Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[C:8]([C:11]2[CH:16]=[CH:15][C:14](OC)=[CH:13][CH:12]=2)[N+:9]=1[O-:10])([CH3:4])([CH3:3])[CH3:2].N(=C(C(C1C=NC=CC=1)=O)C1C=CC(OC)=CC=1)O>>[C:1]([C:5]1[NH:6][C:7]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N+:9]=1[O-:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(-c2c(-c3cccnc3)[nH]c(C(C)(C)C)[n+]2[O-])cc1
Agent: COc1ccc(C(=NO)C(=O)c2cccnc2)cc1
Product: CC(C)(C)c1[nH]c(-c2cccnc2)c(-c2ccccc2)[n+]1[O-]

Procedure:
2-tert.butyl-4-(p-methoxyphenyl)-5(3-pyridyl)-imidazole-3-oxide (m.p. 245° - 247°C), starting from 12.8 g of (α-hydroximino-p-methoxy-benzyl)-(3-pyridyl)-ketone.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH2:25])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=O)(C)(C)C.[CH2:33](N)[CH2:34][CH3:35].C(OCC)(=O)C>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH:25][CH2:33][CH2:34][CH3:35])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(N)=O)C1
Reactant: CCCN
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCNC(=O)Nc1cn(-c2cccc(F)c2)cc1C(=O)N[C@H]1CCCNC1
Yield: 65 %

Procedure:
Following general method 6, employing (S)-3-{[1-(3-fluorophenyl)-4-ureido-1H-pyrrole-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester and propylamine, afforded the crude desired product. Column chromatography (silica, 12 g column, ISCO, 0-50% ethyl acetate in DCM) afforded the title compound as glass (100 mg, 65%); LCMS (method B): RT=3.89 min, M+H+=488.
Reaction SMILES: C1C2C(CO[C:16]([NH:18][C@H:19]([C:36]([O:38][CH3:39])=[O:37])[CH2:20][S:21][CH2:22][CH:23]([C:28](=[O:35])[C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[CH2:24][C:25]([OH:27])=[O:26])=[O:17])C3C(=CC=CC=3)C=2C=CC=1.[CH3:40][O:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[N:48]=C=O>>[CH3:40][O:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[NH:48][C:16]([NH:18][C@H:19]([C:36]([O:38][CH3:39])=[O:37])[CH2:20][S:21][CH2:22][CH:23]([C:28](=[O:35])[C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)[CH2:24][C:25]([OH:27])=[O:26])=[O:17]
Reactant: COc1ccccc1N=C=O
Reactant: COC(=O)[C@H](CSCC(CC(=O)O)C(=O)c1cccnc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Product: COC(=O)[C@H](CSCC(CC(=O)O)C(=O)c1cccnc1)NC(=O)Nc1ccccc1OC
Yield: 14 %

Procedure:
The title compound was prepared from 3-({(2R)-2-[(fluoren-9-ylmethoxy)carbonylamino]-2-(methoxycarbonyl)ethylthio}methyl)-4-oxo-4-(3-pyridyl)butanoic acid and 2-methoxyphenyl isocyanate as described in Example 16 in a 14% yield; ESMS, (M+1)+476.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](Cl)([CH3:17])([CH3:16])[CH3:15]>Cl.[Al+3].[Cl-].[Cl-].[Cl-]>[CH3:15][C:14]([C:4]1[CH:5]=[CH:6][C:1]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:1]([CH3:7])([CH3:6])[CH3:2])=[CH:12][CH:13]=2)=[CH:2][CH:3]=1)([CH3:17])[CH3:16]
Reactant: c1ccc(Cc2ccccc2)cc1
Reactant: CC(C)(C)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)(C)c1ccc(Cc2ccc(C(C)(C)C)cc2)cc1
Reaction time: 0.08 h
Yield: 139.8 %

Procedure:
In a 500-ml flask, to a mixture of 16.8 g (100 mmol) of diphenylmethane and 21.3 g (230 mmol) of tert-butyl chloride, 67 mg (0.5 mmol) of anhydrous AlCl3 were added, at room temperature, under vigorous stirring, resulting in immediate HCl gas emission. The reaction mixture turned red. After 5 min, a second portion of 67 mg (0.5 mmol) of AlCl3 were added. After 5 min of vigorous stirring, the reaction mixture became hard. After about 1 h, the hard mass obtained was recrystallised from about 100 mL of hot isopropanol. The crystalline product precipitated from this solution at a temperature of −30° C. after a period of time of about 2 to 3 h. It was separated, washed with 50 ml of cold isopropanol, and dried in vacuum under a reduced pressure of 10 to 20 mm Hg. 19.6 g of product were obtained with a yield of 70%. The procedure was repeated with a yield ranging between 67 and 74%.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[CH2:6][CH2:7][CH2:8][C:9]3[S:13][C:12]([NH:14][C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])=[N:11][C:10]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C1COCC1>[F:1][C:2]1[CH:23]=[CH:22][C:5]2[CH2:6][CH2:7][CH2:8][C:9]3[S:13][C:12]([NH:14][C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][S:32]([CH3:31])(=[O:34])=[O:33])=[N:11][C:10]=3[C:4]=2[CH:3]=1
Reactant: NCCCCC(=O)Nc1nc2c(s1)CCCc1ccc(F)cc1-2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)NCCCCC(=O)Nc1nc2c(s1)CCCc1ccc(F)cc1-2
Temperature: 25 °C
Reaction time: 6 h
Yield: 37.9 %

Procedure:
N1-(9-fluoro-5,6-dihydro-4H-benzo[6,7]cyclohepta[d][1,3]thiazol-2-yl)-5-aminopentanamide (115 mg, 0.34 mmole) was dissolved in 2 ml of dry THF, cooled with an ice bath, triethylamine was added (96 μl, 0.69 mmole) followed by addition of 27 μl of methane sulfonyl chloride (0.35 mmole). The reaction mixture was stirred at room temperature for 6 hours, quenched with saturated sodium carbonate solution and extracted with 3×3 ml of ethyl acetate. The combined ethyl acetate extracts were washed with saturated sodium chloride solution, concentrated and chromatographed (12 g of silica gel, EtOAc/hexanes/7N NH3 in MeOH, 50:50:2) to give 53 mg of the desired product as a white solid (38%): m.p. 145-147° C.; 412 (ESMS, MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12](O)=O)=[CH:2]1.[CH3:15][NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23]>C(Cl)(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]2[N:16]([CH3:15])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:23]=2)=[CH:2]1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Reactant: CNc1ccccc1N
Solvent: ClC(Cl)Cl
Product: Cn1c(CCc2c[nH]c3ccccc23)nc2ccccc21
Temperature: 130 °C

Procedure:
A mixture of 3-indolepropionic acid (2.85 g, 15 mmol) and N-methyl-1,2-phenylenediamine (611 mg, 5.0 mmol) was stirred at 130° C. for 5H, during which a dark brown viscous mass forms, which was dissolved in chloroform (100 ml). The organic solution was then washed with 10% strength Na2CO3 solution (2×30 ml) and water, dried over Na2SO4 and concentrated i. vac. and the residue was purified by flash chromatography with cyclohexane/EA (1:1). Yield: 863 mg (Ind-54, 63%), colourless solid
Reaction SMILES: [I:1][CH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[CH:9]1[CH:14]=[CH:13][C:12]([P:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1.CCOCC>CC#N>[I-:1].[C:22]1([P+:15]([C:12]2[CH:11]=[CH:10][CH:9]=[CH:14][CH:13]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:2][CH:3]2[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: ICC1CCOCC1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CC#N
Product: [I-]
Product: c1ccc([P+](CC2CCOCC2)(c2ccccc2)c2ccccc2)cc1
Temperature: 20 °C

Procedure:
A stirred solution of 4-iodomethyltetrahydropyran (3.43 g, 15.2 mmol) and PPh3 (3.98 g, 15.2 mmol) in anhydrous MeCN (10 mL) was heated under reflux for 19 h. On cooling to 20° C., Et2O (50 mL) was added. The precipitate formed was collected, washed with Et2O (150 mL), and recrystallised (MeCN) to give the title compound: m/z (ES+)=361.2 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)[O:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]([OH:20])=O)=[CH:17][C:11]=3[O:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)[O:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:20])=[CH:17][C:11]=3[O:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)c1ccc2c(c1)OC(c1cc(Cl)cc(Cl)c1)(c1cc(Cl)cc(Cl)c1)O2
Reactant: C1COCCN1
Product: O=C(c1ccc2c(c1)OC(c1cc(Cl)cc(Cl)c1)(c1cc(Cl)cc(Cl)c1)O2)N1CCOCC1

Procedure:
This compound was prepared from 2,2-bis-(3,5-dichloro-phenyl)-benzo[1,3]dioxole-5-carboxylic acid and morpholine according to Example 269f; waxy solid,
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH2:16].C(OCC)(=O)C>CS(C)=O>[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH:16][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CN(C)CCN
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CN(C)CCNc1cc(F)ccc1[N+](=O)[O-]
Temperature: 23 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
To a stirred solution of 2,4-difluoronitrobenzene (3.18 g., 20 mmole) In DMSO (5 ml) was added portion-wise N,N-dimethylethylene-diamine (3.52 g., 40 mmole). The mixture was stirred at 23° C. for 1 hour and poured into crushed ice. Ethyl acetate (200 ml) was added to dissolve the orange-yellow solid. The organic phase separated was washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was chromatographed on a silica gel column eluting with CH2Cl2 /MeOH (20:1) to afford the compound (15) (2.8 g., 62%) which solidified on standing.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)(=[O:4])=[O:3].[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18][NH2:19]>CS(C)=O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:19][CH2:18][CH2:17][N:16]([CH3:20])[CH3:15])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN(C)CCN
Solvent: CS(C)=O
Product: CN(C)CCNc1ccc(S(C)(=O)=O)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 77.8 %

Procedure:
A mixture of 4-chloro-3-nitrophenyl methyl sulfone (4 g, 17 mmole) and N,N-dimethylethylenediamine (3.3 g, 37 mmole) in DMSO (20 ml) was stored at 75° C. for 1 hour and poured into crushed ice. The yellow solid precipitate was collected by filtration and was dissolved in ethyl acetate. The organic phase was washed with water-brine mixture twice and brine, dried over sodium sulfate, and evaporated under reduced pressure to give the sulfone (22) (3.8 g, 78%) as a yellow solid. A pure sample (m.p. 130°-131° C.) was obtained by recrystallization from ethyl acetate.
Reaction SMILES: O1CCOCC1.Cl.[CH:8]1(/[CH:13]=[C:14](/[C:23]2[N:28]=[C:27]([O:29]C)[C:26]([CH:31]3[CH2:33][CH2:32]3)=[CH:25][CH:24]=2)\[C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1>O>[CH:8]1(/[CH:13]=[C:14](/[C:23]2[NH:28][C:27](=[O:29])[C:26]([CH:31]3[CH2:33][CH2:32]3)=[CH:25][CH:24]=2)\[C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: COc1nc(/C(=C/C2CCCC2)c2ccc(SC)cc2)ccc1C1CC1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CSc1ccc(/C(=C\C2CCCC2)c2ccc(C3CC3)c(=O)[nH]2)cc1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 77 %

Procedure:
A 4 M hydrogen chloride-1,4-dioxane solution (4.5 mL) was added to a suspension of 6-{(E)-2-cyclopentyl-1-[4-(methylsulfanyl)phenyl]ethenyl}-3-cyclopropyl-2-methoxypyridine (150 mg) in water (1.5 mL), and the mixture was stirred at 90° C. for 1.5 hours. The reaction solution was cooled to room temperature and extracted with chloroform twice. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered, after which the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in a hexane-ethyl acetate solution with heating, and then recrystallization by cooling to room temperature gave the title compound as a colorless powder (111 mg, 77%).
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:8](=O)[CH2:7][CH2:6][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4]1.[CH3:17][NH:18][CH3:19].S1C=CC=C1.[H][H]>CO.[Pd]>[CH3:1][O:2][C@H:3]1[C@@H:8]([N:18]([CH3:19])[CH3:17])[CH2:7][CH2:6][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4]1
Reactant: COC1CN(Cc2ccccc2)CCC1=O
Reactant: [H][H]
Reactant: CNC
Agent: [Pd]
Solvent: c1ccsc1
Solvent: CO
Product: CO[C@@H]1CN(Cc2ccccc2)CC[C@@H]1N(C)C
Yield: 100 %

Procedure:
A mixture of 24.2 parts of 3-methoxy-1-(phenylmethyl)-4-piperidinone, 16 parts of N-methylmethanamine, 1 part of a thiophene solution in methanol and 520 parts of methanol was hydrogenated at normal pressure and at 50° C. with 3 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 27.3 parts (100%) of cis-3-methoxy-N,N-dimethyl-1-(phenylmethyl)-4-piperidinamine (int. 27).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si](C(C)(C)C)(C)C)[CH2:9][C@H:8]1[CH2:20][C:21]#[N:22])=[O:6])[CH:2]=[CH2:3].Cl.C[O-].[Na+]>CO>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH2:20][C:21]#[N:22])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CC#N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1CC#N
Temperature: 5 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a solution of (2R, 4R) -1-allyloxycarbonyl-2-cyanomethyl-4-t-butyldimethylsilyloxypyrrolidine (4.65 g) in methanol (23.3 ml) was added conc. hydrochloric acid (2.38 ml) at ice-cooling. After stirring at 15°-25° C. for 1 hour, the solution was cooled at 5° C. 28% Sodium methoxide in methanol (5.52 ml) was added to the cold solution and the mixture was stirred at 0°-10° C. for 10 minutes. After removal of insoluble material by filtration, the filtrate was concentrated under reduced pressure. Acetonitrile (23.3 ml) was added to the residue and the solution was evaporated. The residue was washed with n-hexane (20 ml) five times and evaporated to give (2R,4R)-1-allyloxycarbonyl-2-cyanomethyl-4-hydroxypyrrolidine (2.99 g).
Reaction SMILES: [CH3:1][CH:2]1[C:5]([CH3:7])([CH3:6])[C:4]2([CH2:11][CH2:10][N:9]([C:12]([O:14]C(C)(C)C)=O)[CH2:8]2)[O:3]1.CC1(C)C2(CCN(C(OC(C)(C)C)=O)C2)OCC1.C(O)(C(F)(F)F)=O.CN(C)C=O.[Cl:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2(C(O)=O)[CH2:58][CH2:57]2)=[CH:52][CH:51]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>>[Cl:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2([C:12]([N:9]3[CH2:10][CH2:11][C:4]4([O:3][CH2:1][CH2:2][C:5]4([CH3:6])[CH3:7])[CH2:8]3)=[O:14])[CH2:58][CH2:57]2)=[CH:52][CH:51]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Reactant: CC1OC2(CCN(C(=O)OC(C)(C)C)C2)C1(C)C
Agent: CC(C)(C)OC(=O)N1CCC2(C1)OCCC2(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)CCOC12CCN(C(=O)C1(c3ccc(Cl)cc3)CC1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl 2,3,3-trimethyl-1-oxa-6-azaspiro[3.4]octane-6-carboxylate (25.0 mg, 0.0000979 mol) and tert-butyl 4,4-dimethyl-1-oxa-7-azaspiro[4.4]nonane-7-carboxylate (25.0 mg, 0.0000979 mol) was treated with 1 mL of TFA at rt for 30 min. The volatiles were removed in-vacuo and the resultant TFA salt was used directly in next step. To a mixture of the above made TFA salt in N,N-dimethylformamide (0.50 mL, 0.0064 mol) were added 1-(4-chlorophenyl)cyclopropanecarboxylic acid (38.5 mg, 0.000196 mol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (104 mg, 0.000235 mol), followed by N,N-diisopropylethylamine (0.0853 mL, 0.000490 mol). The mixture was stirred at rt for 2 h and then the product was isolated and purified by RP-HPLC. LCMS (M+H) 334.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:6]2.[H-].[Na+].F[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=1)=[C:8]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:7]([CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:6]2
Reactant: COc1ccc2c(O)c(-c3ccccc3)c(CC(C)C)cc2c1
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3ccccc3)c(CC(C)C)cc2c1
Yield: 83 %

Procedure:
6-(Methyloxy)-3-(2-methylpropyl)-2-phenyl-1-naphthalenol (105) (0.66 g, 2.16 mmol) was treated with NaH in DMF followed by addition of 4-fluorobenzaldehyde to give 0.74 g (83%) of the title compound (106) as a light yellow foam. 1H NMR (400 MHz, CDCl3): δ 0.75 (d, J=6.8 Hz, 6H), 1.60-1.70 (m, 1H), 2.47 (d, J=7.1 Hz, 2H), 3.94 (s, 3H), 6.67 (d, J=8.8 Hz, 2H), 7.05 (dd, J1=9.1 Hz, J2=2.4 Hz, 1H), 7.07-7.12 (m, 2H), 7.15-7.25 (m, 4H), 7.56 (s, 1H), 7.61 (d, J=8.6 Hz, 2H), 7.67 (d, J=9.1 Hz, 1H), 9.79 (s, 1H). LCMS (ESI): m/z 411 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][C:13]1[C:14]([NH2:18])=[N:15][NH:16][CH:17]=1.[C:19](OC)(=[O:25])[CH2:20][C:21](OC)=[O:22].C[O-].[Na+]>CO>[CH3:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][C:13]1[CH:17]=[N:16][N:15]2[C:21](=[O:22])[CH2:20][C:19](=[O:25])[NH:18][C:14]=12
Reactant: Cc1c(Cc2c[nH]nc2N)cccc1C(F)(F)F
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(Cc2cnn3c2NC(=O)CC3=O)cccc1C(F)(F)F
Reaction time: 0.17 h

Procedure:
To a solution of 4-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-amine (1.71 g, 6.7 mmol) in methanol (10 mL) was added dimethyl malonate (0.93 g, 7.0 mmol), followed by adding a 25% sodium methoxide solution (2.95 g, 13.40 mmol). The reaction vessel was sealed and irradiated (microwave) to 125° C. for 45 minutes. After the reaction mixture was cooled, precipitate was collected by filtration. The solid was washed with cooled methanol (5 mL×2). Product was dried under air. The product was then suspended with 1 N HCl (30 mL), stirred for 10 minutes. Product was obtained by filtration. It was dried under vacuum oven and was used in next step. (2.13 g, 98%). LC/MS: MS (ES+) m/e 324 (MH+)
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:25])[CH:9]([NH:14][C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH3:23])[N:18]=[C:17](Cl)[N:16]=1)[CH2:10][CH:11]([CH3:13])[CH3:12])[CH3:2].[F:26][C:27]([F:39])([F:38])[O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:25])[CH:9]([NH:14][C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH3:23])[N:18]=[C:17]([C:32]2[CH:31]=[CH:30][C:29]([O:28][C:27]([F:26])([F:38])[F:39])=[CH:34][CH:33]=2)[N:16]=1)[CH2:10][CH:11]([CH3:13])[CH3:12])[CH3:2]
Reactant: CCCc1cc(NC(CC(C)C)C(=O)NCCCOCC)nc(Cl)n1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCCc1cc(NC(CC(C)C)C(=O)NCCCOCC)nc(-c2ccc(OC(F)(F)F)cc2)n1
Temperature: 80 °C
Yield: 32.1 %

Procedure:
A mixture of 2-(2-chloro-6-propyl-pyrimidin-4-ylamino)-4-methyl-pentanoic acid (3-ethoxy-propyl)-amide (31.4 mg), 4-(trifluoromethoxy)phenylboronic acid (19 mg), sodium carbonate (0.4M aqueous solution, 0.5 mL), and acetonitrile (0.5 mL) was degassed with argon for five minutes. Tetrakis(triphenylphosphine) palladium(0) was added and the mixture was heated to 80° C. for 4 hours. The reaction mixture was taken up in ethyl acetate, washed twice with brine, and the volatiles were removed in vacuo. The product was purified on silica gel, using 50% ethyl acetate/hexanes as the mobile phase, to give 13.5 mg of 4-methyl-2-[6-propyl-2-(4-trifluoromethoxyphenyl)pyrimidin-4-ylamino] pentanoic acid (3-ethoxypropyl) amide. ESI-MS (m/z) 497 [M+H]+.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C@H:7]2[C@H:11]([OH:12])[CH2:10][N:9]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:8]2)=O)[CH2:3][CH2:2]1.O.C(N(CC)CC)C>O1CCCC1>[CH:1]1([NH:4][CH2:5][C@H:7]2[C@H:11]([OH:12])[CH2:10][N:9]([C:13]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:14])[CH2:8]2)[CH2:3][CH2:2]1
Reactant: O=C(NC1CC1)[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1C[C@@H](CNC2CC2)[C@H](O)C1
Reaction time: 7 h
Yield: 103.5 %

Procedure:
To a solution of benzyl(3R,4S)-3-(N-cyclopropyl)carbamoyl-4-hydroxypyrrolidine-1-carboxylate (14.5 g, 47.6 mmol) in 116 mL of dehydrated tetrahydrofuran, 122 mL of a tetrahydrofuran solution of borane-tetrahydrofuran complex (1.17 mol/L, 143 mmol) was added dropwise over 20 minutes at an internal temperature of 40 to 44° C. The mixture was stirred at the same temperature for 7 hours. Subsequently, the reaction mixture was cooled to an internal temperature of 25° C. or below. At an internal temperature of 15 to 25° C., 14.5 mL of water was added dropwise and the mixture was stirred for 20 minutes. At an internal temperature of 10 to 18° C., 39.8 mL of triethylamine (286 mmol) was added dropwise and the mixture was stirred for 5 minutes. The mixture was then refluxed for 15 hours. Subsequently, the mixture was allowed to cool and concentrated under reduced pressure. To the resulting residue, 44 mL of water was added and the mixture was extracted with 102 mL of ethyl acetate. The organic layer was washed with 73 mL of water and extracted with 60 mL of 2 mol/L hydrochloric acid. The aqueous layer was cooled in a water bath under stirring and 60 mL of a 2 mol/L sodium hydroxide solution was added at an internal temperature of 20 to 28° C. to adjust the pH to about 12. This mixture was extracted with 102 mL of ethyl acetate. The organic layer was washed with 73 mL of 28% brine. To the organic layer, 20.2 g of anhydrous sodium sulfate was added and the mixture was stirred for 1 hour. Subsequently, the mixture was filtered through a cotton plug and washed with 22 mL of ethyl acetate. The filtrate and the wash were combined and concentrated under reduced pressure. The product was dried at room temperature under reduced pressure for 1 hour to give 14.3 g of a crude product of the title compound as a pale yellow oil. This product was used in the subsequent step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH:17]([C:23]([CH3:25])=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(O)C>[CH2:9]([O:8][C:7]1[C:2]2[N:3]([C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:23]([CH3:25])[N:1]=2)[CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ncccc1OCc1ccccc1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2c(OCc3ccccc3)cccn12
Temperature: 100 °C

Procedure:
25 g (124.8 mmol) of 2-amino-3-benzyloxypyridine were dissolved in 781 ml of ethanol, 102.7 g (624.2 mmol) of ethyl 2-chloroacetoacetate and two tablespoons of 4 A molecular sieve were added, and the reaction mixture was then heated at reflux (bath temperature 100° C.) for 2 days. The mixture was concentrated, and excess ethyl 2-chloroacetoacetate was removed on a rotary evaporator with dry ice cooling. The residue was purified by silica gel chromatography (mobile phase cyclohexane:ethyl acetate gradient 9:1, 4:1). This gave 20.81 g of the target compound (54% of theory, purity 99%).