Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.N([C:11]([C:14](=[NH:16])N)([CH3:13])C)=N[C:5]([C:8](=N)[NH2:9])(C)[CH3:6].[CH3:17][C:18](C)=O>>[ClH:1].[CH2:17]([CH:13]=[CH:11][CH2:14][NH2:16])[CH3:18].[ClH:1].[CH2:8]([NH2:9])[CH:5]=[CH2:6]
Reactant: CC(C)=O
Reactant: CC(C)(N=NC(C)(C)C(=N)N)C(=N)N
Agent: Cl
Product: C=CCN
Product: CCC=CCN
Temperature: 60 °C
Reaction time: 48 h

Procedure:
A 64.2% aqueous solution of N-ethylallylamine hydrochloride (hereinafter, abbreviated as EAA.HCl) was propared by adding 52.1 g of 35% hydrochloric acid to 42.58 g (0.5 mole) of N-ethylallylamine while cooling the reaction mixture. On the other hand, 28.54 g (0.5 mole) of allylamine was neutralized with 52.1 g of 35% hydrochloric acid while cooling the reaction mixture, and then the mixture was concentrated by means of rotary evaporator to obtain a 69.8% aqueous solution of allylamine hydrochloride (hereinafter, abbreviated as AA.HCl). Then, 18.94 g of the aqueous solution of EAA.HCl and 13.40 g of aqueous solution of AA.HCl, obtained above, were mixed together and heated to 60° C. Then, 0.645 g of 2,2'-azobis(2-amidinopropane) dihydrochloride was added, and a polymerization reaction was carried out at that temperature for 48 hours. After the reaction, the reaction mixture (a solution) was poured into a large amount of acetone to precipitate the reaction product. The precipitate was collect by filtration using a glass filter and dried at 50° C. under reduced pressure. Thus, a copolymer of N-ethylallylamine hydrochloride and allylamine hydrochloride was obtained.
Reaction SMILES: [F:1][C:2]1([CH:12]([O:17][Si](CC)(CC)CC)[C:13]([F:16])([F:15])[F:14])[CH2:7][CH2:6][N:5]([S:8]([CH3:11])(=[O:10])=[O:9])[CH2:4][CH2:3]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>O1CCCC1>[F:1][C:2]1([CH:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH2:7][CH2:6][N:5]([S:8]([CH3:11])(=[O:10])=[O:9])[CH2:4][CH2:3]1
Reactant: CC[Si](CC)(CC)OC(C(F)(F)F)C1(F)CCN(S(C)(=O)=O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N1CCC(F)(C(O)C(F)(F)F)CC1
Yield: 55 %

Procedure:
By use of 4-fluoro-1-methanesulfonyl-4-[2,2,2-trifluoro-1-(triethyl-siloxy)ethyl]piperidine (309 mg, 0.785 mmol) dissolved in tetrahydrofuran (5 mL) and a 1 mol/L solution of tetrabutylammonium fluoride in tetrahydrofuran (1.18 mL, 1.18 mmol), the mixture was stirred and reacted at room temperature for 30 minutes. The reaction was stopped by addition of water to the reaction mixture, and extraction with ethyl acetate was performed, followed by drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give Compound EAS (120 mg, yield: 55%).
Reaction SMILES: O.[NH2:2][NH2:3].[IH:4].[CH2:5]([NH:12][C:13](=[N:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)SC)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)C>[IH:4].[NH2:2][NH:3][C:13]([NH:12][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CSC(=NCc1ccccc1)NCc1ccccc1
Reactant: NN
Agent: I
Solvent: O
Solvent: CCO
Product: NNC(=NCc1ccccc1)NCc1ccccc1

Procedure:
A solution of 6 ml. of hydrazine hydrate and the solution of 1,3-dibenzyl-2-methylthiopseudourea hydroiodide from Example 13 in 500 ml. of absolute ethanol is heated at reflux for 4 hours and then evaporated to dryness under reduced pressure. The residual solid is crystallized from isopropyl alcohol twice giving the desired product as colorless crystals, m.p. 135°-137° C.
Reaction SMILES: [F:1][C:2]1([F:32])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[C:24]([OH:30])=[N:25][CH:26]=[C:27]([CH3:29])[CH:28]=5)[C:20]([CH3:31])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:40][C:41]([O:43][CH3:44])=[O:42]>CN(C=O)C>[F:32][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[C:24](=[O:30])[N:25]([CH2:40][C:41]([O:43][CH3:44])=[O:42])[CH:26]=[C:27]([CH3:29])[CH:28]=5)[C:20]([CH3:31])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[F:32][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[C:24]([O:30][CH2:40][C:41]([O:43][CH3:44])=[O:42])=[N:25][CH:26]=[C:27]([CH3:29])[CH:28]=5)[C:20]([CH3:31])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: COC(=O)CCl
Reactant: Cc1cnc(O)c(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ncc(C)cc1-c1nc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)ccc1C
Product: COC(=O)Cn1cc(C)cc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)c1=O
Temperature: 80 °C
Reaction time: 21 h
Yield: 59.3 %
Yield: 24 %

Procedure:
To a solution of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-hydroxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (0.029 g, 0.06556 mmol) in DMF (1 mL) was added K2CO3 (0.091 mg, 0.6556 mmol) and methyl chloroacetate (28.82 μL, 0.3278 mmol). The reaction was stirred at 80° C. for 21 hours to yield a mixture of N-alkylated product and O-alkylated product. The reaction was filtered using ethyl acetate and the solvent was evaporated under reduced pressure. The crude products were separated by column chromatography on silica gel (0-100% ethyl acetate in hexane) to yield methyl 2-(3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-5-methyl-2-oxopyridin-1(2H)-yl)acetate [20 mg, 59.3%; ESI-MS m/z calc. 511.47. found 512.5 (M+1)+, retention time 1.74 minutes] and methyl 2-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3,5′-dimethyl-2,3′-bipyridin-2′-yloxy)acetate [8 mg, 24%; ESI-MS m/z calc. 511.47. found 512.5 (M+1)+, retention time 2.13 minutes].
Reaction SMILES: C(OC(=O)C1C=CC(NC2CCCCC2)=C(NC(C2C=C3C(=CC=2)N=C(C2C(C4C=CC(Cl)=CC=4)=CC=C(C(N4CCCC4)=O)C=2)C=C3)=O)C=1)C.ClC1C=CC([C:57]2[C:62]([C:63]3[CH:72]=[CH:71][C:70]4[C:65](=[CH:66][CH:67]=[C:68]([C:73]5[N:77]([CH:78]6[CH2:83][CH2:82][CH2:81][CH2:80][CH2:79]6)[C:76]6[CH:84]=[CH:85][C:86]([C:88]([OH:90])=[O:89])=[CH:87][C:75]=6[N:74]=5)[CH:69]=4)[N:64]=3)=[CH:61][C:60](C(N3CCCC3)=O)=[CH:59][CH:58]=2)=CC=1.[Br:100]C1C=CC=CC=1C(=O)C.C(C1C=CC=CC=1)(=O)C>>[Br:100][C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][C:62]=1[C:63]1[CH:72]=[CH:71][C:70]2[C:65](=[CH:66][CH:67]=[C:68]([C:73]3[N:77]([CH:78]4[CH2:83][CH2:82][CH2:81][CH2:80][CH2:79]4)[C:76]4[CH:84]=[CH:85][C:86]([C:88]([OH:90])=[O:89])=[CH:87][C:75]=4[N:74]=3)[CH:69]=2)[N:64]=1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4-c4ccc(Cl)cc4)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)c1ccccc1Br
Agent: CCOC(=O)c1ccc(NC2CCCCC2)c(NC(=O)c2ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4-c4ccc(Cl)cc4)ccc3c2)c1
Solvent: CC(=O)c1ccccc1
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4Br)ccc3c1)n2C1CCCCC1

Procedure:
The title compound was synthesized in four steps as described for Compound 13, Compound 25, Compound 27 Q=ethyl and Compound 204, respectively, except 2′-bromoacetophenon was used in the first step instead of acetophenone.
Reaction SMILES: [C:1]([Cl:4])(=[O:3])C.[NH:5]1[CH:9]=[C:8](C(O)=O)[CH:7]=[N:6]1.[CH3:13][OH:14]>>[ClH:4].[NH:6]1[CH:7]=[CH:8][C:9]([C:13]([O:3][CH3:1])=[O:14])=[N:5]1
Reactant: CO
Reactant: CC(=O)Cl
Reactant: O=C(O)c1cn[nH]c1
Product: COC(=O)c1cc[nH]n1
Product: Cl
Yield: 90 %

Procedure:
10 mL of methanol at 0° C. was treated dropwise with lmL acetyl chloride, followed by addition of 2.0 g(17.84 mmol) of 4-pyrazolcarboxylic acid, followed by warming the mixture at reflux for 18 h. The solution was cooled and concentrated in vacuo to afford 2.6 g(90%) of the title compound as a white solid. 1H NMR (CD3OD) δ8.25, 3.86.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:17][C:14]3([CH2:16][CH2:15]3)[N:13]([S:18]([NH2:21])(=[O:20])=[O:19])[CH2:12][CH2:11]2)=[N:3][CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].[O:28](C(OC(C)(C)C)=O)[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=O.O>CN(C=O)C>[C:32]([O:31][C:29]([N:7]1[C:6]2[N:1]=[CH:2][N:3]=[C:4]([N:10]3[CH2:17][C:14]4([CH2:16][CH2:15]4)[N:13]([S:18](=[O:20])(=[O:19])[NH2:21])[CH2:12][CH2:11]3)[C:5]=2[CH:9]=[CH:8]1)=[O:28])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NS(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1ccc2c(N3CCN(S(N)(=O)=O)C4(CC4)C3)ncnc21
Temperature: 0 °C
Reaction time: 16 h

Procedure:
7-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diaza-spiro[2.5]octane-4-sulfonic acid amide (intermediate 1) (1.5 g, 4.86 mmol) was dissolved in dry DMF (20 ml), added Cs2CO3 (1.59 g, 4.86 mmol) and cooled to 0° C. A solution of BOC2O (1.06 g, 4.86 mmol) in dry DMF (10 mL) was added and the reaction mixture was allowed to warm up to rt and stirred at rt for 16 h. The crude mixture was treated with water (150 mL) and extracted with EtOAc (3×100 mL). The combined organic phases were washed with H2O (2×50 mL), brine (2×50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica using EtOAc in heptane as eluent.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[C:4]([C:10]([F:13])([F:12])[F:11])[N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:19]>C(#N)C.CCOC(C)=O>[OH:9][CH2:8][C:7]1[C:2]([CH3:1])=[N+:3]([O-:19])[C:4]([C:10]([F:11])([F:13])[F:12])=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nc(C(F)(F)F)ccc1CO
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1c(CO)ccc(C(F)(F)F)[n+]1[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 25 %

Procedure:
To a stirring solution of (2-methyl-6-(trifluoromethyl)pyridin-3-yl)methanol (2.70 g, 14.1 mmol) in acetonitrile (20 mL) at room temperature was added dropwise a solution of 3-chloroperoxybenzoic acid (77% pure, 3.8 g, 16.9 mmol) in acetonitrile. The reaction mixture was stirred at room temperature for 16 h before concentration under reduced pressure. The residue was diluted with EtOAc, and the EtOAc solution was washed with 5% aqueous Na2S2O3, water, then saturated aqueous NaCl, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (40 g) eluted with a gradient of EtOAc (30-100%) in hexanes to afford 730 mg (25%) of the title compound as a white solid. HPLC/MS: retention time=0.92 min, [M+H]+=208.0. In addition, (2-methyl-6-(trifluoromethyl)pyridin-3-yl)methanol (1.90 g) was recovered.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]([F:15])([F:14])[CH:11]1[CH2:13][O:12]1>>[CH2:1]([NH:8][CH2:13][CH:11]([OH:12])[C:10]([F:15])([F:14])[F:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: FC(F)(F)C1CO1
Product: OC(CNCc1ccccc1)C(F)(F)F

Procedure:
Starting material: benzylamine and 2-(trifluoromethyl)oxirane
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)([O-:3])=[O:2].[H-].[Na+].[Cl:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1.CN(C=O)C>C1COCC1>[ClH:16].[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:29][CH2:30][CH2:31][CH2:32][N:33]1[CH2:34][CH2:35][O:36][CH2:37][CH2:38]1)[N:20]=[CH:19][N:18]=[C:17]2[CH:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][C:8]1=[O:13]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2c(C3C(=O)Nc4ccc([N+](=O)[O-])cc43)ncnc2cc1OCCCN1CCOCC1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
A solution of 5-nitrooxindole (1.26 g, 7.1 mmol), (prepared as described for the starting material in Example 21), in THF (10 ml) was added dropwise to sodium hydride (284 mg, 7.1 mmol, prewashed with THF) in THF (15 ml). The mixture was stirred for 30 minutes at ambient temperature and a solution of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (600 mg, 1.8 mmol, (prepared as described for the starting material in Example 5), in THF (10 ml) and DMF (3 ml) was added dropwise. The mixture was stirred for 30 minutes at ambient temperature, then heated at 75° C. for 1.5 hours. DMF (4 ml) was added and the mixture stirred for 12 hours at ambient temperature. The solvent was removed by evaporation, the residue was partitioned between ethyl acetate and water and the aqueous layer was adjusted to pH8 with 2M hydrochloric acid. The precipitated product was collected by filtration, washed with water and dried under vacuum. The solid was dissolved in a mixture of DMF and dilute hydrochloric acid (pH2) and was purified on a Diaion (trade mark of Mitsubishi) HP20SS resin column, eluting with a gradient of methanol and dilute hydrochloric acid (pH2). The purified solid was dissolved in methanol and 7M ethanolic hydrogen chloride (1.5 ml) was added. The volatiles were removed by evaporation and the solid residue was triturated with a mixture of methanol and ether. The solid was collected by filtration and dried under vacuum to give 6-methoxy-7-(3-morpholinopropoxy)-4-(5-nitrooxindol-3-yl)-quinazoline hydrochloride (275 mg, 29%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH:16]=[CH:15][C:14](NC2C=CC(N)=CC=2)=[CH:13][CH:12]=1.Cl.Cl.N1C2C(=CC=CC=2)C=[CH:29][C:28]=1C1C=CC(N)=CC=1.C(OC([NH:51]C1C=CC(B(O)O)=CC=1)=O)(C)(C)C.C(N(CC)CC)C>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]#[C:16][C:15]1[CH:14]=[CH:13][C:12]([NH2:51])=[CH:29][CH:28]=1
Reactant: Nc1ccc(-c2ccc3ccccc3n2)cc1
Reactant: Nc1ccc(Nc2ccc(-c3ccc4ccccc4n3)cc2)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1ccc(C#Cc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-(4-(Quinolin-2-yl)phenyl)benzene-1,4-diamine *3TFA: T447 To a solution of 4-(quinolin-2-yl)aniline dihydrochloride (7.6 mg, 0.026 mmol) in DCM (1.0 mL) was added 4-(tert-butoxycarbonylamino)phenylboronic acid (12.4 mg, 0.052 mmol), Cu(OAc)2 (4.8 mg, 0.026 mmol) and triethylamine (0.036 mL, 0.26 mmol). The mixture was stirred at room temperature for 3 hrs. LCMS showed that the desired product was formed. To the mixture was added 4 N HCl in dioxane (1.0 mL) and stirred for another hour. The mixture was concentrated in vacuo and purified by HPLC (acetonitrile/water) to give T447 as a brown solid (4.3 mg, 25%). 1H NMR (400 MHz, CD3OD): δ 8.77 (d, J=8.8 Hz, 1H), 8.16 (m, 2H), 8.10 (d, J=8.4 Hz, 1H), 8.01 (m, 2H), 7.96 (m, 1H), 7.73 (m, 1H), 7.21-729 (m, 6H); MS (ESI): 312 (M+H+).
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[Mg+2].FC(F)(F)S([O-])(=O)=O.[Si:18]([O:25][C@@H:26]([CH3:29])[CH2:27][OH:28])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].[O:30]1[CH2:32][C@H:31]1[C:33]([O:35][CH3:36])=[O:34].O1CC1>CCOC(C)=O>[Si:18]([O:25][C@@H:26]([CH3:29])[CH2:27][O:28][CH2:32][C@H:31]([OH:30])[C:33]([O:35][CH3:36])=[O:34])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: COC(=O)[C@@H]1CO1
Reactant: C[C@@H](CO)O[Si](C)(C)C(C)(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: C1CO1
Product: COC(=O)[C@@H](O)COC[C@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 80 °C
Reaction time: 24 h
Yield: 41.9 %

Procedure:
Magnesium trifluoromethanesulfonate (1.779 g, 5.52 mmol) was added in one portion to (S)-2-(tert-butyldimethylsilyloxy)propan-1-ol (Intermediate AS4) (4.2 g, 22.06 mmol) and (S)-methyl oxirane-2-carboxylate (2.252 g, 22.06 mmol) in EtOAc (25 mL). The resulting suspension was stirred at 80° C. for 24 hours. A further 1.5 g of the oxirane was added and the reaction stirred for 4 days. The reaction mixture was diluted with EtOAc, filtered through celite and evaporated to dryness. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in isohexane to afford the product (2.70 g, 41.8%). 1H NMR (400 MHz, CDCl3) δ 0.00 (6H, d), 0.82 (9H, s), 1.06 (3H, d), 3.04 (1H, d), 3.25-3.39 (2H, m), 3.65-3.78 (5H, m), 3.83-3.92 (1H, m), 4.19-4.27 (1H, m)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=2[Cl:15])=[CH:2]1.Cl.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1>>[ClH:15].[Cl:15][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:8]=1[O:7][CH2:6][C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)[NH:14][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: Nc1ccc(OCc2ccoc2)c(Cl)c1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Product: COc1cc2ncnc(Nc3ccc(OCc4ccoc4)c(Cl)c3)c2cc1OC
Yield: 79 %

Procedure:
Using an analogous procedure to that described in Example 1 except that the reaction mixture was heated to reflux for 6 hours, 4-amino-2-chlorophenyl 3-furylmethyl ether was reacted with 4-chloro-6,7-dimethoxyquinazoline hydrochloride to give 4-[3-chloro-4-(3-furylmethoxy)anilino]-6,7-dimethoxyquinazoline hydrochloride salt in 79% yield, m.p. 244°-246° C.;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][C:15]([CH2:38][CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])=[C:16]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:17]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)[C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[N+]([O-])([O-])=O.[NH4+].[Ce]>C(#N)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:17]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:31][CH:32]=2)[C:16]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:15]([CH2:38][CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])[N:14]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C1=C(CCCC(C)C)NC([C@@H]2CCCN2C(=O)OC(C)(C)C)=C(C(=O)OCC)C1c1ccc(C(=O)O)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(CCCC(C)C)nc([C@@H]2CCCN2C(=O)OC(C)(C)C)c(C(=O)OCC)c1-c1ccc(C(=O)O)cc1
Reaction time: 0.75 h

Procedure:
4-[2-[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]-3,5-bis(ethoxycarbonyl)-6-(4-methylpentyl)-1,4-dihydro-4-pyridinyl]benzoic acid was dissolved in a 50:50 mixture of acetonitrile:H2O. To the mixture cerium ammonium nitrate was added (6.65 g, 10.3 mmol) and allowed to stir for 45 minutes. The reaction mixture was dissolved in 100 mL of ethyl acetate and washed with H2O (2×50 mL) and brine. The organics were then dried over sodium sulfate, filtered and concentrated to yield a orange/red oil which was purified by column chromatography (ethyl acetate/hexanes (4:1)) to give 2.0 g of a solid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.[N:27]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1)=C=O.[CH:38]1([NH2:41])[CH2:40][CH2:39]1>>[CH:38]1([NH:41][C:24]([C@@H:9]2[CH2:10][C:11](=[N:13][O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[CH2:12][N:8]2[C:6]([NH:27][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=2)=[O:7])=[O:26])[CH2:40][CH2:39]1
Reactant: COc1cccc(N=C=O)c1
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccc(Cl)c(Cl)c2)C[C@H]1C(=O)O
Reactant: NC1CC1
Product: COc1cccc(NC(=O)N2CC(=NOCc3ccc(Cl)c(Cl)c3)C[C@H]2C(=O)NC2CC2)c1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, 1-isocyanato-3-methoxybenzene, and cyclopropylamine the title compound was obtained in 45% purity by LC/MS. MS(ESI+): m/z=491.6.
Reaction SMILES: C(O[C:4]1[CH2:8][CH:7]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:6][N:5]=1)C.[CH:19]([NH:21][NH2:22])=O.C(O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C(OCC)(=O)C>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][S:9][CH:7]2[CH2:6][N:5]3[C:4](=[N:22][N:21]=[CH:19]3)[CH2:8]2)=[CH:16][CH:15]=1
Reactant: CCOC1=NCC(SCc2ccc(OC)cc2)C1
Reactant: NNC=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(CSC2Cc3nncn3C2)cc1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-ethoxy-4-p-methoxybenzylthio-1-pyrroline (1.06 g) in ethanol (50 ml) there was added 0.36 g of formylhydrazine and heated to 80° C. under argon atmosphere while stirring. After 1.5 hours, 0.24 g of formylhydrazine was further added and stirred under heating for 30 minutes at the same temperature. Then, 0.6 g of acetic acid was added, stirred for 30 minutes at that temperature and then cooled to room temperature. To the cooled product were added ethyl acetate and 5% aqueous solution of sodium carbonate to distribute the product between these two liquids. The resulting organic phase was washed with saturated NaCl aqueous solution, dried over Na2SO4 and distilled off the solvent under reduced pressure to obtain the objective product.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:27][S@@:28]([C:30]([CH3:33])([CH3:32])[CH3:31])=[O:29])([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22]C(F)(F)F)[CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:15])([F:14])[F:13])[CH:6]=1)#[N:2].[NH2:34][OH:35].CO.C(O)([C:40]([F:43])([F:42])[F:41])=O>CCO.O>[OH:35][N:34]=[C:1]([NH2:2])[CH2:3][C:4]([NH:27][S:28]([C:30]([CH3:33])([CH3:32])[CH3:31])=[O:29])([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:40]([F:41])([F:42])[F:43])[CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:13])([F:15])[F:14])[CH:6]=1
Reactant: CC(C)(C)[S@@](=O)NC(CC#N)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Reactant: NO
Reactant: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCO
Solvent: CO
Product: CC(C)(C)S(=O)NC(CC(N)=NO)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Temperature: 62.5 °C

Procedure:
(R)—N-(2-Cyano-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (140 mg, 0.28 mmol) was stirred in EtOH (3 mL) and NH2OH in H2O (3 mL) in a capped microwave tube. The mixture was heated in an oil bath at 60-65° C. for 2 h. LC-MS (ESI) 528.42 (M+H), retention time=3.46 min (10-90% MeOH in H2O with 0.1% TFA in a 4-min run). The cap was removed and the solvents were concentrated. The residue was dissolved in CH2Cl2, washed with H2O, dried over MgSO4, filtered, and concentrated to give crude N′-hydroxy-3-(2-methylpropan-2-ylsulfinamido)-3,3-bis(3-(trifluoromethoxy)phenyl)propanamidine. After drying under vacuum for 2 h, the residue was dissolved in CH2Cl2 (5 mL). Et3N (0.25 mL, mmol, eq) was added followed by the addition of Ac2O (0.1 mL). The resulting mixture was stirred at room temperature for 24 h. LC-MS (ESI) 570.49 (M+H), 592.49 (M+Na), retention time=3.92 min (10-90% MeOH in H2O with 0.1% TFA in a 4-min run). CH2Cl2 (5 mL) was added. The organic layer was washed with H2O, dried over MgSO4, filtered, and concentrated to dryness to give colorless film (0.255 g). This residue was dissolved in HOAc (5 mL) and was heated at 90° C. for 4 h. After cooling, H2O was added. The mixture was extracted with CH2Cl2 (2×) and the combined organic portion washed with sat'd NaHCO3 (2×), H2O and brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, EtOAc/Hexanes=0 to 100%) to give 2-methyl-N-(2-(3-methylisoxazol-5-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)propane-2-sulfinamide as colorless oil (52 mg, total yield for 3 steps: 41%). LC-MS (ESI) 441.29 (M-NH2), retention time=3.14 min (10-90% MeOH in H2O with 0.1% TFA in a 4-min run); 1H NMR (400 MHz, CDCl3) δ ppm 7.26-7.19 (m, 5H), 7.00 (m, 3H), 3.57 (s, 2H), 2.39 (s, 3H).