Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27]>>[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:18](=[O:19])[C:17]2[CH:16]=[CH:15][C:14]([S:11]([N:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:4][CH2:3][CH2:2]3)(=[O:13])=[O:12])=[CH:22][CH:21]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Reactant: Nc1cccc(Cl)c1
Product: O=C(Nc1cccc(Cl)c1)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with 3-chloroaniline (31 mg, 0.24 mmol) using method B. The residue was purified using flash chromatography eluting with 0-20% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give N-(3-chlorophenyl)-4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzamide as a white solid. Yield: 24 mg (23%). 1H-NMR: 10.60 (s, 1H), 8.05 (d, J=8.5 Hz, 2H), 7.93 (t, J=2.0 Hz, 1H), 7.76 (d, J=8.5 Hz, 2H), 7.66 (ddd, J=8.5, 2.0, 1.0 Hz, 1H), 7.63 (d, J=8.5 Hz, 1H), 7.39 (t, J=8.0 Hz, 1H), 7.24-7.16 (m, 2H), 7.12-7.07 (m, 2H), 3.86-3.80 (m, 2H), 2.45 (t, J=7.0 Hz, 2H), 1.67-1.59 (m, 2H).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]([CH3:14])[NH:12][C:11](=[O:15])[C:10]1([CH3:17])[CH3:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:1]([O:8][C@H:9]1[C@H:13]([CH3:14])[N:12]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:28])([F:30])[F:29])[CH:20]=2)[C:11](=[O:15])[C:10]1([CH3:16])[CH3:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(I)cc1C(F)(F)F
Reactant: C[C@@H]1NC(=O)C(C)(C)[C@H]1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: C[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Using (4R,5S)-4-(tert-butyldimethylsilyloxy)-3,3,5-trimethylpyrrolidin-2-one (266.6 mg), 4-iodo-2-(trifluoromethyl)benzonitrile (340 mg), cesium carbonate (505 mg), tris(dibenzylideneacetone)dipalladium(0) (47 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (120 mg), and in the same manner as in Reference Example 3, the title compound was obtained as a colorless oil (yield: 391.7 mg, yield: 89%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:9]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[N:8]=[C:7]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[S:6]1.[N:29]#[C:30]Br.C(N(CC)CC)C>C(Cl)Cl>[F:22][C:16]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=1[C:7]1[S:6][C:5]([CH2:4][CH2:3][CH2:2][NH:1][C:30]#[N:29])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:9]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[N:8]=1
Reactant: N#CBr
Reactant: CC(C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCN)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCNC#N)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methylpropan-1-one (33 mg, 0.0817867 mmol) was weighed into a 10 ml flask and dissolved in 1.0 mL of CH2Cl2, followed by addition of cyanogen bromide (11.2618 mg, 0.106323 mmol) and dropwise addition of triethylamine (0.0398980 mL, 0.286253 mmol). The reaction was then stirred at ambient temperature for 1 hour. The reaction was then concentrated in vacuo and the resulting tan foam was used in the next step without purification.
Reaction SMILES: C([O:5][C:6](=[O:45])[CH:7]([NH:21][C:22]1[C:27]([NH:28][CH2:29][S:30]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)(=[O:32])=[O:31])=[CH:26][N:25]=[C:24]([N:40]([CH2:43][CH3:44])[CH2:41][CH3:42])[N:23]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:20])[N:17]([CH3:19])[CH3:18])=[CH:11][CH:10]=1)(C)(C)C.[ClH:46]>C(O)=O>[ClH:46].[CH2:43]([N:40]([CH2:41][CH3:42])[C:24]1[N:23]=[C:22]([NH:21][CH:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:20])[N:17]([CH3:18])[CH3:19])=[CH:11][CH:10]=2)[C:6]([OH:45])=[O:5])[C:27]([NH:28][CH2:29][S:30]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)(=[O:31])=[O:32])=[CH:26][N:25]=1)[CH3:44]
Reactant: CCN(CC)c1ncc(NCS(=O)(=O)c2ccc(F)cc2)c(NC(Cc2ccc(OC(=O)N(C)C)cc2)C(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: O=CO
Product: CCN(CC)c1ncc(NCS(=O)(=O)c2ccc(F)cc2)c(NC(Cc2ccc(OC(=O)N(C)C)cc2)C(=O)O)n1
Temperature: 70 °C
Reaction time: 336 h
Yield: 97.3 %

Procedure:
A formic acid (500 mL) solution of 2-{2-diethylamino-5-[(4-fluorobenzenesulfonyl)methylamino]-pyrimidin-4-ylamino}-3-(4-dimethylcarbamoyloxyphenyl)propionic acid t-butyl ester (28.69 g, 0.044 mol) was heated to 70° C. for 2 h, and then concentrated in vacuo. The residue was dissolved again in formic acid (500 mL), and then heated again at 70° C. for 2 h, and then concentrated again in vacuo. The residue was dissolved again in formic acid (500 mL), and then heated again at 70° C. for 1 h. The solution was reduced in volume by 90%, and then treated with 1.0 M HCl (44 mL, 0.044 mol) and distilled water (490 mL). The resulting homogeneous solution was concentrated in vacuo, and then distilled water (100 mL) was added, and the homogenous solution was lyophilized over 14 days to yield 26.76 g (96%) the title compound, as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:10][CH2:11][CH2:12][N:13]2C(=O)C3=CC=CC=C3C2=O)=[CH:4][CH:3]=1.O.NN.ClCCl>CO>[NH2:13][CH2:12][CH2:11][CH2:10][N:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:24](=[O:25])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N(CCCN1C(=O)c2ccccc2C1=O)Cc1ccc(F)cc1
Agent: NN
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCCN)Cc1ccc(F)cc1
Yield: 83.3 %

Procedure:
To a solution of N-[5-(p-fluorophenyl)-4-(tert-butoxycarbonyl)-4-azapentyl]phthalimide (2.1 g, 5.1 mmol) in methanol (20 ml) was added hydrazine monohydrate (0.4 ml) and the mixture was heated under reflux for 3 hours. After cooling, to the reaction mixture was added dichloromethane (50 ml) and then washed with aqueous ammonia (50 ml×2). The organic layer was dried over anhydrous potassium carbonate and the solvent was distilled off under reduced pressure to give 1.2 g of the title compound as a colorless oily substance. Yield=85%.
Reaction SMILES: [NH2:1][C@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:7][CH2:6]1)=[O:4].CCN(C(C)C)C(C)C.[NH:39]1[C:43](=[O:44])[CH2:42][CH2:41][CH:40]1[C:45](O)=[O:46].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C@@H:2]([NH:1][C:45]([CH:40]2[CH2:41][CH2:42][C:43](=[O:44])[NH:39]2)=[O:46])[C:3]([N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:17][S:18]([CH3:21])(=[O:19])=[O:20])[CH2:7][CH2:6]2)=[O:4])=[CH:28][CH:27]=1
Reactant: O=C1CCC(C(=O)O)N1
Reactant: CS(=O)(=O)Nc1ccccc1C1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)C2CCC(=O)N2)CC1

Procedure:
The title compound was prepared according to the procedure described in Example 1, Step (f) using (2R)-2-amino-3-(4-chlorophenyl)-1-(4-(2-[(methylsulfonyl)-amino]phenyl)piperidyl)propan-1-one (Example 1, Step g) (118 mg, 0.25 mmol), DIEA (Aldrich) (0.05 mL, 0.25 mmol), DL-pyroglutamic acid (Aldrich) (344 mg, 0.5 mmol), HOAT (Aldrich) (68.2 mg, 0.5 mmol) and EDC (Aldrich) (95.8 mg, 0.5 mmol) in DMF (3 mL). Purification by silica gel chromatography (100% EtOAc) provided the title compound as a colorless film (82 mg). MS (ESI, pos. ion) m/z: 547 (M+1); (ESI, neg. ion) in/z: 545 (M−1). Calc'd for C26H31ClN4O5S: 546.17.
Reaction SMILES: [N+](C1C=CC(/C(=C\C2C=CC(O)=C(OC)C=2)/C([O-])=O)=CC=1)([O-])=O.[N+](C1C=CC(CC([O-])=O)=CC=1)([O-])=O.C(O)C(N)(CO)CO.Cl.[N+:46]([C:49]1[CH:54]=[CH:53][C:52]([O-:55])=[CH:51][CH:50]=1)([O-:48])=[O:47]>CS(C)=O.C([O-])(=O)C.[Na+]>[CH:50]1[C:49]([N+:46]([O-:48])=[O:47])=[CH:54][CH:53]=[C:52]([OH:55])[CH:51]=1
Reactant: O=[N+]([O-])c1ccc([O-])cc1
Agent: CC(=O)[O-]
Agent: COc1cc(/C=C(/C(=O)[O-])c2ccc([N+](=O)[O-])cc2)ccc1O
Agent: Cl
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(O)cc1
Reaction time: 0.17 h

Procedure:
A p-nitrophenylferulate stock solution is made by dissolving p-nitrophenylacetate in dimethylsulfoxide (DMSO) to constitute a 0.1 M solution. Before assay, a sample of the stock solution is diluted 100-fold in 50 mM sodium acetate pH 5.0 to make a 1 mM solution. A 100 μl volume of 1 mM p-nitrophenylferulate is mixed with each dilution of the enzyme and then incubated at 25° C. for 10 minutes. Substrate alone, enzyme alone, and buffer alone are run as controls. p-Nitrophenol standard solutions of 0.25, 0.2, 0.1, 0.05, and 0.02 mM are prepared by diluting a 10 mM stock solution in 50 mM sodium acetate pH 5.0. At 10 minutes, 50 μl of 1.0 M Tris-HCl pH 8.0 buffer is added to each well (including samples, substrate control, enzyme control, reagent control, and standards), mixed, and the absorbance at 405 nm immediately measured on a SPECTRAMAX™ 340 PC plate reader (Molecular Devices, Sunnyvale, Calif., USA). One unit of feruloyl esterase activity is defined as the amount of enzyme capable of releasing 1 μmole of p-nitrophenolate anion per minute at pH 5, 25° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C@H:11]([NH:15][S:16]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][C:27]3=[O:32])[C:20]=2[O:33][CH3:34])(=[O:18])=[O:17])[C:12](O)=[O:13])=[O:8])=[CH:4][CH:3]=1.[NH:35]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>CN(C=O)C>[N:35]1([C:12](=[O:13])[C@@H:11]([NH:15][S:16]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][C:27]3=[O:32])[C:20]=2[O:33][CH3:34])(=[O:18])=[O:17])[CH2:10][NH:9][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:8])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: C1CCCNCC1
Reactant: COc1c(N2CCOCC2=O)cc(F)cc1S(=O)(=O)N[C@@H](CNC(=O)c1ccc(Cl)s1)C(=O)O
Solvent: CN(C)C=O
Product: COc1c(N2CCOCC2=O)cc(F)cc1S(=O)(=O)N[C@@H](CNC(=O)c1ccc(Cl)s1)C(=O)N1CCCCCC1

Procedure:
Intermediate 23 (225 mg, 0.42 mmol) and azepane (57 μl, 0.462 mmol) were coupled in close analogy to the procedure described in 3.5) using DMF as solvent. The mixture was purified by prep. HPLC. Yield after lyophilization: 199 mg, 77%, colorless, amorphous solid. MS (ES+): m/e=617.1/619.1, chloro pattern.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13](B(O)O)[C:14]([F:17])=[N:15][CH:16]=1.C([O-])(=O)C.[K+].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCO.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>[Cl:10][C:11]1[CH:12]=[C:13]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[CH:3]=2)[C:14]([F:17])=[N:15][CH:16]=1
Reactant: Cc1nc(N)cc(Cl)n1
Reactant: OB(O)c1cc(Cl)cnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1nc(N)cc(-c2cc(Cl)cnc2F)n1
Temperature: 105 °C
Yield: 69 %

Procedure:
A mixture of 6-chloro-2-methylpyrimidin-4-amine (1.03 g, 7.17 mmol) (SynChem Inc,), 5-chloro-2-fluoropyridin-3-ylboronic acid (1.572 g, 8.97 mmol) (Combi-Blocks Inc.), PdCl2AmPhos (0.254 g, 0.359 mmol) and potassium acetate (2.11 g, 21.52 mmol) in 8 mL of dioxane, 1 mL of EtOH and 4 mL of water in a sealed glass tube was heated in a microwave at 105° C. for 45 min. Crude liquid chromatography/mass spectropscopy indicated the reaction was not completed. To the reaction mixture was added 83 mg of Pd(PPh3)4, 300 mg of 5-chloro-2-fluoropyridin-3-ylboronic acid and 0.3 mL of 2 N Na2CO3. It was heated in a microwave at 115° C. for 20 min. The precipitated yellow solid was filtered, washed with 3 mL of 1 N NaOH, followed by 3 mL of water and 5 mL of EtOAc. The yellow crystalline solid was dried in a vacuum oven at 45° C. for 18 h to provide 6-(5-chloro-2-fluoropyridin-3-yl)-2-methylpyrimidin-4-amine (1.18 g, 68% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.59 (dd, J=8.4, 2.7 Hz, 1H), 8.40 (m, 1H), 7.08 (br, 2H), 6.82 (d, J=1.8 Hz, 1H), 2.40 (s, 3H). m/z (ESI, positive ion) 238.9 (M+H)+.
Reaction SMILES: C(OC([N:8]1[C@@H:12](/[CH:13]=[C:14](/[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)\[CH2:15][CH3:16])[CH2:11][O:10]C1(C)C)=O)(C)(C)C.Cl.[OH-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[NH2:8][C@@H:12](/[CH:13]=[C:14](/[C:17]1[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=1)\[CH2:15][CH3:16])[CH2:11][OH:10]
Reactant: CC/C(=C\[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC/C(=C\[C@H](N)CO)c1ccc(Cl)cc1
Temperature: 35 °C
Reaction time: 3.5 h
Yield: 103.6 %

Procedure:
To a stirred solution of (S)-4-[(E)-2-(4-chloro-phenyl)-but-1-enyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (820 mg) at r.t. in dioxane (8 ml) was added 4 M HCl solution in dioxane (11.2 ml). The mixture was stirred at 35° C. for 3.5 h. The mixture was then diluted with ethyl acetate and made basic by addition of 2 N aq sodium hydroxide solution. The phases were separated and the organic phase was washed with saturated brine, dried over sodium sulphate and concentrated in vacuo to give (E)-(S)-2-amino-4-(4-chloro-phenyl)-hex-3-en-1-ol (524 mg, quant.) as a yellow oil. MS (ISP): 228.2 ([{37Cl}M+H]+), 226.2 ([{35Cl}M+H]30).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([F:30])[C:23]=2[F:31])[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC(OC)=C(F)C=2F)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:17]1([CH2:16][N:15]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([F:30])[C:23]=2[F:31])[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:32])=[O:3])=[CH:8][N:9]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(OC)c(F)c2F)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: COc1ccc(NCC2CCCC2)c(F)c1F
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Product: COc1ccc(N(CC2CCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)c(F)c1F

Procedure:
The title compound was prepared via {2-[3-(2,3-difluoro-4-methoxy-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(2,3-difluoro-4-methoxy-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: O=[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:3]=O.[F:11][C:12]1[CH:25]=[CH:24][C:15]([CH2:16][C:17]2[N:18]([NH2:23])[C:19]([NH2:22])=[N:20][N:21]=2)=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:25]=[CH:24][C:15]([CH2:16][C:17]2[N:18]3[N:23]=[CH:3][C:2]([C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[N:22][C:19]3=[N:20][N:21]=2)=[CH:14][CH:13]=1
Reactant: O=CC(=O)c1ccccc1
Reactant: Nc1nnc(Cc2ccc(F)cc2)n1N
Product: Fc1ccc(Cc2nnc3nc(-c4ccccc4)cnn23)cc1

Procedure:
General procedure A was followed with the reaction of oxo-phenyl-acetaldehyde and 5-(4-fluoro-benzyl)-[1,2,4]triazole-3,4-diamine to provide 3-(4-fluoro-benzyl)-7-phenyl-[1,2,4]triazolo[4,3-b][1,2,4]triazine and the desired product 3-(4-fluoro-benzyl)-6-phenyl-[1,2,4]triazolo[4,3-b][1,2,4]triazine (example 4).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[C:12](OC)=[O:13].[H-].C([Al+]CC(C)C)C(C)C.O>O1CCCC1.CCCCCC>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[CH2:12][OH:13]
Reactant: COC(=O)c1c(Cl)ccc2nn(C)cc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: Cn1cc2c(CO)c(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a solution of methyl 5-chloro-2-methyl-2H-indazole-4-carboxylate (3.00 g, 13.4 mmol) in tetrahydrofuran (129 mL) was slowly added a solution (1 M, 40.1 mL, 40.1 mmol) of diisobutylaluminum hydride in hexane at −78° C., and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/2) to give the title compound (2.63 g, yield 99%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][CH2:3]1.CN(C)C=O.S(Cl)(Cl)=O.[NH2:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24](=[O:33])[C:25]([C:30]([OH:32])=[O:31])=[CH:26][NH:27]2)=[CH:22][CH:21]=1.C(N(CC)CC)C.Cl[Si](C)(C)C>ClCCl>[O:33]=[C:24]1[C:23]2[C:28](=[CH:29][C:20]([NH:19][C:7]([CH:5]3[CH2:4][CH2:3][C:2](=[O:1])[NH:6]3)=[O:9])=[CH:21][CH:22]=2)[NH:27][CH:26]=[C:25]1[C:30]([OH:32])=[O:31]
Reactant: Nc1ccc2c(=O)c(C(=O)O)c[nH]c2c1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C1CCC(C(=O)Nc2ccc3c(=O)c(C(=O)O)c[nH]c3c2)N1
Temperature: 0 °C
Yield: 74.9 %

Procedure:
A mixture of 3.87 g (30 mmol) of 5-oxo-L-proline, 2.32 ml (30 mmol) of dimethylformamide, 2.19 ml (30 mmol) of thionyl chloride, and 75 ml of dichloromethane is stirred with cooling for 50 minutes. A mixture of 4.08 g (20 mmol) of 7-amino-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 8.4 ml (60 mmol) of triethylamine, 7.6 ml (60 mmol) of chlorotrimethylsilane, and 200 ml of dichloromethane is stirred at room temperature for 50 minutes and then cooled to 0° C. The cold acid chloride solution is added to the cold silylated quinoline and is stirred with cooling for 3 hours and at room temperature overnight. The reaction mixture is evaporated to dryness and the residue is treated with water and ethanol. The solid is filtered to give 4.72 g of 1,4-dihydro-4-oxo-7-[[(5-oxo-2-pyrrolidinyl)carbonyl]amino]-3-quinolinecarboxylic acid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]=[CH:11][C:10]=2[CH:14]=1)[CH3:2].C([Li])CCC.C([O:23][B:24](OC(C)C)[O:25]C(C)C)(C)C>C1COCC1>[CH2:1]([O:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([B:24]([OH:25])[OH:23])=[CH:11][C:10]=2[CH:14]=1)[CH3:2]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCOCOc1ccc2occc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOCOc1ccc2oc(B(O)O)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
To a stirred solution of 5-ethoxymethoxy-benzofuran (3) (265 mg, 1.38 mmol) in THF (5 mL) at −78° C., n-butyllithium (2.5M solution in hexane, 0.56 mL, 1.44 mmol) was added drop wise. After the reaction mixture was stirred for 1 hour, triisopropylborate (0.635 mL, 2.76 mmol) was added slowly and the stirring was continued for additional 20 minutes at −78° C. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and was allowed to warm to room temperature. Water (10 mL) was added and the resulting mixture was extracted in diethyl ether (2×50 mL). The combined extracts were washed with brine, dried over MgSO4, and concentrated under reduced pressure. Purification of the crude product by recrystallization from ethyl acetate and hexane afforded the desired compound (4) (170 mg) as a white solid.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[S:5][C:6](/[CH:18]=[CH:19]/[C:20](=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[N:8]=1.Cl>O.C(O)(C)C>[CH3:3][C:4]1[S:5][C:6](/[CH:18]=[CH:19]/[CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[N:8]=1
Reactant: CCCCCC(=O)/C=C/c1sc(C)nc1CCCCCCC(=O)O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CCCCCC(O)/C=C/c1sc(C)nc1CCCCCCC(=O)O
Reaction time: 8 h
Yield: 69.4 %

Procedure:
The solution of 76 mg of sodium borohydride in 6 ml of water was added to the solution of 351 mg of 2-methyl-4-(6-carboxyhexyl)-5-(3-keto-1-trans-octenyl)-thiazole (Ib, R1 = CH3) in 4 ml of isopropanol. The reaction mixture was allowed to stand overnight at room temperature, then diluted with 50 ml of water, acidified with 1 N hydrochloric acid and extracted with 3 × 25 ml of ethyl acetate. The ethyl acetate extract was dried over sodium sulphate and evaporated in vacuo. The obtained 317 mg of evaporation residue was purified by preparative thin layer chromatography in the way specified in Example 6. Thus, 245 mg of 2-methyl-4-(6-carboxyhexyl)-5-(3-hydroxy-1-trans-octenyl)-thiazole (Id, R1 = CH3) were obtained. IR spectrum (film): ν OH 3500-2300, ν CH 3000-2860, ν C=O 1710, ν C=C 1640 cm -1.
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]([NH:20][C:21]3[N:26]=[C:25]([CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH2:35][C:36]([O-])=[O:37])[C:24]([C:39]([F:42])([F:41])[F:40])=[CH:23][N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].O[N:45]1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.C(N(CC)C(C)C)(C)C.C(=O)([O-])[O-].[NH4+].[NH4+]>C1COCC1.CN(C=O)C>[NH2:45][C:36](=[O:37])[CH2:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][CH2:27][C:25]1[C:24]([C:39]([F:40])([F:42])[F:41])=[CH:23][N:22]=[C:21]([NH:20][C:17]2[CH:16]=[CH:15][C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]3)=[CH:19][CH:18]=2)[N:26]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(=O)[O-])n3)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
Lithium 2-(2-(2-(2-((4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (I7) (0.195 g, 0.333 mmol) was dissolved in dry THF (10 mL) and dry DMF (2 mL) under an atmosphere of nitrogen. To the solution were added 1-hydroxybenzotriazole (0.049 g, 0.37 mmol) and EDCI (0.070 g, 0.37 mmol) and N,N-diisopropylethylamine (0.232 mL, 1.33 mmol) and the reaction mixture was stirred at room temperature for 10 minutes. Ammonium carbonate (0.128 g, 1.332 mmol) was added in one portion, and the reaction was stirred room temperature for 20 hours. The volatiles were removed in vacuo and the residual solution was diluted with EtOAc (70 mL) and sat. aq. NaHCO3 (70 mL). The layers were separated and the organic layer was washed with water (70 mL), brine (70 mL), dried (MgSO4), filtered and concentrated in vacuo to give the crude product which was purified by silica gel chromatography (Biotage Isolera, 12 g Si Cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-10% methanol in EtOAc) to give the title compound (I8) (0.133 g, 68% yield) as a pale yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.01 (s, 1H), 8.61 (s, 1H), 7.65-7.56 (m, 2H), 7.44 (s, 1H), 7.26-7.13 (m, 4H), 6.98-6.89 (m, 3H), 3.52-3.41 (m, 6H), 3.13-2.95 (m, 8H), 1.42 (s, 9H). LCMS Method C: rt 6.18 min; m/z 585.3 [M+H]+.