Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([CH:19]=O)[CH:15]=[CH:14][C:13]=2[C:12]2[N:21]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[N:22]=[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:27][CH2:26]3)[C:11]=2[N:10]=1.Cl.[NH2:44][OH:45]>N1C=CC=CC=1.CCOC(C)=O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([CH:19]=[N:44][OH:45])[CH:15]=[CH:14][C:13]=2[C:12]2[N:21]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:41])([CH3:42])[CH3:40])[N:22]=[C:23]([NH:24][CH:25]3[CH2:26][CH2:27][N:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:29][CH2:30]3)[C:11]=2[N:10]=1
Reactant: C[Si](C)(C)CCOCn1nc(NC2CCN(S(C)(=O)=O)CC2)c2nc(-c3c(F)cccc3F)c3cc(C=O)ccc3c21
Reactant: NO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C[Si](C)(C)CCOCn1nc(NC2CCN(S(C)(=O)=O)CC2)c2nc(-c3c(F)cccc3F)c3cc(C=NO)ccc3c21
Temperature: 25 °C
Reaction time: 64 h
Yield: 85.1 %

Procedure:
A 100 ml round-bottomed flask equipped with a magnetic stirrer and with a septum having a top-mounted argon intake is charged with 211 mg of 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline-7-carbaldehyde in 8.5 ml of pyridine, 36 mg of hydroxylamine hydrochloride are added, and the mixture is stirred at RT for 64 h. It is concentrated under RP and the solid obtained is taken up in AcOEt, washed with a 1M aqueous solution of potassium phosphate and then with saturated aqueous NaCl solution, dried over MgSO4, filtered and concentrated under RP. Purification is carried out by flash chromatography on silica gel (20-45 μm), eluting with a mixture of DCM and AcOEt (75/25 by vol.), to give 184 mg of 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline-7-carbaldehyde oxime (yellow solid). MS (E/I): m/z=630 (M+); 1H NMR: 0.04 (s, 9H); 0.89 (m, 2H); 1.61 (m, 2H); 2.11 (m, 2H); 2.74 (m, 2H); 2.85 (s, 3H); 3.58 (m, 2H); 3.67 (m, 2H); 4.46 (m, 1H); 5.65 (s, 2H); 6.50 (d, J=8.3 Hz, 1H); 7.33 (broad t, J=8.1 Hz, 2H); 7.65 (m, 1H); 7.72 (broad s, 1H); 8.01 (dd, J=8.4, 17 Hz, 1H); 8.27 (s, 1H); 8.35 (d, J=8.4 Hz, 1H); 11.39 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[OH:34][CH2:35][CH2:36][O:37][CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20]([N:41]4[CH2:42][CH2:43][CH:38]([O:37][CH2:36][CH2:35][OH:34])[CH2:39][CH2:40]4)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Reactant: OCCOC1CCNCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)N4CCC(OCCO)CC4)c3)n2)n1
Yield: 49.1 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with 4-(2-hydroxyethoxy)piperidine [CAS-no. 40256-14-2] (0.297 g, 2.05 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.120 g, 49%) as a white foam. MS (ISP) 598.3 [(M+H)+].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[S:11][S:10][C:9](=S)[CH:8]=1.Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>CO.O>[OH:15][N:14]=[C:9]1[CH:8]=[C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[S:11][S:10]1
Reactant: NO
Reactant: S=c1cc(-c2cnccn2)ss1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: ON=c1cc(-c2cnccn2)ss1
Temperature: 65 °C
Yield: 72.6 %

Procedure:
A suspension of 5-(pyrazin-2-yl)-1,2-dithiole-3-thione (31.85 g.) in methanol (1,400 cc.) is heated at a temperature of about 65° C. Hydroxylamine hydrochloride (24 g.), followed by sodium acetate (35 g.) dissolved in water (75 cc.), are then added. The reaction mixture is then heated for 3 hours at a temperature of about 65° C. After cooling to a temperature of about 20° C., the insoluble product is filtered off and is then washed with methanol (4 × 100 cc.) and with carbon disulphide (4 × 100 cc.). The product is dissolved in dimethylformamide (300 cc.) at 100° C. and is then reprecipitated by adding water (600 cc.). After filtration and drying, 3-hydroxyimino-5-(pyrazin-2-yl)-1,2-dithiole (23 g.) melting at 262° C. is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([NH:19][S:20]([C:23]2[S:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)(=[O:22])=[O:21])[CH2:10][C:9]1([CH2:17][NH2:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]([CH3:38])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.C(O)(=O)C>[C:1]([O:5][C:6]([C:8]1([NH:19][S:20]([C:23]2[S:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)(=[O:22])=[O:21])[CH2:10][C:9]1([CH2:17][NH:18][CH:36]([CH3:38])[CH3:35])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1(NS(=O)(=O)c2ccc(-c3ccc(Cl)cc3)s2)CC1(CN)c1ccccc1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)NCC1(c2ccccc2)CC1(NS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)s1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 66.8 %

Procedure:
To the obtained 2-aminomethyl-1-[5-(4-chloro-phenyl)-thiophene-2-sulfonylamino]-2-phenyl-cyclopropanecarboxylic acid t-butyl ester (60 mg, 0.12 mmol) in tetrahydrofuran (1.0 mL) were added acetone (13 μL, 0.17 mmol) and sodium triacetoxyborohydride (37 mg, 0.17 mmol) at 0° C. under argon atmosphere, and the mixture was stirred at room temperature for 20 hours. To the obtained solution was added acetic acid (50 μL), and the mixture was further stirred for 21 hours. Then saturated aqueous sodium hydrogen carbonate solution (2.0 mL) was added and the aqueous layer was extracted with ethyl acetate (3.0 mL). The organic layer was washed with water (2.0 mL) and saturated aqueous sodium chloride solution (2.0 mL), and dried over magnesium sulfate. After filtration and evaporation, the obtained residue was purified by silica gel chromatography (chloroform:methanol=25:2) to give the title compound (45 mg, yield 69%) as a pale-yellow oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:14]1[CH2:18][C@H:17]([S:19][C:20]([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)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][C@H:15]1[C:39]([NH:41][NH2:42])=[O:40])(=[O:13])=[O:12].C(N(C(C)C)C(C)C)C.[Br:52][CH2:53][CH2:54][CH2:55][C:56](Cl)=[O:57]>C1COCC1>[Br:52][CH2:53][CH2:54][CH2:55][C:56]([NH:42][NH:41][C:39]([C@@H:15]1[CH2:16][C@@H:17]([S:19][C:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:18][N:14]1[S:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:13])=[O:12])=[O:40])=[O:57]
Reactant: O=C(Cl)CCCBr
Reactant: NNC(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCBr)NNC(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
(step 27) To 150 mg (0.25 mmol) (2S,4R)-1-(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid hydrazide in 65 ml THF were added 52 μl (0.3 mmol, 1.2 eq) iPr2EtN and 29 μl (0.25 mmol) 4-bromobutyryl chloride at 0° C. The solution was stirred at RT for 2 h, the solution was concentrated and redissolved in ethyl acetate/H2O. The inorganic phase was extracted with ethyl acetate and, the organic phase was washed with brine and dried over Na2SO4. Column chromatography with ethyl acetate:hexane 1:1 yields 170 mg (92%) (2S,4R)-1(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid N′-(4-bromo-butyryl)-hydrazide which was dissolved in 120 ml DMF and treated with 17 mg (0.38 mmol, 55% in mineral oil). NaH and the solution stirred for 2 h, was concentrated and dissolved in ethyl acetate/H2O. The inorganic phase was extracted with ethyl acetate, the organic phase washed with brine and dried over Na2SO4. The crude product was purified by column chromatography yielding 75 mg (45%) (2S,4R)-4-tritylsulfanyl -1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid (2-oxo-pyrrolidin-1-yl)-amide as white foam and 40 mg (25%) (2S,4R)-1-[4-tritylsulfanyl-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carbonyl]-tetrahydro-pyridazin-3-one as white foam. The two compounds were treated separately in TFA (2 ml/mmol tritylsulfanyl) with 10 eq triethylsilane at 0° C. to RT, until no educt could be detected, to yield (2S,4R)-4-Mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid (2-oxo-pyrrolidin-1-yl)-amide as white foam, MS: 420 (MH+) and (2S,4R)-1-[4-Mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carbonyl]-tetrahydro-pyridazin-3-one as white foam, MS: 420 (MH+), respectively.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[CH3:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15]([N:17]=[C:18]=[S:19])=[O:16]>CCOCC>[CH3:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15]([NH:17][C:18]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5])=[S:19])=[O:16]
Reactant: Cc1ccccc1C(=O)N=C=S
Reactant: CNC(=O)c1ccccc1N
Solvent: CCOCC
Product: CNC(=O)c1ccccc1NC(=S)NC(=O)c1ccccc1C
Yield: 93.4 %

Procedure:
To a stirred mixture of 5.4 g of 2-amino-N-methylbenzamide and 200 ml of ether was added dropwise, a solution of 6.67 g of 2-methylbenzoyl isothiocyanate in 100 ml of ether over 15 minutes. After several hours the solid was collected, giving 11 g of 2-methyl-N-[[[2-[(methylamino)carbonyl]phenyl]amino]thioxomethyl]benzamide
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=[O:4].C([Li])CCC.CON(C)[C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1.CCCCCC>[C:29]([C:7]1[CH:8]=[C:9]([N:12]2[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]2)[CH:10]=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[C:2]([CH3:20])([CH3:19])[CH3:1])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CN1CCN(c2ccc(NC(=O)C(C)(C)C)cc2)CC1
Reactant: CON(C)C(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN1CCN(c2ccc(NC(=O)C(C)(C)C)c(C(=O)c3ccccc3)c2)CC1
Temperature: -70 °C
Reaction time: 3 h
Yield: 16.6 %

Procedure:
A solution of 1.375 g (5 mmol) of 2,2-dimethyl-N-[4-(4-methyl-piperazin-1-yl)-phenyl]-propionamide was dissolved in 25 ml tetrahydrofuran and cooled to −70° C. Under argon 7.8 ml (12.5 mmol) of a 1.6 M n-butyl lithium solution in hexane was added slowly at this temperature. The cooling bath was removed and the mixture was stirred for 3 h at room temperature. The reaction mixture was cooled down again to −70° C. and a solution of 1.234 g N-methoxy-N-methyl benzamide (7.2 mmol) in 5 ml tetrahydrofuran was added slowly at −70° C. After 10 min the cooling bath was removed and stirring was continued at room temperature for 1 hour. Water (50 ml) was added to quench the reaction and the mixture was extracted with diethylether (three times 50 ml). The organic layer was dried with magnesium sulfate and evaporated to give a brown oil, which was purified by flash chromatography with dichloromethane/methanol to yield 315 mg (17%)of the product as a light orange solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]=1[CH:14]=[O:15].[N:16]1([CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C1C=CN=CC=1>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([O:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][CH2:23][CH2:22][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:26][CH:27]=1)=[C:3]([CH:14]=[O:15])[CH2:4][CH2:5]2
Reactant: COc1ccc2c(c1)CCC(C=O)=C2Cl
Reactant: Oc1ccc(OCCN2CCCCC2)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc2c(c1)CCC(C=O)=C2Oc1ccc(OCCN2CCCCC2)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 122.4 %

Procedure:
To a 3-necked round bottom flask, add 1-chloro-6-methoxy-3,4-dihydronaphthalene-2-carbaldehyde (2.25 g, 10.1 mmol), 4-(2-(piperidin-1-yl)ethoxy)phenol (1.8 g, 8.24 mmol), tetra-N-butylammonium iodide (50 mg, 0.14 mmol), potassium carbonate (4.1 g, 29.8 mmol), and 4-dimethylaminopyridine (120 mg, 0.99 mmol). Purge the reaction vessel with nitrogen. Add dimethylformamide (30 mL) slowly to the reaction. Heat the mixture to 100° C. with stirring and hold for 4 hours. Cool the reaction mixture to room temperature and quench with ice-water. Extract the mixture with ethyl acetate three times. Dry the combined organic layers over MgSO4, filter, and concentrate to give 6-methoxy-1-(4-(2-(piperidin-1-yl)ethoxy)phenoxy)-3,4-dihydronaphthalene-2-carbaldehyde (4.11 g).
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[O:7].[Br:14][CH2:15][CH2:16][CH2:17]Br.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCCCCC>[Br:14][CH2:15][CH2:16][CH2:17][O:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1/[CH:4]=[CH:5]/[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)C=Cc1ccccc1O
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: COC(=O)/C=C/c1ccccc1OCCCBr
Yield: 89.4 %

Procedure:
To a solution of methyl 2-hydroxycinnamate (1.31 g; 7.33 mmol) in 50 ml acetone was added 1,3-dibromopropane (1.50 ml; 14.8 mmol) and K2CO3 (4.36 g; 13.4 mmol). The mixture was heated to reflux for 12 h, cooled to r.t, diluted with hexane (50 ml), filtered and finally concentrated to afford the title product (1.96 g; 50% pure), which was used as such in the next step.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@@H:7]([C:12](O)=[O:13])[CH2:6][CH2:5]2.B.C1COCC1.O.C([O-])(O)=O.[Na+]>C1COCC1>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@@H:7]([CH2:12][OH:13])[CH2:6][CH2:5]2
Reactant: O=C(O)[C@H]1CCc2cc(I)ccc2O1
Agent: B
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OC[C@H]1CCc2cc(I)ccc2O1
Temperature: 45 °C
Reaction time: 1.5 h

Procedure:
To a solution of (2R)-6-iodo-3,4-dihydro-2H-chromene-2-carboxylic acid (Example 7, 19.5 mmol, 1.0 eq.) in THF (45 mL) at 10° C. was added dropwise a solution of borane-THF complex (1M in THF, 23.4 mmol, 1.2 eq). The resulting reaction mixture was stirred at 45° C. for 1.5 hours and was then cooled to 10° C. Next, water was added followed by saturated NaHCO3 solution. The resulting two-phase mixture was separated and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, concentrated to afford the product as a white solid in quantitative yield that was used without further purification. GC-MS m/z 290 (M+)
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]=2[CH:4]=1)=[CH2:2].[OH-:16].C([N+](C)(C)C)C1C=CC=CC=1>N1C=CC=CC=1>[CH:1]([C:3]1[C:4](=[O:16])[C:5]2[C:13](=[CH:14][CH:15]=1)[C:12]1[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH:6]=2)=[CH2:2]
Reactant: [OH-]
Reactant: C=Cc1ccc2c(c1)Cc1ccccc1-2
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: c1ccncc1
Product: C=CC1=CC=C2C(=Cc3ccccc32)C1=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
The 2-vinylfluorene prepared in Example I is dissolved in 800 milliliters of pyridine and cooled to 0° C. One-half milliliter of a 40% solution of benzyltrimethyl ammonium hydroxide in pyridine is slowly added with air being bubbled through the reaction solution. The initially formed red coloration fades over a period of 1 to 2 hours and the solution is poured into water and extracted with benzene to yield 9 grams (90% theory) of a yellow solid. The residue is chromatographed on alumina (Woehlm basic) and eluted with benzene. Recrystallization from hexane gives 2-vinylfluorenone as a pale yellow material (melting point 69°-70° C). The structure of the product is confirmed by nuclear magnetic resonance and elemental analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:32]([O:35][CH2:36][C:37](Cl)=[O:38])(=[O:34])[CH3:33]>O1CCCC1>[CH:18]1([CH2:17][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:37]([CH2:36][O:35][C:32](=[O:34])[CH3:33])=[O:38])=[CH:7][CH:6]=2)[C:9](=[O:10])[NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Reactant: CC(=O)OCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 22.9 %

Procedure:
A solution of 2-(4-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (prepared in Example 3, 105 mg, 0.33 mmol) in tetrahydrofuran (10 mL) was treated with N,N-diisopropylethylamine (0.068 mL, 0.40 mmol) and acetoxy acetyl chloride (0.03 mL, 0.33 mmol). The reaction mixture was stirred at 25° C. for 5 h. At this time, the reaction was concentrated in vacuo. High pressure liquid chromatography (Chromegasphere SI-60, 10 μM, 60 Å, 25 cm×23 cm ID, 50/50 heptane/ethyl acetate) afforded acetic acid {4-[2-cyclopentyl-1-(thiazol-2-ylcarbamoyl)-ethyl]-phenylcarbamoyl}-methyl ester (31.4 mg, 22.7%) as a white solid: mp 90-95° C.; EI-HRMS m/e calcd for C21H25N3O4S (M+) 415.1565, found 415.1567.
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]=1[CH2:17][CH2:18][NH:19][C:20](N1C=CN=C1)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCCC>C1(C)C(C)=CC=CC=1>[CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]2[C:20](=[O:21])[NH:19][CH2:18][CH2:17][C:9]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCc1[nH]c2ccccc2c1Cc1ccccc1)n1ccnc1
Solvent: Cc1ccccc1C
Solvent: CCCCCC
Product: O=C1NCCc2c(Cc3ccccc3)c3ccccc3n21
Yield: 62.3 %

Procedure:
A solution of N-[2-(3-benzylindol-2-yl)ethyl]-1-imidazolecarboxamide (2.4 g) in xylene (50 ml) was refluxed for 3 hours. After cooling, the mixture was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (5%-methanol-chloroform) to give a crystalline product. The product was pulverized with n-hexane to give 5-benzyl-3,4-dihydropyrimido[1,6-a]indol-1(2H)-one (1.2 g).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[NH2:3].[OH-].[Na+].[C:15]([CH2:18][S:19][C:20](=S)[S:21]CC(O)=O)(O)=[O:16]>O>[O:16]=[C:15]1[CH2:18][S:19][C:20](=[S:21])[N:3]1[NH:2][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: NNc1ccccc1C(=O)O
Reactant: O=C(O)CSC(=S)SCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccccc1NN1C(=O)CSC1=S
Temperature: 25 °C
Yield: 82.2 %

Procedure:
To a water (20 mL) solution of 2-hydrazino-benzoic acid hydrochloride (2.508 g, 13.30 mmol) was added water solution of sodium hydroxide (1.029 N, d=1.040, 26.81 g, 26.60 mmol) followed by bis(carboxymethyl)trithiocarbonate (3.006 g, 13.28 mmol). The mixture was stirred at reflux temperature for 10 h, cooled to room temperature and stirred for 50 h. The solid product was filtered off and washed on funnel successively with water (2×10 ml), ether (5 mL) and hexane (20 mL). The material was dried in a vacuum oven at 80° C. for 5 h to afford 2-(4-oxo-2-thioxo-thiazolidin-3-ylamino)-benzoic acid (2.93 g, 82%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 4.33 (1H, bs), 6.66 (1H, m), 6.90 (1H, m), 7.40 (1H, m), 7.89 (1H, m), 13.37 (1H, bs). ESI-MS: 267.0.
Reaction SMILES: [Na].CS([O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)=O.[CH2:17](O)[CH2:18][OH:19]>COCCOC.O>[O:10]([CH2:9][CH2:8][CH2:7][O:6][CH2:17][CH2:18][OH:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCCO
Reactant: CS(=O)(=O)OCCCOc1ccccc1
Agent: [Na]
Solvent: COCCOC
Solvent: O
Product: OCCOCCCOc1ccccc1
Reaction time: 2 h
Yield: 98.7 %

Procedure:
Sodium (2.80 g) was dissolved in 1,2-ethanediol (22.00 g) at ca 100° under nitrogen and 3-phenoxy-1-propanol methanesulphonate (25.5 g) in 1,2-dimethoxyethane (50 ml) was added dropwise at 100° under nitrogen. The mixture was stirred at 150° for 2 h and then carefully diluted with water (150 ml) and extracted with diethyl ether (2×150 ml). The combined organic extracts were washed with water (2×150 ml), dried and evaporated in vacuo to give the title compound (21.45 g) as an oil. T.l.c. System B (1:1) Rf 0.13.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[CH2:11]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=3)[CH:24]=2)=[CH:19][CH:18]=1)[CH2:12][CH2:13][CH2:14][CH3:15].Cl.C(N=C=NCCCN(C)C)C.O>ClCCl>[N:2]1([O:1][C:32](=[O:33])[C:31]2[CH:30]=[CH:29][C:28]([C:25]3[CH:24]=[C:23]([C:20]4[CH:21]=[CH:22][C:17]([O:16][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:18][CH:19]=4)[O:27][N:26]=3)=[CH:36][CH:35]=2)[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1
Reactant: CCCCCOc1ccc(-c2cc(-c3ccc(C(=O)O)cc3)no2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCCCCOc1ccc(-c2cc(-c3ccc(C(=O)On4nnc5ccccc54)cc3)no2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 90.9 %

Procedure:
To a solution of 1-hydroxybenzotriazole (244 mg) and 4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoic acid (528 mg) in dichloromethane (10 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (WSCD•HCl) (430 mg) and the mixture was stirred for 4.5 hours at ambient temperature. The reaction mixture was added to water. The organic layer was taken and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 4-[5-(4-pentyloxyphenyl)isooxazol-3-yl]benzoic acid benzotriazol-1-yl ester (640 mg).
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([NH:42][CH2:43][CH2:44][F:45])=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][NH:42][CH2:43][CH2:44][F:45])=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CCl)NCCF
Product: CCN(Cc1ccc(OCCNCCF)cc1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 40.7 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-N-(2-fluoroethyl)acetamide (13 mg) according to an analogous synthetic method to Example 567 and purified by LC-MS, the title compound (10 mg) was obtained.