Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:31])=[C:7]2[CH2:29][CH2:28][N:27]([CH3:30])[C:8]2=[N:9][C:10]=1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])(=O)C.CC(C[AlH]CC(C)C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+].CO.C(Cl)Cl.[C:58]([OH:64])([C:60]([F:63])([F:62])[F:61])=[O:59]>C(Cl)Cl.CC#N>[F:61][C:60]([F:63])([F:62])[C:58]([OH:64])=[O:59].[CH3:30][N:27]1[C:8]2=[N:9][C:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:5]([OH:4])[C:6]([CH3:31])=[C:7]2[CH2:29][CH2:28]1
Reactant: CCCCCCCCCCCCCCCCc1nc2c(c(C)c1OC(C)=O)CCN2C
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCCc1nc2c(c(C)c1O)CCN2C
Temperature: 78 °C
Reaction time: 1 h

Procedure:
To a solution of 15.0 mg (34.8 μmol) of 2c in 1 mL of CH2Cl2 was added 105 μL (105 μmol, 1.0 M in hexanes) of DIBAL-H at 78° C. The reaction mixture was stirred at 78° C. for 1 h and then 2 mL of sat aq sodium potassium tartrate was added slowly. The reaction mixture was slowly warmed to room temperature over a period of 30 min. The solution was extracted with three 5-mL portions of ethyl acetate. The combined organic layer was washed with brine, dried (MgSO4) and concentrated under diminished pressure to give the crude product as a yellow oil: silica gel TLC Rf 0.22 (1:9 MeOH/CH2Cl2). The residue was then dissolved in 1 mL of CH3CN and 1% aq TFA, frozen and lyophilized. The crude product was purified on a Prepex C8 reversed phase semi-preparative (250 mm×10 mm) HPLC column using a gradient of methanol and water. Linear gradients were employed using 1:4 methanol/water→4:1 methanol/water over a period of 20 min, and then 4:1 methanol/water→methanol over a period of 40 min, at a flow rate of 3.5 mL/min (monitoring at 260 nm). Fractions containing the desired product eluted at 37.5 min, and were collected, frozen, and lyophilized to give 1c as a light yellow solid: yield 11.0 mg (82%); 1H NMR (CD3CN) δ 0.89 (t, 3H, J=6.4 Hz), 1.27-1.36 (m, 28H), 1.55 (quint, 2H, J=7.2 Hz), 2.13 (s, 3H), 2.70 (t, 2H, J=8.0 Hz), 3.00 (t, 2H, J=8.4 Hz), 3.06 (s, 3H) and 3.73 (t, 2H, J=8.4 Hz); 13C NMR (CDCl3) δ 13.0, 13.4, 22.4, 24.4, 27.2, 28.6, 28.7, 28.99, 29.06, 29.07, 29.2, 29.30, 29.33, 29.36, 29.39, 29.39, 29.39, 31.6, 32.4, 53.1, 117.3, 126.2, 131.9, 140.2, 141.4 and 152.1; mass spectrum, m/z 388.3 (M)+ (theoretical 388.3); mass spectrum (APCI), m/z 389.3526 (M+H)+ (C25H45N2O requires 389.3532).
Reaction SMILES: C([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][CH3:13])[CH:8]([CH3:14])[CH2:7]1)(OCC)=O>[OH-].[Na+]>[CH3:13][NH:12][CH:9]1[CH2:10][CH2:11][NH:6][CH2:7][CH:8]1[CH3:14]
Reactant: CCOC(=O)N1CCC(NC)C(C)C1
Agent: [Na+]
Agent: [OH-]
Product: CNC1CCNCC1C
Temperature: 110 °C
Reaction time: 24 h

Procedure:
1-Carbethoxy-4-methylamino-3-methylpiperidine (4.0 g, 18.34 mmol) was suspended in 5 M NaOH solution (15 ml), stirred at 110° C. for 24 hr, cooled, extracted with ethyl acetate, dried (Na2SO4) and concentrated to dryness to afford 4-methylamino-3-methyl-piperidine. Yield 1.8 g (77%), C7H16N2, m/z 129 (M+1), PMR (CDCl3): 0.92 (dd, 3H), 1.54 (m, 1H), 2.12 (m, 2H), 2.38 (s, 3H), 2.6 (m, 1H), 2.8 (m, 1H), 3.02 (m, 1H), 3.42 (m, 1H), 3.68 (m, 1H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2([CH2:19][O:18][C:17]3[CH:20]=[C:21]4[C:25](=[CH:26][C:16]2=3)[CH2:24][CH2:23][O:22]4)[C:8]1=[O:27].C(OC)(C)(C)C>C(#N)C>[O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@:9]2([CH2:19][O:18][C:17]3[CH:20]=[C:21]4[C:25](=[CH:26][C:16]2=3)[CH2:24][CH2:23][O:22]4)[C:8]1=[O:27]
Reactant: O=C1N(C[C@H]2CCCO2)c2ccccc2C12COc1cc3c(cc12)CCO3
Solvent: CC#N
Solvent: COC(C)(C)C
Product: O=C1N(C[C@H]2CCCO2)c2ccccc2[C@]12COc1cc3c(cc12)CCO3
Yield: 66 %

Procedure:
1′-[(2R)-Tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was resolved on chiral semi-prep HPLC IA column with 99% tert-butylmethyl ether and 1% acetonitrile to afford (3S)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (66%): 1H NMR (300 MHz, CDCl3) δ7.34-6.97 (m, 4H), 6.48 (s, 1H), 6.38 (s, 1H), 4.77 (ABq, 2H), 4.50 (t, J=8.6 Hz, 2H), 4.32-4.21 (m, 1H), 3.92-3.68 (m, 4H), 2.96 (t, J=8.4 Hz, 2H), 2.10-1.64 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 178.2, 161.7, 161.2, 142.8, 132.7, 128.6, 123.6, 123.2, 120.4, 119.8, 118.9, 109.5, 93.1, 80.7, 76.8, 72.3, 68.1, 57.6, 44.5, 29.0, 29.0, 25.6; MS (ES+) m/z 363.8 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[C:25]([CH2:27][CH2:28][C:29]4[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=4)[C:32]([O-:34])=O)[C:24]([C:38]([F:41])([F:40])[F:39])=[CH:23][N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].O[N:44]1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.C(N(CC)C(C)C)(C)C.C(=O)([O-])[O-].[NH4+].[NH4+]>C1COCC1.CN(C=O)C>[C:32]([C:31]1[CH:30]=[C:29]([CH:37]=[CH:36][CH:35]=1)[CH2:28][CH2:27][C:25]1[C:24]([C:38]([F:41])([F:39])[F:40])=[CH:23][N:22]=[C:21]([NH:20][C:17]2[CH:16]=[CH:15][C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9][CH2:10]3)=[CH:19][CH:18]=2)[N:26]=1)(=[O:34])[NH2:44]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4cccc(C(=O)[O-])c4)n3)cc2)CC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4cccc(C(N)=O)c4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
Lithium 3-(2-(2-((4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)benzoate (I34) (0.100 g, 0.173 mmol) was dissolved in dry THF (7 mL) and dry DMF (1 mL) under an atmosphere of nitrogen. To the solution were added 1-hydroxybenzotriazole (0.028 g, 0.21 mmol) and EDCI (0.040 g, 0.21 mmol) and N,N-diisopropylethylamine (0.121 mL, 0.693 mmol) and the reaction mixture was stirred at room temperature for 10 minutes. Ammonium carbonate (0.067 g, 0.69 mmol) was added in one portion, and the reaction was stirred room temperature for 60 hours. The volatiles were removed in vacuo and the residual solution was diluted with EtOAc (70 mL) and sat. aq. NaHCO3 (70 mL). The layers were separated and the aqueous layer was extracted with EtOAc (70 mL), the combined organic layers were washed with water (70 mL), brine (70 mL), dried (MgSO4), filtered and concentrated in vacuo to give an off-white solid. The crude product was purified by silica gel chromatography (Biotage Isolera, 12 g Si Cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I35) (0.073 g, 74% yield) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.00 (s, 1H), 8.61 (s, 1H), 7.95 (s, 1H), 7.79 (s, 1H), 7.75-7.68 (m, 1H), 7.54 (d, J=8.6 Hz, 2H), 7.40-7.29 (m, 3H), 6.93 (d, J=9.1 Hz, 2H), 3.50-3.41 (m, 4H), 3.14-3.00 (m, 8H), 1.42 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:24]2[C:8]3[N:9]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:10]4[C:15]([C:16](=[O:17])[C:7]=3[CH2:6][CH2:5][C:4]=2[CH:3]=1)=[CH:14][CH:13]=[CH:12][N:11]=4.[H][H]>[Pd].C(O)C>[OH:1][C:2]1[CH:26]=[CH:25][C:24]2[C:8]3[N:9]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:10]4[NH:11][CH2:12][CH2:13][CH2:14][C:15]=4[C:16](=[O:17])[C:7]=3[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: O=c1c2c(n(-c3ccccc3)c3ncccc13)-c1ccc(O)cc1CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=c1c2c(n(-c3ccccc3)c3c1CCc1cc(O)ccc1-3)NCCC2

Procedure:
Charge a Paar bottle with 5,6-dihydro-3-hydroxy-12-phenyl-naphtho[1,2-b][1,8]naphthyridin-7(12H)-one, an equal weight of 5% Pd on carbon, and ethanol. Pressurize the bottle with hydrogen to about 50 psi, and shake the contents in a Paar apparatus at 25° C. Monitor the progress of hydrogenation by pressure changes or by thin-layer chromatography. When hydrogen uptake ceases, remove catalyst by filtration and ethanol by evaporation. Crystallize the residue to obtain 5,6,8,9,10,11-hexahydro-3-hydroxy-12-phenyl-naphtho[1,2-b][1,8]naphthyridin-7(12H)-one, m.p. >330° C. after crystallization from C2H5OH.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11](Cl)[N:10]=[C:9]([S:18][CH3:19])[N:8]=1.[OH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([N:29]2[CH2:30][CH2:31][CH:26]([OH:25])[CH2:27][CH2:28]2)[N:10]=[C:9]([S:18][CH3:19])[N:8]=1
Reactant: COC(=O)c1c(Cl)nc(SC)nc1NCc1ccc(OC)c(Cl)c1
Reactant: OC1CCNCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COC(=O)c1c(NCc2ccc(OC)c(Cl)c2)nc(SC)nc1N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-chloro-2-methylthiopyrimidine (prepared in the above (3)) 100 mg, 4-hydroxypiperidine 78 mg, triethylamine 0.11 ml and N,N-dimethylacetamide 3 ml is stirred at room temperature for 1 hour. The reaction mixture is diluted a 10% aqueous citric acid solution and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo to give 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-(4-hydroxypiperidin-1-yl)-2-methylthiopyrimidine as a colorless caramel 132 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:33]1([CH2:39][C:40](Cl)=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl>[CH3:19][C:17]1([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=2)[NH:9][CH:8]1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:40](=[O:41])[CH2:39][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:7][CH:6]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(N)cc1)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(NC(=O)Cc3ccccc3)cc1)N2
Yield: 81 %

Procedure:
To a solution of methyl 2-(4-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (80 mg, 0.26 mmol) and N,N-diisopropylethylamine (0.09 mL, 0.52 mmol) in dichloromethane (5 mL) was added 2-phenylacetyl chloride (0.05 mL, 0.34 mmol). The resultant mixture was stirred at room temperature for 16 hrs under nitrogen. The solvent was removed and the residue was washed with dichloromethane/petroleum ether, the precipitate was collected to afford methyl 3,3-dimethyl-2-(4-(2-phenylacetamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate as a yellow solid, 90 mg, yield: 81%.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][N:6]1[CH:11]=[C:10]([C:12]([O:14]CC)=[O:13])[C:9](=[O:17])[C:8]2[CH:18]=[CH:19][CH:20]=[CH:21][C:22](=[O:23])[C:7]1=2)C>Cl>[C:12]([C:10]1[C:9](=[O:17])[C:8]2[CH:18]=[CH:19][CH:20]=[CH:21][C:22](=[O:23])[C:7]=2[N:6]([CH2:5][C:4]([OH:24])=[O:3])[CH:11]=1)([OH:14])=[O:13]
Reactant: CCOC(=O)Cn1cc(C(=O)OCC)c(=O)c2ccccc(=O)c21
Agent: Cl
Product: O=C(O)Cn1cc(C(=O)O)c(=O)c2ccccc(=O)c21
Yield: 76.6 %

Procedure:
A suspension of 3-(ethoxycarbonyl)-4,9-dihydro-4,9-dioxo-1H-cyclohepta[b]pyridine-1-acetic acid ethyl ester (2.2 g, described in example 3) in 5% aqueous HCl (v/v, 90 ml) was heated at reflux for 2 hr. The precipitate was collected by filtration and washed with water to give 1.4 g of the title compound; mp>250° C. (after recrystallization from ethanol); nmr (DMSO-d6) δ5.1 (s, 2H), 7.2 (m, 3H), 7.95 (m, 1H), 8.95 (s, 1H); ir (Nujol*) 2850, 1730, 1707, 1640 cm-1 ; uv λ max (MeOH) 344 nm (ε13,030), 235 (19,030); Anal Calcd for C13H9NO6 : C, 56.73% H, 3.30% N, 5.09%; Found: C, 56.76% H, 3.40% N, 5.05%.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:6][C:5]=1[C:18]([O:20]C)=O)#[N:2].[BH4-].[Na+].[NH4+].[Cl-].O>CO.O.O.O.O.O.O.[Co](Cl)Cl.CCOC(C)=O>[O:20]=[C:18]1[C:5]2[CH:6]=[C:7]([O:14][CH:15]([CH3:17])[CH3:16])[CH:8]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH2:3][CH2:1][NH:2]1
Reactant: COC(=O)c1cc(OC(C)C)cc(C(=O)OC)c1CC#N
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(OC(C)C)cc2c1CCNC2=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
Dimethyl 2-(cyanomethyl)-5-(propan-2-yloxy)benzene-1,3-dicarboxylate (Cpd D, 1.04 g, 3.57 mmol) and cobalt (II) chloride hexahydrate (2.56 g, 10.7 mmol) were dissolved in MeOH (60 mL) and cooled in an ice bath. NaBH4 (853 mg, 21.4 mmol) was added portionwise and the reaction mixture was stirred at 0° C. for 0.5 hours. To the reaction mixture was added NH4Cl (sat., aq., 25 mL), H2O (25 mL), and EtOAc (50 mL). The solution was allowed to sit at room temperature overnight. The residual solids were filtered and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (1×50 mL), dried over sodium sulfate, concentrated under vacuum, and purified by column chromatography (0-60%, EtOAc/heptanes) to afford methyl 1-oxo-7-(propan-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate (Cpd E, 644 mg, 69% yield) as a white solid. 1H NMR (400 MHz, chloroform-d) δ 1.35 (s, 3H) 1.36 (s, 3H) 3.35 (t, J=6.57 Hz, 2H) 3.52 (td, J=6.57, 3.03 Hz, 2H) 3.91 (s, 3H) 4.61-4.72 (m, 1H) 5.91 (br. s., 1H) 7.62 (d, J=3.03 Hz, 1H) 7.83 (d, J=3.03 Hz, 1H); MS 264.1 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH3:12]>>[CH2:11]([O:13][C:14](=[O:19])[CH:15]([C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH:16]([CH3:18])[CH3:17])[CH3:12]
Reactant: CCOC(=O)CC(C)C
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: CCOC(=O)C(C(=O)c1ccc(Cl)cc1)C(C)C
Yield: 82 %

Procedure:
4-Chlorobenzoyl chloride (2.5 ml) and isovaleric acid ethyl ester (1.5 ml) were subjected to reaction and post-treatment in a similar manner to that described in Reference example 8(a) to obtain the title compound (2.2 g, 82%) as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:25])[C@H:4]([NH:8][S:9]([C:12]1[CH:24]=[CH:23][C:15]2[N:16]=[C:17]([S:19][CH2:20][CH2:21][CH3:22])S[C:14]=2[CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].[Li+].[OH-:27]>C1COCC1.O>[CH3:6][CH:5]([CH3:7])[C@@H:4]([NH:8][S:9]([C:12]1[CH:24]=[CH:23][C:15]2[N:16]=[C:17]([S:19][CH2:20][CH2:21][CH3:22])[O:27][C:14]=2[CH:13]=1)(=[O:11])=[O:10])[C:3]([OH:2])=[O:25]
Reactant: [OH-]
Reactant: CCCSc1nc2ccc(S(=O)(=O)N[C@@H](C(=O)OC)C(C)C)cc2s1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCSc1nc2ccc(S(=O)(=O)N[C@@H](C(=O)O)C(C)C)cc2o1

Procedure:
(2R)-3-methyl-2-[(2-propylthiobenzthiazol-6-sulfonyl)amino]butanoic acid methylester (0.19 g, 0.48 mmol) was dissolved in THF/H2O (2 mL/2 mL), and LiOH (0.10 g, 5 equi.) was added. After reflux for 6 hours, the reaction solution was distilled under reduced pressure and treated with 1N HCl. The product was extracted with ethylacetate (10 mL). The separated organic phase was washed with NaCl solution, dried over MgSO4, distilled under reduced pressure and dried under vacuum to prepare the titled compound, (2R)-3-methyl-2-[(2-propylthiobenzoxazol-6-sulfonyl)amino]butanoic acid (0.14 g, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[CH:23][CH:22]=4)=[O:19])[CH2:14][CH2:13]3)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:34]([O-])=O>C(O)(=O)C.[Zn]>[NH2:34][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[Cl:1])[N:9]=[CH:8][N:7]=[C:6]2[N:12]1[CH2:17][CH2:16][N:15]([C:18]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:25][CH:26]=2)=[O:19])[CH2:14][CH2:13]1
Reactant: O=C(Nc1ccc(Oc2ccccc2)cc1)N1CCN(c2ncnc3cc(Cl)c([N+](=O)[O-])cc23)CC1
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1cc2c(N3CCN(C(=O)Nc4ccc(Oc5ccccc5)cc4)CC3)ncnc2cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
To a solution of 628.8 mg (1.25 mmol) of 4-(7-chloro-6-nitro-4-quinazolinyl)-N-(4-phenoxyphenyl)-1-piperazinecarboxamide obtained in Example 357 in 15 ml of acetic acid was added 407.9 mg (6.24 mmol) of zinc dust, followed by overnight stirring in an atmosphere of argon at room temperature. After the zinc dust was separated by filtration using Celite, the filtrate was washed with a chloroform-methanol mixture. After the solvent was evaporated with triethylamine, the residue was purified by silica gel chromatography to give the desired compound as colorless crystals.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1.[C:16]1([CH3:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>C(Cl)Cl>[CH3:22][C:16]1[CH:21]=[CH:20][C:19]([C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=2)=[O:14])=[CH:18][CH:17]=1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: Cc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cccc(C(=O)c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of AlCl3 (1.1 equivalents) in CH2Cl2 (40 ml) a solution of m-anisoylchloride (12.0 g) and toluene (1 equivalent) in CH2Cl2 (10 ml) is dropwise added. The resulting mixture is stirred at room temperature for 4 hours, then poured into 200 ml of a mixture ice-37% by weight HCl (1/1 v/v). The organic phase and the aqueous phase are separated. The organic phase is dehydrated with sodium sulphate. Filtration is then effected and the organic solvent evaporated. 4-methyl-3′-methoxybenzophenone is obtained. Yield: quantitative. IR (nujol) (λ=cm−1) 1690 (C═O); 1H-NMR (CDCl3) δ 2.44 (s, 3H); 3.86 (s, 3H); 7.08-7.18 (m, 1H); 7.20-7.40 (m, 5H); 7.73 (d, 2H, J=8.4 Hz). Anal. calc. for C15H14O2: C, 79.62; H, 6.24. Found: C, 79.53; H, 6.22.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.C(N(CC)CC)C.[O:17]=[C:18]1[C:26]([C:27]#[N:28])=[C:25]([N:29]2[CH2:34][CH2:33][N:32]([C:35]([C:37]3[S:38][CH:39]=[CH:40][CH:41]=3)=[O:36])[CH2:31][CH2:30]2)[C:24]2[C:20](=[CH:21][S:22][CH:23]=2)[NH:19]1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Cu+2]>[O:17]=[C:18]1[C:26]([C:27]#[N:28])=[C:25]([N:29]2[CH2:30][CH2:31][N:32]([C:35]([C:37]3[S:38][CH:39]=[CH:40][CH:41]=3)=[O:36])[CH2:33][CH2:34]2)[C:24]2[C:20](=[CH:21][S:22][CH:23]=2)[N:19]1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cscc2[nH]c1=O
Reactant: OB(O)c1cccnc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cscc2n(-c2cccnc2)c1=O
Temperature: 25 °C

Procedure:
Cu(OAc)2 (363 mg, 2 mmol), pyridine-3-boronic acid (614 mg, 5 mmol), and triethylamine (560 μL, 4 mmol) were added to a solution of 5-oxo-7-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-4,5-dihydro-2-thia-4-aza-indene-6-carbonitrile (47) (370 mg, 1 mmol) in wet DMF (DMF:H2O::9:1) stirred at room temperature. The solution was further stirred at room temperature for 24 h. The solution was passed through a bed of celite and the solvent was evaporated. The residue was suspended in water and extracted by CH2Cl2. The combined organic phase was partitioned with 10% aqueous HCl solution. The aqueous phase was separated and the pH was adjusted to 5 by 4 N NaOH solution. Then, a saturated solution of NaHCO3 was added until the pH reached to 8. The solids formed were filtered, washed by water, and dried under vacuum at 70° C. to get 5-oxo-4-pyridine-3-yl-7-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-4,5-dihydro-2-thia-4-aza-indene-6-carbonitrile as white solids. Yield 243 mg (54%); MP 282° C.; 1H NMR (400 MHz, DMSO-d6) δ 3.99 (m, 8H), 6.42 (d, J=2.8 Hz, 1H), 7.18 (dd, J=4.0, 4.8 Hz, 1H), 7.52 (d, J=2.8 Hz, 1H), 7.64 (dd, J=4.8, 8.0 Hz, 1H), 7.81 (d, J=4.8 Hz, 1H), 7.88 (dm, 1H), 8.47 (d, J=3.2 Hz, 1H), 8.58 (d, J=2.0 Hz, 1H), 8.71 (d, J=3.6 Hz, 1H) ppm; MS m/z=448 amu (M++1). Anal. (C22H17N5O2S2) N.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].CN(C)C1C=CC=CC=1.C(N(CC)C(C)C)(C)C.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:13][C:17]2[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[CH:22][C:18]=2[C:19]([OH:21])=[O:20])=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cccc([N+](=O)[O-])c1Nc1ccc(OCc2ccccc2)cc1
Yield: 90.6 %

Procedure:
A mixture comprising 2.2 g (11 mmol.) of 4-benzyloxyaniline, 2.0 g (10 mmol) of 2-chloro-3-nitrobenzoic acid, 6 ml of N,N-dimethylaniline and 1.6 ml of N,N-diisopropylethylamine was heated at 100° C. for 12 hours under stirring. After cooling, 30 ml, of chloroform and 30 ml of 1N sodium hydroxide were added thereto. The precipitate thus formed was separated by filtration, stirred together with 5% hydrochloric acid and washed with water to thereby give 3.3 g of 2-((4-benzyloxyphenyl)amino)-3-nitrobenzoic acid. This product was added to 40 ml of chloroform and 0.3 ml of N,N-dimethylaniline and 6 ml of phosphorus oxychloride were further added thereto. After heating under reflux for 30 minutes and then cooling, the crystals thus precipitated were separated by filtration. Thus 2.1 g of the title compound was obtained.