Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH2:9][CH2:8][CH:7]([C:10]([O:12]CC)=[O:11])[C:5]=2[N:6]=1.[OH-].[Li+]>C1COCC1.CO>[CH3:1][C:2]1[S:3][C:4]2[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=[O:11])[C:5]=2[N:6]=1
Reactant: CCOC(=O)C1CCc2sc(C)nc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc2c(s1)CCC2C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 31.5 g (149 mmol) of ethyl 2-methyl-5,6-dihydro-4H-cyclopenta[d][1,3]thiazole-4-carboxylate from step A in a mixture of 450 mL of anhydrous THF and 100 mL of methanol was added a solution of 149 mL of a 1.0 M solution (149 mmol) of lithium hydroxide. The resulting mixture stirred at room temperature for 3 h and then the volatile organics were evaporated in vacuo. The aqueous residue was extracted with Et2O (2×250 ml.) and then acidified to pH=3 with 170 mL of a 1.0 N hydrochloric acid solution. The solution was saturated with solid sodium chloride and then extracted with dichloromethane (3×250 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated in vacuo. The crude residue was then triturated with acetonitrile, filtered and dried under vacuum to give the title compound as an off white solid. 1HNMR (500 MHz, CDCl3) δ: 11.75 (br s, 1H), 4.02 (m, 1H), 3.00 (m, 1H), 2.90-2.66 (m, 6H).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:12]3([CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][NH2:26])[CH:20]=4)[CH2:14][CH2:13]3)[N:11]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)[C:10](=[O:34])[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:35][S:36](Cl)(=[O:38])=[O:37].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH:1]1([NH:7][C:8]2[C:12]3([CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=4)[CH2:25][NH:26][S:36]([CH3:35])(=[O:38])=[O:37])[CH2:14][CH2:13]3)[N:11]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)[C:10](=[O:34])[N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NCc1cccc(CN2CCC3(CC2)C(NC2CCCCC2)=NC(=O)N3c2cccc(F)c2)c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CS(=O)(=O)NCc1cccc(CN2CCC3(CC2)C(NC2CCCCC2)=NC(=O)N3c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 2 mL CH2Cl2 suspension of 0.05 g (0.11 mmol) 4-(cyclohexylamino)-8-[3-(aminomethyl)benzyl]-1-(3-fluorophenyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one (Example (7-12)), 0.02 mL (0.22 mmol) methanesulfonyl chloride and excess K2CO3 was allowed to stir at rt overnight. The reaction was filtered and concentrated. The remaining oil was dissolved in 0.5 mL CH2Cl2 and purified on an Isco automated system affixed with a Biotage Flash 25(S) cartridge eluted at 20 mL/min with 0-5% MeOH in CH2Cl2 over 15 min and hold at 5% MeOH for 30 min. The product eluted second, pure by HPLC/MS and NMR. 1H NMR (400 MHz, CDCl3) δ 7.79-7.83 (m, 1H), 7.45-7.54 (m, 2H), 7.33-7.4 (m, 2H), 7.12-7.14 (m, 1H), 6.96-7.05 (m, 3H), 4.31-4.39 (m, 1H), 3.92-4.05 (m, 1H), 3.48-3.52 (m, 1H), 2.65-2.80 (m, 2H), 2.4-2.50 (m, 2H), 1.90-2.20 (m, 6H), 1.62-1.8 (m, 4H), 1.55 (s, 3H), 1.30-1.50 (m, 2H), 1.15-1.30 (m, 4H). MS 542.4
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[CH:9]=[CH:8][C:7]=1[O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21]C(=O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[CH:9]=[CH:8][C:7]=1[O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21]
Reactant: COC(=O)CCc1cc(C(C)=O)ccc1OCCCCCOC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)CCc1cc(C(C)=O)ccc1OCCCCCO
Temperature: 25 °C
Reaction time: 21 h
Yield: 96.8 %

Procedure:
A solution of 4.22 g (12.06 mmol) of 2-[[5-(acetyloxy)pentyl]oxy]-5-acetylbenzenepropanoic acid methyl ester and 0.1 g of p-toluenesulfonic acid monohydrate in 50 mL of methanol was stirred and refluxed for 3.5 hr and stirred at room temperature for 21 hr. Most of the methanol was removed in vacuo and the residue was diluted with water and worked-up with ether in the usual manner (the combined ether extracts were additionally washed with saturated aqueous sodium bicarbonate). The product was purified by flash chromatography on silica gel, eluting with 1:2 hexane-ethyl acetate. There was obtained 3.6 g (97%) of 2-[(5-hydroxypentyl)oxy]-5-acetylbenzenepropanoic acid methyl ester as a viscous oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:10]2[CH:9]=[C:8]3[N:11]=[C:12]([NH:14][C:15](=[O:22])[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[NH:13][C:7]3=[CH:6][C:5]=2[N:4]([CH2:23][C:24](=O)[CH2:25][CH3:26])[C:3]1=[O:28].Cl.[CH3:31][O:32][NH2:33]>CO>[CH3:31][O:32]/[N:33]=[C:24](/[CH2:25][CH3:26])\[CH2:23][N:4]1[C:5]2[CH:6]=[C:7]3[NH:13][C:12]([NH:14][C:15](=[O:22])[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[N:11][C:8]3=[CH:9][C:10]=2[C:2]([CH3:1])([CH3:29])[C:3]1=[O:28]
Reactant: CON
Reactant: CCC(=O)CN1C(=O)C(C)(C)c2cc3nc(NC(=O)c4ccccc4)[nH]c3cc21
Agent: Cl
Solvent: CO
Product: CC/C(CN1C(=O)C(C)(C)c2cc3nc(NC(=O)c4ccccc4)[nH]c3cc21)=N/OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.3 %

Procedure:
To a solution of N-[7,7-dimethyl-6-oxo-5-(2-oxo-butyl)-3,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl]-benzamide (80 mg) in MeOH (20 ml) is added O-methyl-hydroxylamine hydrochloride (20.5 mg; 0.25 mmol) and the mixture is stirred at RT for 18 h. After evaporation EtOAc is added and the organic phase is washed three times with saturated K2CO3 solution, dried over MgSO4 and evaporated again. The residue is purified by RP-MPLC eluted with MeCN/water to yield the desired compound (57 mg).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)[O:16][C:17]=2[CH3:18])=[N:9][CH:10]=1.[CH2:24]([O:26][C:27]1[C:31]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][NH:29][N:28]=1)[CH3:25].O>CN(C)C=O>[CH2:24]([O:26][C:27]1[C:31]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][N:29]([CH2:4][C:5]2[CH:10]=[N:9][C:8]([O:11][CH2:12][C:13]3[N:14]=[C:15]([C:19]4[O:20][CH:21]=[CH:22][CH:23]=4)[O:16][C:17]=3[CH3:18])=[CH:7][CH:6]=2)[N:28]=1)[CH3:25]
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(CCl)cn1
Reactant: CCOC(=O)Cc1c[nH]nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)nc2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
Sodium hydride (60%, oily, 39.4 mg) was added to a solution of 5-chloromethyl-2-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]pyridine (300 mg), ethyl 3-ethoxy-1H-pyrazol-4-ylacetate (195 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-ethoxy-1-[6-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-pyridylmethyl]-1H-pyrazol-4-ylacetate (364 mg, yield 79%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:21]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2cccc3[nH]ccc23)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2c(OCc3ccccc3)cccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-benzyloxy-1H-indole (CAS#20289-26-3, 10.85 g, 48.6 mmol) in N,N-dimethylformamide (200 mL) at 0° C., was added sodium hydride (60% dispersion in oil, 2.24 g, 55.9 mmol). The reaction was permitted to stir for 15 minutes at 0° C. Then iodomethane (3.19 mL, 51.0 mmol) was added to the reaction mixture. The reaction was put at room temperature and permitted to stir 30 minutes. The reaction was then quenched with saturated aqueous ammonium chloride. The mixture was diluted with water and extracted with diethyl ether. The layers were separated and the aqueous layer was then extracted two additional times with diethyl ether. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 4-benzyloxy-1-methyl-1H-indole; MS: (ES+) m/z 238.4 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7][C:6]=2[C:5]([NH2:15])=[C:4]([Br:16])[CH:3]=1.N1C=CC=CC=1.[C:23](Cl)(=[O:25])[CH3:24]>ClCCl>[Br:1][C:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7][C:6]=2[C:5]([NH:15][C:23](=[O:25])[CH3:24])=[C:4]([Br:16])[CH:3]=1
Reactant: CC(=O)Cl
Reactant: Nc1c(Br)cc(Br)c2c1oc1ccccc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1c(Br)cc(Br)c2c1oc1ccccc12
Yield: 70.2 %

Procedure:
In a 2 L round-bottomed flask, 1,3-dibromodibenzo[b,d]furan-4-amine (76 g, 223 mmol) in dichloromethane (800 mL) and pyridine (180 mL, 2229 mmol) were cooled by ice bath. Acetyl chloride (31.7 mL, 446 mmol) was added dropwise while stirring. Then the ice bath was removed. The reaction was stirred at room temperature for 1 h. The residue was collected by filtration and washed by water and dichloromethane to give N-(1,3-dibromodibenzo[b,d]furan-4-yl)acetamide (60 g, 70.3% yield) as brown solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].[Cl-].[Al+3].[Cl-].[Cl-].Cl[C:16]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:17].Cl>ClCC(Cl)(Cl)Cl.O>[OH:10][C:3]1[C:2]([CH3:1])=[C:7]([CH3:8])[CH:6]=[C:5]([CH3:9])[C:4]=1[C:16]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:17]
Reactant: Cc1cc(C)c(C)c(O)c1
Reactant: CCOC(=O)CCCCC(=O)Cl
Agent: Cl
Agent: ClCC(Cl)(Cl)Cl
Agent: [Al+3]
Solvent: O
Product: CCOC(=O)CCCCC(=O)c1c(C)cc(C)c(C)c1O

Procedure:
To a solution of 2,3,5-trimethylphenol(formula VII wherein R=H3C, X=H, Y=OH) (1.4 part) in tetrachloroethane (10 volume parts), there was added a solution of aluminum chloride dust (3.5 parts) and ethyl 5-chloroformylpentanoate (3 parts) in tetrachloroethane (5 volume parts) at 0° C. and in a current of nitrogen gas and the mixture was heated at 110°-120° C. for 17 hours. To the reaction mixture was added cold water (50 volume parts) and the dilution was acidified with dilute hydrochloric acid and extracted with chloroform (200 volume parts). The residue (2.7 parts) obtained from the extract was subjected to column chromatography on silicic acid (60 parts) and eluted with chloroform-diethyl ether (20:1) (300 volume parts). The eluate was evaporated to dryness and the residue was recrystallized from ethanol. The procedure provided colorless needles of ethyl 5-(2'-hydroxy-3',4',6'-trimethylbenzoyl)pentanoate (formula II-1 wherein R=H3C, X=H, Y=OH, n=4, in the form of ethyl ester) (1.9 part) melting at 72°-73° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:14]=[CH:13][S:12][C:11]=1[C:15]1[S:16][C:17]([CH3:20])=[CH:18][CH:19]=1.C(OC(=O)C)(=O)C.CCOCC>C(O)(=O)C.O>[Br:9][C:10]1[CH:14]=[C:13]([Br:1])[S:12][C:11]=1[C:15]1[S:16][C:17]([CH3:20])=[CH:18][CH:19]=1
Reactant: Cc1ccc(-c2sccc2Br)s1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc(-c2sc(Br)cc2Br)s1

Procedure:
N-Bromosuccinimide (15.55 g, 87 mmol) was added portionwise to stirred solution of 3-bromo-5′-methyl-2,2′-bithiophene (20.56 g, 79 mmol) in glacial acetic acid (200 mL) containing acetic anhydride (25 mL) at RT. The mixture was stirred and monitored by TLC. After completion (1.5 h) the reaction was diluted with water (200 mL) and the oily phase was taken into ether and separated. The aqueous phase was extracted with ether. The combined organic phases were washed with 1 M NaOH solution followed by water. Removal of the solvent left a solidifying oil, which was sonicated in methanol yielding after filtration and drying 3,5-dibromo-5′-methyl-2,2′-bithiophene as off-white solid (single spot on TLC). Yield: 20.6 g (77%). 1H NMR (600 MHz, CD2Cl2) ppm 7.13 (d, J=3.6 Hz, 1H), 6.97 (s, 1H), 6.74-6.72 (m, 1H), 2.48-2.47 (m, 3H)
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1.COC(=O)C(O)C(C)C.[CH2:35]([O:37][C:38](=[O:42])[C@@H:39](O)[CH3:40])[CH3:36].CO>C(OCC)(=O)C>[CH2:35]([O:37][C:38](=[O:42])[C@H:39]([O:23][C:21]1[CH:20]=[CH:19][C:16]2[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]=2[CH:22]=1)[CH:10]=[C:9]([C:8]1[N:4]([CH2:3][C:2]([F:24])([F:1])[F:25])[N:5]=[CH:6][N:7]=1)[N:18]=3)[CH3:40])[CH3:36]
Reactant: Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2
Reactant: CCOC(=O)[C@H](C)O
Agent: COC(=O)C(O)C(C)C
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](C)Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2

Procedure:
Following the procedure of Example 426, 2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol, 2-hydroxy-3-methyl-butyric acid methyl ester and (S)-2-hydroxypropionic acid ethyl ester were reacted and the crude product was subjected to flash chromatography (SiO2, gradient 0-10% methanol in ethyl acetate) to give (R)-2-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-propionic acid ethyl ester as a yellow oil contaminated with triphenylphosphine oxide, no further purification was undertaken. LCMS: RT=3.51 min, [M+H]+=452
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[CH3:8][Si:9]([C:12]#[C:13][Si](C)(C)C)([CH3:11])[CH3:10].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:8][Si:9]([CH3:11])([CH3:10])[C:12]#[C:13][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:1]
Reactant: C[Si](C)(C)C#C[Si](C)(C)C
Reactant: O=C(Cl)CCCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C[Si](C)(C)C#CC(=O)CCCCl
Reaction time: 0.33 h

Procedure:
To a stirred solution of 16.8 grams of 4-chlorobutyryl chloride and 20.4 grams of bis-trimethylsilylacetylene in 300 ml of dry methylene chloride, cooled in an ice bath, is added powdered anhydrous aluminum chloride, portionwise, over a period of 20 minutes. The mixture is stirred for 5 minutes, then the cooling bath is removed and the mixture stirred at room temperature for 4 hours. The mixture is poured into 500 ml of ice-water. The organic layer is separated, washed with water and brine, dried over anhydrous sodium sulfate and filtered through diatomaceous earth. The mother liquor is evaporated to dryness giving a brownish residue. The residue is Kugelrohr-distilled to give a colorless liquid.
Reaction SMILES: [CH3:1][N:2]([S:29]([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)(=[O:31])=[O:30])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]=[C:15]([CH2:17][CH:18](C(OCC)=O)[C:19]([O:21]CC)=[O:20])[N:16]=1)=[CH:8]2.[OH-].[Na+].O1CCCC1>CO>[CH3:1][N:2]([S:29]([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:31])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]=[C:15]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[N:16]=1)=[CH:8]2
Reactant: CCOC(=O)C(Cc1csc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)n1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(c1cccc2cc(-c3nc(CCC(=O)O)cs3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 50 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
A mixture of diethyl [(2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazol-4-yl)methyl]malonate (0.43 g), 1N aqueous sodium hydroxide solution (3.2 mL), tetrahydrofuran (4 mL) and methanol (4 mL) was stirred at 50° C. for 2 hr. The reaction mixture was concentrated, 1N hydrochloric acid (3.2 mL) and ethylene glycol (6 mL) were added to the residue, and the mixture was stirred at 140° C. for 1 hr. Water was added to the reaction mixture and the resulting crystals were collected by filtration, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (0.13 g, yield 37%) was obtained as colorless crystals from a fraction eluted with tetrahydrofuran-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 200-201° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[C@H:10]([C:23]([OH:25])=[O:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si](C=[N+]=[N-])(C)(C)[CH3:27]>C(Cl)Cl.CO>[C:17]1([C@H:15]([NH:14][C@@H:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][C@H:10]2[C:23]([O:25][CH3:27])=[O:24])[CH3:16])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C[C@@H](N[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(=O)O)c1ccccc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 261A (280 mg, 0.80 mmol) in 6 mL of 1:1 CH2Cl2/MeOH was added a solution of TMSCHN2 (0.82 ml, 1.64 mmol, 2N in hexane). The mixture was stirred at room temperature for 30 min, then concentrated in vacuo and purified by flash chromatography (hexane/EtOAc: 80:20) on silica gel to give Compound 261B as an oil. It had an analytical HPLC retention time=2.187 min. (Chromolith SpeedROD column 4.5×50 mm, 10-90% aqueous methanol containing 0.1% TFA over 4 min, 4 mL/min, monitoring at 220 nm). Mass (M+1)+=363.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.[CH:28]1([S:31](Cl)(=[O:33])=[O:32])[CH2:30][CH2:29]1.O>C(Cl)Cl>[CH:28]1([S:31]([NH:1][CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][CH:7]([CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:6][CH2:5]2)(=[O:33])=[O:32])[CH2:30][CH2:29]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCN)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NCC1CCN(CCNS(=O)(=O)C2CC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
At 15° C., to a solution of tert-butyl (1-(2-aminoethyl)piperidin-4-yl)methylcarbamate (2.00 g, 7.78 mmol) and DIPEA (3.00 g, 23.3 mmol) in CH2Cl2 (40 mL) was added slowly cyclopropylsulfonyl chloride (3.40 g, 25.0 mmol) under Ar. The reaction mixture was stirred at room temperature for 2 hrs. Water (30 mL) was added, and the mixture was extracted with CH2Cl2 (3×30 mL). The combined extract was washed with saturated NaHCO3 (40 mL) and dried over anhydrous Na2SO4. After filtration the solvent was removed in vacuo, and the residue was applied to flash column chromatography (3-7% CH3OH in CH2Cl2) to provide tert-butyl (1-(2-(cyclopropanesulfonamido)ethyl)piperidin-4-yl)methylcarbamate as pale yellow oil (2.2 g, 78%).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[C:6]([CH:14]([CH3:16])[CH3:15])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=O.[NH2:17][C:18]([NH2:20])=[S:19].CC(O)=O>O1CCOCC1>[CH:14]([C:6]1[C:5]([C:3]2[NH:17][C:18](=[S:19])[NH:20][CH:2]=2)=[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][N:8]2[N:7]=1)([CH3:16])[CH3:15]
Reactant: CC(C)c1nn2ccccc2c1C(=O)CCl
Reactant: NC(N)=S
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CC(C)c1nn2ccccc2c1-c1c[nH]c(=S)[nH]1
Yield: 121 %

Procedure:
A mixture of 200 mg (0.63 mmol) of 2-chloro-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)ethanone, 100 mg of thiourea and 100 μl of HOAc were stirred in 1.5 ml of dioxane at 60-700 C for 30 minutes. 197 mg of 4-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-1H-imidazole-2(3H)-thione was obtained after workup. Compound 1085.
Reaction SMILES: [CH2:1]([C:4]1[C:17]([OH:18])=[C:16]([Cl:19])[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:20])[C:6]=2[CH:5]=1)[CH:2]=C.ClC1C=CC=C(C(OO)=O)C=1.C(Cl)(Cl)Cl.[C:36](=[O:39])([O-])[O-:37].[K+].[K+]>O>[Cl:19][C:16]1[C:15]2[O:14][C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:7](=[O:20])[C:6]=2[CH:5]=[C:4]2[CH2:1][CH:2]([C:36]([OH:37])=[O:39])[O:18][C:17]=12
Reactant: O=C([O-])[O-]
Reactant: C=CCc1cc2c(=O)c3ccccc3oc2c(Cl)c1O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(O)C1Cc2cc3c(=O)c4ccccc4oc3c(Cl)c2O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.7 %

Procedure:
A mixture of 2-allyl-4-chloro-3-hydroxy-9-oxo-9H-xanthene (2.0 g), m-chloroperbenzoic acid (3.6 g) and chloroform (100 ml) was stirred at room temperature for 5 hours and thereafter left to stand overnight. To the mixture, potassium carbonate (8 g) and water (200 ml) were added and the resulting mixture was extracted with chloroform. The chloroform layer was dried and the solvent was distilled off. The residue was dissolved in acetone (400 ml) and to the stirred solution, a mixture of chromium trioxide (1.7 g), water (10 ml) and concentrated sulfuric acid (3 g) was added dropwise at room temperature. After standing overnight, the mixture was filtered and the filtrate was evaporated to dryness under vacuum. After addition of water, the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 0.9 g of 11-chloro-2,3-dihydro-5-oxo-5H-furo[3,2-b]xanthene-2-carboxylic acid. m.p. 290°-293° C. This compound exhibited a mass spectrum having a molecular ion peak at m/e 316.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][NH:16][CH3:17])=[CH:11][C:10]=2[Br:18])=[CH:5][CH:4]=1.[F: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>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH3:17])[S:28]([C:25]3[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=3)(=[O:30])=[O:29])=[CH:11][C:10]=2[Br:18])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CNCc1ccc(OCc2ccc(OC)cc2)c(Br)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(COc2ccc(CN(C)S(=O)(=O)c3ccc(F)cc3)cc2Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
To a solution of intermediate 33 (2.7 g, 8.0 mmol, 1 eq) in DCM (10 mL) was added 4-fluorobenzene-1-sulfonyl chloride (1.9 g, 9.6 mmol, 1.2 eq) and DIEA (2.8 mL, 16.0 mmol, 2 eq). After stirring at room temperature for 1 h, the reaction was washed with saturated NaHCO3 and brine, dried (Na2SO4), and concentrated in vacuo. The crude product was purified via silica gel chromatography (0-40% EtOAc/hexane) to give 2.48 g (63%) of N-(4-(4-methoxybenzyloxy)-3-bromobenzyl)-4-fluoro-N-methylbenzenesulfonamide (34).
Reaction SMILES: [NH2-:1].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4]>>[NH2:1][C:9]1[CH:8]=[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[CH:12]=[CH:11][N:10]=1
Reactant: [NH2-]
Reactant: CC(C)(C)c1ccncc1
Agent: [Na+]
Product: CC(C)(C)c1ccnc(N)c1
Temperature: 150 °C
Reaction time: 6 h
Yield: 55.2 %

Procedure:
To 790 mg of sodium amide were added 20 mL of N,N-dimethylanaline and 2.74 g of 4-t-butyl pyridine at r.t. The mixture was stirred at 150° C. for 6 hours. During this period, 3 more portions of sodium amide (790 mg each) were added. The reaction was cooled down to r.t. The mixture was partitioned between EtOAc and water. Aqueous layer was extracted with EtOAc (3×). The combined organic phase was washed with brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography with 50% EtOAc in hexanes followed by 100% EtOAc to give 1.68 g of the title compound as a solid: 1H NMR (500 MHz, CDCl3) δ1.21 (s, 9H), 4.55 (br, 2H) 6.44 (t, J=1.1 Hz, 1H), 6.62 (dd, J=5.5, 1.8 Hz, 1H), 7.94 (d, J=5.5Hz, 1H).