Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[C:14]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:19]=CC=C[CH:15]=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.CC(O)C.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C1COCC1>[CH:14]([O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:11])([F:12])[F:13])([CH3:19])[CH3:15]
Reactant: N#Cc1ccc(O)c(C(F)(F)F)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(C#N)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91 %

Procedure:
Under an atmosphere of nitrogen a mixture of 4-hydroxy-3-(trifluoromethyl)benzonitrile (5.89 g, 31.5 mmol) and triphenylphosphine (13.21 g, 50.4 mmol) in anhydrous THF (200 mL) was stirred for 5 min. at ambient temperature. To the solution DBAD (11.60 g, 50.4 mmol) was added, stirred 5 min before the addition of 2-propanol (3.03 mL, 39.3 mmol). The mixture was stirred at ambient temperature for 72 hr. The solvent was removed under reduced pressure. The resulting oil was triturated with 30-60° C. pet/ether (200 mL), filtered to remove phosphine oxide and the crude product was purified further by elution through silica with heptane/ethyl acetate (4:1). The isolated oil was dissolved in dichloromethane (200 mL) and stirred with TFA (4.85 mL, 63.0 mmol) for 90 min. at ambient temperature. The solution was basified with 2.5N NaOH (30 mL) and the product was partitioned between DCM and the basic aqueous phase to give the crude 4-isopropoxy-3-(trifluoromethyl)benzonitrile (6.56, 91%). LCMS (Table 1, Method a) Rt=2.32 min, 1H NMR (400 MHz, CDCl3) 7.85 (d, 1H), 7.75 (dd, 1H), 7.06 (d, 1H), 4.73 (m, 1H), 1.41 (dd, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[CH:9]=[N:10][NH:11][C:3]=12.[H-].[Na+].Br[CH2:15][C:16]([NH:18][CH3:19])=[O:17]>C1COCC1>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[CH:9]=[N:10][N:11]([CH2:15][C:16]([NH:18][CH3:19])=[O:17])[C:3]=12.[Cl:1][C:2]1[C:3]2[C:4](=[CH:9][N:10]([CH2:15][C:16]([NH:18][CH3:19])=[O:17])[N:11]=2)[N:5]=[CH:6][C:7]=1[F:8]
Reactant: CNC(=O)CBr
Reactant: Fc1cnc2cn[nH]c2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNC(=O)Cn1cc2ncc(F)c(Cl)c2n1
Product: CNC(=O)Cn1ncc2ncc(F)c(Cl)c21
Temperature: 25 °C

Procedure:
7-Chloro-6-fluoro-1H-pyrazolo[4,3-b]pyridine (100 mg, 0.583 mmol) and NaH (28.0 mg, 60% in oil, 0.699 mmol) in THF (2.0 mL) was stirred at 0° C. for 15 minutes. 2-Bromo-N-methylacetamide (89 mg, 0.583 mmol) was added and the reaction was allowed to warm to room temperature for 12 hours. The reaction mixture was then concentrated in vacuo to give 2-(7-chloro-6-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)-N-methylacetamide and 2-(7-chloro-6-fluoro-2H-pyrazolo[4,3-b]pyridin-2-yl)-N-methylacetamide which were used without further purification.
Reaction SMILES: Cl[CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1=O.[NH2:8][C:9]([NH2:11])=[S:10]>O1CCOCC1>[S:10]1[C:3]2[CH2:4][CH2:5][CH2:6][C:2]=2[N:8]=[C:9]1[NH2:11]
Reactant: NC(N)=S
Reactant: O=C1CCCC1Cl
Solvent: C1COCCO1
Product: Nc1nc2c(s1)CCC2
Temperature: 25 °C
Yield: 106.9 %

Procedure:
2-Chlorocyclopentanone (9.01 g, 74.4 mmol) was added slowly to a 95° C. stirred mixture of thiourea (5.77 g, 75.0 mmol) in 1,4-dioxane (150 mL). After full addition, the temperature was maintained for an hour then the mixture was cooled to room temperature. It was then filtered and washed with 1,4-dioxane and diethyl ether, and dried under air suction to afford 11.15 g white solid. This was partitioned between diethyl ether and saturated aqueous sodium carbonate. The ether layer was washed with brine, dried with Na2SO4, and solvent removed by rotoevaporation to afford 9.8 g beige solid. (Modified procedure from US Patent application 64 699, 2008, Florjancic, A. S.; et al).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=O)=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH2:14]([N:21]=[C:22]=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:21]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:22](=[O:23])[NH:13][N:12]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Reactant: O=C=NCc1ccccc1
Product: O=c1[nH]nc(-c2ccc3[nH]cnc3c2)n1Cc1ccccc1

Procedure:
The compound was synthesized starting from benzimidazol-5-carbohydrazide (176 mg; 1 mmol) and benzylisocyanate (0.133 g; 0.123 ml; 1 mmol); Yield: 0.077 (26%); MS m/z: 292.4 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 4.92 (s, 2H); 7.02-7.04 (m, 2H); 7.23-7.27 (m, 3H); 7.52 (dd, 1H, 4J=1.7 Hz, 3J=8.7 Hz); 7.76 (d, 1H, 3J=8.7 Hz); 7.81 (m, 1H); 8.99 (s, 1H), 12.08 (s, 1H); HPLC (METHOD [A]): rt 8.28 min (100%)
Reaction SMILES: [CH2:1]([N:3]1[CH2:10][CH:9]2[CH:5]([CH2:6][CH2:7][CH2:8]2)[CH:4]1[CH2:11][NH:12][C:13](=[O:27])[C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([NH:21]C(=O)C)=[CH:16][C:15]=1[O:25][CH3:26])[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([N:3]1[CH2:10][CH:9]2[CH:5]([CH2:6][CH2:7][CH2:8]2)[CH:4]1[CH2:11][NH:12][C:13](=[O:27])[C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([NH2:21])=[CH:16][C:15]=1[O:25][CH3:26])[CH3:2]
Reactant: CCN1CC2CCCC2C1CNC(=O)c1cc(Cl)c(NC(C)=O)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN1CC2CCCC2C1CNC(=O)c1cc(Cl)c(N)cc1OC

Procedure:
7 parts of N-ethyl-2-(2-methoxy-4-acetylamino-5-chloro benzamido methyl)-3-azabicyclo (3,3,0) octane were heated for 30 minutes in the presence of 17.7 parts of a 2 N solution of sodium hydroxide and 15 parts of ethanol. After cooling, the precipitate was filtered and recrystallized in 40 parts of acetonitrile. There were obtained 5 parts of N-ethyl-2-(2-methoxy-4-amino-5-chloro benzamido methyl)-3-azabicyclo(3,3,0) octane, M.P. 128°-129° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[I-:10].[K+].CN(C)C=O.Cl>[Cu](I)I.C(OCC)(=O)C>[I:10][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: O=Cc1ccc(Br)cc1
Agent: I[Cu]I
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1ccc(I)cc1
Reaction time: 1 h

Procedure:
8.0 g (43.2 mmol) of 4-bromobenzaldehyde, 107.6 g (0.65 mmol) of potassium iodide, 41.1 g (0.22 mmol) of copper iodide and 130 mL of dimethylformamide (DMF) were put in a 300 mL three-neck flask, and refluxed in a nitrogen atmosphere for 3 hours. After it was put back at a room temperature, 1N of hydrochloric acid and ethyl acetate were added, and stirred for 1 hour. It was filtered to remove potassium iodide and copper iodide, and the filtrate was washed with sodium sulfate and water, and dried with magnesium sulfate. It was distilled under a reduced pressure to obtain 4-iodobenzaldehyde (compound A). A synthesis scheme is shown below.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]1(B(O)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:16][O:17][CH2:18][CH2:19][O:20][CH2:21][N:22]([C:32]1[O:36][N:35]=[C:34]([CH3:37])[C:33]=1[CH3:38])[S:23]([C:26]1[S:27][C:28](Br)=[CH:29][CH:30]=1)(=[O:25])=[O:24]>C(O)C.C1C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][O:17][CH2:18][CH2:19][O:20][CH2:21][N:22]([C:32]1[O:36][N:35]=[C:34]([CH3:37])[C:33]=1[CH3:38])[S:23]([C:26]1[S:27][C:28]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:29][CH:30]=1)(=[O:25])=[O:24]
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccc(Br)s1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: CCO
Product: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccc(-c2ccccc2)s1
Yield: 61.9 %

Procedure:
Sodium carbonate (2 mL of a 2 M aqueous solution) followed by phenyl boronic acid (86 mg, 0.71 mmol) in 2 mL of 95% ethanol were added to a solution of N-(methoxyethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide (200 mg, 0.47 mmol) and tetrakis(triphenylphosphine)palladium (0) (23 mg, 0.02 mmol) in dry benzene (4 mL) under argon. The mixture was refluxed for 12 h, diluted with 5 mL of water and extracted into ethyl acetate (3×25 mL). The combined organic extracts was washed with brine (1×25 mL), dried and evaporated. The residue was flash chromatographed on silica gel using 25% ethyl acetate/hexanes to afford 123 mg (62%) of the sulfonamide as a colorless gum.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1)(=[O:3])[CH3:2].CC(C)=[O:16].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[C:1]([O:4][CH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]([OH:16])=[O:11])=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(C)=O
Reactant: CC(=O)OCc1ccc(C=O)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CC(=O)OCc1ccc(C(=O)O)cc1

Procedure:
4-[acetyloxy-methyl]benzaldehyde (15.3 g, 86.5 mmol) in acetone (250 ml) was then reacted with Jones reagent (33.0 ml, a three-fold excess) while stirring (exothermal reaction). This was stirred for 2 h before filtering out the green solid. The green solid was then dried under reduced pressure and dissolved in ethyl acetate (400 ml) and washed with sodium carbonate solution and water until neutral. After removal of solvent, a crop of yellow crystals (13.3 g) was obtained which was then recrystallised in chloroform-hexane to give a white crystal (3) (12.62 g, 76%). m.p. 120-123° C.; Rf 0.29 (1:1 Hexane-ether v/v).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)CC)C.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34])[C:27](Cl)=[O:28]>C(Cl)Cl>[N+:33]([C:32]1[CH:31]=[CH:30][C:26]([C:27]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:28])=[CH:25][C:24]=1[O:23][CH3:22])([O-:35])=[O:34]
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.2 %

Procedure:
To a solution of 0.55 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 8 ml of methylene chloride is added 0.55 g of triethylamine followed by 0.97 g of 3-methoxy-4-nitrobenzoyl chloride. The reaction mixture is stirred at room temperature for 2 hours and then quenched with 10 ml of 1N NaOH. The methylene chloride layer is evaporated and the resulting suspension filtered. The precipitate is washed with 1N NaOH (2×5 ml), water (3×5 ml) and hexane (2×5 ml). The collected solid is dried in vacuo to give 1.13 g of off-white solid. MS(CI):364(M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]=[C:12]=[O:13].[CH3:14][Si:15]([CH3:20])([CH3:19])[CH2:16][CH2:17][OH:18]>C1COCC1>[CH3:14][Si:15]([CH3:20])([CH3:19])[CH2:16][CH2:17][O:18][C:12](=[O:13])[NH:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: O=C=Nc1cc([N+](=O)[O-])ccc1F
Reactant: C[Si](C)(C)CCO
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOC(=O)Nc1cc([N+](=O)[O-])ccc1F
Temperature: 50 °C
Reaction time: 11 h
Yield: 75.8 %

Procedure:
To a solution of 1-Fluoro-2-isocyanato-4-nitro-benzene (9.82 g, 54 mmol) in THF (40 ml) at 23° C. under an atmosphere of argon was added 2-Trimethylsilanyl-ethanol (7.72 ml, 54 mmol). The resulting mixture was stirred for 11 hours then heated to 50° C. for 2 hours. The reaction mixture was allowed to cool to 23° C. quenched with saturated NaHCO3 (aq) and extracted with EtOAc (3×100 ml). The pooled ethyl acetate was washed with 1N HCl (aq) (2×90 ml) water (90 ml) and brine (90 ml), dried with Na2SO4, filtered and concentrated to a yellow solid. Silica gel chromatography (2:8 ethyl acetate-hexane) provided (2-Fluoro-5-nitro-phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester (12.3 g, 77%). 1H NMR (300 MHz, CDCl3) δ 9.06 (dd, 1H, J=6.89 Hz, J=2.63 Hz), 7.89 (m, 1H), 7.20 (m, 1H), 6.91 (bs, 1H), 4.31 (t, 2H, J=8.67 Hz), 1.06 (t, 2H, J=8.67 Hz), 0.05 (s, 9H). LCMS (ESI−) [M+H]/z Calc'd 299, found 299.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:3]=1[C:14](=[O:16])[CH3:15].[O:17]=[C:18]1[NH:27][C:26]2[N:25]=[C:24]([O:28][CH2:29][CH2:30][CH2:31][CH:32]=O)[CH:23]=[CH:22][C:21]=2[CH:20]=[CH:19]1>>[C:14]([C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:24]2[N:25]=[C:26]3[C:21]([CH:20]=[CH:19][C:18](=[O:17])[NH:27]3)=[CH:22][CH:23]=2)[CH2:10][CH2:9]1)(=[O:16])[CH3:15]
Reactant: CC(=O)c1c(Cl)cccc1N1CCNCC1
Reactant: O=CCCCOc1ccc2ccc(=O)[nH]c2n1
Product: CC(=O)c1c(Cl)cccc1N1CCN(CCCCOc2ccc3ccc(=O)[nH]c3n2)CC1

Procedure:
In a manner similar to that of other examples above, 1-(2-chloro-6-piperazin-1-yl-phenyl)-ethanone was coupled by reductive amination to 4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound. MS: APCI: M+1: 455.2 (Exact Mass: 454.18).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:8][NH2:9])([CH3:4])([CH3:3])[CH3:2].C[O:18][C:19]([C:21]1[N:22]=[C:23]([C:39]#[N:40])[C:24]2[C:29]([C:30]=1[OH:31])=[CH:28][CH:27]=[C:26]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:25]=2)=O.C1CCN2C(=NCCC2)CC1>CC(N(C)C)=O>[C:1]([O:5][C:6](=[O:16])[CH:7]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:8][NH:9][C:19]([C:21]1[N:22]=[C:23]([C:39]#[N:40])[C:24]2[C:29]([C:30]=1[OH:31])=[CH:28][CH:27]=[C:26]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:25]=2)=[O:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(CN)c1ccccc1
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Solvent: CC(=O)N(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)C(CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)c1ccccc1
Temperature: 150 °C
Yield: 72.5 %

Procedure:
A mixture of 3-amino-2-phenyl-propionic acid tert-butyl ester (108 mg), 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (52 mg) and DBU (0.036 mL) in DMA (0.5 mL) was heated in an oil bath (150° C.) for 1.5 h. After cooling, the reaction mixture was partitioned between EtOAc and diluted HCl solution; EtOAc phase was separated and washed with water, diluted NaCl solution respectively and dried over anhydrous sodium sulfate solution, filtered, concentrated and silica gel column purified to give desired product as brown solid (60 mg). LC-MS ESI+: 510 (M+1)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.CCN(CC)CC.[CH3:20][Si:21](Cl)([CH3:23])[CH3:22]>C1COCC1>[CH3:20][Si:21]([CH3:23])([CH3:22])[O:12][C:9]1[CH:10]=[CH:11][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:7][CH:8]=1
Reactant: Oc1ccc(-c2cccs2)cc1
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)Oc1ccc(-c2cccs2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(2-thienyl)phenol in anhyd. THF (10 mL) was added Et3N (0.9 mL, 6.5 mmol), followed by TMSCl (0.4 mL, 3.2 mmol). The reaction mixture was stirred at room temperature overnight, then filtered and concentrated under reduced pressure to give 2-(4-trimethylsilyloxyphenyl)thiophene: TLC (20% EtOAc/hex) Rf 0.69. This material was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3I)[CH3:2].Cl.N1C=C[CH:26]=[CH:25][CH:24]=1>>[CH2:1]([C:3]1([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[C:24]#[C:25][CH3:26])[CH3:2]
Reactant: c1ccncc1
Reactant: CCC1(CC(=O)OC)OCCc2c1[nH]c1c(I)cccc21
Agent: Cl
Product: CC#Cc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3

Procedure:
A mixture of 1-ethyl-8-iodo-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, methyl ester (5.93 g, 14.86 mmol), copper (I) methyl acetylide (3.05 g, 29.72 mmol), and 75 mL of dry pyridine was refluxed, under a flow of nitrogen, for 6 hours. The mixture was then poured into 100 mL of 1N HCl and the aqueous solution was extracted with ether. The combined extracts were washed with 1N HCl and saturated NaCl, dried over magnesium sulfate, filtered and concentrated to give the crude product. The material was purified by flash chromatography (15% ethyl acetate/hexane, silica gel) to give the pure title compound (2.16 g).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([C:12]2([OH:33])[C:16]3[CH:17]=[C:18]([NH:23][C:24](=[O:30])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:19]([CH3:22])=[C:20]([CH3:21])[C:15]=3[O:14][C:13]2([CH3:32])[CH3:31])[CH:9]=[CH:10][CH:11]=1.O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(C)=O>[CH:2]([C:6]1[CH:7]=[C:8]([C:12]2([OH:33])[C:16]3[CH:17]=[C:18]([NH:23][C:24](=[O:30])[CH2:25][C:26]([CH3:27])([CH3:28])[CH3:29])[C:19]([CH3:22])=[C:20]([CH3:21])[C:15]=3[O:14][C:13]2([CH3:32])[CH3:31])[CH:9]=[CH:10][CH:11]=1)=[O:1]
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2(O)c1cccc(C2OCCO2)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: O
Product: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2(O)c1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
To a solution of 2-(3-bromophenyl)-1,3-dioxolane (1.65 mL, 10.9 mmol) in THF (20 mL) was added dropwise at −78° C. under an argon atmosphere n-butyllithium (1.59 M hexane solution, 6.4 mL, 10.2 mmol), and the resulting mixture was stirred for 30 minutes. To the reaction solution was added dropwise at −78° C. a solution of 3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamide (1.0 g, 3.30 mmol) obtained in Reference Example 65 in THF (10 mL), and the resulting mixture was stirred for 30 minutes. The reaction solution was warmed to room temperature and stirred for 1 hour, and water was added to the reaction solution and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:3) to obtain 1.38 g (yield: 92%) of N-(3-(3-(1,3-dioxolan-2-yl)phenyl)-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide as an amorphous powder. To a mixed solution of the obtained N-(3-(3-(1,3-dioxolan-2-yl)phenyl)-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (300 mg, 0.66 mmol) in acetone (4 mL)-water (0.3 mL) was added pyridinium p-toluenesulfonate (5 mg, 0.03 mmol), and the mixture was stirred for 30 minutes. The reaction solution was cooled to room temperature, and water was added to the reaction solution and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from THF-diisopropyl ether to obtain 194 mg (yield: 72%) of the title compound. Melting point: 189-190° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](C(OCC)=O)=[N:4][CH:5]=[N:6][CH:7]=1.ClC1[C:15]([C:20]([OH:22])=O)=NC=NC=1.B(F)(F)F.C[CH2:28][O:29]CC.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)C>[Cl:1][C:2]1[C:3]([O:22][CH2:20][CH3:15])=[N:4][C:5](=[C:28]=[O:29])[NH:6][CH:7]=1
Reactant: CCOCC
Reactant: CCOC(=O)c1ncncc1Cl
Reactant: O=C(O)c1ncncc1Cl
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCOC1=NC(=C=O)NC=C1Cl

Procedure:
5-Chloro-4-ethoxycarbonylpyrimidine can be prepared by treating 5-chloro-4-carboxypyrimidine (40 g) with ethanol (400 cc) and boron trifluoride etherate (80 cc). After heating for 24 hours under reflux, the volatile materials are eliminated and then methylene chloride (250 cc) is added. An 8% (w/v) aqueous sodium bicarbonate solution (100 cc) is added and then the pH is adjusted to 6 by the addition of sodium bicarbonate powder. A further extraction is carried out with methylene chloride (300 cc). The solvent is evaporated off and then the residue distilled. 5-Chloro-4-ethoxy-carbonylpyrimidine (23 g), b.p. 132°-133° C./33 mm Hg, is obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[CH2:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CC=CC=1>CN(C)C=O>[CH2:19]([N:26]1[CH2:31][CH2:30][N:29]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:4][C:3]=2[N+:16]([O-:18])=[O:17])[CH2:28][CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CC1CC(=O)NN=C1c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC1CC(=O)NN=C1c1ccc(N2CCN(Cc3ccccc3)CC2)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 95.7 %

Procedure:
16.1 g (60 mmol) of 6-(4-chloro-3-nitro-phenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone, 15.9 g (90 mmol) of 1-benzyl-piperazine and 7.3 ml (90 mmol) of pyridine are stirred into 60 ml of dimethyl formamide at 100° C. A further 5.8 g (33 mmol) of 1-benzyl-piperazine is added after 7 hours and stirring of the reaction mixture is continued for 12 hours at 100° C. When the reaction mixture is cold it is poured out on 300 ml of ice water and the solid which precipitates is suction filtered. The aqueous phase is extracted twice with 200 ml of dichloromethane. The combined organic phases are washed with water and saturated sodium chloride solution, dried, filtered and concentrated by evaporation in vacuo. The solid residue obtained is recrystallized from 500 ml of ethanol together with the solid initially obtained. 23.4 g (95%) of orange red crystals melting at 220° to 221° C. are obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:21]([Cl:29])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[ClH:29].[C:21]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=2)[C:8]([C:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=2)=[CH:9]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CN1CC=C(c2c[nH]c3ccc(C(F)(F)F)cc23)CC1
Reactant: O=C(Cl)c1ccccc1
Product: CN1CC=C(c2cn(C(=O)c3ccccc3)c3ccc(C(F)(F)F)cc23)CC1
Product: Cl

Procedure:
(20.3 mg, 74%); from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-trifluoromethyl-1H-indole (Example 4i, 20 mg, 0.071 mmol) and benzoyl chloride (15.0 mg, 0.107 mmol), HRMS-FAB+ for C22H19N2OF3, calculated MH+ : 385.15277; found: 385.15480.
Reaction SMILES: [NH:1]1CCNCC1.[Cl:7][C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[CH:10][N:9]=1>C(#N)C.ClCCl>[Cl:7][C:8]1[C:13]([C:12]#[N:1])=[N:14][CH:11]=[CH:10][N:9]=1
Reactant: C1CNCCN1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CC#N
Solvent: ClCCl
Product: N#Cc1nccnc1Cl
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
Piperazine (1.5 mmol) and 2-chloro-3-nitro-pyridine (1 mmol) were dissolved in acetonitrile (3 mL) and stirred for 30 min at 85° C. The reaction mixture was diluted with dichloromethane and washed with water. The organic layer was isolated, washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The product was purified (SPE column chromatography, silica gel, 0-10% methanol in ethyl acetate).