Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:8][C:9]1[C:10]([CH3:29])=[C:11]([CH3:28])[C:12]2[O:16][C:15]([CH3:18])([CH3:17])[CH:14]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:13]=2[C:26]=1[CH3:27])C1C=CC=CC=1.C1(C)C=CC=CC=1.C(O)(C)C>[Pd].[C].O>[CH3:17][C:15]1([CH3:18])[CH:14]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)[C:13]2[C:26]([CH3:27])=[C:9]([NH2:8])[C:10]([CH3:29])=[C:11]([CH3:28])[C:12]=2[O:16]1
Reactant: Cc1ccc(C2c3c(C)c(NCc4ccccc4)c(C)c(C)c3OC2(C)C)cc1
Agent: [Pd]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(C2c3c(C)c(N)c(C)c(C)c3OC2(C)C)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
To a mixture of N-benzyl-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine (80 g), toluene (240 mL) and isopropanol (80 mL) was added 10% Pd-carbon (a product containing 50% water, 4 g), and the mixture was hydrogenated at 35° C. under atmospheric pressure. After completion of the reaction, the catalyst was filtered. Concentrated hydrochloric acid (19.2 mL) was added to the filtrate and the mixture was stirred at 10° C. or below for 1 hour. Precipitated crystals were filtered. The crystals were added to a mixture of methanol (560 mL) and water (80 mL) and the mixture was heated to 50° C. to dissolve the crystals. Then, 25% aqueous ammonia water was added dropwise to the solution to adjust to pH 8.5. Precipitated crystals were filtered to obtain the title compound (54.32 g, 88.6%).
Reaction SMILES: C(SC1C=C(O)C(=O)NC=1)C1C=CC=CC=1.COC[O:20][C:21]1[C:22](=[O:42])[N:23](COC)[CH:24]=[C:25]([S:27][CH2:28][C:29]2[CH:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=2)[CH:26]=1>>[OH:20][C:21]1[C:22](=[O:42])[NH:23][CH:24]=[C:25]([S:27][CH2:28][C:29]2[CH:30]=[N:31][C:32]([C:35]([F:36])([F:38])[F:37])=[CH:33][CH:34]=2)[CH:26]=1
Reactant: COCOc1cc(SCc2ccc(C(F)(F)F)nc2)cn(COC)c1=O
Agent: O=c1[nH]cc(SCc2ccccc2)cc1O
Product: O=c1[nH]cc(SCc2ccc(C(F)(F)F)nc2)cc1O

Procedure:
Prepared as described for 5-(benzylsulfanyl)-3-hydroxypyridin-2(1H)-one (Example 12) from 3-(methoxymethoxy)-1-(methoxymethyl)-5-({[6-(trifluoromethyl)pyridin-3-yl]methyl}sulfanyl)pyridin-2(1H)-one (Intermediate 18).
Reaction SMILES: Br.[Br:2]/[C:3](/[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18]C)[N:12]=1)=[CH:4]\[C@@H:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1.O>O1CCOCC1>[Br:2]/[C:3](/[C:11]1[NH:12][C:13](=[O:18])[C:14]([Cl:17])=[CH:15][CH:16]=1)=[CH:4]\[C@H:5]1[CH2:6][CH2:7][C:8](=[O:10])[NH:9]1
Reactant: COc1nc(/C(Br)=C/[C@H]2CCC(=O)N2)ccc1Cl
Agent: Br
Solvent: O
Solvent: C1COCCO1
Product: O=C1CC[C@H](/C=C(\Br)c2ccc(Cl)c(=O)[nH]2)N1
Temperature: 65 °C
Reaction time: 1 h
Yield: 36.3 %

Procedure:
48% hydrobromic acid (2 mL) was added to a solution of (5R)-5-[(Z)-2-bromo-2-(5-chloro-6-methoxypyridin-2-yl)ethenyl]pyrrolidin-2-one (115 mg) in 1,4-dioxane (3 mL), and the mixture was stirred at 65° C. for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=10:0→4:1) to give the title compound as a colorless powder (40 mg, 37%).
Reaction SMILES: [NH2:1][C:2]([CH3:9])([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]#[N:4].Cl[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+].Cl.N([O-])=O.[Na+]>O.CO>[N:1]([C:2]([CH3:9])([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]#[N:4])=[N:1][C:2]([CH3:9])([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]#[N:4]
Reactant: CC(C)CC(C)(N)C#N
Agent: Cl
Agent: O=N[O-]
Agent: O=S([O-])([O-])=S
Solvent: CO
Solvent: O
Product: CC(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)C
Temperature: 10 °C
Reaction time: 0.17 h

Procedure:
To a solution of 63.2 parts of 2-amino-2,4-dimethylpentanonitrile in 592 parts of methanol are added over a 20 minute period at -10°C. with agitation 377 parts of a 15% aqueous sodium hypochlorite solution. The reaction was then allowed to warm to 10°C. and held for 10 minutes. At this point methanol constitutes 74 volume percent of the aqueous solvent. The resulting reaction product was diluted with 500 parts of water and titrated with standard sodium thiosulfate as described in Example 1. About 0.015 equivalent of oxidizing agent was present. The resulting slurry was then acidified to a pH of 1.0 with 15% hydrochloric acid and 0.52 gram of sodium nitrite (0.015 equivalent) were stirred into the mixture. The precipitated 2,2'-azobis (2,4-dimethylvaleronitrile) was isolated by filtration and found to be non-oily, white and dry with a purity of 98%.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.O.[NH2:13]N.O>COCCOCCO>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([NH:11][NH2:13])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: Nc1nc2c(Cl)cccc2s1
Solvent: COCCOCCO
Solvent: O
Product: NNc1nc2c(Cl)cccc2s1
Temperature: 110 °C
Reaction time: 22 h
Yield: 78 %

Procedure:
4-Chloro-2-aminobenzothiazole (2.0 g.; 0.0108 mole) was dissolved in 10 milliliters of diethylene glycol monomethyl ether and 0.9 milliliter of concentrated HC1 added with stirring. 85% Hydrazine hydrate (1.92 g.) was then added to the mixture, and the reaction mixture was heated to 110°C., under N2 atmosphere, on an oil bath. The reaction was continued for 22 hours, the final reaction temperature being 120°C. The 4-chloro-2-hydrazinobenzothiazole product was isolated by addition of water and separated by filtration, 1.69 g. (78% yield), m.p. 232°-235°C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:20][C@H:19]2[C@H:11]([C:12](=[O:22])[C:13]3[C:18]2=[CH:17][CH:16]=[CH:15][C:14]=3Br)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1B(O)O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH2:1]([N:8]1[CH2:20][C@H:19]2[C@H:11]([C:12](=[O:22])[C:13]3[C:18]2=[CH:17][CH:16]=[CH:15][C:14]=3[C:27]2[CH:26]=[CH:25][C:24]([Cl:23])=[CH:29][C:28]=2[Cl:30])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: O=C1c2c(Br)cccc2[C@H]2CN(Cc3ccccc3)CC[C@@H]12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Ba+2]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2c(-c3ccc(Cl)cc3Cl)cccc2[C@H]2CN(Cc3ccccc3)CC[C@@H]12
Yield: 41.2 %

Procedure:
The title compound (90 mg, 0.21 mmol) was prepared by following the procedure of example 3 from cis-3-benzyl-8-bromo-1,2,3,4,4a,9a-hexahydro-3-aza-fluoren-9-one (172 mg, 0.51 mmol), 2,4-dichlorophenylboronic acid (153 mg, 0.80 mmol), barium hydroxide octahydrate (317 mg, 1.0 mmol) and triphenylphosphine (18 mg, 0.067 mmol) and palladium(II) acetate (3.8 mg, 0.017 mmol) in DMF (6.0 mL)/H2O (1.2 mL): MS (ES) 422.1 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[NH:10][CH2:11][C:12]1[C:23](=[O:24])[N:22]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:15]2[N:16]=[C:17]([S:20][CH3:21])[N:18]=[CH:19][C:14]=2[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:38])C=CC=CC=1>ClCCl>[CH2:1]([O:8][C:9](=[O:30])[NH:10][CH2:11][C:12]1[C:23](=[O:24])[N:22]([CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[C:15]2[N:16]=[C:17]([S:20]([CH3:21])=[O:38])[N:18]=[CH:19][C:14]=2[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CSc1ncc2cc(CNC(=O)OCc3ccccc3)c(=O)n(C3CCCC3)c2n1
Solvent: ClCCl
Product: CS(=O)c1ncc2cc(CNC(=O)OCc3ccccc3)c(=O)n(C3CCCC3)c2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.6 %

Procedure:
(8-Cyclopentyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-ylmethyl)-carbamic acid benzyl ester (1.67 g, 3.93 mmol) and 2-benzenesulfonyl-3-phenyl-oxaziridine (1.34 g, 5.11 mmol) were dissolved in dichloromethane (20 mL) and stirred at ambient temperature for 12 hours. The reaction mixture was then purified by silica gel chromatography to give (8-cyclopentyl-2-methanesulfinyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-ylmethyl)-carbamic acid benzyl ester as a white solid (0.98 g, 56.6%). 1H NMR δ (400 MHz, CDCl3) 8.89 (s, 1H), 7.68 (s, 1H), 7.32 (m, 5H), 5.96 (m, 1H), 5.52 (t, J=6.4 Hz, 1H), 5.09 (s, 2H), 4.32 (d, J=6.3 Hz, 2H), 2.95 (s, 3H), 2.22 (m, 2H), 2.12 (m, 2H), 1.95 (m, 2H), 1.69 (m, 2H).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][C:23]([F:26])([F:25])[F:24])[N:7]=1)(=[O:4])=[O:3].C1N=CN([C:32](N2C=NC=C2)=[O:33])C=1>CO.[Pd]>[CH3:1][S:2]([O:5][C:6]1[N:7]=[C:8]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][C:23]([F:26])([F:25])[F:24])[C:32]([OH:33])=[N:12][C:9]2=[CH:10][CH:11]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Oc1ccc([N+](=O)[O-])c(Nc2ccccc2OC(F)(F)F)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)Oc1ccc2nc(O)n(-c3ccccc3OC(F)(F)F)c2n1
Reaction time: 2 h
Yield: 61.7 %

Procedure:
5-Nitro-6-(2-(trifluoromethoxy)phenylamino)pyridin-2-yl methanesulfonate (1.8 g, 4.58 mmol) was dissolved in MeOH (45 mL) and catalytic amount of 10% Pd/C was added. The reaction flask was purged with nitrogen and placed under an atmosphere of hydrogen for 2 h. The reaction mixture was filtered through Celite® and the solvent was removed under reduced pressure. The residue was immediately dissolved in THF (35 mL) and CDI (1.8 g, 11.0 mmol) added. The mixture was stirred overnight and concentrated under reduced pressure. The residue was added EtOAc, washed with water and 1 M HCl, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (1.1 g). LCMS m/z=390.3 [M+H]+.
Reaction SMILES: [C:1](O)(C(F)(F)F)=[O:2].[CH2:8]([N:10]([CH2:36][CH3:37])[C:11]([C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:27]3[CH2:33][CH:32]4[N:34](C)[CH:29]([CH2:30][CH2:31]4)[CH2:28]3)[C:18]3[C:23]([O:24][C:25]=2[CH:26]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:12])[CH3:9].ClC(OC(Cl)C)=O>C(Cl)Cl>[CH2:8]([N:10]([CH2:36][CH3:37])[C:11]([C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:27]3[CH2:33][CH:32]4[NH:34][CH:29]([CH2:30][CH2:31]4)[CH2:28]3)[C:18]3[C:23]([O:24][C:25]=2[CH:26]=1)=[C:22]([O:2][CH3:1])[CH:21]=[CH:20][CH:19]=3)=[O:12])[CH3:9]
Reactant: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccccc1N2C1CC2CCC(C1)N2C
Reactant: O=C(O)C(F)(F)F
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc2c(c1)Oc1c(OC)cccc1N2C1CC2CCC(C1)N2
Yield: 44.8 %

Procedure:
To a solution of the TFA salt of 10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic acid diethylamide, 4e (110 mg, 0.25 mmol) in methylene chloride (10 mL) was added 1-chloroethyl chloroformate (0.58 mL, 0.75 mmol). The mixture was heated to reflux for 2 h. The mixture was evaporated, dissolved in methanol (5 mL), and heated for 2 h at reflux. Water was added, and the solution was extracted with methylene chloride. The organic phase was separated, evaporated, and purified via reverse phase HPLC to yield 69 mg (44.8%) of title compound 10-(8-aza-bicyclo[3.2.1]oct-3-yl)-6-methoxy-10H-phenoxazine-3-carboxylic acid diethylamide, 5e, as a TFA salt. MS m/z=422 (M+1).
Reaction SMILES: O[C@H:2]([C:22]1[CH:23]=[CH:24][C:25]2[O:30][C@H:29]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[CH:41]=4)=[CH:34][CH:33]=3)[CH:28]=[CH:27][C:26]=2[CH:47]=1)[C@H:3]([O:19][CH2:20][CH3:21])[C:4]([N:6]1[C@@H:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][O:8][C:7]1=[O:18])=[O:5].C([SiH](CC)CC)C>FC(F)(F)C(O)=O.CCOCC>[CH2:20]([O:19][C@H:3]([C:4]([N:6]1[C@@H:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][O:8][C:7]1=[O:18])=[O:5])[CH2:2][C:22]1[CH:23]=[CH:24][C:25]2[O:30][C@H:29]([CH2:31][C:32]3[CH:33]=[CH:34][C:35]([O:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[CH:41]=4)=[CH:36][CH:37]=3)[CH:28]=[CH:27][C:26]=2[CH:47]=1)[CH3:21]
Reactant: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc2c(c1)C=C[C@@H](Cc1ccc(OCc3cccc(F)c3)cc1)O2
Agent: CC[SiH](CC)CC
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CCO[C@@H](Cc1ccc2c(c1)C=C[C@@H](Cc1ccc(OCc3cccc(F)c3)cc1)O2)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Yield: 48.3 %

Procedure:
(R)-6-{(1R, 2S)-1-Hydroxy-2-ethoxy-3-[(S)-4-benzyl-2-oxo-3-oxazolidinyl]-3-oxopropyl}-2-[4-(3-fluorobenzyloxy)benzyl]-2H-benzopyran (80 mg, 0.13 mmol) was dissolved in trifluoroacetic acid (2 ml) and triethylsilane (0.20 ml) was added. After 30 minutes the solution was diluted with ether, washed with water (2×) and saturated sodium bicarbonate (2×), dried over magnesium sulfate and concentrated. The product was purified by flash chromatography (hexanes/ethyl acetate, 2:1) and obtained as an oil (39 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH:12]=[N:11][C:10]([OH:13])=[N:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[P:20](=[S:28])(Cl)([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23]>C(#N)C>[P:20](=[S:28])([O:13][C:10]1[N:11]=[CH:12][N:8]([C:5]2[N:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1)([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23]
Reactant: Oc1ncn(-c2ccc(Cl)nn2)n1
Reactant: CCOP(=S)(Cl)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOP(=S)(OCC)Oc1ncn(-c2ccc(Cl)nn2)n1
Temperature: 70 °C
Yield: 38.5 %

Procedure:
Into a 500-ml three-necked flask equipped with a stirrer and reflux condenser were placed 6.5 g (0.033 m) of 1-(6-chloro-3-pyridazinyl)-1H-1,2,4-triazol-3-ol, 5 g (0.033 m) of potassium carbonate, 0.5 g of mercuric chloride and 100 mls of acetonitrile. The mixture was stirred and heated to 70° C. for one hour and cooled. To this mixture was added 5.6 g (0.03 m) of O,O-diethyl phosphorochloridothioate and the mixture was heated at 60° C. for 6 hours and cooled. The insolubles which formed were removed by filtration and the solvent was then removed by evaporation at 60° C. under reduced pressure. The oil which remained was taken up in 250 mls of methylene chloride sequentially washed with 200 mls of water, 200 mls of a 2 percent sodium hydroxide solution and 200 mls of water and then separated, dried over anhydrous sodium sulfate, filtered and the solvent removed by evaporation under reduced pressure leaving 4 grams of an oil product. The O,O-diethyl O-(1-(6-chloro-3-pyridazinyl)-1H-1,2,4-triazol-3-yl) phosphorothioate product was crystallized from warm hexane in a yield of 1.7 grams (15 percent of theoretical). The product melted at 46°-49° C. NMR (60 MHz) (CDCl3, δ): 9.00 (s,1H); 8.18 (d, J=10.0 1H); 7.00 (d, J=10.0 1H); 4.35 (d of q, J=10.5, 6.5, 4H); 1.43 (t w/fine coupling, J=6.5, 6H). (Compound 5).
Reaction SMILES: [O-:1][N+:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[N:12]3[C@@H:18]([CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17][O:16][CH2:15][C:13]3=[N:14][C:4]=2[CH:3]=1.[NH4+:30].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C(Cl)Cl>[NH4+:2].[OH-:1].[NH2:30][C:3]1[C:4]2[N:14]=[C:13]3[CH2:15][O:16][CH2:17][C@H:18]([CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[N:12]3[C:5]=2[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:2]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@H]1COCc2nc3c[n+]([O-])c4ccccc4c3n21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NCCC[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Reaction time: 2 h

Procedure:
tert-Butyl 3-[(11S)-5-oxido-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]propylcarbamate (850 mg, 2.15 mmol) was dissolved in 25 mL of CH2Cl2 and treated with 3 mL of concentrated NH4OH solution. The mixture was stirred rapidly and then p-toluenesulfonyl chloride (451 mg, 2.37 mmol) was carefully added. Rapid stirring was continued for 2 hours. The reaction mixture was treated with 25 mL of CH2Cl2 and 25 mL of H2O. The layers were separated and the organic portion was washed with 2% Na2CO3 solution (3×25 mL), H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 4% methanol/CHCl3 with 0.4% concentrated NH4OH) gave tert-butyl 3-[(11S)-6-amino-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]propylcarbamate (734 mg) as an off-white foam.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[H-].C([Al+]CC(C)C)C(C)C.CO.Cl>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: OCc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 20.0 (0.105 mole) portion of 2,3-dichlorobenzoic acid in 100 ml of toluene was treated with 254 ml (0.315 mole) of diisobutylaluminum hydride (25% in hexane), under a stream of dry nitrogen, at 15°-20° over 0.5 hours using rapid stirring. The reaction mixture was allowed to warm to room temperature over 0.5 hours, heated to reflux over 0.5 hours, refluxed for 1.5 hours, allowed to cool slowly to room temperature, and stored overnight at room temperature. The reaction mixture was then treated with a solution of 100 ml of methanol in 100 ml of water at 10°-15°, followed by 100 ml of concentrated hydrochloric acid at 20°-25°, and 165 ml of water. The organic layer was separated, washed with 50 ml of 5% sodium bicarbonate, 50 ml of water, dried over magnesium sulfate overnight and filtered. The filtrate was concentrated to dryness to given 17.0 g (91%) of a light tan solid, m.p. 81°-84°.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([S:7]([NH:10][C@@H:11]([CH2:15][NH2:16])[C:12]([OH:14])=[O:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:18][C:19](=[CH2:21])[CH3:20].OS(O)(=O)=O>O1CCOCC1.C(OCC)(=O)C>[C:19]([C@:11]([NH:10][S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:17])=[CH:6][CH:5]=1)(=[O:8])=[O:9])([CH2:15][NH2:16])[C:12]([OH:14])=[O:13])([CH3:21])([CH3:20])[CH3:18]
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](CN)C(=O)O)cc1
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)N[C@@](CN)(C(=O)O)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
Acid 14-3 (5.0 g, 19.4 mmol) was suspended in dioxane (100 ml) in a 1-L pressure bottle. The bottle was cooled to -15° and isobutylene (100 ml) was condenced into the dioxane. Concentrated H2SO4 (5 ml) was added and the bottle sealed and stirred at room temperature for 36 h. The bottle was opened and the excess isobutylene carefully vented. The solution was diluted with ethyl acetate (200 ml) and washed with 1N NaOH (200 ml). The organic layer was dried (Na2SO4), filtered and evaporated to give 14-4 as a white crystaline solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].[C:14]([O:18][C:19](ON=C(C1C=CC=CC=1)C#N)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C>O.O1CCOCC1>[C:14]([O:18][C:19]([NH:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NC1CCc2ccccc2NC1=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCc2ccccc2NC1=O

Procedure:
A solution of 3-amino-2,3,4,5-tetrahydro-1H[1]benzazepin-2-one (4.0 g), 2-t-butyloxycarbonyloxyimino-2-phenylacetonitrile (6.1 g) and triethylamine (5 ml) in water (20 ml) and dioxane (25 ml) was stirred at room temperature for 18 hours. The resulting solid was filtered off and washed with water. Recrystallization from ethyl acetate gave 3-t-butyloxycarbonylamino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one, m.p. 199°-201°.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[C:12]2[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=3[F:23])=[CH:10][CH:9]=[N:8][C:7]=2[N:6](S(C2C=CC(C)=CC=2)(=O)=O)[CH:5]=1.O.C(OCC)(=O)C>C(O)C>[F:3][C:4]1[C:12]2[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=3[F:23])=[CH:10][CH:9]=[N:8][C:7]=2[NH:6][CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(F)c3c(Nc4ccc([N+](=O)[O-])cc4F)ccnc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(Nc2ccnc3[nH]cc(F)c23)c(F)c1
Reaction time: 8 h

Procedure:
0.4 ml of a 20% strength aqueous sodium hydroxide solution is added to a solution of 80 mg (0.18 mmol) of 3-fluoro-N-(2-fluoro-4-nitrophenyl)-1-[(4-methylphenyl)-sulfonyl]-1H-pyrrolo[2,3-b]pyridine-4-amine in 5 ml of ethanol, and the mixture is stirred overnight. The reaction solution is then poured into a mixture of water and ethyl acetate, and the aqueous phase is extracted two more times with ethyl acetate. Purification by preparative HPLC gives the target compound.
Reaction SMILES: Cl[CH2:2][O:3][CH2:4][CH2:5][Si:6]([CH3:9])([CH3:8])[CH3:7].[OH-].[Na+].[Br:12][C:13]1[CH:14]=[C:15]2[N:21]=[CH:20][NH:19][C:16]2=[N:17][CH:18]=1.C(OC(=O)C)C>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl.CCCCCC>[Br:12][C:13]1[CH:14]=[C:15]2[N:21]=[CH:20][N:19]([CH2:2][O:3][CH2:4][CH2:5][Si:6]([CH3:9])([CH3:8])[CH3:7])[C:16]2=[N:17][CH:18]=1
Reactant: Brc1cnc2[nH]cnc2c1
Reactant: C[Si](C)(C)CCOCCl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cnc2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 14.4 %

Procedure:
(2-Chloromethoxy-ethyl)-trimethyl-silane (508.6 mg, 3.0456 mmol), catalytic amount of benzyl triethyl-ammonium chloride and NaOH (203.04 mg, 5.076 mmol) were added to a solution of 6-bromo-3H-imidazo[4,5-b]pyridine (500 mg, 2.538 mmol) in DCM (10 mL) at 0° C. The resulting mixture was stirred room temperature for 6 hours. The reaction was monitored by TLC (80% ethylacetate in hexane). The reaction mixture was partitioned between DCM and water. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (20% ethylacetate in hexane) afforded 120 mg of the product (14.4% yield).
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[C:15]1([CH2:21][C:22](O)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C=O)C>[C:1]([C:5]1[C:6]([NH:14][C:22](=[O:23])[CH2:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Reactant: O=C(O)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)c1c(NC(=O)Cc2ccccc2)nn2cccnc12
Yield: 72.9 %

Procedure:
A mixture from Example 105B (103.8 mg, 0.55 mmol), phenylacetic acid (138.6 mg, 1.02 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCL (206.7 mg, 1.08 mmol) in pyridine (1.5 mL) and DMF (1.5 mL) was stirred at ambient temperature for 5 hours. The mixture was concentrated. Purification by reverse phase HPLC afforded 123.7 mg (74%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.39 (s, 9H), 3.63 (s, 2H), 6.99 (dd, J=7.1, 4.1 Hz, 1H), 7.23-7.34 (m, 5H), 8.48 (dd, J=4.1, 1.7 Hz, 1H), 8.91 (dd, J=7.1, 1.7 Hz, 1H), 9.93 (s, 1H); MS (DCI) m/z 309 (M+H)+.
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8](OC)[O:9]C)(=[O:5])[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([O:6][CH2:7][CH:8]=[O:9])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)OCC(OC)OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC(=O)OCC=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Compound 43a (176 mg, 1.0 mmol) was dissolved in 8 mL of CH2Cl2 and 4 mL of TFA (containing 5% H2O) was added. The mixture was stirred for 30 min at room temperature. The solution was then concentrated in vacuo to give the product 44a that was used immediately for the next step. 1H NMR (400 MHz, CDCl3) δ 0.92 (m, 3H), 1.64 (m, 2H), 2.24 (t, J=7.04 Hz, 2H), 4.72 (s, 2H), 9.60 (s, 1H).