Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([C:11]1[C:23](OB(O)O)=[CH:22][C:21]2[C:20]3[C:15](=[C:16]([F:28])[CH:17]=[CH:18][CH:19]=3)[CH2:14][C:13]=2[C:12]=1[F:29])[CH2:9][CH3:10].IC1C=CC(C)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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(O)C>[CH3:7][C:1]1[CH:6]=[CH:5][C:4]([C:17]2[C:16]([F:28])=[C:15]3[C:20]([C:21]4[CH:22]=[CH:23][C:11]([CH2:8][CH2:9][CH3:10])=[C:12]([F:29])[C:13]=4[CH2:14]3)=[CH:19][CH:18]=2)=[CH:3][CH:2]=1
Reactant: CCCc1c(OB(O)O)cc2c(c1F)Cc1c(F)cccc1-2
Reactant: Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccc(I)cc1
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCCc1ccc2c(c1F)Cc1c-2ccc(-c2ccc(C)cc2)c1F

Procedure:
To 200 ml of toluene was added 8.2 g of (2-propyl-1,8-difluorofluorenyl)boric acid (K-5), 7.4 g of p-iodotoluene, 31 ml of 2M aqueous sodium carbonate, 0.5 ml of ethanol and 1.0 g of tetrakis(triphenylphosphine)palladium, and the mixture was refluxed under heat for 20 hours. The reaction mixture was then washed sequentially with water and a saturated aqueous solution of sodium chloride, dried, and then purified by silica gel chromatography to yield 7.1 g of 7-(4-methylphenyl)-2-(n-propyl)-1,8-difluorofluorene (II-I1).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:5]([O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1)[CH3:6])[CH2:3][OH:4].[CH2:14](I)[CH2:15][CH2:16][CH3:17].[H-].[Na+].C(OCC)(=O)C>CN(C=O)C>[CH2:14]([O:4][CH2:3][CH:2]([CH3:1])[CH:5]([O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1)[CH3:6])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCI
Reactant: C[C@H](CO)[C@H](C)OC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCOCC(C)C(C)OC1CCCCO1

Procedure:
1.88 g (10 retool) of the crude (2R,3S)-2-methyl-3-tetrahydropyranyloxy-l-butanol was dissolved in 30 ml of DMF. Thereto was added 18.4 g of n-BuI. Thereto was further added carefully by small portions 4 g of oily sodium hydride (about 60%), with ice cooling. To the reaction mixture was added 300 ml of ethyl acetate. The insoluble materials were removed by filtration. The filtrate was washed with two 100 ml-portions of water, dried and concentrated under reduced pressure to obtain crude 1-butoxy-2-methyl-3-tetrahydropyranyloxybutane as an oily material. This crude product was dissolved in 150 ml of methanol. 5 g of Amberlist 15 was added thereto, and the mixture was stirred for 2 days at room temperature. The Amberlist 15 was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was subjected to Kugelrohr distillation to obtain 0.90 g of the title compound as an oily material.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:34][CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[C:14]([NH:16][C:17]3[S:18][C:19]([O:22][C:23]4[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=4)[C:26]([O:28]CC)=[O:27])=[CH:20][N:21]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.CO.[Li+].[OH-]>C1COCC1>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:34][CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[C:14]([NH:16][C:17]3[S:18][C:19]([O:22][C:23]4[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=4)[C:26]([OH:28])=[O:27])=[CH:20][N:21]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cccc(Oc2cnc(NC(=O)C(OC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)s2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cccc(Oc2cnc(NC(=O)C(OC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)s2)c1
Reaction time: 0.25 h

Procedure:
Ethyl3-[2-[[2-(4-cyclopropylsulfonylphenyl)-2-tetrahydropyran-4-yloxy-acetyl]amino]thiazol-5-yl]oxybenzoate (Example A2; 16 g, 27 mmol) was taken in THF (200 mL) and Methanol (100 mL) in a 1 L single necked round bottom flask at 20-25° C. To it was added solution of LiOH (11.44 g in 200 mL water, 272 mmol) slowly under vigorous stirring for 15 minutes and further continued to stir for 16 hours. Completion of reaction was confirmed by TLC. Organic solvent was removed under reduced pressure. The obtained residue was diluted with water (200 mL) and washed with ethyl acetate (2×150 mL). The aqueous layer was acidified with 1N HCl to pH 1-2 and extracted with Ethyl acetate (3×150 mL). The combined organic layer was washed with brine (150 mL) dried over anhydrous sodium sulphate and the solvent was removed under vacuum to get the pure product.
Reaction SMILES: [Cl:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([CH2:12][C:13](Cl)=[O:14])([CH2:5]3)[CH2:3]1)[CH2:9]2.[NH2:16][N:17]1[C:22](=[O:23])[C:21]2[CH:24]=[CH:25][S:26][C:20]=2[N:19]=[C:18]1[CH2:27][CH3:28]>>[Cl:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([CH2:12][C:13]([NH:16][N:17]4[C:22](=[O:23])[C:21]5[CH:24]=[CH:25][S:26][C:20]=5[N:19]=[C:18]4[CH2:27][CH3:28])=[O:14])([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: O=C(Cl)CC12CC3CC(CC(Cl)(C3)C1)C2
Reactant: CCc1nc2sccc2c(=O)n1N
Product: CCc1nc2sccc2c(=O)n1NC(=O)CC12CC3CC(CC(Cl)(C3)C1)C2

Procedure:
The product from Example 50A and 3-amino-2-ethylthieno[2,3-d]pyrimidin-4(3H)-one (Enamine) were processed using the method described in Example 42C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.20 (t, J=7.3 Hz, 3 H) 1.46-1.81 (m, 6H) 1.94-2.13 (m, 6 H) 2.14-2.23 (m, 2 H) 2.23 (s, 2 H) 2.55-2.86 (m, 2 H) 7.41 (d, J=5.5 Hz, 1 H) 7.59 (d, J=5.5 Hz, 1 H); MS (ESI+) m/z 406 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[O:14]1[CH:16]([CH2:17][CH3:18])[CH2:15]1.[F-].[K+]>O.C(Cl)Cl>[C:2]1([NH:1][CH2:15][CH:16]([OH:14])[CH2:17][CH3:18])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CCC1CO1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCC(O)CNc1ccccc1

Procedure:
Aniline, (102.3 g, 1.1 mole) was added to 50 ml of dioxane, 108 g of 1,2-epoxy butane and 1 g of potassium fluoride in 25 ml of water. The mixture heated to reflux for 30 hours. The mixture was poured into water, taken up in 200 ml of methylene chloride, dried over anhydrous magnesium sulfate and stripped under vacuum. The residue was distilled under vacuum and the product, b.p. 98°-106° C. at 0.15 mm, weighed 94 g and was 97% pure by GLPC. It was characterized by IR and NMR.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:21]([CH3:23])[CH3:22])[C:13]([N:15]3[CH2:18][CH:17]([C:19]#[N:20])[CH2:16]3)=[O:14])[C:8](=[O:24])[C:7]3=[CH:25][NH:26][C:5]([C:6]=23)=[N:4][CH:3]=1.[CH3:27][Al](C)C>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.O1CCOCC1>[CH3:22][CH:21]([CH3:23])[C@@H:12]([N:9]1[C:8](=[O:24])[C:7]2=[CH:25][NH:26][C:5]3[C:6]2=[C:11]([C:2]([CH3:27])=[CH:3][N:4]=3)[CH2:10]1)[C:13]([N:15]1[CH2:18][CH:17]([C:19]#[N:20])[CH2:16]1)=[O:14]
Reactant: C[Al](C)C
Reactant: CC(C)[C@H](C(=O)N1CC(C#N)C1)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1cnc2[nH]cc3c2c1CN([C@@H](C(=O)N1CC(C#N)C1)C(C)C)C3=O
Temperature: 120 °C
Yield: 144 %

Procedure:
(R)-1-(2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoyl)azetidine-3-carbonitrile (30 mg, 0.081 mmol), Pd(Ph3P)4 (47 mg, 0.04 mmol), and dioxane (2 mL) were combined in a 5 mL microwave vial. The mixture was purged with nitrogen, and trimethylaluminum (2.0M/toluene, 0.24 mL, 0.48 mmol) was added. The vial was sealed and the reaction mixture was heated in a Biotage Initiator™ microwave for 1 h at 120° C. The reaction was repeated 4 times at the same scale. The reaction mixtures were combined, and the resulting mixture was quenched with water (0.5 mL), concentrated, and purified by preparative HPLC (10-30% AcCN/H2O with 0.035% TFA) followed by flash chromatography (5% MeOH/95% DCM) to give the title compound as a light yellow solid (41 mg, 29%). 1H NMR (500 MHz, CD3OD) δ 0.92 (d, J=6.8 Hz, 3H), 1.07 (dd, J=15.9, 6.1 Hz, 3H), 2.42 (d, J=6.35 Hz, 3H), 3.69-3.77 (m, 1H), 4.19-4.22 (m, 1H), 4.32-4.34 (m, 1H), 4.53-4.59 (m, 1H), 4.68-4.72 (m, 1H), 5.20-5.33 (m, 3H), 7.98 (d, J=19.5 Hz, 1H), 8.27 (s, 1H). [M+H] calc'd for C19H21N5O2, 352; found, 352.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:10]([C:18](=O)[CH2:19][CH2:20][CH:21]2[CH2:23][CH2:22]2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:27][NH2:28]>C(O)C>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:10]([C:18]2[CH:19]=[C:20]([CH:21]3[CH2:23][CH2:22]3)[NH:28][N:27]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)OC(=O)Nc1cc(C(=O)CCC2CC2)cc(S(C)(=O)=O)c1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc(-c2cc(C3CC3)[nH]n2)cc(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
[3-(3-Cyclopropyl-propionyl)-5-methanesulfonyl-phenyl]-carbamic acid tert-butyl ester (250 mg; 0.688 mmol) was diluted in 5 ml of ethanol and hydrazine hydrate (0.186 ml; 3.439 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Then, it was concentrated under vacuum. 200 mg (0.53 mmol; 77% yield) of [3-(5-cyclopropyl-1H-pyrazol-3-yl)-5-(methylsulfonyl)-phenyl]-carbamic acid tert butyl ester were obtained.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:21]=[C:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:24][CH2:23]1>C1COCC1>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:22]2([OH:21])[CH2:23][CH2:24][N:25]([C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])[CH2:26][CH2:27]2)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(O)(c2ccc(OCc3ccccc3)cc2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 37.7 %

Procedure:
n-Butyllithium (1.6M in hexane, 42.9 ml, 107.18 mmol) was added dropwise to 1-(benzyloxy)-4-bromobenzene (28.2 g, 107.18 mmol, CAS 6793-92-6) in THF (367 ml) at −78° C. over a period of 15 minutes under nitrogen. The resulting solution was stirred at −78° C. for 1 hour then benzyl 4-oxopiperidine-1-carboxylate (20 g, 85.74 mmol) in THF (122 ml) was added dropwise. The resulting mixture was stirred at −78° C. for 10 minutes, then allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was evaporated to dryness and quenched with saturated ammonium chloride (50 mL), then then extracted with EtOAc (500 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 1 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford crude product. The crude product was further purified by flash silica chromatography, elution gradient 0 to 3% MeOH in DCM. Pure fractions were evaporated to dryness to afford benzyl 4-[4-(benzyloxy)phenyl]-4-hydroxypiperidine-1-carboxylate (13.49 g, 30.1%) as a gum.
Reaction SMILES: [NH:1]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([NH:13][C@H:14]([C:16]([NH:18][CH2:19][C:20](OC)=[O:21])=[O:17])[CH3:15])=[O:12])=[O:8])=[O:4].O.[NH2:32][NH2:33]>CO>[C:27]([O:26][C:24]([NH:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([NH:13][C@H:14]([C:16]([NH:18][CH2:19][C:20]([NH:32][NH2:33])=[O:21])=[O:17])[CH3:15])=[O:12])=[O:8])=[O:4])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: NN
Reactant: COC(=O)CNC(=O)[C@H](C)NC(=O)CNC(=O)CNC(=O)CNC(=O)OC(C)(C)C
Solvent: O
Solvent: CO
Product: C[C@H](NC(=O)CNC(=O)CNC(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)NN

Procedure:
A solution of Boc-Gly-Gly-Gly-Ala-Gly-OMe (1.0 g, 2.32 mmole, described in Example 16) and hydrazine hydrate (1 ml, 23.2 mmole) in methanol (30 ml) is stirred at 0° C for 4 hr. After evaporation the residue is triturated with diethyl ether and dried to give the title compound, mp 221° - 223° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[C:6]([Br:9])[C:7]=1[F:8].[Cl:16][C:17]1[CH:18]=[C:19]([C:24](=[O:26])[CH3:25])[CH:20]=[CH:21][C:22]=1[CH3:23]>C(OCC)(=O)C>[Cl:16][C:17]1[CH:18]=[C:19]([C:24](=[O:26])[CH2:25][C:10]([C:4]2[CH:3]=[C:2]([Br:1])[C:7]([F:8])=[C:6]([Br:9])[CH:5]=2)([OH:15])[C:11]([F:14])([F:12])[F:13])[CH:20]=[CH:21][C:22]=1[CH3:23]
Reactant: O=C(c1cc(Br)c(F)c(Br)c1)C(F)(F)F
Reactant: CC(=O)c1ccc(C)c(Cl)c1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)CC(O)(c2cc(Br)c(F)c(Br)c2)C(F)(F)F)cc1Cl
Temperature: 50 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
To a stirred solution of 1-(3,5-dibromo-4-fluorophenyl)-2,2,2-trifluoroethanone (0.99 g) and 1-(3-chloro-4-methylphenyl)ethanone (0.48 g) in ethyl acetate (3 mL) was added dithylamine (0.062 g). The mixture was stirred at 50° C. for 2 hours. The reaction mixture was then concentrated under reduced pressure and the crude product was purified by liquid chromatography (medium pressure collection apparatus: Purif-α2 manufactured by Moritex Corporation) eluted with ethyl acetate-hexane (1:10) to afford the title compound as a pale yellow oil (1.40 g).
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([O:30][CH3:31])=[CH:12][CH:13]=[C:14]2[C:19]=1[NH:18][C:17](=[O:20])[CH:16]=[C:15]2NC1C(Cl)=CN=CC=1Cl.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:1][N:2]([CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([O:30][CH3:31])=[CH:12][CH:13]=[C:14]2[C:19]=1[NH:18][C:17](=[O:20])[CH:16]=[CH:15]2
Reactant: CNC
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc2ccc(=O)[nH]c2c1OCCCCN(C)C
Reaction time: 2.5 h

Procedure:
A solution of dimethylamine (1.5 mL, 2M tetrahydrofuran, 3 mmol) was added to a solution of 8-(4-bromobutoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (146 mg, 0.3 mmol) and DMSO (3 mL). After 2.5 h, the reaction was poured into 10% K2CO3 (30 mL) and extracted with dichloromethane (40 mL×2). The combined extracts were dried, filtered, concentrated, and purified by silical gel chromatography (1:0→4:1; dichloromethane:methanol w/1% conc. NH4OH solution) and then reverse-phase HPLC (1:9→1:1; acetonitrile:water) to give 443,5-dichloropyridin-4-ylamino)-8-(4-(dimethylamino)butoxy)-7-methoxyquinolin-2(1H)-one: 1H NMR (400 MHz, DMSO-d6): δ 10.29 (s, 1H), 8.81 (s, 1H), 8.75 (s, 2H), 7.87 (d, 1H), 7.04 (d, 1H), 4.77 (s, 1H), 3.99 (t, 2H), 3.90 (s, 3H), 2.27 (t, 2H), 2.13 (s, 6H), 1.73 (m, 2H), 1.54 (m, 2H); MS (ESI): 451.0.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]([C:24]4[CH:33]=[CH:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:25]=4)=[N:20][NH:21]3)=[CH:17][CH:16]=2)=[CH:11][C:10]=1[O:34][CH3:35])C1C=CC=CC=1>C(OCC)(=O)C.C1C=CC=CC=1.CO.[Pd]>[CH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][C:24]=1[C:19]1[C:18]2[C:22](=[CH:23][C:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([O:34][CH3:35])[CH:11]=3)=[CH:16][CH:17]=2)[NH:21][N:20]=1
Reactant: COc1cc(-c2ccc3c(-c4ccc5ccccc5c4)n[nH]c3c2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: c1ccccc1
Product: COc1cc(-c2ccc3c(-c4ccc5ccccc5c4)n[nH]c3c2)ccc1O
Temperature: 23 °C
Reaction time: 72 h
Yield: 39.7 %

Procedure:
6-(4-Benzyloxy-3-methoxy-phenyl)-3-naphthalen-2-yl-1H-indazole (25 mg, 0.055 mmol) was dissolved in a mixture of ethyl acetate (2 mL), benzene (2 mL) and methanol (2 mL). To this solution was added palladium on carbon (25 mg, 10% wt) and the reaction vessel was vacuum/purged with hydrogen gas for five cycles. The reaction mixture was allowed to stir for 3 days (d) at 23° C. and was filtered through a plug of Celite. Concentration and purification by silica gel chromatography afforded 3-(Naphthalen-2-yl)-6-(3-methoxy-4-hydroxy-phenyl)-1H-indazole (8 mg, 40%): 1H NMR (CDCl3) δ 10.3 (bs, 1H), 8.50 (s, 1H), 8.20 (d, 1H, J=8 Hz), 7.98 (d, 1H, J=8Hz), 7.90 (m, 1H), 7.7-6.8 (m, 9H), 3.98 (s, 3H). MS (ES) [m+H]/z Calc'd 367, found 367, [m−H]/z Calc'd 365, found 365.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[CH2:7][CH:6]3[CH2:23][O:24][CH2:25][CH2:26][N:5]3[C:4]=2[N:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:43]=[CH:42][CH:41]=[C:40]3[C:36]=2[CH:37]=[CH:38][NH:39]3)O1>O1CCOCC1.C([O-])(O)=O.[Na+].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]>[NH:39]1[C:40]2[C:36](=[C:35]([C:2]3[N:11]=[CH:10][C:9]4[N:8]([CH2:12][C:13]5[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=5)[CH2:7][CH:6]5[CH2:23][O:24][CH2:25][CH2:26][N:5]5[C:4]=4[N:3]=3)[CH:43]=[CH:42][CH:41]=2)[CH:37]=[CH:38]1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: CC(C)(O)c1ccc(CN2CC3COCCN3c3nc(Cl)ncc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: CC(C)(O)c1ccc(CN2CC3COCCN3c3nc(-c4cccc5[nH]ccc45)ncc32)cc1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 2 using 2-(4-((2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)methyl)phenyl)propan-2-ol (PREPARATION x8, 39 mg, 0.104 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (50.6 mg, 0.208 mmol), and PdCl2(dppf) (6.09 mg, 8.32 μmol) in dioxane (8 mL) and aqueous saturated NaHCO3 (2 mL). 1H NMR (400 MHz, DMSO-d6) δ 1.42 (s, 6 H), 3.18 (m, 4 H), 3.58-3.66 (m, 1 H), 3.94-4.04 (m, 2 H), 4.08-4.15 (m, 1 H), 4.56 (s, 2 H), 4.70-4.79 (m, 1 H), 6.99-7.05 (m, 1 H), 7.23-7.37 (m, 3 H), 7.45-7.51 (m, 3 H), 7.58 (s, 1 H), 7.60-7.69 (m, 2 H), 11.45-11.63 (m, 1 H). ESI-MS m/z [M+H]+ calc'd for C27H29N5O2, 456.23; found 456.5.
Reaction SMILES: C(=O)(O)[O-].[Na+].CNC1C=CC=CC=1.P(OCC)(OCC)OCC.[I-].[C:25]([CH2:28][N+:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([C:37]2[N:38]=[CH:39][N:40]3[CH:44]=[C:43]([C:45]4[C@H:46]([CH3:62])[C@@H:47]5[C@@H:57]([C@H:58]([OH:60])[CH3:59])[C:56](=[O:61])[N:48]5[C:49]=4[C:50]([O:52]CC=C)=[O:51])[S:42][C:41]=23)=[O:36])[CH:30]=1)(=[O:27])[NH2:26]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(O)C.O>[C:25]([CH2:28][N+:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([C:37]2[N:38]=[CH:39][N:40]3[CH:44]=[C:43]([C:45]4[C@H:46]([CH3:62])[C@@H:47]5[C@@H:57]([C@H:58]([OH:60])[CH3:59])[C:56](=[O:61])[N:48]5[C:49]=4[C:50]([O-:52])=[O:51])[S:42][C:41]=23)=[O:36])[CH:30]=1)(=[O:27])[NH2:26]
Reactant: C=CCOC(=O)C1=C(c2cn3cnc(C(=O)c4ccc[n+](CC(N)=O)c4)c3s2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCOP(OCC)OCC
Solvent: CC(C)O
Solvent: CNc1ccccc1
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cn4cnc(C(=O)c5ccc[n+](CC(N)=O)c5)c4s3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 16.2 %

Procedure:
Sodium bicarbonate (6.72 g), 10.4 ml of N-methylaniline, and 4.8 ml of triethyl phosphite were added in that order to 320 ml of a mixed liquid of 2-propanol:water=3:2. The atmosphere was replaced by argon, and the mixture was stirred at room temperature for 15 min. Palladium acetate (0.90 g) was then added thereto, and the mixture was stirred for 10 min. A solution of 59.31 g of allyl (1S,5R,6S)-2-[7-(1-carbamoylmethylpyridinium-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate iodide in 400 ml of a mixed liquid of 2-propanol:water=3:2 was added to the reaction mixture, and the mixture was stirred at 30° C. for one hr. 2-Propanol (80 ml) was added to the reaction mixture, and the mixture was stirred in an ice-water bath for one hr. The resultant precipitate was then collected by filtration and was washed with 265 ml of a cooled mixed liquid of 2-propanol:water=2:1, 53 ml of 2-propanol, and 106 ml of acetone in that order to give 7.168 g of (1S,5R,6S)-2-[7-(1-carbamoylmethylpyridinium-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate. This product was analyzed by NMR. The results were in agreement with the results of analysis in Example A-2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:10][C:11]1[C:16]([F:17])=[C:15]([F:18])[C:14]([F:19])=[C:13]([F:20])[C:12]=1[F:21]>ClCCl.[OH-].[Na+].CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[NH2:1][C:2]1[C:7]([O:8][CH2:10][C:11]2[C:12]([F:21])=[C:13]([F:20])[C:14]([F:19])=[C:15]([F:18])[C:16]=2[F:17])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ncccc1O
Reactant: Fc1c(F)c(F)c(CBr)c(F)c1F
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: Nc1ncccc1OCc1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.5 %

Procedure:
To a solution of 2-amino-3-hydroxypyridine (8.1 g, 73.6 mmol) in dichloromethane (65 ml) and 40% sodium hydroxide (65 ml) was added Adogen 464 (5 ml) and alpha -bromo-2,3,4,5,6-pentafluorotoluene (20 g, 81 mmol) with vigorous stirring. The mixture was stirred at room temperature for 16 hours and the resulting solid was filtered off, washed and dried to yield the title compound (14 g), m.p.130°-134° C.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=O)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:23]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C>[Cl:23][C:4]1[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc2[nH]ccc2c(=O)[nH]1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: CN(C)c1ccccc1
Solvent: CC#N
Product: Nc1nc(Cl)c2cc[nH]c2n1
Temperature: 85 °C
Yield: 45.1 %

Procedure:
To a solution of 2-amino-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (5.00 g, 33.3 mmol), dimethylaniline (4.22 mL, 41.0 mmol) and benzyltriethylammonium chloride (15.2 g, 66.6 mmol) in acetonitrile (25 mL) at room temperature under argon was added POCl3 (18.6 mL, 200 mmol) dropwise for 30 min. The mixture was refluxed at 85° C. for 3 h and cooled to room temperature. The reaction was concentrated in vacuo to brown oil and to the oil was added an ice cold H2O (10 mL). The pH of the solution was adjusted to 5 by the addition of an aqueous NH4OH solution. Silica gel chromatography (CH2Cl2:MeOH=95:5) yielded 2.53 g (45%) of 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine as a light yellow solid. The product was then benzylated at N7 using standard techniques.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:6]([O:7][CH3:8])=[C:4]([OH:5])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.[Cl-].[Na+].O>[CH2:19]([O:5][C:4]1[CH:3]=[C:2]([CH:10]=[CH:9][C:6]=1[O:7][CH3:8])[C:1]([O:12][CH2:1][C:2]1[CH:10]=[CH:9][CH:6]=[CH:4][CH:3]=1)=[O:11])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(C(=O)O)cc1O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 180.4 %

Procedure:
To an ice cold mixture of isovanillic acid 1 (4.3 g, 25.5 mmol) and K2CO3 (10.5 g, 0.152 mol) in anhydrous DMF (40 mL) was added benzyl bromide (8.7 g, 6.05 mL, 51.1 mmol). The resulting reaction mixture stirred at RT overnight. An additional aliquot of benzyl bromide was added (1.0 ml) and stirring was continued for 1.5 h. The reaction mixture was poured into brine (100 mL) and the solid was collected via filtration, washed with water and dried under high vacuum to give benzyl 3-(benzyloxy)-4-methoxybenzoate as a white solid (7.99 g, 23.0 mmol, 90%).