Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][CH2:2][C:3]([O:5][CH:6]([C:9]1[CH:25]=[C:24]2[N:12]([CH2:13][C:14]3[C:15]2=[N:16][C:17]2[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11](=[O:26])[C:10]=1[CH3:27])[CH2:7][CH3:8])=[O:4].[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O>[I-:1].[CH3:27][C:10]1[C:11](=[O:26])[N:12]2[C:24](=[CH:25][C:9]=1[CH:6]([O:5][C:3](=[O:4])[CH2:2][N+:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:7][CH3:8])[C:15]1=[N:16][C:17]3[C:22]([CH:23]=[C:14]1[CH2:13]2)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: c1ccncc1
Reactant: CCC(OC(=O)CI)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Solvent: O
Product: CCC(OC(=O)C[n+]1ccccc1)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Product: [I-]

Procedure:
The title compound was prepared according to the procedure in Example 13 except using (±)-7-[1-[(iodoacetyl)oxy]propyl]-8-methylindolizino[1,2-b]quinolin-9(11H)-one and pyridine. 1H NMR (CDCl3 /MeOH-d4) d 9.09 (d, J=5.5 Hz, 2H), 8.65 (t, J=7.9 Hz, 1H), 8.51 (s, 1H), 8.17 (m, 3H), 7.99 (d, J=8.1 Hz, 1H). 7.89 (m, 1H), 7.70 (m, 1H), 7.50 (s, 1H), 6.05 (d, J=17.2 Hz, 1H), 6.02 (m, 1H).5.87 (d, J=17.2 Hz, 1H), 5.30 (s, 2H), 2.31 (s, 3H), 2.18-1.94 (m, 2H), 1.09 (t, J=7.4 Hz, 3H). Anal. Calcd for C26H24IN3O3.1/4 H2O: C, 55.97; H, 4.43; N, 7.53. Found: C, 55.72; H, 4.30; N, 7.26.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](/[CH:11]=[CH:12]/[C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][C:17]([Cl:23])=[CH:18][CH:19]=3)[N:14]=2)[CH:6]=1)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>CO>[Cl:23][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13](/[CH:12]=[CH:11]/[C:7]3[CH:6]=[C:5]([OH:4])[CH:10]=[CH:9][CH:8]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: CC(=O)Oc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: Oc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A mixture of (E)-3-(7-chloro-2-quinolinylethenyl)phenyl acetate (7.4 g, 22.9 mmol) and anhydrous sodium carbonate (606 mg, 5.7 mmol) in 135 ml of methanol is stirred at room temperature for 36 hours. pH 7 buffer (250 ml) is added and the precipitated solid filtered and dried to afford (E)-3-(7-chloro-2-quinolinylethenyl)phenol which is used directly in the next step.
Reaction SMILES: CS(O[C@H:6]1[CH2:10][C@@H:9]([CH2:11][OH:12])[C@@H:8]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:7]1)(=O)=O.CN(C)C=O.[N-:26]=[N+:27]=[N-:28].[Na+]>>[N:26]([C@@H:6]1[CH2:10][C@@H:9]([CH2:11][OH:12])[C@@H:8]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:7]1)=[N+:27]=[N-:28]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@@H](OS(C)(=O)=O)C[C@H]1CO
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](N=[N+]=[N-])C[C@H]1CO
Temperature: 55 °C

Procedure:
To a solution of (1S,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-(hydroxymethyl)-cyclopentyl methanesulfonate (0.470 g, 0.00145 mol) in N,N-Dimethylformamide (6 mL, 0.08 mol) was added sodium azide (0.4 g, 0.006 mol) 23° C., and the mixture was heated at 55° C. for 3 hours. The reaction was cooled to 23° C., quenched by addition of water and extracted with Et20 (3×), dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (10 to 25% ethyl acetate/hexane) to obtain 211 mg (53.7%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8].[CH2:15]([NH:22][C:23]([C:25]1[S:29][C:28]([NH2:30])=[N:27][C:26]=1[CH3:31])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([NH:22][C:23]([C:25]1[S:29][C:28]([NH:30][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][CH:12]=[C:4]([O:3][C:2]([F:14])([F:13])[F:1])[CH:5]=2)=[N:27][C:26]=1[CH3:31])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Product: Cc1nc(NC(=O)c2cccc(OC(F)(F)F)c2)sc1C(=O)NCc1ccccc1
Yield: 28 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 3-trifluoromethoxybenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 28% yield; m.p. 230-232° C.; 1H NMR (CDCl3, 300 MHz) δ 7.78 (d, J=7.8 Hz, 1H), 7.76 (s, 1H), 7.54-7.24 (m, 7H), 6.00 (t, J=4.8 Hz, 1H), 4.58 (d, J=5.6 Hz, 2H), 2.38 (s, 3H); MS (ES+) m/z 436.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=1.[CH:19]([C:21]1[N:22]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:23]([CH3:26])=[CH:24][CH:25]=1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:15]([O:14][C:12](=[O:13])[CH2:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][CH2:26][C:23]3[N:22]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:21]([CH3:19])=[CH:25][CH:24]=3)[CH:10]=2)[CH:6]=[CH:7]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1ccc(C=O)n1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(N)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(CNc2ccc3ccn(CC(=O)OC(C)(C)C)c3c2)n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
A solution of tert-butyl 2-(6-amino-1H-indol-1-yl)acetate (intermediate A—for synthesis see above) (1.7368 mmol, 1.1 equiv.) in DCM (3 ml) was added at 0° C. to tert-butyl 2-formyl-5-methyl-1H-pyrrole-1-carboxylate (1.5789 mmol, 1.0 equiv.), dissolved in DCM (12 ml), and the mixture was stirred for 30 min at 25° C. At 0° C., Na(OAc)3BH (4.7368 mmol, 3.0 equiv.) was added in portions, and then the mixture was stirred for 12 h at 25° C. The reaction mixture was diluted with DCM (100 ml), washed with water and sat. NaCl solution (in each case 2×50 ml), dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (5% ethyl acetate in hexane). Yield: 58%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])=[N:6][CH:7]=1.[C:18]([N:25]1[CH2:33][CH2:32][CH:28]([C:29](O)=[O:30])[CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:29]([CH:28]2[CH2:32][CH2:33][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:26][CH2:27]2)=[O:30])=[N:6][CH:7]=1
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Reaction time: 15 h
Yield: 17.9 %

Procedure:
To a stirred solution of N-(5-chloropyridin-2-yl)-2-aminobenzamide (0.5 g, 1.79 mmol) and Boc-isonipecotic acid (0.41 g, 1.79 mmol) in N,N-dimethylformamide (30 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.69 g, 3.58 mmol). After stirring for 15 h, the solvent was removed in vacuo. The residue was partitioned between ethyl acetate and water, and the layers separated. The organic phase was washed with saturated aqueous sodium chloride, dried (magnesium sulfate), filtered, and concentrated in vacuo. The solid was suspended in ether, sonicated, and filtered to give 0.147 g (18%) of a tan solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:19].CCN(C(C)C)C(C)C.Cl.[C:30]([O:34][NH2:35])([CH3:33])([CH3:32])[CH3:31].CCN=C=NCCCN(C)C.Cl.C(Cl)CCl>C(Cl)Cl>[C:30]([O:34][NH:35][C:13](=[O:15])[C@H:12]([NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:19])[CH:4]=1)(=[O:9])=[O:10])[CH:16]([CH3:18])[CH3:17])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)ON
Reactant: Cc1cc(S(=O)(=O)N[C@@H](C(=O)O)C(C)C)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1cc(S(=O)(=O)N[C@@H](C(=O)NOC(C)(C)C)C(C)C)ccc1F
Reaction time: 0.5 h

Procedure:
2(R)-[(4-Fluoro-3-methylphenylsulfonyl)]amino-3-methylbutyric acid (2.64 g, 9.12 mmol) was dissolved in DCM (30 ml), followed by addition of DIEA (3.18 ml, 2 eq.) and O-t-butylhydroxylamine hydrochloride (2.3 g, 2 eq.). EDC.HCl (2.1 g, 1.2 eq.) was then added portionwise as solid. More EDC (0.6, 0.5 eq.) was added after 40 min and the reaction was stirred for another 30 min. The solvent was removed on a rotavap at room temperature, and residue was partitioned with ethylacetate (80 ml), 1N HCl (50 ml). The organic layer was washed with 1N HCl, brine, and dried over Na2SO4. The crude product was flash column purified with 5% to 12% ethylacetate in DCM gradient solvent to give product N-t-butoxy-2(R)-[(4-fluoro-3-methylphenylsulfonyl)]amino-3-methylbutyramide as a white foam. TLC (1:10 ethylaceate:DCM) Rf 0.16. NMR (500 MHz, CD3OD) δ: 0.89 (d, 3H), 0.90 (d, 3H), 1.08 (s, 9H), 1.86 (m, 1H), 2.30 (d, 3H), 3.44 (d, 1H), 7.18 (t, 1H), 7.70 (m, 1H), 7.77 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([N:20]4[CH2:25][CH2:24][CH:23]([NH:26][CH3:27])[CH2:22][CH2:21]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([N:20]4[CH2:21][CH2:22][CH:23]([N:26]([CH3:27])[S:29]([CH3:28])(=[O:31])=[O:30])[CH2:24][CH2:25]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CNC1CCN(c2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CN(C1CCN(c2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1)S(C)(=O)=O

Procedure:
Prepared from Compound 153 in Example 1 by reaction with methanesulphonyl chloride and triethylamine. Melting point: 225°-227° C.; Rf : 0.53 (alumina; petroleum ether/ethyl acetate/methanol=10:10:1); Calculated: C 48.97 H 4.54 N 21.04; Found: 49.07 4.59 20.75
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[N:5][N:4]=[N:3]1.[CH2:14]([N:16](CC)[CH2:17][CH3:18])[CH3:15].ClC(OCC(C)C)=O.C(NCC)C>CN(C)C=O>[CH2:14]([N:16]([CH2:17][CH3:18])[C:11](=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1[N:2]([CH3:1])[N:3]=[N:4][N:5]=1)[CH3:15]
Reactant: CCN(CC)CC
Reactant: Cn1nnnc1CCCCC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCN(CC)C(=O)CCCCc1nnnn1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-(1-Methyl-1,2,3,4-tetrazol-5-yl)valeric acid (1.8 g) is dissolved in dimethylformamide (50 ml), and thereto is added triethylamine (1.1. g). To the mixture is added dropwise with stirring isobutyl chloroformate (1.5 g) under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. To the mixture is added dropwise with stirring diethylamine (0.9 g) at rood temperature, and the mixture is stirred for 2 hours. Dimethylformamide is distilled off under reduced pressure, and the residue is purified by column chromatography (Wakogel C-200). After eluting with benzene-chloroform (1:1), the eluate is distilled under reduced pressure to give N,N-diethyl-5-(1-methyl-1,2,3,4-tetrazol-5-yl)-valeramide (0.7 g), colorless liquid, b.p. 190°-200° C. (bath temperature)/0.07 mmHg, nD25 =1.4907.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[C:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:25])[C@@H:15]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:16][CH3:17]>C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.CN(C)C=O>[NH:1]1[C:2]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:8]=[C:9]1[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:25])[C@@H:15]([NH:18][C:19](=[O:24])[C:20]([F:21])([F:22])[F:23])[CH2:16][CH3:17]
Reactant: CC[C@H](NC(=O)C(F)(F)F)C(=O)NCCCC#Cc1ccccc1N
Agent: Cl[Pd]Cl
Solvent: CN(C)C=O
Solvent: N#Cc1ccccc1
Product: CC[C@H](NC(=O)C(F)(F)F)C(=O)NCCCc1cc2ccccc2[nH]1
Temperature: 80 °C

Procedure:
A 50 mL round bottom flask was charged with N-[5-(2-aminophenyl)pent-4-ynyl]-2-(S)-(2,2,2-trifluoroacetylamino)butyramide (130 mg, 0.37 mmol), dichlorobis(benzonitrile)palladium (II) (38.0 mg, 0.099 mmol), and dimethylformamide (4.1 mL) and the resulting mixture heated to 80° C. for 22 h. The resulting mixture was then concentrated in-vacuo and the resulting residue purified via flash silica gel chromatography (Analogix IF-280, SF25-40 g column, gradient 90:10-50:50 Heptane:EtOAc) to yield (S)—N-(3-(1H-indol-2-yl)propyl)-2-(2,2,2-trifluoroacetamido)butanamide. 1H NMR (300 MHz, CDCl3) δ 7.48-7.53 (m, 1H), 7.32 (d, J=7.9 Hz, 1H), 7.04-7.15 (m, 2H), 6.23 (s, 1H), 4.32-4.39 (m, 1H), 3.31-3.38 (m, 2H), 2.71-2.75 (m, 2H), 1.82-1.95 (m, 3H), 1.63-1.77 (m, 1H), and 0.90-0.95 (m, 3H); MS (ES+) 356 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=1)[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][N:16]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[NH2:42][OH:43]>C(O)C>[CH2:27]([O:26][C:24]1[CH:23]=[C:11]([CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:25]=1)[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:42][OH:43])=[NH:22])=[CH:17][N:16]=1)=[O:13])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NO
Reactant: N#Cc1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)nc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: N=C(NO)c1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)nc1

Procedure:
A mixture of 3,5-bis(benzyloxy)-N-(5-cyanopyridin-2-yl)benzamide (212 mg, 0.49 mmol), triethylamine (170 μL, 1.22 mmol) and hydroxylamine hydrochloride (85 mg, 1.22 mmol) in ethanol (5 mL) was heated at reflux overnight. The mixture was cooled and concentrated under reduced pressure. The residue was purified by MPLC on silica eluting with 5% methanol/DCM then 15% methanol/DCM. The title compound was obtained as a colourless solid (171 mg, 75%). 1H NMR δ (d6-DMSO): 5.19 (4H, s); 5.92 (2H, s), 6.87 (1H, s); 7.28-7.48 (12H, m); 8.06 (1H, dd); 8.17 (1H, d), 8.65 (1H, s); 9.68 (1H, s); 10.85 (1H, br s); m/z (LCMS; ESI+) 469 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([C:10]#[CH:11])[CH:3]=1.Br[C:13]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=1[NH:20]C(=O)C(F)(F)F.O>CCCC[N+](CCCC)(CCCC)CCCC.[F-].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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([C:10]2[NH:20][C:14]3[C:13]([CH:11]=2)=[C:18]([F:19])[CH:17]=[CH:16][CH:15]=3)[CH:3]=1
Reactant: C#Cc1cc(Cl)ccc1OC
Reactant: O=C(Nc1cccc(F)c1Br)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: COc1ccc(Cl)cc1-c1cc2c(F)cccc2[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 25.9 %

Procedure:
A mixture of 4-chloro-2-ethynyl-1-methoxybenzene (255 mg, 1.5 mmol), N-(2-bromo-3-fluorophenyl)-2,2,2-trifluoroacetamide (400 mg, 1.4 mmol), Pd(PPh3)2Cl2 (30 mg, 0.04 mmol) was stirred in TBAF.3H2O (1.43 g, 7 mmol) at 110° C. for 12 hours. The reaction mixture was cooled to 25° C. and added to water, then extracted with ethyl acetate and washed with brine, dried over Na2SO4. After concentrated, the crude product of 2-(5-chloro-2-methoxyphenyl)-4-fluoro-1H-indole (100 mg, yield: 20%) was obtained. MS (M+H)+: 276/278.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:25])=[C:18](/[F:24])\[C:19](OCC)=[O:20])[C:3]=1[O:26][CH:27]([CH3:29])[CH3:28].[H-].C([Al+]CC(C)C)C(C)C>>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:25])=[C:18](/[F:24])\[CH2:19][OH:20])[C:3]=1[O:26][CH:27]([CH3:29])[CH3:28]
Reactant: CCOC(=O)/C(F)=C(/C)c1cc2c(c(Br)c1OC(C)C)C(C)(C)CC=C2C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: C/C(=C(\F)CO)c1cc2c(c(Br)c1OC(C)C)C(C)(C)CC=C2C(C)C

Procedure:
Following General Procedure G-1, ethyl (2E)-3-(4-bromo-3-isopropoxy-8-isopropyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-2-fluoro-but-2-enoate (Compound A-128, 282 mg, 0.60 mmol) and diisobutylaluminum hydride (1 M in methylene chloride, 2.4 mL, 2.4 mmol) were reacted to give the title compound as a colorless oil after purification by flash chromatography (silica gel, 10% ethyl acetate in hexanes).
Reaction SMILES: C(O[C:4](=[O:22])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[C:15]([CH3:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=S)[CH3:6])C.O.[NH2:24][NH2:25]>CCO>[CH3:6][CH:5]1[N:7]2[C:8]([CH2:9][O:10][C:11]3[C:12]2=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[C:15]([CH3:17])[CH:16]=3)=[N:25][NH:24][C:4]1=[O:22]
Reactant: CCOC(=O)C(C)N1C(=S)COc2cc(C)c([N+](=O)[O-])cc21
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1cc2c(cc1[N+](=O)[O-])N1C(=NNC(=O)C1C)CO2
Temperature: 120 °C
Yield: 76.9 %

Procedure:
To a solution of 2-(7-methyl-6-nitro-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (0.130 g, 0.40 mmol) in EtOH (8 mL) was added hydrazine hydrate (98%, 1.4 mmol, 0.070 g) and the reaction mixture was heated at 120° C. for 4 h. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo to give 4,7-dimethyl-6-nitro-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.085 g, 75%) as yellow solid, which was used directly in the next step. TLC (eluting with 25% EtOAc in petroleum ether) Rf=0.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]I)=[CH:14][CH:13]=3)[CH:10]([CH2:25][CH2:26][CH:27]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[OH:28])[C:9]2=[O:36])=[CH:4][CH:3]=1.[CH3:37][NH:38][CH2:39][CH:40]([OH:49])[CH:41]([OH:48])[CH:42]([OH:47])[CH:43]([OH:46])[CH2:44][OH:45]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:38]([CH3:37])[CH2:39][CH:40]([OH:49])[CH:41]([OH:48])[CH:42]([OH:47])[CH:43]([OH:46])[CH2:44][OH:45])=[CH:14][CH:13]=3)[CH:10]([CH2:25][CH2:26][CH:27]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[OH:28])[C:9]2=[O:36])=[CH:4][CH:3]=1
Reactant: CNCC(O)C(O)C(O)C(O)CO
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCCCCCI)cc2)N1c1ccc(F)cc1
Solvent: CN(C)C=O
Product: CN(CCCCCOc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)CC(O)C(O)C(O)C(O)CO
Temperature: 50 °C
Reaction time: 2 h

Procedure:
170 mg of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4-(5-iodopentyloxy)phenyl]azetidin-2-one are dissolved in 5 ml of absolute dimethylformamide. 220 mg of 6-methylaminohexane-1,2,3,4,5-pentaol are then added, and the reaction solution is stirred at 50° C. for 2 h. After concentration using a rotary evaporator and oil pump vacuum at 40° C., the residue is purified by preparative HPLC. The product is obtained as an oil. C36H46F2N2O8 (672) MS (ESI): M+
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[CH:18]=[C:17]([C:19]([OH:21])=O)SC=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[C:28]([NH:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)(=[O:30])[CH3:29]>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[C:13]4[O:21][C:19]([C:34]5[CH:33]=[C:32]([NH:31][C:28](=[O:30])[CH3:29])[CH:37]=[CH:36][CH:35]=5)=[CH:17][C:18]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1cc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc2s1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Product: CC(=O)Nc1cccc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3o2)c1

Procedure:
2-Chloro-6-iodo-4-morpholinofuro[3,2-d]pyrimidine 45 from Example 27 was reacted with 3-acetamidophenylboronic acid via General Procedure A to give the corresponding intermediate, after purification by flash chromatography, which was then reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to give, after purification by reverse phase HPLC, 341. MS (Q1) 455 (M+)
Reaction SMILES: [F:1][C:2]1([C:18](O)=[O:19])[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:4][CH2:3]1.[F:21][C:22]([F:32])([F:31])[O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>>[F:21][C:22]([F:31])([F:32])[O:23][C:24]1[CH:25]=[CH:26][C:27]([NH:28][C:18]([C:2]2([F:1])[CH2:3][CH2:4][N:5]([S:8]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)(=[O:9])=[O:10])[CH2:6][CH2:7]2)=[O:19])=[CH:29][CH:30]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: Cc1ccc(S(=O)(=O)N2CCC(F)(C(=O)O)CC2)cc1
Product: Cc1ccc(S(=O)(=O)N2CCC(F)(C(=O)Nc3ccc(OC(F)(F)F)cc3)CC2)cc1
Yield: 32.7 %

Procedure:
This material was made in analogy to example 1 from 4-fluoro-1-(toluene-4-sulfonyl)-piperidine-4-carboxylic acid (0.2 g) and 4-trifluoromethoxy-aniline (0.118 g) to give the desired 4-fluoro-1-(toluene-4-sulfonyl)-piperidine-4-carboxylic acid (4-trifluoromethoxy-phenyl)-amide (0.1 g) as a white solid. MS (ESI): 461.2 MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[I:30][CH3:31]>CO>[I-:30].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH2:23][N+:24]3([CH3:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CI
Reactant: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCCN2CCCCC2)CC1
Solvent: CO
Product: C[N+]1(CCCN2CCN(C(=O)C=Cc3ccc(Cl)c(Cl)c3)CCC2=O)CCCCC1
Product: [I-]
Reaction time: 8 h
Yield: 97.3 %

Procedure:
To a solution of 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one (example 4) (27 mg, 62 umol) in MeOH (0.5 ml) was added iodomethane (40 uL, 620 umol) and the reaction left for overnight at room temperature. Concentration of the mixture affording the title product (35 mg, 98%) as a white solid. MS: 452.2 (M+, 2Cl).
Reaction SMILES: C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[CH:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1.[NH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=1)[C:28]([C:42]([O:44][CH2:45]C)=[O:43])=[C:27]2[C:47]1[CH:52]=[CH:51][C:50]([C:53]([CH3:56])([CH3:55])[CH3:54])=[CH:49][CH:48]=1>ClCCl>[C:53]([C:50]1[CH:49]=[CH:48][C:47]([C:27]2[C:26]3[C:30](=[CH:31][CH:32]=[C:24]([NH:23][C:20]([CH:17]4[CH2:19][CH2:18]4)=[O:21])[CH:25]=3)[N:29]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=3)[C:28]=2[C:42]([O:44][CH3:45])=[O:43])=[CH:52][CH:51]=1)([CH3:56])([CH3:54])[CH3:55]
Reactant: CCOC(=O)c1c(-c2ccc(C(C)(C)C)cc2)c2cc(N)ccc2n1Cc1cccc(OC)c1
Reactant: O=C(Cl)C1CC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1c(-c2ccc(C(C)(C)C)cc2)c2cc(NC(=O)C3CC3)ccc2n1Cc1cccc(OC)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 36.6 %

Procedure:
Triethylamine (0.12 mL, 91 mg, 0.90 mmol), dimethylaminopyridine (20 mg, 0.16 mmol), and cyclopropanecarbonyl chloride (82 μL, 94 mg, 0.90 mmol) were added successively to a cooled (0° C.) and stirred solution of methyl 5-amino-3-(4-tert-butylphenyl)-1-(3-methoxybenzyl)-1H-indole-2-carboxylate (Example 160, 140 mg, 0.31 mmol) in dichloromethane (10 mL). The reaction was warmed to rt and stirred for 16 h. The solution was diluted with dichloromethane (50 mL), washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. Flash chromatography of the residue over silica gel using 4:1 hexane/ethyl acetate afforded 58 mg (37%) of desired product. The product had: 1H NMR (300 MHz, acetone-D6) δ 9.38 (s, 1 H), 8.02 (d, 1 H), 7.37-7.65 (m, 6 H), 7.19 (dd, 1 H), 6.80 (dd, 1 H), 6.6-6.74 (m, 2 H), 5.81 (s, 2 H), 3.73 (s, 3 H), 3.62 (s, 3 H), 1.70-1.80 (m, 1 H), 1.40 (s, 9 H), 0.82-0.90 (m,2H),0.70-0.78 (m,2H).