Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:16][C:17]1[CH:18]=[C:19]([CH:24]=[C:25]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:26]=1)[C:20](OC)=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>CCOCC>[CH2:28]([O:27][C:25]1[CH:24]=[C:19]([CH:18]=[C:17]([O:16][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:26]=1)[CH2:20][OH:21])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCOc1cc(OCCCCCCCCC)cc(C(=O)OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCCCCCCCOc1cc(CO)cc(OCCCCCCCCC)c1
Reaction time: 1 h
Yield: 71.8 %

Procedure:
To a flame dried 1 L RBF containing a stir bar, lithium aluminum hydride (2.166 g, 57.0 mmol) was added. The RBF was placed in an ice bath and the reaction was capped with a septum containing a nitrogen gas line and an out-vent. Dry ether (10 mL) was added through the septum while the mixture was stirring. Methyl 3,5-dinonyloxybenzoate (20 g, 47.5 mmol) was added and dissolved in 60 mL dry ether, drop-wise through the septum. After this addition, the reaction mixture became clumpy and would not stir so about 150 mL more of dry ether was added to dilute the mixture. After 1 hour, the nitrogen line and the out-vent were removed and the septum was changed. The mixture was stirred overnight. The RBF was then placed in an ice bath. Distilled water (150 mL) was added drop-wise through the septum until the mixture turned a white-grey color. The reaction mixture was allowed to stir at room temperature for 10 minutes and then 100 mL 1M hydrochloric acid was added until the pH reached less than 2. The mixture was then extracted with ether 4 time (200 mL) and the ether layers were combined and then washed with 200 mL distilled water, then with 200 mL aqueous sodium carbonate (5%), then with 200 mL distilled water, then with 200 mL brine, and then dried with magnesium sulfate and gravity filtered. The solvent was removed under reduced pressure, producing a waxy white solid. The solid was air dried overnight. The solid was purified by silica gel flash chromatography using a solvent system of 1 L 20% ether and hexanes and 2 L 40% ether and hexanes. The product was collected and the solvent was removed under reduced pressure. The resulting oil was covered with the septum and allowed to stand over night where it is partially solidified. There was a 13.22 g yield or a 71.8% yield of the derivative. The NMR characterization data for this derivative is as follows. 1H NMR (300 MHz, CDCl3): 0.88 (t, J=6.3, 6H, CH2CH3), 1.1-1.55 (m, 28H, CH2(CH2)6), 1.76 (p, J=6.6, 4H, OCH2CH2), 3.92 (t, J=7.0, 4H, OCH2CH2), 4.62 (d, J=6.1, 2H, CHCH2CH), 5.29 (s, 1H, CH2OH), 6.63 (t, J=2.2, 1H, ArH), 7.15 (d, J=2.2, 2H, ArH). 13C (75 MHz, CDCl3): 160.54, 143.33, 105.07, 100.54, 68.12, 31.98, 29.65, 29.50, 29.37, 29.35, 26.14, 22.78, 14.21.
Reaction SMILES: C1(C(C2C3C(=C(CSC)C=CC=3)NC=2)(C2C=CC([C:12]([F:15])([F:14])[F:13])=CC=2)C)CC1.Cl[C:29]1[CH:34]=[CH:33][C:32]([C:35]([C:40]2[C:48]3[C:43](=[C:44]([CH2:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH:45]=[CH:46][CH:47]=3)[NH:42][CH:41]=2)([CH:37]2[CH2:39][CH2:38]2)[CH3:36])=[CH:31][CH:30]=1>>[CH:37]1([C:35]([C:40]2[C:48]3[C:43](=[C:44]([CH2:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH:45]=[CH:46][CH:47]=3)[NH:42][CH:41]=2)([C:32]2[CH:33]=[CH:34][C:29]([C:12]([F:15])([F:14])[F:13])=[CH:30][CH:31]=2)[CH3:36])[CH2:39][CH2:38]1
Reactant: CC(c1ccc(Cl)cc1)(c1c[nH]c2c(CS(C)(=O)=O)cccc12)C1CC1
Reactant: CSCc1cccc2c(C(C)(c3ccc(C(F)(F)F)cc3)C3CC3)c[nH]c12
Product: CC(c1ccc(C(F)(F)F)cc1)(c1c[nH]c2c(CS(C)(=O)=O)cccc12)C1CC1

Procedure:
The title compound was prepared starting from 153 mg (0.39 mmol) of the compound from Example 185 in analogy to the synthesis of the compound from Example 209. 63 mg (38% of theory) of the target compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Cl.[N:11]([O-])=O.[Na+].[O:15]=[C:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1C(O)=O>O>[Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][N:11]=[C:17]1[CH2:18][CH2:19][CH2:20][CH2:21][C:16]1=[O:15]
Reactant: O=N[O-]
Reactant: Nc1cccc(Cl)c1Cl
Reactant: O=C(O)C1CCCCC1=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C1CCCCC1=NNc1cccc(Cl)c1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 57 %

Procedure:
To ethyl 2-oxocyclohexanecarboxylate (2.0 g, 0.01 mmol), 5N NaOH (0.56 g, 0.014 mmol) dissolved in water (3.0 mL) was added at room temperature and stirred for 16 h. The reaction mixture was cooled to 0° C., conc. HCl (1.2 mL) was added and stirred for 45 min. to give 2-oxocyclohexanecarboxylic acid. In another setup, 2,3-dichloroaniline (1.8 g, 11.0 mmol), dissolved in H2O (10 mL) was cooled to 0° C., conc. HCl (6 mL) was added slowly and stirred for 20 min. NaNO2 (0.77 g, 11.0 mmol) in water (5.0 mL) was added and stirred at 0° C. for 30 min., filtered, the filtrate was cooled to 0° C. and 2-oxocyclohexanecarboxylic acid (prepared above) (1.6 g, 11.6 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 30 min. during which time a yellow solid was precipitated. The solid was filtered and air dried to give the title compound as a yellow solid (1.7 g, 56%). 1H NMR (200 MHz, CDCl3, δ in ppm) 13.87 (bs, 1H), 7.65 (dd, J=8.4, 1.8 Hz, 1H), 7.26-7.04 (m, 2H), 2.77-2.71 (m, 2H), 2.61-2.54 (m, 2H), 1.91-1.85 (m, 4H).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[K].[CH3:11][O:12][C:13]1[CH:31]=[CH:30][C:16]([C:17]([C:19]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)=[O:18])=[CH:15][C:14]=1[CH3:32].Br[CH2:34][C:35]1[N:40]=[C:39]([NH:41][C:42](=[O:47])[C:43]([F:46])([F:45])[F:44])[CH:38]=[CH:37][CH:36]=1.O>O1CCCC1.C(OCC)(=O)C>[F:46][C:43]([F:44])([F:45])[C:42]([NH:41][C:39]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:34][N:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28](=[O:29])[C:19]([C:17](=[O:18])[C:16]3[CH:30]=[CH:31][C:13]([O:12][CH3:11])=[C:14]([CH3:32])[CH:15]=3)=[CH:20]2)[N:40]=1)=[O:47]
Reactant: COc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Reactant: O=C(Nc1cccc(CBr)n1)C(F)(F)F
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [K]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)c2cn(Cc3cccc(NC(=O)C(F)(F)F)n3)c3ccccc3c2=O)cc1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 173.9 %

Procedure:
Potassium hexamethyldisilazane (2.44 mL, 1.22 mmol, 0.5 M in THF) was added to a solution of 3-(4-Methoxy-3-methyl-benzoyl)-1H-quinolin-4-one (0.30 g, 1.02) in 10 mL of tetrahydrofuran. After the reaction was stirred at rt for 20 minutes, N-(6-Bromomethyl-pyridin-2-yl)-2,2,2-trifluoro-acetamide (0.35 g, 0.246 mmol) was added and stirred overnight at room temperature. Water and ethyl acetate were added and the two phases were separated. The aqueous phase was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried with magnesium sulfate, filtered and concentrated in vacuo. The crude brown solid was purified by reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to yield 212 mg of 2,2,2-Trifluoro-N-{6-[3-(4-methoxy-3-methyl-benzoyl)-4-oxo-4H-quinolin-1-ylmethyl]-pyridin-2-yl}-acetamide
Reaction SMILES: [C:1](Cl)(=O)[CH3:2].[N+:5]([C:8]1[C:9]([C:13]([OH:15])=[O:14])=[N:10][NH:11][CH:12]=1)([O-:7])=[O:6]>C(O)C>[N+:5]([C:8]1[C:9]([C:13]([O:15][CH2:1][CH3:2])=[O:14])=[N:10][NH:11][CH:12]=1)([O-:7])=[O:6]
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Reactant: CC(=O)Cl
Solvent: CCO
Product: CCOC(=O)c1n[nH]cc1[N+](=O)[O-]

Procedure:
Acetyl chloride (50 mL) was added dropwise to ethanol (450 mL) at 0° C. with stirring. After addition was complete, the ice-bath was removed, and the mixture was stirred at room temperature for 30 minutes. To this mixture was added 4-nitro-1H-pyrazole-3-carboxylic acid (Aldrich) (10 g, 63.65 mmol), and the resulting homogeneous mixture was stirred at room temperature for a total of 48 hours. The reaction was monitored by TLC. The solvent was removed under reduced pressure and then co-evaporated with ethyl acetate four times. The residue was concentrated under high vacuum to give the title compound as a white powder (11.426 g, (M−H)+=184, M.P.=128.0-130.1° C.).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]([C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[N:19]1[C:23]([CH2:24]Cl)=[N:22][C:21]([C:26]([NH2:28])=[O:27])=[N:20]1)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[I-].[Na+]>CO>[ClH:18].[C:4]([C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[N:19]1[C:23]([CH2:24][N:2]([CH3:3])[CH3:1])=[N:22][C:21]([C:26]([NH2:28])=[O:27])=[N:20]1)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CNC
Reactant: NC(=O)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CN(C)Cc1nc(C(N)=O)nn1-c1ccc(Cl)cc1C(=O)c1ccccc1
Product: Cl

Procedure:
4.0 ml of 33% ethanolic dimethylamine solution is added to a mixture of 3.75 g (0.01 mole) of 1-(2-benzoyl-4-chlorophenyl)-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxamide and 0.15 g of sodium iodide in 70 ml of methanol, and the whole is refluxed for 4 hours with stirring. The reaction mixture is subsequently concentrated in vacuo. Water and saturated sodium carbonate solution are added until the pH-value has reached 10, and extraction is performed twice with ethyl acetate. The organic phase is washed twice with water and once with saturated sodium chloride solution; it is then dried over magnesium sulphate and filtered. To the filtrate there is added ethereal hydrogen chloride solution until the pH-value has reached 3. The product precipitating in crystalline form is filtered off with suction and washed with ethyl acetate and ether. After drying in vacuum, there is obtained 1-(2-benzoyl-4-chlorophenyl)-5-[(dimethylamino)-methyl]-1H-1,2,4-triazole-3-carboxamide-hydrochloride, m.p. 250° with decomposition.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[CH:6]=[C:7]([CH:9]=[O:10])[S:8][C:4]=2[CH:3]=1.[CH2:13]([B-](F)(F)F)[CH2:14][CH2:15][CH3:16].[K+]>>[CH2:13]([C:2]1[CH:12]=[CH:11][C:5]2[CH:6]=[C:7]([CH:9]=[O:10])[S:8][C:4]=2[CH:3]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCC[B-](F)(F)F
Reactant: O=Cc1cc2ccc(Br)cc2s1
Agent: [K+]
Product: CCCCc1ccc2cc(C=O)sc2c1
Yield: 85.6 %

Procedure:
The compound was synthesized as in Example 3.1 using 6-bromobenzothiophene-2-carbaldehyde (110 mg, 0.46 mmol) in place of 5-bromo-2-formylfuran and potassium butyltrifluoroborate (113 mg, 0.69 mmol) in place of hexylboronic acid to give 6-butylbenzothiophene-2-carbaldehyde (86 mg, 78%). Used without further characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=[C:13]2[N:12]=[C:11]([CH3:23])[C:10]=1[CH2:24]O.CS([Cl:30])(=O)=O.CCN(CC)CC>C(Cl)Cl>[Cl:30][CH2:24][C:10]1[C:11]([CH3:23])=[N:12][C:13]2[N:14]([CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=2)[C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: CCOC(=O)c1cn2c(-c3ccc(Cl)cc3Cl)c(CO)c(C)nc2n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cn2c(-c3ccc(Cl)cc3Cl)c(CCl)c(C)nc2n1
Reaction time: 10 h
Yield: 100.3 %

Procedure:
To a stirred solution of ethyl 5-(2,4-dichlorophenyl)-6-(hydroxymethyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxylate (430 mg, 1.12 mmol) in CH2Cl2 (10 mL) was added MsCl (0.1 mL, 1.35 mmol) and Et3N (0.24 mL, 1.69 mmol). After 10 h, the reaction was concentrated under reduced pressure and diluted with EtOAc. The mixture was extracted with H2O and brine before drying over MgSO4. Filtration and concentration under reduced pressure gave ethyl 6-(chloromethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxylate (448 mg, 100% crude yield) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=2)[C:10]([CH:18]=[CH:19][C:20](O)=[O:21])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:23][C:24]1[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=1)[C:27]([NH:29][NH:30][CH:31]([CH3:33])[CH3:32])=[O:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[F:23][C:24]1[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=1)[C:27]([NH:29][N:30]([C:20](=[O:21])/[CH:19]=[CH:18]/[C:10]1[C:11]2[C:16](=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:9]=1)[CH:31]([CH3:33])[CH3:32])=[O:28]
Reactant: Cc1ccc2c(C=CC(=O)O)cn(C(=O)OC(C)(C)C)c2c1
Reactant: CC(C)NNC(=O)c1cccc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(/C=C/C(=O)N(NC(=O)c3cccc(F)c3)C(C)C)cn(C(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing 3-(1-(tert-butoxycarbonyl)-6-methyl-1H-indol-3-yl)acrylic acid (200.0 mg, 0.66 mmol), 3-fluoro-N′-isopropylbenzohydrazide (195.4 mg, 1.00 mmol) and HATU (378.6 mg, 1.00 mmol) dissolved in DMF (5.0 ml), N,N-diisopropylethylamine (DIPEA)(0.16 ml, 1.00 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (50% EtOAc) for refinement and dried so that white (E)-tert-butyl 3-(3-(2-(3-fluorobenzoyl)-1-isopropylhydrazinyl)-3-oxoprop-1-enyl)-6-methyl-1H-indole-1-carboxylate was obtained (161.0 mg, 50.9%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:24]5[S:25][CH:26]=[CH:27][CH:28]=5)[CH:22]=4)[NH:17][C:16]=3[OH:29])=[N+:12]([O-])[CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.P(Cl)(Cl)[Cl:31].Cl>C(Cl)(Cl)Cl.CO.C(OCC)C>[ClH:31].[N:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:24]5[S:25][CH:26]=[CH:27][CH:28]=5)[CH:22]=4)[NH:17][C:16]=3[OH:29])=[N:12][CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: ClP(Cl)Cl
Reactant: [O-][n+]1cc(CN2CCOCC2)ccc1-c1c(O)[nH]c2ccc(-c3cccs3)cc12
Agent: Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Oc1[nH]c2ccc(-c3cccs3)cc2c1-c1ccc(CN2CCOCC2)cn1
Yield: 9 %

Procedure:
The title compound was prepared as described for Example 86 using 3-[5-(morpholin-4-ylmethyl)-1-oxidopyridin-2-yl]-5-thien-2-yl-1H-indol-2-ol and phosphorus trichloride. The base was dissolved in chloroform/methanol, (3:1), and a solution of HCl in diethyl ether (1 M) was added until acidic pH. The formed precipitation was filtered, washed with diethyl ether and dried. Yield: 9% of the title compound as an yellow solid: 1H NMR (DMSO-d6, 400 MHz) δ 11.10 (br s, 1 H), 10.55 (s, 1 H), 8.21 (s, 1 H), 8.02-7.90 (m, 1 H), 7.85-7.62 (m, 2 H), 7.54-7.46 (m, 1 H), 7.46-7.37 (m, 1 H), 7.18 (d, J=8 Hz, 1 H), 7.15-7.06 (m, 1 H), 6.92 (d, J=8 Hz, 1 H), 4.24 (s, 2 H), 4.03-3.89 (m, 2 H), 3.84-3.51 (m, 2 H), 3.39-3.28 (m, 2 H) 3.16-3.05 (m, 2 H); MS (ES) m/s 392 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][C:10]([F:13])([F:12])[F:11].CN(C=O)C.Cl[C:20]1[N:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:20]2[N:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=2)=[CH:4][C:3]=1[O:9][C:10]([F:12])([F:11])[F:13]
Reactant: Oc1ccc(Br)c(OC(F)(F)F)c1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc(Oc2ccc(Br)c(OC(F)(F)F)c2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-bromo-3-[(trifluoromethyl)oxy]phenol (257 mg, 1.0 mmol) in dry DMF (4 mL) potassium carbonate (276 mg, 2 mmol) and then 2-chloro-5-nitropyrimidine (319 mg, 2.0 mmol) were added and the reaction mixture was stirred for 2 hours at r.t. The reaction was quenched with water (1 mL), diluted with brine (5 mL) and extracted with ethyl acetate (2×15 mL). The organic layer was dried (Na2SO4), filtered and evaporated to give crude 2-({4-bromo-3-[(trifluoromethyl)oxy]phenyl}oxy)-5-nitropyrimidine. This crude was dissolved in THF/water (2:1) (6 mL) and Iron (279 mg, 5 mmol) and NH4Cl (267.5 mg, 5 mmol) were added and the reaction mixture was stirred overnight at r.t. The solid was filtered off and the solution was diluted with an aqueous saturated solution of NaHCO3 (5 mL) and extracted with ethyl acetate (2×20 mL). The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography on silica gel (SNAP 25 g) eluting from 75:25 to 40:60 cyclohexane/ethyl acetate to afford the title compound (280 mg) as light yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:9]1[S:10][C:11]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([S:26]([CH3:28])=[O:27])[N:21]=2)=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:13]=1>O1CCCC1.O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:9]2[S:10][C:11]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([S:26]([CH3:28])=[O:27])[N:21]=3)=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: CS(=O)c1nccc(-c2sc(Cl)nc2-c2ccccc2)n1
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(c2nc(-c3ccccc3)c(-c3ccnc(S(C)=O)n3)s2)CC1
Temperature: 25 °C

Procedure:
A solution of N-methylpiperazine (0.6 g, 6.0 mmol) in tetrahydrofuran (5 ml) is added to a well stirred solution of 4-(2-chloro-4-phenyl-thiazol-5-yl)-2-methylsulfinyl-pyrimidine (1.0 g, 3.0 mmol) in tetrahydrofuran (20 ml) at +5° C. The reaction mixture is allowed to warm to room temperature over night. Evaporation of the solvent leaves a crystalline residue that is suspended in water, filtered with suction, washed with diethyl ether and dried under vacuum. The product 4-[2-(4-methylpiperazin-1-yl)-4-phenyl-thiazol-5-yl]-2-methylsulfinyl-pyrimidine shows a m.p. of 166–169° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:5]([N:8]=[C:9]=[O:10])([CH3:7])[CH3:6].[C-]#N.[CH3:17][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:5]([NH:8][C:9](=[O:10])[N:18]([CH3:17])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:7])[CH3:6]
Reactant: CNc1ccccc1
Reactant: CC(C)(N=C=O)c1ccc(Cl)c(Cl)c1
Agent: [C-]#N
Solvent: c1ccccc1
Product: CN(C(=O)NC(C)(C)c1ccc(Cl)c(Cl)c1)c1ccccc1
Reaction time: 8 h
Yield: 86 %

Procedure:
4.6 g of 3,4-dichloro-α,α-dimethylbenzyl isocyanate, prepared from the corresponding cyanide in the same way as in Synthesis Example 1, was added to a solution of 2.2 g of N-methylaniline in 20 ml of benzene and the mixture was heated under reflux for 2 hours. After allowing the mixture to stand overnight, the reaction solution was washed with a 2N aqueous hydrochloric acid solution, a 2N aqueous sodium hydroxide solution and water in that order, and the organic layer was dried over sodium sulfate. The layer was concentrated by evaporating off the solvent to obtain crystals, which were recrystallized from n-hexane to obtain 5.8 g of the title compound as crystals.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].[NH2:22][C:23]1[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=1>>[CH2:30]([O:29][C:27]([C:26]1[CH:25]=[CH:24][C:23]([NH:22][S:2]([C:5]2[CH:14]=[CH:13][C:12]3[NH:11][C:10](=[O:15])[C:9]4[NH:16][CH:17]=[CH:18][C:8]=4[C:7]=3[CH:6]=2)(=[O:3])=[O:4])=[CH:33][CH:32]=1)=[O:28])[CH3:31].[CH2:18]([C:19]([O-:21])=[O:20])[CH3:17]
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Reactant: CCOC(=O)c1ccc(N)cc1
Product: CCC(=O)[O-]
Product: CCOC(=O)c1ccc(NS(=O)(=O)c2ccc3[nH]c(=O)c4[nH]ccc4c3c2)cc1
Yield: 3.6 %

Procedure:
This compound is prepared according to synthesis 25, from 150 mg (0.46 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 2) and 91 mg (0.55 mmol) of ethyl 4-amino-benzoate. After purification by chromatography on silica (eluent dichloromethane/methanol 96/4) then trituration in methanol, 4 mg (2%) of 8-(4-ethoxycarbonyl-phenylsulfamoyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a white solid.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][C:9](=O)[C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:20][O:21][CH3:22].CCOCC>C1C=CC=CC=1>[CH3:22][O:21][CH2:20][CH:16]1[CH2:17][CH2:18][CH2:19][N:15]1[N:14]=[C:9]1[CH2:10][CH2:11][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]1=[O:13]
Reactant: O=C1CCN(c2ccccc2)C1=O
Reactant: COCC1CCCN1N
Solvent: CCOCC
Solvent: c1ccccc1
Product: COCC1CCCN1N=C1CCN(c2ccccc2)C1=O

Procedure:
A solution of the product of Example 61 and chiral 1-amino-2-methoxymethylpyrrolidine (SAMP or RAMP; 1 equiv) in benzene is refluxed under Dean-Stark conditions for 20 h. After cooling, Et2O is added and the mixture is washed with water. The organic layer is dried (MgO4) and evaporated to give a residue which is chromatographed on silica gel to give the title compound.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[N:11][CH:12]=1.CN([CH:18]=[O:19])C>C1COCC1>[CH3:14][O:13][C:10]1[N:11]=[CH:12][C:7]([CH:18]=[O:19])=[CH:8][CH:9]=1
Reactant: COc1ccc(Br)cn1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C=O)cn1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of n-butyllithium (3.46 mL of a 1.6 M solution in hexanes) in THF (18 mL) was cooled to -78° C. and treated with a solution of 5-bromo-2-methoxypyridine (Johnson, C. R.; Sirisoma, N. S. Tetrahedron Lett. 1998, 39, 2059) 18-1 (1.04 g, 5.53 mmol) in THF (2 mL). The heterogeneous mixture was stirred for 40 min and neat DMF (1.5 mL) was added. The solution was stirred for 90 min at -78° C. and quenched with satd aq NH4Cl solution (2 mL). The cold bath was removed and the mixture warmed to room temperature. The mixture was extracted with EtOAc (2×30 mL) and the combined organic solutions washed with brine, dried over MgSO4, filtered, and concentrated to the desired aldehyde 18-2.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])=[C:10]([O:20][CH3:21])[CH:9]=2)[C:4](=[O:22])[CH:3]=1.[F:23][C:24]([F:36])([F:35])[O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C(Cl)Cl.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>[OH:19][C:16]([CH3:18])([CH3:17])[CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([N:5]2[CH:6]=[CH:7][C:2]([C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]([F:23])([F:35])[F:36])=[CH:31][CH:30]=3)=[CH:3][C:4]2=[O:22])=[CH:9][C:10]=1[O:20][CH3:21]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: COc1cc(-n2ccc(Cl)cc2=O)ccc1OCC(C)(C)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(-n2ccc(-c3ccc(OC(F)(F)F)cc3)cc2=O)ccc1OCC(C)(C)O
Temperature: 60 °C
Reaction time: 17 h
Yield: 63.6 %

Procedure:
A mixture of 4-chloro-1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyridin-2(1H)-one Part D (25 mg, 0.08 mmol), 4-(trifluoromethoxy)phenylboronic acid (28 mg, 0.14 mmol), tribasic potassium phosphate (49 mg, 0.23 mmol), and palladium tetrakis (9 mg, 7.7 μmol) in DMF (0.4 mL) was stirred at 60° C. under nitrogen for 17 hours. The reaction mixture was diluted with CH2Cl2, filtered and concentrated. The crude was purified using preparative HPLC (C18 column/10:90:0.1 to 90:10:0.1 MeOH—H2O-TFA). This material further purified by ISCO flash chromatography (silica gel/hexanes-ethyl acetate 100:0 to 0:100 gradient) to afford the title compound 1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)-4-(4-(trifluoromethoxy)-phenyl)pyridin-2(1H)-one B-1 (23.2 mg, 0.049 mmol, 63.6% yield) as a light yellow solid. LC/MS 450 (M+H)+, tR 0.95 min (method 5). 1H NMR (500 MHz, chloroform-d) δ 7.65 (2H, d, J=8.88 Hz), 7.43 (1H, d, J=7.49 Hz), 7.34 (2H, d, J=8.05 Hz), 6.97-7.02 (2H, m), 6.93 (1H, dd), 6.85 (1H, s), 6.48 (1H, dd), 3.89 (3H, s), 3.88 (2H, s), 1.37 (6H, s).