Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([CH:20]=[C:21]([S:23]([F:28])([F:27])([F:26])([F:25])[F:24])[CH:22]=2)[C:17]([OH:19])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:60][C:61]1[CH:67]=[CH:66][C:64]([NH2:65])=[CH:63][C:62]=1[N:68]1[C:75]2[N:71]([N:72]=[C:73]([C:76]3[CH:77]=[N:78][NH:79][CH:80]=3)[CH:74]=2)[CH:70]=[CH:69]1.N>CN(C=O)C>[CH3:60][C:61]1[CH:67]=[CH:66][C:64]([NH:65][C:17]([C:16]2[CH:15]=[C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)[CH:22]=[C:21]([S:23]([F:26])([F:28])([F:27])([F:24])[F:25])[CH:20]=2)=[O:19])=[CH:63][C:62]=1[N:68]1[C:75]2[N:71]([N:72]=[C:73]([C:76]3[CH:77]=[N:78][NH:79][CH:80]=3)[CH:74]=2)[CH:70]=[CH:69]1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cn[nH]c3)cc12
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(C(=O)O)cc(S(F)(F)(F)(F)F)c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cc(N3CCN(C(=O)OC(C)(C)C)CC3)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cn[nH]c3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound from Example 16A (320 mg, 0.74 mmol) was dissolved in 2.3 ml of DMF, HATU (309 mg, 0.81 mmol) and then 4-methylmorpholine (0.32 ml) were added, and the mixture was stirred at RT for 30 min. At −5° C., the compound of Example 7A (103 mg, 0.37 mmol) was then added and the mixture was stirred at RT for 16 h. A few milliliters of concentrated aqueous ammonia solution were then added. The mixture was stirred at RT for 15 min and then extracted with ethyl acetate. The organic phase was washed with conc. sodium chloride solution, dried over sodium sulphate, filtered and concentrated. The crude product was purified by preparative HPLC (Method 28). This gave 210 mg (purity 61%, 50% of theory) of the title compound which was used without further purification for the next synthesis step.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=2)=O)[CH2:12][C:13](=O)[CH3:14])=[CH:7][CH:6]=1.O>C(O)C>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([CH3:14])[N:3]=[N:2][C:16]=2[C:18]2[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=2)=[CH:7][CH:6]=1
Reactant: NN
Reactant: CSc1ccc(C(=O)C(CC(C)=O)c2ccc(Cl)cc2)cc1
Solvent: O
Solvent: CCO
Product: CSc1ccc(-c2nnc(C)cc2-c2ccc(Cl)cc2)cc1
Temperature: 80 °C
Reaction time: 7 h
Yield: 64.4 %

Procedure:
Hydrazine hydrate (72 mg, 1.44 mmol) was added to a solution of 4-(4-chlorophenyl)-5-[4-(methylthio)phenyl]pentane-2,5-dione (317 mg, 0.953 mmol) in ethanol (6 ml), and the resulting mixture was stirred for 7 hours at a bath temperature of 80° C. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was washed successively with water and brine, and was then dried over anhydrous sodium sulfate. The solvent was distilled off and the residue (320 mg) was dissolved in chloroform. The thus-obtained solution was stirred at room temperature for 7 hours to conduct air oxidation. The solvent was distilled off and the residue (296 mg) was separated and purified by preparative thin-layer chromatography on silica gel (developing solvent: chloroform), whereby the title compound was obtained as a pale yellow oil (200.5 mg, 64.3%).
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:4])=[O:3].[ClH:14].[H][H]>C(O)C.[Pt]=O>[ClH:14].[CH3:1][S:2]([NH:5][CH2:6][CH2:7][CH:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)(=[O:3])=[O:4]
Reactant: [H][H]
Reactant: CS(=O)(=O)NCCc1ccncc1
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)NCCC1CCNCC1
Reaction time: 8 h

Procedure:
4-(2-methanesulphonamidoethyl)pyridine (8.4 g.) in ethanol (85 ml.) was acidified to pH 2 with 2 N HCl and hydrogenated at room temperature and a pressure of 50 p.s.i. over a platinum oxide catalyst until hydrogen uptake ceased. The catalyst was then removed by filtration and the filtrate was taken to dryness in vacuo to give a white solid which was dissolved in the minimum volume of hot ethanol, filtered quickly, and left at room temperature overnight. The resultant white crystals were collected by filtration and dried to yield 4-(2-methanesulphonamidoethyl)piperidine hydrochloride (8.3 g.), m.p. 165°-167° C.
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5]([CH:11]=[O:12])=[CH:4][CH:3]=1.Cl[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>S1(CCCC1)(=O)=O>[CH:11]([C:5]1[C:6]2[CH:10]=[CH:9][S:8][C:7]=2[C:2]([O:1][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=2)=[CH:3][CH:4]=1)=[O:12]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: O=Cc1ccc(O)c2sccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: N#Cc1ccc(Oc2ccc(C=O)c3ccsc23)nc1
Temperature: 80 °C

Procedure:
A suspension of 7-hydroxybenzo[b]thiophene-4-carbaldehyde (Preparation 69) (100 mg, 0.62 mmol), 6-chloronicotinonitrile (86 mg, 0.62 mmol) and K2CO3 (258 mg, 1.87 mmol) in sulfolane (3 mL) was heated in a microwave reactor at 130 W/80° C. for 4 h. The mixture was cooled, poured onto ice water and the resulting solid filtered and air-dried to give the title compound: RT=3.40 min; m/z (ES+)=265.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.I[CH3:10]>C1C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[C:3]([O:8][CH3:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ncccc1Br
Reactant: CI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: COc1ncccc1Br
Reaction time: 24 h
Yield: 62.5 %

Procedure:
Under an argon atmosphere, a mixture of 3-bromo-2-hydroxypyridine (3.49 g, 20 mmol), silver carbonate (3.67 g, 13.31 mmol), and iodomethane (1.5 mL, 24.1 mmol) in benzene (30 mL) was stirred in the dark at 40° C. to 50° C. for 24 hours, cooled in an ice bath, and filtered. The filtrate was washed once with 2% aqueous sodium bicarbonate and twice with water, dried (MgSO4), the benzene was evaporated at atmospheric pressure, and the residue was purified by flash chromatography (eluting with hexane/ethyl acetate, 2:1) to obtain the title compound (2.35 g, 12.5 mmol, 62%).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17].CCN(CC)CC>C(Cl)Cl>[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(Br)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccc(Br)c([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 94.4 %

Procedure:
2,2-dimethylpropanoyl chloride (28 g, 232.2 mmol) was added to a stirred solution of 4-bromo-3-nitro-aniline (42 g, 193.5 mmol) and Et3N (51 mL, 366 mmol) in anhydrous DCM (200 mL) at 0° C. under an atmosphere of N2. The cooling bath was removed and the stirring was continued at room temperature for 2 h. The reaction mixture was poured into ice (500 g) and extracted with CH2Cl2. The combined organic layer was dried over Na2SO4 and evaporated in vacuo to afford crude product N-(4-bromo-3-nitrophenyl)pivalamide (55 g, 94%) which was used directly in the next step. 1H NMR (300 MHz, CDCl3) δ: 8.18-8.17 (m, 1H), 7.64-7.63 (m, 2H), 7.50 (br s, 1H), 1.32 (s, 9H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([S:16]([NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])=[O:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][C:5]=1[F:24])(=O)[CH3:2].II.[NH2:27][C:28]([NH2:30])=[S:29]>CCO>[NH2:30][C:28]1[S:29][CH:2]=[C:1]([C:4]2[CH:9]=[CH:8][C:7]([C:10]3[C:11]([S:16]([NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])=[O:17])=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:6][C:5]=2[F:24])[N:27]=1
Reactant: CC(=O)c1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Reactant: NC(N)=S
Agent: II
Solvent: CCO
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2csc(N)n2)c(F)c1
Temperature: 25 °C

Procedure:
A solution of 4′-acetyl-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide (100 mg, 0.29 mmol), iodine (94.6 mg, 0.37 mmol), thiourea (44.01, 0.57 mmol) in EtOH (1.1 mL) was heated at 100 Celcius for 48 h. The reaction mixture was cooled to rt and the precipitate collected by filtration thus providing the title compound. MS (ESI): mass calcd. for C19H20FN3O2S2, 405.10; m/z found, 406.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.71 (s, 2H), 8.19 (d, J=7.9, 1H), 7.94 (m, 1H), 7.59 (m, 1H), 7.54 (dd, J=11.6, 3.8, 1H), 7.44 (dd, J=12.1, 1.6, 1H), 7.38 (dd, J=8.1, 1.7, 1H), 7.33 (dd, J=7.5, 1.3, 1H), 6.96 (d, J=1.3, 1H), 1.08 (s, 9H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1.Br[C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([Cl:17])=[CH:12][C:11]=1[O:18]C.[Mg].[Cl-].[NH4+]>C1COCC1>[Cl:17][C:13]1[C:14]([CH3:16])=[CH:15][C:10]([C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:8])=[C:11]([OH:18])[CH:12]=1
Reactant: COc1cc(Cl)c(C)cc1Br
Reactant: O=Cc1cccnc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)c2cccnc2)c(O)cc1Cl
Reaction time: 1 h
Yield: 47.2 %

Procedure:
A solution of 3-pyridinecarbaldehyde (2.2 g) in THF (50 ml) was treated dropwise with a solution (50 ml) of Grignard reagent prepared from 1-bromo-4-chloro-2-methoxy-5-methylbenzene (5.0 g) and magnesium (0.8 g) in THF at 0° C., and stirred for 1 hour. The reaction solution was combined with a saturated aqueous solution of ammonium chloride, and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The resultant residue was used in the next step without purification, combined with toluene (150 ml) and manganese dioxide (15 g), and heated under reflux with dehydrating using Deen Stark for 1 hour. After the reaction was completed, the reaction solution was filtered using celite, the filtrate was concentrated under reduced pressure. The resultant residue was combined with methylene chloride (50 ml) and a 1 N solution of BBr3/methylene chloride (60 ml), and stirred at room temperature overnight. After the reaction was completed, water was added, and the solvent was distilled off under reduced pressure. The resultant residue was neutralized with the addition of a saturated aqueous solution of sodium hydrogen carbonate, and then extracted with ethyl acetate. The extract was washed with water, and then dried over magnesium sulfate, and concentrated under reduced pressure. The resultant residue was purified by a silica gel column (eluent: ethyl acetate) to obtain the title compound as an oil (2.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][N:20]=1>CN(C)C(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:7][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][N:20]=2)[CH:8]=1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(Nc2cc(Cl)ccc2[N+](=O)[O-])nc1
Temperature: 130 °C
Yield: 700.2 %

Procedure:
To a well stirred solution of 5-chloro-2-nitroaniline (2.0 g, 11.0 mmol) in dry N,N-dimethylacetamide (DMA; 15 ml), cesium carbonate (Cs2CO3; 757 mg, 2.3 mmol) and 6-chloronicotinonitrile (193 mg, 1.3 mmol) were added and reaction mixture was heated at 130° C. for 3 h. After completion of the reaction, the reaction mixture was cooled to room temperature, extracted with ethyl acetate (2×100 ml), and the combined organic layers were washed with water (2×50 ml), brine (20 ml), dried (Na2SO4), filtered and concentrated under reduced pressure to yield 2.5 g of the product.
Reaction SMILES: CN(C)[C:3](=[O:5])[CH3:4].P(Cl)(Cl)(Cl)=O.[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[CH3:22]>>[C:3]([C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]([CH3:12])[C:14]=1[CH3:22])(=[O:5])[CH3:4]
Reactant: Cc1cc2ccccc2n1C
Reactant: CC(=O)N(C)C
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)c1c(C)n(C)c2ccccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 6 moles of N,N-dimethylacetamide and cooled at 0° C., 1.5 moles of phosphorus oxychloride was added dropwise in 30 minutes with stirring. After further adding 1 mole of 1,2-dimethylindole thereto, the reaction was carried out at 85°-90° C. for 2 hours. Then, the reaction solution was poured into 2 liters of ice water. The reaction solution was made alkaline, extracted with 0.5 liter of ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was recrystallized from ethyl acetate to give yellow crystals in yield of 80%.
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3]([OH:5])=O.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3]([N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:5]
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Reactant: C1CCNC1
Product: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)N1CCCC1

Procedure:
Starting materials: 2,6,10,14,18-pentamethyl-22-oxo-2,6,10,14,18-tricosapentaenoic acid and pyrrolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH:15]([O:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH:15]([O:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCC(CCCNS(=O)(=O)c1ccc(Cl)cc1)Oc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CCCC(CCCNS(=O)(=O)c1ccc(Cl)cc1)Oc1cccnc1

Procedure:
Ethyl 8-(p-chlorophenylsulfonamido)-5-(3-pyridyloxy)-octanoate is hydrolyzed with 1N aqueous sodium hydroxide and dioxane and the product is purified using preparative thin layer chromatography on silica gel using 4:1 ethyl acetate/hexane/1% acetic acid as eluent to give 8-(p-chlorophenylsulfonamido)-5-(3-pyridyloxy)-octanoic acid; 1H NMR (CDCl3): delta 8.16 (br s,1H), 8.08 (d,1H), 4.39 (m,1H), 2.86 (t,2H).
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][CH:5]1[N:10]([N:11]([CH3:24])[CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[C:9](=[O:25])[CH2:8][N:7]([S:26]([C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([Cl:39])[CH:35]=3)[CH:30]=2)(=[O:28])=[O:27])[CH2:6]1.C(N(CC)CC)C.[C:47](OC(=O)C)(=[O:49])[CH3:48]>C(Cl)Cl>[ClH:39].[ClH:1].[Cl:39][C:34]1[CH:35]=[C:36]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([S:26]([N:7]1[CH2:8][C:9](=[O:25])[N:10]([N:11]([CH3:24])[CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH:5]([CH2:4][NH:3][C:47](=[O:49])[CH3:48])[CH2:6]1)(=[O:27])=[O:28])[CH:38]=[CH:37]2
Reactant: CC(=O)OC(C)=O
Reactant: CN(C1CCN(c2ccncc2)CC1)N1C(=O)CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCC1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC(=O)N1N(C)C1CCN(c2ccncc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 6-(aminomethyl)-4-[(6-chloro-2-naphthyl)sulfonyl]-1-[methyl[1-(4-pyridinyl)-4-piperidinyl]amino]-2-piperazinone dihydrochloride (0.14 g) obtained in Example 113, triethylamine (0.16 ml) and methylene chloride (3 ml) was combined with acetic anhydride (0.043 ml) with stirring at room temperature and then stirred for 24 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified on a CHP-20 column (water→1% 1N hydrochloric acid-containing 30% aqueous solution of acetonitrile) to obtain the title compound (0.12 g) as a colorless powder.
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[Cl:7][C:8]1[CH:9]=[C:10]([C@@H:17]([CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][C:23]2=[O:27])[C:18]([OH:20])=[O:19])[CH:11]=[CH:12][C:13]=1[S:14]([CH3:16])=[O:15]>O.CO>[Cl:7][C:8]1[CH:9]=[C:10]([C@@H:17]([CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][C:23]2=[O:27])[C:18]([OH:20])=[O:19])[CH:11]=[CH:12][C:13]=1[S:14]([CH3:16])(=[O:2])=[O:15]
Reactant: CS(=O)c1ccc([C@@H](CC2CCCC2=O)C(=O)O)cc1Cl
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2=O)C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.5 %

Procedure:
A solution of potassium permanganate (101 mg, 0.64 mmol) in water (1.83 mL) was treated with a solution of 2(R)-(3-chloro-4-methanesulfinyl-phenyl)-3-(2-oxo-cyclopentyl)-propionic acid (191.5 mg, 0.58 mmol) in methanol (5.8 mL). The reaction was stirred at 25° C. for 1 h. At this time, the reaction was diluted with methanol and then was filtered through a pad of celite. The filtrate was concentrated in vacuo and was azeotroped with acetonitrile. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 90/10 methylene chloride/methanol with glacial acetic acid) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(2-oxo-cyclopentyl)-propionic acid (87 mg, 43%) as an off-white foam: EI-HRMS m/e calcd for C15H17ClO5S (M−H2O)+ 326.0379, found 326.0378.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]2[CH2:16][CH2:15][O:14][C:12]2=O)=[C:6](C(OC)=O)[CH:5]=1)(=[O:3])[CH3:2].[Cl-].[Na+]>C1CCN2C(=NCCC2)CC1.CN(C)C=O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:10][C:11]3([C:12](=[O:14])[C:8]=2[CH:9]=1)[CH2:16][CH2:15]3)(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(C(C)=O)ccc1OC1CCOC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1)C(=O)C1(CC1)O2
Yield: 56.5 %

Procedure:
A mixture of α-[(4-acetyl-2-methoxycarbonylphenyl)oxy]-γ-butyrolactone (2.8 g), 1,8-diazabicyclo[5,4,0]-7-undecene (0.056 g), sodium chloride (0.6 g) and N,N-dimethylformamide (28 ml) was heated at 150°-155° C. for 4 hours. The solvent was removed in vacuo and the resulting residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with water and dried. The residue obtained by removal of the solvent in vacuo was chromatographed on silica gel. The fraction eluted with dichloromethane was crystallized from ethanol to give 5-acetylspiro[benzo[b]furan-2(3H), 1'-cyclopropane]-3-one (1.15 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]2[C:3]=1[C:4]([OH:19])=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[N:7]2.C([O-])([O-])=O.[K+].[K+].[C:26]1([CH2:32][CH2:33]Br)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[F:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:19])[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][N:7]2[CH2:33][CH2:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCCc1ccccc1
Reactant: CCOC(=O)c1cnc2cc(F)c(F)c(F)c2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CCc2ccccc2)c2cc(F)c(F)c(F)c2c1=O
Temperature: 90 °C
Reaction time: 27 h
Yield: 33 %

Procedure:
A mixture of ethyl 5,6,7-trifluoro-4-hydroxy-3-quinolinecarboxylate (2.00 g, 7.37 mmol), K2CO3 (3.06 g, 22.1 mmo) and 2-phenylethyl bromide (1.50 mL, 11.1 mmol) in DMF (16 mL) was stirred at 90° C. for 27 h and concentrated in vacuo. After dilution of the residue with CHCl3, the mixture washed with water, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Flash chromatography of the residue (EtOAc: MeOH 10:1) gave ethyl 5,6,7-trifluoro-1,4-dihydro-4-oxo-1-(2-phenylethyl)-3-quinolinecarboxylate (913 mg, 33%) as a pale yellow powder.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[C:24]([O:25]C(=O)C)=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7](=[O:20])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1.[NH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1>C(#N)C.O>[OH:25][C:24]1[C:4]2[O:3][C:2]([NH:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[C:6]([C:7]([C:8]3[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=3)=[O:20])[C:5]=2[CH:21]=[CH:22][C:23]=1[O:29][CH3:30]
Reactant: COc1cc(C(=O)c2c(Br)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Reactant: Nc1cccnc1
Solvent: CC#N
Solvent: O
Product: COc1cc(C(=O)c2c(Nc3cccnc3)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Reaction time: 6 h
Yield: 24.4 %

Procedure:
A mixture of 2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzofuran (50 mg, 0.10 mmol) and 3-amino-pyridine (30 mg, 0.30 mmol) in a mixture of solvent acetonitrile:water (8:2, 5 mL) was refluxed with stirring for 6 hours. The solvent was distilled under vacuum and the residue was purified over silica gel column to afford the title compound as yellow solid (11 mg, 23%); 1H NMR (300 MHz, CDCl3) δ 11.22 (s, 1H), 8.77 (b, 1H), 8.42 (b, 1H), 8.01 (bd, 1H), 7.28 (b, 1H), 7.03 (s, 2H, benzoyl Hs), 6.71 (d, 1H, J=8.82 Hz), 6.63 (d, 1H, J=8.37 Hz), 3.94 (s, 3H, OMe), 3.90 (s, 3H, OMe), 3.86 (s, 6H, 2×OMe).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([N:12]2[CH2:16][CH2:15][CH2:14][C@H:13]2[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: CCOC(=O)[C@@H]1CCCN1
Product: CCOC(=O)[C@@H]1CCCN1c1ncc(Br)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
5-bromo-2-chloro-3-nitropyridine (5.94 g, 25 mmol) and (S)-ethyl pyrrolidine-2-carboxylate (7.52 g, 52.5 mmol) were combined and stirred at 90° C. for 10 min in a closed vial. The crude material was purified by flash column chromatography (20-30% EtOAc in hexanes to afford (S)-ethyl 1-(5-bromo-3-nitropyridin-2-yl)pyrrolidine-2-carboxylate (8.43 g, 24.49 mmol, 98% yield) as a yellow viscous oil. [M+H] calc'd for C12H14BrN3O4, 344; found, 344.
Reaction SMILES: [CH:1]1([O:7][CH:8](C)[CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>C(N(CC)CC)C.ClCCl>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O:10][CH2:9][CH2:8][O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CC(CO)OC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(OCCOC1CCCCC1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.7 %

Procedure:
To a solution of 2-cyclohexyloxy-1-propanol (4.0 g, 28 mmol) in triethylamine (5.8 ml) and dichloromethane (250 ml) was added 4-bromobenzenesulfonyl chloride (7.87 g, 31 mmol) at 0° C. under nitrogen, and the resulting mixture was stirred for 16 h at room temperature. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution, water and brine (100 ml each), dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by silica (200 g) column chromatography using a gradient elution of hexane:ethyl acetate (6:1 to 1:1) to give the title compound as a white crystalline solid (8.0 g, 80%).