Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:18])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][O:15][CH3:16])[CH2:9][CH2:8][C:7]=2[CH:17]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[CH:29][C:28]=2[O:40][CH3:41])[C:23]([Cl:42])=[CH:22][N:21]=1>>[Cl:42][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[CH:29][C:28]=2[O:40][CH3:41])=[N:25][C:20]([NH:18][C:4]2[C:3]([O:2][CH3:1])=[CH:17][C:7]3[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][O:15][CH3:16])[CH2:11][CH2:12][C:6]=3[CH:5]=2)=[N:21][CH:22]=1
Reactant: COCCN1CCc2cc(N)c(OC)cc2CC1
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1nc(Cl)ncc1Cl
Product: COCCN1CCc2cc(Nc3ncc(Cl)c(Nc4ccc(N5CCN(C)CC5)cc4OC)n3)c(OC)cc2CC1

Procedure:
The title compound was prepared from 8-Methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as tan solid (0.022 g, 23%). MP: 54-75° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 8.26 (d, 1H, J=8.8 Hz), 8.11 (s, 1H), 8.02-8.00 (m, 1H), 7.55 (s, 1H), 7.42 (s, 1H), 6.63 (s, 1H), 6.58-6.55 (m, 1H), 6.55-6.50 (m, 1H), 3.91 (s, 3H), 3.86 (s, 3 h), 3.57-3.51 (m, 2H), 3.37 (s, 3H), 3.24-3.16 (m, 4H), 2.92-2.83 (m, 4H), 2.77-2.67 (m, 6H), 2.64-2.58 (m, 4H), 2.37 (s, 3H). MS: 582.24 (MH)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.[CH3:17][O:18][C:19](=[O:48])[N:20]=[C:21]([S:46][CH3:47])[C:22]([C:36]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[C:38]([OH:44])[C:37]=1[F:45])=[N:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:34]=[C:33]([CH3:35])[O:32][N:31]=2)=[CH:26][CH:25]=1.O>CN(C=O)C.C(OCC)(=O)C>[CH3:17][O:18][C:19](=[O:48])[N:20]=[C:21]([S:46][CH3:47])[C:22]([C:36]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[C:38]([O:44][CH2:8][CH2:9][O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[C:37]=1[F:45])=[N:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:34]=[C:33]([CH3:35])[O:32][N:31]=2)=[CH:26][CH:25]=1
Reactant: BrCCOC1CCCCO1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(OCCOC2CCCCO2)c1F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
After adding 200 mg of potassium carbonate and 0.1 ml of 2-(2-bromoethoxy)tetrahydro-2H-pyran to a solution of 80 mg of [2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester (Example 3d) in 1 ml of DMF, the mixture was stirred at room temperature for 14 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and dried through PRESEP™. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (69 mg) as a yellow oil.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][CH2:10][CH2:11][CH2:12][CH2:13]C.[C:15]([O:18][CH2:19][CH3:20])(=O)[CH3:16].CCCCCC>ClC(Cl)C>[Br:1][C:11]1[C:12]([CH3:13])=[CH:16][C:15]2[O:18][CH:19]=[CH:20][C:9]=2[CH:10]=1
Reactant: CCOC(C)=O
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCC
Solvent: CC(Cl)Cl
Product: Cc1cc2occc2cc1Br
Yield: 22 %

Procedure:
Part E. A solution of the above compound (780 mg) and N-bromosuccinimide (1.24 g, 6.97 mmol) in dichloroethane (10 mL) was heated to reflux overnight, then cooled, filtered and evaporated. Column chromatography (hexane, then 2:98 ethyl acetate-hexane) gave first 5-bromo-6-methylbenzofuran (270 mg, 1.27 mmol, 22%), then 5-bromo-6-methyl-2,3-dihydrobenzofuran (923 mg, 4.33 mol, 75%), both as solids. For the dihydro product: TLC RF 0.35 (2:98 ethyl acetate-hexane). 1H NMR (300 MHz, CDCl3): d 7.31 (1H, s), 6.68 (1H, s), 4.56 (2H, t, J=8.8 Hz), 3.17 (2H, t, J=8.8 Hz), 2.33 (3H, s). MS (H2O-GC/MS): m/e 215 (76), 213 (100).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([CH3:22])[N:14]=[C:13]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:12]=1.[CH3:29][SH:30].[Na]>O1CCCC1>[CH3:22][C:15]1[N:14]=[C:13]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:12]=[C:11]([C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[S:30][CH3:29])[C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CS
Reactant: CCOC(=O)c1c(C)nc(-c2ccccc2)nc1-c1cc([N+](=O)[O-])ccc1Cl
Agent: [Na]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)nc(-c2ccccc2)nc1-c1cc([N+](=O)[O-])ccc1SC
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.4 %

Procedure:
To a solution of tetrahydrofuran (25 ml), methylmercaptan-diemthylformamide solution (methylmercaptan 66 g/DMF 306 g) (5 ml) and ethyl 4-(2-chloro-5-nitrophenyl)-6-methyl-2-phenyl-5-pyrimidinecarboxylate (2 g), sodium methylmercaptan (0.42 g) was added, stirred for 3 h at ambient temperature. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture of water (50 ml) and ethyl acetate (100 ml). The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off. The residue was chromatographed on silica gel, eluting with a mixture of n-hexane and ethyl acetate (10:1). The fractions containing the object compound were combined and concentrated in vacuo. The crystalline residue was recrystallized from diethyl ether to afford ethyl 6-methyl-4-(2-methylthio-5-nitrophenyl)-2-phenyl-5-pyrimidinecarboxylate (0.4 g).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]C)=[CH:8][CH:7]=1.C(=O)=O.CC(C)=O.B(Br)(Br)Br>ClCCl>[OH:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3](=[O:14])[C:2]([F:1])([F:15])[F:16])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCC(=O)C(F)(F)F)cc1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: O=C(CCc1ccc(O)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
To a solution of 1,1,1-trifluoro-4-[4-methoxyphenyl]-2-butanone (43.5 g, 0.187 mol) in dichloromethane (500 ml) at −78° C. (dry ice-acetone) was added dropwise boron tribromide (53 ml, 0.561 mol). The mixture was then stirred at 0° C. (ice bath) for 3 h, and cautiously quenched by dropwise addition of ice-water (200 ml) over a period of 1 h. The aqueous phase was saturated with solid sodium chloride, extracted with dichloromethane (500 ml) followed by diethyl ether (500 ml). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by bulb-to-bulb distilation (96-100° C., 0.2 mmHg) to afford the title compound (34.4 g, 84%) as a yellow liquid which solidified upon standing.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([C:15]4[O:16][C:17]([CH:20]=O)=[CH:18][CH:19]=4)[CH:11]=[C:10]([C:22]([NH:24][CH2:25][C:26]4[C:27](=[O:34])[NH:28][C:29]([CH3:33])=[CH:30][C:31]=4[CH3:32])=[O:23])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:35][S:36]([CH2:39][CH2:40][NH2:41])(=[O:38])=[O:37].CCN(C(C)C)C(C)C.[BH3-]C#N.[Na+]>CO>[CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([C:15]4[O:16][C:17]([CH2:20][NH:41][CH2:40][CH2:39][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:18][CH:19]=4)[CH:11]=[C:10]([C:22]([NH:24][CH2:25][C:26]4[C:27](=[O:34])[NH:28][C:29]([CH3:33])=[CH:30][C:31]=4[CH3:32])=[O:23])[C:9]=3[CH:8]=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)CCN
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)o3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CNCCS(C)(=O)=O)o3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Reaction time: 3 h

Procedure:
To a stirred solution 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-methyl)-6-(5-formylfuran-2yl)-1H-indazole-4-carboxamide (0.09 g, 0.19 mmol) in methanol (2 mL), 2-(methylsulfonyl)ethanamine (0.072 g, 0.581 mmol) and DIPEA (0.05 g, 0.39 mmol) was added at room temperature and reaction stirred for 3 h. Then NaBH3CN (0.012 g, 0.196 mmol) was added and reaction stirred at room temperature for 18 h. On completion, methanol was removed under reduced pressure and then water was added to the residue. The aqueous phase was extracted with 10% MeOH/DCM and the combined organic layers were dried over sodium sulfate and concentrated to obtain crude material which was purified by column chromatography to afford 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(5-(((2-(methylsulfonyl)ethyl)amino)methyl)furan-2-yl)-1H-indazole-4-carboxamide. LCMS: 566.90 (M+1)+; HPLC: 90.05% (@ 254 nm) (Rt; 5.253); 1H NMR (MeOD, 400 MHz) δ 8.31 (s, 1H), 8.07 (s, 1H), 7.87 (s, 1H), 6.92 (s, 1H), 6.44 (s, 1H), 6.13 (s, 1H), 5.18-5.42 (m, 1H), 4.59 (s, 2H), 4.57 (s, 2H), 3.91 (s, 2H), 3.16 (t, 2H, J=6.4 Hz), 3.02 (s, 3H), 2.42 (s, 3H), 2.25 (s, 3H), 2.19-2.23 (m, 2H), 2.11-2.14 (m, 2H), 1.98 (m, 2H), 1.80 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[CH3:21][N:22]([CH3:32])[C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[CH3:21][N:22]([CH3:32])[C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:25][CH:24]=1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: CN(C)c1ccc(B(O)O)cc1
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(N(C)C)cc3)ccn2c1=O
Yield: 39.8 %

Procedure:
Methyl 8-(4-(dimethylamino)-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (77 mg, 0.26 mmol) and (4-(dimethylamino)-phenyl)-boronic acid (56 mg, 0.34 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (39 mg, 31%).
Reaction SMILES: [F:1][C:2]1[C:24]([S:25]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]([CH3:37])([CH3:36])[CH2:34][OH:35])[CH2:29][CH2:28]2)=[O:26])=[CH:23][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH3:22])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.C(O)(C(F)(F)F)=[O:39].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[F:1][C:2]1[C:24]([S:25]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]([CH3:37])([CH3:36])[CH2:34][OH:35])[CH2:29][CH2:28]2)(=[O:39])=[O:26])=[CH:23][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:20])[CH3:21])[N:17]=[C:16]([CH3:22])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(S(=O)C4CCN(C(C)(C)CO)CC4)c(F)cc2OCC3)n(C(C)C)n1
Reactant: O=C(O)C(F)(F)F
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2cc(S(=O)(=O)C4CCN(C(C)(C)CO)CC4)c(F)cc2OCC3)n(C(C)C)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 38.2 %

Procedure:
To an ice-cooled solution of 2-{4-[8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-sulfinyl]piperidin-1-yl}-2-methylpropan-1-ol 212 (41 mg, 0.0767 mmol) in DCM (8 mL) was added TFA (30 μL, 0.383 mmol) followed by a slow addition of a solution of m-CPBA (17 mg, 0.10 mmol) in DCM (1.5 mL) and the resulting mixture was stirred for 3 h at 0° C. Volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (C18, gradient 10-45% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3 in MeOH. Further purification by column chromatography (Si-PCC, gradient 3-15% MeOH in DCM) afforded 219 as a white solid (16 mg, 38%). LCMS: RT 2.72 min [M+H]+ 547.1. 1H NMR (DMSO, 400 MHz): δ 8.87 (1H, d, J=8.22 Hz), 7.93 (1H, s), 7.24 (1H, d, J=11.15 Hz), 5.66-5.55 (1H, m), 4.70-4.52 (4H, m), 4.21 (1H, t, J=5.47 Hz), 3.24-3.14 (3H, m), 3.08-2.99 (2H, m), 2.25 (3H, s), 2.12 (2H, bt, J=11.72 Hz), 1.86 (2H, bd, J=11.95 Hz), 1.55-1.43 (8H, d, J=6.62 Hz), 0.88 (6H, s)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1.[H-].[Na+].C[O:17][CH:18](OC)[CH2:19]Br>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[CH:4]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1)[CH2:19][CH:18]=[O:17]
Reactant: COC(CBr)OC
Reactant: COC(=O)Cc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(CC=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.6 %

Procedure:
A mixture of 25 g (114 mmol) (3,4-dichloro-phenyl)-acetic acid methyl ester (commercially available), 5.7 g (131 mmol) NaH (55%) and 23.1 g (137 mmol) bromoacetaldehyde dimethylacetal in 80 mL DMF was stirred at room temperature for 3 h. The mixture was poured onto ice/water and extracted with ethyl acetate. The combined organic phases were washed with NaCl aq., dried with Na2SO4 and evaporated to dryness. The residue was dissolved in 250 mL THF and treated with 300 mL 1 N HCl at room temperature for 20 h. Water was added and the mixture was extracted with ethyl acetate. The combined organic phases were washed with NaCl aq., dried with Na2SO4, evaporated to dryness and subjected to column chromatography on silica eluting with a gradient formed from heptane and ethyl acetate. The product containing fractions were evaporated to yield 9.7 g (32%) of the title compound as light yellow oil. MS (m/e): 260.1/262.2 (MH+).
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Br:43][C:44]1[CH:52]=[C:51](/[CH:53]=[CH:54]/[CH:55]([C:60]2[CH:65]=[C:64]([Cl:66])[C:63]([Cl:67])=[C:62]([Cl:68])[CH:61]=2)[C:56]([F:59])([F:58])[F:57])[CH:50]=[CH:49][C:45]=1[C:46](O)=[O:47].[NH2:69][CH2:70][CH2:71][NH:72][C:73](=[O:79])[O:74][C:75]([CH3:78])([CH3:77])[CH3:76]>C(Cl)Cl>[Br:43][C:44]1[CH:52]=[C:51](/[CH:53]=[CH:54]/[CH:55]([C:60]2[CH:61]=[C:62]([Cl:68])[C:63]([Cl:67])=[C:64]([Cl:66])[CH:65]=2)[C:56]([F:59])([F:58])[F:57])[CH:50]=[CH:49][C:45]=1[C:46]([NH:69][CH2:70][CH2:71][NH:72][C:73](=[O:79])[O:74][C:75]([CH3:76])([CH3:78])[CH3:77])=[O:47]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.7 %

Procedure:
PyBOP (420 mg, 0.82 mmol) and DIPEA (0.410 mL, 2.46 mmol) were added to a stirred solution of (E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid (400 mg, 0.82 mmol) and tert-butyl 2-aminoethylcarbamate (130 mg, 0.82 mmol) in CH2Cl2 (10 mL) and the reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was partitioned between water and CH2Cl2 (25 mL). The organic layer was washed with 2N HCl followed by saturated NaHCO3 and brine. The organic layer was dried (Na2SO4), filtered, concentrated and the residue was purified by column chromatography on silica (100-200 mesh) eluting with 40% EtOAc in petroleum ether to afford the title compound as a brown solid (200 mg, 39%): 1H NMR (400 MHz, DMSO-d6) δ 8.38 (t, J=5.2 Hz, 1H), 7.91-7.89 (m, 3H), 7.58 (d, J=6.8 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H), 6.99 (dd, J=15.6, 9.2 Hz, 1H), 6.84 (t, J=6.0 Hz, 1H), 6.76 (t, J=15.6 Hz, 1H), 4.84-4.80 (m, 1H), 3.24-3.20 (m, 2H), 3.11-3.08 (m, 2H), 1.30 (s, 9H); ESIMS m/z 628.80 ([M+H]+); IR (thin film) 3365, 1701, 1167, 699, 555 cm−1.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[O:13]([CH2:20][CH2:21][NH2:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>>[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([NH:22][CH2:21][CH2:20][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:10]3)=[CH:27][CH:26]=1
Reactant: COc1ccc(CN)cc1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: NCCOc1ccccc1
Product: COc1ccc(CNc2ccc3nc(NCCOc4ccccc4)ccc3c2)cc1

Procedure:
The title compound, MS: m/e=400.1 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 2-phenoxyethylamine and 4-methoxybenzylamine.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[OH:21])[C:14]([O:16][CH3:17])=[O:15])[CH:9]=[CH2:10]>N1C=CC=CC=1>[C:1]([O:21][C:20]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=1[CH2:8][CH:9]=[CH2:10])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCc1cc(C(=O)OC)ccc1O
Solvent: c1ccncc1
Product: C=CCc1cc(C(=O)OC)ccc1OC(C)=O
Reaction time: 14 h
Yield: 87.7 %

Procedure:
Acetic anhydride (200 μL, 218 mg, 2.13 mmol) was added dropwise to a solution of phenol 5 (315 mg, 1.64 mmol) in pyridine (1.5 mL) at room temperature. The mixture was stirred for 14 hours before the solvent was removed. The residue was purified by chromatography (10:1, hexanes:EtOAc) to afford 6 (337 mg, 88%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 7.95-7.90 (m, 2H), 7.11 (d, J=8.2 Hz, 1H), 5.92-5.83 (m, 1H), 5.12-5.03 (m, 2H), 3.88 (s, 3H), 3.33 (d, J=6.5 Hz, 2H), 2.29 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 169.2, 166.8, 153.0, 135.6, 132.7, 132.4, 129.4, 128.4, 123.0, 117.2, 52.6, 35.0, 21.3; IR (neat) νmax 3080, 3005, 2980, 2953, 2916, 2845, 1765, 1722, 1639, 1609, 1589, 1493, 1437, 1418, 1369, 1285, 1263, 1190, 1163, 1121 cm−1; HRMS (ESI+) m/z 235.1076 (M+H+, C13H15O4 requires m/z 235.0970).
Reaction SMILES: C(OC(N1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[S:31]1C=[CH:34][CH:33]=[C:32]1CCN>>[S:31]1[CH:32]=[CH:33][CH:34]=[C:12]1[CH2:11][CH2:10][NH:13][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15]
Reactant: NCCc1cccs1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: O=C(NCCc1cccs1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using thiophene-2-ethylamine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 369 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 12.00 (1H, br. s.) 10.44 (1H, s) 8.30 (1H, t, J=5.56 Hz) 8.06 (1H, d, J=6.25 Hz) 7.85 (1H, d, J=5.47 Hz) 7.37-7.43 (2H, m) 7.29 (1H, dd, J=5.08, 1.17 Hz) 6.89 (1H, dd, J=5.08, 3.32 Hz) 6.86 (1H, dd, J=3.32, 0.98 Hz) 6.78 (1H, d, J=6.44 Hz) 6.59 (1H, d, J=3.51 Hz) 3.42-3.49 (2H, m) 3.00 (2H, t, J=7.13 Hz)
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[F:20][C:21]1[CH:30]=[CH:29][C:24]2[NH:25][C:26](=[O:28])[O:27][C:23]=2[CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[F:20][C:21]1[CH:30]=[CH:29][C:24]2[N:25]([CH2:2][C:3]([N:5]3[CH2:10][CH2:9][N:8]([C:11]4[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=4)[CH2:7][CH2:6]3)=[O:4])[C:26](=[O:28])[O:27][C:23]=2[CH:22]=1
Reactant: O=c1[nH]c2ccc(F)cc2o1
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cc(N2CCN(C(=O)Cn3c(=O)oc4cc(F)ccc43)CC2)ccc1Cl

Procedure:
In a 4 mL vial was added 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (59 mg, 0.20 mmol, 1.0 equiv), 6-fluoro-3H-benzooxazol-2-one (30 mg, 0.20 mmol, 1.00 equiv), K2CO3 (110 mg, 0.80 mmol, 4.0 equiv) and 800 μL of NMP. A stir bar was placed in the vial and the vial was then capped. The resultant mixture stirred at 60° C. overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 6-fluoro-3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (18): HPLC retention time, 2.35 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 419.8, found, 419.9.
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH3:12])[N:9]=1.[Cl-:13].[NH4+:14]>CO>[ClH:13].[CH2:10]([CH:8]1[NH:9][C:3](=[NH:14])[CH2:4][CH2:5][CH2:6][CH2:7]1)[CH2:11][CH3:12]
Reactant: [NH4+]
Reactant: CCCC1CCCCC(OC)=N1
Reactant: [Cl-]
Solvent: CO
Product: CCCC1CCCCC(=N)N1
Product: Cl
Yield: 96.3 %

Procedure:
The product of EXAMPLE 112 (560 mg, 3.3 mmol) in 20 mL of MeOH was reacted with ammonium chloride (150 mg, 2.8 mmol) by the method of EXAMPLE 27 to yield 514 mg (78%) of the title material.
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)(=O)=O.C(OC([N:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1Cl)=O)(C)(C)C>>[N:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[NH:34][C:33]=1[C:7]1[N:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)n1c(Cl)nc2ccccc21
Reactant: CN1CCC(c2c[nH]c3ccc(OS(=O)(=O)C(F)(F)F)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(-c4nc5ccccc5[nH]4)nc23)CC1

Procedure:
O-Trifluoromethanesulfonyl-3-(1-methylpiperidin-4-yl)-5-hydroxy-4-aza-1H-indole (150 mg, 0.413 mmol) and 1-t-butyloxycarbonyl-2-chlorobenzimidazole (104 mg, 0.413 mmol) were converted to the title compound by the procedure of Example 7 except that after chromatography there was a mixture of protected and de-protected products. Therefore, 80 mg of the mixture was dissolved in 20 mL of dichloromethane and 1 mL of trifluoroacetic acid was added. The mixture was stirred for 2 hours and then taken up in water. The reaction was partitioned between 3 mL of 1N aqueous sodium hydroxide and 3 mL of 3:1 chloroform:isopropanol to give 51.2 mg. (37%). MS(FD) m/e 331.8 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH2:11][CH2:12][NH:13]C(=O)OC(C)(C)C)=[O:9])[C:3]=1[CH3:21].FC(F)(F)C(O)=O>>[ClH:1].[NH2:13][CH2:12][CH2:11][NH:10][C:8]([C:4]1[C:3]([CH3:21])=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=1)=[O:9]
Reactant: Cc1c(Cl)ccnc1C(=O)NCCNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Cl)ccnc1C(=O)NCCN
Product: Cl

Procedure:
12.5 g of t-butyl [2-(4-chloro-3-methylpyridine-2-carboxamido)ethyl]carbamate were reacted with trifluoroacetic acid in an analogous manner to that described in Example 2, paragraph 2. The residue was converted into the hydrochloride which was recrystallized from ethanol/ether, whereby there was obtained N-(2-aminoethyl)-4-chloro-3-methylpyridine-2-carboxamide hydrochloride as white crystals, m.p. 180°-181°.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.C(OC([N:18]([CH3:20])C)N(C)C)(C)(C)C.Cl.Cl.[NH2:23]N>C(O)=O>[N:23]1[NH:18][CH:20]=[C:2]2[C:1]=1[CH2:6][CH2:5][CH2:4][C:3]2=[O:7]
Reactant: NN
Reactant: O=C1CCCC(=O)C1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Agent: Cl
Solvent: O=CO
Product: O=C1CCCc2n[nH]cc21
Yield: 83.5 %

Procedure:
To 1,3-cyclohexane dione (22.4 g, 0.19 mol), add tert-butoxybis(dimethylamino)methane (23.1 g, 0.19 mol). Stir the reaction at room temperature for 5 minutes. Add hydrazine dihydrochloride (20.55 g, 0.19 mol) to the reaction and stir at room temperature for 1 hour. Add formic acid (50 mL) to the mixture. Bring the reaction to 100° C. and stirred for 2 hours. Cool the reaction and extract with 3:1 chloroform:IPA (10×60 mL each). Combine the organics and dry over sodium sulfate. After filtration and concentration, load the residue on silica gel column and flash with ethyl acetate to afford 21.6 g (82%) of the desired product as white-grey solid. NMR matches the structure. MS (m/z): 137 [M+H]+.