Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[C:8](=[O:11])[CH2:9][CH3:10].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[NH:21][CH:22]=[CH:23][C:24]=2[CH3:25])=[CH:16][CH:15]=1.O.O.O.C([O-])(=O)C.[Na+]>ClCCCl.O>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[NH:21][C:22]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:23][C:24]=2[CH3:25])=[CH:18][CH:19]=1
Reactant: Cc1cc[nH]c1-c1ccc(Cl)cc1
Reactant: CCC(=O)N(C)C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCC(=O)c1cc(C)c(-c2ccc(Cl)cc2)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
Phosphorus oxychloride (1.496 g, 0.896 ml, 9.76 mmol) was added dropwise to previously cooled (0 to 5° C.) N,N-dimethyl propionamide (0.987 g, 1.073 ml, 9.76 mmol) maintaining the temperature between about 0° C. to about 5° C. The resulting reaction mixture was then allowed to warm to room temperature (about 25° C.), which was then stirred at room temperature (about 25° C.) for 15 minutes. The reaction mixture was then diluted with 1,2-dichloroethane (17 ml), the resulting mixture was cooled to 0° C., to it was then added 2-(4-chlorophenyl)-3-methyl-1H-pyrrole (prepared according to the procedure given in Tetrahedron Letters 46 (2005) 4539-4542, 1.7 g, 8.87 mmol) in 1,2-dichloroethane (17 ml) dropwise. The reaction mixture so formed was heated to reflux for 30 minutes. The progress of the reaction was monitored by TLC. The reaction mixture was then allowed to cool to room temperature, and to it was then added a solution of sodium acetate trihydrate (6.64 g, 48.8 mmol) in 14 ml water. The reaction mixture so obtained was heated to reflux for 30 minutes. Two phases formed in the reaction mixture were then separated. The aqueous layer was extracted with dichloromethane (3×50 ml). The combined organic layer was washed with saturated sodium bicarbonate solution (1×50 ml) followed by washing with water (1×50 ml), and then the organic layer was dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product. The crude product was then purified by flash column chromatography using 10% ethyl acetate in hexanes as an eluent to obtain the title compound (1.82 g, 83%)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([C:19]5[CH:24]=[CH:23][C:22]([CH2:25][N:26]6[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]6)=[CH:21][CH:20]=5)[CH:17]=4)[N:12](S(C4C=CC(C)=CC=4)(=O)=O)[CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(N(CC)CC)C.CS(O[CH2:54][C:55]([F:58])([F:57])[F:56])(=O)=O>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([C:19]5[CH:24]=[CH:23][C:22]([CH2:25][N:26]6[CH2:31][CH2:30][N:29]([CH2:54][C:55]([F:58])([F:57])[F:56])[CH2:28][CH2:27]6)=[CH:21][CH:20]=5)[CH:17]=4)[NH:12][CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(-c4ccc(CN5CCNCC5)cc4)cnc32)cc1
Reactant: CS(=O)(=O)OCC(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: FC(F)(F)CN1CCN(Cc2ccc(-c3cnc4[nH]cc(-c5ccc6[nH]ccc6c5)c4c3)cc2)CC1

Procedure:
3-(1H-indol-5-yl)-5-(4-(piperazin-1-ylmethyl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (50 mg) was dissolved in THF (1 mL) and treated with triethylamine (13 uL), and 2,2,2-trifluoroethyl methanesulfonate (13 uL); the reaction was allowed to stir for approximately hours, diluted water and extracted with EtOAC and washed with 1 N sodium hydroxide, water and brine and evaporated. The product was suspended in MeOH and (2 mL) detosylated directly by the addition of 0.5 mL sodium hydroxide solution, heated to 50 C for one hour. The reaction was diluted with water, extracted with dichloromethane and purified by MPLC, on silica gel, eluting with methanol in dichloromethane to yield 6 mg of an analytical sample (490 M+H).
Reaction SMILES: [CH3:1][C:2]([NH:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)([CH3:5])[CH2:3]O.S(Cl)(Cl)=O>C(OCC)C>[Br:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]2[O:15][CH2:3][C:2]([CH3:1])([CH3:5])[N:6]=2)=[CH:13][CH:12]=1
Reactant: CC(C)(CO)NC(=O)c1ccc(Br)cc1
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: CC1(C)COC(c2ccc(Br)cc2)=N1
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To the title compound of Example 2 (0.1 moles) was added dropwise, in the cold, thionyl chloride (0.4 moles) over 35 min. After stirring for one hour, the reaction was transferred to an addition funnel and added dropwise to rapidly stirring diethyl ether (700 ml). After stirring for 20 hours, the white solid was filtered under reduced pressure and washed well with diethyl ether. The dry solid was treated with 20% sodium hydroxide (75 ml). After stirring for 30 minutes the product was extracted into diethyl ether, and the aqueous layer was washed with ether. The combined ether extracts were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure to an oil. The oil was distilled under vacuum to yield 20.0 g of the title compound as a colorless liquid, b.p. 69°-73° C./0.04 mm Hg.
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[CH:6]=[C:7]2[C:11]=1N[N:9]=[CH:8]2.BrC1C=C2C([CH:22]=[C:23]([O:28][CH3:29])N=C2)=CC=1>>[CH3:29][O:28][C:23]1[N:9]=[CH:8][C:7]2[C:11]([CH:22]=1)=[CH:3][CH:4]=[C:5]([C:12]([OH:14])=[O:13])[CH:6]=2
Reactant: COc1cc2ccc(Br)cc2cn1
Reactant: O=C(O)c1cc(C(F)(F)F)c2[nH]ncc2c1
Product: COc1cc2ccc(C(=O)O)cc2cn1

Procedure:
The title compound was prepared by a method analogous to that described in Steps 3-4 of Intermediate 21, using 7-bromo-3-methoxyisoquinoline. +ESI (M+H) 204.2; 1H NMR (400 MHz, CD3OD, δ): 9.08 (s, 1H), 8.71 (s, 1H), 8.14 (dd, J=8.78, 1.56 Hz, 1H), 7.83 (d, J=8.78 Hz, 1H), 7.17 (s, 1H), 4.02 (s, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][NH:15][C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:17])[CH:6]=1)=[O:4].CO.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]([NH:15][CH2:14][CH2:13][CH2:12][N:7]2[C:8](=[O:11])[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6]2)=[O:17])[CH:19]=1
Reactant: COC(=O)c1ccc(=O)n(CCCNC(=O)c2cccnc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(=O)n(CCCNC(=O)c2cccnc2)c1

Procedure:
1,6-dihydro-1-[3-(3-pyridinylcarbonylamino)propyl]-6-oxo-3-pyridinecarboxylic acid methyl ester (0.18 g, 0.57 mmol) was hydrolysed in a mixture consisting of methanol (0.7 ml), water (0.7 ml), and 15% aqueous sodium carbonate (0.7 ml) at 60° C. for 1.3 hours. The solution was acidified (to pH 5.5 with acetic acid). The precipitated product was recovered by filtration, washed with water, and dried, MP: 218°-220° C.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([CH3:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[NH2:34][CH:35]1[CH2:38][NH:37][CH2:36]1.CN1CCCC1>C(O)C>[NH2:34][CH:35]1[CH2:38][N:37]([C:20]2[C:21]([Cl:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[C:10]([CH3:30])=[CH:9][C:8]([F:31])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:36]1
Reactant: NC1CNC1
Reactant: Cc1cc(F)c(N)nc1-n1cc(C(=O)O)c(=O)c2cc(F)c(F)c(Cl)c21
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1cc(F)c(N)nc1-n1cc(C(=O)O)c(=O)c2cc(F)c(N3CC(N)C3)c(Cl)c21
Temperature: 85 °C
Reaction time: 0.75 h
Yield: 79.2 %

Procedure:
To 250 mg of N,N-dimethylformamide were added 80 mg of 1-(6-amino-5-fluoro-3-methylpyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 60 mg of 3-aminoazetidine dihydrochloride, and 120 mg of N-methylpyrrolidine, and the mixture was stirred at 85° C. for 45 minutes. After adding 0.5 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 72 mg of the title compound as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:32](O)(=[O:36])[C:33]#[C:34][CH3:35]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][CH2:28][N:27]3[C:32](=[O:36])[C:33]#[C:34][CH3:35])=[N:9][C:10]=2[C:11]2[CH:12]=[CH:13][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)=[O:16])=[CH:24][CH:25]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CC#CC(=O)O
Reactant: Nc1nccn2c([C@@H]3CCCCN3)nc(-c3ccc(C(=O)Nc4ccncn4)cc3)c12
Product: CC#CC(=O)N1CCCC[C@H]1c1nc(-c2ccc(C(=O)Nc3ccncn3)cc2)c2c(N)nccn12
Yield: 26.9 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from (S)-4-(8-amino-3-(piperidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyrimidin-4-yl)benzamide (intermediate 31) and 2-butynoic acid, to afford the title compound (10.3 mg, 26.9%). Data: UPLC(C) Rt: 1.91 min; m/z 481.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7](=O)[C:8]3[C:13]([NH:14][C:15]=2[CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1(C)C=CC=CC=1.[OH-].[Na+]>C(OCC)C.C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C:8]3[C:13]([NH:14][C:15]=2[CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: COc1ccc2c(=O)c3ccccc3[nH]c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)Nc1ccccc1C2
Temperature: 0 °C
Yield: 98 %

Procedure:
To a stirred solution of 15.29 g of 3-methoxyacridone (67.9 mmol) in 200 mL of diethyl ether was added 7.73 g of LiAlH4 slowly portionwise. Once evolution of H2 ceased, 200 mL of dry toluene was added under inert atmosphere and the reaction was stirred at reflux for 2 h. The reaction mixture was cooled to 0° C. and dropwise addition of 8.0 mL of water, 8.0 mL of 15% NaOH (aq) and 24.0 mL of water were performed sequentially. 500 mL of CH2Cl2 was added and the resultant precipitate was filtered, washed with 500 mL of CH2Cl2 and discarded. The filtrate was concentrated in vacuo, resuspended in hexanes, and again concentrated to afford 14.06 g of 3-methoxyacridan (98%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1.C(OC([NH:30][CH:31]1[CH2:35][CH2:34][NH:33][CH2:32]1)=O)(C)(C)C.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:33]2[CH2:34][CH2:35][CH:31]([NH2:30])[CH2:32]2)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1c(N2CCC(N)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32.1 %

Procedure:
A mixture of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (90 mg), 3-t-butoxycarbonylaminopyrrolidine (115 mg), DBU (50 mg) and anhydrous acetonitrile (4 ml) was refluxed for 20 hours. After cooling, the resulting precipitate was collected by filtration and added to concentrated hydrochloric acid-methanol (1:1, 2 ml). The mixture was stirred for 10 minutes at room temperature, then neutralized with concentrated aqueous ammonia, and the precipitate was collected by filtration. A solution of the precipitate in cold water was acidified with concentrated hydrochloric acid below pH 1 and allowed to stand in a refrigerator. The resulting precipitate was collected by filtration and washed with cold diluted aqueous hydrochloric acid to give the title compound (35 mg) as yellow needles, mp 254°-257° C. (decompd.).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)=[CH:15][C:14]=3[O:25][CH2:26][CH3:27])[N:10]=[CH:11][C:6]=2[CH:5]=[CH:4][N:3]=1.[NH2:28][CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH2:26]([O:25][C:14]1[CH:15]=[C:16]([C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)[CH:17]=[CH:18][C:13]=1[NH:12][C:9]1[N:10]=[CH:11][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:7]=2[N:8]=1)[CH3:27]
Reactant: NC1CCOCC1
Reactant: CCOc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(Cl)c2n1
Product: CCOc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(NC3CCOCC3)c2n1
Yield: 9 %

Procedure:
The title compound was prepared according to the method described for Example 99 using 8-chloro-N-(2-ethoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine (Preparation 114) and 4-aminotetrahydropyran. The residue was further purified by passage through a SCX-2 cartridge eluting with 100% MeOH—1M NH3 in MeOH to give the title compound (3 mg, 9%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3C(=O)C4C(=CC=CC=4)C3=O)[CH:8]=2)[CH:2]=1.O.NN>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:11][N:10]=[C:9]([CH2:12][NH2:13])[CH:8]=2)[CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc(-c2cccnc2)on1
Agent: NN
Solvent: O
Product: NCc1cc(-c2cccnc2)on1

Procedure:
2-[(5-Pyridin-3-ylisoxazol-3-yl)methyl]-1H-isoindole-1,3(2H)-dione (2.95 g, 9.67 mmol) was treated with hydrazine hydrate (1.14 g, 19.3 mmol) according to the method described in Part E of Example 35 to provide (5-pyridin-3-ylisoxazol-3-yl)methylamine as a pale yellow solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[CH3:38][N:39]([C:43]1[CH:48]=[CH:47][C:46](B2OC(C)(C)C(C)(C)O2)=[CH:45][CH:44]=1)[C:40](=[O:42])[CH3:41].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[C:40]([N:39]([CH3:38])[C:43]1[CH:48]=[CH:47][C:46]([C:2]2[N:3]=[C:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[NH:8][C:7]4[N:15]=[CH:16][CH:17]=[CH:18][C:6]=4[N:5]3[C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([C:26]3([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:35])[CH3:36])[CH2:27][CH2:28][CH2:29]3)=[CH:22][CH:21]=2)=[CH:45][CH:44]=1)(=[O:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Br)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reactant: CC(=O)N(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N(C)c1ccc(-c2nc3n(c2-c2ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1
Yield: 53.2 %

Procedure:
A mixture of tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50 mg, 0.090 mmol), N-methyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide (49 mg, 0.18 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (6 mg, 0.009 mmol), and 2M Na2CO3 aq. (0.090 mL, 0.18 mmol) in DMF (3 mL) was treated with microwave (160° C. for 1 hour). The mixture was diluted with AcOEt, washed with water(×3), brine, dried over Na2SO4, then filtrated through Celite pad. The filtrate was concentrated and the residue was purified by preparative thin-layer chromatography (n-hexane/AcOEt=1:4) to afford the desired product (30 mg, 53%) as a pale pink solid. 1HNMR (CDCl3) 400 MHz δ: 8.16 (dd, J=8.0 Hz and 1.7 Hz, 1H), 8.02 (d, J=2.9 Hz, 1H), 7.63 (d, J=8.0 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 7.32 (td, J=8.0 Hz and 1.7 Hz, 2H), 7.18 (d, J=8.0 Hz, 2H), 7.16 (t, J=8.0 Hz, 1H), 7.06 (d, J=8.0 Hz, 2H), 6.96 (d, J=8.0 Hz, 1H), 6.81 (d, J=8.0 Hz, 1H), 6.61 (dd, J=8.0 Hz and 4.6 Hz, 1H), 6.27 (s, 1H), 5.13 (br s, 1H), 3.26 (s, 3H), 2.58-2.52 (m, 2H), 2.51-2.39 (m, 2H), 2.19-2.13 (m, 1H), 1.95-1.85 (m, 4H), 1.39 (br s, 9H). LCMS: 627 [M+H].
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:35]1[C:36]([F:47])=[C:37]2[C:42](=[C:43]([O:45][CH3:46])[CH:44]=1)[O:41][CH2:40][CH2:39][CH2:38]2)=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>CN(C=O)C>[F:47][C:36]1[C:35]([CH:21]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:33]=[C:32]([CH3:34])[O:31][N:30]=3)=[CH:25][CH:24]=2)[C:20]2[NH:19][C:18](=[O:17])[N:1]([C:3]3[N:8]=[CH:7][CH:6]=[CH:5][N:4]=3)[N:2]=2)=[CH:44][C:43]([O:45][CH3:46])=[C:42]2[C:37]=1[CH2:38][CH2:39][CH2:40][O:41]2
Reactant: NNc1ncccn1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c2c(c1F)CCCO2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c(F)c2c1OCCC2
Temperature: 85 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
After adding 23 mg of 2-hydrazinopyrimidine and 35 μl of triethylamine to a solution of 113 mg of [2-(5-fluoro-8-methoxychroman-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester in 2 ml of DMF, the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 5 ml of methanol and 0.5 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the reaction mixture it was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 5-{(5-fluoro-8-methoxychroman-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one (82 mg) as a light brown solid.
Reaction SMILES: Br[C:2]1[C:3]([CH3:22])=[C:4]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:5]([NH:7][CH2:8][C:9]1[C:10](=[O:17])[NH:11][C:12]([CH3:16])=[CH:13][C:14]=1[CH3:15])=[O:6].[SH:23][CH:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1.CCN(C(C)C)C(C)C>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Cl:21][C:19]1[CH:20]=[C:2]([S:23][CH:24]2[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]2)[C:3]([CH3:22])=[C:4]([CH:18]=1)[C:5]([NH:7][CH2:8][C:9]1[C:10](=[O:17])[NH:11][C:12]([CH3:16])=[CH:13][C:14]=1[CH3:15])=[O:6]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)cc(Br)c2C)c(=O)[nH]1
Reactant: O=C1CCC(S)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(CNC(=O)c2cc(Cl)cc(SC3CCC(=O)CC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 8 h
Yield: 126.9 %

Procedure:
A solution of 3-bromo-5-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-methyl)-2-methylbenzamide (0.35 g, 0.91 mmol.), 4-mercaptocyclohexanone (0.142 g, 1.09 mmol) and DIPEA (0.235 g, 1.82 mmol) in dioxane was purged with argon for 10 min. Then, Pd(OAc)2 (0.01 g, 0.044 mmol) and Xantphos (0.052 g, 0.089 mmol) were added and argon was purged again for 10 min. The reaction mixture was stirred at 100° C. overnight. After completion of the reaction, water was added and extraction was carried out using ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to afford the title compound (0.50 g, 88%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]([N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([CH3:40])[CH:38]=2)[C:33]([C:41]([OH:43])=O)=[CH:32]1)([CH3:30])[CH3:29].[NH2:44][C:45]1[S:46][CH:47]=[CH:48][N:49]=1>C(Cl)Cl>[S:46]1[CH:47]=[CH:48][N:49]=[C:45]1[NH:44][C:41]([C:33]1[C:34]2[C:39](=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)[N:31]([CH:28]([CH3:29])[CH3:30])[CH:32]=1)=[O:43]
Reactant: Nc1nccs1
Reactant: Cc1ccc2c(C(=O)O)cn(C(C)C)c2c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc2c(C(=O)Nc3nccs3)cn(C(C)C)c2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 41.6 %

Procedure:
A solution of triphenylphosphine (628 mg, 2.39 mmol) in methylene chloride (5 mL) cooled to 0° C. was treated with N-bromosuccinimide (425 mg, 2.39 mmol). The reaction was stirred at 0° C. for 15 min and then was treated with 1-isopropyl-6-methyl-1H-indole-3-carboxylic acid (400 mg, 1.84 mmol). The reaction was stirred at 0° C. for 15 min and then was allowed to warm to 25° C. where it was stirred for 30 min. The reaction was then treated with 2-aminothiazole (424 mg, 4.23 mmol) and stirred at 25° C. for 16 h. At this time, the mixture was partitioned between water (75 mL) and ethyl acetate (75 mL) and treated with a 1N aqueous hydrochloric acid solution (40 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (1×40 mL) and a saturated aqueous sodium chloride solution (1×40 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 1/1 hexanes/ethyl acetate) afforded 1-isopropyl-6-methyl-1H-indole-3-carboxylic acid thiazol-2-ylamide (229 mg, 41.5%) as a tan solid: mp 215-217° C.; EI-HRMS m/e calcd for C16H17N3OS (M+) 363.0041, found 363.0034.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[NH:26]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1)[NH2:27]>>[F:23][C:21]([F:22])([F:24])[O:20][C:17]1[CH:16]=[CH:15][C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:26]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=4)[N:27]=[CH:3][CH:4]=3)=[N:8]2)=[CH:19][CH:18]=1
Reactant: NNc1ccnc(C(F)(F)F)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1ccnc(C(F)(F)F)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and 4-hydrazino-2-trifluoromethylpyridine according to the method described for example 91. MS: M=468.1 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[CH:4][C:5]([F:23])=[C:6]([C:8]2[C:9](=[O:22])[N:10]([CH2:20][CH3:21])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)[CH:7]=1.C([O-])(O)=O.[Na+].Cl[C:31]([O:33][C:34]([CH3:36])=[CH2:35])=[O:32]>CCOC(C)=O>[CH2:20]([N:10]1[C:11]2[C:16](=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=2)[CH:17]=[C:8]([C:6]2[C:5]([F:23])=[CH:4][C:3]([F:24])=[C:2]([NH:1][C:31](=[O:32])[O:33][C:34]([CH3:36])=[CH2:35])[CH:7]=2)[C:9]1=[O:22])[CH3:21]
Reactant: C=C(C)OC(=O)Cl
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2F)cc2cnc(NC)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(NC)cc3n(CC)c2=O)c(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
A suspension of Example A8 (0.078 g, 0.236 mmol) in EtOAc (1.5 mL) was treated with satd. NaHCO3 (1.5 mL) followed by isopropenyl chloroformate (0.036 mL, 0.331 mmol) and the bi-phasic mixture stirred vigorously at RT overnight. The layers were separated, the organic layer washed with brine, dried over MgSO4 and concentrated to dryness to afford prop-1-en-2-yl (5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)carbamate (86 mg, 88% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.64 (s, 1H), 8.41 (s, 1H), 7.83 (s, 1H), 7.61 (s, 1H), 7.36 (t, J=10.2 Hz, 1H), 7.06 (m, 1H), 6.23 (s, 1H), 4.71 (d, J=7.9 Hz, 2H), 4.13 (q, J=7.1 Hz, 2H), 2.85 (d, J=4.9 Hz, 3H), 1.91 (s, 3H), 1.20 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 415.1 [M+H]+.