Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](=[N:9][N:10]=[C:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>CN(C)C1C=CC=CC=1>[CH3:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[N:9][N:10]=1
Reactant: Nc1ccccc1
Reactant: Cc1ccccc1C(Cl)=NN=C(Cl)c1ccccc1
Agent: Cl
Solvent: CN(C)c1ccccc1
Product: Cc1ccccc1-c1nnc(-c2ccccc2)n1-c1ccccc1
Temperature: 120 °C
Reaction time: 7 h
Yield: 62 %

Procedure:
Then, 5.1 g (17.6 mmol) of [chloro(2-methylphenyl)methanone][chloro(phenyl)methylidene]hydrazone obtained in Step 2, 60 ml of dimethylaniline, and 4.9 g (52.8 mmol) of aniline were put into a 500-ml recovery flask and heated and stirred at 120° C. for 7 hours. After the stirring, the reacted solution was added to 1N hydrochloric acid and the mixture was stirred for 30 minutes. Then, an organic layer was extracted with dichloromethane. This organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated brine. Purification by column chromatography was then performed. A mixed solvent of toluene and ethyl acetate in a ratio of 1:1 was used as a developing solvent. The obtained fraction was concentrated to give 3.4 g of a white solid of Hmpptz in a yield of 63%. A synthesis scheme of Step 3 is shown in (a-3).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([C@@H:13]3[CH2:17][NH:16][C@@H:15]([C:18]([OH:20])=O)[CH2:14]3)[CH:12]=2)=[CH:4][C:3]=1[C:21]1[S:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1.[CH3:30][NH:31][CH3:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:30][N:31]([CH3:32])[C:18]([C@H:15]1[CH2:14][C@H:13]([N:11]2[CH:12]=[C:8]([C:5]3[CH:6]=[N:7][C:2]([NH2:1])=[C:3]([C:21]4[S:22][C:23]5[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=5[N:25]=4)[CH:4]=3)[CH:9]=[N:10]2)[CH2:17][NH:16]1)=[O:20]
Reactant: CNC
Reactant: Nc1ncc(-c2cnn([C@@H]3CN[C@@H](C(=O)O)C3)c2)cc1-c1nc2ccccc2s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)[C@H]1C[C@H](n2cc(-c3cnc(N)c(-c4nc5ccccc5s4)c3)cn2)CN1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of (2R,4S)-4-[4-(6-amino-5-benzothiazol-2-ylpyridin-3-yl)-pyrazol-1-yl]-pyrrolidine-2-carboxylic acid (10.00 mg, 0.019 mmol), dimethylamine (0.009 g, 0.2 mmol), TBTU (12.4 mg, 0.0388 mmol), and DMF (1 mL) was charged with DIPEA (0.03 mL, 0.2 mmol) and allowed to stir at rt for 10 min. The solution was used directly for HPLC purification. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=2.40-2.51 (m, 1H), 2.87 (d, J=6.1 Hz, 1H), 3.04 (s, 3H), 3.09 (s, 3H), 3.72 (br. s., 1H), 3.85 (dd, J=12.5, 6.4 Hz, 1H), 5.02 (t, J=8.7 Hz, 1H), 5.29 (br. s., 1H), 7.42-7.48 (m, 1H), 7.54 (td, J=7.7, 1.3 Hz, 1H), 7.96 (s, 1H), 8.02 (dd, J=15.2, 7.6 Hz, 2H), 8.14 (s, 1H), 8.21 (d, J=2.3 Hz, 1H), 8.33 (d, J=2.3 Hz, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[C:15]2[C:10](=[CH:11][C:12]([CH3:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][CH:7]=1>[Pd].C(O)C.[Pt]=O>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]1[C:15]2[C:10](=[CH:11][C:12]([CH3:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1
Reactant: COc1cc2c(cc1C)CCC=C2c1ncc[nH]1
Agent: O=[Pt]
Agent: [Pd]
Solvent: CCO
Product: COc1cc2c(cc1C)CCCC2c1ncc[nH]1

Procedure:
This compound was prepared in a manner analogous to that of Step C of Example 7, by the hydrogenation of 0.7 gram (0.003 mole) of 4-imidazol-2-yl-6-methoxy-7-methyl-1,2-dihydronaphthalene (xiii) using a Parr hydrogenator, in the presence of 0.1 gram (catalyst) of platinum oxide and 0.1 gram (catalyst) of 10% palladium on carbon in 50 mL of ethanol. The yield of the subject compound was 0.34 gram, mp 168-169° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:29]O.Cl>CO.O>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][C@H:10]1[CH2:9][C@H:8]([C:6]2[O:7][NH:29][C:4](=[O:3])[CH:5]=2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2ccccc2F)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccccc1F
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 44.7 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-fluorobenzyl)piperidine-1-carboxylate (1.145 g, 3.13 mmol) (from example 101, step 1) was dissolved in methanol (10 mL) and cooled to −40° C. Sodium hydroxide (0.194 g, 4.84 mmol) dissolved in water (1.000 mL) was added dropwise and continued to stir at −40° C. for 30 min. Hydroxylamine (50% by weight in water, 0.192 mL, 3.13 mmol) was added dropwise. The resulting solution was stirred at −40° C. for 2 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (15 mL, 90.00 mmol) and the mixture continued to stir at 80° C. for 55 min. The solvent was evaporated and MTBE/water added. The phases were separated and the organic phase dried over Na2SO4 and evaporated to a yellow foam. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) with a gradient of 15-75% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Trans-methyl 2-(2-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)-piperidine-1-carboxylate (468 mg, 45%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.46-1.77 (m, 2H), 1.80-2.13 (m, 2H), 2.28-3.23 (m, 4H), 3.38-3.80 (m, 3H), 4.04-4.34 (m, 1H), 4.50-4.80 (m, 1H), 5.65 (s, 1H), 6.99-7.12 (m, 2H), 7.12-7.30 (m, 2H). MS m/z 335 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[CH:11]=[CH:10][O:9][C:8]=12.[CH2:12]=[O:13]>>[CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[CH:11]=[C:10]([CH2:12][OH:13])[O:9][C:8]=12
Reactant: COc1nccc2ccoc12
Reactant: C=O
Product: COc1nccc2cc(CO)oc12

Procedure:
Starting from 7-methoxyfuro[2,3-c]pyridine (2.06 g) and formaldehyde (27 ml). Purification by column chromatography on silica eluting with 50% hexane in ethyl acetate gave the title compound (1.4 g) as a white solid.
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][CH:9]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1)[S:10][C:11]1[C:16]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=2)=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:7])(=O)C>CO.O1CCCC1.[OH-].[Na+].C(OCC)(=O)C>[OH:4][CH2:5][C:6]([NH:8][CH:9]([C:31]1[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=1)[S:10][C:11]1[C:16]([C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]([F:28])([F:29])[F:30])=[CH:24][CH:25]=2)=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:7]
Reactant: CC(=O)OCC(=O)NC(Sc1ncccc1C(=O)Nc1ccc(OC(F)(F)F)cc1)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CO)NC(Sc1ncccc1C(=O)Nc1ccc(OC(F)(F)F)cc1)c1ccncc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.2 %

Procedure:
2-(2-Acetoxyacetylaminopyridin-4-ylmethylthio)-N-(4-trifluoromethoxyphenyl)pyridine-3-carboxamide (Compound No. 10-2, 25 mg, 0.048 mmol) was dissolved in the mixture of methanol (2.0 mL) and tetrahydrofuran (1.0 mL), and 4 N aqueous sodium hydroxide solution (60 μL) was added thereto under ice-cooling. The mixture was stirred for 15 minutes at room temperature and diluted with ethyl acetate (30 mL), and then the whole was washed with saturated aqueous sodium hydrogen carbonate solution (30 mL) and brine (30 mL). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 23 mg of the target compound quantitatively as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH:11]([N:12]2[C:16]([CH:17]=O)=[CH:15][N:14]=[CH:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:19])[O:3]1.[CH2:21]([NH2:23])[CH3:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH2:21]([NH:23][CH2:17][C:16]1[N:12]([CH:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:19])[O:3][C:2]2([CH3:20])[CH3:1])[CH:13]=[N:14][CH:15]=1)[CH3:22]
Reactant: CCN
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCNCc1cncn1C1c2ccccc2C(=O)OC1(C)C
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of 3-(3,3-dimethyl-1-oxo-isochroman-4-yl)-3H-imidazole-4-carbaldehyde (0.133 g, 0.49 mmol) (Example 9a) in dichloroethane (2 mL) is added ethylamine (0.37 mL, 0.738 mmol) and sodium triacetoxyborohydride (0.313 g, 1.477 mmol). The reaction mixture is stirred at 50° C. for 5 h. The mixture is cooled to room temperature, washed with saturated aqueous sodium bicarbonate and is extracted with ethyl acetate. The organic phase is dried over Na2SO4 and concentrated in vacuo. The residue is dissolved in methanol (5 mL) and purified by reverse phase HPLC to give 4-(5-ethylaminomethyl-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one; HRMS (ESI) m/z 300.1705 [(M+H)+: Calcd for C17H22N3O2: 300.1712]; 1H NMR (400 MHz, MeOD) of the TFA salt δ ppm 1.27 (s, 3 H), 1.46 (t, J=6.8 Hz, 3 H), 1.59 (s, 3 H), 3.35-3.40 (m, 2 H), 4.65 (br. s, 2 H), 5.82 (s, 1 H), 7.51 (br. s, 1 H), 7.64 (d, J=7.3 Hz, 1 H), 7.75 (td, J=7.8, 1.0 Hz, 1 H), 7.84 (td, J=7.6, 1.3 Hz, 1 H), 7.92 (br. s, 1 H), 8.30 (dd, J=7.8, 1.3 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)[C:6]([CH3:22])=[C:5]2[C:23]([OH:25])=[O:24].[C:26](Cl)(=O)C(Cl)=O.CO>ClCCl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=1)[C:6]([CH3:22])=[C:5]2[C:23]([O:25][CH3:26])=[O:24]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1c(-c2cccc(C(F)(F)F)c2)nc2ccc(Br)cc2c1C(=O)O
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2ccc(Br)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 152.6 %

Procedure:
A solution of 6-bromo-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (50 g, 122 mmol) in dichloromethane (700 mL) was cooled to 0° C., and DMF (1.416 mL, 18.28 mmol) was added. To the cooled solution, oxalyl chloride (16.01 mL, 183 mmol) was added dropwise (slowly) and the mixture was stirred at 0° C. for 1 h. Methanol was added and after 2 h the mixture was warmed to room temperature overnight. The solvent was removed under reduced pressure. The residue was treated with water (200 mL) and saturated aqueous NaHCO3 (300 mL) and extracted with methylene chloride (500 mL). The aqueous phase was extracted with methylene chloride (300 mL). The organic phase was washed with saturated aqueous NaHCO3 and brine, dried, filtered, and concentrated. The resulting solid was combined with material from a separate experiment (51 g) and the material was suspended in 400-500 mL of acetonitrile. The mixture was heated to 75° C. until the solid completely dissolved. The mixture was cooled, and the resulting precipitate was collected by filtration and dried. The filtrate was concentrated and the recrystallization procedure was repeated to give additional product. Both batches were combined to afford methyl 6-bromo-3-(methyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (79 g, 73% overall yield). MS (m/z) 426.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[S:15][C:14]([C:16](O)=[O:17])=[C:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.CC[N:27]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl-].[NH4+]>CCOC(C)=O.O.CN(C=O)C.C(N(CC)CC)C>[CH3:1][C:2]1[C:10]([C:11]2[S:15][C:14]([C:16]([NH2:27])=[O:17])=[C:13]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:12]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1nn2ccccc2c1-c1cc(-c2ccccc2)c(C(=O)O)s1
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1nn2ccccc2c1-c1cc(-c2ccccc2)c(C(N)=O)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.2 %

Procedure:
A mixture of 5-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-3-phenylthiophene-2-carboxylic acid (100 mg, 0.299 mmol), EDCI (450 mg, 2.35 mmol), HOBt (95 mg, 0.703 mmol), triethylamine (2.5 mL), ammonium chloride (870 mg, 16.3 mmol) and DMF (35 mL) was stirred for 16 h at rt. To the mixture, were added water and EtOAc and the resulting biphasic mixture was vigorously stirred for 30 min. The organic phase was washed with water and brine and then dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was washed with EtOAc and diisopropyl ether to yield the title compound (72 mg, 71%) as a pale yellow solid. 1H NMR (300 MHz, d6-DMSO) δ: 8.68 (d, J=7.0 Hz, 1H), 7.92 (d, J=9.1 Hz, 1H), 7.70-7.53 (m, 2H), 7.53-7.31 (m, 4H), 7.26 (s, 1H), 7.11-6.71 (m, 3H), 2.59 (s, 3H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].C(O)C>[CH3:30][O:29][C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][C@H:9]2[CH2:10][NH:11][CH2:12][CH2:13][NH:8]2)[CH:28]=[CH:27][CH:26]=1
Reactant: COc1cccc(CC[C@H]2CN(Cc3ccccc3)CCN2Cc2ccccc2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COc1cccc(CC[C@H]2CNCCN2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
Combine (S)-1,4-dibenzyl-2-(2-(3-methoxy-phenyl)-ethyl)-piperazine (2.15 g, 5.37 mmol), ammonium formate (1.69 g, 26.84 mmol), 5% Pd/C (259.7 mg), and ethanol (100 mL). Stir and heat the mixture at reflux. After 3 hours, cool to ambient temperature and remove the catalyst by vacuum filtration through celite. Reduce the filtrate to residue and purify it on silica gel using dichloromethane/7N ammonia in methanol (90:10) to give (1.11 g, 94%) of the title compound as a white solid: mp 53–57° C.; mass spectrum (ion spray): m/z=221.1 (M+1); Analysis for C13H20N2O: calcd: C, 70.87; H, 9.15; N, 12.72; found: C, 70.52; H, 9.06; N, 12.74.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9](=[CH2:17])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]>>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([C:9]([CH3:17])([CH3:8])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:3][CH:2]=1
Reactant: C=C(C)CCCC(=O)OC
Reactant: Oc1ccccc1
Product: COC(=O)CCCC(C)(C)c1ccc(O)cc1

Procedure:
94 Parts of phenol, 14.2 parts of methyl 5-methyl-hex-5-enoate, and 5.0 parts of Fulmont 237® were stirred at 110° C. for 20 hours. The partly cooled reaction mixture was then filtered free of catalyst and distilled. After recovering 82 parts of phenol there was obtained methyl 5-(4-hydroxyphenyl)-5-methyl-hexanoate b0.85 167°-72° C. with the following percentage composition by weight.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[N:19]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:27][C:28]1[N:29]=[C:30]([CH:33]=[CH:34][C:35]2[CH:40]=[CH:39][C:38]([S:41]([C:43]([F:46])([F:45])[F:44])=[O:42])=[CH:37][CH:36]=2)[O:31][CH:32]=1>CN(C)C=O>[C:1]([O:5][C:6](=[O:23])[N:7]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[N:19]2)=[CH:10][CH:9]=1)[CH2:27][C:28]1[N:29]=[C:30]([CH:33]=[CH:34][C:35]2[CH:36]=[CH:37][C:38]([S:41]([C:43]([F:46])([F:44])[F:45])=[O:42])=[CH:39][CH:40]=2)[O:31][CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(c1ccc(C=Cc2nc(CCl)co2)cc1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1ccc(C=CCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1coc(C=Cc2ccc(S(=O)C(F)(F)F)cc2)n1)c1ccc(C=CCCn2ccnn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.3 %

Procedure:
A solution of [4-(4-[1,2,3]triazol-1-yl-but-1-enyl)-phenyl]-carbamic acid tert-butyl ester (0.157 g, 0.5 mmol) in N,N-dimethyl formamide (4 ml) was treated with sodium hydride (0.014 g, 0.5 mmol) and stirred for 30 min at room temperature. After addition of 4-chloromethyl-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazole (0.168 g, 0.5 mmol) and stirring for 12 h the reaction was quenched by the addition of a sat. NH4Cl solution (8 ml). Extraction with ethyl acetate (3×10 ml), washing with water, drying over sodium sulfate and concentration in vacuo yields crude [4-(4-[1,2,3]triazol-1-yl-but-1-enyl)-phenyl]-{2-[2-(4-trifluoromethane-sulfinyl-phenyl)-vinyl]-oxazol-4-ylmethyl}-carbamic acid tert-butyl ester (0.28 g) which was used in the next step without any further purification.
Reaction SMILES: [CH2:1]([CH:5]1[C:9]2([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[O:8][C:7](=[O:15])[NH:6]1)[CH2:2][CH2:3][CH3:4].[CH3:16][C:17]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:18]=1[C:19]([N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)=[O:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O.N>C(Cl)Cl>[CH2:1]([CH:5]1[C:9]2([CH2:14][CH2:13][N:12]([CH:24]3[CH2:25][CH2:26][N:21]([C:19](=[O:20])[C:18]4[C:28]([CH3:32])=[CH:29][CH:30]=[CH:31][C:17]=4[CH3:16])[CH2:22][CH2:23]3)[CH2:11][CH2:10]2)[O:8][C:7](=[O:15])[NH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1NC(=O)OC12CCNCC2
Reactant: Cc1cccc(C)c1C(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCC1NC(=O)OC12CCN(C1CCN(C(=O)c3c(C)cccc3C)CC1)CC2
Reaction time: 24 h
Yield: 73 %

Procedure:
To a solution of 4-butyl-1-oxa-3,8-diaza-spiro[4.5]decane-2-one (12: R=H; R′=n-Bu; 1.09 g; 5.1 mmol)) in 30 mL DCM was added 1.24 g (5.4 mmol) of 1-(2,6-dimethyl-benzoyl)-piperidin-4-one followed by 2.1 mL (7.1 mmol) of Ti(IV)(O-i-Pr)4 The reaction mixture stirred under nitrogen for 18 h. of Sodium triacetoxyborohydride (1.6 g: 7.7 mmol) was added to the reaction mixture followed by glacial HOAc (0.365 mL; 6.4 mmol). The reaction mixture stirred for 24 h. Aqueous ammonia (20 mL; 10% aqueous solution) was added and the solution stirred for an additional 10 min. The mixture was filtered by gravity through a cartridge of ChemElute™. The organics were evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel with gradient elution (2% to 10% methanol in ethyl acetate with 0.4% ammonia) to provide 1.6 g (73%) of 4-butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-oxa-3,8-diaza-spiro[4.5]decane-2-one: ms [M]+=428.
Reaction SMILES: [CH3:1][C:2]([CH:4]=[CH:5][CH3:6])=[CH2:3].[CH3:7][CH:8]([CH3:16])/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[CH3:6][CH:5]1[CH:4]=[C:2]([CH3:3])[CH2:1][CH:9]([CH:8]([CH3:16])[CH3:7])[CH:10]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: C=C(C)C=CC
Reactant: CCOC(=O)/C=C/C(C)C
Product: CCOC(=O)C1C(C)C=C(C)CC1C(C)C

Procedure:
A mixture of 82 g (1.0 mol) of 2-methyl-1,3-pentadiene and 92.3 g (0.65 mol) of ethyl trans-4-methyl-2-pentenoate was heated at 175°-185° C. in an autoclave for 6 hours. After cooling, the reaction mixture was distilled. 57 g were obtained of the desired compound as a mixture of approx. 60% cis-trans- and 40% trans-trans-isomer. b.p.: 90°-91° C./0.7 kPa, NMR (cis-trans-isomer): 0.75 (3H, d, J=7 Hz); 0.8-1.0 (6H, d.d., J=7 Hz); 1.25 (3H, t, J=7 Hz); 1.64 (3H, broad s); 1.5-2.6 (6H); 4.09 (2H, k, J=7 Hz); 5.30 (1H). NMR (trans-trans-isomer): 0.8-1.0 (9H, 3xd, J=7 Hz); 1.27 (3H, t, J=7 Hz); 1.64 (3H, broad s); 1.5-2.6 (6H); 4.13 (2H, m); 5.12 (1H).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn(Cc4ccccc4)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc2c(C)cc(-c3cn(Cc4ccccc4)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-benzyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: Cl.[CH:2]([N:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]([C:14]2[N:27]([CH2:28][C:29]3[CH:33]=[C:32]([C:34]4[S:35][C:36]([Cl:39])=[CH:37][CH:38]=4)[O:31][N:30]=3)[C:17]3=[CH:18][N:19]=[C:20]([O:22][CH2:23][CH2:24][O:25]C)[CH:21]=[C:16]3[CH:15]=2)=[O:13])[CH2:7][CH2:6]1)([CH3:4])[CH3:3].B(Br)(Br)Br.Cl>C(Cl)Cl>[CH:2]([N:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]([C:14]2[N:27]([CH2:28][C:29]3[CH:33]=[C:32]([C:34]4[S:35][C:36]([Cl:39])=[CH:37][CH:38]=4)[O:31][N:30]=3)[C:17]3=[CH:18][N:19]=[C:20]([O:22][CH2:23][CH2:24][OH:25])[CH:21]=[C:16]3[CH:15]=2)=[O:13])[CH2:7][CH2:6]1)([CH3:4])[CH3:3]
Reactant: COCCOc1cc2cc(C(=O)NC3CCN(C(C)C)CC3)n(Cc3cc(-c4ccc(Cl)s4)on3)c2cn1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: CC(C)N1CCC(NC(=O)c2cc3cc(OCCO)ncc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 600 mg (1.01 mmol) of 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide hydrochloride (example 10 (vi)) in 50 mL CH2Cl2 2 mL (2.02 mmol) of a 1M solution of BBr3 in CH2Cl2 were added. The mixture was stirred at room temperature for 6 h. After standing over night the solvent was removed in vacuo and the residue was purified by preparative HPLC (eluent: CH3CN/H2O/0.1% CF3COOH). The fractions containing the product were combined and concentrated in vacuo. The residue was dissolved in CH2Cl2 an washed with 0.1N NaOH solution. The solvent was removed in vacuo and the residue lyophilized with 2.5 equivalents of 1N HCl yielding 464 mg (79%) of the hydrochloride salt of the desired product.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[CH3:17])[C:11]([OH:13])=[O:12])=[C:5]([CH3:7])[N:6]=1.IC1NC(C2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=NC=1C.IC1NC(C)=NC=1C>>[CH3:17][C:16]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[C:4]1[NH:3][C:2]([CH:1]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[N:6][C:5]=1[CH3:7]
Reactant: Cc1nc(C2CCOCC2)[nH]c1I
Reactant: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Agent: Cc1nc(C)c(I)[nH]1
Product: Cc1ccc(C(=O)O)cc1-c1[nH]c(C2CCOCC2)nc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.7, except 5-iodo-4-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazole (compound 164.1) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5).