Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:21]2[C:16](=[CH:17][C:18](F)=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][C:13]=1[C:25]#[N:26].[CH3:27][N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH2:35][CH2:36][NH2:37])[CH2:30][CH2:29]1>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([NH:37][CH2:36][CH2:35][CH2:34][CH:31]3[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]3)=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][C:13]=1[C:25]#[N:26]
Reactant: COc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1F
Reactant: CN1CCC(CCCN)CC1
Solvent: CN1CCCC1=O
Product: COc1cc(Nc2c(C#N)cnc3cc(NCCCC4CCN(C)CC4)c(OC)cc23)c(Cl)cc1Cl
Yield: 38.4 %

Procedure:
Following the procedure used to prepare Example 27, 250 mg (0.64 mmol) of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-fluoro-6-methoxyquinoline-3-carbonitrile is reacted with 600 mg (3.80 mmol) of 3-(1-methylpiperidin-4-yl)propylamine in 2 mL of 1-methyl-2-pyrrolidinone at 105° C. for 18 hours to yield 130 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-{[3-(1-methylpiperidin-4-yl)propyl]amino}quinoline-3-carbonitrile as a white solid, mp 122-124° C.
Reaction SMILES: [CH2:1]([N:5]([CH2:23][CH2:24][CH2:25][CH3:26])[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([CH:14]=[CH:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[C:8]([O:21][CH3:22])[CH:7]=1)[CH2:2][CH2:3][CH3:4].C([Li])CCC.CN(C)[CH:34]=[O:35].C(Cl)(Cl)Cl>O1CCCC1>[CH2:23]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:7]=[C:8]([O:21][CH3:22])[C:9]([CH:14]=[CH:15][C:16]2[S:17][C:18]([CH:34]=[O:35])=[CH:19][CH:20]=2)=[C:10]([O:12][CH3:13])[CH:11]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCN(CCCC)c1cc(OC)c(C=Cc2cccs2)c(OC)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCCCN(CCCC)c1cc(OC)c(C=Cc2ccc(C=O)s2)c(OC)c1
Temperature: 0 °C
Yield: 100 %

Procedure:
In a stream of argon, in 10 ml of tetrahydrofuran was dissolved 0.75 g (2.00 mmol) of 2-[2-(4-dibutylamino-2,6-dimethoxyphenyl)vinyl]thiophene, and 1.27 ml of n-butyllithium (1.6 M solution in hexane) (2.03 mmol) was added dropwise thereto under cooling. The mixture was stirred for hour. To this mixture, 0.20 ml (1.20 mmol) of N,N-dimethylformamide was added dropwise and reacted. The temperature was then allowed to rise gradually, and the mixture was allowed to react at room temperature for 12 hours. After the mixture was poured into 100 ml of ice water, extraction with 200 ml of chloroform, washing with a saturated saline solution, drying over anhydrous magnesium sulfate, and concentration were performed. The residue was purified by silica gel chromatography to give 482 mg (yield: 60%) of 5-[2-(4-dibutylamino-2,6-dimethoxyphenyl)vinyl]thiophene-2-carboaldehyde as a dark purple crystal (mp: 105-106° C.).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:18][C:19]2[NH:20][C:21](=[O:29])[CH:22]3[CH2:28][O:27][CH2:26][CH2:25][CH:23]3[N:24]=2)[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]2)=[O:7])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[C:39]1([SH:45])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:39]1([S:45][C:15]([CH:12]2[CH2:11][CH2:10][N:9]([CH2:8][C:6](=[O:7])[N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[CH2:18][C:19]3[NH:20][C:21](=[O:29])[CH:22]4[CH2:28][O:27][CH2:26][CH2:25][CH:23]4[N:24]=3)[CH2:14][CH2:13]2)=[O:17])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(O)C1CCN(CC(=O)N(CC2=NC3CCOCC3C(=O)N2)CC2CC2)CC1
Reactant: Sc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Sc1ccccc1)C1CCN(CC(=O)N(CC2=NC3CCOCC3C(=O)N2)CC2CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
To a solution of 1-{[cyclopropylmethyl-(4-oxo-3,4a,5,7,8,8a-hexahydro-4H-pyrano[4,3-d]pyrimidin-2-ylmethyl)-carbamoyl]-methyl}-piperidine-4-carboxylic acid (0.5 g, 1.24 mmol, 1 eq.) in 5 mL of DMF was added DIEA (0.432 mL, 2.47 mmol, 2 eq.), thiophenol (0.14 mL, 1.36 mmol, 1.1 eq.), followed by HATU (0.517 g, 1.36 mmol, 1.1 eq.) at 0° C. The resulting mixture was allowed to warm to room temperature and stirred overnight. After 18 h, the reaction mixture was concentrated in vacuo to give an oil. This oil was purified by silica gel column chromatography (98/1/1 to 95/4/1 dichloromethane/MeOH/NH4OH) to give the title compound as an orange sticky oil (0.4 g). 1H NMR (400 MHz, chloroform-d) δ ppm 7.48-7.58 (m, 2H), 7.33-7.48 (m, 3H), 4.54-4.64 (m, 2H), 4.48-4.54 (m, 1H), 4.34-4.46 (m, 1H), 3.91-4.06 (m, 2H), 3.23-3.42 (m, 3H), 2.92-3.08 (m, 1H), 2.80-2.89 (m, 1H), 2.54-2.76 (m, 2H), 2.18-2.37 (m, 2H), 1.60-1.84 (m, 6H), 0.92-1.01 (m, 1H), 0.41-0.63 (m, 2H), 0.19-0.35 (m, 2H). Exact mass calculated for C26H33N4O4S1 497.2. MS (ESI) m/z 497.2 (M+H)+ (5-95% CH3CN/H2O over 2 min with 0.1% formic acid, Inertsil 3×3 mm C-8-3 column with flow rate of 2 mL/min).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:37][CH2:36][C:35]2[NH:34][N:33]=[CH:32][C:31]=2[CH2:30]1.[H-].[Na+].CN(C)C(=O)C.[CH3:46][C:47]1([CH3:50])[CH2:49][O:48]1>O.C(OCC)(=O)C>[OH:48][C:47]([CH3:50])([CH3:49])[CH2:46][N:33]1[CH:32]=[C:31]2[C:35]([CH2:36][CH2:37][CH:29]([N:3]3[C:2](=[O:1])[C:7]([CH2:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]5[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=5)=[CH:13][CH:14]=4)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]4[N:26]=[CH:27][N:28]=[C:4]34)[CH2:30]2)=[N:34]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCc3[nH]ncc3C2)c2ncnn12
Reactant: CC1(C)CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCc3nn(CC(C)(C)O)cc3C2)c2ncnn12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 11 %

Procedure:
A mixture of 4′-{[5-oxo-7-propyl-4-(4,5,6,7-tetrahydro-1H-indazol-5-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.36 g), sodium hydride (0.044 g) and N,N-dimethylacetamide (3 mL) was stirred at 0° C. for 5 min and then at room temperature for 20 min. 2,2-Dimethyloxirane (0.65 mL) was added, and the mixture was stirred at 120° C. for 1.5 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.047 g, 11%).
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[CH:33]1([CH2:36]Br)[CH2:35][CH2:34]1.[Cl-].[NH4+]>CN(C)C=O>[CH:33]1([CH2:36][N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:30])[CH2:3][CH2:4]2)=[O:9])[CH2:35][CH2:34]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: BrCC1CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3CC2CC2)CC1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
The suspension of 0.15 g (0.36 mmol) (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32) and 17 mg (0.36 mmol; 55% dispersion in mineral oil) sodium hydride in 2 mL N,N-dimethylformamide was stirred for 30 min. at 70° C. Then, 42 μL (58 mg, 0.43 mmol) cyclopropylmethyl bromide were added and the solution was stirred another 45 min. at 70° C. After cooling to room temperature the reaction was poured on 10% aqueous ammonium chloride solution and the phases were separated. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed twice with water, followed by brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel with dichloromethane:methanol:ammonia (9:1:0.1 v/v) as eluant to give 0.16 g (97%) of the desired compound as a colorless foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:25])[N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)=[O:17])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([C@H:12]([CH3:25])[N:13]([C:16]([C:18]4[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=4)=[O:17])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: CC1c2ccccc2-c2ccc(Cl)cc2N1C(=O)c1ccc(O)cc1
Solvent: ClC(Cl)Cl
Product: C[C@H]1c2ccccc2-c2ccc(Cl)cc2N1C(=O)c1ccc(O)cc1

Procedure:
The enantiomers of 4-[(3-chloro-6-methylphenanthridin-5(6H)-yl)carbonyl]phenol (400 mg, 1.14 mmol) were separated by automated, on-column solvent change, preparative, normal phase, chiral chromatography on a Chiralpak AD (20 mm×250 mm) column eluting with 20% ethanol in hexane at a flow rate of 12 mL/min with. After combination of fractions and evaporation of the solvent in vacuo, one peak (99.8%) with a retention time of 8.078 minutes was isolated as a white solid (200 mg, 100% based upon a 1:1 ratio of enantiomers with a theoretical maximum amount of 200 mg). mp 273.7-276° C.; [α]D25=+393° (c=0.010 g/mL, CHCl3); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21 (d, J=6.73 Hz, 3 H) 5.67 (q, J=6.73 Hz, 1 H) 6.71 (d, J=8.79 Hz, 2 H) 6.79 (d, J=2.07 Hz, 1 H) 7.17 (d, J=8.54 Hz, 2 H) 7.26 (dd, J=8.41, 2.20 Hz, 1 H) 7.41 (m, 3 H) 7.98 (m, 2 H) 10.04 (s, 1 H); MS (ESI) m/z 350/352 ([M+H]+); MS (ESI) m/z 348/350 ([M−H]−).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][CH3:20])[C:8]([O:10]CCC)=[O:9])[CH2:2][CH3:3].[OH-].[K+].O>O1CCOCC1>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][CH3:20])[C:8]([OH:10])=[O:9])[CH2:2][CH3:3]
Reactant: CCCOC(=O)c1ccc(OCCC)c(OCCC)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCOc1ccc(C(=O)O)cc1OCCC
Yield: 94 %

Procedure:
A mixture of the product of Step A (0.94 g; 3.35 mmol), KOH (0.56 g; 10 mmol), H2O (2 ml) and dioxane was stirred at reflux overnight. After evaporation of solvents under reduced pressure, the residue was dissolved on H2O (5 ml) and insoluble material was removed by filtration. The filtrate was acidified to pH˜3 with diluted HCl and the product was taken up by extraction with CH2Cl2 (3×15 ml). The combined organic phase was dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness to give the title compound (0.75 g; 94%) as creamy solid. 1H-NMR (CDCl3) 1.02-1.08 (m, 6H); 1.79-1.93 (m, 4H); 3.98-4.05 (m, 4H); 6.87 (d, 1H, J=8.5 Hz); 7.57 (d, 1H, J=2 Hz)); 7.7 (dd, 1H, J=2, 8.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8]C(=O)C2C=CC=CC=2)[CH:5]=[C:4]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[CH:23][N:24]=3)[N:19](S(C3C=CC=CC=3)(=O)=O)[CH:18]=2)[CH:3]=1.Cl>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[CH:23][N:24]=3)[NH:19][CH:18]=2)[CH:3]=1
Reactant: O=C(Nc1cc(-c2cn(S(=O)(=O)c3ccccc3)c3nccnc23)cc(Cl)n1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: Nc1cc(-c2c[nH]c3nccnc23)cc(Cl)n1
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 71.4 %

Procedure:
A mixture of EXAMPLE 17A (0.130 g, 0.265 mmol) and concentrated hydrochloric acid (0.15 mL) in ethanol (6 mL) was heated at 95° C. for 24 h. The mixture was concentrated and the residue treated with saturated aqueous sodium bicarbonate, sonicated, filtered, and washed with water. The intermediate was suspended in dioxane (3.5 mL), treated with 20% sodium hydroxide (0.3 mL) and heated at 50° C. for 2 h. After concentration, the residue was treated with 6 mL of water. The solid was filtered, washed with water, and purified by reversed-phase HPLC (Zorbax RX-C18 column (250×21.2 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile: 0.1% aqueous trifluoroacetic acid over 40 min at a flow rate of 15 mL/minute). The filtrate was also separately purified by HPLC to obtain a combined 46.5 mg (49%) of the title compound as the trifluoroacetate salt. 1H NMR (500 MHz, DMSO-d6) 7.28 (s, 1H), 7.47 (s, 1H), 8.34 (d, J=2.4 Hz, 1H), 8.52 (d, J=2.8 Hz, 1H), 8.58 (d, J=3.1 Hz, 1H), 12.55 (s, 1H). MS (ESI) m/z 246.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[C:16](=[O:21])[CH2:15]2)[C:3]=1[CH3:22].[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[C:31]([NH2:35])[CH:32]=[N:33][CH:34]=2)[CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:35][C:31]1[CH:32]=[N:33][CH:34]=[C:29]([N:26]3[CH2:27][CH2:28][O:23][CH2:24][CH2:25]3)[CH:30]=1)=[C:3]([CH3:22])[C:4]([N:14]1[CH2:19][CH2:18][N:17]([CH3:20])[C:16](=[O:21])[CH2:15]1)=[N:5]2
Reactant: Cc1c(N2CCN(C)C(=O)C2)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cncc(N2CCOCC2)c1
Solvent: Cc1ccccc1
Product: Cc1c(N2CCN(C)C(=O)C2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure H using 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-1-methylpiperazin-2-one (31.0 mg, 0.095 mmol) and 5-morpholinopyridin-3-amine in toluene to give 4-(5,7-difluoro-3-methyl-4-((5-(4-morpholinyl)-3-pyridinyl)amino)-2-quinolinyl)-1-methyl-2-piperazinone. 1H NMR (400 MHz, chloroform-d) δ ppm 7.95 (1H, br. s.), 7.71 (1H, br. s.), 7.31 (1H, ddd, J=9.8, 2.6, 1.3 Hz), 6.94 (1H, d, J=13.1 Hz), 6.83 (1H, ddd, J=13.9, 8.6, 2.5 Hz), 6.60 (1H, s), 4.07 (2H, s), 3.84-3.91 (4H, m), 3.67 (2H, t, J=5.4 Hz), 3.53 (2H, t, J=5.4 Hz), 3.13-3.21 (4H, m), 3.03 (3H, s), 2.08 (3H, s). Mass Spectrum (ESI) m/e=469.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][N:12]([C@H:17]3[CH2:22][CH2:21]C[CH2:19][C@@H:18]3[OH:23])[C:13]2=[O:16])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.N[C@H]1CCCC[C@@H]1[OH:31]>>[Br:1][C:2]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][N:12]([C@@H:17]3[C@@H:18]([OH:23])[CH2:19][O:31][CH2:21][CH2:22]3)[C:13]2=[O:16])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: N[C@H]1CCCC[C@@H]1O
Reactant: O=c1c2cc(Br)c3cccnc3c2ccn1[C@H]1CCCC[C@@H]1O
Product: O=c1c2cc(Br)c3cccnc3c2ccn1[C@H]1CCOC[C@@H]1O

Procedure:
1,5-Anhydro-3-(5-bromo-7-oxo-1,8-phenanthrolin-8(7H)-yl)-2,3-dideoxy-L-threo-pentitol was prepared by the procedure described for the synthesis of 5-bromo-8-[(1S,2S)-2-hydroxycyclohexyl]-1,8-phenanthrolin-7(8H)-one in Example 1, substituting (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol for (1S,2S)-2-aminocyclohexanol.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10][NH2:11])=[CH:8][CH:9]=1.[F:27][C:28]1[CH:29]=[C:30]2[C:35](=[C:36]([O:38][CH2:39][CH2:40][CH2:41][O:42][CH3:43])[CH:37]=1)[N:34]=[C:33]([CH:44]=O)[CH:32]=[CH:31]2.C(O)C.C(O)(=O)C.C(O)(=O)C.I(C1C=CC=CC=1)=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:26][C:2]([F:25])([F:1])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH2:13]1)[C:4]1[CH:9]=[CH:8][C:7]2[N:6]([C:44]([C:33]3[CH:32]=[CH:31][C:30]4[C:35](=[C:36]([O:38][CH2:39][CH2:40][CH2:41][O:42][CH3:43])[CH:37]=[C:28]([F:27])[CH:29]=4)[N:34]=3)=[N:11][N:10]=2)[CH:5]=1
Reactant: COCCCOc1cc(F)cc2ccc(C=O)nc12
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Agent: O=C([O-])O
Agent: O=Ic1ccccc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COCCCOc1cc(F)cc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 53.9 %

Procedure:
A solution of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (0.15 g, 0.36 mmol) and 6-fluoro-8-(3-methoxypropoxy)quinoline-2-carbaldehyde (0.095 g, 0.36 mmol) in ethanol (1.8 mL, 0.36 mmol) was allowed to stir at ambient temperature for 12 hours. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (1.8 mL) and iodosobenzene diacetate (0.13 g, 0.39 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 hour. Ethyl acetate (20 mL) and saturated sodium bicarbonate (10 mL) were added. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography on a C18 column (0-100% acetonitrile/water) to give the title compound (0.12 g, 55%).
Reaction SMILES: Cl[CH:2]1[C:6]([CH3:8])([CH3:7])[C:5]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:4]=2[O:3]1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[C:13]([C:10]1[CH:11]=[CH:12][C:4]2[O:3][CH:2]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:6]([CH3:8])([CH3:7])[C:5]=2[CH:9]=1)#[N:14]
Reactant: C1COCCN1
Reactant: CC1(C)c2cc(C#N)ccc2OC1Cl
Product: CC1(C)c2cc(C#N)ccc2OC1N1CCOCC1
Temperature: 0 °C

Procedure:
2-Chloro-5-cyano-2,3-dihydro-3,3-dimethylbenzofuran (4.1 g), prepared as in Example 45 was heated under reflux at about 130° C. in morpholine (20 ml) for 4 hours. Addition to ice-water, followed by extraction with diethyl ether, gave, after water washing, drying over sodium sulphate and running down, 3.3 g of crude title product. Recrystallisation from isopropanol gave 2.3 g of pure product, mp 105°-107° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:33]=[C:18]4[C:19]([O:23]CC5C=CC=CC=5C#N)=[CH:20][CH:21]=[CH:22][N:17]4[N:16]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1>[Pd].CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:33]=[C:18]4[C:19]([OH:23])=[CH:20][CH:21]=[CH:22][N:17]4[N:16]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc(Nc3nc4c(OCc5ccccc5C#N)cccn4n3)cc2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(c2ccc(Nc3nc4c(O)cccn4n3)cc2)CC1
Reaction time: 3 h

Procedure:
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ol was prepared from combining 2-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yloxymethyl}-benzonitrile (30.0 mg, 0.68 mmol) and 10% palladium on carbon (50% Wet) (5:45:50, palladium:carbon black:water, 30. mg, 0.14 mmol) in methanol (10.0 mL) and shaking under an atmosphere of Hydrogen (45 psi) for 3 hours. Product was isolated as a mustard colored solid (14.0 mg, 63%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.45 (bs, 1H), 9.12 (s, 1H), 8.21 (dd, J=6.4 Hz, 1.0 Hz, 1H), 7.53 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H), 6.80-6.76 (m, 2H), 3.04-3.02 (m, 4H), 2.47-2.44 (m, 4H), 2.22 (s, 3H). MS=325.2 (MH)+.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:18]3[O:22][N:21]=[C:20]([CH3:23])[N:19]=3)=[C:14]([Cl:17])[CH:15]=2)[C:10]([CH3:25])([CH3:24])[CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:17][C:14]1[CH:15]=[C:16]2[C:11]([C:10]([CH3:24])([CH3:25])[CH2:9][NH:8]2)=[CH:12][C:13]=1[C:18]1[O:22][N:21]=[C:20]([CH3:23])[N:19]=1
Reactant: Cc1noc(-c2cc3c(cc2Cl)N(C(=O)OC(C)(C)C)CC3(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1noc(-c2cc3c(cc2Cl)NCC3(C)C)n1
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
6-Chloro-3,3-dimethyl-5-(3-methyl-[1,2,4]oxadiazol-5-yl)-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (36 mg, 0.11 mmol) was dissolved in 50% TFA in DCM (0.534 mL) and the mixture was stirred for 30 minutes and concentrated. The residue was dissolved in methanol, loaded onto an SCX column and eluted with methanol then 2.0M ammonia in methanol to release the amine and fractions concentrated, to give the title compound (26 mg), MS: [M+H]+=264.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@@H:13]([CH3:17])[CH2:14][O:15][CH3:16])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N:18]1([C:22]([C:24]2[CH:29]=[N:28][C:27](Cl)=[CH:26][N:25]=2)=[O:23])[CH2:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O.C(OCC)(=O)C>[N:18]1([C:22]([C:24]2[N:25]=[CH:26][C:27]([O:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@@H:13]([CH3:17])[CH2:14][O:15][CH3:16])[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])=[N:28][CH:29]=2)=[O:23])[CH2:21][CH2:20][CH2:19]1
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)OC)c1
Reactant: O=C(c1cnc(Cl)cn1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(C(=O)OC)c1
Temperature: 45 °C
Reaction time: 0.25 h
Yield: 93 %

Procedure:
To a flask fitted with overhead stirrer, condenser, thermometer and nitrogen line was added methyl 3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]benzoate (1.0 eq), 2-(azetidin-1-ylcarbonyl)-5-chloropyrazine (1.05 eq), cesium carbonate (1.5 eq) and dimethylsulfoxide (10 vols) under a nitrogen atmosphere. The contents of the flask were heated to 45° C. for 1.5 hours, then cooled to 22° C. Ethyl acetate (6 vols) and water (6 vols) were added to the flask, the mixture was agitated for 15 minutes, then the layers were separated. Water (3 vols) was added to the organic layer, the batch agitated for 15 minutes, then the layers were separated. This process was repeated with water (3 vols) then saturated brine (6 vols), then with water (6 vols). The organic layer was evaporated on the rotary evaporator to yield the title compound as an oil (93% yield corrected for assay). 1H NMR δ (400 MHz) DMSO: 8.62 (s, 1H), 8.50 (s, 1H), 7.34 (s, 1H), 7.30 (s, 1H), 7.17 (s, 1H), 4.68-4.64 (m, 1H), 4.54-4.49 (t, 2H), 4.07-4.03 (t, 2H), 3.81 (s, 3H), 3.49-3.41 (m, 2H), 3.25 (s, 3H), 2.29-2.22 (m, 2H), 1.20-1.18 (d, 3H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:32][CH2:33][CH2:34][C:35]1[CH:43]=[CH:42][CH:41]=[C:40]2[C:36]=1[CH2:37][C:38](=[O:44])[NH:39]2.[CH:45]([C:48]1[CH:53]=[CH:52][C:51](O)=[CH:50][CH:49]=1)([CH3:47])[CH3:46]>O1CCCC1>[CH:45]([C:48]1[CH:53]=[CH:52][C:51]([O:32][CH2:33][CH2:34][C:35]2[CH:43]=[CH:42][CH:41]=[C:40]3[C:36]=2[CH2:37][C:38](=[O:44])[NH:39]3)=[CH:50][CH:49]=1)([CH3:47])[CH3:46]
Reactant: O=C1Cc2c(CCO)cccc2N1
Reactant: CC(C)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1ccc(OCCc2cccc3c2CC(=O)N3)cc1
Reaction time: 0.25 h
Yield: 37.2 %

Procedure:
Diethyl azodicarboxylate (1.58 mL, 10 mmol) was added to a solution of triphenylphosphine (2.62 g, 10 mmol) in tetrahydrofuran (20 mL) under nitrogen atmosphere. The mixture was stirred for 15 minutes. To it was then added 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (1.77 g, 10 mmol) followed by 4-isopropylphenol (1.36 g, 10 mmol). The mixture was stirred at room temperature for one day and the solvent was evaporated. The residue was chromatographed on silica gel eluting with ethyl acetate:hexane 2:8 to give 1.1 g (37%) of 4-[2-(4-isopropyl-phenoxy)-ethyl]-1,3-dihydro-indol-2-one as a light yellow solid.