Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]2[S:19][CH:20]=[C:21]([CH2:23][C:24]([O:26]CC)=[O:25])[N:22]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.C1COCC1>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[C:8]([C:18]2[S:19][CH:20]=[C:21]([CH2:23][C:24]([OH:26])=[O:25])[N:22]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)Cc1csc(-c2cnn(C(C)(C)C)c2-c2ccc(OC)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(-c2c(-c3nc(CC(=O)O)cs3)cnn2C(C)(C)C)cc1
Yield: 91.3 %

Procedure:
A mixed solution of the compound (920 mg, 2.30 mmol) obtained in step 12 and 1N aqueous sodium hydroxide solution (3.45 mL, 3.45 mmol) in ethanol (10 mL) and THF (10 ml) was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. 1N Hydrochloric acid was added thereto, and the precipitate was collected by filtration to give 2-(2-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid (780 mg, 2.10 mmol, 91%) as a white powder.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19](O)=[O:20])=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:24]1CCOCC1.ClC(OCC(C)C)=O.N>O1CCCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([NH2:24])=[O:20])=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCOCC1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
2-(3-Benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid (1.50 g, 4.72 mmol) and 4-methylmorpholine (0.60 mL, 5.45 mmol) in tetrahydrofuran (100 mL) was added isobutyl chloroformate (0.62 mL, 4.73 mmol) at 0° C. The resulting mixture was stirred at ambient temperature for 1 hour and followed by the addition of ammonia (7.0 N solution in methanol, 10 mL, 70 mmol). The reaction mixture was kept stirring at ambient temperature for 19 hours. The solvent was removed in vacuo and the residue was triturated with 10% sodium hydroxide solution. The solid was collected by filtration and washed with water to afford the title compound in 30% yield (0.47 g): mp 217-218° C. (water); 1H NMR (300 MHz, DMSO-d6) δ 7.42-7.27 (m, 7H), 4.40 (s, 2H), 3.93-3.88 (m, 2H), 3.48-3.42 (m, 2H), 2.42 (s, 3H); MS (ES+) m/z 317.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8]Br)[CH:5]=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18].[CH3:19][S-:20].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])[CH2:8][S:20][CH3:19]
Reactant: C[S-]
Reactant: Fc1ccc(Oc2ccc(CBr)cc2Br)c(F)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCc1ccc(Oc2ccc(F)cc2F)c(Br)c1
Yield: 99.9 %

Procedure:
A mixture of Example 52C (1.512 g, 4.00 mmol) and sodium thiomethoxide (0.280 g, 4.00 mmol) in dimethylformamide (8 mL) was stirred at room temperature for 6 hours. The reaction mixture was partitioned with ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride twice, dried with anhydrous sodium sulfate, filtered, and concentrated to provide the title compound (1.38 g, 100%).
Reaction SMILES: [OH-].[Na+].[N:3]#[C:4][NH2:5].Cl[CH2:7][CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12].C(Cl)Cl>O>[C:4]([N:5]1[CH2:7][CH2:8][CH2:9][CH2:10][C:11]1=[O:12])#[N:3]
Reactant: N#CN
Reactant: O=C(Cl)CCCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: N#CN1CCCCC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
59.4 g (1.484 moles) of sodium hydroxide are dissolved in 370 ml of water and the solution is cooled to 0° C. To this solution are added 13.2 g (0.742 mole) of cyanamide in portions. Then 115 g (0.742 mole) of δ-chlorovaleryl chloride are added dropwise, at 0°-8° C., over 1 hour to the clear, colourless cyanamide solution. The ensuing reaction is strongly exothermic, so that intensive cooling is necessary. When the dropwise addition is complete, the mixture is stirred for 1 hour at 0° C. Then 740 ml of methylene chloride are added and the reaction mixture is subsequently warmed for 1 hour to reflux temperature (40° C.). The two phases are separated in a separating funnel. The aqueous phase is extracted once more with 740 ml of methylene chloride. The combined organic phases are dried over sodium sulfate, filtered, and the solvent is removed in a water jet vacuum. Yield: 79.6 g (86.4% of theory). The crude product is a pale yellowish liquid which, according to gas chromatographic analysis, contains 79.95% of N-cyanopiperidone. An isomer is not detected. High vacuum distillation of the crude product yields 44 g (47.8% of theory) of N-cyanopiperidone as a pale yellowish liquid with a boiling point of 125° C./13.3 Pa. Gas chromatographic analysis shows the product to be 99.19% pure.
Reaction SMILES: [O:1]=[C:2]([CH2:20][CH3:21])[C:3](=[N:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)[C:4]([O:6][CH3:7])=[O:5].[CH3:22]OC(OC)N(C)C>>[CH3:21][C:20]1[C:2](=[O:1])[C:3]([C:4]([O:6][CH3:7])=[O:5])=[N:8][N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[CH:22]=1
Reactant: COC(OC)N(C)C
Reactant: CCC(=O)C(=NNc1cccc(C(F)(F)F)c1)C(=O)OC
Product: COC(=O)c1nn(-c2cccc(C(F)(F)F)c2)cc(C)c1=O
Temperature: 25 °C
Yield: 87 %

Procedure:
A solution of methyl 3-oxo-2-{[3-(trifluoromethyl)phenyl]hydrazono}pentanoate (4.00 g, 13.2 mmol) in N,N-dimethylformamide dimethylacetal (33 mL) was heated at reflux for 2.5 hours. After that time, the reaction was cooled to room temperature and the resulting solid was collected by filtration and washed with a small amount of hexanes to give methyl 5-methyl-4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxylate (3.55 g, 87%) as a pale yellow solid.
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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[C:49]1[N:54]=[C:53]([C:55]([F:58])([F:57])[F:56])[N:52]=[C:51]([CH2:59][C:60]([O:62][CH3:63])=[O:61])[CH:50]=1>O1CCCC1>[CH3:63][O:62][C:60](=[O:61])[CH2:59][C:51]1[N:52]=[C:53]([C:55]([F:57])([F:58])[F:56])[N:54]=[C:49]([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:50]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COC(=O)Cc1cc(O)nc(C(F)(F)F)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)nc(C(F)(F)F)n1
Reaction time: 0.17 h

Procedure:
To tert-butyl 4-hydroxypiperidine-1-carboxylate (213 mg, 1.06 mmol, Aldrich) in tetrahydrofuran (2.0 mL) was added Triphenylphosphine (0.284 g, 1.08 mmol), followed by diisopropyl azodicarboxylate (0.215 mL, 1.09 mmol). After 10 minutes, methyl [6-hydroxy-2-(trifluoromethyl)pyrimidin-4-yl]acetate (0.20 g, 0.85 mmol, from Step 1) was added. The reaction was stirred for 1 hour and solvent was removed in vacuo. Flash chromatography on a 40 g silica gel cartridge, eluting with a gradient from 0-20%) EtOAc in hexanes afforded product as a viscous oil (127 mg, 25%). LCMS (M+H)+: 420.0.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:15][C:16]1[C:21](O)=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=1[F:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:21]2[C:20]([F:23])=[C:19]([F:24])[C:18]([F:25])=[C:17]([F:26])[C:16]=2[F:15])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: Fc1c(F)c(F)c(OC2CCN(Cc3ccccc3)CC2)c(F)c1F
Temperature: 10 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
A stirred mixture of 10.33 g of 1-benzyl-4-hydroxy piperidine, 9.93 g of pentafluorophenol, and 15.58 g of triphenylphosphine in 200 ml of benzene was cooled to 10° C. At this temperature, a solution of 10.35 g of diethyl azodicarboxylate in 50 ml of benzene was added, dropwise, over one hour. After stirring for 20 hours at ambient temperature, the reaction mixture was filtered and concentrated to an oil. The oil was purified by means of high pressure liquid chromatography (silica gel; elution with ethylacetate/dichloromethane 1:1). Evaporation of the appropriate fractions afforded 14.5 g of 1-benzyl-4-(2,3,4,5,6-pentafluorophenoxy)piperidine as an oil. Conversion of the free base to the corresponding hydrochloride salt afforded 8.2 g (42%) of 1-benzyl-4-(2,3,4,5,6-pentafluorophenoxy)piperidine hydrochloride, m.p. 244°-246° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.[CH:16](Br)([CH3:18])[CH3:17]>>[C:2]1([CH3:1])[CH:7]=[CH:6][C:5]([C:8]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1
Reactant: CC(C)Br
Reactant: Cc1ccc(C(=O)Cn2cncn2)cc1
Product: Cc1ccc(C(=Cn2cncn2)OC(C)C)cc1

Procedure:
Analogously to Example 1a,b, after reacting 1-(4-methylphenyl)-2-[1,2,4]triazol-1-yl-ethanone with isopropyl bromide there was obtained 1-[2-(4-tolyl)-2-isopropoxy-vinyl]-1H-[1,2,4]triazole. After reaction with HCl in dioxan there was obtained a salt of the composition C14H17N3O.HCl. [M+H]+=243.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[C:24]([O:32][CH2:33][CH3:34])=[N:25][C:26]([O:29][CH2:30][CH3:31])=[N:27][CH:28]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:35][N:36]([CH3:46])[C:37](=[O:45])[CH2:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:42]3[CH2:41][CH2:40][N:39]([CH2:38][C:37]([N:36]([CH3:46])[CH3:35])=[O:45])[CH2:44][CH2:43]3)=[O:21])[C:10]([C:23]3[C:24]([O:32][CH2:33][CH3:34])=[N:25][C:26]([O:29][CH2:30][CH3:31])=[N:27][CH:28]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1ncc(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)Cl)c(OCC)n1
Reactant: CN(C)C(=O)CN1CCNCC1
Product: CCOc1ncc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)N2CCN(CC(=O)N(C)C)CC2)c(OCC)n1

Procedure:
cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 8) was reacted with N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) to give cis-2-{4-[4,5-bis-(4-chloro-phenyl)-2-(2,4-diethoxy-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N,N-dimethyl-acetamide in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C32H37N7O4Cl2 [(M+H)+] 654.2357, observed 654.2355.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[CH3:14][O:15][C:16]1[C:17]([NH2:22])=[CH:18][CH:19]=[CH:20][CH:21]=1>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:22][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][CH3:14])=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: COc1ccccc1N
Reactant: CSc1ncnc2cc(N)ncc12
Product: COc1ccccc1Nc1ncnc2cc(N)ncc12
Temperature: 180 °C
Reaction time: 2.5 h
Yield: 46.6 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (227 mg, 1.18 mmole) and o-anisidine (1.00 mL, 8.87 mmol) is stirred under N2 at 180° C. for 2.5 h. The resulting product is chromatographed over silica gel (5% EtOH/EtOAc) to give 7-amino-4-(2-methoxyanilino)pyrido[4,3-d]pyrimidine (147 mg, 47%) as a yellow solid. 1H NMR (DMSO) δ 9.44 (1H, brs), 9.25 (1H, s), 8.22 (1H, s), 7.54 (1H, dd, J=7.7, 1.4 Hz), 7.24 (1H, ddd, J=8.1, 7.4, 1.5 Hz), 7.10 (1H, dd, J=8.2, 1.2 Hz), 6.98 (1H, dt, Jd=1.3 Hz, Jt=7. 5 Hz), 6.52 (2H, brs), 6.41 (1H, s), 3.79 (3H, s).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[O:24][C:11]2([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[CH2:10][NH:9][CH2:8]1.C(=O)([O-])O.[Na+].FC(F)(F)S(O[CH2:36][CH:37]([F:39])[F:38])(=O)=O>C(O)C.C(Cl)Cl>[F:38][CH:37]([F:39])[CH2:36][N:9]1[CH2:8][CH:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[O:24][C:11]2([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:13][CH2:12]2)[CH2:10]1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCC(c1ccccn1)O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(CC(F)F)CC(c1ccccn1)O2
Temperature: 80 °C

Procedure:
To tert-butyl 10-(2-pyridyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (63 mg, 0.19 mmol) in ethanol was added sodium hydrogen carbonate (64 mg, 0.76 mmol) followed by the addition of 2,2-difluoroethyl trifluoromethanesulfonate (49 mg, 0.23 mmol) and reaction mixture was heated at 80° C. for 40 minutes. The reaction mixture was cooled to room temperature and diluted with DCM and the organic layer was washed with 1:1 NaOH:NaHCO3 solution. The organics were separated, dried over Na2SO4, filtered and concentrated in vacuo to give tert-butyl 8-(2,2-difluoroethyl)-10-(2-pyridyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate as an oil. To the oil was added HCl (237.5 μL of 4 M in dioxane, 0.95 mmol) at room temperature under an atmosphere of nitrogen and the reaction mixture was stirred for 30 minutes. The solvent was removed in vacuo and the residue was triturated with ether to give 8-(2,2-difluoroethyl)-10-(2-pyridyl)-11-oxa-3,8-diazaspiro[5.5]undecane (45 mg, 79%). ESI-MS m/z calc. 297.3. found 298.4 (M+1)+; Retention time: 0.35 minutes (3 min run).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10](=[O:14])[NH:11]2)=[CH:6][CH:5]=1)(=O)[CH3:2].[Cl:15][C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][C:30]=1[F:31])[C:19]([NH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:20].[BH3-]C#N.[Na+].C([O-])(O)=O.[Na+]>CC(O)=O.CO>[Cl:15][C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][C:30]=1[F:31])[C:19]([NH:21][CH:22]1[CH2:23][CH2:24][N:25]([CH:1]([C:4]2[CH:13]=[C:12]3[C:7]([CH2:8][CH2:9][C:10](=[O:14])[NH:11]3)=[CH:6][CH:5]=2)[CH3:2])[CH2:26][CH2:27]1)=[O:20]
Reactant: O=C(NC1CCNCC1)c1ccc(F)c(Cl)c1
Reactant: CC(=O)c1ccc2c(c1)NC(=O)CC2
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(c1ccc2c(c1)NC(=O)CC2)N1CCC(NC(=O)c2ccc(F)c(Cl)c2)CC1
Temperature: 25 °C

Procedure:
To a MeOH solution (15 mL) of the compound (206 mg) obtained in Step 51-2, the compound (560 mg) obtained in Step 51-3 and AcOH (327 mg), NaBH3CN (274 mg) was added at room temperature and the mixture was refluxed for 12 hours. After the reaction mixture was cooled to room temperature, NaBH3CN (274 mg) was added and the mixture was refluxed for 72 hours. After a saturated aqueous NaHCO3 solution was added, a water layer and an organic layer were separated. The water layer was extracted three times with CHCl3. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography [(silica gel 60 N, mobile phase: MeOH/CHCl3=0/100 to 20/80; v/v) and (Chromatorex NH, mobile phase MeOH/CHCl3=0/100 to 10/90; v/v) in this order] to obtain the titled compound (7 mg, a colorless solid).
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:14]([NH2:16])=[O:15])=[CH:11][CH:10]=[C:9]([OH:17])[CH:8]=2)=[O:3].[H-].[Na+].F[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1>CN(C)C=O.O>[NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:14]([NH2:16])=[O:15])=[CH:11][CH:10]=[C:9]([O:17][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)[CH:8]=2)=[O:3]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: NC(=O)Nc1[nH]c2cc(O)ccc2c1C(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)Nc1[nH]c2cc(Oc3ccc([N+](=O)[O-])cc3)ccc2c1C(N)=O
Reaction time: 0.08 h
Yield: 61.4 %

Procedure:
Under ice-cooling, 2-aminocarbonylamino-6-hydroxyindole-3-carboxamide (Compound No.2-1, 1.3 g, 5.5 mmol) in anhydrous N,N-dimethylformamide (7 mL) was added dropwise to a suspension of 60% sodium hydride (450 mg, 11 mmol) in anhydrous N,N-dimethylformamide (15 mL) over a period of 5 minutes and the mixture was stirred for 5 minutes. Moreover 4-fluoronitrobenzene (640 μL, 6.0 mmol) was added thereto, and the mixture was stirred for 15 minutes at room temperature and stirred overnight at 60° C. After cooling, the reaction solution was diluted with water (300 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (200 mL) and brine (200 mL), and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained solid was filtered off and washed with a mixed solvent of chloroform-diethyl ether solution (1:2, 60 mL). The solid was dried at 40° C. for 1 hour under reduced pressure to give the title compound (1.2 g) as a brown solid (59%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH:11]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH3:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(OC([N:29]1[CH2:34][CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH2:31][CH2:30]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>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.O1CCOCC1.O>[Cl:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=1[CH:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:32]3[CH2:33][CH2:34][NH:29][CH2:30][CH:31]=3)[CH:3]=2)[NH:8][CH:9]=1)[CH3:12]
Reactant: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(Br)cc12
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(C3=CCNCC3)cc12
Temperature: 90 °C

Procedure:
A mixture of 5-bromo-3-[1-(2,6-dichloro-3-fluorophenyl)ethyl]-1H-pyrrolo[2,3-b]pyridine (60.0 mg, 0.155 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (95.6 mg, 0.309 mmol), Pd(PPh3)4 (40 mg, 0.03 mmol), potassium carbonate (64.1 mg, 0.464 mmol) and 4:1 dioxane/H2O (10 mL) was heated to 90° C. for 2 h. The solution was loaded into an SCX cartridge, washed with MeOH (30 mL) and ejected with 2M NH3 in MeOH (10 mL). The filtrate was concentrated in vacuo, redissolved in dioxane, and 4M HCl in dioxane (1 mL) was added. The solution was heated to 40° C. for 2 h. The material was loaded into an SCX cartridge, washed with MeOH (30 mL) and ejected with 2M NH3 in MeOH (10 mL). The filtrate was concentrated in vacuo, redissolved in MeOH (0.5 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.88 (d, J=7.3 Hz, 3 H), 2.65-2.73 (m, 2 H), 3.45 (t, J=6.1 Hz, 2 H), 3.76-3.86 (m, 2 H), 5.28 (d, J=7.3 Hz, 1 H), 5.95 (dt, J=3.3, 1.7 Hz, 1 H), 7.19 (t, J=8.6 Hz, 1 H), 7.34 (d, J=2.3 Hz, 1 H), 7.36-7.50 (m, 2 H), 8.26 (d, J=2.0 Hz, 1 H). MS (ES+): m/z 390.00 (100) [MH+]. HPLC: tR=2.48 min (ZQ3, polar—5 min).
Reaction SMILES: [Cl:1][C:2]([C:12]([F:15])([F:14])[F:13])=[CH:3][C@@H:4]1[C@H:6]([C:7](Cl)=[O:8])[C:5]1([CH3:11])[CH3:10].[C:16]([C:18]1[C:19]([CH3:27])=[C:20]([CH2:25][OH:26])[C:21]([CH3:24])=[CH:22][CH:23]=1)#[N:17].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]([C:12]([F:15])([F:14])[F:13])=[CH:3][C@@H:4]1[C@H:6]([C:7]([O:26][CH2:25][C:20]2[C:21]([CH3:24])=[CH:22][CH:23]=[C:18]([C:16]#[N:17])[C:19]=2[CH3:27])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: Cc1ccc(C#N)c(C)c1CO
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc(C#N)c(C)c1COC(=O)[C@H]1[C@@H](C=C(Cl)C(F)(F)F)C1(C)C
Yield: 16 %

Procedure:
Cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylic acid chloride (4.28 g, 0.018 mole) was added dropwise to a cooled solution of (3-cyano-2,6-dimethylphenyl)-methanol (2.93 grams, 0.018 mole) and pyridine (1.5 grams, 0.02 mole) in toluene (100 ml), and the mixture was allowed to come to room temperature. The solution was poured over crushed ice and extracted with methylene chloride. The combined organic extracts were washed successively with water, 5% aqueous hydrochloric acid, water, and saturated aqueous sodium bicarbonate solution. The organic phase was dried with magnesium sulfate, filtered and the solvent evaporated. The residue was chromatographed on a silica gel column, elution with heptane, then heptane/methylene chloride to give (3-cyano-2,6-dimethylphenyl)methyl cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylate (1.11 grams, mp 98°).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH2:6]2.Cl.[N:13]1([CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([Cl:29])=[O:28])=[CH:25][CH:24]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(Cl)Cl>[ClH:29].[N:13]1([CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([N:7]3[CH2:6][C:5]4[C:9](=[CH:10][CH:11]=[C:3]([F:2])[CH:4]=4)[CH2:8]3)=[O:28])=[CH:30][CH:31]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(Cl)c1ccc(OCCCN2CCCCC2)cc1
Reactant: Fc1ccc2c(c1)CNC2
Agent: Cl
Solvent: ClCCl
Product: O=C(c1ccc(OCCCN2CCCCC2)cc1)N1Cc2ccc(F)cc2C1
Yield: 27.3 %

Procedure:
A stirred mixture of 5-fluoroisoindoline hydrochloride (D8) (183 mg) and diethylaminoethylpolystyrene (626 mg, 3.2 mmol/g) in DCM (10 ml) at rt was treated with 4-(3-piperidin-1-ylpropoxy)-benzoyl chloride hydrochloride (223 mg) (D3). After 1 h the reaction mixture was chromatographed directly [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM)]. Fractions containing the required product were evaporated, redissolved in DCM, treated with excess hydrogen chloride (4M solution in dioxan) and then evaporated. The residue was triturated with acetone, filtered, washed with acetone and dried to yield the title compound (E11) (80 mg). MS electrospray (+ion) 383 (MH+). 1H NMR δ (DMSO-d6): 10.21 (1H, s), 7.61 (2H, d, J=8.8 Hz), 7.05-7.50 (3H, m), 7.01 (2H, d, J=8.8 Hz), 4.81 (4H, m), 4.13. (2H, t, J=6 Hz), 3.46 (2H, m), 3.15 (2H, m), 2.88 (2H, m), 2.21 (2H, m), 1.28-1.92 (6H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: BrCc1ccccc1
Product: Brc1ccc2c(ccn2Cc2ccccc2)c1
Yield: 77.7 %

Procedure:
The title compound was prepared from 5-bromoindole (5.02 g, 25.6 mmol) and benzyl bromide (6.7 mL, 56 mmol), following the procedure described in Step 1 of Example 5. Purification by flash chromatography on Biotage apparatus using hexane as an eluant yielded 1-benzyl-5-bromo-1H-indole as a white solid (5.69 g, 78%), mp 93-95° C. Mass spectrum (+ESI, [M+H]+) m/z 286; 1HNMR (500 MHz, DMSO-d6): δ 7.7 (d, 1H, J=1.8 Hz), 7.55 (d, 1H, J=3.1 Hz), 7.4 (d, 1H, J=8.7 Hz), 7.15-7.30 (m, 6H), 6.45 (dd, 1H, J=3.2 Hz and 0.6 Hz), and 5.45 ppm (s, 2H). Elemental Analysis for C15H12BrN: Calculated: C, 62.96; H, 4.23; N, 4.89. Found: C, 63.36; H, 4.31; N, 4.73.