Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)CCO.C(C=C)=O.[C:10]1([CH3:20])[CH:15]=CC(S(O)(=O)=O)=C[CH:11]=1.[CH:21]([CH:23]1[O:28]CCC[O:24]1)=[CH2:22]>O>[CH:21]([CH:23]1[O:28][CH2:11][CH:10]([CH3:20])[CH2:15][O:24]1)=[CH2:22]
Reactant: C=CC1OCCCO1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=CC=O
Solvent: OCCCO
Solvent: O
Product: C=CC1OCC(C)CO1
Temperature: 26 °C

Procedure:
For the sake of comparison, a mixture of 0.5 mole 1,3-propanediol and 0.55 mole acrolein were reacted at 50° C in the presence of 0.3 g. p-toluenesulfonic acid. Layers did not separate until the reaction mixture was cooled to 26° C. The mixture gave 18 g. of an aqueous layer which contained about 40% diol, 21% acrolein, 10% 2-vinyl-1,3-dioxane and 25% water. The acetal layer of 49 g. contained 63% 2-vinyl-1,3-dioxane, 23% acrolein, 8% diol and 5% water, conversion to acetal was about 60% which represents only a negligible increase over equilibrium conversion.
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:7]([F:33])[C:6]=1[F:34])[CH3:3].CC(C)([O-])C.[K+].[CH2:41]([O:45][C:46]1[CH:51]=[CH:50][C:49]([C@H:52]2[CH2:57][CH2:56][C@H:55]([CH:58]=O)[CH2:54][CH2:53]2)=[C:48]([F:60])[C:47]=1[F:61])[CH2:42]CC.O>C1COCC1>[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12]/[CH:13]=[CH:58]/[C@H:55]2[CH2:54][CH2:53][C@H:52]([C:49]3[CH:50]=[CH:51][C:46]([O:45][CH2:41][CH3:42])=[C:47]([F:61])[C:48]=3[F:60])[CH2:57][CH2:56]2)=[C:7]([F:33])[C:6]=1[F:34])[CH3:3]
Reactant: CCOc1ccc(CCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c1F
Reactant: CCCCOc1ccc([C@H]2CC[C@H](C=O)CC2)c(F)c1F
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc(CC/C=C/[C@H]2CC[C@H](c3ccc(OCC)c(F)c3F)CC2)c(F)c1F
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Well-dried 3-(4-ethoxy-2,3-difluorophenyl)propyl triphenylphosphonium bromide (s23) (6.6 g) was mixed with THF (100 ml) under an atmosphere of nitrogen, and the solution was cooled to −10° C. Potassium t-butoxide (t-BuOK; 1.4 g) was added in two portions in the temperature range of −10° C. to −5° C. After 60 minutes of stirring at −10° C., the compound (s25) (3.0 g) dissolved in THF (30 ml) was added dropwise in the temperature range of −10 to −5° C. After 30 minutes of stirring at 0° C., the reaction mixture was treated with water, and the aqueous layer was extracted with toluene. The combined organic layers were washed with water, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder. The purified product was mixed with sodium benzenesulfonate dihydrate (6.1 g) and Solmix A-11 (100 ml). Then, 6N-hydrochloric acid (20 ml) was added, and the mixture was heated to reflux for 2 hours. The reaction mixture was treated with water, and the aqueous layer was extracted with toluene (100 ml). The combined organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder, and then by recrystallization from a mixed solvent of ethyl acetate and Solmix A-11 (ethyl acetate:Solmix=1:4 by volume) to give (E)-1-ethoxy-2,3-difluoro-4-(4-(trans-4-(4-ethoxy-2,3-difluorophenyl)cyclohexyl)but-3-en-1-yl)benzene (No. 82) (4.6 g). The yield based on the compound (s13) was 41.9%.
Reaction SMILES: [OH:1]C1C=C(C=CC=1)C(N(OC)C)=O.[C:14]1([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1CO.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:27]1([P:20](=[O:1])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CON(C)C(=O)c1cccc(O)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: OCc1ccccn1
Solvent: C1CCOC1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of 1.21 g (10.0 mmol) B2, 2.89 g (11.0 mmol) triphenylphosphine and 1.20 g (11.0 mmol) pyridine-2-methanol in 30 ml dry tetrahydrofuran a solution of 1.92 g (11.0 mmol) diethyl azodicarboxylate in 5 ml dry tetrahydrofuran was added and the mixture was stirred at room temperature for 2 hours. After removal of the solvent and column chromatography on Silica (hexane/ethyl acetate 2:1) 2.81 g B3 were obtained as a light yellow oil (72% yield assuming 30 mol % impurity of triphenylphosphine oxide (measured by NMR)). Due to the problems with the separation of the impurities in this particular example the experiment was repeated with PS-bound triphenylphosphine to give pure B3 in 58% yield.
Reaction SMILES: Cl[C:2]1[C:7]2=[C:8]([CH:11]([CH3:13])[CH3:12])[CH:9]=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[F:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[OH:24].C1N2CCN(CC2)C1>CC#N>[F:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[O:24][CH:2]1[C:7]2=[C:8]([CH:11]([CH3:13])[CH3:12])[CH:9]=[CH:10][N:6]2[N:5]=[CH:4][NH:3]1
Reactant: CC(C)c1ccn2ncnc(Cl)c12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: CC(C)c1ccn2c1C(Oc1ccc([N+](=O)[O-])cc1F)NC=N2
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 77.7 %

Procedure:
To a mixture of 4-chloro-5-isopropylpyrrolo[2,1-f][1,2,4]triazine (0.038 g, 0.194 mmol, 1.0 equiv) and 2-fluoro-4-nitrophenol (0.062 g, 0.388 mmol, 2.0 equiv) in anhydrous CH3CN (2 mL), stirred for five minutes under a nitrogen atmosphere then was added DABCO (0.044 g, 0.388 mmol, 2.0 equiv) and the reaction mixture was heated at 50° C. for 2 h. The mixture was cooled to room temperature and quenched with 1 N HCl. The solution was extracted with CH2Cl2 (3×30 ml), the combined organic extracts dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel (Merck KGaA, 230–400 mesh particle size) flash chromatography, eluting with 2/1 hexane/ethyl acetate, afforded the title compound (0.048 g, 79%). 1H NMR (CDCl3) δ 8.07–8.13 (m, 2H), 7.77 (s, 1H), 7.68–7.69 (m, 1H), 7.46–7.50 (m, 1H), 6.71–6.72 (m, 1H), 3.53–3.56 (m, 1H), 1.29–1.31 (m, 6H); HRMS(ESI), calc, 317.1050 (M+H)+ found, 317.1039.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:18]([NH:20][CH2:21][CH2:22][CH3:23])=[O:19]>CS(C)=O>[Cl:15][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:16][C@H:17]([C:18](=[O:19])[NH:20][CH2:21][CH2:22][CH3:23])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:11]([C:12]([OH:14])=[O:13])=[CH:10]2
Reactant: CCCNC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Solvent: CS(C)=O
Product: CCCNC(=O)[C@H](Cc1ccccc1)Nc1nc2ccc(Cl)cc2cc1C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-phenyl-N-propyl-propionamide [Chem. Lett. 2003, 32 (4), 372-373.] in DMSO to provide the title compound in good yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=2)=[N:12][CH:13]=1)=[O:6].ClC1C=CC=C(C(OO)=[O:39])C=1.CO>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([S:14]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=2)=[O:39])=[N:12][CH:13]=1)=[O:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)CCc1ccc(Sc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)cc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCc1ccc(S(=O)c2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-{4-[5-(3,4-dichlorobenzoylamino)pyridin-2-ylsulfanyl]phenyl}propionate (1.00 g, 2.17 mmol) in dichloromethane (20 mL) was added m-chloroperbenzoic acid (0.620 g, 2.60 mmol) at 0° C. The resulting solution was stirred for 1 hour at 0° C. To the reaction solution was added methanol and stirred for some time. To the resulting solution was then added water, and extracted with dichloromethane. The dichloromethane layer was washed with water, a saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and evaporated. The obtained residue was recrystallized from ethanol 3 times, to thereby yield 0.790 g of the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1OS(C1C=CC(C)=CC=1)(=O)=O)(=[O:3])[CH3:2].[C:22]([C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1)#[CH:23]>CCCCCCC.CCOC(C)=O>[NH2:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]#[C:23][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:1](=[O:3])[CH3:2])=[CH:25][CH:26]=1
Reactant: C#Cc1ccc(N)cc1
Reactant: CC(=O)Nc1ccccc1OS(=O)(=O)c1ccc(C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(=O)Nc1ccccc1C#Cc1ccc(N)cc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 2-acetylamino-phenyl ester and 4-ethynyl-phenylamine following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 9:1; yield (47 mg, 50%); 1H NMR δ (CDCl3): 8.39 (d, J=8.52 Hz, 1H), 7.9 (br s, 1H), 7.59-7.67 (m, 2H), 7.58-7.52 (m, 2H), 7.41-7.35 (m, 2H), 7.02 (t, J=7.21 Hz, 1H), 3.82 (b, 2H), 2.21 (s, 3H); LCMS m/z: 250.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]1([CH:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:21][CH2:22][Cl:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[ClH:23].[ClH:23].[C:14]1([CH:20]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:21][CH2:22][N:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: ClCCC(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: Cl
Product: c1ccc(CN2CCN(CCC(c3ccccc3)c3ccccc3)CC2)cc1
Yield: 170 %

Procedure:
To a solution containing 17.62 g (0.1 mole) of N-benzyl-piperazine in 100 ml of xylene were added 23.05 g (0.1 mole) of 3,3-diphenylpropyl chloride and 10.1 g (0.1 mole) of triethylamine, and the resulting solution was heated at the refluxing temperature for 2.5 hours. The reaction liquid was left to cool, and the triethylamine hydrochloride which precipitated was filtered out. Then, dry hydrogen chloride gas was passed through this solution, while the solution was cooled so as to precipitate 1-(3,3-diphenyl-propyl)-4-benzylpiperazine dihydrochloride. The crystals were recovered by filtration, and recrystallized from an ethanol and ether mixed solvent to obtain 37.7 g of pure crystals (85.0% yield) with a melting point of 187°- 188°C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[OH-].[Na+].[S].CC(C)=O>O.CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(CCOc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Na+]
Agent: [OH-]
Agent: [S]
Solvent: CO
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(CCOc2ccc(N)cc2)cc1
Yield: 96.8 %

Procedure:
4-[2-(4-Methylphenyl)ethoxy]nitrobenzene (VI) (5.14 g, 0.02 mole), sodium hydroxide powder (3.0 g) and sulfur (1.6 g, 0.05 mole) were added to a mixture of acetone (20 ml) and methanol (20 ml), followed by heating under reflux for 5 hours. After cooling, the reaction mixture was diluted with water, extracted with ether and treated in the same manner as in Example 18 to obtain 4.4 g of 4-[2-(4-methylphenyl)ethoxy]aniline (V) (yield, 96.9%).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4](O)=[O:5].C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[Cl:23][C:24]1[C:29]2[C:30](=[O:44])[N:31]3[CH2:43][CH2:42][C@H:32]3[C:33]3[N:34]([CH:35]=[N:36][C:37]=3[C:38](=[N:40]O)[NH2:39])[C:28]=2[CH:27]=[CH:26][C:25]=1[F:45]>CN(C)C=O>[Cl:23][C:24]1[C:29]2[C:30](=[O:44])[N:31]3[CH2:43][CH2:42][C@H:32]3[C:33]3[N:34]([CH:35]=[N:36][C:37]=3[C:38]3[N:40]=[C:4]([CH2:3][N:2]([CH3:7])[CH3:1])[O:5][N:39]=3)[C:28]=2[CH:27]=[CH:26][C:25]=1[F:45]
Reactant: CN(C)CC(=O)O
Reactant: NC(=NO)c1ncn2c1[C@@H]1CCN1C(=O)c1c-2ccc(F)c1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CN(C)C=O
Product: CN(C)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c-3ccc(F)c2Cl)no1
Reaction time: 3.5 h
Yield: 24.3 %

Procedure:
1.24 g (12 mmol) of N,N-dimethylglycine were dissolved in 20 ml of N,N-dimethylformamide and treated portionwise with 2.43 g (15 mmol) of 1,1'-carbonyldiimidazole. After completion of the CO2 evolution the solution was stirred at 70° for 30'. Then, 3.35 g (10 mmol) of (S)-8-chloro-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamidoxime were added and the mixture was stirred at 90° for 3.5 hours. By evaporation of the solution, chromatography of the residue on 300 g of silica gel while eluting with ethyl acetate/methanol 9/1 and crystallization from ethyl acetate and hexane there was obtained 0.98 g (24%) of (S)-8-chloro-7-fluoro-12,12a-dihydro-1-[5-(dimethylaminomethyl)-1,2,4-oxadiazol-3-yl]-9H,11H- azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one of m.p. 166°-169°, which was converted into the hydrochloride of m.p. 223°-227°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]([CH3:14])[CH2:12][CH2:11][NH:10][C:9]2=[O:15])=[CH:4][CH:3]=1.[C:16](=O)(OC(Cl)(Cl)Cl)[O:17]C(Cl)(Cl)Cl.[NH2:28][C:29]1[CH:50]=[CH:49][C:32]([O:33][C:34]2[CH:35]=[CH:36][C:37]3[N:38]([CH:40]=[C:41]([NH:43][C:44]([CH:46]4[CH2:48][CH2:47]4)=[O:45])[N:42]=3)[CH:39]=2)=[C:31]([F:51])[CH:30]=1.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C.O1CCCC1>[CH:46]1([C:44]([NH:43][C:41]2[N:42]=[C:37]3[CH:36]=[CH:35][C:34]([O:33][C:32]4[CH:49]=[CH:50][C:29]([NH:28][C:16]([N:10]5[CH2:11][CH2:12][CH:13]([CH3:14])[N:8]([C:5]6[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=6)[C:9]5=[O:15])=[O:17])=[CH:30][C:31]=4[F:51])=[CH:39][N:38]3[CH:40]=2)=[O:45])[CH2:48][CH2:47]1
Reactant: CC1CCNC(=O)N1c1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1CCN(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)C(=O)N1c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 3.5 h
Yield: 9.1 %

Procedure:
To a solution of 1-(4-fluorophenyl)-6-methyltetrahydropyrimidin-2(1H)-one (240 mg, 1.1 mmol) in tetrahydrofuran (5 mL) was added bis(trichloromethyl) carbonate (170 mg, 0.57 mmol), and the mixture was stirred at 70° C. for 3.5 hr. The mixture was cooled to room temperature, a solution of N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (250 mg, 0.76 mmol) in tetrahydrofuran (8 mL) and N,N-diisopropylethylamine (300 mg, 2.3 mmol) were added to the mixture, and the mixture was stirred at room temperature for 1 hr. Ethyl acetate/tetrahydrofuran and saturated aqueous sodium hydrogen carbonate solution were added to the mixture, and the aqueous layer was extracted 3 times with ethyl acetate/tetrahydrofuran. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate/hexane=50/50→100/0) to give the title compound (29 mg, 7%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][C@@H:20]([CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)[C:21]([O:23][CH3:24])=[O:22].Cl.N1C=CC(CCl)=CC=1>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][C@@H:20]([CH2:25][C:26]2[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=2)[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)[C@@H](N)Cc1ccncc1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Agent: ClCc1ccncc1
Product: COC(=O)[C@H](Cc1ccncc1)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl (S)2-amino-3-(4-pyridyl)propionate hydrochloride (prepared by the method set forth above using 4-picolylchloride hydrochloride), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.49 in 10% MeOH/DCM) and the product was purified by silica gel column chromatography.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[N:20])[CH:14]=2)[C@@H:10]([NH2:12])[CH3:11])=[CH:4][CH:3]=1.[CH3:21][C:22]([O:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][N:29]=1)([CH3:26])[C:23]([OH:25])=O.CN1CC[O:42][CH2:41]C1>C(Cl)Cl>[C:19]([C:15]1[CH:14]=[C:13]([C@H:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:42][CH3:41])=[CH:3][CH:4]=2)[C@@H:10]([NH:12][C:23](=[O:25])[C:22]([O:27][C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][N:29]=2)([CH3:21])[CH3:26])[CH3:11])[CH:18]=[CH:17][CH:16]=1)#[N:20]
Reactant: CC(C)(Oc1cc(C(F)(F)F)ccn1)C(=O)O
Reactant: CN1CCOCC1
Reactant: C[C@H](N)[C@@H](Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Solvent: ClCCl
Product: COc1ccc(C[C@@H](c2cccc(C#N)c2)[C@H](C)NC(=O)C(C)(C)Oc2cc(C(F)(F)F)ccn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(1S, 2S)-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]amine (Reference Example 4, 0.60 g, 2.1 mol) and 2-(4-trifluoromethyl-2-pyridyloxy)-2-methylpropionic acid (Reference Example 13, 0.58 g, 2.4 mmol) in 10 mL of CH2Cl2 was added N-methylmorpholine (0.46 mL, 4.2 mmol) and tris(pyrrolindinyl)phosphonium hexafluorophosphate (1.6 g, 3.2 mmol). After stirring at room temperature overnight, the reaction mixture was loaded onto a silica gel column eluted with 30% EtOAc in hexane to give the title compound. 1H NMR (500 MHz, CD3OD): δ 8.19 (d, 1H), 7.48 (d, 1H), 7.38-7.35 (m, 2H), 7.31 (d, 1H), 7.18 (s, 1H), 7.11 (d, 1H), 7.03 (d, 2H), 6.67 (d, 2H), 4.23 (m, 1H), 3.01 (dd, 1H), 2.83 (m, 1H), 2.61 (dd, 1H), 1.76 (s, 3H), 1.72 (s, 3H), 0.79 (d, 3H).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][CH2:3]1.[CH3:6][C:7]([O:10][C:11]([NH:13][CH2:14][CH2:15][C:16](O)=[O:17])=[O:12])([CH3:9])[CH3:8].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(N(CC)CC)C>[N:2]1([C:16](=[O:17])[CH2:15][CH2:14][NH:13][C:11](=[O:12])[O:10][C:7]([CH3:6])([CH3:8])[CH3:9])[CH2:5][CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: C1CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCC(=O)N1CCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.3 %

Procedure:
After adding azetidine hydrochloride (2.96 g) to a solution of triethylamine (4.42 ml) in N,N-dimethylformamide, the mixture was stirred for 10 minutes at room temperature. Boc-beta-ALA-OH (5.00 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.59 g) and 1-hydroxybenzotriazole (5.35 g) were added thereto, and the mixture was stirred at room temperature for 3 days. The reaction mixture was partitioned between ethyl acetate and brine. The organic layer was washed with brine and dried over anhydrous sodium sulfate. It was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate, then ethyl acetate:methanol=10:1). Fractions containing the target compound were concentrated under reduced pressure to provide the title compound (5.99 g, 99.4%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]=[CH:6][C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][NH:10][C:9]=2[N:8]=1)[CH3:2].[H][H]>CCO.[Pd].[C]>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][NH:10][C:9]=2[N:8]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C=Cc1ccc2c(n1)NCCC2
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc2c(n1)NCCC2

Procedure:
A mixture of 4-8 (1.4 g, 6.03 mmol) and 10% Pd/carbon (1 g) in EtOH (30 mL) was stirred under a balloon of hydrogen for 18 h. Filtration and evaporative removal of the solvent gave 4-9 as a white solid.
Reaction SMILES: O=C[C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1>[Ni]>[C:5]1([O:6][CH3:7])[C:8](=[CH:10][CH:11]=[CH:3][CH:4]=1)[OH:9].[C:5]1([C:8](=[CH:10][CH:11]=[CH:3][CH:4]=1)[OH:9])[OH:6]
Reactant: COc1cc(C=O)ccc1O
Agent: [Ni]
Product: COc1ccccc1O
Product: Oc1ccccc1O

Procedure:
It is known that aromatic aldehydes decarbonylate when heated over hydrogenation catalysts. Of the aromatic aldehydes containing a phenolic group, vanillin is reported to decarbonylate over nickel at 370°-390° C., giving guaiacol and catechol. It is reported (Synthesis, December, 1969, p. 164) that salicylaldehyde in refluxing toluene and in the presence of a stoichiometric amount of chloro-tris(triphenyl phosphine)-rhodium complex yields phenol in 70% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:41])[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[N:19]=[C:20]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:21]3[CH2:27][CH2:26][N:25](CC4C=CC=CC=4)[CH2:24][C:22]=3[N:23]=2)=[CH:13][CH:12]=1.C1CC=CCC=1>[Pd].C(O)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10](=[O:41])[C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]2[N:19]=[C:20]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:21]3[CH2:27][CH2:26][NH:25][CH2:24][C:22]=3[N:23]=2)=[CH:15][CH:16]=1
Reactant: Cc1cccc(C)c1NC(=O)c1ccc(Nc2nc3c(c(-c4ccccc4)n2)CCN(Cc2ccccc2)C3)cc1
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CCO
Product: Cc1cccc(C)c1NC(=O)c1ccc(Nc2nc3c(c(-c4ccccc4)n2)CCNC3)cc1
Temperature: 80 °C
Yield: 62.7 %

Procedure:
A mixture of N-(2,6-dimethylphenyl)-4-{[4-phenyl-7-(phenylmethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl]amino}benzamide (60 mg, 0.11 mmol), prepared as described in Example 249, 1,4-cyclohexadiene (11 μL, 0.11 mmol) and 10% palladium on carbon (8 mg) in ethanol (2 mL) were heated to 80° C. overnight. Upon cooling to rt, the reaction mixture was filtered through celite and concentrated on a rotary evaporator. The resulting residue was purified by preparative reverse phase HPLC to give N-(2,6-dimethylphenyl)-4-[(4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)amino]benzamide (31 mg, 62%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.87 (s, 1H), 9.52 (s, 1H), 7.96 (m, 4H), 7.62 (m, 2H), 7.52 (m, 3H), 7.11 (m, 3H), 3.75 (m, 2H), 3.05 (m, 2H), 2.79 (m, 2H), 2.17 (s, 6H). MS (EI) for C28H27N5O: 450.2 (MH+).