Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([NH:16][C:17]2[C:26]3[C:21](=[C:22]([C:27](=[O:29])[NH2:28])[CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH3:15])[CH:9]=1)(C)(C)C.Cl>CO>[NH2:7][C:8]1[CH:9]=[C:10]([CH:14]([NH:16][C:17]2[C:26]3[C:21](=[C:22]([C:27]([NH2:28])=[O:29])[CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH3:15])[CH:11]=[CH:12][CH:13]=1
Reactant: CC(Nc1ncnc2c(C(N)=O)cccc12)c1cccc(NC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CO
Product: CC(Nc1ncnc2c(C(N)=O)cccc12)c1cccc(N)c1
Reaction time: 8 h

Procedure:
To a solution of crude {3-[1-(8-Carbamoyl-quinazolin-4-ylamino)-ethyl]-phenyl}-carbamic acid tert-butyl ester in methanol (20 ml) was added methanolic hydrogen chloride (22.46 ml; 4.00 M; 89.83 mmol; 10.00 eq.). Stirred overnight and the resulting solid was filtered to obtain 2.0 g of the title product in 64% overall yield MS (M+1) 307
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(OC(C)(C)C)=O.Br[C:15]1[C:16]([CH3:22])=[N:17][C:18](C)=[CH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:19][C:18]1[C:1]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:20][CH:15]=[C:16]([CH3:22])[N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ccc(Br)c(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1ccc(N2CCNCC2)c(C)n1
Yield: 97.9 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 88 and using 1-Boc-piperazine (2.0 g) and 3-bromo-2,6-dimethylpyridine (2.0 g), a compound was obtained. To the compound were added water and potassium carbonate, and the mixture was extracted with ethyl acetate. The solvent was evaporated to give the title compound (2.01 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([CH3:10])[O:7][N:6]=1)=O.O.[NH2:12][NH2:13]>C(O)CCC>[CH3:10][C:8]1[O:7][N:6]=[C:5]([C:3]([NH:12][NH2:13])=[O:2])[CH:9]=1
Reactant: NN
Reactant: COC(=O)c1cc(C)on1
Solvent: CCCCO
Solvent: O
Product: Cc1cc(C(=O)NN)no1
Yield: 64 %

Procedure:
As described for example 112a, 5-methyl-isoxazole-3-carboxylic acid methyl ester in butanol was reacted with hydrazine hydrate (2 equivalents) at 100° C. for 2 h. Evaporation of all volatiles and chromatography (SiO2, dichloromethane:methanol:aq.ammonia (25%)=100:0:0 to 90:10:1) afforded the title compound as a white solid (yield: 64%). 1H-NMR (300 MHz, DMSO): δ=2.44 (d, J=1 Hz, 3H), 4.57 (s, 2H), 6.52 (d, J=1 Hz, 1H), 9.94 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[S:10](=[O:12])(=[O:11])[N:9]=[C:8](OCC)[C:7]=2[CH:16]=1.[CH3:19][N:20]([CH2:22][C:23]1[O:27][C:26]([CH2:28][S:29][CH2:30][CH2:31][NH2:32])=[CH:25][CH:24]=1)[CH3:21]>C1(C)C=CC=CC=1>[CH3:21][N:20]([CH2:22][C:23]1[O:27][C:26]([CH2:28][S:29][CH2:30][CH2:31][NH:32][C:8]2[C:7]3[CH:16]=[C:3]([O:2][CH3:1])[C:4]([O:17][CH3:18])=[CH:5][C:6]=3[S:10](=[O:11])(=[O:12])[N:9]=2)=[CH:25][CH:24]=1)[CH3:19]
Reactant: CCOC1=NS(=O)(=O)c2cc(OC)c(OC)cc21
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)S(=O)(=O)N=C2NCCSCc1ccc(CN(C)C)o1
Yield: 47.5 %

Procedure:
A toluene (50 ml) solution of 5,6-dimethoxy-3-ethoxy-1,2-benzoisothiazole-1,1-dioxide (D5) (0.13 g) was heated under reflux with 2-[(5-dimethylaminomethylfuran-2-yl)methylthio]ethylamine (0.2 g) for 18 h. Evaporation of the solvent and purification of the residue by column chromatography on silica gel using 5% methanolic chloroform as eluant afforded the title compound (0.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[Li+].[Cl-].C([Cu])#N.[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19](Cl)=[O:20]>C1COCC1>[Cl:1][C:2]1[C:7]([C:19]([C:15]2[O:14][CH:18]=[CH:17][CH:16]=2)=[O:20])=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)c1ccco1
Reactant: Clc1cc(Cl)ncn1
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(c1ccco1)c1c(Cl)ncnc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.8 %

Procedure:
4,6-Dichloropyrimidine 6 (149 mg, 1.0 mmol) in THF (2 mL) was added to a solution of TMPZnCl.LiCl (2) (1.3 M in THF, 0.85 mL, 1.1 mmol) at 25° C. and the reaction mixture was then stirred at this temperature for 45 min according to TP 2. CuCN.2LiCl (1.0 M solution in THF, 1.1 mL, 1.1 mmol) was slowly added at −20° C. and the reaction mixture was stirred at the same temperature for 30 min. Then, furan-2-carbonyl chloride (261 mg, 2.0 mmol) was dropwise added at −20° C. and the resulting mixture was allowed to warm up slowly to 25° C. overnight. The reaction mixture was quenched with a sat. aq. NH4Cl solution (30 mL), extracted with diethyl ether (5×30 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo. Purification by flash-chromatography (CH2Cl2/n-pentane 1:1) furnished 8b as a colourless solid (172 mg, 71%).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[CH:14]=[C:15]2[C:19]3=[C:20]([CH2:22][O:23][CH2:24][CH2:25][N:18]3[C@H:17]3[CH2:26][CH2:27][NH:28][CH2:29][C@@H:16]23)[CH:21]=1.I[CH2:31][CH3:32].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[CH2:31]([N:28]1[CH2:27][CH2:26][C@@H:17]2[N:18]3[CH2:25][CH2:24][O:23][CH2:22][C:20]4[CH:21]=[C:13]([NH:12][C:3]5[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:10])([F:11])[F:9])[C:2]=5[F:1])[CH:14]=[C:15]([C:19]3=4)[C@@H:16]2[CH2:29]1)[CH3:32]
Reactant: CCI
Reactant: Fc1c(Nc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCOC3)cccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CC[C@H]2[C@@H](C1)c1cc(Nc3cccc(C(F)(F)F)c3F)cc3c1N2CCOC3
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of (7bR,11aS)-N-[2-fluoro-3-(trifluoromethyl)phenyl]-1,2,7b,8,9,10,11,11a-octahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indol-6-amine free base from EXAMPLE 95 (41 mg, 0.1 mmol) in 5 mL tetrahydrofuran was added iodoethane (0.020 mL, 0.22 mmol) and sodium carbonate (21 mg, 0.22 mmol). The reaction was stirred at 60° C. for 3 h and then was cooled, quenched with water, extracted with ethyl acetate, washed with brine, dried (MgSO4) and concentrated. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA) and the product containing fractions were concentrated, free-based with aq ammonium hydroxide, extracted with chloroform, washed with brine, dried (K2CO3) and concentrated to afford the title compound of EXAMPLE 144. 1H NMR(CDCl3) δ: 7.15 (t, 1H, J=7.3 Hz), 7.05-6.95 (m, 2H), 6.91 (d, 1H, J=1.9 Hz), 6.77 (d, 1H, J=1.8 Hz), 5.73 (d, 1H, J=2.9 Hz), 4.63 (ABq, 2H, JAB=14.3 Hz), 4.25 (app d, 1H, J=12.9 Hz), 3.75 (app t, 1H), 3.43-3.36 (m, 2H), 3.27 (dd, 1H, J=12.8, 2.9 Hz), 2.97-2.80 (m, 2H), 2.75 (app t, 1H), 2.55-2.45 (m, 2H), 2.40-2.30 (m, 1H), 2.15-2.00 (m, 2H), 1.88 (app t, 1H), 1.15 (t, 3H, J=7.2 Hz). LRMS (ES)+: 436.4 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:5]([NH2:8])=[N:6][CH:7]=1.C1N=CN([C:20](N2C=NC=C2)=[O:21])C=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]([CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:20]([OH:21])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCC(CC)Nc1cc(Br)cnc1N
Solvent: C1COCCO1
Product: CCC(CC)n1c(O)nc2ncc(Br)cc21
Temperature: 25 °C
Yield: 74 %

Procedure:
To a 100° C. solution of 5-bromo-N3-(pentan-3-yl)pyridine-2,3-diamine (2.0 g, 8.1 mmol, 1.0 equiv) in dioxane (10 mL) was added CDI portionwise until starting material was consumed as judged by TLC (50% EtOAC/Hexanes; UV). Approximately 10 equiv of carbonyldiimidazole were required. The resulting reaction mixture was cooled to room temperature, and the excess carbonyldiimidazole was quenched by the careful addition of water. The mixture was diluted with dichloromethane, and the layers were separated. The organic layer was washed with satd. aq. NaHCO3 twice, and brine once. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel MPLC provided 6-bromo-1-(pentan-3-yl)-1H-imidazo[4,5-b]pyridin-2-ol as a white solid (2.0 g, 74%). m/z=284.0 [M+H]+
Reaction SMILES: [CH2:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](Br)=[CH:6][C:5]=1[SiH:15]([CH3:17])[CH3:16])[CH:2]=[CH2:3].C([Li])(C)(C)C.CN([CH:26]=[O:27])C.[NH4+].[Cl-]>C1COCC1>[CH2:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH:26]=[O:27])=[CH:6][C:5]=1[SiH:15]([CH3:17])[CH3:16])[CH:2]=[CH2:3]
Reactant: CN(C)C=O
Reactant: C=CCc1c([SiH](C)C)cc(Br)c2ccccc12
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCc1c([SiH](C)C)cc(C=O)c2ccccc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
To a solution 1-allyldimethylsilyl-4-bromo-naphthalene (1 Scheme 26, 3.0 g, 10 mmol) in dry THF (150 mL) at −78° C. was added t-butyllithium (6.0 mL, 1.7 M solution in pentane, 10.2 mmol) over a period of 10 min. After 30 min stirring at −78° C., anhydrous DMF (1.5 mL, 20 mmol) was added dropwise. The reaction mixture was stirred further for 1 h and warmed to room temperature. Concentrated NH4Cl (5 mL) was added to the solution, and the reaction mixture was concentrated. The residue was extracted with ethyl acetate (50 mL) and brine (10 mL), and the organic layer was dried (Na2SO4), concentrated. The crude product was purified by column chromatography (1:20 ethyl acetate/hexanes) to afford a colorless oil (2.1 g, 88%); 1H NMR (300 MHz, CDCl3) δ 0.53 (s, 6 H), 2.03 (d, J=7.80 Hz, 2 H), 4.88-4.97 (2 H), 5.79 (m, 1 H), 7.60-7.70 (2 H), 7.84 (d, J=7.50 Hz, 1 H), 7.89 (d, J=6.90 Hz, 1 H), 8.20 (d, J=8.10 Hz, 1 H), 9.35 (d, J=8.10 Hz, 1 H), 10.39 (s, 1 H); 13C NMR (75 MHz, CDCl3) −1.7 (2C), 24.2, 114.5, 126.1, 126.9, 128.6, 128.7, 132.9, 134.3, 135.4, 137.6, 146.8, 194.1.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH3:15][O:16][C:17](=[O:43])[C:18]([O:21][C:22]1[CH:23]=[C:24]([CH:40]=[CH:41][CH:42]=1)[CH2:25][N:26]1[C:34]2[C:29](=[CH:30][C:31]([C:35](O)=[O:36])=[CH:32][CH:33]=2)[C:28]([CH3:38])=[C:27]1[CH3:39])([CH3:20])[CH3:19]>>[C:2]([C:6]1[CH:7]=[CH:8][C:9]([C@@H:12]([NH:14][C:35]([C:31]2[CH:30]=[C:29]3[C:34](=[CH:33][CH:32]=2)[N:26]([CH2:25][C:24]2[CH:23]=[C:22]([CH:42]=[CH:41][CH:40]=2)[O:21][C:18]([CH3:19])([CH3:20])[C:17]([O:16][CH3:15])=[O:43])[C:27]([CH3:39])=[C:28]3[CH3:38])=[O:36])[CH3:13])=[CH:10][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: C[C@H](N)c1ccc(C(C)(C)C)cc1
Reactant: COC(=O)C(C)(C)Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Agent: Cl
Product: COC(=O)C(C)(C)Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4ccc(C(C)(C)C)cc4)ccc32)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(4-(tert-butyl)phenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the 1-(3-((1-methoxy-2-methyl-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C:14]2[C:13](=[O:15])[CH:12]=[CH:11][C:10](=[O:16])[C:9]=2[CH2:8][C@H:7]([CH2:17][CH3:18])[O:6]1)(=[O:3])[CH3:2].C(O[CH:23]=[CH:24][CH:25]=[CH2:26])(=O)C>C1(C)C=CC=CC=1>[O:16]=[C:10]1[C:9]2[CH2:8][C@H:7]([CH2:17][CH3:18])[O:6][C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[C:14]=2[C:13](=[O:15])[C:12]2[C:11]1=[CH:23][CH:24]=[CH:25][CH:26]=2
Reactant: CC[C@H]1CC2=C(C(=O)C=CC2=O)[C@H](NC(C)=O)O1
Reactant: C=CC=COC(C)=O
Solvent: Cc1ccccc1
Product: CC[C@H]1CC2=C(C(=O)c3ccccc3C2=O)[C@H](NC(C)=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the starting quinone from step 1 herein (56 mg; 0.22 mmol) in toluene (50 ml) was added 1-acetoxy-1,3-butadiene (30 μl; 11 eq). The mixture was stirred overnight at room temperature and was then concentrated and applied to a column of silica gel using 1-15% acetone in benzene to elute the product which was then recrystallized from dichloromethane:pentane affording the title compound as a yellow solid (10 mg; 15%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([C:18]3[CH:19]=[N:20][C:21]([N:24]4[CH2:29][CH2:28][C:27]([CH3:35])([C:30]([O:32]CC)=[O:31])[CH2:26][CH2:25]4)=[N:22][CH:23]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].[OH-].[Na+].Cl.C(Cl)Cl>C(O)C.O>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([C:18]3[CH:19]=[N:20][C:21]([N:24]4[CH2:25][CH2:26][C:27]([CH3:35])([C:30]([OH:32])=[O:31])[CH2:28][CH2:29]4)=[N:22][CH:23]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)c(OC)cc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)c(OC)cc2s1
Temperature: 60 °C

Procedure:
Ethyl 1-[5-[2-(ethylcarbamoylamino)-6-methoxy-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (101 mg, 0.20 mmol) was suspended in ethanol (2 mL) and sodium hydroxide solution (2 mL, 1 M, aq) was added to give a pale yellow solution and the mixture heated to 60° C. for 1 h 40 minutes then left to cool to rt overnight. The mixture was acidified to pH 3 with HCl solution (1 M, aq) and diluted with water. DCM was added but the material did not dissolve so the mixture was concentrated under reduced pressure to remove the DCM then filtered through a PTFE filter (the filter was treated with ˜2 mL DCM to make it more permeable to aqueous suspensions) and rinsed with water (2 mL). A white solid was obtained which was dried in a vacuum oven at 40° C. to give Compound 198, 75 mg (79%). 1H NMR (DMSO): δ 1.11 (3H, t, J=7.1 Hz), 1.21 (3H, s), 1.40 (2H, ddd, J=13.8, 9.9 and 3.8 Hz), 2.02 (2H, dt, J=13.8 and 3.8 Hz), 3.20 (2H, dt, J=12.8 and 7.1 Hz), 3.33 (2H, m), 3.83 (3H, s), 4.28 (2H, dt, J=13.8 and 4.5 Hz), 6.71 (1H, br t, J=5.7 Hz), 7.56 (1H, s), 7.65 (1H, s), 8.53 (2H, s), 10.56 (1H, br s), 12.44 (1H, br s). MS: 471.13 [M+H]+.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([O:12][CH2:13][CH3:14])(=[O:11])[CH:9]=[CH2:10].C(Cl)(Cl)Cl>C(N(CC)CC)C>[C:1]1([S:7][CH2:10][CH2:9][C:8]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC(=O)OCC
Reactant: Sc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCSc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
To a solution of 12.12 g (0.11 mol) of thiophenol, 10.01 g (0.10 mol) ethyl acrylate, 20 mL of HCCl3 at 0° C. in a 100-mL, round-bottom flask, 0.50 mL of triethylamine was added under N2. The ice bath was removed after the addition of triethylamine and the solution was allowed to stir at room temperature for 3 hours. The resulting solution was idluted with 150 mL of ether and washed with 10% NaOH, H2O, and saturated NaCl solution. The mixture was dried (Na2SO4, overnight) and the solvents were removed. Vacuum distillation gave 19.36 g (92.1%) of ethyl 3-(phenylthio)propionate as a clear, colorless liquid: bp 112°-115° C./0.2 mm [literature reports 117° C./2.5 mm; see K. Iwai, H. Kosugi, A. Miyazaki, and Huda, Synthetic Communications, 6, 357 (1976)]; IR (neat) 1740 cm-1 (C=O); 1H NMR (DCCl3) δ1.14 [t, 3H, CO2CH2CH3 ], 2.54 [t, 2H, CH2CO2CH2CH3 ], 3.10 [t, 2H, ArSCH2 ], 4.06 [q, 2H, CO2CH2CH3 ], 7.13-7.32 [m, 5H, ArH]; 13C NMR (DCCl3) ppm 13.6 [CO2CH2CH3 ], 28.3 [ArSCH2 ], 33.8 [CH2CO2CH2CH3 ], 60.0 [CO2CH2CH3 ], 125.8, 128.4, 129.3, 134.8, 170.9 [C=O]. Both hydrogen and carbon-13 NMR spectra shifts were measured from tetramethylsilane (TMS) standard on a Varian XL-300 spectrometer confirming the correct hydrogen distribution and carbon atom assignments. ##STR11##
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:21])=[CH:4][C:5]([Cl:20])=[C:6]([C:8]2[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:13]=2)[CH:7]=1.Br[CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>O>[Cl:20][C:5]1[CH:4]=[C:3]([Cl:21])[C:2]([NH:1][CH:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:29])=[CH:7][C:6]=1[C:8]1[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:13]=1
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc(N)c(Cl)cc2Cl)c1=O
Reactant: CCOC(=O)C(C)Br
Solvent: O
Product: CCOC(=O)C(C)Nc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(Cl)cc1Cl
Temperature: 150 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
A mixture of 0.15 g of 3-(5-amino-2,4-dichlorophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-334) and 172 μl of ethyl 2-bromopropionate was stirred at 150° C. for 3 hours. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 92 mg (yield, 48%) of 3-{2,4-dichloro-5-[1-(ethoxycarbonyl)ethylamino]phenyl}-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-336).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][N:5]([CH3:13])[N:4]=1.[OH-].[Na+]>CO>[F:15][C:2]([F:1])([F:14])[C:3]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]([CH3:13])[N:4]=1
Reactant: CCOC(=O)c1cn(C)nc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1cc(C(=O)O)c(C(F)(F)F)n1
Reaction time: 8 h
Yield: 93.4 %

Procedure:
Ethyl 3-(trifluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate (22.3 g) was added to a solution of sodium hydroxide (4.4 g) in methanol (200 mL). The contents were heated at reflux for 1 h, then cooled and stirred overnight. The contents were concentrated in vacuo and diluted with water. The aqueous solution was made acidic with 2N HCl and the precipitated white solid was filtered to give the desired acid (18.2 g).
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]([NH:15][CH:16]([CH3:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[N:7][C:8]3[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.[C:24]1([C:30]#[CH:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N#N>CCN(CC)CC.O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:24]1([C:30]#[C:31][C:2]2[CH:23]=[CH:22][C:5]3[C:6]([NH:15][CH:16]([CH3:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[N:7][C:8]4[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=4[C:4]=3[CH:3]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C#Cc1ccccc1
Reactant: CC(Nc1nc2cc[nH]c(=O)c2c2cc(Br)ccc12)C(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: N#N
Solvent: O
Solvent: CCN(CC)CC
Product: CC(Nc1nc2cc[nH]c(=O)c2c2cc(C#Cc3ccccc3)ccc12)C(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of 9-bromo-6-[(1,2,2-trimethylpropyl)amino]benzo[c]-1,6-naphthyridin-1(2H)-one (150 mg, 0.040 mmol) in Et3N (3.0 mL) was added the phenylacetylene (50 mg, 0.05 mmol), CuI (10 mg) and PdCl2(PPh3)2 (10 mg). The mixture was stirred under reflux and N2 atmosphere for 12 h. After cooling to room temperature, the mixture was diluted with water (5 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with brine (5 mL), dried over magnesium sulfate, filtered, and concentrated to a crude residue that was purified by preparative TLC to afford 9-(phenylethynyl)-6-[(1,2,2-trimethylpropyl)amino]benzo[c]-1,6-naphthyridin-1(2H)-one. 1H-NMR (300 MHz, MeOH): δ 10.03 (s, 1H), 8.26 (d, J=8.3 Hz, 1H), 7.70 (d, J=9.0 Hz, 1H) 7.39 (m, 1H), 6.62 (m, 4H), 3.30 (s, 1H), 1.27 (d, J=6.9 Hz, 2H), 1.03 (s, 9H). LRMS calculated for C26H25N3O [M+H]+, 396; found 396.
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([C:46]([CH3:49])([CH3:48])[CH3:47])=[N:43][C:42]=2[C:50]2[C:51]([F:58])=[C:52]([NH2:57])[CH:53]=[CH:54][C:55]=2[F:56])[CH:38]=[CH:37][N:36]=1.[F:59][C:60]1[CH:61]=[C:62]([S:66](Cl)(=[O:68])=[O:67])[CH:63]=[CH:64][CH:65]=1>>[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([C:46]([CH3:49])([CH3:48])[CH3:47])=[N:43][C:42]=2[C:50]2[C:51]([F:58])=[C:52]([NH:57][S:66]([C:62]3[CH:63]=[CH:64][CH:65]=[C:60]([F:59])[CH:61]=3)(=[O:68])=[O:67])[CH:53]=[CH:54][C:55]=2[F:56])[CH:38]=[CH:37][N:36]=1
Reactant: CC(C)(C)c1nc(-c2c(F)ccc(N)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Agent: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)(C)c1nc(-c2c(F)ccc(NS(=O)(=O)c3cccc(F)c3)c2F)c(-c2ccnc(Cl)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using {3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}amine (500 mg, 1.313 mmol) and 3-fluorobenzenesulfonyl chloride (0.210 mL, 1.575 mmol), the title compound was obtained as an yellow foam (690 mg, 98% yield).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[CH2:6][CH2:7][NH2:8].C(O[CH:16](OCC)[CH2:17][NH:18][C:19]1[NH:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1)C.Cl.C(=O)(O)[O-].[Na+].[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41]>C(O)CCC.O.CO>[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41].[N:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[NH:23][C:19]=1[NH:18][CH2:17][CH:16]1[C:9]2[C:5](=[CH:4][C:3]([OH:2])=[C:11]([OH:12])[CH:10]=2)[CH2:6][CH2:7][NH:8]1
Reactant: CCOC(CNc1nc2ccccc2[nH]1)OCC
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])O
Solvent: CO
Solvent: CCCCO
Solvent: O
Product: Oc1cc2c(cc1O)C(CNc1nc3ccccc3[nH]1)NCC2
Temperature: 110 °C
Reaction time: 10 h
Yield: 85.5 %

Procedure:
A solution of 3,4-dihydroxyphenethylamine hydrochloride (1.37 g.), 2-benzimidazolylaminoacetaldehyde diethyl acetal (2.0 g.) and conc. hydrochloric acid (0.8 ml.) in a mixture of n-butanol (7 ml.) and water (3 ml.) was stirred for 10 hours at 110° C. The reaction mixture was allowed to stand at ambient temperature and precipitating crystals were collected by filtration and washed with a mixture of methanol and ether to give crystals (2.92 g.). The crystals were dissolved in water and the solution was neutralized by adding sodium bicarbonate and extracted 3 times with methyl ethyl ketone. The combined extracts were washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off to give oil, which was dissolved in methanol (10 ml.). Fumaric acid (0.7 g.) was added thereto and the mixture was stirred and allowed to stand to precipitate crystals. The crystals were collected by filtration and washed with methanol to give 1-(2-benzimidazolyl)aminomethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline fumarate (2.2 g.). This material was recrystallized from a mixture of dimethylsulfoxide and water to give pure compound (1.0 g.), mp 257° to 259° C (dec.).