Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[CH3:15])[C:6]=2[CH:5]=[C:4]([CH3:16])[CH:3]=1.[Li][CH2:18][CH2:19]CC.ICC>>[CH3:1][C:2]1[C:14]2[CH:13]([CH2:18][CH3:19])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[CH3:15])[C:6]=2[CH:5]=[C:4]([CH3:16])[CH:3]=1
Reactant: Cc1cc(C)c2c(c1)-c1cccc(C)c1C2
Reactant: [Li]CCCC
Solvent: CCI
Product: CCC1c2c(C)cccc2-c2cc(C)cc(C)c21

Procedure:
The substitution reaction at the 9-position was performed according to the general procedure for the synthesis of 9-substituted fluorenes described above in item IV(i). 1,3,8-Trimethylfluorene (54) (1.2 g, 5.77 mmol) was used instead of fluorene, n-BuLi (3.0 ml, 2.5 M in hexane, 7.5 mmol), RX=1-iodoethane (1.35 g, 8.65 mmol). 55 was isolated to give a white solid (1.36 g, quant.).
Reaction SMILES: [O:1]([CH:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]=O.[ClH:17].[CH3:18][NH:19][CH3:20]>C(O)(=O)C.CC(=O)CC>[ClH:17].[CH3:18][N:19]([CH2:15][CH:10]1[CH2:9][CH:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12][C:11]1=[O:14])[CH3:20]
Reactant: O=C1CCC(Oc2ccccc2)CC1
Reactant: C=O
Reactant: CNC
Agent: Cl
Solvent: CCC(C)=O
Solvent: CC(=O)O
Product: CN(C)CC1CC(Oc2ccccc2)CCC1=O
Yield: 40.2 %

Procedure:
9.5 g (50 mmole) 4-phenoxy-cyclohexanone (26), 0.765 g (25 mmole) paraformaldehyde and 2.08 g (25 mmole) dimethylamine hydrochloride were heated for 20 minutes in 17 ml acetic acid in an oil bath at a temperature of 105° C. Thereafter the solvent was distilled off under vacuum, the residue was treated twice with 2-butanone, and the 2-butanone was subsequently distilled off under vacuum. The salt obtained was taken up in 30 ml 2-butanone. 2.85 g of compound (27) (40% theoretical) were obtained.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14])=[O:8])(=[O:3])[CH3:2].[CH2:26](O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([S:4][CH2:5][CH:6]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([O:15][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:14])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)Nc1cccc(C(=O)O)c1
Reactant: OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(=O)SCC(Cc1ccccc1)C(=O)Nc1cccc(C(=O)OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
3-[(2-Acetylthiomethyl-3-phenylpropionyl)amino]-benzoic acid prepared in Example 68-(b)-[1](0.3 g),4-dimethylaminopyridine (0.01 g) and benzyl alcohol (0.1 g) are dissolved in dichloromethane (25 ml), and thereto is added EDC·HCl (0.18 g), and the mixture is stirred at room temperature three nights. The reaction mixture is washed with saturated aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate solution and water in this order, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue is purified by a silica gel column chromatography (eluant, chloroform) to give the title compound (0.26 g).
Reaction SMILES: [F-:1].[Na+].[CH2:3]([C:7]([F:9])=[O:8])[C:4]([F:6])=[O:5].[F:10]F>>[C:3]([C:7]([F:9])=[O:8])([C:4]([F:6])=[O:5])([F:10])[F:1]
Reactant: O=C(F)CC(=O)F
Reactant: FF
Reactant: [F-]
Agent: [Na+]
Product: O=C(F)C(F)(F)C(=O)F

Procedure:
To a 1 L monel metal reactor charged with 18 g (0.43 mol) of NaF, 12.1 g (0.112 mol) of CH2(COF)2 was charged with condensation, and thereto, 0.1 g/h of fluorine gas was blown gradually while controlling increasing the inner pressure with keeping the reactor at 0° C., and the reaction was conducted. When the total pressure increased by the product reached to 0.44 atm, the blowing of fluorine gas was finshed. The reaction product was separated and purified, and 1.7 g (0.0118 mol) of CF2(COF)2 was obtained. It was confirmed with FT-IR and 19F-NMR that the resulting compound was CF2(COF)2. The yield thereof was 10%.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:15][C:16]#[N:17]>CN(C)C=O.C(OCC)(=O)C>[C:16]([CH2:15][N:6]1[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])#[N:17]
Reactant: CCOC(=O)c1ccc(C)[nH]1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C)n1CC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.8 %

Procedure:
A solution of ethyl 5-methyl-1H-pyrrole-2-carboxylate (1 g, 6.53 mmol) in anhydrous N,N-dimethylformamide (20 mL) under nitrogen at 0° C. was treated with a 60% dispersion of sodium hydride in mineral oil (392 mg, 9.79 mmol). After effervescence ceased, the reaction was treated with a solution of 2-bromoacetonitrile (1.17 g, 9.79 mmol) in N,N-dimethylformamide (2 mL). The resulting mixture was allowed to warm to room temperature and was stirred at room temperature for 30 min. At this time, the reaction was diluted with ethyl acetate (200 mL), washed with water (2×100 mL) and a saturated aqueous sodium chloride solution (2×100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (80 g silica gel column, 0-20% ethyl acetate/hexanes) afforded ethyl 1-(cyanomethyl)-5-methyl-1H-pyrrole-2-carboxylate (0.5 g, 39.8%). LC-MS calcd. for C10H13N2O2 [(M+H+] 193, obsd. 193.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]1[CH:13]=[N:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)=[O:5])[CH3:2].[NH:32]1[CH:36]=[CH:35][CH:34]=[N:33]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:1]([O:3][C:4]([C:6]1([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]1[CH:13]=[N:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][N:32]3[CH:36]=[CH:35][CH:34]=[N:33]3)=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)=[O:5])[CH3:2]
Reactant: c1cn[nH]c1
Reactant: CCOC(=O)C1(C(=O)OCC)CCC(=O)N1c1ccc(Oc2ccc(CBr)cc2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)OCC)CCC(=O)N1c1ccc(Oc2ccc(Cn3cccn3)cc2)nc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of 1-[6-(4-bromomethyl-phenoxy)-pyridin-3-yl]-5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.2 g, 0.4 mmol) in 0.8 mL of dimethylformamide was added pyrazole (0.056 g, 0.82 mmol) and potassium carbonate (0.11 g, 0.82 mmol). After stirring for 24 hours at 50° C., the mixture was diluted with water, extracted three times with ethyl acetate, and the combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo, affording the crude product as a colorless syrup that was used directly in the next step. MS (APCl, m/z): 479.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=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.[NH:44]1[C:52]2[C:47](=[C:48]([C:53]3[CH:54]=[C:55]([NH2:62])[C:56]4[CH:57]=[N:58][NH:59][C:60]=4[CH:61]=3)[CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45]1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:62][C:55]2[CH:54]=[C:53]([C:48]3[CH:49]=[CH:50][CH:51]=[C:52]4[C:47]=3[CH:46]=[CH:45][NH:44]4)[CH:61]=[C:60]3[C:56]=2[CH:57]=[N:58][NH:59]3)=[O:10])=[N:6][CH:7]=1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: O=C(O)c1ccc(Br)cn1
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: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.3 %

Procedure:
To a solution of 5-bromo-2-pyridinecarboxylic acid (980 mg, 4.83 mmol, available from Alfa Aesar) in DMF (15 ml) was added HATU (1840 mg, 4.83 mmol) and DIPEA (2.53 ml, 14.50 mmol). The mixture was stirred at room temperature for 30 mins then 6-(1H-indol-4-yl)-1H-indazol-4-amine (600 mg, 2.41 mmol) was added and the mixture stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to approx. 5 ml volume and was applied to 2×50 g aminopropyl cartridges that had been pre-conditioned with MeOH. The reaction mixture remained on the cartridges for 2 h before being eluted with MeOH. The eluent was concentrated in vacuo and a precipitate formed, which was collected by filtration to give the title compound (430 mg) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:11]([CH3:16])[C:12]([F:15])([F:14])[F:13])=[C:6]([CH:9]=1)[C:7]#[N:8].[Li]CCCC.[C:22](=[O:24])=[O:23].[OH-].[Na+]>CCCCCC.C1(C)C=CC=CC=1.C1COCC1>[C:7]([C:6]1[CH:9]=[C:2]([CH:3]=[CH:4][C:5]=1[O:10][CH:11]([CH3:16])[C:12]([F:15])([F:14])[F:13])[C:22]([OH:24])=[O:23])#[N:8]
Reactant: O=C=O
Reactant: CC(Oc1ccc(Br)cc1C#N)C(F)(F)F
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(Oc1ccc(C(=O)O)cc1C#N)C(F)(F)F
Reaction time: 0.5 h

Procedure:
To 5-bromo-2-(2,2,2-trifluoro-1-methylethoxy)benzonitrile in a mixed solvent of toluene/THF (4:1) was added a solution of n-BuLi in n-hexane at −78° C. With passing a CO2 gas therethrough, the solution was stirred for 0.5 hour. To the reaction solution was added a 1M aqueous NaOH solution to complete the reaction, and followed by extraction with diethyl ether. The organic layer was acidified by adding 1M HCl, extracted with EtOAc, dried over anhydrous MgSO4, and concentrated. The residue was purified by silica gel chromatography (chloroform:CH3OH=97:3 to 90:10) to obtain 3-cyano-4-(2,2,2-trifluoro-1-methylethoxy)benzoic acid as a white solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]([C:9]1[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[CH:15]=[C:11]([C:12]([NH2:14])=O)[C:10]=1[OH:21])([CH3:8])[CH3:7]>N1C=CC=CC=1>[OH:21][C:10]1[C:9]([CH:6]([CH3:7])[CH3:8])=[CH:17][C:16]([CH:18]([CH3:20])[CH3:19])=[CH:15][C:11]=1[C:12]#[N:14]
Reactant: CC(C)c1cc(C(N)=O)c(O)c(C(C)C)c1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)c1cc(C#N)c(O)c(C(C)C)c1
Temperature: 25 °C
Yield: 60 %

Procedure:
To a solution of phosphorous oxychloride (1.35 g, 8.8 mmole) and dry pyridine (12 mL) cooled to 0° C., a solution of 3,5-diisopropyl salicylamide (1.10 g, 5 mmole) and dry pyridine (5 mL) was slowly added drop by drop. The reaction mixture was stirred at room temperature, whereat the colour changed from colourless over violet to red. After extraction with ethyl acetate and washing with a saturated sodium chloride solution and 2N hydrochloric acid, the organic layer was dried and evaporated under reduced pressure. The obtained solid residue was recrystallized from acetonitrile, whereat there were obtained 610 mg (60%) of 2-hydroxy-3,5-diisopropyl benzonitrile.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([Br:7])=[C:3]1[C:8]([NH:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[O:9].[C:19]([O:23][C:24]([NH:26][C@@H:27]([CH3:31])[C:28](O)=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[Br:7][C:4]1[CH:5]=[CH:6][N:2]([NH:1][C:28](=[O:29])[C@@H:27]([NH:26][C:24](=[O:25])[O:23][C:19]([CH3:21])([CH3:20])[CH3:22])[CH3:31])[C:3]=1[C:8](=[O:9])[NH:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1
Reactant: Nn1ccc(Br)c1C(=O)Nc1cc(F)cc(F)c1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1ccc(Br)c1C(=O)Nc1cc(F)cc(F)c1
Yield: 54.4 %

Procedure:
The title compound was prepared from 1-amino-3-bromo-N-(3,5-difluorophenyl)-1H-pyrrole-2-carboxamide (7.87 g, 24.9 mmol) and (S)-2-(tert-butoxycarbonylamino)propanoic acid (purchased from Aldrich, 5.65 g, 29.9 mmol) following the experimental procedure described in Preparation 45a. 6.6 g (51% yield) of the desired compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.[CH2:19]([N:22]=[C:23](SC)[O:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH3:21]>C(O)CC>[I:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[C:23]([O:24][CH2:25][CH2:26][CH3:27])[N:22]([CH2:19][CH2:20][CH3:21])[C:4]2=[O:6]
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: CCCN=C(OCCC)SC
Solvent: CCCO
Solvent: CCN(CC)CC
Product: CCCOc1nc2ccc(I)cc2c(=O)n1CCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.4 %

Procedure:
To a solution of 0.38 g (1.44 mmoles) of 2-amino-5-iodobenzoic acid and 0.14 g (1.38 mmol) of triethylamine in 7.15 mL of n-propanol was added 0.25 g (1.143 mmol) of S-methyl O-propyl propylcarbonimidothioate. The reaction mixture was stirred at room temperature for 18 h, heated to 60° C. for 24 h, and then heated to reflux for 6 h. The reaction was then concentrated under reduced pressure to give about 0.6 g of crude material, which was purified by flash chromatography on silica (93:7 hexanes:ethyl acetate) to give 0.21 g of the title compound, 1H NMR (400 MHz, CDCl3): δ0.96 (t,3H); 1.06 (t,3H); 1.64-1.79 (m,2H); 1.81-1.92 (m,2H); 4.05 (t,2H); 4.43 (t,2H), 7.19 (d,1H); 7.85 (dd,1H); 8.49 (d,1H). In addition, 0.11 g of propyl-5-iodoanthranilate was obtained from the flash chromatography, 1H NMR (400 MHz, CDCl3): δ1.02 (t,3H); 1.76-1.86 (m,2H); 4.23 (t,2H); 5.8 (br s,2H); 6.45 (d,1H); 7.45 (dd, 1H); 8.13 (d,1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7](Cl)=[O:8].[NH4+:22].[OH-]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]2[CH:13]=[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([NH2:22])=[O:8]
Reactant: [NH4+]
Reactant: O=C(Cl)c1sc2ccc(OCc3ccccc3)cc2c1Cl
Agent: [OH-]
Solvent: Cc1ccccc1
Product: NC(=O)c1sc2ccc(OCc3ccccc3)cc2c1Cl
Yield: 84 %

Procedure:
To a warm solution of 3-chloro-5-(phenylmethoxy)benzo[b]thiophene-2-carbonyl chloride (2.0 g, 6 mmol) [Connor D. T., et al., J. Med. Chem, 35, 935, (1992)] in 20 mL of toluene is added dropwise 10 mL of aqueous NH4OH. The resulting precipitate is collected by filtration washing with ethyl alcohol to provide 3-chloro-5-(phenylmethoxy)benzo[b]thiophene-2-carboxamide in 84% yield; mp=205.5°-206° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16](O)[CH3:17].Cl.CN(C)CCCN=C=NCC.C(OCC)(=O)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:16][CH2:17][O:11][C:10]([C@@H:9]1[CH2:13][CH2:14][CH2:15][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 62.2 %

Procedure:
N-tert-Butoxycarbonylprolin (24.38 g, 113 mmol) was dissolved in dichloromethane (60 ml). Ethanol (7.9 ml, 135 mmol) and 4-dimethylaminopyridine (1.52 g, 12.5 mmol) were added. The solution was cooled to 0° C. N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (23.88 g, 125 mmol) was added. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. Ethyl acetate (400 ml) was added. It was washed with a 10% aqueous solution of sodium hydrogen sulfate (300 ml). The aqueous phase was extracted with ethyl acetate (3×200 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate (300 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (400 g), using ethyl acetate (1:4) as eluent, to give 17.11 g of (2S)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH:13]=[CH:12][C:11]=1[C:19]([OH:21])=O.[CH3:22][C:23]1([CH3:31])[O:27][C@@H:26]([CH2:28][O:29][NH2:30])[CH2:25][O:24]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C1COCC1.C(OCC)(=O)C>[CH3:22][C:23]1([CH3:31])[O:27][C@H:26]([CH2:28][O:29][NH:30][C:19]([C:11]2[CH:12]=[CH:13][C:14]3[N:15]([CH:16]=[N:17][CH:18]=3)[C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[O:21])[CH2:25][O:24]1
Reactant: O=C(O)c1ccc2cncn2c1Nc1ccc(I)cc1F
Reactant: CC1(C)OC[C@H](CON)O1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OC[C@@H](CONC(=O)c2ccc3cncn3c2Nc2ccc(I)cc2F)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.3 %

Procedure:
To a solution of 5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (326 mg, 0.82 mmol) in THF (4.1 ml) was added O—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (362 mg, 2.46 mmol), DIPEA (1.26 ml, 7.4 mmol), HOBt (327 mg, 2.46 mmol) and EDCI (471 mg, 2.46 mmol), the mixture stirred for 18 hours at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate followed by water and then brine. The organic phase was isolated, dried (Na2SO4), filtered and concentrated in vacuo. Purification of the resultant residue by flash chromatography (Si-PPC, gradient 0% to 10%, methanol in dichloromethane) afforded the title compound as a pale yellow solid (364 mg, 84%). LCMS (method B): RT=2.58 min, [M+H]+=527.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6]([CH3:8])([CH3:7])[NH:5][C:4](=[O:9])[NH:3]1.[CH2:11]([Li])CCC.CCCCCC.CI.P([O-])(O)(O)=O.[K+]>O1CCCC1>[CH3:11][N:3]1[C:2]([CH3:10])([CH3:1])[C:6]([CH3:8])([CH3:7])[NH:5][C:4]1=[O:9]
Reactant: [Li]CCCC
Reactant: CC1(C)NC(=O)NC1(C)C
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CCCCCC
Product: CN1C(=O)NC(C)(C)C1(C)C
Reaction time: 0.08 h

Procedure:
To a solution of 4,4,5,5-tetramethylimidazolidin-2-one (100 mg; 0.70 mmol) in dry tetrahydrofuran (5 ml), a 1.57 N solution of n-butyl lithium in hexane (0.49 ml; 0.77 mmol) was added at 0° C. After stirring at the same temperature for 5 minutes, a solution of methyl iodide (109 mg; 0.77 mmol) in tetrahydrofuran (1 ml) was added at 0° C., followed by stirring at room temperature for 10 minutes. To the reaction mixture, a saturated aqueous solution of potassium dihydrogen phosphate was added to decompose the excess reaction agent, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give an oily residue, which was purified by thin layer chromatography (chloroform:acetone=1:1) to give 1,4,4,5,5-pentamethylimidazolidin-2-one as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([C:26]1[N:31]=[CH:30][C:29](Br)=[CH:28][N:27]=1)[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[N:19]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:20][CH3:21].C([O-])(=[O:44])C.[K+].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.O>CS(C)=O.C(OCC)(=O)C>[F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[N:19]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:20][CH3:21])[C:26]1[N:31]=[CH:30][C:29]([OH:44])=[CH:28][N:27]=1
Reactant: CCCCN(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Reactant: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCCCN(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(O)cn1
Temperature: 80 °C
Reaction time: 1 h
Yield: 9.7 %

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-(5-bromopyrimidin-2-yl)-[2-(butyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amine (3.0 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium methylene chloride complex (112 mg), potassium acetate (1.34 g) and bis(pinacolato)diboron (1.74 g) are dissolved in dimethylsulfoxide (20 ml) and the mixture is heated to 80° C. under nitrogen atmosphere and stirred for 1 hour. The reaction solution is cooled to room temperature, and thereto are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (70 ml) and thereto is added dropwise a 30% aqueous hydrogen peroxide solution (15 ml) under ice-cooling. One hour thereafter, thereto is added a saturated aqueous sodium thiosulfate solution under ice-cooling to consume the excess hydrogen peroxide, and thereto are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→3:1) to give 2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-ol (263 mg). MS (m/z): 595 [M+H]+
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:7][CH2:6][CH:5]([C:8]2[N:12]3[C:13]4[C:18]([NH:19][C:20](=[O:21])[C:11]3=[N:10][N:9]=2)=[CH:17][C:16]([C:22](O)=[O:23])=[C:15]([CH3:25])[CH:14]=4)[CH2:4][CH2:3]1.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH2:32][CH2:31]2.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>O.CN(C)C=O>[F:26][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[N:12]3[C:13]4[C:18]([NH:19][C:20](=[O:21])[C:11]3=[N:10][N:9]=2)=[CH:17][C:16]([C:22]([N:33]2[C:34]3[C:30](=[CH:29][C:28]([F:27])=[CH:36][CH:35]=3)[CH2:31][CH2:32]2)=[O:23])=[C:15]([CH3:25])[CH:14]=4)[CH2:6][CH2:7]1
Reactant: Cc1cc2c(cc1C(=O)O)[nH]c(=O)c1nnc(C3CCC(F)(F)CC3)n12
Reactant: Fc1ccc2c(c1)CCN2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1C(=O)N1CCc3cc(F)ccc31)[nH]c(=O)c1nnc(C3CCC(F)(F)CC3)n12
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
To a mixture of 150 mg of 1-(4,4-difluorocyclohexyl)-8-methyl-4-oxo-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylic acid, 62.5 mg of 5-fluoroindoline, 0.25 mL of diisopropylethylamine, and 3 mL of N,N-dimethylformamide was added 146 mg of TBTU, followed by stirring at room temperature overnight. To the reaction liquid were added water and a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 95/5). The obtained solid was washed with a mixed solution of hot diethyl ether and normal hexane to obtain 108 mg of 1-(4,4-difluorocyclohexyl)-7-[(5-fluoro-2,3-dihydro-1H-indol-1-yl)carbonyl]-8-methyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[C:4]([CH3:10])[N:3]=1.[O:11](C(OC(C)(C)C)=O)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=O.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(OCC)(=O)C>[C:15]([O:14][C:12]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[C:4]([CH3:10])[N:3]=1)=[O:11])([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1nc(N)ccc1C#N
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1nc(NC(=O)OC(C)(C)C)ccc1C#N
Reaction time: 3 h

Procedure:
A mixture of 2-amino-5-cyano-6-methylpyridine (10.0 g, 75.1 mmol), (BOC)2O (16.39 g, 75.1 mmol), triethylamine (11.5 ml, 82.6 mmol) and DMAP (0.92 g, 7.5 mmol) in methylene chloride (200 ml) was stirred for 3 h. More triethylamine (4.22 ml) and (BOC2)O (1.64 g) were added and after 16 h the reaction was diluted with ethyl acetate and was washed with 1 M AcOH (3 times), dried (Na2SO4) and evaporated in vacuo to give dark brown solid. The crude product was purified by flash column chromatography (10% ethylacetate/hexanes) to give the title compound as a white solid: