Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])(C)(C)[CH3:2].[NH2:12]C1C=CC=CC=1>>[O:11]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:1]=[CH:2][NH:12]1
Reactant: CC(C)(C)c1ccccc1O
Reactant: Nc1ccccc1
Product: C1=Cc2ccccc2ON1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
1 mol of tertiary butylphenol, 2.2 mol of p-formaldehyde, and 1.1 mol of aniline were mixed and stirred without a solvent at 100° C. for 1 hour to produce a crude product. The crude product was washed twice with a 1N NaOH aqueous solution and once with distilled water. The washed crude product was then dried with magnesium sulfate. Then, the resultant was filtered. The resultant was dried in a vacuum to obtain the benzoxazine monomer represented by Formula 4. The benzoxazine monomer of Formula 4 was produced with a 95% yield. NMR spectrum of the benzoxazine monomer of Formula 4 is shown in FIG. 10.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:16][C:17](=[O:19])[CH3:18])=[C:9]([O:14][CH3:15])[CH:10]=2)/[C:5]/1=[CH:20]/[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][C:30](=[O:32])[CH3:31])[CH:22]=1)(=[O:3])[CH3:2].C(O)C>C(Cl)Cl>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:16][C:17](=[O:19])[CH3:18])=[C:9]([O:14][CH3:15])[CH:10]=2)[C@H:5]1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][C:30](=[O:32])[CH3:31])[CH:22]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(/C=C2/c3cc(OC(C)=O)c(OC)cc3CCN2C(C)=O)cc1OC(C)=O
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(C[C@@H]2c3cc(OC(C)=O)c(OC)cc3CCN2C(C)=O)cc1OC(C)=O
Temperature: 23 °C
Reaction time: 62 h
Yield: 87.8 %

Procedure:
In a dried Schlenk-tube having its atmosphere displaced with argon, 118.6 mg (0.270 mmol) of (Z)-N-acetyl-7-acetoxy-1-(3-acetoxy-4-methoxyphenylmethylene)-6-methoxy-1,2,3,4-tetrahydroisoquinoline was charged and dissolved in 1.5 ml of methylene chloride. To the solution was further added 7.5 ml of ethanol, followed by degasification by freezing three times. Separately, in a dried Schlenk-tube having its atmosphere displaced with argon, 1.1 mg (6.5×10-4 mmol) of Ru2Cl4 ((R)-(+)-BINAP)2N(C2H5)3 was charged and dissolved in 1.5 ml of methylene chloride which had been previously degassed by freezing three times. To the solution was further added 7.5 ml of ethanol. Both the solutions were transferred to a pressure bottle and subjected to hydrogenation under a hydrogen pressure of 4 atms. at 23° C. for 62 hours while stirring. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel: 15 g, eluent: ethyl acetate/hexane=3:1 by volume) to give 104.7 mg (0.237 mmol) of (R)-N-acetyl-7-acetoxy-1-(3-acetoxy-4-methoxyphenylmethyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline (hereinafter referred to as acetylated N-acetylnorreticurine) in a yield of 88%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1.[C:13]([Li])([CH3:16])(C)[CH3:14].[CH2:18]([Si:21](Cl)(C)[CH3:22])C=C>C1COCC1>[CH2:14]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[C:4]([SiH:21]([CH3:22])[CH3:18])[CH:3]=1)[CH:13]=[CH2:16]
Reactant: [Li]C(C)(C)C
Reactant: Brc1ccc(C2OCCO2)cc1
Reactant: C=CC[Si](C)(C)Cl
Solvent: C1CCOC1
Product: C=CCc1ccc(C2OCCO2)c([SiH](C)C)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of 2-(4-bromophenyl)-1,3-dioxolane (2 Scheme 18, 6.0 g, 26.2 mmol) in dried THF (200 mL) at −78° C. was added t-butyllithium (15.4 mL, 1.7 M solution in pentane, 26.2 mmol) over a period of 5 min. After 30 min of further stirring at −78° C., allylchlorodimethylsilane (3.7 g, 27.5 mmol) in THF (20 mL) was added dropwise over a period of 10 min. The reaction mixture was stirred for 1 h and warmed to room temperature. THF was removed under reduced pressure, and the residue was extracted with cold water/ethyl acetate. The organic layer was washed with brine, dried (Na2SO4), and concentrated to give a colorless oil (5.4 g, 91%); 1H NMR (300 MHz, CDCl3) δ 0.31 (s, 6 H), 1.78 (d, J=7.95 Hz, 2 H), 4.02-4.18 (4 H), 4.85 (s, 1 H), 4.90 (m, 1 H), 5.78 (m, 1 H), 5.85 (s, 1 H), 7.50 (d, J=7.95 Hz, 2 H), 7.58 (d, J=7.95 Hz, 2 H); 13C NMR (75 MHz, CDCl3) −3.4 (2C), 23.7, 65.4 (2C), 103.7, 113.6, 125.8 (2C), 133.8 (2C), 134.6, 138.8, 139.9; HRMS calcd for C14H20O2Si 248.1233, found 248.1230.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=1.C(N(CC)CC)C.[NH2:26][CH2:27][CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:3]=[C:2]([NH:26][CH2:27][CH2:28][C:29]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[NH:31][CH:30]=3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: NCCc1c[nH]c2ccccc12
Reactant: CP(C)(=O)c1ccc(Nc2ncnc(Cl)n2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CP(C)(=O)c1ccc(Nc2ncnc(NCCc3c[nH]c4ccccc34)n2)cc1

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine (prepared as in Example 92: 0.12 mmol) in 2 mL of ethanol is added 50 L of triethylamine and Tryptamine (18 mg, 0.12 mmol). The mixture is microwaved at 120 degrees until formation of the desired compound. The reaction mixture is filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[O:8]1[CH2:10][CH2:9]1>>[O:1]1[CH2:6][CH2:5][CH:4]([O:7][CH2:10][CH2:9][OH:8])[CH2:3][CH2:2]1
Reactant: OC1CCOCC1
Reactant: C1CO1
Product: OCCOC1CCOCC1
Temperature: 0 °C

Procedure:
Into a 50-mL 3-necked round-bottom flask, was placed FeCl3 (800 mg, 4.94 mmol, 0.10 equiv). This was followed by the addition of oxan-4-ol (5 g, 48.96 mmol, 1.00 equiv) at 0° C. To this was added oxirane (20 mL) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 2×50 mL of ethyl acetate and the organic layers combined. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:30-1:1). Purification afforded 2.25 g (crude) of 2-(oxan-4-yloxy)ethan-1-ol (54.2) as a colorless oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[OH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.O>[OH:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:2][CH2:3][CH2:4][N:5]2[C:9](=[O:10])[C:8]3[C:7](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]2=[O:15])[CH2:19][CH2:18]1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCN1CCC(O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
N-(3-bromopropyl)phthalimide (26.8 g), 4-hydroxypiperidine (15.0 g) and potassium carbonate (27.6 g) were added to N,N-dimethylformamide; and the reaction mixture was stirred at room temperature overnight. After the addition of water, extraction was performed with ethyl acetate; the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield the title compound (13.9 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[C:8]([CH3:24])=[C:9]2[C:13](=[C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:15]=1[CH3:16])[NH:12][CH2:11][CH2:10]2)=[O:5])[CH3:2]>C1(C)C(C)=CC=CC=1.[Pd]>[CH2:1]([O:3][C:4]([CH2:6][C:7]1[C:8]([CH3:24])=[C:9]2[C:13](=[C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:21])([CH3:20])[CH3:22])[C:15]=1[CH3:16])[NH:12][CH:11]=[CH:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C)c2c(c(NC(=O)C(C)(C)C)c1C)NCC2
Agent: [Pd]
Solvent: Cc1ccccc1C
Product: CCOC(=O)Cc1c(C)c(NC(=O)C(C)(C)C)c2[nH]ccc2c1C
Yield: 90.5 %

Procedure:
N-(5-ethoxycarbonylmethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (1.0 g) was dissolved in xylene (75 ml), and 10% Pd-C (250 mg) was added, which was followed by refluxing for 1 hr. Pd-C was filtered off and xylene was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: benzene-CHCl3) to give 0.9 g of N-(5-ethoxycarbonylmethyl-4,6-dimethylindol-7-yl)-2,2-dimethylpropanamide.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:24]=[CH:23][C:9]([C:10]([NH:12][C:13]2[C:14](=[C:18]([Cl:22])[CH:19]=[CH:20][CH:21]=2)[C:15]([OH:17])=[O:16])=O)=[CH:8][CH:7]=1>ClCCCl>[F:5][C:6]1[CH:24]=[CH:23][C:9]([C:10]2[O:16][C:15](=[O:17])[C:14]3[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:13]=3[N:12]=2)=[CH:8][CH:7]=1
Reactant: O=C(Nc1cccc(Cl)c1C(=O)O)c1ccc(F)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: O=c1oc(-c2ccc(F)cc2)nc2cccc(Cl)c12
Reaction time: 1 h
Yield: 82.7 %

Procedure:
15.5 parts of thionyl chloride are added to a suspension of 29 parts of N-(4'-fluorobenzoyl)-6-chloroanthranilic acid in 250 parts of 1,2-dichloroethane at room temperature, and the mixture is then stirred for one hour under reflux. Thereafter, it is evaporated down and the residue is taken up in methylene chloride; this solution is extracted once with water, and then with twice 100 parts by volume of 0.5 N sodium hydroxide solution. Thereafter, it is dried, chromatographed on neutral alumina and evaporated down, 22.5 parts of 2-(4'-fluorophenyl)-5-chloro-4H-3,1-benzoxazin-4-one, of melting point 159°-162° C., being isolated; yield: 82.7%.
Reaction SMILES: [CH3:1][C:2]1[C:17]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[C:20]=2[CH3:29])=[C:5]2[N:6]=[C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:8]=[C:9]([NH2:10])[N:4]2[N:3]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>CN(C=O)C>[CH3:1][C:2]1[C:17]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[C:20]=2[CH3:29])=[C:5]2[N:6]=[C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:8]=[C:9]([NH:10][C:30](=[O:32])[CH3:31])[N:4]2[N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nn2c(N)cc(N3CCOCC3)nc2c1Cc1cccc(C(F)(F)F)c1C
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(N2CCOCC2)nc2c(Cc3cccc(C(F)(F)F)c3C)c(C)nn12
Reaction time: 8 h
Yield: 11.2 %

Procedure:
To a solution of 2-methyl-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-5-(4-morpholinyl)pyrazolo[1,5-a]pyrimidin-7-amine (120 mg, 0.3 mmol), prepared as described in Example 17, in DMF (1 mL) was added acetic anhydride (30 mg, 0.3 mmol). Reaction mixture was stirred overnight. Reaction mixture was concentrated to dryness and dissolved with DMSO (1 mL). The crude product was purified by reversed phase HPLC to provide the titled compound (15 mg, 11%); LC/MS: MS (ES+) m/e 448 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (s, 3H) 2.30 (s, 3H) 2.44-2.48 (m, 3H) 3.38-3.50 (m, 4H) 3.61-3.70 (m, 4H) 3.95 (s, 2H) 7.20 (s, 1H) 7.28 (d, J=7.83 Hz, 1H) 7.37 (d, J=7.07 Hz, 1H) 7.51 (d, J=7.83 Hz, 1H) 10.60 (s, 1H).
Reaction SMILES: [C:1]([NH:11][CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].CO.Cl>C1COCC1>[C:1]([NH:11][C@@H:12]1[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][CH2:13]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C1CCC(NC(=O)OCc2ccccc2)CC1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(N[C@H]1CC[C@@H](O)CC1)OCc1ccccc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
This ketone (2.36 g, 9.55 mmol) in THF (5 mL) was added dropwise to a stirred solution of L-selectride in THF (1M, 19.1 mL, 9.55 mmol) under N2 at -78° C. The reaction mixture was stirred at -78° C. for 3 hours, methanol (0.5 mL) was added, and the reaction mixture was allowed to warm to room temperature. 1N hydrochloric acid (5 mL) was added and the mixture stirred overnight. The reaction mixture was extracted with ethyl acetate (2×20 mL) and the combined organic layers were washed with brine (2×20 mL), dried over anhydrous sodium sulfate, filtered, and the solvent removed in vacuo to yield 2.73 g crude oil. The crude product was purified by MPLC on silica gel (70-230 mesh, 1.5×45 cm column) using a 1:1 hexane/ethyl acetate, 2:1 hexane/ethyl acetate, and ethyl acetate step gradient. Fractions containing pure product were pooled and concentrated in vacuo to give a clear oil (cis-N-Cbz-4-aminocyclohexanol) (1.35 g, 57% yield): 1H NMR (300 MHz) δ 7.35 (m, 5H), 5.10 (s, 2H), 4.74 (br, 1H), 3.91 (br, 1H), 3.62 (br, 1H), 1.18 (m, 8H); MS: (M+H)+ =250, (M+H+NH3)+ =267.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][NH2:34])=[CH:29][CH:28]=2)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[C:42](OC(=O)C)(=[O:44])[CH3:43]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:42](=[O:44])[CH3:43])=[CH:29][CH:28]=2)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(CN(c2ccc(CN)cc2)C2CCN(C(=O)OCc3ccccc3)CC2)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCc1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a solution of the above amine (462 mg, 1.02 mmol) in CH2Cl2 (10 mL) were added Et3N (0.45 mL, 3.23 mmol) followed by acetic anhydride (0.20 mL, 2.12 mmol) and the mixture was stirred at room temperature overnight to afford 4-[[4-(acetylamino-methyl)-phenyl]-(3-cyano-benzyl)-amino]-piperidine-1-carboxylic acid benzyl ester as a white solid (463 mg, 91%) following work-up and purification.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3]([CH3:8])([CH2:6][CH3:7])[C:4]#[N:5].[C:10]1([Li])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[BH4-].[Na+].CC(N1CCCC1)(C)C(N)C1C=CC=CC=1>C(OCCCC)CCC.C1COCC1.CO>[NH2:5][CH:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([N:2]([CH3:9])[CH3:1])([CH3:8])[CH2:6][CH3:7]
Reactant: CCC(C)(C#N)N(C)C
Reactant: [Li]c1ccccc1
Agent: CC(C)(C(N)c1ccccc1)N1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCOCCCC
Solvent: CO
Product: CCC(C)(C(N)c1ccccc1)N(C)C
Yield: 93 %

Procedure:
The title compound (15 g, 93%) was prepared from 2-(dimethylamino)-2-methylbutanenitrile D23 (9.9 g, 0.078 mol) and phenyllithium in dibutylether (87.3 ml of a 1.8M solution; 0.157 mol) in THF (400 ml), followed by reaction with sodium borohydride (5.25 g, 0.138 mol) in methanol (450 ml) in a similar manner to that described in D5. Mass spectrum (Electrospray LC/MS), ES+: Found 207 (MH+). C13H22N2 requires 206. Ret. times 0.83 and 1.10 min.
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:9]1[CH:10]=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:15](S(C1SC2C=CC=CC=2N=1)(=O)=O)[CH3:16].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[C:4]([O:3][C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:9]1/[CH:10]=[CH:15]/[CH3:16])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CCS(=O)(=O)c1nc2ccccc2s1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C/C=C/[C@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of Boc-D-Prolinal (0.53 g, 2.65 mmol) and 2-(ethyl sulfonyl)-1,3-benzothiazole (1.5 g, 6.62 mmol) in tetrahydrofuran (4 mL) at −78° C. was added 1M Lithium bis(trimethylsilyl)amide in THF (4 mL) and continued stirring for 30 min. Then the mixture was warmed to 0° C. and stirred for an additional 3 hr. Upon completion via LC-MS, the reaction mixture was quenched with 20% ammonium chloride solution and extracted with ethyl ether. The ether layer washed with brine, dried over sodium sulfate anhydrous, filtered and dried in vacuo to yield crude product which was further purified on an ISCO normal phase HPLC using a 100% to 75% gradient of hexane to ethyl acetate as mobile phase. Pure tert-butyl-(2R)-2-[(1E)-prop-1-enyl]pyrrolidine-1-carboxylate was isolated from the combined fractions (0.09 g). 1H NMR (CD3OD, 400 Mhz) 5.51-5.44 ppm (m, 1H), 5.39-5.31 (m, 1H), 4.20-4.12 (m, 1H), 3.38-3.30 (m, 3H), 1.91-1.81 (m, 2H), 1.79-1.66 (m, 4H), 1.425 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].Cl.C1C(O)=CC=CC=1C.[CH3:19][NH:20][C:21]#[N:22].[OH-].[Na+]>CCOCC>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:21]([NH:20][CH3:19])=[NH:22]
Reactant: Cc1cccc(C)c1N
Reactant: CNC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: Cc1cccc(O)c1
Product: CNC(=N)Nc1c(C)cccc1C

Procedure:
To 40.5 g. (0.315 mole) of 2,6-dimethylaniline is added 0.4 moles of ethereal HCl and 200 ml. of m-cresol. The mixture is then stirred and heated on a steam bath to drive off the ether and excess hydrogen chloride. To the resultant mixture is then added 17.7 g. (0.315 mole) of methyl cyanamide then heated for 2 hours on a steam bath. The reaction mixture is then cooled, added to 150 ml. of conc. sodium hydroxide solution, cooled and extracted with 2 liters of ether. The ether layer is washed with 2 × 1 liter of water, dried over sodium sulfate, charcoaled and evaporated. The residue is triturated with hexane and the precipitate is filtered off and washed with ether and dried to obtain 1-(2,6-dimethylphenyl)-3-methylguanidine.
Reaction SMILES: [C:1]([N:8]1[CH2:16][C@H:14]([OH:15])[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=N[C:27]2[CH:28]=[CH:29][CH:30]=[N:31][C:26]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.S(C1C=CC(C)=CC=1)([O-])(=O)=O.C([NH2+]C1CC1)=C.[CH3:67][CH2:68][O:69][C:70](C)=[O:71]>>[CH2:68]([O:69][C:70]([C@@:30]1([NH:31][C:10]([C@@H:9]2[CH2:13][C@@H:14]([OH:15])[CH2:16][N:8]2[C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])=[O:12])[CH2:29][C@H:28]1[CH:27]=[CH2:26])=[O:71])[CH3:67]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C=C[NH2+]C1CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C)C(=O)OCC
Reaction time: 0.75 h

Procedure:
To a stirring slurry of N-Boc-hydroxy proline (78 g), HATU (128 g), and EtOAc (558 g), at 0° C., was added diisopropylethylamine (65 g). After 45 min, a solution containing vinylcyclopropylammonium tosylate (100 g), diisopropylethylamine (65.0 g), and EtOAc (366 g) was added to the activated ester solution. After 3 h at 10° C., the reaction slurry was filtered and the resulting cake was rinsed with EtOAc (1.8 kg). The resulting filtrate was washed with a 10% aqueous solution of NaCl (5×770 g). The product-containing organic layer was filtered, concentrated under reduced pressure, diluted with EtOAc (450 g), and then filtered again. The assay yield of the final product-containing solution was determined to be 85%.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28](I)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:32]([C:34]1[O:38][C:37](B(O)O)=[CH:36][CH:35]=1)=[O:33].C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:37]5[O:38][C:34]([CH:32]=[O:33])=[CH:35][CH:36]=5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1ccc(B(O)O)o1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3ncnc4ccc(I)cc34)c2)no1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3ncnc4ccc(-c5ccc(C=O)o5)cc34)c2)no1
Temperature: 55 °C
Yield: 87 %

Procedure:
A mixture of 1-(5-tert-butylisoxazol-3-yl)-3-[3-(6-iodoquinazolin-4-yloxy)phenyl]urea from the previous step (0.21 g, 0.4 mmol), 5-formylfuran-2-ylboronic acid (0.07 g, 0.51 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.035 g, 0.05 mmol), and 1.0 M Na2CO3 solution (3 mL) in EtOH (2 mL) and 1,2-dimethoxyethane (3 mL) was heated at 55° C. for 1 hour. It was quenched with water and extracted with CH2Cl2. Extracts were dried over MgSO4 and concentrated under reduced pressure. It was purified by silica gel chromatography with 30-60% EtOAc/hexane as eluants to afford 1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-(5-formylfuran-2-yl)quinazolin-4-yloxy]phenyl}urea as solid (0.172 g, 87%). 1H NMR (300 MHz, CDCl3) δ 9.75 (s, 1H), 9.53 (br, 1H), 8.80 (d, 1H), 8.78 (s, 1H), 7.32 (dd, 1H), 8.07 (d, 1H), 7.67 (m, 2H), 7.34-7.54 (m, 3H), 7.07 (d, 1H), 7.01 (d, 1H), 5.94 (s, 1H), 1.32 (s, 9H); LC-MS (ESI) m/z 498 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([N:18]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[C:19](=[O:21])[CH3:20])[CH2:10][CH:9]2[CH3:29])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:40][CH2:41][N:42]=[C:43]=[O:44]>C(Cl)Cl>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([N:18]([C@H:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([N:1]4[CH2:40][CH2:41][NH:42][C:43]4=[O:44])=[CH:31][CH:30]=3)[C@@H:9]([CH3:29])[CH2:10]2)[C:19](=[O:21])[CH3:20])=[CH:27][CH:26]=1
Reactant: CC(=O)N(c1ccc(Cl)cc1)C1CC(C)N(C(=O)c2ccc(N)cc2)c2ccccc21
Reactant: O=C=NCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(N3CCNC3=O)cc2)c2ccccc21
Temperature: 25 °C

Procedure:
N-[1-(4-Amino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-(4-chloro-phenyl)-acetamide (156 mg, 0.373 mmol) was dissolved in methylene chloride (3 mL) and was added triethylamine (0.078 mL, 0.559 mmol) and 1-chloro-2-isocyanato-ethane 0.038 mL, 0.448 mmol). The reaction was stirred at room temperature over night, and the reaction was quenched with sat. aq. NaHCO3. The residue was partitioned between methylene chloride and water, then extracted three times with methylene chloride, dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography (ethyl acetate) to afford the product.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23](=[NH:26])[NH:24][OH:25])=[CH:13][CH:12]=2)[C:8]2[C:27]([C:31]([O:33][CH3:34])=[O:32])=[CH:28][CH:29]=[CH:30][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[C:42](OC(=O)C)(=[O:44])[CH3:43]>ClCCl>[C:42]([O:25][NH:24][C:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:9]2[C:8]3[C:27]([C:31]([O:33][CH3:34])=[O:32])=[CH:28][CH:29]=[CH:30][C:7]=3[N:6]=[C:5]2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:12][CH:13]=1)=[NH:26])(=[O:44])[CH3:43]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2C(=N)NO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2C(=N)NOC(C)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 2-butyl-1-[[2'-(hydroxycarbamimidoyl)biphenyl-4-yl]methyl]bezimidazole-7-carboxylate (1.83 g) in dichloromethane (20 ml) was added triethylamine (0.46 g) and acetic anhydride (0.46 g), and the reaction mixture was stirred at room temperature for 2 hours. After evaporation of the solvent, the residue was partitioned between ethylacetate and water and the organic layer was washed with an aqueous solution of NaHCO3 and water. The solution was dried and concentrated to dryness to give a pale yellow solid (1.99 g, quant.)