Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2](Cl)(Cl)[S:3][Cl:4].[OH2:7].[C:8]([NH2:16])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(C)C=CC=CC=1>OS(O)(=O)=O>[Cl:1][C:2]([S:3][Cl:4])=[O:15].[C:9]1([C:8]2[O:15][C:2](=[O:7])[S:3][N:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClSC(Cl)(Cl)Cl
Reactant: O
Reactant: NC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: O=C(Cl)SCl
Product: O=c1oc(-c2ccccc2)ns1
Reaction time: 1 h
Yield: 73 %

Procedure:
Chlorocarbonylsulfenyl chloride was prepared by a literature procedure. A mixture of 784.9 g (4.22 mol) of trichloromethanesulfenyl chloride and 76 g (4.22 mol) of water dissolved in 886 ml of concentrated H2SO4 was stirred at 45°-50° for 1 hour in a 51. flask, at which time the initially-copious HC1 evolution had ceased. (Foaming presented problems in the beginning.) The mixture was transferred to a separatory funnel, and after 15 minutes, the layers were separated. The top, fluid layer, which amounted to 404.3 g (3.08 mol, 73% yield) of fairly pure chlorocarbonylsulfenyl chloride, was added to 373 g (3.08 mol) of benzamide in 1 1. of toluene in a 5 1. flask fitted with stirrer and reflux condenser. The mixture was stirred vigorously and was heated gently to 58°. A mildly exothermic reaction carried the temperature to 65° with foaming and vigorous gas evolution. The mixture was heated at 65° for 20 minutes, at 70° for 8 hours, at 70°-110° for 0.5 hours, and at 110° for 0.75 hours, at which time gas evolution had ceased. The reaction mixture was concentrated under vacuum to 1.5 mm and 90°. The residue was heated with 650 ml of methylcyclohexane; the mixture was treated with charcoal, filtered, and allowed to cool. The resultant solid was recrystallized from 650 ml of methylcyclohexane, heated to 75 (charcoal treatment and filtration) to give 375 g of very pale yellow solid, 5-phenyl-1,3,4 -oxathiazol-2-one, m.p. 64°-67°. An additional 27.2 g of product, m.p. 64°-67°, was obtained from the filtrates. The total yield, 412.2 g, corresponds to 75% of the theoretical amount.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:9]([N:11]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=O.[NH3:28].CO>C1COCC1>[CH3:7][N:8]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:9]([N:11]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[NH:28]
Reactant: N
Reactant: CC(C)CN(C)C(=O)N(C1CCCCC1)C1CCCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CN(C)C(=N)N(C1CCCCC1)C1CCCCC1

Procedure:
A solution of dicyclohexylamine (3.6 mL, 18 mmol) and triethylamine (5.6 mL, 40 mmol) in THF (64 mL) was added dropwise to a stirred solution of triphosgene (1.98 g, 6.7 mmol) in THF (35 mL) at room temperature. The reaction mixture was stirred overnight. Then, a solution of N-methylisobutylamine (2.2 mL, 18 mmol) and triethylamine (5.5 mL, 40 mmol) in THF (35 mL) was added. The reaction mixture was stirred overnight at reflux temperature. The reaction mixture was filtered and the filtrate was evaporated to dryness, yielding N-methyl-N-isobutyl-N′,N′-dicyclohexylurea as a dark yellow oil. Yield: 4.8 g (90%). Oxalyl chloride (8 mL, 16 mmol, 2 M solution in dichloromethane) was added to a stirred solution of the urea (4.8 g, 16 mmol) in THF (65 mL). The reaction mixture was heated to reflux overnight and evaporated to dryness. Ammonia in methanol (7 mL, 49 mmol, 7 M solution in methanol) was added to a suspension of the formed solid in THF. The reaction mixture was heated to reflux overnight and evaporated to dryness. The product was neutralized and purified by treatment with aqueous sodium hydroxide solution. The organic layer was extracted with diethyl ether and dried over magnesium sulfate. Evaporation to dryness yielded the desired guanidine as a brown oil. Yield: 2.95 g (75%). 1H NMR (CDCl3, 300 MHz): δ 0.80 (d, 6 H), 1.20 (d, 12 H), 1.8 (sept, 1 H), 2.7 (s, 3 H), 2.83 (d, 2 H), 3.52 (sept, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ 19.1, 20.7, 25.6, 36.8, 46.4, 57.2, 164.7 ppm.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:10]=[C:11]([Cl:17])[C:12]([C:15]#[N:16])=[N:13][CH:14]=2)[CH2:4]1.[C:18](O)(=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[Cl:17][C:11]1[N:10]=[C:9]([N:5]2[CH2:6][CH2:7][CH2:8][C@@H:3]([NH:2][C:18](=[O:27])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH2:4]2)[CH:14]=[N:13][C:12]=1[C:15]#[N:16]
Reactant: N#Cc1ncc(N2CCC[C@@H](N)C2)nc1Cl
Reactant: COc1ccc(C(=O)O)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N[C@@H]2CCCN(c3cnc(C#N)c(Cl)n3)C2)cc1
Temperature: 25 °C

Procedure:
(R)-tert-butyl 1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-ylcarbamate (87) (1.5 g) was treated with 30 mL “4N HCl in dioxane” at RT for 1 h. The mixture was concentrated in vacuo to dryness to afford (R)-5-(3-aminopiperidin-1-yl)-3-chloropyrazine-2-carbonitrile hydrochloride (134) in quantitative yield. Compound 134 (1.20 g, 4.4 mmol) and p-anisic acid (1.34 g, 8.8 mmol) were dissolved in 20 mL DMF with DIEA (3.82 mL, 22.0 mmol). To it was added PyBOP (4.58 g, 8.8 mmol). The mixture was stirred at RT for 30 m. It was diluted with EtOAc (200 mL), washed with 1N NaOH and water. The organic phase was dried, concentrated and subjected to flash column with 0 to 50% EtOAc in DCM to isolate (R)—N-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-4-methoxybenzamide, compound 135 (yield >90%).
Reaction SMILES: Cl[CH:2]([CH:13]1[CH2:15][CH2:14]1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:4]=1.[CH3:16][C@@H:17]1[CH2:22][NH:21][CH2:20][CH2:19][NH:18]1>CC#N>[CH:13]1([CH:2]([C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:4]=2)[N:18]2[CH2:19][CH2:20][NH:21][CH2:22][C@H:17]2[CH3:16])[CH2:15][CH2:14]1
Reactant: FC(F)(F)c1cccc(C(Cl)C2CC2)c1
Reactant: C[C@@H]1CNCCN1
Solvent: CC#N
Product: C[C@@H]1CNCCN1C(c1cccc(C(F)(F)F)c1)C1CC1
Temperature: 90 °C
Yield: 96 %

Procedure:
A mixture of 1-(chloro(cyclopropyl)methyl)-3-(trifluoromethyl)benzene (2.5 g, 11 mmol) and (R)-2-methylpiperazine (3.2 g, 32 mmol) in 30 mL of MeCN was heated at 90° C. overnight. The solvent was evaporated and the solid residue was submitted to column chromatography (SiO2, EtOAc to EtOAc/2M NH3 in MeOH=100:20) to give crude (2R)-1-(cyclopropyl(3-(trifluoromethyl)phenyl)methyl)-2-methylpiperazine (3.15 g) which was directly used in next step.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[OH:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][CH2:14][NH:15][C:16]([CH:18]2[CH2:20][CH2:19]2)=[O:17])[CH:9]=[CH:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][CH2:14][NH:15][C:16]([CH:18]2[CH2:19][CH2:20]2)=[O:17])[CH:9]=[CH:10][CH:11]=1)[C:2]#[CH:3]
Reactant: C#CCBr
Reactant: O=C(NCCCc1cccc(O)c1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1cccc(CCCNC(=O)C2CC2)c1
Temperature: 25 °C

Procedure:
Propargyl bromide (80% in toluene, 0.091 ml) was added dropwise to a mixture of cyclopropanecarboxylic acid [3-(3-hydroxy-phenyl)-propyl]-amide (122 mg) and potassium carbonate (154 mg) in dry DMF (10 ml) in an ice bath under nitrogen. The mixture was allowed to warm to room temperature, then heated at 65° C. for 18 h. The cooled mixture was partitioned between water (50 ml) and ethyl acetate (3×15 ml). The combined organic extracts were washed with brine/water 1:1 (3×20 ml) and dried (MgSO4). The solvent was evaporated and the residue purified by column chromatography on silica. Elution with hexane/ethyl acetate 2:1 gave the title compound as a colourless solid (79 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([Mg]Cl)C.[CH2:13]([O:15]CC)C>C1(C)C=CC=CC=1.C(O)C.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:13]=[O:15])=[C:4]([OH:8])[CH:3]=1
Reactant: CCOCC
Reactant: Oc1cccc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CC[Mg]Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: O=Cc1ccc(Cl)cc1O
Temperature: 25 °C

Procedure:
Modification of a procedure described by G. Casiraghi et al., (J. Chem. Soc., Perkin Transac. I., 1978, 318), was utilized in the preparation of substituted salicylaldehydes. To a mixture of 26 g of 3-chlorophenol dissolved in 200 mL, of toluene at 10° C. was added dropwise 100 mL, of a 2M solution of ethylmagnesium chloride in diethyl ether. The ether was distilled off and the reaction mixture was cooled to room temperature and 26.0 g of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) was added followed by 15.0 g of paraformaldehyde. The reaction mixture was heated at 70° C. for 18 h, cooled to 10° C. and a solution of 20 mL of concentrated HCl in 100 g of ice was added followed by 200 mL of hexane. The organic phase was separated and washed twice with 100 mL of water, once with 100 mL of brine, dried over anhydrous MgSO4, filtered and concentrated under vacuum to afford a viscous oil. This was taken up in 150 mL of ethanol and a solution of 15.0 g of copper (II) acetate dissolved in 150 mL of H2O was added dropwise. The resulting precipitate was filtered, washed with water and then with ether and added to a solution of 200 mL of ether and 20 mL of concentrated H2SO4 in 100 g of ice. The mixture was stirred until ail solids were dissolved, 100 mL of hexane was added, and the organics were washed with 100 mL of H2O, then 100 mL of brine, dried over anhydrous MgSO4, filtered and concentrated under vacuum to afford 15.0 g of a yellow solid, mp 47°-48° C. 1H NMR (CDCl3) δ6.98 (d, 1H), 7.01 (s, 1H), 7.50 (d, 1H), 9.85 (s, 1H), 11.18 (s, 1H). IR (Nujol) 3300-2800, 1670 cm-1.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9]([C@@H:11]2[CH2:17][CH2:16][C@@H:15]3[CH2:18][N:12]2[C:13](=[O:24])[N:14]3[O:19][S:20]([O-:23])(=[O:22])=[O:21])=[O:10])[CH2:3][CH2:2]1.C([N+](CCCC)(CCCC)CCCC)CCC.FC(F)(F)C(O)=O>ClCCl>[NH:1]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9]([C@@H:11]2[CH2:17][CH2:16][C@@H:15]3[CH2:18][N:12]2[C:13](=[O:24])[N:14]3[O:19][S:20]([OH:23])(=[O:21])=[O:22])=[O:10])[CH2:3][CH2:2]1
Reactant: O=C(N[C@H]1CCCNCC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@H]1CCCNCC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Reaction time: 2 h

Procedure:
To a solution of N,N,N-tributylbutan-1-aminium {[((2S,5R)-2-{[(4S)-azepan-4-ylamino]carbonyl}-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl)oxy]sulfonyl}oxidanide (30.9 mg, 0.067 mmol) in anhydrous dichloromethane (7 mL) at 0° C. under nitrogen was added trifluoroacetic acid (0.5 mL, 6.5 mmol) dropwise. The reaction mixture was stirred for two hours then concentrated under vacuum. Ether was added to the residue and the resulting white precipitate was collected by centrifugation. The precipitate was purified by HPLC on a Phenomenex Synergy Polar-RP 80A column and lyophilized to afford the title compound as a white solid. LC-MS (negative ionization) m/e 361 (M−H); LC-MS (positive ionization) m/e 385 (M+Na); 1H NMR (600 MHz, D2O; unreferenced) (δ, ppm) 4.17 (1H, br d, J=3 Hz), 3.96-4.03 (2H, m), 3.27-3.38 (3H, m), 3.15-3.22 (2H, m), 3.02 (1H, d, J=12 Hz), 1.62-2.18 (m, 12H).
Reaction SMILES: [CH2:1]([S:3]([NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=O)=[CH:16][CH:15]=2)[N:11]=1)(=[O:5])=[O:4])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:36]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])(=[O:39])[NH:37][NH2:38].O>O1CCCC1>[CH2:1]([S:3]([NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][C:21]([NH:38][NH:37][C:36]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:23])=[CH:18][CH:19]=2)[N:11]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)Nc1nc(CCc2ccc(CC(=O)O)cc2)cs1
Reactant: CC(C)(C)OC(=O)NN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: CCS(=O)(=O)Nc1nc(CCc2ccc(CC(=O)NNC(=O)OC(C)(C)C)cc2)cs1
Temperature: 42.5 °C
Reaction time: 1 h

Procedure:
To a suspension of [4-(2-{2-[(ethylsulfonyl)amino]-1,3-thiazol-4-yl}ethyl)phenyl]acetic acid (700 mg, 1.98 mmol) in anhydrous tetrahydrofuran (5 ml) was added 1,1′-carbonyldiimidazole (480 mg, 2.96 mmol), and the mixture was stirred at 40-45° C. for 1 hr. After cooling to 0° C., tert-butyl carbazate (914 mg, 6.91 mmol) was added, and the mixture was stirred at room temperature for 4 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The combined organic layer was washed with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) to give tert-butyl 2-{[4-(2-{2-[(ethylsulfonyl)amino]-1,3-thiazol-4-yl}ethyl)phenyl]acetyl}hydrazinecarboxylate (989 mg, quantitatively) as a white solid.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][C:30]([CH2:36]Br)=[CH:29][C:28]=2[CH:38]([CH3:40])[CH3:39])=[O:25])[C:6]1=[O:41])[CH2:2][CH2:3][CH3:4].C1(=O)[NH:46]C(=O)C2=CC=CC=C12.[K].O>CN(C)C=O>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][C:30]([CH2:36][NH2:46])=[CH:29][C:28]=2[CH:38]([CH3:40])[CH3:39])=[O:25])[C:6]1=[O:41])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cc(CBr)cc2C(C)C)c(-c2cccc(OC)c2)c2cccnc21
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cc(CN)cc2C(C)C)c(-c2cccc(OC)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
To a solution of N-[1-butyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N′-(2,6-diisopropyl-4-bromomethylphenyl)urea (400 mg, 0.65 mmol) in dimethylformamide (10 ml) is added potassium phthalimide (144 mg, 0.78 mmol) at room temperature, and the mixture is stirred at room temperature for 3 hours. To the mixture is added water, and the mixture is extracted with ethyl acetate. The organic layer is washed twice with water, and dried over anhydrous magnesium sulfate. The solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound (393 mg, 0.57 mmol) as colorless amorphous.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH2:7].[CH:8]([C:10]1[CH:21]=[CH:20][C:13]([O:14][CH2:15][C:16]([NH:18][CH3:19])=[O:17])=[CH:12][CH:11]=1)=O.[Si]([O:29][N:30]=[C:31]1[C:39]2[C:34](=[CH:35][C:36]([N+:40]#[C-:41])=[CH:37][CH:38]=2)[CH2:33][CH2:32]1)(C(C)(C)C)(C)C>C(Cl)Cl.CO.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Sc+3]>[OH:29][N:30]=[C:31]1[C:39]2[C:34](=[CH:35][C:36]([NH:40][C:41]3[N:1]4[CH:6]=[CH:5][N:4]=[CH:3][C:2]4=[N:7][C:8]=3[C:10]3[CH:21]=[CH:20][C:13]([O:14][CH2:15][C:16]([NH:18][CH3:19])=[O:17])=[CH:12][CH:11]=3)=[CH:37][CH:38]=2)[CH2:33][CH2:32]1
Reactant: Nc1cnccn1
Reactant: CNC(=O)COc1ccc(C=O)cc1
Reactant: [C-]#[N+]c1ccc2c(c1)CCC2=NO[Si](C)(C)C(C)(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)COc1ccc(-c2nc3cnccn3c2Nc2ccc3c(c2)CCC3=NO)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of pyrazin-2-amine (12) (1.1 eq.), 2-(4-formylphenoxy)-N-methylacetamide (9) (1.1 eq.) and a catalytic amount of Sc(OTf)3 was stirred in 2 mL of 1:1 DCM/MeOH at room temperature for 30 minutes. To this was added 5-isocyano-2,3-dihydroinden-1-one O-tert-butyldimethylsilyl oxime (1 eq.) as a 2 mL solution in 1:1 DCM/MeOH and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated under vacuum and the residue taken up in EtOAc (with a small amount of methanol added to help with dissolution) and purified by column using 1-5% MeOH/EtOAc+1% NH4OH. The desired product (14) was isolated as a light yellow solid. MS (APCI) m/z 443.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[CH:10]=[C:9]([Sn](C)(C)C)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Br[C:17]1[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=1>>[CH3:1][O:2][C:3]1[C:11]2[CH:10]=[C:9]([C:17]3[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2oc([Sn](C)(C)C)cc12
Reactant: Cn1ccnc1Br
Product: COc1cccc2oc(-c3nccn3C)cc12
Yield: 53.4 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 87 using 4-methoxy-2-(trimethylstannyl)benzo(b)furan (5.26 g), 2-bromo-1-methylimidazole (2.72 g) and bistriphenylphosphinepalladium dichloride (593 mg), the title compound (2.06 g) was obtained as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14](O)=[CH:13][CH:12]=1)=[O:10].IC.[C:20](=[O:23])([O-])[O-].[K+].[K+].[CH3:26]C(C)=O>O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:26])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:23][CH3:20])=[CH:13][CH:12]=1)=[O:10]
Reactant: O=C([O-])[O-]
Reactant: O=C(c1ccc(O)cc1)c1cc(O)ccc1O
Reactant: CC(C)=O
Agent: [K+]
Solvent: CI
Solvent: O
Product: COc1ccc(C(=O)c2cc(OC)ccc2O)cc1
Reaction time: 6 h
Yield: 60 %

Procedure:
A mixture of (2,5-dihydroxyphenyl)(4-hydroxyphenyl)methanone (1.8 g, 7.8 mmol), iodomethane (2.3 g, 16.4 mmol), potassium carbonate (5.4 g, 39 mmol) and acetone (25 mL) was heated to reflux. After 6 h, the reaction was cooled, poured into water and extracted with EtOAc. The organic layer was dried over MgSO4, concentrated and the crude product was purified by column chromatography (eluent 10% EtOAc/hexanes) to give a yellow solid (1.2 g, 60% yield, mp 70-72° C.); 1H NMR(DMSO-d8) 11.4 (s, 1H), 7.75 (d, 2H, J=8.5 Hz), 7.15-7.11 (m, 2H), 7.03-6.98 (m, 3H), 3.90 (s, 3H), 3.73 (s, 3H); MS m/e 257 (M−H)+.
Reaction SMILES: [F:1][C:2]1([F:23])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:22])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]([O:10][C@@H:11]2[CH2:15][CH2:14][NH:13][CH2:12]2)=[O:9])[CH2:3]1.[Cl:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29]Cl>C(#N)C>[Cl-:24].[F:23][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:22])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]([O:10][C@@H:11]2[CH2:15][CH2:14][N+:13]3([CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH2:12]2)=[O:9])[CH2:3]1
Reactant: O=C(O[C@@H]1CCNC1)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1
Reactant: ClCCOCCCl
Solvent: CC#N
Product: O=C(O[C@@H]1CC[N+]2(CCOCC2)C1)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1
Product: [Cl-]
Reaction time: 12 h
Yield: 19.2 %

Procedure:
To an acetonitrile solution containing 11 mg of (3R)-pyrrolidin-3-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, 30 mg of 1-chloro-2-(2-chloroethoxy)ethane was added at room temperature, followed by 12 hours' heating under reflux. Distilling the solvent off under reduced pressure, the residue was purified on preparative thin layer chromatography (Aluminiumoxide™60F254 Art5713 (Merck), chloroform/methanol=10/1) to provide 2.8 mg of the title compound as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:16][CH2:17][CH2:18][CH2:19][OH:20])(=[O:11])=[O:10].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:16][CH2:17][CH2:18][CH:19]=[O:20])(=[O:11])=[O:10]
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc(Cl)c2Cl)c1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2cccc(Cl)c2Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
Sulfur trioxide pyridine complex (720 mg, 4.5 mmol) was added to a solution of 3-[3-(2,3-dichlorophenylsulfonyloxy)-5-methylphenoxy]propanol (580 mg, 1.5 mmol), as prepared in the preceding step, N,N-diisopropylethylamine (0.7 mL, 5.5 mmol) and anhydrous dimethyl sulfoxide (0.3 mL, 4.2 mmol) in dichloromethane (15 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then quenched with 10% aqueous citric acid (50 mL). The mixture was extracted into dichloromethane (3×50 mL), and the dichloromethane solution was washed with 10% aqueous citric acid (40 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane) to give the title compound as a colorless oil (545 mg, 93%). 1H-NMR (300 MHz, CDCl3) δ 9.84 (s, 1 H), 7.92 (d, J=8.0 Hz, 1 H), 7.76 (d, J=8.0 Hz, 1 H), 7.34(t, J=8.0 Hz, 1 H), 6.61 (s, 1 H), 6.57 (s, 1 H), 6.50 (s, 1 H), 4.21 (t, J=6.0 Hz, 2 H), 2.87 (t, J=6.0 Hz, 2 H), 2.26 (s, 3 H).
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:14]1(C2CCNCC=2)[CH:19]=[CH:18]C=[CH:16][CH:15]=1.OC1(C2C=CC=CC=2)CCN(CCCC[N:37]2[CH:46]([OH:47])[C:45]3[CH:48]=[CH:49][CH:50]=[C:43]4[C:44]=3[C:39](=[CH:40][CH:41]=[CH:42]4)[C:38]2=[O:51])CC1>>[OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][N:5]([CH2:16][CH2:15][CH2:14][CH2:19][CH2:18][N:37]2[CH:46]([OH:47])[C:45]3[CH:48]=[CH:49][CH:50]=[C:43]4[C:44]=3[C:39](=[CH:40][CH:41]=[CH:42]4)[C:38]2=[O:51])[CH2:4][CH2:3]1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: O=C1c2cccc3cccc(c23)C(O)N1CCCCN1CCC(O)(c2ccccc2)CC1
Product: O=C1c2cccc3cccc(c23)C(O)N1CCCCCN1CCC(O)(c2ccccc2)CC1

Procedure:
Following the procedure of example 5 but substituting 4-hydroxy-4-phenylpiperidine for the 4-phenyl-1,2,3,6-tetrahydropyridine in part (b), one obtains the titled compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[F:24][C:25]1[C:30](B(O)O)=[CH:29][CH:28]=[CH:27][N:26]=1>>[F:24][C:25]1[C:30]([C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][C:11]4[S:10][C:9]([C:15]5[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=5)=[N:8][C:7]=4[C:6]=3[CH:23]=2)=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: OB(O)c1cccnc1F
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3cccnc3F)cc1-2

Procedure:
Following the procedure for 128, 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 and 2-fluoropyridin-3-ylboronic acid were reacted to give 306. MS (ESI(+)): m/z 408.1 (M+H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([OH:19])[C:5]2[N:6]=[CH:7][N:8]([C:17]=2[N:18]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]1.[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1>COCCO>[N:24]1([CH2:23][CH2:22][CH2:21][NH:20][C:2]2[NH:3][C:4](=[O:19])[C:5]3[N:6]=[CH:7][N:8]([C:17]=3[N:18]=2)[C@@H:9]2[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]2)[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)nc(Cl)nc32)C[C@@H]1O
Reactant: NCCCn1ccnc1
Solvent: COCCO
Product: O=c1[nH]c(NCCCn2ccnc2)nc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Temperature: 0 °C

Procedure:
A solution of the nucleoside 102 (10.31 g, 36 mmol) and 1-(3-amino-propyl) imidazol (9 g, 72 mmole) in 2-methoxyethanol (60 ml) was heated in a steel bomb at 120° C. (oil bath) for 24 hrs. The bomb was cooled to 0° C., opened carefully and the precipitated solid was filtered. The solid was washed with methanol (50 ml) and acetone (50 ml), and dried over sodium hydroxide to give 9 g (67%) of pure 103. A small amount was recrystallized from DMF for analytical purposes. mp 245-47°.