Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.CCN(CC)CC.CS(Cl)(=O)=O.Cl.[Na+].[I-:27]>C(Cl)Cl>[I:27][CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1
Reactant: N#Cc1ccc(CCCO)cc1
Reactant: [I-]
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(CCCI)cc1

Procedure:
To a solution of 4-(3-hydroxypropyl)benzonitrile (1.8 g, 11.2 mmol) in CH2Cl2 (50 mL) at 0° C., Et3N (1.06 mL, 13.4 mmol) and then MsCl (0.95 mL, 12.5 mmol) were added. Upon completion, the reaction mixture was poured into 0.5M HCl and extracted with EtOAc. The crude mesylate was dissolved in acetone and treated with NaI (3.0 g, 20.0 mmol) in the dark at room temperature. When complete, the reaction was purified by flash chromatography on silica gel eluting with 15% EtOAc in Hexanes to afford the title compound.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[Br:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[F:21])[C:15]([OH:17])=O.[CH3:22][C:23]([CH3:44])([CH3:43])[CH2:24][CH2:25][NH:26][C:27](=[O:42])[C@H:28]([CH3:41])[CH2:29][C@H:30]([OH:40])[C@@H:31]([NH2:39])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C.ClCCl>[CH2:32]([C@H:31]([NH:39][C:15](=[O:17])[C:14]1[CH:18]=[CH:19][C:20]([F:21])=[C:12]([Br:11])[CH:13]=1)[C@@H:30]([OH:40])[CH2:29][C@H:28]([C:27](=[O:42])[NH:26][CH2:25][CH2:24][C:23]([CH3:22])([CH3:43])[CH3:44])[CH3:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)c1ccc(F)c(Br)c1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NCCC(C)(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1ccc(F)c(Br)c1)C(=O)NCCC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Cyclohexylcarbodiimide-N′-methyl polystyrene (265 mg @ 1.70 mmol/g; ex. Novabiochem) was treated with a solution of 1-hydroxybenzotriazole (0.45 mmol) in DMF (1.0 ml) followed by 3-bromo-4-fluorobenzoic acid (99 mg, 0.45 mmol), dichloromethane (1 ml) and (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (3,3-dimethylbutyl)-amide (D2) (90 mg, 0.30 mmol) in dichloromethane (0.5 ml)/DMF (0.5 ml). After stirring gently overnight at room temperature, methylisocyanate polystyrene (150 mg @ 1.80 mmol/g; ex. Novabiochem) and tris-(2-aminoethyl)-amine polystyrene (250 mg @ 3.20 mmol/g; ex. Novabiochem) were added and the mixture was stirred for a further 1.5 h. It was then filtered and the spent resins were washed with DMF and dichloromethane. The combined filtrates were evaporated to dryness and the residue was filtered through a short column of silica gel to give the title compound, 126 mg.
Reaction SMILES: [C:1]1([C:14]([OH:16])=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3][CH:2]=1.[NH2:17][CH2:18][C@@H:19]([OH:36])[CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)[CH2:23][CH2:22]1.C(N(CC)CC)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN1CCCC1=O>[Cl:35][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][C:31]=1[Cl:34])[O:27][CH:24]1[CH2:23][CH2:22][N:21]([CH2:20][C@H:19]([OH:36])[CH2:18][NH:17][C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:1]([C:14]([OH:16])=[O:15])=[CH:2][CH:3]=2)=[O:13])[CH2:26][CH2:25]1
Reactant: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reactant: O=C(O)c1ccc(C(=O)O)c2ccccc12
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(C(=O)NC[C@@H](O)CN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)c2ccccc12
Reaction time: 16 h
Yield: 21 %

Procedure:
To a solution of naphthalene-1,4-dicarboxylic acid (0.100 g), (2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.147 g) and triethylamine (0.193 mL) in N-methyl-2-pyrolidinone (20 mL) was added PyBrOP (0.258 g). The reaction mixture was stirred for 16 h and the solvent was removed in vacuo. The residue was purified by RPHPLC (Symmetry, 0.1% ammonium acetate/acetonitrile) to afford the title compound as a colourless solid (0.050 g, 20%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([NH2:13])[CH2:8][CH2:7][CH2:6]2.[Cl:14][C:15]1[CH:24]=[CH:23][C:18]([CH2:19][N:20]=[C:21]=[S:22])=[CH:17][CH:16]=1>C(OCC)(=O)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][NH:20][C:21]([NH:13][CH:9]2[C:10]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=3)[CH2:6][CH2:7][CH2:8]2)=[S:22])=[CH:23][CH:24]=1
Reactant: S=C=NCc1ccc(Cl)cc1
Reactant: COc1ccc2c(c1)CCCC2N
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)CCCC2NC(=S)NCc1ccc(Cl)cc1
Reaction time: 18 h
Yield: 98.7 %

Procedure:
The compound 32-1 (100 mg) prepared according to the same procedure as described in Step 1 was dissolved in ethyl acetate (4 ml) and to the solution were added a solution of 4-chlorobenzylisothiocyanate (123 mg) in ethyl acetate (2 ml), followed by stirring at room temperarure for 18 hours. The obtained reaction mixture was concentrated under reduced pressure and purified by column-chromatography (hexane/ethyl acetate=2/1) to yield the compound 32-2 (201 mg, 99%).
Reaction SMILES: C(O)C.Cl.C([N:12]([C@@H:19]1[C:25](=[O:26])[N:24]([CH2:27][C:28]([OH:30])=[O:29])[C:23]2[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=2[S:21][CH2:20]1)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])C1C=CC=CC=1>[C].[Pd].C(OCC)(=O)C>[CH2:17]([O:16][C:14]([CH2:13][NH:12][C@@H:19]1[C:25](=[O:26])[N:24]([CH2:27][C:28]([OH:30])=[O:29])[C:23]2[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=2[S:21][CH2:20]1)=[O:15])[CH3:18]
Reactant: CCOC(=O)CN(Cc1ccccc1)[C@H]1CSc2ccccc2N(CC(=O)O)C1=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CN[C@H]1CSc2ccccc2N(CC(=O)O)C1=O
Yield: 82.4 %

Procedure:
A mixture of 20 ml of ethanol and 0.5 g of 3(R)-(N-benzyl-N-ethoxycarbonylmethylamino)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid hydrochloride obtained in Reference Example 35 is catalytic reduction over 0.5 g of 10% palladium-carbon (containing 50% of moisture) as a catalyst at ordinary temperature and at atmospheric pressure. After the absorption of hydrogen stops, the catalyst is filtered off, and the filtrate is concentrated to give crystals. Ethyl acetate is added to the crystals, and the deposited substance are collected by filtration to yield 0.3 g of 3(R)-ethoxycarbonylmethylamino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid as colorless prisms, m.p. 223°-226° C.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[CH:18]2)([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH3:14])[CH:6]=1)[OH:4].[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:25][C:2]([F:1])([F:24])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH3:14])[CH:6]=1)([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([C:28]1[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=1)[N:19]=[CH:18]2)[OH:4]
Reactant: c1ccncc1
Reactant: Cn1cc(C(O)(c2ccc3[nH]ncc3c2)C(F)(F)F)c2ccccc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: Cn1cc(C(O)(c2ccc3c(cnn3-c3cccnc3)c2)C(F)(F)F)c2ccccc21
Temperature: 25 °C
Yield: 23.7 %

Procedure:
A mixture of 70 mg (0.20 mmol) of 2,2,2-trifluoro-1-(1H-indazol-5-yl)-1-(1-methyl-1H-indol-3-yl)ethanol, 65 mg (1.97 mmol) of 3-pyridyl boronic acid ester, 55 mg (0.3 mmol) of copper acetate and 50 μL (0.62 mmol) of pyridine in dry dichloromethane was stirred at room temperature. Oxygen gas was bubbled into the solution for 5 minutes and the mixture was stirred in a sealed tube. The reaction was monitored by LC-MS indicating partial conversion to product at 3 hours. The mixture was stirred overnight for 18 hours and then diluted with brine and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, and absorbed onto silica gel and first purified by Combiflash chromatography using a 0-80% EtOAc-hexanes gradient and then by preparative TLC using 20% EtOAc-hexanes. Crystallization from ether-hexanes to gave 20 mg (26%) of the title compound as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[S:20])[CH2:10][N:9]=1.[OH-].[Na+].CO.Cl.Cl[CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>O>[N:29]1([CH2:28][CH2:27][S:20][C:11]2[CH2:10][N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:14]3[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=3[N:12]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCC(SCCN1CCCC1)=N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 9.6 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-1,4-benzodiazepine-2-thione in a solvent mixture comprising 40 ml of a 10% aqueous sodium hydroxide solution and 40 ml of methanol is added at room temperature 4.4 g of 1-chloro-2-(1-pyrrolidinyl)ethane hydrochloride, and the resulting mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate and, thereafter, the solvent is distilled off under reduced pressure to obtain an oily 2-[2-(1-pyrrolidinyl)ethylthio]-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine. The oily product thus obtained is treated, according to usual procedure, with fumaric acid and recrystallized from isopropyl alcohol to obtain 6.9 g of 2-[2-(1-pyrrolidinyl)ethylthio]-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine fumarate, m.p. 184°-188° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([Cl:7])[C:3]=1[Cl:8].[F:9][P-:10]([F:15])([F:14])([F:13])([F:12])[F:11].[CH3:16]COCC>>[F:9][P-:10]([F:15])([F:14])([F:13])([F:12])[F:11].[CH3:16][N+:5]1[S:6][C:2]([Cl:1])=[C:3]([Cl:8])[C:4]=1[Cl:7]
Reactant: CCOCC
Reactant: Clc1nsc(Cl)c1Cl
Agent: F[P-](F)(F)(F)(F)F
Product: C[n+]1sc(Cl)c(Cl)c1Cl
Yield: 61 %

Procedure:
Trichloroisothiazole (15 ml) and 6.2 g (0.03 mol) of trimethyloxomium hexafluorophosphate were heated at 90° for 1 hr under nitrogen. After cooling, ether (100 ml) was added and the solid collected to yield 6.3 g (61%) of product, mp >240. Spectral data (NMR & IR) were consistent with the assigned structure.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:4]([O:6]C)=[O:5].[OH-].[Li+]>CO.O1CCCC1>[OH:1][CH2:2][CH:3]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:4]([OH:6])=[O:5]
Reactant: COC(=O)C(CO)NC(=O)N1CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(CO)NC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
200 mg (0.869 mmol) of methyl 3-hydroxy-2-[(1-piperidinylcarbonyl)-amino]propionate was dissolved in 6 ml of a solvent mixture of methanol:tetrahydrofuran (1:1). 1.04 ml (1.04 mmol) of 1 N aqueous lithium hydroxide solution was added to the obtained solution, and they were stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the concentrate was acidified with 1 N aqueous hydrochloric acid solution. After extracting with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[Cl:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1>N1C=CC=CC=1>[Cl:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[CH:11][CH:10]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(Cl)cc1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
Trimethylacetyl chloride (35 g) was added drop wise to a solution of 4-chloroaniline (31.9 g) in dry pyridine and the reaction was stirred under nitrogen overnight. About half of the pyridine was removed by rotary evaporation, then the mixture was treated with 6M hydrochloric acid and extracted with ethyl acetate. The extracts were washed with saturated aqueous NaHCO3 and with water, then were dried (MgSO4), filtered and concentrated by rotary evaporation. The resulting crystalline product was vacuum filtered and dried at high vacuum to constant weight, resulting in a good yield of N-(4-chloro-phenyl)-2,2-dimethyl-propionamide as fine needles. EDC (10 g) and 2-methyl-nicotinic acid (7.15 g) were magnetically stirred in acetonitrile-THF with N,O-dimethylhydroxylamine hydrochloride (9.75 g) and triethylamine (25 mL). After stirring overnight at ambient temperature, the resulting white suspension was added to ice water and extracted with ethyl acetate (3×100 mL). The extracts were dried, filtered, and concentrated to give a light amber oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH2:11].[CH2:13]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)[CH2:14][CH2:15][CH3:16].C(N(CC)CC)C.[BH4-].[Na+]>CO>[CH3:2][O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([CH2:13][CH2:14][CH2:15][CH3:16])=[CH:18][CH:19]=1
Reactant: CCCCc1ccc(C=O)cc1
Reactant: COC(=O)CCCCCCN
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCCc1ccc(CNCCCCCCC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 7-amino-heptanoic acid methyl ester hydrochloride, prepared of Preparation 1, (1.12 g, 5.9 mmol), 4-butyl-benzaldehyde (0.915 g, 5.65 mmol) and triethylamine (0.83 mL, 5.98 mmol) in 20 mL MeOH was stirred at room temperature for 3 hours. After cooling to 0° C., NaBH4 (0.342 g, 9.04 mmol) was added and the reaction was stirred for 15 minutes at room temperature. The mixture was quenched with 1:1 NaHCO3:H2O and the MeOH was removed in vacuo. The resulting residue was diluted with CH2Cl2 and the organic solution was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound of Step A (1.4 g). 1H NMR (400 MHz, CDCl3) δ 7.08-7.38 (m, 4H), 3.62 (s, 2H), 3.29 (s, 3H), 2.52-2.66 (m, 4H), 2.25 (t, 2H), 1.53-1.63 (m, 6H), 1.25-1.40 (m, 6H), 0.85 (t, 3H); MS 306 (M+1).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][CH:10]=2)O1.I[C:25]1[C:33]2[C:28](=[N:29][CH:30]=[N:31][C:32]=2[NH2:34])[N:27]([C@H:35]2[CH2:40][CH2:39][C@@H:38]([N:41]3[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]3)[CH2:37][CH2:36]2)[N:26]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:34][C:32]1[N:31]=[CH:30][N:29]=[C:28]2[N:27]([C@H:35]3[CH2:40][CH2:39][C@@H:38]([N:41]4[CH2:42][CH2:43][N:44]([CH3:47])[CH2:45][CH2:46]4)[CH2:37][CH2:36]3)[N:26]=[C:25]([C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:13][CH:14]=3)[C:33]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(NC(=O)OC(C)(C)C)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Yield: 80.2 %

Procedure:
A mixture of tert-butyl N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (3.71 g, 0.0116 mol), cis-3-iodo-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4.46 g, 0.0101 mol), tetrakis-(triphenylphosphine)palladium (0.700 g, 0.00061 mol) and sodium carbonate monohydrate (3.13 g, 0.0253 mol) was heated in a mixture of ethylene glycol dimethyl ether (140 mL) and water (70 mL) at 80° C. for sixteen hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate solution (300 mL) and ethyl acetate (300 mL), the organic layer separated and the aqueous layer further extracted with ethyl acetate twice (150 mL each). The combined organic extracts were dried over magnesium sulfate. The solvents were evaporated under reduced pressure to leave a tan solid which was purified by flash column chromatography on silica using dichloromethane/triethylamine/methanol (95:4:1) as a mobile phase to give cis-tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)carbamate (4.1 g, 0.0081 mol) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.CN1CCOCC1.[C:24]1([CH2:30][S:31](Cl)(=[O:33])=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[CH2:30]([S:31]([NH:1][C:2]1[C:3](=[O:16])[N:4]([CH2:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH:5]=[CH:6][CH:7]=1)(=[O:33])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)Cn1cccc(N)c1=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)Cn1cccc(NS(=O)(=O)Cc2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a solution of 3-amino-1-(tert-butoxycarbonylmethyl)-2-pyridinone (1.12 g, 5.0 mmol), and N-methylmorpholine (1.5 mL, 10.0 mmol) in methylene chloride (40 mL) was added α-toluenesulfonyl chloride (950 mg, 5.0 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. Additional methylene chloride (50 mL) was added. The resulting solution was washed with saturated NaHCO3 (2×50 mL), 10% citric acid (3×50 mL) and brine (50 mL), and dried over Na2SO4 and filtered and the filtrate was concentrated to give a solid which was washed with ethyl acetate/hexane (1:2, 60 mL) to give the title compound as a white solid (1.8 g, 96%). 1H-NMR (300 MHz, CDCl3) δ7.42 (br s, 1H), 7.36 (d, J=7.3 Hz, 1H), 7.31 (m, 5H), 6.92 (d, J=7.0 Hz, 1H), 6.14 (t, J=7.2 Hz, 1H), 4.58 (s, 2H), 4.34 (s, 2H), 1.51 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([S:10][CH3:11])=[C:5]([CH3:9])[C:6]=1[CH:7]=[O:8].[BH4-].[Na+]>C(O)C>[CH3:1][C:2]1[S:3][C:4]([S:10][CH3:11])=[C:5]([CH3:9])[C:6]=1[CH2:7][OH:8]
Reactant: CSc1sc(C)c(C=O)c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CSc1sc(C)c(CO)c1C
Temperature: 20 °C

Procedure:
15.0 G. of 2,4-dimethyl-5-(methylthio)thiophene-3-carboxaldehyde was dissolved in 150 m. fo dry ethanol with stirring at 20° C. 0.8 G. of sodium borohydride was added and the mixture was stirred for 30 minutes, then poured into ice water and extracted with ethyl ether. The combined ether extracts were washed with a solution of 5% sodium carbonate and saturated sodium chloride solution, dried over sodium sulfate, filtered, and evaporated to yield 2,4-dimethyl-3-hydroxymethyl-5-(methylthio)thiophene.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][N:20]=[CH:19]2.C(O)(=O)C.C(=O)([O-])O.[Na+]>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[CH:19]3)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Nc1ccc2[nH]ncc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: c1ccc(CN2CCC(Nc3ccc4[nH]ncc4c3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.3 %

Procedure:
1-Benzyl-4-piperidone (635 mg), 5-aminoindazole (532 mg), and acetic acid (0.20 ml) were dissolved in methanol (10 ml), and a borane-pyridine complex (0.51 ml) was added dropwise to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. A saturated aqueous sodium hydrogencarbonate solution (10 ml) was then added thereto, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel [chloroform/methanol] to give the title compound (1.00 g, yield 82%).
Reaction SMILES: [N+](/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-])=O.BrBr.N12CCCN=C1CCCCC2.[OH:25][C:26]1[C:27](=[O:37])[C:28]2[C:33]([C:34](=[O:36])[CH:35]=1)=[CH:32][CH:31]=[CH:30][CH:29]=2>ClCCl>[C:6]1([C:5]2[C:35]3[C:34](=[O:36])[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:27](=[O:37])[C:26]=3[O:25][CH:4]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Agent: BrBr
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)c2c(-c3ccccc3)coc21
Yield: 69.7 %

Procedure:
To the solution of 5 grams (33.5 mmoles) of [(E)-2-nitroethenyl]benzene in 100 mL of dichloromethane, 5.6 grams (35.2 mmoles) of bromine was added. The mixture was refluxed for 12 hours, and then evaporated to dryness. To the residue solution in 150 mL of tetrahydrofuran cooled in ice bath, 5.3 grams (35.2 mmoles) of 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) was dropped slowly over 20 minutes while stirring vigorously. The reaction mixture was further stirred for 30 minutes in ice bath, then 5.8 grams (33.5 mmoles) of 2-hydroxy-1,4-naphthoquinone and 5.3 grams (35.2 mmoles) of 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) were added. The mixture was reflux for 3 hours, and then evaporated to sticky residue. The residue was dissolved in 300 mL of dichloromethane, and washed with 300 mL of water, 300 mL of 2% aqueous citric acid solution, successively, and dried with 30 grams of anhydrous sodium sulfate. The 3-phenyl-naphtho[2,3-b]furan-4,9-dione product was purified with silica gel column using dichloromethane/hexane (3:1) as elution solvent. 6.4 grams of product (overall yield 70%) was obtained and characterized by 1H NMR and mass spectrum. 1H NMR (in DMSO) δ 7.44-7.52 (m, 3H), 7.77-7.79 (m, 2H), 7.89-7.93 (m, 2H), 8.10-8.15 (m, 2H), 8.58 (s, 1H). Mass (M+H) is 275.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:60][O:61][C:62]1[CH:67]=[CH:66][C:65]([C:68]2([CH2:71]O)[CH2:70][CH2:69]2)=[CH:64][CH:63]=1>O1CCCC1>[CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[N:9]([CH2:71][C:68]3([C:65]4[CH:64]=[CH:63][C:62]([O:61][CH3:60])=[CH:67][CH:66]=4)[CH2:70][CH2:69]3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: COc1ccc(C2(CO)CC2)cc1
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCc1cc2c(=O)n(CC3(c4ccc(OC)cc4)CC3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.2 %

Procedure:
A mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.3 g), tributylphosphine (1.6 mL), [1-(4-methoxyphenyl)cyclopropyl]methanol (0.46 g) and tetrahydrofuran (30 mL) was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, to the residue was added diisopropyl ether (50 mL), and the mixture was stirred at room temperature for 1 hr. Insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.71 g, 50%).