Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1[CH:10]=[C:9]([NH2:11])[NH:8][N:7]=1.CN1CCOCC1.O>C(Cl)Cl>[CH3:5][C:6]1[CH:10]=[C:9]([NH:11][C:1](=[O:3])[CH3:2])[NH:8][N:7]=1
Reactant: Cc1cc(N)[nH]n1
Reactant: CC(=O)Cl
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1cc(C)n[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.6 %

Procedure:
Acetyl chloride (41 g, 0.530 mol) was added dropwise to a solution of 3-methyl-1H-pyrazol-5-amine (25.6 g, 0.264 mol) and N-methylmorpholine (58 mL, 0.530 mol) in CH2Cl2 (250 mL) at 0° C. under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 16 h. Water was added to the reaction mixture and the organic layer concentrated in vacuo. The residue was taken up in a mixture of MeOH/THF (100 mL/100 mL), cooled to 10° C. and treated with 1M NaOH solution. The reaction mixture was stirred for 0.25 h, acidified to pH 5 and organic solvents were removed in vacuo. The resulting precipitate was filtered, washed (water, diethyl ether) and dried to provide the title compound as a white solid (29.6 g).
Reaction SMILES: [CH:1]1([CH:6]2[C:15]3[C:14](=[O:16])[CH2:13][C:12]([CH3:18])([CH3:17])[CH2:11][C:10]=3[NH:9][C:8]([CH:19]([O:21][CH3:22])[CH3:20])=[C:7]2[C:23](=[O:34])[C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C>ClCCl.C1CCCCC1.C(OC(=O)C)C>[CH:1]1([C:6]2[C:15]3[C:14](=[O:16])[CH2:13][C:12]([CH3:17])([CH3:18])[CH2:11][C:10]=3[N:9]=[C:8]([CH:19]([O:21][CH3:22])[CH3:20])[C:7]=2[C:23](=[O:34])[C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(C)C1=C(C(=O)c2ccc(C(F)(F)F)cc2)C(C2CCCC2)C2=C(CC(C)(C)CC2=O)N1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: COC(C)c1nc2c(c(C3CCCC3)c1C(=O)c1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)C2
Temperature: 0 °C

Procedure:
4.7 g 4-Cyclopentyl-2-(1-methoxy-ethyl)-7,7-dimethyl-3-(4-trifluoromethyl-benzoyl)-4,6,7,8-tetrahydro-1H-quinolin-5-one are dissolved in 100 ml dichloromethane, cooled to 0° C. and 2.5 g 2,3-dichloro-5,6-dicyano-p-benzoquinone are added portionwise. The temperature is raised during 3 hours to room temperature. Then the volume is reduced to approximately 60 ml by evaporation in vacuo, the mixture is filtered and the filter cake is washed 5 times with 50 ml of dichloromethane. The combined organic phases are evaporated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethylacetate 90:10 to 50:50). The product thus obtained is dissolved in cyclohexane/ethylacetate 70:30 and treated with charcoal. The mixture is filtered and the charcoal is washed 3 times with 100 ml cyclohexane/ethylacetate 70:30. The combined organic phases are evaporated in vacuo.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH3:7])[CH:6]=1.C([Li])CCC.[Cl:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18](=[O:24])[C:19](=[O:23])[NH:20]2)=[CH:16][CH:15]=1>O1CCCC1>[Cl:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18]([OH:24])([C:2]3[CH:3]=[N:4][N:5]([CH3:7])[CH:6]=3)[C:19](=[O:23])[NH:20]2)=[CH:16][CH:15]=1
Reactant: Cn1cc(Br)cn1
Reactant: O=C1Nc2cc(Cl)ccc2C1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cc(C2(O)C(=O)Nc3cc(Cl)ccc32)cn1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-bromo-1-methyl-1H-pyrazole (0.98 g, 6.0 mmol) in tetrahydrofuran (10 mL) at −78° C. was added n-butyllithium (2.5 M in hexanes, 2.76 mL, 6.90 mmol) (Aldrich) dropwisely. The mixture was stirred at −78° C. for 10 minutes. To the obtained brownish solution was added a solution of 6-chloroisatin (0.5 g, 2.76 mmol) (Crescent) in tetrahydrofuran (5 mL). The reaction mixture was warmed up to room temperature and stirred at room temperature for 3 hours. The reaction was quenched with saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate three times. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography (ethyl acetate:dichloromethane, 1:1 V/V) to give rac-6-chloro-3-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydro-indol-2-one as a yellow solid. (Yield 0.22 g, 30%).
Reaction SMILES: Br[C:2]1[C:3]([F:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]1.C1(CNCC2CCCCC2)CCCCC1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:8][C:3]1[C:2]([C:11]2[CH2:12][CH2:13][CH2:14][C:9](=[O:15])[CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Fc1ncccc1Br
Reactant: O=C1C=CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C1CCC(CNCC2CCCCC2)CC1
Solvent: C1COCCO1
Product: O=C1C=C(c2cccnc2F)CCC1
Temperature: 25 °C

Procedure:
A solution of 3-bromo-2-fluoropyridine (11 g, 62.5 mmol), 2-cyclohexen-1-one (24.03 g, 250 mmol), N,N-dicyclohexylmethylamine (30.5 g, 156 mmol) and bis(tri-t-butylphosphine)palladium (0) (0.958 g, 1.875 mmol) in dioxane (80 mL) was heated to 105° C. for 6 h. The mixture was cooled to RT and the dioxane was evaporated under reduced pressure. Water (200 ml) was added and the mixture layer was extracted with EtOAc (2×200 ml). The combined organic layers were washed with brine and dried over sodium sulfate. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (20% to 50% EtOAc in hexanes) afforded 3-(2-fluoropyridin-3-yl)cyclohex-2-enone as colorless crystals. MS (ESI, pos. ion) m/z: 191.9 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([C:11](OCC)=[O:12])[N:10]=[C:4]2[CH:3]=1.CC(C[AlH]CC(C)C)C.Cl.[OH-].[Na+]>ClCCl.C1(C)C=CC=CC=1.O.CO>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([CH2:11][OH:12])[N:10]=[C:4]2[CH:3]=1
Reactant: CCOC(=O)c1cn2ccc(Br)cc2n1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: OCc1cn2ccc(Br)cc2n1
Temperature: -19 °C
Yield: 52.1 %

Procedure:
To a suspension of 0.25 g (0.93 mmol) of ethyl 7-bromoimidazo[1,2-a]pyridine-2-carboxylate, prepared according to the protocol described in step 8.1, in 4 mL of anhydrous dichloromethane, stirred at −19° C. under an inert atmosphere, are added dropwise 2.09 mL (2.09 mmol) of a molar solution of DIBAL-H in toluene. The reaction mixture is stirred at −19° C. for 3 hours and then hydrolysed at −40° C. by successive addition of 0.1 mL of methanol, 0.1 mL of water and 10 mL of 5N HCl. The reaction mixture is then basified with aqueous sodium hydroxide solution (24%) and then extracted with three times 100 mL of dichloromethane. The combined organic phases are dried over sodium sulfate and then concentrated under reduced pressure. The crude reaction product is then purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol. 110 mg of the expected product are thus obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([C:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH:17]=2)[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([CH:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:16][CH2:17]2)[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc(C2=CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Yield: 88.8 %

Procedure:
A solution of 3′,6′-dihydro-2′H-[2,4′]bipyridinyl-6,1′-dicarboxylic acid 1′-tert-butyl ester 6-ethyl ester (1.12 g, 3.37 mmol) in ethanol (67 mL) was pumped through Pd/C cartridge using H-Cube apparatus (20° C., 10 bar, 2 mL/min.). The solvent was then evaporated under reduce pressure to give 3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-6,1′-dicarboxylic acid 1′-tert-butyl ester 6-ethyl ester (1.001 g, 89%), which can be used in the next step without further purification. 1H-NMR (400 MHz, d6-DMSO): δ=1.31-1.38 (t, 3H), 1.47 (s, 9H), 1.55-1.65 (m, 2H), 1.79-1.88 (m, 2H), 2.91-2.99 (m, 2H), 3.42-3.48 (m, 1H), 4.05-4.12 (m, 2H), 4.31-4.37 (q, 2H), 7.55 (d, 1H), 7.84-7.92 (m, 2H). MS: m/z=333 (M+1. MS: m/z=335 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:10][OH:11])[C:5]([C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([CH2:36][CH3:37])(=[N:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:29])=[CH:24][CH:23]=1>>[CH2:34]([O:33][C:31]([N:30]=[S:28]([CH2:36][CH3:37])([C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:2]2[N:7]=[C:6]([NH:8][C@H:9]([CH2:10][OH:11])[CH2:12][CH:13]([CH3:15])[CH3:14])[C:5]([C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)=[CH:4][N:3]=2)=[CH:23][CH:24]=1)=[O:29])=[O:32])[CH3:35]
Reactant: CC(C)C[C@@H](CO)Nc1nc(Cl)ncc1-c1ccsc1
Reactant: CCOC(=O)N=S(=O)(CC)c1ccc(N)cc1
Product: CCOC(=O)N=S(=O)(CC)c1ccc(Nc2ncc(-c3ccsc3)c(N[C@H](CO)CC(C)C)n2)cc1
Yield: 59 %

Procedure:
In the reaction (S)-2-(2-chloro-5-thiophen-3-yl-pyrimidine-4-ylamino)-4-methyl-pentan-1-ol (312 mg, 1.00 mmol) with (RS)—S-(4-amino-phenyl)-N-(ethoxycarbonyl)-S-ethylsulfoximide (231 mg, 0.90 mmol) according to procedure 5b, the desired product is obtained in 59% yield (282 mg) after chromatographic purification (silica gel, dichloromethane/methanol (0%-10% methanol)).
Reaction SMILES: [Br-].O1CCCOC1CC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CC(C)([O-])C.[CH2:39]([C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([CH:54]3[CH2:59][CH2:58][CH2:57][CH2:56][C:55]3=O)=[CH:50][CH:49]=2)=[CH:44][CH:43]=1)[CH2:40][CH3:41]>CCOCC>[CH2:39]([C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:49]=[CH:50][C:51]([CH:54]3[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]3)=[CH:52][CH:53]=2)=[CH:44][CH:43]=1)[CH2:40][CH3:41]
Reactant: CCCc1ccc(-c2ccc(C3CCCCC3=O)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: c1ccc([P+](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCc1ccc(-c2ccc(C3CCCCC3)cc2)cc1
Reaction time: 1 h

Procedure:
Into a three-necked flask equipped with a dropping funnel, a three-way cock and a thermometer was placed 2-(1,3-dioxan-2-yl)ethyltriphenylphosphonium bromide (22.9 g, 50 mmols), followed by adding tetrahydrofuran (100 ml), suspending, stirring the suspension under ice cooling till the liquid temperature reached 10° C. The resulting reaction mixture is added pottasium t-butoxide (5.6 g, 50 mmols), followed by elevating the temperature up to room temperature under ice cooling for one hour, stirring for one hour, dropwise adding a tetrahydrofuran (100 ml) solution of (4-(4-propylphenyl)phenyl)cyclohexanone (14.0 g, 48 mmols) over 30 minutes from the dropping funnel, further stirring the reaction liquid for 5 hours after completion of the dropwise addition, adding ether (200 ml), allowing to stand for one hour, filtering off deposited insoluble substance, concentrating the filtrate under reduced pressure and isolating and purifying the resulting pale brown oil by means of silica gel column chromatography, to obtain 1-(2-(1,3-dioxane-2-yl)ethylidene)-4-(4-(4-propylphenyl)-phenylcyclohexane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[O:12])[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[OH:12])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCNc1cccc(Br)c1)c1ccccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OC(CCNc1cccc(Br)c1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 3-(3-bromophenylamino)-1-(2-chlorophenyl)propan-1-one (50 mg, 0.148 mmol) in 4:1 THF/methanol (5 mL) was cooled to 0° C. NaBH4 (11 mg, 2 equiv) was added. After 10 min, the mixture was warmed up to rt slowly and stirred for 2 h. The mixture was concentrated, diluted with EtOAc (7 mL), washed with 1% aq HCl (1 mL), and dried over Na2SO4. Filtration and concentration afforded crude 3-(3-bromophenylamino)-1-(2-chlorophenyl)propan-1-ol which was used without further purification. LC-MS (3 min) tR=1.93 min, m/z=342,343(M+1).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.[Br:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:2][C:3]2[N:4]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=2)=[CH:23][CH:22]=1
Reactant: Oc1ccc(Br)cc1
Reactant: FC(F)(F)c1cn(-c2c(Cl)cccc2Cl)c(CBr)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC(F)(F)c1cn(-c2c(Cl)cccc2Cl)c(COc2ccc(Br)cc2)n1

Procedure:
Into a 250 mL flask was weighed 570 mg (1.52 mmol) of 2-Bromomethyl-1-(2,6-dichlorophenyl)-4-trifluoromethyl-1H-imidazole, 394 mg (2.25 mmol) of 4-bromophenol, 310 mg (2.25 mmol) of potassium carbonate, and 20 mL of acetonitrile. The flask was heated in an oil bath to reflux for 4 h. The crude reaction was washed into a separatory funnel with ethyl acetate and water. The organic layer was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel flash chromatography by column chromatography eluting with MeOH-DCM (0:100 to 2:98) to afford 2-(4-Bromophenoxymethyl)-1-(2,6-dichloro-phenyl)-4-trifluoromethyl-1H-imidazole as an off white solid (417 mg, 59%); 1H NMR (400 MHz, CDCl3): δ 7.96 (d J=8.6 Hz 2H), 7.68 (d J=8.3 Hz 2H), 7.46 (m, 5H), 7.32 (m, 1H), 6.88 (d J=8.84 Hz 2H), 5.10 (s, 2H), 3.08 (s, 3H), MS (ES): 465 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:19])=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:27]([F:32])([F:31])C([O-])=O.[Na+]>C(#N)C.O>[Cl:1][C:2]1[C:3]([O:19][CH:27]([F:32])[F:31])=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(Cl)c(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1nccc2c1c(=O)n(C)c1cc(Cl)c(OC(F)F)cc21
Temperature: 80 °C
Yield: 10.6 %

Procedure:
To the stirred solution of 8-chloro-9-hydroxy-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (0.5 g, 1.456 mmol), prepared as described in Example 89, Part B in acetonitrile (5 mL) was added K2CO3 (0.604 g, 4.37 mmol) followed by sodium 2-chloro-2,2-difluoroacetate (0.444 g, 2.91 mmol). The mixture was heated to 80° C. for 18 h. After cooling, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×80 mL). The organic layer was washed with brine solution, dried over Na2SO4, filtered and concentrated under reduced pressure to afford 8-chloro-9-(difluoromethoxy)-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (50 mg, 0.154 mmol, 11% crude yield) as a semi solid. The material was carried on without further purification. LC/MS (ESI) m/e 325.0 [(M+H)+, calcd for C15H12ClF2N2O2 325.04]; LC/MS retention time (method C): tR=2.39 min.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH:9]1[N:13]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=3)[N:15]=2)[C:12](=[O:26])[C:11]2[S:27][CH2:28][CH:29]([O:32][CH3:33])[CH2:30][S:31][C:10]1=2.Cl.Cl[C:36]([N:38]1[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]1)=[O:37].N1C=CC=CC=1>C(Cl)Cl>[CH3:33][O:32][CH:29]1[CH2:30][S:31][C:10]2[C:9](=[O:8])[N:13]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=4)[N:15]=3)[CH:12]([O:26][C:36]([N:38]3[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]3)=[O:37])[C:11]=2[S:27][CH2:28]1
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: COc1ccc2ccc(N3C(=O)C4=C(SCC(OC)CS4)C3O)nc2n1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COc1ccc2ccc(N3C(=O)C4=C(SCC(OC)CS4)C3OC(=O)N3CCN(C)CC3)nc2n1
Temperature: 45 °C
Yield: 52.3 %

Procedure:
Triethylamine (34.5 cc) is added, at about 15° C., to a suspension of 6-hydroxy-3-methoxy-7-(7-methoxy-1,8-naphthyridin-2-yl)-8-oxo-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (10.7 g) and 1-chlorocarbonyl-4-methylpiperazine hydrochloride (16.4 g) in anhydrous methylene chloride (440 cc), and anhydrous pyridine (195 cc) is then added to the resulting mixture. The reaction mixture is heated for 3 hours at 45° C. After cooling, the mixture is diluted by adding methylene chloride (300 cc). The organic phase is washed three times with distilled water (total 600 cc), dried over anhydrous sodium sulphate and evaporated. The resulting residue (41.0 g) is treated with boiling methanol (150 cc). After cooling the mixture for 1 hour at 2° C., the crystals are filtered off, washed twice with ice-cooled methanol (total 40 cc) and dried under reduced pressure (20 mm Hg) at 20° C. The resulting product (9.0 g; m.p. 215° C.) is dissolved in boiling methanol (175 cc). After cooling the solution for 2 hours at 2° C., the resulting crystals are filtered off, washed twice with ice-cooled methanol (total 20 cc) and dried under reduced pressure (0.2 mm Hg) at 50° C. 3-Methoxy-7-(7-methoxy-1,8-naphthyridin-2-yl)-6-(4-methylpiperazin-1-yl)carbonyloxy-8-oxo-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (7.4 g), melting at 218° C., is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[Mn]([O-])(=O)(=O)=[O:17].[K+]>O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2].O1CCCC1>[Br:1][C:2]1[C:3](=[O:17])[C:4]2[C:12](=[CH:13][CH:14]=1)[C:11]1[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=1)[CH:5]=2
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1C(Br)=CC=C2C1=Cc1cc(Br)ccc12
Temperature: 177.5 °C
Yield: 86 %

Procedure:
2,7-Dibromofluorene (20.00 g, 61.72 mmol), potassium permanganate (31.61 g, 200.0 mmol) and copper(II) sulphate pentahydrate (49.94 g, 200.0 mmol) were ground together to afford a fine powder. The powder was heated at 175-180° C. for 6 h. After cooling to room temperature, tetrahydrofuran (1 L) was added and the mixture was sonicated for 30 minutes before being filtered through celite. The solvent was removed under reduced pressure to afford a crude product, which was triturated with hot methanol (300 mL) and filtered before being dried under reduced pressure to afford 2,7-dibromofluorenone (1) (17.94 g, 86%) as a yellow solid, purity 100% (GC): 1H and 13C NMR spectra as expected; M+=338 (t).
Reaction SMILES: C([O:3][C:4](=[O:42])[CH:5]([O:40][CH3:41])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)=[C:9]([CH:32]=[CH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:8]=1)C>C(O)C>[OH:31][CH:24]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][CH2:14][O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([O:40][CH3:41])[C:4]([OH:42])=[O:3])=[CH:8][C:9]=2[CH2:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:19][CH:20]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCCOc2ccc(C(=O)c3ccccc3)cc2)c(C=Cc2ccccc2)c1)OC
Solvent: CCO
Product: COC(Cc1ccc(OCCCOc2ccc(C(O)c3ccccc3)cc2)c(CCc2ccccc2)c1)C(=O)O

Procedure:
A solution of 3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-3-styryl-phenyl}-2-methoxy-propionic acid ethyl ester from Example 145, was dissolved in ethanol and treated with H2 under balloon pressure. Filtered through a pad of celite and concentrated to dryness. The compound thus obtained was treated under standard hydrolysis procedure C to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([CH3:12])[CH:3]=1.[CH3:13][N:14]1[C:22]2[C:17](=[CH:18][C:19]([CH2:23][NH2:24])=[CH:20][CH:21]=2)[CH:16]=[CH:15]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:24][CH2:23][C:19]2[CH:18]=[C:17]3[C:22](=[CH:21][CH:20]=2)[N:14]([CH3:13])[CH:15]=[CH:16]3)(=[O:10])=[O:9])=[C:4]([CH3:12])[CH:3]=1
Reactant: Cc1cc(Br)ccc1S(=O)(=O)Cl
Reactant: Cn1ccc2cc(CN)ccc21
Product: Cc1cc(Br)ccc1S(=O)(=O)NCc1ccc2c(ccn2C)c1

Procedure:
The titled compound was prepared according to the procedure described in step-1 of Example 1 from 4-bromo-2-methylbenzene-1-sulfonyl chloride and (1-methyl-1H-indol-5-yl)methanamine.
Reaction SMILES: [O:1]=[C:2]([CH3:42])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([CH:25]2[CH2:29][CH2:28][CH:27]([C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)[O:26]2)[CH:10]=[C:11]([O:17]CC2C=CC=CC=2)[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5]>C(O)(=O)C.C(OCC)(=O)C.[Pd]>[O:1]=[C:2]([CH3:42])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([CH:25]2[CH2:29][CH2:28][CH:27]([C:30]3[CH:31]=[C:32]([O:40][CH3:41])[C:33]([O:38][CH3:39])=[C:34]([O:36][CH3:37])[CH:35]=3)[O:26]2)[CH:10]=[C:11]([OH:17])[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:5])=[O:6]
Reactant: CCCOc1c(OCc2ccccc2)cc(C2CCC(c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCOc1c(O)cc(C2CCC(c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)=O
Reaction time: 0.75 h

Procedure:
A mixture of 1.2 g of 2-[3-(2-oxopropylsufonyl)-4-n-propoxy-5-benzyloxy- phenyl]-5-(3,4,5-trimethoxyphenyl) tetrahydrofuran, 400 mg 10% Pd/C, 1-2 drops of acetic acid in 100 mL of ethyl acetate was stirred under H2 at 40 psi for 45 minutes. The reaction mixture was filtered over a bed of celite and evaporated in vacuo to yield the title compound: NMR(200 MHz, CDCl3) δ 1.10 (t, CH2CH2CH3), 1.92 (m, CH2CH2CH3), 1.9-2.6 (m, 3-CH2 & 4-CH2), 2.40 (s, CH3C(O)CH2), 3.86 (s, OCH3), 3.90 (s, 2 OCH3), 4.12 (t, OCH2CH2CH3), 4.42 (s, CH3C(O)CH2), 5.10-5.28 (m, 2-CH & 5-CH), 6.64 (s, 5-ArH), 7.35 & 7.47(2 d, 2-ArH).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@@H:7]([OH:11])[CH:6]=[C:5]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1N2CCN(CC2)C1>C1COCC1.C(N(CC)CC)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][C@H:5]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc2c(c1)C(c1ccccc1)=C[C@@H]2O
Agent: C1CN2CCN1CC2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)[C@H](c1ccccc1)CC2=O
Yield: 91 %

Procedure:
5-Methyl-3-phenyl-(S)-1H-inden-1-ol (750 mg, 3.41 mmol) and DABCO (190 mg, 1.71 mmol) were dissolved in dry THF:triethylamine 20:1 (15 ml) and refluxed for 3 h. The reaction mixture was evaporated to dryness. Flash chromatography eluting with ethyl acetate:pentane 5:95 gave 690 mg (92%) of the title compound. Rf 0.62 (ethyl actetate:penttanie 20:80) (ChiralCel OD-H) 0.5 ml/min of hexane/isopropanol: 95/5 (S)-isomer 19.12 min, (R)-isomer 22.33 min, 89% ee. IR (neat cm−1): 3027, 2361, 1710, 1605, 1280, 1238, 1040. 1H NMR δ: 2.39 (s, 3H), 2.69 (dd, J=3.0, 19.2Hz, 1H), 3.23 (dd, J=8.0, 19.2Hz, 1H), 4.53 (q, J=4Hz, 1H), 7.07 (s, 1H), 7.14 (d, J=8.4Hz, 1H), 7.15 (s, 1H), 7.26 (m, 2H), 7.33 (m, 2H), 7.72 (d, J=7.6Hz, 1H). 13C NMR δ: 22.1, 44.3, 46.9, 123.2, 126.9, 127.0, 127.6, 128.9, 134.5, 143.8, 146.3, 158.4, 205.5. MS (EI 70 eV) m/z (rel. intensity): 220 (100) [M+], 207 (55), 194 (19), 178 (60), 144 (10).