Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[C:37]([CH3:38])=[C:11]2[C:12](=[O:36])[N:13]([CH2:24][CH:25]([F:35])[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:14]3[CH:15]=[C:16]4[CH2:23][CH2:22][CH2:21][CH2:20][C:17]4=[CH:18][C:19]=3[C:10]2=[N:9]1)C1C=CC=CC=1>[Pd].CN(C=O)C.CO>[F:35][CH:25]([CH2:24][N:13]1[C:14]2[CH:15]=[C:16]3[CH2:23][CH2:22][CH2:21][CH2:20][C:17]3=[CH:18][C:19]=2[C:10]2=[N:9][NH:8][C:37]([CH3:38])=[C:11]2[C:12]1=[O:36])[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32]
Reactant: Cc1c2c(=O)n(CC(F)CNC(=O)OC(C)(C)C)c3cc4c(cc3c2nn1Cc1ccccc1)CCCC4
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1[nH]nc2c1c(=O)n(CC(F)CNC(=O)OC(C)(C)C)c1cc3c(cc21)CCCC3
Temperature: 23 °C
Reaction time: 72 h

Procedure:
A mixture of tert-butyl 3-(2-benzyl-3-methyl-4-oxo-2,4,7,8,9,10-hexahydro-5H-benzo[g]pyrazolo[4,3-c]quinolin-5-yl)-2-fluoropropylcarbamate (1-10) (0.10 g, 0.19 mmol, 1 equiv) and 10% palladium on carbon (300 mg) in DMF (10 mL) and methanol (10 mL) was stirred under a hydrogen balloon at 23° C. for 72 h. The resulting suspension was filtered and the filtrate was concentrated to yield tert-butyl 2-fluoro-3-(3-methyl-4-oxo-2,4,7,8,9,10-hexahydro-5H-benzo[g]pyrazolo[4,3-c]quinolin-5-yl)propylcarbamate (1-11). LRMS m/z (M+H) 429.2 found, 429.2 required.
Reaction SMILES: [CH3:1][C:2]1[C:11]2([CH2:13][CH2:12]2)[C@:10]([OH:15])([CH3:14])[C:8](=[O:9])[C:7]2[C:3]=1[C@@H:4]([OH:18])[C:5]([CH3:17])([CH3:16])[CH:6]=2.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl.C(OCC)C>[CH3:1][C:2]1[C:11]2([CH2:12][CH2:13]2)[C@:10]([OH:15])([CH3:14])[C:8](=[O:9])[C:7]2=[CH:6][C:5]([CH3:16])([CH3:17])[C:4](=[O:18])[C:3]=12
Reactant: CC1=C2C(=CC(C)(C)[C@@H]2O)C(=O)[C@](C)(O)C12CC2
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC1=C2C(=O)C(C)(C)C=C2C(=O)[C@](C)(O)C12CC2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of illudin M (200 mg) and pyridinium dichromate (1 g) in dry dichloromethane (60 ml) was stirred at room temperature in a flask equipped with a rubber septum so that an atmosphere of argon could be maintained. After 20 hours, the reaction mixture was diluted with diethyl ether (20 ml) and filtered through a short column of silica gel. The column was further eluted with more diethyl ether and the combined filtrate was concentrated, giving a residue which was chromatographed on silica gel with hexane-ethyl acetate (10:1) as eluent. The desired compound was obtained in early fractions from the chromatography. The yield was 140 mg of white crystals melting at 64°-65° C. NMR spectral data were recorded for this compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([NH:22][C:24]4[C:33]5[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=5)[N:27]=[CH:26][CH:25]=4)=[CH:20][CH:21]=3)[CH2:13][CH2:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: COc1cccc(N2CCN(Cc3ccc(N)cc3)CC2)c1
Product: COc1cccc(N2CCN(Cc3ccc(Nc4ccnc5cc(Cl)ccc45)cc3)CC2)c1

Procedure:
In the manner given in Example 1C, 1-(m-methoxyphenyl)-4-[(4-aminophenyl)methyl]piperazine and 4,7-dichloroquinoline are reacted together at reflux to give 4-[[4-[[4-(m-methoxyphenyl)-1-piperazinyl]methyl]phenyl]amino]-7-chloroquinoline.
Reaction SMILES: [CH3:1][N:2]([CH:4]=[N:5][S:6]([C:9]1[C:10]([O:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[C:11]([N+:19]([O-])=O)[CH:12]=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15])(=[O:8])=[O:7])[CH3:3]>CN(C)C=O.[Ni]>[NH2:19][C:11]1[CH:12]=[C:13]([CH:18]=[C:9]([S:6]([N:5]=[CH:4][N:2]([CH3:1])[CH3:3])(=[O:7])=[O:8])[C:10]=1[O:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Oc2cccnc2)c(S(=O)(=O)N=CN(C)C)c1
Agent: [Ni]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N)c(Oc2cccnc2)c(S(=O)(=O)N=CN(C)C)c1

Procedure:
150 g of methyl 5-dimethylaminomethyleneaminosulfonyl-3-nitro-4-(3-pyridyloxy)-benzoate are hydrogenated in dimethylformamide at 50° C. and under 50 atmospheres for 15 hours in an autoclave, using Raney nickel as the catalyst. The reaction mixture is then filtered, the filtrate is concentrated and the residue is recrystallized from dimethylformamide/CH3OH.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38](Cl)=[O:39]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[C:38](=[O:39])[C:37]3[CH:41]=[CH:42][CH:43]=[CH:44][C:36]=3[F:35])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N(Cc3ccc4ccc(C#N)cc4c3)C(=O)c3ccccc3F)cc2)CC1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, 2-fluorobenzoyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[CH2:4][CH2:5][CH2:6][N:7]([C:15](=[O:40])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([O:23][CH2:24][CH2:25][N:26](C(OC(C)(C)C)=O)[C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[CH:17]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14].[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[CH3:1][O:2][C:3](=[O:41])[CH2:4][CH2:5][CH2:6][N:7]([C:15](=[O:40])[C:16]1[CH:17]=[C:18]([O:23][CH2:24][CH2:25][NH:26][C:27]2[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=2)[CH:19]=[C:20]([Cl:22])[CH:21]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14]
Reactant: COC(=O)CCCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)c1ccccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CCCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)c1ccccc1F
Reaction time: 16 h

Procedure:
A solution of 4-[{3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoyl}-(2-fluoro-phenyl)-amino]-butyric acid methyl ester (0.020 g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 16 h and then concentrated under reduced pressure to give the title compound (0.022 g) as a colourless gum.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.[CH2:14]([O:16][C:17](=[O:22])[CH:18]([NH2:21])[C:19]#[N:20])[CH3:15].C(N(CC)CC)C>ClCCl.CN(C=O)C>[CH2:14]([O:16][C:17](=[O:22])[CH:18]([C:19]#[N:20])[NH:21][C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:9])[CH3:15]
Reactant: CCOC(=O)C(N)C#N
Reactant: O=C(O)c1ccccn1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C(C#N)NC(=O)c1ccccn1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A solution of 2-picolinic acid (540 mg, 4.4 mmol) in dichloromethane (5 ml) was treated with thionyl chloride (0.4 ml, 5.5 mmol) and a drop of DMF at ambient temperature. The reaction mixture is stirred at 40° C. overnight whereupon another equivalent of thionyl chloride was added and stirring was continued at 40° C. for another 2 h. All volatiles were removed and the acid chloride was suspended in dichloromethane (5 ml) and added to a pre-cooled (0° C.) solution of amino-cyano-acetic acid ethyl ester (470 mg, 3.7 mmol) and triethylamine (2.5 ml, 18.3 mmol) in dichloromethane (5 ml). The resulting reaction mixture was slowly warmed-up to 40° C. and stirred at that temperature for 4 h. The reaction mixture was partitioned between potassium hydrogen sulfate (10% aqueous solution) and dichloromethane and extracted. The organic phase was washed with water and brine, dried and the solvent was evaporated. The product was obtained after purification by silica gel chromatography using a heptane/ethyl acetate gradient as light yellow viscous oil (334 mg, 39%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.[CH3:13][NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:14]([CH3:13])[C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:17][CH:16]=2)[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1
Reactant: CNc1ccc(OC(F)(F)F)cc1
Reactant: FC(F)(F)c1cc(Cl)nc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(c1ccc(OC(F)(F)F)cc1)c1cc(C(F)(F)F)nc(Cl)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.6 %

Procedure:
2,4-Dichloro-6-trifluoromethylpyrimidine (XXVII) (1.00 g, 4.6 mmol) was dissolved in dry THF (5 mL). To this solution was added N-methyl-4-trifluoromethoxyaniline (0.88 g, 4.6 mmol) and diisopropylethylamine (0.8 mL, 4.6 mmol). The resulting solution was stirred at room temperature for 18 hrs, then the volatiles were removed in vacuo and the residue was dissolved in CH2Cl2 (50 mL). The CH2Cl2 solution was washed with 2N HCl, dried over MgSO4, filtered and then concentrated in vacuo to give a brown color oil. Purification of the brown oil by chromatography (silica, hexane/EtOAc) afforded the product (XXVIII) as a yellow solid (0.95 g, 56%): 1H NMR (CDCl3) δ 7.42-7.27 (m, 4H), 6.4 (s, 1H), 3.5 (s, 3H); GC/MS m/z (relative intensity) 374 (26), 373 (45), 372 (76), 370 (100).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH3:11])[CH:10]=2)[CH:7]=1.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)#[CH:13]>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]#[C:13][C:2]2[CH:3]=[N:4][C:5]3[N:6]([N:8]=[C:9]([CH3:11])[CH:10]=3)[CH:7]=2)=[CH:15][CH:16]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: Cc1cc2ncc(Br)cn2n1
Product: Cc1cc2ncc(C#Cc3ccc(F)cc3)cn2n1

Procedure:
The title compound, light yellow solid, MS: m/e=252.1 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-methylpyrazolo[1,5-a]pyrimidine and 1-ethynyl-4-fluoro-benzene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14](Cl)[N:13]=[CH:12][C:11]=2[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20](B1OC(C)(C)C(C)(C)O1)([CH3:22])=[CH2:21]>>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([C:20]([CH3:22])=[CH2:21])[N:13]=[CH:12][C:11]=2[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(Cl)cc21
Product: C=C(C)c1cc2c(cn1)C(C)(C)CN2C(=O)OC(C)(C)C

Procedure:
Prepared from 6-chloro-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert butyl ester and 2-isopropenyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane using a procedure analogous to that of Preparation 379. MS: [M+H]+=289.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:13]2[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[N:15]([CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[C:14]2=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].C(O)(=O)C(O)=O.CS(O[CH:40]1[CH2:43][N:42]([CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)[CH2:41]1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C>[CH:44]1([N:42]2[CH2:43][CH:40]([NH:1][C:2]3[CH:3]=[C:4]([N:13]4[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[N:15]([CH2:21][C:22]5[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=5)[C:14]4=[O:28])[CH:5]=[CH:6][C:7]=3[O:8][C:9]([F:10])([F:11])[F:12])[CH2:41]2)[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1
Reactant: CS(=O)(=O)OC1CN(C2CCCCC2)C1
Reactant: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)c(N)c2)C(=O)N1Cc1ccncc1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)c(NC3CN(C4CCCCC4)C3)c2)C(=O)N1Cc1ccncc1

Procedure:
300 mg (0.76 mmol) of 3-(3-amino-4-trifluoromethoxyphenyl)5,5-dimethyl-1-pyridin-4-ylmethylimidazolidine-2,4-dione were dissolved in 15 ml of ethyl acetate, admixed with 492 mg (1.52 mmol) of 1-cyclohexylazetidin-3-yl methanesulphonate oxalate and 631 mg (4.56 mmol) of K2CO3, and heated under reflux for 4 h. To complete the reaction, a further 49 mg (0.15 mmol) of 1-cyclohexylazetidin-3-yl methanesulphonate oxalate and 63 mg (0.46 mmol) of K2CO3 were added, and the mixture was stirred under reflux once again for 2 h. Subsequently, the mixture was concentrated and the residue purified by flash chromatography (150 g of silica gel/95:5 CH2C12:CH3OH).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH2:11])[CH:5]=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].O>C(O)(=O)C>[CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(C)c1C(=O)O
Temperature: 25 °C
Yield: 85 %

Procedure:
A suspension of 15.2 g (100 mmoles) of 6-methyl-2-aminobenzoic acid (obtained from the Aldrich Chemical Company, Inc., Milwaukee Wis.) in 150 mL of glacial acetic acid was heated in a water bath to promote homogeneity. Acetic anhydride, 15 mL (159 mmole), was added and the resultant solution kept in the hot water bath for 40 minutes. Upon cooling to near room temperature, the dark solution was poured over crushed ice. When all ice had melted, the pale beige solid which had separated was collected and air-dried. 16.4 g (85% yield) 6-methyl-2-acetylaminobenzoic acid was obtained. NMR(DMSO-d6): 2.00(s,3H), 2.33(s,3H), 7.05(d,1H,J=7.5 Hz), 7.29(t,1H,J=7.8 Hz), 7.41(d,1H,J=7.8 Hz), 9.60(bs,1H). MS(m/z): 193(M+).
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-:19])=O)=[C:10]([C:14]([O-:16])=O)[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH3:23][O:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH2:28].Cl>>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:6][C:7]2=[CH:8][C:9]3[C:17](=[O:19])[N:28]([CH2:27][C:26]4[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=4[O:24][CH3:23])[C:14](=[O:16])[C:10]=3[CH:11]=[C:12]2[CH2:13]1)[CH2:21][CH3:22]
Reactant: COc1ccccc1CN
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1ccccc1OC)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.35 g, 1.0 mmol) was treated with o-methoxybenzylamine (0.18 mL, 1.4 mmol). Purification using silica gel, eluting with 5:1 CH2Cl2 /acetone, afforded an oil that was converted to an HCl salt and recrystallized from hot MeOH/EtOAc to give 103 as a white solid (m.p.205° C.).
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1B(O)O.Br[C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC.COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:1]1([CH3:12])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: Cc1cc(C)c(B(O)O)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCCO
Solvent: O
Product: Cc1cc(C)c(-c2ccc(C(=O)O)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of mesitylboronic acid (10 9) and 4-bromobenzoic acid (12.9 g) in 1-propanol (150 mL) and DME (200 mL) were added triphenylphosphine (0.128 g), 2M sodium carbonate solution (37 mL) and water (30 mL). To the mixture was added palladium acetate (82 mg) under nitrogen atmosphere. The mixture was heated to reflux overnight. After the heat source was removed, 100 mL of water was added and stirred for 2.5 h while cooling to room temperature. The darkened mixture was diluted with 150 mL of ethyl acetate and the two phases were separated. The organic layer was washed several times with saturated sodium bicarbonate solution until TLC indicated that 4-bromobenzoic acid (Rf=0.55, eluant: CH2Cl2/CH3OH=5) was completely removed. The solution was extracted three times with 200 mL of 1N NaOH solution. To the combined aqueous layers was added about 50 mL of 12 N HCl to pH 3. The resultant precipitate were filtered, washed with water, and dried to give 4-Mesitylbenzoic acid as a white solid (8.81g). Rf=0.75 (eluant: CH2Cl2/CH3OH=5) 1H-NMR (300 MHz, CDCl3): δ1.997 (s,6 H), 2.340 (s,3 H), 6.961 (s,2 H), 7.274 (d,J=8.1 Hz,2 H), 8.177 (d,J=8.1Hz,2 H).
Reaction SMILES: P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.Br[C:15]1[CH:31]=[CH:30][C:18]2[N:19]([CH:24]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25]3)[CH2:20][CH2:21][CH2:22][CH2:23][C:17]=2[CH:16]=1.[Li+].C[Si]([N-:37][Si](C)(C)C)(C)C.Cl.[OH-].[Na+]>C1COCC1.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]>[CH3:29][N:26]1[CH2:27][CH2:28][CH:24]([N:19]2[CH2:20][CH2:21][CH2:22][CH2:23][C:17]3[CH:16]=[C:15]([NH2:37])[CH:31]=[CH:30][C:18]2=3)[CH2:25]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CN1CCC(N2CCCCc3cc(Br)ccc32)C1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CN1CCC(N2CCCCc3cc(N)ccc32)C1
Temperature: 100 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
A suspension of Pd2(dba)3 (105 mg, 0.11 mmol) and PtBu3 (10% wt in hexanes, 1.40 mL, 0.46 mmol) in anhydrous THF (5 mL) was treated with a solution of compound 5 (713 mg, 2.30 mmol) in THF (10 mL) followed by LiHMDS (1 M in THF, 4.6 mL, 4.60 mmol) at room temperature. The resulting dark brown mixture was heated to 100° C. and stirred for 3 hours in a sealed tube. The reaction mixture was cooled to room temperature and treated with 1 N HCl (20 mL) and stirred for 15 min, then basified with 1 N NaOH (50 mL). The product was extracted into CH2Cl2 (2×50 mL) and the combined organic fractions were washed with brine (25 mL), dried (MgSO4), filtered and concentrated to give a dark brown residue. The crude product was purified by column chromatography (2 N NH3 in MeOH:CH2Cl2, 5:95) to give compound 6 (531 mg, 94%) as a syrup.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH3:25])=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:8]2[N:9]([N:11]=[C:12]([NH2:14])[N:13]=2)[CH:10]=1)=[O:4].[OH-].[Li+]>C1COCC1.O>[NH2:14][C:12]1[N:13]=[C:8]2[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:16]=3)=[C:6]([CH3:25])[C:5]([C:3]([OH:4])=[O:2])=[CH:10][N:9]2[N:11]=1
Reactant: COC(=O)c1cn2nc(N)nc2c(-c2cccc(C(F)(F)F)c2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Temperature: 45 °C
Reaction time: 1.75 h
Yield: 61.4 %

Procedure:
To a suspension of 2-amino-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid methyl ester (Int. 35, 1.0 g, 2.857 mmol) in THF (10 mL) and water (5 mL) was added lithium hydroxide (273 mg, 11.34 mmol) and the reaction mixture was stirred at 45° C. for 1.75 hrs. Cooled then acidified to pH 1. The resultant precipitate was collected by filtration, washing with water, to afford the title compound as a white solid (590 mg).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24](O)=[O:25])=[CH:18][CH:17]=1.S(Cl)(Cl)=O.[NH2:31][C:32]([NH2:34])=[O:33]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][C:24]([NH:31][C:32]([NH2:34])=[O:33])=[O:25])=[CH:20][CH:21]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)O)cc1
Reactant: NC(N)=O
Solvent: O=S(Cl)Cl
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)NC(N)=O)cc1
Temperature: 100 °C
Yield: 49.9 %

Procedure:
To 3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propionic acid (1.00 g, 2.85 mmol) obtained in Example 17 was added thionyl chloride (1.7 ml), and the mixture was stirred under heating for 1 hr at 100° C. Excess thionyl chloride was evaporated under reduced pressure and urea (257 mg, 4.28 mmol) was added to the obtained residue. The mixture was stirred under heating for 1 hr at 120° C. and purified by silica gel column chromatography (developing solvent; dichloromethane: methanol=10:1) to give the title compound (560 mg, yield 50%) as a white solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:38]2[CH2:50][CH2:49][N:41]3[C:42]4[CH2:43][CH2:44][CH2:45][CH2:46][C:47]=4[CH:48]=[C:40]3[C:39]2=[O:51])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH:31]4[CH2:34][O:33][CH2:32]4)[CH2:27][C@H:26]3[CH3:35])=[CH:21][N:20]=2)[C:15](=[O:36])[N:14]([CH3:37])[CH:13]=1)(=O)C.O.[Li+].[OH-]>CC(O)C.O1CCCC1>[OH:4][CH2:5][C:6]1[C:7]([N:38]2[CH2:50][CH2:49][N:41]3[C:42]4[CH2:43][CH2:44][CH2:45][CH2:46][C:47]=4[CH:48]=[C:40]3[C:39]2=[O:51])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH:31]4[CH2:34][O:33][CH2:32]4)[CH2:27][C@H:26]3[CH3:35])=[CH:21][N:20]=2)[C:15](=[O:36])[N:14]([CH3:37])[CH:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)C[C@H]4C)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: C[C@@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CCCC6)C4=O)c3CO)cn(C)c2=O)nc1
Temperature: 30 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
To a solution of 137a (200 mg, 0.29 mmol) in propan-2-ol (8 mL), tetrahydrofuran (8 mL), and water (2.0 mL) was added LiOH (690 mg, 29 mmol). The mixture was stirred at 30° C. for 2 h. It was then evaporated and the residue was purified by reverse-phase prep-HPLC to afford 137 (143 mg, 76%) as a white solid. LCMS: (M+H)+ 651.4. 1H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J=2.0, 1H), 8.49 (d, J=5.0, 1H), 8.45 (s, 1H), 7.84 (d, J=2.5, 1H), 7.47 (d, J=2.0, 1H), 7.37-7.39 (m, 1H), 7.35 (d, J=5.5, 1H), 7.25 (d, J=9.5, 1H), 6.58 (s, 1H), 4.95 (t, J=4.0, 1H), 4.54-4.58 (m, 2H), 4.40-4.49 (m, 4H), 4.11-4.26 (m, 3H), 3.86-3.88 (m, 1H), 3.68 (s, 1H), 3.61 (s, 3H), 3.37-3.42 (m, 1H), 3.08-3.11 (m, 1H), 2.95 (t, J=9.0, 1H), 2.62-2.67 (m, 1H), 2.54-2.59 (m, 2H), 2.48 (t, J=6.0, 2H), 2.30-2.36 (m, 2H), 2.19 (t, J=8.0, 1H), 1.81 (s, 2H), 1.68-1.72 (m, 2H), 0.93 (d, J=6.0, 3H)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:12]1[CH:16]=[CH:15][S:14][CH:13]=1)([OH:11])[CH3:10].[Cl:17][CH2:18][C:19](Cl)=[O:20]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:19](=[O:20])[CH2:18][Cl:17])=[C:3]([C:9]([OH:11])([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH3:10])[CH:4]=1
Reactant: O=C(Cl)CCl
Reactant: CC(O)(c1ccsc1)c1cc(Br)ccc1N
Product: CC(O)(c1ccsc1)c1cc(Br)ccc1NC(=O)CCl

Procedure:
Prepared from 1-(2-amino-5-bromophenyl)-1-thien-3-ylethanol and chloroacetyl chloride generally according to the procedure described in example 1. 1H-NMR (DMSO-d6) δ 10.80 (s, 1H), 8.03 (d, J=7.5 Hz, 1H), 7.52-7.43 (m, 2H), 7.40 (m, 2H), 7.00 (s, 1H), 6.93 (m, 1H), 4.30 (d, J=15.00 Hz, 1H), 4.23 (d, J=15.00 Hz, 1H), 1.90 (s, 3H); MS (ES) m/z 372/374/376 ([M−H]−, 100%).