Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=CC=1C(F)(F)F.[CH3:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)=O.[BH4-].[Na+]>CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C.CO>[CH3:30][O:29][C:23]1[CH:22]=[C:21]([CH:19]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH3:18])[CH:26]=[CH:25][C:24]=1[O:27][CH3:28]
Reactant: FC(F)(F)c1cc(N2CCNCC2)ccc1Cl
Reactant: COc1ccc(C(C)=O)cc1OC
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(C)N2CCNCC2)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A quantity of 0.17 g (0.6 mmole, 1 eq) of 1-(4-chloro-3-trifluoromethyl-phenyl)-piperazine and 0.1 g (0.6 mmole, 1 eq) of 3,4-dimethoxyacetophenone and 2 mL of Ti(OiPr)4 are warmed to 70° C. for 2 hours. The reaction solution is cooled to room temperature and 20 mL of anhydrous methanol is added followed by 1.0 g of NaBH4 and the resulting solution is stirred at room temperature for 2 hours. The reaction is quenched by the addition of 1 N NaOH and extracted with CH2Cl2. The CH2Cl2 extracts are dried over anhydrous MgSO4 and concentrated in vacuo. The residue is chromatographed on SiO2 with ethyl to afford 1-[4-chloro-3-trifluoromethyl)phenyl]-4-[1-(3,4-dimethoxyphenyl)ethyl]piperazine (compound 2). Analysis 1H NMR (400 MHz, CDCl3): 7.31 (1H, d), 7.19 (1H, m), 6.90 (4H, m), 3.89 (6H, d), 3.38 (1H, m), 3.20 (4H, m), 2.61 (4H, m). MS (LC-MS): Calculated for C21H24ClF3N2O2 428.88, found 429.30 (M+). III. 3-{1-4-(4-Bromo-3-methoxy-phenyl)-piperazin-1-yl]-ethyl}-quinoline via Scheme C
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7](B3OC(C)(C)C(C)(C)O3)=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:20].O.C(=O)([O-])[O-].[Na+].[Na+].Br[C:29]1[CH:30]=[N:31][CH:32]=[C:33]([CH:37]=1)[C:34]([NH2:36])=[O:35]>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.C(O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:29]3[CH:30]=[N:31][CH:32]=[C:33]([CH:37]=3)[C:34]([NH2:36])=[O:35])=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:20]
Reactant: NC(=O)c1cncc(Br)c1
Reactant: CN1C(=O)Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN1C(=O)Cc2cc(-c3cncc(C(N)=O)c3)ccc21
Temperature: 150 °C

Procedure:
To a solution of 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one, prepared as described in Example 3a (75 mg, 0.26 mmol) in 12-dimethoxyethane (0.7 mL) was added water (0.3 mL) and ethanol (0.2 ml). The solution was then charged with sodium carbonate (27.6 mg, 0.26 mmol) and 5-bromonicotinamide (CAS#28733-43-9, 53.5 mg, 0.26 mmol) and dichlorobis(triphenylphosphine)palladium (II) (CAS#13965-03-2, 9.1 mg, 0.013 mmol). The reaction vessel was sealed and was heated by microwave irradiation at 150° C. for 10 minutes. The reaction mixture was cooled to room temperature, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (methanol-dichloromethane, 0 to 10%) to furnish 5-(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-nicotinamide; MS: (ES+) m/z 268 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.16 (s, 3H), 3.63 (s, 2H), 7.11 (d, J=8.8 Hz, 1H), 7.62 (br. s., 1H), 7.69-7.75 (m, 2H), 8.22 (br. s., 1H), 8.42 (t, J=2.0 Hz, 1H), 8.94 (dd, J=18.9, 1.96 Hz, 2H).
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10](S(C)(=O)=O)[N:11]=[C:12]([CH3:13])[C:7]=2[CH:6]=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]1=[O:24])[CH3:2].[CH2:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)[CH3:26]>CS(C)=O>[CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:37][C:36]3[CH:35]=[CH:34][C:33]([N:30]4[CH2:29][CH2:28][N:27]([CH2:25][CH3:26])[CH2:32][CH2:31]4)=[CH:39][CH:38]=3)[N:11]=[C:12]([CH3:13])[C:7]=2[CH:6]=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]1=[O:24])[CH3:2]
Reactant: CCn1c(=O)c(-c2ccccc2)cc2c(C)nc(S(C)(=O)=O)nc21
Reactant: CCN1CCN(c2ccc(N)cc2)CC1
Solvent: CS(C)=O
Product: CCN1CCN(c2ccc(Nc3nc(C)c4cc(-c5ccccc5)c(=O)n(CC)c4n3)cc2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
8-Ethyl-4-methyl-2-(methylsulfonyl)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one (275 mg, 0.80 mmol) and 4-(4-ethylpiperazin-1-yl)aniline (197 mg, 1.2 equiv.) were added to dimethyl sulfoxide (5 mL) and the resulting mixture was heated to 100° C. and stirred overnight. After cooling to room temperature, the reaction was partitioned between aqueous and organic layers with ethyl acetate and H2O, organic layer was dried with anhydrous magnesium sulfate, filtered and evaporated, and directly applied to prep-LC to provide the title compound in (210.0 mg, 56% yield): 1H NMR (400 MHz, CDCl3): δ 7.80 (s, 1H), 7.62 (d, 2H), 7.60 (d, 2H), 7.40 (m, 2H), 7.18 (s, 1H), 6.95 (d, 2H), 4.50 (q, 2H), 3.22 (m, 4H), 2.70 (m, 4H), 2.60 (s, 3H), 2.50 (m, 2H), 1.40 (t, 3H), 1.20 (t, 3H); MS (EI) for C28H32N6O: 469.10 (MH+).
Reaction SMILES: [ClH:1].[CH3:2][C:3]([CH3:16])([NH2:15])[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[CH:10][CH:9]=[CH:8]2>C(O)(=O)C.O=[Pt]=O>[ClH:1].[CH3:2][C:3]([CH3:16])([NH2:15])[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH2:10][CH2:9][CH2:8]2
Reactant: CC(C)(N)Cc1ccc2ccccc2c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)(N)Cc1ccc2c(c1)CCCC2
Reaction time: 1 h
Yield: 84.4 %

Procedure:
A solution of 1.0 g (4.2 mmol) of 6-(1,1-dimethyl-1-aminoethyl)naphthalene hydrochloride in glacial acetic acid (100 mL) was treated under Argon atmosphere with PtO2 (350 mg). The mixture was hydrogenated in a Parr shaker at 50 psi for 1 h. and filtered through a plug of celite. The filtrate was concentrated in vacuo and concentrated from ether. The residue was triturated with ether and the white crystalline solid (850 mg, 85% yield) was collected, washed with ether and dried. MS(ES) m/z 204.2(M+H)+; Elemental analysis: theoretical for C14H21N.HCl.1/2 H2O: C, 67.58; H, 9.31; N, 5.63. found: C, 67.51; H, 9.31; N, 5.63.
Reaction SMILES: [CH3:1][C:2]([CH3:13])=[CH:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9].[BH4-].[Na+].O.C(OCC)C>C(O)C>[CH3:1][C:2]([CH3:13])=[CH:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][OH:9]
Reactant: CC(C)=CCc1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: CC(C)=CCc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
170 mg of the aldehyde compound was dissolved in 20 ml of ethanol, and 100 mg of sodium borohydride was added. The mixture was stirred at room temperature for 1 hour. Water and ethyl ether were added to the reaction mixture to dilute it, and it was then worked up in a customary manner to give 158 mg (yield 92%) of 3-(3-methyl-2-butenyl)benzyl alcohol.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=1>O.CS(C)=O>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:3])=[CH:5][CH:6]=2)=[N:13][CH:14]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Nc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
11.2 g (0.2 mole) of potassium hydroxide in 15 ml of water are added dropwise under nitrogen atmosphere to 22 g (0.2 mole) of 4-aminophenol in 100 ml of diemthylsulfoxide. 36 g (0.2 mole) of 2-chloro-5-(trifluoromethyl)pyridine in 30 ml of dimethylsulfoxide are added dropwise at 25° C. The reaction mixture is stirred for 3 hours at room temperature, then poured into ice-water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated by evaporation. The residue is dissolved in ether and the ether solution is extracted with 1 N hydrochloric acid. The acid phase is made alkaline with concentrated NaOH solution and extracted with ether. The ether phase is dried over sodium sulfate and concentrated by evaporation, affording 4-(5-trifluoromethylpyridin-2-yl-oxy)aniline as a brown oil.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[Cl:5][C:6]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:7]=1[CH:8]=[C:9]1[NH:13][C:12](=[O:14])[CH:11]=[C:10]1[OH:15]>C(O)(=O)C>[Cl:5][C:6]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:7]=1[CH:8]=[C:9]1[NH:13][C:12](=[O:14])[C:11](=[N:1][OH:3])[C:10]1=[O:15]
Reactant: O=C1C=C(O)C(=Cc2c(Cl)cccc2Cl)N1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=Cc2c(Cl)cccc2Cl)C(=O)C1=NO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An aqueous solution of 1.1 mmol (0.075 g) sodium nitrite was added dropwise to an ice-cooled solution of 2 mmol 5-(2,6-dichlorobenzylidene)-4-hydroxy-1,5-dihydropyrrol-2-one (prepared in accordance with H. Poschenrieder et al (Arch. Pharm. Pharm. Med. Chem. 1998, 331, 389-394) and H.-D. Stachel et al (J. Heterocycl. Chem. 1980, vol. 17, pp. 1195-1199 and Liebigs Ann. Chem. 1985, pp. 1692-1696)) in 5 ml glacial acetic acid, while stirring. The resulting solution was then stirred at room temperature for 30 minutes and concentrated in vacuo. The residue is purified by recrystallization from ethanol. The yield of 5-(2,6-dichlorobenzylidene)-pyrrolidine-2,3,4-trione 3-oxime was 65%, with a melting point of 232° C.
Reaction SMILES: [NH2:1][C@@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[OH-].[Na+].[C:13](Cl)(=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>CC(C)=O>[C:13]([NH:1][C@@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])(=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCC(=O)Cl
Reactant: N[C@H](CCC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCCCCCC(=O)N[C@H](CCC(=O)O)C(=O)O
Temperature: 10 °C
Yield: 83 %

Procedure:
A solution of 75.0 g (510 mmol) of D-glutamic acid in one liter of aqueous acetone (50:50) was adjusted to pH 9.0 with 2N sodium hydroxide. The resulting solution was cooled to 10° C. and treated over 45 minutes with 114.2 g (770 mmol) of heptanoyl chloride, maintaining the pH at 9.0 with 2N sodium hydroxide. The reaction was allowed to warm to room temperature for three hours. The acetone was removed under vacuum, and the resulting aqueous solution was acidified with dilute hydrochloric acid and extracted three times with 700 ml portions of ethyl acetate. The extracts were combined, dried over magnesium sulfate, filtered and concentrated. The resulting oil was triturated with hexane to give 109.8 g (83%) of desired product: mp 92°-96° C.; IR (Nujol) 3300, 2700-3250, 1720, 1625 cm-1 ; NMR (D6 -DMSO) delta 4.20 (m, 1H), 2.28 (t, 2H), 2.20 (t, 2H), 1.85-2.05 (m, 1H), 1.65-1.85 (m, 1H), 1.40-1.60 (m, 2H), 1.15-1.30 (m, 6H), 0.75 (t, 3H); [alpha]D =+9.6 (C=1.0, MeOH).
Reaction SMILES: [Na].[C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[OH:14])[N:10]=[CH:9][CH:8]=[C:7]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[O:24])=[C:18]([F:33])[CH:17]=1)#[N:3].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:42][CH:43]1[CH2:48][CH2:47][CH2:46][N:45]([CH3:49])[CH2:44]1.O>CN(C)C=O>[C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:42][CH:43]1[CH2:48][CH2:47][CH2:46][N:45]([CH3:49])[CH2:44]1)[N:10]=[CH:9][CH:8]=[C:7]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[O:24])=[C:18]([F:33])[CH:17]=1)#[N:3]
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)ccnc2cc1O
Reactant: CN1CCCC(CCl)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCCC(COc2cc3nccc(Oc4ccc(NC(=O)Nc5ccc(F)cc5)c(F)c4)c3cc2C#N)C1
Reaction time: 8 h
Yield: 3.9 %

Procedure:
After dissolving 6-cyano-4-(4-(4-fluoroanilinocarbonyl)amino-3-fluorophenoxy)quinolin-7-ol sodium salt (222 mg), potassium carbonate (162 mg) and 3-chloromethyl-1-methylpiperidine hydrochloride (86 mg) in dimethylformamide (1.7 ml) and stirring the mixture overnight at 70–80° C., water was added, and extraction was performed with a tetrahydrofuran and ethyl acetate mixed solvent prior to concentration under reduced pressure and purification of the residue with NH Silica (Fuji Silysia Chemical). The obtained solid was washed with ether and dried to obtain the title compound (10 mg).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH3:13])[CH:9]=[C:10]([OH:12])[CH:11]=1.[CH3:16][N:17]=[C:18]=[O:19]>C(N(CC)CC)C.C1C=CC=CC=1>[CH3:16][NH:17][C:18](=[O:19])[O:12][C:10]1[CH:9]=[C:8]([CH3:13])[CH:7]=[C:6]([O:5][CH2:4][CH:3]([O:2][CH3:1])[O:14][CH3:15])[CH:11]=1
Reactant: COC(COc1cc(C)cc(O)c1)OC
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CNC(=O)Oc1cc(C)cc(OCC(OC)OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(2,2-Dimethoxyethoxy)-5-hydroxytoluene (2.50 grams), benzene (50 ml) and triethylamine (4 drops) were charged into a glass reaction vessel equipped with a mechanical stirrer. Methyl isocyanate (1.0 ml) was added to the vessel, and the resulting mixture was stirred at room temperature for a period of about 2 hours. The mixture was then allowed to stand at ambient temperature over the weekend. After this time the reaction mixture was stripped of benzene, leaving a viscous liquid residue. This residue was distilled under vacuum to yield the desired product O-[3-(2,2-dimethoxyethoxy)-5-methylphenyl] N-methylcarbamate as an oil.
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[C:7]([N:12]2[C:16](=[O:17])[NH:15][C:14]([CH:18]([NH:32][C:33]3[CH:41]=[CH:40][C:36]([C:37]([NH2:39])=[NH:38])=[CH:35][CH:34]=3)[C:19]3[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21](OCCO)[C:20]=3[F:31])=[N:13]2)=[N:8][CH:9]=[CH:10][CH:11]=1.COC(=O)N=C(SC)C(C1C(F)=C2C(=C(OC)C=1)[O:67][CH2:66][CH2:65][CH2:64]2)=NC1C=CC(C2N=C(C)ON=2)=CC=1.[F:77][C:78]([F:83])([F:82])[C:79]([OH:81])=[O:80].COC(=O)N=C(SC)C(C1C=C(OC)C=C(OCCO[Si](C(C)(C)C)(C)C)C=1F)=NC1C=CC(C2N=C(C)ON=2)=CC=1>C(O)(=O)C>[F:77][C:78]([F:83])([F:82])[C:79]([OH:81])=[O:80].[NH2:5][C:6]1[C:7]([N:12]2[C:16](=[O:17])[NH:15][C:14]([CH:18]([NH:32][C:33]3[CH:41]=[CH:40][C:36]([C:37]([NH2:39])=[NH:38])=[CH:35][CH:34]=3)[C:19]3[C:20]([F:31])=[C:21]4[C:22](=[C:23]([O:25][CH3:26])[CH:24]=3)[O:67][CH2:66][CH2:65][CH2:64]4)=[N:13]2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccc3N)c(=O)[nH]2)c1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c2c(c1F)CCCO2
Agent: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(OCCO[Si](C)(C)C(C)(C)C)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: COc1cc(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccc3N)c(=O)[nH]2)c(F)c2c1OCCC2

Procedure:
The same procedure was carried out as in Examples (200b) to (200c), except that [2-(5-fluoro-8-methoxychroman-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester (Example (33d)) and 0.1% trifluoroacetic acid were used instead of respectively the (2-{3-[2-(t-butyldimethylsilanyloxy)ethoxy]-2-fluoro-5-methoxyphenyl}-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene)carbamic acid methyl ester in Example (200b) and 0.1% acetic acid in Example (200c), to give the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:15][NH:16][CH:17]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18]1>>[CH3:15][N:16]([CH:17]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18]1)[S:11]([C:8]1[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=1)(=[O:13])=[O:12]
Reactant: CNC1CCN(C)C1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)N(C)C2CCN(C)C2)cc1

Procedure:
4-Acetylaminobenzenesulfonyl chloride and methyl-(1-methylpyrrolidin-3-yl)amine are reacted according to the method described in Example 10, intermediate 2. The title compound obtained in the form of a slightly yellowish solid can be reacted further without further purification. (MS-ES+: 312.1; LCMS Rt=0.698 min)
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)(=[O:35])[CH3:34]
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)c(OCC2CC2)c1
Reactant: CC(=O)Cl
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(C)=O)CC4)c[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A150) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C([CH2:3][NH:4][C:5]1[NH:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:7][C:6]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O.B.[ClH:24].[C:25](=O)([O-])O.[Na+]>O1CCCC1>[ClH:24].[CH3:25][N:4]([CH3:3])[C:5]1[NH:9][C:8]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[N:7][C:6]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C([O-])O
Reactant: O=CCNc1[nH]c(-c2ccc(F)cc2)nc1-c1ccccc1
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)c1[nH]c(-c2ccc(F)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-formylmethylamino-2-(4-fluorophenyl)-4-phenylimidazole (200 mg) in tetrahydrofuran (5 ml) was added dropwise 10M borane.dimethylsulfide complex (0.34 ml), and the mixture was stirred under argon atmosphere at room temperature for overnight. To the reaction mixture was slowly added 10% hydrochloric acid, and the mixture was refluxed for one hour. After cooling, the mixture was neutralized by adding a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel flush column chromatography (solvent: hexane:ethyl acetate=5:1), and then, treated with hydrogen chloride-methanol solution to obtain 5-dimethylamino-2-(4-fluorophenyl)-4-phenylimidazole hydrochloride (174 mg) as colorless powder.
Reaction SMILES: Br[C:2]1[C:3]([N:8]2[CH2:11][CH:10]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[O:22]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)[CH3:23].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:23][O:22][C:24]1[CH:29]=[C:28]([C:2]2[C:3]([N:8]3[CH2:11][CH:10]([C:12]4[CH:21]=[CH:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[N:13]=4)[CH2:9]3)=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Brc1cccnc1N1CC(c2ccc3ccccc3n2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(-c2cccnc2N2CC(c3ccc4ccccc4n3)C2)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
To a solution of 2-[1-(3-bromo-pyridin-2-yl)-azetidin-3-yl]-quinoline, as prepared in the above Step 1 of Example 59, (150 mg, 0.44 mmol), 3-methoxyl-phenylboronic acid (80 mg, 0.51 mmol) and K3PO4 (211 mg, 1 mmol) in 1,4-dioxane (12 mL) and H2O (3 mL) was added Pd(dppf)Cl2 (35 mg, 0.05 mmol) then the reaction mixture was stirred at 110° C. under N2 overnight. The reaction mixture was filtered through CELITE™ and washed with CH2Cl2 (50 mL). The organic layer was concentrated and the crude product was purified by silica gel column to give 2-{1-[3-(3-methoxy-phenyl)-pyridin-2-yl]-azetidin-3-yl}-quinoline (70 mg, 0.19 mmol, yield 35%).
Reaction SMILES: C(OP([CH:9]([CH2:17][CH3:18])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(OCC)=O)C.C([Li])CCC.[O:24]([C@@H:42]1[CH2:47][CH2:46][CH2:45][C@H:44]([CH2:48][CH:49]=O)[CH2:43]1)[Si:25]([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>O1CCCC1.CCCCCC>[Si:25]([O:24][C@@H:42]1[CH2:47][CH2:46][CH2:45][C@H:44]([CH2:48][CH:49]=[C:9]([CH2:17][CH3:18])[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:43]1)([C:38]([CH3:41])([CH3:40])[CH3:39])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCOP(=O)(OCC)C(CC)C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](O[C@@H]1CCC[C@H](CC=O)C1)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(=CC[C@H]1CCC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1)C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 1 h

Procedure:
6.43 g of tert-butyl 2-(diethoxyphosphoryl)butyrate are dissolved in 90 ml of tetrahydrofuran, and 7.32 ml of a 2.7 M solution of n-butyllithium in n-hexane are added at −20° C. After 1 hour of stirring at −20° C., 4.36 g of [cis-3-(tert-butyl-diphenylsilanoxy)cyclohexyl]acetaldehyde, dissolved in 40 ml of tetrahydrofuran, are added dropwise. The reaction mixture is slowly warmed to room temperature. 50 ml of water are then added, and the mixture is extracted three times with in each case 200 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is then removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate=30:1. This gives 3.11 g of tert-butyl 4-[cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]-2-ethylbut-2-enoate as an oil. C32H46O3Si (506.81), Rf(n-heptane:ethyl acetate=5:1)=0.73.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.[CH2:21]([O:28][C:29]1[CH:34]=[C:33]([C:35]([C:37]2[CH:47]=[C:46]([CH3:48])[C:40]3[N:41]([CH3:45])[C:42](=[O:44])[O:43][C:39]=3[CH:38]=2)=[O:36])[CH:32]=[C:31](Cl)[N:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN1C(=O)CCC1>[CH2:21]([O:28][C:29]1[N:30]=[C:31]([N:17]2[CH2:18][CH2:19][CH:14]([N:10]3[CH2:9][CH2:8][C:7]4[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[NH:12][C:11]3=[O:13])[CH2:15][CH2:16]2)[CH:32]=[C:33]([C:35]([C:37]2[CH:47]=[C:46]([CH3:48])[C:40]3[N:41]([CH3:45])[C:42](=[O:44])[O:43][C:39]=3[CH:38]=2)=[O:36])[CH:34]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(C(=O)c2cc(Cl)nc(OCc3ccccc3)c2)cc2oc(=O)n(C)c12
Solvent: CN1CCCC1=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)cc(OCc4ccccc4)n3)CC1)C(=O)N2
Temperature: 120 °C
Reaction time: 8 h

Procedure:
991 mg (3.60 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 500 mg (1.22 mmol) 6-(2-benzyloxy-6-chloro-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one were combined in 10 mL NMP and stirred overnight at 120° C. The reaction mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and evaporated down.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]1[CH2:16][CH2:15][CH2:14][N:13]=1.[C:17]([Cl:20])(=[O:19])[CH3:18]>C(#N)C.C(OCC)C>[ClH:20].[CH3:3][C:4]1[CH:9]=[C:8]([NH:10][C:17](=[O:19])[CH3:18])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]1[CH2:16][CH2:15][CH2:14][N:13]=1
Reactant: Cc1cc(N)ccc1NC1=NCCC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCOCC
Solvent: CC#N
Product: CC(=O)Nc1ccc(NC2=NCCC2)c(C)c1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of 1.0 g (3.8 mmole) of the product compound of Example 9 and 30.5 mmole of acetyl chloride in 40 ml of acetonitrile was stirred at room temperature for 18 to 20 hours. The reaction mixture was then diluted eight-fold with diethyl ether. The resultant solid was collected and washed with three portions of ether, then dried in a high vacuum over 5A molecular sieves, giving the title compound as the hydrochloride salt. Structure assignment was supported by the nmr spectrum and by elemental analysis.