Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.Cl.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][NH2:21].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>C1COCC1>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][NH:21][C:4](=[O:6])[C:3]1[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=1[NH2:1]
Reactant: Nc1cccc(F)c1C(=O)O
Reactant: NNc1ccccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Nc1cccc(F)c1C(=O)NNc1ccccc1F
Temperature: -12 °C
Reaction time: 0.08 h
Yield: 64.3 %

Procedure:
2-Amino-6-fluorobenzoic acid (2.00 g, 12.89 mmol) was combined with 2-fluorophenylhydrazine hydrochloride (2.096 g, 12.89 mmol) and HOBt (3.949 g, 25.79 mmol) in dry THF (75 ml) and cooled to about −12° C. N-Methylmorpholine (2.835 ml, 25.79 mmol) was added, the mixture was stirred for 5 minutes, then EDC hydrochloride (2.66 g, 13.88 mmol) was added. The mixture was maintained at a temperature between −14 and −10° C. for 1 hour, then allowed to slowly warm to room temperature and stirred for 18 hours. The mixture was cooled to 0° C., then filtered through CELITE® (diatomaceous earth). The filtrate was diluted with EtOAc, treated with saturated NaHCO3 and the layers separated. The organic layer was washed twice with 50% saturated NaHCO3 and then dried over MgSO4 and concentrated. The resulting solid was triturated with dichloromethane, filtered, rinsed with a very small amount of dichloromethane and dried. The filtrate from the trituration was re-triturated with a small amount of dichloromethane, filtered, rinsed with a tiny amount of dichloromethane and dried. The filtrate was concentrated to dryness, triturated with a small amount of Et2O, filtered, rinsed with a tiny amount of ether and dried. The three solids were combined to afford a total of 2.182 g (64%) of 2-amino-6-fluoro-benzoic acid N′-(2-fluoro-phenyl)-hydrazide (Intermediate 44) as an off-white solid. MS (APCI): (M−1)=262.0.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][C:16]=3[CH3:23])=[O:13])[CH:7]=2)[CH2:3][CH2:2]1.[CH3:27][NH:28][CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][N:28]([CH3:29])[CH3:27])=[CH:17][C:16]=3[CH3:23])=[O:13])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(C=O)cc2C)ncn1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: ClCCl
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(CN(C)C)cc2C)ncn1
Reaction time: 18 h

Procedure:
A solution of 6-((cyclopropylmethyl)(propyl)amino)-N-(4-formyl-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 29, 100 mg; 0.28 mmol) in DCM (5 ml) was treated with dimethylamine (Aldrich, 0.25 ml, 2M in THF; 0.5 mmol) followed by polymer supported triacetoxy borohydride (150 mg). After stirring for 18 hours the mixture was filtered and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as an off-white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[NH:11][C:10]2[CH:20]=[CH:21][CH:22]=[N:23][C:9]1=2)=[O:7].C(=O)([O-])[O-].[Na+].[Na+].[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>C(O)C>[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[O:19])[NH:11][C:10]3[CH:20]=[CH:21][CH:22]=[N:23][C:9]2=3)=[O:7])[CH2:33][CH2:32]1
Reactant: CN1CCNCC1
Reactant: O=C1Nc2cccnc2N(C(=O)CCCCCl)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CN1CCN(CCCCC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Yield: 37 %

Procedure:
A mixture of 5.0 g of 11-(5-chlorovaleryl)-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one, 1.6 g of sodium carbonate and 3 ml of 1-methylpiperazine in 100 ml of ethanol was refluxed for 20 hours and then the hot mixture was vacuum filtered. The filtrate was evaporated to dryness in vacuo and the residue was chromatographed over silica gel to obtain a 37% yield of 5,11-dihydro-11-[5-(4-methyl-1-piperazinyl)-valeryl]-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one melting at 151°-153° C. after crystallization from ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1>CO.O=[Pt]=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][NH:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cccnc2c1
Agent: O=[Pt]=O
Solvent: CO
Product: COc1ccc2c(c1)NCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To a solution of 7-methoxyquinoline (2.0 g, 12.56 mmol) in methanol (60 ml) was added PtO2 (180 mg, 0.79 mmol). H2 (g) was introduced into above solution and the reaction was stirred overnight at room temperature and then the solids were filtered off. The organics were concentrated in vacuo to give a residue, which was purified by silica gel column chromatography with 3% ethyl acetate in petroleum ether to afford 7-methoxy-1,2,3,4-tetrahydroquinoline as a light yellow oil (1.5 g, 73%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH2:13][CH3:14])[C:9]([O:11][CH3:12])=[O:10])=[C:4]([CH2:15][N:16]([CH3:58])[C:17](=[O:57])[CH:18]([NH:30][C:31]2[CH:32]=[C:33]3[C:38](=[CH:39][CH:40]=2)[C:37]([N:41]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[N:36][CH:35]=[C:34]3[F:56])[C:19]2[CH:24]=[CH:23][C:22]([C@@H:25]([CH3:28])[CH2:26][OH:27])=[C:21]([CH3:29])[CH:20]=2)[CH:3]=1.[C:59](Cl)(Cl)=[O:60]>C(#N)C.ClCCl>[C:52]([O:51][C:49]([N:41]([C:42]([O:44][C:45]([CH3:48])([CH3:46])[CH3:47])=[O:43])[C:37]1[C:38]2[C:33](=[CH:32][C:31]([NH:30][C@H:18]3[C:17](=[O:57])[N:16]([CH3:58])[CH2:15][C:4]4[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=4[C@@H:8]([CH2:13][CH3:14])[C:9]([O:11][CH3:12])=[O:10])[NH:1][C:59](=[O:60])[O:27][CH2:26][C@H:25]([CH3:28])[C:22]4[CH:23]=[CH:24][C:19]3=[CH:20][C:21]=4[CH3:29])=[CH:40][CH:39]=2)[C:34]([F:56])=[CH:35][N:36]=1)=[O:50])([CH3:55])([CH3:54])[CH3:53]
Reactant: O=C(Cl)Cl
Reactant: CC[C@@H](C(=O)OC)c1ccc(N)cc1CN(C)C(=O)C(Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc(F)c2c1)c1ccc([C@@H](C)CO)c(C)c1
Solvent: ClCCl
Solvent: CC#N
Product: CC[C@@H](C(=O)OC)c1ccc2cc1CN(C)C(=O)[C@H](Nc1ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc(F)c3c1)c1ccc(c(C)c1)[C@@H](C)COC(=O)N2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 33 %

Procedure:
A solution of 13F (235 mg, 0.293 mmol) in acetonitrile (4 mL) and dichloromethane (2 mL) was cooled to 0° C. To this solution was added phosgene (20% in toluene, 0.159 mL, 0.322 mmol). The mixture was stirred at 0° C. for 5 min, and rt for 1 h. The mixture was bubbled with Ar for 10 min to remove excess phosgene. The resulting solution was added dropwise over 3 h via a syringe pump into a solution of TEA (0.408 mL, 2.93 mmol) in CH2Cl2 (100 mL) at rt. The solution was stirred at rt for 16 h. The reaction mixture was concentrated and purified by flash chromatography to give a mixture of diastereoisomers (198 mg, 82% yield). The diastereoisomers (169 mg, 0.204 mmol) were separated by a prep chiral HPLC to give 13G (80 mg, 47.3% yield). MS (ESI) m/z: 827.9 (M+H)+.
Reaction SMILES: [C:1]([O:9][C@:10]1([C@:31]2([CH3:32])[C@H:17]([C@H:18]3[C@H:28]([C@@H:29]([OH:33])[CH2:30]2)[C@:26]2([CH3:27])[C:21](=[CH:22][C:23](=[O:34])[CH:24]=[CH:25]2)[C@@H:20]([CH3:35])[CH2:19]3)[CH2:16][CH2:15]1)[C:11](=[O:14])[CH2:12][OH:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>>[C:36]([O:13][CH2:12][C:11](=[O:14])[C@:10]1([O:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@:31]2([CH3:32])[C@H:17]([C@H:18]3[C@H:28]([C@@H:29]([OH:33])[CH2:30]2)[C@:26]2([CH3:27])[C:21](=[CH:22][C:23](=[O:34])[CH:24]=[CH:25]2)[C@@H:20]([CH3:35])[CH2:19]3)[CH2:16][CH2:15]1)(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H]1C[C@@H]2[C@H]([C@@H](O)C[C@@]3(C)[C@H]2CC[C@]3(OC(=O)c2ccccc2)C(=O)CO)[C@@]2(C)C=CC(=O)C=C12
Product: CC(=O)OCC(=O)[C@@]1(OC(=O)c2ccccc2)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C

Procedure:
1.9 g of 17-benzoyloxy-11β,21-dihydroxy-6α-methyl-1,4-pregnadiene-3,20-dione is reacted, analogously to Example 2c, with acetic anhydride and worked up. The crude product is purified on 200 g of silica gel with a methylene chloride-acetone gradient (0-12% acetone), thus isolating 1.8 g of 21-acetoxy-17-benzoyloxy-11β-hydroxy-6α-methyl-1,4-pregnadiene-3,20-dione, mp 258° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[O:8][C:9]3[N:26]=[C:25]([C:27]4[CH:37]=[CH:36][C:30]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])=[CH:29][CH:28]=4)[CH:24]=[CH:23][C:10]=3[CH:11]([C:12]([CH3:22])([CH3:21])[C:13](=[O:20])[NH:14][C:15]3[S:16][CH:17]=[N:18][N:19]=3)[C:5]2=[CH:4][CH:3]=1.[C:38]1(B(O)O)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH3:21][C:12]([CH:11]1[C:5]2[C:6](=[N:7][C:2]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:3][CH:4]=2)[O:8][C:9]2[N:26]=[C:25]([C:27]3[CH:37]=[CH:36][C:30]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])=[CH:29][CH:28]=3)[CH:24]=[CH:23][C:10]1=2)([CH3:22])[C:13](=[O:20])[NH:14][C:15]1[S:16][CH:17]=[N:18][N:19]=1
Reactant: CN(C)C(=O)c1ccc(-c2ccc3c(n2)Oc2nc(Cl)ccc2C3C(C)(C)C(=O)Nc2nncs2)cc1
Reactant: OB(O)c1ccccc1
Product: CN(C)C(=O)c1ccc(-c2ccc3c(n2)Oc2nc(-c4ccccc4)ccc2C3C(C)(C)C(=O)Nc2nncs2)cc1

Procedure:
Using a two-step sequence for the synthesis of Example 64, Example 65 was synthesized from the acid from Step 4 of Example 54 and phenylboronic acid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.90 (1H, s), 8.13 (2H, d, J=8.31 Hz), 8.08 (2H, d, J=6.80 Hz), 7.43-7.67 (9H, m), 4.64 (1H, s), 3.18 (3H, s), 3.05 (3H, s), 1.29 (3H, br. s), 1.28 (3H, br. s); MS (ES+) m/z: 577 (M+H); LC retention time: 3.96 min (analytical HPLC Method A).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]([CH2:22][NH2:23])[CH2:17][CH2:16][CH2:15]3)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[O-:24][C:25]#[N:26].[K+]>O>[F:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][NH:23][C:25]([NH2:26])=[O:24])[CH2:17][CH2:16][CH2:15]3)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: N#C[O-]
Reactant: NCC1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)NC[C@@H]1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Temperature: 60 °C
Yield: 79.8 %

Procedure:
C-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine hydrochloride (0.5 gms, 1.41 mmole) and potassium cyanate (0.137 g, 1.69 mmol) added to to 30 mL stirring water, and the mixture was heated to 60° C. for five minutes. The reaction mixture was then cooled to room temperature, and the resulting white precipitate was collected by filtration, washed with cold water, and dried under vacuum to give 0.408 g of (R)-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-urea, M+H=363.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C(=O)([O-])[O-].[Cs+].[Cs+].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28](OS(C)(=O)=O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C.O>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([O:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:10])([F:11])[F:1])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: Oc1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2C(F)(F)F)CC1
Temperature: 60 °C
Yield: 33.8 %

Procedure:
To a stirred solution of 2-trifluoromethyl-phenol (1 g, 0.00617 mole) in DMF (10 mL) was added cesium carbonate (4.01 g, 0.0123 mole), followed by 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (1.72 g, 0.00616 mole). The reaction mixture was heated at 60° C. overnight. The mixture was then diluted with water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (0.1% ethyl acetate in hexane) to afford 0.72 g (34%) of 4-(2-trifluoromethyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester. LCMS: 346.16 (M+1)+, 94.42%. A solution of 4-(2-trifluoromethyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (0.72 g, 0.00208 mole) in dichloromethane was stirred at 0-5° C. To the cold solution was added TFA (1 mL) dropwise and stirring was continued at 10° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was washed with ether and dried to afford 0.22 g (99%) of 4-(2-trifluoromethyl-phenoxy)-piperidine trifluoracetate. LCMS: 360.1 (M+1)+, 99.3%, 1H NMR (CDCl3): δ 8.9-8.5 (bd, 2H), 7.62-7.6 (d, 1H), 7.56-7.46 (t, 1H), 7.1-7.02 (t, 1H), 7.0-6.94 (d, 1H), 5.0-4.8 (m, 1H), 3.5-3.3 (s, 4H), 2.3-2.2 (s, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH:5]=[CH:6][CH:7]([N:18]([CH3:35])[C:19](=[O:34])[C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=1)[CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[CH3:2].ClC1C=CC=CC=1Cl>O1CCCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:36])[CH2:5][CH2:6][CH:7]([N:18]([CH3:35])[C:19](=[O:34])[C:20]1[CH:25]=[C:24]([C:26]([F:28])([F:27])[F:29])[CH:23]=[C:22]([C:30]([F:31])([F:32])[F:33])[CH:21]=1)[CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)C=CC(Cc1c[nH]c2ccccc12)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: Clc1ccccc1Cl
Solvent: C1CCOC1
Product: CCOC(=O)CCC(Cc1c[nH]c2ccccc12)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
A solution of 34.3 g of 4-[N-methyl-N-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(1H-indol-3-yl)-pent-2-enoic acid ethyl ester in 340 ml of tetrahydrofuran is hydrogenated at 20° C. for 80 minutes in the presence of 3.4 g of palladium/activated carbon (10%) and 0.4 g of 1,2-dichlorobenzene. The reaction mixture is then filtered and concentrated by evaporation. In this way the title compound is obtained in the form of a brownish resin.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12](C)[CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[F:21][C:22]1[C:23]([CH:32]2[CH2:34][O:33]2)=[CH:24][C:25]([O:30][CH3:31])=[C:26]([CH:29]=1)[C:27]#[N:28]>>[F:21][C:22]1[C:23]([CH:32]([OH:33])[CH2:34][N:17]2[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][C:3]3[CH:4]=[CH:5][C:6]4[C:7](=[O:11])[O:8][CH2:9][C:10]=4[C:2]=3[CH3:1])[CH2:19][CH2:18]2)=[CH:24][C:25]([O:30][CH3:31])=[C:26]([CH:29]=1)[C:27]#[N:28]
Reactant: Cc1c(C(C)CN2CCNCC2)ccc2c1COC2=O
Reactant: COc1cc(C2CO2)c(F)cc1C#N
Product: COc1cc(C(O)CN2CCN(CCc3ccc4c(c3C)COC4=O)CC2)c(F)cc1C#N

Procedure:
5-fluoro-4-(1-hydroxy-2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-2-(methyloxy)benzonitrile was prepared in a similar fashion to that described for the synthesis of EXAMPLE 12 starting from 4-methyl-5-(1-methyl-2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one and 5-fluoro-2-(methyloxy)-4-oxiran-2-ylbenzonitrile.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[C:17]([O:18][CH3:19])=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1.CN(C)CCN(C)C.CN([CH:31]=[O:32])C>CCCCCC.CCOCC>[CH3:19][O:18][C:17]1[C:8]([O:7][CH3:6])=[CH:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]=1[CH:31]=[O:32]
Reactant: CN(C)C=O
Reactant: COc1cc2ccccc2cc1OC
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1cc2ccccc2c(C=O)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
n-Butyl lithium in hexane (1.6 N, 31.3 ml) was gradually added to a solution of 2,3-dimethoxynaphthalene (9.4 g) and N,N,N′,N′-tetramethylethylenediamine (7.4 ml) in ether (150 ml) under argon at 0° C. The reaction mixture was stirred at room temperature for two hours, cooled to 0° C. and DMF (7.3 g) in ether (20 ml) added. The reaction mixture was stirred at room temperature overnight and poured in ice water. The product was extracted with ether, washed with water, dried, evaporated and recrystallized from ether. Yield: 4.2 g.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH2:4]Br.[N-:11]=[N+:12]=[N-:13].[Na+]>CS(C)=O.O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH2:4][N:11]=[N+:12]=[N-:13]
Reactant: Clc1cccc(Cl)c1CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
24 g (0.1 mol) of 2,6-dichlorobenzyl bromide in 50 ml of dimethyl sulphoxide are added at room temperature to a suspension of 7.2 g (0.11 mol) of sodium azide in 50 ml of dimethyl sulphoxide and the whole is stirred for 2 hours at room temperature. The mixture is then diluted with 250 ml of water and extracted with cyclohexane and the organic phase is washed several times with water. After drying over sodium sulphate, the cyclohexane is distilled off in vacuo at 50°. 2,6-dichlorobenzyl azide is obtained in the form of a colourless liquid. It is used without further purifification.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH:14]=O)=[CH:10][C:9]([CH2:16][CH2:17][CH3:18])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][CH:20]1[CH2:25][NH:24][CH2:23][CH2:22][N:21]1[C:26]1[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:19][CH:20]1[CH2:25][N:24]([CH2:14][CH2:13][CH2:12][C:11]2[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=[C:9]([CH2:16][CH2:17][CH3:18])[CH:10]=2)[CH2:23][CH2:22][N:21]1[C:26]1[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1cccc(N2CCNCC2C)c1
Reactant: CCCc1cc(CCC=O)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3cccc(C)c3)C(C)C2)n(-c2ccccc2)n1

Procedure:
132 mg (94%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propanal (75 mg, 0.310 mmol), 2-methyl-1-m-tolylpiperazine (59 mg, 0.310 mmol), DIPEA (0.081 mL, 0.465 mmol) and NaBH(OAc)3 (197 mg, 0.930 mmol).
Reaction SMILES: [Br:1]C1C(C)=NC(C2C=CC(Cl)=CC=2Cl)=C(C)N=1.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[C:26]1[C:27]([CH2:35][CH3:36])=[N+:28]([O-])[CH:29]=[C:30]([CH2:32][CH3:33])[N:31]=1>>[Br:1][C:29]1[C:30]([CH2:32][CH3:33])=[N:31][C:26]([C:20]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=2[Cl:18])=[C:27]([CH2:35][CH3:36])[N:28]=1
Reactant: CCc1c[n+]([O-])c(CC)c(-c2ccc(Cl)cc2Cl)n1
Reactant: Cc1nc(-c2ccc(Cl)cc2Cl)c(C)nc1Br
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1Br

Procedure:
Following the procedure of 2-bromo-5-(2,4-dichlorophenyl)-3,6-dimethylpyrazine but substituting 3-(2,4-dichlorophenyl)-2,5-diethylpyrazine 1-oxide and making non-critical variations provided the title compound as an oil: 1H NMR (CDCl3) δ 1.19 7.5, 1.33, 2.63, 3.02, 7.28, 7.39, 7.54; MS (ESI+) for C14H13Br1Cl2N2 m/z 361.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]2[C:23](=[O:24])[C:22]3[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=3[O:20][CH2:19]2)=[CH:11][CH:10]=1)[C:5]([OH:7])=[O:6])[CH3:2].C[O-].[Na+:31].C(OCC)C>CO>[CH2:1]([O:3][CH:4]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][N:18]2[C:23](=[O:24])[C:22]3[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=3[O:20][CH2:19]2)=[CH:13][CH:14]=1)[C:5]([O-:7])=[O:6])[CH3:2].[Na+:31]
Reactant: CCOC(Cc1ccc(OCCN2COc3ccccc3C2=O)cc1)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CCOC(Cc1ccc(OCCN2COc3ccccc3C2=O)cc1)C(=O)[O-]
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a stirred suspension of (±)-2-ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoic acid (100 mg, 0.26 mmol), obtained in Example 3 in methanol (3 mL) was added a solution of sodium methoxide (54 mg, 1.0 mmol) in methanol (1 mL) dropwise at 30° C. The reaction mixture was stirred for further 1 h. Diethylether (5 mL) was added and the white solid precipitated was filtered and dried to afford the title compound (85 mg, 80%): mp 186-188° C.
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([N:14]([C:20](=[O:22])[CH3:21])[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[C:10]([N+:23]([O-])=O)[CH:9]=2)=[N:6][NH:5][C:4](=[O:26])[CH2:3]1.O.NN>C(O)C.[Ni]>[CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([N:14]([C:20](=[O:22])[CH3:21])[CH2:15][CH2:16][CH:17]([CH3:18])[CH3:19])=[C:10]([NH2:23])[CH:9]=2)=[N:6][NH:5][C:4](=[O:26])[CH2:3]1
Reactant: CC(=O)N(CCC(C)C)c1ccc(C2=NNC(=O)CC2C)cc1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(=O)N(CCC(C)C)c1ccc(C2=NNC(=O)CC2C)cc1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6 gm of 5-methyl-6-{3-nitro-4-[N-acetyl-N-(3-methyl-butyl)-amino]-phenyl}-4,5-dihydro-2H-pyridazine-3-one were dissolved in 150 ml of ethanol. 4 gm of Raney-nickel and 3 ml of 98% hydrazine hydrate were added, and the solution was stirred for 30 minutes at room temperature. The catalyst was filtered off, the filtrate was evaporated, and the residue was processed further without further purification.
Reaction SMILES: [C:1]([C:3]([C@H:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].Br[CH2:23][CH2:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[CH2:30][CH2:29][CH2:28]2.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]([C@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:23][CH2:24][C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[CH2:30][CH2:29][CH2:28]3)[CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: BrCCc1ccc2c(c1)CCC2
Reactant: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCCN(CCc2ccc3c(c2)CCC3)C1

Procedure:
A mixture containing 3-(R)-(+)-(1-cyano-1,1-diphenylmethyl)piperidine (0.28 g), 5-(2-bromoethyl)indane (0.23 g--see Preparation 4), anhydrous potassium carbonate (0.3 g) and acetonitrile (10 ml) was heated under reflux for 5 hours. The mixture was partitioned between dichloromethane (30 ml) and 10% aqueous potassium carbonate (20 ml), the layers separated, and the aqueous layer extracted with dichloromethane (3×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with hexane containing dichloromethane (30% up to 70%) then dichloromethane containing methanol (0% up to 5%). The product-containing fractions were combined and concentrated in vacuo to give an oil which was crystallised from acetonitrile to give the title compound as colourless rhombs, yield 0.13 g, m.p. 88°-91° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].[C:11](OC(=O)C)(=O)[CH3:12]>S(=O)(=O)(O)O>[CH3:11][C:12]1[O:9][C:8](=[O:10])[C:7]2[C:2](=[CH:3][N:4]=[CH:5][CH:6]=2)[N:1]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cnccc1C(=O)O
Agent: O=S(=O)(O)O
Product: Cc1nc2cnccc2c(=O)o1
Yield: 49 %

Procedure:
A mixture of 3-aminopyridine-4-carboxylic acid (3.38 g, 24.5 mmol), acetic anhydride (15 mL), and sulfuric acid (3 drops) was refluxed 4 hours. The reaction was cooled and carefully quenched with solid sodium bicarbonate. The mixture was filtered through Celite® (trademark). The filtrate was extracted with ethyl acetate. This organic phase was washed with brine, dried over magnesium sulfate and concentrated to give 2-methyl-3-oxa-1,7-diaza-naphthalen-4-one (1.95 g, 49%) as a brown crystalline material.