Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:21])/[C:4](/[C:8]1[N:9]=[C:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[S:11][CH:12]=1)=[CH:5]\[CH2:6][CH3:7].[OH-].[Na+].Cl>C(O)(C)C.O>[C:17]([O:16][C:14]([NH:13][C:10]1[S:11][CH:12]=[C:8](/[C:4](=[CH:5]/[CH2:6][CH3:7])/[C:3]([OH:21])=[O:2])[N:9]=1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC/C=C(\C(=O)OC)c1csc(NC(=O)OC(C)(C)C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC/C=C(\C(=O)O)c1csc(NC(=O)OC(C)(C)C)n1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 77.8 %

Procedure:
To a solution of (Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl) -2-pentenoic acid methyl ester (425 mg : 1.4 mMol.) in isopropanol (1.3 ml) and water (3.7 ml) is added sodium hydroxide (163 mg : 4.1 mMol.), and the mixture is stirred at 65° C. for 90 minutes. The reaction mixture is adjusted to pH 4.7 with 35% hydrochloric acid and kept at 20° C. for 1 hour. The separating crystals are collected by filtration, washed with isopropanol, and dried to give (Z)-2-(2-t-butoxycarbonylaminothiazol-4- yl) -2-pentenoic acid (325 mg).Yield: 86%. mP. 187° C. (decomposition). NMR δ (CDC13) ppm: 1.09(t, J=7.6Hz, 3H), 1.55(s, 9H) 2.64(qd, J=7.6Hz, 2H), 6.69(t, J=7.6Hz, 1H), 6.96(s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[C:22]3[NH:21][CH2:20][CH2:19][CH2:18][C:17]=3[C:16](=[O:23])[N:15](CC3C=CC(OC)=CC=3)[C:14]=2[CH:33]=1>>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[C:22]3[NH:21][CH2:20][CH2:19][CH2:18][C:17]=3[C:16](=[O:23])[NH:15][C:14]=2[CH:33]=1
Reactant: COc1ccc(Cn2c(=O)c3c(c4ccc(OC)cc42)NCCC3)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c3c(c(=O)[nH]c2c1)CCCN3
Temperature: 100 °C
Reaction time: 20 h
Yield: 85.4 %

Procedure:
Trifluoroacetic acid (2 ml) was added to the compound (102.9 mg, 0.294 mmol) prepared in step 4 and the mixture was stirred in sealed-tube for 20 hours at 100° C. Once the reaction was completed, the reaction mixture was cooled to a room temperature and extracted with dichloromethane. The organic layer was washed with sodium bicarbonate aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was stirred in ethylacetate/hexane/diethylether and the resulting solid was filtered. The filtered solid was washed with diethylether and dried in vacuo to obtain the title compound (57.8 mg, yield: 85.5%, ivory solid).
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[C:8]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:9]=2[S:10][CH:11]=1)[C:3]([OH:5])=[O:4].S(Cl)(Cl)=O.[CH3:21]O>C(=O)(O)[O-].[Na+]>[CH3:21][O:4][C:3](=[O:5])[CH:2]([NH2:1])[CH2:6][C:7]1[C:8]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:9]=2[S:10][CH:11]=1
Reactant: NC(Cc1csc2ccc(Cl)cc12)C(=O)O
Reactant: CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: COC(=O)C(N)Cc1csc2ccc(Cl)cc12
Temperature: 25 °C

Procedure:
To a mixture of 2-Amino-3-(5-chloro-benzo[b]thiophen-3-yl)-propionic acid (255.7 mg, 1.0 mmol) in methanol was added thionyl chloride (0.08 mL) at 0° C. The resulting mixture was heated at reflux for 7 h, allowed to cool to room temperature, diluted with saturated sodium bicarbonate and extracted with ethyl acetate (2×30 mL). The organic extracts were combined, washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow oil (2-amino-3-(5-chloro-benzo[b]thiophen-3-yl)-propionic acid methyl ester).
Reaction SMILES: [F:1][C:2]1([F:20])[CH2:8][O:7][CH2:6][C:5]([NH2:9])=[N:4][C@@:3]21[C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=1)[CH2:12][CH2:11][CH2:10]2.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1>>[NH2:9][C:5]1[CH2:6][O:7][CH2:8][C:2]([F:1])([F:20])[C@@:3]2([C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:28](=[O:29])[C:25]4[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][N:26]=4)[CH:17]=3)[CH2:12][CH2:11][CH2:10]2)[N:4]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: NC1=N[C@@]2(CCCc3ccc(N)cc32)C(F)(F)COC1
Product: NC1=N[C@@]2(CCCc3ccc(NC(=O)c4ccc(Cl)cn4)cc32)C(F)(F)COC1
Yield: 45 %

Procedure:
The condensation of (R)-6′,6′-difluoro-3,4,6′,7′-tetrahydro-2H,2′H-spiro[naphthalene-1,5′-[1,4]oxazepine]-3′,7-diamine (intermediate C4.1) and 5-chloropicolinic acid yielded the title compound (45% yield) as an off-white solid. MS (ISP): m/z=421.1 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][C:12]=1[C:21]1[NH:26][C:25](=[O:27])[N:24]2[C:28]([CH3:34])=[N:29][C:30]([CH2:31][CH2:32][CH3:33])=[C:23]2[N:22]=1)[CH3:9]>ClCCl>[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)(=[O:19])=[O:18])=[CH:13][C:12]=1[C:21]1[NH:26][C:25](=[O:27])[N:24]2[C:28]([CH3:34])=[N:29][C:30]([CH2:31][CH2:32][CH3:33])=[C:23]2[N:22]=1)[CH3:9]
Reactant: OC1CCNCC1
Reactant: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nc12
Solvent: ClCCl
Product: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCC(O)CC4)ccc3OCC)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
74 mg (0.73 mmol) of 4-hydroxylpiperidine are added to a solution of 100 mg (0.24 mmol) of 4-ethoxy-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-α][1,3,5]triazin-2-yl)-benzenesulfonyl chloride (example VI) in 5 ml of dichloromethane and the reaction mixture is stirred at room temperature for 2 hours. After chromatographic purification (dichloromethane/methanol=95:5), 100 mg (87%) of 2-[2-ethoxy-5-(4-hydroxyl-piperidine-1-sulfonyl)-phenyl]-6-methyl-8-propyl-3H-imidazo[1,5-α][1,3,5]triazin4-one are obtained.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]#[N:18])=[N:9][CH:8]=1.FC(F)(F)C(O)=O>>[NH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]#[N:18])=[N:9][CH:8]=1
Reactant: COc1ccc(CNc2cnc(C#N)c3ccccc23)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ncc(N)c2ccccc12
Yield: 88.7 %

Procedure:
Compound 470C (50 mg, 0.16 mmol) was treated with trifluoroacetic acid (0.5 mL) for 1 h. The highly colored mixture was partitioned between ethyl acetate (30 mL) and 1N NaOH (30 mL). After washing with brine (15 mL), the organic layer was dried over magnesium sulfate and concentrated in vacuo to afford 24 mg (92%) of compound 470D as a yellow solid. HPLC: 99% at 1.09 min (retention time) (Phenomenex C-18, 5 micron column, 4.6×30 mm, eluting with 10-90% aqueous methanol over 2 min containing 0.1% TFA, 4 mL/min, monitoring at 254 nm). MS (ES+): m/z 170.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[NH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10](=O)[C:5]=2[S:4][CH:3]=1.P(Cl)(Cl)([Cl:19])=O>>[CH3:1][C:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([Cl:19])=[C:5]2[S:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c[nH]c2c(C)csc2c1=O
Product: CCOC(=O)c1cnc2c(C)csc2c1Cl

Procedure:
3-Methyl-6-ethoxycarbonylthieno[3,2-b]pyridin-7(4H)-one (7.0 g, 0.0295 mol) and phosphorus oxychloride (35 ml) were heated under reflux for 2 hours. The excess phosphorus oxychloride was removed by distillation under reduced pressure. The residue was poured onto ice, basified with 2N.NaOH and extracted with chloroform (3×100 ml). The combined chloroform extracts were washed with water, dried and evaporated to dryness to give a buff-coloured solid. This was collected, washed with petroleum ether (b.p. 40°-60°) and dried to give ethyl 3-methyl-7-chlorothieno[3,2-b]pyridine-6-carboxylate, 6.8 g, m.p. 113°-115°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:12]([O:16][C:17](=[O:29])[NH:18][CH2:19][C:20]1[C:21]([O:27][CH3:28])=[N:22][C:23]([NH2:26])=[CH:24][CH:25]=1)([CH3:15])([CH3:14])[CH3:13].N1C=CC=CC=1>C(Cl)Cl>[C:12]([O:16][C:17](=[O:29])[NH:18][CH2:19][C:20]1[C:21]([O:27][CH3:28])=[N:22][C:23]([NH:26][S:8]([C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=2)(=[O:10])=[O:9])=[CH:24][CH:25]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Reactant: COc1nc(N)ccc1CNC(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1nc(NS(=O)(=O)c2cccnc2Cl)ccc1CNC(=O)OC(C)(C)C
Yield: 64.4 %

Procedure:
The title compound (1.51 g, 3.53 mmol) was prepared from 2-chloropyridine-3-sulfonyl chloride (1.16 g, 5.48 mmol), tert-butyl(6-amino-2-methoxypyridin-3-yl)methylcarbamate (IntC7) (1.53 g, 6.03 mmol) and pyridine (1.33 mL, 16.4 mmol) in DCM (20 mL) at rt using the methods of (IntC1).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl>O>[CH2:17]([O:16][C:14]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])=[O:15])[CH3:18]
Reactant: CCOC(=O)Cl
Reactant: C[C@H](N)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)N[C@@H](C)C(=O)O
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Production of 3-(methyl ONN azoxy)-2,2-propylene dioxy-butane [Compound (IV):R3 =H, R4 =-CH2CH2CH2 -]: (a) In 700 ml of water were dissolved 40 g of L-alanine and 127 g of sodium carbonate. Then 64 ml of ethyl chloroformate was added dropwise to the mixture under ice-cooling and its stirring was conducted at room temperature for 30 minutes. A 35% hydrochloric acid was added to the reaction liquid to make this acidic and the reaction liquid was adsorbed on the column (6.5×60 cm) of diaion HP-20. After washing with water this was eluted with 70% methanol. The eluate was condensed under vacuum thereby to obtain 69 g (yield of 96%) of N-ethoxycarbonyl alanine as an oily substance.
Reaction SMILES: [NH2:1][O:2][CH2:3][CH2:4][OH:5].[F:6][C:7]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:8]=1[NH:9][C:10]1[C:11]([C:18](O)=[O:19])=[CH:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=1.C1COCC1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CO>[F:6][C:7]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:8]=1[NH:9][C:10]1[C:11]([C:18]([NH:1][O:2][CH2:3][CH2:4][OH:5])=[O:19])=[CH:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=1
Reactant: NOCCO
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(F)cc2F)cc1=O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cc(C(=O)NOCCO)c(Nc2ccc(F)cc2F)cc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.3 %

Procedure:
2-(Aminooxy)ethanol (0.05 g, 0.6 mmol) in MeOH (1 ml) was added to 4-(2,4-difluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid (0.15 g, 0.5 mmol) in MeOH (20 ml). THF was added dropwise until the reagents dissolved. The solution was stirred at RT for 30 min, after which DMT-MM (0.18 g, 0.6 mmol) was added. After stirring at RT for 60 h, the reaction had not gone to completion. Further 2-(aminooxy)ethanol (0.05 g, 0.6 mmol) and DMT-MM (0.18 g, 0.6 mmol) were added and the reaction mixture stirred for a further 2 h at RT. The solvent was then removed under reduced pressure and the residue dissolved in EtOAc. After washing with water ×2, sat. NaHCO3 and brine, the organic layer was dried (Na2SO4), concentrated and further purified by flash chromatography on silica gel (EtOAc followed by 10% MeOH/CH2Cl2) to give 4-(2,4-difluoroanilino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (0.07 g, 39%) as a white solid; m.p. (EtOAc/Hexane) 232-238° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.62 (br s, 1H), 9.21 (br s, 1H), 8.11 (s, 1H), 7.51-7.38 (m, 2H), 7.17-7.11 (m, 1H), 5.30 (s, 1H), 4.76 (br s, 1H), 3.92 (t, J=4.8 Hz, 2H), 3.62 (t, J=4.8 Hz, 2H), 3.34 (s, 3H). LCMS (ACPI+) 340 (100%). Anal. Calcd for C15H15F2N3O4.0.25 H2O: C, 52.4; H, 4.5; N, 12.2. Found C, 52.6; H, 4.5; N, 12.1
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:16][CH:15]([C:17]([C:19]3[CH:24]=[CH:23][C:22](F)=[CH:21][CH:20]=3)=[O:18])[CH2:14]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:16][CH:15]([C:17]([C:19]3[CH:24]=[CH:23][C:22]([N:26]4[CH:30]=[CH:29][N:28]=[CH:27]4)=[CH:21][CH:20]=3)=[O:18])[CH2:14]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: c1c[nH]cn1
Reactant: COc1ccc(CCN2CC(C(=O)c3ccc(F)cc3)C2)cc1OC
Product: COc1ccc(CCN2CC(C(=O)c3ccc(-n4ccnc4)cc3)C2)cc1OC

Procedure:
In a manner similar to Example 26, react [1-[2-(3,4-dimethoxyphenyl)ethyl]azetidin-3-yl](4-fluorophenyl)-methanone with 1H-imidazole to obtain the title compound.
Reaction SMILES: [CH3:1][Li].[C:3]([C:6]1[CH:14]=[CH:13][C:9]2[O:10][CH2:11][O:12][C:8]=2[CH:7]=1)(=[O:5])[CH3:4].O>O1CCCC1>[O:10]1[C:9]2[CH:13]=[CH:14][C:6]([C:3]([OH:5])([CH3:1])[CH3:4])=[CH:7][C:8]=2[O:12][CH2:11]1
Reactant: [Li]C
Reactant: CC(=O)c1ccc2c(c1)OCO2
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc2c(c1)OCO2
Temperature: -20 °C
Reaction time: 1 h

Procedure:
About 600 ml of 1.5M methyllithium (solution in ether) was added to 500 ml of tetrahydrofuran. A suspension of 93.45 g of 5-acetyl-1,3-benzodioxole in 900 ml of tetrahydrofuran was added thereto under cooling at -20° C. The mixture was stirred under these conditions for 1 h. Water was added to the reaction mixture. The product was extracted with ethyl acetate, washed with a saturated aqueous common salt solution and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to obtain 97 g of the intended compound in the form of an oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[CH3:14][C:15]1[C:16]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[N:17][CH:18]=[C:19]([CH3:21])[CH:20]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:25]2[CH2:26][CH2:27][N:22]([C:16]3[C:15]([CH3:14])=[CH:20][C:19]([CH3:21])=[CH:18][N:17]=3)[CH2:23][CH2:24]2)=[O:8])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3[N+](=O)[O-])CC2)c(C)c1
Yield: 90.3 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 60 and using 4-bromo-2-nitrobenzoic acid (2.3 g) and 1-(3,5-dimethylpyridin-2-yl)piperazine (1.91 g) described in Preparation Example 47, the title compound (3.54 g) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[C:12]([OH:14])=O.[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:18][CH2:17]1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[C:12]([NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:18][CH2:17]1)=[O:14]
Reactant: NC1CCN(CCCc2ccccc2)CC1
Reactant: Cc1[nH]c2ccc(O)cc2c1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: Cc1[nH]c2ccc(O)cc2c1C(=O)NC1CCN(CCCc2ccccc2)CC1

Procedure:
To a mixture of 3.2 g of 5-hydroxy-2-methylindole-3-carboxylic acid and 3.7 g of 4-amino-1-(3-phenylpropyl)piperidine in 60 ml of tetrahydrofuran was added 3.8 g of dicyclohexylcarbodiimide, and the whole mixture was refluxed for 2 hours. After cooling, the precipitated dicyclohexylurea was filtered off and the filtrate was concentrated. The residue was crystallized from ethyl acetate. The crystals were filtered with suction, and recrystallized from a mixture of ethyl acetate and methanol to give 5-hydroxy-2-methyl-N-[1-(3-phenylpropyl)-4-piperidyl]indole-3-carboxamide, melting at 181°-184° C. The compound was precipitated as a monohydrate at first, but the water of crystallization was evaporated by vacuum drying over 3 hours at 90° C.
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][C:8]([N:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13][CH2:12]3)=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:20][C:21]([O:23]C)=[O:22].[OH-].[Na+]>C1COCC1.CO>[F:1][C:2]1[C:10]2[O:9][C:8]([N:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13][CH2:12]3)=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:20][C:21]([OH:23])=[O:22]
Reactant: COC(=O)Cc1ccc2nc(N3CCc4ccccc43)oc2c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc2nc(N3CCc4ccccc43)oc2c1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 90 %

Procedure:
To methyl (7-fluoro-2-(1-indolinyl)-6-benzoxazolyl)acetate (330 mg, 1.01 mmol) were added THF/methanol (2:1, 12 ml) and 1N NaOH (4 ml). After stirring at room temperature for 14 hours, the reaction mixture was distilled under reduced pressure to remove the solvent. The residue was acidified with 1N HCl. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give (7-fluoro-2-(1-indolinyl)-6-benzoxazolyl)acetic acid (284 mg, 90%) as a pale brown solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]([Br:22])[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOC(C)=O.[H][H]>[Pt]=O.CCO>[CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]([Br:22])[C:9]1=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=c1c(Br)c(C#Cc2ccccc2)ccn1Cc1ccccc1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=c1c(Br)c(CCc2ccccc2)ccn1Cc1ccccc1

Procedure:
A mixture of 1-benzyl-3-bromo-4-(phenylethynyl)pyridin-2(1H)-one (0.3 g), and platinum oxide (0.05 g) in a solvent mixture of EtOAc (10.0 mL) and EtOH (10.0 mL) was stirred in an atmosphere of hydrogen at 15 psi in a Fischer porter bottle for 45 min. The catalyst was removed by filtration, and filtrate was concentrated. The resulting residue was purified by silica gel flash chromatography using 25% EtOAc in hexanes as the eluent. The appropriate fractions (visualized under an UV lamp) were combined and concentrated under reduced pressure. 1H-NMR (CD3OD) δ: 7.56 (d, 1H, J=6.8 Hz), 7.31-7.17 (m, 10H), 6.24 (d, 1H, J=6.8 Hz), 5.19 (s, 2H), 2.96 (m, 2H), and 2.91 (m, 2H); ES-MS m/z=368 (MH+); HR-MS m/z (MH+) calcd C20H19NOBr 368.0650, found 368.0630.
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].CON(C)[C:8](=[O:18])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.CCOCC>C1COCC1>[F:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:9][C:8](=[O:18])[C:1]#[CH:2])=[CH:16][CH:15]=1
Reactant: CON(C)C(=O)COc1ccc(F)cc1
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CC(=O)COc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 209.7 %

Procedure:
A solution of ethynylmagnesium bromide (0.5 M in THF, 508 mL, 254 mmol), was added slowly, as a stream down the side of the flask, to an ice water cooled solution of N-methoxy-N-methyl-2-(4-fluorophenoxy)ethanamide (20.00 g, 74 mmol) in THF (100 mL). After an additional 30 minutes at 0° C., the reaction mixture was poured into a vigorously stirred mixture of 1M NaH2SO4 (1700 mL) and ether (1 L). The layers were separated and the aqueous layer then extracted with ether (700 mL). The combined organic phases were washed with brine and dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by eluting through a plug of silica gel (10 cm×3 cm) with 1:4 ether:pet. ether to afford 27.65 g (91% yield) of 4-(4-fluorophenoxy)-1-butyn-3-one, a compound of formula (AA), as a low melting solid; 1H NMR (CDCl3) δ3.40 (s, 1H), 4.70 (s, 2H), 6.85 (m, 2H), 7.0 (t, 2H) ppm.
Reaction SMILES: Cl.[F:2][C:3]([F:41])([F:40])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:7]=1[CH2:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([N:29]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH2:32][O:31][C:30]2=[O:39])[CH2:25][CH2:24]1)=[O:22].[C:42](OC(=O)C)(=[O:44])[CH3:43].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:41][C:3]([F:2])([F:40])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:14][CH2:15][CH:16]([NH:19][C:42](=[O:44])[CH3:43])[CH2:17][CH2:18]2)[CH:9]=[CH:8][C:7]=1[CH2:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([N:29]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH2:32][O:31][C:30]2=[O:39])[CH2:25][CH2:24]1)=[O:22]
Reactant: NC1CCC(Oc2ccc(CC(=O)N3CCC(N4C(=O)OCc5ccccc54)CC3)c(OCC(F)(F)F)c2)CC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC1CCC(Oc2ccc(CC(=O)N3CCC(N4C(=O)OCc5ccccc54)CC3)c(OCC(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(1-(2-(2,2,2-trifluoroethoxy)-4-(1-aminocyclohex-4-yl oxy)phenylacetyl)piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one hydrochloride (0.090 g, 0.15 mmol) from Example 41 in CH2Cl2 (4 mL) was added acetic anhydride (0.031 mL, 0.3 mmol) and DIEA (0.052 mL, 0.3 mmol). The solution was stirred at ambient temperature for 1 h and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with 0.25 M aqueous citric acid (20 mL), H2O (10 mL), and saturated aqueous NaHCO3 (20 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give the title compound as an amorphous solid.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[S:22](O)(=[O:24])=[O:23])=[CH:12][CH:11]=2)[C:7]2[CH:26]=[C:27]([C:31]3[N:35]([CH3:36])[C:34]4[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=4[N:32]=3)[CH:28]=[C:29]([CH3:30])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[N:41]1C=CC=CC=1>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[S:22](=[O:24])(=[O:23])[NH2:41])=[CH:12][CH:11]=2)[C:7]2[CH:26]=[C:27]([C:31]3[N:35]([CH3:36])[C:34]4[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=4[N:32]=3)[CH:28]=[C:29]([CH3:30])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2S(=O)(=O)O)cc1
Reactant: c1ccncc1
Product: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1

Procedure:
1.2 g of 4'-[(2-n-Propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-sulpho-biphenyl are stirred with 10 ml of pyridine at 60° C. for 1 hour. The solution is then evaporated down, the residue is stirred with acetone and suction filtered. It is then taken up in 15 ml of thionylchloride and stirred for 1 hour at 60° C. After evaporation the residue is taken up in 10 ml of dimethylformamide and stirred into 10 ml of dimethylformamide saturated with ammonia. After 15 minutes stirring at ambient temperature the mixture is evaporated down and chromatographed on silica gel with dichloromethane/ethanol (98:2).
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:20]=O)=[N:9]2)=[CH:4][CH:3]=1.[NH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[NH2:23]>CCO>[Br:1][C:2]1[C:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:20]=[N:23][NH:22][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1c(Br)ccc2ccc(C=O)nc12
Reactant: NNc1ccccn1
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)Oc1c(Br)ccc2ccc(C=NNc3ccccn3)nc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.9 %

Procedure:
To the product from Step C (2.95 g, 8.05 mmol) was added EtOH (30 mL, anhydrous). To this solution was added 2-hydrazinylpyridine (0.967 g, 8.86 mmol). The mixture was stirred at ambient temperature for 24 hours. The resulting precipitate was isolated by vacuum filtration and washed with cold EtOH and then dried in vacuo to afford 2.98 g (73%) of the desired product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][CH:15]=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1.[Cl:16]N1C2C=CC=CC=2N=N1>ClCCl>[Cl:16][C:15]1[CH:14]=[N:13][N:12]2[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:8][CH:9]=[N:10][C:11]=12
Reactant: c1cncc(-c2ccnc3ccnn23)c1
Reactant: Cln1nnc2ccccc21
Solvent: ClCCl
Product: Clc1cnn2c(-c3cccnc3)ccnc12

Procedure:
A mixture of 3.92 g. of 7-(3-pyridyl)pyrazolo[1,5-a]-pyrimidine and 3.40 g. of N-chlorobenzotriazole in 100 ml. of dichloromethane is heated on a steam bath for 15 minutes. The mixture is poured into 100 ml. of ice cold 2.5 N sodium hydroxide and the dichloromethane layer is separated and dried over anhydrous sodium sulfate. The dichloromethane extract is passed through a column of hydrous magnesium silicate and the eluent is concentrated and diluted with hexane to give 2.75 g. of the product of the example, m.p. 225°-226° C.