Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Br:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][CH:15]=1.C([Li])CCC.CCCCCC.C(Cl)(=O)C.O>O1CCCC1>[Br:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[CH:2]=[C:3]([O:13][C:14]1[C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][CH:15]=1)[CH:4]=[CH:5]2
Reactant: COc1cc2nccc(Oc3ccc4cc(Br)ccc4c3Br)c2cc1OC
Agent: [Li]CCCC
Solvent: CC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2nccc(Oc3ccc4cc(Br)ccc4c3)c2cc1OC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 51.4 %

Procedure:
4-[(1,6-Dibromo-2-naphthyl)oxy]-6,7-dimethoxyquinoline (65 mg) was dissolved in tetrahydrofuran (3 ml) to prepare a solution which was then cooled to −78° C. A 1.59 M n-butyllithium/hexane solution (0.4 ml) was added thereto, and the mixture was stirred at −78° C. for 20 min. Acetyl chloride (0.2 ml) was added to the reaction solution, and the mixture was stirred at room temperature overnight. Further, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (28 mg, yield 51%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:26])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:19]([CH2:20][N:21]([CH3:23])[CH3:22])=[N:18][N:17]=[C:16]1[CH2:24]O.CS(Cl)(=O)=O.[CH2:32]([NH2:35])[CH:33]=[CH2:34]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:26])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:19]([CH2:20][N:21]([CH3:23])[CH3:22])=[N:18][N:17]=[C:16]1[CH2:24][NH:35][CH2:32][CH:33]=[CH2:34]
Reactant: CN(C)Cc1nnc(CO)n1-c1ccccc1C(=O)c1ccccc1Cl
Reactant: C=CCN
Agent: CS(=O)(=O)Cl
Product: C=CCNCc1nnc(CN(C)C)n1-c1ccccc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 47, 2'-chloro-2-[3-(hydroxymethyl)-5-[(dimethylamino)methyl]-4H-1,2,4-triazol-4-yl]benzophenone is treated first with methanesulfonyl chloride followed by allylamine to give 2'-chloro-2-[3-[(allylamino)methyl]-5-[(dimethylamino)methyl]-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11](Br)[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:9]1[C:25]([N:27]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:28])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][S:35]([O-:37])=[O:36].[Na+].CS(C)=O.CNCCNC>ClCCl.O>[CH2:1]([N:8]1[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([S:35]([CH3:34])(=[O:37])=[O:36])[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:9]1[C:25]([N:27]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:28])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CC(C)(C)C)C(=O)c1c(-c2ccc(Cl)cc2)c(Br)c(C(F)(F)F)n1Cc1ccccc1
Reactant: CS(=O)[O-]
Agent: CNCCNC
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: CN(CC(C)(C)C)C(=O)c1c(-c2ccc(Cl)cc2)c(S(C)(=O)=O)c(C(F)(F)F)n1Cc1ccccc1
Temperature: 140 °C
Yield: 50 %

Procedure:
1-Benzyl-4-bromo-3-(4-chlorophenyl)-N-(2,2-dimethylpropyl)-N-methyl-5-(trifluoromethyl)pyrrole-2-carboxamide (100 mg, 0.18 mmol) followed by SODIUM METHANESULFINATE (4.0 equiv., 0.078 g, 0.74 mmol), COPPER(I) TRIFLATE BENZENE COMPLEX (0.1 equiv., 0.010 g, 0.018 mmol), DIMETHYL SULFOXIDE (0.6 mL) and N,N′-DIMETHYLETHYLENEDIAMINE (0.2 equiv., 0.003 g, 0.037 mmol) added to reactivial. Flushed with Nitrogen and heated at 140° C. for 18 hours (overnight). Black solid residue formed. Work Up: Diluted with 50 ml Dichloromethane and 100 ml Water then filtered to remove solids. Dichloromethane/Water shaken and separated. Aqueous extracted 2×50 ml Dichloromethane. Organics combined and filtered through hydrophobic frit, then reduced under vacuum. Purification: Purified via Preparative HPLC over 2 injections using 50-95% acetonitrile/water (0.1% Formic Acid) over 15 minutes collecting at 254 nm. Pure fractions combined and reduced under vacuum to yield product as 51.4 mg (0.09 mmol) beige solid.
Reaction SMILES: [OH-].[Li+].[O:3]=[C:4]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[CH2:7][CH2:6][N:5]1[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C@@H:24]([C:38]([O:40]CC)=[O:39])[CH2:25][C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[C:29]([NH2:36])=[C:28]([Cl:37])[CH:27]=2)=[O:22])[CH2:17][CH2:16]1.C1COCC1.Cl>O>[O:3]=[C:4]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[CH2:7][CH2:6][N:5]1[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C@@H:24]([C:38]([OH:40])=[O:39])[CH2:25][C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:33])[F:34])[C:29]([NH2:36])=[C:28]([Cl:37])[CH:27]=2)=[O:22])[CH2:17][CH2:16]1
Reactant: CCOC(=O)[C@@H](Cc1cc(Cl)c(N)c(C(F)(F)F)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 804 mg (33.5 mmol) lithium hydroxide dissolved in 80 ml of water was added dropwise to a mixture of 13.0 g (22.3 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-ethoxycarbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-benzo[d]-[1,3]diazepin-3-yl)-piperidine-1-carboxylate and 120 ml THF. The mixture was stirred for 3 hours at ambient temperature, freed from THF under reduced pressure, combined with 150 ml of water, and acidified by the addition of aqueous 4-molar hydrochloric acid solution. Then the aqueous phase was extracted with 300 ml of ethyl acetate, the organic phase was dried and evaporated down under reduced pressure. The residue was recrystallised from 50 ml isopropanol.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[C:9]([O:10][C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([Br:18])=[CH:13][C:12]=2[Cl:19])=[CH:8][C:7]([CH3:20])=[N:6][CH:5]=1.O.O.[OH-].[Li+].Cl>O1CCOCC1.ClCCl>[Br:18][C:14]1[C:15]([Cl:17])=[CH:16][C:11]([O:10][C:9]2[C:4]([C:3]([OH:21])=[O:2])=[CH:5][N:6]=[C:7]([CH3:20])[CH:8]=2)=[C:12]([Cl:19])[CH:13]=1
Reactant: COC(=O)c1cnc(C)cc1Oc1cc(Cl)c(Br)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cc(Oc2cc(Cl)c(Br)cc2Cl)c(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.8 %

Procedure:
To a solution of 185 mg (0.473 mmol) 4-(4-bromo-2,5-dichloro-phenoxy)-6-methyl-nicotinic acid methyl ester in 3 mL dioxane was added 3 mL water and 30 mg (0.710 mmol) lithium hydroxide monohydrate. The reaction mixture was stirred for 4 hours at room temperature, poured on 30 mL 1M aqueous hydrochloric acid and 30 mL dichloromethane and the layers were separated. The aqueous layer was extracted with 30 mL dichloromethane and the combined organic layers were washed with 30 mL brine, dried over magnesium sulfate, filtered and concentrated under vacuum to afford 178 mg (100%) of the title compound as a colorless solid. MS (ESI): m/z=377.912 [M+H]+.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH2:5]([O:12][C:13]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(C)[C:14](O)=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O.C1(C)C=CC=CC=1>[CH2:5]([O:12][CH:13]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:14][C:1]([Cl:4])=[O:2])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Cl)Cl
Reactant: CC(OCc1ccccc1)(Oc1ccccc1)C(=O)O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)CC(OCc1ccccc1)Oc1ccccc1
Temperature: 80 °C

Procedure:
A three-liter, round-bottom flask was obtained and fitted with an overhead stirrer, a thermocouple, a temperature controller, an addition funnel with a cold trap overhead, and a line leading to a phosgene cyclinder. Also it was fitted with an exit line to a nitrogen/vacuum source, a heating mantle, and a catch basin. The exit line went to a condenser and a caustic scrubber. Into this flask was placed 183.2 g (0.67 mole) benzyloxyphenoxypropionic acid, 900 ml of toluene, and 2.9 g (0.04 mole) dimethylformamide. The phosgene cyclinder was turned on and 75 ml (1.05 moles) phosgene was allowed to accumulate in the funnel. The reactants were heated to 80° C. with stirring while the phosgene was added thereto. During the course of the phosgene addition, solids formed in the flask; however, ultimately they went into solution. After the phosgene addition, nitrogen was slowly added to the flask. The reaction was stopped, and a vacuum pulled on the flask to boil off the excess phosgene. The flask was then placed under a nitrogen atmosphere. The solvent was stripped off, leaving 233.2 g of yellow solids, which were identified by suitable analytical techniques as being the subject compound.
Reaction SMILES: C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+].[CH3:13][O:14][N:15]=[C:16]([C:36](=[O:39])[CH2:37][Br:38])[C:17]([NH:19][CH:20]1[C:34](=[O:35])[N:22]2[CH:23]([C:31]([OH:33])=[O:32])[CH:24](OC(=O)C)[CH2:25][S:26][C@H:21]12)=[O:18].Cl>CN(C)C=O.O1CCCC1>[CH3:13][O:14][N:15]=[C:16]([C:36](=[O:39])[CH2:37][Br:38])[C:17]([NH:19][CH:20]1[C:34](=[O:35])[N:22]2[C:23]([C:31]([OH:33])=[O:32])=[CH:24][CH2:25][S:26][C@H:21]12)=[O:18]
Reactant: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)C(OC(C)=O)CS[C@H]12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Temperature: 28 °C
Yield: 51.7 %

Procedure:
Acetic anhydride (0.2 ml.), sodium acetate (0.12 g.) and N,N-dimethylformamide (2 drops) were added to a solution of 7-(2-methoxyimino-3-oxo-4-bromobutyramido)3-acetoxy-cepham-4-carboxylic acid (syn isomer, 200 mg.) in dry tetrahydrofuran (2 ml.), and stirred at 28° C. for an hour. 6 N Hydrochloric acid (0.2 ml.) was added to the resultant solution and the solvent was evaporated in vacuo. Water was added to the residue. The precipitates were collected by filtration, washed with water and dried to give a mixture (0.09 g.) of 7-(2-methoxyimino-3-oxo-4-bromobutyramido)-3-cephem-4-carboxylic acid (syn isomer) and 7-(2-methoxyimino-3-oxo-4-chlorobutyramido)-3-cephem-3-carboxylic acid (syn isomer). [7-(2-methoxyimino-3-oxo-4-bromobutyramido)-3-cephem-4-carboxylic acid (syn isomer)]
Reaction SMILES: C([N:4]1[CH:8]([C:9](=[O:11])[CH3:10])[CH2:7][CH2:6][C:5]1=[O:12])(=O)C.[C:13](OCC)(=[O:15])[CH3:14]>C(O)(=O)C.[Pt](=O)=O>[C:13]([O:11][CH:9]([CH:8]1[NH:4][C:5](=[O:12])[CH2:6][CH2:7]1)[CH3:10])(=[O:15])[CH3:14]
Reactant: CC(=O)C1CCC(=O)N1C(C)=O
Reactant: CCOC(C)=O
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CC(=O)OC(C)C1CCC(=O)N1
Reaction time: 17 h
Yield: 46 %

Procedure:
1,5-Diacetylpyrrolidin-2-one (10.6 g) is hydrogenated at 875 psi at 100° C. over 0.5 g of platinum dioxide in 50 ml of ethyl acetate. The conversion after about 17 hours is about 40 percent. The mixture is freed of the catalyst and solvent and is then hydrogenated again in 50 ml of acetic acid over 1.0 g of platinum dioxide for about 19 hours. The conversion is now about 50 percent by nuclear magnetic resonance analysis. This product mixture is distilled at 0.15 mm Hg to give 5.35 g (50 percent), of unreacted 1,5-diacetylpyrrolidin-2-one. The residue upon bulb-to-bulb distillation (140° C. bath temperature, 0.15 mm) gives 4.85 g (46 percent yield, 92 percent selectivity) of 5-(1-acetoxyethyl)pyrrolidin-2-one, containing a very small amount of 1,5-diacetylpyrrolidin-2-one.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH2:29]([NH2:32])[CH2:30][CH3:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:29]([NH:32][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:27])([F:26])[F:28])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13])[CH2:30][CH3:31]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 78.1 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid propylamide (86 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylic acid (100 mg), propylamine (16 mg), HBTU (111 mg), and DIEA (64 uL). LC/MS: m/z 450.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.38 (bs, 1H), 8.42 (s, 1H), 8.07 (s, 1H), 7.90 (s, 1H), 7.75 (d, 1H), 7.72 (d, 1H), 7.46 (d, 1H), 7.34 (d, 1H), 3.62 (bs, 3H), 3.22 (q, 2H), 1.60-1.45 (m, 2H), 0.90 (t, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.[CH2:9]([NH:11][CH2:12][C:13]([CH2:19][NH:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[N:24][N:25]2[C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)([OH:18])[C:14]([F:17])([F:16])[F:15])[CH3:10]>>[CH2:9]([N:11]([CH2:12][C:13]([CH2:19][NH:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[N:24][N:25]2[C:30]1[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=1)([OH:18])[C:14]([F:16])([F:17])[F:15])[C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)=[O:8])[CH3:10]
Reactant: CCNCC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Reactant: O=C(O)c1ccsc1
Product: CCN(CC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1ccsc1

Procedure:
Prepared similarly to Example 1 from 3-thiophenecarboxylic acid and 3-(ethylamino)-1,1,1-trifluoro-2-({[1-(4-fluorophenyl)-1H-indazol-4-yl]amino}methyl)-2-propanol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29]2)[CH2:25][CH2:24]1)=[O:22].[CH3:37][S:38]([NH2:41])(=[O:40])=[O:39]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:41][S:38]([CH3:37])(=[O:40])=[O:39])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29]2)[CH2:25][CH2:24]1)=[O:22]
Reactant: Cc1ccccc1Nc1c(C(=O)N2CCC3(C=Cc4ccccc43)CC2)cnc2c(C(=O)O)cnn12
Reactant: CS(N)(=O)=O
Product: Cc1ccccc1Nc1c(C(=O)N2CCC3(C=Cc4ccccc43)CC2)cnc2c(C(=O)NS(C)(=O)=O)cnn12
Yield: 7.5 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-methylphenyl)amino-6-(spiro[inden-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.080 g, 0.167 mmol) obtained in step 2 and methanesulfonamide (0.080 g, 0.834 mmol), the title compound (0.007 g, 7.5%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[C:12]2[N:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][C:36](O)=[O:37])[CH:30]=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.C(=O)(O)[O-].[Na+]>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[C:12]2[N:17]=[CH:16][C:15]([CH2:18][NH:19][C:36](=[O:37])[CH2:35][C:31]3[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1cccnc1
Reactant: NCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1cccnc1)NCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 90.4 %

Procedure:
The [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine (30 mg, 0.073 mmol) obtained in Example 63, 3-pyridylacetic acid hydrochloride (16 mg, 0.092 mmol), 4-(dimethylamino)pyridine (5 mg, 0.04 mmol) and triethylamine (0.025 ml, 0.18 mmol) were dissolved in dichloromethane (5 ml). To the resulting solution was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (17 mg, 0.089 mmol) at room temperature. The resulting mixture was stirred at room temperature for 14 hours. To the reaction mixture was added a saturated aqueous solution (0.1 ml) of sodium bicarbonate. The residue obtained by concentrating the reaction mixture under reduced pressure was subjected to flash silica gel chromatography. The fraction obtained from the dichloromethane:methanol=30:1 elute was concentrated under reduced pressure to afford a white solid. The resulting solid was washed with ether to give the title compound (35 mg, 0.066 mmol, 90%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:22]([N+:23]([O-])=O)=[CH:21][CH:20]=[C:19]([Cl:26])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[C:11]2[O:17][CH3:18].[Sn](Cl)Cl.[OH-].[Na+].ClCCl>CO>[NH2:23][C:22]1[C:2]([Cl:1])=[C:3]([C:19]([Cl:26])=[CH:20][CH:21]=1)[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[C:11]2[O:17][CH3:18]
Reactant: COc1cc(C)nc2c(OCc3c(Cl)ccc([N+](=O)[O-])c3Cl)cccc12
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C)nc2c(OCc3c(Cl)ccc(N)c3Cl)cccc12
Yield: 71.8 %

Procedure:
To a suspension of 8-(2,6-dichloro-3-nitrobenzyloxy)-4-methoxy-2-methylquinoline (1.75 g) in methanol (17 ml) was added tin (II) chloride (3.37 g) at ambient temperature. The mixture was refluxed for 1 hour. After cooling, the mixture was adjusted to pH 10 with 1 N sodium hydroxide solution. To this mixture was added dichloromethane (50 ml) and the precipitate was removed by filtration. The filtrate was extracted with dichloromethane twice. The organic layer was washed with water and brine. After dried over magnesium sulfate, the solvent was removed in vacuo to give 8-(3-amino-2,6-dichlorobenzyloxy)-4-methoxy-2-methylquinoline (1.16 g) as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1>CN(C)C=O>[C:14]([Si:11]([CH3:13])([CH3:12])[O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc2[nH]ccc2c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]ccc2c1

Procedure:
A solution of 5-hydroxyindole 1-3 (5.50 g, 41.3 mmol, 1 equiv), tert-butyldimethylsilyl chloride (7.47 g, 49.6 mmol, 1.20 equiv), and imidazole (7.03 g, 103 mmol, 2.50 equiv) in N,N-dimethylformamide (20 mL) was stirred at 23° C. for 20 h. The reaction mixture was concentrated, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water (3×), then dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (40% dichloromethane in hexanes, then 60% dichloromethane in hexanes) to give 5-(tert-butyl-dimethyl-silanyloxy)-1H-indole as a colorless oil which solidified upon standing. 1H NMR (400 MHz, CDCl3) δ 8.00 (br s, 1H), 7.22 (d, 1H, J=8.7 Hz), 7.17 (t, 1H, J=2.8 Hz), 7.06 (d, 1H, J=2.3 Hz), 6.76 (dd, 1H, J=8.6, 2.3 Hz), 6.44 (m, 1H), 1.00 (s, 9H), 0.19 (s, 6H).
Reaction SMILES: [C:1]([C:5]1[CH:28]=[CH:27][C:8]([C:9]([NH:11][C@H:12]([C:23]([O:25][CH3:26])=[O:24])[CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC(C)C.[CH2:44]([O:51][C:52]1[CH:61]=[CH:60][C:55]([C:56]([NH:58][NH2:59])=[O:57])=[CH:54][CH:53]=1)[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C@@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:59][NH:58][C:56](=[O:57])[C:55]3[CH:60]=[CH:61][C:52]([O:51][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:53][CH:54]=3)=[O:19])=[CH:21][CH:22]=2)[C:23]([O:25][CH3:26])=[O:24])=[O:10])=[CH:27][CH:28]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCOc1ccc(C(=O)NN)cc1
Reactant: COC(=O)[C@H](Cc1ccc(C(=O)O)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCCCCCCOc1ccc(C(=O)NNC(=O)c2ccc(C[C@H](NC(=O)c3ccc(C(C)(C)C)cc3)C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a stirring solution of (S)-4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoic acid INT-1 (260 mg, 0.68 mmol) in THF (5 mL) were added 4-methylmorpholine (0.15 mL, 1.36 mmol) and isobutyl carbonochloridate (0.09 mL, 0.71 mmol). After stirring at room temperature for 2 h, 4-(heptyloxy)benzohydrazide (187 mg, 0.75 mmol) was added and stirring continued for another 2 h. The reaction mixture was poured onto NaHCO3 (50 mL) and extracted with DCM (3×20 mL). The combined organics were dried over MgSO4 and evaporated. The crude product was purified by column chromatography (100% EA in iso-hexanes) to afford 297 mg (71%) of (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(2-(4-(heptyloxy)benzoyl)hydrazinecarbonyl)phenyl)propanoate INT-3 as an off-white foam. LCMS-ESI (m/z) calculated for C36H45N3O6: 615.8 found 616.0 [M+H]+, tR=2.89 min. (Method 4).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5].N1C=CN=C1.[Si:14](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[C:27]([Si:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[O:1][CH2:2][C@H:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H](C)CO
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)[C@@H](C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl (S)-(+)-3-hydroxy-2-methylpropionate (1.06 g; 8.99 mmol) (Aldrich) was dissolved in dichloromethane (10 mL, dried over molecular sieves). Imidazole (0.85 g; 12.41 mmol) (Aldrich) and tert-butyl-diphenylsilyl chloride (2.30 mL; 8.85 mmol) (Aldrich) were added and the mixture was stirred at ambient temperature for 3 hours. The reaction was diluted with additional dichloromethane, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield methyl (S)-(+)-3-(tert-butyl-diphenyl-silanyloxy)-2-methyl-propionate as an oil. (Yield 3.17 g; 98.8%).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]([CH3:16])([CH2:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[CH2:7][OH:8])=[O:4].[Br:17]N1C(=O)CCC1=O>CN(C)C=O>[CH3:1][O:2][C:3]([NH:5][C:6]([CH3:16])([CH2:9][CH2:10][C:11]1[S:12][C:13]([Br:17])=[CH:14][CH:15]=1)[CH2:7][OH:8])=[O:4]
Reactant: COC(=O)NC(C)(CO)CCc1cccs1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: COC(=O)NC(C)(CO)CCc1ccc(Br)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.2 %

Procedure:
2-Methoxycarbonylamino-2-methyl-4-(2-thienyl)butan-1-ol (11.7 g, 48.0 mmol) obtained in Example 1 (d) was dissolved in dimethylformamide (120 ml), and N-bromosuccinimide (10.8 g, 60.8 mmol) was added thereto in an ice bath followed by stirring for 4 hours at room temperature under a nitrogen atmosphere. The reaction mixture was poured into ice-cold 10% hydrochloric acid (300 ml), and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was concentrated in vacuo, and the residue was purified by flash chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=4:1-1:3) to afford the title compound (12.4 g, 80% yield) as a pale yellow oil.