Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[Cl:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([NH:32]N)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([N:32]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:24][CH:23]=1
Reactant: NNc1ccc(Cl)c2ccccc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Product: O=c1ccn(-c2ccccc2)nc1-c1ccnn1-c1ccc(Cl)c2ccccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and (4-chloro-naphthalen-1-yl)-hydrazine according to the method described for example 1. MS: M=399.1 (M+H)+
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH:13]2[CH:11]([C:12]2([CH3:16])[CH3:15])[C:10]1=[O:17])=O)(C)(C)C>C1(C)C=CC=CC=1>[CH3:15][C:12]1([CH3:16])[CH:11]2[CH:13]1[CH2:14][NH:9][C:10]2=[O:17]
Reactant: CC(C)(C)OC(=O)N1CC2C(C1=O)C2(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: CC1(C)C2CNC(=O)C21

Procedure:
To this solution was added 569.5 g of 1% hydrochloric acid and mixed, and liquid-partitioning was caused. An organic layer obtained by liquid-partitioning was washed with 262.5 g of a 5% sodium hydrogen carbonate aqueous solution, further washed with 262.5 g of water, then, 1652.8 g of a toluene solution containing 349.7 g (1.552 mol) of 3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-one was obtained. The yield with respect to 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-one was 99.4%.
Reaction SMILES: CC1[N:3]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[CH2:17][C@@H:18]2[CH2:22][C@@H:21]([O:23][CH3:24])[CH2:20][N:19]2[CH3:25])C(C)=CC=1.Cl.NO.C(N(CC)CC)C>CC(O)C>[NH2:3][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:17][C@@H:18]1[CH2:22][C@@H:21]([O:23][CH3:24])[CH2:20][N:19]1[CH3:25]
Reactant: CO[C@@H]1C[C@@H](Cc2c[nH]c3ccc(-n4c(C)ccc4C)cc23)N(C)C1
Agent: Cl
Agent: NO
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CO[C@@H]1C[C@@H](Cc2c[nH]c3ccc(N)cc23)N(C)C1
Yield: 99.4 %

Procedure:
A mixture of 5-(2,5-dimethyl-1H-pyrrolyl)-3-[(2R,4R)-N-methyl-4-methoxypyrrolidin-2-ylmethyl]-1H-indole (2.20 g, 6.52 mmol), hydroxylamine hydrochloride (7.25 g, 104 mmol, 16 eq), and triethylamine (7.28 mL, 52.2 mmol, 8 eq) in 2-propanol (22 mL) was heated at reflux under nitrogen for 8 hours. The resulting reaction solution was evaporated under reduced pressure, and the residue was partitioned between ethyl acetate (50 mL) and a saturated solution of sodium hydrogen carbonate (50 mL). The ethyl acetate layer was removed, and the aqueous layer was extracted with methylene chloride (3×50 mL). All organic extracts were combined, dried (MgSO4), and evaporated under reduced pressure to afford the title compound (1.68 g, 100%) as an off-white amorphous solid: Rf =0.4 in 9:1:0.1 [methylene chloride/methanol/ammonium hydroxide]; 1H NMR (CD3OD) δ7.14 (d, J=8.5 Hz, 1H), 6.99 (s, 1H), 6.94 (br s, 1H), 6.68 (br d, J=8.5 Hz, 1H), 4.90 (s, 3-NH), 3.86-3.77 (m, 1H), 3.24 (s, 3H), 3.24-3.13 (m, 2H), 2.93-2.80 (m, 1H), 2.69 (dd, J=13.7 and 9.7 Hz, 1H), 2.51 (s, 3H), 2.40-2.18 (m, 2H), 1.73-1.63 (m, 1H); 13C NMR (CD3OD) δ139.7, 133.4, 129.3, 124.4, 114.4, 112.8, 111.2, 105.5, 79.3, 68.3, 66.1, 56.7, 40.7, 39.5, 30.1.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#N)=[C:4]([Cl:10])[CH:3]=1.CC(C[AlH]CC(C)C)C.C[OH:21].Cl>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:21])=[C:4]([Cl:10])[CH:3]=1
Reactant: CO
Reactant: N#Cc1ccc(Br)cc1Cl
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccc(Br)cc1Cl
Temperature: -50 °C
Reaction time: 0.17 h

Procedure:
To 4-bromo-2-chlorobenzonitrile (2.0 g, 9.2 mmol) in toluene (50 mL) at −78° C. under argon was added DIBAL (1M solution in toluene, 13.9 mL, 13.9 mmol). The mixture was allowed to warm to −50° C. over 4 h. MeOH (4.5 mL) and water (4.5 mL) were added and the mixture stirred for 10 min at −50° C. The mixture was allowed to warm to rt, acidified with 2N HCl (pH<7) and extracted with EtOAc (200 mL) and water (100 mL). The aqueous was further extracted with EtOAc (2×50 mL), the combined organics were then washed with brine and dried (MgSO4). The solvent was removed in vacuo and the residue purified by column chromatography (25% DCM: Iso-hexane) to give 4-bromo-2-chlorobenzaldehyde. To a solution of 4-bromo-2-chlorobenzaldehyde (750 mg, 3.4 mmol) in DME (22 mL) and EtOH (15 mL) was added 3-carboxamidobenzene boronic acid (676 mg, 4.1 mmol) and 2M Na2CO3 solution (15 mL). Argon was bubbled through the mixture for 15 min. Bis(triphenylphosphino) palladium dichloride (120 mg, 0.17 mmol) was added and the reaction heated to 75° C. for 6.5 h before cooling to rt. The mixture was partitioned between water (200 mL) and EtOAc (200 mL), the aqueous was extracted with EtOAc (2×50 mL) and the combined organics dried (MgSO4). The solvent was removed in vacuo and the residue purified by column chromatography (50% EtOAc: Iso-hexane to 100% EtOAc) to give the title compound: RT=3.19 min; m/z (ES+)=301.0 [M+H+MeCN]+.
Reaction SMILES: [N+:1]([C:4]1[C:13]([Br:14])=[C:12]([Br:15])[CH:11]=[C:10]2[C:5]=1[NH:6][C:7](=[O:17])[C:8](=[O:16])[NH:9]2)([O-:3])=[O:2].[OH-].[K+].[NH2:20]OS(O)(=O)=O>O>[NH2:20][N:9]1[C:10]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[C:13]([Br:14])=[C:12]([Br:15])[CH:11]=2)[NH:6][C:7](=[O:17])[C:8]1=[O:16]
Reactant: NOS(=O)(=O)O
Reactant: O=c1[nH]c2cc(Br)c(Br)c([N+](=O)[O-])c2[nH]c1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nn1c(=O)c(=O)[nH]c2c([N+](=O)[O-])c(Br)c(Br)cc21
Reaction time: 0.08 h
Yield: 63.8 %

Procedure:
The procedure of Shin, S. C. and Lee. Y. Y., Taehan Hwahakhoe Chi 27(5):382-4 (1983) was adapted. To a stirred red solution of 5-nitro-6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione (120 mg, 0.33 mMol) and 3N KOH (2 mL) in distilled water (5 mL) at 65° C. was dropwise added a colorless solution of NH2OSO3H (56 mg, 0.50 mMol) in distilled water (0.5 mL) with stirring, whereupon a yellow precipitate came out after 5 mins. The mixture was stirred at 65° C. for 1 h and allowed to stand at room temperature overnight, then the precipitate was collected by filtration at 50° C., washed with distilled water (2 mL), then air dried at 50° C. overnight, affording 80 mg (64%) of crude 1-amino-5-nitro-6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione (free base Na+ by NMR, D2O), as a yellow amorphous solid (80% desired 1-amino-5-nitro-6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione with 20% starting material by NMR). (It is not known if the reaction actually gave the 1-amino or 4-amino isomer.) A 80 mg sample of crude 1(4)-amino-5-nitro-6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione (0.211 mMol) was dissolved into distilled water (10 mL) at 50° C., then acidified with AcOH to pH=5. After the insoluble material was removed by filtration, it was heated at 60°-70° C. until a clear solution was obtained, then slowly cooled, and a yellow precipitate came out. The precipitate was crystallized from hot EtOH, collected by filtration, and washed with cold ethanol (2 mL), then dried in the air at 60° C. for 4 h, affording 57 mg (45.6%) of pure 1(4)-amino-5-nitro-6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione (free base H). NH2OSO3H (40 mg, 0.35 mMol) was added to the mother liquid, and allowed to react at 65°-70° C. for 30 min to give a second crop of pure 1(4)-amino-5-nitro-6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione (26 mg, 21%), using the same procedure as above. The total yield is 66%. Mp was measured: the color of 1(4)-amino-5-nitro-6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione changed to dark yellow at 301° C.; the decomposition of 1(4)-amino-5-nitro-6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione is obvious at 310° C. and it melted to a black liquid at 320°-1° C. IR (KBr, cm-1): 3414; 3211; 1745; 1728; 1682; 1631; 1546. NMR (1H, DMSO-d6): δ5.832 (s, 2H); 8.047 (s, 1H); 12.565 (s, 1H). HRMS: calcd for C8H4N4O4Br2 (M+) m/z: 377.8613; found: 377.8583.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([N:11]2[CH2:16][C@@H:15]3[CH2:17][C@H:12]2[CH2:13][N:14]3C(OC(C)(C)C)=O)=[CH:3][CH:2]=1.[ClH:25]>O1CCOCC1>[ClH:25].[C@H:15]12[CH2:17][C@H:12]([N:11]([C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=[CH:2][CH:3]=3)[CH2:16]1)[CH2:13][NH:14]2
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1ccnc2ccccc12
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc2c(N3C[C@@H]4C[C@H]3CN4)ccnc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl (1S,4S)-5-(4-quinolyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (325 mg from step A) was dissolved in a 4M solution of HCl in anhydrous dioxane (4 ml) and stirred for one hour at room temperature. The volatiles were evaporated under reduced pressure, the residue was triturated two times with diethylether and the supernatant removed. The residue was dried in vacuo to obtain 317 mg of a solid. MS (APCI) m/z=225.9 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]=1[F:15])=[O:5].[O:21]1CCOC[CH2:22]1>>[Br:20][C:18]1[CH:19]=[C:2]2[C:3]([C:4](=[O:5])[N:6]([CH2:7][C:8]3[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]=3[F:15])[C:22](=[O:21])[NH:1]2)=[CH:16][CH:17]=1
Reactant: C1COCCO1
Reactant: Nc1cc(Br)ccc1C(=O)NCc1ccc(Br)cc1F
Product: O=c1[nH]c2cc(Br)ccc2c(=O)n1Cc1ccc(Br)cc1F
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
2-Amino-4-bromo-N-(4-bromo-2-fluorobenzyl)benzamide (2.90 g) and N,N'-carbonyldiimidazole (4.68 g) were dissolved in dioxane (50 ml). The solution was evaporated to give a residue, which was stirred at 150° C. for 30 minutes. After cooling, the precipitates were collected by filtration and washed with ethanol to give 7-bromo-3-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (2.92 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH2:9])=[O:8].C=O.[C:12](=O)([O-])[O-:13].[K+].[K+]>>[OH:13][CH2:12][NH:9][C:7](=[O:8])[CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)Cc1cccs1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [K+]
Product: O=C(Cc1cccs1)NCO
Temperature: 0 °C

Procedure:
A mixture of 2-thienylacetamide, formaldehyde solution (37%, 1 equivalent) and a catalytic amount of potassium carbonate is warmed on a steam bath until a homogeneous solution is obtained. The solution is cooled to 0° C. overnight and the resulting solid collected by filtration.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:39])/[C:6](/[NH:18][C:19](=[O:38])[C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:36])[CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[CH:22][C:21]=1[Cl:37])=[CH:7]/[C:8]1[CH:9]=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2>CO.O1CCCC1>[Cl:37][C:21]1[CH:22]=[C:23]([C:26](=[O:36])[CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)[CH:24]=[CH:25][C:20]=1[C:19]([NH:18]/[C:6](=[CH:7]\[C:8]1[CH:9]=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)/[C:5]([OH:39])=[O:4])=[O:38]
Reactant: COC(=O)/C(=C/c1cnc2ccccc2c1)NC(=O)c1ccc(C(=O)CCc2cccc(O)c2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)/C(=C/c1cnc2ccccc2c1)NC(=O)c1ccc(C(=O)CCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.5 %

Procedure:
An aqueous 1N solution of sodium hydroxide (0.9 mL, 0.9 mmol) was added to a solution of (Z)-2-[[2-chloro-4-[3-(3-hydroxyphenyl)-1-oxopropan-1-yl]benzoyl]amino]-3-(quinolin-3-yl)propenoic acid methyl ester (Example 226; 140 mg, 0.272 mmol) in methanol/tetrahydrofuran (1:1; 3.6 mL). The solution was stirred at room temperature for 16 h and the solvent was evaporated. Water (7 mL) was added and the mixture was extracted with diethyl ether. The diethyl ether extract was discarded and the water layer was filtered through Celite® and then acidified with 1N hydrochloric acid solution (1 mL). The resulting solid was filtered off, washed with water, dried and crystallized from tetrahydrofuran/methanol/water to give (Z)-2-[[2-chloro-4-[3-(3-hydroxyphenyl)-1-oxopropan-1-yl]benzoyl]amino]-3-(quinolin-3-yl)propenoic acid (96 mg, 70% yield) as a colorless solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12](C(O)=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[C:18]([OH:21])(=[O:20])C.Br>O>[OH:2][C:3]1[CH:4]=[C:5]([C:18]([OH:21])=[O:20])[C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: CC(=O)O
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: Br
Solvent: O
Product: O=C(O)c1cc(O)ccc1-c1ccccc1
Yield: 90 %

Procedure:
25 g of 4'-methoxybiphenyl-4-carboxylic acid, 1 liter of acetic acid and 200 ml of 48% hydrobromic acid were refluxed for 12-14 hours and then the mixture was thrown into 2.5 liter of water. After cooling, the crystals were collected to obtain 4-hydroxybiphenylcarboxylic acid with a melting point of 288°-291° C. and at a yield of 90-95%.
Reaction SMILES: [BH4-].[Li+].C([C@@H]1COC(=O)N1[C:16](=[O:24])[C@H:17]([CH3:23])[CH2:18][C:19]([F:22])([F:21])[F:20])C1C=CC=CC=1.O>C(OCC)C>[F:20][C:19]([F:22])([F:21])[CH2:18][C@@H:17]([CH3:23])[CH2:16][OH:24]
Reactant: C[C@H](CC(F)(F)F)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: C[C@@H](CO)CC(F)(F)F
Temperature: 25 °C
Yield: 86.9 %

Procedure:
A solution of lithium borohydride (23 mL, 2.0 M in THF, 45 mmol) was added dropwise to a solution of (4R)-4-benzyl-3-[(2R)-4,4,4-trifluoro-2-methylbutanoyl]-1,3-oxazolidin-2-one (12.9 g, 40.9 mmol) and water (810 μL, 45.0 mmol) in diethyl ether (200 nL) at 0° C. The reaction mixture was allowed to warm to 25° C. and, after 1 h, was cooled to 0° C. and quenched with aqueous 1 N NaOH (124 mL). The mixture was warmed to 25° C. and stirred until both layers were homogeneous. The layers were separated and the organic extract was washed with brine, dried using MgSO4 and concentrated. Flash chromatography (eluent: 3:7 ether-petether) provided (2R)-4,4,4-trifluoro-2-methylbutan-1-ol (5.05 g, 87%) as a colorless oil. 1H NMR was identical to that which was found in the literature (J. Med. Chem. 37: 1282–1297 (1994)).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([N:11]2[CH2:16][CH2:15][NH:14][C@H:13]([CH3:17])[CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=1.[Cl:18][C:19]1[CH:20]=[C:21]([N:25]2[CH:29]=[N:28][C:27]([C:30](O)=[O:31])=[N:26]2)[CH:22]=[CH:23][CH:24]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]([N:25]2[CH:29]=[N:28][C:27]([C:30]([N:14]3[CH2:15][CH2:16][N:11]([C:9]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=4)=[O:10])[CH2:12][C@H:13]3[CH3:17])=[O:31])=[N:26]2)[CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)c1ncn(-c2cccc(Cl)c2)n1
Reactant: COc1cccc(C(=O)N2CCN[C@H](C)C2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc(C(=O)N2CCN(C(=O)c3ncn(-c4cccc(Cl)c4)n3)[C@H](C)C2)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 71 mg (0.30 mmol) (6-methoxy-pyridin-2-yl)-((R)-3-methyl-piperazin-1-yl)-methanone, 67 mg (0.30 mmol) 1-(3-chloro-phenyl)-1H-[1,2,4]-triazole-3-carboxylic acid, 0.11 g (0.33 mmol) TBTU and 77 μL (0.45 mmol) DIPEA in 1.5 mL DMF was stirred at RT for 12 h. The reaction mixture was purified by HPLC.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:30])=[C:5]([C:26]([O:28][CH3:29])=[O:27])[CH:6]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][NH2:16])=[O:9].[C:31]1([O:37][CH2:38][CH:39]2[O:41][CH2:40]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(O)C>[CH3:1][C:2]1[NH:3][C:4]([CH3:30])=[C:5]([C:26]([O:28][CH3:29])=[O:27])[CH:6]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][NH:16][CH2:40][CH:39]([OH:41])[CH2:38][O:37][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:9]
Reactant: c1ccc(OCC2CO2)cc1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOCCN)C1c1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOCCNCC(O)COc2ccccc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 35.8 %

Procedure:
In 20 ml of ethanol were dissolved 1.8 g of 2-(2-aminoethoxy)ethyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and 0.64 g of glycidyl phenyl ether, and the solution was stirred at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography. The product was eluted with chloroform-methanol (95.5 v/v), and 0.87 g of 2-[2-(2-hydroxy-3-phenoxypropylamino)ethoxy]ethyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate was obtained. The product was treated with an ethanol solution of hydrochloric acid to provide 0.8 g of hydrochloric acid salt as amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([F:32])[CH:31]=1)[CH2:27]Br.O>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[CH:7][N:8]2[CH2:27][C:26]2[CH:25]=[C:24]([F:23])[CH:31]=[C:30]([F:32])[CH:29]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)C(F)(F)F
Reactant: Fc1cc(F)cc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: O=C(c1cn(Cc2cc(F)cc(F)c2)c2cc(Cl)ccc12)C(F)(F)F
Temperature: 80 °C
Yield: 62.6 %

Procedure:
A mixture of 2.0 g (9.4 mmol) 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone, 4.59 g (14.1 mmol) cesium carbonate and 2.14 g (10.4 mmol) 3,5-difluorobenzyl bromide in 90 ml acetonitrile was heated at 80° C. for 3 h. After cooling to room temperature addition of 150 ml water was followed by extraction with three 150-ml portions of tert-butyl methyl ether. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated in 30 ml hot cyclohexane. Filtration gave 2.2 g (64%) of the crude title compound as light brown solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[N:20]([C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)=[N+:21]=[N-:22].S(=O)(=O)(O)O>C(Cl)Cl>[OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][NH:10][S:29]([C:26]2[CH:25]=[CH:24][C:23]([N:20]=[N+:21]=[N-:22])=[CH:28][CH:27]=2)(=[O:30])=[O:31])=[CH:6][CH:5]=1
Reactant: [N-]=[N+]=Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCc1ccc(CCO)cc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=Nc1ccc(S(=O)(=O)NCCc2ccc(CCO)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice cold solution of 5.5 g. (33 mmole) 4-(2-hydroxyethyl)-phenethylamine, 100 ml. methylene chloride and 3.4 g. (33 mmole) triethylamine is slowly added dropwise a solution of 7.2 g. (33 mmole) 4-azidobenzenesulphonyl chloride in 50 ml. methylene chloride. Subsequently, the reaction is allowed to continue for 1 hour with ice cooling. The reaction mixture is now shaken out twice with dilute sulphuric acid, then twice with water, dried with anhydrous sodium sulphate and finally evaporated. The residue is recrystallised twice from toluene to give 7.8 g. (64% of theory) of desired product; m.p. 90°-92° C. (recrystallised from toluene).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[CH:6]2.[C:13]1(=[O:23])[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12>C(Cl)CCl>[C:12]1([C:7]2[NH:8][C:9]3[C:5]([C:6]=2[C:16]([C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[C:13]([OH:18])=[O:23])=[O:17])=[CH:4][CH:3]=[CH:11][CH:10]=3)[CH:5]=[CH:4][CH:3]=[CH:11][CH:10]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COc1ccc2[nH]c(C)cc2c1
Solvent: ClCCCl
Product: O=C(O)c1ccccc1C(=O)c1c(-c2ccccc2)[nH]c2ccccc12
Temperature: 25 °C

Procedure:
A mixture of 5.0 g (0.03 mole) of 5-methoxy-2-methylindole and 4.6 g (0.03 mole) of phthalic anhydride in 25 ml of ethylene dichloride was refluxed for ten hours, cooled to room temperature and the separated solid was collected by filtration and dried to obtain 2-[(2-methyl-5-methoxy-3-indolyl)carbonyl]-benzoic acid (Formula VIII: R°=R1 =R2 =R3 =R6 =H; R5 =CH3 ; Y1 =OCH3), as a pale pink-colored solid which decomposed at 203°-204° C. The nuclear magnetic resonance and infrared spectra were consistent with the assigned structure.
Reaction SMILES: C[N:2](C)[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)CN.C(N(CC)CC)C.C1C[O:23]CC1>>[C:3]([NH2:2])(=[O:23])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C1CCOC1
Reactant: CN(C)C(CN)c1ccccc1
Solvent: CCN(CC)CC
Product: NC(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
After cooling N,N-dimethyl-1-phenylethane-1,2-diamine represented by Formula 101 (292 mg, 1.78 mmol, purchased from Alfa Aesar Co.) and triethylamine (0.55 mL, 3.95 mmol) in THF (8 mL) at 0° C. under a nitrogen atmosphere, 4-n-benzyloxy-3,5-dimethoxybenzoic acid chloride represented by Formula 85 (606 mg, 1.98 mmol) prepared in Preparative Example 1 in THF (12 mL) was slowly added to the cooled solution. After agitating the above solution at the same temperature for 30 minutes, this was left alone at room temperature for 18 hours. A precipitate generated during the reaction was filtered and discarded, the remaining solution was diluted using chloroform and washed with a potassium carbonate solution, followed by separation and drying with sodium sulfate. The solvent was removed again under reduced pressure. The obtained vacuum-concentrated mixture was subjected to separation and purification through column chromatography (ethyl acetate/hexane/triethylamine, 2:1:0.1, v/v/v) using silica gel (SiO2), resulting in a benzamide compound represented by Formula 19 as a desired product (VVZ-020; 451.3 mg, 52% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:33])=[C:24]([C:27](=[O:32])N(OC)C)[CH:25]=2)[NH:20][C:19](=[O:34])[C:18]=1[C:35]1[CH:40]=[C:39]([CH3:41])[CH:38]=[C:37]([CH3:42])[CH:36]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:33])=[C:24]([CH:27]=[O:32])[CH:25]=2)[NH:20][C:19](=[O:34])[C:18]=1[C:35]1[CH:36]=[C:37]([CH3:42])[CH:38]=[C:39]([CH3:41])[CH:40]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CON(C)C(=O)c1cc2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c(-c3cc(C)cc(C)c3)c(=O)[nH]c2cc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(C=O)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
To a solution of 2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-(methoxy-methylcarbamoyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (1.18 g in dry tetrahydrofuran) was added 3.9 mL of a 1M solution of lithium aluminum hydride and the mixture stirred at room temperature. After 2 hours, the reaction was quenched by the addition of saturated ammonium chloride solution. The mixture was filtered through diatomaceous earth and the filtrate extracted with ethyl acetate. The organics were then dried over magnesium sulfate and concentrated in vacuo to give the crude title compound (900 mg).