Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:16][C:15](=[O:17])[C:14]2=[C:18]([CH3:30])[N:19]=[C:20]([CH2:21][CH:22]([CH2:28][CH3:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:13]2[N:12]=1)[CH2:2][CH3:3].[S:31](Cl)([Cl:34])(=[O:33])=[O:32]>>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:31]([Cl:34])(=[O:33])=[O:32])=[CH:7][C:6]=1[C:11]1[NH:16][C:15](=[O:17])[C:14]2=[C:18]([CH3:30])[N:19]=[C:20]([CH2:21][CH:22]([CH2:28][CH3:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:13]2[N:12]=1)[CH2:2][CH3:3]
Reactant: CCCCCC(CC)Cc1nc(C)c2c(=O)[nH]c(-c3ccccc3OCCC)nn12
Reactant: O=S(=O)(Cl)Cl
Product: CCCCCC(CC)Cc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCCC)nn12

Procedure:
The preparation is carried out analogously to the procedure of Example 27A using 1.4 g (3.41 mmol) of 2-(2-propoxyphenyl)-5-methyl-7-(2-ethylheptyl)-3H-imidazo-[5,1-f]-[1,2,4]-triazin-4-one (Example 20A). This gives 1.4 g (80.6%) of sulphonyl chloride as a white foam which is directly reacted further.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:22]([CH:23]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH3:24])=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[C:15]([F:33])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O.[OH-].[Li+].Cl>O1CCCC1.O>[C:1]12([CH2:11][O:12][C:13]3[C:22]([CH:23]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28])[CH3:24])=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[C:15]([F:33])[CH:14]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: COC(=O)c1cc(C(C)O[Si](C)(C)C(C)(C)C)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(O[Si](C)(C)C(C)(C)C)c1cc(C(=O)O)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of methyl 4-(adamantan-1-ylmethoxy)-5-(1-((tert-butyldimethylsilyl)oxy)-ethyl)-2-fluorobenzoate in tetrahydrofuran (10 mL) was added a solution of lithium hydroxide monohydrate (0.151 g, 3.6 mmol) in water (5 mL) at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 2 days. After adjusting the reaction mixture to pH 5 with 1 N hydrochloric acid, the mixture was extracted with dichloromethane (3×20 mL). The combined organic phase was washed with brine (5 mL), dried over anhydrous sodium sulfate, and filtered. Concentration of the filtrate in vacuo yielded the title compound as a yellowish oil (0.33 g, quant.), which was used without further purification: MS (ES+) m/z 461.4 (M−1).
Reaction SMILES: C(#N)C.[C:4]1([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:12])=[O:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CO.O>[C:4]1([S:10]([N:13]([C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)(=[O:12])=[O:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc(NS(=O)(=O)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(N(C(=O)c2ccccc2)S(=O)(=O)c2ccccc2)cc1
Yield: 95.8 %

Procedure:
250 ml of an acetonitrile solution containing 60 g (0.24 mole) of N-benzenesulfonyl-p-toluidine synthesized by the same method as in Synthesis Example 1 and 37 ml (0.27 mole) of triethylamine was cooled to below 10° C. and while maintaining this temperature, 35.8 g (0.26 mole) of benzoyl chloride was added dropwise. After the addition, the mixture was further reacted at room temperature for 30 minutes. The reaction mixture was then added to 1 liter of water. The precipitate was collected by filtration, washed with water and then with methanol to give 80.8 g (0.23 mole) of the captioned compound.
Reaction SMILES: [OH:1][C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].CC1C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1.[O:27]1[CH:32]=[CH:31][CH2:30][CH2:29][CH2:28]1.C(OCC)C>ClCCl>[CH3:8][C:2]([O:1][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][O:27]1)([CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: C1=COCCC1
Reactant: CCOC(=O)C(C)(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(C)(C)OC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a solution of ethyl 2-hydroxy-2-methylpropanoate (5.20 mL, 38.06 mmol) in dichloromethane (100 mL) were sequentially added pyridine 4-methylbenzenesulfonate (1.0 g, 3.80 mmol) and 3,4-dihydro-2H-pyran (5.20 ml, 57.0 mmol). The resulting mixture was stirred at room temperature overnight. Ethyl ether was added (600 mL) and the resulting organic layer was washed with brine (3×100 ml), dried over anhydrous sodium sulphate and the solvent removed under reduced pressure to give the title compound (7.85 g, 95%).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[CH:23])=[CH:18][CH:17]=2)=[CH:11][C:10]=1[C:24]([F:27])([F:26])[F:25].Cl[C:29]1[CH:39]=[C:33]2[N:34]([CH3:38])[CH2:35][CH2:36][CH2:37][N:32]2[C:31](=[O:40])[N:30]=1>C1COCC1.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]#[C:23][C:29]3[CH:39]=[C:33]4[N:34]([CH3:38])[CH2:35][CH2:36][CH2:37][N:32]4[C:31](=[O:40])[N:30]=3)=[CH:20][CH:21]=2)=[CH:11][C:10]=1[C:24]([F:25])([F:26])[F:27]
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: C#Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCCn2c1cc(C#Cc1ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc1)nc2=O
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 13 %

Procedure:
A suspension of bis(triphenylphosphine)palladium(II) chloride (70.3 mg, 0.1 mmol) and copper(I) iodide (19.1 mg, 0.1 mmol) in anhydrous THF (12 mL), was purged with Ar for 10 mins at rt. The suspension was treated with triethylamine (0.42 mL, 3.0 mmol), and 1-chloro-4-(4-ethynylphenoxy)-2-(trifluoromethyl)benzene (446 mg, 1.5 mmol) was added under an Ar atmosphere, which produced a dark amber color. After 5 mins, 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one (100 mg, 0.5 mmol) was added, and stirred for 2 h at 50° C. The reaction mixture was diluted with EtOAc, washed with water, and then concentrated. The residue was purified by MDAP to afford the title compound (30 mg) as a pale yellow solid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6]3[C:7](=[C:12]([S:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:13]=[CH:14][C:5]=3[C:4](=[O:22])[N:3]1[CH2:23][C:24]([OH:26])=[O:25])[CH:8]=[CH:9][CH:10]=2.[CH2:27](O)[CH3:28].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:27]([O:25][C:24](=[O:26])[CH2:23][N:3]1[C:4](=[O:22])[C:5]2[CH:14]=[CH:13][C:12]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:7]3[C:6]=2[C:11](=[CH:10][CH:9]=[CH:8]3)[C:2]1=[O:1])[CH3:28]
Reactant: CCO
Reactant: O=C(O)CN1C(=O)c2cccc3c(Sc4ccccc4)ccc(c23)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CN1C(=O)c2cccc3c(Sc4ccccc4)ccc(c23)C1=O

Procedure:
1,3-Dioxo-6-(phenylthio)-1H-benz[de]isoquinoline-2(3H)-acetic acid (3.55 g, 9.77 mmoles; described in Example 1), anhydrous pure ethanol (12 ml), toluene (30 ml) and p-toluenesulfonic acid hydrate (0.2 g) were heated at reflux for 16 hr in a Soxhlet apparatus in which the thimble was filled with hydrated alkali-aluminium silicate (3 A Molecular Sieves). The resulting clear mixture was washed with water (2×80 ml), 5% sodium bicarbonate (2×80 ml) and brine (100 ml), dried (MgSO4) and concentrated to dryness. The residue was crystallized from isopropyl ether-carbon tetrachloride (1:1, 60 ml) to give 2.85 g of the title compound; mp 132°-134° C.; UV (MeOH) 231 and 344 nm, ε=25,170 and 7,360 respectively; IR (CHCl3) 1743, 1695 and 1660 cm-1 ; NMR (CDCl3) δ1.25 (t, 3H, J=7 Hz), 4.15 (q, 2H, J=7 Hz), 4.85 (s, 2H), 7.15-8.65 (m, 10H); Anal. Calc'd.: C, 67.50%; H, 4.38%; N, 3.58%; Found: C, 67.87%; H, 4.44%; N, 3.50%.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][O:8][C:4]=2[CH:3]=1.C([Li])CCC.Br[C:17]1[CH:25]=[CH:24][C:20]([CH2:21][C:22]#[N:23])=[C:19]([F:26])[CH:18]=1.C([O-])(O)=O.[Na+]>C1COCC1.[Cl-].[Cl-].[Zn+2].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:26][C:19]1[CH:18]=[C:17]([C:7]2[O:8][C:4]3[CH:3]=[C:2]([CH3:1])[CH:10]=[CH:9][C:5]=3[N:6]=2)[CH:25]=[CH:24][C:20]=1[CH2:21][C:22]#[N:23]
Reactant: Cc1ccc2ncoc2c1
Reactant: N#CCc1ccc(Br)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1ccc2nc(-c3ccc(CC#N)c(F)c3)oc2c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 6-methylbenzoxazole (173 mg, 1.3 mmol) in THF (5 mL) at −78° C., was added n-Butyllithium (640 μL, 2.5M in hexanes, 1.6 mmol). The resulting reaction mixture was stirred for 15 min at −78° C. and ZnCl2 (3.9 mL, 1M in Et2O, 3.9 mmol) was added via a syringe. After warming up the reaction mixture at 0° C. for 1 h, a solution of 4-bromo-2-fluoro benzyl cyanide (214 mg, 1.0 mmol) in THF (2 mL) was added, along with Pd0 (a fresh suspension prepared as follows: 200 μL n-Butyllithium, 2.5M in hexanes added to 144 mg of PdCl2(PPh3)2 in 5 mL of THF). The mixture was then heated under reflux overnight. The mixture was hydrolized with sat. NaHCO3 (50 mL) and extracted with EtOAc (3×150 mL). The organic layers were combined, washed with H2O (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel using a mixture of hexanes:EtOAc (5:1) as eluant to afford [2-fluoro-4-(6-methyl-1,3-benzoxazol-2-yl)phenyl]acetonitrile as yellow solid. 1H NMR (CD3OD, 300 MHz), δ8.07 (d, 1H), 7.95(d, 1H), 7.64(m, 2H), 7.40(s, 1H), 7.20(d, 11H), 3.90(s, 1H). MS (ESI) 267 (M+H)+.
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[CH:19]1([NH2:22])[CH2:21][CH2:20]1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>O1CCCC1>[N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[CH:19]1([NH-:22])[CH2:21][CH2:20]1
Reactant: NC1CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: [NH-]C1CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 124.6 g (0.5 mol) of Z-Pro-OH, 34.8 ml of cyclopropyl amine and 67.5 g HOBt in 200 ml of absolute tetrahydrofurane 110 g of DCC were added at 0° C, the solution was stirred for one hour at 0° C and allowed to stand over night at room temperature. The deposit was suction-filtered and the filtrate was concentrated. The residue was taken up in ethyl acetate and extracted with saturated NaHCO3 -solution, 2N HCl, saturated NaHCO3 -solution and water, dried over Na2SO4 and concentrated. The residue was triturated with petroleum ether and suction-filtered. The ethyl acetate/petroleum ether was recrystallized.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]([CH3:16])[CH2:12][C@H:13]1[CH2:15][O:14]1)(=[O:10])=[O:9].[CH3:17][C:18]([NH2:31])([CH3:30])[CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1.Cl([O-])(=O)(=O)=O.[Li+].O>C(#N)C.[Cl-].[Na+].O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]([CH2:12][C@H:13]([OH:14])[CH2:15][NH:31][C:18]([CH3:30])([CH3:17])[CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)[CH3:16])(=[O:10])=[O:9]
Reactant: CN(C[C@H]1CO1)S(=O)(=O)c1ccccc1Br
Reactant: CC(C)(N)Cc1ccc2ccccc2c1
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CN(C[C@H](O)CNC(C)(C)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccccc1Br
Temperature: 25 °C
Yield: 78.7 %

Procedure:
(S)-2-Bromo-N-methyl-N-(oxiran-2-ylmethyl)benzenesulfonamide (Exp. 1-1, 3.06 g) was dissolved in acetonitrile (25 mL), 2-methyl-1-(naphthalen-2-yl)propan-2-amine (am1, 1.99 g) and lithium perchlorate (KANTO, 1.06 g) were added thereto followed by reflux for 6 hours and 35 minutes. After cooling to room temperature, same amount of water and brine was added to the reaction solution and extraction was carried out with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography to obtain the target compound (3.97 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:16]([O:20][C:21]([N:23]1[C@@H:27]([CH:28]=O)[CH2:26][O:25][C:24]1([CH3:31])[CH3:30])=[O:22])([CH3:19])([CH3:18])[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.ClCCl>[C:16]([O:20][C:21]([N:23]1[C@@H:27]([CH2:28][N:13]2[CH2:14][CH2:15][CH:10]([C:8](=[O:9])[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:11][CH2:12]2)[CH2:26][O:25][C:24]1([CH3:30])[CH3:31])=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1[C@@H](C=O)COC1(C)C
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](CN2CCC(C(=O)c3ccc(F)cc3)CC2)COC1(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (4-fluoro-phenyl)-piperidin-4-yl-methanone (3.5 g, 17 mmol) in dry tetrahydrofuran (50 ml) is added (R)-4-formyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (3.9 g, 17 mmol) and sodium triacetoxyborohydride (5.4 g, 25 mmol), and the reaction mixture stirred for 18 hours at ambient temperature. The reaction mixture is filtered and the solvent evaporated to give a white solid. The solid is taken up in dichloromethane (50 ml) and washed with saturated sodium bicarbonate solution (50 ml), water (2×50 ml) and brine (50 ml). The organic phase is dried over magnesium sulphate and evaporated to afford the product, [MH]+420.9.
Reaction SMILES: C1(C(C2C=CC=CC=2)CC(O)=O)C=CC=CC=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:27][C:28]([OH:30])=O)[CH:22]=[CH:23][C:24]=1[Cl:25]>>[Cl:18][C:19]1[CH:20]=[C:21]([CH:26]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:28](=[O:30])[CH2:27]2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: O=C(O)CC(c1ccccc1)c1ccc(Cl)c(Cl)c1
Agent: O=C(O)CC(c1ccccc1)c1ccccc1
Product: O=C1CC(c2ccc(Cl)c(Cl)c2)c2ccccc21

Procedure:
The intermediate 3-(3,4-dichlorophenyl)-1-indanone was prepared using a procedure similar to that described in Example 1a except replacing the 3,3-diphenylpropionic acid used therein with 3-(3,4-dichlorophenyl)-3-phenylpropionic acid.
Reaction SMILES: [H-].[Na+].[Cl:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[OH:10].[Cl:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:11][C:12]1[CH:17]=[C:16]([O:10][CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]2[Cl:3])[N:15]=[CH:14][N:13]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OC1CCCCC1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Clc1cc(OC2CCCCC2Cl)ncn1
Temperature: 0 °C
Yield: 46 %

Procedure:
In 4.7 ml of tetrahydrofuran was suspended 0.12 g of sodium hydride (60% in oil), to which 1 ml of a tetrahydrofuran solution containing 0.45 g of 2-chlorocyclohexanol was slowly added dropwise with stirring at 0° C. The mixture was stirred at 0° C. for 10 minutes, to which 1 ml of a tetrahydrofuran solution containing 0.5 g of 4,6-dichloropyrimidine was added at 0° C., followed by further stirring for 20 minutes. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.38 g of 4-chloro-6-(2-chlorocyclohexyloxy)pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12](=[N:25][OH:26])[CH2:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH:33]1([CH2:36]Br)[CH2:35][CH2:34]1.O>CN(C)C=O>[Cl:1][C:2]1[C:3](/[C:12](=[N:25]/[O:26][CH2:36][CH:33]2[CH2:35][CH2:34]2)/[CH2:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])=[N:4][CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CC(=NO)c1ncc(C(F)(F)F)cc1Cl
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1C/C(=N\OCC1CC1)c1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.6 %

Procedure:
To 300 mg of N-[2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-2-(hydroxyimino)ethyl]phthalimide in 5 ml of N,N-dimethylformamide, 324 mg of potassium carbonate and 158 mg of cyclopropylmethyl bromide were added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was mixed with 5 ml of water and extracted with ethyl acetate (5 ml×3), the resulting organic layers were combined, washed with water and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure liquid chromatography (preparative medium pressure chromatograph: YFLC-Wprep manufactured by Yamazen Science, Inc.) using ethyl acetate-hexane (with a gradient of from 1:19 to 4:16) as the eluent to obtain 98 mg of the desired product as a pale yellow resinous substance.
Reaction SMILES: [S:1]1[C:8]2[CH:7]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[NH:5][C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[CH3:15][Si:16]([CH2:19][CH2:20][O:21][CH2:22]Cl)([CH3:18])[CH3:17]>C1COCC1>[CH3:15][Si:16]([CH3:18])([CH3:17])[CH2:19][CH2:20][O:21][CH2:22][N:5]1[C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:8]2[S:1][CH:2]=[CH:3][C:4]1=2
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)c1cc2sccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cc2sccc2n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 312.9 %

Procedure:
Methyl 4H-thieno[3,2-b]pyrrole-5-carboxylate (2.8 g, 15.45 mmol) was dissolved in 150 mL anhydrous THF. NaH (3.0 g, 60% oil dispersion, 75 mmol) was added and the reaction stirred for 15 min at rt. SEMCl [(2-trimethylsilyl)-ethoxymethyl chloride] (0.7 mL, 3.95 mmol) was added dropwise over 5 min. The reaction was stirred 1 h at rt and then CAUTIOUSLY poured onto 25 g crushed ice with stirring. The aqueous was extracted with EtOAc, dried (Na2SO4), filtered and evaporated in vacuo to give a green residue. The residue was chromatographed over silica gel (EtOAc in heptane, 3%-10%, 3 h, TLC visualized with KMnO4 with heat) to give methyl 4-(2-trimethylsilanyl-ethoxymethyl)-4H-thieno[3,2-b]pyrrole-5-carboxylate (3.85 g, 80% yield). 1H NMR (400 MHz, (CD3)2CO) δ ppm −0.08 (s, 9H) 0.84 (t, J=7.83 Hz, 2H) 3.54 (t, J=7.88 Hz, 2H) 3.83 (s, 3H) 5.94 (s, 2H) 7.21-7.25 (m, 1H) 7.26 (s, 1H) 7.55 (d, J=5.37 Hz, 1H).
Reaction SMILES: C([N:5]1[CH2:8][C:7]([N+:12]([O-:14])=[O:13])([N+:9]([O-:11])=[O:10])[CH2:6]1)(C)(C)C.[N+:15](C1([N+]([O-])=O)CNC1)([O-:17])=[O:16].B(F)(F)F.CCOCC.C(OC(=O)C)(=O)C.[N+]([O-])(O)=O>>[CH2:6]1[N:5]([N+:15]([O-:17])=[O:16])[CH2:8][C:7]1([N+:9]([O-:11])=[O:10])[N+:12]([O-:14])=[O:13]
Reactant: CC(C)(C)N1CC([N+](=O)[O-])([N+](=O)[O-])C1
Reactant: O=[N+]([O-])C1([N+](=O)[O-])CNC1
Agent: FB(F)F
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Solvent: O=[N+]([O-])O
Product: O=[N+]([O-])N1CC([N+](=O)[O-])([N+](=O)[O-])C1
Yield: 90 %

Procedure:
The upper reaction scheme is the conversion of the N-tertiarybutyl,3,3 dinitroazetidine to the N-acetyl, 3,3 dinitroazetidine. The reaction conditions are a catalytic amount of boron trifluoride etherate as the Lewis acid and acetic anhydride as the solvent-reactant. The temperature is 125 degrees C. As shown there was about a 90% yield. The compound is nitrated with 70% nitric acid and heated to give TNAZ.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[O:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1.N1([C:23](=[O:33])[CH:24]([O:31][CH3:32])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)C=CN=C1.C(O)(=O)C>C1(C)C=CC=CC=1.O>[CH3:32][O:31][CH:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:23]([CH:13]1[C:14](=[O:17])[CH2:15][CH2:16][O:11][CH2:12]1)=[O:33]
Reactant: COC(C(=O)n1ccnc1)c1ccccc1
Reactant: O=C1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(C(=O)C1COCCC1=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 19.2 %

Procedure:
Lithium bis(trimethylsilyl)amide (2.024 mL, 10.78 mmol) was added to a stirred solution of tetrahydro-4H-pyran-4-one (0.948 mL, 10.27 mmol) in toluene (3 mL) at 0° C. After 2 minutes 1-(1H-imidazol-1-yl)-2-methoxy-2-phenylethanone (1.110 g, 5.13 mmol) was added and the mixture was stirred at 0° C. for 5 minutes. The reaction was quenched with acetic acid (0.882 mL, 15.40 mmol) in 5 mL water. The organic layer was separated and concentrated. The crude product was purified by silica flash chromatography using ethyl acetate (0 to 40%) in heptane giving 3-(2-methoxy-2-phenylacetyl)dihydro-2H-pyran-4(3H)-one (0.245 g, 19%). MS (ES−) m/z 247 (M−H)−
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][C:20]([CH3:26])([CH3:25])[C:19]=3[CH:27]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].I([O-])(=O)(=O)=[O:29].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][C:20]([CH3:25])([CH3:26])[C:19]=3[CH:27]=2)=[O:29])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(Cl)c(Cl)c3)cc21
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1(C)OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(Cl)c(Cl)c3)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
An amount of 2.14 gm (0.005 mol) of 6-[4-(3,4-dichlorophenyl-mercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one is dissolved in 50 ml of methanol, mixed with a solution of 1.3 gm (0.06 mol) of sodium metaperiodate in 10 ml of water, and stirred for two hours at ambient temperature. Then, the mixture is refluxed for three hours, the volume of the reaction mixture is reduced by evaporation to about three-quarters, and water is added. The oil precipitated is separated by decanting of the solvent and is taken up in hot isopropanol/disiopropylether. Upon cooling, crystals are obtained which have a melting point of 138°-139° C.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][N:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([Li])CCC.C([O:25][B:26](OC(C)C)[O:27]C(C)C)(C)C>C(OCC)C.CCCCCC>[CH2:1]([O:9][C:10]1[N:11]=[CH:12][C:13]([B:26]([OH:27])[OH:25])=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(Br)cn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCCCCCCOc1ccc(B(O)O)cn1
Temperature: -75 °C
Reaction time: 0.25 h

Procedure:
2.75 g (10 mmol) of 2-octyloxy-5-bromopyridine are dissolved in 60 ml of absolute diethyl ether, and the solution is cooled to -75° C. under inert gas. 16 mmol of 1.6M butyllithium solution in hexane are added, and the mixture is additionally stirred at -75° C. for 15 minutes. 4.5 g of triisopropylborate in 50 ml of absolute diethyl ether are then added dropwise. The cooling device is then removed. After the batch has warmed to room temperature, 50 ml of 10% HCl are added, and the mixture is additionally stirred at room temperature for 30 minutes. The phases are separated, and the organic phase is washed twice with saturated NaCl solution. The solvent is distilled off in vacuo, and the residue is recrystallized from acetonitrile, giving 6-octyloxypyridine-3-boronic acid.