Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([C:7]2[S:8][C:9]3[CH2:18][C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:10]=3[N:11]=2)[CH2:4][C:3]1=O.Cl.CO>O1CCCC1>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([C:7]2[S:8][C:9]3[CH2:18][C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:10]=3[N:11]=2)[CH2:6]1
Reactant: CN1CC(c2nc3c(s2)Cc2ccccc2-3)CC1=O
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCC(c2nc3c(s2)Cc2ccccc2-3)C1
Yield: 38.3 %

Procedure:
To a solution of 0.11 g of 2-(1-methyl-2-oxo-4-pyrrolidinyl)-8H-indeno[1,2-d]thiazole in 4 ml of tetrahydrofuran, a 1.6 ml of a 1M solution of a borane-tetrahydrofuran complex in tetrahydrofuran was added, followed by heating under reflux for 2 hours. After cooling, a mixed solution of 10 ml of concentrated hydrochloric acid and 10 ml of methanol was added to the reaction mixture, followed by heating under reflux for 1.5 hours. The solvent was evaporated, and ethyl acetate and water were added to the resulting residue, followed by extraction with 1N hydrochloric acid. The aqueous layer was neutralized with sodium bicarbonate, followed by extraction with chloroform and drying over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was subjected to silica gel column chromatography, whereby 0.04 g of 2-(1-methyl-3-pyrrolidinyl)-8H-indeno[1,2-d]thiazole was obtained from the fraction eluted with chloroform-methanol-29% aqueous ammonia (300:10:1). The product was dissolved in methanol. Fumaric acid was added to the resulting solution, followed by crystallization from acetone to give a fumarate.
Reaction SMILES: O[C@H]1[C@H](OC2C=CC(C)=C(C)C=2)CCNCC1.[OH:18][C@H:19]1[C@H:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)[CH2:24][CH2:23][N:22](C)[CH2:21][CH2:20]1.Cl.O[C@H]1[C@H](OC2C=CC(C(F)(F)F)=CC=2)CCN(C)CC1>>[OH:18][C@H:19]1[C@H:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: CN1CC[C@@H](O)[C@H](Oc2ccc(Cl)c(Cl)c2)CC1
Agent: CN1CC[C@@H](O)[C@H](Oc2ccc(C(F)(F)F)cc2)CC1
Agent: Cc1ccc(O[C@@H]2CCNCC[C@H]2O)cc1C
Agent: Cl
Product: O[C@@H]1CCNCC[C@H]1Oc1ccc(Cl)c(Cl)c1

Procedure:
Analogously to Example 20, the 1-methyl derivatives corresponding to the compounds indicated below are obtained using, in each case, 0.04 mol of the indicated compounds, i.e. trans-3-hydroxy-4-(m-chlorophenoxy)-1-methyl-piperidine is obtained from 9.12 g of trans-3-hydroxy-4-(m-chlorophenoxy)-piperidine (Example 21), trans-3-hydroxy-4-phenylthio-1-methyl-piperidine is obtained from 8.36 g of trans-3-hydroxy-4-phenylthio-piperidine (Example 13), trans-3-hydroxy-4-(5,6,7,8-tetrahydro-1-naphthyloxy)-1-methyl-piperidine is obtained from 9.88 g of trans-3-hydroxy-4-(5,6,7,8-tetrahydro-1-naphthyloxy)-piperidine (Example 33), trans-3-hydroxy-4-(p-fluorophenoxy)-1-methyl-piperidine is obtained from 8.44 g of trans-3-hydroxy-4-(p-fluorophenoxy)-piperidine (Example 31), trans-3-acetoxy-4-(3,4-dimethyl-phenoxy)-1-methyl-piperidine is obtained from 10.60 g of trans-3-acetoxy-4-(3,4-dimethylphenoxy)-piperidine (Example 9), trans-3-hydroxy-4-(p-trifluoromethylphenoxy)-1-methyl-piperidine is obtained from 10.44 g of trans-3-hydroxy-4-(p-trifluoromethyl-phenoxy)-piperidine (Example 36), trans-4-hydroxy-5-(3,4-dimethyl-phenoxy)-1-methyl-hexahydro-1H-azepine and its hydrochloride are obtained from 9.40 g of trans-4-hydroxy-5-(3,4-dimethyl-phenoxy)-hexahydro-1H-azepine (Example 40), trans-4-hydroxy-5-(3,4-dichloro-phenoxy)-1-methyl-hexahydro-1H-azepine and its hydrochloride are obtained from 11.04 g of trans-4-hydroxy-5-(3,4-dichloro-phenoxy)-hexahydro-1H-azepine (Example 40) and trans-4-hydroxy-5-(p-trifluoromethyl-phenoxy)-1-methyl-hexahydro-1H-azepine and its hydrochloride are obtained from 11.0 g of trans-4-hydroxy-(p-trifluoromethyl-phenoxy)-hexahydro-1H-azepine (Example 40).
Reaction SMILES: N[C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)[OH:13].N([O-])=O.[Na+].NC(N)=O.N([O-])=O>O.O.[N+]([O-])([O-])=O.[Cu+2].O.O.O.O.[N+]([O-])([O-])=O.[Cu+2].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[Cu-]=O.C1C(NC2N=C(N)N=C(Cl)N=2)=CC(NS(C2C=CC3C(=C4NC5[N-]C(=C6C=5C=C(S([O-])(=O)=O)C=C6)NC5NC(=C6C=5C=CC(S([O-])(=O)=O)=C6)NC5[N-]C(=C6C=5C=C(S([O-])(=O)=O)C=C6)NC=3N4)C=2)(=O)=O)=C(S([O-])(=O)=O)C=1.[Na+].[Na+].[Na+].[Na+].[Cu+2]>[OH:13][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=S(=O)(O)O
Reactant: Cc1c(N)cccc1C(=O)O
Agent: O=[Cu-]
Agent: [Cu+2]
Agent: NC(N)=O
Solvent: O
Product: Cc1c(O)cccc1C(=O)O
Temperature: 2.5 °C
Yield: 36 %

Procedure:
A one-necked 100 mL round-bottomed flask (magnetic stirring) was charged with 1.0 gram (6.6 mM) 3-amino-2-methylbenzoic acid. A warm mixture of 2.3 mL conc. sulfuric acid in 4.3 mL water was added to the flask, the resulting slurry was cooled below 15° C. in an ice bath, and 6.6 grams of ice was added. The reaction mixture was treated via subsurface addition with a solution of 0.6 gram (8.6 mM) sodium nitrite in 6.6 mL ice water with the reaction temperature maintained at 0-5° C. during the addition. After stirring at 0-5° C. for 30 min., a few crystals of urea were added to decompose the excess nitrite. The reaction mixture was then poured into a room temperature solution of 23.8 grams (102.3 mM) copper (II) nitrate hemipentahydrate in 200 mL water. With vigorous stirring, the reaction mixture was treated with 0.9 gram (6.0 mM) copper (I) oxide. The reaction mixture foamed and changed from turquoise blue to dark green in color. Reaction was left stirring for 30 min. The reaction mixture was extracted with diethyl ether (3×), and the organic extracts were combined. The organic extracts were concentrated to approximately one-fourth the original volume, then extracted with 25 mL 1N sodium hydroxide solution. The layers were separated, and the dark-red aqueous layer was acidified to pH=2 using 1N hydrochloric acid solution. The acidified aqueous layer was then extracted with diethyl ether (3×), and the ether extracts were combined, dried (MgSO4), and concentrated to yield a reddish-colored oil. Purification by flash chromatography on silica gel using a gradient of 0-7% methanol/methylene chloride afforded 0.39 grams (36%) of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClC1C=C(N=C=S)C=C(Cl)C=1C#N.[CH3:29][S:30]([N:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1)(=[O:32])=[O:31].C([BH3-])#N.[Na+]>CO.C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH:15][CH:36]3[CH2:37][CH2:38][N:33]([S:30]([CH3:29])(=[O:32])=[O:31])[CH2:34][CH2:35]3)[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CS(=O)(=O)N1CCC(=O)CC1
Reactant: Nc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Agent: N#Cc1c(Cl)cc(N=C=S)cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)(=O)N1CCC(Nc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)CC1
Reaction time: 2 h
Yield: 8 %

Procedure:
To a stirred solution of N3-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 2 (122 mg, 0.50 mmol) in methanol (8 mL) at rt, was added 1-(methylsulfonyl)piperidin-4-one (89 mg, 0.50 mmol). The mixture was stirred for 2 hrs, after which, sodium cyanoborohydride (94.2 mg, 1.5 mmol) and three drops of acetic acid were added. The reaction mixture was stirred at rt for 6 hrs, then diluted with water (25 mL) and extracted with EtOAc (3×10 mL). The extracts were dried with sodium sulfate and the solvent was removed under reduced pressure. The residue was chromatographed on a silica gel column to give 16 mg (8%) of desired product as a white solid. MS +m/z: 404.9 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].C(Cl)(=O)C([Cl:19])=O.CN(C=O)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:19])=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(C(=O)O)cc1C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)Cl)cc1C(F)(F)F

Procedure:
The title compound was prepared from 4-methoxy-3-trifluoromethylbenzoic acid with oxalyl chloride and DMF in chloroform at room temperature [D. Levin, Chem. Br., 1977, 201] followed by evaporation in vacuo.
Reaction SMILES: O.[OH-].[Li+].C([O:7][CH2:8][CH2:9][CH:10]([N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][C:20]([Br:25])=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:14]=[C:13]1[CH2:26][O:27]C(=O)C)[CH3:11])(=O)C>CO>[Br:25][C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[N:12]([CH:10]([CH3:11])[CH2:9][CH2:8][OH:7])[C:13]([CH2:26][OH:27])=[N:14][C:15]=3[CH:16]=[N:17][C:18]=2[CH:19]=1
Reactant: CC(=O)OCCC(C)n1c(COC(C)=O)nc2cnc3cc(Br)ccc3c21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(CCO)n1c(CO)nc2cnc3cc(Br)ccc3c21
Temperature: 25 °C
Reaction time: 48 h
Yield: 29 %

Procedure:
Lithium hydroxide hydrate (5.3 g, 126 mmol) was added to a solution of 3-{2-[(acetyloxy)methyl]-7-bromo-1H-imidazo[4,5-c]quinolin-1-yl}butyl acetate (9.14 g, 21.0 mmol) in methanol (150 mL). The resulting mixture was stirred for two days at room temperature and filtered. The methanol was removed from the filtrate under reduced pressure. The crude product mixture was partitioned between dichloromethane and 10% aqueous sodium carbonate. The aqueous fraction was extracted with dichloromethane, and the combined organic fractions were concentrated under reduced pressure. The resulting solid was triturated with acetonitrile, isolated by filtration, and washed with cold acetonitrile to provide 2.13 g of 3-[7-bromo-2-(hydroxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butan-1-ol. A portion of this material was mixed with material from a separate run.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9](=[O:26])[NH:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH2:24][CH3:25])[C:16]3[C:21]([C:22]=2[CH:23]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3)(C)(C)C.Cl.C(O)C>>[NH2:7][CH2:8][C:9]([NH:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH2:24][CH3:25])[C:16]3[C:21]([C:22]=2[CH:23]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:26]
Reactant: CCn1c2ccccc2c2cc(NC(=O)CNC(=O)OC(C)(C)C)ccc21
Agent: Cl
Solvent: CCO
Product: CCn1c2ccccc2c2cc(NC(=O)CN)ccc21
Yield: 91.3 %

Procedure:
The [(9-ethyl-9H-carbazol-3-ylcarbamoyl)-methyl]-carbamic acid tert-butyl ester (9.1 g, 25 mmol) was stirred for 1 hour in 1:1 concentrated aqueous HCl/ethanol to give a gray solid that was concentrated under reduced pressure. The residue was then extracted from saturated aqueous Na2CO3 with CH2Cl2, the combined organic layers were dried (Na2SO4) and then concentrated under reduced pressure to afford 2-amino-N-(9-ethyl-9H-carbazol-3-yl)-acetamide (6.1 g, 93%) as an off-white solid. MS m/z @ 268 (M+1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:15][CH2:14][C:13](=[O:16])[C:12]=2[O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][CH:6]=1)(=O)=O.C1CCN2C(=NCCC2)CC1>CO>[CH3:1][S:2][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH2:15][CH2:14][C:13](=[O:16])[C:12]=2[O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:9][CH:10]=1
Reactant: CS(=O)(=O)c1ccc(C2=C(Oc3ccccc3)C(=O)CC2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: CSc1ccc(C2=C(Oc3ccccc3)C(=O)CC2)cc1
Temperature: 60 °C

Procedure:
To the diketone of Step 1 (120 mg) in methanol (80 mL) was added DBU (0.1 mL). The resulting mixture was heated at 60° C. for 18 h. The methanol was then evaporated and to the crude mixture was added saturated aqueous ammonium chloride, the mixture was then extracted with EtOAc, the organic layer was dried over MgSO4, filtered, and the solvent evaporated under vacuum. The residue was purified by silica gel chromatography (20% EtOAc/hexane) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH:3]=1.[CH:14]([O:17][C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][N:19]=1)([CH3:16])[CH3:15].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1COCC1>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[N:5]=[C:6]([C:21]2[CH:20]=[N:19][C:18]([O:17][CH:14]([CH3:16])[CH3:15])=[CH:23][CH:22]=2)[CH:7]=1
Reactant: CC(C)Oc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Clc1cc(Cl)nc(-c2nccs2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2cc(Cl)cc(-c3nccs3)n2)cn1
Reaction time: 6 h
Yield: 46.6 %

Procedure:
To a 2 dram vial equipped with a stir bar was added 2-(4,6-dichloropyridin-2-yl)thiazole (50 mg, 0.22 mmol), 2-isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (85 mg, 0.33 mmol), Pd(dppf)Cl2 (8.0 mg, 11 μmol) and K3PO4 (344 mg, 1.62 mmol). The vial was capped with a septum screw-cap and then placed under N2 atmosphere. To the vial was added THF (1 mL) and water (0.50 mL). The mixture was placed in a 60° C. oil bath with stirring for 6 h. The reaction mixture was diluted with EtOAc (4 mL) and the aqueous phase was decanted away. The organic phase was diluted with EtOAc to a volume of 40 mL. The solution was dried over MgSO4; filtered; then concentrated in vacuo to afford a dark residue. This material was subjected to silica gel chromatography (hexanes:EtOAc, 100:0 to 85:15) to afford 2-(4-chloro-6′-isopropoxy-[2,3′-bipyridin]-6-yl)thiazole as a white solid (34 mg, 47%). 1H-NMR (400 MHz, CDCl3) δ 8.92-8.87 (m, 1H), 8.32-8.25 (m, 1H), 8.13 (d, J=1.8 Hz, 1H), 7.96 (d, J=3.0 Hz, 1H), 7.68 (d, J=1.8 Hz, 1H), 7.50 (d, J=3.0 Hz, 1H), 6.82 (dd, J=8.8, 0.5 Hz, 1H), 5.41 (spt, J=6.2 Hz, 1H), 1.41 (d, J=6.3 Hz, 6H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].C(O)(=O)C.[C:11]([N:18]1[CH2:24][CH2:23][CH2:22][C@H:19]1[CH:20]=O)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>CO>[C:14]([O:13][C:11]([N:18]1[CH2:24][CH2:23][CH2:22][C@H:19]1[CH2:20][NH:1][CH2:2][C:3]([OH:5])([CH3:6])[CH3:4])=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(O)CN
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(O)CNC[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 108.4 %

Procedure:
4.34 g of 1-amino-2-methylpropan-2-ol (48.68 mmol) are placed in 50 ml of MeOH. 2.79 ml of acetic acid (48.68 mmol) and then 4.72 ml of N-Boc-L-prolinal (24.34 mmol), diluted beforehand in 20 ml of MeOH, are successively added dropwise. The reaction mixture is stirred at room temperature for 30 minutes and 3.22 g of sodium cyanoborohydride (48.68 mmol) are then added portionwise. After stirring at room temperature for 18 hours, the medium is poured into 400 ml of saturated aqueous NaHCO3 solution. The aqueous phase is extracted with 3 times 150 ml of DCM. The organic phases are combined, washed with 200 ml of water, with 200 ml of brine, dried over MgSO4, filtered and evaporated. 7.19 g of (S)-2-[(2-hydroxy-2-methyl propylamino)methyl]pyrrolidine-1-carboxylic acid tert-butyl ester are obtained.
Reaction SMILES: N1C=CC=CC=1.Cl.[NH2:8][C:9]1[CH:36]=[CH:35][C:12]([CH2:13][N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=3)[C:15]2=[O:34])=[CH:11][CH:10]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>O.C1COCC1>[C:30]([C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:16]2[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:14]([CH2:13][C:12]3[CH:11]=[CH:10][C:9]([NH:8][S:38]([CH3:37])(=[O:40])=[O:39])=[CH:36][CH:35]=3)[C:15]2=[O:34])=[CH:29][CH:28]=1)([CH3:31])([CH3:32])[CH3:33]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)c1ccc(Cn2c(=O)n(Cc3ccc(N)cc3)c3ccccc32)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(Cn2c(=O)n(Cc3ccc(NS(C)(=O)=O)cc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Pyridine (0.3 mL, 3.72 mmol) was added to a suspension of the hydrochloride of 1-(4-aminobenzyl)-3-(4-tert-butylbenzyl)-1,3-dihydrobenzimidazol-2-one (Q) (717 mg, 1.7 mmol) in abs. THF (20 mL). The reaction mixture was stirred at RT for 10 min, methanesulphonyl chloride (0.13 mL, 1.7 mmol, dissolved in abs. THF (1 mL)) was added within a period of 5 min, and the reaction mixture was again stirred at RT over a period of 17 h. To the reaction mixture there was then added H2O (10 mL) followed, after 10 min, by H2O (100 mL). After an hour the precipitated solid matter was separated through a frit and then dried in vacuo. The desired product N-{4-[3-(4-tert-Butyl-benzyl)-2-oxo-2,3-dihydrobenzoimidazol-1-ylmethyl]phenyl}methanesulfonamide (60) was obtained in a yield of 680 mg (86% of theory, mp: 228-230° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1)(=[O:11])=[O:10].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[C:25]([N+:33]([O-:35])=[O:34])[CH:24]=1>C(Cl)Cl.N1C=CC=CC=1>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[CH:13]=2)(=[O:11])=[O:10])(=[O:30])=[O:31])=[C:25]([N+:33]([O-:35])=[O:34])[CH:24]=1
Reactant: Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Reactant: COc1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2ccccc2NS(=O)(=O)c2cc3ccccc3s2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a solution of benzo[b]thiophene-2-sulfonic acid (2-aminophenyl) amide (1 mmol, prepared as in Example 1) in DCM (2 mL) and pyridine (2 mL), 4-methoxy-2-nitrobenzenesulfonyl chloride (1.1 mmol) was added at RT and the reaction mixture was then allowed to stir at RT overnight. The reaction mixture was then diluted with DCM (10 mL). The organic phase was washed with 10% aqueous HCl (10 mL), water (10 mL) and brine (10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to obtain 348 mg of benzo[b]thiophene-2-sulfonic acid [2-(4-methoxy-2-nitro-benzenesulfonylamino)phenyl]-amide. LC: Tr 1.09 min; MS: 520.7 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8](S(C)(=O)=O)=[C:9]([C:25]#[N:26])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]#[N:24])=[CH:13][CH:12]=1)=[O:5])[CH3:2].[CH3:31][NH:32][CH3:33]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([N:32]([CH3:33])[CH3:31])=[C:9]([C:25]#[N:26])[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]#[N:24])=[CH:15][CH:16]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(S(C)(=O)=O)c(C#N)c1-c1ccc(-c2ccccc2C#N)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(N(C)C)c(C#N)c1-c1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Add 4-cyano-3-(2′-cyano-biphenyl-4-yl)-5-methanesulfonyl-thiophene-2-carboxylic acid ethyl ester (100 mg, 0.23 mmol) to 3 mL of 2N dimethylamine in THF and stir under nitrogen at room temperature for 90 minutes. Evaporate to a tan solid which is used without further purification. MS(ES+, m/e)=402 (M++1); HPLC=89%.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8](=[N:10][OH:11])[CH3:9].F[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[C:21]([C:23]1[CH:28]=[C:27]([CH2:29][CH2:30][CH3:31])[C:26]([O:32][CH3:33])=[CH:25][C:24]=1[CH2:34][CH2:35][CH3:36])=[O:22]>C1COCC1>[CH3:20][O:19][C:17]1[CH:18]=[CH:13][C:14]([C:21](=[O:22])[C:23]2[CH:28]=[C:27]([CH2:29][CH2:30][CH3:31])[C:26]([O:32][CH3:33])=[CH:25][C:24]=2[CH2:34][CH2:35][CH3:36])=[C:15]([O:11][N:10]=[C:8]([CH3:9])[CH3:7])[CH:16]=1
Reactant: CCCc1cc(C(=O)c2ccc(OC)cc2F)c(CCC)cc1OC
Reactant: CC(C)=NO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCc1cc(C(=O)c2ccc(OC)cc2ON=C(C)C)c(CCC)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of potassium tert-butoxide (2.18 g, 19.4 mmol, heat-gunned under high vacuum) in THF (60 mL) was added acetone oxime (1.42 g, 19.4 mmol). The white slurry was stirred at room temperature for 1 h and then a solution of (2-fluoro-4-methoxyphenyl)(4-methoxy-2,5-dipropylphenyl)methanone (2.23 g, 6.47 mmol) in THF (10 mL ) was added. The mixture was stirred at 65° C. for 3 h and then quenched with a small amount of water. Most of the THF was removed in vacuo and extraction was performed in EtOAc (3×60 mL) with 50% saturated brine (50 mL). The crude product was employed in the ensuing cyclization. A portion of the crude product was subjected to preparative TLC (15% EtOAc/hexanes) to yield the title compound as a light green oil: 1H NMR (300 MHz, CDCl3) δ 0.87 (t, 3H, J=7.2 Hz), 0.92 (t, 3H, J=7.1 Hz), 1.42 (s, 3H), 1.48 (m, 2H), 1.60 (m, 2H), 1.89 (s, 3H), 2.46 (t, 2H, J=7.7 Hz), 2.77 (t, 2H, J=7.9 Hz), 3.85 (s, 3H), 3.87 (s, 3H), 6.59 (dd, 1H, J=8.6, 2.5 Hz), 6.68 (s, 1H), 7.08 (d, 1H, J=2.4 Hz), 7.13 (s, 1H), 7.55 (d, 1H, J=8.6 Hz); MS m/e 398 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH2:12])=[NH:11])=[CH:5][CH:4]=1)#[N:2].C([O-])(=O)C.[Na+].C([O:20][C:21](=O)[C:22](=COCC)[C:23](OCC)=O)C.O>CN1CCCC1=O>[O:20]=[C:21]1[CH:22]=[CH:23][NH:12][C:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[N:11]1
Reactant: N#Cc1ccc(NC(=N)N)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1ccc(Nc2nc(=O)cc[nH]2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
A mixture of 64 g (0.4 mol) of (4-cyanophenyl)guanidine, 98.4 g (1.2 mol) sodium acetate and 76.6 g (0.44 mol) diethyl(ethoxymethylene)malonate in 600 ml N-methyl-pyrrolidinone (NMP) was heated to 100° C. and stirred for 1 hour at that temperature. 81 ml of demineralized water was added and the reaction mixture was further heated to reflux temperature. About 120 ml of the solvent was evaporated until the temperature of the reaction mixture reached the range of 155° C. to 160° C. Subsequently the reaction mixture was refluxed during 72 hours. The whole is allowed to cool to 20-25° C. and 25 g filtration aid was added. After stirring the mixture for 1 hour at 20-25° C., the precipitate was filtered off and washed with 50 ml of NMP. The solvent was distilled off under vacuum and the residue was heated to 130° C. 375 ml acetic acid was added dropwise (during 15 minutes) to the heated residue while keeping the temperature at 130° C. After addition of the acetic acid, the mixture was heated to 150° C. and stirred at that temperature for 15 minutes. Subsequently, the mixture was allowed to cool to 20-25° C. The formed precipitate was filtered off and washed with ethanol (1×250 ml and 1×100 ml). 500 ml ethanol was added to the washed precipitate and this mixture was heated and refluxed for 1 hour. After cooling to 20-25° C., the precipitate was filtered off, washed with 100 ml ethanol and dried at 50° C. under vacuum during 16 hours. Yield: 80.5 g of 4-[(1,4-dihydro-4-oxo-2-pyrimidinyl)amino]benzonitrile (75.9% yield).