Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][NH2:28])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.O.[C:30]([OH:34])(=[O:33])[CH:31]=O.Cl>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][NH:28][CH2:31][C:30]([OH:34])=[O:33])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:18][CH2:19]1)[N:11]=2
Reactant: O=CC(=O)O
Reactant: NCCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=C(O)CNCCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)-ethanamine (83 mg, 0.213 mmol) was added glyoxylic acid monohydrate (39 mg, 0.426 mmol) and DCM (1 mL) before it was stirred for 5 h at ambient temperature. The reaction mixture was concentrated before adding concentrated hydrochloric acid (2.13 mL, 4.26 mmol) and heating to reflux for 16 h. The reaction mixture was diluted with 75 mL of DCM, added to a separatory funnel, partitioned with water, washed 1 time with 50 mL of water, separated, dried over sodium sulfate, and concentrated via rotovap to give the title compound after preparatory LC. MS (ESI) m/z: Calculated: 447.1; Observed: 448.1 (M++H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[C:10]([CH3:18])=[C:9]1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.ClCCl>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:31]3[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)=[CH:14][CH:15]=2)[C:10]([CH3:18])=[C:9]1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1c(C)n(Cc2ccccc2)c2ccc(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc3c(c2)c(C)c(C)n3Cc2ccccc2)cc1

Procedure:
The desired product was prepared using a procedure similar to step 3 of example 3. Thus, 1-benzyl-5-bromo-2,3-dimethyl-1H-indole (1.872 g, 5.958 mmol) was reacted with aqueous 2M K2CO3 (6.0 ml), 4-methoxyphenylboronic acid (1.087 g, 7.150 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.097 g, 0.119 mmol) in dioxane (60 ml) to give the product (0.925 g, 2.709 mmol, 45%) as a brown oil. 1H NMR (DMSO-d6) δ 2.24 (s, 3H), 2.28 (s, 3H), 3.78 (s, 3H), 5.39 (s, 2H), 6.97-6.99 (m, 4H), 7.20 (t, J=7.2 Hz, 1H), 7.25-7.29 (m, 3H), 7.37 (d, J=8.4 Hz, 1H), 7.59 (d, J=8.7 Hz, 2H), 7.61 (s, 1H); [ESI(+)], m/z 342 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.P(Cl)(Cl)(Cl)=O.[C:23](=O)([O-])[OH:24].[Na+]>CN(C=O)C.O>[N:12]1([C:10]([C:7]2[CH:8]=[C:9]3[C:4]([C:3]([CH:23]=[O:24])=[CH:2][NH:1]3)=[CH:5][CH:6]=2)=[O:11])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=C(c1ccc2cc[nH]c2c1)N1CCOCC1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=Cc1c[nH]c2cc(C(=O)N3CCOCC3)ccc12

Procedure:
A solution of (1H-indol-6-yl)(morpholino)methanone (200 mg, 0.869 mmol, 1.0 eq) in DMF (3.0 ml) was added dropwise at 0° C. to phosphorus oxychloride (0.34 mL, 2.60 mmol, 3.0 eq) in DMF (5.0 mL) under stirring. The mixture was stirred at room temperature for 3 h, then neutralized with saturated sodium hydrogen carbonate solution, diluted with water (20 mL), and extracted with ethyl acetate (2×10 mL). The organic layers were combined, washed with brine (20 mL), dried over sodium sulfate and evaporated. The residue was purified by silica gel column chromatography [100-200 mesh; methanol/dichloromethane=1:9]. White solid. Yield: 100 mg (45% of theory).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[N:13]=[C:12]([C:14]3[CH:27]=[CH:26][C:17]([CH2:18][N:19]4[CH2:23][C:22](=[O:24])[NH:21][C:20]4=[O:25])=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH2:36][C:37]([F:40])([F:39])[F:38]>CN(C=O)C>[N:1]1([CH2:7][C:8]2[N:13]=[C:12]([C:14]3[CH:27]=[CH:26][C:17]([CH2:18][N:19]4[CH2:23][C:22](=[O:24])[N:21]([CH2:35][CH2:36][C:37]([F:40])([F:39])[F:38])[C:20]4=[O:25])=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1CN(Cc2ccc(-c3cccc(CN4CCCCC4)n3)cc2)C(=O)N1
Reactant: FC(F)(F)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CN(Cc2ccc(-c3cccc(CN4CCCCC4)n3)cc2)C(=O)N1CCC(F)(F)F
Temperature: 25 °C
Yield: 32.9 %

Procedure:
A solution of 1-(4-(6-Piperidin-1-ylmethyl-pyridin-2-yl)benzyl)imidazolidine-2,4-dione (example 134) (120 mg, 0.33 mmol), potassium carbonate (137 mg, 0.99 mmol) and 3-bromo-1,1,1-trifluoropropane (117 mg, 0.66 mmol) in DMF (2.5 ml) was stirred during 17 h at 50° C. After cooling to room temperature the reaction mixture was quenched by the addition of water. The product was extracted into ethylacetate and the combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography afforded the title compound (50 mg) as a white solid.
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]([S:19]([CH3:22])(=[O:21])=[O: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.C([N:30]1[C:34]2=[CH:35][N:36]=[CH:37][C:38](B(O)O)=[C:33]2[CH:32]=[CH:31]1)(=O)C>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]>[CH3:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:8]2[CH2:7][CH:6]3[CH2:23][O:24][CH2:25][CH2:26][N:5]3[C:4]3[N:3]=[C:2]([C:38]4[CH:37]=[N:36][CH:35]=[C:34]5[NH:30][CH:31]=[CH:32][C:33]=45)[N:11]=[CH:10][C:9]2=3)=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)c1ccc(CN2CC3COCCN3c3nc(Cl)ncc32)cc1
Reactant: CC(=O)n1ccc2c(B(O)O)cncc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(CN2CC3COCCN3c3nc(-c4cncc5[nH]ccc45)ncc32)cc1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 3 using 2-chloro-5-(4-(methylsulfonyl)benzyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x9, 75 mg, 0.190 mmol), 1-acetyl-1H-pyrrolo[2,3-c]pyridin-4-ylboronic acid (77 mg, 0.380 mmol) and PdCl2(dppf) (6.95 mg, 9.50 μmol) in dioxane (2 mL) and aqueous saturated NaHCO3 (0.4 mL). 1H NMR (400 MHz, DMSO-d6) δ 3.08-3.19 (m, 1 H), 3.21 (m, 2 H), 3.23-3.34 (m, 2 H), 3.47-3.56 (m, 1 H), 3.57-3.67 (m, 1 H), 3.70-3.81 (m, 1 H), 3.93-4.01 (m, 2 H), 4.06-4.15 (m, 1 H), 4.49-4.58 (m, 1 H), 4.64-4.80 (m, 2 H), 7.55-7.68 (m, 3 H), 7.69-7.75 (m, 1 H), 7.88-7.98 (m, 2 H), 8.28-8.37 (m, 1 H), 8.86-8.96 (m, 1 H), 9.05-9.15 (m, 1 H), 12.85-12.97 (m, 1 H). ESI-MS m/z [M+H]+ calc'd for C24H24N6O3S, 477.16; found 477.5.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[Br:21]CCBr.CO>C1COCC1>[C:1]1([NH:7][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[Br:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCBr
Reactant: O=C(Nc1ccccc1)c1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccccc1)c1ccncc1Br
Temperature: -69 °C
Reaction time: 8 h

Procedure:
As described in Synthetic Communications 1997, 27, 1075-1086, a 4-necked RBF equipped with an overhead stirrer and a J-Kem internal temperature probe was placed N-phenylisonicotinamide (35.7 g, 0.18 mol) and anhydrous THF (700 ml). All material appeared to go into solution. This mixture was cooled to −69° C. in a dry ice/IPA bath. To this was slowly added nBuLi (158 ml of a 2.5 M solution in Hexanes) in three portions. While adding the first equivalent of nBuLi, an exotherm was observed raising the temperature to ca. −41° C. The orange reaction mixture was slightly heterogeneous. This was allowed to slowly warm to −5 to 0° C. over 1.5 hrs in a ice/brine bath. The reaction mixture was recooled to −72° C. and 1,2-dibromoethane (36 g, 0.189 mol) in 15 ml of THF was added. A slight exotherm was observed rising to −62° C. The reaction mixture was allowed to stir overnight. The reaction mixture was poured into a flask containing 10 vol. SiO2. Methanol (100 ml) was added and the mixture was concentrated under reduced pressure. The dried silica gel was then placed on top of a bed of silica gel. The plug of silica gel was washed with 40% ethyl acetate/Hexane as eluent. Concentration of 10 liters of solvent afforded an off-white solid. The material was placed in vacuum drying at 60° C. overnight to provide 34 g (68% th) of an off-white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:16])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:6][CH:7]=1.BrC1C=CC(N)=NC=1.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1B(O)O.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[O:16]=[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([C:26]2[S:25][CH:29]=[CH:28][CH:27]=2)=[CH:7][N:6]=1)[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CCC(=O)Nc1ccc(Br)cn1
Reactant: OB(O)c1cccs1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: Nc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: COC(=O)CCC(=O)Nc1ccc(-c2cccs2)cn1
Temperature: 130 °C

Procedure:
In a microwave tube was charged with methyl 4-[(5-bromo-2-pyridyl)amino]-4-oxo-butanoate (commercially available or prepared as described in example II using as starting material the commercially available: 5-bromo-2-aminopyridine; 200 mg, 0.696 mmol, 1 equiv.), 2-thienylboronic acid (3 equiv., 2.09 mmol, 3 equiv.), bis(tri-tert-butylphosphine)palladium(0) (22 mg, 0.043 mmol, 0.06 equiv.), potassium carbonate (179 mg, 1.28 mmol, 1.8 equiv.) and dissolved in glycol dimethyl ether (5 ml)/water (2 ml). The reaction mixture was heated at 130° C. for 20 minutes in the microwave. The reaction was stopped and the solution was partitioned between ethyl acetate and alkaline water. The aqueous layer was separated and extracted with ethyl acetate (2×). The combined organic layer was dried on magnesium sulfate, and then concentrated under vacuum. The solid obtained was purified by flash chromatography (RF-machine) eluting with a gradient of cyclohexane-ethyl acetate to give methyl 4-oxo-4-[[5-(2-thienyl)-2-pyridyl]amino]butanoate A71 (8%). %). LC-MS (Method F) RT 0.85, 291 (M+H+). The aqueous layer was acidified with hydrogen chloride until pH 1-2 and extracted with ethyl acetate (2×). The combined organic layer was dried on magnesium sulfate, and then concentrated under vacuum. The solid was washed with ethyl acetate, filtered and dried to give 4-oxo-4-[[5-(2-thienyl)-2-pyridyl]amino]butanoic acid A72 (31% yield). %). LC-MS (Method F) RT 0.74, 277 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:12][O:11][NH:10][C:9]1=[O:13])([CH3:4])([CH3:3])[CH3:2].[CH3:15]C(C)([O-])C.[K+].C(I)I.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:14])[NH:7][C@@H:8]1[CH2:12][O:11][N:10]([CH3:15])[C:9]1=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)NC1CONC1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ICI
Solvent: O
Product: CN1OC[C@@H](NC(=O)OC(C)(C)C)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
(3-Oxo-isoxazolidin-4-yl)-carbamic acid tert-butyl ester (1.01 g, prepared from (D)-cycloserine as described in Chem. Pharm. Bull. 2002, 50(4) 554-557) was dissolved in dimethylformamide (5 ml), the solution was cooled to 0° C. and 616 mg of potassium t-butoxide was added portionwise. The reaction mixture was stirred at 0° C. for 1 hour then 710 mg methylene iodide was added and the reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was poured into water and extracted with diethyl ether. The organic phase was then washed several times with water, dried over sodium sulphate and the solvent removed in vacuo. Crude ((R)-2-methyl-3-oxo-isoxazolidin-4-yl)-carbamic acid tert-butyl ester (140 mg) was obtained as a white solid. LCMS (method A) 1.11 min, MH+ 217; 1H-NMR (CDCl3, 400 MHz): 5.20 (m, 1H), 4.70 (m, 1H), 4.55 (m, 1H), 4.00 (dd, 1H), 3.20 (s, 3H), 1.40 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-])=O)[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]#[C:12][C:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:15][CH:14]=1.[NH4+].[Cl-].CN(C=O)C.O>[Fe].CCO>[NH2:31][C:29]1[CH:28]=[CH:27][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[C:11]#[C:12][C:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:15][CH:14]=2)=[C:2]([F:1])[CH:30]=1
Reactant: CC(C)(C)OC(=O)NC1CC=C(C#Cc2cnccc2Oc2ccc([N+](=O)[O-])cc2F)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1CC=C(C#Cc2cnccc2Oc2ccc(N)cc2F)CC1
Temperature: 100 °C
Yield: 103.3 %

Procedure:
A mixture of tert-butyl 4-(2-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)ethynyl)cyclohex-3-enylcarbamate (110 mg, 0.24 mmol), iron powder, ˜325 mesh (150 mg, 2.7 mmol), NH4Cl (280 mg, 5.3 mmol), DMF (1 mL), H2O (1 mL) and EtOH (1 mL) was heated at 100° C. for 30 minutes. The mixture was filtered through a pad of Celite® using DMF to wash the filter cake and the filtrate made basic to pH 8 with saturated aq. NaHCO3 solution. The mixture was extracted twice with EtOAc and dried (MgSO4) and concentrated in vacuo to give the title compound (105 mg) which was used without any further purification. MS (ESI+): m/z 424.27 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.Cl.[CH:23]1([NH:26][CH2:27][C:28]2([OH:33])[CH2:32][CH2:31][NH:30][CH2:29]2)[CH2:25][CH2:24]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:30]4[CH2:31][CH2:32][C:28]([CH2:27][NH:26][CH:23]5[CH2:24][CH2:25]5)([OH:33])[CH2:29]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: OC1(CNC2CC2)CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC(O)(CNC4CC4)C3)c(F)cc2c1=O

Procedure:
1-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is reacted analogously to Example 6 with 3-cyclopropylaminomethyl-3-hydroxypyrrolidine dihydrochloride to give 1-cyclopropyl-7-(3-cyclopropylaminomethyl-3-hydroxy-1-pyrrolidinyl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 161°-162° (with decomposition).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[CH3:21])=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][C:4]=2[N:3]=1.I[CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][P:42](=[O:49])([O:46][CH2:47][CH3:48])[O:43][CH2:44][CH3:45].C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>CN(C=O)C>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][P:42]([O:46][CH2:47][CH3:48])([O:43][CH2:44][CH3:45])=[O:49])=[CH:16][C:15]=3[CH3:21])=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][C:4]=2[N:3]=1
Reactant: CCOC(=O)CCc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3C)cc12
Reactant: CCOP(=O)(CCOCCOCCI)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCCOCCOCCP(=O)(OCC)OCC)cc3C)cc12
Temperature: 60 °C

Procedure:
To a solution of ethyl 3-(5-amino-2-(4-hydroxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoate (13) (1.0 equiv.) dissolved in DMF (0.14M) was added a solution of diethyl 2-(2-(2-iodoethoxyl)ethoxy)ethylphosphonate (14): from step 11 above (1.3 equiv.) in DMF (0.7M) and cesium carbonate (4 equiv.). The reaction was stirred at 60° C. After 1.5 hours (or until reaction is complete by LCMS), DCM (2 volume equivalent) was added to the reaction. The solids (inorganic) were filtered, and the filtrate was concentration. The crude product was purified by Combiflash using 0-5% MeOH in DCM to give ethyl 3-(5-amino-2-{2-[4-(2-{2-[2-(diethoxyphosphoryl)ethoxy]ethoxy}ethoxy)-2-methylphenyl]ethyl}benzo[f]1,7-naphthyridin-8-yl)propanoate (15).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=CC(S(Cl)(=O)=O)=C[CH:2]=1.[Cl:12][C:13]1[N:18]=[C:17]([C:19]([OH:21])=[O:20])[C:16]([CH3:22])=[CH:15][CH:14]=1.N1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(O)(C)(C)C.O>[Cl:12][C:13]1[N:18]=[C:17]([C:19]([O:21][C:1]([CH3:11])([CH3:6])[CH3:2])=[O:20])[C:16]([CH3:22])=[CH:15][CH:14]=1
Reactant: Cc1ccc(Cl)nc1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: c1ccncc1
Product: Cc1ccc(Cl)nc1C(=O)OC(C)(C)C
Reaction time: 24 h
Yield: 93.1 %

Procedure:
p-Toluenesulfonyl chloride (10.5 g, 55.1 mmol) was added to a solution of 6-chloro-3-methylpyridine-2-carboxylic acid (4.73 g, 27.6 mmol) as a known compound in tert-butyl alcohol (150 ml) and pyridine (21 ml) at room temperature, and the mixture thus obtained was then stirred at the same temperature as above for 24 hours. Thereafter, a solution of sodium hydrogen carbonate (11.6 g, 138 mmol) in water (300 ml) was added to the resulting solution, and the mixed solution was then stirred. Then, the solvent was distilled away from the reaction solution under reduced pressure. While being washed with water, the solid thus generated was collected by filtration, and was then dried to obtain the title compound (5.85 g, yield: 93%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:23]=[C:14]3[CH2:15][N:16]([CH:19]4[CH2:22][O:21][CH2:20]4)[CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:24]([O:27][CH2:28][C:29]1[C:30]([N:44]2[N:53]=[CH:52][C:51]3[C:46](=[C:47]([F:58])[CH:48]=[C:49]([C:54]([CH3:57])([CH3:56])[CH3:55])[CH:50]=3)[C:45]2=[O:59])=[N:31][CH:32]=[CH:33][C:34]=1B1OC(C)(C)C(C)(C)O1)(=[O:26])[CH3:25].C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C([O-])([O-])=O.[Cs+].[Cs+]>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].O.O1CCOCC1>[C:24]([O:27][CH2:28][C:29]1[C:30]([N:44]2[N:53]=[CH:52][C:51]3[C:46](=[C:47]([F:58])[CH:48]=[C:49]([C:54]([CH3:56])([CH3:55])[CH3:57])[CH:50]=3)[C:45]2=[O:59])=[N:31][CH:32]=[CH:33][C:34]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:23]=[C:14]3[CH2:15][N:16]([CH:19]4[CH2:22][O:21][CH2:20]4)[CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Reactant: Cn1nc(Cl)cc(Nc2cc3n(n2)CCN(C2COC2)C3)c1=O
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C3COC3)C4)c(=O)n(C)n2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 110 °C
Yield: 16.3 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 155c (367 mg, 1.1 mmol), 3-(acetoxymethyl)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)pyridine-4-ylboronic acid 116c (908.6 mg, 2.2 mmol), Pd2(dba)3 (100.6 mg, 0.11 mmol), P(cy)3 (122.8 mg, 0.44 mmol), Cs2CO3 (717 mg, 2.2 mmol), dioxane (20 mL), and water (0.5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 110° 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 35:1 dichloromethane/methanol to afford 155d (120 mg, 16%) as a yellow solid. MS-ESI: [M+H]+ 669.8
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].COC(=O)CC.[H][H]>CO>[CH:3]([OH:2])=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: [H][H]
Reactant: CCCCCCCCC=CC(=O)OC
Solvent: CCC(=O)OC
Solvent: CO
Product: CCCCCCCCCC=CO
Reaction time: 5 h

Procedure:
In about the same way as described under Example 2, an experiment was carried out with difference being that 10 ml methyl-undecenoate was included in the autoclave instead of 10 ml methylpropionate, while after 5 min hydrogen was added until a pressure increase of 30 bar was reached. The autoclave was kept at 80° C. for 5 hours giving a yield of 2.4 g methanol and about 1 g 1-undecenol.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH:18]=[N:17][NH:16][C:15]3=[O:19])[CH2:10][CH2:9]2)C=CC=CC=1.C1CC=CCC=1.C(O)C>[OH-].[Pd+2].[OH-].O>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:18]=[N:17][NH:16][C:15]2=[O:19])[CH2:12][CH2:13]1
Reactant: O=c1[nH]ncn1C1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1=CCC=CC1
Product: O=c1[nH]ncn1C1CCNCC1
Temperature: 100 °C
Yield: 50.3 %

Procedure:
2,4-Dihydro-4-[1-(phenylmethyl)-4-piperidinyl]-3H-1,2,4-triazol-3-one (Example 64(b)) (2.2 g) was divided between 2, 10 mL vials. 1,4-Cyclohexadiene (5 mL) and palladium hydroxide (270 mg, 20 wt. % on carbon) were added to each vial and the reactions were heated at 100° C. for 30 minutes within a microwave. The reaction mixtures were combined, ethanol (50 mL) and water (50 mL) were added and the mixture was filtered through diatomaceous earth and evaporated to give the sub-title compound as a solid (720 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3](/[C:7](=[N:14]\[O:15][CH2:16][C:17]2[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=2)/[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:4][S:5][N:6]=1.N1C=CC=CC=1.[C:30](Cl)(=[O:36])[O:31][CH2:32][C:33]#[C:34][CH3:35]>O1CCOCC1.C(Cl)Cl.O>[CH3:1][C:2]1[C:3]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([NH:23][C:30](=[O:36])[O:31][CH2:32][C:33]#[C:34][CH3:35])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:4][S:5][N:6]=1
Reactant: Cc1nsnc1/C(=N\OCc1cccc(N)n1)c1ccccc1
Reactant: CC#CCOC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC#CCOC(=O)Nc1cccc(CON=C(c2ccccc2)c2nsnc2C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
To a stirred solution of 6-[({[(Z)-(4-methyl-1,2,5-thiadiazol-3-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-amine (100 mg, 0.31 mmol) in dry 1,4-dioxane (5 mL) were added pyridine (37 μL, 0.46 mmol) and but-2-yn-1-yl carbonochloridate (82 mg, 0.62 mmol). The reaction mixture was stirred at room temperature for 18 h, then diluted with DCM (10 mL) and water (10 mL), the organic layer was dried (MgSO4) and concentrated in vacuo. Purification on silica gel afforded but-2-yn-1-yl {6-[({[(4-methyl-1,2,5-thiadiazol-3-yl)(phenyl)methylidene]-amino}oxy)methyl]pyridin-2-yl}carbamate as a colourless oil [120 mg, yield 93%; HPLC/MS: m/z=422 (M+H); log P(HCOOH)=4.28].