Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH3:25])([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:25][C:11]1([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:22])[F:23])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(Oc2ccccc2C(F)(F)F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(Oc2ccccc2C(F)(F)F)CCNCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 4-methyl-4-(2-trifluoromethylphenoxy)piperidine-1-carboxylic acid tert-butyl ester (0.025 g, 0.070 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL). The resulting mixture was stirred at ambient temperature for 24 hours and then quenched with saturated aqueous solution of Na2CO3 (5 mL). The organic phase was washed with water (10 mL), saturated NaCl (10 mL), dried over MgSO4 and then concentrated in vacuo. The crude title compound was obtained and used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[C:16]([F:22])[C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:23]1([NH2:26])[CH2:25][CH2:24]1.O>C(O)C>[Cl:1][C:2]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[C:16]([F:22])[C:3]=1[C:4]([C:6](=[CH:12][NH:26][CH:23]1[CH2:25][CH2:24]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: NC1CC1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(F)cc(Cl)c(F)c1Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1c(F)cc(Cl)c(F)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
15.6 g of ethyl 2-(2,4-dichloro-3,6-difluorobenzoyl)-3-ethoxy-acrylate are dissolved in 50 ml of ethanol, and 2.75 g of cyclopropylamine are added dropwise, while cooling. The mixture is stirred at room temperature for 1 hour, 50 ml of water are added, while cooling with ice, and the precipitate is filtered off with suction, rinsed with ethanol/H2O (1:1) and dried. 14.1 g of ethyl 2-(2,4-dichloro-3,6-difluorobenzoyl)-3-cyclopropylamino-acrylate of melting point 106°-107° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16](O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:21])=O.[OH-].[Na+]>>[Cl:21][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(-c2ccc(Cl)cc2)nc2ccccc12
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccc(-c2cc(Cl)c3ccccc3n2)cc1
Temperature: 25 °C

Procedure:
A mixture of 21.6 g of 2-(4-chlorophenyl)-4-quinolinol and 46 ml of phosphorus oxychloride was heated under reflux for 45 min., cooled to room temperature, and poured carefully onto 750 ml of ice water. This mixture was neutralized with 146 ml of 50% sodium hydroxide and extracted with 600 ml of methylene chloride in three portions. The extracts were combined, filtered through 15 g of Florisil, and concentrated in vacuo to leave 19.35 g of the above-named compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([NH:13][C@@H:14]([C:29](=[O:31])[NH2:30])[CH2:15][CH2:16][C:17]([NH:19][C@H:20]([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])=[O:18])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:32](O)(=[O:36])[CH2:33][CH2:34][CH3:35]>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([NH:13][C@@H:14]([C:29](=[O:31])[NH2:30])[CH2:15][CH2:16][C:17]([NH:19][C@H:20]([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:32](=[O:36])[CH2:33][CH2:34][CH3:35])=[O:18])=[O:12])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](CCC(=O)N[C@@H](CCCCN)C(=O)O)C(N)=O
Reactant: CCCC(=O)O
Product: CCCC(=O)NCCCC[C@H](NC(=O)CC[C@@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(N)=O)C(=O)O

Procedure:
In the same manner as described in Example 1-(2), 1.50 g of Nα -(t-butyloxycarbonyl-alanyl-D-isoglutaminyl)-lysine and 1.01 g of an N-hydroxy-5-norbornene-2,3-dicarboxyimide active ester of butyric acid were reacted to obtain 1.57 g of Nα -(t-butyloxycarbonyl-alanyl-D-isoglutaminyl)-Nε -butyryl-lysine; melting point: 84°-87° C. (decomp.); [α]D25 -12.2° (c 0.9, methanol).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=2)[NH:7][CH:6]=1>[Pd].C(O)C>[NH2:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH3:17]
Reactant: CN(C)CCc1c[nH]c2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CCO
Product: CN(C)CCc1c[nH]c2ccc(N)cc12
Reaction time: 6 h
Yield: 99.2 %

Procedure:
A mixture of 3-(2-dimethylaminoethyl)-5-nitroindole (1.85 g, 7.93 mmol) and 10% palladium on carbon (0.40 g, 20% by weight) in absolute ethanol (30 mL) was shaken under a hydrogen atmosphere (3 atm) for 6 hours. The resulting mixture was filtered through Celite®, and the celite pad was washed generously with absolute ethanol. The combined filtrates were evaporated under reduced pressure to afford the title compound (1.60 g, 7.87 mmol, 99%) as a clear, slightly dark, hygroscopic oil: IR (CHCl3) 3480, 1610, 1585, 1460, 1335 cm-1 ; 1H NMR (CDCl3) δ8.10 (br m, NH), 7.12 (d, J=8.5 Hz, 1H), 6.91 (d, J=2.3 Hz, 1H), 6.88 (d, J=2.2 Hz, 1H), 6.64 (dd, J=2.2 and 8.5 Hz, 1H), 2.89-2.84 (m, 2H), 2.64-2.58 (m, 2H), 2.34 (s, 6H); --C NMR (CDCl3) δ139.1, 131.2, 128.3, 122.2, 113.1, 112.9, 111.7, 103.8, 60.3, 45.4, 23.7; LRMS (m/z, relative intensity) 203 (9, M+), 158 (2), 145 (6), 83 (66), 58 (100). HRMS calculated for C12H17N3 203.1424, found 203.1418. Anal. calcd for C12H17N3.1/2 H2O: C, 67.89; H, 8.55; N, 19.79. Found: C, 67.71; H, 8.60; N, 19.41.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:17][CH2:18][C:19]1[CH:24]=[C:23]([F:25])[C:22]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[C:21]([F:31])[CH:20]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]([NH:17][CH2:18][C:19]2[CH:20]=[C:21]([F:31])[C:22]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[C:23]([F:25])[CH:24]=2)=[O:13])=[CH:14][CH:15]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)Nc1c(F)cc(CN)cc1F
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(OCC(=O)NCc2cc(F)c(NS(C)(=O)=O)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To an N,N-dimethylformamide (DMF) (10 ml) solution of (4-tert-butylphenoxy)acetic acid (330 mg, 1.50 mmol) and N-[4-(aminomethyl)-2,6-difluorophenyl]methanesulfonamide hydrochloride (491 mg, 1.80 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (431 mg, 2.25 mmol), 4-(dimethylamino)pyridine (DMAP) (55 mg, 0.45 mmol) and triethylamine (607 mg, 6.0 mmol) were added and the mixture was stirred for 15 hours at ambient temperature. The reaction mixture was then quenched with saturated aqueous solution of sodium bicarbonate and then crude products were extracted with methylene dichloride The organic layer was then washed with brine, dried over sodium sulfate. After filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give a residue, which was applied to an amino bound silica gel chromatography column and eluted with methylene dichloride/methanol=10/1 to furnish the title compound. Further, the title compound was recrystallized from ethyl acetate and hexane to furnish 199 mg (31% yield) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([OH:8])=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:17](Br)[CH3:18]>CC(C)=O.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH:17]([CH3:18])[O:9][C:4]=2[CH:3]=1
Reactant: CC(Br)Br
Reactant: Oc1ccc(Br)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC1Oc2ccc(Br)cc2O1

Procedure:
To a solution of 4-bromobenzene-1,2-diol (500 mg, 2.65 mmol) in acetone (4 mL) was added cesium carbonate (1.90 g, 5.82 mmol) and 1,1-dibromoethane (1.09 g, 5.82 mmol). The mixture was microwaved to 120° C. for 3 h. After cooling, the reaction mixture was diluted with EtOAc, extracted with H2O, brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give the product. 1H-NMR: 400 MHz, (CDCl3) δ 6.93-6.89 (m, 2H), 6.63 (d, J=8 Hz, 1H), 6.27 (q, J=9.6 Hz, 1H), 1.67 (d, J=4.4 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]([CH2:12][OH:13])[CH2:9][CH2:8][CH2:7]2.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]([CH:12]=[O:13])[CH2:9][CH2:8][CH2:7]2
Reactant: Cc1cccc2c1C(CO)CCC2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1cccc2c1C(C=O)CCC2
Reaction time: 2 h

Procedure:
(8-Methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-methanol (0.03 g, 0.17 mmol) was dissolved in dichloromethane (0.5 mL). To the solution was then added 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H)-one, also known as Dess-Martin periodinane (0.087 g, 0.20 mmol). The reaction mixture was stirred for 2 hrs then partitioned with an aqueous saturated solution of thiosulfate and dichloromethane. The organic layer was washed with an aqueous saturated solution of thiosulfate, an aqueous saturated solution of sodium bicarbonate, brine, dried with Na2SO4, filtered and the solvent evaporated in vacuo to yield 8-methyl-1,2,3,4-tetrahydro-naphthalene-1-carbaldehyde as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](O)(=O)[C:9]1C(=CC=C[CH:17]=1)C(O)=O.[BH4-].[Na+].[OH-].[Na+]>CC(C)=O.O1CCCC1>[CH:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:17])[CH3:8]
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccccc1C(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC(C)Nc1ccccc1
Temperature: 10 °C

Procedure:
N-isopropylaniline is synthesized as follows: A mixture of 233 g. (2.5 moles) of aniline, 5 l. of tetrahydrofuran and 250 ml. of acetone is stirred at 24°-25° C. under nitrogen for 2 hours and coooled to 10° C., 675 g. (4.06 moles) of phthalic acid is added rapidly, the resulting suspension is stirred at 10° C. under nitrogen, and 100 g. (2.64 moles) of powdered 98% sodium borohydride is added over a period of 25 minutes with stirring under nitrogen, during the course of which the temperature rises to 28° C. The reaction mixture is stirred under nitrogen at 28° C. for 15 minutes and at 60°-61° C. for 2 hours, cooled to 25° C. and siphoned portionwise into 2.0 l. of 20% sodium hydroxide solution at a rate such that the temperature does not exceed 20° C. The organic phase is separated, 1.0 kg. of anhydrous potassium carbonate is added, the mixture is stirred at 20°-25° C. for 20 minutes, the solid is removed by filtration and washed twice with 250 ml. portions of tetrahydrofuran, the washings are combined with the filtrate, and the tetrahydrofuran is distilled at 20-100 mm. Hg. and a maximum temperature of 55° C. The resulting residual oil is fractionally distilled through a 35 cm. Vigreux column to obtain the 97.4% pure product (295 g. (84.4%)). B.p. 62°-64° C./1 mm. Hg.
Reaction SMILES: [OH:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4](=[O:16])[C:3]=1[C:17]([NH:19][CH2:20][C:21]([O:23]CC)=[O:22])=[O:18].CI.[C:28](=O)([O-])[O-].[Na+].[Na+].Cl>CN(C)C=O>[OH:1][C:2]1[N:7]([CH3:28])[C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4](=[O:16])[C:3]=1[C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CNC(=O)c1c(O)[nH]c(=O)n(Cc2ccccc2)c1=O
Agent: Cl
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(O)c(C(=O)NCC(=O)O)c(=O)n(Cc2ccccc2)c1=O
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 28.2 %

Procedure:
A mixture of ethyl N-{[6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycinate (295 mg, 0.85 mmoles), methyl iodide (62 uL, 1.0 mmoles) and sodium carbonate (320 mg, 3.0 mmoles) in dimethylformamide (5.0 mL) was stirred under argon at 100° C. for 2.5 hours. The mixture was cooled, poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The ester was hydrolysed by stirring in a mixture of ethanol (5 mL) and 1 molar sodium hydroxide solution (4 mL) for 4 hours. The mixture was acidified and extracted with ethyl acetate. Purification by preparative HPLC (acetonitrile-water—0.1% TFA, 20-100%) and crystallization from ether-hexane gave the title compound (80 mg, 28%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.11 (br. s., 1 H), 10.09 (br. s., 1 H), 7.28-7.36 (m, 4 H), 7.19-7.29 (m, 1 H), 5.01 (s, 2 H), 4.14 (d, J=5.81 Hz, 2 H), 3.21 (s, 3 H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:20][N:21]1[C:25](=[O:26])[C:24](Br)=[C:23]([Br:28])[C:22]1=[O:29].Cl>O1CCCC1>[Br:28][C:23]1[C:22](=[O:29])[N:21]([CH3:20])[C:25](=[O:26])[C:24]=1[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CN1C(=O)C(Br)=C(Br)C1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1C(=O)C(Br)=C(c2c[nH]c3ccccc23)C1=O
Reaction time: 0.75 h

Procedure:
A solution containing 1.445 g of indole, dissolved in 29 ml of dry tetrahydrofuran, is held between −20 and −10° C. under argon, and then 26 ml of LiHMDS (1M in hexane) are added, dropwise, over the course of 15 minutes. After 45 minutes at −10° C., the solution is diluted with 15 ml of additional tetrahydrofuran, and a solution containing 2 g of N-methyl-2,3-dibromomaleimide dissolved in 17 ml of tetrahydrofuran is added dropwise over the course of 30 minutes. After 15 minutes at −10° C. and 15 minutes at 0° C., the reaction is stopped by the addition, at 0° C., of 50 ml of 0.3N hydrochloric acid solution. The reaction mixture is extracted with ethyl acetate, and the organic phases are washed with saturated NaCl solution, dried over MgSO4 and then evaporated under reduced pressure. The desired product is precipitated using methanol.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1.[BrH:28].S(=O)(=O)(O)O>C(O)(=O)C>[Br:28][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCCCCCCO)cc1
Reactant: Br
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1
Temperature: 0 °C

Procedure:
A mixture of 16 g. of 4-(16-hydroxyhexadecylamino)benzoic acid and 150 g. of 30-32% hydrogen bromide in acetic acid is treated with 30 ml. of concentrated sulfuric acid, stirred under reflux for 8 hours, poured into ice-water, and filtered. The product is washed with water, dried and recrystallized from ether-petroleum ether to yield 4-(16-bromohexadecylamino)benzoic acid as a white, crystalline solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:14][C:15](=[O:34])[NH:16][C@@H:17]([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[C:35]([O:39][C:40](=[O:80])[CH2:41][N:42]([CH2:72][C:73](=[O:79])[O:74][C:75]([CH3:78])([CH3:77])[CH3:76])[C:43](=[O:71])[CH2:44][N:45]1[CH:49]=[CH:48][N:47]=[C:46]1[CH2:50][N:51]([CH2:60][C:61]1[CH:66]=[CH:65][C:64]([O:67][CH2:68][C:69]#[CH:70])=[CH:63][CH:62]=1)[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][C:57](O)=[O:58])([CH3:38])([CH3:37])[CH3:36].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>ClCCCl>[C:75]([O:74][C:73](=[O:79])[CH2:72][N:42]([CH2:41][C:40](=[O:80])[O:39][C:35]([CH3:38])([CH3:37])[CH3:36])[C:43](=[O:71])[CH2:44][N:45]1[CH:49]=[CH:48][N:47]=[C:46]1[CH2:50][N:51]([CH2:60][C:61]1[CH:66]=[CH:65][C:64]([O:67][CH2:68][C:69]#[CH:70])=[CH:63][CH:62]=1)[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][C:57](=[O:58])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[NH:14][C:15](=[O:34])[NH:16][C@H:17]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])([CH3:78])([CH3:76])[CH3:77]
Reactant: C#CCOc1ccc(CN(CCCCCC(=O)O)Cc2nccn2CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)cc1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCN)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#CCOc1ccc(CN(CCCCCC(=O)NCCCC[C@H](NC(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)Cc2nccn2CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)cc1
Yield: 76.7 %

Procedure:
A solution of (S)-di-tert-butyl 2-(3-((S)-6-amino-1-(tert-butoxy)-1-oxohexan-2-yl)ureido)pentanedioate (0.742 g, 1.52 mmol), 6-(((1-(2-(bis(2-(tert-butoxy)-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)(4-(prop-2-yn-1-yloxy)benzyl)amino)hexanoic acid (0.244 g, 0.38 mmol), EDCI (0.290 g, 1.52 mmol), HOBt (0.051 g, 0.38 mmol) and DIPEA (0.40 mL) in DCE (5.0 mL) was stirred at room temperature for 4 h. The solvent was evaporated to give a residue, which was purified by Biotage SP4 eluting with DCM/MeOH to give (14S,18S)-tri-tert-butyl 1-(1-(2-(bis(2-(tert-butoxy)-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)-8,16-dioxo-2-(4-(prop-2-yn-1-yloxy)benzyl)-2,9,15,17-tetraazaicosane-14,18,20-tricarboxylate (0.3237 g, 77%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.64 (t, J=5.4 Hz, 1H), 7.17 (d, J=8.4 Hz, 2H), 6.93 (s, 1H), 6.87 (d, J=8.8 Hz, 2H), 6.74 (s, 1H), 6.26 (d, J=8.4 Hz, 1H), 6.22 (d, J=8.0 Hz, 1H), 5.02 (s, 2H), 4.72 (d, J=2.0 Hz, 2H), 4.24 (s, 2H), 4.03-3.89 (m, 4H), 3.51 (t, J=2.0 Hz, 1H), 3.48 (s, 2H), 3.39 (s, 2H), 2.95 (q, J=6.3 Hz, 2H), 2.22-2.15 (m, 4H), 1.94 (t, J=7.4 Hz, 2H), 1.85-1.04 (m, 34H); MS (ESI), 1111.6 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:12]([OH:15])[C:13]#[CH:14].C(N(CC)CC)C>C([O-])(O)=O.[Na+].[Cu]I>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([C:14]#[C:13][CH2:12][OH:15])[CH:3]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: C#CCO
Agent: [Cu]I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: OCC#Cc1cnc2ccccc2c1
Yield: 88.3 %

Procedure:
To a dry 2-L three-necked flask previously purged with nitrogen was charged 3-bromoquinoline (118.77 g, 570 mmol), propargyl alcohol (71.9 g, 1.28 mol, 2.25 equiv), triethylamine (1500 mL), copper(I) iodide (3.62, 19 mmol, 0.033 equiv) and dichlorobis(triphenyl-phosphine) palladium(II) (6.67 g, 9.5 mmol). The mixture which resulted was mechanically stirred and heated to reflux for 3 hours. Upon cooling the triethylamine solution was mechanically stirred and heated to reflux for 3 hours. Upon cooling, the triethylamine solution was filtered and washed with triethylamine (300 mL). The filtrate was then concentrated under reduced pressure to provide solids which were suspended in 5% aq. NaHCO3 (600 mL) and extracted with ethyl acetate (1×600 mL). The solids which were left after filtration were treated in the same manner. The combined ethyl acetate extracts were stirred with silica gel (15 g) and decolorizing carbon (3 g) before being filtered through a bed of celite. The filtrate was concentrated under reduced pressure to provide a tan colored solid which was vacuum oven dried at 45° C. overnight. The 3-(3-quinolyl)-2-propyn-1-ol was isolated in 92.14 g (88.3% yield). MS(CI): (M+H)+ at 184; 1H NMR (300 MHz CDCl3) δ: 4.56 (s, 2H), 4.70 (s, broad, 1H), 7.57 (m, 1H), 7.70 (m, 1H), 7.77 (d, 1H), 8.10 (d, 1H), 8.10 (s, 1H), 9.05 (s, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:17]=[CH:16][C:15](I)=[C:14]([CH3:19])[N:13]=2)[C:10]=1[CH3:11])=[O:5])C.[CH2:20](OC(C1C=NN(C2C=CC(Br)=CN=2)C=1C)=O)[CH3:21]>>[CH2:20]([C:15]1[CH:16]=[CH:17][C:12]([N:9]2[C:10]([CH3:11])=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]2)=[N:13][C:14]=1[CH3:19])[CH3:21]
Reactant: CCOC(=O)c1cnn(-c2ccc(I)c(C)n2)c1C
Reactant: CCOC(=O)c1cnn(-c2ccc(Br)cn2)c1C
Product: CCc1ccc(-n2ncc(C(=O)O)c2C)nc1C

Procedure:
1-(5-Iodo-6-methylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester described n Reference Example 31 was used in place of 1-(5-bromopyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester in Reference Example 28, and reacted and treated in a similar manner to give the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].[F:12][C:13]([F:17])([F:16])[CH2:14]I>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:14][C:13]([F:17])([F:16])[F:12])[N:6]=[C:5]2[I:11]
Reactant: FC(F)(F)CI
Reactant: Fc1ccc2[nH]nc(I)c2c1
Product: Fc1ccc2c(c1)c(I)nn2CC(F)(F)F
Yield: 46 %

Procedure:
The title compound was prepared in 46% yield from 5-fluoro-3-iodo-indazole and 1,1,1-trifluoro-2-iodoethane according to the general procedure for Preparation 10A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 4.91-4.97 (2H, m), 7.17 (1H, dd, J=2.0, 8.0 Hz), 7.30 (1H, td, J=2.0, 8.4 Hz), 7.38 (1H, dd, J=3.6, 9.2 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([CH:31]=1)[O:7][CH2:8][C:9]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=2[O:26][CH3:27])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:30])=[CH:12][C:13]([CH3:29])([CH3:28])[NH:14]2.[CH3:33][N:34]([CH3:38])[C:35](Cl)=[O:36]>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:33][N:34]([CH3:38])[C:35]([O:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[C:9]([CH2:8][O:7][C:6]3[CH:31]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:32])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:28])([CH3:29])[CH:12]=[C:11]3[CH3:30])=[C:20]([O:26][CH3:27])[CH:21]=1)=[O:36]
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Reactant: CN(C)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1cc(OC(=O)N(C)C)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Temperature: 100 °C
Reaction time: 3 h
Yield: 29 %

Procedure:
5-(5-Fluoro-2-methylphenoxymethyl)-6-(4-hydroxy-2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 5-1, 25 mg, 0.058 mmol) was dissolved in pyridine (1 mL), N,N-dimethylcarbamoyl chloride (6.9 μL, 0.075 mmol) was added thereto, and then the mixture was stirred at 100° C. for 3 hours. N,N-Dimethylcarbamoyl chloride (3.0 μL, 0.033 mmol) was added to the reaction mixture and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL). The mixture was washed with 0.2 N aqueous HCl solution (75 mL), water (50 mL), and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (1st time: hexane-ethyl acetate, 2nd time: toluene-ethyl acetate) to give the titled compound (8.5 mg) as a colorless amorphous product. (Yield 29%)