Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=O)[CH3:11])=[CH:5][CH:4]=1.[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:19]([O:18][C:16](=[O:17])[C:15]([C:13]#[N:14])=[C:10]([CH3:11])[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH3:20]
Reactant: CCOC(=O)CC#N
Reactant: COc1ccc(CC(C)=O)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=C(C)Cc1ccc(OC)cc1
Temperature: 25 °C
Yield: 64.5 %

Procedure:
In a flask equipped with a Dean-stark trap was prepared a solution of 1-(4-Methoxy-phenyl)-propan-2-one (40 g), ethyl cyanoacetate (27.56 g), ammonium acetate (9.40 g), acetic acid (14.64 g) and toluene (150 ml) at room temperature. The solution was heated to reflux overnight. The solution was cooled to room temperature, washed with water and brine, and concentrated. The crude product was purified on a silica gel column, eluting with 10% ethyl acetate/hexane to afford colorless oil (40.76 g). The 1H NMR was consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5]1[N:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[N:6]=1.[F:17][C:18]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[CH:20][C:19]=1[C:33]1[CH:34]=[N:35][C:36]([NH2:39])=[N:37][CH:38]=1>>[CH3:12][C:7]1[CH:8]=[C:9]([CH3:11])[N:10]=[C:5]([O:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[C:22]2[CH:21]=[CH:20][C:19]([C:33]3[CH:38]=[N:37][C:36]([NH2:39])=[N:35][CH:34]=3)=[C:18]([F:17])[CH:23]=2)[N:6]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: Cc1cc(C)nc(Oc2ccccc2Br)n1
Product: Cc1cc(C)nc(Oc2ccccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)n1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 2-(2-bromophenoxy)-4,6-dimethylpyrimidine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C22H18FN5O, 387.15; m/z found, 388.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 2H), 7.52-7.46 (m, 2H), 7.44-7.39 (m, 1H), 7.35-7.25 (m, 3H), 7.18 (d, J=8.0, 1H), 6.90 (s, 1H), 6.85 (s, 2H), 2.24 (s, 6H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]1[C:29]2[C:24](=[C:25]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[CH3:36])[N:26]=[CH:27][CH:28]=2)[NH:23][C:22](=[O:37])[CH:21]=1>ClCCl>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]1[C:29]2[C:24](=[C:25]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[CH3:36])[N+:26]([O-:9])=[CH:27][CH:28]=2)[NH:23][C:22](=[O:37])[CH:21]=1
Reactant: Cc1ccccc1-c1nccc2c(-c3ccc(F)cc3F)cc(=O)[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccccc1-c1c2[nH]c(=O)cc(-c3ccc(F)cc3F)c2cc[n+]1[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
Meta-chloroperbenzoic acid (77%) (1.37 g, 6.12 mmol) was added portionwise to a solution of the title compound from Example 5 (1.40 g, 4.02 mmol) in dichloromethane (22 mL) at 0° C. and the reaction mixture was stirred overnight at room temperature. Then, more dichloromethane was added (100 mL) and the solution was washed with 4% aqueous sodium bicarbonate (4×30 ml) and brine. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to yield the title compound (1.40 g, 96%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](SC)=[N:7][C:6]=2[CH:18]=1.C(OC([NH:26][CH:27]1[CH2:31][CH2:30][NH:29][CH2:28]1)=O)(C)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([N:29]3[CH2:30][CH2:31][CH:27]([NH2:26])[CH2:28]3)=[N:7][C:6]=2[CH:18]=1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: CSC1=Nc2cc(Cl)ccc2Nc2ccccc21
Product: NC1CCN(C2=Nc3cc(Cl)ccc3Nc3ccccc32)C1
Yield: 11.8 %

Procedure:
8-Chloro-11-methylsulfanyl-5H-dibenzo[b,e][1,4]diazepine (166JO50) (100 mg, 0.22 mmol) and 3-(tert-butoxycarbonylamino)pyrrolidine (73 mg, 0.4 mmol) were reacted according to GP8 to give 8.1 mg of the title compound (166JO64). MS (ESI) 313 (MH+). Purity for MH+ (UV/MS) 100/94.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[CH:16][CH2:17][OH:18])[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:22][CH:23]1[CH2:25][CH2:24]1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[CH:16][CH2:17][O:18][CH2:22][CH:23]1[CH2:25][CH2:24]1)[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=CCO)C2
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C2CCC1CC(=CCOCC1CC1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.9 %

Procedure:
A reaction flask was charged with 3-(2-hydroxyethylidene)-8-azabicyclo[3.2.1]octane-8-carboxylic acid t-butyl ester (0.380 g, 1.5 mmol) in dry DMF (2 mL) under Argon. NaH (60% in oil, 0.060 g, 1.5 mmol) was added in portions and the mixture was stirred at 50° for 1 h. The mixture was cooled to rt and bromomethylcyclopropane (0.202 g, 1.5 mmol) was added followed by stirring at rt for 20 h under Argon. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography (SiO2; n-heptane/EtOAc 1:1) to give the title compound (0.115 g, 25%). 1H NMR (CDCl3) d 5.38-5.32 (m, 1H), 4.36-3.96 (m, 2H), 3.88-3.75 (m, 2H), 3.09 (d, 2H), 2.48-1.66 (m, 6H), 1.48-1.36 (m, 2H), 1.30 (s, 9H), 0.94-0.33 (m, 1H), 0.40-0.33 (m, 2H), 0.05-0.00 (m, 2)
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39]O)=[CH:33][CH:32]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[N:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])=[CH:33][CH:32]=1
Reactant: OCCCc1ccncc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCCc1ccncc1
Temperature: 25 °C

Procedure:
Cool a mixture of phthalimide (5.4 g, 37 mmol) and PPh3 (9.6 g, 37 mmol) in tetrahydrofuran (80 mL) to 0° C. Add dropwise a solution of 4-pyridine propanol (5.0 g, 37 mmol) and diethyl azodicarboxylate (5.8 mL, 37 mmol) in tetrahydrofuran (55 mL). After 2 hours warming to room temperature, concentrate the reaction mixture to a brown paste and perform flash-chromatography on silica gel eluting with 20% of a 80:18:2 CHCl3/MeOH/concentrated NH4OH) solution in methylene chloride to afford 2-(3-pyridin-4-yl-propyl)isoindole-1,3-dione as a yellow solid. TLC (SiO2): Rf=0.68 [20% of a 80:18:2 CHCl3/MeOH/concentrated NH4OH solution in methylene chloride].
Reaction SMILES: CS([O:5][CH2:6][CH2:7][N:8]([S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28])(=[O:20])=[O:19])[CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])(=O)=O.C([O-])([O-])=O.[K+].[K+].O[C:37]1[CH:42]=[C:41]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[N:40]=[C:39]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH:38]=1>CN(C=O)C>[C:14]([O:13][C:11]([CH2:10][CH2:9][N:8]([S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28])(=[O:20])=[O:19])[CH2:7][CH2:6][O:5][C:37]1[CH:38]=[C:39]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[N:40]=[C:41]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:42]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCOC(=O)c1cc(O)cc(C(=O)OCC)n1
Reactant: CC(C)(C)OC(=O)CCN(CCOS(C)(=O)=O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCCN(CCC(=O)OC(C)(C)C)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc(C(=O)OCC)n1
Temperature: 60 °C
Yield: 47 %

Procedure:
To a solution of 10.6 g of tert-butyl 3-[(2-methanesulfonyloxy-ethyl)-(2-nitro-benzenesulfonyl)-amino]-propionate in 220 ml of DMF was added 16.2 g of K2CO3 and 5.6 g of diethyl 4-hydroxy-pyridine-2,6-dicarboxylate. The mixture was heated for 20 hours at 60° C. and then concentrated under reduced pressure and taken up in 200 ml of water and 200 ml of EtOAc. The aqueous phase was extracted 2× with EtOAc. The organic phases were combined, washed with saturated NaCl solution, dried over MgSO4, concentrated under reduced pressure and purified by flash chromatography on silica (Merck EasyVarioPrep 600 g column, Si60 15-40 μm), using a gradient of 0 to 20% EtOAc in DCM. The fractions containing the desired product were combined and concentrated under reduced pressure. 6.56 g of diethyl 4-{2-[(2-tert-butoxycarbonyl-ethyl)-(2-nitro-benzenesulfonyl)-amino]-ethoxy}-pyridine-2,6-dicarboxylate were obtained. LC/MS (C): tr=4.14 min; [M+H]+: m/z 596.
Reaction SMILES: C([O:9][C@H:10]1[C@@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][C@@H:11]1[N:34]1[N:38]=[C:37]([C:39]([O:41]C)=O)[C:36]([C:43]([O:45]C)=O)=[N:35]1)(=O)C1C=CC=CC=1.[NH3:47].CO.[NH3:50]>>[C@H:11]1([N:34]2[N:35]=[C:36]([C:43]([NH2:47])=[O:45])[C:37]([C:39]([NH2:50])=[O:41])=[N:38]2)[O:12][C@@H:13]([CH2:24][OH:25])[C@H:14]([OH:15])[C@@H:10]1[OH:9]
Reactant: COC(=O)c1nn([C@H]2O[C@@H](COC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)nc1C(=O)OC
Reactant: N
Solvent: CO
Product: NC(=O)c1nn([C@H]2O[C@@H](CO)[C@H](O)[C@@H]2O)nc1C(N)=O
Temperature: 95 °C
Yield: 89 %

Procedure:
Compound 31 (6.0 g, 9.5 mmol) was dissolved in MeOH/NH3 (dry MeOH sat. with anhydrous NH3 at 0° C., 60 mL) were placed in a steel reaction vessel. The vessel was heated at 95° C. for 16 h. The reaction vessel was cooled, opened carefully and the NH3 was allowed to evaporate at room temperature. The MeOH was evaporated to dryness and the residue was triturated with hot toluene (3×50 mL) and filtered. The brown residue was crystallized from aqueous EtOh (95) to furnish 2.40 g (89%) of 32: mp 210-212° C.; 1H NMR (Me2SO-d6) δ3.45-3.59 (m, 2H, C5′H), 3.98 (m, 1H, C4′H), 4.25 (m, 1H, C3′H), 4.54 (m, 1H, C2′H), 4.78 (t, 1H, C5′OH, D2O exchangeable), 5.27 and 5.67 (2d, 2H, C2′3′OH, D2O exchangeable), 5.89 (d, 1H, J1′,2′=3.85 Hz, C1′H), 8.05 and 9.05 (2br s, 4H, 2 CONH2). Anal. Calc. for C9H13N5O6 (287.23): C, 37.63; H, 4.56; N, 24.38. Found: C, 37.52; H, 4.19; N, 24.59.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([OH:16])=O)=[CH:8]2)=[O:4].[OH-].[NH4+:18]>O1CCCC1>[C:14]([C:9]1[NH:10][C:11]2[C:7]([CH:8]=1)=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:13][CH:12]=2)(=[O:16])[NH2:18]
Reactant: COC(=O)c1ccc2[nH]c(C(=O)O)cc2c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2[nH]c(C(N)=O)cc2c1
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 5-(methoxycarbonyl)-1H-indole-2-carboxylic acid (2.50 g, 11.4 mmol) in tetrahydrofuran (20 mL) was added 1,1-carbonyldiimidazole (3.70 g, 22.8 mmol). The yellow suspension was stirred for 2 hours. Then concentrated ammonium hydroxide (20 mL) was added and the mixture was stirred at room temperature for 5 hours. The pale green suspension was filtered, washed with water and 5 mL of methanol, and air dried to give methyl 2-carbamoyl-1H-indole-5-carboxylate (2.04 g, 82%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6, δ): 11.93 (br. s., 1 H), 8.32 (d, J=1.2 Hz, 1 H), 8.06 (br. s., 1 H), 7.79 (dd, J=8.6, 1.6 Hz, 1 H), 7.48 (d, J=8.6 Hz, 1 H), 7.45 (br. s., 1 H), 7.27 (s, 1 H), 3.32 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:15])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:16][N:17]1[C:21](=[O:22])[CH2:20][CH:19]([C:23](O)=[O:24])[C:18]1([CH3:27])[CH3:26]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:23]([CH:19]3[CH2:20][C:21](=[O:22])[N:17]([CH3:16])[C:18]3([CH3:27])[CH3:26])=[O:24])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: Nc1cc(Cl)cc2c1[nH]c1cnccc12
Reactant: CN1C(=O)CC(C(=O)O)C1(C)C
Product: CN1C(=O)CC(C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)C1(C)C
Yield: 68 %

Procedure:
The desired compound was prepared according to Method B from 6-chloro-9H-β-carboline-8-ylamine and 1,2,2-trimethyl-5-oxo-pyrrolidine-3-carboxylic acid in 68% yield.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]2[C:10]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:9][CH:8]=[C:7]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]4)=[N:21][CH:22]=3)[N:6]2[CH:36]=1.[H-].[Na+].Cl[C:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[N:41]=1>CN(C=O)C>[N:41]1[C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:48]=[CH:49][C:40]=1[O:1][CH2:2][C:3]1[N:4]=[C:5]2[C:10]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:9][CH:8]=[C:7]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:27][CH2:28]4)=[N:21][CH:22]=3)[N:6]2[CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(C4CCOCC4)c4nc(CO)cn34)cn2)CC1
Reactant: Clc1ccc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(C4CCOCC4)c4nc(COc5ccc6ccccc6n5)cn34)cn2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 69.7 %

Procedure:
Into a 10 mL round-bottom flask was placed a solution of compound 90j (150 mg, 0.300 mmol) in DMF (2 mL), followed by the addition of sodium hydride (30.0 mg, 1.25 mmol) at 0° C. The mixture was stirred for 15 min at 0° C., and 2-chloroquinoline (74.2 mg, 0.460 mmol) was added. The reaction mixture was stirred overnight at 70° C. Upon cooling, the reaction was quenched with water. The resulting mixture was extracted with DCM (3×10 mL). The combined organic layers were concentrated under reduced pressure. The resultant residue was purified by flash column chromatography on silica gel (EtOAc/petroleum ether (1:3 v/v)) to obtain compound 91a as a light yellow solid (130 mg, 69% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C35H39N7O4: 622.3 (M+H). found: 622.2.
Reaction SMILES: [NH2:1][C:2](=[O:36])[C@@H:3]([NH:20][C:21]([C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=1.Br[C:38]1[CH:50]=[CH:49][C:41]2[N:42]([CH2:46][CH2:47][OH:48])[C:43](=[O:45])[S:44][C:40]=2[CH:39]=1>>[NH2:1][C:2](=[O:36])[C@@H:3]([NH:20][C:21]([C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:38]2[CH:50]=[CH:49][C:41]3[N:42]([CH2:46][CH2:47][OH:48])[C:43](=[O:45])[S:44][C:40]=3[CH:39]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@@H](Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(N)=O
Reactant: O=c1sc2cc(Br)ccc2n1CCO
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc3c(c2)sc(=O)n3CCO)cc1)C(N)=O

Procedure:
The subtitle compound was prepared by the method of Example 96 step (a) using (S)-tert-butyl 2-((S)-1-amino-1-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamoyl)piperidine-1-carboxylate and 6-bromo-3-(2-hydroxyethyl)benzo[d]thiazol-2(3H)-one.
Reaction SMILES: [H-].[Na+].[C:3]([C:11]1[CH:15]=[C:14]([CH3:16])[N:13]([CH:17]([CH3:20])[CH2:18][OH:19])[C:12]=1[CH3:21])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:22]I>C(COC)OC>[CH3:22][O:19][CH2:18][CH:17]([N:13]1[C:14]([CH3:16])=[CH:15][C:11]([C:3](=[O:10])[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[C:12]1[CH3:21])[CH3:20]
Reactant: Cc1cc(C(=O)c2ccccc2)c(C)n1C(C)CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COCC(C)n1c(C)cc(C(=O)c2ccccc2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
Sodium hydride (50% content, 115 mg, 2.3 mmoles) was washed with 20 ml of petroleum ether twice, and 15 ml of dimethoxyethane was added. To the mixture was added 300 mg (1.17 mmoles) of 2-(3-benzoyl-2,5-dimethylpyrrol-1-yl)-2-methylethanol, and the mixture was stirred at room temperature for 2 hours. Then, 5 ml of methyl iodide was added, and the mixture was further stirred at room temperature for 5 hours. After the reaction, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated to afford 270 mg of a crude product. The product was chromatographed on a column of silica gel using cyclohexane/ethyl acetate (4/1) as an eluent to afford compound (206) (220 mg, 0.81 mmole, 69.4%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([C:30]([NH2:32])=[O:31])[C:14]3[NH:15][C:16]4[C:21]([C:22]=3[CH:23]=2)=[CH:20][CH:19]=[C:18]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:17]=4)=[CH:7][C:6]=1[Cl:33].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:33][C:6]1[CH:7]=[C:8]([C:11]2[CH:12]=[C:13]([C:30]([NH2:32])=[O:31])[C:14]3[NH:15][C:16]4[C:21]([C:22]=3[CH:23]=2)=[CH:20][CH:19]=[C:18]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:17]=4)[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1
Reactant: C1COCCN1
Reactant: NC(=O)c1cc(-c2ccc(OCCBr)c(Cl)c2)cc2c1[nH]c1cc(N3CCOCC3)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccc(OCCN3CCOCC3)c(Cl)c2)cc2c1[nH]c1cc(N3CCOCC3)ccc12
Temperature: 75 °C
Yield: 86.8 %

Procedure:
3-(4-(2-Bromoethoxy)-3-chlorophenyl)-7-morpholino-9H-carbazole-1-carboxamide (110 mg, 0.146 mmol, Example 407A) was dissolved in DMF (5 ml). Morpholine (0.045 ml, 0.517 mmol) and K2CO3 (66 mg, 0.478 mmol) were added and the mixture heated to 75° C. for 1 hour. Additional morpholine (0.10 ml, 1.148 mmol) was added and the mixture heated for one additional hour. The mixture was concentrated to a volume of ˜1 ml, then diluted with 3 ml DMSO+3 ml MeOH, filtered through a 0.45 um Nylon filter and purified by prep HPLC. Product containing fractions were evaporated to dryness to give 67.8 mg 3-(3-chloro-4-(2-morpholinoethoxy)phenyl)-7-morpholino-9H-carbazole-1-carboxamide. MS (ESI) m/e+=535/537, m/e−=533/535 [1 Cl isotope pattern]. HPLC retention time 15.81 min. (Sunfire C18 3.5 μm, 3.0×150 mm column, 15 min gradient, 10-100% B, 0.5 mL/min. Solvent A: 5% CH3CN—95% H2O—0.1% TFA; Solvent B: 95% CH3CN—5% H2O—0.1% TFA), then isocratic at 100% B. 1H NMR (DMSO-d6) δ ppm 11.13 (s, 1H), 8.49 (d, 1H, J=1.5), 8.34 (b, 1H), 8.14 (d, 1H, J=1.5), 8.07 (d, 1H, J=8.5), 7.99 (d, 1H, J=2.3), 7.82 (dd, 1H, J=8.6, 2.4), 7.51 (b, 1H), 7.31 (d, 1H, J=8.8), 7.24 (d, 1H, J=2.0), 6.94 (dd, 1H, J=8.8, 2.0), 4.26 (t, 2H, J=5.8), 3.83-3.79 (m, 4H), 3.64-3.59 (m, 4H), 3.22-3.17 (m, 4H), 2.79 (t, 2H, J=5.8), 2.58-2.54 (m, 4H).
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]3)[CH2:13][CH2:12]2)[C:8]2[CH:26]=[CH:27][O:28][C:7]=2[CH:6]=1.[O:29]1[CH2:34][CH2:33][CH:32]([CH2:35][C:36](O)=[O:37])[CH2:31][CH2:30]1>>[CH3:4][C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:20][CH2:21][C@H:22]([NH:25][C:36](=[O:37])[CH2:35][CH:32]4[CH2:33][CH2:34][O:29][CH2:30][CH2:31]4)[CH2:23][CH2:24]3)[CH2:15][CH2:16]2)[C:8]2[CH:26]=[CH:27][O:28][C:7]=2[CH:6]=1
Reactant: O=C(O)CC1CCOCC1
Reactant: Cc1cc2occc2c(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)n1
Agent: Cl
Product: Cc1cc2occc2c(N2CCN(CC[C@H]3CC[C@H](NC(=O)CC4CCOCC4)CC3)CC2)n1

Procedure:
The title compound, off-white solid (131 mg, 93%), MS (ISP) m/z=469.5 [(M+H)+], mp 212.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(6-methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate D) (136 mg, 0.3 mmol) and tetrahydropyran-4-yl-acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:21][C:22]([O:24]C)=[O:23])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1)=[O:10].[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:21][C:22]([OH:24])=[O:23])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1)=[O:10]
Reactant: COC(=O)Cc1ccc(NC(=O)c2nccc3ccccc23)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(NC(=O)c2nccc3ccccc23)c(Cl)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 97.8 %

Procedure:
Methyl (3-chloro-4-((1-isoquinolinylcarbonyl)amino)phenyl)acetate (1.14 g, 3.21 mmol) was dissolved in THF (33 ml). To the resulting solution was added 0.25N NaOH (19.3 ml, 4.82 mmol), and the mixture was stirred at room temperature for 14 hours. The reaction mixture was poured into 1N HCl (5.0 ml). The crystals thus precipitated were collected by filtration under reduced pressure, washed with water, and dried under reduced pressure to give (3-chloro-4-((1-isoquinolinylcarbonyl)amino)phenyl)acetic acid (1.07 g, 98%) as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]3[N:16]=[C:17]([CH2:20][O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18](I)=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[B:28](OC)([O:31]C)[O:29]C>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]3[N:16]=[C:17]([CH2:20][O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]([B:28]([OH:31])[OH:29])=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: COB(OC)OC
Reactant: O=C(c1ccc(F)cc1)N1CCn2nc(COc3ccccc3)c(I)c2C1
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1)N1CCn2nc(COc3ccccc3)c(B(O)O)c2C1
Temperature: -78 °C
Reaction time: 0.02 h
Yield: 126.5 %

Procedure:
A 1.3M solution of isopropylmagnesium chloride lithium chloride complex solution (39 mL, 0.5 mmol) was added to a stirred solution of (4-fluoro-phenyl)-(3-iodo-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone (0.2 g, 0.42 mmol) in THF (4 mL) at −78° C. and under N2. The mixture was stirred at −78° C. for 1 minute and then trimethyl borate (0.093 mL, 0.84 mmol) was added. The mixture was stirred−78° C. for 30 minutes and at room temperature for 1 hour. The mixture was diluted with water and extracted with AcOEt. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo to yield {5-[(4-fluorophenyl)carbonyl]-2-(phenoxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl}boronic acid (0.21 g, 56% yield) as a yellow oil that was used in the next step without further purification.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.[CH:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:7]([N:4]1[CH2:5][CH2:6][C@H:2]([OH:1])[CH2:3]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccccc1
Reactant: O[C@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O[C@H]1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.2 %

Procedure:
A solution of (3S)-3-hydroxypyrrolidine (2.0 g, 25 mmol) in 50 mL CH2Cl2, under a nitrogen atmosphere, was cooled to 0° C. and benzaldehyde (2.92 g. 27.5 mmol) was added, followed by 1 g of powdered 4A molecular sieves. Sodium triacetoxyborohydride (7.4 gm, 35 mmol)was added in several portions over 30 min, and the reaction was allowed to stir at room temperature for 18 h. The reaction was again cooled to 0° C. and quenched by addition of 10 mL methanol, followed by 5 mL of 1N HCl. The molecular sieve solids were removed by filtration through a glass fiber paper, and the filtrate was extracted with 20 mL diethyl ether. The organic phase was discarded, and the aqueous phase was first basified by addition of conc. ammonium hydroxide, and then extracted with EtOAc (3×20 mL). The combined extracts were washed with 20 mL brine, dried (MgSO4), filtered, and concentrated in vacuo to furnish 3.2 g (73%) of clear yellow oil, which required no further purification. 1H-NMR (400 MHz, CDCl3) δ 7.2-7.4 (m, 5H), 4.33 (m, 1H), 3.63, (s, 2H), 2.83-3.89 (m, 1H), 2.67 (d, J=9.9 Hz, 1H), 2.53-2.55 (m, 1H), 2.23-2.34 (m, 1H), 2.14-2.20 (m, 2H), 1.70-1.77 (m, 1H).