Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][C:13](NC1C=CC(C(O)=O)=CN=1)=[O:14])[N:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:7]2=[O:33].[NH2:34][C:35]1[N:36]=[N:37][C:38]([Cl:41])=[CH:39][CH:40]=1>>[Cl:41][C:38]1[N:37]=[N:36][C:35]([NH:34][C:13](=[O:14])[CH2:12][CH2:11][CH:9]2[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[F:1])[C:7](=[O:33])[N:8]2[CH2:25][C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)=[CH:40][CH:39]=1
Reactant: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1ccc(C(=O)O)cn1
Reactant: Nc1ccc(Cl)nn1
Product: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1ccc(Cl)nn1

Procedure:
The product of Example 11, Part D (150 mg, 0.453 mmol) and 3-amino-6-chloropyridazine (57.3 mg, 0.453 mmol) were converted to the title compound in a manner analogous to the method described in Example 27 (112 mg, 18%). 1H NMR (400 MHz, CDCl3) δ 9.71 (s, 1H), 8.45 (d, J=9 Hz, 1H), 7.61 (d, J=8 Hz, 1H); 7.49 (d, J=9 Hz, 1H); 7.39 (m, 1H); 7.30 (m, 2H), 7.17 (t, J=9 Hz, 1H); 7.01 (t, J=8.5 Hz, 2H); 5.29 (d, J=15 Hz, 1H), 4.69 (m, 1H), 4.25 (d, J=15 Hz, 1H), 2.63-2.52 (m, 2H); 2.29-2.17 (m, 2H). MS: m/z (MH+) 443.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1cccc(N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
A mixture of 3-(3-nitro-phenyl)-acrylic acid ethyl ester (16.5 g, 74.6 mmol) and Pd/C (1.65 g) in methanol (200 mL) was stirred under 40 psi of H2 at RT for 2 h then filtered over celite. After removal the solvent, 14 g of 3-(3-amino-phenyl)-propionic acid ethyl ester was obtained and used directly without further purification. 1H-NMR (400 MHz, CDCl3): 7.11 (t, J=5.6 Hz, 1H), 6.67 (d, J=7.2 Hz, 1H), 6.63-6.61 (m, 2H), 4.13 (q, J=7.2 Hz, 2H), 2.87 (t, J=8.0 Hz, 2H), 2.59 (t, J=7.6 Hz, 2H), 1.34 (t, J=6.8 Hz, 3H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:19])C)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(O)(=[O:22])C>C([O-])(=O)C.[Co+2].C([O-])(=O)C.C([O-])(=O)C.[Mn+2].C([O-])(=O)C>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([OH:19])=[O:22])=[CH:15][CH:16]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(-c2ccc(C(C)=O)cc2)cc1
Reactant: CC(=O)O
Agent: [Co+2]
Agent: [Mn+2]
Agent: CC(=O)[O-]
Product: CC(=O)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reaction time: 4 h
Yield: 51 %

Procedure:
500 ml of glacial acetic acid, 50.8 g of 4-acetoxy-4'-acetylbiphenyl, 0.8 g of cobalt(II) acetate and 12.0 g of manganese(II) acetate were refluxed in a 1 l double-walled flanged reactor equipped with an intensive stirrer and baffles, and the mixture was gassed with air via a valve in the base. After 4 hours, the mixture was cooled and the product was filtered off under suction, washed with water and dried. 26.1 g (51% yield) of 4-acetoxybiphenyl-4'-carboxylic acid having a purity of >98% (HPLC) were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:16][C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]2)=[N:4][CH:5]=[C:6](/[CH:8]=[C:9](\[F:15])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=1.[ClH:30].C(OC(C)C)(C)C>CCO.O1CCOCC1>[ClH:1].[ClH:30].[Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[C:9](\[F:15])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[N:4][C:3]=1[NH:16][C@@H:17]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]1
Reactant: CCOC(=O)/C(F)=C/c1cnc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c(Cl)c1
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)/C(F)=C/c1cnc(N[C@@H]2CCCNC2)c(Cl)c1
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl (3R)-3-({3-chloro-5-[(1Z)-3-ethoxy-2-fluoro-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-piperidinecarboxylate (3.3 g) in EtOH (19.3 ml) was added solution of 4N HCl in dioxane (19.3 ml) at ambient temperature and the mixture was stirred at same temperature for 1.5 hr. Diisopropylether was added to the mixture and precipitate was collected by filtration to give ethyl (2Z)-3-{5-chloro-6-[(3R)-3-piperidinylamino]-3-pyridinyl}-2-fluoroacrylate dihydrochloride (2.98 g).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:42])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:34]=[CH:33][C:32]([C:35]([N:37]6[CH2:41][CH2:40][CH2:39][CH2:38]6)=[O:36])=[CH:31][CH:30]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[CH3:42][C:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:29]5[CH:34]=[CH:33][C:32]([C:35]([N:37]6[CH2:41][CH2:40][CH2:39][CH2:38]6)=[O:36])=[CH:31][CH:30]=5)=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ccc(C(=O)N6CCCC6)cc5)cc4)CC3)n2CCS1
Agent: Cl
Solvent: CO
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5ccc(C(=O)N6CCCC6)cc5)cc4)CC3)n2CCS1
Yield: 77.1 %

Procedure:
A solution of the compound (385 mg, 0.64 mmol) obtained in Example 13-1) and 4 M hydrochloric acid (1,4-dioxane solution, 2 mL) in methanol (3 mL) was stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (241 mg, 77%) as a colorless solid.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)(O)=[O:2].S(Cl)([Cl:14])=O.CN(C=O)C>C1(C)C=CC=CC=1>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1]([Cl:14])=[O:2])=[CH:5][CH:6]=1)=[O:9]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(C(=O)Cl)cc1
Temperature: 100 °C

Procedure:
A solution of 4-carboxybenzaldehyde (30.0 g, 0.200 mol) in toluene (300 mL) was treated with thionyl chloride (28.6 g, 0.240 mol) and DMF (1.0 mL). The reaction mixture was heated at 100° C. for 2 h, during which time the solids dissolved to yield a pale yellow colored solution. The reaction mixture was cooled to 0° C. to yield a solution of the title compound in toluene, which was used without further manipulation.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1.[Br:16][C:17]1[NH:25][C:24]2[C:19](=[N:20][C:21]([Cl:26])=[CH:22][CH:23]=2)[CH:18]=1>CN(C=O)C.C(OCC)(=O)C>[Br:16][C:17]1[N:25]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[C:24]2[C:19](=[N:20][C:21]([Cl:26])=[CH:22][CH:23]=2)[CH:18]=1
Reactant: Clc1cccc(CBr)c1
Reactant: Clc1ccc2[nH]c(Br)cc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1cccc(Cn2c(Br)cc3nc(Cl)ccc32)c1

Procedure:
K2CO3 (0.97 g, 7.0 mmol) and 1-(bromomethyl)-3-chlorobenzene (0.74 mL, 5.6 mmol, Aldrich) were added to a solution of 2-bromo-5-chloro-1H-pyrrolo[3,2-b]pyridine (1.5 g, 4.7 mmol, from Step 1) in DMF (20 mL). After a reaction time of 75 minutes, the reaction was diluted with ethyl acetate and washed with water three times, followed by one wash with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. Flash chromatography, loading in DCM, eluting with a gradient from 0-10% EtOAc in hexanes, afforded product as a white solid. Yield (1.3 g, 70%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[N+:6]([O-])=[CH:7][CH:8]=[C:9]([Cl:11])[CH:10]=1)[CH3:2].P(Cl)(Cl)([Cl:16])=O>>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:16])[N:6]=1)[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc(Cl)cc[n+]1[O-]
Product: CCOC(=O)c1cc(Cl)cc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
4-Chloropicolinic acid ethyl ester N-oxide (1.6 g, 8 mmol) was added to 4 mL of phosphorus oxychloride at 0° C. and stirred at 0° C. for one hour. The solution was then heated at 100° C. for four hours. Excess POCl3 was removed in vacuo, and the residue was dissolved in ethyl acetate, washed with cold sodium bicarbonate solution, and extracted with ethyl acetate. Removal of the solvent gave 4,6-dichloropicolinic acid ethyl ester (compound A) as an off-white solid (1.12 g, 64%). The methyl ester can be made by an analogous procedure.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=O>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[CH:30][C:29]3[CH:32]=[CH:33][CH:34]=[C:27]([O:26][CH3:25])[CH:28]=3)[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: COc1cccc(C=O)c1
Solvent: CC(=O)N(C)C
Product: COc1cccc(C=Nn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3sccc32)c1
Temperature: 25 °C
Yield: 71.7 %

Procedure:
The product of Example 268D (0.10 g, 0.27 mmol) was reacted with 3-methoxybenzaldehyde (0.5 g, 3.7 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 135° C. for 60 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.093 g 72%).
Reaction SMILES: [OH:1][C:2]([CH:15]1[CH2:20][CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl>CC#N>[C:9]1([C:2]([CH:15]2[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]2)([OH:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCCCCCC(O)(c1ccccc1)C1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CC#N
Product: CCCCCCC(O)(c1ccccc1)C1CCCNC1
Reaction time: 0.05 h

Procedure:
A mixture of tert-Butyl 3-(1-hydroxy-1-phenylheptyl)piperidine-1-carboxylate, obtained as described above, in CH3CN (40 mL) and 2 N HCl (40 mL) was vigorously stirred at rt for 20 h. 60 mL of the reaction mixture was quenched with saturated NaHCO3, extracted three times with EtOAc, and dried over Na2SO4. The crude product (0.2709 g, 80% in two steps) was used without further purification. LC-MS (3 min) tR=1.29 min in 3 min chromatography, m/z 276 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[C:5]([NH:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1)=O.CN(C)C=O.C(Cl)(Cl)Cl.O>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[N:10]3[CH:11]=[CH:12][C:13]4[C:18]([C:9]3=[N:8][N:7]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:19]=[CH:20][CH:21]=1
Reactant: O=C(NNc1nccc2ccccc12)c1cccc(Br)c1
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: Brc1cccc(-c2nnc3c4ccccc4ccn23)c1
Temperature: 120 °C
Reaction time: 9 h
Yield: 94.3 %

Procedure:
To a 500-mL three-neck flask were added 6.2 g (18 mmol) of N′-(3-bromobenzoyl)-N-(1-isoquinolyl)hydrazine and 200 mL of N,N-dimethylformamide (DMF). This mixture was stirred at 120° C. for 9 hours under a nitrogen stream. After a predetermined time elapsed, this mixture was cooled to room temperature, and chloroform and water were added thereto. Organic substances were extracted from the aqueous layer with chloroform. The obtained extract solution was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated brine, and the organic layer was dried over magnesium sulfate. The obtained mixture was gravity-filtered, and the filtrate was concentrated to give a solid. The obtained solid was purified by silica gel column chromatography (chloroform:ethyl acetate=10:1) to give a solid. A methanol suspension of this solid was irradiated with ultrasonic waves, and a solid was collected by suction filtration, so that the substance which was the object of the synthesis was obtained as 5.5 g of a white powder in 92% yield.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:20]=[C:21]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:22]([C:25]4[CH:30]=[CH:29][N:28]=[C:27]([O:31][CH3:32])[CH:26]=4)=[N:23][CH:24]=3)[CH:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:20]=[C:21]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:22]([C:25]4[CH:30]=[CH:29][N:28]=[C:27]([O:31][CH3:32])[CH:26]=4)=[N:23][CH:24]=3)[CH:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cccc(COc2cnc(-c3ccnc(OC)c3)c(CC(C)(C)C)c2)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(-c2ncc(OCc3cccc(C(CC(=O)O)C4CC4)c3)cc2CC(C)(C)C)ccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.4 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((2′-methoxy-3-neopentyl-[2,4′-bipyridine]-5-yl)oxy)methyl)phenyl)propanoate (27 mg) in THF (1.0 mL) and methanol (1.0 mL) was added 1N aqueous sodium hydroxide solution (1.0 mL), and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added 1N hydrochloric acid (1.0 mL), and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (21 mg) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.BrC1C=C(O)C=CC=1.[C:21]1([CH:27]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30](=[O:37])[C:29]2=[O:38])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.FC(F)(F)C1OC(CN2C3C(=CC=CC=3)C(=O)C2=O)=CC=1>>[Cl:1][C:2]1[C:3]([OH:12])=[C:4]([C:30]2([OH:37])[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:28]([CH:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:29]2=[O:38])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: Oc1cc2c(cc1Cl)OCCO2
Agent: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21
Agent: Oc1cccc(Br)c1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1c(O)c(Cl)cc2c1OCCO2

Procedure:
Following the procedure as described in PREPARATION 2A and making non-critical variations using 7-chloro-2,3-dihydrobenzo[b][1,4]dioxin-6-ol to replace 3-bromophenol, and 1-(diphenylmethyl)-1H-indole-2,3-dione to replace 1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione, 3-(7-chloro-6-hydroxy-2,3-dihydro-1,4-benzodioxin-5-yl)-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one was obtained (18%) as a colorless solid: MS (ES+) m/z 522.1 (M+23), 524.1 (M+23).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2([C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH2:10]2)[CH2:6][CH2:5]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>CN(C=O)C>[F:19][C:2]([F:1])([F:18])[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2([C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:10]2)[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: FC(F)(F)CN1CCC2(CC1)CNc1ccccc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CC2(CCN(CC(F)(F)F)CC2)c2ccccc21

Procedure:
A solution of 1′-(2,2,2-trifluoroethyl)-1,2-dihydrospiro[indole-3,4′-piperidine] from Step A (64.0 mg, 0.237 mmol), potassium carbonate (49.0 mg, 0.355 mmol), potassium iodide (59.0 mg, 0.355 mmol), and tert-butyl bromoacetate (0.042 mL, 0.284 mmol) in DMF (2 mL) was stirred at 50° C. for 1 h. The reaction mixture was quenched with H2O. The aqueous layer was extracted with CH2Cl2 (3×20 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound. MS: m/z=385 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH3:18])=[O:16])[CH:11]([CH3:19])[CH2:10]2)=[C:4]([N+:20]([O-])=O)[CH:3]=1.[H][H]>[Ni].O1CCCC1>[NH2:20][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH3:18])=[O:16])[CH:11]([CH3:19])[CH2:10]1
Reactant: [H][H]
Reactant: COC(=O)N1CCC(Nc2ccc(Cl)cc2[N+](=O)[O-])CC1C
Agent: [Ni]
Solvent: C1CCOC1
Product: COC(=O)N1CCC(Nc2ccc(Cl)cc2N)CC1C

Procedure:
A mixture of 39.6 parts of methyl 4-(4-chloro-2-nitrophenylamino)-2-methyl-1-piperidinecarboxylate and 450 parts of tetrahydrofuran is hydrogenated at 40 lbs./sq. inch and at room temperature with 2 parts of raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off. The filtrate is evaporated, yielding methyl 4-(2-amino-4-chlorophenylamino)-2-methyl-1-piperidinecarboxylate as an oily residue.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.F[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([NH:18][C:19]2[N:24]=[C:23]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]([CH3:34])[CH:26]=3)[C:22]([CH3:35])=[CH:21][N:20]=2)=[C:11]([O:36][CH3:37])[CH:10]=1>FC(F)(F)CO.C(O)C>[CH3:37][O:36][C:11]1[CH:10]=[C:9]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]=1[NH:18][C:19]1[N:24]=[C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH3:34])[CH:26]=2)[C:22]([CH3:35])=[CH:21][N:20]=1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(C)c(-c2cn(C)c3ccccc23)n1
Reactant: CN1CCNCC1
Solvent: OCC(F)(F)F
Solvent: CCO
Product: COc1cc(N2CCN(C)CC2)c([N+](=O)[O-])cc1Nc1ncc(C)c(-c2cn(C)c3ccccc23)n1
Temperature: 120 °C
Yield: 62.3 %

Procedure:
1-Methylpiperazine (0.453 mL, 4.08 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 79, 554 mg, 1.36 mmol) in 2,2,2-trifluoroethanol (10 mL). The mixture was heated in a microwave at 120° C. for 1 h. The mixture was then concentrated in vacuo and the residue was dissolved in CH2Cl2 (50 mL). This solution was washed water (2×50 mL) and sat. brine (50 mL), then dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 1-10% CH3OH in CH2Cl2 gave an orange gum. This gum was dissolved in ethanol (25 mL) and a solid precipitated. This solid was collected by filtration and washed with ethanol to give the title compound (413 mg, 62%) as a yellow/orange solid; 1H NMR: 2.25 (3H, s), 2.39 (3H, s), 2.45-2.54 (4H, m), 3.03-3.10 (4H, m), 3.91 (3H, s), 3.98 (3H, s), 6.86 (1H, s), 7.06 (1H, dd), 7.22-7.28 (1H, m), 7.51 (1H, d), 8.02 (1H, s), 8.07 (1H, s), 8.26-8.30 (1H, m), 8.38 (1H, d), 8.69 (1H, s); m/z: ES+ MH+ 488.29.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:14])[C:4]([CH2:12][OH:13])=[CH:5][CH:6]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:8]=1.[H-].[Na+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O.ClCCl>[CH2:17]([O:1][C:2]1[C:3](=[O:14])[C:4]([CH2:12][OH:13])=[CH:5][CH:6]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:8]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)c1ccc(CO)c(=O)c(O)c1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)c1ccc(CO)c(=O)c(OCc2ccccc2)c1
Temperature: 80 °C
Yield: 43.3 %

Procedure:
A solution of 2-hydroxy-7-hydroxymethyl-4-isopropyl-2,4,6-cycloheptatrien-1-one (1.15 g, 5.92 mmol) in dimethylformamide (5 ml) was stirred while 60% oily sodium hydride (260 mg, 6.50 mmol) was gradually added thereto. Subsequently, benzyl chloride (1 ml, 8.41 mmol) was added, then the reaction solution was heated at 80° C. for 4 hours. The reaction solution was diluted with dichloromethane, washed with water and dried over sodium sulfate. After solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography [eluent:hexane/ethyl acetate (1:1)] to give 729 mg of 2-benzyloxy-7-hydroxymethyl-4-isopropyl-2,4,6-cycloheptatrien-1-one (yield: 43%) as a pale yellowish brown oil.
Reaction SMILES: [N:1]1([C:6]2[C:7](=[O:13])[NH:8][C:9](=[O:12])[NH:10][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH2:22][CH2:23][Cl:24].O>CN(C=O)C>[Cl:24][CH2:23][CH2:22][CH2:21][N:10]1[CH:11]=[C:6]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:7](=[O:13])[NH:8][C:9]1=[O:12]
Reactant: O=c1[nH]cc(N2CCCC2)c(=O)[nH]1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c(=O)n(CCCCl)cc1N1CCCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 5-(1-pyrrolidinyl)-2,4(1H,3H)-pyrimidinedione (507 mg, commercially available from Interchim Intermediates) and K2CO3 (386 mg) in dry DMF (10 mL) was stirred for 1 hour at room temperature. 1-Bromo-3-chloropropane (0.28 mL) was added and the mixture was stirred at room temperature for 20 hours. Water was added and the resulting mixture was extracted with ethyl acetate. The organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by a silica flash chromatography (eluting with A: dichloromethane, B: dichloromethane/methanol=9/1 at ratio A:B=6:4) to give the title compound as a colourless oil (150 mg).
Reaction SMILES: [N+:1]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][N:5]=1)([O-])=O>CCOC(C)=O.CO.[Pd]>[NH2:1][C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: COc1cccnc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cccnc1N
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a solution of 2-nitro-3-methoxypyridine (32 g, 208 mmol) in EtOAc (150 mL) and MeOH (35 mL) under a nitrogen atmosphere was added 10% palladium on carbon (1.5 g, 1.4 mmol). This mixture was purged with H2 three times and the mixture was stirred for 3 h under a hydrogen atmosphere. The reaction mixture was purged with N2 three times, filtered through Celite, and the filter cake was washed with EtOAc (2×35 ml). The combined filtrate were concentrated and dried over high vacuum to afford 25.8 grams (100%) of 2-amino-3-methoxypyridine: LCMS (m/z): 125.0 (MH+); 1H NMR (300 MHz, CDCl3): 7.66 (m, 1H), 6.90 (m, 1H), 6.61 (m, 2H), 4.64 (s, br, 2H), 3.83 (s, 3H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([OH:14])=O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[O:15]1[CH:19]=[CH:18][N:17]=[C:16]1[C:20]1[S:21][CH:22]=[CH:23][C:24]=1[NH2:25]>>[CH:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([NH:25][C:24]3[CH:23]=[CH:22][S:21][C:20]=3[C:16]3[O:15][CH:19]=[CH:18][N:17]=3)=[O:14])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Nc1ccsc1-c1ncco1
Reactant: O=C(O)Cc1cccc2cnccc12
Product: O=C(Cc1cccc2cnccc12)Nc1ccsc1-c1ncco1

Procedure:
2-(Isoquinolin-5-yl)-N-(2-(oxazol-2-yl)thiophen-3-yl)acetamide was prepared from 2-(isoquinolin-5-yl)acetic acid (48 mg, 0.246 mmol) and 2-(oxazol-2-yl)thiophen-3-amine (41 mg, 0.246 mmol) according to protocol A. Retention time (min)=2.206, method [7], MS (ESI) 336.1 (M+H); 1H NMR (300 MHz, CDCl3) δ 10.79 (s, 1H), 9.71 (s, 1H), 8.59 (d, J=6.5 Hz, 1H), 8.36 (d, J=6.5 Hz, 1H), 8.28 (d, J=8.2 Hz, 1H), 8.07-8.13 (m, 2H), 7.95 (dd, J=8.3, 7.3 Hz, 1H), 7.55 (s, 1H), 7.36 (d, J=5.3 Hz, 1H), 6.95 (s, 1H), 4.36 (s, 2H).