Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([N:8]1[CH:11]([CH2:12][CH:13]([O:15][C:16](=[O:18])[CH3:17])[CH3:14])[CH2:10][C:9]1=[O:19])(C(C)(C)C)(C)C>Cl.CO>[C:16]([O:15][CH:13]([CH3:14])[CH2:12][CH:11]1[NH:8][C:9](=[O:19])[CH2:10]1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)CC1CC(=O)N1[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CO
Product: CC(=O)OC(C)CC1CC(=O)N1
Reaction time: 2.5 h

Procedure:
1(t-butyldimethylsilyl)-4-(2-acetoxypropyl)-2-azetidinone (2.4 g) is dissolved in a solution of HCl in MeOH (0.25N, 10 ml) and allowed to stand 2.5 hours at room temperature. The solvent is evaporated under reduced pressure and the residue is chromatographed on silica gel to give 4-(2-acetoxypropyl)-2-azetidinone.
Reaction SMILES: [CH3:1][N:2]([C:4]([N:6]=[C:7]([NH2:9])[NH2:8])=[NH:5])[CH3:3].Cl.[OH-].[Na+].C(Cl)Cl>C(O)C>[CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3]
Reactant: CN(C)C(=N)N=C(N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CN(C)C(=N)NC(=N)N
Yield: 83.3 %

Procedure:
10.0 g of metformin hydrochloride and 2.40 g of sodium hydroxide were stirred in 100 ml of ethylalcohol at a temperature of 70° C., and then methylene chloride was added thereto. The produced inorganic salt was filtered, and ethyl acetate was added thereto, thus preparing metformin free-base. The produced crystal was filtered and dried in hot air, thus obtaining 6.50 g (yield: 83.4%) of metformin free-base.
Reaction SMILES: Cl[C:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:16]=3[CH3:17])=[C:5]2[O:4][N:3]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH3:17][C:16]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:10]1[CH:9]=[CH:8][N:7]=[C:6]2[C:2]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[N:3][O:4][C:5]=12
Reactant: Cc1ccncc1-c1ccnc2c(Cl)noc12
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cc1ccncc1-c1ccnc2c(N3CCOCC3)noc12
Temperature: 90 °C
Yield: 75 %

Procedure:
To a suspension of 3-chloro-7-(4-methylpyridin-3-yl)isoxazolo[4,5-b]pyridine (0.0069 g, 0.028 mmol) and morpholine (0.025 ml, 0.281 mmol) in DMSO (Volume: 0.100 ml) was added cesium carbonate (0.027 g, 0.084 mmol). The vial was sealed, heated at 90° C. for 4 hr, and then allowed to cool to room temperature. The reaction mixture was filtered through a disposable fritted funnel and the filter cake washed with CH2Cl2. The solvent was concentrated to afford a yellow liquid, which was further dried under high vacuum overnight. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (4 g column, 18 mL/min, 70-100% EtOAc in hexanes over 14 min, tr=4.5 min) gave 7-(4-methylpyridin-3-yl)-3-morpholinoisoxazolo[4,5-b]pyridine (6.5 mg, 0.021 mmol, 76% yield) as a white solid. ESI MS (M+H)+=297.2. HPLC Peak tr=1.56 minutes. Purity=97%. HPLC Conditions: C.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2.C(O)(=O)C.C(=O)([O-])O.[Na+]>CO>[CH:1]1([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[CH:12]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCC1
Reactant: Nc1ccc2[nH]ncc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: c1cc2[nH]ncc2cc1NC1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.8 %

Procedure:
Cyclohexanone (59 mg), 5-aminoindazole (67 mg), and acetic acid (0.02 ml) were dissolved in methanol (1 ml), and a borane-pyridine complex (0.06 ml) was added dropwise to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was then added thereto, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC [chloroform/methanol] to give the title compound (94 mg, yield 87%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([OH:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH:19]([O:24][C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)[C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:17]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Oc1ccc(F)cc1
Reactant: COC(=O)C(O)Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)C(Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1)Oc1ccc(F)cc1
Yield: 58.5 %

Procedure:
In a similar manner to that described in Example 122, a reaction was carried out using methyl 3-[4-(2-t-butoxycarbonylaminoethoxy)phenyl]-2-hydroxypropionate (420 mg), which is obtained in a similar manner to that described in Reference example 39(a), 4-fluorophenol (284 mg), triphenylphosphine (666 mg) and solution of diethylazodicarboxylate in toluene (40%, 1.10 ml) and the reaction mixture was treated to afford the desired compound (314 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11](OS(C(F)(F)F)(=O)=O)[C:10]=1[N+:23]([O-:25])=[O:24].Cl.[CH:27]1([CH:30]([NH2:34])[CH2:31][CH2:32][CH3:33])[CH2:29][CH2:28]1>>[CH:27]1([CH:30]([NH:34][C:11]2[C:10]([N+:23]([O-:25])=[O:24])=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[CH:14]=[CH:13][N:12]=2)[CH2:31][CH2:32][CH3:33])[CH2:29][CH2:28]1
Reactant: CCCC(N)C1CC1
Reactant: O=[N+]([O-])c1c(-c2ccc(Cl)cc2Cl)ccnc1OS(=O)(=O)C(F)(F)F
Agent: Cl
Product: CCCC(Nc1nccc(-c2ccc(Cl)cc2Cl)c1[N+](=O)[O-])C1CC1
Yield: 72.3 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2,4-dichloro-phenyl)-3-nitro-pyridin-2-yl-ester (1.0 g, 2.40 mmol), prepared substantially as described in Part C of Example 19a, and 1-cyclopropyl-butylamine HCl (1.0 g, 4.79 mmol) were treated substantially as described in Part C of Example 19a to produce 0.66 g (72%) of crude (1-cyclopropyl-butyl)-[4-(2,4-dichloro-phenyl)-3-nitro-pyridin-2-yl]-amine: MS (AP) m/z 380.3 [(M+H)+, 100].
Reaction SMILES: CN(C=O)C.O.[Na].[CH3:8][CH:9]([SH:12])[CH2:10][CH3:11].[NH2:13][C:14]1[N:22]=[C:21](Cl)[N:20]=[C:19]2[C:15]=1[N:16]=[CH:17][N:18]2[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>[Cl-].[Na+].O>[NH2:13][C:14]1[N:22]=[C:21]([S:12][CH:9]([CH2:10][CH3:11])[CH3:8])[N:20]=[C:19]2[C:15]=1[N:16]=[CH:17][N:18]2[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCC(C)S
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)Sc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 100 °C
Yield: 35.2 %

Procedure:
To DMF suspension (10 ml) containing sodium hydrate (300 mg, 7.5 mmol, 60%in mineral oil) were added 2-butanethiol (1 ml, 11 mmol) and 6-amino-9-benzyl-2-chloropurine (200 mg, 0.77 mmol) in order. The mixture was stirred under heating at 100° C. for 5 hours. Brine was added thereto and the mixture was extracted with chloroform. The organic layer was dried on magnesium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (85 mg, yield 35%).
Reaction SMILES: C([O:4][C:5](=[O:25])[C:6]1[CH:11]=[C:10]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([CH3:19])[N:14]([CH3:20])[C:13]2=[O:21])[C:9]([F:22])=[CH:8][C:7]=1[C:23]#[N:24])(C)C.[OH-].[Na+]>CO.O>[C:23]([C:7]1[CH:8]=[C:9]([F:22])[C:10]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([CH3:19])[N:14]([CH3:20])[C:13]2=[O:21])=[CH:11][C:6]=1[C:5]([OH:25])=[O:4])#[N:24]
Reactant: Cc1cc(=O)n(-c2cc(C(=O)OC(C)C)c(C#N)cc2F)c(=O)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(=O)n(-c2cc(C(=O)O)c(C#N)cc2F)c(=O)n1C
Reaction time: 23 h

Procedure:
A solution of 30.5 g of 2-cyano-5-[3,6-dihydro-3,4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-4-fluorobenzoic acid isopropyl ester (see Example 1) in 150 ml of methanol is maintained at 1°-3° C. for 15 minutes with 4.0 g of sodium hydroxide in 50 ml of water and then stirred for 23 hours. The solution is substantially concentrated by evaporation under reduced pressure and the residue is adjusted to a pH value of 2 with 2N hydrochloric acid. The resulting precipitate is filtered off with suction and subsequently washed with n-hexane to yield 2-cyano-5-[3,6-dihydro-3,4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-4-fluorobenzoic acid, m.p. 232° C. (with decomposition).
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([CH:14]3[CH2:20][CH:19]4[CH:21]([CH:22](C(O)=O)[C:23]([OH:25])=[O:24])[CH:16]([CH2:17][CH2:18]4)[CH2:15]3)[NH:6][C:5]=2[C:4](=[O:29])[N:3]1[CH2:30][CH2:31][CH3:32].[OH-].[K+]>CO>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([CH:14]3[CH2:20][CH:19]4[CH:21]([CH2:22][C:23]([OH:25])=[O:24])[CH:16]([CH2:17][CH2:18]4)[CH2:15]3)[NH:6][C:5]=2[C:4](=[O:29])[N:3]1[CH2:30][CH2:31][CH3:32]
Reactant: CCCn1c(=O)c2[nH]c(C3CC4CCC(C3)C4C(C(=O)O)C(=O)O)nc2n(CCC)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(C3CC4CCC(C3)C4CC(=O)O)nc2n(CCC)c1=O

Procedure:
2-[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.2.1]oct-8-yl]-malonic acid was converted to the product by refluxing in MeOH in the presence of 1N KOH (1 ml) for 2 days. Mass (ES+403).
Reaction SMILES: [Cu][C:2]#[N:3].[I-].[K+].[F:6][C:7]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](Cl)=[O:10]>C1(C)C(C)=CC=CC=1>[F:6][C:7]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([C:2]#[N:3])=[O:10]
Reactant: O=C(Cl)c1cccc(F)c1F
Reactant: N#C[Cu]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: N#CC(=O)c1cccc(F)c1F
Temperature: 165 °C
Yield: 71.8 %

Procedure:
Copper(1) cyanide (6.6 g, 0.07 mol), potassium iodide (12.2 g, 0.07 mol) and xylene (70 ml) were heated at reflux for 24 h using a Dean-stark apparatus. A solution of 2,3-difluorobenzoyl chloride (10.8 g, 0.06 mol) in xylene (40 ml) was added. The resulting suspension was refluxed under N2 at 165° C. for 3 days using a Dean-Stark apparatus. After cooling, inorganic salts were removed by filtration and the filtrate concentrated in vacuo. The residue was azeotroped with toluene (2×30 ml) to give the product (7.2 g) as a brown solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]2[C:20](=[O:28])[NH:21][NH:22][C:23]=2[C:24]([F:27])([F:26])[F:25])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][C:30]([O:32][CH2:33][C@H:34]1[O:39][C@H:38](Br)[C@H:37]([O:41][C:42]([CH3:44])=[O:43])[C@@H:36]([O:45][C:46]([CH3:48])=[O:47])[C@@H:35]1[O:49][C:50]([CH3:52])=[O:51])=[O:31].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]2[C:20]([O:28][C@@H:38]3[O:39][C@H:34]([CH2:33][O:32][C:30](=[O:31])[CH3:29])[C@@H:35]([O:49][C:50](=[O:51])[CH3:52])[C@H:36]([O:45][C:46](=[O:47])[CH3:48])[C@H:37]3[O:41][C:42](=[O:43])[CH3:44])=[N:21][NH:22][C:23]=2[C:24]([F:27])([F:26])[F:25])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=c1[nH][nH]c(C(F)(F)F)c1Cc1ccc(CCCOCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(F)(F)F)c2Cc2ccc(CCCOCc3ccccc3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 60 °C
Reaction time: 20 h
Yield: 41.8 %

Procedure:
To a solution of 4-({4-[3-(benzyloxy)propyl]phenyl}methyl)-5-trifluoromethyl-1,2-dihydro-3H-pyrazol-3-one (0.83 g) and acetobromo-α-D-glucose (1.5 g) in acetonitrile (12 mL) was added potassium carbonate (0.55 g), and the mixture was stirred at 60° C. for 20 hours. Insoluble materials were removed by filtration, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/1-1/2) to give 4-({4-[3-(benzyloxy)propyl]phenyl}methyl)-5-trifluoromethyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.64 g).
Reaction SMILES: [F:1][C:2]1[C:3]([N+:24]([O-])=O)=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[F:12])[N:8]([C@@H:14]1[CH2:16][C@@H:15]1[F:17])[CH:7]=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5]2=[O:23].CO>[Ni].O1CCOCC1>[NH2:24][C:3]1[C:2]([F:1])=[C:11]([F:12])[C:10]([CH3:13])=[C:9]2[C:4]=1[C:5](=[O:23])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:7][N:8]2[C@@H:14]1[CH2:16][C@@H:15]1[F:17]
Reactant: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(C)c(F)c(F)c([N+](=O)[O-])c2c1=O
Agent: [Ni]
Solvent: CO
Solvent: C1COCCO1
Product: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(C)c(F)c(F)c(N)c2c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
A 3.91 g (37.6 mmol) portion of ethyl 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-5-nitro-4-oxoquinoline-3-carboxylate was suspended in 1 liter of a 1:1 mixture of methanol and 1,4-dioxane. This was mixed with 200 ml of Raney nickel and stirred for 10 minutes at room temperature. After completion of the reaction, the reaction solution was filtered and the resulting filtrate was concentrated. The resulting residue was dissolved in 300 ml of chloroform and filtered through celite. By concentrating the filtrate, 12.5 g (98%) of the title compound was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:15][C@@H:14]([C:16]([OH:18])=O)[C:13]1([CH3:20])[CH3:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21]1[CH:22]=CC2N(O)N=[N:27][C:25]=2[CH:26]=1.N1CCCC1.CCN(CC)CC>C(Cl)Cl>[CH3:19][C:13]1([CH3:20])[C@H:14]([C:16]([N:27]2[CH2:22][CH2:21][CH2:26][CH2:25]2)=[O:18])[CH2:15][C@@H:12]1[NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: CC1(C)[C@@H](NC(=O)OCc2ccccc2)C[C@H]1C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCNC1
Product: CC1(C)[C@@H](NC(=O)OCc2ccccc2)C[C@H]1C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.5 %

Procedure:
To a stirred solution of (1R,3S)-3-(benzyloxycarbonylamino)-2,2-dimethylcyclobutanecarboxylic acid (Intermediate 1-Step 3, 0.650 g, 2.346 mmol) in DCM (5 ml) EDCI (0.674 g, 3.519 mmol) and HOBt (0.475 g, 3.519 mmol) were added at about 0° C., after 10 minutes pyrrolidine (0.40 ml, 4.692 mmol) and Et3N (0.65 ml, 4.692 mmol) were added drop wise and the reaction mixture was stirred at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, saturated NaHCO3 solution, water, 1N HCl, water and saturated brine and the organic layer was concentrated under reduced pressure, the resulting crude purified by silica gel column (100-200 mesh, elution 20% EtOAC in hexane) to afford the title compound as an off white solid. Wt: 0.600 g; Yield: 77.5%; 1H NMR (300 MHz, CDCl3): δ 7.40-7.28 (m, 5H), 5.18-4.99 (m, 3H), 3.97-3.87 (m, 1H), 3.77-3.67 (m, 1H), 3.49-3.28 (m, 3H), 2.83 (t, 1H, J=8.4 Hz), 2.47-2.20 (m, 2H), 3.65-3.41 (m, 6H), 1.35 (s, 3H), 0.87 (s, 3H); Mass: [M+1]+ 331 (20%), [M+Na]+ 353 (100%); IR (KBr, cm−1): 3304, 3035, 2954, 1716, 1618, 1529, 1497, 1439, 1387, 1368, 1311, 1253, 1222, 1159, 1041, 912, 753.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O-:10])=O)[CH:5]=[CH:4][CH:3]=1.[K+].O=[C:13]1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.[NH2:28][C:29]1[C:38]([CH3:39])=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][C:30]=1[CH3:40].C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:28][C:29]2[C:30]([CH3:40])=[CH:31][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:37][C:38]=2[CH3:39])=[O:10])[C:5]([CH3:13])=[CH:4][CH:3]=1
Reactant: O=C([O-])c1cccc(Cl)n1
Reactant: COC(=O)c1cc(C)c(N)c(C)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)c1cc(C)c(NC(=O)c2nc(Cl)ccc2C)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
To a suspension of potassium 6-chloropyridine-2-carboxylate (52 g, 265.8 mmoles) in dimethylformamide (676 mL) is added bis(2-oxo-3-oxazolidinyl)phosphonic chloride (115 g, 451.8 mmoles). The mixture is stirred at ambient temperature for 30 minutes. Methyl 4-amino-3,5-dimethyl-benzoate (42.9 g, 239.2 mmoles, see preparation 12) and diisopropylethylamine (115.9 mL, 664.5 mmoles) are added. The reaction is stirred at ambient temperature for 16 hours. The mixture is then poured into water (2000 mL) and is stirred for 30 minutes. The resulting solid is filtered and dried under reduced pressure at 45° C. The dry material is triturated with hexane (1400 mL) over 2 hours. The solid is filtered and dried under vacuum to give the title compound (69 g, 78%) as a white solid. Mass spectrum (m/z): 333.05 (M+1). 1H NMR (300 MHz, DMSO): 10.16 (s, 1H), 7.89 (d, J=8.2 Hz, 1H), 7.73 (s, 2H), 7.63 (d, J=8.2 Hz, 1H), 3.85 (s, 3H), 2.49 (s, 3H), 2.28 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[Cl:8].CCCCCC.C([Li])CCC.[C:24](=[O:26])=[O:25]>O1CCCC1>[Cl:8][C:7]1[C:2]([F:1])=[C:3]([C:4]([C:9]([F:12])([F:10])[F:11])=[CH:5][CH:6]=1)[C:24]([OH:26])=[O:25]
Reactant: Fc1cc(C(F)(F)F)ccc1Cl
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)c1c(C(F)(F)F)ccc(Cl)c1F
Temperature: -78 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
77.0 g of 3-fluoro-4-chlorobenzotrifluoride was dissolved in 750 ml of dried tetrahydrofuran, and to the solution, 250 ml of hexane solution of n-butyl lithium (1.6 mol/l) was added dropwise over 15 minutes at -78° C. under a nitrogen atmosphere. After stirring the solution at -78° C. for 2 hours. 50 g of dry ice was gradually added to the solution at the same temperature. After elevating the temperature of the solution up to room temperature, 500 ml of ice water was added to the solution to separate the resulting solution. While cooling down the aqueous layer, the layer was adjusted to a pH value of 1 with concentrated hydrochloric acid. The aqueous layer was then extracted with ether, washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure, and the oily residue obtained was crystalized with n-hexane, followed by a filtration and then dried to obtain 88.4 g of the title compound(mp. 92-93° C.).
Reaction SMILES: [OH:1][C:2]1([CH2:15][OH:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[S:26](Cl)(Cl)=[O:27].C(=O)(O)[O-].[Na+]>C1COCC1.C(OCC)(=O)C>[O:1]1[C:2]2([CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][CH2:3]2)[CH2:15][O:16][S:26]1=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CO)CC1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC2(CC1)COS(=O)O2
Reaction time: 1 h
Yield: 117.1 %

Procedure:
To a solution of tert-butyl 4-hydroxy-4-(hydroxymethyl)piperidine-1-carboxylate (Bioorganic & Medicinal Chemistry Letters 2008, 18(21), 5804-5808) (400 mg, 1.73 mmol) and DIPEA (1.2 mL, 7.0 mmol) in THF (10 mL) cooled to 0° C. was added thionyl chloride (0.65 mL, 8.6 mmol) in a dropwise manner and the mixture was stirred at this temperature for 1 h. The mixture was then partioned with saturated aqueous sodium bicarbonate and ethyl acetate. The organic phase was extracted with ethyl acetate (3×) and the combined organic layers were washed with brine then dried over anhydrous sodium sulfate, filtered and concentrated to afford 1,1-dimethylethyl 1,3-dioxa-2-thia-8-azaspiro[4.5]decane-8-carboxylate 2-oxide (562 mg) as an amber oil that was used without further purification. GC-MS (EI) for C11H19NO5S: 277 (M+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13]([F:16])([F:15])[F:14].[O:17]=[CH:18][C:19]1[CH:27]=[CH:26][C:24]([OH:25])=[C:21]([O:22][CH3:23])[CH:20]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[F:14][C:13]([F:16])([F:15])[C:4]1[CH:5]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:3]=1[CH2:2][O:25][C:24]1[CH:26]=[CH:27][C:19]([CH:18]=[O:17])=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1cc(C=O)ccc1O
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Temperature: 70 °C
Reaction time: 15 h
Yield: 100.2 %

Procedure:
To a flask was added 1-bromomethyl-2,4-bis-trifluoromethyl-benzene (2.27 g, 7.39 mmol), vanillin (1.12 g, 1 equiv), DMF (23 mL) and fine mesh K2CO3 (5.11 g, 37 mmol). The reaction slurry was stirred at 70° C. for 15 h. The reaction solution was diluted with EtOAc (120 mL), filtered through a Buchner funnel, washed with sat NH4Cl (50 mL×2), dried over Na2SO4, filtered, and concentrated. The crude material was chromatographed (SiO2, Hex/EtOAc: 100:0 to 70:30) to yield intermediate product (2.79 g, 86%). 1H NMR (400 MHz, CDCl3) δ 9.88 (s, 1H), 7.97 (d, J=8 Hz, 1H), 7.96 (s, 1H), 7.85 (d, J=8 Hz, 1H), 7.48 (s, 1H), 7.42 (d, J=8 Hz, 1H), 6.93 (d, J=8 Hz, 1H), 5.48 (s, 2H), 3.99 (s, 3H); MS (ESI) 379 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]2[NH:6][N:7]=[N:8][C:4]=2[CH:3]=1.[Br:12]Br>C(O)(=O)C>[Br:12][C:9]1[C:5]2[N:6]=[N:7][NH:8][C:4]=2[CH:3]=[C:2]([CH3:1])[C:10]=1[CH3:11]
Reactant: BrBr
Reactant: Cc1cc2nn[nH]c2cc1C
Solvent: CC(=O)O
Product: Cc1cc2[nH]nnc2c(Br)c1C
Temperature: 25 °C

Procedure:
To a solution of 25.0 grams of 5,6-dimethylbenzotriazole in 250 milliliters of acetic acid at 50° C. is slowly added 30.5 grams of bromine in 75 ml. of the same solvent over a 11/4 hour period. The temperature is held at 50° C. for an additional hour and then the reaction mixture is allowed to cool to room temperature. The product is collected by filtration, 19.2 grams (56%), m.p. 255°-262° C. The analytical sample has a m.p. of 259°-261° C.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[C:8](=[O:25])[CH2:9][CH:10]([C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][C:20](=[O:23])[NH:19][C:18]=3[CH:24]=2)[CH2:11][C:12]=1[OH:13])(=[O:6])[CH2:4][CH3:5].[CH2:26](Br)[CH:27]=[CH2:28]>CCCCCC>[C:3]([C:7]1[C:8](=[O:25])[CH2:9][CH:10]([C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][C:20](=[O:23])[N:19]([CH2:28][CH:27]=[CH2:26])[C:18]=3[CH:24]=2)[CH2:11][C:12]=1[OH:13])(=[O:6])[CH2:4][CH3:5]
Reactant: CCC(=O)C1=C(O)CC(c2ccc3c(c2)NC(=O)CO3)CC1=O
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: C=CCN1C(=O)COc2ccc(C3CC(=O)C(C(=O)CC)=C(O)C3)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sixty percent sodium hydride in mineral oil 0.60 g (15 mmol NaH) was washed once with 15 mL of hexane, decanting via pipette. To this was added 1.6 g (5.1 mmol) of 2-propionyl-3-hydroxy-5-(3-oxo-(2H, 4H)-1,4-benzoxazin-6-yl)cyclohex-2-en-1-one in solid portions. The mixture was stirred at room temperature for 15 minutes, treated with 1.4 g (12 mmol) of allyl bromide and stirred at room temperature for 30 minutes. The mixture was poured into 100 mL of ice cold 0.2N HCl and extracted twice with 30 mL portions of a 5:1 ether-ethyl acetate mixture. The extracts were combined, washed with water, an aqueous NaCl solution, dried over MgSO4, filtered and the solvent evaporated off to give the crude product, as a yellow solid. Recrystallization from ethanol afforded the above-named product in a yield of 1.4 g (77 percent of theoretical). The product melted at 129°-131.5° C.; 1 H NMR (CDCl3): d1.10 (t, J=7 Hz, 3H, --CH3), 2.55-3.56 (m, 7H), 4.52-4.73 (m including s at 4.50 for OCH2, 4H, --NCH2), 5.12-5.42 (m, 2H, --CH=CH2), 5.70-6.15 (m, 1H, --CH=CH2), 6.82-7.10 (m, 3H, aromatic H's), 18.10 (broad s, 1H, enol O--H).