Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].[F:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][C:44]=1[CH:45]=[O:46]>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:41]3[CH:42]=[CH:43][C:44]([CH:45]=[O:46])=[C:39]([F:38])[CH:40]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: O=Cc1ccc(B(O)O)cc1F
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4ccc(C=O)c(F)c4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene obtained in Example 128-(4) and 3-fluoro-4-formylphenylboronic acid were treated in a manner similar to Example 168-(1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(3-fluoro-4-formylphenyl)-2-thienylmethyl)benzene as colorless foam. APCI-Mass m/Z 678/680 (M+NH4). (2) 1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(3-fluoro-4-formylphenyl)-2-thienylmethyl)benzene was treated in a manner similar to Example 178-(2) and (3) to give the desired 1-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-difluoromethyl-3-fluorophenyl)-2-thienylmethyl)benzene as a colorless foam. APCI-Mass m/Z 532/534 (M+NH4).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])=[CH:11][N:10]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[O:36][CH:37]=[CH:38][CH:39]=5)[O:32][C:33]=4[CH3:34])=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C.Cl>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:11][N:10]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[O:36][CH:37]=[CH:38][CH:39]=5)[O:32][C:33]=4[CH3:34])=[CH:25][CH:26]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)nc1-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccco2)nc1COc1ccc(Cn2cc(CCC(=O)O)c(-c3ccc(F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.3 %

Procedure:
A mixture of ethyl 3-[3-(4-fluorophenyl)-1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (350 mg), 1N aqueous sodium hydroxide solution (2 ml), ethanol (4 ml), and tetrahydrofuran (4 ml) was stirred at room temperature for 2 hours. The reaction mixture was acidified with dilute hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[3-(4-fluorophenyl)-1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (150 mg, yield: 45%). This was recrystallized from ethyl acetate-hexane. Melting point: 125–126° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:11]([O:15][C:16](=[O:31])[C:17]2[CH:22]=[CH:21][C:20]([O:23]CC3C=CC=CC=3)=[CH:19][CH:18]=2)[C@H:10]([NH:32][C:33](=[O:50])[C:34]2[CH:39]=[CH:38][C:37]([O:40][C:41](=[O:49])[C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=3)=[CH:36][CH:35]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:11]([O:15][C:16](=[O:31])[C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)[C@H:10]([NH:32][C:33](=[O:50])[C:34]2[CH:39]=[CH:38][C:37]([O:40][C:41](=[O:49])[C:42]3[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=3)=[CH:36][CH:35]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](OC(=O)c2ccc(OCc3ccccc3)cc2)[C@H](NC(=O)c2ccc(OC(=O)c3ccc(F)cc3)cc2)C1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](OC(=O)c2ccc(O)cc2)[C@H](NC(=O)c2ccc(OC(=O)c3ccc(F)cc3)cc2)C1
Reaction time: 2 h
Yield: 80.6 %

Procedure:
80mg (3R,4R)-4-(4-Benzyloxy-benzoyloxy)-3-[4-(4-fluoro-benzoyloxy)-benzoylamino]-azepane-1-carboxylic acid tert-butyl ester was dissolved in tetrahydrofuran. 10 mg 5% palladium on charcoal was added and the mixture hydrogenated at atmospheric pressure and room temperature for 2 hours. The catalyst was filtered on, the pad washed with tetrahydrofuran and the filtrate evaporated under reduced pressure. The residue was purified by chromatography on silica gel (10 g, AcOEt/Hexane 1:1eluent) to afford 56 mg (80% yield) (3R,4R)-3-[4-(4-Fluoro-benzoyloxy)-benzoylamino]-4-(4-hydroxy-benzoyloxy)-azepane-1-carboxylic acid tert-butyl ester as a colorless foam
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[Cl:11][CH2:12][C:13](=O)[CH2:14][C:15](OCC)=[O:16]>>[Cl:11][CH2:12][C:13]1[N:1]=[C:2]2[S:3][CH:4]=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]2[C:15](=[O:16])[CH:14]=1
Reactant: Nc1nc(C(F)(F)F)cs1
Reactant: CCOC(=O)CC(=O)CCl
Product: O=c1cc(CCl)nc2scc(C(F)(F)F)n12

Procedure:
This compound was synthesized from 2-amino-4-trifluoromethylthiazole, Step 1 intermediate (3.70 g, 22.541 mmol) and ethyl chloroacetoacetate (5.194 g, 31.558 mmol) in polyphosphoric acid (30.0 g) according to the procedure described in Step 1, Intermediate 2 to afford 4.0 g of the desired compound: 1H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H), 2.60 (s, 3H), 4.52 (s, 1H), 6.25 (s, 1H); ESI-MS (m/z) 269.22 (M+H)+.
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[N:11]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[CH:18][CH:17]=3)[N:12]=[C:13]([CH3:15])[CH:14]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:29]1(=O)[CH2:33][CH2:32][CH2:31][CH2:30]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:1]1([NH:7][C:8]([C:10]2[N:11]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH:23]4[CH2:24][CH2:25][N:26]([CH:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)[CH2:27][CH2:28]4)=[CH:20][CH:21]=3)[N:12]=[C:13]([CH3:15])[CH:14]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cc(C(=O)NC2CCCCC2)n(-c2ccc(OC3CCNCC3)cc2)n1
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(C(=O)NC2CCCCC2)n(-c2ccc(OC3CCN(C4CCCC4)CC3)cc2)n1
Reaction time: 1 h
Yield: 3.4 %

Procedure:
To a solution of 5-methyl-2-[4-(piperidin-4-yloxy)phenyl]-2H-pyrazole-3-carboxylic acid cyclohexylamide (60 mg, 0.157 mmol) in methylene chloride (9 mL) was added cyclopentanone (21 μL, 0.24 mmol) and acetic acid (150 μL). After 1 hour at room temperature, sodium triacetoxyborohydride (51 mg, 0.24 mmol) was added and the reaction was allowed to stir for an additional 4 hours. The reaction was quenched with 10% NaOH and extracted with methylene chloride. The methylene chloride solution was dried (MgSO4) and concentrated. The residue was purified by semi-prep LC-MS to give 2.4 mg of the desired product. LC-MS (C27H38N4O2 calculated 450) m/z 451 (M+H); 1H NMR (300 MHz, CDCl3) δ 7.34-7.31 (m, 2H), 7.01-6.98 (m, 2H), 6.78 (d, J=8.4 Hz, 1H), 6.70 (s, 1H), 4.42 (m, 1H), 3.95-3.93 (m, 1H), 2.87-2.83 (m, 2H), 2.68-2.54 (m, 3H), 2.23 (s, 3H), 2.15-1.14 (m, 22H).
Reaction SMILES: [OH:1]O.[CH3:3][S:4][CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=2[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:10][CH2:9][C:8]1=[O:25].O.N>C(O)(=O)C>[CH3:3][S:4]([CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=2[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:10][CH2:9][C:8]1=[O:25])=[O:1]
Reactant: CSCCN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Reactant: OO
Agent: N
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)CCN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 10 ml of 15% aqueous hydrogen peroxide is added with ice-cooling to a mixture of 1.5 g of 1-(β-methylthioethyl)-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one and 20 ml of acetic acid. The resultant mixture is stirred at 0° C for 30 minutes and then at room temperature for 1 hour. The reaction mixture is poured into ice water, basified with ammonia water and extracted with chloroform. The chloroform extracts are combined, dried over anhydrous sodium sulfate, and the solvent is removed under reduced pressure. The residue is allowed to stand to form crystals. Recrystallization from ethylacetate gives 1-(β-methylsulfinylethyl)-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one, m.p. 166° - 167° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:34])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[C:27]([CH3:32])[C:26]=4[F:33])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[NH2:35][C:36]1[CH:37]=[C:38]([O:42][CH2:43][CH2:44][N:45]([CH3:47])[CH3:46])[CH:39]=[CH:40][CH:41]=1>CC(O)C.Cl.C(Cl)Cl>[CH3:46][N:45]([CH3:47])[CH2:44][CH2:43][O:42][C:38]1[CH:37]=[C:36]([NH:35][C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:17]4[CH:18]=[C:19]([NH:23][C:24](=[O:34])[C:25]5[C:30]([F:31])=[CH:29][CH:28]=[C:27]([CH3:32])[C:26]=5[F:33])[CH:20]=[CH:21][CH:22]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)[CH:5]=[CH:4][N:3]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: Cc1ccc(F)c(C(=O)Nc2cccc(-c3nn4ccccc4c3-c3ccnc(Cl)n3)c2)c1F
Reactant: CN(C)CCOc1cccc(N)c1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: Cc1ccc(F)c(C(=O)Nc2cccc(-c3nn4ccccc4c3-c3ccnc(Nc4cccc(OCCN(C)C)c4)n3)c2)c1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a suspension of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluoro-3-methylbenzamide (100 mg, 0.21 mmol) (prepared in a manner similar to that described in Example 186) and {2-[(3-aminophenyl)oxy]ethyl}dimethylamine (47 mg, 0.26 mmol) in 2-propanol (3 mL) was added 2 drops of concentrated HCl. The reaction was stirred at 80° C. overnight. After 16 h, the mixture was diluted with DCM, washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered, and adsorbed onto silica. The crude product was purified by column chromatography to generate the title compound in 86% yield (112 mg, 0.18 mmol). 1H NMR (400 MHz, d6-DMSO) δ 10.90 (s, 1H), 9.55 (s, 1H), 8.86 (d, J=6.7 Hz, 1H), 8.51 (d, J=8.6 Hz, 1H), 8.28 (d, J=5.2 Hz, 1H), 8.01 (s, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.45-7.52 (m, 4H), 7.36 (d, J=7.3 Hz, 1H), 7.27 (d, J=8.1 Hz, 1H), 7.12-7.16 (m, 3H), 6.53 (d, J=5.1 Hz, 1H), 3.97 (t, J=5.6 Hz, 2H), 2.58 (t, J=5.8 Hz, 2H), 2.26 (s, 3H), 2.17 (s, 6H). MS (ESI) m/z=620 [M+H]+.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1.O[N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.Cl.C(OCC)(=O)C>[CH3:20][N:17]1[CH2:18][CH2:19][CH:14]([O:13][N:22]2[C:23](=[O:32])[C:24]3=[CH:31][CH:30]=[CH:29][CH:28]=[C:25]3[C:26]2=[O:27])[CH2:15][CH2:16]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CN1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCC(ON2C(=O)c3ccccc3C2=O)CC1
Temperature: 20 °C
Reaction time: 18 h
Yield: 27.5 %

Procedure:
N-(1-Methyl-4-piperidyloxy)phthalimide may be obtained in the following manner: diethyl azodicarboxylate (53.8 g) is added in the course of 90 minutes at a temperature in the region of 0° C. to a suspension of 4-hydroxy-1-methylpiperidine (30.6 g), N-hydroxyphthalimide (43.7 g) and triphenylphosphine (68.3 g) in tetrahydrofuran (450 cc). The suspension obtained is stirred at a temperature in the region of 20° C. for 18 hours and the reaction mixture is then concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the region of 40° C. The product obtained is taken up with ethyl acetate (500 cc) and the suspension obtained is filtered. The filtrate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the region of 40° C. The product obtained is redissolved in N aqueous hydrochloric acid solution (500 cc). The suspension obtained is filtered and the filtrate is extracted 3 times with ethyl ether (300 cc in total) and brought to a pH in the range of 10 by adding N aqueous sodium hydroxide solution (500 cc) The crystals which appear are separated by filtration, washed 3 times with distilled water (300 cc in total) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the region of 20° C. N-(1-Methyl-4-piperidyloxy)phthalimide (19 g) is thereby obtained in the form of beige crystals, m.p. 90° C.
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.O[CH:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1.[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1([F:18])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:17])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:8]([O:10][CH:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]2)=[O:9])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=C(O)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(OC(=O)[C@](O)(c2ccccc2)[C@@H]2CCC(F)(F)C2)CC1
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
To a solution of 128 mg of (2R)-2-((1R)-3,3-difluorocyclo-pentyl)-2-hydroxy-2-phenylacetic acid in 3 ml of dimethylformamide, 81 mg of carbonyldiimidazole was added and stirred for 30 minutes. Then 121 mg of 4-hydroxy-1-t-butoxycarbonylpiperidine and 10 mg of sodium hydride were added successively, followed by another 30 minutes' stirring. The reaction liquid was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the residue obtained was purified on silica gel column chromatography (eluent: hexane/ethyl acetate=3/1) to provide 121 mg of the title compound.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)=[O:19]
Reactant: CN1CCC(ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCC(ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)CC1
Reaction time: 2 h
Yield: 100.4 %

Procedure:
A mixture of (2S,5R)-6-(benzyloxy)-N-[(1-methylpiperidin-4-yl)oxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 51 (0.065 g, 0.167 mmol) and Pd/C (0.060 g) in methanol (30 mL) was hydrogenated at 35 psi at room temperature for 2 h. The mixture was filtered through a Celite pad and concentrated to provide 52 (0.050 g, quantitative) as alight yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([NH2:9])[N:3]=1.[C:10]([O:14][C:15]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C([O-])([O-])=O.[Na+].[Na+]>>[NH2:9][C:4]1[N:3]=[C:2]([C:20]2[CH:21]=[CH:22][C:17]([C:15]([O:14][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:16])=[CH:18][CH:19]=2)[C:7]([CH3:8])=[CH:6][N:5]=1
Reactant: CC(C)(C)OC(=O)c1ccc(B(O)O)cc1
Reactant: Cc1cnc(N)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cnc(N)nc1-c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 120 °C
Yield: 50.2 %

Procedure:
To 4-chloro-5-methylpyrimidin-2-amine (150 mg, 1.04 mmol), tetrakistriphenylphosphine Palladium (0) (60 mg, 0.052 mmol) and 4-(tert-butoxycarbonyl)phenylboronic acid (347 mg, 1.56 mmol), 1,2-DME (3 mL) and Na2CO3 (1.04 mL, 2 M, 2.08 mmol) were added and heated to 120° C. in a microwave reactor for 30 minutes. The reaction mixture was filtered using EtOAc and the filtrate was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to yield tert-butyl 4-(2-amino-5-methylpyrimidin-4-yl)benzoate (149 mg, 50%). ESI-MS m/z calc. 285.1, found 286.3 (M+1)+. Retention time 1.36 minutes.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5].[CH:8](OCC)=[O:9]>>[CH:8]([NH:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5])=[O:9]
Reactant: CC(C)(N)CCO
Reactant: CCOC=O
Product: CC(C)(CCO)NC=O
Temperature: 25 °C

Procedure:
3-Amino-3-methyl-1-butanol (20.60 g, 0.20 mol) was added to ethyl formate (29.60 g, 0.40 mol), and the resulting clear solution was heated to reflux under nitrogen for 2 hours, and then allowed to cool to room temperature. The ethyl formate and ethanol by-product were removed by rotary evaporation (35° C., 25 Torr). The resulting oil was dried under vacuum (25° C., 0.1 Torr) to yield 25.86 g (99%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([O:14][CH3:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH3:17][N:18]1[CH:22]([CH2:23][CH2:24]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:21][N:20]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[C:19]1=[O:47].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([O:14][CH3:15])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:24][CH2:23][CH:22]2[CH2:21][N:20]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:45])([F:46])[F:44])=[CH:39][CH:38]=3)[C:19](=[O:47])[N:18]2[CH3:17])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OC
Reactant: Cc1ccc(S(=O)(=O)OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1)OC
Temperature: 55 °C
Yield: 65.5 %

Procedure:
A mixture of 3-(4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester 0.027 g, 0.120 mmol), toluene-4-sulfonic acid 2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethyl ester (0.061 g, 0.133 mmol) and Cs2CO3 (0.059 g, 0.181 mmol) in DMF (4 mL) was heated to 55° C. under N2 for 16 h. The reaction was cooled and quenched with 1 N HCl (10 mL) and worked up extractively with Et2O and water. The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford crude product that was purified by flash chromatography using 4:1 then 3:1 hexanes:acetone to afford 0.040 g (64%) 2-methoxy-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester. 1H NMR. MS (ES+) Calc'd for C26H32N2O5F3 (M+1) 509. Found m/z 509 (100%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[CH2:17]([O:19][C:20]([CH:22]1[CH2:27][CH2:26][N:25]([C:28]([C:30]2[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=2)[NH2:33])=[O:29])[CH2:24][CH2:23]1)=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([CH:22]1[CH2:23][CH2:24][N:25]([C:28]([C:30]2[CH:31]=[C:32]([NH:33][C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=4)[C:5]([F:16])=[CH:4][N:3]=3)[CH:34]=[CH:35][CH:36]=2)=[O:29])[CH2:26][CH2:27]1)=[O:21])[CH3:18]
Reactant: CCOC(=O)C1CCN(C(=O)c2cccc(N)c2)CC1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Product: CCOC(=O)C1CCN(C(=O)c2cccc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)c2)CC1

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and 3-[[4-(ethoxycarbonyl)piperidino]carbonyl]aniline were reacted to provide N2-[3-[[4-(ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.92 (d, 1H, J=3.6 Hz), 7.82 (s, 1H), 7.62 (td, 1H, J=1.2 and 8.4 Hz), 7.30 (t, 1H, J=8.4 Hz), 7.19-7.09 (m, 3H), 6.93 (d, 1H, J=7.5 Hz), 6.55 (td, 1H, J=1.2 and 7.5 Hz), 4.43 (bd, 1H, J=12.3 Hz), 4.13 (q, 2H, J=6.9 Hz), 3.7 (bd, 1H, J=11.7 Hz), 3.10-2.92 (m, 2H), 2.67-2.55 (m, 1H), 2.06-1.50 (m, 4H), 1.24 (t, H, J=6.9 Hz); 19F NMR (282 MHz, CD3OD): −47299; LCMS: purity: 99%; MS (m/e): 480 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][CH:30]([C:33]([O:35]CC)=[O:34])[CH2:29][CH2:28]1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1(C)C=CC=CC=1>[CH3:18][N:16]1[C:15](=[O:19])[CH:14]=[CH:13][C:12]([C:10](=[O:11])[CH2:9][C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([N:27]3[CH2:28][CH2:29][CH:30]([C:33]([OH:35])=[O:34])[CH2:31][CH2:32]3)=[CH:7][CH:6]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])=[CH:17]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)c1)c1ccc(N2CCC(C(=O)O)CC2)cc1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-5-(3-(4-bromophenyl)-3-o-tolylpropanoyl)-1-methylpyridin-2(1H)-one (example 223, step 3; 500 mg, 1.22 mmol) in toluene (7 mL) was added ethyl piperidine-4-carboxylate (293 mg, 1.83 mmol), sodium tert-butoxide (234 mg, 2.44 mmol), tris(di-benzylideneacetone)dipalladium(0) (22.3 mg, 24.4 μmol) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (23.7 mg, 48.7 μmol) and the reaction mixture was stirred for 1 h at 85° C. The reaction mixture was evaporated and the residue chromatographed to afford the title compound (101 mg, 18%; light yellow foam, MS (ESI−): m/z=: 457.4 [M−H]−) and (R)-methyl 1-(4-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxo-1-o-tolylpropyl)phenyl)piperidine-4-carboxylate (174 mg, 30%; light yellow foam, MS (ESI+): m/z=: 487.4 [M+H]+).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH:8]1[C:17](=O)[C:16]2[C:15]([C:19](OC)=[O:20])=[CH:14][CH:13]=[CH:12][C:11]=2[NH:10][CH:9]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:2].O.[NH2:30][NH2:31]>CO>[CH2:1]([N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH:8]1[C:17]2=[N:30][NH:31][C:19](=[O:20])[C:15]3[CH:14]=[CH:13][CH:12]=[C:11]([C:16]=32)[NH:10][CH:9]1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:2]
Reactant: CCn1ccnc1C1C(=O)c2c(cccc2C(=O)OC)NC1c1ccccc1
Reactant: NN
Solvent: O
Solvent: CO
Product: CCn1ccnc1C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
Methyl 3-(1-ethyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (190 mg, 0.49 mmol) and hydrazine monohydrate (2 mL) were added to methanol (15 mL) and the mixture was stirred room temperature for 3 hrs. Methanol was evaporated and then filtered. The filtrate was concentrated to give 9-(1-ethyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one as a white solid (50 mg, yield 28%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm); 0.96 (t, 3H), 3.74-3.79 (m, 2H), 4.61 (d, 1H), 4.95 (d, 1H), 6.78 (dd, 1H), 6.91 (dd, 1H), 7.16 (d, 1H), 7.23-7.31 (m, 4H), 7.37 (s, 3H), 7.57 (t, 1H). LC-MS (ESI) m/z: 358 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:5]2[O:6][C:7]([CH3:12])([CH3:11])[CH:8]3[O:10][CH:9]3[C:4]=2[CH:3]=1.[OH-].[Na+].C(O)C.Cl[O-].[Na+]>O>[CH3:11][C:7]1([CH3:12])[O:6][C:5]2=[CH:13][C:14]3[C:2]([CH:3]=[C:4]2[CH:9]2[O:10][CH:8]12)=[N:1][O:16][N+:15]=3[O-:17]
Reactant: CC1(C)Oc2cc([N+](=O)[O-])c(N)cc2C2OC21
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(C)Oc2cc3c(cc2C2OC21)no[n+]3[O-]

Procedure:
To a mixture of 4.41 g (18.9 m mol) of 6-amino-3,4-dihydro-2,2-dimethyl-3,4-epoxy-7-nitro-2H-benzo [b] pyran, 1.29 g (32 m mol) of sodium hydroxide, 400 ml of ethanol and 40 ml of water were added slowly dropwise 32.2 g (26 m mol) of 6% sodium hypochlorite solution at the room temperature with stirring.