Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl: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.[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)#[N:21]>>[Cl: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:31]1[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[C:20]#[N:21])[CH2:33][CH2:32]1)=[O:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Reactant: N#Cc1ccccc1N1CCNCC1
Product: COc1nc2ccc(Cl)cc2nc1NC(=O)N1CCN(c2ccccc2C#N)CC1
Yield: 91 %

Procedure:
Ethyl N-(6-chloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(2-cyanophenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound (yield, 91%). 1H NMR (300 MHz, CDCl3): δ 3.25-3.32 (m, 4H), 3.84 (s, 3H), 4.08-4.15 (m, 4H), 7.06-7.08 (m, 2H), 7.21 (m, 1H), 7.41-7.67 (m, 4H), 7.82 (s, 1H).
Reaction SMILES: [O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH2:17])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][N:30]=1)[C:25](O)=[O:26]>>[O:4]1[CH2:5][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH:17][C:25](=[O:26])[C:24]4[CH:28]=[CH:29][N:30]=[C:22]([O:21][CH3:20])[CH:23]=4)=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:7][O:1][CH2:2][CH2:3]1
Reactant: COc1cc(C(=O)O)ccn1
Reactant: COc1ccc(C2COCCOC2)c2sc(N)nc12
Product: COc1cc(C(=O)Nc2nc3c(OC)ccc(C4COCCOC4)c3s2)ccn1

Procedure:
Using 7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine and 2-methoxy-isonicotinic acid, the title compound was prepared. MS: m/e=416(M+H+). Following the general method of example 1 the compounds of examples 17 to 34 were prepared.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:26][C:27]1([NH2:31])[CH2:30][O:29][CH2:28]1>>[CH3:26][C:27]1([NH:31][C:21]([C:17]2[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9][O:10][C:11]=3[CH2:24][OH:25])[CH:16]=2)=[O:22])[CH2:30][O:29][CH2:28]1
Reactant: Cn1nc(OCc2c(-c3ccc(F)cc3)noc2CO)cc1C(=O)O
Reactant: CC1(N)COC1
Product: Cn1nc(OCc2c(-c3ccc(F)cc3)noc2CO)cc1C(=O)NC1(C)COC1
Yield: 50 %

Procedure:
As described for example 97, 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (100 mg, 0.29 mmol) was converted, using 3-methyl-3-oxetanamine instead of rac-3-aminotetrahydrofuran, to the title compound (60 mg, 50%) which was obtained as a white foam. MS: m/e=415.1 [M−H]−.
Reaction SMILES: [NH2:1][C@@:2]([C:13]1[C:14]([F:20])=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=1)([CH3:12])[CH2:3][S:4]([C:7]([CH3:11])([CH3:10])[C:8]#[N:9])(=[O:6])=[O:5].C[Al](C)C.Cl>ClCCCl>[NH2:9][C:8]1[C:7]([CH3:10])([CH3:11])[S:4](=[O:6])(=[O:5])[CH2:3][C@:2]([C:13]2[C:14]([F:20])=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=2)([CH3:12])[N:1]=1
Reactant: CC(C)(C#N)S(=O)(=O)C[C@](C)(N)c1cc(Br)cnc1F
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCCl
Product: CC1(C)C(N)=N[C@](C)(c2cc(Br)cnc2F)CS1(=O)=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 79 %

Procedure:
To a solution of N#R)-2-(5-bromo-2-fluoropyridin-3-yl)-1-((2-cyanopropan-2-yl)sulfonyl)propan-2-yl)-2-methylpropane-2-sulfinamide (1.63 g, 3.48 mmol) in methanol (25 mL) was added hydrogen chloride (4.0 M in 1,4-dioxane, 4.35 mL, 17.4 mmol) and stirred at room temperature for 40 min until the starting material was consumed. The mixture was concentrated, diluted with DCM, and neutralized with 10% aqueous Na2CO3 and 1 M NaOH. The organic phase was dried over Na2SO4, filtered, and concentrated to afford (R)-2-((2-amino-2-(5-bromo-2-fluoropyridin-3-yl)propyl)sulfonyl)-2-methylpropanenitrile as a pale yellow oil. The (R)-2-((2-amino-2-(5-bromo-2-fluoropyridin-3-yl)propyl)sulfonyl)-2-methylpropanenitrile was dissolved in 1,2-dichloroethane (100 mL) and trimethylaluminum (2 M in toluene, 2.78 mL, 5.57 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 17 h. The mixture was cooled to 0° C. and hydrochloric acid (1 M, 17.40 mL, 17.40 mmol) was added dropwise via an addition funnel (slowly at first until the vigorous reaction subsided) and stirred at room temperature. The aqueous solution was extracted with DCM. The pH of the aqueous phase was adjusted to pH>10 with 10 M NaOH and extracted with DCM. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 0-100% EtOAc/hexanes) gave (R)-5-amino-3-(5-bromo-2-fluoropyridin-3-yl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide (1.0 g, 2.8 mmol, 79% yield) as a light yellow solid. LC/MS (ESI) m/z=364 (M+H).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.Cl[C:17](=[O:23])[CH2:18][C:19]([O:21][CH3:22])=[O:20].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:22][O:21][C:19](=[O:20])[CH2:18][C:17]([NH:2][CH:3]1[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]1)=[O:23]
Reactant: COC(=O)CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CC(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
The mixture of tert-butyl 4-aminopiperidine-1-carboxylate hydrochloride (512 mg, 2.16 mmol), methyl 3-chloro-3-oxopropanoate (232 μL, 2.16 mmol), and DIPEA (828 μL, 4.75 mmol) in DCM (20 mL) was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (eluent EtOAc) to afford tert-butyl 4-(3-methoxy-3-oxopropanamido)piperidine-1-carboxylate as a white solid (500 mg, 78%). MS (m/z): 301.1 (M+H). This material (500 mg, 1.67 mmol) was dissolved in MeOH/THF/H2O (2 mL/2 mL/1 mL), and LiOH×H2O (280 mg, 6.75 mmol) was added to the solution. The reaction mixture was stirred for 2 hrs, the solvent was removed under reduced pressure and the residue was purified by flash chromatography (eluent CH3Cl/MeOH/AcOH) to afford the title compound 42 (300 mg, 63% yield) as yellowish syrup. MS (m/z): 287.1 (M+H).
Reaction SMILES: [H-].[Na+].[C:3]1([C@H:9]([OH:11])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=3)[CH:26]=[CH:25][C:24]=2[OH:35])=[N:15][N:14]=1>O1CCCC1>[CH3:34][O:33][C:30]1[CH:31]=[C:32]2[C:27]([CH:26]=[CH:25][C:24]([OH:35])=[C:23]2[C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]([O:11][C@@H:9]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH3:10])=[N:14][N:15]=2)=[CH:28][CH:29]=1
Reactant: COc1ccc2ccc(O)c(-c3nnc(Cl)c4ccccc34)c2c1
Reactant: C[C@@H](O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2ccc(O)c(-c3nnc(O[C@H](C)c4ccccc4)c4ccccc34)c2c1
Reaction time: 0.25 h
Yield: 86.7 %

Procedure:
To a suspension of sodium hydride (0.80 g, 33 mmol) in tetrahydrofuran (80 ml) was added a solution of (R)-phenylethanol (2.0 g, 17 mmol) in tetrahydrofuran (3 ml) cautiously over 10 min at 23° C. The mixture was stirred for 15 min, then 1-(4-chlorophthalazin-1-yl)-7-methoxy-naphthalen-2-ol (5.1 g, 15 mmol) was added portionwise. The resulting red suspension was stirred for 20 hrs at 23° C., then the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane and poured into brine. The organic layer was separated and the aqueous layer was extracted two times with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (hexane/EtOAc 4:1 to 1:1) to give 5.5 g (13 mmol) of the title compound as a 1:1 mixture of diastereomers, as a white foam.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([S:15][C:16]4[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=4[C:18](O)=[O:19])=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:3][CH2:2]1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:26]([NH:33][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=1[S:15][C:12]1[CH:13]=[CH:14][C:9]2[N:10]([CH:25]=[C:7]([NH:6][C:4]([CH:1]3[CH2:2][CH2:3]3)=[O:5])[N:8]=2)[N:11]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(O)c1ccccc1Sc1ccc2nc(NC(=O)C3CC3)cn2n1
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccccc1)c1ccccc1Sc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 88.9 %

Procedure:
In the same manner as in Example 278 and using 2-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)benzoic acid (250 mg, 0.71 mmol), benzylamine (212 mg, 2.0 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (380 mg, 1.0 mmol), N,N-diisopropylethylamine (270 mg, 2.0 mmol) and N,N-dimethylformamide (7 mL) as starting materials, the title compound (280 mg, 89%) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10](Cl)=[O:11])=[CH:5][CH:4]=1.[NH2:13][C:14]1[CH:15]=[C:16]([C:20]2[C:24]([Br:25])=[CH:23][N:22]([CH3:26])[N:21]=2)[CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:25][C:24]1[C:20]([C:16]2[CH:15]=[C:14]([NH:13][C:10]([O:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:11])[CH:19]=[CH:18][CH:17]=2)=[N:21][N:22]([CH3:26])[CH:23]=1
Reactant: Cn1cc(Br)c(-c2cccc(N)c2)n1
Reactant: COc1ccc(OC(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(OC(=O)Nc2cccc(-c3nn(C)cc3Br)c2)cc1
Reaction time: 16 h
Yield: 59.7 %

Procedure:
To 4-methoxyphenylchloroformate (19 mg, 0.10 mmol) in CH2Cl2 (0.5 mL) was added dropwise a solution of 3-(3-aminophenyl)-4-bromo-1-methylpyrazole (25 mg, 0.10 mmol) and triethylamine (14 μL, 0.10 mmol) in CH2Cl2 (0.5 mL). The mixture was stirred for 16 h and concentrated. Chromatography on flash silica (40% EtOAc/hexane) gave the title compound as a colourless solid (24 mg, 526), m.p. 140.3-141.8° C. (EtOAc/hexane).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]#[N:18])=[CH:12][C:11]=2[O:19][CH3:20])=[CH:4][CH:3]=1.N>O1CCCC1.[Ni]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH2:18])=[CH:12][C:11]=2[O:19][CH3:20])=[CH:21][CH:22]=1
Reactant: COc1cc(CC#N)ccc1OCCOc1ccc(F)cc1
Agent: [Ni]
Agent: N
Solvent: C1CCOC1
Product: COc1cc(CCN)ccc1OCCOc1ccc(F)cc1
Reaction time: 2 h

Procedure:
A mixture of {4-[2-(4-fluoro-phenoxy)-ethoxy]-3-methoxy-phenyl}-acetonitrile (14.8 g), liquid ammonia (8.4 g) and Raney-nickel (4.5 g) in tetrahydrofuran (120 ml) is shaken in an autoclave under hydrogen (130 bar) at +60° C. for 2 hours. The reaction mixture is filtered and evaporated. 2-{4-[2-(4-Fluoro-phenoxy)-ethoxy]-3-methoxy-phenyl}-ethylamine is obtained as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[C:15]([F:21])[CH:14]=3)[C:11]([CH3:23])(O)[O:10][N:9]=2)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[C:15]([F:21])[CH:14]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CSc1ccc(C2C(c3ccc(Br)cc3)=NOC2(C)O)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CSc1ccc(-c2c(-c3ccc(Br)cc3)noc2C)cc1F
Yield: 96.9 %

Procedure:
A mixture of 3-(4-bromophenyl)-4-(3-fluoro-4-methylthiophenyl)-5-methyl-4,5-dihydro-5-isoxazolol (630 mg, 1.59 mmol) and p-toluenesulfonic acid monohydrate (274 mg, 1.59 mmol) in methanol (10 ml) was refluxed for 2 h. The mixture was evaporated, dissolved in ethyl acetate (100 ml), washed with saturated sodium bicarbonate (50 ml×2), and dried over anhydrous sodium sulfate. Removal of solvent gave 583 mg (97%) of the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.[NH2:35][C:36]1([CH3:49])[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]1.O>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:35][C:36]5([CH3:49])[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:41]5)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Reactant: CC1(N)CCN(C(=O)OC(C)(C)C)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(C)CCN(C(=O)OC(C)(C)C)CC4)c3n2)c2ccc(F)cc21
Reaction time: 16 h
Yield: 61.6 %

Procedure:
To a stirred solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.32 mmol) in 10 mL of DMF were added EDCI (122 mg, 0.64 mmol), tert-butyl 4-amino-4-methylpiperidine-1-carboxylate (103 mg, 0.48 mmol) and DMAP (78 mg, 0.64 mmol) in one portion at room temperature. Then the reaction mixture was stirred for 16 hours, then was poured into 50 mL of water and filtered. The filter cake was washed with water (10 mL) and passed through a pad of silica gel (200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate (1:2, v/v) to give tert-butyl 4-(2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)-4-methylpiperidine-1-carboxylate (100 mg, 61.6%) as a white solid which was used for the next step without further purification. MS: (M+H)+=508.2.
Reaction SMILES: [CH3:1][N:2]([CH3:37])[CH:3]1[CH2:6][N:5]([C:7]([C@@H:9]2[CH2:13][C@H:12]([S:14]CC3C=CC(OC)=CC=3)[CH2:11][N:10]2[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)=[O:25])=[O:8])[CH2:4]1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O>C1(OC)C=CC=CC=1>[CH3:1][N:2]([CH3:37])[CH:3]1[CH2:4][N:5]([C:7]([C@@H:9]2[CH2:13][C@H:12]([SH:14])[CH2:11][N:10]2[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)=[O:25])=[O:8])[CH2:6]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC(N(C)C)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C1CN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 1 h
Yield: 88.9 %

Procedure:
1.47 g of (2S,4S)-2-(3-dimethylaminoazetidin-1-ylcarbonyl)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (a) above] were dissolved in 3.02 ml of anisole, and 10.71 ml of trifluoroacetic acid and 0.488 ml of trifluoromethanesulfonic acid were added to the resulting solution, after which the mixture was stirred at the same temperature for 1 hour. The solvent was then removed by distillation under reduced pressure, and the residue was washed by repeated decantation, in turn, with hexane and with diethyl ether. Ethyl acetate was added to the residue and the mixture was made alkaline by the addition of a saturated aqueous solution of sodiumhydrogencarbonate. The ethyl acetate layer was separated, washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, to give 1.01 g of the title compound as a powder.
Reaction SMILES: CN(C)C=O.Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[I:18][C:19]1[CH:24]=[C:23]([I:25])[CH:22]=[C:21]([I:26])[C:20]=1[OH:27].C(=O)([O-])[O-].[K+].[K+]>O>[I:18][C:19]1[CH:24]=[C:23]([I:25])[CH:22]=[C:21]([I:26])[C:20]=1[O:27][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CCCCCCBr
Reactant: Oc1c(I)cc(I)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCOc1c(I)cc(I)cc1I
Temperature: 25 °C
Reaction time: 24 h
Yield: 187.8 %

Procedure:
Dimethylformamide (DMF, 20 mL) was added with ethyl 7-bromoheptanoate (4.7 g) and 2,4,6-triiodophenol (2.4 g), further added with potassium carbonate (2.1 g) and stirred at room temperature for one day. The reaction solution was added with water and extracted twice with ethyl acetate, and the organic layer was washed three times with water and dried over anhydrous magnesium sulfate. Then, the solvent was removed, and the resulting residue was purified by silica gel column chromatography to obtain ethyl 7-(2,4,6-triiodophenoxy)heptanoate (6.0 g, yield: 96%).
Reaction SMILES: C[O-].[Na+].[C:4](=O)([S:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1)C.CI.C(=O)([O-])O.[Na+]>CO>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@H:8]2[CH2:7][S:6][CH3:4])=[O:21])=[CH:15][CH:16]=1
Reactant: CC(=O)SC[C@@H]1CCCN1C(=O)c1ccc(Br)cc1
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: CSC[C@@H]1CCCN1C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.9 %

Procedure:
Sodium methoxide (0.22 ml, 0.876 mmol) (28% in methanol) was added to a solution of 100 mg (0.292 mmol) of the title compound produced in step (iv) of Reference Example 8 in methanol (1 ml), and the mixture was stirred at room temperature for 15 min. Thereafter, 0.11 ml (1.75 mmol) of methyl iodide was added thereto, and the mixture was stirred at room temperature for 20 hr. The reaction was stopped by adding a saturated aqueous sodium hydrogencarbonate solution, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, was dried over anhydrous sodium sulfate, and was then filtered. The filtrate was concentrated under the reduced pressure, and the residue was purified by preparative thin layer chromatography (hexane:ethyl acetate=1:4) to give 55 mg (yield 60%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[CH2:16][CH2:15][NH:14][CH:13]=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]=3[NH:9][C:10]=2[CH:11]=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:22]([N:14]1[CH2:15][CH2:16][C:7]2[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][C:10]=3[NH:9][C:8]=2[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1cc(OC)ccc21
Reactant: O=C(Cl)c1ccccc1
Product: CCOC(=O)C1=CN(C(=O)c2ccccc2)CCc2c1[nH]c1cc(OC)ccc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2A by using ethyl 8-methoxy-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate and benzoyl chloride; 1H-NMR (CDCl3): δ 10.41 (1H, br s), 7.98 (1H, s), 7.56 (2H, m), 7.52 (1H, m), 7.46 (2H, m), 7.39 (1H, d), 6.86 (1H, d), 6.79 (1H, dd), 4.22 (2H, q), 4.19 (2H, t), 3.86 (3H, s), 3.23 (2H, t), 1.20 (3H, t); MS (ES): 391 (MH+).
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)(=[O:5])=[O:4].[S-:20][C:21]#[N:22].[K+].BrBr.[ClH:26]>C(O)(=O)C.C(O)C>[ClH:26].[CH3:1][NH:2][S:3]([CH2:6][CH2:7][N:8]1[C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]([F:17])([F:19])[F:18])=[CH:13][C:14]=2[S:20][C:21]1=[NH:22])(=[O:4])=[O:5]
Reactant: CNS(=O)(=O)CCNc1ccc(OC(F)(F)F)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)O
Product: CNS(=O)(=O)CCn1c(=N)sc2cc(OC(F)(F)F)ccc21

Procedure:
The procedure is as in Example 3, starting with N-methyl-2-(p-trifluoromethoxyanilino)ethanesulphonamide (3.5 g), potassium thiocyanate (4.7 g) and bromine (2.2 g) in acetic acid (30 cc). After 18 hours at a temperature in the region of 20° C., neutralization with 30% strength sodium hydroxide and extraction with ethyl acetate, a crude product is obtained, which product is converted to a hydrochloride by adding 4.2N ethereal hydrogen chloride (3 cc) in ethanol (25 cc) and recrystallized in absolute ethanol (50 cc). The N-methyl-2-(2-imino-6-trifluoromethoxy-3-benzothiazolinyl)ethanesulphonamide hydrochloride thereby obtained (2.1 g) melts at 242° C.
Reaction SMILES: [NH:1]([C:8]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:9]=1[C:10]([NH2:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](Cl)(=O)[C:20]([CH3:23])([CH3:22])[CH3:21]>ClC(Cl)C>[C:20]([C:23]1[N:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:8]2[C:9]([C:10](=[O:11])[N:12]=1)=[CH:13][CH:14]=[C:15]([O:17][CH3:18])[CH:16]=2)([CH3:22])([CH3:21])[CH3:19]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1ccc(C(N)=O)c(Nc2ccccc2)c1
Solvent: CC(Cl)Cl
Product: COc1ccc2c(=O)nc(C(C)(C)C)n(-c3ccccc3)c2c1

Procedure:
To a solution of 2-anilino-4-methoxybenzamide (150 mg) in 5 mL dichloroethane was added pivaloyl chloride (0.229 mL), and the reaction was heated at reflux for 7 h. The reaction was cooled and partially concentrated, then diluted with ethyl ether, and the resulting precipitate was isolated by filtration to give 180 mg of a solid product. This material was dissolved in CH2Cl2 and washed with 10% sodium carbonate. The organic solution was dried (Na2SO4) and concentrated to give the titled compound.
Reaction SMILES: C([Li:5])CCC.[CH2:6]([C:10]1[CH:19]=[CH:18][C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[N:11]=1)[CH2:7][CH2:8][CH3:9]>>[CH2:6]([C:10]1[CH:19]=[CH:18][C:17]2[CH2:16][CH2:15][CH2:14][CH:13]([Li:5])[C:12]=2[N:11]=1)[CH2:7][CH2:8][CH3:9]
Reactant: [Li]CCCC
Reactant: CCCCc1ccc2c(n1)CCCC2
Product: [Li]C1CCCc2ccc(CCCC)nc21

Procedure:
By the method described in Example 7 using n-butyl lithium solution (9% w/v, 13.5 g, 0.03 mol) and 2-n-butyl-5,6,7,8-tetrahydroquinoline (6 g., 0.03 mol) the title compound is prepared and converted in situ to methyl 2-n-butyl-5,6,7,8-tetrahydroquinoline-8-carboxylate and then to the corresponding 8-thioamide by the procedure described in U.S. Ser. No. 460,265.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.CN(CCN(C)C)C.[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.N>CO.O>[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[N:8][O:9][C:10]=3[CH3:11])[N:3]=[CH:2]2)=[CH:29][CH:28]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: OB(O)c1ccc(F)cc1
Agent: CN(C)CCN(C)C
Agent: N
Solvent: O
Solvent: CO
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(F)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.3 %

Procedure:
To a mixture of 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (112.6 mg, 0.5 mmol) containing [Cu(OH).TMEDA]2Cl2 (23.2 mg, 0.05 mmol) in dry methanol (5 mL) was added 4-fluorophenylboronic acid (140 mg, 1.0 mmol) under an air atmosphere and the resulting mixture stirred at room temperature overnight. After this time, concentrated ammonia solution (2 mL) was added and then the resulting mixture was diluted with water (20 mL) and extracted with ethyl acetate. The organic extracts were then dried over sodium sulphate and evaporated. Purification by preparative HPLC on reversed phase eluting with an acetonitrile/water [0.1% aq NH3 (25%)] gradient afforded the title compound (34 mg, 21%) which was obtained as a white solid. MS (ESI): m/e=320.0 [M+H]+.