Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH-].[NH4+:22]>O>[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH4+:22]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]

Procedure:
272 ml. of water, 10 g. of Gelvatol 1-90 polyvinylalcohol and 5 g. of Acrysol WS-32 acrylic polymer were heated until the binders dissolved. 50 g. of stearic acid was then added and melted to form a liquid layer floating on the aqueous solution. 23 ml. of ammonium hyroxide (28% solution), which was the stoichiometric amount to form ammonium stearate, was then added dropwise to the gently stirred liquid. An intractable gel is formed which was transferred to a vigorously-stirred Waring Blendor, and then 20 g. of calcium chloride dissolved in 20 ml. of water slowly added until the mixture became solid. 50 ml. of water was then added with stirring until a creamy paste formed. After drying on a substrate this material gave a pressure-sensitive film with excellent hiding power. The formation of ammonium stearate in situ is the preferred method of preparation because it allows a higher solids content to be obtained and yields smaller particles of calcium stearate. The density of the dry coating was 0.5 g./cc which is equivalent to about 50% void volume.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11])[CH2:7][N:6]1[C:24](=S)[CH2:25][C:26](=O)[CH3:27])=[O:4].[F:30][C:31]([F:41])([F:40])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][NH2:39])=[CH:34][CH:33]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[C:20]([F:23])([F:21])[F:22])(=[O:12])=[O:11])[CH2:7][N:6]1[C:24]1[N:38]([C:35]2[CH:34]=[CH:33][C:32]([C:31]([F:30])([F:40])[F:41])=[CH:37][CH:36]=2)[N:39]=[C:26]([CH3:27])[CH:25]=1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1C(=S)CC(C)=O
Reactant: NNc1ccc(C(F)(F)F)cc1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1c1cc(C)nn1-c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester (example 266 c) was reacted with 4-(trifluoromethyl)phenylhydrazine (CAS Reg. No. 368-90-1) to give the title compound as yellow solid. MS (ESI): m/z=580.3 [M+H]+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([C:12](=[O:14])[CH3:13])=[CH:10][CH:9]=[CH:8][N:7]=1)(=O)C>Cl>[C:12]([C:11]1[C:6]([CH2:5][OH:4])=[N:7][CH:8]=[CH:9][CH:10]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OCc1ncccc1C(C)=O
Agent: Cl
Product: CC(=O)c1cccnc1CO
Temperature: 100 °C
Yield: 100.5 %

Procedure:
A mixture of 2-acetoxymethyl-3-acetylpyridine (1.03 g) and 6N aqueous hydrochloric acid (30 ml) was heated for 3 hours at ca. 100° C. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was taken up with saturated sodium carbonate aqueous solution and extracted with chloroform. The extract was dried over sodium sulfate, filtered and concentrated in vacuo to give 3-acetyl-2-hydroxymethylpyridine (0.81 g) as a brown oil.
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](I)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[NH:23]1[CH:30]=[CH:29][C:27](=[O:28])[NH:26][C:24]1=[O:25].OC1C=CC=C2C=1N=CC=C2.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[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:23]4[CH:30]=[CH:29][C:27](=[O:28])[NH:26][C:24]4=[O:25])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: O=C(NCc1cn(-c2ccc(I)cc2)nn1)c1ccc(Cl)s1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: O=C(NCc1cn(-c2ccc(-n3ccc(=O)[nH]c3=O)cc2)nn1)c1ccc(Cl)s1
Temperature: 120 °C
Reaction time: 15 h

Procedure:
The mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (100 mg, 0.23 mmol), uracil (100 mg, 0.90 mmol), CuI (23 mg, 0.12 mmol), 8-hydroxyquinoline (18 mg, 0.12 mmol), potassium carbonate (96 mg, 0.69 mmol) in 2 mL DMSO in a sealed tube was stirred for 15 hrs at 120° C. The title compound was isolated directly from the reaction mixture using reverse phase prep HPLC. MS found for C18H13ClN6O3S (M+H)+ 429.1, 431.1 (Cl pattern).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:14][OH:15])[CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C=O)C.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:14][O:15][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(CO)CC(=O)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CO[Si](C)(C)C(C)(C)C)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1 g of DL-3-tert-butoxycarbonylamino-4-hydroxy-butyric acid in a mixture of DMF/DCM 1:5, 1.24 g of imidazole and 1.7 g of tert-butyldimethylsilyl chloride were added. The solution was left stirring at room temperature overnight. The solution was extracted three times with 5% aq. NaHSO4 and the aqueous phases were washed twice with DCM. The organic extracts were dried over anh. sodium sulfate and the solvent evaporated under vacuum to provide 2.1 g of the title compound.
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=2)[CH:4]=1.[NH2:29][C:30]1[CH:31]=[C:32]([S:36]([NH:39][CH2:40][CH3:41])(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>>[CH2:40]([NH:39][S:36]([C:32]1[CH:31]=[C:30]([NH:29][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:28])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:35]=[CH:34][CH:33]=1)(=[O:38])=[O:37])[CH3:41]
Reactant: CCOc1cc(-c2cc(C(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Reactant: CCNS(=O)(=O)c1cccc(N)c1
Product: CCNS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)c(OCC)c4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-ethoxy-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.12) and 3-amino-N-ethyl-benzenesulfonamide [CAS 56445-08-0] according to general procedure II. Yellow solid. MS (ISP) 582.0 [(M−H)−]; mp 222° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:27](I)[CH:28]([CH3:30])[CH3:29]>CN(C=O)C.CCOC(C)=O>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)CI
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)COc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 62.5 %

Procedure:
To a solution of 1-Boc-4-(2-hydroxy-phenyl)-piperazine (560 mg, 2.0 mmol) in 10 mL of DMF was added K2CO3 (835 mg, 6 mmol). After stirring for about 5 minutes, isobutyl iodide (350 uL, 3 mmol) was added. After stirring overnight at 60° C., the solution was warmed to about 80° C. After stirring for about 4 hours, the solution was cooled to r.t. diluted with EtOAc, washed with water and brine, and then dried (Na2SO4), filtered and concentrated. Purification by silica gel chromatography (35 g SiO2, 10 to 30% EtOAc/hexanes, over 45 minutes at 35 mL/min) afforded about 418 mg (1.25 mmol, 62%) of N-Boc-4-(2-isobutoxy-phenyl)-piperazine as a colorless oil. LRMS (ESI+): 335.1 [M+1].
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15](S(C)=O)[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[NH2:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[OH:31].CCN(C(C)C)C(C)C.CN1C(=O)CCC1>CCOC(C)=O>[CH3:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15]([NH:24][C@@H:25]5[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]5[OH:31])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: Cc1ccc2c(c1)ncn2Cc1ccc2nc(S(C)=O)sc2c1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 130 °C
Yield: 26.5 %

Procedure:
A stirred mixture of 6-((5-methyl-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (0.26 g, 0.76 mmol) from the previous step, (1R,2R)-2-aminocyclohexanol (0.26 g, 2.2 mmol), DIEA (0.98 g, 7.6 mmol) and NMP (2 mL) was heated at 130° C. for 12 h. The reaction mixture was cooled to rt, diluted with EtOAc (30 mL), and washed with water (10 mL×2). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 3% MeOH in DCM to afford (1R,2R)-2-((6-((5-methyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (79 mg, 89%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.91 (d, J=7.5 Hz, 1H), 7.61 (d, J=2.0 Hz, 1H), 7.39-7.42 (m, 2H), 7.28 (d, J=8.1 Hz, 1H), 7.16 (dd, J=8.4, 1.8 Hz, 1H), 7.02 (d, J=7.2 Hz, 1H), 5.42 (s, 2H), 4.69 (d, J=5.1 Hz, 1H), 3.39 (m, 1H), 3.33 (m, 1H), 2.38 (s, 3H), 2.03 (m, 1H), 1.86 (m, 1H), 1.59-1.63 (m, 2H), 1.21-1.23 (m, 4H); LCMS (ESI) m/z 393 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([N:17]1[CH:21]=[C:20]([C@@:22]([NH:27][C:28]([C:30]2[CH:34]=[CH:33][S:32][CH:31]=2)=[O:29])([CH:24]([CH3:26])[CH3:25])[CH3:23])[N:19]=[N:18]1)[C:14](O)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.[Cl:42][C:43](OCC(C)C)=O.[N+](=C)=[N-].Cl>C1COCC1.O.C(OCC)(=O)C.C(O)(=O)C>[Cl:42][CH2:43][C:14](=[O:15])[C@@H:13]([N:17]1[CH:21]=[C:20]([C@@:22]([NH:27][C:28]([C:30]2[CH:34]=[CH:33][S:32][CH:31]=2)=[O:29])([CH:24]([CH3:26])[CH3:25])[CH3:23])[N:19]=[N:18]1)[CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)COC(=O)Cl
Reactant: CC(C)[C@](C)(NC(=O)c1ccsc1)c1cn([C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)O)nn1
Agent: C=[N+]=[N-]
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)[C@](C)(NC(=O)c1ccsc1)c1cn([C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)CCl)nn1
Reaction time: 1 h

Procedure:
To a stirred solution of carboxylic acid 9 (50 mg, 100.9 μmol) in 5 ml dry THF under argon atmosphere at −60° C. was added N-methylmorpholine (14 μl, 126.3 μmol, 1.25 equiv.) and isobutyl chloroformate (14.9 μl, 116.7 μmol, 1.15 equiv.). After 30 min an etheral solution of diazomethane (0.95 ml 0.6 M, 0.57 mmol, 5.6 equiv.) was added to above solution at −60° C. and the reaction mixture was stirred for 1 hr. A 1:1 solution of conc. HCl and glacial acetic acid was added dropwise to the reaction mixture, before ethyl acetate and water were added. The organic layer was washed with brine, sat. aq. NaHCO3 and dried over MgSO4. Concentration in vacuo afforded the crude title compound, which was used without purification. 1H NMR (400 MHz, CDCl3+MeOD) δ ppm 7.89 (dd, J=1.5 Hz, J=3.0 Hz, 1H), 7.71 (s, 1H), 7.39 (dd, J=1.2 Hz, J=5.2 Hz, 1H), 7.36 (dd, J=2.9 Hz, J=5.2 Hz, 1H), 7.06 (s, 1H), 5.59 (dd, J=4.6 Hz, J=10.0 Hz, 1H), 4.80 (s, 1H), 4.17 (s, 2H), 3.06 (m, 2H), 2.83 (m, 2H), 2.30 (m, 1H), 2.11 (m, 1H), 1.88 (s, 3H), 1.48 (m, 2H), 1.42 (s, 9H), 1.34 (m, 1H), 1.22 (m, 1H), 0.99 (d, J=6.8 Hz, 3H), 0.80 (d, J=6.8 Hz, 3H). MS (ESI): m/z calcd for C24H36C1N5O4S+H+ 526.2 [M+H]+. found 526.3.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:23]2[O:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:26][N:27]=2)[C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.[CH2:34]1[C:38]2([CH2:42][CH2:41][NH:40][CH2:39]2)[CH2:37][N:36]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:35]1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:11]([O:10][C:9]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:5]1[N:6]=[CH:7][C:2]([N:40]2[CH2:41][CH2:42][C:38]3([CH2:34][CH2:35][N:36]([C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44])[CH2:37]3)[CH2:39]2)=[N:3][C:4]=1[C:23]1[O:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:26][N:27]=1)=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1nnc(-c2ccccc2)o1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2)C1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c4nnc(-c5ccccc5)o4)n3)C2)C1
Temperature: 90 °C
Yield: 60.3 %

Procedure:
A mixture of tert-butyl N-[5-bromo-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (70 mg, 0.14 mmol), tert-butyl 3,7-diazaspiro[4.4]nonane-3-carboxylate (31 mg, 0.14 mmol) and DIEA (35 mg, 47 μL, 0.27 mmol) in DMF (1 mL) was heated at 90° C. for 2 h. The reaction mixture was allowed to cool to room temperature and diluted with EtOAc. The organic layer was washed with brine (2×), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography using 0-35% EtOAc in hexanes to yield tert-butyl 7-[5-[bis(tert-butoxycarbonyl)amino]-6-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]-3,7-diazaspiro[4.4]nonane-3-carboxylate (56 mg, 62%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.15-8.04 (m, 3H), 7.71-7.60 (m, J=7.5 Hz, 3H), 3.74-3.62 (m, 2H), 3.59-3.53 (m, 2H), 3.39 (s, 2H), 2.89 (s, 1H), 2.73 (s, 1H), 2.10-1.99 (m, 2H), 1.98-1.84 (m, 2H), 1.41 (d, J=7.3 Hz, 9H), 1.29 (s, 18H). LC/MS m/z 664.7 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5](=[O:13])[C:4]2[CH:14]=[C:15]([CH2:18][C:19]([O:21]C)=O)[CH:16]=[CH:17][C:3]1=2.Cl.[NH2:24][OH:25].C[O-].[Na+]>CO>[CH3:1][N:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5](=[O:13])[C:4]2[CH:14]=[C:15]([CH2:18][C:19]([NH:24][OH:25])=[O:21])[CH:16]=[CH:17][C:3]1=2
Reactant: NO
Reactant: COC(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CN2C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1Cc2ccccc2C(=O)c2cc(CC(=O)NO)ccc21
Yield: 53.2 %

Procedure:
Methyl 5,6-dihydro-5-methyl-11-oxodibenz[b,e]azepine-2-acetate (1.5 g) was dissolved in methanol (80 ml), and hydroxylamine hydrochloride (1.0 g) was added to make a homogeneous solution. Then, a 28% solution (6 g) of sodium methylate in methanol was added to the homogeneous solution, and the mixture was heated for 3 hours. Then, the reaction mixture was concentrated, and after addition of water (20 ml) and dry ice (1 g), was extracted with chloroform. The extract was dried over MgSO4, and then, chloroform was distilled off. The residue was stirred with benzene to form crystals. The crystals were recrystallized from benzene-tetrahydrofuran to obtain the desired compound (0.8 g) as yellow prismatic crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][S:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)=[CH:4][CH:3]=1.[CH2:18]([C:25]([C:27]([F:30])([F:29])[F:28])=O)[C:19]([C:21]([F:24])([F:23])[F:22])=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][S:9][C:10]2[N:14]=[C:13]3[N:15]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[C:25]([C:27]([F:28])([F:30])[F:29])[N:12]3[N:11]=2)=[CH:16][CH:17]=1
Reactant: Nc1nc(SCCOc2ccc(Cl)cc2)n[nH]1
Reactant: O=C(CC(=O)C(F)(F)F)C(F)(F)F
Product: FC(F)(F)c1cc(C(F)(F)F)n2nc(SCCOc3ccc(Cl)cc3)nc2n1
Yield: 32 %

Procedure:
The title compound was prepared according to the experimentals described for Example 23 above from 3-{[2-(4-chlorophenoxy)ethyl]sulfanyl}-1H-1,2,4-triazol-5-amine and hexafluoroacetylacetone in 32% yield; EM (calc.): 442.0; MS (ESI) m/e: 443.0 (M+H)+. 1H NMR (DMSO-d6, 400 MHz) δ ppm: 8.40 (s, 1H), 7.32 (d, 2H), 7.01 (d, 2H), 4.36 (t, 2H), 3.71 (t, 2H). 19F NMR (DMSO-d6, 376 MHz) δ ppm: −66.84 (s), −67.45 (s).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[CH2:6]2.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]=[C:29]=[O:30])[C:23]=1[CH3:31].Cl>C(#N)C>[Cl:21][C:22]1[C:23]([CH3:31])=[C:24]([NH:28][C:29]([NH:1][CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[N:7]([CH:13]2[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]2=[O:20])[CH2:6]3)=[O:30])[CH:25]=[CH:26][CH:27]=1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1c(Cl)cccc1N=C=O
Agent: Cl
Solvent: CC#N
Product: Cc1c(Cl)cccc1NC(=O)NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
TEA (0.28 ml, 2 mmol) was added to a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (0.37 g, 1 mmol) and 1-chloro-3-isocyanato-2-methyl-benzene (0.13 ml, 1 mmol) in acetonitrile (10 mL) under nitrogen. The mixture was stirred at ambient temperature for 1 h, during which time it remained a suspension. The reaction was then monitored and determined to be complete. A 3.5% aqueous HCl solution (10 mL) was added, and the mixture stirred for 10 minutes. The solid was isolated by filtration, and the solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL), yielding 1-(3-chloro-2-methyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (400 mg, 91%). HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4 in H2O: tR=3.23 min (97%); mp. 252-254° C. 1H NMR (DMSO-d6) δ 1.93-2.08 (m, 5H, CHH), 2.25 (s, 3H, CH3), 2.33-2.47 (m, 1H, CHH), 2.61-2.64 (m, 1H, CHH), 2.82-3.01 (m, 1H, CHH), 4.25-4.55 (m, 4H, CH2+CH2), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NC h, 6.98-7.20 (m, 3H, Ar), 7.46 (d, J=7.9 Hz, 1H, Ar), 7.53 (s, 1H, NH), 7.67-7.83 (m, 2H, Ar), 8.02 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.62, 22.49, 31.20, 42.90, 47.12, 51.58, 120.32, 121.96, 123.01, 125.74, 126.78, 126.95, 130.35, 133.39, 139.61, 142.42, 144.61, 155.31, 167.93, 170.99, 172.86. LCMS MH=441. Anal Calcd for: C22H21ClN4O3+0.05HCl: C, 59.69; H, 4.79; N, 12.66; Cl, 8.41. found: C, 59.44; H, 4.57; N, 12.51; Cl, 8.43.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:36]=[CH:35][C:14]([C:15]([N:17]([CH3:34])[C@:18]([CH3:33])([C:23]([NH:25][O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)=[O:24])[C:19]([NH:21][CH3:22])=[O:20])=[O:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)=O.[CH2:37]1[CH2:43][O:42][CH2:41][CH2:40][NH:39][CH2:38]1.Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(OCC)(=O)C.O.C(Cl)(Cl)Cl.C(O)(=O)C>[CH3:22][NH:21][C:19](=[O:20])[C@:18]([CH3:33])([N:17]([CH3:34])[C:15](=[O:16])[C:14]1[CH:35]=[CH:36][C:11]([C:10]#[C:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:1][N:39]3[CH2:38][CH2:37][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:4][CH:5]=2)=[CH:12][CH:13]=1)[C:23]([NH:25][O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)=[O:24]
Reactant: C1CNCCOC1
Reactant: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(C#Cc2ccc(C=O)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(C#Cc2ccc(CN3CCCOCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 69.1 %

Procedure:
TEA (1.6 mL) and acetic acid (0.8 mL) were added to a chloroform (13 mL) solution of (2S)-2-[{4-[(4-formylphenyl)ethynyl]benzoyl}(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (3.7 g) as obtained in Example 16-(1) and homomorpholine hydrochloride (1.6 g). Under ice cooling, sodium triacetoxyborohydride (2.6 g) was added in divided portions in a nitrogen atmosphere, and the mixture was stirred for 3.5 hours at room temperature. Water and ethyl acetate were added, the mixture was adjusted to pH 7.5 with a 1 mol/L sodium hydroxide aqueous solution, and then the organic layer was isolated. The extract was washed with brine, and dried over anhydrous sodium sulfate. Then, the desiccant was filtered out, and the solvent was distilled off under reduced pressure. The resulting residue was purified by OH type silica gel column chromatography (gradient elution with chloroform/acetone=100/0→60/40, followed by chloroform/methanol=90/10) to obtain (2S)-N,2-dimethyl-2-[methyl(4-{[4-(1,4-oxazepan-4-ylmethyl)phenyl]ethynyl}benzoyl)amino]-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (light yellow solid) (3.0 g, 69%).
Reaction SMILES: C(OCCO)C.Br[C:8]1[N:13]([C:14]2C=CC(C)=C[CH:15]=2)[C:12](=[O:21])[CH:11]=[C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:9]=1.C(N)C[NH2:30]>>[O:21]=[C:12]1[N:13]2[CH2:14][CH2:15][NH:30][C:8]2=[CH:9][C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:11]1
Reactant: Cc1ccc(-n2c(Br)cc(-c3ccccc3)cc2=O)cc1
Reactant: NCCN
Solvent: CCOCCO
Product: O=c1cc(-c2ccccc2)cc2n1CCN2

Procedure:
In 3 ml. of 2-ethoxyethanol were refluxed 1.05 g. of 6-bromo-1-(4-methylphenyl)-4-phenyl-2-pyridone and 0.4 g. of ethylenediamine for 5 hours. Then, by treating the reaction mixture as in Example 5, 0.35 g. of 5-oxo-7-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyridine was obtained.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[CH3:12][C:13]1[CH:34]=[CH:33][CH:32]=[CH:31][C:14]=1[C:15]([O:17][CH:18]([O:20][C:21](ON1C(=O)CCC1=O)=[O:22])[CH3:19])=[O:16]>CC(OC)(C)C.CC(C)=O.O>[CH3:12][C:13]1[CH:34]=[CH:33][CH:32]=[CH:31][C:14]=1[C:15]([O:17][CH:18]([O:20][C:21]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:22])[CH3:19])=[O:16]
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: Cc1ccccc1C(=O)OC(C)OC(=O)ON1C(=O)CCC1=O
Solvent: CC(C)=O
Solvent: COC(C)(C)C
Solvent: O
Product: Cc1ccccc1C(=O)OC(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (780 mg, 5.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]ethyl 2-methylbenzoate (700 mg, 2.2 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 25 (290 mg, 36% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.88-0.97 (m, 2H), 1.22-1.38 (br. m, 3H), 1.57 (d, J=5.6 Hz, 3H), 1.72-1.76 (m, 2H), 1.89-1.92 (m, 2H), 2.13 (tt, J=12, 3.6 Hz, 1H), 2.50 (s, 3H), 2.87 (t, J=2.8 Hz, 2H), 6.89 (q, J=5.6 Hz, 1H), 7.32-7.37 (m, 2H), 7.50-7.59 (m, 2H), 7.77 (dd, J=7.2, 1.2 Hz, 1H), 12.00 (s, 1H). MS (ESI) m/z 386.12 (M+Na)+; 362.07 (M−H)−.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[CH3:34][NH2:35]>C1COCC1>[F:29][C:28]([F:30])([F:31])[C:27]([C:24]1[CH:25]=[CH:26][C:21]([N:8]2[CH2:9][CH2:10][N:11]([S:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:15])[CH2:12][C@@H:7]2[CH2:6][NH:35][CH3:34])=[CH:22][CH:23]=1)([OH:33])[CH3:32]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Reactant: CN
Solvent: C1CCOC1
Product: CNC[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1

Procedure:
This compound was synthesized following the procedure outlined for Example 84 The reaction of ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (Intermediate B) and methanamine (10 equivalents of a 1.0M solution in THF, Sigma-Aldrich, St. Louis, Mo.) followed by purification via column chromatography on silica gel (0 to 10% MeOH in CH2Cl2) delivered 1,1,1-trifluoro-2-(4-((2S)-2-((methylamino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol as a mixture of two isomers after column chromatography on silica gel (0-10% MeOH in CH2Cl2)