Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[S:10][C:11]([C:15]2[N:16]=[C:17]([CH2:20][C:21]#[N:22])[S:18][CH:19]=2)=[C:12]([CH3:14])[N:13]=1.[CH:23]1[N:27]=[CH:26][N:25]([C:28](N2C=NC=C2)=[O:29])[CH:24]=1.CN(C=O)C>C(Cl)Cl>[C:21]([CH2:20][C:17]1[S:18][CH:19]=[C:15]([C:11]2[S:10][C:9]([NH:8][C:28]([N:25]3[CH:24]=[CH:23][N:27]=[CH:26]3)=[O:29])=[N:13][C:12]=2[CH3:14])[N:16]=1)#[N:22]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1nc(N)sc1-c1csc(CC#N)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(NC(=O)n2ccnc2)sc1-c1csc(CC#N)n1
Temperature: 45 °C

Procedure:
Triethylamine (0.65 ml; 4.69 mmol; 1.49 eq.) is added to a suspension of (2′-amino-4′-methyl-4,5′-bi-1,3-thiazol-2-yl)acetonitrile (1 000 mg; 3.15 mmol; 1 eq.) and CDI (1 372.3 mg; 8.46 mmol; 2.68 eq.) in dry DCM (65 ml). DMF (4 ml) is added and the mixture is heated at 45° C. for one night. The reaction is cooled down to rt. The resulting precipitate is filtered and washed with Et2O, affording N-[2-(cyanomethyl)-4′-methyl-4,5′-bi-1,3-thiazol-2′-yl]-1H-imidazole-1-carboxamide, which is used in the next step without further purification (822.8 mg; 79%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(OC(=O)C)C>[N+:1]([C:15]1[CH:14]=[C:13]([O:12][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:18]=[CH:17][C:16]=1[OH:19])([O-:4])=[O:2]
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: O=[N+]([O-])O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1O
Temperature: 25 °C
Yield: 37 %

Procedure:
Fumic nitric acid (d=1.52, 43.6 g, 0.70 mole) was dropwise added under stirring to 4-benzyloxyphenol (138.0 g, 0.69 mole) in ethylacetate (500 ml) at 0° C. The resulting solution was raised at room temperature and then washed in separatory funnel with sodium hydrogen carbonate in water (saturated solution). The organic layer was separated and evaporated under vacuum and the residual solid was crystallized from methanol (100 ml) to give nitrophenol (Yield of (a): 62.54 g, 36%) as yellow prisms. The product structure was confirmed by NMR and IR spectra.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:17])[C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:6][CH:7]=1.[C:18]([O-])(O)=[O:19].[Na+].ClC(OC1C=CC=CC=1)=O.[OH-].[Na+]>CO.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:9][CH2:10][N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:18](=[O:19])[NH:17][C:4]=2[CH:3]=1
Reactant: Nc1cc(Br)ccc1NCCN1CCOCC1
Reactant: O=C([O-])O
Agent: O=C(Cl)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=c1[nH]c2cc(Br)ccc2n1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 500-mL round-bottomed flask, mix 4-bromo-N1-(2-morpholin-4-yl-ethyl)-benzene-1,2-diamine 13.25 g, 44.1 mmol), NaHCO3 (5.4 g, 66.2 mmol), water (50 mL) and methanol (250 mL). Slowly add phenyl chloroformate (8.3 mL,66.2 mmol). Stirr the reaction for 1 h at room temperature and then add 5N NaOH (20 mL) and stir overnight at room temperature. Collect the solid by vacuum filtration and wash with methanol. HPLC (ISO60-10M) t=1.42 (97%), MS (ES) 326 (M+1).
Reaction SMILES: [BH4-].CC(C)=O.[Cl:6][C:7]1[CH:8]=[C:9](/[CH:19]=[CH:20]/[C:21](=[O:23])[CH3:22])[CH:10]=[CH:11][C:12]=1[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[Cl:6][C:7]1[CH:8]=[C:9]([CH2:19][CH2:20][C:21](=[O:23])[CH3:22])[CH:10]=[CH:11][C:12]=1[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC(=O)/C=C/c1ccc(C2CCCCC2)c(Cl)c1
Agent: [BH4-]
Solvent: CC(C)=O
Product: CC(=O)CCc1ccc(C2CCCCC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a hydrogenation apparatus 15 gm (0.06 mol) of nickel(II)acetate tetrahydrate, dissolved in 600 ml of 95% ethanol, were reduced in an atmosphere of hydrogen with 60 ml of a 1 M sodium borohydride solution, to yield black colloidal nickel boride (P-2-catalyst). In order to remove any unreacted borohydride, 14 gm (0.24 mol) of acetone were added, and the resulting mixture was shaken for 1 hour at room temperature and, after addition of 32.32 gm (0.123 mol) of (E)-4-(3-chloro-4-cyclohexyl-phenyl)-3-butene-2-one, it was hydrogenated at 5 atmospheres of hydrogen pressure until hydrogen absorption has ceased. The catalyst was filtered off, and the filtrate was concentrated by evaporation in vacuo. The residue shaken with a mixture of water and ethyl acetate, the organic phase was isolated, dried over sodium sulfate and evaporated, and the residue was distilled in vacuo. 19.0 Gm (58% of theory) of a colorless, viscous oil, b.p. 140°-148°C at 0.03 mm Hg were obtained.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:32]=[CH:31][C:12]([O:13][CH2:14][C:15]3([CH3:30])[CH2:24][CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:25]([O:27]CC)=[O:26])[CH:21]=4)[O:16]3)=[CH:11][CH:10]=2)[S:3]1.Cl>C(O)(=O)C>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:32]=[CH:31][C:12]([O:13][CH2:14][C:15]3([CH3:30])[CH2:24][CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:25]([OH:27])=[O:26])[CH:21]=4)[O:16]3)=[CH:11][CH:10]=2)[S:3]1
Reactant: CCOC(=O)c1ccc2c(c1)CCC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Agent: Cl
Solvent: CC(=O)O
Product: CC1(COc2ccc(CC3SC(=O)NC3=O)cc2)CCc2cc(C(=O)O)ccc2O1
Yield: 78.9 %

Procedure:
A procedure similar to that described in Example 15 was repeated, except that 1.1 g of ethyl 2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-2-methylchroman-6-carboxylate (prepared as described in Example 17), 10 ml of acetic acid and 5 ml of 3N aqueous hydrochloric acid were used, to afford 814 mg of the title compound as colorless crystals, melting at 223°-225° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:18]([O-])=O)[C:15]=2[CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:18][C:14]1[C:15]([CH3:17])=[C:16]2[C:11]([CH2:10][CH2:9][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:12][CH:13]=1
Reactant: Cc1c([N+](=O)[O-])ccc2c1N(C(=O)OC(C)(C)C)CC2
Agent: [Pd]
Solvent: CO
Product: Cc1c(N)ccc2c1N(C(=O)OC(C)(C)C)CC2
Reaction time: 8 h
Yield: 93.4 %

Procedure:
1-t-Butoxycarbonyl-2,3-dihydro-7-methyl-6-nitroindole (0.58 g; 2.2 mmol) is dissolved in methanol (5 mL), treated with a catalytic amount of 10% palladium on carbon and placed under an atmosphere of hydrogen. The solution is allowed to stir overnight. The black suspension is filtered through Celite and the solvent is removed by rotary evaporation to afford 0.51 g of 6-amino-1-t-butoxycarbonyl-2,3-dihydro-7-methylindole as a white solid. (99% yield)
Reaction SMILES: Br[C:2]([C:4]([F:7])([F:6])[F:5])=[CH2:3].[N+:8](=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N-:9]>C(OCC)C>[CH2:14]([O:13][C:11]([C:10]1[CH:3]=[C:2]([C:4]([F:7])([F:6])[F:5])[NH:9][N:8]=1)=[O:12])[CH3:15]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=C(Br)C(F)(F)F
Solvent: CCOCC
Product: CCOC(=O)c1cc(C(F)(F)F)[nH]n1
Temperature: 25 °C

Procedure:
To a solution of 2-bromo-3,3,3-trifluoro-1-propene (1 g, 5.716 mmol) in diethyl ether (2 ml) cooled with ice-bath under N2 atmosphere a solution of ethyl diazoacetate (1.06 ml, 8.574 mmol) in diethyl ether (3 ml) was added drop wise. The mixture was warmed to RT and then refluxed for 3 hours. The volatiles were removed under vacuum. Vacuum distillation provided the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9]C)=[O:8].[C:14]([N:21]1[CH2:26][CH2:25][CH:24](O)[CH2:23][CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>>[C:17]([O:16][C:14]([N:21]1[CH2:26][CH2:25][CH:24]([O:13][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=2[C:7]([OH:9])=[O:8])[CH2:23][CH2:22]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)c1ccc(OC)cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Product: COc1ccc(C(=O)O)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1

Procedure:
Using methyl 4-methoxysalicylate and 1-Boc-piperidin-4-ol, the acid is obtained using procedures similar to those described at Example 1-G and 1-H.
Reaction SMILES: C(OC([N:8]1[CH2:28][CH2:27][C:11]2([NH:15][C:14](=[O:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:12]2=[O:26])[CH2:10][CH2:9]1)=O)(C)(C)C.O1CCOCC1.[ClH:35]>O1CCOCC1>[ClH:35].[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][N:13]2[C:12](=[O:26])[C:11]3([CH2:10][CH2:9][NH:8][CH2:28][CH2:27]3)[NH:15][C:14]2=[O:16])=[CH:23][CH:22]=1
Reactant: COc1ccc(CN2C(=O)NC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(CN2C(=O)NC3(CCNCC3)C2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 1.15 g (2.95 mmol) of 3-(4-methoxybenzyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester was added 8 mL of dioxan and 6 mL of 4N solution of dioxane/HCl. The reaction mixture was stirred for 2 hours at room temperature and concentrated in vacuo. The crude was dissolved in a minimum of methanol and diethyl ether was added to obtain, after filtration, the 3-(4-methoxybenzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride as a white solid (644 mg, 67%).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])C.[CH2:34]([CH2:36][NH2:37])[OH:35]>>[OH:35][CH2:34][CH2:36][NH:37][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5]
Reactant: NCCO
Reactant: CCOC(=O)c1cncc2c(COc3cccc(NC(=O)c4ccc(OC)cc4)c3)csc12
Product: COc1ccc(C(=O)Nc2cccc(OCc3csc4c(C(=O)NCCO)cncc34)c2)cc1

Procedure:
3-[3-(4-Methoxy-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide was prepared from 3-[3-(4-methoxy-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (from Example 15 supra) and ethanolamine (Aldrich) following the procedure described in Example 16 as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[O:11][CH2:12][CH2:13][CH2:14][CH3:15].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C(=O)N([Br:42])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Br:42])=[CH:6][C:5]=1[O:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCOc1cc(C)ccc1C(=O)OC
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCOc1cc(CBr)ccc1C(=O)OC
Temperature: 70 °C
Yield: 52.4 %

Procedure:
A mixture of 2-butoxy-4-methyl-benzoic acid methyl ester (0.85 g, 3.8 mmol), dibenzoyl peroxide (100 mg), and NBS (0.68 g, 3.8 mmol) in CCl4 (20 mL) is heated to 70° C. overnight. The solid is filtered off and the filtrate is concentrated to a residue. The residue is purified by flash chromatography to give 4-Bromomethyl-2-butoxy-benzoic acid methyl ester as a syrup (0.6 g, 52%). LC-MS: 301.0 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11](O)=O)=[CH:5][CH:4]=1)#[N:2].[C:14]1([N:20]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:21](=[O:31])[C:22]2[CH:27]=[CH:26][C:25]([NH:28][CH3:29])=[C:24]([NH2:30])[CH:23]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[C:14]1([N:20]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:21]([C:22]2[CH:27]=[CH:26][C:25]3[N:28]([CH3:29])[C:11]([CH2:10][NH:9][C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)=[N:30][C:24]=3[CH:23]=2)=[O:31])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc(NC)c(N)c1)c1ccccc1
Reactant: N#Cc1ccc(NCC(=O)O)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccccc1

Procedure:
6.17 g (0.035 mol) of N-(4-cyanophenyl)glycine and 5.68 g (0.035 mol) of N,N'-carbonyldiimidazole were refluxed in 300 ml of tetrahydrofuran for 30 minutes, then 10.6 g (0.032 mol) of 3-amino-4-methylamino-benzoic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide were added and the mixture was refluxed for a further five hours. Then the solvent was distilled off in vacuo, the residue was dissolved in 150 ml of glacial acetic acid and refluxed for one hour. Then the glacial acetic acid was distilled off in vacuo, the residue was dissolved in about 300 ml of dichloromethane, the solution was washed twice with about 150 ml water and then dried over sodium sulphate. After evaporation of the solvent the crude product thus obtained was purified by column chromatography (800 g silica gel; eluant: dichloromethane with 1-2% ethanol). Yield: 8.5 g (57% of theory), Rf value: 0.51 (silica gel; dichloromethane/ethanol=19:1)
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]([CH2:18][CH3:19])[C:7](=[O:17])[CH:8]([NH:11][C:12](=[O:16])[CH2:13][O:14][CH3:15])[CH2:9][CH2:10][C:4]=2[C:3]=1[O:22][CH3:23].Cl[C:25]1[N:30]=[C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[S:38]([N:41]([CH3:43])[CH3:42])(=[O:40])=[O:39])[C:28]([Cl:44])=[CH:27][N:26]=1>>[Cl:44][C:28]1[C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[S:38](=[O:40])(=[O:39])[N:41]([CH3:42])[CH3:43])=[N:30][C:25]([NH:1][C:2]2[CH:21]=[CH:20][C:5]3[N:6]([CH2:18][CH3:19])[C:7](=[O:17])[CH:8]([NH:11][C:12](=[O:16])[CH2:13][O:14][CH3:15])[CH2:9][CH2:10][C:4]=3[C:3]=2[O:22][CH3:23])=[N:26][CH:27]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)C(NC(=O)COC)CCc2c1ccc(N)c2OC
Product: CCN1C(=O)C(NC(=O)COC)CCc2c1ccc(Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)c2OC

Procedure:
Following a procedure analogous to Example 113, N-(7-Amino-1-ethyl-6-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-2-methoxy-acetamide (100 mgs) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide were converted to the title compound (10 mgs) as a white powder. 1H-NMR (CDCl3): 9.45 (s, 1H), 8.54 (d, J=8.1 Hz, 1H), 8.28 (d, J=8.8 Hz, 1H), 8.21 (s, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.65 (t, J=7.8 Hz, 1H), 7.54 (s, 2H), 7.32-7.28 (m, 1H), 6.91 (d, J=8.3 Hz, 1H), 4.59-4.52 (m, 1H), 4.38-4.32 (m, 1H), 3.93-3.80 (m, 4H), 3.46 (s, 3H), 3.12-3.10 (m, 1H), 2.79 (s, 3H), 2.78 (s, 1H), 2.68-2.53 (m, 2H), 2.05-1.98 (m, 1H), 1.27-1.16 (m, 5H). LC/MS. (M+H)+ found 632.22.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@@H:8]([C:20](=[O:41])[N:21]([CH3:40])[C@@H:22]([C:34]1[O:38][N:37]=[C:36]([CH3:39])[N:35]=1)[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[CH3:6][NH:7][C@H:8]([CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[C:20]([N:21]([CH3:40])[C@@H:22]([C:34]1[O:38][N:37]=[C:36]([CH3:39])[N:35]=1)[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)=[O:41]
Reactant: Cc1noc([C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)[C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccc2ccccc2c1)c1nc(C)no1
Yield: 55.7 %

Procedure:
N-Methyl-N-{(1R)-1-{N-methyl-N-[(1R)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]carbamoyl}-2-(2-naphthyl)ethyl}carbamic acid tert-butylester (2.4 g, 4.2 mmol) was dissolved in a mixture of trifluoroacetic acid (40 ml) and dichloromethane (40 ml) at 20° C. After 10 min the reaction mixture was concentrated in vacuo and coevaporated from heptane (80 ml) and dichloromethane (80 ml). The residue was crystallised from ethyl acetate to give 1.12 g of (2R)-2-methylamino-N-methyl-N-[(1R)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]-3-(2-naphthyl)propionamide, trifluoroacetic acid.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=3[O:13][N:12]=2)=[CH:7][CH:6]=1.[CH2:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][NH:22]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[F:20][C:18]1[CH:17]=[CH:16][C:15]2[C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:22]4[CH2:23][CH2:24][C:25]5[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:21]4)=[CH:6][CH:7]=3)=[N:12][O:13][C:14]=2[CH:19]=1
Reactant: Fc1ccc2c(-c3ccc(OCCBr)cc3)noc2c1
Reactant: c1ccc2c(c1)CCNC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc2c(-c3ccc(OCCN4CCc5ccccc5C4)cc3)noc2c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 56.2 %

Procedure:
Combine 3-[4-(2-bromo-ethoxy)-phenyl]-6-fluoro-benzo[d]isoxazole (200 mg, 0.595 mmol), 1,2,3,4-tetrahydroisoquinoline (0.08 mL, 0.595 mmol), potassium carbonate (181 mg, 1.31 mmol), potassium iodide (10 mg, 0.06 mmol) and 4% aqueous acetonitrile. Stir at 70° C. for 18 hours and cool to room temperature. Filter the reaction mixture and wash the solids with dichloromethane. Evaporate the filtrate to give the title compound as a brown solid (130 mg, 56% Yield). Purity by LC/MS=68%, [M+H]+=389.
Reaction SMILES: C[O:2][C:3](=[O:11])[C@H:4]([CH3:10])[N:5]([C:7](=[O:9])[CH3:8])[CH3:6]>CO.[OH-].[Na+]>[C:7]([N:5]([CH3:6])[C@H:4]([C:3]([OH:11])=[O:2])[CH3:10])(=[O:9])[CH3:8]
Reactant: COC(=O)[C@H](C)N(C)C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N(C)[C@@H](C)C(=O)O
Reaction time: 2 h

Procedure:
The ester obtained above is dissolved in a mixture of 100 ml methanol and 170 ml 1 N-aqueous sodium hydroxide. The solution is allowed to stand at a room temperature for 2 hours, and the methanol is removed under reduced pressure. The alkaline aqueous solution is extracted with chloroform. The water layer is brought to pH 1 with concentrated hydrochloric acid under ice-cooling and extracted with ethyl acetate (140 ml×5). The extract is dried over anhydrous sodium sulfate and concentrated under reduced pressure to recover a white solid. Recrystallization from ethyl acetate-hexane yields 8.1 g of N-acetyl-N-methyl-L-alanine as colorless needles.
Reaction SMILES: [NH:1]([C:22]([O:24]CC1C=CC=CC=1)=O)[CH2:2][C:3]([N:5]([CH3:21])[C@H:6]([C:14]([NH:16][NH:17][C:18]([NH2:20])=[O:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[NH:32]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@@H:33](C(O)=O)[CH2:34][C:35](=[O:37])[NH2:36].C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>CO.CN(C=O)C>[NH:32]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@@H:33]([C:22]([NH:1][CH2:2][C:3]([N:5]([CH3:21])[C@H:6]([C:14]([NH:16][NH:17][C:18]([NH2:20])=[O:19])=[O:15])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:4])=[O:24])[CH2:34][C:35](=[O:37])[NH2:36]
Reactant: CN(C(=O)CNC(=O)OCc1ccccc1)[C@@H](Cc1ccccc1)C(=O)NNC(N)=O
Reactant: CC(C)(C)OC(=O)N[C@H](CC(N)=O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C(=O)CNC(=O)[C@@H](CC(N)=O)NC(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)NNC(N)=O
Reaction time: 15 h

Procedure:
0.85 g of Z-Gly-MePhe-NHNHCONH2 is subjected to catalytic reduction in methanol, dissolved in 10 ml of DMF, and after ice-cooling, 0.46 g of BOC-(D)-Asn-OH, 0.40 g of HONB and 0.45 g of DCC are added. The mixture is stirred for 15 hours. The precipitated DCU is filtered off, the solvent is distilled off and the residue is dissolved in n-butanol. The solution is washed with saturated aqueous sodium hydrogen carbonate and aqueous sodium chloride in that order and dried over anhydrous sodium sulfate. The solvent is distilled off, ether is added to the residue and the mixture is filtered to obtain a powder. Yield 0.78 g; m.p. 133°-136° C.; [α]D24 -36.5° (c=1.0, DMF); Rf1 0.09.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:12][CH2:13][OH:14])[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:2]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[C:20](Cl)=[O:21].C(=O)(O)[O-].[Na+]>ClCCl.CO>[CH3:29][O:28][C:24]1[CH:23]=[C:19]([CH:18]=[C:17]([O:16][CH3:15])[C:25]=1[O:26][CH3:27])[C:20]([N:9]1[CH2:10][CH2:11][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)([CH2:12][CH2:13][OH:14])[CH2:8]1)=[O:21]
Reactant: OCCC1(c2cccnc2)CCNC1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCC(CCO)(c3cccnc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 5.2.2 using 3-(pyrid-3-yl)-3-(2-hydroxyethyl)pyrrolidine, 3,4,5-trimethoxybenzoyl chloride, and sodium bicarbonate to give, after chromatography on silica gel eluting with dichloromethane/methanol 5/1, the title compound.
Reaction SMILES: C([N:8]1[CH2:40][CH2:39][C:11]2[N:12]=[C:13]([C:31]3[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:32]=3[CH3:38])[N:14]=[C:15]([N:16]3[C@H:21]([CH3:22])[CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:18]([CH3:30])[CH2:17]3)[C:10]=2[CH2:9]1)C1C=CC=CC=1.C(O)(=O)C>C1COCC1.O.[OH-].[OH-].[Pd+2]>[CH3:38][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([CH3:37])[C:31]=1[C:13]1[N:14]=[C:15]([N:16]2[C@H:21]([CH3:22])[CH2:20][N:19]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[C@@H:18]([CH3:30])[CH2:17]2)[C:10]2[CH2:9][NH:8][CH2:40][CH2:39][C:11]=2[N:12]=1
Reactant: Cc1cccc(C)c1-c1nc2c(c(N3C[C@H](C)N(C(=O)OC(C)(C)C)C[C@H]3C)n1)CN(Cc1ccccc1)CC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cccc(C)c1-c1nc2c(c(N3C[C@H](C)N(C(=O)OC(C)(C)C)C[C@H]3C)n1)CNCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of racemic tert-butyl 4-(6-benzyl-2-(2,6-dimethylphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)-(trans)-2,5-dimethylpiperazine-1-carboxylate (0.43 g, 0.794 mmol) in THF (9 mL) and water (3 mL) was added acetic acid (227 μL, 3.97 mmol) and 20% Pd(OH)2 on carbon (50% wet) (0.167 g, 0.238 mmol). The flask was evacuated and purged with hydrogen gas and then placed under a hydrogen atmosphere. After stirring at rt for 1 h the mixture was filtered over Celite®, and the Celite® pad was washed with EtOAc. The filtrate was washed with sat aq NaHCO3 and then the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain racemic tert-butyl 4-(2-(2,6-dimethylphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)-(trans)-2,5-dimethylpiperazine-1-carboxylate. MS (ESI+) m/z 452.3 (M+H)+.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]2[CH2:17][O:16]2)=[CH:9][CH:8]=1)(C)(C)C.[CH3:20][C:21]1[C:29]2[C:28]([N:30]3[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]3)=[N:27][CH:26]=[N:25][C:24]=2[S:23][CH:22]=1>>[OH:16][CH:15]([CH2:17][NH:36][CH:33]1[CH2:32][CH2:31][N:30]([C:28]2[C:29]3[C:21]([CH3:20])=[CH:22][S:23][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:35][CH2:34]1)[CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([OH:6])=[CH:12][CH:11]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(OCC2CO2)cc1
Reactant: Cc1csc2ncnc(N3CCC(N)CC3)c12
Product: Cc1csc2ncnc(N3CCC(NCC(O)COc4ccc(O)cc4)CC3)c12
Yield: 11 %

Procedure:
Synthesis followed SP6 (3 h), using 150 μmol tert-butyldimethyl(4-(oxiran-2-ylmethoxy)phenoxy)silane and 1-(5-methylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine to give O-silylated intermediate upon purification by prep. HPLC (reversed phase) with 11% yield. Product was obtained by deprotection according to SP7 and purification by prep. HPLC (reversed phase) with 76% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[O:10]C(=O)[NH:8][C:5]2=[N:6][CH:7]=1.[OH-].[Na+].C(=O)=O>>[NH2:8][C:5]1[C:4]([OH:10])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1
Reactant: O=c1[nH]c2ncc(Br)cc2o1
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Product: Nc1ncc(Br)cc1O
Temperature: 25 °C
Yield: 94.2 %

Procedure:
6-Bromo-3H-oxazolo[4,5-b]pyridin-2-one (21.5 g, 100 mmol) was suspended in NaOH solution (2N, 250 mL, 500 mmol). The mixture was refluxed overnight and a clear solution was obtained. After cooling to room temperature, the reaction solution was neutralized to pH˜7. A lot of CO2 was released and also precipitate was observed. The product was filtered, washed with water, and dried under high vacuum to provide 2-amino-5-bromo-pyridin-3-ol as an off-white solid (17.8 g, 98% yield).