Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C@H:15]1[O:62][C@H:61]([CH2:63][O:64][C:65](=[O:77])[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH3:76])[C@H:46]([O:47][C:48](=[O:60])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C@H:31]([O:32][C:33](=[O:45])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C@H:16]1[O:17][C:18](=[O:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=O)CCCCCCCCCCC.[C:78]([OH:81])(=[S:80])[CH3:79].[Sn](Cl)(Cl)(Cl)Cl.Cl>C1(C)C=CC=CC=1>[C:78]([S:80][C@H:15]1[O:62][C@H:61]([CH2:63][O:64][C:65](=[O:77])[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH3:76])[C@H:46]([O:47][C:48](=[O:60])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C@H:31]([O:32][C:33](=[O:45])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C@H:16]1[O:17][C:18](=[O:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:81])[CH3:79]
Reactant: CC(O)=S
Reactant: CCCCCCCCCCCC(=O)OC[C@H]1O[C@H](OC(=O)CCCCCCCCCCC)[C@H](OC(=O)CCCCCCCCCCC)[C@@H](OC(=O)CCCCCCCCCCC)[C@H]1OC(=O)CCCCCCCCCCC
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCC(=O)OC[C@H]1O[C@H](SC(C)=O)[C@H](OC(=O)CCCCCCCCCCC)[C@@H](OC(=O)CCCCCCCCCCC)[C@H]1OC(=O)CCCCCCCCCCC
Reaction time: 1 h
Yield: 21 %

Procedure:
To compound 1 (20.0 g, 18.2 mmol) and thioacetic acid (27.0 mL, 20 eq.) in dry toluene (80 mL) under argon was added tin (IV) chloride (21.3 mL) dropwise at room temperature. The reaction was monitored by Tlc carefully. After 1 h, 600 mL of 1M aqueous HCl was added to the vigorously stirred mixture and the resulting mixture was filtered through Celite to remove the emulsion of tin salts. The mixture was diluted with pentane (800 mL), washed with water (2×400 mL), saturated sodium hydrogen carbonate (300 mL) and water (300 mL), dried with Na2SO4 and concentrated. The residue was purified by column chromatography three times (SiO2, pentane/EtOAc 20:1, 30:1, 40:1) to give 1-S-acetyl-2,3,4,6-tetra-O-lauroyl-1-thio-α-D-galactopyranose (3.65 g, 21%). 1H-Nmr data (CHCl3): δ 6.26 (d, 1H, J 5.5 Hz, H-1), 5.47 (dd, 1H, J 11.0 Hz, 5.5 Hz, H-2), 5.46 (d, 1H, J 3.5 Hz, H-4), 5.04 (dd, 1H, J 11.0 Hz, 3.5 Hz, H-3), 4.17 (t, 1H, J 6.5 Hz, H-5), 4.06 (d, 2H, J 6.5 Hz, H-6a and H-6b), 2.38 (t, 8H, J 7.0 Hz, --COCH2 --), 2.40 (s, 3H, --SAc), 0.87 (t, 15H, J 7.0 Hz, --CH3).
Reaction SMILES: Cl.C1[O:18][C:5]2([CH2:10][CH2:9][C:8]([NH2:17])([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)OC1.I[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]I.C(=O)([O-])[O-].[K+].[K+].Cl>C(OCC)C.O.C(O)C>[C:11]1([C:8]2([N:17]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:7][CH2:6][C:5](=[O:18])[CH2:10][CH2:9]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: NC1(c2ccccc2)CCC2(CC1)OCCO2
Reactant: ICCCCCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: O=C1CCC(c2ccccc2)(N2CCCCC2)CC1
Yield: 61 %

Procedure:
A reaction mixture consisting of the free base from 2.88 gm. (0.011 mole) of 4-amino-4-phenylcyclohexanone ethylene ketal hydrochloride (prepared in Example 32, above), 3.47 gm. 1,5-diiodopentane 2.95 gm. potassium carbonate and 25 ml. ethanol is heated at the reflux temperature, with stirring, for eighteen (18) hours. After cooling and removing most of the liquid and voltiles by evaporation under reduced pressure, the residue thus obtained is dispersed in a mixture of 100 ml. of diethyl ether and 10 ml. of water. The ether layer is allowed to separate and is recovered. It is washed with water and with brine, before removing the ether by evaporation under reduced pressure. The residue thus obtained is dissolved in diethyl ether and an amount of 3 N hydrogen chloride in diethyl ether is added so as to form the hydrochloride acid addition salt which precipitates. The salt is collected on a filter and then recrystallized from a mixture of methylene chloride and ethyl acetate. There is thus obtained 2.26 gm. (61% yield) of 4-phenyl-4-(1-piperidinyl)cyclohexanone, ethylene ketal hydrochloride having a melting range from 228° to 231° C. An analytical sample has a melting point at 234° to 235.5° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:9](=[O:17])[C@:10]([OH:16])([CH3:15])[C:11]([F:14])([F:13])[F:12].C(N(CC)CC)C.[C:25]([C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)#[N:26]>CCOC(C)=O>[CH3:1][C@H:2]1[CH2:7][N:6]([S:33]([C:30]2[CH:29]=[CH:28][C:27]([C:25]#[N:26])=[CH:32][CH:31]=2)(=[O:35])=[O:34])[C@H:5]([CH3:8])[CH2:4][N:3]1[C:9](=[O:17])[C@:10]([OH:16])([CH3:15])[C:11]([F:14])([F:12])[F:13]
Reactant: C[C@@H]1CN(C(=O)[C@@](C)(O)C(F)(F)F)[C@@H](C)CN1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(C(=O)[C@@](C)(O)C(F)(F)F)[C@@H](C)CN1S(=O)(=O)c1ccc(C#N)cc1

Procedure:
To a stirred solution of (R)-[(2S,5R)-2-methyl-5-methyl-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropionyl)piperazine] (J. Med. Chem., 1999, 42, 2741-2746] (254 mg, 1.0 mmol) and triethylamine (0.17 ml, 1.2 mmol) in EtOAc (15 ml) was added a solution of 4-cyanobenzene sulphonyl chloride (220 mg, 1.1 mmol) in EtOAc (10 ml). The resultant mixture was stirred at ambient temperature for 2 hours, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue was recrystallized from EtOAc/hexane to give the title compound as a solid (280 mg, 0.56 mmol). Mp: 186-187° C.; NMR: 0.95 (d, 3H), 1.25 (d, 3H), 1.75 (s, 3H), 3.25 (dd, 1H), 3.35 (d, 1H), 3.5 (dd, 1H), 4.2 (m, 3H), 4.75 (s, 1H), 7.8 (d, 2H), 7.9 (d, 2H); m/z 418.
Reaction SMILES: [CH:1]([C:3]12[CH2:17][CH:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=31)[C:9]1[C:4]2=[CH:5][CH:6]=[CH:7][CH:8]=1)=[O:2].CC(C)=[O:20].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.O>[CH:5]1[C:4]2[C:3]3([C:1]([OH:20])=[O:2])[CH2:17][CH:10]([C:11]4[C:16]3=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)=O
Reactant: O=CC12CC(c3ccccc31)c1ccccc12
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)C12CC(c3ccccc31)c1ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 9-formyl-9,10-dihydro-9,10-methanoanthracene (3.5 g) in acetone (17 ml) was dropwise added Jones' reagent (5.0 ml) at room temperature. The reaction mixture was stirred at room temperature for 1 hour, diluted with water and extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give 9,10-dihydro-9,10-methanoanthracene-9-carboxylic acid. M.P. 199.5°-200.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][CH2:28][CH2:27]2.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20](=[O:22])[NH:23][C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[CH2:29][CH2:28][CH2:27]4)=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: Nc1ccc2c(c1)CCC2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)Nc3ccc4c(c3)CCC4)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-(4-carboxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (918 mg, 3 mmol) and 5-aminoindan (399 mg, 3 mmol) in methylene chloride (30 mL) was added EDCI (580 mg, 3 mmol) and DMAP (20 mg, 0.16 mmol). The mixture was stirred at room temperature overnight and then extracted with methylene chloride (50 mL) and aqueous hydrochloric acid (1N, 20 mL). The organic layer was washed with water, then sodium hydroxide solution and finally with water and brine. The solution was dried over sodium sulfate and filtered. Solvents were evaporated and the residue was crystallized from ethyl acetate (40 mL) to give 4-[4-(indan-5-ylcarbamoyl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester. This intermediate was dissolved in methylene chloride (5 mL) and trifluoroacetic acid (3 mL). The mixture was stirred at room temperature for 1 hr and solvents were evaporated. The residue was extracted with methylene chloride and 1N sodium hydroxide solution. The organic layer was washed with brine and dried over sodium sulfate. The product, N-indan-5-yl-4-piperazin-1-yl-benzamide was obtained after solvent evaporation (450 mg, Yield: 47%). LCMS calc for C20H23N3O (m/e) 321.42, obsd 322.5 (M+H).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([O:14][CH3:15])[CH:5]=1)[NH2:3].CO[CH:18](OC)[CH2:19][C:20](=O)[CH3:21]>Cl.O.CO>[CH3:15][O:14][C:6]1[CH:5]=[C:4]([N:2]2[CH:18]=[CH:19][C:20]([CH3:21])=[N:3]2)[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(NN)cc1OC
Reactant: COC(CC(C)=O)OC
Agent: Cl
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(-n2ccc(C)n2)cc1OC
Temperature: 90 °C
Yield: 53.7 %

Procedure:
To a stirred solution of 4-hydrazino-2-methoxybenzoic acid, methyl ester hydrochloride (0.88 g) from Example 104 and one drop of concentrated hydrochloric acid in a 1:1 water/methanol (10 ml) mixture was added acetylacetaldehyde dimethylacetal (0.53 g). The reaction was heated to 90° C. for 5 minutes. The reaction was concentrated in vacuo and partitioned between 1 N sodium hydroxide (10 ml) and ethyl acetate (50 ml). The organic phase was removed and washed with brine, dried over anhydrous magnesium sulfate and filtered. Evaporation of the solvent in vacuo afforded a brown oil which was combined with a previous lot (0.54 g) and recrystallized three times from diisopropyl ether to give 2-methoxy4-(3-methyl-pyrazol-1-yl)-benzoic acid, methyl ester (0.5 g). m.p. 167-169° C., MS, m/z: 246 (M)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH:13]2[CH:9]1[CH2:10][NH:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16]([C:21](O)=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH:13]2[CH:9]1[CH2:10][N:11]([C:21]([C:16]1[C:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:22])[CH2:12]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC21
Reactant: O=C(O)c1ccccc1-c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2CN(C(=O)c3ccccc3-c3ccccc3)CC21
Temperature: 23 °C
Reaction time: 1 h

Procedure:
Intermediate 18 (0.72 mmol), biphenyl-2-carboxylic acid (0.72 mmol), and HATU (1.66 mmol) were taken up in DMF at 0.2 M. DIPEA (2.17 mmol) was added. The mixture was allowed to stir at 23° C. for ˜1 hr. The mixture was diluted water and extracted with diethyl ether. The aqueous was extracted with ether again. The other fractions were combined and concentrated to provide the crude product. The product was purified on the silica gel chromatography (30-100% ethyl acetate/hexanes) over 12 minutes, then flushed with 100% ethyl acetate for 20 minutes to provide 3-(Biphenyl-2-carbonyl)-3,6-diaza-bicyclo[3.2.0]heptane-6-carboxylic acid tert-butyl ester, 91%. MS (ESI) mass calcd. for C23H26N2O3, 378.46; m/z found, 379.2 [M+H]+. This material was taken up in DCM and TFA was added. The mixture was allowed to stir at 23° C. for 1 hr. It was then concentrated after checking by MS and LCMS to provide a yellow viscous oil. The oil was taken up and DCM and 1M NaOH were added, and the resulting solution was allowed to stirred for 5 minutes. The layers were separated, and the organic layer was concentrated to provide Intermediate 19 as a light yellow foamy solid. MS (ESI) mass calcd. for C18H18N2O, 278.35; m/z found, 279.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:18](=[N:20][NH:21][C:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[O:23])[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.CO.[OH-].[Na+].Cl>O>[OH:1][C:2]1[C:3]([C:18](=[N:20][NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=2)=[O:23])[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(C(F)(F)F)cc3)c2O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=NNC(=O)c1ccc(C(=O)O)cc1)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To methyl 4-{[2-(1-{4-hydroxy-1-methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}ethylidene)hydrazino]carbonyl}benzoate (0.116 mmol, 53.4 mg), methanol (2 mL) was added, and 1 M aqueous sodium hydroxide (5 eq., 0.580 mL) was added at room temperature. After 30 minutes of stirring at room temperature and 1 hour of stirring at 60° C., the reactor was cooled to room temperature, and 1 M hydrochloric acid (5 eq., 0.580 mL) and water were added. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump to give the desired product as a yellow solid (37.7 mg, yield 73%).
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[NH:10][C:11](=S)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.O>C(OCCO)C>[N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[N:10]=[C:11]([NH:17][CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: S=C1Nc2ccccc2Nc2ncccc21
Reactant: NCc1cccnc1
Solvent: O
Solvent: CCOCCO
Product: c1cncc(CNC2=Nc3ccccc3Nc3ncccc32)c1
Yield: 52.8 %

Procedure:
A solution of 0.5 g (2.2 mmol) of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-thione [(European Published Patent Application EP-393,604); C.A. 114, 143455] in 10 mL 2-ethoxyethanol was treated with 0.24 mL (10.8 mmol) of 3-(aminomethyl)pyridine and heated at reflux for 2 days. The mixture was poured into H2O and extracted with EtOAc. The EtOAc was washed three times with H2O, then saturated NaHCO3 solution and saturated NaCl solution. Drying over MgSO4 and removal of the solvent under reduced pressure left the crude product. Chromatography on silica gel, eluting with a gradient of CH2Cl2 /hexane (90/10) to CH2Cl2 /MeOH (94/6) gave 0.35 g (53% yield) of the product as a yellow solid, mp 192-194° C. The structure was confirmed by NMR and mass spectroscopy. (m+H)+ =302.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[C:9]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[N:7]=[CH:6][N:5]([CH3:9])[C:4](=[O:8])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1cc(Br)nc[nH]1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1cnc(Br)cc1=O
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution 6-bromopyrimidin-4(3H)-one (696 mg, 2.0 mmol) in DMF (3.0 mL) was added K2CO3 (828 mg, 6.0 mmol), CH3I (568 mg, 4.0 mmol), the reaction mixture was stirred at 50° C. for 30 minutes. The mixture was cooled to ambient temperature, diluted with EtOAc (20 mL), washed with sodium bicarbonate (10 mL) and brine (10 mL), dried over MgSO4, filtered and concentrated. The residue was purified with silica gel column (Petroleum ether:ethyl acetate=1:1) to obtain product: LC/MS m/z=189.01 (M+H)+.
Reaction SMILES: O[C:2](=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].N1C=CC=CC=1.[F:21][C:22]([F:35])([F:34])[S:23]([O:26]S(C(F)(F)F)(=O)=O)(=[O:25])=[O:24].[ClH:36].C([O-])(O)=O.[Na+]>ClCCl>[Cl:36][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[O:26][S:23]([C:22]([F:35])([F:34])[F:21])(=[O:24])=[O:25])/[CH:8]=[CH:2]/[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(O)=Cc1ccccc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1
Temperature: 20 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
To the ethyl hydroxycinnamate (5.02 g, 22.1 mmol), prepared in Step 3, and pyridine (4.0 mL, 50.0 mmol) in dichloromethane (50 mL) at 0° C. under argon was added trifluoromethanesulfonic anhydride (4.0 mL, 23.7 mmol) over a 30-minute period. The mixture was stirred for 4 hours, warmed to 20° C., then worked-up (10% hydrochloric acid and 5% NaHCO3 washes) to afford ethyl (E)-3-chloro-4-(trifluoromethanesulfonyloxy)cinnamate as a white solid (7.90 g, 98% yield): m.p. 59–61° C.; Rf0.49 (20% ethyl acetate/hexane); 1H NMR spectrum (300 MHz, CDCl3) δ 1.35 (t, J=7.1 Hz, 3, CH3), 4.28 (q, J=7.1 Hz, 2, CH2), 6.45 (d, J=16.0 Hz, 1, HC═CCO), 7.38 (d, J=8.5 Hz, 1, ArH), 7.48 (dd, J=8.5, 1.8 Hz, 1, ArH), 7.59 (d, J=16.0 Hz, 1, C=CHCO), 7.67 ppm (d, J=1.9 Hz, 1, ArH).
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][CH:6]=1.Cl.[OH-].[NH4+]>C1COCC1.C(Cl)(Cl)Cl.C(O)(C)C>[F:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([OH:12])[CH3:1])=[CH:7][CH:6]=1
Reactant: C[Mg]Br
Reactant: O=Cc1ccc(F)nc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: CC(O)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
Add methyl magnesium bromide (3 M in ether, 12 mL, 36 mmol) at 0° C. under nitrogen to a solution of 6-fluoro-pyridine-3-carbaldehyde (3 g, 24 mmol) in THF (20 mL). Continue to stir the mixture for overnight at room temperature. Hydrolyze the mixture with 1 N HCl and follow the basification with diluted ammonium hydroxide to ˜pH 9. Abstract the product with chloroform/isopropyl alcohol (3/1). Dry over sodium sulfate. Concentrate the solution in vacuo to yellow oil. Purify by column chromatography (10% methanol in dichloromethane) to give the product as a colorless oil (2.3 g, 68%). MS (ES) m/z 142 [M+1]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][OH:9])[CH:2]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C1COCC1>[CH3:17][S:18]([O:9][CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)(=[O:20])=[O:19]
Reactant: OCCc1cccnc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1cccnc1

Procedure:
The 2-(3-pyridyl)ethan-1-ol (Maybridge, 0.15 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[O:18]=[C:19]1[C@@H:22]([NH:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[C@H:21]([CH3:34])[N:20]1[S:35]([O-:38])(=[O:37])=[O:36].[OH:39][C:40]1[CH:41]=[CH:42][CH:43]=[C:44]2[C:49]=1[N:48]=[CH:47][CH:46]=[CH:45]2>O.C(#N)C>[OH:39][C:40]1[CH:41]=[CH:42][CH:43]=[C:44]2[C:49]=1[NH+:48]=[CH:47][CH:46]=[CH:45]2.[O:18]=[C:19]1[C@@H:22]([NH:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[C@H:21]([CH3:34])[N:20]1[S:35]([O-:38])(=[O:36])=[O:37]
Reactant: Oc1cccc2cccnc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[C@H]1[C@H](NC(=O)OCc2ccccc2)C(=O)N1S(=O)(=O)[O-]
Solvent: CC#N
Solvent: O
Product: Oc1cccc2ccc[nH+]c12

Procedure:
(3S-trans)-2-Oxo-3-[[(phenylmethoxy)carbonyl]amino]-4-methyl-1-azetidinesulfonic acid, tetrabutylammonium salt (500 mg, 0.9 mmol) was dissolved in a mixture of water and acetonitrile. The solution was passed through an AGMP-50 ion-exchange resin column (H⊕ form, 7 ml, 1.7 meq/ml) eluting with water. The eluate was run into a flask containing 8-hydroxyquinoline (131 mg, 0.9 mmol). Acetonitrile was removed from the resulting solution under reduced pressure at <35° C. and the remaining aqueous solution was lyophilized yielding a solid. Trituration with ether and drying in vacuo afforded the desired product as a yellow powder (398 mg), melting point 61°-68° C.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([F:17])[C:11](S(=S)(O)=O)=[N:12][C:5]=2[N:4]([CH:18]2[CH2:20][CH2:19]2)[C:3]1=[O:21].[C:22]([O:26][C:27](=[O:36])[NH:28][C@@H:29]([C@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1)[CH3:30])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>C(#N)C>[C:22]([O:26][C:27](=[O:36])[NH:28][C@H:29]([C@@H:31]1[CH2:35][CH2:34][N:33]([C:11]2[C:10]([F:17])=[CH:9][C:6]3[C:7](=[O:8])[N:2]([NH2:1])[C:3](=[O:21])[N:4]([CH:18]4[CH2:20][CH2:19]4)[C:5]=3[N:12]=2)[CH2:32]1)[CH3:30])([CH3:23])([CH3:24])[CH3:25]
Reactant: Nn1c(=O)c2cc(F)c(S(=O)(O)=S)nc2n(C2CC2)c1=O
Reactant: C[C@@H](NC(=O)OC(C)(C)C)[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@H](NC(=O)OC(C)(C)C)[C@@H]1CCN(c2nc3c(cc2F)c(=O)n(N)c(=O)n3C2CC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.7 %

Procedure:
A solution of 0.12 g (0.38 mmol) of 3-amino-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidine-7-thiosulfonic acid (Compound 24c) in 10 mL of acetonitrile is treated with 0.24 g (1.14 mmol) of ((R)-(S)-1-pyrrolidin-3-ylethyl)carbamic acid tert-butyl ester (J. Het. Chem., 1992; 29:1481), 0.25 g (2.5 mmol) of triethylamine and stirred at room temperature for 18 hours then 50° C. for 1 hour. The solvent is removed in vacuo and the residue is partitioned between ethyl acetate (50 mL) and water (25 mL). The organic layer is washed with water, dried (MgSO4), filtered and evaporated in vacuo to give 0.28 g. Chromatography on flash grade silica gel (230–400 mesh) column (2×12 cm) eluting with dichloromethane/ethanol (95:5) provided 0.1 g of the title compound, mp 175–177° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:7][C:8]2[N:9]([N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:15]=2)[C:10](=O)[CH:11]=1.O=P(Cl)(Cl)[Cl:24].CN(C)C1C=CC=CC=1>C(#N)C.C(Cl)(Cl)Cl>[Cl:24][C:10]1[N:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:15]=[C:8]2[N:7]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(-c2ccco2)[nH]c2cc(-c3ccccc3)nn12
Solvent: CC#N
Solvent: ClC(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Clc1cc(-c2ccco2)nc2cc(-c3ccccc3)nn12
Temperature: 80 °C
Yield: 83.5 %

Procedure:
A mixture of 5-(furan-2-yl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (0.277 g, 1.0 mmol, 1.0 eq), POCl3 (0.613 g, 4.0 mmol, 4.0 eq), N-benzyl-N,N,N-triethylethanaminium chloride (0.456 g, 2.0 mmol, 2.0 eq) and N,N-dimethylaniline (0.121 g, 1.0 mmol, 1.0 eq) in acetonitrile (5.0 mL) was heated at 80° C. for 4 hr. The completed reaction was diluted with CHCl3 (20 mL), washed with H2O (10 mL), and the separated organic layers were dried (MgSO4) and concentrated. The residue was purified by chromatography (Biotage25 g, EtOAc/Hexane) to afford 7-chloro-5-(furan-2-yl)-2-phenylpyrazolo[1,5-a]pyrimidine (0.247 g, 84%) as a yellow solid. 1H-NMR (400 MHz, CDCl3) δ 7.97-7.94 (m, 2H), 7.56 (m, 1H), 7.43-7.39 (m, 2H), 7.36-7.34 (m, 1H), 7.19 (s, 1H), 7.17 (dd, J=3.5, 0.5 Hz, 1H), 6.97 (s, 1H), 6.54 (dd, J=3.5, 1.7 Hz, 1H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][NH2:9])=O.[CH3:10][O:11][C:12]1[CH:21]=[CH:20][C:15]([CH2:16][N:17]=[C:18]=[S:19])=[CH:14][CH:13]=1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([S:19][C:18]1[N:17]([CH2:16][C:15]2[CH:20]=[CH:21][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[N:8][N:9]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(CN=C=S)cc1
Reactant: NNC(=O)c1ccco1
Product: COc1ccc(Cn2c(SCc3ccccc3)nnc2-c2ccco2)cc1

Procedure:
This compound was synthesized using the same methodology as described in Example 1 above, using 2-furancarboxylic acid hydrazide, 4-methoxybenzyl isothiocyanate and benzyl bromide as the starting materials.