Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](=[O:19])[CH3:18])=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[H-].[Na+].[C:22](OC)(=[O:27])[CH2:23][C:24]([CH3:26])=[O:25].C([Li])CCC>C1COCC1>[OH:25][C:24]1[CH2:26][C:17]([CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)([CH3:18])[O:19][C:22](=[O:27])[CH:23]=1
Reactant: COC(=O)CC(C)=O
Reactant: CC(=O)CCc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(CCc2ccc(O)cc2)CC(O)=CC(=O)O1

Procedure:
The title compound was prepared as described in General Method 6 using 16.9 g (60.9 mmol) of 4-(4-tert-butyldimethylsilyloxyphenyl)-2-butanone (prepared in Example R), 7.32 g (183 mmol) of 60% NaH dispersion in mineral oil, 21.2 g (183 mmol) of methyl acetoacetate, 114 mL (1.64M, 183 mmol) of n-butyllithium and 360 mL of THF. The reaction mixture was quenched with 0.1N HCl and the product was extracted into EtOAc. The organic layer was dried (MgSO4) and the solvents were evaporated.
Reaction SMILES: S(=O)(=O)(O)O.O.[CH:7]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][C:20]3[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][C:23](CC#N)=[CH:22][C:21]=3[C:33]([F:36])([F:35])[F:34])[CH:17]=2)[NH:12][CH:11]=1)([CH3:9])[CH3:8].C(OCC)(=O)C.[C:43]([OH:46])(=[O:45])[CH3:44]>>[CH:7]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][C:20]3[C:25]([C:26]([F:27])([F:29])[F:28])=[CH:24][C:23]([CH2:44][C:43]([OH:46])=[O:45])=[CH:22][C:21]=3[C:33]([F:36])([F:34])[F:35])[CH:17]=2)[NH:12][CH:11]=1)([CH3:9])[CH3:8]
Reactant: CC(C)c1c[nH]c2ccc(Oc3c(C(F)(F)F)cc(CC#N)cc3C(F)(F)F)cc12
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)c1c[nH]c2ccc(Oc3c(C(F)(F)F)cc(CC(=O)O)cc3C(F)(F)F)cc12
Temperature: 105 °C
Reaction time: 4 h

Procedure:
A mixture of 5 ml of concentrated sulphuric acid and 5 ml of water is added dropwise to a solution of 0.35 g (0.82 mmol) of nitrile derivative from Example VIII in 5 ml of acetic acid (100% strength). The reaction solution is stirred at 105° C. for 4 hours, then cooled to room temperature and treated with ice-cold water and ethyl acetate. The organic phase is separated off, the aqueous solution is extracted again with ethyl acetate, and the combined organic phases are dried over sodium sulphate, filtered and concentrated to give an oil. The crude product (120.3 mg) is chromatographed on silica gel 60 by means of methylene chloride/methanol (95:5 and95:11).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([N:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23]2)[CH:17]=1)=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@@H:8]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([N:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23]2)[CH:17]=1)=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ccnc(N2CCc3ccccc32)c1)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](C(=O)N1CCC[C@H]1c1ccnc(N2CCc3ccccc32)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of ((S)-1-Cyclohexyl-2-{(S)-2-[2-(2,3-dihydro-indol-1-yl)-pyridin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-carbamic acid tert-butyl ester (120 mg, 0.24 mmol) in DCM (5 mL) is added TFA (6 mL). After stirring at room temperature for 1 h, the reaction mixture is concentrated down to give crude (S)-2-Amino-2-cyclohexyl-1-{(S)-2-[2-(2,3-dihydro-indol-1-yl)-pyridin-4-yl]-pyrrolidin-1-yl}-ethanone, which is used in next step without further purification.
Reaction SMILES: S(Cl)(Cl)=O.C(OCCC(O)=O)C.C(OCCC(Cl)=O)C.[CH2:21]([O:23][CH2:24][CH2:25][C:26]([N:28]=[C:29]=[S:30])=[O:27])[CH3:22].[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][C:42]=1[O:43][CH3:44])[N:39]=[CH:38][CH:37]=[C:36]2[O:45][C:46]1[CH:52]=[CH:51][C:49]([NH2:50])=[CH:48][CH:47]=1>C(O)C.C1(C)C=CC=CC=1>[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][C:42]=1[O:43][CH3:44])[N:39]=[CH:38][CH:37]=[C:36]2[O:45][C:46]1[CH:47]=[CH:48][C:49]([NH:50][C:29]([NH:28][C:26](=[O:27])[CH2:25][CH2:24][O:23][CH2:21][CH3:22])=[S:30])=[CH:51][CH:52]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CCOCCC(=O)N=C=S
Agent: CCOCCC(=O)Cl
Agent: CCOCCC(=O)O
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CCOCCC(=O)NC(=S)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 3-ethoxypropanoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 3-ethoxypropanoyl isothiocyanate was prepared using the resultant 3-ethoxypropanoyl chloride as a starting compound according to the description of the literature. 3-Ethoxypropanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (55 mg, yield 72%).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][S:6][CH2:5][CH:4]([C:9]([OH:11])=O)[NH:3]1.N[CH2:13][CH2:14][N:15]1[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]1[CH3:21].C1([N:28]=C=NC2CCCCC2)CCCCC1.O>CN(C)C=O.C(Cl)Cl>[CH3:21][C:16]1[N:15]([CH2:14][CH2:13][CH:5]2[CH:4]([C:9]([NH2:28])=[O:11])[NH:3][C:2](=[O:1])[CH2:8][CH2:7][S:6]2)[C:19]([CH3:20])=[CH:18][CH:17]=1
Reactant: O=C1CCSCC(C(=O)O)N1
Reactant: Cc1ccc(C)n1CCN
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(C)n1CCC1SCCC(=O)NC1C(N)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3.5 g (0.02 mol) of 5-oxoperhydro-1,4-thiazepine-3-carboxylic acid and 2.8 g (0.02 mol) of 1-(2-aminoethyl)-2,5-dimethylpyrrole are dissolved in 10 ml of dimethylformamide. After addition of 4.2 g (0.02 mol) of dicyclohexylcarbodiimide, dissolved in 10 ml of methylene chloride, to the mixture at 0° C., it is stirred at room temperature for 24 h, then water is added and the mixture is filtered with suction. The filtrate is extracted with methylene chloride, and the extract is chromatographed over a silica gel column using ethyl acetate as the mobile phase. Yield: 1.2 g (20% of theory), Melting point: 181°-183° C. Elemental analysis: C14H21N3O2S (295.41) calculated: C 56.9 H 7.2 N 14.2 0 10.8 S 10.9 found: C 57.4 H 6.9 N 13.8 0 11.2 S 10.8
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[CH2:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[Si](C)(C)[O:23][C:24]([CH:26]=[CH2:27])=[CH2:25].Cl>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[F:20])[CH2:27][CH2:26][C:24](=[O:23])[CH2:25][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C=C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Reactant: C=CC(=C)O[Si](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 130 °C
Yield: 89.3 %

Procedure:
A solution of 2-[1-[(4-chlorophenyl)sulfonyl]ethenyl]-1,4-difluorobenzene (Example 3) (100 g, 0.32 mol) in xylenes (500 ml) was azeotropically distilled at 38° C., 20 mmHg, until 300 mL solvent had been removed. 2-Trimethylsilyloxybutadiene (90.4 g, 0.64 mol) was then added under a nitrogen atmosphere and the mixture heated to 130° C. After the reaction was completed, the mixture was distilled in vacuo to remove residual diene, whilst maintaining a constant volume by the addition of xylenes (400 mL). The mixture was cooled to 50° C. and THF (500 mL) and 3M HCl (424 mL, 1.27 mol) were added. After the hydrolysis was complete, the layers were separated. The organic layer was washed with water (300 mL) and then concentrated by atmospheric distillation until 350 mL of solvent had been removed. The solution was allowed to cool until crystallisation started, heptane (600 mL) was added and the resulting mixture cooled to ambient. The solids were filtered and washed sequentially with heptane:xylenes (3:1, 200 ml) and then heptane (200 ml). Drying overnight in vacuo at 40° C. furnished 4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexanone (110 g, 90% yield). 1H NMR CDCl3 7.43-7.37 (4H, m), 7.22-7.1 (2H, m), 6.97-6.9 (1H, m), 3.05-2.98 (4H, m) and 2.61-2.53 (4H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:15]=[N:16][C:17]([CH2:20][NH2:21])=[CH:18][CH:19]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:22].CCN(C(C)C)C(C)C.Cl[C:33](=[O:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:15]=[N:16][C:17]([CH2:20][NH:21][C:33](=[O:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:18][CH:19]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:22]
Reactant: Cc1cc(-c2ncccc2-c2ccc(CN)nc2)ccc1F
Reactant: CCOC(=O)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C(=O)NCc1ccc(-c2cccnc2-c2ccc(F)c(C)c2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirring solution of (2′-(4-fluoro-3-methylphenyl)-[3,3′-bipyridin]-6-yl)methanamine (2.0 g) in CH2Cl2 (30 mL) under nitrogen atmosphere, i-Pr2NEt (2.6 mL) was added and stirred for 10 min at room temperature. Ethyl 2-chloro-2-oxoacetate (1.1 mL) as neat was added dropwise for 10 min. After 1 h, the reaction mixture was concentrated, partitioned between CH2Cl2 (75 mL)/aq. NaCl (20 mL) and the organic layer was separated. Usual workup and purification by chromatography (Combiflash® companion System® with RediSep® silica gel column 40 g and 50-100% EtOAc/hexanes as an elutant) provided 1.4 g of ethyl 2-(((2′-(4-fluoro-3-methylphenyl)-[3,3′-bipyridin]-6-yl)methyl)amino)-2-oxoacetate as an off-white solid. 1H NMR (300 MHz, DMSO-d6): δ 9.41 (t, J=6.2 Hz, 1H), 8.67 (dd, J=4.7, 1.7 Hz, 1H), 8.30 (dd, J=2.4, 0.9 Hz, 1H), 7.87 (dd, J=7.8, 1.7 Hz, 1H), 7.56 (dd, J=8.1, 2.3 Hz, 1H), 7.49 (dd, J=7.8, 4.8 Hz, 1H), 7.29-7.22 (m, 2H), 6.98 (dd, J=7.7, 1.1 Hz, 2H), 4.42 (d, J=6.1 Hz, 2H), 4.23 (q, J=7.1 Hz, 2H), 2.21-2.09 (m, 3H), 1.26 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[N+:12]([O-:15])([OH:14])=[O:13].[N:16]#[C:17][NH2:18]>C(O)C.O>[CH3:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[N+:12]([O-:15])([OH:14])=[O:13].[NH2:16][C:17]([NH2:4])=[NH:18]
Reactant: N#CN
Agent: Cc1ccc([N+](=O)[O-])cc1N
Solvent: CCO
Solvent: O
Solvent: O=[N+]([O-])O
Product: N=C(N)N
Temperature: 0 °C

Procedure:
2-Methyl-5-nitroaniline (100 g, 0.657 mol) was dissolved in ethanol (250 ml), and 65% aqueous nitric acid solution (48 ml, 0.65 mol) was added thereto. When the exothermic reaction was stopped, cyanamide (41.4 g) dissolved in water (41.4 g) was added thereto. The brown mixture was reacted under reflux for 24 hours. The reaction mixture was cooled to 0° C., filtered, and washed with ethanol:diethyl ether (1:1, v/v) to give 2-methyl-5-nitrophenyl-guanidine nitrate (2) (98 g). Rf=0.1 (Methylene chloride:Methanol:25% Aqueous ammonia=150:10:1). MS: 195.2 (M+H); 1H-NMR (DMSO-d6)=1.43 (s, 3H), 6.59 (s, 3H), 6.72-6.76 (d, 1H), 7.21-7.27 (m, 1H), 8.63-8.64 (br, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].Cl.[CH3:27]O>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:27])=[O:23])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(CCCCCCCCCC(=O)O)=C(C)C1=O
Reactant: CO
Agent: Cl
Product: COC(=O)CCCCCCCCCC1=C(C)C(=O)C(OC)=C(OC)C1=O

Procedure:
2,3-Dimethoxy-5-methyl-6-(9'-carboxynonyl)-1,4-benzoquinone (formula I-2 wherein R=H3CO, n=8, in the free form) (4 parts) was esterified with methanol (500 volume parts) saturated with hydrogen chloride gas in a manner similar to that described in Example 13. The procedure provided 2,3-dimethoxy-5-methyl-6-(9'-methoxycarbonylnonyl)-1,4-benzoquinone (formula I-2 wherein R=H3CO, n=8, in the form of methyl ester) (4.2 parts) as orange-colored needles melting at 37°-37.5° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH:5]([O:8][CH3:9])[CH2:6]O.Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1.[OH2:21]>CN(C=O)C>[CH3:9][O:8][C:5]([O:4][CH3:3])([O:21][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1)[CH3:6]
Reactant: Clc1nccc2ccccc12
Reactant: COC(CO)OC
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(C)(OC)Oc1nccc2ccccc12
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a stirred suspension of sodium hydride (60% oil dispersion, 1.2 g, 30 mmol) in DMF (6 mL) was added dropwise 2-hydroxyacetaldehyde dimethyl acetal (3.2 g, 30 mmol). The resulting mixture was left to stir for 0.5 h, then a solution of 1-chloroisoquinoline (1.6 g, 10 mmol) in DMF (2 mL) was added and the mixture was stirred at 80° C. for 24 h. The mixture was then poured into water (150 mL) and extracted with ether (2×150 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel chromatography (10% ethyl acetate in hexane) to give 1-isoquinolinyloxyacetaldehyde dimethyl acetal (1.5 g, 64%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[S:7][C:8]([CH:11]([CH3:14])[CH2:12][NH2:13])=[CH:9][CH:10]=2)=[CH:2]1.[S:15](C[N+]#[C-])([C:18]1[CH:24]=CC(C)=C[CH:19]=1)(=[O:17])=[O:16].CC(C)([O-])C.[K+].O>COCCOC.C(O)(C)(C)C>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[S:7][C:8]([CH:11]([CH3:14])[CH2:12][NH:13][S:15]([CH:18]([CH3:24])[CH3:19])(=[O:17])=[O:16])=[CH:9][CH:10]=2)=[CH:2]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CC(CN)c1ccc(-c2ccsc2)s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CC(C)(C)O
Solvent: O
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccsc2)s1
Temperature: -5 °C
Reaction time: 2 h
Yield: 22 %

Procedure:
2-[2-(thien-3-yl)-5-thienyl]propylamine To a −15° C. solution of 1.1 g (5.3 mmol) of the material prepared in step A and 1.05 g (5.35 mmol) of tosylmethyl isocyanide in 18 ml of DME, a hot solution of 1.07 g (9.54 mmol) of potassium tert-butoxide in 5 ml of tert-butanol was added slowly. The mixture was stirred at −5° C. for 45 min and 2 h at ambient temperature. Water was added and extracted three times with diethyl ether. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The crude material was dissolved in 15 ml of diethyl ether and then was added to a suspension of 218 mg (5.75) of lithium aluminum hydride in 5 ml of diethyl ether. The mixture was stirred at ambient temperature for 2 h. Na2SO410H2O was added, and the mixture stirred for 30 min at ambient temperature. The solid was filtered and the organic solution was concentrated in vacuo. Chromatography (150 g of silica gel, ethyl acetate/hexane/methanol 10/10/1) of the residue afforded 250 mg (22%) of the title compound.
Reaction SMILES: [C:1]1([CH2:7][N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[C:27]([CH2:29][C@@H:30]([OH:37])[CH2:31][C:32](OCC)=[O:33])#[N:28].Cl>O1CCCC1.O1CCCC1.CCCCCCC>[C:27]([CH2:29][C@@H:30]([OH:37])[CH2:31][C:32](=[O:33])[CH2:10][C:9]([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:11])#[N:28]
Reactant: CCOC(=O)C[C@H](O)CC#N
Reactant: CC(=O)N(Cc1ccccc1)Cc1ccccc1
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(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.5 h

Procedure:
To a stirred -10° C. solution of N,N-bis(phenylmethyl)acetamide (prepared from N,N-bis(phenylmethyl)amine and acetyl chloride by refluxing for 2 hours in toluene) (120 g, 0.5 mol) in tetrahydrofuran (0.5 L) is slowly added a solution of lithium diisopropylamide in tetrahydrofuran-heptane (0.25 L of 2M) while maintaining the temperature between -30° C. to -45° C., and the mixture is stirred at -20° C. to -30° C. for 30 minutes. (R)-4-cyano-3-hydroxybutyric acid, ethyl ester (Brower, supra) (20 g, 0.125 mol) as a solution in 200 mL of tetrahydrofuran is then added to the previous mixture. The reaction mixture is stirred for 30 minutes at -35° C. to -20° C., and transferred to a 2.2N aqueous hydrochloric acid solution (0.5 L). The aqueous layer is extracted with 300 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-bis(phenylmethyl)hexanamide as an oil. This oil, approximately 0.1 mol, is dissolved in tetrahydrofuran (200 mL) and methanol (100 mL) under a nitrogen atmosphere. The solution is cooled to -20° C., and a 50% solution of methoxydiethylborane in tetrahydrofuran (50 mL) is added. The reaction is cooled to -78° C., and sodium borohydride (12 g, 0.32 mol) is added over 30 minutes. The reaction is maintained at -78° C. for 5 hours and allowed to warm to room temperature and stand for 10 hours under a nitrogen atmosphere. The reaction is quenched by the addition of acetic acid (20 mL) and concentrated by vacuum distillation to an oil. The residue is dissolved with methanol (300 mL), concentrated by vacuum distillation, redissolved with methanol (300 mL), and reconcentrated by vacuum distillation to give a yellow oil. The oil is taken up in ethyl acetate (300 mL) and washed with deionized water (300 mL). The ethyl acetate solution is concentrated by vacuum distillation to give crude [R-(R*,R*)]-6-cyano-3,5-dihydroxy-N,N-bis(phenylmethyl)hexanamide as an oil which is used without further purification;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[CH:9]=1)[CH2:5][OH:6].CCN(C(C)C)C(C)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[S:25]([O:6][CH2:5][C:4]1[CH:7]=[C:8]([O:10][C:11]([F:12])([F:13])[F:14])[CH:9]=[C:2]([Cl:1])[CH:3]=1)(=[O:27])(=[O:26])[CH3:24]
Reactant: OCc1cc(Cl)cc(OC(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cc(Cl)cc(OC(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 100.1 %

Procedure:
To a solution of 3-chloro-5-trifluoromethoxybenzyl alcohol (6.1 g, 26.9 mmol; see Example 6(v) above) in CH2Cl2 (250 mL) at 0° C. under a nitrogen atmosphere was added DIPEA (4.2 g, 32.3 mmol) and methanesulfonyl chloride (3.4 g, 29.6 mmol). The solution was stirred at 0° C. for 1.5 hours and quenched with H2O. The organics were separated and then washed with H2O (1×), 1N HCl (1×), H2O (1×) and aqueous NaHCO3 (1×) and then dried (Na2SO4), filtered and concentrated to afford the sub-title compound (8.2 g, 99%) as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[C:19]([O:23][C:24]([NH:26][C@H:27]([C:43](O)=[O:44])[CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]([C:43](=[O:44])[C@H:27]([CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:34])[NH:26][C:24]([O:23][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:25])[CH:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CNC1Cc2ccccc2C1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Product: CC(C)(C)OC(=O)CN(C(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Yield: 69.3 %

Procedure:
By reacting 8.2 g of N-(indan-2-yl)glycine tert-butyl ester with 13 g of Nα -tert-butoxycarbonyl-Nε -carbobenzoxy-L-lysine as in Reference Example 5, there is obtained 14 g of Nα -tert-butoxycarbonyl-Nε -carbobenzoxy-L-lysyl-N-(indan-2-yl)glycine tert-butyl ester as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([OH:17])=O)=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.[NH:26]1[CH2:34][CH2:33][CH:29]([C:30]([NH2:32])=[O:31])[CH2:28][CH2:27]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O.ClCCl>[F:18][C:2]([F:1])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([N:26]2[CH2:34][CH2:33][CH:29]([C:30]([NH2:32])=[O:31])[CH2:28][CH2:27]2)=[O:17])=[CH:7][CH:8]=1
Reactant: NC(=O)C1CCNCC1
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)C1CCN(C(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.1 %

Procedure:
4′-(Trifluoromethyl)-2-biphenylcarboxylic acid (20.5 g; 77 mmol) is dissolved in 340 ml of dimethylformamide and 200 ml of dichloromethane. The reaction medium is placed at 0° C. and oxalyl chloride (1.8 eq.; 138.6 mmol; 12 ml) is added. The reaction medium is stirred at room temperature for 3 hours and then evaporated to dryness. The crude product is taken up in 270 ml of dichloromethane, followed by addition of a solution of isonipecotamide (0.97 eq.; 74.7 mmol; 9.57 g) and triethylamine (2.7 eq.; 207.9 mmol; 29 ml) in 270 ml of dichloromethane, placed at 0° C. The mixture is allowed to warm to room temperature over 12 hours, saturated aqueous sodium hydrogen carbonate solution is then added (in a 1/1 proportion) and the resulting mixture is stirred for 30 minutes. The organic phase is washed with 1M sodium hydroxide solution and then with water, dried over sodium sulfate and evaporated to dryness. The crude product is dispersed in diisopropyl ether and then filtered off and dried to give 23.09 g of coupling product.
Reaction SMILES: [Na].[CH3:2][CH:3]([S-:5])[CH3:4].Br[C:7]1[N:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=1.O>CN(C=O)C>[CH:3]([S:5][C:7]1[N:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=1)([CH3:4])[CH3:2]
Reactant: CC(C)[S-]
Reactant: Nc1cnc(Br)cn1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Sc1cnc(N)cn1
Temperature: 100 °C

Procedure:
Sodium-2-propanethiolate (2.256 g, 20.69 mmol) was added to a stirred solution of 5-bromopyrazin-2-amine (3 g, 17.24 mmol) in DMF (15 mL) and heated at 100° C. under microwave conditions for 4 hours. A further portion of sodium-2-propanethiolate (2.256 g, 20.69 mmol) was added the reaction heated for a further 1 hour at 100° C. under microwave conditions. Water was added and the mixture extracted with EtOAc (×2). The combined organic layers were washed with water (×3), brine (×1), dried, (MgSO4), filtered and concentrated in vacuo to give the sub-title compound as a beige oil which was used without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH2:10][C@H:9]2[NH2:15])=[O:5].CCN(C(C)C)C(C)C.[Cl:25][C:26]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>ClCCl.C(OCC)(=O)C>[Cl:25][C:26]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:15][C@H:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([C:4]([O:3][CH3:2])=[O:5])[CH:7]=2)[CH2:11][CH2:10]1)=[O:29]
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CC2
Reactant: O=C(Cl)c1cccc(F)c1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)[C@H](NC(=O)c1cccc(F)c1Cl)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
(3R)-3-Amino-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester hydrochloride (A-01) (0.2 mmol, 1 eq) was dissolved in dichloromethane, and DIPEA (2.5 eq) and 2-chloro-3-fluorobenzoic acid chloride (1.2 eq) were added under a protecting gas atmosphere at 0° C. The reaction mixture was stirred for 2 h at RT. Then the reaction mixture was diluted with ethyl acetate, washed 1× with sat. NaHCO3 solution, 1× with 10% ammonium chloride solution and 1× with sat. NaCl solution, dried over magnesium sulfate and purified by column chromatography (silica gel, cyclohexane:ethyl acetate 4:1). Yield: 92%