Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=C2C(CCC(C(O)=O)C2)=CC=1.[CH3:16][O:17][C:18]1[CH:27]=[C:26]2[C:21]([CH2:22][CH2:23][CH2:24][C:25]2=[O:28])=[CH:20][CH:19]=1.[CH2:29]([O:31][C:32](=O)[O:33]CC)[CH3:30].[H-].[Na+]>O1CCCC1.O.C(O)(=O)C>[CH2:29]([O:31][C:32]([CH:24]1[CH2:23][CH2:22][C:21]2[C:26](=[CH:27][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[C:25]1=[O:28])=[O:33])[CH3:30]
Reactant: COc1ccc2c(c1)C(=O)CCC2
Reactant: CCOC(=O)OCC
Agent: COc1ccc2c(c1)CC(C(=O)O)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1CCc2ccc(OC)cc2C1=O
Temperature: 60 °C
Yield: 96.4 %

Procedure:
The starting 7-methoxy-1,2,3,4-tetrahydronaphthalen-2-carboxylic acid, which is a known product, can be prepared as follows: a solution of 7-methoxy-3,4-dihydronaphthalene-1(2H)-one (66.4 g, 0.376 mol) in anhydrous tetrahydrofuran (350 ml) is added in 1 hour to a mixture of distilled diethylcarbonate (116 ml, 0.957 mol), 80% sodium hydride (39.7 g, 1.32 mol) and anhydrous tetrahydrofuran (350 ml) heated to 60° C. The thus obtained reaction mixture is refluxed for 4 hours and then cooled. Acetic acid is then added dropwise up to acidic pH and water is added until complete dissolution of the precipitate occurs. The solution is extracted with ethyl ether, the organic phase is washed with water and with a sodium bicarbonate solution, dried and evaporated to dryness. The thus obtained oily product is purified by distillation under reduced pressure yielding 90 g of 7-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-carboxylic acid ethyl ester. B.p.0.4 mmHg 160°-165° C.
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[CH2:14][CH2:15][C:16]([OH:18])=O)[CH2:4][CH2:3][CH2:2]1.[CH:19]([NH:22][NH:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:21])[CH3:20].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[CH2:14][CH2:15][C:16]([N:22]([CH:19]([CH3:21])[CH3:20])[NH:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:18])[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(O)CCc1cc(F)ccc1OCC1CCC1
Reactant: CC(C)NNC(=O)c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1cc(F)ccc1OCC1CCC1
Yield: 17 %

Procedure:
A solution of 3-(2-cyclobutylmethoxy-5-fluoro-phenyl)-propionic acid (195 mg, 0.77 mmoles) and benzoic acid N′-isopropyl-hydrazide (115 mg, 0.64 mmoles) in DMF (5 mL) was treated with diisopropylethylamine (0.28 mL, 1.61 mmoles), and PyBroP (450 mg, 0.97 mmoles) at room temperature for 48 h. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-40% ethyl acetate/hexanes gradient to afford the product as a solid (45 mg, 14%). LC-MS m/e 413.32(M+H+)
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:28]([CH3:29])=[CH:27][C:15]2[N:16]=[C:17]([C:19]3[C:24]([F:25])=[CH:23][N:22]=[C:21](Cl)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:37][N:38]1[C:46]2[C:41](=[CH:42][C:43](B(O)O)=[CH:44][CH:45]=2)[CH:40]=[N:39]1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C@@H:6]([C:12]1[C:28]([CH3:29])=[CH:27][C:15]2[N:16]=[C:17]([C:19]3[C:24]([F:25])=[CH:23][N:22]=[C:21]([C:43]4[CH:42]=[C:41]5[C:46](=[CH:45][CH:44]=4)[N:38]([CH3:37])[N:39]=[CH:40]5)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1ncc2cc(B(O)O)ccc21
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cc(Cl)ncc3F)sc2c1-c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cc(-c4ccc5c(cnn5C)c4)ncc3F)sc2c1-c1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
A microwave vial containing (S)-ethyl 2-(tert-butoxy)-2-(2-(2-chloro-5-fluoropyridin-4-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)acetate (22 mg, 0.04 mmol) was charged with (1-methyl-1H-indazol-5-yl)boronic acid (19 mg, 0.11 mmol), then Pd(PPh3)4 (9 mg, 0.008 mmol). The vial was flushed with argon, diluted with dioxane (2.0 mL) and to this was added 2M aqueous K2CO3 (0.10 mL, 0.20 mmol). The vial was sealed, heated to 120° C. for 3 hours, and then allowed to cool to room temperature. The mixture was diluted with EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (10-40% EtOAc/Hex gradient) to afford the desired product. LCMS-ESI+: calc'd for C35H33ClFN4O3S: 643.2 (M+H+); Found: 643.2 (M+H+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH:14]1[C:22]2[C:17](=[CH:18][C:19]([CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([C:30]4[CH:31]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:33]=[CH:34][CH:35]=4)[CH2:26][CH2:25]3)=[CH:20][CH:21]=2)[CH:16]=[CH:15]1>>[C:3]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:14]1[C:22]2[C:17](=[CH:18][C:19]([CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([C:30]4[CH:31]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:39])[CH3:40])[CH:33]=[CH:34][CH:35]=4)[CH2:26][CH2:25]3)=[CH:20][CH:21]=2)[CH:16]=[CH:15]1
Reactant: Ic1ccccc1-c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4c(ccn4-c4ccccc4-c4ccccc4)c3)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 2-iodo-1,1′-biphenyl and N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 528.3 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[C:3]([C:10]([OH:12])=[O:11])[CH:2]=1>C(OC(=O)C)(=O)C>[N:1]1[CH:6]=[CH:5][C:4]2[C:7]([O:12][C:10](=[O:11])[C:3]=2[CH:2]=1)=[O:9]
Reactant: O=C(O)c1ccncc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2cnccc21
Yield: 75.5 %

Procedure:
A mixture of 3,4-pyridine-dicarboxylic acid (15 g) and acetic anhydride (30 ml) is refluxed for 2 hours. The acetic anhydride in excess is distilled off and the residue is purified by sublimation (123° C. at 3 mmHg) to give 10.1 g of 3,4-pyridine-dicarboxylic acid anhydride, a white solid, m.p. 74-76° C.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cc[nH]c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-Methoxyindole (1.47 g, 10.00 mmol) was cooled to 0° C. in methylene chloride and BBr3 (2 M in methylene chloride, 25 mL, 50.00 mmol) was added. After stirring 16 h at room temperature, TLC analysis indicated the reaction was complete. The reaction was quenched with water and the layers separated. The organic layers were washed with 1 N NaOH. The basic aqueous layers were acidified with conc. HCL, extracted with methylene chloride, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the crude 6-hydroxyindole which was used directly for the next reaction.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH:16]([CH3:18])[CH3:17])[C@H:9]([CH2:14][CH3:15])[C:10](OC)=[O:11])[C:5]([N+:19]([O-])=O)=[CH:4][N:3]=1.[H][H]>C(O)(=O)C.[Ni]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:19][C:10](=[O:11])[C@@H:9]([CH2:14][CH3:15])[N:8]([CH:16]([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: [H][H]
Reactant: CC[C@H](C(=O)OC)N(c1nc(Cl)ncc1[N+](=O)[O-])C(C)C
Agent: [Ni]
Solvent: CC(=O)O
Product: CC[C@@H]1C(=O)Nc2cnc(Cl)nc2N1C(C)C
Temperature: 75 °C
Reaction time: 2 h
Yield: 206.5 %

Procedure:
Methyl (2R)-2-[(2-chloro-5-nitro-pyrimidin-4-yl)-isopropyl-amino]butanoate 22b (7.30 g, 23 mmol) was dissolved in 100 mL acetic acid followed by the addition of 5 g Raney nickel, repeated filled with hydrogen for three times. The reaction mixture was heated to 75° C., stirred for 2 hours and filtered. The filtrate was concentrated under reduced pressure, added with 30 mL of ice water resulting in the formation of precipitate. The precipitate was filtered. the filter cake was dried by heat to obtain the crude title compound (7R)-2-chloro-7-ethyl-8-isopropyl-5,7-dihydropteridin-6-one 22c (12.10 g, yield: 71.7%) as a gray solid, which was used in the next step without further furification.
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])=[C:10]([OH:21])[C:9]3[CH2:22][S:23][CH2:24][C:8]2=3)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[C:33]1([CH3:42])[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>CC(N(C)C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:21][C:10]1[C:9]2[CH2:22][S:23][CH2:24][C:8]=2[N:7]([CH2:6][C:5]2[CH:25]=[CH:26][C:2]([C:36]3[CH:37]=[CH:38][C:33]([CH3:42])=[CH:34][CH:35]=3)=[CH:3][CH:4]=2)[C:12](=[O:13])[C:11]=1[C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15]
Reactant: O=C(O)CNC(=O)c1c(O)c2c(n(Cc3ccc(Br)cc3)c1=O)CSC2
Reactant: Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc(-c2ccc(Cn3c4c(c(O)c(C(=O)NCC(=O)O)c3=O)CSC4)cc2)cc1
Temperature: 115 °C
Reaction time: 0.25 h

Procedure:
The product of Example 2 (2-1) (0.08 g, 0.16 mmol) was dissolved in DMA (2 mL) in a 10 mL reaction tube of a CEM Corporation Discover 300 Watt microwave reactor. An aq solution of Na2CO3 (2 M, 0.8 mL, 1.6 mmol), 4-tolylboronic acid (40 mg, 0.29 mmol) and bis(triphenylphosphine)palladium(II) chloride (11 mg, 0.016 mmol) were added and the tube was purged with nitrogen, capped and inserted into the microwave reactor. It was heated at 115° C., 50 watts maximum power, for 15 min. The reaction was diluted with EtOAc, washed with 2 M HCl, dried (Na2SO4), filtered and concentrated. The residue was purified by semi-preparative reverse phase HPLC on a C18 column eluted with 0-100% MeCN in water. The desired fractions were concentrated, dissolved in EtOAc and washed with water. The organic layer was dried (Na2SO4), filtered and concentrated affording the title compound (25-1). 450.9 (M+1); Rt=3.52 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([OH:20])[C:5]=1[O:21][CH3:22])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=1>C(#N)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([O:20][CH2:30][C:31]2[CH:32]=[CH:33][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:35][CH:36]=2)[C:5]=1[O:21][CH3:22])[CH3:2]
Reactant: CCOc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OC
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1ccc(-c2ccc3c(c2)COC3=O)c(OCc2ccc(S(C)(=O)=O)cc2)c1OC
Temperature: 80 °C
Yield: 16 %

Procedure:
To a stirring solution of 5-(4-ethoxy-2-hydroxy-3-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.266 mmol) in acetonitrile (7 mL) was added potassium carbonate (110 mg, 0.80 mmol) and 1-(bromomethyl)-4-(methylsulfonyl)benzene (99 mg, 0.399 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 0-40% ethyl acetate in pet ether) afforded title compound as a solid (20 mg, 16%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.[CH2:19]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)[CH2:20][CH2:21][CH3:22]>>[CH2:19]([C:23]1[S:24][C:25]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]3)[N:3]=2)=[CH:26][CH:27]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCc1cccs1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Product: CCCCc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)s1

Procedure:
The title compound was prepared analogous to Method C, starting from (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and 2-butyl-thiophene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=4)[C:24]([OH:26])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.[CH3:42][NH:43][S:44]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)(=[O:46])=[O:45].ClCCCl>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[CH:28][CH:27]=[C:23]([C:24](=[O:26])[N:43]([CH3:42])[S:44]([C:47]5[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=5)(=[O:46])=[O:45])[CH:22]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)O)c3)cc12
Reactant: CNS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)N(C)S(=O)(=O)c4ccccc4)c3)cc12
Yield: 55.3 %

Procedure:
In a 1 dram vial with stir bar were combined 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (35 mg, 0.090 mmol), DMAP (33 mg, 0.27 mmol), EDC hydrochloride (26 mg, 0.14 mmol), and N-methylbenzenesulfonamide (50 μL, 0.26 mmol). 1,2-Dichloroethane (0.5 mL) and DMF (0.5 mL) were added, the vial was capped, and the reaction was stirred at r.t. overnight. The reaction was filtered, purified by prep HPLC, and concentrated on a SPEEDVAC® to give 27 mg (55% yield) of the title compound as a white powder. 1H NMR (500 MHz, CDCl3) δ ppm 7.91-8.02 (m, 5H) 7.75-7.82 (m, 2H) 7.65 (t, J=7.48 Hz, 1H) 7.47-7.60 (m, 6H) 7.15-7.24 (m, 2H) 5.91 (d, J=4.27 Hz, 1H) 3.36 (s, 3H) 3.04 (d, J=4.88 Hz, 3H). LC/MS was performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters MICROMASS®. LC/MS method: solvent A=10% CH3CN/90% H2O/0.1% TFA, Solvent B=90% CH3CN/10% H2O/0.1% TFA, start % B=0, final % B=100, gradient time=2 min, stop time=3 min, flow rate=4 ml/min, column: Sunfire C18 5 μm 4.6×50 mm; HPLC Rt=1.89 min, (ES+) m/z (MH+)=543. Analytical HPLC were performed using a Shimadzu-VP instrument with UV detection at 220 nm and 254 nm. Analytical HPLC method: solvent A=5% CH3OH/95% H2O/10 mM NH4HCO3, solvent B=95% CH3OH/5% H2O/10 mM NH4HCO3, start % B=10, final % B=100, gradient time=15 min, stop time=18 min, flow rate=1 ml/min. Column: PHENOMENEX® Gemini C18, 4.6 mm, 3 μm, Rt=17.42 min, purity=92%; column: Waters XBridge phenyl 4.6×150 mm, 3.5 μm, Rt=17.86 min, purity>90%.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:6]=[CH:7][C:8]([C:16]([OH:18])=O)=[N:9][C:10]=2[O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[CH2:3][CH2:2]1.[NH2:19][C:20]([CH3:24])([CH3:23])[CH2:21][OH:22]>>[OH:22][CH2:21][C:20]([NH:19][C:16]([C:8]1[CH:7]=[CH:6][C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)=[C:10]([O:11][CH2:12][CH:13]2[CH2:14][CH2:15]2)[N:9]=1)=[O:18])([CH3:24])[CH3:23]
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1ccc(NC2CC2)c(OCC2CC2)n1
Product: CC(C)(CO)NC(=O)c1ccc(NC2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropylamino-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 133 b) and 2-amino-2-methyl-1-propanol (CAN 124-68-5) as starting materials, MS (EI): m/e=401.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH3:13])[C:5]2([CH3:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:27][C:28]1[C:32](B(O)O)=[C:31]([CH3:36])[O:30][N:29]=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:27][C:28]1[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[N:6]([CH3:13])[C:5]3([CH3:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:31]([CH3:36])[O:30][N:29]=1
Reactant: CN1C(=O)Nc2ccc(Br)cc2C1(C)c1ccccc1
Reactant: Cc1noc(C)c1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1noc(C)c1-c1ccc2c(c1)C(C)(c1ccccc1)N(C)C(=O)N2
Temperature: 100 °C

Procedure:
To a solution of 6-Bromo-3,4-dimethyl-4-phenyl-3,4-dihydro-1H-quinazolin-2-one (140 mg, 0.42 mmol) in dioxane (10 mL) is added Na2CO3 (67 mg, 0.64 mmol) and 3,5-dimethylisoxazole-4-boronic acid (78 mg, 0.55 mmol) and Pd(dppf)Cl2 then the mixture is refluxed at 100° C. overnight. The reaction is concentrated and is purified by chromatography on silica gel to give the desired product.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][C:6]=1[C:7]([N:9]1[CH2:13][CH2:12][CH:11]([O:14]S(C)(=O)=O)[CH2:10]1)=[O:8])([CH3:3])[CH3:2].[F:27][C:28]([F:41])([F:40])[C:29]1[CH:30]=[C:31](O)[CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1>>[F:27][C:28]([F:40])([F:41])[C:29]1[CH:30]=[C:31]([CH:32]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:34]=1)[O:14][CH:11]1[CH2:12][CH2:13][N:9]([C:7]([C:6]2[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:5]=2[O:4][CH:1]([CH3:3])[CH3:2])=[O:8])[CH2:10]1
Reactant: Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(OS(C)(=O)=O)C1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(Oc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Yield: 19 %

Procedure:
Prepared in analogy to Example 3(c) from rac-methanesulfonic acid 1-(2-isopropoxy-5-methanesulfonyl-benzoyl)-pyrrolidin-3-yl ester (Example 14(a)) and 3,5-bis(trifluoromethyl)phenol. The crude material was purified by reversed phase HPLC (acetonitrile/water) to yield the title compound as an amorphous white solid (yield 19%). MS (m/e): 540.3 (M+H+, 100%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)=[O:16])[CH2:12][CH:11]([C:22]([OH:24])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[N:26]=[C:27]([NH2:32])[CH2:28][CH2:29][O:30][CH3:31]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH:11]([C:22]3[O:24][N:32]=[C:27]([CH2:28][CH2:29][O:30][CH3:31])[N:26]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)=[O:16])[CH2:14]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CC(O)C3)C2)cc1
Reactant: COCCC(N)=NO
Product: CCc1ccc(C2CC(c3nc(CCOC)no3)CN(C(=O)N3CC(O)C3)C2)cc1

Procedure:
60 mg (0.18 mmol) of the compound from Example 138A and 43 mg (0.27 mmol) of N′-hydroxy-3-methoxypropanimidamide were reacted according to the General Method 2. Yield: 25 mg (33% of theory)
Reaction SMILES: C(O[CH:10]=[C:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[C:12]1=[O:23])(=O)C1C=CC=CC=1.[H][H]>C(O)(C)C.[Pt]=O>[CH3:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[C:12]1=[O:23]
Reactant: COc1ccc2c(c1)CCC(=COC(=O)c1ccccc1)C2=O
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(C)O
Product: COc1ccc2c(c1)CCC(C)C2=O
Yield: 73.3 %

Procedure:
2-Benzoyloxymethylene-6-methoxy-1-tetralone (4.6 g, 0.015 mole) was hydrogenated over platinum oxide (160 mg) in isopropyl alcohol (150 mL) at 55 psi in a Parr hydrogenation apparatus. After about 90 minutes hydrogen uptake ceased and the reaction was stopped. The catalyst was removed by filtration and the solvents were removed in vacuo. The title compound (2.0 g, 0.011 mole, 70% yield) was obtained after purification by flash chromatography [gradient 10:1 to 5:1 EtOAc:Hexanes].
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].C([O-])(=O)C.C([O-])(=O)C.[Pb+4:17]>C1COCC1>[C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[Pb+2:17]
Reactant: [Pb+4]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: [Pb+2]

Procedure:
The hydroxyimine compound (6.31 g, 0.02 mol) synthesized from the above step was dissolved in 300 ml of THF, and 9.35 g of lead tetraacetate (95%) was slowly added thereto with stirring. The reaction mixture was vigorously stirred for 2 hours, and lead diacetate crystals produced as a by-product was removed by filtration. After recrystallization from THF, 2-(4-nitrophenyl)-6-[N-methyl-N-(2-hydroxyethyl)amino]benzoxazole was obtained as dark red crystals [yield: 5.31 g, 85%].
Reaction SMILES: C([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][N:13]([CH:21]=[O:22])[CH2:14]2)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[CH:21]([N:13]1[CH2:12][CH2:11][C:10]2[C:15](=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[C:9]=2[OH:8])[CH2:14]1)=[O:22]
Reactant: COc1ccc2c(c1OCc1ccccc1)CCN(C=O)C2
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc2c(c1O)CCN(C=O)C2
Yield: 92 %

Procedure:
89.2 g of 5-benzyloxy-2-formyl-1,2,3,4-tetrahydro-6-methoxy-isoquinoline are dissolved in 450 ml of glacial acetic acid and hydrogenated at room temperature and normal pressure in the presence of 4.5 g of 5 percent palladium black. After conclusion of hydrogen absorption, the reaction mixture is separated from the catalyst by filtration and evaporated to dryness under reduced pressure. Recrystallization of the residue from ethanol gives 57.2 g of 2-formyl-1,2,3,4-tetrahydro-5-hydroxy-6-methoxy-isoquinoline. m.p. = 172.5° - 173.5° C.
Reaction SMILES: Cl.O1CCOCC1.[O:8]=[S:9]1(=[O:37])[CH2:14][CH2:13][CH:12]([CH2:15][S:16]([C:19]2[CH:20]=[C:21]([C:25](=[O:36])[CH2:26][CH2:27][NH:28]C(=O)OC(C)(C)C)[CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH2:11][CH2:10]1>C(Cl)Cl>[NH2:28][CH2:27][CH2:26][C:25]([C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([S:16]([CH2:15][CH:12]2[CH2:11][CH2:10][S:9](=[O:37])(=[O:8])[CH2:14][CH2:13]2)(=[O:17])=[O:18])[CH:20]=1)=[O:36]
Reactant: CC(C)(C)OC(=O)NCCC(=O)c1cccc(S(=O)(=O)CC2CCS(=O)(=O)CC2)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCCC(=O)c1cccc(S(=O)(=O)CC2CCS(=O)(=O)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HCl/dioxane (4N, 5 mL) was added at 0° C. to a solution of tert-butyl (3-(3-(((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)sulfonyl)phenyl)-3-oxopropyl)carbamate (0.40 g, 0.87 mmol) in CH2Cl2 (10 mL) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to give after purification by preparative HPLC Example 24 as a white solid. Yield (200 mg, 50%); 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.31 (d, J=7.6 Hz, 1H), 8.20 (d, J=7.6 Hz, 1H), 7.88 (m, 4H), 3.56-3.52 (m, 2H), 3.50-3.47 (m, 2H), 3.20-3.17 (m, 4H), 3.05-3.02 (m, 2H), 2.31 (bs, 1H), 2.17-2.14 (m, 2H), 1.85-1.77 (m, 2H); MS: m/z 360.18 [M+H]+.