Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].Cl.[CH:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH:8]1[NH2:17])[CH2:14]2.C(N(CC)CC)C>C(OCC)C.C(Cl)Cl>[CH:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH:8]1[NH:17][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:14]2
Reactant: C=CC(=O)Cl
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)NC1C2CC3CC(C2)CC1C3
Reaction time: 12 h

Procedure:
A solution of acryloyl chloride (4.52 g, 0.05 mole) in ethyl ether (20 ml) was added dropwise to a stirring mixture of 2-adamantylamine hydrochloride (9.35 g, 0.05 mole) and triethylamine (30.65 ml) in methylene chloride (200 ml) and ethyl ether (200 ml) over a 30 minute period. The solution was stirred for 12 hours, the solid filtered and washed with ethyl ether and the filtrate stripped to an oily material which was taken up in ethyl acetate and hexane and allowed to stand overnight. The solid was filtered, the filtrate concentrated and chilled and the product as an orange solid filtered and dried. The structure was confirmed by NMR.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH:12]([OH:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=O)[CH3:3].C(OCC)(=O)[CH2:16][C:17]([CH3:19])=[O:18]>S(=O)(=O)(O)O>[CH3:3][CH:2]([N:4]1[CH:5]([CH2:16][C:17](=[O:18])[CH3:19])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]1=[O:13])[CH3:1]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)N1C(=O)c2ccccc2C1O
Agent: O=S(=O)(O)O
Product: CC(=O)CC1c2ccccc2C(=O)N1C(C)C
Yield: 50.1 %

Procedure:
A solution of 2-(1-methylethyl)-3-hydroxy-1,3-dihydro-2H-isoindol-1-one (6.1 g, described in Example 12) and ethyl acetoacetate (12.4 g) in conc. sulfuric acid (60 ml) is stirred at 40° C. for 24 hr and poured into ice. The solution is extracted with ethyl acetate and the organic extract is washed with 5% aqueous sodium bicarbonate and water, dried and evaporated. The residue is chromatographed on silica gel using hexane-ethyl acetate (2:3) and the eluates are evaporated to give 3.7 g of the title compound, nmr (DMSO-d6) δ 1.25 (d, 3H), 1.35 (d, 3H), 2.05 (s, 3H), 2.5-3.4 (m, 2H), 3.95 (m, 1H), 4.9 (m, 1H) and 7.4 (m, 4H).
Reaction SMILES: [CH3:1][C:2]([O:16][C:17](=[O:28])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27])([CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=O.C1CCN2C(=NCCC2)CC1.ClCCl>C(#N)C>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[O:19][C:18]1[C:17](=[O:28])[O:16][C:2]([CH3:15])([CH3:1])[C:3]=1[C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: CC(C)(OC(=O)COc1ccc(F)cc1F)C(=O)c1ccc(S(C)(=O)=O)cc1
Solvent: CC#N
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)OC(=O)C(Oc2ccc(F)cc2F)=C1c1ccc(S(C)(=O)=O)cc1
Temperature: 50 °C
Yield: 27.1 %

Procedure:
To a solution of 2-(2,4-difluorophenoxy)acetic acid 2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one-2-yl ester (Step 2) (470 mg, 1.14 mmol) in acetonitrile (7 mL) was added DBU (187 μL, 1.25 mmol) and the resulting solution was heated at 50° C. for 20 minutes. After cooling to r.t. dichloromethane was added and the mixture was washed with 1 N HCl, brine, filtered over cotton and the solvent evaporated under vacuum. Purification by silica gel chromatography followed by a swish in EtOAc/Et2O afforded 122 mg of the title compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[OH:5][CH:6]([CH3:39])[CH2:7][S:8]([C:11]1[CH:12]=[C:13]([C@H:22]2[CH2:26][CH2:25][C@H:24]([C:27]3[CH:32]=[C:31]([O:33][CH3:34])[C:30]([O:35][CH3:36])=[C:29]([O:37][CH3:38])[CH:28]=3)[O:23]2)[CH:14]=[C:15]([OH:21])[C:16]=1[O:17][CH2:18][CH2:19][CH3:20])(=[O:10])=[O:9].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:5][CH:6]([CH3:39])[CH2:7][S:8]([C:11]1[CH:12]=[C:13]([C@H:22]2[CH2:26][CH2:25][C@H:24]([C:27]3[CH:28]=[C:29]([O:37][CH3:38])[C:30]([O:35][CH3:36])=[C:31]([O:33][CH3:34])[CH:32]=3)[O:23]2)[CH:14]=[C:15]([O:21][CH2:3][CH2:2][Br:1])[C:16]=1[O:17][CH2:18][CH2:19][CH3:20])(=[O:9])=[O:10]
Reactant: CCCOc1c(O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1c(OCCBr)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)O
Temperature: 70 °C
Reaction time: 7 h

Procedure:
1,2-Dibromoethane (1.12 mL, 13 mmol) was added to a solution of trans-2-[3-(2-hydroxy-n-propylsulfonyl)-4-n-propoxy-5-hydroxyphenyl]-5-(3,4,5-trimethoxyphenyl) tetrahydrofuran (331 mg, 0.65 mmol) (Example 18) in DMF (5 mL) containing potassium carbonate (550 mg, 3.9 mmol). The reaction mixture was heated with stirring at 70° C. for 7 h and, cooled, and partitioned between ethyl ether and water. The ethereal layer was separated and the aqueous layer was re-extracted twice with ether. The organic extracts were combined, dried, and evaporated to dryness. The product was purified by flash column chromatography on silica gel using hexane-ethyl acetate (2:1, v/v) as the eluant: Rf 0.42 (hexane-ethyl acetate; 1:2, v/v); NMR (CDCl3) δ 1.06 (t, CH2CH2CH3). 1.25 (d, CH2CHOHCH3), 1.90 (m, CH2CH2CH3), 3.74 (t, CH2CH2Br), 3.83 (s, OCH3), 3.88 (s, 2 OCH3), 5.16-5.28 (m, H-2 & H-5), 6.62 (s, 2 H, C5ArH), 7.28 and 7.54 (2 d, 2 H, C2ArH).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[N+:13]([O-])([OH:15])=[O:14].[OH-].[Na+]>S(=O)(=O)(O)O>[F:1][C:2]([F:11])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1)=[O:4]
Reactant: O=C(c1ccccc1)C(F)(F)F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(c1cccc([N+](=O)[O-])c1)C(F)(F)F
Temperature: -10 °C
Reaction time: 1 h

Procedure:
20.0 g (114.9 mmol) of 2,2,2-trifluoroacetophenone were initially charged in 80 ml of conc. sulphuric acid, and the mixture was cooled to −10° C. A solution, prepared beforehand at −10° C., of 4.8 ml (114.8 mmol) of nitric acid in 20 ml of conc. sulphuric acid was added dropwise to this mixture such that the reaction temperature did not exceed −5° C. After the addition had ended, the reaction mixture was stirred between −10° C. and 0° C. for 1 h and then added carefully to ice-water. By addition of 50% strength aqueous sodium hydroxide solution, the pH of the mixture was adjusted to about 9-10. The mixture was extracted three times with ethyl acetate, and the combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase initially cyclohexane/dichloromethane 2:1 to 1:1, finally pure dichloromethane). This gave 19.2 g of the target product (76.2% of theory).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].[CH:15]1([NH2:18])[CH2:17][CH2:16]1.CO>>[CH:15]1([N:18]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[N+:1]([O-:3])=[O:2])[C:9]2=[O:14])[CH2:17][CH2:16]1
Reactant: NC1CC1
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Solvent: CO
Product: O=c1c2cccc([N+](=O)[O-])c2ccn1C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Nitro-isochromen-1-one (5 g, 0.03 mol), cyclopropylamine (2 g, 0.04 mol) were refluxed in methanol (50 mL, 1 mol) for 2 hours and then room temperature stirring overnight. The resulting yellow solid was collected via filtration. The volatiles were removed under vacuum, the residue was purified via flash chromatography (120 g of silica gel, 0-20% EtOAc/Hexane) to give a yellow solid. MS m/z (M+H) 231.3.
Reaction SMILES: Br.[NH2:2][C:3]1[CH:8]=[CH:7][N:6]2[CH:9]=[C:10]([C:12]3[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=3)[N:11]=[C:5]2[N:4]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20].N1C=CC=CC=1.C([O-])(O)=O.[Na+]>O>[NH2:2][C:3]1[CH:8]=[CH:7][N:6]2[CH:9]=[C:10]([C:12]3[CH:13]=[C:14]([O:18][C:19](=[O:21])[CH3:20])[CH:15]=[CH:16][CH:17]=3)[N:11]=[C:5]2[N:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccn2cc(-c3cccc(O)c3)nc2n1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Oc1cccc(-c2cn3ccc(N)nc3n2)c1
Temperature: 120 °C

Procedure:
To a microwave vial were added 3-(7-aminoimidazo[1,2-a]pyrimidin-2-yl)phenol hydrobromide (500 mg, 1.63 mmol), acetic anhydride (199 mg, 185 μA, 1.95 mmol) and pyridine (5.00 ml). The vial was capped and heated in the microwave at 120° C. for 15 min. H2O was added to the reaction mixture and the pH was installed around 7-8 by addition of 10% NaHCO3 aq. solution. The product was extracted with CH2Cl2, then the solvent was partially evaporated and the formed solid was collected and purified by flash chromatography (SiO2 cartridge; eluent: CH2Cl2/MeOH/NH3aq. 140:10:1). White solid (207 mg, 45%).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][O:7][N:8]=[C:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[C:34](=[S:36])=[S:35].[CH3:37]I>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][N:8]=[C:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:34]([S:36][CH3:37])=[S:35])=[CH:21][CH:22]=1
Reactant: Fc1ccc(CON=C2CCCCC2c2cccnc2)cc1
Reactant: CI
Reactant: S=C=S
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSC(=S)C1(c2cccnc2)CCCCC1=NOCc1ccc(F)cc1
Temperature: 20 °C
Yield: 52.5 %

Procedure:
A stirred solution of 2-(4-fluorobenzyloxyimino) -1-pyrid-3-ylcyclohexane (150 mg, 0.5 mmol) in tetrahydrofuran (2 ml) at -78° C. was treated with 1.5M butyl lithium in hexane (0.44 ml, 0.65 mmol) over 5 minutes. After 30 minutes at -78° C. the solution was treated with carbon disulphide (57 mg, 0.75 mmol) in tetrahydrofuran (0.5 ml). The temperature of the reaction mixture was then allowed to rise, over 30 minutes to 0° C., and was then treated with a solution of methyl iodide (107 mg, 0.75 mmol) in tetrahydrofuran (0.5 ml) over 10 minutes. The reaction mixture was allowed to warm to 20° C. over 30 minutes, and then concentrated in vacuo. The crude oil was dissolved in dichloromethane (10 ml) and washed successively with water (2×2 ml), and saturated brine (2 ml) then dried over magnesium sulphate. The solution was filtered then concentrated in vacuo to give an amber oil which was purified by flash chromatography over silica gel eluting with ethyl acetate to yield methyl 2-(4-fluorobenzyloxyimino)-1-pyrid-3-ylcyclohexanecarbodithioate (102 mg).
Reaction SMILES: [CH3:1][S-:2].[Na+].[CH3:4][O:5][C:6]([C:8]1[S:9][C:10]([N+]([O-])=O)=[C:11]([S:13]([C:16]2[CH:21]=[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:19]=[C:18]([Br:27])[CH:17]=2)(=[O:15])=[O:14])[CH:12]=1)=[O:7].C(O)(=O)C>C1COCC1.CCOC(C)=O>[CH3:4][O:5][C:6]([C:8]1[S:9][C:10]([S:2][CH3:1])=[C:11]([S:13]([C:16]2[CH:21]=[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:19]=[C:18]([Br:27])[CH:17]=2)(=[O:15])=[O:14])[CH:12]=1)=[O:7]
Reactant: C[S-]
Reactant: COC(=O)c1cc(S(=O)(=O)c2cc(Br)cc(OC(C)(C)C)c2)c([N+](=O)[O-])s1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(S(=O)(=O)c2cc(Br)cc(OC(C)(C)C)c2)c(SC)s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
Sodium thiomethoxide (1M in EtOH, 4.4 mL, 4.4 mmol) was added dropwise to a −78° C. solution of 4-(3-bromo-5-tert-butoxy-benzenesulfonyl)-5-nitro-thiophene-2-carboxylic acid methyl ester (1.91 g, 4.0 mmol) in THF (40 mL). The solution was stirred for 30 min at −78° C. and glacial acetic acid (1 mL) was added. The solution was diluted with EtOAc (60 mL), extracted with NaHCO3 (2×30 mL), water (2×20 mL), brine (30 mL), and was dried over sodium sulfate. Concentration of the solution in vacuo followed by SiO2 flash chromatography of the residue yielded the title compound (1.48 g, 76%). 1H-NMR (CDCl3): δ 8.01 (d, 1H, J=0.5 Hz), 7.74 (m, 1H), 7.66 (m, 1H), 7.37 (m, 1H), 3.99 (s, 3H), 2.48 (s, 3H), 1.41 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:31][O:32][CH2:33][CH3:34])[N:14]([CH2:15][CH2:16][N+:17]3([O-])[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([Br:35])=[CH:5][C:4]=2[N:3]=1.P(Cl)(Cl)[Cl:37]>C(Cl)(Cl)Cl.O>[ClH:37].[ClH:37].[Br:35][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[N:14]([CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:13]([CH2:31][O:32][CH2:33][CH3:34])=[N:12][C:11]=3[C:2]([NH2:1])=[N:3][C:4]=2[CH:5]=1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CC[N+]1([O-])CCN(C(=O)OC(C)(C)C)CC1
Reactant: ClP(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCN1CCNCC1
Product: Cl
Temperature: 4 °C
Reaction time: 0.75 h
Yield: 84.2 %

Procedure:
A solution of tert-butyl 4-[2-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-4-oxidopiperazine-1-carboxylate (8.84 g, 16.1 mmol) in chloroform (400 mL) was cooled to 4° C. Phosphorous trichloride (9.82 mL, 113 mmol) was added dropwise, and the reaction was stirred for 45 minutes at 4° C. Water (one drop) was added to the reaction, which was allowed to warm to ambient temperature. The chloroform was removed under reduced pressure, and the residue was dissolved in ethanol (150 mL). Hydrogen chloride (21.5 mL of a 3 M solution in ethanol) was added, and the reaction was heated at reflux for 25 minutes. The reaction was allowed to cool to room temperature; a precipitate formed and was isolated by filtration to provide 6.86 g of 7-bromo-2-ethoxymethyl-1-(2-piperazin-1-ylethyl)-1H-imidazo[4,5-c]quinolin-4-amine dihydrochloride as a light yellow solid.
Reaction SMILES: [OH-].[Na+].S(O)(O)(=O)=O.[CH3:8][S:9][C:10](=[NH:12])[NH2:11].[NH2:13][C:14]1[C:15]([C:26](OC(C)=CC(=O)NC(C)(C)C)=[O:27])=[N:16][C:17]([Cl:25])=[C:18]([NH:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)[N:19]=1>C1COCC1>[NH2:13][C:14]1[C:15]([C:26]([NH:12][C:10]([S:9][CH3:8])=[NH:11])=[O:27])=[N:16][C:17]([Cl:25])=[C:18]([NH:20][CH2:21][CH:22]2[CH2:23][CH2:24]2)[N:19]=1
Reactant: CSC(=N)N
Reactant: CC(=CC(=O)NC(C)(C)C)OC(=O)c1nc(Cl)c(NCC2CC2)nc1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CSC(=N)NC(=O)c1nc(Cl)c(NCC2CC2)nc1N

Procedure:
To NaOH (2 mol/l in water; 9.07 ml; 18.1 mmol) is added S-methylisothiourea sulphate (5.05 g; 18.1 mmol). The mixture is stirred until complete solution is achieved. The resulting solution is added to 1-(tert-butylcarbamoyl)prop-1-en-2-yl 3-amino-6-chloro-5-[(cyclopropylmethyl)amino]pyrazine-2-carboxylate (example 5) (2.31 g; 6.05 mmol) in THF (50 ml). The mixture is stirred at r.t. for 3 d, then volatiles are evaporated. The residue is purified by RP-HPLC (modifier: trifluoro acetic acid (TFA) (C11H15ClN6OS).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH2:50])[CH:46]([O:51][CH2:52][CH2:53][CH3:54])[CH2:45]2)[CH:7]([CH3:56])[CH2:6][CH2:5][C:4]1=[O:57])[CH3:2].C(N(CC)CC)C.Cl[C:66]([O:68][CH2:69][CH3:70])=[O:67]>C(Cl)Cl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH:50][C:66]([O:68][CH2:69][CH3:70])=[O:67])[CH:46]([O:51][CH2:52][CH2:53][CH3:54])[CH2:45]2)[CH:7]([CH3:56])[CH2:6][CH2:5][C:4]1=[O:57])[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CCCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1NC(=O)OCC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-amino-3"-propyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (40 mg) in methylene chloride (2 ml) is added triethylamine (10 μl), followed by ethyl chloroformate (15 μl) at 0° C. with stirring. The reaction mixture is warmed to room temperature and the reaction progress is followed by tlc analysis. The solution is quenched with a drop of methanol and purified by preparative tlc on silica to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:27][C:28]1[C:37]2[C:32](=[CH:33][C:34]([S:38](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:40])=[O:39])=[CH:35][CH:36]=2)[CH:31]=[CH:30][N:29]=1>C1COCC1>[Cl:27][C:28]1[C:37]2[C:32](=[CH:33][C:34]([S:38]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=3)[C:9]3[CH:14]=[CH:13][N:12]=[CH:11][N:10]=3)(=[O:40])=[O:39])=[CH:35][CH:36]=2)[CH:31]=[CH:30][N:29]=1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Cl)nccc2c1
Reactant: COc1ccc(CNc2ccncn2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 39.7 %

Procedure:
A 100-mL round-bottom flask was charged with N-(4-methoxybenzyl)pyrimidin-4-amine (Intermediate OO; 0.796 g, 3.70 mmol) and THF (16.08 ml). The flask was cooled in a dry ice-acetone bath for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (3.70 ml, 3.70 mmol) was added drop wise. The flask was removed from the cooling bath for 5 min, then recooled for 5 min. A solution of perfluorophenyl 1-chloroisoquinoline-6-sulfonate (see EXAMPLE 73, STEP 1, 1.515 g, 3.70 mmol) in THF (4 mL with a 1-mL flask wash) was added drop wise. After 20 min, the flask was switched to an ice-water bath. The mixture was stirred for 20 min, then an additional portion of LHMDS solution (1 mL) was added drop wise. The mixture was warmed to room temperature and quenched by the addition of saturated aq. ammonium chloride. The mixture was extracted with EtOAc (2×), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (40-g Redi-Sep Gold column, 25-g silica gel loading column, 0-50% EtOAc/Heptante) to give 1-chloro-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (648 mg, 1.470 mmol, 39.7% yield) as a tan foam. m/z (ESI) 441.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[C:11]([O:13][CH2:14]C)=[O:12].[C:16]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>N1C=CC=CC=1.O>[C:16]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:1][C:2]2[C:10]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[S:4][C:3]=2[C:11]([O:13][CH3:14])=[O:12])(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CCOC(=O)c1sc2ncccc2c1N
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1sc2ncccc2c1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 12.8 %

Procedure:
To a solution of ethyl 3-aminothieno[2,3-b]pyridine-2-carboxylate (0.3 g; 1.35 mmol) in pyridine (10 mL) was added 4-tert-butylbenzenesulfonyl chloride (0.48 g; 2.03 mol). The reaction was stirred at room temperature for 18 hours and then diluted with water and extracted with ethyl acetate. The organic layer was separated and successively washed with aqueous hydrochloric acid (2N) and aqueous saturated sodium chloride solution, dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography eluting with hexanes/ethyl acetate to yield the title compound as a white solid (0.070 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].CC(C)=O.[I-:14].[Na+]>C(Cl)Cl>[I:14][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CCCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCOC(=O)CCCI
Yield: 69.2 %

Procedure:
Mix ethyl 4-chlorobutyrate (80 g), acetone (400 mL) and sodium iodide (100 g). Reflux for 8 hours, cool and add methylene chloride (400 mL). Filter and evaporate the filtrate to a residue. Partition the residue between methylene chloride (200 mL) and water (200 mL). Separate the organic phase, dry (MgSO4) and evaporate to an oil. Purify by distillation to give the title compound (89 g); bp 64° C.@0.5 mm Hg.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11].[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O.N1CCCCC1.C(O)(=O)C>C(O)(C)C>[Cl:15][C:16]1[CH:17]=[C:18]([CH:19]2[CH:9]([C:10]([O:12][CH3:13])=[O:11])[C:8](=[O:14])[C:3]3[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=3)[O:1]2)[CH:21]=[CH:22][CH:23]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: COC(=O)CC(=O)c1ccccc1O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: COC(=O)C1C(=O)c2ccccc2OC1c1cccc(Cl)c1
Temperature: 25 °C
Yield: 42.3 %

Procedure:
A mixture of methyl 3-(2-hydroxyphenyl)-3-oxopropanoate (prepared according to Cushman, M. et al., J. Med. Chem. 1991, 34, 798; 250 mg, 1.29 mmol) and 3-chlorobenzaldehyde (146 μL, 1.29 mmol) in isopropanol (5.0 mL) was treated with piperidine (13 μL, 129 μmol) and acetic acid (7.4 μL, 129 μmol) and heated to reflux for 17 h. After this time, the mixture was cooled to rt. The cooled solution was concentrated under vacuum and the resulting residue was purified by rotary TLC, eluting with 9:1 hexane-ethyl acetate, to provide a colorless gum. The colorless gum was crystallized from a hot isopropanol/water solution to provide methyl 2-(3-chlorophenyl)-4-oxochroman-3-carboxylate as an off-white solid (173 mg, 42%). The NMR indicated predominantly the enolic form. 1H NMR (400 MHz, CDCl3) δ ppm 3.78 (s, 3 H) 6.21 (s, 1 H) 6.82 (d, J=8.1 Hz, 1 H) 6.97 (t, J=7.9 Hz, 1 H) 7.18-7.32 (m, 4 H) 7.34 (m, 1 H) 7.69 (dd, J=7.9, 1.8 Hz, 1 H) 12.28 (br. s, 1 H). High resolution mass spec (M+H)+ calc. 317.0581, found 317.0597.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[OH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:17]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Yield: 100.3 %

Procedure:
2-Chloro-5-nitropyridine (500.0 mg), methyl 4-hydroxybenzenecarboxylate (958.6 mg) and potassium carbonate (1.31 g) were suspended in acetonitrile (5 mL), and heated under reflux for 16 hours. Water (50 mL) was added to the reaction liquid, extracted with ethyl acetate (50 mL), and the organic layer was washed with aqueous 2 N sodium hydroxide solution (50 mL), water (50 mL) and saturated saline water (50 mL) in that order. The organic layer was dried with magnesium sulfate, and evaporated under reduced pressure to obtain the entitled compound (867.7 mg) as a brown solid.