Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([Cl:21])=[CH:19][N:18]=[CH:17][C:16]=2[Cl:22])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[O:30]1C[CH:31]1[CH2:33][N:34]1[C:42]2[CH2:41][CH2:40][N:39]([C:43](=[O:45])[CH3:44])[CH2:38][C:37]=2[C:36]([C:46]2[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:48][CH:47]=2)=[N:35]1>C(Cl)Cl>[Cl:21][C:20]1[CH:19]=[N:18][CH:17]=[C:16]([Cl:22])[C:15]=1[O:14][CH:11]1[CH2:10][CH2:9][N:8]([CH2:6][CH:31]([OH:30])[CH2:33][N:34]2[C:42]3[CH2:41][CH2:40][N:39]([C:43](=[O:45])[CH3:44])[CH2:38][C:37]=3[C:36]([C:46]3[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:48][CH:47]=3)=[N:35]2)[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2c(Cl)cncc2Cl)CC1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC2CO2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(O)CN2CCC(Oc3c(Cl)cncc3Cl)CC2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
A solution of 103 mg (0.30 mmol) of 4-(3,5-dichloro-pyridin-4-yloxy)-piperidine-1-carboxylic acid tert-butyl ester in CH2Cl2 (2 mL) was treated with trifluoroacetic acid (0.5 mL) at room temperature overnight. The solvent was then removed and the crude product dissolved in MeOH and stirred over 100 mg of sodium bicarbonate for 1 h. The solid was filtered off and the filtrate concentrated. The crude piperidine was then dissolved in 4 mL EtOH and treated with 100 mg (0.27 mmol) of 1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone. The solution was heated to 60° C. overnight. The solvent was then removed by rotary evaporation and the crude product was purified by column chromatography (silica, 0-10% MeOH/EtOAc) to afford 90 mg (54%) of a white solid. MS (electrospray): exact mass calculated for C28H30Cl2F3N5O3, 611.17. m/z found, 612.2 [M+H]+. 1H NMR (CDCl3, 400 MHz, a mixture of amide rotamers): 8.44 (s, 2H), 7.77 (d, J=8.41 Hz, 1H), 7.72 and 7.68 (A and B of AB quartet, J=8.41 Hz, 2H), 7.65 (d, J=8.41 Hz, 1H), 4.88 and 4.76 (A and B of AB quartet, J=15.65 Hz, 1H), 4.66 (br s, 1H), 4.55 (br s, 1H), 4.26-4.08 (m, 2H), 4.08-3.98 (m, 2H), 3.91-3.69 (m, 2H), 3.03-2.92 (m, 1.6H), 2.91-2.85 (m, 0.8H), 2.85-2.75 (m, 1.6H), 2.52-2.40 (m, 3H), 2.35-2.24 (br m, 1H), 2.22 (s, 1.5H), 2.17 (s, 1.5H), 2.03-1.90 (m, 4H).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([S:13][C:14]2[C:19]([CH3:20])=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[F:22][C:23]1[CH:28]=[C:27]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:26]=[CH:25][C:24]=1[NH2:33].CC(C)([O-])C.[Na+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([S:13][C:14]2[C:19]([CH3:20])=[C:18]([NH:33][C:24]3[CH:25]=[CH:26][C:27]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:28][C:23]=3[F:22])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(N)c(F)c1
Reactant: Cc1c(Cl)ncnc1SC1CCN(C(=O)OC(C)C)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1COCCO1
Product: Cc1c(Nc2ccc(S(C)(=O)=O)cc2F)ncnc1SC1CCN(C(=O)OC(C)C)CC1
Temperature: 120 °C
Yield: 33.7 %

Procedure:
A mixture of 4-(6-chloro-5-methyl-pyrimidin-4-ylsulfanyl)-piperidine-1-carboxylic acid isopropyl ester (1.2234 g, 3.7 mmol), 2-fluoro-4-methanesulfonyl-phenylamine (702 mg, 3.7 mmol), palladium acetate (84.3 mg, 0.37 mmol), 2-(di-t-butylphosphino)biphenyl (11 mg, 0.037 mmol), and sodium tert-butoxide (891.8 mg, 9.28 mmol) in 15 mL 1,4-dioxane was heated in microwave for 2 hours at 120° C. The mixture was purified by HPLC to give Compound E1 as a tanned solid (TFA salt, 601.1 mg, 27%). 1H NMR (MeOH-d4, 400 MHz) δ 1.16-1.17 (d, J=6.32 Hz, 6H), 1.49-1.58 (m, 2H), 2.00-2.04 (m, 2H), 2.14 (s, 3H), 3.07 (s, 3H), 3.21-3.23 (m, 2H), 3.90-3.94 (m, 2H), 4.01-4.08 (m, 1H), 4.75-4.81 (m, 1H), 7.66-7.68 (d, J=8.08 Hz, 2H), 8.01-8.05 (m, 1H), 8.27 (s, 1H). Exact mass calculated for C21H27FN4O4S2 482.15, found 483.4 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]([O:13][Si](C(C)(C)C)(C)C)[CH2:4][C:5](=[CH2:12])[C:6]=1[CH2:7][C:8]([F:11])([F:10])[F:9].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.F.C(O)(=O)C(O)=O>O1CCCC1>[CH3:1][C:2]1[CH:3]([OH:13])[CH2:4][C:5](=[CH2:12])[C:6]=1[CH2:7][C:8]([F:9])([F:10])[F:11]
Reactant: C=C1CC(O[Si](C)(C)C(C)(C)C)C(C)=C1CC(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: F
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Product: C=C1CC(O)C(C)=C1CC(F)(F)F
Temperature: 0 °C
Yield: 80 %

Procedure:
After 10.5 g of (RS)-2-methyl-4-methylidene-3-(2,2,2-trifluoroethyl)-1-t-butyldimethylsilyloxy-2-cyclopentene was dissolved in 50 ml of dry tetrahydrofuran, a mixture of 10.5 ml of a 1M tetrabutylammonium fluoride/tetrahydrofuran solution and 5 ml of hydrofluoric acid was added under cooling and stirred at ambient temperatures for twelve hours. The reaction solution was then added to 100 ml of an ice-cooled 5% aqueous oxalic acid, and extracted with diethyl ether (300 ml×3 times). The combined ether layer was washed successively with a saturated sodium hydrogencarbonate solution and a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the residue was treated by silica gel column chromatography (eluent: n-hexane:ethyl acetate=3:1 (v/v)) to yield 5.27 g of (RS)-2-methyl-4-methylidene-3-(2,2,2-trifluoroethyl)cyclopent-2-en-1-ol.
Reaction SMILES: [Na+].[Cl:2][C:3]1[C:8]([CH2:9][CH3:10])=[CH:7][C:6]([NH:11][CH2:12][C:13]([O-])=[O:14])=[C:5]([N+:16]([O-])=O)[CH:4]=1.O.O.[Sn](Cl)Cl>C(O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:6]([NH:11][CH2:12][C:13](=[O:14])[NH:16]2)=[CH:7][C:8]=1[CH2:9][CH3:10]
Reactant: CCc1cc(NCC(=O)[O-])c([N+](=O)[O-])cc1Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCc1cc2c(cc1Cl)NC(=O)CN2
Temperature: 25 °C

Procedure:
A suspension of N-(4′-Chloro-5′-ethyl-2′-nitrophenyl)glycine sodium salt (0.082 g, 0.31 mmol) and tin (II) chloride dihydrate (0.215 g, 0.953 mmol) in ethanol (1.0 mL) was refluxed for 45 min. It was then cooled to room temperature and the precipitated solid was filtered, washed with ethanol (1.0 mL), and dried under vacuum to yield 0.048 g (72%) pure (1H NMR) title compound as a light yellow powder; 1H NMR (DMSO-d6) δ 1.05 (t, 3H, J=7.2 Hz), 2.52 (d, 2, J=7.2), 3.67 (s, 2H), 6.04 (s, 1H), 6.54 (s, 1H), 6.67 (s, 1H), 10.25 (s, 1H).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH:18]=[C:19]2[S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:15]2[C@@:6]1([F:32])[C@:7]1([CH3:31])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:30])[CH:9]=[CH:8]1)(=[O:3])[CH3:2].[CH2:33]([SH:35])[CH3:34].B(F)(F)F.CCOCC>ClCCl.C(Cl)(Cl)Cl>[C:1]([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C:19]2([S:35][CH2:33][CH3:34])[S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:15]2[C@@:6]1([F:32])[C@:7]1([CH3:31])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:30])[CH:9]=[CH:8]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1C[C@]2(C)C(Sc3ccccc3)=CC[C@H]2[C@@H]2CCC3=CC(=O)C=C[C@]3(C)[C@@]12F
Reactant: CCS
Agent: FB(F)F
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CCSC1(Sc2ccccc2)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(C)=O)C[C@@]21C
Temperature: -10 °C
Reaction time: 2.5 h

Procedure:
A solution of 1.0 g of 11β-acetyloxy-9-fluoro-17-(phenylthio)androsta-1,4,16-trien-3-one, 12 ml of dry dichloromethane and 0.5 ml of ethanethiol is cooled to -10° C. under nitrogen. Boron trifluoride etherate is then added. The solution is stirred at -10° C. under nitrogen for 2.5 hours. The resulting solution is diluted with dichloromethane, washed with saturated sodium bicarbonate and water, dried over anhydrous Na2SO4 and evaporated in vacuo to give a foamy solid. This is dissolved in chloroform and chromatographed on two precoated silica gel TLC plates (E. Merck, 20 cm×20 cm×2 mm, 1:4 ethyl acetate-chloroform for development) to give 800 mg of slightly impure title compound. This is crystallized from ethyl acetate-hexane to give 500 mg of title compound, melting point 145°-148° C., with consistent spectral data.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH:13]1[CH2:15][CH2:14]1)[C:7]2=[O:12].N([O-])=O.[Na+].CS(C)=O.[IH:24].C([O-])([O-])=O.[Na+].[Na+]>>[CH:13]1([N:6]2[CH:5]=[CH:4][C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[I:24])[C:7]2=[O:12])[CH2:15][CH2:14]1
Reactant: Nc1cccc2c(=O)n(C3CC3)ccc12
Reactant: I
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=c1c2cccc(I)c2ccn1C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Amino-2-cyclopropylisoquinolin-1(2H)-one (2.0 g, 0.0095 mol) was added to a solution of sodium nitrite (3 g, 0.04 mol) in dimethyl sulfoxide (100 mL, 2 mol) at room temperature. Aqueous hydrogen iodide (10 mL, 0.08 mol) in dimethyl sulfoxide (100 mL, 2 mol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized with saturated aq. Na2CO3 and extracted with methylene chloride (3×200 mL). The combined methylene chloride extracts were washed with brine and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was chromatographed on 120 g of silica gel column (0-25% EtOAc/Hexane) to give the desired product as a yellow solid. MS m/z (M+H) 312.2.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1CCO[CH:9]1[CH2:13][N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][C:15]1=[O:26]>>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18]([N:17]=[CH:16][C:15](=[O:26])[N:14]2[CH2:13][CH:9]=[O:8])=[CH:19][CH:20]=1
Reactant: COc1ccc2ncc(=O)n(CC3OCCO3)c2c1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2ncc(=O)n(CC=O)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into 40 mL of an 80% aqueous trifluoroacetic acid solution, 1.00 g of 1-(1,3-dioxolan-2-ylmethyl)-7-methoxyquinoxalin-2(1H)-one was dissolved, and the mixture was stirred at room temperature for 8 hours. The solvent was removed under reduced pressure, the reaction mixture was alkalified with an aqueous saturated sodium hydrogen carbonate solution, and then extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 236 mg of a pale yellow oily substance, (7-methoxy-2-oxoquinoxalin-1(2H)-yl)acetaldehyde.
Reaction SMILES: C(OC([N:6]1[CH2:9][C:8]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][NH:19][S:20]([CH2:23][CH:24]3[CH2:26][CH2:25]3)(=[O:22])=[O:21])[CH:11]=2)[CH2:7]1)=O)C.[OH-].[Na+].CCO>[Cl-].[Na+].O>[CH2:27]([C:8]1([C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[O:16][CH2:17][CH2:18][NH:19][S:20]([CH2:23][CH:24]2[CH2:25][CH2:26]2)(=[O:22])=[O:21])[CH2:7][NH:6][CH2:9]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)N1CC(Cc2ccccc2)(c2cccc(OCCNS(=O)(=O)CC3CC3)c2)C1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=S(=O)(CC1CC1)NCCOc1cccc(C2(Cc3ccccc3)CNC2)c1

Procedure:
To 3-benzyl-3-[3-(2-cyclopropylmethanesulfonylamino-ethoxy)-phenyl]-azetidine-1-carboxylic acid ethyl ester (50 mg, 0.11 mmol) was added 4 ml 2N NaOH/EtOH. The mixture was heated for 1 hour in a microwave. After cooling to room temperature 50% brine was added and the mixture extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium bicarbonate, filtered and the solvent evaporated. The residue was purified on 4 g SiO2 using 10% methanol in dichloromethane affording the desired product as a clear oil. m=15.5 Mg
Reaction SMILES: C([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)#C.[O:11]=[C:12](CC)[CH2:13][C:14](OC)=O.CC1(C)CC(=O)CC(=O)C1.C([O-])(=O)C.[NH4+].II>C(O)C>[CH2:12]([O:11][C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[O:8])=[CH:9][CH:10]=1)[C:13]#[CH:14]
Reactant: CCC(=O)CC(=O)OC
Reactant: C#Cc1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: CC1(C)CC(=O)CC(=O)C1
Agent: II
Solvent: CCO
Product: C#CCOc1ccc(C=O)cc1
Reaction time: 5.5 h
Yield: 136.2 %

Procedure:
A mixture of 4-ethynylbenzaldehyde (1) (171 mg, 1.27 mmol), methyl 3-oxopentanoate (175 mg, 1.27 mmol), dimedone (181 mg, 1.27 mmol), ammonium acetate (101 mg, 1.27 mmol), I2 (97 mg, 0.38 mmol), and ethanol (10 drops) is stirred under argon for 5.5 h, quenched with 5% Na2S2O3 (30 mL), and extracted with ethyl acetate (50 mL and 30 mL). The extract is washed (5% Na2S2O3, H2O, and brine) and dried. After solvent removal at reduced pressure, the residue is purified on silica gel (33% to 60% ethyl acetate/hexane) to give 277 mg (60%) of 2 (BI-3029) as a cream solid, mp 234-236° C. IR 3332, 2933, 1704, 1610, 1482, 1214 cm−1; 1H NMR (CDCl3) δ 0.93 (s, 3H, CH3), 1.10 (s, 3H, CH3), 1.26 (t, J=7.2 Hz, 3H, CH2CH3), 2.07-2.42 (m, 4H, COCH2, CH2), 2.76-2.89 (m, 2H, CH2CH3), 3.02 (s, 1H, CH≡C), 3.63 (s, 3H, OCH3), 5.09 (s, 1H, CH), 5.90 (bs, 1H, NH), 7.27 (d, J=8.1 Hz, 2H, 3,5-ArH), 7.37 ppm (d, J=8.1 Hz, 2H, 2,6-ArH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=1)=[O:12].O>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[O:12])[CH:7]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: N#Cc1ccc(C(=O)Cn2cc(Cl)cnc2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.3 %

Procedure:
A suspension of 5-chloropyrimidin-2-one (412 mg) and 2-bromo-4'-cyanoacetophenone (677 mg) in triethylamine (1 ml) and ethanol (20 ml) was stirred at ambient temperature for one hour. Water (100 ml) was added and the collected solid was crystallised from ethyl acetate to give the title pyrimidinone (375 mg,); m.p. 236°-240°; λmaxEtOH 248 nm (ε 26140), 289 nm (ε 2130), λinf 254 (ε 22800).
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[N:21]([C:28]4[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=4[Cl:35])[N:22]=[N:23][C:24]=3[CH:25]([CH3:27])[CH3:26])=[CH:14][C:13]=2[CH3:36])[CH:5]=1.[OH-].[Li+].CCCCCC.C(OCC)(=O)C>C1COCC1>[Cl:35][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([Cl:34])[C:28]=1[N:21]1[C:20]([CH2:19][O:18][C:15]2[CH:16]=[CH:17][C:12]([CH:11]=[CH:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:37])=[O:2])=[C:13]([CH3:36])[CH:14]=2)=[C:24]([CH:25]([CH3:27])[CH3:26])[N:23]=[N:22]1
Reactant: COC(=O)c1cccc(C=Cc2ccc(OCc3c(C(C)C)nnn3-c3c(Cl)cccc3Cl)cc2C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(OCc2c(C(C)C)nnn2-c2c(Cl)cccc2Cl)ccc1C=Cc1cccc(C(=O)O)c1
Temperature: 55 °C

Procedure:
To a solution of 3-(2-(4-(3-(2,6-dichloro-phenyl)-5-isopropyl-3-H-(1,2,3)triazol-4ylmethyoxy)-2-methyl-phenyl)-vinyl)-benzoic acid methyl ester (0.025 g, 0.046 mmol) in THF (3 mL) is added lithium hydroxide (0.005 g, 0.21 mmol). The reaction mixture is heated to 55° C. The reaction is determined to be incomplete due to the presence of starting material by TLC (1:1 hexane/ethyl acetate). An additional amount of lithium hydroxide (0.050 g) is added and the reaction is heated to 60° C. for 3 h. The reaction is quenched with aqueous 1 N HCl and is extracted with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate, filtered, and concentrated to give the title compound. ES/MS m/e 521.8 (M+1).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[C:22](=[O:23])[N:21]2[CH:17]([CH2:18][CH:19]([O:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][N:26]=3)[CH2:20]2)[C:16](=[O:35])[NH:15][C:14]2([C:36]([NH:38][S:39]([CH:42]3[CH2:44][CH2:43]3)(=[O:41])=[O:40])=[O:37])[CH:12]([CH2:13]2)[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.Cl[C:55]([O:57][CH3:58])=[O:56].CO.C(Cl)Cl>C(Cl)Cl.CCOC(C)=O>[CH3:58][O:57][C:55](=[O:56])[NH:3][CH:4]1[C:22](=[O:23])[N:21]2[CH:17]([CH2:18][CH:19]([O:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][N:26]=3)[CH2:20]2)[C:16](=[O:35])[NH:15][C:14]2([C:36]([NH:38][S:39]([CH:42]3[CH2:43][CH2:44]3)(=[O:40])=[O:41])=[O:37])[CH:12]([CH2:13]2)[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: COC(=O)Cl
Reactant: NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: COC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
To a mixture of cyclopropanesulfonic acid [14-amino-18-(isoquinolin-1-yloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carbonyl]-amide bis hydrochloride (50 mg, 0.075 mmol) in 2 mL of DCM was added 44 μL (0.25 mmol)of DIPEA and 9 mg (0.10 mmol) of methyl chloroformate. The mixture was stirred at rt for 2 h. It was then diluted with EtOAc and washed with pH 4 buffer (2×) and brine (1×). The organic phase was dried (MgSO4) and concentrated in vacuo to give the crude product. Flash chromatography (2% MeOH/DCM) gave 40 mg (82%) of the desired product as a white solid: LC-MS (Method A, retention time: 3.05 min), MS m/z 654 (M++1).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:11][C:12]1[CH:13]=[C:14]([NH:19][CH2:20][CH:21]([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24])[CH:15]=[CH:16][C:17]=1[CH3:18].N1C=CC=CC=1.C(=O)([O-])O.[Na+]>ClCCl>[Br:11][C:12]1[CH:13]=[C:14]([N:19]([CH2:20][CH:21]([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24])[S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:15]=[CH:16][C:17]=1[CH3:18]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(CNc1ccc(C)c(Br)c1)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(CN(c1ccc(C)c(Br)c1)S(=O)(=O)c1ccccc1)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
Under a nitrogen stream, benzenesulfonyl chloride (3.12 mL g, 24.48 mmol) was added dropwise under ice cooling to a mixture of (3-bromo-4-methylphenyl)-(2,2-diethoxyethyl)-amine (4.91 g, 16.25 mmol), pyridine (10.1 mL, 124.88 mmol) and dichloromethane (41 mL), and the resultant mixture was then stirred at the same temperature for 1 hour. After stirring at room temperature for 2 hours, the reaction mixture was added to saturated aqueous sodium hydrogen carbonate. The resultant mixture was extracted with dichloromethane. The organic layer was washed with 5% aqueous hydrochloric acid and dried (anhydrous potassium carbonate). Solvent was then removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solution=ethyl acetate:n-hexane (1:4)), to thereby obtain the titled compound (5.94 g, 83%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([OH:16])[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[C:22]([F:24])[CH:23]=1.CCN(CC)CC>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:20]2[CH:19]=[C:18]([F:17])[CH:23]=[C:22]([F:24])[CH:21]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(Oc2cc(F)cc(F)c2)c2c(c1)OC(C)(C)C2
Temperature: 25 °C
Reaction time: 48 h
Yield: 26.6 %

Procedure:
A mixture of 4-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxy-lic acid methyl ester (3e) (1 g, 0.0045 mol), 3,5-difluorophenylboronic acid (1.07 g, 0.0068 mol), Cu(OAc)2 (0.9 g, 0.005 mol), freshly activated 4A molecular sieves (4g) and Et3N (4 mL) in CH2Cl2 (25 mL) was stirred at room temperature under N2 for 48 hrs. The mixture was filtered through Celite and the filter cake was washed with CH2Cl2. The filtrate was concentrated to give a dark liquid. The crude liquid was purified by column chromatography eluting with EtOAc/petroleum ether (1/5) to give the title compound (0.4 g, 26.6%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.18 (s, 1 H), δ 7.14 (s, 1 H), 6.47 (m, 1 H), δ 6.36 (dd, 2 H), 3.81 (s, 3 H), 2.83 (s, 2 H), 1.41 (s, 6 H).
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[CH2:14]([N:21]1[CH2:11][C:5]2[C:4](=[C:9]([I:10])[CH:8]=[CH:7][CH:6]=2)[C:3]1=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)c1c(I)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1c2c(I)cccc2CN1Cc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 55.9 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (1.07 g, 3.0 mmol), benzylamine (0.34 mL, 3.1 mmol), and K2CO3 (0.83 g, 6 mmol) in toluene (10 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-benzyl-7-iodo-2,3-dihydro-isoindol-1-one 0.586 g, 56%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.16 (s, 2H), 4.82 (s, 2H) 7.18-7.40 (m, 7H), 7.90 (d, 1H). GC-MS: m/z 349 (M)+.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:13]([CH2:14][O:15][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[S:12][CH:11]([N:33]2[CH:41]=[N:40][C:39]3[C:34]2=[N:35][C:36]([Cl:43])=[N:37][C:38]=3Cl)[C@H:10]1[F:44])C1C=CC=CC=1.ClB(Cl)Cl.CO.C(=O)([O-])O.[Na+].[NH3:56].C(O)C>C(Cl)Cl>[F:44][C@H:10]1[C@H:9]([OH:8])[C@@H:13]([CH2:14][OH:15])[S:12][C@H:11]1[N:33]1[CH:41]=[N:40][C:39]2[C:34]1=[N:35][C:36]([Cl:43])=[N:37][C:38]=2[NH2:56]
Reactant: CC(C)(C)[Si](OC[C@H]1SC(n2cnc3c(Cl)nc(Cl)nc32)[C@@H](F)[C@@H]1OCc1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: Nc1nc(Cl)nc2c1ncn2[C@@H]1S[C@H](CO)[C@@H](O)[C@@H]1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
360 mg of the 9-(3-O-benzyl-5-O-t-butyldiphenylsilyl-2-deoxy-2-fluoro-4-thio-D-arabinofuranosyl)-2,6-dichloropurine was dissolved in 11 ml of methylene chloride. To this solution, 2.70 ml of 1 M trichloroboran was added dropwise at -78° C. under a stream of argon. The mixture was allowed to warm up to room temperature, and then stirred for 30 minutes. To this was added 1.0 ml of methanol at -78° C. The resulting mixture was stirred for a further 30 minutes, and then allowed to warm up to room temperature. To this mixture was added a saturated aqueous solution of sodium hydrogencarbonate. The solvent was distilled off, and the residue was azeotropically distilled with methanol three times. The residue was then separated into the alpha-anomer and the beta-anomer by silica gel column chromatography. 115 mg of the beta-anomer obtained was dissolved in 20 ml of a saturated ammonia/ethanol solution, and allowed to react in a sealed tube at 80° C. for 7 hours. The solvent was distilled off, and the residue was dissolved in 5 ml of DMF. To this solution was added 137 mg of ammonium fluoride, and the mixture was stirred at room temperature overnight. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 51 mg (yield 31%) of the title compound.