Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH3:19])[C:7]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:9]=1.B1([C:26]2[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=2)OCCCO1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[C:7]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:9]=1
Reactant: c1cncc(B2OCCCO2)c1
Reactant: Cc1cncc(Cl)c1-c1nc(-c2ccccn2)no1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1cncc(-c2cccnc2)c1-c1nc(-c2ccccn2)no1
Yield: 6.2 %

Procedure:
A mixture of 5-(3-chloro-5-methyl-pyrid-4-yl)-3-(2-pyridyl)-1,2,4-oxadiazole (75 mg, 0.275 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (75 mg, 0.46 mmol), and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, 30 mg, 0.026 mmol), in a solution of ethylene glycol dimethyl ether (1 mL) and 2M sodium carbonate (1 mL) was heated in a sealed vial at 100° C. for 1 hour. The reaction was cooled, diluted with dichloromethane, washed with water and saturated brine, filtered, and concentrated. Silica gel chromatography using a gradient of 40% ethyl acetate in hexane to 100% ethyl acetate afforded 5.4 mg (7.4%) of 5-[3-methyl-5-(3-pyridyl)-pyrid-4-yl]-3-(2-pyridyl)-1,2,4-oxadiazole. 1H-NMR (CDCl3), δ (ppm): 9.32 (s, 1H), 8.87 (d, 1H), 8.70 (d, 1H), 8.30 (m, 2H), 8.25 (s, 1H), 8.00 (s, 1H), 7.90 (d, 1H), 7.47 (m, 2H), 2.77 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].Cl.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[CH:29]([OH:34])[C:30](=N)OC>C(O)C.C(=O)([O-])O.[Na+].O>[NH2:1][C:2]1[C:3]2[N:9]([CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[C:30]([CH:29]([C:23]3[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:22]=3[Cl:21])[OH:34])=[N:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=N)C(O)c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)NCCNc1c(N)cccc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCn1c(C(O)c2ccc(Cl)cc2Cl)nc2cccc(N)c21
Reaction time: 12 h
Yield: 99.5 %

Procedure:
To a stirred solution of tert-butyl {2-[(2,6-diaminophenyl)amino]ethyl}carbamate (5.00 g, 18.8 mmol) in ethanol (38 mL) was added methyl 2-(2,4-dichlorophenyl)-2-hydroxyethanimidoate hydrochloride (5.59 g, 20.7 mmol) at room temperature. After 12 h, the reaction mixture was diluted with aqueous sodium hydrogen carbonate and water. The resultant mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate to give the title compound as a brown amorphous solid (8.46 g, 18.7 mmol, 99%).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:37])(=[O:36])=[N:10][C:11](=[O:35])[C:12]2[CH:17]=[C:16]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]4[O:30][CH:31]=[CH:32][C:33]=4[CH3:34])=[O:28])[CH:21]=3)[CH:15]=[N:14][CH:13]=2)=[CH:5][CH:4]=1.C(Br)(Br)(Br)[Br:39].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:39][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:37])(=[O:36])=[N:10][C:11](=[O:35])[C:12]2[CH:17]=[C:16]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]4[O:30][CH:31]=[CH:32][C:33]=4[CH3:34])=[O:28])[CH:21]=3)[CH:15]=[N:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccc(CO)cc3)c2)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccc(CBr)cc3)c2)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
N-{[4-(hydroxymethyl)phenyl] (methyl)oxido--sulfanylidene}-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide (0.1 g, 0.195 mmol) and CBr4 (0.097 g, 0.293 mmol) were dissolved in CH2Cl2 (0.485 mL) and the resulting solution was cooled to 0° C. PPh3 (0.858 g, 0.293 mmol) was dissolved in CH2Cl2 (0.250 mL) and then added dropwise to the 0° C. reaction mixture. Subsequently the reaction was allowed to warm to room temperature and stir for ˜1.5 h. The reaction was then diluted with CH2Cl2 (5 mL) and the resulting organic mixture was washed with a saturated aqueous solution of NaHCO3 (5 mL), then with brine (5 mL). The organic layer was dried anhydrous Na2SO4(s), filtered and concentrated in vacuo. The crude product was then taken on without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([CH3:21])[CH:15]=3)[CH:11]=[C:10]([C:22]([F:25])([F:24])[F:23])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:11]=[C:10]([C:22]([F:25])([F:24])[F:23])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:30]4[CH:31]=[CH:32][C:27]([NH2:26])=[N:28][CH:29]=4)[CH:7]=[CH:6][CH:5]=3)[N:13]=2)=[CH:15][C:16]=1[CH3:21]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)ccc1Cl
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(-c4ccc(N)nc4)c3)n2)ccc1Cl

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(4-chloro-3-methylphenyl)-6-trifluoromethyl-pyrimidine (example E.41) (0.21 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a white solid (0.13 g, 60%). MS (ISP) 441.1 [(M+H)+]; mp 168.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16](O)=[O:17])[N:9]=1.C(Cl)(=O)C([Cl:25])=O>CN(C)C=O.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([Cl:25])=[O:17])[N:9]=1
Reactant: O=C(O)c1cccc(-c2noc(-c3ccccc3F)n2)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc(-c2noc(-c3ccccc3F)n2)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
Compound 25 of the present invention may be prepared according to Scheme A as follows. A slurry of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]benzoic acid (Compound A1, 15.0 g; 52.8 mmol) and 100 μL of dimethylformamide catalyst in 250 mL of anhydrous dichloromethane is allowed to cool to 0° C. Oxalyl chloride (9.2 mL, 105.5 mmol, 2.0 eq.) is added to this slurry over 3 minutes. The reaction mixture is then allowed to warm to room temperature, and is stirred for 16 h. The resultant yellow solution is concentrated in vacuo, azeotroped several times with anhydrous dichloromethane (2×50 mL) and dried under high vacuum for 2 hrs to give 15.5 g of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]benzoyl chloride (Compound A2) as a white solid (97%): 1H NMR (CDCl3) δ 7.23-7.38 (m, 2H), 7.58-7.71 (m, 2H), 8.22-8.29 (m, 2H), 8.50 (d, J=7.8 Hz, 1H), 8.91 (t, J=1.6 Hz, 1H).
Reaction SMILES: C([O:4][C:5]1[C:14]([O:15]C(=O)C)=[CH:13][C:12]2[C:7](=[CH:8][C:9]([S:19](Cl)(=[O:21])=[O:20])=[CH:10][CH:11]=2)[CH:6]=1)(=O)C.[NH3:23].[Na+].C(OC1C=C2C(=CC=1OC(=O)C)C=C(S([O-])(=O)=O)C=C2)(=O)C>O1CCCC1>[OH:4][C:5]1[C:14]([OH:15])=[CH:13][C:12]2[C:7](=[CH:8][C:9]([S:19]([NH2:23])(=[O:21])=[O:20])=[CH:10][CH:11]=2)[CH:6]=1
Reactant: N
Reactant: CC(=O)Oc1cc2ccc(S(=O)(=O)Cl)cc2cc1OC(C)=O
Agent: CC(=O)Oc1cc2ccc(S(=O)(=O)[O-])cc2cc1OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc2cc(O)c(O)cc2c1
Reaction time: 8 h

Procedure:
A solution of 20.0 g. (0.0583 mole) of 2,3-diacetoxy-7-naphthalenesulfonyl chloride in 300 ml. of tetrahydrofuran was treated with 8.7 ml. (0.13 mole) of aqueous 28% ammonia. The solid (9.9 g., infrared spectrum identical with that of 6,7-diacetoxy-2-naphthalenesulfonic acid sodium salt) was removed by filtration and the filtrate evaporated to dryness. The residue was dissolved in 150 ml. of ethyl acetate. The residue from evaporation of the dried (anhydrous sodium sulfate) solution was slurried with four 100-ml. portions of ether and then dissolved in 150 ml. of 3A alcohol. The solution was saturated with hydrogen chloride, allowed to stand overnight, and then concentrated at the water pump to give 9.7 g. of colorless residue. Recrystallization from 50 ml. of water gave 5.1 g. (37%) of pale violet solid, m.p. 218°-228° C.
Reaction SMILES: C([O:8][C:9](=[O:16])[CH2:10][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:14][N:13]([CH3:15])[CH2:12][CH2:11][CH2:10][C:9]([OH:16])=[O:8]
Reactant: [H][H]
Reactant: CN(C)CCCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CN(C)CCCC(=O)O

Procedure:
85 g (380 mMol) 4-dimethylamino butyric acid benzylester 19 was stirred with 1 g Pd/C (5%) in 500 ml methanol. The reaction mixture was treated with hydrogen for 4 h. After removing the catalyst, methanol was distilled. A small volume of ethylacetate was added to the remaining residue so that the product would crystallise. The product was then filtered off and washed with ethylacetate.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:31]=[C:30]([O:32][CH2:33][CH3:34])[CH:29]=[CH:28][C:27]=1B(O)O>>[Cl:25][C:26]1[CH:31]=[C:30]([O:32][CH2:33][CH3:34])[CH:29]=[CH:28][C:27]=1[C:5]1[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: CCOc1ccc(B(O)O)c(Cl)c1
Product: CCOc1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)c(Cl)c1
Yield: 2.4 %

Procedure:
Using the conditions of General Procedure A for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 2-chloro-4-ethoxyphenylboronic acid (available from Combi-Blocks Inc.; 100 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2′-chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-ethoxy-biphenyl-2-carboxylic acid (3 mg, 2%). 1H NMR (300 MHz, DMSO-d6) δ 13.02 (br s, 1H), 8.48 (s, 2H), 8.33 (d, J=1.9 Hz, 1H), 8.24 (d, J=7.9 Hz, 1H), 8.09 (dd, J=8.4, 2.0 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.43 (d, J=7.9 Hz, 1H), 7.25 (d, J=8.5 Hz, 1H), 7.08 (d, J=2.4 Hz, 1H), 6.90-7.02 (m, 2H), 4.10 (q, J=7.0 Hz, 2H), 1.36 (t, J=6.9 Hz, 3H).
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=1[CH2:13]O.CN(C=O)C>ClCCl>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=1[CH2:13][Cl:3]
Reactant: OCc1cc(I)ccc1Br
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: ClCc1cc(I)ccc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Thionyl chloride (13 mL) is added to a suspension of 4-bromo-3-hydroxymethyl-1-iodo-benzene (47.0 g) in dichloromethane (100 mL) containing DMF (0.1 mL). The mixture is stirred at ambient temperature for 3 h. Then, the solvent and the excess reagent is removed under reduced pressure. The residue is triturated with methanol and dried.
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[NH:5][C:4]=2[N:3]=1.I[CH2:17][CH3:18].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:17][CH3:18])[C:4]=2[N:3]=1
Reactant: CCI
Reactant: C=CCn1c(Cl)nc2[nH]c(=O)[nH]c(=O)c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CC
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.7 %

Procedure:
A solution of 8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (10 g, 0.044 mol) in anhydrous DMF (100 ml) was treated with iodoethane (5.4 ml, 0.068 mol) and Na2CO3 (4.9 g, 0.046 mol). The reaction mixture was left to stir at rt under nitrogen for 2 days. Iodoethane (0.35 ml, 0.0044 mol) was added and the mixture was left to stir at rt for 1 day. The mixture was partitioned between EtOAc and 2M HCl. The organic layer was separated, washed sequentially with saturated sodium sulphite solution and brine, dried (MgSO4) and concentrated. The crude solid was washed with Et2O to give the title compound as a white solid (8.37 g, 75%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][C:8]=1[NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])(=O)=O.[C:30]([Sn](CCCC)(CCCC)CCCC)#[C:31][CH2:32][CH3:33]>>[CH2:21]([O:20][C:18]([NH:17][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:7]=1[C:30]#[C:31][CH2:32][CH3:33])[C:13]([O:15][CH3:16])=[O:14])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(NC(=O)OCc2ccccc2)c1
Reactant: CCC#C[Sn](CCCC)(CCCC)CCCC
Product: CCC#Cc1ccc(C(=O)OC)cc1NC(=O)OCc1ccccc1
Yield: 45.6 %

Procedure:
Methyl 3-benzyloxycarbonylamino-4-(1-butynyl)benzoate (646 mg) was prepared from 2-benzyloxycarbonylamino-4-methoxycarbonylphenyl trifluoromethanesulfonate (1.82 g) and 1-butynyl(tributyl)stannane (1.51 g) in a similar manner to that of Preparation 1 (2).
Reaction SMILES: [H-].[Na+].Cl.[CH3:4][N:5]([CH2:7][CH2:8]Cl)[CH3:6].[CH3:10][N:11]1[C:17]2[CH:18]=[C:19]([CH3:23])[C:20]([CH3:22])=[CH:21][C:16]=2[NH:15][C:14](=[O:24])[C:13]2=[CH:25][S:26][CH:27]=[C:12]12>CN(C)C=O>[CH3:4][N:5]([CH3:6])[CH2:7][CH2:8][N:15]1[C:16]2[CH:21]=[C:20]([CH3:22])[C:19]([CH3:23])=[CH:18][C:17]=2[N:11]([CH3:10])[C:12]2=[CH:27][S:26][CH:25]=[C:13]2[C:14]1=[O:24]
Reactant: CN(C)CCCl
Reactant: Cc1cc2c(cc1C)N(C)c1cscc1C(=O)N2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1C)N(C)c1cscc1C(=O)N2CCN(C)C
Reaction time: 18 h

Procedure:
A mixture of 0.36 g. of 55% sodium hydride-mineral oil dispersion and 0.58 g. of dimethylaminoethylchloride hydrochloride in 25 ml. of dry dimethylformamide is stirred at room temperature for 0.5 hours. To the mixture is added 0.52 g. of 4,9-dihydro-4,6,7-trimethyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and stirring is continued for 18 hours. The reaction mixture is cooled, quenched with water, and extracted with chloroform. The dried chloroform extracts are concentrated to an oil, which is purified by preparative thin layer chromatography (tlc) on silica gel with 10:1 benzene:methanol as eluent. The oil obtained is crystallized from hexane to give white crystals, m.p. 119°-120° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[N:10]([CH2:12][CH2:13][CH2:14][C:15](=O)[NH:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[CH:19][C:18]=1[NH2:27])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.CN(C=O)C>[CH2:1]([O:8][C:9](=[O:29])[N:10]([CH2:12][CH2:13][CH2:14][C:15]1[NH:27][C:18]2[CH:19]=[C:20]([O:25][CH3:26])[C:21]([O:23][CH3:24])=[CH:22][C:17]=2[N:16]=1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(N)c(NC(=O)CCCN(C)C(=O)OCc2ccccc2)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc2nc(CCCN(C)C(=O)OCc3ccccc3)[nH]c2cc1OC
Temperature: 150 °C

Procedure:
To a mixture of crude [3-(2-amino-4,5-dimethoxy-phenylcarbamoyl)-propyl]-methyl-carbamic acid benzyl ester acid (obtained from 4-(methylamino)butyric acid and benzylchloroformate) in 6 mL toluene were added a few drops of DMF and 358 mg of TsOH and the reaction mixture was heated at 150° C. for 2 h in the microwave. Saturated aq. NaHCO3 solution was added, the phases were separated and the organic phase was washed with brine. The combined organic phases were dried over MgSO4, and concentrated in vacuo. Purification by CC EtOAc-MeOH (95:5) yielded 0.65 g of [3-(5,6-dimethoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-carbamic acid benzyl ester as brown oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:26][CH3:27])=[C:23]([CH:25]=1)[NH2:24]>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:26][CH3:27])=[C:23]([CH:25]=1)[NH:24][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cnccn2)n1
Reactant: COc1ccc(Cl)cc1N
Product: COc1ccc(Cl)cc1Nc1cc(C(F)(F)F)nc(-c2cnccn2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine (30 mg, 0.115 mmol) and 5-chloro-2-methoxyaniline (27 mg, 0.173 mmol) similar to Example 185 and was isolated as a solid (10 mg, 23% yield). 1H NMR (CDCl3): 9.72 (d, J=1.2 Hz, 1H), 8.82 (t, J=1.8 Hz, 1H), 8.72 (d, J=2.4 Hz, 1H), 8.23 (brs, 1H), 7.71 (brs, 1H), 7.15 (dd, J=8.4, 2.4 Hz, 1H), 7.04 (s, 1H), 6.88 (d, J=8.4 Hz, 1H), 3.90 (s, 3H).
Reaction SMILES: FC1C=CC(CN2C3C=CC=CC=3N=C2)=CC=1.C([Li])CCC.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][CH:36]([C:39](OC)=[O:40])[CH2:35][CH2:34]2)=[CH:27][CH:26]=1>C1COCC1.CCCCCC>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][CH:36]([CH:39]=[O:40])[CH2:35][CH2:34]2)=[CH:27][CH:26]=1
Reactant: COC(=O)C1CCN(CCc2ccc(OC)cc2)CC1
Agent: Fc1ccc(Cn2cnc3ccccc32)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(CCN2CCC(C=O)CC2)cc1
Reaction time: 0.29 h

Procedure:
To a stirred, -78° C., solution of 1-[(4-fluorophenyl)methyl]-1H-benzimidazole (1.13 g, 5.00×10-3 mole) and dry THF (12 ml) under argon was added a 2.5 molar hexane solution of n-butyl lithium (2.1 ml, 5.25×10-3 mole). After 15-20 minutes at -78° C., a solution of 1-[2-(4-methoxyphenyl)ethyl]-4-piperidinecarboxylic acid, methyl ester (1.39 g, 5.01×10-3 mole) and dry THF (6 ml) was added dropwise via syringe. After 5-10 minutes, the cooling bath was removed and the reaction was allowed to warm. After ca. 30 minutes, the reaction was quenched by the addition of saturated aqueous NH4Cl. The reaction was transferred to a separatory funnel where the aqueous mixture was extracted two times with ethyl acetate. The ethyl acetate extracts were combined, washed with saturated aqueous NaCl, and dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure affording a viscous oil. This was purified by a combination of flash chromatography (ethyl acetate) and crystallization (cyclohexane) affording 1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl][1-[2-(4methoxyphenyl)ethyl]-4-piperidinyl]methanone as off white matted needles: 0.90 g (38%), m.p. 109-111° C.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([C:10]([NH:12][OH:13])=[NH:11])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[C:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=O)=[CH:19][CH:18]=1)(=[O:16])[CH3:15]>>[CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([C:10]3[N:11]=[C:21]([C:20]4[CH:24]=[CH:25][C:17]([C:14](=[O:16])[CH3:15])=[CH:18][CH:19]=4)[O:13][N:12]=3)[CH2:6][CH2:5]2)[CH2:2][CH2:3]1
Reactant: CC(=O)c1ccc(C(=O)Cl)cc1
Reactant: N=C(NO)C1CCN(C2CC2)CC1
Product: CC(=O)c1ccc(-c2nc(C3CCN(C4CC4)CC3)no2)cc1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 35a, starting from 1-cyclopropyl-N-hydroxypiperidine-4-carboxamidine and 4-acetylbenzoyl chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4][CH:3]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:41]([Si:43]([CH3:46])([CH3:45])[CH3:44])#[CH:42]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([C:42]#[C:41][Si:43]([CH3:46])([CH3:45])[CH3:44])=[CH:3][CH:4]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: C#C[Si](C)(C)C
Reactant: CCCCCCOc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCOc1ccc(C#C[Si](C)(C)C)cc1
Temperature: 90 °C

Procedure:
To a 500 mL N2 filled round bottom flask was added 1-bromo-4-(hexyloxy)benzene (20.5 g, 80.0 mmol, 1 equiv.) and DMF (160 mL, 0.5 M). The mixture was then sparged with bubbling N2. To this mixture was added N2-sparged triethylamine (39.0 mL, 280 mmol, 3.5 equiv.) via syringe. Finally, copper (I) iodide (254.0 mg, 1.33 mmol, 1.7%), triphenylphosphine (603.0 mg, 2.67 mmol, 3.3%) and PdCl2(PPh3)2 (933.0 mg, 1.33 mmol, 1.7%) were added as a single portion and the head space was flushed with N2. Ethynyltrimethylsilane (16.9 mL, 120.0 mmol, 1.5 equiv.) was added via syringe to the mixture. The flask was sealed with a ground glass stopper, Teflon tape, and then electrical tape and heated to 90° C. for 48 hours. After 48 hours the mixture was diluted with hexanes and extracted with 10% H3PO4 then 5% K2CO3. The organic layer was then dried with MgSO4 and filtered through a plug of SiO2 with 100% hexanes. Upon evaporation, ((4-(hexyloxy)phenyl)ethynyl)trimethylsilane was isolated as a clear oil (16.45 g, 60.2 mmol, 75%). 1H NMR (400 MHz, CDCl3) δ7.42 (d, J=9.2 Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 3.98 (t, J=6.4 Hz, 2H), 1.85-1.73 (m, 2H), 1.52-1.42 (m, 2H), 1.41-1.26 (m, 4H), 0.94 (t, J=7.6 Hz, 3H), 0.27 (s, 9H).
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:11]2[C:6](=[C:7]([CH2:12][CH2:13]O)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]1[CH3:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1.[Br:40]N1C(=O)CCC1=O>>[Br:40][CH2:13][CH2:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH2:5][CH:4]([CH3:15])[CH:3]2[O:2][CH3:1]
Reactant: COC1c2cccc(CCO)c2CC1C
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC1c2cccc(CCBr)c2CC1C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a mixture of 12.9 g (62.5 mmol) of 2-(1-methoxy-2-methyl-2,3-dihydro-1H-inden-4-yl)ethanol and 16.4 g (62.5 mmol) of PPh3 in 300 ml of THF 11.1 g (62.5 mmol) of N-bromosuccinimide was added at vigorous stirring for 5 minutes at 0° C. This mixture was stirred for 2 hours at room temperature and then evaporated to dryness. A solution of the residue in 200 ml of hexanes was filtered through glass frit (G3), and the precipitate was additionally washed by 3×100 ml of hexanes. The combined organic extract was evaporated to dryness. The product was isolated from the residue using flash chromatography on silica gel 60 (40-63 μm, eluent: hexanes-ether=20:1, vol.). Yield 12.1 g (72%) of ca. 1 to 1 mixture of the diastereomers A and B. Anal. calc. for C13H17BrO: C, 58.01; H, 6.37. Found: C, 58.24; H, 6.22. 1H NMR (CDCl3): δ 7.30 (m, 2H, 6-H in indenyl of A and B), 7.20 (m, 2H, 7-H in indenyl of A and B), 7.12 (m, 2H, 5-H in indenyl of A and B), 4.52 (m, 1H, 1-H in indenyl of A), 4.41 (m, 1H, 1-H in indenyl of B), 3.53 (m, 4H, CH2CH2Br of A and B), 3.47 (s, 3H, OMe of B), 3.42 (s, 3H, OMe of A), 3.22 (dd, J=15.8 Hz, J=7.6 Hz, 1H, 3-H in indenyl of B), 3.15 (m, 4H, CH2CH2Br of A and B), 2.92 (dd, J=14.9 Hz, J=6.7 Hz, 1H, 3-H in indenyl of A), 2.48-2.71 (m, 3H, 2,3-H in indenyl of A and 2-H in indenyl of B), 2.42 (dd, J=15.8 Hz, J=4.8 Hz, 1H, 3-H in indenyl of B), 1.18 (d, J=7.1 Hz, 3H, 2-Me in indenyl of B), 1.13 (d, J=6.6 Hz, 3H, 2-Me in indenyl of A). 13C{1H} NMR (CDCl3): δ 143.1, 142.6, 142.2, 141.7, 135.1, 135.0, 128.5, 128.4, 126.8, 126.5, 124.1, 123.8, 91.3, 85.9, 56.7, 56.5, 39.4, 38.5, 36.80, 36.78, 36.7, 36.5, 31.7, 31.6, 19.4, 13.6.