Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)(OCC)C)C.C([Li])CCC.[Cl:19][C:20]1[CH:34]=[CH:33][C:23]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[O:25])=[CH:22][CH:21]=1.Cl>CCOCC.CCCCCC>[Cl:19][C:20]1[CH:34]=[CH:33][C:23]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)([C:13]2[NH:12][CH:11]=[N:10][N:9]=2)[OH:25])=[CH:22][CH:21]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CCOC(C)(OCC)n1cncn1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1nnc[nH]1
Yield: 72 %

Procedure:
A solution of 9.25 g of 1-(1,1-diethoxyethyl)-1,2,4-triazole in 150 ml of ether was treated first with 38.5 ml of 1.3M n-butyllithium in hexane and then with 12.6 g of 4,4'-dichlorobenzophenone in the same manner as Exaample 1. The mixture was added to ice and hydrochloric acid producing a white suspension which was recovered by filtration. The solid was recrystallized from 600 ml of methanol/200 ml of water to provide 11.52 g of the desired title product, m.p. 233°-234° C.
Reaction SMILES: [Cl:1]Cl.[Cl:3][CH2:4][C:5]([F:11])([F:10])[C:6]([F:9])([F:8])[F:7]>>[Cl:3][CH:4]([Cl:1])[C:5]([F:11])([F:10])[C:6]([F:9])([F:8])[F:7]
Reactant: ClCl
Reactant: FC(F)(F)C(F)(F)CCl
Product: FC(F)(F)C(F)(F)C(Cl)Cl

Procedure:
These solvents are readily prepared from commercially available materials by standard and well-known organic syntheses techniques. For example, to prepare 1,1-dichloro-2,2,3,3,3-pentafluoropropane, 2,2,3,3,3-pentafluoro-1-propanol and p-toluenesulfonate chloride are reacted together to form 2,2,3,3,3-pentafluoropropyl-p-toluenesulfonate. Then, N-methylpyrrolidone, lithium chloride, and the 2,2,3,3,3-pentafluoropropyl-p-toluenesulfonate are reacted together to form 1-chloro-2,2,3,3,3-pentafluoropropane. Chlorine and the 1-chloro-2,2,3,3,3-pentafluoropropane are then reacted together to form 1,1-dichloro-2,2,3,3,3-pentafluoropropane.
Reaction SMILES: [N:1]1[C:14]2[N:8]3[C:9](=[O:13])[NH:10][CH:11]=[CH:12][C:7]3=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:17](Cl)[O:18][CH3:19]>CN(C=O)C>[CH3:17][O:18][CH2:19][N:10]1[CH:11]=[CH:12][C:7]2=[CH:6][C:5]3[CH:4]=[CH:3][CH:2]=[N:1][C:14]=3[N:8]2[C:9]1=[O:13]
Reactant: COCCl
Reactant: O=c1[nH]ccc2cc3cccnc3n12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCn1ccc2cc3cccnc3n2c1=O
Reaction time: 0.17 h
Yield: 83.2 %

Procedure:
To a cooled (0° C.) solution of 11a (250 mg, 1.4 mmol) in DMF (10 ml), NaH (65 mg, 1.6 mmol) was added. The mixture was stirred for 10 min. and MOMCl (103 μl, 1.4 mmol) was dropwise added. The mixture was stirred at 0° C. for 1 h and quenched with water (1 ml). The solvent was evaporated and the residue dissolved in CH2Cl2. The organic solution was washed with aq. Na2CO3, evaporated and purified by flash column chromatography. Elution with CH2Cl2/MeOH (95/5) gave 12 (267 mg, 87%) as a white solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]2[S:11][C:12](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[C:13](=[O:15])[N:14]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH:30][C@@H:31]([CH2:44][NH2:45])[CH2:32][O:33][C:34]1[C:42]2[NH:41][C:40](=[O:43])[NH:39][C:38]=2[CH:37]=[CH:36][CH:35]=1>>[OH:30][C@@H:31]([CH2:44][NH:45][CH:26]1[CH2:25][CH2:24][N:23]([C:20]2[CH:19]=[CH:18][C:17]([CH:16]=[C:12]3[S:11][C:10]([NH:9][CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[N:14][C:13]3=[O:15])=[CH:22][CH:21]=2)[CH2:28][CH2:27]1)[CH2:32][O:33][C:34]1[C:42]2[NH:41][C:40](=[O:43])[NH:39][C:38]=2[CH:37]=[CH:36][CH:35]=1
Reactant: O=C1CCN(c2ccc(C=C3SC(NCCN4CCOCC4)=NC3=O)cc2)CC1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Product: O=C1N=C(NCCN2CCOCC2)SC1=Cc1ccc(N2CCC(NC[C@H](O)COc3cccc4[nH]c(=O)[nH]c34)CC2)cc1

Procedure:
The title compound was prepared from 1-{4-[2-(2-morpholin-4-ylethylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-one (which was obtained in Intermediate 20) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (Jesudason, C. D., et al., EP 0 764 640) according to the procedure of Example 1 as a pale yellowish solid; mp>140° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ1.20-1.45 (m, 2 H), 1.75-2.00 (m, 2 H), 2.43 (t, J=4.7 Hz, 2 H), 2.50-3.70 (m, 13 H), 3.59 (t, J=4.7 Hz, 2 H), 3.75-4.15 (m, 5 H), 4.86 (brs, 1 H), 6.57 (d, J=7.5 Hz, 1 H), 6.62 (d, J=7.5 Hz, 1 H), 6.87 (t, J=8.1 Hz, 1 H), 7.02 (d, J=9.0 Hz, 2 H), 7.38 (d, J=9.0 Hz, 2 H), 7.47 (s, 1 H), 9.47 (s, 1 H), 10.57 (s, 1 H), 10.70 (brs, 1 H); MS (ES) m/z: 311.5 ((M+2H)2+, 100%); 621.9 (MH+, 15%); HRMS Calcd. for C31H40N7O5S (MH+): 622.2812. Found: 622.2811.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[OH-].[Na+].C(O)C>O>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][C:8]2[CH:18]=[CH:17][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1ccc(Cc2ccc(OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(Cc2ccc(C(=O)O)cc2)cc1

Procedure:
A mixture of 120 g. of ethyl 4-(4-methoxybenzyl)-benzoate, 500 ml. of 2 N sodium hydroxide solution and 250 ml. of ethanol was heated at reflux for two hours. The reaction mixture was cooled, diluted with water and extracted with ether. The aqueous layer was acidified with hydrochloric acid and the precipitate which formed was collected and dried to give 100 g. of 4-(4-methoxybenzyl)benzoic acid, m.p. 152°-153° C. when recrystallized from aqueous ethanol.
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=[O:7].[C:8]([O-:11])(=O)[CH3:9].[Na+].O>C(O)C>[CH2:6]([N:1]1[C:8]([OH:11])=[CH:9][C:4]([CH3:5])=[C:3]([C:2]#[N:1])[C:2]1=[O:7])[CH2:5][CH2:4][CH3:3]
Reactant: CC(=O)[O-]
Reactant: O=c1cccc[nH]1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCn1c(O)cc(C)c(C#N)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 239.9 %

Procedure:
To a mixture of 1.0 grams (4.85 mmol) of the pyridone and 6.6 grams (48.5 mmol, 10 eq) of sodium acetate in 50 mL of ethanol was added 1.27 grams (4.85 mmol, 1 eq) of 4-diazo-N,N'-diethylaniline tetrafluoroborate. The reaction mixture turned blue immediately upon addition of the diazo compound. The mixture was stirred at room temperature for two hours and 50 mL of water was added. The blue solid was collected and washed with water and dried. This material was recrystallized from approximately 200 mL of ethanol to give 1.2 grams (65% yield) of the desired product. This material decomposes at 180°-185° C. with effervescence.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][CH2:8][NH2:9])([O-:3])=[O:2].[C:13](Cl)(=[O:15])[CH3:14].O>N1C=CC=CC=1>[C:13]([NH:9][CH2:8][CH2:7][C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)Cl
Reactant: NCCc1cccc([N+](=O)[O-])c1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)NCCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
In pyridine (33 ml) was dissolved 5.559 g of 3-nitrophenethylamine (Preparation Example 25), followed by dropwise addition of acetyl chloride (2.5 ml) under ice-cooling. After stirring at room temperature for 0.5 hour, the mixture was again ice-cooled. Water was added thereto, followed by extracting with ethyl acetate, The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give the title compound (6.323 g, 91%) as a yellow oil.
Reaction SMILES: N1(O[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([C:23]2[NH:27][N:26]=[C:25]([NH:28][C:29]3[CH:30]=[N:31][C:32]([N:37]4[CH:41]=[C:40]([Cl:42])[N:39]=[CH:38]4)=[C:33]([O:35][CH3:36])[CH:34]=3)[N:24]=2)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CC(=O)CC>[Cl:42][C:40]1[N:39]=[CH:38][N:37]([C:32]2[N:31]=[CH:30][C:29]([NH:28][C:25]3[N:24]=[C:23]4[CH:15]([C:16]5[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=5)[CH2:14][CH2:13][CH2:12][CH2:11][N:27]4[N:26]=3)=[CH:34][C:33]=2[O:35][CH3:36])[CH:41]=1
Reactant: COc1cc(Nc2n[nH]c(C(CCCCOn3nnc4ccccc43)c3ccc(F)cc3)n2)cnc1-n1cnc(Cl)c1
Solvent: CCC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2nc3n(n2)CCCCC3c2ccc(F)cc2)cnc1-n1cnc(Cl)c1
Temperature: 180 °C
Yield: 5.7 %

Procedure:
A microwave vial was charged with N-(5-(5-(1H-benzo[d][1,2,3]triazol-1-yloxy)-1-(4-fluorophenyl)pentyl)-1H-1,2,4-triazol-3-yl)-6-(4-chloro-1H-imidazol-1-yl)-5-methoxypyridin-3-amine (300 mg, 0.509 mmol), DIEA (0.089 mL, 0.509 mmol), and 2-butanone (5 mL). The mixture was heated in a microwave at 180° C. for 4 h. The reaction mixture was concentrated in vacuo. The crude product was purified using silica gel column chromatography (10-80% EtOAc/chloroform, linear gradient) to afford N-(6-(4-chloro-1H-imidazol-1-yl)-5-methoxypyridin-3-yl)-9-(4-fluorophenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine (13 mg, 0.029 mmol, 6% yield) as white solid. LC-MS (M+H)+ 454.2. 1H NMR (500 MHz, chloroform-d) δ ppm 8.13 (d, J=1.53 Hz, 1 H) 8.03 (d, J=2.44 Hz, 1 H) 7.82 (d, J=2.44 Hz, 1 H) 7.58 (d, J=1.83 Hz, 1 H) 7.13-7.21 (m, 2H) 7.06 (t, J=8.70 Hz, 2H) 6.77 (s, 1 H) 4.16-4.34 (m, 3 H) 3.88 (s, 3 H) 1.78-2.28 (m, 6 H).
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[CH3:14][Mg]Br.[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[Cl:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]([OH:7])[CH3:14])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COc1cc(C=O)cc(OC)c1Cl
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(C(C)O)cc(OC)c1Cl
Reaction time: 1 h

Procedure:
To a solution of 4-chloro-3,5-dimethoxybenzaldehyde (1.0 g) in tetrahydrofuran (20 mL) was added dropwise a 3M solution of methylmagnesium bromide in diethyl ether (1.83 mL) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. Then, thereto was added aqueous ammonium chloride solution under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated saline, and then dried over magnesium sulfate and concentrated under reduced pressure to give a crude product of 1-(4-chloro-3,5-dimethoxyphenyl)ethanol [REx(22-2)] (1.23 g) as a colorless powder.
Reaction SMILES: [OH:1][C@H:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4].C(N(CC)CC)C.[CH2:15]=[C:16]1[O:20][C:18](=[O:19])[CH2:17]1>C1(C)C=CC=CC=1>[O:20]=[C:16]([CH3:15])[CH2:17][C:18]([O:1][C@H:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4])=[O:19]
Reactant: C=C1CC(=O)O1
Reactant: COC(=O)[C@@H](C)O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](C)OC(=O)CC(C)=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Methyl (2R)-2-hydroxypropanoate (5.0 g, 48 mmol) and triethylamine (49 mg, 0.48 mmol) are dissolved in toluene (40 ml). At 90° C., diketene (5.2 g, 62.4 mmol) is added dropwise. The reaction mixture is stirred at 100° C. for one hour. After cooling to room temperature, the mixture is poured into ice-water. The phases are separated and the aqueous phase is extracted with toluene two times. The combined organic phases are dried over sodium sulfate, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane/ethyl acetate mixtures as eluent.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([NH:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=2)[N:9]=[N:8][C:7]=1[C:22]([NH:24][CH:25]1[CH2:27][CH2:26]1)=[O:23])#[N:2].[Cl-].[OH:29][NH3+:30].C(=O)([O-])O.[Na+]>CS(C)=O.[Cl-].[Na+].O>[NH2:2]/[C:1](=[N:30]\[OH:29])/[CH2:3][CH2:4][CH2:5][C:6]1[N:10]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([NH:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:16]=2)[N:9]=[N:8][C:7]=1[C:22]([NH:24][CH:25]1[CH2:26][CH2:27]1)=[O:23]
Reactant: [NH3+]O
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCC#N)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCC/C(N)=N/O)cc1
Yield: 78.9 %

Procedure:
A solution of 5-(3-cyanopropyl)-N-cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxamide (366 mg, 1.0 mmol) obtained in Example 1207, hydroxyammonium chloride (139 mg, 2.0 mmol, 2.0 eq.) and sodium hydrogen carbonate (168 mg, 2.0 mmol, 2.0 eq.) in DMSO (5 ml) was stirred at 90° C. for 5 hr. Saturated brine (10 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 ml×3), and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column (hexane/ethyl acetate=1/1 to ethyl acetate/methanol=4/1) to give the title compound as a colorless powder (315 mg, 79%).
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH3:2].[Br:13][CH2:14][CH2:15][CH2:16]Br.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[Br:13][CH2:14][CH2:15][CH2:16][O:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[N:3]([CH2:1][CH3:2])[CH2:11][CH3:12]
Reactant: BrCCCBr
Reactant: CCN(CC)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCN(CC)c1cccc(OCCCBr)c1
Reaction time: 24 h
Yield: 17.4 %

Procedure:
To a solution of 3-(diethylamino)phenol (0.0104 g, 0.631 mmol) in acetonitrile (4 mL) was added 1,3-dibromopropane (0.640 mL, 6.30 mmol) followed by Cs2CO3 (0.313 g, 0.961 mmol). The reaction mixture was stirred for 24 h and then concentrated under vacuum. The resulting residue was treated with H2O (4 mL) and extracted with DCM (8 mL). The organic layer was dried through a phase separator and concentrated under vacuum. The residue was taken up in DMSO and purified by preparatory HPLC (without TFA) to give the title compound (0.0314 g, 17.4%). EI-MS m/z 286(M+H+) Rt (1.59 min).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)[C:3]=1[C:4]#[N:5].CN(C)C(=O)C.[CH3:27][NH:28][NH2:29]>O>[CH3:27][N:28]1[C:2]2[C:3](=[C:6]([O:10][C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=3)[CH:7]=[CH:8][CH:9]=2)[C:4]([NH2:5])=[N:29]1
Reactant: N#Cc1c(F)cccc1Oc1ccc2ccccc2c1
Reactant: CNN
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cn1nc(N)c2c(Oc3ccc4ccccc4c3)cccc21
Temperature: 130 °C
Yield: 97 %

Procedure:
To a 20 mL vial containing 2-fluoro-6-(naphthalen-2-yloxy)-benzonitrile (966 mg, 3.67 mmol) and a magnetic stir bar was added anhydrous N,N-dimethylacetamide and the mixture was stirred until solution was achieved. Methyl hydrazine (390 uL, 7.34 mmol) was added, the vial was capped, the reaction mixture was placed in an oil bath at 120° C. and stirred at that temperature overnight. The reaction mixture was heated at 130° C. for an additional 3 h. The cooled reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×30 mL). The combined organics were washed with water (3×15 mL), dried (Na2SO4), filtered and concentrated to give 1.03 g of a tan solid. This residue was purified via flash chromatography on silica gel (120 g) utilizing CH2Cl2 and then 9:1 CH2Cl2/EtOAc as eluent to give 770 mg of I-190 an off-white solid. This material was deemed of sufficient purity to be utilized in subsequent reactions. 1H NMR, MS.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][C@@H:14]3[CH2:18][S:17](=[O:20])(=[O:19])[CH2:16][C@H:15]3[NH2:21])[CH2:8]2)=[CH:4][CH:3]=1.[ClH:24].[N+](C1C=CC([O:34][C:35](=O)[NH:36][CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=CC=1)([O-])=O.C(N(CC)CC)C>CN(C)C=O>[ClH:24].[ClH:24].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][C@@H:14]3[CH2:18][S:17](=[O:19])(=[O:20])[CH2:16][C@H:15]3[NH:21][C:35]([NH:36][CH2:37][CH2:38][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[O:34])[CH2:8]2)=[CH:22][CH:23]=1
Reactant: O=C(NCCN1CCOCC1)Oc1ccc([N+](=O)[O-])cc1
Reactant: N[C@@H]1CS(=O)(=O)C[C@H]1CN1CCC[C@@H](Cc2ccc(F)cc2)C1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCCN1CCOCC1)N[C@@H]1CS(=O)(=O)C[C@H]1CN1CCC[C@@H](Cc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 67 h
Yield: 149.9 %

Procedure:
(3S,4S)-4-[(S)-3-(4-fluorobenzyl)-piperidin-1-ylmethyl]-1,1-dioxo-tetrahydrothiophen-3-ylamine (47 mg, 137 μmol) and (2-morpholin-4-yl-ethyl)-carbamic acid 4-nitro-phenyl ester hydrochloride (55 mg, 164 μmol) were dissolved in N,N-dimethylformamide (1 mL) and treated with triethylamine (23 μL, 164 μmol). The mixture was stirred at room temperature for 67 h, and then concentrated. The residue was purified by flash column chromatography (3% methanol/dichloromethane containing 0.3% aqueous ammonium hydroxide). After isolation, the product was dissolved in 1N hydrochloric acid and water and lyophilized to provide a fluffy white solid (70 mg, 90%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:23][CH2:22][C:11]2[N:12]=[CH:13][N:14]=[C:15]([O:16][C@H:17]3[CH2:21][CH2:20][NH:19][CH2:18]3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:24]1[CH2:29][CH2:28][CH:27]([C:30](Cl)=[O:31])[CH2:26][CH2:25]1.CCN(CC)CC>C(Cl)Cl>[CH2:1]([N:8]1[CH2:23][CH2:22][C:11]2[N:12]=[CH:13][N:14]=[C:15]([O:16][C@H:17]3[CH2:21][CH2:20][N:19]([C:30]([CH:27]4[CH2:28][CH2:29][O:24][CH2:25][CH2:26]4)=[O:31])[CH2:18]3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CN2CCc3ncnc(O[C@H]4CCNC4)c3C2)cc1
Reactant: O=C(Cl)C1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C1CCOCC1)N1CC[C@H](Oc2ncnc3c2CN(Cc2ccccc2)CC3)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
To a solution of 6-benzyl-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (420 mg, 1.35 mmol) in 4 mL of CH2Cl2 was added tetrahydro-pyran-4-carbonyl chloride (0.210 mL, 1.637 mmol) and Et3N (0.380 mL, 2.73 mmol). The reaction mixture was stirred at room temperature for 30 min then was quenched with H2O, extracted with CH2Cl2, filtered and evaporated under vacuum. Purification by flash-chromatography on silica gel (CH2Cl2/MeOH 95/5) gave [(S)-3-(6-benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidin-1-yl]-(tetrahydro-pyran-4-yl)-methanone (420 mg, 73% yield) as a yellow foam. 1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 1.37-1.64 (m, 4H) 1.95-2.29 (m, 2H) 2.56-2.83 (m, 4H) 3.28-3.91 (m, 13H) 5.54-5.68 (m, 1H) 7.24-7.36 (m, 5H) 8.54-8.59 (m, 1H). LCMS: [M+H]+=423.6, Rt(7)=0.68.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:11][CH2:12][CH2:13][CH3:14])=[C:8]([OH:10])[CH:9]=1.C(N(CC)CC)C.CO[CH:24]=[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([N:35]3[CH:39]=[CH:38][CH:37]=[CH:36]3)[CH:33]=2)[C:28](=[O:40])[NH:27][C:26]1=[O:41]>CN(C)C=O>[OH:10][C:8]1[CH:9]=[C:4]([CH:5]=[CH:6][C:7]=1[O:11][CH2:12][CH2:13][CH3:14])[CH2:3][NH:2][CH:24]=[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([N:35]3[CH:39]=[CH:38][CH:37]=[CH:36]3)[CH:33]=2)[C:28](=[O:40])[NH:27][C:26]1=[O:41]
Reactant: CCCOc1ccc(CN)cc1O
Reactant: COC=C1C(=O)NC(=O)c2ccc(-n3cccc3)cc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCOc1ccc(CNC=C2C(=O)NC(=O)c3ccc(-n4cccc4)cc32)cc1O
Reaction time: 0.25 h

Procedure:
A mixture of 5-aminomethyl-2-propoxy-phenol hydrochloride (109 mg, 0.50 mmole), 4 mL of N,N-dimethylformamide and triethylamine (75 μL, 0.54 mmole) is stirred for 15 minutes. Then (4-methoxymethylene-6-pyrrol-1-yl-4H-isoquinoline-1,3-dione (134 mg, 0.50 mmole) is added and the reaction mixture stirred for one hour. The reaction mixture is evaporated to dryness, taken up in 5% methanol in chloroform and passed through a short pad of Florisil eluting with 5% methanol in chloroform. The eluate is evaporated in vacuo and treated with acetonitrile, filtered and dried to give a beige solid, 94 mg, (45%), mp 215-216° C. dec; MS (ES+): m/z 418.2 (M+H).
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([OH:12])[CH2:8][CH2:7]1)=O)C.O.[NH2:14][NH2:15]>>[OH:12][C@H:9]1[CH2:10][CH2:11][C@H:6]([C:4]([NH:14][NH2:15])=[O:3])[CH2:7][CH2:8]1
Reactant: NN
Reactant: CCOC(=O)[C@H]1CC[C@H](O)CC1
Solvent: O
Product: NNC(=O)[C@H]1CC[C@H](O)CC1

Procedure:
A mixture of cis/trans-4-hydroxycyclohexane carboxylic acid ethyl ester (5.0 g, 29 mmol) and hydrazine hydrate (1.4 g, 29 mmol) was heated at reflux for 24 h. Residual water was removed by azeotropic distillation with toluene. The residue was triturated from tert-butyl methyl ether. The precipitate was collected by filtration and dried in vacuo to give the title compound as white solid in 91% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]#[N:11].[NH2:12][C:13]1[C:18]([CH:19]=O)=[CH:17][N:16]=[C:15]([CH3:21])[N:14]=1>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:10]([NH2:11])=[N:12][C:13]2[N:14]=[C:15]([CH3:21])[N:16]=[CH:17][C:18]=2[CH:19]=1
Reactant: N#CCc1c(Cl)cccc1Br
Reactant: Cc1ncc(C=O)c(N)n1
Product: Cc1ncc2cc(-c3c(Cl)cccc3Br)c(N)nc2n1

Procedure:
Following the procedure for Example 1, 2-bromo-6-chlorophenylacetonitrile is condensed with 4-amino-2-methylpyrimidin-5-carboxaldehyde to give 6-(2-bromo-6-chlorophenyl)-2-methylpyrido[2,3-d]-pyrimidin-7-amine, mp 272°-274° C., after recrystallization from acetonitrile.
Reaction SMILES: [C:1]([C:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28]Br)=[CH:24][CH:23]=1.O>CN(C=O)C>[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13](=[O:14])[C:4]([C:1](=[O:3])[CH3:2])=[CH:5]2)=[CH:24][CH:23]=1
Reactant: CC(=O)c1c[nH]c2ccccc2c1=O
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1cn(Cc2ccc(F)cc2)c2ccccc2c1=O
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 22.4 %

Procedure:
A solution of 3-acetyl-4(1H)-quinolinone (1a) (0.8 g, 45 mmol) in dry DMF (40 mL) was treated with anhydrous K2CO3 (0.86 g, 62 mmol) and 4-fluorophenylmethylbromide (2.46 g, 13 mmol) and the resulting suspension was stirred for 1.5 hours at 100° C. After cooling, water was added (100 mL) and the precipitate that formed was filtered, washed with water, light petroleum ether in turn and then dried under IR lamp to provided compound 2a (0.86 g, 65%); mp 213-214° C. (toluene). Analogs 2b (R1═C1, R2═H) and 2c (R1═H, R2═Cl) were similarly prepared by this method. Compound 2b: 92% yield; mp 214-216° C. (toluene/cyclohexane); compound 2c: 73% yield; mp 185-187° C. (toluene/cyclohexane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:19])[C:15]=1[C:16](O)=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=2.S(Cl)(C)(=O)=O.[CH2:32]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:26][O:25][C:21]1[CH:20]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:22]=1[O:23][CH3:24])[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:19])[C:15]=1[C:16]([N:42]1[CH2:43][CH2:44][N:39]([CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:40][CH2:41]1)=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: COc1cc(-c2oc3ccccc3c(=O)c2C(=O)O)cc(OC)c1OC
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COc1cc(-c2oc3ccccc3c(=O)c2C(=O)N2CCN(Cc3ccccc3)CC2)cc(OC)c1OC

Procedure:
Under the conditions given in Example 1 (a), 6 g of 3',4',5'-trimethoxy-flavone-3-carboxylic acid with 4.1.g 4-dimethylaminopyridine and 1 6 ml mesylchloride in absolute dichloromethane were converted into the mixed anhydride. This was reacted with 3.3 ml 1-benzylpiperazine analogously to Example 1 (b). The reaction mixture was worked up analogously to Example 1 (b). 7.0 g of pure 3',4',5'-trimethoxy-3-[(4-benzylpiperazin-1-yl)-carbonyl] flavone were obtained