Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.CCO.[Cl-].[NH4+]>[Zn].O>[F:13][C:12]([F:14])([F:15])[O:11][C:9]1[CH:10]=[C:4]([NH2:1])[C:5]([NH2:6])=[CH:7][CH:8]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: Nc1ccc(OC(F)(F)F)cc1N
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-nitro-4-(trifluoromethoxy)aniline (1.17 g) and EtOH (20 mL) were added ammonium chloride (565 mg) and water (5 mL), followed by further adding zinc powder (1.73 g) at 60° C., and heating and stirring at 60° C. for 1 hour. The reaction mixture was cooled to room temperature, filtered over Celite, and washed with EtOAc. This filtrate was washed with a saturated aqueous NaHCO3 solution and brine in this order, dried over MgSO4, and then concentrated under reduced pressure to obtain 4-(trifluoromethoxy)benzene-1,2-diamine.
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]([C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:26])[CH2:13][CH2:14][C:15](=[O:25])[N:16]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:17])=[O:6])C.C(=O)([O-])[O-].[K+].[K+].CO>O>[OH2:3].[CH2:18]([N:16]([CH3:17])[C:15]([CH2:14][CH2:13][C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:5](=[O:6])[C:4]([OH:27])=[O:3])=[O:26])=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(=O)[C@@H]1CCCN1C(=O)CCC(=O)N(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CN(Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(=O)C(=O)O
Reaction time: 1 h
Yield: 150.4 %

Procedure:
A mixture of 2-[(2S)-1-[3-(N-benzyl-N-methylcarbamoyl) propanoyl]pyrrolidin-2-yl]-2-oxoacetic acid ethyl ester (626 mg), potassium carbonate (277 mg), methanol (7 ml) and water (4 ml) was stirred for 1 hr. at room temperature. Water was added to the reaction solution. The mixture was extracted with EtOAc. The extract was washed, dried and evaporated to give the title compound (458 mg) having the following physical data:
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[S:4][C:3]=1/[CH:8]=[CH:9]/[C:10](N(C)C)=O.[N+]([O-])(O)=O.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[NH:27][C:28]([NH2:30])=[NH:29].[OH-].[Na+]>COCCO>[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[NH:27][C:28]1[N:30]=[C:8]([C:3]2[S:4][C:5]([CH3:7])=[N:6][C:2]=2[CH3:1])[CH:9]=[CH:10][N:29]=1
Reactant: N=C(N)Nc1ccc(F)cc1F
Reactant: Cc1nc(C)c(/C=C/C(=O)N(C)C)s1
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: COCCO
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(F)cc3F)n2)s1
Yield: 78.5 %

Procedure:
A mixture of 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone (1.0 mmol, 0.21 g) and N-(2,4-difluoro-phenyl)-guanidine nitrate (2 mmol, 0.47 g) in 2-methoxyethanol (5 mL) was treated with NaOH (40 mg). After 24 h refluxing under N2 the solvent was evaporated to dryness and the residue was purified by flash chromatography (EtOAc/PE, 2:1) and recrystallisation from EtOAc/PE to afford the title compound as a brown powder (250 mg, 79%). 1H-NMR (300 MHz, CDCl3) δ2.69 (s, 3H, CH3), 2.71 (s, 3H, CH3), 6.93 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 7.01 (m, 2H, Ph-H), 7.58 (m, 2H, Ph-H), 8.40 (d, 1H, J=5.3 Hz, pyrimidinyl-H).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:4]=1Cl.FC1C=CC(C=O)=CC=1[C:23]([F:26])([F:25])[F:24]>>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[C:5]([C:23]([F:26])([F:25])[F:24])[CH:4]=1
Reactant: CS(=O)(=O)c1ccc(CBr)c(Cl)c1
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Product: CS(=O)(=O)c1ccc(CBr)cc1C(F)(F)F

Procedure:
The titled compound is prepared analogously to 1-bromomethyl-2-chloro-4-methanesulfonyl-benzene by replacing 2-chloro-4-fluorobenzaldehyde (step 90a) with 4-fluoro-3-trifluoromethylbenzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Cl[CH2:25][C:26]([C:28]1[N:29](COCC[Si](C)(C)C)[CH:30]=[CH:31][N:32]=1)=[O:27]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:25]=1[C:26]([C:28]1[NH:29][CH:30]=[CH:31][N:32]=1)=[O:27]
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Reactant: C[Si](C)(C)CCOCn1ccnc1C(=O)CCl
Product: COC(=O)Cc1c(C(=O)c2ncc[nH]2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and 2-chloroacetyl-l-[2-(trimethylsilyl)ethoxymethyl]imidazole.*
Reaction SMILES: C(OC([NH:8][CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]([C:22]3[C:31](=[O:32])[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)=[O:21])[CH:17]=2)[CH2:12][CH2:11][CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:8][CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]([C:22]3[C:31](=[O:32])[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)=[O:21])[CH:17]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCCc2ccc(NC(=O)c3c[nH]c4ccccc4c3=O)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCCc2ccc(NC(=O)c3c[nH]c4ccccc4c3=O)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
To a solution of [7-[(4-oxo-1H-quinolin-3-yl)carbonylamino]tetralin-1-yl]aminoformic acid tert-butyl ester (273) (250 mg, 0.6 mmol) in dichloromethane (2 mL) was added TFA (2 mL). The reaction was stirred at room temperature for 30 min. More dichloromethane (10 mL) was added to the reaction mixture and the solution was washed with sat. NaHCO3 solution (5 mL). A precipitate began to form in the organic layer so the combined organic layers were concentrated to yield N-(1-aminotetralin-7-yl)-4-oxo-1H-quinoline-3-carboxamide (273-I) (185 mg, 93%). HPLC ret. time 1.94 min, 10-99% CH3CN, 5 min run; ESI-MS 334.5 m/z (MH+).
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:12][N:13]1[CH:17]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:15]=[N:14]1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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>[CH3:12][N:13]1[CH:17]=[C:16]([C:2]2[S:6][CH:5]=[N:4][C:3]=2[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:15]=[N:14]1
Reactant: CCOC(=O)c1ncsc1Br
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1ncsc1-c1cnn(C)c1

Procedure:
To a suspension of ethyl 5-bromothiazole-4-carboxylate, 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and Pd(PPh3)4 in dioxane was added a 2 M aqueous Na2CO3 solution, followed by heating under reflux for 4 hours. To the reaction mixture was added water and the aqueous layer was extracted with EtOAc. The organic layer was dried over MgSO4 and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane:EtOAc) to obtain ethyl 5-(1-methyl-1H-pyrazol-4-yl)-1,3-thiazole-4-carboxylate as a brown solid.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([F:28])=[C:24](I)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:29]1[CH2:33][CH2:32][O:31][CH:30]1[C:34]1[O:38][C:37]([Sn](CCCC)(CCCC)CCCC)=[CH:36][CH:35]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([F:28])=[C:24]([C:37]4[O:38][C:34]([CH:30]5[O:31][CH2:32][CH2:33][O:29]5)=[CH:35][CH:36]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Fc1cc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2cc1I
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Fc1cc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2cc1-c1ccc(C2OCCO2)o1
Temperature: 100 °C
Reaction time: 4 h
Yield: 59.4 %

Procedure:
Synthesized according to Procedure B from a solution of (4-benzyloxyphenyl)-(6-iodo-7-fluoro-quinazolin-4-yl)-amine hydrochloride (508 mg, 1 mmole), 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan (645 mg, 1.5 mmole), diisopropylethyl amine (650 mg, 5 mmole), and dichlorobis(triphenylphosphine) palladium (140 mg, 0.2 mmole) in 6 ml of DMF under nitrogen was stirred at 100° C. (oil bath temperature) for 4 hours. The cooled reaction mixture was extracted with water (100 ml) and ethyl acetate (100 ml). The organic phase was washed with brine (100 ml). The aqueous layers were combined and washed with additional ethyl acetate (100 ml). The organic layers were combined, dried with MgSO4, filtered and concentrated to a residue. The residue was chromatographed on silica gel with a methanol-chloroform mixture. Fractions were collected, combined, and concentrated. The resultant solid was suspended in dichloromethane (10 ml) and diethyl ether was added facilitate precipitation. The solid was filtered and dried under vacuum at room temperature to yield a yellowish solid 287 mg (59%). 1H NMR (400 MHz, DMSO-d6) δ: 10.1(s, 1H), 8.85(d, 1H), 8.45(s, 1H), 7.6(m, 3H), 7.44(d, 2H), 7.38(m, 2H), 7.31(m, 1H), 7.03(m, 2H), 6.94(m, 1H), 6.74(d, 1H), 6.01(s, 1H), 5.1(s, 2H), 4.10(m, 2H), 3.96(m, 2H). ESI-MS m/z 482(M−1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.Cl[CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]2[NH:33][C:32](=[O:34])[O:31][C:30]([CH3:36])([CH3:35])[C:29]=2[CH:37]=1>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:26]=[CH:27][C:28]3[NH:33][C:32](=[O:34])[O:31][C:30]([CH3:36])([CH3:35])[C:29]=3[CH:37]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Reactant: Sc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(Br)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Quantities of 6.23 gm (0.033 mol) of 4-bromothiophenol and 8.28 gm (0.06 mol) of potassium carbonate are stirred into 100 ml of dimethylsulfoxide, dried over a molecular sieve in a nitrogen atmosphere at ambient temperature for 15 minutes, and then mixed with 8.51 gm (0.03 mol) of 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one. After stirring for one hour at ambient temperature, water is added in batches until a thick crystal slurry is produced. This is subjected to suction filtration, dried, and recrystallized from ethyl acetate/diisopropyl ether.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([CH2:11][C:12]3[N:16]4[N:17]=[C:18]([C:21]5[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=5)[CH:19]=[CH:20][C:15]4=[N:14][CH:13]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>COCCOC.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>[CH3:26][N:24]1[CH:25]=[C:21]([C:18]2[CH:19]=[CH:20][C:15]3[N:16]([C:12]([CH2:11][C:8]4[CH:9]=[CH:10][C:5]5[N:6]([C:2]([C:31]6[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=6)=[CH:3][N:4]=5)[CH:7]=4)=[CH:13][N:14]=3)[N:17]=2)[CH:22]=[N:23]1
Reactant: Cn1cc(-c2ccc3ncc(Cc4ccc5ncc(Br)n5c4)n3n2)cn1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccc3ncc(Cc4ccc5ncc(-c6cnn(C)c6)n5c4)n3n2)cn1
Temperature: 150 °C

Procedure:
3-(3-Bromo-imidazo[1,2-a]pyridin-6-ylmethyl)-6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazine (Example 296, 77 mg, 0.189 mmol) was dissolved in DME (0.629 mL) with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (39.2 mg, 0.189 mmol), 2 M Na2CO3 solution (0.339 mL, 0.679 mmol) and tetrakis(triphenylphosphine)palladium (10.9 mg, 0.009 mmol). The RM was heated at 150° C. 5 min under microwave irradiations. It was taken up with EtOAc and washed with 10% Na2CO3 solution and brine. Then it was dried over Na2SO4, filtered and concentrated. The residue was dissolved in MeOH and passed through an SPE cartridge of PL-Thiol MP to remove the palladium. Then the filtrate was purified by preparative HPLC with acetonitrile and water (+0.1% TFA). The fractions were joined and acetonitrile was removed. The aqueous solution was basified with 5% NaHCO3 solution and was extracted with EtOAc twice. Combined organic layers was washed with brine and dried over Na2SO4. It was filtered to afford after evaporation of the solvent the title compound as a white solid (tR 0.7 min (conditions 2), MH+=410).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:31]=[CH:30][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][C:22]=3[O:28][CH3:29])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1.Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:34]>O.C1COCC1>[Cl:3][C:4]1[CH:31]=[CH:30][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:33]([O:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:34])=[CH:23][C:22]=3[O:28][CH3:29])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)[C:6]=2[CH:5]=1
Reactant: COc1cc(N)ccc1S(=O)(=O)n1c(=O)n(C2CCCCC2)c2cc(Cl)ccc21
Reactant: O=C(Cl)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(NC(=O)Oc2ccccc2)ccc1S(=O)(=O)n1c(=O)n(C2CCCCC2)c2cc(Cl)ccc21
Reaction time: 5 h

Procedure:
0.24 g of NaOH pellets in 2 ml of water was added at 5° C., with stirring, to a solution of 1.05 g of the compound obtained in Example 7 in 25 ml of THF. 1 ml of phenyl chloroformate was then added with continued stirring. The reaction mixture was then stirred for 5 hours, the temperature being allowed to rise to 20° C. The mixture was then concentrated under vacuum, the residue was taken up with water, extracted with ether and washed with water and the organic phase was dried over sodium sulfate and concentrated under vacuum. 1.35 g of the expected product were obtained by crystallization from iso ether. M.p.=236° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([NH:5][CH:6]1[CH2:10][CH2:9][NH:8][CH2:7]1)=[O:4].C(O)C.Cl[C:17]1[N:26]=[C:25]2[C:20]([C:21](=[O:34])[C:22]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23][N:24]2[CH:27]=[CH2:28])=[CH:19][C:18]=1[F:35]>C(N(CC)CC)C>[F:35][C:18]1[CH:19]=[C:20]2[C:25](=[N:26][C:17]=1[N:8]1[CH2:9][CH2:10][CH:6]([NH:5][C:3](=[O:4])[C:2]([F:1])([F:11])[F:12])[CH2:7]1)[N:24]([CH:27]=[CH2:28])[CH:23]=[C:22]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:21]2=[O:34]
Reactant: O=C(NC1CCNC1)C(F)(F)F
Reactant: C=Cn1cc(C(=O)OCC)c(=O)c2cc(F)c(Cl)nc21
Solvent: CCN(CC)CC
Solvent: CCO
Product: C=Cn1cc(C(=O)OCC)c(=O)c2cc(F)c(N3CCC(NC(=O)C(F)(F)F)C3)nc21
Yield: 84.8 %

Procedure:
A mixture of 3-trifluoroacetylaminopyrrolidine (5.46 g), ethanol (60 ml) and triethylamine (3 g) was added to ethyl 7-chloro-6-fluoro-1,4-dihydro-4-oxo-1-vinyl-1,8-naphthyridine-3-carboxylate (5.93 g) obtained according to Reference Example 1. The mixture was heated under reflux for one hour. After ice-cooling, the resulting crystals were collected by filtration and washed with ethanol. Recrystallization of the crude crystals from ethanol-chloroform gave 7.5 g of ethyl 6-fluoro-7-(3-trifluoroacetylamino-1-pyrrolidinyl)-1,4-dihydro-4-oxo-1-vinyl-1,8-naphthyridine-3-carboxylate, m.p. 280°-282° C. A solution of the compound (4.4 g) thus obtained in 1 N sodium hydroxide (80 ml) was stirred for 2 hours at 60° C. At the same temperature the mixture was adjusted to pH 7-8 by addition of acetic acid. After ice-cooling, the resulting crystals were collected by filtration, washed with water, and dissolved in hot 10% acetic acid, followed by treating with charcoal.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[N:4]=[C:5](O)[C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:5]1[C:6]2[C:11](=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2)[CH:12]=[C:3]([N:2]([CH3:16])[CH3:1])[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(O)nc(N(C)C)cc2c1
Product: COc1ccc2c(Cl)nc(N(C)C)cc2c1
Yield: 52.6 %

Procedure:
A solution of 3-(dimethylamino)-6-methoxyisoquinolin-1-ol (700 mg, 3.21 mmol) in POCl3 (2 ml, 21.46 mmol) was refluxed for 4 h. The reaction mixture was concentrated. The residue was dissolved in DCM and the pH was adjusted to 7 with 4N NaOH. The organic phase was collected and dried over sodium sulfate, filtered, then concentrated under vacuum. The crude material was purified by silica gel chromatography using 50% DCM in hexanes as eluent. The product fractions were collected and the solvent was removed under vacuum to give 1-chloro-6-methoxy-N,N-dimethylisoquinolin-3-amine (400 mg, 53% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.96 (d, J=9.3 Hz, 1H), 6.87 (dd, J=9.2, 2.4 Hz, 1H), 6.80 (d, J=2.3 Hz, 1H), 6.43 (s, 1H), 3.91 (s, 3H), 3.14 (s, 6H); MS m/z 237.0 (M++1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.O>N1C=CC=CC=1>[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:14][CH:13]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: c1ccncc1
Solvent: O
Product: O=[N+]([O-])c1ccccc1Nc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 51.3 %

Procedure:
2-Fluoronitrobenzene (3.0 g) and 4-chloroaniline (2.5 g) were dissolved in pyridine (30 ml) and stirred at 80° C. for 18 hours. The resultant solution was allowed to cool, and thereafter, water (100 ml) was added thereto and the mixture was extracted with ethyl acetate (50 ml×3). The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was re-crystallized from ethyl acetate-hexane, to thereby yield the target compound (2.5 g) as pale-brown crystals.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[NH:17][C:18]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21])=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:32]I>CN(C=O)C>[C:3]([O:7][C:8]([N:10]([CH3:32])[C@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[NH:17][C:18]1[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CI
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1N[C@H]1CCCC[C@@H]1NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(F)(F)F)cc1N[C@H]1CCCC[C@@H]1N(C)C(=O)OC(C)(C)C

Procedure:
In DMF and in the presence of sodium hydride, methyl 2-({(1S,2S)-2-[(tert-butoxycarbonyl)amino]cyclohexyl}amino)-4-(trifluoromethyl)benzoate was allowed to react with methyl iodide at 70° C. for 1 hour. By post-treating the reaction liquid, methyl 2-({(1S,2S)-2-[(tert-butoxycarbonyl)(methyl)amino]cyclohexyl}amino)-4-(trifluoromethyl)benzoate was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[CH2:10]([C@@H:12]1[CH2:17][O:16][CH2:15][CH2:14][NH:13]1)[CH3:11].CCN(C(C)C)C(C)C>CC#N>[Cl:8][C:6]1[CH:7]=[C:2]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][C@H:12]2[CH2:10][CH3:11])[N:3]=[C:4]([NH2:9])[N:5]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CC[C@@H]1COCCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H]1COCCN1c1cc(Cl)nc(N)n1
Temperature: 150 °C
Yield: 86.6 %

Procedure:
To 4,6-dichloro-2-pyrimidinamine (240 mg, 1.46 mmol) in CH3CN (8 mL) were added (3R)-3-ethylmorpholine (244 mg, 1.61 mmol) and Hunig's base (1.02 mL, 5.85 mmol), and the reaction mixture was heated in a microwave at 150° C. for a total of 3 hours, checking the progression of the reaction at regular intervals. The mixture was evaporated under vacuum, and the resulting residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2×) and CH2Cl2 (2×). The organics were washed with water and brine, dried (MgSO4), filtered and evaporated. The resulting material was triturated with Et2O and dried in vacuo to afford the title compound (307 mg). LC-MS (ES) m/z=243, 245 [M+H]+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:11]=[C:12]([O:17][C:18]2[C:23]([F:24])=[C:22]([CH3:25])[CH:21]=[CH:20][C:19]=2[Cl:26])[CH:13]=[C:14]([Cl:16])[CH:15]=1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:9][C:10]1[CH:11]=[C:12]([O:17][C:18]2[C:23]([F:24])=[C:22]([CH2:25][Br:1])[CH:21]=[CH:20][C:19]=2[Cl:26])[CH:13]=[C:14]([Cl:16])[CH:15]=1
Reactant: Cc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1c(CBr)ccc(Cl)c1Oc1cc(Cl)cc(Br)c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 81.8 %

Procedure:
N-bromosuccinimide (1.95 g, 10.94 mmol) was added to a solution of 2-[(3-bromo-5-chlorophenyl)oxy]-1-chloro-3-fluoro-4-methylbenzene (3.20 g, 9.12 mmol) in CCl4 (300 mL) at RT. The solution was heated to 90° C. for 5 min under N2 and AIBN (0.070 g, 0.46 mmol) was added. After 4 h, more AIBN (0.070 g, 0.46 mmol) was added and the solution was heated at 90° C. for an additional 2 h. The solution was cooled to 0° C., filtered through Celite and concentrated. The yellow oil was purified by column chromatography (0% to 30% EtOAc/hexanes gradient) to afford the title compound (3.2 g, 60%) as a clear oil 1H NMR (400 MHz, DMSO-d6): δ ppm 7.58-7.49 (m, 3H), 7.13-7.12 (m, 1H), 7.06-7.05 (m, 1H), 4.73 (s, 2H). In addition, 2.25 g (48%) of the di-brominated material, 12-[(3-bromo-5-chlorophenyl)oxy]-1-chloro-4-(dibromomethyl)-3-fluorobenzene was also obtained as a clear oil. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.72-7.68 (m, 1H), 7.61 (dd, 1H), 7.51 (t, 1H), 7.47 (s, 1H), 7.19-7.18 (m, 1H), 7.11 (t, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:18])[N:14]=2)[NH:9][CH:8]=1)=[O:6].[H-].[Na+].[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]Br)[N:27]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:18])[N:14]=2)[N:9]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=2)[CH:8]=1)=[O:6]
Reactant: Cc1cccc(CBr)n1
Reactant: Cc1ccc2[nH]cc(C(=O)c3ccc(C)c(C)c3)c(=O)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2cc(C(=O)c3ccc(C)c(C)c3)c(=O)c3nc(C)ccc32)n1

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1 were used with 65 mg (0.222 mmol) of 3-(3,4-Dimethyl-benzoyl)-6-methyl-1H-[1,5]naphthyridin-4-one, 11 mg (0.267 mmol, 60% dispersion in oil) of sodium hydride, 49.6 mg (0.267 mmol) of 2-methyl-6-bromomethyl-pyridine and 2.0 mL of N,N-dimethylformamide. The crude brown solid was purified by reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to yield 3-(3,4-Dimethyl-benzoyl)-6-methyl-1-(6-methyl-pyridin-2-ylmethyl)-1H-[1,5]naphthyridin-4-one as an off white solid. LC-MSD, m/z for C25H23N3O2 [M+H]: 398.18 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 2.0 min.