Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2([CH2:22]OS(C)(=O)=O)[CH2:13][CH:12]3[N:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][S-:29].[Na+].C(OCC)C>CN(C=O)C>[CH:1]1([C:7]2([CH2:22][S:29][CH3:28])[CH2:13][CH:12]3[N:14]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(COS(C)(=O)=O)(C1CCCCC1)C2
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CSCC1(C2CCCCC2)CC2CCC(C1)N2C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 72 h

Procedure:
To a solution of tert-butyl 3-cyclohexyl-3-{[(methylsulfonyl)oxy]methyl}-8-azabicyclo[3.2.1]octane-8-carboxylate (3-4) (1.01 g, 2.69 mmol) in 50 mL of DMF was added sodium thiomethoxide (0.943 g, 13.5 mmol). The mixture was stirred at 60° C. for 3 days. After cooling to room temperature, 200 mL of diethyl ether was added. The solid was filtered and the filtrates were washed with water three times. The organics were dried over anhydrous MgSO4, filtered, and concentrated to give (3-5) as a clear yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>CC(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:12]1[C:21]3[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=1)[CH2:6][CH2:5]2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Fc1ccc2c(c1)CCN2
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCc4cc(F)ccc43)c2cc1OC
Yield: 81 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 81% yield from 5-fluoro-indoline (1.1 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq)in i-PrOH. (M.P. 190°-191° C.; LC-MS: 326 (MH+); anal. RP18-HPLC RT: 4.40 min.).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:10]([C:12]1[C:17]2[N:18]=[C:19]([C:21](=[S:23])[NH2:22])[O:20][C:16]=2[C:15]([F:24])=[C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:13]=1[CH3:31])#[N:11].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>O.C1(C)C=CC=CC=1>[C:10]([C:12]1[C:17]2[N:18]=[C:19]([C:21]3[S:23][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:22]=3)[O:20][C:16]=2[C:15]([F:24])=[C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:13]=1[CH3:31])#[N:11]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(N)=S)nc2c1C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1csc(-c2nc3c(C#N)c(C)c(-c4ccccc4)c(F)c3o2)n1
Temperature: 125 °C
Yield: 91.3 %

Procedure:
Ethyl 3-bromopyruvate (72.2 μl, 0.518 mmol) was added to a toluene (10 ml) solution of 4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-2-carbothioamide (I-196-1) (124 mg, 0.398 mmol), followed by heating under reflux in an oil bath at 125° C. for 2 hours. After cooling to room temperature, p-toluenesulfonic acid monohydrate (15.2 mg, 0.080 mmol) was added to the reaction liquid, followed by heating under reflux in an oil bath at 125° C. for 15 hours. After cooling to room temperature, an aqueous saturated sodium hydrogencarbonate solution (50 ml) and water (50 ml) were added, followed by extraction with ethyl acetate (50 ml×2). The organic layer was washed with an aqueous saturated sodium hydrogencarbonate solution (50 ml) and saturated brine (50 ml), and dried over anhydrous sodium sulfate. After concentration, the resulting residue was purified by silica gel column chromatography (eluent, chloroform:ethyl acetate=100:1→25:1) to obtain the entitled compound (148 mg, 91.2%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:22](Cl)(=[O:25])[CH:23]=[CH2:24]>CCOCC>[CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]1[C:22](=[O:25])[CH:23]=[CH2:24])=[O:5])[CH3:2]
Reactant: C=CC(=O)Cl
Reactant: CCOC(=O)C1Cc2ccccc2N1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CC(=O)N1c2ccccc2CC1C(=O)OCC
Yield: 78.3 %

Procedure:
To a chilled and stirred mixture of 2,3-dihydroindole-2-carboxylic acid ethyl ester (14.34 g.), triethylamine (7.65 g.) and anhydrous ether (600 ml.) was added dropwise acryloyl chloride (7.1 g.) dissolved in a small amount of ether. The ice bath was removed, and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was chilled in ice, then a precipitate was removed by filtration. The filter residue was washed with ether. The combined filtrate and washing were washed with water, then with saline, and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure on a rotary evaporator gave the titled compound (14.4 g.) as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][OH:23].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([O:23][CH2:22][CH2:21][N:20]([CH3:24])[CH3:19])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CN(C)CCO
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CN(C)CCOc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, 2-dimethylaminoethanol and DBU in DME. ES-MS m/e (%): 274 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:31]=[CH:30][C:14]([CH2:15][NH:16][C:17]3[CH:29]=[CH:28][C:20]4[O:21][C:22]([CH3:27])([CH3:26])[O:23][C:24](=[O:25])[C:19]=4[CH:18]=3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[CH:32](=O)[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(O)(=O)C>[CH2:32]([N:16]([CH2:15][C:14]1[CH:30]=[CH:31][C:11]([C:10]#[C:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:12][CH:13]=1)[C:17]1[CH:29]=[CH:28][C:20]2[O:21][C:22]([CH3:27])([CH3:26])[O:23][C:24](=[O:25])[C:19]=2[CH:18]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: COc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Reactant: CCCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCCCCCN(Cc1ccc(C#Cc2ccc(OC)cc2)cc1)c1ccc2c(c1)C(=O)OC(C)(C)O2
Temperature: 70 °C
Yield: 103.5 %

Procedure:
To a solution of 6-({4-[(4-methoxyphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one (416 mg; 1.01 mmol) in anhydrous DCE (15 mL) were added hexanal (Aldrich, 181 μl; 1.51 mmol), sodium triacetoxyborohydride (426 mg, 2.01 mmol) and acetic acid (115 μl). The resulting mixture was heated at 70° C. under nitrogen atmosphere for 24 h and poured into a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with DCM (twice) and combined organic layers were washed with brine, dried over magnesium sulfate, filtrated and concentrated. Purification by flash chromatography on silica gel (EtOAc/c-Hex 5:95 then 10:90) gave 520 mg of the title compound (quantitative). HPLC, Rt : 5.82 min (purity: 99.9%). LC/MS, M+(ESI): 498.7. 1H NMR (CDCl3) δ: 7.43 (d, J=8.9 Hz, 4H), 7.21 (s, 1H), 7.16 (d, J=8.1 Hz, 2H), 6.74-6.86 (m, 4H), 4.48 (s, 2H), 3.80 (s, 3H), 3.34 (t, J=7.8 Hz, 2H), 1.68 (s, 6H), 1.61 (m, 2H), 1.27 (s, 6H), 0.86 (m, 3H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[C:18]([O:20][CH3:21])=[O:19])[C:12]([OH:14])=[O:13]>C(O)(=O)C>[NH:8]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[C:18]([O:20][CH3:21])=[O:19])[C:12]([OH:14])=[O:13])[C:1]([CH3:2])=[O:3]
Reactant: COC(=O)c1ccc(C(=O)O)cc1N
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C(=O)O)cc1NC(C)=O
Yield: 89.4 %

Procedure:
Acetic anhydride (1.89 mL, 20 mmol) was added to a suspension of 3-amino-4-methoxycarbonylbenzoic acid (1.95 g, 10 mmol) in acetic acid (10 mL), and the mixture was heated with reflux for 6 hours. After cooling, the precipitated solid was filtered to obtain 2.12 g of the desired product as a colorless solid (yield 89%).
Reaction SMILES: [CH2:1]([S:8][CH2:9][C:10]([CH2:16][S:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH2:13][CH2:14][CH3:15])[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][Mg]I.[Cl-].[NH4+]>C(OCC)C>[CH2:18]([S:17][CH2:16][C:10]([CH2:9][S:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH2:13][CH2:14][CH3:15])[CH:11]([OH:12])[CH3:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCCC(C=O)(CSCc1ccccc1)CSCc1ccccc1
Reactant: C[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCC(CSCc1ccccc1)(CSCc1ccccc1)C(C)O
Reaction time: 0.5 h

Procedure:
A solution of 2,2-di-(benzylthiomethyl)pentanal (3.54 g) in dry diethyl ether was added dropwise to a stirred solution of methyl magnesium iodide [prepared from methyl iodide (1.2 ml) and magnesium (0.48 g)] in dry diethyl ether (60 ml). The reaction mixture was refluxed for 2 hours and then cooled. Saturated aqueous ammonium chloride solution was added. The mixture was stirred for 30 minutes and extracted with diethyl ether. The ethereal extracts were dried over anhydrous magnesium sulphate and the solvent was removed in vacuo. 3,3-Di-(benzylthiomethyl)hexan-2-ol was obtained as a yellow oil (1.7 g)
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[CH3:15].BrN1C(=O)CCC1=O.[CH:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH2:32])=[CH:26][CH:25]=1>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])=[CH:4][C:3]=1[CH2:15][NH:32][CH2:31][CH2:30][C:27]1[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=1
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1F
Reactant: NCCc1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)c1ccc(F)c(CNCCc2ccccc2)c1
Yield: 64.6 %

Procedure:
According to the procedure of Preparation 4(b), except using tert-butyl 4-fluoro-3-methylbenzoate (6.25 g, 29.7 mmole), N-bromosuccinimide (5.75 g, 32.3 mmole), benzoyl peroxide (375 mg, 1 .6 mmole ), CCl4 (50 gL), and 2-phenethylamine (19 mL, 151 mmole ), the title compound (6.32 g, 64%) was prepared as a yellow oil following flash chromatography on silica gel (gradient: 20-40% EtOAc/hexanes): MS (ES) m/e 330.1 (M+H)+.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.[F:16][C:17]([F:41])([F:40])[CH2:18][NH:19][C:20]([C:22]1([CH2:35][CH2:36][CH2:37][CH2:38]Br)[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:21]>>[F:16][C:17]([F:40])([F:41])[CH2:18][NH:19][C:20]([C:22]1([CH2:35][CH2:36][CH2:37][CH2:38][N:13]2[CH2:14][CH2:15][N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=3)[CH2:11][CH2:12]2)[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:21]
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Agent: Cl
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3cccc(Cl)c3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 b from 1-(3-chlorophenyl)-piperazine dihydrochloride and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: C([C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH3:17])=[C:9]2[C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:5][CH:4]=1)#N.Cl.[C:27](=[O:30])(O)[O-:28].[Na+]>C(O)(=O)C>[C:27]([C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH3:17])=[C:9]2[C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:5][CH:4]=1)([OH:28])=[O:30]
Reactant: O=C([O-])O
Reactant: Cc1c(-c2cccnc2)n(Cc2ccc(C#N)cc2)c2ccccc12
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1c(-c2cccnc2)n(Cc2ccc(C(=O)O)cc2)c2ccccc12
Temperature: 0 °C

Procedure:
A solution of 1-(4-cyanobenzyl)-3-methyl-2-(3-pyridyl)indole 5.8 g) in 100 ml of a 1:1 mixture of 20% aqueous hydrochloric acid and glacial acetic acid is heated at reflux for 20 hours. After cooling, the solution is poured into ice water (100 ml) and the pH is adjusted to 4.5-5 with saturated sodium bicarbonate solution. The resulting precipitate is extracted with ethyl acetate, the ethyl acetate extract is washed with water and evaporated to dryness to give 1-(4-carboxybenzyl)-3-methyl-2-(3-pyridyl)indole, m.p. 273°-275°.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:14]=3[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:30](=[O:35])(OCC)[NH2:31].C(O)C>[Cl-].[Zn+2].[Cl-].C(Cl)(Cl)Cl>[C:1]12([CH2:11][N:12]3[C:13]4[C:14](=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=4)[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:31][C:30]3=[O:35])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CCOC(N)=O
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1NCC12CC3CC(CC(C3)C1)C2
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=c1nc(-c2ccccc2)c2cc([N+](=O)[O-])ccc2n1CC12CC3CC(CC(C3)C1)C2
Reaction time: 1 h

Procedure:
A mixture of 3.9 g of 2-(1-adamantylmethyl-amino)-5-nitrobenzophenone, 6.4 g of ethyl carbamate and 0.45 g of anhydrous zinc chloride was heated at 170°- 180°C for 1 hour, and then, distillating off the produced ethanol, heating was continued at that temperature for additional 1 hour. After cooling, chloroform was added thereto and insoluble material was filtered off. The chloroform layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residual oil was chromatographed on silica gel using chloroform as eluting solvent to give 1-(1-adamantylmethyl)-4-phenyl-6-nitro-2(1H)-quinazolinone, m.p. 230°- 233°C, following recrystallization from a mixture of ethanol and chloroform.
Reaction SMILES: O.Cl.Cl.[NH2:4][C:5]1[CH:6]=[C:7]([C:11]2[N:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH:13]=[CH:14][C:15](=[O:21])[NH:16]3)[CH:8]=[CH:9][CH:10]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[OH2:21].[C:22]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[N:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH:13]=[CH:14][C:15](=[O:21])[NH:16]3)[CH:8]=[CH:9][CH:10]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(-c2nccc3[nH]c(=O)ccc23)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1cccc(-c2nccc3[nH]c(=O)ccc23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture containing 6.57 g of 5-(3-aminophenyl)-1,6-naphthyridin-2(1H)-one dihydrochloride monohydrate and 63 ml of pyridine was added dropwise over a period of 5 minutes 4.8 ml of acetic anhydride. The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated on a rotary evaporator to dryness. The residue was slurried with water; and, the solid was collected, washed with water and dried in a vacuum oven at 90° C. to yield 5.4 g of 5-(3-acetylaminophenyl)-1,6-naphthyridin-2(1H)-one monohydrate, m.p. 258°-262° C.
Reaction SMILES: [C:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=2)[CH3:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.[CH3:33][CH:34]([CH3:38])[C:35](=[O:37])[CH3:36].[Cl-].[NH4+]>O1CCCC1>[C:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]([CH2:12][C:13]2[CH:14]=[C:15]([C:35]([OH:37])([CH:34]([CH3:38])[CH3:33])[CH3:36])[CH:16]=[CH:17][CH:18]=2)[CH3:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)C(C)C
Reactant: CN(Cc1ccc(C(C)(C)C)cc1)Cc1cccc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)C(C)(O)c1cccc(CN(C)Cc2ccc(C(C)(C)C)cc2)c1
Temperature: -40 °C
Yield: 43.3 %

Procedure:
Compound 78 (2.00 g; 5.78 mmol) was dissolved in tetrahydrofuran (20 ml). While the solution was stirred at −40° C. under nitrogen atmosphere, n-butyl lithium in n-hexane (1.56 M: 3.7 ml; 5.8 mmol) was added dropwise. After completion of the addition, the mixture was cooled to −75° C., an 3-methyl-2-butanone (2.00 g) in a small amount of tetrahydrofuran was added dropwise thereto. The resultant mixture was gradually brought to room temperature, and the reaction was stopped by dropwise addition of saturated aqueous ammonium chloride solution, followed by extraction with diethyl ether (100 ml). The organic layer was washed with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), to thereby yield 0.86 g of the target compound as brown oily matter (yield: 43.3%).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([C@@H:12]1[O:20][C@H:19]2[C@H:15]([N:16]=[C:17]([N:21]([CH3:23])[CH3:22])[S:18]2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[CH3:40][S:41]([O:11][CH2:10][C@H:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:12]1[O:20][C@H:19]2[C@H:15]([N:16]=[C:17]([N:21]([CH3:23])[CH3:22])[S:18]2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:13]1[O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)(=[O:43])=[O:42]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]([C@@H](C=O)OCc3ccccc3)O[C@@H]2S1
Solvent: ClCCl
Product: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H]([C@H](COS(C)(=O)=O)OCc3ccccc3)O[C@@H]2S1
Reaction time: 2 h
Yield: 79.8 %

Procedure:
To a solution of 102 (1.2 g, 2.2 mmol) (Prepared according to the synthesis of Examples 151 and 152, step 1) in dichloromethane (30 mL) was added TEA (664 mg, 6.6 mmol) and MsCl (499 mg, 4.4 mmol) at 0° C. After kept 2 hours at room temperature, the reaction was quenched by water (100 mL) and extracted with dichloromethane (3×30 mL). The combined organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrates were concentrated to give a residue, which was purified by silica gel column with 10%-30% ethyl acetate in petroleum ether to give the title compound (1.1 g, 80%) as brown syrup; (ES, m/z): [M+H]+ 627.0; 1H NMR (300 MHz, CDCl3) δ 7.22-7.45 (m, 15H), 6.35 (d, J=6.3 Hz, 1H), 5.03-5.15 (m, 2H), 4.61-4.80 (m, 4H), 4.47-4.53 (m, 2H), 4.25-4.36 (m, 1H), 4.08-4.12 (m, 1H), 3.89-3.92 (m, 1H), 3.46-3.78 (m, 2H), 3.06 (s, 6H), 3.01 (s, 3H).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([O:16][C:17]([N:19]([C:39]1[C:44]([O:45][CH3:46])=[N:43][C:42]([CH3:47])=[CH:41][N:40]=1)[S:20]([C:23]1[C:24]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][C:36]([CH3:38])=[CH2:37])=[CH:31][CH:30]=2)=[N:25][CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:21])=[O:18])[CH:13]([CH3:15])[CH3:14]>>[O:6]1[CH2:37][C:36]1([CH3:38])[CH2:35][C:32]1[CH:33]=[CH:34][C:29]([C:24]2[C:23]([S:20]([N:19]([C:17]([O:16][CH2:12][CH:13]([CH3:14])[CH3:15])=[O:18])[C:39]3[C:44]([O:45][CH3:46])=[N:43][C:42]([CH3:47])=[CH:41][N:40]=3)(=[O:22])=[O:21])=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:30][CH:31]=1
Reactant: C=C(C)Cc1ccc(-c2ncccc2S(=O)(=O)N(C(=O)OCC(C)C)c2ncc(C)nc2OC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(CC2(C)CO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.6 %

Procedure:
3-Chloroperoxybenzoic acid (50%, 2.4 g) was added over 5 minutes to a solution of N-(isobutoxycarbonyl)-N-(3-methoxy-5-methylpyrazin-2-yl)-2-[4-(2-methylprop-2-enyl)phenyl]pyridine-3-sulphonamide (1.8 g) in dichloromethanc (75 ml) at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred a further 1 hour. The mixture was washed with saturated aqueous sodium hydrogen carbonate solution (20 ml), water and saturated sodium chloride solution then dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by suction flash chromatography followed by gradient elution with 0-40% ethyl acetate/hexane through a silica gel Mega Bond Elut column to give 2-[4-(2,3-epoxy-2-methylpropyl)phenyl]-N-(isobutoxycarbonyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (0.16 g) as a solid, 1H NMR (CDCl3): 0.65 (d, 6 H), 1.3 (s, 3 H), 1.7 (m, 1 H), 2.5 (s, 3 H), 2.65 (dd, 2 H), 2.9 (q, 2 H), 3.85 (d, 2 H), 4.0 (s, 3 H), 7.3 (d, 2 H), 7.5 (dd, 1 H), 7.6 (d, 2 H), 7.95 (s, 1 H), 8.85 (dd, 1 H), 8.95 (dd, 1 H); mass spectrum (+ve ESP): 527 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].CC1C=CC(S([O:24][CH2:25][C@@H:26]2O[CH2:27]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CCOCC>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]2[O:12][CH2:27][CH:26]([CH2:25][OH:24])[O:1][C:2]=2[C:3]=1[CH3:13])=[O:6]
Reactant: COC(=O)c1ccc(O)c(O)c1C
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1C)OC(CO)CO2
Temperature: 60 °C
Yield: 78 %

Procedure:
To a round bottom flask equipped with magnetic stirring and a nitrogen inlet was added methyl 3,4-dihydroxy-2-methylbenzoate (24.0 g, 132 mmol), (2R)-(−)-glycidyl tosylate (30.1 g, 132 mmol), potassium carbonate (21.8 g, 158 mmol), and DMF (264 mL). This mixture was heated to 60° C. for 5 hours. The mixture was cooled to room temperature, diluted with ether, and washed once with water. The aqueous wash was back extracted once with ether and the ethereal solutions combined. These organic solutions were then washed 3 times with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to give a brown oil. This oil was chromatographed on silica gel eluting with 25% ether in hexanes to give a yellow oil, 3-hydroxymethyl-5-methyl-2,3-dihydrobenzo[1,4]dioxine-6-carboxylic acid methyl ester, (24.6 g, 103 mmol) in 78% yield. 1H-NMR (300 MHz, CD3COCD3) δ (ppm): 2.42 (s, 2H), 3.80 (s, 3H), 3.83 (m, 1H), 4.12 (dd, 1H), 4.23 (m, 2H), 4.42 (dd, 1H), 6.75 (d, 1H), 7.42 (d, 1H); TLC Rf=0.40 (1:1 ethyl acetate/hexane).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17]C(=O)C)=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[N:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([NH:7][C:5]2[S:6][C:2]([CH3:1])=[N:3][N:4]=2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(C)s2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1nnc(NS(=O)(=O)c2ccc(N)cc2)s1
Yield: 72.5 %

Procedure:
Compound 106 (250 mg, 0.8 mmol) was suspended in 3 N HCl (4 mL) and the suspension heated to reflux for 30 min. Following neutralization with saturated aqueous Na2CO3 solution, the precipitated product was collected by filtration, washed with water (3×20 mL), and dried under vacuum. The residue was crystallized from MeOH to give the product (155 mg, 0.58 mmol, 72%) as a solid, mp 207-208° C. (lit mp 208)1; 1H NMR (500 MHz, DMSO) δ 2.47 (3, s), 5.89 (2, s), 6.58 (2, d, J=8.5 Hz), 7.40 (2, d, J=8.5 Hz), 10.48 (1, s); 13C NMR (125 MHz, DMSO) δ 16.0, 112.5, 127.2, 127.6, 152.4, 153.6, 166.8.