Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([N+:22]([O-:24])=[O:23])=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[C:8](=[O:13])[N:7]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:6]=2[CH:21]=1.[C:25](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([N:7]2[C:6]3[CH:21]=[C:2]([CH3:25])[C:3]([N+:22]([O-:24])=[O:23])=[CH:4][C:5]=3[O:10][C:9]([CH3:12])([CH3:11])[C:8]2=[O:13])=[CH:15][CH:16]=1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)Oc2cc([N+](=O)[O-])c(Cl)cc2N(c2ccc(F)cc2)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cc2c(cc1[N+](=O)[O-])OC(C)(C)C(=O)N2c1ccc(F)cc1
Yield: 5.3 %

Procedure:
To a mixture of 6-chloro-4-(4-fluorophenyl)-2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (compound obtained in Reference Example 50(2); 200 mg), potassium carbonate (236 mg), tetrakis(triphenylphosphine)palladium(0) (66 mg) and dioxane (2 mL) was added trimethylboroxin (80 μL) under argon atmosphere, and the mixture was refluxed under heating for 18 hours. After cooling, the reaction mixture was filtered through a celite pad, and the insolubles were washed with tetrahydrofuran. The filtrate and the washings were combined and concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (solvent; n-hexane/ethyl acetate=9/1) to give 4-(4-fluorophenyl)-2,2,6-trimethyl-7-nitro-2H-1,4-benzoxazin -3(4H)-one (10 mg) as a pale yellow powder.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.C(OCC)(=O)C>C1COCC1>[NH2:9][CH2:8][C:7]1[C:2]([NH2:1])=[N:3][C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:5][C:6]=1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17]
Reactant: N#Cc1c(N)nc(-c2ccccc2)nc1-c1ccc(Cl)cc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: NCc1c(N)nc(-c2ccccc2)nc1-c1ccc(Cl)cc1Cl
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Under an atmosphere of argon, a solution of 4-Amino-6-(2,4-dichloro-phenyl)-2-phenyl-pyrimidine-5-carbonitrile (1.16 g, 0.34 mmol) in THF (6 ml) was added slowly to a suspension of LiAlH4 in THF (3 ml). After stirring for 2 h at 40° C., the reaction mixture was cooled to −20° C. and water (0.6 ml) was added. After 15 min, ethyl acetate was added and the mixture was filtered through Decalite. The organic phase was then separated, washed with water, and dried over sodium sulfate. Purification by flash chromatography (silica gel, methanol, dichloromethane) afforded the title compound, MS: m/e=344.2 (M+), as a light yellow solid (0.446 g, 40%).
Reaction SMILES: [O:1]([C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:24]([CH2:25][CH2:26][C@:10]12[CH3:11])[C:23]1[CH:22]=[CH:21][C:20]([O:27][CH3:28])=[CH:19][C:18]=1[CH:17]([OH:29])[CH2:16]3)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]>ClCCl.[O-2].[O-2].[Mn+4]>[O:1]([C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:24]([CH2:25][CH2:26][C@:10]12[CH3:11])[C:23]1[CH:22]=[CH:21][C:20]([O:27][CH3:28])=[CH:19][C:18]=1[C:17](=[O:29])[CH2:16]3)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: COc1ccc2c(c1)C(O)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1ccc2c(c1)C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
17β-(t-Butyldimethylsiloxy)-3-methoxyestra-1,3,5(10)-trien-6-ol (14.4 g, 34.5 mmol) was dissolved in dichloromethane (250 ml). Manganese dioxide (29 g) and molecular sieves 4A powder (7.2 g) were added to the resulting solution followed by stirring for 1 hour at room temperature. The reaction mixture was filtered through cellite and the filtrate was concentrated under reduced pressure. The residue was recrystallized from hexane to give 17β-(t-butyldimethylsiloxy)-3-methoxyestra-1,3,5(10)-trien-6-one (11.36 g, Yield 79%).
Reaction SMILES: NC1C=CC=CC=1.[CH2:8]([OH:30])[C@H:9]1[O:14][C@H:13]([O:15]C[C@H]2OC(O)(CO)[C@@H](O)[C@@H]2O)[C@H:12]([OH:27])[C@@H:11]([OH:28])[C@@H:10]1[OH:29].[CH2:31]([OH:53])[C@H:32]1[O:37][C@H:36]([O:38]CC([C@@H](O)[C@H](O)[C@H](O)CO)=O)[C@H:35]([OH:50])[C@@H:34]([OH:51])[C@@H:33]1[OH:52].[CH2:54]([OH:76])[C@H:55]1[O:60][C@H:59]([O:61][C@:62]2([CH2:71][OH:72])[O:66][C@H:65]([CH2:67][OH:68])[C@@H:64]([OH:69])[C@@H:63]2[OH:70])[C@H:58]([OH:73])[C@@H:57]([OH:74])[C@@H:56]1[OH:75]>C(OC(=O)C)C>[O:15]=[CH:13][C@@H:12]([C@H:11]([C@@H:10]([C@@H:9]([CH2:8][OH:30])[OH:14])[OH:29])[OH:28])[OH:27].[OH:53][CH2:31][C:32]([C@H:33]([C@@H:34]([C@@H:35]([CH2:36][OH:38])[OH:50])[OH:51])[OH:52])=[O:37].[CH2:54]([OH:76])[C@H:55]1[O:60][C@H:59]([O:61][C@:62]2([CH2:71][OH:72])[O:66][C@H:65]([CH2:67][OH:68])[C@@H:64]([OH:69])[C@@H:63]2[OH:70])[C@H:58]([OH:73])[C@@H:57]([OH:74])[C@@H:56]1[OH:75]
Reactant: OC[C@H]1O[C@H](OC[C@H]2OC(O)(CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: O=C(CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Solvent: CCOC(C)=O
Solvent: Nc1ccccc1
Product: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
TLC was performed by spotting 3 microliters of the supernatants of the growth media onto AL SIL G silica gel plates (Whatman) and developed twice in a solvent consisting of 3 parts ethylacetate: 3 parts acetic acid: 1 part distilled water. After drying, the plates were sprayed with a dye mixture consisting of 4 milliliters aniline, 4 g diphenylamine, 200 milliliters acetone, and 30 milliliters 80% phosphoric acid. Isomaltulose and trehalulose were distinguished from other sugars, such as sucrose, by their relative mobility and by the distinct colors produced when they reacted with aniline dye. Greenish yellow indicates the presence of isomaltulose, red indicates the presence of trehalulose, and brown/black indicates the presence of sucrose. The monosaccharides, glucose and fructose, produced by hydrolysis of sucrose were blue or red-orange respectively.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:14]([N:27]1[CH2:30][CH:29](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:28]1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([CH:29]1[CH2:30][N:27]([CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:28]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ccc(S(=O)(=O)C2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of sodium hydride (4.97 g, 0.129 mol) in 130 mL of anhydrous dimethyl formamide was added diethyl malonate (22.7 mL, 0.142 mol) dropwise at 0° C. and this reaction mixture was stirred at room temperature for 2 h. 1-Benzhydryl-3-(toluene-4-sulfonyl)-azetidine was added to it dropwise at 0° C. and reaction mixture was refluxed at 110° C. for 20 h. Excess sodium hydride was quenched with ammonium chloride, DMF was removed, and the reaction mixture was partitioned between chloroform and water; the aqueous layer was extracted with chloroform, the solvent was removed in vacuo, and purification by (neutral alumina) chromatography and 30% ethyl acetate/hexanes as eluent provided 2-(1-benzhydryl-azetidin-3-yl)-malonic acid diethyl ester. 1H-NMR (400 MHz, CDCl3), δ ppm 7.41-7.17 (m, 10H), 4.34 (s, 1H), 4.25-4.09 (m, 3H), 3.66 (d, 1H, J=3.66 Hz), 3.41-3.37 (m, 2H), 3.07-2.99 (m, 1H), 2.93-2.90 (m, 2H), 1.25-1.23 (m, 6H)
Reaction SMILES: [CH2:1]([N:8]([CH2:20]/[C:21](/[CH3:24])=[CH:22]/[CH3:23])[C:9]([CH:11]1[C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>BrC1C=CC=CC=1>[CH2:1]([N:8]1[C:9](=[O:10])[C@H:11]2[C@@:21]([CH3:24])([C@@H:22]([CH3:23])[CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=32)[CH2:20]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C/C=C(\C)CN(Cc1ccccc1)C(=O)C1Cc2c(Cl)cccc21
Solvent: Brc1ccccc1
Product: C[C@H]1Cc2c(Cl)cccc2[C@H]2C(=O)N(Cc3ccccc3)C[C@@]21C
Temperature: 190 °C
Yield: 69.4 %

Procedure:
(E)-N-Benzyl-3-chloro-N-(2-methylbut-2-enyl)-1,2-dihydrocyclobutabenzene-1-carboxamide (0.971 mmol, 330 mg) was dissolved in bromobenzene (6 ml) and heated in a microwave reactor at 190° C. for 1 hour. The solvent was removed in vacuo and the resulting residue was purified by silica column chromatography (eluting with heptane then 5-20% ethyl acetate in heptane) to give (3aR*,4S*,9bR*)-2-benzyl-6-chloro-3a,4-dimethyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindol-1-one (229 mg) 1H NMR (400 MHz, CDCl3) ppm 7.42 (1H, d, ArH), 7.33-7.22 (7H, m, ArH), 4.57 (1H, d, CHHPh), 4.34 (1H, d, CHHPh), 3.34 (1H, s, CH), 3.24 (1H, d, CH), 3.01 (1H, d, CH), 2.90 (1H, dd, CH), 2.38 (1H, dd, CH), 1.77 (1H, m, CH), 1.04 (3H, s, CH3), 0.91 (3H, d, CH3) and (3aR*,4S*,9bS*)-2-benzyl-6-chloro-3a,4-dimethyl-2,3,3a,4,5,9b-hexahydro-H-benzo[e]isoindol-1-one (96 mg) 1H NMR (400 MHz, CDCl3) ppm 8.36 (1H, d, ArH), 7.45-7.13 (7H, m, 7×ArH), 4.55 (1H, d, CHHPh), 4.47 (1H, d, CHHPh), 3.40 (1H, s, CH), 3.07-2.94 (3H, m, 3×CH), 2.40 (1H, dd, CH), 2.21-2.10 (1H, m, CH2), 0.99 (3H, d, CH3), 0.68 (3H, s, CH3).
Reaction SMILES: [Br:1][C:2]1[C:3]([Br:21])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([S:11][CH3:12])=[N:6]2.C(Cl)Cl.C1C=C(Cl)C=C(C(OO)=[O:33])C=1>>[Br:1][C:2]1[C:3]([Br:21])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([S:11]([CH3:12])=[O:33])=[N:6]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccccc1-c1c(Br)c(Br)c2cnc(SC)nn12
Solvent: ClCCl
Product: COc1ccccc1-c1c(Br)c(Br)c2cnc(S(C)=O)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
Into a Round bottom flask, [A] 5,6-Dibromo-7-(2-methoxy-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.460 g, 0.00107 mol) and Methylene chloride (2 mL, 0.03 mol) were added. m-CPBA 70-75% (70:30, m-Chloroperbenzoic acid:3-Chlorobenzoic acid, 0.291 g, 0.00118 mol) was added portion wise over 20 minutes. The reaction was stirred at room temperature for one hour. The reaction was partitioned with DCM (200 mL) and saturated NaHCO3 (200 mL). The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum to give a yellow solid. The solid was washed with hexane to give 5,6-Dibromo-2-methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine as a yellow solid (0.465 g, 97%). NMR 1H (DSMO-d6)-9.27 (s, 1H), 7.50-7.62 (m, 2H), 7.40-7.48 (m, 2H), 3.80 (s, 3H), 2.90 (s, 3H)
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:15]([F:16])=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][N:7]=2)[CH2:3][CH2:2]1.C1COCC1.[OH-].[Li+].Cl>CO>[CH:1]1([CH2:4][O:5][C:6]2[C:15]([F:16])=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][N:7]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1cnc(OCC2CC2)c(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cnc(OCC2CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 73.7 %

Procedure:
A mixture of methyl 6-(cyclopropylmethoxy)-5-fluoronicotinate (1.75 g), THF (15 mL), methanol (1.7 mL) and 2 M aqueous lithium hydroxide solution (7.8 mL) was stirred at room temperature for 20 min. The reaction mixture was neutralized with 1 M hydrochloric acid at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure, and the obtained solid was washed with diethyl ether to give the title compound (1.21 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: ClCc1ccccn1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CC[C@@H](OCc2ccccn2)C1

Procedure:
The title compound is synthesized by coupling of (R)-3-Hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester and 2-chloromethyl-pyridine HCl salt analogously to the preparation of Intermediate 193.2 as a white solid; ES-MS: M+=279.2: AtRet=2.81.
Reaction SMILES: ClS([N:5]=[C:6]=O)(=O)=O.CC(OC([N:15](C(OC(C)(C)C)=O)[C:16]1[CH:17]=[N:18][CH:19]=[C:20]([C:22]2[N:23]([CH3:32])[C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[C:26]([Cl:31])[CH:25]=3)[CH:21]=1)=O)(C)C.CN(C=O)C>C(#N)C>[NH2:15][C:16]1[CH:21]=[C:20]([C:22]2[N:23]([CH3:32])[C:24]3[C:29]([C:30]=2[C:6]#[N:5])=[CH:28][CH:27]=[C:26]([Cl:31])[CH:25]=3)[CH:19]=[N:18][CH:17]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Cn1c(-c2cncc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2)cc2ccc(Cl)cc21
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cn1c(-c2cncc(N)c2)c(C#N)c2ccc(Cl)cc21
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
Chlorosulfonyl isocyanate (1.63 g, 11.5 mmol) is added to a solution of 3-[bis[[(1,1-dimethylethyl)oxy]carbonyl]amino]-5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridine (0.91 g, 1.99 mmol) in acetonitrile (200 mL) and the reaction mixture is stirred for 10 min. DMF (3 mL) is added and the reaction mixture is stirred for 3 h. 20 g silica gel is added to the mixture and the solvent is removed in vacuo. The resulting solid is heated to 65° C. under high vacuum for 2 h. The mixture is cooled to room temperature and then purified by silica gel flash chromatography (dichloromethane-methanol-triethylamine, 83:8:9) to afford 2-(5-amino-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.76 (s, 3H), 5.72 (s, 2H), 7.15 (t, J=2.3 Hz, 1H), 7.35 (dd, J=8.5, 1.9 Hz, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.92 (d, J=1.8 Hz, 1H), 7.97 (d, J=1.8 Hz, 1H), 8.12 (d, J=2.5 Hz, 1H). MS (ESI) m/z 283.0 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:23][F:24]>CN(C=O)C>[F:24][CH2:23][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([F:13])([F:14])[F:15]
Reactant: COC(=O)c1ccc(O)c(C(F)(F)F)c1
Reactant: FCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCF)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 86.9 %

Procedure:
To a cooled (−78° C.) mixture of methyl 4-hydroxy-3-(trifluoromethyl)benzoate (2.45 g, 11.13 mmol) and cesium carbonate (5.44 g, 16.7 mmol) in DMF in a pressure vessel was bubbled chlorofluoromethane (7.00 g, 102 mmol). The vessel was sealed and the reaction was stirred at room temperature for 120 h. The reaction was filtered through Celite®. The filtrate was diluted with EtOAc, washed with water (4 times), dried over MgSO4, filtered and concentrated under vacuum to give the title compound as a solid (2.44 g). LCMS m/z=253.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.88 (s, 3H), 5.98-6.20 (d, J=52.5 Hz, 2H), 7.59 (d, J=8.84 Hz, 1H), 8.18 (d, J=2.02 Hz, 1H), 8.28 (dd, J=8.84, 2.15 Hz, 1H); 19F NMR (376 MHz, DMSO-d6) δ ppm −153.52 (s, 1F), −61.08 (s, 3F).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([CH:20]=[CH:21][CH:22]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH:16]=O)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[NH2:24][C:25]1([C:31]([OH:33])=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[Cl:1][C:2]1[C:3]([F:23])=[C:4]([NH:5][C:6]2[C:15]3[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH2:16][NH:24][C:25]4([C:31]([OH:33])=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:14]=3)[N:9]=[CH:8][N:7]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C=O
Reactant: NC1(C(=O)O)CCOCC1
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNC1(C(=O)O)CCOCC1

Procedure:
4-(3-Chloro-2-fluoroanilino)-7-methoxyquinazoline-6-carbaldehyde was coupled with 4-aminotetrahydro-2H-pyran-4-carboxylic acid using an analogous method to that described for the equivalent step in Example 1 to give 4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)amino]tetrahydro-2H-pyran-4-carboxylic acid; 1H NMR Spectrum: (DMSO-d6) 1.62-1.74 (m, 2H), 1.92-2.03 (m, 2H), 3.46-3.56 (m, 2H), 3.76 (s, 2H), 3.76-3.85 (m, 2H), 3.94 (s, 3H), 7.18 (s, 1H), 7.23-7.31 (m, 1H), 7.43-7.57 (m, 2H), 8.38 (s, 1H), 8.42 (s, 1H), 9.81 (brs, 1H). Mass Spectrum: (M+H)+ 461.
Reaction SMILES: CC(OC([NH:8][C@H:9]([C:20]([OH:22])=O)[CH2:10][CH2:11][CH2:12][N:13]=[C:14]([NH:16][N+:17]([O-:19])=[O:18])[NH2:15])=O)(C)C.[Cl:23][C:24](OCC(C)C)=O.CN1CCOCC1.[ClH:38].C(O)C>O1CCCC1>[NH2:8][C@H:9]([C:20]([CH2:24][Cl:23])=[O:22])[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[NH:15])[NH:16][N+:17]([O-:19])=[O:18].[ClH:38]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCN=C(N)N[N+](=O)[O-])C(=O)O
Reactant: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Solvent: CN1CCOCC1
Product: N=C(NCCC[C@H](N)C(=O)CCl)N[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Boc Arg(NO2)OH (5.0 g, 15.6 mmol) was dissolved in 60 ml of tetrahydrofuran (THF) and was allowed to react with isobutyl chloroformate (2.06 ml, 15.6 mmol) in the presence of N-methylmorpholine (1.72 ml, 15.6 mmol) for 10 min at -20° C. The mixed anhydride preparation was filtered, and the filtrate was added to 120 ml of ethereal diazomethane. After stirring the reaction solution for 30 min at 0° C., 80 ml of ether was added. The product crystallized from the reaction solution in the cold. The Boc-Arg(HO2)CHNH2 product was dissolved in a minimum volume of THF and was allowed to react with ethanol HCl (20 mmol) at room temperature until nitrogen evolution ceased.
Reaction SMILES: C(=[N:14][C:15]1[CH:20]=[C:19]([C:21]([C:23]2[C:31]3[C:30](Cl)=[N:29][CH:28]=[N:27][C:26]=3[N:25]([CH:33]([CH3:35])[CH3:34])[CH:24]=2)=[O:22])[CH:18]=[C:17]([O:36][CH3:37])[N:16]=1)(C1C=CC=CC=1)C1C=CC=CC=1.[OH-].[NH4+:39]>O1CCOCC1>[NH2:39][C:30]1[C:31]2[C:23]([C:21]([C:19]3[CH:18]=[C:17]([O:36][CH3:37])[N:16]=[C:15]([NH2:14])[CH:20]=3)=[O:22])=[CH:24][N:25]([CH:33]([CH3:34])[CH3:35])[C:26]=2[N:27]=[CH:28][N:29]=1
Reactant: [NH4+]
Reactant: COc1cc(C(=O)c2cn(C(C)C)c3ncnc(Cl)c23)cc(N=C(c2ccccc2)c2ccccc2)n1
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc(C(=O)c2cn(C(C)C)c3ncnc(N)c23)cc(N)n1
Temperature: 45 °C
Reaction time: 12 h
Yield: 73 %

Procedure:
[2-(Benzhydrylidene-amino)-6-methoxy-pyridin-4-yl]-(4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (7.31 g, 14.3 mmol) was added to a solution of ammonium hydroxide (150 mL) in dioxane (150 mL) and stirred at 45° C. in a sealed tube for 12 h. The reaction mixture was concentrated in vacuo, dissolved in hot CH2Cl2 (150 mL), and washed with water (3×100 mL). The aqueous layer was extracted with CH2Cl2 (3×100 mL) and the combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to provide the title compound as a yellow solid (3.43 g, 73%). MS: 327.2 (MH−); HPLC Rf: 2.1 min. (HPLC method 2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH:21]=2)[CH2:16][CH:15]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:30][O:31]C1C=C(C=CC=1CC1C2C(=CC=C(NC(=O)C(F)(F)F)C=2)C=C1)C(OC)=O.N12CCCN=C1CCCCC2>O1CCCC1>[CH3:1][O:2][C:3]1([O:31][CH3:30])[C:12]([CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([NH:23][C:24](=[O:29])[C:25]([F:27])([F:28])[F:26])[CH:21]=3)[CH2:16][CH:15]=2)=[CH:11][CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH2:4]1
Reactant: COC(=O)c1ccc(CC2C=Cc3ccc(NC(=O)C(F)(F)F)cc32)c(OC)c1
Reactant: COC(=O)c1ccc(CC2=CCc3ccc(NC(=O)C(F)(F)F)cc32)c(OC)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COC(=O)C1=CC=C(CC2=CCc3ccc(NC(=O)C(F)(F)F)cc32)C(OC)(OC)C1
Yield: 27 %

Procedure:
A solution of n-butyllithium in hexane (1.4M, 38.82 ml) was added to a -78° C. solution of diisopropylamine (7.85 ml) in tetrahydrofuran (25 ml). After stirring for 15 min, a solution of 6-(trifluoroacetamido)-3H-indene (5.92 g) in tetrahydrofuran (25 ml) was added and stirred for 1 h. The reaction mixture was cooled to -100° C. and a solution of methyl 4-bromomethyl-3-methoxybenzoate (8.44 g) in tetrahydrofuran (35 ml) was added. The mixture was allowed to warm to room temperature and stirred for 18 h. The reaction mixture was added to saturated ammonium chloride (100 ml) and ethyl acetate (150 ml). The mixture was washed (water, brine), dried (MgSO4) and evaporated. The residue was recrystallized from 10:1 methylene chloride:hexane to give methyl 3-methoxy-4-[6-(trifluoroacetamido)-3H-inden-1-ylmethyl]benzoate (1.48 g, 14%). The residue derived from the filtrate was recrystallized from 3:1 methylene chloride:hexane to give a mixture of methyl 3-methoxy-4-[6-(trifluoroacetamido)-3H-inden-1-ylmethyl]benzoate and methyl 3-methoxy-4-[6-(trifluoroacetamido)-1H-inden-1-ylmethyl]benzoate (1.92 g). This mixture was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.11 g) and tetrahydrofuran (20 ml) for 18 h. After partitioning between ethyl acetate (85 ml) and 1N hydrochloric acid, the organic layer was washed (brine) and dried (MgSO4). Evaporation and trituration with methylene chloride gave a colorless solid. This was combined with the above material to give methyl 3-methoxy-4-[6-(trifluoroacetamido)-3H-inden-1-ylmethyl]-3-methoxybenzoate (2.81 g, 27% total yield from 6-(trifluoroacetamido)-3H-indene); mp 198.5°-200.0° C.; MS(CI), m/e=406(M+H).
Reaction SMILES: Cl.[F:2][C:3]1([F:19])[O:7][C:6]2[CH:8]=[CH:9][C:10]([CH2:12][CH:13]3[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)=[CH:11][C:5]=2[O:4]1.CCN(CC)CC.C1([O:33][C:34](=O)[NH:35][C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)C=CC=CC=1>CC#N>[N:38]1[CH:39]=[CH:40][CH:41]=[C:36]([NH:35][C:34]([N:15]2[CH2:16][CH2:17][CH2:18][CH:13]([CH2:12][C:10]3[CH:9]=[CH:8][C:6]4[O:7][C:3]([F:2])([F:19])[O:4][C:5]=4[CH:11]=3)[CH2:14]2)=[O:33])[CH:37]=1
Reactant: FC1(F)Oc2ccc(CC3CCCNC3)cc2O1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1cccnc1)N1CCCC(Cc2ccc3c(c2)OC(F)(F)O3)C1
Temperature: 35 °C
Yield: 94 %

Procedure:
To a solution of 3-[(2,2-difluoro-1,3-benzodioxol-5-yl)methyl]-piperidine hydrochloride (100 mg, 0.34 mmol) in CH3CN (2 mL) was added Et3N (0.07 mL, 0.52 mmol). To this reaction mixture, pyridin-3-yl-carbamic acid phenyl ester (77.0 mg, 1.05 mmol) was added and the reaction mixture was heated overnight at 35° C. The reaction mixture was then concentrated and the crude residue was purified (FCC, 2 N NH3 in MeOH/DCM) to give 3-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethyl)-piperidine-1-carboxylic acid pyridin-3-ylamide (120 mg, 93%). MS (ESI+): calcd for C19H19F2N3O3 m/z 375.14, found 376.2 (M+H)+. 1H NMR (d4-methanol): 8.54 (d, J=2.3, 1H), 8.17-8.13 (m, 1H), 7.86 (ddd, J=8.4, 2.6, 1.4, 1H), 7.34-7.30 (m, 1H), 7.10-7.06 (m, 2H), 6.99 (dd, J=8.2, 1.5, 1H), 4.05-3.95 (m, 2H), 3.04-2.98 (m, 1H), 2.74-2.64 (m, 2H), 2.58-2.53 (m, 1H), 1.86-1.74 (m, 3H), 1.56-1.47 (m, 1H), 1.30-1.22 (m, 1H).