Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:19])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[O:11])[CH:9]=1.[C:20]([CH2:24]OS(C(F)(F)F)(=O)=O)([F:23])([F:22])[F:21].[NH4+].[Cl-]>CN(C=O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:19])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:24][C:20]([F:23])([F:22])[F:21])=[CH:14][CH:13]=2)=[O:11])[CH:9]=1
Reactant: O=C(c1ccc(O)cc1)c1cc(Br)ccc1Cl
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(OCC(F)(F)F)cc1)c1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
At 0° C., NaH (1.6 g) was added into a solution of (5-bromo-2-chlorophenyl)(4-hydroxyphenyl)methanone (6.2 g) in dry DMF (40 mL). The mixture was stirred at room temperature for 1 h. Then CF3CH2OTf (9.3 g) was slowly added into the mixture at 0° C. The mixture was stirred at room temperature for 0.5 h. Saturated NH4Cl aqueous solution was added slowly into the mixture, and the mixture was extracted with EtOAc. The organic phases were combined, dried over Na2SO4 and concentrated to obtain the crude product, then the crude product was purified by silica-gel column chromatography (PE/EA=20/1) to obtain 5.0 g of (5-bromo-2-chlorophenyl)(4-(2,2,2-trifluoroethoxy)phenyl)methanone.
Reaction SMILES: [CH2:1]([NH:5][C:6]([C:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:26]=[N:27][C:28]([C:31]([OH:34])([CH3:33])[CH3:32])=[CH:29][CH:30]=3)[CH:20]=2)[CH:9]=1)=[O:7])[CH:2]([CH3:4])[CH3:3].C(Cl)Cl.CO.O.O.O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:50].[Mg+2]>CCOCC>[CH2:1]([NH:5][C:6]([C:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:26]=[N+:27]([O-:50])[C:28]([C:31]([OH:34])([CH3:32])[CH3:33])=[CH:29][CH:30]=3)[CH:20]=2)[CH:9]=1)=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CNC(=O)c1cn(-c2cccc(-c3ccc(C(C)(C)O)nc3)c2)c2ncccc2c1=O
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: CC(C)CNC(=O)c1cn(-c2cccc(-c3ccc(C(C)(C)O)[n+]([O-])c3)c2)c2ncccc2c1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of N-isobutyl-1-{3-[6-(1-hydroxy-1-methylethyl)pyridin-3-yl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from Example 46 in 13:1 methylene chloride/methanol (33 ml/mmol) at room temperature was added magnesium monoperoxyphthalate hexahydrate (MMPP, 1.1 molareq) and the resulting mixture was stirred at room temperature for 24 hours. The mixture was filtered through a bed of celite and the filtrate was washed with aqueous sodium carbonate, then water and dried. The crude product was chromatographed on silica gel eluting with 8% ethanol in ethyl acetate and the solid obtained was stirred at room temperature in ether for several hours and filtered to afford the title compound as a light pink solid.
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3]([OH:5])=[O:4].[CH:7]1[C:12]2=[N:13][S:14][N:15]=[C:11]2[C:10]([NH:16][C:17]2[NH:21][CH2:20][CH2:19][N:18]=2)=[C:9]([Cl:22])[CH:8]=1.C(OCC)(=O)C>C(O)(C)C>[CH:7]1[C:12]2=[N:13][S:14][N:15]=[C:11]2[C:10]([NH:16][C:17]2[NH:21][CH2:20][CH2:19][N:18]=2)=[C:9]([Cl:22])[CH:8]=1.[Cl:1][CH:2]([Cl:6])[C:3]([O-:5])=[O:4]
Reactant: O=C(O)C(Cl)Cl
Agent: Clc1ccc2nsnc2c1NC1=NCCN1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: O=C([O-])C(Cl)Cl
Temperature: 2.5 °C

Procedure:
To a solution of 3.0 g of dichloroacetic acid in 5 ml of isopropyl alcohol, 3.0 g of tizanidine base (99.15% HPLC) are added. After short heating to boil a solution results, from which, after addition of ethyl acetate, a crystalline precipitated product starts to separate. After cooling to 0 to 5° C. and aspiration 4.15 g tizanidine dichloroacetate are obtained.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.O[C:11]1[N:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:19][CH:18]=2)=[N:15][CH:16]=1>>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:11]1[N:12]=[CH:13][C:14]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[CH:21][CH:22]=3)=[N:15][CH:16]=1)[CH2:2]2
Reactant: OC1CN2CCC1CC2
Reactant: O=C(Nc1ccc(-c2cnc(O)cn2)cc1)OCc1ccccc1
Product: O=C(Nc1ccc(-c2cnc(OC3CN4CCC3CC4)cn2)cc1)OCc1ccccc1

Procedure:
3-Quinuclidinol (Aldrich, 610 mg, 4.8 mmol) was treated with benzyl 4-(5-hydroxypyrazin-2-yl)phenylcarbamate (Ref. EP146282, 1.28 g, 4 mmol) according to the procedure of Example 5A. The title product was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3H2O, 90:10:1, Rf. 0.30) as solid (0.68 g, yield, 40%). 1H NMR (MeOH-d4, 300 MHz) δ 1.47-1.62 (m, 1H), 1.65-1.92 (m, 2H), 1.97-2.14 (m, 1H), 2.22-2.28 (m, 1H), 2.74-3.05 (m, 5H), 3.33-3.46 (m, 1H), 5.10-5.18 (m, 1H), 5.20 (s, 2H), 7.30-7.46 (m, 5H), 7.56 (d, J=8.8 Hz, 2H), 7.88 (d, J=8.8 Hz, 2H), 8.24 (d, J=1.4 Hz, 1H), 8.55 (d, J=1.4 Hz, 1H) ppm. MS (DCl/NH3) m/z 431 (M+H)+.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[C:23]([CH3:24])=[CH:22][C:7]2[NH:8][C:9]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=C(C#N)[CH:18]=4)[NH:13][N:12]=3)=[N:10][C:6]=2[CH:5]=1.[C:25]([OH:28])(=[O:27])[CH3:26]>>[CH3:24][C:23]1[C:4]([CH3:3])=[CH:5][C:6]2[NH:10][C:9]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:26]([C:25]([OH:28])=[O:27])[CH:18]=4)[NH:13][N:12]=3)=[N:8][C:7]=2[CH:22]=1
Reactant: CC(=O)O
Reactant: Cc1cc2nc(-c3n[nH]c4ccc(C#N)cc34)[nH]c2cc1C
Agent: Cl
Product: Cc1cc2nc(-c3n[nH]c4ccc(C(=O)O)cc34)[nH]c2cc1C
Temperature: 100 °C

Procedure:
A stirred suspension of 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carbonitrile dihydrochloride [200 mg, Reference Example 6(aq)] in acetic acid/concentrated hydrochloric acid (4 ml, 1:1 v/v) was heated at 100° C. for 16 hours. The reaction mixture was cooled to ambient temperature and filtered. The precipitate was washed with water and dried in vacuo to give 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carboxylic acid (195 mg) as a white solid. LC-MS (METHOD B): RT=2.52 minutes, 307 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@@H:11]1[CH2:15][C@H:14]([NH:16][C:17]([O:19][CH2:20][CH:21]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:27]3[C:22]2=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[CH2:13][N:12]1[C:34](=[O:50])[C@@H:35]([NH:42]C(OC(C)(C)C)=O)[CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:51]>O1CCOCC1>[ClH:51].[CH2:1]([O:8][C:9]([C@@H:11]1[CH2:15][C@H:14]([NH:16][C:17]([O:19][CH2:20][CH:21]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:27]3[C:22]2=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[CH2:13][N:12]1[C:34](=[O:50])[C@@H:35]([NH2:42])[CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)OCc1ccccc1)C1CCCCC1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H](C(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)OCc1ccccc1)C1CCCCC1
Reaction time: 1 h

Procedure:
(2S,4S)-1-((S)-2-tert-Butoxycarbonylamino-2-cyclohexyl-acetyl)-4-(9H-fluoren-9-ylmethoxycarbonylamino)-pyrrolidine-2-carboxylic acid benzyl ester (1.07 g, 1.77 mmol) was dissolved in 4 M HCl in 1,4-dioxane (6 mL) at 0° C. and stirred for 1 h, the cooling bath removed and the reaction stirred for 1 h. The mixture was concentrated and the residue triturated with diethyl ether to give (2S,4S)-1-((S)-2-amino-2-cyclohexyl-acetyl)-4-(9H-fluoren-9-ylmethoxycarbonylamino)-pyrrolidine-2-carboxylic acid benzyl ester hydrochloride (0.97 g) as a light yellow solid which was used without further purification or characterization.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH2:11][CH3:12])=[C:4]([CH2:13][CH3:14])[CH:3]=1.[CH2:15]([Sn](CCCC)(CCCC)CCCC)[CH:16]=[CH2:17].O>CN(C=O)C.Cl[Pd](Cl)(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:17]([C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH2:11][CH3:12])=[C:4]([CH2:13][CH3:14])[CH:3]=1)[CH:16]=[CH2:15]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: CCOCOc1ccc(Br)cc1CC
Agent: Cl[Pd](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: C=CCc1ccc(OCOCC)c(CC)c1
Temperature: 120 °C

Procedure:
15 g (58 mmol) of 4-bromo-1-ethoxymethoxy-2-ethylbenzene are dissolved in 150 ml of DMF. 26.9 ml (87 mmol) of allyltributyltin are added, and then the mixture is degassed with a nitrogen stream. 1.2 g (1.8 mmol) of dichlorobis (triphenylphosphino)palladium are added, and the medium is heated at 120° C. for 10 hours. The reaction medium is poured into water, and then extracted with ethyl acetate. The residue obtained after drying and concentration is purified by chromatography on a silica column (eluent heptane, and then heptane 95/ethyl acetate 5). A yellow oil is obtained (m=13.6 g, y=100%).
Reaction SMILES: [OH:1][C:2]1[C:17]([CH:18]=[N:19]O)=[C:6]2[CH:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)[O:9][C:5]2=[C:4]([O:21][CH3:22])[CH:3]=1.[H-].[Na+].[OH-].[Na+].Cl>CC(OC(C)=O)=O.CO>[OH:1][C:2]1[C:17]([C:18]#[N:19])=[C:6]2[CH:7]=[C:8]([C:10]3[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=3)[O:9][C:5]2=[C:4]([O:21][CH3:22])[CH:3]=1
Reactant: COc1cc(O)c(C=NO)c2cc(-c3ccc(O)cc3)oc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: COc1cc(O)c(C#N)c2cc(-c3ccc(O)cc3)oc12
Temperature: 100 °C

Procedure:
The crude 7 oxime 72 was heated in neat Ac2O at 100° C. for 30 minutes. The Ac2O was removed and the crude product was dissolved in EtOAc, washed with brine and dried over MgSO4. The solution was concentrated down and the crude triacetate was dissolved in DMF (10 mL) and treated with NaH (0.1 g, 60% dispersion in mineral oil, 2.5 mmol) and the reaction mixture was heated to 100° C. for 15 min. After cooling to rt, the solution was treated with a 20% NaOH aq solution and enough MeOH to get everything in one phase. This solution was then heated briefly (long enough to hydrolyze the acetates as determined by TLC analysis) and allowed to cool back to rt. The solution was acidifed with 2N HCl aq and the solution was extracted with EtOAc. The EtOAc extract was washed with NaHCO3 and brine and dried over MgSO4. The solution was filtered, concentrated and chromatographed on silica gel (2:8 to 4:6 EtOAc/hexanes) to yield 80 mg of the pdt nitrile 73 as a white solid: Mp=286-288° C.; 1H NMR (DMSO-d6) δ 10.9 (br s, 1 H), 9.98 (br s, 1 H), 7.77 (d, 2 H, J=8.7 Hz), 7.20 (s, 1 H), 6.87 (d, 2 H, J=8.7 Hz), 6.48 (s, 1 H), 3.97 (s, 3 H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([Cl:25])[C:7]2[C:8]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13][C:9]=3[NH:10][C:11]=2[CH:12]=1.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([Cl:25])[C:7]2[C:8]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][CH2:13][C:9]=3[N:10]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:11]=2[CH:12]=1
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3cc(Cl)cc(Cl)c3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c2c(c3c(Cl)cc(Cl)cc31)CCN(C(=O)OC(C)(C)C)CC2
Reaction time: 0.33 h
Yield: 75.5 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.25 g, 6.3 mmol) was added to a solution of tert-butyl 8,10-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (1.5 g, 4.2 mmol) in DMF (15 mL). After 20 min, ethyl bromoacetate(0.94 mL, 8.4 mmol) was added. The reaction was quenched with saturated aqueous NH4Cl after 1.5 h and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40M) with heptane/EtOAc (3:1) followed by crystallization from MeOH/EtOAc to give 1.4 g (78%) of a white solid: mp 144.5-147.0° C.; IR (diffuse reflectance) 2982, 2972, 1748, 1690, 1456, 1411, 1373, 1366, 1352, 1252, 1222, 1202, 1159, 1115, 824cm−1; MS (EI) m/z 440 (M+), 442, 440, 386, 384, 310, 300, 298, 86, 84, 57; Anal. Calcd for C21H26Cl2N2O4: C, 57.15; H, 5.94; N, 6.35; found: C, 57.15; H, 6.04; N, 6.37.
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([NH2:12])=[O:11].[NH:16]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C@H:17]([C:26](ON1C(=O)CCC1=O)=[O:27])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=1>CN(C=O)C>[NH:16]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C@H:17]([C:26]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([NH2:12])=[O:11])=[O:27])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([I:25])=[CH:23][CH:24]=1
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)N1CCC[C@H]1C(N)=O
Reaction time: 16 h

Procedure:
Triethylamine (163.8 ml, 1.17 mmol) was added to a solution of H-ProNH2*HCl (118.5 mg, 0.782 mmol) in dry DMF (10 ml). Boc-p-Iodo-Phe-OSu (0.42 g, 0.86 mmol) was added in one portion and the mixture stirred for 16 h under an argon atmosphere. The solvent was evaporated and the residue treated in a standard way, i.e. the residue was partitioned between ethylacetate (60 ml) and 0.3N KHSO4 solution (10 ml). The organic layer was further washed with saturated NaCHO3 solution (10 ml), water (10 ml)and brine (5 ml). The solution was dried and evaporated at reduced pressure.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][C:16]=1[CH3:24].O[N:26]=[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36])[NH2:28].CCN(C(C)C)C(C)C>>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:23][N:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])[N:26]=2)=[CH:17][C:16]=1[CH3:24]
Reactant: COc1ccccc1-c1ccc(C(=O)O)cc1C
Reactant: COc1ccccc1C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1noc(-c2ccc(-c3ccccc3OC)c(C)c2)n1

Procedure:
Oxalyl chloride (126 μL; 1.5 mmol; 3 eq.), Intermediate 26 (120 mg; 0.5 mmol; 1 eq.), Intermediate 1 (82 mg; 0.5 mmol, 1 eq.) and DIEA (256 μL; 1.5 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography c-hexane/ethyl acetate, 90/10) followed by precipitation from n-pentane afforded the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)[CH:16]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)[CH:16]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(OCc2cccc(OCc3ccc4ccccc4n3)c2)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)O)ccc1OCc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 60 °C

Procedure:
A mixture of 2.6 g of methyl 3-methoxy-4-[3-(2-quinolinylmethyloxy)benzyloxy]benzoate and 0.6 g of NaOH in 15 ml of THF and 2 ml of H2O are heated at 60° C. overnight. The reaction mixture is diluted with 20 ml of H2O and acidified to pH 4. The product is collected on a filter and dried to give 3-methoxy-4-(3-(2-quinolinylmethyloxy)benzyloxy)benzoic acid. (M.P. 188°-190° C.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9](=[N:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=1)[NH2:10].N1C=CC=CC=1.[C:26](Cl)(Cl)=[O:27]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:26](=[O:27])[N:12]([C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=2)[N:11]=1
Reactant: NC(=NNc1ccc(I)cc1)c1c(F)cccc1Cl
Reactant: O=C(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(I)cc1
Yield: 41.7 %

Procedure:
The title a compound was prepared according to the procedure described in step-4 of Intermediate-1 using 2-chloro-6-fluoro-N′-(4-iodophenyl)benzene carbohydrazonamide (0.900 g, 2.31 mmol), pyridine (0.65 mL, 5.79 mmol), phosgene (2.50 mL, 4.63 mmol) and CHCl3 (20 mL). The obtained crude product was purified with column chromatography on silica gel eluting with 1.0% MeOH:DCM to afford 0.400 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.47 (t, J=9.0 Hz, 2H), 7.54-7.82 (m, 5H), 12.62 (s, 1H). MS (m/z): 414.25 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[C:5]3[CH:16]=[CH:15][S:14][C:6]=3[NH:7][C:8](=[O:13])[C:9]=2[CH:10]=[CH:11][CH:12]=1.[Cl-].CC=[N+]=CC.[CH3:23][N:24]([CH:26]=O)[CH3:25]>C(#N)C>[CH3:23][N:24]([CH2:26][C:15]1[S:14][C:6]2[NH:7][C:8](=[O:13])[C:9]3[CH:10]=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[C:4]=3[C:5]=2[CH:16]=1)[CH3:25]
Reactant: COc1cccc2c(=O)[nH]c3sccc3c12
Reactant: CN(C)C=O
Agent: CC=[N+]=CC
Agent: [Cl-]
Solvent: CC#N
Product: COc1cccc2c(=O)[nH]c3sc(CN(C)C)cc3c12
Reaction time: 1.5 h

Procedure:
9-Methoxy-4H-thieno[2,3-c]isoquinolin-5-one (12.7 g; 54.9 mmol) and N,N-dimethylmethyleneammonium chloride (8.53 g; 91.14 mmol) were placed in a 0.5 L three neck round bottle flask under nitrogen atmosphere. Under stirring, DMF (75 mL) was added followed by acetonitrile (ACN) (190 mL) and the reaction mixture was placed into a preheated oil bath (90° C.). The reaction was complete after 1.5 hrs indicated by a worked up NMR sample.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH:14]([C:18]([N:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=4[CH3:33])[CH2:22][CH2:21]3)=[O:19])[CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:41][CH2:42][CH2:43][CH2:44][CH3:45].O>CC(C)=O>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:14]([C:18]([N:20]3[CH2:21][CH2:22][N:23]([C:26]4[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=4[CH3:33])[CH2:24][CH2:25]3)=[O:19])[CH2:13]2)(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: CCCCCBr
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccc(Cl)cc4)CCN3)CC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCN1CCN(S(=O)(=O)c2ccc(Cl)cc2)CC1C(=O)N1CCN(c2cc(C)ccc2C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [4-(4-chloro-benzenesulfonyl)-piperazin-2-yl]-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone hydrochloride (100 mg) in acetone (4 mL) was added cesium carbonate (254 mg), followed by 1-bromopentane (27 μL). The reaction mixture was stirred at ambient temperature for 1 h. Additional cesium carbonate (127 mg) and 1-bromopentane (14 μL) were added and stirring was continued at reflux over night. Water was added and the reaction mixture was extracted with ethyl acetate (×2). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. Purification by chromatography (SiO2, n-heptane/ethyl acetate 3:1) yielded [4-(4-chloro-benzenesulfonyl)-1-pentyl-piperazin-2-yl]-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone as a white foam, MS: 547.3 ([M+H, 1Cl]+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]([N:21]2[CH2:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH2:19][NH2:20])=[CH:14][N:13]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:15]1[CH:16]=[N:17][C:12]([CH3:11])=[N:13][CH:14]=1)[N:21]1[CH2:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: Cc1ncc(C(CN)N2CCCOCC2)cn1
Product: Cc1ncc(C(CNC(=O)c2ccccc2Cl)N2CCCOCC2)cn1

Procedure:
From 2-chlorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(1,4-oxazepan-4-yl)ethanamine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[Cl:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:30]1[CH2:29][CH2:28][N:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([Cl:20])[CH:22]=3)[CH2:32][CH2:31]1)=[O:19])=[N:5]2
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(F)ccc2nc1OC
Product: COc1nc2ccc(F)cc2nc1NC(=O)N1CCN(c2cccc(Cl)c2)CC1
Yield: 70 %

Procedure:
Ethyl N-(6-fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound (yield, 70%). 1H NMR (200 MHz, CDCl3): δ 3.30 (s, 4H), 3.76 (s, 3H), 4.13 (s, 4H), 6.77-6.91 (m, 3H), 7.15-7.33 (m, 3H), 7.44-7.58 (d, J=10.0 Hz, 1H), 7.58-7.75 (m, 1H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]1[O:15][CH2:14][CH2:13][O:12]1)(=[O:3])[CH3:2].[F:16][C:17]1[C:18](=[O:24])[NH:19][C:20](=[O:23])[NH:21][CH:22]=1>ClCCl.C[Si](C1NC(=O)N([Si](C)(C)C)C(=O)C=1F)(C)C>[OH:12][CH2:13][CH2:14][O:15][CH:11]([N:21]1[CH:22]=[C:17]([F:16])[C:18](=[O:24])[NH:19][C:20]1=[O:23])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][C:1](=[O:3])[CH3:2]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: CC(=O)Oc1ccccc1C1OCCO1
Agent: C[Si](C)(C)c1[nH]c(=O)n([Si](C)(C)C)c(=O)c1F
Solvent: ClCCl
Product: CC(=O)Oc1ccccc1C(OCCO)n1cc(F)c(=O)[nH]c1=O
Yield: 16.1 %

Procedure:
2-Hydroxygenzaldehyde (10 g) was dissolved in acetic anhydride (30 ml) and pyridine (30 ml) followed by stirring at room temperature for 3 hours. The reaction mixture was poured into ice-water and the resulting precipitate was recovered by filtration. The precipitate was dissolved in chloroform (100 ml), washed with water, dried and evaporated to give 2-acetoxybenzaldehyde. To a solution of 2-acetoxy-benzaldehyde (13 g) and ethyleneglycol (10 ml) in benzene (80 ml) was added Amberlist 15 (Rohm and Haas Co.) (3 g) and followed by refluxing for 5 hours. Water generated during refluxing was removed as an azeotropic mixture. The reaction mixture was washed with an aqueous solution of sodium bicarbonate, and then with water, and dried and evaporated. The residue was distilled under reduced pressure to collect a fraction distilled out at 115°-125° C./4 mmHg to give 10 g of 2-(2-acetoxyphenyl)-1,3-dioxolan. To a solution of 2-(2-acetoxy-phenyl)-1,3-dioxolan (19.6 g) in dichloromethane (50 ml), bis(trimethylsilyl)-5-fluorouracil prepared as in Example 1 from 5-fluorouracil (10 g) was added and treated as in Example 10 to give 4.2 g of crystalline 1-[α-(2-hydroxyethoxy)-2-acetoxybenzyl]-5-fluorouracil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[NH2:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:29][CH2:28]1.C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:19](=[O:20])[C:18]1[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=1[C:16]([NH:26][CH:27]1[CH2:28][CH2:29][N:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:31][CH2:32]1)=[O:25]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(NC(=O)C2=C(C(=O)Nc3cc(OC4CCCC4)c(Cl)cc3F)CCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), ethyl 4-amino-1-piperidinecarboxylate (0.620 g, 3.60 mmol), triethylamine (0.310 g, 3.06 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the resulting crude product was recrystallized from ether to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(1-ethoxycarbonyl-4-piperidyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.732 g, 50.9% yield).