Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][C@@H:5]2[CH2:7][CH2:8][C@@H:9]([N:10]3[C:18]4[C:17]([F:19])=[CH:16][N:15]=[C:14](F)[C:13]=4[N:12]=[CH:11]3)[C@@H:4]2[O:3]1.CC1(C)O[C@@H]2CC[C@@H]([N:31]3C4C(F)=NC=C(F)C=4N=C3)[C@@H]2O1>N>[CH3:1][C:2]1([CH3:21])[O:6][C@@H:5]2[CH2:7][CH2:8][C@@H:9]([N:10]3[C:18]4[C:17]([F:19])=[CH:16][N:15]=[C:14]([NH2:31])[C:13]=4[N:12]=[CH:11]3)[C@@H:4]2[O:3]1
Reactant: CC1(C)O[C@H]2[C@H](n3cnc4c(F)ncc(F)c43)CC[C@H]2O1
Reactant: CC1(C)O[C@H]2[C@H](n3cnc4c(F)cnc(F)c43)CC[C@H]2O1
Agent: N
Product: CC1(C)O[C@H]2[C@H](n3cnc4c(N)ncc(F)c43)CC[C@H]2O1
Temperature: 85 °C

Procedure:
Liquid ammonia (200 mL) was added to a mixture of 1-[(3aS,4R,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-4,7-difluoro-1H-imidazo[4,5-c]pyridine (1-6) (2.4 g, 8.1 mmol, 1 equiv) and 3-[(3aS,4R,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-4,7-difluoro-3H-imidazo[4,5-c]pyridine (1-5) (2.5 g, 8.5 mmol, 1 equiv). The resulting solution was heated in a high pressure vessel to 85° C. for 5 days. The mixture was then concentrated and purified via flash chromatography on a 120 g silica gel column (gradient elution 0 to 100% ethyl acetate in dichloromethane and then 100% methanol to elute 1-7) to yield 1-[(3aS,4R,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-7-fluoro-1H-imidazo[4,5-c]pyridin-4-amine (1-7) as a tan solid in addition to 3-[(3aS,4R,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-7-fluoro-3H-imidazo[4,5-c]pyridin-4-amine (1-8) and recovered starting material 1-5. 1H NMR (1-7) (500 MHz, CD3 OD): δ 8.13 (s, 1H); 7.62 (d, J=3.7 Hz, 1H); 4.95-4.87 (m, 3H); 2.52-2.42 (m, 1H); 2.21-1.99 (m, 3H); 1.50 (s, 3H); 1.33 (s, 3H). LRMS m/z (M+H) 293.0 found, 293.1 required. 1H NMR (1-8) (500 MHz, CDCl3): δ 7.86-7.81 (m, 1H); 7.76-7.73 (m, 1H); 5.07 (s, 1H); 5.01 (s, 2H); 4.87 (t, J=4.6 Hz, 1H); 4.62 (d, J=6.2 Hz, 1H); 2.66-2.57 (m, 1H); 2.46-2.38 (m, 1H); 2.24-2.17 (m, 2H); 1.57 (s, 3H); 1.35-1.30 (m, 3H). LRMS m/z (M+H) 293.0 found, 293.1 required.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:9]([C:12]2[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].[CH:22]1([CH2:25][NH2:26])[CH2:24][CH2:23]1.O>CN1CCCC1=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:26][CH2:25][CH:22]3[CH2:24][CH2:23]3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: NCC1CC1
Reactant: Nc1ccc(OS(=O)(=O)c2ccc(F)cc2)cc1[N+](=O)[O-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Nc1ccc(OS(=O)(=O)c2ccc(NCC3CC3)cc2)cc1[N+](=O)[O-]

Procedure:
A solution of 4-fluoro-benzenesulfonic acid 4-amino-3-nitro-phenyl ester (800 mg) and cyclopropylmethylamine (890 μl) in N-methylpyrrolidinone (8 ml) was heated at 110° C. in a sealed tube for 14 hours. The reaction mixture was then poured into water (150 ml) and extracted three times with ethyl acetate (40 ml). The combined extracts were dried over magnesium sulfate and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and heptane (50:50, v/v) to give 4-(cyclopropylmethyl-amino)-benzenesulfonic acid 4-amino-3-nitro-phenyl ester (786 mg) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:14][CH:13]([S:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1C.Cl[S:43]([OH:46])(=[O:45])=[O:44]>ClCCl>[CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:14][C@@H:13]([S:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:12][N:11]1[S:43]([OH:46])(=[O:45])=[O:44])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc(COCC2CC(SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2)cc1
Solvent: ClCCl
Solvent: Cc1ccccn1
Product: O=S(=O)(O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 2-benzyloxymethyl-4-tritylsulfanyl-pyrrolidine (0.435 g) in dichloromethane (30.0 ml) was treated with 2-picoline (2.11 ml) and chlorosulphonic acid (0.186 ml). The reaction mixture was stirred for 5 h at room temperature and evaporated to dryness. The residue was quenched with ice/water and extracted with EtOAc. The aqueous layer was saturated with sodium chloride and acidified with 1 molar HCl to pH 3.4 and extracted again with EtOAc. The organic phase was washed with brine, dried over magnesium sulphate and concentrated to obtain (2S,4R)-2-benzyloxymethyl-4-tritylsulfanyl-pyrrolidine-1-sulfonic acid (0.26 g) as an oil, MS: 544 (M−H)−.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=O)[CH2:13][CH3:14].[OH-:22].[K+]>C(O)C.O>[CH3:14][C:13]1[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:1][C:11]2[C:6]([C:4]=1[C:2]([OH:22])=[O:3])=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: O=C1Nc2ccccc2C1=O
Reactant: [OH-]
Reactant: CCC(=O)c1ccccc1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1c(-c2ccccc2)nc2ccccc2c1C(=O)O
Yield: 85 %

Procedure:
A solution of isatin (5.00 g, 34.0 mmol), propiophenone (5.47 g, 5.43 mL, 40.8 mmol), and potassium hydroxide pellets (6.73 g, 102 mmol) in ethanol (40 mL) was stirred at reflux for 23 h. After cooling, the solvent was removed in vacuo to give a brown residue. The residue was dissolved in water (75 mL) and washed with diethyl ether (4×100 mL). The aqueous layer was cooled by the addition of ice (˜50 g) and acidified to pH˜1 via dropwise addition of concentrated HCl with stirring. A solid precipitate was collected by filtration, washed with water and dried to provide the title compound as a yellowish-tan solid (7.59 g, 85%), which was used without further purification. MS (API+): M+1: 264 (45%), 220 (100); %); 1H NMR (300 MHz, DMSO-d6) d 2.39 (s, 3H), 7.49-7.57 (m, 3H), 7.59-7.72 (m, 7.76-7.84 (m, 2H), 8.06 (d, J=8.5 Hz, 1H), 14.20 (v br s, 1H, exchangeable).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]([C:5]1[O:6][C:7]([C:10](=[O:12])[CH3:11])=[CH:8][CH:9]=1)=[O:4].[Br:14]Br>C(O)(=O)C>[CH3:13][N:2]([CH3:1])[C:3]([C:5]1[O:6][C:7]([C:10](=[O:12])[CH2:11][Br:14])=[CH:8][CH:9]=1)=[O:4]
Reactant: BrBr
Reactant: CC(=O)c1ccc(C(=O)N(C)C)o1
Solvent: CC(=O)O
Product: CN(C)C(=O)c1ccc(C(=O)CBr)o1

Procedure:
A mixture of 1.81 g. (0.01 mole) of N,N-dimethyl-5-acetylfuran-2-carboxamide, 1.59 g. (0.01 mole) of bromine and 40 ml. of glacial acetic acid was stirred at room temperature for 18 hours, and then the acetic acid was removed by evaporation in vacuo. The residue was partitioned between water and ethyl acetate and the layers were separated. The aqueous layer was further extracted with ethyl acetate, and the combined ethyl acetate solutions were washed with sodium bicarbonate solution followed by water, dried (Na2SO4) and evaporated in vacuo. This afforded 2.6 g. of the title compound as a solid.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([NH:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[O:14])[C:10]1([CH3:23])[CH3:22])=O)(C)(C)C.CCN(CC)CC>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([NH:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[O:14])[C:10]1([CH3:23])[CH3:22]
Reactant: COC(=O)CCNC(=O)[C@H]1C[C@@H](NC(=O)OC(C)(C)C)C1(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COC(=O)CCNC(=O)[C@H]1C[C@@H](N)C1(C)C
Yield: 100 %

Procedure:
A stirred solution of methyl 3-((1S,3R)-3-(tert-butoxycarbonylamino)-2,2-dimethylcyclobutanecarboxamido)propanoate (step 1, 0.336 g, 1.024 mmol) in TFA:DCM (1:4) (4 ml) at 0° C.-room temperature for about 1 hour and after completion of the reaction, the solvent was evaporated and the crude dissolved in DCM and basified with Et3N (0.87 ml, 6.29 mmol) then the resulting solution as such used for the next reaction. Wt: 0.233 g (Based on 100% yield calculated and proceeded for next reaction).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH2:9][OH:10])[C:6]([O:11]C)=[C:5]([CH3:13])[C:4]=1[CH3:14].C([O-])(=O)C.[Na+].C(#N)C>O>[CH3:14][C:4]1[C:3](=[O:2])[CH:8]=[C:7]([CH2:9][OH:10])[C:6](=[O:11])[C:5]=1[CH3:13]
Reactant: COc1cc(CO)c(OC)c(C)c1C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC1=C(C)C(=O)C(CO)=CC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of intermediate E (1.8 g, 9 mmole), sodium acetate (7.5 g, 91 mmole), acetonitrile (134 ml) and water (29 ml), silver dipicolinate complex (19.2 g, 44 mmole, prepared by the method described by K. Kloc et al in Chem. Lett., 725. 1980) was added slowly with vigorous stirring over 30 minutes at room temperature. The mixture was stirred over 30 minutes longer, water (150 ml) was added, and the silver salts were filtered off and washed with chloroform. The filtrate was extracted several times with chloroform. The combined extracts were dried, concentrated to a small volume and chromatographed (silica, dichloromethane:ethyl acetate, 95:5). There was obtained 900 mg of ETA I, mp 71°-72° C. Calculated elemental analysis for C9H10O3 is C, 65.1, H, 6.1, and 0, 28.9. Elemental analysis found was C, 64.9, H, 5.9, and 0, 28.7.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:41][C:18]3=[N:19][CH:20]=[C:21]([C:39]#[N:40])[C:22]([NH:23][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]4)=[C:17]3[C:16]=2[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CCOC(C)=O.[Pd]>[C:39]([C:21]1[C:22]([NH:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)=[C:17]2[C:16]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)[O:41][C:18]2=[N:19][CH:20]=1)#[N:40]
Reactant: CC(C)(C)OC(=O)N1CCN(CCNc2c(C#N)cnc3oc(-c4ccc(OCc5ccccc5)cc4)c(-c4ccccc4)c23)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(CCNc2c(C#N)cnc3oc(-c4ccc(O)cc4)c(-c4ccccc4)c23)CC1

Procedure:
A mixture of 8c (200 mg, 0.303 mmol, 1.0 equiv) and 10% Pd on carbon (30 mg) in EtOAc at 25° C. was exposed to a hydrogen atmosphere (balloon). Upon consumption of the starting material as indicated by TCL, the mixture was filtered and solvent removed in vacuo. The resulting phenol 8b was advanced without further purification. MS (MH+) 540; Calculated 539.3 for C31H33N5O4.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([OH:16])[C@@H:11]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].CS(O[CH2:28][C:29]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([N:39]2[C:43]([CH3:44])=[N:42][N:41]=[N:40]2)[CH:30]=1)(=O)=O.C(=O)([O-])O.[Na+]>CN(C)C=O.O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([O:16][CH2:28][C:29]2[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[C:31]([N:39]3[C:43]([CH3:44])=[N:42][N:41]=[N:40]3)[CH:30]=2)[C@@H:11]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: Cc1nnnn1-c1cc(COS(C)(=O)=O)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)[C@@H]1c1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nnnn1-c1cc(CO[C@H]2CCCN(C(=O)OC(C)(C)C)[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.4 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 24 mg, 0.6 mmol) was added to a stirred, cooled (0° C.) solution of [2S,3S]-1-tert-butoxycarbonyl-2-phenylpiperidin-3-ol (138 mg, 0.5 mmol) in N,N-dimethylformamide (2 ml). The mixture was stirred at room temperature for 30 minutes, cooled in ice and 1-(methanesulfonyloxymethyl)-3-(5-methyltetrazol-1-yl)-5-(trifluoromethyl)benzene (168 mg, 0.5 mmol) in N,N-dimethylformamide (2 ml) was added. The mixture was stirred at room temperature for 66 hours, saturated aqueous sodium hydrogen carbonate (20 ml) and water (10 ml) were added and the mixture was extracted with ethyl acetate (3×20 ml). The combined organic fractions were washed with saturated aqueous sodium hydrogen carbonate (4×20 ml) and brine (20 ml), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by MPLC on silica gel, eluting with ethyl acetate/hexane (40:60 increasing to 60:40) to give [2S,3S]-1-tert-butoxycarbonyl-2-phenyl-3-[3-(5-methyltetrazol-1-yl)-5-(trifluoromethyl)phenylmethoxy]piperidine as a pale yellow oil (133 mg, 51%), 1H (CDCl3) δ 7.69 (1H, s), 7.65 (1H, s), 7.52 (3H, m), 7.31-7.19 (3H, m), 5.68 (1H, br s), 4.77 (2H, s), 3.92 (2H, m), 2.78 (1H, m), 2.58 (3H, s), 2.00 (2H, m), 1.66 (2H, m), and 1.45 (9H, s). m/z 518 (M+H+).
Reaction SMILES: CC1NC([N+]([O-])=O)=CN=1.S(OC)(OC)(=O)=O.[CH3:17][N:18]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][N:20]=[C:19]1[CH3:26].[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[O-]CC.[Na+]>C(O)C.C1C=CC=CC=1>[CH3:17][N:18]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][N:20]=[C:19]1[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1ncc([N+](=O)[O-])n1C
Reactant: O=Cc1ccccc1
Agent: CC[O-]
Agent: Cc1ncc([N+](=O)[O-])[nH]1
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CCO
Solvent: c1ccccc1
Product: Cn1c([N+](=O)[O-])cnc1C=Cc1ccccc1

Procedure:
The novel compounds coming within the scope of the generic formula, supra, are readily synthesized starting with commercially available 2-methyl-5-nitroimidazole. This starting compound is allowed to react with a suitable alkylating agent, such as dimethyl sulfate, in a suitable solvent, for example benzene, to yield the comopound identified as 1,2-dimethyl-5-nitroimidazole. This latter compound is in turn allowed to react with benzaldehyde in the presence of a base, for example sodium ethoxide in absolute ethanol, to yield 1-methyl-5-nitro-2-styrylimidazole.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([O-:3])=O.[Cl:12][C:13]1[CH:14]=[C:15]([CH:20]2[CH2:25][C:24](=[O:26])[CH2:23][C:22](=O)[CH2:21]2)[CH:16]=[CH:17][C:18]=1[Cl:19].O.[ClH:29]>C(O)(=O)C.CO>[Cl:29][C:9]1[CH:8]=[C:5]2[C:4]([N:1]([OH:3])[C:22]3[CH2:21][CH:20]([C:15]4[CH:16]=[CH:17][C:18]([Cl:19])=[C:13]([Cl:12])[CH:14]=4)[CH2:25][C:24](=[O:26])[C:23]=3[C:6]2=[O:7])=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: Cl
Reactant: O=C1CC(=O)CC(c2ccc(Cl)c(Cl)c2)C1
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: O=C1CC(c2ccc(Cl)c(Cl)c2)Cc2c1c(=O)c1cc(Cl)ccc1n2O
Temperature: 80 °C

Procedure:
A mixture of 3.25 g of 2-nitrobenzaldehyde and 5.5 g of 5-(3,4-dichlorophenyl)-1,3-cyclohexanedione in 20 ml of glacial acetic acid and 20 ml of concentrated hydrochloric acid is heated at 80° C. for 0.5 hr, cooled and poured into 300 ml of water. The solid is digested in hot methanol and dried in vacuo to give 7-chloro-3-(3,4-dichlorophenyl)-3,4-dihydro-10-hydroxy-1,9(2H,-10H)-acridinedione; mp 268°-269° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C@H:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)[CH:13]=1)=[O:11].C(N(CC)CC)C.[C:35](Cl)(=[O:38])[O:36][CH3:37]>C(Cl)Cl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C@H:23]2[CH2:27][CH2:26][N:25]([C:35]([O:36][CH3:37])=[O:38])[CH2:24]2)[CH:13]=1)=[O:11]
Reactant: COC(=O)Cl
Reactant: O=C(Nc1c(Cl)cccc1Cl)c1cn([C@H]2CCNC2)c2ncccc2c1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CC[C@H](n2cc(C(=O)Nc3c(Cl)cccc3Cl)c(=O)c3cccnc32)C1
Reaction time: 0.67 h
Yield: 67 %

Procedure:
Then, to a 4 ml anhydrous methylene chloride solution of (S)-N-(2,6-dichlorophenyl)-1-(3-pyrrolidyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide, 28 μl (0.20 mmol) of triethylamine and 12.4 μl (0.16 mmol) of methyl chlorocarbonate were added at room temperature and stirred for 40 minutes. The reaction solution was concentrated under vacuum and the residue was purified by a silica gel chromatography (hexane/ethyl acetate=1/2) to obtain 55 mg (67%) of the above-identified compound as a colorless oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[N:14]4[C@@H:15]([CH3:19])[CH2:16][O:17][CH2:18][C:13]4=[N:12][C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[NH4+:31].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>O.C(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[N:14]4[C@@H:15]([CH3:19])[CH2:16][O:17][CH2:18][C:13]4=[N:12][C:7]=3[C:8]([NH2:31])=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[C@H]1COCc2nc3cnc4cc(Br)ccc4c3n21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: C[C@H]1COCc2nc3c(N)nc4cc(Br)ccc4c3n21
Temperature: 25 °C

Procedure:
A 2-L, three-necked, Morton flask, equipped with mechanical stirrer, was charged with (11S)-3-bromo-11-methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline (9.12 g, 28.7 mmol) and CH2Cl2 (500 mL). The mixture was stirred at ambient temperature and MCPBA (10.35 g, 50% purity) was then added slowly in portions. The reaction was stirred at ambient temperature for 2 hours. Concentrated aqueous NH4OH solution (200 mL) was then slowly added to the reaction mixture followed by careful addition of p-toluenesulfonyl chloride (6.29 g, 33.0 mmol) in small portions. The reaction was stirred rapidly at ambient temperature overnight. The reaction was then treated with H2O (500 mL) and vigorous stirring was maintained for 2 hours. The layers were allowed to separate and a tan precipitate formed. The aqueous layer was removed and the organic layer, containing the precipitate, was filtered to give 6.0 g of (11S)-3-bromo-11-methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine as a tan solid. The product was used in subsequent reactions without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:14])[N:6]([CH2:9][C:10]([F:13])([F:12])[F:11])[C:7]=1[CH3:8].[F:15][C:16]1[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=1B(O)O.[F-].[Cs+]>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:8][C:7]1[N:6]([CH2:9][C:10]([F:13])([F:12])[F:11])[C:5](=[O:14])[CH:4]=[CH:3][C:2]=1[C:17]1[CH:18]=[C:19]([F:23])[CH:20]=[C:21]([F:22])[C:16]=1[F:15]
Reactant: OB(O)c1cc(F)cc(F)c1F
Reactant: Cc1c(Br)ccc(=O)n1CC(F)(F)F
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(-c2cc(F)cc(F)c2F)ccc(=O)n1CC(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Argon was bubbled through a stirred solution of 5-bromo-6-methyl-1-(2,2,2-trifluoroethyl)pyridin-2(1H)-one (9.43 g, 34.9 mmol) in THF (280 mL) for 15 min. To this solution were added 2,3,5-trifluorophenylboronic acid (12.3 g, 69.8 mmol), then cesium fluoride (10.6 g, 69.8 mmol), and finally bis(tri-tert-butylphosphine)palladium(0) (892 mg, 1.75 mmol), and argon was bubbled through the mixture for 5 min after each addition. The reaction mixture was stirred at ambient temperature for 90 min and was then partitioned between saturated aqueous sodium bicarbonate (500 mL) and EtOAc (600 mL). The organic layer was removed and the aqueous phase was extracted further with EtOAc (300 mL). The combined organic extracts were washed with brine, then dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=322.0 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[C:15]3[C:10]([N:11]=[CH:12][CH:13]=[N:14]3)=[C:9]([NH:17][CH:18]3[CH2:23][CH2:22][CH:21]([NH:24]C(=O)OC(C)(C)C)[CH2:20][CH2:19]3)[CH:8]=2)[CH2:3][CH2:2]1.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].C(=O)(O)[O-].[Na+]>ClCCl>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[C:15]3[C:10]([N:11]=[CH:12][CH:13]=[N:14]3)=[C:9]([NH:17][CH:18]3[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]3)[CH:8]=2)[CH2:3][CH2:2]1.[F:32][C:33]([F:38])([F:37])[C:34]([O-:36])=[O:35]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2cc(N3CCOCC3)cc3nccnc23)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: NC1CCC(Nc2cc(N3CCOCC3)cc3nccnc23)CC1
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
As shown in step 3-iv of Scheme 3, to a solution of tert-butyl (-4-((7-morpholinoquinoxalin-5-yl)amino)cyclohexyl)carbamate (900 mg, 2.00 mmol) in dichloromethane (16 mL) was added trifluoroacetic acid (3 mL, 38.9 mmol). The resulting black reaction mixture was stirred under an atmosphere of nitrogen at room temperature for 2 hours. Saturated aqueous sodium bicarbonate (150 mL) was added slowly until the color turned from black to orange. The mixture was extracted with dichloromethane (2×100 mL) and the combined organics washed with brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to provide-N1-(7-morpholinoquinoxalin-5-yl)cyclohexane-1,4-diamine, trifluoroacetate (compound 1005): 1H NMR (300 MHz, CDCl3) δ 8.64 (d, J=1.9 Hz, 1H), 8.36 (d, J=1.9 Hz, 1H), 6.59 (d, J=2.3 Hz, 1H), 6.34 (d, J=2.3 Hz, 1H), 6.20 (d, J=7.9 Hz, 1H), 3.95-3.84 (m, 4H), 3.69 (s, 1H), 3.41-3.25 (m, 4H), 2.93 (d, J=8.9 Hz, 1H), 2.09-1.87 (m, 2H), 1.90-1.68 (m, 6H), 1.58 (dd, J=11.2, 8.7 Hz, 2H); ESMS (M+H+)=328.34. This compound was used as is without further purification.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].Br[C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[O:25][CH:26]([CH3:28])[CH3:27]>>[NH2:15][C:7]1[C:6]([C:4]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[O:25][CH:26]([CH3:28])[CH3:27])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Reactant: CC(C)Oc1ccc(F)cc1Br
Product: CCSc1ncc(C(=O)c2cc(F)ccc2OC(C)C)c(N)n1

Procedure:
The compound was prepared from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide, Example 1, and 2-bromo-4-fluoro-1-isopropoxy-benzene (prepared from 2-bromo-4-fluoro-phenol, Aldrich) in an analogous manner as described in Example 169.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O>[CH2:21]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([F:9])[CH:4]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Oc1ccc(Br)c(F)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cc(OCc2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 102.9 %

Procedure:
To a mixed solution of a commercially available product of 4-bromo-3-fluorophenol (15.0 g, 78.5 mmol) and DMF (30 mL) were added potassium carbonate (21.7 g, 157 mmol) and benzyl bromide (10.2 mL, 86.4 mmol) at room temperature, and the resultant mixture was stirred at room temperature for 20 minutes and then at 70° C. for 40 minutes. The reaction mixture was cooled to room temperature, then water was added to the reaction mixture, and the resultant solution was extracted with ethyl acetate. An organic layer was washed with water and then with saturated brine. An organic layer was dried over anhydrous magnesium sulfate and then filtrated. The solvent was evaporated under a reduced pressure, and the resultant residue was purified by silica gel column chromatography (heptane:ethyl acetate=5:1) to give the title compound (22.7 g, yield: quantitative).