Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([OH:26])=[CH:10][C:11]([CH2:17][C:18]3[C:19]([NH2:25])=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)=[CH:12][C:13]=2[O:14][CH2:15][CH3:16])[CH:5]=[CH:6][CH:7]=1.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[S:32](Cl)(=[O:34])=[O:33]>>[NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH2:15][CH3:16])=[CH:12][C:11]([CH2:17][C:18]3[C:19]([NH2:25])=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)=[CH:10][C:9]=2[O:26][S:32]([C:28]2[S:27][CH:31]=[CH:30][CH:29]=2)(=[O:34])=[O:33])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(O)c1-c1cccc(N)c1
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)c2cccs2)c1-c1cccc(N)c1
Yield: 51.7 %

Procedure:
Starting from 3′-amino-4-(2,4-diamino-pyrimidin-5-ylmethyl)-6-ethoxy-biphenyl-2-ol (100 mg; 0.28 mmol) and 2-thienylsulfonyl chloride (94 mg; 0.51 mmol), 72 mg of the title compound are isolated as a yellow foam.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3]1.ClC1C=CC=C(C(OO)=[O:27])C=1.C(OCC)C>ClCCl>[CH3:1][C:2]1([CH3:18])[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=2[O-:27])[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3]1
Reactant: CC1(C)C=C(c2ccccn2)c2ccccc2O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOCC
Product: CC1(C)C=C(c2cccc[n+]2[O-])c2ccccc2O1
Yield: 2 %

Procedure:
1.61 g of 2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran were dissolved in 10 ml of dichloromethane at room temperature and 2.0 g of m-chloroperbenzoic acid were added. After 1 hour the mixture was washed with sodium bisulphite solution, sodium bicarbonate solution and water. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/ethanol/formic acid (40:4:1) for the elution. The product was obtained as an oil which solidified upon trituration with diethyl ether. Recrystallization from toluene gave 0.034 g of 2-(2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide of melting point 148°-150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:27][C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([CH3:37])[C:35]=1O)[C:31]#[N:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[CH2:14][O:15][C:35]3[C:34]([CH3:37])=[CH:33][C:30]([C:31]#[N:32])=[CH:29][C:28]=3[CH3:27])[C:11]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(C#N)cc(C)c1O
Reactant: OCC(C1CCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Product: Cc1cc(C#N)cc(C)c1OCC(C1CCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclopentyl-ethanol, 3,5-dimethyl-4-hydroxybenzonitrile (commercially available), tri-n-butylposphine and N′N′N′N-tetramethylazodicarboxamide. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 60:40). The product containing fractions were pooled and evaporated. The resulting light yellow foam was dissolved in acetonitrile, upon which crystallisation occurred. The suspension was filtered, washed with a small amount of acetonitrile and dried under high vacuum. White solid (34%). MS (Turbo Spray): m/z=506.182 [M+H].
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[NH:5][C:4](=O)[CH2:3]1.C(OP(Cl)(OCC)=O)C.[N+:24]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])#[C-:25].C(O)(=O)C>CN(C)C=O.O>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:25]=[N:24][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:4]2[CH2:3]1
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: CN1CC(=O)Nc2ccccc2C1=O
Agent: CCOP(=O)(Cl)OCC
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
16.5 g of 4-methyl-3,4-dihydro-2H-1,4-benzodiazepine-2,5(1H)-dione and 11.7 g of K-t-butoxide was dissolved in 100 ml of dry dimethyl formamide (DMF) and the mixture was stirred for 10 minutes. Then 13.2 ml of diethylchlorophosphate was added and the resulting mixture was cooled to -20° C. and stirred for 10 minutes. A mixture of 10.8 g K-t-butoxide and 10.5 ml ethyl isocyanoacetate in 30 ml of dry DMF was added to the above prepared mixture at -10° to --20° C. and the resulting mixture was stirred for one hour at RT, whereafter it was poured into 8.7 ml acetic acid in 300 ml water. This mixture was extracted 2 times with 150 ml methylene chloride. The organic phase was dried and evaporated. The resulting residue was crystallized leaving 10 g of the title compound as crystals.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:18][CH3:19])=[C:7]([CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:13]=1)[C:8]([OH:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Zn+2:34]>O>[C:1]([C:5]1[C:6]([O:18][CH3:19])=[C:7]([CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:13]=1)[C:8]([O-:10])=[O:9])([CH3:4])([CH3:2])[CH3:3].[Zn+2:34].[C:1]([C:5]1[C:6]([O:18][CH3:19])=[C:7]([CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:13]=1)[C:8]([O-:10])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(C(=O)O)cc(C(C)(C)C)cc1C(C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1c(C(=O)[O-])cc(C(C)(C)C)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Five parts of 3,5-di-t-butyl-2-methoxybenzoic acid was added to 48 parts of water, followed by the dropwise addition of an aqueous solution of 1.2 parts of 96% potassium hydroxide in 2 parts of water. The resulting mixture was converted into a solution by heating to a temperature of 40° to 50° C. An aqueous solution of 2.7 parts of zinc sulfate heptahydrate in 10 parts of water was dropped into the solution at 60° C. over a period of 15 minutes. After the completion of the dropping, the obtained mixture was stirred at that temperature for 2 hours, cooled to a room temperature and filtered to recover a white crystalline precipitate. This precipitate was dispersed in 60 parts of water, washed therewith and filtered. The filter cake was dried to give 3.8 parts of a white crystal. The melting point thereof was 263° to 265° C.
Reaction SMILES: [F:1][C:2]([F:33])([C:25](=[O:32])[N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:3](=[N:18][S:19]([C:21]([CH3:24])([CH3:23])[CH3:22])=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[CH:6][CH:5]=1.[Si]([C:38]([F:41])([F:40])[F:39])(C)(C)C>CCCC[N+](CCCC)(CCCC)CCCC.C1C=CC([Si-](F)(F)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C.C1COCC1>[CH3:22][C:21]([S:19]([NH:18][C:3]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[CH:8][CH:9]=1)([C:2]([F:1])([F:33])[C:25](=[O:32])[N:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1)[C:38]([F:41])([F:40])[F:39])=[O:20])([CH3:24])[CH3:23]
Reactant: CC(C)(C)S(=O)N=C(c1ccc(OCCCC(F)(F)F)cc1)C(F)(F)C(=O)N1CCCCC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: F[Si-](F)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)S(=O)NC(c1ccc(OCCCC(F)(F)F)cc1)(C(F)(F)F)C(F)(F)C(=O)N1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 57.9 %

Procedure:
To a solution of TBAT (3.43 g, 6.36 mmol) in DMF (5.89 mL) was added a solution of Intermediate 103C (1.17 g, 2.356 mmol) in THF (5.89 mL). The solution was cooled to 0° C., and then 2 M TMSCF3 (3.53 mL, 7.07 mmol) in THF was added dropwise. The reaction was stirred at 0° C. for 1 h, and then quenched with brine (20 mL) at 0° C. The mixture was warmed to rt and diluted with water and EtOAc. The layers were separated. The aqueous layer was washed with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (80 g silica gel, eluted with EtOAc in hexanes) to afford the desired product (773 mg, 58%) as a yellow gum. LCMS Anal. Calc'd for C23H30F8N2O3S 566.18, found [M+H] 567.1. 1H NMR (500 MHz, CD3OD) δ 7.69 (d, J=8.53 Hz, 2H), 6.91 (d, J=9.08 Hz, 2H), 4.03 (t, J=5.91 Hz, 2H), 3.50-3.62 (m, 2H), 3.34-3.45 (m, 2H), 2.23-2.35 (m, 2H), 1.98-2.07 (m, 2H), 1.48-1.69 (m, 6H), 1.26 (s, 9H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:16][CH3:17])=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=2)[C:6]([CH3:19])([CH3:18])[CH2:5]1)(=O)C.Cl.O1CCOCC1>CO>[CH3:18][C:6]1([CH3:19])[C:7]2[C:12](=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([O:16][CH3:17])[CH:8]=2)[NH:4][CH2:5]1
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(C)=O)CC2(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc2c(cc1[N+](=O)[O-])NCC2(C)C
Temperature: 70 °C
Yield: 109.1 %

Procedure:
A solution of 1-acetyl-3,3-dimethyl-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (2.55 g, 9.65 mmol) in methanol (75 mL) was treated with 4.0N HCl in dioxane (19.30 mL, 77 mmol) and maintained at 70° C. for 16 hours. The solution was concentrated under reduced pressure, solids were triturated with diethyl ether and the slurry was filtered to afford 3,3-dimethyl-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (2.340 g, 94% yield) as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.68 (s, 1 H), 7.36 (s, 1 H), 3.89 (s, 3 H), 3.41 (s, 2 H), 1.33 (s, 6 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([Cl:20])[N:11]=1>>[C:1]([O:5][C:6](=[O:8])[CH2:7][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([Cl:20])[N:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)OC(C)(C)C
Reactant: Clc1cc2ccccc2c(Cl)n1
Product: CC(C)(C)OC(=O)Cc1nc(Cl)cc2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
After stirring at RT for 10 minutes, the clear dark red solution is cooled to −10° C. Acetic acid tert-butyl ester (15.7 ml, 13.5 g, 116.1 mmol) is added during 5 min. After 10 minutes at −10° C., 1,3-Dichloro-isoquinoline (10.0 g, 50.49 mmol) is added in one portion. The dark red solution is allowed to warm to RT. After 30 minutes at RT, TLC analysis indicates complete conversion of the starting material. The reaction mixture is filtered through a 2-cm pad of silica, which is rinsed with EtOAc/MeOH 98:2. After concentration, the residue is purified by FCC (toluene/CH2Cl2 2:1 to toluene/EtOAc 100:0 to 99:1 to 98:2 to 97:3 to 96:4 to 94:6 to 90:10) to afford (3-Chloro-isoquinolin-1-yl)-acetic acid tert.-butyl ester. This compound is dissolved in a saturated ethanolic solution of HCl (200 ml) and refluxed for 15 minutes. Concentration affords the title compound in quantitative yield. 1H NMR (DMSO, 400 MHz) δ 1.17 (t, J=8.8, 3H), 4.11 (q, J=8.8, 2H), 4.28 (s, 2H), 7.51-7.57 (m, 1H), 7.61 (s, 1H), 7.61-7.66 (m, 1H), 7.72 (d, J=8.8, 1H), 7.98 (d, J=8.8, 1H); ES-MS: 250 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[N+](N[C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH3:33])[CH3:32])=[CH:26][CH:25]=2)=[CH:18][N:17]=1)([O-])=O>C(O)C>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH3:32])[CH3:33])=[CH:26][CH:25]=2)=[CH:18][N:17]=1
Reactant: Cc1[nH]cnc1CSCCN
Reactant: CN(C)Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cc1
Solvent: CCO
Product: Cc1[nH]cnc1CSCCNc1ncc(Cc2ccc(CN(C)C)cc2)c(=O)[nH]1

Procedure:
A mixture of 2-(5-methyl-4-imidazolylmethylthio)ethylamine (1.37 g) and 2-nitroamino-5-(4-dimethylaminomethylbenzyl)-4-pyrimidone (2.27 g) in ethanol (12 ml) was heated under reflux for 24 hr. The ethanol was evaporated at reduced pressure giving 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(4-dimethylaminomethylbenzyl)-4-pyrimidone which was washed by mixing it with water, warming the mixture, allowing it to cool over about 16 hr. and decanting the water. The residue was reacted with ethanolic hydrochloric acid (7 ml) and ethanol removed at reduced pressure. The residue was recrystallised from methanol/ethanol to give the trihydrochloride (2.14 g) as a white solid m.p. 213.5°-216° C.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[N:12]=[C:13]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=12.C(N(CC)C(C)C)(C)C.[CH:36](O)=[O:37]>C(Cl)Cl>[NH2:20][C:16]1[C:15]2[N:14]([C:13]([CH:21]3[CH2:26][CH2:25][N:24]([CH:36]=[O:37])[CH2:23][CH2:22]3)=[N:12][C:11]=2[C:3]2[NH:2][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:19]=[CH:18][N:17]=1
Reactant: Nc1nccn2c(C3CCNCC3)nc(-c3cc4ccccc4[nH]3)c12
Reactant: O=CO
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1nccn2c(C3CCN(C=O)CC3)nc(-c3cc4ccccc4[nH]3)c12
Reaction time: 8 h
Yield: 432.5 %

Procedure:
To a solution of 1-(1H-indol-2-yl)-3-piperidin-4-ylimidazo[1,5-a]pyrazin-8-amine hydrochloride (30.00 mg, 0.0068 mmol) in DCM (0.5 mL, 0.008 mol) was added N-(3-dimethylaminopropyl)-N-ethylcarbodihnide hydrochloride (0.0195 g, 0.102 mmol), N,N-diisopropylethylamine (0.047 mL), 1-hydroxbenzotriaxole hydrate (0.0104 g, 0.0679 mmol) and formic acid (4.7 mg, 0.10 mmol). The reaction was stirred at it overnight then diluted with DCM, washed with saturated NaHCO3 (2×25 mL) and brine (2×25), then dried over Na2SO4 and concentrated in vacuo. The material thus isolated was crystallized from EtOAc to afford 10.6 mg of desired product. 1H NMR (400 MHz, CDCl3): δ 2.04-2.12 (m, 4H), 2.99-3.00 (m, 1H), 3.27-3.32 (m, 2H), 3.85 (m, 1H), 4.49 (m, 1H), 5.70 (br, 2H), 6.80 (s, 1H), 7.13-7.24 (m, 4H), 7.45 (d, J=8.4 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H), 8.10 (s, 1H), 8.97 (br, 1H). MS (ES+): m/z 361.16 [MH+].
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH2:23][O:24]C(=O)C)[C@@H:7]([CH2:8][CH:9]=[C:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3([OH:35])[CH2:12][CH2:13][C@@H:14]2[O:28]C(=O)C(C)(C)C)[CH2:6]1)(=O)C.[OH-].[K+].C(O)(=O)C.O>C(OCC)(=O)C>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH2:23][OH:24])[C@@H:7]([CH2:8][CH:9]=[C:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3([OH:35])[CH2:12][CH2:13][C@@H:14]2[OH:28])[CH2:6]1
Reactant: CC(=O)OC[C@]12CC[C@H](OC(C)=O)C[C@@H]1CC=C1[C@@H]2CC[C@]2(C)[C@@H](OC(=O)C(C)(C)C)CC[C@]12O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@]12CC[C@H]3C(=CC[C@H]4C[C@@H](O)CC[C@@]43CO)[C@@]1(O)CC[C@@H]2O

Procedure:
A mixture of 20 mg of 3β ,19-diacetoxy-14β-hydroxy-17β-pivaloxy-5α-androst-7-ene and 1.0 ml of 0.2 N methanolic potassium hydroxide was heated under nitrogen at 70° C. for 20 hours whereupon a solution of 0.2 N acetic acid in ethyl acetate was added and the mixture was evaporated. The residue obtained was treated with water and the mixture was then extracted with ethyl acetate. Evaporation of the ethyl acetate solution gave 3β ,14β ,17β ,19-tetrahydroxy-5α-androst-7-ene as indicated by tlc analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2C(=O)[O:12][N:11]=[C:10]2[C:15]2[C:19]([CH2:20][NH:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[N:18][O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8].CCN(C(C)C)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(#N)C.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:15]2[C:19]([CH2:20][N:21]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[N:18][O:17][N:16]=2)=[N:11][OH:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=c1onc(-c2nonc2CNCCN2CCOCC2)n1-c1ccc(F)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: CO
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N(CCN1CCOCC1)Cc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 6.2 %

Procedure:
4-(3-Chloro-4-fluorophenyl)-3-(4-[(2-morpholin-4-ylethyl)amino]methyl-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one (20 mg, 0.047 mmol) was dissolved in anhydrous ACN (200 μL) followed by addition of DIPEA (40 μL, 0.2 mmol) and methanesulfonyl chloride (4.0 μL, 0.052 mmol). The reaction was stirred at 40° C. for 2 hrs. The reactions was then diluted with MeOH and purified by HPLC. The purified fractions were concentrated to dryness, redissolved in EtOH (1 mL) and 2 M of sodium hydroxide in water (0.26 mL) was added. The reaction was stirred at rt for 2 hrs, quenched with acetic acid, diluted with MeOH and purified by preparative LCMS to afford the desired product (1.4 mg). MF=C17H22ClFN6O5S; LCMS calculated for C17H23ClFN6O5S(M+H)+: m/z=477.1.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]([C:7]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[C:8]1[S:12][CH:11]([O:13][C:14]([CH2:16]Cl)=[O:15])[CH2:10][S:9]1)=[O:6])[CH3:3].[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>O1CCCC1>[CH3:25][CH2:24][N:26]([CH2:16][C:14]([O:13][CH:11]1[S:12][C:8](=[C:7]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[C:5]([O:4][CH:2]([CH3:3])[CH3:1])=[O:6])[S:9][CH2:10]1)=[O:15])[CH2:27][CH3:28]
Reactant: CCNCC
Reactant: CC(C)OC(=O)C(C(=O)OC(C)C)=C1SCC(OC(=O)CCl)S1
Solvent: C1CCOC1
Product: CCN(CC)CC(=O)OC1CSC(=C(C(=O)OC(C)C)C(=O)OC(C)C)S1
Yield: 74 %

Procedure:
3.8 Grams (0.01 mole) of the diisopropyl ester of 4-chloroacetoxy-1,3-dithiolan-2-ylidene malonic acid obtained in Example 2 was dissolved in 50 ml of tetrahydrofuran. To the resulting solution was added 1.5 g (0.02 mole) of diethylamine, and the resulting mixture was refluxed for 3 hours. After the reaction, the formed diethylamine hydrochloride was removed by filtration, and then the tetrahydrofuran was removed by distillation. The residue was washed with water and then extracted with 1N-HCl. The extract was neutralized with a dilute aqueous sodium hydroxide solution to form an oily substance. This oily substance was extracted with ether, and the ether extract was washed with water, dried and then freed from the ether by distillation, whereby 3.5 g of crude crystals of the desired product were obtained. Subsequently, the crude crystals were recrystallized from n-hexane to obtain 3.1 g of white crystals, m.p. 70.5° - 71° C, yield 74 %.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=3[C:8]=2[CH:9]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]2[C:6]3[CH2:5][C:4]4[S:3][C:2]([C:37]5[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=5)=[CH:9][C:8]=4[C:7]=3[N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:28])[CH3:27])[N:11]=2)=[CH:18][CH:17]=1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4cccnc4)cc2-3)cc1
Temperature: 100 °C
Yield: 65 %

Procedure:
A mixture of the corresponding 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.76 g, 1.5 mmol), 3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (0.3 g, 2.3 mmol), Na2CO3 (2 M, 3.7 mL), and Pd(PPh3)2Cl2 (14.6 mg, 0.012 mmol) in toluene/ethanol (1:1, 10 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (20% EtOAc in hexane) to give 6-(4-Methoxy-phenyl)-2-pyridin-3-yl-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as brown solid in 65% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]#[N:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:19]=[N+:20]=[N-:21].[Na+]>CC(O)C.O.C(OCC)(=O)C.[Br-].[Zn+2].[Br-]>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[NH:21][N:20]=[N:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: O
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCC(c2nnn[nH]2)CC1
Temperature: 120 °C
Reaction time: 72 h
Yield: 132.3 %

Procedure:
A mixture of 4-cyano-piperidine-1-carboxylic acid benzyl ester (0.73 g, 3.0 mmol), sodium azide (0.39 g, 6.0 mmol) and zinc bromide (0.33 g, 1.5 mmol) in 2-propanol (5 mL) and water (10 mL) was stirred at 120° C. for 3 days into a pressure tube. The reaction mixture was then partitioned between aqueous 3.0N HCl (1.5 mL) and ethyl acetate and then stirred vigorously until 2 clear phases were obtained. Aqueous layer was then extracted with ethyl acetate and combined ethyl acetate layers dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude residue. The residue was dissolved in ethyl acetate (10 mL) and washed with 0.25N aqueous sodium hydroxide. Aqueous layer was acidified to pH=1 with aqueous 3.0N HCl and extracted with ethyl acetate. Ethyl acetate layer was dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude gum. The gum was purified via flash chromatography (4% methanol in dichloromethane) to yield 4-(1H-Tetrazol-5-yl)-piperidine-1-carboxylic acid benzyl ester as a gum (1.14 g, 66%).
Reaction SMILES: [OH:1][C:2]1[C:9]([Br:10])=[C:8]([Cl:11])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:17][OH:18].C(O)C.C(=O)(O)[O-].[Na+]>O1CCCC1.O>[OH:1][C:2]1[C:9]([Br:10])=[C:8]([Cl:11])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:6][C:3]=1[CH:4]=[N:17][OH:18]
Reactant: CC(C)(C)c1cc(C=O)c(O)c(Br)c1Cl
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C=NO)c(O)c(Br)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
A mixture of 2.25 g (7.72 mmol) of 2-hydroxy-3-bromo-4-chloro-5-(1,1-dimethylethyl)benzaldehyde and 0.59 g (8.49 mmol) of hydroxylamine hydrochloride in 15 ml of 1:1:1 tetrahydrofuran:ethanol:water was cooled in an ice-water bath. Sodium bicarbonate (0.78 g, 9.26 mmol) was added in small portions over 15 minutes. After stirring overnight at ambient temperature, water (25 ml) was added and the solid was filtered and dried. There was obtained 2.00 g (6.52 mmol, 85%) of 2-hydroxy-3-bromo-4-chloro-5-(1,1-dimethylethyl)benzaldehyde oxime as a white solid after crystallization from cyclohexane mp 175°-177° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2].Cl[C:11]([CH3:19])([CH2:13][CH2:14][C:15](Cl)([CH3:17])[CH3:16])[CH3:12].C1(O)C=CC=CC=1>>[CH2:1]([C:3]1[C:4]([OH:9])=[CH:5][C:6]2[C:11]([CH3:19])([CH3:12])[CH2:13][CH2:14][C:15]([CH3:17])([CH3:16])[C:7]=2[CH:8]=1)[CH3:2]
Reactant: CCc1ccccc1O
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Solvent: Oc1ccccc1
Product: CCc1cc2c(cc1O)C(C)(C)CCC2(C)C

Procedure:
In a manner similar to Example 7(a) above, by the reaction of 15 g (0.123 mol) of 2-ethylphenol with 22.5 g (0.123 mol) of 2,5-dichloro-2,5-dimethylhexane, 25.4 g (89%) of the expected phenol of melting point 88-9° C. were obtained after chromatography on a silica column eluted with dichloromethane.