Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:22])[CH:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)C(NS(=O)(=O)c1ccc(Br)cc1)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(C(=O)OC(C)(C)C)C(C)C)cc2)cc1
Temperature: 25 °C

Procedure:
A solution of the 4-bromobenzenesulfonamide derivative (1 g, 2.64 mmol) prepared in Step (a) and 4-methoxybenzeneboronic acid (0.48 g, 3.17 mmol) in toluene (10 mL) was treated with tetrakis(triphenylphosphine)palladium(0) (0.15 g, 0.1 mmol) and aqueous sodium carbonate (0.5 g/5 mL H2O), respectively. The reaction mixture was refluxed for 3 hours, then cooled to room temperature. Ethyl acetate (25 mL) and aqueous HCl (1M, 25 mL) were added, the layers separated, and the organic portion was dried (MgSO4), filtered, and the filtrate was concentrated in vacuo. The resulting solid was triturated with hexane/ethyl acetate (3:1) and was collected by filtration. Yield: 0.68 g (62%);
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH2:5][C:6]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)=O.[C:25]([CH2:27][C:28]([O:30][CH3:31])=[O:29])#[N:26]>O>[Cl:24][C:21]1[CH:20]=[C:7]2[C:6](=[CH:23][CH:22]=1)[N:5]=[C:25]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[N:26]=[C:8]2[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: COc1ccc(C(=O)c2cc(Cl)ccc2N)cc1OC
Reactant: COC(=O)CC#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: COC(=O)Cc1nc(-c2ccc(OC)c(OC)c2)c2cc(Cl)ccc2n1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 55 %

Procedure:
Powdered aluminium chloride (0.21 g) was added to a mixture of 2-amino-5-chloro-3',4'-dimethoxybenzophenone (0.23 g) and methyl cyanoacetate (5 ml), and the resulting mixture was stirred at 100° C. for 2.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with hexane/ethyl acetate (4/1, v/v) gave methyl 6-chloro-4-(3,4-dimethoxyphenyl)quinazoline-2-acetate (0.161 g, 55%) which was then recrystallized from isopropyl ether. Colorless needles. mp. 144°-145° C.
Reaction SMILES: CC1[O:3][C@H:4]([C:10]([O:12][CH3:13])=[O:11])[C@H:5]([CH2:7][CH2:8][CH3:9])[N:6]=1.[ClH:14]>CO>[ClH:14].[NH2:6][C@@H:5]([CH2:7][CH2:8][CH3:9])[C@H:4]([OH:3])[C:10]([O:12][CH3:13])=[O:11]
Reactant: CCC[C@@H]1N=C(C)O[C@@H]1C(=O)OC
Agent: Cl
Solvent: CO
Product: CCC[C@H](N)[C@H](O)C(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
Methyl (4S,5S)-2-methyl-4-propyl-4,5-dihydro-1,3-oxazole-5-carboxylate (0.2 g, 1.1 mmol), methanol (2 ml) and concentrated hydrochloric acid (0.25 ml) were mixed, and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated away under reduced pressure to obtain the title compound as a white solid (0.1 g, yield: 50%).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]3[CH2:15][CH:16]([CH2:17]O)[CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br-:19].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:17][CH:16]1[CH:6]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:14]=3[CH:13]([C:12]3[C:7]2=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:15]1
Reactant: OCC1CC2c3ccccc3C1c1ccccc12
Reactant: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCC1CC2c3ccccc3C1c1ccccc12

Procedure:
9,10-Dihydro-9,10-ethanoanthracene-11-methanol (2 gm) was combined with triphenylphosphine dibromide (5.3 gm) in carbon tetrachloride (60 ml). The mixture was heated to reflux 1 hour, filtered, and the filtrate was concentrated on a rotary evaporator. The residue was boiled in n-heptane (75 ml), filtered hot, and the filtrate cooled. The white precipitate was filtered and air dried to provide the product (mp=103-106° C.).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:19])=[C:9](OS(C(F)(F)F)(=O)=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:27][Si:28]([C:31]#[CH:32])([CH3:30])[CH3:29].CN(C)C=O>CCCCCC>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:19])=[C:9]([C:32]#[C:31][Si:28]([CH3:30])([CH3:29])[CH3:27])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccc(C(C)(C)C)cc1OS(=O)(=O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: Cc1ccc(C(C)(C)C)cc1C#C[Si](C)(C)C
Yield: 69.6 %

Procedure:
Following General Procedure D and using trifluoro-methanesulfonic acid 5-tert-butyl-2-methyl-phenyl ester (Intermediate 108, 0.28 g, 0.94 mmol), triethyl amine (3 mL), trimethylsilyl acetylene (1 mL, 7 mmol), N,N-dimethylformamide (6 mL) and dichlorobis(triphenylphosphine)palladium(11) (0.053 g, 0.076 mmol) followed by flash column chromatography over silica gel (230–400 mesh) using hexane as the eluent, the title compound (0.16 g, 69%) was obtained.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([NH:19]C(=O)C)([CH2:11][C:12]#[C:13][CH2:14][NH:15]C(=O)C)C(OCC)=O)C.[ClH:24]>C(O)(=O)C>[ClH:24].[ClH:24].[NH2:19][CH:5]([CH2:11][C:12]#[C:13][CH2:14][NH2:15])[C:4]([OH:23])=[O:3]
Reactant: CCOC(=O)C(CC#CCNC(C)=O)(NC(C)=O)C(=O)OCC
Agent: Cl
Solvent: CC(=O)O
Product: NCC#CCC(N)C(=O)O

Procedure:
Acetamido(4-acetamido-2-butynyl)-malonic acid diethyl ester (7.64 g) was dissolved in a mixture of acetic acid (140 ml) and a 6M hydrochloric acid solution (290 ml), and heated overnight at 95° C. The mixture was concentrated in vacuo. The residue was crystallized from ethanol/water yielding 2,6-diamino-4-hexynoic acid dihydrochloride as a crystalline powder (4.0 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH:7]([OH:13])[CH2:8][O:9][CH2:10][CH2:11][Cl:12])[S:5][CH:6]=1.[CH3:14][NH:15][CH3:16].[I-].[K+].Cl.Cl.C(O)C>C(O)C.C(OCC)C.O.C(OCC)(=O)C>[ClH:12].[CH3:1][C:2]1[N:3]=[C:4]([CH:7]([OH:13])[CH2:8][O:9][CH2:10][CH2:11][N:15]([CH3:16])[CH3:14])[S:5][CH:6]=1
Reactant: Cc1csc(C(O)COCCCl)n1
Reactant: CNC
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1csc(C(O)COCCN(C)C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1.2 g of 1-(4-methyl-2-thiazolyl)-2-(2-chloroethoxy)ethanol, 3 ml of a 50% aqueous dimethylamine solution, 0.45 g of potassium iodide and 20 ml of ethanol was refluxed for 3 hours. To the reaction mixture was added 3 ml of a 50% aqueous dimethylamine solution. The resulting mixture was refluxed for 3 hours. The solvent was removed by distillation under reduced pressure. To the residue thus obtained were added 30 ml of ethyl acetate and 30 ml of water. The resulting mixture was adjusted to pH 1.5 with 6N hydrochloric acid. The aqueous layer was separated and washed with 10 ml of ethyl acetate. Thereto was added 30 ml of ethyl acetate. The resulting mixture was adjusted to pH 10.5 with potassium carbonate. The organic layer was separated, washed with 10 ml of water and 10 ml of a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was dissolved in 6 ml of ethanol. To the solution were added 0.6 ml of a 5N dry hydrogen chloride-ethanol solution and 6 ml of diethyl ether. The mixture was stirred at room temperature for 1 hour. The resulting crystals were collected by filtration, washed with 2 ml of a 1:1 mixture of diethyl ether and ethanol, and dried to obtain 390 mg of 1-(4-methyl-2-thiazolyl)-2-[2-(N,N-dimethylamino)ethoxy]ethanol hydrochloride (compound No. 361).
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN.[ClH:26]>C(O)C>[ClH:26].[C:1]1([S:7]([CH2:10][CH2:11][NH2:12])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)c1ccccc1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCS(=O)(=O)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 32.3 g (0.102 mole) of 2-[2-(phenylsulfonyl)ethyl]-1H-isoindole-1,3-(2H)-dione and 11.8 g (0.2 mole) of 85% hydrazine hydrate in 500 ml of absolute ethanol was refluxed for 6 hr. The reaction mixture was cooled to room temperature, filtered and concentrated. The concentrate was dissolved in chloroform and extracted with a 5% sodium hydroxide solution. The chloroform layer was dried and evaporated to give a clear oil. The oil (the free base of the title compound) was reacted with ethereal hydrogen chloride. Recrystallization of the precipitated salt from methanol-diethyl ether gave white crystalline product (40.5% yield), m.p. 151°-154° C.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH:12]([OH:17])=[CH:13][CH:14]([CH3:16])[CH3:15].CCCCCC>CN(C1C=CN=CC=1)C.ClCCl>[S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)([O:17][CH2:12][CH2:13][C:14]([CH3:16])=[CH2:15])(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)C=CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCCCCC
Product: C=C(C)CCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 3 h
Yield: 85.3 %

Procedure:
2.32 mmol (442 mg) of tosyl chloride and 2.55 mmol (312 mg) of 4-(N,N-dimethylamino)pyridine are introduced while stirring with a magnetic stirrer into 5 ml of anhydrous dichloromethane in a glass reaction vessel which is equipped for handling under an inert atmosphere and has been carefully dried. 2.32 mmol (200 mg) of isopentenol dissolved in approx. 1 ml of dichloromethane are slowly added to this mixture through a septum using a syringe. The reaction is monitored by thin-layer chromatography on silica (silica gel 60 F-254; eluent: pentane/ethyl acetate 85/15 vol./vol.; Rf (product)=0.4 and Rf (TsCl)=0.5). After approx. 3 hours' stirring under a nitrogen atmosphere, the reaction mixture is diluted in a large volume of hexane (approx. 100 ml), resulting in the immediate formation of a white precipitate. The mixture is then filtered and the filtrate concentrated by evaporation under reduced pressure. The solution is then diluted with diethyl ether and refiltered. Once the solvent has evaporated, a yellowish oil is obtained. The product is purified by preparative chromatography through a silica column (silica gel 60; eluent: pentane/ethyl acetate 85/15). In this manner, 1.98 mmol (475 mg) of 3-methyl-3-butene-1-yl tosylate (85% isolated yield) are obtained. The compound (colorless oil) is stored at +4° C. in an anhydrous medium.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]=[N+:14]=[N-:15])[C@H:9]1[C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[C:21]([F:28])=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH2:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]=[N+:14]=[N-:15])[C@H:9]1[C:16](=[O:18])[NH:24][CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[C:20]([Cl:19])[C:21]=1[F:28])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N=[N+]=[N-])[C@H]1C(=O)O
Reactant: NCc1cccc(Cl)c1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](N=[N+]=[N-])[C@H]1C(=O)NCc1cccc(Cl)c1F
Reaction time: 20 h

Procedure:
To (2S,3R)-3-azido-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (170 mg, 0.663 mmol) in CH2Cl2 (12 mL) were added successively 3-chloro-2-fluorobenzylamine (0.092 mL, 0.730 mmol), HBTU (377 mg, 0.995 mmol) DIPEA (0.232 mL, 1.33 mmol) and stirring was continued at RT for 20 h. The reaction mixture was diluted with CH2Cl2 and the organics were washed with 1N aqueous HCl (2×), aqueous 1N NaOH 1N (2×) and brine, dried (Phase separator) and concentrated in vacuo. The crude product was purified in two steps: first by preparative HPLC (Macherey-Nagel Nucleosil 100-10 C18, 5 μm, 40×250 mm; flow: 20 mL/min; eluent: 20-100% CH3CN/H2O for 20 min, 100% CH3CN for 2 min, CH3CN and H2O containing 0.1% TFA) and subsequently by flash column chromatography on silica (EtOAc/c-hexane gradient 1:3 to 1:1) to afford the title compound as a colorless wax. TLC Rf (EtOAc/c-hexane 1:1)=0.41; MS (LC/MS): 420 [M+Na]+, 342 [MH−tBu]+, 298 [MH−Boc]+; tR (HPLC conditions b): 4.66 min.
Reaction SMILES: [C:1]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=3)[N:14]=2)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[N:33]1([CH2:38][C:39]#[N:40])[CH:37]=[N:36][CH:35]=[N:34]1.N1CCCCC1.C(OCC)(=O)C.CCCCCC>C(O)C>[C:1]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH:21]=[C:38]([N:33]4[CH:37]=[N:36][CH:35]=[N:34]4)[C:39]#[N:40])=[CH:23][CH:24]=3)[N:14]=2)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:30])[CH3:31])[CH:8]=1)(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: N#CCn1cncn1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=O)cc3)nc12
Solvent: C1CCNCC1
Solvent: CCO
Solvent: CCCCCC
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=C(C#N)n4cncn4)cc3)nc12
Yield: 43.6 %

Procedure:
To a 50 ml three necked round bottom flask, 4-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)-methyl)-5H-pyrrolo[2,3-b]pyrazine-2-ylamino)benzaldehyde (0.1 g, 0.22 mmole) and 2-(1H-1,2,4-triazol-1-yl)acetonitrile (0.0716 g, 0.66 mmole) was taken in ethanol (5 mL). To this reaction mixture, piperidine (0.2 mL) was added drop wise at RT. After completion of the addition, the reaction mass was refluxed for 16 hrs and the completion of the reaction was monitored on TLC using ethyl acetate:hexane (5:5) as a mobile phase. After completion of the reaction, ethanol was distilled out and water was added to residue. Aqueous was extracted with ethyl acetate, organic layers were combined, dried over Na2SO4, filtered and concentrated to afford crude product. The crude compound was purified using column purification by eluting the compound with 40% ethyl acetate in hexanes triturated with n-pentane, pentane layer was decanted and solid was dried under vacuum to yield 0.052 g of 3-(4-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)phenyl)-2-(1H-1,2,4-triazol-1-yl)acrylonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10]([Cl:12])([Cl:11])[C:9](=[N:13][OH:14])[CH2:8][CH:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH3:23])[C:16]=2[F:24])[NH:6]1)=[O:4].[C:25]([O:28]C(=O)C)(=[O:27])[CH3:26]>C(O)(=O)C>[CH3:1][O:2][C:3]([CH:5]1[C:10]([Cl:11])([Cl:12])/[C:9](=[N:13]/[O:14][O:28][C:25](=[O:27])[CH3:26])/[CH2:8][CH:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH3:23])[C:16]=2[F:24])[NH:6]1)=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)C1NC(c2ccc(Cl)c(OC)c2F)CC(=NO)C1(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)C1NC(c2ccc(Cl)c(OC)c2F)C/C(=N\OOC(C)=O)C1(Cl)Cl
Temperature: 80 °C
Yield: 88.5 %

Procedure:
3-Chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-chloro-4-hydroxyimino-1,4,5,6-tetrahydropyridine-2-carboxylic acid methyl ester (34, 756 mg, 2.08 mmol) was slurried in glacial acetic acid (10 mL). Acetic anhydride (241 mg, 2.36 mmol) was added dropwise at room temperature. The reaction mixture was heated at 80° C. for 2 h. The solution was concentrated under vacuum, and the residue was dissolved in CH2Cl2 (50 mL) and washed with saturated aqueous NaHCO3 solution. The extracts were washed with brine, dried (MgSO4) and evaporated to give 3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-4-[(E)-acetoxyoximino]-3-chloro-1,4,5,6-tetrahydropyridine-2-carboxylic acid methyl ester (35; 842 mg, 99%) as a light orange solid: 1H NMR (400 MHz, CDCl3) δ 7.21 (dd, JF-H=1.5 Hz, JH-H=8.4 Hz, 1H, aromatic), 7.11 (dd, JF-H=6.9 Hz, JH-H=8.4 Hz, 1H, aromatic), 5.24 (br s, 1H, NH), 4.76 (dd, J=4.2, 12.3 Hz, 1H, H5a), 3.98 (d, JF-H=1.5 Hz, 3H, OMe), 3.94 (s, 3H, CO2Me), 3.40 (ddd, JF-H=1.8 Hz, JH-H=4.2, 16.5 Hz, 1H, H6), 2.72 (dd, J=12.3, 16.5 Hz, 1H, H5b), 2.23 (s, 3H, NOAc). HRMS calcd for C16H15Cl2FN2O5: 404.034. Found: 404.034.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[CH:8]=[C:9]([CH:13]2[C:22]([CH3:24])([CH3:23])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:25]([O:27]C)=[O:26])[CH:19]=3)[NH:14]2)[CH:10]=[CH:11][CH:12]=1)=[O:6])([CH3:3])[CH3:2].[OH-].[Na+].C(OCC)(=O)C.Cl>CO.O>[CH:1]([NH:4][C:5]([C:7]1[CH:8]=[C:9]([CH:13]2[C:22]([CH3:23])([CH3:24])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:25]([OH:27])=[O:26])[CH:19]=3)[NH:14]2)[CH:10]=[CH:11][CH:12]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)NC(C)C)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)NC(=O)c1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Yield: 79.7 %

Procedure:
A mixture of methyl 2-(3-(isopropylcarbamoyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (120 mg, 0.315 mmol) in methanol (4.8 mL) and 2N sodium hydroxide aqueous solution (3.2 mL, 6.4 mmol) was heated to reflux for 2 h. Thin layer chromatography (petroleum ether:ethyl acetate=3:1) and LC-MS showed the reaction was complete. The solvent was removed in vacuo to give white solid, which was dissolved in water and acidified with 1N hydrochloric acid solution to pH=6, extracted with ethyl acetate/tetrahydrofuran, washed with brine and dried over anhydrous sodium sulfate. Removal of the solvent in vacuo gave 92 mg of 2-(3-(isopropylcarbamoyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a white solid. Yield: 80%. LC-MS (M+1)=367.2.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([CH:12]([O:15][CH3:16])[O:13][CH3:14])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:17](=[O:19])=[O:18].Cl>C1COCC1>[C:1]([C:5]1[CH:10]=[C:9]([F:11])[C:8]([C:17]([OH:19])=[O:18])=[C:7]([CH:12]([O:13][CH3:14])[O:15][CH3:16])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=O
Reactant: COC(OC)c1cc(F)cc(C(C)(C)C)c1
Agent: Cl
Solvent: C1CCOC1
Product: COC(OC)c1cc(C(C)(C)C)cc(F)c1C(=O)O
Temperature: -70 °C
Reaction time: 1 h

Procedure:
1-tert-Butyl-3-dimethoxymethyl-5-fluoro-benzene (333 g, 1.47 moles) was dissolved in THF (10 vol, 3.3 L) and cooled to −70° C. secBuLi (1.4M in cyclohexanes, 1.0 eq, 1000 mL) was added drop-wise over 1.5 hours. The solution was stirred at −70° C. for one hour and then CO2 gas was added to the reaction via a sintered glass gas dispersion tube, while maintaining vigorous stirring. The reaction was allowed to warm with vigorous stirring with adequate venting for release of excess CO2 from the solution. Once the internal temperature had reached +10° C. the reaction was quenched with water (3 L) followed by conc. HCl (1.15 eq, 140 mL). The aqueous fraction was extracted to ethyl acetate (1 L) and the combined organic fractions were combined and washed with water (2×1 L), and then concentrated with solvent replacement with heptanes. The resulting fine crystals were filtered, washed with heptanes and then dried at room temperature under vacuum with N2 sweep to provide 220.3 g (55.3%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8]O.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.Cl.[Na+].[I-:23]>N1C=CC=CC=1.CC(C)=O.O>[I:23][CH2:8][CH2:7][CH2:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: OCCCc1ccco1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: ICCCc1ccco1
Temperature: 0 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
To a solution of 3-furan-2-yl-propan-1-ol (6.3 g, 50 mmol) in pyridine (40 mL) at −15° C. was added p-toluenesulfonyl chloride (11.4 g, 60 mmol) in portions and the reaction was stirred for 3 h. Water (10×0.5 mL) was added and the mixture was poured into a mixture of concentrated HCl (65 mL) and ice (200 gm). The product was extracted into Et2O and the organic solution was dried over MgSO4, filtered, and concentrated to provide a yellow oil. The oil was added to a mixture of NaI (9 g, 60 mmol) in acetone (70 mL) and the reaction was stirred for 15 h. The insolubles were removed by filtration and the filtrate was concentrated in vacuo. Purification by flash chromatography (hexanes) provided the title compound (7.2 g). 1H NMR (400 MHz, CDCl3) δ 7.30 (m, 1H), 6.28 (m, 1H), 6.04 (m, 1H), 3.19 (t, 2H), 2.75 (t, 2H), 2.14 (m, 2H).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:12]=[C:11]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:24][C@H:25]3[CH2:29][NH:28][CH2:27][C@H:26]3[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH2:37](Br)[C:38]#[CH:39]>>[CH3:2][C:3]1[CH:12]=[C:11]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:24][C@H:25]3[CH2:29][N:28]([CH2:39][C:38]#[CH:37])[CH2:27][C@H:26]3[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: C#CCBr
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CNC[C@H]3C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Agent: Cl
Product: C#CCN1C[C@H](NS(=O)(=O)c2ccc(OCc3cc(C)nc4ccccc34)cc2)[C@H](C(=O)OC(C)(C)C)C1
Yield: 55.1 %

Procedure:
According to the procedure of Example 17, Step 3, 228.2 mg of tert-butyl cis-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-3-carboxylate hydrochloride was reacted with 51 mg of propargyl bromide to provide 126 mg of tert-butyl cis-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]-1-prop-2-yn-1-ylpyrrolidine -3-carboxylate in 55% yield. MS: 536.3(M+H)+
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[C:30]([O:32][CH3:33])[C:29](I)=[CH:28][C:27]=2[F:35])=[CH:22][C:21]=1[CH3:36].COC1CCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:1]([S:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:29]2[C:30]([O:32][CH3:33])=[CH:31][C:26]([C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[C:21]([CH3:36])[CH:22]=3)=[C:27]([F:35])[CH:28]=2)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(SCc2ccccc2)cc1[N+](=O)[O-]
Reactant: COc1cc(-c2ccc(Cl)c(C)c2)c(F)cc1I
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: COC1CCCC1
Product: COc1cc(-c2ccc(Cl)c(C)c2)c(F)cc1Nc1ccc(SCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 72.8 %

Procedure:
A RBF was charged with 4-(benzylthio)-2-nitroaniline (1.80 g, 6.91 mmol), 4′-chloro-2-fluoro-4-iodo-5-methoxy-3′-methyl-1,1′-biphenyl (2.86 g, 7.61 mmol), xantphos (0.200 g, 0.346 mmol), Pd2(dba)3 (0.158 g, 0.173 mmol), CPME (13.83 ml) and cesium carbonate (3.15 g, 9.68 mmol). A reflux condenser was attached and the flask was lowered into a 110° C. heating for 3 hours. The mixture was cooled to room temperature, diluted with EtOAc, and filtered through celite with the aid of EtOAc. The filtrate was concentrated. The oily residue was purified using Biotage and eluting with 0-50% EtOAc/Heptane to give N-(4-(benzylthio)-2-nitrophenyl)-4′-chloro-2-fluoro-5-methoxy-3′-methyl-[1,1′-biphenyl]-4-amine (2.56 g, 5.03 mmol, 72.7% yield) as a bright-yellow solid. m/z (ESI) 509.1 (M+H)+.