Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=C1OC(=O)C1.[ClH:7].[C:8]([Cl:14])(=[O:13])[CH2:9][C:10]([CH3:12])=[O:11]>>[Cl:7][CH:9]([C:10]([CH3:12])=[O:11])[C:8]([Cl:14])=[O:13].[Cl:7][Cl:14]
Reactant: CC(=O)CC(=O)Cl
Reactant: Cl
Agent: C=C1CC(=O)O1
Product: CC(=O)C(Cl)C(=O)Cl
Product: ClCl

Procedure:
Diketene is converted at a temperature of +30° to -40° C. with HCl into the acetoacetic acid chloride. 2-Chloroacetoacetic acid chloride is then formed by introduction of chlorine at a temperature of +30° to -40° C. The chloride is converted by the addition of 1 mole of the corresponding amine and 1 mole of tertiary base, such as triethylamine, or 2 moles of the corresponding amine into the corresponding 2-chloroacetoacetic acid amine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[C:19]1[CH:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:28][CH:27]=2)[C:22]([N+:40]([O-:42])=[O:41])=[CH:21][N:20]=1.O>C1COCC1.CN(C=O)C>[N+:40]([C:22]1[C:23]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:30][CH:31]=2)=[CH:24][C:19]([O:1][C:2]2[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=2)=[N:20][CH:21]=1)([O-:42])=[O:41]
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Nc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2cc(Nc3ccc(OCc4ccccc4)cc3)c([N+](=O)[O-])cn2)c1
Temperature: 60 °C
Yield: 92.1 %

Procedure:
A solution of 1,1-Dimethylethyl (3-hydroxyphenyl)carbamate (7.05 g, 33.7 mmol) in THF (20 mL) was added dropwise to a suspension of NaH (60% dispersion in oil, 1.34 g, 33.7 mmol) in THF (50 mL). The product of Step 1 (12.0 g, 33.7 mmol) in DMF (100 mL) was then added and the mixture was heated to 60° C. overnight. The reaction mixture was then cooled, poured into H2O and extracted with EtOAc. The combined extracts were washed with brine, dried (MgSO4), filtered and the filtrates were concentrated to give the title compound as a yellow solid (16.4 g, 92%) which was used without purification. MS (ES+) m/e 529 [M+H]+.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.C([CH:24](O)[C:25]([OH:27])=[O:26])C.N1CCC[CH2:31][CH2:30]1>C(O)C>[C:25]([CH:24]=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])([O:27][CH2:30][CH3:31])=[O:26]
Reactant: CCC(O)C(=O)O
Reactant: C1CCNCC1
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Solvent: CCO
Product: CCOC(=O)C=C1SC(=O)N(CCCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 3.21 g (10 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 1.12 g (11 mmol) of ethylglycolic acid in 50 ml of ethanol, 0.01 ml (1.0 mmol) of piperidine was added, followed by refluxing for 16 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/1→1/4→ethyl acetate) to yield 0.70 g (17.3%, yellow crystal) of the desired product.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11](=[O:19])[NH:12][C@H:13]1[CH2:17][CH2:16][NH:15][C:14]1=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:20](Br)[C:21]#[CH:22]>C1COCC1.CN(C=O)C>[CH2:3]([O:10][C:11](=[O:19])[NH:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH2:22][C:21]#[CH:20])[C:14]1=[O:18])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C#CCBr
Reactant: O=C(N[C@H]1CCNC1=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C#CCN1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Reaction time: 0.08 h
Yield: 100 %

Procedure:
Sodium hydride (1.11 g, 27.7 mmol, 60% mineral oil dispersion) is added to a solution of [2-oxopyrrolidin-3-(S)-yl]-carbamic acid benzyl ester (6.20 g, 26.4 mmol) in THF/DMF (88 mL, 3/1 v/v) at 0° C. The mixture is stirred for 5 min. then propargyl bromide (4.4 mL, 49.4 mmol) is added dropwise. The resulting solution is stirred for 1 h then brought to room temperature and stirred for 2 h. The reaction is quenched with saturated ammonium chloride solution then diluted with ethyl acetate and washed with water (×4) and brine. The organic layer is dried over MgSO4, filtered and concentrated to dryness. The residue is purified by column chromatography eluting with 5% MeOH/CH2Cl2 to give the product (7.20 g, 26.4 mmol) as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:14](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1.C(OCC)(=O)C>[CH3:3][C:4]1[N:5]([C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=[N:7][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1[nH]cnc1C
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Reaction time: 0.17 h
Yield: 10.2 %

Procedure:
Sodium hydride (900 mg, 80% oil dispersion, 30 mmol) was added in portions over 5 minutes to a stirred solution of ethyl 4-methyl-imidazole-5-carboxylate (3.85 g, 25 mmol) in dry tetrahydrofuran (100 ml) at room temperature under nitrogen. After 10 minutes, trityl chloride (8.36 g, 30 mmol) was added in one portion. After 1 h, the mixture was diluted with ethyl acetate (500 ml) and washed with water (200 ml). The washings were extracted with ethyl acetate (2×75 ml) and the combined organic solutions were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with hexane/ethyl acetate to give ethyl 5-methyl-1-(triphenylmethyl)imidazole-4-carboxylate (1.01 g, 10%) as a white solid.
Reaction SMILES: CS([O:5][S:6]([CH3:9])(=[O:8])=[O:7])(=O)=O.O[C:11]1[CH:20]=[C:19]2[C:14]([N:15]=[CH:16][C:17]([O:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([NH:30][C:31]([C:33]4[CH:34]=[CH:35][C:36]5[S:41][CH2:40][C:39](=[O:42])[NH:38][C:37]=5[CH:43]=4)=[O:32])[CH2:26][CH2:25]3)=[N:18]2)=[CH:13][CH:12]=1.C(N(CC)CC)C>CN(C)C=O>[O:42]=[C:39]1[NH:38][C:37]2[CH:43]=[C:33]([C:31]([NH:30][CH:27]3[CH2:26][CH2:25][N:24]([CH2:23][CH2:22][O:21][C:17]4[CH:16]=[N:15][C:14]5[C:19]([N:18]=4)=[CH:20][C:11]([O:5][S:6]([CH3:9])(=[O:7])=[O:8])=[CH:12][CH:13]=5)[CH2:29][CH2:28]3)=[O:32])[CH:34]=[CH:35][C:36]=2[S:41][CH2:40]1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: O=C1CSc2ccc(C(=O)NC3CCN(CCOc4cnc5ccc(O)cc5n4)CC3)cc2N1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Oc1ccc2ncc(OCCN3CCC(NC(=O)c4ccc5c(c4)NC(=O)CS5)CC3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.9 %

Procedure:
Methanesulfonic anhydride (519 mg, 2.92 mmol, 20.0 eq) is added at 0° C. to a stirred solution of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid {1-[2-(7-hydroxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide (70 mg, 0.15 mmol, 1.0 eq) in N,N-dimethylformamide (2 mL), followed by triethylamine (610.4 μL, 4.38 mmol, 30.0 eq). After 30 minutes stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×5 mL) and water (5 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford methanesulfonic acid 3-(2-{4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-piperidin-1-yl}-ethoxy)-quinoxalin-6-yl ester as an off-white powder (25 mg, 26% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:6][CH:7]=1.[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[F:15][C:16]1[CH:21]=[C:20]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:6][CH:7]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc(-c2cccc(F)c2)cn1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
To a reaction flask was added tert-butyl 5-bromopicolinate 33-4 (516 mg, 2.00 mmol), 3-fluorophenylboronic acid 6-6 (280 mg, 2.00 mmol), Pd(PPh3)4 (140 mg, 0.20 mmol), toluene (10 mL), ethanol (2 mL) and 2M Na2CO3 (3 mL). The reaction mixture was bubbled with nitrogen for 2 minutes and stirred at 90° C. for 10 hours with the flask sealed. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with saturated NaHCO3 aqueous solution, H2O and brine. The organic phase was dried over Na2SO4 and concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography, and eluted with 30% hexanes in ethyl acetate to give tert-butyl 5-(3-fluorophenyl)picolinate 33-5 as a white solid. MS m/z 274.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH:5]([CH:8]=O)[CH2:4][CH2:3]1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH:5]([CH2:8][NH:18][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][CH2:3]1
Reactant: NCc1ccccc1
Reactant: CC1(C)CCC(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC1(C)CCC(CNCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4,4-dimethylcyclohexanecarbaldehyde (6.6 g, 0.047 mol), benzylamine (5.0 g, 0.047 mol) and acetic acid (1 mL) in methanol (60 mL) was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (10.0 g, 0.047 mol) was added in one portion and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated in vacuo and partitioned between dichloromethane and water. The organic phase was washed with brine, silica gel was added and the mixture was concentrated in vacuo. The residue was purified by flash chromatography (CH2Cl2/MeOH), affording [(4,4-dimethyl cyclohexyl)methyl](phenylmethyl)amine as a white solid. (M+H) 232, 1.76 min. (LC/MS method B).
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10]([OH:12])=O)=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.Cl.[Cl:52][C:53]1[CH:65]=[CH:64][C:63]([F:66])=[CH:62][C:54]=1[O:55][CH:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1>CN(C=O)C.O>[C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:2]=[CH:3][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10]([N:59]2[CH2:58][CH2:57][CH:56]([O:55][C:54]3[CH:62]=[C:63]([F:66])[CH:64]=[CH:65][C:53]=3[Cl:52])[CH2:61][CH2:60]2)=[O:12])=[CH:5][CH:6]=1
Reactant: Fc1ccc(Cl)c(OC2CCNCC2)c1
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(CC(=O)N1CCC(Oc2cc(F)ccc2Cl)CC1)Nc1ccc(-c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 13.2 %

Procedure:
To a stirred solution of N-biphenyl-4-yl-malonamic acid (0.1 g, 0.00039 mole) in DMF (2 mL) was added HOBt (0.065 g, 0.00047 mole) and DIPEA (0.126 g, 0.00098 mole). The mixture was cooled to 10° C. and EDCI.HCl (0.090 g, 0.00047 mole) followed by 4-(2-chloro-5-fluoro-phenoxy)-piperidine hydrochloride (0.114 g, 0.00043 mole) were added. The resulting mixture was stirred at the ambient temperature overnight. The mixture was then diluted with cold water and the resulting precipitate was isolated by filtration. Purification by column chromatography using silica gel 60-120 mesh (35% ethyl acetate in hexane) afforded 0.024 g (13%) of N-biphenyl-4-yl-3-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-3-oxo-propionamide. LCMS: 467 (M+1)+, 97.5%, 1H NMR (CDCl3): δ 10.0 (s, 1H), 7.66 (d, 2H), 7.58 (m, 4H), 7.42 (t, 2H), 7.34 (m, 2H), 6.68 (m, 2H), 4.64 (m, 1H), 4.3 (m, 1H), 3.7 (m, 3H), 3.52 (s, 2H), 1.96 (m, 4H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]=[N+:18]=[N-:19])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22]>>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[CH:25]=[C:24]([Si:21]([CH3:23])([CH3:22])[CH3:20])[N:19]=[N:18]4)=[CH:15][CH:16]=3)[N:10]=2)[CH:7]=1
Reactant: [N-]=[N+]=Nc1ccc(-c2cn3cc(I)ccc3n2)cc1
Reactant: C#C[Si](C)(C)C
Product: C[Si](C)(C)c1cn(-c2ccc(-c3cn4cc(I)ccc4n3)cc2)nn1

Procedure:
Then, 6-iodo-2-(4-azidophenyl)imidazo[1,2-a]pyridine as prepared above is allowed to react with trimethylsilyl acetylene to obtain 6-iodo-2-[4-(4-trimethylsilyl-1H-1,2,3,-triazole-1-yl)phenyl]imidazo[1,2-a]pyridine (FIG. 1, step 2) in accordance with known methods (for example, the method described in a literature, James T. Fletcher et al., Tetrahedron Lett, 2008, 49, p. 7030-7032), and then trimethylsilyl group is removed (FIG. 1, step 3), to obtain 6-iodo-2-[4-(1H-1,2,3,-triazole-1-yl)phenyl]imidazo[1,2-a]pyridine.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([C:12]([O-:14])=[O:13])[C:5]2[C:10]([CH3:11])=[N:9][NH:8][C:6]=2[N:7]=1.P(Br)(Br)([Br:17])=O.[C:20](#N)[CH3:21]>>[Br:17][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH2:20][CH3:21])=[O:13])[C:5]2[C:10]([CH3:11])=[N:9][NH:8][C:6]=2[N:7]=1
Reactant: Cc1n[nH]c2nc(O)cc(C(=O)[O-])c12
Reactant: CC#N
Reactant: O=P(Br)(Br)Br
Product: CCOC(=O)c1cc(Br)nc2[nH]nc(C)c12
Yield: 77.8 %

Procedure:
6-Hydroxy-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (2.5 g, 11.3 mmol) was suspended in acetonitrile (25 mL) and POBr3 (6.5 g, 22.6 mmol) was added to it. The reaction mixture was refluxed for 6 h. On completion of reaction, acetonitrile was removed under reduced pressure and residue neutralized with saturated NaHCO3. Extraction was carried out using EtOAc and the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to provide the target compound (2.5 g, 77.8%).
Reaction SMILES: [Cl:1][C:2]([F:10])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]Cl.[CH2:11]1[O:19][C:18]2[CH:17]=[CH:16][C:15]([OH:20])=[CH:14][C:13]=2[O:12]1.[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]([F:10])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:20][C:15]1[CH:16]=[CH:17][C:18]2[O:19][CH2:11][O:12][C:13]=2[CH:14]=1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: FC(Cl)=CCCCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(Cl)=CCCCCCOc1ccc2c(c1)OCO2
Yield: 63 %

Procedure:
Operating as described in Example 8 (part B), from 3 g of 1,7-dichloro-1-fluoro-1-heptene, 2.14 g of 3,4-methylendioxyphenol, 0.69 g of NaH and 30 ml of N,N-dimethylformamide there were obtained 2.8 g of the product of the above-cited formula, a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8](=O)[CH3:9])=[CH:4][CH:3]=1.C(OCC)(=O)C(OCC)=O.C(OC(=O)C(=O)CC(=O)COC1C=CC=CC=1)C.C(OC(C1NN=C(COC2C=CC=CC=2)C=1)=O)C.C(OC([C:64]1[N:65]([CH2:77][CH:78]([NH:80][C:81]([O:83]C(C)(C)C)=O)C)[N:66]=C(COC2C=CC=CC=2)C=1)=O)C.O(CC1C=C2C(=O)NCCN2N=1)C1C=CC=CC=1>>[F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]2[CH:9]=[C:64]3[C:81](=[O:83])[NH:80][CH2:78][CH2:77][N:65]3[N:66]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)COc1ccc(F)cc1
Reactant: CCOC(=O)c1cc(COc2ccccc2)nn1CC(C)NC(=O)OC(C)(C)C
Agent: CCOC(=O)C(=O)CC(=O)COc1ccccc1
Agent: CCOC(=O)c1cc(COc2ccccc2)n[nH]1
Agent: O=C1NCCn2nc(COc3ccccc3)cc21
Solvent: CCOC(=O)C(=O)OCC
Product: O=C1NCCn2nc(COc3ccc(F)cc3)cc21

Procedure:
The compound was prepared from 1-(4-fluoro-phenoxy)-propan-2-one and diethyl oxalate using the methods described in the preceding examples 3 (2,4-dioxo-5-phenoxy-pentanoic acid ethyl ester), 4 (5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester), 7 ((rac)-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester) and 6 (2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one).
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[CH3:6][O:7][C:8](=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[C:10]=1[NH2:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:6][O:7][C:8]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]2[O:15][CH2:2][C:3](=[O:4])[NH:16][C:10]=12)=[O:17]
Reactant: COC(=O)c1cccc(O)c1N
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1NC(=O)CO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
At RT chloro-acetyl chloride (8.06 mmol) is added dropwise to a solution of 2-amino-3-hydroxy-benzoic acid methyl ester (7.33 mmol) in DMF (50 mL). After 20 min K2CO3 (34.9 mmol) is added portionwise, the mixture is stirred for 16 h at RT and the solvents are removed in vacuo. Water and DCM are added, the layers are separated and the organic layer is washed with brine and dried over Na2SO4. The solvents are removed in vacuo to give a crude product which is purified by CC (heptane to heptane/EtOAc 6/4). LC-MS: tR=0.82 min; [M+CH3CN+H]+=249.0.
Reaction SMILES: [SH:1][CH:2](C)[C:3]([OH:5])=[O:4].[SH:7][CH:8](C)[C:9]([OH:11])=[O:10].SC(C)[C:15]([OH:17])=[O:16].[CH2:19]([C:21]([CH2:26][OH:27])([CH2:24][OH:25])[CH2:22][CH3:23])[OH:20].ClN1C(=O)CCC1=O.[C:36]([Cl:40])(Cl)(Cl)Cl>>[S:7]=[CH:8][CH:36]([Cl:40])[C:3]([OH:5])=[O:4].[S:1]=[CH:2][CH:36]([Cl:40])[C:9]([OH:11])=[O:10].[S:1]=[CH:2][CH:36]([Cl:40])[C:15]([OH:17])=[O:16].[CH2:19]([C:21]([CH2:26][OH:27])([CH2:24][OH:25])[CH2:22][CH3:23])[OH:20]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(S)C(=O)O
Agent: CCC(CO)(CO)CO
Agent: O=C1CCC(=O)N1Cl
Product: O=C(O)C(Cl)C=S
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of trimethylolpropane tris(mercaptopropionate) (4.0 grams, 0.010 mol.) in carbon tetrachloride (10 milliliters) was added dropwise to a slurry of N-chlorosuccinimide (4.15 grams, 0.031 mol.) and carbon tetrachloride (30 milliliters) in a 3-neck round bottom flask equipped with a magnetic stir-bar, nitrogen inlet, pressure-equalizing dropping funnel and a thermocouple. The exothermic reaction was controlled to less than 27° C. using an ice-bath. The mixture was allowed to stir at ambient temperature for an additional 5 hours. The reaction mixture was filtered to remove succinimide by-product to give a yellow solution of trimethylolpropane tris(3-sulfenylchloropropionate). 1H NMR (CDCl3) δ: 4.09 (s, 6H), 3.37 (m, 6H), 2.89 (t, J=6.5 Hz, 6H); 1.52 (q, J=6.5 Hz, 2H); 0.96 (t, J=7.4 Hz, 3H). 13C NMR (CDCl3): 170.8, 64.2, 41.4, 36.7, 33.7, 23.3, 7.8 ppm.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][C:19]2[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=2)=[O:17])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Mn]([O-])(=O)(=O)=[O:28].[K+].S(=O)(O)[O-].[Na+]>CC(C)=O.O>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]([OH:28])=[O:24])=[CH:21][CH:20]=2)=[O:17])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(C(=O)Oc2ccc(C=O)cc2)cc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.8 %

Procedure:
2.0 g (5.6 mmol) of 4-(4-octyloxyphenylcarbonyloxy)benzaldehyde was dissolved in 100 ml of acetone and then 900 mg (5.6 mmol) of potassium permanganate was added dropwise thereto over about 5 minutes. After the mixture was stirred at room temperature for a night, 1.0 g (9.6 mmol) of sodium bisulfite dissolved in 20 ml of water was added thereto to adjust pH to not more than 1. After the acetone was distilled off, the white precipitate was taken out by filtration and recrystallized from 60 ml of ethanol to obtain 1.8 g (yield: 85%) of a white crystal.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C@@H:13]([C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH2:47]([O:49][C:50](=[O:54])[CH2:51][CH2:52][NH2:53])[CH3:48]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C@@H:13]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([NH:53][CH2:52][CH2:51][C:50]([O:49][CH2:47][CH3:48])=[O:54])=[O:22])=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCN
Reactant: CCC[C@H](c1ccc(C(=O)O)cc1)C(c1ccc(OC)cc1)c1ccc(F)c2ccccc12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)OCC)cc1)C(c1ccc(OC)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-{(1S)-1-[(4-fluoro-1-naphthyl)(4-methoxyphenyl)methyl]butyl}benzoic acid in THF (5 mL) was added CDI (150 mg, 0.925 mmol) After stirring at room temperature for 30 minutes, β-alanine ethyl ester hydrochloride (150 mg, 0.977 mmol) was added, then the mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc then washed with water, then brine. The organic layer was dried over MgSO4, filtered, then concentrated. The residue was purified by preparative reverse phase HPLC eluting with acetonitrile/water+0.1% TFA to afford the two diastereomers of the title compound.
Reaction SMILES: [CH4:1].[OH2:2].CO.[CH2:5]([OH:8])[CH2:6][CH3:7]>N#N>[C:5]([OH:2])(=[O:8])[CH2:6][CH3:7].[C:5]([OH:2])(=[O:8])[CH2:6][CH2:7][CH3:1]
Reactant: CCCO
Reactant: O
Reactant: C
Agent: N#N
Solvent: CO
Product: CCC(=O)O
Product: CCCC(=O)O

Procedure:
Carbon black waste gas containing about 14 percent CO, 17 percent H2 and 4 percent CH4 in N2 is spared into a 1 L CSTR operating at 37° C. and a few inches of water pressure. The medium in the reactor is a basal salts mixture containing water, B-vitamins, salts and minerals. The single or mixed culture in the reactor produces a liquid phase product of methanol, propanol, buytanol, propionic acid, butyric acid or other desirable products. The system is set up essentially the same as in Example 8.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][N:7]([C:14]1[C:19]([N+:20]([O-])=O)=[CH:18][N:17]=[C:16]([Cl:23])[N:15]=1)[CH:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[CH2:9]1)[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][N:7]([C:14]1[C:19]([NH2:20])=[CH:18][N:17]=[C:16]([Cl:23])[N:15]=1)[CH:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[CH2:9]1)[CH3:2]
Reactant: CCOC(=O)CCN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCC(C)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCN(c1nc(Cl)ncc1N)C1CCC(C)C1
Yield: 85.5 %

Procedure:
A mixture of 3.3 g (0.0093 mole) of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-(3-methyl-cyclopentyl)-amino]-propanoic acid ethyl ester (IV-58) in 30 mL of ethyl acetate and 0.5 g of 5% palladium on carbon catalyst was stirred under an atmosphere of hydrogen until hydrogen uptake was complete. The mixture was filtered through a pad of Celite, washing the filter pad with dichloromethane. Concentration of the filtrate under reduced pressure gave 2.6 g of (rac)-3-[(5-amino-2-chloro-pyrimidin-4-yl)-(3-methyl-cyclopentyl)-amino]-propanoic acid ethyl ester (V-58). This material was used directly in the next step without further purification.