Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](I)[CH:4]=[N:3]1.[C:8]1([C:14]#[CH:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(NC(C)C)(C)C.C(OCC)(=O)C.[Cu](I)I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[C:5]([C:15]#[C:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[N:3]1
Reactant: C#Cc1ccccc1
Reactant: Cn1cc(I)cn1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: Cn1cc(C#Cc2ccccc2)cn1
Reaction time: 3 h

Procedure:
To a solution of 1-methyl-4-iodopyrazole (208 g, 1 mol) and phenylacetylene (112 g, 1.1 mol) in diisopropylamine (2 l) are added, under nitrogen, copperiodide (2 g), triphenylphosphine (0.1 g) and bis-(triphenylphosphine) palladiumdichloride (0.5 g). The mixture is kept during 3 hours at ca. +35° C. and then heated for 1 hour at +90° C. The cooled reaction mixture is diluted with ethyl acetate and filtrated. Concentration of the filtrate and distillation yields the title compound: b.p. 116°-118° C./0.3 mbar, m.p. 70°-72° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[CH:23])[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24]([C:28]([N:30]1[CH:34]=[CH:33][N:32]=[C:31]1I)=[O:29])([CH3:27])([CH3:26])[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C(N(CC)CC)C.[Cu]I>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:31]4[N:30]([C:28]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:29])[CH:34]=[CH:33][N:32]=4)[CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH2:20]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCC(=O)CC1
Reactant: CC(C)(C)C(=O)n1ccnc1I
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(C2(C#Cc3nccn3C(=O)C(C)(C)C)CCC(=O)CC2)cc1OC1CCCC1
Yield: 43.2 %

Procedure:
To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-one (0.28g, 0.9 mmol) and 1-tert.-butylcarbonyl-2-iodoimidazole (0.29 g, 0.97 mmol) in triethylamine (5 mL) under an argon atmosphere were added tetrakis(triphenyl-phosphine)palladium(0) (0.042 g, 4%), copper(I) iodide (0.005 g, 6%), and a small crystal of triphenylphosphine, and the mixture was heated at 80°-85° C. for 1 h. Water was added and the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 3:7 ethyl acetate:hexanes provided 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(1-tert-butylcarbonylimidazol-2-ylethynyl)cyclohexan-1-one (0.18 g, 4%), as a colorless oil. 1H-NMR (400 MHz, CDCl3) δ 7.36 (s, 1H), 7.20 (d, J=2.1 Hz, 1H), 7.17 (dd, J=8.5, 2.1 Hz, 1H), 7.01 (s, 1H), 6.85 (d, J=8.5 Hz, 1H), 4.85 (m, 1H), 3.84 (s, 3H), 3.18 (m, 2H), 2.44 (m, 4H), 2.22 (m, 2H), 1.8-2.0 (m, 6H), 1.6 (m, 11H) ppm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].CN([CH:19]=[O:20])C>C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([CH:19]=[O:20])=[N:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: Clc1ccc(Br)nc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1ccc(Cl)cn1
Temperature: 0 °C
Yield: 57.2 %

Procedure:
To a solution of 2-bromo-5-chloropyridine (14.8 g, 77 mmol) in THF (38.5 mL) was added dropwise a a solution of i-PrMgCl.LiCl (14% in THF, 81 mL, 85 mmol) at 0-5° C. and the resulting mixture stirred at 0° C. for 1 h. Then DMF (7.7 mL, 100 mmol) was added dropwise at −5° C. and the temperature maintained at 0° C. for 2 h. The reaction mixture was then poured into ice cold saturated brine (500 mL) and then extracted with ethyl acetate (2×300 mL). The combined organic layers were washed with saturated sodiumhydrogencarbonate solution, brine, dried over sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=1:0 to 9:1) afforded the title compound (6.24 g, 57%) which was obtained as a brown solid. MS: m/e=141.0 [M]+.
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1)=[NH:6])C.[CH3:18][NH:19][CH3:20]>C(O)C>[CH3:18][N:19]([CH3:20])[C:5]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1)=[NH:6]
Reactant: CCOC(=N)c1ccc(C(=O)OCC)cc1
Reactant: CNC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc(C(=N)N(C)C)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
1 g (3.9 mmol) of ethyl 4-ethoxycarbonimidoylbenzoate hydrochloride was stirred in a mixture of 3 ml of ethanol and 10 ml of 50% aqueous dimethylamine solution overnight. The solvent was evaporated, and 10 ml of dioxane containing 4 N hydrogen chloride and 1 ml of ethanol were added to the residue. They were stirred at room temperature for 5 days, and the solvent was evaporated. 1 N sodium hydroxide was added to the residue. After the extraction with dichloromethane, the organic layer was washed with saturated aqueous common salt solution and then dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.CO[CH:12]1[CH2:16][CH2:15][CH:14](OC)O1>C1(C)C=CC=CC=1>[N:1]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH:12]=[CH:16][CH:15]=[CH:14]1
Reactant: N#Cc1ccc(N)cc1
Reactant: COC1CCC(OC)O1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(-n2cccc2)cc1
Yield: 60.2 %

Procedure:
A mixture of 4-aminobenzonitrile (50 g., 0.42 mole), 2,5-dimethoxytetrahydrofuran (56 g., 0.42 mole) and 4A molecular sieves (184 g) in toluene (560 ml) was heated under reflux for 24 hrs. The residue from evaporation was washed with pet. ether and then recrystallized from diisopropyl ether to yield 42.5 g (60%) of 4-(1-pyrrolyl)benzonitrile, m.p. 104°-106° C.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@:13]([CH:23]=[CH:24][CH2:25][CH2:26][CH3:27])([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][C@@H:11]([N:28]2[CH:36]=[C:34]([CH3:35])[C:32](=[O:33])[NH:31][C:29]2=[O:30])[C:10]1(O)[OH:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:39]1[CH:44]=[CH:43][C:42]([O:45][C:46](Cl)=[S:47])=[CH:41][CH:40]=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH2:1]([O:8][C@@H:9]1[C@@:13]([CH:23]=[CH:24][CH2:25][CH2:26][CH3:27])([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][C@@H:11]([N:28]2[CH:36]=[C:34]([CH3:35])[C:32](=[O:33])[NH:31][C:29]2=[O:30])[C@@H:10]1[O:37][C:46]([O:45][C:42]1[CH:43]=[CH:44][CH:39]=[CH:40][CH:41]=1)=[S:47])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC=C[C@]1(COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C(O)(O)[C@@H]1OCc1ccccc1
Reactant: S=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCCC=C[C@]1(COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@H](OC(=S)Oc2ccccc2)[C@@H]1OCc1ccccc1
Reaction time: 8 h

Procedure:
The nucleoside 20 (2.8 g, 5.7 mmol) was evaporated thrice with dry pyridine and dissolved in the same. To this pre-cooled solution was added DMAP (0.69 g, 5.7 mmol) and then dropwise was added phenyl chlorothionoformate (1.15 mL, 8.55 mmol) and reaction stirred overnight. Reaction was quenched with saturated solution of NaHCO3 and extracted with dichloromethane. Organic layer was dried over MgSO4 concentrated and chromatographed over silica gel (10-30% ethyl acetate in cyclohexane, v/v) to give 21 as yellowish foam (2.1 g, 3.42 mmol, 60%). Rf=0.60 (30% ethyl acetate in cyclohexane, v/v). 1H NMR (600 MHz, CDCl3) δ: 8.32 (1H, br s, NH), 7.48 (1H, s, H6), 7.48-6.99 (15H, m), 6.4 (1H, d, JH1′,H2′=6.3 Hz, H1′), 5.94 (1H, app t, J=6.0 Hz, H2′), 5.77 (1H, m, H8′), 4.97 (2H, m, H9′ and H9″), 4.77 (1H, d, Jgem=12 Hz, CH2Bn), 4.55 (3H, d, Jgem=12 Hz, CH2Bn), 4.53 (1H, d, JH2′,H3′=5.8 Hz, H3′), 3.74 (1H, d, JH5′,H5″=9.9 Hz, H5″), 3.47 (1H, d, JH5′,H5″=9.9 Hz, H5′), 2.22 (1H, m, H7′), 2.06 (1H, m, H7″), 1.94 (1H, m, H6′), 1.66 (1H, m, H6″), 1.53 (3H, thymine CH3); 13C NMR (125.7 MHz, CDCl3) δ: 194.4 (C═S), 163.3 (C4), 153.3, 150.2 (C2), 138.1 (C8′), 137.3, 137.0, 135.6 (C6), 129.5-121.9 (aromatic), 114.8 (C9′), 111.5 (C5), 87.6 (C4′), 85.1 (C1′), 82.9 (C2′), 78.1 (C3′), 74.9 (CH2Bn), 73.7 (C5′), 73.6 (CH2Bn), 31.6 (C6′), 27.6 (C7′), 12.0 (CH3 thymine); MALDI-TOF m/z [M+H]+ found 629.09, calcd 629.73.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].[BH4-].[Na+].C(O)(=O)C.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19]>CO>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH2:2][NH:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:6][CH:7]=1
Reactant: O=C(CCl)c1ccc(F)cc1
Reactant: CC(C)(C)N
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)NCC(O)c1ccc(F)cc1
Temperature: -5 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
50 g (0.289 mol) of α-chloro-p-fluoroacetophenone are dissolved in 900 ml of methanol. The mixture is cooled to -5° C. and 5.80 g of NaBH4 are added. It is left in contact for 1 hour then 10 ml of acetic acid are added. 151 ml of tertiary-butylamine are added and the mixture is refluxed for 12 hours. It is evaporated to dryness and the residue of evaporation is taken up in distilled water. The free base which has crystallised is filtered off and, by recrystallisation in hexane, 39 g (yield 63%) of 1-(4-fluorophenyl)-2-tertiary-butylamino-1-ethanol are obtained. m.p. 117° C.
Reaction SMILES: [CH:1]1([C:6]2([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.[C:17](Cl)(=[O:21])[C:18]([CH3:20])=[CH2:19].C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)C>[C:17]([O:11][C:6]1([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:7][CH2:8][CH2:9][CH2:10]1)(=[O:21])[C:18]([CH3:20])=[CH2:19]
Reactant: C=C(C)C(=O)Cl
Reactant: OC1(C2CCCC2)CCCC1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OC1(C2CCCC2)CCCC1
Temperature: 25 °C
Yield: 91 %

Procedure:
To a 1-L 3-necked round bottom flask equipped with a 250-mL pressure equalizing addition funnel, a nitrogen inlet with thermocouple and an overhead stirrer was added 56 g (0.364 mol) of 1-cyclopentyl-1-cyclopentanol and 400 mL of anhydrous tetrahydrofuran. The addition funnel was charged with 250 mL (0.4 mol) of n-butyllithium (1.6M in hexane) which was then added to the cooled alcohol over 2 hours. The addition funnel was then charged with a solution of 41 g (0.39 mol) of freshly distilled methacryloyl chloride in 100 mL of dry tetrahydrofuran which was then added slowly with cooling over 1.5 hours. The reaction mixture was allowed to warm to room temperature with stirring overnight after which 100 mL of saturated sodium bicarbonate was carefully added with stirring. The mixture was stirred for 1 hour at which time it was diluted with 1 L of diethyl ether and the organics washed with water, brine and dried for 1 hour over anhydrous magnesium sulfate. Filtration and removal of the solvent at reduced pressure resulted in a light-colored oil which was eluted with hexane through a column of 600 g of silica gel. The UV active fractions were collected and the solvent removed at reduced pressure to yield 74 g (91%) of the title compound as a clear, colorless oil.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][CH:12]=[CH2:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C12CCCC(CCC1)B12[H]B2(C3CCCC2CCC3)[H]1.Br[C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[C:37]([F:43])[CH:36]=1>C1COCC1.Cl[Pd]Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:39]([C:38]1[CH:41]=[CH:42][C:35]([CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:10])=[CH:36][C:37]=1[F:43])#[N:40]
Reactant: N#Cc1ccc(Br)cc1F
Reactant: C=CNC(=O)OCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(CCNC(=O)OCc2ccccc2)cc1F
Temperature: -10 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
Into a 100 mL single neck flask was placed (phenylmethoxy)-N-vinylcarboxamide (5.54 g, 31.25 mmol) in THF (15 mL). The mixture was cooled down to −10° C. while treated dropwise with a solution of 9-BBN dimer (3.81 g, 15.62 mmol) in THF (20 mL). The reaction mixture was warmed up to RT while stirring for additional 2 hours. The reaction mixture was quenched with 3N NaOH (2mL) and the mixture was stirred for 10 minutes before its addition to a solution of 4-bromo-2-fluorobenzonitrile (5 g, 25 mmol) and [1,1′bis(diphenylphosphino)-ferrocene] dichloropalladium (II), PdCl2(dppf), (0.4 g, 0.5 mmol) in THF (10 mL). The mixture was stirred at RT for 12 hour and then was quenched with a 2:1 mixture of pH=7 buffer hydrogen peroxide (10 mL). The product was extracted with EtOAc and the organic layer was separated and washed twice with H2O, dried over anhydrous Na2SO4, filtered, and concentrated under reduced vacuum. The resulting semi-solid was further purified via flash chromatography (Silica gel, isocratic) and eluting with a solvent of Hexanes/EtOAc 50% to provide the intermediate title compound, N-[2-(4-cyano-3-fluorophenyl)ethyl](phenylmethoxy)carboxamide, (6.4 g, 86%) as a white solid. Electron spray M.S. 299 (M*+H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH2:7]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH2:16][CH3:17])[C:10]=1[CH:18]1[C:26](=[O:27])[CH:25]2[CH:20]([CH:21]3[O:28][CH:24]2[CH2:23][CH2:22]3)[C:19]1=[O:29])[CH3:8].C(N(CC)CC)C>ClCCl>[CH2:5]([O:4][C:2](=[O:3])[O:29][C:19]1[CH:20]2[CH:25]([C:26](=[O:27])[C:18]=1[C:10]1[C:11]([CH2:16][CH3:17])=[CH:12][C:13]([CH3:15])=[CH:14][C:9]=1[CH2:7][CH3:8])[CH:24]1[O:28][CH:21]2[CH2:22][CH2:23]1)[CH3:6]
Reactant: CCc1cc(C)cc(CC)c1C1C(=O)C2C3CCC(O3)C2C1=O
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)OC1=C(c2c(CC)cc(C)cc2CC)C(=O)C2C3CCC(O3)C12
Temperature: 25 °C

Procedure:
A solution of ethyl chloroformate (0.071 g, 0.65 mmol) in dichloromethane (0.5 ml) is added dropwise to a solution of (1RS,2SR,6RS,7SR)-4-(2,6-diethyl-4-methylphenyl)-10-oxatricyclo[5.2.1.02,6]decane-3,5-dione (0.172 g, 0.55 mmol) in dichloromethane (2 ml) at 0° C. and the reaction mixture is stirred. A solution of triethylamine (0.066 g, 0.65 mmol) in dichloromethane (1 ml) is added and the reaction mixture is stirred at room temperature for 17 hours, warming slowly to room temperature. The reaction mixture is diluted with dichloromethane (3 ml) and washed with saturated aqueous sodium bicarbonate solution. The organic phase is separated, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give carbonic acid (1RS, 2SR,6RS,7SR)-5-oxo-4-(2,6-diethyl-4-methylphenyl)-10-oxatricyclo-[5.2.1.02,6]-dec-3-en-3-yl ester ethyl ester as a colourless solid.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:5][C:6]2[CH:12]=[C:11]([C:13]([O:15]C)=[O:14])[CH:10]=[C:9]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:7]=2[CH:8]=1.C1COCC1>CO>[CH3:3][C:4]1[O:5][C:6]2[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[C:9]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:7]=2[CH:8]=1
Reactant: COC(=O)c1cc(OCC(C)C)c2cc(C)oc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2c(OCC(C)C)cc(C(=O)O)cc2o1
Temperature: 50 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
Sodium hydroxide solution (2.28 ml of 1M, 2.28 mmol, 3 eq) was added to a solution of 2-methyl-4-isobutoxy-6-methoxycarbonylbenzofuran (Method 7; 200 mg, 0.76 mmol; contained ca 15 mol % of isobutyl ester) in MeOH (2.28 ml)/THF (2.28 ml). After 2 hours at 50° C. the reaction mixture was stirred at ambient temperature overnight and then concentrated to half-volume in vacuo. The resulting solution was diluted with water and acidified to pH 5 (1M HCl), and the resulting flocculent precipitate filtered and dried to give the title compound as a colourless solid (165 mg, 88%). NMR: 1.02 (d, 6H), 2.06 (sept, 1H), 2.45 (s, 3H), 3.90 (d, 2H), 6.64 (s, 1H), 7.24 (s, 1H), 7.64 (s, 1H), 12.83 (bs, 1H); m/z 247 (M−H)−, 94.6% by LC-MS.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([OH:12])=O)=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.Cl.Cl.[N:15]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[CH:17]([NH2:23])[CH2:16]2.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[N:15]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[CH:17]([NH:23][C:10]([C:3]1[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=1)=[O:12])[CH2:16]2
Reactant: Nc1nc(N)c(C(=O)O)nc1Cl
Reactant: NC1CN2CCC1CC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1nc(N)c(C(=O)NC2CN3CCC2CC3)nc1Cl

Procedure:
A solution of 3,5-diamino-6-chloropyrazine-2-carboxylic acid (Intermediate 1.1.1, 2.50 g, 13.1 mmol), 1-aza-bicyclo[2.2.2]oct-3-ylamine dihydrochloride (2.87 g, 14.4 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (4.62 g, 14.4 mmol) and triethylamine (6.72 mL, 39.3 mmol) in dry N,N-dimethylformamide (25 mL) is stirred overnight at room temperature under nitrogen atmosphere. The resulting solid is collected by filtration, washed with diethyl ether and dried at 50° C. under vacuum.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[CH:3]([C:30]1[CH:35]=[C:34]([Cl:36])[C:33]([Cl:37])=[C:32]([Cl:38])[CH:31]=1)/[CH:4]=[CH:5]/[C:6]1[CH:25]=[CH:24][C:9]([C:10]([NH:12][C:13]2([C:16](=O)[NH:17][CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:15][CH2:14]2)=[O:11])=[C:8]([C:26]([F:29])([F:28])[F:27])[CH:7]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:42].C[Si](C)(C)O[Si](C)(C)C>C(Cl)Cl>[F:1][C:2]([F:40])([F:39])[CH:3]([C:30]1[CH:35]=[C:34]([Cl:36])[C:33]([Cl:37])=[C:32]([Cl:38])[CH:31]=1)/[CH:4]=[CH:5]/[C:6]1[CH:25]=[CH:24][C:9]([C:10]([NH:12][C:13]2([C:16](=[S:42])[NH:17][CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:15][CH2:14]2)=[O:11])=[C:8]([C:26]([F:29])([F:28])[F:27])[CH:7]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C(NC1(C(=O)NCC(F)(F)F)CC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1C(F)(F)F
Solvent: C[Si](C)(C)O[Si](C)(C)C
Solvent: ClCCl
Product: O=C(NC1(C(=S)NCC(F)(F)F)CC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Yield: 36.3 %

Procedure:
To a stirred solution of (E)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-N-(1-(2,2,2-trifluoroethylcarbamoyl)cyclopropyl)-2-(trifluoromethyl)benzamide (200 mg, 0.31 mmol) in CH2Cl2 (20 mL) was added P4S10 (34 mg, 0.155 mmol) and hexamethyldisiloxane (HMDO, 0.1 mL, 0.517 mmol) and the reaction mixture was refluxed for 4 h. The reaction mixture was cooled to room temperature and another portion of P4S10 (34 mg, 0.155 mmol) and HMDO (0.1 mL, 0.517 mmol) were added and the reaction mixture was refluxed for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica (100-200 mesh) eluting with 10% EtOAc in hexane to give the title compounds as yellow gum (37 mg, 18%). Characterization data for this molecule is listed in Table 2.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]#[C:19][CH3:20])=[CH:12][CH:11]=1)(=[O:9])=[O:8])C.[OH-].[Na+].Cl>C1COCC1.CO>[CH2:17]([O:16][C:13]1[CH:12]=[CH:11][C:10]([S:7]([NH:6][CH2:5][C:4]([OH:21])=[O:3])(=[O:9])=[O:8])=[CH:15][CH:14]=1)[C:18]#[C:19][CH3:20]
Reactant: CC#CCOc1ccc(S(=O)(=O)NCC(=O)OCC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)NCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
To a solution of 0.30 g (0.965 mmol) of the product of Example 20 in 10 mL of THF/methanol (1:1) was added 4.8 mL of a 1.0N sodium hydroxide solution and the reaction was stirred overnight at room temperature and then acidified to pH 2 with 10% HCl solution. The resulting mixture was extracted with dichloromethane and the combined organics were dried over MgSO4, filtered and concentrated in vacuo to provide 0.238 g (83%) of the sulfonamide as a white solid. Electrospray Mass Spec 281.9 (M−H)−
Reaction SMILES: N12CCCN=C1CC[CH2:4][CH2:3][CH2:2]2.IC(C)C.[OH:16][C@H:17]([C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:33](=[O:34])[CH2:32][O:31][C@@H:30]2[CH2:35][CH2:36][CH2:37][C:38]2[S:42][C:41]([C:43]([OH:45])=[O:44])=[CH:40][CH:39]=2)=[CH:25][CH:24]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CC(C)=O>[OH:16][C@H:17]([C:23]1[CH:24]=[CH:25][C:26]([N:29]2[C:33](=[O:34])[CH2:32][O:31][C@@H:30]2[CH2:35][CH2:36][CH2:37][C:38]2[S:42][C:41]([C:43]([O:45][CH:3]([CH3:4])[CH3:2])=[O:44])=[CH:40][CH:39]=2)=[CH:27][CH:28]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCCCC[C@H](O)c1ccc(N2C(=O)CO[C@@H]2CCCc2ccc(C(=O)O)s2)cc1
Solvent: CC(C)I
Solvent: CC(C)=O
Product: CCCCC[C@H](O)c1ccc(N2C(=O)CO[C@@H]2CCCc2ccc(C(=O)OC(C)C)s2)cc1
Reaction time: 72 h
Yield: 72.2 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU, 5.5 μL, 0.037 mmol) and 2-iodopropane (65 μL, 0.65 mmol) were added to a solution of acid 12i (8 mg, 0.019 mmol) in acetone (0.19 mL) at rt under nitrogen. After 3 d at room temperature, the volatiles were evaporated under a stream of nitrogen. The residue was diluted with water (1 mL), acidified with 1.0 N HCl (1 mL) and extracted with EtOAc (3×10 mL). The combined extracts were washed with brine (5 mL), then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on 4 g silica (hexanes→EtOAc, gradient) afforded 6.5 mg (74%) of 12j.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]3[C:16]4[CH:29]=[CH:28][S:27][C:17]=4[C:18](=[O:26])[NH:19][C:20]=3[CH:21]=[CH:22][C:23]=2[O:24][CH3:25])=[CH:10][CH:9]=1)(=[O:7])=[O:6].CCN(S(F)(F)[F:36])CC>C(Cl)Cl.C1COCC1>[F:36][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]3[C:16]4[CH:29]=[CH:28][S:27][C:17]=4[C:18](=[O:26])[NH:19][C:20]=3[CH:21]=[CH:22][C:23]=2[O:24][CH3:25])=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(S(=O)(=O)NCCO)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(S(=O)(=O)NCCF)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 74.3 %

Procedure:
To a solution of N-(2-hydroxyethyl)-4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)benzenesulfonamide (120 mg, 0.28 mmol) in methylene chloride (10 mL) and THF (6 mL) under nitrogen at −78° C. was added DAST (89 mg, 0.56 mmol) and the reaction mixture was stirred at −78° C. for 2 h and warmed to room temperature and stirred for 16 h. The reaction mixture was concentrated and the residue was purified by column chromatography (silica gel, ethyl acetate/hexanes gradient). The resulting crude residue was triturated in methylene chloride and filtered to afford the desired product (90 mg, 75%) as a off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 11.92 (s, 1H), 8.10 (t, J=5.9 Hz, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.76 (d, J=5.4 Hz, 1H), 7.56 (d, J=9.1 Hz, 1H), 7.51 (d, J=8.4 Hz, 2H), 7.43 (d, J=9.2 Hz, 1H), 5.75 (d, J=5.4 Hz, 1H), 4.51 (t, J=4.9 Hz, 1H), 4.42 (t, J=4.9 Hz, 1H), 3.71 (s, 3H), 3.24 (q, J=5.2 Hz, 1H), 3.19 (q, J=5.2 Hz, 1H); ESI MS m/z 433 [C20H17FN2O4S2+H]+; HPLC 93.4% (AUC), tR=15.64 min.