Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7]O)=[CH:2]1.C(N(CC)CC)C.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[N-:27]=[N+:28]=[N-:29].[Na+]>C(Cl)Cl.CN(C=O)C.CCOC(C)=O>[S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][N:27]=[N+:28]=[N-:29])=[CH:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: OCCc1ccsc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCc1ccsc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
2-(3-Thienyl)ethyl alcohol (2.62 g, 20.4 mmol) was dissolved in DCM (100 mL) and cooled to 0° C. After addition of triethylamine (3.10 g, 30.6 mmol) and solid tosyl chloride (3.89 g, 20.4 mmol), the reaction was stirred at room temperature overnight. DCM was evaporated, the mixture was diluted with EtOAc and washed subsequently with aqueous hydrochloric acid (1 N), water, saturated sodium hydrogen carbonate and brine. Drying and evaporation afforded an oil, which was dissolved in anhydrous DMF (20 mL). Sodium azide (2.65 g, 40.8 mmol) was added and the mixture heated to 40° C. for 3 h. After cooling to room temperature, EtOAc was added and the solution was washed with water (4×) and brine, then dried and evaporated. The resulting oil was filtered over silica gel (100 g) with the aid of PE/EtbAc (10:1) to obtain 2-(3-thienyl)ethyl azide (2.45 g, 78% ) as a colorless liquid. 1H-NMR (CDCl3) δ 7.3 (dd, J=2.9, 4.9 Hz, 1 H), 7.07 (m, 1 H), 6.98 (dd, J=1.2, 4.9 Hz, 1 H), 3.51 (t, J=7.1 Hz, 2 H), 2.94 (t, J=7.1 Hz, 2 H).
Reaction SMILES: ClC1C=CC=CC=1CN1C(CC(O)=O)=CN=C1SCCC.[CH2:22]([C:26]1[N:27]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[Cl:50])[C:28](/[C:31](/C)=C(\C2C=CN=CC=2)/C(O)=O)=[CH:29][N:30]=1)[CH2:23][CH2:24][CH3:25].[CH2:51]([CH:58]([C:64]1[S:65][CH:66]=[CH:67][CH:68]=1)[CH2:59][C:60]([O:62]C)=[O:61])[C:52]1[CH:57]=[CH:56]C=CC=1>>[CH2:22]([C:26]1[N:27]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[Cl:50])[C:28](/[CH:31]=[C:59](\[CH:58]([C:64]2[S:65][CH:66]=[CH:67][CH:68]=2)[CH2:51][CH2:52][CH2:57][CH3:56])/[C:60]([OH:62])=[O:61])=[CH:29][N:30]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCc1ncc(/C(C)=C(/C(=O)O)c2ccncc2)n1Cc1ccccc1Cl
Reactant: COC(=O)CC(Cc1ccccc1)c1cccs1
Agent: CCCSc1ncc(CC(=O)O)n1Cc1ccccc1Cl
Product: CCCCc1ncc(/C=C(/C(=O)O)C(CCCC)c2cccs2)n1Cc1ccccc1Cl

Procedure:
The title compound was prepared using the procedure of Example 1 (i, ii, iii, iv [Method B]) replacing methyl 3(2-thienyl)propanoate with methyl 3-benzyl-3-(2-thienyl)propanoate [prepared following the procedure described in Tetra. 44 (7) 2055 (1988)]; mp 200°-202° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)[OH:4].[CH:18]1[N:22]=[CH:21][N:20]([C:23](N2C=NC=C2)=[O:24])[CH:19]=1>C(#N)C>[N:20]1([C:23]([O:4][CH:3]([C:5]2[CH:6]=[N:7][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:10]=2)[CH:2]([CH3:17])[CH3:1])=[O:24])[CH:19]=[CH:18][N:22]=[CH:21]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)C(O)c1ccc(-c2ccccc2)nc1
Solvent: CC#N
Product: CC(C)C(OC(=O)n1ccnc1)c1ccc(-c2ccccc2)nc1

Procedure:
Synthesized using compound 43a (81 mg, 0.36 mmol), CDI (289 mg, 1.78 mmol) and acetonitrile (5 mL) according to Method E. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (4:1) as eluent. White solid. Yield: 90.0 mg, 90%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=0.95 (d, J=6.9 Hz, 3H), 1.14 (d, J=6.6 Hz, 3H), 2.37 (m, 1H), 5.70 (d, J=8.2 Hz, 1H), 7.09 (dd, J=1.6, 0.6 Hz, 1H), 7.40-7.51 (m, 4H), 7.72-7.79 (m, 2H), 7.98-8.03 (m, 2H), 8.19 (t, J=0.9 Hz, 1H), 8.71 (dd, J=2.2, 0.6 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=18.7, 18.8, 33.6, 83.7, 117.2, 120.4, 127.1, 129.0, 129.5, 131.1, 131.8, 135.6, 137.2, 138.8, 148.7, 158.0; MS (ESI): m/z=322.32 [M+H]+.
Reaction SMILES: [CH2:1]([CH:9]1[C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11][C:10]1=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C)C=O>[CH2:1]([C:9]1([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11][C:10]1=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCOC(=O)CBr
Reactant: CCCCCCCCC1C(=O)NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCC1(CC(=O)OCC)C(=O)NC(=O)NC1=O
Reaction time: 3 h

Procedure:
4.05 g of 5-octylbarbituric acid (preparation 7) are dissolved in 25 ml of dimethylformamide, 1.16 g of sodium carbonate are added. Ethyl bromoacetate (2.25 ml) is added dropwise to the reaction mixture in 5 minutes, then the mixture is kept at room temperature under stirring for about 3 hours. The reaction mixture is then partitioned between 400 ml of water, 17 ml of 1 N hydrochloric acid and 150 ml of ethyl acetate. The organic phase is separated and washed with 150 ml of water and 100 ml of brine, then it is dried over sodium sulfate. The aqueous phases are extracted with 100 ml of ethyl acetate and the organic extracts are pooled, dried over sodium sulfate and evaporated to dryness, to give 6.5 g an oily residue. This residue is purified by silica gel chromatography (eluant methylene chloride/ethyl acetate 9 1) to give 3.87 g of the product.
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[C:11]([C:14]1[S:15][CH:16]=[C:17]([CH3:19])[N:18]=1)(=[O:13])[CH3:12].CC(O)=O>CCCC(C)C.C1(C)C=CC=CC=1.O>[CH3:19][C:17]1[N:18]=[C:14]([C:11](=[O:13])[CH2:12][C:3]([O:7][CH2:8][CH3:9])=[O:10])[S:15][CH:16]=1
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1nc(C)cs1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCCC(C)C
Product: CCOC(=O)CC(=O)c1nc(C)cs1
Temperature: 80 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
NaH (60% in oil, 1.34 g, 33.5 mmol) was washed with isohexane (2×14 mL), suspended in toluene (25 mL), treated with diethyl carbonate (4.7 mL, 4.6 g, 38.8 mmol), heated to 80° C., treated dropwise over 20 min with a solution of 2-acetyl-4-methylthiazole (2.72 g, 19.2 mmol) in toluene (5 mL) and stirred at 80° C. for 2 h. The mixture was cooled to 0° C., treated dropwise with HOAc (4.65 mL, 4.9 g, 81 mmol) followed by ice (25 g) and water (50 mL) and stirred for 30 min. The aqueous phase was extracted with toluene (50 mL), the combined organic phase was washed with water (50 mL), dried (MgSO4) and concentrated in vacuo to give the crude product (3 g, 74%) as a dark red oil, used in the next step without further purification; NMR δH (400 MHz, CDCl3) 1.26 (3H, t, J 7.2 Hz), 2.92 (3H, s), 4.14 (2H, s), 4.18-4.25 (2H, m) and 7.31 (1H, s).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([NH:11]C(=O)C2C=CC=CC=2)=[S:10])[CH:5]=[CH:4][CH:3]=1.CC(C)=O.[OH-].[Na+]>CO>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([NH2:11])=[S:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC(=S)Nc1cccc(Br)n1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)=O
Product: NC(=S)Nc1cccc(Br)n1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
4.933 g (14.67 mmol) N-{[(6-bromopyridin-2-yl)amino]carbonothioyl}benzamide was suspended in 40 mL methanol and additionally combined with 7 mL acetone. After addition of 1 N sodium hydroxide solution (40.0 mmol) the reaction mixture became completely clear with a light brown color. The mixture was heated for 40 min at 65° C. (oil bath temperature) and then stirred for 1 hr at room temperature. A solid crystallized out. The organic solvent was removed under vacuum, and after cooling on an ice bath the solid was filtered off and washed with water. The solid was dried over phosphorus pentoxide in a dessicator under high vacuum (4×10 mbar). The desired product N-(6-bromopyridin-2-yl)thiourea was obtained in the form of colorless needles in a yield of 3.158 g (13.61 mmol, 93%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C:4]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:6]([C:7]([NH:9][CH:10]2[CH2:15][CH2:14][N:13](CC3C=C(OCC)C(F)=C(OCC)C=3)[CH2:12][CH2:11]2)=[O:8])[CH:5]=1.[CH:36]([O:39][C:40]1[CH:41]=[C:42]([CH:45]=[C:46]([O:48][CH:49]([CH3:51])[CH3:50])[CH:47]=1)[CH:43]=O)([CH3:38])[CH3:37].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:35])[C:4]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:6]([C:7]([NH:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:43][C:42]3[CH:41]=[C:40]([O:39][CH:36]([CH3:38])[CH3:37])[CH:47]=[C:46]([O:48][CH:49]([CH3:51])[CH3:50])[CH:45]=3)[CH2:14][CH2:15]2)=[O:8])[CH:5]=1
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(C(=O)OC)c3)CC2)cc(OCC)c1F
Reactant: CC(C)Oc1cc(C=O)cc(OC(C)C)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(OC)cc(C(=O)NC2CCN(Cc3cc(OC(C)C)cc(OC(C)C)c3)CC2)c1

Procedure:
In analogy to the procedure described in example 50k), 5-methoxy-N-piperidin-4-yl-isophthalamic acid methyl ester (example 143) was reacted with 3,5-diisopropoxy-benzaldehyde (example 126b), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50-C to yield the title compound as colorless oil. MS: 499.3 (MH+).
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][CH:8]=[C:9]2[C:14](=[O:15])OC(C)(C)OC2=O)[CH:2]=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[C:19]1([C:1]2[CH:2]=[C:3]3[C:4]([C:14]([OH:15])=[CH:9][CH:8]=[N:7]3)=[CH:5][CH:6]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC1(C)OC(=O)C(=CNc2cccc(-c3ccccc3)c2)C(=O)O1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Oc1ccnc2cc(-c3ccccc3)ccc12
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 96.7 %

Procedure:
5-(Biphenyl-3-ylaminomethylene)-2,2-dimethyl-[1,3]dioxane-4,6-dione (160.2 g, 496 mmol) was dissolved in 800 mL of DOWTHERM A heat transfer fluid at 100° C. and added over 40 min by way of a cannula line to 1.3 L of preheated DOWTHERM A heat transfer fluid to 215° C. After complete addition, the reaction was held at 215° C. for 90 min and then cooled to RT. The resulting solid was collected by filtration, sequentially washed with diethyl ether (1.7 L) and acetone (500 mL), and then dried in a vacuum oven at 70° C. overnight. The resulting product (74.5 g) contained approximately 5% of the undesired isomer. This product was combined with material from a separate run (51.4 g) and slurried in 440 mL of refluxing ethanol. Filtration of the slurry while hot followed by sequential ethanol and diethyl ether rinses afforded 106.1 g of 7-phenylquinolin-4-ol as a tan solid.
Reaction SMILES: C(Cl)(Cl)Cl.[N+:5]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[C:10]([F:16])[CH:9]=1)([O-:7])=[O:6].[CH2:17]([Si](C)(C)C)[CH:18]=[CH2:19]>C(OCC)(=O)C.[Ti](Cl)(Cl)(Cl)Cl>[F:16][C:10]1[CH:9]=[C:8]([N+:5]([O-:7])=[O:6])[CH:15]=[CH:14][C:11]=1[CH:12]([OH:13])[CH2:19][CH:18]=[CH2:17]
Reactant: C=CC[Si](C)(C)C
Reactant: O=Cc1ccc([N+](=O)[O-])cc1F
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: C=CCC(O)c1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.65 ml of titanium tetrachloride was added to a chloroform (12 ml) solution of 2.00 g of 4-nitro-2-fluoro-benzaldehyde produced according to the method described in U.S. Pat. No. 6,239,152, and the reaction liquid was stirred at room temperature for 10 minutes, and then 2.4 ml of allyl-trimethyl-silane was added to it, and the reaction liquid was stirred at room temperature for 20 minutes. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=3/1) to obtain the entitled compound as an orange solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]2[CH:11]=[C:12]([N+:18]([O-:20])=[O:19])[C:13]([C:16]#[N:17])=[N:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].O.C([O-])([O-])=[O:23].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]2[CH:11]=[C:12]([N+:18]([O-:20])=[O:19])[C:13]([C:16]([NH2:17])=[O:23])=[N:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#Cc1ncc(Cc2ccc(F)c(F)c2)cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: NC(=O)c1ncc(Cc2ccc(F)c(F)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-[(3,4-difluorophenyl)methyl]-3-nitro-2-pyridinecarbonitrile (3.39 g, 12.32 mmol) in acetone (60 ml), was added water (23 ml), urea-hydrogen peroxide complex (19.69 g, 209 mmol), and K2CO3 (2.04 g, 14.78 mmol). The reaction mixture was stirred at room temperature for 30 minutes and the acetone was evaporated without using heat. The resulting precipitate was collected by filtration and thoroughly washed with water to afford a yellow solid. 1H NMR (d6-DMSO) δ 8.79 (1H, s), 8.33 (1H, s), 8.21 (1H, br s), 7.87 (1H, s), 7.49-7.40 (1H, m), 7.38-7.33 (1H, m), 7.19-7.16 (1H, m), 4.12 (2H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C@@H:11]1/[CH:17]=[CH:18]/[CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C@@H:11]1[CH2:17][CH2:18][CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: [H][H]
Reactant: CCCCCC(O)/C=C/[C@H]1CCCC(=O)N1CCCCCCC(=O)OC
Agent: [Pd]
Solvent: CO
Product: CCCCCC(O)CC[C@H]1CCCC(=O)N1CCCCCCC(=O)OC
Reaction time: 18.5 h
Yield: 8.4 %

Procedure:
Palladium on carbon (10 wt. %, 7 mg) was added to a solution of 7-[(R)-2-((E)-3-hydroxy-oct-1-enyl)-6-oxo-piperidin-1-yl]-heptanoic acid methyl ester (33 mg, 0.90 mmol) in MeOH (3.0 mL). A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 18.5 h. The reaction mixture was filtered through celite, washing with MeOH, and the filtrate was concentrated in vacuo to afford 28 mg (84%) of the title compound.
Reaction SMILES: ON=[C:3]([C:9]1[N:10]=[C:11]([NH2:14])[S:12][CH:13]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].C([OH:17])C.S(=O)(O)[O-].[Na+]>O>[NH2:14][C:11]1[S:12][CH:13]=[C:9]([C:3](=[O:17])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:10]=1
Reactant: CCO
Reactant: CCOC(=O)C(=NO)c1csc(N)n1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(=O)c1csc(N)n1
Reaction time: 12 h

Procedure:
A mixture of ethyl 2-hydroxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (a mixture of syn and anti isomers) (0.37 g), ethanol (5 ml), water (5 ml) and sodium bisulfite (0.72 g) was stirred for 12 hours at 65° to 70° C. The reaction mixture was concentrated and water (10 ml) was added to the residue. The resulting mixture was subjected to salting-out and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated to give yellow crystals of ethyl 2-(2-amino-1,3-thiazol-4-yl)glyoxylate (0.18 g), mp 115° to 120° C.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH2:8])[CH3:3].C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+].[CH2:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][C:20]1=O>CO>[ClH:1].[CH2:2]([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH:8][CH:20]1[CH2:19][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)[CH3:3]
Reactant: O=C1Cc2ccccc2C1
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CO
Product: CCOC(=O)CCNC1Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 43.8 %

Procedure:
In a solution of 13 g of 2-indanone in 100 ml of methanol, there is dissolved 13 g of β-alanine ethyl ester hydrochloride, and, with ice cooling and stirring, 6.5 g of sodium cyanoborohydride is added portionwise. After standing at room temperature overnight, the mixture is poured into 500 ml of ice water, made alkaline with sodium hydrogen carbonate and extracted with 200 ml of chloroform. The extract is washed with water, and dried, followed by distilling off chloroform under reduced pressure. To the residue, 10 ml of 20% ethanolic hydrochloric acid and 50 ml of ethyl ester are added successively, and the mixture is allowed to stand at room temperature. The resulting precipitate is collected by filtration and dried to give 10 g of N-(indan-2-yl)-β-alanine ethyl ester hydrochloride as colorless scales melting at 150°-151° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]([C:16]([O:18]C)=[O:17])=[CH:12][C:3]=1[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][S:7][C:6]1=[O:11].[OH-:20].[Na+]>C1COCC1>[C:16]([C:13]1[CH:14]=[CH:15][C:2]([Cl:1])=[C:3]([CH2:4][CH:5]([CH2:10][CH2:9][CH2:8][SH:7])[C:6]([OH:11])=[O:20])[CH:12]=1)([OH:18])=[O:17]
Reactant: [OH-]
Reactant: COC(=O)c1ccc(Cl)c(CC2CCCSC2=O)c1
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cl)c(CC(CCCS)C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
A solution of 3-(2-Chloro-5-methoxycarbonylbenzyl)-tetrahydrothiopyrane-2-one IV (9.26 g, 31.0 mmol) in THF (70 mL) was purged for 15 minutes with nitrogen. A degassed aqueous sodium hydroxide solution (2.2 M, 70 mL, 154 mmol) was added to the solution and the mixture was stirred at room temperature under nitrogen overnight. The reaction mixture was washed with ether, acidified by 3N HCl at 0° C., and extracted with ether. The extract was dried over MgSO4 and concentrated to afford 5-carboxy-2-chloro-alpha-(3-mercaptopropyl)benzenepropanoic acid 10 (8.42 g, 27.8 mmol, 90%) as a white solid: 1H NMR (CD3OD) δ 1.50-1.80 (m, 4H), 2.35-2.50 (m, 2H), 2.65-2.75 (m, 1H), 2.91 (dd, J=6.2, 13.8 Hz, 1H), 2.96 (dd, J=8.8, 13.8 Hz, 1 H), 7.39 (d, J=8.3 Hz, 1H), 7.76 (dd, J=2.0, 8.3 Hz, 1H), 7.86 (d, J=2.0 Hz, 1H); 13C NMR (CD3OD) δ 25.1, 32.5, 33.2, 37.4, 46.8, 130.8, 131.2, 134.0, 139.1, 140.5, 169.2, 178.9. Anal. Calcd for C13H15ClO4S: C, 51.57; H, 4.99; S, 10.59; Cl, 11.71. Found: C, 51.59; H, 4.94; S, 10.43; Cl, 11.80.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1[C:39](C)=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:41].C(N1C=CC(N)=N1)C1C=CC=CC=1>C(Cl)Cl>[CH2:21]([N:18]1[CH:19]=[CH:20][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([Cl:1])[CH:3]=2)[CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)=[N:17]1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:41]=1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reactant: Cc1cccc(C)n1
Agent: Nc1ccn(Cc2ccccc2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3ccccc3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
To a solution containing 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 100 mg, 0.30 mmol) in methylene chloride (20 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (181 μL, 0.36 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (70 μL, 0.61 mmol) was added to the solution at 0° C. After 1 h, crude 1-benzyl-1H-pyrazol-3-ylamine (0.42 mmol based on theory) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford N-(1-benzyl-1H-pyrazol-3-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (101 mg, 69%) as a white solid: ESI-LRMS m/e calcd for C25H28ClN3O3S [M+] 485.2, found 486.4 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.05-1.18 (m, 2H, CH2), 1.40-1.91 (m, 8H, 4×CH2), 2.10-2.31 (m, 1H, CH), 3.23 (s, 3H, SO2CH3), 3.56 (t, J=7.6 Hz, 1H, CH), 5.12 (s, 2H, NCH2), 6.69 (d, J=2.3 Hz, 1H, Ar), 7.12 (dd, Jo=7.2, Jm=1.7 Hz. 2H, Ar), 7.26-7.33 (m, 4H, Ar), 7.43 (dd, Jo=8.2, Jm=1.6 Hz. 1H, Ar), 7.57 (d, Jm=1.6 Hz, 1H, Ar), 8.04 (d, Jo=8.2 Hz. 1H, Ar), 8.27 (brs, 1H, NH).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:7]([N:24]=[C:25]([NH2:27])[N:26]=3)[C:8]([CH2:12][C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=4)[NH:15][CH:14]=3)=[N:9][C:10]=2[CH:11]=1.O1C2C=CC(CC3N4N=C(N)N=C4C4C=CC(F)=CC=4N=3)=CC=2OC1.[OH:53][CH2:54][CH2:55][NH2:56]>>[NH2:27][C:25]1[N:26]=[C:6]2[N:7]([C:8]([CH2:12][C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=4)[NH:15][CH:14]=3)=[N:9][C:10]3[CH:11]=[C:2]([NH:56][CH2:55][CH2:54][OH:53])[CH:3]=[CH:4][C:5]=32)[N:24]=1
Reactant: NCCO
Reactant: COc1ccc2[nH]cc(Cc3nc4cc(F)ccc4c4nc(N)nn34)c2c1
Agent: Nc1nc2c3ccc(F)cc3nc(Cc3ccc4c(c3)OCO4)n2n1
Product: COc1ccc2[nH]cc(Cc3nc4cc(NCCO)ccc4c4nc(N)nn34)c2c1
Yield: 35 %

Procedure:
Operating as in Example 54, but employing 8-fluoro-5-(5-methoxy-1H-indol-3-ylmethyl)-[1,2,4]triazolo[1,5-c]quinazolin-2-ylamine, prepared as described in Example 32, instead of 5-benzo[1,3]dioxol-5-ylmethyl-8-fluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-ylamine and 2-hydroxy-ethylamine instead of morpholine, the title compound was obtained in 35% yield.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH2:2]1.C([Li])CCC.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Br>C1COCC1.CCCCCC.C(Cl)Cl>[F:12][C:13]1[CH:14]=[C:15]([CH2:16][CH:2]2[S:3][CH2:4][CH2:5][CH2:6][S:1]2)[CH:18]=[CH:19][CH:20]=1
Reactant: C1CSCSC1
Reactant: Fc1cccc(CBr)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCCCCC
Product: Fc1cccc(CC2SCCCS2)c1
Temperature: -23 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
1,3-Dithiane (12 g, 0.1 mol) was dissolved in 150 mL of anhydrous THF under a nitrogen atmosphere. The resultant solution was cooled to -78° C. and n-butyllithium (44 mL of a 2.5M solution of in hexane, 0.11 mol) was added. The reaction mixture was warmed to -23° C. and then stirred at -23° C. for 0.5 h. The reaction mixture was recooled to -78° C. and 25 g (0.135 mol) of 3-fluorobenzyl bromide was added over a 15 minute period. The reaction mixture was stirred for 3 h at ambient temperature and then diluted with methylene chloride, washed with aqueous ammonium chloride solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was distilled to afford 15.2 g (66.7% yield) of the title compound, b.p. 135°-140° C. (0.5 mm Hg); MS DCI-NH3M/Z: 229 (M+H)+ ; 1H NMR (CDCl3) δ1.77-1.95 (1H, m), 2.05-2.18 (1H, m), 2.8-2.9 (4H, m), 3.02 (2H, d, J=7.5 Hz), 4.23 (1H, t, J=7.5 Hz), 6.9-7.1 (3H, m), 7.23-7.33 (1H, m).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]=2[N:4]=[C:3]1[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH4-].[Na+].O>CO>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]([OH:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]=2[N:4]=[C:3]1[CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)CC(=O)c1cccc2c1nc(CCc1ccccc1)n2C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)CC(O)c1cccc2c1nc(CCc1ccccc1)n2C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 48.5 %

Procedure:
To a suspension of ethyl 3-(1-methyl-2-(2-phenylethyl)benzimidazol-4-yl)-3-oxopropanoate (0.80 g) obtained in Inventive Example 10 in anhydrous methanol (16 mL), was added sodium borohydride in small portions which was cooled in an ice bath. After stirring for 20 minutes at room temperature, the reaction solution was poured into water and concentrated under a reduced pressure. The thus obtained residue was extracted with ethyl acetate, and the organic layer was washed with water and brine in that order. The organic layer was dried over anhydrous sodium sulfate and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain the title compound as white crystal (0.39 g).