Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([N:14]2[CH2:17][CH:16]([NH:18][CH2:19][CH2:20][CH3:21])[CH2:15]2)[S:7][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])([CH3:3])[CH3:2].[Cl:22][C:23]1[N:24]=[C:25]([C:30](O)=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>>[Cl:22][C:23]1[N:24]=[C:25]([C:30]([N:18]([CH2:19][CH2:20][CH3:21])[CH:16]2[CH2:17][N:14]([C:6]3[S:7][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=3)[CH2:15]2)=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCCNC1CN(c2nc(C(C)C)c(C(=O)OCC)s2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCCN(C(=O)c1nc(Cl)c(CC)[nH]1)C1CN(c2nc(C(C)C)c(C(=O)OCC)s2)C1
Yield: 61.2 %

Procedure:
The same operation as in Example (221c) was performed using ethyl 4-isopropyl-2-[3-(n-propylamino)azetidin-1-yl]-1,3-thiazole-5-carboxylate obtained in Example (229b) (91 mg, 0.29 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (51 mg, 0.29 mmol), WSC hydrochloride (168 mg, 0.88 mmol), 1-hydroxybenzotriazole (39 mg, 0.29 mmol) and N-methylmorpholine (0.06 mL, 0.58 mmol), to obtain 83 mg of the title compound as a colorless oily substance (61%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(CC)CC)C.[CH2:22]([N:25]=[C:26]=[S:27])[CH2:23][CH3:24]>CC(O)C>[CH2:22]([N:25]1[C:12](=[O:14])[C:3]2[C:2](=[CH:11][C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[CH:4]=2)[NH:1][C:26]1=[S:27])[CH2:23][CH3:24]
Reactant: Nc1cc2ccccc2cc1C(=O)O
Reactant: CCCN=C=S
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCCn1c(=S)[nH]c2cc3ccccc3cc2c1=O
Temperature: 25 °C
Yield: 72.6 %

Procedure:
To a suspension of 1.88 g of 3-amino-2-naphthalic acid in 25 mL of 2-propanol was added 1.39 mL of triethylamine followed by 1.02 g of n-propyl isothiocyanate with stirring. The mixture was heated at reflux for 2 h, and then allowed to cool to room temperature. The resulting solid was collected by filtration and washed with cold 2-propanol to give 1.97 g of the title compound of Step A as a yellow solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C(N(CC)CC)C.[CH3:14][SiH:15]([CH3:17])Cl>O1CCCC1>[CH3:14][SiH:15]([CH3:17])[N:3]1[CH2:4][CH2:5][O:1][C:2]1=[O:6]
Reactant: O=C1NCCO1
Reactant: C[SiH](C)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[SiH](C)N1CCOC1=O

Procedure:
A 3-dimethylsilyl-2-oxazolidinone was prepared in accordance with the following procedure. To a stirred mixture of 34.8 grams of 2-oxazolidinone and 40.4 grams of triethylamine in 600 ml of a tetrahydrofuran solvent, 45 ml of dimethylchlorosilane was added dropwise over a 30-minute period. The mixture was then heated in a distillation apparatus with continuous reflux for a period of 30 minutes. The resultant mixture was cooled and then filtered.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:22])=[CH:3]\[C:4]([O:6][CH2:7][CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]2[NH:18][CH:19]=[CH:20][N:21]=2)=[CH:12][CH:11]=1)=[O:5].[F:23][C:24]([F:41])([F:40])[C:25]1[CH:26]=[C:27]([CH:37]=[CH:38][CH:39]=1)[CH:28]=[C:29]([C:34]([CH3:36])=O)[C:30]([O:32][CH3:33])=[O:31]>C1(C)C=CC=CC=1>[CH3:22][C:2]1[NH:1][C:34]([CH3:36])=[C:29]([C:30]([O:32][CH3:33])=[O:31])[CH:28]([C:27]2[CH:37]=[CH:38][CH:39]=[C:25]([C:24]([F:23])([F:40])[F:41])[CH:26]=2)[C:3]=1[C:4]([O:6][CH2:7]/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]2[NH:21][CH:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)=[O:5]
Reactant: C/C(N)=C/C(=O)OCC=Cc1ccc(Cc2ncc[nH]2)cc1
Reactant: COC(=O)C(=Cc1cccc(C(F)(F)F)c1)C(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC/C=C/c2ccc(Cc3ncc[nH]3)cc2)C1c1cccc(C(F)(F)F)c1

Procedure:
297 mg (1 mM) of 3-{4-(1-imidazolylmethyl)phenyl}-2-propen-1-yl 3-aminocrotonate and 272 mg (1mM) of methyl 2-(3-trifluoromethylbenzylidene)acetoacetate were dissolved in 5 ml of toluene and refluxed for six hours. After cooling, the crystals produced were filtered off and recrystallized from methanol, whereby the captioned compound was obtained. The yield was 394 mg (71.5%).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:16][C:15]3=[O:30])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[CH3:31][NH:32][CH3:33].[ClH:34]>O1CCCC1.ClCCl>[ClH:34].[CH3:31][N:32]([CH3:33])[CH2:3][C@H:2]([OH:1])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:22][CH:21]=4)=[CH:16][C:15]3=[O:30])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(cnn2C[C@@H]2CO2)c1
Reactant: CNC
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C[C@H](O)Cn1ncc2cc(-n3ccc(-c4ccc(C(F)(F)F)cc4)cc3=O)ccc21
Temperature: 45 °C
Yield: 71 %

Procedure:
To (R)-1-(1-(oxiran-2-ylmethyl)-1H-indazol-5-yl)-4-(4-(trifluoromethyl)-phenyl)pyridin-2(1H)-one (230 mg, 0.56 mmol) in tetrahydrofuran (5 mL) was added LiClO4 (892 mg, 8.38 mmol) followed by dimethylamine (2.8 ml of a 2 M solution in tetrahydrofuran, 5.6 mmol). The reaction mixture was heated in a 45° C. oil bath for 3.75 h. The reaction mixture was cooled to ambient temperature, diluted with dichloromethane (50 ml), washed with water (25 mL) and brine (25 mL), dried (Na2SO4), and concentrated under reduced pressure. The material was purified by column chromatography (silica gel, 9:1 CH2Cl2/MeOH to 90:9:1 CH2Cl2/MeOH/conc. NH4OH). The dried residue (198 mg, 0.43 mmol) was dissolved in dichloromethane (2 mL), and HCl (1.25 M solution in methanol, 0.38 mL, 0.47 mmol) was added. The mixture was concentrated under reduced pressure and dried to afford the title compound (198 mg, 71%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 9.42 (br s, 1H), 8.20 (s, 1H), 8.02-8.00 (m, 2H), 7.88-7.80 (m, 5H), 7.46 (dd, J=8.5, 1.5 Hz, 1H), 6.89 (d, J=2.0 Hz, 1H), 6.74 (dd, J=7.0, 2.0 Hz, 1H), 5.60 (br s, 1H), 4.56-4.52 (m, 1H), 4.48-4.44 (m, 1H), 4.27 (br s, 1H), 2.92-2.88 (br m, 2H), 2.58 (br s, 6H); ESI MS m/z 457 [M+H]+; HPLC (Method B)>99% (AUC), tR=14.5 min; [α]23D −9.5° (c 0.14, Methanol).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[NH2:12][C@H:13]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[C:23]3[CH2:30][S:29][CH2:28][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:18][CH2:17]1)=[O:15]>C(Cl)Cl.CO>[NH2:12][C@H:13]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[C:23]3[CH2:30][S:29](=[O:9])[CH2:28][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:18][CH2:17]1)=[O:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3c2CSC3)CC1
Solvent: ClCCl
Solvent: CO
Product: N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3c2CS(=O)C3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.7 %

Procedure:
m-CPBA (77%, 67 mg, 0.30 mmol) was added to a solution of (R)-2-amino-3-(4-chlorophenyl)-1-(4-(5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one (120 mg, 0.30 mmol) in DCM (10 mL) and MeOH (1 mL). The mixture was stirred at room temperature for 2 hours. The solvent was removed, and the residue was subject to column chromatography, eluted by DCM/MeOH (4:1-1:1) to afford (R)-2-amino-3-(4-chlorophenyl)-1-(4-(6-oxido-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one (21 mg, 17%) as the free amine. LCMS: 420.2 [M+H+] (APCI+).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14]([NH2:16])=O)[N:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:18]>N1C=CC=CC=1>[CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14](=[S:18])[NH2:16])[N:2]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: NC(=O)c1cc2c(cn1)[nH]c1ccccc12
Solvent: c1ccncc1
Product: NC(=S)c1cc2c(cn1)[nH]c1ccccc12

Procedure:
A stirred mixture of 5.0 g of β-carbolin-3-carboxamide dissolved in 100 ml of dry pyridine and 5.0 g of phosphorus pentasulfide is boiled under reflux for 4 hours. The cooled reaction mixture is concentrated to about 25 ml in vacuo and poured into 1 liter of ice water. After adjusting the pH of the mixture to 8.5 with aqueous ammonia, a solid is filtered off, washed thoroughly with water and dried. The substance formed (3.2 g) is recrystallized from n-butyl alcohol to form β-carbolin-3-carbothioamide of a melting point of 274°-276° C.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][O:9][C:10]1[CH:15]=[C:14]([CH2:16][O:17][CH3:18])[CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[C:21]1[N:22]2[N:28]=[C:27]([O:29][CH3:30])[C:26]([NH:31][CH2:32][CH2:33][CH3:34])=[C:23]2[S:24][CH:25]=1.Br[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1.CC(C)([O-])C.[Na+]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O>[CH3:8][O:9][C:10]1[CH:15]=[C:14]([CH2:16][O:17][CH3:18])[CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[C:21]1[N:22]2[N:28]=[C:27]([O:29][CH3:30])[C:26]([N:31]([CH2:32][CH2:33][CH3:34])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)=[C:23]2[S:24][CH:25]=1
Reactant: Brc1ccccn1
Reactant: CCCNc1c(OC)nn2c(-c3c(OC)cc(COC)cc3OC)csc12
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCN(c1ccccn1)c1c(OC)nn2c(-c3c(OC)cc(COC)cc3OC)csc12
Temperature: 100 °C
Reaction time: 5 h
Yield: 21.7 %

Procedure:
To a toluene (0.9 mL) solution of 3-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-6-methoxy-N-propylpyrazolo[5,1-b][1,3]thiazole-7-amine (70 mg, 0.179 mmol) were added 2-bromopyridine (56.6 mg, 0.358 mmol), sodium tert-butoxide (25.8 mg, 0.269 mmol) and bis(tri-tert-butylphosphine)palladium (4.57 mg, 0.009 mmol), and the mixture was stirred at 100° C. for five hours. After the reaction mixture was returned to room temperature, water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate, and the solvent was distilled off under reduced pressure. The residue was purified by medium pressure amino silica gel column chromatography (n-heptane/ethyl acetate: 10% then 50%) to obtain the title compound (18.2 mg, 0.0388 mmol).
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[C:7]([CH3:15])[C:8]([CH3:14])=[C:9]([OH:13])[C:10]=2[CH3:12])[O:5][C:4]([CH2:17][O:18][C:19]2[CH:32]=[CH:31][C:22]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:21][CH:20]=2)([CH3:16])[CH2:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>CN(C)C=O>[OH:13][C:9]1[C:10]([CH3:12])=[C:11]2[C:6](=[C:7]([CH3:15])[C:8]=1[CH3:14])[O:5][C:4]([CH2:17][O:18][C:19]1[CH:32]=[CH:31][C:22]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:21][CH:20]=1)([CH3:16])[CH:3]=[CH:2]2
Reactant: Cc1c(C)c2c(c(C)c1O)C(O)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: Cc1c(C)c2c(c(C)c1O)C=CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2

Procedure:
A mixture of 140 mg of 5-[4-(4,6-dihydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione (prepared as described in Example 30), 10 mg of p-toluenesulfonic acid, 10 ml of benzene and 0.5 ml of dimethylformamide was heated under reflux for 1 hour. The reaction solution was cooled, washed with a saturated aqueous solution of sodium bicarbonate and then with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography eluted with a 4:1 by volume mixture of benzene and ethyl acetate, to give the title compound, softening at 173°-176° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(N)C1C=CC=CC=1.[CH3:18][C:19]([CH3:23])([CH3:22])[CH:20]=[CH2:21].Cl>C1COCC1>[CH3:18][C:19]([CH3:23])([CH3:22])[CH2:20][CH2:21][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)c1ccccc1
Reactant: C=CC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: NCc1ccccc1
Product: CC(=O)c1ccccc1CCC(C)(C)C
Temperature: 150 °C
Yield: 95.5 %

Procedure:
In a 500 ml pressure reactor, acetophenone 26 mg (0.22 mmol), benzylamine 12 mg (0.11 mmol), tristriphenylphosphine rhodium (I) chloride 10.0 mg (0.011 mmol) and 3,3-dimethyl-1-butene 91 mg (1.1 mmol) were placed. While the reactor was stopped with a stopper, the reactants were heated at 150° C. for 6 hours with stirring. After completion of the on, a reactant mixture was dissolved in THF 3 ml and added with 1 N HCl soln. 10 ml, followed by hydrolysis with stirring for 12 hours at room temperature. After the mixture was two or three times extracted with Et2O and CH2Cl2, the organic layer was dried over MgSO4 and then filtered, and the solvent was evaporated under reduced pressure. The reactant mixture of the organic layer was purified by column chromatography on silica gel (5:2 hexane:ethyl acetate) to obtain 2-(3,3-dimethylbutyl)phenyl-1-ethanone 42 mg (0.21 mmol). Yield: 95%. Under the same conditions, various olefins were employed, and the results are given in Table 7, below.
Reaction SMILES: [C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].OC[CH2:9][N:10]1[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][CH:11]1C>>[C:1]([O:6][CH2:12][C:13]([CH3:16])([CH3:15])[CH2:14][N:10]([CH3:11])[CH3:9])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CC1CC(C)(C)CN1CCO
Reactant: C=C(C)C(=O)[O-]
Product: C=C(C)C(=O)OCC(C)(C)CN(C)C

Procedure:
Methacrylate of N-hydroxyethyl-2,4,4-trimethylpyrrolidine
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:13])[C:5]2[N:11]=[C:10](Cl)[CH:9]=[CH:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:3]=[C:4]([NH2:13])[C:5]2[N:11]=[C:10]([C:23]3[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:21]([Cl:20])[CH:22]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: COc1ccc(B(O)O)cc1Cl
Reactant: Nc1nc(N)c2nc(Cl)ccc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2ccc3nc(N)nc(N)c3n2)cc1Cl
Yield: 38.7 %

Procedure:
A suspension of 2,4-diamino-6-chloropyrido[3,2-d]pyrimidine (464 mg, 2.37 mmole), K2CO3 (1332 mg, 9.64 mmole), 3-chloro-4-methoxyphenyl boronic acid (907 mg, 4.86 mmole) in 1,4-dioxane (35.5 ml) and water (7 ml) was purged with a stream of nitrogen for 15 minutes. Then, tetrakis(triphenylphosphine)palladium(0) (278 mg, 0.24 mmole) was added and the reaction mixture was heated at reflux under a N2 atmosphere for 4 hours. Upon cooling, the mixture was partitioned between CH2Cl2 and a saturated aqueous sodium bicarbonate solution. The organic phase was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified by silica gel flash chromatography, using methanol and 1% Et3N in CH2Cl2 as eluent, gradually increasing the methanol concentrations from 5% to 10%, to afford the pure title compound (277 mg, yield 39%) which was characterized by its mass spectrum as follows: MS (m/z): 302 ([M+H]+, 100).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][CH3:23])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[CH3:28][N:29]([CH3:34])[CH2:30][C:31](O)=[O:32].O=P(Cl)(Cl)Cl>CO>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]([CH3:23])[C:31](=[O:32])[CH2:30][N:29]([CH3:34])[CH3:28])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: CN(C)CC(=O)O
Reactant: CNc1ccc(-n2cc(CNC(=O)c3ccc(Cl)s3)nn2)cc1
Agent: O=C([O-])[O-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CO
Product: CN(C)CC(=O)N(C)c1ccc(-n2cc(CNC(=O)c3ccc(Cl)s3)nn2)cc1

Procedure:
5-Chloro-N-((1-(4-(methylamino)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (34 mg, 0.1 mmol), prepared as shown in Example 17, was dissolved in 10 mL methanol and treated with MP-carbonate for 1 hr. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in 3 mL pyridine and N,N-dimethylglycine (16 mg, 0.1 mmol) was added. The mixture was then stirred in ice bath. POCl3 (28 μL, 0.3 mmol) was added. The reaction was stirred for 20 min and quenched with methanol. The mixture was concentrated and directly subjected to prep HPLC to isolate the title compound. MS found for C19H21ClN6O2S (M+H)+ 433.1, 435.1 (Cl pattern).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([OH:9])[C:6]([CH3:10])=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]2[N:30]=[C:29](S(C3C=CC(C)=CC=3)(=O)=O)[S:28][N:27]=2)=[CH:20][CH:19]=1>C(#N)C>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:29]2[S:28][N:27]=[C:26]([CH2:25][CH2:24][C:21]3[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=3)[N:30]=2)[C:6]([CH3:10])=[CH:5][C:3]=1[NH2:4]
Reactant: Cc1cc(N)c(Cl)cc1O
Reactant: Cc1ccc(S(=O)(=O)c2nc(CCc3ccc(Cl)cc3)ns2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(N)c(Cl)cc1Oc1nc(CCc2ccc(Cl)cc2)ns1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
1.45 g (9.24 mmol) of 2-chloro-4-hydroxy-5-methylaniline are introduced into 18 ml of acetonitrile, treated with 1.53 g (11.08 mmol) of potassium carbonate at ambient temperature and stirred at ambient temperature for 30 min. Subsequently, 3.50 g (9.24 mmol) of 3-[2-(4-chlorophenyl)ethyl]-5-[(4-methylphenyl]sulphonyl]-1,2,4-thiadiazole are added and the reaction mixture is stirred at 50° C. for 12 h. After cooling, the mixture is concentrated on a rotary evaporator, the residue is taken up in dichloromethane and the solution is extracted twice with water, dried over Na2SO4 and freed from the solvent under vacuum. 3.11 g of product are obtained (94.3% purity, 83.4% yield, log P (pH 2.3)=4.50).
Reaction SMILES: O[C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=O.C([O-])(=O)C.[Na+].Cl.[N+:25]([C:28]1[CH:33]=[CH:32][C:31]([NH:34][NH2:35])=[CH:30][CH:29]=1)([O-:27])=[O:26]>>[OH:18][C:16]1[CH:17]=[C:2]2[C:3]([C:4]([C:6]3[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=3[OH:13])=[N:35][N:34]2[C:31]2[CH:32]=[CH:33][C:28]([N+:25]([O-:27])=[O:26])=[CH:29][CH:30]=2)=[CH:14][CH:15]=1
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(-n2nc(-c3ccc(O)cc3O)c3ccc(O)cc32)cc1
Yield: 17.4 %

Procedure:
Prepared according to Method B from 2,2′,4,4′-tetrahydroxybenzophenone (0.400 g, 1.60 mmol), sodium acetate (0.267 g, 3.3 mmol) and 4-nitrophenylhydrazine hydrochloride (0.463 g, 2.5 mmol) to give 0.101 g of product as a pink solid.
Reaction SMILES: [F:1][C:2]1([F:18])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]1=[O:12].[C:19]1(=[O:25])[O:24][C:22](=[O:23])[CH2:21][CH2:20]1>C(O)C>[C:22]([CH2:21][CH2:20][C:19]([O:9][CH2:8][C@H:5]1[O:4][C@@H:3]([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[C:2]([F:1])([F:18])[C@@H:6]1[OH:7])=[O:25])([OH:24])=[O:23]
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Reactant: O=C1CCC(=O)O1
Solvent: CCO
Product: Nc1ccn([C@@H]2O[C@H](COC(=O)CCC(=O)O)[C@@H](O)C2(F)F)c(=O)n1

Procedure:
Dry 2'-deoxy-2',2'-difluorocytidine (311 mg) was added to dry ethanol and brought to reflux. Succinic anhydride (2.5 g) was added in portions over a half hour period and the mixture was refluxed an additional 1/2 hour. The mixture was concentrated in vacuo and the resulting crude product was placed on a silica gel column and eluted with a step gradient of 5%, 20%, and 50% methanol in methylene chloride. The desired product was isolated in the 50% methanol in methylene chloride wash and contained 148 mg of material. This product was combined with product from a similar experiment providing a total of 253 mg of material. This material was taken up in 8 ml of 0.01M ammonium acetate solution. The pH was adjusted with ammonium hydroxide to 8.6 and the solution placed on a freshly packed mono-Q anion exchange column (Pharmacia Inc., 800 Centennial Avenue, Piscataway, N.J. 08854). Desired fractions were combined, frozen, and lyophilized. The residue was dissolved in distilled water, frozen, and lyophilized several more times, then dissolved in a small amount of methanol and benzene, frozen, and lyophilized providing 60 mg of the desired title product. The proton NMR spectra was consistent with the structure of the desired product:
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[NH:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15].[NH2:27][C@H:28]([C:36]([NH:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[NH:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:14]([C:17]([NH:27][C@H:28]([C:36]([NH:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:19])([CH3:15])[CH3:16]
Reactant: N[C@@H](Cc1ccccc1)C(=O)Nc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.6 %

Procedure:
4.04 g (22.1 mmol) of EDCl was added to 60 ml of THF solution of 2.99 g (14.7 mmol) of Boc-Aib-OH (manufactured by Sigma-Aldrich Corporation), and 3.53 g (14.7 mmol) of H-Phe-NHPh obtained in Synthesis Example 6-2, followed by stirring for 6 hours at room temperature. After a reaction mixture was concentrated under reduced pressure, the concentrate was extracted by adding water and ethyl acetate. After an organic layer was washed sequentially with a diluted hydrochloric acid, an aqueous solution of sodium hydrogen carbonate and water (one time for each), it was concentrated under reduced pressure, thereby obtaining crude amide. The obtained amide compound was purified by a silica gel column chromatography (hexane/ethyl acetate=5/1 to 1/1 (volume ratio)), thereby obtaining 5.79 g of the product with a yield of 92.6%.
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[C:8]([CH3:27])=[C:9]2[C:14](=[C:15]([F:18])[C:16]=1F)[N:13]([C@@H:19]1[CH2:21][C@@H:20]1[F:22])[CH:12]=[C:11]([C:23]([OH:25])=[O:24])[C:10]2=[O:26].Cl.Cl.[N:30]12[CH2:37][CH:34]([CH2:35][CH2:36]1)[NH:33][CH2:32][CH2:31]2>C(N(CC)CC)C>[N:30]12[CH2:37][CH:34]([CH2:35][CH2:36]1)[N:33]([C:16]1[C:15]([F:18])=[C:14]3[C:9]([C:10](=[O:26])[C:11]([C:23]([OH:25])=[O:24])=[CH:12][N:13]3[C@@H:19]3[CH2:21][C@@H:20]3[F:22])=[C:8]([CH3:27])[C:7]=1[F:6])[CH2:32][CH2:31]2
Reactant: C1CN2CCC(C2)N1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(F)c(N2CCN3CCC2C3)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Temperature: 100 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
To 5 ml of dried N,N-dimethylformamide were added 211 mg of 6,7,8-trifluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 372 mg of 1,4-diazabicyclo[3.2.1]octane dihydrochloride, and 2 ml of triethylamine, and the mixture was stirred at 100° C. for 1 hour. After allowing to cool, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in a 1N sodium hydroxide aqueous solution while cooling with ice. After neutralizing with 1N hydrochloric acid, the mixture was extracted with chloroform, and the extract was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting crude crystals were recrystallized from a mixed solvent of ethanol and 28% aqueous ammonia. The precipitated crystals were collected by filtration, washed with diethyl ether, and dried at 60° C. in vacuo overnight to yield 170 mg of the titled compound as a yellow powder.