Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([CH2:5][S:6]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])=[O:7])(=[O:4])=[O:3].[OH-].[Na+].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>O>[CH3:1][S:2]([CH:5]([S:19]([CH3:18])(=[O:21])=[O:20])[S:6]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:7])=[O:8])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)CS(=O)(=O)Oc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)C(S(C)(=O)=O)S(=O)(=O)Oc1ccccc1
Temperature: 2.5 °C
Yield: 80 %

Procedure:
The above phenyl methylsulfonylmethanesulfonate (25 g, 0.1 mole) was dissolved in a solution of 75 mL of water and 8 g (0.1 mole) of 50% sodium hydroxide. The solution was cooled to 0-5° C. and treated with 11.4 g of methanesulfonyl chloride which was added dropwise over 45 min. The resulting slurry was filtered (starting material precipitates during the addition) and the solid (14.3 g after drying) was washed with 75 mL of water. The filtrate was treated with conc HCl until no more solid precipitated. The phenyl bis(methylsulfonyl)methanesulfonate product was filtered and washed with ice-water. After drying in a 60° C. vacuum oven the product (12.9 g, mp 154-156° C.) was recrystallized from ethyl acetate with a hot clarification to give 11.3 g, (34.4% conversion, 80% yield) of phenyl bis(methylsulfonyl)methanesulfonate as a white solid, mp 159-160° C. H1NMR: δ 7.36-7.44 (m, 5H); δ 2.65 (s, 6H). No major impurities were detected by HPLC-MS.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:6]2[C:7](=[O:9])[CH:8]=1.[C:19]([O-:22])(=[O:21])[CH3:20].[K+]>CN(C)C=O>[C:19]([O:22][CH2:2][C:3]1[N:4]=[C:5]2[CH:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:6]2[C:7](=[O:9])[CH:8]=1)(=[O:21])[CH3:20]
Reactant: O=c1cc(CCl)nc2ccn(-c3ccccc3)n12
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1cc(=O)n2c(ccn2-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
5-chloromethyl-1-phenyl-1H,7H-pyrazolo[1,5-a]pyrimidine-7-one (5.2 g), prepared according to Example 1, was dissolved in dimethylformamide (30 ml) and reacted with anhydrous potassium acetate (4 g) under stirring at room temperature for 20 hours. After dilution with ice water the precipitate was filtered and washed with water to give 5-acetoxymethyl-1-phenyl-1H,7H-pyrazolo[1,5-a]pyrimidine-7-one, m.p. 172°-175° C., (4.9 g) which was hydrolized by treatment with 8% HCl (50 ml) under stirring at 90° C. for 30 minutes. The reaction mixture was neutralized with 35% NaOH and the precipitate was filtered and washed with water to give 5-hydroxymethyl-1-phenyl-1H,7H-pyrazolo[1,5-a]pyrimidine-7-one, m.p. 241°-242° C., (4.1 g), which was reacted with dicyclohexylcarbodiimide (8 g) in benzene (60 ml) and dimethylsulphoxide (15 ml) in the presence of trifluoroacetic acid (0.6 ml) and pyridine (1 ml) under stirring at room temperature for 20 hours. After treatment with oxalic acid bihydrate (1.8 g) at room temperature, the precipitate of dicyclohexylurea was filtered off and the organic solution was evaporated in vacuo to dryness: the residue was purified over a SiO2 column using chloroform: ethyl acetate=95:5 as eluent. The 7-formyl-1-phenyl-1H,7H-pyrazolo[1,5-a]pyrimidine-7-one so obtained (2.5 g) was reacted with the ylide obtained by treatment of (3-pyridyl)-methyl-triphenylphosphonium chloride (4.2 g) with potassium tert-butoxide (1.25 g) in dimethylsulphoxide (20 ml) at room temperature for 30 minutes. After dilution with ice water the precipitate was filtered and washed with water: crystallization from isopropyl alcohol gave 2.05 g of 1-phenyl-5-trans-[2-(3-pyridyl)ethenyl]-1H,7H-pyrazolo[1,5-a]pyrimidine-7-one, m.p. 221°-224° C.
Reaction SMILES: [C:1](=[O:81])([O:32][C@H:33]([C:67]1[CH:72]=[C:71]([C:73]([F:76])([F:75])[F:74])[CH:70]=[C:69]([C:77]([F:80])([F:79])[F:78])[CH:68]=1)[C@@H:34]([N:36]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:37][C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[CH:40][C:39]=1[C:48]1[CH:53]=[C:52]([CH:54]([CH3:56])[CH3:55])[C:51]([F:57])=[CH:50][C:49]=1[O:58][CH3:59])[CH3:35])[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][P:12]([O:22]CC2C=CC=CC=2)([O:14]CC2C=CC=CC=2)=[O:13])=[CH:5][C:4]=1[O:30][CH3:31]>[Pd].C(O)C>[C:1](=[O:81])([O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][P:12]([OH:14])([OH:22])=[O:13])=[CH:5][C:4]=1[O:30][CH3:31])[O:32][C@H:33]([C:67]1[CH:72]=[C:71]([C:73]([F:76])([F:75])[F:74])[CH:70]=[C:69]([C:77]([F:78])([F:79])[F:80])[CH:68]=1)[C@@H:34]([N:36]([C:60]([O:62][C:63]([CH3:64])([CH3:65])[CH3:66])=[O:61])[CH2:37][C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[CH:40][C:39]=1[C:48]1[CH:53]=[C:52]([CH:54]([CH3:55])[CH3:56])[C:51]([F:57])=[CH:50][C:49]=1[O:58][CH3:59])[CH3:35]
Reactant: COc1cc(CCOP(=O)(OCc2ccccc2)OCc2ccccc2)ccc1OC(=O)O[C@H](c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H](C)N(Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)c(F)cc1OC)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: COc1cc(CCOP(=O)(O)O)ccc1OC(=O)O[C@H](c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H](C)N(Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)c(F)cc1OC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A suspension of 10% palladium on carbon (7.9 mg, 0.074 mmol) in a solution of 4-(2-{[bis(benzyloxy)phosphoryl]oxy}ethyl)-2-methoxyphenyl (1R ,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-((tert-butoxycarbonyl){[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)propyl carbonate (86.2 mg, 0.074 mmol) in ethanol (5.7 mL) was stirred under H2 (double balloon pressure) at 25° C. for 5 h. The reaction mixture was filtered through a plug of Celite and the filtrate was concentrated in vacuo to afford (1R,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-((tert-butoxycarbonyl){[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)propyl 2-methoxy-4-[2-(phosphonooxy)ethyl]phenyl carbonate. LCMS calc.=1008.8; found=1008.8 (M+Na)+.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10].[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C=O)C>[N:11]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10])=[N+:12]=[N-:13]
Reactant: OCCOCCOCCCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCOCCOCCO
Temperature: 100 °C
Reaction time: 12 h
Yield: 84.4 %

Procedure:
To a solution in which 2-(2-(2-chloroethoxy)ethoxy)ethanol (3.48 g, 20.63 mmol) of Chemical Formula 7 was dissolved in DMF (15 mL), sodium azide (4.02 g, 61.89 mmol) was added at room temperature, and the mixture was heated to 100° C. and stirred for 12 hours. After the reaction, DMF was removed by vacuum distillation, and the residue was partitioned to distilled water (40 mL) and ethyl acetate (150 mL). The organic layer was separated, washed with saturated salted water (15 mL), dried with anhydrous sodium sulfate, and vacuum distilled, and the residue obtained was column chromatographed on silica gel (hexane/ethyl acetate (2:1)) to give 2-(2-(2-azidoethoxy)ethoxy)ethanol (3.05 g, 84%). 1H NMR (500 MHz, CDCl3) δ 3.72-3.74 (m, 2H), 3.65-3.69 (m, 6H), 3.60-3.62 (m, 2H), 3.39 (t, 2H, J=5.0 Hz).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([N:11]2[C:15]3[C:16]([O:32][C@@H:33]([C@H:35]4[CH2:39][NH:38][C:37](=[O:40])[CH2:36]4)[CH3:34])=[N:17][C:18]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:22][CH:21]=4)=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH2:10][CH2:9]1.C(N(CC)CC)C.FC(F)(F)S(OCC(F)F)(=O)=O>C(Cl)Cl>[CH:8]1([N:11]2[C:15]3[C:16]([O:32][C@@H:33]([C@H:35]4[CH2:39][NH:38][C:37](=[O:40])[CH2:36]4)[CH3:34])=[N:17][C:18]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][N:29]([CH2:3][CH:2]([F:7])[F:1])[CH2:28][CH2:27]5)=[CH:22][CH:21]=4)=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH2:9][CH2:10]1.[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4]
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CCNCC3)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: O=S(=O)(OCC(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](Oc1nc(-c2ccc(N3CCN(CC(F)F)CC3)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In an appropriate sized vial the trifluoroacetic acid salt of (R)-4-((R)-1-((3-cyclopropyl-6-(4-(piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one 3.42 (25 mg, 0.044 mmol) and triethylamine (27 mg, 0.27 mmol) were dissolved in DCM (1.5 mL). To this mixture 2,2-difluoroethyl trifluoromethanesulfonate (11 mg, 0.051 mmol) was added and mixture was stirred at room temperature for 30 min. The solution was concentrated under reduced pressure and the residue was purified via prep HPLC (2-65% acetonitrile in water, 0.1% trifluoroacteic acid) to isolate (R)-4-((R)-1-((3-cyclopropyl-6-(4-(4-(2,2-difluoroethyl)piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one 3.46 as a trifluoroacetic acid salt.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.[NH2:48][C:49]1[C:50]([C:67]2[O:71][C:70](=O)[NH:69][N:68]=2)=[N:51][C:52]([C:55]2[CH:60]=[CH:59][C:58]([S:61]([CH:64]([CH3:66])[CH3:65])(=[O:63])=[O:62])=[CH:57][CH:56]=2)=[CH:53][N:54]=1.Cl>CN(C=O)C.CS(C)=O.CCOC(C)=O.C(=O)([O-])O.[Na+]>[NH2:48][C:49]1[C:50]([C:67]2[O:71][C:70]([NH:10][CH:11]3[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)=[N:69][N:68]=2)=[N:51][C:52]([C:55]2[CH:60]=[CH:59][C:58]([S:61]([CH:64]([CH3:65])[CH3:66])(=[O:63])=[O:62])=[CH:57][CH:56]=2)=[CH:53][N:54]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3n[nH]c(=O)o3)n2)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(NC4CCCNC4)o3)n2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 20.2 %

Procedure:
DIPEA (173.6 4, 1.0 mmol), tert-butyl 3-aminopiperidine-1-carboxylate (99.7 mg, 0.50 mmol) and bromo(tripyrrolidin-1-yl)phosphonium hexafluorophosphate (340.6 mg, 0.73 mmol) were added to a mixture of 5-[3-amino-6-(4-isopropylsulfonylphenyl)pyrazin-2-yl]-3H-1,3,4-oxadiazol-2-one (120 mg, 0.33 mmol) in DMF (600 μL) and DMSO (600 4). The resulting mixture was stirred at room temperature for 4.5 h. The reaction mixture was diluted with EtOAc (5 mL) and saturated aqueous sodium hydrogen carbonate solution (5 mL). The aqueous layer was washed with EtOAc (3×5 mL) and the combined organic extracts dried over MgSO4, filtered and concentrated in vacuo. The residue was taken up in methanol (1.2 mL) and HCl (332 μL, 1.0 mmol, 3M solution in methanol) and the resulting solution stirred at room temperature overnight. The reaction mixture was evaporated to dryness and the solid triturated with acetonitrile and then purified further by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The product fractions were passed through a bicarbonate cartridge and lypholised to give the title compound as a yellow solid (29.6 mg, 20%); 1H NMR (400.0 MHz, DMSO) d 1.19 (d, 6H), 1.43-1.48 (m, 2H), 1.64-1.67 (m, 1H), 1.99-2.01 (m, 1H), 2.40-2.46 (m, 2H), 2.77-2.80 (m, 1H), 3.10-3.14 (m, 1H), 3.46-3.55 (m, 2H), 7.80 (br s, 1H), 7.95 (d, 2H), 8.23 (t, 2H), 8.27 (s, 1H) and 8.89 (s, 1H) ppm; MS (ES+) 444.25
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]([O:16][C:17]2[C:22]([CH:23]=CC)=[CH:21][CH:20]=[C:19]([F:26])[C:18]=2[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])[CH:14]=C)(=[O:10])=[O:9])=[CH:4][CH:3]=1>ClCCCl.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH:14]=[CH:23][C:22]3[C:17](=[C:18]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=4[Cl:34])[C:19]([F:26])=[CH:20][CH:21]=3)[O:16]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C=C[C@H](COS(=O)(=O)c1ccc(C)cc1)Oc1c(C=CC)ccc(F)c1-c1ccc(Cl)cc1Cl
Agent: Cl[Ru](Cl)=Cc1ccccc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3ccc(F)c(-c4ccc(Cl)cc4Cl)c3O2)cc1
Yield: 63.5 %

Procedure:
Treatment of (2R)-2-(2′,4′-dichloro-6-fluoro-3-(prop-1-enyl)biphenyl-2-yloxy)but-3-enyl 4-methylbenzenesulfonate (0.6 g, 1.15 mmol) with benzylidene-bis(tricyclohexylphosphine)dichlororuthenium (0.30 g, 0.36 mmol) in 1,2-dichloroethane (30 mL) according to the procedure described for Example 69, Step 7 provided 0.35 g (63%) of ((2R)-8-(2,4-dichlorophenyl)-7-fluoro-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate as a brown oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][C:17]([N:19]4[CH2:24][CH2:23][S:22][CH2:21][CH2:20]4)=[CH:18][C:12]=3[N:11]=2)[CH:7]=[CH:6][C:5]=1[NH2:25])([O-])=O>[Pd].C(OCC)(=O)C.CO>[N:19]1([C:17]2[CH:16]=[CH:15][C:13]3[NH:14][C:10]([C:8]4[CH:9]=[C:4]([NH2:1])[C:5]([NH2:25])=[CH:6][CH:7]=4)=[N:11][C:12]=3[CH:18]=2)[CH2:20][CH2:21][S:22][CH2:23][CH2:24]1
Reactant: Nc1ccc(-c2nc3cc(N4CCSCC4)ccc3[nH]2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2nc3cc(N4CCSCC4)ccc3[nH]2)cc1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-nitro-4-(5-thiomorpholin-4-yl-1H-benzoimidazol-2-yl)-phenylamine (1.0 g, 2.8 mmol) in 4:1 ethyl acetate/methanol (80 ml) under nitrogen, was added 5% palladium on carbon (240 mg) and the mixture was first evacuated and then stirred at room temperature under an atmosphere of hydrogen for 1 day. The reaction mixture was then filtered through Celite, washed with 1:1 ethyl acetate/methanol (10 mL), and the combined filtrate and washings were concentrated to give the crude 4-(5-thiomorpholin-4-yl-1H-benzoimidazol-2-yl)-benzene-1,2-diamine as a red oil that was used in the next step without any purification.
Reaction SMILES: F[C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:11]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([O:20][CH3:21])[CH:14]=1)[CH3:12].[OH-].[K+]>C(#N)C>[CH2:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][C:2]2[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=2)=[C:15]([O:20][CH3:21])[CH:14]=1)[CH3:12]
Reactant: O=[N+]([O-])c1ncccc1F
Reactant: CCc1ccc(O)c(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCc1ccc(Oc2cccnc2[N+](=O)[O-])c(OC)c1
Temperature: 80 °C
Yield: 84.2 %

Procedure:
To a stirred solution of 3-Fluoro 2-nitro pyridine (1.6 g, 0.01126 mol) in dry Acetonitrile (20 ml) was added 4-Ethyl-2-methoxy phenol (1.71 g, 11.3 mmol) in dry acetonitrile (10 ml) followed by potassium hydroxide (0.696 g, 12.4 mmol). The reaction mixture was heated to 80° C. and maintained for 2 hours. The solvent was evaporated and taken in ethyl acetate (200 ml). The organic layer was washed with water followed by brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2.6 g of crude product purified by column chromatography (5% Ethyl acetate in Petroleum ether) to yield: 1.75 g (56%) of title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])=[CH:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14]O.C([Li])CCC.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[NH:39]1[CH2:44][CH2:43][CH2:42][C@@H:41]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:40]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C1(C)C=CC=CC=1.CC(C)=O>[CH2:48]([O:47][C:45]([C@@H:41]1[CH2:42][CH2:43][CH2:44][N:39]([CH2:14][CH2:13][CH2:12][O:11][CH2:10][CH:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:40]1)=[O:46])[CH3:49]
Reactant: CCOC(=O)[C@@H]1CCCNC1
Reactant: Cc1ccccc1C(=CCOCCCO)c1ccccc1C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: CCOC(=O)[C@@H]1CCCN(CCCOCC=C(c2ccccc2C)c2ccccc2C)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.5 %

Procedure:
A solution of 3-(3,3-bis(2-methylphenyl)-2-propen-1-yloxy)-1-propanol (3.45 g, 11.6 mmol) in dry toluene (150 ml) was cooled in an ice-bath and a solution of n-butyllithium in hexanes (5.1 ml, 2.5 M) was added dropwise. The reaction mixture was stirred for 15 minutes at room temperature and p-toluenesulphonyl chloride (2.44 g, 12.8 mmol) was added. The mixture was stirred at room temperature for 3 h. Ethyl (R)-3-piperidinecarboxylate (4.5 g, 23.3 mmol) and potassium carbonate (3.2 g, 23.3 mmol) were added and the mixture was stirred at room temperature for 0.5 h and then at 75° C. for 12 h. Potassium iodide (1.0 g) and acetone (40 ml) were added and the mixture was heated at reflux temperature for 15 h. Acetone (50 ml) was added and the cooled reaction mixture was filtered and the solvent evaporated in vacuo. Flash chromatography of the residue on silica gel (280 g) using a gradient of n-heptane in ethyl acetate as eluent afforded 2.6 g (52%) of (R)-N-(3-(3,3-bis(2-methylphenyl)-2-propen-1-yloxy)-1-propyl)3-piperidinecarboxylic acid ethyl ester as an oil. TLC: rf=0.52 (SiO2 ; methanol/ethyl acetate=1:9).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH2:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[Cl:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18].C(N(CC)CC)C>ClCCl>[Cl:13][CH2:14][CH2:15][CH2:16][C:17]([NH:12][C:9]([C:6]1[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=1)([CH3:10])[CH3:11])=[O:18]
Reactant: CC(C)(N)c1ccc(Cl)cc1
Reactant: O=C(Cl)CCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(NC(=O)CCCCl)c1ccc(Cl)cc1

Procedure:
In a similar manner to Example 52b, 1-(4-chlorophenyl)-1-methylethylamine hydrochloride (2.5 g) was treated with 4-chlorobutyryl chloride (1.7 g) in dichloromethane (30 ml) containing triethylamine (3.4 ml) to give 4-chloro-N-[1-(4-chlorophenyl)-1-methylethyl]butyramide which was used directly in part (b) below.
Reaction SMILES: COC1C=CC(C[N:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][C@H:19]4[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20]4)[CH:14]=3)[C:9]2=[O:25])=CC=1.CO>C(O)(C(F)(F)F)=O>[NH2:24][C@H:21]1[CH2:22][CH2:23][C@H:19]([O:18][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:25])[NH:8][CH:17]=[CH:16]3)[CH2:20]1
Reactant: COc1ccc(Cn2ccc3cc(O[C@H]4CC[C@H](N)C4)ccc3c2=O)cc1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC[C@H](Oc2ccc3c(=O)[nH]ccc3c2)C1
Temperature: 150 °C
Yield: 50.6 %

Procedure:
125 mg (0.34 mmol) of 2-(4-methoxy-benzyl)-6-((1S,3S)-3-amino-cyclopentyloxy)-2H-isoquinolin-1-one (39) were dissolved in 1 mL of TFA and heated in a microwave oven at 150° C. for 3 h. Methanol was added and the reaction mixture was evaporated. The solution was taken up in 1N HCl and extracted three times with dichloromethane. The combined dichloromethane layers were extracted with 1N HCl twice and the combined HCl layers were lyophilized. The residue was dissolved in water and lyophilized again to yield 42 mg of 6-((1S,3S)-3-amino-cyclopentyloxy)-2H-isoquinolin-1-one (43) as hydrochloride. Rt=0.86 min (Method E). Detected mass: 245.1 (M+H+).
Reaction SMILES: [C:1]([C:4]1[C:5]([F:25])=[C:6]([N:10]([CH2:22][O:23][CH3:24])[S:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].C1C=C[NH+]=CC=1.[Br:32][Br-]Br>C1COCC1>[Br:32][CH2:2][C:1]([C:4]1[C:5]([F:25])=[C:6]([N:10]([CH2:22][O:23][CH3:24])[S:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: COCN(c1cccc(C(C)=O)c1F)S(=O)(=O)c1cc(F)ccc1F
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: COCN(c1cccc(C(=O)CBr)c1F)S(=O)(=O)c1cc(F)ccc1F
Temperature: 80 °C

Procedure:
100 mg (0.27 mmol) of N-(3-acetyl-2-fluorophenyl)-2,5-difluoro-N-(methoxymethyl)benzenesulfonamide were dissolved in 10 mL of dry THF and 100 mg (0.3 mmol) of pyridinium bromide perbromide were added. The resulting solution was heated in a microwave apparatus at 80° C. for 15 min. The solvent was then evaporated, the residue taken up with DCM and washed with 0.5 N HCl. The organic layer was then dried over Na2SO4 and evaporated to give the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[CH2:10][OH:11])[C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[S:5]2.[H-].[Na+].[CH3:18]I>CN(C)C=O>[CH3:18][O:11][CH2:10][C:9]1[N:8]2[C:4]([S:5][C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=32)=[N:3][C:2]=1[CH3:1]
Reactant: CI
Reactant: Cc1nc2sc3ccccc3n2c1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1c(C)nc2sc3ccccc3n12
Temperature: 25 °C
Yield: 60.8 %

Procedure:
In 30 ml of dry dimethylformamide was suspended 2.18 g of 2-methylimidazo[2,1-b]benzothiazole-3-methanol and, 0.50 g of 60% sodium hydride was added to the suspension followed by stirring at room temperature for minutes. After 1.74 g of methyl iodide was added thereto, the mixture was stirred for one hour. Then ice water was added to the reaction mixture followed by extracting with ethyl acetate. After the ethyl acetate was removed, 1.41 g of the title compound was obtained.
Reaction SMILES: [C:1]([CH2:20][CH2:21][S:22][CH2:23][CH2:24][OH:25])([C:4]([C:7]([C:10]([C:13]([C:16]([F:19])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[C:26](OC(=O)C)(=[O:28])[CH3:27].N1C=CC=CC=1>>[C:26]([O:25][CH2:24][CH2:23][S:22][CH2:21][CH2:20][C:1]([F:3])([F:2])[C:4]([F:6])([F:5])[C:7]([F:9])([F:8])[C:10]([F:12])([F:11])[C:13]([F:14])([F:15])[C:16]([F:17])([F:18])[F:19])(=[O:28])[CH3:27]
Reactant: OCCSCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCSCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 4 h

Procedure:
C6F13CH2CH2SCH2CH2OH (40.1 g, 0.094 mole, undistilled), acetic anhydride (16.2 g, 0.15 mole) and pyridine (0.98 g, 12.4 mmole) was heated at 65°-66° for 4 hours and 89° for 17 hours under total reflux. A sample after 4 hours showed incomplete reaction and after 17 hours, only a trace of C6F13CH2CH2SCH2CH2OH was present (GC analysis). The product was washed with saturated sodium bicarbonate (20 ml), extracted into ether, dried and the solvent removed by distillation; wt. 47.77 g. Total product was 49.3 g, 100% of theory. NMR was consistent for structure: proton resonances at 2.03 ppm, 3 protons, s, CH3 ; at 2.42 ppm, multiplet, 2 protons, CH2A ; at 2.78 ppm, multiplet, 4 protons, CH2A ; at 2.78 ppm, multiplet, 4 protons, CH2B and CH2C ; and at 4.24 ppm, t, 2 protons CH2D for C6F13CH2ACH2BSCH2CCH2DO2CCH3.
Reaction SMILES: [CH:1]1([N:5]([CH3:27])[C:6]2[C:7]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:8][C:9]3[C:14]([N:15]=2)=[CH:13][C:12]([C:16]([O:18]C)=[O:17])=[CH:11][CH:10]=3)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].O>CO>[CH:1]1([N:5]([CH3:27])[C:6]2[C:7]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)=[N:8][C:9]3[C:14]([N:15]=2)=[CH:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11][CH:10]=3)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N(C)C3CCC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1)C1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
To a solution of methyl 3-(cyclobutyl(methyl)amino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (70.0 mg, crude) in MeOH (15 mL) was added sodium hydroxide (18.0 mg, 0.45 mmol) and water (0.5 mL). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (10 mL) and adjusted to pH 3 with hydrochloric acid (1N). The solids were collected by filtration to afford 3-(cyclobutyl(methyl)amino)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a yellow solid (30 mg).