Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=2[CH3:19])=[CH:8][CH:7]=1.C(Cl)CCl.[CH3:58][C:59]1[O:60][C:61]([CH3:67])=[C:62]([C:64](O)=[O:65])[N:63]=1>C(Cl)Cl>[Cl:52][C:47]1[CH:46]=[C:45]([CH:50]=[CH:49][C:48]=1[Cl:51])[CH2:44][O:43][C:40]1[CH:41]=[CH:42][C:37]([C@@H:35]2[CH2:34][O:33][C:29]3=[CH:30][C:31]4[CH2:32][C@@H:23]([C:21]([NH:20][C@@H:4]([CH2:5][C:6]5[CH:7]=[CH:8][C:9]([C:12]6[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=6[CH3:19])=[CH:10][CH:11]=5)[C:3]([OH:2])=[O:53])=[O:22])[N:24]([C:64]([C:62]5[N:63]=[C:59]([CH3:58])[O:60][C:61]=5[CH3:67])=[O:65])[CH2:25][C:26]=4[CH:27]=[C:28]3[O:36]2)=[CH:38][CH:39]=1
Reactant: Cc1nc(C(=O)O)c(C)o1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1nc(C(=O)N2Cc3cc4c(cc3C[C@H]2C(=O)N[C@@H](Cc2ccc(-c3ccnc(C)c3C)cc2)C(=O)O)OC[C@@H](c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)O4)c(C)o1
Reaction time: 0.67 h

Procedure:
(S)-2-({(3R,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (35 mg) was dissolved in 2 mL DCM. In a separate vial EDC (5 equiv) and 2,5-dimethyl-oxazole-4-carboxylic acid (10 equiv) were dissolved in DCM and stirred 40 min. This solution was added to the above mixture stirred 4 hours. The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+2% MeOH). The resulting compound was hydrolyzed according to General Procedures B to give the title compound (10 mg). LCMS (m/z): 862.
Reaction SMILES: C[O:2][C:3]1[C:4]([C:21]#[C:22][C:23]2[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=2)=[N:5][CH:6]=[C:7]([O:19][CH3:20])[C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.F[B-](F)(F)F.[IH2+:34].N1C=CC=CC=1.N1C=CC=CC=1>C1COCC1>[I:34][C:21]1[C:4]2=[N:5][CH:6]=[C:7]([O:19][CH3:20])[C:8]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:3]2[O:2][C:22]=1[C:23]1[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=1
Reactant: COc1ccc(COc2c(OC)cnc(C#Cc3cnn(C)c3)c2OC)cc1
Reactant: [IH2+]
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(COc2c(OC)cnc3c(I)c(-c4cnn(C)c4)oc23)cc1
Yield: 63 %

Procedure:
To a stirred solution of 3,5-dimethoxy-4-(4-methoxy-benzyloxy)-2-(1-methyl-1H-pyrazol-4-ylethynyl)pyridine (80 mg, 0.21 mmol) in dry THF (2 ml) was added bispyridine iodonium tetrafluoroborate (94 mg, 0.25 mmol) and the reaction was refluxed for 0.5 hours. After cooling, the reaction was quenched with 10% Na2S2O3 (aq) and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated onto silica-gel under reduced pressure. The solid residue was purified by flash chromatography (silica-gel, eluted with EtOAc:hexanes, 3:2) to give the product as a white solid (65 mg, 63%). 1H—NMR (300 MHz, CDCl3) δ 8.23 (s, 1H), 8.16 (s, 1H), 8.15 (s, 1H), 7.38 (d, J=8.6 Hz, 2H), 6.86 (d, J=8.6 Hz, 2H), 5.60 (s, 2H), 3.99 (s, 3H), 3.93 (s, 3H), 3.77 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1.[O:30]=[C:31]1[NH:35][CH:34]([C:36](O)=[O:37])[CH2:33][S:32]1>>[CH3:1][N:2]([C:36]([C@@H:34]1[CH2:33][S:32][C:31](=[O:30])[NH:35]1)=[O:37])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([N:17]3[CH2:18][CH2:19][CH:20]([C:23]4[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=4)[CH2:21][CH2:22]3)=[O:16])=[CH:12][CH:13]=2)[CH2:4]1
Reactant: CN[C@@H]1CCN(c2ccc(NC(=O)N3CCC(c4ccc(Cl)cc4)CC3)cc2)C1
Reactant: O=C1NC(C(=O)O)CS1
Product: CN(C(=O)[C@@H]1CSC(=O)N1)C1CCN(c2ccc(NC(=O)N3CCC(c4ccc(Cl)cc4)CC3)cc2)C1

Procedure:
(R)-4-(4-Chlorophenyl)piperidin-1-carboxylic acid [4-(3-methylamino-pyrrolidin-1-yl)phenyl]amide was reacted with 2-oxothiazolidine-4-carboxylic acid by method E. This resulted in the product with the molecular weight of 542.10 (C27H32CIN5O3S); MS (ESI): 542 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: COc1ccc(C)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C)c(Oc2ccc([N+](=O)[O-])cn2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 43.7 %

Procedure:
To a solution of 2-methyl-5-(methyloxy)phenol (Intermediate 12, 2 g) and 2-chloro-5-nitropyridine (2.1 g, 13.2 mmol) in DMF (50 mL) was added potassium carbonate (2.76 g, 20 mmol) and the reaction mixture was stirred at 100° C. overnight. The mixture was evaporated under vacuum and water (100 mL) was added. It was extracted with ethyl acetate (3 times 100 mL) and the combined organic layers were dried over sodium sulphate and evaporated to afford a brown oil, which was purified by column chromatography on silica gel (mobile phase: EtOAc/PE=1/50-1/20) to give the title compound (1.5 g).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.C(N(CC)CC)C.[C:35](Cl)(=[O:38])[O:36][CH3:37]>ClCCl>[CH3:37][O:36][C:35](=[O:38])[NH:27][C@H:24]1[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]2[CH2:17][CH2:18][N:13]([C:12]3[C:7]4[O:6][CH2:5][O:4][C:8]=4[CH:9]=[CH:10][CH:11]=3)[CH2:14][CH2:15]2)[CH2:22][CH2:23]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Temperature: 0 °C

Procedure:
The title compound was prepared from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25 mg, 0.068 mmol) and triethylamine (20.6 mg, 28.4 μl, 204 μmol) in dichloromethane (1 mL). Methyl carbonochloridate (7.06 mg, 5.78 μl, 0.075 μmol) was added to the mixture stirring at 0° C. The ice bath was removed and the reaction mixture was stirred for 1 hour at room temp. The reaction was diluted with dichloromethane and quenched with sat NaHCO3 (4 mL). The aqueous layer was extracted with DCM (1×5 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 0% to 15% MeOH in dichloromethane) to yield the title compound as a white solid (9 mg, 34%), MS (ISP) m/z=390.3 [(M+H)+].
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([OH:9])=O.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][CH:43]=1)[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1>CN(C)C(=O)C.O1CCCC1>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:23]=[C:22]([NH:21][C:7]([C:3]5[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=5)=[O:9])[CH:43]=[CH:42][CH:41]=4)=[N:31][N:30]3[CH:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: Cn1cccc1C(=O)O
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1cccc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Yield: 49.1 %

Procedure:
Using 1-methyl-1H-pyrrole-2-carboxylic acid (97 mg, 0.78 mmol), tetrahydrofuran (4.0 mL), N,N-dimethylformamide (30 μL, 0.39 mmol), oxalyl chloride (135 μL, 1.55 mmol), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropylcarboxamide (200 mg, 0.65 mmol) and N,N-dimethylacetamide (4.0 mL), and in the same manner as in Example 119, the title compound (133 mg, 49%) was obtained as a white powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:15])=[CH:4][C:5](Br)=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]=1.[CH3:16][N:17](C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:3]([F:15])=[CH:4][C:5]([C:16]#[N:17])=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]=1
Reactant: CCOC(=O)Cc1cc(N)c(F)cc1Br
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)Cc1cc(N)c(F)cc1C#N
Temperature: 100 °C
Yield: 25 %

Procedure:
A solution of Example C5 (3 g, 10.9 mmol) in DMF (50 mL) was treated with ZnCN2 (1.7 g, 16.4 mmol) and Pd(PPh3)4 (1.26 g, 1.09 mmol), sparged with N2 and heated at 100° C. for 12 h. The mixture was cooled to RT, treated with water and extracted with EtOAc (3×). The combined organics were washed with brine (3×), dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/pet ether) to afford ethyl 2-(5-amino-2-cyano-4-fluorophenyl)acetate (600 mg, 25% yield). 1H NMR (400 MHz, CDCl3): δ 7.19 (d, J=2.4 Hz, 1H), 6.67 (d, J=8.4 Hz, 1H), 4.13-4.11 (q, J=6.8 Hz, 2H), 3.66 (s, 2H), 1.23-1.19 (t, J=6.8 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[C:17]([N+:23]([O-:25])=[O:24])[CH:16]=1.[BH4-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH2:19][C:18]2[CH:21]=[CH:22][C:15]([Cl:14])=[CH:16][C:17]=2[N+:23]([O-:25])=[O:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccc(Cl)cc2[N+](=O)[O-])C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-Amino-pyrrolidine-1-carboxylic acid tert-butyl ester (2 g, 10.7 mmol) in methanol (20 mL) was added 4-Chloro-2-nitro-benzaldehyde (1.98 g, 10.7 mmol). The resultant solution was heated at 60° C. overnight. The reaction mixture was cooled to 0° C. and to it was added NaBH4 (629 mg, 10 mmol). After 1 h, the reaction solution was quenched with saturated NaHCO3 solution and extracted with ethyl acetate. The organic extract was dried over MgSO4, filtered and concentrated to provide the crude product as an oil. The crude product was used in the subsequent reaction without further purification. LCMS (retention time=10.28, ES+; 356).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([C:11]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)=[O:12])=[CH:9][CH:8]=[C:7]([CH3:22])[N:6]=1)=[O:4].C1C=C(Cl)C=C(C(OO)=[O:31])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C([O-])(O)=O.[Na+]>ClCCl>[CH3:22][C:7]1[N+:6]([O-:31])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:10]([C:11]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)=[O:12])=[CH:9][CH:8]=1
Reactant: COC(=O)c1nc(C)ccc1C(=O)c1ccc2c(c1)OCO2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1c(C(=O)c2ccc3c(c2)OCO3)ccc(C)[n+]1[O-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.1 %

Procedure:
To a dichloromethane(20 ml) solution of 6-methyl-3-(3,4-methylenedioxyphenylcarbonyl)pyridine-2-carboxylic acid methyl ester(1.75 g,5.85 mmol) was added mCPBA(1.73 g) under ice-cooling. The mixture was stirred at room temperature for 20 h and an aqueous solution of sodium thiosulfate was added to the mixture to quench the reaction. The mixture was neutralized with a saturated aqueous solution of NaHCO3 and extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4 and concentrated under reduce pressure to give 6-methyl-3-(3,4-methylenedioxyphenylcarbonyl)-2-methoxycarbonylpyridine N-oxide(1.57 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+].Cl[CH2:19][CH:20]([OH:29])[CH2:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1>O>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([CH2:22][CH2:21][CH:20]([OH:29])[CH2:19][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[S:9][CH:10]=[CH:11][N:12]=3)=[CH:6][CH:7]=2)[CH:24]=1
Reactant: Oc1ccc(-c2nccs2)cc1
Reactant: OC(CCl)CCc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OC(CCc1cccnc1)COc1ccc(-c2nccs2)cc1

Procedure:
Prepared according to the method as described in Example 24b) from 2-(4-hydroxyphenyl)thiazole (1 g), ethanol (20 ml), sodium hydroxide (0.255 g), water (5 ml) and (±)-α-(chloromethyl)-3-pyridinepropanol (1 g, from Example 24a)) to give the title compound after purification as a white solid (0.42 g).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:14][CH2:15][C:16]3(C(F)(F)F)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:6][C:7]([F:13])=[C:8]([CH:12]=2)[C:9](O)=[O:10])[CH2:3][CH2:2]1.C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)CCCCC1.CS(N)(=O)=O.[CH3:52][O:53][CH2:54][CH2:55][S:56]([NH2:59])(=[O:58])=[O:57]>>[CH:16]1([CH2:15][O:14][C:5]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:12][C:8]([C:9]([NH:59][S:56]([CH2:55][CH2:54][O:53][CH3:52])(=[O:58])=[O:57])=[O:10])=[C:7]([F:13])[CH:6]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O=C(O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Reactant: COCCS(N)(=O)=O
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC2CCCCC2)cc1F
Product: COCCS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2CCCCC2)cc1F

Procedure:
Following the procedure as described in Example 158 step 5, and making variations as required to replace 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoic acid with 4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid and to replace methanesulfonamide with 2-methoxyethanesulfonamide, the title compound was obtained (0.16 g, 40%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.70-8.59 (m, 1H), 7.58-7.51 (m, 1H), 6.61-6.51 (m, 1H), 3.90-3.74 (m, 6H), 3.31 (s, 3H), 2.11-1.99 (m, 1H), 1.95-1.67 (m, 6H), 1.41-1.04 (m, 5H), 0.98-0.89 (m, 2H), 0.69-0.61 (m, 2H); MS (ES−) m/z 412.3 (M−1);
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:4][C:3]=1OC.BrCCCC1C=CC=CC=1>>[O:23]([C:20]1[CH:21]=[CH:22][C:17]([CH:14]2[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][CH2:8][C:5]3[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=3)[CH2:16][CH2:15]2)=[CH:18][CH:19]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1cc(/C=C/CN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)ccc1O
Agent: BrCCCc1ccccc1
Product: c1ccc(CCCN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)cc1

Procedure:
The same procedure was followed as in Example 11 using the compound (9) synthesized in Example 2 and 1-bromo-3-phenylpropane to produce the above.
Reaction SMILES: [H-].[Na+].[OH:3][N:4]=[C:5]([CH:11]([CH3:13])[CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7].Cl[CH2:15][C:16]1[CH:35]=[CH:34][C:19]([O:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:18][CH:17]=1.Cl.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:13][CH:11]([CH3:12])/[C:5](=[N:4]/[O:3][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:34][CH:35]=1)/[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: CCOC(=O)C(=NO)C(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)C(C)C
Reaction time: 1 h
Yield: 23.1 %

Procedure:
Sodium hydride (60% in oil, 225 mg) was added under a nitrogen atmosphere to a solution of ethyl 2-hydroxyimino-3-methylbutyrate (Z:E=2.3:1, 1.01 g) and 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (2.00 g) in N,N-dimethylformamide (20 ml) at room temperature and the mixture was stirred for 1 hour. After adding 1N HCl (10 ml), aqueous sodium bicarbonate was added, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain as a first product ethyl Z-3-methyl-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyrate (640 mg, yield 23%) as a colorless oil from a fraction eluted with ethyl acetate-hexane-dichloromethane (1:10:10, v/v).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[C:8](OC)(=[O:18])[C:9]1[CH:17]=[CH:16][C:12]([C:13]([O-:15])=[O:14])=[CH:11][CH:10]=1>ClCCl.Cl>[N:1]1([C:8]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Reactant: C1CCNCC1
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(O)c1ccc(C(=O)N2CCCCC2)cc1
Reaction time: 2 h

Procedure:
6 ml of piperidine was stirred in dichloromethane at 0° C., and a solution of 3 g (15 mmol) of monomethyl terephthalate chloride in dichloromethane was added to the resultant mixture. The temperature was elevated to room temperature, and they were stirred for 2 hours and then diluted with 1 N hydrochloric acid. After the extraction with dichloromethane, the organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and then with saturated aqueous NaCl solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was stirred in ethanol. 30 ml of 1 N aqueous sodium hydroxide solution was added to the resultant mixture, and they were stirred at room temperature overnight. The solvent was evaporated, and the reaction liquid was concentrated and then diluted with 1 N hydrochloric acid. After the extraction with ethyl acetate, the organic layer was washed with saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([N:26]4[CH2:30][CH2:29][NH:28][C:27]4=[O:31])[CH:23]=[CH:24][CH:25]=3)[CH2:14][CH2:13]2)[N:3]=1.[CH3:32]I.[H-].[Na+]>C1COCC1>[CH3:32][N:28]1[CH2:29][CH2:30][N:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([CH2:19][CH2:18][N:15]3[CH2:16][CH2:17][N:12]([C:8]4[CH:7]=[CH:6][CH:5]=[C:4]5[C:9]=4[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]5)[CH2:13][CH2:14]3)[CH:21]=2)[C:27]1=[O:31]
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N5CCNC5=O)c4)CC3)cccc2n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5CCN(C)C5=O)c4)CC3)cccc2n1
Reaction time: 1 h
Yield: 45 %

Procedure:
To a stirred solution of 1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone (E85) in THF was added methyl iodide (1 eq.), followed by sodium hydride (1.2 eq), and the reaction was stirred for 60 minutes. The mixture was loaded onto an ion-exchange cartridge (SCX-2) and eluted with methanol followed by ammonia in methanol (1M). The basic fractions were concentrated under vacuum and purified by column chromatography (SPE cartridge, Silica) using as eluent a gradient from DCM-methanol (99:1) to DCM-methanol (98:2) affording the final compound (45% yield).
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][OH:20])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:41]1[C:45](=[O:46])[C:44]2=[CH:47][CH:48]=[CH:49][CH:50]=[C:43]2[C:42]1=[O:51].N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(=O)(O)[O-].[Na+]>O1CCCC1.O.C(Cl)(Cl)Cl>[CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][O:20][N:41]2[C:45](=[O:46])[C:44]3[C:43](=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:42]2=[O:51])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Product: CCCc1nc2cnc3ccccc3c2n1CCCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
A solution of 3-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propan-1-ol (20.0 grams (g), 74.3 millimoles (mmol)) in tetrahydrofuran (300 milliliters (mL)) was cooled to approximately 0° C.; triphenylphosphine (23.4 g, 89.1 mmol) and N-hydroxyphthalimide (14.5 g, 89.1 mmol) were then added. After five minutes of stinring, diisopropyl azodicarboxylate (17.5 mL, 89.1 mmol) was added dropwise over a period of 15 minutes (min). The reaction was allowed to warm to room temperature and stirred overnight. The solvent was removed under reduced pressure, and the residue was dissolved in chloroform (300 mL). A solution of hydrochloric acid (150 mL of 6 molar (M) was then added, and approximately 50 mL of the solvent was removed under reduced pressure to provide a white precipitate, which was stirred for ten minutes and isolated by filtration. Additional salt eventually precipitated from the filtrate and was isolated by filtration. Chloroform (300 mL) and water (300 mL) were added to the salt, and solid sodium bicarbonate was added to the mixture to adjust to pH 8. The organic solution was then dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 28.4 g of 2-[3-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propoxy]-1H-isoindole-1,3(2H)-dione as a white solid.
Reaction SMILES: C(N(CC)CC)C.[O:8]([CH2:26][CH2:27][C:28]1([CH2:34][CH2:35][OH:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[Si:9]([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:37][S:38]([O:36][CH2:35][CH2:34][C:28]1([CH2:27][CH2:26][O:8][Si:9]([C:22]([CH3:24])([CH3:25])[CH3:23])([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1)(=[O:40])=[O:39]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](OCCC1(CCO)CCCCC1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OCCC1(CCOS(C)(=O)=O)CCCCC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 104.1 %

Procedure:
After adding triethylamine (2.20 mL, 15.8 mmol) to a solution of 2-[1-(2-tert-butyldiphenylsiloxyethyl)cyclohexyl]ethanol (3.24 g, 7.80 mmol) in methylene chloride (25 mL), methanesulfonyl chloride (0.91 mL, 11.7 mmol) was added dropwise while cooling on ice. The mixture was stirred at room temperature for 40 minutes, and then saturated aqueous sodium hydrogencarbonate (300 mL) was added, extraction was performed with chloroform and the organic layer was washed with saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure to obtain the title compound as a yellow oil (3.97 g).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][CH2:6][C:7]1[O:11][C:10]([CH:12]=[O:13])=[CH:9][CH:8]=1.OP([O-])(O)=O.[Na+]>C(Cl)Cl.N1C=CC=CC=1>[C:1]([O:5][CH2:6][C:7]1[O:11][C:10]([CH:12]=[O:13])=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: O=Cc1ccc(CO)o1
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCc1ccc(C=O)o1
Temperature: 20 °C

Procedure:
10.05 cm3 of acetyl chloride is added at 5° C. to a solution containing 16.2 g of 5-(hydroxy methyl) 2-furan-carboxaldehyde and 200 cm3 of methylene chloride. Then 11.4 cm3 of pyridine and 50 cm3 of methylene chloride are added. The reaction mixture is maintained under agitation for 3 hours at 20° C. It is then treated with an aqueous solution of sodium acid phosphate and extracted with methylene chloride, followed by drying and concentrating. After chromatography on silica eluting with a hexane--ethyl acetate mixture (7-3), 19.35 g of desired product is obtained.