Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:13])[CH2:4][CH2:5][O:6][N:7]=[C:8]([O:10][CH2:11][CH3:12])[CH3:9].[CH:14]([NH2:17])([CH3:16])[CH3:15]>CO>[CH2:11]([O:10][C:8](=[N:7][O:6][CH2:5][CH2:4][C:3](=[O:13])[NH:17][CH:14]([CH3:16])[CH3:15])[CH3:9])[CH3:12]
Reactant: CC(C)N
Reactant: CCOC(C)=NOCCC(=O)OC
Solvent: CO
Product: CCOC(C)=NOCCC(=O)NC(C)C
Temperature: 55 °C
Reaction time: 14 h
Yield: 13 %

Procedure:
To a known compound, 3-(1-ethoxy-ethylideneaminooxy)-propanoic acid methyl ester (CAS No. 97164-30-2, 300 mg, 1.585 mmol) were added methanol (3 ml) and isopropylamine (1.4 ml), and the mixture was stirred at 55° C. for 14 hours. Additional isopropylamine (1.0 ml) was added, and the mixture was stirred for 3 hours using a focused microwave synthesis system (Discover™, CEM) at 100 W. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give N-(2-isopropylcarbamoyl-ethoxy)-acetimidic acid ethyl ester (46 mg, 13% yield).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[N:15]=[CH:14][C:13]([C:16]([O:18]CC)=[O:17])=[CH:12][N:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].C(O)C.[OH-].[Na+].Cl>O>[CH2:1]([C@H:4]1[CH2:5][CH2:6][C@H:7]([C:10]2[N:11]=[CH:12][C:13]([C:16]([OH:18])=[O:17])=[CH:14][N:15]=2)[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](c2ncc(C(=O)OCC)cn2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC[C@H]1CC[C@H](c2ncc(C(=O)O)cn2)CC1
Reaction time: 1 h

Procedure:
35.6 g of crude ethyl trans-2-(4-propylcyclohexyl)-5-pyrimidinecarboxylate are treated with 62 ml of ethanol and a solution of 46.6 g of sodium hydroxide in 312 ml of water and heated to boiling for 1 hour. After cooling, the mixture is acidified with 220 ml of half-concentrated hydrochloric acid, left to stand for 1 hour in an ice-bath and then suction filtered. The material on the suction filter is washed with water and dried in vacuo at 50° C. over potassium hydroxide. For purification, the crude product is recrystallized from dioxan/water. There is obtained trans-2-(4-propylcyclohexyl)-5-pyrimidinecarboxylic acid; m.p. 184°-185.5° C.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][C:18]([N:21]5[C@@H:25]([CH:26]([CH3:28])[CH3:27])[CH2:24][O:23][C:22]5=[O:29])=[N:17][C:16]=34)=[CH:8][CH:7]=2)=[N:2]1.C([O-])([O-])=O.[Cs+].[Cs+].[P:36]([O:48][CH2:49]Cl)([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>CN(C=O)C>[P:36]([O:48][CH2:49][N:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][C:18]([N:21]5[C@@H:25]([CH:26]([CH3:27])[CH3:28])[CH2:24][O:23][C:22]5=[O:29])=[N:17][C:16]=34)=[CH:10][CH:11]=2)=[N:2]1)([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:37]
Reactant: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Reactant: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)cc3)c2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COP(=O)(OC(C)(C)C)OC(C)(C)C)n4)cc3)c2n1
Temperature: 80 °C
Yield: 15.5 %

Procedure:
To a mixture of (S)-3-(3-(4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-isopropyloxazolidin-2-one (1.72 g, 4.42 mmol), Cs2CO3 (1.58 g, 4.86 mmol) and DMF (40 mL) was added di-tert-butyl chloromethyl phosphate (1.54 g, 5.96 mmol). The reaction mixture was heated at 80° C. for 2 hours. After cooling, the reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by column chromatography (1:1 to 4:1 EtOAc:hexane) to give (S)-di-tert-butyl (3-(4-(5-(4-isopropyl-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenyl)-1H-1,2,4-triazol-1-yl)methyl phosphate (0.42 g, 16%). LCMS (APCI+) m/z 612 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].[H-].[Na+].[CH3:13]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:13])[C:5]#[N:6]
Reactant: CI
Reactant: N#Cc1ccc(O)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C#N)cc1Cl
Temperature: 70 °C
Reaction time: 18 h

Procedure:
Under N2, a solution of 3-chloro-4-hydroxybenzonitrile (15.4 g, 0.1 mole) in dry DMF (75 ml) was added rapidly dropwise to a stirred suspension of sodium hydride (4.0 g, 0.1 mole, 60% oil dispersion) in dry DMF (25 ml). After heating at 70° C. for 2 hours, the mixture was cooled to 20° C. and a solution of methyliodide (30 ml) in dry DMF (50 ml) was added dropwise. Following an 18 hour period at room temperature, the precipitate of sodium iodide was removed by filtration and the solvent was stripped from the filtrate under reduced pressure. The crystalline residue was slurried in water and the product was collected to yield 16.8 g (quant.) of 26, m.p. 105°-108° C. A sample recrystallized from IPA-H2O melted at 107°-109° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([N+:19]([O-])=O)=[CH:14][N:13]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]>C(O)C.C(O)(=O)C.[C].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([NH2:19])=[CH:14][N:13]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2cc(C)c([N+](=O)[O-])cn2)c1C
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2cc(C)c(N)cn2)c1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.5 %

Procedure:
To a solution of 5-methyl-1-(4-methyl-5-nitropyridin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (22.3 g) in ethanol (600 ml) and acetic acid (50 ml) was added palladium carbon (1.0 g), and stirred at room temperature for 6 hours under hydrogen atmosphere (1 atm). After completion of the reaction, the mixture was filtered through Celite, then the filtrate was concentrated, and the obtained residue was dissolved in chloroform. The organic layer was washed with saturated sodium bicarbonate water and water sequentially, dried over anhydrous sodium sulfate, and then the solvent was evaporated. To the obtained residue was added a small amount of diethyl ether and n-hexane, the precipitated solid was collected by filtration, and heat-dried in vacuo at 60° C. to give 1-(5-amino-4-methylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (18.3 g) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([I:19])=[C:11]([N:20]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH2:22][CH2:23][CH:24]=C)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[O:35]C(C)=O>C1COCC1.O>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([I:19])=[C:11]([N:20]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH2:22][CH2:23][CH:24]=[O:35])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCCCN(C(=O)OC(C)(C)C)c1cc(OCc2ccccc2)c2ccccc2c1I
Reactant: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCCC=O)c1cc(OCc2ccccc2)c2ccccc2c1I
Temperature: 25 °C
Reaction time: 6 h
Yield: 80 %

Procedure:
A solution of 81 (44 mg, 81 μmol) in THF (3 mL) was treated sequentially with a solution of NaIO4 (35 mg, 162 μmol, 2 equiv) in 0.5 mL H2O and a solution of OSO4 (7.5 mM in THF, 0.53 mL, 4 μmol, 0.05 equiv). The reaction mixture was stirred for 6 h at 25° C. EtOAc (20 mL) was added and the organic layer was dried (Na2SO4), filtered through Celite, and the solvent removed under vacuum. Chromatography (SiO2, 1×15 cm, 15% EtOAc-hexane) afforded 110 (35 mg, 80%) as an oil: 1H NMR (CDCl3, 400 MHz) δ 9.73 (t, J=1.3 Hz, 1H), 8.32 (d, J=8.2 Hz, 1H), 8.20 (d, J=8.4 Hz, 1H), 7.61-7.49 (m, 4H), 7.42-7.32 (m, 3H), 6.77 and 6.72 (two s, 1H), 5.32-5.25 (m, 2H), 3.86 (ddd, J=14.0, 8.6 Hz, 6.7 Hz, 1H), 3.47 (m, 1H), 2.48 (m, 2H), 1.93-1.75 (m, 2H), 1.29 and 1.23 (two s, 9H); IR (film) νmax 3064, 3032, 2975, 2930, 2722, 1638, 1616, 1590, 1407, 1160 cm31 1; FABHRMS (NBA-CsI) m/z 678.0095 (M+Cs+, C26H28INO4 requires 678.0117).
Reaction SMILES: [CH3:1][CH2:2][CH:3]([C:50]([OH:52])=[O:51])[CH:4]1[O:9][CH:8]([CH:10]([CH:12]([OH:48])[CH:13]([C:15]([CH:17]([CH:20]2[O:25][C:24]3([O:30][C:29]4([O:34][C:33]([CH:36]5[O:41][CH:40]([CH3:42])[C:39]([OH:45])([CH2:43][CH3:44])[CH2:38][CH2:37]5)([CH3:35])[CH2:32][CH2:31]4)[CH2:28][CH:27]=[CH:26]3)[CH:23]([CH3:46])[CH2:22][CH:21]2[CH3:47])[CH2:18][CH3:19])=[O:16])[CH3:14])[CH3:11])[CH:7]([CH3:49])[CH2:6][CH2:5]1.C(OCC)(=[O:55])C.CO>CCCCCC.C(OCC)(=O)C>[CH3:1][CH2:2][C@@H:3]([C:50]([OH:52])=[O:51])[C@@H:4]1[O:9][C@@H:8]([C@H:10]([C@H:12]([OH:48])[C@@H:13]([C:15]([C@@H:17]([C@H:20]2[O:25][C@@:24]3([O:30][C@:29]4([O:34][C@@:33]([C@@H:36]5[O:41][C@@H:40]([CH3:42])[C@@:39]([OH:45])([CH2:43][CH3:44])[CH2:38][CH2:37]5)([CH3:35])[CH2:32][CH2:31]4)[C@H:28]([OH:55])[CH:27]=[CH:26]3)[C@H:23]([CH3:46])[CH2:22][C@@H:21]2[CH3:47])[CH2:18][CH3:19])=[O:16])[CH3:14])[CH3:11])[C@@H:7]([CH3:49])[CH2:6][CH2:5]1.[CH3:1][CH2:2][CH:3]([C:50]([OH:52])=[O:51])[CH:4]1[O:9][CH:8]([CH:10]([CH:12]([OH:48])[CH:13]([C:15]([CH:17]([CH:20]2[O:25][C:24]3([O:30][C:29]4([O:34][C:33]([CH:36]5[O:41][CH:40]([CH3:42])[C:39]([OH:45])([CH2:43][CH3:44])[CH2:38][CH2:37]5)([CH3:35])[CH2:32][CH2:31]4)[CH2:28][CH:27]=[CH:26]3)[CH:23]([CH3:46])[CH2:22][CH:21]2[CH3:47])[CH2:18][CH3:19])=[O:16])[CH3:14])[CH3:11])[CH:7]([CH3:49])[CH2:6][CH2:5]1
Reactant: CCOC(C)=O
Agent: CCC(C(=O)O)C1CCC(C)C(C(C)C(O)C(C)C(=O)C(CC)C2OC3(C=CCC4(CCC(C)(C5CCC(O)(CC)C(C)O5)O4)O3)C(C)CC2C)O1
Solvent: CO
Solvent: CCCCCC
Product: CC[C@@H](C(=O)[C@@H](C)[C@@H](O)[C@H](C)[C@@H]1O[C@@H]([C@@H](CC)C(=O)O)CC[C@@H]1C)[C@H]1O[C@]2(C=C[C@@H](O)[C@]3(CC[C@@](C)([C@H]4CC[C@](O)(CC)[C@H](C)O4)O3)O2)[C@H](C)C[C@@H]1C

Procedure:
The mother liquor separated from crystals in the process in (D) is concentrated to dryness to give 9.7 kg of the complex containing SY-1 through -8. The complex is dissolved in 100 liters of a 2:1 mixture of hexane-ethyl acetate, applied to the column of 20 kg of almina in the same manner as described in Example 2 (E) and developed with 30 liters of a 100:2 mixture of ethyl acetate-methanol to elute SY-1, SY-3 and SY-7. The effluent is treated in the same manner as described in Example 2 (E) to give 400 g of salinomycin-SY-1 mixture and 130 g of crude powder containing SY-3 and SY-7.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.C(N(CC)CC)C.Cl[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[O:18]([CH2:17][N:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[N:6][C:5]1=[O:8])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCOc1ccccc1
Reactant: O=c1ncc(Cl)c[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1ncc(Cl)cn1COc1ccccc1
Temperature: 25 °C

Procedure:
5-Chloropyrimidin-2-one (5 mmol) and triethylamine (5 mmol) were stirred together in dichloromethane (50 ml). When all the solid had dissolved a solution of chloromethoxybenzene (see Preparation 2) (5 mmol) in dichloromethane (25 ml) was added with stirring at room temperature. The resultant mixture was stirred for 24 h at this temperature before the solvent was distilled off. The residue was triturated with water (30 ml), extracted into chloroform (3×20 ml), and the dried (MgSO4) solution evaporated to yield a mixture of the title compound and the O-alkylated isomer in the ratio 3:1; yield 7.00 g (85%). The N-isomer was separated by column chromatography on silica gel; m.p. 146° C.
Reaction SMILES: CC(C)([O-])C.[K+].[N:7]#[C:8][NH2:9].CS([C:13]1[S:14][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)=[N:16][N:17]=1)=O>C(O)(C)(C)C>[CH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[CH:27][C:18]=1[C:15]1[S:14][CH:13]([NH:9][C:8]#[N:7])[NH:17][N:16]=1
Reactant: CS(=O)c1nnc(-c2ccc3ccccc3c2)s1
Reactant: N#CN
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: N#CNC1NN=C(c2ccc3ccccc3c2)S1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.6 %

Procedure:
To a stirred solution of potassium tert-butoxide (0.46 g, 4.08 mmol) in tert-butanol (25 ml) was added cyanamide (0.32 g, 7.65 mmol) and the resulting mixture was stirred for 15 min. at room temperature. To this mixture was added 2-methanesulfinyl-5-naphthalen-2-yl-[1,3,4]thiadiazole (0.7 g, 2.55 mmol) and the mixture was heated at reflux temperature for 15 min. followed by addition of an additional portion of cyanamide (0.2 g, 4.76 mmol). Heating was continued for an additional 2 h. The cooled reaction mixture was quenched by addition of 1 N sodium hydroxide (150 ml) and diluted by addition of diethyl ether. The organic phases were separated and the aqueous phase was acidified to pH=1 with concentrated hydrochloric acid. The precipitate was filtered off, washed with water (2×10 ml) and diethyl ether (2×10 ml) and dried at 50° C. which afforded 0.25 g (39%) of the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH2:14]([CH:16]1[C:21]2[CH:22]=[CH:23][S:24][C:20]=2[CH2:19][CH2:18][NH:17]1)[CH3:15]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:17]3[CH2:18][CH2:19][C:20]4[S:24][CH:23]=[CH:22][C:21]=4[CH:16]3[CH2:14][CH3:15])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CCC1NCCc2sccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CCC1c2ccsc2CCN1C(=O)c1cc2ncc(Br)cn2n1
Yield: 79 %

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 4-ethyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]([NH:6][C:7]2[C:15]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=2[N+:20]([O-])=O)=[CH:4][CH:3]=1.[N+](C1C=C(C=C(S(=O)(=O)N)C=1OC1C=CC=CC=1)C(O)=O)([O-])=O>>[NH2:20][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([S:16](=[O:19])(=[O:18])[NH2:17])[C:7]=1[NH:6][C:5]1[CH:23]=[CH:24][C:2]([OH:1])=[CH:3][CH:4]=1)[C:11]([OH:13])=[O:12]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Nc1ccc(O)cc1
Agent: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Oc1ccccc1
Product: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Nc1ccc(O)cc1

Procedure:
By substituting 4-(p-hydroxyanilino)-3-nitro-5-sulphamyl-benzoic acid (10 g) for the 3-nitro-4-phenoxy-5-sulphamyl-benzoic acid of Example 1 B, the above compound was obtained with a melting point of 296° C (decomp.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:11])[N:6]([CH:8]([F:10])[F:9])[CH:7]=1.[Br:12]Br>C(O)(=O)C>[Br:12][C:4]1[C:5](=[O:11])[N:6]([CH:8]([F:9])[F:10])[CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: BrBr
Reactant: O=c1ccc(Br)cn1C(F)F
Solvent: CC(=O)O
Product: O=c1c(Br)cc(Br)cn1C(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.6 %

Procedure:
To a stirred solution of 5-Bromo-1-difluoromethyl-1H-pyridin-2-one (1 g, 4.46 mmol) in 7 ml acetic acid was added bromine (0.24 ml, 4.46 mmol) drop wise at 0° C. and then the reaction mixture was stirred at rt for 12 hrs. Acetic acid was removed under reduced pressure. To this was added ethylacetate and washed with aq NaHCO3 solution. Organic layer was dried over any sodium sulphate and concentrated under reduced pressure. It was purified by column chromatography using 5% ethyl acetate in hexane to afford 3,5-Dibromo-1-difluoromethyl-1H-pyridin-2-one (900 mg, 66.5%).
Reaction SMILES: [CH2:1]1[CH2:5][C:4]2([CH2:12][C:10](=[O:11])[O:9][C:7](=O)[CH2:6]2)[CH2:3][CH2:2]1.[NH2:13][C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21]C)=[O:19])=[CH:16][CH:15]=1.CC1(C)CC(=O)OC(=O)C1>>[O:11]=[C:10]1[N:13]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:23][CH:24]=2)[C:7](=[O:9])[CH2:6][C:4]2([CH2:3][CH2:2][CH2:1][CH2:5]2)[CH2:12]1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C1CC2(CCCC2)CC(=O)O1
Agent: CC1(C)CC(=O)OC(=O)C1
Product: COC(=O)c1ccc(N2C(=O)CC3(CCCC3)CC2=O)cc1

Procedure:
The desired product was prepared by substituting methyl 4-aminobenzoate and 3,3-tetramethyleneglutaric anhydride for ethyl 4-aminobenzoate and 3,3-dimethylglutaric anhydride, respectively, in Example 119A. MS (DCI) m/e 302 (M+H)+.
Reaction SMILES: N[C@H](C(O)=O)C[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1C=CC([CH2:19][C@H:20]([OH:24])[C:21]([OH:23])=[O:22])=CC=1>>[C:4]1([O:23][C:21](=[O:22])[CH:20]([CH3:19])[OH:24])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C(O)[C@@H](O)Cc1ccccc1
Product: CC(O)C(=O)Oc1ccccc1
Reaction time: 24 h

Procedure:
In a case in which 5 mM of L-phenylalanine was added to the culture medium, L-phenylalanine ceased to be detected after 24 hours of culture, and instead an equal level (5.7 mM) of D-3-phenyllactate had accumulated. This led to the conclusion that the present strain converts L-phenylalanine to D-3-phenyllactate. Specifically, it is thought that the present strain has an enzyme that produces optically active phenyllactate.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH2:19][NH2:20])=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[CH2:19][NH:20][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[CH3:1])=[CH:14][CH:13]=1
Reactant: NCC(c1ccc(F)cc1)N1CCOCC1
Reactant: Cc1ccccc1C(=O)O
Product: Cc1ccccc1C(=O)NCC(c1ccc(F)cc1)N1CCOCC1

Procedure:
From 2-methylbenzoic acid and 2-(4-fluoro-phenyl)-2-morpholin-4-yl-ethylamine.
Reaction SMILES: Br[CH:2]1[C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:9][C:8]2[C:4](=[N:5][N:6]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:7]=2)[CH:3]1[O:30]C.CC(C)([O-])C.[K+].Cl>O1CCCC1.O>[C:26]([N:6]1[CH:7]=[C:8]2[C:4]([C:3](=[O:30])[CH2:2][C:10]3([CH2:9]2)[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:12][CH2:11]3)=[N:5]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: COC1c2nn(C(C)(C)C)cc2CC2(CCN(C(=O)OCc3ccccc3)CC2)C1Br
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)n1cc2c(n1)C(=O)CC1(CCN(C(=O)OCc3ccccc3)CC1)C2
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
Benzyl 6-bromo-2-tert-butyl-7-methoxy-2,4,6,7-tetrahydrospiro[indazole-5,4′-piperidine]-1′-carboxylate (150 mg, 0.31 mmol) was dissolved in 5 mL tetrahydrofuran and treated with potassium tert-butoxide (0.61 mL, 0.61 mmol, 1 M tetrahydrofuran) and stirred for 30 minutes. Aqueous 2 N HCl (5 mL) was added and the mixture was stirred for 15 minutes at room temperature. The mixture was then diluted with 50 mL water and extracted with ethyl acetate (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (10-80% ethyl acetate/heptanes) to yield 86 mg (71%) of the title compound as a clear oil. +ESI (M+H) 396.5; 1H NMR (400 MHz, CDCl3, δ): 7.38 (s, 1 H), 7.27-7.35 (m, 5 H), 5.11 (s, 2 H), 3.48 (t, J=5.8 Hz, 4 H), 2.71 (s, 2 H), 2.57 (s, 2 H), 1.57-1.66 (m, 9 H), 1.47-1.59 (m, 4 H).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=2)=[O:16])[C@@H:7]([CH3:24])[CH2:6]1)=[O:4].[CH3:25][O-:26].[Na+].CO.Cl>COCCOC>[CH3:25][O:26][C:20]1[N:19]=[CH:18][C:17]([C:15]([N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:5]([C:3]([OH:2])=[O:4])[CH2:6][CH:7]2[CH3:24])=[O:16])=[CH:22][CH:21]=1
Reactant: C[O-]
Reactant: COC(=O)[C@@H]1C[C@H](C)N(C(=O)c2ccc(Cl)nc2)c2ccccc21
Agent: Cl
Agent: [Na+]
Solvent: COCCOC
Solvent: CO
Product: COc1ccc(C(=O)N2c3ccccc3C(C(=O)O)CC2C)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 32 %

Procedure:
To a solution of cis-1-(6-chloro-pyridine-3-carbonyl)-2-methyl-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid methyl ester (620 mg, 1.8 mmol) in ethylene glycol dimethyl ether (6.00 mL) was added at 0° C. a 5M solution of sodium methoxide in methanol (3.3 mL, 16.2 mmol). The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was acidified to pH 1 by addition of aqueous 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to yield 1-(6-methoxy-pyridine-3-carbonyl)-2-methyl-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (190 mg, 32%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([O:24][CH3:25])[CH:18]=3)[C:15]([S:26][CH2:27][C:28]3[C:40]([F:41])=[CH:39][C:31]([C:32]([O:34]C(C)(C)C)=[O:33])=[CH:30][C:29]=3[F:42])=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([O:24][CH3:25])[CH:18]=3)[C:15]([S:26][CH2:27][C:28]3[C:29]([F:42])=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:39][C:40]=3[F:41])=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(-n2c(C(C)(C)c3ccc(Cl)c(Cl)c3)cnc2SCc2c(F)cc(C(=O)OC(C)(C)C)cc2F)ccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-n2c(C(C)(C)c3ccc(Cl)c(Cl)c3)cnc2SCc2c(F)cc(C(=O)O)cc2F)ccc1F
Reaction time: 0.67 h

Procedure:
A solution of tert-butyl 4-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorobenzoate (540 mg, 0.85 mmol) in DCM (2 mL) was treated with TFA (2.0 mL) at ambient temperature. After 40 min, the reaction mixture was concentrated under reduced pressure to afford a colorless oil. This oil was taken up in DCM and toluene and again concentrated under reduced pressure to remove any residual TFA and to provide the title compound. MS (EI) m/z 581 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:12]2[O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[C:4](N)[N:3]=1.NC1N=C2C(N=CN2[C@@H]2O[C@H](CO)[C@@](CCCCN3C=CN=C3)(O)[C@H]2[OH:42])=C(N)N=1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1O>CS(C)=O>[N:18]1([CH2:17][CH2:16][CH2:15][CH2:14][O:13][C@@H:12]2[C@H:23]([OH:24])[C@@H:25]([CH2:27][OH:28])[O:26][C@H:11]2[N:8]2[C:9]3[N:10]=[C:2]([NH2:1])[NH:3][C:4](=[O:42])[C:5]=3[N:6]=[CH:7]2)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3OCCCCn3ccnc3)c2n1
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@](O)(CCCCn4ccnc4)[C@H]3O)c2n1
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: CS(C)=O
Product: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCCCn2ccnc2)c(=O)[nH]1

Procedure:
A mixture of the 2,6-diamino-9-[2′-O-(imidazol-1-yl)butyl-β-D-ribofuranosyl]purine and 2,6-diamino-9-[3′-(imidazol-1-yl)butyl-β-D-ribofuranosyl]purine isomers in 0.1 M tris buffer (pH 7.4), 0.1 M NaSO4 buffer (pH 7.4) and DMSO is treated with adenosine deaminase at RT for 5 days as per the procedure of Example 3. The product containing fractions are purified by silica gel chromatography and the product containing fraction evaporated to give the product.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].CP(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:27][C:28]1[CH:33]=[C:32]([CH3:34])[N:31]=[C:30]([O:35][CH3:36])[C:29]=1[CH:37]=O>C1(C)C=CC=CC=1>[CH3:36][O:35][C:30]1[C:29]([CH:37]=[CH2:1])=[C:28]([CH3:27])[CH:33]=[C:32]([CH3:34])[N:31]=1
Reactant: COc1nc(C)cc(C)c1C=O
Reactant: CC(C)(C)[O-]
Agent: C[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=Cc1c(C)cc(C)nc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
Potassium tert-butoxide (1.63 g, 14.54 mmol) is added to a suspension of methyl triphenylphosphine (5.20 g, 14.54 mmol) in toluene (70 mL) and the mixture is stirred at room temperature of 0.5 hr. To this yellow-orange mixture is added a solution of 4,6-dimethyl-2-methoxypyridine-3-carbaldehyde (1.20 g, 7.27 mmol) in toluene (10 mL). After 1.5 hr. the reaction mixture is washed with water (150 mL), with brine (150 mL), dried, filtered and concentrated and the residue is purified by chromatography eluting with cyclohexane-5% ethyl acetate. Product containing fractions are combined and concentrated to afford 2-methoxy-4,6-dimethyl-3-vinylpyridine (0.66 g, 55.5% yield) as an oil containing triphenylphosphine oxide.