Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH:9]2[CH2:10][C:5]3([OH:12])[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[CH2:13]([O:20][C:21]([N:23]1[CH2:27][C:26]([F:29])([F:28])[CH2:25][C@H:24]1[C:30](O)=[O:31])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[CH2:13]([O:20][C:21]([N:23]1[CH2:27][C:26]([F:29])([F:28])[CH2:25][C@H:24]1[C:30](=[O:31])[NH:1][CH:2]1[CH:3]2[CH2:11][CH:7]3[CH2:6][C:5]([OH:12])([CH2:10][CH:9]1[CH2:8]3)[CH2:4]2)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Reactant: O=C(O)[C@@H]1CC(F)(F)CN1C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NC1C2CC3CC1CC(O)(C3)C2)[C@@H]1CC(F)(F)CN1C(=O)OCc1ccccc1
Reaction time: 0.17 h
Yield: 78.9 %

Procedure:
To a solution of 4-amino-adamantan-1-ol (0.58 g, g, 0.0035 mol) in DMF (12 mL) was added (S)-4,4-difluoro-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (1.0 g, CAS: 72180-27-9, Journal of Medicinal Chemistry, 2007, 50(20), 4953-4975), NMM (0.9 mL) and HOBT (0.644 g), and the reaction was stirred for 10 minutes. EDCI (0.80 g) was then added and the reaction mixture was stirred at room temperature for 5 h. The reaction was diluted with water (30 mL). The aqueous layer was extracted with ethyl acetate (3×10 mL). The organic layer was separated and dried over anhydrous Na2SO4. Concentration of the organic layer under reduced pressure using rotary evaporator gave sticky crude material, which was purified through column chromatography (10-20% ethyl acetate:hexane, silica 100-200, Diameter of column—2.5 cm, Height of silica—approx. 7 inch) to give the desired (S)-4,4-difluoro-2-(5-hydroxy-adamantan-2-ylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester (1.2 g, 78%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]#[N:27])=[N:4][CH2:5][C:6]1([C:12]2[S:13][CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=2)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.[BH4-].[Na+]>CO.O>[F:32][C:2]([F:1])([F:31])[CH:3]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]#[N:27])[NH:4][CH2:5][C:6]1([C:12]2[S:13][CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=2)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: N#Cc1cccc(C(=NCC2(c3nc(-c4ccccc4)cs3)CCOCC2)C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1cccc(C(NCC2(c3nc(-c4ccccc4)cs3)CCOCC2)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 50.4 %

Procedure:
3-(2,2,2-trifluoro-1-(((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)imino)ethyl)benzonitrile (600 mg, 1.3 mmol) was dissolved in MeOH—H2O (20 mL, 8:2 v/v) and cooled to 0° C. Sodium borohydride (250 mg, 6.6 mmol) was added to this solution portionwise. The reaction mixture was allowed to warm up to room temperature, stirred for 2 h, and then quenched with water and concentrated under reduced pressure to remove the MeOH. The aqueous mixture was diluted with EtOAc and the organic layer was washed with H2O and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluant 15-20% EtOAc in petroleum ether) to afford 3-(2,2,2-trifluoro-1-(((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)amino)ethyl)benzonitrile (300 mg, yield 50%). 1H NMR (300 MHz, CDCl3) δ 7.89-7.86 (m, 2H), 7.63-7.60 (dt, J=7.6 Hz, 1.4 Hz, 1H), 7.55-7.51 (m, 2H), 7.50 (s, 1H), 7.47-7.41 (m, 3H), 7.39-7.36 (m, 0.1H), 4.16-4.03 (m, 1H), 3.84-3.74 (m, 2H), 3.71-3.61 (m, 2H), 2.95 (d, J=11.4 Hz, 1H), 2.76 (d, J=11.4 Hz, 1H), 2.36-2.24 (m, 2H), 2.01-1.92 (ddd, J=13.5 Hz, 9.0 Hz, 4.1 Hz, 2H). MS (ESI) m/z: Calculated for C24H22F3N3OS: 457.14. found: 458.2 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:38])=[C:5]([C:29]([O:36]C)=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:21][CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:33][O:32][C:31]1[C:3](=[O:2])[C:4]([CH3:38])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:21][CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[C:11]([CH:20]=2)[C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:13])[C:29](=[O:36])[C:30]=1[O:34][CH3:35]
Reactant: COc1c(C)c(Cc2ccc(OCc3cccnc3)c(C(=O)N3CCCCC3)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)N3CCCCC3)c2)=C(C)C1=O
Yield: 62 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(3-pyridylmethyloxy)benzoyl]piperidine (0.380 g, 0.731 mmol) was dissolved in a mixed solution of acetonitrile (12 ml) and water (4 ml) and after adding thereto CAN (1.00 g, 1.83 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to obtain the titled compound (0.222 g, 0.453 mmol, 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:30]([F:33])([F:32])[F:31])[O:14][N:13]=[C:12]([C:15]3[S:19][C:18]([C:20]([NH:22][CH2:23][C:24]([OH:26])=O)=[O:21])=[C:17]4[CH2:27][CH2:28][CH2:29][C:16]=34)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].C(N(CC)C(C)C)(C)C.[F:43][CH2:44][CH2:45][NH2:46].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[F:43][CH2:44][CH2:45][NH:46][C:24]([CH2:23][NH:22][C:20]([C:18]1[S:19][C:15]([C:12]2[CH2:11][C:10]([C:4]3[CH:5]=[C:6]([Cl:9])[C:7]([F:8])=[C:2]([Cl:1])[CH:3]=3)([C:30]([F:31])([F:32])[F:33])[O:14][N:13]=2)=[C:16]2[CH2:29][CH2:28][CH2:27][C:17]=12)=[O:21])=[O:26]
Reactant: NCCF
Reactant: O=C(O)CNC(=O)c1sc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2c1CCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(CNC(=O)c1sc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2c1CCC2)NCCF
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To a solution of compound ({3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carbonyl}-amino)-acetic acid (100 mg, 0.19 mmol) in acetonitrile (5 mL) is added N,N-diisopropylethylamine (49.3 mg, 0.38 mmol), 2-fluoro-ethylamine (14.4 mg, 0.23 mmol) and HATU (108.8 mg, 0.29 mmol), after finished the mixture is stirred at room temperature for 1 hour. After being detected by TLC and LCMS, the reaction mixture is concentrated and the residue is purified by column chromatography to afford desired product (100 mg, 92%). MS (m/z): 570.1 (M+1).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.C[Al](C)C.[NH2:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1[C:23](OC)=[O:24].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:23]([C:19]2[S:20][CH:21]=[CH:22][C:18]=2[NH2:17])=[O:24])=[CH:6][CH:5]=1
Reactant: COC(=O)c1sccc1N
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Nc1ccsc1C(=O)Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4-trifluoromethoxyaniline (7.8 g, 44.5 mmol) in toluene (50 mL) under nitrogen was added trimethylaluminum (2M in toluene, 26.7 mL, 53.4 mmol). The mixture was stirred at RT for 16 h. Methyl 3-amino-2-thiophenecarboxylate (7 g, 44.5 mmol) was added and the resulting solution was stirred at reflux (oil bath temperature: 130° C.) under nitrogen for 24 h. After cooling to RT, saturated sodium bicarbonate solution (100 mL) was added dropwise with caution and the mixture was stirred at RT for 30 min. The product was extracted into dichloromethane (3×100 mL), and the organic layer was dried over Na2SO4, and concentrated to yield a thick oil, which was then triturated with a mixture of hexane/ethyl acetate to afford N-(4-trifluoromethoxyphenyl) 3-Aminothiophene-2-carboxamide as a brown solid. 1H-NMR (400 MHz/CD3OD): δ=6.65 (d, J=5.6 Hz, 1H), 7.23 (d, J=8.4 Hz, 2H), 7.39 (d, J=5.2 Hz, 1H), 7.67 (d, J=9.2 Hz, 2H). MS (ES+): 303 [MH+].
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([N:13]1[C:17]([CH3:18])=[CH:16][C:15]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[N:14]1)=[CH:8]2>Cl>[OH:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([N:13]1[C:17]([CH3:18])=[CH:16][C:15]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[N:14]1)=[CH:8]2
Reactant: COc1cccc2cc(-n3nc(OCCN4CCOCC4)cc3C)ccc12
Agent: Cl
Product: Cc1cc(OCCN2CCOCC2)nn1-c1ccc2c(O)cccc2c1

Procedure:
A solution of 4-{2-[1-(5-methoxynaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}morpholine (400 mg, 1.08 mmol) in HCl conc. (25 ml) was heated at 90° C. during 7 hrs, cooled down, and evaporated to dryness in a rotavapor. A remaining crude of 4-{2-[1-(5-hydroxynaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}morpholine chlorhydrate was left, which was crystallized in isopropyl alcohol-petroleum ether obtaining 0.32 g (76%) of the product in a solid amorphous form with a melting point m.p.<70° C., and highly hygroscopic.
Reaction SMILES: [CH:1]([N:3]([C:12]([C:14]1[C:23]2[C:18](=[C:19]([C:26]([F:29])([F:28])[F:27])[C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:13])[CH2:4][C:5]([O:7]C(C)(C)C)=[O:6])=[O:2]>FC(F)(F)C(O)=O.O>[CH:1]([N:3]([C:12]([C:14]1[C:23]2[C:18](=[C:19]([C:26]([F:27])([F:29])[F:28])[C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:13])[CH2:4][C:5]([OH:7])=[O:6])=[O:2]
Reactant: COc1ccc2c(C(=O)N(C=O)CC(=O)OC(C)(C)C)cccc2c1C(F)(F)F
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(C(=O)N(C=O)CC(=O)O)cccc2c1C(F)(F)F
Yield: 45.8 %

Procedure:
A solution of N-formyl-N-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]glycine, 1,1-dimethylethyl ester (12.86 g, 31.3 mmole) in trifluoroacetic acid (100 mL) was stirred at room temperature for 5 minutes. The reaction was diluted with water (700 mL) and the resultant precipitate was collected by suction filtration. The solid was washed with water (2×25 mL) and recrystallized in 2:1 hexane:chloroform to provide the product as white needles (5.09 g, 46%), m.p. 142°-144° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:21][CH3:22])=[C:10]([N:13]3[CH2:18][C@H:17]([CH3:19])[NH:16][C@H:15]([CH3:20])[CH2:14]3)[CH:11]=2)[CH2:6][CH2:5]1)(=O)C.C([O-])([O-])=O.[K+].[K+]>Cl>[CH3:20][C@H:15]1[NH:16][C@@H:17]([CH3:19])[CH2:18][N:13]([C:10]2[CH:11]=[C:12]3[C:7]([CH2:6][CH2:5][NH:4]3)=[CH:8][C:9]=2[O:21][CH3:22])[CH2:14]1
Reactant: COc1cc2c(cc1N1C[C@@H](C)N[C@@H](C)C1)N(C(C)=O)CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc2c(cc1N1C[C@@H](C)N[C@@H](C)C1)NCC2
Yield: 107.1 %

Procedure:
A stirred solution of D2 (1.6 g, 5 mmole) in 2M HCl acid (50 ml) was heated under reflux for 2 h, then allowed to cool, basified with K2CO3 and extracted with DCM. The extract was dried (Na2SO4) and concentrated under vacuum to afford the title compound as a pale orange solid (1.4 g, 100%). MH+ 276.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](I)=[CH:4][C:3]=1[CH3:10].[CH3:11][N:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][C:13]1=[O:21]>>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:15]2[CH:16]=[CH:17][N:12]([CH3:11])[C:13](=[O:21])[CH:14]=2)=[CH:4][C:3]=1[CH3:10]
Reactant: Cn1ccc(B(O)O)cc1=O
Reactant: Cc1cc(I)cc(C)c1Br
Product: Cc1cc(-c2ccn(C)c(=O)c2)cc(C)c1Br

Procedure:
The title compound is prepared from 2-bromo-5-iodo-1,3-dimethylbenzene and 1-methyl-2-oxo-1,2-dihydropyridin-4-ylboronic acid following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 11): tR=1.04 min; Mass spectrum (ESI+): m/z=292, 294 [M+H]+.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:10]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][N:20]=2)[N:9]=1)=[O:7])C.Cl>CO.O1CCCC1>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([N:10]2[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:12][C:8]([C:6]([OH:7])=[O:5])=[N:9]2)=[N:20][CH:21]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(-c2ccc(OC)cn2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(C(=O)O)cc2-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
Aqueous 1N sodium hydroxide (3.5 mL) was added to the above-obtained 1-(5-methoxy-2-pyridyl)-5-phenylpyrazole-3-carboxylic acid ethyl ester (700 mg) in a mixture of methanol (7 mL) and tetrahydrofuran (7 mL), followed by stirring at room temperature for 2 hours. To the reaction mixture, under cooling with ice, aqueous 1N hydrochloric acid (3.6 mL) was added. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine, and then dried over magnesium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, to thereby give the title compound as a solid (602 mg, 94%).
Reaction SMILES: [CH3:1][CH:2]1[S:6][C:5]([NH:7][C@H:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH3:9])=[N:4][C:3]1=[O:17].[CH3:18][O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=1.CC1(C2C=CC(C#N)=CC=2)SC(N[C@H](C2C=CC=CC=2C(F)(F)F)C)=NC1=O.[Li]N([Si](C)(C)C)[Si](C)(C)C>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:8]([NH:7][C:5]2[S:6][C:2]([C:24]3[CH:25]=[CH:26][C:21]([C:20]([O:19][CH3:18])=[O:28])=[CH:22][CH:23]=3)([CH3:1])[C:3](=[O:17])[N:4]=2)[CH3:9])=[CH:11][CH:12]=1
Reactant: CC1SC(N[C@@H](C)c2ccc(F)cc2)=NC1=O
Reactant: COC(=O)c1ccc(Br)cc1
Agent: C[C@H](NC1=NC(=O)C(C)(c2ccc(C#N)cc2)S1)c1ccccc1C(F)(F)F
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Product: COC(=O)c1ccc(C2(C)SC(N[C@@H](C)c3ccc(F)cc3)=NC2=O)cc1

Procedure:
The title compound was prepared from the reaction of 5-methyl-2-((S)-1-(4-fluorophenyl)ethylamino)thiazol-4(5H)-one with methyl-4-bromobenzoate using the procedure described for 2a. 2.0 equivalent of NaN(SiMe3)2 or LiN(SiMe3)2 with reaction temperature of 50° C. was used. MS (ESI, pos. ion) m/z: 387 (M+1).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:15])[C:10]1[N:16]([CH3:29])[C:17](=[O:28])[C:18]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])=[CH:19][C:9]2=1)=[O:5].[CH2:30]([O:37][CH2:38][C:39](O)=[O:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:30]([O:37][CH2:38][C:39]([NH:2][CH2:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:15])[C:10]1[N:16]([CH3:29])[C:17](=[O:28])[C:18]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])=[CH:19][C:9]2=1)=[O:5])=[O:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(C(=O)CN)ccc3n(C)c21
Reactant: O=C(O)COCc1ccccc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(C(=O)CNC(=O)COCc4ccccc4)ccc3n(C)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.7 %

Procedure:
500 mg (1.11 mmol) of 6-(aminoacetyl)-3-(2,4-dichlorophenyl)-1,9-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one, hydrochloride described in Example 18A above, 175 μL (1.22 mmol) of benzyloxyacetic acid, 635 mg (1.22 mmol) of PyBop and 580 μL (3.33 mmol) of diisopropylethylamine are dissolved in 6 ml of CH2Cl2. The mixture is stirred at ambient temperature for 16 h. A saturated NH4CL solution is added, the mixture is then extracted with CH2CL2 and the organic phase is dried over MgSO4, filtered and concentrated under vacuum. Purification is carried out on a silica column, elution being carried out with EtOAc and then with EtOAc/5% MeOH. 454 mg of yellow crystals are obtained.
Reaction SMILES: [OH:1][N:2]([C@@H:6]([C:8]#[CH:9])[CH3:7])[C:3]([NH2:5])=[O:4].I[C:11]1[S:12][C:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:14][CH:15]=1.C(NC(C)C)(C)C.[NH4+].[OH-]>C(OC(=O)C)(C)C.CC#N.CC#N.Cl[Pd]Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCCC>[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][C:13]2[S:12][C:11]([C:9]#[C:8][C@H:6]([N:2]([OH:1])[C:3]([NH2:5])=[O:4])[CH3:7])=[CH:15][CH:14]=2)=[CH:18][CH:19]=1
Reactant: C#C[C@@H](C)N(O)C(N)=O
Reactant: Fc1ccc(Cc2ccc(I)s2)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [NH4+]
Solvent: CCCCCCC
Solvent: CC(=O)OC(C)C
Solvent: CC(C)NC(C)C
Product: C[C@H](C#Cc1ccc(Cc2ccc(F)cc2)s1)N(O)C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
To the (R)-N-hydroxy-N-(3-butyn-2-yl)urea prepared in step 3 above was added a solution of 2-iodo-5-(4-fluorophenylmethyl)thiophene (45 mmol), in isopropylacetate, followed by diisopropylamine (10 mL, 7.2 g, 71 mmol), bis(acetonitrile)palladium(II) chloride (65 mg, 0.25 mmol), copper(I)iodide (95 mg, 0.50 mmol), and triphenylphosphine (131 mg, 0.50 mmol), and the reaction mixture was stirred under nitrogen at ambient temperature for 2 hours. The reaction mixture was poured into 20% aqueous NH4OH (200 mL) and stirred for 20 min. Heptane (300 mL) was added and the mixture was cooled in an ice-water bath and stirred for 15 min. The solid was filtered off, washed with H2O, heptane, 25% CH2Cl2 /heptane, and dried in vauco to give 10.2 g (64% yield from (S)-O-p-toluenesulfonyl-3-butyn-2-ol) of (R)-N-{3-[5-(4-fluorophenylmethyl)thien-2-yl]-1-methyl-2-propynyl)-N-hydroxyurea (98% ee by chiral HPLC). m.p. 135°-136° C.(dec). 1H NMR (DMSO-d6, 300 MHz) δ1.32 (d, J=6.0 Hz, 3H), 4.11 (s, 2H), 5.10 (q, J=6.0 Hz, 1H), 6.54 (s, 2H), 6.81 (d, J=3.0 Hz, 1H), 7.08 (d, J=3.0 Hz, 1H), 7.10-7.18 (m, 2H), 7.25-7.32 (m, 2H), 9.33 (s, 1H). MS (DCI/NH3) m/e 319 (M+H)+. [α]D23° =+47.8° (C=1 MeOH). Anal calcd for C16H15FN2O2S: C, 60.36; H, 4.75; N, 8.80. Found: C, 60.31; H, 4.79; N, 8.50.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][N:11]=1)(=[O:9])=[O:8].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[Cl:59][C:60]1[CH:72]=[CH:71][C:63]([CH2:64][N:65]2[CH:69]=[C:68]([NH2:70])[CH:67]=[N:66]2)=[CH:62][CH:61]=1.CN(C)C(=O)C.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:59][C:60]1[CH:72]=[CH:71][C:63]([CH2:64][N:65]2[CH:69]=[C:68]([NH:70][C:13]3[CH:14]=[CH:15][C:10]([S:7]([NH:6][C:2]4[S:1][CH:5]=[CH:4][N:3]=4)(=[O:9])=[O:8])=[N:11][CH:12]=3)[CH:67]=[N:66]2)=[CH:62][CH:61]=1
Reactant: Nc1cnn(Cc2ccc(Cl)cc2)c1
Reactant: O=S(=O)(Nc1nccs1)c1ccc(Br)cn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CC(=O)N(C)C
Product: O=S(=O)(Nc1nccs1)c1ccc(Nc2cnn(Cc3ccc(Cl)cc3)c2)cn1
Temperature: 120 °C
Yield: 19.8 %

Procedure:
Into a Vial was added the 5-Bromo-pyridine-2-sulfonic acid thiazol-2-ylamide (50 mg, 0.0002 mol), 9,9-DIMETHYL-4,5-BIS(DIPHENYLPHOSPHINO)XANTHENE (11 mg, 0.000019 mol), Tris(dibenzylideneacetone)dipalladium(0) (5.7 mg, 0.0000062 mol), 1-(4-Chloro-benzyl)-1H-pyrazol-4-ylamine (39 mg, 0.00019 mol) and N,N-Dimethylacetamide (2.1 mL, 0.022 mol). The mixture was sparged with argon for ˜5 min. Sodium tert-butoxide (75 mg, 0.00078 mol) was added and the reaction mixture was heated at 120° C. for 30 min in microwave. The reaction mixture was filtered through celite. The filtrate was diluted with Ethyl acetate and washed with 0.1 N HCl solution, water (3×) and brine, dried over sodium sulfate, filtered and was concentrated to give the crude product that was purified on ISCO (40% to 100% Ethyl acetate). 16.8 mg of the product was obtained as a light tan solid.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])#[N:2].C1(C)C=CC=CC=1.[N-:23]=[N+:24]=[N-:25].[Na+].Cl.C(N(CC)CC)C>O>[N:2]1[NH:23][N:24]=[N:25][C:1]=1[C@@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1C#N
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1c1nn[nH]n1
Temperature: 130 °C
Reaction time: 24 h
Yield: 88.9 %

Procedure:
A mixture of tert-butyl [(1S,2R)-2-cyanocyclopentyl]carbamate (2.8 g), toluene (50 ml), sodium azide (2.1 g), and triethylamine hydrochloride (4.5 g) was stirred at 130° C. for 24 hours. To the reaction mixture was added water (40 ml) at room temperature. The aqueous layer was separated, citric acid was added thereto under ice-cooling, and the solid precipitated was collected by filtration and washed with water to obtain tert-butyl [(1S,2R)-2-(2H-tetrazole-5-yl)cyclopentyl]carbamate (3.0 g).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH3:26])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:24][C:23]3[CH2:22][CH2:21][NH:20][C:19](=[O:25])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].[CH3:27][C:28](OC(C)=O)=[O:29]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:28]([N:20]1[CH2:21][CH2:22][C:23]2[NH:24][C:16]([C:13]3[CH:12]=[CH:11][CH:10]=[C:9]4[C:14]=3[N:15]=[C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([CH3:26])=[N:8]4)=[CH:17][C:18]=2[C:19]1=[O:25])(=[O:29])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)N1CCc2[nH]c(-c3cccc4nc(C)c(NC(C)(C)C)nc34)cc2C1=O
Temperature: 50 °C
Reaction time: 24 h
Yield: 22.8 %

Procedure:
A mixture of 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (193) (0.13 g, 0.37 mmol), DMAP (0.45 g, 3.75 mmol), and Ac2O (0.35 mL, 3.75 mmol) in pyridine (2 mL) was stirred at 50° C. in 24h. The reaction mixture was cooled, concentrated to dryness, purified by ISCO (0-30% EtOAc/DCM) to give the title compound (33 mg, 22%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.11 (1H, br. s.), 7.75-7.88 (1H, m), 7.54-7.67 (1H, m), 7.35 (1H, t, J=7.8 Hz), 7.30 (1H, d, J=2.2 Hz), 6.01 (1H, s), 4.14 (2H, t, J=6.3 Hz), 2.94 (2H, t, J=6.4 Hz), 2.55 (3H, s), 2.44 (3H, s), 1.56 (9H, s). m/z (ESI, +ve) 392.0 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:11]1[N:15]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=[N:13][CH:12]=1.[Li]CCCC.CN([CH:32]=[O:33])C>>[CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:11]1[N:15]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:14]([CH:32]=[O:33])=[N:13][CH:12]=1
Reactant: C[Si](C)(C)CCOCn1cncc1-c1ccc2c(c1)CCCC2
Reactant: CN(C)C=O
Agent: [Li]CCCC
Product: C[Si](C)(C)CCOCn1c(-c2ccc3c(c2)CCCC3)cnc1C=O
Yield: 56.8 %

Procedure:
Reaction of 5-(5,6,7,8-tetrahydro-naphthalen-2-yl)-1-(2-trimethylsilanyl ethoxymethyl)-1H-imidazole (268 mg, 0.82 mmol), 2.5 M n-BuLi (424 uL, 1.06 mmol), and DMF (253 uL, 3.27 mmol) for 2 h at −40° C. followed by column chromatography on silica gel (EtOAc/hexane 9:1) gave the title compound (166 mg, 57%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ0.00 (s, 9H), 0.94 (t, 2H, J=7.5 Hz), 1.80-1.85 (m, 4H), 2.80-2.83 (m, 4H), 3.60 (t, 2H, J=9.0 Hz), 5.81 (s, 2H), 7.13 (d, 1H, J=6.0 Hz), 7.51 (d, 1H, J=6.0 Hz), 7.57 (s, 1H), 7.60 (s, 1H). 9.88 (s, 1H).