Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:16])[CH2:10][CH:11]([CH3:15])[C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1.Br.[CH3:18][C:19](O)=O>>[CH2:18]([O:13][C:12](=[O:14])[CH:11]([CH3:15])[CH2:10][C:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)=[O:16])[CH3:19]
Reactant: COc1ccc(C(=O)CC(C)C(=O)O)cc1
Reactant: CC(=O)O
Agent: Br
Product: CCOC(=O)C(C)CC(=O)c1ccc(OC)cc1
Yield: 93 %

Procedure:
A solution of 4-(4-methoxyphenyl)-2-methyl-4-oxobutyric acid (10 g, 45 mmol) and 150 mL of 48% HBr in 20 mL of AcOH was heated to 100° C. for 48 h. The solvent was evaporated and EtOH (3×30 mL) was added and evaporated to give 4-(4-methoxy-phenyl)-2-methyl-4-oxobutyric acid ethyl ester (9.96 g, 93%); MS m/z 259 (M+23).
Reaction SMILES: Cl[CH:2]([C:15]1[CH:19]=[C:18]([Si:20]([CH3:23])([CH3:22])[CH3:21])[O:17][CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C)C=O>[N:24]([CH:2]([C:15]1[CH:19]=[C:18]([Si:20]([CH3:23])([CH3:22])[CH3:21])[O:17][CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[N+:25]=[N-:26]
Reactant: CCCCCCCCCCCCC(Cl)c1coc([Si](C)(C)C)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCC(N=[N+]=[N-])c1coc([Si](C)(C)C)c1
Reaction time: 144 h

Procedure:
A mixture of 3-(1-chlorotridecyl)-5-trimethylsilylfuran (468 mg, 1.31 mmol) and sodium azide (852 mg, 13.1 mmol) in dry dimethylformamide (2 ml) was stirred at 60 degrees for 6 days. Most of the solvent was evaporated under high vacuum and the residue dissolved in water. Extraction (ethyl ether) and evaporation of the dried (magnesium sulfate) extracts gave an oil, which was flash chromatographed on silica using 5% ethyl ether/hexane. Fractions with Rf of about 0.73 on evaporation gave the title azide as a very pale yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH:20]([C:22](=[O:30])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][N:18]([C:31]([C:33]3([NH:36]C(=O)OC(C)(C)C)[CH2:35][CH2:34]3)=[O:32])[CH2:17]2)=[CH:12][CH:11]=1)[CH3:9]>ClCCl>[NH2:36][C:33]1([C:31]([N:18]2[CH2:17][CH:16]([C:13]3[CH:14]=[CH:15][C:10]([CH2:8][CH3:9])=[CH:11][CH:12]=3)[CH2:21][CH:20]([C:22]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:30])[CH2:19]2)=[O:32])[CH2:34][CH2:35]1
Reactant: CCc1ccc(C2CC(C(=O)Nc3ccccc3)CN(C(=O)C3(NC(=O)OC(C)(C)C)CC3)C2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(C(=O)Nc3ccccc3)CN(C(=O)C3(N)CC3)C2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Under argon and at RT, 190 μl (2.5 mmol, 15 eq.) of trifluoroacetic acid were added to a solution of 81 mg (0.16 mmol) of tert-butyl (1-{[3-(4-ethylphenyl)-5-(phenylcarbamoyl)piperidin-1-yl]carbonyl}cyclopropyl)carbamate in 2 ml of dichloromethane. The reaction mixture was stirred at RT for 20 h, then concentrated under reduced pressure and repeatedly coevaporated with toluene. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 29 mg (45% of theory)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19](O)=[O:20])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[NH2:28][CH:29]([CH3:32])[CH2:30][OH:31]>>[OH:31][CH2:30][CH:29]([NH:28][C:19]([C:17]1[S:18][C:13]2[C:12]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[N:11][C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH:3]=[N:2][NH:1]4)=[N:15][C:14]=2[CH:16]=1)=[O:20])[CH3:32]
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Reactant: CC(N)CO
Product: CC(CO)NC(=O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (30 mg) was coupled to 2-aminopropan-1-ol via General Procedure B. The product was purified via reverse phase HPLC to give 22.3 mg of 260. MS (Q1) 438.8 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:22]([CH:24]1[C:28]2[S:29][CH:30]=[CH:31][C:27]=2[C:26](=O)[O:25]1)[CH3:23].Cl>C1COCC1>[CH2:22]([CH:24]1[C:28]2[S:29][CH:30]=[CH:31][C:27]=2[C:26](=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[O:25]1)[CH3:23]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CCC1OC(=O)c2ccsc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1OC(=C2C(=O)Nc3ccc(F)cc32)c2ccsc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 32.5 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (440 mg, 2.9 mmol.) in THF (3 mL) is cooled to 0° C. under an Argon atmosphere and treated with a solution of lithium bis(trimethylsilyl)amide (5.8 mL of a 1 M solution in THF, 5.8 mmol) dropwise. The resulting solution is stirred at 0° C. for 10 min and warmed to room temperature. A solution of 6-ethyl-6H-thieno[2,3-c]furan-4-one, (328 mg, 1.94 mmol) in THF (4 mL) and added dropwise to the reaction mixture. The resulting solution is stirred for 4 h. The reaction mixture is poured into aqueous 10% HCl solution (100 mL.). The resulting mixture is heated to 90° C. for 45 min and stirred at room temperature for 36 h. The precipitate which formed is collected by filtration and dried. The solid obtained is purified by chromatography (30% EtOAc/hexane). The product containing fractions are concentrated to give the title compound as a yellow solid (190 mg, 33%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CN.[CH2:14]([N:16](CC)CC)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:16][CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: CN
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(Br)cc1
Reaction time: 18 h
Yield: 78.1 %

Procedure:
Add a solution of 4-bromo-benzenesulfonyl chloride (5.0 g, 19.2 mmol) in 10 mL THF at r.t. to a solution of methylamine (9.6 ml, 2 M in THF, 19.2 mmol) and triethylamine (2.72 mL, 19.2 mmol) over a period of 60 min and stir for 18 h. Add further methylamine (9.6 ml, 2 M in THF, 19.2 mmol) and triethylamine (2.72 mL, 19.2 mmol) and stir for 18 h. Evaporate the solvent under vacuum and add dichloromethane. Wash the organic layer with saturated aqueous sodium bicarbonate solution, followed by saturated sodium chloride solution. Filter through a hydrophobic filter paper and remove the solvent under vacuum. Further purify this material via column chromatography on silica gel, eluting with a gradient of 0-50% ethyl acetate in hexane to afford the title compound (3.75 g) as a white solid. MS (m/e): 251 (M+H).
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:29][CH:5]2[CH:6]([C:19]3[CH:24]=[CH:23][C:22]([O:25]COC)=[CH:21][CH:20]=3)[O:7][C:8]3[C:9]([CH3:18])=[CH:10][C:11]([O:14]COC)=[CH:12][C:13]=3[CH:4]2[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)(O)[C:52]#[N:53].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:30][C:2]1([F:1])[CH2:29][CH:5]2[CH:6]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[O:7][C:8]3[C:9]([CH2:18][C:52]#[N:53])=[CH:10][C:11]([OH:14])=[CH:12][C:13]=3[CH:4]2[CH2:3]1
Reactant: CC(C)(O)C#N
Reactant: COCOc1ccc(C2Oc3c(C)cc(OCOC)cc3C3CC(F)(F)CC32)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#CCc1cc(O)cc2c1OC(c1ccc(O)cc1)C1CC(F)(F)CC21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of preparation 20 (58 mg, 0.132 mmol) and triphenyl phosphine (175 mg, 0.67 mmol) and acetone cyanohydrin (0.125 mL, 1.37 mmol) in 1 mL of THF at 0° C. add dropwise via syringe diisopropylazodicarboxylate (0.13 mL, 0.66 mmol). Let the solution warm slowly to room temperature overnight. Concentrate the solution, adsorb the material to silica gel, and purify by silica gel flash chromatography (10 g, 0-30% A/B, A=EtOAc, B=10% CH2Cl2 in hexanes). Dissolve the material in 2 mL of THF and add 1 mL of 5 M aqueous HCl. Stir the solution overnight. Dilute the solution with EtOAc and a little methanol for solubility, wash with saturated aqueous sodium bicarbonate, brine, dry over Na2SO4, filter and concentrate. Adsorb the material to silica gel and purify by silica gel flash chromatography (4 g, 10-60% A/B, A=10% methanol in EtOAc, B=hexanes) to afford example 10. HRMS calc. for C20H17F2NNaO3: 380.1074; found: 380.1060 (M+Na).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([N:17]2[C@@:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)([CH3:22])[C@@:20]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)([CH3:30])[N:19]=[C:18]2[C:38]2[CH:39]=[N:40][C:41]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:42][C:43]=2[O:44][CH2:45][CH3:46])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]([N:17]2[C@@:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)([CH3:22])[C@@:20]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)([CH3:30])[N:19]=[C:18]2[C:38]2[CH:39]=[N:40][C:41]([C:47]([CH3:48])([CH3:50])[CH3:49])=[CH:42][C:43]=2[O:44][CH2:45][CH3:46])=[O:16])[CH2:12][CH2:13]1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)NC1CCNCC1
Reaction time: 2 h
Yield: 96.8 %

Procedure:
A solution of 4-{[(4S,5R)-2-(6-tert-Butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (640 mg, 0.885 mmole, example 205) in dichloromethane (6 mL) was treated with trifluoroacetic acid (6 mL) at 0° C. and allowed to stir for 2 h before concentrated to dryness under reduced pressure. The residue was then taken up in dichloromethane (100 mL), washed with aqueous sodium carbonate (2×15 mL), water (15 mL) and concentrated to give (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carboxylic acid piperidin-4-yl amide (533.3 mg) which was used without purification.
Reaction SMILES: C(OC([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:34])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH2:24][CH:23]1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.[ClH:42].C(OCC)(=O)C.C(OC(C)C)(C)C>C(OCC)(=O)C>[ClH:42].[F:41][C:37]1[CH:36]=[C:35]([CH:23]2[CH:22]([CH2:21][NH:8][C@@H:9]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:13][CH:12]=3)[CH3:10])[CH2:27][CH2:26][N:25]([C:28](=[O:34])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH2:24]2)[CH:40]=[CH:39][CH:38]=1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCN(C(=O)CCC(=O)O)CC1c1cccc(F)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Product: C[C@@H](NCC1CCN(C(=O)CCC(=O)O)CC1c1cccc(F)c1)c1cccc2ccccc12
Reaction time: 2 h

Procedure:
To a solution of 174 mg of 4-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]-4-oxobutanoic acid in 1.0 mL of ethyl acetate was added 1.00 mL of a 4 M hydrogen chloride/ethyl acetate solution at room temperature, followed by stirring for 2 hours. Diisopropylether was added thereto, and the resulting precipitate was collected by filtration, and then dried under reduced pressure to obtain 100 mg of 4-[3-(3-fluorophenyl)-4-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)piperidin-1-yl]-4-oxobutanoic acid hydrochloride as a white solid.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([CH2:5][CH2:6][OH:7])[CH2:2]1.C1N2CCN(CC2)C1.[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>C(Cl)Cl>[O:1]1[CH2:4][CH:3]([CH2:5][CH2:6][O:7][S:16]([C:19]2[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCC1COC1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC2COC2)cc1
Reaction time: 0.25 h

Procedure:
At 0° C., to a solution of 2-(3-oxetanyl)ethanol (according to the synthesis procedure in the reference: Journal of American Chemical Society, 2009, 131, 2786-2787.) (193 mg, 1.89 mmol) in CH2Cl2 (15 mL) was added DABCO (847 mg, 7.56 mmol) and TsCl (1.43 g, 7.56 mmol) was then added dropwise, the mixture was stirred for 15 minutes. After filtration, the filter cake was washed with CH2Cl2 and the filtrate was washed twice with water. The organic phase was dries over anhydrous sodium sulphate. The solvent was evaporated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 5:1) to afford the target compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8]O)=[N:4][CH:5]=[CH:6][N:7]=1.[C:10]1(=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[NH:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:3]([CH2:8][N:11]2[C:12](=[O:19])[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]2=[O:20])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: OCc1nccnc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1nccnc1Cl

Procedure:
A solution of (3-chloropyrazin-2-yl)-methanol (47 g, 0.33 mol), isoindole-1,3-dione (58.3 g, 0.396 mol, 1.2 eq.), and triphenylphosphine (89.7 g, 0.396 mol, 1.2 eq.) in anhydrous THF (1.5 L) was charged with DIAD (80.2 g, 0.396 mol, 77.1 mL, 1.2 eq.) dropwise at rt, under N2, making sure the internal temperature did not surpass 40° C. The crude material was adsorbed onto silica gel, dry loaded, and purified by chromatography on silica gel [6″×16″ column, 2.75 kg silica gel, eluting with Hex:CH2Cl2 1:1→neat CH2Cl2→MeCN:CH2Cl2→2→10%.] Material was combined and concentrated in vacuo. Residue was dissolved as best as possible in hot CH2Cl2 (500 mL), after which i-PrOH was added and a white crystalline solid began to precipitate out of solution. Solid was filtered, washed with i-PrOH, and oven-dried to remove all traces of solvent, affording the title compound, as an off-white solid; 1H NMR (400 MHz, CDCl3) δ 5.10 (s, 1H), 7.75-7.80 (m, 2H), 7.89-7.94 (m, 2H), 8.26 (1H, d, J=2.45 Hz), 8.31 (1H, d, J=2.49 Hz); MS (ES+): m/z 274.21/276.19 (100/50) [MH+]; HPLC: tR=3.35 min (OpenLynx, nonpolar—7min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:13].[BH4-].[Na+]>CO.ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH:8]2[OH:13]
Reactant: COc1cccc2c1CCCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cccc2c1CCCC2O

Procedure:
To a solution of 5-methoxy-3,4-dihydro-2H-naphthalen-1-one (CAS#33892-75-0, 10 g, 5.67 mmol) in methanol (40 mL) and dichloromethane (5 mL) at 0° C. is added sodium borohydride (0.579 g, 8.51 mmol) in one portion. The cooling bath is removed and after 1.5 hours, the mixture is poured into water (75 mL) and the volatile organics are removed in vacuo. Extraction with dichloromethane, drying over sodium sulfate, filtering through a cotton plug and concentration affords 5-methoxy-1,2,3,4-tetrahydro-naphthalen-1-ol, which is used in the next step without further purification.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C@H:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].C(=O)([O-])[O-].[K+:14].[K+]>O>[OH2:3].[C:1]([O-:9])(=[O:8])[C@H:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[K+:14]
Reactant: O=C(O)C[C@H](O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)C[C@H](O)C(=O)[O-]
Temperature: 10 °C
Yield: 143.6 %

Procedure:
134.1 g (one mole) of L-malic acid are dissolved in 400 ml of water, and 84.3 g (0.61 mole) of potassium carbonate are added to the L-malic acid solution under stirring. The solution (pH 4.4) is concentrated under reduced pressure at 60° C. to make the total volume thereof about 250 ml. The concentrated aqueous solution is gradually cooled to 10° C. Then, the mixture thus obtained (i.e., the mixture of the concentrated aqueous solution and crystals precipitated) is stirred at the same temperature for 2 hours. After stirring, the mixture had a pH of 5.5. The crystalline precipitates are collected by filtration, washed with an aqueous 80% methanol solution and dried at 35° C. in air for 24 hours. 136.6 g of monopotassium L-malate monohydrate are obtained as crystals. Yield: 71.8% The product loses its intramolecular water at 98° to 100° C. and decomposes at 184° to 185° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:26](OCC)[O:27]CC)=[C:5]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].Cl>CC(C)=O>[CH3:1][C:2]1[NH:3][C:4]([CH:26]=[O:27])=[C:5]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(C(OCC)OCC)=C(C(=O)OCC)C1c1ccccc1OC
Agent: Cl
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1ccccc1OC
Temperature: 25 °C
Yield: 100 %

Procedure:
ppm : 1.2 (6H, t, J=7 Hz), 2.4 (3H, s), 3.92 to 4.38 (4H, m), 5.72 (1H, s),7.06 (1H, s), 7.24 to 7.62 (4H, m). (7) To a solution of diethyl 2-methyl-4-(2-methoxyphenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (447.5 mg) in acetone (7.5 ml) was added 6 N-hydrochloric acid (0.2 ml) and stirred at room temperature for an hour. The resultant mixture was treated in a similar manner to Example 2-4), to give reddish yellow crystals of diethyl 2-methyl-4-(2-methoxypheny)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (373.2 mg). The product was recrystallized from a mixture of diethyl ether and n-hexane to give the pure product, m.p. 111° to 112° C.
Reaction SMILES: [Br:1][C:2]1([Br:18])[CH2:4][CH:3]1[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([N+:14]([O-])=O)=[CH:9][C:8]=1[CH3:17].C(O)(=O)C>[Fe].O>[Br:1][C:2]1([Br:18])[CH2:4][CH:3]1[CH2:5][O:6][C:7]1[C:8]([CH3:17])=[CH:9][C:10]([NH2:14])=[C:11]([CH3:13])[CH:12]=1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1OCC1CC1(Br)Br
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(OCC2CC2(Br)Br)c(C)cc1N
Temperature: 80 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
A mixture of 0.37 g of 1-[(2,2-dibromocyclopropyl)methoxy]-2,5-dimethyl-4-nitrobenzene, 0.29 g of iron powder, 20 mL of acetic acid and 5 mL of water was stirred at 80° C. for 1 hour. The reaction mixture was cooled to around room temperature, and then concentrated under reduced pressure. The resulting residue was converted into basic with an aqueous 1 N sodium hydroxide solution, then ethyl acetate was added, and the mixture was filtered. The filtrate was extracted with ethyl acetate, and then the organic layer was washed with water and saturated salt water, and dried over anhydrous magnesium sulfate. The resulting residue was subjected to silica gel column chromatography to obtain 0.19 g of 4-[(2,2-dibromocyclopropyl)methoxy]-2,5-dimethylphenylamine
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([CH2:22][C:23]([O:25]CC)=O)[CH:19]=[C:18]([CH2:28][O:29][CH2:30][C:31]([F:34])([F:33])[F:32])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[C-]#[N:36].[K+].O>[OH-].[NH4+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([CH2:22][C:23]([NH2:36])=[O:25])[CH:19]=[C:18]([CH2:28][O:29][CH2:30][C:31]([F:33])([F:34])[F:32])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: CCOC(=O)Cc1cc(COCC(F)(F)F)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Reactant: [C-]#N
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(CC(N)=O)n2)ccc1-n1cnc(C)c1
Temperature: 65 °C
Reaction time: 96 h

Procedure:
Ethyl 2-(2-{[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]amino}-6-[(2,2,2-trifluoro-ethoxy)methyl]pyrimidin-4-yl)acetate (140 mg, 0.30 mmol, 1.0 eq) was suspended in ammonium hydroxide (3 mL) with few crystals of potassium cyanide in a sealed tube. The mixture was stirred 4 days at 65° C. The reaction mixture was cooled down to rt, water was added and the aqueous layer was extracted with DCM (5×). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified on a silica gel cartridge eluting with 0% to 10% MeOH/DCM (1% ammonium hydroxide) to give the title compound as a solid, 68 mg (50%).
Reaction SMILES: [Cl: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]=[C:4](I)[N:3]=1.C([Li])CCC.[CH:22](=[O:24])[CH3:23]>C1COCC1>[Cl: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]=[C:4]([CH:22]([OH:24])[CH3:23])[N:3]=1
Reactant: CC=O
Reactant: Clc1nc(I)ccc1OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)c1ccc(OCc2ccccc2)c(Cl)n1
Temperature: 22 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
2-Chloro-3-benzyloxy-6-iodo-pyridine (416 mg, 1.2 mmol) in THF (4 mL) was cooled to -78° C. and treated with n-butyllithium (1.2 mL of 1.6M in hexanes, 1.92 mmol). After 60 minutes, acetaldehyde (237 mg, 5.4 mmol) was added and the reaction was allowed to warm to 22° C. over 2 hours. The reaction was quenched with water (5 mL) and concentrated in vacuo. The remaining solution was extracted several times with ethyl acetate, dried over MgSO4, and concentrated in vacuo to yield an oil. The oil was chromatographed 1:1 hexane/ethyl acetate to yield 220 mg (70%) of 2-chloro-3-benzyloxy-6-(1-hydroxyethyl)-pyridine.
Reaction SMILES: S(=O)(=O)(O)O.Cl.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14]N)=[CH:10][CH:9]=1.[CH:16]1([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]2=O)[CH2:18][CH2:17]1>O1CCOCC1>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]2[NH:14][C:22]3[CH2:23][CH2:24][N:19]([CH:16]4[CH2:18][CH2:17]4)[CH2:20][C:21]=3[C:10]=2[CH:9]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: O=C1CCCCN1C1CC1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: Clc1ccc2[nH]c3c(c2c1)CN(C1CC1)CC3
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sulfuric acid is added to a solution of 4-Chloro phenyl hydrazine hydrochloride (1 equiv.) in dioxane and stirred for 5 min. at RT. N-cyclopropyl piperidone (1 equiv.) is added and the mixture is heated at 80° C. for 2 h. After completion, as monitored by TLC, the reaction mixture is concentrated under reduced pressure and basified to pH 10 using 10% aqueous KOH solution. The reaction product is extracted with EtOAc, dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator to provide the desired compound.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH:7]=[C:8]([C:11]([NH:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[O:12])[CH:9]=[CH:10][C:5]2=[N:4][N:3]1[CH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24](C(OCC2C=CC=CC=2)=O)[CH2:23][CH2:22]1.I[Si](C)(C)C>C(#N)C>[O:1]=[C:2]1[N:6]2[CH:7]=[C:8]([C:11]([NH:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[O:12])[CH:9]=[CH:10][C:5]2=[N:4][N:3]1[CH2:19][CH2:20][CH:21]1[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]1
Reactant: CC(NC(=O)c1ccc2nn(CCC3CCN(C(=O)OCc4ccccc4)CC3)c(=O)n2c1)C(=O)O
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: CC(NC(=O)c1ccc2nn(CCC3CCNCC3)c(=O)n2c1)C(=O)O
Reaction time: 0.5 h

Procedure:
A solution of 1-6 (64 mg, 0.129 mmole) in acetonitrile (15 ml) at 0° was treated with iodotrimethylsilane (107.0 mg, 0.533 mmole) and the reaction stirred 0.5 h. The reaction was quenched into water, extracted with diethyl ether and chromatographed on silica using EtOH/NH4 OH/H2O (10/1/1) to give upon concentration a white foam. Crystallization from ethanol gave 1-7 as a white solid, mp 267°-269°. ##STR40## 2(S)-[6-Butylsulfonyl)amino]-3[[[2,3-dihydro-3-oxo-2-[2-(N-CBZ-Piperidin-4-yl)ethyl]-1,2,4 -triazolo[4,3-a]Pyridin-6-yl]carbonyl[amino Propionic acid (1-8)