Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:37])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:31][C@@H:32]([OH:36])[C:33]([OH:35])=[O:34])[NH:16][C:17]([C:19]3[O:23][N:22]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[F:30])[CH:20]=3)=[O:18])=[CH:10][CH:9]=2)[CH:7]=1.CCN=C=NCCCN(C)C.Cl.C1C=C2N=NN(O)C2=CC=1.O.C(Cl)Cl.[F:64][C:65]([F:72])([C:68]([F:71])([F:70])[F:69])[CH2:66]O>>[F:64][C:65]([F:72])([C:68]([F:71])([F:70])[F:69])[CH2:66][O:34][C:33](=[O:35])[C@H:32]([OH:36])[CH2:31][N:15]([CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:37])=[CH:9][CH:10]=1)[NH:16][C:17]([C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[CH:20]=1)=[O:18]
Reactant: O=C(NN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)c1cc(-c2ccccc2F)no1
Reactant: OCC(F)(F)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: O=C(NN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)OCC(F)(F)C(F)(F)F)c1cc(-c2ccccc2F)no1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 12.8 %

Procedure:
A mixture of (R)-3-{N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-[3-(2-fluorophenyl)isoxazole-5-carbonyl]hydrazino}-2-hydroxypropionic acid (30.0 mg, 57 μmol), EDC HCl (65.4 mg, 341 μmol), and HOBt hydrate (52.2 mg, 341 μmol) in DCM (0.5 mL, 8 mmol) was stirred at room temperature for 10 minutes. 2,2,3,3,3-Pentafluoro-1-propanol (45.3 μL, 455 μmol) was added and the resulting mixture was stirred at room temperature for 1 hour then concentrated. The residue was dissolved in AcOH (2 mL), filtered, and purified by reverse phase prep HPLC to yield the title compound (4.8 mg, purity 90.2%) as a TFA salt. MS m/z [M+H]+ calc'd for C29H21ClF7N3O5, 660.11. found 660.3.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH:23]=C)=[CH:19][C:18]=2[F:25])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].CC(C)=[O:28].C(=O)=O.[BH4-].[Na+]>CO>[F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][OH:28])=[CH:19][C:18]=2[F:25])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: C=Cc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Reactant: CC(C)=O
Agent: O=C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(CO)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The product of Example 4, 3,4-Difluoro-2-(2-fluoro-4-vinylanilino)-N-(2-hydroxyethoxy)benzamide (170 mg, 0.48 mmol) was dissolved in MeOH (50 mL) and the solution cooled to −78° C. (acetone/dry ice). Ozone was bubbled through the solution until a pale blue-grey solution was obtained, then nitrogen bubbled through the solution until the blue colour disappeared. A solution of NaBH4 (92 mg, 2.41 mmol) in MeOH (10 mL) was added, the reaction mixture removed from the cold bath and allowed to stir for 0.5 h. at RT. The MeOH was removed from the mixture under reduced pressure and the resulting residue partitioned between EtOAc (50 mL) and 1 M HCl (50 mL). The EtOAc layer was washed with water (50 mL) and brine (50 mL), then dried (Na2SO4) and the solvent removed under reduced pressure to afford an oil which was purified by chromatography on silica gel (10% EtOAc as eluant). 3,4-Difluoro-2-[2-fluoro-4-(hydroxymethyl)anilino]-N-(2-hydroxyethoxy)benzamide was isolated as a pale yellow crystalline solid (99 mg, 58%); m.p. (Et2O/hexane) 108-1 10C. 1H NMR [400 MHz, (CD3)2SO] δ 11.86 (br s, 1 H), 8.74 (br s, 1 H), 7.44-7.37 (m, 1 H), 7.16-7.08 (m, 2 H), 7.02-6.97 (m, 1 H), 6.86 (ddd, J=8.6, 8.6, 4.5 Hz, 1 H), 5.18 (t, J=5.7 Hz, 1 H), 4.71 (br s, 1 H), 4.43 (d, J=5.8 Hz, 2 H), 3.85 (t, J=4.7 Hz, 2 H), 3.60-3.52 (m, 2 H). Anal. calcd. for C16H15F3N2O4: C, 53.9; H, 4.2; N, 7.9. Found C, 54.2; H, 4.6; N, 7.6.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([N:14]2[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]2)[CH:11]=[CH:10][CH:9]=1.[I:28]I>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[OH:1][C:2]1[C:7]([I:28])=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([N:14]2[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]2)[CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3O)n2)c1C(F)(F)F
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2cccc(-c3cccc(I)c3O)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of the title compound from Example 5 Step B (4.0 g, 10.6 mmol) and silver sulfate (3.31 g, 10.6 mmol) in ethanol (20 mL) was added iodine (2.69 g, 10.6 mmol), and the resulting mixture was vigorously stirred at room temperature. After 2 h, the reaction mixture was quenched with water and sodium bisulfite solution, extracted with ethyl acetate and concentrated in vacuo. Purification by chromatography on silica gel (0 to 15% EtOAc in hexanes, then 15 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 503.7 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 13.08 (s, 1 H),8.17 (s, 1 H),8.10 (t, J=8.0 Hz, 1 H),8.06 (d, J=8.0 Hz, 1 H),7.86 (dd, J=7.5, 1.5 Hz, 1 H),7.82 (dd, J=8.0, 1.5 Hz, 1 H),7.52 (d, J=7.5 Hz, 1 H),6.75 (t, J=8.0 Hz, 1 H),4.33 (q, J=7.0 Hz, 2 H),1.43 (t, J=7.0 Hz, 3 H).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6]CC)=O)#[N:2].[CH3:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1>COCCO>[CH3:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:15][C:4](=[O:6])[CH2:3][C:1]#[N:2])=[CH:12][CH:11]=1
Reactant: Cc1ccc(CN)cc1
Reactant: CCOC(=O)CC#N
Solvent: COCCO
Product: Cc1ccc(CNC(=O)CC#N)cc1

Procedure:
A solution of 93 g. (0.825 mole) of ethyl cyanoacetate and 100 g. (0.825 mole) of 4-methylbenzylamine in 150 ml. of 2-methoxyethanol is refluxed for 2 hr. After cooling the solid product is isolated by vacuum filtration, washed with pentane and dried to give 90 g. (57.6%) of amide as a white solid: m.p. 124°-6° C.;ν3220 (NH), 2230 (CN), and 1630 cm.-1 (C= O)δ8.77 broad, 1H, NH); 7.17 (s, 4H, phenyl protons), 4.28 (d, 2H, benzyl methylene), 3.67 (s, 2H, CH2CO), and 2.28 (s, 3H, CH3).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1)=[O:3].[OH-].[K+].[CH3:15][N:16]([CH3:20])[C:17](Cl)=[S:18]>O.C1COCC1.[OH-].[Na+]>[C:2]([C:4]1[CH:12]=[CH:11][C:9]([O:10][C:17](=[S:18])[N:16]([CH3:20])[CH3:15])=[C:6]([O:7][CH3:8])[CH:5]=1)(=[O:3])[CH3:1]
Reactant: COc1cc(C(C)=O)ccc1O
Reactant: CN(C)C(=S)Cl
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(C)=O)ccc1OC(=S)N(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of acetovanillone (8.31 g, 50 mmol) and 2.81 g KOH (50 mmol) in H2O (34 mL), at 0°, is added a solution of dimethylthiocarbamoyl chloride (8.28 g, 67 mmol) in THF (14 mL), dropwise, at such a rate as to keep the reaction temperature below 12°. The reaction mixture is warmed to room temperature, and stirred for 30 minutes. It is then diluted with 1 N NaOH (100 mL) and extracted with EtOAc (3×80 mL). The combined organic phase is washed with H2O (1×100 mL) and brine (1×50 mL), dried over MgSO4, and concentrated in vacuo to give dimethylthiocarbamic acid O-(4-acetyl-2-methoxy-phenyl) ester. To a thick walled pyrex tube is aded dimethylthiocarbamic acid O-(4-acetyl-2-methoxy-phenyl) ester (9.81 g, 38.77 mmol). The tube is flushed with nitrogen, sealed, and then heated to 250° for 1 hour. After cooling, the residue is chromatographed (silica gel, 1:1 EtOAc/hexane) to yield dimethylthiocarbamic acid S-(4-acetyl-2-methoxy-phenyl) ester.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])=[CH:9][C:7]=2[CH:8]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH3:28][S:29]([O:1][CH2:2][CH2:3][C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]3[CH:20]=[CH:19][CH:18]=[C:15]([C:16]#[N:17])[CH:14]=3)=[CH:9][C:7]=2[CH:8]=1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1cccc(-c2ccc3oc(CCO)cc3c2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1cc2cc(-c3cccc(C#N)c3)ccc2o1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The product from Example 112C (170 mg, 0.65 mmol) and triethylamine (100 μL, 0.72 mmol) were dissolved into CH2Cl2 (3 mL) and cooled to 0° C. The solution was treated with methanesulfonyl chloride (55 μL, 0.71 mmol), and after 10 minutes it was permitted to slowly warm to room temperature. More methanesulfonyl chloride (10 μL, 0.13 mmol) and triethylamine (10 μL, 0.072 mmol) were added. The mixture was stirred until the reaction was nearly complete and then washed consecutively with water and brine, dried (Na2SO4), concentrated, and used without further purification in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:23])[C:15]2([CH:18]3[CH2:22][CH2:21][NH:20][CH2:19]3)[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24]1([N:27]2[C:36]3[C:31](=[CH:32][C:33]([F:40])=[C:34](F)[C:35]=3[O:37][CH3:38])[C:30](=[O:41])[C:29]([C:42]([OH:44])=[O:43])=[CH:28]2)[CH2:26][CH2:25]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:23])[C:15]2([CH:18]3[CH2:22][CH2:21][N:20]([C:34]4[C:35]([O:37][CH3:38])=[C:36]5[C:31]([C:30](=[O:41])[C:29]([C:42]([OH:44])=[O:43])=[CH:28][N:27]5[CH:24]5[CH2:26][CH2:25]5)=[CH:32][C:33]=4[F:40])[CH2:19]3)[CH2:16][CH2:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C1CCN(C(=O)OC(C)(C)C)CC1)C1(C2CCNC2)CC1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1c(N2CCC(C3(N(C)C4CCN(C(=O)OC(C)(C)C)CC4)CC3)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 75 °C
Yield: 55 %

Procedure:
A solution of 4-[methyl-(1-pyrrolidin-3-yl-cyclopropyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.31 mmol) in acetonitrile (30.0 mL) was added 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (98 mg, 0.33 mmol) and DBU (0.23 mL, 1.53 mmol). The suspension was heated to 75° C. overnight. The reaction mixture was partitioned between ethyl acetate and 5% citric acid. The separated organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (10% methanol in dichloromethane) to give the title compound as a yellow solid (102 mg, 62%). ESI MS m/z 599.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH:13][CH3:14])=[CH:6][C:5]=1Cl.[F:17][C:18]1([F:23])[CH2:22][CH2:21][NH:20][CH2:19]1.Cl.CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH:13][CH3:14])=[CH:6][C:5]=1[N:20]1[CH2:21][CH2:22][C:18]([F:23])([F:17])[CH2:19]1
Reactant: CNc1cc(Cl)c(C(=O)OC)cc1[N+](=O)[O-]
Reactant: FC1(F)CCNC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cc(N2CCC(F)(F)C2)c(C(=O)OC)cc1[N+](=O)[O-]

Procedure:
The sub-title compound is prepared in analogy to procedure 6a from methyl-2-chloro-4-methylamino-5-nitro-benzoate (1.00 g, 4.09 mmol), 3,3-difluoro-pyrrolidine×HCl (880 mg, 6.13 mmol), DIPEA (2.8 mL, 16 mmol) and dioxane (10 mL).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][CH:4]=[N:3]1.[C:24](Cl)(=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([NH:23][C:24](=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:5][CH:4]=[N:3]1
Reactant: CCCCCC(=O)Cl
Reactant: Cn1ncnc1C(=NOCc1cccc(N)n1)c1ccccc1
Solvent: ClCCl
Product: CCCCCC(=O)Nc1cccc(CON=C(c2ccccc2)c2ncnn2C)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 724.1 %

Procedure:
To a solution of 6-[({[(1-methyl-1H-1,2,4-triazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-amine (0.151 g, 0.486 mmol, 1 eq.) in 2 ml of DCM was added TEA (0.098 g, 0.973 mmol, 2 eq.) followed by hexanoyl chloride (0.072 g, 0.053mmol, 1.1 eq.). The reaction was stirred 4 h at room temperature and the solvent was evaporated. The crude was purified by chromatography on silica gel to give N-{6-[({[(1-methyl-1H-1,2,4-triazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}hexanamide (0.156 g, 79% yield) as a clear viscous oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH:11]([CH3:22])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O>ClCCl>[CH3:22][CH:11]1[CH2:10][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[CH2:14][CH2:13][NH:12]1
Reactant: CC1CC(c2ccc(C#N)cc2)CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CC(c2ccc(C#N)cc2)CCN1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.2 %

Procedure:
To a solution of tert-butyl 4-(4-cyanophenyl)-2-methylpiperidine-1-carboxylate (compound 176.2, 500 mg, 1.50 mmol, 1.00 equiv, 90%) in dichloromethane (3 mL) was added TFA dropwise (1 mL). The resulting mixture was stirred for 1.5 h at room temperature, then diluted with 30 mL of dichloromethane. The resulting mixture was washed with sodium bicarbonate (aq., 1 M. Note: significant gas evolution). The aqueous phase was extracted with 2×50 mL of dichloromethane and the combined organic layers were dried (Na2SO4), and concentrated in vacuo. The residue was purified using silica gel column chromatography with methanol/dichloromethane (1:50-1:20) as eluent to yield 280 mg (93%) of 4-(2-methylpiperidin-4-yl)benzonitrile as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[N:10]=[N:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20].N12CCN(CC1)CC2.O>CN(C)C=O>[Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[N:10]=[N:9][C:8]([O:11][C:19](=[O:20])[N:18]([CH3:17])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:7][CH:6]=1
Reactant: Oc1ccc(Cc2ccc(Cl)cc2Cl)nn1
Reactant: CN(C(=O)Cl)c1ccccc1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)Oc1ccc(Cc2ccc(Cl)cc2Cl)nn1)c1ccccc1
Yield: 80.7 %

Procedure:
A solution of 6-(2,4-dichlorobenzyl)-3-pyridazinol (98 mg, 0.38 mmol), N-methyl-N-phenylcarbamoyl chloride (65 mg, 0.38 mmol) and 1,4-diazabicyclo[2.2.2]octane (43 mg, 0.38 mmol) in dimethylformamide (10 ml) was stirred at room temperature for 2 hours. Water was added and the solution was extracted twice with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (40:60)) yielding the title compound (119 mg, 80% yield) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([O:13][C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(O)cc(OC)c1OC
Product: COc1cc(OC(C)=O)cc(OC)c1OC
Temperature: 0 °C
Yield: 93 %

Procedure:
A solution of 3,4,5-trimethoxyphenol (5.52 g, 30 mmol) in acetic anhydride (15 mL) was refluxed for 4 h. The reaction mixture was poured onto crushed ice (50 g). The resulting precipitate was collected and washed with water. The residue was dried in vacuum at 50° C. for 24 h to afford white crystals (6.31 g, 93%), 74-75° C.; 1H NMR (CDCl3, 200 M Hz) δ 6.34 (s, 2H), 3.83 (s, 6H), 3.82 (s, 3H), 2.29 (s, 3H); 13C NMR (CDCl3, 50 M Hz) δ 169.6 (s), 153.5 (s, 2C), 146.7 (s), 135.8 (s), 99.1 (d, 2C), 60.9 (q), 56.1 (q, 2C), 21.1 (q).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[N:8]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=O)[CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.[O:19]1CCOCC1>[OH-].[K+]>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([C:11]3[CH:13]=[CH:18][CH:17]=[CH:16][C:15]=3[CH:14]=[O:19])[CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1
Reactant: C1COCCO1
Reactant: O=C(c1ccccc1)n1ccc2ccc(Br)nc21
Agent: [K+]
Agent: [OH-]
Product: O=Cc1ccccc1-n1ccc2ccc(Br)nc21
Temperature: 25 °C

Procedure:
(6-bromo-1H-pyrrolo[2,3-b]pyridin-1-yl)(phenyl)methanone, 586 was dissolved in 20 mL of dioxane and 20 mL of 2M KOH (aq). This was stirred at ambient temperature until analysis indicated all of the starting material had been consumed (2 to 4 hours). The reaction was diluted with 50 mL of ethyl acetate and washed with 2×25 mL of NaHCO3 (aq. satd.) and 25 mL of brine. The organic layer was dried with sodium sulfate, evaporated and purified by column chromatography. Combined steps 2 and 3 gave approximately 65% overall yield.
Reaction SMILES: [CH3:1][Si:2]([CH3:5])(Cl)[Cl:3].O1CCCC1.[CH3:11][C:12]1[CH:13]([Li])[C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2>CCCCCC>[CH3:1][Si:2]([Cl:3])([CH3:5])[CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[C:12]1[CH3:11]
Reactant: [Li]C1C(C)=Cc2ccccc21
Reactant: C[Si](C)(Cl)Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1=Cc2ccccc2C1[Si](C)(C)Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
In a three-necked flask equipped with a mechanical stirrer were charged 44.5 g (345 mmol) of dimethyldichlorosilane, 300 ml of tetrahydrofuran and n-hexane, to which was added at -78° C. a 2-methylindenyllithium solution, followed by stirring at room temperature for 3 hours. After the solvent was distilled off under reduced pressure, 100 ml of hexane was added and insoluble matter was removed by centrifugation. After the solvent was distilled off under reduced pressure, distillation under reduced pressure (113° C./7mmHg) afforded 14.9 g (67 mmol, yield: 58%) of dimethyl(2-methylindenyl)silyl chloride as a pale yellow liquid.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].[CH2:8]([C:15]1[C:16](=[O:26])[C:17]2[C:22]([C:23](=[O:25])[CH:24]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[NH2:2][C:1]1[O:25][C:23]2[C:22]3[C:17]([C:16]([OH:26])=[C:15]([CH2:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:24]=2[C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[CH:18][CH:19]=[CH:20][CH:21]=3
Reactant: O=C1C=C(Cc2ccccc2)C(=O)c2ccccc21
Reactant: COC(=O)CC#N
Product: COC(=O)c1c(N)oc2c1c(Cc1ccccc1)c(O)c1ccccc12

Procedure:
The title compound was prepared by reaction of methyl cyanoacetate with 2-benzyl-1,4-naphthoquinone following the procedure outlined for example 1. Obtained as tan crystals (55%); m.p. 170°-171° C.; 1H NMR (CDCl3): 3.66(s, 3H), 4.05(s,2H), 5.07(s,2H), 7.17-7.53(m, 8H), 7.98(d, 1H), 8.10(d,1H); IR (nujol): 3309, 3479, 3566, 1725, 1604; Chemical ionization mass spectrum m/z (rel. intensity) 348 (M+H, 100); calculated for C21H17NO4C 72.61, H 4.93; measured C 72.79, H 4.68, N 4.00.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:27][CH:26]3[CH:12]([C:13](=[O:33])[N:14]([CH3:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH:21]4[C:23]([C:29]([OH:31])=O)([NH:24][C:25]3=[O:28])[CH2:22]4)[CH2:11]2)[CH:6]=[C:5]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[N:4]=1.[CH:42]1([S:45]([NH2:48])(=[O:47])=[O:46])[CH2:44][CH2:43]1.CCN=C=NCCCN(C)C.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:27][CH:26]3[CH:12]([C:13](=[O:33])[N:14]([CH3:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH:21]4[C:23]([C:29]([NH:48][S:45]([CH:42]5[CH2:44][CH2:43]5)(=[O:47])=[O:46])=[O:31])([NH:24][C:25]3=[O:28])[CH2:22]4)[CH2:11]2)[CH:6]=[C:5]([C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)[N:4]=1
Reactant: COc1ccc(-c2cc(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)nc(OC)n2)cc1
Reactant: NS(=O)(=O)C1CC1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(-c2cc(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)nc(OC)n2)cc1
Yield: 44 %

Procedure:
The acid 16f (195 mg, 0.34 mmol) was reacted with cyclopropane sulfonamide (53 mg, 0.44 mmol), EDAC (85 mg, 0.44 mmol) and DBU (137 mg, 0.9 mmol) in dry DCM (3 ml) according to the procedure described in Example 13 step f. Purification by column chromatography on silica gel eluted with diethyl ether-ethyl acetate gave the title compound, (100 mg, 45%), (M+H)+668.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([CH2:12][NH:13][CH3:14])[CH2:9][CH:10]=[CH2:11])[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([CH2:9][CH:10]=[CH2:11])[CH2:12][N:13]([CH3:14])[S:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:32])=[O:31])[CH:5]=[CH:6][CH:7]=1
Reactant: C=CC[C@H](CNC)c1cccc(Cl)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC[C@H](CN(C)S(=O)(=O)c1ccccc1)c1cccc(Cl)c1
Reaction time: 16 h
Yield: 103.2 %

Procedure:
A solution of 2.0 g (9.53 mmol) of (S)-4-(3-chorophenyl)-5-methylamino-1-pentene (prepared as described by J. Hale et al., Bioorganic and Medicinal Chemistry Letters, 1993, 3, 319-322) and 5.0 mL (28.6 mmol) of diisopropylethylamine (DIPEA) in 20 mL of methylene chloride was cooled in an ice/ethanol bath. To this was added 1.46 mL (11.4 mmol) of benzenesulfonyl chloride and after 5 min the ice bath was removed. After stirring for 16 h, the reaction mixture was diluted with methylene chloride and washed with water containing 20 mL of 2 N HCl. The aqueous layer was reextracted with methylene chloride and the organic layers were washed with brine, combined, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (FCC) eluting with 15% ethyl acetate/hexanes to afford 3.44 g of the title compound. 1H NMR (400 MHz, CDCl3): δ 2.38 (p, J=8, 1H), 2.55 (m, 1H), 2.59 (s, 3H), 2.94 (m, 2H), 3.37 (m, 1H), 4.95 (m, 2H), 5.60 (m, 1H), 7.05-7.3 (m, 4H), 7.46 (m, 2H), 7.55 (m, 1H), 7.69 (dd, J=1.5 and 6, 2H).
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:12]Br)[CH2:10]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:14]([NH2:17])([CH3:16])[CH3:15]>O>[CH2:1]([O:8][CH:9]1[CH2:12][N:17]([CH:14]([CH3:16])[CH3:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCC(CBr)OCc1ccccc1
Reactant: CC(C)N
Solvent: O
Product: CC(C)N1CC(OCc2ccccc2)C1
Temperature: 80 °C

Procedure:
11 Parts of 2-benzyloxy-1,3-dibromo-propane, 30 parts of iso-propylamine and 30 parts of water were added to a stainless autoclave, and the mixture was heated at 80° C. for 2 hours with agitation. The reaction mixture was cooled and treated in the same manner as in Example 29, followed by distillation under reduced pressure. As a result, 18 parts of 3-benzyloxy-1-(iso-propyl)azetidine boiling at 104°-107° C. under 2 mm Hg were obtained.