Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.[C:24](Cl)(=[O:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:7]2[C:6](=[O:23])[C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[CH2:3][NH:2][C:24](=[O:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:9]=[C:8]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: CCCCCCC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCCCCC(=O)NCc1cccc2nc(C)n(C3CCC(=O)NC3=O)c(=O)c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45.3 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.49 g, 1.5 mmol) in acetonitrile (10 mL), was added heptanoyl chloride (0.34 mL, 2.2 mmol) and N,N-diisopropyl ethylamine (0.60 mL, 3.7 mmol). The mixture was stirred at room temp for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give heptanoic acid [3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-amide as a light yellow solid (280 mg, 47% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 6.10 min (97.8%); mp, 208-210° C.; 1HNMR (DMSO-d6)0.86 (t, J=6 Hz, 3H, CH3), 1.25-2.21 (m, 11H, CH2CH2CH2CH2CH2, CHH), 2.57-2.89 (m, 6H, CHCH2, CH3), 4.68-4.84 (m, 2H, CH2NH), 5.23 (dd, J=6, 12 Hz, 1H, CH), 7.29-7.75 (m, 3H, Ar), 8.18 (t, J=6 Hz, 1H, CH2NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 13.87, 20.77, 21.98, 23.27, 25.22, 28.31, 30.59, 31.96, 35.37, 38.68, 38.96, 39.23, 39.51, 39.79, 40.07, 40.35, 41.39, 56.47, 117.63, 124.30, 125.39, 133.78, 141.23, 148.44, 154.75, 160.95, 169.51, 172.29, 172.59. LCMS MH=413; Anal Calcd For C22H28N4O4: C, 64.06; H, 6.84; N, 13.58. Found: C, 64.05; H, 6.80; N, 13.58.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:31]=[C:30]3[C:26]([CH2:27][C:28](=[O:32])[NH:29]3)=[CH:25][CH:24]=2)[CH:20]=[CH:21][CH:22]=1)[CH3:15]>N1CCCCC1.C(O)C>[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:31]=[C:30]3[C:26]([C:27](=[CH:11][C:8]4[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=4[CH3:13])[C:28](=[O:32])[NH:29]3)=[CH:25][CH:24]=2)[CH:20]=[CH:21][CH:22]=1)[CH3:15]
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Reactant: CCOc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]cc(CCC(=O)O)c2C)c1
Yield: 96.1 %

Procedure:
4-(2-carboxyethyl)-2-formyl-3-methylpyrrole (90.5 mg), 127 mg 6-(3-ethoxyphenyl)-2-oxindole and 2 drops piperidine in 2 mL of ethanol were heated at 90° C. overnight. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 200 mg (96%) of the title compound as a brown solid.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[NH:10][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[N:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:20][Si:21]([CH3:28])([CH3:27])[CH2:22][CH2:23][O:24][CH2:25]Cl>CN(C=O)C>[C:3]1([C:9]2[N:10]([CH2:25][O:24][CH2:23][CH2:22][Si:21]([CH3:28])([CH3:27])[CH3:20])[CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)[N:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(-c2nc(-c3ccncc3)c[nH]2)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(-c2ccncc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
60% Sodium hydride (200 mg, 5.0 mmol) was added slowly into a solution of 4-(2-phenyl-1H-imidazol-4-yl)pyridine (1.0 g, 4.5 mmol; Example 1, Step 1) in dry DMF (5 mL) at 0° C. The reaction mixture was stirred at rt for 1 h and re-cooled to 0° C. and 2-(trimethylsilyl)ethoxymethyl chloride (SEM chloride; 0.88 mL, 0.83 g, 5.0 mmol) was added. The reaction was stirred at 10° C. for 2 h and quenched with water (40 mL). The mixture was partitioned and extracted with EtOAc (3×60 mL) and the organic layers were combined, dried (Na2SO4), and concentrated. The resulting residue was purified by flash chromatography (SiO2, 100:0-90:10 DCM-MeOH) to give 1.2 g (75%) of 4-(2-phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyridine: 1H NMR (CDCl3) δ 8.61 (d, J=6.0, 1.2 Hz, 2H), 7.81 (d, J=8.0, 1.6 Hz, 2H), 7.74 (d, J=6.0, 1.2 Hz, 2H), 7.58 (s, 1H), 7.49 (m, 3H), 5.30 (s, 2H), 3.60 (t, J=8.0 Hz, 2H), 0.94 (t, J=8.0 Hz, 2H), 0.00 (s, 9H).
Reaction SMILES: N#N.[O:3]1[CH2:8][CH2:7][CH:6](O)[CH2:5][CH2:4]1.[I:10][C:11]1[NH:15][N:14]=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[I:10][C:11]1[N:15]([CH:6]2[CH2:7][CH2:8][O:3][CH2:4][CH2:5]2)[N:14]=[CH:13][CH:12]=1
Reactant: OC1CCOCC1
Reactant: Ic1ccn[nH]1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Ic1ccnn1C1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.1 %

Procedure:
To a round-bottomed flask equipped with a stirring bar and a N2 tee, tetrahydro-2H-pyran-4-ol (1.05 g, 10.31 mmol), 5-iodo-1H-pyrazole (2.00 g, 10.31 mmol), triphenylphosphine (3.33 g, 12.68 mmol), (g, mmol) and THF (22.9 mL) were added. Followed by the addition of DIAD (2.71 g, 13.4 mmol), the resulting mixture was stirred at room temperature for 3 hrs. The mixture was removed most solvents in vauo, and ethyl acetate (200 mL) was added. The resulting solution were washed with H2O (50 mL×1), brine (50 mL×1), and dried over Na2SO4. The organic phase was filtered and removed solvent in vacuo, and passed a silica gel column (ethyl acetate: hexanes=0:100 to 100:0), off-white solids were obtained as the desired product. 920 mg (yield 32.1%). 1H NMR (300 MHz, DMSO-d6) δ 7.63-7.47 (m, 1H), 6.62-6.38 (m, 1H), 4.48 (tt, J=11.4, 4.3 Hz, 1H), 3.96 (ddt, J=11.8, 4.7, 1.2 Hz, 2H), 3.49 (td, J=12.0, 2.1 Hz, 2H), 2.00 (dddd, J=13.1, 12.0, 11.2, 4.6 Hz, 2H), 1.90-1.71 (m, 2H) ppm; MS (ESI+) m/z 279.30 (M+H).
Reaction SMILES: [CH:1]([C:3]1[N:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=2[CH3:20])[CH:5]=[C:6]([C:10](=[O:12])[CH:11]=1)[C:7]([OH:9])=[O:8])=O.[CH2:21]([O:23][C:24]([CH:26]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:25])[CH3:22]>CO>[CH2:21]([O:23][C:24]([CH:26]=[CH:1][C:3]1[N:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=2[CH3:20])[CH:5]=[C:6]([C:10](=[O:12])[CH:11]=1)[C:7]([OH:9])=[O:8])=[O:25])[CH3:22]
Reactant: Cc1cc(O)ccc1-n1cc(C(=O)O)c(=O)cc1C=O
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CO
Product: CCOC(=O)C=Cc1cc(=O)c(C(=O)O)cn1-c1ccc(O)cc1C
Yield: 32 %

Procedure:
In 5 ml of methanol was dissolved 0.15 g of 6-formyl-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihydronicotinic acid, and 0.19 g of ethoxycarbonylmethylenetriphenylphosphorane was added thereto. They were reacted at room temperature for one hour. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue was purified by a column chromatography (Wako Silica Gel C-200; eluent: chloroform/ethanol (50:1 by volume) mixture) to obtain 0.06 g of 6-(2-ethoxycarbonylethenyl)-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihydronicotinic acid having a melting point of 185°-189° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:23])[C:13]([C:20]([OH:22])=[O:21])=[CH:14][N:15]3[CH2:18][CH3:19])=[CH:10][C:9]=2[F:24])[S:6][CH:7]=1.[CH3:25][NH2:26]>>[CH2:18]([N:15]1[C:16]2[C:11](=[CH:10][C:9]([F:24])=[C:8]([C:5]3[S:6][CH:7]=[C:3]([CH2:2][NH:26][CH3:25])[N:4]=3)[CH:17]=2)[C:12](=[O:23])[C:13]([C:20]([OH:22])=[O:21])=[CH:14]1)[CH3:19]
Reactant: CN
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(-c3nc(CCl)cs3)cc21
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(-c3nc(CNC)cs3)cc21

Procedure:
A solution of 0.40 g 7-(4-chloromethyl-2-thiazolyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 100 ml 40% aqueous methyl amine was stirred at room temperature overnight and evaporated to dryness. The resulting solid was crystallized from water to afford 0.33 g of the title compound, mp 216°-218° C. (dec).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[CH2:4][NH:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[Cl:17][C:18]1[CH:19]=[C:20]([NH:25][CH:26]([CH3:30])[C:27](O)=[O:28])[CH:21]=[CH:22][C:23]=1[Cl:24].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:17][C:18]1[CH:19]=[C:20]([NH:25][CH:26]([CH3:30])[C:27]([N:5]([CH2:4][CH:3]([O:15][CH3:16])[O:2][CH3:1])[CH2:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:28])[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: COC(CNCCCN1CCCCC1)OC
Reactant: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(CN(CCCN1CCCCC1)C(=O)C(C)Nc1ccc(Cl)c(Cl)c1)OC
Yield: 70.2 %

Procedure:
To a solution of (2,2-dimethoxy-ethyl)-(3-piperidin-1-yl-propyl)-amine (400 mg, 1.74 mmol) in N,N-dimethylformamide (4 mL) were added 2-(3,4-dichloro-phenylamino)-propionic acid (intermediate 11; 337 mg, 1.91 mmol), 4-methylmorpholine (527 mg, 5.21 mmol) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (990 mg, 2.61 mmol) at RT, then after 2 h the reaction mixture was partitioned between EtOAc and sat. aq. NaHCO3 solution. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2; CH2Cl2/MeOH/25% aq. ammonia solution 90:10:0.25) afforded the title compound (545 mg, 70%). Yellow viscous oil, MS: 446.2 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[NH:28]1>>[CH:23]1([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:4]=[CH:3][C:2]([N:28]5[C@H:27]([CH3:26])[CH2:31][O:30][C:29]5=[O:32])=[N:7][CH:6]=4)=[O:9])[CH2:11][CH2:12]3)=[CH:18][CH:19]=2)[CH2:25][CH2:24]1
Reactant: C[C@@H]1COC(=O)N1
Reactant: O=C(c1ccc(Br)nc1)N1CCC(Oc2ccc(C3CC3)cc2)CC1
Product: C[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCC(Oc3ccc(C4CC4)cc3)CC2)cn1
Yield: 59.8 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (6-bromopyridin-3-yl)[4-(4-cyclopropylphenoxy)piperidin-1-yl]methanone (401 mg) described in Preparation Example 152 and (R)-4-methyloxazolidin-2-one (111 mg) described in Preparation Example 25, the title compound (252 mg) was obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([C:21]([F:32])([F:31])[F:20])[CH:27]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: COc1ccc2c(-c3cccc(C(F)(F)F)c3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-trifluoromethyl-phenylboronic acid to give [6-methoxy-1-(3-trifluoromethyl-phenyl)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 385(MH+).
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:53]=[CH2:54])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:55][C:56]1([CH3:62])[N+:60]([O-:61])=[CH:59][CH2:58][CH2:57]1>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:31]=[N:30][N:29]=3)=[CH:20][CH:21]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C@H:53]3[O:61][N:60]4[C:56]([CH3:62])([CH3:55])[CH2:57][CH2:58][C@@H:59]4[CH2:54]3)[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC1(C)CCC=[N+]1[O-]
Reactant: C=Cc1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)c(=O)c2c1
Solvent: Cc1ccccc1
Product: CCCCc1nc2ccc([C@@H]3C[C@H]4CCC(C)(C)N4O3)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 57.2 %

Procedure:
To a solution of 0.500 g of 2-Butyl-6-ethenyl-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone in 25 ml of toluene is added 0.161 g of 5,5-dimethyl-1-pyrroline N-oxide and the reaction mixture heated at reflux for 6 hours. The reaction mixture is cooled and concentrated in vacuo to a residue which is purified by chromatography on silica gel by elution with 2:1 ethyl acetate-hexanes to give 0.332 g of the desired product. FAB mass spec 818 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=1.[CH3:12][C:13]1([CH3:27])[C:18]2[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:17]=2[NH:16][C:15](=[O:26])[O:14]1>O>[CH3:12][C:13]1([CH3:27])[O:14][C:15](=[O:26])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:2]3[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=3)=[CH:19][C:18]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: N#CCc1ccc(Br)cc1F
Solvent: O
Product: CC1(C)OC(=O)Nc2ccc(-c3ccc(CC#N)c(F)c3)cc21

Procedure:
Prepared according to procedure B from 4-bromo-2-fluorophenylacetonitrile (T. Alessi A. H. P. U.S. Pat. No. 4,895,862) and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid. A grey solid; mp 253-256° C. 1H NMR (DMSO-d6) δ 10.35 (s, 1H) 7.67-7.49 (m, 5H), 6.97 (d, 1H, J=8.6 Hz) 4.09 (s, 2H) 1.67(s, 6H), MS [M−H]−m/z 309. Anal. Calc. For C18H15N2FO2.0.15 H2O: C, 69.07; H, 4.93; N, 8.95. Found C, 69.27; H 5.05; N, 8.50.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].Br.C(OC(=O)C)(=O)C>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1ccc(Cl)c([N+](=O)[O-])c1
Agent: Br
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(O)ccc1Cl
Yield: 83.8 %

Procedure:
There were mixed 20 g of 4-chloro-3-nitroanisole, 67 ml of acetic acid and 83 ml of 47% (w/w) hydrobromic acid. Thereto was added 50 ml of acetic anhydride. The mixture was refluxed for 8.5 hours. After the completion of the reaction, the solvent was removed by distillation under reduced pressure. The residue was mixed with 300 ml of ethyl acetate and 500 ml of water. The resulting organic layer was separated, washed with a saturated aqueous sodium hydrogencarbonate solution, water and a saturated aqueous sodium chloride solution in this order, and then dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The resulting crystal was recrystallized from toluene to obtain 15.5 g (yield: 83.6%) of 4-chloro-3-nitrophenol having a melting point of 123.5°-125.5° C.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16]([S:22](Cl)(=[O:24])=[O:23])=[CH:17]2)(=[O:10])[CH3:9].[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>O1CCCC1>[C:8]([O:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16]([S:22]([NH:33][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:24])=[O:23])=[CH:17]2)(=[O:10])[CH3:9]
Reactant: CC(=O)Oc1cccc2cc(S(=O)(=O)Cl)ccc12
Reactant: NCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cccc2cc(S(=O)(=O)NCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
Triethylamine (50 μl, 0.36 mmol) and 5-(acetyloxy)naphthalene-2-sulfonyl chloride (84.9 mg, 0.30 mmol) were added to benzylamine (32.1 mg, 0.30 mmol) dissolved in tetrahydrofuran (3 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (eluent; n-hexane: ethyl acetate=2:1→1:1) to give the title compound as a light yellow white crystal (72.1 mg, 67.6%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C([BH3-])#N.[Na+]>CO>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:25][CH:24]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1
Reactant: C1CCNCC1
Reactant: O=Cc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: c1cnc2c(c1)CCCC2N(Cc1ccc(CN2CCCCC2)cc1)Cc1nc2ccccc2[nH]1
Reaction time: 5 h
Yield: 29.8 %

Procedure:
Using General Procedure A: To a stirred solution of 4-{[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzaldehyde (AMD9882) (144 mg, 0.36 mmol) in dry MeOH (5 mL) was added piperidine (0.040 mL, 0.40 mmol) and sodium cyanoborohydride (44 mg, 0.70 mmol) and the mixture stirred for 5 h. Purification of the crude product by radial chromatography on silica gel (1 mm plate, CH2Cl2/MeOH/NH4OH, 50:1:1) afforded the desired adduct (50 mg, 30%) as a white foam.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=3)[CH2:11][C:10](=O)[C:9]2=[O:25])=[CH:4][CH:3]=1.[CH3:26][C@@H:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:21])[F:22])[CH:14]=3)[CH:11]=[C:10]([NH:34][C@@H:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH3:26])[C:9]2=[O:25])=[CH:4][CH:3]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: O=C1CC(c2cccc(OC(F)(F)F)c2)N(c2ccc(Br)cc2)C1=O
Solvent: ClCCl
Product: C[C@@H](NC1=C[C@@H](c2cccc(OC(F)(F)F)c2)N(c2ccc(Br)cc2)C1=O)c1ccccc1

Procedure:
Dissolve (±)-1-(4-bromo-phenyl)-5-(3-trifluoromethoxy-phenyl)-pyrrolidine-2,3-dione (14.6 g, 35.2 mmol) in dichloromethane (35 mL). Add (R)-(+)-α-methylbenzylamine (6.8 mL, 52.8 mmol) and stir overnight at ambient temperature. Concentrate the reaction mixture under reduced pressure and purify by silica gel chromatography (ethyl acetate-hexane) to yield (S)-1-(4-bromo-phenyl)-3-((R)-1-phenyl-ethylamino)-5-(3-trifluoromethoxy-phenyl)-1,5-dihydro-pyrrol-2-one-eluting first (6.6 g, 36%): MS (m/z): 517.0 (M+1). RP HPLC: Tr=5.53 min (Method 3) and eluting second (R)-1-(4-bromo-phenyl)-3-((R)-1-phenyl-ethylamino)-5-(3-trifluoromethoxy-phenyl)-1,5-dihydro-pyrrol-2-one (5.8 g, 32%): MS (m/z): 517.0 (M+1). RP HPLC: Tr=5.44 min. (Method 3)
Reaction SMILES: [H-].[Na+].[C:3]([N:10]1[CH2:15][CH2:14][C:13]([CH2:22][NH:23][S:24]([CH3:27])(=[O:26])=[O:25])([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH3:28]I>CN(C)C=O.C(OCC)(=O)C>[CH3:28][N:23]([CH2:22][C:13]1([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:12][CH2:11][N:10]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:15][CH2:14]1)[S:24]([CH3:27])(=[O:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC(CNS(C)(=O)=O)(C2CCCCC2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(CC1(C2CCCCC2)CCN(C(=O)OC(C)(C)C)CC1)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.28 h
Yield: 72.2 %

Procedure:
A 10-mL, round-bottomed flask was purged with nitrogen and then charged with a 60% sodium hydride dispersion in mineral oil (0.005 g, 0.125 mmol), and the flask was cooled at 0° C. in an ice-water bath. A solution of the sulfonamide from Step B (0.040 g, 0.107 mmol) in 0.8 mL of dimethylformamide was then added dropwise via syringe. The resulting mixture was stirred at 0° C. for 17 min, warmed to room temperature, and stirred for 10 min. The resulting thick mixture was then charged with methyl iodide (0.033 mL, 0.535 mmol), and the clear mixture was then stirred at room temperature for 5 days. The reaction mixture was then diluted with ethyl acetate and washed with two portions of 1 N HCl solution, saturated sodium bicarbonate solution, water, and saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated to give the title compound (0.030 g) as a light yellow oil.
Reaction SMILES: ClC([O:4][CH2:5][CH3:6])=O.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)CNCC1[C:22]([S:32][CH2:33][CH2:34][CH3:35])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:31]>C1COCC1.C(Cl)Cl>[CH3:30][C:29]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:24]=1[N:23]=[C:22]([S:32][CH2:33][CH2:34][CH3:35])[C:6]([CH:5]=[O:4])=[CH:31]2
Reactant: CCOC(=O)Cl
Reactant: CCCSc1nc2c(C)cccc2cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCSc1nc2c(C)cccc2cc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 229 %

Procedure:
To ethyl chloroformate (0.4 ml, 4.2 mmol) and potassium carbonate (0.875 g, 6.3 mmol) were added to (3,5-bis-trifluoromethyl-benzyl)-(8-methyl-2-propylsulfanyl-quinolin-3-ylmethyl)-amine (1.058 g, 2.1 mmol) which was dissolved in anhydrous THF (10 mL). The resulting mixture was stirred at room temperature for overnight. The mixture was diluted with methylene chloride, and was washed one time with water. The organic phase was dried over potassium carbonate and concentrated by rotary evaporation. The resulting sample was dried under vacuum gave a light yellow solid (1.18 g, 97%).
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=2[NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:4]([Cl:23])[CH:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Sn](CCCC)(CCCC)CCCC>O1CCOCC1.O>[Cl:13][C:11]1[CH:10]=[CH:9][C:8]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:7]([O:6][C:5]2[CH:21]=[CH:22][C:2]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)=[CH:3][C:4]=2[Cl:23])[CH:12]=1
Reactant: CCOC(=O)CNc1ccc(Cl)cc1Oc1ccc(Br)cc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CNc1ccc(Cl)cc1Oc1ccc(-c2ccccn2)cc1Cl

Procedure:
The subtitle compound was prepared by using the product from example 30 step ii) (0.20 g) which was dissolved in dry dioxane (10 ml). 2-pyridyl tributyl tin (0.181 g) and palladium (0) tetrakistriphenylphosphine (0.028 g) were added and the mixture was heated at 80 C for 16 hours. The mixture was diluted with water, extracted with ethyl acetate, dried and concentrated under reduced pressure to give an oil. Yield 0.20 g.