Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.[CH2:36]([NH:38][CH3:39])[CH3:37].O>C1COCC1>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:26]2[S:27][CH:28]=[C:24]([CH2:23][S:22][C:4]3[C:5]([C:20]#[N:21])=[C:6]([C:10]4[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=4)[C:7]([C:8]#[N:9])=[C:2]([N:38]([CH2:36][CH3:37])[CH3:39])[N:3]=3)[N:25]=2)=[CH:34][CH:33]=1
Reactant: CCNC
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCN(C)c1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N

Procedure:
At RT, 60 mg (0.11 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 0.019 ml (0.22 mmol) of N-ethylmethylamine were stirred in 1.5 ml of THF for 30 min. About 15 ml of water were added to the reaction mixture, and the aqueous phase was extracted 3× with ethyl acetate. The combined organic phases were washed once with sodium chloride solution, dried over sodium sulfate, concentrated by evaporation and dried under high vacuum. This gave 63 mg (99% of theory) of the desired target compound.
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7]([CH2:17][N:18]([CH:28]([CH3:30])[CH3:29])[S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)(=[O:21])=[O:20])[CH:8]=[C:9]2[C:14]=1[O:13][C:12]([CH3:16])([CH3:15])[CH:11]=[CH:10]2.O>O1CCCC1.Cl>[OH:4][C:5]1[CH:6]=[C:7]([CH2:17][N:18]([CH:28]([CH3:30])[CH3:29])[S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)(=[O:21])=[O:20])[CH:8]=[C:9]2[C:14]=1[O:13][C:12]([CH3:15])([CH3:16])[CH:11]=[CH:10]2
Reactant: COCOc1cc(CN(C(C)C)S(=O)(=O)c2ccccn2)cc2c1OC(C)(C)C=C2
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N(Cc1cc(O)c2c(c1)C=CC(C)(C)O2)S(=O)(=O)c1ccccn1
Reaction time: 3 h

Procedure:
N-[(8-Methoxymethoxy-2,2-dimethyl-2H-chromen-6-yl)methyl]-N-(propan-2-yl)pyridine-2-sulfonamide (31 mg, 0.07 mmol) was dissolved in a cosolvent of tetrahydrofuran (1 mL) and 6 N aqueous HCl (1 mL), and the reaction stirred for 3 h. Ten milliliters of water was added to the reaction mixture, and then tetrahydrofuran was evaporated. The remaining aqueous phase was extracted by methylene chloride (10 mL×3), washed with brine, dried with anhydrous magnesium sulfate, and concentrated in vacuo. 6h (19 mg, 49%) was purified by silica gel chromatography with ethyl acetate/hexane (1/1). 1H NMR (CDCl3): δ 0.77 (d, J=6.45 Hz, 6H), 1.44 (s, 6H), 1.72-1.79 (m, 1H), 3.11 (d, J=7.62 Hz, 2H), 4.39 (s, 2H), 5.61 (d, J=9.67 Hz, 1H), 6.25 (d, J=9.96 Hz, 1H), 6.50 (d, J=1.76 Hz, 1H), 6.65 (d, J=1.76 Hz, 1H), 7.43-7.47 (m, 1H), 7.84-7.97 (m, 2H), 8.69 (d, J=4.40 Hz, 1H). HRMS (m/z): [M+Na]+ calcd 425.15055, found 425.15091. HPLC-1: flow rate 2 mL/min, tR=2.9 min, purity=100%; flow rate 1 mL/min, tR=5.6 min, purity=100%. HPLC-2: tR=5.172 min, purity=100%.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])=O.[CH2:13]([O:15][CH:16]([O:25][CH2:26][CH3:27])[C:17](=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:14].C(O)(=O)C.N1CCCCC1>C1C=CC=CC=1>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][CH:11]=[CH:12][C:3]=1[CH:1]=[C:18]([C:17]([CH:16]([O:15][CH2:13][CH3:14])[O:25][CH2:26][CH3:27])=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:6]
Reactant: COC(=O)c1ccccc1C=O
Reactant: CCOC(=O)CC(=O)C(OCC)OCC
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)C(=Cc1ccccc1C(=O)OC)C(=O)C(OCC)OCC
Yield: 116.3 %

Procedure:
To a mixture of methyl 2-formylbenzoate (4.92 g), ethyl 4,4-diethoxyacetoacetate (7.2 g) and acetic acid (0.36 g) in benzene (15 ml) was added portionwise each one third portion of a solution of piperidine (306 mg) in benzene (5 ml) for each 20 minutes' interval, and the mixture was heated to reflux for 3 hours under removing off azeotropically the resulting water. After cooling, the reaction mixture was diluted with additional benzene (25 ml), washed three times with water and successively with diluted aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give reddish oil (12.7 g) of crude ethyl 2-(2-methoxycarbonylbenzyliden)-4,4-diethoxyacetoacetate which was used in the following reaction without any further purification.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]2[N:6]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[O:19][C:18](=[O:20])[N:17]([CH3:21])[N:16]=3)=[N:8][C:4]=2[CH:3]=1.[NH2:28][C:29]1[N:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:28][C:29]1[N:34]=[CH:33][C:32]([C:2]2[CH:27]=[CH:26][C:5]3[N:6]([C:22]([CH3:23])([CH3:25])[CH3:24])[C:7]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[C:15]4[O:19][C:18](=[O:20])[N:17]([CH3:21])[N:16]=4)=[N:8][C:4]=3[CH:3]=2)=[CH:31][N:30]=1
Reactant: Cn1nc(-c2ccccc2-c2nc3cc(Br)ccc3n2C(C)(C)C)oc1=O
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1nc(-c2ccccc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)oc1=O
Temperature: 110 °C
Yield: 25.3 %

Procedure:
To a sealed vial is added 5-[2-(5-bromo-1-tert-butyl-1H-benzimidazol-2-yl)-phenyl]-3-methyl-3H-[1,3,4]oxadiazol-2-one (92 mg, 0.215 mmol) in DMF (3 mL), followed by the addition of 2-aminopyrimidine-5-boronic acid pinacol ester (57 mg, 0.258 mmol), tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.022 mmol) and 2M aq. Na2CO3 (0.45 ml, 0.9 mmol). The reaction mixture is heated under Argon at 110° C. for 3 hours. The residue is diluted with EtOAc (20 mL), washed with brine, dried under anhydrous Na2SO4, filtered and concentrated. The residue is purified by silica gel flash column chromatography with 0-4% 7M NH3 in MeOH/CH2Cl2 as the eluent to afford the title compound (24 mg, 25%) as a off-white solid. LCMS (ESMS): m/z 442.43 (M++1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:38][N:39](C1CC1)[CH2:40][CH2:41][CH2:42][CH:43]=[CH2:44])[C:10]([N:12]1[CH2:16][C@H:15]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:14][C@H:13]1[C:25]([NH:27][C@:28]1([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:30][C@H:29]1C=C)=[O:26])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:10](=[O:11])[N:12]2[C@@H:13]([CH2:14][C@@H:15]([O:17][Si:18]([C:21]([CH3:23])([CH3:22])[CH3:24])([CH3:19])[CH3:20])[CH2:16]2)[C:25](=[O:26])[NH:27][C@@:28]2([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C@@H:30]([CH2:29]2)[CH:44]=[CH:43][CH2:42][CH2:41][CH2:40][NH:39][CH2:38]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C=CCCCN(C[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C)C1CC1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2)c(C)c1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCNC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)N2
Solvent: ClCCl
Product: CCOC(=O)[C@@]12C[C@H]1C=CCCCNC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 1(R)-[1-[2(S)-(tert-butoxycarbonylamino)-3-[N-cyclopropyl-N-(pent-4-enyl)amino]propanoyl]-4(R)-(tert-butyldimethylsilyloxy)pyrrolidine-2(S)-carboxamido]-2(S)-vinylcyclopropanecarboxylate (1.45 g, 2.14 mmoL) in 1 L of methylene chloride was added 181 mg (0.21 mmoL) of Grubb's 2nd generation catalyst [(1,3-Bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium]. The mixture was heated at reflux for 1 h. A second fraction of the catalyst (50 mg, 0.058 mmol) was added, and the mixture was stirred at rt overnight. The residue was concentrated in vacuo, and then purified by flash chromatography eluting with 50% ether/hexane to give 0.84 g (62%) of (1S,4R,6S,14S,18R)-7-cis-14-tert-Butoxycarbonylamino-18-(tert-butyldimethylsilyloxy)-2,15-dioxo-3,12,16-triazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid, ethyl ester as a white solid: LC-MS (Phenomenex 10 μm C18HPLC column: 3.0×50 mm length. Gradient: 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B. Gradient time: 2 min. Hold time: 1 min. Flow rate: 5 mL/min. Detector Wavelength: 220 nM. Solvent A: 10% MeOH/90% H2O/0.1% TFA. Solvent B: 10% H2O/90% MeOH/0.1% TFA.) (Retention time: 2.43 min), MS m/z 649 (M++1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH3:18]O>O>[CH3:18][O:11][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CO
Reactant: O=C(O)CCCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)CCCc1ccccc1
Temperature: 49 °C
Yield: 90 %

Procedure:
1800 g (10.98 moles) of 4-phenylbutyric acid, crystalline in a glass bottle was heated with a heating blanket for 2 h to melt the acid. The liquid was poured in 8 L of methanol in a 22 L reaction flask (3-necked round-bottom flask fitted with stirrer and thermometer adapters). The solution was stirred under Argon, temperature 20° C.-33° C., and 400 mL concentrated sulfuric acid was added in 50 mL portions. The temperature increased to 49° C. The solution was stirred under argon over the week-end and allowed to cool to ambient temperature. The solution was transferred to a quench tank and diluted with 8 L of water. The oil formed was separated and the aqueous phase was extracted with 2×1 L of ethyl acetate. The extracts were combined with the oil and the solution concentrated to give 1753 g of clear oil in 90% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:13]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:12][N:11]([C:19]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]([C:29]4([CH3:32])[CH2:31][CH2:30]4)=[O:28])[CH2:23][CH2:22]3)=[O:20])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:34]([O:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)=[O:35]>>[F:43][C:40]1[CH:41]=[CH:42][C:37]([O:36][C:34](=[O:35])[N:14]([C@H:13]2[C@H:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10][N:11]([C:19]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]([C:29]4([CH3:32])[CH2:30][CH2:31]4)=[O:28])[CH2:23][CH2:22]3)=[O:20])[CH2:12]2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:38][CH:39]=1
Reactant: CC(C)CN[C@@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)Oc1ccc(F)cc1
Product: CC(C)CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 1 (step h), the title compound rac-{(3S,4R)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-isobutyl-carbamic acid 4-fluoro-phenyl ester was prepared from rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-isobutylamino-pyrrolidin-1-yl]-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone instead of rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using 4-fluorophenyl chloroformate and was obtained as a colorless foam. MS m/e: 618.5 [M]+.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:6]2([CH3:7])[C@@H:5]1[OH:24])[C:18]1[CH:17]=[CH:16][C:15]([O:22][CH3:23])=[CH:14][C:13]=1[CH2:12][CH2:11]3)=[N+]=[N-].O.NN>[Ni].CO>[NH2:1][C@@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:6]2([CH3:7])[C@@H:5]1[OH:24])[C:18]1[CH:17]=[CH:16][C:15]([O:22][CH3:23])=[CH:14][C:13]=1[CH2:12][CH2:11]3
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@H](O)[C@H](N=[N+]=[N-])C[C@@H]12
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@H](O)[C@H](N)C[C@@H]12

Procedure:
2.0 g 16α-azido-3-methoxy-estra-1,3,5(10)-triene-17α-ol are reduced with 40 ml methanol, 4 ml of 80% hydrazine hydrate and 2 spatula tips Raney nickel in the above described manner. Recrystallization is performed from methanol/ether. Yield: 1.3 g (71%), F: at 145° C. conversion, at 193-198° C. melting; [α]D+44° (pyridine);
Reaction SMILES: [CH2:1]([N:8]([CH2:13][CH:14]([CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([F:24])[CH:18]=1)[OH:16])[C:9](=[O:12])[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH:14]([CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([F:24])[CH:18]=2)[O:16][CH2:10][C:9]1=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(CN(Cc1ccccc1)C(=O)CCl)C(O)c1ccc(Cl)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC1CN(Cc2ccccc2)C(=O)COC1c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
To a solution of N-benzyl-N-[(2RS,3SR)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-(4-chloro-3-fluorophenyl)-3-hydroxypropyl]-2-chloroacetamide (34.5 g) in THF (1340 mL) was added 1 N aqueous sodium hydroxide solution (80.0 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (31.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:29]=[CH:30][C:31]=2[CH3:32])[CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[C:28]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:29]=[CH:30][C:31]=4[CH3:32])[CH2:22][CH2:21]3)=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCC1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C2(c3ccc(Cl)cc3)CCCC2)CC1

Procedure:
Example 81 was prepared from 1-(4-chlorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.44 (d, 1H, J=2.0 Hz), 7.37–7.34 (m, 2H), 7.31–7.25 (m, 4H), 7.09 (d, 1H, J=8.0 Hz), 6.50 (brs, 1H), 3.29 (dd, 2H, J=6.4, 12.0 Hz), 2.92 (d, 2H, J=11.6 Hz), 2.66 (m, 1H), 2.54–2.48 (m, 3H), 2.33–2.29 (m, 5H), 2.03–1.94 (m, 4H), 1.83–1.59 (m, 10H), 1.26 (d, 6H, J=6.8 Hz); ESMS m/e: 524.3 (M+H)+.
Reaction SMILES: C1C2C(COC([NH:18][CH2:19][C:20]([CH3:69])([CH3:68])[C:21]([NH:23][C@H:24]([C:28]([N:30]([CH3:67])[C@@H:31]([C@@H:63]([CH3:66])[CH2:64][CH3:65])[C@H:32]([O:61][CH3:62])[CH2:33][C:34]([N:36]3[CH2:40][CH2:39][CH2:38][C@H:37]3[C@H:41]([O:59][CH3:60])[C@@H:42]([CH3:58])[C:43]([NH:45][C@H:46]([C:54]([O:56][CH3:57])=[O:55])[CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:44])=[O:35])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])=O)C3C(=CC=CC=3)C=2C=CC=1.C1COCC1.C(NCC)C>>[NH2:18][CH2:19][C:20]([CH3:69])([CH3:68])[C:21]([NH:23][C@H:24]([C:28]([N:30]([CH3:67])[C@@H:31]([C@@H:63]([CH3:66])[CH2:64][CH3:65])[C@H:32]([O:61][CH3:62])[CH2:33][C:34]([N:36]1[CH2:40][CH2:39][CH2:38][C@H:37]1[C@H:41]([O:59][CH3:60])[C@@H:42]([CH3:58])[C:43]([NH:45][C@H:46]([C:54]([O:56][CH3:57])=[O:55])[CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)=[O:44])=[O:35])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)CNC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: CCNCC
Solvent: C1CCOC1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)CN)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.1 %

Procedure:
To a stirring solution of #125 (235 mg, 0.246 mmol, 1.00 eq.) in 2 mL of THF, (1 mL, 10 mM, 40.6 eq.) of diethylamine was added. The reaction was allowed to stir at room temperature for 3 hours. Reaction was concentrated in vacuo and the residue was purified by silica chromatography (Gradient: 0%-30% methanol in ethyl acetate) producing #126 (101 mg, 56%) as a white solid. LC-MS (Protocol Q): m/z 732.2 [M+H+] retention time=1.32 minutes. 1H NMR (400 MHz, DMSO-d6), δ 8.51 (dd), 8.28 (d), 7.15-7.29 (m), 5.77 (s), 4.55-4.77 (m), 4.44-4.54 (m), 3.94-4.10 (m), 3.73-3.79 (m), 3.66 (d), 3.49-3.60 (m), 3.40-3.48 (m), 3.10-3.36 (m), 3.00-3.09 (m), 2.83-2.98 (m), 2.57-2.77 (m), 2.19-2.46 (m), 1.87-2.14 (m), 1.61-1.86 (m), 1.36-1.55 (m), 1.23-1.36 (m), 1.12-1.22 (m), 0.97-1.11 (m), 0.82-0.96 (m), 0.73-0.81 (m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:33]2[CH:38]=[CH:37][C:36]([C:39](O)=[O:40])=[CH:35][CH:34]=2)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)[C:10]1=[O:31].Cl.[F:43][C:44]([F:52])([F:51])[CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:33]2[CH:34]=[CH:35][C:36]([C:39]([N:48]3[CH2:49][CH2:50][CH:45]([C:44]([F:52])([F:51])[F:43])[CH2:46][CH2:47]3)=[O:40])=[CH:37][CH:38]=2)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][Si:21]([CH:22]([CH3:23])[CH3:24])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:26])[CH3:27])[CH2:16][CH2:15]2)[C:10]1=[O:31]
Reactant: FC(F)(F)C1CCNCC1
Reactant: CC(C)[Si](O[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)O)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Agent: Cl
Product: CC(C)[Si](O[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)N5CCC(C(F)(F)F)CC5)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C

Procedure:
Prepare the title compound in a 51% yield by coupling procedure 1 starting from 3′,5′-dichloro-4′-[(R)-2-oxo-trans-1-(4-triisopropylsilanyloxy-cyclohexyl)-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylic acid and 4-trifluoromethyl-piperidine hydrochloride.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]#[N:29])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>CN(C)C=O.C(OCC)(=O)C>[CH2:3]([O:10][C:11]([N:13]1[CH2:14][CH2:15][CH:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]#[N:29])[CH:26]=3)[N:21]([S:31]([CH3:30])(=[O:33])=[O:32])[CH:20]=2)[CH2:17][CH2:18]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N#Cc1ccc2[nH]cc(C3CCN(C(=O)OCc4ccccc4)CC3)c2c1
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)n1cc(C2CCN(C(=O)OCc3ccccc3)CC2)c2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
Sodium hydride (115 mg, 4.8 mmol) was added to a solution of 1-benzyloxycarbonyl-4-(5-cyanoindol-3-yl)piperidine (1.5 g, 4.17 mmol) [prepared as described in Step 1 above] in dimethylformamide (12 ml) at 0° C. After 30 min., methanesulfonyl chloride (0.81 ml, 10.43 mmol) was added and after stirring for 2.5 h the reaction mixture was allowed to warm to RT over 1 h. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with water, brine and dried over MgSO4. The organics were evaporated in vacuo and the residue was chromatographed (PTLC, SiO2, 40% ethyl acetate/hexanes) to give 1-benzyloxycarbonyl-4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine (54%) as a pale yellow oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C@H:11]([OH:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.ClCCl.C(=O)(O)[O-].[Na+]>FC(F)(F)S(O)(=O)=O.C1CCCCC1>[CH2:28]([O:23][C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCCCCCCCCCC[C@@H](O)CCO[Si](C)(C)C(C)(C)C
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CCCCCCCCCCC[C@H](CCO[Si](C)(C)C(C)(C)C)OCc1ccccc1
Yield: 88.6 %

Procedure:
Trifluoromethanesulphonic acid (0.14 mL, 1.6 mmol) was added to a mixture of alcohol 10 (6.9 g, 20 mmol) and benzyl trichloroacetimidate (12.3 g, 49 mmol) in a 1:1 mixture of dichloromethane and cyclohexane (320 mL) at room temperature. After completion of the reaction (5 h) a saturated solution of sodium bicarbonate (50 mL) was added and the phases were separated. The aqueous phase was extracted with ethyl acetate (2×50 mL) and the organic phases were washed with brine (50 mL), dried (MgSO4), and concentrated in vacuo. The product was purified by flash chromatography to afford compound 45 as an oil (Rf 0.18, silica, 2% ethyl acetate in hexane, 7.7 g, 88%).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH:24]1[O:28][CH2:27][CH2:26][O:25]1.C(=O)([O-])[O-].[K+].[K+]>>[O:25]1[CH2:26][CH2:27][O:28][CH:24]1[CH2:23][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH:2]2[OH:1])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: BrCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCC3OCCO3)cc2)C(O)C1

Procedure:
In an analogous manner to the procedure described in Example 14, by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-(4-hydroxy-phenyl)-piperidine-1-carboxylate with 2-bromomethyl-1,3-dioxolane in the presence of potassium carbonate there was obtained tert-butyl (3RS,4RS)-4-[4-([1,3]dioxolan-2-ylmethoxy)-phenyl]-3-hydroxy-piperidine-1-carboxylate as a colourless solid; m.p.: 136-137° C. (hexane).