Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][C@@H:9]1[CH2:11][C@H:10]1[C:12]1[C:13]2[C:17]([CH:18]=[CH:19][CH:20]=1)=[N:16][N:15]([CH3:21])[CH:14]=2)([CH3:4])([CH3:3])[CH3:2].CC(NCCC#N)CC1C=CC=CC=1.Cl.CCCCCC>C(O)C>[C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][C@H:9]1[CH2:11][C@@H:10]1[C:12]1[C:13]2[C:17]([CH:18]=[CH:19][CH:20]=1)=[N:16][N:15]([CH3:21])[CH:14]=2)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cn1cc2c([C@@H]3C[C@H]3CNC(=O)OC(C)(C)C)cccc2n1
Agent: CC(Cc1ccccc1)NCCC#N
Agent: Cl
Solvent: CCO
Solvent: CCCCCC
Product: Cn1cc2c([C@H]3C[C@@H]3CNC(=O)OC(C)(C)C)cccc2n1
Yield: 49.5 %

Procedure:
Trans-tert-butyl{[2-(2-methyl-2H-indazol-4-yl)cyclopropyl]methyl}carbamate (5.90 g) was fractionated by high performance liquid chromatography (instrument: Prep LC 2000 (manufactured by Nihon Waters K.K.), column: CHIRALPAK AD (50 mm ID×500 mm L, manufactured by Dicel Chemical Industries, Ltd.), mobile phase: A) hexane 100%, B) ethanol 100%, mixing ratio: A/B=900/100, flow rate: 80 mL/min, column temperature: 30° C., sample injection amount: 200 mg (dissolved in 100 mL of mobile phase). A fraction solution containing an optically active compound having a shorter retention time under the above-mentioned high performance liquid chromatography conditions was concentrated to give the title compound (2.92 g, 99.6% ee). Enantiomer excess (ee) was measured by high performance liquid chromatography (column: CHIRALPAK AD (4.6 mm ID×250 mm L, manufactured by Dicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol=900/100, flow rate: 1.0 mL/min, column temperature: 30° C., sample concentration: 0.5 mg/mL (mobile phase), injection volume: 10 μL).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([O:12][CH3:13])=[CH:6][C:5]=1[NH:14]C(=O)C>CCO.O>[Cl:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([O:12][CH3:13])=[CH:6][C:5]=1[NH2:14]
Reactant: COc1cc(NC(C)=O)c(Cl)c(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(N)c(Cl)c(OC)c1
Yield: 81.6 %

Procedure:
Potassium hydroxide (2.19 g, 39.18 mmol) was added to a solution of N-(2-chloro-3,5-dimethoxyphenyl)acetamide (1.8 g, 7.837 mmol) in EtOH (100 mL) and water (10 mL) and the reaction mixture heated to reflux for 12 h. Excess EtOH was removed under reduced pressure to obtain a residue. The residue was then partitioned between water and diethyl ether. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under vacuum to afford the title compound (1.2 g, 82% of yield) as a white solid. 1HNMR (CDCl3, 300 MHz): δ 5.97 (s, 2H), 4.08 (brs, 2H), 3.84 (s, 3H), 3.75 (s, 3H); MS (ESI): 188.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)=O)[CH:7]=[CH:8][CH:9]=1.[N+:25](CS(C1C=CC(C)=CC=1)(=O)=O)#[C-:26].C(O[K])(C)(C)C.O>COCCOC>[F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:5]=[C:6]([CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[C:26]#[N:25])[CH:7]=[CH:8][CH:9]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=C(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: COCCOC
Product: N#CC(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
At 0° C. to a solution of bis(3-(trifluoromethoxy)phenyl)methanone (3 g, 8.6 mmol), prepared as described in Procedure 11, in DME (60 mL) was added 1-(isocyanomethylsulfonyl)-4-methylbenzene (3.3 g, 17.1 mmol) and tBuOK (25.7 mL, 1.0 M solution in tBuOH, 25.7 mmol). The reaction mixture was allowed to warm to rt and stirred for 18 h. H2O (100 mL) was added to the reaction mixture and the aqueous layer was extracted with DCM (3×100 mL). The combined organic layers were washed with sat. NaCl (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by ISCO chromatography (150 g) using hexane/EtOAc (0-5% over 30 min, 5-20% over 20 min) to give 2,2-bis(3-(trifluoromethoxy)phenyl)acetonitrile as a yellow oil at a retention time of 46 min (1.4 g, 45% yield). HPLC: RT=4.13 min, Purity 100% (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm). NMR: 400 MHz 1H (CDCl3) 7.45 ppm, 2H, t, J=8.13 Hz; 7.30 ppm, 2H, d, J=7.91 Hz; 7.23 ppm, 2H, d, J=9.23 Hz; 7.17 ppm, 2H, s; 5.17 ppm, 1H, s.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH:4](/[CH:5]=[CH:6]\[C:7](=[O:13])[O:8][CH2:9][CH:10]([F:12])[F:11])[CH:3]1[C:14]([OH:16])=[O:15].[CH2:18]([N:21]1[CH2:25][C:24](=[O:26])[N:23]([CH2:27]O)[C:22]1=[O:29])[C:19]#[CH:20]>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:13])[O:8][CH2:9][CH:10]([F:11])[F:12])[C@H:3]1[C:14]([O:16][CH2:27][N:23]1[C:24](=[O:26])[CH2:25][N:21]([CH2:18][C:19]#[CH:20])[C:22]1=[O:29])=[O:15]
Reactant: C#CCN1CC(=O)N(CO)C1=O
Reactant: CC1(C)C(/C=C\C(=O)OCC(F)F)C1C(=O)O
Solvent: ClC(Cl)Cl
Product: C#CCN1CC(=O)N(COC(=O)[C@@H]2[C@H](/C=C\C(=O)OCC(F)F)C2(C)C)C1=O

Procedure:
Using the procedure of Step F of Example 9, (1R, cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-(2,2-difluoroethoxy)-1-propenyl]-cyclopropane-carboxylic acid and [3-propargyl-2,5-dioxo-imidazolidinyl]-methanol were reacted to obtain [3-propargyl-2,5-dioxo-imidazolidinyl]-methyl (1R,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-(2,2-difluoroethoxy-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+18°±2° (c=1% in CHCl3).
Reaction SMILES: [N:1]#CBr.[CH3:4][N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[O:13])[CH2:6]1>C1C=CC=CC=1>[C:4]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[O:13])[CH2:6]1)#[N:1]
Reactant: CN1CCCC(CC(=O)c2ccccc2F)C1
Reactant: N#CBr
Solvent: c1ccccc1
Product: N#CN1CCCC(CC(=O)c2ccccc2F)C1
Yield: 66.8 %

Procedure:
The procedure of Example 19 was repeated, using 9.5 g of cyanogen bromide, 19.3 g of 1-methyl-3-(2-fluorophenacyl)piperidine (Example 5), and an additional 130 ml of benzene. The final residue, 16.3 g, was vacuum distilled to give 13.5 g of 1-cyano-3-(2-fluorophenacyl)piperidine, bp 190°-195°/0.5 mm. The following elemental analysis was obtained:
Reaction SMILES: [CH2:1]([N:8]1[CH2:11][CH:10](C#N)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14](=[O:16])=[O:15]>[OH-].[Ba+2].[OH-]>[CH2:1]([N:8]1[CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC1CN(Cc2ccccc2)C1
Reactant: O=C=O
Agent: [Ba+2]
Agent: [OH-]
Product: O=C(O)C1CN(Cc2ccccc2)C1

Procedure:
1.5 g of 13B in 10 ml of saturated barium hydroxide solution was heated under reflux for 30 hours. The reaction mixture was cooled, saturated with gaseous carbon dioxide and filtered. The solvent was removed from the filtrate under reduced pressure to give 1-benzylazetidine-3-carboxylic acid (13C).
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[O:15][CH2:14][CH2:13][O:12]2)=[CH:7][CH:6]=1.[C:16]1(=[O:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C1COCC1>[O:12]1[CH2:13][CH2:14][O:15][CH:11]1[C:8]1[CH:9]=[CH:10][C:5]([C:16]2([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(C2OCCO2)cc1
Reactant: O=C1CCCCC1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: OC1(c2ccc(C3OCCO3)cc2)CCCCC1
Temperature: 5 °C
Reaction time: 2 h
Yield: 33.3 %

Procedure:
Magnesium turnings (14.6 g, 600 mmol) was placed in a dry 4-necked flask. Dry THF (50 mL) and a crystal of iodine were added. A mixture of 2-(4-bromophenyl)-[1,3]-dioxolane (Tetrahedron, 57, No.28, (2001), 5991-6002) (135 g, 589 mmol) in dry THF (200 mL) was slowly added to initiate the reaction. After the reaction had started, the addition of 2-(4-bromophenyl)-[1,3]-dioxolane was continued at such a rate that the temperature was maintained between 35 and 40° C. After the addition was complete the mixture was stirred for 2 hours and then cooled to 5° C. on an ice bath. Cyclohexanone (57.8 g, 580 mmol) was added dropwise while maintaining the temperature below 10° C. The mixture was stirred for 18 hours at room temperature and two third of the THF was removed in vacuo. The residue was poured into a mixture of ammonium chloride (65 g) in ice water (1 liter) and extracted with ethyl acetate. The organic phase was washed with water, dried (magnesium sulphate), filtered and evaporated in vacuo. The residual oil was slurred in petroleum ether to afford 48 g of 1-(4-[1,3]dioxolan-2yl-phenyl)cyclohexanol as a solid.
Reaction SMILES: C(O)(=O)C.[C:5]([N:9]1[C:14](=[O:15])[C:13]([S:16][CH3:17])=[C:12]([N+:18]([O-])=O)[CH:11]=[N:10]1)([CH3:8])([CH3:7])[CH3:6]>C(OCC)(=O)C>[NH2:18][C:12]1[CH:11]=[N:10][N:9]([C:5]([CH3:6])([CH3:7])[CH3:8])[C:14](=[O:15])[C:13]=1[S:16][CH3:17]
Reactant: CSc1c([N+](=O)[O-])cnn(C(C)(C)C)c1=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CSc1c(N)cnn(C(C)(C)C)c1=O
Temperature: 65 °C
Yield: 78.7 %

Procedure:
Into 10 ml of an acetic acid solution of 1.45 g of 2-tert-butyl-4-methylthio-5-nitropyridazin-3-(2H)-one, 1.33 g of reduced iron was gradually added in a few times over a period of 10 minutes with stirring at 65° C. During the addition, the temperature of the system was maintained from 65° to 75° C. After completion of the addition, the mixture was stirred at a temperature of from 65° to 70° C. for one hour and then left to cool. 100 ml of ethyl acetate was added thereto, and the mixture was filtered through celite. The filtrate was washed twice with water and then with a dilute potassium carbonate aqueous solution, and then it was dried over anhydrous sodium sulfate and concentrated to obtain 1.0 g of 5-amino-2-tert-butyl-4-methylthiopyridazin-3-(2H)-one as a residual powder.
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]2[O:7][CH2:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11](=[O:12])[C:5]=2[CH:4]=1)#N.C(O)=[O:20]>[Ni]>[O:12]=[C:11]1[C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[CH2:8][O:7][C:6]2[CH:17]=[CH:18][C:3]([CH:1]=[O:20])=[CH:4][C:5]1=2
Reactant: O=CO
Reactant: N#Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: [Ni]
Product: O=Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Temperature: 25 °C

Procedure:
Heat a mixture of 5.0 gm. of 2-cyano-6.11-dihydro-11-oxodibenz[b,e]oxepin and 4.0 gm. of Raney nickel alloy in 60 ml. of 75% (v/v) aqueous formic acid at reflux for 1.5 hours. Cool to room temperature and filter. Concentrate to small volume and extract with methylene chloride. Wash the extract with water and with 1 N sodium bicarbonate until neutral. Dry the neutral extract over sodium sulfate and concentrate to dryness to obtain the title product.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[Br:12][C:13]1[CH:14]=[CH:15][C:16](F)=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1>CS(C)=O>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(C(=O)OC)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
Dimethyl malonate (13 mL) was added dropwise to 2.7 g sodium hydride suspended in 20 mL dimethylsulfoxide. The mixture was heated to 100° C. for 10 minutes and then cooled to room temperature. 5-Bromo-2-fluoronitrobenzene (5.0 g) in 25 mL of dimethylsulfoxide was added and the mixture was heated at 100° C. for 2 hours. The reaction mixture was cooled and quenched with 300 mL of saturated ammonium chloride solution and extracted three times with ethyl acetate. The extracts were combined, washed with saturated ammonium chloride, water and brine, dried over anhydrous sodium sulfate and concentrated to give crude dimethyl 4-bromo-2-nitrophenylmalonate as a pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH2:10][CH2:11][C:6]2=[N:5][N:4]=1.[C:27]([N:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37]O)[CH2:32][C@@H:31]1[CH3:39])(=[O:29])[CH3:28]>>[C:27]([N:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][O:24][C:21]2[CH:20]=[CH:19][C:18]([CH:15]3[CH2:16][CH2:17][N:12]([C:9]4[CH2:10][CH2:11][C:6]5[N:7]([C:3]([C:2]([F:1])([F:25])[F:26])=[N:4][N:5]=5)[N:8]=4)[CH2:13][CH2:14]3)=[CH:23][CH:22]=2)[CH2:32][C@@H:31]1[CH3:39])(=[O:29])[CH3:28]
Reactant: Oc1ccc(C2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Reactant: CC(=O)N1CCN(CCO)C[C@@H]1C
Product: CC(=O)N1CCN(CCOc2ccc(C3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)C[C@@H]1C
Yield: 41 %

Procedure:
Obtained in 41% yield by an analogous method to Example 51, starting from 4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenol and (S)-2-(4-acetyl-3-methylpiperazin-1-yl)ethanol (obtained by an analogous method to the R enantiomer as described in Example 51, preparation of starting materials).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].CC(C[AlH]CC(C)C)C.Cl[Si:18]1([CH3:22])[CH2:21][CH2:20][CH2:19]1.O>CCCCCC>[CH3:22][Si:18]1([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:21][CH2:20][CH2:19]1
Reactant: C[Si]1(Cl)CCC1
Reactant: C#CCCCCC
Agent: CC(C)C[AlH]CC(C)C
Solvent: O
Solvent: CCCCCC
Product: CCCCCC#C[Si]1(C)CCC1
Temperature: 50 °C
Reaction time: 48 h
Yield: 4 %

Procedure:
To a solution of 1-heptyne (2.62 mL, 1.91 g, d=0.7328, 20.0 mmol) in n-hexane (7 mL) was added a solution of DIBAL-H (20 mL, 1.0 M in n-hexane, 20.0 mmol 1.0 equiv) at −78° C. The reaction mixture was heated at 50° C. for 2 h, then was cooled to 0° C. 1-Chloro-1-methylsilacyclobutane (2.41 g, 20.0 mmol, 1.0 equiv) was added dropwise with syringe to the reaction mixture at 0° C., which was stirred for 48 h at 50° C. Cold water (1.28 mL, 71 mmol, 3.5 equiv) was added to the action solution carefully at 0° C. The resulting white suspension was filtered through Celite and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography (SiO2, pentane) and distillation to afford 2.96 g (81%) of (E)-1 as a colorless oil. 1-Methyl-(1-heptynyl)silacyclobutane (145 mg, 8%) was also isolated after column chromatography.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([CH:11]([S:15][C:16]2[CH:21]=[C:20]([CH3:22])[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[C:18]([CH3:33])[CH:17]=2)[CH:12]([CH3:14])[CH3:13])=[CH:9][CH:10]=1)=[O:5])C.[OH-].[Li+].Cl>C1COCC1>[CH3:33][C:18]1[CH:17]=[C:16]([S:15][CH:11]([C:8]2[S:7][C:6]([C:4]([OH:5])=[O:3])=[CH:10][CH:9]=2)[CH:12]([CH3:14])[CH3:13])[CH:21]=[C:20]([CH3:22])[C:19]=1[C:23]1[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1ccc(C(Sc2cc(C)c(-c3ccc(C(F)(F)F)cc3)c(C)c2)C(C)C)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(SC(c2ccc(C(=O)O)s2)C(C)C)cc(C)c1-c1ccc(C(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To a mixture of (±)-5-[1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-ylsulfanyl)-2-methyl-propyl]-thiophene-2-carboxylic acid ethyl ester (0.458 g, 0.961 mmol) in THF (9.0 mL) is added lithium hydroxide (1N aqueous, 9.0 mL). The mixture is warmed to 70° C. and stirred overnight. The reaction mixture is cooled to rt, acidified with 1N HCl (9.5 mL), extracted into ethyl acetate (3×25 mL), dried over MgSO4, and concentrated to provide (±)-5-[1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-ylsulfanyl)-2-methyl-propyl]-thiophene-2-carboxylic acid (0.431 g, 96%) as a white foam. MS (ES): 463.2 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].ClC(Cl)C>C(O)(=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=3)[CH2:6][CH2:7]2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Brc1ccc2c(c1)NCC2
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CCc3ccc(Br)cc32)CC1
Reaction time: 8 h
Yield: 64 %

Procedure:
Triacetoxylated sodium borohydride (11.7 g) was added to a mixture of 6- bromoindoline (8.3 g), 1-(t-butoxycarbonyl)-4-piperidone (10 g, [CAS Registry No. 7909-07-3]), acetic acid (14.9 g) and dichloroethane (200 ml) followed by stirring overnight. Then the reaction solution was concentrated under reduced pressure, and the pH value thereof was adjusted to 9 with ethyl acetate, an 8 N aqueous solution of sodium hydroxide and water and the layers were separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (10.3 g) (yield: 64%).
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:16](OC(=O)C2C=CC=CC=2)[C@@H:15]([O:26][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:14]([CH3:35])[O:13][C:11]1=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCN(CC)CC.C(Cl)(Cl)Cl>[C:1]([O:9][C:10]1[C:11]([O:13][C@@H:14]([CH3:35])[C@H:15]([O:26][C:27](=[O:34])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:16]=1)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1OC(=O)[C@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C[C@@H]1OC(=O)C(OC(=O)c2ccccc2)=C[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
The compound (VII) (13.2 g, 27.8 mmol) is dissolved in Et3N:CHCl3 (1:4, 500 ml) under N2 current and stirred for 16 hours at a room temperature. After the reaction is finished, it is washed by water. An organic layer is dried using anhydrous MgSO4. The solution is vacuum concentrated and then the compound (VIII) (6.37 g, 65%) is isolated using flash column chromatography (toluene/EtOAc, 10:1, v/v).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[F:19][C:20]([F:32])([F:31])[C:21]1[CH:22]=[C:23]([CH2:27][C:28](Cl)=[O:29])[CH:24]=[CH:25][CH:26]=1>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:28](=[O:29])[CH2:27][C:23]4[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:31])([F:19])[F:32])[CH:22]=4)[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Reactant: O=C(Cl)Cc1cccc(C(F)(F)F)c1
Product: O=C(Cc1cccc(C(F)(F)F)c1)Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Yield: 33.3 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]-pyridin-2(3H)-one and 2-(3-trifluoromethylphenyl)-acetyl chloride to afford the title compound (30 mg, 33.3%). 1H-NMR (δ, ppm, DMSO-d6): 3.77 (s, 2H, CH2), 6.43 (d, 1H, HPy,5, J=5.9 Hz), 6.83-6.86 (m, 1H, Harom), 7.34-7.64 (m, 7H, Harom), 7.67 (s, 1H, Harom), 7.78 (d, 1H, HPy,6, J=5.9 Hz), 10.39 (s, 1H, NHamide), 11.21 (s, 1H, NHPy7), 11.42 (s, 1H, NHPy9). LC-MS, tR=4.56 minutes, m/z: 429.05 (M+H)+, calculated for C21H16N4O3F3. HRMS (EI): m/z [M+H] calculated for C21H16N3O4F3: 429.1175; found: 429.1175.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:24][C:25]1([NH2:28])[CH2:27][CH2:26]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:28][C:25]5([CH3:24])[CH2:27][CH2:26]5)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Reactant: CC1(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(C)CC4)c3n2)c2ccc(F)cc21
Yield: 53.7 %

Procedure:
A solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (70 mg, 0.23 mmol), 1-methylcyclopropanamine (21 mg, 0.29 mmol), HATU (110 mmol, 0.29 mmol) and DIPEA (46 mg, 0.36 mmol) in 6 mL of DMF was stirred at room temperature for 16 hours. The solvent was evaporated at 70° C. under reduced pressure and the residue was triturated with dichloromethane (10 mL), methanol (10 mL) then decanted and dried to give 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-N-(1-methylcyclopropyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (45 mg, 54.9%) as a white solid. MS: (M+H)+=365; 1H NMR (300 MHz, DMSO): δ 9.09 (s, 1H), 8.54 (s, 1H), 8.48-8.42 (m, 2H), 7.71 (dd, 1H, J=9.9, 2.1 Hz), 7.25-7.24 (m, 1H), 4.16 (s, 3H), 1.49 (s, 3H), 0.81 (brs, 2H), 0.80 (brs, 2H).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].FC(F)(F)C(O)=O.N[C:13]1[CH:14]=[C:15]([C:19]([NH:21][CH2:22][C:23]([NH:25][CH:26]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[CH2:27][C:28]([O:30]CC)=[O:29])=[O:24])=[O:20])[CH:16]=[CH:17][CH:18]=1.[OH-].[K+].C(O)(C(F)(F)F)=O.[ClH:48]>>[ClH:48].[NH2:1][C:2]([NH:4][C:17]1[CH:16]=[C:15]([C:19]([NH:21][CH2:22][C:23]([NH:25][CH:26]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[CH2:27][C:28]([OH:30])=[O:29])=[O:24])=[O:20])[CH:14]=[CH:13][CH:18]=1)=[O:3]
Reactant: NC(N)=O
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(N)c1)c1cccnc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)Nc1cccc(C(=O)NCC(=O)NC(CC(=O)O)c2cccnc2)c1

Procedure:
Urea (4 g) and ethyl β-[[2-[[(3-aminophenyl)-carbony]amino]acetyl]amino]pyridine-3-propanoate trifluoroacetate salt (4 g) were dissolved in 20% aqueous HCl (50 ml) and refluxed for 6 hours. The reaction was made basic with KOH (pH>12). After 4 hours the reaction was acidified with TFA and purified by HPLC (RP--CH3CN/H2O). The white solid was dissolved in 1:1 CH3CN:H2O (100 ml) and subjected to the resin exchange described in Example 43, Step C. Lyophilization gave the desired product (3.2 g). MS, 1H-NMR and CHNCl were consistent with the desired product.
Reaction SMILES: CC(C)([O:4][C:5]1[N:10]=[C:9]([O:11]C(C)(C)C)[C:8]([C:16]2(O)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH:20]=[CH:19][C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]2=3)=[CH:7][N:6]=1)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH:27]1[C:18]2[CH:19]=[CH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH:16]([C:8]3[C:9](=[O:11])[NH:10][C:5](=[O:4])[NH:6][CH:7]=3)[C:17]=2[CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)Oc1ncc(C2(O)c3ccccc3C=Cc3ccccc32)c(OC(C)(C)C)n1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]cc(C2c3ccccc3C=Cc3ccccc32)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of the 5-(2,4-bis(1,1-dimethylethoxy)pyrimidin-5-yl)-5H-dibenzo[a,d]cyclohepten-5-ol and triethylsilane (64 ml) in dry dichloromethane (400 ml) at 0° C. was added trifluoroacetic acid (150 ml) dropwise over ten minutes. The cooling bath was removed and the solution was stirred at room temperature overnight. Toluene (300 ml) was added and solution was evaporated under vacuum. The residue was azeotroped with toluene (3 times). The oil was treated with diethyl ether and the precipitated product collected as a white powder (44 g).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br.[NH2:14][CH2:15][CH2:16][Br:17].N1C=CC=CC=1>C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:14][CH2:15][CH2:16][Br:17])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NCCBr
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Br
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(NCCBr)c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
In 30 ml of chloroform were added 3 g of 4-nitrobenzoyl chloride, 3.3 g of 2-aminoethyl bromide hydrobromide and 3.9 ml of pyridine under ice cooling, and they were stirred at the same temperature for 1 hour. The reaction mixture was then washed with water, and the resulting organic layer was concentrated to obtain a crude product of 2-(4-nitrobenzoylamino)ethyl bromide. Afterward, the latter was recrystallized from hexane/ethanol, the resulting crystals were collected by filtration, washed and dried to prepare 2.9 g of 2-(4-nitrobenzoylamino)ethyl bromide (compound 46).