Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([O:24][CH3:25])=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21](=[O:23])[CH3:22])[CH:16]=3)[CH:14]=2)=[CH:4][CH:3]=1.C(O)(=O)C.[O-:30][C:31]#[N:32].[Na+]>O>[C:21]([C:17]1[CH:16]=[C:15]([C:13]2[C:12]([O:24][CH3:25])=[CH:11][CH:10]=[C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:31]([NH2:32])=[O:30])=[CH:7][CH:6]=3)[CH:14]=2)[CH:20]=[CH:19][CH:18]=1)(=[O:23])[CH3:22]
Reactant: N#C[O-]
Reactant: COc1ccc(Nc2ccc(N)cc2)cc1-c1cccc(C(C)=O)c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(Nc2ccc(NC(N)=O)cc2)cc1-c1cccc(C(C)=O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47 %

Procedure:
In an 8 mL vial equipped with a stir bar was placed 1-[5′-(4-amino-phenylamino)-2′-methoxy-biphenyl-3-yl]-ethanone synthesized above (free base) (60.0 mg, 0.180 mmol), water (600 μL), acetic acid (300 μL) and sodium cyanate (46.8 mg, 0.720 mmol). The mixture was stirred at room temperature for 4 hours and then water (20 mL) was added followed by an P-traction with (2×30 mL). The organic portions were combined, washed with brine (30 mL), dried (MgSO4) and concentrated. The crude material was purified by column utilizing 75% acetone/DCM as the eluent to produce 32 mg of [4-(3′-acetyl-6-methoxy-biphenyl-3-ylamino)-phenyl]-urea (P-268) as a light brown solid in 47% yield. MS (APCI+): 376.1 (M+1); LC-MS: 94%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]2[O:8][C:9]3[C:14]([C:15](=[O:18])[C:16]=2[CH3:17])=[CH:13][CH:12]=[CH:11][C:10]=3[C:19](O)=[O:20])=[CH:5][CH:4]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[CH2:37]([N:39]([CH2:43][CH3:44])[CH2:40][CH2:41][NH2:42])[CH3:38]>O1CCCC1>[CH2:37]([N:39]([CH2:43][CH3:44])[CH2:40][CH2:41][NH:42][C:19]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[O:8][C:7]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:23][CH:22]=1)=[C:16]([CH3:17])[C:15]2=[O:18])=[O:20])[CH3:38]
Reactant: CCN(CC)CCN
Reactant: COc1ccc(-c2oc3c(C(=O)O)cccc3c(=O)c2C)cc1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CC)CCNC(=O)c1cccc2c(=O)c(C)c(-c3ccc(OC)cc3)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
To a solution of 6.00 g of 4'-methoxy-3-methylflavone-8-carboxylic acid and 2.70 ml of triethylamine in 70 ml of anhydrous tetrahydrofuran was added a solution of 2.03 ml of ethyl chlorocarbonate in 10 ml of anhydrous tetrahydrofuran and the mixture was stirred for 1 hour under ice-cooling. To the reaction mixture was added a solution of 2.25 g of N,N-diethylethylenediamine in 10 ml of anhydrous tetrahydrofuran and the mixture was stirred for 1.5 hours under ice-cooling and further 16 hours at room temperature. The reaction mixture was treated by the same procedure as in Example 3(b), to give 3.55 g of pale yellow crystals, which were recrystallized from ethyl acetate as colorless needles, m.p. 125.5°-127° C. This compound was identical with the product obtained in Example 36(a) in NMR and IR spectra, and mixed m.p.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[SH:7].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([NH:25][CH:26]([CH2:31][CH:32]3[O:34][CH2:33]3)[C:27]([O:29]C)=[O:28])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1>>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([NH:25][CH:26]([CH2:31][CH:32]([OH:34])[CH2:33][S:7][C:6]3[CH:5]=[CH:4][O:3][C:2]=3[CH3:1])[C:27]([OH:29])=[O:28])(=[O:23])=[O:24])=[CH:20][CH:21]=2)=[CH:14][CH:15]=1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Reactant: Cc1occc1S
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3ccoc3C)C(=O)O)cc2)cc1

Procedure:
Example 43 is prepared from 2-methyl-3-furanthiol and 1d using the procedure described for compound 20.
Reaction SMILES: N1CCOCC1.[CH:7]1([CH:10]2[CH:15]=[CH:14][C:13]3=[C:16]([C:24](OC)=[O:25])[CH:17]=[C:18]([O:22][CH3:23])[C:19]([O:20][CH3:21])=[C:12]3[O:11]2)[CH2:9][CH2:8]1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH:7]1([CH:10]2[CH:15]=[CH:14][C:13]3=[C:16]([CH:24]=[O:25])[CH:17]=[C:18]([O:22][CH3:23])[C:19]([O:20][CH3:21])=[C:12]3[O:11]2)[CH2:8][CH2:9]1
Reactant: COC(=O)c1cc(OC)c(OC)c2c1C=CC(C1CC1)O2
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1COCCN1
Product: COc1cc(C=O)c2c(c1OC)OC(C1CC1)C=C2
Temperature: -15 °C
Reaction time: 4 h

Procedure:
A solution of 48 ml of morpholine in 50 ml of toluene was added dropwise over 1 hr. under argon to an ice-cold solution of 143 ml of sodium dihydrido-bis-(2-methoxyethoxy) aluminate (3.5M in toluene) diluted with 200 ml of toluene. The resulting reduction solution was then added dropwise under argon during 1 hr. to a solution, cooled to -35° C., of 46 g of methyl (RS)-2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-carboxylate in 200 ml of toluene and the mixture was stirred at -15° C. for a further 4 hrs. The reaction was stopped by the cautious addition of 40 ml of 3N NaOH and the mixture was left to warm. Extraction: 3×600 ml of ice-water, 1×600 ml of toluene. Chromatography: silica gel, hexane/ethyl acetate 5:1. Crystallization from diethyl ether/ hexane. (RS)-2-Cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-carbaldehyde was obtained as a solid.
Reaction SMILES: [N:1]1([C:6]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:22]([O:24][C:25]([O:27][C:28]1[CH:38]=[CH:37][C:31]([CH:32]=[CH:33][C:34](Cl)=[O:35])=[CH:30][CH:29]=1)=[O:26])[CH3:23]>C(Cl)(Cl)Cl>[CH2:22]([O:24][C:25]([O:27][C:28]1[CH:29]=[CH:30][C:31]([CH:32]=[CH:33][C:34]([N:12]2[CH2:11][CH2:10][N:9]([CH2:8][C:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[O:7])[CH2:14][CH2:13]2)=[O:35])=[CH:37][CH:38]=1)=[O:26])[CH3:23]
Reactant: O=C(CN1CCNCC1)N1CCCC1
Reactant: CCOC(=O)Oc1ccc(C=CC(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)Oc1ccc(C=CC(=O)N2CCN(CC(=O)N3CCCC3)CC2)cc1
Yield: 54 %

Procedure:
In 140 ml of chloroform were dissolved 17.7 g of 1-(pyrrolidinocarbonylmethyl)piperazine and 8.4 ml of triethylamine. To the solution was added 15.2 g of 4-(ethoxycarbonyloxy)cinnamoylchloride with ice-cooling, followed by stirring the resultant mixture overnight at room temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and dissolved in ethyl acetate. Any insoluble matter was removed by filtration, and the filtrate was extracted with 140 ml of 1N-hydrochloric acid. The extract was washed with ethyl acetate, neutralized with sodium bicarbonate and then extracted with chloroform. The chloroform layer was successively washed with water and then with brine. The layer was then dried and subjected to distillation to remove the solvent. The resultant crystals were recrystallized from ethyl acetate, thereby obtaining 13.4 g (yield: 54.0%) of 1-[4-(ethoxycarbonyloxy)cinnamoyl]-4-(pyrrolidinocarbonylmethyl)piperazine as crystals having a melting point of 128°-130° C.
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:7]=1)[C:3](O)=[O:4].Cl.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2([NH2:35])[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:1][CH:2]([C:6]1[CH:11]=[C:10]([C:12]([F:13])([F:15])[F:14])[CH:9]=[C:8]([C:16]([F:17])([F:18])[F:19])[CH:7]=1)[C:3]([NH:35][C:28]1([C:25]2[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=2)[CH2:29][CH2:30][C:31](=[O:34])[CH2:32][CH2:33]1)=[O:4]
Reactant: CC(C(=O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NC1(c2ccc(F)cc2)CCC(=O)CC1
Agent: Cl
Product: CC(C(=O)NC1(c2ccc(F)cc2)CCC(=O)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
Prepared from (RS)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetic acid (Description 4) and 1-(4-fluorophenyl)-4-oxocyclohexylamine hydrochloride (Description 182) according to the method of Example 1. 1H NMR (400 MHz, CDCl3) δ 7.81 (1H, s), 7.71 (2H, s), 7.29–7.25 (2H, m), 7.01–6.96 (2H, m), 5.73 (1H, s), 3.69 (1H, q, J 7.0 Hz), 2.80–2.77 (1H, m), 2.62–2.57 (1H, m), 2.44–2.28 (6H, m), and 1.51 (3H, d, J 7.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH3:12].[CH:13](O)=O.[OH-].[NH4+]>O>[CH3:12][C:3]1[C:2]2[NH:1][CH:13]=[N:8][C:7]=2[CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1c([N+](=O)[O-])ccc(N)c1N
Reactant: O=CO
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Cc1c([N+](=O)[O-])ccc2nc[nH]c12
Temperature: 25 °C

Procedure:
A mixture of 2,3-diamino-6-nitrotoluene (11.81 g), formic acid (88%, 390 mL) and 12N HCI (38 mL) is heated to reflux for 1 hour. The resulting mixture is cooled to room temperature and rotary evaporated. The residue is diluted with water (200 mL), then basified with ammonium hydroxide (28-30%). The suspension is extracted with ethyl acetate (3×200 mL). The combined extracts are dried over magnesium sulfate (MgSO4) and evaporated to afford 4-methyl-5-nitrobenzimidazole as an orange solid.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[Li]CCCC.[F:12][CH2:13][C:14](N1CCOCC1)=[O:15]>C1COCC1>[F:12][CH2:13][C:14](=[O:15])[C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: O=C(CF)N1CCOCC1
Reactant: C#C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CC(=O)CF
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
A 0° C. solution of trimethylsilylacetylene (42.0 g, 429 mmol) in THF (400 mL) was treated with n-BuLi (2.5 M in n-hexane; 171 mL, 428 mmol) over 20 min maintaining the internal temperature below 10° C. using dry ice-acetone bath (−20° C.). After stirring for 30 min at 0° C., the mixture was treated with a solution of 2-fluoro-1-morpholin-4-yl-ethanone (8, 48.4 g, 329 mmol) in THF (50 mL+10 mL for wash), and stirring was continued for further 1 h at 0° C. The reaction was quenched by adding to a 0° C. mixture of acetic acid (250 mL) and water (150 mL) over 1 h maintaining the internal temperature below 5° C. After addition of more water (150 mL), the organic layer was separated, washed with water (200 mL), and dried over anhydrous MgSO4, and concentrated in vacuo. The residue was evaporated again with toluene (200 mL) to remove the residual acetic acid, and vacuum distillated (8 mbar, b.p. 54° C.) to give the title compound (33.7 g, 64.8%). 1H NMR (500 MHz, CDCl3) δ 4.90 (d, J=47.1 Hz, 2H), 0.26 (s, 9H). 13C NMR (125 MHz, CDCl3) d 181.0 (d, J=21.5 Hz), 104.0, 98.1, 84.8 (d, J=187 Hz).
Reaction SMILES: CC(OC([N:8](C(OC(C)(C)C)=O)[N:9]([C:17]1[C:22]([F:23])=[C:21]([N:24]2[CH2:28][CH:27]([N:29]([CH3:31])[CH3:30])[CH2:26][C:25]2([CH3:33])[CH3:32])[N:20]=[C:19]([Cl:34])[N:18]=1)C(OC(C)(C)C)=O)=O)(C)C.Cl>CO.O1CCOCC1>[Cl:34][C:19]1[N:20]=[C:21]([N:24]2[C:25]([CH3:33])([CH3:32])[CH2:26][CH:27]([N:29]([CH3:30])[CH3:31])[CH2:28]2)[C:22]([F:23])=[C:17]([NH:9][NH2:8])[N:18]=1
Reactant: CN(C)C1CN(c2nc(Cl)nc(N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2F)C(C)(C)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CN(C)C1CN(c2nc(Cl)nc(NN)c2F)C(C)(C)C1
Reaction time: 72 h
Yield: 95.5 %

Procedure:
To a solution of tris(1,1-dimethylethyl)2-{2-chloro-6-[4-(dimethylamino)-2,2-dimethyl-1-pyrrolidinyl]-5-fluoro-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (2.2004 g, 3.648 mmol) in MeOH (22 mL) was added 4 N HCl in dioxane (22 mL). The solution was stirred for 3 days and then concentrated in vacuo. The residue was azeotroped with MeOH (50 mL), and then partitioned between DCM (100 mL) and sat. aq. NaHCO3 (100 mL). The aqueous phase was extracted with fresh DCM (2×50 mL), and the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 1-(2-chloro-5-fluoro-6-hydrazino-4-pyrimidinyl)-N,N,5,5-tetramethyl-3-pyrrolidinamine (1.0552 g, 96%) as an orange foam. LCMS: (M+H)+: 303.1.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9]([OH:11])=[O:10])=[CH:3]1.[C:12](Cl)(=O)C(Cl)=O>ClCCl>[CH3:12][O:10][C:9]([C:4]1[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1)=[O:11]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1cc(C(=O)O)ccc1=O
Solvent: ClCCl
Product: COC(=O)c1ccc(=O)n(C)c1
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
The mixture obtained in Example 26 (˜2.5 g total) was dissolved in dichloromethane (30 mL). Oxalyl chloride (2 M in dichloromethane, 16.3 mL. 32.6 mmol) was added and the reaction was stirred for 30 min. The reaction was quenched with methanol, then diluted with dichloromethane and washed with water. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated, then chromatographed in 20-50% ethyl acetate in hexanes to yield the title product 1.55 g, 26% (2 steps).
Reaction SMILES: [CH:1]1([N:4]([C:12]2[N:17]3[N:18]=[CH:19][C:20]([CH:21]=[O:22])=[C:16]3[N:15]=[C:14]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=3)[CH:13]=2)C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([NH:4][C:12]2[N:17]3[N:18]=[CH:19][C:20]([CH:21]=[O:22])=[C:16]3[N:15]=[C:14]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=3)[CH:13]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(c1cc(-c2cccc(O)c2)nc2c(C=O)cnn12)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1cnn2c(NC3CC3)cc(-c3cccc(O)c3)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.7 %

Procedure:
To tert-butyl cyclopropyl(3-formyl-5-(3-hydroxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl)carbamate (400 mg, 1.01 mmol) in methylene chloride (20 mL) was added TFA (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The volatiles were removed by rotary evaporation and the residue was purified by silica gel chromatography (0%-40% EtOAc/hexanes) to provide 103 mg of 7-(cyclopropylamino)-5-(3-hydroxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde. (35%). LCMS (M+1=295)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][C@@H:6]1[C@H:9]([NH:10][C:11](=[O:38])/[C:12](=[N:26]\[O:27][C:28]([CH3:37])([CH3:36])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])/[C:13]2[N:14]=[C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[S:16][CH:17]=2)[C:8](=[O:39])[NH:7]1.[C:40]([O:44][C:45](=[O:50])[NH:46][CH2:47][CH:48]=O)([CH3:43])([CH3:42])[CH3:41].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:22]([O:21][C:19]([NH:18][C:15]1[S:16][CH:17]=[C:13](/[C:12](=[N:26]/[O:27][C:28]([CH3:37])([CH3:36])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])/[C:11]([NH:10][C@@H:9]2[C:8](=[O:39])[NH:7][C@@H:6]2[CH2:5][NH:4][CH2:3][CH2:2][NH:1][CH2:48][CH2:47][NH:46][C:45](=[O:50])[O:44][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[N:14]=1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2CNCCN)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCNCCNC[C@H]1NC(=O)[C@H]1NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c1csc(NC(=O)OC(C)(C)C)n1
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 2-(((Z)-(2-(((2R,3S)-2-(((2-aminoethyl)amino)methyl)-4-oxoazetidin-3-yl)amino)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoethylidene)amino)oxy)-2-methylpropanoate (100 mg, 0.176 mmol) in DCE (1.8 mL) was added tert-butyl(2-oxoethyl)carbamate (27.9 mg, 0.176 mmol). After stirring for 2 h, sodium triacetoxyborohydride (112 mg, 0.527 mmol) was added. After 12 h, the reaction mixture was quenched with saturated NaHCO3 (aq) and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. It was used as crude in step 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][C:8]=1[O:9][CH3:10])[C:13](=[O:15])[CH2:12][CH2:11]2
Reactant: COc1ccc(CCC(=O)O)cc1OC
Solvent: O
Product: COc1cc2c(cc1OC)C(=O)CC2
Yield: 88.8 %

Procedure:
For example, Non-Patent Document 1 discloses that 1 g of 3-(3,4-dimethoxyphenyl)propionic acid and 10 g of polyphosphoric acid were reacted at 65° C. for 25 minutes, followed by addition of cold water. Then, the resulting mixture was extracted with diethyl ether or ethyl acetate, and the organic layer thus extracted was washed with a 10% aqueous solution of sodium bicarbonate and purified by crystallization with ethanol to give 0.812 g (yield 90%) of 5,6-dimethoxy-1-indanone. However, it is also reported that the yield dropped to 71% when the reaction time was extended to 70 minutes in the above method. Generally, each unit operation is time-consuming in an industrial-scale production, and thus, it is difficult to perform operations in such a way that reactions are completed within only several tens of minutes. In view of the foregoing, the method described in the above document is far from an industrially efficient production method.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]3[CH:19]=[C:18](I)[N:17]=[CH:16]3)[N:9]=2)=[CH:4][CH:3]=1.[C:21]([NH:25][S:26]([C:29]1[S:30][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:33]=1)(=[O:28])=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([NH:25][S:26]([C:29]1[S:30][C:31]([C:18]2[N:17]=[CH:16][N:15]([C:10]3[N:11]=[C:12]([CH3:14])[CH:13]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=3)[CH:19]=2)=[CH:32][CH:33]=1)(=[O:27])=[O:28])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(I)c2)n1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1

Procedure:
N-tert-Butyl-5-{1-[6-(4-chloro-phenyl)-4-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonamide was prepared from 4-(4-chloro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-methyl-pyrimidine (example E.69) (0.40 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.41 g, 1.2 mmol) according to the general procedure VI. Obtained as a light brown solid (0.15 g) which was subsequently deprotected.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([N+:32]([O-])=O)=[C:7]([CH:31]=1)[C:8]([NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)=[O:9].Cl.O>[Fe].CCO>[NH2:32][C:6]1[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:31][C:7]=1[C:8]([NH:10][CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:16][CH2:17]1)=[O:9]
Reactant: CSc1ccc([N+](=O)[O-])c(C(=O)NCC2CCN(C(c3ccccc3)c3ccccc3)CC2)c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CSc1ccc(N)c(C(=O)NCC2CCN(C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Step 2): A mixture of 5-methylthio-2-nitro-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide (500 mg, 1.05 mmol), Fe powder (587 mg, 1.05 mmol), conc. HCl (0.05 ml), H2O (8 ml) and EtOH (35 ml) was refluxed overnight. The insoluble precipitates were filtered off and then the filtrate was evaporated to give 2-amino-5-methylthio-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide as colorless powder, 450 mg (96%): mp 156°-157° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:9][CH2:10][N:11]([CH3:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])=[CH:4][CH:3]=1.[C:26]([NH:28][C:29](=[N:37][CH2:38][CH2:39][S:40][CH2:41][C:42]1[N:43]=[C:44]([NH:47][C:48]([NH2:50])=[NH:49])[S:45][CH:46]=1)OC1C=CC=CC=1)#[N:27]>C(OCC)(=O)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:29]([NH:28][C:26]#[N:27])=[N:37][CH2:38][CH2:39][S:40][CH2:41][C:42]2[N:43]=[C:44]([NH:47][C:48]([NH2:50])=[NH:49])[S:45][CH:46]=2)[CH3:19])=[CH:4][CH:3]=1
Reactant: N#CNC(=NCCSCc1csc(NC(=N)N)n1)Oc1ccccc1
Reactant: CN(CCCCCCN)CCC(c1ccc(Cl)cc1)c1ccccn1
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(CCCCCCNC(=NCCSCc1csc(NC(=N)N)n1)NC#N)CCC(c1ccc(Cl)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.5 g (1.4 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,6-hexanediamine and 0.52 g (1.4 mmol) of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography (eluant: methylene chloride/methanol 95+5) analogously to Example 1 yields the purified title compound in the form of a dry foam; MS (+FAB method): m/z (rel. int.[%])=641 ([M+H]+, 5), 230 (47), 154 (100); IR (KBr): 2161 cm-1 (C≡N).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-])=O)=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CCO.[Pd]>[C:1]([C:5]1[CH:10]=[C:9]([F:11])[C:8]([NH2:12])=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(F)c([N+](=O)[O-])cc1O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)c1cc(F)c(N)cc1O
Yield: 159.7 %

Procedure:
To a refluxing solution of 2-tert-butyl-4-fluoro-5-nitrophenol (400 mg, 1.88 mmol) and ammonium formate (400 mg, 6.1 mmol) in EtOH (20 mL) was added 5% Pd—C (260 mg). The mixture was refluxed for additional 1 h, cooled and filtered through Celite. The solvent was removed by evaporation to give 2-tert-butyl-5-amino-4-fluorophenol (550 mg). 1H NMR (400 MHz, DMSO-d6) δ 8.83 (br s, 1H), 6.66 (d, J=13.7 Hz, 1H), 6.22 (d, J=8.5 Hz, 1H), 4.74 (br s, 2H), 1.26 (s, 9H); HPLC ret. time 2.58 min, 10-99% CH3CN, 5 min run; ESI-MS 184.0 m/z (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([C:7]1[C:12]([O:13]COC)=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6].S(=O)(=O)(O)O.CC(C)=O.[OH-].[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([C:7]1[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6]
Reactant: COCOc1cccnc1C(=O)c1cccc(Br)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(c1cccc(Br)c1)c1ncccc1O
Yield: 93.1 %

Procedure:
A mixture of 2-(3-bromobenzoyl)-3-methoxymethoxy pyridine (5.55 g), 3.6N-sulfuric acid (11 mL) and acetone (30 mL) was subjected to reflux for 3 hours. The reaction mixture was poured into water, neutralized with an aqueous solution of sodium hydroxide, and extracted with ethyl acetate. The extract was washed with water and a saturated aqueous saline solution, successively, and dried (sodium sulfate) and then concentrated. The concentrate was purified by means of a silica gel column (ethyl acetate--hexane) to afford 2-(3-bromobenzoyl)-3-hydroxypyridine (4.46 g) (compound C-1). Physical properties and spectrum date of the product are shown in Table 5 and Table 6. In substantially the same manner as above, compounds C-2 to C-4 and C-6 to C-9 shown in Table 5 were produced.
Reaction SMILES: [OH:1][C:2]([CH3:30])([CH3:29])[CH2:3][N:4]1[CH2:8][C@H:7]([C:9]2[CH:14]=[C:13]([CH3:15])[N:12]([CH2:16][C:17]([O:19]CC)=[O:18])[C:11](=[O:22])[CH:10]=2)[C@H:6]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:5]1.[OH-].[Na+].Cl>>[OH:1][C:2]([CH3:30])([CH3:29])[CH2:3][N:4]1[CH2:8][C@H:7]([C:9]2[CH:14]=[C:13]([CH3:15])[N:12]([CH2:16][C:17]([OH:19])=[O:18])[C:11](=[O:22])[CH:10]=2)[C@H:6]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:5]1
Reactant: CCOC(=O)Cn1c(C)cc([C@H]2CN(CC(C)(C)O)C[C@H]2c2ccccc2)cc1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc([C@H]2CN(CC(C)(C)O)C[C@H]2c2ccccc2)cc(=O)n1CC(=O)O

Procedure:
A solution of 4-(1-(2-hydroxy-2-methylpropyl)-cis-3-phenylpyrrolidin-4-yl)-6-methyl-1-ethoxycarbonylmethyl-2-pyridinone from step 7 above (0.10 g, 0.23 mmol) and aqueous NaOH (0.11 mL of a 4.0N solution, 0.46 mmol) was stirred at ambient temperature for 18 h. Aqueous HCl was added (0.076 mL of a 6.0 N solution, 0.46 mmol) and the solvents were removed in vacuo to give the title compound as an amorphous solid mixed with NaCl (HPLC RT=3.94 min, method A).