Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([OH:23])[C:21]=1[OH:22])[C:5]1[O:6][C:7]2[C:12]([C:13](=[O:18])[C:14]=1[C:15]([OH:17])=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=2.C(O[C:28](=[O:30])[CH3:29])(=O)C.Cl>N1C=CC=CC=1.ClCCl>[C:2]([O:23][C:20]1[CH:19]=[C:4]([CH:3]=[C:2]([O:1][C:28](=[O:30])[CH3:29])[C:21]=1[O:22][C:5](=[O:6])[CH3:4])[C:5]1[O:6][C:7]2[C:12]([C:13](=[O:18])[C:14]=1[C:15]([OH:17])=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:1])[CH3:21]
Reactant: O=C(O)c1c(-c2cc(O)c(O)c(O)c2)oc2ccccc2c1=O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(-c2oc3ccccc3c(=O)c2C(=O)O)cc(OC(C)=O)c1OC(C)=O
Reaction time: 2 h

Procedure:
3',4',5'-Trihydroxyflavone-3-carboxylic acid was dissolved in 4 ml absolute pyridine, and the solution was reacted with 0.57 ml acetic anhydride and stirred for two hours. Then it was worked up by diluting with 20 ml dichloromethane, pouring onto a mixture of dilute hydrochloric acid/ice water and shaking with dichloromethane. Here care must be taken that the aqueous phase remains acid (if necessary some dilute hydrochloric acid must be added). The dichloromethane phase was separated, washed with water, dried over sodium sulfate and evaporated. 0.8 g crude 3',4',5'-triacetoxyflavone-3-carboxylic acid were obtained which was immediately processed further without additional purification.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2=[N:6][O:7][N:8]=[C:4]2[CH:3]=1.[Cl-].[Li+].[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15]>C1(C)C=CC=CC=1.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>[CH2:15]([C:2]1[CH:10]=[CH:9][C:5]2=[N:6][O:7][N:8]=[C:4]2[CH:3]=1)[CH:14]=[CH2:13]
Reactant: Brc1ccc2nonc2c1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1ccc2nonc2c1

Procedure:
5-Bromo-2,1,3-benzoxadiazole (10 g, 50.3 mmol) was dissolved in toluene (300 mL) and treated with lithium chloride (6.39 g, 151 mmol), Pd(Ph3P)4 (2.90 g, 2.51 mmol), and allyltributylstannane (18.66 ml, 60.3 mmol). Degassed and refluxed the mixture under N2 for 3 hrs. The reaction mixture turned black. Poured the reaction mixture into water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried, and evaporated to dryness. The residue was chromatographed through 120 g ISCO Redi-Sep column and eluted with 0-10% ethyl acetate/hexane to yield 5-(prop-2-en-1-yl)-2,1,3-benzoxadiazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:10]=1.Br[C:36]1[CH:37]=[C:38]([CH2:42][C:43]([OH:45])=[O:44])[CH:39]=[CH:40][CH:41]=1.C1COCC1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:36]3[CH:37]=[C:38]([CH2:42][C:43]([OH:45])=[O:44])[CH:39]=[CH:40][CH:41]=3)[CH:16]=2)[N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:33])[CH3:34])[N:10]=1
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(CC(=O)O)c3)cc12
Yield: 66.8 %

Procedure:
To a mixture of 3-(2-Methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (500 mg, 1.04 mmol) and 3-bromophenylacetic acid (268 mg, 1.25 mmol) in a 20 mL microwave reaction flask was added THF (3 mL), acetonitrile (3 mL) and sodium carbonate (3 mL, 1 N aqueous solution, 3 mmol). The mixture was bubbled with N2 for 1 min. dichloro[1,1′-bis(diphenyl-phosphino)ferrocene]palladium(II) (73 mg, 10% mol) was added and the bubbling continued for another minute. The flask was sealed and irradiated with microwave in Emrys Optimizer at 120° C. for 20 min. The reaction mixture was partitioned between aqueous saturated sodium chloride and ethyl acetate (15 mL: 15 mL). The aqueous layer was extracted with ethyl acetate (10 mL×2). Normal work up of the combined organic layers and purification with flash chromatography on silica gel using a gradient of methanol in dichloromethane yielded {3-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-acetic acid as a yellow solid (340 mg, 67% yield). MS: m/z 490 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][CH2:18][OH:19])[CH2:13][CH2:12]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>>[C:1]([O:5][C:6]([N:7]([CH3:8])[CH2:9][CH2:10][C@H:11]1[CH2:12][CH2:13][C@H:14]([CH2:17][CH2:18][O:19][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:15][CH2:16]1)=[O:20])([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(CC[C@H]1CC[C@H](CCO)CC1)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Product: CN(CC[C@H]1CC[C@H](CCOS(C)(=O)=O)CC1)C(=O)OC(C)(C)C

Procedure:
In analogy to the procedures described in examples 11.13, 11.14 and 11.15, trans-{2-[4-(2-hydroxy-ethyl)-cyclohexyl]-ethyl}-methyl-carbamic acid tert-butyl ester was reacted with methanesulfonyl chloride to give trans-methanesulfonic acid 2-{4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexyl}-ethyl ester, which was subsequently treated with 4N hydrogen chloride in dioxan to yield trans-methanesulfonic acid 2-[4-(2-methylamino-ethyl)-cyclohexyl]-ethyl ester HCl salt as colorless solid; treatment of the trans-methanesulfonic acid 2-[4-(2-methylamino-ethyl)-cyclohexyl]-ethyl ester HCl salt with 4-chloro-benzene sulphonyl chloride then yielded trans-methanesulfonic acid 2-(4-{2-[(4-chloro-benzenesulfonyl)-methyl-amino]-ethyl}-cyclohexyl)-ethyl ester as colorless oil, MS: 438 (MH+, 1Cl).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:36][N:35]([CH3:37])[CH2:34][CH2:33][O:32][CH2:31][CH2:30][NH:29][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: CN(C)CCOCCN
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCOCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 21 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(2-dimethylamino-ethoxy)-ethyl]-amide (25 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (93 mg), [2-(2-amino-ethoxy)-ethyl]-dimethyl-amine (60 mg), HBTU (103 mg), and DIEA (59 uL). LC/MS: m/z 523.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1B(O)O.Cl[C:17]1[C:26]2[C:21](=[C:22]([CH3:45])[C:23]([S:27]([N:30](CC3C=CC(OC)=CC=3)[C:31]3[S:32][CH:33]=[CH:34][N:35]=3)(=[O:29])=[O:28])=[CH:24][CH:25]=2)[N:20]=[CH:19][CH:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:17]1[C:26]2[C:21](=[C:22]([CH3:45])[C:23]([S:27]([NH:30][C:31]3[S:32][CH:33]=[CH:34][N:35]=3)(=[O:28])=[O:29])=[CH:24][CH:25]=2)[N:20]=[CH:19][CH:18]=1
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)ccnc3c2C)cc1
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C(F)(F)F)ccc1-c1ccnc2c(C)c(S(=O)(=O)Nc3nccs3)ccc12

Procedure:
To a microwave vial charged with (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (52.6 mg, 0.239 mmol), 4-chloro-N-(4-methoxybenzyl)-8-methyl-N-(thiazol-2-yl)quinoline-7-sulfonamide (100 mg, 0.217 mmol), potassium phosphate tribasic (54.0 μl, 0.652 mmol) and 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(II) chloride (15.39 mg, 0.022 mmol) was added dioxane (872 μl) and water (291 μl). The mixture was irradiated at 100° C. for 30 min affording conversion to desired product according to LC-MS. The organic layer was decanted and the aqueous extracted with EtOAc. The combined organics were dried under reduced pressure. The crude material was dissolved in DCM (3.0 ml) and TFA (1.0 ml) was added. The brown solution was stirred at room temperature for 1 hr affording complete PMB cleavage according to LC-MS. The light brown solution was dried under reduced pressure and the crude material purified with a 25 g Interchim column ramping EtOAc in heptane (0-100%) affording product (elution at 100% polar eluent) 4-(2-methoxy-4-(trifluoromethyl)phenyl)-8-methyl-N-(thiazol-2-yl)quinoline-7-sulfonamide (84 mg, 0.175 mmol, 81% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ=12.81 (s, 1H), 9.08 (d, J=4.3 Hz, 1H), 8.03 (d, J=8.9 Hz, 1H), 7.62-7.45 (m, 4H), 7.43 (d, J=8.9 Hz, 1H), 7.26 (d, J=4.6 Hz, 1H), 6.81 (d, J=4.6 Hz, 1H), 3.13 (s, 3H). m/z (ESI) 480.0 (M+H)+.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH:16]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>C(O)C.O.O.O.O.O.O.[Co](Cl)Cl>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C2=CS(=O)(=O)CC2)cc1OC1CCCC1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C2CCS(=O)(=O)C2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 61.3 %

Procedure:
A stirred solution of 3-(3-cyclopentyloxy-4-methoxyphenyl)-4,5-dihydrothiophene 1,1-dioxide (1.2 g; which is prepared as described in Example 13) in ethanol (50 mL) is treated with sodium borohydride (0.45 g) followed by cobalt dichloride hexahydrate (0.94 g), and the purple mixture is stirred at room temperature for 6 hours. It is then filtered through a pad of diatomaceous earth, and the pad is washed with dichloromethane (150 mL). The combined flitrate and washings are evaporated, and the resulting residue is subjected to flash chromatography on silica gel, using a mixture of ethyl acetate and toluene as eluent, to give an oil which slowly crystallizes. It is recrystallized from ethyl acetate at -40° C., to give 3-(3-cyclopentyloxy-4methoxyphenyl)tetrahydrothiophene 1,1-dioxide (0.74 g) in the form of a white solid, m.p. 89°-90° C. [Elemental analysis: C,61.8; H,7.10; S,10.4%; calculated: C,61.91; H,7.1; S,10.33%].
Reaction SMILES: [O:1]=[C:2]1[C:10](=[CH:11][C:12]2[NH:13][C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=3[C:20]=2[CH2:21][CH2:22][C:23]([OH:25])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[C:26](N1C=CN=C1)([N:28]1C=CN=[CH:29]1)=O.CNC.O>CN(C)C=O>[CH3:26][N:28]([CH3:29])[C:23](=[O:25])[CH2:22][CH2:21][C:20]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[NH:13][C:12]=1[CH:11]=[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: O=C(O)CCc1c(C=C2C(=O)Nc3ccccc32)[nH]c2c1CCCC2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)CCc1c(C=C2C(=O)Nc3ccccc32)[nH]c2c1CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
3-[2-(2-Oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionic acid (10 g) was dissolved in 100 mL of dimethylformamide. Carbonyldiimidazole (6.3 g) was added and the mixture stirred at ambient temperature for 1 hour. Dimethylamine (2.7 g) and 30 mL of dimethylformamide were added and the stirring continued overnight at room temperature. Fifty mL of water was added to the mixture and stirring was continued for 10 minutes. The precipitate was collected by vacuum filtration, washed with 20 mL of water and then 20 mL of ethanol. The solid was slurry-washed in 30 mL of refluxing ethanol for 5 minutes and cooled to room temperature. The solid was collected by vacuum filtration, washed with 20 mL of ethanol and vacuum dried to give 8.9 g (83% yield) of N,N-dimethyl-3-[2-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionamide.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]2[CH:10]([CH2:11]2)[C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][Li].[Cl-].[NH4+]>O1CCCC1.CCOCC>[CH2:1]([N:8]1[C:13]([OH:14])([CH3:16])[CH:12]2[CH:10]([CH2:11]2)[C:9]1=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C2CC2C(=O)N1Cc1ccccc1
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(O)C2CC2C(=O)N1Cc1ccccc1
Temperature: -78 °C

Procedure:
3-benzyl-3-azabicyclo[3.1.0]hexane-2,4-dione(U.S. Pat. No. 4,183,857, 1.9 gm, 9.5 mmol) was dissolved in 100 ml of tetrahydrofuran and cooled to −78° C. Methyllithium (10.5 ml of a 0.98M solution in ether, 10.2 mmol) was added dropwise. Saturated aqueous ammonium chloride was added to the cold reaction mixture; the mixture was then extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate, filtered and concentrated in vacuo to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:14][CH3:15])=[N:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]=[C:24]=[O:25].O>C1COCC1>[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24](=[O:25])[NH:1][C:2]1[C:3]([O:14][CH3:15])=[N:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(N)c(OC)n1
Reactant: O=C=Nc1ccccc1Br
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(NC(=O)Nc2ccccc2Br)c(OC)n1
Reaction time: 8 h
Yield: 93.1 %

Procedure:
To a stirred solution of ethyl 3-amino-2-methoxy-6-pyridylacetate (1.61 g, 7.66 mmol) in THF (10 ml) were added 2-bromophenylisocyanate (948 ml, 7.66 mmol) and Et3 N (107 ml, 0.776 mmol). After stirring overnight, the mixture was poured into H2O (100 ml) and extracted with CHCl3-MeOH (4:1, 2×200 ml). The combined extracts were dried over MgSO4 and evaporated. The residue was recrystallized from CHCl3-MeOH-hexane to give ethyl 3-[N′-(2-bromophenyl)ureido]-2-methoxy-6-pyridylacetate (2.91 g, 93%) as a colorless crystalline powder. mp 160–163° C.; 1H-NMR (DMSO-d6) δ 1.19 (dt, J=7.1, 0.7 Hz, 3 H), 3.69 (s, 2 H), 3.95 (s, 3 H), 4.07–4.13 (m, 2 H), 6.90 (d, J=7.8 Hz, 1 H), 6.99 (t, J=7.8 Hz, 1 H), 7.33 (t, J=7.8 Hz, 1 H), 7.61 (d, J=7.8 Hz, 1 H), 7.96 (dd, J=7.8, 1.5 Hz, 1 H), 8.31 (d, J=7.8 Hz, 1 H), 8.82 (s, 1 H), 9.12 (s, 1 H); MS (FAB) m/z 408 (M+), 410 (M++2); Anal. Calcd for C17H18BrN3O4.0.25 H2O: C, 49.47; H, 4.52; 9.96. Found: C, 49.34; H, 4.48; N, 9.96.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[NH:16][C:15]2=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl[CH2:26][CH2:27][N:28]([CH3:30])[CH3:29].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]([CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[C:15]2=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCn1c(=O)n(C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21

Procedure:
To a solution of 320 mg (1 mmol) of 4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester in 5 ml of DMF were added 218 mg (1.5 mmol, 1.5 eq.) of (2-chloro-ethyl)-dimethyl-amine hydrochloride and 418 mg (3 mmol, 3 eq.) of K2CO3. Stirring was continued at 60° C. over night. The mixture was poured on water and the product extracted with EtOAc. The organic phases were dried over Na2SO4 and concentration in vacuo afforded crude 4-[3-(2-dimethylamino-ethyl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester as an off-white solid. This crude material was then dissolved in 5 ml of CH2Cl2 and 1 ml of TFA was added. After 2 hours at RT, the reaction was quenched by addition of aq. NaHCO3 (pH=9), and the product extracted with CH2Cl2. Concentration in vacuo afforded 200 mg (61%) of the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[C:14]([Cl:20])[CH:13]=1>CN(C)C=O>[CH2:3]([O:10][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[C:14]([Cl:20])[CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)cc1Cl
Temperature: 0 °C
Yield: 72.3 %

Procedure:
Sodium hydride (404.8 mg, 10.12 mmol, 60% dispersed oil) was slowly added to benzylalcohol (1 g, 9.2 mmol) dissolved in dried dimethylformamide (30 ml) under nitrogen at room temperature while stirring. Then, the mixture was further stirred at room temperature for 30 minutes. Thereto, 4-fluoro-2-chlorobenzaldehyde (1.46 g, 9.2 mmol) dissolved in dried dimethylformamide was added over 10 minutes and stirred at room temperature for 18 hours until the initial reaction product disappeared. Subsequently, ice water was added thereto, and the reaction mixture was extracted with ethyl acetate and water. The organic layer was washed with water several times, dried with anhydrous magnesium sulfate, filtered and solvent-evaporated. The residual oil was chromatographed on a silica gel column (hexane:ethyl acetate=20:1) to afford the intermediate, 4-(benzyloxy)-2-chlorobenzaldehyde (1.64 g, yield: 71.9%).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([C:22]([OH:24])=O)[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[NH3:26]>>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([C:22]([NH2:26])=[O:24])[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1nccc1-c1cn2c(n1)-c1cc(C(=O)O)ccc1OCC2
Reactant: N
Product: CC(C)n1nccc1-c1cn2c(n1)-c1cc(C(N)=O)ccc1OCC2

Procedure:
Following the procedure in Example 51, 2-(1-Isopropyl-1H-pyrazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylic acid was coupled with ammonia to give 115. MS (ESI+): 338.1. 1H NMR (400 MHz, DMSO) δ 8.94 (d, J=2.2, 1H), 7.94 (s, 1H), 7.77 (dd, J=8.5, 2.2, 1H), 7.69 (s, 1H), 7.44 (d, J=1.4, 1H), 7.25 (s, 1H), 7.08 (d, J=8.5, 1H), 6.40 (d, J=1.7, 1H), 5.34 (dt, J=13.0, 6.4, 1H), 4.52 (dd, J=11.0, 5.6, 4H), 1.44 (d, J=6.6, 6H).
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+:7]([CH3:9])C.[CH3:10][C:11]1([CH3:18])[CH2:16][NH:15]C(=O)[CH2:13][CH2:12]1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:10][C:11]1([CH3:18])[CH2:12][CH2:13][C:6]([O:7][CH3:9])=[N:15][CH2:16]1
Reactant: CC1(C)CCC(=O)NC1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC1=NCC(C)(C)CC1
Reaction time: 14 h

Procedure:
Trimethyloxonium tetrafluoroborate (97%, 11.9 g, 78 mmol) was added to the dry dichloromethane (156 mL) solution of 5,5-dimethyl-2-piperidone (9.93 g, 78 mmol) at room temperature and stirred for 14 h. The reaction mixture was neutralized with 10% sodium hydrogen carbonate aqueous solution, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (3×120 mL), then the combined organic layer was washed with 10% sodium hydrogen carbonate aqueous solution and brine. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure and the titled compound was obtained as pale yellow oil (9.0 g, 82.0%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:11]([C:12]([O:14]C(C)(C)C)=[O:13])=[C:10]([C:19]([F:22])([F:21])[F:20])[NH:9][C:6]2=[N:7][CH:8]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]2[C:11]([C:12]([OH:14])=[O:13])=[C:10]([C:19]([F:22])([F:20])[F:21])[NH:9][C:6]2=[N:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)c1c(C(F)(F)F)[nH]c2ncc(C#N)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cnc2[nH]c(C(F)(F)F)c(C(=O)O)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 109.7 %

Procedure:
1,1-Dimethylethyl 5-cyano-2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (Intermediate 2, 2.77 g, 8.90 mmol) was dissolved in DCM (40 mL), treated with TFA (10 mL) and the resulting mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure to give the title compound as a brown solid (2.49 g);
Reaction SMILES: [N+:1]([O-])([OH:3])=[O:2].C1(O)C=CC(C)=C(C)C=1.[N+:14]([C:17]1[C:22]([CH3:23])=[C:21]([CH3:24])[CH:20]=[CH:19][C:18]=1[OH:25])([O-:16])=[O:15].[N+](C1(C)C=CC(O)=CC1C)([O-])=O>ClCCl>[N+:14]([C:17]1[C:22]([CH3:23])=[C:21]([CH3:24])[CH:20]=[C:19]([N+:1]([O-:3])=[O:2])[C:18]=1[OH:25])([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(O)c([N+](=O)[O-])c1C
Agent: CC1C=C(O)C=CC1(C)[N+](=O)[O-]
Agent: Cc1ccc(O)cc1C
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1C
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A mixture of 630 grams (5 moles/of a 50% aqueous nitric acid and 400 ml dichloromethane were introduced in a two liter flask fitted with a stirrer, a reflex condenser, a dropping funnel and a thermometer. To this stirred mixture was added dropwise a solution of 245 g (2 moles) 3,4-xylenol in 400 ml dichloromethane, during two hours, maintaining the temperature at 20°-25° C. After another hour stirring at the same temperature the reaction mixture was heated to reflux (about 40° C.) until the starting product and the two intermediate products (2-nitro-3,4-xylenol and 4-nitro-3,4-xylenol) have disappeared (followed by GC analysis). This occurs in about three hours. The mixture was cooled to ambient temperature and allowed to separate in two phases. The lower organic phase was separated from the aqueous acidic layer and washed twice with water. Water (400 ml) was added to the organic phase and dichloromethane was removed by distillation. The slurry of the dinitro compound in water was cooled and filtered and dried at 70° C. A product of 93.7%. 2,6-dinitro-3,4-xylenol pure was obtained which was 74.5% of the theoretical yield. After crystallization from ethyl alcohol it has a melting point of 124°-125° C.