Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[N:8]1(C(OC(C)(C)C)=O)[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1>CCO>[N:8]1([CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1
Reactant: C=CC(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCNCC2)CC1
Solvent: CCO
Product: CCOC(=O)CCN1CCC(C2CCNCC2)CC1
Reaction time: 8 h

Procedure:
4.4 mL (40.6 mmol) ethyl acrylate were added to a solution of 10.0 g (37.3 mmol) tert. butyl [4,4′]bipiperidinyl-1-carboxylate in 100 mL EtOH and the reaction mixture was refluxed for 2 h. To complete the reaction a further 1 mL (9.2 mmol) ethyl acrylate were added, the mixture was refluxed for 1 h and left overnight at RT. The solvent was eliminated i. vac. and the crude product was further reacted without any purification.
Reaction SMILES: [F:1][C:2]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:3]=1[CH2:4][C:5]1[C:6]([NH:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])=[C:7]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=2)[C:8]2[C:15](=[O:16])[N:14]3[C@@H:10]([CH2:11][CH2:12][CH2:13]3)[C:9]=2[N:17]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[NH2:62][C@H:63]1[C:71]2[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=2)[CH2:65][CH2:64]1>ClCCl>[F:1][C:2]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:3]=1[CH2:4][C:5]1[C:6]([NH:27][C:28](=[O:33])[C:29]([F:30])([F:32])[F:31])=[C:7]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH:62][C@H:63]3[C:71]4[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=4)[CH2:65][CH2:64]3)=[O:24])=[CH:20][CH:19]=2)[C:8]2[C:15](=[O:16])[N:14]3[C@@H:10]([CH2:11][CH2:12][CH2:13]3)[C:9]=2[N:17]=1
Reactant: O=C(O)c1ccc(-c2c(NC(=O)C(F)(F)F)c(Cc3ccc(F)cc3F)nc3c2C(=O)N2CCC[C@@H]32)cc1
Reactant: N[C@@H]1CCc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: O=C(N[C@@H]1CCc2ccccc21)c1ccc(-c2c(NC(=O)C(F)(F)F)c(Cc3ccc(F)cc3F)nc3c2C(=O)N2CCC[C@@H]32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the 2.0 ml dichloromethane solution containing the acid (G, 4-{(9aS)-2-(2,4-difluorobenzyl)-5-oxo-3-[(trifluoroacetyl)amino]-7,8,9,9a-tetrahydro-5H-pyrido[2,3-a]pyrrolizin-4-yl}benzoic acid, 956 mg, 1.8 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (691 mg, 3.6 mmol) and 1-hydroxybenzotriazole hydrate, 480 mg (R)-(−)-1-aminoindan (3.6 mmol) was added. The resulting mixture was stirred at room temperature for 3 hours. Diluted with dichloromethane. Washed with water and brine subsequently. Dried with sodium sulfate. Upon the removal of the solvent, the residue was purified with flash chromatography. 320 mg of the title compound as a light yellowish solid was obtained. NMR (400 MHz, CDCl3) δ 7.95 (m, 2H), 7.32 (m, 5H), 6.95 (m, 4 m), 5.62 (m, 1H), 4.59 (m, 1H), 4.15 (m, 1H), 3.55 (s, 2H), 3.15 (m, 1H), 3.06 (m, 1H), 2.90 (m, 1H), 2.58 (m, 1H), 2.32 (m, 2H), 2.02 (m, 1H), 1.25 (m, 1H) ppm. ESI-MS m/z 647 (M+H)+, 645 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1O[C:4]([CH3:9])=[CH:5][C:6](=[O:8])[CH:7]=1.[NH3:10]>C(O)C>[CH3:1][C:2]1[NH:10][C:4]([CH3:9])=[CH:5][C:6](=[O:8])[CH:7]=1
Reactant: N
Reactant: Cc1cc(=O)cc(C)o1
Solvent: CCO
Product: Cc1cc(=O)cc(C)[nH]1
Temperature: 25 °C

Procedure:
To a solution of 2,6-dimethyl-pyran-4-one (ALDRICH, 7.44 g) in ethanol (40 ml) was added commercial 30% aqueous ammonia (140 ml). The mixture was heated to 140° C. in steel reactor for 8 h, then allowed to cool to room temperature overnight. The mixture was filtered and the ethanol removed under vacuum. The precipitate formed was isolated by filtration to afford a first crop of 1.9 g of the title compound. The filtrate was concentrated to dryness to afford a second crop of 5.2 g of the title compound, which were not further purified.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.Cl[CH2:13][Si:14]([CH3:23])([CH3:22])[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CS(C)=O.C(OCC)C>[CH3:13][Si:14]([CH2:23][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1)([CH3:22])[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1
Reactant: CC(=O)Cc1ccc(O)cc1
Reactant: C[Si](C)(CCl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CC(=O)Cc1ccc(OC[Si](C)(C)c2ccc(F)cc2)cc1
Temperature: 0 °C

Procedure:
30 g of 1-(4-hydroxyphenyl)-propan-2-one and 45.5 g of chloromethyl-dimethyl-(4-fluorophenyl)-silane in 400 ml of dimethyl sulfoxide are stirred with 42 g of potassium carbonate and 2 g of potassium iodide for 12 hours at 70° C. The reaction mixture is poured into 1.6 liters of ice water and 500 ml of diethyl ether are added; the ether phase is extracted by washing several times with water and saturated sodium chloride solution and dried over sodium sulfate; the solvent is evaporated off. Distillation at 150° C. (0.01 mbar) yields the title product.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([CH2:16][N:17]([CH:33]4[CH2:35][CH2:34]4)[C:18]([C@@H:20]4[O:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]4)=[O:19])=[CH:13][CH:14]=3)[N:9]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[H][H]>C(O)C.[C].[Pd]>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([CH2:16][N:17]([CH:33]4[CH2:34][CH2:35]4)[C:18]([C@@H:20]4[O:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH2:21]4)=[O:19])=[CH:13][CH:14]=3)[N:9]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: COCCCn1nc(C2=CCCCC2)c2ccc(CN(C(=O)[C@H]3CN(C(=O)OC(C)(C)C)CCO3)C3CC3)cc21
Agent: [Pd]
Solvent: CCO
Product: COCCCn1nc(C2CCCCC2)c2ccc(CN(C(=O)[C@H]3CN(C(=O)OC(C)(C)C)CCO3)C3CC3)cc21
Yield: 34.9 %

Procedure:
10% Palladium-Carbon (30 mg) was added to a solution of tert-butyl(2R)-2-{[{[3-cyclohex-1-ene-1-yl-1-(3-methoxypropyl)-1H-indazol-6-yl]methyl}(cyclopropyl)amino]carbonyl}morpholin-4-carboxylate (300 mg) in ethanol (5 ml) and the mixture was stirred under normal pressure of hydrogen atmosphere at room temperature for 5 hours. Insolble materials were filtered through Celite and the filtrate was concentrated in vacuo. The resulted residue was purified with a silica gel column chromatography (eluting solvent: n-hexane to n-hexane/ethyl acetate=1/2) to give tert-butyl(2R)-2-{[{[3-cyclohexyl-1-(3-methoxypropyl)-1H-indazol-6-yl]methyl}(cyclopropyl)amino]carbonyl}morpholin-4-carboxylate (105 mg) as a colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.C(N(CC)CC)C.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.C([NH+](CC)CC)C>C1COCC1>[C:13]([N:1]1[CH:5]=[N:4][N:3]=[N:2]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1nnn[nH]1
Reactant: O=C(Cl)c1ccccc1
Agent: CC[NH+](CC)CC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)n1cnnn1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a stirring suspension of 1H-tetrazole (7.0 g, 0.1 mol) and triethylamine (15 ml, 0.12 mol) in anhydrous THF (300 ml), in a bath maintained at 0° C., was added benzoyl chloride (99%, 12.8 ml, 0.11 mol) slowly over 30 min. When addition was complete, the mixture was stirred for an additional 45 min. A precipitate formed, identified as triethylammonium hydrochloride (using NMR spectroscopy), was removed by filtration through a pad of Celite 545. The solvent was removed under reduced pressure while the bath temperature was maintained below 30° C. A residual oil was obtained. Crystallization of the residual oil in hexanes yielded N-benzoyltetrazole as colorless crystals. The crystals were removed by filtration, washed with hexanes (2×15 ml) and dried under vacuum for approximately 15 hours at room temperature. Yield: 15 g, 86%; m.p. 56-58iC; 1H NMR, (CDCl3) δ 9.43 (s, 1H), 8.26-8.22 (d, J=, 2H), 7.79-7.54 (m, 3H); 13C NMR, (CDCl3) 162.9, 143.7, 136.3, 132.7, 129.7 and 129.5. HRMS: (FAB) for C8H7N4O (MH+) 175.0620, found 175.0627.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:12][NH:13][O:14][CH3:15].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN1CCOCC1.ClCCl>[NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([N:13]([O:14][CH3:15])[CH3:12])=[O:5]
Reactant: Nc1ncc(Br)cc1C(=O)O
Reactant: CNOC
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.6 %

Procedure:
To a solution of 2-amino-5-bromonicotinic acid (7 g, 32.3 mmol), N,O-dimethylhydroxylamine (5.99 g, 61.37 mmol) in N-methylmorpholine (60 ml) and dichloromethane (500 ml) at 0° C. was added PyBop (25.2 g, 48.45 mmol) portionwise. The solution was allowed to warm to room temperature and the mixture was stirred at room temperature for 18 hours. The reaction mixture was washed with a 2M aqueous solution of NaOH and with a 10 wt % solution of citric acid. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was dissolved in ether and the formed solid was filtered off. The mother liquors were concentrated in vacuo to approximatively half of the original volume. This solution was diluted with dichloromethane and stirred vigorously while adding a 2M HCl solution in diethylether until complete formation of the precipitate. The solid was filtered off and partitioned between a 2M aqueous solution of NaOH and EtOAc. The organic layer was collected, dried over sodium sulfate, filtered and concentrated to dryness to afford the title compound as a cream solid (5.26 g, 63% yield).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.[Cl:12][C:13]1[CH:14]=[C:15]([CH:20]([CH:26]([N:28]([CH3:30])[CH3:29])[CH3:27])[C:21](OCC)=[O:22])[CH:16]=[CH:17][C:18]=1[Cl:19]>O>[Cl:12][C:13]1[CH:14]=[C:15]([CH:20]([CH:26]([N:28]([CH3:30])[CH3:29])[CH3:27])[CH2:21][OH:22])[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: CCOC(=O)C(c1ccc(Cl)c(Cl)c1)C(C)N(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC(C(CO)c1ccc(Cl)c(Cl)c1)N(C)C

Procedure:
To a suspension of 10 g. of lithium aluminum hydride in 300 ml. of diethyl ether, 18.7 g. of ethyl 2-(3,4-dichlorophenyl)-3-dimethylaminobutyrate is added dropwise with stirring. The mixture is refluxed for 40-45 hours and after cooling with an ice bath, 50 ml. of water is added very slowly. After filtering off and thoroughly washing out the inorganic salts, the dried organic filtrate is evaporated and the residue is distilled in vacuo at 115° C/0.4 mm Hg to yield 13 g. of the title compound. The hydrochloride salt melts at 188°-190° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[Sn:13](Cl)([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17].[Cl-].[NH4+]>C1COCC1>[CH2:22]([Sn:13]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:18][CH2:19][CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH2:23][CH2:24][CH3:25]
Reactant: Brc1ccccn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 2-bromopyridine (XCVI) (10 g, 63 mmol, 1.00 eq) in THF (150 mL) was added n-BuLi (25.3 mL, 63 mmol, 1.00 eq) and the mixture was stirred at −70° C. for 30 min under nitrogen atmosphere. Then n-Bu3SnCl (21.7 g, 67 mmol, 1.06 eq) was added and the mixture was stirred at the same temperature for another 2 h. Saturated ammonium chloride solution (150 mL) was added to the solution and extracted with ethyl acetate (150 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to afford the crude 2-(tributylstannyl)pyridine (XCVII) (25.9 g, 63 mmol, 100% yield) as a yellow oil. The crude product was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:8]2[C:9](=[O:15])[NH:10][C:11](=[O:14])[NH:12][CH:13]=2)=[C:5]([CH3:7])[N:6]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][Cl:27].O>CN(C=O)C>[Cl:27][CH2:26][CH2:25][CH2:24][CH2:23][N:12]1[CH:13]=[C:8]([C:4]2[O:3][C:2]([CH3:1])=[N:6][C:5]=2[CH3:7])[C:9](=[O:15])[NH:10][C:11]1=[O:14]
Reactant: ClCCCCBr
Reactant: Cc1nc(C)c(-c2c[nH]c(=O)[nH]c2=O)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(C)c(-c2cn(CCCCCl)c(=O)[nH]c2=O)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
5-(2,4-Dimethyl-oxazol-5-yl)-1H-pyrimidine-2,4-dione (Prep61, 300 mg, 1.45 mmol) was dissolved in dry DMF (4 ml) and K2CO3 (300 mg, 2.17 mmol) was added. The mixture was stirred at room temperature for 1 h, then a solution of 1-bromo-4-chloro-butane (commercially available from Aldrich, 496 mg, 2.9 mmol) in dry DMF (1 ml) was added. After stirring the reaction at room temperature for 48 hours, water was added and the mixture was extracted with diethylether. The aqueous layer was then extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered and evaporated; the crude was used without further purification in the next step (200 mg, 47% yield).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:12](=O)[CH2:13][CH2:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([O-])(=O)C.[NH4+:35]>C(O)(=O)C.C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([C:12]2[NH:35][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[CH:14][CH:13]=2)[CH2:24][CH:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ccccn2)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3ccccn3)[nH]2)cc1
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 85.7 %

Procedure:
To a solution of 5-[4-(methylsulfonyl)phenyl]-1-(pyridin-2-yl)-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (525 mg) in acetic acid (6 mL) was added ammonium acetate (1.50 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. The residue was subjected to silica gel column chromatography, and the title compound (430 mg, yield 86%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 411 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=3)=[CH:12][C:11]([C:21]([OH:23])=O)=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(N2C(C3C=NC=C(F)C=3)=CC(C([N:46]3[CH2:50][C:49](=[O:51])[NH:48][CH2:47]3)=O)=N2)C=CC=1F.Cl.N1C=CNC1=O>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=3)=[CH:12][C:11]([C:21]([N:46]3[CH2:50][C:49](=[O:51])[NH:48][CH2:47]3)=[O:23])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1CN(C(=O)c2cc(-c3cncc(F)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Reactant: O=C(O)c1cc(-c2cncc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Agent: Cl
Agent: O=c1[nH]cc[nH]1
Product: O=C1CN(C(=O)c2cc(-c3cncc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1

Procedure:
100 mg (0.28 mmol) of the compound of Example 61A is reacted analogously to the synthesis of the compound of Example 98 with 38 mg (0.31 mmol) of 4-imidazolinone-hydrochloride. 62 mg (52% of theory) of the title compound is obtained.
Reaction SMILES: [H-].[K+].[Cl:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:18][CH3:19])[C:10]=2[C:14]([F:17])([F:16])[F:15])[C:5]=1[C:20]([NH:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:21].Cl[C:32]([O:34][CH3:35])=[O:33]>O1CCCC1>[Cl:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:18][CH3:19])[C:10]=2[C:14]([F:17])([F:16])[F:15])[C:5]=1[C:20]([N:22]([C:32]([O:34][CH3:35])=[O:33])[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:21]
Reactant: COc1ccc2c(C(=O)NCC(=O)OC(C)(C)C)c(Cl)ccc2c1C(F)(F)F
Reactant: COC(=O)Cl
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)N(CC(=O)OC(C)(C)C)C(=O)c1c(Cl)ccc2c(C(F)(F)F)c(OC)ccc12
Reaction time: 0.42 h
Yield: 67 %

Procedure:
To a suspension of potassium hydride (0.9 g, 1.2 eq, 35% by weight dispersion in mineral oil) in dry tetrahydrofuran (20 mL) under argon at room temperature was added dropwise a solution of N-[[2-chloro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]glycine, 1,1-dimethylethyl ester (2.73 g, 6.53 mmol) in dry THF (30 mL). After stirring 25 minutes the reaction was cooled in an ice bath and a solution of methyl chloroformate (0.7 mL, 1.4 eq) in dry THF (18 mL) was added dropwise over a period of 20 minutes. After stirring 1 hour the reaction was quenched with saturated aqueous ammonium chloride and diluted with ether (300 mL). The ether layer was separated, and dried over magnesium sulfate. Silica gel was added and the ether was removed. The silica absorbate was flash chromatographed (4:1 petroleum ether:EtOAc) to give the title compound as a white solid (2.10 g, 67%). A small sample was further purified by trituration with petroleum ether, m.p. 117°-118° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:46]=[C:47]([Cl:49])[CH:48]=1)[CH2:5][N:6]([CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1[C:35]1[CH:40]=[C:39]([CH:41]([CH3:43])[CH3:42])[CH:38]=[CH:37][C:36]=1[O:44][CH3:45])[C:7]1[N:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])=[CH:9][N:8]=1.Cl.O1CCOCC1>[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:46]=[C:47]([Cl:49])[CH:48]=1)[CH2:5][N:6]([CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[CH:27][C:26]=1[C:35]1[CH:40]=[C:39]([CH:41]([CH3:43])[CH3:42])[CH:38]=[CH:37][C:36]=1[O:44][CH3:45])[C:7]1[N:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:11][N:12]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(Cl)cc(Cl)c1)c1ncc(OCCCC(=O)OC(C)(C)C)cn1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(Cl)cc(Cl)c1)c1ncc(OCCCC(=O)O)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
To tert-butyl 4-{2-[(3,5-dichloro-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (180 mg) is added 4N-hydrochloric acid/dioxane solution (2 ml) and the mixture is stirred at room temperature for 4 hours. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→19:1) to give 4-{2-[(3,5-dichlorobenzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyric acid (136 mg). MS (m/z): 664/662 [M+H]+
Reaction SMILES: [C:1]([C:3]1[C:4]([C:27]2[CH2:28][CH2:29][O:30][CH2:31][CH:32]=2)=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH:22]([O:25][CH3:26])[O:23][CH3:24])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2]>CO.C1COCC1.[Pd]>[C:1]([C:3]1[C:4]([CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH:22]([O:25][CH3:26])[O:23][CH3:24])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2]
Reactant: COC(OC)c1ccc2c(n1)N(C(=O)Nc1cc(C3=CCOCC3)c(C#N)cn1)CCC2
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(OC)c1ccc2c(n1)N(C(=O)Nc1cc(C3CCOCC3)c(C#N)cn1)CCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-(5-cyano-4-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 27, 35 mg, 0.080 mmol) was dissolved in MeOH (1 ml) and THF (3 ml). The solution was treated with palladium (10% on charcoal, 8.55 mg, 8.04 μmol) and stirred under a H2 atmosphere at room temperature for 16 h. The reaction mixture was filtered through a celite plug. The plug was rinsed with EtOAc and the filtrate was concentrated under vacuum. The residue was purified by normal phase chromatography (4 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) to give the title compound as a white solid. (UPLC-MS 3) tR 1.18 min; ESI-MS 438.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([OH:18])=[C:6]([N+:15]([O-:17])=[O:16])[C:7]([N+:12]([O-:14])=[O:13])=[C:8]([CH:11]=1)[CH:9]=[O:10])[CH3:2].CN(C)C=O.C([O-])([O-])=O.[K+].[K+].[CH2:30](Br)[CH3:31]>C(OCC)C>[CH2:30]([O:18][C:5]1[C:4]([O:3][CH2:1][CH3:2])=[CH:11][C:8]([CH:9]=[O:10])=[C:7]([N+:12]([O-:14])=[O:13])[C:6]=1[N+:15]([O-:17])=[O:16])[CH3:31]
Reactant: CCBr
Reactant: CCOc1cc(C=O)c([N+](=O)[O-])c([N+](=O)[O-])c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)c([N+](=O)[O-])c([N+](=O)[O-])c1OCC

Procedure:
5-Ethoxy-4-hydroxy-2,3-dinitro-benzaldehyde (3.77 g), N,N-dimethylformamide (35 ml), K2CO3 (3.877 g) and ethyl bromide (50 ml) were refluxed 24 hours. To the reaction solution was added diethyl ether (100 ml) and then it was washed with water and 1M sodium hydroxide. The solution was dried and evaporated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]=[CH:10][C:11]([NH:13][C@H:14]([C:24]([O:26]C)=[O:25])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:12].[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]=[CH:10][C:11]([NH:13][C@H:14]([C:24]([OH:26])=[O:25])[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)=[O:12]
Reactant: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1c(F)cccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C[C@H](NC(=O)C=Cc2c(F)cccc2F)C(=O)O)cc1
Yield: 97 %

Procedure:
The same procedures as in Example 64 were carried out from the compound obtained in Example 46 (3.0 g), 1 mol/L of an aqueous sodium hydroxide solution (12 mL), and methanol (120 mL), to give the captioned compound (2.8 g, 95%) as crystals,
Reaction SMILES: [O:1]=[C:2]1[CH2:7][C@@H:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH2:5][C@H:4](CC([O-])=O)[CH2:3]1.CS(C)=[O:22]>P([O-])([O-])([O-])=O>[OH:22][C@@H:4]1[CH2:5][C@H:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH2:7][C:2](=[O:1])[CH2:3]1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC(=O)C[C@@H](CC(=O)[O-])C1
Reactant: CS(C)=O
Agent: O=P([O-])([O-])[O-]
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC(=O)C[C@H](O)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 75 %

Procedure:
3-Oxo-5-(tert.butyldimethylsilyloxy)-(1S, 5S)-cyclohexylacetate (6, 1.2 parts, 4.2 mmol ) was dissolved in DMSO (10 parts) and 0.1 M phosphate buffer (pH 6.5, 90 parts). To the mixture, PLE (0.1 parts) was added and the reaction mixture was stirred for 48 hr at room temperature. It was filtered through ceilite and filtrate was extracted with ethyl acetate (3×100 parts). Organic extracts were combined and washed with brine. Organic layer was dried on anhydrous sodium sulphate and concentrated under vacuum. Residue was chromatographed on silica gel to afford 3-hydroxy-5-(tertbutyldimethylsilyloxy)-(3R,5S)-cyclohexan-1-one 7 (0.77 parts, 75%).
Reaction SMILES: [N:1]([CH2:4][C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)=[N+]=[N-]>CO.[OH-].[OH-].[Pd+2]>[O:6]1[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=[C:5]1[CH2:4][NH2:1]
Reactant: [N-]=[N+]=NCc1cc2ccccc2o1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: NCc1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 2-(azidomethyl)benzofuran and 267 mg of 20% Pd(OH)2 in 10 mL of MeOH was stirred at r.t. under H2 balloon for 2.5 h. The mixture was filtered through Celite and concentrated to give the crude benzofuran-2-ylmethanamine which was used without further purification.