Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH2:2][CH:3]([CH3:5])[CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:12][C:13]1[CH:22]=[C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]>CN(C=O)C>[Cl:12][C:13]1[CH:22]=[C:21]([N:23]([CH2:2][CH:3]([CH3:5])[CH3:4])[S:24]([CH3:27])(=[O:26])=[O:25])[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: CC(C)CI
Reactant: COC(=O)c1ccc(NS(C)(=O)=O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N(CC(C)C)S(C)(=O)=O)cc1Cl
Temperature: 140 °C
Reaction time: 0.5 h

Procedure:
175 μL of 1-iodo-2-methylpropane and 740 mg of Cesium Carbonate were added to 200 mg of methyl 2-chloro-4-(methylsulfonamido)benzoate in 2 mL of DMF and stirred in the microwave at 140° C. for 30 minutes. The reaction mixture was extracted in Ethyl Acetate twice with water, dried over Magnesium Sulfate, filtered, concentrated and purified on ISCO Combi-Flash to give methyl 2-chloro-4-(N-isobutylmethylsulfonamido)benzoate. 120 mg of methyl 2-chloro-4-(N-isobutylmethylsulfonamido)benzoate was hydrolyzed via Procedure M to yield 110 mg of crude 2-chloro-4-(N-isobutylmethylsulfonamido)benzoic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(N-isobutylmethylsulfonamido)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-isobutylmethylsulfonamido)benzamide. MS (Q1) 492 (M)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:23]=[CH:22][C:8]([C:9]([NH:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:21])=[O:10])=[CH:7][CH:6]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:23]=[CH:22][C:8]([C:9]([NH:11][C@@H:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C@H:13]2[OH:21])=[O:10])=[CH:7][CH:6]=1
Reactant: COCOc1ccc(C(=O)NC2Cc3ccccc3C2=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COCOc1ccc(C(=O)N[C@@H]2Cc3ccccc3[C@H]2O)cc1
Temperature: 0 °C
Yield: 59.4 %

Procedure:
To an ice-cooled solution/suspension of 2-(4-methoxymethoxybenzamido)-1-indanone (475 mg, 1.5 mmol) in methanol (100 mL) was added NaBH4 (13.9 mg, 3.75 mmol) portionwise. After reaction at rt for 15 min, volatiles were removed in vacuo and the residue triturated in MeOH to afford exclusively trans-2-(4-methoxymethoxybenzamido)-1-indanol as a white solid (279 mg). The mother liquid was chromatographed (silica gel, Hexane:EtOAc/7:1 to 1:1) to afford an additional 82 mg of the product (360 mg in total, 75%).
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH:2]=[CH2:3]>C(O)(=O)C.C(O)C.C(OCC)(=O)C.[Fe]>[CH2:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCc1cccc([N+](=O)[O-])c1C(=O)OC
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: C=CCc1cccc(N)c1C(=O)OC
Temperature: 25 °C

Procedure:
To a stirred suspension of Step 1 intermediate (4.2 g, 19.98 mmol) in a mixture of 50% aqueous acetic acid (100 ml) and ethanol (100 ml) was added iron powder (5.3 g, 99.9 g atom) and the mixture was refluxed for 3 h. The mixture was cooled to room temperature and filtered through a celite bed. The filtrate was concentrated and the residue obtained was diluted with ethyl acetate and washed with water (2×50 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated to give 3.2 g of the product as a brown oil; 1H NMR (δ ppm, CDCl3, 300 MHz): 7.15-7.07 (m, 1H); 6.62-6.55 (m, 2H); 5.99-5.82 (m, 1H); 5.05-4.95 (m, 2H); 3.86 (s, 3H); 3.53 (d, J=6.0, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:16]2[O:15][C:9]3([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[CH2:8][C:7](=[O:17])[C:6]=2[C:5]([O:18]C)=[CH:4][C:3]=1[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].B(Cl)(Cl)Cl>ClCCl>[Cl:1][C:2]1[C:16]2[O:15][C:9]3([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]3)[CH2:8][C:7](=[O:17])[C:6]=2[C:5]([OH:18])=[CH:4][C:3]=1[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)COc1cc(OC)c2c(c1Cl)OC1(CCCCC1)CC2=O
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)COc1cc(O)c2c(c1Cl)OC1(CCCCC1)CC2=O
Reaction time: 1.5 h
Yield: 77.4 %

Procedure:
Ethyl 2-{(8-chloro-5-methoxy-3,4-dihydro-4-oxospiro[2H-1-benzopyran-2,1'-cyclohexan ]-7-yl)oxy}acetate (65-3, prepared in Preparation 65) (0.575 g, 1.50 mmol) is dissolved in dry dichloromethane (3 ml). To the solution is added dropwise a 2M boron trichloride solution in dichloromethane (1.5 ml, 3.0 mmol) at -75° to -70° C. After stirring at -70° to -50° C. for 1.5 hours, ice-cold water is added thereto and the mixture is extracted with dichloromethane. Organic layer is separated, washed with aqueous sodium bicarbonate, dried, and concentrated. The residue is applied to a silica gel column and eluted with a mixture of acetonitrile and dichloromethane (1:9) to yield the title compound as a crystalline solid (0.428 g, yield 77.4%). Recrystallization from diethyl ether gives a product having a melting point of 110°-111° C.
Reaction SMILES: [CH2:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH:2]([CH3:4])[CH3:3].[H-].[Na+].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.O>CC(N(C)C)=O>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[S:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)(=[O:8])=[O:7])=[CH:22][CH:21]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: COc1ccc(S(=O)(=O)NCC(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc(S(=O)(=O)N(Cc2ccc(Cl)cc2)CC(C)C)cc1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 66.7 %

Procedure:
To a solution of N-isobutyl-4-methoxy-benzenesulfonamide (1.03 g, 4.2 mmol) in anhydrous dimethylacetamide (20 mL) at 0° C. was added NaH (60% dispersion in mineral oil, 186 mg, 4.6 mmol) until no more gas evolved then stirred for a further 10 minutes. 4-Chlorobenzylbromide (951 mg, 4.6 mmol) was added and the reaction heated at 90° C. for 2 hours. The reaction was left to cool to room temperature, water was added, extracted with DCM, filtered through a phase separator, concentrated then purified by silica gel column chromatography (0-50% DCM in cyclohexane) to give N-(4-chloro-benzyl)-N-isobutyl-4-methoxy-benzenesulfonamide (1.03 g, 67%). LCMS (m/z, Method A)) ES+ 368 [M+1]+.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:17][CH:16]=1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[C:28]([O:27][C:25](=[O:26])[NH:24][CH2:23][CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH2:10])=[CH:16][CH:17]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCOc1ccc(CCCCN)cc1
Reaction time: 8 h
Yield: 98.4 %

Procedure:
{4-[4-(2-tert-Butoxycarbonylaminoethoxy)phenyl]butyl}carbamic acid benzyl ester 1 (2.5 g, 5.60 mmol), ethanol (20 mL), and 10% palladium on carbon (1 g), were subject to one atmosphere of hydrogen for 4 h, and then allowed to stand overnight. After stirring under nitrogen purge, the catalyst was removed by filtering the reaction mixture through Celite and rinsing with methylene chloride. Evaporation followed by 2 h under high vacuum afforded the product (1.7 g, 98%) as an oil. 1H NMR (300 MHz, CDCl3) δ 1.45 (s, 9H), 1.47 (m, 2H), 1.61 (m, 2H), 1.75 (br s, 2H), 2.56 (t, 2H), 2.71 (t, 2H), 3.51 (m, 2H), 3.99 (t, 2H), 5.07 (br s, 1H), 6.80 (d, 2H), 7.08 (d, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH2:16].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:16][CH2:15][CH2:14][N:13]([CH3:17])[CH3:12])=[O:8])=[CH:4][C:3]=1[CH3:11]
Reactant: CN(C)CCN
Reactant: Cc1cc(C(=O)O)ccc1Br
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(C(=O)NCCN(C)C)ccc1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-bromo-3-methylbenzoic acid (430 mg), N,N-dimethylethylenediamine (180 mg), 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloride (600 mg) and 4-dimethylaminopyridine (244 mg) in dichloromethane (20 mL) was stirred at ambient temperature for 4 hours, diluted with ethyl acetate (200 mL), washed with water and brine, and dried (Na2SO4), filtered and concentrated. The concentrate was purified by flash column chromatography with 10% ethyl acetate in ammonia saturated dichloromethane.
Reaction SMILES: OCC([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](N3C4C(=CC=CC=4)C(C4CCNCC4)=N3)[N:16]=2)[N:11](COCC[Si](C)(C)C)[CH:10]=1)=[O:8])(C)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[N:16]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:11][CH:10]=[C:9]([C:7]([NH2:6])=[O:8])[C:17]=12
Reactant: CC(C)(CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3nc(C4CCNCC4)c4ccccc43)nc12
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1c[nH]c2nccnc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 198.6 %

Procedure:
To a stirred solution of N-(1-hydroxy-2-methylpropan-2-yl)-2-(3-(piperidin-4-yl)-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (100 mg, 177 μmol) in methanol (4 mL), cooled to 0° C. with an ice bath, was added 37% aqueous formaldehyde (1 mL, 13.4 mmol), followed by the addition of sodium triacetoxyborohydride (84.6 mg, 399 μmol). The reaction mixture was stirred at room temperature for 15 h then concentrated in vacuo. Purification by chromatography (silica, 4 g Analogix column, 0-6% methanol containing 10% ammonium hydroxide in dichloromethane) gave N-(1-hydroxy-2-methylpropan-2-yl)-2-(3-(1-methylpiperidin-4-yl)-1H-indazol-1-yl)-5-(2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (57 mg, 56%). MS (M+H)+=578.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C@H:18]([NH:20]C(OC(C)(C)C)=O)[CH3:19])=[C:14]([F:28])[CH:13]=2)=[CH:7][CH:8]=[CH:9][C:10]=1[Cl:11])=[O:4].Cl.O1CCOCC1>>[ClH:11].[CH3:1][O:2][C:3]([C:5]1[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C@H:18]([NH2:20])[CH3:19])=[C:14]([F:28])[CH:13]=2)=[CH:7][CH:8]=[CH:9][C:10]=1[Cl:11])=[O:4]
Reactant: COC(=O)c1c(Cl)cccc1-c1ccc([C@@H](C)NC(=O)OC(C)(C)C)c(F)c1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1c(Cl)cccc1-c1ccc([C@@H](C)N)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4′-((R)-1-tert-Butoxycarbonylamino-ethyl)-3-chloro-3′-fluoro-biphenyl-2-carboxylic acid methyl ester (350 mg, 858 μmol, step A) was added to a solution of HCl in dioxane (4N, 4.29 ml, 17.2 mmol) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated to dryness and the remaining solid was triturated with heptane/EtOAc 2:1 for 4 h. Filtration delivered the title compound as white solid (217 mg, 74%). MS: 308.2 [M+H]+.
Reaction SMILES: ClC1C=CC=CC=1.[C:8]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[OH:19])([CH3:11])([CH3:10])[CH3:9].[CH3:20][O:21]C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl.O>[C:8]([C:12]1[C:13]([OH:19])=[CH:14][C:15]([CH3:18])=[C:16]([CH:17]=1)[CH:20]=[O:21])([CH3:11])([CH3:10])[CH3:9]
Reactant: COC(Cl)Cl
Reactant: Cc1ccc(C(C)(C)C)c(O)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Clc1ccccc1
Solvent: O
Product: Cc1cc(O)c(C(C)(C)C)cc1C=O
Temperature: 5 °C

Procedure:
Chlorobenzene (100 mL) and 2-tert-butyl-5-methylphenol (20.6 gm, 125 mmol) were combined and the mixture stirred and cooled to 5° C. Titanium tetrachloride (27.5 mL) and dichloromethyl methyl ether (19 mL, 210 mmol) were added separately and simultaneously over 45 minutes while holding the reaction temperature between 4 and 7° C. The resulting mixture was stirred at 0-5° C. for 3 hours. Water (100 mL) was cautiously added over 18 minutes to the reaction mixture while holding the temperature below 14° C. The mixture was extracted with ethyl acetate (200 mL) and the resulting organic layer was extracted with 12% hydrochloric acid (2×75 mL). The combined aqueous acid layers were diluted with water (50 mL) and back extracted with ethyl acetate (100 mL). This extract was combined with the first ethyl acetate extract and the whole extracted with 15% KOH (3×100 mL). The KOH extracts were combined and the pH adjusted to 3 with 37% hydrochloric acid (62.8 gm). The resulting mixture was extracted with 1:1 ethyl acetate/toluene (2×150 mL). These organic extracts were combined and back extracted with water (2×50 mL) and the organic solution concentrated to approximately 75 mL. 5-tert-Butyl-4-hydroxy-2-methylbenzaldehyde seed crystals were added and the mixture stirred and cooled to 25° C. The mixture was filtered and the product washed with toluene (30 mL) and vacuum dried at 40° C. to give 5-tert-butyl-4-hydroxy-2-methylbenzaldehyde (1): 15 g (78 mmol, 62%): mp: 168-170° C.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[S:15][C:14](S)=[N:13][C:12]=2[CH:17]=1>C1COCC1.CCOC(C)=O>[Cl:4][C:14]1[S:15][C:11]2[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:17][C:12]=2[N:13]=1
Reactant: COc1ccc2sc(S)nc2c1
Reactant: O=S(=O)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2sc(Cl)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
Sulfuryl chloride (1.64 mL) was added to a solution of 5-methoxy-2-mercaptobenzothiazole in THF (20 mL). After stirring overnight, ice water was added. The reaction mixture was allowed to warm to rt and was diluted with EtOAc (100 mL). This was washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified by column chromatography (0 to 3% EtOAc in hexanes gradient), yielding 0.407 g (20%) of the title compound as a white solid. LC-MS: RT=9.05 min., [M+H]+=200.0. Rf=0.38 in 10% EtOAc/Hexanes.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH3:17])(=O)=O)=CC=1.[CH3:19][C@H:20]1[NH:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(#N)C>[CH2:16]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][N:25]1[CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][C@H:20]1[CH3:19])[CH3:17]
Reactant: CCOCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOCCCCN1CCN(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: 90 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
A mixture of 3 g of 4-ethoxybutyl p-toluenesulfonate, 2.65 g of tert-butyl (3R)-3-methylpiperazine-1-carboxylate, 3.07 mL of triethylamine, and 30 mL of acetonitrile was stirred at 90° C. for 3 hours. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 3.1 g of tert-butyl (3R)-4-(4-ethoxybutyl)-3-methylpiperazine-1-carboxylate.
Reaction SMILES: [O:1]1[C:5]([CH2:6][CH2:7][CH2:8][CH2:9][OH:10])=[CH:4][C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]1=2.[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br.[OH-].[Na+]>O>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1[O:1][C:2]2[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=2[CH:4]=1
Reactant: BrCCCCCCBr
Reactant: OCCCCc1cc2ccccc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCCCCCOCCCCc1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-benzo[b]furanbutanol (2 g), 1,6-dibromohexane (7.7 ml), TAB (500 mg) in 50% w/v sodium hydroxide solution (100 ml) was stirred at room temperature overnight. Water (100 ml) was added and the mixture extracted with ethyl acetate (2×100 ml). The combined organic extracts were dried and concentrated to give an oil. Purification by FCC eluting with hexane:ethyl acetate, 100:0→95:5) gave the title compound as a clear oil (2.1 g), t.l.c. (ether) Rf 0.83.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([CH:9]=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)([OH:13])N.Cl([O-])=O.[Na+].C(OCC)(=O)C>O1CCOCC1.O>[N+:1]([C:4]1[S:8][C:7]([C:9]([OH:13])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc([N+](=O)[O-])s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 193.9 %

Procedure:
A mixture of 5-nitrothiophene-2-carbaldehyde (1.685 g, 10.72 mmol) and sulfamic acid (1.249 g, 12.87 mmol) in dioxane (30 ml) was cooled to 0° C., and a solution of sodium chlorite (1.940 g, 21.44 mmol) in water (14 ml) was added drop-wise. The mixture was allowed to warm to RT and stirred for 2 hours. A second batch of 5-nitrothiophene-2-carbaldehyde (1.966 g, 12.51 mmol) was reacted under the same conditions using the molar ratios described above. The two reaction mixtures were combined and portioned between ethyl acetate and water. The organic layer was extracted twice with 5% NaHCO3 and the organic phase was discarded. The basic aqueous phase was acidified with 2N HCl (pH=2) and extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate; the solvent was removed affording 5-nitrothiophene-2-carboxylic acid (Int. 53) (3.6 g, 20.79 mmol, MS/ESI+173.9 [MH]+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[N:26][N:27]([CH3:34])[C:28]2=[O:33]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:21][O:20][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[C:5]2[C:4]=1[C:8]([CH3:18])([CH3:19])[CH2:9][C:10]([OH:17])([C:13]([F:14])([F:15])[F:16])[CH:11]2[NH:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[N:26][N:27]([CH3:34])[C:28]2=[O:33]
Reactant: Cn1ncc2c(N)cccc2c1=O
Reactant: COc1c(C)cccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1c(C)ccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2c(=O)n(C)ncc12
Yield: 4.3 %

Procedure:
Analogously to Example 10, the corresponding imine is produced starting from 600 mg of 4-(3-methyl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 316 mg of 5-amino-2-methylphthalazin-1-one. As in Example 3, 460 mg of the imine is reacted by reaction with 5.2 ml of titanium tetrachloride (1 M in dichloromethane) in 23 ml of dichloromethane, and 36 mg of title compound is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[F:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([F:17])[C:15]=1[F:16])[CH2:11]Br>>[F:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([F:17])[C:15]=1[F:16])[CH2:11][N:4]1[CH:5]=[N:6][C:2]([NH2:1])=[N:3]1
Reactant: Nc1nc[nH]n1
Reactant: Fc1cc(CBr)cc(F)c1F
Product: Nc1ncn(Cc2cc(F)c(F)c(F)c2)n1

Procedure:
Prepared in analogy to example 3a) starting with 3-amino-1,2,4-triazole and 3,4,5-trifluorobenzyl bromide. A pure fraction of the title compound was obtained as a colorless solid (Yield=4%). MS ISP (m/e): 229.2 (100) [(M+H)+].
Reaction SMILES: [Br:1]N1C(=O)NC(=O)N(Br)C1=O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[C:21]([O:29][CH:30]([CH3:32])[CH3:31])[CH:20]=2)=[CH:15][CH:14]=1.CN(C=O)C>O>[Br:1][C:24]1[CH:23]=[C:22]([C:25]([O:27][CH3:28])=[O:26])[C:21]([O:29][CH:30]([CH3:32])[CH3:31])=[CH:20][C:19]=1[C:16]1[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(-c2ccc(F)cc2)cc1OC(C)C
Reactant: O=c1[nH]c(=O)n(Br)c(=O)n1Br
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Br)c(-c2ccc(F)cc2)cc1OC(C)C
Yield: 127.9 %

Procedure:
Dibromoisocyanuric acid (4.60 g) was added to a mixture of methyl 4′-fluoro-3-isopropoxybiphenyl-4-carboxylate (6.61 g) and DMF (60 mL), and the resultant mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (7.53 g).
Reaction SMILES: [CH:1]1([N:6]([C@H:20]2[CH2:25][CH2:24][C@H:23](OC)[CH2:22][CH2:21]2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:28]1(N)CCC=CC1.C1(=O)CCCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:1]1([N:6]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:13]=2)[CH2:5][CH2:4][CH:3]=[CH:2][CH2:28]1
Reactant: CO[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCC2)CC1
Reactant: NC1CC=CCC1
Agent: CCOC(=O)CSc1cnc(N)s1
Solvent: O=C1CCCCC1
Product: O=C(O)CSc1cnc(NC(=O)N(C2CC=CCC2)C2CCCCC2)s1

Procedure:
Prepared in accordance with the procedure for the synthesis of {2-[3-cyclopentyl-3-(trans-4-methoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using cyclohex-3-enylamine, cyclohexanone and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester as starting material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[CH:11][C:12]([C:19]([F:22])([F:21])[F:20])=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:25])=O>O1CCOCC1>[Cl:25][C:16]1[C:15]2[C:10](=[CH:11][C:12]([C:19]([F:22])([F:21])[F:20])=[CH:13][CH:14]=2)[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:17]=1
Reactant: O=c1[nH]c(-c2ccc(Cl)cc2)nc2cc(C(F)(F)F)ccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc2c(Cl)nc(-c3ccc(Cl)cc3)nc2c1
Temperature: 25 °C

Procedure:
To a stirred suspension of 2-(4-chlorophenyl)-7-trifluoromethyl-3H-quinazolin-4-one (50 g, 0.15 mol) in dioxane (400 mL) was added dropwise phosphorus oxychloride (43 mL, 0.46 mol). The suspension was then heated at reflux for 2 h then allowed to cool to room temperature and evaporated under reduced pressure. The remaining solid was dissolved in dioxane (1 L) and an aqueous solution of sodium hydroxide (50 mL, 10% weight/weight (w/w)) was added dropwise maintaining the internal temperature≦10° C.). Water (1 L) was then added to the resultant suspension followed by the dropwise addition of a further quantity of aqueous sodium hydroxide (90 mL, 10% w/w). The precipitate was isolated by vacuum filtration washing with water (3×500 mL) and dried under vacuum (10 mbar, 50° C.). Yield=49 g, 93%; LC-MS: 4.7 min, 343 (M+); 1H NMR (dimethylsulfoxide (DMSO)-d6) δ 7.68 (d, 2 H, J=8.9 Hz), 8.12 (dd, 1 H, J=8.9, 1.8 Hz), 8.48-8.54 (m, 4 H).
Reaction SMILES: [H-].[Na+].[C:3]([N:6]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:8](=[O:20])[CH2:7]1)(=[O:5])[CH3:4].[C:21](OCC)(=[O:27])[C:22](OCC)=[O:23]>CS(C)=O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:9]2[CH:10]=[CH:11][N:6]3[C:3](=[O:5])[CH:4]=[C:21]([OH:27])[C:22]([OH:23])=[C:7]3[C:8]2=[O:20])=[CH:14][CH:15]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)N1C=CN(Cc2ccc(F)cc2)C(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=c1c2c(O)c(O)cc(=O)n2ccn1Cc1ccc(F)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of anhydrous DMSO and sodium hydride (0.24 g, 60% oil dispersion, washed 3× with hexane) under an atmosphere of nitrogen was heated with stirring at 50° C. for 3 h. After cooling to room temperature, a solution of 4-acetyl-1-(4-fluorobenzyl)-3,4-dihydropyrazin-2(1H)-one (0.5 g, 2.0 mmol; Example 2, Step 3) in anhydrous DMSO (5 mL) was added over a period of 10 min and the resultant mixture stirred at room temperature for 30 min. The mixture was then treated with diethyl oxalate (0.29 mL, 2.1 mmol) and stirred at room temperature overnight. The product mixture was subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound.