Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](I)[CH:2]=[CH2:3].[CH2:5]([O:7][C:8](=[O:22])[C@@H:9]1[CH2:13][C@@H:12]([OH:14])[CH2:11][N:10]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH3:6]>CN(C)C=O.[Ag]=O>[CH2:5]([O:7][C:8](=[O:22])[C@@H:9]1[CH2:13][C@@H:12]([O:14][CH2:3][CH:2]=[CH2:1])[CH2:11][N:10]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH3:6]
Reactant: C=CCI
Reactant: CCOC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: C=CCO[C@@H]1C[C@@H](C(=O)OCC)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94 %

Procedure:
Freshly prepared silver oxide (5.32 g, 3 eq.) and allyl iodide (15 mL, 4 eq.) were added to a solution of N-(tert-butoxycarbonyl)-trans-4-hydroxy-L-proline ethyl ester (2.2 g, 7.71 mmol) in dimethylformamide (15 mL) under a nitrogen atmosphere. The reaction mixture was stirred at 25° C. for 12 hours, then at 55° C. for 5 hours. The reaction mixture was filtered, poured into ethyl acetate, washed twice with water, once with brine, dried (Na2SO4), concentrated and purifed by flash chromatography (20% ethyl acetate/hexane) to give the title compound (2.18 g, 94%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 1.38 (m, 3H), 1.48, 1.54 (2s, 9H), 2.17 (m, 1H), 2.23 (m, 1H), 3.58 (bd, J=12.4 Hz, 0.5H), 3.70 (m, 1.5H), 4.05 (m, 2H), 4.22 (m, 3H), 4.43 (m, 1H), 5.29 (dd, J=10.1; 0.7 Hz, 1H), 5.39 (dd, J=17.6; 0.6 Hz, 1H) and 5.99 (m, 1H).
Reaction SMILES: [OH-].[Li+].[N+](C1C=CC(C([O:12][CH:13]([CH:24]([CH3:26])[CH3:25])[C@@H:14]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH3:15])=O)=CC=1)([O-])=O>CO>[OH:12][CH:13]([CH:24]([CH3:26])[CH3:25])[C@@H:14]([NH:16][C:17](=[O:18])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH3:15]
Reactant: CC(C)C(OC(=O)c1ccc([N+](=O)[O-])cc1)[C@H](C)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C(O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
A 1M lithium hydroxide aqueous solution (30 ml) was added to an MeOH (10 ml) solution containing (2S)-2-((tert-butoxycarbonyl)amino)-4-methylpentan-3-yl 4-nitrobenzoate (10 g) obtained in the 3rd step, followed by stirring at room temperature for 1 hour. The solvent was distilled away under reduced pressure, followed by extraction with ethyl acetate. The organic layers were washed with a saturated sodium hydrogen carbonate aqueous solution and saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. Yellow oily matter of tert-butyl ((2S)-3-hydroxy-4-methylpentan-2-yl)carbamate (5.3 g) was thus obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:19])=[C:7]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([Cl:18])[CH:17]=2)[C:13]#[N:14])[CH:8]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:19][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][S:28]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=2)(=[O:30])=[O:29])=[CH:8][C:7]=1[O:9][C:10]1[CH:11]=[C:12]([C:13]#[N:14])[CH:15]=[C:16]([Cl:18])[CH:17]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1cc(Cl)cc(Oc2cc(CN)ccc2Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2)cc1
Yield: 76.2 %

Procedure:
A solution of 3-{[5-(aminomethyl)-2-chlorophenyl]oxy}-5-chlorobenzonitrile (0.025 g, 0.085 mmol), 4-(methyloxy)benzenesulfonyl chloride, (0.025 g, 0.13 mmol) and DIPEA (0.05 mL, 0.25 mmol) in CH2Cl2 (2 mL) was stirred overnight. The solvent was concentrated and purification was accomplished by RP-HPLC (water/acetonitrile/0.1% TFA). The desired fractions were lyophilized and EtOAc (25 mL) and sat. NaHCO3 (10 mL) were added. The layers were separated and the aqueous layer extracted with EtOAc (2×10 mL). The organic extracts were combined, dried over Na2SO4, filtered and concentrated to afford N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]phenyl}methyl)-4-(methyloxy)benzenesulfonamide (0.030 g, 75%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.03 (t, 1H), 7.80 (d, 1H), 7.66 (d, 2H), 7.51 (d, 1H), 7.38 (dd, 1H), 7.32 (t, 1H), 7.15 (dd, 1H), 6.99-7.10 (m, 3H), 3.96 (d, 2H), 3.78 (s, 3H). MS: m/z 485 (M+23).
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH3:9][S:10][C:11]1[N:16]=[C:15]([C:17](=[O:19])[CH3:18])[CH:14]=[CH:13][N:12]=1>>[CH3:6][N:4]([CH3:5])/[CH:3]=[CH:18]/[C:17]([C:15]1[CH:14]=[CH:13][N:12]=[C:11]([S:10][CH3:9])[N:16]=1)=[O:19]
Reactant: COC(OC)N(C)C
Reactant: CSc1nccc(C(C)=O)n1
Product: CSc1nccc(C(=O)/C=C/N(C)C)n1
Yield: 69.4 %

Procedure:
1,1-Dimethoxy-N,N-dimethylmethanamine (9.87 mL, 74.3 mmol) was added to 1-(2-(methylthio)pyrimidin-4-yl)ethanone (0.50 g, 2.97 mmol). The mixture was heated at reflux overnight. The reaction mixture was concentrated to half volume and treated with Et2O. The resulting solid was collected by vacuum filtration to yield the desired (E)-3-(dimethylamino)-1-(2-(methylthio)pyrimidin-4-yl)prop-2-en-1-one (0.46 g, 2.06 mmol, 69.3% yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[S:5][C:6]=1[NH:7][C:8](=[O:14])[CH:9]([CH3:13])[CH2:10][S:11][CH3:12].[C:21](=O)([O-])[O-].[Cs+].[Cs+].IC.O>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[S:5][C:6]=1[N:7]([CH3:21])[C:8](=[O:14])[CH:9]([CH3:13])[CH2:10][S:11][CH3:12]
Reactant: CSCC(C)C(=O)Nc1sc(-c2cccnc2)nc1Cl
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CSCC(C)C(=O)N(C)c1sc(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.2 %

Procedure:
To a dry 50 ml round bottom flask equipped with magnetic stirrer, addition funnel, and nitrogen inlet was charged 1.0 g (3.05 mmoles) of N-(4-chloro-2-(pyridin-3-yl)-1,3-thiazol-5-yl)-2-methyl-3-(methylthio)propanamide and 10 mLs of anhydrous N,N-dimethyl formamide. To the resulting solution was then added 1.1 g (3.36 mmoles) of cesium carbonate powder in one portion, followed by the dropwise addition of 0.476 g (3.36 mmoles) of iodomethane in 5 mLs of anhydrous N,N-dimethylformamide. The heterogeneous mixture was stirred at ambient temperature for 12 hours, and then poured into 200 mLs of water and extracted with methylene chloride (3×100 mLs). The combined organic extracts were washed with water (100 mLs), saturated aqueous sodium chloride solution (100 mLs) dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum on a rotary evaporator. The crude product was purified by silica gel flash chromatography, eluting with a gradient of 100% hexane to 100% ethyl acetate over 20 minutes to yield a yellow oil (0.93 g, 89%): 1H NMR (400 MHz, CDCl3) δ 9.12 (d, J=1.4 Hz, 1H), 8.73 (d, J=3.8 Hz, 1H), 8.34-8.09 (m, 1H), 7.43 (dd, J=7.9, 4.9 Hz, 1H), 3.30 (s, 3H), 3.06-2.70 (m, 2H), 2.49 (d, J=7.4 Hz, 1H), 2.04 (s, 3H), 1.21 (d, J=6.4 Hz, 3H); 13C NMR (101 MHz, DMSO-d6) δ 175.22, 162.37, 151.91, 146.53, 136.46, 134.64, 133.35, 127.98, 124.27, 37.47, 36.71, 36.47, 17.56, 15.44.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1)[CH3:11].C(NC(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[CH2:10]([O:12][C:13](=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:7]([C:5]2[O:6][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:9])[CH:16]=1)[CH3:11]
Reactant: CCOC(=O)Cc1cccc(N)c1
Reactant: O=C(O)c1ccc(Br)o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.4 %

Procedure:
To a solution of 5-bromo-2-furoic acid (1.14 g) and 3-aminophenylacetic acid ethyl ester (1.06 g) in anhydrous DMF (15 ml) was added diisopropylamine (2.1 ml) and then O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (2.25 g). The solution was stirred at room temperature for 16 hours then partitioned between ethyl acetate and water. The organic layer was separated, washed twice with 1M hydrochloric acid, water, aqueous sodium carbonate solution, brine, dried over sodium sulphate and evaporated in vacuo. Compound 11 (1.8 g) was obtained following silica gel column chromatography of the residue in 2:1 ethyl acetate:petroleum ether.
Reaction SMILES: C(O)(=O)C(O)=O.[CH2:7]([NH:9][NH2:10])[CH3:8].[C:11]([C:13]1[CH:14]=[C:15]([C:19](=O)[CH2:20][C:21](OCC)=[O:22])[CH:16]=[CH:17][CH:18]=1)#[N:12].C(N(CC)CC)C>C(O)C>[CH2:7]([N:9]1[C:21](=[O:22])[CH:20]=[C:19]([C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=2)[C:11]#[N:12])[NH:10]1)[CH3:8]
Reactant: CCNN
Reactant: CCOC(=O)CC(=O)c1cccc(C#N)c1
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCn1[nH]c(-c2cccc(C#N)c2)cc1=O
Temperature: 80 °C
Yield: 122.8 %

Procedure:
Ethyl hydrazine oxalate (15.6 g, 104 mmol, 1.50 equiv) was added to a solution of ethyl 3-(3-cyanophenyl)-3-oxopropanoate (15.0 g, 69.1 mmol, 1 equiv) and triethylamine (14.4 mL, 104 mmol, 1.50 equiv) in ethanol (345 mL). The reaction mixture was heated to 80° C. for 70 min, then was removed from heat an concentrated to ˜¼ volume by rotary evaporation. The residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, and the washed solution was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated to afford 3-(1-ethyl-5-oxo-2,5-dihydro-1H-pyrazol-3-yl)benzonitrile as a light-yellow solid (18.1 g) of sufficient purity to use in the next step without further purification. Calcd (M+1)+: 214.1. Found: 214.1.
Reaction SMILES: [F:1][C:2]1([F:36])[CH2:5][CH:4]([CH2:6][O:7][C:8]2[CH:35]=[CH:34][C:11]3[N:12]=[C:13]([C:15]4[N:20]=[CH:19][C:18]([O:21][CH2:22][C@@H:23]([NH:25]C(=O)OC(C)(C)C)[CH3:24])=[CH:17][C:16]=4[F:33])[O:14][C:10]=3[CH:9]=2)[CH2:3]1.Cl.[C:38](OCC)(=[O:40])[CH3:39]>C(OCC)(=O)C>[F:36][C:2]1([F:1])[CH2:5][CH:4]([CH2:6][O:7][C:8]2[CH:35]=[CH:34][C:11]3[N:12]=[C:13]([C:15]4[N:20]=[CH:19][C:18]([O:21][CH2:22][C@@H:23]([NH:25][C:38](=[O:40])[CH3:39])[CH3:24])=[CH:17][C:16]=4[F:33])[O:14][C:10]=3[CH:9]=2)[CH2:3]1
Reactant: C[C@@H](COc1cnc(-c2nc3ccc(OCC4CC(F)(F)C4)cc3o2)c(F)c1)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1cnc(-c2nc3ccc(OCC4CC(F)(F)C4)cc3o2)c(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of tert-butyl {(1S)-2-[(6-{6-[(3,3-difluorocyclobutyl)methoxy]-1,3-benzoxazol-2-yl}-5-fluoropyridin-3-yl)oxy]-1-methylethyl}carbamate (390 mg), 4 M hydrogen chloride/ethyl acetate (3 mL), and ethyl acetate (3 mL) was stirred at room temperature for 4 hr. The mixture was concentrated under reduced pressure. The residue was mixed with pyridine (3 mL) and acetic anhydride (1 mL). The mixture was stirred at room temperature for 3 days. 1 M hydrochloric acid was added, and the mixture was extracted with ethyl is acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate/methanol) and recrystallization (ethyl acetate) to give the title compound (218 mg) as white crystals.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][N:4]=1)[CH3:2].[CH2:10](C([Sn])=C(CCCC)CCCC)[CH2:11]CC>CN(C=O)C.C1COCC1.O.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>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:10]=[CH2:11])=[CH:5][N:4]=1)[CH3:2]
Reactant: CCc1ccc(Br)cn1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1ccc(CC)nc1
Temperature: 100 °C
Yield: 93.3 %

Procedure:
The title compound was prepared by following general procedure 2. 2-Ethyl-5-bromopyridine (0.6 g, 0.00322 mol) was dissolved in DMF:THF (3:1 6 mL), and to this solution, tributylvinyltin (1.03 mL, 0.00354 mol) and Pd(PPh3)4 (0.048 g, 0.000041 mol) were added at RT under nitrogen and the mixture heated at 100° C. for 30 min. After completion of the reaction (TLC), the reaction mixture was cooled to RT and diluted with water (60 mL) and extracted with DCM (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator below 40° C. The crude was purified through column chromatography (2% ethylacetate:hexane in silica 100-200 mesh, Diameter of column—5.0 cm, Height of silica—approx. 5 inch) to provide 2-ethyl-5-vinylpyridine as a light yellow liquid (0.4 g, 93% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[CH:6][CH:5]=[CH:4][N:3]=1.OB(O)[C:11]1[S:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][C:14]=2[CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:1][C:2]1[C:7]([C:11]2[S:12][C:13]3[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][C:14]=3[CH:15]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ncccc1I
Reactant: O=C(O)c1ccc2sc(B(O)O)cc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Nc1ncccc1-c1cc2cc(C(=O)O)ccc2s1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To the degassed mixture of 2-amino-3-iodpyridine (1.12 g, 5.09 mmol, 1 eq), 2-(dihydroxyboryl)-1-benzothiophene-5-carboxylic acid, [2-(dihydroxyboryl)-1-benzothiophene-5-carboxylic acid (1.3 g, 1.15 eq)], and aqueous sodium carbonate (2M, 7.6 mL, 3 eq) in dioxane (10 mL) was added Ph3P (267 mg, 0.2 eq) and Pd(OAc)2 (114.3 mg, 0.1 eq). The mixture was heated to 50° C. with vigorous stirring for 30 minutes. The yellow mixture was then partitioned between aq NH4Cl and MeOH—CHCl3 (1:5). Some solids precipitation was observed. After the pH was carefully adjusted to around 6, the whole mixture was filtered through a Buchner funnel to obtain a yellow solid. The solid was further triturated with MeOH/H2O to give 2-(2-aminopyridin-3-yl)-1-benzothiophene-5-carboxylic acid as a white-off solid in amount of 1.18 g after dried in vacuo (86%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][C:18]=1[N+:19]([O-])=O)[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1)([CH3:3])[CH3:2]>C(O)C.[Pd]>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:8][N:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]2)[CH:16]=[CH:17][C:18]=1[NH2:19])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cc(CN2CCN(C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CC(C)Oc1cc(CN2CCN(C)CC2)ccc1N
Reaction time: 3 h
Yield: 100.8 %

Procedure:
A mixture of 4.2 g of 1-(3-isopropoxy-4-nitrobenzyl)-4-methylpiperazine and 420 mg of 10% palladium-on-carbon in 145 ml of ethanol is hydrogenated at 25° C. under 1 bar for 3 h. The mixture is filtered on Clarcel and the Clarcel is rinsed with ethanol. The filtrate is concentrated to dryness under reduced pressure, so as to give 3.8 g of 2-isopropoxy-4-(4-methylpiperazin-1-ylmethyl)phenylamine in the form of a brown oil.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][C:2]1=[O:7].[CH2:8](O)[C:9]#[C:10][CH2:11][OH:12].CC1C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[C:10][CH2:11][OH:12]
Reactant: OCC#CCO
Reactant: O=C1CCC=CO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Product: OCC#CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 39 %

Procedure:
3,4-Dihydro-2H-pyron (18.3 mL, 0.196 mol) in dichloromethane (30 mL) was added dropwise over 30 minutes to a stirred solution of 2-butyne-1,4-di-ol (16.832 g, 0.194 mol) and p-TsOH (2.236 g, 11.58 mmol) in DCM (250 mL) at 0° C. After addition, the mixture was stirred at room temperature for 4 hours. Sodium bicarbonate (858 mg) was added. The mixture was stirred for another hour. Water (10 mL) was added, followed by addition of saturated aqueous potassium carbonate (150 mL). The organic phase was separated and washed with brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure (temperature below 25° C.). The residue was separated by flash column chromatography on silica gel using 5-25% EtOAc/hexane to afford 12.88 g of product (yield: 39%), along with 12.05 g of di-protected side product. 1H-NMR (CDCl3): δ 4.78 (t, J=3.0-3.3 Hz, 1 H), 4.37-4.21 (m, 4 H), 3.86-3.78 (m, 1 H), 3.55-3.50 (m, 1 H), 1.83-1.64 (m, 6 H).
Reaction SMILES: ClCCl.[NH:4]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:7](=[O:8])[C:5]1=[O:6].[S:15]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16]1.C(N(CC)CC)C>C(OC(=O)C)(=O)C.C(N(CC)CC)C.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C([O-])(=O)C.[Cu+3].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[S:15]1[CH:19]=[CH:18][C:17]([N:4]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:7](=[O:8])[C:5]2=[O:6])=[CH:16]1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: OB(O)c1ccsc1
Agent: [Cu+2]
Agent: [Cu+3]
Agent: CC(=O)[O-]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1C(=O)N(c2ccsc2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.4 %

Procedure:
Copper(II) acetate monohydrate (4.25 g, 23.4 mmol) was heated at reflux in acetic anhydride (30 mL) for 2 h. The mixture was filtered and washed with anhydrous ether (500 mL). The solid was dried in vacuo at 55° C. for 16 h. Dichloromethane (1 mL) was added to a mixture of copper(III) acetate (62 mg, 0.34 mmol), isatin (50 mg, 0.34 mmol), and thiophene-3-boronic acid (87 mg, 0.68 mmol), followed by triethylamine (0.10 mL, 0.68 mmol) under argon. The resulting solution was stirred for 16 h at room temperature. The reaction mixture was then recharged with 0.10 mmol copper(II) acetate, 0.10 mmol of 3-thiophene boronic acid, and 1 drop of triethylamine, and the mixture was heated at 50° C. for 6 h. The crude material was purified by preparative TLC using 3:97 methanol in chloroform as the eluent, giving the desired product as a yellow solid (25 mg, 0.11 mmol, 33%). 1H NMR (400 MHz): δ 7.70 (d, J=7.5, 1H), 7.58 (t, J=7.8, 1H), 7.50 (d, J=5.1, 1H), 7.48 (s, 1H), 7.24 (d, J=5.1, 1H), 7.18 (t, J=7.51, 1H), 7.05 (d, J=8.0, 1H).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][CH:20]3[CH2:24][CH2:23][N:22]([CH3:25])[C:21]3=[O:26])=[CH:16][CH:17]=2)[C:12]([CH2:27][C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][C:29]=2[O:38][CH3:39])=[CH:11]1>ClCCl>[Cl:1][C:11]1[N:10]([CH3:9])[C:18]2[C:13]([C:12]=1[CH2:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][C:29]=1[O:38][CH3:39])=[CH:14][C:15]([CH2:19][CH:20]1[CH2:24][CH2:23][N:22]([CH3:25])[C:21]1=[O:26])=[CH:16][CH:17]=2
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(CC4CCN(C)C4=O)cc23)c(OC)c1
Solvent: ClCCl
Product: COC(=O)c1ccc(Cc2c(Cl)n(C)c3ccc(CC4CCN(C)C4=O)cc23)c(OC)c1
Reaction time: 0.25 h

Procedure:
N-Chlorosuccinimide (0.282 mg) was added in one portion to a stirred solution of methyl 4-[1-methyl -5-(1-methyl-2-oxopyrrolidin-3-ylmethyl)indol-3-ylmethyl]-3-methoxybenzoate (0.9 g) in dry dichloromethane (20 ml), under a nitrogen atmosphere. After 15 minutes, the solvent was evaporated, and the product was purified by flash chromatography, eluting with ethyl acetate, to give methyl 4-[2-chloro-1-methyl-5-(1-methyl-2-oxopyrrolidin -3-ylmethyl)indol-3-ylmethyl](65%) as a yellow oil: NMR (300 MHz, DMSO-d6): 1.45-1.61 (m, lH), 1.75-1.90 (m, lH), 2.50-2.70 (m, 5H), 2.90-3.18 (m, 3H), 3.72 (s, 3H, CH3), 3.82 (s, 3H, CH3), 3.92 (s, 3H, CH3), 4.02 (s, 2H), 6.99-7.10 (m, 2H), 7.20 (s, 1), 7.38 (d, lH), 7.40-7.50 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:19]([O-:21])=[O:20])[C:5]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])=[N:6][C:7]=1F.CCN(C(C)C)C(C)C.[CH3:31][C:32]1[NH:36][N:35]=[C:34]([NH2:37])[CH:33]=1>C1COCC1>[F:1][C:2]1[C:7]([NH:37][C:34]2[CH:33]=[C:32]([CH3:31])[NH:36][N:35]=2)=[N:6][C:5]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])=[C:4]([N+:19]([O-:21])=[O:20])[CH:3]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: C[C@H](Nc1nc(F)c(F)cc1[N+](=O)[O-])c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cc3)c([N+](=O)[O-])cc2F)n[nH]1
Temperature: 55 °C
Yield: 69.7 %

Procedure:
To a solution of (S)-5,6-difluoro-N-(1-(4-fluorophenyl)ethyl)-3-nitropyridin-2-amine (Method 53, 0.70 g, 2.3 mmol) in THF (12 ml) was added DIEA (0.39 g, 3.0 mmol) and 5-methyl-1H-pyrazol-3-amine (0.45 g, 4.7 mmol). The reaction was heated to 55° C. for 24 hours, cooled to room temperature, and quenched with water. The reaction was extracted with DCM (2×75 ml), and the combined organic fractions were dried over Na2SO4, filtered, and concentrated. The resulting oil was purified by column chromatography (DCM-MeOH=100:1) to give the title compound (0.60 g, 68%). MS: Calcd.: 374. Found: [M+H]+ 375.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:31](Cl)(=[O:33])[CH3:32]>C(O)(=O)C>[C:31]([NH:30][S:27]([C:24]1[CH:25]=[CH:26][C:21]([C:20]2[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][N:10]3[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[CH:12][C:11]=23)=[CH:22][CH:23]=1)(=[O:29])=[O:28])(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: NS(=O)(=O)c1ccc(-c2c(-c3cccc(F)c3)nn3cc(C(F)(F)F)ccc23)cc1
Solvent: CC(=O)O
Product: CC(=O)NS(=O)(=O)c1ccc(-c2c(-c3cccc(F)c3)nn3cc(C(F)(F)F)ccc23)cc1
Yield: 77 %

Procedure:
A mixture of 4-[2-(3-fluoro-phenyl)-6-trifluoromethyl-pyrazolo[1,5-a]pyridin-3-yl]benzenesulfonamide (0.2 g, 0.46 mmol) and acetyl chloride (Aldrich) (1 ml) in acetic acid (1 ml) was heated at 95° for 1 hr. The solvent was removed and the resulting oil was dissolved in ethyl acetate (30 ml), washed with M Na2CO3 (10 ml) and brine (10 ml). Drying (MgSO4) and removal of solvent gave a white solid which was triturated with 40-60 petroleum ether, filtered and dried to give the title compound (0.17 g 77%). MH− 476
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:5]=[O:6].[CH3:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][CH2:26][CH2:27][S:28][CH3:29])[CH:21]=[C:20]([CH3:30])[C:19]=1B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.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]>[CH3:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][CH2:26][CH2:27][S:28][CH3:29])[CH:21]=[C:20]([CH3:30])[C:19]=1[C:2]1[C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1
Reactant: O=Cc1ccc(Oc2ccccc2)c(Br)c1
Reactant: CSCCCOc1cc(C)c(B(O)O)c(C)c1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CSCCCOc1cc(C)c(-c2cc(C=O)ccc2Oc2ccccc2)c(C)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 69.5 %

Procedure:
3-Bromo-4-phenoxybenzaldehyde (1.11 g, 4.00 mmol), {2,6-dimethyl-4-[3-(methylthio)propoxy]phenyl}boronic acid (1.02 g, 4.00 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (0.263 g, 0.640 mmol) and tripotassium phosphate (1.70 g, 8.00 mmol) were dissolved in a mixed solvent of toluene (20 mL) and water (4 mL). After argon substitution, tris(dibenzylideneacetone)dipalladium(0) (0.147 g, 0.160 mmol) was added. The reaction mixture was stirred at 100° C. for 18 hr under argon atmosphere. The reaction mixture was allowed to cool, and water was added. The mixture was diluted with ethyl acetate, and the insoluble substance was filtered off through celite. The organic layer of the filtrate was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-20:80) to give the title compound (1.13 g, yield 70%) as a yellow oil.