Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[C:25]([NH:28][CH2:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:27])[CH3:26]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:34]4[CH:35]=[C:30]([CH:31]=[CH:32][CH:33]=4)[CH2:29][NH:28][C:25](=[O:27])[CH3:26])[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Reactant: CC(=O)NCc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(=O)NCc1cccc(-c2ccc3c(c2)C2(CC(c4ccccc4)O3)N=C(N)N(C)C2=O)c1
Temperature: 120 °C
Yield: 10.6 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL CEM test tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-(acetamidomethyl)phenylboronic acid (19.3 mg, 0.1 mmol). The mixture was heated in a microwave reactor at 120° C. for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure N-(3-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro-[chroman-4,4′-imidazole]-6-yl)benzyl)acetamide (2.5 mg, 11%). 1H-NMR (MeOD): 2.01 (s, 3H), 2.16 (d, 1H), 2.32 (t, 1H), 3.17 (s, 3H), 4.40 (s, 2H), 5.92 (d, 1H), 7.03 (d, 1H), 7.23 (d, 2H), 7.36 (m, 2H), 7.41 (t, 4H), 7.48 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[Li]CCCC.[CH3:18][C:19]([CH3:21])=[O:20]>C1COCC1>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:19]([OH:20])([CH3:21])[CH3:18])=[CH:3][C:4]=1[C:9]([F:12])([F:11])[F:10]
Reactant: CC(C)=O
Reactant: Cc1ccc(Br)cc1C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(C)(C)O)cc1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of 4-Bromo-1-methyl-2-trifluoromethyl-benzene (3.4 g, 14.2 mmol) in THF was added n-BuLi at −78° C. After the reaction mixture was stirred at −78° C. for 30 minutes, dry acetone was slowly added. The resulting content was maintained at −78° C. for 3 hours and slowly warmed up to RT overnight. The reaction mixture was then partitioned between ethyl acetate and water. The ethyl acetate layer was then washed with brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude oil. The crude solid was purified via flash chromatography (15% EtOAc in n-hexane) yielded the title compound as an oil (2.7 g, 86%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH2:25][CH:24]([NH:28][CH:29]2[CH2:31][CH2:30]2)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>ClCCl>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH2:25][CH:24]([N:28]([CH:29]2[CH2:30][CH2:31]2)[S:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=2)(=[O:11])=[O:10])[CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCCC(NC2CC2)C1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)C1
Temperature: 37 °C
Reaction time: 48 h
Yield: 45 %

Procedure:
3-Trifluoromethylphenylsulfonyl chloride (4) (12 g, 49 mmol, Aldrich) was added to a mixture of the crude compound 3, triethylamine (TEA, 10 mL) and dichloromethane (DCM, 10 mL) at room temperature. The resulting mixture was heated and stirred at 37° C. for 2 days. The reaction mixture was cooled to room temperature, washed with water (10 mL) and then with brine, and concentrated and purified by column (silica gel) eluting with EtOAc/hexanes (3/7) to afford 3-[N-cyclopropyl-N-(3-trifluoromethylbenzenesulfonyl)amino]piperidine-1-carboxylic acid tert-butyl ester (5) as a sticky oil (10 g, yield 45% in two steps), which was dissolved in 100 mL of 1,4-dioxane. HCl (10 mL, concentrated aq.) was added to the 1,4-dioxane solution at room temperature. The resulting mixture was stirred at room temperature for 48 hours, and concentrated under vacuum. The residue was washed with ethyl ether, and dried to obtain the desired title compound 6 as an oil (6.5 g, 81%). 1H NMR (400 MHz, CD3OD): δ 8.22 (d, j=7.9 Hz, 1H), 8.17 (s, 1H), 8.06 (d, j=7.8 Hz, 1H), 7.90 (d, 1H, j=7.8 Hz, 1H), 4.17-4.24 (m, 1H), 3.34-3.38 (m, 2H), 3.22-3.29 (m, 1H), 2.87-2.95 (m, 1H), 1.98-2.18 (m, 3H), 1.68-1.82 (m, 2H), 1.04-1.09 (m, 1H), 0.79-0.92 (m, 3H); LC: 100%; MS: m/z=349 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([OH:13])[CH:7]=[CH:6]2.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:20][CH:21](Br)[CH3:22]>CN(C=O)C>[Br:20][CH2:21][CH2:22][O:13][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1
Reactant: COc1ccc2cc(O)ccc2c1
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc2cc(OCCBr)ccc2c1
Temperature: 55 °C
Yield: 30.1 %

Procedure:
To a solution of 6-methoxynaphthalen-2-ol (1.07 g, 6.14 mmol) in DMF (4 mL) were added cesium carbonate (3.11 g, 9.55 mmol) and dibromoethane (2.5 mL, 29 mmol). The mixture was stirred and heated at 55° C. for 48 h. The reaction mixture was cooled, filtered, diluted with EtOAc, and washed with brine (2×30 mL). The organic layer was dried (Na2SO4) and concentrated. The crude product was purified using radial chromatography (2:98 to 25:75 EtOAc:Hex) to give the title compound as a white solid (0.52 g, 30%): 1H NMR (400 MHz, CDCl3) δ 3.61 (t, J=6.1 Hz, 2H), 3.82 (s, 3H), 4.30 (t, J=6.4 Hz, 2H), 7.01-7.08 (m, 4H), 7.56 (dd, J=12.0, 9.0 Hz, 2H).
Reaction SMILES: [Cl:1][S:2]([C:5]1[C:6]([C:10](Cl)=[O:11])=[CH:7][S:8][CH:9]=1)(=[O:4])=[O:3].[CH3:13][OH:14].Cl>C(Cl)(Cl)Cl>[CH3:13][O:14][C:10]([C:6]1[C:5]([S:2]([Cl:1])(=[O:4])=[O:3])=[CH:9][S:8][CH:7]=1)=[O:11]
Reactant: O=C(Cl)c1cscc1S(=O)(=O)Cl
Reactant: CO
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cscc1S(=O)(=O)Cl

Procedure:
44.1 G. (0.18 mol) of the obtained 4-chlorosulfonylthiophene-3-carboxylic acid chloride are dissolved in 450 ml. of absolute chloroform, 9.6 g. (0.3 mol) of absolute methanol are added and the solution is heated to reflux for 9 hours [until termination of the hydrogen chloride evolution]. The mixture is then evaporated to dryness in vacuo, the residue crystallizing out. There is obtained 4-chlorosulfonylthiophene-3-carboxylic acid methyl ester, which can be converted into the 4-hydroxy-2-methyl-N-(2-thiazolyl)-2H-thieno[3,4-e]-1,2-thiazine-3-carboxamide 1,1-dioxide in a manner analogous to that described in the last four paragraphs of Example 5.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[CH3:15][C:16](=O)[CH2:17][CH2:18][CH:19]=[CH2:20]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:19]([CH3:20])[CH2:18][CH2:17][CH:16]=[CH2:15])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Reactant: C=CCCC(C)=O
Product: C=CCCC(C)Nc1c(C)noc1-c1ccc(Br)cc1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and hex-5-en-2-one.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([C:14]([O:16][CH3:17])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]1([CH:28]=O)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:28][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[CH:10]([C:14]([O:16][CH3:17])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=Cc1cccc2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1Cc1cccc2ccccc12
Reaction time: 8 h

Procedure:
The product from Step B was dissolved in methanol (20 mL) with naphthalene-1-carboxaldehyde (0.67 mL, 4.7 mmol), sodium cyanoborohydride (0.350 g, 5.6 mmol) at pH 6 (adjusted with acetic acid) and the reaction stirred overnight. The solvent was evaporated and the residue partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate. The crude product was chromatographed on silica gel with ethyl acetate in hexane, and the title compound isolated as an oil. NMR (CDCl3, 300 MHz) d 8.34 (1H, d, J=7 Hz), 7.85 (1H, dm, J=7 Hz), 7.79 (1H, m), 7.51 (2H, m), 7.39 (2H, m), 4.34 (1H, d, J=12 Hz), 3.98 (1H, br s), 3.91 (1H, dd, J=12, 6 Hz), 3.75 (3H, s), 3.60 (1H, br s), 3.44 (1H, d, J=12 Hz), 3.27 (1H, t, J=3 Hz), 3.19 (1H, d, J=12 Hz), 3.09 (1H, td, J=10, 3 Hz), 2.42 (1H, br s), 1.44 (9H, s).
Reaction SMILES: [CH3:1][C:2]([C:11]([OH:13])=[O:12])([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:3].[CH2:14]=O.[ClH:16]>>[ClH:16].[CH3:1][C:2]1([C:11]([OH:13])=[O:12])[CH2:4][C:5]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:14][NH:3]1
Reactant: C=O
Reactant: CC(N)(Cc1ccccc1)C(=O)O
Agent: Cl
Product: CC1(C(=O)O)Cc2ccccc2CN1
Temperature: 60 °C
Reaction time: 48 h
Yield: 40 %

Procedure:
To a suspension of alpha-methyl-DL-phenylalanine (2.00 g, 11.2 mmol) in conc. HCl (30 mL) was added formaldehyde (37%, 4.0 mL, 4.36 g, 4.81 mmol) and the resulting suspension was stirred at 60° C. for 48 h. The precipitated solid was collected and dried in vacuo to give 1.02 g (40%) of 3-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride. 1H NMR (400 MHz, CD3OD): δ 7.33-7.24 (m, 4H), 4.53 (d, J=16.8 Hz, 1H), 4.42 (d, J=16.0 Hz, 1H), 3.43 (d, J=17.6 Hz, 1H), 3.18 (d, J=17.2 Hz, 1H), 1.67 (s, 3H); LC-MS (EI) m/z: 192.0 (M+H+). Using the same method as for VP-2851, 3-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride (1.01 g, 4.436 mmol) was converted to yield methyl 7-amino-3-methyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate hydrochloride (600 mg, 38% yield, 2 steps) as a grey solid. 1H NMR (400 MHz, CD3OD): δ 7.48 (d, J=7.6 Hz, 1H), 7.38 (s, 1H), 7.37 (dd, J=8.0, 2.4 Hz, 1H), 4.83 (d, J=15.2 Hz, 1H), 4.78 (d, J=15.2 Hz, 1H), 3.63 (s, 3H), 3.27 (d, J=14.8 Hz, 1H), 3.15 (d, J=14.4 Hz, 1H), 1.51 (s, 3H); LC-MS (EI) m/z: 317.0 (M+H+). Using general method M, methyl 7-amino-3-methyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate hydrochloride (0.600 g, 1.70 mmol) and pivaloylacetonitrile (0.21 g, 1.7 mmol) were combined to afford methyl 7-(5-amino-3-t-butyl-1H-pyrazol-1-yl)-3-methyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (240 mg, 30% yield) as a yellow foam. LC-MS (EI) m/z: 439.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:19]([NH2:20])=[N:18][C:12]2[N:13]=[C:14]([CH3:17])[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH3:21][N:22]=[C:23]=[O:24]>CCOCC>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:19]([NH:20][C:23]([NH:22][CH3:21])=[O:24])=[N:18][C:12]2[N:13]=[C:14]([CH3:17])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: Cc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Reactant: CN=C=O
Solvent: CCOCC
Product: CNC(=O)Nc1nc2nc(C)ncc2cc1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A slurry of 3.0 g of 6-(2,6-dichlorophenyl)-2-methylpyrido[2,3-d]-pyrimidin-7-amine in 20 ml of methyl isocyanate is heated at reflux for 3 hours to obtain a yellow solution. This is stirred overnight at room temperature and diluted with 20 ml of ether. The solvent and excess isocyanate are evaporated and the solid residue of crude product is purified by recrystallization from ethyl acetate to give N-[6-(2,6-dichlorophenyl)-2-methylpyrido[2,3-d]-pyrimidin-7-yl]-N'-methylurea, mp 168°-171° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>C(Cl)Cl.Cl>[CH3:1][O:2][C:3]([CH:5]1[CH:9]([O:10][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)C1C(O)CCN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)C1C(O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 5 h
Yield: 98.3 %

Procedure:
A solution containing alcohol 38 (14.8 g, 60 mmol) in DCM (150 mL) was cooled to 0° C. To this solution was added imidazole (5.4 g, 79 mmol) followed by t-butyl-dimethylsilyl-chloride (10 g, 66 mmol) in two portions. The reaction mixture was warmed to ambient temperature over 1 h. After 5 h, the solution was diluted with 1M HCl and extracted twice with DCM. The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to afford 21.2 g (99%) of 39 as a yellow oil. 1H NMR (CDCl3, 300 MHz) δ4.38-4.34 (m, 1H), 4.18 (bs, rotomers, 0.5H), 4.04 (app d, J, =2.1 Hz, rotomers, 0.5H), 3.74 (s, 3H), 3.62-3.50 (m, 2H), 2.04-1.96 (m, 1H), 1.85-1.78 (m, 1H), 1.46 (s, minor rotomer), 1.41 (s, 9H), 0.92 (s, minor rotomer), 0.86 (s, 9H), 0.11 (s, 6H), 0.09 (s, minor rotomer) ppm.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:9][C:8](=[O:10])[NH:7][C:6]1([CH3:12])[CH3:11])=[O:4].[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([NH:20][CH2:2][C:3]([N:5]1[CH2:9][C:8](=[O:10])[NH:7][C:6]1([CH3:12])[CH3:11])=[O:4])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC1(C)NC(=O)CN1C(=O)CBr
Reactant: NCc1ccccc1
Product: CC1(C)NC(=O)CN1C(=O)CNCc1ccccc1

Procedure:
A solution of 1-(2-bromoacetyl)-2,2-dimethyl-4-imidazolidinone (1.9 g) in 8.8 ml of benzylamine was stirred at room temperature for 4 hours. The excess of benzylamine was removed under reduced pressure (about 5 mmHg) at 80° C. The residue was taken up with ethyl acetate and the precipitate filtered off. The filtrate was evaporated and the residue was chromatographed on a silica gel column by eluting with dichloromethane/methanol 7:3. The selected fractions were collected and evaporated. Trituration of the residue with ether gave 1 g of the title compound as a white powder, m.p. 131°-132° C.
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([N:16]1[CH:20]=[C:19]([C:21]([O:23]CC)=[O:22])[CH:18]=[N:17]1)[NH:10][C:9]2=O.[CH:32]1([NH2:35])[CH2:34][CH2:33]1>>[CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([N:16]1[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[N:17]1)[N:10]=[C:9]2[NH:35][CH:32]1[CH2:34][CH2:33]1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(NCc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Reactant: NC1CC1
Product: Cc1cccc(C)c1CNc1ccc2nc(-n3cc(C(=O)O)cn3)nc(NC3CC3)c2c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-((2,6-dimethylbenzyl)amino)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and cyclopropylamine in step E. MS (ESI/CI): predicted mass C24H24N6O2, 428.2.
Reaction SMILES: [CH2:1]([N:8]1[C@H:13]([CH3:14])[CH2:12][CH:11]([NH:15][C:16]2[C:17]([CH3:30])=[C:18]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:10][C@H:9]1[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32](=O)[CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CC(O)=O>[CH2:1]([N:8]1[C@H:13]([CH3:14])[CH2:12][CH:11]([N:15]([CH2:32][CH3:33])[C:16]2[C:17]([CH3:30])=[C:18]([CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:10][C@H:9]1[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC=O
Reactant: COC(=O)c1cc(C(F)(F)F)cc(NC2C[C@@H](C)N(Cc3ccccc3)[C@H](C)C2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCN(c1cc(C(F)(F)F)cc(C(=O)OC)c1C)C1C[C@@H](C)N(Cc2ccccc2)[C@H](C)C1
Temperature: 23 °C
Reaction time: 7 h
Yield: 79.7 %

Procedure:
To a stirred solution of methyl 3-{[(2R,6R)-1-benzyl-2,6-dimethylpiperidin-4-yl]amino}-2-methyl-5-(trifluoromethyl)benzoate (278 mg, 0.640 mmol) in CH2Cl2 (5 mL) and AcOH (500 uL) was added acetaldehyde (359 mg, 6.40 mmol) and sodium triacetoxyborohydride (428 mg, 1.92 mmol) at 0° C. The reaction mixture was stirred at 23° C. for 7 hours. Then the reaction mixture was quenched with aq. NaHCO3 until pH8-9. The content was extracted with ethylacetate, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH—SiO2; heptane/ethylacetate=5/1) to give the titled compound as a light yellow oil (236 mg, 80% yield.). 1H-NMR (400 MHz, CDCl3) δppm; 7.79 (s, 1H), 7.43 (s, 1H), 7.21-7.36 (m, 5H), 3.92 (s, 3H), 3.87 (d, J=14.0 Hz, 1H), 3.38 (d, J=14.0 Hz, 1H), 3.04-3.15 (m, 4H), 2.73-2.80 (m, 1H), 2.53 (s, 3H), 1.76-1.82 (m, 1H), 1.51-1.63 (m, 2H), 1.34-1.42 (m, 1H), 1.06 (d, J=6.0 Hz, 3H), 0.93 (d, J=6.8 Hz, 3H), 0.86 (t, J=6.8 Hz, 3H).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:12]([O:17][CH2:18][C@@H:19]1[O:21][CH2:20]1)(=[O:16])[CH2:13][CH2:14][CH3:15]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[C:12]([O:17][CH2:18][C@H:19]([OH:21])[CH2:20][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:16])[CH2:13][CH2:14][CH3:15]
Reactant: CCCC(=O)OC[C@H]1CO1
Reactant: Oc1cccc2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: Cc1ccccc1
Product: CCCC(=O)OC[C@H](O)COc1cccc2ccccc12
Reaction time: 4 h
Yield: 75 %

Procedure:
To a solution of 144 g (1 mol) of 1-naphthol and 7.4 g (0.02 mol) of tetrabutylammonium iodide in 200 ml of toluene was added 144 g (1 mol) of (R)-glycidyl butyrate over a period of 15 min at a temperature of 120° C., and the mixture was kept at this temperature for a further 4 h. Conventional subsequent treatment of the reaction mixture gave the required compound as an oil, yield about 75%.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14]([OH:16])=[O:15].[CH2:17]([O:24][C:25](=[O:38])[C@@H:26]([O:35][CH2:36][CH3:37])[CH2:27][C:28]1[CH:33]=[CH:32][C:31](O)=[CH:30][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(Cl)CCl.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:17]([O:24][C:25](=[O:38])[C@@H:26]([O:35][CH2:36][CH3:37])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:15][C:14](=[O:16])[CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:30][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1oc(-c2ccccc2)nc1CC(=O)O
Reactant: CCO[C@@H](Cc1ccc(O)cc1)C(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: CCO[C@@H](Cc1ccc(OC(=O)Cc2nc(-c3ccccc3)oc2C)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (5-methyl-2-phenyl-oxazol-4-yl)-acetic acid (3.29 g, 15.2 mmol) and (S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid benzyl ester (4.56 g, 15.2 mmol) in dry DCM (70 mL) was added EDC×HCl (3.49 g, 18.22 mmol) and DMAP (0.37 g, 3.03 mmol) under nitrogen atmosphere. After stirring for 1 h at ambient temperature the mixture was extracted with saturated aq. NaHCO3, aq. HCl (0.05N) and with saturated aq. NaHCO3 again. The organic layer was dried and the remaining crude product purified by HPLC. The title compound was obtained as an oil (4.15 g, 54.7%). 1H NMR (400 MHz, CDCl3): δ 7.99-7.80 (d, 2H), 7.25-7.43 (m, 8H), 7.18-7.20 (d, 2H), 6.99-7.01 (d, 2H), 5.12 (s, 2H), 4.01-4.04 (m, 1H), 3.80 (s, 2H), 3.57-3.61 (m, 1H), 3.31-3.35 (m, 1H), 2.98-3.00 (m, 2H), 2.41 (s, 3H), 1.11-1.15 (t, 3H).
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[N:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8]1.CN([CH:21]=[O:22])C.O>C1COCC1>[CH3:6][N:7]1[C:11]([CH:21]=[O:22])=[N:10][C:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[N:8]1
Reactant: CN(C)C=O
Reactant: Cn1cnc(-c2ccccc2)n1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cn1nc(-c2ccccc2)nc1C=O
Temperature: -40 °C
Yield: 86.4 %

Procedure:
BuLi (10.6 mL, 1.6 M in hexane, 17.0 mmol) was added dropwise to at solution of 1-methyl-3-phenyl-1H-1,2,4-triazole (2.7 g, 17.0 mmol) in THF (85 mL) at −78° C. The mixture was warmed to −40° C. over 15 min and recooled to −78° C. DMF (1.32 mL, 17 mmol) was added dropwise and the mixture was warmed to ambient temperature over 2 h. Water was added to the mixture and it was extracted with EtOAc (3×). The organics were combined, washed with brine, dried (Na2SO4) and concentrated. Purification by flash chromatography (EtOAc, hexanes) yielded 2.75 g of Intermediate 386.1 as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 4.22 (s, 3H) 7.34-7.56 (m, 3H) 8.10 (dd, J=7.58, 1.71 Hz, 2H) 10.03 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:15]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(N(C(C)C)CC)(C)C>C(#N)C>[C:18]([O:17][C:15]([N:22]1[CH2:27][CH2:26][N:25]([C:5]2[N:4]=[N:3][C:2]([Cl:1])=[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=2)[CH2:24][CH2:23]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: Clc1cc(-c2ccccc2)c(Cl)nn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2cc(-c3ccccc3)c(Cl)nn2)CC1
Temperature: 180 °C
Reaction time: 0.67 h
Yield: 20.1 %

Procedure:
A mixture of 3,6-dichloro-4-phenyl-pyridazine (0.41 g, 1.82 mmol), prepared by following the procedure described in WO-2005/013907, N-Boc-piperazine (0.509 g, 2.73 mmol) and diisopropylethylamine (0.634 ml, 3.64 mmol) in acetonitrile (7.5 ml) was stirred at 180° C. for 40 min., under microwave irradiation, and then for a further 30 min. After this period, additional amounts of diisopropylethylamine (0.1 ml, 0.57 mmol) and N-Boc-piperazine (0.1 g, 0.54 mmol) were added and the resulting mixture was stirred at 180° C. for 40 min. The solvent was evaporated in vacuo and then, dichloromethane and a saturated solution of ammonium chloride were added. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The residue was then purified by column chromatography (silica gel; dichloromethane and heptane/ethyl acetate 8:2 to 7:3). The desired fractions were collected and evaporated in vacuo to yield D13 (0.137 g, 20%) as a white solid. C19H23ClN4O2 requires 374; Found 375 (MH+).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([O:25][CH2:26][CH3:27])[C:22](O)=[O:23])=[CH:16][CH:15]=2)[CH2:3][CH2:2]1.[NH3:28]>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([O:25][CH2:26][CH3:27])[C:22]([NH2:28])=[O:23])=[CH:16][CH:15]=2)[CH2:3][CH2:2]1
Reactant: N
Reactant: CCOC(Cc1ccc(OCCN2CCOc3ccccc32)cc1)C(=O)O
Product: CCOC(Cc1ccc(OCCN2CCOc3ccccc32)cc1)C(N)=O
Yield: 80 %

Procedure:
The title compound (0.2 g, 80%) was prepared as a white solid from 3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (0.25 g, 0.67 mmol) obtained in example 26 and aqueous ammonia (4 mL) by an analogous procedure to that described in example 31.mp: 107-109° C.