Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH:24]1([CH2:29][CH2:30][C:31](Cl)=[O:32])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([CH2:29][CH2:30][C:31]([NH:1][C:2]2[C:3]([C:7]3[NH:23][C:10]4=[CH:11][C:12]5[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=5[CH:17]=[C:9]4[N:8]=3)=[N:4][NH:5][CH:6]=2)=[O:32])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)CCC4CCCC4)nc3cc21

Procedure:
3-Cyclopentyl-N-[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-propionamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and cyclopentylpropionyl chloride (136 ml, 0.89 mmol. The title compound was obtained as brown powder (177 mg, 50%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[C:10]([OH:17])[CH:9]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>CN(C=O)C>[CH2:18]([O:17][C:10]1[CH:9]=[C:8]([F:7])[CH:13]=[CH:12][C:11]=1[C:14](=[O:16])[CH3:15])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)c1ccc(F)cc1O
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(F)cc1OCc1ccccc1
Reaction time: 18 h
Yield: 97.2 %

Procedure:
Potassium carbonate (4.02 g, 29.10 mmol) was added to a solution of 4′-fluoro-2′-hydroxyacetophenone (2.0 mL, 2.56 g, 16.60 mmol) in DMF (15 mL). Benzyl bromide (2.07 mL, 2.98 g, 17.50 mmol) was added dropwise over 5 minutes at room temperature, and the mixture stirred for 18 h. The mixture was poured into hydrochloric acid (1.0 M in H2O; 200 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were dried (MgSO4) and the solvents removed in vacuo. Pure 2′-(benzyloxy)-4′-fluoroacetophenone (3.94 g, 97%) was obtained as a white powder after trituration with hexane. Rf 0.44 (9:1 hexane:EtOAc); δH (CDCl3) 7.82 (1H, dd, J=8.6 and 7.0 Hz), 7.43-7.38 (5H, m), 6.75-6.69 (2H, m), 5.13 (2H, s), 2.56 (3H, d, J=3.2 Hz); LCMS retention time 2.68 min, M+H+ 245.1.
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]([NH:18][C:19](=[O:37])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:22][CH:21]=2)[CH:6]=1)=[O:4].C(O)C.Cl>C(OCC)(=O)C>[OH:4][CH2:3][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]([NH:18][C:19](=[O:37])[C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:24][CH:25]=2)[CH:6]=1
Reactant: CCOC(=O)COc1ccc(C=O)cc1NC(=O)c1ccc(OCCCCc2ccccc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)COc1ccc(CO)cc1NC(=O)c1ccc(OCCCCc2ccccc2)cc1
Reaction time: 2 h
Yield: 73.3 %

Procedure:
Under ice cooling 0.2 g of sodium borohydride was added to a mixture of 2.8 g of ethyl 4-formyl-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate obtained in Reference Example 64 and 30 ml of ethanol. The mixture was stirred for 2 hours and 50 ml of ethyl acetate was added thereto. The mixture was rendered acidic with diluted hydrochloric acid. The ethyl acetate layer was fractionated, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethanol to obtain 2.06 g of ethyl 4-hydroxymethyl-2-[p-(4phenylbutoxy)benzamido]phenoxyacetate.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[C:19]1[C:23]([C:24](Cl)=[O:25])=[C:22]([CH3:27])[O:21][N:20]=1>>[CH3:2][O:3][C:4](=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:24]([C:23]1[C:19]([C:13]2[C:14]([F:18])=[CH:15][CH:16]=[CH:17][C:12]=2[Cl:11])=[N:20][O:21][C:22]=1[CH3:27])=[O:25]
Reactant: COC(=O)CCCCN
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Agent: Cl
Product: COC(=O)CCCCNC(=O)c1c(-c2c(F)cccc2Cl)noc1C
Yield: 89.1 %

Procedure:
Methyl-5-aminopentanoate hydrochloride (694 mg, 4.14 mmol) and 3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-oyl chloride (1.24 g, 4.52 mmol) were converted to 1.36 g of the title compound by the procedure of Preparation 10. (100%). EA calculated for: C17H18N2O4ClF: C, 55.37; H, 4.92; N, 7.60. Found: C, 55.44; H, 5.00; N, 7.52. MS(FD) m/z 368 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][OH:22])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][O:22][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:11])=[CH:23][CH:24]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)Cl
Reactant: CC(=O)S[C@H]1C[C@@H](CO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)OC[C@@H]1C[C@H](SC(C)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
(2S,4S)-1-(p-Nitrobenzyloxycarbonyl)-2-hydroxymethyl-4-acetylthiopyrrolidine (177 mg), 76 mg of triethylamine and 61 mg of 4-N,N-dimethylaminopyridine were dissolved in 2 ml of dry dichloromethane. Ethyl chloroformate (81 mg) was added thereto under ice-cooling in a nitrogen stream. The mixture was stirred under ice-cooling for 3.5 hours, washed successively with water, dilute hydrochloric acid, water, a saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and distilled to obtain (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-ethoxycarbonyloxymethyl-4-acetylthiopyrrolidine.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([C:15]3[C:16]4[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][N:21](COCC[Si](C)(C)C)[C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1)#[N:2].C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(OCC)(=O)C>[C:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([C:15]3[C:16]4[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: CCOC(=O)c1cn(COCC[Si](C)(C)C)c2ncnc(-c3cccc(-c4ccnc(C#N)n4)c3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(-c4ccnc(C#N)n4)c3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 4-(3-(2-cyanopyrimidin-4-yl)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (17 mg, 0.035 mmol) was treated with TFA (500 μL) and stirred at room temperature for 1 hour. To the resulting mixture was added 1 N sodium hydroxide solution (1 mL) and ethyl acetate (3 mL), then allowed to keep stirring for 30 minutes. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (×3). The combined organic layers were concentrated under reduced pressure and then purified by chromatography on silica eluting with 60-80% ethyl acetatehexane to give ethyl 4-(3-(2-cyanopyrimidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calc'd for C20H15N6O2[M+H]+: 371, found 371. 1H NMR (600 MHz, DMSO-D6) δ 13.04 (bs, 1H), 9.07 (d, J=5.28 Hz, 1H), 8.97 (s, 1H), 8.49 (m, 2H), 8.38 (m, 2H), 7.91 (d, J=7.63 Hz, 1H), 7.72 (t, J 7.63 Hz, 1H), 3.84 (q, J=7.04 Hz, 2H), 0.84 (t, J=7.04 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]([N:8]1[C@H:11]([S:12]SC2SC3C=CC=CC=3N=2)[CH2:10][C:9]1=[O:23])=[C:5]([CH3:7])[CH3:6].[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(O)(=O)C.[Zn]>[CH3:1][O:2][C:3](=[O:24])[C:4]([N:8]1[C@H:11]([S:12][C:25](=[O:27])[CH3:26])[CH2:10][C:9]1=[O:23])=[C:5]([CH3:6])[CH3:7]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)C(=C(C)C)N1C(=O)C[C@H]1SSc1nc2ccccc2s1
Agent: [Zn]
Solvent: CC(=O)O
Product: COC(=O)C(=C(C)C)N1C(=O)C[C@H]1SC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1 g of zinc powder is added in portions over a period of one hour to a solution, stirred under nitrogen and in an ice bath, of 380 mg (1 mmol) of 2-[(4R)-4-(benzthiazol-2-yl-dithio)-2-oxoazetidin-1yl]-3-methylcrotonic acid methyl ester in 3 ml of acetic anhydride and 5 ml of glacial acetic acid. The reaction mixture is further stirred for one hour at room temperature, filtered and concentrated in vacuo. The residue is taken up in methylene chloride and washed in succession with 25% aqueous ammonium chloride solution and aqueous sodium bicarbonate solution. The combined aqueous phases are reextracted with methylene chloride, all the methylene chloride phases are combined, dried with sodium sulphate and concentrated in vacuo. The residue is chromatographed over 40 g of silica gel (deactivated with 10% water) with toluene and toluene/ethyl acetate (19:1) and yields the optically pure title compound having a melting point of 78°-80°;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:33]1([NH2:38])[CH2:37][CH2:36][CH2:35][CH2:34]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:38][CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: NC1CCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)NC1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.9 %

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-chlorophenyl)-3H-imidazo [4,5-b]pyridine-3-acetic acid (4.0 g, 0.014 mole) and 1,1'-carbonyldiimidazole (2.27 g, 0.014 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 3 hours. Cyclopentylamine (2.38 g, 0.028 mole) was added and the reaction mixture was allowed to stir at room temperature overnight. The tetrahydrofuran was evaporated to dryness and the residue was treated with water. The solid was collected by filtration, washed with water, and dried under high vacuum overnight. The solid was recrystallized from isopropyl alcohol-ethanol, collected by filtration, washed with cold isopropyl alcohol, and dried under high vacuum over the weekend to give 3.67 g (74%) of crystals, mp 260°-261° C.
Reaction SMILES: FC(F)(F)C([N:5]([CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.C([O:40][C:41](=[O:45])[C@H:42]([CH3:44])[NH2:43])C>CCOCC>[CH2:15]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:43][C@H:42]([C:41]([OH:45])=[O:40])[CH3:44])=[O:11])=[CH:13][CH:14]=1)[CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCC=CCCCN(C(=O)C(F)(F)F)c1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)[C@H](C)N
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCCCCCCC=CCCCNc1ccc(C(=O)N[C@@H](C)C(=O)O)cc1

Procedure:
A solution of 4.75 g. of N-trifluoroacetyl-4-(4-tetradecenylamino)benzoyl chloride and 1.2 g. of triethylamine in 200 ml. of warm ether is treated with 1.55 g. alanine ethyl ester and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the combined filtrate and washings are evaporated. After treatment of the residue with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields the product a white, crystalline solid.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[CH:11]=[CH2:12])(=[O:4])=[O:3].ClC1C=CC=C(C(OO)=[O:21])C=1>C(Cl)Cl>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[CH:11]1[CH2:12][O:21]1)(=[O:4])=[O:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CC1CCCCN1S(C)(=O)=O
Solvent: ClCCl
Product: CS(=O)(=O)N1CCCCC1C1CO1
Temperature: 25 °C
Reaction time: 65 h
Yield: 31.2 %

Procedure:
To a solution of 1-(methylsulfonyl)-2-vinylpiperidine (0.369 g, 2.0 mmol) in anhydrous methylene chloride (10 mL) was added purified 3-chloroperbenzoic acid (100%, 1.0 g, 6 mmol). The reaction was stirred at room temperature for 65 hours. The reaction mixture was filtered, saturated aqueous sodium sulfite added, and the biphasic solution was stirred for 5 mins. The mixture was diluted with ethyl acetate, and the organic layer successively washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride solutions, dried (anhydrous sodium sulfate), filtered, and concentrated. The crude product was purified by silica gel column chromatography (30-60% ethyl acetate in hexanes) to give a white semi-solid (0.128 g, 31%). 1H NMR (CDCl3, 300 MHz) δ 3.78-3.74 (br d, 1H, J=13.2 Hz), 3.66-3.61 (m, 1H), 3.37-3.32 (m, 1H), 3.24-3.15 (m, 1H), 2.98 (s, 3H), 2.88-2.85 (dd, 1H, J=4.8, 4.2 Hz), 2.68-2.66 (dd, 1H, J=4.8, 2.6 Hz), 1.81-1.60 (m, 6H). ESI (m/z): 205.9 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([O:20][CH2:21][C:22]([NH2:25])([CH3:24])[CH3:23])=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C1C=CC=CC=1.[C:32](Cl)(=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]>C(N(CC)CC)C>[C:12]([C:9]1[CH:8]=[C:7]([CH2:16][CH2:17][C:18]([O:20][CH2:21][C:22]([NH:25][C:32](=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])([CH3:24])[CH3:23])=[O:19])[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:14])([CH3:15])[CH3:13]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CC(C)(N)COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCCC(=O)NC(C)(C)COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 4 h

Procedure:
In a 500 ml, three-neck, round-bottom flask equipped with a thermometer, stirrer and dropping funnel were placed 26 g (0.75 mole) of 2-amino-2-methylpropyl 3-(3,5-di-t-butyl-4-hydroxyphenyl)propionate, 200 ml of benzene and 8.2 g of triethylamine. To this stirred mixture was added 22.5 g (0.075 mole) of stearoyl chloride, and the mixture stirred for 4 hours. The triethylamine hydrochloride was removed by filtration and the solvent was stripped off. The residue was dissolved in hot hexane. After crystallization, filtration and drying, the title compound melted at 46°-48° C.
Reaction SMILES: [Br:1][C:2]([F:22])([F:21])[C:3]([F:20])([F:19])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[Br:14])[CH:6]=1.[Cl:23][S:24](O)(=[O:26])=[O:25].Cl>C(Cl)(Cl)Cl>[Br:1][C:2]([F:21])([F:22])[C:3]([F:19])([F:20])[O:4][C:5]1[CH:6]=[C:7]([O:11][C:12]([F:17])([F:18])[C:13]([F:15])([F:16])[Br:14])[CH:8]=[CH:9][C:10]=1[S:24]([Cl:23])(=[O:26])=[O:25]
Reactant: FC(F)(Br)C(F)(F)Oc1cccc(OC(F)(F)C(F)(F)Br)c1
Reactant: O=S(=O)(O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(OC(F)(F)C(F)(F)Br)cc1OC(F)(F)C(F)(F)Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
In a 250 mL of round-bottom flask resting in an ice-bath were placed 23.35 g (0.05 mol) of this 1,3-di(2-bromotetrafluoroethoxy)benzene and 100 mL of chloroform. Then 116 g of chlorosulfonic acid was added dropwise into the solution. After the initial evolution of hydrogen chloride had subsided, the mixture was brought to room temperature. The reaction mixture was stirred at room temperature for 1 hour, then heated at 35° C. for another day. The contents of the flask were poured into a 1 L beaker filled with crushed ice. The chloroform layer was separated and washed with ice cold water to neutral. The organic layer was dried over sodium sulfate. After the removal of the solid materials by filtration, the chloroform was evaporated off completely. The crude product was purified by distillation under the reduced pressure to collect the fraction boiling at 127-129° C./10−2 torr. A total of 25.1 g (0.0443 mol) of 2,4-bis(2-bromotetrafluoroethoxy)benzenesulfonyl chloride was obtained in 88.7% yield. The quantity of hydrogen by-product was below 3%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]([CH3:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][N:22]([CH2:25][CH2:26][OH:27])[N:21]=1)=[CH:16][CH:15]=3.Br[CH2:34][CH:35]1[CH2:37][CH2:36]1>>[CH:35]1([CH2:34][O:27][CH2:26][CH2:25][N:22]2[CH:23]=[CH:24][C:20]([C:17]3[CH:18]=[C:19]4[C:14](=[CH:15][CH:16]=3)[N:13]([CH3:28])[C:12]3[N:29]([CH3:32])[C:30](=[O:31])[C:9]([C:3]5[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=5[Cl:1])=[CH:10][C:11]4=3)=[N:21]2)[CH2:37][CH2:36]1
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn(CCO)n4)ccc3n(C)c21
Reactant: BrCC1CC1
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn(CCOCC5CC5)n4)ccc3n(C)c21

Procedure:
The process is carried out as in Example 101 above, with the compound from Example 51, 3-(2,4-dichlorophenyl)-6-[1-(2-hydroxyethyl)-1H-pyrazol-3-yl]-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and (bromomethyl)cyclopropane.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:16]([O:17][CH3:18])=[CH:15][C:14]([OH:19])=[CH:13][C:11]=3[CH:12]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.[OH-].[Na+].Cl.[C:28]([O-])(O)=[O:29].[Na+]>CN(C=O)C>[OH:19][C:14]1[C:13]([CH:28]=[O:29])=[C:11]2[CH:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)[O:9][C:10]2=[C:16]([O:17][CH3:18])[CH:15]=1
Reactant: COc1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(O)c(C=O)c2cc(-c3ccc(O)cc3)oc12

Procedure:
A solution of 62 (0.25 g, 1.0 mmol) in DMF (20 mL) was treated with POCl3 (1 mL, 11 mmol) and heated at 80° C.–100° C. for 15 minutes. The reaction mixture was worked up by allowing to cool and then poured into crushed ice. 2N NaOH aq was added and the solution stirred for several minutes and then the mixture was acidified with 2N HCl aq and then neutralized with NaHCO3 aq. The mixture was then extracted with EtOAc and washed with brine, dried over MgSO4, filtered, concentrated and chromatographed on silica gel (2:8 to 4:6 EtoAc/hexanes) to yield a solid which still contained some starting material, but that was purified by trituration with EtOAc to yield 47 mg the desired pdt as a white solid: Mp=254–255° C.; 1H NMR (DMSO-d6) δ 10.29 (s, 1 H), 10.0 (br s, 1 H), 7.73 (d, 2 H, J=8.7 Hz), 7.59 (s, 1 H), 6.88 (d, 2 H, J=8.7 Hz), 6.46 (s, 1 H), 4.00 (s, 3 H); MS 281 (M−H)−.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]1.[C:7](Cl)([Cl:9])=[O:8].C1(C)C=CC=CC=1>C(Cl)Cl>[Cl:9][C:7]([O:6][C@H:3]1[CH2:4][CH2:5][O:1][CH2:2]1)=[O:8]
Reactant: O[C@H]1CCOC1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(Cl)O[C@H]1CCOC1
Temperature: 25 °C
Yield: 85 %

Procedure:
A stirred solution of (S)-tetrahydrofuran-3-ol (7.9 g, 90 mmol) in anhydrous CH2Cl2 (50 mL) under an N2 atmosphere was cooled in an ice bath, and a 20% solution of phosgene in toluene (134 mL, 270 mmol) was slowly added. The reaction was allowed to warm to room temperature overnight, and the solvent was removed under vacuum to afford (S)-tetrahydrofuran-3-yl chloroformate (12.1 g, 85%) as a clear liquid. 1H NMR (400 MHz, CDCl3) δ 5.42-5.39 (m, 1H), 4.01-3.84 (m, 4H), 2.31-2.13 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].[Cl:23][CH2:24][C:25](Cl)=O>>[C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][N:10]1[C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:21]=[C:25]1[CH2:24][Cl:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)NCCNc1c(N)cnc2ccccc12
Product: CC(C)(C)OC(=O)NCCn1c(CCl)nc2cnc3ccccc3c21
Yield: 72 %

Procedure:
Using the general method of Example 5 Part A, tert-butyl[2-(3-aminoquinolin-4-ylamino)ethyl]carbamate (43.5 g, 144 mmol) was reacted with chloroacetyl chloride (17.72 g, 158 mmol) to provide 37.39 g of tert-butyl[2-(2-chloromethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH:9]1([CH2:15][C:16]2[N:20]([CH3:21])[C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.O>C1COCC1>[Br:8][C:17]1[CH:18]=[C:19]([S:22]([NH2:25])(=[O:24])=[O:23])[N:20]([CH3:21])[C:16]=1[CH2:15][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1c(CC2CCCCC2)ccc1S(N)(=O)=O
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(S(N)(=O)=O)cc(Br)c1CC1CCCCC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 103.5 %

Procedure:
To a solution of NBS (68.7 mg, 386 μmol) was added a solution of compound 25e (104 mg, 410 μmol) in THF at −78° C. and stirred for 2 h at −78° C. Water (30 mL) was added and the reaction mixture was extracted with EA (150 mL). The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by CC (hexane/EA=3/1) to give compound 25f (134 mg, 61%).
Reaction SMILES: [H-].[Na+].Br[CH:4]([CH3:6])[CH3:5].[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:10]=1[CH2:11][C:12]#[N:13].Cl>CN(C)C=O.O>[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:10]=1[CH:11]([C:12]#[N:13])[CH:4]([CH3:6])[CH3:5]
Reactant: COc1ccc(Cl)cc1CC#N
Reactant: CC(C)Br
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1C(C#N)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of sodium hydride (2.4 g) in dimethylformamide (100 ml) was added a solution of 2-bromopropane and 2-methoxy-5-chlorobenzyl cyanide (18.2 g) in dry dimethylformamide (50 ml), keeping the temperature at 20°-30° C. The mixture was then stirred for 30 minutes, water was added cautiously, and the mixture was then poured into ice-water. Hydrochloric acid was then added and the mixture was extracted with dichloromethane, washed with water then with sodium chloride solution, then dried over magnesium sulphate, filtered, and the solvent was then removed to give 25 g of a brown oil. Distillation gave the title product (15 g) as a colourless oil, bp 180° C./20 mm Hg.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:34])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10](=[O:27])[C:9]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:8]2)=[O:4].[NH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39].C[O-].[Na+]>>[OH:34][C:6]1[C:5]([C:3]([NH:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:4])=[N:14][C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[C:12]2[C:7]=1[CH:8]=[C:9]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:10](=[O:27])[N:11]2[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2-c2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2-c2ccccc2)c1O
Temperature: 25 °C
Yield: 64.9 %

Procedure:
A mixture of 5-hydroxy-2-oxo-1,3-diphenyl-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (34 mg, 0.076 mmol), β-alanine (675 mg, 7.6 mmol) and NaOMe solution (11 mL, 5.7 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 25 mg of the title compound. MS: (+) m/z 507.30 (M+1).