Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([N:9]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:10][C:11]([CH3:17])([CH3:16])[C:12]([NH:14][CH3:15])=[O:13])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][C:25]=1[O:34][CH3:35].O.Cl>CCO>[Br:1][C:2]1[C:3]([N:9]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:10][C:11]([CH3:17])([CH3:16])[C:12]([NH:14][CH3:15])=[O:13])=[N:4][C:5]([NH:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][C:25]=2[O:34][CH3:35])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(N)c(OC)c1
Reactant: CNC(=O)C(C)(C)CN(c1nc(Cl)ncc1Br)C1CCCC1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CNC(=O)C(C)(C)CN(c1nc(Nc2ccc(C(=O)OC)cc2OC)ncc1Br)C1CCCC1
Temperature: 90 °C
Yield: 23 %

Procedure:
3-[(5-bromo-2-chloro-pyrimidin-4-yl)-cyclopentyl-amino]-N,2,2-trimethyl-propanamide (266 mg, 0.6825 mmol) and methyl 4-amino-3-methoxy-benzoate (185.5 mg, 1.024 mmol) were dissolved in EtOH (2 mL) and Water (8 mL) and treated with HCl (134.5 μL of 37% w/v, 1.365 mmol). Heat at 90° C. overnight. Cool to ambient temperature and remove solvent in vacuo. The reaction mixture was diluted with EtOAc/NaHCO3 and extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filter and concentrated. The crude residue was purified by column chromatography (0 to 100% EtOAc/Petrol) to give the sub-title compound as a beige oil (84 mg, 23%); NMR (400.0 MHz, DMSO) d 0.97 (s, 6H), 1.44-1.69 (m, 8H), 2.45 (d; J=4.4 Hz, 3H), 3.58 (br s, 2H), 3.84 (s, 3H), 3.96 (s, 3H), 4.11 (quin, 1H), 7.32-7.34 (m, 1H), 7.52 (d, J=1.8 Hz, 1H), 7.61 (d, 1H), 8.07 (s, 1H), 8.38 (s, 1H) and 8.43 (d, J=8.5 Hz, 1H); MS ES(+) 536.0, ES (−) 534.1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[N:4][N:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][OH:27])[CH:21]=1.C1CCN2C(=NCCC2)CC1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([O:27][CH2:26][C:22]3[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=3)=[N:3][N:4]=2)=[CH:14][CH:15]=1
Reactant: Clc1ccc(Nc2nnc(Cl)c3ccccc23)cc1
Reactant: OCc1cccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: Clc1ccc(Nc2nnc(OCc3cccnc3)c3ccccc23)cc1
Temperature: 25 °C
Yield: 55.9 %

Procedure:
A dry 50-mL round-bottomed flask was equipped with a stir bar and an argon inlet. The flask was charged with 1-chloro-4-(4-chlorophenylamino)-phthalazine (R. D. Haworth and S. Robinson, J. Chem. Soc. 1948, pp.777-782) (2.00 g; ˜6.12 mmol), 3-pyridyl-carbinol (Aldrich) (10.02 g, 91.85 mmol), and DBU (18.3 mL, ˜18.7 g, ˜123 mmol). The reaction was heated at 125 C for 28 h. The mixture was cooled to room temperature and distilled water (400 mL) was added with stirring. The aqueous phase was extracted with ethyl acetate (3×300 mL). The combined organics were dried (MgSO4) and concentrated to yield a tan solid, which was purified by silica gel chromatography (100% dichloromethane→50% acetone/dichloromethane) to give the clean desired compound as a white solid (1.24 g, 3.42 mmol; 56% yield). TLC (20% acetone/dichloromethane): Rf=0.48.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:25])=[C:13]([NH:15][C:16]([C:18]3[N:22]([CH3:23])[N:21]=[C:20]([CH3:24])[CH:19]=3)=[O:17])[CH:14]=2)=[CH:4][CH:3]=1.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>N1C=CC=CC=1>[CH3:23][N:22]1[C:18]([C:16]([NH:15][C:13]2[CH:14]=[C:9]([O:8][C:5]3[CH:6]=[N:7][C:2]([NH:1][S:32]([C:29]4[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=4)(=[O:34])=[O:33])=[CH:3][CH:4]=3)[CH:10]=[CH:11][C:12]=2[CH3:25])=[O:17])=[CH:19][C:20]([CH3:24])=[N:21]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc(N)nc3)ccc2C)n(C)n1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3ccc(C)c(NC(=O)c4cc(C)nn4C)c3)cn2)cc1
Yield: 76.6 %

Procedure:
In the same manner as in Reference Example 4 and using N-{5-[(6-aminopyridin-3-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (2.61 g, 7.75 mmol), p-toluenesulfonyl chloride (1.77 g, 9.31 mmol) and pyridine (15 mL) as starting materials, the title compound (2.92 g, 77%) was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][CH:3]=1.[F:23][C:24]1[CH:25]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>N1C=CC=CC=1>[F:23][C:24]1[CH:25]=[C:26]([S:30]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]3[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=4)[NH:9]3)=[CH:6][CH:7]=2)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: c1ccncc1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(NS(=O)(=O)c2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a solution of 2-(4-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (50 mg, 0.17 mmol) in 5 mL of pyridine was added 3-fluorobenzene-1-sulfonyl chloride (41 mg 0.21 mmol) below 0° C. The mixture was stirred at room temperature under nitrogen overnight. Pyridine was removed in vacuo and the residue was purified by preparative thin layer chromatography to afford 2-(4-(3-fluorophenylsulfonamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a yellow solid, 43 mg, yield: 62%. MS (ESI+APCI) M+1=455.50.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@:13]([CH2:24][OH:25])([N:21]=[N+:22]=[N-:23])[O:12]1.C[Si](Cl)(C)C.[C:31](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:32].CO>N1C=CC=CC=1>[N:21]([C@@:13]1([CH2:24][OH:25])[C@H:14]2[O:18][C:17]([CH3:20])([CH3:19])[O:16][C@H:15]2[C@H:11]([N:6]2[CH:5]=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[NH:1][C:31](=[O:32])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:12]1)=[N+:22]=[N-:23]
Reactant: CC1(C)O[C@H]2[C@H](n3cnc4c(N)ncnc43)O[C@@](CO)(N=[N+]=[N-])[C@H]2O1
Reactant: O=C(Cl)c1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Solvent: CO
Product: CC1(C)O[C@H]2[C@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)O[C@@](CO)(N=[N+]=[N-])[C@H]2O1
Reaction time: 1 h
Yield: 91.8 %

Procedure:
Compound 36.2 (300 mg, 0.86 mmol) was dissolved in 8.6 mL anhydrous pyridine, and treated with TMSCl (1.09 mL, 8.6 mmol). The mixture was stirred for 1 h, and then treated with BzCl (1.0 mL, 8.6 mmol), stirred for overnight. MeOH was added to the mixture after the reaction was completed. The mixture was stirred for another 5 min and then concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with sat. NaHCO3 twice and the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography eluting with 50% EtOAc in hexane to give compound 36.3 (357 mg, 74% yield).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[OH:19].Cl[CH2:21][C:22]#[N:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:14]1([C:7]2([CH3:13])[CH2:6][C:5]3[C:9](=[C:10]([Cl:11])[C:2]([Cl:1])=[C:3]([O:19][CH2:21][C:22]#[N:23])[CH:4]=3)[C:8]2=[O:12])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C2CCCC2)Cc2cc(OCC#N)c(Cl)c(Cl)c2C1=O
Reaction time: 3 h
Yield: 102.1 %

Procedure:
A mixture of (+) 6,7-dichloro-2-cyclopentyl-5-hydroxy-2-methyl-2,3-dihydro-1H-inden-1-one (3.29 g, 11 mmole), chloroacetonitrile (1.25 g, 16.5 mmole), and potassium carbonate (3.04 g) in dimethylformamide (30 ml) was stirred at 60°-65° for three hours. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, and concentrated in vacuo to give the title compound as an oil (3.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH:12]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:27])=[CH:22][CH:21]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:5]2.O1CCCC1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH:12]([NH:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[CH:24][CH:25]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:5]2
Reactant: CCCCCCC(Nc1ccc(C(=O)NCCC(=O)OCC)cc1)c1cc2cc(Cl)ccc2n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCC(Nc1ccc(C(=O)NCCC(=O)O)cc1)c1cc2cc(Cl)ccc2n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
To a mixture of ethyl 3-{[(4-{[1-(5-chloro-1-methyl-1H-indol-2-yl)heptyl]amino}phenyl)carbonyl]amino}propanoate (349 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (302 mg, 92%) as a pale-brown solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][C:10]2[NH:14][N:13]=[C:12]([CH:15]3[CH2:17][CH2:16]3)[CH:11]=2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([C@@H:25]([NH2:27])[CH3:26])=[N:23][CH:24]=1.CCN(C(C)C)C(C)C>CCCCO>[Br:1][C:2]1[C:3]([NH:9][C:10]2[CH:11]=[C:12]([CH:15]3[CH2:17][CH2:16]3)[NH:13][N:14]=2)=[N:4][C:5]([NH:27][C@H:25]([C:22]2[CH:21]=[CH:20][C:19]([F:18])=[CH:24][N:23]=2)[CH3:26])=[N:6][CH:7]=1
Reactant: C[C@H](N)c1ccc(F)cn1
Reactant: Clc1ncc(Br)c(Nc2cc(C3CC3)n[nH]2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncc(Br)c(Nc2cc(C3CC3)[nH]n2)n1)c1ccc(F)cn1
Temperature: 175 °C
Yield: 86 %

Procedure:
A mixture of 5-bromo-2-chloro-N-(3-cyclopropyl-1H-pyrazol-5-yl)pyrimidin-4-amine (Method 8; 0.062 g, 0.196 mmol), (S)-1-(5-fluoropyridin-2-yl)ethanamine (Method 6; 0.025 g, 0.178 mmol), and DIEA (0.04 ml, 0.214 mmol) in n-BuOH (2 ml) was heated in a sealed tube at 175° C. for 20 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane:EtOAc=1:1) to give the title compound as a white solid (0.064 g, 86%). 1H NMR (400 MHz) 12.48 and 12.09 (s, 1H), 9.32 (s, 1H), 8.48 (d, J=2.4 Hz, 1H), 8.00 (b, 1H), 7.92 (s, 1H), 7.64 (m, 1H), 7.41 (m, 1H), 5.94 and 5.85 (b, 1H), 5.06 (m, 1H), 1.84 (m, 1H), 1.45 (d, J=7.2 Hz, 3H), 0.95 (m, 1H), 0.86 (m, 1H), 0.74 (m, 1H), 0.63 (m, 1H). MS: Calcd.: 417. Found: [M+H]+418.
Reaction SMILES: [CH2:1](I)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Na].[C:14]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:15][C:16]([CH3:18])=[O:17]>C(O)C>[CH2:1]([CH:15]([C:16]([CH3:18])=[O:17])[C:14]([O:20][CH2:21][CH3:22])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCI
Reactant: CCOC(=O)CC(C)=O
Agent: [Na]
Solvent: CCO
Product: CCCCCCCCCCCC(C(C)=O)C(=O)OCC

Procedure:
Ethyl 2-(n-undecyl)-acetoacetate was prepared from undecyl iodide (26.6 .g) by reaction with an equivalent amount of the sodium derivative of ethyl acetoacetate in ethanol (5 hours, reflux temperature). After cooling the solvent is removed on a rotary evaporator, 300 ml of hexane is added to the residue, and the precipitate of salt is now easily filtered. The product is of sufficient purity (g.c-m.s.) to dispense with further work-up. Reaction of it (6.80 g) with 3.5-difluoroaniline (3.1 g) and 0.30 g of p-toluenesulfonic acid monohydrate in 100 ml of benzene (water separator, 3 days) produced the anilinocrotonic ester with very little of the starting materials left. After removal of the solvent, the crude product was added quickly to 30 ml of boiling Dowtherm A and kept at boiling temperature for about 10 minutes. The product crystallizes out upon cooling and is isolated by filtration and washing with hexane (50 ml).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:20])(C)(C)C.CC1(C)O[C:27](=[O:29])[CH:26]=[C:25]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:14]1([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:25]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=4)[CH2:26][C:27](=[O:29])[NH:20][C:9]=3[CH:10]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC1(C)OC(=O)C=C(c2cccc(C(F)(F)F)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(C(F)(F)F)c2)=Nc2ccc(-c3ccccc3)cc2N1
Yield: 62.6 %

Procedure:
Prepared from (3-amino-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G9) (284 mg, 1.0 mmol) and 2,2-dimethyl-6-(3-trifluoromethyl-phenyl)-[1,3]dioxin-4-one (Example J5) (408 mg, 1.2 mmol) according to the general procedure K. The obtained material (392 mg) was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (238 mg).
Reaction SMILES: [CH:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:9]2[N:13]=[CH:12][N:11]([CH2:14][CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[N:10]=2)[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][N:38]2[C:46](=[O:47])[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39]2=[O:48])=[CH:32][CH:31]=1.C(N(CC)CC)C>C(#N)C>[CH:21]1([C@@:7]([OH:8])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:9]2[N:13]=[CH:12][N:11]([CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([CH2:28][CH2:29][C:30]4[CH:31]=[CH:32][C:33]([CH2:36][CH2:37][N:38]5[C:46](=[O:47])[C:45]6[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=6)[C:39]5=[O:48])=[CH:34][CH:35]=4)[CH2:17][CH2:16]3)[N:10]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C1c2ccccc2C(=O)N1CCc1ccc(CCBr)cc1
Reactant: OC(c1ccccc1)(c1ncn(CC2CCNCC2)n1)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCc1ccc(CCN2CCC(Cn3cnc([C@](O)(c4ccccc4)C4CCCCC4)n3)CC2)cc1
Temperature: 90 °C
Reaction time: 48 h
Yield: 28 %

Procedure:
Cyclohexyl-phenyl-(1-piperidin-4-ylmethyl-1H-[1,2,4]triazol-3-yl)-methanol (Preparation 4, 8.2 g, 2.98 mmol), 2-{2-[4-(2-Bromo-ethyl)-phenyl]-ethyl}-isoindole-1,3-dione (Preparation 11, 7.56 g, 21.1 mmol), and triethylamine (13.3 ml, 95.9 mmol) were dissolved in acetonitrile (100 ml). After stirring at 90° C. for 48 hours the solvent was removed in vacuo, and the residue partitioned between dichloromethane (200 ml) and water (200 mL). The organic layer was separated, dried over magnesium sulphate, filtered and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (98:2:0.2, by volume) and the resulting material then triturated in tert-butyl methyl ether to furnish title compound as a clear solid in 28% yield, 3.4 g.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[I-].C[N+]1C=CN([C:26]([N:28]2[CH2:33][CH2:32][CH2:31][CH:30]([CH3:34])[CH2:29]2)=[O:27])C=1>>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:26]([N:28]3[CH2:33][CH2:32][CH2:31][CH:30]([CH3:34])[CH2:29]3)=[O:27])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: CC1CCCN(C(=O)n2cc[n+](C)c2)C1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: [I-]
Product: CC1CCCN(C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)C1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 1-methyl-3-(3-methyl-piperidine-1-carbonyl)-3H-imidazol-1-ium iodide. The crude product was purified by flash chromatography using a Quad flash 25 (ethyl acetate/heptane (1:6), (75%, white crystals). HPLC-MS m/z=381.1 (M+1), Rt: 5.4 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].Cl[C:9]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.CO.N>ClCCl>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:9]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: NCCCCCN
Reactant: COc1cc(Cl)nc2ccccc12
Agent: N
Solvent: CO
Solvent: ClCCl
Product: COc1cc(NCCCCCN)nc2ccccc12

Procedure:
The title compound was prepared by an analogous procedure to that described in example 1a from 1,5-diaminopentane (5 g, 49 mmol) and 2-chloro-4-methoxyquinoline (0.93 g, 4.8 mmol) to yield, after chromatography over silica gel eluting with an increasing concentration of 9:1 methanol/ammonia in dichloromethane, a cream coloured solid (30%). δH (CDCl3) 1.0-1.8 (8H, envelop), 2.72 (2H, t), 3.4-3.5 (2H, m), 3.97 (3H, s), 4.6-4.79 (1H, m), 5.94 (1H, m), 7.18 (1H, t), 7.51 (1H, t), 7.60 (1H, d), 7.96 (1H, d). MS (ES+) 260 (90%) MH+.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:9]=3[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>>[CH3:18][O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([C:11]1[S:10][C:9]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:8]=2[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:23]
Reactant: COc1ccccc1C(=O)Cl
Reactant: COc1ccc2c(-c3ccccc3)csc2c1
Product: COc1ccc2c(-c3ccccc3)c(C(=O)c3ccccc3OC)sc2c1
Yield: 97 %

Procedure:
3-Phenyl-6-methoxybenzo[b]thiophene and 2-methoxybenzoyl chloride were converted to the title compound by the procedure of Example 1 in 97% yield, after crystallization from methanol.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([CH:10]=[O:11])=[CH:2]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=Cc1cn(S(=O)(=O)c2ccc(Cl)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
A solution of 1H-indole-3-carboxaldehyde (0.290 g, 2.00 mmol) in methylene chloride (4 mL) was added with 4-chlorophenylsulfonyl chloride (0.507 g, 2.40 mmol) and diisopropylethylamine (0.310 g, 2.40 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate to terminate the reaction, and then extracted three times with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain 1-(4-chlorophenylsulfonyl)-1H-indole-3-carboxaldehyde (0.575 g, 89%).
Reaction SMILES: [CH:1]1([NH:6][C:7]([C:9]2([CH2:22][CH2:23][CH2:24][CH2:25]Br)[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:27]1([C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH:1]1([NH:6][C:7]([C:9]2([CH2:22][CH2:23][CH2:24][CH2:25][N:30]3[CH2:31][CH2:32][N:27]([C:33]4[CH:42]=[CH:41][C:40]5[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:34]=4)[CH2:28][CH2:29]3)[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NC1CCCC1)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Product: O=C(NC1CCCC1)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2b from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(cyclopentyl)-amide and 2-(piperazin-1-yl)-quinoline.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([F:21])[C:14]=1[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[NH:11][N:10]=[C:9]2[NH:22][C:23](=[O:27])[CH2:24][CH2:25][CH3:26].[BrH:28]>O>[Br:28][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([F:21])[C:14]=1[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[NH:11][N:10]=[C:9]2[NH:22][C:23](=[O:27])[CH2:24][CH2:25][CH3:26]
Reactant: CCCC(=O)Nc1n[nH]c2c(F)c(N3CCOCC3)c(N)cc12
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCCC(=O)Nc1n[nH]c2c(F)c(N3CCOCC3)c(Br)cc12
Reaction time: 0.75 h

Procedure:
A solution of 213 mg of sodium nitrite in 9 cm3 of water is added dropwise to a suspension, cooled to 5° C., of 900 mg of N-(5-amino-7-fluoro-6-morpholino-1H-indazol-3-yl)butanamide, prepared as previously, in 9 cm3 of water and 0.94 cm3 of 48% hydrobromic acid, and the mixture is stirred at 0° C. This suspension is added portionwise to a refluxing solution of 482 mg of cuprous bromide, 4.5 cm3 of water and 4.5 cm3 of 48% hydrobromic acid. Refluxing is continued for 45 minutes and the reaction medium is then filtered through a sinter funnel, dissolved in 75 cm3 of tetrahydrofuran and purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 15-40 μm; diameter 3 cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.) and the residue is taken up in 10 cm3 of ethyl acetate, filtered off and washed with 2×5 cm3 of ethyl acetate and with 20 cm3 of diisopropyl ether. After filtration and drying (90 Pa; 45° C.), 60 mg of N-(5-bromo-7-fluoro-6-morpholino-1H-indazol-3-yl)butanamide are obtained in the form of white crystals melting at 240° C.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:10]3[S:11][C:12]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)=[C:13]([O:14]C)[C:9]=3[C:8](=[O:27])[N:7]([CH3:28])[N:6]=2)[CH2:3][CH2:2]1.B(Br)(Br)Br.O>ClCCl>[CH:1]1([CH2:4][C:5]2[C:10]3[S:11][C:12]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)=[C:13]([OH:14])[C:9]=3[C:8](=[O:27])[N:7]([CH3:28])[N:6]=2)[CH2:2][CH2:3]1
Reactant: COc1c(Cc2cccc(C(F)(F)F)c2)sc2c(CC3CC3)nn(C)c(=O)c12
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cn1nc(CC2CC2)c2sc(Cc3cccc(C(F)(F)F)c3)c(O)c2c1=O
Temperature: -15 °C
Reaction time: 72 h
Yield: 53 %

Procedure:
7-Cyclopropylmethyl-3-methoxy-5-methyl-2-[(3-trifluoromethylphenyl)methyl]-thieno[2,3-d]pyridazin-4(5H)-one (8.8 g) was dissolved in dichloromethane (250 ml) and cooled to −15° C. Boron tribromide in dichloromethane (1M, 24 ml) was added. The reaction was allowed to warm to room temperature and left to stir for 72 hours. Water was added and the mixture was extracted with ethyl acetate. The ethyl acetate was dried, filtered and concentrated. The residue was purified by chromatography, eluting with 1:1 isohexane:ether, and then recrystallised from isohexane to give the sub-title compound (4.5 g).
Reaction SMILES: [CH2:1]([C:3]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)([CH2:7][CH3:8])[C:4](Cl)=[O:5])[CH3:2].[CH3:16][NH:17][C@H:18]1[CH2:37][N:22]2[C:23]3[C:28]([C:29]([CH2:30][C:31]([O:33]CCC)=[O:32])=[C:21]2[CH2:20][CH2:19]1)=[CH:27][CH:26]=[CH:25][CH:24]=3>>[CH2:1]([C:3]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)([CH2:7][CH3:8])[C:4]([N:17]([CH3:16])[C@H:18]1[CH2:37][N:22]2[C:23]3[C:28]([C:29]([CH2:30][C:31]([OH:33])=[O:32])=[C:21]2[CH2:20][CH2:19]1)=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:5])[CH3:2]
Reactant: CCC(CC)(C(=O)Cl)c1ccc(F)cc1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: CCC(CC)(C(=O)N(C)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1)c1ccc(F)cc1

Procedure:
The title compound was prepared using analogous procedures described in Example 2 (Method B) from 2-ethyl-2-(4-fluorophenyl)butanoyl chloride and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido [1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 451.