Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][CH2:22][CH2:23][N:24]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]2=[O:34])[CH:13]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:45](Br)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][CH2:22][CH2:23][N:24]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]2=[O:34])[CH:13]=1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)c1cn(CCCN2C(=O)c3ccccc3C2=O)c2ccccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)c1cn(CCCN2C(=O)c3ccccc3C2=O)c2ccccc12
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 78.1 %

Procedure:
2-(N-tert-butoxycarbonylamino)-1-{1-[3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-propyl]-3-indolyl}-1-ethanone (0.30 g, 0.65 mmol) was dissolved in dry THF (7.5 ml) and cooled to −10° C. Sodium bis(trimethylsilyl)amide (0.65 ml, 1 M in THF, 0.65 mmol) was added and the resulting yellow solution stirred for 15 minutes. Benzylbromide (0.16 ml, 1.30 mmol) was added and the stirring continued for 15 minutes at −10° C., the cooling bath was removed and stirring continued for 4 hours. Saturated NH4Cl(aq) was added followed by removal of the aqueous phase. The organic solvent was evaporated in vacuum and the residue chromatographed furnishing the sub-title product (0.28 g, 79%).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2)#N.[H-].C([Al+]CC(C)C)C(C)C.[O:22]1CCOCC1.O.Cl>CCOCC.CCCCCC>[CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2)=[O:22]
Reactant: N#Cc1cccc2[nH]ccc12
Reactant: C1COCCO1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: O=Cc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Two grams of 4-cyanoindole, prepared by the method of Uhle J.A.C.S., 71, 761 (1949), were dissolved in 20 ml of anhydrous ether. 15 Milliliters of a 20% solution of diisobutylaluminum hydride (DiBAl) in hexane were added in dropwise fashion. The reaction mixture was stirred at room temperature for about 30 minutes and then heated to refluxing temperature for about three hours. The reaction mixture was then cooled and 10 ml of a 4:1 dioxane-water solution added with stirring over a period of five minutes. 30 Milliliters of 1 N HCl were added over a 30 minute period with stirring. The aqueous mixture was extracted with several portions of ethyl acetate and the ethyl acetate extracts combined. The combined extracts were washed with 10 percent aqueous sodium carbonate and with saturated aqueous sodium chloride and were then dried. Evaporation of the solvent yielded 2.24 g of 4-formylindole. 4-Formylindole was purified by chromatography over Florisil using a hexane-ether solvent mixture (2:1) as the eluant. Recrystallization of the chromatographed 4-formylindole from an ether-hexane solvent mixture yielded yellow needles of 4-formylindole melting at 136°-137° C. Infrared spectrum; peak at 1670 cm-1 ; nmr (D6 acetone) δ 10.35 (s, 1H, CHO), 7.2-7.9 (m, 6H, Ar.); mass spectrum; molecular ion at 145.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([S:30](Cl)(=[O:32])=[O:31])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:30]([C:24]2[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:22]([O:21][CH3:20])[CH:23]=2)(=[O:32])=[O:31])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Product: COc1ccc(S(=O)(=O)Nc2cnc(Oc3cnc4ccccc4c3)c(Cl)c2)cc1OC

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 1) and 3,4-dimethoxybenzene-1-sulfonyl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH2:22]Br)[CH:7]=1)[CH3:2].[CH2:25]([SH:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[H-].[Na+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH2:22][S:32][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:7]=1)[CH3:2]
Reactant: SCc1ccccc1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Cl)cc2CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Cl)cc2CSCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To [3-(2-bromomethyl-4-chloro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester (0.15 g, 0.36 mmol) and benzyl mercaptan (0.06 mL, 0.4 mmol) in 1,4-dioxane (10 mL) was added sodium hydride (60% in mineral oil; 0.05 g, 1.25 mmol), and the reaction was stirred for 1 hour at room temperature. After work-up, the crude material was purified by preparative HPLC to give the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.Br[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:39][CH:38]=1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:39][CH:38]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2ccc(C(C)(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 10 min, 1-(bromomethyl)-4-tert-butylbenzene (0.62 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.86 g, 61%).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]=[C:8]([C:14]([OH:16])=O)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[C:19]([O:23][C:24]([NH:26][NH:27][CH:28]([CH3:30])[CH3:29])=[O:25])([CH3:22])([CH3:21])[CH3:20].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:19]([O:23][C:24]([NH:26][N:27]([C:14]([C:8]1[S:9][C:10]2[CH2:11][CH2:12][O:13][C:4]3[CH:3]=[C:2]([Br:1])[CH:18]=[CH:17][C:5]=3[C:6]=2[N:7]=1)=[O:16])[CH:28]([CH3:30])[CH3:29])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CC(C)NNC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(NC(=O)OC(C)(C)C)C(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.4 %

Procedure:
To a mixture of 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (5.20 g, 16.0 mmol) and N′-isopropyl-hydrazinecarboxylic acid tert-butyl ester (3.33 g, 19.1 mmol) in DMF (100 mL) at 0° C. was added DIPEA (6.93 mL, 39.9 mmol) followed by HATU (9.09 g, 23.9 mmol). The reaction mixture was stirred at RT for 72 h before being concentrated in vacuo. The resultant residue was treated with water then extracted with DCM (×3) before the combined organic extracts were washed with 10% citric acid, then saturated sodium bicarbonate solution followed by brine. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give a brown oil. The oil was extracted with diethyl ether (×5) and the diethyl ether extracts concentrated in vacuo before being triturated with pentane to give the title compound as a light brown solid (6.14 g, 12.7 mmol, 80%). LCMS: RT=5.02 min, [M+H]+=482/484.
Reaction SMILES: CC(C)(OC([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:12][S:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28])=O)C.BrC1C=CC2C(NC(=O)C2(C=CCC)C=1)=O.C1(=O)NC(=O)C2=CC=CC=C12.[ClH:57].O1CCOCC1>C(Cl)Cl>[ClH:57].[NH:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:12][S:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CSC/C=C\CN1C(=O)c2ccccc2C1=O
Agent: CCC=CC12C=C(Br)C=CC1C(=O)NC2=O
Agent: Cl
Agent: O=C1NC(=O)c2ccccc21
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1C/C=C\CSC[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To a solution of (S,Z)-2-[4-[[[1-[(1,1-dimethylethoxy)carbonyl]-2-pyrrolidinyl]methyl]thio]2-butenyl]-1H-isoindole-1,3(2H)-dione, (prepared as in Example I, Part A, except substituting 4-bromo-2-butenyl phthalimide for the corresponding phthalimide) (3.60 mmol)) in 2 mL of CH2Cl2 was added 18 mL of 4N HCl/dioxane at 0° C. The ice bath was removed and the reaction was stirred at room temperature for 3 hrs. The reaction mixture was concentrated in vacuo to give title compound (92% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][CH:17]1[CH2:22][C:21](=[O:23])[CH2:20][CH2:19][O:18]1.Cl>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:21]2([OH:23])[CH2:20][CH2:19][O:18][CH:17]([CH3:16])[CH2:22]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CC(=O)CCO1
Reactant: Brc1cccc(OCc2ccccc2)c1
Agent: Cl
Product: CC1CC(O)(c2cccc(OCc3ccccc3)c2)CCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.1 %

Procedure:
Using the procedure described in the portion of Example 1 which is concerned with the preparation of starting materials, a Grignard reagent was prepared from 3-benzyloxybromobenzene (10.5 g) and 2-methyltetrahydropyran-4-one (2.28 g) was added. The mixture was stirred at ambient temperature for 3 hours, acidified by the addition of 2N hydrochloric acid solution and extracted with ethyl acetate. Column chromatography, using a 10:3 v/v mixture of toluene and ethyl acetate as eluent, gave a less polar isomer, (2RS,4SR)-4-(3-benzyloxyphenyl)-4-hydroxy-2-methyltetrahydropyran (2.45 g, 41%), as an oil,
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[C:5](Br)[CH:4]=1.Cl.[F:17]C1C=C(NN)C=CC=1C>>[ClH:1].[F:17][C:14]1[C:3]([CH3:2])=[CH:4][CH:5]=[C:6]2[C:13]=1[C:9]([CH2:10][CH2:11][NH2:12])=[CH:8][NH:7]2
Reactant: Cc1cc(Br)c2[nH]cc(CCN)c2c1
Reactant: Cc1ccc(NN)cc1F
Agent: Cl
Product: Cc1ccc2[nH]cc(CCN)c2c1F

Procedure:
4-Fluoro-5-methyltryptamine hydrochloride was prepared (2.20 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 7, except using 3-fluoro-4-methyl-phenylhydrazine hydrochloride (6.00 g) as starting material.
Reaction SMILES: [S:1](=[O:4])(=O)=[O:2].N1C(C)=CC=CC=1C.[CH2:13]([NH:16][CH2:17][CH2:18][C:19]#[N:20])[CH:14]=[CH2:15].P(Cl)(Cl)([Cl:23])=O>ClCCCl>[CH2:13]([N:16]([CH2:17][CH2:18][C:19]#[N:20])[S:1]([Cl:23])(=[O:4])=[O:2])[CH:14]=[CH2:15]
Reactant: O=S(=O)=O
Reactant: O=P(Cl)(Cl)Cl
Reactant: C=CCNCCC#N
Solvent: ClCCCl
Solvent: Cc1cccc(C)n1
Product: C=CCN(CCC#N)S(=O)(=O)Cl
Temperature: 22 °C
Reaction time: 0.25 h

Procedure:
64.8 g (0.641 mol) of sulfur trioxide were added as a 57% solution in 1,2-dichloroethane at from 0 to 5° C. with stirring within 15 minutes to a solution of 90.6 g (0.846 mol) of 2,6-lutidine in 200 ml of 1,2-dichloroethane, followed by washing with 40 ml of 1,2-dichloroethane and stirring for 15 minutes until the temperature had risen to 22° C. Subsequently, 42.4 g (0.385 mol) of N-allyl-N-(2-cyanoethyl)amine were added at from 20 to 30° C. with stirring within 15 minutes, followed by washing with 40 ml of 1,2-dichloroethane and stirring at 50° C. for 15 minutes. After cooling to 22° C., 70.8 g (0.61 mol) of phosphorus oxychloride were added with stirring at from 20 to 30° C. within 15 minutes, followed by washing with 120 ml of 1,2-dichloroethane and heating to 70° C. After stirring at this temperature for 1 hour, the reaction mixture was allowed to cool to 25° C., concentrated under reduced pressure and distilled through a Normag column head with a 10 cm column. 32.3 g (40% of theory) of the title compound with a b.p. of from 110 to 116° C./0.4 mbar were obtained. Refractive index: nD23=1.4948.
Reaction SMILES: [Cl:1][C:2]1[C:18]([N+:19]([O-])=O)=[CH:17][C:5]([C:6]([N:8]([CH3:16])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[O:7])=[C:4]([F:22])[CH:3]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>O.C1COCC1>[NH2:19][C:18]1[C:2]([Cl:1])=[CH:3][C:4]([F:22])=[C:5]([CH:17]=1)[C:6]([N:8]([CH3:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=[O:7]
Reactant: Cc1ccccc1N(C)C(=O)c1cc([N+](=O)[O-])c(Cl)cc1F
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1N(C)C(=O)c1cc(N)c(Cl)cc1F

Procedure:
To 4-chloro-2-fluoro-N-methyl-5-nitro-N-o-tolyl-benzamide (6.6 g, 20.3 mmol) was stirred vigorously in a mixture of water (30 mL) and THF (30 mL) containing Na2S2O4 (17.6 g, 101.2 mmol) for 12 hrs. The organic layer was then separated and the water layer was further extracted with ethyl acetate. The combined organic solutions were washed with brine and dried over MgSO4. Concentration yielded 5-amino-4-chloro-2-fluoro-N-methyl-N-o-tolyl-benzamide as a crude solid which was washed with ether to give a light yellow product (3.3 g). MS: 292.9 (M+H)+, tR=1.90 min (method 1)
Reaction SMILES: [NH2:1][C:2]1[N:24]=[C:23](Cl)[CH:22]=[CH:21][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:12]=[CH:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH:9]=1)=[O:5].[CH3:26][NH2:27]>CS(C)=O.C(N(CC)C(C)C)(C)C.[Cl-].[Na+].O>[NH2:1][C:2]1[N:24]=[C:23]([NH:27][CH3:26])[CH:22]=[CH:21][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:12]=[CH:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH:9]=1)=[O:5]
Reactant: CN
Reactant: Nc1nc(Cl)ccc1C(=O)NCc1ccn(Cc2cccc(F)c2)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CNc1ccc(C(=O)NCc2ccn(Cc3cccc(F)c3)c2)c(N)n1
Temperature: 135 °C
Yield: 15 %

Procedure:
2-Amino-6-chloro-N-(1-(3-fluoro-benzyl)-1H-pyrrol-3-ylmethyl)-nicotinamide described in Preparation Example A+-5 (50 mg, 0.14 mmol) was dissolved in a mixture solution of dimethylsulfoxide (1 mL) and N,N-diisopropylethylamine (0.5 mL), methylamine (2.0 M tetrahydrofuran solution) (1 mL, 2 mmol) was added thereto, and the solution was heated in a sealed tube for 15 hours (oil bath temperature: 135° C.). The reaction mixture was allowed to room temperature, poured into brine, and the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate then concentrated, the obtained residue was purified by NH silica gel column chromatography (ethyl acetate), and the title compound (7.3 mg, 0.021 mmol, 15%) was obtained.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[OH:6][CH2:7][CH:8]1[CH2:13][CH2:12][C:11]([CH3:20])([C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])[CH2:10][CH2:9]1.Cl>N1C=CC=CC=1>[S:1]([O:6][CH2:7][CH:8]1[CH2:13][CH2:12][C:11]([CH3:20])([C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])[CH2:10][CH2:9]1)([CH3:4])(=[O:3])=[O:2]
Reactant: C=CCOC(=O)C1(C)CCC(CO)CC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: C=CCOC(=O)C1(C)CCC(COS(C)(=O)=O)CC1

Procedure:
4.5 ml of mesyl chloride was added to a solution of 2.1 g of allyl 4-hydroxymethyl-1-methyl-1-cyclohexanecarboxylate (Example 44) in 50 ml of pyridine. The solution was reacted for 3 hours at room temperature. After reaction, 100 ml of 2N hydrochloric acid was added to the reaction solution. The solution was extracted three times with 30 ml of ethyl acetate. The organic layer obtained was washed once with an aqueous sodium hydrogencarbonate solution and twice with an aqueous sodium chloride solution, and was dried over magnesium sulfate. Thereafter, the solvent was removed in vacuo. The oily substance obtained was subjected to column chromatography using 20 g of silica gel. From the fraction eluted with hexane and ethyl acetate=2:1, the solvent was removed in vacuo, yielding 2 g of allyl 4-mesyloxymethyl-1-methyl-1-cyclohexanecarboxylate as a pale yellow oil, which had the following physiochemical properties:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=[CH:7][C:8]=1SC.[CH:14]1C=C(Cl)C=C(C(OO)=O)C=1.[O-:25][S:26]([O-:28])=O.[Na+].[Na+]>C(Cl)Cl.CO>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=[CH:7][C:8]=1[S:26]([CH3:14])(=[O:28])=[O:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc([N+](=O)[O-])cc1CO
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)c1ccc([N+](=O)[O-])cc1CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.5 %

Procedure:
To a solution of 3-hydroxymethyl-4-(methylthio)nitrobenzene from step 1 (20 g, 0.10 mol) in CH2Cl2 (500 mL) and MeOH (100 mL), m-CPBA (74 g, 0.30 mol) was added portionwise at 0° C. and the mixture was stirred for 16 h at room temperature. The mixture was added aqueous Na2SO3 (20 g in 200 mL of water) at 0° C. Organic layer was separated and washed with saturated aqueous NaHCO3 (300 mL), dried over MgSO4, and concentarted in vacuo gave the title compound (15.6 g, 65%).
Reaction SMILES: [CH:1]([NH2:3])=[O:2].[CH2:4]([Cl:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[ClH:11].[CH2:4]([C:1](=[NH:3])[OH:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NC=O
Reactant: ClCc1ccccc1
Product: Cl
Product: N=C(O)Cc1ccccc1

Procedure:
The product was assayed by NMRδ (DMSO) 5.7 (s, 2H, φCH2), 7.5 (s, 5H, φ), 9.0 (s, 1H, HC=N). The product is thermally unstable. It decomposes to formamide and benzyl chloride at 0° C. and above. However, no appreciable decomposition was detected on storage at -20° C. for 2 months.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:16](OCC)=[O:17].C(O)(=O)C>COCCOC>[CH:16]([CH:10]([CH2:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:17]
Reactant: CCOC(=O)CCc1ccccc1
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COCCOC
Product: CCOC(=O)C(C=O)Cc1ccccc1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a suspension of NaH (2.338 g, 58.5 mmol) in DME (20 mL) was added dropwise a solution of ethyl 3-phenylpropanoate (3.2 g, 19.49 mmol) and ethyl formate (6.28 mL, 78 mmol) in DME (20 mL) at room temperature. The reaction mixture was then stirred overnight. It was neutralized with acetic acid (4 mL), then extracted with EtOAc. The organic phase was collected, washed with brine, dried over Na2SO4, filtered, and concentrated affording the crude title compound (4.02 g, 100% yield). LCMS: rt=2.82 and 3.51 min (a mixture of ketone and enol isomer), [M+H+]=207.1
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10](=O)[CH3:11])[CH:3]=1.[H-].[Na+].Cl.[CH2:16]([N:18](CCCl)[CH2:19][CH3:20])[CH3:17].C(O)C>CN(C)C=O.C(O)(=O)C>[CH2:16]([N:18]([CH2:19][CH3:20])[CH2:11][CH2:10][NH:9][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=1)[CH3:17]
Reactant: CCN(CC)CCCl
Reactant: CC(=O)Nc1cc(C)cc(C)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CC(=O)O
Product: CCN(CC)CCNc1cc(C)cc(C)n1
Reaction time: 18 h

Procedure:
To 32.8 g (0.2 m) N-(4,6-dimethyl-2-pyridyl)acetamide dissolved in 300 ml dimethylformamide, sodium hydride (50%) (9.67 g 0.21 m) is added at 30°-40° in three portions with stirring. Ten minutes after this addition diethylaminoethylchloride hydrochloride (37.2 g, 0.216 m) is added and the mixture stirred 20 minutes. Sodium hydride (50%) (10.55 g, 0.229 M) is added in three portions at 40°-45°, the mixture stirred at 50°-55° for 1/2 hour and finally at 90° for 21/2 hours. On cooling ethanol, 50 ml. followed by acetic acid, 25 ml, are added. The mixture is concentrated under vacuum, the residue dissolved in dilute hydrochloric acid, and extracted with hexane. The aqueous is made alkaline with sodium hydroxide, 10 N and extracted with methylene chloride. The organic extracts are washed with water, concentrated and the residue distilled. The fraction distilling at 127°-140°/1.3 mm, weight 35.5 g is collected, hydrolyzed by refluxing in sulfuric acid (85 ml), water (80 ml) and acetic acid (170 ml) for 18 hours. The mixture is cooled in an ice bath and sodium hydroxide solution equivalent to the sulfuric acid is added. Ethanol is added and the salts filtered off. The filtrate is concentrated under vacuum and the residue taken up in dilute sodium hydroxide. The mixture is extracted with methylene chloride, the organic extracts washed with brine, dried over sodium sulfate and concentrated to obtain the 2-(2-diethylaminoethylamino)-4,6-dimethylpyridine as an oil, weight 30 g.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH:7]=[O:8])=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[CH3:15][O:16][CH2:17]Cl.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:15][O:16][CH2:17][O:1][C:2]1[C:6]([CH:7]=[O:8])=[CH:5][N:4]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:3]=1
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Reactant: COCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCOc1nn(-c2ccccc2)cc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
A mixture of 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (1.88 g), chloromethyl methyl ether (0.835 mL), N,N-diisopropylethylamine (2.09 mL) and tetrahydrofuran (30 mL) was stirred at room temperature for 2 hrs. Saturated aqueous sodium hydrogen carbonate was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with diisopropyl ether-hexane to give 3-(methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde as white crystals (1.34 g, yield 58%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 106-107° C.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=3)=[CH:10][C:5]=2[CH2:4][O:3]1.C1N=C[N:23](C(N2C=NC=C2)=O)C=1.C(=O)([O-])[O-].[NH4+].[NH4+].O>CN(C=O)C>[OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:23])=[O:17])=[CH:14][CH:13]=3)=[CH:10][C:5]=2[CH2:4][O:3]1
Reactant: O=C(O)c1ccc(Oc2ccc3c(c2)COB3O)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ccc3c(c2)COB3O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 40 mL scintillation vial containing 4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzoic acid (77 mg, 0.28 mmol, 1.0 eq.) and CDI (101.3 mg, 0.62 mmol), 2.5 eq.) in DMF (3.0 mL) was added Ammonium carbonate (123.3 mg, 1.28 mmol, 4.5 eq.). The mixture was stirred at room temperature overnight. The mixture was treated with H2O (5 mL) and the layers were separated. The aqueous was extracted with EtOAc (2×5 mL), combined organic phase was washed with brine (10 mL), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The residue was applied to silica chromatography eluting with MeOH/DCM (0:100 to 10:90) to give 4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzamide as a white solid. LCMS (m/z) 270 (M+H); 1H NMR (DMSO-d6) δ: 9.14 (s, 1H), 7.87-7.92 (m, 2H), 7.73 (d, J=7.8 Hz, 1H), 7.05 (d, J=8.8 Hz, 4H), 4.93 (s, 2H).