Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:8]=[C:7]([CH:25]2[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]2)[C:3]=1[C:4](O)=[O:5].Cl.CN.[CH2:41]([N:43](CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>>[NH2:1][C:2]1[C:3]([C:4]([NH:43][CH3:41])=[O:5])=[C:7]([CH:25]2[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:32])[CH2:26]2)[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:10]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3OCc3ccccc3)nc(N)c2C(=O)O)C1
Reactant: CCN(CC)CC
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Product: CNC(=O)c1c(C2CCCN(C(=O)OC(C)(C)C)C2)cc(-c2ccccc2OCc2ccccc2)nc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.4 %

Procedure:
To a solution of 2-amino-6-[2-(benzyloxy)phenyl]-4-[1-(tert-butoxycarbonyl)-3-piperidinyl]nicotinic acid (0.500 g, 0.993 mmol) which was derived from the product in the step (1) of Example 9-1, methylamine hydrochloride (0.134 g, 1.896 mmol), triethylamine (0.277 mL, 1.986 mmol), and 1-hydroxybenzotriazole (0.215 g, 1.589 mmol) in dichloromathane (10.0 mL), at 0° C. under an argon atmosphere was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.228 g, 1.191 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, then extracted with ethyl acetate and water. The separated organic phase was washed with brine, dried over MgSO4, filtered, then concentrated under reduced pressure. The resulting residue was purified by column chromatography on Silica-gel (dichloromathane/methanol=19/1) to give tert-butyl 3-{2-amino-6-[2-(benzyloxy)phenyl]-3-[(methylamino)carbonyl]-4-pyridinyl}-1-piperidinecarboxylate as a yellow oil (0.11 g, 21%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].C(O)CO>O>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[N:13]=[C:14]1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[CH3:2]
Reactant: CCOC(=O)CNc1ncccc1NC(=O)c1cccc(F)c1
Solvent: OCCO
Solvent: O
Product: CCOC(=O)Cn1c(-c2cccc(F)c2)nc2cccnc21
Temperature: 195 °C
Yield: 91.2 %

Procedure:
A mixture of N-[3-[(3-fluorobenzoyl)amino]-2-pyridinyl]glycine ethyl ester (20.44 g, 0.065 mole), and ethylene glycol (75 ml) was heated at 195° C. for 40 minutes. Water was added to the cooled reaction mixture and the solid was collected by filtration. The solid was suspended in water (2×100 ml) and collected by filtration to give 17.75 g of crude 2-(3-fluorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid ethyl ester. A portion of this solid (6.0 g, 0.02 mole) together with sodium hydroxide pellets (0.9 g, 0.0231 mole), and 50 ml of ethanol-water (1:1) was refluxed for 1 hour. The ethanol was evaporated. The residual aqueous mixture was cooled, diluted with water (50 ml) and extracted with diethyl ether (2×25 ml). The aqueous portion was acidified to a pH of 3 with concentrated hydrochloric acid. After precipitation was complete, the solid was collected by filtration. The filter cake was suspended in ethanol and filtered, giving 4.94 g (91%). Recrystallization of a 1.2-g sample from tetrahydrofuran gave 1.1 g of an off-white solid, mp 243°-245° C. with decomposition.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=2[C:17]2[C:18]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([NH:29][CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[O:28])[C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:4][CH2:3]1.C([O:39][CH2:40][C:41](Cl)=[O:42])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:15])([F:14])[F:16])=[CH:9][C:8]=2[C:17]2[C:18]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([NH:29][CH:30]4[CH2:31][CH2:32][N:33]([C:40](=[O:39])[CH2:41][OH:42])[CH2:34][CH2:35]4)=[O:28])[C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:3][CH2:4]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCN(C(=O)CO)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(trifluoromethyl)phenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f31) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:9][CH:8]=1.C[O:21][B:22](OC)[O:23]C.O>C1COCC1>[BH:22]([OH:23])[OH:21].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:19])[C:15]([CH3:17])([CH3:16])[CH3:18])=[CH:9][CH:8]=1
Reactant: COB(OC)OC
Agent: CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: OBO
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
(Method G-2) Under an atmosphere of nitrogen, n-butyllithium (22.75 mL, 2.2 eq) was slowly added to a solution of 4-chloropivaloylamino benzene (16.5 g, 0.078 mol) in dry THF (360 mL) at 0° C. After 2 hrs the mixture was cooled to −78° C. and trimethylborate (19.5 mL, 2.2 eq) slowly added. The mixture was allowed to warm to −15° C. and stirred for 2.5 hrs giving a clear colourless solution. Water (90 mL) was added, the lower, aqueous layer removed, washed with dichloromethane (150 mL) and acidified (90 mL 2M HCl) giving the title compound as a white solid (12.6 g, 0.049 mol, 63.2%). See, for example, Timari et al, 1996.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:14])=[CH:11][N:10]=2)[C:6]=1[O:7][CH3:8].[C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[C:29]([CH3:36])[CH:28]=1)#[N:26].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:25]([C:27]1[CH:32]=[CH:31][C:30]([C:2]2[CH:3]=[N:4][N:5]([C:9]3[CH:24]=[CH:23][C:12]([C:13]([NH:15][CH2:16][CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[O:14])=[CH:11][N:10]=3)[C:6]=2[O:7][CH3:8])=[C:29]([CH3:36])[CH:28]=1)#[N:26]
Reactant: Cc1cc(C#N)ccc1B(O)O
Reactant: COc1c(Br)cnn1-c1ccc(C(=O)NCC2CCOCC2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: COc1c(-c2ccc(C#N)cc2C)cnn1-c1ccc(C(=O)NCC2CCOCC2)cn1
Temperature: 110 °C
Yield: 100.4 %

Procedure:
Combined 6-(4-bromo-5-methoxy-1H-pyrazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide (25 mg, 0.063 mmol), (4-cyano-2-methylphenyl)boronic acid (30.5 mg, 0.190 mmol), sodium carbonate (26.6 mg, 0.316 mmol), and PdCl2(dppf)-CH2Cl2 adduct (2.58 mg, 3.16 μmol) in dioxane (0.2 mL) and water (0.05 mL) and purged with nitrogen. The reaction mixture was heated in a microwave on high absorbance for 1 hour at 110° C., cooled to 23° C. and diluted with water (1 mL) to give a residue. The residue was extracted with EtOAc (2×1 mL), the organic layers were combined, washed with brine (0.5 mL), dried over Na2SO4, filtered through a Hydrophilic PTFE 0.45 um filter (Millipore Millex™-LCR), rinsed with EtOAc, and dried in vacuo to provide 6-(4-(4-cyano-2-methylphenyl)-5-methoxy-1H-pyrazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide (27.3 mg, 100% yield) as a brown oil. MS m/z [M+H]+ 432.5.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:12]=[O:13].[CH:14]1([Mg]Br)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[Cl-].[NH4+]>O1CCCC1>[CH:14]1([CH:12]([C:3]2[O:4][C:5]3[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=3[C:2]=2[CH3:1])[OH:13])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Br[Mg]C1CCCCC1
Reactant: Cc1ccc2oc(C=O)c(C)c2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc2oc(C(O)C3CCCCC3)c(C)c2c1
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution (20 mL) of 3,5-dimethyl-1-benzofuran-2-carbaldehyde (1.00 g) synthesized above in tetrahydrofuran was added a 1.0M solution (8.61 mL) of cyclohexylmagnesium bromide in tetrahydrofuran at 0° C., and the mixture was stirred for 1 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, tetrahydrofuran was evaporated in an evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25% ethyl acetate/hexane) to give the title object compound (1.13 g, 76%) as a pale-yellow solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:21]=[CH:20][C:10]([O:11][CH:12]([CH2:18][CH3:19])[C:13]([O:15]CC)=[O:14])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[O:1]1[CH2:2][CH2:3][CH:4]([C:7]2[CH:8]=[CH:9][C:10]([O:11][CH:12]([CH2:18][CH3:19])[C:13]([OH:15])=[O:14])=[CH:20][CH:21]=2)[CH2:5][CH2:6]1
Reactant: CCOC(=O)C(CC)Oc1ccc(C2CCOCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC(Oc1ccc(C2CCOCC2)cc1)C(=O)O
Temperature: 20 °C
Reaction time: 24 h
Yield: 92.4 %

Procedure:
A mixture of 14.6 g of ethyl 2-[p-(4-tetrahydropyranyl)-phenoxy]-butanoate, 100 ml of ethanol and 40 ml of 2N sodium hydroxide was stirred at 20° C for 24 hours and then refluxed for an hour. The ethanol was evaporated and the residue was taken up in 100 ml of 0.5N sodium hydroxide. The solution was washed with ether and acidified with concentrated hydrochloric acid and was extracted with methylene chloride. The extracts were dried and evaporated to dryness to obtain 13.2 g of raw product which was crystallized from cyclohexane to obtain 12.2 g of 2-[p-(4-tetrahydropyranyl)-phenoxy]-butanoic acid melting at 127° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[CH3:41][O:42][C:43]1[C:52]([C:53](O)=[O:54])=[C:51]([CH3:56])[C:50]2[C:45](=[CH:46][C:47]([C:57]([F:60])([F:59])[F:58])=[CH:48][CH:49]=2)[N:44]=1>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:53]([C:52]2[C:43]([O:42][CH3:41])=[N:44][C:45]3[C:50]([C:51]=2[CH3:56])=[CH:49][CH:48]=[C:47]([C:57]([F:59])([F:60])[F:58])[CH:46]=3)=[O:54])=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: COc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 57.1 %

Procedure:
87 μl (0.8 mmol) 4-fluorobenzylamine, 266 mg (0.7 mmol) HATU and 281 μl (2.0 mmol) NEt3 were added consecutively to a solution of 199 mg (0.7 mmol) 2-methoxy-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid in THF (5 ml) and the solution was then stirred for 72 h at RT. The solution was subsequently diluted with EtOAc and washed with a 4N aq. NH4Cl sol., a 1M aq. Na2CO3 sol. and brine. The organic phase was dried over MgSO4, filtered through silica gel and concentrated in a vacuum. After crystallisation (EtOAc/hexane 1:2) of the residue, 161 mg (0.4 mmol, 59%) N-[(4-fluorophenyl)-methyl]-2-methoxy-4-methyl-7-(trifluoromethyl)-quinoline-3-carboxylic acid amide (example 5) was obtained. MS: m/z 393.1 [M+H]+.
Reaction SMILES: F[C:2]1[CH:9]=[N:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Na+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O-:20])=[O:19])=[CH:14][CH:13]=1>CS(C)=O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([C:2]2[CH:9]=[N:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=S([O-])c1ccc(F)cc1
Reactant: O=Cc1ccncc1F
Agent: [Na+]
Solvent: CS(C)=O
Product: O=Cc1ccncc1S(=O)(=O)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
A solution of 3-fluoroisonicotinaldehyde (0.25 mL) in dimethyl sulfoxide (2.0 mL) was treated with a solution of 4-fluorobenzene sulfinic acid sodium salt (0.5 g) in dimethyl sulfoxide (3.0 mL), and the resulting mixture was stirred at 100° C. for 3 days. The mixture was cooled to room temperature, partitioned between water and ethyl acetate (20 mL), and the aqueous phase extracted with ethyl acetate. The combined organic solution was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1:0 to 4:1 by volume) to afford the title compound as a white solid (0.38 g).
Reaction SMILES: C(OCCCC)C1OC1.C(OCC(CC)CCCC)C1OC1.[OH:23][C:24]1[CH:29]=[C:28]([O:30][CH2:31][CH:32]([OH:43])[CH2:33][O:34][CH2:35][CH:36](CC)[CH2:37][CH2:38]CC)[CH:27]=[CH:26][C:25]=1[C:44]1[N:49]=[C:48]([C:50]2[CH:55]=[CH:54][C:53]([O:56][CH2:57][CH:58]([OH:69])[CH2:59][O:60][CH2:61][CH:62](CC)[CH2:63][CH2:64]CC)=[CH:52][C:51]=2[OH:70])[N:47]=[C:46]([O:71][CH3:72])[N:45]=1>>[OH:23][C:24]1[CH:29]=[C:28]([O:30][CH2:31][CH:32]([OH:43])[CH2:33][O:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:27]=[CH:26][C:25]=1[C:44]1[N:49]=[C:48]([C:50]2[CH:55]=[CH:54][C:53]([O:56][CH2:57][CH:58]([OH:69])[CH2:59][O:60][CH2:61][CH2:62][CH2:63][CH3:64])=[CH:52][C:51]=2[OH:70])[N:47]=[C:46]([O:71][CH3:72])[N:45]=1
Reactant: CCCCC(CC)COCC(O)COc1ccc(-c2nc(OC)nc(-c3ccc(OCC(O)COCC(CC)CCCC)cc3O)n2)c(O)c1
Agent: CCCCC(CC)COCC1CO1
Agent: CCCCOCC1CO1
Product: CCCCOCC(O)COc1ccc(-c2nc(OC)nc(-c3ccc(OCC(O)COCCCC)cc3O)n2)c(O)c1

Procedure:
If the butyl glycidyl ether is replaced by 2-ethylhexyl glycidyl ether, 2,4-di{2-hydroxy-4-[3-(2-ethylhexoxy)-2-hydroxypropoxy]phenyl}-6-methoxy-1,3,5-triazine having a melting point of 98°-99° C. is obtained.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[CH:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li]CCCC.[CH3:22][O:23][CH2:24][O:25][C:26]1[CH:47]=[CH:46][C:29]2[C:30](=[O:45])[C:31]([C:35]3[CH:40]=[CH:39][C:38]([O:41][CH2:42][O:43][CH3:44])=[CH:37][CH:36]=3)([CH3:34])[CH2:32][O:33][C:28]=2[CH:27]=1.O>O1CCCC1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:30]1([OH:45])[C:29]2[CH:46]=[CH:47][C:26]([O:25][CH2:24][O:23][CH3:22])=[CH:27][C:28]=2[O:33][CH2:32][C:31]1([C:35]1[CH:36]=[CH:37][C:38]([O:41][CH2:42][O:43][CH3:44])=[CH:39][CH:40]=1)[CH3:34])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C#CCCCCCCO[Si](C)(C)C(C)(C)C
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2=O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2(O)C#CCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
8-(t-Butyldimethylsilyloxy)oct-1-yne (0.6 g, 2.5 mmol) was dissolved in dry tetrahydrofuran (8 ml) under argon atmosphere and then cooled to -78° C. 2.5M n-BuLi (0.94 ml, 2.35 mmol) was slowly added dropwise thereto and then the mixture was stirred for 30 minutes. To the mixture was added dropwise 7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-3-methyl-2,3-dihydro-4H-benzopyran-4-one (300 mg, 0.84 mmol) dissolved in dry tetrahydrofuran (4 ml), and then the reaction mixture was slowly warmed to room temperature. After 3 hours, water was added to the reaction mixture. The reaction solution was extracted with ethyl acetate and the organic layer was dried over magnesium sulfate. The residue was subjected to column chromatography (n-hexane:ethyl acetate=4:1) to obtain 500 mg (yield: ~100%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][C@@H:18]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([N+:31]([O-])=O)[CH:25]=2)[CH2:19]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C>[Pd].CO>[NH2:31][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=1[Cl:30])[CH2:23][N:20]1[CH2:21][CH2:22][C@@H:18]([NH:17][C:15](=[O:16])[CH2:14][NH:13][C:11](=[O:12])[C:10]2[CH:34]=[C:35]([C:38]([F:40])([F:41])[F:39])[CH:36]=[CH:37][C:9]=2[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:19]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)c([N+](=O)[O-])c2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)c(N)c2)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]-1-(4-chloro-3-nitrobenzyl)pyrrolidine prepared above, 10% Pd-activated carbone (22 mg), ethyl acetate (2.7 mL) and methanol (0.3 mL) was stirred under a hydrogen atmosphere at room temperature for 15 h. The Pd catalyst was filtered off, and the filtrate was concentrated to afford (R)-1-(3-amino-4-chlorobenzyl)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (89.7 mg, quant.): Any remarkable by-products were not detected in TLC.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[C:14]([CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])[CH:13]=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[C:14]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:13]=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CCc1cccc(CO[Si](C)(C)C(C)(C)C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CCC(=O)O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.8 %

Procedure:
Ethyl 3-[6-(t-butyldimethylsilanyloxymethyl)pyridin-2-yl]propionate (5.07 g) was dissolved in 100 mL of ethanol, and 23.5 mL of 1N aqueous sodium hydroxide was added to the solution, and then the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to approximate half volume thereof under reduced pressure, after adding ice-water, the solution was acidified with hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (chloroform-methanol=10:1) to give 2.77 g of 3-[6-(t-butyldimethylsilanyloxymethyl)pyridin-2-yl]propionic acid as a colorless powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11](Br)[CH:10]=2)=[O:5])[CH3:2].[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][CH:20]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([NH:25][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([F:18])=[CH:20][CH:21]=1)[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2cc(Br)ccc2c1O
Reactant: NC(=O)c1ccc(F)cc1
Product: CCOC(=O)c1ncc2cc(NC(=O)c3ccc(F)cc3)ccc2c1O

Procedure:
7-(4-Fluoro-benzoylamino)-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester was prepared from 7-Bromo-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester under conditions analogous to Example 116(a) using 4-Fluorobenzamide. 1H NMR (200 MHz, CDCl3): δ ppm=11.87 (s, 1H), 8.79 (s, 1H), 8.58 (s, 1H), 8.36 (d, 1H), 8.12 (br s, 1H), 7.95 (m, 2H), 7.74 (d, 1H), 7.15-7.24 (m, 3H), 4.56 (q, 2H), 1.51 (t, 3H.)
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.C(O)(=O)C.BrBr.Br>O>[CH3:1][C:2]1[C:3]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[N:4][NH:5][C:6](=[O:8])[CH:7]=1
Reactant: CC1CC(=O)NN=C1c1ccc(C#N)cc1
Agent: Br
Agent: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(=O)[nH]nc1-c1ccc(C#N)cc1

Procedure:
200 g. portion of p-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)benzonitrile [Journal of Medicinal Chemistry 17,281 (1974)] is suspended in 500 ml. of glacial acetic acid with overhead stirring at stream bath temperature, then 56 ml. of liquid bromine is dissolved in an additional 500 ml. of acetic acid and this solution is added to the stirring mixture all at once. After approximatley half an hour of heating, a vigorous exothermic reaction occurs with the expulsion of the excess bromine and hydrogen bromide. The reaction mixture is the diluted with 4 liters of distilled water and the resulting solid is filtered and the filter cake is copiously washed with water and is air dried. This material is recrystallized from a large amount of ethyl alcohol to afford the product p-(1,6-dihydro-4-methyl-6-oxo-3-pyridazinyl)benzonitrile as a white solid.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH3:22][CH:23]1[CH2:27][C:26]([CH3:29])([CH3:28])[CH2:25][C:24]1=[CH:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35]>ClCCl>[CH3:22][CH:23]1[CH2:27][C:26]([CH3:28])([CH3:29])[CH2:25][C:24]1=[CH:30][CH2:31][CH2:32][CH2:33][CH:34]=[O:35]
Reactant: CC1CC(C)(C)CC1=CCCCCO
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC1CC(C)(C)CC1=CCCCC=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thereafter 2.5 equivalents of PDC (pyridinium dichromate) and 1 equivalent of 5-(2,4,4-trimethylcyclopentylidene)-pentan-1-ol in proportion 68:32 in dichloromethane are placed in the flask. The suspension is agitated vigorously at ambient temperature overnight. When the conversion is satisfactory (>95%), the reaction medium is filtered on Celite® and then on silica. The filtrate thus obtained is washed with an aqueous 1% HCl solution and then with a saturated aqueous sodium bicarbonate solution, and then with water. After drying on magnesium sulfate, filtration on paper and evaporation of the solvent, the crude product, containing two isomers in proportion 68:32 of 5-(2,4,4-trimethylcyclopentylidene)-pentanal, is distilled under reduced pressure: its boiling point is 52° C. at 0.3 torr.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([CH3:19])=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]([CH3:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[C:20]([NH:1][C:2]1[NH:3][C:4]([CH3:19])=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]([CH3:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:22])[CH3:21]
Reactant: CCOC(=O)C1=C(C)NC(N)=C(C(=O)OCC)C1C
Reactant: CC(=O)OC(C)=O
Product: CCOC(=O)C1=C(C)NC(NC(C)=O)=C(C(=O)OCC)C1C

Procedure:
8 g (0.03 mol) of diethyl 2-amino-4,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate in 100 ml of acetic anhydride were boiled under reflux for 4 hours. The mixture was concentrated to dryness in vacuo, and the residue was recrystallized from ethanol. Yield: 5.4 g (58% of theory) of m.p.: 105° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[C:12]([C:14](OC)=[O:15])[C:11]([CH3:18])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[C:12]([CH:14]=[O:15])[C:11]([CH3:18])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1cn(-c2cccc(OC)c2)nc1C
Agent: [Mn+4]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cccc(-n2cc(C=O)c(C)n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
A solution (20 mL) of methyl 1-(3-methoxyphenyl)-3-methyl-1H-pyrazole-4-carboxylate (3.9 g) synthesized in the above-mentioned (1) in tetrahydrofuran was added to an ice-cooled solution (80 mL) of lithium aluminum hydride (0.6 g) in tetrahydrofuran. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr. The mixture was ice-cooled again, and water (1.6 mL), 1N aqueous sodium hydroxide solution (7.8 mL) and water (1.6 mL) were successively added dropwise to quench the reaction. The residue was filtered through celite, and the filtrate was concentrated under reduced pressure to give a crude product (1.9 g) of 1-(3-methoxyphenyl)-3-methyl-1H-pyrazole-4-methanol as a pale-yellow oil. This was dissolved in toluene (30 mL), manganese dioxide (3.0 g) was added, and the mixture was heated for 30 min with a Dean-Stark trap. The reaction mixture was allowed to cool to room temperature, and manganese dioxide was collected by filtration. The solvent was evaporated under reduced pressure to give the title object compound (1.2 g, 64%) as a colorless solid.