Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)CCl.Cl.[O:6]=[C:7]1[NH:16][C:15]2[N:14]=[CH:13][C:12](/[CH:17]=[CH:18]/[C:19]([OH:21])=O)=[CH:11][C:10]=2[CH2:9][CH2:8]1.[CH3:22][NH:23][CH2:24][C:25]1[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[N:27]2[CH2:34][CH2:35][CH2:36][C:26]=12.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C.O>[CH2:36]1[C:26]2=[C:25]([CH2:24][N:23]([CH3:22])[C:19](=[O:21])/[CH:18]=[CH:17]/[C:12]3[CH:13]=[N:14][C:15]4[NH:16][C:7](=[O:6])[CH2:8][CH2:9][C:10]=4[CH:11]=3)[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:27]2[CH2:34][CH2:35]1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CNCc1c2n(c3ccccc13)CCC2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCCl
Product: CN(Cc1c2n(c3ccccc13)CCC2)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reaction time: 8 h
Yield: 25 %

Procedure:
EDC (0.192 g, 1.0 mmole) was added to a solution of (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride salt (0.254 g, 1.0 mmole), 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[α]indene (0.2 g, 1.0 mmole), HOBt.H2O (0.135 g, 1.0 mmole), and Et3N (0.15 mL, 1.1 mmole) in DMF (20 mL) at RT. The reaction was stirred overnight, then was poured into H2O (50 mL) and extracted with CH2Cl2 (2×30 mL). The combined extracts were washed with brine and dried (MgSO4). Flash chromatography on silica gel (5% MeOH/CH2Cl2) gave the title compound (0.1 g, 25%) a yellow solid: MS (ES) m/e 401 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].C1(O)CCCCC1>O.C1(C)C=CC=CC=1>[C:8]([N:5]1[CH2:4][CH2:3][CH:2]([NH:1][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[N+:21]([O-:23])=[O:22])[CH2:7][CH2:6]1)([O:10][CH2:11][CH3:12])=[O:9]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: CCOC(=O)N1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: OC1CCCCC1
Product: CCOC(=O)N1CCC(Nc2ccc(Cl)cc2[N+](=O)[O-])CC1
Temperature: 150 °C
Reaction time: 40 h

Procedure:
A mixture of 0.25 mole of ethyl 4-amino-1-piperidinecarboxylate, 0.3 mole of 1,4-dichloro-2-nitrobenzene, 0.3 mole of sodium carbonate, 0.2 g of potassium iodide and 160 ml of cyclohexanol was stirred at 150° C. for 40 hours. After the mixture had been cooled, toluene and water were added and the organic layer was separated off, washed three times with water, dried and evaporated. The oily residue was dissolved in hot diisopropyl ether and the solution was stirred under reflux with active charcoal, filtered and left to crystallize. Melting point: 116° C.
Reaction SMILES: [N:1]1([NH:7][C:8](=[O:31])[CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]([C:21](=[O:29])[C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[C:11]=2[CH3:30])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:32]1(=O)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH:32]1([N:4]2[CH2:5][CH2:6][N:1]([NH:7][C:8](=[O:31])[CH2:9][C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=4)[N:12]([C:21](=[O:29])[C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)[C:11]=3[CH3:30])[CH2:2][CH2:3]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: COc1ccc2c(c1)c(CC(=O)NN1CCNCC1)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc2c(c1)c(CC(=O)NN1CCN(C3CCCCC3)CC1)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 0.112 g (0.26 mmol) of N-(piperazin-1-yl)-1-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetamide and 0.03 mL (0.25 mmol) of cyclohexanone in 2 mL of anhydrous tetrahydrofuran was added 0.02 mL (0.32 mmol) of acetic acid then 0.078 g (0.37 mmol) of sodium triacetoxyborohydride. The reaction was stirred at room temperature for 20 hr then partitioned between ethyl acetate (20 mL) and saturated sodium bicarbonate (20 mL). The organic phase was washed with more bicarbonate (2×20 mL) then dried (MgSO4), filtered and evaporated. Preparative HPLC was used to isolate the title compound.
Reaction SMILES: [C:1]([N:11](C)[C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:20]([C:24]1[CH:25]=[C:26]([CH2:31][CH:32]([NH2:38])[C:33]2[O:34][CH:35]=[N:36][N:37]=2)[CH:27]=[CH:28][C:29]=1[OH:30])([CH3:23])([CH3:22])[CH3:21].O>C1COCC1>[C:20]([C:24]1[CH:25]=[C:26]([CH2:31][CH:32]([NH:38][C:16](=[O:18])[CH:12]([NH:11][C:1]([O:3][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2])[CH:13]([CH3:14])[CH3:15])[C:33]2[O:34][CH:35]=[N:36][N:37]=2)[CH:27]=[CH:28][C:29]=1[OH:30])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1cc(CC(N)c2nnco2)ccc1O
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)c1nnco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
To a solution of Z-N-Me-Val-OH (914 mg, 3.45 mmol), 2-(3-t-butyl-4-hydroxyphenyl)-1-(1,3,4-oxadiazol-2-yl)ethylamine (0.75 g, 2.87 mmol) and CMPI (881 mg, 3.45 mmol) in THF (30 ml), TEA (0.96 ml) was added under cooling with ice and stirred at room temperature for 2 hours. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:1), giving 2-benzyloxycarbonylamino-3-methylbutyric acid 2-(3-t-butyl-4-hydroxyphenyl)-1-(1,3,4-oxadiazol-2-yl)ethylamide (1.28 g, 88%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7]4=[C:8]([C:17](=[O:20])[NH:18][N:19]=[C:6]4[C:5]=2[CH:4]=1)[CH:9]=[CH:10][CH:11]=3.C(N(CC)CC)C.C([N:45]1[CH2:52][CH2:51][CH2:50][C@H:46]1[C:47](Cl)=[O:48])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.O>CN(C=O)C.N1CCCCC1>[O:20]=[C:17]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[O:13][C:14]4[CH:15]=[CH:16][C:3]([CH2:2][NH:1][C:47]([CH:46]5[CH2:50][CH2:51][CH2:52][NH:45]5)=[O:48])=[CH:4][C:5]=4[C:6]([C:7]=23)=[N:19][NH:18]1
Reactant: O=C(Cl)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: NCc1ccc2c(c1)-c1n[nH]c(=O)c3cccc(c13)O2
Solvent: C1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc2c(c1)-c1n[nH]c(=O)c3cccc(c13)O2)C1CCCN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
To a solution of compound 49 (0.5 mmol) in DMF was added triethylamine (0.6 mmol) and Fmoc-L-Proline chloride (0.6 mmol) slowly. The reaction mixture was stirred at room temperature for 3 hours. Water was poured into the reaction mixture. A white precipitate was formed and collected through filtration. The white solid was recrystallized to afford a white solid in 65% yield. The white solid was dissolved in 20% piperidine in DMF. The solution was stirred at room temperature for 2 hours. Water was added to the solution. Aqueous layer was extracted with ethyl acetate. Organic layer was collected, washed with brine, and dried. Solvent was removed to afford a white solid 53 in 54% yield. MS (ES+): 363; 1H-NMR (DMSO-d6, 400 MHz): 12.64 (s, 1H), 8.59 (t, J=5.8 Hz, 1H), 7.98 (d, J=2.0 Hz, 1H), 7.90-7.82 (m, 2H), 7.72 (dd, J=7.5 and 2.0 Hz, 1H), 7.43 (dd, J=8.5 and 2.0 Hz, 1H), 7.36 (d, J=8.5 Hz, 1H), 4.35 (d, J=3.8 Hz, 2H), 3.62 (m, 1H), 2.98 (t, J=5.2 Hz, 1H), 2.87 (m, 1H), 1.99 (m, 1H), 1.73 (m, 1H), 1.64 (m, 2H); Anal. Calcd. for C20H18N4O3.(1.2H2O): C, 62.56; H, 5.35; N, 14.59. Found: C, 62.75; H, 5.34; N, 14.52.
Reaction SMILES: C([C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)NC1CC[CH:9]([N:17]3C(=O)C4=CC=CC=C4C3=O)[CH2:8][C:7]2=1)(O)=O.[N+](C1C=CC(C=CCN)=CC=1)([O-])=O>>[C:6]1([CH2:7][CH2:8][CH2:9][NH2:17])[CH:14]=[CH:15][CH:16]=[CH:4][CH:5]=1
Reactant: O=C(O)c1ccc2[nH]c3c(c2c1)CC(N1C(=O)c2ccccc2C1=O)CC3
Agent: NCC=Cc1ccc([N+](=O)[O-])cc1
Product: NCCCc1ccccc1

Procedure:
Using 6-carboxy-3-phthalimido-1,2,3,4-tetrahydrocarbazole (0.60 g) and 3-(4-nitrophenyl)prop-2-enyl amine (0.32 g) (N. J. Malek and A. E. Moorman J. Org. Chem. 1982, 47, 5395) instead of 3-phenylpropylamine in the method of Example 1(b) gave, after recrystallisation from methanol/diethyl ether, the title compound (0.045 g) m.p. 139°-141° C. M/Z: C22H22N4O3 =391 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[S:6].Cl[CH:12]([CH3:16])[C:13](=O)[CH3:14]>CCO.CCOC(C)=O>[CH3:16][C:12]1[N:7]=[C:5]([C:4]2[CH:3]=[C:2]([NH2:1])[CH:10]=[CH:9][CH:8]=2)[S:6][C:13]=1[CH3:14]
Reactant: NC(=S)c1cccc(N)c1
Reactant: CC(=O)C(C)Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1nc(-c2cccc(N)c2)sc1C
Temperature: 100 °C

Procedure:
To a solution of 3-amino-thiobenzamide (200 mg, 1.31 mmol, 1 eq.) in EtOH (4 mL) is added 3-chloro-2-butanone (140 mg, 1.31 mmol, 1 eq.). The mixture is heated at 100° C. for 72 h. After cooling to room temperature, the reaction is diluted with EtOAc and sequentially washed with saturated aqueous NaHCO3, H2O and saturated aqueous NaCl. The organic solution is dried over Na2SO4. After concentration, the residue is purified by silica gel chromatography (2:1 hexanes/EtOAc) to give 3-(4,5-Dimethyl-thiazol-2-yl)-phenylamine as a yellow oil. [MS: (ES+) 205.1 (M+1)+].
Reaction SMILES: C(O)(=O)C.[C:5]([O:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([F:53])=[C:14]([CH:20]([NH:43][C:44]2[CH:49]=[CH:48][C:47]([C:50](=[NH:52])[NH2:51])=[CH:46][CH:45]=2)[C:21]2[N:22]=[C:23]([O:32][CH2:33][O:34][C:35](=[O:42])[C:36]([CH3:41])([CH3:40])[CH2:37][O:38][CH3:39])[N:24]([C:26]3[N:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[N:25]=2)[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1)(=[O:7])[CH3:6].C(N(CC)CC)C.[N+](C1C=CC([O:70][C:71](=O)[O:72][CH2:73][C:74]([CH3:76])=[CH2:75])=CC=1)([O-])=O.CN(C=O)C>O.C(OCC)(=O)C>[C:5]([O:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([F:53])=[C:14]([CH:20]([NH:43][C:44]2[CH:49]=[CH:48][C:47]([C:50]([NH2:51])=[N:52][C:71]([O:72][CH2:73][C:74]([CH3:76])=[CH2:75])=[O:70])=[CH:46][CH:45]=2)[C:21]2[N:22]=[C:23]([O:32][CH2:33][O:34][C:35](=[O:42])[C:36]([CH3:41])([CH3:40])[CH2:37][O:38][CH3:39])[N:24]([C:26]3[N:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[N:25]=2)[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1)(=[O:7])[CH3:6]
Reactant: COCC(C)(C)C(=O)OCOc1nc(C(Nc2ccc(C(=N)N)cc2)c2cc(OC)cc(OCCOC(C)=O)c2F)nn1-c1ncccn1
Reactant: C=C(C)COC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(C)COC(=O)N=C(N)c1ccc(NC(c2nc(OCOC(=O)C(C)(C)COC)n(-c3ncccn3)n2)c2cc(OC)cc(OCCOC(C)=O)c2F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 95.1 %

Procedure:
A mixture of 3-methoxy-2,2-dimethylpropionic acid 5-[[3-(2-acetoxyethoxy)-2-fluoro-5-methoxyphenyl]-(4-carbamimidoylphen ylamino)methyl]-2-pyrimidin-2-yl-2H-[1,2,4]triazol-3-yloxymethyl ester acetate (13 mg), triethylamine (0.0074 mL), carbonic acid 2-methylallyl ester 4-nitrophenyl ester (5.6 mg), and DMF (2 mL) was stirred for 3 days at room temperature. The resulting mixture was poured into ethyl acetate (100 mL) and water (30 mL). After shaking the mixture, the organic layer was collected, sequentially washed twice with water (30 mL) and with saturated aqueous sodium chloride solution (30 mL), and dried over anhydrous magnesium sulfate. The resulting mixture was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by NAM silica gel column chromatography (mixed solvent of methanol-ethyl acetate) to obtain the captioned compound (13 mg).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[O:6][CH:7]=1.ClC1C=C(C(OO)=[O:29])C=CC=1>ClCCl>[Cl:1][CH2:2][C:3]1[N:4]=[C:5]([CH:8]=[CH:9][C:10]2[CH:11]=[CH:12][C:13]([S:16]([C:17]([F:20])([F:19])[F:18])=[O:29])=[CH:14][CH:15]=2)[O:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)(F)Sc1ccc(C=Cc2nc(CCl)co2)cc1
Solvent: ClCCl
Product: O=S(c1ccc(C=Cc2nc(CCl)co2)cc1)C(F)(F)F
Temperature: 25 °C
Yield: 31.3 %

Procedure:
A mixture of 17.6 g (55 mmol) 4-chloromethyl-2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-oxazole and 14.93 g (60 mmol) 3-chloro-benzenecarboperoxoic acid in 200 ml dichloromethane was stirred at room temperature over night. After filtration, the filtrate was washed three times with sodium hydroxide solution, then with water, dried over sodium sulfate, filtered and evaporated. Purification on silica, after elution with heptane/ethyl acetate 5:1, yielded 5.78 g (31%) 4-chloromethyl-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazole as off-white solid melting at 102-104° C.
Reaction SMILES: C([Li])CCC.[Br-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[CH2:12][PH3+].[CH2:21]([O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[C:27]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[C:26]=1[O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[CH:22]=[CH2:23].O>C1COCC1>[Si:34]([O:33][C:27]1[C:28](/[CH:29]=[CH:12]\[C:11]2[CH:10]=[C:9]([O:8][CH3:7])[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:31][CH:32]=[C:25]([O:24][CH2:21][CH:22]=[CH2:23])[C:26]=1[O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:43])[CH3:44])([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]
Reactant: C=CCOc1ccc(C=O)c(O[Si](C)(C)C(C)(C)C)c1O[Si](C)(C)C(C)(C)C
Reactant: COc1cc(C[PH3+])cc(OC)c1OC
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C=CCOc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)c(O[Si](C)(C)C(C)(C)C)c1O[Si](C)(C)C(C)(C)C
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 58.9 %

Procedure:
n-Butyllithium (0.37 mL, 0.59 mmol, 1.6 M in hexanes) was added dropwise over 5 min to a solution of 3,4,5-trimethoxybenzylphosphonium bromide (0.27 g, 0.52 mmol) in THF (3 mL) at −10° C. The reaction mixture was stirred at this temperature for 15 min then cooled to −70° C. and a solution of 41 (0.10 g, 0.24 mmol) in THF (3 mL) was added and the reaction mixture was allowed to warm to rt with stirring overnight (16 h). The reaction mixture was cooled to 0° C. and water was added. The reaction mixture was extracted with t-BuOMe (3×) and the organic phase was washed successively with water and brine, dried (Na2SO4) and evaporated to dryness to give crude product (0.3 g). Purification by column chromatography (SiO2 2:98 EtOAc:cyclohexane) gave 42 (83 mg, 60%) as an 85:15 mixture of Z:E isomers.
Reaction SMILES: N1CCNCC1.BrCCOC(=O)[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][CH3:21].[N-]=C=O>CN(C=O)C>[CH2:20]([O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH2:12])[CH3:21]
Reactant: CCOc1ccccc1NC(=O)OCCBr
Agent: C1CNCCN1
Agent: [N-]=C=O
Solvent: CN(C)C=O
Product: CCOc1ccccc1N
Reaction time: 18 h

Procedure:
5 μl of TEA (0.033 mmol, 1.1 eq) is added then 500 μl of piperazine (0.03 mmol, 1 eq) dissolved in DMF to 300 μl of 0.2 M 2-bromoethyl-N-(2-ethoxyphenyl)carbamate (0.06 mmol, 2 eq) dissolved in DMF. After 18 hours at room temperature and evaporation of the solvents, the mixtures are taken up in 1 ml of CH2Cl2 and treated with isocyanate resin (Argonaut, 1.51 mmol/g, 0.09 mmol/g, 0.09 mmol, 3 eq) for 18 hours. Next, the mixtures are purified on cation exchange resins according to the protocol described hereinabove. The desired compounds are then obtained after elimination of the solvents.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]2[S:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>[OH-].[Na+].CO>[C:19]1([CH:18]=[CH:2][C:1]([C:4]2[CH:5]=[CH:6][C:7]([CH:10]=[C:11]3[S:15][C:14](=[O:16])[NH:13][C:12]3=[O:17])=[CH:8][CH:9]=2)=[O:3])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1ccc(C=C2SC(=O)NC2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1NC(=O)C(=Cc2ccc(C(=O)C=Cc3ccccc3)cc2)S1
Reaction time: 72 h
Yield: 29.8 %

Procedure:
A solution of 5-(4-acetylphenylmethylene)thiazolidine-2,4-dione (1.0 g, 4.0 mmol) and benzaldehyde (0.62 ml, 6.1 mmol) in 1N NaOH (14 ml) and methanol (25 ml}was stirred for 1 hour at 0° C. and then at room temperature for 3 days, the precipitate was collected and dissolved in water, and this solution was acidified with 2N HCl and extracted with ethyl acetate (2×30 ml). The combined extracts were washed with brine (30 ml), dried over sodium sulfate and concentrated in vacuo, leaving the free acid form of title product (0.4 g, 29%) as a yellow solid. The latter was converted to sodium salt according to the method of Example 42.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[F:17][CH:18]([F:35])[O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28][CH:27]=2)=[N:24][CH:25]=1>>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([NH:12][C:32](=[O:33])[C:29]4[CH:28]=[CH:27][C:26]([C:23]5[CH:22]=[CH:21][C:20]([O:19][CH:18]([F:35])[F:17])=[CH:25][N:24]=5)=[CH:31][CH:30]=4)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(-c2ccc(OC(F)F)cn2)cc1
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Product: Cc1c(C2CC2)nc2ccc(NC(=O)c3ccc(-c4ccc(OC(F)F)cn4)cc3)cn12

Procedure:
Conducting the operations similar to those of Example 1 using 2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 4-[5-(difluoromethoxy)-2-pyridyl]benzenecarboxylic acid, the title compound was obtained as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][N:16]=2)[CH2:9][CH2:8]1)=[O:5]>[O-2].[Mn+4].[O-2].C(Cl)Cl>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:8][CH2:9][C@H:10]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][N:16]=2)[CH2:11][CH2:12]1)=[O:5]
Reactant: O=C(N[C@H]1CC[C@H](CNc2ccc(CO)cn2)CC1)c1cc(C(F)(F)F)ccc1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ccc(NC[C@H]2CC[C@H](NC(=O)c3cc(C(F)(F)F)ccc3Cl)CC2)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Trans-2-Chloro-N-{-4-[(5-hydroxymethyl-pyridin-2-ylamino)-methyl]-cyclohexyl}-5-trifluoromethyl-benzamide (Example 19.20) (100 mg, 0.23 mmol) is placed in a flask with DCM (10 mL) and manganese (IV) oxide (297 mg, 3.4 mmol). The reaction mixture is stirred at RT for 4 hours and manganese (IV) oxide is removed by filtration. The solvent was removed in vacuo to afford the title compound; NMR (400 MHz, DMSO-d6) δ 9.66 (1H, s), 8.49 (2H, m), 7.77 (5H, m), 6.58 (1H, d), 3.70 (1H, m), 3.23 (2H, m), 1.93 (2H, m), 1.81 (2H, m), 1.53 (1H, m), 1.23 (2H, m), 1.09 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32]([NH2:34])=[O:33]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[NH:31][C:32]([NH2:34])=[O:33])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: NC(=O)Nc1ccccc1Br
Product: NC(=O)Nc1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 1-(2-bromophenyl)urea. MS (ESI): mass calcd. for C17H14FN5O, 323.12; m/z found, 323.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.02 (s, 1H), 7.95 (m, 1H), 7.86 (d, J=8.9, 1H), 7.56 (s, 1H), 7.36-7.19 (m, 4H), 7.08 (m, 1H), 6.73 (s, 2H), 6.01 (s, 2H).
Reaction SMILES: Br[CH2:2][CH:3]1[O:7][CH:6]([CH3:8])[CH:5]([CH3:9])[O:4]1.[CH3:10][C:11]([NH2:15])([CH3:14])[C:12]#[CH:13].[OH-].[Na+]>O>[CH3:10][C:11]([NH:15][CH2:2][CH:3]1[O:7][CH:6]([CH3:8])[CH:5]([CH3:9])[O:4]1)([CH3:14])[C:12]#[CH:13]
Reactant: CC1OC(CBr)OC1C
Reactant: C#CC(C)(C)N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C#CC(C)(C)NCC1OC(C)C(C)O1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
2-Bromomethyl-4,5-dimethyl-1,3-dioxolane (20 grams) and 1,1-dimethylprop-2-ynylamine (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at a temperature of about 100° C. for a period of about 3 hours. After this time sodium hydroxide (10 grams) dissolved in water (100 ml) is added and the resulting mixture is stirred for a period of about 30 minutes. The reaction mixture is then extracted with ether. The ether extract is dried over anhydrous magnesium sulfate, filtered and stripped of solvent to yield the desired product N-(1,1-dimethylprop-2-ynyl)-N-(4,5-dimethyl-1,3-dioxolan-2-ylmethyl)amine.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.[CH3:30][O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][C:33]=1[OH:40].[OH-].[Na+]>C(Cl)Cl.O>[OH:40][C:33]1[CH:34]=[C:35](/[CH:36]=[CH:8]/[C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:29][CH:28]=2)[CH:38]=[CH:39][C:32]=1[O:31][CH3:30]
Reactant: COc1ccc(C=O)cc1O
Reactant: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(/C=C/c2ccc(OC)c(O)c2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 3.3 %

Procedure:
To a stirred mixture of 4-methoxybenzyltriphenylphosphonium chloride (5.51 g, 13mmol) and 4-methoxy-3-hydroxybenzaldehyde (2 g, 13 mmol) in CH2Cl2 was added a cooled aqueous solution of NaOH(62.5 eq) in H2O. The mixture was stirred at room temperature for 48 h. The aqueous layer was then acidified to pH 5 and the precipitated solid was filtered and dried. Purification by silica gel chromatography using hexane/ethyl acetate (1:1) gave the title E-trans product as a colourless solid 0.11 g (3%): 1H NMR (DMSO) δ 9.3 (1H, bs). 7.6 (2H, d), 7.2 (7H, m), 3.5 (6H, s): Mass Spectrum (FAB) 257 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]=2[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[CH2:25]=O>C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH3:25])[CH2:15][CH2:14]3)[C:9]=2[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: C=O
Reactant: Clc1ccc(-c2[nH]nc(N3CCNCC3)c2-c2ccncc2)cc1
Solvent: O=CO
Product: CN1CCN(c2n[nH]c(-c3ccc(Cl)cc3)c2-c2ccncc2)CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
The compound of Example A-170 was also synthesized in the following manner. 1-[5-(4-Chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]piperazine (12.2 g, 36 mmol, prepared as set forth in Example A-169), 88% formic acid (20 mL), and formaldehyde (37% formalin solution; 44 g, 540 mmol) were combined and stirred at 60° C. for 16 hours under a nitrogen atmosphere. Excess solvent was removed on the rotary evaporator and the residue was dissolved in water (150 mL). The pH was adjusted to 8-9 by addition of solid sodium bicarbonate. The resulting precipitate was filtered and air dried. It was then treated with hot methanol (400 mL), filtered and blown down to a volume of 75 mL, cooled and filtered. After drying in a vacuum oven at 80° C. overnight, there was obtained 8.75 g (68%) of 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-methylpiperazine, m. p. 262-264° C. Anal. Calc'd. for C19H20N5Cl: C, 64.49; H, 5.70; N, 19.79. Found: C, 64.04; H, 5.68; N, 19.63.