Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][C@H:13]([CH3:17])[C:14](O)=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:27])=O>CN(C)C=O.CCOCC>[F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][C@H:13]([CH3:17])[C:14]([Cl:27])=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: C[C@@H](Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C[C@@H](Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-2-[4-(4-trifluoromethylphenoxy)phenoxy]-propanoic acid (1.62 g., 4.96 mm), ether (20 ml) and dimethylformamide (about 2 drops) is added slowly oxalyl chloride (0.8 ml., 2 eq.). After addition of oxalyl chloride, the reaction mixture is stirred at room temperature for one hour. The mixture is then concentrated to give the acid chloride, (R)-2-[4-(4-trifluoromethylphenoxy)phenoxy]propanoyl chloride.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][C:9](=[O:16])/[C:8]/2=[CH:17]/OC)([CH3:4])([CH3:3])[CH3:2].[NH2:20][CH2:21][C:22]1[CH:27]=[C:26]([OH:28])[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:24][N:23]=1>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][C:9](=[O:16])[C:8]2=[CH:17][NH:20][CH2:21][C:22]1[CH:27]=[C:26]([OH:28])[C:25]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:24][N:23]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1cc(O)c(-c2ccccc2)cn1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(C(C)(C)C)cc21
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc2c(c1)C(=CNCc1cc(O)c(-c3ccccc3)cn1)C(=O)NC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
An amount of 40.0 mg (0.154 mmol) of (4E)-6-t-butyl-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (based on a sample that is 39% pure by weight), is dissolved in N,N-dimethylformamide (3 mL), followed by the addition of 31 mg (0.154 mmol) of 2-aminomethyl-5-phenyl-pyridin-4-ol. All solids dissolved and after the mixture is stirred at room temperature for 2 hours, the solution is evaporated to dryness in vacuo, treated with acetonitrile, filtered and washed several times with fresh acetonitrile and dried to give 44 mg of the title compound as a pink solid (66% yield); mp 195-218° C. dec, MS data ES(+) 428.4 m/e.
Reaction SMILES: C(=[N:14][NH:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([F:23])=[CH:18][N:17]=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl>C1(C)C=CC=CC=1.O>[F:23][C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([NH:15][NH2:14])=[N:17][CH:18]=1
Reactant: Cc1cc(F)cnc1NN=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(F)cnc1NN
Temperature: 110 °C
Yield: 87 %

Procedure:
A solution of Intermediate 105a (194 mg, 0.635 mmol) in toluene (13 mL) was treated with HCl (37%, 3.5 mL) and heated at 110° C. for 1.5 h. After cooling to RT, the reaction mixture was diluted with water and extracted with toluene (×3). The aqueous layer was cooled to 0° C., neutralised with 5N NaOH and extracted with DCM (×3). The combined organic layers were dried (MgSO4) and concentrated in vacuo to afford the title compound (78 mg, 86%) as a silver/green solid. LCMS (Method 4): Rt 0.29 min, m/z 142 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:35])[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1.[NH:36]1[CH2:41][CH2:40][NH:39][CH2:38][C:37]1=[O:42]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:35])[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:39]3[CH2:40][CH2:41][NH:36][C:37](=[O:42])[CH2:38]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C1CNCCN1
Reactant: COc1ccc(C2=NC(C)(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1
Product: COc1ccc(C2=N[C@@](C)(c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)N2CCNC(=O)C2)c(OC(C)C)c1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazinone (Avocado Organics) to give the title compound. LC-MS: 595.2 [(M+H)+]
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][NH:12][C:11](=O)[CH2:10][O:9]2)=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:9][CH2:10][CH2:11][NH:12][CH2:13]2)=[CH:4][C:3]=1[C:15]([F:18])([F:16])[F:17]
Reactant: O=C1CO[C@H](c2ccc(F)c(C(F)(F)F)c2)CN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Fc1ccc([C@@H]2CNCCO2)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
(R)-6-(4-Fluoro-3-(trifluoromethyl)phenyl)morpholin-3-one (486 mg, 1.85 mmol) was dissolved in 2 mL of THF and 10 mL of ether. To this solution under ice bath was added powder LiAlH4 (72 mg, 1.85 mmol). The mixture was stirred at 0° C. for 1 h and then at room temperature overnight. LC/MS indicated only the starting material. To this mixture was added LiAlH4 (1M) in THF (2 mL, 2 mmol) under ice bath. The mixture was stirred at room temperature for 15 h. LC/MS indicated complete consumption of the starting material and the formation of the desired MW (250, M+1). Under ice bath, 2.5 mL of water was added and the mixture was stirred for 30 min. The top solution was decanted and concentrated. The slurry residue was treated with methylene chloride and water. The organic layer was combined with the dichloromethane solution from the decanted top solution, washed and dried. Solvents were evaporated to give (R)-2-(4-fluoro-3-(trifluoromethyl)phenyl)morpholine as a pale green oil (460 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.74 (dd, J=12.13, 10.36 Hz, 1H) 2.86-2.96 (m, 1H) 2.96-3.03 (m, 1H) 3.08 (dd, J=12.38, 2.53 Hz, 1H) 3.80 (td, J=11.37, 3.03 Hz, 1H) 4.06 (dd, J=11.37, 3.03 Hz, 1H) 4.52 (dd, J=10.36, 2.53 Hz, 1H) 7.14-7.23 (m, 1H) 7.50-7.58 (m, 1H) 7.64 (dd, J=6.69, 2.15 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.C[Al](C)C.C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]#[C:22][C:23]2[C:24]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:25][O:26][C:27]=2[CH3:28])[CH:16]=1.S([O-])([O-])(=O)=O.[Mg+2]>O1CCOCC1.O>[CH3:28][C:27]1[O:26][N:25]=[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]=1[C:22]#[C:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][N:18]=1)[C:14]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1)=[O:13]
Reactant: COC(=O)c1ccnc(C#Cc2c(-c3ccccc3)noc2C)c1
Reactant: Cc1csc(N)n1
Agent: C[Al](C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1COCCO1
Solvent: O
Product: Cc1csc(NC(=O)c2ccnc(C#Cc3c(-c4ccccc4)noc3C)c2)n1
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 92.2 %

Procedure:
To a solution of 2-amino-4-methylthiazole (57 mg, 0.50 mmol) in dioxane (1.2 mL) was added trimethylaluminium (2 M in heptane, 251 μl, 0.50 mmol). The resulting red-brown solution was stirred for 1 h at ambient temperature before 2-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-isonicotinic acid methyl ester (40 mg, 0.13 mmol) was added. The reaction mixture was heated for 2.25 h at 110° C. before cooling to ambient temperature. Water (29 μL) was added and the mixture was stirred for 10 min at ambient temperature. Magnesium sulfate was added and the mixture was filtered over Hyflo®. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 0:100) was followed by separation between hydrochloric acid (1 M, 30 mL) and ethyl acetate (100 mL). The organic layers were washed with brine, dried over sodium sulfate and were concentrated affording the title compound (48 mg, 96%) as an off-white solid. MS: m/e=401.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O>C(O)C>[Cl:11][CH2:12][C:13]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=2)[O:7][CH:15]=1
Reactant: Cc1ccc(C(N)=O)cc1
Reactant: O=C(CCl)CCl
Solvent: CCO
Product: Cc1ccc(-c2nc(CCl)co2)cc1
Yield: 50.8 %

Procedure:
4-Methylbenzamide (10.0 g) and 1,3-dichloroacetone (9.4 g) were dissolved in ethanol (100 mL), and the mixture was refluxed for 8 hr. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1 to 7:1) to give the title compound (7.8 g) as a white solid.
Reaction SMILES: [CH:1]([O:4][S:5]([C:8]1[C:17]([N:18]=[N:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:16]([OH:28])[C:15]2[C:10](=[CH:11][C:12]([NH2:29])=[CH:13][CH:14]=2)[CH:9]=1)(=[O:7])=[O:6])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>ClCCl>[CH:1]([O:4][S:5]([C:8]1[C:17]([N:18]=[N:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:16]([OH:28])[C:15]2[C:10](=[CH:11][C:12]([NH:29][C:39](=[O:46])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:13][CH:14]=2)[CH:9]=1)(=[O:6])=[O:7])([CH3:3])[CH3:2]
Reactant: COc1ccc(N=Nc2c(S(=O)(=O)OC(C)C)cc3cc(N)ccc3c2O)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(N=Nc2c(S(=O)(=O)OC(C)C)cc3cc(NC(=O)c4ccccc4)ccc3c2O)cc1
Reaction time: 16 h
Yield: 47.9 %

Procedure:
7-Amino-4-hydroxy-3-(4-methoxy-phenylazo)-napthalene-2-sulfonic acid isopropyl ester (Example 6, 200 mg, 0.48 mmol ) was dissolved in dichloromethane (3 mL) and diisopropylethylamine (160 μL, 114 mg, 0.96 mmol) was added. Benzoyl chloride (85 mg, 0.60 mmol ) was then added under nitrogen. The reaction mixture was allowed to stir for 16 h. The suspension was filtered to provide the title compound (120 mg, 0.23 mmol, 48%) as a red solid: NMR (DMSO-d6): δ 16.25 (s, 1H), 10.81 (s, 1H), 8.52 (m, 1H), 8.37 (d, J=9 Hz, 1H), 8.08 (d, J=9 Hz, 1H), 8.02 (d, J=9 Hz, 2H), 7.81 (d, J=9 Hz, 2H), 7.64 (m, 3H), 7.18 (d, J=9 Hz, 2H), 4.82 (m, 1H), 3.83 (s, 3H), 1.25 (d, J=6 Hz, 6H); Analytical HPLC: 95% pure; MS (ES-NEG): [M−H] 518; Anal. Calc. for C27H24N3O6SNa: C, 62.42, H, 4.85, N, 8.09. Found: C, 60.61, H, 4.77, N, 7.70.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:13][CH2:14][C:15]1[N:19]([C:20]2[S:21][C:22]([CH2:34][CH3:35])=[CH:23][C:24]=2[C:25](=[O:33])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[C:18]([CH3:36])=[N:17][N:16]=1>>[Cl:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:25]([C:24]1[CH:23]=[C:22]([CH2:34][CH3:35])[S:21][C:20]=1[N:19]1[C:18]([CH3:36])=[N:17][N:16]=[C:15]1[CH2:14][NH:13][S:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)(=[O:11])=[O:10])=[O:33]
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNS(=O)(=O)c2ccc(Cl)c(Cl)c2)s1

Procedure:
3,4-Dichlorobenzenesulfonyl chloride and 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazole are reacted, and treated in the same manner as in Example 48 to give N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)-3,4-dichlorobenzenesulfonamide.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([O:15][CH:16]([CH3:18])[CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>>[CH:16]([O:15][CH:9]([CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][C:28]([NH:27][C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:26][CH:25]=2)=[O:29])[CH:3]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH3:17])[CH3:18]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(Cc1cccc(O)c1)OC(C)C
Product: CCOC(=O)C(Cc1cccc(OC(=O)Nc2ccc(C(F)(F)F)cc2)c1)OC(C)C

Procedure:
Using ethyl 3-(3-hydroxyphenyl)-2-isopropoxypropanoate and α,α,α-trifluoro-p-tolylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [CH3:1][Si:2]([CH3:18])([CH3:17])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9]2)=[CH:5][CH:4]=1.Cl[CH2:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1.[H-].[Na+]>>[CH3:1][Si:2]([CH3:17])([CH3:18])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:9]2[CH2:20][C:21]2[S:22][CH:23]=[CH:24][N:25]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cc2ccc([Si](C)(C)C)cc2[nH]1
Reactant: ClCc1nccs1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cc2ccc([Si](C)(C)C)cc2n1Cc1nccs1
Yield: 66.5 %

Procedure:
This compound was prepared according to a process similar to that described in step 20.2, by reacting 570 mg (2.18 mmol) of ethyl 6-trimethylsilyl-1H-indole-2-carboxylate with 440 mg (3.27 mmol) of 2-(chloromethyl)thiazole in the presence of 0.14 g (3.27 mmol) of sodium hydride (55%). The crude reaction product is then purified by flash chromatography on a column of silica gel in a mixture of heptane and ethyl acetate, to give 520 mg of the expected product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C@H:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35]>>[C:1]([O:5][C:6](=[O:27])[C@H:7]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:24][CH:25]=1)[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Reactant: COCCOCCBr
Product: COCCOCCOc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc1

Procedure:
7.43 g (20 mmol) of N-benzyloxycarbonyl-tyrosine-tert-butyl ester is reacted with 1-bromo-2-(2-methoxyethoxy)-ethane to alkylated phenol analogously to Example a).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].O=C1CCC(=O)N1O[C:26](=O)[CH:27]([NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:28][CH3:29].CN(C1C=CC=CN=1)C.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[CH2:34]([O:33][C:31](=[O:32])[NH:30][CH:27]([C:26]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4](=[O:5])[C:3]2[C:2](=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:17])[N:1]=1)[CH2:28][CH3:29])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCC(NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: Cc1cccc(N)c1C(=O)Nc1ccccc1
Agent: CN(C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCC(NC(=O)OCc1ccccc1)c1nc2cccc(C)c2c(=O)n1-c1ccccc1
Temperature: 110 °C
Reaction time: 22 h

Procedure:
Compound 15 (1.20 g, 5.30 mmol) was combined with 2-benzyloxycarbonylaminobutyric acid 2,5-dioxo-pyrrolidin-1-yl ester (2.13 g, 6.36 mmol), dimethylaminopyridine (915 mg, 7.49 mmol), and diisopropylethylamine (1.10 mL, 6.36 mmol) in toluene (15 mL). The mixture was heated to 110° C. and stirred at that temperature for 22 hours. After cooling, the reaction Was purified by flash chromatography to provide the quinazolinone (16) as a pale yellow solid. MS (ES): m/z 428 (M+H). 1H NMR (300 MHz, DMSO-d6) δ 10.26 (s, 1H), 7.75 (d, 2H, J=7.9 Hz), 7.32 (t, 2H, J=7.8 Hz), 7.07 (t, 1H, J=7.3 Hz), 7.00 (t, 1H, J=7.8 Hz), 6.58 (d, 1H, J=8.1 Hz), 6.46 (d, 1H, J=7.4 Hz), 4.98 (br. s, 2H), 2.21 (s, 3H). The reaction described above and compound 16 are shown below.
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:9]([C:13]([OH:16])([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[N+:32]([O-:34])=[O:33].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>O1CCCC1>[CH2:17]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]([C:13]([O:16][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[N+:32]([O-:34])=[O:33])([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: CC(C)(O)C(C(=O)O)N(Cc1ccccc1)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(Oc1ccc(F)cc1[N+](=O)[O-])C(C(=O)O)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.6 %

Procedure:
1.41 g (4.51 mmol) 2-dibenzylamino-3-hydroxy-3-methyl-butyric acid and 0.54 ml (4.95 mmol) 2,5-difluoronitrobenzene in 46 ml tetrahydrofuran were treated at 0° C. with 19.8 ml (9.9 mmol) potassium bis(trimethylsilyl)amide (0.5 M in toluene). The solution was stirred overnight at room temperature and was then poured on ice/water. Extraction with ethylacetate and chromatography on silicagel with diethylether/heptane (30:70 to 75:25) and yielded 0.40 g (20%) 2-dibenzylamino-3-(4-fluoro-2-nitro-phenoxy)-3-methyl-butyric acid as yellow solid, MS m/e (%): 453.4 (M+H+, 100).
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].[CH2:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:6]([NH:13][CH2:1][CH:2]([OH:3])[CH2:4][OH:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCC1CO1
Reactant: NCc1ccccc1
Product: OCC(O)CNCc1ccccc1

Procedure:
Glycerol glycid and benzylamine are reacted in a known manner to give 3-benzylamino-1,2-propanediol (boiling point 160°-170° C./0.01 mm Hg).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:17])[CH3:16])([O-:8])=[O:7].[C:18]([OH:22])(=[O:21])[CH:19]=O>>[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([CH:16]=[CH:19][C:18]([OH:22])=[O:21])=[O:17])([O-:8])=[O:7]
Reactant: O=CC(=O)O
Reactant: CC(=O)c1ccccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: O=C(O)C=CC(=O)c1ccccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 30.3 %

Procedure:
To a solution of 225 ml of glacial acid and 8.5 ml of concentrated sulfuric acid is added 49.54 g (0.30 mol) of 2'-nitroacetophenone and 47.02 g (0.50 mol) of glyoxylic acid (hydrated). The mixture is heated at 100° C. for 16 hours. The mixture is cooled and poured over crushed ice. After the ice melts, the mixture is filtered and the solid washed with cold water. The solid is dried and recrystallized from dichloromethane-hexane to give 20.1 g of 3-(2-nitrobenzoyl)acrylic acid as white crystals, m.p. 153°-158° C. A solution of the proceeding compound (9.0 g) in 80 ml of ethanol and 1.6 g of palladium-on-carbon is hydrogenated in a Parr hydrogenator under 30 pounds per square inch of hydrogen for 20 hours. The mixture is filtered through diatomaceous earth and the solvent is removed. The residue (7.0 g) is chromatographed on silica gel with hexane-ethyl acetate (1:1) as solvent to give 4.0 g of 3-(2-aminobenzoyl)propionic acid as an orange solid, m.p. 103°-107° C. A 0.50 g sample of the preceding compound, 0.36 ml of triethylamine and 0.43 ml of diphenoxyphosphinyl cyanide in 20 ml of dichloromethane is stirred at room temperature for 5 days. The solvent is removed, ethyl acetate is added and the mixture washed with water, 2N citric acid, 1M NaHCO3, brine and dried (Na2SO4). The solvent is removed and the residue purified by chromatography over silica gel with ethyl acetate-hexane (1:1) as solvent to give 0.190 g of light brown crystals, m.p. 168°-170° C.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1B(O)O>>[Cl:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[C:5]1[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1
Reactant: COc1ccc(B(O)O)c(Cl)c1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: COc1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)c(Cl)c1
Yield: 4.9 %

Procedure:
Using the conditions of General Procedure A for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 2-chloro-4-methoxyphenylboronic acid (available from Combi-Blocks Inc.; 93 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2′-chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-methoxy-biphenyl-2-carboxylic acid (6 mg, 5%). 1H NMR (300 MHz, DMSO-d6) δ 13.00 (br s, 1H), 8.46-8.51 (m, 2H), 8.33 (d, J=2.1 Hz, 1H), 8.24 (dd, J=8.1, 1.9 Hz, 1H), 8.09 (dd, J=8.5, 2.1 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.27 (d, J=8.5 Hz, 1H), 7.10 (d, J=2.4 Hz, 1H), 6.99 (dd, J=8.5, 2.6 Hz, 1H), 3.83 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH:29]1([C:32]2[O:36][C:35]([CH3:37])=[N:34][C:33]=2[CH2:38]OS(C)(=O)=O)[CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:38][C:33]2[N:34]=[C:35]([CH3:37])[O:36][C:32]=2[CH:29]2[CH2:31][CH2:30]2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Reactant: Cc1nc(COS(C)(=O)=O)c(C2CC2)o1
Product: Cc1nc(Cn2cc(C(=O)N3CCC4(CC3)OC(=O)c3cc(F)ccc34)c3ccc(Cl)cc32)c(C2CC2)o1

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with methanesulfonic acid 5-cyclopropyl-2-methyl-oxazol-4-ylmethyl ester (prepared by mesylation of (5-cyclopropyl-2-methyl-oxazol-4-yl)-methanol) gave the title compound. ES-MS m/e (%): 534.2(M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[C:13]([CH3:14])=[N:12][CH:11]=[N:10]1.[Cu][C:16]#[N:17]>CN1CCCC1=O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]#[N:17])=[C:3]([N:9]2[C:13]([CH3:14])=[N:12][CH:11]=[N:10]2)[CH:4]=1
Reactant: Cc1ncnn1-c1cc(F)ccc1Br
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: Cc1ncnn1-c1cc(F)ccc1C#N
Temperature: 145 °C

Procedure:
To a solution of 1-(2-bromo-5-fluorophenyl)-5-methyl-1H-1,2,4-triazole (4.1 g, 16 mmol) in N-methylpyrrolidone (NMP, 30 mL) was added copper (I) cyanide, CuCN (1.72 g, 19.2 mmol; Aldrich) and the mixture was stirred in an oil bath heated at 140-150° C. under a nitrogen atmosphere for 3 h. After cooling, the solvent was removed in vacuo and the residue mixed with CH2Cl2 (50 mL), water (50 mL), and conc-NH4OH (50 mL). The mixture was stirred for 30 min, and the insoluble material was filtered through Celite®. The aqueous filtrate was extracted again with CH2Cl2. The combined CH2Cl2 filtrate and extracts were washed again with dilute NH4OH, dried (MgSO4), filtered and concentrated to a dark solid which was triturated with diethyl ether to give 1.6 g of the title compound as an off-white solid. An additional amount (750 mg) of the title compound was obtained from the mother liquor by column chromatography (SiO2, 5% Et2O—CH2Cl2) followed by trituration with Et2O. Total yield, 2.35 g (11.6 mmol, 73% yield); HPLC: 1.29 min (AP 99% at 254 nm); LC/MS m/z 203 (M+H); 1H NMR (CDCl3, 500 MHz) δ ppm 2.50 (3H, s, 10-Me), 7.25 (1H, dd, J=8, 2.5 Hz, 3-CH), 7.30-7.36 (1H, m, 5-CH), 7.85 (1H, dd, J=8.8, 5.5 Hz, 6-CH), 8.00 (1H, s, 9-CH); 13C NMR (CDCl3, 125.8 Hz) δ ppm 12.7 (10-Me), 107.2 (d, J=Hz, 1-C), 114.6 (7-CN), 116.2, (d, J=25 Hz, 3-CH), 117.9 (d, J=23 Hz, 5-CH), 136.1 (d, J=10 Hz, 6-CH), 141.5 (d, J=l 1 Hz, 2-C), 152.3 (9-CH), 153.9 (8-C), 164.9 (d, J=261 Hz, 4-CF).