Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]([C:16](=[O:25])[C:17]3[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=3)[C:6]=2[CH:26]=1.Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[C:7]([C:16](=[O:25])[C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[C:6]=2[CH:26]=1
Reactant: COc1ccc(C(=O)c2c(-c3ccccc3)oc3ccc(Cl)cc23)cc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(c1ccc(O)cc1)c1c(-c2ccccc2)oc2ccc(Cl)cc12

Procedure:
Demethylation of 5-chloro-3-(4-methoxybenzoyl)-2-phenylbenzofuran with pyridine hydrochloride as described above gives 5-chloro-3-(4-hydroxybenzoyl)-2-phenylbenzofuran.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].C(N(CC)CC)C.[C:15]([OH:25])(=[O:24])[C:16]1[C:17](=[CH:19][CH:20]=[C:21]([CH:23]=1)[OH:22])[OH:18].C(OCC)(=O)C>O1CCCC1>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([O:22][C:21]1[CH:20]=[CH:19][C:17]([OH:18])=[C:16]([CH:23]=1)[C:15]([OH:25])=[O:24])=[O:6]
Reactant: O=C(Cl)CCCBr
Reactant: O=C(O)c1cc(O)ccc1O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCCBr)Oc1ccc(O)c(C(=O)O)c1

Procedure:
In a solution of 4-bromobutyrylchloride (3 g, 16.17 mmoles) in tetrahydrofuran (50 ml), cooled at 0° C., triethylamine (4.5 ml, 32.34 mmoles) and then gentisic acid (2.4 g, 16.16 mmol) are dropped under stirring. It is allowed to react at 0° C. for 4 hours, under stirring, then it is evaporated at reduced pressure. The obtained crude product is treated with ethyl acetate, the organic phase is washed with HCl 1% and then brine. The organic phase is anhydrified with sodium sulphate and dried. The obtained residue is purified by chromatography on silica gel column, eluting with methylene chloride/methanol 95/5, obtaining the 5-(4-bromobutyryloxy)-2-hydroxy-benzoic acid.
Reaction SMILES: Cl.[C:2]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]#[C:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])=[CH:12][CH:13]=2)[C@H:8]([NH2:27])[CH2:7][C@@H:6]1[CH3:28])(=[O:4])[CH3:3].CC(C)([O-])C.[Na+].C[N:36]([CH3:62])[C:37]1[CH:42]=[CH:41][CH:40]=C[C:38]=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.BrC1C=CC=C(C)N=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:2]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]#[C:16][Si:17]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:24]([CH3:26])[CH3:25])=[CH:12][CH:13]=2)[C@H:8]([NH:27][C:62]2[CH:40]=[CH:41][CH:42]=[C:37]([CH3:38])[N:36]=2)[CH2:7][C@@H:6]1[CH3:28])(=[O:4])[CH3:3]
Reactant: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: CC(=O)N1c2ccc(C#C[Si](C(C)C)(C(C)C)C(C)C)cc2[C@H](N)C[C@@H]1C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cc1cccc(Br)n1
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(C#C[Si](C(C)C)(C(C)C)C(C)C)cc2[C@H](Nc2cccc(C)n2)C[C@@H]1C
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 124 %

Procedure:
A flask was charged with (2S,4R)-1-acetyl-2-methyl-6-{[tris(1-methylethyl)silyl]ethynyl}-1,2,3,4-tetrahydro-4-quinolinamine hydrochloride (for a preparation see Intermediate 108) (200 mg, 0.475 mmol), sodium tert-butoxide (228 mg, 2.375 mmol), tris(dibenzylideneacetone)dipalladium(0) (435 mg, 0.475 mmol) and 2-(dimethylamino)-2′-(dicyclohexylphosphino)biphenyl (DavePhos) (374 mg, 0.950 mmol) then filled with degassed toluene (6 mL) and the resulting mixture was treated with 2-bromo-6-methylpyridine (0.162 mL, 1.425 mmol) then stirred at 100° C. under nitrogen for 1.5 h then cooled to room temperature and partitioned between water and AcOEt. The two layers were filtered through celite then separated. The aqueous phase was extracted with AcOEt and the combined organic phases were washed with water then brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by SP4 using a 25 G silica cartridge (gradient:13 to 63% AcOEt in Hexanes) gave (2S,4R)-1-acetyl-2-methyl-N-(6-methyl-2-pyridinyl)-6-{[tris(1-methylethyl)silyl]ethynyl}-1,2,3,4-tetrahydro-4-quinolinamine (280 mg, 0.589 mmol, 124% yield) contaminated with palladium ligand residues as a brown foam which was used in the next step without further purification.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.CN([CH:18]=[O:19])C>C1COCC1>[S:1]1[C:2]([CH:18]=[O:19])=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2
Reactant: c1ccc2sccc2c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc2ccccc2s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of benzothiophene (2 g, 14.9 mmol) in 100 mL of THF cooled to −78° C. was added 1.6 M n-butyl lithium in hexanes (10.25 mL, 16.39 mmol). The mixture was stirred at −78° C. for 1 h, warmed to 0° C., stirred for 5 min, recooled to −78° C. and treated with DMF (4.62 mL, 59.61 mmol). The temperature was allowed to rise slowly overnight. The reaction was quenched with saturated aqueous ammonium chloride and extracted with diethyl ether. The combined organic extracts were washed with water and brine, dried over MgSO4 and concentrated to afford the title compound as an oil. (2.216 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][N:9]([CH2:20][C:21]2[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=2)[CH2:24][N:25]2[CH:29]([C:30](O)=[O:31])[CH2:28][CH2:27][S:26]2(=[O:34])=[O:33])[C@H:10]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:6]([F:38])[C:5]([O:39][CH3:40])=[CH:4][CH:3]=1.[C:41]12([NH2:51])[CH2:50][CH:45]3[CH2:46][CH:47]([CH2:49][CH:43]([CH2:44]3)[CH2:42]1)[CH2:48]2>>[C:41]12([NH:51][C:30]([C@@H:29]3[CH2:28][CH2:27][S:26](=[O:33])(=[O:34])[N:25]3[CH2:24][C:23]3[CH:35]=[CH:36][CH:37]=[C:21]([CH2:20][N:9]([CH2:8][C:7]4[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]([O:39][CH3:40])[C:6]=4[F:38])[C@H:10]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:11][C:12]([CH3:14])([CH3:15])[CH3:13])[CH:22]=3)=[O:31])[CH2:48][CH:47]3[CH2:46][CH:45]([CH2:44][CH:43]([CH2:49]3)[CH2:42]1)[CH2:50]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: COc1ccc(Cl)c(CN(Cc2cccc(CN3C(C(=O)O)CCS3(=O)=O)c2)[C@H](CN(C)C)CC(C)(C)C)c1F
Product: COc1ccc(Cl)c(CN(Cc2cccc(CN3[C@H](C(=O)NC45CC6CC(CC(C6)C4)C5)CCS3(=O)=O)c2)[C@H](CN(C)C)CC(C)(C)C)c1F
Yield: 62 %

Procedure:
(S)-2-(3-{[(6-Chloro-2-fluoro-3-methoxy-benzyl)-((S)-1 dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid (Intermediate 7 (Epimer 1), 0.071 g, 0.119 mmol) was reacted with 1-adamantanamine (available from Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233, USA; 0.022 g, 0.144 mmol) to form (S)-2-(3-{[(6-Chloro-2-fluoro-3-methoxy-benzyl)-((S)-1-dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid adamantan-1-ylamide (Epimer 1) (0.054 g, 61%). m/z=731 (M+1); HRMS: calcd for C39H57ClFN4O4S. Calc [M+H+] 731.3768. found 731.3765.
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.Cl[S:32]([C:35]1[CH:36]=[C:37]([CH:42]=[CH:43][CH:44]=1)[C:38]([O:40][CH3:41])=[O:39])(=[O:34])=[O:33]>>[CH:12]([C:9]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:11]([S:32]([C:35]2[CH:36]=[C:37]([CH:42]=[CH:43][CH:44]=2)[C:38]([O:40][CH3:41])=[O:39])(=[O:34])=[O:33])[CH:10]=1)=[O:13]
Reactant: COC(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: O=Cc1c[nH]c(-c2ccccc2)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cccc(S(=O)(=O)n2cc(C=O)cc2-c2ccccc2)c1
Yield: 68.8 %

Procedure:
Using 5-phenyl-1H-pyrrole-3-carbaldehyde (1.32 g), sodium hydride (60% in oil, 444 mg), 15-crown-5 (2.04 g) and methyl 3-(chlorosulfonyl)benzoate (2.17 g), a procedure as in Reference Example 219 was performed to give the title compound as a pale-yellow oil (yield 1.96 g, 69%).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[CH2:27][C:28](O)=[O:29]>>[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[CH2:27][C:28]([NH:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16])=[O:29]
Reactant: O=C(O)Cc1ccc2ccccc2c1
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Product: O=C(Cc1ccc2ccccc2c1)Nn1nc(C(F)(F)F)c2ccccc2c1=O

Procedure:
The product of Example 11B and 2-napthylacetic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.44 (ddd, J=8.0, 1.4, 0.6 Hz, 1H), 8.12-8.16 (m, 1H), 8.01-8.09 (m, 2H), 7.87-7.97 (m, 4H), 7.48-7.59 (m, 3H), 3.91 (s, 2H); MS (ESI−) M/Z 396 (M−H)−.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[CH3:18][O:19][C:20]1[CH:32]=[CH:31][C:23]([O:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:22][CH:21]=1>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:28]1[CH2:27][CH2:26][CH:25]([O:24][C:23]2[CH:31]=[CH:32][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[CH2:30][CH2:29]1)=[O:9])([CH3:2])[CH3:3]
Reactant: COc1ccc(OC2CCNCC2)cc1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: COc1ccc(OC2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)CC2)cc1
Yield: 73 %

Procedure:
Prepared in analogy to Example 1 from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 4-(4-methoxy-phenoxy)-piperidine. The crude material was purified by reversed phase HPLC (acetonitrile/water) to yield the title compound as an amorphous white solid (yield 73%). MS (m/e): 448.2 (M+H+, 100%).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([CH2:25][OH:26])=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([C:21]([F:24])([F:23])[F:22])[CH2:17][CH2:16]3)[N:13]=2)=[CH:5][CH:4]=1.[H-].[Na+].[F:31][CH:32]([F:43])[O:33][C:34]1[CH:41]=[C:40](F)[CH:39]=[CH:38][C:35]=1[C:36]#[N:37].O>CN(C)C=O>[F:31][CH:32]([F:43])[O:33][C:34]1[CH:41]=[C:40]([O:26][CH2:25][C:11]2[S:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:27])[F:28])=[CH:4][CH:5]=3)=[N:13][C:12]=2[CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21]([F:22])([F:24])[F:23])[CH2:17][CH2:16]2)[CH:39]=[CH:38][C:35]=1[C:36]#[N:37]
Reactant: N#Cc1ccc(F)cc1OC(F)F
Reactant: OCc1sc(-c2ccc(C(F)(F)F)cc2)nc1CN1CCC(C(F)(F)F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CN2CCC(C(F)(F)F)CC2)cc1OC(F)F
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
To a solution of 3 g of [2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-yl]-methanol in 12 mL of dimethylformamide at 5° C. was added 319 mg of a 55% suspension of sodium hydride in mineral oil. The resulting mixture was stirred for 30 minutes at 5° C. 4.7 mL of the resulting solution was slowly added to a solution 319 mg of 2-difluoromethoxy-4-fluoro-benzonitrile in 1.2 mL of dimethylformamide at 5° C. The resulting mixture was stirred at 5° C. allowing the temperature to warm up to room temperature. It was then heated in a sealed tube to 60° C. under microwave irradiation for 15 minutes. After allowing it to cool down to room temperature, the mixture was poured into water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient from heptane 100 to heptane 50/ethyl acetate 50) to give 0.83 g of 2-difluoromethoxy-4-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-ylmethoxy]-benzonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]2)=[C:7]([NH2:9])[CH:8]=1.[CH3:22][C:23]([CH3:25])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].N>O1CCCC1.C(O)(=O)C>[CH:23]([NH:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=2)[CH2:11]1)([CH3:25])[CH3:22]
Reactant: CC(C)=O
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NC(C)C)C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (300 mg) in tetrahydrofuran (8 ml) were sequentially added acetone (0.4 ml), acetic acid (0.1 ml) and sodium triacetoxyborohydride (780 mg), and the solution was stirred for 2 days at room temperature. The solution was neutralized with ammonia solution, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (309 mg).
Reaction SMILES: C([C@@H]1COC(=O)[N:9]1[C:14]([C@@H:16]([S:28][C:29]1[CH:39]=[CH:38][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][C:30]=1[N+]([O-])=O)[CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:15])C1C=CC=CC=1.C(O)C>[Pd].C(O)(=O)C>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][CH2:18][CH2:17][C@H:16]2[C:14](=[O:15])[NH:9][C:30]3[CH:31]=[C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:38]=[CH:39][C:29]=3[S:28]2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1ccc(S[C@@H](CCCc2ccc(OC)cc2)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1ccc2c(c1)NC(=O)[C@H](CCCc1ccc(OC)cc1)S2
Temperature: 25 °C
Reaction time: 3 h
Yield: 471.7 %

Procedure:
Ethyl 4-{[(1S)-1-{[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}-4-(4-methoxyphenyl)butyl]thio}-3-nitrobenzoate (Reference Example 22) (0.62 g, 0.11 mmol), ethanol (10 ml), acetic acid (5 ml) and 10% Pd—C (1.5 g) were mixed, and the mixture was stirred for 3 hours at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through Celite and the filtrate was concentrated. The residue was purified by a silica gel chromatography (40 g, ethyl acetate:hexane=1:3) to obtain ethyl (2S)-2-[3-(4-methoxyphenyl)propyl]-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate (0.2 g, 98.3% e.e.), i.e., the compound described in Example 7.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[C:20]2[C:21]([O:26][CH3:27])=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[N:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1.C(=O)([O-])[O-:29].[K+].[K+].OO.O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]([NH2:17])=[O:29])=[CH:14][C:13]=2[C:20]2[C:21]([O:26][CH3:27])=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[N:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1
Reactant: O=C([O-])[O-]
Reactant: COc1ncccc1-c1cc(C#N)ccc1Oc1cnc(C2CC2)c(Cl)c1
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ncccc1-c1cc(C(N)=O)ccc1Oc1cnc(C2CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 105 %

Procedure:
To a solution of 4-(5-chloro-6-cyclopropylpyridin-3-yloxy)-3-(2-methoxypyridin-3-yl)benzonitrile (Preparation 39, 478 mg, 1.27 mmol) in dimethyl sulfoxide (5 mL) was added potassium carbonate (1.05 g, 7.62 mmol) followed by a 30% aqueous solution of hydrogen peroxide (650 μL, 6.35 mmol). The reaction was stirred 1 hour at room temperature. Water (50 mL) was added and the solution was extracted by ethyl acetate (3×20 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with 3% methanol in dichloromethane to afford the title compound as a white solid (528 mg, 87%).
Reaction SMILES: [C:1]([N-]CC=C)(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]C=C.F[P-](F)(F)(F)(F)F.C[N+]1C=C[N:27]([CH2:30][CH2:31][CH2:32][CH3:33])C=1>C(C1C=CC=C(C(C)C)C=1N=CC1C=C([N+]([O-])=O)C=CC=1[O-])(C)C.C(=[Ru+]Cl)C1C=CC=CC=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>[NH2:27][CH:30]1[CH2:31][CH:32]=[CH:33][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:12]
Reactant: CCCCn1cc[n+](C)c1
Reactant: C=CCCCCCCCCC(=O)[N-]CC=C
Agent: Cl[Ru+]=Cc1ccccc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(C)c1cccc(C(C)C)c1N=Cc1cc([N+](=O)[O-])ccc1[O-]
Product: NC1CC=CCCCCCCCCC1=O
Yield: 80 %

Procedure:
58 mg (0.25 mmol) of 10-undecenoyl-allylamide and 10 mg of (tricyclohexylphosphine)-benzylidene-chloro-ruthenium-(IV) 2-[(2,6-diisopropylphenyl)imino]methyl-4-nitro-phenoxide (5 mol %) were dissolved in 3 g of 1-methyl-3-butylimidazolium hexafluorophosphate. The mixture was allowed to react at 40° C. for 14 hours. The ionic phase was extracted with dichloromethane. After filtration through a very short silica gel column (length about 0.5 cm), about 80% of the desired product were obtained (yield determined by means of gas chromatography). The trans/cis ratio of the product is about 5:1.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2=[CH:16][S:17][C:18]([CH3:19])=[C:5]12)=[O:3].[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][NH2:34])[CH2:23][CH3:24])[CH3:21]>C(#N)C>[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][NH:34][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2=[CH:16][S:17][C:18]([CH3:19])=[C:5]12)=[O:3])[CH2:23][CH3:24])[CH3:21]
Reactant: Cc1scc2c1N(C(=O)Cl)c1ccccc1NC2=O
Reactant: CCN(CC)CC1CCCCN1CCN
Solvent: CC#N
Product: CCN(CC)CC1CCCCN1CCNC(=O)N1c2ccccc2NC(=O)c2csc(C)c21
Yield: 39 %

Procedure:
Prepared analogously to Example 2 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 2-[2-[(diethylamino)methyl]-piperidin-1-yl]ethanamine in a yield of 39% of theory. Colourless cystals, m.p. 138°-140° C. (acetonitrile).
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.FC(F)(F)C(O)=O.[Cl:27][CH2:28][CH2:29][CH2:30][C:31](=[CH:35][C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH:46]=[C:45]([CH3:47])[N:44]=[CH:43]2)=[C:38]([O:48][CH3:49])[CH:37]=1)[C:32]([OH:34])=O.[F:50][C:51]1[CH:56]=[CH:55][CH:54]=[C:53]([F:57])[C:52]=1[CH:58]([NH2:60])[CH3:59]>CN(C=O)C.C(OCC)(=O)C.O.C(Cl)CCl>[F:50][C:51]1[CH:56]=[CH:55][CH:54]=[C:53]([F:57])[C:52]=1[CH:58]([NH:60][C:32](=[O:34])[C:31](=[CH:35][C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH:46]=[C:45]([CH3:47])[N:44]=[CH:43]2)=[C:38]([O:48][CH3:49])[CH:37]=1)[CH2:30][CH2:29][CH2:28][Cl:27])[CH3:59]
Reactant: CC(N)c1c(F)cccc1F
Reactant: COc1cc(C=C(CCCCl)C(=O)O)ccc1-n1cnc(C)c1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C=C(CCCCl)C(=O)NC(C)c2c(F)cccc2F)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
IPEA (1 mL.), EDC (257 mg) and HOBT (181 mg) were added to a solution of 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (200 mg) and 1-(2,6-difluorophenyl)ethylamine (purity: 50 wt %, 210 mg) in DMF (5 mL), and the reaction solution was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (1-(2,6-difluorophenyl)ethyl)amide. Sodium hydride (containing mineral oil at 40%, 30 mg) was added to a solution of the resulting 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (1-(2,6-difluorophenyl)ethyl)amide in DMF (5 mL), and the reaction solution was stirred at room temperature for 5 minutes. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 105 mg of the title compound as a racemate. The compound (15 mg) was fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm: mobile phase: hexane:ethanol=1:1) to obtain the title optically active substance with a retention time of 29 minutes (6.9 mg; >99% ee) and the title optically active substance with a retention time of 34 minutes (6.2 mg; >93% ee). The physical properties of the compounds are as follows.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>C(Cl)(Cl)Cl>[C:17]([NH:6][C@H:5]([C:4]([O:3][CH3:2])=[O:9])[CH2:7][OH:8])(=[O:19])[CH3:18]
Reactant: COC(=O)[C@@H](N)CO
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CO)NC(C)=O

Procedure:
To a suspension of about 46.57 g of L-serine methyl ester hydrochloride in about 3 liters of chloroform was added about 84 ml of triethylamine. This mixture was stirred until solution was complete, then about 21 ml of acetyl chloride was added dropwise. The mixture was then stirred under argon for about 2 days and the chloroform removed under reduced pressure. The residue was suspended in ethanol, filtered through a sintered glass funnel and the ethanol removed, giving about 49 g of the desired title compound [α]D26 =+36°±1° (CHCl3, 1.039%).
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:14](C(OC(C)(C)C)=O)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=O>CC#N.CN(C1C=CN=CC=1)C>[C:18]([O:17][C:15]([N:9]1[CH2:10][CH2:11][CH2:12][CH2:13][C@H:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:14])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCCN1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)[C@@H]1CCCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (S)-piperidine-2-carboxylic acid tert-butyl ester (M. Egbertson and S. J. Danishefsky, J. Org. Chem., 1989, 54, 1, 11-12) (5.78 g, 31.2 mmol) in CH3CN (30 mL) at 0° C. was added DMAP (763 mg, 6.2 mmol) followed by BOC2O (10.22 g, 46.8 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 20 h. The solvents were evaporated under reduced pressure and the residue was purified by flash chromatography (10% ethyl acetate in hexane). The title compound was obtained as a colourless oil which crystallized upon standing (8.33 g, 94%): 1H NMR (400 MHz, CDCl3) δ 1.21-1.32 (2H, m), 1.47-1.48 (18H, 2 s), 1.59-1.72 (3H, m), 2.18 (1H, m), 2.85-3.00 (1H, m), 3.89-4.01 (1H, 2 d, J 11.9 Hz), 4.47-4.58 (1H, 2 br s). Method H: