Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([C@@H:23]4[CH2:27][CH2:26][C@@H:25]([NH:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH2:24]4)=[N:21][N:22]=3)[C:14]=2[CH:13]=[CH:12]1)(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+].CC(O)=O>O1CCOCC1>[C:20]1([C@@H:23]2[CH2:27][CH2:26][C@@H:25]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:24]2)[N:19]2[C:14]3[CH:13]=[CH:12][NH:11][C:15]=3[N:16]=[CH:17][C:18]2=[N:22][N:21]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@@H]4CC[C@@H](Nc5ccccc5)C4)n23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: c1ccc(N[C@@H]2CC[C@@H](c3nnc4cnc5[nH]ccc5n34)C2)cc1
Temperature: 60 °C
Yield: 74.3 %

Procedure:
To N-((1R,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)aniline (0.106 g, 0.224 mmol) in 1,4-dioxane (1 mL) was added NaOH (1 N aqueous, 1.12 mL, 1.12 mmol). The reaction mixture was heated at about 60° C. for about 1 h. AcOH (0.5 mL) was added and the crude reaction mixture was purified by RP-HPLC (Table 1, Method j) to give N-((1R,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)aniline (0.053 g, 74%) as a light yellow solid: LC/MS (Table 1, Method b) Rt=1.84 min; MS m/z: 319 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:3]=1[C:20](O)=[O:21].[NH2:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[S:25]1[CH:26]=[CH:27][N:28]=[C:24]1[NH:23][C:20]([C:3]1[C:4]([CH2:16][CH:17]([CH3:19])[CH3:18])=[N:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([F:14])([F:15])[F:13])=[O:21]
Reactant: CC(C)Cc1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)O
Reactant: Nc1nccs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CC(C)Cc1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Yield: 31.9 %

Procedure:
Using the procedure of Step F of Example 6, 10.02 g of the product of Step E and 3.2 g of 2-aminothiazole were reacted in the presence of dicyclohexylcarbodiimide in dimethylformamide to obtain 4.03 g of N-(2-thiazolyl)-4-hydroxy-2-(2-methylpropyl)-8-trifluoromethyl-quinoline-3-carboxamide in the form of colorless crystals melting at 170°-171° C after crystallization from isopropanol.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[CH:6]([CH2:9][C:10](O)=[O:11])[O:7][CH2:8][C:4]=2[CH:3]=1>C1COCC1>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[CH:6]([CH2:9][CH2:10][OH:11])[O:7][CH2:8][C:4]=2[CH:3]=1
Reactant: O=C(O)CC1OCc2cc(Cl)ccc21
Solvent: C1CCOC1
Product: OCCC1OCc2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(5-Chloro-1,3-dihydro-2-benzofuran-1-yl)acetic acid (1.91 g, 9.0 mmol) was dissolved in dry THF (8 mL) under nitrogen and cooled to 0° C. Borane-dimethylsulfide complex (0.155 mL, 1.64 mmol) was added by syringe. After 1 h the cooling bath was removed and the solution was stirred at room temperature for 2 h. The solution was partitioned between saturated aqueous sodium hydrogen carbonate and diethyl ether. The aqueous layer was further extracted with ether, and the combined organic layers washed with brine, dried (MgSO4), filtered and concentrated in vacuo. This yielded the title compound as a white solid (>98% ee by chiral HPLC).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:30][CH2:29][CH2:28][C@@H:27]([CH2:31][O:32][Si:33]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])[CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C>[CH:40]([Si:33]([CH:34]([CH3:36])[CH3:35])([CH:37]([CH3:39])[CH3:38])[O:32][CH2:31][C@@H:27]1[CH2:28][CH2:29][CH2:30][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:26]1)([CH3:41])[CH3:42]
Reactant: CC(C)[Si](OC[C@@H]1CCCN(c2nnc3ccc(F)cn23)C1)(C(C)C)C(C)C
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)[Si](OC[C@@H]1CCCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)C1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 57.1 %

Procedure:
To a solution of Intermediate A (140 mg, 0.860 mmol) in dry DMF (2 mL) at RT under Ar was added NaH (60% dispersion in oil, 49.0 mg, 1.23 mmol) (CARE: gas evolution) and the resulting brown suspension was stirred at RT for 45 min. A solution of Intermediate 77b (333 mg, 0.819 mmol) in dry DMF (2 mL) was added and the resulting dark brown solution stirred at 60° C. under Ar for 2.5 h. The solution was concentrated in vacuo, redissolved in MeOH (2 mL) and AcOH (0.100 mL), then applied to and SCX-2 cartridge, and washed with MeOH (100 ml). The product was eluted with 2M NH3 in MeOH (75 mL); concentration in vacuo left a viscous dark brown oil. FCC, using 2-7% [2M NH3 in MeOH] in DCM, gave the title compound as a yellow-brown viscous oil (257 mg, 57%). LCMS (Method 3): Rt 3.27 min, m/z 550 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][N:29]2[CH:33]=[CH:32][N:31]=[CH:30]2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26]C)=[O:25])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl>>[ClH:1].[C:24]([CH2:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[CH:12]([NH:11][S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:10])=[O:9])[CH2:28][N:29]2[CH:33]=[CH:32][N:31]=[CH:30]2)=[CH:17][CH:18]=1)([OH:26])=[O:25]
Reactant: COC(=O)CCc1ccc(NC(=O)C(Cn2ccnc2)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: Cl
Product: O=C(O)CCc1ccc(NC(=O)C(Cn2ccnc2)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 191.3 %

Procedure:
The procedure described in Example 92 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)-N-(4-(2-methoxycarbonylethyl)phenyl) propanamide (74 mg) was hydrolyzed, and then reacted with HCl to obtain (RS)-N-(4-(2-carboxyethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide hydrochloride (74 mg).
Reaction SMILES: C1COCC1.[C:6](#[N:8])[CH3:7].C([Li])CCC.[CH3:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][N:24]=1)[C:18]([O:20]C)=O>CC(O)=O>[CH3:14][C:15]1[CH:16]=[C:17]([C:18](=[O:20])[CH2:7][C:6]#[N:8])[CH:22]=[CH:23][N:24]=1
Reactant: COC(=O)c1ccnc(C)c1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc(C(=O)CC#N)ccn1
Temperature: -78 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a 50 ml flask was added 8 ml of THF, acetonitrile (156 μl, 2.98 mmole), the mixture was cooled to −78° C. and then n-butyllithium (1191 μl, 2.98 mmole, 2.5 m in hexanes) was added. The reaction was stirred for 30 minutes at which time methyl 2-methylisonicotinate 16.1.B (150 mg, 0.99 mmoles) was added as a 2 ml THF solution. After 2 hour at −78° C., 500 μL of AcOH was added and the reaction was warmed to room temperature. The solvent was removed and the crude was purified on a silica gel column (eluting with 2% MeOH in DCM) to give 3-(2-methylpyridin-4-yl)-3-oxopropanenitrile 16.1.C as a light orange solid (170 mg 100% yield).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([O:27][CH3:28])[CH:10]=2)=[O:4].CO.[OH-].[Li+].Cl>O1CCCC1>[CH3:28][O:27][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[CH:5]([C:3]([OH:4])=[O:2])[CH:18]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH:17]1[CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: COC(=O)C1c2ccc(OC)cc2C2CCCCC2C1c1ccc(OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C2C(C(=O)O)c3ccc(OC)cc3C3CCCCC32)cc1
Reaction time: 18 h
Yield: 97.7 %

Procedure:
Combine 6-methoxy-10-(4-methoxy-phenyl)-1,2,3,4,4a,9,10,10a-octahydro-phenanthren-9-carboxylic acid methyl ester (1.03 g, 2.71 mmol), Methanol (20.0 mL), tetrahydrofuran (2 mL), and lithium hydroxide aqueous (5 mL), stir at reflux. After 18 hours, add 5N HCl until reaction is acidic, then extract with ethyl acetate and wash with brine. Dry the organic phase with anhydrous sodium sulfate then concentrate to yield the titled compound (0.97 g, 97%) as a white solid. TLC Rf=0.41 in 3% methanol in DCM. 1H NMR (DMSO): 12.30 (s, 1H), 7.25 (m, 3H), 6.92 (m, 3H), 6.82 (dd, 1H, J=8.6, 2.4 Hz), 4.18 (d, 1H, J=12.3 Hz), 3.76 (m, 6H), 3.42 (dd, 1H, J=12.6, 2.4 Hz), 3.27 (s, 1H), 2.50 (m, 1H), 1.89 (m, 1H), 1.59 (m, 2H), 1.40 (m, 1H), 1.23 (m, 1H), 0.99 (m, 3H); MS m/z 322 (M−44, decarbonylation).
Reaction SMILES: [OH:1][O:2][S:3]([OH:6])(=[O:5])=[O:4].[C:7]([OH:10])(=[O:9])[CH3:8]>>[OH:1][O:2][S:3]([OH:6])(=[O:5])=[O:4].[C:7]([O:10][OH:1])(=[O:9])[CH3:8]
Reactant: CC(=O)O
Agent: O=S(=O)(O)OO
Product: CC(=O)OO
Temperature: 35 °C
Reaction time: 1 h

Procedure:
The Caro's acid mixture was cooled to 25° C., and 240.0 g of glacial acetic acid (4.0 moles) was added at once with rapid stirring. Temperature of the mixture rose to 42° C. The mixture was cooled to 35° C. and stored for one hour. At the end of this period a sample of the mixture was removed to determine its residual hydrogen peroxide and its active oxygen content as peracid (assumed to be a mixture of Caro's acid and peracetic acid). This was done by first analyzing the sample for hydrogen peroxide by the standard ceric sulfate titration method. Potassium iodide was then added to the titrated sample and the active oxygen content of the sample was measured by titrating the iodine released (from the reaction of the iodide with the peracid) with sodium thiosulfate. The results are shown below:
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].I[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].N1CCC[C@H]1C(O)=O>CS(C)=O.O.[Cu]I>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:5]=1)([O-:3])=[O:2]
Reactant: FC(F)(F)c1cccc(I)c1
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccn(-c2cccc(C(F)(F)F)c2)n1
Temperature: 85 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of 3-nitro-1H-pyrazole (10 g, 88.50 mmol, 1.00 equiv) in DMSO (100 mL), 1-iodo-3-(trifluoromethyl)benzene (29 g, 106.62 mmol, 1.20 equiv), potassium carbonate (24 g, 173.91 mmol, 1.97 equiv), copper(I) iodide (2.6 g, 13.68 mmol, 0.15 equiv), and L-proline (2.5 g, 21.74 mmol, 0.25 equiv). The resulting solution was stirred overnight at 85° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting solution was diluted with 500 mL of water, extracted with 7×200 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×200 mL of water and 2×200 mL of brine. The mixture was dried over sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (10:1-5:1) to give 14 g (62%) of 3-nitro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazole as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][NH:11][CH2:10][C@H:9]2[C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Br[C:27]1[S:28][CH:29]=[CH:30][N:31]=1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11]([C:27]3[S:28][CH:29]=[CH:30][N:31]=3)[CH2:10][C@H:9]2[C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:3]=1
Reactant: Brc1nccs1
Reactant: COC(=O)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1CN(c2nccs2)C[C@H]1c1ccc(Cl)cc1
Reaction time: 0.33 h
Yield: 24.2 %

Procedure:
The product of Step A in Preparation 17, methyl (3S,4R)-4-(4-chlorophenyl)pyrrolidine-3-carboxylate (0.46 g, 1.92 mmol) was dissolved in 1,4-dioxane (2 ml). DIPEA (1.34 ml, 7.67 mmol) and 2-bromo-1,3-thiazole (1.57 g, 9.6 mmol) were added. The reaction was conducted at 180° C. for 20 minutes with microwave. Then, the reaction mixture was concentrated in vacuo. The obtained residue was diluted with EtOAc, washed with water and purified by column chromatography (eluent: EtOAc/Hex=1/3) to give the title compound (0.15 g, 25%).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:14])[C:4]([C:12]#[N:13])=[C:5]([C:10]#[N:11])[C:6](=[O:9])[C:7]=1[Cl:8]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[C:5]([C:10]#[N:11])=[C:4]([C:12]#[N:13])[C:3]=1[OH:14]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: N#Cc1c(O)c(Cl)c(Cl)c(O)c1C#N
Temperature: 0 °C

Procedure:
By way of general guidance,a toluene solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone is added to a toluene solution of a compound of formula (III-i) while maintaining a reaction temperature of about 0° C. to about 10° C. after which the reaction temperature is maintained at about 0° C. for about 1 hour to form a toluene slurry of 2,3-dichloro-5,6-dicyano-1,4-dihydroxybenzene and a compound of formula (IV-i). The slurry is filtered to remove the 2,3-dichloro-5,6-dicyano-1,4-dihydroxybenzene; the resulting waste cake of the 2,3-dichloro-5,6-dicyano-1,4-dihydroxybenzene is washed with toluene. The filtrate and toluene washings are combined and concentrated in vacuo with addition of methanol to remove most of the toluene and produce the compound of formula (IV-i) in methanol at a temperature of about 40° C. to about 45° C. To this solution an aqueous solution of sodium hydroxide is added dropwise to form a clear solution of the amino alcohol (V-i) and p-methoxybenzaldehyde upon which a solution of NaBH4 in an aqueous solution of sodium hydroxide is added dropwise, all the time maintaining a reaction temperature of about 40° C. to about 45° C. Upon addition of the solution of NaBH4 in an aqueous solution of sodium hydroxide, the reaction solution is stirred for about 30 minutes after which glacial acetic acid is added to neutralize the reaction to a pH of about 8 to about 9. Upon neutralization water is added to form a slurry and the slurry is cooled to about -15° C. to about 0° C. for about 1 hour. The cooled slurry of the amino alcohol (V-i) is filtered and washed with water to give the crude crystalline amino alcohol (V-i) as a pale yellow solid.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.[Cl:7][CH2:8][CH:9]=O.C([O-])(O)=O.[Na+]>CO.CC(O)=O.Cl>[Cl:7][CH2:8][CH2:9][N:4]1[CH2:5][CH2:6][C@@H:2]([OH:1])[CH2:3]1
Reactant: O=CCCl
Reactant: O[C@@H]1CCNC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O[C@@H]1CCN(CCCl)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.1 %

Procedure:
To a solution of (R)-3-hydroxypyrrolidine (0.47 g, 5.5 mmol) in MeOH (14.4 mL) and AcOH (1.44 mL) was added chloroacetaldehyde (0.86 mL, 5.5 mmol, 50% in H2O solution) and picolineborane complex (0.58 g, 5.5 mmol). The reaction mixture was stirred at ambient temperature for 0.5 h. Then additional picoline borane complex (0.29 g, 2.7 mmol) was added. The reaction mixture was stirred for an additional 0.5 h. Then the reaction mixture was diluted with HCl (30 mL, 10% in H2O) and stirred for 0.5 h at ambient temperature. The mixture was slowly basified with solid NaHCO3 (7.85 g) and extracted with EtOAc (3×20 mL). The organics extracts were dried (Na2SO4) and concentrated to yield the title compound (0.19 g, 23%) as a light yellow oil. 1H NMR (300 MHz, CD3OD) δ 4.36-4.32 (m, 1H), 3.63 (t, J=6.6 Hz, 2H), 2.91-2.76 (m, 4H), 2.66-2.52 (m, 3H), 2.16-2.09 (m, 1H), 1.74-1.70 (m, 1H).
Reaction SMILES: [OH-].[Li+].[CH3:3][C:4]([C:11]#[C:12][Se:13][C:14]1[CH:23]=[CH:22][C:21]2[C:20]([CH3:25])([CH3:24])[CH2:19][CH2:18][C:17]([CH3:27])([CH3:26])[C:16]=2[CH:15]=1)=[CH:5][C:6]([O:8]CC)=[O:7].O.CO.Cl>C1COCC1.C(OCC)C.O>[CH3:3][C:4]([C:11]#[C:12][Se:13][C:14]1[CH:23]=[CH:22][C:21]2[C:20]([CH3:25])([CH3:24])[CH2:19][CH2:18][C:17]([CH3:27])([CH3:26])[C:16]=2[CH:15]=1)=[CH:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C=C(C)C#C[Se]c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C#C[Se]c1ccc2c(c1)C(C)(C)CCC2(C)C)=CC(=O)O

Procedure:
Lithium hydroxide (500 mg) is added to a solution of ethyl 3-methyl-5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)pent-2-en-4-ynoate (500 mg, 1.24 mmol) in 10 ml of THF. 2 ml of a water/methanol mixture (1/1) are added. The reaction medium is refluxed for 8 h. It is then poured into an ethyl ether/water mixture, acidified to pH 1 with concentrated hydrochloric acid solution and extracted with ethyl ether. After separation of the phases by settling, the organic phase is washed twice with water, dried over anhydrous magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24]Br)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:31][NH:32][CH2:33][CH2:34][OH:35]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24][N:32]([CH2:33][CH2:34][OH:35])[CH3:31])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CNCCO
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCBr
Solvent: CN(C)C=O
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN(C)CCO
Reaction time: 48 h
Yield: 74.1 %

Procedure:
4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide (250 mg, 0.51 mmol.) and 2-(methylamino)-ethanol(97 mg, 1.02 mmol.) were dissolved with stirring, under nitrogen, in 9 ml anhydrous dimethylformamide. After 48 hours, the mixture was partitioned between saturated sodium bicarbonate solution, and ethyl acetate. The organic phase was seperated, dried over magnesium sulfate, filtered, and evaporated to give a gum. It was chromatographed on silica gel, and eluted with 40/4/1 (ethyl acetate/methanol/triethylamine) producing 183 mg (74%) of the purified product as a yellow solid: mp 210-214° C.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][O:6][CH:5]([C:9]([OH:11])=O)[CH2:4]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:45]1[C:53]2[C:48](=[C:49]([C:54]3[CH:55]=[C:56]([NH2:63])[C:57]4[CH:58]=[N:59][NH:60][C:61]=4[CH:62]=3)[CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46]1>CN(C=O)C>[NH:45]1[C:53]2[C:48](=[C:49]([C:54]3[CH:62]=[C:61]4[C:57]([CH:58]=[N:59][NH:60]4)=[C:56]([NH:63][C:9]([CH:5]4[O:6][CH2:7][CH2:8][N:3]([CH3:2])[CH2:4]4)=[O:11])[CH:55]=3)[CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46]1
Reactant: CN1CCOC(C(=O)O)C1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
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
Product: CN1CCOC(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)C1
Reaction time: 0.08 h

Procedure:
4-Methyl-2-morpholinecarboxylic acid hydrochloride (40 mg, 0.22 mmol) was treated with HATU (84 mg, 0.22 mmol) in DMF (0.250 mL) and DIPEA (0.069 mL, 0.40 mmol). The mixture was shaken for five minutes prior to treatment with 6-(1H-indol-4-yl)-1H-indazol-4-amine (25 mg, 0.1 mmol) in DMF (0.25 mL). Reaction mixture was left to stand at room temperature for 18 hrs. Solvent was removed in vacuo and the product re-dissolved in chloroform (0.3 mL) prior to application on to a pre-conditioned (methanol then chloroform) NH2 cartridge (0.5 g). Product was eluted after 2 hr with ethyl acetate/methanol (1:1, 3 mL), and concentrated under a stream of nitrogen using blow down apparatus. Purification by MDAP (Method D) afforded the title compound.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:32]2[N:41]=[CH:40][C:39]3[C:34](=[C:35]([F:46])[CH:36]=[C:37]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:38]=3)[C:33]2=[O:47])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:29]=[C:22]3[CH2:23][N:24]([CH3:28])[C:25](=[O:27])[CH2:26][N:21]3[N:20]=2)[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=1)(=O)C.[OH-].[Li+]>C1COCC1.C(O)(C)C.O>[C:42]([C:37]1[CH:38]=[C:39]2[C:34](=[C:35]([F:46])[CH:36]=1)[C:33](=[O:47])[N:32]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:29]=[C:22]5[CH2:23][N:24]([CH3:28])[C:25](=[O:27])[CH2:26][N:21]5[N:20]=4)[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=3)[CH:10]=[CH:9][N:8]=1)[N:41]=[CH:40]2)([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CC(=O)N(C)C4)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CN1Cc2cc(Nc3cc(-c4ccnc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)cn(C)c3=O)nn2CC1=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 43.7 %

Procedure:
To a solution of 146f (110 mg, 0.172 mmol) in THF/i-propanol/water (4/2/2 mL) was added lithium hydroxide (21 mg, 0.86 mmol). The mixture was stirred at 30° C. for 1 h. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layer was dried and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 146 as a white solid (45 mg, 44%). MS-ESI: [M+H]+ 599.2. 1H NMR (500 MHz, DMSO-d6) δ 8.57 (d, J=5.0 Hz, 1H), 8.54 (d, J=2.5 Hz, 1H), 8.41 (s, 1H), 8.08 (d, J=2.5 Hz, 1H), 7.91 (d, J=1.5 Hz, 1H), 7.78 (d, J=13.0 Hz, 1H), 7.51 (d, J=5.0 Hz, 1H), 7.42 (d, J=2.5 Hz, 1H), 6.08 (s, 1H), 4.91-4.89 (m, 1H), 4.62 (s, 2H), 4.57 (s, 2H), 4.45-4.43 (m, 2H), 3.61 (s, 3H), 2.98 (s, 3H), 1.40 (s, 9H).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[C:8]([C:12]1C=C(O)C(=C[CH:18]=1)O)(C)(C)[CH3:9].S(CCC(OCCCCCCCCCCCC)=O)CCC(OCCCCCCCCCCCC)=O.O=O>>[CH2:9]1[CH:2]2[C:1]([O:6][C:4](=[O:5])[CH:3]2[CH2:18][CH:12]=[CH:8]1)=[O:7]
Reactant: CC(C)(C)c1ccc(O)c(O)c1
Reactant: O=C1C=CC(=O)O1
Agent: CCCCCCCCCCCCOC(=O)CCSCCC(=O)OCCCCCCCCCCCC
Agent: O=O
Product: O=C1OC(=O)C2CC=CCC12

Procedure:
3Me--THPA was produced by a combination of replacement and liquid phase aeration method. Thus, the reaction procedure of Example 8 was repeated except that the respective amounts of maleic anhydride, radical polymerization inhibitor p-tert-butylcatechol and auxiliary polymerization inhibitor dilauryl thiodipropionate were melted at 60° C. and the internal atmosphere was replaced with nitrogen gas containing 1 volume % of oxygen. Then, the same oxygen-containing nitrogen gas was introduced into the liquid phase at a rate of 5 ml/min. The procedure gave 164 g of 3Me--THPA. The investigation revealed no gels in the product.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[O:9][N:8]=1)(=O)=O.[N-:16]=[N+:17]=[N-:18].[Na+].O>CN(C=O)C>[N:16]([CH2:6][C:7]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[O:9][N:8]=1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCc1cc(C(F)(F)F)on1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cc(C(F)(F)F)on1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.8 %

Procedure:
To a solution of 8.7 g (5-(trifluoromethyl)isoxazol-3-yl)methyl methanesulfonate in 87 mL DMF was added 9.23 g sodium azide. The reaction mixture was stirred 3 h at RT. 80 mL water was added under cooling. The mixture was extracted with diethyl ether (3×100 mL) and the organic layers were washed with water (3×100 mL) and then with sat. NaCl solution (1×100 mL). The combined organic layer was dried over Na2SO4, filtered off and concentrated in vacuo to yield 6.26 g of the title compound as a brown oil.