Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]([CH2:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH2:3][C:4]#[C:5][CH:6]([OH:8])[CH3:7]>C1COCC1.[O-2].[O-2].[Mn+4]>[CH3:1][C@H:2]([CH2:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH2:3][C:4]#[C:5][C:6](=[O:8])[CH3:7]
Reactant: CC(O)C#CC[C@H](C)COC1CCCCO1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: CC(=O)C#CC[C@H](C)COC1CCCCO1
Reaction time: 48 h
Yield: 94.1 %

Procedure:
A 300 g (1.3255 mol) solution of (2RS,6S)-6-methyl-7-[(RS)-(3,4,5,6-tetrahydro-2H-pyran-2-yl)oxy]hept-3-in-2-ol, dissolved in 600 ml of THF, is added by stirring to a suspension of 1500 g manganese dioxide in 2250 ml of THF, and stirring is continued at room temperature for 48 hours. The suspension is then filtered over silica gel and the solvent is removed in vacuo. 280 g of the product is obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:3]1.[Li]CCCC.[CH2:18]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=[O:24])[CH3:19].[Cl-].[NH4+]>C1COCC1>[CH2:18]([C:20]1[CH:21]=[C:22]([CH:23]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:5]=2)[OH:24])[CH:25]=[CH:26][CH:27]=1)[CH3:19]
Reactant: CCc1cccc(C=O)c1
Reactant: Cn1cnc(-c2ccccc2)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1cccc(C(O)c2nc(-c3ccccc3)nn2C)c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 79.5 %

Procedure:
To a solution of 1-methyl-3-phenyl-1H-1,2,4-triazole (284 mg, 1.8 mmol, see J. Chem. Soc., 1954, 3319-3322) in THF (112 mL) at −78° C. was added BuLi (1.15 mL, 1.6 M in hexanes, 1.8 mmol). The reaction was stirred for 5 minutes at -78° C. and a solution of intermediate 370.1 (200 mg, 1.5 mmol) in THF (2 mL) was added dropwise. The mixture was warmed to ambient temperature over 2 h. Ammonium chloride (80 mg) was added to the mixture and it was concentrated. Purification of the crude material afforded 350 mg of intermediate 370.2 as a white solid. LCMS 294.2 (M+H)+.
Reaction SMILES: [N:1]([C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[CH:6][C:5]=1[CH:11]=O)=[N+:2]=[N-:3].[NH2:13][C:14]1[C:21]([Cl:22])=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=1[Cl:23].C(N(CC)CC)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:1]([C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:13]/[C:14]1[C:15]([Cl:23])=[CH:16][C:17]([C:18]#[N:19])=[CH:20][C:21]=1[Cl:22])=[N+:2]=[N-:3]
Reactant: N#Cc1cc(Cl)c(N)c(Cl)c1
Reactant: [N-]=[N+]=Nc1c(Cl)cncc1C=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cc(Cl)c(/N=C/c2cncc(Cl)c2N=[N+]=[N-])c(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a cooled (0° C.) solution of 4-azido-5-chloropyridine-3-carbaldehyde (2.0 g, 10.95 mmol), 4-amino-3,5-dichlorobenzonitrile (2.05 g, 10.95 mmol) and triethylamine (4.6 mL, 6.57 mmol) in DCM (48 mL) was added titanium tetrachloride (1M in DCM, 6.6 mL, 6.57 mmol) dropwise over 10 minutes. The reaction mixture was stirred for 20 minutes, warmed to room temperature, and stirred for an additional 30 minutes. The resultant mixture was concentrated to dryness under reduced pressure to afford the title compound which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[CH:12]([N:15](CC)C(C)C)(C)C.CN.CN.C1COCC1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH2:12][NH2:15])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: C1CCOC1
Product: NCc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 105 °C
Reaction time: 0.33 h

Procedure:
A solution of 4-bromo-2-fluoronitrobenzene (1.2 g) in THF (10 ml) is heated in the presence of N,N-diisopropylethylamine (690 μl) and of methylamine (2M in THF, 3 ml) in a microwave reactor (10° C., 20 min). After 20 min, 100 μl of methylamine THF (2M) are added and the resulting mixture is heated at 105° C. for a further 5 minutes. The reaction medium is concentrated and then taken up in ethyl acetate, and washed with water and then with brine. The organic extracts are combined, dried over magnesium sulphate, filtered and evaporated under reduced pressure. (5-Bromo-2-nitrophenyl)methylamine (1.2 g) is isolated in the form of an orange solid which is used as it is in the next stage.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]([CH3:16])[C:9]([CH:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)=[O:10].[Cl:17][C:18]1[C:24](Cl)=[CH:23][C:21]([NH2:22])=[C:20]([N+:26]([O-:28])=[O:27])[CH:19]=1>CS(C)=O.CCOC(C)=O>[Cl:17][C:18]1[C:24]([N:12]2[CH2:13][CH2:14][CH2:15][CH:11]2[C:9](=[O:10])[N:8]([CH3:16])[CH3:7])=[CH:23][C:21]([NH2:22])=[C:20]([N+:26]([O-:28])=[O:27])[CH:19]=1
Reactant: CN(C)C(=O)C1CCCN1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)C1CCCN1c1cc(N)c([N+](=O)[O-])cc1Cl
Temperature: 120 °C
Reaction time: 2.5 h

Procedure:
Potassium carbonate (1.00 g, 7.3 mmol) was added to a mixture of pyrrolidine-2-carboxylic acid dimethylamide (1.00 g, 7.0 mmol) and 4,5-dichloro-2-nitroaniline (1.00 g, 4.8 mmol) in DMSO (6 mL). The reaction mixture was stirred at 120° C. for 2.5 h, diluted with EtOAc and washed with water and sat.aq. NaCl. The organic layer was dried over Na2SO4, concentrated and the crude was purified by chromatography to give the sub-title compound.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH:34]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:34][C:33]3[CH:36]=[CH:37][CH:38]=[C:31]([O:30][CH3:29])[CH:32]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(C=O)c1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: COc1cccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 3-methoxy-benzaldehyde according to the procedure of Example 66. MS (ESI) m/z 498.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](N)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15]C)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.C(ON=O)(C)(C)C>C(O)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[O:15][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:5]2=[CH:4][CH:3]=1
Reactant: COc1ccccc1-c1ccc(Cl)nc1N
Agent: CC(C)(C)ON=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Clc1ccc2c(n1)oc1ccccc12
Reaction time: 0.5 h
Yield: 53.3 %

Procedure:
6-chloro-3-(2-methoxyphenyl)pyridin-2-amine (4.0 g, 17.04 mmol) was dissolved in glacial acetic acid (100 mL) and concentrated sulfuric acid (1 mL). A solution of t-butylnitrite (6.1 mL, 51.2 mmol) in 6 mL of acetic acid was added drop wise and stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure, dissolved in methylene chloride. The reaction mixture neutralized by saturated aq. NaHCO3 solution and the organic phase was separated from the aqueous phase. The aqueous phase extracted with methylene chloride and the combined organic layers was dried over sodium sulfate, concentrated and the residue was purified by silica column using hexanes and ethyl acetate as eluent to give 1.85 g of title compound.
Reaction SMILES: [F:1][CH:2]([F:27])[C:3]1[CH:26]=[CH:25][C:6]([O:7][C:8]2[C:13]3[CH:14]=[C:15]([C:17](O)=[O:18])[O:16][C:12]=3[CH:11]=[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=2)=[CH:5][CH:4]=1.[CH3:28][N:29](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:30].F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.CNC>CN(C=O)C.O>[F:1][CH:2]([F:27])[C:3]1[CH:26]=[CH:25][C:6]([O:7][C:8]2[C:13]3[CH:14]=[C:15]([C:17]([N:29]([CH3:30])[CH3:28])=[O:18])[O:16][C:12]=3[CH:11]=[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cc(Oc2ccc(C(F)F)cc2)c2cc(C(=O)O)oc2c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
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: CCOC(=O)c1cc(Oc2ccc(C(F)F)cc2)c2cc(C(=O)N(C)C)oc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.4 %

Procedure:
To a solution of 4-[4-(difluoromethyl)phenoxy]-6-(ethoxycarbonyl)-1-benzofuran-2-carboxylic acid (300 mg, 0.80 mmol) in DMF (10 mL) was added HATU (606 mg, 1.59 mmol), DIEA (515 mg, 4.0 mmol) and the solution was stirred at 0° C. for 15 min. Dimethylamine hydrochloride (97.5 mg, 1.20 mmol) was added and the solution was warmed gradually to room temperature and stirred for 14 h. Water was added to the reaction and the product was extracted with CHCl3. The combined organic layers were washed with water twice, dried over MgSO4, and concentrated. The product was purified via gradient silica gel chromatography using CHCl3/MeOH (100/0 to 95/5) to give the title compound (240 mg, 70%) as a light yellow solid. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.38 (t, J=7.16 Hz, 3 H) 3.13 (s, 3 H) 3.32 (s, 3 H) 4.38 (q, J=7.16 Hz, 2 H) 6.64 (t, J=56.61 Hz, 1 H) 7.09 (d, J=8.48 Hz, 2 H) 7.16 (s, 1 H) 7.50 (d, J=8.48 Hz, 2 H) 7.55 (s, 1 H) 8.05 (s, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:43][C:44]1[S:45][CH:46]=[C:47]([CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])[N:48]=1>>[CH2:53]([O:52][C:50]([CH2:49][C:47]1[N:48]=[C:44]([NH:43][C:17](=[O:19])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[S:45][CH:46]=1)=[O:51])[CH3:54]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Product: CCOC(=O)Cc1csc(NC(=O)C(Cc2ccccc2)NC(=O)OC(C)(C)C)n1
Yield: 84.1 %

Procedure:
Alternatively, by working in a way similar to that above reported and by using N-tert-butoxycarbonyl-L-phenylalanine (10 g; 37.7 mmoles), N-hydroxysuccinimide (4.78 g; 41.5 mmoles), dicyclohexylcarbodiimide (8.56 g; 41.5 mmoles) and ethyl (2-amino-4-thiazolyl)acetate (7 g; 37.7 mmoles), a crude was obtained which, chromatographed on silica gel (eluent ligroin:ethyl acetate 6:4) and further crystallized from ligroin, afforded N-(4-ethoxycarbonylmethyl-2-thiazolyl)-3-phenyl-2-(tert-butoxycarbonyl)amino-propanamide (13.74 g; 84.14% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([Si:10]([CH3:23])([CH3:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16](Cl)[CH:15]=2)=[CH:6][CH:5]=1)[CH3:2].[C:24]1([O-:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Na+]>[Cu]Cl.COCCOCCOCCOCCOC>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([Si:10]([CH3:23])([CH3:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([O:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:15]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: [O-]c1ccccc1
Reactant: CCOc1ccc([Si](C)(C)CCCc2ccc(F)c(Cl)c2)cc1
Agent: Cl[Cu]
Agent: COCCOCCOCCOCCOC
Agent: [Na+]
Product: CCOc1ccc([Si](C)(C)CCCc2ccc(F)c(Oc3ccccc3)c2)cc1
Temperature: 90 °C
Yield: 43.9 %

Procedure:
A mixture of 456.2 g (1.30 mol) of (4-ethoxyphenyl)-(dimethyl)-(3-(3-chloro-4-fluorophenyl)propyl)silane, 232.2 g (2.00 mol) of sodium phenolate, 13 g of copper(I) chloride and 500 ml of tetraglyme was heated to 240°-255° C. for 1.5 h. After cooling the reaction mixture to 90° C., a larger part of the solvent was removed by distillation at 90°-140° C. internal temperature and 0.4 Torr (about 400 g). The crude product was then stirred at room temperature with 500 ml of 2N sodium hydroxide solution and extracted twice using 800 ml of hexane each time. The organic extracts were washed five times with 300 ml of water each time, dried over sodium sulfate and evaporated. The crude product thus obtained (486.1 g/92%) was distilled over a 50 cm split tube column. 233 g (44%) of (4-ethoxyphenyl)-(dimethyl)-(3-(4-fluoro-3-phenoxyphenyl)propyl)silane were obtained as a colorless oil of b.p.0.04 =208°-212° C., the purity of which was determined to be 95.2% by gas chromatography.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[O:12])[CH:9]=2)[CH2:4][CH2:3]1>C1(C)C=CC=CC=1.C1COCC1>[OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[O:12])[CH:9]=2)[CH2:4][CH2:3]1
Reactant: C[Si](C)(C)CCOC(=O)c1ccc2c(c1)C(=O)CC2
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOC(=O)c1ccc2c(c1)[C@@H](O)CC2

Procedure:
To a solution of R-CBS reagent (90 μL, 1M sol.) and BH3DMS (220 μL, 2.34 mmol) in 3.6 ml of toluene at −10° C. was dropwise added over about 2 h, a solution of the product from Step 1 (500 mg, 1.8 mmol) in 1.8 mL of THF. After addition was complete, the reaction mixture was quenched with 0.5 N HCl. The resulting mixture was transferred to a seperatory funnel and the aqueous layer was washed 3× with EtOAc. The organic layers were combined, dried over MgSO4, filtered and concentrated to yield an oil, which was was purified by chiral HPLC (77% ee prior to chiral separation) to afford the title compound.
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]([O:7][C@H:8]([CH2:21][CH2:22][CH:23]=[CH2:24])[CH2:9][C@H:10]1[C@H:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:12](=[O:20])[O:11]1)=[O:6])=[O:2]>[Pd].C(Cl)Cl>[CH:1]([NH:3][CH2:4][C:5]([O:7][C@H:8]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:9][C@H:10]1[C@H:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:12](=[O:20])[O:11]1)=[O:6])=[O:2]
Reactant: C=CCC[C@H](C[C@@H]1OC(=O)[C@H]1CCCCCC)OC(=O)CNC=O
Agent: [Pd]
Solvent: ClCCl
Product: CCCCCC[C@@H]1C(=O)O[C@H]1C[C@@H](CCCC)OC(=O)CNC=O
Yield: 94.4 %

Procedure:
Prepared according to representative procedure described in Example 63, above. β-lactone 17f (6.2 mg, 0.018 mmol) and 5 wt % palladium on carbon (5 mg) in 2 mL of CH2Cl2 was stirred at ambient temperature for 12 h under H2 atmosphere. Filtration and chromatography (SiO2, 40% EtOAc:hexanes) gave the desired β-lactone 23b (5.8 mg, 95.1%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].N1C=CN=C1.[C:15]([Si:19]([CH3:22])([CH3:21])Cl)([CH3:18])([CH3:17])[CH3:16]>ClCCl.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][Si:19]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(Cl)c(Br)c1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Cl)c(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
To a stirred solution of 3-bromo-4-chlorophenol (25.0 g, 120.5 mmol) in dichloromethane at 0° C. was added imidazole (9.0 g, 132.5 mmol) and t-butyldimethylchlorosilane (TBSC1) (19.0 g, 126.5 mmol). The solution was stirred at 0° C. for 30 min, then at room temperature for 14 h. The reaction mixture was diluted with deionized water, extracted with dichloromethane (2×200 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 0-10% ethyl acetate in hexanes) to afford (3-bromo-4-chlorophenoxy)-t-butyldimethylsilane as colorless oil (37.0 g, 115.0 mmol, 98%). MS: (ES) m/z calculated for C12H19BrClOSi [M+H]+ 321.0. found 321.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:35][C:36]([F:48])([F:47])[C:37]([N:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[C:44](Cl)=[O:45])=[O:38].C(Cl)Cl>CN(C1C=CN=CC=1)C.CCN(CC)CC>[F:48][C:36]([F:35])([F:47])[C:37]([N:39]1[CH2:43][CH2:42][CH2:41][C@@H:40]1[C:44]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:45])=[O:38]
Reactant: O=C(Cl)C1CCCN1C(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)[C@H]5CCCN5C(=O)C(F)(F)F)c4)nc4ccccc34)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (20 mg, 0.044 mmol) and 1-(2,2,2-trifluoroacetyl)pyrrolidine-2-carbonyl chloride (880 μL, 0.088 mmol, 0.1M solution in CH2Cl2) was added Et3N (12 μL, 0.088 mmol), catalytic amount of DMAP, and CH2Cl2 (1 mL). The reaction mixture was stirred at RT for 2 h after which 2 equivalents each of 1-(2,2,2-trifluoroacetyl)pyrrolidine-2-carbonyl chloride and Et3N were added. Continued to stir at ambient temperature for 16 hours. The reaction was concentrated in vacuo and the residue was purified by flash chromatography on silica (10:1 CH2Cl2:MeOH). The product tert-butyl 5-(2-(3-((R)-1-(2,2,2-trifluoroacetyl)pyrrolidine-2-carboxamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate was isolated. (130 mg, 46%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC1
Yield: 42.5 %

Procedure:
A N,N-dimethylformamide solution (2.2 mL) of 6-bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (280 mg, 0.99 mmol), and tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate (300 mg, 1.08 mmol) is heated at 90° C. for 0.5 h. After cooling in the refrigerator, the precipitate is collected, and washed with N,N-dimethylformamide and ether to give 222 mg (42%) of the title compound as a yellow solid. MS (ESI) m/z 527.529 (M+H)+1
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17](Br)[CH:18]=[C:13]3[C:12]([C:20]#[N:21])=[CH:11]2)(=O)=O)C=CC=CC=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.CCO>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:17]1[CH:18]=[C:13]2[C:12]([C:20]#[N:21])=[CH:11][NH:10][C:14]2=[N:15][CH:16]=1
Reactant: N#Cc1cn(S(=O)(=O)c2ccccc2)c2ncc(Br)cc12
Reactant: OB(O)c1ccccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: N#Cc1c[nH]c2ncc(-c3ccccc3F)cc12
Yield: 37.9 %

Procedure:
Compound 10 was synthesized according to the procedure used for the preparation of 9 using 8 (40.0 mg, 0.11 mmol), 2-fluorophenylboronic acid (23.2 mg, 0.11 mmol), PdCl2(PPh3)2 (7.8 mg, 0.011 mmol), LiCl (14.0 mg, 0.33 mmol), 1M Na2CO3 (276 mL), EtOH (0.66 mL) and toluene (0.66 mL) with refluxing for 1 h. Obtained 10 (9.9 mg, 38%) as a white solid; 1H NMR (400 MHz, CDCl3+4 drops d4-MeOH) δ 8.54 (t, J=1.9 Hz, 1H), 8.25 (dd, J=2.0, 1.3 Hz, 1H), 7.89 (s, 1H), 7.46 (dt, J=7.7, 1.8 Hz, 1H), 7.37 (m, 1H), 7.30-7.10 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.C([Sn](CCCC)(CCCC)[C:20]([O:22][CH2:23][CH3:24])=[CH2:21])CCC.[F-].[K+]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:23]([O:22][C:20]([C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1)=[CH2:21])[CH3:24]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(OCC)c1nc(SC)ncc1C(=O)OCC
Temperature: 25 °C

Procedure:
A solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (10 g, 43.0 mmol), tributyl(1-ethoxyvinyl)stannane (16 ml, 47.3 mmol) and bis(triphenylphosphine)palladium dichloride (1.508 g, 2.149 mmol) in N,N-dimethylformamide (100 mL) was heated to 70° C. for 5 hours. After cooling, the mixture was treated with an aqueous solution of KF (6 g in 12 mL water) and stirred over the weekend at room temperature. The mixture was filtered through diatomaceous earth and washed with ethyl acetate. The filtrate was partitioned between ethyl acetate and brine. The organic phase was washed with brine twice and concentrated. The residue was separated by flash chromatography (0-20% gradient ethyl acetate in hexane) to give the title compound. MS (DCI/NH3) m/z 269 (M+H)+.
Reaction SMILES: C(OP([CH2:9][C:10]1[C:11]([NH:16][C:17](=O)[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:12][CH:13]=[CH:14][CH:15]=1)(=O)OCC)C.C(O[K])(C)(C)C>C1(C)C=CC=CC=1.O1CCCC1>[C:20]1([CH2:19][CH2:18][C:17]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOP(=O)(Cc1cccnc1NC(=O)CCc1ccccc1)OCC
Agent: CC(C)(C)O[K]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: c1ccc(CCc2cc3cccnc3[nH]2)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 25.2 %

Procedure:
To a solution of diethyl[[2-[(3-phenylpropionyl)amino]-3-pyridyl]methyl]phosphonate (13.56 g, 36.03 mmol) in toluene (150 mL) was added a suspension of tert-butoxy potassium (11.41 g, 86.47 mmol) in tetrahydrofuran (86.47 mL), and the resulting mixture was stirred at 90° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-0/1) and recrystallized from hexane/ethyl acetate to give the title compound (2.02 g, yield 25%) as colorless crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1(/[CH:11]=[CH:12]/[C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[CH:18][C:19]([C@H:23]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH3:24])=[N:20]3)=[CH:15][CH:14]=2)[CH2:10][O:9][CH2:8][CH2:7][O:6]1)=[O:4].O.[OH-].[Li+]>O1CCCC1.O>[C:29]([O:28][C:26]([NH:25][C@@H:23]([C:19]1[CH:18]=[CH:17][C:16]2[C:21](=[CH:22][C:13](/[CH:12]=[CH:11]/[C:5]3([C:3]([OH:4])=[O:2])[CH2:10][O:9][CH2:8][CH2:7][O:6]3)=[CH:14][CH:15]=2)[N:20]=1)[CH3:24])=[O:27])([CH3:30])([CH3:31])[CH3:32]
Reactant: COC(=O)C1(/C=C/c2ccc3ccc([C@@H](C)NC(=O)OC(C)(C)C)nc3c2)COCCO1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)OC(C)(C)C)c1ccc2ccc(/C=C/C3(C(=O)O)COCCO3)cc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.4 %

Procedure:
A solution of 2-{(E)-2-[2-((R)-1-tert-butoxycarbonylamino-ethyl)-quinolin-7-yl]-vinyl}-[1,4]dioxane-2-carboxylic acid methyl ester (157 mg, 0.35 mmol) in tetrahydrofuran (6 mL) was stirred at 5° C. under nitrogen. A solution of lithium hydroxide monohydrate (30 mg, 0.71 mmol) in water (1.5 mL) was added and the reaction mixture was stirred at room temperature for 18 h. The majority of the organic solvent was evaporated. The solution was acidified to pH 2 with 2 M hydrochloric acid and the mixture was extracted with dichloromethane. The organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated to afford the title compound (149 mg, 100%) as a pale yellow foam and as a 1:1 mixture of diastereoisomers. LCMS (m/z) 429.1 [M+H], Tr=1.87 min.