Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].O1CCOCC1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([C@H:35]2[N:39](C(OC(C)(C)C)=O)[C:38]([CH3:48])([CH3:47])[CH2:37][CH2:36]2)[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:25]4[C@H:32]([CH3:33])[CH2:31][C@@H:30]([OH:34])[C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:20][CH2:19]2)=[O:17])=[C:11]([F:49])[CH:10]=1>C(Cl)Cl>[ClH:8].[ClH:1].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([C@@H:35]2[CH2:36][CH2:37][C:38]([CH3:48])([CH3:47])[NH:39]2)[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:25]4[C@H:32]([CH3:33])[CH2:31][C@@H:30]([OH:34])[C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:20][CH2:19]2)=[O:17])=[C:11]([F:49])[CH:10]=1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Cl)cc4F)[C@@H]4CCC(C)(C)N4C(=O)OC(C)(C)C)CC3)c21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Cl)cc4F)[C@@H]4CCC(C)(C)N4)CC3)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
4N HCl in dioxane (3 mL, 0.191 mmol) was added to a solution of (S)-tert-butyl 5-((S)-1-(4-chloro-2-fluorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (0.115 g, 0.191 mmol) in dry DCM (30 mL) and stirred at room temperature for 2 hours. The reaction was concentrated to dryness to reveal (S)-2-(4-chloro-2-fluorophenyl)-2-((S)-5,5-dimethylpyrrolidin-2-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)ethanone dihydrochloride (0.093 g, 0.162 mmol, 84.7% yield). HPLC, 220 nM=1.93 minutes, 100% purity. LC/MS=2.22 minutes, (APCI+) m/z=502 [M+H]+. 1H NMR (400 MHz, D2O) 8.38 (s, 1H), 7.27 (d, J=10.54 Hz, 1H), 7.21-7.15 (m, 2H), 5.22 (t, J=7.81 Hz, 1H), 4.43 (d, J=8.98 Hz, 1H), 4.19 (dd, J1=8.59 Hz, J2=14.8 Hz, 1H), 4.15-4.05 (m, 1H), 3.87-3.75 (m, 2H), 3.74-3.46 (m, 5H), 3.42 (q, J=7.03 Hz, 2H), 3.39-3.25 (m, 2H), 2.19 (dd, J1=7.08 Hz, J2=13.27 Hz, 1H), 2.07-1.97 (m, 1H), 1.90-1.72 (m, 4H), 1.36 (s, 3H), 1.31 (s, 3H), 1.04 (t, J=7.03 Hz, 2H), 0.97 (d, J=7.03 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][C@H:8]([CH:22]([CH3:24])[CH3:23])[CH2:9][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@@H:11]2[CH2:13][O:12]2)=[CH:5][C:4]=1[O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32].[NH2:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=O.[OH-].[Na+].Cl>C(O)(C)C>[OH:12][C@H:11]([C@@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])[CH2:9][C@H:8]([CH2:7][C:6]1[CH:25]=[CH:26][C:3]([O:2][CH3:1])=[C:4]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:5]=1)[CH:22]([CH3:23])[CH3:24])[CH2:13][N:33]1[CH2:34][CH2:35][CH2:36][C:37]1=[O:39]
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H]2CO2)C(C)C)ccc1OC
Reactant: NCCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN2CCCC2=O)C(C)C)ccc1OC
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A solution of 0.025 g of tert-butyl {3(S)-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methyl-1(S)-(R)-oxiranylpentyl}carbamate (Example 1b) in 0.50 ml of isopropanol is admixed successively with 0.027 g of 4-aminobutyric acid and 0.13 ml of 1M NaOH and stirred at 60° C. over 3 hours. The reaction mixture is cooled to 0° C. and admixed with 0.13 ml of 1M HCl and concentrated by evaporation to dryness. The residue is dissolved in 2.5 ml of dichloromethane, admixed successively with 0.016 g of N,N-dicyclohexylcarbodiimide and 0.012 mg of 1-hydroxybenzotriazole, and stirred at room temperature over 18 hours. The reaction solution is admixed with 1M sodium hydrogen carbonate solution and extracted with ethyl acetate (2×). The combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a colourless oil. Rf=0.32 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=4.51 (gradient I).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]3C(C)(C)[N:19]([CH2:22][CH2:23][OH:24])[C:20](=[O:21])[CH:14]3[CH2:13]2)=[CH:4][CH:3]=1.Cl>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH:14]([C:20]([NH:19][CH2:22][CH2:23][OH:24])=[O:21])[CH2:13]2)=[CH:6][CH:7]=1
Reactant: CC1(C)N(CCO)C(=O)C2CN(CCCC(c3ccc(F)cc3)c3ccc(F)cc3)CCN21
Agent: Cl
Solvent: O
Product: O=C(NCCO)C1CN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CCN1
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of 40 parts of 7-[4,4-bis(4-fluorophenyl)butyl]hexahydro-2-(2-hydroxyethyl)-3,3-dimethylimidazo[1,5-a]pyrazin-1(5H)-one, 19 parts of hydrochloric acid solution 10.5N and 400 parts of water was stirred for one hour in a boiling water-bath on a Rotavapor. After cooling, the reaction mixture was washed twice with 140 parts of 1,1'-oxybisethane. The aqueous phase was alkalized with ammonium hydroxide. The product was extracted twice with 140 parts of 1,1'-oxybisethane. The combined extracts were dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using first a mixture of trichloromethane and methanol (90:10 by volume) and then a mixture of trichloromethane and methanol saturated with ammonia (90:10 by volume) as eluents. The pure fractions were collected and the eluent was evaporated, yielding 33.7 parts (100%) of 4-[4,4-bis(4-fluorophenyl)butyl]-N-(2-hydroxyethyl)-2-piperazinecarboxamide (intermediate 95).
Reaction SMILES: C(OC1C=CC(C(C2CCN(CC(O)=O)CC2)=O)=CC=1)C.FC1C=CC(C(C2CCN(CC(O)=O)CC2)=O)=CC=1.C1(CO)CC1.[CH:46]1([CH2:49][O:50][C:51]2[CH:68]=[CH:67][C:54]([C:55]([CH:57]3[CH2:62][CH2:61][N:60]([CH2:63][C:64]([OH:66])=[O:65])[CH2:59][CH2:58]3)=[O:56])=[CH:53][CH:52]=2)[CH2:48][CH2:47]1.[NH2:69][CH2:70][C:71]1[NH:72][C:73](=[O:81])[C:74]2[CH2:80][O:79][CH2:78][CH2:77][C:75]=2[N:76]=1.C(O)(C(F)(F)F)=O>C(#N)C.O>[CH:46]1([CH2:49][O:50][C:51]2[CH:68]=[CH:67][C:54]([C:55]([CH:57]3[CH2:62][CH2:61][N:60]([CH2:63][C:64]([OH:66])=[O:65])[CH2:59][CH2:58]3)=[O:56])=[CH:53][CH:52]=2)[CH2:48][CH2:47]1.[CH:46]1([CH2:49][O:50][C:51]2[CH:52]=[CH:53][C:54]([C:55]([CH:57]3[CH2:58][CH2:59][N:60]([CH2:63][C:64]([NH:69][CH2:70][C:71]4[NH:72][C:73](=[O:81])[C:74]5[CH2:80][O:79][CH2:78][CH2:77][C:75]=5[N:76]=4)=[O:65])[CH2:61][CH2:62]3)=[O:56])=[CH:67][CH:68]=2)[CH2:48][CH2:47]1
Reactant: NCc1nc2c(c(=O)[nH]1)COCC2
Agent: CCOc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1
Agent: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Agent: O=C(O)CN1CCC(C(=O)c2ccc(OCC3CC3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: O=C(CN1CCC(C(=O)c2ccc(OCC3CC3)cc2)CC1)NCc1nc2c(c(=O)[nH]1)COCC2

Procedure:
2-[4-(4-Cyclopropylmethoxy-benzoyl)-piperidin-1-yl]-acetic acid was prepared following the general procedures for the synthesis of 2-(4-(4-ethoxybenzoyl)piperidin-1-yl)acetic acid from 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid and cyclopropyl-methanol. The title compound (44.7 mg, 0.088 mmol) was prepared following the general procedure of Example 1 from 2-[4-(4-cyclopropylmethoxy-benzoyl)-piperidin-1-yl]-acetic acid and 2-aminomethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one. MS (ESI) m/z 481.5 (M+H+); HPLC (Insertsil ODS3 100×3 mm C-18 column: mobile phase: 5-95% acetonitrile/water with 0.1% TFA, at 1 mL/min over 7.75 min.) t=1.27 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.26-0.41 (m, 2H), 0.48-0.68 (m, 2H), 1.14-1.29 (m, 1H), 1.65-1.83 (m, 4H), 2.18-2.33 (m, 2H), 2.51 (br. s., 2H), 2.84-3.08 (m, 3H), 3.32 (br. s., 2H), 3.83 (br. s., 2H), 3.91 (d, J=6.06 Hz, 2H), 4.20 (br. s., 2H), 4.34 (br. s., 2H), 7.03 (d, J=7.07 Hz, 2H), 7.94 (d, J=7.58 Hz, 2H), 8.21 (br. s., 1H), 12.38 (br. s., 1H). HRMS calculated for C26H33N4O5: 481.2451 (M+H). found (ESI, [M+H]+): 481.2459.
Reaction SMILES: [CH3:1][C:2](=[CH:5][CH2:6][O:7][C:8](=[O:10])[CH3:9])[CH:3]=[O:4].CO.N1C2C(=CC=CC=2)C=C[CH:14]=1>C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:8]([O:7][CH:6]=[CH:5][C:2]([CH3:1])=[CH:3][O:4][CH3:14])(=[O:10])[CH3:9]
Reactant: c1ccc2ncccc2c1
Reactant: CC(=O)OCC=C(C)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC=C(C)C=COC(C)=O
Yield: 990.3 %

Procedure:
28.4 g (0.2 mole) of 2-methyl-4-acetoxy-2-butenal is dripped into a mixture of 23.3 g (0.22 mole) of o-formic acid methyl ester, 12.8 g (0.4 mole) of methanol and 0.35 g (2millimoles) of p-toluene-sulfonic acid. Acetalization takes place while the temperature rises. After 1 hour 2 g (15 millimoles) of quinoline is added and the whole is heated at 185° to 190° C (internal temperature) and at a pressure of 200 mm Hg for 20 minutes The methanol which is eliminated is distilled off in a 20-cm column. Then the pressure is adjusted to 20 mm Hg with the result that 23.2 g of 1-acetoxy-3-methyl-4-methoxy-1,3-butadiene in the form of a mixture of two geometric iosmers is obtained. The yield is 75% of the theory.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[N:4]=[C:3]1[N+:10]([O-:12])=[O:11].[N+:13]([O-])([OH:15])=[O:14].S(=O)(=O)(O)O>>[CH3:1][N:2]1[C:6]([N+:13]([O-:15])=[O:14])=[C:5]([N+:7]([O-:9])=[O:8])[N:4]=[C:3]1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: Cn1cc([N+](=O)[O-])nc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: Cn1c([N+](=O)[O-])nc([N+](=O)[O-])c1[N+](=O)[O-]
Reaction time: 0.42 h

Procedure:
Nitration of 1-methyl-2,4-dinitroimidazole with nitric acid and sulfuric acid Fuming nitric acid (4.0 ml, excess, d. 1.544 g/ml) was added to 1-methyl-2,4-dinitroimidazole (0.40 g, 2.33 mmol) at room temperature, following by sulfuric acid (2.0 ml, fuming 30% SO3) with stirring. The reaction temperature was then brought to 105° C. within 25 minutes and kept the temperature for further 2.0 hours. The reaction mixture was poured onto ice and the product was extracted with methylene chloride (3×20 ml). The combined organic phase was washed with water (15 ml), 10% aq. NaHCO3 (15 ml), and water (15 ml) and dried over Na2SO4. Evaporation of the solvent gave 1-methyl-2,4,5-trinitroimidazole as white solid, 110 mg (21%). 1H NMR (400 MHz, acetone-d6) δ 4.37. 13C NMR (100 MHz, acetone-d6) δ 139.9, 136.1, 133.4, 37.7.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][C:26]=1[Cl:27])[N:23]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:22]=[C:21]2[NH:36][C:37](=[O:41])[CH2:38][CH2:39][CH3:40]>O.O1CCOCC1.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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][C:26]=2[Cl:27])[N:23]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:34])([CH3:35])[CH3:33])[N:22]=[C:21]3[NH:36][C:37](=[O:41])[CH2:38][CH2:39][CH3:40])=[CH:4][CH:3]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(Br)cc12
Reactant: OB(O)c1ccc(F)cc1
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: O
Solvent: C1COCCO1
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(-c3ccc(F)cc3)cc12

Procedure:
470 mg of 4-fluorophenylboronic acid, 593 mg of sodium carbonate in 40 cm3 of water and 155 mg of tetrakis(triphenylphosphine)palladium are added to 1 g of N-[5-bromo-6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described in Example 58, in 40 cm3 of dioxane. The mixture is refluxed for 18 hours and the reaction medium is filtered through a sinter funnel packed with Celite. 60 cm3 of ethyl acetate and 50 cm3 of distilled water are added to the filtrate. The organic phase is washed with 2×20 cm3 of saturated aqueous sodium chloride solution and then separated out after settling of the phases has taken place and dried over magnesium sulphate. After filtration, the filtrate is concentrated to dryness under reduced pressure (2 kPa; 50° C.) and the residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 4.5 cm), eluting with a cyclohexane/ethyl acetate mixture (90/10 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). After drying (90 Pa; 45° C.), 0.75 g of N-[5-(4-fluorophenyl)-6-chloro-1-[(2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide is thus obtained in the form of a yellow wax.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:11]3[N:16]=[C:15]([N:17]4[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:18]4)[CH:14]=[N:13][CH:12]=3)[C:4]=2[CH:3]=1.[CH2:31]([N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1)[CH3:32].C([O-])(=O)C.[K+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.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].ClCCl>[CH2:31]([N:33]1[CH:37]=[C:36]([C:2]2[N:7]=[CH:6][C:5]3[CH:8]=[N:9][N:10]([C:11]4[N:16]=[C:15]([N:17]5[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:18]5)[CH:14]=[N:13][CH:12]=4)[C:4]=3[CH:3]=2)[CH:35]=[N:34]1)[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cncc(-n3ncc4cnc(Cl)cc43)n2)CC1
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CC#N
Product: CCn1cc(-c2cc3c(cn2)cnn3-c2cncc(N3CCCN(C(=O)OC(C)(C)C)CC3)n2)cn1
Temperature: 150 °C
Yield: 102.7 %

Procedure:
A mixture of tert-butyl 4-[6-(6-chloropyrazolo[4,3-c]pyridin-1-yl)pyrazin-2-yl]-1,4-diazepane-1-carboxylate (0.2526 mmol; 108.6 mg), 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (0.3789 mmol; 84.16 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.02526 mmol; 21.1 mg), potassium acetate (0.3789 mmol; 0.38 mL) and sodium carbonate (0.3789 mmol; 0.38 mL) in Acetonitrile (10 mL) in a pressure tube was heated under microwave at 150° C. for 15 min. The mixture was cooled to room temperature. The layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were concentrated. The residue was purified on silica eluted with 0 to 5% MeOH in DCM with 1% NH4OH to afford tert-butyl 4-[6-[6-(1-ethylpyrazol-4-yl)pyrazolo[4,3-c]pyridin-1-yl]pyrazin-2-yl]-1,4-diazepane-1-carboxylate (127 mg, ˜100%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][NH:16][C:15](=[O:19])[CH2:14]1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH:29]=O)=[N:21]1.N1CCCCC1>CO>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](/[CH:29]=[C:7]2\[O:8][C:4]3[C:3]([CH2:12][N:13]4[CH2:18][CH2:17][NH:16][C:15](=[O:19])[CH2:14]4)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[N:21]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: O=C1CN(Cc2c(O)ccc3c2OCC3=O)CCN1
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1CN(Cc2c(O)ccc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)CCN1
Temperature: 60 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
A solution of 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazin-2-one (0.131 g, 0.500 mmol) in methanol (2 mL) was added with indazole-3-carbaldehyde (0.0731 g, 0.500 mmol), and piperidine (0.00426 g, 0.0500 mmol) at room temperature, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, then added with methanol (6 mL), suspended in methanol and thereby washed, and the solid was collected by filtration to obtain (Z)-4-({2-[(1H-indazol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazin-2-one (0.122 g, 62%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][CH2:24][C@@:11]2([O:15][C:14](=[O:16])[N:13]([C:17]3[CH:18]=[N:19][C:20]([NH2:23])=[CH:21][CH:22]=3)[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][N:28]([CH3:46])[C:29]([C:31]1[N:40]([CH:41]2[CH2:45][CH2:44][CH2:43][CH2:42]2)[C:34]2[N:35]=[C:36](Cl)[N:37]=[CH:38][C:33]=2[CH:32]=1)=[O:30]>>[C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][CH2:24][C@@:11]2([O:15][C:14](=[O:16])[N:13]([C:17]3[CH:18]=[N:19][C:20]([NH:23][C:36]4[N:37]=[CH:38][C:33]5[CH:32]=[C:31]([C:29](=[O:30])[N:28]([CH3:27])[CH3:46])[N:40]([CH:41]6[CH2:45][CH2:44][CH2:43][CH2:42]6)[C:34]=5[N:35]=4)=[CH:21][CH:22]=3)[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@]2(CC1)CN(c1ccc(N)nc1)C(=O)O2
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C[C@]5(CCCN(C(=O)OC(C)(C)C)CC5)OC4=O)cn3)nc2n1C1CCCC1
Yield: 66 %

Procedure:
Following general N—C coupling procedure 1, (R)-3-(6-Amino-pyridin-3-yl)-2-oxo-1-oxa-3,8-diaza-spiro[4.6]undecane-8-carboxylic acid tert-butyl ester was combined with 2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide which gave (R)-3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2-oxo-1-oxa-3,8-diaza-spiro[4.6]undecane-8-carboxylic acid tert-butyl ester as a white solid (0.175 g, 0.272 mmol) in 66% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42 (s, 9H) 1.61-1.78 (m, 3H) 1.79-1.96 (m, 3H) 1.96-2.14 (m, 7H) 2.38-2.48 (m, 2H) 3.06 (d, J=10.54 Hz, 6H) 3.20-3.33 (m, 2H) 3.36-3.63 (m, 2H) 3.82-3.97 (m, 2H) 4.75 (quin, J=8.78 Hz, 1H) 6.63 (5, 1H) 7.98 (d, J=9.03 Hz, 1H) 8.34 (d, J=9.54 Hz, 1H) 8.44 (s, 1H) 8.81 (s, 1H) 9.78 (s, 1H). MS m/z 619.5 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([F:12])[CH:5]=1)[CH:2]=C.N1C=CC=CC=1.[O:19]=[O+][O-]>C(Cl)Cl.CO>[F:12][C:6]1[CH:5]=[C:4]([CH2:1][CH:2]=[O:19])[CH:11]=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: O=[O+][O-]
Reactant: C=CCc1ccc(C#N)c(F)c1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: N#Cc1ccc(CC=O)cc1F
Temperature: -78 °C
Reaction time: 8 h

Procedure:
A solution of 4-allyl-2-fluorobenzonitrile (1 g, 6.2 mmol) in 1:1 CH2Cl2/MeOH (40 mL) containing pyridine (1 mL, 12.4 mmol) was cooled to −78° C., and O3 was passed through until a blue color was present. N2 was then bubbled through to discharge the blue color and Me2S (5 ml) was added. The reaction mixture was allowed to warm and left overnight. The mixture was washed with 1 N HCl and aqueous NaHCO3 and then dried and concentrated to give crude 2-fluoro-4-(2-oxoethyl)benzonitrile. The material was carried on as the crude.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:28][C:29]([NH:31][C@@H:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C@H:35]([O:42][C:43]3[CH:44]=[CH:45][C:46]4[N:47]([C:49]([N:52]5[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]5)=[N:50][N:51]=4)[CH:48]=3)[CH2:34][CH2:33]2)=[O:30])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH2:18][CH2:19][CH2:20][O:21]C3CCCCO3)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:58][S:59](Cl)(=[O:61])=[O:60].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:28][C:29]([NH:31][C@@H:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C@H:35]([O:42][C:43]3[CH:44]=[CH:45][C:46]4[N:47]([C:49]([N:52]5[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]5)=[N:50][N:51]=4)[CH:48]=3)[CH2:34][CH2:33]2)=[O:30])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([CH:11]=2)[O:17][CH2:18][CH2:19][CH2:20][O:21][S:59]([CH3:58])(=[O:61])=[O:60])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2ccc(Cl)c(OCCCOC3CCCCO3)c2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2ccc(Cl)c(OCCCOS(C)(=O)=O)c2)n1
Yield: 100.2 %

Procedure:
A mixture of Example 75 (193 mg, 0.27 mmol), methanesulfonyl chloride (63 μL, 0.81 mmol) and DIPEA (200 μL, 1.08 mmol) in DCM (10 mL) was stirred at RT for 1 h. The volatiles were evaporated under reduced pressure to afford the title compound (214 mg, Quantitative). LCMS (Method 4): Rt 3.57 min, m/z 791 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]2[C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][C:9]=1[NH:10]2.C1C(=O)N([Cl:30])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[C:14]([Cl:30])=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]2[C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][C:9]=1[NH:10]2
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Cl)c(Br)c12
Yield: 65 %

Procedure:
A mixture of ethyl 5-bromo-8-carbamoyl-9H-carbazole-2-carboxylate [synthesized according to the procedure described in U.S. Pat. No. 8,084,620, Intermediate 48-1] (0.100 g, 0.277 mmol) and NCS (recrystallized from toluene; 0.037 g, 0.277 mmol) in CCl4 (10 mL) and DMF (2 mL) was stirred at room temperature for 112 h. The mixture was filtered, and the collected precipitate was washed with CCl4 and dried overnight under vacuum. The residue was purified by column chromatography on silica gel (40 g), eluting with hexanes, then with EtOAc-hexanes (30%, then 50%), to give ethyl 5-bromo-8-carbamoyl-6-chloro-9H-carbazole-2-carboxylate as a fluffy white solid (0.071 g, 65% yield). Mass spectrum m/z 395, 397, (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 12.13 (s, 1H), 8.77 (d, J=8.6 Hz, 1H), 8.53 (d, J=1.1 Hz, 1H), 8.36 (br. s., 1H), 8.29 (s, 1H), 7.89 (dd, J=8.4, 1.5 Hz, 1H), 7.74 (br. s., 1H), 4.38 (q, J=7.0 Hz, 2H), 1.38 (t, J=7.0 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]([NH:16][CH2:17][CH2:18][C:19]([O:21]CC1C=CC=CC=1)=[O:20])/[C:3](/[CH2:11][S:12]C(=O)C)=[CH:4]\[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Li+].[OH-]>C1COCC1.O>[O:1]=[C:2]([NH:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])/[C:3](/[CH2:11][SH:12])=[CH:4]\[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)SC/C(=C/c1ccccc1)C(=O)NCCC(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCNC(=O)/C(=C\c1ccccc1)CS
Yield: 63 %

Procedure:
To a solution of 2 mmol of the diester obtained in Example 1 (step D) dissolved in a THF/H2O (75/25) mixture, are added, at 0° C. and under an argon atmosphere, 8 mmol of LiOH with stirring for 2 hours. The THF is evaporated off and the aqueous phase is washed with ether and acidified with aqueous 3N HCl solution. It is extracted with ether and the ether extract is washed with saturated aqueous NaCl solution and dried over MgSO4. It is filtered and evaporated. Yield: 63% (after flash chromatography, eluent: ether) m.p. 80° C. IR (nujol): 3340, 1700, 1630, 1610 cm-1. 1H NMR (acetone D6): 10.90 to 10.60 (m, 1H); 7.65 (m, 1H); 7.45 to 7.35 (m, 5H); 7.20 (s, 1H); 3.75 to 3.50 (m, 4H); 2.60 (t, 2H, J=6.75 Hz); 2.30 (t, 1H, J=7.50 Hz) Microanalysis: C13H15O3NS Calc. % C=58.85 H=5.70 N=5.28 Found. % C=58.68 H=5.78 N=5.17