Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH:5]1[CH:18]=[C:17]2[C:8](=[C:9]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=3[C:32]([OH:34])=[O:33])[C:10]3[C:15]([O:16]2)=[CH:14][C:13]([O:19]C(=O)C)=[CH:12][CH:11]=3)[CH:7]=[CH:6]1)(=O)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:49]([S:56][C:57](=[O:60])[CH2:58][NH2:59])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>C1COCC1.CN(C=O)C>[CH2:49]([S:56][C:57]([CH2:58][NH:59][C:27](=[O:29])[C:26]1[CH:25]=[C:24]([C:23]([C:9]2[C:10]3[C:15]([O:16][C:17]4[C:8]=2[CH:7]=[CH:6][CH:5]([OH:4])[CH:18]=4)=[CH:14][C:13]([OH:19])=[CH:12][CH:11]=3)=[CH:31][CH:30]=1)[C:32]([OH:34])=[O:33])=[O:60])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: CC(=O)Oc1ccc2c(c1)OC1=CC(OC(C)=O)C=CC1=C2c1ccc(C(=O)O)cc1C(=O)O
Reactant: NCC(=O)SCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCCl
Product: O=C(CNC(=O)c1ccc(C2=C3C=CC(O)C=C3Oc3cc(O)ccc32)c(C(=O)O)c1)SCc1ccccc1
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
To a solution of 13 (0.424 g, 0.92 mmol) in dry THF was added EDC (0.176 g, 0.92 mmol) and HOBt (0.14 g, 0.92 mmol). The solution was stirred for 30 minutes under ice-cold conditions, followed by addition of 8 (0.2523 g, 1.16 mmol) dissolved in minimal amount of DMF. The resulting solution was stirred further for 6 hours at RT. Upon removal of the solvent in vacuo, the residue was taken into ethyl acetate and washed with 1 N HCl (2×30 ml), water (2×30 ml) and brine (2×30 ml). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford a crude mixture, which was further purified by flash chromatography (silica gel, dichloromethane/methanol=9:1) to afford 2 (0.32 g, 56%). 1H-NMR (300 MHz, CDCl3) δ 8.52 (s, 1H), 8.22 (d, J=8.04 Hz, 1H), 7.25-7.21 (m, 6H), 7.12-7.09 (m, 2H), 6.81-6.75 (m, 4H), 4.39 (d, J=5.61 Hz, 2H), 4.15 (s, 2H), 2.3 (s, 6H). 3C-NMR (60 MHz, DMSO) δ 196.52, 168.78, 168.37, 165.84, 155.31, 152.20, 151.42, 136.72, 134.08, 129.58, 127.74, 127.50, 127.33, 126.45,125.61, 124.50, 123.91, 115.53, 110.46, 82.09, 49.48, 32.90, 20.98. MS (ESI): m/z 623.9 [(M+1)]+.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:22][C:23]([C:29]4[S:30][CH:31]=[CH:32][N:33]=4)=[CH:24][C:25]=3[C:26]([NH2:28])=O)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Cl-].O>CN(C)C=O>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:22][C:23]([C:29]4[S:30][CH:31]=[CH:32][N:33]=4)=[CH:24][C:25]=3[C:26]#[N:28])[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:2][CH2:3]1
Reactant: NC(=O)c1cc(-c2nccs2)[nH]c1C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(-c2nccs2)[nH]c1C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.7 %

Procedure:
To a solution of 2-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-3-carboxamide (0.147 g) in N,N-dimethylformamide (5 mL) was added cyanuroyl chloride (0.061 g) under ice-cooling, m and the mixture was warmed to room temperature and stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-70:30, volume ratio), and recrystallized from hexane-diethyl ether to give the title compound (0.093 g, yield 66%) as colorless crystals. MS: 468 (MH+). melting point 114-116° C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][O:16][CH:17]3[CH:22]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=5[O:41][CH3:42])=[CH:25][CH:24]=4)[CH2:21][CH2:20][N:19]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:18]3)[CH:13]=2)[C:8]([CH3:51])([CH3:50])[CH2:7]1)=[N+]=[N-].N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O.CO>[NH2:1][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][O:16][CH:17]3[CH:22]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=5[O:41][CH3:42])=[CH:25][CH:24]=4)[CH2:21][CH2:20][N:19]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:18]3)[CH:13]=2)[C:8]([CH3:51])([CH3:50])[CH2:7]1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3c(c2)N(CCN=[N+]=[N-])CC3(C)C)cc1
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3c(c2)N(CCN)CC3(C)C)cc1
Reaction time: 1 h

Procedure:
The solution of 0.347 g of tert-butyl 3-[1-(2-azidoethyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-ylmethoxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 1.5 ml of tetrahydrofuran is admixed with stirring at room temperature successively with 0.32 ml of water, 1.40 ml of methanol, 0.32 ml of conc. ammonia and 0.210 g of triphenylphosphine, and stirred over 1 hour. The reaction mixture is admixed with water (40 ml) and extracted with tert-butyl methyl ether (2×40 ml). The organic phases are washed successively with water (40 ml) and brine (40 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.41 (200:20:1 dichloromethane-methanol-conc. ammonia); Rt=5.54.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH2:5][F:6])[C:3]#[N:4].C(=O)([O-])[O-].[K+].[K+].Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>C1CCCCC1.C(OCC)(=O)C>[C:3]([C:2]([NH:1][C:15](=[O:16])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:7])[CH2:5][F:6])#[N:4]
Reactant: CC(N)(C#N)CF
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CC(C#N)(CF)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
1.34 g (11.83 mmol, about 90%) of rac-2-amino-3-fluoro-2-methylpropanonitrile from Example 53A in 29 ml of THF/water (9/1) were admixed with 5.07 g (36.67 mmol) of potassium carbonate. At 0° C., 1.69 ml (11.83 mmol) of benzyl chloroformate were slowly added dropwise and the reaction mixture was stirred at RT overnight. The solvent was decanted off and the aqueous phase was twice extracted by shaking with THF and then decanting off the THF. The combined organic phases were dried over sodium sulphate, filtered and concentrated. The residue was separated by means of silica gel chromatography (eluent:cyclohexane/ethyl acetate gradient) and the product fractions were concentrated by evaporation on a rotary evaporator. 1.89 g of the target compound were obtained (66% of theory, 97% purity).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:26]=[CH:25][C:7]([O:8][C:9]2[CH:24]=[CH:23][C:12]([CH2:13][NH:14][C:15]3[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:16]=3[NH2:17])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)[CH3:2].[C:27](O)(=O)[CH3:28]>>[CH3:27][C:28]1[N:14]([CH2:13][C:12]2[CH:23]=[CH:24][C:9]([O:8][C:7]3[CH:25]=[CH:26][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=3)=[CH:10][CH:11]=2)[C:15]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1
Reactant: CC(=O)O
Reactant: CCOc1ccc(Oc2ccc(CNc3c(C)cccc3N)cc2)cc1
Product: CCOc1ccc(Oc2ccc(Cn3c(C)nc4cccc(C)c43)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-[4-(4-ethoxyphenoxy)benzylamino)-3-methylaniline (0.348 g) and acetic acid (5 ml) was heated under reflux for 6 hours and then cooled to room temperature. Excess acetic acid was removed by distillation under reduced pressure, and toluene (100 ml) and a 5% sodium hydroxide solution (50 ml) were added thereto, followed by stirring for 10 minutes. The toluene layer was separated, washed with water, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove toluene. The residue was purified by silica gel column chromatography to give 2,7-dimethyl-1-[4-(4-ethoxyphenoxy)benzyl]benzimidazole (0.315 g) as white crystals. m.p., 124.1° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([NH2:10])=[O:9])[N:5]([CH3:7])[CH:6]=1.[C:11]([C:15]1[CH:16]=[C:17]2[C:22](=[C:23]([F:25])[CH:24]=1)[C:21](=[O:26])[N:20]([C:27]1[CH:37]=[CH:36][CH:35]=[C:34](B3OC(C)(C)C(C)(C)O3)[C:28]=1[CH2:29][O:30]C(=O)C)[N:19]=[CH:18]2)([CH3:14])([CH3:13])[CH3:12]>>[C:11]([C:15]1[CH:16]=[C:17]2[C:22](=[C:23]([F:25])[CH:24]=1)[C:21](=[O:26])[N:20]([C:27]1[C:28]([CH2:29][OH:30])=[C:34]([C:2]3[CH:3]=[C:4]([C:8]([NH2:10])=[O:9])[N:5]([CH3:7])[CH:6]=3)[CH:35]=[CH:36][CH:37]=1)[N:19]=[CH:18]2)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Reactant: Cn1cc(Br)cc1C(N)=O
Product: Cn1cc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc1C(N)=O
Yield: 60 %

Procedure:
This compound was prepared with the same method as described in Example 1 by using 4-bromo-1-methyl-1H-pyrrole-2-carboxylic acid amide (intermediate-3) and acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl ester (intermediate 5). The desired compound was prepared in two steps (60% yield). 1H NMR (300 MHz, d6-DMSO) δ 8.49-8.48 (m, 1H), 7.86 (s, 1H), 7.73 (d, J=13.2 Hz, 1H), 7.44-7.42 (m, 3H), 7.25-7.23 (m, 2H), 7.06 (br s, 2H), 4.56 (s, 1H), 4.36 (s, 2H), 3.88 (s, 3H), 1.37 (s, 9H). LC-MS calcd for C25H25FN4O3 (m/e) 448.19, obsd 449.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13](Br)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]C(C)(C)C.Cl([O-])(=O)(=O)=O.[CH2:26]1[C:33]2[CH2:32][CH2:31][CH2:30][N+:29]=2[CH2:28][CH2:27]1>CCOCC.CCCCC>[CH2:1]([O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:33]23[CH2:32][CH2:31][CH2:30][N:29]2[CH2:28][CH2:27][CH2:26]3)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cncc(OCc2ccccc2)c1
Reactant: C1CC2=[N+](C1)CCC2
Agent: [Li]C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCCCC
Solvent: CCOCC
Product: c1ccc(COc2cncc(C34CCCN3CCC4)c2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 21.7 %

Procedure:
3-Benzyloxy-5-bromopyridine (1.18 g, 4.47 mmol) was dissolved in Et2O and cooled to -78° C. A solution of 2.5M t-BuLi (5.8 mL, 9.83 mmol) in pentane was added, and the reaction was stirred for 10 minutes. 1,2,3,5,6,7-hexahydropyrrolizinium perchlorate (1.4 g, 6.70 mmol) was added, and the reaction mixture was allowed to stir for 3 hours at -78° C. then allowed to warm to -20° C. and stir for 2 hours. The cold bath was removed, 2N HCl was added, and the mixture was extracted with Et2O. The phases were separated, and the aqueous phase was basified with 15% NaOH and extracted with CH2Cl2 (2×). The CH2Cl2 fractions were combined, dried (MgSO4) and concentrated, and the residue was chromatographed (silica gel; CHCl3 /MeOH, 98:2) to afford a clear oil (286 mg, 22%): mp 45°-49° C. 1H NMR (CDCl3, 300 MHz) δ1.58-1.69 (m, 2H), 1.78-1.83 (m, 2H), 1.89-2.03 (m, 4H), 2.63-2.72 (m, 2H), 3.05-3.18 (m, 2H), 5.12 (s, 2H), 7.31-7.54 (m, 6H), 8.17 (d, J=3.0 Hz, 1H), 8.29 (d, J=1.7 Hz, 1H); MS (CI/NH3) m/z: 295 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[C:2]=[O:3].[CH:9]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([NH2:19])[C:13]=2[CH:12]=[CH:11][N:10]=1.BrC1C=CC(CN=C=O)=CC=1>>[CH:9]1[C:18]2[C:13](=[C:14]([NH:19][C:2]([NH:1][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[O:3])[CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1
Reactant: CCCCCN=C=O
Reactant: Nc1cccc2cnccc12
Agent: O=C=NCc1ccc(Br)cc1
Product: CCCCCNC(=O)Nc1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 60F using 1-isocyanatopentane and 5-isoquinolinamine instead of the product from Example 60E and 1-bromo-4-(isocyanatomethyl)benzene. NMR (DMSO-d6) δ 9.70 (s, 1H), 9.19 (s, 1H), 8.64 (d, 1H), 8.57 (m, 2H), 8.01 (d, 1H), 7.84 (d, 1H), 7.85 (t, 1H), 6.95 (m, 1H), 3.17 (m, 2H), 2.48 (m, 2H), 1.23 (m, 4H), 0.86 (m, 3H); MS (ESI) (M+H)+ 339.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:31]=[CH:30][C:13]([CH2:14][NH:15][CH:16]3[C:25]4[CH:24]=[C:23]([C:26]([O:28][CH3:29])=[O:27])[CH:22]=[CH:21][C:20]=4[CH2:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:32]1([CH2:37][CH2:38][C:39](Cl)=[O:40])[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:32]1([CH2:37][CH2:38][C:39]([N:15]([CH2:14][C:13]2[CH:12]=[CH:11][C:10]([C:9]#[C:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:31][CH:30]=2)[CH:16]2[C:25]3[CH:24]=[C:23]([C:26]([O:28][CH3:29])=[O:27])[CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18][CH2:17]2)=[O:40])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: COC(=O)c1ccc2c(c1)C(NCc1ccc(C#Cc3ccc(F)cc3)cc1)CCC2
Reactant: O=C(Cl)CCC1CCCC1
Product: COC(=O)c1ccc2c(c1)C(N(Cc1ccc(C#Cc3ccc(F)cc3)cc1)C(=O)CCC1CCCC1)CCC2

Procedure:
The titled compound was prepared following the procedure B using methyl 8-({4-[(4-fluorophenyl)ethynyl]benzyl}amino)-5,6,7,8-tetrahydro-2-naphthalenecarboxylate and 3-cyclopentylpropionyl chloride as a white powder (80%). 1H NMR (CDCl3, 300 MHz) δ 1.06 (m, 2H), 1.41-2.10 (m, 11H), 2.27-2.60 (m, 2H), 2.77 (m, 2H), 3.87 (s, 3.4H), 4.07 (d, J=17.9 Hz, 0.6H), 4.52 (d, J=18.5 Hz, 0.6H), 4.86 (d, J=15.6 Hz, 0.4H), 5.10 (m, 0.4H), 6.06 (m, 0.6H), 7.00-7.20 (m, 5H), 7.36 (d, J=8.1 Hz, 1H), 7.48 (m, 3H), 7.66 (d, J=10.4 Hz, 1H), 7.78 (m, 1H). HPLC, Rt: 5.83 min (Purity: 99.4%).
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:22]=[CH:21][C:9]2[CH2:10][CH2:11][N:12]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:13][CH2:14][C:8]=2[C:7]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29]C>ClCCl>[Cl:5][C:6]1[CH:22]=[CH:21][C:9]2[CH2:10][CH2:11][N:12]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:13][CH2:14][C:8]=2[C:7]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29]
Reactant: COc1ccccc1-c1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(N1CCc2ccc(Cl)c(-c3ccccc3O)c2CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.8 %

Procedure:
Cool boron tribromide (3.5 mL, 1M solution in dichloromethane) in dichloromethane at 0° C. and add dropwise a solution of 7-chloro-6-(2-methoxyphenyl)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (840 mg, 2.19 mmol) in dichloromethane (5 mL). Stir at room temperature for 6 h. Partition between iced water and EtOAc. Dry the organic layer over Na2SO4, filter and concentrate in vacuo to obtain the desired intermediate as a white solid (800 mg, 99%).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:20])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=2)=[N:5]1.[C:21]([C:24]1[CH:28]=[C:27]([C:29](O)=[O:30])[NH:26][N:25]=1)(=[O:23])[CH3:22]>>[C:21]([C:24]1[NH:25][N:26]=[C:27]([C:29]([NH:1][C@@H:2]([CH3:20])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=3)=[N:5]2)=[O:30])[CH:28]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c([N+](=O)[O-])c2)n1
Product: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c([N+](=O)[O-])c3)n2)n[nH]1
Yield: 42.9 %

Procedure:
(S)-5-acetyl-N-(1-(3-(4-cyano-3-nitrophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-3-carboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-nitrobenzonitrile (500 mg, 1.843 mmol) and 3-acetyl-1H-pyrazole-5-carboxylic acid (341 mg, 2.212 mmol). The product was triturated twice using diethyl ether. Yield 42.9%. 1H-NMR (400 MHz; DMSO-d6): δ 1.11-1.27 (m, 3H), 2.48 (s, 3H), 4.21-4.57 (m, 3H), 7.03 (d, 1H), 7.29 (s, 1H), 7.86 (d, 1H), 8.09-8.72 (m, 4H), 14.1 (bs, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[O:7][C:6]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:5]2.CO.[NH3:23]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:7])[NH:23][C:6]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:5]2
Reactant: N
Reactant: COC(=O)CCCCc1cc2cc(Br)ccc2c(=O)o1
Solvent: CO
Product: COC(=O)CCCCc1cc2cc(Br)ccc2c(=O)[nH]1
Reaction time: 8 h

Procedure:
A mixture of methyl 5-(6-bromo-1-oxo-1H-isochromen-3-yl)pentanoate (1.5 g, 4.42 mmol) in 7 N ammonia in MeOH (63.2 ml, 442 mmol, 100.0 equiv.) was left standing at room temperature overnight. The mixture was concentrated, diluted with EtOAc, and added 1 N HCl until pH 4. The mixture was vigorously stirred for 10 min, extracted with EtOAc (2×20 mL), washed with brine, dried over Na2SO4, filtered and evaporated to dryness to yield 1.26 g of methyl 5-(6-bromo-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate which was used as such without any further purification.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1>CCOCC>[CH2:2]1[CH:1]2[CH:5]3[CH:4]=[CH:3][CH:2]([CH:5]2[CH:4]=[CH:3]1)[CH2:1]3
Reactant: C1=CCC=C1
Solvent: CCOCC
Product: C1=CC2C3C=CC(C3)C2C1

Procedure:
84.5 g (0.485 mol) of Compound (k) and 100 ml of ether were cooled to 5° C. or lower. With stirring, 60 ml of an ether solution containing 48.1 g (0.728 mol) of cyclopentadiene, produced by pyrolysis of dicyclopentadiene, were added dropwise thereto. The reaction system was then stirred for one hour, and the solvent was removed by distillation under reduced pressure. By further distillation under reduced pressure, 101 g (86%) of Compound (m) were obtained as a colorless liquid, having a boiling point of 104° to 105° C./0.48 mmHg.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:31])(=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[CH:17][C:16]=2[N+:32]([O-])=O)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>O.C(O)C.C(OCC)(=O)C.[Fe]>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:30])(=[O:31])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[CH:17][C:16]=2[NH2:32])=[CH:10][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Sc2ccc(S(=O)(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(Sc2ccc(S(=O)(=O)Nc3ccc(Br)cc3)cc2N)cc1
Temperature: 25 °C
Yield: 90.1 %

Procedure:
The product of Example 149C (510 mg, 0.879 mmol), iron powder (302 mg, 5.40 mmol), and ammonium chloride (308 mg, 5.76 mmol) in water (4 mL) and ethanol (8 mL) were heated at 80° for 40 minutes. The reaction was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with water (2×50 mL) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation under vacuum to provide the title compound as a white foam (436 mg, 90%).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][C:8]=1[CH3:15])[CH2:4][CH3:5])[CH3:2].[OH:16][CH2:17][C:18]([NH:20][CH2:21][C@H:22]([OH:38])[CH2:23][O:24][C:25]1[C:30]([CH3:31])=[CH:29][C:28]([C:32](=[NH:35])[NH:33]O)=[CH:27][C:26]=1[O:36][CH3:37])=[O:19]>>[CH2:4]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:14][N:33]=[C:32]([C:28]3[CH:29]=[C:30]([CH3:31])[C:25]([O:24][CH2:23][C@@H:22]([OH:38])[CH2:21][NH:20][C:18](=[O:19])[CH2:17][OH:16])=[C:26]([O:36][CH3:37])[CH:27]=3)[N:35]=2)=[CH:9][C:8]=1[CH3:15])[CH2:1][CH3:2])[CH3:5]
Reactant: COc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO
Reactant: CCN(CC)Cc1sc(C(=O)O)cc1C
Product: CCN(CC)Cc1sc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(OC)c3)no2)cc1C
Yield: 9.9 %

Procedure:
The title compound (6 mg) is prepared starting from 5-diethylaminomethyl-4-methyl-thiophene-2-carboxylic acid (30 mg, 130 μmol) and (S)-2-hydroxy-N-(2-hydroxy-3-[4-(N-hydroxycarbamimidoyl)-2-methoxy-6-methyl-phenoxy]-propyl)-acetamide (38 mg, 117 μmol) according to Method A; LC-MS: tR=0.51 min; [M+1]+=519.17.
Reaction SMILES: C[N:2]([CH3:19])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([CH2:13][NH:14][C:15](=[O:18])[O:16][CH3:17])[CH:10]=[CH:11][CH:12]=1)=O.NC1[C:25]([C:26]([C:28]2[O:29][CH:30]=[CH:31][CH:32]=2)=[O:27])=[CH:24][NH:23][N:22]=1>C(O)(=O)C>[O:29]1[CH:30]=[CH:31][CH:32]=[C:28]1[C:26]([C:25]1[CH:24]=[N:23][N:22]2[C:5]([C:7]3[CH:8]=[C:9]([CH2:13][NH:14][C:15](=[O:18])[O:16][CH3:17])[CH:10]=[CH:11][CH:12]=3)=[CH:4][CH:3]=[N:2][C:19]=12)=[O:27]
Reactant: COC(=O)NCc1cccc(C(=O)C=CN(C)C)c1
Reactant: Nc1n[nH]cc1C(=O)c1ccco1
Solvent: CC(=O)O
Product: COC(=O)NCc1cccc(-c2ccnc3c(C(=O)c4ccco4)cnn23)c1
Yield: 77.1 %

Procedure:
A reaction mixture comprising 2.62 g of [3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]methylcarbamic acid, methyl ester, 1.77 g of 3-amino-4-furoylpyrazole and 100 ml of glacial acetic acid was reacted as described in Example 29, giving 2.90 g of the desired product, mp 152°-154° C.
Reaction SMILES: C([N:11]1[CH2:15]C[C@H:13]([NH:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12]1)(OCC1C=CC=CC=1)=O.[C:23]([NH:30][C@H:31]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=1)[C:32]([NH:34]N1CC(=O)C1)=[O:33])([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>>[C:23]([NH:30][C@H:31]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=1)[C:32]([NH:34][N:11]1[CH2:12][CH:13]([NH:16][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[CH2:15]1)=[O:33])([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24]
Reactant: O=C(OCc1ccccc1)N1CC[C@H](NC2CCCCC2)C1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)NN1CC(=O)C1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)NN1CC(NC2CCCCC2)C1

Procedure:
The title compound was prepared following the procedure described in Intermediate 2 using (2R)-2-(BOC-amino)-N-(3-oxo-azetidine-1-yl)-3-(4-chlorophenyl)propionamide prepared in Intermediate 201 and cyclohexylamines.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:16][OH:17]>>[N:1]1([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][C:11](=[N:16][OH:17])[CH2:10][CH2:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C1CCN(CCN2CCCC2)CC1
Agent: Cl
Product: ON=C1CCN(CCN2CCCC2)CC1

Procedure:
1-(2-(1-pyrrolidinyl)ethyl)-4-piperidone oxime is prepared from 1-(2-(1-pyrrolidinyl)ethyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:19])=[C:9]2[C:13]=1[NH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10]2.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH3:27][S:28]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:19])=[C:9]2[C:13]=1[NH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10]2)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1cc2c(C)ccc(OCCO)c2[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(C)ccc(OCCOS(C)(=O)=O)c2[nH]1
Temperature: -10 °C

Procedure:
A mixture of ethyl 7-(2-hydroxyethoxy)-4-methyl-1H-indole-2-carboxylate (1.10 g, 4.18 mmol), triethylamine (0.93 g, 9.19 mmol) and dichloromethane (30 ml) was cooled to -10° C., after which methanesulfonyl chloride (0.57 g, 5.01 mmol) was added dropwise with stirring at -10° C. After completion of the dropwise addition, the resulting mixture was stirred at -10° C. for another 2 hours and the reaction mixture was poured into ice water, followed by extraction with chloroform (three times). The extract solution was washed successively with a saturated aqueous ammonium chloride solution, a saturated aqueous sodium hydrogencarbonate solution and a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain ethyl 7-(2-methanesulfonyloxyethoxy)-4-methyl-1H-indole-2-carboxylate. This compound was used in the subsequent reaction without further purification.