Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[C:6]([CH3:14])([C:12]#[N:13])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.[SH2:15].C(N(CC)CC)C>N1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[C:6]([CH3:14])([C:12](=[S:15])[NH2:13])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: S
Reactant: Cc1cnc2c(c1)CCCC2(C)C#N
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Cc1cnc2c(c1)CCCC2(C)C(N)=S

Procedure:
3,8-dimethyl-8-cyano-5,6,7,8-tetrahydroquinoline is treated with H2S in pyridine in the presence of triethylamine following the general procedure of Example 5 and the title compound is isolated and recrystallised from benzene as the quarter hydrate, colorless meedles m.p. 164° C. This was converted to the hydrochloride by treatment in isopropanol with a solution of dry HCl gas in ether. The title compound hydrochloride crystallised as colorless needles m.p. 277° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([N:12]=[C:13]=[S:14])[CH2:4][CH2:3]1.C(O)C.[CH2:18]([NH2:20])[CH3:19]>C(Cl)Cl>[CH2:18]([NH:20][C:13]([NH:12][CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2](=[O:1])[CH2:3][CH2:4]1)=[S:14])[CH3:19]
Reactant: CCN
Reactant: O=C1CCC(N=C=S)c2ccccc21
Solvent: ClCCl
Solvent: CCO
Product: CCNC(=S)NC1CCC(=O)c2ccccc21
Reaction time: 18 h

Procedure:
To a solution of 1,2,3,4-tetrahydro-4-oxo-1-naphthyl isothiocyanate (5.0 g) in methylene chloride (100 ml), ethylamine is added via ethanol (15 ml) saturated with ethylamine. After stirring for 18 hours, the mixture is heated at reflux for 2 hours, cooled and evaporated to dryness in vacuo. The residue is triturated with water and the title compound collected and dried; m.p. 134° to 138° C.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:13](=O)[CH3:14].C.Cl.[CH3:18][O:19][NH2:20].C([O-])(=O)C.[Na+]>O>[CH3:18][O:19][N:20]=[C:13]([C:3]1[N:4]=[C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:6][C:2]=1[CH3:1])[CH3:14]
Reactant: CON
Reactant: CC(=O)c1nc(-c2cccnc2)[nH]c1C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CON=C(C)c1nc(-c2cccnc2)[nH]c1C
Temperature: 5 °C

Procedure:
A 4.0 g (0.002 mole) amount of 1-[5-methyl-2-(3-pyridinyl)-1H-imidazol-4-yl]ethanone was dissolved in 150 ml of boiling water. The solution was clarified by treatment with activated charcoal, then filtered. The filtrate was added to a mixture of 2.0 g (0.025 mole) of O-methylhydroxylamine hydrochloride, 2.0 g (0.025 mole) of sodium acetate and 10 ml of water. This mixture was stirred and heated on a steam bath for 16 hours. The hot solution was clarified with activated charcoal and filtered. A 150 ml volume of water was added to the filtrate which had developed a heavy precipitate. The mixture was stirred and heated to boiling and ethanol was added in small portions to effect solution. The hot solution was clarified with activated charcoal and filtered. The filtrate was cooled at 5° C. with formation of a precipitate. The solid was collected by filtration, washed with cold water and dried and gave 1.7 g of the desired product as a white solid, mp 203°-205° C.
Reaction SMILES: I.C(OC(=O)C)(=O)C.[O:9]=[C:10]1[N:14]([CH2:15][C:16]([O:18]CC)=[O:17])[C:13]2[CH:21]=[C:22]([O:25]C)[CH:23]=[CH:24][C:12]=2[S:11]1.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[O:9]=[C:10]1[N:14]([CH2:15][C:16]([OH:18])=[O:17])[C:13]2[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:12]=2[S:11]1
Reactant: CCOC(=O)Cn1c(=O)sc2ccc(OC)cc21
Agent: I
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(O)Cn1c(=O)sc2ccc(O)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.6 %

Procedure:
To a mixture of 57% hydriodic acid (50 ml) and acetic anhydride (15 ml) was added a solution of ethyl 2-oxo-5-methoxy-3-benzothiazolineacetate (2.67 g) in acetic acid (15 ml). The reaction mixture was refluxed with stirring for 1.5 hours and then cooled to ambient temperature. To the resultant mixture were added ice-water and a small volume of sodium bisulfite. The mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give crystalline 2-oxo-5-hydroxy-3-benzothiazolineacetic acid (1.7 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([C:16]#[N:17])=[C:14]([S:18][CH3:19])[S:13][C:12]=2[C:20]([NH2:22])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC#N.[N-:26]=[N+:27]=[N-:28].[Na+].[Si](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([C:16]#[N:17])=[C:14]([S:18][CH3:19])[S:13][C:12]=2[C:20]2[NH:22][N:28]=[N:27][N:26]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1sc(C(N)=O)c(-c2ccc(C(C)(C)C)cc2)c1C#N
Reactant: [N-]=[N+]=[N-]
Agent: Cl[Si](Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: CSc1sc(-c2nnn[nH]2)c(-c2ccc(C(C)(C)C)cc2)c1C#N

Procedure:
Combine 3-(4-tert-butyl-phenyl)-4-cyano-5-methylsulfanyl-thiophene-2-carboxylic acid amide (0.142 mmol) and 1.5 ml CH3CN with NaN3 (0.43 mmol) and SiCl4 (0.142 mmol) in CH2Cl2 and reflux the mixture for 16 hrs. MS shows desired product and starting material. Conc. to dryness and purification by radial chromatography (Si) on a 1000 micron plate eluting with 5% MeOH/0.5% AcOH/CH2Cl2. Concentrate desired fractions to provide the desired title compound: 1H NMR (400 MHz, CDCl3) δ 7.40 (q, 4H, J=22 Hz), 2.73 (s, 3H), and 1.35 (s, 9H), MS found (M+1) 356.2.
Reaction SMILES: [CH2:1]([N:3]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][C:23]([CH2:26]O)=[CH:24][N:25]=1)=[CH:17]2)[S:4]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)(=[O:6])=[O:5])[CH3:2].CN(C)C=O.O1CCCC1.S(Cl)([Cl:40])=O>C(OCC)(=O)C.[Cl-].[Na+].O>[Cl:40][CH2:26][C:23]1[S:22][C:21]([C:18]2[NH:19][C:20]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[N:3]([CH2:1][CH3:2])[S:4]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)(=[O:6])=[O:5])=[N:25][CH:24]=1
Reactant: CCN(c1cccc2cc(-c3ncc(CO)s3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: O=S(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CCN(c1cccc2cc(-c3ncc(CCl)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a mixture of N-ethyl-N-{2-[5-(hydroxymethyl)-1,3-thiazol-2-yl]-1H-indol-7-yl}thiophene-2-sulfonamide (3.43 g), N,N-dimethylformamide (0.05 ml) and tetrahydrofuran (50 ml) was added thionyl chloride (1.56 g), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and saturated brine, and the organic layer was washed with saturated brine, and dried over magnesium sulfate, and filtrated. The filtrate was concentrated, and the obtained solid was washed with ether-hexane (1:1) to give the title compound (3.27 g, yield 91%) as a pale-yellow solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH:6]1[CH:10]=[N:9][CH:8]=[N:7]1.[C:11]([NH:14][C:15]1(N)[NH:24][C:23](=O)[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=3)[N:21]=2)[NH:16]1)(=[O:13])[CH3:12]>N1C=CC=CC=1>[C:11]([NH:14][C:15]1[N:24]=[C:23]([C:10]2[N:9]=[CH:8][NH:7][N:6]=2)[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=3)[N:21]=2)[N:16]=1)(=[O:13])[CH3:12]
Reactant: COc1ccc(-c2cnc3c(n2)C(=O)NC(N)(NC(C)=O)N3)cc1OC
Reactant: c1nc[nH]n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(-c2cnc3nc(NC(C)=O)nc(-c4nc[nH]n4)c3n2)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
To a solution of phosphorus oxychloride (1.68 ml, 18 mmoles) and 1,2,4-triazole (4.96 g, 72 mmoles) in dry pyridine (110 ml) was added the compound of example 49 (2.45 g, 7.18 mmoles). The suspension was stirred at room temperature for 4 hours. The precipitate was filtered off, washed with pyridine, toluene and diethyl ether. The resulting solid was dried over P2O5 under vacuum, providing the title compound as a yellow powder (2 g, yield: 80%) which afforded the following mass spectrum: 392 ([M+H]+, 100).
Reaction SMILES: [NH2:1][NH2:2].Cl[C:4]1[CH:17]=[CH:16][C:15]2[C:14](=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=O)[C:6]=2[CH:5]=1>N1C=CC=CC=1>[N:1]1[NH:2][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:8]=2[C:7]=1[C:6]1[C:15]([C:14]3=[O:18])=[CH:16][CH:17]=[CH:4][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)c2cc(Cl)ccc21
Reactant: NN
Solvent: c1ccncc1
Product: O=C1c2ccccc2-c2n[nH]c3cccc1c23
Temperature: 100 °C

Procedure:
Anhydrous hydrazine is added to a solution of 2-chloroanthraquinone (Aldrich) in 10 mL, pyridine, and the mixture heated at 100° C. for 16 hours. The mixture is cooled and the solvent is evaporated in vacuo. The residue is taken in hot 6N HCl, and the solid is collected by filtration. Flash chromatography of the crude material on silica gel affords anthra[1,9cd]pyrazol-6(2H)-one (“Compound 1”) as yellow solids.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([CH2:25][C:26]([O:28]CC2C=CC=CC=2)=[O:27])[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>CO>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([CH2:25][C:26]([OH:28])=[O:27])[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)OCc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 78.7 %

Procedure:
Potassium hydroxide (6.2 g) was added to a solution of benzyl 3,4-dibenzyloxyphenylacetate (16.0 g) in methanol (200 ml), followed by stirring at room temperature for 6 hours. The reaction mixture was adjusted to pH 4.0 with 5N hydrochloric acid solution. The solvent was distilled off and to the residue was added water. The precipitated crystal was collected by filtration, washed with water and dried to obtain as colorless crystal 3,4-dibenzyloxyphenylacetic acid (10.0 g).
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([F:16])[CH:12]=3)[N:7]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:6]=2[CH2:5][CH2:4]1.C(OC(N[C@H]1CC2C3C(=CC=C(F)C=3)N(CC(OCC)=O)C=2CC1)=O)C1C=CC=CC=1>>[ClH:1].[NH2:2][C@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([F:16])[CH:12]=3)[N:7]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:6]=2[CH2:5][CH2:4]1
Reactant: CCOC(=O)Cn1c2c(c3cc(F)ccc31)C[C@@H](N)CC2
Agent: CCOC(=O)Cn1c2c(c3cc(F)ccc31)C[C@H](NC(=O)OCc1ccccc1)CC2
Agent: Cl
Product: CCOC(=O)Cn1c2c(c3cc(F)ccc31)C[C@H](N)CC2

Procedure:
Following the same procedure as (S)-ethyl 2-(3-amino-6-fluoro-3,4-dihydro-1H-carbazol-9(2H)-yl)acetate hydrochloride but using (R)-ethyl 2-(3-(((benzyloxy)carbonyl)amino)-6-fluoro-3,4-dihydro-1H-carbazol-9(2H)-yl)acetate, the title compound was obtained as a white solid.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH:16]([NH:18]/[C:19](=[CH:23]/[CH:24]([CH3:36])[CH2:25][P:26]([O:32][CH:33]([CH3:35])[CH3:34])([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])/[C:20]([OH:22])=[O:21])=[O:17].[CH2:37](O)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C1C=CN=CC=1)C.ClCCl>[CH:16]([NH:18][CH:19](/[CH:23]=[C:24](\[CH3:36])/[CH2:25][P:26]([O:28][CH:29]([CH3:30])[CH3:31])([O:32][CH:33]([CH3:35])[CH3:34])=[O:27])[C:20]([O:22][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:21])=[O:17]
Reactant: OCc1ccccc1
Reactant: CC(/C=C(/NC=O)C(=O)O)CP(=O)(OC(C)C)OC(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C/C(=C\C(NC=O)C(=O)OCc1ccccc1)CP(=O)(OC(C)C)OC(C)C
Temperature: 25 °C
Reaction time: 10 h

Procedure:
11.5 g (56.4 mmols) of dicyclohexylcarbodiimid are added to a solution of 18.1 g (56.4 mmols) of E-2-formylamino-4-methyl-5-diisopropylphosphono-pentenoic acid, 6.1 g (56.4 mmols) of benzyl alcohol and 0.7 g of 4-(N,N-dimethylamino)pyridine in 140 ml of dichloromethane. The reaction mixture is stirred 2 hours in an ice bath and 10 hours at room temperature. The reaction solution is filtrated clear, washed with diluted hydrochloric acid and twice with water, dried over magnesium sulfate and chromatographed over silica gel with first ethyl acetate and then ethyl acetate/isopropanol as eluent. Benzyl E-2-formylamino-4-methyl-5-diisopropylphosphono-3-pentenoate is obtained as an orange-colored oil which can be crystallized from diethyl ether/hexane; m.p. 50°-58°.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14](O)([CH3:16])[CH3:15])[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].CCN(S(F)(F)[F:24])CC.O>C(Cl)(Cl)Cl>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]([F:24])([CH3:16])[CH3:15])[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1cc(OCC(C)(C)O)ncn1
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC#CCOc1cc(OCC(C)(C)F)ncn1
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
First, 0.33 g of 4-(2-butynyloxy)-6-(2-hydroxy-2-methylpropyloxy)pyrimidine was dissolved in 3 ml of chloroform, to which 0.5 ml of a solution containing 0.25 g of DAST in chloroform was added dropwise at 0° C., followed by stirring for 30 minutes. The reaction mixture was then poured into water, which was extracted three times with chloroform. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.21 g of 4-(2-butynyloxy)-6-(2-fluoro-2-methylpropyloxy)pyrimidine (the present compound (28)).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:17][Mg]Cl>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:16])([CH3:17])[C:12]([F:13])([F:14])[F:15])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Br)ccc12)C(F)(F)F
Reactant: C[Mg]Cl
Product: CC(O)(c1c[nH]c2cc(Br)ccc12)C(F)(F)F

Procedure:
1-(6-Bromo-1H-indol-3-yl)-2,2,2-trifluoro-ethanone is treated with methylmagnesiumchloride at −78° C. to rt to obtain 2-(6-bromo-1H-indol-3-yl)-1,1,1-trifluoro-propan-2-ol, which is coupled with 8-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine following general procedure 2.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH2:15][OH:16])[CH:14]=1)[C:8]([O:10]C)=[O:9])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH2:15][OH:16])[CH:14]=1)[C:8]([OH:10])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(CO)cc(C(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cc(CO)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of methyl 3-tert-butyl-5-(hydroxymethyl)benzoate (3.0 g, 0.013 mol) in MeOH (20 mL) was added sodium hydroxide (0.54 g, 0.013 mol) in water (10 mL). The reaction mixture was allowed to stir at rt overnight and then concentrated. To the residue was added 1M HCl added (pH 5) and the resulting precipitate was collected by filtration to give 3-tert-butyl-5-(hydroxymethyl)benzoic acid (92%). LCMS ES−207.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[NH:5][C:6]=1[CH3:7].[NH2:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][C@@H:13]1[O:23][CH2:24][CH3:25].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][C@@H:13]2[O:23][CH2:24][CH3:25])=[O:10])[NH:5][C:6]=1[CH3:7]
Reactant: CCOC(=O)N1CC[C@@H](N)[C@@H](OCC)C1
Reactant: Cc1[nH]c(C(=O)O)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)N1CC[C@@H](NC(=O)c2cc(Cl)c(C)[nH]2)[C@@H](OCC)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To a solution of 4-chloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 27, 0.87 g, 5.55 mol) and ethyl (3S,4R)-4-amino-3-ethoxypiperidine-1-carboxylate (Intermediate 24, 1.2 g, 5.55 mmol) in dichloromethane (150 mL) was added HOBT (850 mg, 0.55 mmol) and N-methyl morpholine (1.82 mL, 1.66 mmol). The reaction mixture was stirred for 1 h at room temperature and EDC HCl (1.9 g, 9.99 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with the addition of 2N HCl (120 mL). The organic layer was washed with sodium bicarbonate (150 mL), water (150 mL) and brine, dried over anhydrous sodium sulphate, filtered, concentrated under vacuum. Purification by column chromatography (silica, 35% ethyl acetate in pet ether) afforded Ethyl (3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidine-1-carboxylate 1.6 g (80%) as brown solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@@H:5]([C:7]([O:9]C(C)(C)C)=[O:8])[N:4]([C:14](=[O:22])[C@H:15]([CH3:21])[CH2:16][S:17][C:18](=[O:20])[CH3:19])[C:3]1=[O:23].FC(F)(F)C(O)=O>>[CH3:1][N:2]1[CH2:6][C@@H:5]([C:7]([OH:9])=[O:8])[N:4]([C:14](=[O:22])[C@H:15]([CH3:21])[CH2:16][S:17][C:18](=[O:20])[CH3:19])[C:3]1=[O:23]
Reactant: CC(=O)SC[C@@H](C)C(=O)N1C(=O)N(C)C[C@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)SC[C@@H](C)C(=O)N1C(=O)N(C)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
A mixture of 0.72 g of tert.-butyl (4S)-1-methyl-3-[(2S)-3-acetylthio-2-methylpropionyl]-2-oxo-imidazolidine-4-carboxylate and 3.5 ml of trifluoroacetic acid is stirred at room temperature for one hour. Then, the reaction mixture is treated in the same manner as described in Example 1-(5). 0.6 g of (4S)-1-methyl-3-[(2S)-3-acetylthio-2-methylpropionyl]-2-oxo-imidazolidine-4-carboxylic acid is obtained as colorless syrup. Yield: quantitative.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C:4](Cl)=[O:5].[C:8]([SiH2:12][O:13][C:14]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:15]1[CH:20]=[CH:19][N:18]2[N:21]=[C:22]([CH3:24])[CH:23]=[C:17]2[CH:16]=1)([CH3:11])([CH3:10])[CH3:9].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[CH3:1][O:2][C:3](=[O:7])[C:4]([C:23]1[C:22]([CH3:24])=[N:21][N:18]2[CH:19]=[CH:20][C:15]([C:14]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[O:13][SiH2:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:16][C:17]=12)=[O:5]
Reactant: Cc1cc2cc(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)ccn2n1
Reactant: COC(=O)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1c(C)nn2ccc(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)cc12
Temperature: 120 °C
Yield: 91.8 %

Procedure:
In a reaction tube, chloro-oxo-acetic acid methyl ester (2.47 ml, 26.0 mmol, 4.0 equiv) is added to a solution of 5-(tert-butyl-diphenyl-silanyloxymethyl)-2-methyl-pyrazolo[1,5-a]pyridine (2.6 g, 6.49 mmol) in THF (20 ml) under an atmosphere of argon. The tube is sealed under argon, and the reaction mixture is heated under microwave irradiation for 15 minutes at 120° C. After cooling, the reaction mixture is carefully poured into an aqueous solution of sodium carbonate. After three extractions with EtOAc, the combined organic layers are dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (hexane/EtOAc 4:1) affords the title compound (2.9 g, 92%). 1H NMR (400 MHz, d6-DMSO): δ=8.76 (d, J=7.8 Hz, 1H), 8.11 (br s, 1H), 7.61-7.59 (m, 4H), 7.44-7.35 (m, 6H), 7.10 (dd, J=7.1/1.9 Hz, 1H), 4.88 (s, 2H), 3.82 (s, 3H), 2.41 (s, 3H), 1.03 (s, 9H). MS (ES+): 487 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]([NH:13][C:14]1[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:16][CH:15]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>CO>[CH2:3]([O:10][C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:25][CH:26]=1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)COc1ccc(NC(=O)OCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)COc1ccc(NC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
1.67 ml (1.67 mmol) of a 1N aqueous solution of sodium hydroxide were added, whilst ice-cooling, to a solution of 500 mg (1.52 mmol) of ethyl 4-(benzyloxycarbonylamino)phenoxyacetate (prepared as described in Preparation 14) in 10 ml of methanol, and the mixture was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was neutralized by the addition of 1N aqueous hydrochloric acid, and the solvent was removed by distillation under reduced pressure. The residue was diluted with ethyl acetate, and the resulting organic solution was washed with a 5% w/v aqueous solution of citric acid and with a saturated aqueous solution of sodium chloride, in that order. The reaction mixture was then dried over sodium sulfate, and the organic solvent was removed by distillation under reduced pressure. The concentrate was triturated with diethyl ether, to give 417 mg of the title compound as colorless crystals, melting at 152°-154° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([NH2:13])[CH2:7]2.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=O>C(O)C.[Pd]>[CH2:19]([O:18][C:14](=[O:17])[CH2:15][NH:13][CH:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][C:10]([F:12])=[CH:11][C:2]=2[F:1])[CH2:7]1)[CH3:20]
Reactant: NC1CCc2c(F)cc(F)cc2C1
Reactant: CCOC(=O)C=O
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CNC1CCc2c(F)cc(F)cc2C1
Yield: 85.1 %

Procedure:
A mixture of 5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine (6.0 g, 32.8 mmol), prepared as in Example 8, and ethyl glyoxylate (4.6 g, 36.0 mmol) in 300 mL of ethanol was hydrogenated over 10% palladium on carbon (0.75 g) for 10 hours. The mixture was filtered and concentrated by evaporation. Purification of the residue by column chromatography on silica gel (elution: 30% ethyl acetate/hexane) gave ethyl[(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino]acetate (7.5 g, 27.9 mmol) as an oil.
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:8]([C@@H:13]([C@H:15]([C:17]([O:19]CC)=O)[OH:16])[OH:14])([O:10]CC)=O.CO>O>[CH2:1]([NH:7][C:8](=[O:10])[C@@H:13]([C@H:15]([C:17]([NH:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[O:19])[OH:16])[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Reactant: CCCCCCN
Solvent: O
Solvent: CO
Product: CCCCCCNC(=O)[C@H](O)[C@@H](O)C(=O)NCCCCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14 %

Procedure:
N,N′-Di-n-hexyl L-tartaramide was prepared by the reaction of n-hexyl amine with diethyl L-tartrate. Diethyl L-tartrate (20.007 g, 1.0 eq) and HPLC grade methanol (40 mL) were weighed into a 250 mL round-bottomed flask equipped with a teflon coated magnetic stir bar. n-Hexyl amine (20.614 g, 2.0 eq) was slowly poured into the stirring diethyl L-tartrate solution. Some fuming and a color change from water-white to pale yellow were observed. Additional methanol (10 mL) was used to rinse all of the amine into the reaction flask. The product precipitated after stirring the solution for 30 min at ambient temperature. The white, waxy solid was filtered, washed with methanol (3×30 mL), washed with diethyl ether (2×30 mL), and dried under vacuum. The first crop of product was obtained in 14% yield (4.366 g, 13.80 mmole). A second crop of product was obtained by adding the combined filtrates to 50 mL of water. After filtering, washing with diethyl ether (2×30 mL), and drying under vacuum, 9.382 g of white, waxy solid were obtained. The combined reaction yield was 45%.