Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([N:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]3[N:18]=[N:19][N:20]=[C:9]3[C:8]=2[N:7]=[CH:6]1)(C)C.Cl.[OH-].[Na+]>O>[N:18]1[N:10]2[C:11]3[C:16]([C:17]4[NH:5][CH:6]=[N:7][C:8]=4[C:9]2=[N:20][N:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3
Reactant: CC(C)(C)n1cnc2c1c1ccccc1n1nnnc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc2c(c1)c1[nH]cnc1c1nnnn21
Temperature: 25 °C
Yield: 81.4 %

Procedure:
6-(1,1 -Dimethylethyl)-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline (1 g, 3.8 mmole, Example 20) was added to hydrochloric acid (5 mL of 6N); water (20 mL) was added and the mixture was heated on a steam bath for 1 hour. The reaction mixture was allowed to cool to ambient temperature then made basic (pH 11) by the addition of sodium hydroxide solution. The resulting precipitate was isolated by filtration, dried then recrystallized from N,N-dimetllylformamide to provide 0.65 g of the desired product as a solid. A sample of this material was refluxed in a large amount of dichloromethanetmethanol, isolated by filtration, then dried to provide 6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline as a solid, m.p. >300° C. Analysis: Calculated for C10H6N6: %C, 57.14; %H, 2.88; %N, 39.98; Found: %C, 56.89; %H, 3.10; %N 39.34. The structure was confirmed by both mass spectroscopy and nuclear magnetic resonance spectroscopy.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].Cl[CH2:11][C:12](=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.[I-].[K+]>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:11][C:12](=[O:14])[CH3:13]
Reactant: CC(=O)CCl
Reactant: Oc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)COc1ccc(F)cc1Br
Yield: 109.3 %

Procedure:
A mixture of 1.9 gm (10 mMol) 2-bromo-4-fluorophenol, 0.92 gm (10 mMol) chloroacetone, 0.1 gm potassium iodide, and 1.4 gm (10 mMol) potassium carbonate in 100 mL tetrahydrofuran was heated at reflux for 4 hours. The mixture was concentrated under reduced pressure and the residue partitioned between dichloromethane and 1 N sodium hydroxide. The phases were separated and the aqueous phase extracted well with dichloromethane. The organic phases were combined, washed with 1 N sodium hydroxide, dried over sodium sulfate and concentrated under reduced pressure. The residual was subjected to silica gel chromatography, eluting with hexane containing 20% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 2.7 gm (100%) of the desired compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.C([O-])(O)=O.[Na+].Br[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:15])[CH:7]=[CH:6]2
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2cc([C@H](C)C(=O)OCC(=O)OC(C)(C)C)ccc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 3 g, 13.0 mmol), NaHCO3 (1.4 g, 16.7 mmol) and tert-butyl bromoacetate (5.08 g, 26.0 mmol) in DMF (30 mL) was stirred at room temperature for 2 days and the solvent was evaporated under high vacuo. The residue was then diluted with CH2Cl2, the solvent removed by filtration and the residue was recrystallized from a mixture of CH2Cl2/EtOAc/Hex to give the title compound as a white solid in quantitative yield. Mp 85-86° C. 1H NMR (300 MHz, CDCl3) δ 7.69-7.70 (m, 3H), 7.43 (dd, J=1.6 and 8.6 Hz, 1H), 7.10-7.15 (m, 2H), 4.47 (ABq, JAB=15.7 Hz, ΔvAB=40.7 Hz, 2H), 3.97 (q, J=7.2 Hz, 1H), 3.90 (s, 3H), 1.63 (d, J=7.2 Hz, 3H), 1.42 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 174.2, 166.9, 157.8, 135.4, 133.9, 129.5, 129.1, 127.3, 126.5, 126.3, 119.1, 105.8, 82.5, 61.7, 55.5, 45.3, 28.1, 18.8. Mass spectrum (API-TIS) m/z 345 (MH+), 362 (MNH4+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][C:11]#[C:12][CH2:13][CH3:14])=[C:5]([O:15][CH3:16])[CH:4]=1.[OH:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28].[OH-].[K+]>CN(C)C=O.CO>[CH3:16][O:15][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[O:9][CH2:10][C:11]#[C:12][CH2:13][CH3:14])[CH2:2][O:17][N:18]1[C:22](=[O:23])[C:21]2[C:20](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19]1=[O:28]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CCC#CCOc1ccc(CCl)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CCC#CCOc1ccc(CON2C(=O)c3ccccc3C2=O)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Chloromethyl-2-methoxy-1-pent-2-ynyloxy-benzene (28 g, 0.12 mol) and N-hydroxyphthalimide (19.5 g, 0.12 mol) are dissolved in 180 ml of N,N-dimethylformamide. The reaction mixture is heated to +70° C. and potassium hydroxide (24 ml of a 5 M solution in methanol, 0.12 mol) is added at this temperature. The reaction is stirred for 1 hour at +70° C., subsequently cooled to room temperature and poured on water. This mixture is stirred for one further hour and filtered. The resulting crystalls are washed with water and recrystallized from methanol/acetone (8:1) to yield 2-(3-methoxy-4-pent-2-ynyloxy-benzyloxy)-isoindole-1,3-dione as colourless crystalls.
Reaction SMILES: [OH:1][C:2]1(C#N)[CH2:15][C:14]([CH3:16])=[CH:13][CH2:12][CH2:11][C:10]([CH3:17])=[CH:9][CH2:8][CH2:7][C:6]([CH3:18])=[CH:5][CH:4]=[C:3]1[CH:19]([CH3:21])[CH3:20].C(=O)([O-])O.[Na+]>C(OCC)C>[CH3:21][CH:19]([C:3]1[C:2](=[O:1])[CH2:15][C:14]([CH3:16])=[CH:13][CH2:12][CH2:11][C:10]([CH3:17])=[CH:9][CH2:8][CH2:7][C:6]([CH3:18])=[CH:5][CH:4]=1)[CH3:20]
Reactant: CC1=CC=C(C(C)C)C(O)(C#N)CC(C)=CCCC(C)=CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CC1=CC=C(C(C)C)C(=O)CC(C)=CCCC(C)=CCC1
Reaction time: 0.17 h
Yield: 81 %

Procedure:
A solution of the cyanohydrin which is 1-hydroxy-2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-cyclotetradecatetraenecarbonitrile (78.0 mg, 0.25 mmol) in ethyl ether (4 ml) is added to a saturated aqueous sodium hydrogen carbonate solution (2 ml) on an ice-water bath and the mixture is stirred for 10 minutes under nitrogen atmosphere. After confirming disappearance of the starting compound, the organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated. The resulting residue is subjected to silica gel column chromatography (eluent: n-hexane/ethyl acetate=7:1) to give the desired ketone, 2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-cyclotetradecatetraene -1-on (58.0 mg, 75%).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[N:5][NH:6][C:7]=1[N:8]=[CH:9][N:10](C)C)#[N:2].Cl.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)N>CO>[Cl:23][C:24]1[CH:30]=[C:29]([NH:2][C:1]2[N:10]=[CH:9][N:8]=[C:7]3[NH:6][N:5]=[C:4]([NH:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=4)[C:3]=23)[CH:28]=[CH:26][CH:25]=1
Reactant: COc1cccc(Nc2n[nH]c(N=CN(C)C)c2C#N)c1
Reactant: Nc1cccc(Cl)c1
Agent: Cl
Solvent: CO
Product: COc1cccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1

Procedure:
A mixture of 1.38 g (4.85 mmol) of 4-cyano-5-(dimethylamino-methyleneamino)-3-(3-methoxy-phenylamino)-pyrazole, 0.915 g (5.58 mmol) of 3-chloro-aniline hydrochloride and 20 ml of methanol is heated under reflux for 16 hours. Concentration of the reaction mixture by evaporation in vacuo and recrystallization of the residue from methanol/water yield the title compound; m.p. 202-203° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=2)[N:3]=1>[Zn].O1CCOCC1>[C:8]([C:7]1[CH:6]=[N:5][C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=2)=[N:3][CH:2]=1)#[N:9]
Reactant: CCCOc1ccc(-c2ncc(C#N)c(Cl)n2)cc1
Agent: [Zn]
Solvent: C1COCCO1
Product: CCCOc1ccc(-c2ncc(C#N)cn2)cc1

Procedure:
4.7 G. of 4-chloro-5-cyano-2-(4-n-propoxyphenyl)-pyrimidine are reacted in 230 ml. of 50% dioxane with 20.0 g. of pre-treated zinc dust and worked up after the reaction in a manner analogous to that described in Example 13. There is obtained 5-cyano-2-(4-n-propoxyphenyl)-pyrimidine as colorless crystals having a melting point of 146.2°-146.6° C, which on cooling are nematic (monotropic) at 137.0° C.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH3:35])[C:23](OC3C=CC([N+]([O-])=O)=CC=3)=[O:24])[N:17]=2)=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:2].CN(C)C=O.[CH2:41]([NH2:46])[CH2:42][CH2:43][CH2:44][CH3:45]>O>[CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH3:35])[C:23]([NH:46][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:24])[N:17]=2)=[CH:14][CH:15]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:2]
Reactant: CCCCCN
Reactant: CCO[C@@H](Cc1ccc(-c2cccc(N(C)C(=O)Oc3ccc([N+](=O)[O-])cc3)n2)cc1)C(=O)OC
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(C[C@H](OCC)C(=O)OC)cc2)n1
Yield: 74.4 %

Procedure:
0.65 g (1.1 mmol) of methyl 2(S)-ethoxy-3-(4-{6-[methyl-(4-nitrophenoxycarbonyl)amino]pyrid-2-yl}phenyl)propanoate, 12 ml of dimethylformamide and 1 ml (8.8 mmol) of pentylamine are heated at 80° C. for 18 hours. After addition of water, the reaction medium is extracted with ethyl acetate. The ethyl acetate phase is dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by thin-layer chromatography on silica eluted with a 7/3 and then 6/4 heptane/ethyl acetate mixture. 0.35 g (76%) of methyl 2(S)-ethoxy-3-{4-[6-(1-methyl-3-pentylureido)pyrid-2-yl]phenyl}propanoate is obtained.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C@H:8]([NH2:12])[C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1.[OH-].[Na+].Cl[C:16]1[O:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1.Cl>CS(C)=O>[O:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[NH:12][C@@H:8]([CH2:7][CH:4]1[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]1)[C:9]([OH:11])=[O:10]
Reactant: Clc1nc2ccccc2o1
Reactant: N[C@@H](CC1CCCCC1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(O)[C@H](CC1CCCCC1)Nc1nc2ccccc2o1
Temperature: 25 °C

Procedure:
A slurry of L-cyclohexylalanine (2.44 g, 14.3 mmol) and powdered NaOH (1.14 g, 28.6 mmol) in DMSO (20 mL) was heated to 100° C. for 20 min until the mixture viscosity decreased and stirring was enabled. 2-Chlorobenzoxazole (1.99 g, 13.0 mmol) was added, and the solution was stirred at 100° C. for 4 h. Upon cooling to room temperature, the solution was poured into 1 M HCl. The precipitate was filtered and dried to afford 2-(S)-(benzooxazol-2-ylamino)-3-cyclohexyl propionic acid was isolated as a white powder (1.69 g, 41%). Step B. To a stirring solution of 2-(S)-(benzooxazol-2-ylamino)-3-cyclohexyl propionic acid (288 mg, 1.0 mmol), N1-(4-methoxy-phenyl)-ethane-1,2-diamine.2HCl (239 mg, 1.0 mmol), and iPr2NEt (0.87 mL, 5.0 mmol) in dichloromethane (4 mL) was added HATU (418 mg, 1.1 mmol). The solution was stirred at room temperature for 4 hours and then evaporated to dryness. The crude material was chromatographed over silica gel (Hexanes/EtOAc) to afford the title compound as a white powder (243 mg, 56%). HPLC-MS calcd. for C25H32N4O3 (M+H+) 437.25. found 437.5.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:14]([N:27]1[CH2:30][CH:29](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:28]1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([CH:29]1[CH2:30][N:27]([CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:28]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)C2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of sodium hydride (4.97 g, 0.129 mol) in 130 mL of anhydrous dimethyl formamide was added diethyl malonate (22.7 mL, 0.142 mol) dropwise at 0° C. and this reaction mixture was stirred at room temperature for 2 h. 1-Benzhydryl-3-(toluene-4-sulfonyl)-azetidine was added to it dropwise at 0° C. and reaction mixture was refluxed at 110° C. for 20 h. Excess sodium hydride was quenched with ammonium chloride, DMF was removed, and the reaction mixture was partitioned between chloroform and water; the aqueous layer was extracted with chloroform, the solvent was removed in vacuo, and purification by (neutral alumina) chromatography and 30% ethyl acetate/hexanes as eluent provided 2-(1-benzhydryl-azetidin-3-yl)-malonic acid diethyl ester. 1H-NMR (400 MHz, CDCl3), δ ppm 7.41-7.17 (m, 10H), 4.34 (s, 1H), 4.25-4.09 (m, 3H), 3.66 (d, 1H, J=3.66 Hz), 3.41-3.37 (m, 2H), 3.07-2.99 (m, 1H), 2.93-2.90 (m, 2H), 1.25-1.23 (m, 6H)
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:21]1[N:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH2:25])=[O:24].[OH-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:21]2[C:22]([C:23](=[O:24])[NH2:25])=[CH:26][CH:27]=[CH:28][N:29]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Reactant: NC(=O)c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCc1ccc(Oc2ncccc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
Dissolve [2-(4-hydroxyphenyl)ethyl]carbamic acid tert-butyl ester (Example 377, Part A) (0.500 g, 2.11 mmol) in DMF (10.5 mL). Add NaH (80% in mineral oil) (0.070 g, 2.32 mmol). Stir at room temperature for 30 minutes. Add 2-chloronicotinamide (0.330 g, 2.11 mmol) and heat to 100° C. Remove DMF as an azeotrope with xylenes after 18¾ hours. Take the solid up with ethyl acetate (150 mL) and 1.0 N NaOH (75 mL). Separate the two layers. Extract the aqueous layer with ethyl acetate (1×150 mL). Wash the combined organic layers with brine (1×50 mL), dry over Na2SO4, filter and concentrate. Purify by flash chromatography, eluting with 35-45% ethyl acetate in dichloromethane to give the title compound (0.538 g, 71.4%): MS ES+ 358.3 (M+H)+, base peak ES+ 302.1 (M+2H—C(CH3)3)+, MS ES− 356.4 (M−H)−; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 50-99% over 19 min], tR=12.9 min, 100% purity.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].N1C=CC=CC=1.[CH:16]([O:19][CH:20]([O:35][CH:36]([CH3:38])[CH3:37])[C:21]([CH3:34])([CH3:33])[C:22](=[O:32])[C@H:23]([CH3:31])[C@@H:24]([OH:30])[C@@H:25]([CH3:29])[CH2:26][CH:27]=[CH2:28])([CH3:18])[CH3:17].[Na+].[Cl-]>C(Cl)Cl>[CH:36]([O:35][CH:20]([O:19][CH:16]([CH3:18])[CH3:17])[C:21]([CH3:33])([CH3:34])[C:22](=[O:32])[C@H:23]([CH3:31])[C@@H:24]([O:30][C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3])[C@@H:25]([CH3:29])[CH2:26][CH:27]=[CH2:28])([CH3:38])[CH3:37]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: C=CC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)C(OC(C)C)OC(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CC[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)C(OC(C)C)OC(C)C
Reaction time: 5 h

Procedure:
Trichloroethyl chloroformate (2.5 mL) and pyridine (2.95 mL) are added to a solution of (4R,5S,6S)-1,1-diisopropoxy-5-hydroxy-2,2,4,6-tetramethyl-8-nonen-3-one (3.0 g) in 40 mL of CH2Cl2 at 0° C., and the mixture is stirred for 5 hours before pouring into sat. aq. NaCl and extracting with CH2Cl2. The extract is dried over Na2SO4, filtered, and evaporated. The product is purified by chromatography on SiO2 (2% ethyl acetate/hexanes).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:16]#[N:17])[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:25])C(=O)C1>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:16]#[N:17])[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[Br:25]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#CC1(c2ccc(N)cc2)CCS(=O)(=O)CC1
Solvent: ClCCl
Product: N#CC1(c2ccc(N)c(Br)c2)CCS(=O)(=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
A solution of 4-(4-amino-phenyl)-1,1-dioxo-hexahydro-1λ6-thiopyran-4-carbonitrile (114 mg, 0.455 mmol, as prepared in the previous step) in CH2Cl2 (15 mL) was cooled to 0° C., treated with solid NBS (77.0 mg, 0.433 mmol), and stirred at that temperature for 30 min. The mixture was diluted with CH2Cl2 (20 mL) and washed with satd aq NaHCO3 (1×20 mL). The aqueous layer was extracted with CH2Cl2 (1×20 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 50% EtOAc-hexane afforded the title compound (136 mg, 90%) as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 7.53 (d, 1H, J=2.0 Hz), 7.23 (dd, 1H, J=8.4, 2.0 Hz), 6.79 (d, 1H, J=8.0 Hz), 4.40-4.15 (br s, 2H), 3.60-3.45 (m, 2H), 3.26-3.11 (m, 2H), 2.78-2.63 (m, 2H), 2.51-2.38 (m, 2H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)(=[O:13])=[O:12].Cl[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][N:22]=1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([CH:14]1[CH2:19][CH2:18][N:17]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][N:22]=2)[CH2:16][CH2:15]1)(=[O:12])=[O:13]
Reactant: Clc1nccc2ccccc12
Reactant: O=S(=O)(c1ccc2ccccc2c1)C1CCNCC1
Product: O=S(=O)(c1ccc2ccccc2c1)C1CCN(c2nccc3ccccc23)CC1
Yield: 73.6 %

Procedure:
Using the procedure from Example 7A, Step 7E, 4-(2-naphthylsulfonyl)piperidine (130 mg, 0.51 mmol) was reacted with 1-chloroisoquinoline (164 mg, 1.0 mmol) to afford the title compound (151 mg), a white solid, in 31% yield.
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1[C:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[CH:9][CH:8]=[C:7]([N:17]([CH2:21][CH2:22][Cl:23])[CH2:18][CH2:19][Cl:20])[CH:6]=1.[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][CH2:28][NH2:29]>ClCCl>[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][CH2:28][NH:29][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]1[CH:5]=[CH:6][C:7]([N:17]([CH2:21][CH2:22][Cl:23])[CH2:18][CH2:19][Cl:20])=[CH:8][CH:9]=1
Reactant: O=C(O)CCCc1ccc(N(CCCl)CCCl)cc1
Reactant: CN(C)CCCN
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CN(C)CCCNC(=O)CCCc1ccc(N(CCCl)CCCl)cc1
Temperature: 4 °C
Reaction time: 16 h

Procedure:
1.25 ml of thionyl chloride is added at 0° C., under an inert atmosphere, to a solution of 1.61 mmol of chlorambucil in 5 ml of dichloromethane The reaction mixture is stirred at 4° C. for 16 hours and then excess SOCl2 is evaporated off under reduced pressure. The residue obtained is taken up in 10 ml of dichloromethane. 1.61 mmol of 3-(dimethylamino)propylamine dissolved in 10 ml of dichloromethane are added to the resulting solution at 0° C. under an inert atmosphere. The mixture is then stirred at ambient temperature for 1 hour. At the end of that time, a second addition of 1.61 mmol of diamine is carried out. After 4 hours+ stirring, the reaction mixture is evaporated under reduced pressure. Following neutralisation with a 1N NaHCO3 solution, the aqueous phase is extracted several times with dichloromethane. The different organic phases are combined, washed with water until neutral, dried, filtered and evaporated under reduced pressure. The residue obtained is purified by chromatography on silica gel (eluant: gradient of ethanol in dichloromethane starting from 0 and going up to 50% and then, to finish, the eluant: dichloromethane/ethanol/ammonia, 50/49/1, is used). The expected product is obtained in the form of an oil.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:13]([CH2:21][C:22]([OH:24])=O)[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[CH2:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=1)[CH3:26]>>[CH2:25]([N:27]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=1)[C:22](=[O:24])[CH2:21][N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][N:8]=1)(=[O:11])=[O:12])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)[CH3:26]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)C)cn2)cc1
Reactant: CCNCc1cccc(C)n1
Product: CCN(Cc1cccc(C)n1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)C)cn1

Procedure:
prepared by reaction of [(5-isopropyl-pyridine-2-sulfonyl)-p-tolyl-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.O=[C:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[N:1]1([CH:16]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CCCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.7 %

Procedure:
A solution of 1,2,3,4-tetrahydroquinoline (1.0 mL, 7.94 mmol) in 30 mL 1,2-dichloroethane was treated with tert-butyl 3-oxopyrrolidine-1-carboxylate (2.94 g, 15.87 mmol) followed by sodium triacetoxyborohydride (8.4 g, 39.68 mmol) then acetic acid (2.25 mL). The suspension was stirred at room temperature for 1 day. After this time, the mixture was cooled to 0° C., quenched with 20 mL 1N NaOH and stirred for 20 minutes. The suspension was extracted with 2×100 mL CH2Cl2. The organic layer was rinsed with brine, dried over MgSO4, filtered and concentrated to give a yellow residue which was subjected to flash chromatography on silica gel using 15% EtOAc/Hexanes to give a viscous oil (1.89 g, 78.8%). 1H-NMR (CDCl3) δ 7.07 (pseudo t, J=7.2 Hz, 1H), 6.97 (d, J=7.2 Hz, 1H), 6.69 (d, J=8.1 Hz, 1H), 6.62 (pseudo t, J=7.5 Hz, 1H), 4.44-4.40 (m, 1H), 3.63-3.20 (m, 6H), 2.75 (t, J=6.3 Hz, 2H), 2.13-2.08 (m, 2H), 1.94-1.90 (m, 2H), 1.48 (s, 9H). MS (ESI): 303.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:15][C:16]1[CH:21]=[C:20](Cl)[CH:19]=[CH:18][N:17]=1>CS(C)=O.O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:20]1[CH:19]=[CH:18][N:17]=[C:16]([Cl:15])[CH:21]=1
Reactant: Nc1cccc(O)c1
Reactant: Clc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1cccc(Oc2ccnc(Cl)c2)c1
Reaction time: 0.17 h
Yield: 88.9 %

Procedure:
To a mixture of 3-aminophenol (3.7 g, 34.09 mmol) in DMSO (50 mL) was added Cs2CO3 (30.7 g, 94.46 mmol). The mixture stirred for 10 minutes and then 2,4-dichloropyridine (5.0 g, 33.79 mmol) was added. The mixture was stirred at 120° C. for 1.5 h. The mixture was cooled and diluted with water. The aqueous solution was extracted with EtOAc (3×100 mL). The organic extracts were combined, dried over MgSO4 and concentrated to afford a dark oil. The oil was purified via column chromatography, eluting with 30-40% EtOAc/hexanes, to afford 4-(3-Aminophenoxy)-2-chloropyridine (6.63 g, 89%) as a brown solid.