Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[O:15][N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[N:12]=2)=[C:9]([Cl:19])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[OH:20][C:21]1[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O>[Cl:1][C:2]1[C:10]([C:11]2[O:15][N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[N:12]=2)=[C:9]([Cl:19])[CH:8]=[CH:7][C:3]=1[C:4]([C:22]1[CH:23]=[N:24][N:25]([CH3:26])[C:21]=1[OH:20])=[O:5]
Reactant: CC(C)c1noc(-c2c(Cl)ccc(C(=O)Cl)c2Cl)n1
Reactant: Cn1nccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)c1noc(-c2c(Cl)ccc(C(=O)c3cnn(C)c3O)c2Cl)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.1 %

Procedure:
At 5-10° C., 2.00 g (6.3 mmol) of 2,4-dichloro-3-(3-i-propyl-1,2,4-oxadiazol-5-yl)benzoyl chloride in 10 ml of dimethoxyethane were added dropwise to 0.62 g (6.3 mmol) of 5-hydroxy-1-methyl-1H-pyrazole and 1.74 g (12.6 mmol) of potassium carbonate in 20 ml of dimethoxyethane. After 2.5 hours of stirring at room temperature, the mixture was heated under reflux for 2 hours and then once more stirred at room temperature for 12 hours. The reaction mixture was then taken up in water and washed with methylene chloride or toluene; the aqueous phase that remained was adjusted to pH=3 using hydrochloric acid and the precipitate that had formed was filtered off with suction and dried. 1.90 g (79% of theory) of 4-[2,4-dichloro-3-(3-i-propyl-1,2,4-oxadiazol-5-yl)benzoyl]-5-hydroxy-1-methyl-1H-pyrazole were obtained.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=4)=[CH:16][C:14]=3[CH:15]=2)[CH2:4][CH2:3]1.[O:27]1[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:26][C:23]1[CH:24]=[CH:25][C:20]([C:17]2[CH:18]=[CH:19][C:13]3[O:12][CH2:11][CH2:10][C:9]([CH2:8][N:5]4[CH2:4][CH2:3][CH:2]([NH:1][CH:30]5[CH2:31][CH2:32][O:27][CH2:28][CH2:29]5)[CH2:7][CH2:6]4)=[CH:15][C:14]=3[CH:16]=2)=[CH:21][CH:22]=1
Reactant: O=C1CCOCC1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(CN2CCC(N)CC2)CCO3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(CN2CCC(NC4CCOCC4)CC2)CCO3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.2 %

Procedure:
To 4-amino-1-(7-(4-methylphenyl)-2,3-dihydro-1-benzooxepin-4-yl)methylpiperidine (0.4 g) and tetrahydro-4H-pyran-4-one (0.12 g) dissolved in 1,2-dichloroethane (10 ml) was added under ice cooling sodium triacetoxyborohydride (0.34 g), and the resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction mixture was evaporated to remove the solvent, was neutralized with a 1 N aqueous solution of sodium hydroxide and was then extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, was then dried with anhydrous magnesium sulfate, and was evaporated under reduced pressure to remove the solvent. The residue was subjected to purification using a silica gel column (methanol/triethylamine/ethyl acetate) to obtain crude crystals. The crude crystals were recrystallized from ethyl acetate/hexane to obtain 1-(7-(4-methylphenyl)-2,3-dihydro-1-benzooxepin-4-yl)methyl-4-((tetrahydropyran-4-yl)amino)piperidine (compound 80) (0.17 g) as colorless crystals.
Reaction SMILES: C1(=O)N([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:13]([O:25][CH3:26])[CH:12]=2)[CH2:7][C:8](O)=[O:9])C(=O)C2=CC=CC=C12.C(N1C=CN=C1)([N:35]1C=CN=C1)=O.CN(C1C=CC=CN=1)C.[OH-].[NH4+]>O1CCCC1>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:6][CH2:7][C:8]([NH2:35])=[O:9])=[CH:12][C:13]=1[O:25][CH3:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1cc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)ccc1OCc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)c1ccccn1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(CCC(N)=O)ccc1OCc1ccccc1
Reaction time: 0.25 h

Procedure:
A mixture of 3-phthalimido-3-(4-benzyloxy-3-methoxyphenyl)propionic acid (1.00 g, 2.32 mmol), carbonyldiimidazole (0.406 g, 2.50 mmol) and a catalytic amount of dimethylaminopyridine in 20 mL of dry tetrahydrofuran under nitrogen was stirred for 1 hour. To the reaction solution was then added 0.25 mL of concentrated ammonium hydroxide. After 15 minutes, the reaction mixture was concentrated in vacuo to an oil which was diluted with 20 mL of water and stirred overnight. The resulting slurry was filtered and the solid dried to afford 0.645 g (65%) of 3-phthalimido-,3-(4-benzyloxy-3-methoxyphenyl)propionamide as a white powder: 1H NMR (DMSO-d6)δ 7.84 (m, 4H, Ar), 7.60-7.25 (m, 5H), 7.53 (br s, 1H, CONH), 7.15-6.8 (m, 4H), 5.67 (t, 1H, J=7.8 Hz), 5.04 (s, 2H, OCH2), 3.75 (s, 3H, OMe), 3.19 (d, 2H, J=9, 16.5 Hz);13C NMR (DMSO-d6)8 171.1, 167.6,148.8, 147.2, 137.0, 134.5, 132.0, 131.2, 128.3, 127.7, 127.6, 123.0, 119.3, 113.2, 111.4, 69.8, 55.5, 50.3, 36.9. Anal. Calcd for C25H22N2O5. Theory: C, 69.76; H, 5.15; N, 6.51. Found: C, 69.54; H, 5.13; N, 6.28.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH2:10][CH2:9][C:8](=[O:13])[N:7]([CH2:14][CH2:15][CH2:16][N:17]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]3=[O:27])[C:6]=2[CH:28]=1.[CH3:29][N:30]([CH:32](OC)OC)[CH3:31]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10](=[CH:29][N:30]([CH3:32])[CH3:31])[CH2:9][C:8](=[O:13])[N:7]([CH2:14][CH2:15][CH2:16][N:17]3[C:18](=[O:27])[C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:25]3=[O:26])[C:6]=2[CH:28]=1
Reactant: COC(OC)N(C)C
Reactant: O=C1CCC(=O)N(CCCN2C(=O)c3ccccc3C2=O)c2cc(Cl)ccc21
Product: CN(C)C=C1CC(=O)N(CCCN2C(=O)c3ccccc3C2=O)c2cc(Cl)ccc2C1=O

Procedure:
In a manner similar to that described for method G, 8-chloro-1-(3-(1,3-dioxoisoindolin-2-yl)propyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (I-40-a) and DMF-DMA were converted to I-40-b and carried on crude: MS m/z═452 (M+H).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([O-:14])([O-])=[O:12].[K+].[K+]>C1COCC1>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][C:11](=[O:12])[O:14][C:1]([CH3:7])([CH3:6])[CH3:2])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 189.3 %

Procedure:
Over a solution of (trans)-2-phenylcyclopropanamine (intermediate A, 1.14 g, 1 eq) in 50 mL of THF, 1.25 g (1.05 eq) of K2CO3 was added and stirred 3 hours at room temperature. After removal of the solvent, CH2Cl2 was added, then washed with a saturated solution of NaHCO3 and brine. The organic layer was extracted, dried with MgSO4 and filtered. The crude was purified by silica gel chromatography (Hexane-MTBE 90:10) affording 1.89 g of tert-butyl (trans)-2-phenylcyclopropylcarbamate. Yield: 95%
Reaction SMILES: O[C:2](C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:25]=[C:26]3[CH2:37][CH2:36][NH:35][CH2:34][C:27]3=[N:28][C:29]=2[NH:30][CH:31]([CH3:33])[CH3:32])[CH2:20][CH2:19]1)[C:12]#[N:13].C=O.CCN(C(C)C)C(C)C.[Na]>CO>[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]1[CH2:19][CH2:20][N:21]([C:24]2[N:25]=[C:26]3[CH2:37][CH2:36][N:35]([CH3:2])[CH2:34][C:27]3=[N:28][C:29]=2[NH:30][CH:31]([CH3:33])[CH3:32])[CH2:22][CH2:23]1)[C:12]#[N:13]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(C#N)cc3F)CC1)CCNC2
Agent: C=O
Agent: [Na]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(C#N)cc3F)CC1)CCN(C)C2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 90 %

Procedure:
A solution of 3-fluoro-4-((1-(3-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)oxy)benzonitrile TFA salt (12.8 mg, 0.024 mmol) and formaldehyde (2.2 mg, 0.027 mmol) in MeOH (244 μL) at room temperature was treated with DIPEA (8.5 μL, 0.049 mmol) and sodium triacetoxyhydroborate (10.3 mg, 0.049 mmol). The reaction mixture was stirred for 45 min at room temperature. The crude reaction mixture was purified directly by HPLC Method B, with the exception that a Waters SunFire™ C18, 5 μm, ID 30×75 mm column was used, using a 30% to 55% ACN gradient to give the title compound (about 90% purity), as a TFA salt, as a pale yellow solid. (6.0 mg, 46%). 1H NMR (400 MHz, methanol-d4) δ ppm 1.24 (d, J=6.6 Hz, 6H), 1.98 (m, 2H), 2.19 (m, 2H), 3.08 (m, 7H), 3.38 (m, 3H), 3.76 (br s, 1H), 4.16 (m, 1H), 4.29 (m, 2H), 4.79 (m, 1H), 7.34 (m, 1H), 7.53 (m, 2H); ESI-MS m/z [M+H]+ 425.5.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([CH3:9])[C:5]([O:7][CH3:8])=[O:6].C(Cl)(Cl)Cl.Cl[C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1>>[CH3:8][O:7][C:5](=[O:6])[CH:4]([CH3:9])[CH2:3][NH:2][C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1
Reactant: Clc1nc2ccccc2o1
Reactant: COC(=O)C(C)CN
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)C(C)CNc1nc2ccccc2o1
Temperature: 40 °C
Reaction time: 12 h
Yield: 70.4 %

Procedure:
To the suspension of 0.55 g (4 mmol) methy 3-amino-2-methylpropionate hydrogen chloride salt and 4 ml chloroform 0.52 g (5.2 mmol) triethylamine and 0.3 g (2 mmol) 2-chloro-1,3-benzoxazole are added and the mixture is stirred at 40° C. for 4 hours and at room temperature for 12 hours. The chloroform solution is washed with water, citric acid solution and water, dried over sodium sulfate and evaporated in vacuum. The residue is treated with hexane, the crystals are filtered off and washed. 0.33 g title compound is obtained as white crystals. Mp: 89-90° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.C1(C)C=CC=CC=1.[N+:26]([C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31]Br)([O-:28])=[O:27]>O1CCCC1>[CH3:1][O:2][C:3](=[O:18])[CH:4]([CH:5]1[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:9][CH2:10]1)[CH2:31][C:30]1[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=1[N+:26]([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: COC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccccc1[N+](=O)[O-])C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 41 %

Procedure:
tert-Butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (240 mg, 0.93 mmol) was dissolved in tetrahydrofuran (7 mL). Mixture was cooled to −78° C. A 0.5 M solution of potassium bistrimethylsilyl)amide in toluene (2.2 mL, 1.1 mmol) was added to the mixture drop-wise. Reaction stirred at −78° C. for 20 minutes. A solution of 2-nitrobenzylbromide (240 mg, 1.1 mmol) in tetrahydrofuran (2 mL) was added to the reaction mixture drop-wise. Reaction stirred at −78° C. for 40 minutes. Dry ice bath was removed and the reaction mixture was allowed to warm to room temperature over 30 minutes. Reaction was quenched with aqueous ammonium chloride. Mixture was extracted with ethyl acetate (2×20 mL). Combined extracts were dried (magnesium sulfate), filtered and concentrated in vacuo. Silica gel chromatography afforded the title compound as yellow oil in 41% yield. MS m/e (M−C4H8+H)+=337.3.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[S:8]([CH3:10])=O.[CH2:17](S)[CH2:18][CH2:19]C.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:7]([S:8][CH2:10][CH2:17][CH2:18][CH3:19])=[N:6][C:5]([NH2:11])=[N:4][C:3]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCCCS
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCSc1nc(N)nc(-c2ccco2)c1Br

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, butanethiol and DBU in dioxane. EI-MS m/e (%): 329 (M{81Br}+, 29), 327 (M{79Br}+, 28), 287 ([M{81Br}-C3H6]+, 46), 285 ([M{79Br}—C3H6]+, 45), ), 273 ([M{81Br}—C4H8]+, 98), 271 ([M{79Br}—C4H8]+, 99), 248 ([M—Br]+, 54), 206 (100), 192 (34), 117 (34).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:15](=[O:16])[N:14]3[CH:10]([CH2:11][C:12]([CH3:18])([CH3:17])[CH2:13]3)[C:9]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.ClC1C=CC(C2C(=[O:44])N3C(=CC(C)(C)C3)C=2C2C=CC=CC=2)=CC=1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:15](=[O:16])[N:14]3[C:10]([OH:44])([CH2:11][C:12]([CH3:17])([CH3:18])[CH2:13]3)[C:9]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)CC2C(c3ccccc3)=C(c3ccc(Cl)cc3)C(=O)N2C1
Reactant: CC1(C)C=C2C(c3ccccc3)=C(c3ccc(Cl)cc3)C(=O)N2C1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC1(C)CN2C(=O)C(c3ccc(Cl)cc3)=C(c3ccccc3)C2(O)C1

Procedure:
It was not possible to observe the 2-(4-chlorophenyl)-6,6-dimethyl-1-phenyl-5,6,7,7a-tetrahydro-pyrrolizin-3-one (keto tautomer of 2-(4-chlorophenyl)-6,6-dimethyl-1-phenyl-6,7-dihydro-5H-pyrrolizin-3-ol) expected as a hydrolysis product in any case. After relatively long standing (16 h) of a CHCl3 solution of the product, the 2-(4-chlorophenyl)-6,6-dimethyl-1-phenyl-5,6-dihydropyrrolizin-3-one described in example 29 is obtained as a substance in pure form (H2O elimination).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17]1([NH2:20])[CH2:19][CH2:18]1>>[CH:17]1([NH:20][C:8](=[O:9])[CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:19][CH2:18]1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: NC1CC1
Product: O=C(NC1CC1)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 292° C. and MS: m/e=251 (M+) was prepared in accordance with the general method of example 1 from diphenylacetyl chloride and cyclopropylamine.
Reaction SMILES: [CH:1](=[CH:8][C:9](=O)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH3:20])[CH3:13]>>[CH2:12]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1/[CH:20]=[C:9](\[CH3:10])/[CH:8]=[CH:1]/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:13]
Reactant: CC(=O)C=Cc1ccccc1
Reactant: CCc1cnccc1C
Product: CCc1cnccc1/C=C(C)/C=C/c1ccccc1
Yield: 7.3 %

Procedure:
The procedure of Example 41 was repeated with the exception that 3.5 g of benzal acetone in place of cinnamic aldehyde and 2.26 g o±3-ethyl-4-methylpyridine were used in Example 41, to obtain 0.35 g (yield: 7.3%) of (E,E)-1-(3-ethyl-4-pyridyl)-2-methyl-4-phenyl -1,3-butadiene (hereinafter referred to as compound 57) and 0.22 g (yield: 4.7%) of (Z,E)-1-(3-ethyl-4-pyridyl)-2-methyl-4-phenyl-1,3-butadiene (hereinafter referred to as compound 58). The analytical results are shown below.
Reaction SMILES: Cl.[CH:2]1([N:7]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[C:8]([C:10]2[CH:30]=[CH:29][C:13]3[N:14]([CH3:28])[C:15]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:27])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1.[OH-].[Na+]>>[CH:2]1([N:7]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:8]([C:10]2[CH:30]=[CH:29][C:13]3[N:14]([CH3:28])[C:15]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:26])[NH2:27])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)C1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CCc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCC(=O)O)C3CCCC3)ccc21

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[2-(4-amidinophenyl)ethyl]benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N-(2-ethoxycarbonylethyl)amide hydrochloride and sodium hydroxide solution.
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH:12]=O)=[CH:8][C:7]([CH2:14][CH2:15][CH3:16])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH2:12][N:27]2[CH2:26][CH2:25][N:24]([C:21]3[CH:20]=[CH:19][C:18]([Cl:17])=[CH:23][CH:22]=3)[CH2:29][CH2:28]2)=[CH:8][C:7]([CH2:14][CH2:15][CH3:16])=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: CCCc1cc(CCC=O)n(C(C)(C)C)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(c3ccc(Cl)cc3)CC2)n(C(C)(C)C)n1

Procedure:
171 mg (87%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propanal (100 mg, 0.450 mmol), 1-(4-chlorophenyl)piperazine (121 mg, 0.450 mmol), DIPEA (0.118 mL, 0.675 mmol) and NaBH(OAc)3 (286 mg, 1.350 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([CH:11]=[O:12])=[N:9][CH:10]=1)=[O:4].[NH2:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([CH:23]([CH3:25])[CH3:24])[C:21]=1O)[C:17]#[N:18].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>CO>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([C:11]2[O:12][C:21]3[C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=3[N:13]=2)=[N:7][CH:6]=1)=[O:4]
Reactant: CC(C)c1cc(C#N)cc(N)c1O
Reactant: COC(=O)c1cnc(C=O)nc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CO
Product: COC(=O)c1cnc(-c2nc3cc(C#N)cc(C(C)C)c3o2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.8 %

Procedure:
Methyl-2-formylpyrimidine-5-carboxylate (200 mg, 1.205 mmol) and 3-amino-4-hydroxy-5-isopropylbenzonitrile (212 mg, 1.205 mmol) were dissolved in methanol (5 ml). The mixture was concentrated, and then the residue was dissolved in dichloromethane (5 ml). To the above solution was added 2,3-dichloro-5,6-dicyano-p-benzoquinone (300.9 mg, 1.325 mmol) at room temperature. The solution was stirred at room temperature for 30 min, and then concentrated. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate (3×). The combined organics were washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by flash chromatography (hexanes-ethyl acetate=4:1, then 1:1) to provide of the title compound (139 mg) as a yellow solid. Mass spectrum (ESI) 322.8 (M+1). 1H NMR (500 MHz, CDCl3) δ 9.55 (s, 2H), 8.13 (s, 1H), 7.66 (s, 1H), 4.09 (s, 3H), 3.65 (m, 1H), 1.50 (d, 6H, J=6.8 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.O1CCOCC1.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>O>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: C1CCNC1
Solvent: O
Solvent: C1COCCO1
Product: Nc1nc(N2CCCC2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
2 g (0.012 mol) of 2-amino-6-chloro-3-nitropyridine, 30 ml of dioxane and 20 ml of water, and 1.8 g of pyrrolidine are charged to a fully equipped round-bottomed flask. The mixture is brought to 70° C. for one hour with stirring and then the mixture is poured onto an ice/water mixture with stirring. The precipitate formed is filtered off and dried. 2.2 g of yellow powder are obtained, Yd=88%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Yield: 97.4 %

Procedure:
1,1-Dimethylethyl 4-[3-(methyloxy)-4-nitrophenyl]-1-piperazinecarboxylate (combined batches) (5.16 g, 15.3 mmol) in DCM was cooled with an ice/H2O bath and TFA (30.0 mL, 398 mmol) was added dropwise via an addition funnel. Upon completion by TLC, the reaction was quenched slowly with 1N NaOH until the aqueous layer was basic as determined by pH paper. The mixture was extracted with DCM, dried (MgSO4) and concentrated to provide the title compound of step B (3.52 g, 14.9 mmol, 97%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.34 (br. s., 1H), 2.73-2.77 (m, 4H), 3.26-3.33 (m, 4H), 3.85 (s, 3H), 6.45 (d, J=2.4 Hz, 1H), 6.52 (dd, J=9.4, 2.5 Hz, 1H), 7.83 (d, J=9.3 Hz, 1H).
Reaction SMILES: N(OC(C)(C)C)=O.[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[N:15][N:16]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[C:17]=1N)=[O:12])[CH3:9].[ClH:26]>C(#N)C>[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[N:15][N:16]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[C:17]=1[Cl:26])=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cnn(CCOCCOC)c1N
Reactant: Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: CCOC(=O)c1cnn(CCOCCOC)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a mixture of t-butyl nitrite (8.5 mL, 64.5 mmol), anhydrous cuprous chloride (6.54 g, 66.1 mmol) and anhydrous acetonitrile (80 mL) was added 5-amino-1-[2-(2-methoxyethoxy)-ethyl]-1H-pyrazole-4-carboxylic acid ethyl ester (10.38 g, 40.3 mmol) over 10 minutes at 0° C. The reaction mixture was stirred at room temperature for 1 h, then at 70° C. for 2 h. The mixture was then cooled to room temperature and poured carefully into 6.0 N aqueous HCl (45 mL). The aqueous phase was extracted with methylene chloride (3×150 mL). The combined organic extracts were combined, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to provide the crude material as an oil. The product was purified by column chromatography on silica gel (eluting with ethyl acetate/hexanes, using a gradient of 1:3 to 1:0) to provide 5-chloro-1-[2-(2-methoxyethoxy)-ethyl]-1H-pyrazole-4-carboxylic acid ethyl ester as a light yellow oil (3.43 g, 30%). Mass spectrum: m/z: 277.0 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[N:3]=1.[CH2:17]1[O:26][C:25]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][C:19]=2[O:18]1>>[O:26]1[C:25]2[CH:24]=[CH:23][C:21]([NH:22][C:2]3[N:3]=[C:4]([NH:9][C:10]4[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=4)[N:5]=[C:6]([Cl:8])[N:7]=3)=[CH:20][C:19]=2[O:18][CH2:17]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: Clc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1
Product: Clc1ccc(Nc2nc(Cl)nc(Nc3ccc4c(c3)OCO4)n2)cc1
Yield: 65 %

Procedure:
The reaction of 4,6-dichloro-N-(4-chlorophenyl)-[1,3,5]triazine-2-amine with 3,4-methylenedioxyaniline using the method described for the synthesis of CT-116433 provided CT-31978 (56 mg, 65% yield). 1H NMR (d6-DMSO) δ 10.08–10.37 (m, 2 H), 7.58–7.87 (m, 2 H), 7.21–7.40 (m, 3 H), 6.85–7.03 (m, 2 H), 6.00 (s, 2 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]=[C:12](C(O)=O)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=1)[CH3:2].C(=O)=O.C1(C)C=CC=CC=1>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(C=C(C(=O)O)c2ccccc2)c1
Agent: [Cu]
Agent: O=C=O
Solvent: Cc1ccccc1
Solvent: c1ccc2ncccc2c1
Product: CCOC(=O)c1cccc(C=Cc2ccccc2)c1
Temperature: 220 °C
Yield: 90.1 %

Procedure:
1 g of copper powder was added to 13 g (0.044 mol) of 3-(2-carboxy-2-phenyl-vinyl)-benzoic acid ethyl ester, dissolved in 100 ml of quinoline, and the mixture was heated to 220° C., whilst stirring, until no further evolution of carbon dioxide could be observed (about 1 hour). The mixture was then cooled immediately to room temperature. After adding 300 ml of toluene to the reaction mixture, it was extracted by shaking twice with 100 ml of concentrated hydrochloric acid each time and then washed with 500 ml of water. The organic phase was separated off and dried over magnesium sulphate, the solvent was distilled off under a waterpump vacuum and the residue was distilled in vacuo. 10 g (90.2% of theory) of 3-(2-phenyl-vinyl)-benzoic acid ethyl ester were obtained as a yellow oil with the boiling point 165°-170° C./2 mm Hg (isomer mixture with a cis proportion of about 90%). ##STR61##