Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl>C1COCC1>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:2]2[CH:10]=[N:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:15][CH:14]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(O)c1ccncc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Nc2cnccc2C(=O)O)cc1
Temperature: -78 °C
Yield: 13 %

Procedure:
3-Fluoro-isonicotinic acid (50 mg, 0.354 mmol) and p-anisidine (44 mg, 0.354 mmol) was added to 2 ml dry THF and the mixture was cooled to −78° C. LiHMDS (1M in THF, 1.24 ml) was added and the mixture was allowed to warm to room temperature over night. Hydrochloric acid (1M in methanol, 5 ml) was added and the volatiles were removed in vacuo. The crude material was purified by preparative RP chromatography to give 11 mg (45 μmol; 13% yield) of pure desired product. LC-MS (method V): rt=1.82 min; m/z [M+H]+ 245.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:23])[CH2:7][N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:22])=[C:16]([C:18]([O:20]C)=[O:19])[S:17][C:11]=2[N:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].O.O.[OH-].[Li+]>C1COCC1.CO>[C:1]([NH:5][C:6](=[O:23])[CH2:7][N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:22])=[C:16]([C:18]([OH:20])=[O:19])[S:17][C:11]=2[N:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1sc2ncn(CC(=O)NC(C)(C)C)c(=O)c2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(=O)O)sc2ncn(CC(=O)NC(C)(C)C)c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
To a solution of methyl 3-(2-(tert-butylamino)-2-oxoethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate, (3.3 g, 10 mmol) in THF (30 mL), MeOH (10 mL), and H2O (10 mL) was added lithium hydroxide monohydrate (1.26 g, 30 mmol). The reaction mixture was stirred at RT overnight. The reaction mixture was concentrated, diluted with H2O (30 mL) and washed with DCM (2×30 mL). The aqueous layer was acidified (pH˜2) with 1M HCl and the resultant precipitate was filtered and dried to give 1.8 g of 3-(2-(tert-butylamino)-2-oxoethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid (yield: 55%).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH2:10][CH2:11][CH3:12])=[C:8]([F:13])[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.O[NH3+:16].S(Cl)(Cl)=O.O>CN1CCCC1=O>[Cl:1][C:2]1[C:9]([CH2:10][CH2:11][CH3:12])=[C:8]([F:13])[CH:7]=[CH:6][C:3]=1[C:4]#[N:16]
Reactant: CCCc1c(F)ccc(C=O)c1Cl
Reactant: [NH3+]O
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Solvent: O=S(Cl)Cl
Product: CCCc1c(F)ccc(C#N)c1Cl
Temperature: 100 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a solution of 2-chloro-4-fluoro-3-propylbenzaldehyde (877 mg) in 1-methyl-2-pyrrolidone (15 mL) was added hydroxyammonium hydrochloride (383 mg), and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was ice-cooled, thionyl chloride (1.00 mL) was added dropwise thereto, and the mixture was stirred at the same temperature for 10 min. Water was added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate=15:1→2:1) to give the title compound as a colorless oil (yield: 660 mg).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([OH:18])[N:12]=[CH:11]2.C(O)(C)(C)C.C1(C)C=CC=CC=1.CC(=O)CC.[C:36]([CH:40]1[CH2:45][CH2:44][CH:43](OS(C)(=O)=O)[CH2:42][CH2:41]1)([CH3:39])([CH3:38])[CH3:37]>>[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([O:18][CH:43]1[CH2:44][CH2:45][CH:40]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:41][CH2:42]1)[N:12]=[CH:11]2
Reactant: Oc1ncc2cc(Br)ccc2n1
Reactant: CC(C)(C)C1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Solvent: CCC(C)=O
Product: CC(C)(C)C1CCC(Oc2ncc3cc(Br)ccc3n2)CC1
Temperature: 110 °C
Yield: 20 %

Procedure:
Cesium carbonate (3.1308 g, 9.6089 mmol) was added to a mixture of 6-bromoquinazolin-2-ol (1.0812 g, 4.8044 mmol) in tert-butyl alcohol (15 mL, 160 mmol), toluene (25 mL, 230 mmol) and 2-butanone (10 mL, 100 mmol). The mixture was heated at 110° C. for 1 hour in a sealed tube then cooled to room temperature and methanesulfonic acid 4-tert-butyl-cyclohexyl ester (2.2519 g, 9.6089 mmol) was added. The reaction was then heated at 110° C. overnight. The reaction mixture was cooled to room temperature then filtered through a pad of celite. The filtrate was concentrated under reduced pressure, adsorbed onto silica gel and purified by flash chromatography (80 g SiO2 column; 0-40% EtOAc in heptane eluent) to give the title compound in 20% yield. ESI-MS (M+H+): 365.1
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH:9]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10]1.[CH2:16](I)[CH2:17][CH2:18][CH3:19].Cl>C1COCC1.CCCCCCC.C(C1C=CC=CC=1)C.C1COCC1>[CH2:16]([C:9]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10]1)[CH2:17][CH2:18][CH3:19]
Reactant: O=C(O)C1CCC1
Reactant: CCCCI
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Product: CCCCC1(C(=O)O)CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of LDA (30 mL, 2.0M, 60 mmol) in THF/heptane/ethylbenzene and anhydrous THF (30 mL) at 0° C. was added cyclobutane carboxylic acid (3.0 g, 30 mmol) dropwise. After addition was complete, the cold bath was removed, the reaction mixture was stirred at room temperature for 2 hr. Neat n-BuI (3.41 mL, 30 mmol) was added dropwise at room temperature. The mixture was stirred over night. To the mixture was added 2N HCl and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water and brine to afford the title compound as a light yellow oil (quantitative), which was used in the next step without purification.
Reaction SMILES: [NH:1]([C:47]([CH3:49])=[O:48])[C@H:2]([C:12]([NH:14][C@H:15]([C:27]([NH:29][C@H:30]([C:32]([NH:34][C@H:35]([C:37]([O:39]CC1C=CC=CC=1)=[O:38])[CH3:36])=[O:33])[CH3:31])=[O:28])[CH2:16][C:17](=[O:26])[O:18]CC1C=CC=CC=1)=[O:13])[CH2:3][O:4]CC1C=CC=CC=1.CO.O.ClCl.CC1C=C(C2C=CC(N)=C(C)C=2)C=CC=1N>CCCCO.CC(O)=O.CCOC(C)=O.O.CC(O)=O>[NH:1]([C:47]([CH3:49])=[O:48])[C@H:2]([C:12]([NH:14][C@H:15]([C:27]([NH:29][C@H:30]([C:32]([NH:34][C@H:35]([C:37]([OH:39])=[O:38])[CH3:36])=[O:33])[CH3:31])=[O:28])[CH2:16][C:17](=[O:18])[OH:26])=[O:13])[CH2:3][OH:4]
Reactant: CC(=O)N[C@@H](COCc1ccccc1)C(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1
Agent: Cc1cc(-c2ccc(N)c(C)c2)ccc1N
Agent: ClCl
Solvent: O
Solvent: CCCCO
Solvent: CC(=O)O
Product: CC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)O
Yield: 86.3 %

Procedure:
Ac-Ser(Bzl)-Asp(OBzl)-Ala-Ala-OBzl (0.6 g, 0.888 mmol) was hydrogenated in a Parr apparatus at 50 psi in the presence of 0.62 g catalyst (5% Pd on BaSO4) in a solvent mixture consisting of 35 ml MeOH, 15 ml H2O, and 1 ml HOAc for 4 hours. The catalyst was filtered off and the filtrate concentrated to a smaller volume and lyophilized to give 0.38 g crude material. Tlc showed two minor contaminants in addition to the major component. The compound was then purified on a Bio-Rad AGl×2 column (3×24 cm) which was washed with 0.2 M NaOH, H2O, 0.2 M HOAc, and equilibrated with pH 8.5 buffer of 0.025 M ammonium acetate. The sample was applied at this pH and the column eluted with 250 ml each of the following acetic acid solutions in the order of: 0.25 M, 0.5 M, 1.0 M, 1.5 M, 2.0 M, 2.5 M, 3.0 M, 3.5 M, 4.0 M, and 4.5 M. The flow rate was adjusted to approximately 50 ml/hr and each 10 ml fraction was collected into an LKB fraction collector. The compound was located by spotting a 5 μl portion from each tube on silica get tlc plate (Merck 60, F-254) and developed in the solvent system of n-BuOH:HOAc:EtOAc:H2O (1:1:1:1) and then stained with chlorine-tolidine reaction. The fractions containing the major component were pooled and lyophilized twice to give 310 mg (86.3%) of the desired product; [α]D25 =-77.01° (c 1, 10% HOAc).
Reaction SMILES: [CH3:1][C:2]([S@:5](/[N:7]=[CH:8]/[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][C@@H:14]([NH:19][C:20](=[O:34])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C@@H:29]3[CH2:33][CH2:32][CH2:31][O:30]3)=[CH:23][CH:22]=1)[CH2:13][CH2:12]2)=[O:6])([CH3:4])[CH3:3].[CH2:35](OCC)C.ClCCl.C[Mg]Br>O>[CH3:4][C:2]([S@:5]([NH:7][C@H:8]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][C@@H:14]([NH:19][C:20](=[O:34])[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][C@@H:29]3[CH2:33][CH2:32][CH2:31][O:30]3)=[CH:25][CH:26]=1)[CH2:13][CH2:12]2)[CH3:35])=[O:6])([CH3:1])[CH3:3]
Reactant: CCOCC
Reactant: CC(C)(C)[S@@](=O)/N=C/c1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2
Agent: C[Mg]Br
Solvent: O
Solvent: ClCCl
Product: C[C@H](N[S@](=O)C(C)(C)C)c1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A suspension, cooled to −45° C., of N-((S)-6-{[(E)-(R)-2-methylpropane-2-sulfinylimino]methyl}-1,2,3,4-tetrahydronaphthalen-2-yl)-4-[(S)-1-(tetrahydrofuran-2-yl)methoxy]benzamide (0.34 g), diethyl ether (15 ml) and dichloromethane (15 ml) was admixed with methylmagnesium bromide (1.1 ml; 1.4 M in toluene). After warming to room temperature, the mixture was stirred for another 5 hours. The reaction mixture was hydrolyzed cautiously with water and extracted with ethyl acetate. The organic phase was washed with sodium chloride solution, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluent: ethyl acetate). The product was thus obtained with the molecular weight of 498.69 (C28H38N2O4S); MS (ESI): 499 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:22])[C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[CH3:8].[C:23](N1C=CN=C1)([N:25]1[CH:29]=[CH:28][N:27]=[CH:26]1)=[S:24].O>CN(C)C1C=CN=CC=1.O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([O:22][C:23]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)=[S:24])[C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(C(O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1F
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(OC(=S)n2ccnc2)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1F
Temperature: 25 °C
Yield: 47 %

Procedure:
Tert-butyl (2S)-2-[(3-fluoro-4-methylphenyl)(hydroxy)methyl]pyrrolidine-1-carboxylate (1.30 g, 4.19 mmol), which had been obtained in Example 1 (1b), 1,1′-thiocarbonyldiimidazole (1.12 g, 6.28 mmol), and 4-(dimethylamino)pyridine (0.05 g, 0.42 mmol) were dissolved in tetrahydrofuran (8.4 mL) and stirred with heating under reflux for 16 hours. The reaction solution was cooled to room temperature. Water (20 mL) was added to the reaction solution, which was then extracted with ethyl acetate (20 mL×3). After that, the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=2/1) to give the title compound as a yellow wax like substance (0.83 g, yield 47%).
Reaction SMILES: CO.[CH3:3][O:4][C:5]1[CH:6]=[C:7](/[CH:11]=[CH:12]/[C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:15]([N+:26]([O-])=O)[CH:14]=2)[CH:8]=[CH:9][CH:10]=1>[C].[Pd].C(OCC)(=O)C>[NH2:26][C:15]1[CH:14]=[C:13]([CH2:12][CH2:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH3:3])[CH:6]=2)[CH:25]=[CH:24][C:16]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: COc1cccc(/C=C/c2ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c2)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cccc(CCc2ccc(C(=O)OC(C)(C)C)c(N)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
To a mixed solution of methanol 22 mL and ethyl acetate 22 mL of tert-butyl 4-((E)-2-(3-methoxyphenyl)vinyl)-2-nitrobenzoate 2.2 g was added 10% palladium-carbon 0.66 g, and it was stirred under hydrogen atmosphere at room temperature for 2 hours. The solvent was removed under reduced pressure after insoluble matter was filtrated. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; hexane:ethyl acetate=8:1] to give tert-butyl 2-amino-4-(2-(3-methoxyphenyl)ethyl)benzoate 1.6 g of colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:21]=[C:20]2[C:11]([N:12]3[C:17]([CH2:18][O:19]2)=[N:16][NH:15][C:14](=[O:22])[C@H:13]3[CH3:23])=[CH:10][C:9]=1[C@H:24]([C:26]1([CH3:30])[CH2:29][NH:28][CH2:27]1)[CH3:25].C=O.[BH3-][C:34]#N.[Na+].C([O-])(O)=O.[Na+]>CC(O)=O.CO>[CH3:34][N:28]1[CH2:29][C:26]([C@@H:24]([C:9]2[CH:10]=[C:11]3[C:20](=[CH:21][C:8]=2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[O:19][CH2:18][C:17]2[N:12]3[C@H:13]([CH3:23])[C:14](=[O:22])[NH:15][N:16]=2)[CH3:25])([CH3:30])[CH2:27]1
Reactant: [BH3-]C#N
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)c([C@@H](C)C4(C)CNC4)cc3N21
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)c([C@@H](C)C4(C)CN(C)C4)cc3N21
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.1 %

Procedure:
To a solution of (R)-7-(2-fluoro-phenyl)-4-methyl-6-[(R)-1-(3-methyl-azetidin-3-yl)-ethyl]-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.04 g, 0.098 mmol) in AcOH (0.5 mL) and MeOH (5 mL) was added paraformaldehyde (0.029 g, 0.979 mmol) and the resulting mixture was stirred at ambient temperature for 1 h. NaBH3CN (0.015 g, 0.245 mmol) was added and the reaction mixture was stirred at ambient temperature overnight. Aqueous NaHCO3 (10 mL) was added and the aqueous solution was extracted with EtOAc (3×30 mL). The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated in vacuo and the residue was purified by prep-HPLC (Table 3, Method 25) to give (R)-6-[(R)-1-(1,3-dimethyl-azetidin-3-yl)-ethyl]-7-(2-fluoro-phenyl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.017 g, 40%). 1H NMR (CD3OD, 400 MHz): δ 7.40-7.48 (m, 1H), 7.15-7.32 (m, 3H), 6.91 (s, 1H), 6.84 (s, 1H), 4.83 (m, 1H), 4.58-4.69 (m, 2H), 2.87-3.19 (m, 3H), 2.73-2.87 (m, 2H), 2.10-2.22 (m, 3H), 1.50 (m, 3H), 1.25-1.35 (m, 3H), 1.13-1.23 (m, 3H). LC/MS (Table 1, Method 4) Rt=1.858 min; MS m/z: 423 [M+H]+. SFC (Table 1, Method 15) Rt=1.592 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([CH3:16])[C:3]=1[CH2:17][C:18]1([CH3:40])[C:22](=[O:23])[O:21]C(C2C=CC=CC=2)[N:19]1[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].CO.[OH-].[Na+]>C(Cl)Cl>[CH3:40][C:18]([NH:19][C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])([CH2:17][C:3]1[C:4]([CH3:16])=[CH:5][C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][C:2]=1[CH3:1])[C:22]([OH:23])=[O:21]
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1CC1(C)C(=O)OC(c2ccccc2)N1C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(OCc2ccccc2)cc(C)c1CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reaction time: 3 h
Yield: 86.6 %

Procedure:
The title compound of Example 54 (2.42 g) was dissolved in 5 ml of 1:1 CH2Cl2 : methanol, and added to methanolic NaOH (1N, 100 ml). After 3 hr of stirring, the mixture was concentrated to 75 ml, diluted to 500 ml with water, and extracted twice with ether to remove non-acidic contaminants. The aqueous phase was made acidic with 0.5N KHSO4, and then extracted four times with CH2Cl2. The CH2Cl2 fractions were combined, dried (MgSO4), filtered, and stripped to give the title compound (1.75 g). NMR:α methyl group at ∫2.75.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([C:11]1[NH:15][N:14]=[C:13]([C:16](O)=[O:17])[C:12]=1[N+:19]([O-:21])=[O:20])[CH:8]([CH3:10])[CH3:9].C[N:23](C)C=O>ClCCl>[CH2:7]([C:11]1[NH:15][N:14]=[C:13]([C:16]([NH2:23])=[O:17])[C:12]=1[N+:19]([O-:21])=[O:20])[CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)Cc1[nH]nc(C(=O)O)c1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(C)Cc1[nH]nc(C(N)=O)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (10 ml, 115 mmol) was added dropwise to a suspension of 5-isobutyl-4-nitro-1H-pyrazol-3-carboxylic acid (5.6 g, 26 mmol) in dichloromethane (70 ml) containing dimethylformamide (0.1 ml) under nitrogen at 0° C. The reaction was stirred at 0° C. for 0.5 hours, allowed to warm to room temperature and stirred for a further 2 hours. The solvent was removed under reduced pressure, the residue was azeotroped with dichloromethane (3×50 ml) and the residue was dissolved in toluene (100 ml). Ammonia gas was bubbled into the solution for 2 hours and the reaction was stirred under nitrogen at room temperature for 18 hours, concentrated under reduced pressure and the residue was suspended in methanol (250 ml). After filtration, the filtrates were concentrated under reduced pressure, the residue was dissolved in ethyl acetate (400 ml) and washed with water (50 ml). The organic phase was filtered, the filtrate was dried over MgSO4 and concentrated under reduced pressure. The filtered solid and residue from the filtrates were combined to give 5-isobutyl-4-nitro-1H-pyrazol-3-carboxylic acid amide (4.8 g) as an off-white solid. 1H NMR (400 MHz, DMSO-D6): δ=13.61-13.81 (1H, brs), 7.80-7.96 (1H, brs), 7.50-7.66 (1H, brs), 2.70-2.76 (2H, d), 1.90-2.01 (1H, m), 0.83-0.88 (6H, d) ppm. LRMS (electrospray): m/z [M+Na]+ 235, [2M+Na]+ 447, [M−H]+ 211, [2M−H]+ 423. Anal. Found C, 45.12; H, 5.68; N, 26.31. C8H12N4O3 requires C, 45.28; H, 5.70; N, 26.40%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:13](OC)(=[O:17])[C:14]([CH3:16])=[CH2:15].CC(C)([O-])C.[K+].Cl>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[C:13](=[O:17])[C@@H:14]([CH3:16])[CH2:15][C@@H:8]2[C:9]([O:11][CH3:12])=[O:10]
Reactant: C=C(C)C(=O)OC
Reactant: COC(=O)Cc1cccc(F)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1C[C@H](C)C(=O)c2ccc(F)cc21
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl 3-fluorophenylacetate (prepared from 3 fluorophenylacetic acid (Aldrich Chem. Co., Madison, Wis.) via esterification with methanol catalyzed by gaseous HCl) in anhydrous N,N-dimethylformamide (40 mL) warmed to 70° C. was added methyl methacrylate (5.8 mL) and potassium tertbutoxide (0.55 gm). After 15 minutes, aqueous 1N HCl (75 mL) was added, and the mixture extracted with diethyl ether. The organic extracts were washed with H2O, brine, dried (Na2SO4, filtered and evaporated. The residue was dissolved in concentrated H2SO4 (80 mL)/H2O (20 mL), and warmed to 70° C. for 3 hours, then poured onto crushed ice, and the mixture extracted with ethyl acetate. The extracts were washed with H2O, brine, dried (Na2SO4, filtered and evaporated. The oily residue was dissolved in methanol (250 mL), and the solution saturated with gaseous HCl. After 30 minutes, the mixture was purged with nitrogen, and concentrated under reduced pressure. The oily residue was partitioned between H2O (500 mL), and ethyl acetate, and the organic layer washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo to yield the title compound (10.9 gm, Rf (1:1 diethyl ether/SiO2)=0.4).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([C@@H:14]1[C:20]2=[CH:21][C:22]3[CH2:23][O:24][CH2:25][C:26]=3[CH:27]=[C:19]2[NH:18][CH2:17][CH2:16][CH2:15]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[CH3:37][O:38][C:39](=[O:47])[CH2:40][C:41]([CH3:46])([CH3:45])[CH2:42][CH:43]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.ClCCl>[CH3:37][O:38][C:39](=[O:47])[CH2:40][C:41]([CH3:46])([CH3:45])[CH2:42][CH2:43][N:18]1[C:19]2[C:20](=[CH:21][C:22]3[CH2:23][O:24][CH2:25][C:26]=3[CH:27]=2)[C@@H:14]([N:7]([CH2:6][C:5]2[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=[C:3]([C:2]([F:1])([F:35])[F:36])[CH:4]=2)[C:8]2[N:9]=[N:10][N:11]([CH3:13])[N:12]=2)[CH2:15][CH2:16][CH2:17]1
Reactant: COC(=O)CC(C)(C)CC=O
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCNc3cc4c(cc32)COC4)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COC(=O)CC(C)(C)CCN1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2cc3c(cc21)COC3
Reaction time: 12 h

Procedure:
To a solution of (S)-(3,5-bis-trifluoromethyl-benzyl)-(3,5,6,7,8,9-hexahydro-1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine (0.195 mmol) in dichloroethane (5 mL), add 3,3-dimethyl-5-oxo-pentanoic acid methyl ester (0.585 mmol) along with a catalytic amount of acetic acid. To this stirred solution add sodium triacetoxyborohydride (0.975 mmol). After stirring for 12 h, quench the reaction with aqueous sodium carbonate (5 mL) and dilute with dichloromethane (5 mL). Dry the organic portion, filter, and remove the solvent under vacuum. Chromatograph the product over silica gel, eluting with ethyl acetate/hexane (2-35%) to afford the title compound as a colorless oil. MS (ES+): 655.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Cl.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18]Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=2)=[CH:4][CH:3]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Clc1ccc(SCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 170 %

Procedure:
4-Chlorobenzenethiol (5 g) in warm ethanol (5 ml) was added to a solution of sodium hydroxide (2.8 g) in ethanol (50 ml). To the solution was added a solution of 2-picolyl chloride, hydrochloride (5.7 g) in ethanol (25 ml) and the mixture was stirred at ambient temperature for 6 hours. The mixture was filtered and evaporated and the residue was converted into the hydrochloride with ethereal HCl solution and this was recrystallised from ethanol-ether to give 2-(((4-chlorophenyl)thio)methyl)pyridine, hydrochloride (8 g) mp 196°-8° C. (Found: C,52.95; H,4.1; N,5.15 C12H10ClNS.HCl requires C,53.1; H,4.2; N,4.9%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([C@@H:23]([NH:25][C:26](=[O:28])[CH3:27])[CH3:24])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1>CN(C=O)C.CO>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([C@@H:23]([NH:25][C:26](=[O:28])[CH3:27])[CH3:24])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[N:3][CH:4]=1)[CH3:10]
Reactant: CCOc1ccc(Br)nc1
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCNCC2)cc1
Solvent: CO
Solvent: CN(C)C=O
Product: CCOc1ccc(N2CCC(c3ccc([C@H](C)NC(C)=O)cc3)CC2)nc1
Temperature: 180 °C

Procedure:
250 mg (1.24 mmol) 2-Bromo-5-ethoxy-pyridine are added to 250 mg (1.02 mmol) (S)-N-[1-(4-piperidin-4-yl-phenyl)-ethyl]-acetamide (V.1). The mixture is heated at 180° C. for 1 h. Subsequently the residue is taken up in DMF/methanol and the mixture is purified using reversed phase HPLC (column: Waters XBridge 5 μM; eluent A: water+0.3% NH4OH, eluent B: MeOH+0.3% NH4OH) to yield the desired product.