formylaminoethyl)thioimidazo[5,1-b]thiazole.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3]C1.C(C[C:10]([O:12][CH2:13][CH3:14])=[O:11])#N.C(=O)C>C(O)(=O)C.O>[C:6](/[C:5](=[CH:4]\[CH3:3])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:1]
Reactant: C1CCNCC1
Reactant: CCOC(=O)CC#N
Agent: CC=O
Solvent: CC(=O)O
Solvent: O
Product: C/C=C(\C#N)C(=O)OCC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2 cm3 of piperidine are added dropwise to a solution of 64 cm3 of ethyl cyanoacetate and 34 cm3 of acetaldehyde in 80 cm3 of acetic acid. After stirring for 20 hours at ambient temperature, the reaction mixture is diluted with 200 cm3 of water and extracted with ether (3×200 cm3). The combined organic phases are washed with water and then dried over sodium sulphate and evaporated. Distillation under reduced pressure (97° C./10 torr) of the residue obtained allows 40.44 g of the expected product to be obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C([Li])CCC.[CH:19]([N:22]([CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C:23](=[O:32])[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1)([CH3:21])[CH3:20].OS([O-])(=O)=O.[K+]>C(OCC)C.C1COCC1>[CH:33]1([N:22]([CH:19]([CH3:21])[CH3:20])[C:23](=[O:32])[C:24]2[CH:25]=[CH:26][C:27]([CH:28]([OH:29])[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)=[CH:30][CH:31]=2)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: COc1cc(Br)cc(OC)c1OC
Reactant: CC(C)N(C(=O)c1ccc(C=O)cc1)C1CCCCC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(C(O)c2ccc(C(=O)N(C(C)C)C3CCCCC3)cc2)cc(OC)c1OC
Temperature: -8 °C
Reaction time: 0.17 h

Procedure:
To a stirred, cold (-15° C.) solution of 3,4,5-trimethoxybromobenzene (965 mg, 3.9 mmol) in ethyl ether (15 ml) was added n-butyl lithium (3 ml of 1.6 M solution in hexane). The reaction mixture was stirred at -8° C. for 10 min., diluted with THF (5 ml) and warmed to 0° C. After stirring for 5 min., the reaction was cooled to -30° C. and a solution of terephthalaldehydic acid N-isopropyl-N-cyclohexyl amide (1.063 g, 3.9 mmol) in THF (5 ml) was added. After stirring at -30° C. for 10 min. and warming to room temperature, the reaction mixture was poured onto 0.5N KHSO4 and extracted with ethyl acetate. The organic layer was washed with saturated NaCl solution and dried (MgSO4). The drying agent was filtered and the filtrate concentrated in vacuo to give the crude product. This was chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the title compound as a crystalline solid that could be recrystallized from cyclohexane containing a small amount of ethyl acetate, m. pt. 158-160° C.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][C:12]1(C)[O:17]C(=O)[CH2:15][C:14](=O)[O:13]1.N1C=CC=CC=1>C(Cl)Cl>[O:9]=[C:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:11][C:12]([O:13][CH2:14][CH3:15])=[O:17]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CC(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38.5 %

Procedure:
To a solution of phenylacetyl chloride (1 mL, 7.56 mmol) was added dropwise a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (1.09 g, 7.56 mmol) and pyridine (1.3 mL) in CH2Cl2 (20 mL) at 0° C. The solution was stirred for 30 min at 0° C., then allowed to warm slowly to rt and stirred overnight. The reaction mixture was then washed with 10% aqueous HCl (2×10 mL). The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The crude residue was dissolved in EtOH (20 mL) and heated under reflux conditions for 4 h. The mixture was cooled to rt and then concentrated under reduced pressure. The resulting oil was purified by flash column chromatography (PE/EA=1/4) to afford the title compound (600 mg, 38%) as a yellow oil. [M+H] Calc'd for C12H14O3, 207; Found, 207.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[C:12]1([NH:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1.Cl>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CNc1ccccc1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CN(C(=O)Cc1ccc(Cl)cc1)c1ccccc1
Reaction time: 72 h
Yield: 57 %

Procedure:
Commercial 4-chloro-phenylacetyl chloride (0.95 g) was added dropwise to a stirred solution of commercial ethyl N-phenylglycinate (1 g) and dry pyridine (3 ml) in dichloromethane (20 ml) under nitrogen atmosphere at rt. After stirring for 72 h the mixture was poured into 10% HCl solution and extracted with ethyl acetate. The organic layer was washed with saturated NaCl solution, dried over MgSO4, and concentrated. The residue was purified by flash chromatography on silica gel (hexane/ethyl acetate 4:1) to give ethyl N-(4-chlorophenylacetyl)-N-phenylglycinate (0.95 g) as colourless oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1OS(C1C=CC(C)=CC=1)(=O)=O)(=[O:3])[CH3:2].[CH2:22]([N:24]([CH2:28][CH3:29])[CH2:25][C:26]#[CH:27])[CH3:23]>CCCCCCC.CCOC(C)=O>[CH2:22]([N:24]([CH2:28][CH3:29])[CH2:25][C:26]#[C:27][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[NH:4][C:1](=[O:3])[CH3:2])[CH3:23]
Reactant: CC(=O)Nc1ccccc1OS(=O)(=O)c1ccc(C)cc1
Reactant: C#CCN(CC)CC
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCN(CC)CC#Cc1ccccc1NC(C)=O

Procedure:
This product was prepared from toluene-4-sulfonic acid 2-acetylamino-phenyl ester and diethyl-prop-2-ynyl-amine following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 8:2; yield (73 mg, 60%); 1H NMR δ (CDCl3): 8.47 (d, J=8.52 Hz, 1H), 7.93 (br s, 1H), 7.36 (dm, 1H), 7.31-7.23 (m, 1H), 7.02 (t, J=7.24 Hz, 1H), 3.54 (s, 2H), 2.62 (q, J=7.13 Hz, 4H), 2.21 (s, 3H), 1.11 (t, J=7.11 Hz, 6H); LCMS m/z: 244.
Reaction SMILES: [H-].[Na+].CN(C)C=[O:6].[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[NH:14][CH:13]=[CH:12]2.Br[CH2:21][C:22]([CH3:24])=[CH2:23]>O>[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:21][C:22]([OH:6])([CH3:24])[CH3:23])[CH:13]=[CH:12]2
Reactant: C=C(C)CBr
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)(O)Cn1ccc2cc(Br)ccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, 23 mg of 60% of sodium hydride was added at 0° C. to 2 ml solution of dimethylformamide with 62 mg of 6-bromo-2H-isoquinoline-1-one, and the mixture was stirred for 30 30 min. Then, 0.055 ml of 3-bromo-2-methyl-propene was added at 0° C., and the mixture was stirred at room temperature for 2 hours. Cold water was added to the reaction solution, extracted with chloroform. Chloroform layer was washed with saturated saline solution, and dried with anhydrous sodium sulfate. The solvents were distilled outunder reduced pressure, and the residues were separated and purified by thin-layer chromatography (hexane/ethyl acetate=3/1). The obtained compounds were dissolved in concentrated hydrochloric acid, stirred at 100° C. for 3 hours, and then cooled down to room temperature. After making it alkaline with 50% sodium hydride aqueous solution, the mixture was stirred at room temperature for 3 hours. Cold water was added to the reaction solution, and extracted with chloroform. Chloroform layer was washed with saturated saline solution, and dried with anhydrous sodium sulfate. The solvents were distilled outunder reduced pressure, and the residues were separated and purified by thin-layer chromatography (hexane/ethyl acetate=3/1) to obtain 20 mg of the above compound as a white solid.
Reaction SMILES: Cl[C:2]1[S:9][C:8]2[CH:7]=[C:6]([C:10](N[C@@H]3CC4C(=CC=CC=4)[C@H]3NC=O)=[O:11])[NH:5][C:4]=2[C:3]=1[Cl:25].[OH-:26].[Li+]>CO>[C:10]([C:6]1[NH:5][C:4]2[C:3]([Cl:25])=[CH:2][S:9][C:8]=2[CH:7]=1)([OH:11])=[O:26]
Reactant: O=CN[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Reactant: [OH-]
Agent: [Li+]
Solvent: CO
Product: O=C(O)c1cc2scc(Cl)c2[nH]1
Yield: 99.9 %

Procedure:
3-Chloro-5-methoxycarbonyl-4H-thieno[3,2-b]pyrrole (Method 1; 0.61 g, 2.83 mmol) was taken up in MeOH (10 ml) and was heated under reflux. Aqueous lithium hydroxide (2.0 M, 3.0 ml, 6.0 mmol) was added portionwise over 45 minutes. The mixture was heated under reflux for 30 minutes before being cooled and concentrated. Water (20 ml) was added and the solution was neutralised using aqueous hydrochloric acid (2.0 M, 3.0 ml). The solution was extracted using EtOAc, and the combined organic layers were concentrated to afford the title compound as a yellow solid (0.57 g, 100%). NMR: 12.4 (1H, br), 7.4 (1H, s), 7.0 (1H, s); m/z 200.3.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][N:9]2[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[C:24](C1(C)C(O)=C(C(C)(C)C)C=C(C)C1)(C)(C)[CH3:25].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([CH:24]=[CH2:25])[CH:11]=3)[C:6](=[O:23])[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CC1=CC(C(C)(C)C)=C(O)C(C)(C(C)(C)C)C1
Reactant: CCOC(=O)c1cn(C2CCCCC2)c2cc(Br)ccc2c1=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=Cc1ccc2c(=O)c(C(=O)OCC)cn(C3CCCCC3)c2c1
Temperature: 25 °C
Yield: 9385.9 %

Procedure:
A mixture of 1 g of ethyl 7-bromo-1-cyclohexyl-4-oxo-1,4-dihydro-quinoline-3-carboxylate (Example 13ad)), 60 mg of palladium tetrakis-triphenylphosphine, 1.55 ml of tributyl-vinyl-stannate and 5 mg of 2,6-di-tert-butyl-4-methyl-cresol in 25 ml of toluene is heated at reflux for 1 hr. The reaction mixture is cooled to room temperature, treated with 100 ml of ethyl acetate and washed with 100 ml of 10% aqueous ammonia solution. The aqueous solution is extracted with 50 ml of ethyl acetate. The combined organic phases are washed with 100 ml of saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated. The residue is chromatographed on silica gel with hexane/ethyl acetate 1:1. 0.646 g (75%) of ethyl 1-cyclohexyl-4-oxo-7-vinyl-1,4-dihydro-quinoline-3-carboxylate is obtained as a colourless amorphous solid. Mass spectrum (ISP): 326.3(M++H, 100%).
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-])(=O)=O)=CC=1.CC(C)([O-])C.[K+].[C:20]([O:24][C:25](=[O:51])[NH:26][CH2:27][C:28]1[N:29]([CH2:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C:30](=[O:45])[C:31]2[C:36]([C:37]=1[O:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:35][C:34]([CH:43]=O)=[CH:33][CH:32]=2)([CH3:23])([CH3:22])[CH3:21].CO>COCCOC.O>[C:20]([O:24][C:25](=[O:51])[NH:26][CH2:27][C:28]1[N:29]([CH2:46][C:47]([CH3:49])([CH3:50])[CH3:48])[C:30](=[O:45])[C:31]2[C:36]([C:37]=1[O:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:35][C:34]([CH2:43][C:10]#[N:11])=[CH:33][CH:32]=2)([CH3:21])([CH3:22])[CH3:23]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)(C)C)c(=O)c2ccc(C=O)cc12
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: COCCOC
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)(C)C)c(=O)c2ccc(CC#N)cc12
Temperature: -70 °C
Reaction time: 1 h
Yield: 36.2 %

Procedure:
To a solution of p-toluenesulfonylmetyl isocyanide (0.94 g, 4.8 mmol) in 1,2-dimethoxyethane (20 ml) were added potassium t-butoxide (0.90 g, 8 mmol) and tert-butyl(4-butoxy-6-formyl-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (1.78 g, 4 mmol) at −70° C., and the mixture was stirred at −70° C. for 1 h. To the mixture was added methanol (30 ml), and the mixture was refluxed for 30 min. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[4-butoxy-6-(cyanomethyl)-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.66 g, 36.3%) as an amorphous solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:16]2=[O:37])=[C:11]([OH:38])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:40]I.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]2[C:15]3([CH2:40][O:38][C:11]=2[CH:10]=1)[C:23]1[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[N:17]([CH:24]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:16]3=[O:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCI
Reactant: O=C1C(c2ccc(OCc3ccccc3)cc2O)c2ccccc2N1C(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.4 %

Procedure:
To a stirred solution of 3-[4-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one (7.4 g, 14.8 mmol), chloroiodomethane (2.7 mL, 37.0 mmol) in anhydrous tetrahydrofuran (200 mL) was added cesium carbonate (15.4 g, 47.4 mmol) under argon. The mixture was stirred at ambient temperature for 16 h, then filtered through a pad of celite. The filtrate was concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/hexanes, 1/5) followed by the treatment with diethyl ether/hexanes to afford 6-(benzyloxy)-1′-(diphenylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (4.1 g, 55%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.42-7.25 (m, 15H), 7.16-7.09 (m, 1H), 7.07-6.90 (m, 3H), 6.62-6.38 (m, 4H), 5.03-4.90 (m, 3H), 4.73 (d, J=9.0 Hz, 1H); MS (ES+) m/z 510.1 (M+1).
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]([NH:12][C:13]2[C:14]([N:19]3[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]3=[O:26])=[N:15][N:16]([CH3:18])[CH:17]=2)=[O:11])[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO.[BH4-].[Na+]>C(OCC)(=O)C.O>[CH3:25][C:21]1([CH3:24])[CH2:22][CH2:23][N:19]([C:14]2[C:13]([NH:12][C:10]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([CH:1]([OH:3])[CH3:2])[N:9]=3)=[O:11])=[CH:17][N:16]([CH3:18])[N:15]=2)[C:20]1=[O:26]
Reactant: CC(=O)c1cccc(C(=O)Nc2cn(C)nc2N2CCC(C)(C)C2=O)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(O)c1cccc(C(=O)Nc2cn(C)nc2N2CCC(C)(C)C2=O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
To a mixture of 6-acetyl-N-(3-(3,3-dimethyl-2-oxopyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)pyridine-2-carboxamide (32 mg) and methanol (5.0 mL) was added sodium borohydride (5.3 mg) at room temperature, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, and water was added thereto. The extract was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and the obtained solid was washed with diisopropyl ether, and dried under reduced pressure to give the title compound (25 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27].O>N1C=CC=CC=1>[C:26]([N:6]([CH2:5][C:4]1[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:3]=1[O:2][CH3:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(CNc2ccccc2Oc2ccccc2)c(OC)c1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(CN(C(C)=O)c2ccccc2Oc2ccccc2)c(OC)c1
Temperature: 25 °C
Yield: 96.9 %

Procedure:
To a solution of 1.00 g of N-(2,4-dimethoxy benzyl)-2-phenoxyaniline in 1.18 g of pyridine was added 0.76 g of acetic anhydride, followed by stirring at room temperature for a day. The reaction mixture was poured into water and extracted with ethyl acetate, and the extract was washed with 0.5 N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate-hexane=1:3) to give 1.09 g of N-acetyl-N-(2,4-dimethoxybenzyl)-2-phenoxyaniline as an oil.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]=2[O:19][C:20](=[O:26])[NH:21][S:22](Cl)(=[O:24])=[O:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:27]([C:30]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]([CH3:39])[CH3:38])[C:31]=1[NH2:32])([CH3:29])[CH3:28].C(N(CC)CC)C>O1CCCC1>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]=2[O:19][C:20](=[O:26])[NH:21][S:22]([NH:32][C:31]2[C:33]([CH:37]([CH3:38])[CH3:39])=[CH:34][CH:35]=[CH:36][C:30]=2[CH:27]([CH3:29])[CH3:28])(=[O:24])=[O:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NS(=O)(=O)Cl)Oc1c(-c2ccccc2)cccc1-c1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)c1cccc(C(C)C)c1NS(=O)(=O)NC(=O)Oc1c(-c2ccccc2)cccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of [1,1':3', 1"-terphenyl]-2'-yl(chlorosulfonyl)carbamate (5.0 g, 12.9 mmol) in 75 mL tetrahydrofuran was added dropwise to a solution of 2,6-diisopropyl aniline (2.29 g, 12.9 mmol) and triethylamine (1.3 g, 12.9 mmol) in 100 mL tetrahydrofuran at -15° C. under an atmosphere of nitrogen. The resulting mixture was warmed to room temperature and stirred for 16 hours. Concentrated in vacuo and partitioned the residue between water and ethyl acetate. Dried the organic layer over MgSO4 and evaporated to give an off-white solid. Chromatography on silica gel gave the title compound, mp 166°-168° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:12]=1.C(O)(=O)C.[N-:17]=[N+]=[N-].[Na+].S(=O)(=O)(O)O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7](=[O:11])[NH:17][C:6]=2[CH:12]=1
Reactant: O=C1CCSc2ccc(F)cc21
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1CCSc2ccc(F)cc2N1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 75.1 %

Procedure:
6-fluoro-2,3-dihydro-4H-1-benzothiopyran-4-one (100 mg, 0.54 mmol) was dissolved in acetic acid (0.5 mL, 1.1 eq), sodium azide (71.2 mg, 1.1 mmol) was added and mixture was heated to 50° C. Sulfuric acid (0.13 mL, 4.3 eq) was added slowly and stirred at 50° C. for 1.5 hours. Ice chips (150 mg) were added and a green solid precipitated, this was filtered, washed with water and dried to give 7-fluoro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (80 mg, 24%). 1H NMR (CDCl3, 300 MHz): δ 7.77 (s-broad, 1H), 7.69 (t, 1H, J=7.3 Hz), 6.94–6.82 (m, 2H), 3.42 (t, 2H, J=7 Hz), 2.63 (t, 2H, J=6.7 Hz) ppm.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH:10]([CH3:12])[CH3:11])=[CH:8][C:5]([CH:6]=O)=[C:4]([CH3:13])[CH:3]=1.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].OS([O-])(=O)=O.[Na+]>C(Cl)Cl.O>[CH:10]([C:9]1[CH:8]=[C:5]([CH2:6][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:4]([CH3:13])=[CH:3][C:2]=1[OH:1])([CH3:12])[CH3:11]
Reactant: C1CCNC1
Reactant: Cc1cc(O)c(C(C)C)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(O)c(C(C)C)cc1CN1CCCC1
Yield: 76.5 %

Procedure:
4-Hydroxy-5-isopropyl-2-methyl-benzaldehyde (1.0 g, 5.6 mmol) was added in portions for 30 min to a mixture of pyrrolidine (0.58 mL, 7 mmol) and NaB(OAc)3H (1.49 g, 7 mmol) in CH2Cl2 (10 mL) under vigorous stirring and cooling with an ice bath in an atmosphere of argon. The mixture was stirred for 12 h and cooled with an ice bath. Water (25 mL) and 5N NaHSO4 (to pH 1) were added. The organic layer was separated and discarded. The aqueous one was alkalized with saturated K2CO3 to pH 6 and extracted with chloroform (2×25 mL). The combined extracts were dried with Na2SO4, and evaporated to give the title compound (1.0 g, 80%) was obtained as dark-yellow crystals. LCMS-data: (M+H)+ 234.1 and 235.1 (calculated for C15H23NO 233.4). 1H NMR data (DMSO-d6): 8.88 (br. s, 1H ArOH), 6.90 (s, 1H, Ar—H), 6.54 (s, 1H, Ar—H); 3.40 (s, 2H, ArCH2), 3.13 (m, 1H, CH(CH3)2), 2.33-2.45 (m, 4H, pyrrolidine (CH2)2N), 2.17 (s, 3H, CH3), 1.60-1.70 (m, 4H, CH2CH2CH2CH2), 1.12 (d, 6H, J=6.9 Hz, CH(CH3)2).