Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:13][S:14][C:15]1[N:20]=[C:19](Cl)[CH:18]=[CH:17][N:16]=1>CN(C=O)C>[CH3:13][S:14][C:15]1[N:20]=[C:19]([N:8]2[C:4]3[CH:3]=[C:2]([NH2:1])[CH:10]=[CH:9][C:5]=3[N:6]=[CH:7]2)[CH:18]=[CH:17][N:16]=1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: CSc1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nccc(-n2cnc3ccc(N)cc32)n1
Yield: 11 %

Procedure:
To a stirred solution of 5-aminobenzimidazole (700 mg, 5.26 mmol, 1 eq) in DMF (21 mL) was added NaH (231 mg, 5.78 mmol, 1.1 eq, (60% suspension in oil)). The mixture was allowed to stir until gas evolution ceased. To the DMF solution was added 2-methylthio-4-chloropyrimidine (0.612 mL, 5.26 mmol, 1 eq) dropwise via syringe. The mixture was allowed to stir overnight. The DMF was removed under reduced pressure and the residue was diluted with water and extracted 3× with CH2Cl2. The organic extracts were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The mixture was purified by preparative thin layer chromatography (cluted 2× with 3.5% MeOH/CH2Cl2) to give 149 mg 2-methylthio-4-[6-aminobenzimidazol-1-yl]pyrimidine (faster regioisomer) and 89 mg 2-methylthio-4-[5-aminobenzimidazol-i-yl]pyrimidine (slower regioisomer). 2-methylthio-4-[6-aminobenzimidazol-1-yl]pyrimidine (faster regioisomer): 1H NMR (500 MHz, CD3OD): δ8.68 (1H, s); 8.58 (1H, d, J=5.5 Hz); 7.68 (1H, d, J=2 Hz); 7.45 (2H, m); 6.81 (IH, dd, J=2 Hz, J=8.5 Hz); 2.67 (3H, s). 2-methylthio-4-[5-aminobenzimidazol-1-yl]pyrimidine (slower regioisomer): 1H NMR (500 MHz, CD3OD): δ8.81 (1H, s); 8.56 (1H, d, J=5.5 Hz); 8.11 (1H, d, J=8.5 Hz); 7.46 (1H, d, J=5.5 Hz); 7.04 (1H, d, J=2 Hz); 6.87 (1H, dd, J=2 Hz, J=8.5 Hz); 2.65 (3H, s).
Reaction SMILES: [O:1]=[S:2]1(=[O:33])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:32])[N:14]([N:23]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:33]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:32])[N:14]([NH:23][CH:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1
Reactant: CC(=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc21)c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 243A (0.093 g, 0.20 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.015 mL, 0.42 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.152 mL, 0.30 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of approximately 2-4, diluted with water, and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with dichloromethane to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.31 (m, 3 H) 4.41 (d, J=68.76 Hz, 1 H) 5.85 (m, 1 H) 7.28 (m, J=7.54, 7.54 Hz, 7 H) 7.59 (m, 4 H) 8.07 (m, 2 H) 16.30 (s, 1 H). MS (ESI−) m/z 459 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([F:9])=[CH:4][C:3]=1N.N([O-])=O.[Na+].[I-:15].[K+].C(OC(=O)C)C>O.S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([F:9])=[CH:4][C:3]=1[I:15]
Reactant: Nc1cc(F)c(Cl)cc1Br
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1cc(I)c(Br)cc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
99 mmol of 2-bromo-4-chloro-5-fluoro-phenylamine [120694-11-3] is dissolved in 700 ml of water and 100 ml of concentrated sulfuric acid. The solution is cooled to 0° C. and 109 mmol of sodium nitrite dissolved in 30 ml of water is added. The mixture is stirred for 1 hour at 5-10° C. then a solution of 130 mmol of potassium iodide in 100 ml of water is added slowly whilst the mixture is vigorously stirred. After addition, the mixture is allowed to warm to room temperature. Ethylacetate is added and the phases are separated. The aqueous phase is extracted with ethyl acetate (3×). The combined organic phases are washed successively with 1N NaOH, 1N sodium thiosulfate, 1N HCl, aq.sat. sodium bicarbonate solution and brine, then dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (SiO2 60 F) to afford the title compound which is identified based on the Rf value.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:23][N:24]([C@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1)[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]>>[Br:1][C:2]1[C:3]([N:34]2[CH2:35][CH2:36][C@H:32]([N:24]([CH3:23])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH2:33]2)=[N:4][CH:5]=[C:6]([C:7](=[O:8])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:21]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCNC1
Product: CN(C(=O)OC(C)(C)C)[C@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 93.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2) and (S)-tert-butyl methyl(pyrrolidin-3-yl)carbamate. LC-MS (Condition 6) tR=1.59 min, m/z=558.8/560.8 [M+H]+, m/z=502.9/504.9 [M+H—H2C═C(CH3)2].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12][C:11](=[O:13])[O:10][C:8](=O)[C:7]=12.[CH2:14]1[C@@H:17](C(O)=O)[NH:16][CH2:15]1>CS(C)=O>[Br:1][C:2]1[C:7]2[C:8](=[O:10])[N:16]3[CH2:17][CH2:14][C@H:15]3[C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1CCN1
Reactant: O=c1[nH]c2cccc(Br)c2c(=O)o1
Solvent: CS(C)=O
Product: O=C1Nc2cccc(Br)c2C(=O)N2CC[C@@H]12

Procedure:
25 g (103 mmol) of 6-bromo-isatoic acid anhydride and 10.44 g (103 mmol) of L-azetidine-2-carboxylic acid in 100 ml of dimethyl sulphoxide are stirred at 95° for 25 minutes, the dimethyl sulphoxide is removed in vacuo and the residue is heated to 150° for 3 hours in a high vacuum. By chromatography of the resulting material on silica gel while eluting with ethyl acetate and subsequent recrystallization from ethyl acetate there is obtained (S)-5-bromo-1,10a-dihydroazeto[2,1-c][1,4]benzodiazepine-4,10(2H,9H)-dione of melting point 182°-183°.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1.CCOCC.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([CH:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[N:9]2)=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN1CCC(c2n[nH]c3ccccc23)CC1
Solvent: CCOCC
Product: CN1CCC(c2nn(C(=O)c3ccc(F)cc3)c3ccccc23)CC1
Yield: 53 %

Procedure:
A solution of 3.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole in 15 ml of 4-fluorobenzoyl chloride was heated at 100° for 2 hrs. The reaction mixture was poured into ether and the precipitate was collected. The precipitate was treated with dilute aqueous sodium hydroxide solution and extracted with chloroform The chloroform extract was dried over anhydrous magnesium sulfate and the solvent removed in vacuo to yield 2.5 g (53%) of product, mp 132°-133° C.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13](Br)[CH:14]=[C:15]([O:25][CH3:26])[C:16]=3[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(=O)=O.CC(C)=O.[Li]CCCC.[B:40](OC(C)C)([O:45]C(C)C)[O:41]C(C)C>C1COCC1.CCCCCC>[C:1]12([C:11]3[CH:12]=[C:13]([B:40]([OH:45])[OH:41])[CH:14]=[C:15]([O:25][CH3:26])[C:16]=3[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1cc(Br)cc(C23CC4CC(CC(C4)C2)C3)c1OCc1ccccc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(B(O)O)cc(C23CC4CC(CC(C4)C2)C3)c1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 87.9 %

Procedure:
To a solution of 3-(1-adamantyl)-4-benzyloxy-5-methoxyphenyl bromide (2.85 g, 6.67 mmol) in THF (12 mL) at −78° C. (dry ice/acetone bath) under argon was added 1.6 M n-BuLi (10.7 mmol) in hexane (6.67 mL) in one portion. This mixture was stirred at −78° C. for 15 min. Tri(isopropyl) borate (4.60 mL, 20.0 mmol) was added next, and the resulting solution was stirred at −78° C. for 20 min before being allowed to warm to room temperature with stirring overnight. The mixture was quenched with 1 N HCl (40 mL) and then extracted with EtOAc (100 and 60 mL). The combined organic extracts were washed with brine and dried. Solvents were removed at reduced pressure, and the residue was washed with hexane and dried to give 2.3 g (88%) of 3-(1-adamantyl)-4-benzyloxy-5-methoxyphenylboronic acid as a cream solid, mp 148-151° C. IR 3219, 2903, 2848, 1410, 1340, 1201 cm−1; 1H NMR (CDCl3) δ 1.72 (bs, 6H, AdCH2), 2.03 (bs, 3H, AdCH), 2.17 (m, 6H, AdCH2), 3.99 (s, 3H, OCH3), 5.21 (s, 2H, C6H5CH2), 7.31-7.58 (m, 5H, C6H5), 7.68 (d, J=1.4 Hz, 1H, 6-ArH), 7.92 ppm (d, J=1.4 Hz, 1H, 2-ArH).
Reaction SMILES: C([O:5][C:6](=[O:51])[CH2:7][N:8]([C:18](=[O:50])[C@H:19]([CH2:35][CH2:36][CH2:37][CH2:38][NH:39]C(OCC1C=CC=CC=1)=O)[NH:20][C@@H:21]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)(C)(C)C.[BrH:52].CCOCC>C(O)(=O)C>[BrH:52].[BrH:52].[CH2:33]([O:32][C:30]([C@H:21]([NH:20][C@H:19]([C:18]([N:8]([CH:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17]1)[CH2:7][C:6]([OH:51])=[O:5])=[O:50])[CH2:35][CH2:36][CH2:37][CH2:38][NH2:39])[CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:31])[CH3:34]
Reactant: CCOC(=O)[C@@H](CCc1ccccc1)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)[C@@H](CCc1ccccc1)N[C@@H](CCCCN)C(=O)N(CC(=O)O)C1Cc2ccccc2C1
Reaction time: 0.5 h

Procedure:
Nα -[1-(R)-Ethoxycarbonyl-3-phenylpropyl]-Nε -carbobenzoxy-L-lysyl-N-(indan-2-yl)glycine tert-butyl ester (1 g) is dissolved in 2 ml of acetic acid. To the solution, 8 ml of 25% hydrobromic acid solution in acetic acid is added, and the mixture is allowed to stand at room temperature for 30 minutes. On adding 200 ml of ether and 100 ml of petroleum ether to the reaction mixture, a crystalline precipitate forms. This is collected by filtration and recrystallized from a mixture of methanol and ethyl ether to give 0.8 g of Nα -[1-(R)-ethoxycarbonyl-3-phenylpropyl]-L-lysyl-N-(indan-2-yl)glycine dihydrobromide melting at 128°-133° C. with decomposition.
Reaction SMILES: [O:1]=[S:2]1(=[O:20])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:8]=1.[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[N:29]1[CH2:30][CH2:31][N:32]([C:11]([C:10]2[CH:14]=[CH:15][C:7]([N:3]3[CH2:4][CH2:5][CH2:6][S:2]3(=[O:1])=[O:20])=[CH:8][C:9]=2[S:16]([CH3:19])(=[O:18])=[O:17])=[O:13])[CH2:33][CH2:34]1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: CS(=O)(=O)c1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3S(C)(=O)=O)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
4-(1,1-Dioxo-1λ6-isothiazolidin-2-yl)-2-methanesulfonylbenzoic acid (335 mg) described in Preparation Example 22, 1-(2,4-dimethylphenyl)piperazine (199 mg), 1-hydroxybenzotriazole 1 hydrate (142 mg) were dissolved in N,N-dimethylformamide (5 mL), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (202 mg) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give the title compound (436 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][CH2:12][N:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][C:17]([N+:23]([O-])=O)=[CH:18][CH:19]=2)[CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[Sn](Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:23][C:17]1[CH:16]=[C:15]2[C:20]([CH2:21][CH2:22][N:13]([CH2:12][CH2:11][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:14]2)=[CH:19][CH:18]=1
Reactant: O=C(CCN1CCc2ccc([N+](=O)[O-])cc2C1)OCc1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)CN(CCC(=O)OCc1ccccc1)CC2
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
1.80 g of 2-(2-benzyloxycarbonylethyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline was dissolved in 10 ml of ethanol, and 4.77 g of tin chloride dihydrate was added to the solution. The solution was heated under reflux with stirring for 30 minutes. The resulting solution was neutralized by adding saturated aqueous solution of sodium bicarbonate, and the solution was extracted with ethyl acetate, washed with water and saturated aqueous solution of sodium chloride, and dried with anhydrous sodium sulfate. After separating the desiccant by filtration, the residue was purified by silica gel column chromatography to obtain 1.52 g of 7-amino-2-(2-benzyloxycarbonylethyl)-1,2,3,4-tetrahydroisoquinoline as an oily product. This product, with no further purification, was dissolved in 10 ml of DMF, and 1.52 g of 1-(tertbutoxycarbonyl)-4-(carboxymethoxy)piperidine and 0.41 g of 1-ethyl-3-(3-dimethylaminopopyl)carbodiimide, which had been separately synthesized, were added to this solution. The solution was stirred overnight at room temperature. The resulting solution was extracted with ethyl acetate, washed with water, saturated aqueous solution of sodium bicarbonate, and saturated aqueous solution of sodium chloride, and dried with anhydrous sodium sulfate. After separating the desiccant by filtration, the residue was purified by silica gel column chromatography to obtain 1.84 g of 2-(2-benzyloxycarbonylethyl)-7-[1-(tert-butoxycarbonyl)piperidine-4-yloxyacetylamino]-1,2,3,4-tetrahydroisoquinoline, which was an oily product (yield: 68%).
Reaction SMILES: CC([O:6][CH:7]([C:9]#[CH:10])[CH3:8])OCC.C([Mg]Br)C.[CH3:15][CH:16]1[CH:21]=[CH:20][CH2:19][C:18]([CH3:23])([CH3:22])[C:17]1=[O:24].OS(O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)C>[OH:24][C:17]1([C:10]#[C:9][CH:7]([OH:6])[CH3:8])[C:18]([CH3:23])([CH3:22])[CH2:19][CH:20]=[CH:21][CH:16]1[CH3:15]
Reactant: CC1C=CCC(C)(C)C1=O
Reactant: C#CC(C)OC(C)OCC
Agent: CC[Mg]Br
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CC(O)C#CC1(O)C(C)C=CCC1(C)C
Reaction time: 2 h

Procedure:
5.5 g of 2-(3-oxa-pent-2-yloxy)-but-3-yne (see Example 2, letter a), 14 ml of 40% ethyl-magnesium bromide in diethyl ether and 3.5 g of 2,6,6-trimethyl-cyclohex-3-en-1-one in anhydrous diethyl ether were reacted as described in Example 2 (letter b). The crude reaction mixture was then acidified with 35% aqueous H2SO4 and stirred during 2 hours at 20°. After addition of 10% aqueous Na2CO3 until neutrality, extraction with diethyl ether, drying of the organic phase over Na2SO4 and evaporation, there were isolated 0.4 g of crude material. This latter was purified by means of crystallization in cyclohexane, m.p. 101°-104°, to give the desired compound.
Reaction SMILES: [BH4-].[Na+].[CH:3]1([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl>O.CO>[CH3:16][CH:15]([C:12]1[CH:11]=[CH:10][C:9]([CH:3]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)=[CH:14][CH:13]=1)[OH:17]
Reactant: CC(=O)c1ccc(C2CCCCC2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(O)c1ccc(C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
While cooling well, a solution of 2.5 g of sodium borohydride in 10 ml of water is added dropwise to a solution of 20.2 g of para-cyclohexyl-acetophenone in 250 ml of methanol. The mixture is stirred at room temperature for 1 hour and the pH then adjusted to 2 with semi-concentrated hydrochloric acid. The batch is evaporated completely and the residue extracted several times with ether. The solution is dried and the ether evaporated to obtain methyl-(para-cyclohexylphenyl)-carbinol in the form of colorless crystals melting at 81°-83°C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.C1COCC1.[Cl-].[NH4+].O>CO.[Zn]>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc([N+](=O)[O-])cc2)c1C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(N)cc2)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
To a suspension of [6-fluoro-3-methyl-4-(4-nitro-phenyl)-naphthalen-2-yl]-acetic acid methyl ester (190 mg, 0.54 mmol) in methanol (3 mL) was added THF (2 mL). Then, zinc dust (287.1 mg, 4.4 mmol), and ammonium chloride (287.8 mg, 5.38 mmol) were added followed by water (1.3 mL). The reaction mixture was stirred at room temperature for 30 minutes. Solid was filtered and washed with ethyl acetate (20 mL). The solution was concentrated to remove organic solvent, and then diluted with water (25 mL). The mixture was extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with brine solution (30 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent under vacuum gave [4-(4-amino-phenyl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (118 mg, 67.7%) as a light brown solid. 1H NMR (300 MHz, CDCl3) δ ppm 7.71-7.83 (m, 1 H), 7.69 (s, 1 H), 7.27 (s, 1 H), 7.10-7.22 (m, 1 H), 6.93-7.09 (m, 3 H), 6.83 (d, J=7.8 Hz, 1H), 3.86 (s, 2 H), 3.78 (br. s, 2 H), 3.74 (s, 3 H), 2.19 (s, 3 H). HRMS calcd. for C20H19FNO2 [(M+H)+] 324.1395, obsd. 324.1392.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:22][CH3:23])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:8]([Cl:17])=[C:7]([C:18]([F:21])([F:20])[F:19])[CH:6]=2.C(=O)([O-])[O-].[K+].[K+].I[CH2:31][CH3:32]>CC(C)=O>[NH2:1][C:2]1[C:3]([O:22][CH3:23])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([N:12]([CH2:31][CH3:32])[S:13]([CH3:16])(=[O:15])=[O:14])[C:8]([Cl:17])=[C:7]([C:18]([F:21])([F:20])[F:19])[CH:6]=2
Reactant: COc1nc2cc(C(F)(F)F)c(Cl)c(NS(C)(=O)=O)c2nc1N
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(c1c(Cl)c(C(F)(F)F)cc2nc(OC)c(N)nc12)S(C)(=O)=O
Reaction time: 4 h
Yield: 94 %

Procedure:
A mixture of N-(3-amino-6-chloro-7-trifluoromethyl-2-methoxyquinoxalin-5-yl)methanesulphonamide (Preparation 20, 73 mg, 0.2 mmol) and anhydrous potassium carbonate (33 mg, 0.24 mmol) in acetone was stirred under reflux for 20 mins. Iodoethane (32 μl, 0.4 mmol) was added, and the mixture was heated for a further 2 h. Additional iodoethane (32 μl, 0.4 mmol) was added, and heating was continued for a further 4 h. The mixture was concentrated under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic solution was dried (MgSO4), concentrated under reduced pressure, and the residue was purified by flash chromatography (gradient elution with dichloromethane/methanol) to give N-(3-amino-6-chloro-7-trifluoromethyl-2-methoxyquinoxalin-5-yl)-N-ethyl-methanesulphonamide (75 mg, 96%), as a white solid.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Cl[CH2:7][C:8]([C:10]1[C:11]([CH3:18])=[C:12]([CH:16]=[O:17])[NH:13][C:14]=1[CH3:15])=[O:9]>C1COCC1>[CH3:18][C:11]1[C:10]([C:8](=[O:9])[CH2:7][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[C:14]([CH3:15])[NH:13][C:12]=1[CH:16]=[O:17]
Reactant: CCNCC
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)CCl
Solvent: C1CCOC1
Product: CCN(CC)CC(=O)c1c(C)[nH]c(C=O)c1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Diethylamine (5 ml) was added to a solution of 4-(2-Chloroacetyl)-3,5-dimethylpyrrole-2-carboxaldehyde (1 g, 5 mmol) in THF (20 ml). The mixture was stirred at room temperature for 24 h. The solvent was removed under reduced pressure and the residue was treated with water, NaHCO3 (5%) and extracted with dichloromethane. After drying and filtering, the solvent was removed and the residue was used without further purification.
Reaction SMILES: [C:1]([C:4]([NH:9][C:10]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)=O)([CH3:8])[CH:5]([CH3:7])[CH3:6])(=[O:3])[NH2:2].[H-].[Na+].O>C1(C)C(C)=CC=CC=1>[CH:5]([C:4]1([CH3:8])[C:1](=[O:3])[NH:2][C:10]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[N:9]1)([CH3:7])[CH3:6]
Reactant: CC(C)C(C)(NC(=O)c1ccc2ccccc2n1)C(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(C)C1(C)N=C(c2ccc3ccccc3n2)NC1=O
Yield: 78.3 %

Procedure:
To a slurry of N-(1-carbamoyl-1,2-dimethylpropyl)-2-quinolinecarboxamide (16.04 g, 0.0562 mol) in xylene (610 ml) under nitrogen is added a 50% oil dispersion of sodium hydride (2.7 g, 0.056 mol) at 20° C. The reaction is heated to reflux for 2 hours, cooled and water (50 ml) added. The aqueous layer is extracted with methylene chloride and the organic layers combined and evaporated to give a yellow oil, 17 g. Purification is accomplished by passing through a silica gel column using hexane-ethyl acetate as solvent. A pale yellow solid is obtained and is recrystalized from ethyl acetate to give 11.77 g (78%) of white product, mp 112°-117° C. Anal. calcd. for C16H17N3O: C, 71.88; H, 6.41; N, 15.72. Found: C, 71.91; H, 6.47; N, 15.70.