Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[C:9]1([S:15]([N:18]2[C:26]3[C:21](=[CH:22][C:23]([O:27][CH2:28][CH2:29][NH:30][C:31](=[O:33])[CH3:32])=[CH:24][CH:25]=3)[CH:20]=[CH:19]2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[Cl:1][C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29][NH:30][C:31](=[O:33])[CH3:32])[CH:22]=2)[N:18]([S:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)(=[O:16])=[O:17])[CH:19]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)NCCOc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Solvent: C1CCOC1
Product: CC(=O)NCCOc1ccc2c(c1)c(Cl)cn2S(=O)(=O)c1ccccc1
Temperature: 40 °C
Reaction time: 6 h
Yield: 108.7 %

Procedure:
N-chlorosuccinimide (0.42 g, 3.2 mmol) was added to a solution of N-(2-{[1-(phenylsulfonyl)-1H-indol-5-yl]oxy}ethyl)acetamide (Intermediate 25, 0.95 g, 2.6 mmol) in THF (20 ml) at room temperature. The reaction mixture was stirred at 40° C. for 6 hours. The reaction mixture was evaporated and the crude material was purified by flash chromatography on silica gel using 3% MeOH in DCM as the eluent to give the title compound (1.11 g) as a white solid. MS m/z 393 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][CH:2]=1.[O:11]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:25]1(O)[CH:30]=[CH:29][CH:28]=CC=1>>[CH:28]1([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][N:3]=[C:4]3[NH:22][C:21]2[CH:20]=[CH:19][C:18]([O:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:24][CH:23]=2)[CH2:29][CH2:30][CH2:25]1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: c1ccc2ncncc2c1
Reactant: Oc1ccccc1
Product: c1ccc(Oc2ccc(Nc3ncnc4ccc(C5CCC5)cc34)cc2)cc1
Temperature: 100 °C
Yield: 30.2 %

Procedure:
Quinazoline 16 (50 mg, 0.18 mmol) was combined with 4-phenoxyaniline (67 mg, 0.36 mmol) in phenol (0.45 g). The mixture was heated at 100° C. for a total of 17 hours. Excess phenol was removed by distillation under reduced pressure to provide a residue which was triturated with CH2Cl2 to provide the desired quinazoline 17 (20 mg, 30%) as a yellow solid. 1H NMR (DMSO d6, 400 MHz): δ: 9.76 (s, 1H), 8.47 (s, 1H), 8.31 (s, 1H), 7.77 (d, 2H), 7.69 (m, 2H), 7.36 (t, 2H), 7.11 (t, 1H), 7.03 (d, 2H), 6.98 (d, 2H), 3.69 (m, 1H), 2.35 (m, 2H), 2.23 (m, 2H), 2.01 (m, 1H), 1.86 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:4][N:3]=1.[CH3:11][C:12](=[CH:14][CH3:15])[CH3:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:11][C:12]([N:4]1[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:2]([CH3:1])=[N:3]1)([CH3:13])[CH2:14][CH3:15]
Reactant: CC=C(C)C
Reactant: COC(=O)c1c[nH]nc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCC(C)(C)n1cc(C(=O)OC)c(C)n1
Temperature: 120 °C
Reaction time: 4 h
Yield: 29 %

Procedure:
Methyl 3-methyl-1H-pyrazole-4-carboxylate (10.8 g) synthesized in Example 1(3) was dissolved in acetonitrile (100 mL), 2-methyl-2-butene (16.3 mL) and p-toluenesulfonic acid monohydrate (4.4 g) were added, and the mixture was stirred in a sealed tube at 120° C. for 4 hr. The reaction mixture was poured into aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (4.6 g, 29%) as an oil.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:4]=2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=1.C(C1C=C(B(O)O)C=CC=1)=O.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[C:3]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:12]=[CH:11][C:4]=3[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=2)=[CH:35][CH:34]=1
Reactant: CN1C(=O)CN=C(Cl)c2cc(-c3ccccc3)ccc21
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=Cc1cccc(B(O)O)c1
Product: CN1C(=O)CN=C(c2ccc(Cl)cc2)c2cc(-c3ccccc3)ccc21
Yield: 35 %

Procedure:
Prepared from 5-chloro-1-methyl-7-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one using the same method described for Example 9 and instead of using 3-formylbenzene boronic acid, we used 4-chlorophenyl boronic acid. The title compound was obtained as a pale yellow solid, (yield=35%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])([CH3:4])([CH3:3])[CH3:2].[NH2:31][CH2:32][CH2:33][C:34]1[CH:35]=[C:36]([OH:42])[C:37]([OH:41])=[C:38]([OH:40])[CH:39]=1>>[C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([S:12]([CH3:15])(=[O:14])=[O:13])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:31][CH2:32][CH2:33][C:34]3[CH:35]=[C:36]([OH:42])[C:37]([OH:41])=[C:38]([OH:40])[CH:39]=3)[N:24]=2)[CH:18]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCc1cc(O)c(O)c(O)c1
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Product: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(NCCc3cc(O)c(O)c(O)c3)n2)c1)S(C)(=O)=O

Procedure:
Intermediate 4 was coupled with 5-(2-Amino-ethyl)-benzene-1,2,3-triol following procedure F. LC-MS showed the product had the expected M+H+ of 588. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.2 (m, 2H) 8.0 (m, 1H) 7.6 (m, 2H) 7.3 (m, 3H) 4.8 (m, 1H) 4.5 (s, 2H) 3.9 (m, 2H) 3.3 (m, 2H) 3.0 (m, 2H) 2.9 (m, 5H) 1.6 (m, 2H) 1.4 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:11](I)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:13])[CH:3]=1.[C:14]([Si:16]([CH3:19])([CH3:18])[CH3:17])#[CH:15].CCN(CC)CC>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:11]([C:15]#[C:14][Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:13])[CH:3]=1
Reactant: COC(=O)c1cc(I)c(N)cc1Cl
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cc(C#C[Si](C)(C)C)c(N)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of compound 70n (0.642 mmol, 200 mg), Cut (0.064 mmol, 12.2 mg) and Pd(PPh3)2Cl2 (0.064 mmol, 45 mg) in THF (2 mL) was added ethynyltrimethylsilane (0.963 mmol, 95 mg) followed by Et3N (7.19 mmol, 1 mL) under N2. The reaction mixture was stirred at room temperature for 1.5 h and then partitioned between EtOAc and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/hexanes) to give compound 70p.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2([OH:22])[C:13]1[C:14]([O:19][CH2:20][CH3:21])=[N:15][CH:16]=[CH:17][CH:18]=1)#[N:2].CC(C)([O-])C.[K+].[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.ClCCl.CO>CN(C)C=O>[CH2:20]([O:19][C:14]1[C:13]([C:6]2([OH:22])[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=3)[N:8]([S:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:37])=[O:36])[C:7]2=[O:12])=[CH:18][CH:17]=[CH:16][N:15]=1)[CH3:21]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOc1ncccc1C1(O)C(=O)Nc2ccc(C#N)cc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: CCOc1ncccc1C1(O)C(=O)N(S(=O)(=O)c2ccccc2)c2ccc(C#N)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
2.50 g (7.79 mmol) of (−)-5-cyano-3-hydroxy-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one (prepared as in example 1.2 and racemate resolution into the corresponding enantiomers as described above) were dissolved in 30 ml of dimethylformamide, resulting in a yellow solution. After cooling to 0° C., 1.00 g (8.94 mmol) of potassium tert-butoxide was added in portions so that the temperature was kept between 0° C. and 5° C. The solution changed in color from yellow to dark yellow. It was stirred for 30 minutes and, at 0° C., 1.07 ml (8.20 mmol) of benzenesulfonyl chloride were slowly added dropwise. The solution became turbid and pale orange in color. It was stirred while cooling in ice for one hour. The progress of the reaction was followed by thin-layer chromatography (dichloromethane/methanol 9:1). For working up, the reaction mixture was added dropwise to ice-water. During this, a precipitate separated out and was, after stirring for 5 minutes, filtered off and washed with water. The title compound (2.65 g, 6.09 mmol, 78%) was dried in a vacuum drying oven at 40° C. and used for the next reaction without further purification.
Reaction SMILES: [BrH:1].C(O)(=O)C.[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14](=O)[CH2:15][S:16][C:17]#[N:18].O>C(O)(=O)C>[Br:1][C:17]1[S:16][CH:15]=[C:14]([C:8]2[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:7]=2[F:6])[N:18]=1
Reactant: N#CSCC(=O)c1ccc(F)cc1F
Reactant: Br
Solvent: O
Solvent: CC(=O)O
Product: Fc1ccc(-c2csc(Br)n2)c(F)c1
Temperature: 130 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
A 25% hydrogen bromide/acetic acid (25 ml) solution was added to a solution of 2-(2,4-difluorophenyl)-2-oxoethyl thiocyanate (3.39 g, 15.9 mmol) in acetic acid (25 ml), and the mixture was stirred at 130° C. for 2 hours and stirred at room temperature for 1 hour. Water was poured to the reaction mixture, and crystals were collected by filtration and washed with water to give 3.23 g (73.6%) of the desired product as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.CC(C)([O-])C.[Na+].Cl[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=1>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:23][C:24]3[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=3)[CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: Clc1ncc2c(n1)N1CCOC[C@H]1CN2
Reactant: Cn1cc(CCl)cn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cn1cc(CN2C[C@@H]3COCCN3c3nc(Cl)ncc32)cn1

Procedure:
The title compound was prepared in a manner similar to PREPARATION x5 using (R)-2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 300 mg, 1.324 mmol) in DMSO (6 mL), sodium tert-butoxide (153 mg, 1.588 mmol) and 4-(chloromethyl)-1-methyl-1H-pyrazole (190 mg, 1.456 mmol) (113 mg, 26%). ESI-MS m/z [M+H]+ calc'd for C41H17ClN6O, 321.12. found 321.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:11]1(=[O:16])[CH2:15][CH2:14][CH:13]=[CH:12]1.B(F)(F)F.CCOCC.C(O)C>[N+](C)([O-])=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:13]1[CH2:14][CH2:15][C:11](=[O:16])[CH2:12]1
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: O=C1C=CCC1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCO
Solvent: C[N+](=O)[O-]
Product: O=C1CCC(c2c[nH]c3ccc(F)cc23)C1
Temperature: -20 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
A mixture of 5-fluoroindole (6.0 g, 44.4 mmol) and 2-cyclopenten-1-one (4.5 mL, 53.3 mmol) in nitromethane (22 mL) was cooled to −20° C. in a carbon tetrachloride-dry ice bath. A mixture of boron trifluoride etherate (1.6 mL, 11.1 mmol) and ethanol (2.2 mL, 43 mmol) was added dropwise from an addition funnel. The reaction mixture was stirred at −20° C. for 2 hours, then was quenched with 5% aqueous sodium bicarbonate solution (100 mL), and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), then were dried over anhydrous sodium sulfate, filtered and concentrated to give 9.5 g of the title compound. Trituration with ethyl acetate afforded 5.6 g (58%) of the title compound as a yellow solid. An analytical sample was recrystallized from ethyl acetate/methanol: mp 119-120° C.; MS (ESI) m/z 218 [M+H]+.
Reaction SMILES: FC1C=C(C2N=C(SC)N=C(N3CCOC[C@@H]3C)C=2)C=NC=1.[Cl:23][C:24]1[CH:29]=[C:28](Cl)[N:27]=[C:26]([S:31][CH3:32])[N:25]=1.[F:33][C:34]1[CH:35]=[CH:36][C:37]([S:43][CH3:44])=[C:38](B(O)O)[CH:39]=1>>[Cl:23][C:24]1[CH:29]=[C:28]([C:36]2[CH:35]=[C:34]([F:33])[CH:39]=[CH:38][C:37]=2[S:43][CH3:44])[N:27]=[C:26]([S:31][CH3:32])[N:25]=1
Reactant: CSc1ccc(F)cc1B(O)O
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: CSc1nc(-c2cncc(F)c2)cc(N2CCOC[C@@H]2C)n1
Product: CSc1nc(Cl)cc(-c2cc(F)ccc2SC)n1

Procedure:
Method as described for intermediate 5 using 4,6-dichloro-2-(methylthio)pyrimidine and 5-fluoro-2-(methylthio)phenylboronic acid. The residue was purified further by flash chromatography (0-10% EtOAc in petroleum ether (40:60) to afford 4-chloro-6-(5-fluoro-2-(methylthio)phenyl)-2-(methylthio)pyrimidine as a white solid, (500 mg, 42%)
Reaction SMILES: [CH2:1]([C:4]1[C:17]2[C:8](=[CH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:7]=[CH:6][CH:5]=1)[CH:2]=C.[CH3:18]CCCCC>[Pd]>[CH:1]([C:4]1[C:17]2[C:8](=[CH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:7]=[CH:6][CH:5]=1)([CH3:18])[CH3:2]
Reactant: C=CCc1cccc2cc3ccccc3cc12
Reactant: CCCCCC
Agent: [Pd]
Product: CC(C)c1cccc2cc3ccccc3cc12

Procedure:
Into a 500 milliliter hydrogenation bottle was placed 0.2 grams of 5% palladium on carbon, 10 grams of 1-(2-propenyl) anthracene and 200 milliliters of hexane and the bottle flushed three times with hydrogen. Hydrogen was fed into the bottle at an initial pressure of 23 pounds per square inch which after 3 days had a final pressure of 19 pounds per square inch. The mixture was filtered, evaporated to an oil and chromatographed on basic alumina with hexane. The mixture was washed with a 10:1 mixture of hexane and benzene and distilled to recover a fraction of pure isopropyl anthracene having a melting point of 36°-36.5° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[CH:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].Br[C:21]1[S:22][CH:23]=[CH:24][N:25]=1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:21]2[S:22][CH:23]=[CH:24][N:25]=2)=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: C#Cc1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Reactant: Brc1nccs1
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2nccs2)cc1[N+](=O)[O-]
Yield: 62.3 %

Procedure:
Prepared from (4-ethynyl-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example F2) (262 mg, 1.00 mmol) and 2-bromothiazole (0.14 mL, 1.50 mmol) according to the general procedure F. Obtained as a yellow solid (215 mg). MS (ISN) 344 [(M−H)−]; mp 137° C.
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][C:5]([C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:29])[CH2:13][O:14][C:15]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:18]=[C:17]([C:26](O)=[O:27])[CH:16]=1)=[O:6].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:63][C@H:64]([C:74]([O:76][CH3:77])=[O:75])[CH2:65][CH2:66][C:67](=[O:73])[O:68][C:69]([CH3:72])([CH3:71])[CH3:70].Cl>CN(C=O)C>[CH3:77][O:76][C:74](=[O:75])[C@@H:64]([NH:63][C:26]([C:17]1[CH:16]=[C:15]([O:14][CH2:13][C:12]([N:8]2[CH2:9][CH2:10][CH2:11][C@H:7]2[C:5](=[O:6])[NH:4][CH2:3][CH2:2][F:1])=[O:29])[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:18]=1)=[O:27])[CH2:65][CH2:66][C:67]([O:68][C:69]([CH3:71])([CH3:72])[CH3:70])=[O:73]
Reactant: COC(=O)[C@@H](N)CCC(=O)OC(C)(C)C
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NCCF)n(-c2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NCCF)n(-c2ccccc2)n1
Reaction time: 24 h

Procedure:
To a solution of 950 mg 5-[2-((S)-2-(2-Fluoro-ethylcarbamoyl)-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 15 ml DMF were added 0.39 ml DIPEA, 893 mg HATU and 596 mg H-Glu(OtBu)-OMe hydrochloride. After stirring for 24 h the solution was concentrated, taken up with dichloromethane and subsequently extracted with aqueous LiCl (4%), 0.1 M HCl and saturated NaHCO3. The crude product obtained after evaporation of the solvent was used in the subsequent reaction. Yield: 1.3 g.
Reaction SMILES: [CH:1]1[C:6]([F:7])=[CH:5][C:4]([F:8])=[CH:3][C:2]=1[CH2:9][CH:10]([NH2:14])[C:11]([OH:13])=[O:12].S(Cl)([Cl:17])=O.[CH3:19]O>>[ClH:17].[NH2:14][CH:10]([CH2:9][C:2]1[CH:3]=[C:4]([F:8])[CH:5]=[C:6]([F:7])[CH:1]=1)[C:11]([O:13][CH3:19])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: CO
Reactant: NC(Cc1cc(F)cc(F)c1)C(=O)O
Product: COC(=O)C(N)Cc1cc(F)cc(F)c1
Product: Cl
Temperature: 25 °C
Yield: 98 %

Procedure:
To a stirred suspension of DL-3,5-difluorophenylalanine (3.00 g, 14.9 mmol) in anhydrous methanol (30 mL) was added dropwise thionyl chloride (1.64 mL, 22.5 mmol) at 0° C. The resulting solution was refluxed for 18 hours, cooled to ambient temperature and concentrated in vacuo to dryness. The residue was triturated with diethyl ether to give methyl 2-amino-3-(3,5-difluorophenyl)propanoate hydrochloride as a colorless crystalline solid (3.68 g, 98%): 1H NMR (300 MHz, CD3OD) δ 6.93-6.84 (m, 3H), 4.34 (dd, J=7.4, 6.3 Hz, 1H), 3.78 (s, 3H), 3.30-3.09 (m, 2H).
Reaction SMILES: [Cl-].C([Al+][CH2:5][CH3:6])C.[CH2:7](Cl)Cl.CS(O[C@H]([C:17]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]C)([OH:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])C)(=O)=O>P(=O)(O)(O)O.C(OCC)(=O)C>[CH3:7][C@@H:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:5][CH3:6])[C:17](=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CC[Al+]CC
Reactant: CCCCCCCCC(O)(CCCCCCCC)[C@H](C)OS(C)(=O)=O
Reactant: ClCCl
Agent: O=P(O)(O)O
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: CCCCCCCCC(=O)[C@@H](C)CCCCCCCC
Temperature: 0 °C
Yield: 90 %

Procedure:
After 0.63 ml (0.63 mmol) of diethylaluminum chloride (hexane 1M solution) were added to a dried methylene chloride (3 ml) solution of 89.7 mg (0.24 mmol) of (S)-2-methanesulfonyloxy-3-octyl-3-undecanol (unrefined) at -78° C. under stirring, and stirred for two and a half hours at -78° C., the temperature was raised to 0° C. over an hour and a half. The reaction was stopped with three drops of phosphoric acid buffer solution (pH 7). The resultant suspension was diluted with ethyl acetate, dried with anhydrous sodium sulfate, filtered and concentrated. The oily residue was separated and refined by the use of silica gel column chromatography (hexane/ethyl acetate=35/1) to obtain (S)-10-methyl-9-octadecanone as a colorless oily substance (60.5 mg, yield 90%).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]([CH3:12])[C:9]2[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[CH:7]=[CH:6][C:5]=2[C:4]=1[C:23]([C:25]1[N:29](COCC[Si](C)(C)C)[C:28]2[CH:38]=[CH:39][C:40]([C:42]#[N:43])=[CH:41][C:27]=2[N:26]=1)=[O:24])[CH3:2].C(C1C=C(C)C2N(S(C3C=CC(C)=CC=3)(=O)=O)C=CC=2C=1C(C1N(COCC[Si](C)(C)C)C2C=C(C#N)C=CC=2N=1)=O)C.C[Si](C)(C)[C:89]([F:92])([F:91])[F:90].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(N)CN>C1COCC1.CCOC(C)=O>[CH2:1]([C:3]1[C:4]([C:23]([C:25]2[NH:29][C:28]3[CH:38]=[CH:39][C:40]([C:42]#[N:43])=[CH:41][C:27]=3[N:26]=2)([OH:24])[C:89]([F:92])([F:91])[F:90])=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][CH:7]=[CH:6]2)[CH3:2]
Reactant: CCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(=O)c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(=O)c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Agent: [F-]
Solvent: NCCN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1cc(C)c2[nH]ccc2c1C(O)(c1nc2cc(C#N)ccc2[nH]1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of a mixture of 2-(5-ethyl-7-methyl-1-tosyl-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and 2-(5-ethyl-7-methyl-1-tosyl-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (400 mg, 0.653 mmol) and trimethyl(trifluoromethyl)silane (0.204 mL, 1.30 mmol) in THF (1 mL) was added dropwise TBAF in THF (1M, 1.95 mL, 1.95 mmol) at 0° C., and then the mixture was stirred at room temperature for 0.5 hr. To the mixture were added ethylenediamine (0.441 mL, 6.53 mmol) and TBAF in THF (1M, 6.53 mL, 6.53 mmol), and then the mixture was stirred at 60° C. for 77 h. The reaction mixture was cooled to room temperature. The reaction mixture was diluted with EtOAc and successively washed by 5% aq. NaHCO3, H2O and brine, dried over Na2SO4, and filtered. After concentration the residue was purified by silica gel flash chromatography [heptanes/(30% EtOAc in CH2Cl2)=44/55] to give the title compound. 1H NMR (400 MHz, ACETONITRILE-d3 with about 5 μL TFA) δ ppm 9.25 (br. s., 1H), 8.10 (s, 1H), 7.67 (d, J=8.30 Hz, 1H), 7.61 (dd, J=1.30, 8.30 Hz, 1H), 7.04 (t, J=3.00 Hz, 1H), 6.97 (s, 1H), 6.02 (br. s., 1H), 5.32 (br. s., 1H), 2.92-3.04 (m, 1H), 2.51-2.59 (m, 1H), 2.50 (d, J=0.76 Hz, 3H), 1.12 (t, J=7.33 Hz, 3H). HRMS calcd. for C21H17F3N4O (M+H)+ 399.1427. found 399.1420.
Reaction SMILES: N=C=N.ON1C2C=CC=CC=2N=N1.[CH3:14][N:15]1[C:24]2[C:19](=[CH:20][C:21]([O:25][CH2:26][CH2:27][CH2:28][N:29]([CH2:37][CH2:38][NH:39][CH3:40])[CH2:30][C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]1=[O:41].[O:42]1[C:46]2[C:47]([C:51](O)=[O:52])=[CH:48][CH:49]=[CH:50][C:45]=2[CH2:44][CH2:43]1.C(OC(=O)C)C.[ClH:60]>C(OCC)(=O)C.C1COCC1.C(#N)C>[ClH:60].[ClH:60].[CH3:40][N:39]([CH2:38][CH2:37][N:29]([CH2:28][CH2:27][CH2:26][O:25][C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][CH:22]=1)[N:15]([CH3:14])[C:16](=[O:41])[CH:17]=[CH:18]2)[CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1)[C:51]([C:47]1[C:46]2[O:42][CH2:43][CH2:44][C:45]=2[CH:50]=[CH:49][CH:48]=1)=[O:52]
Reactant: CNCCN(CCCOc1ccc2c(ccc(=O)n2C)c1)Cc1ccncc1
Reactant: O=C(O)c1cccc2c1OCC2
Agent: Cl
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(CCN(CCCOc1ccc2c(ccc(=O)n2C)c1)Cc1ccncc1)C(=O)c1cccc2c1OCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
PS-Carbodiimide resin(1.3 g) and 1-hydroxy benzotriazole (HOBt) (230 mg) were added to acetonitrile and THF solution (4 ml+6 ml) of 1-methyl-6-{3-[(2-methylamino ethyl)pyridin-4-ylmethylamino]propoxy}-1H-quinolin-2-one(304 mg) and 2,3-dihydrobenzofuran-7-carboxylic acid(164 mg). The mixture was stirred at room temperature overnight. After the reaction mixture was filtrated and condensed under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: methanol=1:0→10:1). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution(0.35 ml) was added to an ethyl acetate solution of the residue. The precipitated insoluble matter was separated, washed with ethyl acetate, and dried to give the title compound(324.2 mg) as a white powder.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:22]([O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH2:32])[CH:27]=1)[CH3:23].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:22]([O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:17](=[O:18])[CH2:16][O:15][C:14]2[CH:13]=[CH:12][C:11]([C:1]34[CH2:10][CH:5]5[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]5)[CH2:8]3)[CH2:2]4)=[CH:21][CH:20]=2)[CH:27]=1)[CH3:23]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)c1
Reaction time: 8 h
Yield: 89.7 %

Procedure:
To a mixture of [4-(1-adamantyl)phenoxy]acetic acid (143.2 mg, 0.5 mmol), 3-aminobenzoic acid ethyl ester (123.9 mg, 0.5 mmol), N-(3-dimethylaminopropyl)-N′-ethyl carbodiimide HCl (EDC) (143.8 mg, 0.75 mmol) and 1-hydroxybenzotriazole (HOBt) (101.4 mg, 0.75 mmol) in DMF (6 mL) was added N,N-diisopropylethylamine, redistilled (DIPEA) (97.0 mg, 0.13 mL, 0.75 mmol). The mixture wag stirred overnight, and then partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (n-Hexane:Ethyl acetate:MeOH=6:3:1) to give 3-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-benzoic acid ethyl ester as a white solid (194.4 mg, 89.7% yield).