Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[F:33])[CH2:16][CH2:15][CH:14]([CH2:17][S:18]([N:21]3[CH2:24][C:23](=[O:25])[CH2:22]3)(=[O:20])=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:34][Mg]Br>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[F:33])[CH2:12][CH2:13][CH:14]([CH2:17][S:18]([N:21]3[CH2:24][C:23]([CH3:34])([OH:25])[CH2:22]3)(=[O:19])=[O:20])[CH2:15][CH2:16]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C1CN(S(=O)(=O)CC2CCC(c3cc(F)ccc3F)(S(=O)(=O)c3ccc(Cl)cc3)CC2)C1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC1(O)CN(S(=O)(=O)CC2CCC(c3cc(F)ccc3F)(S(=O)(=O)c3ccc(Cl)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 86.8 %

Procedure:
To a stirred solution of 1-[4-(4-chloro-benzenesulfonyl)-4-(2,5-difluoro-phenyl)-cyclohexylmethanesulfonyl]-azetidin-3-one (Example 31) (58 mg, 0.11 mmol.) in tetrahydrofuran (5 mL) was added a solution of methyl magnesium bromide (3M in diethyl ether, 0.075 mL, 0.22 mmol.) and the mixture stirred at ambient temperature for 45 minutes. The reaction was quenched by the addition of saturated aqueous ammonium chloride (10 mL) and the mixture extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried (MgSO4) and evaporated to leave a residue which was purified by column chromatography on silica, eluting with ethyl acetate:dichloromethane:iso-hexane (1:1:1), to afford the desired product (51 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26]([O:28]CC)=O)[C:5]2[C:6](=O)[CH:7]([C:19]3[N:23]([CH3:24])[N:22]=[CH:21][N:20]=3)[CH:8]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[NH:9][C:10]=2[CH:11]=1.O.[NH2:32][NH2:33]>CO>[F:1][C:2]1[CH:11]=[C:10]2[NH:9][CH:8]([C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)[CH:7]([C:19]3[N:23]([CH3:24])[N:22]=[CH:21][N:20]=3)[C:6]3=[N:32][NH:33][C:26](=[O:28])[C:4]([CH:3]=1)=[C:5]23
Reactant: NN
Reactant: CCOC(=O)c1cc(F)cc2c1C(=O)C(c1ncnn1C)C(c1ccc(F)cc1)N2
Solvent: O
Solvent: CO
Product: Cn1ncnc1C1c2n[nH]c(=O)c3cc(F)cc(c23)NC1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 84 %

Procedure:
To a solution of ethyl 7-fluoro-2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (840 mg, 2.04 mmol) in methanol (2 mL) was added hydrazine monohydrate (1 mL), and the mixture was stirred under 25° C. for 10 hr. Then the mixture was filtered to obtain a white solid (650 mg, yield 84%). LC-MS (ESI) m/z: 381 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.66 (s, 3H), 4.97-5.04 (m, 2H), 6.91-6.94 (dd, J1=11.2 Hz, J2=2.4 Hz, 1H), 7.06-7.09 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.14-7.18 (m, 3H), 7.47-7.51 (m, 2H), 7.72 (s, 1H), 7.80 (s, 1H), 12.35 (s, 1H)
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:10]3[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccccc3)c2c1Cl
Reactant: c1nc[nH]n1
Product: Cc1sc2nc(-n3cncn3)nc(NCc3ccccc3)c2c1Cl

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2,5-dichloro-6-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5-chloro-6-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[C:6]([N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)=[N:5]2.[CH2:26]([O:28][CH:29](OCC)OCC)[CH3:27]>S(=O)(=O)(O)O.CCCCCC>[CH2:26]([O:28][CH:29]=[N:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[C:6]([N:19]1[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]1)=[N:5]2)[CH3:27]
Reactant: CN1CCN(c2nc3ccc(N)cc3nc2N2CCN(C)CC2)CC1
Reactant: CCOC(OCC)OCC
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Product: CCOC=Nc1ccc2nc(N3CCN(C)CC3)c(N3CCN(C)CC3)nc2c1

Procedure:
A 17.05 g. portion of 6-amino-2,3-bis(4-methyl-1-piperazinyl)quinoxaline (prepared as in Example 1) is thoroughly mixed with 100 ml. of triethylorthoformate, then 5 drops of concentrated sulfuric acid is added with magnetic stirring and the mixture is heated at reflux in an oil bath (145°-150° C.). The solid is dissolved in about 30 minutes but shortly thereafter a yellow solid is precipitated out. Stirring is continued and the mixture allowed to reflux overnight at a distillate temperature of about 75°-80° C. After refluxing for 16 hours the reflux condenser is replaced with a takeoff condenser with a 10 cm. Vigreux column attached and 6.5 ml. of distillate with a boiling point of about 80° C. is collected over a 21/2 hour period. The maximum oil bath temperature over this period of time is 180° C. The reaction mixture is cooled and the liquid layer is decanted from a small amount of insoluble material. The decanted liquid is stripped of solvent by water pump evacuation and the residual oil is triturated with 50 ml. of hexane and heated to boiling on the steam bath to dissolve the oil. The solution is cooled in an ice bath to yield a solid yellow mass. Additional hexane is added and the precipitate is filtered, washed on the filter with hexane, and pressed dry with suction to give 18.5 g. of the product of the example as a yellow solid.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:6]([O:7][CH3:8])=[C:4]([OH:5])[CH:3]=1.O.[C:14]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:5][C:4]1[CH:3]=[C:2]([CH:10]=[CH:9][C:6]=1[O:7][CH3:8])[C:1]([O:12][CH3:14])=[O:11]
Reactant: COc1ccc(C(=O)O)cc1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(OC)c(O)c1

Procedure:
A 25 g quantity of isovanillic acid was suspended in 250 ml of methanol, and 1.5 g of p-toluenesulfonic acid monohydrate was added. The mixture was heated and refluxed overnight. After completion of the reaction, methanol was distilled off under reduced pressure. The residue was neutralized with saturated aqueous sodium bicarbonate and then extracted with ethyl acetate. After washing with saturated brine twice, the organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give 24.5 g of white crystalline methyl 3-hydroxy-4-methoxybenzoate.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:16]=[CH2:17])[C:6]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])=[N:7][CH:8]=1.[NH:20]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:21]1.C(N(CC)CC)C>C(O)C>[N:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH:22]1[CH2:23][CH2:24][N:20]([CH2:17][CH2:16][C:5]2[C:6]([N:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]3=[O:15])=[N:7][CH:8]=[C:3]([C:2]([F:1])([F:18])[F:19])[CH:4]=2)[CH2:21]1
Reactant: c1ccc(C2CCNC2)nc1
Reactant: C=Cc1cc(C(F)(F)F)cnc1N1CCCCC1=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1CCCCN1c1ncc(C(F)(F)F)cc1CCN1CCC(c2ccccn2)C1
Temperature: 90 °C
Reaction time: 7 h
Yield: 19 %

Procedure:
To a solution of 1-[5-(trifluoromethyl)-3-vinylpyridin-2-yl]piperidin-2-one a18-2 (310 mg, 1.147 mmol, 1 eq) and 2-pyrrolidin-3-yl pyridine (221 mg, 1.491 mmol, 1.3 eq) in ethanol (10 ml) is added triethylamine (348 mg, 479 μl, 3.441 mmol, 3 eq). The reaction mixture is stirred at 90° C. for 7 hours, then heated overnight at 85° C. The reaction mixture is evaporated to dryness and retaken in dichloromethane. This organic phase is washed with aqueous NH4Cl (1 time), saturated aqueous NaHCO3 (2 times), then dried over MgSO4, filtered and evaporated to dryness. The residue obtained is purified by flash chromatography over silicagel (12 g; gradient: from dichloromethane/MeOH 100/0 to 94/6), dried under vacuum to afford 91.4 mg of 1-[3-{2-[3-(pyridin-2-yl)pyrrolidin-1-yl]ethyl}-5-(trifluoromethyl)pyridin-2-yl]piperidin-2-one 110.
Reaction SMILES: [Cl:1][C:2]([C:12]([F:15])([F:14])[F:13])=[CH:3][C@@H:4]1[C@H:6]([C:7]([OH:9])=[O:8])[C:5]1([CH3:11])[CH3:10].Br[CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([F:24])[CH:19]=1.N12CCCN=C1CCCCC2>C(#N)C>[Cl:1][C:2]([C:12]([F:13])([F:14])[F:15])=[CH:3][C@@H:4]1[C@H:6]([C:7]([O:9][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([F:24])[CH:19]=2)=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: Fc1cc(CBr)ccn1
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)OCc1ccnc(F)c1
Yield: 77.5 %

Procedure:
By the method of Example 21, 0.970 g (0.004 mole) of cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylic acid and 0.75 g (0.004 mole) of 4-bromomethyl-2-fluoropyridine (Example 22) were reacted in the presence of 0.609 g (0.004 mole) of 1,8-diazabicyclo[5.4.0]undec-7-ene in 20 ml of acetonitrile to produce 1.09 g of (2-fluoropyridin-4-yl)methyl cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylate, compound 28 in the Tables below. The ir, proton nmr, and 19c nmr spectra were all consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[CH:17][N:18](C)C)[C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1.N>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[CH:17][NH2:18])[C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=C1C(=O)N(c2cccc(Cl)c2)c2ccccc21
Agent: N
Solvent: CCO
Product: NC=C1C(=O)N(c2cccc(Cl)c2)c2ccccc21
Reaction time: 16 h

Procedure:
Title product of Example A3 (0.3 g, 1 mmole) was stirred with 10 ml of ethanol for 3 minutes and the mixture then perfused with NH3 for 1 hour at 25°, stirred an additional 16 hours, and concentrated to an oil, which crystallized on standing in vacuo. Trituration with pentane gave purified title product, 0.25 g, m.p. 141°-143°.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[F:9][C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]([N+:17]([O-])=O)[C:11]=1[O:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>O.C1COCC1>[F:9][C:10]1[C:11]([O:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)=[C:12]([NH2:17])[CH:13]=[CH:14][C:15]=1[CH3:16]
Reactant: Cc1ccc([N+](=O)[O-])c(Oc2cccc3ccccc23)c1F
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(N)c(Oc2cccc3ccccc23)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
A solution of sodium hydrosulfite (25.8 g, 125 mmol) in water (120 mL) was added dropwise to a solution of 1-[(2-fluoro-3-methyl-6-nitrophenyl)oxy]naphthalene (6.2 g, 20.86 mmol) in THF (60 mL) at room temperature. The mixture was stirred at room temperature for 2 hrs. The reaction mixture was extracted with ethyl acetate (3×50 mL) and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (hexane:ethyl acetate) to give the title compound (3.34 g, 60%) as a light tan oil. 1H NMR (400 MHz, chloroform-d) δ ppm 8.44-8.52 (m, 1H), 7.80-7.90 (m, 1H), 7.45-7.61 (m, 3H), 7.19-7.32 (m, 1H), 6.86 (t, 1H), 6.64 (d, 1H), 6.53 (dd, 1H), 3.59 (br. s., 2H), 2.19 (s, 3H). ES MS m/z 268 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:16]2[C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([NH2:25])[C:19]=3[CH:18]=[N:17]2)([CH2:14][CH3:15])[CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1.CN1CCOCC1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:16]2[C:24]3[C:19](=[C:20]([NH:25][S:34]([CH3:33])(=[O:36])=[O:35])[CH:21]=[CH:22][CH:23]=3)[CH:18]=[N:17]2)([CH2:14][CH3:15])[CH2:9][C:10]([F:13])([F:11])[F:12])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCC(CC(F)(F)F)(c1ccc(Cl)cc1)n1ncc2c(N)cccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(CC(F)(F)F)(c1ccc(Cl)cc1)n1ncc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of the product of Step F (50 mg, 0.13 mmol) and NMM (31 mg, 0.3 mmol) in DCM (3 mL) was added methanesulfonyl chloride (20 mg, 0.21 mmol). The mixture was stirred at room temperature for 3 h, then quenched with saturated ammonium chloride solution (10 mL), and extracted with ethyl acetate. The organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by Pre-HPLC (Mobile phase: acetonitrile/water (0.03% TFA)) to afford the title compound. LC/MS m/z=446.11[M+H]+.
Reaction SMILES: [CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1>>[C:27]([C:26]1[CH:29]=[CH:30][C:23]([NH:22][C:12](=[O:14])[C:11]2[CH:15]=[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=2)=[CH:24][CH:25]=1)#[N:28]
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Reactant: N#Cc1ccc(N)cc1
Product: N#Cc1ccc(NC(=O)c2cnc(OCC(F)(F)F)c(C3CCCCC3)c2)cc1

Procedure:
This compound was prepared following the same procedure as described in Example 11 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (Example 4b) (100 mg, 0.33 mmol) and 4-aminobenzonitrile (CAN 873-74-5, 39.0 mg, 0.33 mmol) as starting materials; off white solid (24 mg, 18.0%). MS (ESI): 402.2 (M+H)+.
Reaction SMILES: O.Cl.[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=[C:9]2[C:23]#[C:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([O-])=O>C(O)C.[Fe]>[NH2:3][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:20])[CH3:21])[N:10]=[C:9]2[C:23]#[C:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: C[Si](C)(C)CCOCn1nc(C#Cc2ccccc2)c2cc([N+](=O)[O-])ccc21
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)CCOCn1nc(C#Cc2ccccc2)c2cc(N)ccc21
Temperature: 20 °C
Yield: 14.2 %

Procedure:
5-Amino-3-phenylethynyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazole can be obtained in the following way: 18 ml of water, 0.2 ml of an aqueous 12N hydrochloric acid solution and 0.36 g of powdered iron are added to a solution of 0.84 g of 5-nitro-3-phenylethynyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazole in 15 ml of absolute ethanol, at the reflux temperature of the solvent. The reaction mixture is then stirred at the reflux of the solvent for 4 hours, and is then cooled to a temperature in the region of 20° C. After filtration through Celite® and washing with absolute ethanol, the filtrate is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 35° C. The residue thus obtained is purified by chromatography under argon pressure (50 kPa), on a column of 60 g of silica (particle size 40-63 μm), eluting successively with cyclohexane/ethyl acetate (95/5; 90/10; 80/20; 70/30; 60/40; 50/50; 30/70 by volume) mixtures, and then with pure ethyl acetate and, finally, with pure ethanol. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 35° C. 0.11 g of 5-amino-3-phenylethynyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazole is thus obtained in the form of a brown oil (Rf=0.47, silica gel thin layer chromatography, eluent: cyclohexane/ethyl acetate (60/40 by volume)). 0.2 g of 5-amino-3-phenylethynyl-1H-indazole is also obtained in the form of a brown oil (Rf=0.17, silica gel thin layer chromatography, eluent: cyclohexane/ethyl acetate (60/40 by volume)).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C@H:5]2[O:7][C@H:8]([C@@H:10]([OH:13])[CH2:11][CH3:12])[CH2:9][C@H:4]2[O:3]1.[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17]>N1C=CC=CC=1.CCOC(C)=O>[CH3:17][CH:16]([CH3:18])[C:15]([O:13][C@H:10]([C@H:8]1[O:7][C@@H:5]2[O:6][C:2]([CH3:1])([CH3:14])[O:3][C@@H:4]2[CH2:9]1)[CH2:11][CH3:12])=[O:19]
Reactant: CC(C)C(=O)Cl
Reactant: CC[C@H](O)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC[C@H](OC(=O)C(C)C)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a cooled solution of (1S)-1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]propan-1-ol (compound 6e, 505.6 mg, 2.5 mmol) in pyridine was added isobutyryl chloride (0.39 mL, 3.72 mmol) dropwise while cooled with an ice-water bath. After the addition, the mixture was warmed to room temperature and stirred at room temperature overnight. The resulting mixture was diluted with EtOAc and washed with a saturated NH4Cl solution. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 0-30% EtOAc in petroleum ether) to afford 470 mg of [(1S)-1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]propyl] 2-methylpropanoate (compound 42a).
Reaction SMILES: CON(C)[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[F:14].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.Cl>O1CCCC1>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([CH:4]=[O:15])=[C:6]([F:14])[CH:7]=1)([O-:13])=[O:12]
Reactant: CON(C)C(=O)c1ccc([N+](=O)[O-])cc1F
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=Cc1ccc([N+](=O)[O-])cc1F
Yield: 86.9 %

Procedure:
Compound 14a (860 mg) was dissolved in tetrahydrofuran (10.0 ml), and the reaction mixture was ice-cooled. Diisobutylaluminum hydride/toluene solution (0.98 mol/l, 5.0 ml) was added thereto, and the mixture was stirred under ice-cooling for 1 hour. After adding a 1N hydrochloric acid aqueous solution, the reaction mixture was returned to room temperature and extracted with ethyl acetate. The organic layer was washed with a 1N hydrochloric acid aqueous solution and saturated sodium-hydrogencarbonate aqueous solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was recrystallized with a mixed solvent of tert-butylmethylether and n-heptane to obtain Compound 14b (554 mg, 86%) as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)[CH3:2].[CH3:15][CH2:16][CH2:17][CH:18]([NH2:22])[CH2:19][CH2:20][CH3:21]>>[CH2:13]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:22][CH:18]([CH2:19][CH2:20][CH3:21])[CH2:17][CH2:16][CH3:15])=[O:10])=[CH:11][CH:12]=1)[CH3:14]
Reactant: CCCC(N)CCC
Reactant: CCN(CC)c1ccc(C(=O)O)cc1
Product: CCCC(CCC)NC(=O)c1ccc(N(CC)CC)cc1

Procedure:
Prepared in a similar manner to example 4 using 4-diethylamino benzoic acid and 4-heptylamine. (31% %). 1H NMR (500 MHz, CDCl3): δ 0.92(t, 6H, J=7.17 Hz), 1.18 (t, 6H, J=7.04 Hz), 1.41(m, 4H), 1.55(m, 4H), 3.39 (m, 4H), 4.15 (m, 1H), 5.62 (m, 1H), 6.64 (d, 2H, J=10.26 Hz), 7.64 (d, 2H, J=10.26 Hz). MS (M+H, 291).
Reaction SMILES: [H-].[Na+].CCCCCC.[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16].[CH3:17][O:18][CH2:19]Br>CN(C)C=O>[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH2:17][O:18][CH3:19]
Reactant: Oc1ccccc1Br
Reactant: COCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COCOc1ccccc1Br
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
The oil was removed from 4.5 g (60% in oil, 112 mmol, Aldrich) of sodium hydride dispersion by three-20 mL washes with hexane then the residue was covered with 75 mL of dimethylformamide (Burdick and Jackson). The resulting mixture was heated to about 50° and 18.1 g (105 mmol, Aldrich) of 2-bromophenol was added dropwise over 15 minutes. Vigorous gas evolution was observed. The reaction was stirred for an additional 30 minutes then the resulting gray-brown solution was cooled to 0° and 9.6 mL (117 mmol, Aldrich) of bromomethyl methyl ether was added dropwise over 15 minutes. The reaction mixture was stirred for 1 hour at 0° then at room temperature for 16 hours. The resulting slurry was partitioned between 200 mL of 1M aqueous sodium hydroxide solution and 150 mL of 4:1 hexane/diethyl ether. The aqueous layer was separated and extracted with an additional 100 mL of 4:1 hexane/diethyl ether. The organic extracts were combined, washed with two-200 mL portions of water, dried (magnesium sulfate) and concentrated in vacuo to give 22.2 g (102 mmol, 97%) of title compound as a pale yellow liquid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1.[F:16][C:17]([F:29])([F:28])[O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>CCOCC.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>[F:16][C:17]([F:28])([F:29])[O:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[N:7]=[C:6]([C:8]3[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: O=Cc1ccc(-c2cccc(Br)n2)cc1
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: C1COCCO1
Solvent: CCOCC
Product: O=Cc1ccc(-c2cccc(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Yield: 75.2 %

Procedure:
4-(6-Bromo-pyridin-2-yl)-benzaldehyde (0.31 mmol), 4-trifluoromethoxyphenyl boronic acid (0.46 mmol), tetrakis(triphenylphosphine)palladium(0) (0.003 mmol), 2M potassium carbonate (0.31 mL) and dioxane (2 mL) were combined in a vial and irradiated by microwave for 10 min at 150° C. The reaction mixture was taken up in ether and washed with brine. The organic layer was dried over magnesium sulfate, was filtered and the solvent removed in vacuo. Purification by silica gel chromatography (EtOAc/hexanes) yielded the product (80 mg) as an off-white solid: mp 109-112° C.; 1H NMR (400 MHz, CDCl3) δ 10.11 (s, 1H), 8.32 (d, J=8.5 Hz, 2H), 8.19 (d, J=8.1 Hz, 2H), 8.03 (d, J=8.4 Hz, 2H), 7.89 (t, J=7.9 Hz, 1H), 7.79 (d, J=7.7 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.35 (d, J=8.3 Hz, 2H); EIMS m/z 343 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])=[CH:20][CH:19]=1)(=[O:17])=[O:16]>ClCCl>[C:2]1([NH:1][S:15]([C:18]2[CH:19]=[CH:20][C:21]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C=Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(O)C=Cc1ccc(S(=O)(=O)Nc2ccccc2)cc1
Yield: 54.3 %

Procedure:
To a mixture of aniline (0.35 g, 3.75 mmol) and pyridine (1 ml) a solution of 3-(4-chlorosulfonyl-phenyl)-acrylic acid (42) (0.45 g, 1.82 mmol) in dichloromethane (3 ml) was added and the resultant solution was stirred at 40° C. for 1 hour. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 6N HCl. The organic layer was washed successively with water, saturated NaCl and dried (Na2SO4). The solvent was evaporated under reduced pressure to give the title compound (0.30 g, 54%). 1H NMR (DMSO-d6, HMDSO), δ: 6.60 (1H, d, J=16.0 Hz); 6.93-7.43 (5H, m); 7.60 (1H, d, J=16.0 Hz); 7.79 (2H, d, J=8.0 Hz); 7.87 (2H, d, J=8.0 Hz); 10.35 (1H, s).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([N:15]=[C:16]=[S:17])[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1.[NH3:18]>C(O)C>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:4]=1
Reactant: N
Reactant: CSc1ccc(-c2ccccc2)c(N=C=S)c1
Solvent: CCO
Product: CSc1ccc(-c2ccccc2)c(NC(N)=S)c1

Procedure:
Reaction of 4-methylthio-2-biphenylylisothiocyanate (11.5 g), ethanol (100 ml) and 25% aqueous ammonia solution (20 ml) at ambient temperature for 15 hours gave N-(4-methylthio-2-biphenylyl)thiourea as a colourless solid (m.p. 166°-167° C.).