Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[SH:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][N:8]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([S:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][N:8]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: Cc1cccnc1S
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Sc1ncccc1C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
1.21 ml (13.9 mole) of propionyl chloride were added dropwise, whilst ice-cooling and under an atmosphere of nitrogen, to a solution of 1.46 g (11.7 mole) of 2-mercapto-3-methylpyridine (prepared as described in Preparation 7) and 1.94 ml (13.9 mmole) of triethylamine in 15 ml of methylene chloride, and the resulting mixture was stirred for 1 hour. At the end of this time, the reaction mixture was mixed with 50 ml of methylene chloride, and the mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate. It was then dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by medium pressure column chromatography through silica gel, using a 5:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.89 g (yield 89%) of the title compound as a light yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][CH:25]1[NH:29][C:28](=[O:30])[CH2:27][CH2:26]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:6]=[N:7][C:2]([N:29]4[CH:25]([CH3:24])[CH2:26][CH2:27][C:28]4=[O:30])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)nn3)CC2)c(C)c1
Reactant: CC1CCC(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CCC4C)nn3)CC2)c(C)c1
Yield: 10.1 %

Procedure:
Using (6-chloropyridazin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 230 and 5-methylpyrrolidin-2-one (54 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (18 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:20])[CH2:10][C:11]2[NH:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[N:12]=2)=[CH:5][CH:4]=1.C[O-].[Na+].[C:24](OC)(=[O:27])[C:25]#[CH:26]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:10]2[CH:26]=[CH:25][C:24](=[O:27])[N:15]3[C:14]4[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=4[NH:12][C:11]=23)=[O:20])=[CH:5][CH:4]=1
Reactant: C#CC(=O)OC
Reactant: COc1ccc(C(=O)Cc2nc3c([nH]2)CCCC3)cc1
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(C(=O)c2ccc(=O)n3c4c([nH]c23)CCCC4)cc1

Procedure:
The compound is prepared as described in example 25 with 200 mg (0.74 mmol) of 1-(4-methoxyphenyl)-2-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)ethanone (example LIII), 80 mg (1.48 mmol) of sodium methylate and 62 mg (0.74 mmol) methyl propiolate.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:24][OH:25])[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:45]([NH:55][C@H:56]([C:60](O)=[O:61])[CH:57]([CH3:59])[CH3:58])([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(OCC)C>[CH2:48]([O:47][C:45]([NH:55][C@H:56]([C:60]([O:25][CH2:24][C:13]1[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=1)=[O:61])[CH:57]([CH3:59])[CH3:58])=[O:46])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: CS(=O)(=O)NCCCCn1c(CO)nc2c(N)nc3ccccc3c21
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1nc2c(N)nc3ccccc3c2n1CCCCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57.8 %

Procedure:
To a stirred suspension of N-[4-(4-amino-2-hydroxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide (2.1 g, 5.8 mmol) in THF was added triphenylphosphine (1.5 equivalents, 8.7 mmol, 2.2 g) followed by CBZ-L-valine (1.5 equivalents, 8.7 mmol, 2.3 g). The suspension was stirred for 5 min after which it was cooled in an ice-bath. To this cooled reaction mixture diisopropyl azodicarboxylate (DIAD, 1.8 equivalents, 10.4 mmol, 2.0 mL) was added and the reaction was warmed to room temperature and stirred overnight. The solvent was evaporated under reduced pressure and the crude solid was purified by prep HPLC (ISCO Combiflash Separation System, Biotage Si 40+M column, eluted with a gradient of 0-8% methanol in dichloromethane with 1% ammonium hydroxide) to provide a solid. The solid was heated in diethyl ether and filtered to afford (4-amino-1-{4-[(methylsulfonyl)amino]butyl}-1H-imidazo[4,5-c]quinolin-2-yl)methyl N-[(benzyloxy)carbonyl]-L-valinate (2 g) as a beige solid, mp 99-100° C.; MS (ESI) m/z 597 (M+H)+; Anal. Calcd for C29H36N6O6S: C, 58.37; H, 6.08; N, 14.08; Found C, 57.98; H, 6.31; N, 13.82.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH:3]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)[CH2:4][C:5]([O:7]CC)=[O:6].[OH-].[Na+]>C1COCC1.CCO>[CH3:1][CH:2]([CH3:19])[CH:3]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)[CH2:4][C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)CC(Cc1cccc(OC)c1)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cccc(CC(CC(=O)O)C(C)C)c1
Temperature: 60 °C
Yield: 100.1 %

Procedure:
Ethyl 4-methyl-3-{[3-(methyloxy)phenyl]methyl}pentanoate (66) (1.72 g, 6.51 mmol) was dissolved in THF (30 mL) and EtOH (30 mL). To this solution was added 1 N NaOH (35 mL). The reaction mixture was heated at 60° C. for 1.5 h. Cooled, the mixture was extracted with EtOAc. The combined extract was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give 1.54 g (100%) of the crude product 67 as a yellow oil. The crude product was used without further purification. 1H NMR (400 MHz, CDCl3): δ 0.91 (d, J=6.9 Hz, 3H), 0.94 (d, J=6.7 Hz, 3H), 1.70-1.80 (m, 1H), 2.10-2.25 (m, 2H), 2.32 (dd, J1=15.3 Hz, J2=6.5 Hz, 1H), 2.46 (dd, J1=13.7 Hz, J2=8.2 Hz, 1H), 2.67 (dd, J1=13.7 Hz, J2=6.4 Hz, 1H), 3.79 (s, 3H), 6.70-6.80 (m, 3H), 7.15-7.25 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[N+:12]([O-:23])[CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(-c2ccc(F)cc2)cn1
Solvent: ClCCl
Product: Cc1ccc(-c2ccc(F)cc2)c[n+]1[O-]

Procedure:
To a solution of 5-(4-fluorophenyl)-2-methylpyridine (420 mg, 2.2 mmol) in CH2C2 (25 mL) is added m-chloroperbenzoic acid (600 mg, 3.4 mmol). After 16 hours the reaction mixture is diluted with CH2Cl2 (50 mL) and the resulting solution washed with 5N NaOH (2×75 mL). The organic phase is then dried with Na2SO4 and concentrated in vacuo to give 5-(4-fluorophenyl)-2-methylpyridine-N -oxide.
Reaction SMILES: [NH2:1][C@H:2]([CH3:35])[C:3]([C:20]1[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=1[O:30][CH2:31][CH2:32][CH2:33][CH3:34])([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[O:15][CH2:16][CH2:17][CH2:18][CH3:19])[OH:4].[CH:36](=O)[C:37]1[C:38](=[CH:40][CH:41]=[CH:42][CH:43]=1)[OH:39]>C(O)C.C1(C)C=CC=CC=1>[CH:36](=[N:1][C@H:2]([CH3:35])[C:3]([C:5]1[CH:10]=[C:9]([C:11]([CH3:13])([CH3:12])[CH3:14])[CH:8]=[CH:7][C:6]=1[O:15][CH2:16][CH2:17][CH2:18][CH3:19])([C:20]1[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=1[O:30][CH2:31][CH2:32][CH2:33][CH3:34])[OH:4])[C:37]1[C:38](=[CH:40][CH:41]=[CH:42][CH:43]=1)[OH:39]
Reactant: O=Cc1ccccc1O
Reactant: CCCCOc1ccc(C(C)(C)C)cc1C(O)(c1cc(C(C)(C)C)ccc1OCCCC)[C@@H](C)N
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCOc1ccc(C(C)(C)C)cc1C(O)(c1cc(C(C)(C)C)ccc1OCCCC)[C@@H](C)N=Cc1ccccc1O
Yield: 99.5 %

Procedure:
0.968 g (2.0 mmol) of (R)-2-amino-1,1-di(2-butoxy-5-t-butylphenyl)-propanol and 0.244 g (2.0 mmol) of salicylaldehyde were dissolved in 20 ml of ethanol and 20 ml of toluene, the solution was heated at reflux for 1 hour. The solvent was distilled off from the reaction mixture and dried to obtain 1.17 g of (R)-N-salicyliden-2-amino-1,1-di(2-butoxy-5-t-butylphenyl)-propanol as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:13]([Li])[CH2:14][CH2:15][CH3:16]>O1CCCC1.[Cl-].[NH4+]>[CH2:13]([C:2]1([OH:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1)[CH2:14][CH2:15][CH3:16]
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCC1(O)CCN(C(=O)OCC)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under an atmosphere of argon, to a solution of ethyl 4-oxo-1-piperidinecarboxylate (1.00 g) in anhydrous tetrahydrofuran (5 mL) was added n-butyl lithium (1.56M hexane solution, 5.62 mL) at −40° C. The reaction mixture was stirred at 0° C. for 2 hours. The reaction mixture was poured in saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic layer was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified with column chromatography on silica gel (hexane:ethyl acetate=7:3) to give the title compound (269 mg) having the following physical data.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH2:3][CH:4]([CH2:8][S:9][C:10](=[O:12])[CH3:11])[C:5]([OH:7])=O.[O:14]=[C:15]1[CH2:32][CH2:31][C:30]2=[CH:33][N:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=32)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][NH:16]1.CC[N:36]=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[C:10]([S:9][CH2:8][CH:4]([CH2:3][CH:2]([CH3:1])[CH3:13])[C:5]([NH:36][C@H:32]1[CH2:31][C:30]2=[CH:33][N:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=32)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][NH:16][C:15]1=[O:14])=[O:7])(=[O:12])[CH3:11]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(=O)SCC(CC(C)C)C(=O)O
Reactant: O=C1CCc2cn(c3ccccc23)CCCCCCN1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)SCC(CC(C)C)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a solution of 4-methyl-2-acetylthiomethylpentanoic acid (612 mg, 3 mmol), (10S)-10-amino-(9-oxo-1,8-diaza-tricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraene (427 mg, 1.5 mmol), and HOBtH2O (230 mg, 1.5 mmol) in dry DMF (30 mL) under argon at room temperature was added EDCI (863 mg, 4.5 mmol) in one portion. After stirring overnight, DMF was removed at 30° C. under high vacuum to give a yellowish semi-solid. It was dissolved in ethyl acetate (50 mL), washed with 1N HCl (30 mL), 5% NaHCO3 solution (30 mL) and finally brine (30 mL). The organic layer was dried (MgSO4) and evaporated to dryness. The resulting pale yellow-oil was stirred in 50% ether-pet. ether (40 mL) to yield 600 mg (85%) of (10S)-2-acetylthiomethyl-4-methyl-N-(9-oxo-1,8-diaza-tricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-yl)pentanamide as 1:1 stereoisomeric mixture. The stereoisomeric mixture was separated in flash column chromatography (LPS-2), eluted with 20% ethyl acetate in pet. ether to give the less polar stereoisomer, m.p. 226° C., and the more polar stereoisomer, m.p. 220° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:23]=[CH:22][C:12]([CH2:13][N:14]2[CH:18]=[C:17]([C:19](O)=[O:20])[CH:16]=[N:15]2)=[CH:11][CH:10]=1.[NH3:24].O>CN(C=O)C.C(Cl)Cl>[CH3:7][O:8][C:9]1[CH:23]=[CH:22][C:12]([CH2:13][N:14]2[CH:18]=[C:17]([C:19]([NH2:24])=[O:20])[CH:16]=[N:15]2)=[CH:11][CH:10]=1
Reactant: COc1ccc(Cn2cc(C(=O)O)cn2)cc1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(C(N)=O)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
According to Scheme 1 Step 3: Oxalyl chloride (227 mmol, 19.5 mL) and three drops of DMF were added to a solution of 1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylic acid (114 mmol, 26.4 g) in DCM (227 mL). The reaction mixture was stirred for 30 minutes at room temperature. After evaporation of the solvent, dry DCM (100 mL) was added to the crude residue. The acyl chloride solution was then added at 0° C. to a solution of ammonia in water (454 mmol, 23.4 g) and the reaction mixture was stirred overnight. After filtration and evaporation to dryness, 1-(4-methoxybenzyl)-1H-pyrazole-4-carboxamide (109 mmol, 25.1 g, 96%) was obtained as a colorless solid. The crude product was used without further purification.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1I)[CH:2]=[CH2:3].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CC#N.CCN(CC)CC.CCOCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:3]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][O:4][CH2:1]1
Reactant: C=CCOCc1ccccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=C1COCc2ccccc21
Temperature: 80 °C

Procedure:
1-[(allyloxy)methyl]-2-iodobenzene (23 g, 83.9 mmol) was dissolved in 100 ml of CH3CN and 58 ml of Et3N. The solution was vacuum degassed (3 cycles) followed by the addition of Pd(OAc)2 (0.9 g, 4.2 mmol) and PPh3 (2.2 g, 8.4 mmol). The mixture was heated to 80° C. until HPLC indicated complete reaction. The mixture was cooled to room temperature and diluted with Et2O (200 ml). The mixture was washed with 1N HCl (2×50 ml); NaHCO3 (2×50 ml); brine (1×50 ml); dried over Na2SO4 and concentrated in vacuo to yield 4-methylene-3,4-dihydro-1H-isochromene (Heterocycles 1994, 39, 497) as an oil. HRMS (ESI+) calcd for C10H10O m/z 146.0732 (M+H)+. Found 146.0728. The crude oil was dissolved in 1:1 CH3OH/CH2Cl2 (500 ml) and 5 ml of pyridine added. The mixture was chilled to −78° C. and ozone was bubbled through the mixture for 1 h, at which time TLC indicated complete reaction. The mixture was purged with N2 at −78° C. and treated with Me2S, then allowed to warm to room temperature and stir for 3 h. The reaction was then diluted with CH2Cl2 and washed with H2O and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to yield 5.1 g of 1H-isochromen-4(3H)-one as a slight yellow oil after flash chromatography (10% EtOAc/Hexanes) Rf=0.25. 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J=7.88 Hz, 1H), 7.59 (m, 1H), 7.43 (appt, J=7.36 Hz, 1H), 7.24 (d, J=7.67 Hz, 1H), 4.91 (s, 2H), 4.39 (s, 2H. Anal calcd for C9H8O2; C, 72.96; H, 5.44; found C, 72.50; H, 5.29. MS (ESI+) for C9H8O2 m/z 148.8 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][C:5]2[N:6]([CH3:10])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.Br[C:23]1[CH:24]=[C:25]([CH2:29][OH:30])[CH:26]=[N:27][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CO.C(Cl)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>[F:1][C:2]1[C:12]([C:23]2[CH:28]=[N:27][CH:26]=[C:25]([CH2:29][OH:30])[CH:24]=2)=[CH:11][C:5]2[N:6]([CH3:10])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1
Reactant: OCc1cncc(Br)c1
Reactant: Cn1c(=O)oc2cc(F)c(B3OC(C)(C)C(C)(C)O3)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Solvent: CO
Product: Cn1c(=O)oc2cc(F)c(-c3cncc(CO)c3)cc21
Temperature: 100 °C
Yield: 44.4 %

Procedure:
A mixture of 6-Fluoro-3-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-benzooxazol-2-one (352 mg, 1.2 mmol), (5-bromopyridin-3-yl)methanol (188 mg, 1 mmol), Na2CO3 (2 M in water, 1 mL, 2 mmol), polymer bound Pd(PPh3)4 (642 mg, 0.07 mmol) in DME (4 mL) was heated by microwave at 100° C. for 1.25 h. The reaction mixture was cooled to room temperature and the mixture was diluted with CH3OH/CH2Cl2 (1:1, 50 mL) and filtered through a pad of celite. The celite pad was further washed with CH2Cl2/CH3OH (50 mL). Ater concentration, the residue was purified by flash column (0-10%, v/v, CH3OH in CH2Cl2) and afforded 121.9 mg of the desired product as a white solid. ESI-MS m/z: 274.9 [M+1]+, Retention time 0.93 min; 1HNMR (MeOD, 400.342 MHz) δ 3.44 (s, 3H), 4.74 (s, 2H), 7.30 (d, J=9.7 Hz, 1H), 7.34 (d, J=6.4 Hz, 1H), 8.03 (s, 1H), 8.55 (s, 1H), 8.64 (s, 1H)
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:6]=2[N:5]=[C:4]([NH2:17])[N:3]=1.C(N(CC)CC)C.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>C(O)C.C(Cl)Cl>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:2]2[C:7]3[CH2:8][CH2:9][O:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:6]=3[N:5]=[C:4]([NH2:17])[N:3]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1nc(Cl)c2c(n1)-c1ccccc1OCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2nc(N)nc3c2CCOc2ccccc2-3)CC1
Temperature: 90 °C

Procedure:
To a solution of Example 29D (29 mg, 0.12 mmol) in ethanol (0.5 mL) was added triethylamine (0.12 mL, 0.82 mmol), piperazine-1-carboxylic acid tert-butyl ester (33 mg, 0.18 mmol) and the mixture heated at 90° C. for 16 hours. The mixture was diluted with CH2Cl2 (25 mL) and washed with 1 M NaOH (10 mL). The layers were separated and the aqueous was extracted with CH2Cl2 (25 mL). The combined CH2Cl2 layers were dried (MgSO4), filtered, concentrated under reduced pressure and chromatographed on silica gel eluting with a gradient of CH2Cl2:EtOAc (5:1, 2:1 and 1:1) to provide the title compound. 1H NMR (CDCl3) δ 1.49 (s, 9H), 2.72 (t, J=5.93 Hz, 2H), 3.26-3.32 (m, 4H), 3.52-3.57 (m, 4H), 4.54 (t, J=5.93 Hz, 2H), 4.78 (s, 2H), 7.09 (dd, J=8.14, 1.36 Hz, 1H), 7.17-7.24 (m, 1H), 7.35-7.42 (m, 1H), 7.89 (dd, J=7.80, 1.70 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][C:21](OCC)=[O:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][C:21]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: C1COCCN1
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCCC(=O)OCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Product: CCOCc1nc2cnc3ccccc3c2n1CCCC(=O)N1CCOCC1
Temperature: 130 °C
Yield: 98.6 %

Procedure:
Ethyl 4-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butanoate (6.25 g, 18.3 mmol) and morpholine (16.0 g, 184 mmol) were sealed and heated in a high-pressure vessel at 130° C. overnight. An analysis by TLC indicated the reaction was incomplete. Pyridinium p-toluenesulfonate (100 mg) was added, and the reaction was heated for three days at 105° C. and for one day at 125° C. The solution was allowed to cool and then poured into water (100 mL). The resulting solution was extracted with dichloromethane (3×75 mL), and the combined extracts were dried over potassium carbonate, filtered, and concentrated under reduced pressure. The residue was mixed with ethyl acetate (50 mL) and hexane (200 mL) and sonicated. The solvent was decanted away to afford 6.9 g of 2-(ethoxymethyl)-1-(4-morpholin-4-yl-4-oxobutyl)-1H-imidazo[4,5-c]quinoline as an oil.
Reaction SMILES: C1(C(C2C=CC=CC=2)([C@H]2CCCN2)O)C=CC=CC=1.B([O-])([O-])[O-].B.C(N(CC)C1C=CC=CC=1)C.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C:43](=[O:58])[CH2:44][CH2:45][C:46]([C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[C:50]([N+:55]([O-:57])=[O:56])[CH:49]=2)=[O:47])=[CH:39][C:38]=1[N+:59]([O-:61])=[O:60]>C1COCC1>[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C@@H:43]([OH:58])[CH2:44][CH2:45][C@@H:46]([C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[C:50]([N+:55]([O-:57])=[O:56])[CH:49]=2)[OH:47])=[CH:39][C:38]=1[N+:59]([O-:61])=[O:60]
Reactant: O=C(CCC(=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: B
Agent: OC(c1ccccc1)(c1ccccc1)[C@H]1CCCN1
Agent: [O-]B([O-])[O-]
Solvent: CCN(CC)c1ccccc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc([C@@H](O)CC[C@H](O)c2ccc(Cl)c([N+](=O)[O-])c2)ccc1Cl
Temperature: 10 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
(R)-(+)-alpha,alpha-diphenyl-2-pyrrolidinemethanol (1.08 g, 4.28 mmol) was dissolved in 70 mL of THF at ambient temperature in a dry flask under nitrogen and the timethyl borate (650 uL, 5.54 mmol) was added dropwise. The resulting solution was stirred for 1 hr. The solution was cooled in a cold bath to ˜10° C. and the N,N-diethylaniline borane (9.18 mL, 51.6 mmol) was added dropwise with some bubbling. After 15 min, this solution was transferred to an addition funnel and added dropwise to 1,4-bis(4-chloro-3-nitrophenyl)butane-1,4-dione (Example 109B) (10.0 g, 25.2 mmol) suspended in 200 mL of THF and cooled to ˜10° C. Bubbling was observed. After the addition, mixture was stirred at ambient temperature for 4 hours. The mixture was cooled in an ice bath and 30 mL MeOH was added dropwise till bubbling stopped, then the mixture was let stir at ambient temperature for 30 min. The mixture was filtered to get rid of a trace of insoluble unreacted SM. The filtrate was concentrated, poured into 1 M HCl and extracted into ethyl acetate, dried over sodium sulfate; concentrated to give the title compound (9.9 g, 99%) as a yellow waxy solid. Chiral HPLC e.e. >99.9% (RR diol was undetectable). 1H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J=1.9 Hz, 2H), 7.69 (d, J=8.4 Hz, 2H), 7.60 (dd, J=8.4, 1.9 Hz, 2H), 4.65 (m, 2H), 1.62 (m, 4H).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:5])[CH3:4].C(N(CC)[P:20]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])C.N1C=NN=N1.C1C=C(Cl)C=C(C(OO)=[O:46])C=1>C1COCC1.ClCCl.C(OCC)(=O)C>[C:27]([O:26][P:20]([O:1][CH2:2][C:3]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])[CH3:5])([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:46])([CH3:28])([CH3:29])[CH3:30]
Reactant: CCN(CC)P(OC(C)(C)C)OC(C)(C)C
Reactant: CC(C)(CO)NC(=O)OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: c1nnn[nH]1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(COP(=O)(OC(C)(C)C)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: -45 °C
Yield: 58.7 %

Procedure:
The product of Example 95A (0.80 g, 3.8 mmol), di-tert-butyl diethylphosphoramidite (1.07 mL, 3.8 mmol), and 1-H-tetrazole (0.63 g, 8.99 mmol) in THF (35 mL) were reacted at room temperature for 12 hours. The reaction was diluted with dichloromethane (35 mL) and cooled to −45° C., and treated with mCPBA (0.90 g, 4.0 mmol) for 0.5 hours then diluted with ethyl acetate (100 mL). The organics were washed with 10% Na2CO3 (2×), brine, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica gel, eluting with a gradient of ethyl acetate in dichloromethane (0-25%) to give the title compound as a colorless oil (0.926 g, 62%).