Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([OH:12])[CH:6]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=[C:7]([O:12][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc(O)cc(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 177.3 %

Procedure:
A mixture of (3,5-dihydroxy-phenyl)-acetic acid methyl ester (from Aldrich, 70 g, 0.385 mol), benzylbromide (137 mL, 1.16 mol), potassium carbonate (160 g, 1.16 mol) and DMF (1.5 L) under N2 was mechanically stirred at room temperature overnight. The resulting reaction mixture was poured into a mixture of 1.5 L of ice-water with stirring. The precipitate was obtained by filtration and washed with heptane successively to remove benzyl bromide to give the title compounds (123.7 g) as a brown solid which was air dried for the next reaction. 1H-NMR(CDCl3): δ 3.60 (s, 2H), 3.71(s,3H), 5.05 (s, 4H), 6.60 (s, 3H), 7.35-7.50 (m, 10H); Calcd for C23H22O4 (M+H) 363.15, Found 363.
Reaction SMILES: [Br-].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:32](Cl)(=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]2[O:2][C:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:12][C:4]=2[CH:5]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(O)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: O=C(Cl)c1ccccc1
Agent: [Br-]
Product: O=[N+]([O-])c1ccc2oc(-c3ccccc3)cc2c1
Yield: 80.4 %

Procedure:
39 g (78 mmol) of (2-hydroxy-5-nitrophenyl) methyltriphenylphosphonium bromide and 18 ml (156 mmol) of benzoyl chloride are treated under conditions analogous to those of step 1 of Example 1. 15 g of product are obtained. Melting point: 159° C.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][NH2:4].[ClH:7].[C:8](=[NH:13])(OCC)[CH3:9]>C(O)C>[ClH:7].[F:1][C:2]([F:6])([F:5])[CH2:3][NH:4][C:8](=[NH:13])[CH3:9]
Reactant: CCOC(C)=N
Reactant: NCC(F)(F)F
Agent: Cl
Solvent: CCO
Product: CC(=N)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 2,2,2-trifluoroethylamine (3 ml), ethyl acetimidate hydrochloride (4.8 g) and ethanol (12 ml) was stirred at room temperature for 90 minutes, and then stirred overnight at 80° C. The reaction mixture was concentrated under reduced pressure to obtain the title compound (6.66 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:46])[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([NH:24][C:25]3[N:26]=[CH:27][C:28]4[N:34]([CH3:35])[C:33](=[O:36])[C:32]([F:38])([F:37])[CH2:31][N:30]([CH:39]5[CH2:43][CH2:42][CH2:41][CH2:40]5)[C:29]=4[N:44]=3)=[CH:18][C:17]=2[F:45])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.ClCCl>ClCCl>[CH:39]1([N:30]2[CH2:31][C:32]([F:38])([F:37])[C:33](=[O:36])[N:34]([CH3:35])[C:28]3[CH:27]=[N:26][C:25]([NH:24][C:19]4[C:20]([O:22][CH3:23])=[CH:21][C:16]([C:15]([NH:14][CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[O:46])=[C:17]([F:45])[CH:18]=4)=[N:44][C:29]2=3)[CH2:40][CH2:41][CH2:42][CH2:43]1
Reactant: COc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)NC2CCNCC2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
To a solution of 0.071 g (0.11 mmole) of 4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-benzoyl-amino]-piperidin-1-carboxylic acid tert-butyl ester (I-177) and 3 mL of dichloromethane was added 6 mL of trifluoroacetic acid-dichloromethane (1:1). The mixture was stirred at room temperature for 18 hours, and then concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with methanol-dichloromethane (gradient, 0:100-25:75) to give 0.050 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-N-piperidin-4-yl-benzamide (I-178).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH:15]=[O:16])=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2].Br[CH2:19][C:20]1[C:21]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:22]=2[S:23][CH:24]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20]2[C:21]3[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:22]=3[S:23][CH:24]=2)[C:8]2[C:13]([C:14]=1[CH:15]=[O:16])=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: Fc1ccc2scc(CBr)c2c1
Reactant: CCOC(=O)c1[nH]c2ccc(F)cc2c1C=O
Product: CCOC(=O)c1c(C=O)c2cc(F)ccc2n1Cc1csc2ccc(F)cc12

Procedure:
Using general procedure B, 5-fluoro-3-formyl-1H-indole-2-carboxylic acid ethyl ester was coupled with 3-bromomethyl-5-fluoro-benzo[b]thiophene (Lit. 18) to give 5-fluoro-1-(5-fluoro-benzo[b]thiophen-3-ylmethyl)-3-formyl-1H-indole-2-carboxylic acid ethyl ester as white solid. MS: 400.1 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[C:29]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])=[CH:28][CH:27]=[C:26]([F:37])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[C:14](I)[N:13]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:10]2=[N:11][CH:12]=1)=[O:5].[CH3:38][N:39]([CH3:43])[CH2:40][C:41]#[CH:42]>[Cu]I.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>[CH3:38][N:39]([CH3:43])[CH2:40][C:41]#[C:42][C:14]1[N:13]([S:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[C:10]2=[N:11][CH:12]=[C:7]([NH:6][C:4](=[O:5])[C:3]3[C:26]([F:37])=[CH:27][CH:28]=[C:29]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:32])=[O:33])[C:2]=3[F:1])[CH:8]=[C:9]2[CH:15]=1
Reactant: C#CCN(C)C
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)cc(I)n3S(=O)(=O)c2ccccc2)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)cc(C#CCN(C)C)n3S(=O)(=O)c2ccccc2)c1F
Temperature: 60 °C
Yield: 64 %

Procedure:
A solution of 2,6-difluoro-N-(2-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (91 mg, 0.14 mmol, 1.0 eq.), N,N-dimethylprop-2-yn-1-amine (2.7 eq.), CuI (0.2 eq.) and PdCl2(PPh3)2 (0.2 eq.) in 1:1 TEA/THF (8 mL) was degassed under argon for 10 minutes. The mixture was heated to 60° C. for 16 hours, and the volatiles were removed under reduced pressure. The resulting residue was diluted with EtOAc and water and filtered through GF/F paper. The layers were separated. The organic layer was dried (MgSO4) and purified by silica gel chromatography (eluting with 100% EtOAc) to afford N-(2-(3-(dimethylamino)prop-1-ynyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide as an oil (54 mg, 64%).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH2:18])=[C:4]2[C:19](O[C:22](=[O:23])[C:3]=12)=[O:20].[CH2:24]([NH2:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CO>[NH2:18][C:5]1[C:4]2[C:19](=[O:20])[N:32]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:22](=[O:23])[C:3]=2[C:2]([NH2:1])=[C:15]2[C:14](=[O:16])[C:13]3[C:8]([C:7](=[O:17])[C:6]=12)=[CH:9][CH:10]=[CH:11][CH:12]=3
Reactant: Nc1c2c(=O)oc(=O)c2c(N)c2c(=O)c3ccccc3c(=O)c12
Reactant: CCCCCCCCN
Solvent: CO
Product: CCCCCCCCn1c(=O)c2c(N)c3c(=O)c4ccccc4c(=O)c3c(N)c2c1=O

Procedure:
(B-Cyan-4) Synthesis of 4,11-diamino-2-n-octyl-1H-naphth[2,3-f] isoindole-1,3,5,10(2H)-tetrone cyan dye. To 120 grams of 15 percent oleum (fuming sulfuric acid having 15 percent sulfur trioxide), 10.0 grams of 1,4-diamino anthraquinone-2,3-dinitrile were added at 30° C. and the mixture stirred for two hours. This reaction mixture was poured into 1,000 grams of ice water and the precipitates were filtered. The wet precipitates were added to 400 grams of cooled water and dissolved by the addition of sodium hydroxide, followed by adjusting pH to 12.5. The temperature was now raised to 100° C. and maintained for two hours. After that period, 20 grams of 50 percent sulfuric acid were added to the mixture and heating was continued for another one hour. The precipitate of 1,4-diamino anthraquinone-2,3-dicarboxylic acid anhydride thus obtained was collected by filtration, washed with water and dried. 3.2 Grams of 1,4-diamino anthraquinone-2,3-dicarboxylic acid anhydride (0.01 mole), 3.2 grams (0.025 mole) of n-octyl amine, and 50 milliliters of methanol were added to a 100 milliliter round-bottom flask equipped with a condenser and the contents refluxed for a period of 24 hours. The reaction mixture was cooled, filtered and washed twice with methanol (100 milliliters each time). The reaction product was dried in air to obtain 4,11-diamino-2-n-octyl-1H-naphth[2,3-f] isoindole-1,3,5,10(2H)-tetrone cyan dye.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11](=O)[CH2:10][CH2:9][C:4]2([O:8][CH2:7][CH2:6][O:5]2)[CH2:3]1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][CH:11]2[CH2:10][CH2:9][C:4]3([O:8][CH2:7][CH2:6][O:5]3)[CH2:3][C:2]2([CH3:13])[CH3:1])=[CH:18][CH:17]=1
Reactant: COc1ccc(CN)cc1
Reactant: CC1(C)CC2(CCC1=O)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CNC2CCC3(CC2(C)C)OCCO3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
7,7-Dimethyl-1,4-dioxaspiro[4.5]decan-8-one (2.8 g, 15.217 mmol, 1 eq) and 4-methoxy-benzylamine (2.08 g, 15.217 mmol, 1 eq) were dissolved in dichloromethane (100 ml) and stirred for 3 h at RT. Na(OAc)3BH (9.67 g, 45.65 mmol, 3 eq) was added in portions at 0° C., and stirring was carried out for 20 h at RT. The reaction solution was diluted with dichloromethane (100 ml), washed with water (100 ml) and sat. NaCl solution (100 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (Alox neutral, 10% ethyl acetate in hexane). Yield: 46% (2.13 g, 6.98 mmol).
Reaction SMILES: [CH3:1][C:2](=[CH:7][CH2:8][C:9]#[CH:10])[CH:3]([OH:6])[C:4]#[CH:5].N1C=CC=CC=1.[CH:17]([CH:20]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:21](Cl)=[O:22])([CH3:19])[CH3:18]>C1C=CC=CC=1>[CH:17]([CH:20]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:21]([O:6][CH:3]([C:2]([CH3:1])=[CH:7][CH2:8][C:9]#[CH:10])[C:4]#[CH:5])=[O:22])([CH3:19])[CH3:18]
Reactant: C#CCC=C(C)C(O)C#C
Reactant: CC(C)C(C(=O)Cl)c1ccc(Cl)cc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: C#CCC=C(C)C(C#C)OC(=O)C(c1ccc(Cl)cc1)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
1.40 Grams (11.4 millimoles) of 4-methylocta-4-ene-1,7-diyne-3-ol is dissolved in 20 ml of a dry benzene, followed by cooling in ice water. Thereafter, 1.80 g (22.8 millimoles) of pyridine is rapidly added thereto at a time and immediately a solution of 2.64 g (11.4 millimoles) of α-isopropyl-4-chlorophenylacetyl chloride in 10 ml of dry benzene is dropwise added thereto for about 30 minutes with stirring. After completion of the addition, stirring is continued for 3 hours at room temperature to complete the reaction. The reaction mixture is poured into 20 g of ice water and the layers are separated. The aqueous layer is extracted with two 10-ml portions of ether. The organic layers obtained is combined and washed once with a 10% hydrochloric acid and three times with water, followed by drying over anhydrous sodium sulfate. After the solvent is removed under reduced pressure, the oily substance obtained is mixed with almost the same amount of pyridine. The mixture is adsorbed to 100 g of silica gel column and purified by developing with a mixed solvent (18:1:1) of carbon tetrachloride:n-hexane:ether. Thus, 3.19 g of the objective ester is obtained as a pale yellow oily substance (85.1% of theoretical yield). nD23.0 1.5233.
Reaction SMILES: CS/[C:3](/[NH:12][C:13](=O)OC(C)(C)C)=[N:4]\[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[Cl:20][C:21]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:22]=1[CH2:23][O:24][C:25]1[CH:26]=[C:27]([NH2:32])C(N)=[CH:29][CH:30]=1>CO.C(O)(=O)C>[Cl:20][C:21]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:22]=1[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:13]2[N:12]=[C:3]([NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10])[NH:32][C:27]=2[CH:26]=1
Reactant: Nc1ccc(OCc2c(Cl)cccc2Cl)cc1N
Reactant: CS/C(=N\C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1nc2ccc(OCc3c(Cl)cccc3Cl)cc2[nH]1
Yield: 67.8 %

Procedure:
add 615 mg of bis(1,1-dimethylethyl) [(Z)-(methylsulphanyl)methylylidene]biscarbamate to a solution of 600 mg of 4-[(2,6-dichlorobenzyl)oxy]benzene-1,2-diamine in a mixture of 30 cm3 of methanol and 127 mg of pure acetic acid. The mixture is refluxed for about 3 hours then concentrated under reduced pressure (0.2 kPa). The residue is taken up in 20 cm3 of a saturated aqueous solution of potassium carbonate and the mixture is extracted three times with 100 cm3 of dichloromethane. The combined organic phases are dried over magnesium sulphate, then filtered and evaporated under reduced pressure. After purification of the residue by silica-column flash chromatography [eluent: dichloromethane/methanol (98/2 by volume)], we obtain 586 mg of 1,1-dimethylethyl {6-[(2,6-dichlorobenzyl)oxy]-1H-benzimidazol-2-yl}carbamate in the form of an orange resin, which has the following characteristics:
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([O:6][CH3:7])=[O:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:47][C:48]1[CH:49]=[C:50](O)[CH:51]=[CH:52][CH:53]=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1>[Br:47][C:48]1[CH:53]=[C:52]([O:1][CH2:2][C@@H:3]([C:4]([O:6][CH3:7])=[O:5])[NH:8][C:9]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:51]=[CH:50][CH:49]=1
Reactant: Oc1cccc(Br)c1
Reactant: COC(=O)[C@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](COc1cccc(Br)c1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
Methyl (2S)-3-hydroxy-2-(triphenylmethylamino)propanoate (5.2 g , 14.4 mmol, 1 equiv; prepared according to Baldwin, J. E.; Spivey, A. C.; Schofield, C. J.; Sweeney, J. B. Tetrahedron 1993, 49, 6309) and triphenylphosphine (4.2 g, 15.8 mmol, 1.1 equiv) were dissolved in toluene (25 mL) at rt (room temperature). The reaction mixture was stirred for 30 min followed by addition of 3-bromo phenol (3.2 g, 18.7 mmol, 1.3 equiv) and DEAD (diethylazo dicarboxylate; 2.8 g, 15.8 mmol, 1.1 equiv) at rt. The reaction mixture was stirred at ambient temperature for 15 h while a white precipitate formed. The precipitate was filtered off and the solvents of the filtrate were removed in vacuuo. The remaining crude product was purified by flash chromatography (cyclohexanes/ethyl acetate 95:5) to give a white solid (5.2 g, 67.3%). 1H NMR (CDCl3, 200 MHz) δ 7.65-7.55 (m, 4 H); 7.41-7.12 (m, 9H); 6.70 (d, 2H); 4.20 (dd, 1H); 4.00 (dd, 1H); 3.75-3.60 (m, 1H); 3.73 (s, 3H); 2.87 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2[C:25](=[O:40])[N:26]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:27]([CH2:30][CH:31]([OH:33])[CH3:32])[C:28]=2[CH3:29])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.[C:41]([N:51]([CH2:53][C:54](O)=[O:55])[CH3:52])([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:44]([O:43][C:41]([N:51]([CH3:52])[CH2:53][C:54]([O:33][C@H:31]([CH3:32])[CH2:30][N:27]1[C:28]([CH3:29])=[C:24]([C:22](=[O:23])[NH:21][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]3[C:18]4[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=4)[N:12]=[CH:11][CH:10]=3)=[C:2]([F:1])[CH:3]=2)[C:25](=[O:40])[N:26]1[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:55])=[O:42])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CN(CC(=O)O)C(=O)OCc1ccccc1
Reactant: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(CC(C)O)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)OC(=O)CN(C)C(=O)OCc5ccccc5)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To a mixture of (R)—N-(3-fluoro-4-(7-methoxyquinolin-4-yloxy)-phenyl-1-(2-hydroxypropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (2.0 g, 3.68 mmol), N-Cbz-sarcosine (1.643 g, 7.36 mmol) and DMAP (0.9 g, 7.36 mmol, Aladdin) in 15 mL of CH2Cl2 was added EDC solid (1.06 g, 5.52 mmol, Aladdin) in portions at 0° C. After stirring at 0° C. for 2 hrs, the reaction mixture was warmed up to room temperature, and continued to stir at rt overnight. The mixture was diluted with 100 mL of CH2Cl2 and the resulted solution was washed with 0.1 N HCl (10 mL×2), followed by saturated NaHCO3 solution (20 mL×2) and water (20 mL). The aqueous phase was extracted with EtOAc (50 mL×3), and the combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc/hexane=2/1) to give the desired compound as a pale yellow solid (2.31 g, 84%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>CN(C)C=O>[C:27]([O:26][C:25]([N:24]([CH2:23][C:10]1[CH:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:12]([S:13]([C:16]2[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=2)[O:22][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])(=[O:14])=[O:15])[CH:11]=1)[CH3:32])=[O:31])([CH3:28])([CH3:29])[CH3:30]
Reactant: CN(Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(O)c2)c1)C(=O)OC(C)(C)C
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2F)c1
Reaction time: 3 h

Procedure:
tert-Butyl ((5-(2-fluorophenyl)-1-((3-hydroxyphenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 1h (100 mg, 0.22 mmol) was dissolved in 20 mL of N,N-dimethylformamide, followed by addition of cesium carbonate (146 mg, 0.45 mmol) and ethyl bromoacetate (102 mg, 0.67 mmol), and then the reaction solution was stirred for 3 h. The reaction solution was concentrated under reduced pressure, 50 mL of water were added, and the reaction solution was extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product ethyl 2-(3-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(2-fluorophenyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)acetate 9a (84 mg, a brown oil) in 70% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:9]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.N1C=CC=CC=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH:9]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:4][C:5]([NH:8][S:35]([CH3:34])(=[O:37])=[O:36])=[N:6][CH:7]=1
Reactant: Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)cc2)c(Cl)cn1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)cc2)c(Cl)cn1
Reaction time: 96 h
Yield: 38 %

Procedure:
To a methylene chloride solution (10.0 ml) of [5-chloro-4-[(2,5-difluorophenyl)-(4-fluorophenylsulfonyl)methyl]pyridin-2-yl]amine (114 mg, 0.276 mmol) was added pyridine (440 μl, 5.5 mmol). To the resulting mixture was added methanesulfonyl chloride (addition of 77 μl once a day for 3 days, 230 μl in total, 3.0 mmol). The resulting mixture was stirred for 4 days in total. The reaction mixture was concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=2:1), followed by crystallization in ether to give the title compound (51 mg, 38%) as a white solid.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>N1C=CC=CC=1>[C:24]1([CH3:25])[CH:26]=[CH:27][C:21]([S:18]([O:17][CH2:16][CH2:15][CH2:14][CH2:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:12][CH:11]=2)(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCc1ccc(CCCCO)cc1
Solvent: c1ccncc1
Product: CCCCCCc1ccc(CCCCOS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 26.7 %

Procedure:
4-(4-Hexylphenyl)butanol (5.0 g) was dissolved in 20 ml of pyridine and 4.88 g of tosyl chloride was added thereto. The reaction mixture was left standing at room temperature overnight. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with 2 N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and saturated brine in order and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:7) to give 2.21 g of 4-(4-hexylphenyl)butyl p-toluenesulfonate as a colorless, oily substance.
Reaction SMILES: O.[NH2:2][C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:10])[NH2:9].[NH:14]([C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])[C@H:15]([C:26](ON1C(=O)CCC1=O)=[O:27])[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1>CN(C=O)C>[NH:14]([C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])[C@H:15]([C:26]([NH:2][C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:9])[NH2:10])=[O:27])[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)ON1C(=O)CCC1=O)OCc1ccccc1
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: N=C(N)NCCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
2.00 equivalents water and 1 equivalent Arg (Mw=174.2) were mixed with DMF and stirred at room temperature until a solution was obtained. 1.03 equivalents of Z-Trp-OSu (Mw=435.45; purity=98%) were dissolved in DMF and poured in the arginine solution. Stirring was then continued at room temperature for at least 5 hours. After checking the termination of the reaction by HPLC, the reaction mixture was precipitated by adding slowly cold acetonitrile (0±5° C.) and kept at this temperature for at least 30 minutes before filtration. The precipitate was washed 3 times with a mixture of CH3CN/IPE(Isopropylether) (1/1) and then 2 times with IPE. The solid was then dried in vacuo at 45° C. A white solid was finally obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.ClC1C=C(C[C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[O:18])C=CN=1>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:17](=[O:18])[CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=2)=[CH:20][CH:21]=1
Reactant: O=C(Cc1ccnc(Cl)c1)c1ccc(F)cc1
Reactant: Cc1ccnc(F)c1
Product: O=C(Cc1ccnc(F)c1)c1ccc(F)cc1

Procedure:
21b was prepared from 2-fluoro-4-methylpyridine (13.9 g; 125 mmol) using the method described in the synthesis of 21a.