Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:19][OH:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:39]=[CH:38][O:37][N:36]=2)=[CH:31][CH:30]=1.ClC1C=CC(S(N(CC2C=CC(C#N)=CC=2)[C@@H]2CCCCC[C@H]2CO)(=O)=O)=CC=1>>[O:37]1[CH:38]=[N:39][C:35]([C:32]2[CH:33]=[CH:34][C:29]([CH2:28][N:11]([C@@H:12]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]3[CH2:19][OH:20])[S:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)(=[O:9])=[O:10])=[CH:30][CH:31]=2)=[N:36]1
Reactant: BrCc1ccc(-c2ncon2)cc1
Reactant: O=S(=O)(N[C@@H]1CCCCC[C@H]1CO)c1ccc(Cl)cc1
Agent: N#Cc1ccc(CN([C@@H]2CCCCC[C@H]2CO)S(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncon2)cc1)[C@@H]1CCCCC[C@H]1CO
Yield: 32.8 %

Procedure:
The title compound was synthesized from 4-chloro-N-(trans-2-(hydroxymethyl)cycloheptyl)benzenesulfonamide (100 mg, 0.32 mmol), cesium carbonate (205 mg, 0.63 mmol), and 3-(4-(bromomethyl)phenyl)-1,2,4-oxadiazole (90 mg, 0.38 mmol) according to the procedure described for 4-Chloro-N-(4-cyanobenzyl)-N-(trans-2-(hydroxymethyl)cycloheptyl)benzenesulfonamide (Example 40) to give N-(4-(1,2,4-oxadiazol-3-yl)benzyl)-4-chloro-N-(trans-2-(hydroxymethyl)cycloheptyl)benzenesulfonamide (50 mg, 33%). 1H NMR (400 MHz, CDCl3) δ ppm 8.75 (1H, s), 8.08 (2H, d, J=8.31 Hz), 7.70-7.79 (2H, m), 7.55 (2H, d, J=8.31 Hz), 7.47-7.52 (2H, m), 4.73 (1H, d, J=15.86 Hz), 4.02 (1H, d, J=15.61 Hz), 3.82 (1H, ddd, J=11.14, 8.75, 3.02 Hz), 3.71 (1H, dd, J=11.71, 3.90 Hz), 3.31 (1H, dd, J=11.58, 2.52 Hz), 2.55 (1H, br. s.), 1.43-1.68 (6H, m), 1.17-1.42 (5H, m). LC/MS R.T.=2.29 min; [M+H]+=476.18. HRMS [M+H]+ calc'd 476.1411, found 476.1398.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19](O)=[O:20]>>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:19](=[O:20])[CH2:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[Cl:11])=[CH:7][CH:6]=1
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: ClCCOc1ccccc1
Product: O=C(Cc1ccccc1Cl)c1ccc(OCCCl)cc1

Procedure:
1-[4-(2-Chloroethoxy)phenyl]-2-(2-chlorophenyl)ethanone is prepared according to the method described in the example 4a using 2-chloroethoxybenzene and 2-chlorophenylacetic acid as starting materials.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[N:6][C:7]=1[F:8].C([Li])CCC.C([Li])(C)(C)C.[CH:28]([Si:31]([CH:46]([CH3:48])[CH3:47])([CH:43]([CH3:45])[CH3:44])[N:32]1[C:36]2=[N:37][CH:38]=[CH:39][CH:40]=[C:35]2[C:34]([CH:41]=[O:42])=[CH:33]1)([CH3:30])[CH3:29].[Cl-].[NH4+]>O1CCCC1>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][NH:9][C:5]1[N:6]=[C:7]([F:8])[C:2]([CH:41]([C:34]2[C:35]3[C:36](=[N:37][CH:38]=[CH:39][CH:40]=3)[N:32]([Si:31]([CH:43]([CH3:45])[CH3:44])([CH:46]([CH3:48])[CH3:47])[CH:28]([CH3:29])[CH3:30])[CH:33]=2)[OH:42])=[CH:3][CH:4]=1
Reactant: Fc1nc(NCc2ccccc2Cl)ccc1Br
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C=O)c2cccnc21
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2ccc(NCc3ccccc3Cl)nc2F)c2cccnc21
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 17.6 %

Procedure:
To (5-bromo-6-fluoro-pyridin-2-yl)-(2-chloro-benzyl)-amine (571, 0.635 g, 2.01 mmol, prepared as described in Example 60, Scheme 177) in tetrahydrofuran (25.0 mL) under an atmosphere of nitrogen at −78° C., a solution of n-butyllithium (2.50 M in hexane, 0.80 mL) was added slowly. After 20 minutes, tert-butyllithium (1.7 M in hexane, 2.40 mL) was added to the reaction and after 30 minutes, 1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (47, 0.575 g, 1.90 mmol, prepared as described in Example 18) in tetrahydrofuran (8.0 mL) was added to the reaction. The reaction mixture was stirred at −78° C. for 60 minutes, then allowed to warm to room temperature for another 10 minutes. The reaction mixture was poured into aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (606, 0.180 g, 17.6%). MS (ESI) [M+H+]+=539.2.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH2:10]([SH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[CH2:10]([S:17][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(I)cc1
Reactant: SCc1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: COc1ccc(SCc2ccccc2)cc1
Yield: 89.4 %

Procedure:
The general procedure in example 39 was followed. 4-Iodoanisole (234 mg, 1.0 mmol), benzylmercaptan (117 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-Propanol (1.0 mL) were used to obtain the 4-benzylsulfanylanisole (206 mg, 90% yield) as colorless solid. Column chromatographic solvent (hexane/ethyl acetate=50/1). Melting point; 48-50° C. Rf=0.3 (hexane/ethyl acetate=40/1). 1H NMR (CDCl3, 300 MHz) δ 7.14-7.24 (m, 7 H), 6.76 (dt, 2 H, J=8.7 Hz, 2.1 Hz), 3.97 (s, 2 H),3.76 (s, 3 H). 13C NMR (CDCl3, 75 MHz) δ 159.3, 138.3, 134.3, 129.1, 128.5, 127.2, 126.2, 114.6, 55.6, 41.6. IR (neat, cm−1) 3043, 3012, 2982, 2861. MS (EI) m/z (relative intensity) 230 (30), 91 (100). Anal Cald for C14H14OS, Cald. C: 73.01, H: 6.13; Found C: 72.86, H: 5.93.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[N:8]=[CH:7][C:6]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=[O:14])=[C:5]2[OH:24].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>N1C=CC=CC=1>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][NH:15][C:13]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[OH:24])=[CH:3][C:2]([NH:1][S:33]([C:30]2[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[CH:32][CH:31]=2)(=[O:35])=[O:34])=[CH:11][C:10]=3[F:12])=[O:14])=[CH:18][CH:19]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2cc(F)c3ncc(C(=O)NCc4ccc(Cl)cc4)c(O)c3c2)cc1
Reaction time: 2 h

Procedure:
To a flask containing 6-amino-N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide from Example No. 186 (0.06 g) and pyridine (1.5 mL) is added 4-methoxyphenylsulfonyl chloride (0.04 g). The reaction mixture is stirred for 2 hours then concentrated under reduced pressure. The residue is triturated with toluene (2×) and dried in vacuo. The residue is adsorbed onto silica and chromatographed on silica eluting with 2% MeOH:CH2Cl2 to 6% MeOH:CH2Cl2. The product-containing fractions are evaporated to give 0.04 g of the title compound as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:26])[CH:21](OCC)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.[NH2:27][C:28]([CH3:43])([CH3:42])[CH2:29][CH2:30][N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]([CH3:40])[C:32]1=[O:41]>>[CH3:43][C:28]([NH:27][CH2:21][CH:20]([C:11]1[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=[C:9]([OH:8])[CH:10]=1)[OH:26])([CH3:42])[CH2:29][CH2:30][N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]([CH3:40])[C:32]1=[O:41]
Reactant: CCOC(O)C(O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Reactant: Cn1c(=O)n(CCC(C)(C)N)c2ccccc21
Product: Cn1c(=O)n(CCC(C)(C)NCC(O)c2cc(O)cc3c2OCC(=O)N3)c2ccccc21

Procedure:
Prepared according to general method 2 from 357 mg (1 mmol) 6-benzyloxy-8-(2-ethoxy-1,2-dihydroxy-ethyl)-4H-benzo[1,4]oxazin-3-one and 233 mg (1 mmol) 1-(3-amino-3-methyl-butyl)-3-methyl-1,3-dihydro-benzimidazol-2-one.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:14][C:13](OS(C(F)(F)F)(=O)=O)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].[B:30]1(B2OCC(C)(C)CO2)[O:35]CC(C)(C)C[O:31]1.CC([O-])=O.[K+]>CS(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:14][C:13]([B:30]([OH:35])[OH:31])=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(OS(=O)(=O)C(F)(F)F)cc(-c3ccccn3)c2s1
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Product: CCNC(=O)Nc1nc2cc(B(O)O)cc(-c3ccccn3)c2s1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 88.6 %

Procedure:
To a stirred solution of xi (25 g, 56.1 mmol) in DMSO (250 mL) at RT was added bis(neopentylglycolato)diboron (25.2 g, 112 mmol) and KOAc (16.5 g, 168 mmol). The resulting reaction mixture was de-gassed by purging N2 for 15-20 min followed by addition of Pd(dppf)Cl2 (6.8 g, 8.4 mmol). The mixture was purged with N2 for 15-20 min and then heated to 80° C. for 90 min. The reaction was poured onto saturated NH4Cl solution (1 L). The resulting precipitate was filtered and dried under vacuum. The solid cake was taken in 2M NaOH (200 mL) and stirred for 45 min at RT. The solution was filtered and the filtrate was acidified up to pH 5-6 and the resulting solid collected by filtration to give Intermediate 1 (17 g, 88%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:12][C:13]([CH3:15])=O.N1CCCC1.Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:13]([CH3:15])([CH3:12])[CH2:9][C:8]2=[O:10]
Reactant: CC(C)=O
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: Cl
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: CC1(C)CC(=O)c2cc(Br)ccc2O1
Yield: 71 %

Procedure:
A solution of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (21.4 g, 0.1 mol), acetone (365 mL) and pyrrolidine (8.4 mL) in toluene (220 mL) is refluxed for 4 h. To the reaction mixture is added acetone (36.5 mL), the mixture is refluxed for 15 h. Then 1 N HCl (220 mL) is added, extracted with ethyl acetate (200 mL 3×). The combined organic layers were washed with water (150 mL), brine (150 mL), dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-2,2-dimethyl-chroman-4-one (18 g, 71%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22].[NH2:23][CH:24]1[CH2:26][CH2:25]1>CCO>[CH:24]1([NH:23][C:2]2[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[CH2:26][CH2:25]1
Reactant: NC1CC1
Reactant: Fc1ccccc1Cn1cnc2c(Cl)nc(C(F)(F)F)nc21
Solvent: CCO
Product: Fc1ccccc1Cn1cnc2c(NC3CC3)nc(C(F)(F)F)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.8 %

Procedure:
A mixture of 100 mg (0.30 mmol) of 6-chloro-9-(2-fluorobenzyl)-2-trifluoromethylpurine, 1 mL (14 mmol) of aminocyclopropane, and 5 mL of EtOH were stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in CH2Cl2, washed with 2×5 mL H2O, 5 mL brine, dried (Na2SO4), and concentrated. Chromatography over silica gel using 33% EtOAc in hexanes as eluant provided 102 mg (97% yield) of the desired product. M.P. 118.5-119.0° C.; 1H NMR (CDCl3) δ 7.892 (s, 1H), 7.50-7.39 (m, 1H), 7.37-7.29 (m, 1H), 7.18-7.05 (m, 2H), 5.95 (bs, 1H), 5.44 (s, 2H), 0.94-0.91 (m, 2H), 0.65-0.64 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][CH2:11][CH:12]1[CH2:17][CH:16]2[CH2:18][CH:14]([C:15]2([CH3:20])[CH3:19])[C:13]1=[CH2:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:23].[OH2:24].C[N+]([O-])(C)C>C(Cl)Cl.[Os](=O)(=O)(=O)=O>[CH2:1]([O:8][C:9](=[O:22])[NH:10][CH2:11][CH:12]1[CH2:17][CH:16]2[CH2:18][CH:14]([C:15]2([CH3:19])[CH3:20])[C:13]1([OH:24])[CH2:21][OH:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C1C(CNC(=O)OCc2ccccc2)CC2CC1C2(C)C
Reactant: O
Agent: O=[Os](=O)(=O)=O
Agent: C[N+](C)(C)[O-]
Solvent: ClCCl
Product: CC1(C)C2CC(CNC(=O)OCc3ccccc3)C(O)(CO)C1C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.9 %

Procedure:
(6,6-Dimethyl-2-methylene-bicyclo[3.1.1]hept-3-ylmethyl)-carbamic acid benzyl ester (2.19 g, 7.32 mmol), prepared in step B of example 47, was dissolved in CH2Cl2 (50 ml). To this solution was added trimethylamine N-oxide dihydrate (894 mg, 8.79 mmol) and osmium tetroxide (136 mg, 0.535 mmol). The solution was stirred at ambient temperature for 16 hours after which time the reaction was concentrated under vacuum and chromatographed on silica gel using a gradient starting with 30% ethyl acetate in hexanes to 50% ethyl acetate in hexanes to give 1.51 g of the titled compound as a brown oil: C.I. m/z 316 [M+1-H2 0]; 1H NMR (CDCl3)δ 7.31-7.39 (m, 5H), 5.59 (br s, 1H), 5.12 (s, 2H), 3.30-3.58 (m, 4H), 1.93-2.28 (m, 4H), 1.52 (m, 1H), 1.24-1.30 (m, 5H), 0.96 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:37]([CH3:44])=[C:38]([CH:41]=[CH:42][CH:43]=1)[C:39]#[N:40].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:39]([C:38]1[C:37]([CH3:44])=[C:36]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:10]3[C:6]=2[CH2:7][CH2:8][C@H:9]3[O:11][C:12]2[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=2)[CH:43]=[CH:42][CH:41]=1)#[N:40]
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1c(Br)cccc1C#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5cccc(C#N)c5C)ccc(F)c43)ccc21
Temperature: 100 °C
Reaction time: 4 h

Procedure:
In a microwave vial, methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (200 mg), 3-bromo-2-methylbenzonitrile (169 mg), K3PO4 (274 mg), Palladium-(II)-acetate (10 mg) and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (S-Phos) (18 mg) are suspended in toluene (10 mL) and water (2 mL) and purged for 10 minutes with argon. The vial is sealed and the mixture is stirred at 100° C. for 4 hours. After cooling to ambient temperature the mixture is partitioned between ethyl acetate and water. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10) to give the title compound. Yield: 124 mg; LC (method 20): tR=8.09 min; Mass spectrum (ESI+): m/z=558 [M+−H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].[CH:20]1([N:26]=[C:27]=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([NH:26][C:27]([NH:19][S:16]([C:14]2[CH:13]=[CH:12][C:9]3[CH2:10][CH2:11][N:5]([C:3](=[O:4])[NH:2][CH3:1])[CH2:6][CH2:7][C:8]=3[CH:15]=2)(=[O:18])=[O:17])=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C=NC1CCCCC1
Reactant: CNC(=O)N1CCc2ccc(S(N)(=O)=O)cc2CC1
Product: CNC(=O)N1CCc2ccc(S(=O)(=O)NC(=O)NC3CCCCC3)cc2CC1

Procedure:
By the reaction of 3-methylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide with cyclohexylisocyanate in a manner analogous to that described in Example 1, there is obtained 1-cyclohexyl-3-[(3-methylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)sulfonyl]urea. The starting material is prepared by the reaction of 2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide with methylisocyanate in a manner analogous to that described in Example 8.
Reaction SMILES: C1(COC([N:11]2[CH2:16][CH2:15][N:14]3[C:17](=[O:26])[O:18][C:19]([CH:23]4[CH2:25][CH2:24]4)([CH:20]4[CH2:22][CH2:21]4)[CH:13]3[CH2:12]2)=O)C=CC=CC=1.[F:27][C:28]1[CH:37]=[CH:36][C:31]([CH2:32][N:33]=[C:34]=[O:35])=[CH:30][CH:29]=1>C(O)C.[C].[Pd]>[CH:23]1([C:19]2([CH:20]3[CH2:22][CH2:21]3)[CH:13]3[CH2:12][N:11]([C:34]([NH:33][CH2:32][C:31]4[CH:30]=[CH:29][C:28]([F:27])=[CH:37][CH:36]=4)=[O:35])[CH2:16][CH2:15][N:14]3[C:17](=[O:26])[O:18]2)[CH2:25][CH2:24]1
Reactant: O=C=NCc1ccc(F)cc1
Reactant: O=C(OCc1ccccc1)N1CCN2C(=O)OC(C3CC3)(C3CC3)C2C1
Agent: [Pd]
Solvent: CCO
Product: O=C(NCc1ccc(F)cc1)N1CCN2C(=O)OC(C3CC3)(C3CC3)C2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
(Phenylmethyl)1,1-dicyclopropyl-tetrahydro-3-oxo-3H-oxazolo[3,4-a]pyrazine-7(1H)-carboxylate (0.18 g, 0.50 mmol) was dissolved in ethanol (10 mL). 10% Palladium carbon (17 mg) was added thereto, and the mixture was stirred under hydrogen atmosphere at room temperature overnight. The reaction solution was filtered through Celite, the Celite was washed with ethanol, and the filtrate was concentrated under reduced pressure. The resulting 1,1-dicyclopropyl-hexahydro-3H-oxazolo[3,4-a]pyrazin-3-one was dissolved in tetrahydrofuran (10 mL). (4-Fluoro)benzyl isocyanate (0.25 mL, 2.0 mmol) was added thereto, and the mixture was stirred at 50° C. for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1 to 1:4) to obtain the title compound (0.16 g, 87% yield from (phenylmethyl) 1,1-dicyclopropyl-tetrahydro-3-oxo-3H-oxazolo[3,4-a]pyrazine-7(1H)-carboxylate).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=2)[CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.Cl.N1C=CC=CC=1.O>CCOCC>[C:1]1([CH2:7][CH2:8][O:9][CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)[CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cccc(C(C)COCCc2ccccc2)c1
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(COCCc1ccccc1)c1cccc(O)c1
Temperature: 190 °C

Procedure:
A mixture of 2-(3-methoxyphenyl)propyl 2-phenylethyl ether (176 mg., 0.65 mmole), pyridine (0.4 ml., 4.96 mmole) and dry pyridine hydrochloride (4 g., 34.6 mmole) is heated at 190° C. for 6 hours. The reaction mixture is cooled and added to a mixture of water (100 ml.) and ether (150 ml.). The ether extract is washed once with water (50 ml.) and, along with a second ether extract (50 ml.) of aqueous phase, is dried over magnesium sulfate and evaporated to an oil. The oil is purified via preparation layer chromatography on silica gel plates, eluted six times with 30% ether-pentane to yield the title product.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12]N)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[C:14]([C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)(=O)[CH3:15].C(=O)([O-])O.[Na+]>>[CH3:2][S:3]([C:6]1[CH:11]=[C:10]2[C:9](=[CH:8][CH:7]=1)[NH:12][C:14]([C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)=[CH:15]2)(=[O:5])=[O:4]
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Reactant: CC(=O)c1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CS(=O)(=O)c1ccc2[nH]c(-c3ccncc3)cc2c1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
To a mixture of 1-(4-methanesulfonyl-phenyl)-hydrazine hydrochloride (1.0 g) and polyphosphoric acid (15 g), 4-acetylpyridine (0.47 ml) was added and the mixture was stirred at 150° C. for 1 hour. The reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with chloroform. The organic layer was concentrated under reduced pressure. The resulting residue was washed with n-hexane to obtain 0.9591 g of the desired product as a white solid.
Reaction SMILES: [N+:1]([C:4]1[C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18]Br)=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:20])[NH:9]2)([O-:3])=[O:2].[C:21]1([SH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[N+:1]([C:4]1[C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][S:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:20])[NH:9]2)([O-:3])=[O:2]
Reactant: Sc1ccccc1
Reactant: O=c1ccc2c([N+](=O)[O-])c(OCCCCBr)ccc2[nH]1
Product: O=c1ccc2c([N+](=O)[O-])c(OCCCCSc3ccccc3)ccc2[nH]1

Procedure:
Prepared analogous to Example 122 from 5-nitro-6-(4-bromo-butoxy)-carbostyril [m.p. 250° C., prepared by nitration of 6-(4-bromo-butoxy)-3,4-dihydro-carbostyril] and thiophenol.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[O:27][C@@H:28]([CH3:33])[C:29]([O:31]C)=O)[N:20]=[CH:19][N:18]=3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH3:33][C@H:28]([O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:12]1[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[N:8]=[CH:9]3)=[N:18][CH:19]=[N:20]2)[C:29](=[O:31])[N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: COC(=O)[C@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12
Reactant: C1CCNC1
Product: C[C@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12)C(=O)N1CCCC1
Yield: 70.1 %

Procedure:
Using the same procedure as in Example 26, methyl (2S)-2-[(4-{[1-(1,3-thiazol-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (250 mg, 0.54 mmol) was reacted with pyrrolidine (0.45 ml, 5.4 mmol) to give the title compound (189 mg, 70%) as a solid, except that the mixture was heated at 55° C. for 20 hours and purified by chromatography on silica gel (eluant: 1-5% methanol in DCM); NMR Spectrum 1.61 (d, 3H), 1.82 (m, 2H), 1.94 (m, 2H), 3.47-3.30 (m, 3H), 3.77 (m, 1H), 5.63 (q, 1H), 6.04 (s, 2H), 7.27 (d, 1H), 7.35 (d, 1H), 7.65 (d, 1H), 7.74 (m, 3H), 7.88 (dd, 1H), 8.20 (s, 1H), 8.52 (s, 1H), 8.56 (s, 1H), 11.09 (br s, 1H); Mass spectrum 500.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][C:13]=1[O:20][CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][C:13]=2[O:20][CH3:21])[CH3:9])=[CH:6][CH:7]=1
Reactant: OCCc1ccc(Cl)cc1
Reactant: COc1cc(C=O)ccc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(C=O)ccc1OC(C)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
4-Chlorophenylmethylcarbinol (643, 0.668 mL, 6.57 mmol) was dissolved in tetrahydrofuran (60.0 mL) at 0° C. under an atmosphere of nitrogen. 4-Hydroxy-3-methoxybenzaldehyde (105, 1.00 g, 6.57 mmol) and triphenylphosphine (2.07 g, 7.89 mmol) were added to the reaction, followed by diisopropyl azodicarboxylate (1.55 mL, 7.89 mmol) over 10 minutes. The reaction was stirred for 2 hours. The mixture was adsorbed onto silica and purified by silica gel chromatography, ethyl acetate:hexanes, to provide the desired compound, (644, 1.14 g, 60%). 1H-NMR was consistent with the desired compound.