Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH2:12][CH2:11]3)[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[CH2:27]([S:29](Cl)(=[O:31])=[O:30])[CH3:28].O>C(Cl)Cl>[CH3:18][N:14]1[C:15]2[C:10](=[CH:9][C:8]([C:4]3[CH:3]=[C:2]([NH:1][S:29]([CH2:27][CH3:28])(=[O:31])=[O:30])[CH:7]=[N:6][CH:5]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:12][C:13]1=[O:19]
Reactant: CCS(=O)(=O)Cl
Reactant: CN1C(=O)CCc2cc(-c3cncc(N)c3)ccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)Nc1cncc(-c2ccc3c(c2)CCC(=O)N3C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.7 %

Procedure:
To a solution of 6-(5-amino-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one (intermediate A-2, 0.02 g, 0.079 mmol) in DCM (0.5 mL) was added triethylamine (0.024 g, 0.237 mmol) followed by ethanesulfonyl chloride (0.01 g, 0.079 mmol) and the reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with DCM, poured into water (5 mL) and the aqueous layer was extracted with DCM (2×20 mL). Combined organics were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 10% MeOH-DCM gradient to give the title compound (0.007 g, 23%) as a brown solid. MS: 346.0 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[CH:6]=[CH:7][CH:8]=1.[CH:32]1([S:35](Cl)(=[O:37])=[O:36])[CH2:34][CH2:33]1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[CH:32]1([S:35]([NH:1][CH2:2][C:3]2[CH:4]=[C:5]([C:9]3[CH:10]=[C:11]4[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=3)[NH:14][CH:13]=[C:12]4[CH:21]3[CH2:22][CH2:23][N:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])[CH2:25][CH2:26]3)[CH:6]=[CH:7][CH:8]=2)(=[O:37])=[O:36])[CH2:34][CH2:33]1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CN)c4)cc23)CC1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNS(=O)(=O)C5CC5)c4)cc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.7 %

Procedure:
To a solution of 5-[3-(aminomethyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (35 mg, 0.079 mmol) in DMF (1.0 mL) and DCM (1.0 mL) was added cyclopropanesulfonyl chloride (11 mg, 0.079 mmol) and DIEA (14 μL, 0.079 mmol). Reaction was stirred at room temperature overnight. Compound was purified by Gilson Preparatory HPLC to give 7.2 mg the title compound (17%).
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:4]1.[N+:26]([O-])([O-:28])=[O:27].[K+]>OS(O)(=O)=O>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:15][C:9]=3[C:8]([N+:26]([O-:28])=[O:27])=[CH:7][C:6]=2[N:5]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:4]1
Reactant: O=C(N1CC(CCl)c2c1ccc1cc(S(=O)(=O)Cl)ccc21)C(F)(F)F
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(N1CC(CCl)c2c1cc([N+](=O)[O-])c1cc(S(=O)(=O)Cl)ccc21)C(F)(F)F
Yield: 66.7 %

Procedure:
A solution of 113(250 mg, 0.63 mmol) in conc. H2SO4 (10 mL) was nitrated with KNO3 (65 mg, 0.65 mmol) in H2SO4 (5 mL) as above, to give 1-(chloromethyl)-5-nitro-3-(trifluoroacetyl)-1,2-dihydro-3H-benzo[e]indole-7-sulfonyl chloride (116) (192 mg, 67%) as a red solid: mp (EtOAc/petroleum ether) 184-189° C.; 1H NMR [(CDCl3)] a 9.34 (s, 1H), 9.28 (d, J=1.8 Hz, 1H), 8.22 (dd, J=9.0, 1.9 Hz, 1H), 8.11 (d, J=9.0 Hz, 1H), 4.77-4.71 (m, 1H), 4.58 (dd, J=11.5, 8.8 Hz, 1H), 4.42-4.33 (m, 1H), 3.95 (dd, J=11.7, 3.5 Hz, 1H 3.73 (dd, J=11.7, 7.7 Hz, 1H); 13C NMR δ 153.4 (q, JC-F 38 Hz), 153.0, 148.2, 147.0, 138.7, 133.2, 129.1, 126.7, 124.5, 122.0, 119.3, 115.9 (q, JC-F 288 Hz), 52.6, 47.3, 41.2. Anal. (C15H9Cl2F3N2O5S) C, H, N, Cl.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.C(OC([CH:70]([NH2:77])[CH:71]1[CH2:76][CH2:75][CH2:74][NH:73][CH2:72]1)=O)(C)(C)C.FC(F)(F)C(O)=O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:73]1[CH2:74][CH2:75][CH2:76][CH:71]([CH2:70][NH2:77])[CH2:72]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(C)(C)OC(=O)C(N)C1CCCNC1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCCC(CN)C3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 3-(tert.-butyloxycarbonyl-aminomethyl)-piperidine in DMSO at ambient temperature and subsequent treatment with trifluoroacetic acid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]1[O:10][C:9]2[CH:11]=[C:12]3[C:17](=[CH:18][C:8]=2[NH:7][C:6]1=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13]3.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1.C(N(CC)CC)C>CN(C)C=O>[F:20][C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][CH:5]3[O:10][C:9]4[CH:11]=[C:12]5[C:17](=[CH:18][C:8]=4[NH:7][C:6]3=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13]5)[CH2:29][CH2:28]2)=[CH:25][CH:26]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: O=C1Nc2cc3c(cc2OC1CCCBr)CCCC3
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1Nc2cc3c(cc2OC1CCCN1CCN(c2ccc(F)cc2)CC1)CCCC3
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 59.3 %

Procedure:
A mixture of 2-(3-bromopropyl)-6,7,8,9-tetrahydro-2H-naphtho[2,3-b][1,4]oxazin-3(4H)-one (3.1 g), 1-(4-fluorophenyl)piperazine (2.3 g), triethylamine (1.5 ml) and N,N-dimethylformamide (DMF)(100 ml) was stirred at 80° C. for 1.5 hour, which was diluted with ice-water and subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), from which the solvent was distilled off. The residue was recrystallized from chloroform-ethyl acetate to give 2.4 g (59.3%) of 2-{3-[4-(4-fluorophenyl)-1-piperazinyl]propyl}-6,7,8,9-tetrahydro-2H-naphtho[2,3-b][1,4]oxazin-3(4H)-one as colorless crystals, m.p. 164°-165° C.
Reaction SMILES: [CH2:1]([N:9]1[C:17]2[C:12](=[C:13]([CH3:32])[C:14]([CH2:26][C:27]([O:29]CC)=[O:28])=[C:15]([CH3:25])[C:16]=2[NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[Na+]>CCO.O>[CH2:1]([N:9]1[C:17]2[C:12](=[C:13]([CH3:32])[C:14]([CH2:26][C:27]([OH:29])=[O:28])=[C:15]([CH3:25])[C:16]=2[NH:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:22])[CH3:23])[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN1CCc2c(C)c(CC(=O)OCC)c(C)c(NC(=O)C(C)(C)C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCN1CCc2c(C)c(CC(=O)O)c(C)c(NC(=O)C(C)(C)C)c21
Temperature: 60 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
N-(1-Octyl-5-ethoxycarbonylmethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (3.5 g) was dissolved in EtOH (50 ml) and a solution of NaOH (1.6 g) in water (20 ml) was added, which was followed by stirring at 60° C. for 1 hr. EtOH was evaporated under reduced pressure. The residue was dissolved in water (20 ml) and the mixture was washed with AcOEt (20 ml). The aqueous layer was neutralized with 2N-hydrochloric acid and extracted with AcOEt (50 ml). The AcOEt layer was washed with saturated brine and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure to give 2.4 g of the title compound.
Reaction SMILES: F[C:2](F)([F:29])[CH2:3][CH2:4][CH2:5][CH:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:9]12[CH3:10])[C@:22]1([CH3:23])[C:17]([CH:18]=[C:19]([CH2:27][OH:28])[CH2:20][CH2:21]1)=[CH:16][CH2:15]3)[OH:7].C[N+]1([O-])CCO[CH2:34][CH2:33]1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:29][C:2]1[CH:34]=[CH:33][C:5]([C:6]([C@H:8]2[CH2:13][CH2:12][C@H:26]3[C@H:25]4[C@H:24]([CH2:14][CH2:11][C@:9]23[CH3:10])[C@:22]2([CH3:23])[C:17]([CH:18]=[C:19]([CH:27]=[O:28])[CH2:20][CH2:21]2)=[CH:16][CH2:15]4)=[O:7])=[CH:4][CH:3]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(CO)CC[C@@]43C)[C@@H]1CC[C@@H]2C(O)CCCC(F)(F)F
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: ClCCl
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
Tetrapropyl ammonium perruthenate is added to a solution of (17β)-17-(5,5,5-trifluoro-1-hydroxypentyl)-androsta-3,5-diene-3-methanol and 4-methylmorpholine N-oxide in CH2Cl2 (2.0 ml) at RT. After 1 h the reaction is flash chromatographed to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3C(C)=NC(C)=C[CH:19]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.[Li]CCCC.[CH3:40][N:41]1C(C=O)=C[N:43]=[CH:42]1.C(=O)=O>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[N:41]([CH3:40])[CH:42]=[N:43][CH:19]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][CH:26]=1
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: Cn1cncc1C=O
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)c3cncn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reaction time: 0.03 h

Procedure:
To a flask containing 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (Intermediate 12: step d, 3.0 g, 6.97 mmol) was added THF (40 ml) and the solution was cooled to −70° C. n-BuLi (2.5 M in hexanes, 2.8 mL, 7 mmol) was added dropwise. After 2 minutes, 1-methyl-1H-imidazole-5-carbaldehyde (1.2 g, 9 mmol, in 10 mL THF) was introduced. After 15 minutes, the dry-ice bath was replaced with a 0° C. bath. After 35 minutes the reaction mixture was quenched with aqueous NH4Cl solution and the aqueous portion was extracted with EtOAc:THF (10:2) 5×50 mL. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated to dryness to give the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:11])=[C:4]([OH:10])[CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Br.[C:22](=[O:25])([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.O>[Br:1][C:2]1[CH:9]=[C:6]([CH:5]=[C:4]([O:10][CH2:7][C:6]2[CH:9]=[CH:2][CH:3]=[C:4]([O:25][CH3:22])[CH:5]=2)[C:3]=1[O:11][CH2:17][C:16]1[CH:19]=[CH:20][CH:21]=[C:14]([O:13][CH3:12])[CH:15]=1)[CH:7]=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COc1cccc(CBr)c1
Reactant: O=Cc1cc(O)c(O)c(Br)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(COc2cc(C=O)cc(Br)c2OCc2cccc(OC)c2)c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 5-bromo-3,4-dihydroxybenzaldehyde (100 mg), 3-methoxybenzyl bromide (71 μl), potassium carbonate (140 mg) and tetrabutylammonium iodide (10 mg) in 5 ml of DMF was stirred at 60° C. for 3 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated in vacuo.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2C(OC(C)(C)C)=O)[CH:5]=[N:6][C:7]=1[Cl:8].[NH2:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[ClH:8].[ClH:8].[NH2:23][C:24]1[CH:29]=[C:28]([C:2]2[CH:3]=[C:4]([O:9][CH2:10][C@H:11]3[CH2:15][CH2:14][CH2:13][NH:12]3)[CH:5]=[N:6][C:7]=2[Cl:8])[CH:27]=[CH:26][CH:25]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cl
Product: Nc1cccc(-c2cc(OC[C@H]3CCCN3)cnc2Cl)c1
Yield: 95.8 %

Procedure:
To a solution of 5-bromo-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine from Example 69a (520 mg, 1.33 mmol) and 3-aminophenylboronic acid (310 mg, 2.0 mmol) in toluene (8 mL) was added Pd(0) (50 mg) and Na2CO3 (2.5 mL of a 2 M solution), and the mixture was heated at reflux for 16 hours. The solvent was removed under vacuum, and the residue was purified by chromatography on a silica gel column, eluting with CHCl3:Et2O 100:5-100:40 to afford 160 mg of the title compound. MS (CI/NH3) m/z 404 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 1.44 (s, 9H), 1.88 (m, 1H), 2.03 (m, 2H), 3.37 (m, 2H), 3.76 (m, 2H), 4.16 (m, 2H), 6.75 (m, 2H), 6.82 (m, 1H), 7.22 (m, 2H), 8.08 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:5]Cl.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:23][C:24]([O:26]C)=[O:25])[CH:19]=[CH:20][C:21]=1[OH:22]>CO.O>[Cl:15][C:16]1[CH:17]=[C:18]([CH2:23][C:24]([OH:26])=[O:25])[CH:19]=[CH:20][C:21]=1[O:22][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH:12]([CH3:13])[CH3:14])=[C:2]([Cl:1])[CH:3]=1
Reactant: CC(C)COc1ccc(CCl)cc1Cl
Reactant: COC(=O)Cc1ccc(O)c(Cl)c1
Solvent: CO
Solvent: O
Product: CC(C)COc1ccc(COc2ccc(CC(=O)O)cc2Cl)cc1Cl

Procedure:
The procedure of Example (1) (e) was repeated wherein 3-chloro-4-isobutyoxybenzyl chloride was reacted with methyl 3-chloro-4-hydroxyphenylacetate to yield 3-chloro-4-(3'-chloro-4'-isobutoxybenzyloxy) phenylacetic acid (52.4yield), m.p. 127.5°-129° C. (methanol-water).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[C:21]1[O:22][CH:23]=[CH:24][N:25]=1.[O:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][N:33]=2)[CH2:28][CH2:27]1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:36](=[O:37])[C:35]3[CH:39]=[CH:40][C:32]([N:29]4[CH2:28][CH2:27][O:26][CH2:31][CH2:30]4)=[N:33][CH:34]=3)=[C:4]([C:21]3[O:22][CH:23]=[CH:24][N:25]=3)[N:5]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1
Reactant: NCc1c(-c2ncco2)n(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: O=C(O)c1ccc(N2CCOCC2)nc1
Product: O=C(NCc1c(-c2ncco2)n(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(N2CCOCC2)nc1

Procedure:
N-(7-Chloro-2-oxazol-2-yl-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-6-morpho-lin-4-yl-nicotinamide was prepared starting from intermediate A and 6-morpholinonicotinic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.47 (d, J=1.76 Hz, 1H) 8.33 (d, J=8.28 Hz, 1H) 8.12 (t, J=4.50 Hz, 1H) 7.98 (d, J=0.75 Hz, 1H) 7.85 (dd, J=9.03, 2.51 Hz, 1H) 7.47-7.57 (m, 4H) 7.36-7.44 (m, 2H) 7.17 (s, 1H) 6.79 (d, J=9.03 Hz, 1H) 6.73 (d, J=2.01 Hz, 1H) 4.24 (d, J=4.52 Hz, 2H) 3.63-3.71 (m, 4H) 3.48-3.55 (m, 4H). MS calcd. for C29H24ClN5O4 [(M+H)+] 542.2, obsd. 542.0.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([CH2:13]Cl)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[C:1]1([C:7]2[N:12]=[C:11]([CH2:13][N:25]3[CH2:26][CH2:27][CH:22]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:23][CH2:24]3)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCc1ccnc(-c2ccccc2)n1
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: c1ccc(CC2CCN(Cc3ccnc(-c4ccccc4)n3)CC2)cc1
Temperature: 25 °C

Procedure:
To a solution of 50 mg of 2-phenyl-4-chloromethylpyrimidine in 5 mL chloroform was added 80 mg 4-benzylpiperidine and 1 mL of N,N-diisopropylethylamine. The reaction mixture was heated at reflux temperature for 4 hr, cooled to room temperature, washed with 5 mL 1 N sodium hydroxide solution and the solvent removed by evaporation under reduced pressure to yield 2-phenyl-4-[(4-benzyl-piperidin-1-yl)rnethyl]-pyrimidine. This material was purified by chromatography on silica gel using 5% methanol in dichloromethane as eluent. Evaporation of the solvent yielded a solid which was treated with ethereal-HCl to give 15 mg of 2-phenyl-4-[(4-benzyl-piperidin-1-yl)methyl]-pyrimidine dihydrochloride (Compound 11), mp 211-213° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([N+:13]([O-])=O)[CH:4]=1.[H][H]>C(OC)(=O)C.[Pt]=S>[NH2:13][C:5]1[CH:4]=[C:3]([S:2][CH3:1])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: [H][H]
Reactant: COC(=O)c1ccc(SC)cc1[N+](=O)[O-]
Agent: S=[Pt]
Solvent: COC(C)=O
Product: COC(=O)c1ccc(SC)cc1N

Procedure:
A mixture of methyl 4-(methylthio)-2-nitrobenzoate (11.3 g, 49.7 mmol) and 5% platinum sulfide on carbon catalyst (0.7 g) in methyl acetate (40 mL) was hydrogenated at 750 psi and 75° C. until hydrogen uptake ceased. The mixture was filtered through Celite®, and the filtrate solvent was rotary evaporated, leaving methyl 2-amino-4-(methylthio)benzoate as a slightly tan crystalline solid (8.7 g melting at 57°-59° C.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.O[N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17].C1(N=C=NC2CCCCC2)CCCCC1.CCOCC>O1CCOCC1>[C:1]([O:9][N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)c1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C(ON1C(=O)CCC1=O)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
Nicotinic acid (4.025 g, 0.0327 mol) and N-hydroxysuccinimide (3.763 g, 0.0327 mol) were dissolved in 130 ml of dioxane. Dicyclohexylcarbodiimide (6.75 g, 0.032 mol) in 20 ml of dioxane was added. The reaction mixture was then stirred at room temperature for 3 hours. The dicyclohexylurea which precipitated was removed by filtration and the solvent was removed by rotary evaporation. The crude product was recrystallized from ethyl acetate to give light yellow crystals which were then waashed with anhydrous ether. The product, obtained in 72% yield (5.2 g) and melting at 129°-131° C., has the formula: ##STR40##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.CCOC=[CH:15][C:16](=O)[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].Cl.[CH2:25](O)C>>[CH2:21]([O:20][C:18]([C:17]1[CH:25]=[N:9][N:8]([C:5]2[C:4]([F:10])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)[C:16]=1[CH3:15])=[O:19])[CH3:22]
Reactant: NNc1ncc(Cl)cc1F
Reactant: CCO
Reactant: CCOC=CC(=O)CC(=O)OCC
Agent: Cl
Product: CCOC(=O)c1cnn(-c2ncc(Cl)cc2F)c1C

Procedure:
5-Chloro-3-fluoro-2-hydrazinylpyridine (5 g) and ethyl (2-ethoxymethylene)-acetoacetate (5.76 g) synthesized according to the method described in J. Chem. Soc. Perkin trans. I, p. 1875 (1988) were added to a mixed solvent of 1 N hydrochloric acid aqueous solution (150 ml) and ethanol (100 ml), and stirred under reflux. After completion of the reaction, the mixture was allowed to cool, and the organic solvent was evaporated in vacuo. Then, the mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated in vacuo. The obtained residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 1-(5-chloro-3-fluoropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (6.95 g) as a pale yellow solid. MS (ESI) m/z: 284 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[N+:11]([O-:18])[CH:12]=[C:13]([CH:17]=1)[C:14]([OH:16])=O.[CH3:19][C:20]1[N:24]=[C:23]([C@H:25]([NH2:27])[CH3:26])[O:22][N:21]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[N+:11]([O-:18])[CH:12]=[C:13]([CH:17]=1)[C:14]([NH:27][C@@H:25]([C:23]1[O:22][N:21]=[C:20]([CH3:19])[N:24]=1)[CH3:26])=[O:16]
Reactant: Cc1ccc(-c2cc(C(=O)O)c[n+]([O-])c2)c(F)c1
Reactant: Cc1noc([C@@H](C)N)n1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3nc(C)no3)c[n+]([O-])c2)c(F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 57.4 %

Procedure:
To a solution of 5-(2-fluoro-4-methylphenyl)nicotinic acid 1-oxide (22.6 mg, 0.09 mmol) in DMF (0.5 mL) were added hydrochloride salt of (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine (23.8 mg, 0.12 mmol), EDC (26.3 mg, 0.14 mmol), HOBT (15.4 mg, 0.10 mmol) and diisopropylethylamine (64 μL, 0.37 mmol). The mixture was stirred at ambient temperature. After 72 h, the mixture was purified by reverse chromatography (C-18, 95% water/acetonitrile→25% water/acetonitrile with 0.1% trifluoroacetic acid) to give the title compound (18.4 mg). HRMS 357.1367 (M+1). 1H NMR (400 MHz, CDCl3): δ 9.02 (s, 1H); 8.73 (d, J=7.6 Hz, 1H); 8.53 (s, 1H); 7.98 (s, 1H); 7.32 (t, J=8.0 Hz, 1H); 7.08 (d, J=8.0 Hz, 1H); 7.02 (d, J=11.8 Hz, 1H); 5.60-5.51 (m, 1H); 2.42 (s, 3H); 2.29 (s, 3H); 1.80 (d, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([C:29]3[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=3)[C:22]3[C:17](=[CH:18][C:19]([OH:43])=[C:20]([O:41][CH3:42])[CH:21]=3)[C:16]2=[O:44])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(Cl)(O[C:56](=[O:62])OC(Cl)(Cl)Cl)Cl.[CH3:64][N:65]1[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]1>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([C:29]3[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=3)[C:22]3[C:17](=[CH:18][C:19]([O:43][C:56]([N:68]4[CH2:69][CH2:70][N:65]([CH3:64])[CH2:66][CH2:67]4)=[O:62])=[C:20]([O:41][CH3:42])[CH:21]=3)[C:16]2=[O:44])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCNCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2cc(OC)c(O)cc2c(=O)n1-c1ccc(NC(=O)OC(C)(C)C)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2cc(OC)c(OC(=O)N3CCN(C)CC3)cc2c(=O)n1-c1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
A solution of the compound obtained in Example 5 (100 mg) and triethylamine (50 mg) in chloroform (10 ml) is cooled to −10° C., and thereto is added dropwise a solution of triphosgene (49 mg) in chloroform. The mixture is warmed to room temperature, and the mixture is stirred for 30 minutes. To the mixture is added a solution of N-methylpiperazine (50 mg) and triethylamine (17 mg) in chloroform, and the mixture is further stirred for two hours. After the reaction is complete, the reaction mixture is washed, dried, and concentrated under reduced pressure. The residue is crystallized from diethyl ether to give 2[4-(tert-butoxycarbonylamino)phenyl]-6-methoxy-3-methoxycarbonyl-7-(4-methylpiperazinylcarbonyloxy)-4-(3,4,5-trimethoxyphenyl)-1(2H)-isoquinolinone (73 mg) as listed in Table 20.
Reaction SMILES: [CH2:1]([CH:8]1[O:13][CH2:12][CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:14][C:15]([F:20])([F:19])[C@@H:16]1[CH2:18][O:17]1>>[CH2:1]([CH:8]1[O:13][CH2:12][CH2:11][N:10]([CH2:18][C@H:16]([OH:17])[C:15]([F:20])([F:19])[F:14])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CC2CNCCO2)cc1
Reactant: FC(F)(F)[C@@H]1CO1
Product: O[C@@H](CN1CCOC(Cc2ccccc2)C1)C(F)(F)F
Reaction time: 0.5 h

Procedure:
In a 25 mL round-bottom flask was placed 2-benzylmorpholine (354 mg, 2 mmol), followed by (S)-2-(trifluoromethyl)oxirane (224 mg, 2 mmol). The mixture was stirred for 30 min. Another 100 uL of (S)-2-(trifluoromethyl)oxirane was added. Reaction mixture was continued at room temperature overnight, then concentrated in vacuo to afford (S)-3-(2-benzyl-morpholin-4-yl)-1,1,1-trifluoro-propan-2-ol a colorless oil (600 mg).