Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:10][C:11](=[O:24])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH3:9])=[N:6][CH:7]=1.Br.Br[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][O:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:10][C:11](=[O:24])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:15]=2)[CH3:9])=[N:6][CH:7]=1
Reactant: BrCc1ccccn1
Reactant: C[C@@H](NC(=O)COc1ccc(C(F)(F)F)cc1)c1ccc(O)cn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)COc1ccc(C(F)(F)F)cc1)c1ccc(OCc2ccccn2)cn1
Temperature: 90 °C
Yield: 89.6 %

Procedure:
A mixture of (R)-N-(1-(5-hydroxypyridin-2-yl)ethyl)-2-(4-(trifluoromethyl)phenoxy)acetamide (30 mg, 0.088 mmol), 2-(bromomethyl)pyridine hydrobromide (22 mg, 0.088 mmol), and cesium carbonate (115 mg, 0.35 mmol) in DMF (3 mL) was heated at 90° C. overnight. After cooling, the mixture was filtered through a pad of celite, washed with dichloromethane, the filtrate was concentrated, and the residue was purified by SCX cartridge to give 34 mg (89% yield) of (R)-N-(1-(5-(pyridin-2-ylmethoxy)pyridin-2-yl)ethyl)-2-(4-(trifluoromethyl)phenoxy)a cetamide as a clear colorless oil; LCMS (Method A) m/z: M+1 obs 432, M−1 obs 430
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][F:23])[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[ClH:1].[F:23][CH2:22][CH2:21][N:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCF)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: FCCN1CCNCC1
Reaction time: 8 h

Procedure:
Add 4N HCl in 1,4-dioxane (86.096 mmoles, 21.524 mL) to a stirred solution of 4-(2-fluoro-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (8.610 mmoles, 2.000 g) in dry dichloromethane (60 mL) at room temperature under nitrogen. Stir overnight under nitrogen. Concentrate under reduced pressure to afford the title compound (8.679 mmoles, 1.780 g). MS (m/z): 133 (M+1).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:15]=[CH:14][C:7]2[N:8]([CH2:12][CH3:13])[C:9]([CH3:11])=[N:10][C:6]=2[CH:5]=1)=[O:3].[CH:16]([CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][CH2:19]1)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl>O1CCCC1.O>[CH2:12]([N:8]1[C:7]2[CH:14]=[CH:15][C:4]([C:2](=[O:3])[CH:1]=[CH:16][CH:18]3[CH2:19][CH2:20][N:21]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:22][CH2:23]3)=[CH:5][C:6]=2[N:10]=[C:9]1[CH3:11])[CH3:13]
Reactant: CCn1c(C)nc2cc(C(C)=O)ccc21
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCn1c(C)nc2cc(C(=O)C=CC3CCN(Cc4ccccc4)CC3)ccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 26.2 %

Procedure:
A mixture of 0.1 g (0.5 mM) of 1-ethyl-2-methylbenzimidazole-5-yl methyl ketone and 0.1 g (0.5 mM) 4-formyl-N-benzylpiperidine in 10 mL of tetrahydrofuran (THF) was cooled to -78° C. under a nitrogen atmosphere. To this mixture were added dropwise 0.5 mL (0.5 mM) of a 1 M solution of lithium bis(trimethylsilyl)amide in THF. The reaction was stirred at -78° C. for 1 hour, then warmed to room temperature. To the reaction was added 10 mL of water and the pH was adjusted to 2.0 with 1 N hydrochloric acid (HCl). The mixture was extracted with 15 mL of ethyl acetate. The pH of the water layer was then sequentially adjusted to 3.0, 4.0, 5.0, 6.5, and 8.5 with 1 N NaOH, each time extracting with 15 mL of ethyl acetate. The ethyl acetate extracts at pH=5.0 and 6.5 were combined, dried with sodium sulfate (Na2SO4) and evaporated to yield 50 mg (26%) of the title compound as an oil.
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:17][C:18]1[C:19]([CH2:24]O)=[N:20][CH:21]=[CH:22][CH:23]=1.C(P(=CC#N)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[F:17][C:18]1[C:19]([CH2:24][O:1][C:2]2[C:3]3[N:4]([C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=3)[CH:5]=[CH:6][CH:7]=2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: OCc1ncccc1F
Reactant: CCOC(=O)c1c(C)nc2c(O)cccn12
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)nc2c(OCc3ncccc3F)cccn12
Temperature: 110 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
A mixture of 2 g of ethyl 8-hydroxy-2-methylimidazo[1,2-a]pyridine-3-carboxylate, 2 g of (3-fluoropyridin-2-yl)methanol, 4 g of (tributylphosphoranyliden)acetonitrile, and 40 ml of toluene was stirred at 110° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, water was added thereto, and the precipitated solid was collected by filtration. The obtained residue was purified by silica gel column chromatography to obtain 2.15 g of ethyl 8-[(3-fluoropyridin-2-yl)methoxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(N(CC)CC)C>>[C:25]([O:24][C:22]([N:16]1[CH2:21][CH2:20][N:19]([S:12]([C:3]2[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[Cl:1])(=[O:14])=[O:13])[CH2:18][CH2:17]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2c(Cl)ccc([N+](=O)[O-])c2Cl)CC1
Yield: 85.8 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (500 mg, 1.72 mmol), tert-butyl 1-piperazinecarboxylate (320 mg, 1.72 mmol) and triethylamine (479 ,μL, 3.44 mmol) were reacted to form the desired product (650 mg, 84%). LC-MS (m/z) 440.2 (M+).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([O:29][CH2:30][CH2:31][CH3:32])=[CH:27][C:26]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:25][C:24]=2O)=[CH:19][CH:18]=1>N1C=CC=CC=1>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:24]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])=[CH:25][C:26]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:27][C:28]=2[O:29][CH2:30][CH2:31][CH3:32])=[CH:21][CH:22]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCCOc1cc(C(=O)OCC)cc(O)c1-c1ccc(F)cc1
Solvent: c1ccncc1
Product: CCCOc1cc(C(=O)OCC)cc(OS(=O)(=O)C(F)(F)F)c1-c1ccc(F)cc1

Procedure:
Trifluoromethanesulfonic anhydride (20.1 mL) was added at 0° C. to a mixture of ethyl 4′-fluoro-2-hydroxy-6-propoxybiphenyl-4-carboxylate (31.5 g) and pyridine (200 mL), and the resultant mixture was stirred at the same temperature as above for 20 minutes. The reaction mixture was passed through a short silica gel (NH) column, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (44.6 g).
Reaction SMILES: [CH2:1]([C@@H:5]1[CH2:10][C@H:9]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:8][CH2:7][C@@H:6]1[NH:16][C:17](=[O:30])[CH2:18][NH:19]C(=O)OCC1C=CC=CC=1)[CH2:2][CH2:3][CH3:4]>CO.[Pd]>[NH2:19][CH2:18][C:17]([NH:16][C@H:6]1[CH2:7][CH2:8][C@@H:9]([NH:11][C:12]([CH3:13])([CH3:14])[CH3:15])[CH2:10][C@H:5]1[CH2:1][CH2:2][CH2:3][CH3:4])=[O:30]
Reactant: CCCC[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1NC(=O)CNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCCC[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1NC(=O)CN
Yield: 82.3 %

Procedure:
A solution of benzyl 2-((1S,2R,4R)-2-butyl-4-(tert-butylamino)cyclohexylamino)-2-oxoethylcarbamate (890 mg, 0.0021 mol), in 40 mL of MeOH was treated with 0.3 g of 10% Pd/C and hydrogenated overnight at 55 psi. The mixture was filtered through Celite and concentrated on a rotary evaporator to give 490 mg of 2-amino-N-((1S,2R,4R)-2-butyl-4-(tert-butylamino)cyclohexyl)acetamide. This was used without further purification.
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[O:6][C:5]=1[NH:15][C@H:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:17][CH3:18])(=O)[CH3:2].[CH:25]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26]1>C(#N)C>[C:19]1([C@@H:16]([NH:15][C:5]([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:14])[N:30]([CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[C:1]=2[CH3:2])=[O:6])[CH2:17][CH3:18])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NC1CCCC1
Reactant: CC[C@H](Nc1oc(=O)c2ccccc2c1C(C)=O)c1ccccc1
Solvent: CC#N
Product: CC[C@H](NC(=O)c1c(C)n(C2CCCC2)c(=O)c2ccccc12)c1ccccc1
Temperature: 170 °C

Procedure:
A mixture of 4-acetyl-3-((S)-1-phenyl-propylamino)-isochromen-1-one (60 mg) and cyclopentylamine (0.06 mL) in acetonitrile (0.2 mL) was heated under microwave irradiation at 170° C. for 15 min. The reaction mixture was partitioned between 2M HCl (3 mL) and ethyl acetate (3 mL). The organic phase was absorbed on SiO2 and flash chromatographed (20 g SiO2 column, gradient heptane-ethyl acetate, the product came out with 40% ethyl acetate) to give 18 mg of the title compound as a colourless solid. LC-MS (m/z) 389.5 (MH+); tR=1.52.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[Li]C(C)(C)C.Cl([O-])(=O)(=O)=O.[CH2:19]1[C:26]2[CH2:25][CH2:24][CH2:23][N+:22]=2[CH2:21][CH2:20]1>CCOCC.CCCCC>[CH3:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:26]12[CH2:25][CH2:24][CH2:23][N:22]1[CH2:21][CH2:20][CH2:19]2
Reactant: Cc1ccncc1I
Reactant: C1CC2=[N+](C1)CCC2
Agent: [Li]C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOCC
Solvent: CCCCC
Product: Cc1ccncc1C12CCCN1CCC2
Temperature: -95 °C
Reaction time: 2 h
Yield: 6.5 %

Procedure:
3-Iodo-4-methylpyridine (330 mg, 3.10 mmol) was dissolved in Et2O and cooled to -95° C. A solution of t-BuLi (1.7M in pentane, 4.0 ml, 6.80 mmol) in pentane was added dropwise. 1,2,3,5,6,7-hexahydropyrrolizinium perchlorate (960 mg, 4.60 mmol) was added, and the reaction mixture was allowed to warm to -10° C. with stirring for 2 hours. The cold bath was removed, 2N HCl was added, and the phases were separated. The aqueous phase was basified with 15% NaOH and extracted with CH2Cl2 (2×). The CH2Cl2 fractions were combined, dried (MgSO4) and concentrated, and the residue was chromatographed (silica gel; CHCl3 /MeOH, 99:1) to afford the title compound as an oil (41 mg, 6%): 1H NMR (CDCl3, 300 MHz) δ1.54-1.69 (m, 2H), 1.77-1.89 (m, 2H), 1.93-2.11 (m, 4H), 2.41 (s, 3H), 2.69-2.77 (m, 2H), 3.08-3.15 (m, 2H), 7.02 (d, J=4.8 Hz, 1H), 8.32 (d, J=4.8 Hz, 1H), 9.06 (s, 1H); MS (CI/NH3) m/z: 203 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:8][C:9]=1[N:10]1[C:15](=[O:16])[CH2:14][C:13](=O)[CH2:12][CH:11]1[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:4].[BH3-]C#[N:32].[Na+].CC(O)=O>CO>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:8][C:9]=1[N:10]1[C:15](=[O:16])[CH2:14][CH:13]([NH2:32])[CH2:12][CH:11]1[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N1C(=O)CC(=O)CC1C1CCCCC1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1sc(-c2ccccc2)cc1N1C(=O)CC(N)CC1C1CCCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-(2-cyclohexyl-4,6-dioxo-piperidin-1-yl)-5-phenyl-thiophene-2-carboxylic acid methyl ester (400 mg, 0.98 mmol, 1.0 equiv) in MeOH (2.0 mL) was added NH4OAc (375 mg, 4.86 mmol, 5 equiv) and the resulting solution was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved MeOH. To the solution was added NaCNBH3 (247 mg, 1.16 mmol, 1.2 equiv) and HOAc (56 mg, 0.97 mmol, 1 equiv). The resulting mixture was stirred at room temperature for 18 hours. The solvent was then removed in vacuo. To the residue was added sat. aq. NaHCO3 solution until pH>8. The mixture was extracted with DCM. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was continued to the next step with no further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:28]=[CH:27][C:8](/[CH:9]=[CH:10]/[C:11]2[N:19]([CH3:20])[C:18]3[C:17](=[O:21])[N:16]([CH2:22][CH3:23])[C:15](=[O:24])[N:14]([CH2:25][CH3:26])[C:13]=3[N:12]=2)=[C:7]([O:29][CH3:30])[CH:6]=1)=[O:4].O1CCCC1.O.[OH-].[Li+].Cl>O.C(O)C>[CH2:22]([N:16]1[C:17](=[O:21])[C:18]2[N:19]([CH3:20])[C:11](/[CH:10]=[CH:9]/[C:8]3[CH:27]=[CH:28][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=3[O:29][CH3:30])=[N:12][C:13]=2[N:14]([CH2:25][CH3:26])[C:15]1=[O:24])[CH3:23]
Reactant: CCn1c(=O)c2c(nc(/C=C/c3ccc(C(=O)OC)cc3OC)n2C)n(CC)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCn1c(=O)c2c(nc(/C=C/c3ccc(C(=O)O)cc3OC)n2C)n(CC)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 24 %

Procedure:
Compound 20 (108 mg, 0.262 mmol) obtained in Example 19 was suspended in a solvent mixture of 2 ml of tetrahydrofuran, 2 ml of ethanol, and 1 ml of water. To the suspension was added 55 mg (1.311 mmol) of lithium hydroxide monohydrate, and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was acidified with 2N HCl, and the precipitated crystals were collected by filtration. The obtained crude crystals were purified by column chromatography (eluent: chloroform/methanol/acetic acid=40/1/1) to give 25 mg (yield 24%) of Compound 22, which was further recrystallized from isopropanol to give a yellow powder.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[S:10][C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:15])[C:12](O)=[O:13].ClC(OCC)=O.[BH4-].[Na+].Cl>O1CC(CCN)C(CCN)C1CCN.O1CCCC1.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[S:10][C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:15])[CH2:12][OH:13]
Reactant: CC(Sc1cc2ccccc2[nH]1)(C(=O)O)c1ccccc1
Agent: CCOC(=O)Cl
Agent: Cl
Agent: NCCC1COC(CCN)C1CCN
Solvent: O
Solvent: C1CCOC1
Product: CC(CO)(Sc1cc2ccccc2[nH]1)c1ccccc1
Reaction time: 1 h
Yield: 50.4 %

Procedure:
To a solution (20 ml) of 2-(1H-indol-2-yl)thio-2-phenylpropionic acid (5.0 g) in anhydrous tetrahydrofuran triethylamine (1.7 g) was added. Thereafter, a solution (8 ml) of ethyl chloroformate (1.8 g) in anhydrous tetrahydrofuran was added dropwise under argon atmosphere with ice cooling. The mixture was stirred at that temperature for one hour. The deposited salt was filtered off to prepare a solution of a mixed acid anhydride in tetrahydrofuran. This mixed acid anhydride solution was added to a suspension of sodium borohydride (2.2 g) in water (30 ml) within the temperature range of from 10° to 15° C., and the mixture was stirred at that temperature for 4 hours. The reaction solution was acidified by adding concentrated hydrochloric acid, and extracted by ethyl acetate. The organic layer was washed with water, and a saturated aqueous sodium chloride solution, and was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (diluting solvent: methylene chloride), and further recrystallized from acetonitrile to give 2.4 g (yield: 48 %) of the product compound as a colorless powder. The melting point was 125.5°-127° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[NH:8][C:9]([C:11](=[O:28])[NH:12][CH:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:14]([F:17])([F:16])[F:15])=[CH:10][C:5]2=[CH:4][C:3]=1[C:29]([O:31][CH3:32])=[O:30].[H-].[Na+].I[CH2:36][CH3:37].O>CN(C)C=O.C(OCC)(=O)C>[CH2:36]([N:8]1[C:6]2=[N:7][C:2]([CH3:1])=[C:3]([C:29]([O:31][CH3:32])=[O:30])[CH:4]=[C:5]2[CH:10]=[C:9]1[C:11](=[O:28])[NH:12][CH:13]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)[C:14]([F:15])([F:16])[F:17])[CH3:37]
Reactant: COC(=O)c1cc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)[nH]c2nc1C
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCn1c(C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc2cc(C(=O)OC)c(C)nc21
Reaction time: 2 h
Yield: 68.6 %

Procedure:
Methyl 6-methyl-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (1.58 g, 3.44 mmol) was dissolved under argon at 0° C. in N,N-dimethylformamide (35 ml). Sodium hydride (60%; 0.165 g, 4.12 mmol) was added and the mixture was stirred with ice cooling for 2 h. Iodoethane (0.643 g, 4.12 mmol) was added and the reaction mixture was thawed with stirring over 18 h. Water and ethyl acetate were added and the phases were separated. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulphate, and the solvent was removed under reduced pressure. The residue was chromatographed with cyclohexane/ethyl acetate (3/1) and gave 1.15 g (66% of theory) of methyl 1-ethyl-6-methyl-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate. HPLC-MS: log P=6.27; mass (m/z): 488.1 (M+H)+; 1HNMR (D6-DMSO): δ 1.20 (t, 3H), 2.83 (s, 3H), 3.87 (s, 3H), 4.59 (q, 2H), 6.30-6.34 (m, 1H), 7.42 (s, 1H), 7.70-7.84 (m, 2H), 8.06 (d, 1H), 7.93-7.97 (m, 1H), 8.21 (s, 1H), 8.67 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[N:12][C:13]([CH:16]([NH:18][C:19](=O)[CH:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])[CH3:17])=[CH:14][N:15]=2)=[CH:5][CH:4]=1.N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:17][C:16]1[N:18]=[C:19]([CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:21])[N:12]2[C:13]=1[CH:14]=[N:15][C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[N:11]2
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)C(C)c3ccccc3)nn2)cc1
Agent: c1nc[nH]n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(Nc2ncc3c(C)nc(C(C)c4ccccc4)n3n2)cc1
Yield: 12.3 %

Procedure:
Applying the Cyclization Procedure 2, using N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]-2-phenylpropanamide (Intermediate 55) (129 mg, 0.34 mmol), pyridine (3.4 mL), 1,2,4 triazole (71 mg, 1.03 mmol) and phosphorus oxychloride (0.048+0.048 mL, 1.03 mmol), to afford 5-methyl-N-[4-(methyloxy)phenyl]-7-(1-phenylethyl)imidazo[5,1-f][1,2,4]triazin-2-amine (15 mg) as a yellow solid. MS m/z 360 (M+1).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[O:7][N:6]=[C:5]([NH:8]C(=O)C2C=CC=CC=2C(OC)=O)[CH:4]=1.O.NN.O>CO>[F:1][C:2]([F:22])([F:21])[C:3]1[O:7][N:6]=[C:5]([NH2:8])[CH:4]=1
Reactant: COC(=O)c1ccccc1C(=O)Nc1cc(C(F)(F)F)on1
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1cc(C(F)(F)F)on1
Temperature: 25 °C
Reaction time: 46 h

Procedure:
In methanol (15 ml) was dissolved 5-trifluoromethyl-3-(2-(methoxycarbonyl)benzoyl)aminoisoxazole (1.57 g, 0.0050 mole) and 90% hydrazine hydrate (0.42 g, 0.0075 mole) was added to the solution. It was allowed to stand to room temperature for 46 hours. Water (30 ml) was added to it and the mixture was stirred at room temperature for 15 minutes. Crystals were filtered off. The filtered off crystals were washed repeatedly with methylene chloride (45 ml) and the filtrate was extracted with these washings. The filtrate was further extracted with methylene chloride (45 ml×2) and the solvent was distilled off from the combined extract at atmospheric pressure by using a distillation apparatus equipped with a fractionating column packed with glass raschig rings (15 mm in diameter, 200 mm in length). The residue was purified by column chromatography on silica gel to give the title compound. Yield: 0.714 g (93.9%).
Reaction SMILES: CC(C)([O-])C.[Na+].[CH3:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1)=[O:9].C([O:19][C:20](=O)[CH2:21][CH2:22][CH2:23][CH3:24])C>C1COCC1>[OH:16][C:13]1[CH:14]=[CH:15][C:10]([C:8](=[O:9])[CH2:7][C:20](=[O:19])[CH2:21][CH2:22][CH2:23][CH3:24])=[CH:11][CH:12]=1
Reactant: CCCCC(=O)OCC
Reactant: CC(=O)c1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC(=O)CC(=O)c1ccc(O)cc1
Temperature: 8 °C
Yield: 64.8 %

Procedure:
Sodium tert-butoxide, 1270 g, is slurried in 1390 g THF and the mixture heated to reflux temperature. A solution of 580 g 4-hydroxyacetophenone and 555 g ethylvalerate in 1390 g THF is added over 30 minutes. The solution is stirred at reflux temperature until the reaction is complete, ca 4.5 h, and then quenched by addition of the reaction mixture to 1270 g 37% HCl. The mixture is concentrated by distillation of THF at reduced pressure and to the residue is added 900 g toluene. The water phase is separated and the toluene phase washed with 900 g 10% aqueous NaCl. The toluene is stripped at reduced pressure and the residual oil diluted with 850 g acetic acid. The solution is cooled to 8° C. and 850 ml water added slowly. The formed slurry is stirred at 5-8° C. for 90 minutes and then filtered and washed with 608 g 20% aqueous acetic acid. Drying under vacuum at 40° C. gives 608 g 1-(4-hydroxyphenyl)-1,3-heptandione.
Reaction SMILES: [F:1][CH:2]([F:6])[C:3](O)=[O:4].[CH2:7]([Li])[CH2:8][CH2:9][CH3:10]>CCOCC>[F:1][CH:2]([F:6])[C:3](=[O:4])[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: [Li]CCCC
Reactant: O=C(O)C(F)F
Solvent: CCOCC
Product: CCCCC(=O)C(F)F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a 3 liter, three-neck, round bottom flask, equipped with a magnetic stirrer, a dropping funnel filled with 39.9 g. of difluoroacetic acid and 200 ml. of ether, and a rubber septum is added 1350 ml. of ether. After cooling in a dry ice-acetone bath under nitrogen, one mole of n-butyl lithium (2.2 M, hexane) is added via a double tip needle. The difluoroacetic acid solution is slowly added to the cooled n-butyl lithium solution via the dropping funnel over 3 hours. The thick mixture is stirred at -78° C. for one hour and then quenched by pouring into a mixture of one liter of 4 N hydrochloric acid and one liter of ice, divided into three flasks, with stirring. The organic layers are combined and washed with water and brine. The 1500 ml. of solution is distilled at atmospheric pressure in a water bath. After the forerun is collected, the residue is fractionally distilled giving 18.8 g (b.p. 100°-110° C.) of product that is 75% real.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(CC(O)=O)(=[O:18])N.C(C1CN1)#N>O1CCCC1>[C:8]([NH:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:18]
Reactant: NC(=O)CC(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N#CC1CN1
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.15 g. Dicyclohexylcarbodiimide are introduced portionwise at 0° to 5° C. into a suspension of 1.03 g. carbamoylacetic acid and 0.68 g. 2-cyanoaziridine in 18 ml. tetrahydrofuran. The reaction mixture is stirred for 1 hour at 0° C. and then for 2 hours at ambient temperature. It is then filtered with suction and the solid material is washed with tetrahydrofuran and diethyl ether into the filtrate, 2.2 g. dicyclohexylurea (m.p. 226°-228° C.) being obtained. The filtrate is evaporated in a vacuum and the evaporation residue is triturated with ether to give 1.3 g. 1-carbamoylacetyl-2-cyanoaziridine; m.p. 115°-119° C.