Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([CH2:13]I)[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:16]1[CH:26]=[CH:25][C:19]2[O:20][C:21]([F:24])([F:23])[O:22][C:18]=2[CH:17]=1>CN(C=O)C.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].II>[C:1]([O:5][C:6]([C@@H:8]([CH2:13][C:26]1[CH:16]=[CH:17][C:18]2[O:22][C:21]([F:23])([F:24])[O:20][C:19]=2[CH:25]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: FC1(F)Oc2ccc(Br)cc2O1
Reactant: COC(=O)[C@@H](CI)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: II
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc2c(c1)OC(F)(F)O2)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.3 %

Procedure:
To a 25 mL RBF was added zinc powder (1.03 g, 15.8 mmol) and iodine (0.0161 g, 0.0633 mmol). The mixture was heated with a heat gun for 5 minutes and the resulting mixture was then flushed with nitrogen 3 times and allowed to cool to rt. A solution of (R)-methyl 2-(tert-butoxycarbonyl)-3-iodopropanoate (3.47 g, 10.5 mmol) in 5 mL of DMF was added dropwise to the mixture over 3 minutes and the resulting grey slurry was stirred at 0° C. for 20 minutes before being warmed to rt. After stirring at rt for 30 minutes, 5-bromo-2,2-difluorobenzo[d][1,3]dioxole (2.50 g, 10.5 mmol), Pd2(dba)3 (0.193 g, 0.211 mmol) and S(Phos) (0.346 g, 0.844 mmol) were added and the reaction mixture was heated to 40° C. for 2 hours. The resulting mixture was cooled to rt and partitioned between ethyl acetate (50 mL) and a solution of ˜9:1 saturated ammonium chloride/ammonium hydroxide pH=9 (250 mL). The aqueous layer was extracted with ethyl acetate (3×100 mL) and the combined organic layers were washed with water, brine, and dried over sodium sulfate. Concentration of the filtered solvents and purification of resulting crude material by silica gel chromatography provided (S)-methyl 2-(tert-butoxycarbonyl)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)propanoate (1.89 g, 49.9% yield) as a slightly brown oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25](OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(O)(C(F)(F)F)=O.ClC1[N:45]=[CH:44][C:43]([CH2:46][CH3:47])=[CH:42][N:41]=1>C(Cl)Cl>[CH2:46]([C:43]1[CH:42]=[N:41][C:25]([N:22]2[CH2:23][CH2:24][CH:19]([CH2:18][O:17][C:14]3[CH:15]=[N:16][C:11]([C:8]4[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=4)=[CH:12][CH:13]=3)[CH2:20][CH2:21]2)=[N:45][CH:44]=1)[CH3:47]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Reactant: CCc1cnc(Cl)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cnc(N2CCC(COc3ccc(-c4ccc(S(C)(=O)=O)cc4)nc3)CC2)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91 %

Procedure:
1,1-Dimethylethyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (prepared as in Example 73, Step 2, 0.15 g, 0.34 mmol) was dissolved in CH2Cl2 (10 mL). TFA (0.35 mL) was added and the mixture was stirred at ambient temperature for 5 h. An excess of TFA and CH2Cl2 was removed under reduced pressure and the residue was taken up in DMSO (6 mL). Potassium carbonate (1 g) was added, followed by addition of 2-chloro-5-ethylpyrimidine (63 μL, 0.50 mmol). The reaction mixture was degassed, purged with N2 and heated at 100° C. overnight. The mixture was cooled to ambient temperature and poured into water and extracted with EtOAc. The combined organic extract was washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a light brown solid. The crude product was triturated with hot hexane containing 1% of MeOH to give 0.14 g (92%) of the title compound as a cream-white solid. 1H NMR (400 MHz, CDCl3): δ 8.40 (d, 1H, J=2.7 Hz), 8.19 (bs, 2H), 8.13 (d, 2H, J=8.6 Hz), 8.00 (d, 2H, J=8.6 Hz), 7.73 (d, 1H, J=8.5 Hz), 7.35-7.25 (m, 1H), 4.90-4.75 (m, 2H), 3.94 (d, 2H, J=6.1 Hz), 3.08 (s, 3H), 3.00-2.90 (m, 2H), 2.55-2.40 (m, 2H), 2.25-2.10 (m, 1H), 2.00-1.90 (m, 2H), 1.50-1.30 (m, 2H), 1.19 (t, 3H, J=7.5 Hz); LRMS (APCI), m/z 453 (M+H).
Reaction SMILES: I[CH2:2][CH:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C=O)C>[N:22]([CH2:2][CH:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[N+:23]=[N-:24]
Reactant: CCCCCCCCCCC(CI)NC(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCC(CN=[N+]=[N-])NC(=O)OC(C)(C)C
Temperature: 110 °C
Reaction time: 12 h
Yield: 50.4 %

Procedure:
tert-Butyl N-[1-(R/S)-(iodomethyl)undecyl]carbamate 62 (250 mg, 0.608 mmol) was dissolved in abs. DMF (10 ml). Sodium azide (79.0 mg, 1.22 mmol) was added to the solution, which was subsequently stirred at 110° C. for 12 hours. Following evaporation, the residue was taken up in CH2Cl2 (50 ml) and was washed with NaHCO3(sat, aq) (1×50 ml). The organic phase was dried over MgSO4, filtered and evaporated. The residue was purified by column chromatography in hexane:ether 10:1 (v/v) to give 63 (100 mg, 54%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([S:12][CH2:13][C:14]([OH:16])=O)[N:11]=[C:4]2[N:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([S:12][CH2:13][C:14]([NH:25][C:22]3[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)=[O:16])[N:11]=[C:4]2[N:3]=1
Reactant: Cc1cc(C)n2nc(SCC(=O)O)nc2n1
Reactant: COc1ccc(N)cc1
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)CSc2nc3nc(C)cc(C)n3n2)cc1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A mixture of 2-({5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}sulfanyl)acetic acid (0.10 g, 0.42 mmol), p-anisidine (52 mg, 0.42 mmol), N,N-dicyclohexylcarbodiimide (87 mg, 0.42 mmol), and N,N-dimethylformamide (2 mL) was added to a 20 mL scintillation vial with a magnetic stirring bar. The mixture was allowed to stir at ambient temperature for 36 h. A white precipitate was removed by filtration and rinsed with N,N-dimethylformamide (0.5 mL) followed by water (1 mL). A precipitate formed in the liquid layer upon standing at ambient temperature for 12 h and was isolated by filtration. The crude precipitate was crystallized from warn ethanol (12 mL). The crystallized material was isolated by filtration, rinsed with ethanol, and allowed to dry. The title compound was obtained as an off-white solid (144 mg, 38% yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm: 10.21 (s, 1H), 7.49 (d, 2H), 7.11 (s, 1H), 6.88 (d, 2H), 4.19 (s, 2H), 3.71 (s, 3H), 2.66 (s, 3H), 2.54 (s, 3H).
Reaction SMILES: [CH:1]1([C@H:4]([NH:12][C:13]([CH2:15][C:16]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:17]=2[C:18](O)=[O:19])=[O:14])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=2)[CH2:3][CH2:2]1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>>[C:26]([C:15]1[C:16]2[C:17](=[C:21]([F:25])[CH:22]=[CH:23][CH:24]=2)[C:18](=[O:19])[O:14][C:13]=1[NH:12][C@@H:4]([CH:1]1[CH2:2][CH2:3]1)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Cc1cccc(F)c1C(=O)O)N[C@H](c1cccc(F)c1)C1CC1
Product: CC(=O)c1c(N[C@H](c2cccc(F)c2)C2CC2)oc(=O)c2c(F)cccc12
Reaction time: 20 h
Yield: 103.5 %

Procedure:
A mixture of 2-({[(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]-carbamoyl}-methyl)-6-fluoro-benzoic acid (12.92 g, 37.41 mmol) and acetic anhydride (100 mL, 1 mol) was stirred at +65° C. for 20 hours and evaporated in vacuo (65° C., 10 mbar, 2 hours) to give the title compound as a thick brown oil, which was used in the next step without purification (14.30 g, yield 103.5%, purity 95% according to 1H NMR). LC-MS (m/z) 370.1 (MH+); tR=1.65. 1H NMR (500 MHz, DMSO-d6): 0.45-0.59 (m, 3H), 0.64 (m, 1H), 1.41 (m, 1H), 2.53 (s, 3H), 4.36 (t (unres. dd), 1H), 7.03 (dd, J=8.3, 10.7 Hz, 1H), 7.12 (dt, J=1.9, 8.5 Hz, 1H), 7.27 (d, J=10.2 Hz, 1H), 7.3 (d, J=7.8 Hz, 1H), 7.42 (q, J=7.8 Hz, 1H), 7.53 (d, 8.5 Hz, 1H), 7.7 (m, 1H), 11.3 (d, J=7.3 Hz, 1H, NH).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:12]=[C:11]([C:13]3[S:17][C:16]([NH2:18])=[N:15][C:14]=3[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=3)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[CH:1]1([NH:6][C:7]2[CH:12]=[C:11]([C:13]3[S:17][C:16]([NH:18][C:33]([NH:32][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:34])=[N:15][C:14]=3[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=3)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cccc(-c2nc(N)sc2-c2ccnc(NC3CCCC3)c2)c1
Reactant: O=C=Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cccc(-c2nc(NC(=O)Nc3ccccc3)sc2-c2ccnc(NC3CCCC3)c2)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 40.8 %

Procedure:
To a solution of [5-(2-cyclopentylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine (0.43 g, 1.2 mmol) in N,N-dimethylacetamide (10 mL) was added phenyl isocyanate (0.19 mL, 1.8 mmol) and the mixture was stirred at 80° C. for 1 hr. Into the reaction mixture was poured aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=1:1). The obtained crude crystals were recrystallized from ethyl acetate to give the title compound (0.23 g, yield 39%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[C:12]([C:15]1[N:19]3[CH:20]=[C:21]([C:24]([OH:26])=O)[CH:22]=[CH:23][C:18]3=[N:17][N:16]=1)[CH:11]=[CH:10]2)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:28][NH:29][O:30][CH3:31].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C.O>[C:1]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[C:12]([C:15]1[N:19]3[CH:20]=[C:21]([C:24]([N:29]([O:30][CH3:31])[CH3:28])=[O:26])[CH:22]=[CH:23][C:18]3=[N:17][N:16]=1)[CH:11]=[CH:10]2)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)c1cccc2ccc(-c3nnc4ccc(C(=O)O)cn34)nc12
Reactant: CNOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)c1ccc2nnc(-c3ccc4cccc(C(C)(C)C)c4n3)n2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
A solution of 3-(8-tert-butylquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (0.60 g, 1.73 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.25 g, 2.60 mmol) and DIEA (0.91 mL, 5.20 mmol) in DMF (1 mL) was added HATU (1.15 g, 3.03 mmol) and the reaction mixture was stirred at ambient temperature for 1 hour. Water (10 mL) and ethyl acetate (30 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (1:3 hexane/ethyl acetate) to give 3-(8-tert-butylquinolin-2-yl)-N-methoxy-N-methyl-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide (0.54 g, 80.6%) as solid.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[CH3:7][S:8][C:9]1[N:10]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11](=[O:20])[CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:13]=1.C(I)C>O1CCCC1.C(OCC)(=O)C>[CH2:1]([C:12]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:11](=[O:20])[N:10]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:9]([S:8][CH3:7])=[N:13]1)[CH3:2]
Reactant: CC(C)(C)[O-]
Reactant: CSC1=NC(c2ccccc2)C(=O)N1Nc1ccccc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCI
Product: CCC1(c2ccccc2)N=C(SC)N(Nc2ccccc2)C1=O
Yield: 40.8 %

Procedure:
0.55 g of potassium tert-butoxide is added to a solution of 1.5 g (5.05 mmol) of 2-methylthio-4-phenyl-1-phenylamino-2-imidazolin-5-one (Compound 5) in 50 ml of anhydrous tetrahydrofuran. The mixture is left to react for 30 minutes at room temperature and then 0.8 g (5.05 mmol) of ethyl iodide is added. The mixture is left to react for 1 hour at room temperature. The mixture is diluted with 150 ml of ethyl acetate. The solution is washed with water and then concentrated under reduced pressure. The product is purified by chromatography on a silica column (Merck 60H silica; eluent: 25% ethyl acetate/75% heptane). 0.65 g of Compound 48 is obtained in the form of a beige powder melting at 147° C.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:6]([NH:16][C:17](=O)[CH2:18][N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)[CH:5]=1.Cl.[OH-].[Na+]>O1CCOCC1>[CH2:12]([CH:11]([N:10]1[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:25])=[CH:5][C:6]=2[N:16]=[C:17]1[CH2:18][N:19]1[CH:23]=[CH:22][CH:21]=[N:20]1)[CH2:14][CH3:15])[CH3:13]
Reactant: CCC(CC)Nc1ccc(C(=O)OC)cc1NC(=O)Cn1cccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCC(CC)n1c(Cn2cccn2)nc2cc(C(=O)O)ccc21
Temperature: 110 °C
Yield: 89.9 %

Procedure:
To 2.28 g 4-(1-Ethyl-propylamino)-3-(2-pyrazol-1-yl-acetylamino)-benzoic acid methyl ester were added 50 ml of 4M hydrochloric acid in dioxane. Divided into five portions the reaction mixture was heated to 110° C. for 15 min in a microwave reactor. After cooling to the reaction mixture 6 ml of 10 M aqueous sodium hydroxide solution were added slowly. After 30 min at rt the reaction mixture was concentrated to a third of its volume and adjusted to pH 4 by the addition of 2M aqueous hydrochloric acid. It was extracted with ethyl acetate three times. The combined organic phases were dried over sodium sulphate and concentrated in vacuo. 1.86 g (90%) of 1-(1-Ethyl-propyl)-2-pyrazol-1-ylmethyl-1H-benzoimidazole-5-carboxylic acid were obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[C:9]([C:10]2[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=2)=[CH:8][N:7]=[CH:6]1.Cl[C:19]1[N:20]=[CH:21][C:22]2[CH:27]=[C:26]([C:28]3[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH:33]=3)[NH:25][C:23]=2[N:24]=1.Cl.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.C(N(CC)C(C)C)(C)C>C(O)CCC.CCOCC.CN(C=O)C>[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[C:9]([C:10]2[CH:11]=[C:12]([NH:16][C:21]3[C:22]4[CH:27]=[C:26]([C:28]5[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH:33]=5)[NH:25][C:23]=4[N:24]=[CH:19][N:20]=3)[CH:13]=[CH:14][CH:15]=2)=[CH:8][N:7]=[CH:6]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3cnc(Cl)nc3[nH]2)CC1
Reactant: CN(C)CCn1cncc1-c1cccc(N)c1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCCCO
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN(C)CCn1cncc1-c1cccc(Nc2ncnc3[nH]c(C4=CCN(C(=O)OC(C)(C)C)CC4)cc23)c1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
3-[3-(2-Dimethylaminoethyl)-3H-imidazol-4-yl]phenylamine (110 mg, 0.478 mmol) was added to a solution of tert-butyl 4-(chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (133 mg, 0.398 mmol) in 1-butanol (2.0 mL). The reaction was stirred at 120° C. for 48 h. 0.8 mL of 1 N HCl in ether was then added and the mixture was stirred further at 120° C. for 15 h. LC-MS showed the displacement reaction was complete and the BOC group in the desired product was completely removed. Di-tert-butyldicarbonate (347 mg, 1.59 mmol) and N,N-diisopropylethylamine (0.347 mL, 1.99 mmol) were added, and the resulting mixture was stirred at rt for 30 min. DMF (z1.5 mL) was added and the mixture was filtered. The filtrate was purified by HPLC purification to give the title compound. 1H-NMR (CD3OD, 400 MHz): δ=1.50 (s, 9H), 2.52 (s, 6H), 2.58 (m, 2H), 3.04 (t, J=6.8 Hz, 2H), 3.67 (m, 2H), 4.13 (m, 2H), 4.53 (t, J=6.8 Hz, 2H), 6.30 (s, br, 1H), 6.72 (s, 1H), 7.18 (s, 1H), 7.19 (d, J=7.6 Hz, 1H), 7.48-7.52 (m, 1H), 7.72 (dd, J=2.4, 8.0 Hz, 1H), 8.06 (s, 1H), 8.12 (m, 1H), 8.26 (s, 1H). MS (ES+): m/z 529 [MH+]. HPLC: tR=2.00 min (ZQ2000, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([CH:20]=1)[O:7][C:8]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:9]=1[C:10]([O:12]C)=[O:11].[OH-].[K+].Cl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([CH:20]=1)[O:7][C:8]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: COC(=O)c1cc(OC)ccc1Oc1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(Oc2cc(Cl)ccc2[N+](=O)[O-])c(C(=O)O)c1
Reaction time: 18 h

Procedure:
To a stirred suspension of 65 g of 2-(5-chloro-2-nitrophenoxy)-5-methoxybenzoic acid, methyl ester, in 600 ml of methanol, was added 97.5 ml of 6M KOH solution. This suspension was stirred for 18 hours and the solution which resulted was neutralized with 200 ml of 10% HCl solution. The precipitated crude acid product was collected by filtration and, after recrystallization from acetonitrile, yielded the title compound, mp 232°-234° C.
Reaction SMILES: [CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]=1[O:29][CH2:30][CH2:31][NH2:32])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].Cl[C:34]([CH:36]=[CH:37][C:38]([O:40][CH3:41])=[O:39])=[O:35]>C(Cl)Cl>[CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:14]=1[O:29][CH2:30][CH2:31][NH:32][C:34](=[O:35])/[CH:36]=[CH:37]/[C:38]([O:40][CH3:41])=[O:39])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC[C@H](NC(=O)c1c(OCCN)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Reactant: COC(=O)C=CC(=O)Cl
Solvent: ClCCl
Product: CC[C@H](NC(=O)c1c(OCCNC(=O)/C=C/C(=O)OC)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 16.9 %

Procedure:
1.4 g (3.3 mmol) of (S)-N-(α-ethylbenzyl)-3-(2-aminoethoxy)-2-phenylquinoline-4-carboxamide (compound of Description 4) were dissolved, under nitrogen atmosphere, in 35 ml of dry CH2Cl2; 0.77 ml (5.5 mmol) of TEA were added, the solution was cooled to 0° C. and 0.4 g (3.4 mmol) of methyl 3-chlorocarbonylpropenoate (compound of Description 5), dissolved in 25 ml of CH2Cl2, were added dropwise. The reaction was stirred at room temperature for 2 days, washed with H2O, 20% citric acid, sat. sol. NaHCO3, sat. sol. NaCl, dried over Na2SO4 and evaporated in vacuo to dryness. The residue was purified by gradient flash column chromatography on 230-400 mesh silica utilising a mixture of hexane/EtOAc 8:2 as starting eluent and a mixture of hexane/EtOAc 3:7 as final eluent. The crude product so obtained was further purified by preparative HPLC to yield 0.30 g of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][CH:14]=2)[C:5]([F:23])=[CH:4][N:3]=1.[CH3:24][O:25][CH2:26][CH2:27][O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>C(O)(CC)(C)C.C(O)(=O)C>[F:23][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][CH:14]=2)=[N:7][C:2]([NH:33][C:32]2[CH:31]=[CH:30][C:29]([O:28][CH2:27][CH2:26][O:25][CH3:24])=[CH:35][CH:34]=2)=[N:3][CH:4]=1
Reactant: COCCOc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Nc2nc(Cl)ncc2F)c1
Solvent: CCC(C)(C)O
Solvent: CC(=O)O
Product: COCCOc1ccc(Nc2ncc(F)c(Nc3cccc(NC(=O)OC(C)(C)C)c3)n2)cc1

Procedure:
tert-Butyl (3-((2-chloro-5-fluoropyrimidin-4-yl)amino)phenyl)carbamate (800 mg, 2.37 mmoL) and 4-(2-methoxyethoxy)aniline (576 mg, 2.84 mmoL) were suspended in tert-amyl alcohol (14 mL) and acetic acid (5 drops). Heated to reflux for 4 h. After cooling, solvent was removed via rotary evaporation. The dark oil was partitioned between water/brine and THF (10 mL each), agitated, and separated layers and dried organic phase over sodium sulfate. The solvent was removed via rotary evaporation to afford a purple solid, 0.55 g. LC/MS (RT=2.997/(M+1)) 470.2. Additional 150 mg of product minus the (BOC) protecting group crystallized from the aqueous layer
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17](Br)[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:21])=[CH:10][CH:11]=3)[N:6]=1.C(NC(C)C)(C)C.[CH3:29][C:30]([CH3:34])([CH3:33])[C:31]#[CH:32]>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.[Cu]I.C1COCC1>[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:32]#[C:31][C:30]([CH3:34])([CH3:33])[CH3:29])[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:21])=[CH:10][CH:11]=3)[N:6]=1
Reactant: C#CC(C)(C)C
Reactant: NC1=N[C@@]2(CO1)c1cc(O)ccc1Oc1ncc(Br)cc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(O)ccc1O2
Temperature: 80 °C

Procedure:
A vial charged with (S)-2′-amino-3-bromo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol (0.250 g, 0.718 mmol), Pd(PPh3)4 (0.083 g, 0.072 mmol), and copper(i) iodide (0.014 g, 0.072 mmol), was treated with 1 mL THF followed by diisopropylamine (1.535 mL, 10.77 mmol). The solution was degassed with argon and 3,3-dimethylbut-1-yne (0.295 g, 3.59 mmol) was added and the vial heated to 80° C. overnight. The reaction mixture was purified directly by column chromatography yielding (S)-2′-amino-3-(3,3-dimethylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol.
Reaction SMILES: [Na].[NH2:2][C:3]([NH2:5])=[O:4].C([O:8][C:9]([C:11]1([C:40](OCC)=[O:41])[CH2:15][CH2:14][CH2:13][N:12]1[C:16]1[CH:17]=[N:18][C:19]([O:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[N:28]([C:32]2[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=2)[N:27]=[CH:26]3)=[CH:20][CH:21]=1)=O)C>C(O)C>[C:38]([C:35]1[CH:36]=[CH:37][C:32]([N:28]2[C:29]3[C:25](=[CH:24][C:23]([O:22][C:19]4[N:18]=[CH:17][C:16]([N:12]5[C:11]6([C:40](=[O:41])[NH:5][C:3](=[O:4])[NH:2][C:9]6=[O:8])[CH2:15][CH2:14][CH2:13]5)=[CH:21][CH:20]=4)=[CH:31][CH:30]=3)[CH:26]=[N:27]2)=[CH:33][CH:34]=1)#[N:39]
Reactant: NC(N)=O
Reactant: CCOC(=O)C1(C(=O)OCC)CCCN1c1ccc(Oc2ccc3c(cnn3-c3ccc(C#N)cc3)c2)nc1
Agent: [Na]
Solvent: CCO
Product: N#Cc1ccc(-n2ncc3cc(Oc4ccc(N5CCCC56C(=O)NC(=O)NC6=O)cn4)ccc32)cc1
Temperature: 80 °C

Procedure:
To a flame dried flask is added ethanol (6 mL) and freshly cut sodium metal (62.4 mg, 2.71 mmol). The solution is stirred until homogenous. Recrystallized urea (98 mg, 1.63 mmol) is added and the solution is stirred at room temperature for 5 minutes. 1-{6-[1-(4-Cyano-phenyl)-1H-indazol-5-yloxy]-pyridin-3-yl}-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.54 mmol) is added, and the solution is heated to 80° C. for 30 minutes, then cooled to 50° C. and stirred for 16 hours. The reaction is then quenched by the addition of 10 mL water, and 1N hydrochloric acid is added to adjust the pH to 5. The aqueous layer is extracted with ethyl acetate (3×20 mL). The combined ethyl acetate layers are washed with saturated sodium chloride, dried with magnesium sulfate, filtered, and concentrated under vacuum to produce crude product. This material is chromatographed on silica gel (ISCO MPLC purification, 30 minutes, 50-100% ethyl acetate gradient, Biotage flash 40s column) to provide 1-{6-[1-(4-Cyano-phenyl)-1H-indazol-5-yloxy]-pyridin-3-yl}-1,7,9-triaza-spiro[4.5]decane-6,8,10-trione.