Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])=[C:7]([C:18]([O:20]CC)=[O:19])[C:6]=2[CH:23]=1.[Li+].[OH-].Cl>O1CCOCC1.O>[Br:1][C:2]1[C:3]([NH:24][S:25]([CH3:28])(=[O:26])=[O:27])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])=[C:7]([C:18]([OH:20])=[O:19])[C:6]=2[CH:23]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2F)oc2cc(NS(C)(=O)=O)c(Br)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)Nc1cc2oc(-c3ccc(F)cc3F)c(C(=O)O)c2cc1Br
Temperature: 110 °C
Reaction time: 3 h
Yield: 71.5 %

Procedure:
To a solution of ethyl 5-bromo-2-(2,4-difluorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylate (653 mg, 1.38 mmol) in 1,4-Dioxane (10 mL) and H2O (1 mL) was added LiOH (289 mg, 6.88 mmol), then the mixture was stirred at 110° C. After 3 hours, 10% HCl (aq) was added until pH reach 4. The mixture was extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to provide 5-bromo-2-(2,4-difluorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylic acid (440 mg, yield: 65%). 1H-NMR (CDCl3, 400 MHz) δ 8.38 (s, 1H), 7.94 (s, 1H), 7.66˜7.94 (m, 1H), 7.08 (d, J=3.0 Hz, 1H), 6.91 (s, 1H), 3.04 (s, 3H). MS (M+H)+: 446/448.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:3]=1[OH:12].CO.[CH2:15]([OH:18])[CH:16]=[CH2:17]>C1(C)C=CC=CC=1>[C:8]([C:4]1[CH:5]=[C:6]([CH2:17][CH2:16][CH2:15][OH:18])[CH:7]=[C:2]([CH3:1])[C:3]=1[OH:12])([CH3:9])([CH3:11])[CH3:10]
Reactant: Cc1cccc(C(C)(C)C)c1O
Reactant: C=CCO
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1cc(CCCO)cc(C(C)(C)C)c1O
Temperature: 210 °C
Yield: 82 %

Procedure:
To the solution obtained above after hydrogen gas evolution had ceased, 45 g (0.27 mol) of 2-methyl-6-t-butylphenol were added, and then heated under reduced pressure, thereby 15 g (0.47 mol) of methanol were removed from the reaction system. Then, 15.9 g (0.27 mol) of allyl alcohol and 13.5 g (0.15 mol) of toluene were added thereto. The resulting solution after the addition of toluene and allyl alcohol were transferred to a pressure container, and the atmosphere thereof was substituted with nitrogen gas, sealed and heated up to 210° C. and maintained at the same temperature for 4 hours. Thereafter the reaction mixture was cooled to room temperature and a sample thereof was analyzed by gas-chromatography. The desired product, 3-(3-t-butyl-4-hydroxy-5-methylphenyl)propanol was obtained in a yield of 82%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH2:11][OH:12])[C:9]=1[Cl:10])=[O:4].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH2:11][O:12][S:21]([CH3:20])(=[O:23])=[O:22])[C:9]=1[Cl:10])=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1scc(CO)c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1scc(COS(C)(=O)=O)c1Cl
Reaction time: 6 h

Procedure:
To a solution of 2-methoxycarbonyl-3-chloro-4-hydroxymethylthiophene (6 g, 29 mmol) in methylene chloride (100 mL) were added triethylamine (8.1 mL, 58 mmol) and methanesulfonyl chloride (2.5 mL, 32 mmol) at ambient temperature. After stirring for 6 hours, the reaction mixture was concentrated to afford 2-methoxycarbonyl-3-chloro-4-(methylsulfonyloxy)methylthiophene. The crude product was dissolved in DMF (150 mL) and excess potassium cyanide was added to the solution. The reaction mixture was stirred at ambient temperature for 16 hours, then poured into water, and extracted with methylene chloride. The combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo to afford 2-methoxycarbonyl-3-chloro-4-cyanomethylthiophene.
Reaction SMILES: CN(C)C=O.[C:6](=[O:26])([O:22][CH:23](Cl)[CH3:24])[O:7][CH2:8][CH2:9][CH2:10][C@@H:11]([O:18][N+:19]([O-:21])=[O:20])[C@H:12]([O:14][N+:15]([O-:17])=[O:16])[CH3:13].[CH2:27]([C:31]1[N:32]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[C:53]3[N:57]([C:58]([C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=4)([C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)[C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)[N:56]=[N:55][N:54]=3)=[CH:43][CH:42]=2)[C:33]([C:37]([OH:39])=[O:38])=[C:34]([Cl:36])[N:35]=1)[CH2:28][CH2:29][CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH2:27]([C:31]1[N:32]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[C:53]3[N:57]([C:58]([C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)([C:71]4[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=4)[C:65]4[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=4)[N:56]=[N:55][N:54]=3)=[CH:45][CH:46]=2)[C:33]([C:37]([O:39][CH:23]([O:22][C:6]([O:7][CH2:8][CH2:9][CH2:10][C@@H:11]([O:18][N+:19]([O-:21])=[O:20])[C@H:12]([O:14][N+:15]([O-:17])=[O:16])[CH3:13])=[O:26])[CH3:24])=[O:38])=[C:34]([Cl:36])[N:35]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(Cl)OC(=O)OCCC[C@@H](O[N+](=O)[O-])[C@@H](C)O[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C(=O)OC(C)OC(=O)OCCC[C@@H](O[N+](=O)[O-])[C@@H](C)O[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A N,N-dimethylformamide (20 mL) solution of (4R,5R)-4,5-bis(nitrooxy)hexyl 1-chloroethyl carbonate (1.15 g, 3.48 mmol) was added to a stirred N,N-dimethylformamide (20 mL) suspension of 2-butyl-4-chloro-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylic acid (2.54 g, 3.74 mmol) and cesium carbonate (1.25 g, 3.84 mmol). The solution was stirred at 70° C. for 2 hours. Water (100 mL) was added, and the solution was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 20-60% ethyl acetate/hexanes to give the title compound as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.90 (d, J=7.4 Hz, 1H), 7.49 (dt, J=1.4, 7.6 Hz, 1H), 7.45 (dt, J=1.1, 7.5 Hz, 1H), 7.31-7.36 (m, 4H), 7.26 (t, J=7.8 Hz, 6H), 7.10 (d, J=8.0 Hz, 6H), 6.93 (d, J=7.8 Hz, 2H), 6.86 (q, J=5.5 Hz, 1H), 6.79 (d, J=8.0 Hz, 2H), 5.54 (d, J=15.4 Hz, 1H), 5.32 (d, J=16.2 Hz, 1H), 5.14-5.24 (m, 2H), 4.10-4.20 (m, 2H), 2.50 (t, J=7.8 Hz, 2H), 1.7-1.9 (m, 4H), 1.62 (quintet, J=7.7 Hz, 2H), 1.54 (d, J=5.5 Hz, 3H), 1.37 (d, J=6.1 Hz, 3H), 1.27 (sextet, J=7.4 Hz, 2H), 0.85 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH:8]([OH:12])[C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.CCOC(C)=O>[CH2:19]([O:10][C:9](=[O:11])[CH:8]([OH:12])[CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)C(O)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.4 %

Procedure:
To a solution of DL-Phenyllactic acid (5.0 g, 30.09 mmol) in DMF (30 mL) was added Cs2CO3 (10.79 g, 33.11 mmol) in portions during 10 minutes period at room temperature. The resulting mixture was stirred for 15 min at room temperature, followed by the addition of benzyl bromide (3.57 mL, 30.09 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (300 mL), washed with saturated NaHCO3, water (100×2) and brine, dried (Na2SO4) and filtered. The filtrate was concentrated to give 7.20 g (89%) of the title compound.
Reaction SMILES: C(=O)(O)O.[NH:5]([C:7](=[NH:9])[NH2:8])[NH2:6].[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[Cl:20])[C:14](Cl)=[O:15].[OH-].[Na+]>N1C=CC=CC=1.O>[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[Cl:20])[C:14]([NH:6][NH:5][C:7](=[NH:8])[NH2:9])=[O:15]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: N=C(N)NN
Agent: O=C(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: N=C(N)NNC(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
To a solution of hydrazinecarboximidamide carbonic acid salt (15.6 g, 114.61 mmol) in pyridine (100 ml) was added 3,4-dichlorobenzoyl chloride (20 g, 95.48 mmol), and the resulting mixture was stirred overnight at room temperature, then concentrated under vacuum to give a residue, which was dissolved in water (30 ml) and adjusted to pH 12 with sodium hydroxide (aq., sat). The product precipitated and was collected by filtration and dried in an oven under reduced pressure to afford 2-(3,4-dichlorobenzoyl)hydrazinecarboximidamide as a light yellow solid (9.5 g, 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:19][CH2:18][C@@H:17]([OH:20])[CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:27].[Na+]>CO.C(#N)C>[NH2:27][CH:12]([C:10]1[C:9]([N:15]2[CH2:19][CH2:18][C@@H:17]([OH:20])[CH2:16]2)=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([Cl:1])[CH:11]=1)[CH3:13]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CC[C@@H](O)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CC[C@@H](O)C1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-8-[(3R)-3-hydroxypyrrolidin-1-yl]quinolin-7-yl}ethanone (95 mg, 0.33 mmol) and ammonium acetate (252 mg, 3.27 mmol) in methanol (1.8 mL) and acetonitrile (1.9 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling, sodium cyanoborohydride (41.1 mg, 0.653 mmol) was added to the resultant mixture. The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature and quenched with saturated sodium bicarbonate. The mixture was then extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness (58 mg, 60%). The residue was used directly in the next step. LCMS calculated for C15H19ClN3O(M+H)+: m/z=292.1; found: 292.1.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[CH:16][CH:17]=3)[N:12]([CH3:22])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:25]([OH:29])[CH2:26][C:27]#[CH:28]>C(NCC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:28]#[C:27][CH2:26][CH2:25][OH:29])[CH:15]=[CH:16][CH:17]=3)[N:12]([CH3:22])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cccc(I)c21
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cccc(C#CCCO)c21

Procedure:
A solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.22 g) from Preparation No. 48, copper iodide (0.029 g), bis(triphenylphosphine)palladium(II) chloride (0.013 g), and 3-butyn-1-ol (0.040 mL) in diethylamine (15 mL) is stirred at room temperature for 18 h. Hexanes are added to the reaction mixture and the resulting solid is filtered and dried. The solid is dissolved in CH2Cl2/MeOH and adsorbed onto silica. Purification by chromatography (eluent CH2Cl2 (1 L), 1.5% MeOH:CH2Cl2 (1 L), 2% MeOH:CH2Cl2 (2 L), 3% MeOH:CH2Cl2 (1 L)) affords the title compound as a light yellow solid (0.16 g).
Reaction SMILES: S(=O)(=O)(O)O.C(O)(=O)C.C(OC([CH:15](C(OCC)=O)[C:16]([C:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)[N:20]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[N:19]=1)=[O:17])=O)C>O>[C:16]([C:18]1[CH:22]=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=2)[N:20]([C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)[N:19]=1)(=[O:17])[CH3:15]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(F)cc2)n1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(F)cc2)n1

Procedure:
A mixture of sulfuric acid (3.9 ml), acetic acid (23.6 ml) and water (19.6 ml) was added to 3-bis(ethoxycarbonyl)acetyl-1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole. The mixture was refluxed for 5 hours and concentrated. The residue was dissolved in ethyl acetate, and the solution was washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel (150 g) eluting with a mixture of chloroform and ethyl acetate (3:1) to give pale brown crystals of 3-acetyl-1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole (4.2 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[N:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.Cl.[CH3:23][NH:24][O:25][CH3:26]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([N:24]([O:25][CH3:26])[CH3:23])=[O:10])[CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cncc(Cl)n1
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CON(C)C(=O)c1cncc(Cl)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.3 %

Procedure:
To a 100 ml round bottom flask, 6-chloropyrazine-2-carboxylic acid (1 g, 6.31 mmol) was suspended in dry CH2Cl2 (30 ml). Oxalyl chloride (3.78 ml, 7.57 mmol) was added along with a few drop of DMF, the mixture was stirred at room temperature for 12 hrs, N,O-Dimethylhydroxylamine hydrochloride (0.800 g, 8.20 mmol) was added, the resulting mixture was cooled down to 5° C., TEA (2.64 ml, 18.92 mmol) was added via a dropping funnel, the reaction mixture was stirred at room temperature for 30 minutes, filtered and the filter cake was washed with EtOAc, the combined filtrate was washed with saturated sodium bicarbonate and brine, concentrated to an oil, purified on silica gel with Hexanes/EtOAc solvents to give product (1.06 g).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14](O)=[N:13][CH:12]=[N:11][C:10]=3[O:9][C:8]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C1C=CC=CC=1.P(Br)(Br)[Br:33]>>[Br:33][C:14]1[C:15]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:9][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: BrP(Br)Br
Reactant: Oc1ncnc2oc(-c3ccccc3)c(-c3ccccc3)c12
Solvent: CN(C)c1ccccc1
Product: Brc1ncnc2oc(-c3ccccc3)c(-c3ccccc3)c12
Temperature: 120 °C

Procedure:
A mixture of 68 (8.2 g, 0.028 mol), phosphorous tribromide (80 mL) and N,N-dimethylaniline (5 mL) was heated to 120° C. for 3 h. After cooling, the reaction mixture was carefully poured into ice, extracted with EtOAc, and purified by silica gel column chromatography, providing 69(2.5 g) as a yellow solid. MS: 349.1, 351.1 (M+1). 1HNMR (DMSO-d6) ppm 8.82 (s, 1H), 7.55-7.41 (m, 10H).
Reaction SMILES: [C:1]1(=O)[C:9]2[CH2:8][CH:7]=[CH:6][CH2:5][C:4]=2[C:3](=[O:10])[O:2]1.O.[NH2:13][NH2:14]>C1(C)C=CC=CC=1>[C:3]1(=[O:10])[C:4]2[CH2:5][CH:6]=[CH:7][CH2:8][C:9]=2[C:1](=[O:2])[NH:14][NH:13]1
Reactant: NN
Reactant: O=C1OC(=O)C2=C1CC=CC2
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1[nH][nH]c(=O)c2c1CC=CC2

Procedure:
A suspension of isobenzofuran-1,3(4H,7H)-dione (4.2 g, 28 mmol) in 45 mL toluene was heated at reflux and charged with hydrazine hydrate (1.63 mL, 33.6 mmol) dropwisely in a round bottom flask equipped with a condenser. The reaction mixture was heated at reflux for 2 h. The mixture was filtered to afford the titled compound a white solid (4.2 g, yield: 91%).
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][C:17]=2[N+:18]([O-:20])=[O:19])[NH:14][C:13](=[O:21])[N:12]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[C:11]3=[O:27])[CH:4]=1)=[O:2].CO>C(O)(=O)C>[OH:2][CH2:1][C:3]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][C:17]=2[N+:18]([O-:20])=[O:19])[NH:14][C:13](=[O:21])[N:12]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[C:11]3=[O:27])[CH:4]=1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(-n3ccc(C=O)c3)cc2c1=O
Solvent: CC(=O)O
Solvent: CO
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(-n3ccc(CO)c3)cc2c1=O
Reaction time: 0.5 h

Procedure:
To a solution of N-[6-(3-formyl-pyrrol-1-yl)-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide (580 mg, 1.47 mmol, crude from previous step) in methanol (5 ml) sodium borohydride (112 mg, 2.95 mmol) is added at 0° C. and allowed to stir for 30 minutes. A small quantity of acetic acid is added to destroy excess sodium borohydride. The reaction mixture is diluted with ethyl acetate and washed two times with water and the solvent of the organic layer is removed by rotavapor evaporation to give a red-brown oil which is purified by flash chromatography with DCM/methanol from 98:2 to 95:5 to yield the title compound as an orange solid, m.p. 250-270° C. (decomp.).
Reaction SMILES: Br.[NH2:2][C@H:3]([C:5]([N:7]1[CH2:20][CH2:19][CH2:18][C@H:8]1[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10])=[O:6])[CH3:4].C(N(CC)CC)C.[C:28]12([C:38](Cl)=[O:39])[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2>O1CCCC1>[C:28]12([C:38]([NH:2][C@H:3]([C:5]([N:7]3[CH2:20][CH2:19][CH2:18][C@H:8]3[C:9]([NH:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[O:10])=[O:6])[CH3:4])=[O:39])[CH2:35][CH:34]3[CH2:33][CH:32]([CH2:31][CH:30]([CH2:36]3)[CH2:29]1)[CH2:37]2
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)Nc1ccccc1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)C12CC3CC(CC(C3)C1)C2)C(=O)N1CCC[C@H]1C(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3.42 g (0.01 mol) of L-alanyl-L-proline anilide hydrobromide were suspended in 100 ml of dry tetrahydrofuran and the suspension was cooled to 0° C. There were then added 2.8 ml (0.02 mol) of triethylamine followed by 1.72 g (0.001 mol) of 1-adamantoyl chloride. The mixture was stirred at 0° C. for 0.5 hour and at room temperature for 2 hours and then evaporated. The residue was extracted twice with 40 ml of ethyl acetate each time. The combined ethyl acetate extracts were washed successively with two 20 ml portions of 1-N hydrochloric acid, 20 ml of water, two 20 ml portions of 5% sodium bicarbonate solution and two 20 ml portions of water, dried over magnesium sulphate and evaporated. The residue was crystallised from ether/petroleum ether and further purified by chromatography on 100 g of silica gel using chloroform for the elution. Evaporation of the chloroform eluate and crystallisation of the residue from ether/petroleum ether yielded 1.09 g (24%) of pure N-(1-adamantylcarbonyl-L-alanyl-L-proline anilide of melting point 119°-121° C.; [α]D20 =-142.9° (c=1% in methanol).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[S:15][C:16]=1[CH2:17]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:31][C:32]1[CH:39]=[C:38]([OH:40])[CH:37]=[CH:36][C:33]=1[C:34]#[N:35]>CN(C=O)C>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[S:15][C:16]=1[CH2:17][O:40][C:38]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[C:32]([F:31])[CH:39]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(-c2nc(CCCOCc3ccccc3)c(CCl)s2)cc1
Reactant: N#Cc1ccc(O)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCOCc2ccccc2)cc1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 0.82 g of 4-(3-benzyloxy-propyl)-5-chloromethyl-2-(4-trifluoromethyl-phenyl)-thiazole in 12 mL of DMF at 0° C. was added 0.1 g NaH 55%. The reaction mixture was stirred at 0° C. for 10 min then 2-0.264 g of fluoro-4-hydroxybenzonitrile was added at this temperature. The reaction mixture was stirred at 0° C. for 1 h30, allowed to warm up to room temperature and then stirred for 4 h at room temperature. The solvent was removed and the resulting residue was taken up into dichloromethane then water was added. After decantation and separation, the aqueous layer was extracted three times with dichloromethane. The combined organic layers were washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 0.91 g of crude product as a yellow oil. Purification by column chromatography on silica gel (heptane 1/ether 1) gave 840 mg of 4-[4-(3-benzyloxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-fluoro-benzonitrile as a white foam.
Reaction SMILES: [CH3:1][CH:2]1C(=O)C2C=CSC=2CC1.[O:12]1[C:16]2[CH2:17][CH2:18][CH2:19][C:20](=[O:21])[C:15]=2[CH:14]=[CH:13]1.C(I)C>>[CH2:1]([CH:19]1[C:20](=[O:21])[C:15]2[CH:14]=[CH:13][O:12][C:16]=2[CH2:17][CH2:18]1)[CH3:2]
Reactant: O=C1CCCc2occc21
Reactant: CC1CCc2sccc2C1=O
Solvent: CCI
Product: CCC1CCc2occc2C1=O

Procedure:
Following the procedure for the preparation of 5-methyl-6,7-dihydro-1-benzothiophen-4(5H)-one but substituting 6,7-dihydro-1-benzofuran-4(5H)-one and ethyl iodide and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.00, 1.54, 1.95, 2.29, 2.91, 6.67, 7.3; MS (EI) m/z (rel. intensity) 164 (M+, 36), 164 (36), 136 (90), 135 (24), 108 (76), 88 (13), 86 (69), 84 (99), 80 (58), 52 (21), 51 (57). HRMS (FAB) calcd for C10H12O2+H 165.0916, found 165.0919. Anal. Calcd for C10H12O2: C, 73.15; H, 7.37. Found: C, 72.81; H, 7.60.
Reaction SMILES: N[CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1)[OH:4].O=[C:13]([CH3:27])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:26][O:25][C:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:13]([CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=2)[OH:4])[CH3:27])=[CH:21][CH:20]=1)=[O:24]
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Reactant: Cc1cccc(C(O)CN)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc(OCC(C)CC(O)c2cccc(C)c2)cc1
Yield: 56.5 %

Procedure:
Following a procedure similar to that described in Example 3, but using 2.5 g of 2-amino-1-(3-methylphenyl)ethanol (prepared as described in Preparation 44), 4.4 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 80 ml of benzene, 60 ml of absolute methanol and 4.5 g of sodium cyanoborohydride, and then purifying the reaction product by column chromatography through silica gel, using ethyl acetate as the eluent, 3.2 g of the title compound were obtained having an Rf=0.24 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[C:22](OC)=[O:23].[NH2:26][CH2:27][C:28]([CH3:34])([CH3:33])[C:29]([O:31][CH3:32])=[O:30]>CO>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[C:22]([NH:26][CH2:27][C:28]([CH3:34])([CH3:33])[C:29]([O:31][CH3:32])=[O:30])=[O:23]
Reactant: COC(=O)c1ncc2cc(NCc3ccc(OC)cc3)ccc2c1O
Reactant: COC(=O)C(C)(C)CN
Solvent: CO
Product: COC(=O)C(C)(C)CNC(=O)c1ncc2cc(NCc3ccc(OC)cc3)ccc2c1O

Procedure:
Methyl 4-hydroxy-7-(4-methoxybenzylamino)isoquinoline-3-carboxylate (49.0 mg, 0.14 mmol) and methyl 3-amino-2,2-dimethylpropanoate (114.0 mg, 0.87 mmol) in MeOH (3 mL) were heated at 150° C. in a microwave for 4 hours. The solvent was removed in vacuo and the residue oil was purified by flash chromatography (0-10% EtOAc/CH2Cl2) to give the title compound in 15 mg. 1H NMR (CDCl3, 200 MHz): δ=13.10 (s, 1H), 8.40-8.28 (m, 2H), 8.10 (d, 1H, J=9.0 Hz), 7.30 (d, 2H, J=6.6 Hz), 7.05 (d, 1H, J=9.0 Hz), 6.92-6.80 (m, 3H), 5.14 (s, 1H), 4.38 (s, 2H), 3.81 (s, 3H), 3.68 (s, 3H), 3.59 (d, 2H, J=6.6 Hz), 1.28 (s, 6H).