Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH2:15])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3.C(N(CC)CC)C.[Cl:25][CH2:26][C:27](Cl)=[O:28]>C(Cl)Cl>[CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH:15][C:27](=[O:28])[CH2:26][Cl:25])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3
Reactant: O=C(Cl)CCl
Reactant: CC1(C)Oc2cc3nonc3cc2C(N)C1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)Oc2cc3nonc3cc2C(NC(=O)CCl)C1O
Temperature: 25 °C
Yield: 76 %

Procedure:
A mixture of 200 mg (0.85 m mol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole, 130 μl (0.935 m mol) of triethylamine and 20 ml of methylene chloride was added with 74 μl (0.935 m mol) of chloroacetyl chloride with stirring at the room temperature, followed by further stirring for 30 minutes. After the completion of the reaction, the precipitated crystals were separated by filtration to obtain 201 mg (yield: 76%) of the intended compound.
Reaction SMILES: [CH:1]([C:3]1[O:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1)=O.[NH2:13]O.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CO.CN(C=O)C>[C:1]([C:3]1[O:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1)#[N:13]
Reactant: CCOC(=O)c1coc(C=O)n1
Reactant: NO
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CO
Solvent: CN(C)C=O
Product: CCOC(=O)c1coc(C#N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.3 %

Procedure:
A solution of ethyl 2-formyloxazole-4-carboxylate (650 mg, 3.84 mmol) in methanol (25 mL) was cooled to 0° C. and 50% aqueous hydroxylamine (0.22 mL, 7.68 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 3 h. Solvent was removed under reduced pressure and the crude product (0.52 g) obtained was dissolved in DMF (20 mL). T3P (3.4 mL, 5.65 mmol; 50% in EtOAc) was added to the reaction mixture and heated to 100° C. for 2 h. The reaction mixture was quenched with saturated NaHCO3 solution and the organic product was extracted with EtOAc. Solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 10% EtOAc in petroleum ether) to afford ethyl 2-cyanooxazole-4-carboxylate (0.34 g, yield 53%) as an off white solid. 1H NMR (300 MHz, CDCl3) δ 8.39 (s, 1H), 4.48-4.41 (q, J=7.0 Hz, 2H), 1.44-1.39 (t, J=7.0 Hz, 3H).
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH3:10][O:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.CCOC(C)=O>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([CH2:15][N:14]([CH2:13][CH2:12][O:11][CH3:10])[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[CH:17][CH:18]=1)#[N:21]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COCCNCc1ccc(C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COCCN(CC(=O)OC(C)(C)C)Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tert-butyl bromoacetate (1.64 mL, 11.1 mmol) was added into a mixture of 4-{[(2-methoxyethyl)amino]methyl}benzonitrile (958 mg, 5.04 mmol) and K2CO3 (3.06 g, 22.2 mmol) in ACN (20 mL). The resulting mixture was stirred at RT overnight. The reaction mixture was diluted with EtOAc, and then washed with water and brine, dried (MgSO4) and concentrated under vacuum. The residue was purified by flash chromatography (silica, cHex/EtOAc) to give the title compound as a colorless oil. LC/MS (Method B): 305.1 (M+H)+. HPLC (Method A) Rt 3.09 min (Purity: 91.1%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C(#N)C>[CH2:25]([O:24][C:22](=[O:23])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10](=[O:14])[CH:11]([CH3:12])[CH3:13])=[CH:6][CH:7]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)C(=O)CCc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)C(=O)CCc1ccc(NC(=O)OCc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
A solution of 11.9 g (62 mmol) of crude 5-(4-amino-phenyl)-2-methyl-pentan-3-one (prepared in Example GGGGG) in 100 mL of acetonitrile was treated with 24.3 g (75 mmol) of cesium carbonate, and the mixture was stirred at 50° C. for 15 minutes. Benzyl chloroformate (10.7 mL, 75 mmol) was added all at once, and the mixture was stirred at room temperature for 90 minutes. The solvent was evaporated. The residue was partitioned between EtOAc and H2O; the organic layer was separated, washed with brine, dried (MgSO4), and concentrated. The product was chromatographed on silica gel, eluting with EtOAc:hexane (30:70), to give the title compound. 1H NMR (CDCl3) δ 1.01 (d, 6 H), 2.48-2.55 (m, 1 H), 2.67-2.82 (m, 4 H), 5.15 (s, 2 H), 6.58 (br s, 1 H), 7.08 (d, 2 H), 7.25-7.38 (m, 7 H).
Reaction SMILES: [C:1]1([C:12]2[CH2:22]CCC[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=2)CCCCCCCCNN=1.[CH3:23][C:24]1(C)C2C=CC=CC=2[Se:26][NH:25]1>BrCC>[CH3:22][C:12]1([CH3:1])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[Se:26][N:25]1[CH2:24][CH3:23]
Reactant: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Reactant: CC1(C)N[Se]c2ccccc21
Solvent: CCBr
Product: CCN1[Se]c2ccccc2C1(C)C
Temperature: 25 °C
Reaction time: 10 h
Yield: 53 %

Procedure:
Diazabicycloundecene (380 mg; 2.5 mmole) was added to a solution of derivative 3,3-dimethyl-benzisoselenazoline (107 mg; 0.5 mmole) obtained above in bromoethane (1.5 ml). The mixture was stirred at room temperature for 10 h, then the same quantity of diazabicycloundecene was added again. After 14 h at room temperature, the bromoethane was evaporated off under reduced pressure. The desired product was obtained in the form of a very viscous yellow oil after purification by liquid chromatography on a silica column (eluent: cyclohexane-ethyl acetate, 6/1).
Reaction SMILES: C[N:2](/[CH:4]=[C:5]1/[C:6](=[O:15])[NH:7][CH2:8][C:9]2[C:14]/1=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:3].[N:16]1([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27]C(N)=[CH:25][CH:24]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1>C1(C)C=CC=CC=1>[N:16]1([CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][C:3]([NH:2][CH:4]=[C:5]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:8][NH:7][C:6]3=[O:15])=[CH:27][CH:28]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN(C)/C=C1/C(=O)NCc2ccccc21
Reactant: Nc1ccc(CCN2CCCC2)cc1
Solvent: Cc1ccccc1
Product: O=C1NCc2ccccc2C1=CNc1ccc(CCN2CCCC2)cc1
Temperature: 110 °C
Yield: 40.7 %

Procedure:
A mixture of 0.400 g (1.98 mmol) of (4E)-4-[(dimethylamino)methylene]-1,4-dihydro-3(2H)-isoquinolinone and 0.414 g (2.18 mmol) of 4-(2-Pyrrolidin-1-yl-ethyl)-phenylamine in 4 mL of PhCH3 is heated at 110° C. for 2.5 h. The reaction is placed in a freezer and the precipitated material is collected, washed with cold PhCH3(2×) and Et2O and dried in vacuo to give 0.280 g (41%) of gold crystals: mp 169-173° C. (dec); 1H NMR (DMSO-d6) δ 11.4 (d, 1H, J=11.8 Hz), 8.01 (d, 1H, J=11.8 Hz), 7.63 (m, 2H), 7.16 (s, 4H), 7.07 (m, 2H), 4.40 (s, 2H), 2.60 (m, 4H), 2.50 (m, 2H), 1.67 (s (br), 4H); HRMS (ESI) m/e calcd for C22H25N3O 348.20704. found 348.20588 (M+H)+1.
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].[CH3:15][N:16]([CH3:20])[C:17](Cl)=[O:18]>CN(C)C=O.O>[CH3:15][N:16]([CH3:20])[C:17]([NH:1]/[C:2](/[C:9]([F:10])([F:11])[F:12])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:18]
Reactant: CN(C)C(=O)Cl
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C(\NC(=O)N(C)C)C(F)(F)F
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 71.2 %

Procedure:
Ethyl 3-amino-4,4,4-trifluorocrotonate (18.4 g, 100 mmol) is added to a stirred solution of sodium hydride (60% in mineral oil, 9.6 g, 250 mmol) in N,N-dimethyl-formamide (60 mL) at 5° C. under nitrogen over a 60 minute period. The reaction mixture is allowed to warm to and held at room temperature for 15 minutes, cooled to 5° C., and treated with dimethylcarbamoylchloride (21.6 g, 200 mmol) over a 60 minute period. The resultant solution is then warmed to and held at room temperature for 2 hours, diluted with water (150 mL), and extracted with ethyl acetate (2×150 mL). The combined organic layers are dried, filtered and concentrated, and the mineral oil layer is removed to obtain a residue. Flash column chromatography of the residue on silica gel using a 85:15 hexanes/ethyl acetate solution gives the title product as a yellow liquid (18.1 g, 71% yield): 1H NMR (DMSO-d6)δ 9.18 (s,1H), 5.85 (s, 1H), 4.20 (q, 2H), 2.89 (s, 6H), 1.18 (t, 3H) ; 19F NMR δ −65.7 (s).
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:16])[CH:11]=[C:12]([CH3:15])[NH:13][CH:14]=1)C1C=CC=CC=1.[H][H].[ClH:19]>CO.O.[Pd]>[ClH:19].[OH:8][C:9]1[C:10](=[O:16])[CH:11]=[C:12]([CH3:15])[NH:13][CH:14]=1
Reactant: [H][H]
Reactant: Cc1cc(=O)c(OCc2ccccc2)c[nH]1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1cc(=O)c(O)c[nH]1

Procedure:
5-Benzyloxy-2-methyl-1H-pyridin-4-one (15.5 g, 72.0 mmol) was mixed with 10% Pd/C (1.60 g) in methanol (200 mL) and water (35 mL) in a Parr hydrogenator bottle. The mixture was hydrogenated on a Parr hydrogenator for 45 minutes at 50 psi hydrogen pressure. 6N HCl (12 mL) was added. A CELITE™ bed was prepared on a sintered glass, and washed with 6M HCl (100 mL), followed by water (7×50 mL) and then methanol (2×50 mL) under suction. The reaction mixture was filtered through the pre-treated CELITE™ bed. The filtrate was evaporated to dryness and the residue was triturated with acetone, then filtered to give 5-hydroxy-2-methyl-1H-pyridin-4-one hydrochloride 9.30 g as off-white solid. The mother liquor was diluted with hexane and placed at room temperature over night to give an additional 1.63 g of product. Thus, 10.9 g of the title compound was obtained (94% yield). 1H NMR (90 MHz, MeOD) δ (ppm) 7.93 (s, 1H, CH), 7.07 (s, 1H, CH) 2.56 (s, 3H, CH3,). MS-ESI (m/z): 126.1 [M+1]+, 108.2, 110.1.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N+:19]([O-])=[CH:18][CH:17]=3)=[C:10]3[CH2:15][CH2:14][CH2:13][N:11]3[N:12]=2)[CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:30].O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][C:18](=[O:30])[CH:17]=3)=[C:10]3[CH2:15][CH2:14][CH2:13][N:11]3[N:12]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(-c2nn3c(c2-c2cc[n+]([O-])c4ccccc24)CCC3)n1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(-c2nn3c(c2-c2cc(=O)[nH]c4ccccc24)CCC3)n1
Reaction time: 40 h

Procedure:
To a solution of 4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-1-oxide (103 mg, 0.30 mmol) in N,N-dimethylformamide (3 mL) is added trifluoroacetic anhydride (425 μL, 3.0 mmol). The mixture is stirred for 40 h, poured into water, and the pH adjusted to 8 with saturated aqueous sodium bicarbonate solution. The mixture is extracted three times with ethyl acetate, the combined organic extracts washed three times with water and once with brine, dried (sodium sulfate), filtered, and concentrated in vacuo. The residue is triturated with 10% acetone/90% dichloromethane and filtered. The solid is dried under vacuum to yield the title compound, 11.6 mg (10%), as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:10][S:11]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([O:23][CH2:24][C:25]#[CH:26])[CH:20]=[CH:19][C:17]=3[N:18]=2)(=[O:13])=[O:12])=[CH:5][CH:4]=1.[N:41]([C@@H:44]([CH2:71][C:72]1[CH:77]=[CH:76][C:75]([O:78][CH2:79][CH2:80][O:81][S:82]([C:85]2[CH:91]=[CH:90][C:88]([CH3:89])=[CH:87][CH:86]=2)(=[O:84])=[O:83])=[CH:74][CH:73]=1)[C:45]([N:47]([C@@H:55]([CH2:60][C:61]1[CH:66]=[CH:65][C:64]([C:67]([F:70])([F:69])[F:68])=[CH:63][CH:62]=1)[C:56]([O:58][CH3:59])=[O:57])[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[O:46])=[N+:42]=[N-:43].C(N(C(C)C)CC)(C)C>C1COCC1.[Cu]I>[CH3:40][O:39][C:36]1[CH:35]=[CH:34][C:33]([C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:10][S:11]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([O:23][CH2:24][C:25]4[N:43]=[N:42][N:41]([C@@H:44]([CH2:71][C:72]5[CH:73]=[CH:74][C:75]([O:78][CH2:79][CH2:80][O:81][S:82]([C:85]6[CH:91]=[CH:90][C:88]([CH3:89])=[CH:87][CH:86]=6)(=[O:84])=[O:83])=[CH:76][CH:77]=5)[C:45]([N:47]([C@@H:55]([CH2:60][C:61]5[CH:62]=[CH:63][C:64]([C:67]([F:70])([F:69])[F:68])=[CH:65][CH:66]=5)[C:56]([O:58][CH3:59])=[O:57])[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[O:46])[CH:26]=4)[CH:20]=[CH:19][C:17]=3[N:18]=2)(=[O:13])=[O:12])=[CH:38][CH:37]=1
Reactant: COC(=O)[C@H](Cc1ccc(C(F)(F)F)cc1)N(C(=O)OC(C)(C)C)C(=O)[C@H](Cc1ccc(OCCOS(=O)(=O)c2ccc(C)cc2)cc1)N=[N+]=[N-]
Reactant: C#CCOc1ccc2nc(S(=O)(=O)NC(c3ccccc3)(c3ccc(OC)cc3)c3ccc(OC)cc3)sc2c1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(C(F)(F)F)cc1)N(C(=O)OC(C)(C)C)C(=O)[C@H](Cc1ccc(OCCOS(=O)(=O)c2ccc(C)cc2)cc1)n1cc(COc2ccc3nc(S(=O)(=O)NC(c4ccccc4)(c4ccc(OC)cc4)c4ccc(OC)cc4)sc3c2)nn1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
To a stirring solution of N-(bis(4-methoxyphenyl)(phenyl)methyl)-6-(prop-2-ynyloxy)benzo[d]thiazole-2-sulfonamide (83 mg, 0.145 mmol) and the Boc-protected amide 151 (107 mg, 0.145 mmol) in THF (0.7 mL) was added copper(I) iodide (3 mg, 0.0145 mmol) then diisopropylethylamine (28 μL, 0.16 mmol). The mixture was allowed to stir for 2 h at 23° C. then concentrated in vacuo and the crude residue purified by flash chromatgraphy on silica gel using hexanes/ethyl actetate on a Biotage purification system yielding the desired product as a yellow, crystalline solid (145 mg, 82%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:25][C:26]1[CH:27]=[C:28]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]1[CH2:33][CH2:32][CH:31]([N:39]([CH3:41])[CH3:40])[CH2:30][C:29]2=1>CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([NH:25][C:26]3[CH:27]=[C:28]4[C:36](=[CH:37][CH:38]=3)[NH:35][C:34]3[CH2:33][CH2:32][CH:31]([N:39]([CH3:41])[CH3:40])[CH2:30][C:29]4=3)=[O:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccc5[nH]ccc5c4)cc3c2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.9 %

Procedure:
To a solution of 43.5 mg (0.27 mMol) indole-5-carboxylic acid in 1.5 mL dimethylformamide were added 44.3 mg (0.27 mMol) carbonyldiimidazole resulting in immediate gas evolution. The reaction mixture was stirred for 4 hours at room temperature and then 60.0 mg (0.26 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole were added. After 3 days the reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 4:1 dichloromethane:2% ammonium hydroxide in methanol. Fractions shown to contain product were combined and concentrated under reduced pressure to give 66.7 mg (69%) of 6-(indol-5-oyl)amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole. The compound was converted to its corresponding hydrochloride salt, crystallizing from ethanol:diethyl ether.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)CCN(C)C.CC(C)C[Li].[O:27]=[C:28]1[CH2:31][N:30]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:29]1>C(OCC)C>[OH:27][C:28]1([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][N:1]2[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:29][N:30]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:31]1
Reactant: O=C1CN(C(=O)OCc2ccccc2)C1
Reactant: CC(C)(C)OC(=O)N1CCCCC1
Agent: CN(C)CCN(C)C
Agent: [Li]CC(C)C
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCCC1C1(O)CN(C(=O)OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 8 h
Yield: 12.3 %

Procedure:
To a solution of 1,1-dimethylethyl piperidine-1-carboxylate (0.50 g, 2.7 mmol) in anhydrous diethyl ether (9.0 mL) under anhydrous nitrogen gas was added N,N,N′,N′-tetramethylethane-1,2-diamine (0.41 mL, 2.7 mmol), and the solution was cooled to −78° C. To this solution was added (2-methylpropyl)lithium (2.1 mL, 1.4 M in cyclohexane, 3.0 mmol) in small portions. To this anion solution was added phenylmethyl 3-oxoazetidine-1-carboxylate (1.0 g, 5.4 mmol), prepared using procedures as described in Reference 3, in anhydrous ether (2.0 mL), while maintaining the internal temperature at less than −60° C. The solution was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water, and partitioned between water and diethyl ether. The layers were separated and the aqueous layer was extracted with diethyl ether twice. The combined organic layers were dried (magnesium sulfate), filtered and concentrated in vacuo. Chromatography (silica gel, 3:1 hexanes/ethyl acetate) gave 0.13 g (13%) of 1,1-dimethylethyl 2-(3-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}azetidin-3-yl)piperidine-1-carboxylate. 1H NMR (400 MHz, CDCl3): 7.31 (m, 5H), 5.08 (s, 2H), 4.05 (d, 1H), 4.00 (d, 1H), 3.84 (d, 2H), 3.80 (broad s, 1H), 3.55 (broad s, 1H), 3.10 (broad s, 1H), 1.92 (m, 1H), 1.45-1.62 (m, 6H), 1.43 (s, 9H). MS (EI) for C21H30N2O5: 335 (M-tBu), 315 (M-OtBu).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])=[C:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:10]2[C:5](=[CH:6][C:7]([O:31][CH3:32])=[C:8]([O:29][CH3:30])[CH:9]=2)[N:4]=1.[SH:33][C:34]1[N:35]([CH3:39])[CH:36]=[CH:37][N:38]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:30][O:29][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[O:31][CH3:32])[N:4]=[C:3]([CH2:2][S:33][C:34]1[N:35]([CH3:39])[CH:36]=[CH:37][N:38]=1)[C:12]([C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])=[C:11]2[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1
Reactant: CCCOC(=O)c1c(CBr)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: Cn1ccnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOC(=O)c1c(CSc2nccn2C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.3 %

Procedure:
A mixture of propyl 2-bromomethyl-6,7-dimethoxy-4- (3,4-dimethoxyphenyl)quinoline-3-carboxylate (3.3 g), 2-mercapto-1-methylimidazole (821 mg), potassium carbonate (1.08 g) and N,N-dimethylformamide (60 ml) was stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography on silica gel. From the fraction eluted with chloroform/ethyl acetate (7:3, v/v), propyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2- [(1-methylimidazol-2-yl)thiomethyl]quinoline-3-carboxylate (1.77 g, 51%) was obtained and recrystallized from acetone/isopropyl ether.
Reaction SMILES: [C:1]([C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[O:7][C:8]1[C:13]([NH:14][C:15](=[S:18])[NH:16][NH2:17])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:23][CH2:24][C:25](Cl)=O>>[C:1]([C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[O:7][C:8]1[C:13]([NH:14][C:15]2[S:18][C:25]([CH2:24][Cl:23])=[N:17][N:16]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1NC(=S)NN
Product: CC(C)(C)c1ccccc1Oc1ncccc1Nc1nnc(CCl)s1

Procedure:
Example 473a was synthesized following the procedure for Example 1 using 4-(2-(2-tert-butylphenoxy)pyridin-3-yl)thiosemicarbazide (Example 1b) with chloroacetyl chloride.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].N[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O>>[C:14]([CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH2:1])[C:7]([OH:9])=[O:8])(=[O:16])[CH:13]=[CH:12][C:11]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCC(=O)O
Reactant: NCCCCCC(=O)O
Product: NCCCCC(C(=O)O)C(=O)C=Cc1ccccc1
Yield: 77 %

Procedure:
Using 6-aminocaproic acid in lieu of γ-aminobutyric acid, the title compound was synthesized following essentially the procedure described in Example 14. Yield 77%, m.p. 91.6-92.30C.
Reaction SMILES: Cl.C[O:3][C:4](=[O:16])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Br:15])[CH:9]=1)[NH2:6].[Cl:17][C:18]1[C:26]([Cl:27])=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([NH:28][S:29]([C:32]2[C:33]3[N:34]=[CH:35][CH:36]=[N:37][C:38]=3[CH:39]=[CH:40][CH:41]=2)(=[O:31])=[O:30])[CH:19]=1.N1C2C=CC=C(S(Cl)(=O)=O)C=2N=CC=1>>[Br:15][C:10]1[CH:9]=[C:8]([CH2:7][C@H:5]([NH:6][C:22](=[O:23])[C:21]2[CH:25]=[C:26]([Cl:27])[C:18]([Cl:17])=[CH:19][C:20]=2[NH:28][S:29]([C:32]2[C:33]3[N:34]=[CH:35][CH:36]=[N:37][C:38]=3[CH:39]=[CH:40][CH:41]=2)(=[O:31])=[O:30])[C:4]([OH:3])=[O:16])[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: COC(=O)[C@@H](N)Cc1ccc(F)c(Br)c1
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nccnc12
Agent: Cl
Agent: O=S(=O)(Cl)c1cccc2nccnc12
Product: O=C(N[C@@H](Cc1ccc(F)c(Br)c1)C(=O)O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
The title compound was prepared from 3-bromo-4-fluoro-L-phenylalanine methyl ester hydrochloride and 4,5-dichloro-2-(quinoxaline-5-sulfonylamino)-benzoic acid (prepared from quinoxaline-5-sulfonyl chloride as in EXAMPLE 14, Part A) as in Example 1, Part C, followed by hydrolysis of the resulting methyl ester as in EXAMPLE 2, Part E. HPLC: RT=9.91 min. MS (ESI−): mass calcd. for C24H16BrCl2FN4O5S, 642.28; m/z found, 639/641/643 [M−H]−. 1H NMR (400 MHz, acetone-d6): 11.49 (s, 1H), 9.00-8.93 (m, 2H), 8.62-8.57 (m, 1H), 8.37-8.32 (m, 1H), 8.20-8.12 (m, 1H), 8.05-7.97 (m, 1H), 7.93-7.88 (m, 1H), 7.73-7.67 (m, 1H), 7.65-7.61 (m, 1H), 7.41-7.33 (m, 1H), 7.25-7.15 (m, 1H), 5.00-4.90 (m, 1H), 3.38-3.28 (m, 1H), 3.18-3.10 (m, 1H).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[C:7]([O:14][CH3:15])(=[O:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10].Cl[C:17]1[CH:18]=[C:19]([N:26]([C:31]2[C:50]([CH:51]3[CH2:53][CH2:52]3)=[CH:49][C:34]3[C:35]([C:45]([NH:47][CH3:48])=[O:46])=[C:36]([C:38]4[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=4)[O:37][C:33]=3[CH:32]=2)[S:27]([CH3:30])(=[O:29])=[O:28])[CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24]>CN(C=O)C.O>[CH:51]1([C:50]2[C:31]([N:26]([C:19]3[CH:20]=[CH:21][C:22]([N+:23]([O-:25])=[O:24])=[C:17]([CH:8]([C:7]([O:14][CH3:15])=[O:13])[C:9]([O:11][CH3:12])=[O:10])[CH:18]=3)[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:32][C:33]3[O:37][C:36]([C:38]4[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=4)=[C:35]([C:45](=[O:46])[NH:47][CH3:48])[C:34]=3[CH:49]=2)[CH2:53][CH2:52]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Reactant: COC(=O)CC(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(C(C(=O)OC)C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 68 %

Procedure:
To a stirred suspension of Cs2CO3 (17.5 g, 53.8 mmol) in DMF (20 ml) under a nitrogen atmosphere was added dimethyl malonate (2.57 mL, 22.4 mmol) at room temperature. This was followed by the addition of a sonicated solution of 6-(N-(3-chloro-4-nitrophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (10.0 g, 17.9 mmol) in DMF (50 mL) at room temperature by dropwise addition. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with water and extracted with EtOAc (3×40 mL). The organic layer was washed with water (3×50 mL), dried over sodium sulfate and evaporated to dryness. The crude product triturated with ether and the solid collected by filtration to afford the title compound in 68% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.51 (d, J=4.7 Hz, 1H), 8.19 (d, J=9.2 Hz, 1H), 8.04 (s, 1H), 7.90-8.00 (m, 2H), 7.36-7.51 (m, 3H), 7.26-7.31 (m, 1H), 7.14-7.20 (m, 1H), 5.45-5.56 (m, 1H), 3.52-3.64 (m, 9H), 2.84 (d, J=4.5 Hz, 3H), 1.88-2.03 (m, 1H), 0.82-1.00 (m, 2H), 0.69 (d, J=3.1 Hz, 1H), 0.29-0.50 (m, 1H). LCMS (m/z, ES+)=654 (M+H+).