Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH3:15][C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[C:22]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:20][CH:19]=2>C(#N)C>[N+:25]([C:22]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:23]=1[CH:24]=[C:16]([CH3:15])[N:17]2[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([O-:27])=[O:26]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc2c([N+](=O)[O-])cccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)Cn1c(C)cc2c([N+](=O)[O-])cccc21
Temperature: 60 °C

Procedure:
Water (4.5 ml), potassium carbonate (25.9 g, 187 mmol) and ethyl bromoacetate (20.8 ml, 188 mmol) were added sequentially to a suspension of 2-methyl-4-nitro-1H-indole (30 g, 170 mmol) in acetonitrile (225 ml) and the mixture heated at 60° C. for 16 hours. After allowing to cool to ambient temperature, water (225 ml) was added and the resulting mixture was broken up and then filtered. The solid was washed with water (2×75 ml), followed by IMS (2×75 ml) then dried in a vacuum oven to give (4-nitro-2-methyl-1H-indol-1-yl)-acetic acid, ethyl ester, 32.15 g (72%).
Reaction SMILES: F[C:2]1[C:7]([I:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:9]([SH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:9]([S:16][C:2]1[C:7]([I:8])=[CH:6][CH:5]=[CH:4][N:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: SCc1ccccc1
Reactant: Fc1ncccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Ic1cccnc1SCc1ccccc1

Procedure:
A solution of 34.0 g (0.15 mol) of 2-fluoro-3-iodopyridine and 18.6 g (0.15 mol) of benzylmercaptan in 250 ml of acetonitrile is heated under reflux with 22.8 g (0.165 mol) of potassium carbonate for 8 h. The mixture is cooled, the solvent is removed on a rotary evaporator, the residue is taken up in dichloromethane and the organic phase is washed with water. After drying with sodium sulfate, evaporating and distilling the oily residue in vacuo, 37.3 g (76% of theory) of 2-benzylthio-3-iodopyridine of boiling point 150°-153° C. at 0.1 mbar are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]2([S:15][C:16]([F:19])([F:18])[F:17])[CH2:14][CH2:13]2)[CH2:11][O:10]1.[NH:20]1[CH:24]=[N:23][CH:22]=[N:21]1>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([C:12]1([S:15][C:16]([F:19])([F:18])[F:17])[CH2:14][CH2:13]1)[CH2:11][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1
Reactant: Fc1ccc(C2(C3(SC(F)(F)F)CC3)CO2)c(F)c1
Reactant: c1nc[nH]n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: OC(Cn1cncn1)(c1ccc(F)cc1F)C1(SC(F)(F)F)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
A solution of 15.9 g (54 mmol) of 2-(2,4-difluoro- phenyl)-2-[1-(trifluoromethylmercapto)-cycloprop-1-yl]oxirane in 20 ml of absolute dimethylformamide is added dropwise with stirring to a mixture of 12 g (174 mmol) of 1,2,4-triazole and 1.4 g (12.5 mmol) of potassium tert.butylate in 30 ml of absolute dimethylformamide under a nitrogen atmosphere The reaction mixture is stirred at 100° C. for 8 hours. The solvent is then stripped off under reduced pressure, the residue is taken up in ethyl acetate, and the solution is washed twice with water and concentrated under reduced pressure after drying over sodium sulphate The residue is chromatographed on a silica gel column using chloroform as eluent. In this manner, 12.5 g (65 % of theory) of 1-(2,4-difluorophenyl)-1-hydroxy-2-(1,2,4-triazol-1-yl)-1-(1-trifluoromethylmercapto-cycloprop-1-yl)ethane of melting point 103° C. are obtained.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]([C:22]5([CH2:27][O:28][CH3:29])[CH2:26][CH2:25][NH:24][CH2:23]5)=[O:21])[CH:17]=4)[NH:12][N:11]=3)[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1.Cl[CH2:31][C:32]([N:34]1[CH2:39][CH:38]=[C:37]([C:40]2[CH:45]=[CH:44][C:43]([C:46]3[N:51]=[CH:50][C:49]([F:52])=[CH:48][N:47]=3)=[C:42]([F:53])[CH:41]=2)[CH2:36][CH2:35]1)=[O:33].C(N(CC)CC)C>CN(C)C=O>[CH:1]1([C:4]2[CH:9]=[C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]([C:22]5([CH2:27][O:28][CH3:29])[CH2:26][CH2:25][N:24]([CH2:31][C:32]([N:34]6[CH2:35][CH:36]=[C:37]([C:40]7[CH:45]=[CH:44][C:43]([C:46]8[N:47]=[CH:48][C:49]([F:52])=[CH:50][N:51]=8)=[C:42]([F:53])[CH:41]=7)[CH2:38][CH2:39]6)=[O:33])[CH2:23]5)=[O:21])[CH:17]=4)[NH:12][N:11]=3)[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: COCC1(C(=O)Nc2ccc3[nH]nc(-c4ccnc(C5CC5)c4)c3c2)CCNC1
Reactant: O=C(CCl)N1CC=C(c2ccc(-c3ncc(F)cn3)c(F)c2)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCC1(C(=O)Nc2ccc3[nH]nc(-c4ccnc(C5CC5)c4)c3c2)CCN(CC(=O)N2CC=C(c3ccc(-c4ncc(F)cn4)c(F)c3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methoxymethyl-pyrrolidine-3-carboxylic acid [3-(2-cyclopropyl-pyridin-4-yl)-1H-indazol-5-yl]-amide (26AB) (85 mg, 0.217 mmol, 1 equiv) and 2-Chloro-1-{4-[3-fluoro-4-(5-fluoro-pyrimidin-2-yl)-phenyl]-3,6-dihydro-2H-pyridin-1-yl}-ethanone (23AB) (84 mg, 0.239 mmol, 1.1 equiv) were weighed out in a flask and dissolved in anhydrous N,N-dimethylformamide (5 mL). Triethyl amine (33 mg, 46 uL, 0.326 mmol, 1.5 equiv) was added to the reaction mixture and the reaction content was stirred at room temperature overnight.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH3:15])[NH:12]C(=O)N[C:9]1=[O:14].[OH-].[Na+].NC(C1C=CC=CC=1F)(C)[C:20](O)=[O:21].S(Cl)(Cl)=O>CO>[CH3:20][O:21][C:9](=[O:14])[C:8]([NH2:12])([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH3:15]
Reactant: CC(N)(C(=O)O)c1ccccc1F
Reactant: CC1(c2ccccc2F)NC(=O)NC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)C(C)(N)c1ccccc1F

Procedure:
The hydrolysis of the (RS)-5-(2-fluoro-phenyl)-5-methyl-imidazolidine-2,4-dione with 3 N sodium hydroxide solution and esterification of the resulting (RS)-2-amino-2-(2-fluoro-phenyl)-propionic acid with methanol and thionylchloride yielded the (RS)-2-amino-2-(2-fluoro-phenyl)-propionic acid methylester as a light yellow liquid. The purity of the product allowed using it in the next step without further purification. MS (ISP): m/z=198.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:15]2[C:14](=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:19])[C:6]=2[CH:5]=1)([O-])=O.[OH-].[Na+].[H][H]>[Ni]>[NH2:1][C:4]1[CH:17]=[CH:16][C:15]2[C:14](=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:19])[C:6]=2[CH:5]=1
Reactant: O=C1c2ccccc2C(=O)c2cc([N+](=O)[O-])ccc21
Reactant: [H][H]
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc2c(c1)C(=O)c1ccccc1C2=O

Procedure:
A 160 ml. electromagnetically stirred autoclave was charged with 2.53 g (0.01 mole) of 2-nitroanthraquinone, 52 g (0.052 mole) of a 4% aqueous solution of sodium hydroxide, and 0.07 g of Raney nickel, and the 2-nitroanthraquinone was hydrogenated at room temperature and a pressure of 6 to 3 Kg/cm2.G with stirring. The reaction was stopped in 6 hours with the absorption of 0.04 mole of hydrogen. The inside of the reactor was purged with nitrogen, and the reaction mixture was filtered in a stream of nitrogen to separate the catalyst. The filtrate was oxidized with air with stirring at 20° to 30° C. for 2 hours to afford 2.1 g of high purity 2-aminoanthraquinone.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]3[CH2:18][CH2:19][N:20]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])[CH2:21][C:5]=3[C:4]=2[CH:3]=1.[CH2:29]([O:31][C:32](Cl)=[O:33])[CH3:30].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]3[CH2:18][CH2:19][N:20]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:32]([O:31][CH2:29][CH3:30])=[O:33])[CH2:21][C:5]=3[C:4]=2[CH:3]=1
Reactant: NCCCCCCN1CCc2c(c3cc(F)ccc3n2-c2ccc(F)cc2)C1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NCCCCCCN1CCc2c(c3cc(F)ccc3n2-c2ccc(F)cc2)C1

Procedure:
Following the procedure of the preceding Example, 8-fluoro-5-(4-fluorophenyl)-2-(6-amino-1-hexyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.6 g, 4.2 mmoles) was reacted with ethylchloroformate (0.45 ml, 4.6 moles) in methylene chloride (5 ml) in the presence of triethylamine (2.3 ml, 16.7 mmoles), and the title product isolated and purified, except that ethyl acetate was used as eluant in the silica gel chromatography (365 mg, m.p. 159°-162° C.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6](B(O)O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH2:13][C:14]1[CH:19]=[N:18][C:17](Br)=[CH:16][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+].C(COC)OC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:17]3[N:18]=[CH:19][C:14]([NH2:13])=[N:15][CH:16]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: Nc1cnc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1cnc(-c2ccc3[nH]ccc3c2)cn1
Temperature: 90 °C
Yield: 41.2 %

Procedure:
Nitrogen was bubbled through a solution of 5-indolylboronic acid (340 mg, 2.11 mmol), 2-amino-5-bromopyrazine (245 mg, 1.41 mmol), sodium carbonate (493 mg, 4.65 mmol), dimethoxyethane (12 mL), and water (4 mL) for 15 min. After this time, the solution was treated with dichlorobis(triphenylphosphine)palladium(II) (98 mg, 0.14 mmol), and the resulting reaction mixture was heated at 90° C. for 2 d. The reaction was then poured into water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 35/65 hexanes/ethyl acetate) afforded 5-(1H-indol-5-yl)-pyrazin-2-ylamine (122 mg, 41%) as a brown solid: EI-HRMS m/e calcd for C2H10N4 (M+) 210.0905, found 210.0901.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:25]([O:29][C:30](=[O:39])[CH2:31][O:32][CH:33]1[CH2:37][CH:36]([OH:38])[CH:35]=[CH:34]1)([CH3:28])([CH3:27])[CH3:26].O.Cl>CN(C=O)C>[C:25]([O:29][C:30](=[O:39])[CH2:31][O:32][C@H:33]1[CH2:37][C@@H:36]([O:38][C:2]2[C:3]3[C:10]([C:11]4[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=4)=[C:9]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[O:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:35]=[CH:34]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)COC1C=CC(O)C1
Reactant: CCc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(-c2c(-c3ccccc3)oc3ncnc(O[C@H]4C=C[C@@H](OCC(=O)OC(C)(C)C)C4)c23)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Dissolve 390.7 mg (1.17 mmol) of 4-chloro-5-(4-ethylphenyl)-6-phenylfuro[2,3-d]pyrimidine and 250 mg (1.17 mmol) of cis-(+/−)-{[(4-hydroxycyclopent-2-en-1-yl]oxy}acetic acid tert-butyl ester in 0.95 ml of DMF, cool to 0° C. and add 0.58 ml (1.17 mmol) of phosphazene base P2-t-Bu (2 M solution in THF). After the end of the addition, warm the mixture to RT and stir for a further 1 h. Then add the reaction mixture to water, adjust to pH 7 with 1N hydrochloric acid and extract three times with dichloromethane. Combine the organic phases, wash with satd. sodium chloride solution, dry over magnesium sulphate and concentrate under reduced pressure. Isolate the crude product by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 20:1→5:1). 510 mg (85.3% of theory) of the target compound are obtained.
Reaction SMILES: [C:1]([C:5]1[C:6]([S:13][C:14]#[N:15])=[CH:7][C:8]([CH3:12])=[C:9]([OH:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.CN(C=O)C.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>C(=O)(O)[O-].[Na+]>[C:29]([Si:26]([O:11][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]([S:13][C:14]#[N:15])=[CH:7][C:8]=1[CH3:12])([CH3:28])[CH3:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cc(SC#N)c(C(C)(C)C)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cc(SC#N)c(C(C)(C)C)cc1O[Si](C)(C)C(C)(C)C
Reaction time: 8 h

Procedure:
A solution of 2.0 g (9.0 mmol) of 5-tert-butyl-2-methyl-4-thiocyanato-phenol (prepared in Example GGG), imidazole (0.800 g, 11.8 mmol) and DMF (10 mL) was treated with t-butyldimethylsilylchloride (1.64 g, 10.9 mmol) and stirred overnight. The mixture was diluted with saturated sodium bicarbonate and the mixture extracted with hexanes. The hexane layers were combined, dried (Na2SO4), and the solvent removed in vacuo to yield the title compound. 1H NMR (CDCl3) δ 0.23 (s, 6 H), 1.01 (s, 9 H), 1.45 (s, 9 H), 2.16 (s, 3 H), 6.87 (s, 1 H), 7.49 (s, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:12]=[CH:13][C:14]=1[Cl:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:12]=[CH:13][C:14]=1[Cl:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/c1ccc(Cl)c(NC(=O)OC(C)(C)C)c1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CCc1ccc(Cl)c(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (E)-ethyl 3-(3-(tert-butoxycarbonylamino)-4-chlorophenyl)acrylate (6-3) (1.0 equiv.) in ethyl acetate/ethanol (1:1, 0.3 M) was added Wilkinson's catalyst (0.10 equiv.). Hydrogen gas was introduced via a ballon, and the reaction was stirred at room temperature for 24 hours. The mixture was filtered through a pad of celite, washing with dichloromethane. The filtrate was concentrated in vacuo and purified by Combiflash using 0-10% ethyl acetate in hexane to give ethyl 3-(3-(tert-butoxycarbonylamino)-4-chlorophenyl)propanoate (6-4) as a solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([N+:12]([O-])=O)=[CH:7][CH:8]=2)[CH2:3]1>CCOC(C)=O.[Pd]>[CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([NH2:12])=[CH:7][CH:8]=2)[CH2:3]1
Reactant: CN1CCc2ccc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN1CCc2ccc(N)cc2C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 86.9 %

Procedure:
2-Methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline (3.0 g, 15.6 mmol) was dissolved in EtOAc (10 mL) and stirred vigorously with 10% Pd/C (0.3 g) under a hydrogen atmosphere at 55 PSI. The reaction was stirred for 15 h at rt. The reaction was filtered through celite and concentrated to provide 2.2 g (87%) of the desired 2-methyl-1,2,3,4-tetrahydro-7-isoquinolinamine product as a white powder. 1H NMR (400 MHz, DMSO-d6) δ 6.83 (d, J=8.3 Hz, 1H), 6.44 (d, J=8.0 Hz, 1H), 6.24 (s, 1H), 4.97 (s, 2H), 3.87 (m, 2H), 3.11 (t, J=6.4 Hz, 2H), 2.85-2.68 (m, 2H), 2.58 (s, 3H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:8]1.Br[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=1>>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][N:17]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=2)[CH2:16][CH2:15]3)[CH2:8]1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCNC3)C1
Reactant: FC(F)(F)c1ccc(Br)nc1
Product: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCN(c2ccc(C(F)(F)F)cn2)C3)C1

Procedure:
The title compound was synthesized in substantially the same way as Example 1 by condensation of 6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-1,2,3,4-tetrahydro-isoquinoline with 2-bromo-5-trifluoromethyl-pyridine.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[CH3:10].[NH2:11][C:12]1[N:17]([CH3:18])[C:16](=[O:19])[NH:15][C:14](=[O:20])[CH:13]=1.[OH-].[Na+]>C(O)C>[NH2:11][C:12]1[N:17]([CH3:18])[C:16](=[O:19])[N:15]([CH2:10][C:3]2[CH:4]=[CH:5][C:6]([C:8]#[N:9])=[CH:7][CH:2]=2)[C:14](=[O:20])[CH:13]=1
Reactant: Cn1c(N)cc(=O)[nH]c1=O
Reactant: Cc1ccc(C#N)cc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(N)cc(=O)n(Cc2ccc(C#N)cc2)c1=O
Reaction time: 1.75 h
Yield: 12.2 %

Procedure:
α - Bromo - p - tolunitrile (5.41 g, 27.6 mmol) was added at once with stirring to a solution of 6-amino-1-methyluracil (V. Papesch and E.F. Schroeder. J. Org. Chem. (1951), 16, 1879) (3.90 g. 27.6 mmol) in 1:1 ethanol: 1 N sodium hydroxide (56 ml) at 42° C. After 1.75 hours. the mixture was cooled, filtered and washed with water. The resulting solid and second crop obtained by evaporation of the filtrate were combined (5.80 g) and partially purified by silica gel chromatography followed by repeated trituration with 1:2 methanol; ether to give crude 4-[(6-Amino-1,2,3,4-tetrahydro-1-methyl-2,4-dioxo-3-pyrimidinyl)methyl]benzonitrile (0.86 g), indentified by NMR.
Reaction SMILES: [C:1]1([C:14]([OH:16])=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.S(=O)(=O)(O)O.II.[Br:24]Br>>[Br:24][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[C:4]([C:11]([OH:13])=[O:12])=[CH:3][CH:2]=[C:1]2[C:14]([OH:16])=[O:15]
Reactant: BrBr
Reactant: O=C(O)c1ccc(C(=O)O)c2ccccc12
Agent: II
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc(C(=O)O)c2c(Br)cccc12

Procedure:
44 parts of naphthalene-1,4-dicarboxylic acid are introduced in portions into 900 parts of concentrated sulphuric acid and the mixture is stirred to give a homogeneous suspension. A few crystals of iodine and 36 parts of bromine are then added and the whole is stirred overnight at room temperature. For working up, the mixture is discharged onto ice and filtered and the product is washed with water until neutral. 8-Bromo-naphthalene-1,4-dicarboxylic acid, which is thus obtained, can be purified by recrystallisation from glacial acetic acid. Melting point 288°-290°.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]=[C:6]=[O:7])=[O:4].[NH2:8][C:9]1[CH:10]=[C:11]([O:17][CH3:18])[C:12]([O:15][CH3:16])=[CH:13][CH:14]=1>O1CCOCC1>[CH3:18][O:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])=[O:7])[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COc1ccc(N)cc1OC
Reactant: COC(=O)N=C=O
Solvent: C1COCCO1
Product: COC(=O)NC(=O)Nc1ccc(OC)c(OC)c1

Procedure:
To a solution of methoxycarbonylisocyanate (3.78 g. 0.0374 mole) in 45 ml. of dioxane is added 4-aminoveratrole (5.73 g., 0.037 mole) while maintaining a temperature of 20°-30°. After completing the addition, another 45 ml. portion of dioxane is added and the mixture then heated at reflux for a period of one hour. Evaporation of the solvent and crystallization of residual material from nitromethane provides analytically pure 1-(3,4-dimethoxyphenyl)-3-methoxycarbonylurea, m.p. 168°-170°.
Reaction SMILES: [NH2:1][C:2](=[N:23][OH:24])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:22])[CH2:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:10]2)[CH:4]=1.[H-].[Na+].[CH3:27][O:28][CH2:29][C:30](OC)=O>O1CCCC1.C(OCC)(=O)C>[CH3:19][C:18]([CH3:20])([CH3:21])[CH2:17][CH2:16][C:15]([N:12]1[CH2:13][CH2:14][N:9]([C:5]2[CH:4]=[C:3]([C:2]3[N:1]=[C:30]([CH2:29][O:28][CH3:27])[O:24][N:23]=3)[CH:8]=[CH:7][N:6]=2)[CH2:10][CH2:11]1)=[O:22]
Reactant: COCC(=O)OC
Reactant: CC(C)(C)CCC(=O)N1CCN(c2cc(C(N)=NO)ccn2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCc1nc(-c2ccnc(N3CCN(C(=O)CCC(C)(C)C)CC3)c2)no1
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
1-{4-[Amino(hydroxyimino)methyl]pyridin-2-yl}-4-(4,4-dimethylpentanoyl)piperazine (62 mg) was dissolved in tetrahydrofuran (2 mL), then oily sodium hydride (13 mg) was added thereto, stirred at 60° C. for 20 minutes, and methyl methoxyacetate (0.028 mL) was added thereto and heated under reflux for 1 hour. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was isolated and purified through thin-layer silica gel chromatography (hexane/ethyl acetate=1/1) to obtain 44.3 mg of the entitled compound as a colorless solid.
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])[CH:4]=[CH:3]1.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:24]=[N:25][C:26]([C:29]3[CH:30]=[C:31]([CH2:35]O)[CH:32]=[CH:33][CH:34]=3)=[N:27][CH:28]=2)[CH2:19][CH2:18]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>CN(C=O)C>[CH3:16][N:17]1[CH2:18][CH2:19][N:20]([C:23]2[CH:28]=[N:27][C:26]([C:29]3[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=3)[CH2:35][N:7]3[C:2](=[O:1])[CH:3]=[CH:4][C:5]([C:8]4[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=4)[C:11]#[N:12])=[N:6]3)=[N:25][CH:24]=2)[CH2:21][CH2:22]1
Reactant: N#Cc1cccc(-c2ccc(=O)[nH]n2)c1
Reactant: CN1CCN(c2cnc(-c3cccc(CO)c3)nc2)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CN1CCN(c2cnc(-c3cccc(Cn4nc(-c5cccc(C#N)c5)ccc4=O)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
149 mg (0.76 mmol) of 3-(6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile and 256 mg (0.76 mmol) of {3-[5-(4-methylpiperazin-1-yl)pyrimidin-2-yl]phenyl}-methanol are suspended in 5 ml of DMF with 378 mg (1.13 mmol) of polymer-bound triphenylphosphine (about 3 mmol of triphenylphosphine per g) and shaken at room temperature for 30 min. 266 mg (1.134 mmol) of di-tert-butyl azodicarboxylate are added. The reaction mixture is shaken at room temperature for 2 h. A further 378 mg (1.13 mmol) of polymer-bound triphenylphosphine (about 3 mmol of triphenylphosphine per g) and 266 mg (1.134 mmol) of di-tert-butyl azodicarboxylate are added, and the reaction mixture is shaken at room temperature for 2 h. The reaction mixture is filtered, the filtrate is evaporated, and the residue is purified by means of column chromatography on silica gel; yield: 59 mg of “A287”; HPLC: Rt=2.38 min (method C); LC-MS: 464 (M+H).
Reaction SMILES: [CH2:1]1[O:4][CH:2]1[CH3:3].[CH3:5][C:6]1([CH3:17])[CH2:15][CH:14]([CH3:16])[CH:13]2[CH:8]([CH2:9][CH2:10][CH2:11][CH2:12]2)[NH:7]1>C(O)C>[OH:4][CH:2]([CH3:3])[CH2:1][N:7]1[CH:8]2[CH:13]([CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:14]([CH3:16])[CH2:15][C:6]1([CH3:5])[CH3:17]
Reactant: CC1CC(C)(C)NC2CCCCC12
Reactant: CC1CO1
Solvent: CCO
Product: CC(O)CN1C2CCCCC2C(C)CC1(C)C

Procedure:
1-(2'-hydroxypropyl)-2,2,4-trimethyl decahydroquinoline was prepared by the reaction of 30.2 grams (0.52 mole) of propylene oxide with 90.7 grams (0.5 mole) of 2,2,4-trimethyl decahydroquinoline of about 75% cis structure in the presence of 3 grams of ethanol at 170° C. for 49 hours. The reaction mix was distilled using a 4 inch Vigreaux column to yield 73.1 grams of the desired product, boiling at 93° to 96° C. at 0.26 mm Hg. The NMR and mass spectrometer spectra were consistent with the desired product. The formula C15H29NO has calculated contents of 75.25% carbon, 12.21% hydrogen, and 5.85% nitrogen and the measured contents were 75.42% carbon, 12.77% hydrogen, and 5.62% nitrogen.