Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[CH2:11][CH2:10][N:9]([C:12]([O:14][CH:15]3[CH:22]4[CH2:23][C:18]5([OH:25])[CH2:19][CH:20]([CH2:24][CH:16]3[CH2:17]5)[CH2:21]4)=[O:13])[CH2:8]2)=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:34])C=1>C(Cl)Cl.CO>[OH:25][C:18]12[CH2:23][CH:22]3[CH2:21][CH:20]([CH2:24][CH:16]([CH:15]3[O:14][C:12]([N:9]3[CH2:10][CH2:11][CH:7]([C:4]4[CH:5]=[CH:6][N+:1]([O-:34])=[CH:2][CH:3]=4)[CH2:8]3)=[O:13])[CH2:17]1)[CH2:19]2
Reactant: O=C(OC1C2CC3CC1CC(O)(C3)C2)N1CCC(c2ccncc2)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: O=C(OC1C2CC3CC1CC(O)(C3)C2)N1CCC(c2cc[n+]([O-])cc2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 108.2 %

Procedure:
A stirred solution of 1-hydroxy-4-adamantyl 3-(pyridin-4-yl)pyrrolidine-1-carboxylate (476 mg, 1.39 mmol) in CH2Cl2 (50 mL) was cooled in an ice bath and solid m-CPBA (˜70%, 342 mg, ˜1.4 mmol) was added. The ice bath was allowed to melt and the mixture was stirred at rt for 2 days. The mixture was diluted with MeOH (50 mL) and Amberlyst A26 OH− (5 g) was added. The mixture was stirred for 1 h, filtered and the filtrate was concentrated to leave a viscous oil (539 mg). A 35-mg portion was purified by prep HPLC to afford the title compound (10.5 mg) as an oil. LC-MS Method 1 tR=1.02 min, m/z=359, 1H NMR (CDCl3) [selected resonances] 4.67 (s, 0.5H), 4.78 (s, 0.5H), 7.58 (d, 2H), 8.38 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7][CH2:8]Cl)=[CH:5][CH:6]=1.Cl.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)([OH:20])[CH3:19])=[CH:14][CH:13]=1.C([O-])(O)=O.[Na+]>C(#N)C>[Cl:1][C:2]1[S:3][C:4]([CH2:7][CH2:8][N:24]2[CH2:25][CH2:26][CH:21]([C:18]([C:15]3[CH:14]=[CH:13][C:12]([F:11])=[CH:17][CH:16]=3)([OH:20])[CH3:19])[CH2:22][CH2:23]2)=[CH:5][CH:6]=1
Reactant: CC(O)(c1ccc(F)cc1)C1CCNCC1
Reactant: ClCCc1ccc(Cl)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(O)(c1ccc(F)cc1)C1CCN(CCc2ccc(Cl)s2)CC1
Reaction time: 8 h
Yield: 72.7 %

Procedure:
A solution of 0.88 g of 2-chloro-5-(2-chloro-ethyl)thiophene in 10 ml of acetonitrile is treated with 1.3 g of 1-(4-fluorophenyl)-1-piperidin-4-yl-ethanol, hydrochloride and 0.82 g of NaHCO3 and stirred at 80° for 8 hours. After customary working-up, 1.3 g of 1-{1-[2-(5-chlorothiophen-2-yl)ethyl]piperidin-4-yl}-1-(4-fluorophenyl)ethanol are obtained. The residue is dissolved in acetone, treated with ether/HCl and the hydrochloride, m.p. 210-211°, is obtained after crystallization.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:16]=[CH:15][C:6]([CH:7]([NH2:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([NH:29][CH2:30][C:31](O)=[O:32])=[O:28])=[CH:21][CH:20]=1>>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]([NH:14][C:31]([CH2:30][NH:29][C:27](=[O:28])[CH2:26][CH2:25][C:22]2[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=2)=[O:32])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: COc1ccc(CCC(=O)NCC(=O)O)cc1
Agent: Cl
Product: COc1ccc(CCC(=O)NCC(=O)NC(c2ccccc2)c2ccc(Cl)cc2)cc1

Procedure:
Prepared in analogy to example 1.1 from rac-4-chlorobenzhydrylamine hydrochloride and [3-(4-methoxy-phenyl)-propionylamino]-acetic acid (Example 2.2).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:5]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17].[NH:26]1[CH:30]=[CH:29][CH:28]=[N:27]1>>[F:15][C:12]1[CH:11]=[CH:10][C:9]([CH:6]2[N:5]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:4]([CH2:3][CH2:2][N:26]3[CH:30]=[CH:29][CH:28]=[N:27]3)[CH2:8][CH2:7]2)=[CH:14][CH:13]=1
Reactant: c1cn[nH]c1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCl)CCC2c2ccc(F)cc2)cc1
Product: Cc1ccc(S(=O)(=O)N2C(CCn3cccn3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, white solid, m.p.=121° C. and MS: m/e=414.2 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(2-chloro-ethyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 1H-pyrazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH:12]1[CH:16]=[CH:15][N:14]=[C:13]1[SH:17]>>[NH:12]1[CH:16]=[CH:15][N:14]=[C:13]1[S:17][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[Cl:1]
Reactant: Sc1ncc[nH]1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Product: O=[N+]([O-])c1ccc(Sc2ncc[nH]2)c(Cl)c1
Yield: 13 %

Procedure:
Using an analogous procedure to that described in the first paragraph of the portion of Example 8 which is concerned with the preparation of starting materials, 3-chloro-4-fluoronitrobenzene was reacted with 2-imidazolethiol to give a precipitated solid which was partitioned between methylene chloride and 2 h aqueous sodium hydroxide solution. The aqueous phase was acidified by the addition of a concentrated (20%) aqueous citric acid solution and the precipitate was isolated and dried. The material was recrystallised from a mixture of hexane and ethyl acetate to give 2-chloro-4-nitrophenyl 2-imidazolyl sulphide in 13% yield.
Reaction SMILES: O=[C:2]1[CH2:37][C@@H:36]2[C@:23]([CH3:40])([CH2:24][CH2:25][C@H:26]3[C@H:35]2[CH2:34][CH:33]=[C:32]2[C@:27]3([CH3:39])[CH2:28][CH2:29][C@H:30]([OH:38])[CH2:31]2)[C@H:3]1[C@H:4]([CH3:22])[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:21])[CH2:9][N:10]1C(=O)C2=CC=CC=C2C1=O.O.NN.[OH-].[K+].C(O)COCCOCCO>O>[NH2:10][CH2:9][C@@H:8]([CH2:7][CH2:6][CH2:5][C@H:4]([C@@H:3]1[C@:23]2([CH3:40])[C@H:36]([C@H:35]3[C@H:26]([CH2:25][CH2:24]2)[C@:27]2([CH3:39])[C:32]([CH2:31][C@H:30]([CH2:29][CH2:28]2)[OH:38])=[CH:33][CH2:34]3)[CH2:37][CH2:2]1)[CH3:22])[CH3:21]
Reactant: C[C@H](CCC[C@@H](C)[C@H]1C(=O)C[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)CN1C(=O)c2ccccc2C1=O
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCOCCO
Solvent: O
Product: C[C@@H](CN)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 150 °C
Yield: 64.1 %

Procedure:
A mixture of (25R)-16-oxo-26-phthalimidocholesterol (5) (0.70 g, 1.32 mmoles), hydrazine monohydrate (5 ml, 102.8 mmoles), potassium hydroxide (2.85 g, 50.8 mmoles) and triethylene glycol (20 ml) was heated to 150° C. for 30 minutes, then heated to 200° C. over 2 hours during which time water vapor distilled out of the mixture. The reaction mixture was maintained at this temperature for about 16 hours, under nitrogen, until the reaction was complete as determined by thin layer chromatography. Thereafter, the reaction mixture was cooled, poured into water, and extracted with chloroform. The extract was washed with water, dried over sodium sulfate, and evaporated under reduced pressure. Chromatography of the residue on silica gel eluted with CHCl3 gave 0.34 g (66%) of (25R)-26-aminocholesterol. The product was recrystallized from methylene chloride-ether and was found to have a melting point of 150°-152° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[C@H:20]([C:21]([OH:23])=O)[CH2:19][C:18]3[C:13](=[CH:14][C:15]([O:26][CH3:27])=[C:16]([O:24][CH3:25])[CH:17]=3)[CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH3:28][N:29]1[CH2:33][CH2:32][N:31]=[C:30]1[C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=1.C(Cl)CCl>CN(C=O)C.O>[CH3:28][N:29]1[CH2:33][CH2:32][N:31]=[C:30]1[C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:21]([C@@H:20]2[CH2:19][C:18]3[C:13](=[CH:14][C:15]([O:26][CH3:27])=[C:16]([O:24][CH3:25])[CH:17]=3)[CH2:12][N:11]2[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:10])=[O:23])=[CH:36][CH:35]=1
Reactant: CN1CCN=C1c1ccc(N)cc1
Reactant: COc1cc2c(cc1OC)CN(C(=O)Nc1ccc(Cl)cc1)[C@H](C(=O)O)C2
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)CN(C(=O)Nc1ccc(Cl)cc1)[C@H](C(=O)Nc1ccc(C3=NCCN3C)cc1)C2
Reaction time: 2 h
Yield: 57 %

Procedure:
To a solution of (3S)-2N-(4-chlorophenylaminocarbonyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (25 mg, 0.064 mmol) and 4-(1-Methyl-4,5-dihydro-1H-imidazol-2-yl)-phenylamine (23 mg, 0.13 mmol) in DMF (2 mL) and H2O (0.5 mL) at room temperature, EDC (49 mg, 0.26 mmol) was added. The mixture was stirred at room for 2 h. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a white powder (20 mg). MS 548.2 and 550.2 (M+H, Cl pattern).
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C@@H:7]([NH:16][CH2:17][C@@H:18]([OH:30])[C@@H:19]([NH2:29])[CH2:20][C:21]2[CH:26]=[C:25](F)[CH:24]=[C:23](F)[CH:22]=2)[CH2:6]1)[CH:2]=[CH2:3].[CH2:31]([C@H:35]1[CH2:39][CH2:38][N:37]([C@@H:40]([CH2:44][CH:45]=[CH2:46])[C:41](O)=[O:42])[C:36]1=[O:47])[CH:32]([CH3:34])[CH3:33].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C@@H:7]([NH:16][CH2:17][C@@H:18]([OH:30])[C@@H:19]([NH:29][C:41](=[O:42])[C@@H:40]([N:37]2[CH2:38][CH2:39][C@H:35]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:36]2=[O:47])[CH2:44][CH:45]=[CH2:46])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c2cc(OC)ccc21
Reactant: C=CC[C@@H](C(=O)O)N1CC[C@H](CC(C)C)C1=O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC=C)N2CC[C@H](CC(C)C)C2=O)c2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.3 %

Procedure:
Step O (1): (2R,3S)-1-((1S,3R)-3-(Allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-3-amino-4-(3,5-difluorophenyl)butan-2-ol (20 mg, 52.3 μmol) from step E (2), (S)-2-((S)-3-isobutyl-2-oxopyrrolidin-1-yl)pent-4-enoic acid (12.5 mg, 52.3 μmol) from step M (5), EDC (10 mg, 52.3 μmol), HOBt (7.1 mg, 52.3 μmol), DIEA (46.7 μL, 262 μmol) were mixed in 1 mL of DMF. The mixture was stirred at RT for 24 h. Purified with reverse phase Prep-HPLC to give 28.2 mg of (S)—N-((2S,3R)-4-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-2-((S)-3-isobutyl-2-oxopyrrolidin-1-yl)pent-4-enamide as the TFA salt: LC-MS (M+H)+=603.3 HRMS (M+H)+=604.3755 1H NMR (500 MHz, CDCl3) 8 ppm 0.80-0.96 (m, 6H) 1.08 (dd, J=10.53, 8.70 Hz, 1H) 1.23-1.38 (m, 1H) 1.54-1.66 (m, 2H) 1.96-2.06 (m, 1H) 2.26-2.45 (m, 3H) 2.51-2.77 (m, 3H) 2.85-2.95 (m, 1H) 3.03-3.16 (m, 2H) 3.28 (d, J=11.90 Hz, 1H) 3.76-3.84 (m, 3H) 3.92 (d, J=1.83 Hz, 1H) 4.03-4.12 (m, 2H) 4.20-4.29 (m, 1H) 4.46 (dd, J=10.22, 5.34 Hz, 1H) 4.73 (d, J=6.41 Hz, 1H) 4.78-4.87 (m, 1H) 4.95-5.07 (m, 2H) 5.21 (d, J=10.38 Hz, 1H) 5.30 (dd, J=17.40, 1.53 Hz, 1H) 5.54 (dd, J=14.80, 7.78 Hz, 1H) 5.84-5.98 (m, 1H) 6.71 (s, 1H) 6.95 (dd, J=8.24, 2.14 Hz, 1H) 7.11-7.28 (m, 6H) 7.34 (d, J=8.24 Hz, 1H).
Reaction SMILES: [CH2:1]([C:3]1[C:8]2[N:9]=[CH:10][O:11][C:7]=2[CH:6]=[CH:5][C:4]=1[NH:12]C(=O)C(F)(F)F)[CH3:2].O.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CO>[NH2:12][C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:3]=1[CH2:1][CH3:2]
Reactant: CCc1c(NC(=O)C(F)(F)F)ccc2ocnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1c(N)ccc2ocnc12
Temperature: 90 °C

Procedure:
A solution of 4-ethyl-5-trifluoroacetamidobenzoxazole (14.13 mmol) in a 20% mixture of water in methanol (20 mL) is treated with anhydrous potassium carbonate (56.52 mmol). A reflux condenser is attached and the mixture is heated to 90° C. with an oil bath for five hours. The mixture is cooled to room temperature and distributed between ethyl acetate (100 mL) and water (100 mL). The ethyl acetate layer is dried over magnesium sulfate and concentrated under reduced pressure to yield a black residue. This material is purified by chromatography (silica gel, 50% ethyl acetate/hexanes) to afford 5-amino-4-ethylbenzoxazole.
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[CH2:3][O:4][C:5]([N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]3[O:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][C:22]=3[CH:35]=2)=[CH:14][CH:13]=1)=[O:6].FC(F)(F)C(O)=O>ClCCl>[O:27]1[C:21]2[CH:20]=[CH:19][C:18]([C:15]3[CH:14]=[CH:13][C:12]([C:8]4[N:7]([C:5]([O:4][CH2:3][CH:2]([CH3:36])[CH3:1])=[O:6])[CH:11]=[CH:10][N:9]=4)=[CH:17][CH:16]=3)=[CH:35][C:22]=2[CH2:23][NH:24][CH2:25][CH2:26]1
Reactant: CC(C)COC(=O)n1ccnc1-c1ccc(-c2ccc3c(c2)CN(C(=O)OC(C)(C)C)CCO3)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)COC(=O)n1ccnc1-c1ccc(-c2ccc3c(c2)CNCCO3)cc1
Temperature: 25 °C
Yield: 92.1 %

Procedure:
To a solution of 1,1-dimethylethyl 7-[4-(1-{[(2-methylpropyl)oxy]carbonyl}-1H-imidazol-2-yl)phenyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (0.30 g, 0.61 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (20 mL) and the reaction mixture was heated to reflux. After cooling to room temperature the solvent was evaporated. The residue was dissolved in ethyl acetate (250 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (2×100 mL), brine, dried over anhydrous sodium sulfate then filtered and concentrated to give 2-methylpropyl 2-[4-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)phenyl]-1H-imidazole-1-carboxylate (0.22 g, 92%). MS (EI) for C23H25N3O3: 392 (MH+).
Reaction SMILES: Cl.O1CCOCC1.O.C(OC([N:16]1[C:20](=[O:21])[C:19]2([CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]([O:40]C(C)(C)C)=[O:39])=[CH:34][C:33]=3[CH3:45])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:18]=[C:17]1[C:46]1[CH:51]=[C:50]([C:52]([F:55])([F:54])[F:53])[CH:49]=[C:48]([O:56][CH2:57][CH2:58][C:59]#[CH:60])[CH:47]=1)=O)(C)(C)C>>[CH2:57]([O:56][C:48]1[CH:47]=[C:46]([C:17]2[NH:16][C:20](=[O:21])[C:19]3([CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]([OH:40])=[O:39])=[CH:34][C:33]=4[CH3:45])(=[O:29])=[O:28])[CH2:23][CH2:22]3)[N:18]=2)[CH:51]=[C:50]([C:52]([F:54])([F:55])[F:53])[CH:49]=1)[CH2:58][C:59]#[CH:60]
Reactant: C#CCCOc1cc(C2=NC3(CCN(S(=O)(=O)CCc4ccc(C(=O)OC(C)(C)C)cc4C)CC3)C(=O)N2C(=O)OC(C)(C)C)cc(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: C#CCCOc1cc(C2=NC3(CCN(S(=O)(=O)CCc4ccc(C(=O)O)cc4C)CC3)C(=O)N2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4 M hydrochloric acid-dioxane (1.80 ml) and water (0.0173 ml, 0.960 mmol) were added to 8-[2-(4-tert-butoxycarbonyl-2-methyl-phenyl)-ethanesulfonyl]-2-(3-but-3-ynyloxy-5-trifluoromethyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-3-carboxylic acid tert-butyl ester (35.9 mg, 0.048 mmol), and the mixture was stirred at room temperature for five hours. The reaction solution was concentrated under reduced pressure to give 4-{2-[2-(3-but-3-ynyloxy-5-trifluoromethyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-3-methyl-benzoic acid as a white solid.
Reaction SMILES: C(C1C=C(NC(=O)CCCC2C=CC([B:25]([OH:27])[OH:26])=CC=2)C=CC=1S(CC)(=O)=O)#N.[C:29]([O:33][C:34]([NH:36][CH2:37][C:38]1[CH:39]=[C:40]([NH:44][C:45]([O:47][CH2:48][CH2:49][C:50]2[CH:55]=[CH:54][C:53](Br)=[CH:52][C:51]=2[Cl:57])=[O:46])[CH:41]=[CH:42][CH:43]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34]([NH:36][CH2:37][C:38]1[CH:39]=[C:40]([NH:44][C:45]([O:47][CH2:48][CH2:49][C:50]2[CH:55]=[CH:54][C:53]([B:25]([OH:27])[OH:26])=[CH:52][C:51]=2[Cl:57])=[O:46])[CH:41]=[CH:42][CH:43]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)NCc1cccc(NC(=O)OCCc2ccc(Br)cc2Cl)c1
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Product: CC(C)(C)OC(=O)NCc1cccc(NC(=O)OCCc2ccc(B(O)O)cc2Cl)c1
Yield: 44 %

Procedure:
Using a procedure analogous to that used to prepare 6D, 61D (1.84 g, 3.8 mmol) was reacted with 5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to give 61E (750 mg, 44%) as a solid. MS (ESI) m/z 447.1 (M−H)−.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[C:5]([CH3:16])=[CH:4][N:3]=1.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)[CH2:20][CH2:19]1>>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[C:5]([CH3:16])=[CH:4][N:3]=[C:2]([NH:29][C:28]3[CH:27]=[CH:26][C:25]([CH2:24][N:21]4[CH2:20][CH2:19][N:18]([CH3:17])[CH2:23][CH2:22]4)=[CH:31][CH:30]=3)[N:7]=2)[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: Cc1cnc(Cl)nc1-c1ccc(F)c(Cl)c1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Product: Cc1cnc(Nc2ccc(CN3CCN(C)CC3)cc2)nc1-c1ccc(F)c(Cl)c1
Yield: 84 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-chloro-4-(3-chloro-4-fluorophenyl)-5-methylpyrimidine and 4-((4-methylpiperazin-1-yl)methyl)aniline in 84% yield (yellow solid) after purification by flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.30 (s, 1H), 7.70 (m, 1H), 7.56 (d, 2H, J=8.6 Hz), 7.51 (m, 1H), 7.25 (d, 2H, J: not calculated due to overlapping peaks), 7.05 (s, 1H), 3.46 (s, 2H), 2.46 (bs, 8H), 2.28 (s, 3H), 2.25 (s, 3H); MS (ESI): 426.3 [M+H]+, 213.7 [M+2H]2+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][N:7]([C:11]3[S:12][C:13]4[C:14](=[O:22])[NH:15][C:16]([CH3:21])([CH3:20])[CH2:17][C:18]=4[N:19]=3)[C:6]=2[CH:23]=1.[C:24]1(=O)[O:29][C:27](=[O:28])[CH2:26][CH2:25]1>CN(C=O)C>[CH3:20][C:16]1([CH3:21])[NH:15][C:14](=[O:22])[C:13]2[S:12][C:11]([N:7]3[C:6]4[CH:23]=[C:2]([N:1]5[C:27](=[O:28])[CH2:26][CH2:25][C:24]5=[O:29])[CH:3]=[CH:4][C:5]=4[O:10][CH2:9][CH2:8]3)=[N:19][C:18]=2[CH2:17]1
Reactant: O=C1CCC(=O)O1
Reactant: CC1(C)Cc2nc(N3CCOc4ccc(N)cc43)sc2C(=O)N1
Solvent: CN(C)C=O
Product: CC1(C)Cc2nc(N3CCOc4ccc(N5C(=O)CCC5=O)cc43)sc2C(=O)N1
Temperature: 140 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
A mixture of Example 42 (50 mg, 0.15 mmol) and succinic anhydride (20 mg, 0.15 mmol) in DMF (4 mL) was stirred at 140° C. under microwave irradiation for 1 h. The reaction mixture was concentrated in vacuo, dissolved in acetic acid and stirred at 140° C. under microwave irradiation for 1 h. It was concentrated in vacuo and purified by preparative HPLC (Method 7) to give the title compound (21 mg, 34%) as an off-white solid. δH (CDCl3) 8.05 (1H, d, J 2.1 Hz), 7.11-6.91 (2H, m), 5.45 (1H, s), 4.41-4.32 (2H, m), 4.19-4.10 (2H, m), 2.92 (4H, s), 2.88 (2H, s), 1.39 (6H, s). LCMS (ES+) 413.0 (M+H)+, RT 2.58 minutes (Method 2).
Reaction SMILES: [N+:1]1([O-:8])[C:2]([CH3:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.C([O-])(C)(C)C.[K+].[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O>>[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=[CH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N+:1]=1[O-:8]
Reactant: O=Cc1ccccc1F
Reactant: Cc1cccc[n+]1[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: [O-][n+]1ccccc1C=Cc1ccccc1F

Procedure:
Following the general method described in example 2a, 2-picoline-1-oxide was reacted with potassium tert.-butanolate and 2-fluoro-benzaldehyde. After extraction and chromatography the title compound was obtained as a yellow solid material. MS: m/e=215 (M+).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:5]=[N:4][C:3]=1[O:14][CH3:15].[C:16]([O:20][C:21]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]1B(O)O)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>COCCOC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[C:16]([O:20][C:21]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]1[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:5]=[N:4][C:3]=1[O:14][CH3:15])=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: COc1nnc(-c2ccncc2)cc1I
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1nnc(-c2ccncc2)cc1-c1cc2ccccc2n1C(=O)OC(C)(C)C

Procedure:
Argon is passed for 30 min through a suspension of 55 mg 4-Iodo-3-methoxy-6-pyridin-4-yl-pyridazine, 55 mg 1-(tert-butoxycarbonyl)indole-2-boronic acid, 53.5 mg potassium carbonate, and 18.5 mg triphenylphosphine in 0.8 ml DME and 0.7 ml water. 4 mg palladium (II) acetate is added, and the mixture is stirred under reflux for 3 h. The product is isolated by extraction with ethyl acetate and purified by chromatography on silica gel yielding 27.5 mg 2-(3-Methoxy-6-pyridin-4-yl-pyridazin-4-yl)-indole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[CH2:14][C:13]([C:23](O)=[O:24])=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].S(Cl)(Cl)=O.[OH-].[NH4+:31].O>O1CCCC1.CO>[NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)[CH2:14][C:13]([C:23]([NH2:31])=[O:24])=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: [NH4+]
Reactant: Cc1ccc(C2CC(C(=O)O)=NN2c2ccc(S(N)(=O)=O)cc2)cc1
Agent: [OH-]
Solvent: CO
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1ccc(C2CC(C(N)=O)=NN2c2ccc(S(N)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
1-(4-aminosulphonylphenyl)-4,5-dihydro-5-(4-methylphenyl)-1H-pyrazole-3-carboxylic acid (3.7 g, 10.3 mmoles) and thionyl chloride (3 g, 25.8 mmoles) are dissolved in 70 ml of tetrahydrofuran and shaken at room temperature for 16 hours. The mixture is evaporated to dryness with a rotavapour and the crude acid chloride so obtained dissolved in 30 ml of methanol in a globe of inert atmosphere and cooled to 0° C. 9 ml of concentrated ammonium hydroxide solution dissolved in 20 ml of THF is added. The mixture is shaken at room temperature for 16 hours and the solvent eliminated with the rotavapor. Water is added to the residue and the mixture extracted with ethyl acetate, which is washed with water, dried over anhydrous sodium sulphate and evaporated to dryness. The crude residue so obtained is crystallised from ethyl acetate-petrol ether to give 2.6 g (yield: 72%) of the desired compound with a m.p.=210-5° C.
Reaction SMILES: Br[C:2]1[CH:20]=[C:19]([Cl:21])[C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH:9]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[C:8]2=[O:18])=[C:4]([Cl:22])[CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.N#N>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.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>[Cl:22][C:4]1[CH:3]=[C:2]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)[CH:20]=[C:19]([Cl:21])[C:5]=1[CH2:6][N:7]1[CH2:11][CH2:10][CH:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:8]1=[O:18]
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C1C(N2CCCCC2)CCN1Cc1c(Cl)cc(Br)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1C(N2CCCCC2)CCN1Cc1c(Cl)cc(-c2ccc(F)cc2)cc1Cl
Temperature: 90 °C
Yield: 32.1 %

Procedure:
Purge a mixture of 1-(4-bromo-2,6-dichloro-benzyl)-3-piperidin-1-yl-pyrrolidin-2-one (0.150 g, 0.37 mmol) and 4-fluorophenylboronic acid (0.150 g, 1.07 mmol) in toluene (7 mL) and 2M sodium carbonate (1.3 mL) with N2. Treat the reaction with Pd(PPh3)4 (0.043 g, 0.037 mmol) and heat to 90° C. for 4 hours under N2. Cool the reaction, dilute with ethyl acetate, and wash with and water. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify with a 0 to 10% methanol in CH2Cl2 gradient to afford 0.050 g (32%) of the titled product. Rf=0.46 (9/1 CH2Cl2/methanol). ES MS (m/z): 421 (M+).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([CH3:13])[CH:4]=1.[I:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[I:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:2][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]=[C:5]([CH3:13])[CH:4]=2)=[CH:17][CH:16]=1
Reactant: Cc1cc(CCl)c2ccccc2n1
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(COc2ccc(I)cc2)c2ccccc2n1
Yield: 100 %

Procedure:
To a CH3CN (200 mL) solution of 4-chloromethyl-2-methylquinoline (10.22 g, 53.3 mmol) and 4-iodophenol (11.98 g, 1.02 eq) was added K2CO3. The suspension was heated to reflux for 6 h. The mixture was then filtered through Celite® while the solution was still hot. The 4-(4-iodo-phenoxymethyl)-2-methylquinoline (20 g, 100%) was obtained as fine crystals after recrystalization in CH3CN.