Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:33])[C:21]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([CH3:25])[CH2:22][CH2:23][CH3:24])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:51])[C@@H:15]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si](C(C)(C)C)(C)C)[CH2:37]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:33])[C:21]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([CH3:25])[CH2:22][CH2:23][CH3:24])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:51])[C@@H:15]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([OH:43])[CH2:37]2)=[CH:10]1
Reactant: CCCC(C)(Oc1ccccc1)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCC(C)(Oc1ccccc1)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Yield: 49.7 %

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 0.32 g of (4R,6R)-6-([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-[(2RS)-2-phenoxy-2-methylvaleryloxy]-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 88, above] and 6.48 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 0.11 g of the title compound as white crystals, melting at between 151° and 153° C.
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[C:18]([N+:19]([O-])=O)=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=2[S:22](O)=O)=[CH:5][CH:4]=1.[N+](C1C(SC2C=CC=CC=2)=C(S(O)=O)C=C(C=1)C(O)=O)([O-])=O>>[NH2:19][C:18]1[C:10]([S:9][C:6]2[CH:7]=[CH:8][C:3]([CH3:2])=[CH:4][CH:5]=2)=[C:11]([SH:22])[CH:12]=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15]
Reactant: Cc1ccc(Sc2c([N+](=O)[O-])cc(C(=O)O)cc2S(=O)O)cc1
Agent: O=C(O)c1cc([N+](=O)[O-])c(Sc2ccccc2)c(S(=O)O)c1
Agent: [Na]
Product: Cc1ccc(Sc2c(N)cc(C(=O)O)cc2S)cc1

Procedure:
By replacing in Example 11, step B, the mono sodium salt of 4-(p-methylphenylthio)-5-nitro-3-sulfinobenzoic acid for the mono sodium salt of 5-nitro-4-phenylthio3-sulfinobenzoic acid and following the procedure described, 5-amino-3-mercapto-4-(p-methylphenylthio)benzoic acid is obtained with a melting poinr of 178° - 182°C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:14][C@H:15]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[Cl:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH:14][C@H:15]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:25]=[C:26]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:28][CH:29]=3)[CH2:20][CH2:19]2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NS(=O)(=O)c3cc(Cl)cc(Cl)c3O)c3ccccc3)CC2)c1

Procedure:
Prepared Procedure Q1 and Scheme AC using 3,5-dichloro-2-hydroxybenzenesulfonyl chloride and N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 605.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[CH:4]=[N:5][OH:6].ClN1C(=O)CCC1=O.[CH:20]1([C:24](=O)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:23][CH2:22][CH2:21]1.[O-]CC.[Na+]>CN(C)C=O.C1COCC1.O>[CH:20]1([C:24]2[O:6][N:5]=[C:4]([C:3]3[C:2]([Cl:1])=[CH:10][CH:9]=[CH:8][C:7]=3[Cl:11])[C:25]=2[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:21][CH2:22][CH2:23]1
Reactant: ON=Cc1c(Cl)cccc1Cl
Reactant: CCOC(=O)CC(=O)C1CCC1
Agent: CC[O-]
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2c(Cl)cccc2Cl)noc1C1CCC1
Yield: 38.5 %

Procedure:
To a water bath-cooled solution of 2,6-dichlorobenzaldehyde oxime (2.20 g, 11.6 mmol) in N,N-dimethylformamide (7 mL) was added solid N-chlorosuccinimide (1.55 g, 11.6 mmol). The solution was stirred while in the water bath for approximately 20 min and outside the bath for approximately 1 hr. The solution was poured into water and extracted twice with ether. The combined organic layers containing the crude imidoyl chloride were dried over magnesium sulfate and then concentrated. To a separate solution of ethyl 3-cyclobutyl-3-oxopropanoate (2.37 g, 13.9 mmol) in THF (3 mL) at 0° C. was added sodium ethoxide (25 wt % in ethanol, 4.36 mL, 13.9 mmol). The solution was stirred for a few minutes and then the above imidoyl chloride was added. The solution was stirred at 0° C. for 10 minutes and then at ambient temperature overnight. The solution was poured into water and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, concentrated and purified by chromatography (silica gel, 0-5% ethyl acetate in hexanes gradient elution) to afford ethyl 5-cyclobutyl-3-(2,6-dichlorophenyl)-4-isoxazolecarboxylate (1.52 g, 38%). 1H-NMR (400 MHz, DMSO-d6) δ 7.63-7.53 (m, 3H), 4.29-4.20 (m, 1H), 4.02 (q, J=7 Hz, 2H), 2.43-2.36 (m, 4H), 2.15-2.06 (m, 1H), 1.97-1.89 (m, 1H), 0.94 (t, J=7 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[N:14]([C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:16])[C:13]([O:27]C)=[N:12][C:11]([CH3:29])=[C:10]2[C:30]([O:32][CH3:33])=[O:31])[CH:5]=[CH:6][C:7]=1[F:8].[Br:34]Br>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[N:14]([C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:16])[C:13](=[O:27])[NH:12][C:11]([CH2:29][Br:34])=[C:10]2[C:30]([O:32][CH3:33])=[O:31])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)C1=C(C)N=C(OC)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1c1ccc(F)c(F)c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COC(=O)C1=C(CBr)NC(=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1c1ccc(F)c(F)c1
Reaction time: 1.5 h
Yield: 102.6 %

Procedure:
To a well stirred solution of (+)-6-(3,4-difluorophenyl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-[(4-nitrophenyloxy)carbonyl]pyrimidine (1.5 mmol, 0.66 g) in 5 mL of chloroform was added a solution of bromine (1.5 mmol, 0.09 mL) in 3 mL of chloroform at 0° C. and the solution was allowed to attain room temperature over 1.5 h. The solvent was removed in vacuo and the residue was again dissolved in CHCl3 (20 mL) and washed with brine. The organic layer was separated, dried over Na2SO4, filtered and the solvent was removed in vacuo to get 0.81 g of (+)-6-(3,4-difluorophenyl)-1,6-dihydro-2-oxo-5-methoxycarbonyl-4-bromomethyl-1-[(4-nitrophenyloxy)carbonyl]pyrimidine as a yellow foam. It was used in the next step without any purification.
Reaction SMILES: [Br-].[K+].C(=O)(O)[O-].[Na+].[OH:8][CH2:9][C@H:10]1[O:15][C:14]([CH3:17])([CH3:16])[O:13][C@@H:12]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:11]1.Cl[O-].[Na+]>C(Cl)Cl>[C:22]([O:21][C:19](=[O:20])[CH2:18][C@H:12]1[CH2:11][C@@H:10]([CH:9]=[O:8])[O:15][C:14]([CH3:17])([CH3:16])[O:13]1)([CH3:23])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](C=O)OC(C)(C)O1

Procedure:
2,2,6,6-tetramethyl piperidinyl oxy free radical (TEMPO) (0.2 g), potassium bromide (9.6 g) and sodium bicarbonate (90 g) were dissolved in methylene chloride (600 ml) and stirred the contents together at 0–5° C. A solution of (4R-cis)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid, 1,1-dimethylethyl ester of Formula III (100 g) in methylene chloride (400 ml) was added to the above solution at 0–5° C. To this solution 10% sodium hypochlorite solution (159 ml) (NaOCl) was added at 0–5° C. Again sodium bicarbonate (96 g) and followed by 10% sodium hypochlorite solution was added to the reaction mass. Reaction mass was maintained for 1–2 hours at 0–5° C. and filtered through perlite. The organic layer was separated and washed with 10% sodium thiosulfate solution (250 ml), then water (250 ml) followed by saturated sodium chloride solution (250 ml). Organic layer was distilled at below 40° C. under reduced pressure to afford the title product. Yield: 95 g.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=2)[C:5]([O:16]C)=[C:4]([C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[CH:19]=2)[CH:3]=1.O.C(OCC)C>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[CH:19]=2)[C:5]([OH:16])=[C:6]([C:8]2[CH:9]=[C:10]([CH3:15])[CH:11]=[C:12]([CH3:14])[CH:13]=2)[CH:7]=1
Reactant: COc1c(-c2cc(C)cc(C)c2)cc(C)cc1-c1cc(C)cc(C)c1
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)cc(-c2cc(C)cc(-c3cc(C)cc(C)c3)c2O)c1
Yield: 92 %

Procedure:
A mixed solution of 1 mL of water and 4 mL of dimethoxyethane was added into a flask into which 2,6-dibromo-4-methylanisole (400 mg, 1.43 mmol), 3,5-dimethylphenylboronic acid (658 mg, 4.39 mmol), palladium acetate (14 mg, 0.062 mmol), triphenylphosphine (60 mg, 0.23 mmol), and potassium phosphate (940 mg, 4.43 mmol) were already added, and then refluxed at normal temperature for 6 hours. After cooling to normal temperature, an ammonium chloride aqueous solution (5 mL) and 10 mL of diethylether were added thereto to separate an organic layer and extract residues using diethylether. The separated organic layer was dried with magnesium sulfate and volatile materials were removed to produce 453 mg of white 4-methyl-2,6-bis(3′,5′-dimethylphenyl)anisole solid (yield 96%). The anisole thus produced was dissolved in 5 mL of methylene chloride without separate purification, 3 mL of boron tribromide (1 M methylene chloride solution) were dropped thereonto at −78° C., and the reaction was carried out while the temperature was slowly increased to normal temperature. After the reaction, a mixed solution of water (5 mL) and diethylether (10 mL) was added to separate an organic layer and extract an aqueous solution layer using diethylether (5 mL×3), and the separated organic layer was dried. Residues from which volatile components were removed at reduced pressure were purified using a silica gel chromatography tube in a mixed solvent of hexane and methylene chloride to produce 0.41 g of white 4-methyl-2,6-bis(3′,5′-dimethylphenyl)phenol solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][CH3:15])[CH3:2].[Cl:17][S:18](O)(=[O:20])=[O:19]>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:18]([Cl:17])(=[O:20])=[O:19])=[CH:9][C:8]=1[CH2:13][CH2:14][CH3:15])[CH3:2]
Reactant: CCCc1ccccc1OCC(=O)OCC
Reactant: O=S(=O)(O)Cl
Product: CCCc1cc(S(=O)(=O)Cl)ccc1OCC(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
(2-Propyl-phenoxy)-acetic acid ethyl ester (5.0 g, 22.4 mmol) was added to chlorosulfonic acid (6.6 mL) at 0° C. dropwise. After addition, the mixture was warmed to room temperature slowly and stirred for 2 h. The reaction mixture was poured into ice and stirred for 1 h, filtered and the solid product was washed with water, dried in vacuum oven over night giving the title compound (6.0 g, 83.5%).
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[N:9]([NH:17][C:18]([C:20]2[C:21]([CH3:32])=[N:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[N:24][CH:25]=2)=[O:19])[CH:8]=1)([CH3:6])[CH3:5].[OH-].[Na+]>CO>[F:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]([NH:17][C:18]([C:20]1[C:21]([CH3:32])=[N:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[N:24][CH:25]=1)=[O:19])[CH:8]=[C:7]2[C:4]([CH3:6])([CH3:5])[C:3]([OH:33])=[O:2]
Reactant: COC(=O)C(C)(C)c1cn(NC(=O)c2cnc(-c3ccccn3)nc2C)c2ccc(F)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1cc(C(C)(C)C(=O)O)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
A solution of 2-{5-fluoro-1-[(4-methyl-2-pyridin-2-yl-pyrimidine-5-carbonyl)-amino]-1H-indol-3-yl}-2-methyl-propionic acid methyl ester (0.85 mmol) in MeOH (5 mL) is treated with 10% aqueous NaOH (2 mL) and stirred at rt overnight. The mixture is then concentrated, diluted with EtOAc (50 mL), and extracted with 10% aqueous NaOH (3×50 mL). The aqueous layer is acidified with 12 M aqueous HCl, extracted with DCM (3×50 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated. The residue is triturated with Et2O to afford 2-[5-fluoro-1-[(4-methyl-2-pyridin-2-yl-pyrimidine-5-carbonyl)-amino]-1H-indol-3-yl]-2-methyl-propionic acid (100 mg, 27%, 3 steps). MS: 434 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 9.26 (s, 1H), 8.79 (m, 1H), 8.44 (d, 1H), 8.03 (t, 1H), 7.59 (m, 1H), 7.53 (s, 1H), 7.49 (m, 1H), 7.35 (d, 1H), 7.08 (t, 1H), 2.79 (s, 3H), 1.59 (s, 6H).
Reaction SMILES: [Mg].B(O)(O)[C@H:3]1N(C([C@@H](N)C(C)C)=O)CC[CH2:4]1.CS(O)(=O)=O.C(Br)C.[CH3:25][N:26]([CH3:40])[CH2:27][C@H:28]([CH3:39])[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=1)=[O:30].S([O-])(O)(=O)=O.[NH4+]>C(OCC)C.C(Br)C>[CH3:40][N:26]([CH3:25])[CH2:27][C@H:28]([CH3:39])[C@:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=1)([OH:30])[CH2:3][CH3:4]
Reactant: COc1cccc(C(=O)[C@@H](C)CN(C)C)c1
Reactant: CC(C)[C@H](N)C(=O)N1CCC[C@H]1B(O)O
Agent: CS(=O)(=O)O
Agent: O=S(=O)([O-])O
Agent: [Mg]
Solvent: CCBr
Solvent: CCOCC
Product: CC[C@](O)(c1cccc(OC)c1)[C@@H](C)CN(C)C
Temperature: 5 °C
Yield: 98 %

Procedure:
Magnesium turnings (93.57 g, 3.85 mol) were suspended in dry ethyl ether (2 L) in a 10 L double jacket vessel equipped with an electrical impeller stirrer, a gas transition line, Pt100 temperature measuring equipment and an oil based cooling/heating system and ethyl bromide (25 g, 0.23 mol) was added. After the reaction has started further ethyl bromide (438.6 g, 4.02 mol) was added within 90 minutes below a temperature of 35° C. and the reaction mixture was stirred for another hour. The reaction mixture was cooled to 10° C. to 15° C., (S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (774.6 g, 3.5 mol, ee 98%) dissolved in diethyl ether (0.8 L) was added and the reaction mixture was stirred for another two hours. The reaction mixture was cooled to 5° C. and aqueous ammonium hydrogensulfate solution (10% by weight, 2 L) was added. The phases were separated and the organic phase was concentrated in vacuo at 40° C. until a pressure of 5 mbar was reached. (2S,3R)-1-(Dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol (862.3 g, 98%) was obtained as a colorless oil (ee 98%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([CH3:22])([C:17](OCC)=[O:18])[C:12](OCC)=[O:13].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([CH3:22])([CH2:17][OH:18])[CH2:12][OH:13]
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1ccc([N+](=O)[O-])cc1Br
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(CO)(CO)c1ccc([N+](=O)[O-])cc1Br
Reaction time: 0.17 h
Yield: 24.1 %

Procedure:
To a solution of diethyl 2-(2-bromo-4-nitrophenyl)-2-methylmalonate (7.5 g, 20.0 mmol) in anhydrous tetrahydrofuran (80 mL) was slowly added a solution of lithium aluminum hydride (22 mL, 22.0 mmol, 1.0 M in THF) at 0° C. under an atmosphere of nitrogen. After stirring for 10 minutes the reaction was completed. The reaction mixture was quenched by the slow addition of methanol at 0° C. The reaction mixture was then partitioned between dichloromethane and 1 N hydrochloric acid. The layers were separated and the aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give crude product, which was purified by silica gel column chromatography (petroleum ether/EtOAc 2:1) to give 2-(2-bromo-4-nitrophenyl)-2-methylpropane-1,3-diol (1.4 g, 24%) as a red solid. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J=2.4 Hz, 1H), 8.13 (dd, J=2.4, 8.8 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 4.74 (t, J=5.2 Hz, 2H), 3.93 (q, J=5.2 Hz, 2H), 3.79 (m, q, J=5.2 Hz, 2H), 1.38 (s, 3H).
Reaction SMILES: ClC(N(C)C)=C(C)C.[Cl:9][C:10]1[C:15]([CH2:16][NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][CH:13]=[C:12]([Cl:24])[C:11]=1[NH:25][C:26]1[N:30]([CH3:31])[C:29]2[CH:32]=[C:33]([O:39][CH2:40][CH:41]([F:43])[F:42])[C:34]([C:36]([OH:38])=O)=[CH:35][C:28]=2[N:27]=1.[NH2:44][C:45]1[CH:46]=[C:47]([CH:50]=[CH:51][CH:52]=1)[C:48]#[N:49].N1C=CC=CC=1>C(#N)C>[C:48]([C:47]1[CH:46]=[C:45]([NH:44][C:36]([C:34]2[C:33]([O:39][CH2:40][CH:41]([F:42])[F:43])=[CH:32][C:29]3[N:30]([CH3:31])[C:26]([NH:25][C:11]4[C:12]([Cl:24])=[CH:13][CH:14]=[C:15]([CH2:16][NH:17][C:18](=[O:23])[C:19]([CH3:21])([CH3:22])[CH3:20])[C:10]=4[Cl:9])=[N:27][C:28]=3[CH:35]=2)=[O:38])[CH:52]=[CH:51][CH:50]=1)#[N:49]
Reactant: N#Cc1cccc(N)c1
Reactant: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)O)c(OCC(F)F)cc21
Agent: CC(C)=C(Cl)N(C)C
Solvent: CC#N
Solvent: c1ccncc1
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)Nc3cccc(C#N)c3)c(OCC(F)F)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(1-Chloro-2-methyl-propenyl)-dimethylamine (20 μl) is added to a mixture of 2-{2,6-dichloro-3-[(2,2-dimethyl-propionylamino)-methyl]-phenylamino}-6-(2,2-difluoro-ethoxy)-1-methyl-1H-benzimidazole-5-carboxylic acid (53 mg, 0.10 mmol) in 2.0 mL acetonitrile and it is stirred 10 min at rt. Additional (1-chloro-2-methyl-propenyl)-dimethylamine (20 μl) is added and the mixture is stirred for additional 20 min at rt. The crude acid chloride solution is added to a mixture of 3-aminobenzonitrile (12 mg, 0.10 mmol), pyridine (24 μL, 0.30 mmol) and acetonitrile (1.0 mL) and it is stirred for 15 min at rt and additional 5 h at 55° C. The solvent is removed in vacuo and the residue is dissolved in 2 mL of a 19:1 DMF/water-solution and is purified via preparative HPLC to furnish the title compound.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:45])[C:7](=[CH2:44])[CH2:8][C@H:9]([OH:43])[C@@H:10]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:11][C@@H:12]([CH:32]([CH3:34])[CH3:33])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[C:16]([O:24]CC2C=CC=CC=2)[CH:15]=1)[CH2:2][CH2:3][CH3:4]>CO>[CH2:1]([NH:5][C:6](=[O:45])[C@H:7]([CH3:44])[CH2:8][C@H:9]([OH:43])[C@@H:10]([NH:35][C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH2:11][C@@H:12]([CH:32]([CH3:33])[CH3:34])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[C:16]([OH:24])[CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C=C(C[C@H](O)[C@H](C[C@H](Cc1ccc(C(C)(C)C)c(OCc2ccccc2)c1)C(C)C)NC(=O)OC(C)(C)C)C(=O)NCCCC
Solvent: CO
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](C[C@H](Cc1ccc(C(C)(C)C)c(O)c1)C(C)C)NC(=O)OC(C)(C)C

Procedure:
175 mg of N-tert-butoxycarbonyl-2-methylene-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-benzyloxy-4-tert-butyl-phenyl)-octanoic acid (N-butyl)amide are hydrogenated in the presence of 12 mg of [Ru2Cl4 (S-Binap)2 ]·(NEt3) in 30 ml of methanol for 20 hours at room temperature and under 30 bar. The reaction mixture is filtered, concentrated by evaporation and purified by means of FC (hexane/ethyl acetate=1:1). The title compound so obtained (Rf in hexane/ethyl acetate=1:1)=0.15 is deprotected by hydrogenation with 90 mg of 10% Pd/C in 10 ml of methanol at room temperature and under normal pressure to form N-tert-butoxycarbonyl-2(R)-methyl-4(S)-hydroxy-g(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-tert-butyl-phenyl)-octanoic acid (N-butyl)amide.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[H-].[Na+].[CH2:12]([O:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18]Br)[CH3:13].CCOCC>CN(C)C=O>[CH2:12]([O:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9])[CH3:13]
Reactant: CCOC(=O)CCCBr
Reactant: O=Cc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccccc1C=O
Reaction time: 0.25 h
Yield: 47.5 %

Procedure:
A solution of 12.2 g of salicylaldehyde in 20 ml of dimethylformamide is instilled into a suspension of 4.36 g of sodium hydride (55% dispersion in mineral oil) in 80 ml of dimethylformamide by stirring and ice cooling within 15 minutes. After 3 hours, a solution of 21.5 g of 4-bromobutyric acid ethyl ester in 16 ml of dimethylformamide is instilled by ice cooling within 15 minutes, and the mixture is stirred for 72 hours at room temperature. The batch is poured on ice/water, shaken with ether, the organic phase is washed briefly with 1 n sodium hydroxide solution, dried with sodium sulfate and concentrated by evaporation. The crude product is distilled at 130°-140° C./0.1 mbar in a bulb tube and 11.2 g of 4-(2-formylphenoxy)-butyric acid ethyl ester is thus obtained as a colorless oil.
Reaction SMILES: [NH2:1][C:2](=[O:42])[CH2:3][C:4]1[C:5]([CH2:10][CH2:11][C:12]2[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH:29]4[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]4)=[CH:25][CH:24]=3)[N:13]=2)=[N:6][CH:7]=[CH:8][N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:32]1[CH2:31][CH2:30][CH:29]([C:26]2[CH:27]=[CH:28][C:23]([NH:22][C:14]3[N:13]=[C:12]([CH2:11][CH2:10][C:5]4[C:4]([CH2:3][C:2]([NH2:1])=[O:42])=[N:9][CH:8]=[CH:7][N:6]=4)[C:17]([C:18]([F:20])([F:19])[F:21])=[CH:16][N:15]=3)=[CH:24][CH:25]=2)[CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4nccnc4CC(N)=O)n3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)Cc1nccnc1CCc1nc(Nc2ccc(C3CCNCC3)cc2)ncc1C(F)(F)F
Yield: 88 %

Procedure:
tert-Butyl 4-(4-((4-(2-(3-(2-amino-2-oxoethyl)pyrazin-2-yl)ethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I104) (66 mg, 0.11 mmol), DCM (20 mL) and TFA (2 mL) were stirred at room temperature for 17 hours, then concentrated. The residue was suspended in 10% NaOH (10 mL) and brine (10 mL), and the mixture extracted with ethyl acetate (4×20 mL). The combined ethyl acetate phases were washed with brine, dried (sodium sulphate) and evaporated to give the title compound (26) (47 mg, 85% yield) as a yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.05 (s, 1H), 8.64 (s, 1H), 8.42 (d, J=2.5 Hz, 1H), 8.39 (d, J=2.5 Hz, 1H), 7.61 (s, 1H), 7.54 (d, J=6.7 Hz, 2H), 7.14 (d, J=8.4 Hz, 2H), 7.08 (s, 1H), 3.78 (s, 2H), 3.07-2.97 (m, 2H), 2.63-2.53 (m, overlaps with solvent), 1.67 (d, J=12.1 Hz, 2H), 1.55-1.43 (m, 2H), 1.23 (s, 1H). LCMS Method C: rt 4.36 min; m/z 486.1 [M+H]+; m/z 484.1 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(OC([NH:24][CH2:25][C:26]1[CH:27]=[C:28]([CH2:34][CH:35]([O:39][CH:40]([CH3:42])[CH3:41])[C:36]([O-:38])=[O:37])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33])=O)(C)(C)C>>[Cl:1][C:2]1[CH:10]=[C:9]([O:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:8]=[CH:7][C:3]=1[C:4]([NH:24][CH2:25][C:26]1[CH:27]=[C:28]([CH2:34][CH:35]([O:39][CH:40]([CH3:42])[CH3:41])[C:36]([OH:38])=[O:37])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33])=[O:6]
Reactant: COc1ccc(CC(OC(C)C)C(=O)[O-])cc1CNC(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(OC2CCCC2)cc1Cl
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CNC(=O)c1ccc(OC2CCCC2)cc1Cl

Procedure:
Using 2-chloro-4-cyclopentyloxybenzoic acid and 3-[3-([(tert-butoxycarbonyl)amino]methyl)-4-methoxyphenyl]-2-isopropoxypropanoate, 3-(3-[(2-chloro-4-cyclopentyloxybenzoyl)amino]methyl-4-methoxyphenyl)-2-isopropoxypropanoic acid was obtained in the same method as in Example 38).