Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[Br:32][C:33]1[CH:34]=[C:35]([CH:49]=[C:50]([CH3:52])[CH:51]=1)[C:36]([C:38]1[NH:43][C:42](=[O:44])[NH:41][C:40](=[O:45])[C:39]=1[CH:46]([CH3:48])[CH3:47])=[O:37].C(=O)([O-])[O-].[K+].[K+].[I-].[Li+]>C(Cl)(Cl)Cl.CN(C=O)C>[Br:32][C:33]1[CH:34]=[C:35]([CH:49]=[C:50]([CH3:52])[CH:51]=1)[C:36]([C:38]1[N:43]([CH2:8][C:6]2[CH:5]=[C:4]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[N:3]=[C:2]([Cl:1])[CH:7]=2)[C:42](=[O:44])[NH:41][C:40](=[O:45])[C:39]=1[CH:46]([CH3:47])[CH3:48])=[O:37]
Reactant: COc1ccc(CNc2cc(CO)cc(Cl)n2)cc1
Reactant: Cc1cc(Br)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2cc(Cn3c(C(=O)c4cc(C)cc(Br)c4)c(C(C)C)c(=O)[nH]c3=O)cc(Cl)n2)cc1
Yield: 44.9 %

Procedure:
[2-Chloro-6-(4-methoxy-benzylamino)-pyridin-4-yl]-methanol (278 mg, 1 mmol) was dissolved in chloroform (10 ml) and cooled in an ice bath under nitrogen atmosphere. With stirring, triethylamine (210 μl, 1.5 mmol) was added and methanesulfonyl chloride (90 μl, 1.2 mmol) was added dropwise. After stirring for 1.1 hr., the reaction mixture was washed with saturated aqueous sodium bicarbonate, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was further dried in high vacuo for ca. 20 min. and mixed with 6-(3-Bromo-5-methyl-benzoyl)-5-isopropyl-1 H-pyrimidine-2,4-dione (351 mg, 1 mmol), powdered anhydrous potassium carbonate (138 mg, 1 mmol), and lithium iodide (134 mg, 1 mmol). DMF (5 ml) was then added to the mixture at room temperature and stirred for ca. 4 hr. After evaporation of DMF, the residue was dissolved in methanol-chloroform (1:9) and filtered through celite pad. The filtrate was then evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:2); Rf˜0.2 fraction was collected.) to afford 275 mg (45%) of a white solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:15].S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.O>[Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N+:3]=1[O-:15]
Reactant: Cc1ccc(F)c(Br)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1ccc(F)c(Br)[n+]1[O-]
Temperature: 25 °C
Yield: 55.7 %

Procedure:
To an ice-cold solution of 2-bromo-3-fluoro-6-picoline (1.00 g) in chloroform (25 mL) was added 3-chloroperoxybenzoic acid (1.77 g), and the mixture was stirred while warming to room temperature for 22 hr. After cooling in ice again, additional 3-chloroperoxybenzoic acid (590 mg) was added and the mixture was stirred while warming to room temperature for 21 hr. An aqueous sodium thiosulfate solution was added to the reaction mixture, and the resulting mixture was then stirred. Thereafter, saturated aqueous sodium hydrogen carbonate solution and water were added thereto, followed by extraction with chloroform. The organic phase was washed with brine, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=98:2-0:100) to afford 2-bromo-3-fluoro-6-methylpyridine 1-oxide (604 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)=[O:14]>C(OCC)C>[CH2:21]([CH:18]1[CH2:17][CH2:16][N:15]([C:13](=[O:14])[CH2:12][NH:1][C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[N:7][NH:8]3)=[CH:4][CH:3]=2)[CH2:20][CH2:19]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: O=C(CCl)N1CCC(Cc2ccccc2)CC1
Solvent: CCOCC
Product: O=C(CNc1ccc2cn[nH]c2c1)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from 6-aminoindazol and 2-chloro-1-(4-benzyl-piperidin-1-yl)-ethanone (Example 200a) according to the method described in Example 142b. Melting Point: 179-182° C. (diethylether)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[S:20]([Cl:24])(Cl)(=[O:22])=[O:21].[CH2:25]([O:32][C:33]([NH:35][CH2:36][CH2:37]S([O-])(=O)=O)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[Na+]>C(Cl)Cl.CCOC(C)=O>[Cl:24][S:20]([CH2:37][CH2:36][NH:35][C:33](=[O:34])[O:32][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C(NCCS(=O)(=O)[O-])OCc1ccccc1
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(NCCS(=O)(=O)Cl)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
This compound was prepared using the method of T. S. Widlanski and J. Huang, Tet. Lett. 1992, 33: 2657. A solution of triphenylphosphine (17.6 g, 67.4 mmol) in dry CH2Cl2 (90 mL) was cooled to zero degrees C. under nitrogen and treated with neat sulfuryl chloride (5.96 mL, 74.2 mmol) to give a yellow solution. The solution was recooled to 5 degrees C. and crushed solid sodium 2-{[(benzyloxy)carbonyl]amino}ethanesulfonate (12 g, 42.6 mmol) prepared as described by Bricas et al., Biochimica et Biophysica Acta 1955, (18), 358, was added all at once to give a white suspension. The reaction was allowed to warm to room temperature and stirred for 3 hours. The volatiles were removed in vacuo to give an oily/solid residue that was suspended in EtOAc and added to the top of a silica column (3 inches by 150 mm) packed in EtOAc. The product was eluted with EtOAc and the UV active fractions were combined and evaporated to give the product as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19]C(C)(C)C)=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.[N:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)=[CH:29][CH:28]=1>>[Cl:26][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:24][CH:25]=2)[CH3:12])=[O:9])[C:2]([O:39][C:36]2[CH:35]=[CH:34][C:33]([C:30]3[CH:29]=[CH:28][N:27]=[CH:32][CH:31]=3)=[CH:38][CH:37]=2)=[N:3][CH:4]=1
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: Oc1ccc(-c2ccncc2)cc1
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(-c2ccncc2)cc1)c1ccc(C(=O)O)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from tert-butyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 45) and 4-pyridin-4-ylphenol (J. Med. Chem. 2003, 46, 3709): 1H-NMR (CDCl3) δ 8.68 (2H, d, J=6.0 Hz), 8.57 (1H, d, J=2.6 Hz), 8.16 (1H, d, J=2.6 Hz), 8.10 (1H, d, J=7.9 Hz), 7.96 (2H, d, J=8.2 Hz), 7.73 (2H, d, J=8.7 Hz), 7.52 (2H, d, J=6.0 Hz), 7.41 (2H, d, J=8.2 Hz), 7.29 (2H, d, J=8.7 Hz), 5.38 (1H, m), 1.60 (3H, d, J=7.5 Hz), 1.57 (9H, s).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[N:7]=[C:8]([NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]([CH3:15])=[N:10]2)=[O:4].[C:21]([O:25][C:26]([NH:28][C:29]([CH3:39])([CH3:38])[C:30](=[O:37])[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:27])([CH3:24])([CH3:23])[CH3:22].C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>CN(C=O)C>[C:21]([O:25][C:26]([NH:28][C:29]([CH3:38])([CH3:39])[C:30](=[O:37])[CH:31]([CH2:2][C:3]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[N:7]=[C:8]([NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]([CH3:15])=[N:10]2)=[O:4])[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:27])([CH3:23])([CH3:24])[CH3:22]
Reactant: CCOC(=O)CC(=O)C(C)(C)NC(=O)OC(C)(C)C
Reactant: Cc1nc2cccc(C(=O)CBr)c2nc1NC(C)(C)C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(=O)c1cccc2nc(C)c(NC(C)(C)C)nc12)C(=O)C(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 32 %

Procedure:
To a sealable vial was added 2-bromo-1-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)ethanone (606) (1.0 g, 2.97 mmol), ethyl 4-((tert-butoxycarbonyl)amino)-4-methyl-3-oxopentanoate (466a) (0.98 g, 3.57 mmol), DMF (20 mL), and K2CO3 (1.03 g, 7.44 mmol). The solution was stirred at RT for 2 d. The solution was poured into sat NaHCO3 (200 mL) and extracted with EtOAc (3×100 mL). The combined extracts were washed with H2O (3×100 mL), brine (100 mL), dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (0 to 50% EtOAc/hexanes) afforded the title compound as a yellow solid (0.50 g, 0.95 mmol, 32% yield). m/z (ESI, +ve ion) 529.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.87 (dd, J=8.0, 1.6 Hz, 1H), 7.68 (dd, J=7.4, 1.6 Hz, 1H), 7.64 (br. s, 1H), 7.35 (t, J=7.7 Hz, 1H), 6.09 (br. s, 1H), 4.61 (dd, J=10.3, 2.8 Hz, 1H), 4.15 (dd, J=18.5, 10.5 Hz, 1H), 3.98-4.08 (m, 2H), 3.46 (dd, J=18.5, 3.4 Hz, 1H), 2.55 (s, 3H), 1.52 (s, 9H), 1.29 (s, 3H), 1.28 (s, 3H), 1.24 (s, 9H), 1.12 (t, J=7.0 Hz, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:12][C:11](=[O:13])[N:10]([CH2:14][C@H:15]3[CH2:20][CH2:19][C@H:18]([C:21]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[O:22])[CH2:17][CH2:16]3)[C:9]=2[CH:29]=1.[CH3:30]I>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:12]([CH3:30])[C:11](=[O:13])[N:10]([CH2:14][C@H:15]3[CH2:20][CH2:19][C@H:18]([C:21]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[O:22])[CH2:17][CH2:16]3)[C:9]=2[CH:29]=1
Reactant: COc1ccc2[nH]c(=O)n(C[C@H]3CC[C@H](C(=O)N4CCOCC4)CC3)c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)n(C[C@H]1CC[C@H](C(=O)N3CCOCC3)CC1)c(=O)n2C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
NaH (60% in mineral oil, 12 mg, 0.3 mmol) was added to a solution of 6-Methoxy-1-[trans-4-(morpholine-4-carbonyl)-cyclohexylmethyl]-1,3-dihydro-benzoimidazol-2-one (56 mg, 0.15 mmol) in DMF (1.5 ml). MeI (19 μL, 0.3 mmol) was added and the mixture was stirred at room temperature for six hours. The solvent was evaporated, the crude was dissolved in 2 ml of DCM and the solution was washed with H2O. The organic layer was separated and the solvent was removed under reduced pressure. The crude material was purified by column chromatography with EtAc/MeOH (9/1) as eluent. 45 mg (yield 78%) of the title compound were isolated.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23](C)[CH:22]=3)=[CH:16][C:15]=2F)=[O:12])[N:7]([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36](=O)[CH2:37][O:38][CH3:39])=[CH:31][CH:30]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].B.CSC>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:18][CH:19]=2)=[O:12])[N:7]([C:29]2[CH:30]=[CH:31][C:32]([NH:35][CH2:36][CH2:37][O:38][CH3:39])=[CH:33][CH:34]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCC(=O)Nc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(C)c3)cc2F)cc1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: COCCNc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccncc3)cc2)cc1
Temperature: 25 °C
Yield: 6.8 %

Procedure:
To a solution of N-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]-phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)phenyl]-2-methoxyacetamide (500 mg, 0.97 mmol) in anhydrous THF (20 mL) was added borane-methyl sulfide complex (2.0 M solution in THF, 5 mL, 10 mmol), and the reaction was stirred at reflux for 7 h. The reaction mixture was cooled to room temperature, partitioned between EtOAc (50 mL) and water (50 mL), and the organic layer was washed with brine, dried over Na2SO4, and concentrated at reduced pressure. The residue was purified by MPLC (1:1 hexanes/EtOAc) to give 33 mg (7%) of the desired product. 1H-NMR (DMSO-d6) δ 8.65 (s, 1H), 8.42 (d, J=4.8 Hz, 2H), 8.34 (s, 1H), 7.58 (d, J=6.6 Hz, 2H), 7.21 (d, J=6.6 Hz, 2H), 7.06 (d, J=6.9 Hz, 2H), 6.84 (d, J=4.8 Hz, 2H), 6.73 (d, J=6.9 Hz, 2H), 6.43 (s, 1H), 5.23 (s, 1H), 3.57 (t, J=5.7 Hz, 2H), 3.35 to 3.30 (m, 5H), 1.32 (s, 9H); MS LC-MS [M+H]+=529, RT=2.20 min.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][N:5]2[N:8]=[CH:9][CH:10]=[C:4]12.Br[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].O>CN(C=O)C>[N:3]1([CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:7][CH2:6][N:5]2[N:8]=[CH:9][CH:10]=[C:4]12
Reactant: c1cc2n(n1)CCN2
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCCN1CCn2nccc21
Temperature: 0 °C
Reaction time: 66 h
Yield: 30.9 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.3 g, 7.5 mmol) was added portion-wise to a stirred solution of 2,3-dihydro-1H-pyrazolo[1,5-a]imidazole (0.68 g, 6.19 mmol) in anhydrous DMF (5 mL) at room temperature under a nitrogen atmosphere. The mixture was cooled to 0° C. and stirred for 15 min before a solution of tert-butyl 3-bromopropylcarbamate (1.47 g, 6.19 mmol) in DMF (5 mL) was added portionwise over 5 min. The reaction was warmed to room temperature and stirred for 66 hr at room temperature. Water (5 mL) was added dropwise and the mixture was concentrated under reduced pressure. More water was added and the mixture was extracted with EtOAc. The combined organics were dried over MgSO4 and concentrated under reduced pressure. The crude residue was purified via silica gel chromatography (0-100% EtOAc/isohexane) to give tert-butyl 3-(2,3-dihydro-1H-pyrazolo[1,5-a]imidazol-1-yl)propylcarbamate as an orange oil (0.51 g, 31%). To a solution of this oil in conc. H2SO4 at 0° C. was added conc. HNO3 portionwise over 5 min. The reaction was warmed to room temperature and the mixture was stirred for 18 h. The mixture was re-cooled to 0° C., poured into ice water with stirring and basified with 40% aq. NaOH. The product was extracted into DCM and the combined organics were dried over MgSO4 and concentrated under reduced pressure to afford 3-(7-nitro-2,3-dihydro-1H-pyrazolo[1,5-a]imidazol-1-yl)propan-1-amine as a brown gum. This gum was dissolved in DCM (30 mL) and DIPEA (1 mL) and di-tert-butyl dicarbonate (0.5 g, 2.3 mmol) were added. The mixture was stirred at room temperature for 2 hr. The solvents were removed under reduced pressure and the residue was purified via silica gel chromatography (0-100% EtOAc/isohexane) to give tert-butyl 3-(7-nitro-2,3-dihydro-1H-pyrazolo[1,5-c]imidazol-1-yl)propylcarbamate as a pale yellow gum (100 mg, 17% over two steps). 1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 4.82 (s br, 1H), 4.26-4.16 (m, 2H), 4.12-4.00 (m, 2H), 3.84-3.72 (m, 2H), 3.23 (q, J=6.6 Hz, 2H), 1.89-1.78 (m, 2H), 1.44 (s, 9H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:29]C(=O)OC(C)(C)C)[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:19]4[C@H:26]([CH3:27])[CH2:25][CH2:24][C:20]=4[N:21]=[CH:22][N:23]=3)[C@@H:14]([CH3:28])[CH2:13]2)=[O:11])=[CH:4][CH:3]=1.[ClH:37]>C(Cl)Cl>[ClH:1].[ClH:37].[NH2:29][C@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:19]3[C@H:26]([CH3:27])[CH2:25][CH2:24][C:20]=3[N:21]=[CH:22][N:23]=2)[C@@H:14]([CH3:28])[CH2:13]1)=[O:11]
Reactant: C[C@@H]1CCc2ncnc(N3CCN(C(=O)[C@@H](Cc4ccc(Cl)cc4)NC(=O)OC(C)(C)C)C[C@@H]3C)c21
Agent: Cl
Solvent: ClCCl
Product: C[C@@H]1CCc2ncnc(N3CCN(C(=O)[C@H](N)Cc4ccc(Cl)cc4)C[C@@H]3C)c21
Yield: 99 %

Procedure:
tert-Butyl (R)-3-(4-chlorophenyl)-1-((S)-3-methyl-4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate was treated with HCl (4M in dioxane, 2 mL) in DCM (5 mL) for 6 hours to provide (R)-2-amino-3-(4-chlorophenyl)-1-((S)-3-methyl-4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one dihydrochloride (58 mg, 99%). MS (APCI+) [M+H] +414.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13](Br)[C:12]=1[OH:20].Cl>COCCOC.O.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:18][O:17][C:15]1[CH:16]=[C:11]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:12]([OH:20])=[C:13]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1cc(Br)c(O)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Temperature: 80 °C
Yield: 33.4 %

Procedure:
To a stirred solution of phenylboronic acid (0.0842 g, 0.691 mmol), Ba(OH)2.8H2O (0.396 g, 1.26 mmol), and Pd(OAc)2 (0.0014 g, 0.00628 mmol) in DME:H2O (6:1, 7 mL) at room temperature was added 2,6-dibromo-4-methoxyphenol (0.0885 g, 0.314 mmol)). The mixture was then heated at 80° C. for 18 h. The reaction was 50% complete, and an additional 2.2 eq. of phenylboronic acid and 0.02 eq. Pd(OAc)2 were added and continued heating for another 24 h. At this point, the reaction was acidified to pH 1 with 1 N HCl and diluted with EtOAc (100 mL). The organic layer was washed with H2O (10 mL) and brine (10 mL) and then dried (MgSO4). After concentration, the residue was purified by flash chromatography (1 to 5% EtAOc/petroleum ether gradient) to afford the product (0.029 g, 33%) as a clear oil; 1H NMR (CDCl3) δ 3.83 (s, 3H), 5.04 (s, 1H), 6.86 (s, 2H), 7.37-7.42 (m, 2H), 7.45-7.50 (m, 4H), 7.54-7.68 (m, 4H); IR (film) 3540, 3060, 2930, 2820, 1605, 1580, 1500, 1470, 1425, 1360, 1330, 1210, 1175, 1120, 1060, 1040, 1025, 755, 700, and 500 cm−1; mass spectrum [EI], m/z 276 (M)+; Anal. Calcd. for C19H16O2.0.80H2O: C, 78.49; H, 6.10; N, 0.00, Found: C, 78.19; H, 5.54; N, 0.19.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]3[CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:18][C:11]=3[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2)[CH3:2].[CH2:24](Cl)Cl.CCCCCC>>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]3[CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]([CH3:24])[C:11]=3[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2)[CH3:2]
Reactant: CCOC(=O)c1cc2ccc3c(c4ccccc4n3CC)c2[nH]1
Reactant: ClCCl
Solvent: CCCCCC
Product: CCOC(=O)c1cc2ccc3c(c4ccccc4n3CC)c2n1C
Yield: 90.5 %

Procedure:
Using the procedure outlined in Example 34A, ethyl 6-ethyl-1,6-dihydropyrrolo[3,2-c]carbazole-2-carboxylate (H. G. Pars Pharmaceutical Laboratories, Inc.) gave a 90.5% yield of ethyl 6-ethyl-1,6-dihydro-1-methylpyrrolo[3,2-c]carbazole-2-carboxylate, mp 115.5°-116°, (CH2Cl2 /hexane), (C,H,N).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[NH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].ClCCl.CO.C(O)(=O)C>C(O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1
Reactant: NCCC(=O)O
Reactant: Clc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)CCNc1ccc(Cl)nn1
Temperature: 25 °C

Procedure:
To a solution of 3,6-dichloropyridazine (50.0 mmol, 7.45 g) and 3-aminopropionic acid (60.0 mmol, 5.34 g) in absolute ethanol (20 mL) was added potassium carbonate (30.0 mmol, 4.15 g), and the suspension was heated to reflux for 3 hours. The mixture was allowed to cool to room temperature, and the light brown solid residue was partitioned between ethyl acetate (300 mL) and water (300 mL). The pH of the aqueous phase was adjusted to 3.5 with 2M aqueous hydrochloric acid, and the yellow solid was filtered and washed with absolute ethanol (10 mL) and diethyl ether (2×20 mL) to give 5.04 g (50%). The product was pure according to TLC Rf 0.31 (dichloromethane/methanol/acetic acid, 85:10:5).
Reaction SMILES: CS([O:5][CH2:6][CH2:7][CH2:8][C:9]1[N:10]=[C:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=2)[O:12][C:13]=1[CH3:14])(=O)=O.O[CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1.CC(C)([O-])C.[K+]>CN(C)C=O>[C:35]([O:34][C:32]([N:29]1[CH2:30][CH2:31][CH:26]([O:5][CH2:6][CH2:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])[CH2:27][CH2:28]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COC(=O)c1ccc(-c2nc(CCCOS(C)(=O)=O)c(C)o2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CCCOC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 35 °C
Reaction time: 0.58 h
Yield: 126.4 %

Procedure:
To a solution of methyl 4-[4-[3-(methanesulfonyloxy)propyl]-5-methyl-1,3-oxazol-2-yl]benzoate (630 mg, 1.78 mmol, 1.00 equiv) and tert-butyl 4-hydroxypiperidine-1-carboxylate (1 g, 4.97 mmol, 2.79 equiv) in N,N-dimethylformamide (20 mL) maintained under nitrogen at 35° C. was added potassium tert-butoxide (350 mg, 3.12 mmol, 1.75 equiv) in 20 min. The resulting solution was stirred at 35° C. for another 35 min then the reaction was quenched with 50 mL of water. The pH value of the solution was adjusted to 2-3 with 2N hydrochloric acid. The resulting solution was extracted with 50 mL of ethyl acetate. The organic layer was washed with 2×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 1.0 g of crude 4-(4-(3-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)propyl)-5-methyloxazol-2-yl)benzoic acid as a white solid. LC-MS: (ES, m/z): 445[M+H]+, 389, 115.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH3:16])[CH2:4][NH:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1.[CH2:17]([N:19]1[C:31]2[CH:30]=[CH:29][C:28]([C:32](O)=[O:33])=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH3:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([C:6]([NH:5][CH2:4][CH:3]([CH3:16])[CH2:2][NH:1][C:32]([C:28]2[CH:29]=[CH:30][C:31]3[N:19]([CH2:17][CH3:18])[C:20]4[C:25]([C:26]=3[CH:27]=2)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:33])=[O:15])=[CH:8][CH:9]=1)#[N:14]
Reactant: CCn1c2ccccc2c2cc(C(=O)O)ccc21
Reactant: CC(CN)CNC(=O)c1ccc(C#N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c2ccccc2c2cc(C(=O)NCC(C)CNC(=O)c3ccc(C#N)cc3)ccc21
Yield: 50.1 %

Procedure:
A solution of the compound obtained in Step 2 (198 mg, 0.91 mmol), 9-ethyl-9H-carbazole-3-carboxylic acid (218 mg, 0.91 mmol), HATU (450 mg, 1.18 mmol) and TEA (0.381 mL, 2.73 mmol) in DMF (4.5 mL) was stirred at room temperature for 16 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 20 to 100% ethyl acetate/hexane) to give the title compound (200 mg, 0.456 mmol, 50.0%) as a white powder.