Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([O:13][OH:14])([CH2:6][CH2:7][C:8]([CH3:12])([O:10][OH:11])[CH3:9])[CH3:5].[C:15]([N:19]=[N:20][C:21]1(Cl)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)([CH3:18])([CH3:17])[CH3:16]>O1CCOCC1>[CH3:5][C:4]([O:13][O:14][C:21]1([N:20]=[N:19][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)([CH2:6][CH2:7][C:8]([CH3:12])([O:10][O:11][C:21]1([N:20]=[N:19][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH3:9])[CH3:3]
Reactant: CC(C)(C)N=NC1(Cl)CCCCC1
Reactant: CC(C)(CCC(C)(C)OO)OO
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)N=NC1(OOC(C)(C)CCC(C)(C)OOC2(N=NC(C)(C)C)CCCCC2)CCCCC1
Temperature: 30 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To a cooled slurry of 2.47 grams (.0586 moles) of 57% sodium hydride in 80 ml. of dioxane in a 250 ml. 4 neck round bottom flask equipped with a magnetic stirrer, thermometer, addition fummel and gas outlet, was slowly added 3.88 grams (0.0196 moles) of 90% 2,5-dimethyl-2,5-dihydroperoxy-hexane containing 8% water. After the addition was complete the reaction was stirred for 4 hours at 30° C, cooled to 15° C in a cold water bath and 7.96 grams (.0392 moles) of 1-t-butylazo-1-chlorocyclohexane was added dropwise holding the temperature at 15° to 20° C. After the addition was complete the reaction was stirred for 30 minutes at 15° to 20° C and poured into 200 ml. of ice cold water. The product was extracted with 50 ml. of cold pentane, the pentane solution washed with ice cold water, saturated NaHCO3 solution, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure while holding the temperature of the solution below 10° C. The product was a light yellow liquid weighing 8.0 grams (80% yield). The infrared spectrum of the crude azo-peroxide was in agreement with the stucture of the desired product.
Reaction SMILES: [CH2:1]([C:3]1([CH2:14][CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:12])[C:4]1=[O:13])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>S(=O)(=O)(O)O>[CH2:14]([C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:16]([O-:18])=[O:17])[CH:10]=2)[N:5]([CH3:12])[C:4]1=[O:13])[CH3:15]
Reactant: CCC1(CC)C(=O)N(C)c2ccccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCC1(CC)C(=O)N(C)c2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3,3-diethyl-1-methyl-1,3-dihydro-indol-2-one (J. Chem. Soc., 1971, 1375) (7.6 g) in concentrated sulfuric acid (12 ml) is added a mixture of nitric acid (65%, 2.7 ml) and concentrated sulfuric acid (4.4 ml) at 0° C. over a period of 30 min. The reaction mixture is stirred at this temperature for 30 min and then poured into ice water. The precipitate is collected by filtration and washed with water to give the respective compound (9.3 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH:4]=1.[P:20]([O:27]CC)([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23].[I-].[K+]>CCC(C)=O>[O:19]=[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17](=[O:18])[N:9]1[C:5]1[CH:4]=[C:3]([CH2:2][P:20](=[O:27])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])[CH:8]=[CH:7][N:6]=1
Reactant: CCOP(OCC)OCC
Reactant: O=C1c2ccccc2C(=O)N1c1cc(CBr)ccn1
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOP(=O)(Cc1ccnc(N2C(=O)c3ccccc3C2=O)c1)OCC
Temperature: 25 °C

Procedure:
The product from Example 14, triethyl phosphite (7.66 g, 46 mmol) and a catalytic amount of potassium iodide were placed in a flask containing MEK (500 mL) under a N2 atmosphere. The reaction was heated to reflux for 11 h. After cooling to room temperature, the solid was filtered from the reaction mixture, and the filtrate stripped in vacuo. Aqueous K2 CO3 was added to the residue, and the product extracted with EtOAc. The extract was dried (MgSO4), filtered and stripped of all solvent in vacuo to produce the crude product which was purified by flash chromatography (97/3 CHCl3 /EtOH).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]1[C:21]1[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][C:22]=1[O:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[OH:38]>O>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]1[C:21]1[CH:26]=[C:25]([C:27](=[O:38])[NH2:28])[CH:24]=[CH:23][C:22]=1[O:29][CH2:30][C:31]([OH:33])=[O:32])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)COc1ccc(C#N)cc1C1c2ccccc2CCN1C(=O)OCc1ccccc1
Reactant: CCO
Solvent: O
Product: NC(=O)c1ccc(OCC(=O)O)c(C2c3ccccc3CCN2C(=O)OCc2ccccc2)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of (±)-1-(5-cyano-2-ethoxycarbonylmethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (141 mg, 0.30 mmol, 1.0 eq.) in EtOH (0.5 mL) and water (0.12 mL), hydrido(dimethylphosphinous acid-kP)[hydrogen bis(dimethylphosphinito-kP)]platinum(II) (26 mg, 0.06 mmol, 0.2 eq.) was added in one portion at r.t. The reaction mixture was stirred at 70° C. for 1 hour, then allow to cool to r.t. The product solution was then filtered through a short column containing a layer of Na2SO4 on top of a layer of SiO2 (each 1 cm deep), eluting with AcOEt (200 mL). The filtrate was concentrated in vacuo. To a solution of the residue in DMF (2 mL), 1M aq. NaOH (0.5 ml) was added. The resulting solution was stirred at r.t. for 6 hours. The mixture was neutralized with formic acid (0.5 mL), filtered, and purified by prep. HPLC (column: Waters X-Bridge, 19×50 mm, 5 um, UV/MS, acidic conditions) to give the desired acid as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([C:8]2[CH:9]=[N:10][N:11](C(OC(C)(C)C)=O)[CH:12]=2)[CH:7]=1.[C:21]([C:23]1[CH:24]=[C:25]([S:30]([NH:33][C:34]2[S:35][CH:36]=[CH:37][N:38]=2)(=[O:32])=[O:31])[CH:26]=[CH:27][C:28]=1F)#[N:22].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][C:28]2[CH:27]=[CH:26][C:25]([S:30]([NH:33][C:34]3[S:35][CH:36]=[CH:37][N:38]=3)(=[O:31])=[O:32])=[CH:24][C:23]=2[C:21]#[N:22])=[C:6]([C:8]2[CH:12]=[N:11][NH:10][CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc(Cl)ccc2O)cn1
Reactant: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1Oc1ccc(Cl)cc1-c1cn[nH]c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
tert-Butyl 4-(5-chloro-2-hydroxyphenyl)-1H-pyrazole-1-carboxylate (Preparation 205, 624 mg, 2.12 mmol), 3-cyano-4-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide (Preparation 46, 500 mg, 1.76 mmol) and potassium carbonate (732 mg, 5.30 mmol) were stirred in dimethyl sulphoxide (10 ml) at 50° C. for 2 hours. The reaction was cooled to room temperature and the mixture poured dropwise into hydrochloric acid (2M aqueous, 100 ml). The mixture was stirred at room temperature for 18 hours. The precipitate was filtered and suspended in methanol (10 ml). The mixture was treated with hydrogen chloride (4M in dioxane, 2 ml). The mixture was then stirred at room temperature over for 60 hours. The mixture was evaporated in vacuo. The residue was dissolved in methanol (5 ml). The black solution was passed through an ISOLUTE™ SCX cartridge. The cartridge was eluted with methanol (100 ml) followed by ammonia (2M in methanol). The dark ammonia solution was evaporated in vacuo. The residue was dissolved in dichloromethane/methanol (95/5, 5 ml) and passed through a pad of silica. The solution was evaporated in vacuo. The residue was purified using a silica gel column chromatography eluting with dichloromethane:ethyl acetate (gradient 1:0 to 1:9, by volume). Concentration in vacuo afforded the title compound as a white solid. Yield 427 mg, 53%
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:42])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[C:38]([CH3:40])[N:37]=[C:36]([CH3:41])[CH:35]=2)[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:41][C:36]1[CH:35]=[C:34]([C:30]2[CH:29]=[C:28]([C:26]3[CH2:25][C:24](=[O:42])[NH:23][C:9]4[CH:10]=[C:11]([C:19]([F:20])([F:22])[F:21])[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:13][C:8]=4[N:7]=3)[CH:33]=[CH:32][CH:31]=2)[CH:39]=[C:38]([CH3:40])[N:37]=1
Reactant: COCCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)nc(C)c3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(C)nc(C)c3)c1)=N2

Procedure:
The title compound was prepared from [2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-(2-methoxy-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M223) (320 mg, 0.53 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (183 mg,71%).
Reaction SMILES: [OH-:1].[Na+:2].[CH3:3][C:4]1([CH3:9])[O:7][C:6](=[O:8])[CH2:5]1>O>[OH:7][C:4]([CH3:9])([CH3:3])[CH2:5][C:6]([O-:1])=[O:8].[Na+:2]
Reactant: [OH-]
Reactant: CC1(C)CC(=O)O1
Agent: [Na+]
Solvent: O
Product: CC(C)(O)CC(=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of sodium hydroxide (127.3 g; 3.15 mol) in water (1.5 l) was cooled to 0° C. Then, crude 4,4-dimethyloxetan-2-one (=β-isovalerolactone; 336.7 g; 3 mol; obtained by reacting ketene with acetone) was added dropwise in the course of approximately 2¼ h with vigorous stirring, with the temperature being kept from 1.5 to 2° C. The reaction mixture was stirred for a further 15 min at 0° C. and then heated for a further 40 min at 22° C. Then 415 g of water were distilled off at 300 mbar in the course of approximately 3 h. In this manner 1533 g of a solution containing approximately 27.5% by weight of sodium 3-hydroxy-3-methylbutyrate were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12]([C:14]1[N:15]=[C:16]([CH2:19][N:20]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:21](=[O:30])[C:22]#[C:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[S:17][CH:18]=1)=[O:13])[CH3:10]>>[CH2:9]([O:11][C:12]([C:14]1[N:15]=[C:16]([CH2:19][N:20]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)/[C:22](=[C:23](\[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)/[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)/[C:21]2=[O:30])[S:17][CH:18]=1)=[O:13])[CH3:10]
Reactant: Clc1ccc(I)cc1
Reactant: CCOC(=O)c1csc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)n1
Product: CCOC(=O)c1csc(CN2C(=O)/C(=C(\c3ccccc3)c3ccc(Cl)cc3)c3ccccc32)n1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-chloro-4-iodo-benzene (commercially available) and 2-{[phenyl-(3-phenyl-propynoyl)-amino]-methyl}-thiazole-4-carboxylic acid ethyl ester. 1H NMR (300 Hz, CDCl3): δppm 1.39 (t, 3H), 4.44 (q, 2H), 5.27 (s, 2H), 6.58 (d, 1H), 6.78 (t, 1H), 6.88 (d, 1H), 7.13 (t, 1H), 7.31-7.43 (m, 9H), 8.10 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.[CH2:9]([C:11]1[CH:12]=[C:13]([CH3:32])[C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=3)=[O:24])[CH2:19][CH2:18]2)=[N:15][CH:16]=1)[CH3:10]>>[CH2:9]([C:11]1[CH:12]=[C:13]([CH3:32])[C:14]([N:17]2[CH2:18][CH2:19][N:20]([C:23]([C:25]3[CH:30]=[CH:29][C:28]([N:4]4[CH2:3][CH:2]([CH3:1])[CH2:6][S:5]4(=[O:8])=[O:7])=[CH:27][CH:26]=3)=[O:24])[CH2:21][CH2:22]2)=[N:15][CH:16]=1)[CH3:10]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: CC1CNS(=O)(=O)C1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CC(C)CS4(=O)=O)cc3)CC2)c(C)c1
Yield: 9 %

Procedure:
Using 4-methylisothiazolidine 1,1-dioxide (202 mg) described in Preparation Example 9 and [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (500 mg) described in Preparation Example 133 and by the reaction and treatment in the same manner as in Example 1, the title compound (46 mg) was obtained.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:11][OH:12].Cl.C(N(C(C)C)CC)(C)C>C(O)C>[N:5]1[C:4]2[S:8][CH:9]=[CH:10][C:3]=2[C:2]([NH:11][OH:12])=[N:7][CH:6]=1
Reactant: NO
Reactant: Clc1ncnc2sccc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: ONc1ncnc2sccc12
Reaction time: 6 h

Procedure:
4-chlorothieno[2,3-d]pyrimidine (340 mg, 1.99 mmol), hydroxylamine-hydrogen chloride (550 mg, 7.91 mmol), and diisopropylethylamine (1 ml) in absolute ethanol (5 ml) was placed into a preheated oil bath at 75° C. After stirring for 6 h, the solution was concentrated under reduced pressure.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[CH:8]=[C:7]([C:9]([O:11]CC)=[O:10])[N:6]=[C:5]([C:14](=O)[CH2:15]Br)[CH:4]=1.[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH3:33])[C:25]([NH2:27])=[S:26])[CH3:20]>>[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([C:25]2[S:26][CH:15]=[C:14]([C:5]3[CH:4]=[C:3]([N:2]([CH3:1])[CH3:18])[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[N:6]=3)[N:27]=2)[CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH3:33])[CH3:20]
Reactant: CCOC(=O)c1cc(N(C)C)cc(C(=O)CBr)n1
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Product: CCOc1ccc(-c2nc(-c3cc(N(C)C)cc(C(=O)O)n3)cs2)cc1OCC

Procedure:
A reaction was conducted in the same manner as in Example 1, by using 4-dimethylamino-6-ethoxycarbonyl-2-(α--bromoacetyl)pyridine and 3,4-diethoxythiobenzamide. Then, hydrolysis was conducted in the same manner as in Example 2 to obtain 2-(3,4-diethoxyphenyl)-4-(4-dimethylamino-6-carboxy-2-pyridyl)thiazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](Br)[C:5]2[S:9][C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:6]=2[CH:16]=1.[Br-].[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Zn+].Cl>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.O>[Br:1][C:2]1[CH:3]=[C:4]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)[C:5]2[S:9][C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:6]=2[CH:16]=1
Reactant: CCNC(=O)Nc1nc2cc(Br)cc(Br)c2s1
Reactant: [Zn+]c1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: O
Product: CCNC(=O)Nc1nc2cc(Br)cc(-c3ccccn3)c2s1
Temperature: 55 °C
Reaction time: 18 h
Yield: 55.2 %

Procedure:
A stirred mixture of the 1-(5,7-dibromo-benzothiazol-2-yl-3-ethyl urea (2.62 g, 0.00687 mol) and Dichlorobis(triphenylphosphine)-palladium (0.48 g 0.000687 mol), under nitrogen, was treated in one portion, via a syringe, with 2-pyridyl zinc bromide solution (0.5M solution in THF, 7.66 g, 0.0344 mol). The reaction mixture was heated, with stirring, at 55° C. for 18 hours, allowed to cool and poured into 500 ml of water containing ˜5 ml of conc hydrochloric acid. The suspension was stirred and the solid filtered off, washed with water, followed by 20 ml of 1:1 DCM/Methanol mixture to give the crude 1-(5-Bromo-7-pyridin-2-yl-benzothiazol-2-yl)-3-ethyl-urea (1.43 g). This was purified by “flash” silica chromatography using 0 to 100% hexane/ethyl acetate followed by 0 to 100% methanol in ethyl acetate to elute the required product as a beige solid (1.1 g).
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[H-].[Na+].I[CH3:14]>CN(C=O)C.O>[Cl:1][C:2]1[N:6]([CH3:14])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: CI
Reactant: Clc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(Cl)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-1H-benzimidazole (5.03 g, 33.0 mmol) in anhydrous DMF (33 mL) at 0° C. was added portion-wise 95% NaH (871 mg, 36.3 mmol). The ice bath was removed and the resulting mixture was stirred at room temperature for 1 h. Iodomethane (4.68 g, 33.0 mmol) was added and the resulting mixture was stirred at room temperature overnight. The resulting mixture was then diluted with water, and the resulting precipitate was collected by filtration and purified by recrystallization from hexane to yield 2-chloro-1-methyl-1H-benzimidazole. MS 167 (M+1)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1.O[CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][O:32]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:30][CH:31]4[CH2:35][CH2:34][CH2:33][O:32]4)=[CH:17][CH:18]=3)=[O:12])=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Reactant: OCC1CCCO1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCC3CCCO3)cc2)cc1
Yield: 62.6 %

Procedure:
[6-Methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl](4-hydroxyphenyl)methanone (390 mg, 1 mmol) and 2-hydroxymethyl tetrahydrofuran (153 mg, 1.50 mmol) were converted to 297 mg of the title compound by the procedure of Example 9 using 393 mg (31.5 mmol) of triphenylphosphine and 0.24 mL (1.5 mmol) of diethyl azodicarboxylate the only differences being that the chromatography eluent was 3:7 ethyl acetate:hexanes.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]=[O:9]>O>[CH:1]1[CH:2]=[C:3]([CH2:4][C:6]2[C:1]([OH:7])=[CH:2][CH:3]=[CH:4][CH:5]=2)[C:8]([OH:9])=[CH:5][CH:6]=1
Reactant: C=O
Reactant: Oc1ccccc1
Solvent: O
Product: Oc1ccccc1Cc1ccccc1O

Procedure:
Phenol, formaldehyde and an acidic catalyst are introduced into a reactor and reacted at a predetermined temperature over a desired period of time with stirring. Then the acidic catalyst, the water formed through the reaction and the unreacted phenol are removed to give crude bisphenol F.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](Cl)=[N:4][CH:3]=1.CO.[CH2:15]([NH2:17])[CH3:16]>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:17][CH2:15][CH3:16])=[N:4][CH:3]=1
Reactant: Clc1ncc(Br)c2ccccc12
Reactant: CCN
Solvent: CO
Product: CCNc1ncc(Br)c2ccccc12
Temperature: 50 °C
Yield: 88 %

Procedure:
To a suspension of 4-bromo-1 chloroisoquinoline (0.831 g, 3.43 mmol) in MeOH (10.3 mL, 254 mmol) was added ethylamine (70% in water, 1.1 mL). The mixture was heated at 50° C. for 16 h. The mixture was concentrated. The residue was partitioned between water (20 mL) and DCM (20 mL). DCM layer was separated. The aqueous layer was extracted with DCM (10 mL). The combined DCM solutions were dried (Na2SO4). Filtration and concentration gave 4-bromo-N-ethylisoquinolin-1-amine (0.761 g, 88%). LCMS: M+H+=251.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[O:7][CH:8]([CH2:12][CH3:13])[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].[Si:18]([O:25][C@H:26]1[CH2:35][C@H:34](O)[C@H:33]2[C:28]([CH:29]=[CH:30][C@H:31]([CH3:54])[C@@H:32]2[CH2:37][CH2:38][C@H:39]2[O:44][C:43](=[O:45])[CH2:42][C@H:41]([O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48])[CH2:40]2)=[CH:27]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>>[Si:18]([O:25][C@H:26]1[CH2:35][C@H:34]([O:10][C:9](=[O:11])[CH:8]([O:7][C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:12][CH3:13])[C@H:33]2[C:28]([CH:29]=[CH:30][C@H:31]([CH3:54])[C@@H:32]2[CH2:37][CH2:38][C@H:39]2[O:44][C:43](=[O:45])[CH2:42][C@H:41]([O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:48])[CH3:49])[CH2:40]2)=[CH:27]1)([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:20])[CH3:19]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CCC(Oc1ccccc1C(C)(C)C)C(=O)O
Product: CCC(Oc1ccccc1C(C)(C)C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 104.6 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 0.86 g of (2RS)-2-(2-t-butylphenoxy)butyric acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.46 g of the title compound as a colorless foam.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH:13]([OH:26])[C:14]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:19][CH2:18][CH2:17][CH2:16][S:15]1)[CH2:9][CH2:10][CH2:11][CH3:12])(C)(C)C.Cl>O1CCOCC1.C1(C)C=CC=CC=1>[NH2:7][CH:8]([CH2:9][CH2:10][CH2:11][CH3:12])[C@@H:13]([C:14]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:15][CH2:16][CH2:17][CH2:18][S:19]1)[OH:26]
Reactant: CCCCC(NC(=O)OC(C)(C)C)C(O)C1(c2ccccc2)SCCCS1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCCCC(N)[C@H](O)C1(c2ccccc2)SCCCS1
Temperature: 23 °C
Reaction time: 3 h

Procedure:
To {1-[hydroxy-(2-phenyl-[1,3]dithian-2-yl)-methyl]-pentyl}-carbamic acid tert-butyl ester (608 mg, 1.47 mmol) in dioxane (2.7 mL) at 10° C. was added hydrochloric acid (2.7 mL, 4 M in dioxane). The solution was warmed to 23° C. After 3 h, the solution was diluted with toluene (5 mL) and concentrated under reduced pressure. The gummy solid was washed with diethyl ether resulting in the hydrochloride salt of 2-amino-1-(2-phenyl-[1,3]dithian-2-yl)-hexan-1-ol, 414 mg, 82% as a free flowing solid after removal of excess ether under reduced pressure.
Reaction SMILES: C(C(CC1C=CC(OC)=CC=1)[N:11]1[CH:14]([CH2:15][C:16](=[O:33])[C:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])=[N+:18]=[N-:19])[CH:13]([CH:34]([O:36][C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=2)=[O:38])[CH3:35])[C:12]1=[O:50])C1C=CC(OC)=CC=1.O>C(#N)C.O>[N+:47]([C:44]1[CH:43]=[CH:42][C:41]([CH2:40][O:39][C:37]([O:36][CH:34]([CH:13]2[CH:14]([CH2:15][C:16](=[O:33])[C:17]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=3)=[O:21])=[N+:18]=[N-:19])[NH:11][C:12]2=[O:50])[CH3:35])=[O:38])=[CH:46][CH:45]=1)([O-:49])=[O:48]
Reactant: COc1ccc(CC(Cc2ccc(OC)cc2)N2C(=O)C(C(C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)C2CC(=O)C(=[N+]=[N-])C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Solvent: O
Solvent: CC#N
Product: CC(OC(=O)OCc1ccc([N+](=O)[O-])cc1)C1C(=O)NC1CC(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
1.27 g 1-(di-p-anisylmethyl)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-[3-(p-nitrobenzyloxycarbonyl)-2-oxo-3-diazopropyl]-2-azetidinone was dissolved in 50 ml of acetonitrile-water (9:1 by volume), and 2.7 g of ceric ammonium nitrate was added thereto all at once under ice-cooling. After vigorously stirring, the mixture was further stirred at room temperature for 30 minutes. Cool water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over sodium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel chromatography to obtain 3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-[3-(p-nitrobenzyloxycarbonyl)-2-oxo-3-diazopropyl]-2-azetidinone.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:15](Cl)(=[O:17])[CH3:16].CO>C(Cl)Cl>[Cl:1][C:2]1[N:10]=[C:9]2[NH:8][CH:7]=[C:6]([C:15](=[O:17])[CH3:16])[C:5]2=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc[nH]c2n1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)c1c[nH]c2nc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-Chloro-7-azaindole (1 g, 6.55 mmol) was added to a suspension of AlCl3 (4.37 g, 32.8 mmol) in CH2Cl2 (150 mL) under nitrogen atmosphere. The mixture was stirred at RT for 30 min, and acetyl chloride (2.34 mL, 32.8 mmol) was added dropwise. The resulting mixture was further stirred at RT for 2 h. After completion, MeOH (40 mL) was added cautiously and volatils were removed under reduced pressure. The residue was diluted in CH2Cl2 and neutralized by addition of a saturated aqueous solution of NaHCO3. The layers were separated and the organic extracts were dried (Na2SO4), filtered and concentrated. The crude residue was purified twice by flash column chromatography on silica gel (CH2Cl2 to CH2Cl2/MeOH 95-5). TLC, Rf (CH2Cl2/MeOH 9:1)=0.5; MS (UPLC/MS): 195.1/197.1 [M+H]+, 193.1/195.1 [M−H]−; tR (HPLC conditions f): 1.54 min.