Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[Cu]>[Cl:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([S:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:3][CH:4]=1
Reactant: Sc1ccccc1
Reactant: Fc1cc(Cl)cnc1F
Agent: [Cu]
Product: Fc1cc(Cl)cnc1Sc1ccccc1

Procedure:
Starting from 93 g (0.508 mol) of 2,3-difluoro-5-chloropyridine, 58.8 g (0.5276 mol) of 98.7% pure thiophenol and 3.2 mg (0.01 mol %) of copper powder, 121.5 g (99.9% of theory) of the title compound were obtained as a colorless oil after 1.5 h of stirring in a pressure apparatus at 185° C. and work-up by the method of Example 1. 1H NMR (ppm, d6-DMSO) 8.35 (s/1H), 8.05 (d/1H), 7.4-7.6 (m/5H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16](F)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:20]#[N:21])[CH:5]=[CH:6][CH:7]=1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1.CO.C(Cl)(Cl)Cl>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([NH:29][CH2:28][C:27]4[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:20]#[N:21])[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1cccc(Br)c1
Reactant: COc1ccc(CN)cc1
Solvent: CO
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNc2cc3c(Nc4cccc(Br)c4)c(C#N)cnc3cn2)cc1
Yield: 45 %

Procedure:
To 1 g of 4-(3-bromo-phenylamino)-6-fluoro-[1,7]naphthyridine-3-carbonitrile in 25 mL of absolute ethanol was added 2 ml of 4-methoxy-benzylamine. The reaction was refluxed for eight days, stripped of solvents, and passed through a plug of silica gel with 5% methanol/chloroform. Fractions containing product were pooled and further purified by flash chromatography on silica gel with a gradient of 1-2% methanol/chloroform to give 595 mg (45%) of 4-(3-bromo-phenylamino)-6-(4-methoxy-benzylamino)-[1,7]naphthyridine-3-carbonitrile, which was sufficiently pure for further transformations. The product was recrystallized by dissolving in a minimum amount of warm chloroform, diluting with ether, and then adding hexanes to give 195 mg: melting point 82-86° C. (decomposed); mass spectrum (m/e): M+H 460.2, 462.2.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:11])[CH3:10].N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[C:9]([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][Br:1])=[CH:15][CH:14]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)Oc1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Oc1ccc(CBr)cc1
Reaction time: 1.33 h

Procedure:
N-Bromosuccinimide (60.0 g.) was added in portions during 40 minutes to a solution of 4-acetoxytoluene (50.0 g.) and 2,2'-azobis(2-methylpropionitrile) (10 mg.) in carbon tetrachloride (300 ml.) heated under reflux and illuminated by a high energy tungsten lamp (275 watt). Heating and illumination were continuted for 80 minutes after the addition was complete. The mixture was then cooled and filtered. The solid residue was washed with carbon tetrachloride (100 ml.) and the combined filtrate and washings were evaporated to give 4-acetoxybenzyl bromide as a syrupy solid, which was dissolved, without further purification, in ethanol (300 ml.). 1,2,3,6-Tetrahydropyridine (83.0 g.) was then added to the solution during 10 minutes. The subsequent mixture was left at 20°-25° C. for 16 hours, and then evaporated. Water (300 ml.) was added to the residue obtained and the subsequent mixture was acidified to pH2 with dilute hydrochloric acid, and then extracted with ether (2×100 ml.) and the extracts discarded. The aqueous phase was basified to pH9 (sodium hydroxide solution) and extracted with ether (3×100 ml.). The extracts were washed with water (2×50 ml.), dried (MgSO4) and evaporated. The residue was dissolved in acetone (200 ml.), the solution obtained was filtered, and the filtrate acidified to pH2 with ethereal hydrogen chloride. There was thus obtained 1-(4-hydroxybenzyl)-1,2,3,6-tetrahydropyridine hydrochloride which was recrystallised from methanol/ethyl acetate to give pure material (34.6 g.), m.p. 234°-236° C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([S:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=5)=[CH:33][CH:32]=4)=[O:29])=[CH:20][C:19]=3[CH:44]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:53])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([S:37]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=5)=[O:53])=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:44]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(Sc4ccccn4)cc2)CCN3CCC)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)c4ccccn4)cc2)CCN3CCC)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 19.5 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-(2-pyridinylsulfanyl)phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.15 g) was dissolved in methylene chloride (7.5 ml), m-chloroperbenzoic acid (95 mg) was added to the solution at 0° C., and the mixture was stirred for 15 minutes at 0° C. To the mixture was m-chloroperbenzoic acid (95 mg) was added, and the mixture was stirred for 15 minutes. The reaction mixture was added to an aqueous solution of saturated sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-(2-pyridinylsulfinyl)phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 183) (30 mg).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12](=[O:27])[CH2:13][CH:14]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)[C:15]([F:18])([F:17])[F:16])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[CH3:28][Mg]Br>C1COCC1>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]([OH:27])([CH2:13][CH:14]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)[C:15]([F:18])([F:16])[F:17])[CH3:28])=[CH:10][CH:11]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C(CC(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(-n2cncn2)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)(CC(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(-n2cncn2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
To a solution of 1-(4-(1H-1,2,4-triazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobutan-1-one (300 mg, 0.726 mmol) in THF cooled to 0° C. was added methylmagnesium bromide (450 mg, 5 mmol) drop wise. The reaction was stirred for 3 h at 0° C., then the reaction mixture was quenched with sat aqueous NH4Cl solution and extracted with EtOAc. The combined EtOAc layer was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 20%-25% EtOAc in petroleum ether) afforded the title compound as a solid (100 mg, 32%): 1H NMR (400 MHz, CDCl3) δ two diastereoisomers 8.58 (s, 1H, minor), 8.48 (s, 1H, major), 8.13 (s, 1H, minor), 8.09 (s, 1H, major), 7.70 (d, J=9.0 Hz, 2H, minor), 7.53 (d, J=9.0 Hz, 2H, minor), 7.40 (d, J=9.0 Hz, 2H, major), 7.31 (m, 1H, minor), 7.27 (d, J=9.0 Hz, 2H, major), 7.20 (m, 2H, minor), 7.01 (m, 1H, major), 6.75 (m, 2H, major), 350 (m, 1H), 2.50 (m, 2H), 1.56 (s, 3H, major), 1.54 (s, 3H, minor); ESIMS m/z 430.05 ([M+H]+).
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[CH3:22][C:23]1[S:24][C:25]2[CH:31]=[CH:30][C:29]([NH:32][C:33]([N:35]3[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH:36]3[CH2:48][O:49][C:50]3[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=3)=[O:34])=[CH:28][C:26]=2[N:27]=1>CO>[ClH:1].[CH3:22][C:23]1[S:24][C:25]2[CH:31]=[CH:30][C:29]([NH:32][C:33]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH:36]3[CH2:48][O:49][C:50]3[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=3)=[O:34])=[CH:28][C:26]=2[N:27]=1
Reactant: Cc1nc2cc(NC(=O)N3CCN(C(=O)OC(C)(C)C)CC3COc3cccnc3)ccc2s1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2cc(NC(=O)N3CCNCC3COc3cccnc3)ccc2s1
Reaction time: 1 h
Yield: 58 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(2-methylbenzo[d]thiazol-5-ylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate di-TFA salt (129.9 mg, 0.183 mmol) in MeOH (1 mL). After 1 h, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The fractions containing the desired product were combined and brought to pH 12 with 1 N NaOH and were extracted with EtOAc (3×). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was dissolved in MeOH (1 mL) and 4 M HCl in 1,4-dioxane (1 equiv. HCl, 0.028 mL) was added. The mixture was concentrated under reduced pressure to give 44.6 mg (58%) of the title compound as the hydrochloride salt. LC-MS: RT=4.22 min, [M+H]+=384.1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1.[SH:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:16][CH:15]=1>>[O:12]=[C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([S:13][C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[CH:18][CH:19]=2)=[N:3][NH:4]1
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Reactant: CC(C)(C)OC(=O)Nc1ccc(S)cc1
Product: CC(C)(C)OC(=O)Nc1ccc(Sc2n[nH]c(=O)c3ccccc23)cc1

Procedure:
4-chlorophthalazin-1(2H)-one and tert-butyl 4-mercaptophenylcarbamate were processed using a method similar to that described in Example 57A to afford the title compound. MS (APCI+) M/Z 370 (M+H)+.
Reaction SMILES: OO.[C:3]([O:11][CH:12]1[CH2:17][C:16]([CH3:19])([CH3:18])[N:15]([OH:20])[C:14]([CH3:22])([CH3:21])[CH2:13]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:23]S(C)=O.[OH-].[Na+]>O>[C:3]([O:11][CH:12]1[CH2:13][C:14]([CH3:22])([CH3:21])[N:15]([O:20][CH3:23])[C:16]([CH3:18])([CH3:19])[CH2:17]1)(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CS(C)=O
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 81 %

Procedure:
A solution of 5.9 g (52 mmol) of 30% aqueous hydrogen peroxide is added dropwise, under nitrogen, over 90 minutes to a mixture of 10.0 g (36.2 mmol) of 4-benzoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine, 11.2 g (40.3 mmol) of ferrous sulfate heptahydrate, and 135 ml of dimethyl sulfoxide which is initially at 24° C. The reaction temperature increases to 37° C. as the peroxide is added. After the addition is complete, the reaction mixture is stirred for 1.75 hours at ambient temperature. The mixture is cooled in an ice-water bath and diluted with water (80 ml). A solution of 5 g of sodium hydroxide in 45 ml of water is added to make the reaction mixture basic. The mixture is extracted with methylene chloride (250 ml, then 2×150 ml), and the combined organic layers are concentrated at reduced pressure to obtain a light orange liquid. Purification of the crude product by flash chromatography on silica gel (20:1 heptane/ethyl acetate) affords 8.5 g (81% yield) of the title compound, a white solid, mp 67°-69° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH2:3]1.C[O:11][C:12](=O)[C:13]([OH:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Na]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][O:9][C:12](=[O:11])[C:13]([OH:26])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)C(O)(c1ccccc1)c1ccccc1
Reactant: CN1CCC(CO)CC1
Agent: [Na]
Solvent: Cc1ccccc1
Product: CN1CCC(COC(=O)C(O)(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(1-Methyl-piperidin-4-yl)-methanol (2.58 g, 20 mmol) and hydroxy-diphenyl-acetic acid methyl ester (9.69 g, 40 mmol) are suspended in toluene (65 ml). Molecular sieve 4A (1 g) is added and the mixture is stirred at room temperature for 10 minutes. Sodium (0.08 g) is added and the reaction mixture stirred at 80° C. for 3 hours. Additional sodium (0.1 g) is then added and heating maintained at 80° C. for 18 hours. The reaction mixture is cooled to room temperature, solid filtered off, and washed with ethylacetate. The filtrate is washed once with saturated aqueous NaHCO3 solution (50 ml) and twice with aqueous HCl 1M (25 ml each). The combined acidic aqueous layers are basified with saturated aqueous NaHCO3 solution and solid NaHCO3, the resulting precipitate is removed by filtration, drying under vacuum gives the title product as a white solid (M+H)+:340.09.
Reaction SMILES: NC[C:3]([OH:5])=[O:4].N[C@H](C(O)=O)C.[NH2:12][C@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:16])[CH3:15].N[C@H](C(O)=O)[CH2:22][C:23]1[CH:28]=CC=C[CH:24]=1.N[C@H](C(O)=O)CCCCN>>[C:23]([O:5][C:3]([NH:12][C@@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:4])([CH3:28])([CH3:24])[CH3:22]
Reactant: NCC(=O)O
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: C[C@H](N)C(=O)O
Agent: NCCCC[C@H](N)C(=O)O
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O

Procedure:
2Thr, 2.12; Ser, 1.09; Gly, 0.95; Ala, 1.13; Val, 0.98; 3 Phe, 3.09; 2 Lys, 2.00.
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:20])[CH2:6][C:7](=[CH2:19])[CH:8](O)[CH:9]([NH:15][CH:16]=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:3])[CH3:2].S(Br)([Br:23])=O.O>C(Cl)Cl>[C:1]([O:4][CH:5]([CH3:20])[CH2:6][C:7]([CH2:19][Br:23])=[CH:8][CH:9]([NH:15][CH:16]=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:3])[CH3:2]
Reactant: O=S(Br)Br
Reactant: C=C(CC(C)OC(C)=O)C(O)C(NC=O)C(=O)OCC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(C=C(CBr)CC(C)OC(C)=O)NC=O
Reaction time: 1 h

Procedure:
17.0 g (59.1 mmol) of ethyl 6-acetoxy-2-formylamino-3-hydroxy-4-methylene-heptanoate are dissolved in 170 ml of CH2Cl2 and 5.5 ml (71 mmol) of thionyl bromide are then added dropwise at room temperature. After 1 hour, 100 ml of water are added and the batch is vigorously stirred for 10 minutes. The organic phase is separated and washed once with water, once with a 1N solution of KHCO3 and twice with water. The aqueous phases are extracted twice with CH2Cl2. The combined organic phases are dried over MgSO4, filtered and concentrated by evaporation, giving ethyl 6-acetoxy-4-bromomethyl-2-formylamino-hept-3-enoate as a brown oil which is further reacted without purification.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Cs+:16].[Cs+].CC(C)=O>O>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[Cs+:16]
Reactant: O=C(O)c1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: O=C([O-])c1cc(O)ccc1O
Yield: 200 %

Procedure:
1 mol of 2,5-dihydroxybenzoic acid and 0.5 mol of cesium carbonate were added to 200 ml of acetone and 200 ml of water and dissolved therein by stirring. After completely dissolving, the resultant solution was concentrated to dryness to give 1 mol of cesium 2,5-dihydroxybenzoate. 85.8 g (0.3 mol) of cesium 2,5-dihydroxybenzoate, 57.9 g (0.3 mol) of bromooctane and 300 ml of DMF were introduced into a reactor and reacted under a nitrogen gas stream at 100° C. for 3 hours. The reaction solution was concentrated, washed with water and dried to give 78 g (0.29 mol) of 2,5-dihydroxybenzenecarboxylic octane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[C:10]([CH:13]=[O:14])[S:11][CH:12]=2)[CH:3]=1.[CH3:15][Mg]Br.O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[C:10]([CH:13]([OH:14])[CH3:15])[S:11][CH:12]=2)[CH:3]=1
Reactant: C[Mg]Br
Reactant: O=Cc1cc(-c2cc(Cl)ccn2)cs1
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1cc(-c2cc(Cl)ccn2)cs1
Reaction time: 3 h

Procedure:
To a solution of 4-(4-chloro-pyridin-2-yl)-thiophene-2-carbaldehyde (160 mg, 0.72 mmol) in THF (3 mL) was added methylmagnesium bromide (3 M, 1 mL) at −78° C. and the resulting mixture was stirred at the temperature for 3 hours. Water was added and THF was removed. The water solution was extracted with EtOAc and organic layer was concentrated. The resulting residue was purified by silica gel column to yield 1-[4-(4-chloro-pyridin-2-yl)-thiophen-2-yl]-ethanol
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.N1([C:15](=[O:25])[C@@H:16]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH3:17])CCOCC1.C(NC(C)C)(C)C.[Li]>C1COCC1.C1COCC1.CCCCCCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:15](=[O:25])[C@@H:16]([O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)[CH3:17]
Reactant: C[C@H](OC1CCCCO1)C(=O)N1CCOCC1
Reactant: Fc1ccc(F)cc1
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: C[C@H](OC1CCCCO1)C(=O)c1cc(F)ccc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 46.2 %

Procedure:
1,4-Difluorobenzene (1.8 g; 15.8 mmol) and (2S)-1-Morpholin-4-yl-2-(tetrahydro-pyran-2-yloxy)-propan-1-one (3 g; 10.5 mmol) are dissolved in dry THF (15 ml). The mixture is cooled to 0° C. and then lithium diisopropylamine (7.9 ml of a 2M solution in THF/Heptane; 15.8 mmol) is added dropwise over a period of 20 minutes. The mixture is stirred for another 2 hours at 0° C. The reaction is then quenched with a saturated ammonium chloride solution. The reaction mixture is extracted with ethyl acetate. The organic phase is washed with water and brine and then dried over magnesium sulfate. The solids are filtered off and the solvent is removed under reduced pressure. The crude product is chromatographed over silicagel (eluent:Petrol ether/Ethyl acetate 50:1 to 30:1). 1.31 g of yellow crystalline material (yield 44.8%) is obtained with a HPLC purity of 96.2%.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([N:7]=[C:8]=[N:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]=[CH:17][C:18]([O-:20])=[O:19])=[CH:3][CH:2]=1.[CH3:27][NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.[C:39]1(C)C=CC=CC=1>>[C:1]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=[CH:5][C:4]([N:7]2[CH:16]([CH2:17][C:18]([O:20][CH3:39])=[O:19])[C:11]3[C:10](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:9]=[C:8]2[N:28]([CH3:27])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:34]2[CH2:35][CH2:36][CH2:37][CH2:38]2)=[CH:3][CH:2]=1
Reactant: Cc1ccccc1
Reactant: CNCCCCCN1CCCC1
Reactant: O=C([O-])C=Cc1ccccc1N=C=Nc1ccc(-c2ccccc2)cc1
Product: COC(=O)CC1c2ccccc2N=C(N(C)CCCCCN2CCCC2)N1c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To a solution of 3-[2-(4-biphenylyliminomethyleneamino)phenyl]acrylate (11) (0.83 g, 2.35 mmol) in toluene (50 ml) was slowly added N-methyl-N-[5-(pyrrolidin-1-yl)pentyl]amine (6) obtained in Example 5 (0.80 g, 4.70 mmol) at 0° C., and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the resulting reaction mixture was extracted with a saturated 1N NaOH aqueous solution and dichloromethane three times. Then, the combined organic phase was dried with anhydrous magnesium sulfate and distilled under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent: dichloromethane:methnol:ammonia water=100:9:1) to give the target compound (0.63 g, 52%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[I:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[CH:20][C:19]([CH2:22][NH2:23])=[N:18]2)=[CH:13][CH:12]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.O>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:23][CH2:22][C:19]2[CH:20]=[CH:21][N:17]([C:14]3[CH:15]=[CH:16][C:11]([I:10])=[CH:12][CH:13]=3)[N:18]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: NCc1ccn(-c2ccc(I)cc2)n1
Reactant: O=C(O)c1ccc(Cl)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccn(-c2ccc(I)cc2)n1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a solution of 5-chloro-thiophene-2-carboxylic acid (51 mg, 0.31 mmol), (1-(4-iodophenyl)-1H-pyrazol-3-yl)methanamine (78 mg, 0.26 mmol) and TEA (0.100 mL, 0.72 mmol) in DMF (3 mL), BOP (170 mg, 0.38 mmol) was added. The mixture was stirred at room temperature overnight. H2O and EtOAc were added. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo. The residue was purified by a preparative TLC plate (developed in EtOAc/hexane (35/65)) to give 5-chloro-N-((1-(4-iodophenyl)-1H-pyrazol-3-yl)methyl)thiophene-2-carboxamide (60 mg).
Reaction SMILES: [CH:1]([C:3]1[C:13]2[O:12][CH2:11][CH2:10][C:9]([C:14]([O:16][CH3:17])=[O:15])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)=O.Cl.[CH3:19][O:20][NH2:21].C[O-].[Na+]>CO>[CH3:19][O:20][N:21]=[CH:1][C:3]1[C:13]2[O:12][CH2:11][CH2:10][C:9]([C:14]([O:16][CH3:17])=[O:15])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CON
Reactant: COC(=O)C1=Cc2cccc(C=O)c2OCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CON=Cc1cccc2c1OCCC(C(=O)OC)=C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.8 %

Procedure:
Methyl 2,3-dihydro-9-formyl-1-benzoxepin-4-carboxylate (0.5 g) was added to a mixture of O-methylhydroxylamine hydrochloride (0.25 g) and 28% sodium methoxide in methanol (0.5 ml) in methanol (5 ml) and the mixture was stirred at ambient temperature for 4 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo to give methyl 2,3-dihydro-9-methoxyiminomethyl-1-benzoxepin-4-carboxylate (0.55 g).