Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([C:5]1[C:6]([C:15](O)=[O:16])=[CH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3][CH3:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[OH:16][CH2:15][C:6]1[C:5]([CH:2]([OH:1])[CH2:3][CH3:4])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: CCC(=O)c1cc2ccccc2cc1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(O)c1cc2ccccc2cc1CO
Reaction time: 2 h

Procedure:
The above carboxylic acid (11 g) in THF (150 ml) was added to lithium aluminium hydride (6.0 g) in THF (150 ml) over 0.5 hr. The reaction mixture was stirred for 2 hr. and water was carefully added. The resultant slurry was washed with ether (3×100 ml) and the combined ethereal washings were dried (magnesium sulphate) and evaporated to dryness to give 2-hydroxymethyl-3-(1'-hydroxypropyl)naphthalene as an oil; a small portion was recrystallised from light petroleum (b.p. 60°-80°)/chloroform to give a crystalline solid, m.p. 70°.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH2:18])=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>O1CCOCC1.N1C=CC=CC=1>[Br:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[N:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Br)cccc1-2
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Product: N#Cc1ncn2c1[C@@H]1CCN1C(=O)c1c(Br)cccc1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
A suspension of 19 g (54.7 mmol) of (S)-8-bromo-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamide in a mixture of 100 ml of dioxan and 15 ml of pyridine was treated with 15 ml of trifluoroacetic anhydride at 7° to 10°. The suspension was stirred at room temperature for 1 hour and poured into 600 ml of water. After 1 hour the suspension was suction filtered. There were obtained 13.1 g (72%) of (S)-8-bromo-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carbonitrile of m.p. 133°-136°.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[CH3:23]C(OC(OC(OC(C)(C)C)=O)=O)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:14]([N:11]1[C:6]2[N:7]=[C:8]([CH2:9][CH3:10])[C:3]([CH2:2][NH:1][CH3:23])=[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[C:5]=2[CH:13]=[N:12]1)[CH3:15]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
To the solution of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-amine (0.303 g, 1.0 mmol) in THF (1 mL) was added Boc2O (0.229 g, 1.05 mmol). This mixture was stirred at room temperature for 30 mins and then LAH (5.0 mL, 1.0 M in THF) was added, and that mixture heated with a microwave machine at 100° C. for 30 mins. The reaction was then quenched with Na2SO4 (sat. aq.) slowly, filtered, dried over Na2SO4, filtered, and concentrated to afford 0.252 g (79%) of the title compound. LC-MS m/z 318 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][C@@H:13]([C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[CH3:14])[C@@H:8]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C@@H:7]1[CH2:36][NH2:37])(=O)C.[C:38]1(=O)[CH2:42][CH2:41][C:40](=[O:43])[CH2:39]1>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[F:23][C:21]([F:24])([F:22])[C:19]1[CH:20]=[C:15]([C@H:13]([O:12][C@H:9]2[CH2:10][CH2:11][C@H:6]([CH2:5][OH:4])[C@@H:7]([CH2:36][NH:37][C:38]3[CH2:42][CH2:41][C:40](=[O:43])[CH:39]=3)[C@@H:8]2[C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[CH3:14])[CH:16]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:18]=1
Reactant: CC(=O)OC[C@H]1CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccc(F)cc2)[C@@H]1CN
Reactant: O=C1CCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C[C@@H](O[C@H]1CC[C@H](CO)[C@@H](CNC2=CC(=O)CC2)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 32.2 %

Procedure:
To a solution of 0.35 g (0.65 mmol) of [(1S,2R,3R,4S)-2-(aminomethyl)-4-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(4-fluorophenyl)cyclohexyl]methyl acetate (from Step N) in 30 mL dry toluene was added cyclopentane-1,3-dione (0.064 g, 0.65 mmol) and a catalytic amount (˜0.5 mg) of PTSA. The resulting mixture was heated at reflux for 1 hr. The solvent was removed under vacuum and the residue was dissolved in 30 mL methanol. Sodium hydroxide (15 mL, 5 N) was added and the resulting mixture was stirred at 50° C. for 2 hr. The methanol and some of water were removed under vacuum. Water (20 mL) was added and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine, dried over Na2SO4 and the solvent was removed under vacuum. The residue was purified by prep. TLC (9:1 ethyl acetate:hexane) to give the title compound (0.12 g). 1H-NMR (CDCl3) δ: 7.70 (1H, s), 7.18 (2H, s), 6.98 (2H, m), 6.93 (2H, m), 5.18 (0.5H, bs), 4.67 (0.5H, bs), 4.22 (1H, m), 3.78 (1H, m), 3.47 (1H, m), 3.27 (1H, m), 3.07 (1H, m), 2.95 (1H, m), 2.30 (1H, t), 2.40-2.20 (5H, m), 1.90 (1H, m), 1.80 (1H, m), 1.70-1.20 (3H, m), 1.33 (3H, d, J=6.4 Hz). MS: (MH)+ 574.1.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[NH:28][CH:29]=[C:30]([C:32]#[N:33])[N:31]=3)=[O:26])=[C:20]([C:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]=3)[CH:19]=2)[CH2:14][CH2:13]1)=[O:11].[BH-](OC(C)=O)(OC(C)=O)[O:41][C:42]([CH3:44])=O.[Na+].C(C=O)=O>C(Cl)Cl>[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:34]1([C:20]2[CH:19]=[C:18]([CH:15]3[CH2:16][CH2:17][N:12]([C:10](=[O:11])[CH2:9][NH:8][CH2:44][CH2:42][OH:41])[CH2:13][CH2:14]3)[CH:23]=[CH:22][C:21]=2[NH:24][C:25]([C:27]2[NH:28][CH:29]=[C:30]([C:32]#[N:33])[N:31]=2)=[O:26])[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(C(=O)CN)CC3)cc2C2=CCCCC2)n1
Agent: O=CC=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(C(=O)CNCCO)CC3)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
A suspension of 4-cyano-1H-imidazole-2-carboxylic acid {4-[1-(2-amino-acetyl)-piperidin-4-yl]-2-cyclohex-1-enyl-phenyl]-amide trifluoroacetic acid salt (as prepared in the previous step, 0.42 g, 0.77 mmol) in CH2Cl2 (20 mL) was treated with Na(OAc)3BH (0.33 g, 1.54 mmol) and solid glyoxal (44.6 mg, 0.77 mmol). The mixture stirred at room temperature for 1 h, and the solvent was evaporated in vacuo. The residue was taken up in MeOH and the solids filtered off, and the filtrate was concentrated in vacuo. Reverse phase HPLC (C-18 column) (20% to 60% acetonitrile in water with 0.1% TFA over 30 min) afforded the title compound (83 mg, 19% over two steps) as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.16-8.09 (m, 1H), 8.05-8.01 (m, 1H), 7.22-7.15 (m, 1H), 7.11-7.06 (m, 1H), 5.84-5.79 (m, 1H), 4.72-4.62 (m, 1H), 4.24-3.91 (m, 2H), 3.89-3.80 (m, 2H), 3.28-3.18 (m, 2H), 2.92-2.79 (m, 2H), 2.28 (br s, 4H), 1.98-1.89 (m, 2H), 1.89-1.76 (m, 4H), 1.76-1.57 (m, 2H). LC-MS (ESI, m/z): Calcd. for C26H32N6O3 477.2 (M+H). found 477.2.
Reaction SMILES: [CH3:1][SiH:2]([Cl:4])[Cl:3].[CH2:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:5]([CH2:1][SiH:2]([Cl:4])[Cl:3])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C=Cc1ccccc1
Reactant: C[SiH](Cl)Cl
Product: Cl[SiH](Cl)CCCc1ccccc1

Procedure:
The intermediate isomeric phenethylmethyldichlorosilane was prepared from methyldichorosilane and styrene using the method described by J. L. Speier at pages 435ff of ADVANCES IN ORGANOMETALLIC CHEMISTRY, Academic Press, Edited by F. G. A. Stone and R. West, 17 (1979). It contained approximately 65% of the 2-phenethyl isomer and 35% of the 1-phenethyl isomer.
Reaction SMILES: [Cl:1][C:2]1[CH2:3][CH2:4][N:5](C(OCC2C=CC=CC=2)=O)[CH2:6][CH2:7][C:8]=1[CH:9]=[O:10].[BrH:21]>C(O)(=O)C>[BrH:21].[Cl:1][C:2]1[CH2:3][CH2:4][NH:5][CH2:6][CH2:7][C:8]=1[CH:9]=[O:10]
Reactant: O=CC1=C(Cl)CCN(C(=O)OCc2ccccc2)CC1
Agent: Br
Solvent: CC(=O)O
Product: O=CC1=C(Cl)CCNCC1

Procedure:
10.5 gm (0.036 mol) of benzyl 4-chloro-5-formyl-2,3,6,7-tetrahydro-1H-1-azepine-carboxylate were mixed with 100 ml of a 40% solution of hydrogen bromide in glacial acetic acid, while stirring and cooling with ice. The mixture was then stirred for 3 hours at room temperature. It was then concentrated by evaporation in a rotary evaporator, and the residue was triturated with ether. After the ether had been decanted several times, the product was suction-filtered and washed twice with absolute ether.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14]C)=[CH:11][CH:12]=2)[N:7]([CH3:16])[C:6]=1[CH2:17][CH3:18])=[O:4].B(Br)(Br)Br>C(Cl)Cl>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[N:7]([CH3:16])[C:6]=1[CH2:17][CH3:18])=[O:4]
Reactant: CCc1c(C(=O)NC)c2ccc(OC)cc2n1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCc1c(C(=O)NC)c2ccc(O)cc2n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
To a solution of 2-ethyl-6-methoxy-1-methyl-1H-indole-3-carboxylic acid methylamide 73f (0.267 g, 1.08 mmole) in 15 ml CH2Cl2 at 0° C. was added BBr3 (1.0 M in CH2Cl2, 3.25 ml, 3.25 mmole). The reaction mixture was stirred at room temperature for 2 h, quenched with saturated NH4OH to make pH˜10. The mixture was diluted with H2O and extracted with 10% CH3OH in CH2Cl2. The organic layer was dried over MgSO4 and concentrated. The residue purified by flash column chromatography (3–5% CH3OH in CH2Cl2) to give pale yellow color solid (0.170 g, 68%). 1H NMR (CDCl3) δ 7.40 (1H, d, J=8.5 Hz), 6.65 (1H, s), 6.59 (1H, d, J=8.5 Hz), 3.53 (3H, s), 3.28 (2H, q, J=7.5 Hz), 2.82 (3H, s), 1.13 (3H, t, J=7.5 Hz). ESIMS (MH+): 233.15.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:14][CH2:13][C@@H:12]([CH2:15][OH:16])[O:11][CH2:10]1)=O)(C)(C)C.[ClH:17].O1CCOCC1>CO>[ClH:17].[NH2:8][C@@H:9]1[CH2:14][CH2:13][C@@H:12]([CH2:15][OH:16])[O:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](CO)OC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N[C@@H]1CC[C@@H](CO)OC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
1,5-Anhydro-2-[(tert-butoxycarbonyl)amino]-2,3,4-trideoxy-D-erythro-hexitol (Eur. J. Org. Chem., 2003, 2418-2427) (6.00 g, 0.03 mol) was dissolved in methanol (20 ml), 4N hydrochloric acid/1,4-dioxane solution (60 ml) was added and the resulting mixture was stirred at room temperature for 1 hour. The reaction solvent was evaporated under reduced pressure to give 4.5 g (100%) of the title compound as a colorless solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[CH3:13][S:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([CH2:24][NH2:25])[CH:21]=[CH:20][C:18]=2[N:19]=1>CN(C=O)C.CCOC(C)=O>[CH3:12][O:11][C:4]1[N:3]=[C:2]([NH:25][CH2:24][C:22]2[CH:21]=[CH:20][C:18]3[N:19]=[C:15]([S:14][CH3:13])[S:16][C:17]=3[CH:23]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: CSc1nc2ccc(CN)cc2s1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(NCc2ccc3nc(SC)sc3c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
To a solution of 2-chloro-6-methoxy-3-nitropyridine (430 mg, 2.3 mmol) in DMF (6 mL) was added (2-(methylthio)benzo[d]thiazol-6-yl)methanamine (437 mg, 2.1 mmol) from Step 4 of this Example slowly at 0° C. The reaction mixture was stirred at rt overnight. The resulting reaction mixture was diluted with 60 mL of EtOAc and washed with saturated aq NaHCO3 and brine. The organic layer was dried over MgSO4, and concentrated under reduced pressure. The crude product was purified on a silica gel column using CH2Cl2 as eluent to give 6-methoxy-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3-nitropyridin-2-amine as a yellow solid (431 mg, 57%). LCMS (ESI) m/z 363 (M+H)+.
Reaction SMILES: [C:1]1([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([CH:9]2[CH2:14][CH2:13][N:12](CC3C=CC=CC=3)[CH2:11][CH2:10]2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(O)C.C(OC(C)C)(C)C>[Pd].C(O)C>[C:1]1([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[OH:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CC(C)OC(C)C
Solvent: CC(C)O
Solvent: CCO
Product: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Reaction time: 72 h

Procedure:
A mixture of 35.8 g (0.1 mole) of α,α-diphenyl-1-(phenylmethyl)-4-piperidinemethanol and 5% palladium on carbon in 500 ml of absolute ethanol was hydrogenated at 60° C. in a Parr apparatus for 3 days. The mixture was filtered through Celite® and the filtrate was concentrated to give a solid residue. The solid was triturated with petroleum ether (30°-60° C.), collected by filtration and dried to give 26.7 g (quantitative) of white solid. An analytical sample, m.p. 160°-161° C. was prepared from 2-propanol-isopropyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:10]([F:12])[F:11])=[C:6]([CH:9]=1)[C:7]#[N:8].C([Br:17])(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]([Br:17])([F:11])[F:12])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: ClC(Cl)(Cl)Br
Reactant: N#Cc1cc(Br)ccc1C(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: N#Cc1cc(Br)ccc1C(F)(F)Br

Procedure:
A mixture of the title compound from Example 302 Step A (2.44 g, 10.5 mmol), CCl3Br (8 mL) and Na2CO3 (480 mg, 4.5 mmol) in a sealed vessel was illuminated by a sunlamp for 30 h. Purification by silica gel flash chromatography using 8:1 to 6:1 to 4:1 hexanes:DCM as mobile phase yielded the title compound: 1H NMR (500 MHz, CD2Cl2) δ 8.03 (s, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.65 (d, J=8.5 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:26])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]([OH:25])=O)[CH:16]=1.C(C1NC=CN=1)([C:29]1[NH:30]C=CN=1)=O.CN>O1CCCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:26])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]([NH:30][CH3:29])=[O:25])[CH:16]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Nc1c(C(=O)c2cccc(OCC(=O)O)c2)cnn1-c1ccc(F)cc1
Agent: CN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)COc1cccc(C(=O)c2cnn(-c3ccc(F)cc3)c2N)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
To a solution of 5-amino-4-[3-(carboxymethyloxy)benzoyl]-1-(4-fluorophenyl)pyrazole (0.5 g, 1.43 mmol) in tetrahydrofuran (10 ml) was added carbonyl diimidazole (0.3 g, 1.85 mmol) and the reaction mixture was heated at 60° C. After 1 h, methylamine (10 ml, 5 mmol, 0.5 M solution in tetrahydrofuran) was added and reaction was continued at 60° C. overnight. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was separated and washed with brine and dried over sodium sulfate. The organics were removed in vacuo and the residue was purified by flash chromatography (elution gradient: 20-30% acetone/hexane) to give 5-amino-1-(4-fluorophenyl)-4-[3-(methylaminocarbonylmethyloxy)benzoyl]pyrazole (0.25 g, mpt. 195.6-196.3° C.) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[N:7][C:6]=1Cl)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:20][S:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>C1(C)C=CC=CC=1.CN1CCCC1.[Cu](I)I>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[N:7][C:6]=1[O:28][C:25]1[CH:26]=[CH:27][C:22]([S:21][CH3:20])=[CH:23][CH:24]=1)[CH3:2]
Reactant: CSc1ccc(O)cc1
Reactant: CCOC(=O)c1cc(F)cnc1Cl
Agent: I[Cu]I
Agent: CN1CCCC1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(F)cnc1Oc1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 69.2 %

Procedure:
To a suspension of ethyl-2-chloro-5-fluoro-nicotinate (2.00 g, 9.82 mmol) and caesium carbonate (4.48 g, 13.8 mmol) in toluene/N-methylpyrrolidine (4:1, 50 ml) was added 4-methylsulfanylphenol (1.51 g, 10.8 mmol) at room temperature under nitrogen. Copper iodide (94 mg, 0.49 mmol) and the reaction was heated to 100° C. and stirred at this temperature for 17 h. The reaction was cooled to room temperature, partitioned between water (100 ml) and ethyl acetate (200 ml) and filtered. The filtrate was separated and the organic phase washed with brine (50 ml), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with toluene:ethyl acetate (95:5, by volume) and the product was triturated with pentane (10 ml) to give 5-fluoro-2-(4-methylsulfanyl-phenoxy)-nicotinic acid ethyl ester (2.09 g) as a yellow oil.
Reaction SMILES: C([O:4][CH:5]1[CH:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[C:11]2Br)[CH2:8][CH:7]([CH2:22][O:23]C(=O)C)[CH:6]1[O:27]C(=O)C)(=O)C.[NH:31]1[CH2:34][CH2:33][CH2:32]1.N>C(O)C>[Cl:19][C:17]1[C:16]([Cl:20])=[CH:15][C:14]2[N:10]([CH:9]3[CH:5]([OH:4])[CH:6]([OH:27])[CH:7]([CH2:22][OH:23])[CH2:8]3)[C:11]([N:31]3[CH2:34][CH2:33][CH2:32]3)=[N:12][C:13]=2[CH:18]=1
Reactant: C1CNC1
Reactant: CC(=O)OCC1CC(n2c(Br)nc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O
Agent: N
Solvent: CCO
Product: OCC1CC(n2c(N3CCC3)nc3cc(Cl)c(Cl)cc32)C(O)C1O
Reaction time: 18 h
Yield: 40.9 %

Procedure:
(±)(1R*, 2S*, 3S*, 5S*)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (500 mg, 0.958 mmol) was dissolved in ethanol (7 mL). Azetidine (Aldrich, 250 mg, 4.4 mmol as 98%) was added and the solution was refluxed under nitrogen for 48 hours. Methanolic ammonia (saturated at 0° C., 20 mL) was added to the cooled solution and this solution was stirred for an additional 18 hours. Volatiles were evaporated, the residue was redissolved in ethanol (10 mL) and 1N sodium hydroxide (0.96 mL) was added. Volatiles were evaporated and the residual solids were triturated with water (3 mL) and filtered. Resolidification of the solid from acetonitrile-methanol gave title compound as white powder (146 mg, 41%), m.p. 221°-222° C.; 1H-NMR(DMSO-d6)δ: 7.78 and 7.53 (both s, 1 each, 2 aromatic CH), 5.05 (t, J=4.3 Hz, 1, OH), 4.91 (d, J=5.3 Hz, 1, OH), 4.59 (d, J=3.7 Hz, 1, OH), 4.45-4.40 (m, 2, OCH and NCH), 4.25-4.15 (m, 4, 2 CH2N), 3.82-3.79 (m, 1, OCH), 3.66-3.43 (both m, 1 each, OCH2), 2.40-2.32 (m, 2, CH2), 2.03-1.95 (m, 3, CH2 and NCH); mass spectrum (CI): 372(M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([C:17]1[N:18]=[CH:19][N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:21]=1)([OH:16])[CH:13]([CH3:15])[CH3:14])[CH:6]=[CH:5]2.Br[CH2:42][CH2:43][CH3:44]>>[NH:20]1[CH:21]=[C:17]([C:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([O:1][CH2:42][CH2:43][CH3:44])[CH:3]=3)[CH:8]=2)([OH:16])[CH:13]([CH3:14])[CH3:15])[N:18]=[CH:19]1
Reactant: CC(C)C(O)(c1ccc2cc(O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCCBr
Product: CCCOc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1

Procedure:
In a similar manner to that described in Example 31-(i), the reaction of 1-(6-hydroxynaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (1.265 g) with 1-bromopropane (0.24 ml) was carried out to give the titled compound (0.711 g) as a colorless solid.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([NH:5][C:6](=[N:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[NH:18][CH:17]=[N:16][C:15]=1[CH3:19])SC)#[N:4]>C(O)C>[C:3]([NH:5][C:6]([NH:2][CH3:1])=[N:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[NH:18][CH:17]=[N:16][C:15]=1[CH3:19])#[N:4]
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Reactant: CN
Solvent: CCO
Product: CNC(=NCCSCc1[nH]cnc1C)NC#N
Reaction time: 2.5 h

Procedure:
A solution of methylamine in ethanol (33%, 75 ml.) was added to a solution of N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea (10.1 g.) in ethanol (30 ml). The reaction mixture was set aside at room temperature for 2.5 hours. Following concentration under reduced pressure, the residue was recrystallised twice from isopropyl alcohol/petroleum ether, affording N-cyano-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine (8.6 g.), m.p. 141°-143°. (Found: C, 47.5; H, 6.3; N, 33.2; S. 12.9. C10H16N6S requires: C, 47.6; H, 6.4; N, 33.3; S, 12.7).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C:17]3[C:18]([CH3:26])=[N:19][N:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=34)[S:11][C:12]=2[C:13]([O:15]C)=[O:14])[CH:5]=[CH:6][CH:7]=1.O1CCCC1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C:17]3[C:18]([CH3:26])=[N:19][N:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=34)[S:11][C:12]=2[C:13]([OH:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1sc(-c2c(C)nn3ccccc23)nc1-c1cccc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nn2ccccc2c1-c1nc(-c2cccc(F)c2)c(C(=O)O)s1
Temperature: 70 °C
Reaction time: 1 h
Yield: 110.1 %

Procedure:
To a solution of methyl 4-(3-fluorophenyl)-2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-1,3-thiazole-5-carboxylate (120 mg, 0.27 mmol) purified above in methanol (15 mL) and tetrahydrofuran (25 mL) was added 8N aqueous sodium hydroxide solution (6 mL), and the mixture was stirred at 70° C. for 1 hr. The reaction solution was cooled to 0° C., 6N hydrochloric acid was added to adjust the solution to about pH 3.0, and the reaction solution was extracted with ethyl acetate (100 mL×2). The collected organic layer was dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the filtrate was concentrated to give the title compound (105 mg, 91%) as a yellow solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[CH:12]1[C:17]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:16][C:15]([NH2:22])=[C:14](O)[CH:13]=1>>[CH3:1][NH:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]2[O:9][C:14]3[CH:13]=[CH:12][C:17]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:16][C:15]=3[N:22]=2)=[CH:10][CH:11]=1
Reactant: Nc1cc(S(=O)(=O)O)ccc1O
Reactant: CNc1ccc(C(=O)O)cc1
Product: CNc1ccc(-c2nc3cc(S(=O)(=O)O)ccc3o2)cc1

Procedure:
In accordance with the procedure of Example 1, 8.0 g of p-methylamino-benzoic acid were reacted with 10.0 g of 2-aminophenol-4-sulfonic acid to yield 2-(p-methylaminophenyl)-benzoxazole-5-sulfonic acid, melting point 333° (with decomposition).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([C:11](N(OC)C)=[O:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH:11]=[O:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)c1coc2c(Br)cccc12
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: O=Cc1coc2c(Br)cccc12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of Compound 7-bromo-N-methoxy-N-methyl-1-benzofuran-3-carboxamide (8.98 g, 31.63 mmol) in 150 mL dry toluene at −78° C. was added DIBAL-H (31.63 mL, 31.63 mmol) dropwise. The reaction mixture was stirred for 1 hour at −78° C. under a nitrogen atmosphere, and quenched slowly with saturated aqueous NH4Cl. After warming to room temperature, the mixture was exacted with EtOAc (300 mL), and washed with brine (50 mL), dried over Na2SO4. The solvent was concentrated in vacua. The residue was separated and purified with silica gel chromatography to give product 7-bromo-1-benzofuran-3-carbaldehyde.