Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17]CC3C=CC=CC=3)=[CH:13][CH:12]=2)[CH2:6]1)=[O:4]>O1CCCC1.[Pd]>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CC(=O)N(c2ccc(OCc3ccccc3)cc2)C1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)C1CC(=O)N(c2ccc(O)cc2)C1
Reaction time: 3 h
Yield: 115.1 %

Procedure:
7.26 g (22.3 mmol) (RS)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester is dissolved in 200 ml tetrahydrofuran. After addition of 726 mg palladium 10% on charcoal hydrogenation is performed at RT and normal pressure. After 3 hours, the catalyst is filtered off and the solvent evaporated to yield 6.04 g of crude product (used in the next step without further purification).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][NH:12]2)=[O:10])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C=O.[C:22]([BH3-])#N.[Na+].O>CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[CH3:22])=[O:10])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18]
Reactant: [BH3-]C#N
Reactant: Nc1ccc(NC(=O)[C@H]2CCCCN2)cc1[N+](=O)[O-]
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CCCC[C@@H]1C(=O)Nc1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 98.7 %

Procedure:
(R)—N-(4-Amino-3-nitrophenyl)piperidine-2-carboxamide (2.09 g, 7.9 mmol) was dissolved in MeOH (50 mL), and paraformaldehyde (0.95 g) and sodium cyanoborohydride (0.50 g, 8.0 mmol) were added. The mixture was stirred at room temperature for 70 min, and water added dropwise. The solvent was evaporated and the residue partitioned between water and EA (150 mL each). The phases were separated and the aqueous phase extracted with EA (2×100 mL). The combined EA layers were washed with brine, dried over magnesium sulfate, and concentrated to give (R)—N-(4-amino-3-nitrophenyl)-1-methylpiperidine-2-carboxamide as an orange foam (2.17 g), which was used without purification.
Reaction SMILES: Br[C:2]1[C:3]2[CH:9]([CH3:10])[CH:8]([CH3:11])[C:7](=O)[C:4]=2[S:5][CH:6]=1.[BH4-].[Na+].O>C1COCC1.CO>[CH3:10][CH:9]1[C:3]2[CH:2]=[CH:6][S:5][C:4]=2[CH:7]=[C:8]1[CH3:11]
Reactant: CC1C(=O)c2scc(Br)c2C1C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1=Cc2sccc2C1C
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a solution of 132.4 g (0.54 mol) of 3-bromo-4,5-dimethyl-4,5-dihydro-6H-cyclopenta[b]thiophen-6-one in 750 ml of THF-methanol (2:1, vol.), 28.6 g (0.75 mol) of NaBH4 was added in small portions while vigorously stirring over 1 h at 5° C. This mixture was stirred overnight at ambient temperature and then added to ca. 1000 cm3 of cold water. The organic layer was separated; the aqueous layer was extracted with 2×300 ml of methyl-tert-butyl ether. The combined extract was dried over K2CO3 and evaporated to dryness. To a hot solution of the residue in 1500 cm3 of toluene, 0.5 g of para-toluenesulfonic acid was added. This mixture was refluxed for 15 min, cooled to room temperature, and passed through a short Silica Gel 60 column (40-63 μm, d 65 mm, 1 150 mm). The column was additionally washed with hexanes to isolate the product. The obtained solution was evaporated to dryness. Fractional distillation gave a colorless oil, bp 101-104° C./2 mm Hg. Yield 92.8 g (75%).
Reaction SMILES: [H][H].C([N:10]1[C:15](=[O:16])[N:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH2:13][CH2:12][O:11]1)C1C=CC=CC=1.C>[Pd](Cl)Cl.C(O)(=O)C>[Cl:24][C:19]1[CH:18]=[C:17]([N:14]2[CH2:13][CH2:12][O:11][NH:10][C:15]2=[O:16])[CH:22]=[CH:21][C:20]=1[Cl:23]
Reactant: [H][H]
Reactant: O=C1N(Cc2ccccc2)OCCN1c1ccc(Cl)c(Cl)c1
Agent: Cl[Pd]Cl
Solvent: CC(=O)O
Product: O=C1NOCCN1c1ccc(Cl)c(Cl)c1
Yield: 96 %

Procedure:
Hydrogen was passed through a mixture of 3.37 g of 2-benzyl-4-(3',4'-dichlorophenyl)-3-oxo-5,6-dihydro-1,2,4-oxadiazine, 70 ml of acetic acid, 680 mg of animal charcoal and 0.6 ml of a 20% palladium chloride solution until absorption ceased and the mixture was filtered. The filter was washed with acetic acid and the filtrate was poured into ice water. The mixture was extracted with methylene chloride and the organic extracts were dried and evaporated to dryness. The crystalline product was taken up in isopropyl ether to obtain 2.37 g of 4-(3',4'-dichlorophenyl)-3-oxo-5,6-dihydro-1,2,4-oxadiazine melting at 152° C.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([CH:18]2[CH2:23][CH:22]3[CH2:24][CH:19]2[CH2:20][CH2:21]3)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH:19]12[CH2:24][CH:22]([CH2:21][CH2:20]1)[CH2:23][CH:18]2[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1)=[O:17]
Reactant: CCOC(=O)C1(NC(=O)C2CC3CCC2C3)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)C1CC2CCC1C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
2-[(Bicyclo[2.2.1]heptane-2-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (148 mg, 0.45 mmol) is dissolved in EtOH (8 mL), and solid KOH (600 mg, 10 mmol) and water (0.8 mL) are added. The mixture is stirred at RT for 30 min then concentrated in vacuo. The residue is dissolved in water (10 mL) and acidified with concentrated HCl until no more white solid precipitated. The solid is collected by vacuum filtration to give product (273) as white solid (105 mg, 77%).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8](I)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[C:24]=1B(O)O>>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[C:24]=1[C:8]1[C:7]2[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=2[C:5]2[C:4]3[CH:3]=[C:2]([OH:1])[CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]=1
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Reactant: COc1cccc(OC)c1B(O)O
Product: COc1cccc(OC)c1-c1cc2[nH]c3ccc(O)cc3c2c2c1C(=O)NC2=O
Yield: 43 %

Procedure:
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione, prepared as in example 7, with 2,6-dimethoxybenzeneboronic acid according to the procedure described in example 8 gave 4-(2,6-dimethoxyphenyl)-9-hydroxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (19) (I, Ar=2,6-dimethoxyphenyl) in a 43% yield; mp 275–277° C. (dec). 1H NMR δ [(CD3)2SO] 11.62 (br s, 1H), 10.83 (br s, 1H), 9.21 (br s, 1H), 8.29 (d, J=2.4 Hz, 1H), 7.42 (s, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.35 (t, J=8.4 Hz, 1H), 7.04 (dd, J=8.4, 2.4 Hz, 1H), 6.75 (d, J=8.4 Hz, 2H), 3.63 (s, 6H). Found: C, 66.31; H, 4.50, N, 6.70. C22H16N2O5,1/2H2O requires C, 66.49; H, 4.31; N, 7.04.
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][CH2:5][CH2:4][CH:3]1[CH2:13][C:14]([OH:16])=O.Cl.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=1.C([O-])(=O)C.[Na+]>C(O)C>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:14](=[O:16])[CH2:13][CH:3]3[CH2:4][CH2:5][S:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[C:2]3=[N:27]2)=[CH:22][CH:21]=1
Reactant: COc1ccc(NN)cc1
Reactant: O=C(O)CC1CCSc2ccccc2C1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(N2N=C3c4ccccc4SCCC3CC2=O)cc1
Yield: 33.2 %

Procedure:
A mixture of 4 g of 5-oxo-2,3,4,5-tetrahydro-[1]benzothiepine-4-acetic acid, 3.5 g of 4-methoxyphenylhydrazine hydrochloride and 1.8 g of sodium acetate in 100 ml of ethanol is refluxed under heating for 12 hours and then the solvent is distilled off. To the residue is added 20 ml of acetic acid and the mixture is refluxed under heating for 2 hours. The solvent is distilled off, and the mixture of the residue in water is extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and the solvent is distilled off. The crude product obtained is purified by column chromatography and recrystallized from ethanol to give 1.9 g of 2-(4-methoxyphenyl)-4,4a,5,6-tetrahydro-[1]benzothiepino[5,4-c]pyridazin-3(2H)-one, melting at 143°-145° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.O.[NH2:24][NH2:25]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:11]([C:12]([NH2:13])=[N:24][NH:25]3)=[CH:14][CH:15]=2)[CH:5]=[C:4]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1
Reactant: N#Cc1ccc(-c2cc(-c3ccccc3)nc(N)n2)cc1F
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nc1nc(-c2ccccc2)cc(-c2ccc3c(N)n[nH]c3c2)n1
Temperature: 95 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
Into a 25 mL sealable tube under argon were added 4-(2-amino-6-phenyl-4-pyrimidinyl)-2-fluorobenzonitrile (0.052 g, 0.18 mmol) and EtOH (5 mL). Hydrazine monohydrate (0.35 mL, 7.17 mmol) was added, the vial was sealed, and the reaction mixture was stirred overnight at 95° C. The reaction was cooled to room temperature and concentrated. The resulting solid was sonicated in a mixture of EtOH (1 mL) and water (10 mL), filtered, washed with water, and dried under vacuum at 40° C. to afford the title compound as a yellow solid (44 mg, 77%). LC-MS (ES) m/z=303 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 5.43 (s, 2H), 6.74 (s, 2H), 7.46-7.59 (m, 3H), 7.69-7.84 (m, 3H), 8.12 (s, 1H), 8.23 (m, 2H), 11.63 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1.[N+:9]([O-])([OH:11])=[O:10].C(=O)([O-])[O-].[Na+].[Na+]>OS(O)(=O)=O>[CH3:8][C:6]1[N:7]=[C:2]([NH2:1])[C:3]([N+:9]([O-:11])=[O:10])=[CH:4][CH:5]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(N)n1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1ccc([N+](=O)[O-])c(N)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 19 %

Procedure:
6-Amino picoline (5.0 g, 46 mmol) was cautiously suspended in H2SO4 (25 ml) and cooled in an ice bath. Fuming nitric acid (5 ml) was added slowly, and care was taken to keep the temperature of the reaction as low as possible. The reaction mixture was allowed to stir 3 h after the addition of the nitric acid was complete. The mixture was added to sodium carbonate (65 g), suspended in about ice water (500 ml). Once the neutralization was complete, the aqueous mixture was extracted four times with ethyl acetate. The combined ethyl acetate washings were washed with brine, dried using MgSO4, and concentrated under vacuum to yield the title product (1.3 g, 19%) as a red oil. 1H NMR (DMSO-d6): δ=8.27 (d, 1H, J=8.5 Hz), 7.88 (bs, 2H), 6.63 (1H, d, J=8.5), 2.39 (s, 3H).
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[C:8]([C:11]1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16]C(O)=C[CH:19]=3)[CH2:14][C:13]=2[CH:12]=1)(=[O:10])[CH3:9].N1C=CC=CC=1>C1COCC1>[C:8]([C:11]1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16][C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:19]=3)[CH2:14][C:13]=2[CH:12]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)c1ccc2c(c1)Cc1cc(O)ccc1-2
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2c(c1)Cc1cc(C(C)=O)ccc1-2

Procedure:
Acetic anhydride (50 mL) was added to a mixture of 2-acetyl-7-hydroxyfluorene (50 g), pyridine (200 mL) and THF (200 mL) at 28° C. The temperature was elevated slowly up to 61° C. by exothermic heat to obtain a yellow transparent reaction mixture. An organic layer obtained by extracting the mixture with chloroform was washed well in order with 3M-hydrochloric acid, saturated sodium hydrogencarbonate and water, and then dried on anhydrous magnesium sulfate. The solvent was distilled off from this organic layer under reduced pressure, and the resulting residue was purified by means of column chromatography (silica gel, eluting solvent: toluene) and recrystallization (ethanol/ethyl acetate) to obtain 2-acetyl-7-acetoxyfluorene (47.3 g) of colorless crystal. Melting point: 125.5-127.6° C.
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](O)([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:18]=3[OH:25])[C:9]2=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C2C=1C(O)(C1C(O)=CC3OCCC=3C=1)C(=O)N2C(C1C=CC=CC=1)C1C=CC=CC=1>>[C:28]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:18]=3[OH:25])[C:9]2=[O:27])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Cc1cc(O)c(C2(O)C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Agent: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Cl)c2C1(O)c1cc2c(cc1O)OCC2
Product: Cc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C

Procedure:
Following the procedure as described in PREPARATION 4C, and making non-critical variations using 1-(diphenylmethyl)-3-hydroxy-3-(2-hydroxy-4,5-dimethylphenyl)-1,3-dihydro-2H-indol-2-one to replace 4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one, 1-(diphenylmethyl)-3-(2-hydroxy-4,5-dimethylphenyl)-1,3-dihydro-2H-indol-2-one was obtained (93%): 1H NMR (300 MHz, CDCl3) δ 7.34-7.27 (m, 11H), 7.06-7.02 (m, 3H), 6.76 (s, 1H), 6.72 (s, 1H), 6.55-6.50 (m, 1H), 5.05 (s, 1H), 2.17 (s, 3H), 2.12 (s, 3H); MS (ES+) m/z 420.2 (M+1).
Reaction SMILES: N1C=CN=C1.[Na].BrCCCCCN1C(=O)C2=CC=CC=C2C1=O.[N:24]1([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:34]2C(=O)C3C(=CC=CC=3)C2=O)[CH:28]=[CH:27][N:26]=[CH:25]1.O.NN.Cl>C(O)C.CN(C)C=O>[N:24]1([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCn1ccnc1
Agent: Cl
Agent: NN
Agent: O=C1c2ccccc2C(=O)N1CCCCCBr
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: NCCCCCn1ccnc1

Procedure:
A mixture of 19.6 g. of sodium imidazole 59.2 g. of N-(5-bromopentyl)phthalimide and 300 ml. of dimethylformamide as stirred in an oil bath at 100° C. for 8 hours and then concentrated to remove the dimethylformamide. The residue was extracted twice with toluene and then concentrated in vacuo, giving 51.5 g. of 2-[5-(1H-imidazol-1-yl)pentyl]-1H-isoindole-1,3(2H)-dione as an oil. This oil was mixed with 8.73 ml. of hydrazine hydrate and 400 ml. of ethanol and heated on a steam bath for 3 hours. After cooling, 360 ml. of 3N hydrochloric acid was added and the mixture was refluxed for 2 hours. This mixture was filtered and the filtrate was concentrated with intermittent filtration to about 60 ml. Potassium carbonate was added to this oil which was then extracted with dichloromethane. The extract was concentrated to an oil which was distilled (Kugelrohr), giving 13.4 g. of the desired intermediate as a clear liquid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][Mg]Br.BrCCCCCCCCC1SC=CC=1.[Mg].BrCCBr.[CH3:35][Si:36]([CH3:45])([CH3:44])[C:37]1[O:41][CH:40]=[C:39]([CH:42]=[O:43])[CH:38]=1>O1CCCC1>[OH:43][CH:42]([C:39]1[CH:38]=[C:37]([Si:36]([CH3:45])([CH3:44])[CH3:35])[O:41][CH:40]=1)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)c1cc(C=O)co1
Reactant: Br[Mg]CCCCCCCCc1cccs1
Agent: BrCCCCCCCCc1cccs1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: C[Si](C)(C)c1cc(C(O)CCCCCCCCc2cccs2)co1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 8-(thiophene-2-yl)octyl magnesium bromide [0.62 mmol, prepared from 1-bromo-8-(thiophen-2-yl)octane; 0.170 g, 0.620 mmol and 1.24 mmol magnesium with a catalytic amount of 1,2 dibromoethane as initiator] in tetrahydrofuran (2 ml) at 0° under argon was added dropwise 5-trimethylsilyl-3-furaldehyde (0.104 g, 0.620 mmol) in tetrahydrofuran (3 ml). The solution was warmed to room temperature, stirred for one hour, quenched with saturated ammonium chloride solution and extracted into ethyl ether. The organic portion was washed with saturated sodium bicarbonate solution, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to a yellow oil. Purification by flash chromatography (silica, 5 to 10% ethyl acetate/hexane) gave the desired alcohol.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:19])=[C:9]([C:11]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=O)[O:10][C:5]2=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1.C(=O)([O-])O.[Na+].C([BH3-])#N.[Na+]>C(Cl)Cl.O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C.C(N(CC)CC)C>[Br:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:19])=[C:9]([CH:11]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=3)[CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[O:10][C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: Cc1c(C(=O)C2CCCCC2)oc2ccc(Br)nc12
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(c2oc3ccc(Br)nc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
To a mixture of (5-bromo-3-methylfuro[3,2-b]pyridin-2-yl)(cyclohexyl)methanone (1.46 g) synthesized above, methyl 4-aminobenzoate (753 mg), triethylamine (5.05 mL) and methylene chloride (15 mL) was added a 1.0M solution (5.44 mL) of titanium (IV) chloride in methylene chloride at 0° C., and the mixture was stirred under argon atmosphere overnight at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a dark brown oil. To a solution (20 mL) of the obtained oil in tetrahydrofuran were added acetic acid (1.30 mL) and sodium cyanoborohydride (569 mg), and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-40% ethyl acetate/hexane) to give the title object compound (1.86 g, 90%) as a pale-brown solid.
Reaction SMILES: [F:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].CN(C=O)C.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>>[F:1][C:2]1[C:10]([O:11][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: NC(=O)c1cccc(O)c1F
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCOc1cccc(C(N)=O)c1F
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To the solution of 2-fluoro-3-Hydroxy-benzamide (0.12 g, 0.774 mmol) in 20 mL DMF 1-bromohexane (0.13 mL, 1.0 mmol), Potassium Carbonate (0.213, 1.4 mmol) was added. The reaction mixture was stirred at 90° C. for 4 h. DMF was distilled off and the reaction mixture was extracted with EtOAc. The obtained crude compound was purified by column chromatography on silica (230-400μ) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound. (0.05 g, 28%). 1H NMR (DMSO-d6, 400 MHz with D2O): δ 0.82-0.99 (m, 3H), 1.10-1.33 (m, 6H), 1.67-1.71 (m, 2H), 3.99-4.15 (t, 2H, J=8.0 Hz), 7.08-7.24 (m, 2H). MS ES+ (214.33), HPLC (method 6) Rt=11.15 min.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[CH:17]=[C:16]([CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])[CH:15]=[CH:14][N:13]=2)=[N:3]1>FC(F)(F)C(O)=O>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[CH:17]=[C:16]([CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:15]=[CH:14][N:13]=2)=[N:3]1
Reactant: CC(C)(C)OC(=O)CCOCCCc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCOCCCc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89 %

Procedure:
A mixture of tert-butyl 3-[3-[2-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propoxy]propanoate (3.9 g, 9.1 mmol) and trifluoroacetic acid (30 ml) was stirred at room temperature for 1.5 hrs. The reaction mixture was concentrated under reduced pressure to obtain crystals which were collected by filtration and recrystallized from chloroform to give the titled compound (3.0 g, 89%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[C:15]([S:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:14]=[CH:13][C:12]=2[O:22][CH2:23][CH2:24][CH3:25])[NH:5][C:6](=[O:10])[C:7]=1[N:8]=O.C(O)C.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[C:15]([S:17][C:18]([CH3:19])([CH3:20])[CH3:21])[CH:14]=[CH:13][C:12]=2[O:22][CH2:23][CH2:24][CH3:25])[NH:5][C:6](=[O:10])[C:7]=1[NH2:8]
Reactant: CCCOc1ccc(SC(C)(C)C)cc1-c1nc(N)c(N=O)c(=O)[nH]1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCOc1ccc(SC(C)(C)C)cc1-c1nc(N)c(N)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
4-Amino-5-nitroso-2-(2-propoxy-5-t-butylthiophenyl)-pyrimid-6-one (6.5 g.) (see Reference Example 7) was dissolved in boiling ethanol (150 ml.), and the solution was added all at once to a solution of sodium dithionite (26 g.) in water (150 ml.) at 80° C. The mixture immediately turned yellow. After 2 minutes, the mixture was cooled to room temperature and diluted with water (700 ml.), and then it was left to stand in an ice bath for 1 hour. The solid formed [4,5-diamino-2-(2-propoxy-5-t-butylthiophenyl)-pyrimid-6-one] was filtered off and washed with water. This material was used immediately for the next stage of the synthesis, because darkening occurred on standing.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[C:8](OCC)(=[O:13])[CH2:9][C:10]([CH3:12])=O.N1CCCCC1>C(O)C>[SH:7][C:4]1[S:3][C:2]2=[N:1][C:10]([CH3:12])=[CH:9][C:8](=[O:13])[N:6]2[N:5]=1
Reactant: Nc1nnc(S)s1
Reactant: CCOC(=O)CC(C)=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(=O)n2nc(S)sc2n1
Reaction time: 8 h
Yield: 63.5 %

Procedure:
To a solution of 2-amino-5-mercapto-l,3,4-thiadiazole (4.0 g) and ethyl acetoacetate (4.3 g) in 50 ml ethanol, piperidine (2.55 g) was slowly added. The mixture was refluxed for seven hours and then allowed to stand overnight at room temperature. The formed crystals were collected by filtration and dissolved in 100 ml of water. The pH was adjusted to 2.0, and the formed crystals were collected and washed with 20 ml of water, affording 3.8 g of the objective compound as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Cl:11][C:12]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:13]=1[CH2:14][OH:15]>>[Cl:11][C:12]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:13]=1[CH2:14][O:15][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: OCc1ccc(Cl)cc1Cl
Reactant: O=[N+]([O-])c1cnccc1Cl
Product: O=[N+]([O-])c1cnccc1OCc1ccc(Cl)cc1Cl
Yield: 89.3 %

Procedure:
In accordance with the same procedures as in Preparation 2, except for using 4-chloro-3-nitropyridine prepared in Step 1 of Preparation 1 and 2,4-dichlorobenzyl alcohol, the titled compound was obtained as a white solid. (Yield: 89.3%)