Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Cl:10][C:11]1[N:16]=[C:15]([C:17](O)([CH3:19])[CH3:18])[C:14]([F:21])=[CH:13][N:12]=1>ClCCl>[Cl:10][C:11]1[N:16]=[C:15]([C:17]([F:7])([CH3:19])[CH3:18])[C:14]([F:21])=[CH:13][N:12]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(O)c1nc(Cl)ncc1F
Solvent: ClCCl
Product: CC(C)(F)c1nc(Cl)ncc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
Diethylaminosulfur trifluoride (6.53 g, 40.5 mmol) is added drop wise to a −78° C. solution of 2-(2-chloro-5-fluoro-pyrimidin-4-yl)propan-2-ol (4.825 g, 25.31 mmol) in dichloromethane (70 mL) under nitrogen. The reaction is stirred at −78° C. for 30 minutes under nitrogen, is then quenched with aqueous saturated sodium bicarbonate and is warmed to room temperature. The reaction mixture is extracted three times with ethyl acetate. The combined organic layers are dried over sodium sulfate and concentrated under vacuum. The resulting crude product is purified over silica gel with a 40 minute, 5% to 100% ethyl acetate in hexanes gradient to give the title compound (4.23 g, 87%). ES/MS (m/e): (35Cl/37Cl) 193/195 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]#[C:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18].O>C(#N)C>[CH2:17]([N:19]([CH2:20][CH3:21])[CH2:2][C:3]#[C:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16])[CH3:18]
Reactant: O=C1c2ccccc2C(=O)N1CC#CCCl
Reactant: CCNCC
Solvent: CC#N
Solvent: O
Product: CCN(CC)CC#CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.4 %

Procedure:
To a solution of 2-(4-chlorobut-2-yn-1-yl)-1H-isoindole-1,3(2H)-dione (200 mg) in acetonitrile (3 mL) was added diethylamine (188 mg) at room temperature. The reaction mixture was stirred at room temperature for 4 hr, and added to water at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (112 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([NH2:18])=[C:8]([NH2:19])[N:7]=1.C(N(CC)CC)C.CN(C)[CH:29]=[O:30]>>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:7]=[C:8]2[NH:19][C:29](=[O:30])[NH:18][C:9]2=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1
Reactant: Nc1cc(-c2ccncc2)c(-c2ncco2)nc1N
Reactant: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=c1[nH]c2cc(-c3ccncc3)c(-c3ncco3)nc2[nH]1
Reaction time: 4 h
Yield: 45 %

Procedure:
A solution of 2-(1,3-oxazol-2-yl)-3,4′-bipyridine-5,6-diamine (Intermediate 10, 0.077 g, 0.3 mmol), N,N′-carbonyldiimidazole (0.146 g, 0.9 mmol) and triethylamine (91 mg, 0.9 mmol) in N,N-dimethylformamide (1 mL) was heated to 100° C. in a sealed tube. After 4 hours, the mixture was cooled and concentrated in vacuo. Water was added to the residue and the solid that separated was washed with water and dried to give the title compound (0.038 g, 45%) as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([C@H:7]([CH2:9][CH3:10])[CH3:8])[NH2:6].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:11])[C@H:5]([C@H:7]([CH2:9][CH3:10])[CH3:8])[NH:6][S:19]([C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: CC[C@H](C)[C@H](N)C(=O)OC
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](C)[C@H](NS(=O)(=O)c1ccc(Cl)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 110.4 %

Procedure:
To a solution of L-isoleucine methyl ester hydrochloride (1.82 g, 10 mmol) and 4-chlorobenzenesulfonyl chloride (2.11 g, 10 mmol) in CH2Cl2 was added triethylamine (4.18 mL, 30 mmol). The mixture was stirred at 25° C. for 16 hours, then filtered and concentrated. The crude product was purified by flash chromatography over silica gel using 10% ethyl acetate in hexane to give N-4-chlorobenzenesulfonyl L-isoleucine methyl ester 3.53 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:20]1[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH:23]2[CH2:24][CH2:25][O:20][CH2:21][CH2:22]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OC1CCOCC1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1cc(F)ccc1F)C1CCOCC1
Yield: 61.4 %

Procedure:
The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (200 mg, 0.661 mmol) obtained in Example 5 and tetrahydro-4H-pyran-4-ol (0.13 ml, 1.36 mmol) were dissolved in toluene (10 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (330 mg, 1.37 mmol). Under an argon atmosphere, the resulting mixture was heated under reflux for 14 hours. After the reaction mixture was allowed to cool down, cyanomethylenetri-n-butylphosphorane (200 mg, 0.829 mmol) was added thereto. Under an argon atmosphere, the mixture was heated under reflux for 14 hours. The reaction mixture was then allowed to cool down. The residue obtained by concentrating the mixture under reduced pressure was subjected to flash silica gel chromatography. The fraction obtained from the hexane:ethyl acetate=4:1 eluate was concentrated under reduced pressure to give a white solid. The white solid was washed with hexane, whereby the title compound (157 mg, 0.406 mmol, 61%) was obtained as a white powder.
Reaction SMILES: C1(SC[Cl:9])C=CC=CC=1.C1(S[CH2:17][N:18]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][C:26]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[S:19]2(=[O:21])=[O:20])C=CC=CC=1.S(Cl)(Cl)(=O)=O>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:9][CH2:17][N:18]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[S:19]1(=[O:21])=[O:20]
Reactant: O=C1c2c(-c3ccccc3)cccc2S(=O)(=O)N1CSc1ccccc1
Reactant: ClCSc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O=S(=O)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C1c2c(-c3ccccc3)cccc2S(=O)(=O)N1CCl
Yield: 93 %

Procedure:
Following a procedure similar to that described in Example 21, the latter (0.33 g, 0.0012 mol) was reacted with 0.3 g (0.0019 mol) of chloromethyl phenyl sulfide in 15 ml of toluene in the presence of 0.08 g (0.0025 mol) of tetrabutyl-ammonium bromide and the product, 2-phenylthiomethyl-4-phenylsaccharin (0.48 g, 100%), treated with sulfuryl chloride in MDC to give 0.36 g (95%) of 2-chloromethyl-4-phenyl-saccharin.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[C:3]=1[C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:18][CH:17]=1)=[O:15].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1.O>[OH:15][CH:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)=[CH:18][CH:17]=1)[C:3]1[C:4]2[C:9](=[CH:8][C:7]([O:12][CH3:13])=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[OH:1]
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(O)ccc2c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(C(O)c3ccc(OCCN4CCCCC4)cc3)c(O)ccc2c1
Temperature: 25 °C

Procedure:
Dissolve (2-hydroxy-6-methoxy-naphthalen-1-yl)-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (12 g, 29.6 mmol) in tetrahydrofuran (200 Add lithium aluminum hydride (3.0 g, 78.0 mmol) and heat the reaction to reflux. Allow to cool to room temperature and add ice. Adjust the pH of the mixture to 7 with 5 M hydrochloric acid. Dilute with water (500 mL). Wash the mixture four times with dichloromethane (500 mL each wash). Combine the organics, dry over sodium sulfate, decant, and concentrate in vacuo to give 1-{hydroxy-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methyl}-6-methoxy-naphthalen-2-ol.
Reaction SMILES: [C:1]1([O:7][CH2:8][CH2:9][CH2:10]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC(N)=[S:14].[OH-].[K+].Cl>C(O)C.CO>[O:7]([CH2:8][CH2:9][CH2:10][SH:14])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(N)=S
Reactant: BrCCCOc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: SCCCOc1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
160 g of 3-bromopropyl phenyl ether and 63 g of thiourea were dissolved in 300 ml of ethanol and the solution was refluxed with heating for 3 hours. A methanol solution containing 194 g of potassium hydroxide was added to the reaction solution and the mixture was stirred at 50° C. for 2 hours. The mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate followed by distillation under reduced pressure to obtain 76.5 g of 3-phenoxypropanethiol. A boiling point was 135° to 138° C. at 17 mm Hg.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:26])=O)=[CH:19][CH:18]=2)[NH:3]1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[O:1]=[C:2]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C:24]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:26])=[CH:19][CH:18]=2)[NH:3]1
Reactant: Nc1ccccc1
Reactant: O=C(O)Cc1ccc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)cc1
Product: O=C(Cc1ccc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)cc1)Nc1ccccc1

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 300 using 302 (50 mg, 0.14 mmol), and aniline to provide 303. LC-MS (M+H=421, obsd.=421).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:13]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:12][C@H:11]2[C@H:7]([N:8]=[C:9]([CH3:19])[O:10]2)[C@H:6]1[O:20][C:21](=[O:23])[CH3:22])(=[O:3])[CH3:2].[CH2:24]([O:31][C:32](=[O:44])[CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][OH:43])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[CH2:24]([O:31][C:32](=[O:44])[CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][C@H:11]1[C@H:7]([NH:8][C:9](=[O:10])[CH3:19])[C@@H:6]([O:20][C:21](=[O:23])[CH3:22])[C@@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@@H:13]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:12]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(COCCOCCOCCO)OCc1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H]2OC(C)=N[C@@H]2[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@H]1[C@H](OCCOCCOCCOCC(=O)OCc2ccccc2)O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Yield: 96.2 %

Procedure:
The above prepared acetic acid (3aR,5R,6R,7R,7aR)-6-acetoxy-5-acetoxymethyl-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-7-yl ester (10.3 g, 26 mmol) and {2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethoxy}-acetic acid benzyl ester (8.62 g, 29 mmol) were mixed in 520 ml, of CH2Cl2 and treated with 63 g of 4 Angstrom molecular sieves. After 1 h trimethylsilyl triflate (6.13 g, 28 mmol) was added. The reaction mixture was stirred over the weekend at ambient temperature. Triethylamine (5.21 ml, 37 mmol) was added, the molecular sieves filtered off, the filtrate diluted with CH2Cl2 and washed with NaHCO3-solution and water. Drying over Na2SO4 and evaporation of the solvent followed by flash chromatography (SiO2, ethyl acetate/AcOH/MeOH/water=60/3/3/2) afforded 15.7 g of the title compound as a brownish oil. MS (ISP): 626.6 [M−H]−.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[C:35]([CH2:39][NH:40][CH2:41][CH2:42][C:43]#[N:44])[CH:36]=[N:37][CH:38]=2)O1.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C[C]1[C-][CH][CH][CH]1)C.C1[C@H]2CC(PC3[C@H]4C[C@H](CC4)C3)[C@H](C2)C1.[CH]1[CH][CH][CH][CH]1.Cl[Pd+].[Fe].CO>[C:43]([CH2:42][CH2:41][NH:40][CH2:39][C:35]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:14]2[CH2:15][CH2:16][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:18][CH2:19]2)[CH:38]=[N:37][CH:36]=1)#[N:44]
Reactant: CC1(C)OB(c2cncc(CNCCC#N)c2)OC1(C)C
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: Cl[Pd+]
Agent: [Fe]
Agent: C1C[C@@H]2C[C@H]1CC2PC1C[C@@H]2CC[C@H]1C2
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CNCCC#N)c4)cc23)CC1
Yield: 17.4 %

Procedure:
To 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.072 mmol) was added 3-({[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amino)propanenitrile (24.8 mg, 0.086 mmol). To this mixture was added dioxane (0.75 mL), followed by a solution of potassium carbonate (60 mg, 0.434 mmol) in water (0.25 mL) and SK-CC02-A (4.4 mg, 0.007 mmol). The vials were capped and reacted in a CEM microwave at 150° C. for 30 min. The reaction was loaded onto a 2 g SCX SPE cartridge primed with 3 mL of methanol. The cartridge was then sequentially eluted with water (3 mL), methanol (9 mL), and 2M NH3 in MeOH (6 mL). The NH3 in MeOH fractions were dried under a stream of N2 at 40° C. The crude product was purified on the Agilent MDAP with UV (230 nm) and MS detection. The desired fractions were passed thru a 5 g CHQAX cartridge primed with 4 mL of methanol and 4 mL of water. The solvents were evaporated under a stream of N2 at 65° C. to give 6.2 mg of the title compound (17.4%).
Reaction SMILES: [Br:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C@@H:15]([NH:23][S@](C(C)(C)C)=O)[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl>ClCCl.CO>[Br:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C@@H:15]([NH2:23])[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)[S@](=O)N[C@@H](Cc1ccccn1)c1ccccc1-c1noc2cc(Br)ccc12
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: N[C@@H](Cc1ccccn1)c1ccccc1-c1noc2cc(Br)ccc12
Yield: 89.8 %

Procedure:
To a solution of (S)—N-((1S)-1-(2-(6-bromobenzo[d]isoxazol-3-yl)phenyl)-2-(pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (Compound 14a) (1.76 g) dissolved in dichloromethane (10 mL) was added 2N hydrochloric acid (10 mL) and the mixture left to stand at room temperature. The resulting mixture was taken up in methanol and loaded onto a 20 g SCX column and eluted with neat methanol, followed by ammonia-methanol and the fractions containing product were evaporated to give the title product (1.25 g) as a clear yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:32])=[C:4]([CH:29]=[CH:30][CH:31]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:26])[CH2:24]Cl)[CH2:19][CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[I-].[Na+].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[Cl:1][C:2]1[C:3]([F:32])=[C:4]([CH:29]=[CH:30][CH:31]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:26])[CH2:24][N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[CH2:19][CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)CCl)CC1
Reactant: C1COCCN1
Agent: [I-]
Agent: [Na+]
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)CN2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 4-(3-chloro-2-fluoroanilino)-6-[1-(chloroacetyl)piperidin-4-yloxy]-7-methoxyquinazoline (0.15 g) (starting material for Example 17) and sodium iodide (0.02 g) in morpholine (5 ml) was stirred at ambient temperature for 16 hours. The mixture was evaporated under vacuum and the residue dissolved in methylene chloride/methanol. This was adsorbed onto silica and purified by column chromatography on silica eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 90/10). The fractions containing the title product were combined and evaporated under vacuum. The residue was triturated with diethylether, filtered and dried under vacuum to give the title product as a beige crystalline solid (0.105 g); 1H NMR Spectrum: (DMSO d6 and CD3COOD) 1.57-1.80 (m, 2H), 1.91-2.12 (m, 2H), 2.40-2.51 (m, 4H), 3.14-3.48 (m, 4H), 3.52-3.61 (m, 4H), 3.81-3.90 (m, 2H), 3.94 (s, 3H), 4.76 (m, 1H), 7.20-7.30 (m, 2H), 7.42-7.54 (m, 2H), 7.85 (s, 1H), 8.36 (s, 1H); Mass Spectrum: (M+H)+ 530.
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]2[C:9](=[O:19])[C:10]3[C:15]([C:16](=[O:17])[C:6]=2[CH:5]=1)=[C:14]([OH:18])[CH:13]=[CH:12][CH:11]=3)(=[O:3])[CH3:2].C(Cl)Cl.C(N(CC)CC)C.C(O)=O>O.Cl>[OH:3][CH:1]([C:4]1[O:8][C:7]2[C:9](=[O:19])[C:10]3[C:15]([C:16](=[O:17])[C:6]=2[CH:5]=1)=[C:14]([OH:18])[CH:13]=[CH:12][CH:11]=3)[CH3:2]
Reactant: CC(=O)c1cc2c(o1)C(=O)c1cccc(O)c1C2=O
Agent: Cl
Solvent: O=CO
Solvent: O
Solvent: CCN(CC)CC
Product: CC(O)c1cc2c(o1)C(=O)c1cccc(O)c1C2=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.1 %

Procedure:
Into a flask were added 2-acetyl-5-hydroxynaphtho[2,3-b]furan-4,9-dione (128 mg, 0.5 mmol), Ru[(S,S)-Tsdpen](p-cymene) (15 mg, 0.025 mmol, 5 mol %), methylene chloride (5 mL) and formic acid-triethylamine mixture (5:2, 1.3 ml). The resulting suspension mixture was stirred at room temperature for 24 hours, and then diluted with water and 10% aqueous hydrochloric acid solution. The aqueous layer was extracted with chloroform twice, and the extract was washed with water and a saturated aqueous sodium chloride solution sequentially, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=2/1) to give 2-(1-hydroxyethyl)-5-hydroxynaphtho[2,3-b]furan-4,9-dione (NQ801) (115 mg, 89%, 96% ee) as a yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9](=[O:20])[CH:10]3[CH:15]([C:16]=2[O:17]C)[CH:14]2[O:19][CH:11]3[CH2:12][CH2:13]2)=[C:4]([CH3:21])[CH:3]=1.Cl>CC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[C:9](=[O:20])[CH:10]3[CH:15]([CH:14]4[O:19][CH:11]3[CH2:12][CH2:13]4)[C:16]2=[O:17])=[C:4]([CH3:21])[CH:3]=1
Reactant: COC1=C(c2cnc(Cl)cc2C)C(=O)C2C3CCC(O3)C12
Agent: Cl
Solvent: CC(C)=O
Product: Cc1cc(Cl)ncc1C1C(=O)C2C3CCC(O3)C2C1=O
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
To a solution of 4-(6-chloro-4-methyl-pyridin-3-yl)-5-methoxy-10-oxa-tricyclo[5.2.1.0*2,6*]dec-4-en-3-one (119 mg) in acetone (1 ml) in a microwave vial is added 2N HCl (0.6 ml) and the resultant solution is heated to 130° C. by microwave irradiation, with stirring, for 30 minutes. The crude reaction mixture is quenched with sodium hydrogen carbonate until the cessation of effervescence, and the reaction partitioned between ethyl acetate (40 ml) and saturated aqueous ammonium chloride (40 ml). The organic layer is removed, washed with saturated brine solution, dried over magnesium sulphate, filtered, and the solvent is removed from the filtrate under reduced pressure to give 4-(6-chloro-4-methyl-pyridin-3-yl)-10-oxa-tricyclo[5.2.1.0*2,6*]decane-3,5-dione (104 mg).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[C:5]([CH3:14])[CH:4]=1.[C:15]([N:18]1[CH2:22][CH2:21][N:20]=[CH:19]1)(=[O:17])[CH3:16]>>[C:15]([N:18]1[CH2:22][CH2:21][N:20]=[C:19]1[NH:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[C:5]([CH3:14])[CH:4]=1)(=[O:17])[CH3:16]
Reactant: Cc1cc(N)n(-c2ccccc2)n1
Reactant: CC(=O)N1C=NCC1
Agent: Cl
Product: CC(=O)N1CCN=C1Nc1cc(C)nn1-c1ccccc1

Procedure:
5-Amino-3-methyl-1-phenyl pyrazole hydrochloride (37.8 g.) and -1-acetyl-2-imidazoline (27.4 g.) were reacted as described in Example I to give 35.4 g. product. mp 153°-162° (crystallized from CH3CN)
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=O)[C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[OH:19])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl.[NH2:22][OH:23].C([O-])(=O)C.[NH4+]>O>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[N:22][OH:23])[C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[OH:19])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: NO
Reactant: COc1ccc(O)c(C(=O)C2CCN(C(C)=O)CC2)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: O
Product: COc1ccc(O)c(C(=NO)C2CCN(C(C)=O)CC2)c1
Yield: 17.1 %

Procedure:
A solution of 15.5 g of 1-acetyl-4-(2-hydroxy-5-methoxybenzoyl)-piperidine, 7.0 g of hydroxylamine hydrochloride, 9.5 g of ammonium acetate and 75 ml of water was heated under reflux for 20 hrs. The solution was poured into water and extracted with dichloromethane. The dichloromethane extract was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to give an oil. The oil was triturated with hot toluene. The toluene was decanted and the oil was triturated with ether to give a solid. The tolulene triturant, upon standing, yielded a solid. The solids were combined and recrystallized from acetonitrile to yield 2.8 g (17.4%) of product, mp, 191°-193°, as a mixture of E- and Z-isomers. The chromatogram showed 2 spots.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1[O:21][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:19][C:18]=1[CH2:28][CH2:29]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:29][CH2:28][C:18]2[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:21][C:17]=2[CH3:16])=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(NC(=O)OC(C)(C)C)cc1
Reaction time: 16 h
Yield: 79.6 %

Procedure:
To a solution of 5.00 g of (4-hydroxy-phenyl)-carbamic acid tert-butyl ester, 7.28 g of 2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethan-1-ol and 9.40 g of triphenylphosphine in 100 ml of THF was added at 0° C. a solution of 7.25 g of diisopropyl azodicarboxylate in 50 ml of THF over 30 min and stirring was continued at 22° C. for 16 h. A further portion of 1.88 g of triphenylphosphine and 1.45 g of diisopropyl azodicarboxylate in 10 ml of THF was added at 0° C. and stirring was continued at 22° C. for 2 h after which time conversion was complete. The mixture was evaporated and the residue purified by chromatography (SiO2, n-hexane/AcOEt 4:1) to give 7.5 g of the title compound as a colorless solid. MS: (M+H)− 395.4.
Reaction SMILES: C(OC([NH:8][C:9](=[N:51]C(OC(C)(C)C)=O)[NH:10][C:11]1[CH:50]=[CH:49][C:14]([C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH:27][C@H:28]([C:41]([O:43]C(C)(C)C)=[O:42])[CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36]C(C)(C)C)=[CH:32][CH:31]=3)=[O:26])=[C:20]([Cl:48])[CH:19]=2)=[O:16])=[CH:13][CH:12]=1)=O)(C)(C)C.Cl>O1CCOCC1>[ClH:48].[NH:10]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH:27][C@H:28]([C:41]([OH:43])=[O:42])[CH2:29][C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=3)=[O:26])=[C:20]([Cl:48])[CH:19]=2)=[O:16])=[CH:49][CH:50]=1)[C:9]([NH2:51])=[NH:8]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1ccc(C(=O)Oc2ccc(CC(=O)N[C@@H](Cc3ccc(OC(C)(C)C)cc3)C(=O)OC(C)(C)C)c(Cl)c2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: N=C(N)Nc1ccc(C(=O)Oc2ccc(CC(=O)N[C@@H](Cc3ccc(O)cc3)C(=O)O)c(Cl)c2)cc1
Reaction time: 8 h
Yield: 171.9 %

Procedure:
To tert-butyl N-{[4-({4-[N′,N″-bis(tert-butoxycarbonyl)carbamimidamido]benzoyl}oxy)-2-chlorophenyl]acetyl}-O-tert-butyl-L-tyrosinate (210 mg) was added a 4 M solution of hydrogen chloride in dioxane (6.38 mL), followed by stirring overnight. The reaction mixture was concentrated under reduced pressure to obtain N-({4-[(4-carbamimidamidobenzoyl)oxy]-2-chlorophenyl}acetyl)-L-tyrosine hydrochloride (120 mg).