Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.CN(C)C=O>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[CH:8]([C:4]2[CH:3]=[C:2]([C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([C:28]([F:39])([F:38])[F:27])[CH:34]=3)[CH:7]=[CH:6][CH:5]=2)[CH2:9][C:10]([C:20]([F:26])([F:25])[C:21]([F:24])([F:22])[F:23])=[N:11]1
Reactant: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2cccc(Br)c2)C1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
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: CN(C)C=O
Product: FC(F)(F)c1cccc(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccccc3Cl)c2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
5-(3-Bromo-phenyl)-1-(2-chloro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (20.0 mg, 0.04 mmol) prepared in Step 1 of Preparation 6, 3-(trifluoromethyl)phenylboronic acid (17.0 mg, 0.09 mmol), Pd(PPh3)4 (2.5 mg, cat.) and a 2N sodium carbonate solution (1.0 mL) were added to N,N-dimethylformamide (2.0 mL). The reaction mixture was stirred at 80° C. for 2 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/8) to give 18.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: O1CCOCC1.C([C:11]1[C:12](Cl)=[N:13][CH:14]=[C:15]([Cl:34])[C:16]=1[CH:17]([S:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[F:25])(C)(C)C.[C:36]([O:40][C:41](=[O:50])[NH:42][CH2:43][CH:44]1[O:49][CH2:48][CH2:47][NH:46][CH2:45]1)([CH3:39])([CH3:38])[CH3:37]>C(OCC)(=O)C>[C:36]([O:40][C:41](=[O:50])[NH:42][CH2:43][CH:44]1[O:49][CH2:48][CH2:47][N:46]([C:12]2[CH:11]=[C:16]([CH:17]([S:26][C:27]3[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=3)[C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])[C:15]([Cl:34])=[CH:14][N:13]=2)[CH2:45]1)([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)c1c(Cl)ncc(Cl)c1C(Sc1ccc(Cl)cc1)c1cc(F)ccc1F
Reactant: CC(C)(C)OC(=O)NCC1CNCCO1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC1CN(c2cc(C(Sc3ccc(Cl)cc3)c3cc(F)ccc3F)c(Cl)cn2)CCO1
Temperature: 25 °C
Yield: 53.9 %

Procedure:
A 1,4-dioxane (1.0 ml) solution of the t-butyl 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine (60 mg, 0.14 mmol) obtained in Example 54 and t-butyl(morpholin-2-yl)methylcarbamate (200 mg) was stirred at 100° C. for 2 days under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 ml). The diluted mixture was washed with water and brine, dried and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ether=5:1) to give the title compound (45 mg, 52%) as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH3:11])[C:6]=2[CH:12]=1.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[C:23]([CH:27]=[O:28])[CH:24]=[N:25][CH:26]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:11][N:7]1[C:6]2[CH:12]=[C:2]([C:21]3[CH:22]=[C:23]([CH:27]=[O:28])[CH:24]=[N:25][CH:26]=3)[CH:3]=[CH:4][C:5]=2[O:9][C:8]1=[O:10]
Reactant: Cn1c(=O)oc2ccc(Br)cc21
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
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: COCCOC
Product: Cn1c(=O)oc2ccc(-c3cncc(C=O)c3)cc21

Procedure:
A mixture of 5-Bromo-3-methyl-3H-benzooxazol-2-one (684 mg, 3 mmol), 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-3-carbaldehyde (699.2 mg, 3 mmol), polymer supported PalladiumTetrakis (0.11 mmol/g, 682 mg, 0.075 mmol), Na2CO3 (2 M in eater, 3 mL, 6 mmol) in DME (6 mL) was heated to reflux for overnight. After filteration and concentration, the residue was purified by flash column and yielded yellow solid. ESI-MS m/z: 255.0 [M+1]+, Retention time 1.03 min.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].ClC1C(C(OO)=[O:22])=CC=CC=1>C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]2[O:22][CH:10]2[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C(OO)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CC=CCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2OC2C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3.29 g of N-BOC-1,2,5,6-tetrahydropyridine in 25 ml of CH2Cl2, a suspension of 6.2 g of chloroperbenzoic acid in 50 ml of CH2Cl2 are added and the mixture obtained is stirred for ca. 12 hours at RT. The mixture obtained is extracted with saturated aqueous NaHCO3-solution and 0.5 m aqueous Na2S5O3-solution and the organic phase obtained is washed, dried and the solvent is evaporated. N-BOC-3,4-epoxy-piperidine is obtained.
Reaction SMILES: Br.[CH3:2][N:3]1[C:7]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19]Br)[CH:14]=2)=[N:6][C:5]([NH2:21])=[N:4]1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)C>[CH3:2][N:3]1[C:7]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:14]=2)=[N:6][C:5]([NH2:21])=[N:4]1
Reactant: C1CCNCC1
Reactant: Cn1nc(N)nc1NCCCOc1cccc(CBr)c1
Agent: Br
Solvent: CCO
Product: Cn1nc(N)nc1NCCCOc1cccc(CN2CCCCC2)c1
Yield: 89.7 %

Procedure:
1-Methyl-N5 -[3-[3-(bromomethyl)phenoxy]propyl]-1H-1,2,4-triazole-3,5-diamine, hydrobromide (0.3 g) was dissolved in ethanol (5 ml) and treated with piperidine (0.3 g) at room temperature. The solvent was evaporated in vacuo and the residue triturated with ethyl acetate to afford the title compound as a white crystalline solid (0.22 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.Br[C:11]1[CH:12]=[CH:13][C:14]2[O:18][CH:17]=[CH:16][C:15]=2[CH:19]=1.C(N(CC)CC)C>CCO>[O:18]1[C:14]2[CH:13]=[CH:12][C:11]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:19][C:15]=2[CH:16]=[CH:17]1
Reactant: Brc1ccc2occc2c1
Reactant: OB(O)c1cccnc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: c1cncc(-c2ccc3occc3c2)c1
Yield: 63.7 %

Procedure:
A solution of 5 pyridin-3-ylboronic acid (390 mg, 3.18 mmol), 5-bromobenzofuran (500 mg, 2.54 mmol), palladiumdichlorobis(triphenylphosphine) (111 mg, 0.16 mmol) and triethylamine (8.8 mL, 63.5 mmol) in EtOH was irradiated in the microwave at 100° C. for 1200 s. Removal of the solvents followed by dissolving in CH2Cl2 and filtering gave the residue after concentration of the solvent under reduced pressure. The compound was purified on ISCO to afford 316 mg of the title compound as a light yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 8.60 (d, 1H), 7.90 (d, 1H), 7.80 (s, 1H), 7.69 (s, 1H), 7.55 (d, 1H), 7.50 (d, 1H) 7.38 (dd, 1H), 6.85 (dd, 1H). MS (ESI) m/z: Calculated: 195.07; Observed: 196.30 (M++1).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH2:10][C:11]2[O:12][C:13]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[C:14]=3[N:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:26](Cl)(=[O:28])[CH3:27]>N1C=CC=CC=1.CO>[C:26]([O:20][C:16]1[C:14]2[N:15]=[C:11]([CH2:10][C:9]3[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:7]([O:6][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:8]=3)[O:12][C:13]=2[CH:19]=[CH:18][CH:17]=1)(=[O:28])[CH3:27]
Reactant: COc1ccc(Cc2nc3c(O)cccc3o2)cc1OC1CCCC1
Reactant: CC(=O)Cl
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(Cc2nc3c(OC(C)=O)cccc3o2)cc1OC1CCCC1
Yield: 53 %

Procedure:
A solution of 2-(3-cyclopentyloxy-4-methoxybenzyl)-4-hydroxybenzoxazole (200 mg) and acetyl chloride (84 μl) in pyridine (6 ml) was stirred at room temperature, under nitrogen, for 3 hours. The reaction mixture was diluted with methanol (20 ml) and evaporated in-vacuo to yield a yellow solid. The solid was purified by flash chromatography (SiO2; dichloromethane; methanol (50:1)) and crystallized from ether/petroleum ether to yield the title compound (119 mg, 53%) as a white crystalline solid (mp 65-67° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)(O)[CH3:13])[C:6]3[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][C:5]=3[C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[OH-].[K+]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](/[C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)\[CH3:13])[C:6]3[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(C)(O)c2ccc(Cl)cc2)C1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
1-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(4-chlorophenyl)propan-2-ol (1 g, 2.57 mmol, 1 equiv.) was refluxed with 25% sulfuric acid (7 mL) for 2 h. The reaction mixture was cooled to 5° C. in ice-water bath. KOH (15% aqueous solution) was added dropwise to the reaction mixture until pH 9-10 was achieved. The reaction mixture was extracted with EtOAc (3×10 mL). The combined organic layer was washed with water (10 mL) followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product was purified by silica gel chromatography (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%) to obtain a mixture of isomers, which were separated by HPLC. 1H NMR (CD3OD, HCl salt) δ (ppm): 7.65 (d, 2H), 7.55 (s, 1H), 7.45 (d, 2H), 7.22 (s, 2H), 7.05 (s, 1H), 4.75 (m, 1H), 4.40 (m, 1H), 3.86 (m, 1H), 3.60 (m, 1H), 3.16 (m, 2H), 3.12 (s, 3H), 1.95 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][C:16](I)=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([C:29]([F:32])([F:31])[F:30])=[C:24]([F:33])[CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)[Cl:35].CO>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][C:16]([Cl:35])=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([C:29]([F:32])([F:31])[F:30])=[C:24]([F:33])[CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCCl
Reactant: CCc1nc(I)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1cc(F)c(C(F)(F)F)c(F)c1
Solvent: CO
Product: CCc1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1cc(F)c(C(F)(F)F)c(F)c1

Procedure:
According to the general procedure (GP12), chlorination of 8-[2-(3,5-difluoro-4-trifluoromethyl-phenyl)-ethyl]-3-ethyl-1-iodo-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (500 mg; 0.854 mmol) and purification by FC (DCM/MeOH=100/3) gave the product 1-chloro-8-[2-(3,5-difluoro-4-trifluoromethyl-phenyl)-ethyl]-3-ethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow solid (179 mg; 42%). LC-MS: tR=1.05 min.; [M+H]+=494.37 g/mol.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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.CN(C=O)C>[CH3:11][O:10][C:8]([C:5]1[CH:4]=[N:3][C:2]([C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:24])([F:23])[F:12])=[CH:15][CH:16]=2)=[CH:7][N:6]=1)=[O:9]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
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: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)cn1
Temperature: 80 °C
Yield: 27.2 %

Procedure:
A solution of 5.18 g (30 mmol) methyl 5-chloropyrazine-2-carboxylate in 150 ml degassed DMF was treated with 3.47 g (0.1 mmol) tetrakis(triphenylphosphine)palladium and heated at 80° C. 6.27 g (33 mmol) of 4-(trifluoromethyl)benzeneboronic acid and 14 66 g (45 mmol) of cesium carbonate were added and heated for 3.5 h. The reaction was cooled to RT and extracted with H2O (0° C.)/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried (NaSO4) and evaporated. Purification by flash-chromatography on silica gel (heptane/AcOEt 95:5 to 2:1) gave 2.3 g (27%) of 5-(4-trifluoromethyl-phenyl)-pyrazine-2-carboxylic acid methyl ester.
Reaction SMILES: [C:1]12([CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)[C:10]1[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:4][CH2:3][CH2:2]2.N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>O>[CH3:23][S:24]([O:16][CH:13]1[CH2:12][CH2:11][C:1]2([C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)[CH2:15][CH2:14]1)(=[O:26])=[O:25]
Reactant: OC1CCC2(CCCc3ccccc32)CC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)OC1CCC2(CCCc3ccccc32)CC1
Temperature: 0 °C
Yield: 94.3 %

Procedure:
To an ice-cooled solution of 3.89 g. (0.018 M) of 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ol -(obtained in Example 17A) in 40 ml. of pyridine, 4 ml. of methane sulfonyl chloride is added. The mixture is allowed to stand in the cold for about 6 hours and then diluted with water. The material that precipitates is extracted with ether and the combined extracts washed successively with ice cold 2.5 N hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and brine and then evaporated to dryness. The residue is recrystallized from cyclohexane to give 5 g. (94.3% yield) of 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ol methane sulfonate(t), having a melting point of 118° to 120° C.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].Cl.[NH2:18][C@@H:19]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]([CH3:30])[CH:22]=1.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([NH:18][C@@H:19]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]([CH3:30])[CH:22]=1)=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: Cn1cc(C[C@@H](N)C(=O)OCc2ccccc2)c2ccccc21
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](Cc1cn(C)c2ccccc12)C(=O)OCc1ccccc1
Yield: 84.6 %

Procedure:
Boc-L-Leu-OH (1.30 g), HCl.H-D-Trp(CH3)-OBzl (1.76 g), WSCD (950 mg) and HOBT (827 mg) in DMF (30 ml) was reacted at 5° C. overnight in a similar manner to that of Preparation 1-1) to give Boc-L-Leu-D-Trp(CH3)-OBzl (2.48 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([B:22]2[O:26][C:25](C)([CH3:27])C(C)(C)[O:23]2)=[C:15]([CH:18]=[CH:19][C:20]=1[CH3:21])C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:31](C)([O-:33])=[O:32].[OH-].[Na+].C1COCC1>O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]2[B:22]([OH:23])[O:26][CH:25]([CH2:27][N+:31]([O-:33])=[O:32])[C:15]=2[CH:18]=[CH:19][C:20]=1[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: Cc1ccc(C=O)c(B2OC(C)(C)C(C)(C)O2)c1OCCCOCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1OCCCOCc1ccccc1)B(O)OC2C[N+](=O)[O-]

Procedure:
Synthesized according to the methods of general procedure 8 in U.S. Pat. Pub. No. 20090227541 (U.S. patent application Ser. No. 12/142,692) using the following reactants and amounts: 3-(3-benzyloxy-propoxy)-4-methyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (1.14 g, 2.78 mmol), nitromethane (0.45 mL, 8.34 mmol), NaOH (0.78 g, 1.95 mmol), THF (3 mL) and water (9 mL). Purification: flash column chromatography (25% EtOAc/hexanes): yield 0.42 g (41%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.41 (s, 1H), 7.37-7.18 (m, 6H), 7.03 (d, J=7.8 Hz, 1H), 5.69 (dd, J=9.2, 2.5 Hz, 1H), 5.28 (dd, J=13.7, 2.7 Hz, 1H), 4.52 (dd, J=13.3, 9.4 Hz, 1H), 4.46 (s, 2H), 4.33 (t, J=6.1 Hz, 2H), 3.58 (t, J=6.1 Hz, 2H), 2.12 (s, 3H), 2.01-1.87 (m, 2H). MS (ESI): m/z=370 (M−1, negative).
Reaction SMILES: C1COCC1.[C:6]([C:8]1[CH:9]=[C:10]([CH2:13][O:14][CH3:15])[O:11][CH:12]=1)#[CH:7].I[C:17]1[CH:42]=[CH:41][C:20]([C:21]([N:23]([CH3:40])[C@:24]([CH3:39])([C:29]([NH:31][O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)=[O:30])[C:25]([NH:27][CH3:28])=[O:26])=[O:22])=[CH:19][CH:18]=1>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.[Cu]I.C(OCC)(=O)C>[CH3:15][O:14][CH2:13][C:10]1[O:11][CH:12]=[C:8]([C:6]#[C:7][C:17]2[CH:42]=[CH:41][C:20]([C:21]([N:23]([CH3:40])[C@:24]([CH3:39])([C:29]([NH:31][O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)=[O:30])[C:25]([NH:27][CH3:28])=[O:26])=[O:22])=[CH:19][CH:18]=2)[CH:9]=1
Reactant: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(I)cc1
Reactant: C#Cc1coc(COC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(C#Cc2coc(COC)c2)cc1
Yield: 82.9 %

Procedure:
PdCl2(PPh3)2 (70 mg), CuI (38 mg) and TEA (1.5 mL) were added to a THF (7.0 mL) solution of 4-ethynyl-2-(methoxymethyl)furan (0.24 g) as obtained in Example 18-(3) and (2S)-2-[(4-iodobenzoyl)(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (Intermediate 15, 0.51 g), and the mixture was stirred for 5.5 hours at room temperature in a nitrogen atmosphere. Ethyl acetate (30 mL), OH type silica gel (1.9 g), cellpure (0.95 g) and activated carbon (50 mg) were added, the insolubles were filtered out, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by OH type silica gel column chromatography (gradient elution with ethyl acetate/hexane=75/25→100/0, followed by gradient elution with chloroform/acetone=100/0→70/30) to obtain (2S)-2-[(4-{[5-(methoxymethyl)furan-3-yl]ethynyl}benzoyl)(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (yellow solid) (0.43 g, 84%).
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[C:3]#[C:4][CH2:5][N:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([Li])CCC.[C:21]1([C:27]2[C:28]3[O:33][CH2:32][O:31][CH:30](Cl)[C:29]=3[CH:35]=[CH:36][C:37]=2[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[NH4+].[Cl-]>O.O1CCCC1>[C:21]1([C:27]2[C:28]3[O:33][CH2:32][O:31][CH:30]([CH:5]([N:6]=[CH:7][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:4]#[C:3][Si:2]([CH3:14])([CH3:1])[CH3:15])[C:29]=3[CH:35]=[CH:36][C:37]=2[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClC1OCOc2c1ccc(-c1ccccc1)c2-c1ccccc1
Reactant: C[Si](C)(C)C#CCN=Cc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)C#CC(N=Cc1ccccc1)C1OCOc2c1ccc(-c1ccccc1)c2-c1ccccc1
Yield: 109.3 %

Procedure:
To a stirred solution of 1-trimethylsilyl-N-benzylidene-3-aminoprop-1-yne (7.609 g.; 34.4 mmol) in 106 ml. of tetrahydrofuran maintained at -78° under N2 was added dropwise 19.5 ml. of 1.63 N n-butyl lithium. To the stirred deep red solution was then added dropwise 11.43 g. (35.4 mmol) of 3,4-diphenylmethylenedioxybenzyl chloride in 35 ml. of tetrahydrofuran. After an additional 30 minutes at -78° water (25 ml.) was added dropwise, the mixture was warmed to 20°, 10% aqueous NH4Cl solution was added and the layers were separated. The aqueous layer was washed twice with benzene, the combined organic phases were washed twice with cold 10% aqueous NH4Cl, once with saturated NaCl solution, dried over Na2SO4 and concentrated to dryness to give 3-(3,4-diphenylmethylenedioxybenzyl)-1-trimethylsilyl-N-benzylidene-3-aminoprop-1-yne as a viscous orange oil (18,86 g).
Reaction SMILES: [F:1][C:2]1[N:3]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1.C([Li])CCC.[C:31]1([N:37]=[C:38]=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[F:1][C:2]1[N:3]([C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:4]=[C:5]([C:38](=[O:39])[NH:37][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:6]=1
Reactant: Fc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C=Nc1ccccc1
Agent: [Li]CCCC
Product: O=C(Nc1ccccc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1

Procedure:
Reaction of 2-fluoro-1-triphenylmethylimidazole with n-butyl lithium at -75° followed by treatment with phenylisocyanate gave 2-fluoro-4-phenylcarbamoyl-1-triphenylmethylimidazole, n.m.r. in CDCl3 : 7.0-7.5 (m, 19H); 7.6 (d, 2H); 8.6 (s, 1H). Reaction of this product with toluene-p-sulphonic acid in DMF at 85° for 15 minutes gave 2-fluoro-4-phenylcarbamoylimidazole, n.m.r. in CDCl3 : 6.9-8.0 (m, 6H); 9.6 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[N:18]1([CH2:23][C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:28][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:30][CH:29]=1
Reactant: Nc1ccc(CN2CCCC2)cc1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: O=C(c1cnc2ccc(Br)cc2c1Nc1ccc(CN2CCCC2)cc1)C1CC1
Yield: 83.4 %

Procedure:
Following general procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (320 mg, 1.03 mmol) was reacted 4-(pyrrolidin-1-ylmethyl)aniline (385 mg, 1.55 mmol) to afford the desired product (387 mg, 83%) as a yellow solid: ESI MS m/z 450 [C24H24BrN3O+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:18]C)[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=2)[C:7]1=[O:20].Br>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:18])[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=2)[C:7]1=[O:20]
Reactant: COc1c2c(cn(C)c1=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: Br
Solvent: CC(=O)O
Product: Cn1cc2c(c(O)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2

Procedure:
A solution of 2-(3-chloro-4-fluorobenzyl)-8-methoxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione (30 mg, 0.086 mmol) and 33% HBr in acetic acid (5 mL) in acetic acid (10 mL) was stirred at room temperature for 2 hours. The product mixture was concentrated under vacuum. The residue was subjected to preparative reverse phase HPLC purification. Collection and lyophilization of appropriate fractions provide the titled compound.