Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:20]1[S:21][C:22]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:23]=2[N:24]=1>C1COCC1>[Cl:29][C:25]1[C:23]2[N:24]=[C:20]([CH2:2][C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3])[S:21][C:22]=2[CH:28]=[CH:27][CH:26]=1
Reactant: Clc1nc2c(Cl)cccc2s1
Reactant: CC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1nc2c(Cl)cccc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
A 1-Liter, 3-necked round bottomed flask fitted with a nitrogen inlet, a 500 mL addition funnel and a septum stopper was charged with t-butyl acetate (26.8 mL, 200 mmol) and anhydrous THF (50 mL). Upon cooling in a dry ice-acetone bath, to the mixture was added lithium bis(trimethylsilyl)amide (1M, THF solution) (200 mL, 200 mmol) via syringe over 15 min. After stirring at that temperature for 30 minutes, to the mixture was added a solution of 2,4-dichloro-benzothiazole (8.15 g, 40 mmol) in THF (100 mL) from the addition funnel over 15 minutes. The cooling bath was removed allowing the reaction to warm to room temperature over 1 hour. The reaction mixture was concentrated, then diluted with EtOAc and a saturated NaHCO3 solution. The organic layer was separated and the aqueous layer was extracted with EtOAc twice. The combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography on silica gel eluting with a gradient mixture of EtOAc/hexanes to give 11.28 g (99%) of the title compound as a yellow solid. 1H-NMR (500 MHz, DMSO-d6) δ (ppm) 8.00 (1H, dd, J=1.0, 8.0 Hz), 7.53 (1H, dd, J=1.0, 8.0 Hz), 7.36 (1H, t, J=8.0 Hz), 4.19 (2H, s), 1.38 (9H, s).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:16][CH2:17][CH3:18])([C:14]#[N:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:19]S(O)(=O)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:16][CH2:17][CH3:18])([C:14]([NH2:15])=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCNC1(C#N)CCN(Cc2ccccc2)CC1
Reactant: O=S(=O)(O)O
Solvent: ClCCl
Product: CCNC1(C(N)=O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A solution of 1-benzyl-4-ethylaminopiperidine-4-carbonitrile I-1A-1e (0.58 g, 2.38 mmol) in methylene chloride (2 ml) cooled in an ice bath was treated with H2SO4 (1.8 ml, 33 mmol), dropwise, while keeping the internal temperature below 20° C. The reaction was then warmed to room temperature and stirred for 19 hours. After stirring was discontinued, the thick pale orange H2SO4 bottom layer was separated, cooled in an ice bath and then carefully quenched with concentrated NH4OH keeping internal temperature below 55° C. The aqueous layer was extracted with methylene chloride (2×10 ml), the combined organic layers were washed with brine (20 ml), dried (Na2SO4), and then concentrated, in vacuo, to afford I-1A-1f as a pale orange oil that solidified to a peach colored solid upon standing (0.54 g, 87%): +APcI MS (M+1) 262.2; 1H NMR (400 MHz, CD2Cl2) δ 7.34–7.30 (m, 4H), 7.29–7.21 (m, 1H), 7.16 (br s, 1H), 3.48 (s, 2H), 2.71–2.68 (m, 2H), 2.47 (q, J=7.0 Hz, 2H), 2.17–2.02 (m, 4H), 1.62–1.58 (m, 2H), 1.41 (br s, 1H), 1.09 (t, J=7.0 Hz, 3H).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([NH:15][C:16]1[C:17]([Cl:37])=[C:18]([CH:24]2[O:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]2)[CH:19]=[C:20]([C:22]#[N:23])[CH:21]=1)=O)(C)(C)C>C(Cl)Cl>[NH2:15][C:16]1[CH:21]=[C:20]([CH:19]=[C:18]([CH:24]2[O:29][CH2:28][CH2:27][NH:26][CH2:25]2)[C:17]=1[Cl:37])[C:22]#[N:23]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(C2CN(C(=O)OC(C)(C)C)CCO2)c1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(N)c(Cl)c(C2CNCCO2)c1
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
TFA (4.5 mL) was added to a solution of tert-butyl 2-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)morpholine-4-carboxylate (252 mg, 0.575 mmol) in DCM (4.5 mL) at room temperature. After 0.5 hr, the solvent was removed. The residue in was dissolved in MeOH and this was applied onto an SCX column. After washing with MeOH, the product was eluted with 2N NH3 in MeOH to give 3-amino-4-chloro-5-(morpholin-2-yl)benzonitrile (132 mg) as an oil. This was dissolved in DCM (7 mL) and TEA (0.096 mL, 0.69 mmol) and BOC2O (0.16 mL, 0.69 mmol) were added. After stirring overnight, the solvent was removed and radial silica gel chromatography eluting with hexane containing 0 to 30% EtOAc afforded tert-butyl 2-(3-amino-2-chloro-5-cyanophenyl)morpholine-4-carboxylate (203 mg).
Reaction SMILES: [CH2:1]([C@H:8]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C@@H:9]([OH:32])[CH2:10][N:11](CC1C=CC=CC=1)[NH:12][C:13](=[O:24])[C@@H:14]([NH:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[H][H]>CO.[OH-].[OH-].[Pd+2]>[CH2:1]([C@H:8]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C@@H:9]([OH:32])[CH2:10][NH:11][NH:12][C:13](=[O:24])[C@@H:14]([NH:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: COC(=O)N[C@H](C(=O)NN(Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: COC(=O)N[C@H](C(=O)NNC[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Yield: 96.4 %

Procedure:
A solution of Example 5F (0.115 g, 0.2 mmol) in methanol (2 mL) was treated with Pd(OH)2 (38 mg) and 4N HCl (52 μL, 1 equivalent) and a hydrogen balloon at 25° C. for 3.5 hrs. The solvents were evaporated, and the crude residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and the solvents were evaporated to give 90 mg (93%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[S:13][C:12]([CH:14]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:16]1C=CC=CC=1.Cl.NO.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C>CN(C)C=O.O>[CH2:1]([O:8][C:9]1[S:13][C:12]([C:14]#[N:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)s1
Reactant: c1ccncc1
Agent: Cl
Agent: NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(OCc2ccccc2)s1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 17.9 %

Procedure:
The resulting 5-benzyloxy-thiophene-2-carbaldehyde (171 mg) was dissolved in N,N-dimethylformamide (4 mL), pyridine (82 μl, 1.02 mmol) and hydroxylamine hydrochloride (65 mg, 0.94 mmol) were added thereto, followed by stirring for 30 minutes at 60° C., then, cooled on an ice bath. 1,1′-Carbonyldiimidazole (635 mg, 3.92 mmol) was added, the solution was warmed again to 60° C. and stirred for 35 minutes, triethylamine (272 μl, 1.96 mmol) was added, and the solution was further stirred for 30 minutes. The reaction mixture was cooled to room temperature, water was added, and the solution was extracted with ethyl acetate. The organic layer was sequentially washed with an aqueous solution of oxalic acid, an aqueous solution of saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate, and then, concentrated in vacuo. The resulting residue was purified by silica gel chromatography (hexane-ethyl acetate), and the title compound (30 mg, 0.14 mmol, 14%) was obtained.
Reaction SMILES: [CH3:1][NH:2][C:3](=[N:6][N+:7]([O-:9])=[O:8])[S:4][CH3:5].C(=O)([O-])[O-].[K+].[K+].[C:16]([O:19]C(=O)C)(=O)[CH3:17].Cl>C(#N)C>[C:16]([N:2]([CH3:1])[C:3](=[N:6][N+:7]([O-:9])=[O:8])[S:4][CH3:5])(=[O:19])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CNC(=N[N+](=O)[O-])SC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CSC(=N[N+](=O)[O-])N(C)C(C)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.6 %

Procedure:
To a mixture of N,S-dimethyl-N'-nitroisothiourea (500 mg), potassium carbonate (695 mg) and acetonitrile (10 ml) was added 376 mg of acetic anhydride at room temperature. After stirring at room temperature for 5 hours, 10 ml of 2N hydrochloric acid was added to the mixture which was then extracted with 40 ml of dichloromethane. The resultant organic layers were washed with aqueous saturated sodium bicarbonate, then dried over anhydrous magnesium sulfate and concentrated to afford 600 mg of N-acetyl-N,S-dimethyl-N'-nitroisothiourea as a white crystal, mp 40°-41° C.
Reaction SMILES: [CH3:1][C:2]([S:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[CH3:8][C:9]([CH3:15])([CH3:14])/[CH:10]=[CH:11]/[CH:12]=O>ClCCl.[O-]S([O-])(=O)=O.[Cu+2]>[CH3:8][C:9]([CH3:15])([CH3:14])/[CH:10]=[CH:11]/[CH:12]=[N:7]/[S:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6]
Reactant: CC(C)(C)/C=C/C=O
Reactant: CC(C)(C)S(N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)/C=C/C=N/S(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
To a solution of 2-methylpropane-2-sulfinamide (3.08 g, 0.025 mol) in dichloromethane (10 ml) was added CuSO4 (5.42 g, 0.034 mol) followed by (2E)-4,4-dimethylpent-2-enal (Journal of Organic Chemistry 1993, 58(9), 2517-22, 1.9 g, 0.017 mol) in dichloromethane (60 ml). The reaction mixture was stirred at RT overnight under nitrogen and then filtered through a pad of celite. The filtrate was evaporated under reduced pressure and purified by chromatography on silica gel eluting with 10% AcOEt/Hexane to give 2.1 g (58%) of the title compound; 1H NMR δ (ppm)(CDCl3, 400 MHz): 8.19 (1 H, d, J=9.2 Hz), 6.53 (1 H, d, J=15.7 Hz), 6.36 (1 H, dd, J=9.2, 15.7 Hz), 1.21 (9 H, s), 1.12 (9 H, s).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][CH2:12][SH:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[SH:14][CH2:15][CH2:16][OH:17]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][CH2:12][S:13][S:14][CH2:15][CH2:16][OH:17])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: OCCS
Reactant: SCCCc1ccc2c(c1)OCO2
Product: OCCSSCCCc1ccc2c(c1)OCO2
Yield: 43.8 %

Procedure:
8.4 g of the title compound was prepared from 27.8 g of 3-(1,3-benzodioxol-5-yl)propanethiol and 5.5 g of 2-mercaptoethanol as a colorless oil according to the same procedure as that described in Example 1.
Reaction SMILES: [OH-].[Na+:2].CC(OC([O:10][C:11]1[CH:16]=[C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:14]=[C:13]([CH:23]([CH3:29])[C:24]([O:26]CC)=[O:25])[N:12]=1)=O)(C)C>O1CCCC1>[N:17]1([C:15]2[N:14]=[C:13]([CH:23]([CH3:29])[C:24]([O-:26])=[O:25])[NH:12][C:11](=[O:10])[CH:16]=2)[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1.[Na+:2]
Reactant: CCOC(=O)C(C)c1nc(OC(=O)OC(C)(C)C)cc(N2CCOCC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C(=O)[O-])c1nc(N2CCOCC2)cc(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.190 ml of 1M sodium hydroxide is added to a solution of 145 mg of ethyl 2-[4-({[(2-methylpropan-2-yl)oxy]carbonyl}oxy)-6-(morpholin-4-yl)pyrimidin-2-yl]propanoate in 5 ml of tetrahydrofuran. After stirring overnight at ambient temperature, the reaction mixture is concentrated to dryness under reduced pressure. 100 mg of sodium 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]propanoate are obtained in the form of a solid which is used as it is in the subsequent stage.
Reaction SMILES: CC(C)(C)C(NC1C=CC(OC2C=C(CC(O)=O)C=CC=2OC)=C(CSCC(F)(F)F)C=1)=O.IC.[H-].[Na+].C[O:39][C:40](=[O:72])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[C:44]([O:50][C:51]2[CH:56]=[CH:55][C:54]([N:57]([C:59](=[O:64])[C:60]([CH3:63])([CH3:62])[CH3:61])[CH3:58])=[CH:53][C:52]=2[CH2:65][S:66][CH2:67][C:68]([F:71])([F:70])[F:69])[CH:43]=1.[OH-].[Li+]>CC#N.CO.O>[CH3:61][C:60]([CH3:63])([CH3:62])[C:59]([N:57]([CH3:58])[C:54]1[CH:55]=[CH:56][C:51]([O:50][C:44]2[CH:43]=[C:42]([CH2:41][C:40]([OH:72])=[O:39])[CH:47]=[CH:46][C:45]=2[O:48][CH3:49])=[C:52]([CH2:65][S:66][CH2:67][C:68]([F:70])([F:69])[F:71])[CH:53]=1)=[O:64]
Reactant: COC(=O)Cc1ccc(OC)c(Oc2ccc(N(C)C(=O)C(C)(C)C)cc2CSCC(F)(F)F)c1
Agent: COc1ccc(CC(=O)O)cc1Oc1ccc(NC(=O)C(C)(C)C)cc1CSCC(F)(F)F
Agent: [H-]
Agent: [Li+]
Solvent: CC#N
Solvent: CI
Solvent: O
Product: COc1ccc(CC(=O)O)cc1Oc1ccc(N(C)C(=O)C(C)(C)C)cc1CSCC(F)(F)F
Temperature: 25 °C

Procedure:
To {3-[4-(2,2-dimethyl-propionylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid (0.128 g, 0.26 mmol) in MeCN (3 mL) was added iodomethane (0.03 mL, 0.53 mmol), followed by sodium hydride (60% in mineral oil; 0.021 g, 0.53 mmol). The reaction was stirred at room temperature, but only starting material was seen by analytical LCMS, so the reaction was heated to 60° C. for 2 hours, and then cooled to room temperature and stirred for 2 days under N2. The mixture was used directly in the hydrolysis step. To a solution of {3-[4-[(2,2-dimethyl-propionyl)-methyl-amino]-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid methyl ester (0.26 mmol) in MeCN was added H2O, MeOH, and lithium hydroxide, and the reaction was heated to 65° C. for 1 hour to give the title compound.
Reaction SMILES: CON(C)[C:4](=[O:14])[CH2:5][CH2:6][C:7]([CH3:13])([CH3:12])[C:8]([O:10][CH3:11])=[O:9].[F:16][C:17]1[CH:18]=[C:19]([Mg]Br)[CH:20]=[C:21]([F:23])[CH:22]=1>C1COCC1>[F:16][C:17]1[CH:18]=[C:19]([C:4](=[O:14])[CH2:5][CH2:6][C:7]([CH3:12])([CH3:13])[C:8]([O:10][CH3:11])=[O:9])[CH:20]=[C:21]([F:23])[CH:22]=1
Reactant: Fc1cc(F)cc([Mg]Br)c1
Reactant: COC(=O)C(C)(C)CCC(=O)N(C)OC
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)CCC(=O)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 5-[methoxy(methyl)amino]-2,2-dimethyl-5-oxopentanoate from Step C (4.68 g, 21.6 mmol) in THF (46.8 mL), cooled to 0° C., was added 3,5-difluorophenyl magnesium bromide (65 mL, 0.5 M in THF, 32.3 mmol) over 30 minutes. The reaction was allowed to stir at ambient temperature for 2 h, after which time no additional reaction progress was observed. Additional 3,5-difluorophenyl magnesium bromide (50 mL, 0.5 M in THF, 25.0 mmol) was added over 30 minutes. After 3 h at 0° C., the reaction was quenched by the rapid addition of a cold (0° C.) solution of EtOH (71 mL) and conc. HCl (5.0 mL). The reaction was then diluted with water (200 mL) and diethyl ether (400 mL). The organics were washed with water (200 mL×3) and brine (100 mL), then dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue. This residue was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:hexanes-50:50 to 100:0, to give the title compound. MS: m/z=239 (M−31(MeO−)).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][O:17]C)[C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])=[N:6][CH:7]=1.[I-].[Na+].C[Si](Cl)(C)C>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:15][CH:16]=[O:17])[C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])=[N:6][CH:7]=1
Reactant: COC=Cc1cc(F)cnc1N1CCCCC1=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: O=CCc1cc(F)cnc1N1CCCCC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-[5-fluoro-3-(2-methoxyvinyl)pyridin-2-yl]piperidin-2-one a19-2 (620 mg, 2.477 mmol, 1 eq) in acetonitrile (25 ml) is added at 0° C. sodium iodide (557 mg, 3.716 mmol, 1.5 eq) and trimethylsilyl chloride (404 mg, 3.716 mmol, 1.5 eq), and the reaction mixture is stirred at room temperature for 16 hours to form in situ [5-fluoro-2-(2-oxopiperidin-1-yl)pyridin-3-yl]acetaldehyde a19-3. In parallel, 2-(pyrrolidin-3-yl)pyridine enantiomer 2 dihydrochloride a1-67 (654 mg, 2.973 mmol, 1.2 eq) is dissolved in acetonitrile, loaded on a carbonate resin, the resin washed with dichloromethane and the pooled filtrates are evaporated to dryness to afford 2-(pyrrolidin-3-yl)pyridine enantiomer 2 as a free base. The residue obtained is added to intermediate a19-3. NaBH(OAc)3 (1050 mg, 4.954 mmol, 2 eq) is added, the reaction mixture is stirred overnight and is still incomplete. Racemic 2-(pyrrolidin-3-yl)pyridine (0.4 eq) is added, the reaction mixture heated overnight at 90° C. and evaporated to dryness. The residue of evaporation is retaken in dichloromethane. This organis phase is washed with saturated aqueous NaHCO3 (2 times), dried over MgSO4, filtered and evaporated to dryness. The residue obtained is dissolved in acetonitrile (12 ml), HCl 5M (approximately 4 ml) is added and the mixture is stirred at 40° C. for 3 hours. Dichloromethane is then added, and the organic phase washed with saturated aqueous NaHCO3 (2 times), dried over MgSO4, filtered and evaporated to dryness. This residue is purified by flash chromatography over silicagel (12 g; gradient: from CH2Cl2/MeOH 100/0 to 94/6), then by reverse phase chromatography (basic conditions: gradient: acetonitrile/H2O/NH4OH from 20/80/0.1 to 50/50/0.1) to afford 38 mg of 1-(5-fluoro-3-{2-[3-(pyridin-2-yl)pyrrolidin-1-yl]ethyl}pyridin-2-yl)piperidin-2-one 112 as a 80/20 mixture of enantiomers.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[C:13]([NH2:18])=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][CH:5]=1)[CH3:3].[H-].[Na+].Cl[CH2:22][CH2:23][S:24](Cl)(=[O:26])=[O:25].C(=O)([O-])O.[Na+]>C1COCC1.C(OCC)(=O)C>[CH3:3][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]#[C:11][C:12]2[C:13]3=[N:18][S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][N:14]3[CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:9]=1)[CH3:1]
Reactant: CC(C)c1ccc(C#Cc2cccnc2N)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)c1ccc(C#CC2=CC=CN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.1 %

Procedure:
A mixture of 3-{[4-(1-methylethyl)phenyl]ethynyl}pyridin-2-amine (150 mg) in dehydrated THF (5 mL) was added to a mixture of sodium hydride (60%, 127 mg) and 2-chloroethanesulfonyl chloride (310 mg) in dehydrated THF (5 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 2 hr, and saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added. The resulting precipitate was collected by filtration, and washed with water and ethyl acetate to give the title compound (110 mg) as a white solid. The obtained solid was crystallized from acetonitrile and diisopropyl ether to give a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:30])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19][O:20][CH3:21])=[C:14]([F:29])[CH:13]=3)[O:11][C:6]=2[C:5]([F:31])=[CH:4][C:3]=1[F:32].[H-].[Na+].Br[CH2:36][CH2:37][CH:38]=[C:39]([CH3:41])[CH3:40].O>CN(C)C=O>[C:25]([O:24][C:22]([N:18]([C:15]1[CH:16]=[CH:17][C:12]([C:10]2[O:11][C:6]3[C:5]([F:31])=[CH:4][C:3]([F:32])=[C:2]([NH:1][CH2:36][CH2:37][CH:38]=[C:39]([CH3:41])[CH3:40])[C:7]=3[C:8](=[O:30])[CH:9]=2)=[CH:13][C:14]=1[F:29])[CH2:19][O:20][CH3:21])=[O:23])([CH3:27])([CH3:28])[CH3:26]
Reactant: CC(C)=CCCBr
Reactant: COCN(C(=O)OC(C)(C)C)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCN(C(=O)OC(C)(C)C)c1ccc(-c2cc(=O)c3c(NCCC=C(C)C)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.9 %

Procedure:
2.70 g (6.00 mmol) of the above 5-amino-2-[4-[N-(tert-butoxycarbonyl)-N-methoxymethylamino]-3-fluorophenyl]-6,8-difluoro-4H-1-benzopyran-4-one was dissolved in 60 mL of dimethylformamide under argon atmosphere, 480 mg (12.0 mmol) of sodium hydride (60% oil dispersion) and 4.0 mL (30 mmol) of 5-bromo-2-methyl-2-pentene were added under ice-cooling and the mixture was stirred at room temperature for 18 hours. The reaction solution was cooled on ice, water was added and the mixture was extracted twice with ethyl acetate. The organic layer was washed twice with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:acetonitrile=30:1) to give 1.21 g of 2-[4-[N-(tert-butoxycarbonyl)-N-methoxymethylamino]-3-fluorophenyl]-6,8-difluoro-5-(4-methyl-3-pentenylamino)-4H-1-benzopyran-4-one (yield: 38%).
Reaction SMILES: CO.[C:3]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[C:13]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH:12]=1)(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>[C].[Pd].C(OCC)(=O)C>[CH2:3]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[C:13]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(c1ccccc1)c1ccc(C(=O)O)c(Nc2ccc(F)cc2)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(Cc2ccccc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 68.2 %

Procedure:
To a mixed solution of methanol 1.3 mL and ethyl acetate 1.3 mL of 4-benzoyl-2-(4-fluoroanilino)benzoic acid 0.13 g was added 5% palladium-carbon 26 mg, and it was stirred under hydrogen atmosphere at room temperature for 6 hours. Insoluble matter was filtrated, and the solvent was removed under reduced pressure. Hexane and diisopropyl ether were added to the obtained residue, and solid matter was filtrated to give 4-benzyl-2-(4-fluoroanilino)benzoic acid 85 mg of white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[CH:5]2.[Cl:21][S:22](O)(=[O:24])=[O:23]>CC#N>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[C:5]2[S:22]([Cl:21])(=[O:24])=[O:23]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3cc(F)ccc32)cc1
Reactant: O=S(=O)(O)Cl
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(S(=O)(=O)Cl)c3cc(F)ccc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
A solution of 5-fluoro-1-(toluene-4-sulfonyl)indole (5.2 g) in dry CH3CN (80 mL) is cooled in an ice-bath and treated drop wise with chlorosulfonic acid (12 mL). The reaction mixture is allowed to warm to rt and stirred for 24 h. The reaction mixture is carefully poured onto ice/water (300 mL). The precipitate is collected by filtration and washed with water to afford 5-fluoro-3-chlorosulfonyl-1-(toluene-4-sulfonyl)-1H-indole (6.8 g, 98%) as a solid. MS: 386 (M−H).
Reaction SMILES: CC(C)=[O:3].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:8]=1[CH2:16][CH2:17][OH:18].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:8]=1[CH2:16][C:17]([OH:3])=[O:18]
Reactant: COc1cccc([N+](=O)[O-])c1CCO
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: COc1cccc([N+](=O)[O-])c1CC(=O)O
Temperature: 0 °C
Yield: 98.4 %

Procedure:
A solution of 4.3 g of 2-(2-methoxy-6-nitrophenyl)-1-ethanol acetone (117 mL) is slowly treated with a solution of Jones Reagent (31 mL). The volatiles are removed under reduced pressure, diluted with 5M sodium hydroxide, cooled to 0° C., and treated slowly with concentrated H2SO4. This solution is extracted four times with ethyl acetate with the combine organics washed with brine, dried over NaSO4, filtered, and concentrated. The crude material is purified by LC (10% MeOH/CH2Cl2) to give 3.5 g of 2-(2-methoxy-6-nitrophenyl)acetic acid as a yellow/gold solid. 1H NMR (300 MHz, DMSO-d6) δ3.84 (s, 3H), 3.87 (s, 2H), 7.42 (d, J=7 Hz, 1H), 7.52 (t, J=8 Hz, 1H), 7.59 (dd, J=1, 8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ157.9, 150.7, 127.5, 120.1, 115.3, 114.8, 56.4, 11.1; IR (drift) 3020, 2983, 2945, 2888, 2840, 1710, 1531, 1471, 1434, 1353, 1274, 1256, 1229, 1058, 799 cm−1. HRMS (FAB) calculated for C9H9NO5+H1 212.0559, found 212.0555.