Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.C([Li])(CC)C.C1CCCCC1.[CH3:21][N:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1>O1CCCC1>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([C:25]2([OH:28])[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CN1CCC(=O)CC1
Reactant: COc1cccc(Br)c1
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: COc1cccc(C2(O)CCN(C)CC2)c1
Temperature: -50 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A suitable dry reaction vessel having a mechanical stirrer, low temperature thermometer and addition funnel was charged with 250 g (1.34 mol) of m-bromoanisole (Aldrich Chemical Company, Milwaukee, Wis.) in 675 ml of dry tetrahydrofuran and the solution was cooled under nitrogen to -50° C. to -55° C. in a dry ice/acetone bath. A solution of 1357 ml. of sec.-butyllithium in cyclohexane (1.71 mol) was added dropwise to the reaction mixture at such a rate so that the temperature did not rise above -50° C. The resulting white suspension was stirred at -50° C. for 1 hour followed by the addition of 174.2 g (1.54 mol) of 1-methyl-4-piperidone (Aldrich Chemical Company) in 440 ml of dry tetrahydrofuran so as to maintain the reaction temperature below -40° C. When the addition was complete the temperature was allowed to rise to approximately -20° C. over approximately 11/2 hours and then to room temperature over a 1 hour period. Residual sec.-butyllithium was quenched by the addition of 350 ml of saturated sodium chloride solution followed by the addition of 525 ml of water. The aqueous phase was separated and extracted twice with 350 ml portions of methylene chloride. The combined organic extracts were extracted in two portions, each with 1250 ml of 1N hydrochloric acid. The separated aqueous extracts were made basic (pH=10) with 28 percent ammonium hydroxide and extracted 3 times with 350 ml portions of methylene chloride. The organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo. The residue was slurried in 1000 ml of hot hexane and the slurry was cooled and filtered. The isolated crystalline product was dried in a vacuum oven to provide 225.6 g of 98% pure product. Yield 74.4%. mp=111°-113° C.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH:12]2[CH2:15][N:14]([CH3:16])[CH2:13]2)=[O:11])=[CH:6][CH:5]=1.[CH2:17](Cl)Cl>>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH:12]2[CH2:17][CH2:13][N:14]([CH3:16])[CH2:15]2)[OH:11])=[CH:8][CH:9]=1
Reactant: CN1CC(C(=O)c2ccc(Br)cc2)C1
Reactant: ClCCl
Agent: [BH4-]
Agent: [Na+]
Product: CN1CCC(C(O)c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
Add sodium tetrahydroborate (0.36 g, 9.52 mmol) in portions to a solution of (4-bromo-phenyl)-(1-methyl-azetidin-3-yl)-methanone (0.64 g, 2.38 mmol) in CH2Cl2 at 0° C. Stir the mixture at RT overnight and quench with water. Adjust the aqueous to pH=10 by using 1 N NaOH and extract with ethylacetate (2×150 mL). Dry the combined organic layers over Na2SO4, filter, and concentrate. Purify the crude material by flash chromatography, collecting all the fractions as the product does not show by UV. Elute with 10% MeOH (2 N NH3)/CH2Cl2 to give 0.22 g (34%) of the title compound. LC-MS/ES m/z (79Br) 270.0 [M+H]+.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[CH:10]=[C:9]1B(O)O)=O)(C)(C)C.[F-].[K+].[CH2:24]([O:31][C:32]1[N:47]=[C:46](Cl)[C:45]([CH2:49][CH3:50])=[C:44]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:33]=1[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:24]([O:31][C:32]1[N:47]=[C:46]([C:9]2[NH:8][C:16]3[C:11]([CH:10]=2)=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=3)[C:45]([CH2:49][CH3:50])=[C:44]([O:51][CH2:52][C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[C:33]=1[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCc1c(Cl)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Reactant: COc1ccc2cc(B(O)O)n(C(=O)OC(C)(C)C)c2c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [F-]
Solvent: C1CCOC1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCc1c(-c2cc3ccc(OC)cc3[nH]2)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
A mixture of (1-(tert-butoxycarbonyl)-6-methoxy-1H-indol-2-yl)boronic acid (437 mg, 1.5 mmol), Pd2dba3 (23 mg, 0.025 mmol), KF (174 mg, 3.0 mmol), t-Bu3PHBF4 (17.4 mg, 0.06 mmol) and benzyl 2,4-bis(benzyloxy)-6-chloro-5-ethylnicotinate (488 mg, 1.0 mmol) in THF (2.0 mL) was stirred at 60° C. under argon overnight. The solvent was then replaced with diphenyl ether (2.0 mL) and the mixture was stirred at 180° C. for 1 h. After cooling, the reaction mixture was loaded on a silica gel column and the product was eluted with ethyl acetate in hexanes (0-30% gradient) to furnish benzyl 2,4-bis(benzyloxy)-5-ethyl-6-(6-methoxy-1H-indol-2-yl)nicotinate (380 mg) in 64% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2].[CH3:25][CH:26]1[O:31][CH:30]([CH3:32])[CH2:29][NH:28][CH2:27]1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:28]3[CH2:27][CH:26]([CH3:25])[O:31][CH:30]([CH3:32])[CH2:29]3)[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(Br)c1)N2
Reactant: CC1CNCC(C)O1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N3CC(C)OC(C)C3)c1)N2
Temperature: 120 °C
Reaction time: 16 h
Yield: 80.4 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (4.0 g, 10.3 mmol), 2,6-dimethyl-morpholine (6.4 mL, 51.6 mmol), copper(I) iodide (785 mg, 4.1 mmol), N,N-dimethylglycine hydrochloride (1.2 g, 8.2 mmol) and potassium carbonate (4.3 g, 30.9 mmol) in dimethyl sulfoxide (20 mL) was stirred at 120° C. for 16 hours. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×200 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-[3-(2,6-dimethyl-morpholin-4-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.5 g, 80%) as a white solid which was used for next step without further purification: LC/MS m/e calcd for C26H34N2O3 (M+H)+: 423.57, observed: 423.0.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[NH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[CH:3]=1.[CH2:16]([C:18]([O-:20])=[O:19])[CH3:17].[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH:22]=[CH2:23]>>[CH2:26]([O:25][C:21]([CH:22]=[CH:23][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[NH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[CH:3]=1)=[O:24])[CH3:27].[CH2:16]([C:18]([O-:20])=[O:19])[CH3:17]
Reactant: O=c1[nH]c2ccc(I)cc2c2cc[nH]c12
Reactant: C=CC(=O)OCC
Agent: CCC(=O)[O-]
Product: CCOC(=O)C=Cc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Yield: 21.6 %

Procedure:
This compound is prepared according to synthesis 68, from 114 mg (0.3 mmol) of 8-iodo-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate and 36 μL (0.33 mmol) of ethyl acrylate. After purification by chromatography on silica (eluent dichloromethane/methanol 98/2) then trituration in ethanol, 23 mg (22%) of 8-(2-ethoxycarbonyl-vinyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[N:17]=[C:18]3[N:22]([C:23]=2[CH:24]=[O:25])[CH2:21][CH2:20][S:19]3)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C(O)(=O)C.O>C(O)C>[C:12]([C:9]1[CH:8]=[C:7]([C:16]2[N:17]=[C:18]3[N:22]([C:23]=2[CH2:24][OH:25])[CH2:21][CH2:20][S:19]3)[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]=1[OH:11])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(-c2nc3n(c2C=O)CCS3)cc(C(C)(C)C)c1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(-c2nc3n(c2CO)CCS3)cc(C(C)(C)C)c1O
Reaction time: 0.17 h
Yield: 74.6 %

Procedure:
In 10 ml of ethanol was dissolved 0.4 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-formyl-2,3-dihydroimidazo[2,1-b]thiazole and after adding 40 mg of sodium borohydride to the solution, the mixture was stirred for 10 minutes. To the reaction mixture were added 0.3 ml of acetic acid and 30 ml of water, and the crystals thus precipitated were recovered by filtration and recrystallized from aqueous ethanol to provide 0.3 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-hydroxymethyl-2,3-dihydroimidazo[2,1-b]thiazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([CH:14]=[O:15])[CH:9]=2)=[C:4]([CH3:16])[CH:3]=1>C1([Mg]Br)CCCCC1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([CH:14]([CH:2]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]3)[OH:15])[CH:9]=2)=[C:4]([CH3:16])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1-c1cc(C=O)c(C)o1
Agent: Br[Mg]C1CCCCC1
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1-c1cc(C(O)C2CCCCC2)c(C)o1
Yield: 156.4 %

Procedure:
An operation similar to that in Example 3 (2) was performed using 5-(4-chloro-2-methylphenyl)-2-methyl-3-furaldehyde (1.6 g) and 1N cyclohexylmagnesium bromide-tetrahydrofuran solution (10 mL) to give the title compound (1.7 g, 77%) as a white crystal.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][CH:29]([C:32](Cl)=[O:33])[CH2:28][CH2:27]1.IC1C=CC=CC=1C(NCCN1C(=O)CC(=O)NC2C3C(C=CC1=2)=CC=CC=3)=O>>[CH3:25][N:26]1[CH2:31][CH2:30][CH:29]([C:32]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[C:22]([CH:23]=[CH:24][C:9]3=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:4][CH:3]=2)=[O:33])[CH2:28][CH2:27]1
Reactant: CN1CCC(C(=O)Cl)CC1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C1CC(=O)N(CCNC(=O)c2ccccc2I)c2ccc3ccccc3c2N1
Product: CN1CCC(C(=O)Nc2ccc(N3C(=O)CC(=O)Nc4c3ccc3ccccc43)cc2)CC1
Yield: 100 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and 1-methylpiperidine-4-carbonyl chloride, the title compound (yield 100%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH:10]([C:14]([NH2:16])=[O:15])[CH2:9]1.[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=1[CH2:27][C:28](O)=[O:29].C(Cl)CCl.C(N(CC)CC)C>CN(C=O)C>[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=1[CH2:27][C:28]([N:11]1[CH2:12][CH2:13][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH2:9][CH:10]1[C:14]([NH2:16])=[O:15])=[O:29]
Reactant: COc1ccc(CC(=O)O)c(OC)c1
Reactant: Cc1ccccc1N1CCNC(C(N)=O)C1
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CC(=O)N2CCN(c3ccccc3C)CC2C(N)=O)c(OC)c1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
4-(2-Methylphenyl)piperazine-2-carboxamide (39 mg, 0.18 mmol), 2,4-dimethoxyphenylacetic acid (42 mg, 0.21 mmol), EDC (42 mg, 0.22 mmol) and HBT (31 mg, 0.23 mmol) were combined in DMF (5 ml) and treated with triethylamine to adjust the pH to ca. 9 (moistened E. Merck colorpHast indicator). The mixture was stirred at ambient temperature for 64 hours. The solvent was removed in vacuo and the residue was chromatographed on silica gel eluted with 2% methanol in methylene chloride. The combined product fractions were evaporated to dryness in vacuo to provide the title compound.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][S:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:14][CH2:13]1)=[CH:9][CH:8]=[C:7]([F:29])[CH:6]=2)[CH3:2].[CH2:30]([O:32][C:33](=[O:41])[C:34]1[CH:39]=[CH:38][C:37](I)=[CH:36][CH:35]=1)[CH3:31].C(=O)([O-])[O-].[K+].[K+].CN1C(=O)CCC1>[Cu](I)I.[O-2].[Zn+2].O>[CH2:30]([O:32][C:33](=[O:41])[C:34]1[CH:39]=[CH:38][C:37]([N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[C:7]([F:29])[CH:6]=3)[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][S:21][C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH2:14][CH2:13]3)=[C:3]2[CH2:1][CH3:2])=[CH:36][CH:35]=1)[CH3:31]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: CCc1[nH]c2cc(F)ccc2c1C1CCN(CCCSc2ccc(F)cc2)CC1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1ccc(-n2c(CC)c(C3CCN(CCCSc4ccc(F)cc4)CC3)c3ccc(F)cc32)cc1
Temperature: 160 °C
Reaction time: 2 h
Yield: 25.7 %

Procedure:
To a mixture of 2-ethyl-6-fluoro-3-{1-[3-(4-fluoro-phenylsulfanyl)-propyl]-piperidin-4-yl}-1H-indole (430 mg), p-iodobenzoic acid ethyl ester (716 mg), potassium carbonate (359 mg), copper iodide (52 mg) and zinc oxide (14 mg) in a reactor vial under argon is added NMP (3 ml) and the reaction heated by microwaves irradiation at 160° C. After 120 min, water is added and the suspension extracted with DCM. Preparative HPLC provides 150 mg pure product (26%) as a beige solid. R.t. 4.81 min.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:10][OH:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(=O)([O-])O.[Na+]>ClCCl>[S:23]([O:11][CH2:10][CH2:9][C:8]1[CH:12]=[CH:13][CH:14]=[C:6]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:7]=1)(=[O:25])(=[O:24])[CH3:22]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1cccc(N2CCCC2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1cccc(N2CCCC2)c1
Reaction time: 8 h

Procedure:
3-Pyrrolidinophenethyl alcohol was dissolved in dichloromethane (20 ml). Triethylamine (3.7 ml, 26.7 ml) and methanesulfonyl chloride (1.9 ml, 24.5 mmol) were added to the obtained solution at 0° C., and they were stirred overnight. The reaction mixture was distributed into 5% aqueous sodium hydrogencarbonate solution and dichloromethane. The organic layer was dried and the solvent was evaporated under reduced pressure. The residue was subjected to the silica gel column chromatography. After the elution with hexane and ethyl acetate (7:3), suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain 3-pyrrolidinophenethyl mesylate in the form of a white solid (5.13 g, 87%).
Reaction SMILES: C([N:9]1[CH2:18][CH2:17][C:16]2[NH:15][C:14](=[O:19])[N:13]3[CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[N:22]=[C:12]3[C:11]=2[CH2:10]1)(=O)C1C=CC=CC=1.[OH-].[Na+].[Cl-].[NH4+]>C(O)C>[F:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:21]1[N:22]=[C:12]2[C:11]3[CH2:10][NH:9][CH2:18][CH2:17][C:16]=3[NH:15][C:14](=[O:19])[N:13]2[CH:20]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c(=O)n3cc(-c4ccccc4F)nc3c2C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: O=c1[nH]c2c(c3nc(-c4ccccc4F)cn13)CNCC2

Procedure:
To a solution of 9-Benzoyl-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e] pyrimidin-5(6H)-one (435 mg, 1.1 mmol) in ethanol (5 mL) was added 5 mL of 50% aqueous sodium hydroxide. The mixture was refluxed for about 1 hour, and then poured into saturated aqueous ammonium chloride and extracted twice with 10% methanol/ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, concentrated, and triturated with methanol/ether to give 2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one, m.p.>310° C.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].CN(C)C=O.[Cl:15][C:16]1[C:17]([F:38])=[C:18]([CH:27]2[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28]2)[C:19]([O:25][CH3:26])=[C:20]([CH:22](O)[CH3:23])[CH:21]=1.O>ClCCl>[Cl:15][C:16]1[C:17]([F:38])=[C:18]([CH:27]2[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28]2)[C:19]([O:25][CH3:26])=[C:20]([CH:22]([Cl:3])[CH3:23])[CH:21]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: COc1c(C(C)O)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: COc1c(C(C)Cl)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.2 %

Procedure:
Cyanuric chloride (140 mg, 0.78 mmol) was added to N,N-dimethylformamide (0.059 mL, 0.77 mmol) at room temperature. After the formation of a white solid (ca. 10 minutes), methylene chloride (4 mL) was added, followed by tert-butyl 3-[3-chloro-2-fluoro-5-(1-hydroxyethyl)-6-methoxyphenyl]azetidine-1-carboxylate (197 mg, 0.547 mmol). After addition, the mixture was stirred at room temperature overnight. Water was added, and then diluted with dichloromethane. The organic phases were washed with sat. NaHCO3 solution, water and brine, dried over MgSO4, and concentrated. The resulting residue was purified on silica gel (eluting with 0 to 30% EtOAc in hexanes) to give the desired product (110 mg, 53%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7]/[C:8](=[N:16]/[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])/S(C(F)(F)F)(=O)=O)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:42][CH:41]([OH:43])[CH2:40]2)=[CH:35][CH:34]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:24])[NH:7]/[C:8](/[NH:32][C:33]1[CH:34]=[CH:35][C:36]([N:39]2[CH2:40][CH:41]([OH:43])[CH2:42]2)=[CH:37][CH:38]=1)=[N:16]/[C:17](=[O:18])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(N2CC(O)C2)cc1
Reactant: CC(C)(C)OC(=O)/N=C(/NC(=O)OC(C)(C)C)S(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)/N=C(/NC(=O)OC(C)(C)C)Nc1ccc(N2CC(O)C2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 80 %

Procedure:
To a solution of {[(Z)-tert-butoxycarbonylimino]-trifluoromethanesulfonyl-methyl}-carbamic acid tert-butyl ester (13.62 g, 34.8 mM) and triethylamine (4.9 ml, 34.8 mM) in dry DCM (183 ml), 1-(4-aminophenyl)azetidin-3-ol (Method 37; 6.0 g, 36.5 mM) was added. The solution was stirred at room temperature under nitrogen for 48 hours. The reaction mixture was diluted with more DCM and washed with water (twice), saturated sodium bicarbonate solution (twice), water and saturated sodium chloride. The solution was then dried with anhydrous sodium sulphate, filtered and evaporated. The crude product was triturated with ether/isohexane (2:1), filtered washed with the same solvent and dried to give the title compound as a yellow solid (11.77 g, 83%). NMR 1.4 (s, 9H), 1.5 (s, 9H), 3.47 (t, 1H), 4.02 (t, 2H), 4.5 (m, 1H), 5.55 (d, 1H), 6.38 (d, 2H), 7.23 (d, 2H), 9.75 (s, 1H), 11.46 (m, 1H); m/z 407.
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[N:6][C:5]([S:9][CH3:10])=[CH:4][N:3]=1.[CH2:11]([OH:14])[C:12]#[CH:13].C(N(CC)CC)C.O>O1CCOCC1.[Cu]I>[NH2:1][C:2]1[C:7]([C:13]#[C:12][CH2:11][OH:14])=[N:6][C:5]([S:9][CH3:10])=[CH:4][N:3]=1
Reactant: CSc1cnc(N)c(Br)n1
Reactant: C#CCO
Agent: [Cu]I
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CSc1cnc(N)c(C#CCO)n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
To a solution of the compound obtained in Example 34 (2) (440 mg) in dioxane (10 ml), 2-propyn-1-ol (168 mg), bistriphenylphosphine palladium dichloride (72 mg), copper(I) iodide (38 mg) and triethylamine (304 mg) were added successively and the mixture was stirred in a sealed tube at 70° C. for 2 hours. After cooling, the reaction solution was poured into water, and the mixture was extracted with chloroform, dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was separated using silica gel column chromatography (chloroform:methanol=10:1) to obtain 347 mg (88.9%) of the desired product as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[C:3]=1[C:9]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH3:19])[O:11][N:10]=1.[CH2:20]([N:22](CC)CC)C.C[Si](C#N)(C)C>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>[CH2:17]([O:16][C:14]([C:13]1[C:9]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[C:20]#[N:22])=[N:10][O:11][C:12]=1[CH3:19])=[O:15])[CH3:18]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1c(-c2c(F)cccc2I)noc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)C#N
Solvent: O
Product: CCOC(=O)c1c(-c2c(F)cccc2C#N)noc1C
Temperature: 25 °C
Yield: 82 %

Procedure:
To a mixture of ethyl 3-(2-fluoro-6-iodo-phenyl)-5-methyl-isoxazole-4-carboxylate (0.25 g, 0.67 mmol), tetrakis(triphenylphosphine)palladium (0.08 g, 0.067 mmol), and triethylamine (5 ml) under N2 was added trimethylsilyl cyanide and heated at reflux overnight. The reaction was cooled to room temperature, diluted with H2O, and extracted with EtOAc (2×). The combined extracts were washed (H2O then brine), dried (MgSO4), filtered, and concentrated. Flash chromatography (silica gel, EtOAc/hexanes gradient) gave the title compound (0.15 g, 82%). Mass Spectrum (ES+) (m/z) 275.0 [M+1].
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[N:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:18]([Mg]Cl)[CH3:19]>C1COCC1.[Cl-].N>[C:1]1([CH3:17])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12]([CH:15]([OH:16])[CH2:18][CH3:19])=[N:11]2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc(C=O)n2)cc1
Reactant: CC[Mg]Cl
Agent: N
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCC(O)c1ccn(S(=O)(=O)c2ccc(C)cc2)n1
Reaction time: 3 h

Procedure:
To a chilled (−40° C.) solution of 1-(toluene-4-sulfonyl)-1H-pyrazole-3-carbaldehyde (1.50 g, 5.99 mmol) in THF was added a 2 M solution of ethylmagnesium chloride (3.00 mL, 6.00 mmol) in THF. After 3 hours, the mixture was diluted with saturated aqueous ammonia chloride and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and the concentrated in vacuo. The residue was purified by reversed-phase HPLC. The major fractions were combined and the solvent was concentrated in vacuo to afford 1-[1-(toluene-4-sulfonyl)-1H-pyrazol-3-yl]-propan-1-ol.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([OH:13])=O.[N:15]1([CH2:20][CH2:21][NH2:22])[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([NH:22][CH2:21][CH2:20][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:13]
Reactant: Cc1[nH]c2c(c1C(=O)O)CCCC2=O
Reactant: NCCN1CCCC1
Product: Cc1[nH]c2c(c1C(=O)NCCN1CCCC1)CCCC2=O
Yield: 72.6 %

Procedure:
Similar procedure as Example 2, 2-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (S4) 0.2 g (1.0 mmol) and 2-(pyrrolidin-1-yl)ethanamine 0.24 g (2.1 mmol) was reacted to give 0.21 g (73%) of the titled compound as a white solid.