Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:38]1([CH2:44][C:45]([N:47]2[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]2)=[O:46])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:41]3[CH2:40][CH2:39][N:38]([CH2:44][C:45]([N:47]4[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]4)=[O:46])[CH2:43][CH2:42]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(CN1CCNCC1)N1CCCCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCCCC2)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 2-piperazin-1-yl-1-piperidin-1-yl-ethanone (Oakwood) to give the title compound. HR-MS (ES, m/z) calculated for C40H51Cl2N6O3 [(M+H)+] 733.3394, observed 733.3392.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([N:10]([CH3:19])[C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16])=[O:12])[CH2:7][N:6]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:4].[OH-].[Na+]>C1COCC1.CO.O>[CH2:20]([N:6]1[CH2:7][C@@H:8]([N:10]([CH3:19])[C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:16])[Cl:17])=[O:12])[CH2:9][C@H:5]1[C:3]([OH:4])=[O:2])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)[C@@H]1C[C@H](N(C)C(=O)OCC(Cl)(Cl)Cl)CN1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CN(C(=O)OCC(Cl)(Cl)Cl)[C@H]1C[C@@H](C(=O)O)N(Cc2ccccc2)C1
Reaction time: 8 h
Yield: 99.2 %

Procedure:
To a solution of (2S,4S)-1-benzyl-4-[methyl-(2,2,2-trichloro-ethoxycarbonyl)-amino]-pyrrolidine-2-carboxylic acid methyl ester (6.4 mmol) in 18 mL of THF and 12 mL of methanol was added a solution of NaOH (12.8 mmol) in 10 mL water, and the reaction mixture was stirred overnight. The solution was diluted with 40 mL of water and extracted with 20 mL of EA. The aqueous layer was separated and acidified with 2N HCl to PH=5-6. Then the solution was extracted with EA (3×40 mL). The combined organic layers were washed by brine (20 mL), dried over Na2SO4, and concentrated to give 2.6 g of title product in 91% yield. MS m/e=410.4 [M+H]+.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[C:30]([CH3:37])[CH:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:31]2[CH:32]=[CH:33][C:28]([F:27])=[CH:29][C:30]=2[CH3:37])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(-c2ccc(F)cc2C)c1

Procedure:
By following a procedure analogous to Example 27 starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 4-fluoro-2-methyl-phenylboronic acid, 5-(4-fluoro-2-methylphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=72%).
Reaction SMILES: [C:1](/[C:4](=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)/[C:5]([O:7][CH3:8])=[O:6])(=O)[CH3:2].S(O)(O)(=O)=O.[CH3:22][O:23][C:24](=[NH:26])[NH2:25].C([O-])(O)=O.[Na+]>C(O)C>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]2[NH:26][C:24]([O:23][CH3:22])=[N:25][C:1]([CH3:2])=[C:4]2[C:5]([O:7][CH3:8])=[O:6])=[CH:11][CH:12]=1
Reactant: COC(=N)N
Reactant: COC(=O)/C(=C\c1ccc(F)cc1)C(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)C1=C(C)N=C(OC)NC1c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A mixture of methyl (2Z)-2-acetyl-3-(4-fluorophenyl)-2-propenoate (0.220 mole, 48.8 g), O-methyl isourea hydrogensulfate (53.40 g, 0.310 mol, 1.5 eq.), NaHCO3 (61.74 g, 0.74 mole, 3.5 equiv.) and ethanol (1.2 L) was refluxed for 24 h, cooled to room temperature, and filtered. The solid was washed with ethanol (200 mL) and the combined filtrate was concentrated in vacuo. The residue was purified by chromatography (silica gel, hexanes/EtOAc/Et3N 50:50:0.1) to yield a mixture of tautomers (4:1, 33.0 g, 53.9%). 1H NMR (CDCl3) δ 7.32-7.24 (m, 2H), 7.04-6.95 (m, 2H), 5.81 (s, 1H), 5.38 (d, 1H, J=2.9 Hz), 4.00 (s, 3H), 3.63 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.[C:19]([O:23][C:24](=[O:39])[C:25]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][C:36](O)=[O:37])[CH:30]=1)([CH3:27])[CH3:26])([CH3:22])([CH3:21])[CH3:20].COC(=O)CC1C=CC=C(O)C=1.BrC(C)(C)C(OC(C)(C)C)=O>>[C:19]([O:23][C:24](=[O:39])[C:25]([CH3:26])([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][C:36](=[O:37])[NH:8][C:7]2[C:2]([CH3:1])=[N:3][C:4]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:18])[F:17])=[CH:11][CH:10]=3)=[CH:5][CH:6]=2)[CH:30]=1)[CH3:27])([CH3:21])([CH3:20])[CH3:22]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CC(=O)O)c1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1N
Agent: CC(C)(C)OC(=O)C(C)(C)Br
Agent: COC(=O)Cc1cccc(O)c1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1NC(=O)Cc1cccc(OC(C)(C)C(=O)OC(C)(C)C)c1

Procedure:
In analogy to the procedures described in example 26B] and 124C], 2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylamine (example 125C]) was reacted with 2-(3-carboxymethyl-phenoxy)-2-methyl-propionic acid tert-butyl ester (prepared from (3-hydroxy-phenyl)-acetic acid methyl ester and tert-butyl alpha-bromoisobutyrate, in analogy to the procedure described in example 52A], followed by saponification in analogy the procedure described in example 124A]) to give 2-methyl-2-(3-{[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylcarbamoyl]-methyl}-phenoxy)-propionic acid tert-butyl ester, which was subsequently cleaved with trifluoroacetic acid to yield the title compound as light yellow amorphous solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH2:32][CH2:33][C:34]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:35]=1[C:36]([NH:38][CH3:39])=[O:37].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN(C)C=O>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:44][C:41]1[CH:42]=[CH:43][C:34]([CH2:33][NH:32][C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:21])[CH3:20])=[O:23])=[C:35]([C:36](=[O:37])[NH:38][CH3:39])[CH:40]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: CNC(=O)c1cc(F)ccc1CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CNC(=O)c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
A 25 mL round-bottom flask was charged with intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid, (0.991 g, 3.0 mmol), intermediate 39, 2-(aminomethyl)-5-fluoro-N-methylbenzamide trifluoroacetic acid salt (1.185 g, 4.0 mmol), 4-dimethylaminopyridine (DMAP, 1.1 g, 9.0 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 1.722 g, 4.5 mmol). Dimethylformamide (20 mL) was added and the mixture stirred for 1 h at ambient temperature. After this, the reaction mixture was diluted with ethyl acetate (100 mL) then washed with water (3×25 mL) and brine (25 mL). The organic layer was dried (Na2SO4), filtered, concentrated and purified by flash chromatography (SiO2), eluting with hexanes/ethyl acetate (1:1 to 1:3) followed by ethyl acetate, to afford the title compound as an off-white solid (1.48 g, 100% yield). 1H NMR (500 MHz, CDCl3) δ ppm: 8.49 (1H, t, J=6.1 Hz), 7.48–7.46 (2H, m), 7.43 (1H, dd, J=8.5, 5.5 Hz), 7.31–7.27 (3H, m), 7.12 (1H, dd, J=8.9, 2.7 Hz), 7.05 (1H, td, J=8.2, 2.7 Hz), 6.52 (1H, br s), 5.26 (2H, s), 4.53 (2H, d, J=6.4 Hz), 4.01 (2H, t, J=4.9 Hz), 3.96 (2H, t, J=4.9 Hz), 2.97 (3H, d, J=4.9 Hz), 1.62 (6H, s). HRMS (M+H) calcd for C26H28FN4O5: 495.2044. found: 495.2032.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:29])[O:13][C:14](=O)[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH3:25])[C:17]=2[S:26][CH3:27])=[CH:3]1.C[N:31](C=O)C>N>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:29])[NH:31][C:14](=[O:13])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH3:25])[C:17]=2[S:26][CH3:27])=[CH:3]1
Reactant: CSc1c(C2=C(c3cn(C)c4ccccc34)C(=O)OC2=O)c2ccccc2n1C
Reactant: CN(C)C=O
Agent: N
Product: CSc1c(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c2ccccc2n1C

Procedure:
A solution of 804 mg of 3-(1-methyl-3-indolyl)-4-[1-methyl-2-(methylthio)-3-indolyl]furan-2,5-dione in 12 ml of DMF and 50 ml of 33% aqueous ammonia was heated to 130° C. for 2 hours. The product was filtered off and dried to give 675 mg of 3-(1-methyl-3-indolyl)-4-[1-methyl-2-(methylthio)-3-indolyl]-1H-pyrrole-2,5-dione, m.p. 281°-283° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[F:39][C:40]1[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=1[NH2:42].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][NH:42][C:41]2[CH:43]=[CH:44][CH:45]=[CH:46][C:40]=2[F:39])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: Nc1ccccc1F
Reactant: COC(=O)c1cc(C)cc(F)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(F)cc(CNc2ccccc2F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl 3-fluoro-5-methylbenzoate (1.0 g, 5.95 mmol), N-bromosuccinimide (1.27 g, 7.14 mmol), and dibenzoylperoxide (145 mg, 0.60 mmol) in CHCl3 (50 mL) was heated to reflux for 6 hours. After cooling to room temperature, the reaction mixture was quenched with saturated aqueous NaHCO3 (50 mL), and the layers were separated. The organic phase was washed with saturated aqueous NaHCO3 (50 mL) and then passed through a hydrophobic frit. The solvent was removed in vacuo and the residue was used directly in the next step without any further purification. To the residue was added 2-fluoroaniline (0.23 mL, 2.41 mmol) and potassium carbonate (454 mg, 3.29 mmL) in DMF (5.5 mL). The mixture was stirred at room temperature for 18 hours and then partitioned between EtOAc (30 mL) and water (20 mL). The layers were separated and the aqueous phase extracted with EtOAc (3×30 mL) The combined organic phases were washed with brine (20 mL) and dried over Na2SO4. The mixture was filtered and the solvent was removed in vacuo. The residue was purified on an SCX cartridge washing with MeOH and eluting with 3 to 10% NH3 in DCM. Further purification via silica gel chromatography, eluting with 0-20% EtOAc in isohexane, gave methyl 3-fluoro-5-(((2-fluorophenyl)amino)methyl)benzoate (CD6) as a yellow oil (133 mg, 8.1% over two steps).
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[N:18]=[C:17]([O:19]CC3C=CC(OC)=CC=3)[C:16]3[C:11](=[CH:12][C:13]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:14][CH:15]=3)[N:10]=2)=CC=1>Cl.O1CCOCC1>[N:29]1([C:13]2[CH:12]=[C:11]3[C:16]([C:17](=[O:19])[NH:18][C:9](=[O:8])[NH:10]3)=[CH:15][CH:14]=2)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: COc1ccc(COc2nc(OCc3ccc(OC)cc3)c3ccc(N4CCOCC4)cc3n2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]c(=O)c2ccc(N3CCOCC3)cc2[nH]1
Reaction time: 3 h
Yield: 94.8 %

Procedure:
232.0 g (0.48 mol) of 2,4-bis(4-methoxybenzyloxy)-7-morpholin-4-ylquinazoline were dissolved in 300 ml of hydrogen chloride/dioxane (4 N) at room temperature and stirred for 3 h. Conventional work-up gave 112.5 g of 7-morpholin-4-yl-1H-quinazoline-2,4-dione; HPLC/MS (M+H)+=248 as solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:19][CH:20]([CH3:22])[CH3:21])=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]([CH:12]([F:14])[F:13])=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[Cl:23][C:24]1[S:25][C:26]([C:33](Cl)=[O:34])=[C:27]([C:29]([F:32])([F:31])[F:30])[N:28]=1>>[Cl:23][C:24]1[S:25][C:26]([C:33]([NH:1][C:2]2[C:3]([CH2:19][CH:20]([CH3:22])[CH3:21])=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]([CH:12]([F:14])[F:13])=[N:6][C:7]=2[C:8]([F:10])([F:11])[F:9])=[O:34])=[C:27]([C:29]([F:30])([F:31])[F:32])[N:28]=1
Reactant: O=C(Cl)c1sc(Cl)nc1C(F)(F)F
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(N)c1CC(C)C
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(NC(=O)c2sc(Cl)nc2C(F)(F)F)c1CC(C)C

Procedure:
Methyl 5-amino-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (example A1 of U.S. Pat. No. 5,114,465) was reacted with 2-chloro-4-(trifluoromethyl)-5-thiazolecarbonyl chloride according to the procedure in example 1 of U.S. Pat. No. 5,114,465 afforded the product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[N:20]1([CH2:26][C:27]2[S:31][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:30]2[S:31][C:27]([CH2:26][N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[CH:28][CH:29]=2)=[CH:6][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:9]
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)s2)OC1(C)C
Reactant: COc1ccc(NC(=O)c2cc(Br)cnc2N)cc1
Product: COc1ccc(NC(=O)c2cc(-c3ccc(CN4CCOCC4)s3)cnc2N)cc1

Procedure:
Reaction of 2-amino-5-bromo-N-(4-methoxyphenyl)pyridine-3-carboxamide with 5-(4-morpholinylmethyl)thiophene-2-boronic acid pinacol ester gives the compound “A39”; HPLC/MS: 1.46 min, [M+H]=425;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11](=O)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[NH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].C(O)(=O)C>C(O)C>[C:25]([O:24][C:23]([NH:22][CH2:21][CH2:20][NH:19]/[C:11](/[C:4]1[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1])=[CH:12]\[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:29])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOC(=O)CC(=O)c1ccc(OC)cc1OC
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)/C=C(\NCCNC(=O)OC(C)(C)C)c1ccc(OC)cc1OC

Procedure:
A solution of ethyl 3-(2,4-dimethoxyphenyl)-3-oxopropanoate (41.91 g, 166 mmol), tert-butyl 2-aminoethylcarbamate (54.7 g, 342 mmol), and acetic acid (16.14 g, 269 mmol) in ethanol (180 mL) was heated at reflux for 5.3 h. After removal of most of the solvent by rotary evaporation, the resulting oil was partitioned between EtOAc (ca. 300 mL) and 10% (w/v) aq. ammonium chloride. The EtOAc layer was separated and then washed with water, 10% (w/v) aq. ammonium chloride (3 mL), and brine (10 mL). The EtOAc layer was washed with sat. aq. sodium bicarbonate, brine (6 mL) was added, and the emulsion was allowed to settle. The EtOAc layer was finally washed with brine and dried over sodium sulfate. Evaporation of the EtOAc layer's volatile components afforded a viscous, amber taffy (62.3 g, 95%). This crude product was used without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:21]=[CH:20][C:8]2[N:9]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[O:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+]>CCO>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[C:10]1[O:11][C:7]2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:21]=[CH:20][C:8]=2[N:9]=1
Reactant: COC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)oc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2nc(-c3c(Cl)cccc3Cl)oc2c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(2,6-dichlorophenyl)-benzooxazole-6-carboxylic acid methyl ester (1.6 g) in EtOH (13 mL) was added 4N NaOH aqueous solution (6.2 mL). The reaction was stirred at 80° C. for 0.5 h. The reaction mixture was concentrated, diluted with water, and treated with Et2O. The aqueous layer was acidified with 1N HCl aqueous solution. The precipitate was filtered, washed with water, and dried in vacuo to give 2-(2,6-dichloro-phenyl)-benzooxazole-6-carboxylic acid as a white solid: MS (m/z) 308.0 (M+1).
Reaction SMILES: [F:1][C:2]([F:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH2:5])=O.B>C1COCC1>[F:1][C:2]([F:12])([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH2:3][NH2:5]
Reactant: NC(=O)C(F)(F)c1ccccc1
Agent: B
Solvent: C1CCOC1
Product: NCC(F)(F)c1ccccc1
Reaction time: 20 h
Yield: 83.9 %

Procedure:
To a s solution of 2,2-difluoro-2-phenyl-acetamide (0.76 g, 4.4 mmol) in THF (5 mL) is added Borane in THF (1 M, 20 mL, 20 mmole) at 10° C. After 70° C. for 20 h, the mixture is quenched with water (10 mL), concentrated, and chromatographed on SiO2 eluting with 90% EtOAc in heptane to afford 2,2-difluoro-2-phenyl-ethylamine (0.58 g). LCMS: RT 0.92 minutes; MS: 158 (M+H); 1H NMR (300 MHz, CDCl3) □7.57-7.45 (5H, m), 3.2 (2H, t).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Br:33])C(=O)C1>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:9]2=[C:10]([Br:33])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2-c1ccc(OC)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CCOC(=O)c1nc(Br)c2c(c1O)c(Br)c(Br)n2-c1ccc(OC)cc1

Procedure:
Prepared in analogy to that of Example 133(a) from 2,3-Dibromo-4-hydroxy-1-(4-methoxy-phenyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester and NBS in MeCN. The title compound, ESI MS (m/z): 547 (M+H)+.
Reaction SMILES: B(O)(O)[C@H]1N(C([C@@H](N)C(C)C)=O)CCC1.CS(O)(=O)=O.[CH3:21][O:22][C:23](=[O:30])[CH2:24][C@H:25]([CH2:28][F:29])[CH2:26]Br.[CH2:31]([O:33][C:34](=[O:44])[CH2:35][NH:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH3:32]>C(#N)C>[CH3:21][O:22][C:23](=[O:30])[CH2:24][C@H:25]([CH2:28][F:29])[CH2:26][N:36]([CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[CH2:35][C:34]([O:33][CH2:31][CH3:32])=[O:44]
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: COC(=O)C[C@H](CF)CBr
Agent: CC(C)[C@H](N)C(=O)N1CCC[C@H]1B(O)O
Agent: CS(=O)(=O)O
Solvent: CC#N
Product: CCOC(=O)CN(Cc1ccccc1)C[C@@H](CF)CC(=O)OC
Temperature: 25 °C
Yield: 100.1 %

Procedure:
In a 2.5-1 four-necked flask equipped with a mechanical stirrer, a reflux condenser, a Pt-100 thermometer, and an argon in/outlet, bromide 2 (110 g, 519 mmol) was dissolved in acetonitrile (880 ml). To this solution was added N-benzylglycine ethyl ester (256 g, 1.30 mol) and the reaction mixture was refluxed for 71 hours, slowly turning dark red during this time. After cooling to room temperature, the mixture was concentrated under reduced pressure. The dark red oil was filtered over silica gel (800 g) using EtOAc:heptane 1:9 as eluent, giving the crude title compound 3 (169 g) as yellow oil which was used without further purification.
Reaction SMILES: CC1N=C(N2C(=O)N(CC3C=CC(C(F)(F)F)=CC=3)N=C2)SC=1C(O)=O.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[C:37](=[O:38])[N:36]([C:39]3[S:40][C:41]([C:45](O)=[O:46])=[C:42]([CH3:44])[N:43]=3)[CH:35]=[N:34]2)=[CH:30][CH:29]=1.[CH3:50][N:51]1[CH:55]=[C:54]([CH2:56][NH2:57])[N:53]=[CH:52]1>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[C:37](=[O:38])[N:36]([C:39]3[S:40][C:41]([C:45]([NH:57][CH2:56][C:54]4[N:53]=[CH:52][N:51]([CH3:50])[CH:55]=4)=[O:46])=[C:42]([CH3:44])[N:43]=3)[CH:35]=[N:34]2)=[CH:48][CH:49]=1
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: Cn1cnc(CN)c1
Agent: Cc1nc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)O
Product: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)NCc1cn(C)cn1
Yield: 71 %

Procedure:
Following the procedure as described in Example 21, making variations as required to replace 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylic acid with 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid to react with (1-methyl-1H-imidazol-4-yl)methanamine, the title compound was obtained as a white solid in 71% yield: mp 225-226° C. (ethyl acetate/hexane); 1H NMR (300 MHz, CDCl3) δ 8.24 (s, 1H), 7.55 (s, 1H), 7.41-7.32 (m, 2H), 7.08-6.97 (m, 2H), 6.91 (s, 1H), 6.78 (t, J=5.3 Hz, 1H), 4.96 (s, 2H), 4.53 (d, J=5.3 Hz, 2H), 3.70 (s, 3H), 2.64 (s, 3H); MS (ES+) m/z 428.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:26])=[C:11]([CH2:13][CH2:14][O:15]S(C3C=CC(C)=CC=3)(=O)=O)[N:12]=2)=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30](=[O:42])[C:31]([O:34][C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1)([CH3:33])[CH3:32])[CH3:28].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:27]([O:29][C:30](=[O:42])[C:31]([O:34][C:35]1[CH:40]=[CH:39][C:38]([O:15][CH2:14][CH2:13][C:11]2[N:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[O:9][C:10]=2[CH3:26])=[CH:37][CH:36]=1)([CH3:33])[CH3:32])[CH3:28]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Yield: 44 %

Procedure:
A mixture of toluene-4-sulfonic acid 2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethyl ester, 2-(4-hydroxyphenoxy)-2-methylpropanoic acid ethyl ester (American Home Products U.S. Pat. No. 3,795,691) (7.06 g, 31.5 mmol) and Cs2CO3 (13.3 g, 41.0 mmol) was heated at 55° C. in DMF (45 mL) for 18 h. The reaction was partitioned between ethyl acetate (250 mL) and H2O (250 mL), and the aqueous phase extracted with ethyl acetate (2×100 mL). The combined organic phases were dried (MgSO4) and concentrated under reduced pressure to an oil which was purified by column chromatography (1500 mL SiO2, hexanes to 10% ethyl acetate/hexanes) to provide 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl propionic acid ethyl ester (6.81 g, 44%) as a off-white solid: Rf-=0.48 in 35% ethyl acetate/hexanes; mp 78-79° C.; 1H NMR (300 MHz, CDCl3) δ7.85-7.82 (m, 2H), 7.57-7.53 (m, 2H), 6.83-6.75 (m, 4H), 4.22 (q, J=7.0 Hz, 2H), 4.18 (t, J=6.6 Hz, 2H), 2.94 (t, J=6.7 Hz, 2H), 2.36 (s, 3H), 1.52 (s, 6H), 1.27 (t, J=7.0 Hz, 3H) and by-product 2-(4-Bromophenyl)-5-methyl-4-vinyloxazole (1.81 g, 22%) as a white solid:
Reaction SMILES: [Cl:1][C@@H:2]([C@H:6]([OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[C:14](=O)(O)[O-].[Na+]>CO>[Cl:1][C@@H:2]([C@H:6]([OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:14])=[O:4]
Reactant: O=C([O-])O
Reactant: O=C(O)[C@@H](Cl)[C@H](O)c1ccccc1
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H](Cl)[C@H](O)c1ccccc1
Reaction time: 1 h

Procedure:
A mixture of (2S,3R)-2-chloro-3-hydroxy-3-phenyl propionic acid (CIV, EXAMPLE 3, 2 g, 10 mmol) in methanol (20 ml, saturated with hydrochloric acid) is stirred at 25° for 1 hr. The reaction mixture is poured into a saturated aqueous sodium bicarbonate (20 ml) and extracted with ethyl acetate (20 ml×3). The combined organic phases are washed with water (20 ml) and dried over magnesium sulfate. Filtration and solvent removal under reduced pressure gives the title compound, [α]25D=−5.0° (c=1.5, CHCl3); NMR (300 MHz, CDCl3) 7.41-7.35, 5.19, 4.51 and 3.70 δ; CMR (300 MHz, CDCl3) 168.4, 138.1, 128.7, 128.5, 126.5, 74.4, 62.8 and 53.0 δ.