Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][C:22]3[NH:26][N:25]=[N:24][N:23]=3)[C@@H:16]2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[Na+].S(OC)(O[CH3:41])(=O)=O>O>[F:12][C:9]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][C:22]3[N:23]=[N:24][N:25]([CH3:41])[N:26]=3)[C@@H:16]2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:8]=1
Reactant: COS(=O)(=O)OC
Reactant: FC(F)(F)c1cc(CO[C@@H]2CCCN(Cc3nnn[nH]3)[C@@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1nnc(CN2CCC[C@@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H]2c2ccccc2)n1
Temperature: 96 °C
Reaction time: 1 h
Yield: 19.4 %

Procedure:
The compound of Example 7 (500 mg) was suspended in water (4 ml) and sodium hydroxide (44 mg) added. This was heated to an external temperature of 96° C. and dimethyl sulphate (65 mg) added. The reaction mixture was allowed to stir under nitrogen at 96° C. for 1 h after which time stirring was continued for 24 h at 5° C. After this time, the product was extracted into dichloromethane and washed with water and brine. The organic layer was dried (MgSO4) and evaporated. The residue was purified on silica using medium pressure chromatography (Lobar), and eluted with 25% ethyl acetate in petrol. The first compound to be eluted was isolated, and this afforded the product (50 mg) as a crystalline solid, which was recrystallised from ether/hexane to afford white crystals: mp 139°-141° C. 1H NMR (360 MHz, DMSO) d 1.44-1.51 (2H, m, CH2), 1.79-1.82 (1H, m, CHH), 2.12-2.15 (1H, m, CHH), 2.19-2.25 (1H, m, CHHN), 2.97-3.00 (1H, m, CHHN), 3.37 (1H, d, J=14 Hz, N--CHH-tetrazole), 3.52 (1H, s, NCHCHO), 3.58 (1H, s, NCHCHO), 3.81 (1H, d, J=14 Hz, N--CHH-tetrazole), 4.03 (1H, d, J=13 Hz, OCHH), 4.31 (3H, s, CH3), 4.60 (1H, d, J=13 Hz, OCHH), 7.23-7.33 (3H, m, ArH), 7.49-7.51 (2H, m, ArH), 7.68 (2H, s, ArH), 7.93 (1H, s, ArH); MS (CI+) m/z 500 ((M+1)+, 100%). Found: C, 55.56; H, 4.76; N, 14.20. Calculated for C23H23N5OF6 : C, 55.31; H, 4.64; N, 14.02%.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[NH2:11][C:12]1[C:13]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:23][CH:22]=3)=[CH:19][N:18]([CH:34]3[CH2:39][CH2:38][CH:37]([CH2:40][CH2:41][OH:42])[CH2:36][CH2:35]3)[C:14]=2[N:15]=[CH:16][N:17]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[NH2:11][C:12]1[C:13]2[C:20]([C:21]3[CH:22]=[CH:23][C:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:25][CH:26]=3)=[CH:19][N:18]([CH:34]3[CH2:35][CH2:36][CH:37]([CH2:40][CH:41]=[O:42])[CH2:38][CH2:39]3)[C:14]=2[N:15]=[CH:16][N:17]=1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(CCO)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(CC=O)CC1
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 52.2 %

Procedure:
Dimethylsulfoxide (0.040 g, 0.51 mmol) was added into a solution of oxalyl chloride (0.033 g, 0.26 mmol) in dichloromethane (3 mL) at −78° C. The mixture was allowed to warm up to −40° C. and stirred for 15 minutes followed by cooling down to −78° C. again. 2-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl}-1-ethanol (0.10 g, 0.23 mmol) was added followed by triethylamine (0.12 mg, 1.165 mmol). The mixture was allowed to warm up to 0° C. and saturated aqueous sodium bicarbonate solution (10 mL) was added to quench the reaction. The organic layer was separated from the aqueous layer and washed with 10% aqueous sodium hydorgensulfate solution (4 mL), saturated aqueous sodium bicarbonate solution (4 mL) and saturated aqueous sodium chloride (4 mL). The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel using methanol/dichloromethane(5:95) as a mobile phase to yield 2-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl}acetaldehyde (0.053 g, 0.12 mmol) as a white solid: 1H NMR (CDCl3, 400 MHz) δ 9.81(s, 1H), 8.33(s, 1H), 7.68(m, 1H), 7.43(d, 2H), 7.38(t, 2H), 7.15(t, 1H), 7.07(m, 4H), 5.14 (br, 2H), 4.72(m, 1H), 2.63-1.72(m, 11H); TLC (methanol/dichloromethane=5:95) Rf 0.41. MS: MH+ 427.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[C:39]1(B2OC(C)(C)C(C)(C)O2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH:40]=1>>[NH2:30][C:29]1[S:28][C:27]([C:39]2=[CH:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]2)=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][NH2:8])[CH2:11][CH2:12]1)=[O:24]
Reactant: CC1(C)OB(C2=CCCCCC2)OC1(C)C
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Product: Cn1ncc(NC(=O)c2nc(C3=CCCCCC3)sc2N)c1N1CCC(CN)CC1
Yield: 28 %

Procedure:
Following the procedure for Example 337 starting with tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and 1-cycloheptenylboronic acid pinacol ester gave 266 as a pale brown solid (25 mg, 28%). 1H NMR (400 MHz, d6-DMSO) δ 8.64 (s, 1H), 7.43 (s, 1H), 7.29 (s, 2H), 6.38 (t, J=6.7 Hz, 1H), 3.64 (s, 3H), 3.08-2.94 (m, 4H), 2.78 (d, J=8.2 Hz, 2H), 2.47 (d, J=6.2 Hz, 2H), 2.35-2.20 (m, 2H), 1.82-1.72 (m, 4H), 1.56-1.49 (m, 4H), 1.33-1.11 (m, 3H). LCMS (ES+) m/z 430 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([OH:12])=[CH:4][CH:3]=1.[H-].[Na+].Br[C:16]1[CH:17]=[N+:18]([O-:25])[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23].O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C:16]2[CH:17]=[N+:18]([O-:25])[CH:19]=[CH:20][C:21]=2[N+:22]([O-:24])=[O:23])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=1
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1Br
Reactant: COC(=O)c1cc(Br)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(Br)ccc1Oc1c[n+]([O-])ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl 5-bromosalicylate (5.78 g, 25.00 mmol) in 30 mL of dry THF was added slowly sodium hydride (0.600 g, 25.00 mmol, 60 wt %) and the solution was stirred at rt for 15 minutes. The solvent was evaporated and the residue was dissolved in 10 mL of dry DMF. To this was added 3-bromo-4-nitropyridine 1-oxide (4.38 g, 20.00 mmol) and the reaction mixture was stirred at 50° C. for 4 h and 40° C. overnight. Water was added and the resulting solid was washed with water, filtered and dried under vacuum. Purification of the crude residue by column chromatography (CH2Cl2 to CH2Cl2/EA=10:1 to 5:1 to 3:1 to 1:1 to pure EA) gave 3-(4-bromo-2-(methoxycarbonyl)phenoxy)-4-nitropyridine 1-oxide as a yellow solid.
Reaction SMILES: O.[OH-].[Li+].[C:4]1(/[C:10](=[N:17]/[O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:32]=[C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:30][N:29]=3)=[CH:22][CH:21]=2)/[CH2:11][CH2:12][C:13]([O:15]C)=[O:14])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.Cl>O1CCCC1.CO>[C:4]1(/[C:10](=[N:17]/[O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:32]=[C:31]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[O:30][N:29]=3)=[CH:22][CH:21]=2)/[CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)CC/C(=N\OCc1ccc(OCc2cc(-c3ccccc3)on2)cc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)CC/C(=N\OCc1ccc(OCc2cc(-c3ccccc3)on2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
Lithium hydroxide monohydrate (73.5 mg) was added to a solution of methyl E-4-phenyl-4-[4-(5-phenyl-3-isoxazolylmethoxy)benzyloxyimino]butyrate (412 mg) in tetrahydrofuran (6 ml)-water (4 ml)-methanol (4 ml) and stirred at room temperature for 2 hours. 1N hydrochloric acid (1.8 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4-phenyl-4-[4-(5-phenyl-3-isoxazolylmethoxy)benzyloxyimino]butyric acid (320 mg, yield 80%) as colorless crystals. m.p. 100-101° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH2:15][C:16]#[N:17])=[C:4]([O:18][CH3:19])[CH:3]=1.[CH3:20][S:21]([C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[C:27](O)=[O:28])(=[O:23])=[O:22]>>[C:16]([CH2:15][N:14]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[O:18][CH3:19])[C:27](=[O:28])[C:26]1[CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=[C:24]([S:21]([CH3:20])(=[O:23])=[O:22])[CH:25]=1)#[N:17]
Reactant: COc1cc(F)ccc1-c1ccncc1NCC#N
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Product: COc1cc(F)ccc1-c1ccncc1N(CC#N)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 90, from 2-(4-(4-fluoro-2-methoxyphenyl)pyridin-3-ylamino)acetonitrile and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (example 114, intermediate a) after a reaction time of 18 hours. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (Flashmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light brown solid (51%). MS (ESI): m/z=508.096 [M+H]+.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[C:7](O)(=[O:10])[CH:8]=[CH2:9].S(=O)(=O)(O)O.C1(C=CC(O)=CC=1)O.C1(C)C=CC=CC=1>>[C:7]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])(=[O:10])[CH:8]=[CH2:9]
Reactant: C=CC(=O)O
Reactant: OCCCCO
Agent: O=S(=O)(O)O
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: C=CC(=O)OCCCCO

Procedure:
Two mols of 1,4-butanediol, 2 mols of acrylic acid, 0.1 ml of sulfuric acid and 0.001 mol of hydroquinone were dissolved in 100 mol of toluene, and the solution was refluxed for 4 hours while removing water generated. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified through silica gel column chromatography using acetone as an eluent to obtain 4-hydroxybutyl acrylate. One mol of 4-hydroxybutyl acrylate obtained, 1 mol of catechol and 1 mol of borane were reacted in dichloromethane at room temperature, and 1 mol of LiBr was further added and dissolved to obtain a desired compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][CH2:12][CH2:13][O:14][CH3:15]>C(O)C.[H][H].[Pd]>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:11][CH2:12][CH2:13][O:14][CH3:15])[NH2:8]
Reactant: [H][H]
Reactant: COCCOc1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CCO
Product: COCCOc1ccc(N)cc1F
Yield: 92.9 %

Procedure:
To a stirred solution of 2-fluoro-1-(2-methoxyethoxy)-4-nitrobenzene (2.5 g, 11.62 mmol, 1.0 eq.) in ethanol (20 mL) was added 10% Pd/C (500 mg) and stirred in hydrogen gas atmosphere for 16 h at RT. The catalyst was filtered over a celite pad and the filtrate was concentrated to get 3-fluoro-4-(2-methoxyethoxy)aniline (2.0 g, 93.9%; TLC system: EtOAc/PE (3:7), Rf: 0.3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[C:13]3[N:22]=[C:21]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[S:20][C:14]=3[C:15](=[O:19])[NH:16][CH2:17][CH:18]=2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+].O>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[C:13]3[N:22]=[C:21]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[S:20][C:14]=3[C:15](=[O:19])[NH:16][CH2:17][CH:18]=2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)ccc1C1=CCNC(=O)c2sc(N3CCOCC3)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(Cl)ccc1C1=CCNC(=O)c2sc(N3CCOCC3)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.7 %

Procedure:
To a solution of methyl 5-chloro-2-[2-(morpholin-4-yl)-4-oxo-5,6-dihydro-4H-[1,3]thiazolo[5,4-c]azepin-8-yl]benzoate (0.125 g, 0.298 mmol) in THF (3.7 mL) and MeOH (1.2 mL) was added a solution of 1M sodium hydroxide in water (3.66 mL, 3.66 mmol). The solution was stirred at room temperature for 16 hours. The solvents were evaporated and the residue was diluted with water and then added 1N hydrogen chloride aqueous solution until pH 7 was reached. Extracted twice with EA and the combined organic layer was then washed with brine then dried over anhydrous sodium sulfate and concentrated to give the product (0.100 g, 83%) which was used directly in the next step. LCMS: (AA) ES+ 406, 408. 1H NMR (400 MHz, d6-DMSO) δ: 12.79 (s, 1H), 7.86 (t, J=4.9 Hz, 1H), 7.68 (d, J=2.4 Hz, 1H), 7.57 (dd, J=8.2, 2.4 Hz, 1H), 7.32 (d, J=8.2 Hz, 1H), 6.21 (t, J=6.9 Hz, 1H), 3.65-3.55 (m, 6H), 3.30-3.26 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([NH2:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C[O:20][C:21](=O)[C:22]1[C:27]([NH:28][C:29]([CH:31]2[CH2:33][CH2:32]2)=[O:30])=[CH:26][CH:25]=[C:24]([Br:34])[C:23]=1[CH2:35]Br.C(N(CC)CC)C>CN(C=O)C>[Br:34][C:24]1[CH:25]=[CH:26][C:27]([NH:28][C:29]([CH:31]2[CH2:32][CH2:33]2)=[O:30])=[C:22]2[C:23]=1[CH2:35][N:18]([C@@H:12]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:21]2=[O:20]
Reactant: CCOc1cc([C@H](N)CS(C)(=O)=O)ccc1OC
Reactant: COC(=O)c1c(NC(=O)C2CC2)ccc(Br)c1CBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3c(Br)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Temperature: 90 °C
Yield: 74.2 %

Procedure:
To a solution of (1S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine (0.35 g, 1.2 mmol) in DMF (10 ml) was added 2-bromomethyl-3-bromo-6-(cyclopropanecarbonyl-amino)-benzoic acid methyl ester (0.45 g, 1.1 mmol) and triethyl amine (0.5 ml, 3.3 mmol). The mixture was heated at 90° C. overnight. The solvent was removed in vacuo. The resulted oil was extracted with ethyl acetate (50 ml) and water (30 ml). The organic layer was washed with water (30 ml×2), brine (30 ml) and dried over magnesium sulfate. The solvent was removed in vacuo and the resulted oil was purified by silica gel column to give (1S)-cyclopropanecarboxylic acid {7-bromo-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as a white solid (450 mg, 74%): mp, 219–221° C.; 1H NMR (CDCl3) δ 0.89–0.93 (m, 2H, c-CH2), 1.08–1.14 (m, 2H, c-CH2), 1.47 (t, J=7.0 Hz, 3H, OCH2CH3), 1.65–1.70 (m, 1H, c-CH), 2.98 (s, 3H, CH3SO2), 3.70 (dd, J=5, 15 Hz, 1H, CHH), 3.87(s, 3H, OCH3), 4.06–4.14 (m, 3H, NCHH+OCH2CH3), 4.19 (dd, J=10, 15 Hz, 1H, CHH), 4.55 (d, J=17 Hz, 1H, CH), 5.75–5.81 (m, 1H, CHN), 6.86–6.96 (m, 3H, Ar), 7.53 (d, J=9 Hz, 1H, Ar), 8.40(d, J=9 Hz, 1H, Ar), 10.38 (s, 1H, NHCO). 13CNMR (CDCl3): δ 9.1, 9.2, 15.4, 16.9, 42.2, 49.1, 52.0, 56.1, 56.7, 65.3, 110.1, 112.3, 112.8, 119.5, 119.9, 120.7, 129.7, 136.8, 138.1, 142.0, 149.6, 150.5, 170.0, 173.3; Anal Calcd for C24H27BrN2O6S: C, 52.27; H, 4.94; N, 5.08. Found: C, 52.57; H, 4.68; N, 4.95.
Reaction SMILES: ClC1C=CC(C2N(C[C@H](O)C(F)(F)F)C(=O)N(CC(NC(C3C=CC=C(F)C=3F)CO)=O)N=2)=CC=1.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[N:47]([CH:48]3[CH2:50][CH2:49]3)[C:46](=[O:51])[N:45]([CH2:52][C:53](O)=[O:54])[N:44]=2)=[CH:39][CH:38]=1.FC(F)(F)C(O)=O.[NH2:63][CH:64]([C:67]1[CH:72]=[CH:71][CH:70]=[C:69]([C:73]([F:76])([F:75])[F:74])[CH:68]=1)[CH2:65][OH:66]>>[Cl:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]2[N:47]([CH:48]3[CH2:50][CH2:49]3)[C:46](=[O:51])[N:45]([CH2:52][C:53]([NH:63][CH:64]([C:67]3[CH:72]=[CH:71][CH:70]=[C:69]([C:73]([F:74])([F:75])[F:76])[CH:68]=3)[CH2:65][OH:66])=[O:54])[N:44]=2)=[CH:41][CH:42]=1
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Reactant: NC(CO)c1cccc(C(F)(F)F)c1
Agent: O=C(Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)NC(CO)c1cccc(F)c1F
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O)NC(CO)c1cccc(C(F)(F)F)c1

Procedure:
In the same way as for the compound from Example 95, 48 mg (0.16 mmol) of [3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetic acid (for preparation see WO 2007/134862, Example 88A) and 58 mg (0.18 mmol) of the compound from Example 91A were reacted. This gave 61 mg (77% of theory) of the target compound.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)=[O:3].[CH3:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([CH3:21])[C:19]=1[OH:20])[CH:15]=O>>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH:1]=[CH:15][C:14]2[CH:17]=[C:18]([CH3:21])[C:19]([OH:20])=[C:12]([CH3:11])[CH:13]=2)=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: Cc1cc(C=O)cc(C)c1O
Product: Cc1cc(C=CC(=O)c2ccc(Br)cc2)cc(C)c1O

Procedure:
This compound was synthesized from 4-bromoacetophenone and 3,5-dimethyl-4-hydroxybenzaldehyde according to general method 1 described hereinabove. Purification was by silica gel chromatography (cyclohexane/ethyl acetate 90:10).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.S1C=CC(C(N2CCOCC2)C#N)=C1.[C:22]([O:26]CC)(=[O:25])[CH:23]=[CH2:24].[OH-].[K+]>C(O)C.O1CCCC1>[CH:2]1[S:1][CH:5]=[CH:4][C:3]=1[C:6]([CH2:24][CH2:23][C:22]([OH:26])=[O:25])=[O:7]
Reactant: C=CC(=O)OCC
Reactant: O=Cc1ccsc1
Agent: N#CC(c1ccsc1)N1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)c1ccsc1

Procedure:
As for Example 6, 99 g. of 3-thiophenecarboxaldehyde is converted to α-(3-thienyl)-4-morpholineacetonitrile (137 g.; m.p. 85°-87° C.). The preceding compound 50.5 g. is reacted with 100 ml. of ethyl acrylate in 500 ml. of tetrahydrofuran in the presence of 50 ml. of 30% potassium hydroxide in ethanol. The solvent is removed from the reaction mixture and the residue is heated with 6 N hydrochloric acid to give 3-(3-thenoyl)propionic acid. As for Example 1, the preceding compound is converted to the product of the Example to give a glass.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[N:18]([C:20]([CH3:29])=[C:21]([C:23](N(OC)C)=[O:24])[N:22]=4)[CH:19]=3)[C:10](=[O:30])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:33][Mg]Br>C1COCC1>[C:23]([C:21]1[N:22]=[C:17]2[CH:16]=[CH:15][C:14]([N:11]3[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:32][CH:31]=4)=[CH:9][C:10]3=[O:30])=[CH:19][N:18]2[C:20]=1[CH3:29])(=[O:24])[CH3:33]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cn2c1C
Solvent: C1CCOC1
Product: CC(=O)c1nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cn2c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 6-(4-((4-fluorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-N-methoxy-N,3-dimethylimidazo[1,2-a]pyridine-2-carboxamide (150 mg) in THF (10 ml) was added methylmagnesium bromide (3 M ether solution, 344 μl) at −78° C., and the resulting mixture was stirred at the same temperature for 2 h. The reaction mixture was then quenched with saturated aqueous NH4Cl (40 ml) at −78° C., and slowly warmed to room temperature. The reaction mixture was concentrated in vacuo and diluted with EtOAc (100 ml). The EtOAc layer was washed with brine (40 ml), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (55 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[CH:20]=[N:19][N:18]=[C:17]2[CH2:21][NH:22][C:23](=[O:36])[CH2:24][NH:25]C(OCC2C=CC=CC=2)=O)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].CCOCC>C1(OC)C=CC=CC=1.Br.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[CH:20]=[N:19][N:18]=[C:17]2[CH2:21][NH:22][C:23](=[O:36])[CH2:24][NH2:25])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: O=C(CNC(=O)OCc1ccccc1)NCc1nncn1-c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: Br
Solvent: COc1ccccc1
Solvent: CCOCC
Solvent: CC(=O)O
Product: NCC(=O)NCc1nncn1-c1ccc(Cl)cc1C(=O)c1ccccc1
Yield: 25.3 %

Procedure:
To a solution of 5-chloro-2-[3-(N-carbobenzoxyglycyl)aminomethyl-4H-1,2,4-triazol-4-yl]-benzophenone (2.1 g) in anisole (4 ml), 30% hydrogen bromide-acetic acid is added. The resultant mixture is stirred for 1 hour and mixed with ether. The precipitate is filtered, washed with ether and dissolved in methylene chloride (20 ml). The methylene chloride layer is washed with saturated aqueous sodium bicarbonate, water and saturated aqueous saline solution in order, dried over sodium sulfate and evaporated under reduced pressure to remove the solvent. The residue is chromatographed on a column of silica gel, which is eluted with methanol to give 5-chloro-2-(3-glycylaminomethyl-4H-1,2,4-triazol-4-yl)-benzophenone as a colorless oil (0.39 g).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][CH2:41][S:42][C:43]2[N:51]=[CH:50][CH:49]=[CH:48][C:44]=2[C:45]([OH:47])=O)=[CH:35][CH:34]=1.[CH3:52][C:53]([CH3:58])([CH3:57])[CH2:54][CH2:55][NH2:56]>C1COCC1.CCCCCC.CC(=O)OCC.CC(=O)OCC>[CH3:52][C:53]([CH3:58])([CH3:57])[CH2:54][CH2:55][NH:56][C:45]([C:44]1[C:43]([S:42][CH2:41][CH2:40][CH2:39][C:36]2[CH:35]=[CH:34][C:33]([F:32])=[CH:38][CH:37]=2)=[N:51][CH:50]=[CH:49][CH:48]=1)=[O:47]
Reactant: CC(C)(C)CCN
Reactant: O=C(O)c1cccnc1SCCCc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)CCNC(=O)c1cccnc1SCCCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.7 %

Procedure:
274 mg (0.72 mmol) of HATU and 100 ml (0.72 mmol) of NEt3 were added to a solution of 200 mg (0.69 mmol) of 2-(3-(4-fluorophenyl)propylthio)nicotinic acid and 92 ml (0.69 mmol) of 3,3-dimethyl-butylamine in THF (11 ml), and the mixture was stirred for 16 h at RT. Dilution with EA was then carried out. The organic phase was separated off, washed with a 1M aq. Na2CO3 sol. and a 4M aq. NH4Cl sol., dried over MgSO4, filtered and concentrated in vacuo. CC (hexane/EA 2:1) of the residue yielded 173 mg (0.46 mmol, 67%) of N-(3,3-dimethyl-butyl)-2-[3-(4-fluorophenyl)-propylsulfanyl]-pyridine-3-carboxylic acid amide. MS: m/z 375.2 [M+H]+.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH2:8][CH3:9])[CH:7]=1.N([O-])=O.[Na+].NC(N)=O.[I-:21].[K+]>S(=O)(=O)(O)O.O>[CH2:8]([C:6]1[CH:7]=[C:2]([I:21])[CH:3]=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11])[CH3:9]
Reactant: CCc1cc(N)ccc1[N+](=O)[O-]
Reactant: [I-]
Agent: NC(N)=O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: CCc1cc(I)ccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
1.66 g (10 mmol) of 5-amino-1-ethyl-2-nitrobenzene (2) are dissolved in a mixture of 3 ml of conc. sulfuric acid and 20 ml of H2O heated to 50° C. and cooled rapidly in an ice bath. At a temperature below 5° C., the mixture is subjected to diazotisation with 760 mg (11 mmol) of sodium nitrite. After 10 minutes, a pinch of urea from a spatula is added and the mixture stirred for another 5 minutes in the ice bath. This reaction mixture is added to a solution of 2.5 g of potassium iodide (15 mmol) in 10 ml of H2O and stirred at room temperature for one hour. The reaction mixture is extracted three times with 50 ml of EE each and the combined organic phases washed once with 50 ml each of In NaOH arid H2O. After drying over Na2SO4, concentration by means of a rotary evaporator is carried out. The crude product is placed on silica gel and purified by flash chromatography (40 g of silica gel, 3.5×13 cm, LM: PE). 1.57 g (5.7 mmol, 57%) of (8) are obtained as a red oil.