Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:19]([NH:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])=[O:20])[C:3]([NH:5][C@@H:6]1[C:12](=[O:13])[N:11]([CH3:14])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[NH:8][CH2:7]1)=[O:4].ClCCl.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.Cl>C(N(CC)CC)C>[C:33]([N:8]1[CH2:7][C@H:6]([NH:5][C:3](=[O:4])[CH:2]([CH3:1])[C:19]([NH:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:26])([F:25])[F:27])=[O:20])[C:12](=[O:13])[N:11]([CH3:14])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]1=2)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@H]1CNc2ccccc2N(C)C1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@H]1CN(C(=O)c2ccccc2)c2ccccc2N(C)C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60.6 %

Procedure:
To a solution of 0.2 g (0.47 mmol) of 2-methyl-N-((3S)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide in 3 ml of dichloromethane 0.096 g (0.95 mmol) of triethylamine and 0.08 mg (0.57 mmol) of benzoylchloride were added. The mixture was stirred for 20 min at room temperature. Hydrochloric acid (10 ml of a 1 N solution) was added and the mixture was extracted two times with dichloromethane. The combined organic layers were extracted with 1N sodiumbicarbonate solution, dried (MgSO4) and concentrated in vacuo. The remaining oil was purified by column chromatography to yield 0.15 g (60%) of a white foam.
Reaction SMILES: [Br:1][C:2]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]2[N:13]=[C:14]([CH2:16][CH3:17])[O:15][C:3]=12.[Cl:18][CH2:19][CH2:20][CH2:21][CH2:22][S:23][C:24]1[N:25]([CH3:40])[C:26]([C:29]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:30]=2[CH:31]=[CH:32][C:33]([CH3:39])=[N:34]3)=[N:27][N:28]=1>>[ClH:18].[Br:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([CH2:19][CH2:20][CH2:21][CH2:22][S:23][C:24]3[N:25]([CH3:40])[C:26]([C:29]4[CH:38]=[CH:37][CH:36]=[C:35]5[C:30]=4[CH:31]=[CH:32][C:33]([CH3:39])=[N:34]5)=[N:27][N:28]=3)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]2[N:13]=[C:14]([CH2:16][CH3:17])[O:15][C:3]=12
Reactant: CCc1nc2cc3c(c(Br)c2o1)CCNCC3
Reactant: Cc1ccc2c(-c3nnc(SCCCCCl)n3C)cccc2n1
Product: CCc1nc2cc3c(c(Br)c2o1)CCN(CCCCSc1nnc(-c2cccc4nc(C)ccc24)n1C)CC3
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 from 10-bromo-2-ethyl-6,7,8,9-tetrahydro-5H-[1,3]oxazolo[4,5-h][3]benzazepine (105 mg) and 5-{5-[(4-chlorobutyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylquinoline (177 mg) and was obtained as a colourless slightly hygroscopic solid (115 mg).
Reaction SMILES: [C:1]([C:3]1([C:15]2[C:24]3[O:23][CH2:22][CH2:21][O:20][C:19]=3[C:18]([O:25][CH3:26])=[CH:17][CH:16]=2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]([O:12]CC)=[O:11])[CH2:5][CH2:4]1)#[N:2].[OH-].[Na+].O.C(OCC)(=O)C>C(O)C>[C:1]([C:3]1([C:15]2[C:24]3[O:23][CH2:22][CH2:21][O:20][C:19]=3[C:18]([O:25][CH3:26])=[CH:17][CH:16]=2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]([OH:12])=[O:11])[CH2:5][CH2:4]1)#[N:2]
Reactant: CCOC(=O)CC1CCC(C#N)(c2ccc(OC)c3c2OCCO3)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(C2(C#N)CCC(CC(=O)O)CC2)c2c1OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.7 %

Procedure:
To a solution of Compound 20 (0.41 g, 1.1 mmol) obtained in Example 19 in ethanol (4.1 mL) was added a 2 mol/L aqueous solution of sodium hydroxide (1.1 mL), and the mixture was stirred at room temperature for 1 hour and then stirred at 60° C. for 20 minutes. The mixture was allowed to cool, and water and ethyl acetate were added to the mixture, followed by separating into an organic layer and an aqueous layer. The aqueous layer was acidified with 6 mol/L aqueous hydrochloric acid and extracted with ethyl acetate, and the extract was washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo, toluene was added to the residue, and the mixture was evaporated in vacuo. To the residue was added diisopropyl ether, and the precipitated solid was collected by filtration and recrystallized from ethanol to give Compound 21 (0.13 g, 36%) as a mixture of isomers in white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=O.[CH2:14]([NH2:16])[CH3:15].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C1COCC1.C(N(CC)CC)C>[CH2:14]([NH:16][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([OH:1])[CH:3]=1)[CH3:15]
Reactant: CCN
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc([N+](=O)[O-])c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 3-hydroxy-4-nitrobenzoic acid (9.16 g) in DMF (100 ml) were successively added 2M ethylamine in THF solution (30 ml), triethylamine (8.3 ml), HOBt (9.19 g) and WSC (11.5 g), and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, ethyl acetate and 1N hydrochloric acid were added to the residue and the insoluble material was filtered off. The filtrate was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a yellow solid (10.6 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-:12].[K+].[K+].[CH2:17](Br)[CH:18]=[CH2:19]>CN(C=O)C>[CH2:17]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=1[C:7]([OH:12])=[O:8])[CH:18]=[CH2:19]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: C=CCBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.9 %

Procedure:
A solution of 5-bromo-salicylaldehyde (20.1 g, 100 mM) in DMF (50 ml) was treated with potassium carbonate (20.7 g, 150 mM) and allyl bromide (12.7 g, 10.5 mM). The reaction was stirred at ambient temperature for 18 hours. The reaction was partitioned between ethyl acetate/water. The organic phase was washed with water four times, dried (MgSO4) and evaporated at reduced pressure to give 2-allyloxy-5-bromobenzoic acid as a pale yellow oil (10.0 g, 41 %).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:29](N1C=CN=C1)(N1C=CN=C1)=[O:30]>O1CCCC1>[CH2:22]([N:19]1[CH2:18][CH2:17][CH:16]([N:15]2[CH:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:3]3[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=3)[NH:1][C:29]2=[O:30])[CH2:21][CH2:20]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1ccccc1C(NC1CCN(Cc2ccccc2)CC1)c1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C(c2ccccc2)N1C1CCN(Cc2ccccc2)CC1
Yield: 81 %

Procedure:
To a solution of 27.6 g (74.4 mmol) of α-(2-aminophenyl)-N-(1-benzylpiperidin-4-yl)benzylamine in 300 mL of tetrahydrofuran was added 12.1 g (74.5 mmol) of 1,1'-carbonyldiimidazole, and the mixture was heated under reflux for 8 hours. After allowing to cool, the reaction mixture was concentrated in vacuo. The residue was purified by means of column chromatography (silica gel, 1:9 methanol:chloroform). The resulting crude crystals were recrystallized from ethanol to give 24.0 g (60.3 mmol) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][N:7]([CH:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:10]([O:12]CC)=O)[CH:8]=1)([O-:3])=[O:2].[CH2:21]([NH2:23])[CH3:22]>C(O)C>[CH2:21]([NH:23][C:10](=[O:12])[CH:9]([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH3:22]
Reactant: CCN
Reactant: CCCCCCC(C(=O)OCC)n1cnc([N+](=O)[O-])c1
Solvent: CCO
Product: CCCCCCC(C(=O)NCC)n1cnc([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
Ethyl 2-(4-nitro-1H-imidazol-1-yl)octanoate (17 moles, 5.0 g) and ethylamine (20 ml) were stirred in 150 ml ethanol at room temperature for 16 hours. The reaction was added to ice water, extracted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. The oil crystallized upon standing to yield 3.9 g of N-Ethyl-2-(4-nitro-1H-imidazol-1-yl)octanoamide. (MS).
Reaction SMILES: [CH:1]1([CH2:11][C:12](=O)[CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1.C([O-])(=O)C.[NH4+].CO.C([BH3-])#[N:23].[Na+]>C(O)(=O)C.C1COCC1>[CH:1]1([CH2:11][CH:12]([NH2:23])[CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1
Reactant: [BH3-]C#N
Reactant: CC(=O)CC1OCCc2ccccc21
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CC(N)CC1OCCc2ccccc21
Reaction time: 0.42 h

Procedure:
A mixture of (-)-(isochroman-1-yl)acetone (LXXXIV, 0.73 g), ammonium acetate (1.48 g), methanol (2.5 ml), and THF (2.5 ml) is stirred for 25 min and then acetic acid (1.5 ml) and sodium cyanoborohydride (0.48 g) are added. After stirring for 2 hr, the mixture is concentrated and the residue is stirred with dichloromethane and sodium hydroxide (4N). The mixture is extracted with dichloromethane and washed with saline/sodium hydroxide (1N). The organic phase is separated and dried over sodium sulfate to give 2-[(-)-isochroman-1-yl]-(±)-1-methylethylamine.
Reaction SMILES: C(N(CC)CC)C.[C:8]([N:15]1[CH:19]=[CH:18]N=C1)(N1C=CN=C1)=[S:9].C(Cl)Cl.NC1C=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[C:26]([N+:33]([O-:35])=[O:34])[CH:25]=1>C(OCC)(=O)C>[N:15]([C:19]1[CH:18]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[C:26]([N+:33]([O-:35])=[O:34])[CH:25]=1)=[C:8]=[S:9]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(C(=O)O)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(N=C=S)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
Triethylamine (55.8 μL, 0.4 mmol) and thiocarbonyldiimidazole (46.3 mg, 0.26 mmol) were added to a methylene chloride solution (0.4 mL) of 4-amino-2-nitrobenzoic acid (36.4 mg, 0.2 mmol) at room temperature, followed by stirring at room temperature for 10 minutes. The reaction mixture was dissolved in ethyl acetate and washed with 1 M hydrochloric acid, the organic layer was separated, and then the organic layer was dried over magnesium sulfate. Thereafter, filtration and concentration under reduced pressure to dryness were carried out to obtain 4-isothiocyanato-2-nitrobenzoic acid as a colorless solid (40 mg, yield: 89%, HPLC purity: 96.4%)
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1.[O:15]1[CH:17]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16]1.O.[CH3:27]O>[OH-].[K+]>[ClH:1].[OH:15][CH:17]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:27])[CH:21]=1)[CH2:16][NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:8][CH:9]=1
Reactant: CO
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1
Reactant: c1ccc(OCC2CO2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc(OCC(O)CNCc2ccc(NS(C)(=O)=O)cc2)c1

Procedure:
Heat a mixture of N-[4-(aminomethyl)phenyl]methanesulfonamide hydrochloride(15.0 g, 63.4 mmol) and 1,2-epoxy-3-phenoxypropane (10.41 g, 63.4 mmol) in 63.4 mL of 1 N KOH in methanol and 10 mL of water for about 3.5 h. Remove the solvent to afford crystals of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][N:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](OCC)=[O:12])=[CH:6][C:5]([Br:22])=[CH:4][N:3]=1.[H-].[Na+].O>CS(C)=O>[Br:22][C:5]1[CH:4]=[N:3][C:2]2[NH:1][C:11](=[O:12])[CH2:10][N:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:8][C:7]=2[CH:6]=1
Reactant: CCOC(=O)CN(Cc1cc(Br)cnc1N)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1CN(c2ccccc2)Cc2cc(Br)cnc2N1
Temperature: 25 °C
Reaction time: 12 h
Yield: 103 %

Procedure:
Ethyl 2-(((2-amino-5-bromopyridin-3-yl)methyl)(phenyl)amino)acetate (3.29 g, 9.0 mmol) was dissolved in anhydrous DMSO (105 mL) under Argon. NaH (361 mg of 60% dispersion in oil, 9.00 mmol) was added and the reaction was stirred for 12 h at room temperature. Water (200 mL) was added and the mixture was extracted with CH2Cl2 (4×100 mL). Combined organic layers were washed with water (200 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated to afford 7-bromo-4-phenyl-4,5-dihydro-1H-pyrido[2,3-e][1,4]diazepin-2(3H)-one (2.95 g, 99%) as an orange solid: 1H NMR (300 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.21 (d, J=2.4 Hz, 1H), 8.10 (d, J=2.4 Hz, 1H), 7.17-7.12 (m, 2H), 6.82-6.80 (m, 2H), 6.71-6.66 (m, 1H), 4.79 (s, 2H), 4.47 (s, 2H).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([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[CH2:6][CH2:5]1.[O:28]1[CH2:32][CH2:31][CH2:30][C@@H:29]1[CH2:33][C:34](O)=[O:35]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34](=[O:35])[CH2:33][C@H:29]5[CH2:30][CH2:31][CH2:32][O:28]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: O=C(O)C[C@H]1CCCO1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(C[C@H]1CCCO1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (87 mg, 79%), MS (ISP) m/z=443.5 [(M+H)+], mp 183° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and (R)-(tetrahydro-furan-2-yl)-acetic acid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:19][O:20][CH2:21]Cl.O>ClCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][CH2:19][O:20][CH3:21])=[CH:4][CH:3]=1
Reactant: COCCl
Reactant: OCc1ccc(Br)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COCOCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 86.7 %

Procedure:
To a solution of 4-bromobenzyl alcohol (2.8 g) and diisopropylethylamine (2.5 g) in dichloromethane (30 mL) was added chloromethyl methyl ether (1.3 g) at 0° C., and the mixture was stirred at room temperature for 14 hours. To the reaction mixture was water, and the mixture was extracted diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to give 1-bromo-4-[(methoxymethyloxy)methyl]benzene (3.0 g).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[C:13]([O:25][CH3:26])[C:14]([O:23][CH3:24])=[C:15]([O:21][CH3:22])[C:16]=2[O:19][CH3:20])[CH2:11]1.[C:27]1([CH:33]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:26][O:25][C:13]1[C:14]([O:23][CH3:24])=[C:15]([O:21][CH3:22])[C:16]([O:19][CH3:20])=[C:17]2[C:12]=1[CH2:11][CH:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:37]1[CH2:38][CH2:39][N:34]([CH:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:35][CH2:36]1)[CH2:18]2
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCI)C2
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCN1CCN(C(c3ccccc3)c3ccccc3)CC1)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.6 %

Procedure:
The mixture of 2-(8-iodooctyl)-4,5,6,7-tetramethoxyindan (1.17 g), 1-diphenylmethylpiperazine (1.24 g) and potassium carbonate (1.70 g) in DMF (10 ml) was stirred at room temperature for 12 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by alumina column chromatography (hexane to hexane:ethyl acetate=10:1) to yield the entitled compound (1.19 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[OH:33]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][C:14]=2[CH2:23][NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[OH:33])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: Nc1ccccc1O
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNc2ccccc2O)c1

Procedure:
Prepared according to the procedure described in Example 25, Step 4, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and 2-aminophenol.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:26]=[C:25]([F:27])[C:24]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:23][C:22]=2[O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.O>ClCCl>[CH2:37]([O:36][C:22]1[CH:23]=[C:24]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:25]([F:27])=[CH:26][C:21]=1[CH:18]1[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(F)c(OCc3ccccc3)cc2OCc2ccccc2)CC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cc(C2CCNCC2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.6 %

Procedure:
280 μl (3.7 mmol, 10 eq) of trifluoroacetic acid are added to a solution of 184 mg (0.37 mmol, 1 eq) of 4-(2,4-bis(benzyloxy)-5-fluorophenyl)piperidine-1-carboxylic acid tert-butyl ester in 3 ml of dichloromethane. The reaction medium is stirred at ambient temperature for 1 hour. The reaction medium is treated with 10 ml of water and then extracted with dichloromethane. The organic phases are combined, washed with a saturated solution of sodium hydrogen carbonate and then with a saturated solution of sodium chloride, dried over magnesium sulphate and evaporated. 150 mg of 4-(2,4-bis(benzyloxy)-5-fluorophenyl)piperidine are obtained. Yield=100%.
Reaction SMILES: C(OC([N:8]1[N:15]2[C:11]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=3)([C:12](=[O:25])[N:13]([C:17]3[CH:22]=[C:21]([Cl:23])[N:20]=[C:19]([Cl:24])[CH:18]=3)[C:14]2=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:33]([C:30]1[CH:29]=[CH:28][C:27]([CH2:26][C:11]23[CH2:10][CH2:9][NH:8][N:15]2[C:14](=[O:16])[N:13]([C:17]2[CH:22]=[C:21]([Cl:23])[N:20]=[C:19]([Cl:24])[CH:18]=2)[C:12]3=[O:25])=[CH:32][CH:31]=1)#[N:34]
Reactant: CC(C)(C)OC(=O)N1CCC2(Cc3ccc(C#N)cc3)C(=O)N(c3cc(Cl)nc(Cl)c3)C(=O)N12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(CC23CCNN2C(=O)N(c2cc(Cl)nc(Cl)c2)C3=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To a solution of the compound from Example 56 (102 mg) in CH2Cl2 (5 mL) at −10° C. was added TFA (1 mL). After warming to room temperature, the reaction mixture was stirred for a total of 1 hour while monitoring the progress by TLC. Upon consumption of the starting material, the reaction mixture was cooled to 0° C. and DIEA (4.5 mL) was added carefully. After 2 hours, water (20 mL) and EtOAc (30 mL) were added and the mixture shaken. The aqueous phase was then separated and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by liquid chromatography (SiO2, EtOAc) and re-crystallization from EtOAc/hexanes to give the titled compound (62 mg). MS (m/z) 402 (M); mp 187° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[C:7]=1[C:19]#[N:20].[C:24]([C:26]([CH3:38])([O:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=[O:33])[CH3:27])#[N:25].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.N1C=CC=CC=1>C(OCC)(=O)C.CN(C)C(=O)C>[C:14]([NH:13][C:11]1[S:12][C:8]2[C:7]([C:19]#[N:20])=[C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:32](=[O:33])[C:31]4[CH:35]=[CH:36][CH:37]=[C:29]([O:28][C:26]([C:24]#[N:25])([CH3:27])[CH3:38])[CH:30]=4)[CH:23]=[CH:22][CH:21]=3)[CH:18]=[CH:17][C:9]=2[N:10]=1)(=[O:16])[CH3:15]
Reactant: CC(C)(C#N)Oc1cccc(C(=O)O)c1
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)c(C#N)c2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)c4cccc(OC(C)(C)C#N)c4)c3)c(C#N)c2s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 68.5 %

Procedure:
A mixture of N-[6-(3-aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]acetamide (150 mg, 0.462 mmol) produced in Example 12(ii), 3-(1-cyano-1-methylethoxy)benzoic acid (114 mg, 0.555 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (211 mg, 0.554 mmol), and pyridine (2 mL)/N,N-dimethylacetamide (1.2 mL) was stirred at room temperature for 6 hr. The reaction mixture was diluted with ethyl acetate (10 ml), washed successively with 5% aqueous sodium hydrogen carbonate solution (5 ml) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=30/70→80/20), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound (162 mg, 69%) as a white powder.
Reaction SMILES: [C:1](=[O:6])([O:3][CH2:4][CH3:5])[NH2:2].C([O:11][CH2:12][CH:13]([CH2:18][CH3:19])[CH2:14][CH2:15][CH2:16][CH3:17])C1OC1.[C:20]([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>CN(CC1C=CC=CC=1)C>[CH2:18]([CH:13]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][O:11][CH2:5][CH:4]1[O:3][C:1](=[O:6])[NH:2][CH2:20]1)[CH3:19]
Reactant: CCCCCCCCCCCC(=O)[O-]
Reactant: CCOC(N)=O
Reactant: CCCCC(CC)COCC1CO1
Agent: CCCC[Sn+2]CCCC
Agent: CN(C)Cc1ccccc1
Product: CCCCC(CC)COCC1CNC(=O)O1
Temperature: 160 °C
Yield: 88 %

Procedure:
8.9 g (0.10 mole) of ethyl carbamate was dissolved in 18.6 g (0.10 mole) of 2-ethylhexyl glycidyl ether. After adding 0.41 g of N, N-dimethylbenzylamine and 0 63 g of di-n-butyltin dilaurate, the solution was heated at 160° C. for 1 hour while blowing nitrogen gas into the reaction mixture. The product was distilled under reduced pressure to give 20.0 g (88% of theory) of 5-(2-ethylhexyl) oxymethyl-2-oxazolidinone.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[NH:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([C:25]3[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=3)[N:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:9][CH:10]=3)[C:22]=12
Reactant: O=Cc1ccc(F)cc1
Reactant: Nc1ncnc2[nH]nc(-c3ccc(Oc4ccccc4)cc3)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2-c1ccc(C=O)cc1
Temperature: 86 °C
Yield: 91.6 %

Procedure:
3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.0 g, 6.59 mmol) was mixed with 4-fluorobenzaldehyde (1.06 mL, 9.89 mmol), cesium carbonate (4.30 g, 13.19 mmol) in DMF (6 mL). The reaction mixture was heated at 86° C. overnight. After cooling to room temperature, the reaction mixture was poured onto ice water. The solid was collected by filtration to give 4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]benzaldehyde (2.46 g, 92%). 1H NMR (CDCl3) δ 7.19 (m, 5H), 7.46 (m, 2H), 7.78 (d, J=8.64 Hz, 2H), 8.10 (d, J=8.70 Hz, 2H), 8.44 (s, 1H), 8.59 (d, J=8.70 Hz, 2H), 10.03 (s, 1H).