Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15]([CH:17]1[CH2:27][CH:26]2[N:28]([S:29]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[CH:19]([CH2:20][C:21]3[NH:22][N:23]=[CH:24][C:25]=32)[CH2:18]1)=[O:16])[CH3:13]>N1C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:22]2[C:21]3[CH2:20][CH:19]4[N:28]([S:29]([C:32]5[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=5)(=[O:31])=[O:30])[CH:26]([C:25]=3[CH:24]=[N:23]2)[CH2:27][CH:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])[CH2:18]4)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:23]2[CH:24]=[C:25]3[CH:26]4[N:28]([S:29]([C:32]5[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=5)(=[O:30])=[O:31])[CH:19]([CH2:20][C:21]3=[N:22]2)[CH2:18][CH:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])[CH2:27]4)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CC2Cc3[nH]ncc3C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1CC2Cc3c(cnn3S(=O)(=O)c3ccc(Cl)cc3)C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Product: CCOC(=O)C1CC2Cc3nn(S(=O)(=O)c4ccc(Cl)cc4)cc3C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 116.3 %

Procedure:
4-Chlorobenzenesulfonyl chloride (0.315 g, 1.49 mmol) was added to a solution of ethyl 10-(4-chlorophenyl)sulfonyl-4,5,6,7,8,9-hexahydro-1H-4,8-epiminocycloocta[c]pyrazole-6-carboxylate (8) (0.51 g, 1.24 mmol) in pyridine (5 mL) and the resulting mixture was stirred at room temperature for 1 h. The resulting solution was diluted with CH2Cl2 and washed with aqueous 1N Ha then saturated aqueous NaHCO3. The organic phase was dried (Na2SO4), filtered, concentrated and purified by silica gel column chromatography (eluant hexane/EtOAc, 20/1 to 1/1) to give ethyl 1,10-bis[(4-chlorophenyl)sulfonyl]-4,5,6,7,8,9-hexahydro-1H-4,8-epiminocycloocta[c]pyrazole-6-carboxylate and ethyl 2,10-bis[(4-chlorophenyl)sulfonyl]-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-6-carboxylate (57) (0.721 mmol, 1.23 mmol, quant). MS (ESI) 584.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[N:10][C:9]=2[O:17][C@@H:18]([CH3:23])[C:19]([F:22])([F:21])[F:20])=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.Cl.[CH3:34][O:35]/[N:36]=[C:37](\[CH:40]1[CH2:42][CH2:41]1)/[CH2:38][NH2:39]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([NH:39][CH2:38]/[C:37](/[CH:40]3[CH2:42][CH2:41]3)=[N:36]/[O:35][CH3:34])=[O:16])[CH:11]=[N:10][C:9]=2[O:17][C@@H:18]([CH3:23])[C:19]([F:22])([F:20])[F:21])=[CH:4][CH:3]=1
Reactant: C[C@H](Oc1ncc(C(=O)O)nc1-c1ccc(Cl)cc1)C(F)(F)F
Reactant: CO/N=C(/CN)C1CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CO/N=C(/CNC(=O)c1cnc(O[C@@H](C)C(F)(F)F)c(-c2ccc(Cl)cc2)n1)C1CC1
Yield: 45.5 %

Procedure:
To a suspension of (S)-6-(4-chlorophenyl)-5-(1,1,1-trifluoropropan-2-yloxy)-pyrazine-2-carboxylic acid (0.2 g, 577 μmol, Eq: 1.00) in dimethylformamide (4 ml) were added under argon TBTU (204 mg, 635 μmol, Eq: 1.1), ethyldiisopropylamine (373 mg, 478 μl, 2.88 mmol, Eq: 5) and (E)-2-amino-1-cyclopropylethanone O-methyl oxime hydrochloride (104 mg, 635 μmol, Eq: 1.1) and the mixture was stirred at room temperature for 18 h overnight. The reaction mixture was partitioned between ethyl acetate and 10% aqueous citric acid, the phases were separated and the organic phase was dried over MgSO4; filtered; concentrated and purified by flash chromatography (silica gel, 20 g, 5% to 50% ethyl acetate in heptane) to yield the title compound as white crystals (0.12 g, 45.5%, m.p.: 149-152° C.). MS (EI): 457.1 (M+H).
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:9][CH2:10][S:11][CH3:12])[C:6]([OH:8])=O)(=[O:3])[CH3:2].S(Cl)(Cl)=O.C(N(CC)CC)C.[CH2:24]([NH2:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>ClCCl>[C:1]([O:4][CH:5]([CH2:9][CH2:10][S:11][CH3:12])[C:6]([NH:36][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:8])(=[O:3])[CH3:2]
Reactant: CSCCC(OC(C)=O)C(=O)O
Reactant: CCCCCCCCCCCCN
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCNC(=O)C(CCSC)OC(C)=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-acetoxy-4-(methylthio)butanoic acid (17.1 g, 89 mmol) in dichloromethane (350 mL) at 0° C. was added thionyl chloride (32.4 mL, 445 mmol) dropwise over 1 hr. The reaction was stirred at 0° C. for 1.5 hrs then the cooling bath was removed and the reaction was warmed to room temperature with stirring for 3 hrs. The solvent was evaporated and the resulting oil was dried under high vacuum for 1 hr to give an orange oil. A solution of the resulting oil in dichloromethane (˜30 mL) was added to a solution of triethylamine (24.8 mL, 178 mmol) and dodecylamine (20.5 mL, 89 mmol) in dichloromethane (150 mL) at 0° C. and the reaction was allowed to warm to room temperature with stirring overnight. The reaction was evaporated, re-dissolved in EtOAc (300 mL) and washed with 1N HCl (3×150 mL), saturated sodium bicarbonate (3×150 mL), and brine (1×150 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated to give an oil. The oil was purified by silica gel chromatography with 0-40% EtOAc/heptane to give a yellow oil. (22.5 g, 70%). m/z 360 (MH+).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH3:15])=[CH:9][CH:8]=1.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.[Cl-].[NH4+]>C1COCC1.O>[CH3:7][CH2:8][CH2:9][CH:10]([CH3:13])[CH3:11].[CH2:13]([C:10]1[CH:11]=[CH:12][C:7]([B:16]([OH:21])[OH:17])=[CH:8][CH:9]=1)[CH2:14][CH3:15]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CCCC(C)C
Product: CCCc1ccc(B(O)O)cc1
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
n-Butyl lithium (34 ml of a 1.6M solution in hexanes) was added dropwise to a stirred solution of 1-bromo-4-propylbenzene (9.96 g) in dry THF (30 ml) at -70° C. under argon. The reaction was stirred for 1 hour at -70° C. before addition of triisopropyl borate (12.7 ml) and then stirred for a further 90 minutes at -70° C. before addition of saturated aqueous ammonium chloride solution (30 ml). The reaction was stirred at -70° C. for a further 10 minutes, water (100 ml) was added and the reaction was allowed to warm to ambient temperature. The reaction mixture was extracted with diethyl ether (3×50 ml), the combined organic layers were dried (MgSO4) and then the solvent was removed by evaporation. Trituration of the resultant clear oil with isohexane gave 4-propylphenylboronic acid as a white solid, 6.7 g, mass spectrum (negative electrospray (-ve ESP)): 163 (M-H)-.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[Li]CCCC.CCCCCC.[O:20]=[C:21]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:22]1>CCOCC.O>[Br:8][C:4]1[N:3]=[C:2]([C:21]2([OH:20])[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[CH2:23][CH2:22]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCCC(O)(c2cccc(Br)n2)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
To a solution of 2,6-dibromopyridine (0.2 g, 0.84 mmol) in Et2O (20 mL) at −78° C. was added 2.5 M solution of n-BuLi in hexane (3.7 mL, 0.928 mmol) over 30 min. The mixture was stirred at −78° C. for 30 minutes. To it was dropped tert-butyl 4-oxoazepane-1-carboxylate (180 mg, 084 mmol) in Et2O (20 mL) over 15 minutes. After the mixture was stirred for one hour, to it was added H2O (100 mL). The aqueous layer was extracted with EtOAc (100 mL×2). The combined organic layers were washed with 10% solution of NaOH and brine, dried over MgSO4, concentrated under reduced pressure. The crude product was purified by silica gel chromatography using petroleum ether/EtOAc (9:1) as eluting solvents to afford tert-butyl 4-(6-bromopyridin-2-yl)-4-hydroxyazepane-1-carboxylate as an oil (200 mg, 62.5%). MS (ESI) m/z: 371 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])([C:6]2[N:7]([CH3:11])[CH:8]=[CH:9][CH:10]=2)O)[CH2:3][CH2:2]1.[Br:19][Si](C)(C)C.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[Br:19][CH2:3][CH2:2][CH:1]=[C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[C:6]1[N:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1
Reactant: C[Si](C)(C)Br
Reactant: Cc1ccccc1C(O)(c1cccn1C)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccccc1C(=CCCBr)c1cccn1C
Temperature: -70 °C
Reaction time: 1.5 h
Yield: 87.4 %

Procedure:
Cyclopropyl-(2-methylphenyl)-(N-methylpyrrol-2-yl)methanol (9.9 g, 0.041 mole) was dissolved in dichloromethane (250 ml) and cooled to -70° C. under nitrogen. Bromotrimethylsilane (6.4 g, 0.042 mole) in dichloromethane (250 ml) was added within 30 min. The reaction mixture was stirred at -70° C. for another 90 min. Pyridine (3.5 ml) was added and when the mixture had reached room temperature, saturated sodium bicarbonate solution (100 ml) was added. The phases were separated and the organic phase was dried (MgSO4) and evaporated leaving the title compound as an oil (10.9 g).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([O:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])=[O:4].[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][C@H:22]1[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[F:1][C:2]([F:13])([F:12])[C:3]([OH:5])=[O:4].[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:6](=[O:11])[C:7]([F:8])([F:9])[F:10])[CH2:23][C@H:22]1[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: NC1CCN(Cc2ccccc2)[C@H](Cc2ccccc2)C1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC1CCN(Cc2ccccc2)[C@H](Cc2ccccc2)C1)C(F)(F)F
Product: O=C(O)C(F)(F)F
Reaction time: 1 h

Procedure:
5.1 ml (36.8 mmol) of trifluoroacetic anhydride are added to a solution of 6.88 g (24.5 mmol) of (2R,4RS)-1,2-dibenzyl-4-piperidinamine in 20 ml of methylene chloride in an ice-water bath, and stirring is then completed at room temperature for 1 hour. The reaction mixture is evaporated to dryness, resulting in the title compound as pale yellow foam; TLC: methylene chloride/methanol/conc. ammonia (190:9:1), Rf =0.41 (cis) and 0.57 (trans) diastereomer; MS: M+ -91 (benzyl)=285 (14%).
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]([OH:24])=[O:23])[CH2:17][CH2:16]1)=O.[CH3:25][NH:26][S:27]([C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34](=[O:39])[CH2:33]2)(=[O:29])=[O:28]>>[CH3:25][NH:26][S:27]([C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34](=[O:39])/[C:33]/2=[CH:1]\[C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]([OH:24])=[O:23])[CH2:17][CH2:16]1)(=[O:29])=[O:28]
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1[nH]c2c(c1CCCN1CCN(CC(=O)O)CC1)CCCC2
Product: CNS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c3c(c1CCCN1CCN(CC(=O)O)CC1)CCCC3)C(=O)N2
Yield: 80 %

Procedure:
{(4-[3-(2-Formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propyl]-piperazin-1-yl}-acetic acid (50 mg, 0.15 mmol) was condensed with 5-methylaminosulfonyloxindole (40 mg, 0.15 mmol) following the procedure used in Example 1. The formed solid was purified by flash chromatography, eluting with (dichloromethane: methanol 6:1 followed by 4:1:0.01 acetic acid) to give 65 mg of the desired product.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.BrN1C(=[O:19])CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1N2CN3CN(C2)CN1C3>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[CH3:12][C:11]1[C:2]([CH:1]=[O:19])=[CH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2ccccc2cc1C
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1cc2ccccc2cc1C=O

Procedure:
2,3-Dimethylnaphthalene (20.0 g), N-bromosuccinimide (22.8 g) and benzoyl peroxide (0.2 g) were refluxed in carbon tetrachloride (160 ml) for 12 hr. After cooling, the mixture was filtered. The filtrate was evaporated under reduced pressure and the residue was dissolved in chloroform. This solution was added dropwise to a vigorously stirred solution of hexamethylenetetramine (1.2 equiv) in chloroform (100 ml) and the mixture was heated at reflux for 12 hr. After cooling the salt was filtered off and was washed with several portions of hexane. The dried salt was heated at reflux with a 50% aqueous acetic acid solution (20 ml/g) for 2 hr. Concentrated hydrochloric acid (2 ml/g) was added and the mixture was heated at reflux for a further 15 min. The solution was poured onto ice-water and the resulting mixture was extracted with ether. The dried (MgSO4) organic fraction was evaporated and the residue was purified by recrystallization (twice) from hexane to give 3-methylnaphthalene-2-carboxaldehyde as cream-coloured clusters, mp 119° C. Pmr spectrum (CDCl3 ; δ in ppm): 2.75 (3H,s); 7.32-7.98 (5H,m); 8.24 (1H,s); 10.27 (1H,s). 6-Methylnaphthalene-2-carboxaldehyde was similarly prepared from 2,6-dimethylnaphthalene and was obtained as a white solid, mp 120° C. Pmr spectrum (CDCl3; δ in ppm): 2.58 (3H,s); 7.38-8.07 (5H,m); 8.30 (1H,s); 10.14 (1H,s).
Reaction SMILES: [BH4-].[Na+].Cl[CH:4]([CH3:27])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:26])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)=[CH:9][CH:8]=1)=[O:6].[OH-].[Na+]>CO>[CH3:25][O:24][C:18]1[CH:17]=[C:16]([CH2:15][C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([CH:5]3[CH:4]([CH3:27])[O:6]3)=[CH:8][CH:9]=2)=[O:26])[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)C(C)Cl)cc2)cc1OC
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CC(=O)Nc2ccc(C3OC3C)cc2)cc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
Sodium tetrahydroborate (0.0502 mol) was added portionwise at 0° C. to a mixture of (±)-N-[4-(2-chloro-1-oxopropyl)phenyl]-3,4-dimethoxybenzeneacetamide (0.0502 mol) in methanol (280 ml). The mixture was stirred at 0° C. for 1 hour, then poured out into a mixture of NaOH (280 ml) and ice, stirred for 1 hour and extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 15.48 g (94%) of (±)-3,4-dimethoxy-N-[4-(3-methyl-2-oxiranyl)phenyl]benzeneacetamide (interm. 11).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[C:15](Cl)(=O)C.[Al+3].[Cl-].[Cl-].[Cl-].[CH2:23]1C[O:26][CH2:25][CH2:24]1>CS(C)=O>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([O:7][C:4]2[CH:3]=[CH:2][C:1]([C:25]([OH:26])([CH3:15])[C:24]#[CH:23])=[CH:6][CH:5]=2)=[CH:13][CH:12]=1
Reactant: CC(=O)Cl
Reactant: Clc1ccc(Oc2ccccc2)cc1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CS(C)=O
Product: C#CC(C)(O)c1ccc(Oc2ccc(Cl)cc2)cc1
Reaction time: 1 h

Procedure:
A solution of 2.47 g. of 4'-chloro-4-acetyldiphenyl ether, which can be prepared from 4-chlorodiphenyl ether and acetyl chloride in the presence of AlCl3, in 6 ml. of THF and 2 ml. of DMSO is added dropwise to a suspension of 1.38 g. of lithium acetylide/ethylenediamine complex in a mixture of 3 ml. of absolute THF and 4 ml. of absolute DMSO, while acetylene is bubbled through the mixture. The mixture is stirred for one hour while under nitrogen blanketing. An aqueous solution of ammonium chloride is added to the solution, which contains lithium 3-[4-(4-chlorophenoxy)phenyl]-but-1-yn-3-olate and the mixture is poured into water and worked up in the customary manner to give 3-[4-(4-chlorophenoxy)phenyl]-3-hydroxybut-1-yne, m.p. 55°-57°.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=2[Cl:19])[N:5]=[C:4]([C:20]#[N:21])[CH:3]=1.[I:22]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([O:14][C:15]([F:17])([F:16])[F:18])=[CH:9][C:8]=2[Cl:19])[N:5]=[C:4]([C:20]#[N:21])[C:3]=1[I:22]
Reactant: N#Cc1cc(N)n(-c2c(Cl)cc(OC(F)(F)F)cc2Cl)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: N#Cc1nn(-c2c(Cl)cc(OC(F)(F)F)cc2Cl)c(N)c1I

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethoxyphenyl)pyrazole (4.17 g) in acetonitrile (20 ml) at room temperature was added N-iodosuccinimide (2.79 g). After 15 minutes the mixture was evaporated to dryness and the residual orange solid was taken up in dichloromethane. The solution was washed with water, then brine, then dried (Na2SO4) and evaporated to provide the title compound as a pale orange solid, m.p. 149.5-150.0° C.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.C([O-])([O-])=O.[K+].[K+].[C:17]([O:21][C:22](=[O:47])[CH2:23][N:24]1[C:28]2[CH:29]=[CH:30][C:31]([NH:33][S:34]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])=[CH:32][C:27]=2[N:26]=[C:25]1[CH2:44][CH2:45][CH3:46])([CH3:20])([CH3:19])[CH3:18]>CC#N.CCOC(C)=O.O>[C:17]([O:21][C:22](=[O:47])[CH2:23][N:24]1[C:28]2[CH:29]=[CH:30][C:31]([N:33]([CH2:4][C:3]3[CH:6]=[CH:7][CH:8]=[C:9]([Cl:10])[C:2]=3[Cl:1])[S:34]([C:37]3[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=3)(=[O:35])=[O:36])=[CH:32][C:27]=2[N:26]=[C:25]1[CH2:44][CH2:45][CH3:46])([CH3:20])([CH3:19])[CH3:18]
Reactant: CCCc1nc2cc(NS(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Reactant: ClCc1cccc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CCCc1nc2cc(N(Cc3cccc(Cl)c3Cl)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2,3-Dichlorobenzyl chloride (0.27 mmol) and K2CO3 (63 mg, 0.45 mmol) were added to a solution of [5-(4-fluoro-benzenesulfonylamino)-2-propyl-benzoimidazol-1-yl]-acetic acid tert-butyl ester (40 mg, 0.09 mmol) in CH3CN (1 mL), and stirred overnight at 80° C. The reaction mixture was diluted with EtOAc and H2O, and then filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was carried onto the next reaction without any further purification or characterization.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]4[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=4[CH3:20])[C:5]=3[C:4]=2[CH:3]=1.[F:25][C:26]1[C:27]([NH:41][CH3:42])=[N:28][CH:29]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:31]=1>>[F:25][C:26]1[CH:31]=[C:30]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]5[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=5[CH3:20])[C:5]=4[C:4]=3[CH:3]=2)[CH:29]=[N:28][C:27]=1[NH:41][CH3:42]
Reactant: Cc1nn(C)c(C)c1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CNc1ncc(B2OC(C)(C)C(C)(C)O2)cc1F
Product: CNc1ncc(-c2ccc3ncc4c(c3c2)n(-c2c(C)nn(C)c2C)c(=O)n4C)cc1F

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate H) and [3-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-methyl-amine (stage 141.1.1) to give the title compound as a yellow foam. (HPLC: tR 2.15 min (Method A); M+H=432 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.92 (s, 1H), 8.05-7.99 (m, 2H), 7.89-7.84 (m, 1H), 7.41-7.36 (m, 1H), 7.35-7.33 (m, 1H), 6.92-6.86 (m, 1H), 3.83 (s, 3H), 3.58 (s, 3H), 2.88 (d, 3H), 2.07 (s, 3H), 1.91 (s, 3H))
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=1[C:17]([F:20])([F:19])[F:18].O[N:22]=[C:23]([C:25]1[CH:33]=[CH:32][C:28]2[NH:29][CH:30]=[N:31][C:27]=2[CH:26]=1)[NH2:24]>>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]2[O:14][N:22]=[C:23]([C:25]3[CH:33]=[CH:32][C:28]4[NH:29][CH:30]=[N:31][C:27]=4[CH:26]=3)[N:24]=2)=[CH:10][C:9]=1[C:17]([F:19])([F:18])[F:20]
Reactant: C[C@H]1CCCCN1c1ccc(C(=O)O)cc1C(F)(F)F
Reactant: NC(=NO)c1ccc2[nH]cnc2c1
Product: C[C@H]1CCCCN1c1ccc(-c2nc(-c3ccc4[nH]cnc4c3)no2)cc1C(F)(F)F

Procedure:
Title compound was prepared following general procedure 3 starting from Intermediate 27 (300 mg; 1.04 mmol; 1 eq.), and Intermediate 1 (183.98 mg; 1.04 mmol; 1 eq.). After evaporation of the solvents, the solid residue was triturated with ACN, filtered and dried under vacuum to give the title compound as an off-white solid. 1H NMR (DMSO-d5) δ 12.78 (br m, 1H), 8.50-8.26 (m, 2H), 8.04-7.68 (m, 3H), 3.16 (m, 1H), 3.02-2.90 (m, 1H), 2.69-2.55 (m, 1H), 1.87-1.20 (m, 6H), 0.78 (d, J=6.1 Hz, 3H). HPLC (Method A), Rt 5.04 min (Purity: 98.4%). LC/MS (Method B): 426.3 (M+H)−; 428.1 (M+1-1)+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([CH:8]([CH3:22])[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([F:21])[CH:10]=2)[O:5][N:4]=1.[C:23]([O-:26])(=[O:25])[CH3:24].[K+]>CN(C=O)C.O>[C:23]([O:26][CH2:2][C:3]1[N:7]=[C:6]([CH:8]([CH3:22])[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([F:21])[CH:10]=2)[O:5][N:4]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)[O-]
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CCl)no1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCc1noc(C(C)c2ccc(-c3ccccc3)c(F)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
To a solution of 1.32 g of 3-chloromethyl-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole in 30 ml of dry DMF was added 1.58 g of potassium acetate. After stirring at room temperature overnight, the reaction mixture was diluted with water and extracted with benzene. The organic phase was washed with water, dried over sodium sulfate and evaporated. The residue was chromatographed over silica gel using benzene to yield 0.96 g of 3-acetoxymethyl-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole, nD23 1.5635.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][NH:18][CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]([O:33][C:34](=[O:39])[NH:35][CH2:36][CH:37]=O)([CH3:32])([CH3:31])[CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH2:37][CH2:36][NH:35][C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:39])[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCN(Cc1nc2ccccc2n1C(=O)OC(C)(C)C)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.7 %

Procedure:
To a solution of 2-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzoimidazole-1-carboxylic acid tert-butyl ester (0.378 g, 1.00 mmol) and (2-oxo-ethyl)-carbamic acid tert-butyl ester (0.159 g, 1.00 mmol) in dichloromethane (5 mL) was added sodium triacetoxyborohydride (0.223 g, 1.05 mmol). The mixture was stirred at room temperature for 15 h and then poured into saturated aqueous NaHCO3 (30 mL). The mixture was extracted with chloroform (3×20 mL). The extracts were dried over Na2SO4 and concentrated. Purification of the crude material by column chromatography on silica gel (98:1:1 CH2Cl2—CH3OH—NH4OH) provided 499 mg (96%) of 2-{[(2-tert-butoxycarbonylamino-ethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylic acid tert-butyl ester as a yellow foam. 1H NMR (CDCl3) δ 1.48 (s, 9 H), 1.64 (s, 9 H), 1.69-1.85 (m, 2 H), 1.94-1.99 (m, 1 H), 2.24 (m, 1 H), 2.61-2.87 (m, 3 H), 3.09-3.19 (m, 3 H), 4.07 (dd, J=9.9 Hz, 5.7 Hz, 1 H), 4.26 (d, J=16.2 Hz, 1 H), 4.52 (d, J=16.2 Hz, 1 H), 6.98 (dd, 1H, J=7.7 Hz, 4.7 Hz, 1 H), 7.26-7.32 (m, 3 H), 7.57 (brs, 1 H), 7.74 (m, 1 H), 7.86 (m, 1 H), 8.41 (d, J=3.9 Hz, 1 H).