Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C[O:5][C:6](=[O:33])[CH:7]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:15]([C:23]3[CH:24]=[CH:25][C:26]4[C:27]([CH:31]=3)=[N:28][O:29][N:30]=4)=[C:14]([Cl:32])[CH:13]=2)[CH2:8][CH:9]([CH3:11])[CH3:10])CC1.[OH-].[K+]>CCO.O>[N:30]1[O:29][N:28]=[C:27]2[CH:31]=[C:23]([C:15]3[C:16]([O:18][CH2:19][CH:20]4[CH2:22][CH2:21]4)=[CH:17][C:12]([CH:7]([CH2:8][CH:9]([CH3:10])[CH3:11])[C:6]([OH:33])=[O:5])=[CH:13][C:14]=3[Cl:32])[CH:24]=[CH:25][C:26]=12
Reactant: CC(C)CC(C(=O)OCC1CC1)c1cc(Cl)c(-c2ccc3nonc3c2)c(OCC2CC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)CC(C(=O)O)c1cc(Cl)c(-c2ccc3nonc3c2)c(OCC2CC2)c1
Yield: 71.3 %

Procedure:
2-(4-Benzo[1,2,5]oxadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.11 g, 0.23 mmol) was dissolved in a mixture of EtOH/H2O (9 mL /1 mL) and KOH (0.1 g, 1.76 mmol) was added. The reaction mixture was refluxed for 2 h and after cooling the solvent was evaporated. Then, 6 N HCl was added to adjust the pH to 5, and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO4 and evaporated under reduced pressure to give 2-(4-benzo[1,2,5]oxadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid as a yellow oil (0.068 g, 70%). 1H NMR (300 MHz, CDCl3/TMS): δ 8.40 (br s, 1H), 7.70 (d, J=9.3 Hz, 1H), 7.62 (s, 1H), 7.19 (d, J=9.3 Hz, 1H), 6.97 (s, 1H), 6.73 (s, 1H), 3.67 (d, J=6.6 Hz, 2H), 3.52 (t, J=7.7 Hz, 1H), 1.90-1.81 (m, 1H), 1.62-1.53 (m, 1H), 1.50-1.39 (m, 1H), 0.98-0.68 (m, 1H), 0.81 (d, J=6.1 Hz, 6H), 0.37-0.31 (m, 2H), 0.15-0.10 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 179.1, 157.1, 149.1, 148.3, 141.0, 138.6, 135.3, 133.7, 126.8, 121.6, 117.4, 115.0, 110.9, 73.4, 49.4, 41.9, 25.9, 22.6, 22.3, 10.0, 3.1.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([OH:12])[CH:6]=1.Cl>[O-2].[O-2].[Mn+4]>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:8]([CH:9]=2)=[O:11])=[O:12])[CH2:4][CH2:3]1
Reactant: CNCCc1ccc(O)c(O)c1
Agent: [Mn+4]
Agent: Cl
Agent: [O-2]
Product: CN1CCC2=CC(=O)C(=O)C=C21
Yield: 52 %

Procedure:
The above-detailed manganese dioxide oxidation was effected on 50 mg (0.19 mmol) of 79% epinine hydrochloride, yielding a deep red solution of epinochrome. This was isomerized over 2.0 g water-washed Amberlyst®A-21 and 10 mL ethyl acetate. After 30 min of rapid stirring, this mixture had a slight yellowish hue. It was again Schlenk-filtered under N2, then it was partitioned. Extractions and drying as above were performed. After an identical acetylation process, 25 mg (52% yield) of DAMI was collected.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[CH2:6][CH2:5]1.[CH2:17]([C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[N:20]=1)[CH3:18].C(=O)([O-])[O-].[Na+].[Na+].CN(C)C(=O)C>O>[CH2:17]([C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:2][CH2:3][CH:4]3[CH2:9][CH2:8][N:7]([C:10]4[N:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=4)[CH2:6][CH2:5]3)=[CH:26][CH:25]=2)[N:20]=1)[CH3:18]
Reactant: CCc1nc(-c2ccc(O)cc2)no1
Reactant: Cc1ccc(N2CCC(CCCl)CC2)nn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCc1nc(-c2ccc(OCCC3CCN(c4ccc(C)nn4)CC3)cc2)no1
Temperature: 110 °C
Reaction time: 8 h
Yield: 33.2 %

Procedure:
A mixture of 3.12 parts of 3-[4-(2-chloroethyl)-1-piperidinyl]-6-methylpyridazine, 2.47 parts of 4-(5-ethyl-1,2,4-oxadiazol-3-yl)phenol, 1.38 parts of sodium carbonate and 94 parts of N,N-dimethylacetamide was stirred overnight at 110° C. After cooling, the reaction mixture was poured into water. The precipitate was filtered off, washed with water and dissolved in trichloromethane. This solution was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CHCl3 /CH3OH 97:3). The eluent of the desired fraction was evaporated and the residue was crystallized from 2-propanone. The product was filtered off and dried, yielding 1.7 parts (33.2%) of 3-[4-[2-[4-(5-ethyl-1,2,4-oxadiazol-3-yl)phenoxy]ethyl]-1-piperidinyl]-6-methylpyridazine; mp. 125.3° C. (comp. 6).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[O:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[N:11][N:12]=2)=[O:7])[CH2:3]1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH3:28][S:29]([O:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[O:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[N:11][N:12]=2)=[O:7])[CH2:3]1)(=[O:31])=[O:30]
Reactant: COc1ccc(-c2nnc(C(=O)N3CC(O)C3)o2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2nnc(C(=O)N3CC(OS(C)(=O)=O)C3)o2)cc1
Reaction time: 7 h
Yield: 177.9 %

Procedure:
A suspension of 4A (5.45 g, 19. 8 mmol) in dichloromethane (100 mL) was cooled in an ice-bath. Triethylamine (4.4 mL, 31.7 mmol) was added followed by methanesulfonyl chloride (2.3 mL, 29.7 mmol). After the addition, the cooling bath was removed. The mixture was stirred for 7 h. The mixture was transferred to a separatory funnel and was washed with water followed by aqueous NaHCO3 (sat.). The organic solution was dried (phase separator) and evaporated. Dichloromethane (50 mL) and diethyl ether (200 mL) were added and the solid product was filtered. The product was washed twice with diethyl ether and then dried in vacuo. There was obtained 5.03 g (72%) of 4B as a solid. 1H NMR (500 MHz, CDCl3): δ 3.13 (s, 3H), 3.90 (s, 3H), 4.42 (dd, 1H), 4.64 (dd, 1H), 4.86 (dd, 1H), 5.11 (dd, 1H), 5.40 (m, 1H), 7.02 (d, 2H), 8.09 (d, 2H), MS (APCI+) m/z 354 [M+H]+.
Reaction SMILES: [CH:1]1[C:13]2[O:12][N:11]=[C:6]3[N:7]=[CH:8][CH2:9][O:10][C:4]([C:5]=23)=[CH:3][CH:2]=1.[H-].[Na+].[CH3:16][N:17]=[C:18]=[O:19]>CN(C)C=O>[CH3:16][NH:17][C:18]([C:3]1[CH:2]=[CH:1][C:13]2[O:12][N:11]=[C:6]3[N:7]=[CH:8][CH2:9][O:10][C:4]=1[C:5]=23)=[O:19]
Reactant: CN=C=O
Reactant: C1=Nc2noc3cccc(c23)OC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc2onc3c2c1OCC=N3
Reaction time: 0.25 h
Yield: 49 %

Procedure:
A solution of 4,5-dihydroisoxazolo[3,4,5-ef][1,4]benzoxazepine of Example 7(b) (3.7 g; 21.0 mmole) in 60 ml dimethylformamide (DMF) was added to a suspension of sodium hydride (1.2 g; 25.2 mmole) in DMF. After 15 minutes, a solution of methylisocyanate in 15 ml DMF was added. The reaction was quenched into a dilute solution of HCl and extracted thrice with ethyl acetate. The organics were washed with water and dried (saturated NaCl solution, MgSO4). The desired urea was purified via flash chromatography (6% ethylacetate/dichloromethne) to give a solid which was triturated with pentane to give 2.4 g (49%) of 4,5-dihydro-3-methylaminocarbonylisoxazolo[3,4,5-ef][1,4]benzoxazepine, mp 177°-179.5° C.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[N:14]=[C:13](Cl)[CH:12]=[C:11]([CH3:16])[N:10]=1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCOCC1>[CH2:17]([NH:24][C:13]1[CH:12]=[C:11]([CH3:16])[N:10]=[C:9]([NH2:8])[N:14]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: Cc1cc(Cl)nc(N)n1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1cc(NCc2ccccc2)nc(N)n1
Temperature: 80 °C
Reaction time: 12 h
Yield: 88.4 %

Procedure:
Triethylamine (3.4 mL, 24.6 mmol) was added to a suspension of 2-amino-4-chloro-6-methylpyrimidine (Aldrich, 1.77 g, 12.3 mmol) and benzylamine (1.98 g, 18.5 mmol) in anhydrous dioxane (20 mL). The reaction was heated to 80° C. and allowed to run for 12 h. Upon cooling to room temperature, a white precipitate formed which was collected by vacuum filtration. The solid was recrystallized from acetone: hexanes to afford N4-benzyl-6-methylpyrimidine-2,4-diamine (2.33 g, 89% yield) as a white solid.
Reaction SMILES: [O-:1]Cl=O.[Na+].[CH:5]1([O:10][C:11]2[CH:12]=[C:13]([C@@H:19]([C:27]3[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=3)[CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[CH2:9][CH2:8][CH2:7][CH2:6]1.CC(=CC)C>O.CC(O)(C)C>[CH:5]1([O:10][C:11]2[CH:12]=[C:13]([C@@H:19]([C:27]3[CH:28]=[CH:29][C:30]([C:31]([OH:1])=[O:32])=[CH:33][CH:34]=3)[CH2:20][C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)[CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: [O-][Cl+][O-]
Reactant: COc1ccc([C@H](Cc2ccncc2)c2ccc(C=O)cc2)cc1OC1CCCC1
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1ccc([C@H](Cc2ccncc2)c2ccc(C(=O)O)cc2)cc1OC1CCCC1
Yield: 101.8 %

Procedure:
A solution of NaClO2 (149 mg, 1.64 mmol) and NaH2PO4 ·H2O (227 mg, 1.64 mmol) in water (1 mL) was added to a solution of aldehyde from Step 3 (508 mg, 1.27 mmol) and 2-methyl-2-butene (0.94 mL, 8.9 mmol) in t-BuOH (6 mL). The reaction mixture was stirred at room temperature for 19 hours before 25% aqueous NH4OAc was added. The mixture was then extracted twice with EtOAc. The organic phase was washed with brine, dried (MgSO4) and evaporated to afford the title compound as a white solid (540 mg). 1H NMR (400 MHz, CDCl3): δ 1.55 (m, 2H), 1.75 (m, 6H), 3.35 (m, 2H), 3.80 (s, 3H), 4.20 (t, 1H), 4.60 (m, 1H), 6.60 (s, 1H), 6.65 (d, 1H), 6.75 (d, 1H), 7.00 (d, 2H), 7.25 (d, 2H), 8.00 (d, 2H), 8.45 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:24][S:25]([C:28]1[S:32][C:31]([C:33](O)=[O:34])=[CH:30][CH:29]=1)(=[O:27])=[O:26].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:33]([C:31]5[S:32][C:28]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:29][CH:30]=5)=[O:34])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)s1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)s1
Yield: 25.8 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (100 mg, 0.32 mmol), 5-(methylsulfonyl)thiophene-2-carboxylic acid (47 mg, 0.33 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (65 mg, 0.34 mmol), 1-hydroxybenzotriazole (46 mg, 0.34 mmol) and N,N-dimethylformamide (5.0 mL) as starting materials and in the same manner as in Example 318, the title compound (41 mg, 26%) was obtained as a white powder.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:29][C:30]1[CH:42]=[CH:41][C:40]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[NH:33][C:32]=2[CH:31]=1>CN(C=O)C>[CH:31]1[C:32]2[NH:33][C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:40]=2[CH:41]=[CH:42][C:30]=1[O:29][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Reactant: Oc1ccc2c(c1)[nH]c1ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4c(c3)[nH]c3ccccc34)ncnc2cc1OCCCN1CCCC1
Temperature: 100 °C
Yield: 21.3 %

Procedure:
To a solution of 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (100 mg, 0.31 mmol), (prepared as described for the starting material in Example 9), in DMF (10 ml) was added potassium carbonate (124 mg, 0.9 mmol, 3 eq.) followed by 2-hydroxycarbazole (66 mg, 0.36 mmol, 1.2 eq.) and the reaction heated at 100° C. for 4 hours. The DMF was removed in vacuo, the residue dissolved in dichloromethane and placed onto a 2g SCX ion-exchange column. Elution with dichloromethane, followed by 20% methanol/dichloromethane then 20% methanol/dichloromethane+3% ammonium hydroxide, gave the crude product as a brown solid. Further purification by silica bond elut chromatography eluting with dichloromethane to 15% methanol/dichloromethane+1% ammonium hydroxide, followed by trituration with ether gave 4-(9H-carbazol-2-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (31 mg, 22%) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH:11]=[N:10][CH:9]=[N:8]1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH:20]2[O:22][CH2:21]2)=[CH:15][CH:14]=1>C(#N)C>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH:20]([OH:22])[CH2:21][N:7]2[CH:11]=[N:10][CH:9]=[N:8]2)=[CH:17][CH:18]=1
Reactant: c1nc[nH]n1
Reactant: Clc1ccc(CC2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OC(Cc1ccc(Cl)cc1)Cn1cncn1

Procedure:
To a suspension of potassium carbonate (8.14 g) and 1,2,4-triazole (8.14 g) in acetonitrile (100 ml) was added 1-(4-chlorophenyl)-2,3-epoxypropane (9.0 g), and the resulting suspension was heated to 70° for 4.5 h. The excess acetonitrile was evaporated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and dried, and the solvent was evaporated to give a colourless oil. Purification by column chromatography on silica, eluting with chloroform/methanol, 95:5 by volume, gave 1-(4-chlorophenyl)-3-(1,2,4-triazol-1-yl)-2-propanol as a colourless oil which crystallised on standing, m.p. 104°-6°.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.[C:9]1([C@H:15]([NH2:17])[CH3:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4]/[C:3]/1=[N:17]\[C@@H:15]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:16]
Reactant: CC1CCCCC1=O
Reactant: C[C@@H](N)c1ccccc1
Solvent: Cc1ccccc1
Product: CC1CCCC/C1=N\[C@H](C)c1ccccc1
Yield: 83.2 %

Procedure:
A stirred solution of 2-methylcyclohexanone (5 g, 44.64 mmol) and (R)-1-phenylethanamine (5.4 g, 44.64 mmol) in toluene (50 mL) was maintained at 140-145° C. for 24 h. The solvent was removed under reduced pressure to afford 8 g (84%) of a diastereomeric mixture of (1R,E)-N-(2-methylcyclohexylidene)-1-phenylethanamine (I-8a) as a pale yellow oil.
Reaction SMILES: [CH2:1]1[CH:5]2[C:6](=[O:16])[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10](=[O:11])[N:4]2[CH2:3][CH2:2]1.[CH3:17][O-].[Na+].CI>C(O)C>[CH3:17][N:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10](=[O:11])[N:4]2[CH2:3][CH2:2][CH2:1][CH:5]2[C:6]1=[O:16]
Reactant: O=C1Nc2ccccc2C(=O)N2CCCC12
Reactant: C[O-]
Agent: [Na+]
Solvent: CI
Solvent: CCO
Product: CN1C(=O)C2CCCN2C(=O)c2ccccc21
Reaction time: 16 h

Procedure:
A mixture of 4.32 g. of 1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5,11(10H)-dione, 1.2 g. of sodium methylate and 40 ml. of ethanol is stirred at room temperature for 3 hours and 3 ml. of methyl iodide is added. The reaction mixture is stirred for 16 hours longer and concentrated. The residue is mixed with benzene and water and the layers are separated. The benzene layer is washed with water and concentrated. The product is further purified by recrystallization from ethyl acetate and melts at 124°-126° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:11]([F:14])([F:13])[F:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH:15]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[N:24]=[N:25][C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:27][CH:28]=2)=[O:22])[CH2:17][CH2:16]1>>[CH:15]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[N:24]=[N:25][C:26]([N:29]3[CH2:34][CH2:33][N:32]([C:5](=[O:6])[C:4]4[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[C:3]=4[C:11]([F:14])([F:13])[F:12])[CH2:31][CH2:30]3)=[CH:27][CH:28]=2)=[O:22])[CH2:17][CH2:16]1
Reactant: O=C(Cl)c1cccc(F)c1C(F)(F)F
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)c3cccc(F)c3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 3-fluoro-2-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder (31% yield). 1H NMR (300 MHz, CDCl3) δ 8.05, 7.97, 7.65-7.59, 7.29, 7.12, 6.99, 4.05-3.99, 3.89-3.72, 3.54, 3.35, 1.50, 0.76-0.71, 0.48-0.42, 0.10-0.05.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[N:11]1([CH2:31][C@H:32]([C:34]2[CH:43]=[CH:42][C:37]3[C:38](=[O:41])[O:39][CH2:40][C:36]=3[C:35]=2[CH3:44])[OH:33])[CH2:16][CH2:15][N:14]([CH2:17][C@H:18]([C:20]2[CH:29]=[CH:28][C:23]3[C:24](=[O:27])[O:25][CH2:26][C:22]=3[C:21]=2[CH3:30])[OH:19])[CH2:13][CH2:12]1>C(Cl)Cl>[OH:19][C@@H:18]([C:20]1[CH:29]=[CH:28][C:23]2[C:24](=[O:27])[O:25][CH2:26][C:22]=2[C:21]=1[CH3:30])[CH2:17][N:14]1[CH2:13][CH2:12][N:11]([CH2:31][C:32]([C:34]2[CH:43]=[CH:42][C:37]3[C:38](=[O:41])[O:39][CH2:40][C:36]=3[C:35]=2[CH3:44])=[O:33])[CH2:16][CH2:15]1
Reactant: Cc1c([C@H](O)CN2CCN(C[C@@H](O)c3ccc4c(c3C)COC4=O)CC2)ccc2c1COC2=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1c(C(=O)CN2CCN(C[C@@H](O)c3ccc4c(c3C)COC4=O)CC2)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of oxalyl chloride (71 uL, 0.82 mmol) in DCM (30 mL) was dropped DMSO (120 uL, 1.6 mmol) at −78° C. After stirring the mixture for 10 minutes, a DCM solution of 5,5′-{piperazine-1,4-diylbis [(1S)-1-hydroxyethane-2,1-diyl]}bis(4-methyl-2-benzofuran-1(3H)-one) (380 mg, 0.82 mmol) was added into the reaction. The reaction was stir for another 20 minutes before TEA (570 uL, 4.1 mmol) was added to the reaction mixture. The reaction was then allowed to warm up to RT slowly. TLC analysis showed two new spots right above the SM. LC analysis suggested formation of the mono-ketone as well as the di-ketone. The reaction was diluted with DCM, washed with water, dried over sodium sulfate, and purified by flash chromatography. The title product was collected after removal of solvent.
Reaction SMILES: CS([O:5][C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]3([CH2:20][CH2:19][CH2:18][CH2:17]3)[O:11][CH2:12][CH2:13]2)=[N:8][C:7]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])(=O)=O.CC[O-].[Na+].CCO>C1COCC1>[OH:5][C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]3([CH2:20][CH2:19][CH2:18][CH2:17]3)[O:11][CH2:12][CH2:13]2)=[N:8][C:7]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1nc2n(c(=O)c1OS(C)(=O)=O)CCOC21CCCC1
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1nc2n(c(=O)c1O)CCOC21CCCC1
Reaction time: 1 h
Yield: 86.2 %

Procedure:
To a stirred suspension of ethyl 3′-(methylsulfonyloxy)-4′-oxo-6′,7′-dihydro-4′H-spiro[cyclopentane-1,9′-pyrimido[2,1-c][1,4]oxazine]-2′-carboxylate (0.6861 g, 1.84 mmol) in THF (50 mL) was added 1M EtONa/EtOH (10 mL). After 1 h, the resulting yellow solution was concentrated, acidified with 1 M aq. HCl (20 mL), extracted with CH2Cl2 (3×35 mL). The combined organic layers dried (Na2SO4), filtered and concentrated to give the title compound as a brown solid (0.4668 g, 86%). 1H NMR (500 MHz, CDCl3) δ: 10.49 (1H, s), 4.44 (2H, q, J=7.0 Hz), 4.03-3.97 (4H, m), 2.28-2.22 (2H, m), 2.06-2.01 (2H, m), 1.93-1.81 (4H, m), 1.42 (3H, t, J=7.0 Hz). HRMS (M+H) calcd for C14H19N2O5: 295.1294; found: 295.1293.
Reaction SMILES: Cl.[C@H:2]12[CH2:18][C@H:5]([N:6]([C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][CH:9]=3)[CH2:7]1)[CH2:4][NH:3]2.C(N(C(C)C)CC)(C)C.[C:28](Cl)(=[O:34])/[CH:29]=[CH:30]/[CH2:31][CH2:32][CH3:33]>ClCCl>[N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([N:6]2[CH2:7][C@@H:2]3[CH2:18][C@H:5]2[CH2:4][N:3]3[C:28](=[O:34])/[CH:29]=[CH:30]/[CH2:31][CH2:32][CH3:33])=[CH:9][CH:10]=1
Reactant: c1ccc2c(N3C[C@@H]4C[C@H]3CN4)ccnc2c1
Reactant: CCC/C=C/C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC/C=C/C(=O)N1C[C@@H]2C[C@H]1CN2c1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 28 %

Procedure:
To 4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-5-yl]quinoline hydrochloride (26.2 mg, 0.1 mmol), dissolved in 0.5 ml anhydrous dichloromethane, polymer-supported diisopropylethylamine (80 mg, 3-4 mmol/g) was added followed by (E)-hex-2-enoyl chloride (19.9 mg, 0.15 mmol) dissolved in anhydrous dichloromethane (1 ml). The mixture was shaken at room temperature for 20 minutes, filtered and the filtrate evaporated to dryness under reduced pressure. The raw product was purified by preparative HPLC (gradient of water containing 0.1% ammonia and acetonitrile) to yield 9 mg of a solid (0.028 mmol, 28%).
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][C:5](Br)=[CH:6][N:7]=1.[CH2:9]([SH:13])[CH2:10][CH2:11][CH3:12]>C(O)C>[NH2:2][C:3]1[S:4][C:5]([S:13][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:6][N:7]=1
Reactant: Nc1ncc(Br)s1
Reactant: CCCCS
Agent: Br
Solvent: CCO
Product: CCCCSc1cnc(N)s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-amino-5-bromothiazole hydrobromide (13.0 g, 0.05 mol, available from Acros Organics) and 1-butanethiol (4.5 g, 0.05 mol) in ethanol (50 ml) was heated under reflux on a steam-bath for 30 h. The mixture was then allowed to stand at room temperature for 18 h before being distilled under reduced pressure. Water (25 ml) was added to the residue followed by the cautious addition of 0.88 ammonia (25 ml). The mixture was stirred at room temperature for 4 h, then the resulting beige solid was filtered off, washed with water and dried to give 2-amino-5-butylthiothiazole, (Yield 6.0 g (63%)).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:21])=[CH:17][N:16]=1
Reactant: Nc1ccccc1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)Nc2ccccc2)cn1
Yield: 70 %

Procedure:
As described for example 15, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using aniline instead of 3-methoxypropylamine, to the title compound (87 mg, 70%) which was obtained as an off white solid. MS: m/e=386.4 [M+H]+.
Reaction SMILES: [C:1]([C:6]1[CH:16]=[CH:15][C:9]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2]>CCO.[Rh]>[CH2:4]([O:3][C:1]([C:6]1[CH:16]=[CH:15][C:9]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:8][CH:7]=1)=[O:2])[CH3:5]
Reactant: CCOC(=O)c1ccc(C=CC(=O)O)cc1
Agent: [Rh]
Solvent: CCO
Product: CCOC(=O)c1ccc(CCC(=O)O)cc1
Yield: 45.1 %

Procedure:
A solution of 4-carbethoxycinnamic acid (4.9 g) in EtOH (120 ml) was hydrogenated over 5% Rh/C (485 mg) at atmospheric pressure for 21 hr. The solution filtered and stripped. The residue was crystallized from cyclohexane to afford 2.23 g (46%) of the title compound as white crystals; mp 108.5°-110.5°.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[NH:25][C:26](=[O:30])[N:27]([CH3:29])[CH3:28].[OH-].[Na+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:16]([CH2:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[NH:25][C:26](=[O:30])[N:27]([CH3:28])[CH3:29])[CH:10]=1
Reactant: CN(C)C(=O)Nc1ccc(Cl)cc1CN
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)C(=O)Nc1ccc(Cl)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Yield: 10.3 %

Procedure:
(Step 5) 2-Cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.5 g) and 3-[2-(aminomethyl)-4-chlorophenyl]-1,1-dimethylurea hydrochloride obtained in Step 4 (1.12 g) were stirred in ethanol (5 ml) overnight at 90° C. The reaction mixture was poured into 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). The obtained residue was dissolved in ethanol, 4N hydrogen chloride-ethyl acetate solution (1 ml) was added, and the mixture was crystallized from ethanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized to give the title compound (46 mg).