Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[CH3:7][CH:8]1OC(C)OC(C)O1.[CH:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][CH:20]=1)([CH3:18])[CH3:17].P(=O)(O)(O)O>O.C(O)=O>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]([NH:25][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([CH:16]([CH3:18])[CH3:17])=[CH:20][CH:21]=1)[CH3:8]
Reactant: Brc1ccsc1
Reactant: CC(C)c1ccc(C(N)=O)cc1
Reactant: CC1OC(C)OC(C)O1
Agent: O=P(O)(O)O
Solvent: O=CO
Solvent: O
Product: CC(C)c1ccc(C(=O)NC(C)c2sccc2Br)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 17 %

Procedure:
3-Bromothiophene (8.15 g, 0.05 mol), paraldehyde (2.20 g, 0.017 mol) and 4-isopropylbenzamide (1.63 g, 0.01 mol) were added to a mixture of formic acid (6 ml) and 85% phosphoric acid (3 ml) and stirred at a room temperature for four hours. Water (50 ml) was added to the reaction mixture. The mixture was extracted with chloroform (50 ml), subjected to a silica gel column chromatography (eluent: chloroform) and recrystallized from chloroform/petroleum benzine (1:2) to obtain the entitled compound (0.6 g) as a colorless plate-shape crystal. Yield: 17.0%. Melting point: 133° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=[O:18])[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[Cl:48][C:49]1[CH:60]=[CH:59][C:52]2[NH:53][C:54]([C@@H:56]([NH2:58])[CH3:57])=[N:55][C:51]=2[CH:50]=1>CN(C=O)C>[Cl:48][C:49]1[CH:60]=[CH:59][C:52]2[NH:53][C:54]([C@@H:56]([NH:58][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][C:11]([N:12]4[CH2:17][CH2:16][CH2:15][CH2:14][C:13]4=[O:18])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH3:57])=[N:55][C:51]=2[CH:50]=1
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: COc1cc(C(=O)O)ccc1N1CCCCC1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1cc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)ccc1N1CCCCC1=O

Procedure:
Prepared analogously to Example 1f from 3-methoxy-4-(piperidin-2-on-1-yl)-benzoic acid, TBTU, NMM and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in DMF and subsequent purification by preparative HPLC.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][CH:10]=O)=[N:6][CH:7]=1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:10]=[N:9][CH:8]=2)[CH:7]=1
Reactant: O=CNCc1ccc(F)cn1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Fc1ccc2cncn2c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 95.7 %

Procedure:
In a round-bottomed flask, N-(5-fluoro-pyridin-2-ylmethyl)-formamide (612 mg, 3.97 mmol) was dissolved in toluene (16 ml) and phosphorus oxychloride (0.68 ml, 7.3 mmol) was added. The reaction mixture was stirred at 100° C. in an oil bath for 4 h then cooled to 0° C. and carefully quenched with ice. Aqueous 25% ammonium hydroxide was added until pH=˜9. The mixture was diluted with water and extracted with dichloromethane (3×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give 517 mg (96%) of 6-fluoro-imidazo[1,5-a]pyridine as a light brown oil. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.16 (s, 1H), 7.84-7.94 (m, 1H), 7.50 (s, 1H), 7.46 (dd, J=9.8, 5.3 Hz, 1H), 6.69 (ddd, J=9.8, 7.7, 2.1 Hz, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.O=S(Cl)Cl.[CH3:18]O>>[CH3:18][O:12][C:11](=[O:13])[C@H:2]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)[NH2:1]
Reactant: CO
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of L-tyrosine (45.3 g, 0.25 mol) in CH3OH (680 mL), SOCl2 (44.6 g, 0.375 mol) was added dropwise at 0° C. After addition, the mixture was allowed to warm to rt and then refluxed for overnight. The reaction mixture was concentrated to give L-tyrosine methyl ester (49.2 g, 100%), which was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:13])[CH:3]=1.CN(C(ON1N=[N:29][C:24]2[CH:25]=[CH:26][CH:27]=[N:28][C:23]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.CN1CC[C@@H](N)C1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([NH:29][C@@H:24]2[CH2:25][CH2:26][N:28]([CH3:27])[CH2:23]2)=[O:8])=[C:4]([F:13])[CH:3]=1
Reactant: COc1cc(C(=O)O)c(F)cc1N
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN1CC[C@@H](N)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N[C@@H]2CCN(C)C2)c(F)cc1N
Reaction time: 2 h

Procedure:
4-amino-2-fluoro-5-methoxybenzoic acid (Intermediate 183; 500 mg, 2.70 mmol), HATU (1.55 g, 4.05 mmol) and (3R)-1-methylpyrrolidin-3-amine di Hydrochloride (Intermediate 184; 631 mg, 3.31 mmol) were stirred in DMF (7.5 mL) and diisopropylethylamine (2.36 ml, 13.50 mmol) added. The reaction mixture was stirred for 2 hours and then absorbed on to an SCX column, which was then washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by column chromatography (2.5% ammonia in methanol/DCM) to yield the title compound as a viscous brown oil. (662 mg, 92%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:20][CH3:21])=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[N:5]=[CH:4][N:3]=1.[Cl:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][CH:27]=[C:28]2[NH2:33].Cl>C(O)(C)C>[ClH:1].[ClH:22].[Cl:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][CH:27]=[C:28]2[NH:33][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:20][CH3:21])=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc(OC2CCN(C)CC2)c2c(Cl)ncnc2c1
Reactant: Nc1cccc2c(Cl)cccc12
Agent: Cl
Solvent: CC(C)O
Product: COc1cc(OC2CCN(C)CC2)c2c(Nc3cccc4c(Cl)cccc34)ncnc2c1
Temperature: 25 °C
Yield: 159.7 %

Procedure:
A mixture of 4-chloro-7-methoxy-5-(N-methylpiperidin-4-yloxy)quinazoline (0.08 g), 5-chloro-1-naphthylamine (0.055 g), 6.2M hydrogen chloride in isopropanol (0.044 ml) and isopropanol (3 ml) was stirred and heated to reflux for 2 hours. The mixture was cooled to ambient temperature and the precipitate was isolated, washed with diethyl ether and dried under vacuum. There was thus obtained the title compound (0.129 g), a portion of which was treated with a saturated methanolic ammonia solution. The mixture was filtered and the filtrate was evaporated to give the free base; NMR Spectrum: (CDCl3) 1.9–2.1 (m, 4H), 2.22 (s, 3H), 2.25–2.4 (m, 2H), 2.6–2.7 (m, 2H), 3.94 (s, 3H), 4.7 (br s, 1H), 6.6 (s, 1H), 6.9 (s, 1H), 7.4 (m, 1H), 7.62 (d, 1H), 7.7 (m, 1H), 8.0 (m, 2H), 8.25 (d, 1H), 8.46 (s, 1H), 9.9 (br s, 1H); Mass Spectrum: M+H+ 449 and 451.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=O.[N+:11]([CH2:14][CH2:15][CH2:16][C:17]([O:19]C)=O)([O-:13])=[O:12].[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH2:29][NH2:30].C([O-])(=O)C.[Na+].C(O)(=O)C>C(O)C>[F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C@@H:4]1[N:30]([CH2:29][CH2:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[F:21])[C:17](=[O:19])[CH2:16][CH2:15][C@H:14]1[N+:11]([O-:13])=[O:12]
Reactant: NCCc1ccccc1F
Reactant: O=Cc1cc(F)ccc1F
Reactant: COC(=O)CCC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C1CC[C@@H]([N+](=O)[O-])[C@H](c2cc(F)ccc2F)N1CCc1ccccc1F
Reaction time: 0.08 h

Procedure:
To a solution of 2,5-difluorobenzaldehyde (0.765 mL, 7.04 mmol) in ethanol (15 mL) was added methyl 4-nitrobutyrate (0.901 mL, 7.04 mmol) and the mixture stirred for 5 minutes. To the reaction mixture was added 2-(2-fluorophenyl)ethylamine (0.87 mL, 7.04 mmol) and the mixture stirred for 10 minutes. To the mixture was added sodium acetate (0.577 g, 7.04 mmol) followed by glacial acetic acid (0.806 mL, 14.07 mmol) and the mixture heated at reflux temperature for 48 h. The solvent was removed in vacuo and to the yellow oil was added saturated aqueous sodium hydrogen carbonate (25 mL) and the aqueous phase extracted with ethyl acetate (4×25 mL). The combined organic phases were washed with saturated aqueous brine (1×25 mL), dried with anhydrous sodium sulfate, filtered and the solvent removed in vacuo. The yellow oil was purified by column chromatography (silica gel Biotage 40S) eluting with ethyl acetate/hexane (gradient from 0% to 60%) to give the racemic trans title compound as a yellow gum. LC/MS 379.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[Cl:37])=[N:10][C:11]([O:16][CH2:17][CH2:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)=[C:12]([CH:15]=2)[C:13]#[N:14])=[CH:4][CH:3]=1.C(#N)C.O.NN>C(O)C>[NH2:19][CH2:18][CH2:17][O:16][C:11]1[N:10]=[C:9]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[Cl:37])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Solvent: CC#N
Product: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCCN
Temperature: 80 °C

Procedure:
To the product of Example 25 (971 mg) was added acetonitrile (14 mL) and ethanol (5 mL). The mixture was heated to 80° C. to dissolve the material before adding hydrazine hydrate (0.60 mL, 12.24 mmol). After 2.3 hours the mixture was filtered through Celite®545 diatomaceous earth and then concentrated. The residue was purified by flash chromatography (silica gel) eluting with 2% triethylamine/4% methanol/94% dichloromethane affording the product. MS (electrospray) m/e 418.0 MH+ (retention time=3.0 min LC/MS).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][C:18](SC)=[CH:17][CH:16]=2)[CH:3]=1.O[O:24][S:25]([O-:27])=O.[K+].[CH3:29]C(C)=O.O>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:25]([CH3:29])(=[O:27])=[O:24])=[CH:17][CH:16]=2)[CH:3]=1
Reactant: CC(C)=O
Reactant: O=S([O-])OO
Reactant: CSc1ccc(Nc2cc(Cl)nc(-c3ccccc3)n2)cc1
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1ccc(Nc2cc(Cl)nc(-c3ccccc3)n2)cc1

Procedure:
(6-Chloro-2-phenyl-pyrimidin-4-yl)-(4-methylsulfanyl-phenyl)-amine (1 g, 3.03 mmol) was treated with oxone in acetone-water at temperature in the range of 20-40° C. for 1 hour to yield the desired compound.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[Cl:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][C:25]=1F)[C:12]([C:14]1[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=1[CH3:22])=[O:13]>CN(C)C=O>[Cl:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][C:25]=1[N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)[C:12]([C:14]1[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=1[CH3:22])=[O:13]
Reactant: c1c[nH]cn1
Reactant: Cc1cc(C)c(C(=O)c2ccc(F)c(Cl)c2)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(C(=O)c2ccc(-n3ccnc3)c(Cl)c2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
To a suspension of 2.3 g of sodium hydride (60% dispersion in mineral oil) in 50 ml of dimethylformamide is added 4.2 g of imidazole over a 5 minute period under occasional ice cooling. After stirring at room temperature for 30 minutes, a solution of 14.2 g of 3-chloro-4-fluoro-2',4',6'-trimethylbenzophenone in 10 ml of dimethylformamide is added and the mixture is stirred at 50° C. for 3 hours. The reaction mixture is poured into ice-cold water and extracted with benzene. After benzene is distilled off, the residue is purified column-chromatographically to give 15.6 g of 3-chloro-4-(1-imidazolyl)-2',4',6'-trimethylbenzophenone as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3](=[O:14])[NH:4][C:5](=[NH:13])[S:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[C:16]([N:20]=[C:21]=[O:22])([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl>[CH3:1][N:2]([CH3:15])[C:3]([N:4]=[C:5]([S:6][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)[NH:13][C:21]([NH:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])=[O:14]
Reactant: CC(C)(C)N=C=O
Reactant: CN(C)C(=O)NC(=N)SC1CCCCC1
Solvent: ClCCl
Product: CN(C)C(=O)N=C(NC(=O)NC(C)(C)C)SC1CCCCC1

Procedure:
A mixture of 5 parts of cyclohexyl 4,4-dimethylthioallophanimidate and 4 parts t-butylisocyanate in 70 parts of methylene chloride is refluxed for 2 hours. After evaporation of the solvent, the oily residue is triturated with petroleum-ether to give solids, which are recrystallized from cyclohexane to give pure cyclohexyl N-dimethylcarbamoyl-4-t-butylthioallophanimidate (a compound of formula I).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[BrH:13].BrBr.S(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[Br:13][CH:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:11]#[N:12])[CH:6]=2)[C:2]1=[O:1]
Reactant: N#Cc1ccc2c(c1)CCC2=O
Reactant: Br
Agent: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1ccc2c(c1)CC(Br)C2=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.93 g of 1-oxoindane-5-carbonitrile are dissolved in 40 ml of glacial acetic acid and, after addition of 0.1 ml of hydrobromic acid (48% strength in water), at room temperature a solution of 1.34 ml of bromine in 8 ml of acetic acid is added dropwise. The reaction mixture is stirred at room temperature for 3 h and then added to a mixture of 20 g of ice and 40 g of water, 0.5 g of sodium bisulfite is added and the mixture is extracted by shaking twice with 50 ml of dichloromethane each time. The organic phase is washed with 50 ml of water, dried over magnesium sulfate, concentrated in vacuo and chromatographed on silica gel with toluene/ethyl acetate 25/1. 2-Bromo-l-oxoindane-5-carbonitrile is obtained with a melting point of 115-118° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.[H-].[Na+].F[C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([NH2:18])=[O:17]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([NH2:18])=[O:17])[CH2:6][CH2:5]2
Reactant: Clc1ccc2c(c1)CCN2
Reactant: NC(=O)c1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: NC(=O)c1ccccc1N1CCc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.3 %

Procedure:
A slurry was prepared comprising 5-chloroindoline (15.3 gm, 0.1 mole), dimethylsulfoxide (DMSO) [50 ml] and sodium hydride (5.28 gm, 50% in oil, washed with hexane). The slurry was permitted to stir at room temperature for 1 hour. To this a solution of o-fluorobenzamide (15.2 gm, 1.1 eq.) in DMSO (20 ml) was added dropwise with the temperature between 17°-19° C. At the end of addition the reaction mixture was stirred at room temperature for 2 hours, then heated to 75°-78° C. for 16 hours. The reaction mixture was partitioned between methylene chloride (300 ml) and water (250 ml). The aqueous phase was separated and extracted twice with methylene chloride (150 ml). The combined organic solution was washed twice with water, twice with HCl (2N, 100 ml), brine (2×50 ml), dried over Na2SO4, concentrated to about 50 ml. Ether (50 ml) was added. The product was crystallized out upon standing overnight (about 16 hours). The yield was 14.2 gm (52%); m.p. 137°-138° C. Recrystallization from methylene chloride and ether yielded 2-(5-chloro-indolin-1-yl)benzamide (11.82 gm) m.p. 137°-138° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][OH:18])[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]([O:24][C:25]([C:27]1[C:35]2[CH2:34][CH2:33][O:32][CH:31]([CH2:36][OH:37])[C:30]=2[S:29][C:28]=1[NH2:38])=[O:26])([CH3:23])([CH3:22])[CH3:21].C(N(C(C)C)CC)(C)C.[CH2:48]([Si:50]([CH2:54][CH3:55])([CH2:52][CH3:53])Cl)[CH3:49]>ClCCl>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][O:18][Si:50]([CH2:54][CH3:55])([CH2:52][CH3:53])[CH2:48][CH3:49])[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:2])[CH3:3].[C:20]([O:24][C:25]([C:27]1[C:35]2[CH2:34][CH2:33][O:32][CH:31]([CH2:36][O:37][Si:50]([CH2:54][CH3:55])([CH2:52][CH3:53])[CH2:48][CH3:49])[C:30]=2[S:29][C:28]=1[NH2:38])=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CO)OC2
Reactant: CC[Si](Cl)(CC)CC
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CCOC2CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[Si](CC)(CC)OCC1Cc2c(sc(N)c2C(=O)OC(C)(C)C)CO1
Product: CC[Si](CC)(CC)OCC1OCCc2c1sc(N)c2C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 69 %
Yield: 16 %

Procedure:
To a solution of a mixture of 2-amino-5-hydroxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester and 2-amino-7-hydroxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (1:4 estimated based on 1H NMR) (200 mg, 0.70 mmol) and diisopropylethylamine (0.25 ml, 1.4 mmol) in dichloromethane (6.0 ml) cooled to 0° C. under nitrogen was added triethylchlorosilane (0.18 ml, 1.1 mmol). The solution was stirred at 0° C. for 5 min. and then stirred at room temperature for 15 min. The solution was washed with saturated sodium bicarbonate and brine, dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using a 5% mixture of ethyl acetate/hexane as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 42 mg (16%) of 2-amino-5-triethylsilanyloxymethy-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (1) and 193 mg (69%) of 2-amino-7-triethylsilanyloxymethy-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (2).
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.Cl[CH:15]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>CN(C)C=O>[CH:22]1([CH:15]([S:3][C:4]2[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=2)[CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: ClC(Cn1ccnc1)C1CCCCC1
Reactant: COC(=O)c1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC(Cn2ccnc2)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
779 mg of a 55% w/w suspension of sodium hydride in mineral oil were added to a solution of 3 g of methyl 4-mercaptobenzoate in 24 ml of dry dimethylformamide, and the resulting mixture was stirred at room temperature for 30 minutes. A solution of 3.8 g of 1-(2-chloro-2-cyclohexylethyl)imidazole in 36 ml of dry dimethylformamide was added to the resulting solution, and the reaction mixture was then heated at 60°-70° C. for 13.5 hours. At the end of this time, the resulting mixture was treated and purified by the same method as described in Example 1, to give 3.3 g of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1[CH:18]=O.Cl.[NH2:21][OH:22].O>CN(C)C=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1[CH:18]=[N:21][OH:22]
Reactant: NO
Reactant: O=CC1=C(Cl)c2ccccc2OC1c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: ON=CC1=C(Cl)c2ccccc2OC1c1ccccc1

Procedure:
A solution of 27 g 4-chloro-3-formyl-flav-3-ene in 25 ml dimethylformamide is refluxed. To this solution one adds 7.7 g hydroxylamine hydrochloride dissolved in 60 ml dimethylformamide. After two hours reflux, the solution is cooled at room temperature before the addition of 400 ml water. The precipitate is formed, filtered, washed with water and dried. The solid is crystallized in diisopropylether. Pure 4-chloro-3-hydroxyiminomethyl-flav-3-ene is obtained as pale yellow crystals; m.p. 199°-200° C.
Reaction SMILES: [Na].[C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[N:12])=[N:9][CH:10]=1)([OH:4])=[O:3].N[CH2:14][CH2:15][SH:16].Cl>O.C(O)C>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:16][CH2:15][CH2:14][N:12]=2)=[N:9][CH:10]=1)([OH:4])=[O:3]
Reactant: NCCS
Reactant: N#Cc1ccc(C(=O)O)cn1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(C2=NCCS2)nc1

Procedure:
Sodium (11 mmol) is added to a flask containing 75 ml of ethanol. As soon as the sodium has dissolved, 10 mmol of 5-carboxy-2-cyanopyridine and 11 mmol of 2-amino-ethanethiol are added and the solution is refluxed for 24 h. The solution is then diluted with 25 ml of water, made acidic (pH=5) with 2N HCl and evaporated. The residue is dissolved in 100 ml of hot chloroform, the salts are filtered off and the filtrate on cooling gives crystals of the title compound, m.p. 234°-235° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:20][CH2:19][C:14]2(OCC[O:15]2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.CC1C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:12][CH2:13][C:14](=[O:15])[CH2:19][CH2:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COCCC2CCC3(CC2)OCCO3)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCC(CCOCc2ccccc2)CC1
Yield: 97 %

Procedure:
8-(2-Benzyloxy-ethyl)-1,4-dioxa-spiro[4.5]decane (Intermediate K1, 1.02 g, 3.70 mmol) (prepared in accordance with the publication Ciufolini et. al. J. Amer. Chem. Soc. 1991, 113, 8016, incorporated herein by reference) was dissolved in acetone (100 mL): H2O (5 mL) and reacted with TsOH (140 mg, 0.74 mmol) at 45° C. for 5 h. After a standard aqueous work-up the material was purified by chromatography on SiO2 to give 4-(2-benzyloxy-ethyl)-cyclohexanone as a colorless oil (97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:4]=1[OH:10].Br[CH2:12][CH2:13]Br.C(=O)([O-])[O-].[K+].[K+].O>OCC(CO)O.[Cu]>[CH3:1][O:2][C:3]1[C:4]2[O:10][CH2:13][CH2:12][O:6][C:5]=2[CH:7]=[CH:8][CH:9]=1
Reactant: BrCCBr
Reactant: COc1cccc(O)c1O
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: OCC(O)CO
Product: COc1cccc2c1OCCO2
Temperature: 110 °C

Procedure:
A heterogeneous mixture containing 1.42 mol of 3-methoxycatechol, 1.57 mol of 1,2-dibromoethane, 1.42 mol of potassium carbonate and 4 g of copper powder in 150 ml of glycerol is heated at 110° C. for 15 hours. After cooling, the mixture is poured into 1 l of water. The aqueous phase is extracted with ethyl ether. The ether phases are then washed with 1N sodium hydroxide, dried and evaporated, and give the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:21](COC)[S:22]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=2)(=[O:24])=[O:23])[C:5]([C:8]([C:10]2[C:18]3[N:17]([CH3:19])[C:16](=[O:20])[NH:15][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[O:9])=[N:6][CH:7]=1.O.CO>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([C:32]([F:35])([F:33])[F:34])[CH:26]=2)(=[O:23])=[O:24])[C:5]([C:8]([C:10]2[C:18]3[N:17]([CH3:19])[C:16](=[O:20])[NH:15][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[O:9])=[N:6][CH:7]=1
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1cccc2[nH]c(=O)n(C)c12)S(=O)(=O)c1ccc(C)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2cccc3[nH]c(=O)n(C)c23)cc1C(F)(F)F
Reaction time: 8 h

Procedure:
A solution of N-[5-Chloro-2-(3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-4-methyl-3-trifluoromethyl-benzenesulfonamide in 4 M HCl in dioxane (2 mL) and water (1 mL) was heated at 95° C. for 7 h, then MeOH (1 mL) and water (2 mL) was added and heating was continued overnight. The resulting mixture was purified by HPLC to provide N-[5-chloro-2-(3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-4-carbonyl)-pyridin-3-yl]-4-methyl-3-trifluoromethyl-benzenesulfonamide. 1H NMR (400 MHz, CDCl3) δ 10.94 (s, 1 H), 8.28 (d, J=2.0 Hz, 1 H), 8.21 (d, J=1.6 Hz, 1H), 8.08 (s, 1 H), 7.95 (d, J=7.6 Hz, 1 H), 7.42 (d, J=8.0 Hz, 1 H), 7.19-7.17 (m, 1 H), 7.01 (t, J=7.6 Hz, 1 H), 6.82 (d, J=7.6 Hz, 1 H), 3.10 (s, 3 H), 2.53 (s, 3H); MS m/z 524.9 (M+H)+.