Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:23]1[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:23]3[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1nccc(C(F)(F)F)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2-Chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine (150 mg, 0.69 mmol) was dissolved in 5 mL dimethyl formamide. Potassium carbonate (190 mg, 1.37 mmol) and 2-chloro-4-trifluoromethyl-pyrimidine (189 mg, 0.66 mmol) were added and the reaction mixture was stirred at 80° C. overnight. The reaction mixture was poured into 70 mL water and extracted three times with ethyl acetate (100 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was recrystallized from diethyl ether and the desired compound was obtained as a white solid (190 mg, 76%), MS: m/e=364.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[CH:6]=[CH:5]2.P(Cl)(Cl)([Cl:15])=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:15][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=1
Reactant: O=c1ccc2cc(F)ccc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Fc1ccc2nc(Cl)ccc2c1
Temperature: 95 °C

Procedure:
A mixture of 6-fluoroquinolin-2(1H)-one from Step C, (0.971 g, 6 mmol), phosphorous oxychloride (2.83 mL, 30 mmol), and toluene (20 mL) is heated at 95° C. for 2 hours. The reaction is cooled in an ice bath and basified with 50% aqueous sodium hydroxide. The mixture is extracted with ethyl acetate and the extracts are dried over anhydrous magnesium sulfate, filtered, and concentrated to an orange solid (1.01 g). The residue is flash chromatographed on silica gel Merck-60 with 5% ethyl acetate in hexane to provide the title compound as a light pink solid, m.p. 99–101° C.
Reaction SMILES: II.C(N(CC)CC)C.[CH2:10]([O:17][C:18](=[O:30])[NH:19][CH2:20][CH2:21][C:22](=[O:29])[NH:23][CH2:24][C:25](=O)[CH2:26][CH3:27])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[CH2:10]([O:17][C:18](=[O:30])[NH:19][CH2:20][CH2:21][C:22]1[O:29][C:25]([CH2:26][CH3:27])=[CH:24][N:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCC(=O)CNC(=O)CCNC(=O)OCc1ccccc1
Agent: II
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cnc(CCNC(=O)OCc2ccccc2)o1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred suspension of polymer supported triphenylphosphene (19.6 g, 58.9 mmol) in DCM (250 ml) is added iodine (14.95 g, 58.9 mmol). After stirring at room temperature for 10 minutes, the mixture is treated with triethylamine (16.4 ml, 117.5 mmol) followed by a solution of [2-(2-oxo-butylcarbamoyl)-ethyl]-carbamic acid benzyl ester (step 2) (6.88 g, 23.5 mmol) in DCM (50 ml). The reaction mixture is stirred overnight and then filtered through Celite™ filter material, washed through with DCM (500 ml) and the solvent removed in vacuo to yield the titled compound as a brown solid.
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][CH2:14][C:13]=34)[O:6][N:5]=2)[CH2:3][CH2:2]1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C1COCC1>[C:22]([N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]2[CH:11]=[N:10][C:9]([C:7]3[O:6][N:5]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[N:8]=3)=[C:13]2[CH2:14]1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc2c(c1)NCc1c(-c3nc(C4CC4)no3)ncn1-2
Solvent: C1CCOC1
Product: CC(=O)N1Cc2c(-c3nc(C4CC4)no3)ncn2-c2ccccc21

Procedure:
A mixture of 3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-4,5-dihydroimidazo[1,5-a]quinoxaline (XXXIII, EXAMPLE 101, 0.201 g) and acetic anhydride (3 ml) in THF (0.7 ml) is heated at 80° for 45 min. The reaction mixture is then cooled, concentrated, and partitioned between dichloromethane and aqueous sodium bicarbonate. The organic phase is separated and filtered through sodium sulfate and concentrated. The crude product is crystallized from dichloromethane and hexane to give the title compound, which is then recrystallized from ethyl ether/ethyl acetate/hexane, mp 202.0°-202.5°; MS (m/z) at 321; IR (mineral oil) 1674, 1639, 1501, 1358 and 1401 cm-1 ; NMR (CDCl3) 1.15, 2.18, 2.29, 5.32, 7.41, 7.62 and 8.15 δ.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4](=[O:8])[O:5][C:6]=1[CH3:7].C1C(=O)N([Br:16])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:16][CH2:1][C:2]1[O:3][C:4](=[O:8])[O:5][C:6]=1[CH3:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1oc(=O)oc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1oc(=O)oc1CBr
Temperature: 80 °C
Yield: 98 %

Procedure:
4,5-dimethyl-2-oxo-1,3-dioxole (5 g, 43.82 mmol), NBS (8.19 g, 46.01 mmol), and benzoyl peroxide (20 mg) were dissolved in CCl4 (30 mL) and heated to 80° C. for 1.5 h. The reaction mixture was cooled to r.t and the solid was filtered off. The filtrate was concentrated. The residue was purified by silica gel column to give 8.29 g of 4-bromomethyl-5-methyl-2-oxo-1,3-dioxole as a yellow oil. TEA (12 mL, 86.1 mmol) was added dropwise to a solution of 4-bromomethyl-5-methyl-2-oxo-1,3-dioxole (6 g, 310.09 mmol) and formic acid (3.36 mL) in CH3CN (96 mL) while keeping the temperature under 20° C. The mixture was stirred at r.t. for 2 h and concentrated. The product was partitioned between H2O and EtOAc (3×). The organic layer was dried with Na2SO4, concentrated and dried in vacuo to give crude formate. The resulting formate was dissolved in MeOH (40 mL) and 0.5 mL of concentrated HCl was added. The mixture was stirred at r.t. for 5 h, concentrated, and co-evaporated with toluene. The crude product was purified by silica gel column to give 2.8 g of 4-hydroxymethyl-5-methyl-2-oxo-1,3-dioxole in 69% yield. 1H NMR (300 MHz, CDCl3): δ 4.40 (s, 2H), 2.60 (broad, s, 1H), 2.20 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O.C(OCC)C>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:4]([CH:3]=1)[CH:5]=[O:6]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1cccc(Br)c1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: O=Cc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-Bromo-benzaldehyde (18.50 g, 99.99 mmol) was added to a stirred solution of concentrated nitric acid (70%, 13.09 mL, 199.98 mmol) in concentrated sulfuric acid (125 mL) at 0° C. After the addition was complete, the ice bath was removed and the reaction was allowed to stir for 5 hours at room temperature. Then, the mixture was poured into ice and the solid was collected by filtration. The filtrate was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was combined with the solid previously obtained via the first filtration and dissolved in diethyl ether. Hexanes were added and after crystallization 14.66 g (64%) of 5-bromo-2-nitro-benzaldehyde was collected by filtration and drying. 1H NMR (400 MHz, d6-DMSO): δ 10.19 (s, 1H), 8.10 (s, 2H), 8.02 (s, 1H).
Reaction SMILES: [CH:1]([NH:3][CH:4]1[C:12]2[CH:11]=[CH:10][S:9][C:8]=2[CH2:7][CH2:6][CH2:5]1)=[O:2].C(O)(=[O:15])C>>[CH:1]([NH:3][CH:4]1[C:12]2[CH:11]=[CH:10][S:9][C:8]=2[C:7](=[O:15])[CH2:6][CH2:5]1)=[O:2]
Reactant: CC(=O)O
Reactant: O=CNC1CCCc2sccc21
Product: O=CNC1CCC(=O)c2sccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 22.4 g of ceric sulfate in 50% aqueous acetic acid is stirred overnight at room temperature and 2 g of N-formyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine is added. After 6 hours, the mixture is filtered, and the filter cake is washed with 50% aqueous acetic acid. The work-up procedure of Example 1 is then followed with the filtrate to give 1.1 g of the title compound, m.p. 102 to 114° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH3:7])[C:4]([OH:6])=[O:5].[CH2:8]([O:15][C:16](Cl)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1.O>[C:16]([NH:1][CH2:2][CH:3]([CH3:7])[C:4]([OH:6])=[O:5])([O:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:17]
Reactant: CC(CN)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CC(CNC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C

Procedure:
In a mixture of 10 ml of pyridine and 10 ml of water was dissolved 500 mg of β-amino-isobutyric acid, and 1.5 ml of benzyloxycarbonyl chloride was dropped thereinto with stirring at 0° C. After completion of the dropping, the resulting mixture was stirring of room temperature for 3 hours, after which the pyridine was removed under reduced pressure. Then, hydrochloric acid was added to the residue, and the resulting mixture was extracted with ethyl acetate. The ethyl acetate layer obtained was washed successively with diluted hydrochloric acid, water and an aqueous sodium chloride solution, and then concentrated to obtain an oily substance. Subsequently, the oily substance was washed with a mixed solvent of ether and hexane to obtain 380 mg of the desired compound.
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].S(=O)(=O)(O)O.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([C:25]([OH:27])=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1.[CH2:28]=[C:29]([CH3:31])[CH3:30]>O.C1(C)C=CC=CC=1>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([C:25]([O:27][C:29]([CH3:31])([CH3:30])[CH3:28])=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reaction time: 0.03 h
Yield: 94.7 %

Procedure:
A 100-ml flask was charged with 5 ml of toluene, 0.24 g (2 mmol) of anhydrous magnesium sulfate and 0.11 ml (2 mmol) of concentrated sulfuric acid, and they were vigorously stirred. To this mixture was added 2.12 g (10 mmol) of 4′-methyl-2-biphenylcarboxylic acid, and isobutene gas (98 mmol) was introduced thereto at a flow rate of 1.2 liter/min for 2 minutes. The resulting mixture was stirred at room temperature for 6 hours. After having confirmed that almost all of the peaks ascribed to 4′-methyl-2-biphenylcarboxylic acid disappeared by HPLC, 4 ml of deionized water was poured into the mixture, and sufficiently stirred. Thereafter, the mixture was allowed to stand to separate into layers. The upper toluene layer was taken out therefrom, and the toluene layer was washed with a 1.5 M aqueous sodium hydroxide, and dried over anhydrous magnesium sulfate. Thereafter, the toluene layer was concentrated by distilling off toluene by using a rotary evaporator, to give 2.54 g of tert-butyl 4′-methyl-2-biphenylcarboxylate as crystals (yield: 95% based on 4′-methyl-2-biphenylcarboxylic acid, purity by HPLC: 99.9%).
Reaction SMILES: [NH:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[N:3]1[CH2:13][CH:14]=[CH2:15].[Br:16]N1C(=O)CCC1=O>CS(C)=O.O>[Br:16][CH2:15][CH:14]1[CH2:13][N:3]2[C:4](=[O:12])[NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]2=[N:1]1
Reactant: C=CCn1c(=O)[nH]c2ccccc2c1=N
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CS(C)=O
Product: O=C1Nc2ccccc2C2=NC(CBr)CN12
Temperature: 25 °C
Yield: 64.3 %

Procedure:
To a solution of 3,4-dihydro-4-imino-3-allyl-2(1H)-quinazolinone (0.5 g, 2.5 mmol) in dimethylsulfoxide (2.5 mL) and water (1 mL) was added N-bromosuccinimide (0.87 g, 5.0 mmol). The mixture was allowed to stir at room temperature and then was quenched with water (100 mL) to get solid. The solid was collected by filtration and washed with water to give 2-bromomethyl-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one (450 mg, 64%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]1([S:15]([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20](B3OC(C)(C)C(C)(C)O3)=[CH:19]2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+]>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.COCCOC>[Cl:1][C:2]1[N:7]=[C:6]([C:20]2[C:21]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[N:18]([S:15]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)(=[O:17])=[O:16])[CH:19]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)OC1(C)C
Reactant: Clc1ccnc(Cl)n1
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: [K+]
Solvent: COCCOC
Product: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Temperature: 85 °C
Yield: 73.8 %

Procedure:
2,4-dichloropyrimidine (0.192 g, 1.29 mmol), 1-(phenylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (0.45 g, 1.17 mmol), K2CO3 (1.17 ml, 2.34 mmol), 1,2-dimethoxyethane (5 ml) and tetrakis(triphenylphosphine)palladium (0.054 g, 0.047 mmol) were placed in a 25 mL of flask. The flask was evacuated and purged with nitrogen. The mixture was heated at 85° C. for 20 min then cooled to room temperature. The reaction mixture was filtered to give the title compound (320 mg, 73.7% yield) as white solids.
Reaction SMILES: [CH2:1]([N:4]([CH:10]([CH3:16])[CH:11](OC)[O:12]C)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:2]=[CH2:3]>C(O)=O>[CH2:1]([N:4]([CH:10]([CH3:16])[CH:11]=[O:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCN(C(=O)OCC)C(C)C(OC)OC
Solvent: O=CO
Product: C=CCN(C(=O)OCC)C(C)C=O
Temperature: 0 °C

Procedure:
76.5 g (0.213 mol) of 64.5% pure N-allyl-N-(1,1-dimethoxyprop-2-yl)-urethane are heated in 180 ml of formic acid at 100° C. for one hour. The mixture is poured into ice-water and extracted with CH2Cl2, the extracts are washed neutral with NaHCO3 solution, dried over MgSO4 and concentrated and the residue is distilled.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[C@@H:12]1[CH2:14][C@H:13]1[CH2:15][NH2:16].C(N(CC)CC)C.[C:24](OC(=O)C)(=[O:26])[CH3:25]>O1CCCC1.C(=O)([O-])O.[Na+]>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[C@@H:12]1[CH2:14][C@H:13]1[CH2:15][NH:16][C:24](=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: Cn1cc2c([C@@H]3C[C@H]3CN)c(F)ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@@H]1C[C@H]1c1c(F)ccc2nn(C)cc12
Yield: 85.7 %

Procedure:
To a solution of trans-1-[2-(5-fluoro-2-methyl-2H-indazol-4-yl)cyclopropyl]methanamine (95.0 mg, 0.433 mmol) and triethylamine (72.4 μL, 0.520 mmol) in tetrahydrofuran (5 mL) was added acetic anhydride (45.1 μL, 0.477 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 5 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate=0/100→5/95) to give the title compound (97 mg, yield 86%).
Reaction SMILES: C(N(CC)CC)C.[C:8]([OH:16])(=[O:15])/[C:9](=[C:11](\[CH:13]=O)/[Br:12])/Br.[CH3:17][S:18][C:19](=[NH:21])[NH2:20].Cl>O>[Br:12][C:11]1[C:9]([C:8]([OH:16])=[O:15])=[N:20][C:19]([S:18][CH3:17])=[N:21][CH:13]=1
Reactant: CSC(=N)N
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CSc1ncc(Br)c(C(=O)O)n1
Temperature: 5 °C
Reaction time: 3 h

Procedure:
At 5° C. triethylamine (16.9 ml) was added dropwise to a solution of mucobromic acid (10.31 g) and 2-methyl-isothiourea (11.13 g) in water (200 ml). After stirring at 5° C. for 3 h, the reaction mixture was allowed to warm up (room temperature) and stirring was continued for another 54 h. The reaction mixture was acidified with conc. HCl (33%). The title product was obtained by filtration. Yield: 4.1 g. MS-ESI: [M+H]+=249/251
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[BH4-].[Na+]>CO>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCC2(CC1)OCCO2
Temperature: -5 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
1,4-dioxaspiro[4.5]decan-8-one (150 g, 0.96 mol) was stirred with MeOH (1200 mL) under N2 until dissolution occurred. Cooled to −5° C. in a drykold/acetone bath and treated portionwise with NaBH4 (72.6 g, 1.82 mol) over 2 hrs. (T<10° C.). On complete addition, the mixture was cooled to −10° C. and then left to warm to room temperature. Stirred overnight at room temperature. The resulting mixture was evaporated and treated with ice-cold 5N NaOH (400 mL) and extracted with CH2Cl2 (2×500 mL) followed by extraction with 4:1 dichloromethane: isopropanol (2×250 mL). The combined extracts were washed with brine (2×200 mL), dried overnight (Na2SO4) and evaporated to give a colourless oil. This was further dried in vacuo to give 1,4-dioxaspiro[4.5]decan-8-ol (141.8 g, 93% yield.) 1H NMR: CDCl3 (250 MHz) 3.91 (4H, m), 3.81 (1H, m), 1.21-1.88 (8H, m, aliphatic H's).
Reaction SMILES: CC1(C)[O:9][C:7](=[O:8])[CH2:6][C:4](=O)O1.C(=O)[C:12]1[CH:21]=[CH:20][C:17]([O:18][CH3:19])=[C:14]([O:15][CH3:16])[CH:13]=1.C(O)=O>C(N(CC)CC)C>[CH3:16][O:15][C:14]1[CH:13]=[C:12]([CH2:4][CH2:6][C:7]([OH:9])=[O:8])[CH:21]=[CH:20][C:17]=1[O:18][CH3:19]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: O=CO
Solvent: CCN(CC)CC
Product: COc1ccc(CCC(=O)O)cc1OC

Procedure:
7.2 g (0.05 mol) of Meldrum's acid and 8.3 g (0.05 mol) of veratraldehyde were weighed to 40 ml of the mixture of formic acid and triethylamine recovered by distillation in Example 3. The reaction was carried out and the final product was separated as described in Example 3. The volume of the mixture of formic acid and triethylamine recovered amounted to 28 ml.
Reaction SMILES: [Cl:1][C:2]1[C:3](O)=[N:4][CH:5]=[C:6]([I:8])[CH:7]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:11].O=P(Cl)(Cl)Cl>C(Cl)Cl>[Cl:11][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([I:8])=[CH:5][N:4]=1
Reactant: Oc1ncc(I)cc1Cl
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: Clc1cc(I)cnc1Cl
Temperature: 130 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
A 100 ml 3-necked round bottom flask, fitted with a condenser topped with a N2 inlet, a mechanical stirrer and a thermometer, was charged with 17.2 g (0.0673 mole) of 3-chloro-2-hydroxy-5-iodopyridine, 14.85 g (0.0713 mole) of PCl5, and 1 ml (1.68 g; 0.0109 mole) of POCl3. The reaction mixture, containing solids, was slowly stirred and slowly heated to 130° C. The reaction mixture was stirred under N2 for 5 hours after which it was cooled to room temperature and allowed to stand overnight. The reaction mixture was cautiously poured into crushed ice and allowed to stand for 1 hour. Methylene chloride (200 ml) was added to the reaction mixture to dissolve the solids present in it. The layers was separated and the organic phase was washed with dilute base, water and saturated NaCl. After drying over anhydrous MgSO4 and filtration, the solvent was evaporated leaving 11.8 g of a yellow solid. The solid was recrystallized from methanol resulting in 6.60 g of solid that had spectral and physical properties identical to the product obtained in Example 1, STEP D.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([C:17]#[N:18])=[CH:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH2:19]([Mg]Br)[CH2:20][CH:21]=[CH2:22].[Cl-].[NH4+]>C1COCC1.[Cu]I>[CH2:1]([O:3][P:4]([CH:9]([C:17]#[N:18])[CH:10]([CH:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)[CH2:22][CH2:21][CH:20]=[CH2:19])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: C=CCC[Mg]Br
Reactant: CCOP(=O)(OCC)C(C#N)=CC1CCOCC1
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCCC(C1CCOCC1)C(C#N)P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of the oil isolated in Step A (51.26 g, 188 mmol) and CuI (1.00 g) in THF (200 mL) at −30° C., 3-butenylmagnesium bromide in THF (0.5 M, 394 mL, 197 mmol) was added slowly. The reaction mixture was stirred at room temperature overnight. Aqueous saturated ammonium chloride solution (300 mL) was then added. The reaction mixture was stirred 30 min at room temperature and then was extracted with ethyl acetate (400 mL) once. The organic solution was washed with saturated ammonium chloride solution three times, with brine one time and then was dried over magnesium sulfate. The reaction mixture was then filtered and concentrated to yield a residue. The residue was purified by Kugelrohr distillation to yield [1-cyano-2-(tetrahydro-pyran-4-yl)-hex-5-enyl]-phosphonic acid diethyl ester as a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]([C:5](=[N:11][O:12][CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:4].[SH:14][CH2:15][CH2:16]O.Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[O:4]1[C:3]([C:5](=[N:11][O:12][CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:2][S:14][CH2:15][CH2:16]1
Reactant: OCCS
Reactant: CCOC(=O)C(=NOC)C(=O)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=NOC)C1=CSCCO1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 29 %

Procedure:
A solution of ethyl 2-chloroacetyl-2-methoxyiminoacetate (65 g.) in dry chloroform (130 ml.) was added to a stirred mixture of 2-mercaptoethanol (25 g.), triethylamino (35 g.) and dry chloroform (70 ml.) at 20° C. over 30 minutes, and stirred at the same temperature for 2.5 hours. After the solution was adjusted to pH 1.0 with 10% hydrochloric acid under ice cooling, the chloroform layer was separated, washed with water twice and dried over magnesium sulfate. The solution was concentrated in vacuo at 40° C. to give yellow oil. The oil was dissolved in toluene (600 ml.), and then p-toluenesulfonic acid (5.5 g.) was added to the toluene solution. The solution was heated under reflux for 2 hours while removing the produced water. The resultant solution was allowed to cool at room temperature and filtered. The filtrate was washed with water (100 ml.) three times, a saturated aqueous solution of sodium bicarbonate (100 ml.) twice and water (100 ml.) twice in turn, and then dried over magnesium sulfate. The solution was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel "Kieselgel 60" [Trademark: manufactured by E. Merck] (1 kg.) and eluted with benzene. After the eluate was concentrated under reduced pressure, the residue was washed with diisopropyl ether and dried to give ethyl 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-methoxyiminoacetate (syn isomer, 21 g.), pale yellow crystals, mp. 64° to 66° C.
Reaction SMILES: CS[C:3]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[C:4]([C:7]#[N:8])[C:5]#[N:6].[NH2:16][NH2:17]>CCO>[NH2:6][C:5]1[NH:17][N:16]=[C:3]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4]=1[C:7]#[N:8]
Reactant: CSC(Nc1ccccc1)=C(C#N)C#N
Reactant: NN
Solvent: CCO
Product: N#Cc1c(Nc2ccccc2)n[nH]c1N
Temperature: 0 °C
Yield: 87.9 %

Procedure:
A mixture of compound 6 (3.2258 g, 14.85 mmol) and hydrazine (742 mg, 23.16 mmol) in EtOH (20 mL) was refluxed for 30 min, at which time the reaction was complete as determined by TLC. The reaction mixture was poured into 100 mL ice water. The resulting precipitate was filtered and dried to give compound 7 (2.599 g, 88.1% yield, 99.8% purity) as a white powder.