Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH2:7][C:8](=[O:10])[CH3:9])[O:6][CH2:5][CH2:4][O:3]1.[C:11](OCC)(=O)[C:12](OCC)=[O:13].[O-]CC.[Na+].[Na].Cl>C(O)C.O>[CH3:1][C:2]1[O:6][C:5]([C:4]([O:13][CH2:12][CH3:11])=[O:3])=[CH:9][C:8](=[O:10])[CH:7]=1
Reactant: CC(=O)CC1(C)OCCO1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(=O)cc(C)o1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 2-methyl-2-(2-oxopropyl)-1,3-dioxolane (49 g) and diethyl oxalate (55 ml) in ethanol (50 ml) was added over 30 minutes to a stirred, cooled, solution of sodium ethoxide prepared by dissolving sodium (9.4 g) in ethanol (150 ml). The solution was stirred for 5 hours at room temperature and then acidified with 5M hydrochloric acid (200 ml) and then stirred for a further hour. The mixture was diluted with water (800 ml) and extracted with ethyl acetate, the extract was dried and evaporated and the residue was distilled under vacuum (bp 110°-120° C./0.2 mm). The distillate (53.8 g) was crystallised from ether-petroleum ether 40°-60° C. to give ethyl 6-methyl-4-oxo-4H-pyran-2-carboxylate (mp 35°-38° C.).
Reaction SMILES: O(Cl)[Cl:2].[P+3].[Cl:5][C:6]1[C:15]2[N:16]=[C:17]([OH:23])[N:18]([CH2:19][CH2:20][CH2:21]O)[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1.O>CN(C=O)C>[Cl:5][C:6]1[C:15]2[N:16]=[C:17]([OH:23])[N:18]([CH2:19][CH2:20][CH2:21][Cl:2])[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: OCCCn1c(O)nc2c(Cl)nc3ccccc3c21
Reactant: ClOCl
Agent: [P+3]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1nc2c(Cl)nc3ccccc3c2n1CCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
Phosphorus(III) oxychloride (7.9 g, 52 mmol) was added dropwise to a stirred solution of 4-chloro-1-(3-hydroxypropyl)-1H-imidazo[4,5-c]quinolin-2-ol (12 g, 43 mmol) in DMF (150 mL), and the reaction was stirred overnight at room temperature. An analysis by LC/MS indicated the presence of starting material, and additional phosphorus(III) oxychloride (7.9 g) was added. The reaction was stirred overnight at room temperature and then cooled to approximately 0° C. Water (300 mL) was slowly added, and a precipitate formed. The mixture was stirred for several minutes, and the precipitate was isolated by filtration, washed with water and diethyl ether, and dried in a vacuum oven to provide 8.2 g of 4-chloro-1-(3-chloropropyl)-1H-imidazo[4,5-c]quinolin-2-ol.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.CC1C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]2)=[CH:16][CH:15]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)N1CCC(=Nc2ccc(Cl)cc2)CC1

Procedure:
A mixture of 171.2 parts of ethyl 4-oxo-1-piperidinecarboxylate, 159.5 parts of 4-chlorobenzenamine, 1520 parts of anhydrous methylbenzene and a few crystals of 4-methylbenzenesulfonic acid is stirred and refluxed for 7 hours. (The reaction vessel is provided with a reflux-condensor and water-separator). The methylbenzene is evaporated and the oily residue is distilled in vacuo, yielding 192 parts of oily ethyl 4-[(4-chlorophenyl)imino]-1-piperidinecarboxylate; bp. 171°-176° C. at 0.4 mm. pressure.
Reaction SMILES: O[CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[N:7]2)[CH3:3].P(Br)(Br)[Br:15]>CCOCC>[Br:15][CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[N:7]2)[CH3:3]
Reactant: CC(O)c1ccc2nccnc2c1
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: CC(Br)c1ccc2nccnc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.7 %

Procedure:
To a solution of 6-(1-hydroxyethyl)quinoxaline (0.4 g, 0.23 mMol) in ether (4 mL) and hexanes (2 mL) at zero degrees was added phosphorus tribromide (0.196 mL, 2.07 mMol) and the mixture stirred at zero degrees for one hour and then allowed to warm to room temperature. After two hours at room temperature the reaction mixture was poured over ice and then partitioned between ethyl acetate (100 mL) and water (100 mL). The aqueous layer was discarded and the organics washed with saturated sodium bicarbonate, then dried (MgSO4), and concentrated to dryness to yield 20 mg (37% yield) of 6-(1-bromo-ethyl)-quinoxaline as a light yellow oil. 1H NMR (CDCl3): δ=8.79 (m, 2H), 8.06 (d, 1H, J=9.0 Hz), 8.04 (d, 1H, J=2.2 Hz), 7.85 (dd, 1H, J=9.0, 2.2 Hz), 5.34 (q, 1H, J=6.9 Hz), 2.10 (d, 3H, J=6.9 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][C:14](=[S:26])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=2)[CH:5]=[C:6]([Cl:12])[C:7]=1[O:8][CH2:9][CH2:10][OH:11].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1.O1CCCC1.C(OCC)(=O)C>[C:23]([NH:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:14](=[S:26])[NH:13][C:4]2[CH:3]=[C:2]([Cl:1])[C:7]([O:8][CH2:9][CH2:10][O:11][S:28]([CH3:27])(=[O:30])=[O:29])=[C:6]([Cl:12])[CH:5]=2)=[CH:17][CH:18]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)Nc1ccc(NC(=S)Nc2cc(Cl)c(OCCO)c(Cl)c2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(NC(=S)Nc2cc(Cl)c(OCCOS(C)(=O)=O)c(Cl)c2)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To an ice cooled solution of N-(4-{3-[3,5-dichloro-4-(2-hydroxy-ethoxy)-phenyl]-thioureido}-phenyl)-acetamide (0.20 g) in pyridine (2 mL) and tetrahydrofuran (0.5 mL) is added methanesulfonyl chloride (0.11 g) and the solution is stirred at 0° C. for 45 minutes. The reaction mixture is then diluted with ethyl acetate, washed successively twice with 2% aqueous hydrochloric acid, once with saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After removing the solvents by evaporation under reduced pressure the resulting residue is recrystallized from acetone-hexanes to give the desired product as a white powder.
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[N:11]([CH2:13][CH2:14][CH2:15][N:16]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH2:20][CH2:19][C:18]2[CH:27]=[CH:28][CH:29]=[CH:30][C:17]1=2)[CH3:12])C.CO.[OH-].[Na+].Cl>O.O1CCCC1>[CH:27]1[C:18]2[CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:16]([CH2:15][CH2:14][CH2:13][N:11]([C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:4]([OH:31])=[O:3])[CH3:12])[C:17]=2[CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1cccnc1N(C)CCCN1c2ccccc2CCc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN(CCCN1c2ccccc2CCc2ccccc21)c1ncccc1C(=O)O
Temperature: 65 °C
Reaction time: 9 h
Yield: 23.6 %

Procedure:
A mixture of the above crude ester (6.60 g), methanol (50 ml), tetrahydrofuran (30 ml) and 4N sodium hydroxide (10 ml) was stirred at room temperature for 24 h, at 65° C. for 9 h and then at room temperature for 48 h. Water (100 ml) and concentrated hydrochloric acid (10 ml) were added and the product was extracted with dichloromethane (3×20 ml). The combined organic extracts were washed with brine (100 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (100 g) using a gradient of heptane and ethyl acetate (1:1→0:1). This afforded 1.93 g (50%) of the title compound as an oil, which crystallised after standing 1 day at room temperature. The product was recrystallised from a mixture of ethyl acetate and heptane to give 1.45 g of the title compound.
Reaction SMILES: CC(C)[C@H](N1CC2C(=CC(C3C=CC(NS(C4C=CC=CC=4)(=O)=O)=CC=3)=CC=2)C1=O)C(O)=O.[CH3:34][CH:35]([CH3:68])[C@H:36]([N:41]1[CH2:49][C:48]2[C:43](=[CH:44][C:45]([C:50]3[CH:55]=[CH:54][C:53]([NH:56][S:57]([CH2:60][C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=4)(=[O:59])=[O:58])=[CH:52][CH:51]=3)=[CH:46][CH:47]=2)[C:42]1=[O:67])[C:37]([O:39]C)=[O:38]>>[CH3:34][CH:35]([CH3:68])[C@H:36]([N:41]1[CH2:49][C:48]2[C:43](=[CH:44][C:45]([C:50]3[CH:51]=[CH:52][C:53]([NH:56][S:57]([CH2:60][C:61]4[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=4)(=[O:59])=[O:58])=[CH:54][CH:55]=3)=[CH:46][CH:47]=2)[C:42]1=[O:67])[C:37]([OH:39])=[O:38]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NS(=O)(=O)Cc4ccccc4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NS(=O)(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NS(=O)(=O)Cc4ccccc4)cc3)cc2C1=O
Yield: 96 %

Procedure:
The compound of example 94 was prepared analogous to compound of example 78 by hydrolysis of compound of example 93.
Reaction SMILES: [CH:1]1([CH:4]([O:7][C:8]2[C:9](Cl)=[N:10][C:11]([Cl:20])=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:5][OH:6])[CH2:3][CH2:2]1.[H-].[Na+]>C1COCC1>[Cl:20][C:11]1[N:12]=[C:13]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:8]2[O:7][CH:4]([CH:1]3[CH2:3][CH2:2]3)[CH2:5][O:6][C:9]=2[N:10]=1
Reactant: OCC(Oc1c(Cl)nc(Cl)nc1N1CCOCC1)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1nc2c(c(N3CCOCC3)n1)OC(C1CC1)CO2
Reaction time: 2 h

Procedure:
To a solution of 2-cyclopropyl-2-(2,4-dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-ethanol (215 mg, 0.64 mmol) in THF (10 mL) was added sodium hydride (71 mg, 1.93 mmol, 65% dispersion in mineral oil) and the reaction stirred for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride solution (15 mL) and water (5 mL) then extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with brine (15 mL), dried (Na2SO4) then concentrated in vacuo to give 2-Chloro-6-cyclopropyl-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine as a white solid (191 mg, quantitative). LCMS: RT=3.18 min, [M+H]+=298/300.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][C@@H:5]2[CH:7]=[CH:8][C@@H:9]([N:10]3[C:18]4[C:17]([F:19])=[CH:16][N:15]=[C:14](F)[C:13]=4[N:12]=[CH:11]3)[C@@H:4]2[O:3]1.CC1(C)O[C@@H]2C=C[C@@H]([N:31]3C4C(F)=NC=C(F)C=4N=C3)[C@@H]2O1>N>[CH3:1][C:2]1([CH3:21])[O:6][C@@H:5]2[CH:7]=[CH:8][C@@H:9]([N:10]3[C:18]4[C:17]([F:19])=[CH:16][N:15]=[C:14]([NH2:31])[C:13]=4[N:12]=[CH:11]3)[C@@H:4]2[O:3]1
Reactant: CC1(C)O[C@H]2[C@H](n3cnc4c(F)ncc(F)c43)C=C[C@H]2O1
Reactant: CC1(C)O[C@H]2[C@H](n3cnc4c(F)cnc(F)c43)C=C[C@H]2O1
Agent: N
Product: CC1(C)O[C@H]2[C@H](n3cnc4c(N)ncc(F)c43)C=C[C@H]2O1
Temperature: 85 °C

Procedure:
Liquid ammonia (30 mL) was added to a mixture of 1-[(3aS,4R,6aR)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-4,7-difluoro-1H-imidazo[4,5-c]pyridine (2-2) (160 mg, 0.55 mmol, 1 equiv) and 3-[(3aS,4R,6aR)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-4,7-difluoro-3H-imidazo[4,5-c]pyridine (2-1) (160 mg, 0.55 mmol, 1 equiv). The resulting solution was heated in a high pressure vessel to 85° C. for 4 days. The mixture was then concentrated and purified via flash chromatography on a 40 g silica gel column (gradient elution 0 to 100% ethyl acetate in dichloromethane and then 100% methanol to elute 2-3) to yield 1-[(3aS,4R,6aR)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-7-fluoro-1H-imidazo[4,5-c]pyridin-4-amine (2-3) as a light yellow solid in addition to 3-[(3aS,4R,6aR)-2,2-dimethyl-4,6a-dihydro-3 aH-cyclopenta[d][1,3]dioxol-4-yl]-7-fluoro-3H-imidazo[4,5-c]pyridin-4-amine (2-4) and recovered starting material 2-2. 1H NMR (2-3) (500 MHz, CDCl3): δ 7.76 (d, J=3.0 Hz, 1H); 7.63 (s, 1H); 6.36 (d, J=5.7 Hz, 1H); 6.03 (d, J=5.7 Hz, 1H); 5.68 (s, 1H); 5.42 (d, J=5.6 Hz, 1H); 5.03 (s, 2H); 4.68 (d, J=5.7 Hz, 1H); 1.50 (t, J=9.7 Hz, 3H); 1.42-1.33 (m, 3H). LRMS m/z (M+H) 291.0 found, 291.1 required. 1H NMR (2-4) (500 MHz, CDCl3): δ 7.77 (d, J=2.3 Hz, 1H); 7.73 (s, 1H); 6.47-6.43 (m, 1H); 6.17-6.14 (m, 1H); 5.87 (s, 1H); 5.41 (d, J=6.0 Hz, 1H); 5.00 (s, 2H); 4.69 (d, J=6.1 Hz, 1H); 1.55 (s, 3H); 1.38 (s, 3H). LRMS m/z (M+H) 291.0 found, 291.1 required.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:15]([NH2:17])[CH3:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:18]([O:20]C=O)C>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:15]([NH:17][CH:18]=[O:20])[CH3:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC=O
Reactant: CC(N)C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Product: CC(NC=O)C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Reaction time: 24 h
Yield: 93 %

Procedure:
50 g (184.4 mmol) of 1-[1-(3,4-Dichloro-phenyl)-cyclohexyl]-ethylamine was dissolved in 1 L of ethylformate and left to stir under an N2 atmosphere for 24 h before removing all volatiles under reduced pressure. The resulting solid was filtered through a plug of SiO2 (using CH2Cl2/MeOH (20:1) as the eluent) to afford 51.32 g (93%) of the title compound after the removal of all volatiles. This material was used in the subsequent step without further purification.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]4[N:18]5[CH:19]=[C:20]([C:23]6[CH:28]=[CH:27][C:26]([C:29]7([C:32]([OH:34])=O)[CH2:31][CH2:30]7)=[CH:25][CH:24]=6)[CH:21]=[N:22][C:17]5=[N:16][CH:15]=4)[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:35]([NH2:37])[CH3:36].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:35]([NH:37][C:32]([C:29]1([C:26]2[CH:25]=[CH:24][C:23]([C:20]3[CH:21]=[N:22][C:17]4[N:18]([C:14]([C:11]5([C:7]6[CH:6]=[C:5]7[C:10](=[CH:9][CH:8]=6)[N:1]=[CH:2][CH:3]=[CH:4]7)[CH2:13][CH2:12]5)=[CH:15][N:16]=4)[CH:19]=3)=[CH:28][CH:27]=2)[CH2:31][CH2:30]1)=[O:34])[CH3:36]
Reactant: O=C(O)C1(c2ccc(-c3cnc4ncc(C5(c6ccc7ncccc7c6)CC5)n4c3)cc2)CC1
Reactant: CCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)C1(c2ccc(-c3cnc4ncc(C5(c6ccc7ncccc7c6)CC5)n4c3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-{4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl}cyclopropanecarboxylic acid (20 mg, 0.045 mmol), ethylamine (2.4 mg, 0.054 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (24 mg, 0.054 mmol), and N,N-diisopropylethylamine (23 μL, 0.13 mmol) in N,N-dimethylformamide (0.5 mL) was stirred at RT for 2 h. The reaction mixture was purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=474.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[S:26]
Reactant: O=C(Nc1ccccc1F)c1ccccn1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Fc1ccccc1NC(=S)c1ccccn1
Yield: 56.8 %

Procedure:
N-(2-fluorophenyl)-2-pyridinecarboxamide (11.81 g, 55 mmol) was reacted with Lawesson's reagent (26.04 g, 64 mmol) in toluene (160 mL) at reflux temperature for 5 hours. The solution was preadsorbed onto silica gel and flash chromatographed (eluted with 2.5% ethyl acetate in petroleum ether) to give N-(2-fluorophenyl)-2-pyridinecarbothioamide as a yellow solid (7.26 g, 39%) m.p. 94°-97° C.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=O)[CH:2]([CH3:4])[CH3:3].C(O)(=O)C.[C:16]([O:20][CH3:21])(=[O:19])[NH:17][NH2:18]>CO>[CH3:21][O:20][C:16](=[O:19])[NH:17][N:18]=[C:1]([CH:2]([CH3:4])[CH3:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)NN
Reactant: CC(C)C(=O)c1ccccc1
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)NN=C(c1ccccc1)C(C)C

Procedure:
To a solution of 44.46 g (0.3 moles) of isobutyrophenone in 200 ml of methanol 3 ml of acetic acid and 27 g of methyl carbazate are added. The reaction mixture is boiled in a flask equipped with a reflux condenser, then clarified and evaporated in vacuo to half of its original volume. The residue is cooled and the separated tallow-like product is filtered off. Yield: 64.2 g (97.3%) M.p.: 78°-80° C. The product can be recrystallized from petrol.
Reaction SMILES: Cl[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:3]1.C([O-])(=O)C.[Na+].[H][H]>[Pd].C(O)(=O)C>[C:4]1([C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2][O:3]1)=[O:5]
Reactant: [H][H]
Reactant: O=C1OC(Cl)c2ccccc21
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1OCc2ccccc21
Yield: 87.4 %

Procedure:
As described in Example 1, an autoclave is charged with 110 g of 3-chlorophthalide, 5 g of palladium-on-charcoal catalyst (metal content 5%), 54 g of sodium acetate and 400 ml of glacial acetic acid, and treated for 1.5 h with hydrogen at 5 to 10 bars of pressure and 20° to 35° C. After filtration and working up by distillation, 76.5 g of phthalide is obtained, melting point 72°-73° C. (gas-chromatographic analysis 99.35).
Reaction SMILES: [CH:1](=[O:5])[CH2:2][CH2:3]C.[N+:6](/[CH:9]=[CH:10]/[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)([O-:8])=[O:7].CC(O)C.CCCCCC>C(Cl)(Cl)Cl>[CH3:3][C@@H:2]([C@H:10]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH2:9][N+:6]([O-:8])=[O:7])[CH:1]=[O:5]
Reactant: O=[N+]([O-])/C=C/c1cccc2ccccc12
Reactant: CCCC=O
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: C[C@H](C=O)[C@@H](C[N+](=O)[O-])c1cccc2ccccc12

Procedure:
The title compound was prepared from butyraldehyde and (E)-1-(2-nitrovinyl)naphthalene according to the general procedure. Both enantiomeric excess and diastereomeric ratio were determined by HPLC with an AD-H column at 220 nm (2-propanol:hexane=0.8:99.2), 1.0 mL/min; major enantiomer tmajor=43.3 min, minor enantiomer tminor=37.6 min. [α]D20=−21.1 (c=2.4, CHCl3).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[CH:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)[CH3:9].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:50][CH2:51][C:52]1[C:53]([OH:60])=[N:54][C:55]([CH3:59])=[CH:56][C:57]=1[CH3:58]>ClCCl>[OH:60][C:53]1[C:52]([CH2:51][NH:50][C:14](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([CH:8]([N:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]3=[O:1])[CH3:9])=[CH:18][CH:17]=2)=[C:57]([CH3:58])[CH:56]=[C:55]([CH3:59])[N:54]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC(c1ccc(C(=O)O)cc1)n1ccccc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)n3ccccc3=O)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 32.8 %

Procedure:
To a solution of 4-(1-(2-oxopyridin-1(2H)-yl)ethyl)benzoic acid (111 mg, 0.46 mmol) in dichloromethane (20 mL) were added o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (285 mg, 0.75 mmol) and triethylamine (151 mg, 1.5 mmol). Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (76 mg, 0.5 mmol) was added. The mixture was stirred at room temperature for 12 hours. The resultant mixture was washed with water (20 mL×3) and the organic layer was concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-(2-oxopyridin-1(2H)-yl)ethyl)benzamide (57 mg, 33%). LRMS (M+H+) m/z: calcd 377.17. found 377. HPLC purity (214 nm): 98%. 1H NMR (300 MHz, d6-DMSO): δ 11.46 (s, 1H), 8.35-8.33 (m, 1H), 7.80 (d, J=8.1 Hz, 2H), 7.60-7.57 (m, 1H), 7.33-7.30 (m, 3H), 6.39 (d, J=9.3 Hz, 1H), 6.22-6.18 (m, 2H), 5.84 (s, 1H), 4.27 (s, 2H), 2.15 (s, 3H), 2.10 (s, 3H), 1.68 (d, J=7.2 Hz, 3H).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[CH2:21][OH:22])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].C(OCC)(=O)C>[O:1]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH2:21][OH:22])=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: OC/C=C/c1ccc(C=CCCCOc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: OCCCc1ccc(CCCCCOc2ccccc2)cc1
Yield: 53.4 %

Procedure:
About 5 mg of palladium on carbon (10%) are added to a solution of 98 mg of (2E)-3-{4-[5-phenoxypent-1-en-1-yl]phenyl}prop-2-en-1-ol in about 5 ml of ethyl acetate, and the mixture is hydrogenated under 1 bar of hydrogen at room temperature overnight. The mixture is filtered to remove catalyst and concentrated, and the residue is puriified on silica gel with cyclohexane/ethyl acetate 3:1. 53 mg of product are obtained.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:9]=[N:10][C:11]([CH3:14])=NC=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1.C[C:32]1[N:33]=CC(C=O)=NC=1>>[CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:9]=[N:10][C:11]([CH3:14])=[CH:32][N:33]=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[C:19]=2[N:20]=1
Reactant: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Reactant: Cc1cnc(C=O)cn1
Product: Cc1cnc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1

Procedure:
Following the procedure for the preparation of 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 5-methylpyrazine-2-carbaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.53 (s, 1H), 8.47 (s, 1H), 8.03 (s, 1H), 4.83-4.79 (m, 1H), 4.12-4.03 (m, 2H), 3.78-3.75 (m, 1H), 3.61-3.55 (m, 2H), 3.46-3.40 (m, 1H), 3.12-3.09 (m, 1H), 2.87 (m, 1H), 2.64 (m, 1H), 2.53 (m, 2H), 2.47-2.28 (m, 4H), 2.16 (m, 2H), 1.91-1.84 (m, 2H), 1.23-1.20 (m, 3H). MS: (M+H m/z 410.3).
Reaction SMILES: C(OC([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[NH:11][C:10](=[O:19])[CH2:9]1)=O)(C)(C)C.[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23]>C(Cl)Cl>[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].[NH:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[CH2:14][NH:8][CH2:9][C:10]1=[O:19]
Reactant: CC(C)(C)OC(=O)N1CC(=O)Nc2ccccc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CNCc2ccccc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a solution of 2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert-butyl ester (300 mg, 1.14 mmol) in dry DCM (10 mL) was added trifluoroacetic acid (3.42 mL, 3 mL/mmol. The reaction mixture was stirred at r.t. for 2 h. After completion of the reaction as confirmed by TLC, excess of trifluoroacetic acid and DCM were removed under vacuo to afford trifluoroacetic acid salt of 1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (295 mg, 93%) as a gummy solid. The crude compound was used as such without further purification for the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([CH3:10])[CH:3]=1.FC1C=C(C2ON=C(C3SC(CN4CC(C(OC)=O)C4)=CC=3C)N=2)C=CC=1OC1C=CC=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)ccc1CO
Agent: COC(=O)C1CN(Cc2cc(C)c(-c3noc(-c4ccc(Oc5ccccc5)c(F)c4)n3)s2)C1
Product: Cc1cc(Br)ccc1C=O

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 24 (24f) using (4-bromo-2-methylphenyl)methanol (3.7 g, 19 mmol) that was obtained in Example 27 (27a) and pyridinium dichromate (11g, 28 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:19 to 1:4) as the eluent to afford the title compound (2.4 g) in a yield of 64% as a colourless oily product.