Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1.[Na+].[I-].Cl.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C([O-])([O-])=O.[K+].[K+]>CC#N.O>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:35][CH2:34][CH2:33][N:32]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[CH:12][C:13](=[O:17])[NH:14]3)=[CH:9][CH:8]=2)[CH2:31][CH2:30]1
Reactant: COc1ccccc1N1CCCNCC1
Reactant: O=c1ccc2ccc(OCCCCBr)cc2[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CC#N
Product: COc1ccccc1N1CCCN(CCCCOc2ccc3ccc(=O)[nH]c3c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.4 %

Procedure:
A mixture of intermediate 15 (150 mg, 0.51 mmol) and NaI (150 mg, 1.02 mmol) in CH3CN was heated to reflux for 30 min and then cooled to rt. Intermediate 29 (124 mg, 0.51 mmol) and anhydrous K2CO3 (282 mg, 2.04 mmol) were added to the mixture. The resulting mixture was heated to reflux and stirred overnight. The reaction solution was diluted with water and extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with DCM/MeOH=30:1) to give 7-(4-(4-(2-methoxyphenyl)-1,4-diazepan-1-yl)butoxy)quinolin-2(1H)-one (compound 10) (61 mg, 26%). 1H NMR (300 MHz, CDCl3) δ 7.69 (d, J=9.6 Hz, 1H), 7.43 (d, J=8.7 Hz, 1H), 6.91-6.85 (m, 5H), 6.79 (d, J=9.0 Hz, 1H), 6.65 (s, 1H) 6.49 (d, J=9.3 Hz, 1H), 4.07 (t, J=6.0 Hz, 2H), 3.83 (s, 3H), 3.34-3.29 (m, 4H), 2.93-2.86 (m, 4H), 2.69-2.65 (m, 2H), 2.06-2.02 (m, 2H), 1.86-1.84 (m, 2H), 1.77-1.73 (m, 2H). HPLC: 95%, RT 1.902 min. MS (ESI) m/z 422.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][OH:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([N:37]3[CH2:42][CH2:41][N:40]([CH:43]([CH3:45])[CH3:44])[CH2:39][CH2:38]3)=[C:30]3[C:34]=2[C:33](=[O:35])[N:32]([CH3:36])[CH2:31]3)[C:22]([Cl:46])=[CH:21][N:20]=1>>[Cl:46][C:22]1[C:23]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([N:37]3[CH2:38][CH2:39][N:40]([CH:43]([CH3:45])[CH3:44])[CH2:41][CH2:42]3)=[C:30]3[C:34]=2[C:33](=[O:35])[N:32]([CH3:36])[CH2:31]3)=[N:24][C:19]([NH:1][C:2]2[C:15]([O:16][CH3:17])=[CH:14][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][OH:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:20][CH:21]=1
Reactant: COc1cc2c(cc1N)CCN(CCO)CC2
Reactant: CC(C)N1CCN(c2ccc(Nc3nc(Cl)ncc3Cl)c3c2CN(C)C3=O)CC1
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(N4CCN(C(C)C)CC4)c4c3C(=O)N(C)C4)n1)CCN(CCO)CC2

Procedure:
The title compound was prepared from 2-(7-amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-ethanol (40 mg, 0.20 mmol) and 7-(2,5-dichloropyrimidin-4-ylamino)-4-(4-isopropylpiperazin-1-yl)-2-methyl-2,3-dihydroisoindol-1-one (74 mg, 0.17 mmol) in an analogous manner to Example 946 to afford an off-white solid (75 mg, 70%). Mp: 198-200° C. LCMS (m/e) 635 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 10.55 (s, 1H), 8.67 (d, J=9 Hz, 1H), 8.11 (s, 2H), 7.40 (s, 1H), 7.10 (d, J=9 Hz, 1H), 6.68 (s, 1H), 4.40 (s, 2H), 3.91 (s, 3H), 3.70 (m, 2H), 3.20 (s, 3H), 3.08 (m, 4H), 2.92 (m, 5H), 2.82-2.64 (m, 11H), 1.13 (d, J=6 Hz, 6H).
Reaction SMILES: [CH:1]1([N:4]([CH3:21])[CH:5]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]3[CH:10]=[C:9]([C:17]#[CH:18])[CH:8]=[C:7]([O:19][CH3:20])[C:6]2=3)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24](=[O:53])[C:25]([C:28]1[CH:33]=[CH:32][C:31](C#CC2C=C(C3CC3)C3OC4(CC4)CC(C)(C)C=3C=2)=[CH:30][CH:29]=1)([CH3:27])[CH3:26].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:22][O:23][C:24](=[O:53])[C:25]([C:28]1[CH:29]=[CH:30][C:31]([C:18]#[C:17][C:9]2[CH:8]=[C:7]([O:19][CH3:20])[C:6]3[CH:5]([N:4]([CH:1]4[CH2:3][CH2:2]4)[CH3:21])[CH2:14][CH2:13][C:12]([CH3:15])([CH3:16])[C:11]=3[CH:10]=2)=[CH:32][CH:33]=1)([CH3:27])[CH3:26]
Reactant: C#Cc1cc(OC)c2c(c1)C(C)(C)CCC2N(C)C1CC1
Reactant: COC(=O)C(C)(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)C(C)(C)c1ccc(C#Cc2cc(OC)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1

Procedure:
Following General Procedure B and using 5-(cyclopropyl-methyl-amino)-2-ethynyl-8,8-dimethyl-4-methoxy-5,6,7,8-tetrahydro-naphthalene (Intermediate 81, 0.090 g, 0.32 mmol), methyl-2-(4-iodophenyl)-2-methyl-propionate (Reagent 2, 0.097 g, 0.3 mmol), triethyl amine (8 mL), copper(I)iodide (0.019 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 5-20% ethyl acetate in hexane as the eluent, the title compound was obtained as a solid (0.09 g, 78%).
Reaction SMILES: S(O[CH2:12][C@H:13]1[O:17][C@@H:16]([N:18]2[CH:25]=[CH:24][C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:15][C@@H:14]1[OH:26])(C1C=CC(C)=CC=1)(=O)=O.[N-:27]=[N+:28]=[N-:29].[Na+]>CN(C=O)C>[N:27]([CH2:12][C@H:13]1[O:17][C@@H:16]([N:18]2[CH:25]=[CH:24][C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:15][C@@H:14]1[OH:26])=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)C[C@@H]2O)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1O
Temperature: 95 °C
Reaction time: 12 h
Yield: 59.7 %

Procedure:
To a solution of 5′-O-tosyl-2′-deoxyuridine (13.591, 0.035 mol) in dry DMF (90 mL) was added NaN3 (9.29 g, 0.141 mol) and the reaction mixture was allowed to stir at 95° C. for 12 h. The reaction mixture was cooled, the solid residue was removed by filtration and the filtrate was concentrated under vacuum to give the crude product. The crude was purified by column chromatography on silica gel (4% methanol in chloroform) which gave the title product (5.29 g, 56%) as a white solid.
Reaction SMILES: [NH:1]1[C:11]2[C:12]3[CH:3]([CH2:4][C:5](=[O:13])[NH:6][C:7]=3[CH:8]=[CH:9][CH:10]=2)[C:2]1=[O:14].[H-].[Na+].Br[CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29]>CN(C=O)C>[O:29]=[C:20]1[C:21]2[C:22](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:24])[N:19]1[CH2:18][C:3]12[C:2](=[O:14])[NH:1][C:11]3[C:12]1=[C:7]([CH:8]=[CH:9][CH:10]=3)[NH:6][C:5](=[O:13])[CH2:4]2
Reactant: O=C1CC2C(=O)Nc3cccc(c32)N1
Reactant: O=C1c2ccccc2C(=O)N1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CC2(CN3C(=O)c4ccccc4C3=O)C(=O)Nc3cccc(c32)N1
Reaction time: 0.17 h

Procedure:
To a stirred solution of (±)-2a,5-dihydropyrrolo[4,3,2-de]quinoline-2,4(1H,3H)-dione (2.00 g, 10.6 mmol, described in Intermediate 18) in degassed DMF (30 mL) at 0° C. was added sodium hydride (468 mg of a 60% dispersion in mineral oil, 11.7 mmol). The mixture was stirred for 10 min, then N-(bromomethyl)phthalimide (2.55 g, 10.6 mmol) was added and stirring was continued for 2 h. An additional portion of N-(bromomethyl)phthalimide (500 mg) was added and stirring was continued for 1 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (100 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 90:10, to give the title compound. MS: m/z=348 (M+1).
Reaction SMILES: Cl.Cl.[OH:3][C@@H:4]1[CH2:11][N:10]([CH2:12][CH2:13][CH2:14][N:15]2[C:21](=[O:22])[CH2:20][CH2:19][NH:18][C@H:17]([CH3:23])[CH2:16]2)[CH2:9][CH2:8][C:5]21[CH2:7][CH2:6]2.[Cl:24][C:25]1[CH:26]=[C:27]([N:32]=[C:33]=[O:34])[CH:28]=[CH:29][C:30]=1[Cl:31].CN1CCOCC1.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:24][C:25]1[CH:26]=[C:27]([NH:32][C:33]([N:18]2[CH2:19][CH2:20][C:21](=[O:22])[N:15]([CH2:14][CH2:13][CH2:12][N:10]3[CH2:9][CH2:8][C:5]4([CH2:6][CH2:7]4)[C@H:4]([OH:3])[CH2:11]3)[CH2:16][C@H:17]2[CH3:23])=[O:34])[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: C[C@@H]1CN(CCCN2CCC3(CC3)[C@H](O)C2)C(=O)CCN1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[C@@H]1CN(CCCN2CCC3(CC3)[C@H](O)C2)C(=O)CCN1C(=O)Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
A solution of 0.120 g (purity: 76% corresponds to 0.25 mmol) of (R)-4-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-2-methyl-[1,4]diazepan-5-one dihydrochloride (example 1E) in 2 ml N,N-dimethylformamide was treated at room temperature with 0.052 g (0.27 mmol, 1.1 eq.) of 3,4-dichlorophenyl isocyanate and 0.136 ml (1.24 mmol, 5 eq.) of 4-methylmorpholine. The reaction was stirred at room temperature overnight. To the solution was added 5 mg (0.02 mmol, 0.1 eq.) of 3,4-dichlorophenyl isocyanate. After 1 h, no starting material was left; the solution was slowly added to a solution of sat. aq. sodium hydrogencarbonate, followed by extraction with ethyl acetate (3 times). The organic phases were washed with a solution of sat. aq. sodium hydrogencarbonate and with 10% aq. sodium chloride solution. The combined organic phases were dried over Na2SO4 and the solvent was removed under vacuum. The crude product was purified by flash chromatography (20 g SiO2-column, dichloro-methane/methanol 2:98, 5:95, 1:9, 1:4) to give 0.061 g (51%) of the title compound as white solid. MS: 483.4 (MH+, 2Cl).
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][N:10]=[C:11]2[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])#[N:5].C([O-])(O)=O.[Na+]>C(O)C>[OH:3][NH:2][C:4](=[NH:5])[C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][N:10]=[C:11]2[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: NO
Reactant: CCOC(=O)CCCc1nccc2c(C#N)cccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCCc1nccc2c(C(=N)NO)cccc12

Procedure:
Hydroxylamine hydrochloride (0.36 g) was added to a suspension of ethyl 4-(5-cyano-1-isoquinolinyl)butanoate (D42; 0.65 g) and NaHCO3 (0.66 g) in ethanol (20 ml). The mixture was heated to reflux for 24 hours. The solvent was evaporated in vacuo. The residue was washed with water (2×10 ml) to afford, after drying, the title compound (0.6 g). MS (ES): C16H19N3O3 requires 301. found 302.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:29][CH:19]3[CH2:20][N:21]([C:23](=O)[C:24]([F:27])([F:26])[F:25])[CH2:22][CH:18]3[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.CSC.B>C1COCC1>[Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:17][CH:18]3[CH2:22][N:21]([CH2:23][C:24]([F:26])([F:25])[F:27])[CH2:20][CH:19]3[CH2:29]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cn1cc(Nc2ncc(Cl)c(NC3CC4CN(C(=O)C(F)(F)F)CC4C3)n2)cn1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: Cn1cc(Nc2ncc(Cl)c(NC3CC4CN(CC(F)(F)F)CC4C3)n2)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 18.3 %

Procedure:
To a solution of 1-[5-[[5-chloro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl]amino]-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]-2,2,2-trifluoro-ethanone (0.89 g, 2.10 mmol) in THF (20 mL) was added a solution of borane dimethyl sulfide complex (1 mmol/L in THF, 6 mL, 6 mmol) at 0° C. After addition, the reaction mixture was stirred at 0° C. for 10 min and then heated to reflux overnight. The reaction was quenched with 6 M HCl aqueous solution (2 mL) then stirred at rt for 1 h and concentrated in vacuo. The residue was adjusted to pH=10 with a 50% NaOH solution, then diluted with water (50 mL), and extracted with EtOAc (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/50) to give the title compound as a beige solid (0.16 g, 19%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[N:19][S:20]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)(=[O:22])=[O:21])[CH:9]=2)=[N:5][N:4]=[N:3]1.ClC1C=C(S(N=C2C3C(=CC=CC=3)C(=O)C(Cl)=C2)(=O)=O)SC=1Cl.S[CH2:52][CH2:53][C:54]([NH:56][CH:57]1[CH2:59][CH2:58]1)=[O:55]>>[CH:57]1([NH:56][C:54](=[O:55])[CH2:53][CH2:52][S:7][C:8]2[C:17](=[O:18])[C:16]3[C:11]([C:10](=[N:19][S:20]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)(=[O:22])=[O:21])[CH:9]=2)=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:59][CH2:58]1.[CH3:1][N:2]1[C:6]([S:7][C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[N:19][S:20]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)(=[O:22])=[O:21])[CH:9]=2)=[N:5][N:4]=[N:3]1
Reactant: O=C(CCS)NC1CC1
Agent: Cn1nnnc1SC1=CC(=NS(=O)(=O)c2cccs2)c2ccccc2C1=O
Agent: O=C1C(Cl)=CC(=NS(=O)(=O)c2cc(Cl)c(Cl)s2)c2ccccc21
Product: O=C(CCSC1=CC(=NS(=O)(=O)c2cccs2)c2ccccc2C1=O)NC1CC1

Procedure:
N-cyclopropyl-3-(1-oxo-4-(thiophen-2-ylsulfonylimino)-1,4-dihydronaphthalen-2-ylthio)propanamide (13h) was prepared according to the procedure for 13d except using 4,5-dichloro-N-(3-chloro-4-oxonaphthalen-1(4H)-ylidene)thiophenesulfonamide (12c) and 3-mercapto-N-cyclopropylpropanamide ( ), which afforded the title compound 20 mg (37%) as a yellow solid, m.p.: ° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:19][C:20]1[C:24](B(O)O)=[C:23]([CH3:28])[O:22][N:21]=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>O.CO.ClCCl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[CH3:19][C:20]1[C:24]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[O:17][CH3:18])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)=[C:23]([CH3:28])[O:22][N:21]=1
Reactant: COc1ccccc1-c1c[nH]c2ncc(Br)cc12
Reactant: Cc1noc(C)c1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccccc1-c1c[nH]c2ncc(-c3c(C)noc3C)cc12
Reaction time: 0.33 h
Yield: 72 %

Procedure:
To 5-bromo-3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine (40 mg, 0.087 mmol), 3,5-dimethyl-isoxazole-4-boronic acid (16 mg, 0.114 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (1:1) (4 mg, 0.0044 mmol) in a Smith process vial was added 0.6 mL of a 1:1 mixture of acetonitrile, and a 2 M solution of sodium carbonate in water. The reaction was run in a Personal Chemistry® microwave reactor at 165° C. for 1200 s. The reaction mixture was diluted with 1:1 methanol/dichloromethane, filtered, and the filtrate was adsorbed on silica gel. Purification on silica gel with a gradient of MeOH/CH2Cl2 afforded 5-(3,5-dimethyl-isoxazol-4-yl)-3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine as beige crystals (20 mg, 71% yield). 1H NMR (500 MHz, DMSO-d6) δ 2.23 (s, 3H), 2.41 (s, 3H), 3.81 (s, 3H), 7.01 (dt, J=1.0, 7.0 Hz, 1H), 7.11 (dd, J=1.0, 8.0 Hz, 1H), 7.28 (dt, J=1.5, 7.0 Hz, 1H), 7.51 (dd, J=2.0, 8.0 Hz, 1H), 7.73 (d, J=3.0 Hz, 1H), 7.90 (d, J=1.5 Hz, 1H), 8.22 (d, J=2.0 Hz, 1H), 11.9 (s, 1H). MS: m/z 320 (M+H+).
Reaction SMILES: C[C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:9][C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[CH:7]=[N:8][C:4]=2[C:3]=1[NH2:18].[N+](C1C2N=CN(CC3C=CN=CC=3)C=2C=CC=1)([O-])=O>>[N:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:6]2[C:5]3[CH:16]=[CH:17][CH:2]=[C:3]([NH2:18])[C:4]=3[N:8]=[CH:7]2)=[CH:11][CH:12]=1
Reactant: Cc1ccc2c(ncn2Cc2ccncc2)c1N
Agent: O=[N+]([O-])c1cccc2c1ncn2Cc1ccncc1
Product: Nc1cccc2c1ncn2Cc1ccncc1

Procedure:
Using the same general procedure as described above for the preparation of 5-methyl-1-(pyridin-4-yl)methyl-1H-benzimidazol-4-ylamine (2d), reduction of 4-nitro-(1-pyridin-4-yl)methyl-1H-benzimidazole 3c (1.71 g) gave 3d as a pale yellow powder.
Reaction SMILES: I.[NH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:7]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)C(=O)[O:13][N:12]=2)=[N:8][O:9][N:10]=1.Cl[S:28]([NH:31]C(=O)OC(C)(C)C)(=[O:30])=[O:29].C(N(CC)CC)C.FC(F)(F)C(O)=O.[OH-].[Na+].O.C(O)(=O)C>ClCCl>[NH2:31][S:28]([NH:2][CH2:3][CH2:4][NH:5][C:6]1[C:7]([C:11](=[N:12][OH:13])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[N:8][O:9][N:10]=1)(=[O:30])=[O:29]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Reactant: NCCNc1nonc1-c1noc(=O)n1-c1cccc(C(F)(F)F)c1
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)NCCNc1nonc1C(=NO)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39 %

Procedure:
In a separate flask, 3-{4[(2-aminoethyl)amino]-1,2,5-oxadiazol-3-yl}-4-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5(4H)-one hydroiodide (26 mg, 0.053 mmol) was suspended in dichloromethane (0.5 mL). A nitrogen atmosphere was established and the temperature brought to 0° C. The tert-butyl [chlorosulfonyl]carbamate solution (prepared as above) was added over 5 minutes to the stirred suspension of the amine salt. After 10 minutes, triethylamine (37 μL, 0.27 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1.5 hours. After concentrating in vacuo, the residue was treated with trifluoroacetic acid (0.5 mL, 6 mmol). This was stirred for 1 hour and the mixture was again concentrated to dryness in vacuo. The dried solids were suspended in methanol (0.5 mL) and a 2.0 N NaOH in water (0.53 mL, 1.1 mmol) was added in one portion. The reaction was heated to 45° C. and stirred for 30 minutes. After neutralization with acetic acid (60 μL, 1.1 mmol), the product was purified by preparative LCMS to give the desired product (8.5 mg, 39%). LCMS calculated for C12H15F3N7O4S (M+H)+: m/z=410.0. 1H NMR (400 MHz, CD3OD): δ 7.36 (t, J=7.8 Hz, 1H), 7.23 (d, J=7.8 Hz, 1H), 7.10 (s, 1H), 7.03 (d, J=7.8 Hz, 1H), 3.48 (m, 2H), 3.29 (m, 2H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:11][C:10]3([CH2:14][NH:13][CH2:12]3)[CH2:9]2)=[CH:4][CH:3]=1.[O:15]1[CH2:18][C:17](=O)[CH2:16]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(O)(=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][C:10]3([CH2:14][N:13]([CH:17]4[CH2:18][O:15][CH2:16]4)[CH2:12]3)[CH2:11]2)=[CH:6][CH:7]=1
Reactant: O=C1COC1
Reactant: Ic1ccc(N2CC3(CNC3)C2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Ic1ccc(N2CC3(C2)CN(C2COC2)C3)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
2-(4-Iodophenyl)-2,6-diazaspiro[3.3]heptane (1.01 g, 3.4 mmol), and 3-oxetanone (0.29 g, 4.0 mmol) was dissolved in DCE (15 mL) and heated to 50° C. for 10 min. Acetic acid (5 drops) and NaBH(OAc)3 (1.07 g, 5.1 mmol) was added and the reaction was stirred for 16 h at 50° C. The mixture was concentrated under reduced pressure and suspended in NaHCO3 (50 mL) and extracted with EtOAc (2×40 mL) and washed with brine. The EtOAc layer was dried (MgSO4), and concentrated to dryness to give the title compound as a white solid (1.15 g, 96%). MS ESI 357.0 [M+H]+, calcd for [C14H17IN2O+H]+357.0.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][C:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])=[CH:16][C:17]=1[C:18]([NH2:20])=[O:19]>>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:15]1[S:14][C:13]([NH:12][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[N:7]=2)=[C:17]([C:18]([NH2:20])=[O:19])[CH:16]=1
Reactant: CC(C)(O)c1cccc(Br)n1
Reactant: NC(=O)c1cc(-c2ccccc2F)sc1N
Product: CC(C)(O)c1cccc(Nc2sc(-c3ccccc3F)cc2C(N)=O)n1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 2-(6-bromopyridin-2-yl)propan-2-ol (65 mg, 0.301 mmol) and 2-amino-5-(2-fluorophenyl)thiophene-3-carboxamide (72.5 mg, 0.307 mmol) as the starting materials.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[CH2:9]([S:13]CCCC)[CH2:10][CH2:11][CH3:12]>>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[S:13][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: Cc1ccccc1I
Reactant: CCCCSCCCC
Product: CCCCSc1ccccc1C

Procedure:
The general procedure was used to convert 2-iodotoluene and n-butyl sulfide to the title product. Purification by flash chromatography (hexane as the eluent) gave the analytically pure product as a clear oil (331 mg, 93% yield). 1H NMR (300 MHz, CDCl3) δ 7.17–6.97 (m, 4H; Ha, Hb, Hc, Hd), 2.80–2.78 (t, J=7.3, 2H; Hf), 2.27 (s, 3H; He), 1.61–1.51 (m, 2H; Hg,), 1.44–1.17 (m, 2H; Hh), 0.87–0.82 (t, J=7.3, 3H; methyl protons). 13C NMR (75 MHz, CDCl3) δ 137 (C1), 136.3 (C6), 129.9 (C5), 127.1 (C2), 126.2 (C3), 125.1 (C4), 32.3 (C8), 31 (C9), 22 (C10), 20.2 (C7), 13.6 (C11). Anal. Calcd. for C11H16S: C, 73.27; H, 8.94; S, 17.78; Found C, 73.23; H, 9.16, S, 17.57.
Reaction SMILES: Br[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[C:14]=2[F:21])[C:4]2[C:9]([C:10]=1[C:11]#[N:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:22][C:23]1[C:27](B(O)O)=[C:26]([CH3:31])[O:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>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.COCCOC.O>[F:21][C:14]1[C:15]([F:20])=[C:16]([OH:19])[CH:17]=[CH:18][C:13]=1[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([C:11]#[N:12])=[C:2]1[C:27]1[C:23]([CH3:22])=[N:24][O:25][C:26]=1[CH3:31]
Reactant: N#Cc1c(Br)n(-c2ccc(O)c(F)c2F)c2ccccc12
Reactant: Cc1noc(C)c1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: COCCOC
Product: Cc1noc(C)c1-c1c(C#N)c2ccccc2n1-c1ccc(O)c(F)c1F
Temperature: 150 °C
Reaction time: 0.17 h

Procedure:
To 2-bromo-1-(2,3-difluoro-4-hydroxyphenyl)-1H-indole-3-carbonitrile (Example 103) was added 1.5 eq 3,5-dimethylisooxazole-4-boronic acid, 4 eq potassium carbonate, 2 eq sodium iodide and 10 mol % tetrakis(triphenylphosphine)palladium. DME:H2O (1:1) was added and the vial was flushed with nitrogen, sealed and stirred at 150° C. for 10 min. The reaction mixture was cooled to rt, diluted with H2O and extracted with DCM. The organic phase was evaporated to dryness and purified on silica column using 1:1 n-heptane:EtOAc as mobile phase. ES/MS m/z: 366.20 (M+H), 364.20 (M−H); NMR (CDCl3, 500 MHz): 7.84 (d, 1H), 7.39 (m, 2H), 7.19 (d, 1H), 6.93 (broad m, 2H), 2.42 (s, 1.5H), 2.24 (s, 1.5H), 2.19 (s, 1.511), 2.01 (s, 1.5H)
Reaction SMILES: OC1C2C(=CC(OC)=CC=2)N=C(C2SC=CN=2)C=1.C([C:22]1[N:23]=[C:24]([C:27]2[CH:36]=[C:35]([O:37][CH:38]3[CH2:56][CH:55]4[N:40]([C:41](=[O:61])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH:48]=[CH:49][CH:50]5[C:52]([C:58]([OH:60])=[O:59])([NH:53][C:54]4=[O:57])[CH2:51]5)[CH2:39]3)[C:34]3[C:29](=[CH:30][C:31]([O:62][CH3:63])=[CH:32][CH:33]=3)[N:28]=2)[S:25][CH:26]=1)(C)C>>[CH3:63][O:62][C:31]1[CH:30]=[C:29]2[C:34]([C:35]([O:37][CH:38]3[CH2:56][CH:55]4[N:40]([C:41](=[O:61])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH:48]=[CH:49][CH:50]5[C:52]([C:58]([OH:60])=[O:59])([NH:53][C:54]4=[O:57])[CH2:51]5)[CH2:39]3)=[CH:36][C:27]([C:24]3[S:25][CH:26]=[CH:22][N:23]=3)=[N:28]2)=[CH:33][CH:32]=1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Agent: COc1ccc2c(O)cc(-c3nccs3)nc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nccs3)nc2c1

Procedure:
The title compound was prepared from 4-hydroxy-7-methoxy-2-(thiazol-2-yl)quinoline and intermediate 7 following the procedure (Step F-H) reported for 18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid 10: m/z=591 (M+H)+.