Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.CN(C)CCN(C)C.[Li]CCCC.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([B:24]([OH:29])[OH:25])=[CH:7][C:6]=2[CH:10]=1
Reactant: Fc1ccc2occc2c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cc2cc(F)ccc2o1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 26.5 %

Procedure:
To a solution of 5-fluorobenzofuran (10 g, 73.53 mmol) in dry tetrahydrofuran (250 mL) was added tetramethylethylenediamine (10.2 g, 87.93 mmol). The solution was kept below −60° C. under nitrogen, while BuLi (93.75 mmol, 2.5M solution in hexane) was added dropwise. It was warmed to −10° C. during 45 min and stirred at this temperature for another 30 min. The mixture was cooled again below −60° C. followed by dropwise addition of triisopropyl borate (41.4 g, 220.21 mmol). After warming to room temperature the mixture was quenched with hydrochloric acid (70 mL, 2N) and stirred for 1 h. The alkaline aqueous layer was brought to pH 5 and extracted with ethyl acetate (3×80 mL). All organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give 5-fluorobenzofuran-2-ylboronic acid (3.5 g, 26%) which was used for the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:20][CH:21]=[CH2:22])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:24][OH:25].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:20][CH:21]=[CH2:22])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:24]\[OH:25])=[CH:4][CH:3]=1
Reactant: C=CCC(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCC(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-phenyl)-hex-5-enoyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI−): m/z=373.1 [M−H]−.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:15](=O)[C:14]2[C:9](=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7]1)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:22])=O.N>C(Cl)(Cl)Cl>[Cl:22][C:15]1[C:14]2[C:9](=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)C1C=Nc2c(cccc2[N+](=O)[O-])C1=O
Agent: N
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Yield: 75 %

Procedure:
A mixture of 3-ethoxycarbonyl-8-nitro-4-oxo-3,4-dihydro-quinoline (10.2 g) and phosphorous oxychloride (10 ml) was stirred at reflux for 2 hours. The warm reaction mixture was added cautiously to a vigorously stirred mixture of ice, concentrated aqueous ammonia and chloroform. The organic layer was separated, washed with water, dried and evaporated to dryness. The residue was purified by flash chromatography on silica using chloroform as eluant to give 4-chloro-3-ethoxycarbonyl-8-nitro-quinoline in 75% yield, mp 253-254° C.
Reaction SMILES: C(=O)([O-])O.[Na+].[CH2:6]([O:13][C:14](Cl)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:17]1[C:22]([NH2:23])=[CH:21][CH:20]=[C:19]([OH:24])[CH:18]=1.Cl>O.O1CCOCC1>[CH2:6]([O:13][C:14]([NH:23][C:22]1[CH:17]=[CH:18][C:19]([OH:24])=[CH:20][CH:21]=1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1ccc(O)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.2 %

Procedure:
10.1 g (0.12 mol) of sodium hydrogencarbonate and 17.2 ml (0.12 mol) of benzyloxycarbonyl chloride were added at 0° C. to a suspension of 12.5 g (0.11 mol) of p-aminophenol in 100 ml of a 1:1 by volume mixture of dioxane and water, and the mixture was stirred at room temperature for 18 hours. At the end of this time, the reaction mixture was acidified with 2N aqueous hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was triturated with a 1:1 by volume mixture of hexane and diethyl ether, to give 22.8 g of the title compound as colorless crystals, melting at 156°-157° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N:9]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]2)[CH:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:15](=[O:17])[CH3:16])=[C:4]([N:9]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]2)[CH:3]=1
Reactant: Cc1cn(-c2cc(F)ccc2N)cn1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(F)cc1-n1cnc(C)c1
Yield: 63.3 %

Procedure:
Reaction of intermediate 2A (17.5 g, 91.4 mmol) and acetic anhydride (90 mL, 914 mmol) provided the product 3A as an off-white powder (13.5 g, 64% yield). EIMS 234.1 [M+H]+.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=O)(C)(C)C.[OH:20][CH2:21][CH2:22][N:23]1[C:28](=[O:29])[CH2:27][CH2:26][CH:25]([N:30]2[C:38](=[O:39])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]2=[O:40])[C:24]1=[O:41]>C(O)(C(F)(F)F)=O.C(Cl)Cl.C(Cl)Cl>[NH2:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11].[OH:20][CH2:21][CH2:22][N:23]1[C:28](=[O:29])[CH2:27][CH2:26][CH:25]([N:30]2[C:31](=[O:40])[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:38]2=[O:39])[C:24]1=[O:41]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C1CCC(N2C(=O)c3ccccc3C2=O)C(=O)N1CCO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
2-(1-(2-hydroxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (S)-2-(tert-butoxycarbonylamino)-3-phenylpropanoate (100 mg) was dissolved in 25% TFA/DCM (10 mL) and stirred on a magnetic strirrer at room temperature. The mixture was allowed to react for 4 hrs. DCM and most of TFA were removed by rotary evaporation in vacuo. The foam obtained was dissolved in DCM (50 mL). The mixture washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and filtered. 52 mg of a solid was obtained after drying in vacuo. 1H NMR (CDCl3, ppm) δ 7.80-7.90 (m, 2H), 7.70-7.80 (m, 2H), 7.10-7.35 (m, 5H), 4.95-5.12 (m, 1H), 4.35-4.45 (m, 1H), 4.15-4.25 (m, 2H), 4.00-4.15 (m, 1H), 3.65-3.72 (m, 1H), 2.95-3.10 (m, 2H), 2.75-2.90 (m, 3H), 2.12-2.20 (m, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][CH:9]([C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:35][N:34]=1)[CH:10]([NH:25][C:26](=[O:32])OC(C)(C)C)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:24])([F:23])[CH:20]([F:22])[F:21])[CH:13]=1.C(=O)([O-])O.[Na+].[C:51]1(C(O)=O)[CH:52]=[CH:53][CH:54]=[C:55]2[CH2:61][CH2:60][CH2:59][CH:58]=[CH:57][C:56]=12.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[OH:8][CH:9]([C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:35][N:34]=1)[CH:10]([NH:25][C:26]([C:54]1[CH:53]=[CH:52][CH:51]=[C:56]2[CH2:57][CH2:58][CH2:59][CH:60]=[CH:61][C:55]=12)=[O:32])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:23])([F:24])[CH:20]([F:22])[F:21])[CH:13]=1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Reactant: CC(C)(C)OC(=O)NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Oc2ccccc2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Oc2ccccc2)cn1)c1cccc2c1C=CCCC2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Trifluoroacetic acid (5 ml) was added to tert-butyl (1RS,2RS)-2-hydroxy-2-(5-phenoxypyridin-2-yl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethylcarbamate (300 mg, 0.56 mmol), and the mixture was stirred at 0° C. for 10 min. The reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate (20 ml×2). The extract was washed with saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. To the residue in acetonitrile (20 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (105 mg, 0.56 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (161 mg, 0.84 mmol) and 1-hydroxybenzotriazole hydrate (86 mg, 0.56 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1). Recrystallization from ethyl acetate-hexane gave the objective substance (140 mg, 41%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.Cl[C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[NH:22][CH:23]=[N:24]2>CN(C=O)C.C([O-])(O)=O.[Na+]>[N:28]1[C:20]([NH:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:10])[CH2:5][CH2:4]2)=[C:21]2[C:25]([NH:24][CH:23]=[N:22]2)=[N:26][CH:27]=1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Clc1ncnc2nc[nH]c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCC(CNc2ncnc3[nH]cnc23)CC1
Reaction time: 18 h

Procedure:
In DMF (5 mL), benzyl 4-(aminomethyl)-1-piperidinecarboxylate (1.20 g, 4.83 mmol) and 6-chloropurine (448 mg, 2.49 mmol) were combined and treated with TEA in a single portion and aged under N2 at 100° C. for 18 h. The resulting reaction was diluted with sat. NaHCO3 and extracted with ethyl acetate (3×). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give a brown oil which was purified by silica gel chromatography (20 g, 32–60 μm silica, 99:1:0.1 to 90:10:1 CH2Cl2:CH3OH:NH4OH) to give benzyl 4-[(9H-purin-6-ylamino)methyl]-1-piperidinecarboxylate as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH2:9][N:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH3:11])=[CH:4][CH:3]=1.OS(O)(=O)=O.[OH-].[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:18]3[C:13](=[C:14]([Cl:20])[CH:15]=[C:16]([Cl:19])[CH:17]=3)[CH2:12][N:10]([CH3:11])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CN(Cc1ccc(Cl)cc1Cl)CC(O)c1ccc(Br)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
5.45 g (14.0 mmol) of 1-(4-bromo-phenyl)-2-[(2,4-dichloro-benzyl)-methyl-amino]-ethanol was introduced into 15 ml of dichloromethane and, at 0° C., 15 ml of conc. H2SO4 are added. After stirring at room temperature for 2 hours, the reaction mixture was poured onto ice and made alkaline with 6 N NaOH. Three extractions with dichloromethane were carried out. The combined organic phases were dried with MgSO4 and concentrated. For further purification, the residue was chromatographed on silica gel, resulting in 2.6 g of the title compound as a yellowish oil. 4-(4-Bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline, Hydrochloride;
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:19]1[C:24](Br)=[CH:23][CH:22]=[CH:21][N:20]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)(C)(C)C.C([Sn](CCCC)(CCCC)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)CCC.[ClH:46]>O1CCOCC1.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>[ClH:46].[ClH:46].[N:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[C:24]1[C:19]([C@H:8]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:13][CH:14]=2)[NH2:7])=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1-c1ccccn1
Temperature: 125 °C
Reaction time: 2 h

Procedure:
A mixture of (S)-tert-butyl(3-bromopyridin-2-yl)(4-(trifluoromethyl)-phenyl)methylcarbamate (Intermediate 40, Step 5) (0.711 g, 1.649 mmol), 2-(tributylstannyl)pyridine (0.910 g, 2.473 mmol), and (Ph3P)4Pd (0.381 g, 0.330 mmol) in 1,4-dioxane (10 mL) was heated by microwave at 125° C. for 30 min. The reaction mixture was then cooled, concentrated, and purified by ISCO (silica gel, 0-60% EtOAc/hexanes). The residue was dissolved in DCM (3 mL) and hydrogen chloride (3.30 mL, 13.19 mmol, 4.0 M in 1,4-dioxane) was added. After stirring for 2 h, the mixture was concentrated to dryness to give the title compound. MS (ESI pos. ion) m/z: 330.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:15])[F:14])[NH:6]2.Cl[CH2:17][C:18]1[S:19][C:20]([CH:23]2[CH2:25][CH2:24]2)=[N:21][N:22]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:14])[F:15])[N:6]2[CH2:17][C:18]1[S:19][C:20]([CH:23]2[CH2:25][CH2:24]2)=[N:21][N:22]=1
Reactant: ClCc1nnc(C2CC2)s1
Reactant: N#Cc1ccc2[nH]c(C(F)F)cc2c1Cl
Product: N#Cc1ccc2c(cc(C(F)F)n2Cc2nnc(C3CC3)s2)c1Cl

Procedure:
Synthesized as described in Example 39 from 4-chloro-2-(difluoromethyl)-1H-indole-5-carbonitrile and 2-(chloromethyl)-5-cyclopropyl-1,3,4-thiadiazole: MS (ESI) m/z 365 (M+1).
Reaction SMILES: CCCCCC.C([Li])CCC.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=1.[CH3:20][Si:21](Cl)([CH3:23])[CH3:22]>O1CCCC1>[CH3:20][Si:21]([CH3:23])([CH3:22])[N:12]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=1)[Si:21]([CH3:23])([CH3:22])[CH3:20]
Reactant: Cc1cccc(N)n1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cccc(N([Si](C)(C)C)[Si](C)(C)C)n1
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
A 15% n-hexane solution (636 g.) of n-butyllithium was added to a solution of 2-amino-6-methylpyridin (64.8 g.) in tetrahydrofuran (500 ml.) at -20° to -30° C. over one hour, and stirred at -8° to -10° C. for 30 minutes. To the solution was added trimethylsilylchloride (161.7 g.) at -15° to -5° C. over 40 minutes, and the resultant solution was stirred at room temperature overnight. The solution was filtered through by a column packed with silica gel (180 g.), washed with tetrahydrofuran and then the filtrate was concentrated under reduced pressure. The residue was purified by fractional distillation to give a 2-[N,N-bis(trimethylsilyl)amino]-6-methylpyridine (117.6 g.), b.p. 95° to 97° C./5-6 mmHg.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[C:8]([CH3:20])[CH:7]=1)(=[O:5])=[O:4].C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30]>O1CCCC1>[CH3:1][N:2]([CH3:21])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]([C:29](=[O:31])[CH3:30])[S:13]([C:16]([F:19])([F:17])[F:18])(=[O:15])=[O:14])=[C:8]([CH3:20])[CH:7]=1)(=[O:4])=[O:5]
Reactant: CC(=O)Cl
Reactant: Cc1cc(S(=O)(=O)N(C)C)ccc1NS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N(c1ccc(S(=O)(=O)N(C)C)cc1C)S(=O)(=O)C(F)(F)F
Yield: 76.7 %

Procedure:
To a solution of N,N-dimethyl-3-methyl-4-(trifluoromethanesulfonamido)benzenesulfonamide (1.5 g) and triethylamine (0.65 g) in tetrahydrofuran (40 ml), acetyl chloride (0.51 g) was added, and the resultant mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and solidified with water. The solidified product was recrystallized from a mixture of ethanol and toluene to give 1.29 g of N,N-dimethyl-3-methyl-4-(N-acetyl-N-trifluoromethanesulfonylamino)benzenesulfonamide (Compound No. 21). M.P., 148°-148.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.Cl[C:23]1[C:32]2[C:27](=[CH:28][N:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][N:24]=1.CCN(C(C)C)C(C)C>C(OCCO)C>[CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:23]2[C:32]3[C:27](=[CH:28][N:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][N:24]=2)=[CH:8][CH:7]=1
Reactant: Clc1nccc2cnccc12
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Solvent: CCOCCO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(Nc2nccc3cnccc23)cc1)NC(=O)OC(C)(C)C
Yield: 46.7 %

Procedure:
(S)-3-(4-Amino-phenyl)-2-tert-butoxycarbonylamino propionic acid methyl ester (574 mg, 1.95 mmol), 1-Chloro-2,6-naphthyridine (350 mg, 2.13 mmol) (prepared according to the method of Van der Plas, H. C. et al J. Heterocyclic Chem. 1981, 18, 1349) and DIPEA (372 μl, 2.13 mmol) in 2-ethoxyethanol (0.5 ml) were stirred at 130° C. under N2 overnight. The reaction mixture was partitioned between EtOAc (70 ml) and saturated aqueous NaHCO3 (30 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (3×30 ml). The combined organic extracts were dried (MgSO4) and the solvents eliminated in vacuo. The residue was purified by flash chromatography (5:1 to 1:1 hexanes/EtOAc) to give (S)-2-tert-butoxycarbonylamino-3-[4-([2,6]naphthyridin-1-ylamino)phenyl] propionic acid methyl ester (385 mg, 47%) as an orange foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]([O:10][CH3:11])=[CH:8][C:6]([NH2:7])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.[CH:15]([C:17]([CH3:19])=O)=[CH2:16]>>[CH3:11][O:10][C:9]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]2[C:8]=1[C:17]([CH3:19])=[CH:15][CH:16]=[N:7]2
Reactant: COc1cc(N)c([N+](=O)[O-])cc1OC
Reactant: C=CC(C)=O
Product: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OC
Yield: 27 %

Procedure:
A Skraup reaction of 4,5 -dimethoxy-2-nitroaniline with methyl vinyl ketone gave a 27% yield of 5,6-dimethoxy-4-methyl-8-nitroquinoline. The yellow compound crystallized well from methanol; mp 126°-127.5°.
Reaction SMILES: CS(Cl)(=O)=O.O[C:7]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([CH:24]2[O:28][N:27]=[C:26]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[CH2:25]2)=[O:23])=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8].C(N(CC)CC)C.O>C(Cl)Cl>[C:9]1([C:7]([C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22]([CH:24]3[O:28][N:27]=[C:26]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)[CH2:25]3)=[O:23])=[CH:19][CH:20]=2)=[CH2:8])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(O)(c1ccccc1)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(c1ccccc1)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Temperature: 0 °C
Yield: 27.1 %

Procedure:
) Methanesulfonyl chloride (0.010 mol) was added to a solution of compound (51) (0.005 mol) and triethylamine (0.013 mol) in CH2Cl2 (100 ml, dried over MgSO4), stirred at 0° C. The resulting reaction mixture was stirred for 1 hour at 10° C. Water was added. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by short column chromatography over silica gel (eluent: CH2Cl2/CH3OH 97/3). The pure fractions were collected and the solvent was evaporated under reduced pressure. The residue was crystallized from EtOAc. The precipitate was filtered off, washed with EtOAc, then dried, yielding 0.5 g (27%) of (±)4,5-dihydro-N-[4-(1-phenylethenyl)phenyl]-3-(3-pyridinyl)-5-isoxazolecarboxamide (compound 378).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([NH:10][C:11]2[C:16](=[O:17])[N:15]([CH3:18])[CH:14]=[C:13]([C:19]3[C:24]([CH:25]=[O:26])=[C:23]([N:27]4[CH2:39][CH2:38][C:37]5[N:36]6[C:31]([CH2:32][CH2:33][CH2:34][CH2:35]6)=[CH:30][C:29]=5[C:28]4=[O:40])[N:22]=[CH:21][CH:20]=3)[CH:12]=2)[CH:5]=1.[BH4-].[Na+]>CO>[OH:26][CH2:25][C:24]1[C:23]([N:27]2[CH2:39][CH2:38][C:37]3[N:36]4[C:31]([CH2:32][CH2:33][CH2:34][CH2:35]4)=[CH:30][C:29]=3[C:28]2=[O:40])=[N:22][CH:21]=[CH:20][C:19]=1[C:13]1[CH:12]=[C:11]([NH:10][C:6]2[CH:5]=[C:4]([CH2:3][O:2][CH3:1])[N:8]([CH3:9])[N:7]=2)[C:16](=[O:17])[N:15]([CH3:18])[CH:14]=1
Reactant: COCc1cc(Nc2cc(-c3ccnc(N4CCc5c(cc6n5CCCC6)C4=O)c3C=O)cn(C)c2=O)nn1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COCc1cc(Nc2cc(-c3ccnc(N4CCc5c(cc6n5CCCC6)C4=O)c3CO)cn(C)c2=O)nn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.9 %

Procedure:
To a solution of 336e (100 mg, 0.18 mmol) in methanol (10 mL) was added NaBH4 (41 mg, 1.08 mmol). The mixture was stirred at room temperature for 1 h and LCMS showed the starting material had disappeared. The reaction was quenched with 1.0 M HCl solution (10 mL) and evaporated under reduced pressure until most of methanol was distilled. The residue was extracted with dichloromethane (3×15 mL). The combined organic layer was dried with Na2SO4 and evaporated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 336 as a white solid (41 mg, 41%). MS-ESI: [M+H]+ 544.2. 1H NMR (500 MHz, CDCl3) δ 8.49 (d, J=5.0 Hz, 1H), 7.96 (d, J=2.5 Hz, 1H), 7.73 (d, J=2.5 Hz, 1H), 7.41 (s, 1H), 7.33 (d, J=5.0 Hz, 1H), 6.33 (s, 1H), 5.95 (s, 1H), 4.99-4.96 (m, 1H), 4.67-4.64 (m, 1H), 4.42-4.41 (m, 3H), 4.36-4.26 (m, 1H), 3.98-3.91 (m, 1H), 3.88-3.82 (m, 2H), 3.79 (s, 3H), 3.71 (s, 3H), 3.37 (s, 3H), 3.06-2.91 (m, 2H), 2.87-2.79 (m, 2H), 2.08-2.01 (m, 2H), 1.91-1.86 (m, 2H).
Reaction SMILES: C1(C#C)C=CC=CC=1.[C:9]1([C@H:15]([OH:18])[C:16]#[CH:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:19]([C:22]1[S:23][C:24]([C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[C:25]([CH3:27])[N:26]=1)=[N+:20]=[N-:21]>>[CH2:31]([NH:30][C:28]([C:24]1[S:23][C:22]([N:19]2[CH:17]=[C:16]([C@H:15]([OH:18])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:21]=[N:20]2)=[N:26][C:25]=1[CH3:27])=[O:29])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Cc1nc(N=[N+]=[N-])sc1C(=O)NCc1ccccc1
Reactant: C#C[C@@H](O)c1ccccc1
Solvent: C#Cc1ccccc1
Product: Cc1nc(-n2cc([C@H](O)c3ccccc3)nn2)sc1C(=O)NCc1ccccc1
Yield: 67 %

Procedure:
Following the procedure as described in Example 10, making variations as necessary to replace phenylacetylene with (R)-1-phenyl-2-propyn-1-ol to react with 2-azido-N-benzyl-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 67% yield: mp 146-149° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.12 (s, 1H), 7.50-7.31 (m, 10H), 6.13-6.08 (m, 2H), 4.61 (d, J=6.0 Hz, 2H), 2.96 (d, J=3.0 Hz, 1H), 2.64 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.8, 155.2, 152.9, 152.3, 140.9, 137.3, 128.8, 128.7, 128.2, 127.9, 127.7, 126.3, 124.5, 118.9, 68.9, 44.2, 17.2; MS (ES+) m/z 406.3 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=3)[CH2:13][CH:12]([C:27](O)=[O:28])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:31]=[C:32]([CH:34]1[CH2:36][CH2:35]1)[NH2:33]>>[CH:34]1([C:32]2[N:33]=[C:27]([CH:12]3[CH2:13][CH:14]([C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([C:23]([F:25])([F:26])[F:24])[CH:17]=4)[CH2:15][N:10]([C:8]([N:5]4[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]4)=[O:9])[CH2:11]3)[O:28][N:31]=2)[CH2:36][CH2:35]1
Reactant: NC(=NO)C1CC1
Reactant: Cc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1C(F)(F)F
Product: Cc1ccc(C2CC(c3nc(C4CC4)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1C(F)(F)F

Procedure:
100 mg (0.24 mmol) of the compound from Example 163A and 36 mg (0.36 mmol) of N′-hydroxycyclopropanecarboximidamide were reacted according to the General Method 2. Yield: 60 mg (51% of theory).