Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([S:37][CH2:38][C:39]5[N:43]([CH2:44][CH2:45][CH2:46][CH3:47])[CH:42]=[N:41][N:40]=5)=[CH:33][CH:32]=4)=[O:29])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([S:37]([CH2:38][C:39]5[N:43]([CH2:44][CH2:45][CH2:46][CH3:47])[CH:42]=[N:41][N:40]=5)=[O:57])=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nncn4CCCC)cc2)CCN3CCC)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nncn4CCCC)cc2)CCN3CCC)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-n-butyl-4H-1,2,4-triazol-3-ylmethylthio)phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxamide (1.00 g) in dichloromethane (20 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.55 g) in dichloromethane (10 ml) at −78° C., and the mixture was stirred for 1 hour at −78° C. To the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:5→1:4), and was recrystalized from ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-n-butyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 145) (614.2 mg) as yellow crystals.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([O:13][CH2:14][O:15][C:16](=[O:19])[CH2:17][CH3:18])[CH2:11]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([O-:24])(=[O:23])[CH2:21][CH3:22].[Na+]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH:10]([O:13][CH2:14][O:15][C:16](=[O:19])[CH2:17][CH3:18])[CH2:11][O:24][C:20](=[O:23])[CH2:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)[O-]
Reactant: CCC(=O)OCOC(CCl)COCc1ccccc1
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCC(=O)OCOC(COCc1ccccc1)COC(=O)CC
Temperature: 90 °C

Procedure:
Epichlorohydrin is reacted with benzyl alcohol in the presence of tetrabutylammonium bisulfate in aqueous sodium hydroxide, at room temperature. The product of this reaction, benzyl glycidyl ether, is isolated by conventional means and is then added slowly to a suspension of lithium chloride in tetrahydrofuran and acetic acid, at 40°-70° C., preferably below 60° C. The reaction mixture is allowed to cool to room temperature, and stirred for 2-10 hours, preferably 3-6 hours. The product is isolated by extraction, washed and dried to provide 1-benzyloxy-3-chloro-2-propanol. To this product is then added methoxymethyl propionate, which is prepared by adding propionic anhydride to dimethoxymethane in the presence of an ion exchange resin, e.g., Amberlyst 15, maintaining the temperature between 40°-60° C., preferably between 40°-50° C. during the addition. The reaction mixture is aged and cooled, then filtered, washed and distilled. This product, methoxymethyl propionate, is reacted with 1-benzyloxy-3-chloro-2-propanol in an aprotic solvent, e.g., hexanes, in the presence of p-toluenesulfonic acid hydrate at reflux. Distillation and washing affords the product 1-benzyloxy-3-chloro-2-(propionyloxy)methoxypropane. Finally, to prepare the compounds of Formula (III), 1-benzyloxy-3-chloro-2-(propionyloxy)methoxypropane, is refluxed with an alkali metal alkanoate, e.g., sodium propionate, in an aprotic solvent, e.g., toluene, after which a phase transfer catalyst such as tetrabutylphosphonium chloride is added. The reaction mixture is stirred at 90° C. to reflux temperature for 1-3 days, preferably 2 days, at which time more tetrabutylphosphonium chloride and solvent may be added, if required. The mixture is heated to reflux and the distillate removed, then stirred at 90° C. to reflux temperature for 3-16 hours, preferably 5-10 hours, then cooled to ambient temperature. The mixture is then washed with water and brine, and the organic phase is separated and concentrated to yield 1-benzyloxy-3-propionyloxy-2-(propionyloxy)methoxy propane. In an analogous manner, other glycerol derivatives of Formula (III) may be prepared.
Reaction SMILES: C(Cl)(Cl)Cl.[NH:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7][CH2:6]1.[C:19](OC(=O)C)(=[O:21])C.C(O)=O>O>[CH:19]([N:5]1[CH2:6][CH2:7][CH:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:9][CH2:10]1)=[O:21]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: O=CO
Product: CC(C)(C)OC(=O)NC1CCN(C=O)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A chloroform solution of 2.0 g of tert-butyl piperidin-4-ylcarbamate was added to a mixed solution of 4.7 ml of acetic anhydride and 1.9 ml of formic acid, and the reaction mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture, and this was extracted with EtOAc. The organic layer was washed with 1 M hydrochloric acid, aqueous saturated sodium hydrogencarbonate and brine. This was dried with anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified with silica gel column chromatography (eluent: chloroform/MeOH=50/1) to obtain 1.7 g of tert-butyl (1-formylpiperidin-4-yl)carbamate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[SH:10].CI.[C:13]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:13][S:10][C:2]1[NH:3][C:4]2=[N:5][CH:6]=[CH:7][CH:8]=[C:9]2[N:1]=1
Reactant: Sc1nc2ncccc2[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CSc1nc2cccnc2[nH]1
Reaction time: 10 h
Yield: 45.8 %

Procedure:
To a solution of 1H-imidazo[4,5-b]pyridine-2-thiol (2 g) in acetone (30 mL) were added MeI (0.910 ml) and K2CO3 (5.48 g) at room temperature. After stirring for 10 h, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (NH-silica gel, eluted with 10%-100% EtOAc in hexane) to give 2-(methylsulfanyl)-3H-imidazo[4,5-b]pyridine (1.0 g) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.N1C=CC=CC=1.Cl[C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23].O>O1CCCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:22](=[O:23])[O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc(N)cn2)CC1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(c2ccc(NC(=O)OCC(Cl)(Cl)Cl)cn2)CC1

Procedure:
To a solution of 6-(4-methylpiperazin-1-yl)pyridine-3-amine (1.00 g, 5.20 mmol) and pyridine (0.509 ml, 6.24 mmol) in tetrahydrofuran (17 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (0.509 ml, 6.24 mmol), and the mixture was stirred at room temperature for 1 hour and half. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was poured to the residue, and 349 mg (18.2%) of the desired product as a solid was separated by filtration.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:5][O:6][C:7]1[C:12]([C:13]([OH:15])=O)=[CH:11][C:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:9]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])[N:8]=1.CN(C=O)C.C(Cl)(=O)C([Cl:43])=O>C(Cl)Cl>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:10]2[C:9]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])=[N:8][C:7]([O:6][CH2:5][C:4]3[CH:31]=[CH:32][C:33]([F:34])=[C:2]([F:1])[CH:3]=3)=[C:12]([CH:11]=2)[C:13]([Cl:43])=[O:15])=[CH:17][CH:18]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCc1ccc(F)c(F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(3,4-difluorobenzyloxy)-6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyridine-3-carboxylic acid (120 mg, 0.20 mmol) from Example 77 in methylene chloride (3 mL) was added a drop of DMF (cat.) and oxalyl chloride (0.100 mL, 1.1 mmol). The reaction was stirred at rt for 1 h and was then evaporated to dryness. The acid chloride was dissolved in methylene chloride and used directly in the subsequent amide formation.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[N:9]([C:17]1[C:22]([F:23])=[C:21](Cl)[N:20]=[C:19]([Cl:25])[N:18]=1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])[CH3:3].C(N(CC)CC)C.Cl.[NH2:41][CH2:42][C:43]1[S:44][CH:45]=[CH:46][N:47]=1>C1COCC1.O>[CH3:4][C:2]([O:5][C:6]([N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[N:9]([C:17]1[C:22]([F:23])=[C:21]([NH:41][CH2:42][C:43]2[S:44][CH:45]=[CH:46][N:47]=2)[N:20]=[C:19]([Cl:25])[N:18]=1)[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(Cl)c1F
Reactant: NCc1nccs1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(NCc2nccs2)c1F

Procedure:
Tris(1,1-dimethylethyl)2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (0.988 g, 1.992 mmol) was dissolved in THF (10 mL). To this solution was added triethylamine (0.61 mL, 4.3765 mmol), followed by commercially available 2-aminomethyl thiazole hydrochloride (0.30 g, 1.992 mmol), which was suspended in THF (12 mL). The reaction was left to stir for 2 days during which time an additional 10 mL THF and 2-aminomethyl thiazole hydrochloride (0.061 g, 0.4049 mmol) were added to the reaction mixture. After 3 more days, the reaction mixture was diluted with water and extracted with ethyl acetate. The organics were dried (Na2SO4) and concentrated. The resulting crude material was purified by silica gel chromatography (0-100% ethyl acetate in hexanes) to provide tris(1,1-dimethylethyl)2-{2-chloro-5-fluoro-6-[(1,3-thiazol-2-ylmethyl)amino]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate as a yellow oil (0.5826, 51%). LCMS: (M+H−3 Boc)+=375.0.
Reaction SMILES: [Cl-].[NH4+].Cl[C:4]1[N:14]=[C:13]([CH3:15])[C:12]([C:16]#[N:17])=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]>O1CCOCC1.C1COCC1.CN(C=O)C.CCOC(C)=O.[Zn]>[C:16]([C:12]1[C:13]([CH3:15])=[N:14][CH:4]=[C:5]([CH:11]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:17]
Reactant: CCOC(=O)c1cc(C#N)c(C)nc1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(C)c(C#N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.5 %

Procedure:
Ammonium chloride (3.58 g, 66.7 mmol in 10 mL water) was added to a solution of ethyl 2-chloro-5-cyano-6-methylnicotinate (1.0 g, 4.4 mmol) in dioxane-THF-DMF (50 mL, 3:1:1), followed by zinc powder (2.3 g, 35.6 mmol) portionwise at room temperature. The reaction mixture was allowed to stir at room temperature for 3 h, diluted with EtOAc, and filtered through a pad of Celite. The clear filtrate of organic layer was washed with H2O and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluent 10-15% EtOAc in petroleum ether) to afford ethyl 5-cyano-6-methylnicotinate (230 mg, yield 27%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.25 (d, J=2.0 Hz, 1H), 8.49 (d, J=2.0 Hz, 1H), 7.27 (s, 1H), 4.47-4.42 (q, J=7.2 Hz, 2H), 2.86 (s, 3H), 1.45-1.41 (t, J=7.0 Hz, 3H). MS (ESI) m/z: Calculated for C10H10N2O2: 190.07. found: 191.2 (M+H)+.
Reaction SMILES: N.[CH3:2][O:3][C:4]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:9]([C@H:10]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:13]3([CH2:17][CH:16]([OH:18])[CH2:15][O:14]3)[CH2:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=1.O1CCCC1.[Li]>CO.CC(C)(O)C>[CH3:2][O:3][C:4]1[CH2:5][C:6]2[CH2:7][CH2:8][C@@H:9]3[C@@H:23]([C:24]=2[CH2:25][CH:26]=1)[CH2:22][CH2:21][C@@:19]1([CH3:20])[C@H:10]3[CH2:11][CH2:12][C:13]21[CH2:17][CH:16]([OH:18])[CH2:15][O:14]2
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CCC21CC(O)CO1
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(C)(C)O
Product: COC1=CCC2=C(CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CCC23CC(O)CO3)C1
Reaction time: 0.75 h

Procedure:
To 122 parts of liquid ammonia under reflux is added, with vigorous agitation, a solution of 3 parts of 4',5'-dihydro-3-methoxyspiro[estra-1,3,5(10)-triene 17,2'(3'H)-furan]-4'-ol in a mixture of 81 parts of tetrahydrofuran and 72 parts of 1,1-dimethylethanol, followed -- portionwise -- by 2 parts of lithium wire cut into small pieces. Approximately 2 hours later, 5 parts of methanol is slowly introduced. After an additional 45 minutes, the blue color originally characteristic of the reaction mixture has disappeared, at which point the ammonia is allowed to evaporate and 500 parts of water is added to the residue. The precipitate which forms is filtered off, washed with water, dried in air, and recrystallized from ethyl acetate to give 4',5'-dihydro-3-methoxyspiro[estra-2,5(10)-diene-17,2'(3'H)-furan]-4'-ol melting at 152°-155°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[Cl:19][C:20]1[CH:25]=[C:24]([O:26]C)C=C[C:21]=1[N:28]=C=S>O1CCCC1>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[C:2]=1[NH:1][NH:28][CH2:21][CH:20]([Cl:19])[CH2:25][CH2:24][OH:26]
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCCO
Reactant: COc1ccc(N=C=S)c(Cl)c1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(NNCC(Cl)CCO)c1NCCCCO
Yield: 45.3 %

Procedure:
A solution of methyl 3-amino-4-chloro-2-[(4-hydroxybutyl)amino]benzoate (2.00 g, 7.33 mmol) and 2-chloro-1-isothiocyanato-4-methoxybenzene (2.94 g, 14.7 mmol) in tetrahydrofuran (20 mL) was stirred for 36 h at 70° C. The reaction mixture was concentrated in vacuo and purified by flash column chromatography on silica gel eluting with a 50% ethyl acetate/n-hexane mixture to give the title compound as a pale yellow oil (1.57 g, 3.32 mmol, 45%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH:13]2[CH:9]1[CH2:10][NH:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16]([C:21](O)=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH:13]2[CH:9]1[CH2:10][N:11]([C:21]([C:16]1[C:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:22])[CH2:12]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC21
Reactant: O=C(O)c1ccccc1-c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC2CN(C(=O)c3ccccc3-c3ccccc3)CC21
Temperature: 23 °C
Reaction time: 1 h

Procedure:
Intermediate 18 (0.72 mmol), biphenyl-2-carboxylic acid (0.72 mmol), and HATU (1.66 mmol) were taken up in DMF at 0.2 M. DIPEA (2.17 mmol) was added. The mixture was allowed to stir at 23° C. for ˜1 hr. The mixture was diluted water and extracted with diethyl ether. The aqueous was extracted with ether again. The other fractions were combined and concentrated to provide the crude product. The product was purified on the silica gel chromatography (30-100% ethyl acetate/hexanes) over 12 minutes, then flushed with 100% ethyl acetate for 20 minutes to provide 3-(Biphenyl-2-carbonyl)-3,6-diaza-bicyclo[3.2.0]heptane-6-carboxylic acid tert-butyl ester, 91%. MS (ESI) mass calcd. for C23H26N2O3, 378.46; m/z found, 379.2 [M+H]+. This material was taken up in DCM and TFA was added. The mixture was allowed to stir at 23° C. for 1 hr. It was then concentrated after checking by MS and LCMS to provide a yellow viscous oil. The oil was taken up and DCM and 1M NaOH were added, and the resulting solution was allowed to stirred for 5 minutes. The layers were separated, and the organic layer was concentrated to provide Intermediate 19 as a light yellow foamy solid. MS (ESI) mass calcd. for C18H18N2O, 278.35; m/z found, 279.2 [M+H]+.
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])[N:9]2[CH:22]=[CH:23][CH:24]=[C:8]2[C:7]=1[OH:25])=[O:5])C.[NH2:26][CH2:27][C:28]([O-:30])=[O:29].[Na+]>>[F:20][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([F:21])[C:14]=1[CH2:13][N:10]1[C:11](=[O:12])[C:6]([C:4]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:5])=[C:7]([OH:25])[C:8]2=[CH:24][CH:23]=[CH:22][N:9]12
Reactant: CCOC(=O)c1c(O)c2cccn2n(Cc2c(F)cccc2F)c1=O
Reactant: NCC(=O)[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cccn2n(Cc2c(F)cccc2F)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 1-(2,6-difluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (1.0 eq.) and sodium glycinate (15 eq.). ESI (m/z): 378 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([F:18])=[C:10]([CH:17]=1)[NH:11][C:12](=[O:16])[O:13][CH2:14][CH3:15])(=[O:4])=[O:3].[Cl:19]Cl>C(O)(=O)C.O>[Cl:19][C:7]1[C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:17][C:10]([NH:11][C:12](=[O:16])[O:13][CH2:14][CH3:15])=[C:9]([F:18])[CH:8]=1
Reactant: CCOC(=O)Nc1cc(NS(C)(=O)=O)ccc1F
Reactant: ClCl
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)Nc1cc(NS(C)(=O)=O)c(Cl)cc1F
Yield: 90 %

Procedure:
80.6 g (292 mmol) of ethyl 5-methylsulfonylamino-2-fluorocarbanilate was dissolved in a mixture of 1075 ml of acetic acid and 100 ml of water, and chlorine gas was added to the resultant solution at a temperature of not higher than 25° C. until the starting material disappeared. After the reaction was completed, the surplus chlorine gas was removed by blowing nitrogen gas thereinto, and hexane was added. The precipitates crystals were filtered out to obtain 81.4 g of the objective product (yield: 90%) in the form of yellow crystals.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[I:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:21])=[C:18]([CH:20]=1)[NH2:19].Cl>C(N(CC)CC)C>[I:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:21])=[C:18]([NH:19][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:20]=1
Reactant: Cc1ccc(I)cc1N
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(I)cc1NC(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
2.1 mL of benzoyl chloride was added to 70 mL of a methylene chloride solution containing 3.5 g of 5-iodo-2-methylaniline and 2.5 mL of triethylamine at room temperature and stirred at the same temperature for 30 minutes. 1.0 mol/L hydrochloric acid was added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium hydrogen carbonate aqueous solution, and the solvent was evaporated under reduced pressure. Diisopropyl ether and hexane were added to the obtained residue and a solid substance was separated by filtration to obtain 4.2 g of N-(5-iodo-2-methylphenyl)benzamide as pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[O-:11][C:12]#[N:13].[K+].[OH-].[Na+].Cl>O.C(O)(=O)C>[OH:11][C:12]1[N:13]=[C:4]([OH:5])[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:1]=1
Reactant: N#C[O-]
Reactant: Nc1ccccc1C(=O)O
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Oc1nc(O)c2ccccc2n1
Temperature: 90 °C
Yield: 90.1 %

Procedure:
To a mixture containing 41 g of 2-aminobenzoic acid (0.3M), 21 of water and 34 ml of acetic acid, was dropwise added 54 g of potassium cyanate dissolved in 200 ml of water. The resultant was stirred for an hour and slowly added with 60 g of 0.3M aqueous sodium hydroxide so as not to exceed the reaction temperature of 40° C. The solution, while heated to 90° C., was stirred for 30 minutes, and then cooled to 0° C. The resultant was acidified by adding a concentrated hydrochloric acid and the solids thus produced were filtered to obtain 43.7 g of the title compound.
Reaction SMILES: C12(C3C=CC(OC[C:17]4[O:18][C:19]5[CH:25]=[C:24]([C:26]([OH:28])=O)[CH:23]=[CH:22][C:20]=5[N:21]=4)=CC=3)CC3CC(CC(C3)C1)C2.[CH2:31]([NH2:37])[C:32]1[O:36][CH:35]=[CH:34][CH:33]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C>[O:36]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH2:31][NH:37][C:26]([C:24]1[CH:23]=[CH:22][C:20]2[N:21]=[CH:17][O:18][C:19]=2[CH:25]=1)=[O:28]
Reactant: O=C(O)c1ccc2nc(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)oc2c1
Reactant: NCc1ccco1
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccco1)c1ccc2ncoc2c1
Temperature: 25 °C
Yield: 32.5 %

Procedure:
To solution of 2-(4-adamantan-1-yl-phenoxymethyl)-benzoxazole-6-carboxylic acid (30.1 mg, 0.08 mmol), furfuryl amine (11.0 mg, 0.12 mmol, 0.01 ml), EDC (21.7 mg, 0.12 mmol) and HOBt (15.4 mg, 0.12 mmol) in DMF 3.0 mL was added DIPEA (14.2 mg, 0.12 mmol, 0.02 ml). After stirring at room temperature, the mixture was partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4 anh), and concentrated. The residue was purified by silica gel column chromatography (n-Hexane:EtOAc:MeOH=6:3:1) to give 2-adamantan-1-yl-phenoxymethyl)-benzoxazole-6-carboxylic acid (furan-2-ylmethyl)-amide as a white solid (6.3 mg, 17.4% yield).
Reaction SMILES: [CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[N-:13]=[N+:14]=[N-:15].[Na+].C(O)C>O>[CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:13]=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1c(CCl)cccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1c(CN=[N+]=[N-])cccc1[N+](=O)[O-]
Temperature: 45 °C
Yield: 48.3 %

Procedure:
A mixture of 2-methyl-3-nitrobenzylchloride (0.70 g, 3.77 mmol), sodium azid (1 g, 15.4 mmol), ethanol (10 ml) and water (2 ml) was heated at 45° C. over night. The mixture was filtered, the filtrate was concentrated, and the residue was purified by chromatography on silica (heptane/EtOAc) to give the compound 2-methyl-3-nitrobenzylazide 0.35 g, which was hydrogenated over 5% palladium-charcoal 80 mg in EtOAc/EtOH 1:1 (14 ml), over night. The mixture was filtered through Celite, and the filtrated was concentrated to give 0.23 g (45%) of the title compound as a white solid.