Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:14]2=[N:15][C:16]([OH:19])=[CH:17][CH:18]=[C:13]2[N:12]=[N:11]1.O>C(O)(=O)C>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:14]2=[N:15][C:16]([OH:19])=[C:17]([Br:1])[CH:18]=[C:13]2[N:12]=[N:11]1
Reactant: Oc1ccc2nnn(-c3ccccc3F)c2n1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: Oc1nc2c(cc1Br)nnn2-c1ccccc1F
Yield: 91.2 %

Procedure:
Bromine (0.10 ml, 2 mmol) was added to a stirred solution of 3-(2-fluorophenyl)-5-hydroxy-1,2,3-triazolo[4,5-b]pyridine (0.23 g, 1.0 mmol) in glacial acetic acid (5 ml) at room temperature. After 4 h the solution was poured into water (150 ml). The precipitate was collected, dissolved in 10% methanol-dichloromethane (100 ml), dried (Na2SO4), filtered and concentrated to give 3-(2-fluorophenyl)-5-hydroxy-6-bromo-1,2,3-triazolo[4,5-b]pyridine (0.282 g, 91%) as a beige solid. δH (360 MHz; CDCl3) 7.42-7.47 (2H, m), 7.60-7.71 (2H, m) and 8.48 (1H, s); m/z (ES+) 309, 311 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6]1.[CH:11]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22](=O)[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1)([CH3:13])[CH3:12].[C:35](#[N:38])[CH:36]=[CH2:37]>>[NH2:38][CH2:35][CH2:36][CH2:37][N:7]1[CH2:8][CH2:9][CH2:10][CH:5]([CH2:4][CH2:3][CH2:2][NH:1][CH:22]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)[CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([CH:11]([CH3:13])[CH3:12])=[CH:15][CH:16]=2)[CH2:6]1
Reactant: C=CC#N
Reactant: NCCCC1CCCNC1
Reactant: CC(C)c1ccc(CCC(=O)CCc2ccc(C(C)C)cc2)cc1
Product: CC(C)c1ccc(CCC(CCc2ccc(C(C)C)cc2)NCCCC2CCCN(CCCN)C2)cc1

Procedure:
For example, 3-(3-aminopropyl)piperidine may be converted to a Schiff base with 1,5-di-(4-isopropylphenyl)-3-pentanone, catalytically reduced, then the resulting amine selectively cyanoethylated on the ring nitrogen with acrylonitrile, followed by catalytic hydrogenation to furnish 1-(3-aminopropyl)-3-{3-[1,5-di-(4-isopropylphenyl)-3-pentylamino]propyl}piperidine.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][C:5]([OH:7])=O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[C:27]([C:31]1[N:36]=[CH:35][C:34]([C:37]2[N:38]([C:58]([N:60]3[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]3)=[O:59])[C@@:39]([C:51]3[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][CH:52]=3)([CH3:50])[C@@:40]([C:43]3[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=3)([CH3:42])[N:41]=2)=[C:33]([O:66][CH2:67][CH3:68])[CH:32]=1)([CH3:30])([CH3:29])[CH3:28]>CN(C)C=O>[C:27]([C:31]1[N:36]=[CH:35][C:34]([C:37]2[N:38]([C:58]([N:60]3[CH2:65][CH2:64][N:63]([C:5](=[O:7])[CH2:4][CH2:3][S:2][CH3:1])[CH2:62][CH2:61]3)=[O:59])[C@@:39]([C:51]3[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][CH:52]=3)([CH3:50])[C@@:40]([C:43]3[CH:44]=[CH:45][C:46]([Cl:49])=[CH:47][CH:48]=3)([CH3:42])[N:41]=2)=[C:33]([O:66][CH2:67][CH3:68])[CH:32]=1)([CH3:28])([CH3:29])[CH3:30]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCNCC1
Reactant: CSCCC(=O)O
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)CCSC)CC1
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a solution of 3-(methylthio)propionic acid (30.8 mg, 0.256 mmole, Lancaster) in dimethylformamide (10 mL) were added successively 1-hydroxybenzotriazole (46.3 mg, 0.342 mmole, Chem-Impex), N,N,N′,N′-tetramethyl-O-(1H-Benzotriazol-1-yl)uranium hexafluorophosphate (130.0 mg, 0.343 mmole, Aldrich) and diisopropylethylamine (111.0 mg, 0.857 mmole). The mixture was stirred for 15 min before [(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-piperazin-1-yl-methanone (104.4 mg, 0.171 mmole) was added. The reaction mixture was allowed to stir for 1 h before concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with 1 N sodium hydroxide, brine, dried and concentrated. The crude residue was purified by flash column chromatography (silica gel, eluting with a gradient of 1-10% methanol in methylene chloride) to give the title compound (108.7 mg, 89% yield). HR-MS (ES, m/z) calculated for C37H46Cl2N5O3S [(M+H)+] 710.2693, observed 710.2691.
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.N1CCCCC1>C(O)C>[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[C:5]2[S:1][C:2](=[O:7])[NH:3][C:4]2=[O:6])=[CH:11][CH:10]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc(Cl)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2ccc(Cl)cc2)S1
Yield: 43.3 %

Procedure:
To a solution of 20 g (171 mmol) of 2,4-thiazolidinedione and 17.4 ml (171 mmol) of 4-chlorobenzaldehyde in 350 ml of ethanol, 1.68 ml (17.1 mmol) of piperidine was added, and the mixture was heated under reflux for 5 hours. After cooling, the precipitated crystals were filtered and washed with cooled ethanol to give 17.75 g of the desired compound (43.4% yield, pale yellow crystals).
Reaction SMILES: [Na+].[OH:2][C:3]1[C:16]2[C:15](=[O:17])[CH:14]=[C:13]([C:18]([O-:20])=[O:19])[O:12][C:11]=2[C:10]([CH2:21][CH2:22][CH3:23])=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH2:8]2.P([O-])([O-])([O-])=[O:25].C1C=[N+]([C@H]2O[C@@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)([O-])=O)[C@H](O)[C@@H]2O)C=C(C(N)=O)C=1.C(OP(O)(O)=O)[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O>>[OH:2][C:3]1[C:16]2[C:15](=[O:17])[CH:14]=[C:13]([C:18]([OH:20])=[O:19])[O:12][C:11]=2[C:10]([CH2:21][CH2:22][CH3:23])=[C:9]2[C:4]=1[CH2:5][CH:6]([OH:25])[CH2:7][CH2:8]2
Reactant: CCCc1c2c(c(O)c3c(=O)cc(C(=O)[O-])oc13)CCCC2
Reactant: O=P([O-])([O-])[O-]
Agent: NC(=O)c1ccc[n+]([C@H]2O[C@@H](COP(=O)([O-])OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@H](O)[C@@H]2O)c1
Agent: O=P(O)(O)OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Agent: [Na+]
Product: CCCc1c2c(c(O)c3c(=O)cc(C(=O)O)oc13)CC(O)CC2
Reaction time: 0.5 h

Procedure:
A mixture of 5 parts 6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylic acid sodium salt, 4 parts of 25% w/v supernatant liver fraction, 10 parts of phosphate buffer pH 7.4, one part of nicotinamide adenine dinucleotide phosphate and one part of glucose-6-phosphate was incubated in a shaking incubator at 37° C. for 30 minutes. The reaction was stopped and protein was precipitated by the addition of 5 parts of 2 N hydrochloric acid. The reaction mixture was extracted three times with 100 parts of diethyl ether and after being dried over anhydrous sodium sulphate the extracts were evaporated to dryness at room temperature in a current of air. The 5,7-dihydroxy-6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylic acid and the other dihydroxy compounds identified in Example 1 were isolated by the preparative layer chromatography technique described in Example 1.
Reaction SMILES: C[Mg]Br.[CH2:4]1COCC1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:17][CH:18]=2)[N:13]=[C:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30][CH2:31][CH3:32])[N:11]=1.CN1C(=O)CCC1>C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3].O.C(OCC)(=O)C>[CH2:31]([S:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:12]1[N:11]=[C:10]([CH3:4])[C:19]2[C:14](=[CH:15][C:16]([C:20]([F:22])([F:21])[F:23])=[CH:17][CH:18]=2)[N:13]=1)[CH3:32]
Reactant: CCSc1ccccc1-c1nc(Cl)c2ccc(C(F)(F)F)cc2n1
Reactant: C1CCOC1
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Agent: C[Mg]Br
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: CCSc1ccccc1-c1nc(C)c2ccc(C(F)(F)F)cc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.1 ml of methylmagnesium bromide (a 1 M THF solution) was added to a mixture of 380 mg of 4-chloro-2-(2-ethylsulfanylphenyl)-7-trifluoromethylquinazoline, 72 mg of iron(III) acetylacetonate, 8 ml of THF and 0.8 ml of NMP, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate and water were added to the reaction mixture, and the mixture was filtered. The aqueous layer of the filtrate was extracted with ethyl acetate, combined with the organic layer of the filtrate, sequentially washed with 0.5 N hydrochloric acid, water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The mixture was concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 123 mg of 2-(2-ethylsulfanylphenyl)-4-methyl-7-trifluoromethylquinazoline (Compound of Present Invention 13).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:30])=[C:6]([C@H:8]([O:22][CH2:23][CH2:24][NH:25][C:26]([O:28][CH3:29])=[O:27])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:7]=1.C(=O)(O)[O-].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:30])=[C:6]([C@@H:8]([C@@H:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[O:22][CH2:23][CH2:24][NH:25][C:26](=[O:27])[O:28][CH3:29])[CH:7]=1
Reactant: COC(=O)NCCO[C@@H](c1cc(Cl)ccc1C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)NCCO[C@@H](c1cc(Cl)ccc1C)[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.8 %

Procedure:
(R)-tert-Butyl 3-((R)-(5-chloro-2-methylphenyl)(2-(methoxycarbonylamino)ethoxy)methyl)piperidine-1-carboxylate (1.0 g, 2.27 mmol) was dissolved in a solution of 20% (V/V) TFA/CH2Cl2 (20 mL). The reaction mixture was stirred at room temperature for 2 h, TLC showed the starting material disappeared, a solution of saturated sodium bicarbonate was added dropwise to adjust pH=7-8. The resulting mixture was extracted with CH2Cl2 (3×30 mL), washed with brine, dried over Na2SO4, concentrated in vacuo to afford methyl 2-((R)-(5-chloro-2-methylphenyl)((R)-piperidin-3-yl)methoxy)ethylcarbamate (780 mg, 100%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:25])[C:4]=1[OH:26])[CH3:2].[CH2:27]([CH:29]1[O:31][CH2:30]1)Cl>>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([CH2:21][CH:22]([CH3:23])[CH3:24])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:25])[C:4]=1[O:26][CH2:27][CH:29]1[CH2:30][O:31]1)[CH3:2]
Reactant: ClCC1CO1
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(CC(C)C)c3)n2)cc(C)c1O
Product: CCc1cc(-c2noc(-c3cc(C)nc(CC(C)C)c3)n2)cc(C)c1OCC1CO1

Procedure:
In analogy to Example 14, 2-ethyl-4-[5-(2-isobutyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenol is alkylated with epichlorhydrine to give (RS)-4-[3-(3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-2-isobutyl-6-methyl-pyridine as a colourless oil; LC-MS: tR=1.00 min, [M+1]+=408.18.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([Cl:15])=[C:11](Cl)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:17][C:18]1[S:22][C:21]([CH2:23][OH:24])=[CH:20][CH:19]=1.[OH-:25].[K+]>CN(C)C=O>[Cl:15][C:12]1[C:13](=[O:14])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[CH:10][C:11]=1[O:25][O:24][CH2:23][C:21]1[S:22][C:18]([CH3:17])=[CH:19][CH:20]=1
Reactant: [OH-]
Reactant: O=c1c(Cl)c(Cl)cnn1-c1ccc(Cl)cc1
Reactant: Cc1ccc(CO)s1
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(COOc2cnn(-c3ccc(Cl)cc3)c(=O)c2Cl)s1
Yield: 73.2 %

Procedure:
The procedures in Synthesis Example 11 were repeated by using 2.0 g (7.3 m mol) of 2-(4-chlorophenyl)-4,5-dichloro-3(2H)-pyridazinone, 1.0 g (7.8 m mol) of 5-methyl-2-thiophene methanol, 0.4 g of potassium hydroxide and 80 ml of N,N-dimethylformamide to give 2.0 g of the intended product.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[CH:17][N:16]2[CH:24]=1.[NH2:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([CH2:26][NH:25][C:21]([C:19]2[CH:18]=[CH:17][N:16]3[CH:24]=[C:13]([C:3]4[C:4]([C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=5)=[N:5][O:6][C:2]=4[CH3:1])[N:14]=[C:15]3[CH:20]=2)=[O:23])[CH:28]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)O)cc2n1
Reactant: NCc1cccnc1
Product: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)NCc3cccnc3)cc2n1
Yield: 66 %

Procedure:
As described for Example 11b, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine-7-carboxylic acid (64 mg, 0.2 mmol) was converted, using 3-(aminomethyl)pyridine instead of aminomethylcyclopropane, to the title compound (54 mg, 66%) which was obtained as a light yellow foam. MS: m/e=410.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](OCC)=O.CN1C=CN=C1.[N+](C=C1[NH:27][CH2:26][CH2:25][CH2:24][S:23]1)([O-])=O.CC[O:30]CC>O1CCCC1.O.C(Cl)Cl>[S:23]1[CH2:24][CH2:25][CH2:26][NH:27][C:2]1=[CH:6][C:5](=[O:30])[S:4][CH2:3][CH3:7]
Reactant: CCOC(=O)c1sccc1Cl
Reactant: O=[N+]([O-])C=C1NCCCS1
Reactant: CCOCC
Agent: Cn1ccnc1
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCSC(=O)C=C1NCCCS1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 13.7 g of ethyl chlorothiolformate in 50 ml of dry tetrahydrofuran was added to 9.0 g of 1-methylimidazole in 200 ml of dry tetrahydrofuran at 5°, over a 20-minute period. The mixture was stirred at 5° for 30 minutes, then 16.0 g of 31B was added all at once, and the stirred mixture was allowed to slowly warm to room temperature and was stirred overnight. The solvent was stripped, the residue dissolved in a mixture of water and methylene chloride. The two phases were separated, the water phase was extracted with methylene chloride, the methylene chloride solutions were combined, dried (MgSO4), filtered and the solvent evaporated under reduced pressure, to leave an oil. The oil was stirred with a mixture of water and ether; solid material was filtered off and recrystallized from ethyl alcohol to give nitro(tetrahydro-2H-1,3-thiazin-2-ylidene ethanethioic acid, S-ethyl ester (31C) as a pale yellow solid, m.p.: 124°-124.5°.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=O)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].COC(OC)[N:17]([CH3:19])C.[Sn](Cl)(Cl)(Cl)Cl.[F:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34]N)=[CH:30][C:29]=1[C:36]#[N:37]>C1C=CC=CC=1.C(O)(=O)C>[C:36]([C:29]1[CH:30]=[C:31]([N:34]2[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:19]=[N:17]2)[CH:32]=[CH:33][C:28]=1[F:27])#[N:37]
Reactant: N#Cc1cc(NN)ccc1F
Reactant: CCOC(=O)CC(=O)c1ccco1
Reactant: COC(OC)N(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)c1cnn(-c2ccc(F)c(C#N)c2)c1-c1ccco1
Temperature: 80 °C
Reaction time: 2 h
Yield: 35.1 %

Procedure:
To a solution of ethyl 3-(2-furyl)-3-ketopropionate (2.1 g, 11.5 mmol) in 20 mL of benzene was added dimethylformamide dimethylacetal (2.3 mL, 17.3 mmol). The resulting solution was stirred at 80° C. for 2 h. The reaction was cooled, filtered through a pad of silica gel and concentrated in vacuo. A portion of the residue (0.60 g, 2.54 mmol) was dissolved in 20 mL of glacial acetic acid and then there was added 4-fluoro-3-cyanophenylhydrazine tin chloride (1.05 g, 2.8 mmol). The reaction mixture was stirred at 100° C. for 4 h. The reaction was allowed to cool to room temperature and the acetic acid was removed in vacuo. The residue was diluted with ethyl acetate and the organics were washed with saturated aq NaHCO3 and brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography (elution with gradient of 6:1→3:1 hexanes/ethyl acetate) to afford 0.32 g (39%) of the title compound. LRMS (ES+): 326.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([F:10])=[C:7]([OH:9])[CH:8]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:10][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:11])[F:12])=[CH:8][C:7]=1[O:9][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1cc(C(F)(F)F)ccc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(C(F)(F)F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-(trifluoromethyl)-2-fluorophenol (2.0 g), benzyl bromide (1.45 ml) and potassium carbonate (1.65 g) in dry DMF (20 ml) was stirred at RT overnight. The mixture was quenched with water and the solid filtered and dried, yield 2.20 g.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH2:6][NH:7][CH3:8])[CH3:3].[CH2:10]([O:12][C:13]([C:15]1[N:16]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH:43]([CH3:45])[CH3:44])=[CH:38][CH:37]=2)[C:17]2[C:22]([C:23]=1C=O)=[CH:21][C:20]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=1)=[CH:19][CH:18]=2)=[O:14])[CH3:11].[BH3-][C:47]#N.[Na+].O>CO.C(O)(=O)C>[CH2:10]([O:12][C:13]([C:15]1[N:16]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH:43]([CH3:45])[CH3:44])=[CH:38][CH:37]=2)[C:17]2[C:22]([C:23]=1[CH2:8][N:7]([CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:9])[CH3:47])=[CH:21][C:20]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:33])[CH3:34])=[CH:28][CH:27]=1)=[CH:19][CH:18]=2)=[O:14])[CH3:11]
Reactant: CCOC(=O)CNC
Reactant: [BH3-]C#N
Reactant: CCOC(=O)c1c(C=O)c2cc(-c3ccc(C(C)(C)C)cc3)ccc2n1-c1ccc(OC(C)C)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)CN(C)Cc1c(C(=O)OCC)n(-c2ccc(OC(C)C)cc2)c2ccc(-c3ccc(C(C)(C)C)cc3)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-Methyl glycine ethyl ester hydrochloride (255 mg, 1.66 mmol) was added to a suspension of 5-(4-tert-butylphenyl)-3-formyl-1-(4-isopropoxyphenyl)indole-2-carboxylic acid ethyl ester (400 mg, 0.83 mmol; see step (c) above) in MeOH (20 mL) and the pH was adjusted to 6 by the addition of a few drops of glacial acetic acid. After 1 h at rt, NaCNBH3 (75 mg, 1.18 mmol) was added and the mixture was stirred at rt for 24 h, poured into H2O and extracted with EtOAc. The combined extracts were washed with H2O and brine, dried (Na2SO4), concentrated and purified by chromatography to give the sub-title compound. Yield 400 mg (87%).
Reaction SMILES: [Na].[C:2]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:11])[CH2:3][C:4]([O:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:5].[C:17]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:27])/[CH:18]=[CH:19]\[C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21]>C(O)CCC.Cl>[CH:3]([C:4]([O:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:5])([C:2]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:11])[CH:18]([C:17]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27])[CH2:19][C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21]
Reactant: CCCCOC(=O)/C=C\C(=O)OCCCC
Reactant: CCCCOC(=O)CC(=O)OCCCC
Agent: Cl
Agent: [Na]
Solvent: CCCCO
Product: CCCCOC(=O)CC(C(=O)OCCCC)C(C(=O)OCCCC)C(=O)OCCCC
Reaction time: 0.08 h
Yield: 95.8 %

Procedure:
One half gram of sodium metal is dissolved in 200 mls n-butanol and to this solution is added 108 g (0.5 mol) of dibutyl malonate. After reacting for five minutes, 114 grams (0.5 mole) of dibutyl maleate is added and the reaction mixture is refluxed for 6 hours. The solution is neutralized with a few drops of conc. hydrochloric acid and then filtered. The excess n-butanol is distilled off in vacuo to give 213 grams of a tetrabutyl propane-1,1,2,3-tetracarboxylate. The structure is confirmed by NMR analysis (CDCl3) ##STR11##
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH:15][C:16](=[O:28])[C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:18]=3[O:26][CH3:27])[CH2:9][CH2:8]2)[C:5]2[CH:29]=[CH:30][CH:31]=[CH:32][C:4]=2[NH:3]1.CO.[H][H]>[Ni].O1CCCC1>[OH2:1].[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([NH:15][CH2:14][CH2:13][N:10]2[CH2:9][CH2:8][CH:7]([N:6]3[C:5]4[CH:29]=[CH:30][CH:31]=[CH:32][C:4]=4[NH:3][C:2]3=[O:1])[CH2:12][CH2:11]2)=[O:28])=[C:18]([O:26][CH3:27])[CH:19]=1
Reactant: COc1cc([N+](=O)[O-])ccc1C(=O)NCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(N)ccc1C(=O)NCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Product: O

Procedure:
A mixture of 5.3 parts of N{2-[4-(2,3-dihydro-2-oxo- 1H-benzimidazol-1-yl)-1-piperidinyl] ethyl}-2-methoxy-4-nitrobenzamide in 80 parts of methanol and 90 parts of tetrahydrofuran is hydrogenated at normal pressure and at room temperature with 5 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filered off and the filtrate is evaporated. The residue is crystallized from ethanol 96%, yielding 3.65 parts of 4-amino-N{2-[4-(2,3-dihydro-2-oxo- 1H-benzimidazol-1-yl)-1-piperidinyl] ethyl}-2-methoxybenzamide hydrate; mp. 220.6° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][N:6]=[CH:5]2.[C:12]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)(=O)[CH:13]=O>>[S:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:12]1[CH:13]=[N:11][C:10]2[CH:9]=[C:8]3[NH:7][N:6]=[CH:5][C:4]3=[CH:3][C:2]=2[N:1]=1.[S:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:12]1[CH:13]=[N:1][C:2]2[CH:3]=[C:4]3[CH:5]=[N:6][NH:7][C:8]3=[CH:9][C:10]=2[N:11]=1
Reactant: O=CC(=O)c1cccs1
Reactant: Nc1cc2cn[nH]c2cc1N
Product: c1csc(-c2cnc3cc4[nH]ncc4cc3n2)c1
Product: c1csc(-c2cnc3cc4cn[nH]c4cc3n2)c1

Procedure:
Condensation as shown in Step A of 5,6-diaminoindazole with a glyoxyloylthiophene in the presence of absolute alcohol results in ring formation of a mixture of 6-thienyl-1H-pyrazolo[3,4-g]quinoxaline and 7-thienyl-1H-pyrazolo[3,4-g]quinoxaline. These positional isomers can be separated by standard procedures, such as column chromatography.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)#[N:4].[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15].O>C1COCC1>[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH:9]=[CH:8]2)#[N:4]
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3cc(C#N)ccc32)cc1
Reaction time: 0.17 h
Yield: 89.7 %

Procedure:
In a 100 mL round-bottom flask was placed NaH (0.4 g, 60% dipersion in mineral oil, 10 mmol) and anhydrous THF (10 mL) was added. To the suspension was added a solution of 5-cyanoindole (1.0 g, 7 mmol) in anhydrous THF (10 mL) by syringe at 0° C. The mixture was stirred for 10 min, and tosyl chloride (1.6 g, 8.4 mmol) was added. After stirring at room temperature for 2 h, water (100 mL) was added. The mixture was extracted with ethyl acetate (3×50 mL), dried (MgSO4), and concentrated. The residue was purified by column chromatography using hexane: ethyl acetate=2:1 as eluent to yield 1.86 g (92%) of the desired product.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH3:12])[CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1.BrC1C=CC(N)=CC=1.BrC1C=CC=CC=1C(OCC)=O>C(O)C>[CH2:11]([C:4]1[CH:3]=[C:2]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:19]=2)[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=1)[CH3:12]
Reactant: CCc1cc(Cl)n2nccc2n1
Reactant: CCOC(=O)c1ccccc1-c1ccc(N)cc1
Agent: CCOC(=O)c1ccccc1Br
Agent: Nc1ccc(Br)cc1
Solvent: CCO
Product: CCOC(=O)c1ccccc1-c1ccc(Nc2cc(CC)nc3ccnn23)cc1

Procedure:
A solution of 800 mg (4.4 mmol) 7-chloro-5-ethylpyrazolo[1,5-a]pyrimidine (Example 1, Step B) and 1.0 g (4.1 mmol) ethyl 4'-amino-biphenyl-2-carboxylate (prepared from protected 4-bromoaniline and ethyl 2-bromobenzoate by the method of J. C. Adrian, Jr., C. S. Wilcox, I. Am. Chem. Soc., 1989, 111, 8055) in 40 ml dry ethanol was heated with reflux for 5 h. After cooling to room temperature pale yellow crystals of the title compound precipitated, which were filtered by suction and recrystallized from ethanol,