Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)O[C@H:6]1[CH2:10][C@@H:9]([N:11]2[CH:19]=[N:18][C:17]3[C:12]2=[N:13][C:14]([Cl:38])=[N:15][C:16]=3[NH:20][CH:21]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH:8]=[CH:7]1)C.[NH:40]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH:21]([NH:20][C:16]2[N:15]=[C:14]([Cl:38])[N:13]=[C:12]3[C:17]=2[N:18]=[CH:19][N:11]3[C@@H:9]2[CH2:10][C@H:6]([N:40]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:48]([O:50][C:51]([CH3:52])([CH3:53])[CH3:54])=[O:49])[CH:7]=[CH:8]2)[C:30]2[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)=[CH:27][CH:26]=1
Reactant: CCOC(=O)O[C@@H]1C=C[C@H](n2cnc3c(NC(c4ccc(OC)cc4)c4ccc(OC)cc4)nc(Cl)nc32)C1
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(C(Nc2nc(Cl)nc3c2ncn3[C@H]2C=C[C@@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Carbonic acid (1S,4R)-4-(6-{[bis-(4-methoxy-phenyl)-methyl]-amino}-2-chloro-purin-9-yl)-cyclopent-2-enyl ester ethyl ester (2.00 g, 3.64 mmol), di-t-butyl iminodicarboxylate (0.87 g, 4.00 mmol) and triphenylphosphine (0.14 g, 0.55 mmol) are placed in an oven-dried flask under an atmosphere of argon. Dry deoxygenated THF (20 ml) is added followed by tetrakis(triphenylphosphine)palladium(0) (0.21 g, 0.18 mmol) and the mixture is stirred at room temperature. The reaction is shown to be complete by LCMS after 3 hours. The solvent is removed in vacuo and the title compound is obtained after purification by flash column chromatography (silica, iso-hexane/ethyl acetate 4:1). 1H nmr (CDCl3, 400 MHz); 8.20 (s, 1H), 7.25 (d, 4H), 6.85 (d, 4H), 6.60 (m, 1H), 6.35 (m, 1H), 6.10 (m, 1H), 5.80 (m, 1H), 5.65 (m, 1H), 5.35 (m, 1H), 3.80 (s, 6H), 3.15 (m, 1H), 2.10 (m, 1H), 1.55 (s, 18H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]3[N:20]=[CH:21][N:22]([CH2:24][CH2:25][CH3:26])[CH:23]=3)[S:18][C:11]=12)[NH2:5].[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][C:35](=[O:40])[CH2:36][C:37](O)=[O:38].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:37](=[O:38])[CH2:36][C:35]([NH:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[F:27])=[O:40])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]3[N:20]=[CH:21][N:22]([CH2:24][CH2:25][CH3:26])[CH:23]=3)[S:18][C:11]=12
Reactant: CCCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Reactant: O=C(O)CC(=O)Nc1ccccc1F
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5F)cc4F)c3s2)c1
Reaction time: 1 h
Yield: 36.4 %

Procedure:
To a solution of the amino compound 133 (400 mg, 1.08 mmol) in DMF (20 mL), 3-(2-fluorophenylamino)-3-oxopropanoic acid (29) (427 mg, 2.17 mmol), EDC (352 mg, 2.60 mmol) was added HOBT (499 mg, 2.60 mmol). The reaction mixture was allowed to stir for 1 hr. The solution was extracted with EtOAc and the extract was washed with water, aqueous ammonium chloride and brine then dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (eluents DCM-MeOH, 98:2, 95:5) to afford title compound 130 (215 mg, 36% yield) as a yellow solid. 1H NMR (DMSO-d6). δ (ppm): 10.56 (s, 1H), 10.06 (s, 1H), 8.43 (d, J=5.6 Hz, 1H), 8.10-7.96 (m, 1H), 7.94 (d, J=1.2 Hz, 1H), 7.87 (dd, J=1.6 and 12.8 Hz, 1H), 7.77 (d, J=1.2 Hz, 1H), 7.68 (s, 1H), 7.49 (t, J=8.8 Hz, 1H), 7.42 (dd, J=2.0 and 8.8 Hz, 1H), 7.32-7.25 (m, 1H), 7.22-7.14 (m, 2H), 6.58 (d, J=5.6 Hz, 1H), 3.98 (t, J=7.2 Hz, 2H), 3.62 (s, 2H), 1.78 (sex, J=7.2 Hz, 2H), 0.87 (t, J=7.2 Hz, 3H). MS (m/z): 548.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].[CH3:13][Si:14]([CH3:19])([CH3:18])[CH2:15][CH2:16]O.Cl.CN(C)CCCN=C=NCC.C(OCC)(=O)C>ClCCl.CN(C)C1C=CN=CC=1.CCCCCC>[CH3:13][Si:14]([CH3:19])([CH3:18])[CH2:15][CH2:16][O:11][C:10](=[O:12])[CH2:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1]
Reactant: O=C(O)Cc1ccc(I)cc1F
Reactant: C[Si](C)(C)CCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[Si](C)(C)CCOC(=O)Cc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
A solution of 2-fluoro-4-iodo phenyl acetic acid (0.3 g, 1.07 mmol) and 2-(trimethylsilyl)ethanol (0.28 mL, 1.95 mmol) in anhydrous dichloromethane (5 mL) was treated with 4-(dimethylamino)pyridine (0.275 g, 2.3 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.37 g, 1.95 mmol) and the resulting reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then subjected to flash column chromatography using 5% ethyl acetate in hexane as the eluent to afford the title compound as a white solid (0.37 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17](F)=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[C:5]2[CH:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1.ClC1C=C2C(=CC=1)NC=C2C1CCN(C)CC1.FC1C=CC(S(Cl)(=O)=O)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:12])=[O:13])[CH:6]=[C:5]2[CH:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1
Reactant: CN1CCC(c2cn(S(=O)(=O)c3ccc(F)cc3)c3ccc(Cl)cc23)CC1
Agent: CN1CCC(c2c[nH]c3ccc(Cl)cc23)CC1
Agent: O=S(=O)(Cl)c1ccc(F)cc1
Product: CN1CCC(c2cn(S(=O)(=O)c3ccccc3)c3ccc(Cl)cc23)CC1

Procedure:
(ttt) 5-Chloro-1-(4-fluorophenylsulfonyl )-3-(1-methyl-4-piperidinyl)indole (18.4 mg, 45%) from 5-chloro-3-(1-methyl-4-piperidinyl)-1H-indole (Example 5e, 25 mg, 0.1 mmol) and 4-fluorophenylsulfonyl chloride (29.2 mg, 0.15 mmol), HRMS-FAB+ for C20H20N2O2SClF, calculated MH+ : 407.09964; found: 407.09685.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15]Br.C1(C2(C#N)CCCC2)C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: BrCCCCBr
Agent: N#CC1(c2ccccc2)CCCC1
Product: N#CC1(c2ccc(Cl)cc2)CCCC1
Yield: 94 %

Procedure:
1-(4-chlorophenyl)-cyclopentanecarbonitrile (21-02) (32.01 g, 94%) was synthesized as a yellow liquid from (4-chlorophenyl)-acetonitrile (19-02) (25 g, 165.56 mmol) and 1,4-dibromo-butane (20) (19.7 mL, 165.56 mmol) following the procedure as described for 1-phenyl-cyclopentanecarbonitrile (21-01).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[K].O.[CH:14](=[O:22])[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[OH:17]>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH:7]=1)[O:17][C:16]1[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=1[CH:14]=[O:22]
Reactant: O=Cc1ccccc1O
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Agent: [K]
Solvent: O
Product: O=Cc1ccccc1Oc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 170 °C
Reaction time: 1.5 h

Procedure:
The 2-(5-chloro-2-nitrophenoxy)benzaldehyde was prepared as follows: To 16.2 g of 2,4-dichloronitrobenzene stirred at 170° was added 7.1 g of the potassium salt of salicylaldehyde, monohydrate, in portions over 1.5 hours. The mixture was stirred at 170° C. for two hours, triturated with 150 ml of CH2Cl2 and filtered. The filtrate was evaporated to a red oil and the excess dichloronitrobenzene was removed by steam distillation to leave the product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:17]([CH3:19])([CH3:18])[C:16]([CH3:20])=[N:15][C:5]2=[N+:6]([CH2:8][CH2:9][CH2:10]S([O-])(=O)=O)[CH:7]=1.C1C[O:27][S:24](=[O:26])(=[O:25])[CH2:23]C1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:17]([CH3:18])([CH3:19])[C:16]([CH3:20])=[N:15][C:5]2=[N+:6]([CH2:8][CH2:9][CH2:10][CH2:23][S:24]([O-:27])(=[O:26])=[O:25])[CH:7]=1
Reactant: CC1=Nc2c(cc(Cl)c[n+]2CCCS(=O)(=O)[O-])C1(C)C
Reactant: O=S1(=O)CCCCO1
Product: CC1=Nc2c(cc(Cl)c[n+]2CCCCS(=O)(=O)[O-])C1(C)C

Procedure:
Compound 26 is prepared analogously to compound 5 (Example 5), except that 1,4-butanesultone is used as a starting material.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[OH2:13]>>[CH:2]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)=[O:13]
Reactant: O
Reactant: O=C(O)Cc1ccc(CBr)cc1
Product: O=Cc1ccc(CC(=O)O)cc1

Procedure:
[4-(Bromomethyl)phenyl]acetic acid (4.6 g) and cupric nitrate trihydrate (5 g) were suspended in water (50 mL) and heated at reflux for 1 hr. The solution was allowed to cool and the resulting white solid collected and washed with water to give the subtitle compound (2.06 g); MS multimode (+) 165
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)[CH:9]=[CH:10][CH:11]=1)=[C:2]=[O:3].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([NH2:39])=[S:38])=[C:32]([CH3:40])[CH:31]=1>>[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([NH:39][C:2]([NH:1][CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[N:16]=[CH:15][N:14]([C:17]4[CH:22]=[CH:21][C:20]([O:23][C:24]([F:26])([F:25])[F:27])=[CH:19][CH:18]=4)[N:13]=3)[CH:7]=2)=[O:3])=[S:38])=[C:32]([CH3:40])[CH:31]=1
Reactant: COc1ccc(NC(N)=S)c(C)c1
Reactant: O=C=NCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Product: COc1ccc(NC(=S)NC(=O)NCCc2cccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)c2)c(C)c1

Procedure:
The title compound was prepared as described in Example 75 using 3-(3-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (CA44) and 1-(4-methoxy-2-methylphenyl)thiourea isolated as a white solid (0.105 g, 34%): 1H NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 10.07 (s, 1H), 9.42 (s, 1H), 8.13-8.05 (m, 2H), 8.04-7.96 (m, 2H), 7.66-7.57 (m, 2H), 7.53-7.45 (m, 1H), 7.42-7.32 (m, 2H), 7.01 (t, J=5.7 Hz, 1H), 6.85-6.81 (m, 1H), 6.76 (dd, J=8.7, 2.9 Hz, 1H), 3.74 (s, 3H), 3.45 (q, J=6.6 Hz, 2H), 2.89 (t, J=6.9 Hz, 2H), 2.15 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ −56.97; ESIMS m/z 517 ([M+H]+), 569 [(M−H)+].
Reaction SMILES: [CH3:1][N:2]1[C:10](S(C)(=O)=O)=[N:9][C:8]2[C:7](=[O:15])[NH:6][C:5]3=[CH:16][C:17]([O:19][CH2:20][CH2:21][O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:18][N:4]3[C:3]1=2.[BH4-].[Na+]>CN1C(=O)N(C)CCC1>[CH3:1][N:2]1[CH:10]=[N:9][C:8]2[C:7](=[O:15])[NH:6][C:5]3=[CH:16][C:17]([O:19][CH2:20][CH2:21][O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:18][N:4]3[C:3]1=2
Reactant: Cn1c(S(C)(=O)=O)nc2c(=O)[nH]c3cc(OCCOc4ccccc4)nn3c21
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Product: Cn1cnc2c(=O)[nH]c3cc(OCCOc4ccccc4)nn3c21
Temperature: 25 °C
Reaction time: 20 h
Yield: 44 %

Procedure:
A mixture of Example 84 Part B (1.8575 g, 4.60 mmol) and NiBr2(DME) (142 mg, 0.46 mmol) in DMPU (100 mL) was treated with NaBH4 (697 mg, 18.4 mmol) under stirring at room temperature. After 20 h, there was still significant amount of starting material left, therefore more NaBH4 (500 mg, 13.2 mmol) and NiBr2(DME) (1.44 g, 4.67 mmol) were added. Over the subsequent 24 h, additional NaBH4 (2.0 g, 53 mmol) and NiBr2(DME) (2.7 g, 8.75 mmol) were added to push the reaction to completion. The mixture was then quenched carefully with MeOH at ice temperature and filtered. The filtrate was neutralized with 1.0 N HCl to PH=7.0, precipitating some sticky solid. The solution layer was separated and concentrated. The residual solution was precipitated with EtOAc/hexanes to remove DMPU. The precipitated solid was purified by flash chromatography (MeOH/CHCl3, 3%), giving the title compound (658 mg, 44% yield). ESI m/z=326.25 [(M+H)+; calcd for C16H15N5O3+H: 326.13].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]3[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:31][CH2:30][CH:29]([N:32]5[CH2:33][CH2:34][NH:35][CH2:36][CH2:37]5)[CH2:28][CH2:27]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCN(c3ccc(N)cc3C#N)CC2)CC1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCNCC4)CC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Yield: 41.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 151 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.66 g) and 5-amino-2-[4-(4-tert-butoxycarbonylpiperazin-1-yl)piperidin-1-yl]benzonitrile (1.0 g), the title compound (0.54 g) was obtained, melting point: 226° C.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12]2=[O:20])=[CH:6][CH:5]=1.[Li+].[OH-].Cl>O1CCOCC1>[O:20]=[C:12]1[N:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:21])=[O:2])=[CH:5][CH:6]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[NH:13]1
Reactant: COC(=O)c1ccc(Cn2c(=O)[nH]c3ccccc32)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(Cn2c(=O)[nH]c3ccccc32)cc1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
A solution of 4-(2-Oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-benzoic acid methyl ester (0.25 mmol) in dioxane (1 mL) was treated with aqueous LiOH (1 M, 1.0 mL). After stirring at 23° C. for 2 h, the reaction was neutralized with aqueous HCl (1 M, 2.0 mL) and the resulting solid was isolated by filtration. The filter cake was rinsed with water and allowed to dry in vacuo to yield 4-(2-Oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-benzoic acid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([OH:13])=O)=[CH:9][N:10]=2)[CH:7]=1.[NH2:14][C:15]1[CH:16]=[C:17]([CH:28]=[CH:29][C:30]=1[F:31])[C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].BrC1C=CC2N(N=CC=2C(NC2C=C(C(=O)NCC3C=CC=CC=3N3CCN(C)CC3)C=CC=2C)=O)C=1>>[CH2:21]([NH:20][C:18]([C:17]1[CH:28]=[CH:29][C:30]([F:31])=[C:15]([NH:14][C:11]([C:8]2[N:6]3[CH:7]=[C:2]([I:1])[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[O:13])[CH:16]=1)=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)c1cnc2ccc(I)cn12
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccc1F
Agent: Cc1ccc(C(=O)NCc2ccccc2N2CCN(C)CC2)cc1NC(=O)c1cnn2cc(Br)ccc12
Product: O=C(NCc1ccccc1)c1ccc(F)c(NC(=O)c2cnc3ccc(I)cn23)c1

Procedure:
The title compound was prepared from 6-iodoimidazo[1,2-a]pyridine-3-carboxylic acid (step 1) and 3-amino-N-benzyl-4-fluorobenzamide (step 2) analogously 6-bromo-N-(2-methyl-5-(2-(4-methylpiperazin-1-yl)benzylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (Intermediate 4A);
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3]1=[O:22].Br[CH:24]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[CH2:28]([O:27][C:25]([CH:24]([NH:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:3]1=[O:22])[CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:26])[CH3:29]
Reactant: CCOC(=O)C(Br)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)CN1CC(c2ccco2)SCC(N)C1=O
Product: CCOC(=O)C(CCc1ccccc1)NC1CSC(c2ccco2)CN(CC(=O)OC(C)(C)C)C1=O

Procedure:
Following the procedure described in Example 42(h), 0.40 g of t-butyl α-[6-amino-2-(2-furyl)-5-oxoperhydro-1,4-thiazepin-4-yl]acetate [prepared as described in step (f) above] was N-alkylated using 0.68 g of ethyl 2-bromo-4-phenylbutyrate. The resulting product was subjected to silica gel column chromatography eluted with a 1:20 by volume mixture of ethyl acetate and methylene chloride, to separate it into two isomers, A and B, (ascribed to the asymmetric carbon atom to which the phenethyl group is attached).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH3:14])[N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:7]2=[O:23].C(N(CC)CC)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>C1COCC1>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([NH:2][CH2:3][C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[N:10]=[C:9]([CH3:14])[N:8]([CH:15]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]2=[O:22])[C:7]3=[O:23])=[O:40])=[CH:34][CH:33]=1
Reactant: Cc1nc2ccc(CN)cc2c(=O)n1C1CCC(=O)NC1=O
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc2ccc(CNC(=O)Nc3ccc(Cl)cc3)cc2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
To a stirred suspension of 3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.47 g, 1.4 mmol) and triethylamine (0.27 mL, 2.0 mmol) in THF (8 mL) at 5˜10° C., was added 4-chlorophenyl isocyanate (0.28 g, 1.8 mmol), and the mixture was stirred at room temperature overnight. The mixture was quenched with methanol (−1 mL), and the solvent was evaporated. The residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 1-(4-chloro-phenyl)-3-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-urea as an off-white solid (400 mg, 63% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min. kept 5 min, 6.18 min (98.9%); mp, 225-227° C.; 1HNMR (DMSO-d6) δ 2.15-2.20 (m, 1H, CHH), 2.56-2.91 (m, 6H, CHCH2, CH), 4.41 (d, J=5 Hz, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 6.81 (t, J=6 Hz, 1H, CH2NH), 7.23-7.95 (m, 7H, Ar), 8.80 (s, 1H, NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.93, 23.38, 30.61, 42.33, 56.54, 119.23, 120.01, 123.67, 124.57, 126.53, 128.42, 133.95, 139.05, 139.37, 145.74, 154.53, 155.09, 160.46, 169.47, 172.60. LCMS MH=454, 456; Anal Calcd For C22H20N5O4Cl+0.8H2O: C, 56.43; H, 4.65; N, 14.95; Cl, 7.57. Found: C, 56.45; H, 4.56; N, 14.87; Cl, 7.69.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([CH3:15])[CH:9]=2)=[N+:2]=[N-:3].[CH3:16][C:17]1[C:22]([CH2:23][NH:24][C:25](=[O:28])[CH2:26][CH3:27])=[C:21]([CH3:29])[N:20]=[C:19]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH:18]=1.O.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CC(O)(C)C.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:16][C:17]1[C:22]([CH2:23][NH:24][C:25]([C:26]2[N:3]=[N:2][N:1]([CH2:4][C:5]3[CH:6]=[N:7][C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[C:10]([CH3:15])[CH:9]=4)[CH:27]=2)=[O:28])=[C:21]([CH3:29])[N:20]=[C:19]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH:18]=1
Reactant: Cc1ccc2cc(CN=[N+]=[N-])cnc2c1
Reactant: CCC(=O)NCc1c(C)cc(NC(=O)OC(C)(C)C)nc1C
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1ccc2cc(Cn3cc(C(=O)NCc4c(C)cc(NC(=O)OC(C)(C)C)nc4C)nn3)cnc2c1
Temperature: 23 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(azidomethyl)-7-methylquinoline (46.0 mg, 0.232 mmol) and tert-butyl (4,6-dimethyl-5-(propionamidomethyl)pyridin-2-yl)carbamate (70 mg, 0.231 mmol) in t-BuOH (1.8 ml)/water (1.8 ml) were added copper(II) sulfate pentahydrate (11.52 mg, 0.046 mmol) and sodium ascorbate (45.7 mg, 0.231 mmol). Reaction mixture was stirred overnight at 23° C. Reaction mixture was poured into water and extracted twice with ethyl acetate. Combined organic layers were washed with brine, dried over sodium sulfate and evaporated to afford a crude product, which was purified by silica gel chromatography (cyclohexane/ethyl acetate from 100/0 to 0/100) to afford the title compound. HPLC (Method G) Rt=1.408 min, MS (Method V) [M+H]+=502.4.
Reaction SMILES: [OH2:1].[O:2]=[C:3]1[N:8]([Na:9])[C:7](=[O:10])[CH:6]=[N:5][NH:4]1>O.C(O)C.[Pt]=O>[OH2:2].[OH2:1].[O:2]=[C:3]1[N:8]([Na:9])[C:7](=[O:10])[CH2:6][NH:5][NH:4]1
Reactant: O=c1cn[nH]c(=O)n1[Na]
Agent: O=[Pt]
Solvent: O
Solvent: CCO
Product: O=C1CNNC(=O)N1[Na]

Procedure:
3,5-Dioxo-4-sodio-2,3,4,5-tetrahydro-1,2,4-triazine monohydrate (770 mg) dissolved in water (60 ml) is hydrogenated for 4 hours in the presence of platinum oxide (100 mg) at atmospheric pressure. The catalyst is filtered off, and the filtrate is concentrated in vacuo to give a colorless transparent liquid. The liquid is dissolved in ethanol (30 ml), and the solvent is then removed in vacuo to give amorphous solids of 3,5-dioxo-4-sodio-hexahydro-1,2,4-triazine dihydrate (Compound No. 4). Yield, 850 mg (98.2%). Softening temperature, 122.3° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=3)[C:23]#[N:24])[O:13]CC(C)(C)CO2)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].[CH3:33][N:34](C)C=O>[Cu+]>[C:23]([C:22]1[CH:21]=[C:20]([CH:27]=[CH:26][CH:25]=1)[O:19][CH2:18][CH2:17][CH2:16][C:8]([C:5]1[CH:4]=[CH:3][C:2]([C:33]#[N:34])=[CH:7][CH:6]=1)=[O:13])#[N:24]
Reactant: CC1(C)COC(CCCOc2cccc(C#N)c2)(c2ccc(Br)cc2)OC1
Reactant: CN(C)C=O
Agent: [Cu+]
Agent: O=C([O-])O
Agent: [Na+]
Product: N#Cc1ccc(C(=O)CCCOc2cccc(C#N)c2)cc1

Procedure:
500 mg (1.16 mmol) of 3-[3-[2-(4-bromophenyl)-5,5-dimethyl-1,3-dioxane-2-yl]propoxy]benzonitrile and 114 mg (1.27 mmol) of copper (1) cyamide were stirred in 1 ml of dimethylformamide at 140° C. overnight. Saturated aqueous sodium hydrogencarbonate solution was added to the resultant mixture. After the extraction with ethyl acetate, the organic layer was washed with saturated aqueous NaCl solution, and then dried over anhydrous magnesium sulfate. The solvent was evaporated. 10 ml of ethanol and 2 ml of 6 N hydrochloric acid were added to the residue, and the resultant mixture was heated under reflux for 5 hours. The solvent was evaporated. 1 N hydrochloric acid was added to the residue. After the extraction with ethyl acetate, the extract was washed with saturated aqueous NaCl solution and then dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was purified by the silica gel chromatography with ethyl acetate hexane as the extractant to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=C[C:7]=1[N+:12]([O-])=O)=[S:3].Br.Br[CH2:17]C(C1C=NC=CC=1)=O.[NH4+].[Cl-].ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.CCN(CC)CC>CCO.[Fe].CO>[N:12]1[CH:9]=[CH:10][CH:11]=[C:6]([C:5]2[N:4]=[C:2]([NH2:1])[S:3][CH:17]=2)[CH:7]=1
Reactant: O=C(CBr)c1cccnc1
Reactant: NC(=S)NCc1ccccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Br
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CO
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1nc(-c2cccnc2)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[(2-Nitrophenyl)methyl](4-(3-pyridyl)(1,3-thiazol-2-yl)amine was prepared according to the method described in Example 16 (Step b) by employing amino{[(2-nitrophenyl)methyl]amino}methane-1-thione (1.03 g, 4.9 mmol) (Example 16, Step a), 3-(bromoacetyl)pyridine hydrobromide (Aust. J. Chem. 1989, 42, 1735; 1.37 g, 4.9 mmol), and 50% MeOH (50 mL). The crude yellow oil, iron dust (Aldrich) (1.39 g, 24.9 mmol) and NH4Cl (198 mg, 3.7 mmol) in 50% EtOH (50 mL) was heated at reflux. After 1 h the solvent was removed in vacuo. The residue was dissolved in THF (20 mL) and to this solution was added 4-nitrophenyl chloroformate (Aldrich) (860 mg, 4.2 mmol) followed by Et3N (0.85 mL, 6.1 mmol) and the reaction was heated at reflux. After 1 h the reaction was cooled to RT and stirred overnight. The solvent was removed in vacuo and purified by flash chromatography on silica gel with Hexanes:EtOAc (1:1) to CH2Cl2:MeOH (39:1, 19:1) as eluant to give an off-white solid. Mp: 269–272° C. MS m/z: 309 (M+1). Calc'd for C16H12N4OS—308.07.