Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][C:4]=1[C:14](=[O:16])[CH3:15].[C:17]([C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)([OH:19])=[O:18]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][C:4]=1[C:14](=[O:16])/[CH:15]=[CH:24]/[C:23]1[CH:26]=[CH:27][C:20]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=1
Reactant: COc1cc(-c2cccs2)ccc1C(C)=O
Reactant: O=Cc1ccc(C(=O)O)cc1
Product: COc1cc(-c2cccs2)ccc1C(=O)/C=C/c1ccc(C(=O)O)cc1

Procedure:
The title compound was prepared by condensing 1-(2-methoxy-4-thiophen-2-yl-phenyl)-ethanone (Ex-19A) and 4-carboxybenzaldehyde in a similar manner as described in Ex-17 except an acidic workup. Yellow solid, mp 193–195° C. 1H-NMR (CDCl3) □ 7.70 (d, J=8 Hz, 2H), 7.38 (d, J=8 Hz, 1H), 7.07–7.16 (m, 4H), 6.75–6.80 (m, 4H), 6.42 (d, J=16 Hz, 1H), 3.67 (s, 3H), MS m/z=364 ([M]+, 100%). Anal. Calculated for C21H16O4S: C, 69.21; H, 4.43; S, 8.80; found: C, 69.02; H, 4.56; S, 8.75.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:16]=[C:10]2[CH:9]1[CH:21]([CH:23]1[CH2:25][CH2:24]1)O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(S(F)(F)[F:32])CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:16]=[C:10]2[CH:9]1[CH:21]([CH:23]1[CH2:25][CH2:24]1)[F:32])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCn2nc(C(F)(F)F)nc2C1C(O)C1CC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCn2nc(C(F)(F)F)nc2C1C(F)C1CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 200 mg (0.55 mmol) of [7-N-(tert-butoxycarbonyl)-2-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-α]pyrazin-8-yl](cyclopropyl)methanol (prepared as outlined in Example 3, Step A) in 3.5 mL of dichloromethane was cooled to −78° C. and 0.406 mL (3.31 mmol) of (diethylamino)sulfur trifluoride (DAST) was added. The reaction mixture was stirred at −78° C. for 1 h, then warmed to ambient temperature and stirred overnight. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and dichloromethane. The aqueous phase was extracted with three portions of dichloromethane. The combined organic phases were washed with brine, dried over magnesium sulfate, and concentrated. Purification by HPLC (Gilson, YMC C-18, 10 to 90% acetonitrile/water gradient) gave the title compound.
Reaction SMILES: [F:1][CH:2]([F:39])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[N:8]=[C:7]2[C:14]1[N:15]=[C:16]2[C:22]([C:23]([NH:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])=[O:24])=[CH:21][N:20](COCC[Si](C)(C)C)[C:17]2=[N:18][CH:19]=1.C(O)(C(F)(F)F)=O>ClCCl>[F:39][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[N:8]=[C:7]2[C:14]1[N:15]=[C:16]2[C:22]([C:23]([NH:25][C:26]([CH3:29])([CH3:30])[CH2:27][OH:28])=[O:24])=[CH:21][NH:20][C:17]2=[N:18][CH:19]=1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)CO)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)CO)c3n2)c2cc(OC(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To a pale yellow solution of 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (34.4 mg, 61.4 μmol) in dichloromethane (1.44 mL) was added TFA (426 mg, 288 μL, 3.74 mmol, Eq: 60.9), the reaction mixture turned orange and was stirred at 25° C. overnight then concentrated. The residue was re-dissolved in 5 mL of a solution of (dichloromethane/MeOH/ammonium hydroxide; 60:10:1) and stirred at 25° C. for 3 h, then evaporated to a light yellow solid, dissolved in dichloromethane (containing a few drops of MeOH) and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane to give a mixture of 2 compounds, no pure compound obtained. Mixture combined again and purified by preparative TLC (Silica GF 1000 μm, 20×40 cm (Gypsum Binder, Fluorescent Indicator)) to give the desired 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (20 mg, 46.5 μmol, 75.7%) as white needles. MS (M+H)+=431; 1H NMR (DMSO-d6) δ: 9.07 (s, 1H), 8.37 (s, 1H), 8.21 (d, J=1.9 Hz, 1H), 7.80-7.90 (m, 2H), 7.35-7.42 (m, 1H), 7.18 (t, J=74.4 Hz, 1H), 4.95 (t, J=5.7 Hz, 1H), 4.19 (s, 3H), 3.62 (d, J=5.7 Hz, 2H), 1.42 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:32][CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[C:13](=O)[CH2:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:28][O:27]C(C)(C)[O:25]3)=[CH:20][N:19]=2)=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C([O-])(=O)C.[NH4+:43].Cl>C(O)(=O)C.C(OCC)(=O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([C:13]2[NH:43][C:16]([C:18]3[N:19]=[CH:20][C:21]([CH:24]([OH:25])[CH2:28][OH:27])=[CH:22][CH:23]=3)=[CH:15][CH:14]=2)[CH2:32][CH:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: [NH4+]
Reactant: CC1(C)OCC(c2ccc(C(=O)CCC(=O)C(CC3CCOCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)nc2)O1
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(C(O)CO)cn3)[nH]2)cc1Cl
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 90.1 %

Procedure:
To a solution of 5-[3-chloro-4-(methylsulfonyl)phenyl]-1-[5-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-2-yl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (620 mg) in acetic acid (5 mL) was added ammonium acetate (1.36 g), and the mixture was stirred at 110° C. for 45 min. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated to give a crude product (660 mg). To a solution of the obtained crude product (660 mg) in tetrahydrofuran (5 mL) was added 1M hydrochloric acid (5 mL), and the mixture was stirred at 50° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (500 mg, yield 90%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-methanol (9:1, volume ratio). MS: 507 (MH+). 1H NMR (300 MHz, CDCl3) δ1.24-1.48 (3H, m), 1.51-1.62 (3 H, m), 1.74-1.89 (1 H, m), 1.95-2.09 (1H, m), 2.38 (1 H, brs), 3.01 (1 H, s), 3.19-3.34 (5 H, m), 3.55-3.66 (1 H, m), 3.69-3.80 (1 H, m), 3.85-3.97 (2H, m), 4.02-4.14 (1 H, m), 4.78 (1 H, dd, J=7.8, 3.6 Hz), 6.61-6.68 (1 H, m), 7.24 (1 H, dd, J=8.1, 1.7 Hz), 7.32 (1 H, d, J=1.5 Hz), 7.50 (1 H, d, J=8.3 Hz), 7.59-7.67 (1 H, m), 7.97-8.05 (1 H, m), 8.30 (1 H, s), 9.71 (1 H, brs).
Reaction SMILES: C1([C@H](C)C([O:10][CH2:11][C:12]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])([OH:26])[C:13]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)([CH3:15])[CH3:14])=O)C=CC=CC=1.O.[OH-].[Li+].C(OCC)C>C1COCC1.O>[F:34][C:28]1[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]=1[C:12]([OH:26])([C:13]([S:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)([CH3:15])[CH3:14])[CH2:11][OH:10]
Reactant: COc1ccc(CSC(C)(C)C(O)(COC(=O)[C@@H](C)c2ccccc2)c2ccc(F)cc2F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CSC(C)(C)C(O)(CO)c2ccc(F)cc2F)cc1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
In a mixed solvent of 100 ml of THF and 30 ml of water was dissolved 10.0 g (20.0 mmol) of 2-(2,4-difluorophenyl)-2-hydroxy-3-((4-methoxyphenyl)methylthio)-3-methylbutyl (S)-(+)-2-phenylpropionate ([α]25 +15.9° (c=1.09, MeOH)), and 1.68 g (40.0 mmol) of lithium hydroxide monohydrate was added thereto in divided portions with stirring under ice-cooling. The mixture was warmed to room temperature and stirred for 30 hours. To the reaction mixture was added diethyl ether, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried. The solvent was removed by distillation under reduced pressure, and the residue was subjected to column chromatography using a mixed solvent of hexane and ethyl acetate (5:1) as an eluent. The solvent was removed by distillation under reduced pressure to obtain 7.3 g (99%) of (+)-2-(2,4-difluorophenyl)-3-((4-methoxyphenyl)methylthio)-3-methylbutane-1,2 -diol as a colorless oily substance.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][C:24](O)=[O:25])=[CH:16][CH:15]=1)([O-:13])=[O:12]>>[CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=1
Reactant: O=C(O)CCCCc1ccc([N+](=O)[O-])cc1
Reactant: CN(C)c1ccccc1N
Product: CN(C)c1ccccc1NC(=O)CCCCc1ccc([N+](=O)[O-])cc1

Procedure:
The experimental protocol used is the same as that described for intermediate 5.1), N,N-dimethyl-1,2-benzenediamine replacing 4-(N-methylpiperazinyl)aniline and 5-(4-nitropheny)pentanoic acid replacing 4-(4-nitrophenyl)butanoic acid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[CH2:11]([N:15]=[C:16]=[O:17])[CH2:12][CH2:13][CH3:14].C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>C(N(CC)CC)C.C1C=CC=CC=1>[CH2:11]([NH:15][C:16]([O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1)=[O:17])[CH2:12][CH2:13][CH3:14]
Reactant: Oc1ccc(N=C=S)cc1
Reactant: CCCCN=C=O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCNC(=O)Oc1ccc(N=C=S)cc1

Procedure:
Three and eight-tenths grams (3.8 g.) (0.025 m.) of p-hydroxyphenylisothiocyanate was mixed with 2.5 g. (0.025 m.) of n-butylisocyanate in 50 mls. of benzene. To this mixture was added 3 drops each of triethylamine and dibutyltin dilaurate, and the mixture was allowed to stand at ambient temperature over night. After refluxing on the steam-bath for thirty minutes, the solvent was removed under vacuum by means of a rotary evaporator. The residue was slurried in n-hexane, filtered and air dried. There was obtained 5.4 grams of solid, m.p. 99°-102° C. The structure was confirmed by I.R.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]([NH:18]C(OCC1C=CC=CC=1)=O)=[CH:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=1)[NH:11][N:10]=[CH:9]2>CO.[Pd]>[CH3:1][O:2][C:3](=[O:29])[CH:4]([NH2:18])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([CH:15]([CH3:16])[CH3:17])[CH:14]=1)[NH:11][N:10]=[CH:9]2
Reactant: COC(=O)C(=Cc1cc(C(C)C)c2[nH]ncc2c1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(N)Cc1cc(C(C)C)c2[nH]ncc2c1
Reaction time: 8 h
Yield: 90.3 %

Procedure:
A solution of 2-benzyloxycarbonylamino-3-(7-isopropyl-1H-indazol-5-yl)acrylic acid methyl ester (0.35 g, 0.89 mmol) in methanol (7 mL) was flushed with nitrogen, and treated with palladium on charcoal (10%, 35 mg). The flask was flushed with hydrogen and allowed to stir under an atmosphere of hydrogen overnight. The reaction was flushed with nitrogen, filtered through celite, and concentrated. Column chromatography gave 0.21 g (90%) of the desired material.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][C:7]([N:16]3[CH:20]=[CH:19][CH:18]=[CH:17]3)=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=2)[N:4]=[C:3]1[C:21]([O:23]CC)=[O:22].[OH-].[K+]>C(O)C>[O:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][C:7]([N:16]3[CH:17]=[CH:18][CH:19]=[CH:20]3)=[C:8]([C:12]([F:15])([F:13])[F:14])[CH:9]=2)[N:4]=[C:3]1[C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)c1nc2cc(-n3cccc3)c(C(F)(F)F)cc2[nH]c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1nc2cc(-n3cccc3)c(C(F)(F)F)cc2[nH]c1=O
Yield: 85.7 %

Procedure:
To a solution of ethyl 3,4-dihydro-3-oxo-7-(pyrrole-1-yl)-6-trifluoromethylquinoxaline-2-carboxylate (67.0 mg, 191 μmol) in ethanol (2 ml) was added 1N aqueous solution of potassium hydroxide (382 μl, 382 μmol), and the mixture was refluxed for 1 hour. After cooling, the residue obtained by distilling off the solvent was dissolved into water and the pH value was brought to 2 with 4N hydrochloric acid. This was extracted with ethyl acetate and, after dried over anhydrous sodium sulfate, solvent was distilled off. Small quantity of water was added to the residue obtained. The crystals were collected by filtration, washed with water and then air-dried to obtain 52.9 mg of the title compound as yellowish brown powder. Yield 86%.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH:8]([NH:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:18])[CH3:9])[C:4](=O)[CH3:5])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH2:4]([N:3]([CH2:1][CH3:2])[CH2:7][CH:8]([NH:10][C:11]1[C:12]([CH3:18])=[CH:13][CH:14]=[CH:15][C:16]=1[CH3:17])[CH3:9])[CH3:5]
Reactant: CCN(CC(C)Nc1c(C)cccc1C)C(C)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCN(CC)CC(C)Nc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.7 %

Procedure:
A solution of 0.2 g (0.8 mmoles) of 1-(N-ethyl-acetamido)-2(2,6-dimethylphenyl-amino)-propane, prepared as described in Example 31, in 5 ml of dry diethyl ether is added dropwise, within 10 minutes, to a vigorously stirred suspension of 0.2 g of lithium aluminium hydride in 10 ml of dry diethyl ether at room temperature. The resulting mixture is stirred at room temperature for 3 hours and then processed as described in Example 29. 0.14 g (74%) of 1-diethylamino-2-(2,6-dimethylphenyl-amino)-propane are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]([CH2:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:9]2=[O:14])([O-])=O.CO>>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]([CH2:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:9]2=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1Cn1ccc2c([N+](=O)[O-])cccc2c1=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1Cn1ccc2c(N)cccc2c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a round bottom flask was combined (S)-tert-butyl 2-((5-nitro-1-oxoisoquinolin-2(1H)-yl)methyl)pyrrolidine-1-carboxylate (1.54 g, 0.00412 mol) palladium on C (0.04 g, 0.0004 mol) and methanol (60 mL, 1 mol). The flask was purged and evacuated three times with hydrogen. The mixture was allowed to stir at room temperature under 1 atm for three hours. The mixture was filtered over a bed of celite and the filtrate was reduced in vacuo to yield a light brown oil which was purified by column chromatography on silica gel using a methylene chloride:methanol (0-10%) gradient. The combined pure fractions were reduced in vacuo to yield a tan solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[CH:10]([O:23][CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:35][CH2:36][C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:38]>>[CH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:33]=[CH:34][C:25]=1[CH2:24][O:23][CH:10]1[CH:11]([C:14]2[CH:15]=[CH:16][C:17]([C:18](=[O:19])[NH:35][CH2:36][C:37](=[O:38])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:21][CH:22]=2)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1
Reactant: NCC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)NCC(=O)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 36(b), by condensing (3RS,4RS)-4-(1-tert-butoxycarbonyl-3-naphthalen-2-ylmethoxy-piperidin-4-yl)-benzoic acid with 2-amino-1-phenyl-ethanone there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-(2-oxo-2-phenyl-ethylcarbamoyl)-phenyl]-piperidine-1-carboxylate as a colourless foam; MS: 579 (M+H)+.
Reaction SMILES: Cl[C:2]1[NH:7][C:6](=[O:8])[N:5]2[CH:9]=[CH:10][N:11]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:21]=[N:22][N:23]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOCC>[CH3:30][Si:29]([CH3:32])([CH3:31])[CH2:28][CH2:27][O:26][CH2:25][N:23]1[CH:24]=[C:20]([C:2]2[NH:7][C:6](=[O:8])[N:5]3[CH:9]=[CH:10][N:11]=[C:4]3[CH:3]=2)[CH:21]=[N:22]1
Reactant: CC1(C)OB(c2cnn(COCC[Si](C)(C)C)c2)OC1(C)C
Reactant: O=c1[nH]c(Cl)cc2nccn12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C[Si](C)(C)CCOCn1cc(-c2cc3nccn3c(=O)[nH]2)cn1
Temperature: 25 °C
Yield: 75.9 %

Procedure:
A flask was charged with 7-chloroimidazo[1,2-c]pyrimidin-5(6H)-one (Preparation H, 1.02 g, 6.00 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (Preparation E, 3.24 g, 9.00 mmol), K3PO4 (2.55 g, 12.0 mmol) and XPHOS (0.572 g, 1.20 mmol). Degassed iPrOH (24 mL) and degassed H2O (2 mL) were added and the suspension was sonicated for 1-2 minutes. The mixture was purged with N2 for 10 minutes with vigorous mixing and Pd2dba3 (0.549 g, 0.600 mmol) was added. The mixture was heated at reflux under an N2 atmosphere for 24 hours and was cooled to ambient temperature. The mixture was diluted with EtOAc (20 mL) and was sonicated for 5 minutes. The suspension was filtered through a packed Celite plug (EtOAc elution) and concentrated to give an orange, oily solid. The solid was treated with Et2O and was stirred until a granular suspension formed. The solid was collected, washed with Et2O and H2O and dried in vacuum to give the title compound (1.51 g, 76% yield) as a light tan powder. MS (apci) m/z=332.3 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:12]([O-])=O)=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[CH:15](O)=O>[Pd]>[CH3:11][C:10]1[C:2]2[NH:1][CH:15]=[N:12][C:3]=2[C:4]([C:5]([OH:7])=[O:6])=[CH:8][CH:9]=1
Reactant: Cc1ccc(C(=O)O)c([N+](=O)[O-])c1N
Reactant: O=CO
Agent: [Pd]
Product: Cc1ccc(C(=O)O)c2nc[nH]c12
Temperature: 25 °C

Procedure:
A mixture of 3-amino-4-methyl-2-nitrobenzoic acid (16) (6.883 g, 35.10 mmol), 10% Pd/C [0.3 g, 10% dry Pd/C] and 75% aqueous formic acid (60 mL) is heated to reflux for about 15 hours. The reaction mixture is then cooled to ambient temperature and filtered through a pad of Celite, and the resulting filtrate concentrated in vacuo to a beige solid. The solids are triturated in hot methanol (50 mL), cooled slowly to ambient temperature, and filtered to give 7-Methyl-1H-benzimidazole-4-carboxylic Acid (22), as beige solid (5.26 g, 85% Yield).
Reaction SMILES: [CH2:1]([N:10]=[C:11]=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]=[C:8]=[O:9].[CH3:13][N:14]1[CH2:19][CH2:18][CH2:17][NH:16][CH:15]1[CH:20]([CH3:22])[CH3:21]>C(OCC)(=O)C>[CH2:1]([NH:10][C:11]([N:16]1[CH2:17][CH2:18][CH2:19][N:14]([CH3:13])[CH:15]1[CH:20]([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([N:16]1[CH2:17][CH2:18][CH2:19][N:14]([CH3:13])[CH:15]1[CH:20]([CH3:22])[CH3:21])=[O:9]
Reactant: CC(C)C1NCCCN1C
Reactant: O=C=NCCCCCCN=C=O
Solvent: CCOC(C)=O
Product: CC(C)C1N(C)CCCN1C(=O)NCCCCCCNC(=O)N1CCCN(C)C1C(C)C
Reaction time: 8 h

Procedure:
A mixture of 84 g of hexamethylene diisocyanate and 100 g of ethyl acetate is slowly added at temperatures of from 25° to 35° C. to 142 g of N-methyl-2-isopropylhexahydropyrimidine ##STR17## in 150 ml of ethyl acetate. Stirring is continued for 8 hours at room temperature after the reaction has been completed and the ester is finally removed on a rotary evaporator at 100° C. and at 25 mbar.
Reaction SMILES: [N:1]([CH:4]([CH3:28])[CH2:5][O:6][C:7]1[C:8]([CH3:27])=[C:9]2[N:14]([CH:15]=1)[N:13]=[CH:12][N:11]=[C:10]2[O:16][C:17]1[C:18]([F:26])=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1)=[N+]=[N-].[H][H]>C(OCC)(=O)C.[Pd]>[F:26][C:18]1[C:17]([O:16][C:10]2[C:9]3=[C:8]([CH3:27])[C:7]([O:6][CH2:5][C@H:4]([NH2:1])[CH3:28])=[CH:15][N:14]3[N:13]=[CH:12][N:11]=2)=[CH:22][N:21]=[C:20]2[NH:23][CH:24]=[CH:25][C:19]=12
Reactant: [H][H]
Reactant: Cc1c(OCC(C)N=[N+]=[N-])cn2ncnc(Oc3cnc4[nH]ccc4c3F)c12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1c(OC[C@@H](C)N)cn2ncnc(Oc3cnc4[nH]ccc4c3F)c12
Yield: 56.1 %

Procedure:
Procedures given in Tetrahedron Lett, 1977, 1977, and JACS, 1999, 3637 were modified. Thus, a 10 mL flask was charged with 1-(5-methyl-4-methylsulfanylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)-propan-2-ol (249 mg, 0.98 mmol), and tetrahydrofuran (4.91 mL) and cooled to 0° C. Triphenylphosphine (516 mg, 1.96 mmoles), diethyl azodicarboxylate (310 μL, 1.96 mmol) and diphenylphosphoryl azide (424 μL, 1.96 mmol) were added in order. The mixture was stirred at 23° C. for 15 h and then concentrated in vacuo. The crude material was purified by flash chromatography eluting with a mixture of 20% ethyl acetate in hexane to give (156 mg, 57%) of 6-(2-azidopropoxy)-5-methyl-4-methylsulfanylpyrrolo[2,1-f][1,2,4]triazine as white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.19 (1H, s), 7.85 (1H, s), 4.16 (1H, dd, J=2.8, 9.6 Hz), 4.05-3.96 (m, 2H), 2.60 (3H, s), 2.37 (3H, s), 1.21 (3H, d, J=6.3 Hz). LCMS m/z 254 (M+H+). B. 6-(2-Azido-propoxy)-5-methyl-4-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine and 4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-ol were reacted together according to the procedure described in Example 7 to afford 6-(2-azido-propoxy)-4-(4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-5-methyl-pyrrolo[2,1-f][1,2,4]triazine. The crude material was purified by preparative HPLC. 1H NMR (400 MHz, DMSO-d6) δ 12.18 (1H, s), 8.32 (1H, d, J=9.6 Hz), 8.02 (1H, s) 7.96 (1H, s), 6.60 (1H, d, J=3.6 Hz), 4.21 (1H, d, J=7.0 Hz), 4.09-4.02 (2H, m), 2.42 (3H, s), 1.23 (3H, d, J=6.3 Hz). LCMS m/z 382 (M+H+). C. A solution of 6-(2-azido-propoxy)-4-(4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-5-methyl-pyrrolo[2,1-f][1,2,4]triazine (20 mg, 0.05 mmol) in ethyl acetate (2.0 mL) was stirred in the presence of hydrogen (14 psi) and 10% Pd/C (10 mg) for 12 h. Excess hydrogen was removed and the mixture was filtered through Celite® and evaporated. The residue was purified by preparative HPLC to afford (10 mg, 54%) of the title compound. LCMS: m/z 357 (M+H+). Dihydrochloride salt: 1H NMR (400 MHz, DMSO-d6) δ 12.19 (1H, s), 8.31 (1H, d, J=8.9 Hz), 8.16 (2H, br. s), 8.05 (1H, m), s), 7.97 (1H, s), 7.60 (1H, s), 6.60 (1H, s), 4.19 (2H, m), 4.03 (2H, m), 3.65 (1H, m), 1.30 (3H, d, J=6.8 Hz).