Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:6]3[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:13]([CH2:19][O:20][CH2:21][CH3:22])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[NH:71]1[CH2:75][CH2:74][CH2:73][C:72]1=[O:76]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:21]([O:20][CH2:19][C:13]1[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:6]2[C:5]3[N:4]=[CH:3][C:2]([N:71]4[CH2:75][CH2:74][CH2:73][C:72]4=[O:76])=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:12]=1)[CH3:22]
Reactant: CCOCc1nc2cnc3cc(Br)cnc3c2n1CC(C)C
Reactant: O=C1CCCN1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOCc1nc2cnc3cc(N4CCCC4=O)cnc3c2n1CC(C)C
Temperature: 110 °C

Procedure:
7-Bromo-2-(ethoxymethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine (1.0 g, 2.75 mmol), tris(dibenzylideneacetone)dipalladium(0) (70 mg, 0.068 mmol), cesium carbonate (1.25 g, 3.85 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.118 g, 0.204 mmol), pyrrolidin-2-one (0.25 mL, 3.3 mmol), and dioxane (2.75 mL) were added to a scintillation vial. The vial was sequentially flushed with nitrogen, sealed with a Teflon-lined cap, and heated at 110° C. for about 40 hours. After cooling to room temperature, the reaction mixture was diluted with chloroform and methanol and then filtered through CELITE filter aid. The filtrate was concentrated under reduced pressure to provide a tan solid. This material was purified by column chromatography on a Biotage Horizon™ High-Performance Flash Chromatography instrument using a silica gel cartridge and eluting with a gradient of 1-25% CMA in chloroform to provide 1-[2-ethoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-7-yl]pyrrolidin-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[OH:13].CCN(C(C)C)C(C)C.[Br:23][C:24]1[S:28][C:27]([S:29](Cl)(=[O:31])=[O:30])=[CH:26][CH:25]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][C:7](=[O:12])[CH:6]=[C:5]([O:13][S:29]([C:27]3[S:28][C:24]([Br:23])=[CH:25][CH:26]=3)(=[O:31])=[O:30])[C:4]=2[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: O=c1cc(O)c2cc(Cl)ccc2o1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=c1cc(OS(=O)(=O)c2ccc(Br)s2)c2cc(Cl)ccc2o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 21.3 %

Procedure:
6-Chloro-4-hydroxycoumarin (0.5 mmol, 0.099 g) is suspended in 5 mL of DCM, and enough DIEA is added to bring the pH to 9 as measured by pH paper. The solution is cooled to 0° C., and 5-bromo-thiophene-2-sulfonyl chloride (0.5 mmol, 0.13 g) is added. The solution is warmed to ambient temperature and is stirred 2 hrs. The solvent is removed under reduced pressure and the residue is triturated with Et2O. The resulting solid is filtered, is washed with Et2O, and is dried to afford the title compound (45 mg, 21%). 1H NMR (CDCl3, 300 MHz) δ 7.65 (1H, d, J=4.25 Hz), 7.56 (2H, m), 7.29 (1H, d, J=8.75 Hz), 7.19 (1H, d, J=4.25 Hz), 6.48 (1H, s), MS (ESI, Pos.) calcd for C13H6BrClO5S2 m/z [M+H]=420.9, found 420.9.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:29]1([C:35]2[N:36]=[N:37][NH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:38]4[CH:39]=[C:35]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[N:36]=[N:37]4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: c1ccc(-c2c[nH]nn2)cc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Cn4cc(-c5ccccc5)nn4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 6, Step 3, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 4-phenyl-1H-1,2,3-triazole.
Reaction SMILES: [C:1]1([O:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])=[C:16]([CH:19]=1)[C:17]#[N:18].N1C=CC=CC=1>C(Cl)Cl>[C:17]([C:16]1[CH:19]=[C:12]([NH:11][C:8](=[O:9])[O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:13]=[CH:14][C:15]=1[S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])#[N:18]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCS(=O)(=O)c1ccc(N)cc1C#N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)c1ccc(NC(=O)Oc2ccccc2)cc1C#N
Reaction time: 1 h
Yield: 85 %

Procedure:
Phenylchloroformate (0.63 mL, 5 mmol) was added dropwise to a solution of 6B in methylene chloride (10 mL) and pyridine (0.60 mL, 7.1 mmol) at 0° C. After stirring for 1 h, the reaction mixture was partitioned between 1.0 M HCl (150 mL) and EtOAc (150 mL). The layers were separated and the organic phase was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (0% to 100% EtOAc in hexanes) to yield 25A (1.34 g, 85%) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 1.32 (t, J=7.45 Hz, 3 H) 3.36 (q, J=7.33 Hz, 2 H) 7.14-7.21 (m, J=7.58 Hz, 2 H) 7.26-7.31 (m, J=7.45, 7.45 Hz, 1 H) 7.37-7.45 (m, J=7.83, 7.83 Hz, 2 H) 7.66 (bs, 1 H) 7.83 (dd, J=8.72, 2.15 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:11]([OH:19])(=[O:18])[C:12]([CH2:14][C:15](O)=[O:16])=[CH2:13]>CO>[F:1][C:2]1[CH:3]=[C:4]([N:10]2[C:15](=[O:16])[CH2:14][CH:12]([C:11]([OH:19])=[O:18])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(N)cc1F
Reactant: C=C(CC(=O)O)C(=O)O
Solvent: CO
Product: COc1ccc(N2CC(C(=O)O)CC2=O)cc1F
Temperature: 110 °C

Procedure:
A mixture of 3-fluoro-4-methoxybenzenamine (7.5 g, 0.053 mmol) and itaconic acid (6.9 g, 0.053 mmol) was heated to 110° C. for 2 h. The yellow solid was dissolved in 100 mL of MeOH and concentrated in vacuo. The resulting solid was washed with 50% EtOAc/hexanes to give the title compound as a light yellow solid. MS (ESI pos. ion) m/z: 254.2 (M+H). Calc'd Exact Mass for C12H12FNO4: 253.23.
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([S:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[Cl:24])(=[O:33])=[O:32])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCN(S(=O)(=O)c2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
To an ice cooled solution of 2.04 g (10 mmol) of Boc-homopiperazine, 1.32 g (10 mmol) of DIPEA in 80 ml of methylene chloride was added a solution of 2.18 g (10 mmol) of 2-chlorophenylsulfonyl chloride in 40 ml of methylene chloride. Then the reaction mixture was stirred at RT overnight. The organic phase washed with HCl aq, water, dried over sodium sulphate and evaporated to dryness to give 3.7 g of compound as yellow oil.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:9][CH2:8]1)#[N:2].Cl.[CH2:29]([OH:31])[CH3:30]>>[CH2:29]([O:31][C:1](=[NH:2])[CH2:3][CH2:4][CH2:5][O:6][C@H:7]1[CH2:8][CH2:9][C@H:10]([N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:11][CH2:12]1)[CH3:30]
Reactant: CN([C@H]1CC[C@H](OCCCC#N)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)CCCO[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Reaction time: 48 h

Procedure:
0.35 g (0.87 mmol) trans-N-[4-(3-Cyano-propoxy)-cyclohexyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide in 6 ml ethanol were treated with HCl gas at low temperature for 20 min. The mixture was kept at −20° C. for 48 h, was concentrated under reduced pressure to yield 400 mg (quant.) trans-4-{4-[Methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-butyrimidic acid ethyl ester as light brown oil, MS: 451 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.Cl.[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([CH2:19][O:20][NH2:21])=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20]/[N:21]=[C:8](/[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=2)\[CH3:9])=[CH:22][CH:23]=1)([O-:14])=[O:13]
Reactant: NOCc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)c1cccc(O)c1
Agent: Cl
Product: C/C(=N\OCc1ccc([N+](=O)[O-])cc1)c1cccc(O)c1
Yield: 81.6 %

Procedure:
3′-Hydroxyacetophenone (24) (150 mg, 1.10 mmol) was condensed with compound 19 (248 mg, 1.21 mmol) according to the general procedure II-A defined above. After being heated for 3 h the reaction mixture was cooled and the solvent removed under reduced pressure. The resulting solid was filtered off and washed with cold isopropanol (3.0 mL) to afford the title compound CP30260 (257 mg, 82%) as a white solid, m.p. 123.6-125.3° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]([CH3:19])[CH2:15][C:16](O)=O)=[O:13])[C:6]=2[CH:20]=1.[Cl:21][C:22]1[CH:23]=[C:24]([NH2:30])[C:25]([NH2:29])=[CH:26][C:27]=1[F:28].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CCOC(C)=O.CN(C=O)C>[ClH:1].[Cl:21][C:22]1[C:27]([F:28])=[CH:26][C:25]2[N:29]=[C:16]([CH2:15][N:14]([CH3:19])[C:12](=[O:13])[CH2:11][N:7]3[C:6]4[CH:20]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[S:9][C:8]3=[O:10])[NH:30][C:24]=2[CH:23]=1
Reactant: Nc1cc(F)c(Cl)cc1N
Reactant: CN(CC(=O)O)C(=O)Cn1c(=O)sc2ccc(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(Cc1nc2cc(F)c(Cl)cc2[nH]1)C(=O)Cn1c(=O)sc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 128.8 %

Procedure:
To a mixture of N-[(5-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetyl]-N-methylglycine (150 mg), 4-chloro-5-fluorobenzene-1,2-diamine (81 mg), and DMF (5 mL) were added HOBt (77 mg) and WSC.HCl (107 mg), followed by stirring at room temperature overnight. The reaction mixture was diluted with EtOAc, and washed with water, a saturated aqueous NaHCO3 solution, and brine in this order, dried over Na2SO4, and then concentrated under reduced pressure. To the residue was added acetic acid (5 mL), followed by heating and stirring at 110° C. for 5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with EtOAc. The organic layer was washed with a saturated aqueous NaHCO3 solution and brine in this order, dried over Na2SO4, and then concentrated under reduced pressure. The obtained solid was washed with EtOAc and then with MeOH, and suspended in MeOH (3 mL). 4 M hydrogen chloride/EtOAc (120 μL) was added thereto, followed by stirring at room temperature for 1 hour. The resulting solid was collected by filtration and then washed with MeOH to obtain N-[(6-chloro-5-fluoro-1H-benzimidazol-2-yl)methyl]-2-(5-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)-N-methylacetamide hydrochloride (146 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:19][C:18]3[C:13](=[N:14][C:15]([C:20]([O:22]C)=[O:21])=[CH:16][CH:17]=3)[C:12]=2[NH:24][C:25]([C@H:27]2[CH2:32][CH2:31][C@H:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][C:34]3=[O:39])[CH2:29][CH2:28]2)=[O:26])=[O:10])=[N:6][CH:7]=1.[OH-].[Na+].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:19][C:18]3[C:13](=[N:14][C:15]([C:20]([OH:22])=[O:21])=[CH:16][CH:17]=3)[C:12]=2[NH:24][C:25]([C@H:27]2[CH2:28][CH2:29][C@H:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][C:34]3=[O:39])[CH2:31][CH2:32]2)=[O:26])=[O:10])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N4CCOCC4=O)CC3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N4CCOCC4=O)CC3)c2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl 2-{[(5-Chloropyridin-2-yl)amino]carbonyl}-3-({[trans-4-(3-oxomorpholin-4-yl)cyclohexyl]carbonyl}amino)furo[3,2-b]pyridine-5-carboxylate (9.40 g) obtained in Example 39 is suspended in tetrahydrofuran (135 ml), and thereto is added 1 N aqueous sodium hydroxide solution (34 ml) under ice-cooling. The mixture is warmed to room temperature, and stirred for 3 hours. To the reaction solution is poured 2N hydrochloric acid (17 ml) under ice-cooling, and the reaction solution is concentrated under reduced pressure. The residue is suspended in water and the precipitates are collected by filtration. The resulting solid is washed with water and diethyl ether to give the title compound (7.83 g).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH2:13][C:14](=[O:18])[C:15]([OH:17])=[O:16])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.[OH-].[Na+].CC(OC)(C)C>C1COCC1>[F:1][C:2]([F:19])([F:20])[C:3]1[CH:4]=[C:5]([CH2:13][C@@H:14]([OH:18])[C:15]([OH:17])=[O:16])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(O)C(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: O=C(O)[C@H](O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
16.1 g (53.6 mmol) 3-(3,5-bis-trifluoromethyl-phenyl)-2-oxo-propionic acid in 9.5 (70.0 mmol) triethylamine and 100 mL THF were combined at −35° C. with a solution of 26.0 (81.1 mmol) (1R)—B-chlorodiisopinocampheylborane in 40 mL THF within 30 min, stirred for 1 h at this temperature and stirred overnight at RT. After the reaction had ended the reaction mixture was made alkaline at 0° C. with 160 mL 1 M NaOH, stirred for 15 min, combined with 100 mL TBME and the phases were separated. The organic phase was washed with 50 mL water and 50 mL 1 M NaOH. The combined aqueous phases were acidified with 4 M HCl, exhaustively extracted with TBME, the combined organic phases were dried over Na2SO4, suction filtered through activated charcoal and evaporated down i.vac. The product was reacted further without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19]([OH:21])=O)=[CH:5]2.[NH2:22][C:23]1[CH:24]=[C:25]2[N:31]=[C:30]([CH3:32])[NH:29][C:26]2=[N:27][CH:28]=1>>[CH3:32][C:30]1[NH:29][C:26]2=[N:27][CH:28]=[C:23]([NH:22][C:19]([C:6]3[N:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=4)[C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)=[O:21])[CH:24]=[C:25]2[N:31]=1
Reactant: Cc1nc2cc(N)cnc2[nH]1
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Product: Cc1nc2cc(NC(=O)c3cc4cc(F)ccc4n3Cc3cccc(F)c3)cnc2[nH]1

Procedure:
This compound was prepared according to a process similar to that described in Example 1.2, starting with 5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylic acid, prepared in Example 1.1 and 6-amino-2-methyl-3H-imidazo[4,5-b]pyridine, prepared in the preceding step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=2)[C:9]([O:11]C)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:21]([F:24])([F:22])[F:23])[CH:15]=2)[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)C(Oc1ccc(F)c(C(F)(F)F)c1)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C(Oc1ccc(F)c(C(F)(F)F)c1)c1ccc(Cl)cc1
Yield: 75.7 %

Procedure:
59.3 g (0.163 mol) of methyl 2-(4-chloro-phenyl)-2-(4-fluoro-3-trifluoromethyl-phenoxy)-acetate are added to a solution of 15 g of sodium hydroxide in 400 ml of water. The suspension obtained is stirred and heated at the reflux temperature until a limpid solution is obtained (duration, 4 hours). The reaction mixture is cooled and acidified with a hydrochloric acid solution; an oil precipitates, which is extracted with ether. The ether phase is washed with water and dried and the solvent is driven off. The residue is triturated in petroleum ether until it crystallises, and is recrystallised from a mixture of hexane and cyclohexane (50-50). 43 g (yield: 75%) of 2-(4-chlorophenyl)-2-(4-fluoro-3-trifluoromethyl-phenoxy)-acetic acid are thus obtained. Melting point = 106° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:15][CH:14]3[N:16](C)[CH:11]([CH2:12][CH2:13]3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].ClC(OC(Cl)C)=O.[OH-].[Na+]>ClCCCl.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:10][CH:11]3[NH:16][CH:14]([CH2:13][CH2:12]3)[CH:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1C2C=C(c3ccc(Cl)c(Cl)c3)CC1CC2
Agent: CC(Cl)OC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CO
Solvent: O
Product: Clc1ccc(C2=CC3CCC(C2)N3)cc1Cl
Yield: 50 %

Procedure:
To 1.08 g (4.03 mmol) 3-(3,4-dichloro-phenyl)-8-methyl-8-aza-bicyclo[3.2.1]oct-2-ene in 20 mL Cl(CH2)2Cl is added 1.31 mL (1.73 g, 12.08 mmol) of 1-chloroethyl chloroformate, and the resulting mixture is heated to reflux for 24 h. Evaporation of all volatiles gives an orange oil which is dissolved in methanol (20 mL) and heated to reflux for 1 h. Evaporation of all volatiles yielded an orange solid which is dissolved in 100 H2O and treated with 50 mL of 2.5 N NaOH. Extraction with 3×25 mL CH2Cl2, combining the organics and washing with 1×50 mL H2O, 1×50 mL brine, drying over MgSO4, filtering and evaporation a dark orange oil. Flash chromatography on SiO2 gel, eluting with EtOAc, then 10/1 EtOAc/2.0M NH3 in MeOH), gives 511 mg (2.01 mmol, a 50% yield) of the title compound as an orange solid. The oxalate salt of the title compound may be prepared by combining the title compound with 1 equiv. of oxalic acid in EtOH. A white solid precipitates. mp: 185-186° C. MS (ES) m/z 255 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:28])=[CH:4][C:5]2[O:26][C:25](=[O:27])[C:9]3[CH2:10][N:11]([CH2:14][CH2:15][N:16]4[CH2:22][CH:21]5[CH2:23][CH2:24][CH:18]([CH2:19][CH2:20]5)[CH2:17]4)[CH2:12][CH2:13][C:8]=3[C:6]=2[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)(Cl)Cl>[CH:21]12[CH2:23][CH2:24][CH:18]([CH2:19][CH2:20]1)[CH2:17][N:16]([CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][C:8]3[C:6]4[CH:7]=[C:2]([NH:1][C:35](=[O:42])[C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:3]([CH3:28])=[CH:4][C:5]=4[O:26][C:25](=[O:27])[C:9]=3[CH2:10]1)[CH2:22]2
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc2oc(=O)c3c(c2cc1N)CCN(CCN1CC2CCC(CC2)C1)C3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Cc1cc2oc(=O)c3c(c2cc1NC(=O)c1ccccc1)CCN(CCN1CC2CCC(CC2)C1)C3
Temperature: 0 °C
Yield: 38.2 %

Procedure:
A mixture of 9-amino-3-[2-(3-azabicyclo[3.2.2]non-3-yl)ethyl]-1,2,3,4-tetrahydro-8-methyl-5H-benzopyrano[3,4-c]pyridin-5-one (2.5 g, 0.007 moles), potassium carbonate (2.4 g, 0.017 moles), and benzoyl chloride (1.0 ml, 0.009 moles) is stirred in chloroform (50 ml) at room temperature. After 24 hours the mixture is poured into ice water. The layers are separated, and the aqueous phase is extracted with chloroform (2×60 ml). The combined organic extracts are washed with brine and dried (magnesium sulfate). The solvent is removed under reduced pressure to leave a syrup, which crystallized from ethyl acetate. Recrystallization gave the product (1.3 g), mp 174°-176° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=O)[O:30]CC)=[CH:24][CH:23]=1)[CH3:20]>COC(C)C(O)C>[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:16]=[CH:17][CH:18]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:9]=2)=[O:30])=[CH:24][CH:23]=1)[CH3:20]
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CCOC(=O)Nc1ccc(OCC)cc1
Agent: COC(C)C(C)O
Product: CCOc1ccc(NC(=O)NCCCOc2cccc(CN3CCCCC3)c2)cc1
Yield: 6.4 %

Procedure:
The mixture of 3-(3-piperidinomethylphenoxy)propylamine (4.7 g) and ethyl N-(4-ethoxyphenyl)carbamate (4.0 g) in 3-methoxy-2-butanol (20 ml) was refluxed for 6 hours and then concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane, washed with water, diluted hydrochloric acid solution, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution successively and dried over magnesium sulfate. After removal of the solvent under reduced pressure, the resulting residue was purified by silica gel flash column chromatography to give the precipitate (0.9 g; yield 11.4%). This precipitate was recrystallized from ethanol to give the title compound (0.5 g), mp 109-111° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([CH:10]=O)=[CH:7][CH:8]=[CH:9][C:2]1=2.O.[C:13]([O:16][CH2:17]C)(=O)C>O1CCCC1>[CH3:13][O:16][CH:17]=[CH:10][C:6]1[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(C)=O
Reactant: O=Cc1cccc2sccc12
Solvent: C1CCOC1
Solvent: O
Product: COC=Cc1cccc2sccc12
Temperature: -60 °C
Reaction time: 8 h

Procedure:
In an atmosphere of nitrogen, 4.85 g of (methoxymethyl)triphenylphosphonium chloride is suspended in 40 mL of tetrahydrofuran. Then, 1.5 mL of diisopropylamine is added to the suspension, and cooled to −60° C. After dropwise adding thereto 6.6 mL of 1.6 mol/L solution of n-butyllithium in hexane, the mixture thus obtained is stirred for 30 minutes at an ice-cooled temperature. Then, the reaction mixture is cooled to −60° C., a solution of 1.72 g of benzo[b]thiophene-4-carboaldehyde in 15 mL of tetrahydrofuran is dropwise added, and the resulting mixture is allowed to stand overnight at ambient temperature. The reaction mixture is introduced into a mixture of water and ethyl acetate, and the organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, the residue is treated with diethyl ether, and the deposited crystal is filtered off. The solvent is distilled off from the filtrate under reduced pressure, and the residue thus obtained is purified by column chromatography (eluent: n-hexane:ethyl acetate=100:1 to 50:1) to obtain 1.04 g of 2-benzo[b]thiophen-4-yl-1-ethenyl methyl ether as an oily product.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH:8]1[C:20]2[CH:19]([CH2:21][O:22][C:23]([NH:25][C@@H:26]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=3)[C:27]([O:29][CH3:30])=[O:28])=[O:24])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH:11]=[CH:10][CH:9]=1>>[CH:8]1[C:20]2[CH:19]([CH2:21][O:22][C:23]([NH:25][C@H:26]([C:27]([O:29][CH3:30])=[O:28])[CH2:31][C:32]3[CH:33]=[CH:34][C:35]([NH:38][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])=[CH:36][CH:37]=3)=[O:24])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C1CCC(=O)O1
Product: COC(=O)[C@H](Cc1ccc(NC(=O)CCC(=O)O)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
Succinic anhydride (6.72 g, 67.2 mmol) was added to the solution of (S)-methyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-aminophenyl)propanoate 3C from step 2. The reaction mixture was stirred at room temperature overnight. The solvent was removed, and the residual solid was washed with 30% ethyl acetate/petroleum ether (200 mL) and recrystallized in THF and 30% ethyl acetate/petroleum ether to give (S)-4-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-4-oxobutanoic acid 3D as a white solid (19 g, 66% yield). 1HNMR (DMSO-d6, 300 MHz) δ: 10-9.9 (s, 1H), 8.0-7.9 (m, 3H), 7.8-7.6 (m, 2H), 7.6-7.5(m, 2H), 7.5-7.4(m, 2H), 7.4-7.3(m, 2H), 7.3-7.1(d, 2H), 4.4-4.2 (m, 4H), 3.8-3.6 (s, 3H), 3.1-2.8 (m, 2H), 2.7-2.5 (m, 4H); ESI-MS: m/z 517.3 (M+H)+.