Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][C:22]=1[N:31]=[C:32]=[O:33]>>[F:20][C:21]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][C:22]=1[NH:31][C:32](=[O:33])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1F
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Product: NC(=O)c1[nH]c2ncccc2c1-c1ccc(NC(=O)Nc2cccc(C(F)(F)F)c2F)cc1

Procedure:
79 mg of solid white 3-{4-[3-(2-fluoro-3-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and 2-fluoro-3-trifluoromethylphenyl isocyanate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:25][O:26][C:27](=[O:30])[CH2:28]Br>CN(C)C=O>[CH3:25][O:26][C:27]([CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])=[CH:6][CH:7]=1)=[O:30]
Reactant: COC(=O)CBr
Reactant: O=C(Cc1ccc(O)cc1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(CC(=O)OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a suspension of 8.4 g (0.035 Mol) of benzyl 4-hydroxyphenylacetate and 4.8 g (0.035 Mol) of dried potassium carbonate in 100 ml of dimethylformamide are added slowly, after 45 minutes stirring at ambient temperature, 5.3 g (0.038 Mol) of methylbromoacetate and the mixture is then heated to 80° C. for 5 minutes whilst stirring continues. It is then stirred overnight at ambient temperature. The solid matter is filtered off and the mother liquor is evaporated to dryness under reduced pressure. The residue is purified over a silica gel column, using methylene chloride as eluant. Yield: 7.9 g amorphous solid (72.9% of theory).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[CH2:6]([C@@:9]1([CH3:35])[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[C@@H:12]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N:11]([C@@H:29]([CH2:32][CH3:33])[CH:30]=[O:31])[C:10]1=[O:34])[CH:7]=[CH2:8]>C1COCC1>[CH2:6]([C@@:9]1([CH3:35])[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[C@@H:12]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[N:11]([C@@H:29]([CH2:32][CH3:33])[CH:30]([CH:1]2[CH2:3][CH2:2]2)[OH:31])[C:10]1=[O:34])[CH:7]=[CH2:8]
Reactant: Br[Mg]C1CC1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(O)C2CC2)C1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Cyclopropylmagnesium bromide (0.5 M solution in THF, 2.0 mL, 1.013 mmol) was added dropwise via syringe over a period of 1 min to a stirred solution of (S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal (Example 91, Step C, 150 mg, 0.338 mmol) in THF (1.7 mL) at rt. The reaction mixture was stirred at rt for 20 minutes and then quenched with NH4Cl (30 mL, saturated aqueous solution) and diluted with EtOAc (50 mL). The organic layer was dried over MgSO4, filtered and evaporated in vacuo. Purification by column chromatography (24 g SiO2, Hexanes:EtOAc, 1:0 to 4:1) gave the title compound as a mixture of diastereomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[NH:16][NH:17]C(OC(C)(C)C)=O.[F:25][C:26]([F:39])([F:38])[C:27]1[CH:37]=[CH:36][C:30]([C:31]([N:33]=[C:34]=[O:35])=O)=[CH:29][CH:28]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[N:16]1[C:34](=[O:35])[NH:33][C:31]([C:30]2[CH:36]=[CH:37][C:27]([C:26]([F:39])([F:38])[F:25])=[CH:28][CH:29]=2)=[N:17]1
Reactant: CC(C)(C)OC(=O)NNc1cc(CNC(=O)C(C)(C)C)ccc1Cl
Reactant: O=C=NC(=O)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(C(F)(F)F)cc3)[nH]c2=O)c1
Yield: 36.8 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using tert-butyl 2-(2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}phenyl)hydrazinecarboxylate (Intermediate-94, 0.150 g, 0.420 mmol), 4-(trifluoromethyl)benzoyl isocyanate (Intermediate-59, 0.181 g, 0.84 mmol), DCM (15 mL), and trifluoro acetic acid (3.0 mL) to afford 0.070 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.13 (s, 9H), 4.29 (d, J=5.4 Hz, 2H), 7.36 (d, J=8.7 Hz, 1H), 7.45 (s, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.92 (d, J=8.4 Hz, 2H), 8.06 (d, J=8.4 Hz, 2H), 8.19 (m, 1H), 12.79 (s, 1H); MS (m/z): 456.59 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[C:7]=1[NH2:15].[OH-].[Na+]>C(OCC)(=O)C.C(O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[C:7]=1[NH2:15]
Reactant: COCCOc1cccc([N+](=O)[O-])c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COCCOc1cccc(N)c1N

Procedure:
To a solution of 1 g 2-(2-Methoxy-ethoxy)-6-nitro-phenylamine in 10 mL ethyl acetate and 3 mL ethanol, 4.4 g SnCl2 dihydrate were added and the reaction mixture was heated to reflux for 6 h. Then, after cooling 50 mL 2 M NaOH were added and the inorganic precipitate was filtered and washed extensivley with ethyl acetate. The filtrate was extracted with exthyl acetate (3×100 ml), the combined organic layers were dried over MgSO4, and the solvents were removed under reduced pressure. The remaining product was pure enough for the next reaction step.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C@@H:11]1([NH2:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1>>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:21][C@@H:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1cccc(Cl)c1Cl
Product: Clc1cccc(CN[C@H]2CCCc3ccccc32)c1Cl

Procedure:
2,3-Dichlorobenzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([NH2:22])[CH2:13][C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:30][CH2:31][CH3:32]>C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([NH:22][CH2:30][CH2:31][CH3:32])[CH2:13][C:12]2=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCI
Reactant: NC1CCc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCNC1CCc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Temperature: 25 °C
Reaction time: 60 h
Yield: 39.4 %

Procedure:
To a solution of 0.600 gm (2.05 mMol) 6-benzyloxy-3-amino-1,2,3,4-tetrahydro-9H-carbazole in 35 mL acetonitrile were added 0.283 gm (2.05 mMol) potassium carbonate followed by 240 μL (2.46 mMol) iodopropane and the reaction mixture was stirred at room temperature for 2.5 days. Additional iodopropane was added and the reaction stirred at room temperature until all of the starting material had been consumed. The reaction mixture was then partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane and the combined organic phases were then dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 96.5:3:0.5 dichloromethane:isopropanol:ammonium hydroxide. Fractions shown to contain the desired compound were concentrated under reduced pressure to give 0.270 gm (39%) of the desired compound.
Reaction SMILES: C[O:2][C:3]([CH:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[C:16](=[O:22])[CH2:15][CH2:14]3)[CH2:6]1)=O.[CH3:23][NH2:24]>CO>[CH3:23][NH:24][C:3]([C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[C:16](=[O:22])[CH2:15][CH2:14]3)[CH2:6]1)=[O:2]
Reactant: COC(=O)C1CN(c2ccc3c(c2)CCC(=O)N3C)C(=O)O1
Reactant: CN
Solvent: CO
Product: CNC(=O)[C@H]1CN(c2ccc3c(c2)CCC(=O)N3C)C(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
To a stirred solution of 3-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2-oxo-5-oxazolidinecarboxylic acid methyl ester (EXAMPLE 67, Step 4, 150 mg, 0.49 mmol) in MeOH (2 mL) is added MeNH2 (2 mL, 4.0 mmol, 2.0 M solution in MeOH). The reaction mixture is then stirred for 30 minutes at room temperature. Solvent is removed and the residue is washed with ether to give the title compound as a white solid (120 mg, 80%), 1H NMR (300 MHz, DMSO) δ 8.37 (d, 1H), 7.44-7.07 (m, 3H), 5.04 (dd, 1H), 4.25 (t, 1H), 3.99 (dd, 1H), 3.23 (s, 3H), 2.86 (t, 2H), 2.65 (d, 3H), 2.50 (m, 2H); MS for C15H17N3O4 m/z 304.5 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11].Cl[C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:20]=2[N:21]=1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:26][C:23]1[CH:24]=[CH:25][C:19]2[O:18][C:17]([NH:1][CH2:2][C@@H:3]3[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]3[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[N:21][C:20]=2[CH:22]=1
Reactant: Clc1ccc2oc(Cl)nc2c1
Reactant: C=CCOC(=O)N1CCC[C@@H](C)[C@H]1CN
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=CCOC(=O)N1CCC[C@@H](C)[C@H]1CNc1nc2cc(Cl)ccc2o1
Temperature: 40 °C

Procedure:
A mixture of (2S,3R)-allyl 2-(aminomethyl)-3-methylpiperidine-1-carboxylate (0.804 g, 3.787 mmol), 2,5-dichlorobenzo[d]oxazole (0.712 g, 3.787 mmol) and DIPEA (1 mL, 5.68 mmol) in acetonitrile (15 mL) was heated at 40° C. overnight. The solvent was removed in vacuo and the crude was purified via silica gel with 0˜100% EtOAc/hexanes to obtain the title compound. ESI-MS (m/z): 364 [M+1]+.
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([CH2:8][N:9]2[C:18](=[O:19])[C:17]3[N:16]([CH2:20][C:21]#[C:22][CH3:23])[C:15]([N:24]4[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:25]4)=[N:14][C:13]=3[N:12]([CH3:38])[C:10]2=[O:11])=[CH:5][CH:4]=1)=O.[NH2:39]OS(O)(=O)=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([C:3]1[O:7][C:6]([CH2:8][N:9]2[C:18](=[O:19])[C:17]3[N:16]([CH2:20][C:21]#[C:22][CH3:23])[C:15]([N:24]4[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:32])[CH2:25]4)=[N:14][C:13]=3[N:12]([CH3:38])[C:10]2=[O:11])=[CH:5][CH:4]=1)#[N:39]
Reactant: CC#CCn1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(Cc1ccc(C=O)o1)c(=O)n2C
Reactant: NOS(=O)(=O)O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC#CCn1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(Cc1ccc(C#N)o1)c(=O)n2C

Procedure:
Prepared by reacting 1-[(5-formyl-furan-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine with hydroxylamine-O-sulfonic acid and pyridine in toluene at reflux temperature.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](B(O)O)=[CH:7][CH:6]=[CH:5][N:4]=1.I[C:13]1[C:21]2[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:19][CH:18]=[N:17][C:16]=2[NH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.[Pd]>[CH3:1][O:2][C:3]1[C:8]([C:13]2[C:21]3[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:19][CH:18]=[N:17][C:16]=3[NH:15][CH:14]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1B(O)O
Reactant: Ic1c[nH]c2ncnc(-c3ccccc3)c12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ncccc1-c1c[nH]c2ncnc(-c3ccccc3)c12
Temperature: 170 °C

Procedure:
A mixture of (2-methoxypyridin-3-yl)boronic acid (36 mg, 0.23 mmol), 5-iodo-4-phenyl-7H-pyrrolo[2,3-d]pyrimidine (50 mg, 0.16 mmol), sodium carbonate (83 mg, 0.78 mmol) and SiliaCat® heterogeneous catalysts DPP-Pd (loading=0.28 mmol/g, 111 mg, 0.031 mmol) in dioxane (1.30 mL) and water (0.26 mL) was heated to 170° C. under the microwave irradiation for 15 minutes. The reaction mixture was concentrated, redissolved in DMSO, filtered and the resulting solution was reconcentrated. Purification by reverse phase HPLC using an acetonitrile gradient in water with 0.1% formic acid modifier afforded 5-(2-methoxypyridin-3-yl)-4-phenyl-7H-pyrrolo[2,3-d]pyrimidine. LRMS (ESI) calc'd for C18H15N4O [M+H]+: 303, found 303. 1H NMR (600 MHz, DMSO-D6) δ 12.40 (s, 1H), 8.82 (s, 1H); 7.97 (dd, 1H, J=1.1, 4.3 Hz); 7.65 (s, 1H); 7.64 (dd, 1H, J=1.1, 5.6 Hz); 7.28 (d, 2H, J=6.6 Hz), 7.24 (t, 1H, J=6.1 Hz); 7.08 (dd, 2H, J=6.1, 6.6 Hz); 6.94 (dd, 1H, J=4.3, 5.6 Hz); 3.05 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([CH2:8][C:9]([NH:11][C:12]2([C:20](OC)=[O:21])[CH2:17][CH2:16][C:15]([F:19])([F:18])[CH2:14][CH2:13]2)=[O:10])[CH:7]=1.CN(C)C(=O)C.CC(C)([O-])C.[K+].Cl>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([C:8]2[C:9](=[O:10])[NH:11][C:12]3([CH2:13][CH2:14][C:15]([F:19])([F:18])[CH2:16][CH2:17]3)[C:20]=2[OH:21])[CH:7]=1
Reactant: COC(=O)C1(NC(=O)Cc2cc(Br)ccc2C)CCC(F)(F)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccc(Br)cc1C1=C(O)C2(CCC(F)(F)CC2)NC1=O
Temperature: 30 °C
Reaction time: 1 h

Procedure:
11.0 g (27.2 mmol) of the compound from Example 10A were initially charged in a solution of 22 ml of DMA (N,N-dimethylacetamide), a solution of 10 ml of DMA and 3.54 g (1.1 eq.) of potassium tert-butoxide was added dropwise at 20-30° C. and the mixture was stirred at 30° C. for a further 1 h. The mixture was poured into 200 ml of water and the mixture was adjusted to pH 2 using aqueous 1N hydrochloric acid, the resulting precipitate was filtered off with suction, washed with water and dried in a vacuum drying cabinet at 50° C. The product was suspended in hot methyl tert-butyl ether, n-hexane was added and the mixture was filtered off with suction and dried. This gave 11.0 g (97% of theory) of the title compound in a purity of 89%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[C:3]=1[C:18]#[N:19].O1CCO[CH2:22][CH2:21]1>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:18]([C:3]1[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[N:5][C:6]([S:8][CH3:9])=[N:7][C:2]=1[CH:21]=[CH2:22])#[N:19]
Reactant: COc1cccc(-c2nc(SC)nc(Cl)c2C#N)c1
Reactant: C1COCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=Cc1nc(SC)nc(-c2cccc(OC)c2)c1C#N

Procedure:
6-Chloro-5-cyano-4-(3-methoxyphenyl)-2-methylthio-pyrimidine (example 1b, 1.46 g) was suspended in 1,4-dioxane (10 ml). Tetrakis(triphenylphosphine)palladium(0) (350 mg) was added and the mixture was flushed with a nitrogen atmosphere. Tetravinyltin (1.26 ml) was added and the mixture was refluxed for 5 h. The reaction mixture was then poured in a mixture of EtOAc (100 ml) and H2O (100 ml). The organic layer was washed with sat. aq. NaCl, dried (MgSO4) and concentrated under reduced pressure. The title compound was purified by chromatography on silica gel with hept/CH2Cl2=1/0 to 1/3 (v/v).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([NH2:12])[CH:5]=1.Cl.C(O)CCC.[C:20]1(Cl)[C:26](=O)[C:25](Cl)=[C:24](Cl)[C:22](=O)[C:21]=1Cl>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[CH3:1][O:2][C:3]([C:4]1[C:5]2[CH:26]=[CH:20][C:21]([CH2:22][CH2:24][CH3:25])=[N:12][C:6]=2[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)=[O:13]
Reactant: COC(=O)c1ccc(OC)c(N)c1
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCCCO
Product: CCCc1ccc2c(C(=O)OC)ccc(OC)c2n1
Temperature: 25 °C
Yield: 10.5 %

Procedure:
Methyl-3-amino-4-methoxybenzoate (10.0 g) was treated with concentrated hydrochloric acid (14 ml) and n-butanol (10 ml), under nitrogen, with stirring. The stirred mixture was treated with p-chloranil (13.65 g) and then heated at reflux whilst a mixture of trans-2-hexanal (8 ml) and n-butanol (5 ml) was added dropwise over 2 hours using a syringe pump. After heating at reflux for a further 30 minutes the mixture was treated with a solution of anhydrous zinc chloride (7.52 g) in tetrahydrofuran (60 ml), then allowed to cool slowly to room temperature and then cooled to 0° C. for 18 hours. The reaction mixture was evaporated, then diluted with hydrochloric acid (1M) and then washed with diethyl ether. The pH of the solution was adjusted to 6 and the resulting emulsion was treated with ammonium hydroxide and the solution extracted with diethyl ether. The combined dark green extracts were dried over magnesium sulphate then evaporated. The resulting dark green oil was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and pentane (3:7, v/v) to give the title compound (1.5 g) as an orange oil. NMR(CDCl3): δ 9.36(d, J=8.9 Hz, 1H), 8.26(d, J=8.4 Hz, 1H), 7.47(d, J=8.9 Hz, 1H), 7.03(d, J=8.4 Hz, 1H), 4.14(s, 3H), 3.97(s, 3H), 3.02(m, 2H), 1.86(m, 2H), 1.03(t, J=7.3 Hz, 3H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]([OH:14])=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.OS(O)(=O)=O.[CH3:20]O>ClCCl>[CH3:20][O:13][C:12](=[O:14])[CH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2
Reactant: O=C(O)Cc1ccc2ncccc2c1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COC(=O)Cc1ccc2ncccc2c1

Procedure:
To a stirred solution of quinolin-6-yl-acetic acid (10 g, 53.0 mmol) in 100 ml of methanol was added 2.5 ml of concentrated H2SO4 The mixture was heated to reflux for 3 hours. The reaction mixture was concentrated to give a brown residue, which was diluted with 100 ml of dichloromethane, washed with sat. aq. NaHCO3 and brine, then the organic layer was dried over anhydrous Na2SO4 and concentrated to return the title compound as a brown oil (7.9 g, 73.6%).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=4)=[O:28])=[N:24][CH:25]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[F:36][C:32]1[CH:31]=[C:30]([NH:29][C:27]([NH:26][C:23]2[CH:22]=[CH:21][C:20]([CH2:19][C:12]3[C:13]4[C:14](=[N:15][CH:16]=[CH:17][CH:18]=4)[NH:10][CH:11]=3)=[CH:25][N:24]=2)=[O:28])[CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Nc1cccc(F)c1)Nc1ccc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncccc23)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1cccc(F)c1)Nc1ccc(Cc2c[nH]c3ncccc23)cn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 1-[5-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-3-(3-fluoro-phenyl)-urea (605, 0.100 g, 0.20 mmol) in tetrahydrofuran (10.0 mL) was added tetrabutylammonium fluoride, trihydrate (0.240 g, 0.76 mmol). The reaction was stirred at room temperature for 5 hours, then poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid (P-0412, 17.9 mg, 24.8%). MS (ESI) [M+H]=362.2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([CH2:24][F:25])[CH:13]([CH3:14])[C:12](=O)[N:11]([C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@@:9]1([CH2:24][F:25])[CH:13]([CH3:14])[CH2:12][N:11]([C@@H:16]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH3:17])[CH2:10]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1C(=O)N([C@H](C)c2ccccc2)C[C@@]1(CF)NC(=O)OC(C)(C)C
Agent: B
Solvent: C1CCOC1
Product: CC1CN([C@H](C)c2ccccc2)C[C@@]1(CF)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 75.4 %

Procedure:
To a solution of (3S)-3-(tert-butoxycarbonylamino)-3-fluoromethyl-4-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine (485 mg, 1.38 mmol) in tetrahydrofuran (10 mL), 1.00M solution of borane in tetrahydrofuran (4.57 mL, 4.57 mmol) was added in an ice bath, and the mixture was stirred at room temperature for 15 hours. After concentrating the reaction mixture under reduced pressure, water (1 mL), ethanol (9 mL), and triethylamine (1 mL) were added in an ice bath, and the mixture was heated under reflux for 1.5 hours. After concentrating the reaction mixture under reduced pressure, water (100 mL) was added, and the mixture was extracted with chloroform (100 mL×2). The organic layer was washed with saturated aqueous solution of sodium chloride (100 mL), and dried with anhydrous sodium sulfate. After the filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elusion by hexane ethyl acetate, 12:1→1:1) to obtain 350 mg (75%) of the title compound as a colorless oily substance.
Reaction SMILES: Cl.[CH2:2]([O:4][NH2:5])[CH3:3].[OH-].[Na+].[OH:8][C:9]1[CH2:14][CH:13]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[C:17]([O:23][CH3:24])[C:16]=2[CH3:25])[CH2:12][C:11](=[O:26])[C:10]=1[C:27](=O)[CH2:28][CH3:29]>C(O)C>[CH2:2]([O:4][N:5]=[C:27]([C:10]1[C:11](=[O:26])[CH2:12][CH:13]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[C:17]([O:23][CH3:24])[C:16]=2[CH3:25])[CH2:14][C:9]=1[OH:8])[CH2:28][CH3:29])[CH3:3]
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(OC)c2C)CC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCON=C(CC)C1=C(O)CC(c2c(C)cc(C)c(OC)c2C)CC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.3 %

Procedure:
Ethoxyamine hydrochloride (0.43 g) and then aqueous sodium hydroxide (0.18 g in 10.0 ml of water) were added to a solution of 3-hydroxy-5-(3-methoxy-2,4,6-trimethylphenyl)-2-propionylcyclohex-2-en-1-one (1.35 g) in anhydrous absolute ethanol (200 ml). The mixture was stirred at room temperature for a period of 4 hours and then the ethanol was removed by evaporation under reduced pressure. The residue was treated with dichloromethane and the organic phase was washed twice with dilute aqueous hydrochloric acid and twice with water. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed by evaporation under reduced pressure to give 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-(3-methoxy-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (1.40 g), as a pale yellow oil which slowly solidified on standing. Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 1.20 (3H, t); 1.32 (3H, t); 2.23 (3H, s); 2.34 (6H, s); 2.35-4.00 (7H, m); 3.65 (3H, s); 4.12 (2H, q); 6.83 (1H, s); 14.95 (1H, s).