Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:6]1[C:9](=[O:10])[NH:8][C@@H:7]1[CH2:11][C:12](=[O:27])[CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:15])([CH3:5])[CH3:4].C1(C)C=CC(S([N:37]=[N+:38]=[N-])(=O)=O)=CC=1.C(N(CC)CC)C>C(#N)C>[N+:37](=[C:13]([C:12](=[O:27])[CH2:11][C@@H:7]1[C@@H:6]([C:3]([O:2][CH3:1])([CH3:5])[CH3:4])[C:9](=[O:10])[NH:8]1)[C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=1)=[O:15])=[N-:38]
Reactant: COC(C)(C)[C@H]1C(=O)N[C@@H]1CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(C)(C)[C@H]1C(=O)N[C@@H]1CC(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 86.4 %

Procedure:
To a solution of 4-nitrobenzyl 4-[(2R, 3S)-3-(1-methoxy-1-methylethyl)-4-oxoazetidine-2-yl]-3-oxobutanoate (61.2 mg) in acetonitrile (1.22 ml) was added a solution of p-toluenesulfonyl azide (38.3 mg) in acetonitrile (0.345 ml) at 0° C. After stirring for 10 minutes at 0° C., a solution of triethylamine (81.3 μl) in acetonitrile (0.732 ml) was added dropwise at 0° C. After the resultant solution was stirred for 30 minutes at 0° C., the solvent was distilled off, and the residue was flash-chromatographed on silica gel (0.9 g) eluting with a mixture of methylene chloride and ethyl acetate (40:1 to 3:1) to give 4-nitrobenzyl 2-diazo-4-[(2R, 3S)-3-(1-methoxy-1-methylethyl)-4-oxoazetidin-2-yl]-3-oxobutanoate (56.5 mg) as an amorphous solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[N:6]([CH3:9])[CH:7]=[N:8][C:4]=2[CH:3]=1.[O:12]1[C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1>>[CH3:9][N:6]1[C:5]2[CH:10]=[C:11]([C:19]3([OH:22])[CH2:20][CH2:21][C:16]4([O:15][CH2:14][CH2:13][O:12]4)[CH2:17][CH2:18]3)[CH:2]=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Cn1cnc2cc(Br)ccc21
Product: Cn1cnc2ccc(C3(O)CCC4(CC3)OCCO4)cc21

Procedure:
The title compound was prepared as a white solid from 5-bromo-1-methyl-1H-benzoimidazole (prepared by methylation of 5-bromo-1H-benzoimidazole) and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:22]=[CH:21][C:14]([O:15][CH2:16][C@H:17]([OH:20])[CH2:18][OH:19])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1C=CC(S(O[CH2:40][C@@H:41]2[O:43][CH2:42]2)(=O)=O)=CC=1>C(#N)C>[O:43]1[CH2:42][C@@H:41]1[CH2:40][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:15][CH2:16][C@H:17]([OH:20])[CH2:18][OH:19])=[CH:21][CH:22]=2)([CH3:9])[CH3:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(OC[C@H](O)CO)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(c1ccc(OC[C@H](O)CO)cc1)c1ccc(OC[C@H]2CO2)cc1
Reaction time: 0.33 h
Yield: 91.6 %

Procedure:
To a stirred solution of (R)-3-(4-(2-(4-hydroxyphenyl)propan-2-yl)phenoxy)propane-1,2-diol (3.77 g, 12.49 mmol, 1.0 equiv) in anhydrous acetonitrile (35 mL) at rt was added cesium carbonate (6.1 g, 18.73 mmol, 1.5 equiv), and the mixture was stirred for 20 min under argon atmosphere. A solution of (2R)-(−)-glycidyl tosylate 98% (4.3 g, 18.73 mmol, 1.5 equiv) in anhydrous acetonitrile (8 mL) was added slowly via syringe, and the mixture was allowed to react at 30° C. for 120 h. The reaction mixture was quenched at room temperature with a saturated solution of ammonium chloride (5 mL). The mixture was extracted with ethyl acetate (3×10 mL). The organic layer was washed with deionized water (10 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 5% to 10% methanol in dichloromethane) to provide the title compound (4.1 g, 91%) as a transparent foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@H:4]([NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:8][C:7]=1[CH2:21]O.C(N(CC)CC)C.CS([Cl:46])(=O)=O>ClCCl>[CH3:1][O:2][C:3](=[O:34])[C@H:4]([NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:8][C:7]=1[CH2:21][Cl:46]
Reactant: COC(=O)[C@@H](Cc1cc(C)c(NC(=O)OC(C)(C)C)cc1CO)NC(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](Cc1cc(C)c(NC(=O)OC(C)(C)C)cc1CCl)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
3-(2-Hydroxymethyl-4-tert-butoxycarbonylamino-5-methyl-phenyl)-2-(R)-benzyloxycarbonylamino-propionic acid methyl ester (510 mg, 1.1 mmol) was dissolved in dichloromethane (5 mL). Triethylamine (250 μL, 1.8 mmol ) was added to the mixture followed by methanesulfonyl chloride (100 μL, 1.3 mmol). Mixture was stirred at room temperature for 1.5 hours. Mixture was diluted with dichloromethane then washed once with water, twice with 1N hydrochloric acid, and once with brine. Organics were dried (magnesium sulfate), filtered and concentrated in vacuo. Title compound was obtained as white solid in 91% yield. MS m/e (M+H)+=491.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[C:11]3[C:15]([CH:16]=[C:17](B4OC(C)(C)CC(C)(C)O4)[CH:18]=2)=[N:14][N:13](C2CCCCO2)[CH:12]=3)=[O:8])[N:6]=1.Br[C:36]1[CH:37]=[C:38]([OH:42])[CH:39]=[CH:40][CH:41]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>O.O1CCOCC1.O.C(=O)=O.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]>[OH:42][C:38]1[CH:37]=[C:36]([C:17]2[CH:16]=[C:15]3[C:11]([CH:12]=[N:13][NH:14]3)=[C:10]([NH:9][C:7]([C:5]3[N:6]=[C:2]([CH3:1])[S:3][CH:4]=3)=[O:8])[CH:18]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: Cc1nc(C(=O)Nc2cc(B3OC(C)(C)CC(C)(C)O3)cc3nn(C4CCCCO4)cc23)cs1
Reactant: Oc1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(C(=O)Nc2cc(-c3cccc(O)c3)cc3[nH]ncc23)cs1
Temperature: 140 °C
Reaction time: 8 h
Yield: 5.5 %

Procedure:
2-Methyl-N-[2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-4-yl]-1,3-thiazole-4-carboxamide (50 mg) and 3-bromophenol (18 mg) were added to a microwave vial. Pd(dppf)Cl2 (8 mg) and 1,4-dioxane (1 ml) were then added. Sodium carbonate (44 mg) in water (1 ml) was added and the reaction was heated under microwave irradiation at 140° C. for 20 min. The reaction was filtered through a 1 g silica SPE cartridge, washing with DCM:MeOH (3:1) then evaporated to dryness. The residue was dissolved in a mixture of DMSO (1.2 ml) and MeOH (0.4 ml) and purified by MDAP (method F). The product-containing fraction was left overnight then evaporated to dryness. The residue was taken up in DCM and a few drops of TFA were added before sonicating the reaction overnight. The residue was dissolved in dioxane/water (1:1, v/v, 2 ml), frozen in cardice and freeze-dried overnight to give the title compound (2 mg).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][CH:24]([C:31]1[C:39]2[C:34](=[N:35][CH:36]=[C:37]([C:40]3[CH:45]=[C:44]([O:46][CH3:47])[C:43]([O:48][CH3:49])=[C:42]([O:50][CH3:51])[CH:41]=3)[N:38]=2)[N:33]([Si:52]([CH:59]([CH3:61])[CH3:60])([CH:56]([CH3:58])[CH3:57])[CH:53]([CH3:55])[CH3:54])[CH:32]=1)[C:25]([CH3:30])([CH3:29])[CH2:26][C:27]#[N:28]>ClCCl>[CH3:30][C:25]([CH3:29])([C:24](=[O:23])[C:31]1[C:39]2[C:34](=[N:35][CH:36]=[C:37]([C:40]3[CH:45]=[C:44]([O:46][CH3:47])[C:43]([O:48][CH3:49])=[C:42]([O:50][CH3:51])[CH:41]=3)[N:38]=2)[N:33]([Si:52]([CH:56]([CH3:58])[CH3:57])([CH:53]([CH3:54])[CH3:55])[CH:59]([CH3:61])[CH3:60])[CH:32]=1)[CH2:26][C:27]#[N:28]
Reactant: COc1cc(-c2cnc3c(n2)c(C(O)C(C)(C)CC#N)cn3[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1cc(-c2cnc3c(n2)c(C(=O)C(C)(C)CC#N)cn3[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 61.4 %

Procedure:
Dess-Martin periodinane (0.122 g, 0.289 mmol) was added to a 0-5° C. solution of 4-hydroxy-3,3-dimethyl-4-[5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-butyronitrile (0.152 g, 0.275 mmol) in 2 mL of dichloromethane. The mixture was stirred at 0-5° C. for 3 h, then quenched with water and a sat. aq. NaHCO3 solution and extracted with 30 mL of dichloromethane. The organic layer was dried over MgSO4, filtered and concentrated to a residue. Column chromatography (0→50% EtOAc/hexanes) afforded 0.093 g (61%) of 3,3-dimethyl-4-oxo-4-[5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-butyronitrile as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[CH:13]=2)=[CH:5][CH:4]=1.[OH-].[Na+].Cl>CO.O1CCCC1>[CH3:1][N:2]([CH3:22])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][C:11]3[C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[CH:13]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)c1cccc2cc(-c3ccc(N(C)C)cc3)oc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)c1ccc(-c2cc3cccc(C(=O)O)c3o2)cc1
Temperature: 50 °C
Yield: 99.3 %

Procedure:
920 mg of methyl 2-(4-dimethylaminophenyl)benzofuran-7-carboxylate are dissolved in a mixture of 20 ml of methanol and 20 ml of tetrahydrofuran. 10 ml of an aqueous 1N sodium hydroxide solution are added to the solution and the mixture is heated at 50° C. for 40 minutes. After cooling, the reaction mixture is neutralized with 10% hydrocloric acid and extracted with ethyl acetate. The extract is dried and evaporated to remove solvent to give 870 mg of 2-(4-dimethylaminophenyl)benzofuran-7-carboxylic acid as yellow powder.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:33]=[CH:32][C:14]3[CH2:15][CH2:16][C:17]4[C:18]([C:29]([NH2:31])=[O:30])=[N:19][N:20]([C:22]5[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=5)[C:21]=4[C:13]=3[CH:12]=2)=[O:9])=[C:4]([CH3:34])[CH:3]=1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.O>CN(C)C(=O)C>[F:28][C:25]1[CH:26]=[CH:27][C:22]([N:20]2[C:21]3[C:13]4[CH:12]=[C:11]([NH:10][C:8]([C:5]5[CH:6]=[N:7][C:2]([N:35]6[CH2:40][CH2:39][O:38][CH2:37][CH2:36]6)=[CH:3][C:4]=5[CH3:34])=[O:9])[CH:33]=[CH:32][C:14]=4[CH2:15][CH2:16][C:17]=3[C:18]([C:29]([NH2:31])=[O:30])=[N:19]2)=[CH:23][CH:24]=1
Reactant: Cc1cc(Cl)ncc1C(=O)Nc1ccc2c(c1)-c1c(c(C(N)=O)nn1-c1ccc(F)cc1)CC2
Reactant: C1COCCN1
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(N2CCOCC2)ncc1C(=O)Nc1ccc2c(c1)-c1c(c(C(N)=O)nn1-c1ccc(F)cc1)CC2
Temperature: 100 °C
Reaction time: 27 h

Procedure:
The title compound of Example 246 (1.47 mmoles) and morpholine (23.1 mmoles) were dissolved in 10 mL of N,N-dimethylacetamide. The reaction mixture was then placed under nitrogen and stirred in an oil bath at 100° C. for 27 h. The mixture was partially stripped of solvent then added to water, filtered, and washed with water. The solid was recrystallized from acetonitrile, then dissolved in acetonitrile and dried over anhydrous MgSO4. The solvent was then stripped down to a solid. Mp: 301° C. (decomp.) 1H NMR (d6-DMSO, 400 MHz): δ 2.22 (s, 3H); 2.80-2.94 (m, 4H); 3.46 (t, 4H, J=4.8 Hz); 3.62 (t, 4H, J=4.8 Hz); 6.67 (s, 1H); 7.22-7.27 (m, 3H); 7.31-7.38 (m, 2H); 7.42 (dd, 1H, J=1.9 Hz, 8.2 Hz); 7.49-7.57 (m, 3H); 8.11 (s, 1H); 9.92 (s, 1H). 13C NMR (d6-DMSO, 100 MHz): δ 20.35, 20.38, 29.63, 45.55, 66.54, 108.46, 114.91, 117.02, 117.25, 119.91, 121.23, 122.78, 126.42, 128.64, 128.73, 129.36, 132.60, 136.82, 136.85, 138.38, 139.82, 143.15, 147.70, 148.03, 160.04, 161.39, 163.84, 164.47, 166.18. M+1=527
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][C:17]([OH:19])=O)[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:23])=O>>[C:1]([C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][C:17]([Cl:23])=[O:19])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCc1cccc(C(=O)c2ccccc2)c1
Reactant: O=C(Cl)C(=O)Cl
Product: O=C(Cl)CCc1cccc(C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 10 g of 3-(m-benzoyl-phenyl)-propionic acid and 50 ml of oxalyl chloride was stirred for 4 hours at room temperature and the excess oxalyl chloride was removed under reduced pressure. The resulting oil was taken up twice in 50 ml of benzene and evaporated to dryness under reduced pressure to obtain 10.7 g of 3-(m-benzoyl-phenyl)-propionyl chloride identical to Example I.
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)=[CH:5][C:4]=1[F:26])#[N:2].FC(F)(F)C(O)=O>C(Cl)Cl>[F:26][C:4]1[CH:5]=[C:6]([O:7][CH2:8][CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:24]=[CH:25][C:3]=1[C:1]#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCOc2ccc(C#N)c(F)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(OCCCC2CCNCC2)cc1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 58.6 %

Procedure:
To a methylene chloride (5.5 mL) solution of 0.66 g of tert-butyl 4-[3-(4-cyano-3-fluorophenoxy) propyl]-1-piperidinecarboxylate was dropwise added 1.8 mL of trifluoroacetic acid under cooling with ice over a period of 2 minutes, which was then stirred at room temperature for 6 hours. The solvent was distilled off under reduced pressure, and chloroform and a 1.0 mol/L sodium hydroxide aqueous solution were added to the resultant residue. The organic layer was separated and dried with anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The resultant residue was purified using silica gel column chromatography (eluent; chloroform:methanol=4:1) to provide 0.28 g of 2-fluoro-4-[3-(4-piperidinyl)propoxy] benzonitrile as pale yellow oily form.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=[O:12].Br[CH2:14][CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]([CH2:14][CH2:15][OH:16])[C:5]2=[O:12]
Reactant: O=c1[nH]cnc2ccc(Br)cc12
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=c1c2cc(Br)ccc2ncn1CCO

Procedure:
6-Bromoquinazolin-4(3H)-one Compound 178-A (1.0 g), 2-bromoethanol (1.1 g), and potassium carbonate (610 mg) were heated in DMA (10 mL) at 80° C. for 16 h. Reaction was extracted with water and dichloromethane (3 times), combined organic layers washed with brine, over sodium sulphate and concentrated. Residue was triturated with acetonitrile to yield 6-bromo-3-(2-hydroxyethyl)quinazolin-4(3H)-one Compound 178-B (810 mg) as a white solid. MS m/z (ESI)=268.9 (base peak, 79Br−M+H+); 270.9 (81Br−M+H+); 290.9 (79Br−M+Na+); 292.9 (81Br−M+Na+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([C:17]([CH3:21])([CH3:20])[C:18]#[N:19])=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:22]([O:25][CH2:26][C:27]1[C:28]([N:42]2[N:51]=[CH:50][C:49]3[C:44](=[C:45]([F:56])[CH:46]=[C:47]([C:52]([CH3:55])([CH3:54])[CH3:53])[CH:48]=3)[C:43]2=[O:57])=[N:29][CH:30]=[CH:31][C:32]=1B1OC(C)(C)C(C)(C)O1)(=[O:24])[CH3:23].C([O-])(=O)C.[K+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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].O.C(#N)C>[C:22]([O:25][CH2:26][C:27]1[C:28]([N:42]2[N:51]=[CH:50][C:49]3[C:44](=[C:45]([F:56])[CH:46]=[C:47]([C:52]([CH3:54])([CH3:53])[CH3:55])[CH:48]=3)[C:43]2=[O:57])=[N:29][CH:30]=[CH:31][C:32]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([C:18]#[N:19])([CH3:21])[CH3:20])=[CH:15][N:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:24])[CH3:23]
Reactant: Cn1cc(Br)cc(Nc2ccc(C(C)(C)C#N)cn2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C(C)(C)C#N)cn3)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 95 °C
Yield: 33 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 156d (346 mg, 1.0 mmol), 3-(acetoxymethyl)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)pyridin-4-ylboronic acid 116c (1.65 g, 4.0 mmol), Pd(dppf)Cl2 (82.5 mg, 0.10 mmol), potassium acetate (196 mg, 2.0 mmol), K3PO4 (424 mg, 2.0 mmol), acetonitrile (15 mL), and water (0.5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 95° C. for 2 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 10:1 ethyl acetate/petroleum ether to afford 156e (210 mg, 33%) as a yellow solid. MS-ESI: [M+H]+ 635.8
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10](=[O:13])[CH:11]=[CH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].[BH4-].[Na+]>ClCCl.C(O)C.C(OCC)(=O)C.CCCCCC>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@H:10]([OH:13])[CH:11]=[CH2:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: O
Solvent: CCCCCC
Solvent: CO
Product: C=C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 51.8 %

Procedure:
A solution of 3.03 g (11 mmol) of the resultant compound of Example 1 in 120 ml of 1:1 dichloromethane:methanol was cooled to 0° C., and treated with 4.10 g (11 mmol) of cerium(III) chloride heptahydrate. The resulting solution was immediately cooled to -78° and treated slowly with a solution of 0.63 g (16.5 mmol) of sodium borohydride in 15 ml of ethanol in such a way that the ethanolic solution was precooled by the side of the flask. After 1 h, the solution was quenched by addition of aqueous ammonium chloride, extracted with ether, washed sequentially with aqueous NaHCO3 and saturated brine, dried over MgSO4 and concentrated in vacuo to give a 4.7:1 ratio of diastereomeric products. Silica gel chromatography of the residue using 3:1 hexane:ethyl acetate provided 1.58 g (52%) of the pure desired compound (Rf 0.35, 15% ethyl acetate in chloroform) as a white solid (m.p. 122°-124° C.), along with 0.22 g (7%) of (3R,4S)-4-(t-butyloxycarbonylamino)-3-hydroxy-5-phenyl-1-pentene. 1H NMR (CDCl3) δ 1.37 (s, 9 H), 2.73 (dd, J=15, 9 Hz 1 H), 2.85 (dd J=15, 5 Hz, 1 H), 2.98 (m, 1 H), 3.98 (m, 1 H), 4.24 (m, 1 H), 4.58 (br, 1 H), 5.29 (dt, J=10, 1.5 Hz, 1 H), 5.38 (dt, J=17, 1.5 Hz, 1 H), 5.94 (ddd, J=17, 10, 6 Hz, 1 H), 7.2-7.3 (m, 5 H).
Reaction SMILES: [CH3:1][CH2:2][C:3](=[O:9])[CH2:4][CH2:5][CH:6]=[CH:7][CH3:8]>C(OCC)(=O)C.[Pd]>[C@@H:5]12[CH2:6][CH2:7][CH2:8][C@@H:1]1[CH2:2][C:3](=[O:9])[CH2:4]2
Reactant: CC=CCCC(=O)CC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1C[C@H]2CCC[C@H]2C1
Yield: 104.7 %

Procedure:
A solution of the cis-bicyclo ;3.3.0]oct-6-ene-3-one (6.2 g .05 mol) in 150 mL of ethyl acetate containing 0.50 g of 10% Pd/C was hydrogenated at 25 psi for 11/2 hours. The catalyst was removed by filtering through Celite and the solvent evaporated to give 6.5 g of cis-bicyclo[3.3.0]-octane-3-one (100%). TLC (SiO2CH2Cl2) Rf =0.35 (I2, brown ).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[C:13]([F:15])[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][C:10]=2[F:19])[CH:5]=[CH:4][N:3]=1.[C:20]([NH2:24])(=[O:23])[CH2:21][CH3:22].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:19][C:10]1[CH:11]=[C:12]([N+:16]([O-:18])=[O:17])[C:13]([F:15])=[CH:14][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:24][C:20](=[O:23])[CH2:21][CH3:22])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(F)c(Oc2ccnc(Cl)c2)cc1F
Reactant: CCC(N)=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCC(=O)Nc1cc(Oc2cc(F)c([N+](=O)[O-])cc2F)ccn1
Temperature: 85 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
A solution of Example A1 (35 g, 122 mmol) in anhydrous 1,4-dioxane (900 mL) was degassed with nitrogen for 10 min and to it was added propionamide (10.5 g, 143 mmol), 1,1′-bis(diphenylphosphino) ferrocene (dppf, 6.6 g, 12.0 mmol, 0.1 equiv.), Cs2CO3 (58.4 g, 179 mmol) and Pd2(dba)3 (5.47 g, 5.97 mmol). The mixture was degassed with nitrogen for another 15 min and then heated to 85° C. (internal temp) and stirred at that temp for 4 h. The reaction mixture was cooled to RT, filtered through a bed of diatomaceous earth and washed with EtOAc (1 L). The combined filtrates were concentrated under reduced pressure and purified by a silica gel chromatography (EtOAc/hexanes) to afford 30 g. This material was further purified by a trituration with diisopropyl ether (600 mL) and drying under vacuum at 40° C. to provide N-(4-(2,5-difluoro-4-nitrophenoxy)pyridin-2-yl)propionamide (27.2 g, 69% yield). MS (ESI): m/z 324.1 (M+H+). This material was carried to next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[CH:10][C:11]3[C:17]([OH:18])=[C:16]([C:19]([NH:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[O:20])[C:15](=[O:30])[N:14]([CH3:31])[C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.ClC1N=CC2C(O)=C(C(NCC(OC(C)(C)C)=O)=O)C(=O)N(C)C=2N=1.FC1C=C(B(O)O)C=CC=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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]>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[CH:10][C:11]3[C:17]([OH:18])=[C:16]([C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])[C:15](=[O:30])[N:14]([CH3:31])[C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(=O)c(C(=O)NCC(=O)OC(C)(C)C)c(O)c2cnc(-c3cccc(F)c3)nc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cn1c(=O)c(C(=O)NCC(=O)OC(C)(C)C)c(O)c2cnc(Cl)nc21
Solvent: O
Solvent: C1COCCO1
Product: Cn1c(=O)c(C(=O)NCC(=O)O)c(O)c2cnc(-c3cccc(F)c3)nc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
tert-Butyl 2-(2-(3-fluorophenyl)-5-hydroxy-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamido)acetate. To a mixture of tert-butyl 2-(2-chloro-5-hydroxy-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamido)acetate (100 mg, 1 eq., Method 10), Pd(dppf)Cl2 (0.05 eq.), 3-fluorophenylboronic acid (3.0 eq., available from Aldrich (Milwaukee, Wis.)) in degassed dioxane (4 mL) was added degassed aqueous Na2CO3 (2M, 3 eq.) in a sealed tube. The mixture was stirred overnight at 80° C. The mixture was then cooled to room temperature and diluted with water. The phases were separated and extracted with more CH2Cl2. The combined organic phases were washed with water and brine, dried over Na2SO4 and concentrated. The residue was dissolved in DMA and purified on reversed phase HPLC to give the title compound (48 mg, 41%) as a light brown solid. C21H21FN4O5 (428.4). APCI-MS: 429 ([M+H]+), 373 ([M-(t-Bu)+H]+). 1H-NMR (DMSO-d6): δ 10.21 (br s, 1H), 9.39 (s, 1H), 8.40 (d, J=7.8, 1H), 8.25 (d, J=9.3, 1H), 7.66 (q, J=8.1, 1H), 7.49 (dt, J=8.5, 2.5, 1H), 4.13 (d, J=5.7, 2H), 3.55 (s, 3H), 1.46 (s, 9H).