Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([OH:10])[CH3:9].Cl[C:13]1[C:14]2[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[C:20]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:19][C:15]=2[N:16]=[CH:17][N:18]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([O:10][C:13]1[C:14]2[C:21]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)=[C:20]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[O:19][C:15]=2[N:16]=[CH:17][N:18]=1)[CH3:9]
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Reactant: COC(=O)CCCCC(C)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCCCC(C)Oc1ncnc2oc(-c3ccccc3)c(-c3ccc(OC)cc3)c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Put 1.902 g (11.9 mmol) (+/−)-6-hydroxyheptanoic acid methyl ester under argon in 20 ml THF and cool to 0° C. Add 6 ml (11.9 mmol) of a 2 M solution of the phosphazene base P2-tert.-butyl in THF and stir for a further 10 min at RT. Then cool to 0° C. again. Add 2.00 g (5.94 mmol) 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine and then stir for a further 1 h at RT. Dilute with water, acidify with 10% aqueous citric acid solution and extract twice with ethyl acetate. Combine the ethyl acetate phases and wash once with satd. sodium chloride solution. Dry over magnesium sulphate, concentrate by evaporation and purify the residue by column chromatography on silica gel (solvent: cyclohexane/ethyl acetate 9:1). 1.38 g (78.0% of theor.) of the target compound is obtained.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[NH:4][C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.Br[CH2:12][C:13]([NH2:15])=[O:14].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Br:1][C:2]1[C:3](=[O:10])[N:4]([CH2:12][C:13]([NH2:15])=[O:14])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)c(=O)[nH]c1=O
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cn1cc(Br)c(=O)n(CC(N)=O)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 5-bromo-1-methylpyrimidine-2,4(1H,3H)-dione (200 mg, 0.976 mmol), 2-bromoacetamide (162 mg, 1.171 mmol) and K2CO3 (162 mg, 1.171 mmol) in DMSO (4 mL) was stirred at room temperature for 4 hours. The reaction mixture was subsequently filtered and purified via preparative HPLC, eluting with a gradient of 1-40% ACN (containing 0.035% TFA) in H2O (containing 0.05% TFA) to give the title compound.
Reaction SMILES: [OH-:1].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)C[C:8]([C:13]1[C:22]([N:23]3[C:32]4[C:27](=[CH:28][C:29]([F:33])=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]3)=[N:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:34]([O:36]C)=[O:35])[CH:19]=3)[N:14]=1)=[CH:7]2>CO.O1CCCC1>[F:33][C:29]1[CH:28]=[C:27]2[C:32](=[CH:31][CH:30]=1)[N:23]([C:22]1[C:13]([C:8]3[O:1][C:10]4[CH:11]=[CH:12][C:4]([F:3])=[CH:5][C:6]=4[CH:7]=3)=[N:14][C:15]3[C:20]([N:21]=1)=[CH:19][C:18]([C:34]([OH:36])=[O:35])=[CH:17][CH:16]=3)[CH2:24][CH2:25][CH2:26]2
Reactant: COC(=O)c1ccc2nc(C3=Cc4cc(F)ccc4C3)c(N3CCCc4cc(F)ccc43)nc2c1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2nc(-c3cc4cc(F)ccc4o3)c(N3CCCc4cc(F)ccc43)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
Sodium hydroxide (15.6 mg, 0.39 mmol) was added to a solution of methyl 2-(5-fluoro-1H-inden-2-yl)-3-(6-fluoro-3,4-dihydroquinolin-1(2H)-yl)quinoxaline-6-carboxylate (59 mg, 0.13 mmol) in methanol (25 mL) and tetrahydrofuran (5 mL). The reaction was stirred overnight at room temperature, concentrated in vacuo, dissolved in water (30 mL), and adjusted to pH 5 with hydrogen chloride (3 N). The precipitate was collected by filtration to afford 3-(6-fluoro-3,4-dihydroquinolin-1(2H)-yl)-2-(5-fluorobenzofuran-2-yl)quinoxaline-6-carboxylic acid (32.5 mg, 57%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][N:4]=1.[P:13]([O:20]CC)([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>C1(C)C=CC=CC=1>[F:10][C:9]([F:12])([F:11])[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])=[N:4][CH:5]=1
Reactant: FC(F)(F)c1ccc(CBr)nc1
Reactant: CCOP(OCC)OCC
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1ccc(C(F)(F)F)cn1)OCC

Procedure:
To a solution of 2-(bromomethyl)-5-(trifluoromethyl)pyridine (3.0 g, 12.5 mmol) in toluene (100 ml) was added triethyl phosphite (6.2 g, 37.0 mmol). The reaction was refluxed for 17 hours and was then concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-50% ethyl acetate/n-hexane) to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:17]2[C:21](=[O:22])[NH:20][N:19]=[CH:18]2)[S:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:8].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:34][CH:35]1[CH2:37][C:36]1([F:39])[F:38])(=O)=O>CN(C)C=O.C(OCC)(=O)C>[F:38][C:36]1([F:39])[CH2:37][CH:35]1[CH2:34][N:20]1[C:21](=[O:22])[N:17]([C:4]2[S:5][C:6]([C:7]([NH:9][CH2:10][C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[O:8])=[C:2]([CH3:1])[N:3]=2)[CH:18]=[N:19]1
Reactant: CS(=O)(=O)OCC1CC1(F)F
Reactant: Cc1nc(-n2cn[nH]c2=O)sc1C(=O)NCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(-n2cnn(CC3CC3(F)F)c2=O)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 41 %

Procedure:
To a suspension of 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide (0.15 g, 0.47 mmol) and potassium carbonate (0.10 g, 1.47 mmol) in N,N-dimethylformamide (2 mL) was added (2,2-difluorocyclopropyl)-methyl methanesulfonate (0.13 g, 0.70 mmol). The reaction mixture was kept stirring at ambient temperature for 20 hours, diluted with ethyl acetate (100 mL) and washed with water and brine. The organic solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography to afford the title compound in 41% yield (0.08 g): mp 160-161° C.; 1H NMR (300 MHz, CDCl3) δ 8.53-8.41 (m, 2H), 8.24 (s, 1H), 7.69-7.62 (m, 1H), 7.27-7.16 (m, 2H), 4.54 (d, J=5.8 Hz, 2H), 4.00-3.81 (m, 2H), 2.58 (s, 3H), 2.08-1.91 (m, 1H), 1.56-1.41 (m, 1H), 1.40-1.10 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 161.8, 153.3, 150.9, 149.8, 149.1, 148.7, 135.8, 133.9, 131.1, 123.7, 121.8, 112.7, 43.2, 41.5, 20.8, 17.2, 15.4; MS (ES+) m/z 407.1 (M+1).
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([N:19]3[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])[O:21][C:20]3=[O:29])[CH:16]=2)[N:11]1[CH:30]=[O:31])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[OH:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([N:19]3[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])[O:21][C:20]3=[O:29])[CH:16]=2)[N:11]1[CH:30]=[O:31]
Reactant: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CC(CO[Si](C)(C)C(C)(C)C)N3C=O)C(=O)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CC(CO)N3C=O)C(=O)O1
Temperature: 0 °C
Yield: 76.9 %

Procedure:
A stirred, ice cold mixture of the product from Step 10 (0.35 g, 0.78 mmol) and THF (20 ml), under nitrogen is treated, dropwise stirring 3 min, with 1 M tetrabutylammonium fluoride in THF (3.31 ml). It is kept in the ice bath for 5 min and at ambient temperature for 2 h. It is then diluted with EtOAc, washed with water and brine, dried (MgSO4) and concentrated. Chromatography of the residue over silica gel with acetone gave 0.20 g of the titled product: mp 132-136° C.; HRMS (FAB) calcd for C16H19N3O5+H 334.1403, found 334.1418; 1H NMR [300 MHz, (CD3)2SO] δ1.81 (s, 3H), 2.80, 3.01 (m, m, 1H), 3.38 (m, 5H), 3.69 (m, 1H), 4.06 (m, 1H), 4.45 (m, 1H), 4.68 (m, 1H), 4.89, 5.17 (t, t, 1H), 7.26 (m, 1H), 7.38, 7.86 (d, d, 1H), 7.48 (m, 1H), 8.24 (t, 1H), 8.44, 8.95 (s, s, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:28])[C:17]([NH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:18])=[CH:11][C:10]=1[F:29])C1C=CC=CC=1.Br>C(O)(=O)C>[F:29][C:10]1[CH:11]=[C:12]([NH:15][C:16](=[O:28])[C:17]([NH:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:18])[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: O=C(NCCc1ccccc1)C(=O)Nc1ccc(OCc2ccccc2)c(F)c1
Agent: Br
Solvent: CC(=O)O
Product: O=C(NCCc1ccccc1)C(=O)Nc1ccc(O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(4-benzyloxy-3-fluorophenyl)-N′-(2-phenylethyl)ethanediamide (40 g, 100 mmol) and 38% hydrobromic acid in acetic acid (250 mL) was stirred at room temperature overnight. The resulting solid was filtered, washed with water and dried to give N-(3-fluoro-4-hydroxyphenyl)-N′-(2-phenylethyl)ethanediamide as a slightly yellow solid (30.6 g, 99% yield). 1H NMR (400 MHz, d6-DMSO): δ 10.60 (s, 1H), 9.02 (t, 1H), 7.70 (d, 1H), 7.47 (d, 1H), 7.32-7.20 (m, 3H), 6.91 (t, 1H), 3.43 (m, 2H), 2.81 (m, 2H); 13C NMR (100 MHz, d6-DMSO): δ 160.5, 158.8, 152.0, 149.6, 142.2, 139.8, 130.3, 129.3, 129.0, 126.8, 118.1, 117.4, 109.6, 109.3 IR (cm−1): 3279, 1653, 1518, 1456, 1279, 1190, 742, 696, 584; LC/MS (M+H=303).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[NH:6][C:5]2[N:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[N:10]=[C:11]([CH:12]3[CH2:15][CH2:14][CH2:13]3)[C:4]=2[CH:3]=1.[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[C:25]([Cl:27])[CH:26]=1.[F-].[Cs+]>C(COC)OC.C(Cl)Cl.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>[C:16]([N:9]1[C:5]2[NH:6][C:7](=[O:8])[C:2]([C:23]3[CH:22]=[C:21]([Cl:20])[CH:26]=[C:25]([Cl:27])[CH:24]=3)=[CH:3][C:4]=2[C:11]([CH:12]2[CH2:15][CH2:14][CH2:13]2)=[N:10]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)n1nc(C2CCC2)c2cc(Br)c(=O)[nH]c21
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: ClCCl
Solvent: COCCOC
Product: CC(C)(C)n1nc(C2CCC2)c2cc(-c3cc(Cl)cc(Cl)c3)c(=O)[nH]c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 12 %

Procedure:
To a stirring solution of 5-bromo-1-tert-butyl-3-cyclobutyl-1,7-dihydro -pyrazolo[3,4-b]pyridin-6-one (50.0 mg, 0.15 mmol) in dimethoxyethane (1.5 mL) was added 3,5-dichlorophenyl-boronic acid (32.6 mg, 0.17 mmol), followed by cesium fluoride (51.9 mg, 0.34 mmol), and Pd(PPh3)4 (catalytic amount, 0.005 mmol). The reaction mixture was heated to reflux. After 3 hr, additional amounts of 3,5-dichlorophenyl-boronic acid (32.6 mg, 0.17 mmol), cesium fluoride (51.9 mg, 0.34 mmol), and Pd(PPh3)4 (catalytic amount, 0.005 mmol) were added. After a total of 18 hr, the reaction was cooled to room temperature, diluted with CH2Cl2 and washed with water. The organic layer was dried over MgSO4, filtered through a fritted funnel, and concentrated under reduced pressure. Purification of the resulting material was accomplished by flash chromatography with a Biotage® column, eluting with 5% EtOAc/toluene. The product-containing fractions were collected and concentrated to give the title compound (7.0 mg, 12% yield). LRMS m/z (APCl) 390. 392(M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([C@@H:10]([NH:20][C:21](=[O:39])[CH2:22][N:23]2[C:31]3[C:30]([F:33])([F:32])[CH2:29][CH2:28][C:27]([F:35])([F:34])[C:26]=3[C:25]([CH:36]([F:38])[F:37])=[N:24]2)[CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)=[N:4][C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.Br[C:41]1C([C@@H](NC(=O)CN2C3C(F)(F)CCC(F)(F)C=3C(C(F)F)=N2)CC2C=C(F)C=C(F)C=2)=NC(S(C)(=O)=O)=NC=1.Cl.CNC>>[Br:1][C:2]1[C:3]([C@@H:10]([NH:20][C:21](=[O:39])[CH2:22][N:23]2[C:31]3[C:30]([F:33])([F:32])[CH2:29][CH2:28][C:27]([F:34])([F:35])[C:26]=3[C:25]([CH:36]([F:37])[F:38])=[N:24]2)[CH2:11][C:12]2[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=2)=[N:4][C:5]([N:8]([CH3:41])[CH3:9])=[N:6][CH:7]=1
Reactant: CNc1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1
Reactant: CS(=O)(=O)c1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1
Agent: CNC
Agent: Cl
Product: CN(C)c1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1

Procedure:
The title compound (18A) was prepared according to the method presented for the synthesis of compound 14A of Example 14 utilizing 12C and dimethylamine hydrochloride. MS (m/z) 643.09 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](CC(F)(F)F)[C:6]([C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17])=[CH:5]2.[Cl:24][CH2:25][CH2:26][CH2:27]OC1C=C2C(=CC=1)NC(C(O)=O)=C2.N1CCOCC1>>[Cl:24][CH2:25][CH2:26][CH2:27][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:16]([N:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1)=[O:17])=[CH:5]2
Reactant: O=C(O)c1cc2cc(OCCCCl)ccc2[nH]1
Reactant: O=C(c1cc2cc(O)ccc2n1CC(F)(F)F)N1CCOCC1
Solvent: C1COCCN1
Product: O=C(c1cc2cc(OCCCCl)ccc2[nH]1)N1CCOCC1

Procedure:
In analogy to the procedure described for the synthesis of intermediate 1, step 4, the title compound was synthesized from 5-(3-chloro-propoxy)-1H-indole-2-carboxylic acid (Example 4, step 2) and morpholine. The desired product was obtained as white solid in 84% yield. MS (m/e): 324.0 (MH+, 100%).
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][N:12]1[C:17](=[O:18])[CH:16]=[CH:15][C:14]([C:19]2[S:20][CH:21]=[C:22]([CH3:24])[CH:23]=2)=[N:13]1)C(=O)OC(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][NH:2][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[CH:16]=[CH:15][C:14]([C:19]2[S:20][CH:21]=[C:22]([CH3:24])[CH:23]=2)=[N:13]1
Reactant: Cc1csc(-c2ccc(=O)n(CCN(C)C(=O)OC(C)(C)C)n2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCn1nc(-c2cc(C)cs2)ccc1=O

Procedure:
A solution of tert-butyl methyl(2-(3-(4-methylthiophen-2-yl)-6-oxopyridazin-1(6H)-yl)ethyl)carbamate (340 mg, 973 μmol) in CH2Cl2 (5 mL) and TFA (5 mL) was stirred for 30 min at 23° C. The solvents were removed under reduced pressure and the residue partitioned between CH2Cl2 (20 mL) and 1M NaOH (10 mL). The organic layer was dried over MgSO4, concentrated and purified on silica (12 g) eluting with 0-6% (2M NH3 in MeOH/CH2Cl2) to give the product as an amber oil. MS (ESI pos. ion) m/z (MH+): 250. Calc'd exact mass for C12H15N3OS: 249. 1H NMR (400 MHz, Chloroform-d) δ ppm 1.60 (br. s., 2 H) 2.28 (d, J=0.78 Hz, 3 H) 2.49 (s, 3 H) 3.07 (t, J=6.06 Hz, 2 H) 4.32 (t, J=6.06 Hz, 2 H) 6.88-7.01 (m, 2 H) 7.18 (d, J=1.17 Hz, 1 H) 7.54 (d, J=9.59 Hz, 1 H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([CH2:16][O:17][CH:18]3[CH:23]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][O:34][CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=5[O:42][CH3:43])=[CH:26][CH:25]=4)[CH2:22][CH2:21][N:20]([C:44]([O:46][CH2:47][C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)=[O:45])[CH2:19]3)[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][C:7]1=[O:54].C(=O)([O-])O.[Na+].Cl[C:61]([O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)=[O:62]>C(OCC)(=O)C>[CH2:64]([O:63][C:61]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([CH2:16][O:17][CH:18]3[CH:23]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][O:34][CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=5[O:42][CH3:43])=[CH:26][CH:25]=4)[CH2:22][CH2:21][N:20]([C:44]([O:46][CH2:47][C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)=[O:45])[CH2:19]3)[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][C:7]1=[O:54])=[O:62])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(c2)N(CCCCN)C(=O)CO3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(c2)N(CCCCNC(=O)OCc2ccccc2)C(=O)CO3)cc1
Reaction time: 1 h

Procedure:
The stirred solution of 0.300 g of benzyl 3-[4-(4-aminobutyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 316b) and 3 ml of ethyl acetate is admixed at 0° C. with 3 ml of aqueous 1M sodium hydrogencarbonate solution and 0.072 ml of benzyl chloroformate. After 1 hour, the reaction mixture is poured onto water (40 ml) and extracted with ethyl acetate (2×40 ml). The organic phases are washed with brine (40 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.21 (1:1 EtOAc-heptane); Rt=5.90.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:43])[CH2:5][S:6](=[O:42])(=[O:41])[N:7]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)=[CH:23][CH:22]=1)[CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][C:13]([C:19]#[N:20])=[CH:14][CH:15]=2)[CH:10]=1)[CH3:2].CI.[C:46](=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:37]([O:36][C:34]([N:31]1[CH2:32][CH2:33][CH:28]([O:27][C:24]2[CH:23]=[CH:22][C:21]([N:7]([CH2:8][C:9]3[CH:18]=[CH:17][C:16]4[C:11](=[CH:12][C:13]([C:19]#[N:20])=[CH:14][CH:15]=4)[CH:10]=3)[S:6]([CH:5]([CH3:46])[C:4]([O:3][CH2:1][CH3:2])=[O:43])(=[O:41])=[O:42])=[CH:26][CH:25]=2)[CH2:29][CH2:30]1)=[O:35])([CH3:39])([CH3:38])[CH3:40]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CS(=O)(=O)N(Cc1ccc2ccc(C#N)cc2c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CCOC(=O)C(C)S(=O)(=O)N(Cc1ccc2ccc(C#N)cc2c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 81.1 %

Procedure:
Ethyl[N-[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl]sulfamoyl]acetate (500 mg) was dissolved in 10 ml of acetonitrile, 0.52 ml of methyl iodide and 136 mg of potassium carbonate were added to the solution, and the mixture was stirred under reflux for 5 hours and 30 minutes. After cooling the reaction solution, the precipitate was removed by filtration, and the resulting filtrate was concentrated under a reduced pressure. The resulting residue was applied to silica gel column chromatography, which was eluted with hexane:ethyl acetate (3:1) to give 415 mg of ethyl 2-[N-[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl]sulfamoyl]propionate.
Reaction SMILES: [CH2:1]([C@:3]1([OH:29])[C:26]2[CH:25]=[C:24]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:23])[CH:18]=[C:19]([F:22])[C:20]=3[CH:21]=4)[C:9](=[O:27])[C:8]=2[CH2:7][O:6][C:5](=[O:28])[CH2:4]1)[CH3:2].[F:30][C:31]([F:37])([F:36])[CH2:32][CH2:33]C=O>>[CH2:1]([C@:3]1([OH:29])[C:26]2[CH:25]=[C:24]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:23])[CH:18]=[C:19]([F:22])[C:20]=3[C:21]=4[CH2:33][CH2:32][C:31]([F:37])([F:36])[F:30])[C:9](=[O:27])[C:8]=2[CH2:7][O:6][C:5](=[O:28])[CH2:4]1)[CH3:2]
Reactant: O=CCCC(F)(F)F
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3c(F)cc(F)cc3nc2-1
Product: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cc(F)cc(F)c1c2CCC(F)(F)F

Procedure:
The product of Example 100 is treated with 4,4,4-trifluorobutyraldehyde according to a procedure similar to Stage 95e in order to produce the expected solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].[CH3:16][O:17][C:18]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH3:29])=[CH:23]2)=[O:19].O>C(Cl)Cl>[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8]([C:23]1[C:22]2[C:26](=[CH:27][CH:28]=[C:20]([C:18]([O:17][CH3:16])=[O:19])[CH:21]=2)[NH:25][C:24]=1[CH3:29])=[O:9]
Reactant: COC(=O)c1ccc2[nH]c(C)cc2c1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc2[nH]c(C)c(C(=O)c3ccc(Cl)cc3Cl)c2c1
Reaction time: 41 h
Yield: 62.7 %

Procedure:
Aluminium chloride (0.86 g) is suspended in methylene chloride (30 ml), to which are added 2,4-dichlorobenzoyl chloride (0.67 g) and then 5-(methoxycarbonyl)-2-methylindole (0.50 g), and stirred at 50° C. for 3 hours and then at room temperature for 41 hours. The reaction mixture is poured into water with ice, and extracted twice with ethyl acetate. The organic layer is washed twice with a saturated aqueous sodium hydrogencarbonate solution and then with a saturated saline solution, and thereafter dried with anhydrous sodium sulfate. The drying agent is removed through filtration, and the filtrate is concentrated under reduced pressure. The resulting crystal is washed with t-butyl methyl ether, and dried to obtain a crystal of 3-(2,4-dichlorobenzoyl)-5-(methoxycarbonyl)-2-methylindole (61) (0.60 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[C:22]([OH:23])=[CH:21][CH:20]=[CH:19][N:18]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:23][C:22]1[C:17]([OH:16])=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1cccnc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cccnc3O)c2cc1OC
Temperature: 160 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (252 mg), 2,3-dihydroxypyridine (396 mg), and 4-dimethylaminopyridine (400 mg) were suspended in o-dichlorobenzene (13 ml), and the suspension was stirred at 160° C. overnight. The reaction solution was cooled to room temperature, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give 6,7-dimethoxy-4-(2-hydroxy-pyridin-3-yloxy)-quinoline (84 mg, yield 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]([CH2:18][CH2:19]Cl)[CH3:17])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[NH2:21][CH2:22][CH2:23][CH2:24]O.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:16]([CH3:17])[CH2:18][CH2:19][N:21]3[CH2:22][CH2:23][CH2:24][O:8][C:7]3([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]=2[CH:15]=1
Reactant: NCCCO
Reactant: CN(CCCl)c1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN1CCN2CCCOC2(c2ccccc2)c2cc(Cl)ccc21

Procedure:
A solution of 5.0 g. (16 mmole) of 5-chloro-2-(2-chloroethylmethylamino)benzophenone, 3.75 g. (50 mmole) of 3-aminopropanol, 50 ml. of triethylamine and 250 ml. of ethanol was stirred at reflux for 48 hours. The reaction mixture was then evaporated to a residue which was washed with water, dissolved in methylene chloride and chromatographed over a column of Florisil. The first fraction yielded the recovery of 2.7 g. of starting material. Elution with acetone, ethanol, methanol and finally with ammonial methanol gave a compound a very low Rf on fluorescent silica eluted with ethanol. Crystallization from acetone and recrystallizations from ether-petroleum ether gave the above-titled product as colorless prisms, m.p. 142°-144°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](Cl)=[O:6].[NH2:12][C:13]([CH3:17])([CH3:16])[CH2:14][OH:15]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:12][C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])=[O:6]
Reactant: Cc1ccc(C(=O)Cl)cc1Br
Reactant: CC(C)(N)CO
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC(C)(C)CO)cc1Br
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred 0° C. cooled solution of 3-bromo-4-methylbenzoyl chloride (prepared from the corresponding carboxylic acid; 1.40 g, 6.04 mmol, 1.0 eq) in DCM (10 mL), was added a solution of 2-amino-2-methylpropanol (1.44 mL, 15.11 mmol, 2.5 eq) in DCM (10 mL) drop wise for 15 min and then warmed to room temperature. After stirring for 24 h at room temperature, the reaction mixture was diluted with DCM (50 mL) and the organic layer was washed with water (20 mL) followed by brine (20 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum to afford the 1.7 g of the desired product as a white solid. 1HNMR (400 MHz, DMSO-d6) δ 8.00 (d, J=1.0 Hz, 1H), 7.70 (dd, J=1.0, 8.0 Hz, 1H), 7.62 (s, 1H, D2O exchangeable), 7.40 (d, J=8.0 Hz, 1H), 4.85 (t, J=6.0 Hz, 1H, D2O exchangeable), 3.49 (d, J=6.0 Hz, 2H), 2.37 (s, 3H), 1.28 (s, 6H); ESI-MS (m/z) 286, 288 [(MH)+, Br79,81].