Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:25])[O:3][C:4]1[CH:24]=[CH:23][C:7]([CH2:8][C:9]2[C:10]([CH3:22])=[C:11]([CH3:21])[C:12]([CH:19]=C)=[C:13]([CH:18]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:6][CH:5]=1.CC(C)=[O:28].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[F:25][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[C:10]([CH3:22])=[C:11]([CH3:21])[C:12]([CH:19]=[O:28])=[C:13]([CH:18]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:23][CH:24]=1
Reactant: C=Cc1c(C(=O)OC)cc(Cc2ccc(OC(F)F)cc2)c(C)c1C
Reactant: CC(C)=O
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc(Cc2ccc(OC(F)F)cc2)c(C)c(C)c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-(4-(difluoromethoxy)benzyl)-3,4-dimethyl-2-vinylbenzoate (0.16 g) in a mixed solvent of acetone (3.00 mL)-acetonitrile (3.00 mL)-water (3.00 mL) were added osmium oxide (fixed catalyst I) (0.06 g) and sodium periodate (0.49 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.04 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl[CH2:18][CH2:19][N:20]1[CH:25]=[C:24]([CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21]1=[O:39].O>CCO>[C:27]1([CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:24]2[CH:23]=[CH:22][C:21](=[O:39])[N:20]([CH2:19][CH2:18][NH:1][C:2]3[CH:10]=[CH:9][CH:8]=[C:7]4[C:3]=3[CH:4]=[CH:5][N:6]4[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:25]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCOC(=O)Cn1ccc2c(N)cccc21
Reactant: O=c1ccc(C(c2ccccc2)c2ccccc2)cn1CCCl
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cn1ccc2c(NCCn3cc(C(c4ccccc4)c4ccccc4)ccc3=O)cccc21
Temperature: 50 °C
Reaction time: 24 h
Yield: 41.2 %

Procedure:
To a stirring solution of ethyl (4-amino-1H-indol-1-yl)acetate (94 mg) in EtOH (7 mL) was added 1-(2-chloroethyl)-5-(diphenylmethyl)-2(1H)-pyridinone (70 mg) at ambient temperature. The reaction mixture was warmed to 50° C. After 24 hours, to the mixture was added water and the resulting mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform:EtOAc=5:1) to give ethyl [4-({2-[5-(diphenylmethyl)-2-oxo-1(2H)-pyridinyl]ethyl}amino)-1H-indol-1-yl]acetate (45 mg).
Reaction SMILES: [CH:1]([SH:4])([SH:3])[CH3:2].C([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=O)C.[CH3:14][C:15]1C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:2][C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:4][CH2:15][CH2:14][S:3]1
Reactant: CC(S)S
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(=O)c1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: CC1(c2ccccc2)SCCS1

Procedure:
Ethanedithiol (94 g) and acetophenone (120 g, 1 mole) were dissolved in benzene (500 ml), a trace of pTSA added and the solution refluxed under a Dean-Stark trap for 16 hours, until no more water collected. The solution was cooled, washed with ice-cold dilute caustic soda, then water, and reduced in volume to a viscous, colorless, or yellowish oil. This was distilled under vacuum to give 2-methyl-2-phenyl-1,3-dithiolane as a colorless oil with an unpleasant odor, yield 120 g (61%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(Cl)(=[O:16])CCCCC.[CH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1>[OH:9][CH:4]([CH2:5][CH:6]([Cl:8])[CH2:7][CH2:2][Cl:1])[C:3]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16]
Reactant: c1ccccc1
Reactant: CCCCCC(=O)Cl
Reactant: Oc1cc(Cl)cc(Cl)c1
Solvent: c1ccncc1
Product: O=C(c1ccccc1)C(O)CC(Cl)CCCl
Temperature: 60 °C
Reaction time: 1 h

Procedure:
An amount of 163.0 g of 3,5-dichlorophenol is dissolved in 200 ml of benzene and 79.1 g of anhydrous pyridine; there is then added dropwise at 5°-15° C with stirring, in the course of 1 hour, a solution of 134.6 g of caproic acid chloride in 200 ml of benzene. The temperature of the reaction mixture is allowed to rise to 20° C; the precipitated pyridine hydrochloride is filtered off, the benzene solution washed with water and, after drying over sodium sulphate, completely concentrated in a water-jet vacuum. The caproic acid-3,5-dichlorophenyl ester remaining (255 g) is heated to 60° C, and an addition then made to it at this temperature in the course of 10 minutes, with stirring, of 400 g of anhydrous aluminium chloride. After 5 hours, the liquid reaction mixture is poured, as stirring is maintained, into 3 liters of ice water. The initially oily precipitate fully crystallises during subsequent stirring. It is filtered off, washed with water and dried in vacuo to obtain 210.7 g of 2-hydroxy-4,6-dichlorocaprophenone, M.P. 39°-41° C.
Reaction SMILES: C(Cl)([Cl:3])=O.[CH2:5]([O:7][P:8]([CH2:13][CH2:14][CH3:15])(=[O:12])[O:9]CC)[CH3:6].N#N>>[Cl-:3].[CH2:5]([O:7][P:8]([CH2:13][CH2:14][CH3:15])(=[O:9])[OH:12])[CH3:6]
Reactant: CCCP(=O)(OCC)OCC
Reactant: O=C(Cl)Cl
Agent: N#N
Product: CCCP(=O)(O)OCC
Product: [Cl-]
Reaction time: 1 h

Procedure:
200 g of phosgene were passed into 1 mole of propane-phosphonic acid diethyl ester at 70°-80° C. The mixture was stirred at 70°-80° C. for 1 hour and a dry N2 stream was passed through the reaction mixture overnight at 50° C. The mixture was completely degassed at 50° C. under a waterpump vacuum in a Rotavapor and crude propanephosphonic acid ethyl ester-chloride was obtained. This was rendered basic with absolute pyridine, dissolved in 300 ml of toluene and reacted with a mixture of 1.1 moles of pyridine and 1 mole of allyl alcohol at 20°-30° C. The mixture was allowed to after-react at 80° C. for 2 hours. The solution which was separated off from the hydrochloride by filtration was concentrated and distilled.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:11])=[CH:5][C:6]=1[C:7]([O:9]C)=O.Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.Cl.[NH2:32][CH2:33][C:34]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)=[O:35]>C(Cl)Cl>[CH3:43][O:42][C:39]1[CH:40]=[CH:41][C:36]([C:34](=[O:35])[CH2:33][N:32]2[C:7](=[O:9])[C:6]3[CH:5]=[C:4]([CH3:11])[S:3][C:2]=3[NH:1][C:13]2=[O:15])=[CH:37][CH:38]=1
Reactant: COc1ccc(C(=O)CN)cc1
Reactant: COC(=O)c1cc(C)sc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Cn2c(=O)[nH]c3sc(C)cc3c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 176.1 %

Procedure:
To a solution (100 mL) of methyl 2-amino-5-methylthiophene-3-carboxylate (2 g) in methylene chloride were added triphosgene (1.5 g) and triethylamine (4.24 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture were further added triethylamine (1.8 mL) and 2-amino-1-(4-methoxyphenyl)ethanone hydrochloride (2.6 g), and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (100 mL), sodium methoxide (3.16 g) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was extracted with 1N hydrochloric acid and chloroform. The chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (2.94 g, 76%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:27][CH2:26][CH:25]([N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:24]2)=[N:21][CH:22]=1>>[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]3[CH2:27][CH2:26][CH:25]([N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:33])[CH3:34])[CH2:24]3)=[N:21][CH:22]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)(=[O:14])[CH3:13]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc(N)cn2)C1
Product: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCC(N(C)C(=O)OC(C)(C)C)C2)nc1
Yield: 50.5 %

Procedure:
Following general procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (285 mg, 1.0 mmol) was reacted with tert-butyl (1-(5-aminopyridin-2-yl)pyrrolidin-3-yl)(methyl)carbamate (440 mg, 1.50 mmol) to afford the desired product (273 mg, 51%) as an orange solid. ESI MS m/z 540 [C26H30BrN5O3+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH2:9]([OH:12])[CH2:10][OH:11].[H-].[Na+]>O1CCCC1>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([O:11][CH2:10][CH2:9][OH:12])[CH:7]=1
Reactant: OCCO
Reactant: Clc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCOc1cc(Cl)ncn1
Reaction time: 2 h

Procedure:
To a mixture of 4,6-dichloropyrimidine (5.0 g), ethylene glycol (100 ml) and tetrahydrofuran (100 ml)is added sodium hydride (60% dispersion-type, 1.34 g) under ice-cooling. The mixture is stirred at the same temperature for two hours, and evaporated to remove the solvent. The residue is extracted with ethyl acetate, and the ethyl acetate extract is dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; chloroform/ethyl acetate=5:1~2:1) to give 2-(6-chloropyrimidin-4-yloxy)ethanol (5.67 g) as an oily product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][C:15]1[S:23][C:22]2[CH2:21][CH2:20][NH:19][CH:18]([CH3:24])[C:17]=2[CH:16]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:20][CH2:21][C:22]4[S:23][C:15]([CH3:14])=[CH:16][C:17]=4[CH:18]3[CH3:24])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: Cc1cc2c(s1)CCNC2C
Product: Cc1cc2c(s1)CCN(C(=O)c1cc3ncc(Br)cn3n1)C2C
Yield: 40 %

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 2,4-dimethyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine to provide the title compound.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][NH2:13]>O1CCOCC1>[Cl:11][C:8]1[CH:9]=[N:10][C:2]([NH:13][CH3:12])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Reactant: CN
Solvent: C1COCCO1
Product: CNc1ncc(Cl)cc1C(=O)O
Temperature: 160 °C
Yield: 92 %

Procedure:
A mixture of 2,5-dichloronicotinic acid (1.76 g, 9.17 mmol), 41% aq. methylamine solution (7 mL), and 1,4-dioxane (6 mL) was heated at 160° C. under microwave irradiation for 20 min. After cooling, volatile material was distilled off, and the residue was dissolved in water (30 mL) and acidified to pH 3 by addition of 37% aq. hydrochloric acid solution. The precipitate was collected by filtration and triturated in DCM to produce the title compound (1.60 g, 92%). Off-white solid, MS (ISP): 187.1 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[C:22]([CH3:24])([CH3:23])[CH2:21][CH2:20][C:19](=[O:25])[C:18]=1[CH3:26])(=O)C.C([O-])([O-])=O.[K+].[K+].Cl>CO.O>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[C:22]([CH3:23])([CH3:24])[CH2:21][CH2:20][C:19](=[O:25])[C:18]=1[CH3:26]
Reactant: CC(=O)OCCCCCCCCCCCCC1=C(C)C(=O)CCC1(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC1=C(CCCCCCCCCCCCO)C(C)(C)CCC1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 80.5 %

Procedure:
To a solution of 3-(12-acetoxydodecyl)-2,4,4-trimethyl-2-cyclohexene-1-one (132 mg) in dry methanol (8 ml) was added water (3 drops) and K2CO3(74 mg). After stirring at room temperature for 2.5 hours the solution was neutralized at pH 7 with HCl 5%, extracted with ether, dried with MgSO4 and distilled off under reduced pressure. The residue was purified by chromatography over silica gel to give 3-(12-hydroxydodecyl)-2,4,4-trimethyl-2-cyclohexene-1-one as a colorless oil (94 mg). TLC: (hexane-AcOEt: 7-3) Rf=0.2
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][N:9]=[C:10]=[O:11])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:12]([O:16][CH2:17][CH2:18][OH:19])(=[O:15])[CH:13]=[CH2:14]>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>[CH3:3][C:2](=[CH2:4])[C:1]([O:6][CH2:7][CH2:8][NH:9][C:10]([O:19][CH2:18][CH2:17][O:16][C:12](=[O:15])[CH:13]=[CH2:14])=[O:11])=[O:5]
Reactant: C=C(C)C(=O)OCCN=C=O
Reactant: C=CC(=O)OCCO
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Product: C=CC(=O)OCCOC(=O)NCCOC(=O)C(=C)C
Reaction time: 8 h

Procedure:
In a 4 ounce glass jar were mixed 2-isocyanatoethyl methacrylate (15.5 g, 0.10 mol, available from Aldrich), 2-hydroxyethyl acrylate (11.6 g, 0.10 mol, available from Aldrich), and one drop of di-n-butyltin dilaurate (available from Alfa Aesar) to cause a slight exotherm. The jar was cooled briefly in an ice bath, and then left at room temperature overnight. NMR and IR spectral analyses confirmed the structure of the product.
Reaction SMILES: [CH2:1]([C:6]1[CH:38]=[CH:37][C:9]([CH2:10][N:11]([C:23](=[O:36])[CH:24]=[CH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[C@@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13](O)=[O:14])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.Br.[C:71]([N:88]1[CH2:93][CH2:92][NH:91][CH2:90][CH2:89]1)([O:73][CH2:74][CH:75]1[C:87]2[C:82](=[CH:83][CH:84]=[CH:85][CH:86]=2)[C:81]2[C:76]1=[CH:77][CH:78]=[CH:79][CH:80]=2)=[O:72]>C(#N)C>[CH:86]1[C:87]2[CH:75]([CH2:74][O:73][C:71]([N:88]3[CH2:89][CH2:90][N:91]([C:13](=[O:14])[C@@H:12]([N:11]([CH2:10][C:9]4[CH:37]=[CH:38][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:7][CH:8]=4)[C:23](=[O:36])[CH:24]=[CH:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:34])([F:35])[F:33])=[CH:28][CH:27]=4)[CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:92][CH2:93]3)=[O:72])[C:76]3[C:81](=[CH:80][CH:79]=[CH:78][CH:77]=3)[C:82]=2[CH:83]=[CH:84][CH:85]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CCNCC1
Reactant: CCCCCc1ccc(CN(C(=O)C=Cc2ccc(C(F)(F)F)cc2)[C@@H](Cc2ccccc2)C(=O)O)cc1
Agent: Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCCCc1ccc(CN(C(=O)C=Cc2ccc(C(F)(F)F)cc2)[C@@H](Cc2ccccc2)C(=O)N2CCN(C(=O)OCC3c4ccccc4-c4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.2 %

Procedure:
2-{(4-pentyl-benzyl)-[3-(4-trifluoromethyl-phenyl)-acryloyl]-amino}-(S)-3-phenyl-propionic acid (1.5 g, 2.86 mmol) and TBTU (1.1 g, 3.43 mmol) was dissolved in acetonitrile (30 mL) and DIPEA (1.5 mL, 8.6 mmol) and stirred at rt for 5 min, followed by the addition of Fmoc-piperazine hydrobromide (1.22 g, 3.15 mmol). The reaction mixture was stirred at rt for 16 h and concentrated under reduced pressure. The residue was dissolved in EtOAc (150 ml) and washed with brine (100 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silicagel, EtOAc/heptane=3/7) to give 1.75 g (75%) of 4-(2-{(4-pentyl-benzyl)-[3-(4-trifluoromethyl-phenyl)-acryloyl]-amino}-(S)-3-phenyl-propionyl)-piperazine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester. LC-MS: tR=1.25 min; [M+H]+=814.5.
Reaction SMILES: [CH3:1][C:2]1([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=2)[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][CH:14]=3)=[O:12])=[CH:10][C:4]=2[O:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43]>CC(=O)CC>[CH3:1][C:2]1([C:22]2[CH:23]=[CH:24][C:25]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:26][CH:27]=2)[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]([CH2:39][CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:14]=3)=[O:12])=[CH:10][C:4]=2[O:3]1
Reactant: CC(C)Cc1ccc(C2(C)Oc3ccc(C(=O)c4c[nH]c5ccccc45)cc3O2)cc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCCn1cc(C(=O)c2ccc3c(c2)OC(C)(c2ccc(CC(C)C)cc2)O3)c2ccccc21
Yield: 87 %

Procedure:
A mixture of the compound of part (d) (2.88 g), potassium carbonate (3.9 g), ethyl 4-bromobutyrate (1.7 g) and 2-butanone (25 ml) was heated under reflux for 5 hours. The mixture was cooled, filtered and the filtrate evaporated to give a viscous gum which was purified by flash chromatography (silica, 9:1 hexane/ethyl acetate) to provide the title compound as a clear gum (3.2 g).
Reaction SMILES: C([Li])CCC.N1CCOCC1.Br[C:13]1[O:17][CH:16]=[C:15]([CH:18]=[O:19])[CH:14]=1.Cl[Si:21]([CH3:24])([CH3:23])[CH3:22]>CCCCCC.O1CCCC1>[CH3:22][Si:21]([CH3:24])([CH3:23])[C:13]1[O:17][CH:16]=[C:15]([CH:18]=[O:19])[CH:14]=1
Reactant: O=Cc1coc(Br)c1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1COCCN1
Solvent: CCCCCC
Product: C[Si](C)(C)c1cc(C=O)co1
Reaction time: 0.25 h

Procedure:
n-Butyl lithium (a 1.6M solution in hexane; 31.0 ml, 49.7 mmol) was added dropwise to a solution of morpholine (4.33 ml, 49.7 mmol; freshly distilled from barium oxide) in tetrahydrofuran at -78° under argon. After 15 minutes, a solution of 5-bromo-3-furaldehyde (7.5 g, 49.7 mmol) in tetrahydrofuran was added dropwise. Stirring was continued for 30 min. and n-butyl lithium (a 1.6M solution in hexane; 46.6 ml, 74.5 mmol) was added dropwise. After 1 hour at -78°, chlorotrimethylsilane (18.9 ml, 149 mmol) was added and stirring continued while the cooling bath attained room temperature. The reaction mixture was quenched with 10% hydrochloric acid and the phases were separated. The aqueous phase was stirred, in the presence of ethyl ether (30 ml), with 10% hydrochloric acid at 0° C. for 1/2 hour. The organic phases were combined, washed (brin), dried (magnesium sulfate) and evaporated down. The residue was distilled under vacuum to give the title aldehyde as a colorless oil b.p. 48°-50°/0.25 torr.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH:13]2[C:22]3[C:17](=[C:18]([CH3:27])[CH:19]=[C:20]([C:24]([OH:26])=[O:25])[C:21]=3[CH3:23])[S:16](=[O:29])(=[O:28])[CH2:15][CH2:14]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(Cl)(=O)C(Cl)=O.[C:36]1(=O)[CH2:41][CH2:40][CH2:39][CH2:38][C:37]1=[O:42].C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[C:3]([O:12][CH:13]2[C:22]3[C:17](=[C:18]([CH3:27])[CH:19]=[C:20]([C:24]([O:26][C:41]4[CH2:40][CH2:39][CH2:38][C:37](=[O:42])[CH:36]=4)=[O:25])[C:21]=3[CH3:23])[S:16](=[O:28])(=[O:29])[CH2:15][CH2:14]2)=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: Cc1cc(C(=O)O)c(C)c2c1S(=O)(=O)CCC2Oc1ncc(C(F)(F)F)cc1Cl
Reactant: O=C1CCCCC1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C(=O)OC2=CC(=O)CCC2)c(C)c2c1S(=O)(=O)CCC2Oc1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.56 g (1.2 mmol) of 4-{[3-chloro-5-(trifluoromethyl)-2-pyridyl]oxy}-5,8-dimethyl-1,1-dioxo-1,2,3,4-tetrahydro-1λ6-thiochromene-6-carboxylic acid in 30 ml of methylene chloride was admixed with 2 drops of N,N-dimethylformamide and 0.48 g (3.8 mmol) of oxalyl chloride, and the mixture was boiled under reflux for 3.5 h. The solvents were subsequently stripped off using a rotary evaporator and the residue was taken up in 100 ml of methylene chloride and, at 0° C., admixed with 0.15 g (1.4 mmol) of cyclohexanedione and 0.22 g (3.7 mmol) of triethylamine. The mixture was stirred at room temperature for 4 h and subsequently concentrated using a rotary evaporator, and the residue was purified by chromatography (silica gel, ethyl acetate: hexane=1:1).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:5].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([S:28](Cl)(=[O:30])=[O:29])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>N1C=CC=CC=1>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4](=[O:5])[C:3]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:2]=1[NH:1][S:28]([C:22]1[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:20]([O:19][CH3:18])[CH:21]=1)(=[O:30])=[O:29]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2Cl)cc1OC
Reaction time: 96 h

Procedure:
114 g of 2-amino-5,2'-dichlorobenzophenone and g of 3,4-dimethoxyphenylsulfonyl chloride are mixed in 300 ml of pyridine. After 4 days at RT, the excess pyridine is evaporated off, the residue is taken up with hydrochloric water and extracted with DCM and the extract is dried and concentrated. The expected product then crystallizes from a DCM/isopropyl ether mixture.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])([CH:6]1[CH2:10][CH2:9][C:8](=O)[CH2:7]1)[CH3:5].Cl.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30]N)=[CH:26][CH:25]=1.C([O-])(O)=O.[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:21])[C:4]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])([CH:6]1[CH2:10][C:9]2[NH:30][C:27]3[CH:26]=[CH:25][C:24]([Cl:23])=[CH:29][C:28]=3[C:8]=2[CH2:7]1)[CH3:5]
Reactant: COC(=O)C(C)(C1CCC(=O)C1)S(=O)(=O)c1ccccc1
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)C(C)(C1Cc2[nH]c3ccc(Cl)cc3c2C1)S(=O)(=O)c1ccccc1
Temperature: 70 °C
Yield: 33.6 %

Procedure:
To 100 mg (0.32 mmol) of (RS,SR)-2-benzenesulfonyl-2-(3-oxo-cyclopentyl)-propionic acid methyl ester in glacial acetic acid (3 mL), 63 mg (0.35 mmol, 1.1 eq) of (4-chloro-phenyl)-hydrazine hydrochloride were added and the reaction mixture was heated at 70° C. for about 5 hours. Until completion, the reaction was monitored by HPLC and TLC. An aqueous solution of NaHCO3 was added until pH=7 was reached, and the mixture was extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. A column chromatography on silica gel with heptane/EtOAc 1:1 followed by a trituration with Et2O yielded 45 mg (34%) of (RS,SR)-2-benzenesulfonyl-2-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-propionic acid methyl ester as a light yellow solid, MS: 418 (MH+).
Reaction SMILES: [BrH:1].[O:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10](N)[C:11]([N+:14]([O-:16])=[O:15])=[N:12][CH:13]=2)[CH2:4][CH2:3]1.N([O-])=O.[Na+]>O>[Br:1][C:10]1[CH:9]=[C:8]([N:5]2[CH2:6][CH2:7][O:2][CH2:3][CH2:4]2)[CH:13]=[N:12][C:11]=1[N+:14]([O-:16])=[O:15]
Reactant: Nc1cc(N2CCOCC2)cnc1[N+](=O)[O-]
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ncc(N2CCOCC2)cc1Br
Temperature: -5 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A three neck round bottom flask equipped with a magnetic stir bar, a dropping funnel and a thermometer, was charged with CuBr (629 mg, 4.4 mmol) and HBr (25 mL). The solution was cooled to −5° C. (ice salt bath). Solid 5-morpholino-2-nitropyridin-3-amine (983 mg, 4.4 mmol) was slowly added, followed by the slow addition of a NaNO2 (333 mg, 4.8 mmol) solution in H2O (25 mL) via the dropping funnel, ensuring that the temperature did not rise above 0° C. The reaction mixture was stirred at −5° C. for 1 h, warmed to room temperature and stirred an additional 1.5 h. The reaction was deemed complete by LCMS and the mixture was cooled again to 0° C., quenched with 6 N NaOH to pH 12, diluted with water and extracted with EtOAc. EtOAc was washed with water (×2), brine (×1) dried and concentrated. The residue was azeotroped with EtOH dried under high vacuum, obtaining 4-(5-bromo-6-nitropyridin-3-yl)morpholine (1.21 g, 4.20 mmol, 96% yield) as a light yellow solid. LCMS (m/z): 288.2 (MH+), 0.65 min. 1H NMR (400 MHz, CDCl3) δ ppm 8.08-7.99 (d, J=2.3 Hz, 1H) 7.41 (d, J=2.3 Hz, 1H) 3.98-3.81 (m, 4H) 3.45-3.30 (m, 4H).