Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:10])[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH2:3]1.[H-].[Na+].F[C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][C:15]=1[C:24]1[C:32]2[C:27](=[C:28]([O:33][CH3:34])[N:29]=[CH:30][CH:31]=2)[N:26]([CH3:35])[CH:25]=1>O1CCCC1>[F:1][C:2]1([F:10])[CH2:7][CH2:6][CH:5]([CH2:8][O:9][C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][C:15]=2[C:24]2[C:32]3[C:27](=[C:28]([O:33][CH3:34])[N:29]=[CH:30][CH:31]=3)[N:26]([CH3:35])[CH:25]=2)[CH2:4][CH2:3]1
Reactant: OCC1CCC(F)(F)CC1
Reactant: COc1nccc2c(-c3cc(S(C)(=O)=O)ccc3F)cn(C)c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nccc2c(-c3cc(S(C)(=O)=O)ccc3OCC3CCC(F)(F)CC3)cn(C)c12
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 82.8 %

Procedure:
A solution of (4,4-difluorocyclohexyl)methanol (0.156 g, 1.04 mmol) in anhydrous tetrahydrofuran (4.33 mL) under nitrogen was treated with sodium hydride (0.042 g, 1.040 mmol) at ambient temperature, stirred for 10 minutes, treated with the product from Example 17C (0.087 g, 0.26 mmol) and heated under nitrogen at 60° C. for 18 hours. The mixture was cooled and partitioned into ethyl acetate/water. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous Na2SO4), filtered, and concentrated. Purification by chromatography (silica gel, 0-60% ethyl acetate in heptanes) afforded the title compound (0.1 g, 83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:15][CH3:16])=[CH:5][C:6]2[S:10][C:9]([O:11]CC)=[N:8][C:7]=2[CH:14]=1.Cl>C(O)C>[CH3:1][O:2][C:3]1[C:4]([O:15][CH3:16])=[CH:5][C:6]2[S:10][C:9](=[O:11])[NH:8][C:7]=2[CH:14]=1
Reactant: CCOc1nc2cc(OC)c(OC)cc2s1
Agent: Cl
Solvent: CCO
Product: COc1cc2[nH]c(=O)sc2cc1OC
Yield: 46.8 %

Procedure:
19.7 gm (82 mmols) of 5,6-dimethoxy-2-ethoxybenzothiazole were dissolved in 500 ml of ethanol and admixed dropwise at the boiling point with 64 ml of concentrated aqueous hydrochloric acid. After refluxing the mixture for 3 hours, the solvent was evaporated. The residue was recrystallized from methanol. 8.1 gm (48% of theory) of 5,6-dimethoxy-2(3H)-benzothiazolone having a melting point of 191° C. were obtained.
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[O:20])[CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH:19]([C:15]1[CH:14]=[C:13]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH:11]=[O:12])=[C:2]2[CH:22]2[CH2:23][NH:24][CH2:25][CH2:26][NH:21]2)[CH:18]=[CH:17][CH:16]=1)=[O:20]
Reactant: O=Cc1cccc(-n2c(Cl)c(C=O)c3ccccc32)c1
Reactant: C1CNCCN1
Product: O=Cc1cccc(-n2c(C3CNCCN3)c(C=O)c3ccccc32)c1
Yield: 59 %

Procedure:
2-Chloro-1-(3-formylphenyl)-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 to afford 1-(3-formylphenyl)-2-(piperazin-2-yl)-1H-indole-3-carboxaldehyde (59% yield) as a cream solid. ESI/MS 334 (M+H); RT=2.29 min.
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH2:8][CH2:9][CH3:10])[C:5](O)=O)[CH3:3].S(Cl)(Cl)=O.[C:15]1([NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24]([NH2:26])=[O:25])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClC(Cl)Cl>[CH3:1][N:2]([CH3:3])[CH:4]([CH3:5])[CH2:8][CH2:9][C:10]1[N:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:22]2[C:23]([C:24](=[O:25])[N:26]=1)=[CH:27][CH:28]=[CH:29][CH:30]=2
Reactant: NC(=O)c1ccccc1Nc1ccccc1
Reactant: CCCC(C(=O)O)N(C)C
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CC(CCc1nc(=O)c2ccccc2n1-c1ccccc1)N(C)C
Temperature: 57.5 °C
Reaction time: 1.5 h

Procedure:
3.80 g (20.9 mmol) dimethylamino-pentanoic acid were added to 25 ml thionyl chloride and stirred for 90 min. at 55-60° C. The remaining thionyl chloride was distilled in vacuum and the residue was added to a solution of 2.00 g (9.42 mmol) 2-phenylamino-benzamide (see above) in 30 ml trichloromethane at 0° C. The reaction mixture was boiled for 4 h and stirred overnight at room temperature. The residue was filtrated and dissolved in dichloromethane and saturated sodium bicarbonate solution. The organic solvent was dried over magnesium sulfate and evaporated. The yellow oil slowly crystallized.
Reaction SMILES: O.C(O)(C(F)(F)F)=O.[Cl:9][C:10]1[CH:11]=[C:12]([CH:23]=[C:24]([Cl:50])[C:25]=1[CH2:26][C@@H:27]1[CH2:31][CH2:30][N:29]([N:32]2[CH2:37][CH2:36][CH:35]([O:38][Si](C(C)C)(C(C)C)C(C)C)[CH2:34][CH2:33]2)[C:28]1=[O:49])[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=1.C(OCC)(=O)C>C1COCC1>[Cl:9][C:10]1[CH:11]=[C:12]([CH:23]=[C:24]([Cl:50])[C:25]=1[CH2:26][C@@H:27]1[CH2:31][CH2:30][N:29]([N:32]2[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]2)[C:28]1=[O:49])[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=1
Reactant: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(Oc4ccc(C(N)=O)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NC(=O)c1ccc(Oc2cc(Cl)c(C[C@@H]3CCN(N4CCC(O)CC4)C3=O)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.8 %

Procedure:
Add water (6 mL) and TFA (2 mL) to (R)-4-{3,5-dichloro-4-[2-oxo-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-3-ylmethyl]-phenoxy}-benzamide (0.21 g) in THF (6 mL). Stir the mixture at room temperature for 12 hours. Dilute the reaction with ethyl acetate and wash with sodium bicarbonate (sat. solution), separate the organic layer, dry over sodium sulfate, filter and concentrate. Purify the residue on silica gel column by using ethyl acetate first, then switch to 5% methanol in dichloromethane to afford 0.158 g (100%) of the desired product as white solid. MS (m/z): 478 (M+).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:31]([NH2:33])=[O:32])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH:27]=[N:28][O:29][CH3:30])=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].Cl.C([BH3-])#N.[Na+]>C(Cl)Cl.CO.O1CCOCC1>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:31]([NH2:33])=[O:32])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH2:27][NH:28][O:29][CH3:30])=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(C=NOC)cc4)cc23)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNOC)cc4)cc23)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(methyloxy)imino]methyl}phenyl)-1H-indole-7-carboxamide (21.5 mg, 0.046 mmol) in DCM (3.0 mL) and MeOH (3.0 mL) was added drops of HCl in 1,4-dioxane to maintain pH=4 at 0° C. Sodium cyanoborohydride (29 mg, 0.46 mmol) was then added and stirred overnight at room temperature. Additional HCl in 1,4-dioxane was added to maintain pH=4 in addition to sodium cyanoborohydride (45 mg, 0.72 mmol). Reaction mixture then stirred over 48 h. Additional HCl in 1,4-dioxane was added to maintain pH=4 at 0° C. and stirred till room temperature was achieved. Mixture was quenched with H2O. DCM was then added for aqueous work-up and mixture was concentrated. The reside was then take up in DCM and purified on the SCX SPE cartridge to afford 15.2 mg of the title compound (70%).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[O:18][C:17](=[O:22])[C:16]([C:23]([OH:25])=O)=[CH:15]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:50]1[C:51]([C:59]2[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=2)=[CH:52][N:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=12>CN(C=O)C>[N:50]1[C:51]([C:59]2[CH:60]=[C:61]([NH:65][C:23]([C:16]3[C:17](=[O:22])[O:18][C:19]4[C:14]([CH:15]=3)=[CH:13][C:12]([O:11][CH3:10])=[CH:21][CH:20]=4)=[O:25])[CH:62]=[CH:63][CH:64]=2)=[CH:52][N:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=12
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Reactant: COc1ccc2oc(=O)c(C(=O)O)cc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2oc(=O)c(C(=O)Nc3cccc(-c4cn5ccccc5n4)c3)cc2c1
Temperature: 25 °C
Yield: 83 %

Procedure:
DIEA (43.5 μL, 0.25 mmol) was added to 6-methoxy-3-carboxy-coumarin (50.0 mg, 0.23 mmol) and HATU (95.0 mg, 0.25 mmol) in 1 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (475. mg, 0.23 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 78.5 mg of product in 83% yield: LCMS (ESI) m/z 412 (MH+).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].C1OCCOCCOCCOCCOC1.Br[CH2:57][C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:57][C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)(C)OC(=O)CBr
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](OCC(=O)OC(C)(C)C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 74.9 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregna-5,7,16-triene (158 mg, 0.283 mmol) was treated with sodium hydride (60% in oil, 77 mg, 1.925 mmol), tetrahydrofuran (6 ml), 15-crown-5 (67 mg, 0.304 mmol) and t-butyl bromoacetate (0.25 ml, 1.679 mmol) in the same manner as shown in Example 8(1) (at an external temperature of 85° C. for 11 hours and 40 minutes) and then worked up. The resulting residue was purified by column chromatography (hexane:ethyl acetate=10:1) and preparative thin layer chromatography (0.5 mm×3 plates, hexane:ethyl acetate=20:1, developed twice) to give the titled compound (142.6 mg, 75%) as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:10]([OH:12])=O)[CH2:9][CH2:8]2)[CH:2]=1.Cl.Cl.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH2:24]2)=[N:20][C:21]=1[NH2:22].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[NH2:22][C:21]1[C:16]([NH:15][C:10]([C:7]2([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:8][CH2:9]2)=[O:12])=[CH:17][CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH2:24]2)[N:20]=1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: O=C(O)C1(c2cccnc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1NC(=O)C1(c2cccnc2)CC1
Temperature: 50 °C
Reaction time: 18 h
Yield: 84.5 %

Procedure:
1-(Pyridin-3-yl)cyclopropanecarboxylic acid (30.7 mg, 0.188 mmol), (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (Intermediate 1) (75 mg, 0.19 mmol), and N-methylmorpholine (83 μL, 0.76 mmol) were combined and dissolved in N,N-dimethylformamide (1.0 mL). Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP) (122 mg, 0.207 mmol) was added and the reaction mixture was stirred at 50° C. for 18 h. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane. A saturated aqueous solution of sodium bicarbonate was added. The organics were collected and the aqueous layer was extracted with dichloromethane. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography (0-10% methanol in dichloromethane) to afford (R)—N-(2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)-1-(pyridin-3-yl)cyclopropanecarboxamide (69 mg, 84%). MS (AP+) (M+H) 435.2; LCMS retention time 1.51 min (Method L).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21]O)=[CH:16][CH:15]=1)#[N:13].CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][O:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=2)=[CH:16][CH:15]=1)#[N:13]
Reactant: N#Cc1ccc(CCO)cc1
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(OCCc2ccc(C#N)cc2)cc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
4-Methyl-3-nitrophenol (0.765 g; 5.0 mmol), 2-(4-cyanophenyl)ethanol (0.735 g; 5.0 mmol) and diethylazodicarboxylate (0.87 g; 5.0 mmol) were dissolved in THF (20 mL). Triphenylphosphine (1.31 g; 5.0 mmol), dissolved in THF (5 mL), was added and the solution stirred overnight. Evaporation in vacuo and the addition of diethyl ether afforded a yellow solid that was recrystallized from water:acetone (9:1), affording the sub-title compound as yellowish crystals. Yield: 1.04 g (74%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.C(O)(C(F)(F)F)=O>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]2[C:5]3[NH:6][C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]=3[CH2:3][CH2:2][NH:1]2)=[CH:17][CH:16]=1
Reactant: COc1ccc(C=O)cc1
Reactant: NCCc1c[nH]c2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Yield: 79.2 %

Procedure:
This produce was prepared using the same procedure as for Intermediate 1 with tryptamine (15 g, 94.9 mmol), 4-methoxybenzaldehyde (12.9 g, 1.1 equiv.) and TFA (14.6 mL, 2 equiv.) to give the title compound (20.9 g, 80%) as a brownish powder.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:30]([O-:32])=[O:31])=[C:15]([CH2:18][S:19][C:20]4[N:24]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[N:23]=[N:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[K+].[C:36](=[O:49])([O:41][CH:42]([CH:46]([CH3:48])[CH3:47])[CH:43]([CH3:45])[CH3:44])[O:37][CH:38](I)[CH3:39].C(OCC)(=O)C.[Cl-].[Na+]>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:30]([O:32][CH:38]([O:37][C:36]([O:41][CH:42]([CH:43]([CH3:44])[CH3:45])[CH:46]([CH3:48])[CH3:47])=[O:49])[CH3:39])=[O:31])=[C:15]([CH2:18][S:19][C:20]4[N:24]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[N:23]=[N:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CN(C)CCn1nnnc1SCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3csc(N)n3)[C@H]2SC1
Reactant: CC(I)OC(=O)OC(C(C)C)C(C)C
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(OC(=O)OC(C(C)C)C(C)C)OC(=O)C1=C(CSc2nnnn2CCN(C)C)CS[C@@H]2[C@H](NC(=O)Cc3csc(N)n3)C(=O)N12
Temperature: 0 °C

Procedure:
A mixture of 1.78 g of 1-chloroethyl 2,4-dimethyl-3-pentyl carbonate and 5 g of sodium iodide is stirred in 30 ml of acetonitrile at 70° C. for 4 hours and concentrated. The residue is extracted with ether and concentrated to give crude 1-iodoethyl 2,4-dimethyl-3-pentyl carbonate. In 30 ml of dimethylformamide is dissolved 3.6 g of potassium 7β-[2-(2-aminothiazol-4-yl)acetamido]-3-[[[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thio]methyl]ceph-3-em-4-carboxylate, and with ice-cooling and stirring, the above 1-iodoethyl 2,4-dimethyl-3-pentyl carbonate is added thereto at one stroke, followed by stirring for 5 minutes. The reaction mixture is poured into a mixture of 150 ml of ethyl acetate and 150 ml of ice-cooled 20% aqueous sodium chloride. The organic layer is separated, washed with two 150-ml portions of saturated aqueous sodium chloride and extracted with 40 ml of 1N hydrochloric acid. The extract is subjected to column chromatography using Diaion MCI® GEL CHP-20P (Mitsubishi Chemical Industries Limited, Japan), elution being carried out with acetonitrile-0.01N hydrochloric acid. The fractions containing the desired product are combined and lyophilized to give 940 mg of the title compound as a white powder.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH:8]C(=O)C(C)(C)C)[C:5]([CH:15](O)[CH:16]([CH:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)[C:17](OC)=[O:18])=[CH:4][CH:3]=1.[ClH:35]>CO.O>[ClH:35].[F:1][C:2]1[N:7]=[C:6]2[C:5]([CH:15]=[C:16]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:17](=[O:18])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COC(=O)C(C1CCN(C(=O)OC(C)(C)C)CC1)C(O)c1ccc(F)nc1NC(=O)C(C)(C)C
Agent: Cl
Solvent: CO
Solvent: O
Product: O=c1[nH]c2nc(F)ccc2cc1C1CCNCC1

Procedure:
The mixture of tert-butyl 4-(1-(6-fluoro-2-pivalamidopyridin-3-yl)-1-hydroxy-3-methoxy-3-oxopropan-2-yl)piperidine-1-carboxylate (238 mg, 0.494 mmol), and concentrated HCl (1 mL) in MeOH (1 mL) and H2O (1 mL) was refluxed under N2 over night. The solvents were removed on rotary vacuum, the residue, as a yellow solid, was triturated with cold EtOH (2×3 mL), filtrated and dried under vacuum to afford an expected product, a yellow solid (139 mg, 99% yield); 1H NMR (400 MHz, MeOD) δ ppm 1.27 (s, 1 H), 1.83-1.95 (m, 2 H), 2.13 (d, J=14.10 Hz, 2 H),3.06-3.18 (m, 3 H), 3.49 (d, J=12.84 Hz, 2 H), 6.47 (d, J=8.81 Hz, 1 H), 7.69 (s, 1 H), 7.85 (d, J=9.06 Hz, 1 H); Mass spec. 248.13 (MH+), Calc. for C13H14FN3O 247.11.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([NH:6][C:7]1[C:12]([NH2:13])=[C:11]([C:14]2[C:15]([CH3:22])=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[N:10]=[CH:9][N:8]=1)[CH3:5].[C:23](OCC)(=[O:27])[C:24]([CH3:26])=O>C(O)C>[CH3:1][O:2][CH2:3][C@H:4]([N:6]1[C:7]2[N:8]=[CH:9][N:10]=[C:11]([C:14]3[C:15]([CH3:22])=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[C:12]=2[N:13]=[C:24]([CH3:26])[C:23]1=[O:27])[CH3:5]
Reactant: CCOC(=O)C(C)=O
Reactant: COC[C@@H](C)Nc1ncnc(-c2ccc(OC)nc2C)c1N
Solvent: CCO
Product: COC[C@@H](C)n1c(=O)c(C)nc2c(-c3ccc(OC)nc3C)ncnc21
Reaction time: 18 h

Procedure:
(R)-N4-(2-Methoxy-1-methyl-ethyl)-6-(6-methoxy-2-methyl-pyridin-3-yl)-pyrimidine-4,5-diamine (0.22 g, 0.74 mmol) was diluted in ethanol (8 ml) and ethyl pyruvate was added (0.82 ml, 7.4 mmol). The mixture was stirred for 18 hours at which time the solution was concentrated. After concentrating the solution the product was purified by preparative TLC eluting with 35% ethyl acetate in hexanes to yield 5.0 mg of (R)-8-(2-methoxy-1-methyl-ethyl)-4-(6-methoxy-2-methyl-pyridin-3-yl)-6-methyl-8H-pteridin-7-one (Example 650a). 1H NMR (300 MHz, CDCl3) δ ppm 8.99 (s, 1 H), 7.65 (d, J=8.42 Hz, 1 H), 6.68 (d, J=8.42 Hz, 1 H), 5.71 (m, 1H), 3.99 (s, 3 H), 3.59 (m, 2 H), 3.31 (s, 3 H), 2.50 (s, 3H), 2.50 (s, 3H), 2.50 (s, 3H), 0.85 (d, J=7.69 Hz, 3 H). MS (EI) 356.3 [(M+H)+, 100].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])[S:5][CH:6]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1>>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:2]2[CH:3]=[C:4]([N:7]3[CH2:11][C@:10]4([CH:16]5[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]5)[CH2:12]4)[O:9][C:8]3=[O:19])[S:5][CH:6]=2)[CH:21]=1
Reactant: OB(O)c1cccnc1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1cc(Br)cs1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1cc(-c2cccnc2)cs1

Procedure:
The title compound was prepared by a method analogous to that described in Example 12 from (R)-3′-(4-bromothiophen-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and pyridine-3-boronic acid. The title compound (73 mg) was obtained as a pale solid, m/z 342 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][NH:21][C:15]=2[CH:14]=1.[CH3:23][N:24]([CH3:39])[C:25](=[O:38])[CH:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][C:29]=1[F:37])[OH:27]>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:31]3[CH:32]=[CH:33][C:28]([CH:26]([OH:27])[C:25]([N:24]([CH3:23])[CH3:39])=[O:38])=[C:29]([F:37])[CH:30]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: CN(C)C(=O)C(O)c1ccc(B(O)O)cc1F
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(I)c3cn2)c1Cl
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4ccc(C(O)C(=O)N(C)C)c(F)c4)c3cn2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridine and {4-[2-(dimethylamino)-1-hydroxy-2-oxoethyl]-3-fluorophenyl}boronic acid. LCMS (M+H)+=519.0/521.0.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)=O.[CH:21](=O)[CH2:22][CH3:23]>>[CH3:23][C:22]1[CH:21]=[N:1][C:2]2[C:3]([C:12]=1[C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)=[CH:4][CH:5]=[CH:6][C:7]=2[C:8]([F:11])([F:10])[F:9]
Reactant: CCC=O
Reactant: Nc1c(C(=O)c2cccc(O)c2)cccc1C(F)(F)F
Product: Cc1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1

Procedure:
The title compound was prepared from [2-amino-3-(trifluoromethyl)phenyl]-(3-hydroxy-phenyl)methanone and Propionaldehyde following the procedure of Example 457: MS (ES) m/z 304.28.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([F:20])[C:18]=3[CH3:19])[N+:8]([O-:12])=[CH:9]2)=[CH:4][N:3]=1.[C:21](=[O:28])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH2:22].C1(P(C2CCCCC2)C2C(OC)=CC=C(OC)C=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.ClCCl.CO>[C:24]([O:23][C:21]([NH:22][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([F:20])[C:18]=3[CH3:19])[N+:8]([O-:12])=[CH:9]2)=[CH:4][N:3]=1)=[O:28])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(N)=O
Reactant: Cc1c(F)cncc1-c1cc2cnc(Cl)cc2c[n+]1[O-]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: Cc1c(F)cncc1-c1cc2cnc(NC(=O)OC(C)(C)C)cc2c[n+]1[O-]
Temperature: 100 °C
Yield: 37.9 %

Procedure:
A mixture of 7-chloro-3-(5-fluoro-4-methylpyridin-3-yl)-2,6-naphthyridine 2-oxide (150 mg, 0.52 mmol), tert-butyl carbamate (121 mg, 1.04 mmol), 2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (58 mg, 0.10 mmol), chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoeth yl)phenyl]palladium(II) (42 mg, 0.052 mmol), and cesium carbonate (341 mg, 1.04 mmol) in dioxane (2.5 mL) was heated at 100° C. for 8 hours in a vial sealed with a Teflon cap. The reaction mixture was diluted with dichloromethane (50 mL) and methanol (5 mL), filtered over Celite, and concentrated in vacuo to provide a residue that was purified by flash chromatography (12 g, Silica, 0-10% methanol in dichloromethane). Desired fractions were combined and evaporated in vacuo to afford the title compound as a yellow solid (73 mg, 38%). 1H NMR (400 MHz, DMSO) δ 10.16 (s, 1H), 9.14 (s, 1H), 9.08 (s, 1H), 8.62 (s, 1H), 8.39 (s, 1H), 8.21 (s, 1H), 8.16 (s, 1H), 1.52 (s, 9H).