Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26](=[O:28])[CH3:27])[CH:20]=2)(=[O:17])=[O:16])=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:37])C=1>>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26](=[O:28])[CH3:27])[CH:20]=2)(=[O:17])=[O:16])=[C:9]2[C:14]=1[N+:13]([O-:37])=[CH:12][CH:11]=[CH:10]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cc2cccc(OC(C)=O)c2)c2cccnc12
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CC(=O)Nc1ccc(S(=O)(=O)Cc2cccc(OC(C)=O)c2)c2ccc[n+]([O-])c12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
8-Acetamido-5-(m-acetoxybenzylsulfonyl)-quinoline (3.98 g, 10 mmole) was dissolved in 30 ml of dichlomethane and treated with m-chloroperbenzoic acid (2.03 g). The solution was stirred for 3 days at room temperature. Some m-chlorobenzoic acid which separated was filtered off and the filtrate concentrated to a syrup. On boiling with 40 ml 2-propanol a pale yellow solid was induced to crystallize. After chilling in an ice bath, the solid was filtered off, washed with 2-propanol and ether, and dried to yield 3.8 g (92 percent). The structure was confirmed by NMR.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]2[N:37]=[CH:36][C:35]([C:38]([OH:40])=O)=[CH:34][N:33]=2)[CH2:28][CH2:27]1.CCN(C(C)C)C(C)C.[F:50][C:51]([F:64])([F:63])[C:52]1[NH:53][C:54]2[C:59]([CH:60]=1)=[CH:58][C:57]([CH2:61][NH2:62])=[CH:56][CH:55]=2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:25][CH:26]1[CH2:27][CH2:28][N:29]([C:32]2[N:33]=[CH:34][C:35]([C:38]([NH:62][CH2:61][C:57]3[CH:58]=[C:59]4[C:54](=[CH:55][CH:56]=3)[NH:53][C:52]([C:51]([F:64])([F:50])[F:63])=[CH:60]4)=[O:40])=[CH:36][N:37]=2)[CH2:30][CH2:31]1
Reactant: CC1CCN(c2ncc(C(=O)O)cn2)CC1
Reactant: NCc1ccc2[nH]c(C(F)(F)F)cc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1CCN(c2ncc(C(=O)NCc3ccc4[nH]c(C(F)(F)F)cc4c3)cn2)CC1
Reaction time: 16 h

Procedure:
To a stirred solution of HATU (34.4 mg, 0.090 mmol) in 1 ml DMF was added (2-(4-methyl-1-piperidinyl)-5-pyrimidinecarboxylic acid) (Matrix Scientific, 20 mg, 0.090 mmol) in 0.5 ml DMF, followed by DIPEA (0.016 ml, 0.090 mmol) and finally {[2-(trifluoromethyl)-1H-indol-5-yl]methyl}amine (Intermediate 4, 22.66 mg, 0.090 mmol) in 1 ml DMF. Stirring was continued for 16 hours. 1M citric acid solution (10 ml) was added and the mixture was then extracted with ethyl acetate (20 ml). The organic extract was then washed with 1M citric acid solution (10 ml), brine (10 ml), dried (MgSO4), filtered and evaporated to dryness. The resulting residues where then purified on the MDAP to dryness to give the title compound (19 mg);
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:23])[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:11][C:10]=1[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1)=[O:25].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:23])[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:11][C:10]=1[C:24](=[O:25])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1)=[O:4]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Nc1ccc(C(=O)c2ccc(F)cc2)cc1C(=O)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1)c1ccc(NC(=O)C(Cl)(Cl)Cl)c(C(=O)c2cccc(Cl)c2)c1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
Trichloro-acetylchloride (0.0848 mol) was added dropwise at 5° C. to a mixture of intermediate 3 (0.0707 mol) in DCM (250 ml) under N2 flow. The mixture was stirred at 5° C. for 30 minutes. Triethylamine (0.0848 mol) was added dropwise at 5° C. The mixture was stirred at 5° C. for 1 hour, then at room temperature for 2 hours and poured out into ice water. DCM was added. The mixture was extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was crystallized from diethyl ether/DIPE. The precipitate was filtered off and dried, yielding 33.7 g (95%) of 2,2,2-trichloro-N-[2-(3-chlorobenzoyl)-4-(4-fluorobenzoyl)phenyl]-acetamide (intermediate 4).
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]/[C:4]([CH:6]1[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][CH2:9][C:7]1=[CH2:8])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:8]=[C:7]1[CH2:9][CH2:10][CH2:11][C:12]([CH3:14])([CH3:13])[CH:6]1[CH2:4][CH2:3][CH:2]=[CH2:1]
Reactant: C=C1CCCC(C)(C)C1C(=O)/C=C/C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C=CCCC1C(=C)CCCC1(C)C

Procedure:
A further purification gave a product having b.p. 87°/2.66×102Pa. The product thus obtained was converted into gamma-damascone by isomerization by means of an acid treatment with p-toluenesulfonic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1/[C:23](/[CH3:30])=[CH:24]\[C:25](OCC)=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[OH-].[Na+]>CCOCC.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[CH:23]([CH3:30])[CH2:24][CH2:25][OH:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C(/C)c1cc(OCc2ccccc2)ccc1OCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: CC(CCO)c1cc(OCc2ccccc2)ccc1OCc1ccccc1

Procedure:
A solution of ethyl 3-(2,5-dibenzyloxyphenyl)crotonate (24.1 g., 60 mM) in ether (250 ml.) is added to a mixture of lithium aluminum hydride (3.42 g., 90 mM) and ether (250 ml.). Aluminum chloride (0.18 g., 1.35 mM) is added and the mixture refluxed for 12 hours and then cooled. Water (3.4 ml.), sodium hydroxide (3.4 ml. of 6 N) and water (10 ml.) are then added successively to the reaction mixture. The inorganic salts which precipitate are filtered off and the filtrate is then concentrated in vacuo to give the desired alcohol.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([N+:18]([O-])=O)[CH:9]=2)[CH2:4][CH2:3]1.C(O)C.[H][H]>[Pd].C(O)(=O)C>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[C:10]([NH2:18])[CH:11]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:13]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CN1CCN(c2cc(N)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Into a 100 mL round bottom flask under inert atmosphere was placed 1-methyl-4-(3-nitro-5-(trifluoromethyl)phenyl)piperazine (0.736 g, 2.54 mmol), 10% palladium on carbon (90 mg), ethanol (40 mL), and acetic acid (20 mL). The atmosphere was exchanged with hydrogen gas via balloon. The reaction was allowed to stir 3 days at room temperature, then filtered through celite and concentrated under reduced pressure to afford the crude as an orange oil. The crude mixture was purified via silica column chromatography with a solvent solution of 90%/10%/1% ratio of CH2Cl2/CH3OH/NH4OH, to afford the title compound. MS m/z=260 [M+H]+; Calc'd for C12H16F3N3: 259.3.
Reaction SMILES: C[O:2][C:3]1[CH:17]=[CH:16][C:6]2[N:7]=[C:8]([NH:10][C:11]3[NH:12][CH2:13][CH2:14][N:15]=3)[NH:9][C:5]=2[CH:4]=1.C(OC(=O)C)(=O)C>Br>[OH:2][C:3]1[CH:17]=[CH:16][C:6]2[N:7]=[C:8]([NH:10][C:11]3[NH:12][CH2:13][CH2:14][N:15]=3)[NH:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2nc(NC3=NCCN3)[nH]c2c1
Agent: Br
Solvent: CC(=O)OC(C)=O
Product: Oc1ccc2nc(NC3=NCCN3)[nH]c2c1

Procedure:
2-(5-Methoxybenzimidazolyl)amino-2-imidazoline (prepared as described in Example 22 (2.55 g 0.011 mol) acetic anhydride (60 ml) and hydrogenbromide (48%) (50 ml) were heated under reflux for 4 hours. The mixture was cooled, evaporated under reduced pressure. The resulting sticky solid was dissolved in water and the filtered solution neutralised with sodium bicarbonate. This aqueous solution was extracted with ethyl acetate. The combined extracts were evaporated under reduced pressure to yield a light brown solid (0.87g) m.p. 254°-258°C. Recrystallisation from methanol gave a low recovery of 2-(5-hydroxybenzimidazolyl)amino-2-imidazoline monohydrate (0.16 g) as pale brown microcrystals m.p. 319°C (decomp.).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:31]=[CH:30][C:12]([CH2:13][C:14]3[C:15]4[CH:29]=[CH:28][CH:27]=[CH:26][C:16]=4[S:17][C:18]=3[C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:32]=[S:33]1(=[O:43])[CH2:38][CH2:37][N:36]([CH2:39][C:40](O)=[O:41])[CH2:35][CH2:34]1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.[Cl-].[Na+].O>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:31]=[CH:30][C:12]([CH2:13][C:14]3[C:15]4[CH:29]=[CH:28][CH:27]=[CH:26][C:16]=4[S:17][C:18]=3[C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:40](=[O:41])[CH2:39][N:36]4[CH2:37][CH2:38][S:33](=[O:43])(=[O:32])[CH2:34][CH2:35]4)=[CH:21][CH:20]=3)=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Reactant: O=C(O)CN1CCS(=O)(=O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2cccnc21
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CN1CCS(=O)(=O)CC1)Nc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 92.3 %

Procedure:
3-[4-[2-(1-Pyrrolidinyl)ethoxy]benzyl]-2-(4-aminophenyl)benzo[b]thiophene (50 mg) and (1,1-dioxothiomorpholin-4-yl)acetic acid (30 mg) were dissolved in DMF (2.0 mL), treated with DCC (30 mg) and HOAt (28 mg) sequentially, and allowed to stir at ambient temperature under argon for 19 h. The reaction mixture was diluted with brine (30 mL), extracted with ethyl acetate (20 mL×3). The combined organic layers were dried with sodium sulfate and concentrated. Chromatography with Et3N:MeOH:EtOAc (5:5:90) afforded the title compound (65 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:12][C:11]([OH:22])=[N:10]2)=[CH:5][CH:4]=1.Cl[CH2:24][C:25]([N:27]([CH3:29])[CH3:28])=[O:26]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:12][C:11]([O:22][CH2:24][C:25]([N:27]([CH3:29])[CH3:28])=[O:26])=[N:10]2)=[CH:7][CH:8]=1
Reactant: CN(C)C(=O)CCl
Reactant: COc1ccc(-c2nc(O)nn2-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2nc(OCC(=O)N(C)C)nn2-c2ccc(OC)cc2)cc1
Yield: 72.6 %

Procedure:
2-{[1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazol-3-yl]oxy}-N,N-dimethylacetamide (467 mg, 72.6% yield) was prepared from 1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazol-3-ol and 2-chloro-N,N-dimethylacetamide by the similar manner described for Example 18.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][C:47](=[O:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si](C(C)C)(C(C)C)C(C)C)[CH2:5][C:4]1=[O:66])[CH3:2]>C(#N)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][C:47](=[O:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:66])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(=O)C(OC)C3)C(C)C(O[Si](C(C)C)(C(C)C)C(C)C)CC1=O)C(C)CC2OC
Solvent: CC#N
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(=O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reaction time: 4 h
Yield: 82.6 %

Procedure:
To a stirred solution of 17-ethyl-1-hydroxy-12-[2'-(3"-methoxy-4"-oxocyclohexyl)-1'-methylvinyl]-14-triisopropylsilyloxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]-octacos-18-ene-2,3,10,16-tetraone from Example 19 (870 mg) in acetonitrile (20 ml) was added hydrofluroic acid (48%, 1 ml) at room temperature. The reaction progress was monitored by tlc analysis and after 4 hr. the reaction mixture was quenched with sat'd aqueous sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate three times. Combined organic layers were washed (sat'd NaHCO3, sat'd NaCl), dried (anhydrous Na2SO4), and filtered. Removal of solvent followed by purification (silica gel column chromatography, 50% ethyl acetate/hexane) gave 600 mg of the title compound.
Reaction SMILES: [F:1][CH:2]([F:8])[C:3](OCC)=[O:4].C[O-].[Na+].[CH2:12]1[O:20][C:19]2[CH:18]=[CH:17][C:16]([C:21](=[O:23])[CH3:22])=[CH:15][C:14]=2[O:13]1.Cl>CCOCC>[O:20]1[C:19]2[CH:18]=[CH:17][C:16]([C:21](=[O:23])[CH2:22][C:3](=[O:4])[CH:2]([F:8])[F:1])=[CH:15][C:14]=2[O:13][CH2:12]1
Reactant: CC(=O)c1ccc2c(c1)OCO2
Reactant: CCOC(=O)C(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: O=C(CC(=O)C(F)F)c1ccc2c(c1)OCO2
Reaction time: 16 h

Procedure:
Ethyl difluoroacetate (1.72 g, 11 mmol) was dissolved in ether (25 mL). To the stirred solution was added 25% sodium methoxide (2.38 g, 11 mmol) followed by 3′,4′-(methylenedioxy)acetophenone (1.64 g, 10 mmol). After stirring 16 hours, 1N HCl (25 mL) was added. The organic layer was collected and washed with water (2×25 mL), dried over magnesium sulfate, filtered, and concentrated. The resulting crude dione was used in the next step without further purification of characterization.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:21])[NH:6][C@@H:7]1[CH2:20][C:10]2[NH:11][C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:28][O:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32]Cl>CN(C=O)C.O>[CH:1]([O:4][C:5](=[O:21])[NH:6][C@@H:7]1[CH2:20][C:10]2[N:11]([CH2:32][C:31]3[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=3[O:29][CH3:28])[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2]
Reactant: COc1ccccc1CCl
Reactant: CC(C)OC(=O)N[C@@H]1Cc2[nH]c3ccc(C#N)cc3c2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1Cn1c2c(c3cc(C#N)ccc31)C[C@H](NC(=O)OC(C)C)C2
Temperature: 50 °C
Yield: 98.3 %

Procedure:
A mixture of ((S)-7-cyano-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-carbamic acid isopropyl ester (2.0 g, 7.06 mmol) and cesium carbonate (3.22 g, 9.88 mmol) in DMF (40 mL) is treated with 2-methoxybenzyl chloride (1.16 g, 7.41 mmol). The reaction is heated at 50° C. for 18 h. The reaction is cooled to room temperature and diluted with water (300 mL). The white solid is collected and washed with water. The solid is dried in a 40° C. vacuum oven. After drying, 2.80 g (98%) product is obtained as a white solid. LC-ES/MS m/z 404 [M+H]+, TR=2.83 min.
Reaction SMILES: F[C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][NH:5][C:6]([C@H:8]1[CH2:13][CH2:12][C@@H:11]([CH2:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N)C1C=CC=CC=1>CN(C=O)C>[CH2:4]([NH:5][C:6]([C@H:8]1[CH2:9][CH2:10][C@H:11]([CH2:14][C:15]2[NH:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:12][CH2:13]1)=[O:7])[C:3]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:2]=1
Reactant: O=C(NCc1ccccc1F)[C@H]1CC[C@@H](Cc2nc3ccccc3[nH]2)CC1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: NCc1ccccc1
Product: O=C(NCc1ccccc1)[C@H]1CC[C@H](Cc2nc3ccccc3[nH]2)CC1
Reaction time: 15 h

Procedure:
Example 8 was prepared by the following procedure. To a solution of trans4-(1H-benzimidazol-2-ylmethyl)-cyclohexanecarboxylic acid (F) (444 mg, 1.72 mmol), EDC (328 mg, 1.72 mmol) and HOAt (234 mg, 1.72 mmol) in anhydrous DMF (4 mL) was added benzylamine (184 mg, 1.72 mmol). The resulting reaction mixture was stirred for 15 h. The reaction mixture was partitioned between saturated aqueous NaHCO3 and EtOAc and the organic layer washed 2× with water, and dried with MgSO4. Concentration gave trans4-(1H-benzimidazol-2-ylmethyl)-cyclohexanecarboxylic acid benzylamide (400 mg, 67%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.49 (br s, 2 H), 7.30-7.17 (m, 7 H), 4.34 (s, 2 H), 2.78 (d, 2 H), 2.21 (m, 1 H), 1.84 (m, 5 H), 1.55 (q, 2 H), 1.16 (q, 2 H); mass spectrum m/z 348 [(M+H)+; calcd for C22H26N3O: 348].
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[CH2:9][CH2:8][CH2:7]2.[Br:17]Br>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:5]([Br:17])=[C:6]2[C:11]=1[N:10]([CH3:12])[CH2:9][CH2:8][CH2:7]2
Reactant: BrBr
Reactant: COC(=O)c1ccc2c(c1N)N(C)CCC2
Solvent: ClCCl
Product: COC(=O)c1cc(Br)c2c(c1N)N(C)CCC2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of methyl 8-amino-1-methyl-1,2,3,4-tetrahydroquinoline-7-carboxylate (1.05 g, 4.77 mmol) in CH2Cl2 (19 mL) at 0° C. was added Br2 (1.0 M in CH2Cl2, 4.77 mL, 4.77 mmol). The mixture was warmed slowly to rt and stirred at rt for 20 min. The resulting solution was quenched with 10% aqueous Na2S2O3 (1 mL), basified with 10% aqueous Na2CO3, and extracted with CH2Cl2. The combined extracts were dried (Na2SO4) and concentrated to afford methyl 8-amino-5-bromo-1-methyl-1,2,3,4-tetrahydroquinoline-7-carboxylate in pure form.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:6]=2[CH:17]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](B(O)O)=[CH:28][CH:27]=[N:26]2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[C:29]([C:2]3[CH:3]=[CH:4][C:5]4[N:9]=[CH:8][N:7]([C:10]5[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=5)[C:6]=4[CH:17]=3)=[CH:28][CH:27]=[N:26]2)=[CH:23][CH:24]=1
Reactant: OB(O)c1ccnn1-c1ccc(Cl)cc1
Reactant: Fc1ccc(-n2cnc3ccc(Br)cc32)cc1
Product: Fc1ccc(-n2cnc3ccc(-c4ccnn4-c4ccc(Cl)cc4)cc32)cc1

Procedure:
The title compound, off-white solid (28 mg, 21%), MS (ISP) m/z=389.4 [(M+H)+], mp 180° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-(4-fluoro-phenyl)-1H-benzo[d]imidazole (intermediate G) (100 mg, 344 μmol) and 1-(4-chloro-phenyl)-1H-pyrazol-5-ylboronic acid (intermediate D) (84.0 mg, 378 μmol).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:33]=[CH:34][CH:35]=1)[CH2:8][O:9][N:10]=[C:11]1[C:14]([CH3:16])([CH3:15])[C:13]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[C:12]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([O:3]C)=[O:2].[Li+].[OH-]>C1COCC1.CO.CCOC(C)=O.Cl>[C:1]([C:5]1[CH:6]=[C:7]([CH:33]=[CH:34][CH:35]=1)[CH2:8][O:9][N:10]=[C:11]1[C:14]([CH3:15])([CH3:16])[C:13]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[C:12]1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([OH:3])=[O:2]
Reactant: COC(=O)c1cccc(CON=C2C(c3ccccc3)=C(c3ccc(S(C)(=O)=O)cc3)C2(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)C(=NOCc2cccc(C(=O)O)c2)C(c2ccccc2)=C1c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C

Procedure:
A solution of methyl ester from Example 52 (90 mg) in THF (2 mL) and MeOH (1 mL) was treated with LiOH (2N, 276 μL ). The mixture was heated at reflux for 18 hr, cooled to r.t. and diluted with EtOAc and HCl 1N. The organic phase was washed with brine, dried (MgSO4) and the solvent evaporated to give the title compound as white foam; 1H NMR (300 MHz, Ace-d6): δ 1.64 (s,6H), 3.17 (s, 3H), 5.26 (s, 2H), 7.39 (m, 3H), 7.51 (t, 1H), 7.70 (m, 3H),7.86 (d, 2H), 8.0 (m, 3H), 8.15 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9](Cl)=[O:10])[CH2:6]1.[OH-].[NH4+:18]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]([NH2:18])=[O:10])[CH2:6]1
Reactant: [NH4+]
Reactant: O=C(Cl)N1CC(Oc2ccc(Cl)cc2Cl)C1
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)N1CC(Oc2ccc(Cl)cc2Cl)C1
Reaction time: 5 h
Yield: 87.9 %

Procedure:
A stirred solution of 4.8 g (0.017 mole) of 3-(2,4-dichlorophenoxy)-1-azetidinecarbonyl chloride in 20 mL of tetrahydrofuran was treated with 3.0 mL (0.05 mole) of 57% ammonium hydroxide. After stirring for 5 h, the reaction mixture was diluted with 200 mL of water and the precipitated solid collected by filtration (4.1 g). The crude product was recrystallized from acetonitrile/water to yield 3.9 g (87.9%) of white crystals, mp 169°-170° C.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[CH:10]2)=[CH:5][CH:4]=1.[NH2-:13].[Na+].C(OCC)(=O)C.[BrH:21]>C1(C)C(C)=CC=CC=1>[BrH:21].[NH2:13][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([OH:2])[CH:12]=2)[CH:7]=[CH:8][N:9]=1
Reactant: COc1ccc2ccncc2c1
Reactant: [NH2-]
Agent: Br
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: Nc1nccc2ccc(O)cc12
Temperature: 140 °C
Reaction time: 1 h

Procedure:
5.6 g (35.2 mmol) of 7-methoxyisoquinoline was dissolved in 200 ml of xylene. 26.6 ml (176 mmol) of N,N,N′,N′-tetramethylenediamine and 7.28 g (186 mmol) of sodium amide were added to the obtained solution, and they were stirred at 140° C. for 1 hour. After the treatment with ethyl acetate as the extracting solvent in an ordinary manner, 50 ml of hydrobromic acid was added to the obtained crude product and they were stirred at 140° C. overnight. The solvent was evaporated to obtain the title compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([C:8]([F:11])([F:10])[F:9])[CH:4]([NH2:7])[CH2:5][OH:6].N1C=CC=CC=1.[Cl:20][C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[S:24][C:25]=1[Cl:26]>C1COCC1>[Cl:20][C:21]1[CH:22]=[C:23]([S:27]([NH:7][CH:4]([CH2:5][OH:6])[CH:3]([C:8]([F:9])([F:10])[F:11])[C:2]([F:12])([F:13])[F:1])(=[O:29])=[O:28])[S:24][C:25]=1[Cl:26]
Reactant: NC(CO)C(C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)s1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=S(=O)(NC(CO)C(C(F)(F)F)C(F)(F)F)c1cc(Cl)c(Cl)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 9 %

Procedure:
A solution of 3,3,3-trifluoro-2-(trifluoromethyl)-1-(hydroxymethyl)propylamine (0.192 g, 0.9 mmol) in THF (1 mL) was stirred under nitrogen at 25° C. Pyridine (0.147 mL, 1.82 mmol) was added followed by 4,5-dichlorothiophene-2-sulfonyl chloride (0.226 g, 0.391 mmol) in THF (1 mL), and the resulting solution stirred for 18 h at 25° C. After concentration, the residue was taken up in EtOAc (15 mL) and washed with 1 N aq. HCl (10 mL), brine (10 mL), and then dried (Na2SO4). After concentration, the crude product was purified by preparatory TLC, eluent: 30:70 EtOAc:hexanes, to provide 4,5-dichloro-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide as a white solid (0.037 g, 9% yield, racemic mixture). Mass Spectrum (−ESI): 423.9 (M−H)−.