Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[CH2:3]([CH2:10][C:11](=[O:13])[CH3:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O>CO>[Br:1][CH2:12][C:11](=[O:13])[CH2:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrBr
Reactant: CC(=O)CCc1ccccc1
Solvent: O
Solvent: CO
Product: O=C(CBr)CCc1ccccc1
Temperature: 8.5 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
A freshly prepared solution of bromine (258.9 g) in methanol (600 mL) was added dropwise during 1 h 20 min to a stirred solution of benzylacetone (222.3 g) in methanol (600 mL) at 7-10° C. An exothermic reaction took place, and to maintain the necessary temperature (7-10° C.), the flask should be immersed in a ice-water bath. When orange-red color of bromine disappeared, water (1500 mL) was added to the mixture and the obtained mixture was stirred overnight. The organic layer (on the bottom) was separated, water phase was extracted with dichloromethane (2×600 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated under reduced pressure. The oily residue was dissolved in hexane (2500 mL) and the obtained solution was kept overnight at −10° C. Precipitated fine crystals (needles) were filtered off, washed on filter with cold hexane, dried under reduced pressure at room temperature to give 1-bromo-4-phenyl-2-butanone (213.0 g, 63% yield), mp 39-40° C. 1H NMR (CDCl3) δ 2.95-3.00 (m, 4H); 3.83 (s, 2H); 7.16-7.30 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](I)=[CH:11][C:10]([NH2:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:15][C:16]([F:28])([F:27])[O:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C(=O)([O-])O.[Na+]>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([O:17][C:16]([F:15])([F:27])[F:28])[CH:19]=3)=[CH:11][C:10]([NH2:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: Nc1cc(I)n(-c2cccc(F)c2)n1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: COCCOC
Product: Nc1cc(-c2cccc(OC(F)(F)F)c2)n(-c2cccc(F)c2)n1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution of 1-(3-fluorophenyl)-5-iodo-1H-pyrazol-3-ylamine (263 mg) in ethylene glycol dimethyl ether (5 ml) were sequentially added 3-(trifluoromethoxy)phenylboronic acid (197 mg), a 2M aqueous solution of sodium carbonate (2.5 ml), tricyclohexylphosphine (49 mg), palladium acetate (20 mg), and the mixture was stirred for 2 hours at reflux. This reaction mixture was cooled to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added thereto, and then the mixture was filtered through Celite. The filtrate was extracted with ethyl acetate, the resulting organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1) to give the titled compound (234 mg).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[CH2:8][O:9][CH:10]1[CH2:13][NH:12][CH2:11]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[O:45]=[C:46]1[NH:55][C:54]2[N:53]=[CH:52][C:51](/[CH:56]=[CH:57]/[C:58](O)=[O:59])=[CH:50][C:49]=2[CH2:48][CH2:47]1>CN(C)C=O>[CH3:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[CH2:8][O:9][CH:10]1[CH2:11][N:12]([C:58](=[O:59])/[CH:57]=[CH:56]/[C:51]2[CH:50]=[C:49]3[C:54](=[N:53][CH:52]=2)[NH:55][C:46](=[O:45])[CH2:47][CH2:48]3)[CH2:13]1
Reactant: Cc1ccsc1COC1CNC1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccsc1COC1CN(C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)C1
Reaction time: 8 h
Yield: 43 %

Procedure:
3-((3-methylthiophen-2-yl)methoxy)azetidine hydrochloride (129.0 mg, 0.6 mmol), EDCI (112.0 mg, 0.6 mmol), HOBt (82.0 mg, 0.6 mmol) and diisopropylethylamine (170 μL, 1.0 mmol) were successively added to a solution of (E)-3-(7-Oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acid hydrochloride (100.0 mg, 0.4 mmol) in dimethylformamide (10 mL) at room temperature. The reaction mixture was stirred overnight and then partitioned between ethyl acetate (30 mL) and water (30 mL). The aqueous layer was separated and extracted with ethyl acetate (2×20 mL). The combined organic phases were washed with a saturated solution of sodium chloride (3×30 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel, using dichloromethane/methanol (100:0 to 95:5) as eluent. The residue was triturated in acetone to give a white solid (66.0 mg, 44%).
Reaction SMILES: C([O-])(=O)C.[Ni+2:5].C([O-])(=O)C.CCOCCO.[CH3:16][NH:17][C:18]1[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:20]([OH:22])=[O:21]>O>[Ni:5].[CH3:16][NH:17][C:18]1[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:20]([OH:22])=[O:21]
Reactant: [Ni+2]
Agent: CC(=O)[O-]
Agent: CNc1ccccc1C(=O)O
Solvent: O
Solvent: CCOCCO
Product: [Ni]
Temperature: 50 °C
Reaction time: 1 h

Procedure:
23.8 g (0.1 mol) of nickel acetate was added to 500 ml of ethyl cellosolve and stirred. The mixture was heated to 50° C., and 30.2 g (0.2 mol) of N-methyl-anthranilic acid was gradually added. The mixture was subjected to reaction for 2 hours at about 130° C. under refluxing and then dispersed in 2 liters of water. After 1 hour, the dispersion was subjected to filtration and the precipitate was washed with water until neutrality. The precipitate was then dried at 90° C. to obtain about 29 g of pale blue powder.
Reaction SMILES: [CH2:1]([C:3]1([CH3:14])N=[C:7]([CH2:9][CH3:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4]1)[CH3:2].C(C(C)=[O:18])C.O.O.[Cl-].[Ca+2].[Cl-].[OH-].[Na+]>O>[CH2:1]([C:3]1([CH3:14])[CH:9]([CH3:10])[C:7](=[O:18])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4]1)[CH3:2]
Reactant: CCC1=NC(C)(CC)NC(C)(CC)C1
Reactant: CCC(C)=O
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCC1(C)CC(=O)C(C)C(C)(CC)N1
Temperature: 60 °C
Reaction time: 15 h
Yield: 82.2 %

Procedure:
To an ice-cooled mixture of 39.2 g of 2,4,6-triethyl-2,6-dimethyl-1,2,5,6-tetrahydropyrimidine and 18.0 g of methyl ethyl ketone were added 14.7 g of powdered calcium chloride dihydrate, followed by 3 ml of water. The resulting mixture was heated at 60° C, with stirring, for 15 hours, made alkaline by the addition of a 35% aqueous solution of sodium hydroxide and extracted with diethyl ether. The etheral solution was then dried over potassium carbonate and the diethyl ether was evaporated off. The residue was distilled under reduced pressure, giving 32.4 g of the title compound. Boiling point 91° - 93° C/2.0 mmHg.
Reaction SMILES: C(O[C:4](=[O:10])[CH:5]([CH2:8]Br)[CH2:6]Br)C.[C:11]1(N2CCCC2)[CH2:15]C[CH2:13][CH:12]=1.CCN(C(C)C)C(C)C.CCOC(C)=O>CC#N>[O:10]=[C:4]1[CH:5]2[CH2:6][CH2:15][CH:11]1[CH2:12][CH2:13][CH2:8]2
Reactant: C1=C(N2CCCC2)CCC1
Reactant: CCOC(=O)C(CBr)CBr
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1C2CCCC1CC2

Procedure:
3-Bromo-2-bromomethyl-propionic acid ethyl ester (5.48 g, 20 mmol) was added to a mixture of 1-cyclopent-1-enyl-pyrrolidine (2.74 g, 20 mmol) and Hünig's base (3.5 mL) in MeCN (15 mL) with vigorous stirring. An exothermic reaction ensued, bringing the mixture to reflux. The mixture was refluxed for 16 h, cooled, and poured into 100 mL of EtOAc with stirring. The resulting solid (3.33 g) was collected by filtration, dissolved in 0.5 M aqueous HCl (100 mL) and stirred with EtOAc (100 mL) for 48 h. The organic layer was separated and concentrated to give 8-oxo-bicyclo[3.2.1]octane-endo-3-carboxylic acid ethyl ester (1.0 g, 5.1 mmol) as a colourless oil. This was dissolved in EtOH (50 mL),treated with a solution of hydroxylamine hydrochloride (1.04 g, 15 mmol) and sodium acetate trihydrate (2.04 g, 15 mmol) in water (10 mL) and heated at reflux for 16 h. The solution was cooled, concentrated, diluted with water (100 mL) and extracted with DCM. The DCM extracts were dried (MgSO4), concentrated and purified by flash chromatography (20→30% EtOAc/hexane) to give the oxime (270 mg) as a colourless oil. 1H NMR (CDCl3, 360 MHz) δ 9.85 (1 H, bs, N—OH), 4.20 (2 H, q, J=7.1 Hz, CH2—O), 3.36 (1 H, bs, bridgehead H), 2.63-2.56 (4 H, m), 2.15-2.04 (2 H, m), 1.76-1.69 (4 H, m), 1.30 (3 H, t, J=7.1 Hz, —Me). m/z 212 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=O.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=2)[N:8]=[CH:7][N:6]=1
Reactant: O=c1[nH]cnc2ccc(I)cc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2ccc(I)cc12

Procedure:
6-Iodoquinazolin-4(3H)-one (10 g, 37 mmol) was refluxed in POCl3 (100 mL) overnight. Then POCl3 was removed in vacuo. The residue was dissolved in CH2Cl2 (500 mL). The organic phase was washed with water (100 mL) and dried (MgSO4). Then CH2Cl2 was removed in vacuo and 1404-174 was obtained (5.7 g, 53%): LC-MS: 291 [M+1]+, 1H NMR (CDCl3): δ 7.81 (d, J=9.0 Hz, 1 H), 8.21 (dd, J=9.0 Hz, J2=1.8 Hz, 1 H), 8.65 (d, J=1.8 Hz, 1 H), 9.06 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:19]1[CH:27]=[C:26]2[C:22]([C:23]([NH:36][C:37](=[O:41])[CH2:38][CH2:39][CH3:40])=[N:24][N:25]2[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[CH:21][CH:20]=1>O.O1CCOCC1.C(OCC)(=O)C.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>[Cl:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:27]=[C:26]3[C:22]([C:23]([NH:36][C:37](=[O:41])[CH2:38][CH2:39][CH3:40])=[N:24][N:25]3[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:33])[CH3:34])=[CH:21][CH:20]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Br)ccc12
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3cc(Cl)cc(Cl)c3)ccc12
Yield: 81.6 %

Procedure:
0.44 g of 3,5-dichlorophenylboronic acid, 0.64 g of sodium carbonate dissolved in 18 cm3 of water and 0.186 g of tetrakis(triphenylphosphine)palladium are added to 1 g of N-[6-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 30 cm3 of dioxane, and the mixture is refluxed for 18 hours. The reaction medium is diluted with 75 cm3 of ethyl acetate and 50 cm3 of water and the medium is then filtered through a sinter funnel packed with Celite and is concentrated to dryness under reduced pressure (2 kPa; 50° C.). The work-up and the purification are performed by analogy with Example 41. 0.90 g of N-[6-(3,5-dichlorophenyl)-1-[(2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide is thus obtained in the form of a yellow wax.
Reaction SMILES: CO[C:3](=[O:19])[C@H:4]([CH2:15][CH:16]([CH3:18])[CH3:17])[NH:5][C:6]([NH:8][C:9]1[S:10][C:11](=[S:14])[NH:12][N:13]=1)=[O:7].[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[S:14]=[C:11]1[S:10][C:9]([NH:8][C:6]([NH:5][C@@H:4]([CH2:15][CH:16]([CH3:17])[CH3:18])[C:3]([NH:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])=[O:7])=[N:13][NH:12]1
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)Nc1n[nH]c(=S)s1
Reactant: NCc1ccccc1
Product: CC(C)C[C@H](NC(=O)Nc1n[nH]c(=S)s1)C(=O)NCc1ccccc1

Procedure:
Following the general procedure outlined in EXAMPLE 5, and making non-critical variations but starting with N-[[(4,5-dihydro-5-thioxo-1,3,4-thiadiazol-2-yl)amino]carbonyl]-L-leucine methyl ester (EXAMPLE 28) and benzylamine, the title compound is obtained (mp 206°-208° C.).
Reaction SMILES: [F:1][C:2]1([F:22])[CH2:5][CH:4]([NH:6][C:7](=[O:21])[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:9]=2)[CH2:3]1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][C:25]=1[F:33].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([N:18]2[CH2:17][CH2:16][N:15]([CH2:14][C:10]3[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=3)[C:7]([NH:6][CH:4]3[CH2:5][C:2]([F:1])([F:22])[CH2:3]3)=[O:21])[CH2:20][CH2:19]2)=[O:29])=[CH:26][C:25]=1[F:33]
Reactant: O=C(NC1CC(F)(F)C1)c1cccc(CN2CCNCC2)c1
Reactant: Nc1ccc(C(=O)O)cc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1ccc(C(=O)N2CCN(Cc3cccc(C(=O)NC4CC(F)(F)C4)c3)CC2)cc1F
Reaction time: 1 h
Yield: 54.7 %

Procedure:
N-(3,3-Difluorocyclobutyl)-3-(piperazin-1-ylmethyl)benzamide (5.14 mmol, 1.59 g), 4-amino-3-fluorobenzoic acid (5.14 mmol, 0.797 g) and triethylamine (15.42 mmol, 2.143 mL, 1.560 g) were stirred in dichloromethane (30 mL) at room temperature. 1-Propanephosphonic acid cyclic anhydride (7.71 mmol, 4.59 mL, 4.91 g, 50% solution in ethyl acetate) was added dropwise and the reaction stirred for 1 hour. The reaction mixture was concentrated under vacuum and the residue taken up in ethyl acetate. The organic phase was washed with saturated sodium hydrogen carbonate solution, dried over sodium sulfate and concentrated under vacuum to afford the title compound (1.255 g). MS (ESI) m/z 447.5 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5]#[N:6].C(O)C.[NH2:14][OH:15]>O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5](=[N:14][OH:15])[NH2:6]
Reactant: NO
Reactant: Cc1ccc(C#N)cc1F
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(N)=NO)cc1F
Temperature: 25 °C
Yield: 91.6 %

Procedure:
To a suitable vessel equipped with mechanical stirrer under N2 atmosphere was charged 202.0 g of 3-fluoro-4-methylbenzonitrile followed by 1.0 L of ethanol. Hydroxylamine (144 mL of 50% solution in water) was added via addition funnel over 20 minutes. The mixture was stirred at ambient temperature until HPLC analysis showed that reaction was complete (no starting material remained). Water (3.0 L) was added dropwise to the pale yellow solution over 1 hour to give a thick slurry. The slurry was cooled in an ice water bath to 2° C. for 1.5 hours, filtered and dried under vacuum at 35° C. for 22 hours to give the title compound (230.3 g, 91.6%) as a white solid. 1H-NMR (CDCl3, 500 MHz) δ 7.30 (m, 2H), 7.19 (m, 1H), 4.87 (s, 2H), 2.28 (s, 3H); 13C-NMR (CDCl3, 500 MHz) δ162.15, 160.19, 151.58, 131.82, 131.76, 131.66, 131.62, 127.01, 126.87, 121.06, 112.69, 112.51, 14.48; 19F-NMR (CDCl3, 500 MHz) δ-116.35, −116.37, −116.39. LC-MS M+H169.19,
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13]([NH2:18])=[N:14][CH:15]=[C:16]([I:17])[C:11]=3[O:10][CH:9]=2)=[CH:4][C:3]=1[O:19][CH3:20].[CH3:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[C:31](Cl)=[O:32]>N1C=CC=CC=1>[NH2:18][C:13]1[C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:31]([C:23]4[N:22]([CH3:21])[C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[N:24]=4)=[O:32])=[C:3]([O:19][CH3:20])[CH:4]=3)=[CH:9][O:10][C:11]=2[C:16]([I:17])=[CH:15][N:14]=1
Reactant: COc1cc(-c2coc3c(I)cnc(N)c23)ccc1N
Reactant: Cn1c(C(=O)Cl)nc2ccccc21
Solvent: c1ccncc1
Product: COc1cc(-c2coc3c(I)cnc(N)c23)ccc1NC(=O)c1nc2ccccc2n1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 105.8 %

Procedure:
A solution of 3-(4-amino-3-methoxyphenyl)-7-iodofuro[3,2-c]pyridin-4-amine (1.50 g, 3.94 mmol) in pyridine (18 mL) was cooled to 0° C. and 1-methyl-1H-benzo[d]imidazole-2-carbonyl chloride (0.874 g, 3.33 mmol) was added. The mixture was stirred for 15 minutes at 0° C. and then allowed to rise to ambient temperature over an eighteen hour time period. The solvent was removed in vacuo and the residue was suspended in water (50 mL) and brought to pH 12 with 0.1 N aqueous sodium hydroxide. The suspension was extracted with dichloromethane (4×25 mL) and the combined organic layers were washed with brine (25 mL) and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give the title compound (1.90 g, 90%) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 10.18 (s, 1H), 8.49 (d, 1H), 8.14 (s, 1H), 8.08 (s, 1H), 7.85 (d, 1H), 7.76 (d, 1H), 7.46 (t, 1H), 7.39 (t, 1H), 7.30 (s, 1H), 7.19 (d, 1H), 5.77-5.89 (b, 2H), 4.24 (s, 3H), 4.03 (s, 3H); RP-HPLC (Conditions d) Rt 11.89 min.; MS: MH+ 540.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:31][C:32]([C:34]2[C:35](=[O:47])[N:36]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=3)[CH:37]=[CH:38][CH:39]=2)=[O:33])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:17]([N:18]2[CH2:23][CH2:22][O:21][CH:20]([CH3:24])[CH2:19]2)=[CH:16][C:15]2[C:11](=[CH:12][N:13](C3CCCCO3)[N:14]=2)[CH:10]=1.CO.CS(O)(=O)=O.C(Cl)Cl>CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:31][C:32]([C:34]2[C:35](=[O:47])[N:36]([C:40]3[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=3)[CH:37]=[CH:38][CH:39]=2)=[O:33])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[N:18]1[CH2:23][CH2:22][O:21][CH:20]([CH3:24])[CH2:19]1)[NH:14][N:13]=[CH:12]2
Reactant: CC1CN(c2cc3nn(C4CCCCO4)cc3cc2Oc2ccc(NC(=O)c3cccn(-c4ccc(F)cc4)c3=O)cc2F)CCO1
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: CC1CN(c2cc3[nH]ncc3cc2Oc2ccc(NC(=O)c3cccn(-c4ccc(F)cc4)c3=O)cc2F)CCO1
Temperature: 40 °C
Yield: 69.7 %

Procedure:
To a round bottom flask is added N-(3-fluoro-4-(6-(2-methylmorpholino)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-5-yloxy)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (66 mg, 102.86 μmol) and MeOH (5 mL, 123.54 mmol). To the resulting mixture is added MeSO3H (20.229 μL, 308.57 μmol) and the reaction mixture is heated to 40° C. for 6 hours. The reaction mixture is concentrated and dissolved in DCM (100 mL). The solution is washed with a mixture of saturated aqueous sodium chloride (20 mL) and saturated aqueous sodium bicarbonate solution (1×20 mL). The organic solution is extracted with DCM (1×25 mL) and dried over Na2SO4, filtered and concentrated. The residue is purified on a silica gel column eluting with DCM (A) and a 10% MeOH in DCM solution (B), gradient from 100% (A) to 70%(A):30%(B) over 60 min to give a light yellow solid as the desired product (40 mg, 62% yield). MS (m/z): 557.8 (M+H).
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[NH:3]1.Br[CH2:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[C:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C:7]2[C:2](=[O:1])[N:3]([CH2:30][C:31]3[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=3)[C:4]3[N:5]([N:26]=[CH:27][N:28]=3)[C:6]=2[CH2:23][CH2:24][CH3:25])=[CH:14][CH:13]=1)#[N:22]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(Cc2ccc(C(=O)OC)cc2)c2ncnn12
Temperature: 25 °C
Reaction time: 5 h
Yield: 40 %

Procedure:
A mixture of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (5 g), methyl 4-(bromomethyl)benzoate (3.7 mL), potassium carbonate (2.3 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 5 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution 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 (2.8 g, 40%).
Reaction SMILES: [CH2:1]([C@H:5]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:6]([OH:8])=[O:7])[CH:2]([CH3:4])[CH3:3].C([N-]C(C)C)(C)C.[Li+].[CH2:25](Br)[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(N)CCCCC1>O1CCCC1.CCCCCC>[C:13]([O:12][C:10]([C@@H:9]([C@@H:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:6]([OH:8])=[O:7])[CH2:25]/[CH:26]=[CH:27]/[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:11])([CH3:14])([CH3:16])[CH3:15]
Reactant: CC(C)C[C@H](CC(=O)OC(C)(C)C)C(=O)O
Reactant: BrCC=Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: NC1CCCCC1
Product: CC(C)C[C@@H](C(=O)O)[C@@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
A solution of 5.19 g of 4-tert-butyl hydrogen 2(R)-isobutylsuccinate in 50 ml of dry tetrahydrofuran was cooled to −78° C. while stirring under nitrogen. 25 ml of a 2M solution of lithium diisopropylamide in tetrahydrofuran was added dropwise and the mixture was stirred at −78° C. for 15 minutes. A solution of 5.55 g of cinnamyl bromide in 25 ml of dry tetrahydrofuran was then added dropwise and the mixture was left to come to room temperature gradually. After stirring overnight the tetrahydrofuran was evaporated and the residue was partitioned between ethyl acetate and 5% citric acid solution. The ethyl acetate layer was washed with two further portions of 5% citric acid solution, water and saturated sodium chloride solution and then dried over anhydrous magnesium sulphate. The solvent was evaporated to give an orange oil. This was dissolved in 100 ml of hexane to which 2.35 g of cyclohexylamine were added. The mixture was left to stand for 2 hours and the solid formed was collected by filtration. The solid was suspended in ethyl acetate and shaken with two portions of 2M sulphuric acid to give a clear solution. The ethyl acetate solution was washed twice with water and then with saturated sodium chloride solution and subsequently dried over anhydrous magnesium sulphate. After evaporation of the solvent there were obtained 6.41 g of (E)-2(R)-[1(R)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvaleric acid in the form of a pale cream coloured solid.