Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:15]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:13]([F:12])[CH:14]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Reactant: Cc1cc(Br)c2cn[nH]c2c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(Br)c2cnn(-c3ccc(OCc4ccccc4)c(F)c3)c2c1
Yield: 107 %

Procedure:
The 4-bromo-6-methyl-1H-indazole (950 mg, 4.5 mmol), the {3-fluoro-4-[(phenylmethyl)oxy]phenyl}boronic acid (2.2 g, 9 mmol), copper (II) acetate (1.22 g, 6.75 mmol) and pyridine (0.73 mL, 9 mmol) in DCM (80 mL) were stirred in the presence of molecular sieves (4 A, 2 g) in air. After 40 hours the mixture was filtered through a pad of celite and concentrated to afford 3.3 g of crude material. This was purified by flash chromatography (Biotage SP4, 40+M silica column) with a gradient of EtOAc 0 to 30% in hexane to afford 1.98 g of desired compound (D12) slightly impure but carried forward.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:10][CH2:11][NH:12][C:13](=[O:16])[O:14][CH3:15].[F:17][C:18]1[CH:31]=[CH:30][C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[CH:20][CH:19]=1>CN(C)C=O>[F:17][C:18]1[CH:31]=[CH:30][C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:10][CH2:11][NH:12][C:13](=[O:16])[O:14][CH3:15])=[CH:25][CH:24]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)NCCCl
Reactant: Oc1ccc(Oc2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)NCCOc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 0 °C

Procedure:
3.6 g of powdered potassium carbonate, 1.5 g of finely powdered potassium iodide and 27 g of methyl 2-chloroethylcarbamate are added to a solution of 2.6 g of 4-(4-fluorophenoxy)phenol in 120 ml of dimethyl formamide, and the reaction mixture is heated for 15 hours to 95° C. The cooled reaction mixture is poured into ice-water and extracted repeatedly with ether. The combined ether phases are washed with water, dried over sodium sulfate, and the solvent is completely removed by distillation. After filtration over silica gel, the crude product is recrystallised from diethyl ether/hexane to give methyl 2-[4-(4-fluorophenoxy)phenoxy]-1-ethylcarbamate with a melting point of 64°-66° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[CH:18][CH:17]=[C:16]([OH:23])[CH:15]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:35][CH:36](Br)[CH3:37].C(=O)([O-])[O-].[K+].[K+].[K+].[Br-]>CN(C)C=O>[Br:35][CH2:36][CH2:37][O:23][C:16]1[CH:15]=[C:14]2[C:19]([C:20](=[O:22])[CH:21]=[C:12]([C:11]3[CH:24]=[CH:25][C:26]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:10]=3)[O:13]2)=[CH:18][CH:17]=1
Reactant: O=c1cc(-c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)oc2cc(O)ccc12
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc(-c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)oc2cc(OCCBr)ccc12

Procedure:
This compound (57) was prepared from 3′,4′-dibenzyloxy-7-hydroxy-flavone, 23 (2.3 g, 5.1 mmol), dibromo ethane (1.7 mL, 20.4 mmol) and potassium carbonate (3.5 g, 25.5 mmol) in dry dimethyl formamide (90 mL) using the identical procedure as described for 56. Yield 2.1 g (74%); mp 167-168° C.; MS (FAB) 557/559 (M++1); IR (KBr) 1626; 1H NMR (200 MHz, CDCl3) δ 8.12 (d, J=8.8 Hz, 1H), 7.50-7.32 (m, 12H), 7.01 (d, J=9.1 Hz, 1H), 6.92 (dd, J=8.9 Hz, 2.2 Hz, 1H), 6.91 (s, 1H), 6.60 (s, 1H), 5.24 (s, 4H), 4.39 (t, J=6.2 Hz, 2H), 3.69 (t, J=6.3 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12](N(OC)C)=[O:13])[C:5]([CH3:22])=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]=1.[C:35]([Mg]Cl)#[CH:36]>O1CCCC1>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([C:12](=[O:13])[C:35]#[CH:36])[CH:18]=[CH:19][C:20]=2[CH3:21])[C:5]([CH3:22])=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[N:26]=1
Reactant: C#C[Mg]Cl
Reactant: CON(C)C(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C(F)(F)F)n3)c(Cl)c2=O)c1
Solvent: C1CCOC1
Product: C#CC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C(F)(F)F)n3)c(Cl)c2=O)c1

Procedure:
To a solution of 3-[5-chloro-2-methyl-6-oxo-4-(6-trifluoromethyl-pyridin-2-ylmethoxy)-6H-pyrimidin-1-yl]-N-methoxy-4,N-dimethyl-benzamide from Step B (53 mg, 0.11 mmol) in tetrahydrofuran (1.5 mL), cooled using an ice water bath, was added ethynylmagnesium chloride, 0.5M in tetrahydrofuran, (0.3 mL, 0.15 mmol) in a drop-wise manner. Additional Grignard reagent was added as necessary to ensure full product formation. After thirty minutes, the reaction was quenched into ice cold water and extracted with ethyl acetate. The organic layer was washed with saturated ammonium chloride, water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated. The crude material was used without additional purification.
Reaction SMILES: [CH:1]([N:4]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)([CH3:3])[CH3:2].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=1>N1C(C)=CC(C)=CC=1C>[CH:14]1([N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:13])[C:6]2[CH:11]=[CH:10][C:9]([O:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=3)=[CH:8][CH:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC(C)N(C(=O)c1ccc(Br)cc1)C1CCCCC1
Reactant: COc1cccc(O)c1
Solvent: Cc1cc(C)nc(C)c1
Product: COc1cccc(Oc2ccc(C(=O)N(C(C)C)C3CCCCC3)cc2)c1

Procedure:
The reaction and workup were carried out in the same manner as described in Example 1 using p-bromobenzoic acid N-isopropyl-N-cyclohexyl amide (1.798 g, 5.54 mmol), 3-methoxy phenol (769 mg, 6.19 mmol) and cuprous oxide (403 mg, 2.82 mmol) in 2,4,6-collidine (15 ml). The crude product was chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the title compound as a crystalline solid that could be recrystallized from ethyl acetate and hexane, m. pt. 101.24° C. (DSC).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([N+:17]([O-:19])=[O:18])[C:13]3[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=3[C:11]=2[CH:10]([C:24](OC)=[O:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C>C1COCC1.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([N+:17]([O-:19])=[O:18])[C:13]3[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=3[C:11]=2[CH:10]([CH2:24][OH:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)c2cc([N+](=O)[O-])c3ccccc3c21
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC(CO)c2c1cc([N+](=O)[O-])c1ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
The crude ester 11 (0.85 g, 2.28 mmol) from the preceding procedure was dissolved in THF (25 mL) and added dropwise over 20 min to a stirred solution of DIBAL (9.1 mL of a 1M solution in toluene, 9.1 mmol) in THF (30 mL) under N2 at 0° C. The mixture was stirred for a further 30 min at 0° C., then poured into ice-cold 2 N HCl (40 mL) and extracted twice with EtOAc. The combined extracts were dried (Na2SO4) and concentrated under reduced pressure below 30° C. and the residue was chromatographed on silica gel. Elution with CH2Cl2EtOAc (4:1) afforded a crude product which was crystallised from CH2Cl2 /iPr2O/petroleum ether to give 3-(tert-butyloxycarbonyl)-1-hydroxymethyl-5-nitro,1,2-dihydro-3H-benz[e]indole (12) (0.48 g, 61%). A sample recrystallised from iPr2O/petroleum ether had mp 176° C. 1H NMR (CDCl3) δ(br s, 1 H, H-9), 8.42 (br s, 1 H, H-7), 7.88 (d, J=7.9 Hz, 1 H, H-4), 7.62-7.51 (m, 2 H, H5,6), 4.30 (m, 1 H, H-2), 4.17 (dd, J=11.4, 9.5 Hz, 1 H, H-2), 4.04-3.93 (m, 2 H, H-3, CHHOH), 383-3.74 (m, 1 H, CHHOH), 1.61 (s, 9 H, C(CH3)3).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]2[S:13][C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:11][C:10]=2[C:20]2[C:21]([F:38])=[C:22]([NH:26][S:27]([C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[F:37])(=[O:29])=[O:28])[CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[CH:46]1([C:51](Cl)=[O:52])[CH2:50][CH2:49][CH2:48][CH2:47]1>ClCCl>[F:37][C:31]1[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:30]=1[S:27]([NH:26][C:22]1[C:21]([F:38])=[C:20]([C:10]2[N:11]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[S:13][C:9]=2[C:7]2[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][NH:1][C:51]([CH:46]3[CH2:50][CH2:49][CH2:48][CH2:47]3)=[O:52])[N:8]=2)[CH:25]=[CH:24][CH:23]=1)(=[O:28])=[O:29]
Reactant: O=C(Cl)C1CCCC1
Reactant: NCc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1)C1CCCC1
Yield: 25.6 %

Procedure:
To a suspension of N-{3-[5-[2-(aminomethyl)-4-pyrimidinyl]-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.1 g, 0.178 mmol) in dichloromethane (1.270 ml) was added triethylamine (0.062 ml, 0.444 mmol). A solution of cyclopentanecarbonyl chloride (0.024 g, 0.178 mmol) in dichloromethane (0.508 ml) was added dropwise and stirred. The reaction was quenched with water, extracted 2× with DCM, the organic extracts dried over MgSO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with DCM with MeOH (0% to 10%) and collected fractions to obtain the title compound as a solid (30 mg, 25% yield). MS (ESI): 659 [M+H]+.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].Cl.[Cl:7][CH2:8][CH2:9][CH2:10][NH2:11]>C(#N)C>[Cl:7][CH2:8][CH2:9][CH2:10][NH:11][S:1]([Cl:5])(=[O:3])=[O:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: NCCCCl
Agent: Cl
Solvent: CC#N
Product: O=S(=O)(Cl)NCCCCl

Procedure:
To sulfuryl chloride (5 g, 30.05 mmol) in acetonitrile (30 mL), was added 3-chloropropyl amine hydrochloride (486 mg, 5.00 mmol). The reaction mixture was allowed to react over 18 hr at 75-80° C. After the completion of the reaction, the resultant was concentrated under reduced pressure, extracted with ether and then kept under vacuum for a long time to remove remained sulfuryl chloride, giving 3-chloropropylsulfamoyl chloride that was used without further purification.
Reaction SMILES: O=[C:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:9]([O:11]C)=O.[NH2:13][C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([F:24])[CH:23]=1)[C:17]([O:19][CH3:20])=[O:18].O1CCOCC1>O>[F:24][C:22]1[CH:21]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[C:15]2[C:9](=[O:11])[C:3]3[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:2]=3[NH:13][C:14]=2[CH:23]=1
Reactant: COC(=O)c1cc(N)cc(F)c1
Reactant: COC(=O)C1CCCCCC1=O
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(F)cc2[nH]c3c(c(=O)c12)CCCCC3
Temperature: 130 °C
Yield: 107.2 %

Procedure:
A mixture of methyl 2-oxocycloheptanecarboxylate (0.34 g, 2 mmol), methyl 3-amino-5-fluorobenzoate (0.33 g, 2 mmol), polyphosphoric acid (4.0 g) and dioxane (5 mL) was heated at 130° C. for 5 hours. After cooling to room temperature, the solution was diluted with water (100 mL), and NaOAc.3H2O (7.3 g) was added. Then the resulting precipitate was collected by filtration and dried. The solid was suspended in methanol (20 mL) and SOCl2 (10 mL) was added, the mixture was stirred at reflux for 5 hours, concentrated and treated with water (50 mL), extracted with ethyl acetate (3×50 mL). The organic layer was separated, concentrated and the residue was chromatographed to give the crude product (0.62 g). MS (ESI) m/e [M+1]+290.0.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([S:12](Cl)(=[O:14])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1.CCN(CC)CC.[CH:34]([NH2:37])([CH3:36])[CH3:35]>C(Cl)Cl>[CH:34]([NH:37][S:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:2](=[O:1])[N:3]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:4][CH2:5]2)[CH2:7][CH2:8]1)(=[O:14])=[O:13])([CH3:36])[CH3:35]
Reactant: CC(C)N
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)Cl)CC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)NS(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 15.9 %

Procedure:
A mixture of 74 mg (0.18 mmol) 1-Oxo-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-8-sulfonyl chloride, 73 mg (0.72 mmol) NEt3 and 14.8 mg (0.252 mmol) isopropylamine in 2 mL CH2Cl2 was stirred for 16 h at 50° C. The mixture was evaporated to dryness and the residue was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid. The product containing fractions were evaporated to yield 12.5 mg (16%) of the title compound. MS (ESI): 436.4 (MH+).
Reaction SMILES: ClCC([O:5][C:6]1[CH:14]=[CH:13][C:12]2[N:11]([CH3:15])[C:10]3[C:16](=O)[CH2:17][CH2:18][C:9]=3[C:8]=2[CH:7]=1)=O.[CH:20]1([NH2:23])[CH2:22][CH2:21]1>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH:20]1([N:23]=[C:16]2[C:10]3[N:11]([CH3:15])[C:12]4[CH:13]=[CH:14][C:6]([OH:5])=[CH:7][C:8]=4[C:9]=3[CH2:18][CH2:17]2)[CH2:22][CH2:21]1
Reactant: NC1CC1
Reactant: Cn1c2c(c3cc(OC(=O)CCl)ccc31)CCC2=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cn1c2c(c3cc(O)ccc31)CCC2=NC1CC1
Temperature: -10 °C
Reaction time: 8 h

Procedure:
7-Chloroacetyloxy-1,4-dihydro-4-methylcyclopent[b]indol-3(2H)-one (15.0 g) and cyclopropylamine (9.6 g) were dissolved in 300 ml toluene and cooled to -10° C. Titanium tetrachloride (6.3 g) dissolved in 50 ml toluene was added slowly to the first solution. The reaction mixture was allowed to come up to room temperature and stirred overnight. The next day another 1.5 equivalents of the amine (4.6 g) was added to the reaction mixture and the mixture was stirred for one hour. The reaction mixture was filtered through a pad of silica gel, eluting with 3:1 hexane/ethyl acetate, giving a yellow oil after removal of solvents. 3-Cyclopropylimino-4-methyl-1,2,3,4-tetrahydrocyclopent[b]-indol-7-ol was isolated as a light yellow solid (3.3 g) after flash chromatography and recrystallization from ethyl acetate.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].Cl.[CH2:20]([NH2:24])/[CH:21]=[CH:22]/[CH3:23].C(N(CC)CC)C.O>C(#N)C>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:24][CH2:20]/[CH:21]=[CH:22]/[CH3:23])[N:6]=1)[CH:2]=[CH2:3]
Reactant: C/C=C/CN
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: C=CCNc1nc(NC/C=C/C)nc2ccc([N+](=O)[O-])cc12
Temperature: 50 °C
Reaction time: 6 h
Yield: 80.9 %

Procedure:
150 mg (0.57 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline was dissolved in 2 ml of acetonitrile, and 305 mg (2.83 mmol) of trans-2-butenylamine hydrochloride and 0.39 ml (2.83 mmol) of triethylamine were added thereto, followed by stirring at 50° C. for 6 hours. To the reaction solution was water added, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 138 mg (yield: 80.9%) of the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=3)=O)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[CH3:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH:42]N>>[CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:38]4[C:37](=[C:36]([CH3:35])[CH:41]=[CH:40][CH:39]=4)[NH:42][C:22]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: Cc1ccccc1NN
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc([N+](=O)[O-])c3)CC2)c1
Agent: Cl
Product: Cc1cccc2c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c(-c3cccc([N+](=O)[O-])c3)[nH]c12

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-(3-{1-[5-(3-nitrophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)propanamide and 1-(2-methylphenyl)hydrazine hydrochloride: ESMS m/e: 539.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([CH:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24](=[O:31])[O:23]3)=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33]>Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([CH:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24](=[O:31])[O:23]3)=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:32]([F:35])([F:33])[F:34]
Reactant: COCN(c1cc(Cl)cnc1C1OC(=O)c2ccccc21)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Product: O=C1OC(c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c2ccccc21
Temperature: 25 °C

Procedure:
A solution of 4-chloro-N-[5-chloro-2-(3-oxo-1,3-dihydro-isobenzofuran-1-yl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide in 3 mL HCl (4 M in dioxane) and 1 mL water was refluxed for 2 h. After cooling to room temperature, the mixture was concentrated and the residue was purified via preparative TLC (50% EtOAc in hexane) to provide 11 mg of 4-chloro-N-[5-chloro-2-(3-oxo-1,3-dihydro-isobenzofuran-1-yl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide as an off white solid. MS m/z 503.3 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:54])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:36][C:35]2[CH:34]=[C:33]3[C:28]([O:29][C@@H:30]([C:38]4[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]5[CH:51]=[CH:50][C:49]([Cl:52])=[C:48]([Cl:53])[CH:47]=5)=[CH:40][CH:39]=4)[C:31](=[O:37])[NH:32]3)=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:55]([NH:58][C:59]1[S:60][C:61]([S:65](Cl)(=[O:67])=[O:66])=[C:62]([CH3:64])[N:63]=1)(=[O:57])[CH3:56]>>[CH3:1][O:2][C:3](=[O:54])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:36][C:35]2[CH:34]=[C:33]3[C:28]([O:29][C@@H:30]([C:38]4[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]5[CH:51]=[CH:50][C:49]([Cl:52])=[C:48]([Cl:53])[CH:47]=5)=[CH:40][CH:39]=4)[C:31](=[O:37])[NH:32]3)=[CH:27][C:26]=2[CH2:25][N:24]1[S:65]([C:61]1[S:60][C:59]([NH:58][C:55](=[O:57])[CH3:56])=[N:63][C:62]=1[CH3:64])(=[O:66])=[O:67])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(NC(C)=O)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3
Yield: 81.8 %

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionic acid methyl ester (760 mg) was reacted with 2-acetylamino-4-methyl-thiazole-5-sulfonyl chloride (381 mg) following general procedure E to furnish (S)-2-({(S)-6-(2-acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (800 mg) as a mixture of diastereomers. The diastereomers were separated by flash chromatography over silica (DCM:EtOAc 9:1-6:4). The more polar diasteromer (LC-MS m/z 982, 12 mg) was hydrolyzed using the general procedure B to furnish title compound (8 mg, more polar diastereomer). LC-MS (m/z): 967.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3](O)=O.[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[OH:19])C=O)[CH3:9].NC1C=CC=CC=1.S(=O)(=O)(O)O>N1C=CC=CC=1>[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[OH:19])[CH:3]=[CH:2][C:1]([OH:7])=[O:6])[CH3:9]
Reactant: O=C(O)CC(=O)O
Reactant: CCOc1cc(C=O)ccc1O
Agent: O=S(=O)(O)O
Solvent: Nc1ccccc1
Solvent: c1ccncc1
Product: CCOc1cc(C=CC(=O)O)ccc1O
Reaction time: 3 h
Yield: 52.9 %

Procedure:
Malonic acid (1.56 g) and pyridine (3.0 ml) were placed in an egg-plant type flask (100 ml). Further, 3-ethoxy-4-hydroxybenzaldehyde (1.66 g) and aniline (30 μl) were added thereto and a reaction was performed at 55° C. for 3 hours. The reaction solution was acidified by adding dilute sulfuric acid. The crude crystals were obtained by filtration, washed with water, and then dried to obtain the above-identified compound (1.1 g, 56.1%) as a light yellowish crystal. Melting point: 157°-158° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:6]=[N:5][N:4]=1.[CH2:18]([S:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(=[O:22])=[O:21])[CH3:19].C(N(CC)CC)C>C(#N)C>[CH2:18]([S:20]([N:23]1[CH2:24][CH2:25][N:26]([CH2:2][C:3]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=3)[N:6]=[N:5][N:4]=2)[CH2:27][CH2:28]1)(=[O:22])=[O:21])[CH3:19]
Reactant: CCS(=O)(=O)N1CCNCC1
Reactant: FC(F)(F)c1cccc(-n2nnnc2CCl)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCS(=O)(=O)N1CCN(Cc2nnnn2-c2cccc(C(F)(F)F)c2)CC1
Temperature: 120 °C
Reaction time: 0.33 h

Procedure:
5-(Chloromethyl)-1-[3-(trifluoromethyl)phenyl]-1H-tetrazole (79 mg, 0.301 mmol, commercially available from UkrOrgSynthesis, Kiev, Ukraine) and 1-(ethylsulfonyl)piperazine (53.6 mg, 0.301 mmol, Sigma-Aldrich) were dissolved in acetonitrile (1.5 ml). Triethylamine (0.046 ml, 0.331 mmol) was added, and the mixture was heated in a microwave with stirring at 120° C. for 20 min. The reaction mixture was concentrated in vacuo and the residue purified by high pH MDAP to yield the title compound as a colourless solid (70 mg).
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].C(N(CC)CC)C.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>ClCCl>[N:13]1([S:1]([Cl:5])(=[O:3])=[O:2])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: C1COCCN1
Reactant: O=S(=O)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(Cl)N1CCOCC1
Reaction time: 2 h
Yield: 73.8 %

Procedure:
Under an ice-cooled, dichloromethane solution containing 12 ml (0.15 mol) of sulfurylchloride was cooled, dichloromethane solution containing 21 ml (0.15 mol) of triethylamine and 13 ml (0.15 mol) of morpholine was added dropwise over a period one hour. After stirring for 2 hour, the reaction mixture was washed cooled-0.1N hydrochloric acid and saturated brine and then was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue thus obtained was chromatographed on silica gel column for purification, whereby 20.54 g of morpholine-4-sulfonylchloride was obtained.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2)[C:13]([O:15][CH3:16])=[O:14])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C@@H:12]([CH2:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)[C@H](Cc1ccc2[nH]ccc2c1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H](N)Cc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
To a solution of (S)-methyl 2-(benzyloxycarbonylamino)-3-(1H-indol-5-yl)propanoate (3.27 g, 9.39 mmol) in methanol (30 mL) was added Pd/C (10%, 200 mg). The mixture was stirred under hydrogen atmosphere at ambient temperature for 1 h and then filtered through a pad of Celite. The filtrate was concentrated to afford (S)-methyl 2-amino-3-(1H-indol-5-yl)propanoate (1.8 g, 88% yield) as a light green solid, which was used directly without further purification.