Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(O)(=O)C>ClCCl>[I:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][S:16]([CH3:15])(=[O:18])=[O:17])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(I)nc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1ccc(I)nc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 100 %

Procedure:
To a solution of 6-iodopyridin-3-amine (1.077 gm, 4.90 mmole) in dichloromethane (40 ml) and pyridine (1.98 ml, 24.49 mmole) at ice bath temperature was added methanesulfonyl chloride (0.401 ml, 2.444 mmole). The mixture was allowed to warm to room temperature and stir four days. The reaction mixture was treated with 5% acetic acid and allowed to stir 20 min at room temperature. The organic phase was washed with water (2×50 ml), dried (MgSO4) and concentrated in vacuo. The residue was slowly added in portions to rapidly stirred water (100 ml) and the resulting solid collected by filtration, washed with water and dried in vacuo to give the title compound (0.7287 g, 49.9%).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][Cl:8].[P:9](Cl)([Cl:12])([Cl:11])=[O:10].NC1C=CC(S(C=CC#N)(=O)=O)=CC=1.CCCCCCCC>CC(C)=O.N1C=CC=CC=1>[Cl:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][Cl:8])[P:9]([Cl:12])([Cl:11])=[O:10]
Reactant: O=P(Cl)(Cl)Cl
Reactant: ClCCNCCCl
Agent: Cl
Agent: N#CC=CS(=O)(=O)c1ccc(N)cc1
Solvent: CC(C)=O
Solvent: CCCCCCCC
Solvent: c1ccncc1
Product: O=P(Cl)(Cl)N(CCCl)CCCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Di-(2-chloroethyl)amidophosphorodichloridate is prepared according to H. Brintzinger et al in Chemische Berichte 82, 389-99 (1949) from bis-(2-chloroethyl)amine hydrochloride and phosphoryl chloride in the presence of pyridine. 0.03 mol (7.8 g) of this material is dissolved in 100 ml of acetone and added to an acetone solution of 0.03 mole (6.3 g) of 2-cyanovinyl 4-aminophenyl sulfone. To the stirred mixture is added in 2-3 portions a 10% solution of 1,4-diazabicyclo[2.2.2.]octane in acetone. After a few minutes a yellow slurry forms which is stirred at room temperature for 30 minutes. After filtration to remove the amine hydrochlorides the filtrate is reduced to about half its volume by evaporation and then mixed with chloroform, washed with water and worked up. The light yellow solid is di-(2-chloroethyl)amido-di-4-(2-cyanoethenesulfonylanilido)phosphine oxide: ##SPC57##
Reaction SMILES: [H-].[Na+].P(=O)([O-])O[C:5]([CH2:17][CH3:18])(CC)[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[CH:21]1[C:31]2C=C[C:28]3[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=3[C:26](=O)[C:25]=2[CH:24]=[CH:23][CH:22]=1.[Na+].[Cl-]>CS(C)=O>[N+:12]([C:9]1[CH:8]=[CH:7][C:6]([CH:5]=[C:17]2[C:18]3[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=3[CH:27]=[CH:26][C:25]3[CH:31]=[CH:21][CH:22]=[CH:23][C:24]2=3)=[CH:11][CH:10]=1)([O-:14])=[O:13]
Reactant: O=c1c2ccccc2ccc2ccccc12
Reactant: CCC(CC)(O[PH](=O)[O-])c1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(C=C2c3ccccc3C=Cc3ccccc32)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
150 ml of dimethyl sulfoxide was admixed with 3.60 g (about 90 mmoles) of oily sodium hydride (about 60%) at room temperature. After the addition, the mixture was heated over an oil bath to an inside temperature of about 70° C., and stirred as such for about one hour. Then, the reaction mixture was cooled to room temperature, and a solution of 25.1 g (92 m moles) of the previously obtained diethyl-4-nitrobenzyl phosphonate and 10.0 g (48.5 m moles) of 5H-dibenzo[a,d]cycloheptene-5-on in 50 ml of dimethyl sulfoxide was added thereto dropwise. After the dropwise addition, the mixture was stirred at room temperature for 15 minutes, and then further stirred with heating at an inside temperature of 70° to 80° C. for 2 hours over an oil bath. After the end of reaction, the mixture was cooled to room temperature, poured into about 1 l of an aqueous saturated NaCl solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then the solvent was removed therefrom under reduced pressure. The residue was admixed with methanol, and the thus precipitated crystal was recovered therefrom by filtration. The thus obtained crystal was recrystallized from methanol-acetone solvent mixture, whereby 10.94 g of 5-(4-nitrobenzylidene)-5H-dibenzo[a,d]cycloheptene was obtained (yield: 69.3%). The melting point was 151.5°-152.5° C. The elemental analysis as C22H15NO2 was as follows:
Reaction SMILES: [NH2:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:7](=[O:8])[CH:6]=[CH:5][CH2:4][CH2:3]1.[OH:16][C:17]([CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]1[C@@H:31]2[C@@H:26]([NH:27][C:28]([NH:30]2)=[O:29])[CH2:25][S:24]1)=O.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[C:17]([NH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:7](=[O:8])[CH:6]=[CH:5][CH2:4][CH2:3]1)(=[O:16])[CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]1[C@@H:31]2[C@@H:26]([NH:27][C:28]([NH:30]2)=[O:29])[CH2:25][S:24]1
Reactant: NC1(c2ccccc2Cl)CCC=CC1=O
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)NC1(c2ccccc2Cl)CCC=CC1=O
Yield: 31.7 %

Procedure:
A solution of 6-amino-6-(2-chlorophenyl)-2-cyclohexen-1-one (50 mg, 0.23 mmol), (+)-biotin (56 mg, 0.23 mmol), hydroxybenzotdazole (31 mg, 0.23 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (66 mg, 0.35 mmol) in dimethylformamide (1 ml) was stirred at room temperature for 42 h. The reaction was partitioned between water and ethyl acetate, the organic phase was washed with water, brine, dried (Na2SO4), and the solvent removed by evaporation. Flash chromatography on silica gel eluted with 17:3 ethyl acetate / hexane afforded 6-biotinoylamino-6-(2-chlorophenyl)-2-cyclohexen-1-one (32.7 mg, 32%).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([Cl:13])=[CH:9][C:10]=2[Cl:12])[NH:5][C:4]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:2].C(=O)([O-])[O-].[K+].[K+].[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.O>CN(C)C=O>[CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([Cl:13])=[CH:9][C:10]=2[Cl:12])[N:5]([S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=2)(=[O:33])=[O:32])[C:4]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:2]
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1C=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C=O)c2c(Cl)cc(Cl)cc2n1S(=O)(=O)c1ccc(C)cc1
Reaction time: 18 h

Procedure:
Combine 3-formyl-2-carboethoxy-4,6-dichloroindole (46.3 g. 162 mmol) and anhydrous potassium carbonate (44.9 g, 325 mmol) in dimethylformamide (600 mL). Add p-toluenesulfonyl chloride (42.9 g, 225 mmol). After 18 hours, pour the reaction mixture into water (3 L) and stir to give a solid. Filter, rinse with water and diethyl ether, and recrystallize from acetonitrile/dichloroethane to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[CH:15][N:16]([CH3:18])[CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.O>C(O)C.Cl.[Pt]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH2:15][N:16]([CH3:18])[CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(=CN(C)C)c1ccc(OC)cc1
Agent: [Pt]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(CN(C)C)c1ccc(OC)cc1
Reaction time: 72 h
Yield: 82 %

Procedure:
4.645 g (0.0186 mol) of ethyl α-(p-methoxyphenyl)-β-(dimethylamino)acrylate were dissolved in 225 ml of ethanol in a 1 liter glass reactor, 7,46 g of Pt/C type 18 catalyst were added (4.83% Pt and 59.70% water) and a pressure of 200 psi of H2 was applied. The mixture was left hydrogenating for 3 days, after which it was filtered through Celite® 535 and was washed with 2×40 ml of ethanol. The ethanol was then removed under vacuum, to give a residue weighing 0.72 g. The residue was suspended in 40 ml of 2N hydrochloric acid and was washed with dichloromethane. The operation continued with the acid aqueous phase which was basified with a mixture of sodium carbonate and potassium carbonate (1/1) to pH 11 and the product was extracted with 4×40 ml of dichloromethane. The pooled organic phases were dried with sodium sulfate, were filtered and were evaporated to dryness under vacuum, to give a pale yellow oil weighing 3.82 g corresponding to ethyl α-(p-methoxyphenyl)-β-(dimethylamino)propionate (Yield: 82%).
Reaction SMILES: [O:1]1[C:5]2([CH2:9][CH2:8][N:7](C(OCC3C=CC=CC=3)=O)[CH2:6]2)[O:4][CH2:3][CH2:2]1>CO.[OH-].[Pd+2].[OH-]>[O:1]1[C:5]2([CH2:9][CH2:8][NH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C(OCc1ccccc1)N1CCC2(C1)OCCO2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C1CC2(CN1)OCCO2
Reaction time: 2.5 h
Yield: 100.1 %

Procedure:
To a solution of benzyl 1,4-dioxa-7-azaspiro[4.4]nonane-7-carboxylate (1.1 g) in methanol (30 mL) was added palladium(II) hydroxide (100 mg) at room temperature. The mixture was stirred for 2.5 hr under a hydrogen atmosphere (0.4 MPa). Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (540 mg) as a dark orange liquid.
Reaction SMILES: [NH2:1][C:2]1[C:5](=O)[C:4](=[O:7])[C:3]=1[O:8]C.[N:10]1([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([O:23][CH2:24][CH2:25][CH2:26][NH2:27])[CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>N1C=CC=CC=1>[N:10]1([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([O:23][CH2:24][CH2:25][CH2:26][NH:27][C:5]3[C:4](=[O:7])[C:3](=[O:8])[C:2]=3[NH2:1])[CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: NCCCOc1cc(CN2CCCCC2)ccn1
Reactant: COc1c(N)c(=O)c1=O
Solvent: c1ccncc1
Product: Nc1c(NCCCOc2cc(CN3CCCCC3)ccn2)c(=O)c1=O

Procedure:
1-Amino-2-methoxy-cyclobut-1-ene-3,4-dione is mixed with 3-[4-(piperidinomethyl)pyrid-2-yloxy]prop-1-ylamine in anhydrous pyridine and is heated at reflux temperature to give the title product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@H:10]([OH:13])[CH2:11]Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@@H:10]1[O:13][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.4 %

Procedure:
(2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (0.40 g) and potassium carbonate (0.37 g) were added to methanol (8 ml), and the mixture was stirred at room temperature for 6 hours. The inorganic salt was filtered off from the reaction solution, and the filtrate was then concentrated under reduced pressure. To the residue was added water, and the solution was extracted with methylene chloride. The resulting methylene chloride layer was washed with a 20% citric acid aqueous solution, and the solvent was then distilled off under reduced pressure. Ethyl acetate (2 ml) was added to the residue. The mixture was heat-dissolved, and crystallized by being cooled to room temperature. Further, n-hexane (4 ml) was added thereto, and the resulting mixture was stirred while being cooled with ice. Crystals were separated, and dried to obtain the crystals (0.30 g) of desired (2S,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane in a yield of 85%.
Reaction SMILES: [O:1]=[C:2]1[N:11]2[N:12]=[C:13]([C:15](OCC)=[O:16])[CH:14]=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.[BH4-].[Li+].Cl>O>[OH:16][CH2:15][C:13]1[CH:14]=[C:10]2[N:11]([C:2](=[O:1])[NH:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=32)[N:12]=1
Reactant: CCOC(=O)c1cc2c3ccccc3[nH]c(=O)n2n1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Product: O=c1[nH]c2ccccc2c2cc(CO)nn12
Temperature: 0 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
500 mg (0.0019 mole) of 5,6-dihydro-5-oxopyrazolo[1,5-c]quinazoline-2-carboxylic acid, ethyl ester, prepared as described in Example 2A, is suspended in 10 ml distilled tetrahydrofuran and treated with 99.6 mg (0.0039 mole or 2 equivalents) of 85% lithium borohydride at room temperature. The mixture is stirred overnight (~20 hours), cooled down to 0° C., treated with 4.5 ml of 1.0 N hydrochloric acid and stirred for 30 minutes. The mixture is then diluted with water (25 ml), stirred for 10 minutes and filtered. The white precipitates are dried in a vacuum oven at ~70° for 1.5 hours to give 344 mg of title compound, m.p. 289°-290°; 84% yield. An additional 31.3 mg is obtained from the filtrate on addition of an equal volume of methylene chloride.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:18]=[C:17]2[N:8]([C:9](=[O:19])[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=32)[N:7]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[OH:3][CH2:4][C:6]1[CH:18]=[C:17]2[N:8]([C:9](=[O:19])[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=32)[N:7]=1
Reactant: CCOC(=O)c1cc2c3ccccc3[nH]c(=O)n2n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: O=c1[nH]c2ccccc2c2cc(CO)nn12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
1.28 g (0.005 mole) of 5,6-dihydro-5-oxopyrazolo-[1,5-c]quinazoline-2-carboxylic acid ethyl ester prepared as described in Example 2A is suspended in 100 ml of dichloromethane and treated with 7.9 ml (0.011 mole) of 20% di-isobutylaluminum hydride (Dibal). The resultant yellow solution is stirred at room temperature for 45 minutes, 2.0 ml (0.003 M) of Dibal solution is added and stirring continued for 17 hours.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10](=[O:15])[C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(O)(C(F)(F)F)=O>C(Cl)Cl.O>[CH3:14][C:11]1([CH3:13])[O:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:1]([S:35]([CH3:34])(=[O:37])=[O:36])[S:35]([CH3:34])(=[O:37])=[O:36])=[CH:3][CH:4]=2)=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=2)[C:10]1=[O:15]
Reactant: CC1(C)OC(c2ccc(N)cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Reactant: CS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC1(C)OC(c2ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.2 %

Procedure:
To a stirred solution of 5-(4-aminophenyl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (60 mg, 0.13 mmol) in DCM (5 mL) were added methane sulfonyl chloride (0.012 g, 0.15 mmol) and TFA (0.04 mL, 0.27 mmol) at 0° C. under N2 atmosphere. The reaction mixture was stirred at RT for 10 min. The reaction mixture diluted with water and extracted with DCM (2×10 mL). The combined organic layers were washed with water (2×5 mL), brine and dried over anhydrous Na2SO4. After filtration and evaporation, the crude material was purified by silica gel column chromatography to afford N-(4-(5,5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy)phenyl)-4,5-dihydrofuran-2-yl)phenyl)-N-(methylsulfonyl)methane sulfonamide (25 mg, 30%), as a white color solid. 1H NMR (500 MHz, CDCl3): δ 8.22 (d, J=8.5 Hz, 1 H), 8.10 (d, J=7.9 Hz, 1H), 7.76 (d, J=8.4 Hz, 1 H), 7.80 (d, J=8.2 Hz, 2 H), 7.74 (t, J=8.2 Hz, 1 H), 7.70 (d, J=8.5 Hz, 1 H), 7.56 (d, J=7.5 Hz, 1 H), 7.28 (d, J=7.4 Hz, 2 H), 7.12 (d, J=7.5 Hz, 2 H), 7.08 (d, J=7.6 Hz, 2H), 5.42 (s, 2 H), 3.42 (s, 6 H), 1.58 (s, 6H). MS: [M+Na]: m/z=615.1, [M+H]: m/z=593.1. HPLC: 98.9% (RT-2.52 min), Column: Acquity BEH-C-18, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), ACN (B), Flow rate: 0.5 ml/min (Gradient).
Reaction SMILES: Cl.N1CCCC1.[Cl:7][C:8]1[CH:27]=[CH:26][C:11]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([OH:25])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][N:14]=2)=[C:10]([F:28])[CH:9]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:37][CH2:38][N:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>CN(C=O)C>[Cl:7][C:8]1[CH:27]=[CH:26][C:11]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:37][CH2:38][N:39]4[CH2:43][CH2:42][CH2:41][CH2:40]4)=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][N:14]=2)=[C:10]([F:28])[CH:9]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCN1CCCC1
Temperature: 100 °C
Yield: 9.5 %

Procedure:
1-2-Chloroethyl)pyrrolidine hydrochloride (200 mg, 1.2 mmol) was added to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (403 mg, 1.26 mmol), (prepared as described for the starting material in Example 2), and potassium carbonate (650 mg, 4.7 mmol) in DMF (4 ml). The mixture was heated to 100° C. and further portions of 1-(2-chloroethyl)pyrrolidine hydrochloride (800 mg in total) were added periodically over 4 hours while the reaction mixture was maintained at 100° C. The reaction was then allowed to cool and volatiles were removed by evaporation. The residue was partitioned between methylene chloride and water, separated and the organic phase passed through phase separating paper. Column chromatography eluting with methylene chloride/methanol (95/5) gave 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)quinazoline (50 mg, 10%).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:26]=[CH:25][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20](OCC)=[O:21])=[CH:14][CH:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C(OCC)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O>[CH3:4][C:2]([C:5]1[CH:26]=[CH:25][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][OH:21])=[CH:14][CH:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: CCOC(=O)COc1ccc(NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)c1ccc(C(=O)Nc2ccc(OCCO)cc2)cc1
Yield: 25 %

Procedure:
2.2 g. (6.2 mMol) of the compound prepared in Example 31 in 50 ml. dry diethyl ether are heated with 1 g. lithium aluminium hydride, subsequently poured into water and a little 10% sulphuric acid, extracted with diethyl ether, dried over anhydrous sodium sulphate, filtered and the solvent removed in a vacuum. The residue is then recrystallised from toluene to give the title compound in a yield of 25% of theory; m.p. 136°-142° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[C:4]([CH3:11])[N:3]=1.[CH3:12][O-:13].[Na+]>CO.O>[C:8]([C:7]1[C:2]([O:13][CH3:12])=[N:3][C:4]([CH3:11])=[CH:5][C:6]=1[CH3:10])#[N:9]
Reactant: C[O-]
Reactant: Cc1cc(C)c(C#N)c(Cl)n1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nc(C)cc(C)c1C#N
Temperature: 60 °C
Yield: 64.6 %

Procedure:
A solution of 2-chloro-3-cyano-4,6-dimethylpyridine (4.60 g, 27.7 mmol) in methanol (30 mL) is added to a stirred solution of sodium methoxide (2.09 g, 38.78 mmol) in methanol (20 mL) and the reaction mixture is heated at 60° C. for 4 hr. After cooling, the reaction is diluted with water (150 mL) and the solids are collected by filtration, washed with water and dried to yield 3-cyano-4,6-dimethyl-2-methoxypyridine (2.90 g, 65%) as an off-white solid containing the same impurity as the starting material. LC/MS: MS m/e=163 (M+H); RT 3.29 min; 1H NMR (CDCl3, δ ppm) 6.69, (1H, s), 4.00 (3H, s), 2.43 (6H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=1)[CH2:5][OH:6]>ClCCl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[CH:3]=[C:4]([C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: Cc1ccc([N+](=O)[O-])c(CO)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1ccc([N+](=O)[O-])c(C=O)c1
Reaction time: 9 h
Yield: 83.5 %

Procedure:
A mixture of 3-methyl-6-nitrobenzylalcohol (10 g, 59.8 mmol) and manganese dioxide (80 g) in dichloromethane (100 mL) was stirred for 9 h and passed through a celite short column. The eluent was concentrated and the residue was purified by silica gel column chromatography with 8:1 hexane/ethyl acetate to give 8.25 g of the title compound (84%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:18][OH:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]1[C:35]([F:36])=[CH:34][C:31]([C:32]#[N:33])=[C:30]([F:37])[CH:29]=1.ClC1C=CC(S(N(CC2C=CC(C3OC=CN=3)=C(F)C=2F)[C@@H]2CCCC[C@H]2CO)(=O)=O)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:27][C:28]2[CH:29]=[C:30]([F:37])[C:31]([C:32]#[N:33])=[CH:34][C:35]=2[F:36])[C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:18][OH:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: N#Cc1cc(F)c(CBr)cc1F
Reactant: O=S(=O)(N[C@@H]1CCCC[C@H]1CO)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncco2)c(F)c1F)[C@@H]1CCCC[C@H]1CO
Agent: [Cs+]
Product: N#Cc1cc(F)c(CN([C@@H]2CCCC[C@H]2CO)S(=O)(=O)c2ccc(Cl)cc2)cc1F
Yield: 76.9 %

Procedure:
The title compound was synthesized from 4-chloro-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (300 mg, 1.0 mmol), cesium carbonate (390 mg, 1.20 mmol), and 4-(bromomethyl)-2,5-difluorobenzonitrile (278 mg, 1.20 mmol) according to the procedure described for 4-chloro-N-(2,3-difluoro-4-(oxazol-2-yl)benzyl)-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (Example 20) to give 4-chloro-N-(4-cyano-2,5-difluorobenzyl)-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (350 mg, 77%). 1H NMR (400 MHz, CDCl3) δ ppm 7.74 (m, 2H), 7.59 (dd, J=8.81, 5.79 Hz, 1H), 7.51 (m, 2H), 7.28 (dd, J=8.69, 4.91 Hz, 1H), 4.48 (d, J=15.80 Hz, 1H), 4.39 (d, J=15.80 Hz, 1H), 3.64 (ddd, J=14.00, 9.00, 4.00 Hz, 1H), 3.55 (ddd, J=11.83, 4.78, 3.53 Hz, 1H), 3.16 (ddd, J=11.52, 9.13, 2.27 Hz, 1H), 2.40 (br. s., 1H), 1.68 (d, J=10.58 Hz, 3H), 1.30-1.45 (m, 2H), 0.99-1.21 (m, 4H).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:3]1.[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1.[Cl-].[Na+].C(=O)(O)[O-].[Na+]>CCOCC.CO.C(Cl)Cl>[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[O:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:3]1
Reactant: CCOC(=O)CCCCCCC1=CC(O)CC1=O
Reactant: C1=COCCC1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CCCCCCC1=CC(OC2CCCCO2)CC1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 674 mg. (2.64 mmoles) of 4-hydroxy-2-(6-carbethoxyhexyl)cyclopent-2-en-1-one (Example 29) and 2.22 g. (26.4 mmoles) of dihydropyran in 2.6 ml. of methylene chloride is added 5.0 mg. (0.026 mmoles) of p-toluenesulonic acid monohydrate. After stirring for 20 minutes at room temperature the solution is diluted with ether and poured into saturated sodium chloride solution containing a little sodium bicarbonate. The organic phase is separated and washed with saturated sodium chloride solution. The extract is dried over magnesium sulfate, and volatile matter is evaporated at reduced pressure to give an oil, λmax.MeOH = 224 mμ (7950); θmax. = 1735 (ester carbonyl group), 1710 (ketone carbonyl group), and 1030 cm-1 (tetrahydropyranyloxy group).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](O)=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(OCC)C>[C:17]1([CH:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:14][OH:15])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC(c1ccccc1)c1ccccc1
Yield: 36 %

Procedure:
To lithium aluminum hydride (2.85 g, 23.56 mmol) in anhydrous diethyl ether (150 mL) was added, as a powder, diphenylacetic acid (5.0 g, 56 mmol). The resulting reaction mixture was gently refluxed for one hour. The reaction was quenched with sodium sulfate saturated aqueous solution and the resulting precipitate was filtered off. The filtrate was concentrated in vacuo to yield 4.0 g (86% yield) of the title compound.