Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.C[Li].Cl[S:18]([C:21]1[CH:22]=[CH:23][C:24]([OH:30])=[C:25]([CH:29]=1)[C:26]([OH:28])=[O:27])(=[O:20])=[O:19].[CH:31](N(CC)C(C)C)(C)C.Cl>C(OCC)C.O1CCCC1.CN(C)C=O>[OH:30][C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:6]2[CH:7]([CH3:31])[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)(=[O:20])=[O:19])=[CH:29][C:25]=1[C:26]([OH:28])=[O:27]
Reactant: CCN(C(C)C)C(C)C
Reactant: c1ccc2c(c1)cnc1ccccc12
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1O
Agent: Cl
Agent: [Li]C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 2.9 %

Procedure:
A stirred solution of phenanthridine (7.16 g, 40 mmol) in anhydrous diethyl ether (40 mL) was cooled to −30° C., and treated drop-wise under nitrogen via syringe with a solution of 1.4 M methyllithium in diethyl ether (30 mL, 42 mmol). The yellow solution was warmed to room temperature and stirred for 15 minutes. The mixture was cooled to −78° C., and treated with 5-(chlorosulfonyl)-2-hydroxybenzoic acid (9.47 g, 40 mmol) as a solid in a single aliquot. The reaction mixture was diluted with anhydrous tetrahydrofuran (40 mL), warmed to room temperature, and a solution of N,N-diisopropylethylamine (25.85 g, 200 mmol) in anhydrous dimethylformamide (40 mL) was added. After stirring at room temperature overnight, the reaction mixture was poured into a 1 N hydrochloric acid solution, and extracted with ethyl acetate. The organic phase was washed sequentially with a 1 N aqueous hydrochloric acid solution, water, and a saturated, aqueous, sodium chloride solution. After drying over anhydrous sodium sulfate, the organic phase was filtered and the solvent evaporated in vacuo to yield a crude yellow solid (3.4 g, 21%). The crude solid (1.0 g) was purified by reverse phase preparative chromatography on a Primesphere® 10 C-18 column (25 cm×5 cm), eluting with 56% acetonitrile in water with 0.1% trifluoroacetic acid at a flow rate of 90 mL/min. After evaporation of the acetonitrile solvent, the aqueous phase was extracted with ethyl acetate. The organic phase was washed sequentially with water and a saturated, aqueous, sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent evaporated in vacuo to a colorless solid. Crystallization of the colorless solid from a mixture of diethyl ether-hexane yielded the title compound (0.46 g, 1.16 mmol) as a homogeneous, colorless, crystalline solid, m.p. 225-230° C.;
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][NH2:12].O>ClCCl>[CH3:11][NH:12][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: CN
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: O
Solvent: ClCCl
Product: CNc1ccncc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To a suspension of 4-chloro-3-nitropyridine (2 g, 12.6 mmol) in dichloromethane (15 mL) was cautiously added methyl amine (25% solution in water, 10 mL, 63 mmol). The reaction mixture was heated to 40° C. After stirring for 1 h, the mixture was poured into water (20 mL), and the precipitate was collected by filtration and dried in vacuo to afford the title compound (1.9 g, yield 98%) as a yellow solid. LC-MS (ESI) m/z: 154 (M+1)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]([N:14]2[CH2:19][CH2:18][C:17]3[CH:20]=[CH:21][O:22][C:16]=3[CH2:15]2)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][NH:24][CH3:25].[CH2:26]=O>C(O)(=O)C>[CH3:23][N:24]([CH2:26][C:21]1[O:22][C:16]2[CH2:15][N:14]([C:12]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:13])[CH2:19][CH2:18][C:17]=2[CH:20]=1)[CH3:25]
Reactant: O=C(OCCCCc1ccccc1)N1CCc2ccoc2C1
Reactant: CNC
Reactant: C=O
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CN(C(=O)OCCCCc1ccccc1)CC2
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.085 g (about 0.284 mmol) of the above 6-(4-phenylbutoxycarbonyl)-4,5,6,7-tetrahydrofuro[2,3-c]pyridine in 20 ml of acetic acid, 0.15 g (1.7 mmol) of 50% aqueous dimethylamine and 0.14 g (1.7 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 15 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:6]([OH:8])=[O:7].ClCCl.B(Br)(Br)Br.[C:22](=O)([O-])[O-].[K+].[K+].I[CH2:29][CH3:30]>ClCCl>[CH2:1]([O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:6]([O:8][CH2:29][CH3:30])=[O:7])[CH3:22]
Reactant: CCI
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: O=C([O-])[O-]
Agent: BrB(Br)Br
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)c1cc(OCC)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
3-Methoxy-5-nitrobenzoic acid (10 g, 50.7 mmol) prepared in step 1 of Example 72 was dissolved in dichloromethane (200 ml), added with 1 M boron tribromide dichloromethane solution. The reaction mixture was stirred at room temperature for 8 hours. The mixture was poured into ice water and washed with dichloromethane. The water layer was concentrated under reduced pressure and dried in vacuo. The residue was dissolved in N,N-dimethylformamide (150 ml), added dropwise with potassium carbonate (42 g, 304 mmol) and iodoethane (20.2 ml, 253 mmol). The mixture was then stirred for one day at 60° C. and poured into ice water. The solution was extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (hexane:ethyl acetate=5:1) to obtain the title compound (8.49 g, yield: 70%, yellow solid).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]([NH:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[CH:16]3)=[N:11]2)=[CH:6][CH:5]=1.Cl[C:27]([O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:28].C(OC(C)=O)(C)C.[Cl-].[Na+].O>CN(C=O)C>[CH:30]1([O:29][C:27](=[O:28])[N:19]([C:18]2[N:10]([C:7]3[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=3)[N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][CH:14]=[CH:13]3)[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: O=C(Cl)OC1CCCCC1
Reactant: Clc1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)OC(C)C
Product: O=C(OC1CCCCC1)N(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 4.6 %

Procedure:
To an ice cold suspension of NaH (6 mg, 160 umol) in DMF (3 ml) under an argon atmosphere was added a solution of [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-amine (50 mg, 153 μmol; example 11.1) in DMF (1 ml) within 10 min. The suspension was stirred for 1 h at ambient temperature. A solution of cyclohexyl chloroformate (33 mg, 203 μmol; [13248-54-9]) in DMF (1 ml) was added within 5 min. The reaction mixture was stirred for 14 h at ambient temperature, poured onto ice water/brine 1/1 and extracted two times with iPrOAc. The combined extracts were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by preparative thin layer chromatography (silica gel, iPrOAc/heptane) to give the title compound (3 mg, 7 μmol; 3%) as brown solid. MS: m/e=452.4 [M+H+].
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[S:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]([NH:27][C:28]2[C:33]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:31]=[C:30]([OH:37])[C:29]=2[CH:38]([CH3:40])[CH3:39])=[O:26])[CH2:20][CH2:19]1.C(N(CC)CC)C>C1COCC1.O>[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[S:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]([NH:27][C:28]2[C:33]([CH:34]([CH3:35])[CH3:36])=[CH:32][CH:31]=[C:30]([O:37][S:2]([CH3:1])(=[O:4])=[O:3])[C:29]=2[CH:38]([CH3:40])[CH3:39])=[O:26])[CH2:20][CH2:19]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)c1ccc(O)c(C(C)C)c1NC(=O)CN1CCN(CCSc2nc3ccccc3o2)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)c1ccc(OS(C)(=O)=O)c(C(C)C)c1NC(=O)CN1CCN(CCSc2nc3ccccc3o2)CC1
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
Methanesulfonyl chloride (103 mg, 0.9 mmol) was added to a solution of 2-[4-[2-(benzoxazol-2-ylthio)ethyl]piperazin-1-yl]-N-(2,6-diisopropyl-3-hydroxyphenyl)acetamide (149 mg, 0.3 mmol) and triethylamine (91 mg, 0.9 mmol) in THF (2 ml) with ice-cooling and the mixture was stirred for 30 minutes. Then triethylamine (46 mg, 0.45 mmol) and methanesulfonyl chloride (52 mg, 0.45 mmol) were further added thereto and the mixture was stirred for 20 minutes. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over sodium sulfate and the solvent was evaporated therefrom. The residue was purified by a silica gel column chromatography (20 g of silica gel; developing solvent, chloroform:methanol=20:1) and the resulting crude crystals were recrystallized from acetone and hexane to provide 120 mg (yield 70%) of the desired compound as colorless crystals.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:7]1)=[O:5])C.[CH3:22][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>C1COCC1>[CH2:15]([O:14][C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C:6]([CH3:22])([C:4]([OH:3])=[O:5])[CH2:7]1)=[O:13])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1(C(=O)O)CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
To a −78° C. solution of the product of Example 45A (6.0 g, 20.6 mmoles) in THF (50 mL) was added a solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 22.7 mmoles). After 35 min, iodomethane (1.4 mL, 22.7 mmoles) was added and the reaction was slowly warmed to room temperature and stirred overnight. The reaction was quenched with aqueous sat. ammonium chloride and extracted with Et2O. The organic layer was then rinsed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography employing a solvent gradient (hexane→65:35 hexane:EtOAc). The resulting ester was hydrolyzed overnight at room temperature in THF (15 mL), H2O (10 mL), and EtOH (15 mL) with NaOH (2.5 g). The solution was concentrated under vacuum; the residue was dissolved in saturated ammonium chloride; and, the solution was extracted with ethyl acetate (3×). The combined ethyl acetate extracts were dried over sodium sulfate, filtered, and concentrated under vacuum to yield the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH2:15][C@H:14]2[CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CC[C@H](OS(C2C=CC(C)=CC=2)(=O)=O)C1)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]2[CH2:17][CH2:16][CH2:15][C@H:14]2[CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CCCN1[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cc1ccc(S(=O)(=O)O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Product: C[C@@H]1CCCN1[C@@H]1CCN(C(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared in a manner substantially the same as intermediate (2R,3′S)-2-Methyl-[1,3′]bipyrrolidinyl-1′-carboxylic acid tert-butyl ester by condensing 3-(3S)-(toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester and R-(−)-2-methylpiperindine (obtained from Advanced Asymmetrics). LCMS: RT=1.09 minutes, MS: 255 (M+H).
Reaction SMILES: CN(C)C=O.[N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8](B(O)O)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:26]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[O:30][C:29]([CH3:38])([CH3:37])[CH2:28][N:27]=1>C(OCC)(=O)C.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>[CH3:37][C:29]1([CH3:38])[CH2:28][N:27]=[C:26]([C:8]2[CH:7]=[N:6][C:15]3[C:10]([CH:9]=2)=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[O:30]1
Reactant: CC1(C)CN=C(Cl)c2ccccc2O1
Reactant: OB(O)c1cnc2ccccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)CN=C(c2cnc3ccccc3c2)c2ccccc2O1
Temperature: 90 °C
Reaction time: 14 h
Yield: 52.8 %

Procedure:
After carrying out nitrogen replacement on a dimethylformamide solution (15 mL) of 3-quinoline boronic acid (0.70 g, 4.07 mmol) and 2 M aqueous cesium carbonate solution (4.70 mL, 9.40 mol), tetrakis(triphenylphosphine)palladium (0.72 g, 0.63 mmol) and 5-chloro-2,2-dimethyl-2,3-dihydro-benzo[f][1,4]oxazepine (3.13 mmol) were added to this solution. This solution was then stirred for 14 hours while heating at 90° C. Subsequently, the reaction solution was cooled to room temperature followed by pouring in ethyl acetate (50 mL) and water (50 ml) and filtering with celite. The filtrate was extracted with ethyl acetate (100 mL) and the organic layer was washed with brine (50 mL) followed by drying with magnesium sulfate. After filtering, the solvent was distilled off under reduced pressure to obtain 0.50 g (53%) of the target compound by purifying the resulting residue by silica gel column chromatography (hexane:ethyl acetate=2:1).
Reaction SMILES: ClC1C=C([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28](C)[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)C=CC=1.[CH3:32][O:33][C@H]1CC[C@H](N)CC1.[C:41]1([CH2:47]CCC(O)=O)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:32][O:33][C@H:28]1[CH2:29][CH2:30][C@H:25]([N:11]([CH2:10][CH2:9][CH2:8][CH2:47][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH2:26][CH2:27]1
Reactant: CO[C@H]1CC[C@H](N)CC1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Reactant: O=C(O)CCCc1ccccc1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: CO[C@H]1CC[C@H](N(CCCCc2ccccc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using trans-4-methoxy-cyclohexylamine, 4-phenyl-butyric acid and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[C:14]([C@@H:18]2[C@@H:23]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[N:22]([C@@H:31]([CH2:34][CH3:35])[CH2:32][OH:33])[C:21](=[O:36])[C@@H:20]([CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:19]2)[CH:15]=[CH:16][CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([C@@H:18]2[C@@H:23]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[N:22]([C@@H:31]([CH2:34][CH3:35])[CH:32]=[O:33])[C:21](=[O:36])[C@@H:20]([CH2:37][C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH2:19]2)[CH:15]=[CH:16][CH:17]=1
Reactant: CC[C@@H](CO)N1C(=O)[C@@H](CC(=O)OC(C)(C)C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC[C@@H](C=O)N1C(=O)[C@@H](CC(=O)OC(C)(C)C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of oxalyl chloride (0.261 mL, 2.99 mmol) in DCM (5.87 mL) at −60° C. was added a solution of DMSO (0.512 mL, 5.98 mmol) in DCM (5.87 mL) under N2. After being stirred for 20 min, a solution of tert-butyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-2-oxopiperidin-3-yl)acetate (1.01 g, 1.99 mmol, Example 21, Step B) in DCM (5.87 mL) was added, and the resulting solution was stirred for 15 min. To this solution was added triethylamine (1.39 mL, 9.97 mmol). After being stirred at −60° C. for 5 min, the reaction was allowed to warm to rt, and quenched (H2O). The solution was extracted (3×DCM) and washed (H2O and sat. aq. NaCl solution). The combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the title compound.
Reaction SMILES: [C:1]([O-:9])(=[O:8])[CH2:2][CH2:3][CH2:4][C:5]([O-:7])=[O:6].C1(=O)OC(=O)CCC1.O[N:19]1[C:23](=[O:24])[CH2:22][CH2:21][C:20]1=[O:25].C1(N=C=NC2CCCCC2)CCCCC1>>[C:1]([OH:9])(=[O:8])[CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[C:20]1(=[O:25])[NH:19][C:23](=[O:24])[CH2:22][CH2:21]1
Reactant: O=C([O-])CCCC(=O)[O-]
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCCC(=O)O1
Product: O=C(O)CCCC(=O)O
Product: O=C1CCC(=O)N1

Procedure:
As depicted in above Scheme 2, 6-arm PEG (1) synthesized in the Scheme 1 is reacted with glutarate reagents, e.g., glutaric anhydride to synthesize 6-arm PEG-glutatic acid (6-arm PEG-GA) (2). The compound (2) was reacted with N-hydroxy succinimide (NHS) and N, N′-dicyclohexylcarbodiimide (DCC) to produce 6-arm PEG-succinimide glutarate (6-arm PEG-SG) (3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11](=O)[N:10]([CH2:14][CH2:15][CH3:16])[N:9]=2)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11](=[S:26])[N:10]([CH2:14][CH2:15][CH3:16])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCCN1N=C(c2ccc(Cl)cc2)CC1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCCN1N=C(c2ccc(Cl)cc2)CC1=S
Yield: 131.9 %

Procedure:
A mixture of 1.0 g (3.8 mmol) of 3-(4-chlorophenyl)-1-propyl-4, 5-dihydropyrazol-5-one, 1.2 g (3.0 mmol) of Lawesson's reagent, and 10 ml of toluene was heated under reflux for 2 hours. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=10/1 (v/v)) to give 1.0 g of the object compound as a yellow oil (yield 94%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]([F:39])([F:38])[C:13]([CH2:33][NH:34][CH2:35][CH2:36][CH3:37])([OH:32])[CH2:14][NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:34]([CH2:35][CH2:36][CH3:37])[CH2:33][C:13]([CH2:14][NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1)([OH:32])[C:12]([F:11])([F:39])[F:38])=[O:6]
Reactant: CCCNCC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Reactant: Cc1ccccc1C(=O)O
Product: CCCN(CC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1ccccc1C

Procedure:
Prepared similarly to Example 1 from 2-methylbenzoic acid and 1,1,1-trifluoro-3-{[1-(4-fluorophenyl)-1H-indazol-4-yl]amino}-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[C:10](Cl)(=[O:12])[CH3:11].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[S:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]([C:10](=[O:12])[CH3:11])[CH:8]=[CH:9][C:2]1=2
Reactant: CC(=O)Cl
Reactant: c1ccc2c(c1)CCS2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)CCS2
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
To a solution of 2,3-dihydro-benzo[b]thiophene (1.88 g, 13.8 mmol) in methylene chloride (20 mL) at −10° C. was added dropwise a solution of acetyl chloride (1.85 mL, 25.9 mmol) and aluminum chloride (1.84 g, 13.8 mmol) in methylene chloride (20 mL) keeping the temperature below −6° C. during the addition period. After the addition is complete the reaction mixture was stirred for an additional 30 min at −10° C. and then added ice (40 mL) and concentrated hydrochloric acid (6 mL) and extracted with methylene chloride (3×20 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (80 g column, 10% diethyl ether/hexanes) afforded 1-(2,3-dihydro-benzo[b]thiophen-5-yl)-ethanone (1.93 g, 78%) as a clear colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[C:7]([CH2:13][S:14][CH3:15])=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:25])C=1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[C:7]([CH2:13][S:14]([CH3:15])=[O:25])=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1
Reactant: CSCc1cn(C)c2cc(Cl)ccc2c1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Product: Cn1cc(CS(C)=O)c(=O)c2ccc(Cl)cc21

Procedure:
In a similar manner to that described in Example 4 7-chloro-1-methyl-3-methylthiomethyl-4-quinolone was oxidised with 3-chloroperbenzoic acid to give the novel 7-chloro-1-methyl-3-methylsulphinylmethyl-4-quinolone m.p. 180°-181° (from dichloromethane:petroleum ether (b.p. 60°-80°)).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([C:6]([F:9])=[CH:7][CH:8]=1)[NH2:5].Br.Br[CH:13]([C:15]1[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]2[C:24]=1[O:23][C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:21][C:20]2=[O:31])[CH3:14]>>[Cl:1][C:2]1[C:3]([F:10])=[C:4]([NH:5][CH:13]([C:15]2[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]3[C:24]=2[O:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:21][C:20]3=[O:31])[CH3:14])[C:6]([F:9])=[CH:7][CH:8]=1
Reactant: Nc1c(F)ccc(Cl)c1F
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Br
Product: CC(Nc1c(F)ccc(Cl)c1F)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 47.8 %

Procedure:
3-chloro-2,6-difluoroaniline (133 mg, 0.82 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (100 mg, 0.20 mmol) using an analogous procedure to the one described in Example 3.03 to give 8-(1-(3-chloro-2,6-difluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (47 mg, 47%) as a white solid. Mass Spectrum: M+H+ 492. NMR Spectrum (DMSOd6): 1.56 (d, 3H), 2.74 (bs, 3H), 2.97 (bs, 3H), 3.50-3.58 (m, 4H), 3.70-3.80 (m, 4H), 5.37-5.46 (m, 1H), 5.57 (s, 1H), 5.99 (d, 1H), 6.81 (ddd, 1H), 6.94 (ddd, 1H), 7.72 (d, 1H), 7.76 (d, 1H).