Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)[CH:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:27][O:28][C:29](=[O:32])[CH2:30]Br>ClCCl>[C:1]1([CH:7]([C:13]2[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)[CH:8]2[CH2:12][CH2:11][N:10]([CH2:30][C:29]([O:28][CH3:27])=[O:32])[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccc(C(c2ccccc2)C2CCNC2)c1
Reactant: COC(=O)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CN1CCC(C(c2ccccc2)c2cccc(C)c2)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 41.2 %

Procedure:
A solution of 3-(phenyl(m-tolyl)methyl)pyrrolidine (3.0 g, 12 mmol) and triethylamine (1.8 mL, 12.9 mmol) in dichloromethane (30 mL) was stirred at 0° C. for 10 min, and then methylbromoacetate (1.5 mL, 15.8 mmol) was added dropwise. After stirring the reaction mixture at 0° C. for 3 h, reaction mixture was warmed to room temperature and concentrated under reduced pressure. To the residue was added water and the aqueous layer was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude product. The crude product was dissolved in dichloromethane and precipitated with diethyl ether to afford 1.6 g of methyl 2-(3-(phenyl(m-tolyl)methyl)pyrrolidin-1-yl)acetate.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[F:25][C:26](=[C:32]([F:34])[F:33])[CH2:27][CH2:28][C:29](O)=[O:30]>C(Cl)Cl>[F:25][C:26](=[C:32]([F:34])[F:33])[CH2:27][CH2:28][C:29]([N:3]([O:4][CH3:5])[CH3:2])=[O:30]
Reactant: O=C(O)CCC(F)=C(F)F
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)CCC(F)=C(F)F
Reaction time: 8 h

Procedure:
N,O-dimethylhydroxyamine hydrochloride (3.5 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.9 g) and triethylamine (9.2 mL) were added to a solution of 4,5,5-trifluoropent-4-enoic acid (CAS No. 110003-22-0 (5.0 g)) in methylene chloride solution (64 mL) in a cold-water bath and stirring was carried out at room temperature overnight. The reaction solution was concentrated and diluted with ethyl acetate. The dilute solution was washed with 1 N hydrochloric acid, water and saturated brine; dried with anhydrous sodium sulfate; and concentrated to obtain the title compound (6.4 g) having the following physical properties:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[C:16]2[C:11](=[C:12]([NH2:17])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][N:8]=1.[Cl:23][C:24]1[C:29]([C:30](O)=[O:31])=[C:28]([F:33])[C:27]([CH2:34][NH:35][C:36](=[O:42])[C:37]([CH3:41])([CH3:40])[CH2:38][OH:39])=[CH:26][CH:25]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[C:29]([C:30]([NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:11]=2[N:10]=[CH:9][N:8]=[C:7]3[O:6][C:5]2[CH:18]=[CH:19][CH:20]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=2)=[O:31])=[C:28]([F:33])[C:27]([CH2:34][NH:35][C:36](=[O:42])[C:37]([CH3:40])([CH3:41])[CH2:38][OH:39])=[CH:26][CH:25]=1
Reactant: Nc1cccc2c(Oc3cccc(C(F)(F)F)c3)ncnc12
Reactant: CC(C)(CO)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(CO)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Oc4cccc(C(F)(F)F)c4)ncnc23)c1F
Yield: 2.6 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-(3-(trifluoromethyl)phenoxy)quinazolin-8-amine (Intermediate-8, 200 mg, 0.655 mmol), 6-chloro-2-fluoro-3-((3-hydroxy-2,2-dimethylpropanamido)methyl)benzoic acid (Intermediate-59, 237 mg, 0.78 mmol), oxalyl chloride (166 mg, 1.32 mmol), DMF (1 drop) and DIPEA (253 mg, 1.96 mmol) in CH2Cl2 (3 mL) to afford 10 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.94 (s, 1H), 8.88 (d, 1H), 8.77 (s, 1H), 8.14 (m, 2H), 7.85 (m, 2H), 7.73 (s, 3H), 7.36 (m, 2H), 4.91 (t, 1H), 4.31 (d, 2H), 3.40 (m, 2H), 1.06 (s, 6H); MS [M+H]+: 591.29.
Reaction SMILES: [N+](=C)=[N-].[CH3:4]N(N=O)S(C1C=CC(C)=CC=1)(=O)=O.[C:18]([O:21][C@H:22]1[CH2:43][CH2:42][C@@:41]2([CH3:44])[C:24](=[CH:25][CH2:26][C@@H:27]3[C@@H:40]2[CH2:39][CH2:38][C@@:37]2([CH3:45])[C@H:28]3[CH2:29][CH2:30][C@@H:31]2[C@@H:32]([C:34]([OH:36])=[O:35])[CH3:33])[CH2:23]1)(=[O:20])[CH3:19]>>[CH3:4][O:35][C:34]([C@H:32]([C@@H:31]1[C@:37]2([CH3:45])[C@H:28]([C@H:27]3[C@H:40]([CH2:39][CH2:38]2)[C@:41]2([CH3:44])[C:24]([CH2:23][C@@H:22]([O:21][C:18](=[O:20])[CH3:19])[CH2:43][CH2:42]2)=[CH:25][CH2:26]3)[CH2:29][CH2:30]1)[CH3:33])=[O:36]
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)C(=O)O)[C@@]4(C)CC[C@@H]32)C1
Agent: C=[N+]=[N-]
Product: COC(=O)[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 99.4 %

Procedure:
An ethanolic ethereal solution of diazomethane (CH2N2), generated from N-methyl-N-nitroso-p-toluenesulfonamide (CH3C6H4SO2N(CH3)NO; Diazald), was added dropwise to a suspension of (20S)-3β-acetoxy-5-pregnene-20-carboxylic acid (10.0 g, 25.7 mmole; m.p. 228°-231° C.) in 1:9 ethanol-ether at room temperature until all the solids dissolved and pale yellow color due to an excess diazomethane persisted. Excess diazomethane was removed with a stream of N2 until the solution became colorless. Removal of solvent provided the desired methyl ester, (20S)-3β-acetoxy-5-pregnene-20-carboxylic acid methyl ester (10.3 g; Rf 0.63 on silica gel in 3:7 ethyl acetate-hexane; m.p. 140°-142° C.) in 99.4% yield. Mass spectrum, m/e (relative intensity) 402 (M+, 0), 342 (100), 327 (10), 283 (4), 255 (6), 239 (5), 234 (11 ), 221 (12), 213 (5); NMR (CDCl3) δ0.70 (s, 18--H3), 1.02 (s, 19--H3), 1.19 (d, J=6.8 Hz, 21--H3), 2.03 (s, 3--OCOCH3), 4.60 (m, 3--H), 5.37 (br d, J=4.8 Hz, 6--H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Br)([O-:3])=[O:2].C([N:15](C(C)C)CC)(C)C.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:7][NH:15][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: BrCc1ccccc1
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1cccc(CNCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.2 %

Procedure:
To a solution of m-nitrobenzyl bromide (1.0 g) and diisopropylethylamine (1.19 g) in methanol (50 ml), benzyl bromide (495 mg) was added dropwise under ice cooling. The reaction mixture was stirred at room temperature for 3 days and, after addition of water, extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=4:1) to give 555 mg of the titled compound (yield, 50%).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([NH:6][C@H:7]([C:15]([OH:17])=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:3].N1C=CC=CC=1.[C:24](OC(=O)C)(=[O:26])[CH3:25].O>C(Cl)Cl>[C:24]([NH:1][CH:2]([CH3:3])[C:4]([NH:6][C@H:7]([C:15]([OH:17])=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])(=[O:26])[CH3:25]
Reactant: C[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)NC(C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
L-Ala-L-Phe obtained in Experimental Example 6 (100 mg, 0.423 mmol) is suspended in methylene chloride (10 ml), and pyridine (10 ml) and acetic anhydride (1 ml, 11 mmol) are added to the suspension at room temperature. After stirring at room temperature for 24 hours, water is added and the resulting mixture is extracted three times with chloroform. The organic layer is washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent is distilled away under reduced pressure to obtain N-[2-(acetylamino)propionyl]phenylalanine.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:4]([CH3:12])[CH2:3]1.[CH:13]1([S:16](Cl)(=[O:18])=[O:17])[CH2:15][CH2:14]1>CN(C=O)C>[CH:13]1([S:16]([NH:1][CH:2]2[CH2:6][CH:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:4]([CH3:12])[CH2:3]2)(=[O:18])=[O:17])[CH2:15][CH2:14]1
Reactant: CCOC(=O)C1CC(N)CC1C
Reactant: O=S(=O)(Cl)C1CC1
Solvent: CN(C)C=O
Product: CCOC(=O)C1CC(NS(=O)(=O)C2CC2)CC1C
Reaction time: 0.25 h
Yield: 87.9 %

Procedure:
A solution of ethyl 4-amino-2-methylcyclopentanecarboxylate (15.0 g, 88.0 mmol) in DMF (210 mL) was cooled to about 0° C. in an ice bath. TEA (30.5 mL, 219 mmol) was added and stirring was continued at about 0° C. for about 15 min and then cyclopropanesulfonyl chloride (12.3 g, 88.0 mmol, Matrix) was added drop-wise. The resulting solution was stirred at about 0° C. for about 2 h. The ice bath was removed and the reaction mixture continued stirring at ambient temperature for about 3 h. The reaction was concentrated under reduced pressure and EtOAc (200 mL) and water (100 mL) were added. The layers were separated and the organic layer was washed with saturated aqueous NaHCO3 (60 mL) and brine (60 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give a reddish brown oil. The crude material was purified by silica gel chromatography eluting with a gradient of 10-30% EtOAc in heptane to give ethyl 4-(cyclopropanesulfonamido)-2-methylcyclopentanecarboxylate (21.3 g, 88%) as a yellow oil: 1H NMR (CDCl3) δ 5.25 (d, J=9.9 Hz, 1H), 4.23-4.06 (m, 2H), 4.03-3.90 (m, 1H), 2.80 (td, J=3.1, 7.5 Hz, 1H), 2.46-2.30 (m, 2H), 2.29-2.14 (m, 2H), 1.97 (ddd, J=3.2, 4.2, 14.2 Hz, 1H), 1.42 (ddd, J=7.5, 11.5, 13.1 Hz, 1H), 1.29 (t, J=7.1 Hz, 3H), 1.20-1.14 (m, 2H), 1.02 (d, J=6.9 Hz, 3H), 1.00-0.96 (m, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([F:26])=[CH:7][C:8]([NH2:25])=[C:9]([CH:24]=1)[NH:10][C:11]1[CH:23]=[CH:22][C:14]([O:15][CH:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=1)(=[O:3])[CH3:2].C(O)(=O)C.[N:31]([O-])=O.[Na+]>O1CCCC1.O>[C:1]([NH:4][C:5]1[C:6]([F:26])=[CH:7][C:8]2[N:25]=[N:31][N:10]([C:11]3[CH:23]=[CH:22][C:14]([O:15][CH:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=3)[C:9]=2[CH:24]=1)(=[O:3])[CH3:2]
Reactant: O=N[O-]
Reactant: COC(=O)C(C)Oc1ccc(Nc2cc(NC(C)=O)c(F)cc2N)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)C(C)Oc1ccc(-n2nnc3cc(F)c(NC(C)=O)cc32)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of methyl 2-[p-(5-acetamido-2-amino-4-fluoroanilino)phenoxy]propionate (7 g, 0.019 mol) in tetrahydrofuran is added dropwise to a 50% acetic acid solution at 0° C. To the resultant mixture, a solution of sodium nitrite (2.81 g, 0.041 mol) in water is added dropwise. After the addition is complete, the reaction mixture is warmed to room temperature, stirred for 3 days and poured into water. The aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed sequentially with brine and water, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title product as an orange solid which is identified by NMR spectral analyses.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:9][CH2:10][NH2:11].[CH2:12]([N:14]=[C:15]=S)[CH3:13].[NH2:17][C:18]([NH2:20])=S>>[C:18]([NH:20][C:15]([NH:14][CH2:12][CH3:13])=[N:11][CH2:10][CH2:9][NH:8][CH2:7][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)#[N:17]
Reactant: CCN=C=S
Reactant: NCCNCc1cnccn1
Reactant: NC(N)=S
Product: CCNC(=NCCNCc1cnccn1)NC#N

Procedure:
Reacting N-(2-pyrazinylmethyl)ethylenediamine with ethyl isothiocyanate by the procedure of Example 3 and chromatographing gives N-ethyl-N'-[2-(2-pyrazinylmethylamino)ethyl]thiorea. Reacting this thiourea with lead cyananmide by the procedure of Example 3 gives N-cyano-N'-ethyl-N"-[2-(2-pyrazinylmethylamino)ethyl]-guanidine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]O)[N:3]=1.S(Cl)([Cl:12])=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][Cl:12])[N:3]=1
Reactant: OCc1cccc(Br)n1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.8 %

Procedure:
2-Bromo-6-hydroxymethylpyridine (5.00 g, 25.5 mmol) was dissolved in chloroform (30 ml) and thionyl chloride (2.8 ml, 38.3 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After the reaction solution was concentrated, a saturated aqueous sodium bicarbonate was added to the residue and the precipitates were collected by filtration. After washing with water, the precipitates were dried in vacuo to give the title compound (5.20 g, 99%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][C:14]=2[F:21])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:34][O:35][CH2:36][CH2:37][OH:38]>>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][C:14]=2[F:21])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH:34][O:35][CH2:36][CH2:37][OH:38])=[O:7]
Reactant: CSc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Reactant: NOCCO
Agent: O=C(n1ccnc1)n1ccnc1
Product: CSc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Yield: 80 %

Procedure:
The title compound was prepared from reaction of the product of Example 26, Step C, 3,4-difluoro-2-[[2-fluoro-4-(methylthio)phenyl]amino]benzoic acid, with CDI and 2-(aminooxy)ethanol by the general procedure of Example 1, Step E. Then, after workup, the crude solid triturated with Et2O and washed with pentane to afford 3,4-difluoro-2-[[2-fluoro-4-(methylthio)phenyl]amino]-N-(2-hydroxyethoxy)benzamide as a white solid (80%); m.p. (Et2O) 108–111° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.80 (br s, 1 H), 8.77 (br s, 1 H), 7.40 (ddd, J=9.0, 5.8, 2.0 Hz, 1 H), 7.18 (dd, J=12.0, 2.2 Hz, 1 H), 7.13 (ddd, J=9.9, 9.0, 7.2 Hz, 1 H), 6.99 (ddd, J=8.5, 2.4, 0.8 Hz, 1 H), 6.87 (td, J=8.9, 4.5 Hz, 1 H), 4.71 (br s, 1 H), 3.86 (t, J=4.9 Hz, 2 H), 3.57 (t, J=4.9 Hz, 2 H), 2.45 (s, 3 H). Anal. Calcd for C16H15F3N2O3S: C, 51.6; H, 4.1; N, 7.5. Found: C, 52.1; H, 4.3; N, 7.6.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10]/[CH:11]=[N:12]/[S@:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:19][Mg]Br.C1COCC1>C(Cl)Cl.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH:11]([NH:12][S@:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])[CH3:19])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)[S@](=O)/N=C/CCc1ccc(Cl)c(Cl)c1
Reactant: C[Mg]Br
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(CCc1ccc(Cl)c(Cl)c1)N[S@@](=O)C(C)(C)C
Temperature: 25 °C
Yield: 67 %

Procedure:
To a solution of Intermediate 16B (4.00 g, 13.1 mmol) in DCM (50 mL) was added slowly a solution of methylmagnesium bromide in toluene and THF (13.99 mL, 1.400 M, 19.59 mmol) and the reaction mixture was heated to reflux for 2.5 h. The reaction mixture was allowed to cool to rt and, diluted with DCM, washed with saturated NH4Cl, and the organic portion dried over MgSO4, filtered and concentrated. The residue was purified by ISCO chromatography (EtOAc/Hexanes 0-50% over 30 min, column 330 g, flow rate 100 mL/min) to give Intermediate 16C (2.80 g, 8.69 mmol, 67.0% yield) as a white solid. HPLC/MS (Method D) RT=1.12 min, [M+1]+ 322.1; Chiral HPLC (Method L) RT=4.55 min, PA=100%.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]3[C:24]4[C:19](=[CH:20][C:21]([CH:25]=[C:26]5[C:34]6[C:29](=[CH:30][CH:31]=CC=6)[NH:28][C:27]5=[O:35])=[CH:22][CH:23]=4)[N:18](COCC[Si](C)(C)C)[N:17]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.B(F)(F)F.C[CH2:49][O:50][CH2:51][CH3:52].C(Cl)[Cl:54]>>[ClH:54].[ClH:54].[CH3:49][O:50][C:51]1[CH:52]=[C:34]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:35])[C:26]2=[CH:25][C:21]1[CH:20]=[C:19]2[C:24]([C:16](/[CH:15]=[CH:14]/[C:11]3[CH:12]=[N:13][C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[CH:9][CH:10]=3)=[N:17][NH:18]2)=[CH:23][CH:22]=1
Reactant: ClCCl
Reactant: CN1CCN(c2ccc(/C=C/c3nn(COCC[Si](C)(C)C)c4cc(C=C5C(=O)Nc6ccccc65)ccc34)cn2)CC1
Reactant: CCOCC
Agent: FB(F)F
Product: COc1ccc2c(c1)C(=Cc1ccc3c(/C=C/c4ccc(N5CCN(C)CC5)nc4)n[nH]c3c1)C(=O)N2
Product: Cl
Reaction time: 4 h

Procedure:
To a DCM (50 mL) solution of 5-methoxy-3-(E & Z)-((3-((E)-2-(6-(4-methylpiperazin-1-yl)-pyridin-3-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)methyl-ene)indolin-2-one (0.85 g, 1.36 mmol) was added BF3.OEt2 (1.7 mL, 13.6 mmol) at 0° C. The cooling bath was removed and the reaction mixture was stirred for 4 h. After removal of the solvent under reduced pressure, the residue was heated in EtOH (40 mL) and 2 M aq HCl (20 mL) at 60° C. overnight. The reaction was then stored at 5° C. overnight. A red precipitate was collected and washed separately with EtOAc, MeCN and Et2O to provide the title compound as a 3.3:1 (E:Z) mixture of isomers: an orange-red powder (0.32 g, 42%). 1H NMR (400 MHz, CD3OD) δ ppm 8.87 (s, 0.3 H), 8.53-8.61 (m, 1.0 H), 8.28-8.32 (m, 1H), 8.26 (d, J=8.53 Hz, 0.7 H), 8.13 (d, J=8.28 Hz, 0.3H), 8.00 (t, J=7.99 Hz, 0.3 H), 7.95-8.02 (m, 1.5 H), 7.83-7.90 (m, 3.3 H), 7.30 (d, J=2.3 Hz, 0.3 H), 7.24 (s, 0.7 H), 6.84 (s, 1.4 H), 6.76-6.84 (m, 0.4 H), 4.39-4.59 (br.s, 2 H), 3.64-3.85 (br.s., 4 H), 3.63 (s, 3 H), 3.32-3.60 (br.s., 2 H), 3.03 (s, 3 H); MS ESI [M+H]+ 493.3, calcd for [C29H28N6O2+H]+ 493.6.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([O:12][CH2:13][CH:14]2[CH2:19][CH:18]=[CH:17][CH2:16][N:15]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+](=[CH2:29])=[N-].C(OCC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([O:12][CH2:13][C@@H:14]2[CH2:19][C@@H:18]3[C@@H:17]([CH2:29]3)[CH2:16][N:15]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CC=CCC1COC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2C[C@H]1COC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.67 h

Procedure:
tert-Butyl 2-({[(4-nitrophenyl)carbonyl]oxy}methyl)-3,6-dihydropyridine-1(2H)-carboxylate (10.0 g) produced above was dissolved in 5% diazomethane/diethyl ether (1.4 L), palladium acetate (689 mg) was added at 10° C., and the mixture was stirred at the same temperature for 40 min. The reaction mixture was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give a mixture of tert-butyl 2-({[(4-nitrophenyl)carbonyl]oxy}methyl)-3,6-dihydropyridine-1(2H)-carboxylate and the title compound. The obtained mixture was subjected to 3 repeats of a similar reaction operation to give the title compound (8.4 g).
Reaction SMILES: [C:1]1([N:7]2[C:15]3[CH2:14][CH2:13][CH2:12]/[C:11](=[CH:16]\[CH:17]=O)/[C:10]=3[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19](CN)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[C:28]([BH3-])#[N:29].[Na+]>CO>[CH2:19]([N:29]([CH3:28])[CH2:17]/[CH:16]=[C:11]1/[C:10]2[CH:9]=[N:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:15]=2[CH2:14][CH2:13][CH2:12]/1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C/C=C1\CCCc2c1cnn2-c1ccccc1
Reactant: [BH3-]C#N
Reactant: NCCc1ccccc1
Agent: [Na+]
Solvent: CO
Product: CN(C/C=C1\CCCc2c1cnn2-c1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 36.8 %

Procedure:
A solution of (E)-2-(1,5,6,7-tetrahydro-1-phenyl-4H-indazol-4-ylidene) acetaldehyde (299 mg, 1.25 mmol) and N-benzylmethylamine (0.18 mL, 1.38 mmol) in methanol (20 mL) cooled to 0° C. is left stirring for 20 minutes. Then sodium cyanoborohydride (213 mg, 3.39 mmol) at 0° C. is added, and then it is left to increase to room temperature following the TLC reaction. The solvent is evaporated at reduced pressure, diluted in ethyl acetate, washed with water and with sodium chloride saturated solution, dried and evaporated under reduced pressure. The resulting crude product is purified by means of silica gel chromatography, giving (E)-N-benzyl-2-(6,7-dihydro-1-phenyl-1H-indazol-4(5H)-ylidene)-N-methylethanamine (158 mg, 0.46 mmol, 36%, oil).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][C@H:12]2[CH3:17])[N:3]=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:28][C@H:29]1[CH2:34][O:33][CH2:32][CH2:31][NH:30]1>CC(O)CC.C(Cl)Cl>[CH3:28][C@H:29]1[CH2:34][O:33][CH2:32][CH2:31][N:30]1[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][C@H:12]2[CH3:17])[N:3]=1
Reactant: C[C@@H]1COCCN1c1nc(Cl)nc2[nH]cnc12
Reactant: C[C@H]1COCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1COCCN1c1nc(N2CCOC[C@@H]2C)nc2[nH]cnc12
Temperature: 175 °C
Reaction time: 48 h
Yield: 65.7 %

Procedure:
2-Chloro-6-((R)-3-methyl-morpholin-4-yl)-9H-purine (712 mg, 2.81 mmol), diisopropylethylamine (0.98 mL, 5.61 mmol), and (S)-3-methylmorpholin hydrochloride (579 mg, 4.21 mmol) were stirred in 2-butanol (3 mL) in a closed 5 mL microwave tube under argon at 50° C., until all ingredients were dissolved. The reaction was then stirred at 175° C. for 48 hours. The organic layer was diluted with 200 mL of CH2Cl2 and washed with brine. Drying over Na2SO4, filtering and concentration under reduced pressure gave a residue, which was purified by column chromatography (40 g SiO2, CH2Cl2/EtOH/aq NH3 in a gradient from 100/0/0.1 to 90/10/0.1) to give the product as a solid (588 mg, 66%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O1CCCC1.[CH2:16]([C@@H:23]([CH2:34][OH:35])[C@H:24]([C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=1F)[OH:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CS(C)=O>[CH2:16]([C@@H:23]1[C@@H:24]([OH:25])[C:26]2[C:31](=[CH:30][C:29]([Br:32])=[CH:28][CH:27]=2)[O:35][CH2:34]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OC[C@H](Cc1ccccc1)[C@@H](O)c1ccc(Br)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O[C@H]1c2ccc(Br)cc2OC[C@@H]1Cc1ccccc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 49.3 %

Procedure:
A 1 M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (6.55 L, 6.55 mol) was added over 20 minutes to a solution of (1R,2S)-2-benzyl-1-(4-bromo-2-fluoro-phenyl)-propane-1,3-diol (1975 g, 5.82 mol) in dimethyl sulfoxide (9.88 L) at ambient temperature. The mixture was slowly heated to 60° C. under aspirator vacuum to displace the tetrahydrofuran from the reaction mixture, and then heated at 60 to 65° C. for 5 hours under aspirator vacuum at which point the reaction was judged to be complete according to thin layer chromatography (hexanes/ethyl acetate, 2:1). The reaction mixture was cooled to ambient temperature and quenched by adding water (10 L) followed by 1 N aqueous hydrochloric acid (10 L). The resulting tan suspension was filtered, washed with water (2 L), and dissolved in ethyl acetate (12 L). This solution was washed with water (two times 12 L), concentrated to a low volume, dissolved in isopropyl ether (4 L), and concentrated under atmospheric pressure at 50 to 60° C. to 1.0 L, at which point solids began to precipitate. The resulting suspension was cooled to ambient temperature, stirred for 12 hours, concentrated to one-half its volume, cooled to 0 to 5° C., and filtered giving 916 g (49%) of (3S,4R)-3-benzyl-7-bromo-chroman-4-ol as a white solid. The filtrate was concentrated to a dark oil (906 g), dissolved in isopropyl ether (1.5 L) at reflux, cooled to ambient temperature, stirred, and filtered yielding an additional 82 g of solid. The filtrate was concentrated and chromatographed on silica gel (60-230 mesh) eluting with 3:1 hexanes/ethyl acetate. Product-rich fractions were concentrated and recrystallized from isopropyl ether yielding an additional 82 g of solid. The total yield of (3S,4R)-3-benzyl-7-bromo-chroman-4-ol was 1080 g (58%): 1H NMR (400 MHz, CDCl3) δ7.29-7.33 (m, 2H), 7.21-7.25 (m, 1H), 7.15-7.19(m, 3H), 7.06-7.09 (m, 2H), 4.44 (bs, 1H), 4.21 (dd, J=2.6, 11.3 Hz, 1H), 3.97 (dd, J=4.5, 11.3 Hz, 1H), 2.68 (dd, J=6.5, 13.8 Hz, 1H), 2.51 (dd, J=9.1, 13.8 Hz, 1H), 2.18-2.23 (m, 1H), 1.85 (d, J=4.3 Hz, 1H); IR 3274 (br), 3181 (br), 1598, 1573, 1493, 1480, 1410, 1219, 1070, 1052, 1023, 859, 700 cm−1; mp 143.5-144.0° C.