Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][CH2:7][NH:8][CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)([O-:14])=[O:13]>C(Cl)Cl>[CH3:10][CH:9]([N:8]([CH2:7][CH2:6][CH2:5][NH:4][CH:1]([CH3:3])[CH3:2])[S:21]([C:18]1[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:20][CH:19]=1)(=[O:22])=[O:23])[CH3:11]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)NCCCNC(C)C
Solvent: ClCCl
Product: CC(C)NCCCN(C(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 56.8 %

Procedure:
To N,N'-diisopropyl propane-1,3-diamine (23.43 g) in methylene chloride was added p-nitrobenzenesulfonyl chloride (11.08 g, 0.05 mole) dropwise and the reaction stirred 2 hours. The reaction was filtered, stripped, the residue dissolved in diethyl ether, refiltered after washing with water and the contents of the filtrate chromatographed on dry column silica gel with ethyl acetate to provide 9.75 g of clear product as the free base. Preparation of hydrochloride salt gave 8.22 g, m.r. 183°-185° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2([OH:22])[CH:19]3[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]3)[CH2:15]2)=[CH:8][CH:7]=1.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][C:14]2([OH:22])[CH:19]3[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]3)[CH2:15]2)=[CH:10][CH:11]=1
Reactant: [H][H]
Reactant: COCCOc1ccc(C#CC2(O)CN3CCC2CC3)cc1
Agent: [Pd]
Solvent: CCO
Product: COCCOc1ccc(CCC2(O)CN3CCC2CC3)cc1
Yield: 38.4 %

Procedure:
A mixture of 3-[2-{4-(2-methoxyethoxy)phenyl}ethynyl]-quinuclidin-3-ol (1.8 g) in ethanol (200 ml) and a catalyst of 10% (v/v) palladium on carbon (100 mg) was stirred under an atmosphere of hydrogen until hydrogen uptake ceased. The palladium/carbon catalyst was removed by filtration and the filtrate was evaporated. The residue was crystallised from a 3:1 (v/v) mixture of cyclohexane ethylacetate to give 3-[2-{4-(2-methoxyethoxy)phenyl}ethyl]quinuclidin-3-ol (700 mg) as a solid, mpt 116-117° C. Microanalysis, found C,71.1; H,9.2; N,4.5%; C18H27NO3 requires: C,70.8; H,8.9; N,4.59%; NMR ([CD3 ]2SO): 1.15-1.35 (1H, m), 1.4-1.6 (1H, m), 1.65-1.78 (2H, m), 1.9-2.08 (1H, m), 2.45-2.8 (10H, m), 3.3 (3H, s), 3.6-3.68 (2H, m), 4.0-4.08 (2H, m), 4.3 (1H, br), 6.78-6.86 (2H, d), 7.05-7.13 (2H, d); m/z 306 (M+H).
Reaction SMILES: C([C:5]1[S:13][C:8]2=[CH:9][N:10]=[CH:11][CH:12]=[C:7]2[C:6]=1[NH2:14])(OC)=O.[NH:15]1[CH2:20][CH2:19]N[CH2:17][CH2:16]1>CN1CCCC1=O.O>[N:14]1([C:6]2[C:7]3[C:8](=[CH:9][N:10]=[CH:11][CH:12]=3)[S:13][CH:5]=2)[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1
Reactant: COC(=O)c1sc2cnccc2c1N
Reactant: C1CNCCN1
Solvent: O
Solvent: CN1CCCC1=O
Product: c1cc2c(N3CCNCC3)csc2cn1
Temperature: 25 °C

Procedure:
A mixture of 2-carbomethoxy-3-aminothieno[2,3-c]pyridine (5.0 g), and piperazine (4.13 g) in N-methylpyrrolidinone (30 ml) was heated to 150° until decarboxyalkylation was complete. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The residual 3-aminothieno[2,3-c]pyridine, piperazine (12.5 g), p-toluenesulfonic acid (100 mg), and N-methylpyrrolidinone (50 ml) was heated under reflux (202°) overnight. The mixture was allowed to cool to room temperature, diluted with water, and extracted with dichloromethane. The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated in vacuo, finally at 50° (0.1 mm Hg). The residue was chromatographed on silica, using 1:1 dichloromethane:methanol eluent. The appropriate fractions were combined and concentrated. Crystallization of the residue from ethyl acetate provided 0.66 g (12%) of product, mp 126°-127.5° (dried 80° 0.1 mm Hg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].C([O-])(O)=O.[Na+].Br[CH2:16][CH2:17][CH2:18][CH3:19].O>CS(C)=O>[CH2:16]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH2:5][OH:6])[CH:3]=1)[CH2:17][CH2:18][CH3:19]
Reactant: Nc1cccc(CO)c1
Reactant: CCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCNc1cccc(CO)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 3.69 g (30 mmol) of 3-amino benzyl alcohol in 20 ml DMSO was added 3.78 g (45 mmol) solid NaHCO3 and 2.91 ml (27 mmol) 1-bromobutane. The reaction was allowed to stir at 50° C. for 18 hours (overnight). Reaction was worked up by adding 250 ml water and product was extracted in ethyl acetate. Water was added, and the resultant mixture was extracted with EtOAc. The organic layer was washed with water and brine.
Reaction SMILES: [PH:1](=[O:4])([OH:3])[OH:2].[CH2:5]([C:7]([CH2:35][CH3:36])([CH:9](O)[C:10]1[N:14]=[CH:13][N:12]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1)[CH3:8])[CH3:6].C(N(S(F)(F)[F:43])CC)C>ClCCl>[PH:1](=[O:2])([OH:4])[OH:3].[CH2:5]([C:7]([CH2:35][CH3:36])([CH:9]([F:43])[C:10]1[N:14]=[CH:13][N:12]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1)[CH3:8])[CH3:6]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCC(C)(CC)C(O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=[PH](O)O
Solvent: ClCCl
Product: CCC(C)(CC)C(F)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -70 °C
Reaction time: 2 h
Yield: 49.8 %

Procedure:
A solution of diethyl 3-hydroxy-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (1.0 g, prepared as described in Example 24) in dichloromethane (3 ml) was added dropwise with stirring at -70° C. to a solution of diethylaminosulphur trifluoride (0.37 g) in dichloromethane (7 ml). The mixture was stirred at -70° C. for two hours, allowed to warm to room temperature and, after a further one hour, diluted with dichloromethane, washed with water and sodium bicarbonate solution, dried over magnesium sulphate, and evaporated under reduced pressure. The residue was chromatographed on silica, using dichloromethane-ethanol (19:1) as eluant, to give diethyl 3-fluoro-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (0.50 g, m.p. 97°-98° C.). NMR (CDCl3): δ1.3(6H,t), 1.7-2.0(2H,m), 2.1-2.5(2H,m), 4.1(4H,m), 5.5-5.7(1H,m), 7.1-7.3(15H,m), 7.95(1H,s). M/S: M+ 507.
Reaction SMILES: OO.[N+:3]([C:6]1[CH:7]=[N:8][N:9]([C:16]2[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][N:17]=2)[C:10]=1[NH:11][C:12](=[O:15])[CH2:13][CH3:14])([O-:5])=[O:4].FC(F)(F)C(O)=[O:30]>O>[N+:3]([C:6]1[CH:7]=[N:8][N:9]([C:16]2[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][N+:17]=2[O-:30])[C:10]=1[NH:11][C:12](=[O:15])[CH2:13][CH3:14])([O-:5])=[O:4]
Reactant: O=C(O)C(F)(F)F
Reactant: CCC(=O)Nc1c([N+](=O)[O-])cnn1-c1ncc(C(F)(F)F)cc1Cl
Agent: OO
Solvent: O
Product: CCC(=O)Nc1c([N+](=O)[O-])cnn1-c1c(Cl)cc(C(F)(F)F)c[n+]1[O-]
Reaction time: 0.08 h
Yield: 85 %

Procedure:
2.8 g (0.0413 mol) of 50% strength hydrogen peroxide were added to a mixture of 10 g (0.0275 mol) of 4-nitro-5-propionamido-1-(3-chloro-5-trifluoromethyl-2-pyridyl)pyrazole and 100 ml of trifluoroacetic acid at 20° C. with stirring in the course of 5 minutes and it was stirred at 25° C. for 14 hours. The reaction mixture was poured onto 500 ml of water and extracted 3× with methylene chloride. The organic phase was washed with water, sodium hydrogencarbonate and saturated sodium chloride solution in succession and dried over magnesium sulfate. After concentrating under reduced pressure, stirring with ether/pentane, filtering off with suction and drying, 9.0 g (85% of theory) of 4-nitro-5-propionamido-1-(3-chloro-5-trifluoromethyl-(N-oxido)-2-pyridyl)pyrazole of m.p. 143-146° C. were obtained.
Reaction SMILES: S(=O)(=O)(O)O.B(O)(O)O.[N+]([C:13]1[CH:14]=C(S([O-])(=O)=O)C=C[CH:18]=1)([O-])=O.[Na+].[NH2:24][C:25]1[CH:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=1.[OH-].[Na+]>O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2].O.OCC(CO)O>[CH3:31][C:28]1[CH:29]=[CH:30][C:25]2[C:26](=[CH:18][CH:13]=[CH:14][N:24]=2)[N:27]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Reactant: Cc1ccc(N)cn1
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: OCC(O)CO
Solvent: O
Product: Cc1ccc2ncccc2n1
Temperature: 25 °C
Yield: 55.8 %

Procedure:
A mixture of concentrated sulfuric acid (14 mL), boric acid (1.55 g, 39 mmol), sodium m-nitrobenzenesulfonate (11.30 g, 50 mmol), and iron sulfate heptahydrate (0.90 g, 3.23 mmol) was stirred at room temperature. Glycerol (8 mL) was added to the mixture followed by 3-amino-6-picoline (2.79 g, 25 mmol) and water (14 mL). The mixture was heated at 135° C. for 18 h. The reaction mixture was cooled to room temperature, basified using 4 N aqueous sodium hydroxide to pH 8, and extracted with EtOAc (50 mL×3). The organic extracts were combined, concentrated, and the residue was purified by column chromatography to afford 2-methyl-1,5-naphthyridine (2.01 g) as a light brown crystalline solid. MS (ESI): m/z 145 [M+H]+. See, e.g., J. Med. Chem. 2004, 47, 4494-4506.
Reaction SMILES: O[CH:2]1[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:22])[CH3:21].[F:23][C:24]([F:34])([F:33])[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH2:32]>C(OCC)(=O)C.CCCCCC>[F:23][C:24]([F:33])([F:34])[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][CH:2]1[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:17])([CH3:19])[CH3:18])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:21])[CH3:22]
Reactant: Nc1ccccc1OC(F)(F)F
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2Nc1ccccc1OC(F)(F)F
Yield: 73 %

Procedure:
Using N-(3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 235 and (2-(trifluoromethoxy)phenyl)amine, the title compound was synthesized in the same manner as in Example 297. Yield: 73%. Melting point: 196-197° C. (ethyl acetate-hexane).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]3[CH:20]=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:14]2[N:13]=[C:12]([CH:29]2[CH2:34][NH:33][CH:32]([C:35]([O:37][CH3:38])=[O:36])[CH2:31][CH2:30]2)[CH:11]=1>C(#N)C.CO>[NH2:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]3[CH:20]=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:14]2[N:13]=[C:12]([CH:29]2[CH2:34][NH:33][CH:32]([C:35]([O:37][CH3:38])=[O:36])[CH2:31][CH2:30]2)[C:11]=1[Br:1]
Reactant: COC(=O)C1CCC(c2cc(N)n3ncc(-c4cnc5ccccc5c4)c3n2)CN1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: CO
Product: COC(=O)C1CCC(c2nc3c(-c4cnc5ccccc5c4)cnn3c(N)c2Br)CN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.6 %

Procedure:
N-bromosuccinimide (44 mg, 0.249 mmol) was added into a solution of methyl 5-(7-amino-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-2-carboxylate (100 mg, 0.249 mmol) in acetonitrile (1.5 mL) and methanol (0.5 ml). The resulting solution is stirred at room temperature for 1 hour. The reaction was concentrated in vacuo and purified by prep-LC to afford the title compound (22.32 mg): LC/MS RT=2.56 min. Mass calculated for, M+H 481.09, observed 481.09.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[N:15]=[CH:16][C:17]3[CH2:23][NH:22][CH2:21]C[C:18]=3[N:19]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:24](=[O:29])([O:27][CH3:28])OC.C(N(C(C)C)CC)(C)C>C1COCC1.CCOC(C)=O>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([NH:13][C:14]2[N:19]=[CH:18][C:17]3[CH2:23][N:22]([C:24]([O:27][CH3:28])=[O:29])[CH2:21][C:16]=3[N:15]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(Nc2ncc3c(n2)CCNC3)cc(OC)c1OC
Reactant: COC(=O)OC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1Cc2cnc(Nc3cc(OC)c(OC)c(OC)c3)nc2C1
Temperature: 60 °C
Reaction time: 5 h
Yield: 64 %

Procedure:
A solution of N-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine, Intermediate 1 (0.020 g, 0.063 mmol) in anhydrous THF (2.0 mL) was treated sequentially with dimethyl carbonate (0.006 g, 0.063 mmol) and diisopropylethylamine (0.025 mL, 0.095 mmol). The reaction was heated to 60° C. and allowed to stir for 5 hours. The reaction was cooled to room temperature, then diluted with EtOAc and washed three times with brine. The combined aqueous layers were then washed twice with EtOAc. The organic layers were combined, dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The crude product was then purified over silica using a EtOAc/Hexanes gradient affording the final product in 64% yield (0.015 g, 0.040 mmol).
Reaction SMILES: [CH2:1]([N:4]([CH3:26])[CH2:5]/[CH:6]=[CH:7]/[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:24])[CH2:17][CH:18](O)[CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:12][C:11]=1[F:25])[CH:2]=[CH2:3].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([N:4]([CH3:26])[CH2:5]/[CH:6]=[CH:7]/[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:24])/[CH:17]=[CH:18]/[CH:19]=[C:20]([CH3:21])[CH3:22])=[CH:12][C:11]=1[F:25])[CH:2]=[CH2:3]
Reactant: C=CCN(C)C/C=C/COc1ccc(C(=O)CC(O)C=C(C)C)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=CCN(C)C/C=C/COc1ccc(C(=O)/C=C/C=C(C)C)cc1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 71.1 %

Procedure:
A solution of 4.1 g of (E)-(RS)-1-[4-[4-(allyl-methyl-amino)-but-2-enyloxy]-3-fluoro-phenyl]-3-hydroxy-5-methyl-hex-4-en-1-one (Ex. 21) in 280 ml of toluene is added to 2.6 g of p-toluenesulphonic acid and stirred at room temperature for 2.5 hrs. The reaction mixture is concentrated, the residue is dissolved in methylene chloride, extracted with saturated sodium bicarbonate solution, dried and the residue is concentrated and purified over silica gel with 97.5% methylene chloride/methanol. The free amine is dissolved in methylene chloride/methanol with 0.75 g of fumaric acid, evaporated and recrystallized from ethyl acetate/methanol/ether. There are obtained 2.77 g of (E)-1-[4-[(E)-4-(allyl-methyl-amino)-but-2-enyloxy]-3-fluoro-phenyl]-5-methyl-hexa-2,4-dien-1-one.fumarate (1:1), MS: m/e 344 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][C:4](=[S:7])[N:3]1[CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[O:28][C:27]([CH:29]=O)=[CH:26][CH:25]=1.C(O)(=O)C.C(O)(=O)C.C(N)CN.C(OCC)(=O)C>C(O)C>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[O:28][C:27]([CH:29]=[C:6]2[S:5][C:4](=[S:7])[N:3]([CH:8]3[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]3)[C:2]2=[O:1])=[CH:26][CH:25]=1
Reactant: O=C(O)C1CCCC(N2C(=O)CSC2=S)C1
Reactant: O=Cc1ccc(-c2ccccc2Cl)o1
Solvent: CCOC(C)=O
Solvent: NCCN
Solvent: CCO
Product: O=C(O)C1CCCC(N2C(=O)C(=Cc3ccc(-c4ccccc4Cl)o3)SC2=S)C1
Temperature: 60 °C
Yield: 65.5 %

Procedure:
A mixture of 3-(4-oxo-2-thioxo-thiazolidin-3-yl)-cyclohexanecarboxylic acid (0.038 g, 0.15 mmol), 5-(2-chloro-phenyl)-furan-2-carbaldehyde (0.033 g, 0.16 mmol) (purchased from Aldrich Chemical Company) and ethylenediamine diacetate (0.029 g, 0.16 mmol) in ethanol (5 mL) was heated to 60° C. for 4 h. The mixture was poured into ethyl acetate (250 mL) and washed with 0.6 N aq sodium hydrogensulfite (2×50 mL). The organic layer was isolated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was triturated with a mixture of ether (1 mL) and hexanes (3 mL). The product was filtered off and dried in a vacuum oven at 60° C. for 17 h to afford 3-{5-[1-[5-(2-chloro-phenyl)-furan-2-yl]-methylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-cyclohexanecarboxylic acid as a solid (44 mg, 67%). H NMR (400 MHz, DMSO-d6): δ 1.25-1.31 (1H, m), 1.34-1.41 (1H, m), 1.69 (1H, m), 1.90 (3H, m), 2.28-2.45 (3H, m), 4.95 (1H, m), 7.40 (1H, d, J=3.6), 7.43 (1H, d, J=3.6), 7.46 (1H, m), 7.62 (1H, s), 7.62 (2H, m), 7.92 (1H, m), 12.22 (1H s). LC/MS: APCI 447.33, HPLC 100%.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([NH:6][C@H:7]([C:15]([NH:17][C@H:18]([C:23]([O:25]CC1C=CC=CC=1)=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2]>CO.[C].[Pd]>[CH2:1]([O:3][P:4]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)([NH:6][C@H:7]([C:15]([NH:17][C@H:18]([C:23]([OH:25])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOP(=O)(Cc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(Cc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)O
Reaction time: 1.5 h

Procedure:
A solution of the ester product from part (b) in methanol is treated with 10% palladium-carbon catalyst and hydrogenated in a Parr apparatus at an initial pressure of 45 psi. for 1.5 hours. The mixture is filtered through Celite and evaporated to dryness to give N-[N-[ethoxy(phenylmethyl)phosphinyl]-L-phenylalanyl]-L-leucine.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[C:12]([C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])=C[C:5]2=[N:4][N:3]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.I([O-])(=O)(=O)=[O:23].[Na+]>[Ru](=O)=O>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:13](=[O:23])[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]1[CH:5]=[N:4][N:3]=[C:2]1[CH3:1]
Reactant: Cc1nnc2cc(-c3ccccc3Cl)c3ccccc3n12
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru]=O
Agent: [Na+]
Product: Cc1nncn1-c1ccccc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 3, 1-methyl-5-(o-chlorophenyl)-s-triazolo[4,3-a]quinoline is oxidized at low temperature with sodium periodate and ruthenium dioxide to give 2'-chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][NH:3][C:2]1=[C:6](C(OCC)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl-].[Na+]>CS(C)=O.O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(C(=O)OCC)=C1NC=CS1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)Cc1nccs1

Procedure:
A solution of the product of Example 44B (2.8 g, 11.5 mmoles), sodium chloride (1.3 g, 22.9 mmoles) and water (0.4 ml, 22.9 mmoles) in dimethyl sulfoxide (48.0 ml) was stirred at about 180° C. for about 30 min. The mixture was cooled, diluted with water (100.0 ml) and was extracted twice with (1:1) ethyl acetate/diethyl ether (80.0 ml each). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuum. The crude product was purified by flash column chromatography on silica gel using hexanes/ethyl acetate (2:1) as the mobile phase to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH:6]2[CH2:7][CH2:8][C@@:3]1([CH2:10][S:11]([N:14]1[CH2:19][CH2:18][C:17]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20]3)[CH2:16][CH2:15]1)(=[O:13])=[O:12])[C:4](=O)[CH2:5]2.Cl.[NH2:30][OH:31].O>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:28])[CH:6]2[CH2:7][CH2:8][C@@:3]1([CH2:10][S:11]([N:14]1[CH2:19][CH2:18][C:17]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20]3)[CH2:16][CH2:15]1)(=[O:13])=[O:12])[C:4](=[N:30][OH:31])[CH2:5]2
Reactant: CC1(C)C2CC[C@@]1(CS(=O)(=O)N1CCC3(C=Cc4ccccc43)CC1)C(=O)C2
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC1(C)C2CC[C@@]1(CS(=O)(=O)N1CCC3(C=Cc4ccccc43)CC1)C(=NO)C2
Reaction time: 2 h
Yield: 90.1 %

Procedure:
(1S)-1'-(((7,7-dimethyl-2-oxobicyclo(2.2.1) hept-1-yl)methyl)sulfonyl)spiro(1H-indene-1,4'-piperidine) (30 g, 0.075 mole) in pyridine (500 mL) was heated in an oil bath to 70° C. (internal). Hydroxylamine hydrochloride (30 g) was added in three portions over ca. 20 minutes. After 2 hours, an additional 10 g of hydroxylamine hydrochloride was added (over 10 minutes). At 30, 40, and 50 minutes additional elapsed time, further 3 g lots of hydroxylamine hydrochloride were added. After another 30 minutes, the mixture was poured into water (2 L) and extracted 3 times with ethyl acetate (300 mL portions). The organic layers were combined, washed with 1N HCl (600 mL total), dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. EtOH (abs; ca. 250 mL) was added to the resulting thick syrup and the solution allowed to stand at ambient temperature overnight. The mixture was filtered and the filtrate boiled down to ca. 80 mL. After standing, the mixture was again filtered and boiled down to ca. 20 mL. After a third filtration, the filtered solids were combined to give (1S)-1'-(((7, 7-dimethyl-2-oximinobicyclo(2.2.1)hept-1yl)-methyl) sulfonyl)spiro(1H-indene-1,4'-piperidine) (28 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl.[Br:30]Br>C(Cl)Cl>[Br:30][CH:9]([C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=1)[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:20]
Reactant: BrBr
Reactant: CS(=O)(=O)c1ccc(CC(=O)c2ccc(F)cc2)cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1

Procedure:
To 1-(4-Fluorophenyl)-2-(4-(methylsulfonyl)phenyl)ethanone (1.00 g) in CH2Cl2 containing CHCl3 (1.0 mL) and CCl4 (1.0 mL) was added bromine (0.614 g). After shining light for 1 h, the reaction was quenched with Na2S2O4, extracted with CH2Cl2, dried over Na2SO4 and evaporated to yield the title compound which was used as such for the next step (1.10 g).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[C:4]([F:14])[CH:3]=1.[CH3:15][Mg]Br.[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](=[O:7])[CH3:15])=[C:4]([F:14])[CH:3]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc(Br)cc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 4-bromo-2-fluoro-N-methoxy-N-methylbenzamide (13 g) in THF (4.0 mL) was added dropwise methylmagnesium bromide (3M ethylether solution, 30 mL) at 0° C., and the mixture was stirred at room temperature for 3 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (10 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:21]3[CH:22]=[N:23][C:24]([NH2:38])=[C:25]([O:26][C@@H:27]([C:29]4[C:34]([Cl:35])=[CH:33][CH:32]=[C:31]([F:36])[C:30]=4[Cl:37])[CH3:28])[C:20]=3[O:19][CH:18]=2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.CCOCC>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:21]3[CH:22]=[N:23][C:24]([NH2:38])=[C:25]([O:26][C@@H:27]([C:29]4[C:34]([Cl:35])=[CH:33][CH:32]=[C:31]([F:36])[C:30]=4[Cl:37])[CH3:28])[C:20]=3[O:19][CH:18]=2)=[O:16])[CH2:10][CH2:9]1
Reactant: C[C@@H](Oc1c(N)ncc2c(C(=O)NC3CCN(C(=O)OC(C)(C)C)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@@H](Oc1c(N)ncc2c(C(=O)NC3CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-({6-amino-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]furo[3,2-c]pyridine-3-carbonyl}-amino)-piperidine-1-carboxylic acid tert-butyl ester (6.0 mg, 0.01 mmol) in DCM (0.2 mL) was added 1M HCl in Et2O (0.5 mL). The resulting mixture was stirred at rt overnight. LC-MS showed the reaction was complete and gave the desired product. Evaporation under reduced gave the title compound as a white solid. LC-MS (ES+): 467.00/469.04 [MH+].