Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C(N(CC)CC)C.[C:30]([Si:36]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])Cl)([CH:33]([CH3:35])[CH3:34])([CH3:32])[CH3:31]>C1(C)C=CC=CC=1>[C:1]([O:6][Si:36]([C:30]([CH:33]([CH3:35])[CH3:34])([CH3:32])[CH3:31])([CH:41]([CH3:42])[CH3:43])[CH:38]([CH3:39])[CH3:40])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: CC(C)C(C)(C)[Si](Cl)(C(C)C)C(C)C
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)O[Si](C(C)C)(C(C)C)C(C)(C)C(C)C
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 17.2 g (0.2 mol) of methacrylic acid, 120 ml of toluene, and 0.06 g of 2,6-di-tert-butyl-4-methylphenol. At room temperature, 22.3 g (0.22 mol) of triethylamine was added dropwise over one hour. At the end of dropwise addition, the flask was heated at 80° C. After the internal temperature became constant, 47.0 g (0.20 mol) of thexyldiisopropylchlorosilane was added dropwise over two hours. After the completion of dropwise addition, the reaction solution was stirred for 5 hours at 80° C. The reaction solution was then cooled to room temperature, and the resulting hydrochloric acid salt removed by filtration. The filtrate was distilled, collecting 43.2 g of a fraction having a boiling point of 92-97° C./0.13 kPa.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6]O.[NH:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)(C)C)=O)=N\C(OC(C)(C)C)=O>C1COCC1.O>[O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[NH:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11]
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Reactant: OC[C@H]1CCCO1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NN(C[C@H]1CCCO1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 205.7 %

Procedure:
To (R)-(tetrahydrofuran-2-yl)methanol (4.0 g, 39.2 mmol), di-tert-butyl hydrazine-1,2-dicarboxylate (3.64 g, 15.67 mmol) and triphenylphosphine (15.41 g, 58.7 mmol) in THF (100 mL) was added (E)-di-tert-butyl diazene-1,2-dicarboxylate (13.5 g, 5.87 mmol). The mixture was stirred at ambient temperature for 3 h then diluted with water and extracted with EtOAc (100 mL×2). The organic extract was washed with brine and concentrated. Purification by flash chromatography (silica gel, 5-30% EtOAc/hexane) afforded 10.2 g (82%) of (R)-di-tert-butyl 1-((tetrahydrofuran-2-yl)-methyl)-hydrazine-1,2-dicarboxylate, which was dissolved in a solution of 4M HCl in dioxane (40 mL) and stirred at ambient temperature overnight. The solvent was removed under reduced pressure and ethyl acetate (20 mL) was added with stirring. The solid precipitate was filtered, washed with ether (10 mL) and dried under vacuum to yield 7.8 g (97%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.48-1.63 (m, 1H), 1.73-1.88 (m, 2H), 1.90-2.02 (m, 1H), 2.84-3.01 (m, 2H), 3.61-3.71 (m, 1H), 3.72-3.83 (m, 1H), 3.97-4.08 (m, 1H), 5.76 (br, 5H); MS (ESI) m/z 117 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[CH:5]([OH:9])[C:6]([OH:8])=O.[NH2:14][C@H:15]([C:17]([O:19][CH3:20])=[O:18])[CH3:16]>>[F:13][C:11]1[CH:10]=[C:4]([CH:5]([OH:9])[C:6]([NH:14][C@H:15]([C:17]([O:19][CH3:20])=[O:18])[CH3:16])=[O:8])[CH:3]=[C:2]([F:1])[CH:12]=1
Reactant: O=C(O)C(O)c1cc(F)cc(F)c1
Reactant: COC(=O)[C@H](C)N
Product: COC(=O)[C@H](C)NC(=O)C(O)c1cc(F)cc(F)c1

Procedure:
Following General Procedure E and using (R/S)-3,5-difluoromandelic acid (as set forth in General Procedure H, step A) and L-alanine, methyl ester (Bachem) the title compound was synthesized.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]=[O:13])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].C(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.C1(C)C=CC=CC=1>[CH2:31]([O:30][CH2:29][CH2:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH:12]=[O:13])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:26][CH:25]=1)[CH2:32][CH2:33][CH3:34]
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(C=O)CC1
Reactant: CCCCOCCOc1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
A mixture of methyl 7-bromo-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.25 g), 4-(2-butoxyethoxy)phenyl borate (0.23 g), 1M potassium carbonate solution (2.5 ml), ethanol (2.5 ml) and toluene (25 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.04 g), and the mixture was refluxed overnight under argon atmosphere and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-formyl-2.3-dihydro-1H-1-benzazepine-4-carboxylate (0.23 g) as colorless oil.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[NH:15][C:16](=[O:27])[C:17]2[N:22]([CH3:23])[N:21]=[C:20]([CH2:24][CH2:25][CH3:26])[C:18]=2[N:19]=1)[CH3:6].O>S(=O)(=O)(O)O>[CH2:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:1]([O-:4])=[O:2])=[CH:10][C:9]=1[C:14]1[NH:15][C:16](=[O:27])[C:17]2[N:22]([CH3:23])[N:21]=[C:20]([CH2:24][CH2:25][CH3:26])[C:18]=2[N:19]=1)[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3ccccc3OCC)nc12
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc([N+](=O)[O-])ccc3OCC)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
Concentrated nitric acid (0.5 ml) was added dropwise to a stirred solution of 5-(2-ethoxyphenyl)-1-methyl-3-n-propyl-1.6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (2.0 g, 0.0064 mol) in concentrated sulphuric acid (10 ml) at 0° C., and the resulting orange solution was stirred at room temperature for 18 hours. The reaction solution was then added dropwise to stirred ice and water (200 g) and the solid precipitate collected by filtration. This solid was then dissolved in dichloromethane (50 ml) and the solution washed successively with brine (2×30 ml) and water (30 ml), dried (Na2SO4) and evaporated under vacuum to give a yellow solid. Crystallisation from acetonitrile gave the title compound as yellow needles (1.40 g, 61%), m.p. 214-216° C. Found: C,57.35; H,5.21; N,19.49. C17H19N5O4 requires C,57.13; H,5.36; N,19.60%.
Reaction SMILES: [O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH:17][C:18](=[O:26])[C:19]4[CH:24]=[CH:23][N:22]=[CH:21][C:20]=4Br)=[N:13][C:12]=3[C:11]([O:27][CH3:28])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1.[CH3:29][O:30][CH2:31][CH2:32][NH:33][CH3:34].COCCNC1C=C(C=CN=1)C(NC1SC2C(N3CCOCC3)=CC=C(OC)C=2N=1)=O>>[O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH:17][C:18](=[O:26])[C:19]4[CH:24]=[CH:23][N:22]=[C:21]([N:33]([CH2:32][CH2:31][O:30][CH3:29])[CH3:34])[CH:20]=4)=[N:13][C:12]=3[C:11]([O:27][CH3:28])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccncc3Br)nc12
Reactant: CNCCOC
Agent: COCCNc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1
Product: COCCN(C)c1cc(C(=O)Nc2nc3c(OC)ccc(C4COCCOC4)c3s2)ccn1

Procedure:
N-(7-[1,4]Dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-bromo-isonicotinamide and N-(2-methoxyethyl)-methylamine were reacted as described for 2-(2-methoxy-ethylamino)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide in WO03/043636. Usual workup, preparative reversed-phase HPLC and final dry-freezing afforded the title compound as light brown solid. MS: m/e=473(M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:23]2[CH2:27][CH2:26][CH2:25][CH:24]2[CH2:28][S:29][C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=2)=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].C1C=C(Cl)C=C(C(OO)=[O:48])C=1>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:23]2[CH2:27][CH2:26][CH2:25][CH:24]2[CH2:28][S:29]([C:30]2[CH:31]=[CH:32][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][CH:39]=2)=[O:48])=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(SCC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(S(=O)CC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl 4-[[1-[3-methoxy4-[N′-(2-methyl phenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methylthio]benzoate (264 mg, 0.482 mmol) in CH2Cl2 (5.2 mL) was added m-CPBA (118.8 mg, 0.482 mmol) at 0° C., and the mixture was stirred at room temp for 1 hr. The mixture was diluted with CHCl3, and quenched with sat. Na2S2O3. The separated organic layer was washed with sat. NaHCO3, brine, and dried over Na2SO4. The solvent was removed under a reduced pressure to afford methyl 4-[[1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2 pyrrolidinyl]methylsulfinyl]benzoate as a crude amorphous solid. To a stirred solution of this crude compound in THF (4 mL) and H2O (1mL) was added LiOH (34.6 mg, 1.45 mmol), and the stirring was continued overnight at room temp. The mixture was diluted with CHCl3, washed with 1 N HCl, brine, and dried over Na2SO4. The solvent was removed under a reduced pressure, and the obtained crude solid was recrystallized from n-hexane-CHCl3-MeOH to afford 193.2 mg (73%) 24 as a white crystalline powder. IR (KBr) 3338, 2956, 1708, 1529, 1299, 1207, 1155 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ 1.70–2.06 (m, 4H), 2.24 (s, 3H), 2.90 (dd, J=8.3, 13.2 Hz, 1H), 3.02–3.08 (m, 1H), 3.16–3.25 (m, 1H), 3.41–3.60 (m, 3H), 3.84 (s, 3H), 4.40 (br s, 1H), 6.74 (d, J=7.8 Hz, 1H), 6.87 (s, 1H), 6.94 (d, J=7.3 Hz, 1H), 7.11–7.17 (m, 2H), 7.75–7.81 (m, 3H), 7.98–8.05 (m, 1H), 8.10 (d, J=8.3 Hz, 2H), 8.46 (s, 1H), 8.56 (s, 1H); MS (FAB) m/z 550 (M++1), 572 (M++Na); Anal. Calcd for C29H31N3O6S.3/2H2O: C, 60.40; H, 5.94; N. 7.29. Found: C, 60.15; H, 5.82; N, 6.90.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[NH:13][C:14]([S:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38]>C(#N)C>[C:37]([O:39][CH2:40][CH2:41][N:13]1[C:14]([S:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=[C:12]1[CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:38])[CH3:36]
Reactant: CCOC(=O)CBr
Reactant: CC(C)c1nc(CCCOCc2ccccc2)[nH]c1Sc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OCCn1c(CCCOCc2ccccc2)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 60 °C
Yield: 95.9 %

Procedure:
In 50 ml of dry acetonitrile was dissolved 5.0 g (11.5 mmol) of the imidazole (101e), followed by addition of 3.2 g (23.2 mmol) of potassium carbonate and 2.9 g (17.4 mmol) of ethyl bromoacetate, and the mixture was heated at 60° C. for 11 hours. The reaction mixture was diluted with ice-water and extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2) to provide 5.75 g (yield 96%) of (2-(3-benzyloxypropyl)-5-(3,5-dichlorophenylthio)-4-isopropyl-1H-imidazol-1-yl)-ethyl acetate (136d) as oil.
Reaction SMILES: [C:1](O)(=[O:3])C.C(O)=O.[CH2:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24]3[NH:30][CH2:29][CH2:28][C:27]([C:31]([O:33][CH3:34])=[O:32])=[CH:26][C:25]=3[CH:35]=2)=[CH:17][CH:16]=1)[CH3:9]>C1COCC1>[CH2:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24]3[N:30]([CH:1]=[O:3])[CH2:29][CH2:28][C:27]([C:31]([O:33][CH3:34])=[O:32])=[CH:26][C:25]=3[CH:35]=2)=[CH:17][CH:16]=1)[CH3:9]
Reactant: CCOCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: CC(=O)O
Solvent: O=CO
Solvent: C1CCOC1
Product: CCOCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To anhydrous acetic acid (0.22 ml) was added dropwise formic acid (0.11 ml) under ice-cooling, and the mixture was stirred under nitrogen atmosphere at 50° C. for 2 hours. To the mixture was added THF (2 ml) and then was added dropwise, under ice-cooling, a solution of methyl 7-[4-(3-ethoxypropoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.35 g) in THF (15 ml), and the mixture was stirred at room temperature overnight. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with sodium hydrogen carbonate solution, water and saturated brine, and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give methyl 7-[4-(3-ethoxypropoxy) phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.36 g) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[C:27]1([O:33][CH2:34][C:35](Cl)=[O:36])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([NH:23][C:35](=[O:36])[CH2:34][O:33][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: O=C(Cl)COc1ccccc1
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)COc5ccccc5)c4)CC3)cccc2n1
Yield: 41 %

Procedure:
The title compound was prepared in 41% yield according to the general procedure for the preparation of the amides (Method B) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and (phenyloxy)acetyl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[N:20]=[C:19]3[N:14]([C:15](Cl)=[N:16][C:17]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])=[CH:18]3)[N:13]=2)[CH2:8][CH2:7]1)[CH3:2].Cl.[NH2:32][C:33]1[C:38]([C:39](=[O:44])[C:40]([F:43])([F:42])[F:41])=[CH:37][CH:36]=[C:35]([NH:45][CH2:46][CH2:47][NH2:48])[N:34]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[N:20]=[C:19]3[N:14]([C:15]([NH:48][CH2:47][CH2:46][NH:45][C:35]4[CH:36]=[CH:37][C:38]([C:39](=[O:44])[C:40]([F:42])([F:43])[F:41])=[C:33]([NH2:32])[N:34]=4)=[N:16][C:17]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])=[CH:18]3)[N:13]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: NCCNc1ccc(C(=O)C(F)(F)F)c(N)n1
Reactant: CCOC(=O)CN1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(Cl)n3n2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCOC(=O)CN1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(NCCNc4ccc(C(=O)C(F)(F)F)c(N)n4)n3n2)CC1
Temperature: 130 °C

Procedure:
120 mg (0.23 mmol) of ethyl{4-[5-chlor-7-(2,4-dichlorophenyl)[1,2,4]triazolo[1,5-c]pyrimidin-2-yl]piperidin-1-yl}acetate (Example 55A), 78.7 mg (0.28 mmol) of 1-{2-amino-6-[(2-aminoethyl)-amino]pyridin-3-yl}-2,2,2-trifluoroethanone hydrochloride (Example 13A) and 0.24 ml (1.38 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 141 mg (90% of theory) of the product as a solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4](Cl)[CH:3]=1.S([O:16][CH3:17])(OC)(=O)=O.CC#N.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]([CH3:4])[C:17](=[O:16])[CH:3]=1
Reactant: COc1cnc(Cl)cc1Br
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: COc1cn(C)c(=O)cc1Br
Temperature: 25 °C

Procedure:
A solution of 4-bromo-2-chloro-5-methoxypyridine [1020253-15-9] (1 g, 4.5 mmol) in dimethyl sulfate (1.9 mL, 19.5 mmol) was stirred at 120° C. for 16 h in a sealed tube. After cooling to rt, CH3CN and a saturated aqueous NaHCO3 solution were added and the mixture was stirred at rt over the weekend. CH2Cl2 was added and the phases were separated. The organic layer was dried (Na2SO4), filtered and concentrated to give the title compound as a white powder. ESI-MS: tR=0.57 min; [M+H]+ 218/220 (LC-MS 1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:23])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[O:15])=[C:10]([F:22])[CH:9]=2)[CH:7]=1.CC1C=CC(O[C@H:30]([CH3:35])[C:31]([O:33]C)=[O:32])=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][C@@H:30]([CH3:35])[C:31]([OH:33])=[O:32])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH:17]([CH2:18][CH3:19])[CH2:20][CH3:21])=[O:15])=[C:10]([F:22])[CH:9]=2)[CH:7]=1
Reactant: COC(=O)[C@@H](C)Oc1ccc(C)cc1
Reactant: CCC(CC)NC(=O)c1ccc(-c2cc(Cl)ccc2O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCC(CC)NC(=O)c1ccc(-c2cc(Cl)ccc2O[C@@H](C)C(=O)O)cc1F
Temperature: 50 °C
Reaction time: 16 h

Procedure:
The product of step c) (300 mg), the product of step d) (219 mg) and potassium carbonate (135 mg) in acetonitrile (10 ml) were charged to a flask and stirred at 50° C. for 16 h. The reaction mixture was cooled, diluted with water (20 ml) and extracted with diethyl ether (3×10 ml). The organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting yellow oil was dissolved in a 1:1 mixture of THF/methanol (10 ml) and 1M NaOH added (1.1 ml). The mixture was stirred at room temperature for 4 h and then concentrated in vacuo. The residue was purified by RPHPLC to give the title compound as a white solid (175 mg).
Reaction SMILES: ClC(OC(Cl)=O)C.C[N:9]1[C@@H:18]2[C@H:13]([C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[CH2:16][CH2:17]2)[CH2:12][CH2:11][CH2:10]1.C(N(C(C)C)CC)(C)C>ClCCl.N>[CH2:12]1[C@H:13]2[C@H:18]([CH2:17][CH2:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=32)[NH:9][CH2:10][CH2:11]1
Reactant: CN1CCC[C@H]2c3ccccc3CC[C@@H]21
Agent: CC(Cl)OC(=O)Cl
Agent: N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.6 %

Procedure:
1-Chloroethylchloroformate (2.01 ml, 18.61 mmol) was added with stirring to an ice-cooled solution of cis-and trans-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline (1.66 g, 8.34 mmol) in dichloromethane (60 ml). The mixture was allowed to warm to room temperature and stirred for a further 2 h. Diisopropylethylamine (2.2 ml, 12.6 mmol) was added and the mixture heated at reflux for 1 h. The mixture was cooled and concentrated in vacuo, dissolved in methanol and refluxed for 1 h. After cooling, the solvent was removed and the residue partitioned between saturated aqueous K2CO2 and dichloromethane (4×50 ml). The combined organic extracts were washed with water, dried (Na2SO4) and the solvent evaporated to afford an oil. Chromatography on silica using 10% methanol-ethyl acetate with 6.6 ml/L 0.880 ammonia as eluent gave the trans-isomer of the title compound (260 mg, 33%) as the first eluting product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[Br:12]Br>[Fe]>[Br:12][C:7]1[CH:6]=[C:5]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:4]=[CH:3][C:2]=1[CH3:1]
Reactant: BrBr
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: [Fe]
Product: Cc1ccc(S(N)(=O)=O)cc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of p-toluenesulfonamide (2 g, 1.16 mmol) and iron (0.41 g, 7.36 mmol) was slowly added bromine (6 mL, 116 mmol). The resulting reddish brown solution was stirred at RT for 1 h. The reaction was carefully poured into ice-cold 1 M Na2S2O3 aqueous solution and extracted with CH2Cl2 (2×). The organic extracts were combined and washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. CombiFlash purification (1% to 10% MeOH/CH2Cl2) afforded the title compound as a white solid. 1H NMR (DMSO-d6, 400 MHz): □ 7.98 (s, 1H), 7.71 (d, J=8 Hz, 1H), 7.55 (d, J=8 Hz, 1H), 7.54 (br s, 2H), 2.41 (s, 3H).
Reaction SMILES: I[C:2]1[NH:6][C:5]([CH3:7])=[N:4][C:3]=1[C:8]([F:11])([F:10])[F:9].C([O-])([O-])=O.[K+].[K+].CO.CO[CH2:22][CH2:23]OC>O.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>[CH3:7][C:5]1[NH:6][C:2]([CH:22]=[CH2:23])=[C:3]([C:8]([F:11])([F:10])[F:9])[N:4]=1
Reactant: COCCOC
Reactant: Cc1nc(C(F)(F)F)c(I)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C=Cc1[nH]c(C)nc1C(F)(F)F
Temperature: 80 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
To a solution of 5-iodo-2-methyl-4-(trifluoromethyl)-1H-imidazole (1.98 g, 7.2 mmol) in DME (20 mL) and H2O (4 mL) was added K2CO3 (10 g, 71.9 mmol), trivinylboronic anhydride pyridine complex (1.73 g, 7.19 mmol) and Pd(PPh3)4 (830 mg, 0.719 mmol). The resulting reaction mixture was stirred at 80° C. for 3 h. MeOH (100 mL) was then added to the reaction mixture and the mixture was filtered, concentrated in vacuo, and purified by flash chromatography (SiO2, 10% MeOH/CH2Cl2) to obtain 2-methyl-4-(trifluoromethyl)-5-vinyl-1H-imidazole (911 mg, 5.17 mmol, 72% yield) as a brown syrup.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[Cl:13][C:14]([Cl:19])(Cl)[C:15](Cl)=[O:16].COCCOC>C(OCC)C.[Zn]>[Cl:13][C:14]1([Cl:19])[C:15](=[O:16])[CH2:1][C:2]21[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]2
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C=C1CN(C(=O)OC(C)(C)C)C1
Agent: [Zn]
Solvent: COCCOC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC2(CC(=O)C2(Cl)Cl)C1
Temperature: 10 °C
Reaction time: 14 h

Procedure:
Under an inert atmosphere, 7.728 g (118.19 mmoles) of zinc in nanopowder form are suspended in 100 ml of diethyl ether. 5.00 g (29.55 mmoles) of tert-butyl 3-methylene-azetidine-1-carboxylate (WO 2008124085) are added, then the medium is cooled to 10° C. A solution of 6.60 ml (59.09 mmoles) of trichloroacetyl chloride in ml of 1,2-dimethoxyethane is added drop by drop while maintaining the temperature of the reaction medium between 26 and 30° C. After stirring for 14 hrs at ambient temperature, the medium is filtered over celite, the celite is copiously rinsed with diethyl ether and the filtrate is partially concentrated under reduced pressure. The crude reaction product thus obtained is used as such in the following stage.