Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:17][CH2:16][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1.Br[CH:19]1[CH2:23][CH2:22][N:21]([CH3:24])[C:20]1=[O:25]>CN(C=O)C>[CH3:3][N:4]1[CH2:17][CH2:16][C:7]2[N:8]([CH:19]3[CH2:23][CH2:22][N:21]([CH3:24])[C:20]3=[O:25])[C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1
Reactant: CN1CCC(Br)C1=O
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2C2CCN(C)C2=O)CCN(C)C1
Temperature: 0 °C
Yield: 13.5 %

Procedure:
A suspension of NaH (36 mg, 1.5 mmol) and 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (100 mg, 0.5 mmol) in DMF (5 mL) was stirred at 0° C. 3-bromo-1-methylpyrrolidin-2-one (176 mg, 1.0 mmol) in DMF (3 mL) was added dropwise to the reaction mixture which was stirred at RT for 12 hours. After completion of the reaction, the reaction mixture was quenched with ice cold water and the product extracted with Ethyl Acetate. The organic layer isolated was washed with water and dried over sodium sulfate. The solvent was removed under reduced pressure and the crude obtained was purified by column chromatography to obtain 20 mg of 3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-methylpyrrolidin-2-one. 1H NMR (CDCl3) FREEBASE 7.10 (s, 1H), 7.05 (d, 1H), 6.92 (d, 1H), 5.05 (m, 1H), 4.80 (m, 1H), 3.80 (m, 1H), 3.50 (m, 2H), 3.40 (m, 1H), 3.20 (m, 3H), 3.0 (s, 3H), 2.80 (s, 3H), 2.40 (s, 3H), 2.20 (m, 2H).
Reaction SMILES: [C:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[S:8][CH2:9][CH:10]([CH3:14])[C:11](O)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29]([OH:31])=[O:30].CN1CCOCC1>O1CCCC1.CC(N(C)C)=O>[C:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[S:8][CH2:9][CH:10]([CH3:14])[C:11]([N:27]2[CH2:34][CH2:33][CH2:32][C@H:28]2[C:29]([OH:31])=[O:30])=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CC(=O)N(C)C
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
3-Triphenylmethylthio-2-methylpropanoic acid (1.8 g.) and N,N'-carbonyldiimidazole (0.8 g.) are dissolved in tetrahydrofuran (10 ml.) with stirring at room temperature. After 20 minutes, the solution is added to a mixture of L-proline (0.6 g.) and N-methylmorpholine (1 g.) in dimethylacetamide (20 ml.). The resulting mixture is stirred overnight at room temperature, concentrated to dryness and the residue dissolved in a mixture of ethyl acetate and 10% aqueous potassium bisulfate. The organic layer is separated and dried and concentrated to dryness in vacuo to obtain 1-[3-(triphenylmethylthio)-2-methylpropanoyl]-L-proline. Rf : = 0.4 (Silica gel, Benzene/acetic acid 3:1), Rf 1.0 (Silica gel, Methyl-ethylketone/acetic acid/pyridine/water 14:1:2:1).
Reaction SMILES: [C:1]1([CH:7]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=2[O-:16])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=[O:19])C.OO>[O-][W]([O-])(=O)=O.[Na+].[Na+].O>[C:1]1([CH:7]([S:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=2[O-:16])=[O:19])[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)O
Reactant: CC(Sc1cccc[n+]1[O-])c1ccccc1
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: CC(c1ccccc1)S(=O)c1cccc[n+]1[O-]

Procedure:
To a mixture of 23.2 g (0.1 mole) of 2-(1-phenylethylthio)pyridine N-oxide, 0.2 g of sodium tungstate, and 60 ml of glacial acetic acid were added 10 ml (0.1 mole) of 30% hydrogen peroxide over approximately 0.5 hours. The mixture exothermed somewhat to about 65° C. After completion of the reaction, the reaction mixture was poured slowly into 800 ml of vigorously stirred cold water. A solid separated out and was filtered off and washed with 15 ml of cold ethanol. The solid was air dried, melting point 130–130.5° C. Yield 14.5 g or 59%. An infrared spectrum confirmed the structure.
Reaction SMILES: [CH:1]#[C:2]C.C=C=C.[CH3:7][C:8]([CH3:15])=[CH:9][CH2:10][CH2:11][C:12](=[O:14])[CH3:13].C#C>>[CH3:13][C:12]([OH:14])([CH2:11][CH2:10][CH:9]=[C:8]([CH3:15])[CH3:7])[C:1]#[CH:2]
Reactant: CC(=O)CCC=C(C)C
Reactant: C#CC
Agent: C#C
Agent: C=C=C
Product: C#CC(C)(O)CCC=C(C)C

Procedure:
The invention's composition of matter, and the (Z)-4,8-dimethyl-2,7-nonadien-4-ol essentially pure, can be prepared according to several methods. As reported in the experimental part, one possibility is the addition of prop-1-yn-1-yl Grignard such as prop-1-yn-1-yl magnesium bromide to 6-methyl-5-hepten-2-one. The triple bond of 4-8-dimethylnon-7-en-2-yn-4-ol obtained is then reduced under appropriate conditions in to order to provide selectively (Z)-4,8-dimethyl-2,7-nonadien-4-ol (e.g. Lindlar catalyst). The same intermediate could also be synthesized by the addition of propyne (or allene) to 6-methyl-5-hepten-2-one under basic conditions as described in DE2228333. Another approach starting from the same starting material as above passes through the acetylene addition providing the 3,7-dimethyloct-6-en-1-yn-3-ol then the methylation of the triple bond and finally, as previously described, the stereoselective hydrogenation of the triple bond (e.g. Lindlar catalyst) leading to (Z)-4,8-dimethyl-2,7-nonadien-4-ol. The addition of acetylene or ethynyl Grignard to 6-methyl-5-hepten-2-one is well documented (as non limited literatures: WO 20075025 or J. Am. Chem. Soc. 2002, 124 (18), 5025). A more direct alternative already reported in the literature (U.S. Pat. No. 2,838,576, DE 1005952, Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences 1955, 240, 631) is the addition of the prop-1-en-1-yl Grignard to 6-methyl-5-hepten-2-one.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([Cl:18])=[C:5]([CH2:9][N:10]2[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[CH2:12][O:11]2)[CH:6]=[CH:7][CH:8]=1.N([O-])=O.[Na+].[N-:23]=[N+:24]=[N-].[Na+]>O>[N:2]([C:3]1[C:4]([Cl:18])=[C:5]([CH2:9][N:10]2[C:14](=[O:15])[C:13]([CH3:16])([CH3:17])[CH2:12][O:11]2)[CH:6]=[CH:7][CH:8]=1)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)CON(Cc2cccc(N)c2Cl)C1=O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC1(C)CON(Cc2cccc(N=[N+]=[N-])c2Cl)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
Concentrated hydrochloric acid (25 ml) was added dropwise to a stirred mixture of 2-[(3-amino-2-chlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone (6.45 g, 0.025 mole) and water (75 ml). The reaction mixture was cooled to 0° C., and a solution of sodium nitrite (2.0 g, 0.03 moles) in water (25 ml) was added dropwise. Upon completion of addition, the reaction mixture was stirred at 0° C. for 30 minutes. An insoluble material was removed by filtration. The filtrate was cooled to 0° C., and sodium azide (1.6 g, 0.025 mole) was added portionwise. Upon completion of addition, the reaction mixture was stirred for 15 minutes. The reaction mixture was diluted with water (500 ml) and extracted with methylene chloride (3×100 ml). The dried (sodium sulfate) methylene chloride extract was concentrated under reduced pressure to yield 5.3 g of 2-[(3-azido-2-chlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone as a brown oil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:12]3[NH:13][CH2:14][CH2:15][CH2:16][N:11]3[N:10]=2)=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>ClCCl>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]([C:18]3[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=3)=[C:12]3[NH:13][CH2:14][CH2:15][CH2:16][N:11]3[N:10]=2)=[CH:7][CH:8]=1)=[O:32]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(-c2nn3c(c2-c2ccncc2)NCCC3)cc1
Solvent: ClCCl
Product: CS(=O)c1ccc(-c2nn3c(c2-c2ccncc2)NCCC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
To a solution of 2-(4-methylthiophenyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (190 mg) in dichloromethane (6 ml) was added m-chloroperbenzoic acid (127 mg) under ice cooling. The mixture was stirred at ambient temperature for 30 minutes and diluted with dichloromethane. The solution was washed with an aqueous saturated sodium thiosulfate solution, an aqueous saturated sodium bicarbonate solution and brine, dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel and the obtained crude solid was recrystallized from a mixture of 2-propanol and ether to give 2-(4-methylsulfinylphenyl)-3-(pyridin-4-yl)4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (168 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]([C:14](=[O:16])[CH3:15])[C:8]=2[CH:17]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]([C:14](=[O:16])[CH3:15])[C:8]=2[CH:17]=1
Reactant: CC(=O)N1CCCCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N1CCCCc2ccc(N)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.7 %

Procedure:
A mixture of 1-(8-nitro-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-ethanone (1.3 g, 5.4 mmol) and Pd—C (10%, 100 mg) in EtOH (200 mL) was stirred under H2 (1 atm) at room temperature for 1.5 h. The mixture was filtered through a layer of Celite and the filtrate was concentrated to give 1-(8-amino-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-ethanone (DC-9) as a white solid (1 g, 90%). 1H NMR (CDCl3) δ 7.01 (d, J=6.0 Hz, 1 H), 6.56 (dd, J=6.0, 1.8 Hz, 1 H), 6.50 (d, J=1.8 Hz, 1 H), 4.66-4.61 (m, 1 H), 3.50 (br s, 2 H), 2.64-2.55 (m, 3 H), 1.94-1.91 (m, 5 H), 1.77-1.72 (m, 1 H), 1.32-1.30 (m, 1 H); ESI-MS 204.1 m/z (MH+).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:27][OH:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.O=[Mn]=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:26])([C:22]([F:25])([F:23])[F:24])[C:18]([F:19])([F:20])[F:21])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH:27]=[O:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2n1Cc1ccccc1
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: O=Cc1cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2n1Cc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 33.3 %

Procedure:
To a solution of 1.03 g (2.56 mmol) of 2-(1-benzyl-2-hydroxymethyl-1H-indol-5-yl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (example 41) in 10 mL toluene were added 2.22 g (25.6 mmol) of MnO2 powder. The mixture was stirred at 80° C. overnight. Filtration through decalite, evaporation of the solvent and column chromatography on silica gel with n-heptane/EtOAc 3:1 yielded 0.342 g (33%) of 1-benzyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-1H-indole-2-carbaldehyde, MS: 400 (M−H)−.
Reaction SMILES: [OH:1][CH:2]([CH2:23][OH:24])[CH2:3][S:4]([CH2:7][CH2:8][C:9]([NH:12]C(=O)OCC1C=CC=CC=1)([CH3:11])[CH3:10])(=[O:6])=[O:5].[H][H]>CO.[Pd]>[NH2:12][C:9]([CH3:11])([CH3:10])[CH2:8][CH2:7][S:4]([CH2:3][CH:2]([OH:1])[CH2:23][OH:24])(=[O:6])=[O:5]
Reactant: [H][H]
Reactant: CC(C)(CCS(=O)(=O)CC(O)CO)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(N)CCS(=O)(=O)CC(O)CO
Reaction time: 2 h

Procedure:
A solution of benzyl 4-(2,3-dihydroxypropylsulfonyl)-2-methylbutan-2-ylcarbamate (2.34 g, 10.4 mmol) in methanol (50 ml) was purged with nitrogen and palladium on carbon (10%, 230 mg) was added. The suspension was put under a blanket of hydrogen (1.3 atmospheres) and stirred for 2 hours. The suspension was filtered through Celite® and concentrated in vacuo to afford the title compound which was used without further purification. LRMS (ESI/APCI) m/z 226 [M+H]+.
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][C:11](=[O:16])[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:19][CH2:20][C:21]([CH2:25]O)([CH2:23][OH:24])[CH3:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[OH:19][CH2:20][C:21]1([CH3:25])[CH2:23][O:24][C:11]2([CH2:12][C:13]([CH3:14])([CH3:15])[N:8]([O:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:9]([CH3:18])([CH3:17])[CH2:10]2)[O:16][CH2:22]1
Reactant: CC(CO)(CO)CO
Reactant: CC1(C)CC(=O)CC(C)(C)N1OC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC1(CO)COC2(CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)OC1

Procedure:
The title compound is prepared from by the reaction of 1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-one and 1,1,1-tris(hydroxymethyl)ethane in the presence of p-toluenesulfonic acid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]([F:40])([F:39])[C:13]([CH2:34][NH:35][CH2:36][CH2:37][CH3:38])([OH:33])[CH2:14][NH:15][C:16]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:35]([CH2:36][CH2:37][CH3:38])[CH2:34][C:13]([CH2:14][NH:15][C:16]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)([OH:33])[C:12]([F:11])([F:40])[F:39])=[O:6]
Reactant: O=C(O)c1ccccc1F
Reactant: CCCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Product: CCCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1ccccc1F

Procedure:
Prepared similarly to Example 1 from 2-fluorobenzoic acid and 1,1,1-trifluoro-3-{[1-(4-fluorophenyl)-6-methyl-1H-indazol-4-yl]amino}-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[CH:21]=[C:22]([C:24]4[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=4)[O:23][C:16]=23)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>C1COCC1.[Pd]>[CH3:31][O:30][C:28]1[CH:29]=[C:24]([C:22]2[O:23][C:16]3[C:17](=[N:18][CH:19]=[CH:20][C:15]=3[C:11]3[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=3)[CH:21]=2)[CH:25]=[C:26]([O:34][CH3:35])[C:27]=1[O:32][CH3:33]
Reactant: COc1cc(-c2cc3nccc(-c4cccc(OCc5ccccc5)c4)c3o2)cc(OC)c1OC
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1cc(-c2cc3nccc(-c4cccc(O)c4)c3o2)cc(OC)c1OC
Reaction time: 48 h

Procedure:
7-(3-Benzyloxy-phenyl)-2-(3,4,5-trimethoxy-phenyl)-furo[3,2-b]pyridine (0.137 mmol) is dissolved in THF (10 ml) and Pd—C 5% (0.2 g) is added, and the compound is hydrogenated 2 days at room temperature. The reaction solution is filtered and the filtrate removed in vacuo. The precipitate is suspended in diethylether and filtrated. The product is obtained after drying at 40° C. for 4 h as yellow solid (23 mg, 44%); HPLC (method A): Rt 2.55 min (purity 99.2%); LCMS (ESI+) (method E): Rt 1.995 min, M+H+ 378.1 m/z; 1H NMR (400 MHz, DMSO-d6) δ [ppm] 9.73 (s, 1H), 8.54 (d, J=5.1, 1H), 7.72 (s, 1H), 7.60-7.55 (m, 1H), 7.55-7.48 (m, 2H), 7.42 (t, J=7.9, 1H), 7.32 (s, 2H), 6.96-6.91 (m, 1H), 3.91 (s, 6H), 3.74 (s, 3H).
Reaction SMILES: [C:1]([C:3]1([NH:11][C:12]([C:14]2[N:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH2:24][C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[C:17]3=[N:16][C:15]=2[CH3:33])=[O:13])[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5][CH2:4]1)#[N:2].[Cl-].[NH4+].[N-:36]=[N+:37]=[N-:38].[Na+]>CN(C=O)C>[F:31][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([F:32])[C:25]=1[CH2:24][O:23][C:22]1[C:17]2[N:18]([C:14]([C:12]([NH:11][C:3]3([C:1]4[N:36]=[N:37][NH:38][N:2]=4)[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5][CH2:4]3)=[O:13])=[C:15]([CH3:33])[N:16]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC1(C#N)COC(C)(C)OC1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC1(c2nn[nH]n2)COC(C)(C)OC1
Temperature: 120 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
Under a nitrogen gas flow, to a solution of 27.7 g of N-(5-cyano-2,2-dimethyl-1,3-dioxan-5-yl)-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide in 280 ml of DMF were added 10.0 g of ammonium chloride and 12.0 g of sodium azide at room temperature, followed by stirring at 120° C. for 2 hours. The reaction mixture was left to be cooled to room temperature, and the insoluble materials were then separated by filtration and washed with DMF. The filtrate was added to water, followed by stirring at room temperature for 2 days. The resulting insoluble materials were separated by filtration and washed with water. The obtained residue was dried under reduced pressure to obtain 29.2 g of 8-[(2,6-difluorobenzyl)oxy]-N-[2,2-dimethyl-5-(2H-tetrazol-5-yl)-1,3-dioxan-5-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].Cl.[NH2:9][C:10]1([OH:13])[CH2:12][CH2:11]1.CCN(CC)CC>C1COCC1.C(=O)=O>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([NH:9][C:10]1([OH:13])[CH2:12][CH2:11]1)=[O:6]
Reactant: NC1(O)CC1
Reactant: O=C(Cl)CCCBr
Agent: Cl
Agent: O=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCCBr)NC1(O)CC1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
In a 50 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, 4-bromo-butyryl-chloride (1.69 g, 9.13 mmol) is added onto a suspension 1-aminocyclopropanol hydrochloride (1.0 g, 9.13 mmol; synthesized following the method of Matthies, D.; Buechling, U. in Arch. Pharm. (Weinheim Ger.) 1983, 316, 598-608) and Et3N (2.21 g, 0.022 mol. in dry THF (20 ml at 0° C.). After 4 h, the reaction mixture is left overnight in dry ice and another portion of 4-bromo-butyryl-chloride (0.34 g) and Et3N (0.44 g) are added. After 2 h at room temperature, the reaction mixture is cooled down to 0° C., filtrated and concentrated in vacuo to give the crude 4-bromo-N-(1-hydroxy-cyclopropyl)-butyramide a16 which is used in the next step without any further purification.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[C@@H:19]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=2)[CH2:20]1>CCCCCC.CS(C)=O.C(=O)([O-])O.[Na+].C(OCC)(=O)C>[CH3:35][O:34][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=1)[CH2:27][CH2:26][N:21]1[CH2:22][CH2:23][CH2:24][CH2:25][C@@H:20]1[CH2:19][N:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=2[CH2:12][O:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]1=2
Reactant: COc1cccc(CCN2CCCC[C@@H](Cl)C2)c1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CS(C)=O
Product: COc1cccc(CCN2CCCC[C@@H]2CN2c3ccccc3COc3ccccc32)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% Sodium hydride (27 mg, 0.68 mmol) was washed with hexane under argon atmosphere, and then suspended in dimethyl sulfoxide (5 ml). The obtained suspension was stirred at room temperature for 30 minutes. 5,11-Dihydrodibenzo[b,e][1,4]oxazepine (122 mg, 0.68 mmol) was added to the suspension, and they were stirred at room temperature for 20 minutes and then at 50° C. for 30 minutes. A solution of (R)-3-chloro-1-(3-methoxyphenethyl)homopiperidine (182 mg, 0.68 mmol) in dimethyl sulfoxide (3 ml) was added dropwise into the obtained solution, and they were stirred at 50° C. for 150 minutes. The reaction liquid was distributed in saturated aqueous sodium hydrogencarbonate solution and ethyl acetate. The organic layer was dried, and the solvent was evaporated under reduce pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with hexane and ethyl acetate (10:1) and then with hexane and ethyl acetate (4:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (R)-5,11-dihydro-5-[1-(3-methoxyphenethyl)piperidine-2-ylmethyl] dibenzo[b,e][1,4]oxazepine in the form of a light yellow oil (78 mg, 30%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.C([Li])(C)(C)C.I[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=1>C1COCC1.CCOCC.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>[CH2:8]([C:5]1[CH:6]=[CH:7][C:2]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=2)=[CH:3][CH:4]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCOC(=O)CCc1ccc(I)cc1
Reactant: CCCCc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCc1ccc(-c2ccc(CCC(=O)OCC)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a stirred solution of 3.20 g (15.0 mmol) of 1-bromo-4-butylbenzene (Aldrich Chemical Company #33,576-2) at -78° C. under argon was added, dropwise over 30 min, 18.0 mL (30.6 mmol, 1.7M in pentane) of t-butyllithium solution. The resulting light yellow solution was warmed to 0° C. and stirred for 1 h. To this solution was added 3.4 g (25 mmol) of thrice-fused zinc chloride in 20 mL of THF. The resulting slurry was stirred for 30 min and then a solution of 2.0 g (6.5 mmol) of 4-iodobenzenepropanoic acid, ethyl ester (Example 43, Part B) and 0.4 g (0.35 mmol) of tetrakis(triphenylphosphine)palladium (0) in 5 mL of THF was added. The reaction was stirred for 16 h, diluted with ether and washed once with 10% citric acid. The organic phase was dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel (5×20 cm column) eluted with 1:1 hexanes/dichloromethane gave title compound as a colorless oil, 1.79 g , 91% yield.
Reaction SMILES: FC1C=C(F)C=CC=1NC1C=CC(C(C2C=C(N3C=C(CCO)N=N3)C=CC=2C)=O)=C(C)C=1.Br[C:35]1[CH:40]=[CH:39][C:38]([C:41]([C:43]2[CH:48]=[C:47]([N:49]3[CH:53]=[C:52]([CH2:54][CH2:55][OH:56])[N:51]=[N:50]3)[CH:46]=[CH:45][C:44]=2[CH3:57])=[O:42])=[C:37]([CH3:58])[CH:36]=1.[Cl:59][C:60]1[C:61]([CH3:67])=[C:62]([NH2:66])[CH:63]=[CH:64][CH:65]=1>>[Cl:59][C:60]1[C:61]([CH3:67])=[C:62]([NH:66][C:35]2[CH:40]=[CH:39][C:38]([C:41]([C:43]3[CH:48]=[C:47]([N:49]4[CH:53]=[C:52]([CH2:54][CH2:55][OH:56])[N:51]=[N:50]4)[CH:46]=[CH:45][C:44]=3[CH3:57])=[O:42])=[C:37]([CH3:58])[CH:36]=2)[CH:63]=[CH:64][CH:65]=1
Reactant: Cc1c(N)cccc1Cl
Reactant: Cc1cc(Br)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Agent: Cc1cc(Nc2ccc(F)cc2F)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Product: Cc1cc(Nc2cccc(Cl)c2C)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C

Procedure:
The reaction was carried out similarly as described in the preparation of compound 148, using compound 452 (0.13 mmol) and 3-chloro-2-methyl-phenylamine (0.13 mmol). The crude product was purified by continuous gradient flash chromatography using MeOH/DCM/petroleum ether (40-60) 0:50:50, 0:100:0 and 5:95:0 as the eluent to afford the title compound as yellow solid. 13C NMR (CDCl3) δ 197.0, 148.6, 146.3, 143.5, 142.5, 139.9, 137.0, 135.7, 135.5, 134.6, 132.2, 130.9, 127.5, 127.1, 126.0, 122.4, 121.3, 119.9, 119.9, 117.8, 111.1, 61.6, 28.7, 22.3, 19.5, 15.0
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1.[N+:15]([CH3:18])([O-:17])=[O:16].CN(C)C(=N)N(C)C>C(OCC)C.Cl>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH:5]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)[CH2:18][N+:15]([O-:17])=[O:16]
Reactant: COC(=O)C=Cc1ccc(Cl)c(Cl)c1
Reactant: C[N+](=O)[O-]
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CCOCC
Product: COC(=O)CC(C[N+](=O)[O-])c1ccc(Cl)c(Cl)c1
Reaction time: 72 h

Procedure:
A mixture of 300 g of 3,4-dichlorocinnamic acid methyl ester, 400 g of nitromethane and 26 g of tetramethylguanidine is allowed to stir for 72 hours. The solution is diluted with ethyl ether and aqueous hydrochloric acid solution (1 N, 1 liter) is added. The organic layer is separated, dried over anhydrous magnesium sulfate, and evaporated to give 4-nitro-3-(3,4-dichlorophenyl)butanoic acid methyl ester.