Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[CH:21][C:20]=3[O:31][CH3:32])=[N:16]2)=[CH:11][CH:10]=1.[CH2:33]1[O:36][C@@H:34]1[CH3:35]>O1CCCC1>[CH3:32][O:31][C:20]1[CH:21]=[C:22]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:33][C@H:34]([OH:36])[CH3:35])[CH2:27][CH2:26]2)[CH:23]=[CH:24][C:19]=1[NH:18][C:15]1[N:14]=[CH:13][C:12]2=[CH:11][CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[N:17]2[N:16]=1
Reactant: COc1cc(C2CCNCC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Reactant: C[C@@H]1CO1
Solvent: C1CCOC1
Product: COc1cc(C2CCN(C[C@@H](C)O)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(2-methoxy-4-piperidin-4-yl-phenyl)-amine (70.00 mg, 0.163 mmol) was dissolved in tetrahydrofuran (0.300 mL) and the reaction mixture was placed in a sealed tube. (R)-(−)-Propylene oxide (14.2 mg, 0.244 mmol) was then added at room temperature and the reaction was next stirred overnight at 50° C. The solvent was evaporated under reduced pressure and the product was isolated by flash column chromatography (Silicagel, methanol/dichloromethane 0-10% gradient) to afford (R)-1-(4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-propan-2-ol as a tan solid (39 mg, 49%). MP: 67-74° C.; 1H-NMR (CDCl3) δ 8.69 (s, 1H), 8.29 (d, J=8.1 Hz, 1H), 7.99 (d, J=7.7 Hz, 1H), 7.43 (m, 2H), 7.14 (m, 1H), 7.07 (d, J=8.4 Hz, 1H), 7.02 (d, J=4.4 Hz, 1H), 6.83 (d, J=4.4 Hz, 1H), 6.73 (s, 1H), 6.71 (d, J=8.1 Hz, 1H), 3.90 (s, 3H), 3.89 (m, 1H), 3.84 (s, 3H), 3.15 (m, 1H), 2.94 (m, 1H), 2.35 (m, 4H), 2.06 (m, 1H), 1.79 (m, 4H), 1.30 (br s, 1H), 1.16 (d, J=5.8 Hz, 3H); LC/MS (ESI+): 488.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18](OCCN4CCCC4)=[CH:17][CH:16]=3)=[N:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:29][N:30]1[CH2:35][CH2:34][N:33](C2C=CC(NC(N)=S)=CC=2)[CH2:32][CH2:31]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([N:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)=[CH:19][CH:20]=3)=[N:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CN1CCN(c2ccc(NC(N)=S)cc2)CC1
Reactant: COc1ccc(-c2cnc(Nc3ccc(OCCN4CCCC4)cc3)s2)cc1
Product: COc1ccc(-c2cnc(Nc3ccc(N4CCN(C)CC4)cc3)s2)cc1

Procedure:
The title compound is prepared as described in Example 3 for [5-(4-methoxy-phenyl)-thiazol-2-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine but using [4-(4-methyl-piperazin-1-yl)-phenyl]-thiourea. Purification of the crude product by silica gel (20 g) column chromatography (CH2Cl2/MeOH, 90/10) and subsequent washing of the purified product with MeOH affords the title compound as a light beige solid: ES-MS: 381.0 [M+H]+; single peak at tR=6.13 min (System 1); Rf=0.53 (CH2Cl2/MeOH, 80/20).
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=S)[CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:20][NH2:21]>CO>[C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]([NH:20][NH2:21])[CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=C1CN=C(c2ccccc2)c2ccccc2N1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC1=Nc2ccccc2C(c2ccccc2)=NC1

Procedure:
A stirred mixture of 5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-thione (7.45 g., 0.03 mole) in methanol (300 ml.) was allowed to react with hydrazine hydrate (6.0 g., 0.12 mole) to give 5-phenyl-3H-1,4-benzodiazepin-2-yl hydrazine as an oil. A solution of thio material in tetrahydrofuran (75 ml.) was cooled in an ice bath and treated with a solution of chloroacetyl chloride (3.39 g., 0.03 mole) in tetrahydrofuran (25 ml.) to give 6.43 g. of chloroacetic acid, 2-(5-phenyl-3H-1,4-benzodiazepin-2-yl) hydrazide (A).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]([C:10](=O)[C:11]([O:13]CC)=O)[C:2]1=[O:17].[C:18]1([NH:24][NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)(=O)C>[C:18]1([N:24]2[C:2](=[O:17])[C:3]3[C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=4[NH:1][C:11](=[O:13])[C:10]=3[NH:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C(=O)C1C(=O)Nc2ccccc21
Reactant: NNc1ccccc1
Solvent: CC(=O)O
Product: O=c1[nH]c2ccccc2c2c(=O)n(-c3ccccc3)[nH]c12

Procedure:
Ethyl oxindole-3-glyoxylate (220 rag) in glacial acetic acid (2 ml) was heated under reflux for 10 minutes with phenylhydrazine (0.1 ml). The reaction was cooled and the resulting precipitate filtered and crystallised from methanol to give the title compound, mp>260° C.; 1H nmr (250 MHz, d6 -DMSO) δ5 11.86 (1H, broad s), 8.25 (1H, broad d), 7.86 (2H, d, J=8 Hz), 7.56 (2H, t, J=8 Hz) and 7.22-7.42 (4H, m).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH:12]2[CH2:17][CH2:16][C:15](=[C:18]3[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)=[CH:6][CH:5]=1.C1(C)C=CC(S(NN)(=O)=O)=CC=1>CN(C=O)C.C(OCC)(=O)C.O>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH:12]2[CH2:17][CH2:16][CH:15]([CH:18]3[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CNC2CCC(=C3CC3)CC2)cc1
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CNC2CCC(C3CC3)CC2)cc1
Temperature: 100 °C

Procedure:
4-[(4-Cyclopropylidenecyclohexylamino)methyl]benzoic acid methyl ester (1.1 g, 3.9 mmol) was dissolved in DMF (40 mL) and p-toluenesulfonic acid hydrazide (2.8 g, 15.4 mmol) was added. The reaction was heated to 100° C. for 16 hours. After cooling to room temperature the reaction mixture was diluted with ethyl acetate (75 mL) and water (40 mL) was added. The aqueous phase was extracted with ethyl acetate (25 mL) and the combined organic phases washed with aqueous saturated sodium hydrogen carbonate (2×30 mL) and water (5×30 mL). The organic phase was dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (25 g silica) using heptane and ethyl acetate (1:1) as eluent to give 4-[(4-cyclopropylcyclohexylamino)methyl]benzoic acid methyl ester.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:18]([NH:20][O:21]C4CCCCO4)=[O:19])=[CH:13][CH:14]=3)[CH2:9]2)=[O:7])[CH2:2]1>CO.Cl>[OH:21][NH:20][C:18]([C:12]1[CH:11]=[C:10]2[C:15]([CH2:16][CH2:17][N:8]([C:6]([CH:3]3[CH2:4][CH2:5][O:1][CH2:2]3)=[O:7])[CH2:9]2)=[CH:14][CH:13]=1)=[O:19]
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CN(C(=O)C1CCOC1)CC2
Agent: Cl
Solvent: CO
Product: O=C(NO)c1ccc2c(c1)CN(C(=O)C1CCOC1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.4 %

Procedure:
A mixture of 110 mg 2-(tetrahydrofuran-3-ylcarbonyl)-N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide in 6 ml methanol and 6 ml 0.1 N aqueous hydrochloric acid is stirred overnight at ambient temperature. Subsequently, the reaction mixture is evaporated. The residue is dissolved in a mixture of water and acetonitrile and lyophilized. The crude product is purified by silica gel flash chromatography. 20 mg of the title compound are obtained as colorless solid. MH+=291.1
Reaction SMILES: C[O:2][C:3](=O)[C:4]([NH:34][C:35](=[O:37])[CH3:36])([CH2:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:16][CH:17]=2)[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:11]=1)[C:5](OC)=[O:6].[Li+].[BH4-]>C1COCC1>[C:30]([O:29][C:27]([N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:14]=2)[C:10]([CH2:9][C:4]([NH:34][C:35](=[O:37])[CH3:36])([CH2:3][OH:2])[CH2:5][OH:6])=[CH:11]1)=[O:28])([CH3:31])([CH3:32])[CH3:33]
Reactant: CCCCCCCCc1ccc2c(CC(NC(C)=O)(C(=O)OC)C(=O)OC)cn(C(=O)OC(C)(C)C)c2c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc2c(CC(CO)(CO)NC(C)=O)cn(C(=O)OC(C)(C)C)c2c1
Reaction time: 48 h

Procedure:
Compound 28 (2.50 g, 4.75 mmol) is added to a solution of LiBH4 (0.525 g, 23.8 mmol) in THF (20 mL) at room temperature under inert atmosphere. The reaction is stirred for 2 days, then quenched with water (5.0 mL) and then extracted with methylene chloride (2 and 25 mL). The combined organic layers are dried over MgSO4 and concentrated in vacuo. The residue is purified using silica gel chromatography with methanol (5%)-methylene chloride (95%) to give compound 29.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6](O)[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)([Cl:21])=O>C(OCC)C>[Cl:21][CH:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[CH:3][CH:4]=2)[O:9][CH2:8][CH2:7]1
Reactant: O=S(Cl)Cl
Reactant: OC1CCOc2cc(F)ccc21
Solvent: CCOCC
Solvent: c1ccncc1
Product: Fc1ccc2c(c1)OCCC2Cl
Reaction time: 3 h
Yield: 100.2 %

Procedure:
To a solution of 7-fluorochroman-4-ol (1.80 g, 10.7 mmol, STEP 1) and pyridine (0.35 mL) in diethyl ether (14 mL) was added thionyl chloride (3.9 mL, 53.5 mmol) at 0° C. The reaction mixture was stirred at the same temperature for 3 hours, and evaporated to remove excess thionyl chloride. The residue was quenched with water, and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated in vacuum to afford the title compound as a pale brown solid (2.0 g, quant.):
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:9])[CH2:2]2.CC(C)([O-])C.[K+].[H][H]>CC(O)C>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([OH:9])[CH2:2]2
Reactant: [H][H]
Reactant: O=C1CN2CCC1CC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O[C@H]1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.63 g (13 mmol) of the 3-quinuclidinone (I), 1.1 mg (1.3 μmol) of {[(S)-(6,6′-dimethyl-1,1′-biphenyl-2,2′-diyl)-bis(di-p-tolylphosphine)]ruthenium (II) dichloride (DMF)n} complex, 12.7 ml of 2-propanol and 31 μl (1.55 μmol) of a 0.05 M 2-propanol solution of (2R,3R,4R,5R)-3,4-O-isopropylidenehexane-2,5-diamine were added to an autoclave in which the inside had been replaced with argon followed by carrying out a degassing procedure and stirring for 30 minutes at room temperature. 0.26 mL (0.26 mmol) of a 2-propanol solution of potassium tert-butoxide (1.0 M) were added thereto followed by stirring for 16 hours at 20 to 25° C. at a hydrogen pressure of 2.0 MPa to obtain (R)-3-quinuclidinol (3-R). S/C, conversion rate and enantiomeric excess are indicated below.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=4)[CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][N:8](C(=O)C2C=CC(F)=CC=2)[CH:7]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[Na+].[Na+]>CCO.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=4)[CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1cc(-c3cccc(OC)c3)ccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C1=CNCCc2c1[nH]c1cc(-c3cccc(OC)c3)ccc21
Temperature: 93 °C
Yield: 91.1 %

Procedure:
To a stirred solution of 3-(4-fluorobenzoyl)-8-(3-methoxyphenyl)-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester (48 mg, 0.10 mmol) in 2 mL of EtOH was added 0.30 mL of 1 M Na2CO3 solution at ambient temperature. The reaction mixture was heated at 93° C. reflux under N2 for 3.5 hours and samples monitored by LC-MS. The solution was diluted with DCM (10 mL), washed with brine. The aqueous phase was extracted with DCM (10 mL) twice. The combined organic phase was dried over Na2SO4 and concentrated. The crude product was purified by flash chromatograph on silica gel, eluting with EtOAc-hexane (0-30%) to yield the title compound (33 mg) as a yellow solid; 1H-NMR (CDCl3): δ 10.46 (1H, s), 7.73 (1H, d), 7.47 (1H, d), 7.37 (1H, d), 7.26 (2H, m), 7.12 (1H, m), 7.00 (1H, m), 6.79 (1H, m), 5.25 (1H, s), 4.21(2H, m), 3.80 (3H, s), 3.55 (2H, m), 3.11 (2H, m), 1.26 (3H, t). MS (ESI): 363 (MH+).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]1([CH2:21][SH:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:21]([S:22][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1CCc2cc([N+](=O)[O-])c(Br)cc21
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCc2cc([N+](=O)[O-])c(SCc3ccccc3)cc21
Yield: 38.3 %

Procedure:
Following General Procedure A, the title compound (672 mg, 79%) was prepared from 6-bromo-5-nitro-2,3-dihydro-1H-inden-1-one (1.5 g, 5.86 mmol), phenylmethanethiol (1 ml, 8.79 mmol) and K2CO3 (4.0 g, 29.29 mmol) in DMF (20 ml).
Reaction SMILES: [ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Br[CH2:30][CH2:31][CH:32]1[O:36][CH2:35][CH2:34][O:33]1>>[ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][N:17]([CH2:30][CH2:31][CH:32]4[O:36][CH2:35][CH2:34][O:33]4)[C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: BrCCC1OCCO1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Agent: Cl
Product: O=C1N(CCC2OCCO2)CN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2

Procedure:
The title compound, white solid, m. p. 205° C. and MS: m/e=470.6 (M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride and 2-(2-bromoethyl)-1,3-dioxolane.
Reaction SMILES: [OH:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[C:28](Cl)(=[O:46])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=[CH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>>[C:28]([O:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3][C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5])(=[O:46])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=[CH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: CCCCCCCCC=CCCCCCCCC(=O)Cl
Reactant: CCCCCCCCC=CCCCCCCCC(O)CC(=O)OC(C)(C)C
Product: CCCCCCCCC=CCCCCCCCC(=O)OC(CCCCCCCC=CCCCCCCCC)CC(=O)OC(C)(C)C
Yield: 75.3 %

Procedure:
Starting from tert-butyl 3-hydroxy-11-eicosenoate (11 g) and 9-octadecenoyl chloride (15 g), tert-butyl 3-(9-octadecenoyloxy)-11-eicosenoate (14 g) was obtained as an oil according to a similar manner to that of Preparation A-2 (4).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]2)=[C:4]([F:19])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][N:28]=1>CC(C)=O>[Cl:1][C:2]1[C:7]([O:8][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][N:28]=2)=[CH:6][C:5]([N:9]2[C:13](=[O:14])[N:12]([CH:15]([F:16])[F:17])[C:11]([CH3:18])=[N:10]2)=[C:4]([F:19])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Cc1nn(-c2cc(O)c(Cl)cc2F)c(=O)n1C(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1nn(-c2cc(Oc3ccc([N+](=O)[O-])cn3)c(Cl)cc2F)c(=O)n1C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a stirred mixture of 5.0 g (0.017 mole) of 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one and 2.6 g (0.019 mole) of potassium carbonate in 25 mL of acetone was added 2.7 g (0.017 mole) of 2-chloro-5-nitropyridine. The mixture was stirred at room temperature for one hour, then was heated at reflux for two hours. The mixture was allowed to cool to room temperature and was stirred for approximately 18 hours. The reaction mixture was heated at reflux for an additional four hours, then cooled and stirred at room temperature for approximately 18 hours. The mixture was filtered, and the filtrate was evaporated under reduced pressure to leave an oily residue, which crystallized upon standing to give 7.0 g of 1-[4-chloro-2-fluoro-5-(5-nitropyridin-2-yloxy)phenyl]-4-difluoromethyl -4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one, m.p. 120°-123° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[O:13][CH3:14].[H][H]>C(OCC)(=O)C.CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: [H][H]
Reactant: COc1cc(C=CC(=O)O)ccc1F
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(CCC(=O)O)ccc1F
Yield: 99 %

Procedure:
3-(4-Fluoro-3-methoxy-phenyl)-acrylic acid (6.2 g, 31.6 mmol) and Pd—C (10%, 620 mg) in ethyl acetate and methanol (1:1, 400 ml) was placed in a Parr apparatus. After the appropriate amount of hydrogen was taken up, the catalyst was filtered and the filtrate was concentrated in vacuo to give 6.2 g white solid (99% yield). LC-MS: m/e 197 (M−1)
Reaction SMILES: [C:1]([Cu])#[N:2].Br[C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:20])[N:12]2[CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:7][CH:6]=1>CN(C=O)C.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>[C:1]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:20])[N:12]2[CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:7][CH:6]=1)#[N:2]
Reactant: COC(=O)Cn1c(=O)ccc2ccc(Br)cc21
Reactant: N#C[Cu]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(=O)ccc2ccc(C#N)cc21
Reaction time: 18 h
Yield: 71.4 %

Procedure:
CuCN (0.211 g, 2.36 mmol) and Pd(PPh3)4 (0.136 g, 0.118 mmol) were added to a solution of methyl 2-(7-bromo-2-oxoquinolin-1(2H)-yl)acetate (0.35 g, 1.18 mmol) in DMF (1 mL) in a screw cap vial. The vial was sealed and placed into a oil bath at 120° C. and the reaction mixture was stirred for 18 h. The resulting mixture was diluted with Et2O and washed with brine. The organic phase was separated, dried (Na2SO4), filtered, concentrated under vacuum and the residue was purified on a silica gel column to give methyl 2-(7-cyano-2-oxoquinolin-1(2H)-yl)acetate (0.204 g, 71%). Retention time (min)=1.464, method [1], MS(ESI) 243.1 (M+H).
Reaction SMILES: O[N:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH2:13][CH3:14])[N:4]=[C:3]1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1.P(Cl)(Cl)Cl.O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:24][O:23][C:17]1[CH:16]=[C:15]([C:3]2[NH:2][C:6]([C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)=[C:5]([CH2:13][CH3:14])[N:4]=2)[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: CCc1nc(-c2ccc(OC)c(OC)c2)n(O)c1-c1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClP(Cl)Cl
Solvent: CN(C)C=O
Product: CCc1nc(-c2ccc(OC)c(OC)c2)[nH]c1-c1cccnc1
Reaction time: 2 h
Yield: 50.3 %

Procedure:
To a solution of 1-hydroxy-2-(3,4-dimethoxyphenyl)-4-ethyl-5-(3-pyridyl)imidazole (1.86 g) in N,N-dimethylformamide (38 ml) was added phosphorus trichloride (0.10 ml) under ice-cooling. The mixture was stirred for 2 hours at 5° to 10° C. The reaction mixture was poured into water, neutralized with aqueous sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with water, dried, and evaporated. The residue was subjected to column chromatography on silica gel eluting with a mixture of chloroform and methanol (methanol 1% to 5%). The fractions were collected and evaporated to give 2-(3,4-dimethoxyphenyl)-4-ethyl-5-(3-pyridyl)imidazole (0.89 g), which was diluted with methanol (8 ml). 1.2 Equivalent of hydrogen chloride gas was bubbled thereinto and diethyl ether was added to the mixture under cooling. The precipitate was collected and dried to give 2-(3,4-dimethoxyphenyl)-4-ethyl-5-(3-pyridyl)imidazole hydrochloride (0.43 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[C:18]([O:26][CH2:27][CH3:28])(=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:17])[CH2:9][CH:10]([CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:18]([O:26][CH2:27][CH3:28])=[O:25])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(C=Cc1ccccc1)c1ccc(Br)cc1
Product: CCOC(=O)C(C(=O)OCC)C(CC(=O)c1ccc(Br)cc1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 1-(4-bromophenyl)-3-phenylprop-2-en-1-one and diethyl malonate, diethyl 2-[3-(4-bromophenyl)-3-oxo-1-phenylpropyl]malonate was obtained as colourless solid.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:19]3[CH:15]([N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][CH2:18]3)[CH2:14][O:13][C:11]=2[CH:12]=1.[OH-].[Na+].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C(Cl)Cl.O>[OH:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:19]3[CH:15]([N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][CH2:18]3)[CH2:14][O:13][C:11]=2[CH:12]=1
Reactant: COc1ccc2c(c1)OCC1C2CCN1C(=O)OC(C)(C)C
Agent: BrB(Br)Br
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2c3ccc(O)cc3OCC21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of boron tribromide (88 mL, 1 M, 88 mmol) in DCM was added to a solution of tert-butyl 7-methoxy-1,3a,4,9b-tetrahydrochromeno[3,4-b]pyrrole-3(2H)-carboxylate (8.6 g, 29 mmol) in DCM (204 mL) over 30 min at −78° C. The reaction mixture was kept at −78° C. for 30 min and then stirred at 0° C. for 30 min. Water (29 mL) and an aqueous solution of NaOH (95 mL, 3 M) were then added, followed by di-tert-butyl dicarbonate (11.4 g, 52.3 mmol). After stirring for 3 h, the layers were separated. The organic layer was washed with 0.1 N HCl, H2O, and the solvent was removed. The resulting residue was triturated using heptane. The crude product was recovered via filtration and was used in the next reaction step without further purification. MS m/z 235 [M−tBu+H]+
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([CH:11]1[CH2:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]1)([OH:10])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH3:9]>C(O)(C(F)(F)F)=O.ClCCl>[F:25][C:2]([F:1])([F:24])[C:3]([CH:11]1[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]1)([OH:10])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH3:9]
Reactant: COCCCCC(O)(C1CCCN(C(=O)OC(C)(C)C)C1)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCCCC(O)(C1CCCNC1)C(F)(F)F
Reaction time: 0.5 h

Procedure:
Tert-butyl 3-(1,1,1-trifluoro-2-hydroxy-6-methoxyhexan-2-yl)piperidine-1-carboxylate (20 mg) was dissolved in 1:1 TFA/dichloromethane (4 mL). The mixture was stirred for 30 min. The mixture was concentrated to afford 1,1,1-trifluoro-6-methoxy-2-(piperidin-3-yl)hexan-2-ol which was used without purification.
Reaction SMILES: Cl.[C:2]([C:5]1[N+:6]([O-])=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:8][C:9]=1[CH3:10])(=[O:4])[CH3:3]>C(O)(=O)C.[Zn]>[C:2]([C:5]1[N:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:8][C:9]=1[CH3:10])(=[O:4])[CH3:3]
Reactant: CC(=O)c1c(C)oc(-c2ccccc2)[n+]1[O-]
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(=O)c1nc(-c2ccccc2)oc1C
Yield: 12.6 %

Procedure:
Next, 100 g of 4-acetyl-5-methyl-2-phenyloxazole N-oxide hydrochloride was dissolved in 500 ml of glacial acetic acid and 100 g of zinc powder was added to the solution while cool stirring within a ice water bath. The separation was filtered after addition of 2 l of water and recrystalization was carried out by addition of methanol to produce 10 g of 4-acetyl-5-methyl-2-phenyloxazole (melting point; 74° to 76° C.).