Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]([CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[C:35]([C:40](=[O:42])[NH2:41])[CH:34]=1)[CH2:9][CH:10]([OH:29])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:21]([CH3:28])[N:20]=2)=[CH:15][CH:14]=1)C1C=CC=CC=1.[H][H]>[Pd].CO>[C:40]([C:35]1[CH:34]=[C:33]([CH:38]=[CH:37][C:36]=1[OH:39])[O:32][CH2:31][CH2:30][NH:8][CH2:9][CH:10]([OH:29])[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:21]([CH3:28])[N:20]=2)=[CH:17][CH:18]=1)(=[O:42])[NH2:41]
Reactant: Cn1nc(-c2ccc(OCC(O)CN(CCOc3ccc(O)c(C(N)=O)c3)Cc3ccccc3)cc2)nc1C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cn1nc(-c2ccc(OCC(O)CNCCOc3ccc(O)c(C(N)=O)c3)cc2)nc1C(F)(F)F

Procedure:
After the addition of 2 g of palladium-on-carbon catalyst (5%), a solution of 22 g of crude 1-[N-benzyl-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]]-3-[4-(1-methyl-5-trifluoromethyl-1H-1,2,4-triazol-3-yl)-phenoxy]-2-propanol in 320 ml of methanol is hydrogenated under normal conditions until the calculated quantity of hydrogen has been absorbed (3 hours). The product, which has partly crystallised out, is made into a solution by the addition of 1000 ml of dioxan and heating, the catalyst is filtered off and the filtrate is concentrated by evaporation. The crystalline residue that remains is recrystallised from approximately 400 ml of dioxan and yields 1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(1-methyl-5-(trifluoromethyl)-1H-1,2,4-triazol-3-yl)-phenoxy]-2-propanol having a melting point of 206°-208°.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[OH:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[OH:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: O=Cc1ccc(F)cc1
Reactant: OCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(N2CCC(CO)CC2)cc1
Temperature: 100 °C

Procedure:
A suspension of 4-fluorobenzaldehyde (4.3 mL), 4-hydroxymethylpiperidine (4.8 g), and cesium carbonate (26 g) in DMF (80 mL) was heated to 100° C. for 24 h and cooled to room temperature. Water (400 mL) was added, and the resulting precipitate was collected by filtration to give the title compound as a tan amorphous powder (4.1 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][CH:3]=1.[CH3:11][C:12]([CH3:17])([CH2:15]O)[CH2:13]O>C1(C)C=CC=CC=1>[CH3:11][C:12]1([CH3:17])[CH2:15][O:10][B:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[O:9][CH2:13]1
Reactant: CC(C)(CO)CO
Reactant: OB(O)c1ccc(O)cc1
Solvent: Cc1ccccc1
Product: CC1(C)COB(c2ccc(O)cc2)OC1
Yield: 96.4 %

Procedure:
A solution of 4-hydroxyphenyl boronic acid (15.0 g) and 2,2-dimethyl-1,3-propanediol (11.4 g) in toluene (100 mL) was heated under reflux for 6 hours 30 minutes (using Dean-Stark apparatus). The resultant reaction mixture was allowed to cool and stand still and therefrom, a precipitates were filtered out and the solvent was distilled off under reduced pressure to obtain the subject compound (21.6 g) as a light gray solid.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:24]=[N:25][N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:27]=3)=[CH:13][CH:12]=2)[C:8]2[CH:47]=[CH:48][CH:49]=[CH:50][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]>Cl.O1CCOCC1.O>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]2[CH:47]=[CH:48][CH:49]=[CH:50][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 1.5 h
Yield: 37.4 %

Procedure:
2-Butyl-1-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methyl]benzimidazole (E) (400 mg) was dissolved in an 8M solution of hydrogen chloride in dioxan (5 ml) and water (0.5 ml) was added. The solution was allowed to stand for 1.5 hours and then volatile material was removed by evaporation. The residue was partitioned between sodium hydrogen carbonate solution (10 ml) and ether (10 ml). The aqueous phase was separated, washed with ether (3×10 ml) and acidified to pH4 with 20% aqueous citric acid. The precipitated solid was collected and recrystallised from ethyl acetate to give 2-butyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]benzimidazole (94 mg), as white crystals, m.p. 230°-232° C.; NMR (d6 -DMSO): 0.88(t,3H), 1.35(m,2H), 1.7(m,2H), 2.8(t,2H), 5.5(s,2H), 7.0(s,4H), 7.15(m,2H), 7.4-7.7 (complex, 6H); mass spectrum (-ve FAB, DMSO/NBA): 407 (M-H)-, 379; microanalysis found: C,73.7; H,6.2; N,20.8; C25H24N6 requires: C,73.5; H,5.9; N,20.6%.
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:27])[C:9]=1[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:14]=1)=[O:12]>C(O)(=O)C.C(OCC)(=O)C>[Cl:27][C:8]1[CH:7]=[N+:6]([O-:1])[CH:5]=[C:4]([Cl:3])[C:9]=1[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:14]=1)=[O:12]
Reactant: OO
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)cc1OC1CCCC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(C(=O)Cc2c(Cl)c[n+]([O-])cc2Cl)cc1OC1CCCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Aqueous 27.5% hydrogen peroxide (0.32 mL) is added to a solution of 3-cyclopentyloxy-4-methoxyphenyl 3,5-dichloropyrid-4-ylmethyl ketone (990 mg) in glacial acetic acid (13 mL). The. reaction is heated at 80° C. for 8 hours then allowed to stand overnight at room temperature. A further aliquot of aqueous 27.5% hydrogen peroxide (0.32 mL) is added and the mixture heated at 80° C. for 2 hours. The reaction mixture is diluted with ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate until the washings remained basic. The mixture is washed with brine (50 mL), dried (MgSO4), concentrated and the residue recrystallized from a mixture of dichloromethane/ethyl acetate/heptane to give 3,5-dichloro-4-(2-(3-cyclopentyloxy4-methoxyphenyl)-2-oxoethyl)pyridine-N-oxide as a yellow solid, m.p. 179-180° C. [Elemental analysis: C,57.3; H,4.81; N,3.54; Cl,18.0%; calculated for C19H19Cl2NO4 : C,57.59; H,4.83; N,3.53; Cl,17.89%.]
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([Si:12](Cl)([CH2:15][CH3:16])[CH2:13][CH3:14])[CH3:11].[Br:18][C:19]1[S:23][C:22]2=[C:24]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[N:25]=[CH:26][N:21]2[C:20]=1[CH2:33][OH:34]>CN(C)C=O.C(OCC)(=O)C>[Br:18][C:19]1[S:23][C:22]2=[C:24]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[N:25]=[CH:26][N:21]2[C:20]=1[CH2:33][O:34][Si:12]([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:10][CH3:11]
Reactant: CC[Si](Cl)(CC)CC
Reactant: OCc1c(Br)sc2c(-c3cccnc3)ncn12
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)OCc1c(Br)sc2c(-c3cccnc3)ncn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Diisopropylethylamine (3.1 ml) and 3.0 ml of triethylsilylchloride were added in that order to a solution of 4.05 g of 2-bromo-7-(pyridin-3-yl)hydroxymethylimidazo[5,1-b]thiazole in 30 ml of dimethylformamide, and the mixture was stirred at room temperature for one hr. The reaction mixture was diluted with ethyl acetate, and the diluted reaction mixture was washed with water, a 5% aqueous sodium bicarbonate solution, and a 20% aqueous sodium chloride solution in that order and was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, and the residue was purified by column chromatography on silica gel (2 to 5% methanol/methylene chloride) to give 5.14 g of 2-bromo-7-(pyridin-3-yl)triethylsilyloxymethylimidazo[5,1-b]thiazole.
Reaction SMILES: C[O:2][C:3](=[O:30])[C@@H:4]([O:27][CH2:28][CH3:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[S:17][CH:18]=2)=[CH:8][C:7]=1[Cl:26].[Li+].[OH-]>>[Cl:26][C:7]1[CH:8]=[C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[S:17][CH:18]=2)[CH:10]=[CH:11][C:6]=1[CH2:5][C@H:4]([O:27][CH2:28][CH3:29])[C:3]([OH:30])=[O:2]
Reactant: CCO[C@@H](Cc1ccc(OCc2csc(-c3ccc(Cl)cc3)n2)cc1Cl)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OCc2csc(-c3ccc(Cl)cc3)n2)cc1Cl)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], (2S)-3-{2-chloro-4-[2-(4-chloro-phenyl)-thiazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionic acid methyl ester was treated with LiOH to obtain (2S)-3-{2-chloro-4-[2-(4-chloro-phenyl)-thiazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionic acid as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@H:11]([C:17]([O:19][CH3:20])=[O:18])[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:9])[N:6]=1.[CH3:21][C:22]1[CH:54]=[CH:53][C:25]2[CH:26]([C:36]3[C:37](=[S:52])[NH:38][C:39](=[O:51])[N:40]([CH2:42][C:43]4[O:47][C:46]([C:48](O)=[O:49])=[CH:45][CH:44]=4)[CH:41]=3)[C:27]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:28]=3[CH:29]=[CH:30][C:24]=2[CH:23]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH3:35][C:32]1[CH:33]=[CH:34][C:27]2[CH:26]([C:36]3[C:37](=[S:52])[NH:38][C:39](=[O:51])[N:40]([CH2:42][C:43]4[O:47][C:46]([C:48]([NH:1][C:2]5[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@H:11]([C:17]([O:19][CH3:20])=[O:18])[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:9])[N:6]=5)=[O:49])=[CH:45][CH:44]=4)[CH:41]=3)[C:25]3[CH:53]=[CH:54][C:22]([CH3:21])=[CH:23][C:24]=3[CH:30]=[CH:29][C:28]=2[CH:31]=1
Reactant: COC(=O)C[C@H](NC(=O)Cc1csc(N)n1)C(=O)OC
Reactant: Cc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(Cc2ccc(C(=O)O)o2)c(=O)[nH]c1=S
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C[C@H](NC(=O)Cc1csc(NC(=O)c2ccc(Cn3cc(C4c5ccc(C)cc5C=Cc5cc(C)ccc54)c(=S)[nH]c3=O)o2)n1)C(=O)OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of the product of step (ii) (0.22 g), product of example 11(0.2 g), bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate (0.24 g), 4-dimethylaminopyridine (0.056 g) and N,N-diisopropylethylamine (0.2 ml) in dimethylformamide (5 ml) was stirred at room temperature for 24 hours. The mixture was partitioned between ethyl acetate and brine, washed with saturated aqueous sodium bicarbonate, dilute HCl and brine, dried (MgSO4) and evaporated. Purification was by chromatography eluting with ethyl acetate. Yield 0.24 g.
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[C:4]([NH:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([S:17](=[O:26])(=[O:25])[NH:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:9][CH:8]=1)=[O:5].[C:31](Cl)(=[O:35])[CH2:32][CH2:33][CH3:34].C(N(CC)CC)C>C1COCC1>[C:31]([N:22]1[CH2:23][CH2:24][CH:19]([NH:18][S:17]([C:10]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:16]=3[C:7]([NH:6][C:4](=[O:5])[C:3]3[CH:27]=[CH:28][CH:29]=[CH:30][C:2]=3[CH3:1])=[CH:8][CH:9]=2)(=[O:26])=[O:25])[CH2:20][CH2:21]1)(=[O:35])[CH2:32][CH2:33][CH3:34]
Reactant: CCCC(=O)Cl
Reactant: Cc1ccccc1C(=O)Nc1ccc(S(=O)(=O)NC2CCNCC2)c2c1CCCC2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3ccccc3C)c3c2CCCC3)CC1
Reaction time: 18 h
Yield: 34.6 %

Procedure:
To a 25° C. mixture of sulfonamide (26) (134 mg, 0.29 mmol) in THF (10 mL) was added butyryl chloride (77 mg, 0.725 mmol) and triethylamine (367 mg, 3.625 mmol). The mixture was stirred for 18 hours, followed by filtration to remove the precipitate. The filtrate was concentrated in vacuo and purified via chromatography, resulting in the title compound as white solid (50 mg). 1H NMR (300 MHz, MeOD) δ 7.91 (d, 1H), 7.55 (m, 2H), 7.41 (m, 1H), 7.31 (m, 2H), 4.30 (m, 1H), 3.89 (m, 1H), 3.21 (m, 2H), 3.09 (m, 1H), 2.85 (m, 2H), 2.61 (m, 1H), 2.55 (s, 3H), 2.34 (t, 2H), 1.88 (m, 7H), 1.62 (m, 2H), 1.39 (m, 2H), 0.95 (t, 3H)); LC/MS (M+H)+ m/z 498.
Reaction SMILES: Br[CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[C:7]([F:15])[CH:6]=1)[OH:4].C([O-])([O-])=O.[K+].[K+].CC(C)=O>O>[F:15][C:7]1[CH:6]=[C:5]([C@@H:3]2[CH2:2][O:4]2)[CH:10]=[CH:9][C:8]=1[C:11]([F:14])([F:13])[F:12]
Reactant: O[C@@H](CBr)c1ccc(C(F)(F)F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Fc1cc([C@@H]2CO2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
A mixture of (R)-2-bromo-1-(3-fluoro-4-(trifluoromethyl)phenyl)ethanol (3.0 g, 10 mmol), K2CO3 (2.9 g, 21 mmol) and acetone (50 mL) and was stirred for 18 h at RT, then poured in H2O and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with hexane/EtOAc (9:1) to afford 2.0 g (93%) of (R)-2-(3-fluoro-4-(trifluoromethyl)phenyl)oxirane (312).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([F:19])[CH:18]=1)[C:15]([N:20]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[N:14][CH:13]=[CH:12]2)C1C=CC=CC=1>[OH-].[Pd+2].[OH-].C(O)C>[C:31]([O:30][C:28]([N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:15]1[C:16]2[C:11](=[CH:10][C:9]([NH2:8])=[CH:18][C:17]=2[F:19])[CH:12]=[CH:13][N:14]=1)=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N(Cc3ccccc3)Cc3ccccc3)cc(F)c12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)cc(F)c12

Procedure:
A mixture of 19G (77 mg, 0.14 mmol), 20% palladium(II) hydroxide on carbon (94 mg) and ethanol (20 mL) was hydrogenated (55 psi) for 4 h. The reaction mixture was filtered and concentrated under reduced pressure to give 19H (47 mg, 90%) as a yellow solid. LC-MS m/z: 378.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19]/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[O:11][CH2:19]/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)/C=C/CBr
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)/C=C/COc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
A mixture of 3-fluoro-6-nitrophenol (200 g, 1.27 mol), anhydrous K2CO3 (202 g, 1.46 mol) and NMP (1.2 L) under nitrogen atmosphere was stirred at 25° C. for 30 min. Ethyl 4-bromocrotonate (80% tech., 252 mL, 1464 mmol) was added during 2-3 min to the obtained red suspension and the resulting mixture was stirred over night at ambient temperature. The yellowish suspension was then poured into ice-water (8.0 L) under stirring. After stirring for 1 h the solids were filtered off, washed with water (5×1.0 L), heptane (4×0.50 L) and then dried over night at 50° C. in vacuo affording the title compound (332 g, 1.20 mmol, 98% w/w, 95% yield).
Reaction SMILES: [N:1]1[C:9]2[C:8]([NH:10][CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[N:7][CH:6]=[N:5][C:4]=2[S:3][CH:2]=1.[H-].[Na+].Cl[C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([CH3:33])[N:24]=1>CN(C=O)C.O>[CH3:33][C:25]1[N:24]=[C:23]([O:19][C:16]2[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][NH:10][C:8]3[C:9]4[N:1]=[CH:2][S:3][C:4]=4[N:5]=[CH:6][N:7]=3)=[CH:14][CH:15]=2)[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=1
Reactant: Cc1cc(C(F)(F)F)cc(Cl)n1
Reactant: Oc1ccc(CCNc2ncnc3scnc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C(F)(F)F)cc(Oc2ccc(CCNc3ncnc4scnc34)cc2)n1
Temperature: 150 °C
Yield: 22.6 %

Procedure:
4-[2-(Thiazolo[5,4-d]pyrimidin-7-ylamino)-ethyl]-phenol (0.1 g, 0.37 mmol) was dissolved with magnetic stirring in DMF (1 mL) in a microwave reactor tube, and then treated with NaH (60% dispersion in oil; 13 mg, 0.55 mmol). After bubbling had subsided, 2-chloro-6-methyl-4-trifluoromethylpyridine (86 mg, 0.44 mmol) was added and the reaction mixture was sealed and placed in a CEM Discover® microwave reactor and irradiated for 30 min, with heating to 150° C. After cooling, the reaction mixture was diluted with H2O (5 mL) and partitioned into Et2O (3×10 mL). The pooled organic fractions were diluted with an equal volume of pentane, washed with H2O, dried (Na2SO4) and filtered through a SiO2/Celite plug. The filtrate was concentrated in vacuo to provide a brown wax (126 mg). Prep RP-HPLC purification (CH3CN/H2O eluent; C18 column) afforded {2-[4-(6-methyl-4-trifluoromethylpyridin-2-yloxy)-phenyl]-ethyl}-thiazolo[5,4-d]pyrimidin-7-ylamine (Compound 62; 36 mg) as an off white powder: mp 111-112° C.; 1H NMR (CDCl3) δ 8.76 (s, 1H), 8.55 (s, 1H), 7.31-7.29 (d, J=8.6 Hz, 2H), 7.11-7.07 (m, 3H), 6.83 (s, 1H), 6.22 (br s, 1H), 3.96-3.95 (br m, 2H), 3.05 (t, J=7.2 Hz, 2H), 2.51 (s, 3H); ESIMS m/z 432.2 ([M+H]+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[C:12](=[O:18])[N:11]([OH:19])[C:10]2=[O:20])=[CH:4][CH:3]=1.[C:21]([CH:25]=[CH:26]B(O)O)([CH3:24])([CH3:23])[CH3:22]>>[CH3:22][C:21]([CH3:24])([CH3:23])[CH:25]=[CH:26][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[C:12](=[O:18])[N:11]([OH:19])[C:10]2=[O:20])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C=CB(O)O
Reactant: O=c1c2sccc2n(Cc2ccc(Cl)nc2)c(=O)n1O
Product: CC(C)(C)C=Cc1ccc(Cn2c(=O)n(O)c(=O)c3sccc32)cn1

Procedure:
The title compound was prepared from 1-(6-chloro-pyridin-3-ylmethyl)-3-hydroxy-1H-thieno[3,2-d]pyrimidine-2,4-dione and 2-tert-butyl vinyl boronic acid via general procedure C. The crude product was purified by mass-triggered preparative HPLC. 1H NMR (DMSO-d6) δ 10.8 (bs, 1H), 8.53 (d, 1H, J=2.1 Hz), 8.14 (d, 1H, J=5.4 Hz), 7.62 (dd, 1H, J=2.1, 7.8 Hz), 7.38 (d, 1H, J=5.1 Hz), 7.36 (d, 1H, J=7.8 Hz), 6.78 (d, 1H, J=16.2 Hz), 6.35 (d, 1H, J=16.2 Hz), 5.29 (s, 2H), 1.09 (s, 9H); Electrospray MS: 358 (M+H); retention time: 2.62 min.
Reaction SMILES: C[O:2][C:3](=[O:28])[C@H:4]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)[NH:5][C:6]([C:8]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[N+:29]([C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34](O)=[O:35])([O-:31])=[O:30]>>[N+:29]([C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C@@H:4]([C:3]([OH:2])=[O:28])[NH:5][C:6]([C:8]2([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][CH2:10][CH2:11][CH2:12]2)=[O:7])=[CH:22][CH:23]=1)=[O:35])([O-:31])=[O:30]
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)C1(Cc2ccccc2)CCCC1
Product: O=C(Nc1ccc(C[C@H](NC(=O)C2(Cc3ccccc3)CCCC2)C(=O)O)cc1)c1ccccc1[N+](=O)[O-]
Yield: 62.4 %

Procedure:
4-Amino-N-[[1-(phenylmethyl)cyclopentyl]carbonyl]-L-phenylalanine methyl ester (31.7 mg, 0.083 mmol) and 2-nitrobenzoic acid (38 mg, 0.10 mmol) were reacted as described in example 34 to give 26.7 mg of 4-[[(2-nitrophenyl)carbonyl]amino]-N-[[1-(phenylmethyl)cyclopentyl]carbonyl]-L-phenylalanine, HR—FAB—MS: obs. mass 516.2113. Calcd. mass 516.2134 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([F:10])[F:9])[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:3]=1.[Br:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[Br:21][C:22]1[CH:27]=[C:26]([C:2]2[N:7]=[C:6]([CH:8]([F:10])[F:9])[CH:5]=[C:4]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)[N:3]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Product: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-difluoromethyl-6-(4-trifluoromethylphenyl)-pyrimidine (example A.5) (0.5 g, 1.62 mmol) and commercially available 3-bromo-benzene-boronic acid (0.42 g, 2.20 mmol) according to the general procedure IVb. Obtained as a white solid (0.54 g, 78%). MS (EI) 430.0 [(M)+]; mp 98.5° C.
Reaction SMILES: [Br:1][C:2]1[C:3](=O)[NH:4][C:5]([CH3:15])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.P(Cl)(Cl)([Cl:19])=O>CN(C=O)C>[Br:1][C:2]1[C:3]([Cl:19])=[N:4][C:5]([CH3:15])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)c(Br)c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(Cl)cc2)c(Br)c(Cl)n1
Temperature: 100 °C
Reaction time: 7 h
Yield: 60 %

Procedure:
To a suspension of 3-bromo-4-(4-chlorophenyl)-6-methylpyridin-2(1H)-one (280 mg, 0.94 mmol) in phosphorus oxychloride (5 mL) was added anhydrous DMF (a few drops). The mixture was stirred at 100° C. for 7 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to remove most of the phosphorus oxychloride. The remaining liquid was cooled at 0° C. and carefully quenched by addition of water. The resulting mixture was then adjusted to pH 7-8 by addition of saturated aqueous NaHCO3. The mixture was then extracted with EtOAc (30 mL×3). The combined EtOAc extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified using a silica gel cartridge (12 g) eluted with a gradient of EtOAc (0-70%) in hexanes to obtain 180 mg (60%) of the title compound as a white solid. HPLC/MS: retention time=3.95 min, [M+H]+=316.0.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][C:13]([OH:24])([C:16]3[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH2:12][CH2:11]2)[CH2:7]1)=[O:4].[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([F:36])[C:34]=1[F:35])[C:29](O)=[O:30].CCN=C=NCCCN(C)C>>[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([F:36])[C:34]=1[F:35])[C:29]([NH:1][CH2:2][C:3](=[O:4])[NH:5][CH:6]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][C:13]([OH:24])([C:16]3[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH2:12][CH2:11]2)[CH2:7]1)=[O:30]
Reactant: O=C(O)c1cc(F)c(F)c(F)c1
Reactant: COc1ccc(C2(O)CCC(N3CC(NC(=O)CN)C3)CC2)cn1
Agent: CCN=C=NCCCN(C)C
Product: COc1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cc(F)c(F)c(F)c4)C3)CC2)cn1

Procedure:
The title compound was prepared from 2-amino-N-{1-[4-hydroxy-4-(6-methoxy-pyridin-3-yl)-cyclohexyl]-azetidin-3-yl}-acetamide, as prepared in Step D of Example 16, and 3,4,5-trifluorobenzoic acid by EDCI coupling using the procedure described in Step C of Example 16.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11](OCC)=[O:12])=[CH:8][CH:7]=[C:6]([C:16]([O:18][CH3:19])=[O:17])[CH:5]=2.C([O-])=O.[NH4+].[CH:24]([NH2:26])=O>O>[OH:12][C:11]1[C:10]2[C:9]3[C:4](=[CH:5][C:6]([C:16]([O:18][CH3:19])=[O:17])=[CH:7][CH:8]=3)[NH:3][C:2]=2[N:1]=[CH:24][N:26]=1
Reactant: CCOC(=O)c1c(N)[nH]c2cc(C(=O)OC)ccc12
Reactant: NC=O
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Product: COC(=O)c1ccc2c(c1)[nH]c1ncnc(O)c12
Temperature: 165 °C
Yield: 107.9 %

Procedure:
In a 100 mL round-bottom flask were added 3-ethyl 6-methyl 2-amino-1H-indole-3,6-dicarboxylate (1.1 g, 4.19 mmol), ammonium formate (0.53 g, 8.39 mmol), and formamide (16.7 mL, 419 mmol) to give a tan suspension which was heated to 165° C. for 12 hours. The mixture was allowed to cool to room temperature and water was added. The resulting precipitate was filtered, air-dried and dried under high vacuum overnight to afford 1.1 g of the title compound. LCMS m/z 244.2 (M+H)+, retention time (on analytical HPLC)=1.51 minutes.