Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:7][N:6]=[N:5]1.C(N(CC)CC)C.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>O1CCCC1>[C:28]([CH2:27][NH:1][CH2:2][CH2:3][N:4]1[C:8]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:7][N:6]=[N:5]1)([O:30][CH2:31][CH3:32])=[O:29]
Reactant: COc1ccc(CSc2nnnn2CCN)cc1
Reactant: CCOC(=O)CBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNCCn1nnnc1SCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 62 %

Procedure:
To a solution of 15.0 g. (56 mmol) of 1-(2-aminoethyl)-5-[(4-methoxybenzyl)thio]-1H-tetrazole in 70 ml. of dry tetrahydrofuran was added 7.7 ml. (56 mmol) of triethylamine, and 6.2 ml. (56 mmol) of ethyl bromoacetate. After stirring at room temperature for 15 hours, the mixture was filtered, and the filtrate was evaporated in vacuo to dryness. The residue was dissolved in 70 ml. of chloroform and decolorized with charcoal. The filtrate was chromatographed on silica gel, eluting with a gradient of 0-15% ethyl acetate in chloroform. Fractions containing product by thin layer chromatography were pooled and evaporated to dryness to give 12.5 g. (62% yield) of 1-[2-[[(carbethoxy)methyl]amino]ethyl]-5-[(4-methoxybenzyl)thio]-1H-tetrazole as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.I[CH2:32][CH2:33][CH3:34]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:32][CH2:33][CH3:34])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[N:3]=1
Reactant: CCCI
Reactant: COC(=O)Cc1c(C)nc(Cl)nc1-c1ccc(C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 39.5 %

Procedure:
A solution of methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)acetate (2.5 g; 8.60 mmol) in dry DMF (40 mL) was cooled to −78° C. LHMDS (9.46 mL; 9.46 mmol; 1M in THF) was added dropwise and the mixture was stirred at −78° C. for 15 min followed by the dropwise addition of iodopropane (1.260 ml; 12.90 mmol). After stirring for 2 h at −15° C. the mixture was allowed to warm up to room temperature. After 1 h the reaction was quenched by adding a saturated solution of ammonium chloride. The mixture was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (2-10%) in heptane to give 1.131 g (37%) of the title compound as a yellow oil. ESI/APCI(+): 333 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH3:14])=[CH:7][CH:6]=1)=[O:4].[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[CH2:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1>O1CCOCC1.[Ag]=O>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH2:31][C:30]3[CH:29]=[CH:28][C:27]([O:26][CH2:25][C:16]4[CH:17]=[CH:18][C:19]5[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=5)[N:15]=4)=[CH:34][CH:33]=3)=[CH:10][N:11]2[CH3:14])=[CH:7][CH:6]=1)=[O:4]
Reactant: ClCc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: COC(=O)c1ccc2ccn(C)c2c1
Agent: O=[Ag]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(Cc3ccc(OCc4ccc5ccccc5n4)cc3)cn(C)c2c1
Temperature: 70 °C

Procedure:
To a stirred solution of 1-methylindole-6-carboxylic acid methyl ester (Example 10, part i) (1.5 g) and 4-(quinolin-2-ylmethoxy)benzyl chloride (2.43 g) in dioxan (15 ml), silver oxide (2 g) was added and the suspension heated at 70° C. overnight. The solvent was removed in vacuo, the residue ultrasonicated with ethylacetate and insoluble material removed by filtration through celite. The filtrate was evaporated to dryness and the residue purified by chromatography on flash silica, eluting with petroleum spirit 40°-60° C./diethyl ether (1:1) to give the product as a white solid. A small quantity was crystallised from petroleum spirit 40°-60° C./diethyl ether (1:1).
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].C[O:10][C:11](=O)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1.[Cl-].[NH4+]>C1COCC1>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([CH2:12][C:11](=[O:10])[CH2:7][C:6]#[N:8])[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: COC(=O)Cc1ccc(OC)c(OC)c1
Reactant: CC#N
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)CC#N)cc1OC
Temperature: -78 °C

Procedure:
To a 1.0 L three-necked round-bottomed flask was added 50 mL of THF and the reaction mixture was cooled to −78° C. Butyl lithium (BuLi, 1.6 M, 14.4 mL, 23 mmol) was added dropwise keeping the temperature below −70° C. Acetonitrile (1.3 mL, 25 mmol) in 30 mL of THF was added dropwise to the flask amidst stirring and cooling. After 2 hours (h) of stirring, (3,4-dimethoxyphenyl)acetic acid methyl ester (2.3 g, 11 mmol) was added to the resulting white colloidal mixture in the flask. The reaction mixture was stirred for a further 2 h, followed by the addition of saturated ammonium chloride solution (NH4Cl, 75 mL) at −78° C. The organic layer was separated, dried with sodium sulfate (Na2SO4), filtered to remove the drying agent and evaporated to dryness to give the crude product. This crude product was purified by silica gel column chromatography, eluting with 30-70% ethyl acetate (EtOAc) in hexanes to yield 4-(3,4-dimethoxyphenyl)-3-oxo-butyronitrile in the form of a solidifying amber oil, 1.8 g (75%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22]([OH:24])=O)=[CH:19][C:18]=2[CH:25]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C@H:27]1[CH2:32][CH2:31][C@H:30]([O:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:29][CH2:28]1>>[CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22]([NH:26][C@H:27]3[CH2:32][CH2:31][C@H:30]([O:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:29][CH2:28]3)=[O:24])=[CH:19][C:18]=2[CH:25]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CO[C@H]1CC[C@H](N)CC1
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc2oc(C(=O)O)cc2c1
Product: CC(C)(C)OC(=O)CO[C@H]1CC[C@H](NC(=O)c2cc3cc(C(=N)NC(=O)OCc4ccccc4)ccc3o2)CC1

Procedure:
In the same manner as in Example 15 (3), 5-(benzyloxycarbonyl-amidino)-2-benzofurancarboxylic acid (183 mg, 0.541 mmol) and t-butyl trans-(4-aminocyclohexyloxy)acetate (124 mg, 0.541 mmol) were condensed, and purified by silica gel column chromatography (methylene chloride/methanol=30/1-10/1) to give 251 mg of compound (170) as a colorless solid (84%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([O:18]C)=[O:17])[C:13](=[O:20])[C:12]3([CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:21]3)[N:11]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C1COCC1.[OH-].[Li+].Cl>O>[C:16]([CH2:15][N:14]1[C:13](=[O:20])[C:12]2([CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26]2)[N:11]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:10][C@H:9]1[C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)([OH:18])=[O:17]
Reactant: COC(=O)CN1C(=O)C2(COCCOC2)N(C(=O)OC(C)(C)C)C[C@H]1c1cc(F)cc(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](c2cc(F)cc(F)c2)N(CC(=O)O)C(=O)C12COCCOC2

Procedure:
0.235 g (0.50 mmol) tert-butyl (R)-3-(3,5-difluoro-phenyl)-4-methoxycarbonylmethyl-5-oxo-8,11-dioxa-1,4-diaza-spiro[5.6]dodecane-1-carboxylate, 5 ml THF, 1 ml of water and 13.2 mg (0.55 mmol) lithium hydroxide were stirred for 2 h at RT. Then the mixture was adjusted to pH7 with a 0.1N hydrochloric acid. The reaction mixture was evaporated to dryness by rotary evaporation.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH:13]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)[OH:14])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:13]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[O:14])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(C(O)c3ccc([N+](=O)[O-])cc3)ccnc2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(C(=O)c3ccc([N+](=O)[O-])cc3)ccnc2c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of (7-methoxyquinolin-4-yl)(4-nitrophenyl)methanol (220 mg, 0.709 mmol) and manganese dioxide (247 mg, 2.84 mmol) in CHCl3(20 mL) was heated to 50° C. After 3 hrs, the mixture was cooled to RT and filtered over a silica plug to afford (7-methoxyquinolin-4-yl)(4-nitrophenyl)methanone as a yellow solid that was advanced without further purification. MS: M+H+=309.1.
Reaction SMILES: C([N:8]1[CH2:27][CH2:26][C:11]2([O:16][C:15]([CH3:18])([CH3:17])[CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:12]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH3:17][C:15]1([CH3:18])[CH2:14][N:13]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:12][C:11]2([CH2:26][CH2:27][NH:8][CH2:9][CH2:10]2)[O:16]1
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)OC2(CCN(Cc3ccccc3)CC2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(C)(C)OC2(CCNCC2)C1
Temperature: 25 °C

Procedure:
A mixture of tert-butyl 9-benzyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (Example 271, step b) (0.8 g) dissolved in ethanol (50 mL) and 10% palladium on carbon (0.5 g) was treated with ammonium formate (0.8 g) and the reaction mixture heated at reflux for 30 minutes. The mixture was cooled to room temperature and filtered through diatomacious earth. The solvent was evaporated and the residue azeotroped with acetonitrile (×2) to afford the subtitled compound. Yield 0.55 g.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[H-].[Na+].[CH2:12](Br)[CH:13]=[CH2:14]>C1COCC1>[CH2:14]([O:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[I:1])[CH:13]=[CH2:12]
Reactant: OCc1ccccc1I
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOCc1ccccc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.7 %

Procedure:
To a THF (200 ml) solution of 2-iodo-benzyl alcohol (25 g, 107 mmol), at r.t., was added the NaH (5.12 g, 128 mmol) in small portions. After complete addition of the NaH the allyl bromide (11.1 ml, 128 mmol) was added via syringe. The mixture was stirred overnight at room temperature. The resulting white heterogeneous mixture was quenched with H2O (100 ml) and diluted with 300 ml of Et2O followed by washing with H2O (2×100 ml) and brine (1×100 ml). The organic layer was dried over MgSO4 and concentrated in vacuo to yield 31 g of 1-[(allyloxy)methyl]-2-iodobenzene as a faint yellow oil. HRMS (ESI+) calcd for C10H11IO m/z 273.9857 (M+H)+. Found 273.9855.
Reaction SMILES: [C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[C:25]([CH2:27][C@@H:28]([OH:35])[CH2:29][C:30](OCC)=[O:31])#[N:26].Cl>O1CCCC1.O1CCCC1.CCCCCCC>[C:25]([CH2:27][C@@H:28]([OH:35])[CH2:29][C:30](=[O:31])[CH2:9][C:8]([N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:10])#[N:26]
Reactant: CCOC(=O)C[C@H](O)CC#N
Reactant: CC(=O)N(c1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: N#CC[C@@H](O)CC(=O)CC(=O)N(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a stirred -10° C. solution of N,N-diphenylacetamide (211 g, 1.0 mol) in tetrahydrofuran (1.0 L) is slowly added a solution of lithium diisopropylamide in tetrahydrofuran-heptane (0.5 L of 2M) while maintaining the temperature between -10° C. to -5° C. The mixture is stirred at -0° C. to 20° C. for 30 minutes. (R)-4-cyano-3-hydroxybutyric acid, ethyl ester (Brower, supra) (40 g, 0.25 mol) as a solution in 200 mL of tetrahydrofuran is added to the previously prepared anion. The reaction mixture is stirred for 30 minutes at -5° C. to -20° C., and transferred to a 2.2N aqueous hydrochloric acid solution (1L). The aqueous layer is extracted with 500 mL of ethyl acetate, the aqueous layer is separated and reextracted with 100 mL of ethyl acetate, the extracts are combined and concentrated in vacuo to afford crude (R)-6-cyano- 5-hydroxy-3-oxo-N,N-diphenylhexanamide which is not isolated. A small sample is purified by column chromatography on flash silica gel (60:40 hexane:ethyl acetate) as an oil.
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21][C:5]=3[N:6]([CH2:11][C:12]([NH:14][C:15]3[S:16][CH:17]=[C:18]([CH3:20])[N:19]=3)=[O:13])[C:7]=2[CH:8]=[CH:9][CH:10]=1.C(C(O)=O)(F)(F)F>C(Cl)Cl>[Br:1][C:2]1[C:3]2[C:4]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21][C:5]=3[N:6]([CH2:11][C:12]([NH:14][C:15]3[S:16][CH:17]=[C:18]([CH3:20])[N:19]=3)=[O:13])[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: Cc1csc(NC(=O)Cn2c3c(c4c(Br)cccc42)CCN(C(=O)OC(C)(C)C)CC3)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1csc(NC(=O)Cn2c3c(c4c(Br)cccc42)CCNCC3)n1
Temperature: 25 °C
Reaction time: 46 h
Yield: 28 %

Procedure:
tert-Butyl 10-bromo-6-{2-[(4-methyl-1,3-thiazol-2-yl)amino]-2-oxoethyl}-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.13 g, 0.24 mmol) was dissolved in CH2Cl2 (5 mL). CF3CO2H (0.5 mL, 0.74 g, 6.5 mmol) was added. The reaction mixture was stirred at rt under N2 for 46 h. The reaction mixture was partitioned between 1N NaOH (60 mL) and EtOAc (350 mL). The aqueous layer was back extracted with EtOAc (100 mL). The combined organic layers were washed with brine (25 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was flash chromatographed (10% CH3OH/CH2Cl2 containing 0.05% 7N NH3/CH3OH) and 2-(10-bromo-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(4-methyl-1,3-thiazol-2-yl)acetamide was obtained in 28% yield. 1H NMR (400 MHz, CD3OD) δ 2.33, 3.02-3.09, 3.14-3.21, 3.55-3.63, 5.16, 6.67, 6.97, 7.21, 7.30; MS (ESI+) for C18H19BrN4OS m/z 420.8 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH3:21])[CH2:3][NH:4][S:5]([C:8]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:9]=1[C:10]([O:12]C)=O)(=[O:7])=[O:6].C[O-].[Na+].[CH3:25][NH:26][CH3:27]>CO>[CH3:25][N:26]([CH3:27])[C:10](=[O:12])[C:9]1[C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=[CH:17][C:8]=1[S:5]([NH:4][CH2:3][CH:2]([OH:1])[CH3:21])(=[O:6])=[O:7]
Reactant: CNC
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCC(C)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(O)CNS(=O)(=O)c1cccc([N+](=O)[O-])c1C(=O)N(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.9 %

Procedure:
Methyl 2-[N-(2-hydroxy-1-propyl)aminosulfonyl]-6-nitrobenzoate (2.00g, 628 mmol) was dissolved in 60 ml of methanol. Sodium methoxide (1.0 ml of a 0.1 M solution in methanol) was added and the solution cooled and stirred in an ice-bath while a rapid stream of dimethylamine was passed into the vortex for 15 minutes. Stirring in the ice-bath then was continued for 1 hour, when the flash was removed from the bath and the reaction mixture allowed to stand at room temperature overnight. The methanol and excess dimethylamine then were evaporated under reduced pressure and the residue shaken with ethyl acetate, 80 ml; 0.2N HCl, 10 ml; and saturated NaCl, 10 ml. The ethyl acetate layer was separated, extracted with 3×15 ml of saturated NaCl and evaporated to give a clear yellow oil. After drying 23 hours in vacuo, this product weight 2.03 g. Crystallization had started after 3 days. Recrystallization from a mixture of ethyl acetate and hexane gave 1.33 g (63.9%) of product, m.p., 95.5°-97°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[CH2:19][O:20][CH2:21][C:22](O)=[O:23])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.[N:26]1([CH2:31][CH2:32][O:33][C:34]2([C:47]3[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=3)[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][CH2:35]2)[CH:30]=[CH:29][N:28]=[CH:27]1>>[N:26]1([CH2:31][CH2:32][O:33][C:34]2([C:47]3[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=3)[CH2:39][CH2:38][N:37]([C:22](=[O:23])[CH2:21][O:20][CH2:19][C@@H:14]3[CH2:15][CH2:16][CH2:17][CH2:18][N:13]3[S:10]([C:6]3[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH3:25])(=[O:11])=[O:12])[CH2:36][CH2:35]2)[CH:30]=[CH:29][N:28]=[CH:27]1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCC[C@H]2COCC(=O)O)c(C)c1
Reactant: CC(C)(C)OC(=O)N1CCC(OCCn2ccnc2)(c2cccnc2)CC1
Product: COc1cc(C)c(S(=O)(=O)N2CCCC[C@H]2COCC(=O)N2CCC(OCCn3ccnc3)(c3cccnc3)CC2)c(C)c1
Yield: 60 %

Procedure:
The desired target compound was synthesized under reaction conditions analogously to the process described for Example 61 (see below) from (S)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid [acid D] and tert-butyl 4-(2-(1H-imidazol-1-yl)ethoxy)-4-(pyridin-3-yl)piperidine-1-carboxylate [amine F]. Yield: 60%. MS, Rt=2.7 min, m/z=626.4 [MH]+
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[CH:5]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[C:29]([N:33]=[C:34]=[O:35])([CH3:32])([CH3:31])[CH3:30]>C(Cl)Cl>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[CH:5]([O:14][CH:15]1[CH2:18][N:17]([C:34]([NH:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH2:16]1)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1
Reactant: CC(C)(C)N=C=O
Reactant: COc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: COc1ccc(C(OC2CN(C(=O)NC(C)(C)C)C2)c2ccccc2C(F)(F)F)cc1
Yield: 68.7 %

Procedure:
To a solution of 3-[2-(trifluoromethyl)-4′-methoxybenzhydryloxy]azetidine (157) (100 mg, 0.30 mmol) in anhydrous DCM (4 mL) was added MP-carbonate (3.01 mmol/g; 100 mg, 0.30 mmol) and tert-butyl isocyanate (35 μL, 0.30 mmol). The resultant mixture was shaken at ambient temperature for 5 h, after which time it was poured onto a DCM-wetted SCX-2 (1 g) cartridge. The sample was eluted with DCM (6 mL) followed by DCM-MeOH (6 mL), then evaporated. Purification by flash column chromatography [SiO2; ethyl acetate-iso-hexane (35:65→50:50)] afforded the desired product as a colourless glass (90 mg, 70%).
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:20]=[CH:19][C:11]([CH2:12][C@@H:13]([C:15]([O:17]C)=[O:16])[NH2:14])=[CH:10][CH:9]=2)[N:7]=1)[CH3:2].[OH-].[Na+].Cl>CO>[CH2:1]([C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][C@@H:13]([C:15]([OH:17])=[O:16])[NH2:14])=[CH:19][CH:20]=2)[N:7]=1)[CH3:2]
Reactant: CCc1nc(-c2ccc(C[C@H](N)C(=O)OC)cc2)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1nc(-c2ccc(C[C@H](N)C(=O)O)cc2)cs1
Reaction time: 8 h
Yield: 136.5 %

Procedure:
N-(N-(BOC)-3-phenylsulfonyl)-nipecotyl)-(L)-4-(2-ethyl-4-thiazolyl)-phenylalanine, methyl ester (60 mg, 0.0925 mmol) was dissolved in 2.5 mL of MeOH and treated with 280 μL of 0.5 N NaOH. The reaction mixture was stirred overnight, acidified to pH=2-3 with 1.2 N HCl, and concentrated under vacuo to give a white solid. This solid was purified by preparative TLC on silica gel eluted with CH2Cl2:MeOH:AcOH (v/v/v 95:5:0.5) to afford N-(N-(BOC)-3-phenylsulfonyl)-nipecotyl)-(L)-4-(2-ethyl-4-thiazolyl)phenylalanine (34.9 mg).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:27])[C@@H:6]([O:24][CH2:25][CH3:26])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)=[CH:10][CH:9]=1)[CH3:3].C(N(CC)CC)C.[CH2:35]([O:42][C:43](Cl)=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O1CCCC1>[CH2:2]([O:4][C:5](=[O:27])[C@@H:6]([O:24][CH2:25][CH3:26])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:43]([O:42][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:44])=[CH:21][CH:22]=2)=[CH:10][CH:9]=1)[CH3:3]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(N)cc2)cc1)OCC
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(NC(=O)OCc3ccccc3)cc2)cc1)OCC
Temperature: 25 °C
Yield: 22 %

Procedure:
3-{4-[2-(4-Aminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid ethyl ester hydro chloride (described in Example 41b) (0.6 g; 1.67 mmole, triethylamine (0.17 g; 1.67 mmole) and benzylchloroformate (0.28 g; 1.67 mmole) were mixed in tetrahydrofuran. The reaction mixture was stirred at room temperature over night and then evaporated. The residue was treated with sodium hydrogencarbonate solution and diethyl ether. The organic phase was dried with magnesium sulfate and evaporated. According to NMR spectra there was starting material left. The residue was therefore dissolved in tetrahydrofuran and triethylamine and benzylchloroformate were added. The reaction mixture was stirred at room temperature then evaporated. Work-up up as described above gave a crude product which was purification with preparativ HPLC (Kromasil C8, 7 μm, 50×250 mm) using acetronitrile (70-100%) in ammonium acetate buffer (pH 7) as mobil phase gave 0.180 g (22% yield) of 3-[4-{2-(4-[Benzyloxycarbonylamino]phenyl)ethoxy}phenyl]-(S)-2-ethoxypropanoic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][CH2:11][CH2:10][NH:9][CH2:8][C:7]=2[CH:13]=1.[C:14](Cl)(=[O:17])[CH:15]=[CH2:16]>C(N(CC)CC)C>[C:14]([N:9]1[CH2:8][C:7]2[CH:13]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[S:12][CH2:11][CH2:10]1)(=[O:17])[CH:15]=[CH2:16]
Reactant: COc1ccc2c(c1)CNCCS2
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CCSc2ccc(OC)cc2C1
Yield: 83 %

Procedure:
7-Methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (10.0 g) (refer to preparation examples 1 to 6 as mentioned below), triethylamine (10.2 g) and acryloyl chloride (6.9 g) were reacted in the same manner as in Experimental Example 1 to give 4-acryloyl-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (10.6 g).
Reaction SMILES: [F:1][CH:2]([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:14]([CH3:16])[CH3:15])[C:11](O)=[O:12])=[CH:6][CH:5]=1.S(Cl)([Cl:20])=O>>[F:1][CH:2]([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([Cl:20])=[O:12])=[CH:6][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)C(C(=O)O)c1ccc(OC(F)F)cc1
Product: CC(C)C(C(=O)Cl)c1ccc(OC(F)F)cc1

Procedure:
20 g of 4-difluoromethoxy-α-isopropyl-phenylacetic acid were dissolved in 100 ml of thionyl chloride and the solution was heated to the boil for 1 hour. After distilling off excess thionyl chloride, the residue was distilled under a high vacuum. 4-Difluoromethoxy-α-isopropyl-phenylacetic acid chloride of boiling point 93°-99° C./0.2 mm Hg was obtained.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:15]=[C:14]([Cl:16])[C:11]([C:12]#[N:13])=[C:10]([Cl:17])[CH:9]=2)[N:3]=1.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1.C(O)(=O)C.Cl>CO>[Cl:17][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[N:3]=[C:2]([NH:1][CH2:24][C:23]3[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:28])[F:29])=[CH:27][CH:26]=3)[NH:6][N:5]=2)[CH:15]=[C:14]([Cl:16])[C:11]=1[C:12]#[N:13]
Reactant: N#Cc1c(Cl)cc(Nc2n[nH]c(N)n2)cc1Cl
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: N#Cc1c(Cl)cc(Nc2n[nH]c(NCc3ccc(C(F)(F)F)cc3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.7 %

Procedure:
To a solution of 4-(5-Amino-1H-[1,2,4]triazol-3-ylamino)-2,6-dichloro-benzonitrile (60 mg, 223 μmol) in MeOH (3.5 ml) was added 4-(trifluoromethyl)benzaldehyde (46.6 mg, 268 μmol, Aldrich) followed by acetic acid (36.7 mg, 35 μl, 611 μmol). The reaction was stirred at room temperature for 15 minutes, 2-picoline borane complex (32.2 mg, 349 μmol) was added and the stirring was continued for 4 days. The reaction mixture was poured into 0.1N HCl solution (20 ml) and extracted with EtOAc (3×20 ml). The combined organic solution was washed with brine, dried and concentrated in vacuo. Crystallization from DCM afforded a white solid as desired product (55 mg, 57% yield). MS +m/z: 427 (M+H)+