Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[S:10][C:11]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:12]=2[N:13]=1.[ClH:19]>C(#N)C>[Cl:19][C:9]1[S:10][C:11]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:12]=2[N:13]=1
Reactant: Cl
Reactant: Nc1nc2c(Cl)cccc2s1
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: Clc1nc2c(Cl)cccc2s1
Temperature: 65 °C

Procedure:
Anhydrous CuCl2 (Aldrich, 4.37 g, 32.5 mmol), t-butyl nitrite (Aldrich, 4.83 mL, 40.6 mmol) and anhydrous acetonitrile (EM, 50 mL) were added to a 3-necked round-bottomed flask equipped with a reflux condenser, an additional funnel and a gas outlet tube. The mixture was warmed to 65° C. and a suspension of 2-amino-4-chlorobenzothiazole in 50 mL of acetonitrile. During the addition, the reaction mixture tuned to black and gas evolved. After gas evolution is complete, the reaction was allowed to reach room temperature. The reaction mixture was poured to 300 mL of 20% aqueous HCl, extracted 3× with EtOAc (400 mL). The organic layers were washed twice with a brine solution (300 mL), dried over Na2SO4 and concentrated. The residue was purified by chromatography with 60% CH2Cl2/hexanes to give 4.8 g of product. 1H NMR (400 MHz, DMSO-d6) δ 8.10 (dd, J=8.1, 1.0 Hz, 1H), 7.68 (dd, J=7.9, 1.0 Hz, 1H), 7.51 (t, J=8.0 Hz, 1H).
Reaction SMILES: Cl.[C:2]([O:18][CH3:19])(=[O:17])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][C:9](=[O:16])[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:6].[C:20](Cl)(=[O:22])[CH3:21].C(N(C(C)C)CC)(C)C>ClCCl>[C:5]([O:7][CH2:8][C:9]([N:10]1[CH2:15][CH2:14][N:13]([C:20](=[O:22])[CH3:21])[CH2:12][CH2:11]1)=[O:16])(=[O:6])/[CH:4]=[CH:3]/[C:2]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)/C=C/C(=O)OCC(=O)N1CCNCC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)/C=C/C(=O)OCC(=O)N1CCN(C(C)=O)CC1
Yield: 59.2 %

Procedure:
Methyl 2-oxo-2-piperazinylethyl(2E)but-2-ene-1,4-dioate hydrochloride (14) (0.20 g, 0.68 mmol) was reacted with acetyl chloride (AcCl) (0.60 mL, 0.66 g, 0.84 mmol) and diisopropylethylamine (0.70 mL, 0.52 g, 4.0 mmol) in dichloromethane (DCM). Following aqueous work-up, the crude product was purified by silica gel flash chromatography to afford 0.12 g (54% yield) of the title compound (16) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 6.98-6.93 (m, 2H), 4.86 (s, 2H), 3.83 (s, 3H), 3.66 3.63 (m, 4H), 3.50-3.40 (m, 4H), 2.14 (s, 3H). MS (ESI): m/z 299.12 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([SH:19])[NH:12][C:13]=2[C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:20][C:21]([F:25])=[C:22]([F:24])[F:23]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([S:19][C:22]([F:24])([F:23])[CH:21]([F:25])[F:20])[NH:12][C:13]=2[C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Sc1nc(-c2ccc(Cl)c(Cl)c2)c(-c2cccs2)[nH]1
Reactant: FC(F)=C(F)F
Product: FC(F)C(F)(F)Sc1nc(-c2ccc(Cl)c(Cl)c2)c(-c2cccs2)[nH]1

Procedure:
4-(3,4-Dichlorophenyl)-5-(2-thienyl)-1H-2-imidazolethiol (30.0 g; 92 mmoles) was reacted with 15.0 g of tetrafluoroethylene as described in Example 4 E to give, after chromatography on Silicar CC No. 7 with chloroform, 19.1 g of 4-(3,4-dichlorophenyl)-2-(1,1,2,2-tetrafluoroethylthio)-5-(2-thienyl)-1H-imidazole, m.p. 178°-180° (recrystallized from toluene).
Reaction SMILES: CN(C=O)C.[C:6]([O:10][C:11](=[O:29])[NH:12][C@H:13]([C:17]1[NH:26][C:25](=[O:27])[C:24]2[C:19](=[CH:20][C:21]([Cl:28])=[CH:22][CH:23]=2)[N:18]=1)[CH:14]([CH3:16])[CH3:15])([CH3:9])([CH3:8])[CH3:7].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>O>[C:6]([O:10][C:11](=[O:29])[NH:12][C@H:13]([C:17]1[N:26]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25](=[O:27])[C:24]2[C:19](=[CH:20][C:21]([Cl:28])=[CH:22][CH:23]=2)[N:18]=1)[CH:14]([CH3:16])[CH3:15])([CH3:8])([CH3:9])[CH3:7]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A dry 3-necked, round bottomed flask, equipped with a magnetic stirrer and nitrogen inlet, was charged with 50 mL of DMF, 3.50 g (10 mmol) of (S)-[1-(7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methylpropyl]-carbamic acid tert-butyl ester (the compound of Formula 202 prepared, e.g., as described in Example 3.2), 1.34 mL of benzyl bromide (98%), and 3.04 g of potassium carbonate. The mixture was stirred at room temperature overnight. TLC (hexanes/ethyl acetate 7:3) indicated complete reaction. The mixture was transferred into a Erlenmeyer flask and mixed with 100 mL of water. To the stirring mixture was then added hexanes, 50 mL. The formed white solid was collected by filtration to afford the title compound of Formula 203 (S)-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methylpropyl]-carbamic acid tert-butyl ester (also corresponding to Formula 107). The layers were separated and the organic was concentrated to dryness. The residue was chromatographed to afford an additional yield of the title compound. 1HNMR (300 MHz, DMSO-d6) δ (ppm)8.15(d,1H), 7.65(S,1H), 7.60(d,1H), 7.40–7.20(m,5H), 5.75(d,1H), 5.15(d,1H), 4.40(t,1H), 2.25(m,1H), 1.40–1.15(m,10H), 0.08(d, 3H), 0.35(d,3H).
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:5]=1[O:6][C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][CH:8]=1>C1COCC1.O>[F:3][C:4]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:5]=1[O:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1ccc(Oc2ccc(F)cc2F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Oc2ccc(F)cc2F)cc1
Temperature: 110 °C

Procedure:
0.518 g of potassium hydroxide was added to a solution of 0.428 g of ethyl 4-(2,4-difluorophenoxy)benzoate in 2 ml of THF/water (1:1). The solution was heated at 110° C. for 6 hours. The THF was then removed in vacuo, and the aqueous phase was freeze dried and purified by preparative HPLC. This resulted in the product with the molecular weight of 250.04 (C13H8F2O3); MS (ESI): 251 (M+H+).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1.C(OCC)(=O)C>Br.C(O)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCCC(=O)O)cc1
Agent: Br
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)CCCc1ccc(O)cc1
Yield: 99.2 %

Procedure:
4-(4-methoxyphenyl)butanoic acid (5.0 g) was dissolved in 48% hydrobromic acid (50 mL) and acetic acid (80 mL), then the solution was refluxed by heating for 6 hours. Ethyl acetate (300 mL) is added into the reaction solution, then organic layer was washed with water (100 mL) and saturated sodium chloride solution (50 mL), dried on anhydrous sodium sulfate, filtered and vacuum concentrated, then washed with n-hexane to give the above-identified compound (4.6 g, yield 99%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[C:6]([NH:8][C:9]1[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:7])#[N:2].C(N(CC)CC)C.[C:26]([C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[C:6]([NH:8][C:9]1[C:10]([NH:15][C:34](=[O:35])[C:33]2[CH:37]=[CH:38][C:30]([C:26]([CH3:28])([CH3:27])[CH3:29])=[CH:31][CH:32]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:7])#[N:2]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: N#Cc1cccc(C(=O)Nc2ccccc2N)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2NC(=O)c2cccc(C#N)c2)cc1
Reaction time: 20 h
Yield: 87.5 %

Procedure:
To a solution of N1-(3-cyanobenzoyl)-1,2-benzenediamine (500 mg, 2.1 mmol), triethylamine (0.44 mL, 3.2 mmol) in methylene chloride (100 mL) was added 4-tert-butylbenzoyl chloride (0.41 mL, 2.1 mmol). After stirring for 20 hours, the reaction mixture was concentrated in vacuo. Chromatography (silica gel, 20% ethyl acetate/80% hexanes) yielded 730 mg (87%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].Cl[C:11]([C:13]([O:20][CH3:21])([O:18][CH3:19])[C:14]([O:16][CH3:17])=[O:15])=[O:12].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:11](=[O:12])[C:13]([O:20][CH3:21])([O:18][CH3:19])[C:14]([O:16][CH3:17])=[O:15])[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: COC(=O)C(OC)(OC)C(=O)Cl
Reactant: Nc1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(OC)(OC)C(=O)Nc1cc(Cl)cc(Cl)c1

Procedure:
In a manner similar to the procedure described in Example I, 3,5-dichloroaniline was reacted with methyl chlorocarbonyl(dimethoxy)acetate, prepared as described in Example LXV Part A, employing triethylamine as the acid acceptor in methylene chloride solution. The methyl 3-[(3,5-dichlorophenyl)amino]-2,2-dimethoxy-3-oxopropanoate product (2.31 grams, 0.007 mole) was obtained as colorless crystals having a melting point of 160° C.-164° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][OH:10].[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]=[CH2:19])=[CH:14][CH:13]=1>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:9][OH:10])=[C:2](/[CH:19]=[CH:18]/[C:15]2[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: C=Cc1ccc(F)cc1
Reactant: OCc1ccc(Cl)cc1Br
Product: OCc1ccc(Cl)cc1/C=C/c1ccc(F)cc1

Procedure:
The title compound was prepared from (2-bromo-4-chlorophenyl)methanol and 4-fluoro-1-vinylbenzene according to the procedure for the preparation of Example 119, part B. 1H NMR (400 MHz, CDCl3): δ 1.72 (1H, t, J=5.6 Hz), 4.77 (2H, d, J=5.2 Hz), 6.98-7.08 (3H, m), 7.22-7.34 (3H, m), 7.47-7.50 (2H, m), 7.60 (1H, d, J=1.6 Hz).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:31]1[CH2:36][CH2:35][NH:34][CH2:33][C:32]1=[O:37]>N1C=CC=CC=1>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([N:34]5[CH2:35][CH2:36][NH:31][C:32](=[O:37])[CH2:33]5)[CH:3]=[CH:4][CH:5]=4)=[N:9][N:10]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:11]3=[CH:12][N:13]=2)[CH:18]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(F)n2)c2cc(-c3cccnc3)ncc21
Reactant: O=C1CNCCN1
Solvent: c1ccncc1
Product: C[Si](C)(C)CCOCn1nc(-c2cccc(N3CCNC(=O)C3)n2)c2cc(-c3cccnc3)ncc21
Temperature: 130 °C
Yield: 30.3 %

Procedure:
The mixture of 3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine from Example 271 (211 mg, 0.5 mmol) and piperazin-2-one (100 mg, 1.0 mmol) in pyridine (5 mL) was heated at 130° C. for 16 h, and the reaction was monitored by LCMS. Upon completion of the reaction, the solvent was distilled off and the crude material was purified via flash chromatography, eluting with 5% to 30% acetate in heptane to afford 4-(6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperazin-2-one as a yellow oil (76 mg, 30%). ESI MS m/z=501.23 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][C:14]#[CH:15])=[C:6]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:7]=1.C(N=[C:21]=[O:22])CCC.C(Cl)(Cl)=O>N12CCN(CC1)CC2.C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][C:14]#[CH:15])=[C:6]([S:8]([N:11]=[C:21]=[O:22])(=[O:9])=[O:10])[CH:7]=1
Reactant: CCCCN=C=O
Reactant: C#CCOc1ccc(C)cc1S(N)(=O)=O
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1C
Product: C#CCOc1ccc(C)cc1S(=O)(=O)N=C=O
Temperature: 25 °C
Yield: 112.5 %

Procedure:
A mixture of 22.4 g of 5-methyl-2-propargyloxyphenylsulfonamide, 9.9 g of n-butylisocyanate, 0.3 g of 1,4-diazabicyclo(2,2,2)octane and 350 ml of absolute xylene is refluxed for 30 minutes; and about 20 g of phosgene are subsequently introduced at 115°-120° C. during 2 hours. After the excess of phosgene has been removed from the reaction mixture by feeding in nitrogen, the mixture is cooled to room temperature, filtered, and concentrated in vacuo. There is thus obtained as crude product 28.1 g of 5-methyl-2-propargyloxyphenylsulfonylisocyanate in the form of brown oil. This crude product is used, without further purification, in the subsequent stage.
Reaction SMILES: [CH3:1][C:2]1([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[NH:22][N:21]=[N:20][N:19]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.Cl.[NH2:24][OH:25].C([O-])(=O)C.[Na+]>C(O)C>[CH3:1][C:2]1([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[NH:22][N:21]=[N:20][N:19]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[N:24][OH:25]
Reactant: CC1(COc2ccc(Cc3nnn[nH]3)cc2)CCCCC1=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC1(COc2ccc(Cc3nnn[nH]3)cc2)CCCCC1=NO
Yield: 56.7 %

Procedure:
2-Methyl-2-[[4-(1H-tetrazol-5-yl-methyl)phenoxy]-methyl]cyclohexanone (0.79 g, prepared in Example 3), hydroxylamine hydrochloride (0.22 g), sodium acetate (0.26 g) and ethanol (absolute, 20 ml) were combined and heated to reflux for 4 hours. The ethanol was removed in vacuo. The residue was partitioned between ethyl acetate and 10% HCl solution. The organic phase was washed with saturated aqueous NaCl solution, dried over MgSO4 and concentrated on the rotary evaporator. The product was triturated with dichloromethane-diethyl ether mixture to afford 0.47 g of white solid, mp 153°-156° C. Analytical HPLC showed the product was 97.7% pure.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C:7]2[N:8]=[C:9]([NH2:14])[N:10]=[C:11]([NH2:13])[N:12]=2)=[CH:5][CH:6]=1.[C:15](O)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[NH2:13][C:11]1[N:10]=[C:9]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=2)[N:8]=[C:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[N:12]=1
Reactant: O=C(O)c1cccnc1
Reactant: Nc1nc(N)nc(-c2ccccc2)n1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nc(NC(=O)c2cccnc2)nc(-c2ccccc2)n1

Procedure:
5.7 g of benzoguanamine and 4.0 g of nicotinic acid are dissolved in 300 ml of pyridine, and this solution is stirred with 5.0 g of phosphoryl chloride at room temperature. After continuing agitation at 60° C for 2 hours, the pyridine is removed by evaporation to dryness under vacuum. The residue is washed with water and fractionated and recrystallized from a mixed solution of methanol and dioxane, to yield 2-amino-4-nicotinamido-6-phenyl-s-triazine [mononicotinoylbenzoguanamine], melting point, 240° - 242° C in a yield of 2.8 g, and 2,4-bis(nicotinamido)-6-phenyl-s-triazine [dinicotinoylbenzoguanamine], melting point, 131° - 133° C in a yield of 0.7 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:20])[N:16]=3)[NH:11][CH:10]=2)=[O:8])=[CH:5][C:4]=1[CH3:23].[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Cl>CN(C)C=O>[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][N:11]1[C:12]2[C:17](=[N:16][C:15]([CH3:20])=[CH:14][CH:13]=2)[C:18](=[O:19])[C:9]([C:7](=[O:8])[C:6]2[CH:21]=[CH:22][C:3]([O:2][CH3:1])=[C:4]([CH3:23])[CH:5]=2)=[CH:10]1
Reactant: ClCc1cccc(Cl)c1
Reactant: COc1ccc(C(=O)c2c[nH]c3ccc(C)nc3c2=O)cc1C
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2cn(Cc3cccc(Cl)c3)c3ccc(C)nc3c2=O)cc1C
Yield: 38.9 %

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1 were used with 120 mg (0.390 mmol) of 3-(4-Methoxy-3-methyl-benzoyl)-6-methyl-1H-[1,5]naphthyridin-4-one, 75.2 mg (0.467 mmol) of 3-chlorobenzyl chloride, 19 mg (0.467 mmol, 60% dispersion in oil), and 1 mL of N,N dimethylformamide. The solid was collected by filtration and was purified by flash column chromatography using a gradient of 20-100% ethyl acetate in hexane to yield 65.7 mg of 1-(3-Chloro-benzyl)-3-(4-methoxy-3-methyl-benzoyl)-6-methyl-1H-[1,5]naphthyridin-4-one. LC-MSD, m/z for C25H21ClN2O3 [M+H]: 433.12 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 2.5 min.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[NH:20]1[C:28]2[C:23](=[CH:24][C:25]([NH2:29])=[CH:26][CH:27]=2)[CH:22]=[CH:21]1>CN(C=O)C>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:29][C:25]2[CH:24]=[C:23]3[C:28](=[CH:27][CH:26]=2)[NH:20][CH:21]=[CH:22]3)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CN(C)C=O
Product: CCCCN1C(=O)C(Nc2ccc3[nH]ccc3c2)=C(c2ccccc2)S1(=O)=O
Temperature: 140 °C
Yield: 96.5 %

Procedure:
2-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (110 mg, 0.330 mmol) was dissolved in dry DMF (0.5 mL) under nitrogen atmosphere. 1H-Indol-5-amine (131 mg, 0.991 mmol) was added and the reaction mixture was heated in a microwave reactor at 140° C. for 25 mins. The crude product was purified by preparative HPLC affording the title compound (126 mg, 96.5%). 1H NMR (500 MHz, CD3CN): δ 1.01 (t, 3H), 1.44-1.53 (m, 2H), 1.78-1.86 (m, 2H), 3.75 (t, 2H), 6.20-6.22 (m, 1H), 6.68-6.71 (m, 1H), 6.99-7.18 (m, 8H), 7.76 (bs, 1H), 9.18 (bs, 1H).
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@H:13]([O:14][Si](C(C)(C)C)(C)C)[C@@H:12]([CH2:22][O:23][CH3:24])[O:11][C@H:10]1[N:25]1[CH:33]=[N:32][C:31]2[C:26]1=[N:27][C:28]([CH2:49][CH2:50][NH:51][CH2:52][CH2:53][O:54][CH3:55])=[N:29][C:30]=2[NH:34][CH2:35][CH:36]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>>[C:37]1([CH:36]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:35][NH:34][C:30]2[N:29]=[C:28]([CH2:49][CH2:50][NH:51][CH2:52][CH2:53][O:54][CH3:55])[N:27]=[C:26]3[C:31]=2[N:32]=[CH:33][N:25]3[C@H:10]2[C@H:9]([OH:8])[C@H:13]([OH:14])[C@@H:12]([CH2:22][O:23][CH3:24])[O:11]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COCCNCCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](COC)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COCCNCCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](COC)[C@@H](O)[C@H]3O)c2n1
Yield: 46.8 %

Procedure:
The title compound was prepared by a similar method to example 38 using N-(2-{9-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}ethyl)-N-(2-methoxyethyl)amine (150 mg, 0.19 mmol) (preparation 34) and a 1 molar solution of tetra-n-butylammonium fluoride in tetrahydrofuran (0.5 ml, 0.5 mmol). The compound was purified by column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol:ammonia (94:6:0.6) increasing in polarity to (90:10:1) to give the title compound (50 mg) as a foam. MS: 563 (MH+).
Reaction SMILES: [OH-:1].[Na+].OO.[C:5]([C:7]1([NH:27][C:28](=O)[CH3:29])[CH2:12][CH2:11][CH:10]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH3:25])=[C:19]([CH3:26])[CH:18]=2)(=[O:16])=[O:15])[CH2:9][CH2:8]1)#[N:6]>C(O)C.O>[CH2:24]([O:23][C:20]1[CH:21]=[CH:22][C:17]([S:14]([NH:13][CH:10]2[CH2:9][CH2:8][C:7]3([N:27]=[C:28]([CH3:29])[NH:6][C:5]3=[O:1])[CH2:12][CH2:11]2)(=[O:15])=[O:16])=[CH:18][C:19]=1[CH3:26])[CH3:25]
Reactant: CCOc1ccc(S(=O)(=O)NC2CCC(C#N)(NC(C)=O)CC2)cc1C
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1ccc(S(=O)(=O)NC2CCC3(CC2)N=C(C)NC3=O)cc1C
Temperature: 80 °C
Yield: 48.3 %

Procedure:
5N Sodium hydroxide (320 ul, 1.59 mmol) followed by 50% aqueous hydrogen peroxide (157 ul, 2.55 mmol) were added to solution of N-(1-cyano-4-(4-ethoxy-3-methylphenylsulfonamido)cyclohexyl)acetamide (Intermediate 126, 242 mg, 0.638 mmol) in ethanol (6.4 ml). The reaction was heated to 80° C. for three hours. LCMS indicated approximately 3:1 product:starting material by co-injection. The reaction was diluted with water and extract with four volumes ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrate to 226 mg crude. TLC (10% methanol in ethyl acetate): Rf starting material 0.66; major spot Rf=0.25. The crude was chromatographed on Biotage 12M eluting 0-100% ethyl acetate in (10% methanol in ethyl acetate) to give the product as an off-white solid (117 mg, 0.308 mmol). LCMS [M+H]=380.2.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:8][O:9][C:10](=[O:30])[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:7][CH2:6][CH2:5][O:4]1.[Cl:31][CH2:32][CH2:33][CH2:34][S:35](NCC(OC)CSCCCCCCCCCCCCCCCC)(=[O:37])=[O:36]>>[Cl:31][CH2:32][CH2:33][CH2:34][S:35]([NH:1][CH2:2][C:3]1([CH2:8][O:9][C:10](=[O:30])[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:7][CH2:6][CH2:5][O:4]1)(=[O:37])=[O:36]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC1(CN)CCCO1
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC1(CNS(=O)(=O)CCCCl)CCCO1

Procedure:
2-Aminomethyl-2-octadecylcarbamoyloxymethyltetrahydrofuran IV b2 is allowed to react and worked by the same procedure as described in (4). The summary of the experimental condition and the physical data of the product are listed in the Table 7.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.[OH-].[K+].NC1C2CCN(CC2)C1.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:31]([S:34](=[O:37])(=[O:36])[NH2:35])=[CH:30][C:26]=1[C:27]([Cl:29])=[O:28]>O.O1CCCC1>[OH2:24].[ClH:29].[NH2:35][S:34]([C:31]1[CH:32]=[CH:33][C:25]([O:24][CH3:23])=[C:26]([CH:30]=1)[C:27]([NH:3][CH:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1)=[O:28])(=[O:36])=[O:37]
Reactant: COc1ccc(S(N)(=O)=O)cc1C(=O)Cl
Reactant: NC1CN2CCC1CC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(S(N)(=O)=O)cc1C(=O)NC1CN2CCC1CC2

Procedure:
A solution of 3-aminoquinuclidine dihydrochloride (2.5 g, 0.0126 mole) in 25 ml of water was treated with approximately 5 g of KOH and the resultant slurry/solution taken to complete dryness on the rotary evaporator at 50°/35 mm. The dry residue was carefully extracted by repeated triturations with warm tetrahydrofuran until a total volume of 130 ml had been collected and dried over magnesium sulfate. This solution of 3-aminoquinuclidine base was treated with a solution of 2-methoxy-5-sulfamylbenzoyl chloride (2.92 g, 0.0117 mole) in 50 ml of dry tetrahydrofuran by dropwise addition under nitrogen. The resultant very turbid solution was refluxed gently for about 30 min, then freed of tetrahydrofuran by allowing it to evaporate. The residue was taken up in 90% ethanol containing a few drops of ethereal hydrogen chloride, filtered and chilled. The solid produced was then recrystallized again to yield 4.3 g (97%), m.p. 233°-234° C. NMR, MS, and IR were in support of the structure proposed.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[O:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1>CCO>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[C:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)[C:10]#[N:11])=[CH:5][CH:4]=1
Reactant: O=C1CCOCC1
Reactant: N#CCc1ccc(Cl)cc1
Agent: [Na]
Solvent: CCO
Product: N#CC(=C1CCOCC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 38.9 %

Procedure:
Sodium (152 mg, 6.6 mmol) was added into EtOH (10 ml) and stirred at room temperature for 20 minutes. 2-(4-Chlorophenyl)acetonitrile (500 mg, 3.3 mmol) was added to the solution, after all the sodium had dissolved, and the reaction was stirred at room temperature for 0.5 h. To the resulting mixture was added dihydro-2H-pyran-4(3H)-one (330 mg, 3.3 mmol) and stifled at room temperature for 1.5 h. The solvent was removed. To the residue was added water and extracted with EtOAc (3×20 mL). The combined organic solution were dried over Na2SO4 and concentrated to give crude product, which was purified by flash column chromatography (petroleum ether: EtOAc=10:1) to give compound 2-(4-chlorophenyl)-2-(dihydro-2H-pyran-4(3H)-ylidene)acetonitrile (300 mg) which was used for the next step without further purification.