Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH3:30][N:31]([CH3:38])[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6]([C:5]3[CH:28]=[CH:29][C:2]([N:35]4[CH2:36][CH2:37][CH:32]([N:31]([CH3:38])[CH3:30])[CH2:33][CH2:34]4)=[N:3][CH:4]=3)=[O:7])=[CH:11][N:12]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Reactant: CN(C)C1CCNCC1
Product: CN(C)C1CCN(c2ccc(C(=O)NCc3cn(-c4ccccc4)c4cc(Cl)ccc4c3=O)cn2)CC1

Procedure:
4-Dimethylamino-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-5′-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate E and dimethyl-piperidin-4-yl-amine. MS calcd. for C29H30ClN5O2 [(M+H)+] 516.2, obsd 516.0.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[N:7]=[N:6]1.[NH:16]1[CH2:21][CH:20]=[C:19]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)[CH2:18][CH2:17]1>>[NH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([C:19]2[CH2:20][CH2:21][N:16]([CH2:2][CH2:3][CH2:4][N:5]3[C:10](=[O:11])[C:9]4[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=4[N:7]=[N:6]3)[CH2:17][CH:18]=2)=[CH:23]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: O=c1c2ccccc2nnn1CCCCl
Product: O=c1c2ccccc2nnn1CCCN1CC=C(c2c[nH]c3ccccc23)CC1
Yield: 78.8 %

Procedure:
Starting from 3-(3-chloropropyl)-1,2,3-benzotriazin-4(3H)one (1.49 g, 6.68 mmol) and 3-(1,2,3,6-tetrahydro-4-pyridinyl)1-H-indole (1.32 g, 6.68 mmol), following the same procedure as in example 1, step 3; 2.03 g of 3-[3-(4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)propyl]-1,2,3-benzotriazin-4(3H)-one was isolated as an off white solid. Yield 79%; mp 189° C.; MS: 386.2 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 2.20 (m, 2H), 2.57 (m, 2H), 2.66 (t, 2H), 2.72 (t, 2H), 3.21 (m, 2H), 4.61 (t, J=5.34 Hz, 2H), 6.15 (t, 1H), 7.12–7.21 (band, 2H), 7.26 (s, 1H), 7.35 (d, 1H), 7.75 (t, 1H), 7.87 (m, 2H), 8.13 (d, 1H), 8.36 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([CH:17]=O)[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH:20]1([NH2:23])[CH2:22][CH2:21]1.[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:19])[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([CH2:17][NH:23][CH:20]2[CH2:22][CH2:21]2)[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(Cc1ccc(Cl)c(C=O)c1)C(=O)OC(C)(C)C
Reactant: NC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(Cc1ccc(Cl)c(CNC2CC2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
A mixture of (4-chloro-3-formyl-benzyl)-methyl-carbamic acid tert-butyl ester (95 mg, 0.335 mmol) and cyclopropylamine (0.036 mL, 0.50 mmol) in MeOH (3.30 mL) was heated to reflux for 4 h. The mixture was allowed to cool to rt, and NaBH4 (19 mg, 0.50 mmol) was added in portions. The mixture was stirred for 1 h, and the solvents were removed under reduced pressure. The resulting oil was diluted with EtOAc (20 mL), and this mixture was washed with aq. sat. NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (CH2Cl2/MeOH 90:10) yielded the title compound (81 mg, 75%). LC-MS: tR=0.73 min; ES+: 366.20.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[Cl:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=2)[C:20]([CH2:28][CH2:29][CH:30]=[O:31])=[C:19]([CH3:32])[CH:18]=1>C1COCC1.CCCCCC>[Cl:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=2)[C:20]([CH2:28][CH2:29][CH:30]([OH:31])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH3:8])=[O:6])=[C:19]([CH3:32])[CH:18]=1
Reactant: COC(=O)CC(C)=O
Reactant: Cc1cc(Cl)c2ccc(Cl)cc2c1CCC=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)CC(=O)CC(O)CCc1c(C)cc(Cl)c2ccc(Cl)cc12
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Methyl acetoacetate (0.292 g, 2.64 mmoles) dissolved in dry THF (2 ml) is added dropwise via a syringe through a septum to a stirred suspension of sodium hydride (0.127 g of a 50% NaH in mineral oil, 2.64 mmoles) in dry THF (7 ml) which had been chilled in an ice-water bath. The reaction was stirred in the cold for 15 minutes at which time a clear solution was obtained. To this solution in the cold was added n-butyl lithium (1.80 ml of a 1.47M solution in hexane; 2.64 mmoles) via syringe through the septum dropwise in about 5 minutes. The orange solution is stirred with ice-water bath for 15 minutes and then cooled to -78° C. in a dry ice-acetone bath. To this cold stirred reaction was added dropwise via syringe, 3-(4,7-dichloro-2-methylnaphthalen-1-yl)propanal (0.6715 g, 2.513 mmoles) dissolved in dry THF (5 ml). The reaction is allowed to stir at -78° for 15 minutes, then allowed to warm to 0° by emersing the reaction flask in an ice-water bath. When ice separated from the flask, the reaction was worked up by partitioning it between ether (150 ml) and water containing 0.6 ml of 12N HCl. Extracted the water layer with ether. The combined ether extracts are washed with water twice then with saturated solution of NaHCO3. The ether was dried (MgSO4) and the solvent removed in vacuo to leave 0.96 g of crude title Rf =0.45 (silica, 5% acetone/CH2Cl2) which was used in the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[C:7]([C:12]([O:14]C)=[O:13])[CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[C:3]1C(OCC)=O.Cl>O1CCOCC1>[O:1]=[C:2]1[C:11]2[C:6](=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=2)=[CH:3]1
Reactant: CCOC(=O)c1c(-c2cccc(C(F)(F)F)c2)[nH]c2c(C(=O)OC)cccc2c1=O
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1cccc2c(=O)cc(-c3cccc(C(F)(F)F)c3)[nH]c12
Temperature: 200 °C
Yield: 89.6 %

Procedure:
A 20 mL microwave vial was charged with 3-ethyl 8-methyl 4-oxo-2-(3-(trifluoromethyl)phenyl)-1,4-dihydroquinoline-3,8-dicarboxylate 43 (820 mg, 1.96 mmol), dioxane (8 mL) and 1N HCl (4 mL). The reaction mixture was heated in a microwave reactor at 200° C. for 25 min then concentrated to dryness in vacuo to give 44 (585 mg, 90% yield).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[CH3:19][CH:20]1[CH2:25][CH:24]([CH3:26])[CH2:23][NH:22][CH2:21]1>>[CH3:19][CH:20]1[CH2:25][CH:24]([CH3:26])[CH2:23][N:22]([C:14]([C:10]2[CH:11]=[N:12][O:13][C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:17])=[CH:8][CH:7]=2)=[O:16])[CH2:21]1
Reactant: CC1CNCC(C)C1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Product: CC1CC(C)CN(C(=O)c2cnoc2-c2ccc(C(F)(F)F)cc2)C1

Procedure:
The title compound was prepared from 5-(4-trifluoromethylphenyl)isoxazole-4-carboxylic acid (12.9 mg, 0.050 mmol) and 3,5-dimethylpiperidine (6.8 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (2.2 mg). Calcd for C18H19F3N2O2: 352.1399, found 352.1399.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[C:28]12([N:38]=[C:39]=[O:40])[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2>O1CCCC1.C1CCCCC1>[CH3:1][O:2][C:3](=[O:19])[C:4]([CH2:5][C:6]1[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=1)([CH2:12][C:13]1[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=1)[C:39]([NH:38][C:28]12[CH2:37][CH:32]3[CH2:31][CH:30]([CH2:36][CH:34]([CH2:33]3)[CH2:35]1)[CH2:29]2)=[O:40]
Reactant: COC(=O)C(Cc1ccncc1)Cc1ccncc1
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: COC(=O)C(Cc1ccncc1)(Cc1ccncc1)C(=O)NC12CC3CC(CC(C3)C1)C2
Reaction time: 0.33 h

Procedure:
To a stirred solution of 3-pyridin4-yl-2-pyridin4-ylmethyl-propionic acid methyl ester (24.44 g, 95 mmol) in tetrahydrofuran (300 ml) chilled with a dry ice/acetone bath, lithium diisopropylamide (70 ml of a 1.5M solution in cyclohexane, 105 mmol of lithium diisopropylamide) was added dropwise over 15 minutes. After stirring for 20 minutes, the solution temperature was elevated to -40° C. After 30 minutes of stirring at -40° C., a solution of adamantyl isocyanate (16.92 g, 95 mmol) in tetrahydrofuran (100 ml) was added dropwise over 10 minutes. After 15 minutes stirring, the cooling bath was removed and the reaction was then stirred for 3 hours at ambient temperature. The reaction was then chilled in an ice water bath and glacial acetic acid (14 ml) was added dropwise over 10 minutes. After stirring for 20 minutes at ambient temperature, the solvent was removed in vacuo, and the residue was extracted into water/methylene chloride (300 ml of each). The aqueous phase was extracted three times with 200 ml portions of fresh methylene chloride. The combined organic extracts were dried (anhydrous sodium sulfate), and concentrated in vacuo to an oil (49.6 g).
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][C:8]([F:11])([F:10])[F:9])[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][CH:16]1[CH2:21][NH:20][CH2:19][CH2:18][N:17]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].CCN(C(C)C)C(C)C>CCO>[CH3:15][CH:16]1[CH2:21][N:20]([C:2]2[N:6]([CH2:7][C:8]([F:11])([F:10])[F:9])[N:5]=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:19][CH2:18][N:17]1[C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23]
Reactant: CC1CNCCN1C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1cnn(CC(F)(F)F)c1Br
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC1CN(c2c([N+](=O)[O-])cnn2CC(F)(F)F)CCN1C(=O)OC(C)(C)C
Yield: 47.7 %

Procedure:
A solution of Intermediate 39, 5-bromo-4-nitro-1-(2,2,2-trifluoroethyl)-1H-pyrazole (550 mg, 2.01 mmol), (±) tert-butyl 2-methylpiperazine-1-carboxylate (403 mg, 2.01 mmol), DIPEA (2 mL) in EtOH (6 mL) was stirred at 130° C. for 2 hours in a microwave oven. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using PE:EtOAc (1:1) as eluting solvents to afford tert-butyl (±)-2-methyl-4-(4-nitro-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)piperazine-1-carboxylate as yellow solid (377 mg, 48%). MS (ESI) m/z: 394 [M+H+].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[NH2:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20]>>[C:19]([C:18]1[CH:17]=[C:16]([NH:15][C:2]2[C:11]3[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:13]#[N:14])[CH:23]=[CH:22][CH:21]=1)#[N:20]
Reactant: N#Cc1cccc(N)c1
Reactant: N#Cc1cnc2cnc(F)cc2c1Cl
Product: N#Cc1cccc(Nc2c(C#N)cnc3cnc(F)cc23)c1
Yield: 29.1 %

Procedure:
Following the procedure described above in Example 13, 4-chloro-6-fluoro-1,7-naphthyridine-3-carbonitrile (0.300 g, 1.45 mmol) was reacted with 3-aminobenzonitrile (0.188 g, 1.59 mmol). The crude product was purified by flash chromatography over silica gel (15-30% EtOAc in CH2Cl2) to give pure 4-(3-cyanophenylamino)-6-fluoro-1,7-naphthyridine-3-carbonitrile (0.122 g, 29% yield): 1H NMR (400 MHz, DMSO-D6) δ 7.57-7.80 (m, 3 H) 7.88 (s, 1 H) 8.16 (s, 1 H) 8.75 (s, 1 H) 9.11 (s, 1 H) 10.23 (s, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:22]([CH3:31])([CH3:30])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].O>CN(C)C=O>[CH2:12]([O:11][C:9]([CH2:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][C:22]([CH3:31])([CH3:30])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:10])[CH:13]=[CH2:14]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: C=CCOC(=O)Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)Cc1cccc(OC(C)(C)C(=O)OC(C)(C)C)c1
Temperature: 80 °C
Reaction time: 13 h

Procedure:
Allyl 3-hydroxyphenylacetate (7.63 g, 50.10 mmol), potassium carbonate (13.85 g, 100.3 mmol), and tert-butyl 2-bromoisobutyrate (30.37 g, 100.3 mmol) were dissolved in dimethylformamide (9 mL), and the mixture was stirred for 13 hours at 80° C. The reaction mixture was added to water, and the resultant mixture was extracted with diethyl ether, followed by washing sequentially with water and saturated brine. The mixture was subjected to drying over magnesium sulfate, concentration under reduced pressure, and purification by silica gel column chromatography (n-hexane/ethyl acetate=20/1), whereby the target compound was obtained (3.55 g, 10.62 mmol, 21.2%).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[N:8]([C:24]2[CH:29]=[CH:28][C:27]([C:30](=[O:32])[NH2:31])=[CH:26][C:25]=2[CH3:33])[C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][C:13]=2[O:22][CH3:23])=[CH:10][CH:11]=1)C.[OH-].[Na+]>CO>[C:30]([C:27]1[CH:28]=[CH:29][C:24]([N:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][C:13]=3[O:22][CH3:23])=[CH:10][CH:11]=[C:7]2[CH2:6][CH2:5][C:4]([OH:34])=[O:3])=[C:25]([CH3:33])[CH:26]=1)(=[O:32])[NH2:31]
Reactant: CCOC(=O)CCc1ccc(-c2ccc(C(=O)OC)cc2OC)n1-c1ccc(C(N)=O)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccc(-c2ccc(CCC(=O)O)n2-c2ccc(C(N)=O)cc2C)c(OC)c1
Reaction time: 18 h
Yield: 64.9 %

Procedure:
3-[1-(4-Carbamoyl-2-methylphenyl)-5-(4-methoxycarbonylmethoxy-phenyl)-1H-pyrrol-2-yl]-propionic acid ethyl ester 16B (57 mg, 0.12 mmol) was dissolved in 1 mL methanol. 1 N NaOH (0.25 mL, 0.25 mmoL) was added. After 18 hrs, the reaction was concentrated in vacuo and diluted with water. The pH was adjusted to 1 with 1 M HCl and extracted with EtOAc (3×4 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with hexanes and dried under high vacuum to yield 3-[1-(4-Carbamoyl-2-methylphenyl)-5-(4-methoxycarbonyl-methyoxyphenyl)-1H-pyrrol-2-yl]-propionic acid (16C) (34 mg, 65%, light yellow powder).
Reaction SMILES: [C:1]1([S:7][C:8]2[NH:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][C:14]([Cl:19])([Cl:18])[C:15](Cl)=[O:16]>C(Cl)Cl>[C:1]1([S:7][C:8]2[NH:9][C:10]([C:15](=[O:16])[C:14]([Cl:19])([Cl:18])[Cl:13])=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: c1ccc(Sc2ccc[nH]2)cc1
Solvent: ClCCl
Product: O=C(c1ccc(Sc2ccccc2)[nH]1)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Phenylthiopyrrole (1.75 g., 10 mmoles) was dissolved in 20 ml. of methylene chloride. Trichloroacetyl chloride (1.1 ml., 10 mmoles) was added and the reaction stirred for 3 hours at room temperature. The reaction mixture was washed with 20 ml. of water and concentrated to yield 2-phenylthio-5-trichloroacetylpyrrole, used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].[Cl-].[C:14]([O:19][CH3:20])(=[O:18])[C:15]([O-])=[O:16]>C(=S)=S>[F:1][C:2]1[CH:3]=[C:4]([F:8])[CH:5]=[CH:6][C:7]=1[C:15](=[O:16])[C:14]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C(=O)[O-]
Reactant: Fc1cccc(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COC(=O)C(=O)c1ccc(F)cc1F
Temperature: 20 °C
Reaction time: 2.5 h

Procedure:
50 g (0.44 mol) of 1,3-difluorobenzene is dissolved at 20° C. in 135 ml of carbon disulfide with 73.5 g (0.55 mol) AlCl3 and then 55.15 g (0.45 mol) of methyl oxalate chloride is added and the mixture is stirred for 2.5 hours at 20° C. Ice-cold 2 N aqueous hydrochloric acid is added dropwise while cooling, extracted with ethyl acetate; the organic phase is washed with water and 10% aqueous Na2CO3 solution, dried over MgSO4, and evaporated to dryness. Yield: 38.0 g (43% of theory).
Reaction SMILES: [N+:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][N:2]=1.[N+:8]([O-])([OH:10])=[O:9].C(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O>[N+:8]([C:4]1[CH:5]=[CH:6][N+:1]([O-:7])=[N:2][CH:3]=1)([O-:10])=[O:9]
Reactant: [O-][n+]1ccccn1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=[N+]([O-])c1cc[n+]([O-])nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
With cooling and stirring, 5.1 grams (0.053 mole) of pyridazine-1-oxide was dissolved in 50 ml of fuming sulfuric acid. To this was added 8.83 ml of fuming nitric acid. Upon completion of addition the reaction mixture was warmed to 130°-135° C. where it stirred for two hours. Analysis of the reaction mixture by thin layer chromatography (TLC) indicated the reaction was not complete. The reaction mixture was allowed to cool to ambient temperature where it stood for 16 hours. An additional 1.3 ml of fuming nitric acid was added and the reaction mixture was heated to 130°-135° C. where it stirred for 4 hours. Analysis of the reaction mixture by TLC indicated the reaction still had not gone to completion. An additional 1.3 ml of fuming nitric acid was added to the reaction mixture, which was stirred an additional 4 hours at 130°-135° C. The reaction mixture was poured into ice-water where it stood for several hours. The pH of the mixture was adjusted to near 7 with sodium bicarbonate, then the mixture was extracted with methylene chloride using a continuous extractor. The extract was dried with sodium sulfate and filtered. The filtrate was subjected to column chromatography on silica gel using 10% acetone in methylene chloride as eluent. The appropriate fractions were combined and concentrated under reduced pressure to give 1.1 grams of 4-nitropyridazine-1-oxide, m.p. 149°-151.5° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([CH:19]=O)[C:13]=3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+].O.[N+:27]([CH3:30])([O-:29])=[O:28]>>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([CH:19]=[CH:30][N+:27]([O-:29])=[O:28])[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cccc2c1ccn2S(=O)(=O)c1ccccc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: O=[N+]([O-])C=Cc1cccc2c1ccn2S(=O)(=O)c1ccccc1
Yield: 90 %

Procedure:
To a solution of 1- benzenesulphonyl-1H-indole-4-carboxaldehyde (1.9 g, 6.6 mmol) in nitromethane (12 ml) was added ammonium acetate (205 mg, 2.7 mmol) and the resulting mixture was refluxed for 2 hours. Water (50 ml) was added and products were extracted with ethyl acetate (2×100 ml). The combined organic phases were washed with brine (1×30 ml), dried (MgSO4) and concentrated. Flash chromatography (silica gel, dichloromethane-hexane, 75:25) of the residue gave 1.95 g (90%) of the title compound as a pale yellow solid; δH (250 MHz, CDCl3) 8.27 (1H, d, J=13.7 Hz), 8.14 (1H, d, J=8.2 Hz), 7.92-7.87 (2H, m), 7.75 (1H, d, J=3.7 Hz), 7.65 (1H, d, J=13.7 Hz), 7.62-7.34 (5H, m), 6.89 (1H, dd, J=3.7 and 0.9 Hz); m/z (CI) 299 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:22])[CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[N+:23]([CH:26]([CH3:28])[CH3:27])([O-:25])=[O:24].C(O)C.CC[O-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:22])[CH2:14][CH:15]([C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)[C:26]([CH3:28])([N+:23]([O-:25])=[O:24])[CH3:27])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: CC(C)[N+](=O)[O-]
Reactant: COc1cc(C(=O)C=Cc2ccncc2)cc(OC)c1OC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: COc1cc(C(=O)CC(c2ccncc2)C(C)(C)[N+](=O)[O-])cc(OC)c1OC

Procedure:
A solution of 40 g. of 3',4',5'-trimethoxy-3-(4-pyridyl)-acrylophenone and 24 g. of 2-nitropropane in 270 ml. of ethanol is heated at reflux with stirring under a nitrogen atmosphere. Within 1 hour there is added dropwise a sodium ethylate solution (manufactured from 1.35 g. of sodium and 27 ml. of ethanol). The reaction mixture left standing for a half hour to react further is then evaporated under reduced pressure. The residue results is taken up in methylene chloride, washed with water, dried over sodium sulfate and evaporated under reduced pressure. The product which results is crystallized with chloroform ether to yield 3',4',5'-trimethoxy-4-methyl-4-nitro-3-(4-pyridyl)-valerophenone, melting point 214°-216° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.C([BH3-])#N.[Na+].C(OC)(OC)OC.[CH:40](=O)[CH2:41][CH3:42]>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([N:23]2[CH2:24][CH2:25][N:26]([CH2:40][CH2:41][CH3:42])[CH2:27][CH2:28]2)=[O:22])=[CH:19][CH:20]=1)[CH2:8][C:9]1[NH:13][CH:12]=[CH:11][N:10]=1
Reactant: O=C(c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1)N1CCNCC1
Reactant: CCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: CCCN1CCN(C(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound (48.8 mg) obtained in Example 32-2 was dissolved in anhydrous methanol (1.0 ml) and then added with sodium cyanoborohydride (16.2 mg), trimethyl orthoformate (21.1 μl), propionaldehyde (13.9 μl), followed by stirring overnight at room temperature under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off and the residue was then dissolved in chloroform. A saturated aqueous sodium bicarbonate solution was added to the solution, followed by stirring. The resultant solution was subjected to extraction with chloroform and washed with a saturated aqueous sodium bicarbonate solution and saturated saline solution, and then the organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was then treated with hydrochloric acid. Subsequently, the treated product was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (33.2 mg) of the subject compound as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]([O:13]CC)=[O:12])[CH2:7][CH2:6]1)=[O:4].O.[OH-].[Li+]>CO.O>[CH3:1][N:2]([CH3:16])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]([OH:13])=[O:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: CCOC(=O)C1CCN(C(=O)N(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)C(=O)N1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
Ethyl 1-(N,N-dimethylcarbamoyl)piperidine-4-carboxylate (2.28 g, 10.0 mmol) obtained in Step 1 was dissolved in a mixed solvent of methanol (30 mL) and water (10 mL), lithium hydroxide monohydrate (2.10 g, 50.0 mmol) was added thereto, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and 6 mol/L hydrochloric acid was added to the resulting residue to adjust the pH to 1, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure to afford 1-(N,N-dimethylcarbamoyl)piperidine-4-carboxylic acid (830 mg, 42%).