Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][CH2:6][CH2:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH3:18]>ClCCCl>[Cl:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:17][CH3:18])=[CH:11][C:12]([CH:13]=[O:14])=[C:15]([N+:1]([O-:4])=[O:2])[CH:16]=1
Reactant: COc1cc(C=O)ccc1OCCCl
Reactant: O=[N+]([O-])O
Solvent: ClCCCl
Product: COc1cc(C=O)c([N+](=O)[O-])cc1OCCCl
Temperature: -10 °C
Yield: 40 %

Procedure:
Fuming nitric acid (10 mL) is added dropwise to a −40° C. suspension of 5.00 g (23.36 mmol) of 4-(2-chloroethoxy)-3-methoxybenzaldehyde (Milbank, J. B. J., et. al., J. Med. Chem., 42(4), 649–658, 1999) in 23 mL of 1,2-dichloroethane. The reaction mixture is slowly allowed to warm to −10° C. The mixture is poured onto 300 mL of ice water and then extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Diethyl ether is added to the residue and the pale yellow solid is collected by filtration to provide 2.43 g (40%) of 4-(2-chloroethoxy)-5-methoxy-2-nitrobenzaldehyde, mp 148–150° C.
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][NH:19][CH2:20][C@@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1.[F:23][C:24]([F:35])([F:34])[O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1.C(N(C(C)C)C(C)C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][N:19]([CH2:30][C:29]5[CH:32]=[CH:33][C:26]([O:25][C:24]([F:23])([F:34])[F:35])=[CH:27][CH:28]=5)[CH2:20][C@@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: O=C1CCNC[C@@H]2C[C@H](Oc3cnc(C4CC4)cn3)CN12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: O=C1CCN(Cc2ccc(OC(F)(F)F)cc2)C[C@@H]2C[C@H](Oc3cnc(C4CC4)cn3)CN12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.3 %

Procedure:
To (8S,9aS)-8-[(5-cyclopropylpyrazin-2-yl)oxy]octahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one hydrochloride (50 mg, 0.154 mmol, Part D) in anhydrous dichloroethane (0.7 mL) was added 4-(trifluoromethoxy)benzaldehyde (38 mg, 0.2 mmol), and N-ethyl-N-isopropylpropan-2-amine (39.8 mg, 0.308 mmol). After 10 minutes, sodium triacetoxyborohydride (75 mg, 0.354 mmol) was added. The mixture was stirred at room temperature overnight and then concentrated. The residue was purified by chromatography on silica gel (ethyl acetate) to give 33 mg (46.4% yield) of the title compound as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.83 (m, 2H), 0.98 (m, 2H), 1.82 (m, 1H), 2.12 (m, 1H), 2.20-2.32 (m, 2H), 2.42 (dd, J=12, 8 Hz, 1H), 2.61 (m, 1H), 2.70-2.90 (m, 3H), 3.50 (br d, J=12 Hz, 1H), 3.57 (br d, J=12 Hz, 1H), 3.62-3.72 (m, 2H), 4.12 (m, 1H), 5.29 (m, 1H), 7.31 (d, J=9 Hz, 2H), 7.43 (d, J=9 Hz, 2H), 8.15 (s, 1H), 8.18 (s, 1H); MS (ESI) m/z 463.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[C:4]([F:10])[C:3]=1[F:11].P(Br)(Br)[Br:13]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:13])=[C:4]([F:10])[C:3]=1[F:11]
Reactant: BrP(Br)Br
Reactant: OCc1ccc(Br)c(F)c1F
Solvent: ClCCl
Product: Fc1c(Br)ccc(CBr)c1F
Temperature: 10 °C
Reaction time: 2 h
Yield: 51.5 %

Procedure:
To a solution of (4-bromo-2,3-difluorophenyl)methanol (500 mg, 2.242 mmol) in DCM (10 mL) stirred under N2 at 0° C. was added PBr3 (0.634 mL, 6.73 mmol) in one charge. The reaction mixture was stirred at 10° C. for 2 h. Then the solution was concentrated and distributed between DCM and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by preparative TLC (PE/EA=10:1, Rf 0.6) to yield light yellow oil of 1-bromo-4-(bromomethyl)-2,3-difluorobenzene (330 mg, 1.154 mmol, 51.5% yield): 1H NMR (400 MHz, CDCl3) δ 7.30 (ddd, J=2.0, 6.0, 8.2 Hz, 1H), 7.11-7.03 (m, 1H), 4.46 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[C:9]([Cl:16])=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:17].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:28]([O:35][C:36]1[C:41]([CH2:42]Cl)=[C:40]([CH3:44])[CH:39]=[C:38]([CH3:45])[N:37]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCOCC1>[CH2:28]([O:35][C:36]1[C:41]([CH2:42][N:6]2[CH2:5][CH2:4][C:3]3[C:8](=[C:9]([Cl:16])[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:11][C:2]=3[Br:1])[C:7]2=[O:17])=[C:40]([CH3:44])[CH:39]=[C:38]([CH3:45])[N:37]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1cc(C)c(CCl)c(OCc2ccccc2)n1
Reactant: CC(C)Oc1cc(Br)c2c(c1Cl)C(=O)NCC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cc(C)c(CN2CCc3c(Br)cc(OC(C)C)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.6 %

Procedure:
To a solution of 5-bromo-8-chloro-7-(propan-2-yloxy)-3,4-dihydroisoquinolin-1(2H)-one (77d, 188 mg, 0.590 mmol) in anhydrous 1,4-dioxane (10 mL) was added KHMDS (2.00 mL, 2.00 mmol). Upon addition, a dark red paste was formed. After stirring at room temperature for 30 minutes, 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (Cpd Z, 170 mg, 0.649 mmol) was added. The resulting reaction mixture was stirred at 100° C. for 5 hours. After cooling to room temperature, the reaction mixture was quenched with water, and extracted with ethyl acetate (2×50 mL). The combined organic phases were dried over sodium sulfate, concentrated under vacuum, and purified by column chromatography (0-40% EtOAc/heptanes) to give 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-5-bromo-8-chloro-7-(propan-2-yloxy)-3,4-dihydroisoquinolin-1(2H)-one (77e, 140 mg, 44%).
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].[H-].[Na+].Br[CH2:13][C@@H:14]1O[C@@H](P(OCC)(OCC)=O)CC1>CN(C=O)C>[CH2:13]([N:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3])[CH3:14]
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: CCOP(=O)(OCC)[C@H]1CC[C@H](CBr)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cc(C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.9 %

Procedure:
To a stirring suspension of thymine (551 mg, 3.32 mmol) in dry DMF (3 mL) was added sodium hydride (60% oil dispersion, 133 mg, 3.32 mmol). After stirring the mixture for 30 min at room temperature, a solution of cis-5-bromomethyl-2-diethoxyphosphinoyl-tetrahydrofuran (example 66) (500 mg, 1.66 mmol) in DMF (3 mL) was added via cannula. The mixture was then stirred at 90° C. for 15 h after which the mixture was cooled and quenched with saturated ammonium chloride (5 mL). The volatiles were removed under vacuo and the residue was dissolved in a mixture of dichloromethane (20 mL) and water (10 mL). The mixture was filtered and the aqueous layer was collected and extracted with dichloromethane (2×20 mL). The combined extracts were then washed with brine (20 mL), dried (MgSO4) and concentrated to dryness. Purification by chromatography eluting with EtAc, 5% MeOH in EtAc then 10% MeOH in EtAc yielded first N1 -ethyl thymine (102 mg, 40%) and then the title compound as an oil (126 mg, 22%).
Reaction SMILES: [O:1]1[CH:6]2[CH:2]1[CH2:3][N:4]([CH2:7][CH3:8])[CH2:5]2.[CH2:9]([NH2:13])[CH2:10][CH2:11][CH3:12]>Cl>[CH2:9]([NH:13][C@@H:2]1[CH2:3][N:4]([CH2:7][CH3:8])[CH2:5][C@H:6]1[OH:1])[CH2:10][CH2:11][CH3:12]
Reactant: CCN1CC2OC2C1
Reactant: CCCCN
Agent: Cl
Product: CCCCN[C@@H]1CN(CC)C[C@H]1O
Temperature: 150 °C

Procedure:
A mixture of 22.6 g (0.20 mole) of 3,4-epoxy-1-ethyl-pyrrolidine, 29.2 g (0.40 mol) of n-butylamine and one drop of conc. hydrochloric acid was heated in a bomb at 150° C. for 20 hr. The mixture was cooled to room temperature, diluted with 350 ml of petroleum ether, cooled in an ice bath and the precipitate was collected. The yield of pure compound as white flakes in this step was 18.0 g (48%); m.p. 57.5°-59.0° C. The filtrate was concentrated under high vaccum leaving a residue of 17.5 g (47%) of quite pure product. Total yield in the two steps was 35.5 g (about 95%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4]3[C:5](=[C:23]([CH3:26])[O:24][N:25]=3)[C:6](=[O:22])[N:7]([C:12]3[N:17]=[C:16]([CH2:18][C:19](O)=[O:20])[CH:15]=[CH:14][CH:13]=3)[C:8]=2[CH:9]=[CH:10][CH:11]=1.CCN=C=NCCCN(C)C.[CH3:38][O:39][C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH2:43].CC(C)=O.ClCCl>CN(C1C=CN=CC=1)C.ClCCl>[Cl:1][C:2]1[C:3]2[C:4]3[C:5](=[C:23]([CH3:26])[O:24][N:25]=3)[C:6](=[O:22])[N:7]([C:12]3[N:17]=[C:16]([CH2:18][C:19]([NH:43][C:42]4[CH:44]=[CH:45][CH:46]=[C:40]([O:39][CH3:38])[CH:41]=4)=[O:20])[CH:15]=[CH:14][CH:13]=3)[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1onc2c1c(=O)n(-c1cccc(CC(=O)O)n1)c1cccc(Cl)c21
Reactant: COc1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC(C)=O
Product: COc1cccc(NC(=O)Cc2cccc(-n3c(=O)c4c(C)onc4c4c(Cl)cccc43)n2)c1
Yield: 52.6 %

Procedure:
[6-(9-Chloro-3-methyl4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-pyridin-2-yl]-acetic acid (0.075 g, 0.2 mmol), EDCI (0.055 g, 0.3 mmol), 3-methoxyaniline (0.03 ml, 0.26 mmol), DMAP (0.005 g, 0.04 mmol) in dichloromethane (4.5 ml) and DMP (0.75 ml) react for 5.5 h in a fashion similar to that of Example 3. Column chromatography (silica gel, acetone/dichloromethane gradient) gives the title compound (0.05 g, 53%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1.[OH-].[Na+].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>O1CCOCC1.Cl>[CH2:14]([O:13][C:11]([N:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1)=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)C1CNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Reaction time: 18 h
Yield: 73 %

Procedure:
To a solution of azetidine-3-carboxylic acid (5.00 g, 49.5 mmol) in dioxane (325 ml) were added 1N sodium hydroxide (124 ml, 124 mmol) and benzyl chloroformate (8.44 ml, 59.3 mmol). The reaction was allowed to stir for 18 h. The reaction was diluted with 3N HCl until pH 2 was obtained. The product was extracted with EtOAc (2×), washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified via flash chromatography (silica, 0-70% methanol (0.5% acetic acid)/dichloromethane) to yield 1-[(benzyloxy)carbonyl]azetidine-3-carboxylic acid as a yellow oil (73%). 1H NMR (400 MHz, CD3OD) δ 7.37-7.26 (m, 5H), 5.08 (s, 2H), 4.18 (m, 2H), 4.11 (br s, 2H), 3.44 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=O)[CH3:20])[N:14]=1)[CH3:12].[F:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[N:25][C:24]2[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=2[F:22])[CH3:20])[N:14]=1)[CH3:12]
Reactant: Nc1ccccc1F
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1
Solvent: Cc1ccccc1
Product: CC(=Nc1ccccc1F)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
Monoimine (1, 1.0 g, 3.57 mmol) and 2-fluoroaniline (398 mg, 3.57 mmol) (ex. Aldrich) were dissolved in 50 ml of toluene. To this solution, 4 Å molecular sieves were added. After standing for 20 hrs., with addition of more molecular sieves, the mixture was filtered. The solvent was removed in vacuum and the oily residue was warmed in ethanol (50° C.). The yellow solid, which precipitated after cooling at −20° C., was filtered off and dried in vacuo. Yield 300 mg (23%) of mixed diimine (4).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]1([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C>ClCCl>[O:12]([C:13]1[CH:14]=[CH:15][C:16]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:17][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: O=S(=O)(O)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of chlorosulfonic acid (4.3 mL, 64.6 mmol) in dichloromethane (20 mL) is added dropwise to a solution of diphenyl ether (10 g, 58.8 mmol) in dichloromethane (20 mL) at 0° C. under nitrogen atmosphere. The reaction mixture is slowly warmed up to RT and stirred for 2 h. To the mixture are added oxalyl chloride (6.5 ml, 76.4 mmol) and then DMF (1.5 mL) at RT. After being heated at 40° C. for 1 h, the reaction mixture is stirred at RT for 15 h. The mixture is poured to ice-water and extracted with ether. The organic layer is dried over MgSO4 and evaporated in vacuo to give the title compound quantitatively: NMR (CDCl3) 7.10 (t, 4H, J=8.6 Hz), 7.22-7.30 (m, 1H), 7.46 (t, 2H, J=8.6 Hz), 7.98 (d, 2H, J=9.1 Hz).
Reaction SMILES: [CH2:1]1[O:4][CH:2]1[CH3:3].[CH2:5]([OH:19])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>[OH-].[K+]>[CH3:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:19][CH2:3][CH2:2][CH2:1][OH:4]
Reactant: CCCCCCCCCCCCCCO
Reactant: CC1CO1
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCOCCCO

Procedure:
Propylene oxide was bubbled into 685 g of myristyl alcohol in the presence of potassium hydroxide catalyst until three moles of propylene oxide were added per mole of myristyl alcohol, thus obtaining a pale, yellow liquid (PPG 3 myristyl ether) as the major product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10](S)[NH:11][C:12]=2[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:4][CH:3]=1.[N+]([O-])(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][NH:11][C:12]=2[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2nc(S)[nH]c2-c2cccnc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: O=[N+]([O-])O
Product: Fc1ccc(-c2nc[nH]c2-c2cccnc2)cc1
Reaction time: 8 h
Yield: 73.3 %

Procedure:
4-(4-Fluorophenyl)-5-(3-pyridyl)-1H-2-imidazolethiol (8.2 g) was added portionwise to a mixture of 30 ml. of 35% nitric acid at room temperature. After stirring overnight, the reaction mixture was diluted with water and made basic with sodium carbonate. The product was extracted into ethyl acetate, which, after drying over potassium carbonate was evaporated to yield 5.3 g of 4-(4-fluorophenyl)-5-(3-pyridyl)imidazole.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].Br[CH2:19][CH:20]1[CH2:22][CH2:21]1>CN(C=O)C.CCOC(C)=O>[CH:20]1([CH2:19][O:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)[CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(COCC2CC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.2 %

Procedure:
A solution of N-boc-4-piperidinemethanol (0.500 g, 2.322 mmol) in DMF (10 mL) was added drop wise to a suspension of sodium hydride (60% in mineral oil) (0.186 g, 4.645 mmol) in dry DMF (15 mL) at 0 C. The mixture was stirred at 0 C for 15 minutes and room temperature for 10 minutes before being cooled down again and (bromomethyl)cyclopropane (0.227 mL, 2.322 mmol) was added drop wise. The reaction mixture was stirred at 0 C for 10 minutes, room temperature for 1 h and 80 C for 4 h. The reaction mixture was diluted with EtOAc (60 mL) and washed with water (3×20 mL). The aqueous washes were combined and re-extracted with EtOAc (3×20 mL). The organic extracts were combined, dried over sodium sulfate, filtered and evaporated to provide the title compound as a colorless oil (0.614 g, 98%). Method B HPLC-MS: MH+ requires m/z=270 Found: m/z=214 (MH+-tBu), Rt=2.33 min (83%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[N+:13]2[O-])=[CH:8][CH:7]=1)=[O:5])[CH3:2].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(N(CC)CC)C.[CH3:35][OH:36]>>[CH3:35][O:36][C:12]1[CH:11]=[CH:10][C:9]2[C:14](=[CH:15][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)[N:13]=1
Reactant: CCOC(=O)c1ccc2ccc[n+]([O-])c2c1
Reactant: CO
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc2ccc(OC)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a 0° C. solution of 7-(ethoxycarbonyl)quinoline 1-oxide (150 mg, 0.69 mmol) and toluene-4-sulphonyl chloride (171 mg, 0.89 mmol) in methanol (5 mL) was added triethylamine (0.19 mL, 1.4 mmol). The reaction was stirred at room temperature overnight. LCMS showed the reaction was incomplete. Additional triethylamine (0.05 mL) was added and the reaction was stirred for another 4 hours. The reaction was concentrated and the residue partitioned between ethyl acetate and saturated aqueous sodium carbonate. The layers were separated and the aqueous was extracted two more times with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (0-40% ethyl acetate/heptanes) gave the title compound (130 mg, 81%) as a pale yellow solid. +ESI (M+H) 232.2; 1H NMR (400 MHz, CDCl3, δ): 8.49-8.60 (m, 1H), 7.95-8.05 (m, 2H), 7.75 (d, J=8.19 Hz, 1H), 6.98 (d, J=8.78 Hz, 1H), 4.43 (q, J=7.22 Hz, 2H), 4.08 (s, 3H), 1.43 (t, J=7.12 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:36]=[CH:35][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][N:22]([C:25]5[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=5)[CH2:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([C:37]#[N:38])[CH:3]=1.[CH:39]1(B(O)O)[CH2:41][CH2:40]1>>[C:37]([C:4]1[CH:3]=[C:2]([CH:39]2[CH2:41][CH2:40]2)[C:10]2[O:9][C:8]([C:11]3[CH:36]=[CH:35][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:20][CH2:21][N:22]([C:25]5[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=5)[CH2:23][CH2:24]4)=[O:16])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=1)#[N:38]
Reactant: OB(O)C1CC1
Reactant: N#Cc1cc(Br)c2oc(-c3ccc(C(=O)NCC4CCN(c5ccc(C(F)(F)F)cn5)CC4)cc3)nc2c1
Product: N#Cc1cc(C2CC2)c2oc(-c3ccc(C(=O)NCC4CCN(c5ccc(C(F)(F)F)cn5)CC4)cc3)nc2c1

Procedure:
The title compound was prepared from 4-(7-bromo-5-cyano-1,3-benzoxazol-2-yl)-N-({1-[5-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}methyl)benzamide (EXAMPLE 114, Step B) and cyclopropylboronic acid by a procedure analogous to that described in EXAMPLE 117. Mass spectrum (ESI) 546.3 (M+1). 1H NMR (500 MHz, CDCl3) δ: 8.38 (s, 1H), 8.33 (d, J=8.3 Hz, 2H), 7.95 (d, J=8.1 Hz, 2H), 7.86 (s, 1H), 7.60 (br d, J=8.9 Hz, 1H), 7.23 (s, 1H), 6.65 (d, J=8.9 Hz, 1H), 6.38 (br s, 1H), 4.46 (d, J=13.1 Hz, 2H), 3.44 (t, J=6.4 Hz, 2H), 2.93 (t, J=12.1 Hz, 2H), 2.33 (m, 1H), 2.00 (m, 1H), 1.90 (d, J=12.3 Hz, 2H), 1.33 (m, 2H), 1.22 (m, 2H), 1.06 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:16][C:17]([C:19]2([C:22]3[CH:30]=[CH:29][C:25]4[O:26][CH2:27][O:28][C:24]=4[CH:23]=3)[CH2:21][CH2:20]2)=[O:18])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8]2.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>CN(C=O)C>[O:26]1[C:25]2[CH:29]=[CH:30][C:22]([C:19]3([C:17]([NH:16][C:5]4[CH:6]=[C:7]5[C:11](=[C:3]([CH2:2][NH:1][S:39]([CH3:38])(=[O:41])=[O:40])[CH:4]=4)[NH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8]5)=[O:18])[CH2:20][CH2:21]3)=[CH:23][C:24]=2[O:28][CH2:27]1
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc(CN)c2[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc(CNS(C)(=O)=O)c2[nH]1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
N-(7-(Aminomethyl)-2-tert-butyl-1H-indol-5-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (20 mg, 0.049 mmol) was dissolved in DMF (0.5 mL) containing triethylamine (20.6 μL, 0.147 mmol) and a magnetic stir bar. Methanesulfonyl chloride (4.2 μL, 0.054 mmol) was then added to the reaction mixture. The reaction mixture was allowed to stir for 12 h at room temperature. The crude product was purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-7-(methylsulfonamidomethyl)-1H-indol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 483.2, found 484.3 (M+1)+. Retention time of 1.84 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=3)[N:15]=[C:14]([CH3:25])[N:13]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:26]I.[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=3)[N:15]=[C:14]([CH3:25])[N:13]=2)[CH3:26])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CI
Reactant: COc1ccc(Nc2nc(C)nc3ccc([N+](=O)[O-])cc23)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C)c2nc(C)nc3ccc([N+](=O)[O-])cc23)cc1OC

Procedure:
The title compound was prepared from (3,4-dimethoxy-phenyl)-(2-methyl-6-nitro-quinazolin-4-yl)-amine (105 mg, 0.31 mmol), methyl iodide (0.029 ml, 0.46 mmol), sodium hydride (19 mg, 0.46 mmol, 60% oil dispersion) in DMF similar to example 21 to give 10.1 mg (9.2%) of yellow solids. 1H NMR (CDCl3): 8.30-8.62 (m, 1H), 7.91 (d, J=2.4 Hz, 1H), 7.76 (d, J=9.3 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.86-6.82 (m, 1H), 6.74 (d, J=2.7 Hz, 1H), 3.95 (s, 3H)), 3.81 (s, 3H), 3.66 (s, 3H), 2.73 (s, 3H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[CH3:30][S:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[O:37])=[CH:34][CH:33]=1>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[CH:36]([C:35]2[CH:38]=[CH:39][C:32]([S:31][CH3:30])=[CH:33][CH:34]=2)[OH:37])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Reactant: CSc1ccc(C=O)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSc1ccc(C(O)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 107.9 %

Procedure:
To a suspension of 1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridine (6.0 g, 23.3 mmol) in dry tetrahydrofuran (300 mL) at −78° C. was added n-butyllithium in n-hexane (1.6 M, 10 mL, 16 mmol). The mixture was stirred at −78° C. for 5 min and then treated with 4-methylsulfanylbenzaldehyde (2.4 g, 15.8 mmol) dropwise. The resulting mixture was stirred at −78° C. for 1 h and quenched with brine. The mixture was extracted with ethyl acetate (2×500 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was washed with dichloromethane (2×5 mL) and dried in vacuo to afford (1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-(4-methylsulfanyl-phenyl)-methanol (7.0 g, 73%) as a white solid: LC/MS m/e calcd for C21H18N2O3S2 [M+H]+ 411.52, observed 411.3.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:12]1[CH:20]=[CH:19][C:15]3[O:16][CH2:17][O:18][C:14]=3[CH:13]=1)=[C:6]([OH:21])[C:5]2=[O:22].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[O:16]1[C:15]2[CH:19]=[CH:20][C:12]([C:7]3[O:8][C:9]4[C:4]([C:5](=[O:22])[C:6]=3[OH:21])=[CH:3][C:2]([NH:1][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:11][CH:10]=4)=[CH:13][C:14]=2[O:18][CH2:17]1
Reactant: Nc1ccc2oc(-c3ccc4c(c3)OCO4)c(O)c(=O)c2c1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(Nc1ccc2oc(-c3ccc4c(c3)OCO4)c(O)c(=O)c2c1)c1ccccc1
Yield: 79 %

Procedure:
30 mg (101 pmol) of 6-amino-2-(benzo[1,3]dioxol-5-yl)-3-hydroxy-4H-chromen-4-one obtained in Example 24 was dissolved in 2 ml of methylenechloride, and the mixture was reacted with 10 molar equivalents of benzoylchloride and excess amount of potassium carbonate at room temperature for 10 hours. The resulting product was filtered, washed with methylenechloride and water, and dried to give 32 mg of the title compound in a yield of 79%.