Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][C@@H:13]1[C:47](=[O:48])[N:15]2[C:16]([C:31]([O:33][CH:34]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])=[C:17]([CH2:20][O:21][C:22](=[O:30])[NH:23]C(=O)C(Cl)(Cl)Cl)[CH2:18][S:19][C@H:14]12.C(=O)(O)[O-].[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(Cl)(=O)C.ClCCl>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[NH2:12][C@@H:13]1[C:47](=[O:48])[N:15]2[C:16]([C:31]([O:33][CH:34]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])=[C:17]([CH2:20][O:21][C:22](=[O:30])[NH2:23])[CH2:18][S:19][C@H:14]12
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(=O)NC(=O)C(Cl)(Cl)Cl)CS[C@H]12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: ClCCl
Solvent: CO
Product: NC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reaction time: 5 h
Yield: 64 %

Procedure:
The toluene-p-sulphonic acid salt of diphenylmethyl (6R,7R)-7-amino-3-trichloroacetylcarbamoyloxymethylceph-3-em-4-carboxylate (17.2 g, 22.7 mmole) was dissolved in a mixture of anhydrous methanol (900 ml) and acetyl chloride (45 ml) and left to stand at 20° for 5 hours. Removal of the solvent under reduced pressure gave an oil, which was dissolved in dichloromethane. This solution was shaken with aqueous sodium bicarbonate solution and then washed with water. Toluene-p-sulphonic acid monohydrate (4.3 g, 22.7 mmole) was added and the solvent was evaporated in vacuo. The residue was dissolved in hot isopropanol (ca. 150 ml) and the solution was poured into diisopropyl ether (ca. 600 ml). The precipitated solid was filtered off and dried in vacuo to give the title compound (8.9 g, 64%), m.p. 110° to 112°; [α]D21° -14° (c, 1.0 in CHCl3); λmaxEtOH 259 nm (ε 6,120) and λinf.EtOH 227 nm (ε 15,800).
Reaction SMILES: O[CH:2]=[C:3]1[C:8](=[O:9])[CH:7]=[CH:6][C:5]([CH3:16])([C:10]#[C:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4]1.Cl.[NH2:18]O>C(O)C.O>[CH3:16][C:5]1([C:10]#[C:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4][C:3]2[CH:2]=[N:18][O:9][C:8]=2[CH:7]=[CH:6]1
Reactant: NO
Reactant: CC1(C#C[Si](C)(C)C)C=CC(=O)C(=CO)C1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC1(C#C[Si](C)(C)C)C=Cc2oncc2C1
Yield: 99.5 %

Procedure:
To a solution of 6-(hydroxymethylene)-4-methyl-4-((trimethylsilyl)ethynyl)-cyclohex-2-enone (147 mg, 0.63 mmol) in ethanol (15 mL) was added a solution of hydroxylamine hydrochloride (452 mg) in water (0.65 mL). The mixture was heated under reflux for 1 h. To the mixture was added water (50 mL). The aqueous mixture was extracted with methylene chloride/ether (1:2, 50 mL×3). The extract was washed with saturated aqueous sodium bicarbonate solution (50 mL×1) and brine (50 mL×1), dried over MgSO4, and filtered. The filtrate was evaporated in vacuo to give 9 as a crystalline solid (145 mg, quantitative yield): 1H NMR (CDCl3) δ 8.06 (1H, s), 6.47 (1H, d, J=9.9 Hz), 6.03 (1H, d, J=9.9 Hz), 3.07 (1H, d, J=16.1 Hz), 2.77 (1H, d, J=16.1 Hz), 1.37 (3H, s), 0.14 (9H, s). This material was used without further purification for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[N:21]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[C:22]=[O:23]>CN(C=O)C>[CH:24]1([NH:21][C:22]([N:18]2[CH2:19][CH2:20][CH:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)=[O:23])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C=NC1CCCCC1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Solvent: CN(C)C=O
Product: COc1cc2ncnc(C3CCN(C(=O)NC4CCCCC4)CC3)c2cc1OC
Yield: 50.2 %

Procedure:
A solution of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (30 mg, 0.110 mmol), as prepared in Example 1d, in DMF (1 mL) was treated with isocyanato-cyclohexane (20.6 mg, 0.165 mmol) at RT overnight. The reaction was then partitioned between EtOAc (10 mL) and H2O (10 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. Purification by prep tlc (1:9 MeOH/DCM) afforded the title compound as a light yellow solid (22 mg, 50%). 1H NMR (300 MHz, CDCl3) δ 9.08 (s, 1H), 7.38 (s, 1H), 7.26 (s, 1H), 4.35 (d, 1H), 4.14 (d, 1H), 4.07 (s, 6H), 3.68 (m, 1H), 3.53 (m, 1H), 3.03 (m, 2H), 2.12-1.90 (m, 4H), 1.70-1.55 (m, 5H), 1.40-1.09 (m, 5H); LC/MS (ESI): calcd mass 398.2, found 399.3 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH:17]2[CH2:19][CH2:18]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1)=[N+]=[N-])[CH3:2].[OH:21][CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.N#N.O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH:17]2[CH2:19][CH2:18]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1)[O:21][CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH3:2]
Reactant: CCOC(=O)C(=[N+]=[N-])c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: OC1CCOCC1
Agent: N#N
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of compound 2-[4-(Cyclopropanesulfonyl)phenyl]-2-diazo acetic acid ethyl ester (11.3 g, 38 mmol) in DCM (110 mL) under argon atmosphere, 4-hydroxy tetrahydropyran (4.36 mL, 45 mmol) was added followed by portion wise addition of rhodium(II)acetate dimer (0.354 g, 0.8 mmol). Reaction proceeds with evolution of N2 gas. Reaction mixture was stirred at 25° C. for 0.5 h. Completion of reaction was confirmed by TLC and reaction mixture was poured into water (100 mL). Organic layer was separated; aqueous layer was again extracted with of DCM (250 mL). Combined organic layer was washed with water (100 mL) and then with aqueous saturated sodium bicarbonate (300 mL) followed by brine (75 mL). Organic layer was dried over anhydrous sodium sulfate, sodium sulfate was filtered and washed with DCM (100 mL) and solvent was evaporated under reduced pressure using rotavapour to get required crude product. The crude product was purified by column chromatography using silica gel 100-200 mesh, mobile phase hexanes to 35% ethyl acetate in hexanes. Removal of solvent from appropriate fractions under reduced pressure in rotavapour gave pure product.
Reaction SMILES: [N:1]1([C:5]2[C:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[C:13]([Cl:26])[C:12]3[C:7](=[CH:8][CH:9]=[C:10](Br)[CH:11]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[Li]CCCC.[CH3:33][C:34]1[C:39]([CH:40]=[O:41])=[CH:38][CH:37]=[C:36]([CH3:42])[N:35]=1>C1COCC1>[N:1]1([C:5]2[C:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[C:13]([Cl:26])[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([CH:40]([C:39]4[C:34]([CH3:33])=[N:35][C:36]([CH3:42])=[CH:37][CH:38]=4)[OH:41])[CH:11]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(C=O)c(C)n1
Reactant: FC(F)(F)c1ccc(Cc2c(N3CCC3)nc3ccc(Br)cc3c2Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(O)c2ccc3nc(N4CCC4)c(Cc4ccc(C(F)(F)F)cc4)c(Cl)c3c2)c(C)n1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
2-(Azetidin-1-yl)-6-bromo-4-chloro-3-(4-(trifluoromethyl)benzyl)quinoline (1.09 g, 2.40 mmol, Intermediate 16) was dissolved in THF (20 mL) in a dry round bottom flask under an N2 atmosphere, then cooled to −78° C. in dry ice acetone bath. n-BuLi (1.6 M in hexanes, 1.74 mL, 2.79 mmol) was then added dropwise via syringe over approximately 5 minutes. The contents were stirred at −78° C. for approximately 10 minutes, then a solution of 2,6-dimethyl-pyridine-3-carbaldehyde (0.36 g, 2.6 mmol) in THF (20 mL) was added via cannula and stirred for 10 minutes at −78° C. The dry ice bath was then removed and replaced with an ice water bath and stirred at 0° C. for approximately one hour. The reaction was then quenched with a saturated, aqueous NH4Cl solution then transferred to a separatory funnel with EtOAc. The organic phase was extracted with a saturated, aqueous NH4Cl solution and deionized water, then separated and dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0-100% DCM/(10% of a 2 M NH3 MeOH in DCM)) to afford the title compound. MS (ESI): mass calcd. for C28H25ClF3N3O, 511.2; m/z found, 512.5 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 7.99 (d, J=2.0 Hz, 1H), 7.75 (d, J=7.9 Hz, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.53 (d, J=8.1 Hz, 2H), 7.44 (dd, J=8.7, 2.0 Hz, 1H), 7.24-7.18 (m, 2H), 7.04 (d, J=7.9 Hz, 1H), 6.09 (s, 1H), 4.34 (s, 2H), 4.12 (t, J=7.6 Hz, 4H), 2.74 (s, 1H), 2.51 (s, 3H), 2.46 (s, 3H), 2.29-2.18 (m, 2H).
Reaction SMILES: [CH2:1]([S:5]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH:2]([CH3:4])[CH3:3].[OH-].[Na+]>O1CCOCC1>[CH2:1]([S:5]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccc(S(=O)(=O)CC(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)CS(=O)(=O)c1ccc(C(=O)O)cc1
Temperature: 80 °C
Yield: 98 %

Procedure:
A mixture of methyl 4-isobutylsulfonylbenzoate (1.00 g, 3.90 mmol), NaOH (10 mL of 1.0 M, 10 mmol), and 1,4-dioxane (10 mL) was heated at 80° C. for 1.5 h. The mixture was cooled to rt before it was concentrated in vacuo. The solid residue was taken up in water and was washed with ethyl acetate which was discarded. The aqueous layer was acidified with 1N HCl and was extracted with ethyl acetate (2×). The combined organics were washed with brine, dried over sodium sulfate, and were concentrated in vacuo. Column chromatography (0-100% ethyl acetate/hexanes) on the residue gave 4-(isobutylsulfonyl)benzoic acid (98%). ESI-MS m/z calc. 242.1, found 243.2 (M+1)+; Retention time: 1.73 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J=8.3 Hz, 2H), 8.05 (d, J=8.3 Hz, 2H), 3.03 (d, J=6.5 Hz, 2H), 2.27 (dt, J=13.3, 6.6 Hz, 1H), 1.08 (d, J=6.7 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.[OH-].[NH4+]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1
Reactant: C1=COCCC1
Reactant: Clc1ncnc2nc[nH]c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Clc1ncnc2c1ncn2C1CCCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
To a warmed (60° C.) slurry of 6-chloropurine (20 g, 0.1294 mol) and p-toluenesulfonic acid monohydrate (0.35 g), dihydropyran (13.4 mL, 0.172 mol) was added with stirring over a period of 30 min. After an additional 30 min of heating, the mixture was allowed to cool to room temperature for 1 h. Concentrated ammonium hydroxide (12 mL) was added and stirring was continued for 5 min. The solution was washed with water (4×70 mL) and the organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give a syrup (about 29 g) which slowly crystallized upon standing. Extraction with boiling hexane gave the product as a solid, 24.36 g in two crops (78%), mp 70°-71° C.
Reaction SMILES: [C:1]([O:9][C@H:10]([C@@H:13]1[CH2:17][C@@H:16]([CH3:18])[CH:15]([OH:19])[O:14]1)[CH2:11][CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:1]([O:9][C@H:10]([C@@H:13]1[CH2:17][C@@H:16]([CH3:18])[CH:15]([O:19][C:20](=[O:22])[CH3:21])[O:14]1)[CH2:11][CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@H](OC(=O)c1ccccc1)[C@@H]1C[C@@H](C)C(O)O1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC[C@H](OC(=O)c1ccccc1)[C@@H]1C[C@@H](C)C(OC(C)=O)O1
Yield: 72.5 %

Procedure:
To a solution of [(1S)-1-[(2S,4R)-5-hydroxy-4-methyl-tetrahydrofuran-2-yl]propyl] benzoate (compound 28i, crude, 1.2 g, 4.5 mmol) in pyridine (60 mL) was added acetic acid anhydride (0.918 g, 9 mmol) and DMAP (200 mg) with stirring. After being stirred 25° C. for 2 hours, the mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc (40 mL). The organic layers were combined, washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:20 to 1:5 EtOAc in petroleum ether) to afford 1.0 g of [(1S)-1-[(2S,4R)-5-acetoxy-4-methyl-tetrahydrofuran-2-yl]propyl] benzoate (compound 28j) as a colourless oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:26])=[C:4]([C:15]([NH:18]C(OC(C)(C)C)=O)=[CH:16][CH:17]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].ClCCl.Cl>O1CCOCC1>[NH2:18][C:15]1[C:4]([C:5]([O:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:6])=[C:3]([CH3:26])[C:2]([Br:1])=[CH:17][CH:16]=1
Reactant: Cc1c(Br)ccc(NC(=O)OC(C)(C)C)c1C(=O)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1c(Br)ccc(N)c1C(=O)OCc1ccccc1

Procedure:
A mixture of Example 126A, dichlormethane (20 mL), and 4N HCl in dioxane (30 mL) was stirred for 18 hours, concentrated, and triturated with a 1:1 mixture of hexanes and diethyl ether (150 mL) to provide the desired product. MS (ESI(+)) m/e 320, 322 (M+H)+; (ESI(−)) m/e 318, 320 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 7.40 (m, 5H), 7.31 (d, 1H), 6.56 (d, 1H), 5.33 (s, 2H), 4.92 (br s, 2H), 2.23 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][CH:15]=[C:16]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([C:16]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[CH:15][CH2:14][S:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:31])=[O:3])=[CH:8][CH:9]=2)=[CH:29][CH:28]=1
Reactant: CCOC(=O)COc1ccc(SCC=C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1ccc(SCC=C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Reaction time: 18 h

Procedure:
{4-[3,3-Bis-(4-chlorophenyl)-allylsulfanyl]-phenoxy}-acetic acid ethyl ester (130 mg, 0.27 mmol) was dissolved in warm ethanol (10 ml). 1N NaOH (1 ml) was added at room temperature and the reaction mixture was stirred for 18 h after which it was evaporated. The residue was treated with 1N HCl (1.2 ml) and extracted with ethyl acetate (3×25 ml). The combined organic phases were dried and evaporated to give the title compound in 48 mg (38%) yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:5]=1N.Cl.N([O-])=O.[Na+].[Cu][C:20]#[N:21]>O.C(Cl)(Cl)Cl>[C:20]([C:5]1[C:6]([O:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:13])#[N:21]
Reactant: N#C[Cu]
Reactant: COC(=O)c1cccc(OC)c1N
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)c1cccc(OC)c1C#N
Reaction time: 0.5 h

Procedure:
A suspension of methyl-2-amino-3-methoxybenzoate (Intermediate 36, 2.27 g, 12.5 mmol) in water (10 mL) and con. HCl (2 mL) was cooled to 0 deg. C. and a solution of sodium nitrite (1.04 g, 15 mmol) in water (10 mL) was added dropwise. The resulting solution was stirred cold for 30 min. then added to a suspension of copper(I)cyanide (3.4 g, 38 mmol) in water (100 mL). The resulting suspension was heated at 60 deg. C. for 3 h, cooled, chloroform was added and the mixture was filtered through celite. The organic layer was dried (MgSO4), the solvent was evaporated and the residue was flash chromatographed eluting with 0-50% hexane-ethyl acetate affording Intermediate 37 (0.56 g, 23.5%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 3.99 (s, 6 H), 7.20 (d, J=8.35 Hz, 1 H), 7.61 (t, J=8.13 Hz, 1 H), 7.68 (d, J=7.47 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[N:27]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:4]2[N:3]=1.[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1>CN(C)C(=O)C.C(=O)([O-])O.[Na+]>[CH:28]1([C:31]([NH:1][C:2]2[N:27]=[C:5]3[CH:6]=[CH:7][C:8]([O:10][C:11]4[CH:12]=[C:13]([NH:17][C:18]([C:20]5[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=5)=[O:19])[CH:14]=[CH:15][CH:16]=4)=[CH:9][N:4]3[N:3]=2)=[O:32])[CH2:30][CH2:29]1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc3nc(N)nn3c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.1 %

Procedure:
To a solution of N-{3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]phenyl}-3-methylpyridine-2-carboxamide (120 mg, 0.333 mmol) in N,N-dimethylacetamide (5 mL) was added cyclopropanecarbonyl chloride (30.5 μL, 0.336 mmol), and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (0%→100% ethyl acetate-hexane) to give the title compound (110 mg, 77%) as a white solid.
Reaction SMILES: [C:1]([CH2:3][C:4]([N:6]([CH2:8][CH3:9])[CH3:7])=[O:5])#[N:2].C(N(CC)CC)C.[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[C:20]([N+:27]([O-:29])=[O:28])[CH:19]=1.[OH-].[Na+]>C1COCC1.CCOCC>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([CH:3]([C:1]#[N:2])[C:4]([N:6]([CH2:8][CH3:9])[CH3:7])=[O:5])=[O:23])=[C:20]([N+:27]([O-:29])=[O:28])[CH:19]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CCN(C)C(=O)CC#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCN(C)C(=O)C(C#N)C(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.8 %

Procedure:
2-cyano-N-ethyl-N-methylacetamide (5.56 g; 0.044 mol) and triethylamine (13.36 g; 0.132 mol) were dissolved in dry THF (100 ml) under dry nitrogen, and 4-chloro-2-nitrobenzoyl chloride (9.68 g; 0.044 mol) in dry THF (100 ml) added dropwise over 45 min. The mixture was stirred at room temperature under dry nitrogen for 18 hours, during which time a precipitate was formed. The solution was filtered, washing the solid with THF and adding the washings to the solution, and evaporated, giving a residue which was treated with 2M sodium hydroxide solution (200 ml), and this then washed with CH2Cl2 (2×100 ml). The aqueous solution was acidified to pH 1 with concentrated hydrochloric acid, and extracted into CH2Cl2 (3×200 m). The extracts were combined, dried (Na2SO4), filtered and evaporated, giving a very viscous oil which solidified. Trituration with ether (20 ml) gave 2-(4-chloro-2-nitrobenzoyl)-2-cyano-N-ethyl-N-methylacetamide (6.10 g; 45%) as a solid, m.p. 95°-98° C., (Found, C: 49.60; H: 3.87; N: 13.25; Cl: 12.28. C13H12ClN3O4 requires C: 50.40; H: 3.88; N: 13.57; Cl: 11.47%, d (CDCl3); 60 MHz) 1.3 (3H, t, J=7, Hz), 3.2 (3H, s), 3.7 (2H, q, J=7 Hz), 7.4-7.55 (1H, d, J=8 Hz), 7.6-7.8 (1H, dd, J=8, 2 Hz), 8.1 (1H, d, J=2 Hz) and 16.4 (1H, br, s), vmax (nujol) 2200, 1590 (shoulder) and 1500.
Reaction SMILES: C[NH2:2].[CH2:3]([O:5][C:6]1[CH:15]=[CH:14][C:9]2[N:10]=[C:11]([SH:13])[S:12][C:8]=2[CH:7]=1)[CH3:4]>[OH-].[Na+]>[CH2:3]([O:5][C:6]1[CH:15]=[CH:14][C:9]2[N:10]=[C:11]([SH:13])[S:12][C:8]=2[CH:7]=1)[CH3:4].[CH2:3]([O:5][C:6]1[CH:15]=[CH:14][C:9]2[N:10]=[C:11]([S:13][NH2:2])[S:12][C:8]=2[CH:7]=1)[CH3:4]
Reactant: CN
Agent: CCOc1ccc2nc(S)sc2c1
Agent: [Na+]
Agent: [OH-]
Product: CCOc1ccc2nc(SN)sc2c1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
A solution of 40% aqueous methylamine (80 ml) was placed in a 250 ml 3-necked flask, equipped with a powerful stirrer and two-addition funnels. The solution was cooled to -10° C. with an ice/methanol bath. A solution of 6-ethoxy-2-mercaptobenzothiazole (2.0 g., 0.0095 mol) in 20 ml of 5% NaOH was prepared, cooled to 10° C. and placed into one of the addition flasks. The second addition flask was charged with 40 ml of 5.25% NaOC1 which was cooled to 5° C. The two solutions were added simultaneously to the aqueous methylamine over a period of one hour with the rate of addition of the 6-ethoxy-2-mercaptobenzothiazole solution slightly faster than the addition of the NaOC1 solution The temperature of the reaction was maintained at --5° C.-0° C. The reaction was stirred for 15 minutes upon completing the addition and vacuum filtered to yield 6-ethoxy-2-benzothiazolesulfenamide. The 6-ethoxy-2-benzothiazolesulfenamide was immediately dissolved in 100 ml of acetone and oxidized with 50 ml of 5% KMnO4. The temperature of the oxidation was kept below 30° C. The MnO2 was removed by vacuum filtration and the filter cake washed with 25 ml of 5% NaOH. The 6-ethoxy-N-methyl-2-benzothiazolesulfonamide was precipitated from the solution by acidification with 5% HC1 to yield 1.3g. (yield 50.3%). The product was purified by dissolving it in 10% Na2CO3 and precipitating it with 5% Hl. m.p. 129° C.-131° C.; NMR(DMSO- d6) 8.4(s, lH), 8.3-7.1cm, 3H) 4-1 4-3.9(q,1 2H) 2.7(s, 3H 1.5-1.2(t, 3H. IR(KBr) 3100 cm (N-H) 1345 cm-1, 1155 cm (S=O). Elemental Analyses: C10H12N2O3S2 ; Calculated: C 44.09% H 4.44% N 10.28%. Found: C 44.04% H 4.51% N 10.18%.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:17])[CH2:13][CH:12](Br)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:15]#[N:16])[CH:10]=2)[O:5]1.[N:18]1[C:23]([OH:24])=[CH:22][CH:21]=[C:20]([OH:25])[N:19]=1>CS(C)=O>[CH3:3][C:4]1([CH3:17])[CH2:13][CH:12]([O:24][C:23]2[N:18]=[N:19][C:20]([OH:25])=[CH:21][CH:22]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:15]#[N:16])[CH:10]=2)[O:5]1
Reactant: Oc1ccc(O)nn1
Reactant: CC1(C)CC(Br)c2cc(C#N)ccc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(C)CC(Oc2ccc(O)nn2)c2cc(C#N)ccc2O1
Reaction time: 72 h

Procedure:
1.2 g of 80% NaH are added to a solution of 2.66 g of 2,2-dimethyl-4-bromo-6-cyanochroman (m.p. 89°-92°; obtainable by reduction of 2,2-dimethyl-6-cyano-4-chromanone with NaBH4, in CH3OH to give oily 2,2-dimethyl-6-cyano-4-chromanol and reaction with PBr3 in toluene at 20°) and 2.5 g of pyridazine-3,6-diol in 70 ml of DMSO and the mixture is stirred at 20° for 3 days. After customary working up, 2,2-dimethyl-4-(6-hydroxy-3-pyridazinyloxy)- 6-cyanochroman, m.p. 221°-224°, is obtained.
Reaction SMILES: BrC1C=CC(O)=C([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.C([C:40]1[CH:41]=[CH:42][C:43]([OH:49])=[C:44]([CH:48]=1)[C:45]([NH2:47])=[O:46])(=O)C.[OH-].[K+]>C(O)C>[C:45]([C:44]1[CH:48]=[C:40]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:41]=[CH:42][C:43]=1[OH:49])(=[O:46])[NH2:47]
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)c1ccc(O)c(C(N)=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1cc(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)ccc1O
Yield: 10 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 5-acetyl-2-hydroxy-benzamide (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in Ethanol (506 μL, 0.64 mmol) to produce the title compound (13 mg, 10% yield). MS: 507.24 (M+H+); HPLC Procedure A, retention time=10.36 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)/C=C/c1ccc(Sc2ccc(Cl)cc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccc(Sc2ccc(Cl)cc2)cc1
Reaction time: 3 h

Procedure:
A solution of ester from step 2 in EtOAc (0.2M) containing 10% Pd/C (0.15 g/mmol) was agitated under hydrogen (50 psi, Parr apparatus) for 3 h. The mixture was filtered over Celite and the solvent evaporated to afford the title compound.