Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[O:7]1[CH2:22][CH:8]1[CH2:9][O:10][C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:13][N:12]=1>C(O)C>[OH:7][CH:8]([CH2:22][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[CH2:9][O:10][C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:13][N:12]=1
Reactant: c1ccc(-c2cc(OCC3CO3)no2)cc1
Reactant: C1COCCN1
Solvent: CCO
Product: OC(COc1cc(-c2ccccc2)on1)CN1CCOCC1
Yield: 89.2 %

Procedure:
17.6 g of morpholine were added to a solution of 40.0 g of 3-(2,3-epoxypropoxy)-5-phenylisoxazole (prepared as described in Preparation 4) in 400 ml of ethanol, and the mixture was heated under reflux for 5 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the resulting solid residue was recrystallized from ethyl acetate, to give 50.0 g (yield 89.2%) of the title compound as colorless columnar crystals, melting at 123°-124° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C@H:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:28][N:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[NH:6][C:7](=[O:16])[C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=1)[CH3:2].[CH3:30]I.[H-].[Na+].O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:29])[C@H:5]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[O:28][N:27]=[CH:26][CH:25]=2)=[CH:22][CH:23]=1)[N:6]([C:7](=[O:16])[C:8]1[CH:9]=[C:10]([CH3:15])[CH:11]=[C:12]([CH3:14])[CH:13]=1)[CH3:30])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(-c2ccno2)cc1)NC(=O)c1cc(C)cc(C)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](Cc1ccc(-c2ccno2)cc1)N(C)C(=O)c1cc(C)cc(C)c1
Temperature: 25 °C

Procedure:
A solution of N-(3,5-dimethylbenzoyl)-3-[4-(5-isoxazolyl)-phenyl]-alanine ethyl ester (3,8 g) and methyliodide (1.8 ml) in dry N,N-dimethylformamide (40 ml) is cooled in an ice bath and sodium hydride (60% in oil, 390 mg) is added in portions. The mixture is allowed to warm to room temperature during 5 hours, then poured into water, extracted with ethyl acetate, the organic phase washed with water, and with brine, dried and evaporated. Flash chromatography of the residue on silica gel (hexane/ethyl acetate 3:1) gives pure N-(3,5-dimethylbenzoyl)-N-methyl-3-[4-(5-isoxazolyl)-phenyl]-alanine ethyl ester. NMR (CDCl3, 400 MHz) δ [ppm] 8.30 (d, broad, 1H), 7.75 (m, 2H), 7.41 (d, broad, 1H), 7.12 (d, broad, 1H), 6.97 (s, 0.5H), 6.93 (s, 0.5 H), 6.70 (s, 1H), 6.53 (d, broad, 1H), 6.36 (d, broad, 1H), 5.40 (m, 0.5H), 4.58 (m, 0.5H), 4.27 (m, 2H), 3.54 (m, 0.5H), 3.25 (m, 1H), 3.05 (m, 2H), 2.78 (s, 1.5H), 2.23 (s, 3H), 2.13 (s, 3H), 1.27 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][N:17]=3)[C:12]([OH:19])=[C:11]([CH2:20][CH:21](O)[CH3:22])[C:10]2=[O:24])[CH:5]=[CH:6][C:7]=1[Cl:8].O.C([O-])(O)=O.[Na+]>CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][N:17]=3)[C:12](=[O:19])[C:11]3[CH2:20][CH:21]([CH3:22])[O:24][C:10]2=3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(O)Cc1c(O)c2cccnc2n(-c2ccc(Cl)c(Cl)c2)c1=O
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: CC1Cc2c(n(-c3ccc(Cl)c(Cl)c3)c3ncccc3c2=O)O1

Procedure:
A solution of 1-(3,4-dichlorophenyl)-4-hydroxy-3-(2-hydroxypropyl)-1,8-naphthyridin-2(1H)-one (5 g.) in Eaton's Reagent (10% P2O5 in methanesulfonic acid; 100 ml.), under an atmosphere of nitrogen, was heated at 70° C. for 2 hr. The mixture was cooled and poured into water. The pH was adjusted to 7 with NaHCO3. The product was filtered off, washed with water, dried in air, and recrystallized from isopropanol/charcoal to yield the product, m.p. 218-220.5° C.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:31])[NH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18](C(=O)C)[N:17]=[C:16]2[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=O)C.N.Cl>CO>[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([NH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[C:16]2[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:31]
Reactant: CC(=O)Oc1ccccc1C(=O)Nc1ccc2c(c1)c(-c1ccccc1)nn2C(C)=O
Agent: Cl
Agent: N
Solvent: CO
Product: O=C(Nc1ccc2[nH]nc(-c3ccccc3)c2c1)c1ccccc1O
Reaction time: 3 h
Yield: 56.7 %

Procedure:
A solution of 2-[N-(1-acetyl-3-phenyl-1H-indazole-5-yl)carbamoyl]phenyl acetate (100 mg, 0.241 mmol) in methanol (11 mL) with 0.3% ammonia was allowed to stir for three hours at reflux temperature. The mixture was then acidified with 5% HCl solution until neutral pH. The resulting solid was filtered, dried and triturated with hexanes to give the title compound (45 mg, 57% yield). 1H NMR (DMSO-d6) δ 13.23 (br s, 1H), 11.92 (br s, 1H), 10.47 (s, 1H), 8.45 (s, 1H), 7.96 (m, 3H), 7.51 (m, 6H), 6.95 (d, 2H); ES-MS (m/z) 330 [M+1]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]#[C:7][CH2:8][O:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:14]=[CH:13]1>[Pd].CO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:14]=[CH:13]1
Reactant: C(#Cc1cccs1)COCCn1cnc2cnc3ccccc3c21
Agent: [Pd]
Solvent: CO
Product: c1csc(CCCOCCn2cnc3cnc4ccccc4c32)c1
Yield: 94.7 %

Procedure:
Using the general method of Example 3 Part B, 1-{2-[(3-thien-2-ylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinoline (9.5 g, 28.49 mmol) was reduced with palladium on carbon (10%, 1 g) in methanol (25 mL) to provide 9.1 g of 1-[2-(3-thien-2-ylpropoxy)ethyl]-1H-imidazo[4,5-c]quinoline as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[C:21]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)(=[O:23])[NH2:22]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:28][C:27]3[CH:29]=[CH:30][C:24]([C:21](=[O:23])[NH2:22])=[CH:25][CH:26]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: NC(=O)c1ccc(N)cc1
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: NC(=O)c1ccc(NC(=O)CC2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)cc1
Yield: 56.9 %

Procedure:
A procedure similar to that described in Example 52 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (170 mg, 0.5 mmol) and p-carbamoylaniline (70 mg, 0.51 mmol) to give 130 mg of the title compound (57%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.05 (s, 1H), 10.23 (s, 1H), 7.85 (bs, 1H), 7.83 (d, 2H, J=8.6 Hz), 7.62 (d, 2H, J=8.6 Hz), 7.23 (bm, 2H), 7.17 (bs, 1H), 5.20~5.27 (m, 1H), 3.06 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.84 (dm, 1H, J=17.1 Hz), 2.63 (d, 2H, J=6.9 Hz), 2.12 (dm, 1H, J=13.5 Hz), 1.82~1.96 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=CC=C[CH:9]=2)[N:5]=[C:4]([O:14][CH2:15][CH2:16][CH:17]([CH3:19])C)[CH:3]=1.ClC1C=C(Cl)N=[C:23]([C:28]2C=CC=[CH:30][CH:29]=2)N=1.ClC1C=C(Cl)N=C(C(C)C)N=1.C(C(CCCC)CO)C>CC(C)CCO>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]([CH3:9])[CH3:13])[N:5]=[C:4]([O:14][CH2:15][CH:16]([CH2:17][CH3:19])[CH2:23][CH2:28][CH2:29][CH3:30])[CH:3]=1
Reactant: Clc1cc(Cl)nc(-c2ccccc2)n1
Reactant: CC(C)CCOc1cc(Cl)nc(-c2ccccc2)n1
Agent: CC(C)c1nc(Cl)cc(Cl)n1
Solvent: CC(C)CCO
Solvent: CCCCC(CC)CO
Product: CCCCC(CC)COc1cc(Cl)nc(C(C)C)n1

Procedure:
The compound of Example 23 is prepared analogously to the compound of Example 3, with 4,6-dichloro-2-phenylpyrimidine being replaced by 4,6-dichloro-2-i-propylpyrimidine and 3-methylbutanol by 2-ethylhexanol.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[C:13]([NH2:18])=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][CH:5]=1)[CH3:3]>CO.[C].[Pd]>[CH3:3][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]2[C:13]([NH2:18])=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:9]=1)[CH3:1]
Reactant: CC(C)c1ccc(C#Cc2cccnc2N)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)c1ccc(CCc2cccnc2N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.6 %

Procedure:
A mixture of 10% palladium-carbon (50% wet, 50 mg) and 3-{[4-(1-methylethyl)phenyl]ethynyl}pyridin-2-amine (662.8 mg) in methanol (15 mL) was stirred under a hydrogen atmosphere at room temperature for 3 hr. The reaction mixture was filtered, a saturated aqueous sodium hydrogen carbonate solution was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (246.6 mg) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[CH3:12][C:13]([NH2:17])([CH2:15][CH3:16])[CH3:14].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:11][S:10][C:4]1[N:3]=[C:2]([NH:17][C:13]([CH2:15][CH3:16])([CH3:14])[CH3:12])[C:7]([C:8]#[N:9])=[CH:6][N:5]=1
Reactant: CCC(C)(C)N
Reactant: CSc1ncc(C#N)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(C)(C)Nc1nc(SC)ncc1C#N
Temperature: 70 °C

Procedure:
4-Chloro-2-(methylthio)pyrimidine-5-carbonitrile (500 mg, 2.69 mmol) was dissolved in DMF (5 mL), 2-methylbutan-2-amine (0.378 mL, 3.24 mmol) and DIEA (1.411 mL, 8.08 mmol) were added and the reaction was heated at 70° C. overnight. LCMS showed the desired product mass as the dominant peak and no starting material remaining. The reaction was removed from heat and partitioned between ethyl acetate and water. The organic layer was washed once with brine before drying over magnesium sulfate, filtering, and condensing. The crude material was purified by silica gel chromatography (0-80% ethyl acetate in hexane over 1650 mL; 40 mL/min). Product fractions were combined, evaporated, and dried under high vacuum to afford 2-(methylthio)-4-(tert-pentylamino)pyrimidine-5-carbonitrile (359 mg, 1.519 mmol, 56.4% yield) as a white solid; MS (ESI) m/z 236.9 [M+1]+
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+].[OH:20][C:21]1[CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[S:24][CH:25]=1>O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:20][C:21]2[CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[S:24][CH:25]=2)[N:3]=1
Reactant: Fc1cccc(F)n1
Reactant: Oc1csc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cccc(Oc2csc(C(F)(F)F)c2)n1
Temperature: 80 °C
Yield: 74.3 %

Procedure:
1.00 g of 2,6-difluoropyridine is introduced into 10 ml of DMF under nitrogen and 1.44 g of K2CO3 are added at RT. 1.61 g of 4-hydroxy-2-trifluoromethylthiophene are added and the mixture is heated at 80° C. for 4 h, then cooled to RT and poured into water. After extraction twice with heptane/ethyl acetate (1:1) and twice with ethyl acetate the product is washed with water and saturated sodium chloride solution, dried over MgSO4 and concentrated. Chromatographic purification on silica gel with heptane/ethyl acetate (3:7) as eluent gives 1.7 g of 2-fluoro-6-(2-trifluoromethyl-4-thienyloxy)pyridine as a colorless oil.
Reaction SMILES: [I-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH:4]([CH3:6])[CH3:5].C([Li])CCC.[O:31]1[C:35]2([CH2:40][CH2:39][C:38](=O)[CH2:37][CH2:36]2)[O:34][CH2:33][CH2:32]1.C(OCC)(=O)C>O1CCCC1.CCCCCC.O>[CH3:5][CH:4]([CH3:6])[CH2:3][CH:2]=[C:38]1[CH2:39][CH2:40][C:35]2([O:34][CH2:33][CH2:32][O:31]2)[CH2:36][CH2:37]1
Reactant: CC(C)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [I-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)CC=C1CCC2(CC1)OCCO2
Reaction time: 1 h
Yield: 78 %

Procedure:
In 100 ml of tetrahydrofuran is suspended 39.8 g of isopentyltriphenylphosphonium iodide. At −25° C. to −20° C., 52 ml of a 1.6 mol/L solution of n-butyllithium in n-hexane is dropwise added to the suspension. After stirring the mixture thus obtained at −25° C. to −15° C. for one hour, the temperature is elevated to ambient temperature over a period of one hour. A solution of 10.0 g of 1,4-dioxaspiro[4.5]-decan-8-one in 50 ml of tetrahydrofuran is added to the reaction mixture and stirred at ambient temperature for one hour. The reaction mixture is added to a mixture of ethyl acetate and water, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=95:5) to obtain 10.5 g of 8-(3-methylbutylidene)-1,4-dioxaspiro[4.5]decane as a colorless oily product.
Reaction SMILES: [CH:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[C:10](=[O:25])[CH:9]([N:26]3C(=O)C4=CC=CC=C4C3=O)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.NN>O1CCCC1>[NH2:26][CH:9]1[N:8]=[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:10]1=[O:25]
Reactant: O=C1C(N2C(=O)c3ccccc3C2=O)N=C(C2CCCCC2)c2ccccc2N1Cc1ccccn1
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: NC1N=C(C2CCCCC2)c2ccccc2N(Cc2ccccn2)C1=O
Reaction time: 2 h
Yield: 74.9 %

Procedure:
A stirred solution of (3RS)-5-cyclohexyl-2,3-dihydro-3-phthalimido-1-(pyridin-2-yl)methyl-1H-1,4-benzodiazepin-2-one (0.22 g) in tetrahydrofuran (10 ml) was treated with a solution of hydrazine monohydrate (23 mg) in tetrahydrofuran (1 ml) at ambient temperature, and the mixture was stirred for 2 hours at the same temperature, then heated at reflux temperature for 1 hour. After cooling, the resultant precipitates were filtered off. The filtrate was concentrated in vacuo. The residue was taken up with 1N aqueous hydrohloric acid and washed with isopropyl ether. The aqueous layer was alkalined with sodium carbonate and extracted with chloroform. The extract was dried over sodium sulfate, filtered and concentrated in vacuo to give (3RS)-3-amino-5-cyclohexyl-2,3-dihydro-1-(pyridin-2-yl)methyl-1H-1,4-benzodiazepin-2-one (0.12 g) as an yellow oil which was used in a following reaction step without further purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[C:9]2=[O:26])=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28].[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH2:34]>CN(C)C=O>[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH:34][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[C:9]2=[O:26])=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28]
Reactant: O=c1n(-c2ccc(Oc3ccccc3)cc2)ccn1-c1ccc(F)c([N+](=O)[O-])c1
Reactant: CN(C)CCN
Solvent: CN(C)C=O
Product: CN(C)CCNc1ccc(-n2ccn(-c3ccc(Oc4ccccc4)cc3)c2=O)cc1[N+](=O)[O-]

Procedure:
A solution of 1-(4-fluoro-3-nitrophenyl)-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one (100 mg) in dimethylformamide (2 ml) was shaken with 2-dimethylaminoethylamine (0.3 ml) at 70° C. for 2 hours. Volatiles were removed and the residue was partitioned between dichloromethane and water. The organic phase was dried and concentrated. The product with the molecular weight of 459.51 (C25H25N5O4); MS (ESI): 460 ([M+H]+), was obtained in this way.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1[C@H:13]([OH:16])[CH2:14][OH:15].ClCCl.[C:20](Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]>N1C=CC=CC=1>[C:20]([O:15][CH2:14][C@H:13]([C:3]1[C:4]([CH3:12])=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[Cl:1])[OH:16])(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1cc2ccccc2c(Cl)c1[C@H](O)CO
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc2ccccc2c(Cl)c1[C@H](O)COC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.3 %

Procedure:
To a solution of (S)-1-(1-chloro-3-methylnaphthalen-2-yl)ethane-1,2-diol (4E) (0.920 g, 3.89 mmol) in pyridine (5.0 mL)/dichloromethane (15.0 mL) was added pivaloyl chloride (0.574 mL, 4.67 mmol). The reaction mixture was stirred for 18 h at room temperature. The reaction was incomplete and additional pivaloyl chloride (0.574 mL, 4.67 mmol) was added. After stirring for 1 h, the reaction mixture was quenched with 1 N HCl and diluted with ethyl acetate. The organic layer was washed with 1 N HCl, saturated sodium bicarbonate solution, dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 30% ethyl acetate/hexanes) to give 4F as a colorless oil (1.139 g). LCMS-ESI+ (m/z): [M—O]+ calcd for C18H21ClO2: 304.80. Found: 303.0, 305.0.
Reaction SMILES: Br[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH3:21][O:22][C:23]1[C:28]2[N:29]=[C:30]([CH2:32][O:33][CH3:34])[NH:31][C:27]=2[C:26]([C:35](ON2C3C=CC=CC=3N=N2)=[O:36])=[CH:25][CH:24]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Cl:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][C:3]1[C:2]([C:35]([C:26]2[C:27]3[N:31]=[C:30]([CH2:32][O:33][CH3:34])[NH:29][C:28]=3[C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)=[O:36])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COCc1nc2c(OC)ccc(C(=O)On3nnc4ccccc43)c2[nH]1
Reactant: Clc1cccc(Oc2ncccc2Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCc1nc2c(C(=O)c3cccnc3Oc3cccc(Cl)c3)ccc(OC)c2[nH]1
Temperature: -70 °C
Reaction time: 0.75 h
Yield: 18.8 %

Procedure:
A solution of 3-bromo-2-(3-chlorophenoxy)pyridine (0.43 g, Reference Example 16) in dry tetrahydrofuran (6 ml), at −70° C., was treated with butyl lithium in hexane (0.64 ml, 2.5M). The mixture was then stirred at −70° C. for 45 minutes then treated with a solution of 1-benzotriazolyl 7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxylate [0.177 g, Reference Example 1(a)] in dry tetrahydrofuran (2 ml) and stirring was continued at −70° C. for 10 minutes. The reaction mixture was allowed to warm to room temperature, then stirred at this temperature for 2 hours, then treated with aqueous ammonium chloride solution, and then extracted with ethyl acetate (20 ml). The organic extract was dried and concentrated to give a brown syrup which was purified by flash chromatography on silica eluting initially with a mixture of diethyl ether and pentane (1:1, v/v), then with a mixture of diethyl ether and pentane (7:3, v/v) and then with diethyl ether to give the title compound (0.04 g) as white solid, m.p. 181-183° C. [Elemental analysis:—C,62.17, H,4.32, N,10.15%. Calculated:—C,62.35, H,4.28, N,9.91%]. NMR (CDCl3):—δ 3.52(s,3H), 4.13(s,3H), 4.85(s,2H), 6.73(d,J=8 Hz,1H), 7.00(m,1H), 7.12(t,J=2 Hz,1H), 7.16(m,1H), 7.2(dd,J=7 Hz,J=5 Hz,1H), 7.28(t,J=8 Hz,1H), 7.55(d,J=8 Hz,1H), 7.85(dd,J=8 Hz,J=2 Hz,1H), 8.83(dd,J=4 Hz,J=1 Hz,1H).
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:25])([F:24])[F:23])=[O:16])=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:32]12([C:45](O)=[O:46])[CH2:41][CH:36]3[CH2:37][CH:38]([CH2:40][C:34]([C:42]([OH:44])=[O:43])([CH2:35]3)[CH2:33]1)[CH2:39]2.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C>[C:26]1([C:19]2[O:20][C:21]([C:22]([F:23])([F:25])[F:24])=[C:17]([C:15]([NH:14][C:11]3[CH:12]=[CH:13][C:8]([N:2]4[CH2:7][CH2:6][N:5]([C:45]([C:32]56[CH2:41][CH:36]7[CH2:37][CH:38]([CH2:40][C:34]([C:42]([OH:44])=[O:43])([CH2:35]7)[CH2:33]5)[CH2:39]6)=[O:46])[CH2:4][CH2:3]4)=[CH:9][CH:10]=3)=[O:16])[N:18]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: O=C(O)C12CC3CC(C1)CC(C(=O)O)(C3)C2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(N2CCN(C(=O)C34CC5CC(CC(C(=O)O)(C5)C3)C4)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.4 %

Procedure:
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperazin-1-yl-phenyl)-amide, hydrochloride (51.5 mg, 0.113 mmol), adamantane-1,3-dicarboxylic acid (51 mg, 0.227 mmol), and triethylamine (48 uL, 0.341 mmol) were dissolved in 1 mL of DMF. To this solution was added BOP (52 mg, 0.122 mmol) in one portion. The mixture was stirred at room temperature overnight. 4-N,N-dimethylamino-pyridine (5 mg) was added and the reaction was stirred for an additional 72 hours and then diluted with 30 ml ethyl acetate. The organic phase was washed with saturated ammonium chloride (1×5 mL), 2.5% KHSO4 (3×5 mL), water (2×5 mL) and saturated sodium chloride. The organic layer was dried over MgSO4, filtered, passed through a plug of silica gel and evaporated to dryness under vacuum to a light brown solid. The residue was purified by flash chromatography to yield 3-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-adamantane-1-carboxylic acid as light yellow crystals (9.4 mg, 13%). ES-MS calcd for C33H33F3N4O5 (m/e) 622.65, obsd 623 (M+H).
Reaction SMILES: [C:1]([C:4]1[C:12]2[N:11]=[C:10]([CH:13]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]3C(OCC3C=CC=CC=3)=O)[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[NH2:2]>C(OCC)(=O)C.[Pd]>[NH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:21][CH:13]1[C:10]1[NH:9][C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:12]=2[N:11]=1
Reactant: NC(=O)c1cccc2[nH]c(C3Cc4ccccc4N3C(=O)OCc3ccccc3)nc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc2[nH]c(C3Cc4ccccc4N3)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of benzyl 2-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)indoline-1-carboxylate (800 mg, 1.94 mmol) in ethyl acetate (50 ml) was added 10% Pd/C (80 mg) and the reaction mixture was degassed and stirred under H2 at 1 atmospheric pressure for 2 h at RT. The reaction mixture was filtered, the filtrate concentrated and the crude product was further triturated with ether to afford 2-(indolin-2-yl)-1H-benzo[d]imidazole-4-carboxamide. MS (ES+): m/z 279.1 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:27][N:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:27][N:26]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)Oc1ccc(Br)nc1
Product: CC(C)Oc1ccc(C(=O)C(NC(=O)OC(C)(C)C)c2ccc(Cl)c(Cl)c2)nc1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 2-bromo-5-isopropoxy-pyridine (Intermediate 30) in analogy to Example 1a): MS (ISP): 439.2 and 441.1 (M+H)+, 383.2 and 385.1 ((M-isobutene)+H)+ (100%).
Reaction SMILES: [C:1]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[CH:13]1[CH2:18][CH2:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH:18]12[CH2:17][CH2:16][CH:15]([CH:7]3[C:1](=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]31)[CH:14]=[CH:13]2
Reactant: C1=CCCC=C1
Reactant: O=C1C=CCCCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C1CCCCC2C3C=CC(CC3)C12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of (Z)-cyclohept-2-enone (1.4 g, 10 mmol) in dry toluene was added aluminum chloride (0.67 g, 5 mmol) and the resulting mixture was stirred at room temperature for 40 minutes. A solution of cyclohexadiene (9.62 g, 120 mmol) in toluene was added dropwise, and the mixture was stirred overnight at 40° C. The reaction mixture was filtered through diatomaceous earth and then partition in ethyl acetate/water. The organic layer was washed with sodium bicarbonate solution, dried (magnesium sulfate), filtered, evaporated under vacuum and purified by chromatography on silica gel eluting with 5-10% ether/hexane to provide the title compound: MS (DCl/NH3) m/z 191 (M+H)+, 208 (M+NH4)+.