Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:4][O:3]1.C(N(CC)CC)C.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CN=C1.C([Si](C(C)C)(C(C)C)Cl)(C)C>CN(C=O)C>[O:18]([CH2:1][C@@H:2]([OH:3])[CH3:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[C@H]1CO1
Reactant: Oc1ccccc1
Agent: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](O)COc1ccccc1
Temperature: 150 °C
Yield: 108.6 %

Procedure:
A microwave vessel was charged with (S)-2-methyl-oxirane (0.46 ml, 7.78 mmol), triethylamine (0.33 ml, 2.36 mmol), phenol (222 mg, 2.36 mmol) and DMF (2.0 ml). The mixture was heated by microwave for 20 minutes at 150° C. The reaction was concentrated and dried under reduced pressure. The crude mixture (approximately 9:1) was dissolved in DMF (3.0 ml) and treated with imidazole (160 mg, 2.36 mmol) and Triisopropylchlorosilane (181 mg, 0.94 mmol) overnight at room temperature under nitrogen. The reaction was concentrated under reduced pressure and the crude product was purified via flash chromatography using 3:2/heptane:Ethyl acetate as eluant. Fractions containing product were combined and concentrated to afford (S)-1-Phenoxy-propan-2-ol (390 mg, 62%) as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[Cl:11]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[S:3][C:4]([Cl:11])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1
Reactant: Nc1nc(C(F)(F)F)cs1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Nc1nc(C(F)(F)F)c(Cl)s1

Procedure:
2-Amino-4-trifluoromethylthiazole (10 g) was dissolved in acetonitrile (80 ml) and N-chlorosuccinimide (8.8 g) was added at room temperature with stirring. The mixture was refluxed for 9 hr and the solvent was removed under reduced pressure. The residue was dissolved in chloroform and washed with cold diluted aqueous sodium hydroxide. The chloroform layer was dried over magnesium sulfate and the solvent was removed under reduced pressure to give crude 2-Amino-5-chloro-4-trifuloromethylthiazole (12 g). It was recrystallized from n-hexane-benzene (1:1 mixture) as colorless needles (6.8 g), m. p. 107-108° C.
Reaction SMILES: CCCCCC.[H-].[Na+].COP([CH2:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])(OC)=O.[CH:26]([C:28]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[C:29]=1[C:30]([O:32][CH3:33])=[O:31])=O>C1COCC1>[CH2:19]([O:18][C:16](=[O:17])/[CH:15]=[CH:26]/[C:28]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:39])([F:40])[F:41])[C:29]=1[C:30]([O:32][CH3:33])=[O:31])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1c(C=O)cccc1C(F)(F)F
Reactant: COP(=O)(CC(=O)OCc1ccccc1)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)c1c(/C=C/C(=O)OCc2ccccc2)cccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 97.6 %

Procedure:
To a suspension of hexane-washed sodium hydride (0.42 g of 60% suspension in mineral oil, 10.52 mmol) in 120 mL of THF at 0° C. was added benzyl 2-(dimethoxyphosphoryl)acetate (2.72 g, 10.52 mmol) dropwise in 10 mL of THF. The resulting mixture was stirred 5 min at 0° C. and then was allowed to warm to ambient temperature and stirred for 20 min. To this solution was added methyl 2-formyl-6-(trifluoromethyl)benzoate (2.22 g, 9.56 mmol) dropwise in 10 mL of THF. The resulting solution was stirred at ambient temperature for 1 h. The reaction mixture was quenched with 1N HCl (100 mL) and extracted with ethyl acetate. The organics were washed with sat'd aq NaHCO3 and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo to afford 3.4 g (97%) of the title compound which was sufficiently pure to be used without purification. 1H NMR (CDCl3): δ 7.79 (d, 1H, J=7.9 Hz), 7.72-7.67 (m, 2H), 7.55 (t, 1H, J=7.9 Hz), 7.38-7.30 (m, 5H), 6.47 (d, 1H, J=15.8 Hz), 5.23 (s, 2H), 3.94 (s, 3H). LRMS (ESI): 387.17 (M+H+Na)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH3:32][S:33]([N:36]1[CH2:41][CH2:40][N:39]([CH2:42][CH2:43]OS(C)(=O)=O)[CH2:38][CH2:37]1)(=[O:35])=[O:34]>CN(C=O)C.O>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:43][CH2:42][N:39]4[CH2:40][CH2:41][N:36]([S:33]([CH3:32])(=[O:34])=[O:35])[CH2:37][CH2:38]4)[CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2cc(O)ccc21
Reactant: CS(=O)(=O)OCCN1CCN(S(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(c2cc(F)cc(F)c2)=C(c2cccnc2)C3=O)CC1
Temperature: 80 °C
Yield: 68.7 %

Procedure:
To a solution of 3-(3,5-difluorophenyl)-5-hydroxy-2-(pyridin-3-yl)-1H-inden-1-one (60 mg, 0.18 mmol) obtained in Step 5 of Example 128 in DMF (2 mL) was added K2CO3(75 mg, 0.54 mmol) and methylsulfonyl 2-(4-(methylsulfonyl)piperazin-1-yl)ethyl ether (77 mg, 0.27 mmol). The mixture was heated to 80° C. for 3 h and cooled to room temperature. The resulting solution was diluted with H2O (5 mL) and extracted with EtOAc (5 mL×3). The extracts were washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (2% MeOH/CH2Cl2) to afford the title compound (65 mg, 69%).
Reaction SMILES: BrC1C=CC=C[N+]=1C.[CH2:9]([OH:18])[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:19](O)(=[O:21])[CH3:20].C(N(CCCC)CCCC)CCC>C(Cl)Cl>[C:19]([O:18][CH2:9][CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:21])[CH3:20]
Reactant: OCC=Cc1ccccc1
Reactant: CC(=O)O
Agent: C[n+]1ccccc1Br
Solvent: CCCCN(CCCC)CCCC
Solvent: ClCCl
Product: CC(=O)OCC=Cc1ccccc1
Yield: 82 %

Procedure:
To a suspended CH2Cl2 (2 ml) solution of 2-bromo-1-methylpyridinium (720 mg, 2.4 mmol) was added a mixture of cinnamyl alcohol (268 mg, 2.0 mmol), acetic acid (120 mg, 2.0 mmol) and tri-n-butylamine (888 mg, 4.8 mmol) in CH2Cl2 (2 ml), and the resulting mixture was refluxed for 3 hours. After evaporation of the solvent, the residue was separated by silica gel column chromatography, and cinnamyl acetate was isolated in 82% yield.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH2:33][OH:34])=[CH:20][C:21]2[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=2)=[CH:15][CH:14]=1>ClCCl.C(OCC)C>[F:12][C:13]1[CH:18]=[CH:17][C:16](/[C:19](/[CH:33]=[O:34])=[CH:20]\[C:21]2[CH:26]=[CH:25][C:24]([CH:27]=[CH:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)/C=C/c1ccc(C=C(CO)c2ccc(F)cc2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)C=Cc1ccc(/C=C(/C=O)c2ccc(F)cc2)cc1
Yield: 55.6 %

Procedure:
To a suspension of pyridinium chlorochromate (PCC, 0.75 g, 3.5 mmol) in dichloromethane (20 mL) a dropwise solution of methyl 3-(E)(4-(2-(4-fluorophenyl)-3-hydroxyprop-1-en-1-yl)phenyl)acrylate (0.9 g, 2.9 mmol) in dichloromethane (5 mL) was added under constant stirring and the reaction mixture was stirred at room temperature for 1 hour. The reaction mass was diluted with diethyl ether (200 mL) and filtered through a celite bed, the filtrate was successively washed with saturated aqueous NaHCO3 solution (3×100 mL) and water (1×100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to afford the pure title compound as a white solid (0.5 g, 56% yield).
Reaction SMILES: [CH:1]1([N:7]([CH2:32][CH:33]2[CH2:35][CH2:34]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:31]=[CH:30][C:20]([CH2:21][NH:22][CH:23]([CH2:28][CH3:29])[C:24]([O:26]C)=[O:25])=[CH:19][CH:18]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO.C1COCC1>[CH:1]1([N:7]([CH2:32][CH:33]2[CH2:34][CH2:35]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:21][NH:22][CH:23]([CH2:28][CH3:29])[C:24]([OH:26])=[O:25])=[CH:30][CH:31]=3)=[O:15])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCC(NCc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(NCc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of methyl 2-({4-[({6-[cyclohexyl(cyclopropylmethyl)amino]pyrimidin-4-yl}carbonyl)amino]benzyl}amino)butanoate (Example 74, 50 mg; 0.10 mmol) in a mixture of MeOH (2 ml) and THF (2 ml) was treated with an aqueous solution (5 N) of sodium hydroxide (300 μl; 1.5 mmol) and the reaction mixture was stirred at room temperature for 24 hours. The mixture was acidified with HCl 1N until pH 4. The precipitate was filtered and dried under vacuum to give the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6].C(N(CC)CC)C.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:19]([NH:6][C:5]1[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc(N)cc(OC)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(NCc2ccccc2)cc(OC)c1
Reaction time: 0.04 h

Procedure:
N-benzyl-3,5-dimethoxyaniline was prepared using a system (FRX200, Syrris Limited) including a microflow reactor. For this purpose, 76 mg (0.5 mmol) of 3,5-dimethoxyaniline and 5 ml of dimethylformamide were added to the first storage unit of the system including the microflow reactor, and then 70 μl (0.5 mmol) of triethylamine was added thereto. Meanwhile, 60 μl (0.5 mmol) of benzyl bromide and 5 ml of dimethylformamide were added to the second storage unit of the system. The reactants included in the first and second storage units were transferred through the first and second flow channels to the mixing unit, and then transferred through the third flow channel into the microflow reactor including microchannels. The first and second flow channels could transfer 360 μl (180 μl for each flow channel) of the reactants to the microflow reactor. The microflow reactor was set at a capacity of 250 μl, a temperature of 225° C. and a pressure of 8 bar. The reactants in the first and second storage units were set such that they were passed through the first to third flow channels at a flow rate of 0.05 ml/min and introduced into the microflow reactor. Also, the residence time of the reactants in the microflow reactor was set at 2.5 minutes.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:9]=[C:10]([CH3:24])[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=3[CH3:23])=[C:4]2[N:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(O)C>[CH3:24][C:10]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=2[CH3:23])=[C:4]2[N:3]=[C:2]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:7]=[C:6]([NH2:8])[N:5]2[N:9]=1
Reactant: Cc1nn2c(N)cc(Cl)nc2c1Cc1cccc(C(F)(F)F)c1C
Reactant: C1COCCN1
Solvent: CCO
Product: Cc1nn2c(N)cc(N3CCOCC3)nc2c1Cc1cccc(C(F)(F)F)c1C
Temperature: 140 °C

Procedure:
To a solution of 5-chloro-2-methyl-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}pyrazolo[1,5-a]pyrimidin-7-amine (331 mg, 0.93 mmol) in ethanol (2 mL) was added morpholine (406 mg, 4.7 mmol). Reaction mixture was heated in microwave reactor at 140° C. for 7 hours. Reaction mixture was concentrated to dryness. It was diluted with ethyl acetate (30 mL) and 5% HCl solution (5 mL). Two layers were separated. Organic layer was dried and concentrated to dryness. Product was obtained and used in next step. (270 mg, 71%); LC/MS: MS (ES+) m/e 406 (MH+).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11](=[O:13])[CH3:12].[C:14](O)(=O)C.N1CCCCC1.C=O>CC#N>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10](=[CH2:14])[C:11](=[O:13])[CH3:12]
Reactant: CC(=O)O
Reactant: CC(=O)Cc1c(F)ccc(F)c1F
Agent: C=O
Solvent: C1CCNCC1
Solvent: CC#N
Product: C=C(C(C)=O)c1c(F)ccc(F)c1F
Temperature: 70 °C
Yield: 205 %

Procedure:
A solution of 18 (3.5 g, 18.6 mmol), acetic acid (0.34 ml, 5.58 mmol), piperidine (0.37 ml, 3.72 mmol), formaldehyde (6.0 g, 37% aqueous solution) in MeCN (20 mL) was heated over weekend. The conversion was about 60%. Reaction was heated to 70° C. overnight. The mixture was concentrated and extracted with MTBE and HCl (0.5N). The organic layer was washed with aqueous K2CO3 (0.5N) and water, in turns. The organic layer was concentrated. The product was isolated by chromatography column (hexane and EtOAc), yielding 31 (2.29 g, 61.5%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:12][C:11]([N:13]2[CH2:18][CH2:17][N:16]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C@@H:15]([C:33]([OH:35])=O)[CH2:14]2)=[N:10][C:9]=1[CH3:36])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:37]([C:40]1[N:45]=[CH:44][C:43]([CH2:46][NH2:47])=[CH:42][CH:41]=1)([CH3:39])[CH3:38].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:1]([O:5][C:6]([C:8]1[S:12][C:11]([N:13]2[CH2:18][CH2:17][N:16]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:30])[F:31])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C@@H:15]([C:33](=[O:35])[NH:47][CH2:46][C:43]3[CH:44]=[N:45][C:40]([CH:37]([CH3:39])[CH3:38])=[CH:41][CH:42]=3)[CH2:14]2)=[N:10][C:9]=1[CH3:36])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)c1ccc(CN)cn1
Reactant: Cc1nc(N2CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)[C@@H](C(=O)O)C2)sc1C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(N2CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)[C@@H](C(=O)NCc3ccc(C(C)C)nc3)C2)sc1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 86.5 %

Procedure:
To a mixed solution of the compound (55 mg) obtained in Step 6, [(6-isopropylpyridin-3-yl)methyl]amine (24 mg) and 1-hydroxybenzotriazole hydrate (23 mg) in N,N-dimethylformamide (660 μl) was added, with stirring at room temperature, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (29 mg). After stirring at room temperature for 3 hr, the reaction mixture was partitioned by adding saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by thin layer chromatography (ethyl acetate:n-hexane=3:2) to give the title compound (59 mg).
Reaction SMILES: CO[CH:3]([O:21][CH3:22])[CH2:4][N:5]1[C:10]([C:11]([O:13]C)=O)=[C:9]([O:15][CH3:16])[C:8](=[O:17])[C:7]([C:18]([OH:20])=[O:19])=[CH:6]1.CC(O)=O.CS(O)(=O)=O.[NH2:32][C@H:33](CO)[CH3:34]>CC#N>[CH3:34][C@@H:33]1[N:32]2[C:11](=[O:13])[C:10]3[N:5]([CH:6]=[C:7]([C:18]([OH:20])=[O:19])[C:8](=[O:17])[C:9]=3[O:15][CH3:16])[CH2:4][C@H:3]2[O:21][CH2:22]1
Reactant: COC(=O)c1c(OC)c(=O)c(C(=O)O)cn1CC(OC)OC
Reactant: C[C@H](N)CO
Agent: CS(=O)(=O)O
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1c2n(cc(C(=O)O)c1=O)C[C@H]1OC[C@H](C)N1C2=O
Temperature: 61.5 °C
Reaction time: 15 h

Procedure:
1-[2,2-bis(methyloxy)ethyl]-5-(methyloxy)-6-[(methyloxy)carbonyl]-4-oxo-1,4-dihydro-3-pyridinecarboxylic acid (22.54 g) was dissolved in 220 mL of CH3CN. HOAc (20 mL) and CH3SO3H (1.4 mL) were added at room temperature and the mixture was heated to 58-65° C. for 19.5 h. Alaninol (7.511 g) in CH3CN (15 mL) was added slowly and the resultant mixture was stirred at 64° C. for 18.5 h. The mixture was concentrated, and the residue was redissolved in CH2Cl2 (170 mL). HCl (1 N, 170 mL) was added and the layers were separated. The aqueous layer was extracted with CH2Cl2 (170 mL×2) and the organic layers were combined and concentrated. MeOH (50 mL) was added and the resultant mixture was again concentrated. MeOH (80 mL) was added and the resultant mixture was heated at reflux for 4 h, gradually cooled to 20° C. and held at 20° C. for 15 h. The product was collected by filtration and dried under vacuum.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:9]=[C:8]2[N:10]=[CH:11][C:12]([C:15]#[N:16])=[C:13](Cl)[C:7]2=[CH:6][C:5]=1[NH:17]C(C)=O.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[F:29])[NH2:25].CC(O)C.Cl>CS(O)(=O)=O.O>[NH2:17][C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][C:4]=1[O:3][CH2:2][CH3:1])[N:10]=[CH:11][C:12]([C:15]#[N:16])=[C:13]2[NH:25][C:24]1[CH:26]=[CH:27][C:28]([F:29])=[C:22]([Cl:21])[CH:23]=1
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1NC(C)=O
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1N
Temperature: 84 °C
Reaction time: 8 h
Yield: 102.1 %

Procedure:
A stirred mixture of N-(4-chloro-3-cyano-7-ethoxy-6N-acetylquinoline (274.5 g, 0.947 mol), 3-chloro-4-fluoroaniline (180 g, 1.24 mol), methanesulfonic acid, (5.5 g, 0.057 mol), and 2-propanol (6.7 L) was warmed to reflux (84° C.) for 6.5 hours. After stirring overnight at room temperature, the mixture was warmed to 80° C. Water (3.2 L) containing concentrated hydrochloric acid (655 mL of 38% aqueous HCl) was added. The reaction was kept at reflux for 5 hours. The reaction mixture was cooled to 0° C.-10° C. for 1 hour. The yellow solid product is collected by vacuum filtration and washed with 20% 2-propanol/water (700 mL) and water (2×700 mL). Drying the product in vacuo at 60° C. gave 344.8 g (91%, 99% by HPLC) of 6-Amino-4-(3-chloro-4-fluoro-phenylamino)-7-ethoxy-quinoline-3-carbonitrile as a hydrochloride salt. 1H NMR (DMSO-d6+D2O) δ1.42 (t, 3H), 4.25 (q, 2H), 7.05 (m, 1H), 7.1 (s, 1H), 7.35-7.50 (m, 3H), 7.65 (dd, 1H), 8.65 (s, 1H).
Reaction SMILES: IC1C=C2C(=CC=1)C(=O)NC(=O)C2.[I:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[NH:20][C:19](=[O:26])[C:18]2=[CH:27]OC.[NH2:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([C:39]2[CH:43]=[CH:42][O:41][CH:40]=2)=[C:36]([OH:38])[CH:37]=1>>[O:41]1[CH:42]=[CH:43][C:39]([C:35]2[CH:34]=[CH:33][C:32]([CH2:31][NH:30][CH:27]=[C:18]3[C:17]4[C:22](=[CH:23][CH:24]=[C:15]([I:14])[CH:16]=4)[C:21](=[O:25])[NH:20][C:19]3=[O:26])=[CH:37][C:36]=2[OH:38])=[CH:40]1
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Reactant: NCc1ccc(-c2ccoc2)c(O)c1
Agent: O=C1Cc2cc(I)ccc2C(=O)N1
Product: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccoc2)c(O)c1
Yield: 56 %

Procedure:
Following the same procedure for the preparation of 4-{[(2-Hydroxy-biphenyl-4. -ylmethyl)-amino]-methylene}-6-iodo-4H-isoquinoline-1,3-dione, the title compound is prepared from 6-iodo-4-methoxymethylene-4H-isoquinoline-1,3-dione (85 mg, 0.26 mmol) and 5-Aminomethyl-2-furan-3-yl-phenol in 56% yield: MS (ESI): 487.1 (M+1)+1.
Reaction SMILES: I[CH:2]([CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[N-:17]=[N+:18]=[N-:19].[Na+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[N:17]([CH2:16][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[N+:18]=[N-:19]
Reactant: CC(I)CCCCCCCCCCC(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCCCCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 66751.6 %

Procedure:
A mixture of 6 (0.15 g, 0.44 mmol) sodium azide (0.09 g, 1.4 mmol) and 18-crown-6 (0.015 g, 0.057 mmol) in dimethylformamide (3 ml) was stirred at room temperature for 16 h. DMF was distilled under vacuum, cold 2N HCl (2 ml) was added and the mixture was extracted with ethylacetate (10 ml). The organic phase was washed with water (2×10 ml), dried (Na2SO4) and concentrated under reduced pressure to give a pale yellow solid which was purified by flash chromatography (silica gel) using 20% ethylacetate in hexane to afford the title compound 7 (0,075 g, 67%) as a white solid. 1H NMR (CDCl3) δ: 3.26 (t, 2H, J=6.9 Hz); 2.35 (t, 2H, J=7.5 Hz); 1.62 (m, 4H); 1.35 (m, 14H), FABMS: (m/z), 256 (M+H); 230 and 210. HRMS C13H25N3O2Li calc.: 262.2107, found: 262.2164 (M+Li).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:20]([CH:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].O.[C:30](=O)(O)[O-].[Na+]>C1COCC1.C[Mg]I>[CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:20]([CH:21]2[CH2:26][CH2:25][C:24]([OH:27])([CH3:30])[CH2:23][CH2:22]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccccn3)nc2n1C1CCC(=O)CC1
Reactant: O=C([O-])O
Agent: C[Mg]I
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)c1cc2cnc(Nc3ccccn3)nc2n1C1CCC(C)(O)CC1
Yield: 4 %

Procedure:
To a solution of 7-(4-oxo-cyclohexyl)-2-(pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (25 mg, 0.066 mmol) in THF is added 20 drops of MeMgI. After reaction is completed, added 25 mL of water then 30 mL of aqueous sodium bicarbonate. Extraction with dichloromethane (3×50 mL) and concentrated to give a mixture of diastereomers. Preparative HPLC to give 7-(4-hydroxy-4-methyl-cyclohexyl)-2-(pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (2 mg, 4%). MS (ESI) m/z 395.3 (M+H)+
Reaction SMILES: Cl.[C:2]([C:6]1[CH:7]=[C:8]([C@@H:12]([NH2:14])[CH3:13])[CH:9]=[CH:10][CH:11]=1)([CH3:5])([CH3:4])[CH3:3].[Cl:15][C:16]1[CH:36]=[CH:35][C:19]([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][C:26]([C:30](O)=[O:31])=[CH:27][CH:28]=3)[C:23]([CH3:33])=[C:22]2[CH3:34])=[CH:18][C:17]=1[O:37][C@@H:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40]>>[C:2]([C:6]1[CH:7]=[C:8]([C@@H:12]([NH:14][C:30]([C:26]2[CH:25]=[C:24]3[C:29](=[CH:28][CH:27]=2)[N:21]([CH2:20][C:19]2[CH:35]=[CH:36][C:16]([Cl:15])=[C:17]([CH:18]=2)[O:37][C@@H:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40])[C:22]([CH3:34])=[C:23]3[CH3:33])=[O:31])[CH3:13])[CH:9]=[CH:10][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@H](C)Oc1cc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)ccc1Cl
Reactant: C[C@H](N)c1cccc(C(C)(C)C)c1
Agent: Cl
Product: COC(=O)[C@H](C)Oc1cc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)(C)C)c4)ccc32)ccc1Cl

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-(tert-butyl)phenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride the (S)-1-(4-chloro-3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:13]([CH3:22])[N:12]=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[Br:34]Br.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:1]([O:8][CH2:9][N:10]1[C:14]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:13]([CH3:22])[N:12]=[C:11]1[Br:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ncn(COCc2ccccc2)c1Sc1ccccc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1nc(Br)n(COCc2ccccc2)c1Sc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 92.5 %

Procedure:
In 5 ml of dry tetrahydrofuran is dissolved 300 mg of 1-benzyloxymethyl-4-methyl-5-phenylthioimidazole (I-3) (1 mmol) obtained in Example 3, and the resulting solution is chilled at -78° C. To the solution is added dropwise 1.64M solution of n-butyl lithium in 0.71 ml of hexane (1.16 mmol) and the mixture allowed to stand for 10 minutes, when 185 mg of bromine (1.16 mmol) is added thereto. Fifteen minutes later, the mixture is poured onto ice water. The mixture is neutralized with sodium bicarbonate and extracted with ethyl ether. The extract is washed with water, dried over sodium sulfate, filtered and the filtrate is concentrated. The crude product is chromatographed on a column of silica gel, eluting with ethyl acetate/n-hexane (1:2) to give 360 mg of the product (I-20; mp. 55° C.). Yield, 96%.