Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:5][C:6]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:25])=[O:24])=[CH:19][CH:18]=2)([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[OH:7])[CH2:4][CH2:3][CH2:2]1.[Mn]([O-])(=O)(=O)=[O:27].[K+]>CO.O>[CH:1]1([CH2:5][C:6]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:25])(=[O:27])=[O:24])=[CH:19][CH:18]=2)([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[OH:7])[CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)c1ccc(C(O)(CC2CCC2)c2cc3cccnc3[nH]2)cc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc(C(O)(CC2CCC2)c2cc3cccnc3[nH]2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 32.7 %

Procedure:
To a solution of 2-cyclobutyl-1-(4-methanesulfinyl-phenyl)-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-ethanol (94.2 mg, 0.266 mmol) in methanol (10 mL) at 0° C. was added a solution of potassium permanganate (42.0 mg, 0.266 mmol) in water (5 mL) dropwise. The mixture was stirred for 2 h at 0° C., extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered through a short silical gel pad (QingDao silica gel, 200-300 mesh), and concentrated in vacuo. The residue was purified using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) to afford 2-cyclobutyl-1-(4-methanesulfonyl-phenyl)-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-ethanol (32.2 mg, 33%): LC/MS m/e calcd for C20H22N2O3S [M+H]+ 371.47, observed 371.2; 1H NMR (400 MHz, CD3OD) δ ppm 1.49 (m, 1H), 1.57-1.83 (m, 4H), 1.95 (m, 1H), 2.52 (m, 3H), 3.10 (s, 3H), 6.53 (s, 1H), 7.07 (dd, J=4.9, 7.8 Hz, 1H), 7.79 (d, J=8.7 Hz, 2H), 7.90 (d, J=8.7 Hz, 2H), 7.95 (dd, J=1.5 Hz, J=7.8 Hz, 1H), 7.95 (dd, J=1.5 Hz, J=4.9 Hz, 1H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][N:9]=2)[CH2:4][CH2:3]1.[CH3:17][C:18]1[NH:19][C:20]2[C:25]([C:26]=1[CH2:27][CH2:28][CH2:29]S(C1C=CC=CC=1)(=O)=O)=[CH:24][CH:23]=[CH:22][CH:21]=2.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[O:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:8]([CH:5]2[CH2:4][CH2:3][N:2]([CH2:29][CH2:28][CH2:27][C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][C:18]=3[CH3:17])[CH2:7][CH2:6]2)=[N:9]1
Reactant: Cc1[nH]c2ccccc2c1CCCS(=O)(=O)c1ccccc1
Reactant: c1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1[nH]c2ccccc2c1CCCN1CCC(c2noc3ccccc23)CC1
Reaction time: 4 h
Yield: 61.2 %

Procedure:
A mixture of 1.67 g of 3-(4-piperidyl)-1,2-benzisoxazole hydrochloride, 2.47 g of 2-methyl-3-(phenylsulfonylpropyl)indole, 40 ml of dimethylformamide and 5.0 g of potassium carbonate was stirred under nitrogen at 90° for 4 hrs. The reaction mixture was poured into water. The precipitate was extracted with ethyl acetate and the ethyl acetate was washed with brine, dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to yield an oil. The oil was combined with 1.39 g of previously prepared material and the sample was chromatographed in 120 g of silica gel, using 1% methanol-chloroform as eluent. The eluent was evaporated and the residue was recrystallized two times from ethanol-water to yield 1.60 g (15.4%) of the product, mp 110°-112°.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([O:24][CH3:25])[CH:23]=[C:18]3[N:17]([CH2:26][CH3:27])[C:16]2=[O:28])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CO>[CH2:26]([N:17]1[C:18]2[C:19](=[N:20][CH:21]=[C:22]([O:24][CH3:25])[CH:23]=2)[N:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[C:16]1=[O:28])[CH3:27]
Reactant: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncc(OC)cc21
Agent: [Pd]
Solvent: CO
Product: CCn1c(=O)n(-c2ccc(O)cc2)c2ncc(OC)cc21
Reaction time: 2 h
Yield: 82.2 %

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-1-ethyl-6-methoxy-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (120 mg) and 10% palladium on carbon (40 mg) in MeOH (10 mL) was hydrogenated under balloon pressure at room temperature for 2 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 1-ethyl-3-(4-hydroxyphenyl)-6-methoxy-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (75 mg) as white crystals.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([O:12][CH2:13][CH:14]([C:16]1[CH:17]=[N:18][C:19]([C:22]2[NH:23][C:24]([CH:27]([C:35]3[CH:40]=[CH:39][C:38]([S:41]([CH:44]4[CH2:46][CH2:45]4)(=[O:43])=[O:42])=[CH:37][CH:36]=3)[CH2:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:25][CH:26]=2)=[CH:20][CH:21]=1)[OH:15])=[O:11])=O)(C)(C)C.C(OCC)(=O)C.[ClH:53]>C(OCC)(=O)C.C(OCC)C>[ClH:53].[ClH:53].[NH2:8][CH2:9][C:10]([O:12][CH2:13][CH:14]([C:16]1[CH:17]=[N:18][C:19]([C:22]2[NH:23][C:24]([CH:27]([C:35]3[CH:40]=[CH:39][C:38]([S:41]([CH:44]4[CH2:46][CH2:45]4)(=[O:42])=[O:43])=[CH:37][CH:36]=3)[CH2:28][CH:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)=[CH:25][CH:26]=2)=[CH:20][CH:21]=1)[OH:15])=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)OCC(O)c1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: NCC(=O)OCC(O)c1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
To a solution of 2-[6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridin-3-yl]-2-hydroxyethyl N-(tert-butoxycarbonyl)glycinate (245 mg) in ethyl acetate (5 mL) was added 4M hydrogen chloride-ethyl acetate solution (210 μL), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with diethyl ether, and the resulting precipitate was collected by filtration and dried to give the title compound (44.1 mg, yield 41%) as a pale-yellow solid. MS: 554 (MH+).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[C:9]([CH3:16])=[C:8]2[C:3]=1[CH:4]=[CH:5][NH:6][C:7]2=[O:17].[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1>C([O-])([O-])=O.[Na+].[Na+].COCCOC.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>[CH3:16][C:9]1[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:11][C:2]([C:22]2[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=2)=[C:3]2[C:8]=1[C:7](=[O:17])[NH:6][CH:5]=[CH:4]2
Reactant: Cc1c(OC(C)C)cc(Br)c2cc[nH]c(=O)c12
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: [Na+]
Solvent: COCCOC
Product: Cc1c(OC(C)C)cc(-c2cnn(C)c2)c2cc[nH]c(=O)c12
Temperature: 140 °C
Reaction time: 0.58 h
Yield: 92.9 %

Procedure:
A mixture of 5-bromo-8-methyl-7-(propan-2-yloxy)isoquinolin-1(2H)-one (108h, 150 mg, 0.507 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (210 mg, 1.01 mmol) and Pd(Ph3P)4 (29 mg, 0.025 mmol) in 1M aq. Na2CO3 (1 mL) and DME (5 mL) was degassed with N2 for 3 minutes. The reaction mixture was stirred at 140° C. in the microwave for 35 minutes. The reaction mixture was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (EtOAc) to give 8-methyl-5-(1-methyl-1H-pyrazol-4-yl)-7-(propan-2-yloxy)isoquinolin-1(2H)-one (108i, 0.14 g, 92.9%) as a white solid.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[N:6]2[N:5]=1)=O.[CH3:21][N:22]1[C:26]2[CH:27]=[C:28]([NH2:31])[CH:29]=[CH:30][C:25]=2[N:24]=[CH:23]1>>[CH3:20][O:19][C:16]1[N:15]=[CH:14][C:13]([C:12]2[N:6]3[C:7]([CH:8]=[N:9][C:4]([NH:31][C:28]4[CH:29]=[CH:30][C:25]5[N:24]=[CH:23][N:22]([CH3:21])[C:26]=5[CH:27]=4)=[N:5]3)=[CH:10][CH:11]=2)=[CH:18][CH:17]=1
Reactant: Cn1cnc2ccc(N)cc21
Reactant: COc1ccc(-c2ccc3cnc(S(C)=O)nn23)cn1
Product: COc1ccc(-c2ccc3cnc(Nc4ccc5ncn(C)c5c4)nn23)cn1

Procedure:
Following the synthetic and purification procedures described in Example 1293d, 2-methanesulfinyl-7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazine (60 mg, 0.2 mmol) was coupled to 3-methyl-3H-benzimidazol-5-ylamine (53 mg, 0.36 mmol) at 105° C. for 86 h to afford the title compound. Yield of TFA salt: 33 mg (34%) of brown powder. LC/MS: 372 (M+H); HPLC: 95% pure, RT=2.29 min; 1H NMR: (DMSO, δ) 10.04 (s, 1H), 9.34 (s, 1H), 9.22 (d, J=2.0, 1H), 9.06 (s, 1H), 8.51 (s, 1H), 8.35 (dd, J=8.9, 2.4, 1H), 7.79 (d, J=9.0, 1H), 7.64 (dd, J=9.0, 1.4, 1H), 7.24 (d, J=4.9, 1H), 7.05 (s, 1H), 7.03 (d, J=4.9, 1H), 4.06 (s, 3H), 3.95 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[CH:35]=[CH:34][N:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:11]1[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])=[CH:13][C:8]2[N:7]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[CH:35]=[CH:34][N:33]=[N:32]4)[CH:26]=3)[CH2:23][C:22](=[O:37])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3ccnn3)c1)=N2

Procedure:
The title compound was prepared from {4-chloro-5-(isobutyl-methyl-amino)-2-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M123) (0.17 g, 0.31 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (100 mg, 75%).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]([CH2:25][C:26]2[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][N:27]=2)[CH:15]2[C:24]3[N:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:18][CH2:17][CH2:16]2)=[C:9]([CH2:34][OH:35])[CH:8]=1.Cl>CCO.[OH-].[Na+]>[CH3:32][C:31]1[C:26]([CH2:25][N:14]([CH2:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][NH:5][CH2:4][C:3]([OH:36])=[O:2])=[CH:8][C:9]=2[CH2:34][OH:35])[CH:15]2[C:24]3[N:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:18][CH2:17][CH2:16]2)=[N:27][CH:28]=[C:29]([CH3:33])[CH:30]=1
Reactant: COC(=O)CNCc1ccc(CN(Cc2ncc(C)cc2C)C2CCCc3cccnc32)c(CO)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cnc(CN(Cc2ccc(CNCC(=O)O)cc2CO)C2CCCc3cccnc32)c(C)c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
(4-{[(3,5-Dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-3-hydroxymethyl-benzylamino)-acetic acid methyl ester (0.140 g, 0.29 mmol) was dissolved in a mixture of EtOH (3 mL) and 3M NaOH (7 mL). The colorless mixture was stirred at 90° C. for 16 hours to give an orange/brown solution. 3M HCl was added until pH˜2 followed by the addition of 3M NaOH until the pH˜9 and a white precipitate formed. The white solid was removed via suction filtration and the filtrate was extracted with 95:5 (CHCl3/MeOH) (9×30 mL) and the combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by column chromatography on silica gel (MeCN:MeOH:NH4OH, 6:3:1, v/v/v) afforded (4-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-3-hydroxymethyl-benzylamino)-acetic acid (0.106 g, 78%) as a pale yellow solid. 1H NMR (CD3OD) δ 1.58 (m, 1H), 2.05 (m, 2H), 2.17 (s+m, 4H), 2.27 (s, 3H), 2.65 (m, 1H), 2.83 (m, 1H), 3.43 (s, 2H), 3.74 (m, 4H), 4.16-4.22 (m, 4H), 4.39 (d, 1H, J=11.1 Hz), 7.11 (m, 1H), 7.25-7.42 (m, 5H), 8.10 (s, 1H), 8.28 (s, 1H). 13C NMR (CD3OD) δ 18.2, 18.9, 22.4, 23.2, 30.5, 52.0, 55.0, 55.1, 59.8, 63.2, 123.4, 130.5, 131.1, 133.1, 133.6, 133.8, 134.7, 135.8, 136.9, 138.7, 140.1, 141.3, 143.7, 146.9, 147.8, 154.5, 158.0, 171.5. HPLC: 97%. ES-MS m/z 475 [M+H]+. Anal. Calcd. for C28H34N4O3.1.3H2O: C, 67.53; H, 7.41; N, 11.25. Found: C, 67.65; H, 7.36; N, 11.09.
Reaction SMILES: FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C[Si](C)([O:16][CH2:17][CH2:18][O:19][Si](C)(C)C)C.[C:25]1(=O)[CH2:29][CH:28]=[CH:27][CH2:26]1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[O:16]1[C:28]2([CH2:27][CH:26]=[CH:25][CH2:29]2)[O:19][CH2:18][CH2:17]1
Reactant: O=C1CC=CC1
Reactant: C[Si](C)(C)OCCO[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C1=CCC2(C1)OCCO2
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of trimethylsilyl trifluoromethanesulfonate (CAS number 27607-77-8; 0.22 ml, 1.22 mmol) in DCM (12 ml) at −78° C. was successively added 2,2,7,7-tetramethyl-3,6-dioxa-2,7-disilaoctane (CAS number 7381-30-8; 2.51 g, 12.18 mmol) and cyclopent-3-en-1-one (CAS number 14320-37-7; 1 g, 12.18 mmol). The reaction mixture was stirred at −78° C. for 3 hours, quenched with triethylamine (2 ml, 14.35 mmol), poured into a saturated solution of sodium bicarbonate and extracted with diethyl ether. The organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>C1COCC1>[Cl:14][C:15]1[CH:16]=[C:17]([NH:18][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([NH2:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Nc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)Nc2cccc(Cl)c2)cc1[N+](=O)[O-]
Reaction time: 16 h

Procedure:
A mixture of the product obtained in 434a (11.6 g, 52.0 mmol) in 150 mL THF was added to a stirred mixture of 3-chloro-aniline (5.8 mL, 54.6 mmol) and TEA (10 mL, 72 mmol) in 100 mL THF under nitrogen. After stirring for 16 h, the mixture was filtrated, washed with THF and evaporated to dryness. The residue was triturated with methanol, filtrated and dried at 55° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:21][CH2:22][CH3:23])[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([C:16]2[NH:17][CH:18]=[CH:19][N:20]=2)[CH:15]=1)[C:10]([OH:12])=O)=[O:6])[CH2:2][CH3:3].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:57][C@@H:58]([CH2:72][C:73]1[CH:78]=[C:77]([F:79])[CH:76]=[C:75]([F:80])[CH:74]=1)[C@H:59]([OH:71])[CH2:60][NH:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([CH2:69][CH3:70])[CH:64]=1>C(Cl)Cl>[F:79][C:77]1[CH:78]=[C:73]([CH:74]=[C:75]([F:80])[CH:76]=1)[CH2:72][C@H:58]([NH:57][C:10](=[O:12])[C:9]1[CH:13]=[C:14]([C:16]2[NH:17][CH:18]=[CH:19][N:20]=2)[CH:15]=[C:7]([C:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:21][CH2:22][CH3:23])=[O:6])[CH:8]=1)[C@H:59]([OH:71])[CH2:60][NH:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([CH2:69][CH3:70])[CH:64]=1
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2ncc[nH]2)c1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(CCC)C(=O)c1cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)cc(-c2ncc[nH]2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 3-[(dipropylamino)carbonyl]-5-(1H-imidazol-2-yl)benzoic acid (250 mg, 0.79 mmol), diisopropylethylamine (103 mg, 0.8 mmol), and HBTU (330 mg, 0.87 mmol) in methylene chloride (5 mL) is added a mixture of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol prepared by the method of EXAMPLE SP-272 (322 mg, 0.79 mmol) and diisopropylethylamine (206 mg, 1.6 mmol) in methylene chloride (5 mL). The reaction mixture is stirred at room temperature for 4 h and concentrated under reduced pressure. The residue is diluted with ethyl acetate (20 mL), washed with saturated sodium bicarbonate, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 5:95 methanol/methylene chloride) provides the title compound in pure form. APCI MS m/z 632.3 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[NH:5][C:4]=2[CH2:3]1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:33]=[C:34]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([F:44])[CH:37]=1)[CH3:35]>CN(C=O)C.[Cu]I>[F:44][C:38]1[CH:37]=[C:36]([C:34]([CH3:35])=[CH:33][N:5]2[C:6]3[C:11](=[CH:10][C:9]([CH3:15])=[CH:8][CH:7]=3)[C:12]3[CH2:13][CH2:14][N:2]([CH3:1])[CH2:3][C:4]2=3)[CH:41]=[CH:40][C:39]=1[O:42][CH3:43]
Reactant: COc1ccc(C(C)=CBr)cc1F
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)C3
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: COc1ccc(C(C)=Cn2c3c(c4cc(C)ccc42)CCN(C)C3)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 28.2 %

Procedure:
2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (68 mg, 0.34 mmol) was dissolved in DMF (5 mL). To this solution was added CuI (6 mg, 0.034 mmol), L-proline (8 mg, 0.068 mmol), K3PO4 (145 mg, 0.68 mmol). The reaction mixture was stirred for 10 min at room temperature followed by addition of 4-(1-bromoprop-1-en-2-yl)-2-fluoro-1-methoxybenzene (100 mg, 0.408 mmol). The reaction mixture was heated at 80° C. overnight. Solvent was evaporated under reduced pressure, the residue was diluted with brine and extracted with ethyl acetate. Organic layer was dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to obtain 35 mg of 9-(2-(3-fluoro-4-methoxyphenyl)prop-1-enyl)-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole. 1H NMR (DMSO) OXALATE SALT 7.58 (d, 1H), 7.42 (d, 1H), 7.30 (s, 1H), 7.20 (t, 1H), 7.10 (m, 2H), 6.98 (d, 1H), 4.20 (m, 2H), 3.90 (s, 3H), 3.60 (m, 2H), 2.95 (m, 2H), 2.80 (s, 3H), 2.40 (s, 3H), 1.85 (s, 3H).
Reaction SMILES: [CH2:1]([CH:5]([C:9](O)=O)[C:6]([OH:8])=[O:7])[CH:2]([CH3:4])[CH3:3].C(OCC)(=O)C.C(NCC)C.Cl>CCOCC>[CH2:1]([C:5](=[CH2:9])[C:6]([OH:8])=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CC(C(=O)O)C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCNCC
Solvent: CCOCC
Product: C=C(CC(C)C)C(=O)O
Temperature: 5 °C

Procedure:
To a solution of 72.9 g (0.455 mol) of isobutylmalonic acid in 650 ml of ethyl acetate 54.2 ml (38.3 g, 0.524 mol) of diethylamine was added dropwise at 5° C. To the obtained suspension 19.2 g (0.640 mol) of paraform was added. The resulting mixture was refluxed for 5 h, then cooled to 5° C., and 350 ml of ether and 1000 cm3 of 2M HCl were added. After mixing the organic layer was separated, the aqueous layer was additionally extracted with 2×500 ml of ether. The combined organic extract was dried over Na2SO4 and then evaporated to dryness. Rectification of the residue in vacuum gave the title product, bp 75-77° C./6 mm Hg. Yield 51.5 g (88%) of colorless liquid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:15]2[C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[C:12]3[CH:20]=[CH:21][CH:22]=[CH:23][C:11]=3[C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2.[C:24](OC(=O)C)(=[O:26])[CH3:25]>S(=O)(=O)(O)O>[C:24]([O:1][CH2:2][CH:3]1[C:15]2[C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[C:12]3[CH:20]=[CH:21][CH:22]=[CH:23][C:11]=3[C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: OCC1c2ccccc2-c2c1c1ccccc1c1ccccc21
Agent: O=S(=O)(O)O
Product: CC(=O)OCC1c2ccccc2-c2c1c1ccccc1c1ccccc21
Reaction time: 0.5 h

Procedure:
13-Hydroxymethyldibenzo(a,c)fluorene (215.2 mg, 0.727 mmol) was dissolved in acetic anhydride (5 ml). To this solution was added one drop of sulfuric acid (2M). The reaction mixture was stirred for 30 min. A white precipitate was obtained which was filtered and washed with water (150 ml). The solid was finally dried to constant weight over P2O5 in a vacuum desiccator to afford 13-acetoxymethyldibenzo(a,c)fluorene as a white solid, (206.3 mg, 84%); m.p. 135-136° C.; (Found: C, 84.9; H, 5,33; C24H18O2 requires: C, 85.2; H, 5.33%; t.l.c. Rf(D) 0.57; Rf(E) 0.68; νmax (CH2C2) 3030 (CH stretching, aryl) 2980, 2920 (CH stretching, alkyl) 1735 (CO, ester), 1610, 1600, 1570 (aromatic rings) cm−1; λmax 366 (1184), 338 (25160), 322 (27528), 265 (52688), 246 (53020) nm; δH (CDCl3, 200 MHz), 8.86-8.69 (3H, m aromatic), 9.38 (1H, d, 3J=7.9 Hz, aromatic), 8.30-8.25 (1H, m, aromatic), 7.78-7.35 (7H, m, aromatic), 5.16 (1H, dxd, 3Ja,c=4.1 Hz, 2Ja,b=10.8 Hz, Ha, CH2), 4.56 (1H, dxd, 3Jc,a=4.1 Hz, 3Jc,b=9.3 Hz, Hc), 3.76 (1H, dxd, 2Jb,a=10.8 Hz, 3Jb,c=9.3 Hz, Hb, CH2), 2.17 (3H, s, CH3); δC (CDCl3, 50 MHz) 171.0 (CO, ester), 146.7, 142.1, 138.7, 134.8 131.1, 130.1, 128.7, 128.6 (quaternary aromatic C's), 127.6, 127.0, 126.8, 126.2, 126.1, 125.7, 124.9, 124.8, 124.3, 123.4, 123.3, 122.9 (aromatic CH's), 67.3 (CH2), 46.5 (CH), 20.9 (CH3); m/z (EI) 338, 277, 265, 139, 43.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[N:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([O:20][CH3:21])[CH:19]=1)[NH2:16]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:16][C:15]2[CH:17]=[C:18]([O:20][CH3:21])[CH:19]=[C:13]([O:12][CH3:11])[CH:14]=2)=[O:9])[CH:5]=[N:4][CH:3]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: O=C(Cl)c1cncc(Cl)n1
Solvent: ClCCl
Product: COc1cc(NC(=O)c2cncc(Cl)n2)cc(OC)c1

Procedure:
The product from Example 15B was reacted with 3,5-dimethoxyaniline and TEA in CH2Cl2 as described in Example 15C to afford the title compound. MS (DCI/NH3) m/z 294 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[C:5]#[C:6][CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2].ClC1C=CC=CC=1C(O)=O.[C:20](#[N:23])[CH2:21][CH3:22]>>[C:1]([C:4]1[CH:9]=[C:8]([CH:21]([CH3:22])[C:20]#[N:23])[CH:7]=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: CCC#N
Reactant: O=C(O)c1c#cccc1
Agent: O=C(O)c1ccccc1Cl
Product: CC(C#N)c1cccc(C(=O)O)c1

Procedure:
3-Carboxybenzyne prepared from 2-chlorobenzoic acid in the presence of a strong base is reacted with propionitrile to produce alpha-(m-carboxyphenyl)propionitrile (R. Biehl et al., J. Org. Chem., 31, 602 (1966)). The alpha-(m-carboxyphenyl)propionitrile is converted to alpha-(m-chlorocarbonylphenyl)propionitrile by using thionyl chloride. Friedel-Crafts reaction of alpha-(m-chlorocarbonylphenyl)propionitrile with benzene using aluminum chloride affords alpha-(m-benzoylphenyl)propionitrile. Hydrolysis of the alpha-(m-benzoylphenyl)propionitrile with methanol/sodium hydroxide gives alpha-(m-benzoylphenyl)propionic acid (see British Pat. No. 1,360,560).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[C:9]([CH3:11])=[N:10][C:5]2=[CH:4][CH:3]=1.C(O[CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>C1(C)C=CC=CC=1>[CH2:26]([O:25][C:23]([C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][NH:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[C:9]([CH3:11])=[N:10][C:5]2=[CH:4][CH:3]=1)=[O:24])[CH3:27]
Reactant: Cc1nc2ccc(N)nc2n1C
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNc1ccc2nc(C)n(C)c2n1)C(=O)OCC
Temperature: 0 °C
Yield: 84.3 %

Procedure:
A solution of 5-amino-2,3-dimethyl-3H-imidazo-[4,5-b]pyridine (4.86 g) and 2-ethoxy-1,1-bis-(ethoxycarbonyl)ethene (7.13 g) in toluene (200 ml) was stirred and heated at reflux for 2 hours and then it was evaporated to dryness. The residue was extracted 3 times with boiling petroleum ether (b.p. 80°-100° C.), the extracts were filtered while hot and the filtrate was then cooled to 0° C. The resulting yellow solid was filtered off, to give 1,1-bis(ethoxycarbonyl)-2-(2,3-dimethyl-3H-imidazo-[4,5-b]pyrid-5-ylamino)ethene (8.4 g) in the form of a yellow sold, m.p. 128°-130° C.