Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].[CH2:14]([C@@H:21]1[CH2:25][O:24][C:23](=[O:26])[NH:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)Cl.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.O>[CH2:14]([C@@H:21]1[CH2:25][O:24][C:23](=[O:26])[N:22]1[C:8]1[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(N2C(=O)OC[C@H]2Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9 %

Procedure:
To a mixture of p-(methoxycarbonyl)phenylboronic acid (2.45 g), (R)-4-benzyloxazolidin-2-one (1.205 g) and copper (II) acetate (1.23 g) were added methylene chloride (20 mL) and triethylamine (1.9 mL), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and insoluble materials were filtered off. The filtrate was extracted with chloroform. The solvent was evaporated, and the obtained residue was purified by column chromatography (chloroform) to give the title compound (0.19 g).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]([NH:20][CH2:21][CH2:22][OH:23])=[O:19])[CH2:13][CH:12]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30])=O)C1C=CC=CC=1>CO.[C].[Pd]>[OH:23][CH2:22][CH2:21][NH:20][C:18]([O:17][CH:14]1[CH2:15][CH2:16][NH:11][CH:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH2:13]1)=[O:19]
Reactant: Cc1ccccc1C1CC(OC(=O)NCCO)CCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Cc1ccccc1C1CC(OC(=O)NCCO)CCN1
Temperature: 25 °C
Reaction time: 14 h
Yield: 98 %

Procedure:
In 30 ml of methanol was dissolved 1.33 g of 1-benzyloxycarbonyl-4-(2-hydroxyethylaminocarbonyloxy)-2-(2-methylphenyl)piperidine, and added thereto was 70 mg of 10% palladium-carbon, and the mixture was stirred at room temperature for 14 hours under hydrogen atmosphere. After insoluble matters were removed by filtration, the filtrate was concentrated, to give 880 mg of 4-(2-hydroxyethylaminocarbonyloxy)-2-(2-methylphenyl)piperidine as shown in Table 135 below.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:19][C:18]=1[CH3:28].C(N(CC)CC)C>C(Cl)Cl.O>[CH3:28][C:18]1[CH:19]=[C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:22][C:17]=1[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)Cc1ccc(O)c(C)c1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Temperature: 18 °C
Reaction time: 16 h
Yield: 61.5 %

Procedure:
Trifluoromethane sulfonic anhydride (0.217 mL, 1.32 mmol) was added dropwise to methyl 2-(4-hydroxy-3-methylphenyl)acetate (159 mg, 0.88 mmol), in DCM (4 mL) at 0° C. under nitrogen. The resulting solution was then treated with triethylamine (0.369 mL, 2.65 mmol) and allowed to warm to and stir at 18° C. for 16 hours. The mixture was diluted with DCM (20 mL) and water (20 mL) and the organics separated. The organics were washed with saturated NaHCO3 (aq, 50 mL), brine (10 mL) dried (MgSO4) and evaporated to crude material. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 2-(3-methyl-4-(trifluoromethylsulfonyloxy)phenyl)acetate (169 mg, 61.3%) as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[C:24]([CH2:28][C:29](Cl)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:29](=[O:30])[CH2:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)CC(C)(C)C)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-3,3-dimethyl-butyramide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and tert-butylacetyl chloride (123 μl, 0.89 mmol). The title compound was obtained as brown powder (142 mg, 43%).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(N(CC)CC)C.[Br:20][CH2:21][CH2:22]Br>CN(C=O)C>[Br:20][CH2:21][CH2:22][O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7]
Reactant: BrCCBr
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1OCCBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(2-Bromoethoxy)phthalimide was synthesised by a modification of the procedure of Bauer and Suresh (Bauer et al 1963). N-Hydroxyphthalimide (80 g, 0.49 mol), triethylamine (150 mL, 1.08 mol), and 1,2-dibromoethane (175 mL, 2.30 mol) were combined in DMF (575 mL) and stirred at room temperature overnight. Solids were filtered and washed with DMF and the filtrate was diluted with water (4.0 L) and the resulting precipitate filtered, dissolved in EtOAc (500 mL), and washed with 1 N HCl (2×100 mL), water (1×100 mL), and dried over MgSO4. Volatiles were removed in vacuo, and the resulting solid recrystallised from 95% EtOH to give (9) as a white solid (87.1 g, 70%): mp. 94-96° C.; lit. mp. 94-96° C. 1H NMR (CDCl3): δ 7.82 (m, 4H), 4.49 (t, 2H, J=6.9 Hz), 3.65 (t, 2H, J=6.9 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[CH:25]([OH:26])[CH2:24][C:23]([CH3:28])([CH3:27])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[C:29]([O:26][CH:25]1[C:10]2[C:11](=[N:12][C:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH:9]=2)[O:22][C:23]([CH3:28])([CH3:27])[CH2:24]1)(=[O:31])[CH3:30]
Reactant: CC1(C)CC(O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC1CC(C)(C)Oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc21
Reaction time: 4 h

Procedure:
To the product of Example 68 (25 mg, 0.0575 mmol) was added acetic anhydride (0.25 mL, 2.65 mmol) in pyridine (2 mL). The reaction was stirred 4 h and was concentrated. The residue was diluted with EtOAc and washed with 1 M aq HCl followed by saturated aq NaHCO3/1 M aq NaOH (1:1). The solution was dried (Na2SO4). The concentrated residue was purified by flash chromatography on silica gel eluted with 50% EtOAc in hexane affording the title compound. (LC-2) HPLC/MS: 475.9 (M+1), 477.9 (M+3); Rt=4.29 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1.C(O)C.[CH3:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]([N:38]=[C:39]=[S:40])=[O:37]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:39]([NH:38][C:36](=[O:37])[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH3:29])=[S:40])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Reactant: Cc1ccccc1C(=O)N=C=S
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4C)c([N+](=O)[O-])c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-nitroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 2-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (66 mg, yield 80%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[CH3:15][N:16]([CH2:18][C:19](Cl)=[O:20])[CH3:17]>>[CH3:15][N:16]([CH3:17])[CH2:18][C:19]([N:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=2)[CH2:8][CH2:9][CH2:10]1)=[O:20]
Reactant: CN(C)CC(=O)Cl
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCC2
Agent: Cl
Product: CN(C)CC(=O)N1CCCc2ccc([N+](=O)[O-])cc21

Procedure:
Using the procedure outlined in Description 4 followed by silica SPE chromatography eluting with 20% EtOAc/MeOH the title compound was prepared from 7-nitro-1,2,3,4-tetrahydroquinoline (D1) (178 mg, 1 mmol) and dimethylaminoacetyl chloride hydrochloride (174 mg, 1.1 mmol) as a yellow solid (103 mg). 1H NMR (250 MHz, CDCl3) δ (ppm): 8.74 (d, 1H), 7.92 (dd, 1H), 7.28 (d, 1H), 3.87 (m, 2H), 3.25 (s, 2H), 2.87 (t, 2H), 2.35 (s, 6H), 1.95 (m, 2H).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([F:13])[CH:12]=1.[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:23]=2)[C:18](OS(C(F)(F)F)(=O)=O)=[N:17][CH:16]=1>[Cl-].[Zn+2].[Cl-].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.C1COCC1>[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:23]=2)[C:18]([C:12]2[C:11]([F:13])=[CH:10][N:9]=[CH:8][C:7]=2[F:6])=[N:17][CH:16]=1
Reactant: Fc1cncc(F)c1
Reactant: COC(=O)c1ccc2c(Cl)cnc(OS(=O)(=O)C(F)(F)F)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(Cl)cnc(-c3c(F)cncc3F)c2c1
Reaction time: 1 h
Yield: 20.8 %

Procedure:
Under argon gas atmosphere, n-butyllithium (1.6 M THF solution, 0.7 mL) was added dropwise to a mixture of 3,5-difluoropyridine (123 mg) and THF (3 mL) at −78° C., followed by stirring at the same temperature for one hour. Then, zinc chloride (146 mg) was added, and stirred for an additional hour. Methyl 4-chloro-1-{[(trifluoromethyl)sulfonyl]oxy}isoquinoline-7-carboxylate (330 mg) and tetrakis(triphenylphosphine)palladium (206 mg) were added thereto, followed by heating under stirring in an oil bath at 60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure and purified under silica gel column chromatography (hexane/ethyl acetate) to obtain methyl 4-chloro-1-(3,5-difluoropyridin-4-yl)isoquinoline-7-carboxylate (62 mg).
Reaction SMILES: [N:1]1([C:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:16]Br>C(OCC)C>[Br:16][CH:11]1[CH2:12][CH2:13][CH2:14][CH:9]([C:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:8])[C:10]1=[O:15]
Reactant: BrBr
Reactant: O=C1CCCCC1C(=O)N1CCCCC1
Solvent: CCOCC
Product: O=C1C(Br)CCCC1C(=O)N1CCCCC1
Temperature: 0 °C
Yield: 107 %

Procedure:
2-(piperidine-1-carbonyl)-cyclohexanone (19) (4.0 g, 19 mmol) was dissolved in diethyl ether (5 mL) and cooled to 0° C. under N2. Bromine (5.9 g, 19 mmol, 1.0 mL) was added dropwise over 15 min and the reaction mixture was allowed to warm to room temperature over 90 min. The solid was collected by filtration to give 5.86 g (quantitative) of 2-bromo-6-(piperidine-1-carbonyl)-cyclohexanone (20) as a white solid which was used in the next step without purification. The structure was confirmed by 13C NMR (75 MHz, DMSO-d6) δC 17.3, 24.2, 25.3, 25.8, 32.5, 44.0, 51.6, 1083, 145.5, 167.8.
Reaction SMILES: N1CCC[C@@H]1C(N)=O.C(N(CC)CC)C.[CH3:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1.C(O)=O.C(N(CC)CC)C>C(Cl)Cl.C[Ir-4](Cl)(C)(C)(C)(C)C1C=CC=C1.[Ir](Cl)(Cl)Cl>[CH3:16][CH:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18]1
Reactant: Cc1ccc2ccccc2n1
Agent: C[Ir-4](C)(C)(C)(C)(Cl)C1C=CC=C1
Agent: Cl[Ir](Cl)Cl
Agent: NC(=O)[C@H]1CCCN1
Solvent: ClCCl
Solvent: O=CO
Solvent: CCN(CC)CC
Product: CC1CCc2ccccc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
To 10 ml of methylene chloride, 55.6 mg of a pentamethylcyclopentadienyl iridium(III) chloride dimer ([Cp*IrCl2]2), 16.7 mg of (R)-prolinamide and 15.6 mg of triethylamine were added, and the mixture was stirred under argon atmosphere at room temperature for about 30 minutes to give a catalyst-containing mixture. In 60 ml of methylene chloride, 1.00 g of 2-methylquinoline was dissolved, and a 1/10 amount of the catalyst-containing mixture (equivalent to 0.1 mol % as an iridium chloride dimer) was added. After cooling to −10° C., 8.4 ml of a mixed solvent of formic acid/triethylamine (molar ratio: 5/2) was added dropwise, and the mixture was stirred at the same temperature for 2 days to give 2-methyl-1,2,3,4-tetrahydroquinoline (degree of conversion: 67.4%). The R-enantiomer was in excess and the optical purity was 85.4% ee.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][CH2:9]1)(C)(C)C.[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]>C(Cl)Cl>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[CH3:17][S:14]([N:11]1[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]1)(=[O:16])=[O:15]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(C)(=O)=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCC(N)CC1
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of piperidin-4-yl-carbamic acid tert-butyl ester (1.0 g, 5.0 mmol, Astratech, Inc.) and diisopropylethylamine (4 mL) in tetrahydrofuran (40 mL) was stirred at +5° C. To this was added methanesulfonyl chloride (1.0 g, 8.8 mmol) in a bolus. The reaction was brought to room temperature for 1 hour, poured into water and extracted into methylene chloride (2×50 mL). The combined organic extracts were washed with 5% aqueous sodium bicarbonate. The organic solution was dried (Na2SO4) and solvent was removed under vacuum to give a crude solid. Purification was by trituration with ether/hexane to give (1-methanesulfonyl-piperidin-4-yl)-carbamic acid tert-butyl ester as a white solid. Mass spectrum (ES) H+: 278 B) A suspension of (1-methanesulfonyl-piperidin-4-yl)-carbamic acid tert-butyl ester (1.14 g, 4.1 mmol, from Example 162, Step A) in methylene chloride (15 mL) was treated at room temperature with trifluoroacetic acid (5.3 mL). After stirring for 2 hours, all solvent was removed and the residue was triturated with ether. This was filtered, washed with ether and dried in vacuum to give 1.20 g of 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoro-acetic acid (100% yield). HRMS, observed: 177.0692; Calcd for M+: 177.0698
Reaction SMILES: C([O-])=O.[NH4+].Br[C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([N+:17]([O-])=O)[C:15]=1[CH3:16])[N:12]=[CH:11][N:10]=[C:9]2[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1>C(O)C.[Pd]>[CH3:16][C:15]1[C:14]([NH2:17])=[C:13]2[C:8]([C:9]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=3)=[N:10][CH:11]=[N:12]2)=[CH:7][CH:6]=1
Reactant: Cc1c(Br)cc2c(Nc3cccc(C(F)(F)F)c3)ncnc2c1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1ccc2c(Nc3cccc(C(F)(F)F)c3)ncnc2c1N
Temperature: 140 °C
Yield: 56.1 %

Procedure:
To a microwave vial were added ammonium formate (131 μl, 2664 μmol), 6-bromo-7-methyl-8-nitro-N-(3-(trifluoromethyl)phenyl)quinazolin-4-amine (569 mg, 1332 μmol), and palladium black (11.8 μl, 1332 μmol) in ethanol (10 mL). The reaction mixture was heated to 140° C. for 20 min under microwave conditions and taking care to monitor the pressure in the reaction vessel. On cooling the reaction mixture was filtered through celite and filtrate concentrated in vacuo to afford 7-methyl-N4-(3-(trifluoromethyl)phenyl)quinazoline-4,8-diamine (238 mg, 56.1% yield). MS (M+H)+ 319.
Reaction SMILES: [NH2:1][C:2](=O)[C@@H:3]([NH:23][C:24]([C:26]1([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:25])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[N:19]([CH3:20])[C:18](=[O:21])[CH2:17][S:16][C:15]=3[CH:22]=2)=[CH:7][CH:6]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>ClCCl>[C:2]([C@@H:3]([NH:23][C:24]([C:26]1([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:25])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[N:19]([CH3:20])[C:18](=[O:21])[CH2:17][S:16][C:15]=3[CH:22]=2)=[CH:7][CH:6]=1)#[N:1]
Reactant: CN1C(=O)CSc2cc(-c3ccc(C[C@H](NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)C(N)=O)cc3)ccc21
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: ClCCl
Product: CN1C(=O)CSc2cc(-c3ccc(C[C@@H](C#N)NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)cc3)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.8 %

Procedure:
(S)-tert-Butyl 4-(1-amino-3-(4-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)phenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 28, step (ii), 138 mg) in dichloromethane (10 mL) was treated with Burgess' reagent (116 mg) and stirred at room temperature for 18 h. The solvent was partially evaporated and the residue absorbed onto silica and purified by chromatography on silica eluting with ethyl acetate/isohexane (50:50 to 70:30) to afford the sub-titled compound (120 mg).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Cl:9][C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][CH:23]=1)[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14]>CS(C)=O>[Cl:9][C:10]1[CH:11]=[C:12]([C:13]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:4][O:14]2)[CH:21]=[CH:22][CH:23]=1
Reactant: C[S+](C)(C)=O
Reactant: O=C(c1ccccc1)c1cccc(Cl)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Clc1cccc(C2(c3ccccc3)CO2)c1
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
A 250 mL-round bottom flask was charged with NaH (60% dispersion in mineral oil) (1.92 g, 0.048 mol), washed with petroleum ether, then treated with dry DMSO (40 mL) under N2. To this reaction mixture was added trimethylsulfoxonium iodide (10.56 g, 0.048 mol) through a solid addition funnel over 15 min. After stirring for 0.5 hr, a solution of 3-chlorobenzophenone (8.66 g, 0.04 mol) in DMSO (15 mL) was added dropwise, and the mixture was heated at 55° C. for 2 hr. The mixture was added to ice-water, extracted with ether (3×100 mL), the organics combined, dried (MgSO4), filtered, and concentrated to give the title compound.
Reaction SMILES: CS(O[C@H:6]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@@H:8]([C:18](=[O:33])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][C:27]3=[O:32])=[CH:22][CH:21]=2)[CH2:7]1)(=O)=O.[N-:34]=[N+:35]=[N-:36].[Na+]>CN(C)C=O>[N:34]([C@@H:6]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C@@H:8]([C:18](=[O:33])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][C:27]3=[O:32])=[CH:22][CH:21]=2)[CH2:7]1)=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@@H]1C(=O)Nc1ccc(N2CCOCC2=O)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@H](N=[N+]=[N-])C[C@@H]1C(=O)Nc1ccc(N2CCOCC2=O)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 95.3 %

Procedure:
9.2 A mixture of 5.4 g (11.7 mmol) of tert-butyl (2R,4R)-4-methanesulfonyloxy-2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidine-1-carboxylate and 3.69 g (56.8 mmol) of sodium azide in 50 ml of dimethylformamide (DMF) is stirred at 60° C. for 12 hours. The insoluble matter is subsequently filtered off, and the filtrate is evaporated to dryness under reduced pressure. The residue is then dissolved in 20 ml of water, and the aqueous solution is extracted twice with 10 ml of methylene chloride each time. The combined methylene chloride extracts are finally washed once with 10 ml of saturated sodium chloride solution and dried over sodium sulfate. Removal of the drying agent by filtration and stripping-off of the solvent gives 4.8 g (100%) of tert-butyl (2R,4S)-4-azido-2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidine-1-carboxylate as slightly yellow crystals, ESI 431.
Reaction SMILES: [C:1]([O:9][CH2:10][C@:11]1([O:44][CH2:43][C@@H:33]([O:34][C:35](=[O:42])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@@H:23]([O:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]1[O:14][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[OH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:45]C(C)=O.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O:9][CH2:10][C@:11]1([O:44][CH2:43][C@@H:33]([O:34][C:35](=[O:42])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@@H:23]([O:24][C:25](=[O:32])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:13]1[O:14][C:15](=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[O:12][CH3:45])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC[C@@]1(O)OC[C@@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CO[C@]1(COC(=O)c2ccccc2)OC[C@@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 97.5 %

Procedure:
To a solution of 1,3,4,5-tetra-O-benzoyl-β-D-fructopyranose (10.00 g, 16.8 mmol) in acetone (40 mL) dimethyl sulfate (2.4 ml, 25.16 mmoles, 1.5 eq.) was added followed by potassium carbonate (3.48 g, 25.16 mmoles) and the reaction mixture was stirred at 50° C. under nitrogen for 18 hours. Solvents were removed under vacuo and the resulting residue was dissolved in ethyl acetate (150 ml), washed with 5% citric acid, water, brine, dried over sodium sulfate, filtered and concentrated to an oily solid. Purification on a silica gel column (hexane:ethyl acetate, 4:1) afforded 10.0 g (98%) of title compound as white foam.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.[OH2:21].C(Cl)Cl>N1CCOCC1>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:3]3[CH2:4][CH2:5][O:21][CH2:7][CH2:2]3)[CH:7]=2)=[O:9])=[CH:12][C:13]=1[N+:18]([O-:20])=[O:19]
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1[N+](=O)[O-]
Reactant: O
Solvent: ClCCl
Solvent: C1COCCN1
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
2-Chloro-N-(4-methyl-3-nitrophenyl)pyridine-4-carboxamide (18.33 g) was stirred in morpholine (250 ml) at 100° C. for 18 hours. Reaction was poured into water (250 ml) affording a gummy solid. Methylene chloride (30 ml) was added and stirred for 30 minutes and solid filtered, washed with methylene chloride and dried in a vacuum oven for 18 hours to yield N-(4-methyl-3-nitrophenyl)-2-morpholinopyridine-4-carboxamide the title compound (17.34 g); NMR: 2.48 (s, 3H), 3.52 (m, 4H), 3.71 (m, 4H), 7.1 (d, 1H), 7.25 (s, 1H), 7.49 (d, 1H), 7.97 (m, 1H), 8.29 (m, 1H), 8.49 (m, 1H), 10.62 (s, 1H); m/s: M+H+ 343.