Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:27]=2[NH:26][CH2:25][CH2:24][CH2:23]3)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[NH:26]1[C:27]2[C:22](=[CH:21][CH:20]=[CH:19][C:18]=2[C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7]2)=[O:17])[CH2:23][CH2:24][CH2:25]1
Reactant: CCOC(=O)C1(NC(=O)c2cccc3c2NCCC3)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1cccc2c1NCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
The mixture of 2-[(1,2,3,4-tetrahydro-quinoline-8-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (63) (259 mg, 0.71 mmol) and KOH (1 g, 17.9 mmol) is dissolved in EtOH (15 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (30 mL) and acidified with conc. HCl dropwise until precipitate falls out of the water. After the filtration, the solid is washed by water and collected. The filtrate is acidified with conc. HCl carefully again to see if more precipitate comes out or not. The combined solid is dried in vacuo to give a pure product (64) as a yellow solid (205 mg, 86%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Br:11])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].Cl[Sn]Cl.O.C([O-])(O)=O.[Na+]>C(O)C>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:11])=[CH:4][C:3]=1[C:12]([F:15])([F:13])[F:14]
Reactant: Nc1c([N+](=O)[O-])cc(Br)cc1C(F)(F)F
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cc(Br)cc(C(F)(F)F)c1N
Temperature: 90 °C
Yield: 62 %

Procedure:
To a stirred mixture of 2-amino-5-bromo-3-nitrobenzotrifluoride (261 mg, 0.949 mmol) in ethanol (4 mL) was added SnCl2.2 H2O (1.076 g, 4.745 mmol) in one portion. The mixture was refluxed at 80° C. (oil bath 90° C.) for 1 h. The solution was cooled to room temperature and ice water (20 g) was added. It was adjusted to pH=7 with NaHCO3 and extracted by ethyl acetate (2×4 mL). The extract was dried over Mg2SO4 and evaporated to give 150 mg (64.6%) of 2,3-diamino-5-bromobenzotrifluoride as a brown solid. 1H NMR (CDCl3): δ 3.503 (s, 2H); 3.898 (s, 2H); 6.987 (d, 1H, J=1.8 Hz); 7.123 (d, 1H, J=1.8 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[C:12]2[N:13]=[C:14]([Cl:18])[CH:15]=[C:16](Cl)[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:19]=[C:12]2[N:13]=[C:14]([Cl:18])[CH:15]=[C:16]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: Clc1cc(Cl)n2nc(OCc3ccccc3)cc2n1
Solvent: C1COCCO1
Product: Clc1cc(N2CCOCC2)n2nc(OCc3ccccc3)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
There was dissolved, in 1,4-dioxane (3 mL), 2-benzyloxy-5,7-dichloro-pyrazolo-[1,5-a]-pyrimidine (167 mg, 0.568 mM), then morpholine (99.1 μL, 1.14 mM) was added to the solution and the mixture was stirred at room temperature for one hour. The solvent was distilled off from this reaction mixture, followed by the dilution of the residue with water and the subsequent extraction of the mixture with methylene chloride. The resulting extracts were combined, dried over anhydrous sodium sulfate, the solvent was distilled off and the resulting solid was washed with methanol to thus give the title compound (188 mg, yield: 96%).
Reaction SMILES: [Si]([O:18][C:19]1[CH:62]=[CH:61][C:22]([O:23][CH2:24][C@@H:25]([OH:60])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:59]=[CH:58][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][CH:45](C4C=CC=CC=4)[C:46]4[CH:51]=CC=C[CH:47]=4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH3:47][CH:46]([CH3:51])[CH2:45][CH2:44][NH:43][C:41]([N:38]1[CH2:37][CH2:36][CH:35]([NH:34][C:33]2[CH:58]=[CH:59][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:60])[CH2:24][O:23][C:22]3[CH:21]=[CH:20][C:19]([OH:18])=[CH:62][CH:61]=3)=[CH:31][CH:32]=2)[CH2:40][CH2:39]1)=[O:42]
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)NCC(c4ccccc4)c4ccccc4)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)CCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 38.5 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-N-(2,2-diphenylethyl)-1-piperidinecarboxamide (0.194 g, 0.26 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.05 g, 0.10 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][C:10]=2[CH3:18])=[N:6][CH:7]=1.[CH3:19][N:20]([CH3:30])[C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH2:25])=[O:24]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:25][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[N:20]([CH3:19])[CH3:30])=[O:17])=[CH:11][C:10]=2[CH3:18])=[N:4][CH:3]=1
Reactant: Cc1cc(N=C=O)ccc1Oc1ncc(Br)cn1
Reactant: CN(C)c1ccccc1C(N)=O
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=O)NC(=O)c2ccccc2N(C)C)ccc1Oc1ncc(Br)cn1

Procedure:
A solution of a mixture comprising 3.73 g of 4-(5-bromo-2-pyrimidinyloxy)-3-methylphenyl isocyanate, 2.0 g of 2-(dimethylamino)benzamide and 45 ml of toluene, was reacted under reflux for 4 hours.
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[S:4][C:3]=1[N+:14]([O-:16])=[O:15].[CH3:17][OH:18].C[O-].[Na+]>>[CH2:9]([O:8][CH:7]([O:11][CH2:12][CH3:13])[C:5]1[S:4][C:3]([N+:14]([O-:16])=[O:15])=[C:2]([O:18][CH3:17])[CH:6]=1)[CH3:10]
Reactant: CO
Reactant: CCOC(OCC)c1cc(Br)c([N+](=O)[O-])s1
Agent: C[O-]
Agent: [Na+]
Product: CCOC(OCC)c1cc(OC)c([N+](=O)[O-])s1
Temperature: 120 °C
Yield: 403.1 %

Procedure:
To a solution of 3-bromo-5-(diethoxymethyl)-2-nitrothiophene (Int. 66) (1 g, 3.22 mmol) in MeOH (10 ml) copper(II) oxide (0.051 g, 0.645 mmol), KI (10.7 mg, 0.064 mmol) and sodium methanolate (0.662 g, 12.25 mmol) were added, and the mixture was heated under MW irradiation at 120° C. for 2 hours. The reaction mixture was filtered through a celite pad, the filtrate was concentrated under vacuum and then partitioned between 0.5N HCl and EtOAc. The organic phase was dried over sodium sulfate, filtered and evaporated to give 5-(diethoxymethyl)-3-methoxy-2-nitrothiophene (Int. 67) (680 mg, 2.60 mmol, MS/ESI+261.0 [MH]+). This crude was used without any additional purification.
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[N:26](C3CCCCO3)[N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.Cl.[NH:34]1[CH2:39][CH2:38][CH2:37][C@@H:36]([OH:40])[CH2:35]1>>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)[C:2]([N:34]3[CH2:39][CH2:38][CH2:37][C@@H:36]([OH:40])[CH2:35]3)=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Reactant: O[C@@H]1CCCNC1
Agent: Cl
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CCC[C@@H](O)C2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 85 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2) and (R)-piperidin-3-ol hydrochloride and was obtained as a white solid. UPLC-MS (Condition 3) tR=0.99 min, m/z=464.1[M+H]+, m/z=508.1[M+formic acid-H]−; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19-1.35 (m, 1H) 1.37-1.52 (m, 1H) 1.56-1.69 (m, 1H) 1.79-1.93 (m, 1H) 2.52-2.62 (m, 1H) 2.65-2.79 (m, 1H) 3.43 (d, J=12.72 Hz, 1H) 3.50-3.61 (m, 1H) 3.65 (d, J=12.23 Hz, 1H) 4.76 (d, J=4.52 Hz, 1H) 6.55-6.67 (m, 1H) 7.34 (d, J=8.93 Hz, 2H) 7.52-7.86 (m, 1H) 7.88 (d, J=9.17 Hz, 2H) 8.14-8.36 (m, 1H) 8.72 (d, J=2.32 Hz, 1H) 10.32-10.44 (m, 1H) 12.96-13.18 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[C:13](Cl)(=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1.C(N(CC)CC)C>C1COCC1>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[C:13]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=1)=[O:22]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: Nc1ccc2c(c1)CCCC2=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc(C(=O)Nc2ccc3c(c2)CCCC3=O)c1
Yield: 92 %

Procedure:
Reaction of 6-Amino-3,4-dihydro-2H-naphthalen-1-one (80 mg, 0.50 mmol) in THF (6 mL) with m-anisoyl chloride (90 μL, 0.65 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave 3-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzamide (135 mg, 0.46 mmol, 92% yield) as a white powder after purification by flash chromatography on silica gel (eluent:EtOAc/DCM 0/10 to 2/8).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH3:11])[C:7]=2[CH:12]=1.[CH2:13]([CH:15]([CH2:19][CH3:20])[C:16](Cl)=[O:17])[CH3:14].[N+](C)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-]>O>[CH2:13]([CH:15]([CH2:19][CH3:20])[C:16]([C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:12][C:7]=2[C:8]=1[CH3:11])=[O:17])[CH3:14]
Reactant: CCC(CC)C(=O)Cl
Reactant: COc1ccc2occ(C)c2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C[N+](=O)[O-]
Product: CCC(CC)C(=O)c1oc2ccc(OC)cc2c1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
To a mixture of 5-methoxy-3-methyl-1-benzofuran (2.00 g) synthesized above, 2-ethylbutanoyl chloride (1.85 mL) and nitromethane (30 mL) was added aluminum chloride (3.28 g), and the mixture was stirred at room temperature for 1.5 hr. Water was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (6% ethyl acetate/hexane) to give the title object compound (3.12 g, 97%) as a pale-yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.[CH3:12][NH:13][CH3:14].C([BH3-])#N.[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][N:13]([CH3:14])[CH3:12])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CNC
Reactant: COc1ccc(C=O)cc1Br
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CN(C)C)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 10.0 g of 3-bromo-4-methoxy benzaldehyde in MeOH (155 ml) was added an aqueous solution of 50% dimethylamine (2.52 ml) and the reaction mixture was stirred at room temperature for 30 minutes. Thereafter, to the solution was added 4.38 g of sodium cyanoborohydride, the reaction mixture was stirred for 15 hours under the same temperature condition, and the reaction solution was concentrated under reduced pressure. Water was added to the residue and extracted with CHCl3; the organic layer was washed with saturated brine and dried over MgSO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60; mobile phase: EtOAc/hexane=1/1, then, MeOH/CHCl3=1/9; v/v) to obtain 2.20 g of the title compound (colorless oil).
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([Cl:12])=[O:11])[CH2:3]2.[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[ClH:12].[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:10]([CH:4]2[CH:5]3[CH2:8][CH2:9][N:2]([CH2:7][CH2:6]3)[CH2:3]2)=[O:11])=[CH:16][CH:15]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(Cl)C1CN2CCC1CC2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Br)cc1)C1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.00 g (4.76 mmol) of 3-quinuclidinecarbonyl chloride hydrochloride is added at 0° C. to a solution of 900 mg (5.24 mmol) of 4-bromoaniline and 1.85 g (14.28 mmol) of N,N-diisopropylethylamine in about 10 ml of dry DMF. The mixture is stirred at room temperature overnight. Purification by preparative HPLC is followed by chromatography again on silica gel (mobile phase: dichloromethane/methanol/triethylamine 80:20:2). The product is dissolved in methanol and mixed with 1N HCl in methanol. Finally, the solvent is removed. 0.63 g (31% of theory) of the title compound is obtained. The raw material is employed directly in the next synthesis.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]1[CH2:12][C:13]([OH:15])=O.C(N(CC)CC)C.ClC(OCC)=O.[CH2:29]([NH2:37])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[O:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]1[CH2:12][C:13]([NH:37][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:15]
Reactant: O=C(O)CC1Nc2ccccc2NC1=O
Reactant: NCCc1ccccc1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CC1Nc2ccccc2NC1=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To the solution of (3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl)-acetic acid (510 mg, 2.48 mmol) in THF (18 mL) was added triethylamine (0.38 ml, 2.74 mmol) and ethyl chloroformate (0.24 ml, 2.74 mmol). The mixture was stirred at rt for 1.5 hours and then phenethylamine (0.34 ml, 2.74 mmol) was added. The resulting mixture was again stirred at rt for 4.5 hours. The precipitate was filtered off and washed with small amount of THF a few times. The solvent was removed under the reduced pressure to give the title compound as a yellow solid: 1H NMR (DMSO-d6) δ=10.24 (bs, 1H), 8.03 (t, 1H, J=5.4Hz), 7.30–7.15 (m, 5H), 6.75- 6.70 (m, 3H), 6.61–6.56 (m, 1H), 5.79 (bs, 1H), 4.08–4.04 (m, 1H), 3.30–3.24 (m, 2H), 2.71 (t, 2H, J=7.8 Hz), 2.60 (dd, 1H, J=3.9, 15.3 Hz), 2.31 (dd, 1H, J=8.7, 15.3 Hz).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([O:8][C@@H:9]2[CH2:13][CH2:12][NH:11][C:10]2=[O:14])=[CH:4][CH:3]=1.[CH3:15][CH:16]([S-:18])[CH3:17].[Na+]>>[CH:16]([S:18][C:2]1[N:7]=[CH:6][C:5]([O:8][C@@H:9]2[CH2:13][CH2:12][NH:11][C:10]2=[O:14])=[CH:4][CH:3]=1)([CH3:17])[CH3:15]
Reactant: CC(C)[S-]
Reactant: O=C1NCC[C@H]1Oc1ccc(Br)nc1
Agent: [Na+]
Product: CC(C)Sc1ccc(O[C@@H]2CCNC2=O)cn1

Procedure:
Typical Procedure 8 was followed. Reaction of (R)-3-(6-bromo-pyridin-3-yloxy)-pyrrolidin-2-one with sodium 2-propanethiolate provided the title compound. MS ESI+: m/z=253 [M+H]+.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH2:10]([O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1)[CH3:11]>>[Br:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([O:12][CH2:10][CH3:11])[CH:18]=2)=[N:3][CH:4]=1
Reactant: CCOc1cccc(B(O)O)c1
Reactant: Cc1cc(Br)cnc1Br
Product: CCOc1cccc(-c2ncc(Br)cc2C)c1
Yield: 37 %

Procedure:
Obtained (1.30 g, yield 37%) following the procedure described in Intermediate 27, starting with 2,5-dibromo-3-methylpyridine (11.96 mmol, 3.0 g), 3-ethoxyphenylboronic acid (11.96 mmol, 1.98 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH2:7][S:8][C:9]23[CH:18]=[CH:17][CH:16]=[CH:15][C:10]2=[N:11][CH:12]=[CH:13][C:14]=13)=O)C.[NH3:19]>C(O)C>[S:8]1[C:9]23[CH:18]=[CH:17][CH:16]=[CH:15][C:10]2=[N:11][CH:12]=[CH:13][C:14]3=[C:6]([C:4]([NH2:19])=[O:3])[CH2:7]1
Reactant: N
Reactant: CCOC(=O)C1=C2C=CN=C3C=CC=CC32SC1
Solvent: CCO
Product: NC(=O)C1=C2C=CN=C3C=CC=CC32SC1
Reaction time: 0.25 h
Yield: 89 %

Procedure:
In 30 ml of ethanol was dissolved 487 mg of benzo[b]thieno[2,3-c]pyridine-3-carboxylic acid ethyl ester and ammonia gas was slowly blown into the solution for 15 minutes under ice-cooling. After allowing the solution to stand for 3 days at room temperature, crystals thus deposited were collected by filtration to provide 410 mg (yield of 89%) of benzo[b]thieno[2,3-c]pyridine-3-carboamide.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[NH:14][CH:13]=[C:12]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:10][CH2:9]1)=[O:7].[CH:35]1([CH2:38]Br)[CH2:37][CH2:36]1>>[F:32][C:29]([F:30])([F:31])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[N:14]([CH2:38][CH:35]3[CH2:37][CH2:36]3)[CH:13]=[C:12]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:10][CH2:9]1)=[O:7]
Reactant: BrCC1CC1
Reactant: Cc1ccccc1C1=CNC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Product: Cc1ccccc1C1=CN(CC2CC2)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=537.2 (M+H+), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-4-o-tolyl-2,8-diaza-spiro[4.5]dec-3-en-1-one and cyclopropyl methyl bromide.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.O.[H-].[Na+].C[O:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21](Br)[N:20]=1)=[O:18]>CC(N(C)C)=O.[Cu](I)I>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]([OH:18])=[O:16])=[N:20][C:21]=1[O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1
Reactant: COC(=O)c1ccc(OC)c(Br)n1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: I[Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc(C(=O)O)nc1Oc1cccc(C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 10 h

Procedure:
3-(trifluoromethyl) phenol (1.317 g, 0.0081 mol) was dissolved in 10 ml of dried dimethyl acetamide. While cooling the obtained solution with water, sodium hydride (0.39 g (ca. 60% in mineral oil), 0.0081×1.2 mol) was added to the solution. After completion of the foaming, a solution obtained by dissolving 6-bromo-5-methoxy-2-pyridine carboxylic acid methyl ester (2.0 g, 0.0081 mol) in 10 ml of dried dimethyl acetamide, and then copper iodide (1.55 g, 0.081 mol) were successively added to the solution. The obtained mixture was heated and stirred at 120° C. for 10 hours. Thereafter, the obtained reaction solution was cooled, mixed with 50 ml of water and then with 50 ml of ethyl acetate, and filtered through a glass filter provided with Hyflo Super-Cell. The obtained filtrate was extracted with ethyl acetate to obtain an aimed product. An organic phase was separated from the product, washed with water and then dried with anhydrous sodium sulfate. The dried product was concentrated, and the obtained residues were purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:16]([O:23][C:24]([NH:26][C@@H:27]([CH3:31])[C:28](O)=O)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH2:16]([O:23][C:24](=[O:25])[NH:26][C@H:27]([C:28]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=2[N:8]=1)[CH3:31])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Cc1cccc(N)c1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1cccc2nc([C@H](C)NC(=O)OCc3ccccc3)n(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 90.5 %

Procedure:
To a solution of 3-methyl-N2-phenyl-benzene-1,2-diamine (852 mg, 4.3 mmol) in anhydrous DCM (20 mL) were added (S)-2-benzyloxycarbonylaminopropionic acid (1.44 g, 6.45 mmol), HOBt (639 mg, 4.73 mmol), 4-methylmorpholine (1.04 mL, 9.46 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.24 g, 6.45 mmol). The mixture was stirred at RT for 6.5 h and then partitioned between DCM (100 mL) and water. The organic layer was then washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was dissolved in AcOH (10 mL) and heated to 65° C. for 18 h. After cooling to RT, volatiles were removed under reduced pressure and the residue diluted with EtOAc (100 mL). The organic layer was washed with a saturated solution of NaHCO3, followed by brine, then dried (Na2SO4) and concentrated in vacuo affording [(S)-1-(7-Methyl-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid benzyl ester as brown foam (1.5 g, 90%). LCMS: RT 3.07 min [M+H]+ 386.2.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[Cl:17][C:18]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1>CN(C=O)C>[Cl:17][C:18]1[N:23]=[C:22]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH:21]=[CH:20][N:19]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(Cl)n2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 26 %

Procedure:
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (1.0 g, 5.0 mmol, Aldrich) in DMF (15.0 mL) at 0° C. was added sodium hydride (0.55 g, 15.0 mmol, 65% dispersion in mineral oil, commercially available from Sigma-Aldrich Corporation). in several portions. After stirring at 0° C. for 10 min, 2,4-dichloropyrimidine (745 mg, 5.0 mmol, commercially available from Sigma-Aldrich Corporation) in DMF (10.0 mL) was added. The resulting mixture was stirred at 0° C. for 10 min and at room temperature for 2 h and then quenched with saturated NH4Cl aqueous solution (1.5 mL). The reaction mixture was diluted with EtOAc and H2O and the aqueous solution was extracted further with EtOAc (2×). The combined organic extracts were washed with H2O (3×) and brine, dried (Na2SO4) and evaporated. The residual was purified by flash chromatography (0 to 50% EtOAc/hexanes) to yield 409.3 mg (26%) of the product as an off-white semi-solid. MS (ESI) 314 (M+H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[C:12](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:12]
Reactant: O=C([O-])[O-]
Reactant: Oc1ccccc1C(F)(F)F
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccccc1C(F)(F)F

Procedure:
A mixture of log 2-trifluoromethyl phenol, 17 g potassium carbonate, 150 ml acetone and 7.7 ml iodomethane was heated under reflux for 2 hr. After cooling, the insoluble matters were removed by filtration, and the filtrate was evaporated. The resulting residue was dissolved in ethyl acetate, and washed with water and brine. It was dried over anhydrous magnesium sulfate, filtered, and evaporated to give 12.15 g of 2-trifluoromethyl anisole.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[O:12])[CH2:8][C:9](=[O:11])[CH3:10].[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]([O:22]CC)=O)[CH:15]=1.[H-].[Na+]>O1CCCC1>[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20](=[O:22])[CH2:10][C:9](=[O:11])[CH2:8][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:12])[CH:15]=1
Reactant: CCOC(=O)c1cc(Cl)ccn1
Reactant: CC(=O)CC(=O)c1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CC(=O)c1ccccn1)CC(=O)c1cc(Cl)ccn1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 21.3 g (131 mmol) of 1-pyridin-2-ylbutane-1,3-dione and 36.3 g (196 mmol) of ethyl 4-chloropyridine-2-carboxylate in 100 ml of absolute tetrahydrofuran is added dropwise to 10.43 g (261 mmol, about 60% dispersion) of sodium hydride in 200 ml of absolute tetrahydrofuran at the boiling point over the course of two hours. The mixture is stirred for another two hours at 70° C., evaporated on a rotary evaporator, and 200 ml of water are subsequently added cautiously at 4° C. The mixture is rendered neutral with 5N hydrochloric acid, and 1-(4-chloropyridin-2-yl)-5-pyridin-2-ylpentane-1,3,5-trione is filtered off as a yellowish green solid The dried, sparingly soluble product is processed further without any particular purification steps.