Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][C@@:11]2([C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:22][C:23]([C:25]4[CH:30]=[N:29][C:28]([CH:31]([F:33])[F:32])=[CH:27][N:26]=4)=[O:24])[CH:20]=3)[O:15][C:14]([CH3:35])([CH3:34])[C:13]32[CH2:37][CH2:36]3)[N:12]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:7][C:8]1[O:9][CH2:10][C@@:11]2([C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:22][C:23]([C:25]4[CH:30]=[N:29][C:28]([CH:31]([F:33])[F:32])=[CH:27][N:26]=4)=[O:24])[CH:20]=3)[O:15][C:14]([CH3:35])([CH3:34])[C:13]32[CH2:37][CH2:36]3)[N:12]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(CO1)c1cc(NC(=O)c3cnc(C(F)F)cn3)ccc1OC(C)(C)C21CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC1(C)Oc2ccc(NC(=O)c3cnc(C(F)F)cn3)cc2[C@@]2(COC(N)=N2)C12CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To a solution of tert-butyl[(4′R)-6′-({[5-(difluoromethyl)pyrazin-2-yl]carbonyl}amino)-2′,2′-dimethyldispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-yl]carbamate (373 mg, 0.704 mmol) in chloroform (6 ml) was added trifluoroacetic acid (2 ml). The mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was purified by silica gel column chromatography (precolumn: NH-silica gel, main column: neutral silica gel, chloroform/methanol=100:0-10:1). To the purified product was added a mixture of hexane and ethyl acetate (4:1), and the mixture was stirred at room temperature over night. The resulting precipitate was collected, washed with a mixture of hexane and ethyl acetate (4:1), and dried in vacuo to afford N-[(4′R)-2″-amino-2′,2′-dimethyldispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-6′-yl]-5-(difluoromethyl)pyrazine-2-carboxamide (253 mg).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([CH:16]1[CH2:20][CH2:19][CH:18]([C:21]2[NH:29][C:28]3[C:27](=[O:30])[N:26]([CH2:31][CH2:32][CH3:33])[C:25](=[O:34])[N:24]([CH2:35][CH2:36][CH3:37])[C:23]=3[N:22]=2)[CH2:17]1)(O)=[O:14].[NH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]#[N:45]>ClCCl.O1CCCC1>[C:39]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][NH:45][C:13]([CH:16]1[CH2:20][CH2:19][CH:18]([C:21]2[NH:29][C:28]3[C:27](=[O:30])[N:26]([CH2:31][CH2:32][CH3:33])[C:25](=[O:34])[N:24]([CH2:35][CH2:36][CH3:37])[C:23]=3[N:22]=2)[CH2:17]1)=[O:14])#[N:38]
Reactant: N#CCCCCCN
Reactant: CCCn1c(=O)c2[nH]c(C3CCC(C(=O)O)C3)nc2n(CCC)c1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCn1c(=O)c2[nH]c(C3CCC(C(=O)NCCCCCC#N)C3)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
0.3 g (1.9 mmol) of carbonyldiimidazole are added to a suspension of 0.67 g (1.9 mmol) of 8-(3-carboxycyclopentyl)-1,3-dipropyl-7H-purine-2,6-dione in 20 ml of dichloromethane and 1 ml of tetrahydrofuran and the mixture is stirred for 35 minutes at ambient temperature. After the addition of 0.21 g (1.9 mmol) of 6-aminocapronitrile the mixture is stirred for a further 24 hours, acidified and washed with water. The organic phase is concentrated by evaporation, the residue is taken up in 5% sodium bicarbonate solution and this solution is extracted with dichloromethane. After drying and evaporation of the organic extracts the title compound is obtained in the form of crystals which, are purified with a mixture of dichloromethane/methanol in the ratio 95:5. 0.67 g (79.8% of theory) of the title compound are obtained in the form of colourless crystals.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:33][O:34][CH3:35])[C:8]([NH:10][C@H:11]2[C@@H:14]([C:15]([O:17]CC3C=CC([N+]([O-])=O)=CC=3)=[O:16])[N:13]([S:28]([O-:31])(=[O:30])=[O:29])[C:12]2=[O:32])=[O:9])[N:6]=1.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.O.[Pd]>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:33][O:34][CH3:35])[C:8]([NH:10][C@H:11]2[C@@H:14]([C:15]([OH:17])=[O:16])[N:13]([S:28]([OH:31])(=[O:29])=[O:30])[C:12]2=[O:32])=[O:9])[N:6]=1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1)c1csc(N)n1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1C(=O)O)c1csc(N)n1

Procedure:
In a mixture of 10 ml of tetrahydrofuran and 10 ml of water is dissolved 155 mg of sodium cis-3-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-4-(4-nitrobenzyloxycarbonyl)-2-oxoazetidine-1-sulfonate (syn-isomer). To the solution is added 145 mg of 10% palladium-on-carbon, and the mixture is subjected to catalytic reduction at ambient temperature under normal pressure with stirring. Three hours later, 10 ml of an aqueous solution of 25 mg of sodium hydrogen carbonate is added to the reaction mixture. The catalyst is removed by filtration, and the filtrate is washed with ethyl acetate, and concentrated under reduced pressure. The concentrate is purified by column chromatography on Amberlite XAD-II, followed by lyophilization to give cis-3-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-4-carboxy-1-sulfo-2-oxoazetidine.disodium salt (syn-isomer).
Reaction SMILES: [CH3:1][C:2]([OH:20])([CH3:19])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=2)[CH2:6][CH2:5]1.[H][H]>CO.[Pd]>[NH2:16][C:12]1[CH:11]=[C:10]([N:7]2[CH2:6][CH2:5][N:4]([CH2:3][C:2]([CH3:19])([OH:20])[CH3:1])[CH2:9][CH2:8]2)[CH:15]=[CH:14][CH:13]=1
Reactant: [H][H]
Reactant: CC(C)(O)CN1CCN(c2cccc([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(O)CN1CCN(c2cccc(N)c2)CC1
Yield: 84 %

Procedure:
2-Methyl-1-[4-(3-nitro-phenyl)-piperazin-1-yl]-propan-2-ol (1.60 g, 0.00573 mol) was dissolved in Methanol (40 mL) and the solution was carefully added to a Parr vessel containing 10% Palladium on Carbon (90.10, carbon black. Palladium, 0.750 g, 0.0562 mol) under nitrogen. The reaction was then placed on a Parr apparatus and was allowed to shake until uptake of hydrogen ceased (overnight). Catalyst was filtered and the filtrate was reduced to provide 1.20 grams of 1-[4-(3-Amino-phenyl)-piperazin-1-yl]-2-methyl-propan-2-ol without further purification as a light purple solid. (M+H)=250.06.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([C:4](=[O:7])[CH2:5]Cl)[CH3:3].[F:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]([CH3:8])([C:4](=[O:7])[CH2:5][O:16][C:13]1[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=1)[CH3:3]
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)COc1ccc(F)cc1
Temperature: 25 °C
Yield: 17.2 %

Procedure:
418.3 g (3.11 mols) of 2,2-dimethyl-4-chloro-butan-3-one were added dropwise to a suspension, heated to the boiling point, of 315 g (2.8 mols) of 4-fluorophenol and 386.4 g (2.8 mols) of potassium carbonate in 1,500 ml of acetone. The mixture was stirred under reflux for 4 hours. After cooling to room temperature, the salt which had separated out was filtered off and the filtrate was concentrated in vacuo. The oil which remained was distilled in vacuo. 101.5 g (86.2% of theory) of 2,2-dimethyl-4-(4-fluorophenoxy)-butan-3-one of boiling point 83°-84° C./0.05 mm Hg (nD20 =1.4919) were obtained. ##STR49##
Reaction SMILES: [Br:1][C:2]1[C:7]2[CH:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:9][C:10]3[C:15]([C:6]=2[CH:5]=[CH:4][C:3]=1[C:24](=O)[CH3:25])=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][CH:11]=3.Cl.[NH2:28][OH:29]>CCO.N1C=CC=CC=1>[Br:1][C:2]1[C:7]2[CH:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:9][C:10]3[C:15]([C:6]=2[CH:5]=[CH:4][C:3]=1[C:24](=[N:28][OH:29])[CH3:25])=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][CH:11]=3
Reactant: NO
Reactant: COc1cccc2c1-c1ccc(C(C)=O)c(Br)c1C(c1ccccc1)O2
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: COc1cccc2c1-c1ccc(C(C)=NO)c(Br)c1C(c1ccccc1)O2

Procedure:
A solution of Example 357C (700 mg, 2.03 mmol) and hydroxylamine hydrochloride (2.45 g, 30.4 mmol) in a mixture of EtOH (70 mL) and pyridine (70 mL) was refluxed for 8 hours, cooled and concentrated. The residue was dissolved in EtOAc, washed with water, brine, dried (Na2SO4) and concentrated to provide the desired compound without purifiction.
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][N:25]([CH3:30])[S:26](Cl)(=[O:28])=[O:27]>>[CH2:17]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[C:10]([CH3:16])=[C:11]([NH:15][S:26]([N:25]([CH3:30])[CH3:24])(=[O:28])=[O:27])[CH:12]=[CH:13][CH:14]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1c(N)cccc1N(Cc1ccccc1)Cc1ccccc1
Reactant: CN(C)S(=O)(=O)Cl
Product: Cc1c(NS(=O)(=O)N(C)C)cccc1N(Cc1ccccc1)Cc1ccccc1

Procedure:
The product from Example 2B and N,N-dimethylsulfamoylchloride were processed as described in Example 3 to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ2.25 (s, 3H), 2.33 (m, 6H), 3.88 (s, 4H), 6.72 (dd, 1H), J=7.7, 1.5 Hz), 6.82 (m, 2H), 7.03 (m, 2H), 7.10 (m, 8H), 8.73 (s, 1H); MS (APCI+) m/z 410 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14](=[O:22])[C:15]3[CH:20]=[CH:19][CH:18]=[N:17][C:16]=3F)[CH:11]=2)[C:6]([CH3:24])([CH3:23])[CH2:5]1)(=[O:3])[CH3:2].Cl.Cl.[NH:27]1[C:31]2=[N:32][CH:33]=[CH:34][C:35]([CH2:36][NH2:37])=[C:30]2[CH2:29][CH2:28]1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14](=[O:22])[C:15]3[CH:20]=[CH:19][CH:18]=[N:17][C:16]=3[NH:37][CH2:36][C:35]3[CH:34]=[CH:33][N:32]=[C:31]4[NH:27][CH2:28][CH2:29][C:30]=34)[CH:11]=2)[C:6]([CH3:24])([CH3:23])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC(C)(C)c2ccc(NC(=O)c3cccnc3F)cc21
Reactant: NCc1ccnc2c1CCN2
Agent: Cl
Product: CC(=O)N1CC(C)(C)c2ccc(NC(=O)c3cccnc3NCc3ccnc4c3CCN4)cc21

Procedure:
The titled compound was prepared from N-(1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-fluoro-nicotinamide and C-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-methylamine dihydrochloride by the method described in Step A of Example 1. MS (ES+): 457 (M+H). Calc'd. for C26H28N6O2—456.55.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=1)=O.C(=O)([O-])O.[Na+]>C(O)C>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]2[N:13]=[C:10]3[CH:9]=[CH:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:12][N:11]3[CH:15]=2)=[CH:19][CH:20]=1
Reactant: Nc1ccc(-c2ccccc2)cn1
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Brc1ccc(-c2cn3cc(-c4ccccc4)ccc3n2)cc1
Yield: 49 %

Procedure:
Dissolving crude 5-phenyl-2-amino-pyridine obtained and 8.0 g (29 mmol) of 2,4′-dibromo acetophenone into 100 milliliter of ethanol, adding 3.7 g of sodium hydrogen carbonate, the resultant suspension was refluxed under heating for 3 hours. After completion of the reaction, separation with filtration was carried out and resultant crystals were washed with water and methanol, thereby obtaining 5.4 g of 2-(4-bromo-phenyl)-6-phenyl-imidazo [1,2-a] pyridine (yield: 49%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12].CCOC(C)=O>CN(C1CCCCC1)C>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][S:11](=[O:13])(=[O:12])[N:14]([CH3:16])[CH3:15])=[CH:3][CH:4]=1)=[O:7]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: O=Cc1ccc(O)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C1CCCCC1
Product: CN(C)S(=O)(=O)Oc1ccc(C=O)cc1
Temperature: 92.5 °C

Procedure:
A stirred solution of 4-hydroxybenzaldehyde (1.0 g, 8.02 mmol) in N,N-dimethylcyclohexylamine (7 mL) was heated to 90-95° C. and at this temperature ClSO2NMe2 (0.87 mL, 8.02 mL) was added dropwise. The reaction mixture was then heated at 90-95° C. for 3 h. After cooling to room temperature, EtOAc (100 mL) was added and the organic layer was washed with 1M hydrochloric acid (2×100 mL) and then brine (3×50 mL), dried (Na2SO4), filtered and evaporated to give a yellow oil which solidified to a yellow wax upon storage in the refrigerator (1.82 g, 99%); 1H (270 MHz, CDCl3) 3.08 (6H, s), 7.46 (2H AA′BB′), 7.94 (2H AA′BB′) and 10.0 (1H, s).
Reaction SMILES: [NH2:1][CH:2]([CH:7]([OH:23])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:3]([O:5][CH3:6])=[O:4].C(N(CC)CC)C.[C:31](Cl)(=[O:47])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>C1C=CC=CC=1>[C:31]([NH:1][CH:2]([CH:7]([OH:23])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:3]([O:5][CH3:6])=[O:4])(=[O:47])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CCCCCCCCCCCCCCCC(O)C(N)C(=O)OC
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)NC(C(=O)OC)C(O)CCCCCCCCCCCCCCC
Reaction time: 3 h
Yield: 87 %

Procedure:
10.7 g (0.033 mole) of methyl 2-amino-3-hydoxyoctadecanoate prepared according to Example 1 are dissolved in 200 cm3 of dry benzene and then 3.28 g of triethylamine are added. 8.92 g (0.033 mole) of palmitoyl chloride dissolved in 60 cm3 of benzene are added dropwise to this solution between 20 and 35° C. After 3 hours' stirring, the triethylamine hydrochloride is removed by filtration at 40° C. The organic phase is washed twice with 100 cm3 of water. The benzene solution is dried over sodium sulphate and then part of the benzene is removed by evaporation. 16.3 g of methyl 2-hexadecanoylamino-3-hydroxyoctadecanoate are isolated by crystallization.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([F:17])=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([CH:24]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21][CH2:22][CH3:23])=[O:20]>C1COCC1>[CH2:22]([O:21][C:19](=[O:20])/[CH:24]=[CH:13]/[C:12]1[CH:15]=[C:16]([F:17])[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([F:18])[CH:11]=1)[CH3:23]
Reactant: O=Cc1cc(F)c(OCc2ccccc2)c(F)c1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cc(F)c(OCc2ccccc2)c(F)c1
Reaction time: 1 h
Yield: 78.1 %

Procedure:
4-Benzyloxy-3,5-difluoro-benzaldehyde (1.2 g, 4.83 mmol) obtained in Step B and carbethoxymethylene triphenylphosphorane (2.0 g, 5.78 mmol) was dissolved in THF (10 mL), and the solution was stirred at 65˜75° C. for 1 hour. After the termination of the reaction, the reactant was cooled and concentrated under reduced pressure. The residue was purified by column chromatography (eluent, EtOAc/Hex=1/10) to obtain the title compound (1.2 g, 78%).
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[O:12]1[CH2:17][CH2:16][CH:15](O)[CH2:14][CH2:13]1>>[O:12]1[CH2:17][CH2:16][CH:15]([O:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:14][CH2:13]1
Reactant: OC1CCOCC1
Reactant: CCOC(=O)/C(=N\O)C(C)=O
Product: CCOC(=O)/C(=N\OC1CCOCC1)C(C)=O
Yield: 37 %

Procedure:
Ethyl (Z)-2-(hydroxyimino)-3-oxobutyrate (3.0 g) was reacted with tetrahydro-4H-pyran-4-ol as described in Example 4a, Method 3, to give the title compound as a colourless liquid (1.69 g, 37%). νmax (film) 2950, 1740, 1695 cm-1. δH (CDCl3) 1.34 (3H, t), 1.82 (2H, m), 2.03 (2H, m), 2.40 (3H, s), 3.57 (2H, m), 3.91 (2H, m), 4.37 (2H, q), 4.54 (1H, m).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:19]=[CH:18][C:9]([CH:10]=NC2C=CC=CC=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:20][S:21]([CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])(=[O:23])=[O:22].C(OC(=O)C)(=O)C>CC1C=CC(C)=CC=1>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH:10]=[C:24]([S:25]([CH3:28])(=[O:27])=[O:26])[S:21]([CH3:20])(=[O:23])=[O:22])=[CH:18][CH:19]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C=Nc2ccccc2)cc1
Reactant: CS(=O)(=O)CS(C)(=O)=O
Solvent: Cc1ccc(C)cc1
Solvent: CC(=O)OC(C)=O
Product: CCCCOc1ccc(C=C(S(C)(=O)=O)S(C)(=O)=O)cc1
Temperature: 120 °C
Yield: 54.1 %

Procedure:
A mixture of 2.5 g (0.01 mol) of N-(4-butoxybenzylidene)aniline, 1.9 g (0.011 mol) of di(methylsulfonyl) methane, 1.1 mL of acetic anhydride, and 60 mL of p-xylene were heated at 120° C. for 3 days. Upon cooling, the contents of the reaction were chromatographed on silica gel, using dichloromethane as the eluent. Crystallization from toluene afforded 1.8 g (54%) of (6) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:23])[CH2:9][CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=2)[OH:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([O:23][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:9][CH2:10][CH:11]([O:12][S:32]([CH3:31])(=[O:34])=[O:33])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1cc(C(O)CCC(O)c2ccc(Br)cc2)ccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(Br)cc1
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
The product from Example 191B (3.14 g, 7.84 mmole) was dissolved in 70 mL CH2Cl2 and cooled in an ice-acetone bath to −10° C. Triethylamine (3.82 mL, 27.4 mmole) was added dropwise to the cold solution, followed by dropwise addition of methanesulfonyl chloride (1.53 mL, 19.59 mmole) in 20 mL CH2Cl2 over 10 minutes. The resulting clear solution was stirred in the cold for 90 min. The reaction was deemed complete by LC-MS analysis and the solvent was removed in vacuo leaving a light yellow solid as the title compound, (4.36 g, 100%), that was used directly in the next reaction.
Reaction SMILES: [CH3:1][Si:2]([CH3:10])([CH3:9])[O:3][C:4]([CH3:8])([C:6]#[CH:7])[CH3:5].[Li]CCCC.CON(C)[C:19]([C:21]1[N:22]=[CH:23][S:24][CH:25]=1)=[O:20]>C1COCC1>[CH3:5][C:4]([O:3][Si:2]([CH3:10])([CH3:9])[CH3:1])([CH3:8])[C:6]#[C:7][C:19]([C:21]1[N:22]=[CH:23][S:24][CH:25]=1)=[O:20]
Reactant: C#CC(C)(C)O[Si](C)(C)C
Reactant: CON(C)C(=O)c1cscn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C#CC(=O)c1cscn1)O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
To a stirred solution of trimethyl (2-methylbut-3-yn-2-yloxy)silane (0.56 g, 3.57 mmol) in dry THF (10 mL) was added n-BuLi (1.3 mL, 2.1 mmol, 1.6 M in hexane) dropwise at −78° C. under an inert atmosphere for a period of 5 min. After being stirred for 30 min at −78° C., a solution of N-methoxy-N-methylthiazole-4-carboxamide (0.25 g, 1.78 mmol) in dry THF (5 mL) was added to reaction mixture and stirring was continued for an additional 1 h at −78° C. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2×30 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 2-4% EtOAc in Hexane to afford 4-methyl-1-(thiazol-4-yl)-4-(trimethylsilyloxy)pent-2-yn-1-one (0.15 g, 31.44%) as an oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:11][C@H:10]([CH2:12][P:13]([O:18][CH2:19][CH3:20])(=[O:17])[O:14][CH2:15][CH3:16])[C@@H:9]([N:21]=[N+]=[N-])[C@@H:8]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:7]1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:3])[CH3:2].[BH4-].[Na+].[CH3:42][C:43](OC(C)=O)=[O:44]>CO.C1(C)C=CC=CC=1.Cl[Ni]Cl>[C:1]([O:4][CH2:5][C@H:6]1[O:11][C@H:10]([CH2:12][P:13]([O:18][CH2:19][CH3:20])(=[O:17])[O:14][CH2:15][CH3:16])[C@@H:9]([NH:21][C:43](=[O:44])[CH3:42])[C@@H:8]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:7]1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOP(=O)(C[C@H]1O[C@H](COC(C)=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1N=[N+]=[N-])OCC
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CCOP(=O)(C[C@H]1O[C@H](COC(C)=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1NC(C)=O)OCC
Yield: 76 %

Procedure:
To a stirred solution of 4 (2.50 g, 4.45 mmol) in MeOH (125 mL) a catalytic amount of NiCl2×6H2O was added followed by portions of NaBH4 (in total 0.34 g, 8.9 mmol) every 10 min until no starting material was observed on TLC (system). Ac2O (3 mL) was added after 50 min and the reaction mixture was diluted with toluene, filtered through a plug of silica and concentrated. The residue was purified by silica gel chromatography to give 5 (1.95 g, 3.4 mmol, 76%). 13C-NMR (CDCl3) 170.4, 169.7, 137.3, 137.0 remaining aromatic C 128.5-127.7, 75.3, 72.6, 72.4, 72.1, 72.0, 67.1, 61.91, 61.8, 61.8, 61.3, 61.2, 48.8, 48.6, 28.5 (d, J=142 Hz), 23.0, 20.6, 16.3, 16.2, 16.1; 31P-NMR (CDCl3) 29.5.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1.C(S)C.[Al+3].[Cl-].[Cl-].[Cl-].C([O-])(O)=[O:31].[Na+]>C(Cl)Cl>[OH:31][C:7]1[CH:8]=[CH:3][CH:4]=[CH:5][C:6]=1[CH2:9][C@H:10]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=C([O-])O
Reactant: CCOC(=O)C[C@H](Cc1ccc(OC)cc1)c1cccnc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCS
Solvent: ClCCl
Product: CCOC(=O)C[C@H](Cc1ccccc1O)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A solution of ethyl (S)-4-(4-methoxyphenyl)-3-(pyridin-3-yl)butanoate (9.25 g, 31 mmole) in CH2Cl2 (150 mL) was cooled to 0° C. Ethanethiol (11.5 mL, 155 mmole) was added, then AlCl3 (20.7 g, 155 mmole) was added portionwise. After 2 hr, the mixture was poured over ice, allowed to warm to RT, and neutralized with NaHCO3. The resulting suspension was filtered through celite® and the filter pad was washed with CH2Cl2. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried (MgSO4) and concentrated. Flash chromatography on silica gel (1:1 EtOAc/hexanes) afforded the title compound (6.435 g, 73%) 1H NMR (400 MHz, CDCl3) δ 8.72, 8.41 (dd, J=4.9, 1.5 Hz, 1 H), 8.24 (narrow m, 1 H), 7.26 (dd, J=7.8, 4.9 Hz, 1 H). 6.78 (d, J=8.5 Hz, 2 H), 6.64 (d, J=8.5 Hz, 2 H), 4.03 (q, J=7.1 Hz, 2 H), 3.34-3.48 (m, 1 H), 2.92 (dd, J=13.7, 6.1 Hz, 1 H). 2.69-2.81 (m, 2 H), 2.64 (dd, J=15.6, 8.7 Hz, 1 H), 1.13 (t, J=7.1 Hz, 3 H); MS (ES) m/e 286 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15]CC)=O)[CH:5]=[N:4][C:3]1=2.[NH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21][CH2:20]1.C(#N)C>CCOCC>[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([NH:18][CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:21][CH2:20]3)=[O:15])[CH:5]=[N:4][C:3]1=2
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: CCOCC
Solvent: CC#N
Product: O=C(CCn1cnc2c(=O)[nH]cnc21)NC1CCN(Cc2ccccc2)CC1
Temperature: 120 °C
Reaction time: 17 h
Yield: 95.5 %

Procedure:
250 mg. (1.06 mmol) 3-(1,6-dihydro-6-oxo-9H-purin-9-yl) propionic acid, ethyl ester (AIT-0027) was added to a 10 ml round bottom flask equipped with a magnetic stirring bar, reflux condenser and CaCl2 drying tube. Then, 604 mg (3.17 mmol) 4-amino-1-benzyl-piperidine and 1 ml acetonitrile were added and the solution was brought to reflux. Reflux was continued for 17 hours. Aacetonitrile was evaporated and the mixture was heated at 120° C. for eight hours to yield a dark viscous oil. The oil was treated with ether while stirring. The solution was filtered and the orangebrown solid was washed with additional ether. Upon drying, 385 mg of a brown solid was obtained. The solid was stirred in acetone, filtered, washed with acetone and then with ether. This yielded 200 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-(1-benzylpiperidin-4-yl)propanamide (AIT-0033) as a tan solid. Analysis by HPLC indicated that the product was 65% pure.