Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[C@@H:16]([OH:17])[C:15](=[O:18])[N:14]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[C:13]3[CH:24]=[CH:25][CH:26]=[CH:27][C:12]=3[S:11]2)=[CH:6][CH:5]=1)[CH3:2].C(N(CC)CC)C.[Cl:35][C:36]1[CH:44]=[C:43]([N+:45]([O-:47])=[O:46])[CH:42]=[CH:41][C:37]=1[C:38](Cl)=[O:39]>C1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C@H:10]2[C@@H:16]([O:17][C:38](=[O:39])[C:37]3[CH:41]=[CH:42][C:43]([N+:45]([O-:47])=[O:46])=[CH:44][C:36]=3[Cl:35])[C:15](=[O:18])[N:14]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[C:13]3[CH:24]=[CH:25][CH:26]=[CH:27][C:12]=3[S:11]2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl
Reactant: CCOc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2OC(=O)c2ccc([N+](=O)[O-])cc2Cl)cc1
Yield: 61.3 %

Procedure:
1.04 g of (+)-cis-2-(4-ethoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are dissolved in 20 ml of anhydrous benzene, and 1 ml of triethylamine is added thereto. A solution of 0.62 g of 2-chloro-4-nitrobenzoyl chloride in 2 ml of anhydrous benzene is added to the mixture under stirring, and said mixture is stirred at room temperature for 0.5 hour. After the reaction, the mixture is washed with water, dried and condensed to dryness. The residue is recrystallized from ethanol, whereby 0.94 g of (+)-cis-2-(4-ethoxyphenyl)-3-(2-chloro-4-nitrobenzoyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one is obtained as pale yellow needles. Yield: 61%.
Reaction SMILES: CCN(CC)CC.Cl.[S:9]1[C:13]([NH2:14])=[CH:12][N:11]=[CH:10]1.[CH3:15][C:16](OC(C)=O)=[O:17]>C(Cl)Cl>[S:9]1[C:13]([NH:14][C:16](=[O:17])[CH3:15])=[CH:12][N:11]=[CH:10]1
Reactant: Nc1cncs1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cncs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.1 %

Procedure:
To a solution of Et3N (0.31 mL, 2.20 mmol) and thiazol-5-amine hydrochloride (0.2 g, 1.46 mmol) from example 1.2 in DCM (10 mL) was added Ac2O (0.21 mL, 2.20 mmol). The mixture was stirred at room temperature for 3 h and then concentrated. The resulting mixture was deposited onto silica gel and loaded onto a silica gel column and eluted with EA to give the title compound (0.14 g, 0.98 mmol, 70%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH:9]=[O:10])=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[CH3:18])[N:3]=1.[S-2:19].[Na+].[Na+].O>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[CH3:18])[C:5]([CH:9]=[O:10])=[C:6]([SH:19])[N:7]=1
Reactant: [S-2]
Reactant: Cc1ccc(-c2nc(N)nc(Cl)c2C=O)c(C)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2nc(N)nc(S)c2C=O)c(C)c1
Reaction time: 1 h

Procedure:
2-Amino-4-chloro-6-(2,4-dimethylphenyl)-pyrimidine-5-carbaldehyde was added to a suspension of sodium sulphide (5 eq.) in DMF and the mixture stirred for ˜60 mins, to give a yellow suspension. The suspension was poured into water, and the solution filtered. The filtrate was acidified with acetic acid, to give a yellow precipitate. The solids were removed by filtration and washed with water and hexane, dried in vacuo, to give a yellow powder.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](Cl)=[O:9].[CH3:11][C:12]1[C:17]([NH:18][C:19]2[N:24]=[C:23]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[CH:22]=[CH:21][N:20]=2)=[CH:16][C:15]([NH2:31])=[CH:14][N:13]=1>N1C=CC=CC=1>[CH3:11][C:12]1[N:13]=[CH:14][C:15]([NH:31][C:8](=[O:9])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)=[CH:16][C:17]=1[NH:18][C:19]1[N:24]=[C:23]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:22]=[CH:21][N:20]=1
Reactant: Cc1ncc(N)cc1Nc1nccc(-c2cccnc2)n1
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ncc(NC(=O)c2ccccn2)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.1 %

Procedure:
Picolinoyl chloride hydrochloride salt (96 mg, 0.54 mmol) was added into a solution of 2-methyl-N3-(4-pyridin-3-yl-pyrimidin-2-yl)-pyridine-3,5-diamine (50 mg, 0.18 mmol) in pyridine (1.5 mL). The reaction mixture was stirred at rt under argon atmosphere overnight. After pyridine is removed under reduced pressure, the residue is purified by chromatography to give 10.4 mg of the product as pale yellow solids (Yield: 15%). MS (ESI+) m/z 384.3 [M+H]+
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([NH2:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>C1COCC1>[C:1]([NH:8][C@H:9]([C:13](=[S:25])[NH2:15])[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(N)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(N)=S
Reaction time: 8 h
Yield: 69.4 %

Procedure:
Boc-valineamide (0.5 g) was stirred in dry THF at room temperature under argon. Lawesson's reagent (1.56 g, 0.6 eq) was added and the mixture was stirred overnight. The solvent was evaporated and the residue chromatographed (silica, 2.5% methanol/dichloromethane) to give the title compound as a white solid (0.373 g, 70%). NMR(CDCl3) δ 8.59 (1H, br s), 8.09 (1H, br s), 5.41 (1H, d (br)), 4.20 (1H, dd), 1.99 (1H, m), 1.39 (9H, s), 0.90 (6H, m).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21](=O)[CH2:22]Br.[C:25]([NH2:28])(=[S:27])[CH3:26]>C(O)C>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1[N:28]=[C:25]([CH3:26])[S:27][CH:22]=1
Reactant: CC(N)=S
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C(=O)CBr
Solvent: CCO
Product: Cc1nc(-c2c(C#N)nn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c2N)cs1

Procedure:
To a solution of 5-amino-4-bromoacetyl-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (0.1 g) in ethanol (5 ml) was added thioacetamide (0.0375 g). After 1 hour at room temperature the mixture was evaporated and the residue was purified by column chromatography on silica gel (10 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a white solid, m.p. 226-8° C.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([N:14]([CH2:18][C:19]1[C:24](Cl)=[N:23][C:22]([N:26]([CH3:30])[CH:27]([CH3:29])[CH3:28])=[CH:21][N:20]=1)[CH2:15][CH2:16][OH:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>CN(C=O)C>[CH2:7]([N:14]1[CH2:18][C:19]2[N:20]=[CH:21][C:22]([N:26]([CH3:30])[CH:27]([CH3:29])[CH3:28])=[N:23][C:24]=2[O:17][CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)N(C)c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N(C)c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Reaction time: 1.5 h
Yield: 81.3 %

Procedure:
To a solution of potassium tert-butoxide (5.8 g) in DMF (45 mL) was added dropwise a solution of 2-[benzyl({3-chloro-5-[methyl(1-methylethyl)amino]pyrazin-2-yl}methyl)amino]ethanol (15.1 g) in DMF (30 mL) at 0° C., and the mixture was stirred for 1.5 hr. Water (150 ml) was added, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by basic silica gel column chromatography (eluent: 10% ethyl acetate/hexane) to give the title compound (11 g, 87%) as a pale-yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][C:11]3[C:17]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.FC1C=C([B:28]2[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]2)C=CC=1NC1OC2C=CC=CC=2N=1>>[CH3:35][C:30]1([CH3:36])[C:31]([CH3:34])([CH3:33])[O:32][B:28]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]3[O:10][C:11]4[C:17]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:15]=[CH:14][C:12]=4[N:13]=3)=[CH:4][CH:3]=2)[O:29]1
Reactant: CC1(C)OB(c2ccc(Nc3nc4ccccc4o3)c(F)c2)OC1(C)C
Reactant: CC(C)c1cccc2nc(Nc3ccc(Br)cc3)oc12
Product: CC(C)c1cccc2nc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)oc12

Procedure:
N2-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-7-isopropyl-1,3-benzoxazol-2-amine was prepared from N2-(4-bromophenyl)-7-isopropyl-1,3-benzoxazol-2-amine (0.412 g, 1.24 mmol) in a manner similar to that used for the preparation of N2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazol-2-amine. The compound was formed as an off-white solid (0.346 g, 74%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14](O)[CH2:15]C=C)=[C:12]([CH:19]([CH3:21])[CH3:20])[N:11]=[C:10]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[N:9]=2)=[CH:4][CH:3]=1.CSC.[C:31](=[O:34])([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14]=[CH:15][CH:31]=[O:34])=[C:12]([CH:19]([CH3:21])[CH3:20])[N:11]=[C:10]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: C=CCC(O)c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: CSC
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1C=CC=O
Reaction time: 2 h
Yield: 96.1 %

Procedure:
N-[4-(4-fluorophenyl)-5-(1-hydroxybut-3-enyl)-6-isopropyl-pyrimidin-2-yl]-N-methylmethanesulfonamide (4 g, 10.2 mmol) is diluted in 102 mL methanol. O3 gas is bubbled through the solution at −15° C. to −10° C. for 60 min. Reaction solution is bubbled through with Argon for 2 min to remove the excess of O3. Dimethylsulfide (1.5 ml, 20.3 mmol) is added to the solution, maintaining stirring for 2 hours. To the reaction mixture, potassium carbonate (2.8 g, 20.3 mmol) is added at room temperature. The progress of the reaction is monitored by TLC. Upon completion of the reaction, 150 ml sodium bicarbonate (aq.) is added and methanol is distilled off under reduced pressure. The residue is extracted with ethyl acetate (2×300 mL) and washed with DM water (100 mL) and brine (150 mL). The organic solvent is distilled off under reduced pressure to give 3.7 g (95%) of N-(4-(4-fluorophenyl)-6-isopropyl-5-(3-oxoprop-1-enyl)pyrimidin-2-yl)-N-methyl-methanesulfonamide The product is recrystallized from 20% ethylacetate:cyclohexane at 0° C. to 5° C. to afford 2.4 g (67%) of N-(4-(4-fluorophenyl)-6-isopropyl-5-(3-oxoprop-1-enyl)pyrimidin-2-yl)-N-methyl-methanesulfonamide as an oily white-yellow solid.
Reaction SMILES: [C:1]([O:11]C)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+:14]>O>[C:1]([O-:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[Na+:14]
Reactant: COC(=O)C=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])C=Cc1ccccc1

Procedure:
A separable flask equipped with a stirrer was charged with 16.2 grams (0.10 mol) of methyl cinnamate, and a solution of 4.3 grams of 97 wt. % sodium hydroxide in 200 grams of water, and the mixture was reacted at 80° C. for 15 minutes with vigorous stirring. The aqueous alkaline solution of sodium cinnamate thus obtained was added slowly under stirring with 200 ml of aqueous sulfuric acid solution containing 0.056 mol of sulfuric acid. The formed suspension had pH of approximately 1.5 after cooling to room temperature. The precipitates were filtered with suction, washed with 50 ml of water by stirring in a beaker, filtered again and dried under reduced pressure. Cinnamic acid thus obtained was 14.6 grams (98.5% yield) and had purity of more than 99.9% according to analysis.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]=2[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(OCC)(=O)C>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH:21][C:24](=[O:31])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]=2[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1oc2c(C)c(C)c(N)c(C)c2c1-c1ccc(C(C)C)cc1
Solvent: CCOC(C)=O
Product: Cc1oc2c(C)c(C)c(NC(=O)c3ccccc3)c(C)c2c1-c1ccc(C(C)C)cc1
Yield: 91 %

Procedure:
By using 3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-1-benzofuran-5-amine and benzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 91%. Melting point: 225-227° C. (Ethyl acetate)
Reaction SMILES: C(O[C@@H:5]1[O:20][C@H:19]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@H:11]([O:12][CH3:13])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.[CH2:26]([SH:28])[CH3:27].B(F)(F)F.CCOCC.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][CH3:13])[C@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@@H:19]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[O:20][C@H:5]1[S:28][CH2:26][CH3:27])(=[O:10])[CH3:9]
Reactant: CCS
Reactant: CO[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)O[C@H](COC(C)=O)[C@H]1OC(C)=O
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCS[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC)[C@H]1OC(C)=O
Yield: 53438.8 %

Procedure:
1,2,4,6-Tetra-O-acetyl-3-O-methyl-β-D-glucopyranose 1 (69 g, 0.19 mmol), (B. Helferich et al., J. prakt. Chem., 132, 321 (1932)) is dissolved in toluene (580 ml). Ethanethiol (28 ml, 0.38 mmol) is added, followed by dropwise addition of a solution of trifluoroborane diethyl etherate (1 M in toluene, 190 ml). The mixture is left stirring for 1.5 hours (TLC), solid sodium hydrogen carbonate is introduced and the mixture is filtered, washed with water, dried and concentrated. Chromatography on a column of silica (3/1 cyclohexane/ethyl acetate) gives 2 (37 g, 54%) [α]D−26 (c=1. dichloromethane). 1H NMR (CDCl3). δ 5.05-4.96 (m, 2H, H-2, H-4), 4.39, (d, 1H, J=9.5 Hz, H-1), 4.18-4.12 (m, 2H, H-6, H-6′), 3.60 (m, 1H, H-5), 3.50 (dd, 1H, J=9.3 Hz, H-3), 3.41 (s, 3H, OCH3), 2.65-2.53 (m, 2H, SCH2CH3), 2.12, 2.11, 2.09 (3s, 9H, 3 Ac), 1.25 (t, 1H, SCH2CH3)
Reaction SMILES: Cl.[CH2:2]([NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[C:28]([C:32]1[CH:37]=[CH:36][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1)([CH3:31])([CH3:30])[CH3:29]>N1C=CC=CC=1>[CH2:2]([NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:41][S:38]([C:35]2[CH:36]=[CH:37][C:32]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:33][CH:34]=2)(=[O:39])=[O:40])=[O:24])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CC(C)(C)c1ccc(S(N)(=O)=O)cc1
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1

Procedure:
A solution of 21.1 g. of 4-(hexadecylamino)benzoyl chloride hydrochloride and 10.8 g. of p-tert-butylbenzenesulfonamide in 250 ml. of pyridine was stirred under reflux for 2 hours and evaporated. The residue was partitioned between 1 N hydrochloric acid and CH2Cl2 and the organic layer was separated, washed with water, dried (MgSO4), and evaporated. Crystallization of the residual glass from CH2Cl2 hexane afforded a white solid, melting point 173°-176° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][S:3]1.Cl.[CH3:11][O:12][C:13](=[O:20])[C@H:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[NH2:15]>C1COCC1>[CH3:11][O:12][C:13](=[O:20])[C@H:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[NH:15][C:7]([C@@H:5]1[CH2:4][S:3][C:2](=[O:1])[NH:6]1)=[O:9]
Reactant: O=C1N[C@H](C(=O)O)CS1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CSC(=O)N1

Procedure:
To a solution of (R)-(−)-2-oxo-thiazolidine-4-carboxylic acid (1.49 g, 10.2 mmols), L-Leucine methylester hydrochloride (1.85 g, 10.2 mmols) and N-methylmorpholinee (1.12 ml, 10.2 mmols) in anhydrous THF (15 ml), cooled at 0° C., was added, under stirring, a solution of DCDI (2.10 g, 10.2 mmols) and HBT (13 mg, 1 mmols) in anhydrous THF (8 ml). After standing one night at room temperature, the N,N′-dicyclohexylures and the hydrochloride of N-methylmorpholines were separated by filtration and the filtered substance was concentrated at reduced pressure. The product was purified by dilution of the raw reside with CHCl3 (50 ml) and extraction with saturated NaHCO3 solution (20 ml×2) and saturated NaCl solution (30 ml). Drying of the organic phase reunited on Na2SO4 and the removal of the solvent at reduced pressure provided the N-{[(R)-(2-Oxo-thiazolidine-4-yl)carbonyl]}-L-leucine methylester which was crystallized with EtOAc: 1.94 g (69%); m.p. 125-6° C.; [a]D22=−79° (1, methanol); IR (CHCl3): 3412, 2956, 1734, 1678, 1515, 1434, 1338, 1158 cm−1; 1H-NMR (CHCl3): d 0.90 and 0.95 [two s, 6, CH2CH(CH3)2], 1.42-74 [m, 3, CH2CH(CH3)2], 3.37-3.85 [m, 2, CH2S and 3.63 (s, 3, OCH3)], 4.18-4.69 (two m, 2, aCH and ring CH), 7.16 (d, 1, NH, J=8 Hz). Calculated for C11H17N2O4S: C, 48.34; H, 6.27; N, 10.25. Found C, 48.29; H, 6.80; N, 10.22%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C@@H:6]([NH2:8])[CH3:7])=[CH:4][CH:3]=1.C([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][C:36]([C:40](O)=[O:41])=[CH:37][CH:38]=3)[C:33]([CH3:43])=[C:32]2[CH3:44])=[CH:26][CH:25]=1)=[O:17])(C)(C)C>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C@@H:6]([NH:8][C:40]([C:36]2[CH:35]=[C:34]3[C:39](=[CH:38][CH:37]=2)[N:31]([CH2:30][C:27]2[CH:26]=[CH:25][C:24]([C:19]4[C:18]([C:16]([OH:17])=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:29][CH:28]=2)[C:32]([CH3:44])=[C:33]3[CH3:43])=[O:41])[CH3:7])=[CH:4][CH:3]=1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@H](N)c1ccc(F)cc1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3ccc(F)cc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 4-fluoro-α-(S)-methylbenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. LC-MS 521 (M+H).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:14])[C@@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6]>CO.[Rh]>[ClH:1].[CH3:2][O:3][C:4](=[O:14])[C@H:5]([NH2:6])[CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COC(=O)[C@H](N)Cc1ccccc1
Agent: [Rh]
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](N)CC1CCCCC1
Yield: 97 %

Procedure:
Commercially available D-Phenylalanine methyl ester hydrochloride (12 g) was hydrogenated using 5% rhodium on carbon (1.2 g) in 250 mL of methyl alcohol to yield (2R)-2-amino-3-cyclohexyl propanoic acid methyl ester hydrochloride in 97% yield. This (5.0 g, 18.4 mmole) was coupled with Boc-L-Proline (3.97 g, 18.4 mmole) by using standard methods [(1-hydroxybenzotriazole monohydrate (HOBt) (2.74 g, 20 mmole), N-Methylmorpholine (NMM) (2.23 mL, 20 mmole) and 1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (EDC) (3.89 g, 20 mmole) by the methods described in "Peptide Synthesis", Second Edition, Bodanszky, M.; Klausner, Y. S. and Ondetti, M. A., (1976) in 71% yield. The Boc-group was cleaved, and the obtained prolyl-(2R)-2-amino-3-cyclohexylpropanoic acid methyl ester hydrochloride was reacted with N-alpha-Cbz-N-epsilon-Boc-Lysine in quantitative yield according to the method mentioned above. The N-alpha-Cbz group was removed by hydrogenolysis (20%-palladium on charcoal 10% w/w) in acetic acid-isopropanol, and the obtained product was coupled with Boc-(N-Methyl)Phenylalanine by the method described above to obtain N-Boc-(N-Methyl)Phenylalanyl-Lysyl(N-epsilon-Boc)-Prolyl-{(2R)-2-Amino-3-cyclohexylpropanoic acid methyl ester in quantitative yield. Finally, the methyl ester (7.33 g, 9.5 mmole) was saponified by treatment with 1.5 equivalent molar of lithium hydroxide (598 mg, 14.25 mmole) in 115 mL of methanol-water (2:1) mixture to obtain the title compound in 83% yield.
Reaction SMILES: [CH3:1][C@@:2]12[C:17]([CH3:19])([CH3:18])[C@@H:5]([C:6]3[C:7](=[O:16])[N:8]([CH2:11][C:12]([F:15])([F:14])[F:13])[NH:9][C:10]=31)[CH2:4][CH2:3]2.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.ClCCl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH2:20]([N:9]1[C:10]2[C@@:2]3([CH3:1])[C:17]([CH3:19])([CH3:18])[C@H:5]([CH2:4][CH2:3]3)[C:6]=2[C:7](=[O:16])[N:8]1[CH2:11][C:12]([F:13])([F:14])[F:15])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(CC(F)(F)F)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(CC(F)(F)F)n1Cc1ccccc1
Temperature: 100 °C
Yield: 69.4 %

Procedure:
A mixture of (4S,7R)-7,8,8-trimethyl-2-(2,2,2-trifluoro-ethyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 47; 150 mg, 0.55 mmol), tetrabutylammonium iodide (220 mg, 0.60 mmol) and benzyl bromide (580 μL, 4.9 mmol) in dimethylformamide (2 mL) was heated in a pressure tube in an oil-bath at 100° C. for 20 h. Dichloromethane (75 mL) was added and the solution was washed with water (5×25 mL) and aqueous sodium thiosulfate (25 mL), dried (magnesium sulfate), filtered, evaporated and purified using an ISCO 40 g column, eluting with 20-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, co-evaporated with petroleum ether, triturated with petroleum ether, evaporated, and dried under high vacuum at 70° C. overnight to give (4S,7R)-1-benzyl-7,8,8-trimethyl-2-(2,2,2-trifluoro-ethyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (139 mg, 70%) as a white solid. ES(+)-MS (M+H) 365.
Reaction SMILES: [N:1]1([CH2:6][C:7](=[O:16])[C:8]([CH:11]2[O:15][CH2:14][CH2:13][O:12]2)([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[K+].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1.O>CS(C)=O>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][CH:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[C:7](=[O:16])[C:8]([CH:11]2[O:15][CH2:14][CH2:13][O:12]2)([CH3:10])[CH3:9])=[CH:22][CH:21]=1
Reactant: CC(C)(C(=O)Cn1ccnc1)C1OCCO1
Reactant: ClCc1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C(=O)C(Cc1ccc(Cl)cc1)n1ccnc1)C1OCCO1
Reaction time: 15 h
Yield: 30.6 %

Procedure:
30 g (0.131 mol) of 1-(imidazol-1-yl)-3-(dioxolan-2-yl)-3-methyl-butan-2-one are dissolved in 130 ml of dimethylsulphoxide, 7.5 g of powdered potassium hydroxide are added at 10° C., and 21 g of 4-chlorobenzyl chloride (0.131 mol), dissolved in 30 ml of dimethylsulphoxide, are added dropwise. After stirring has been carried out for 15 hours at 20° C., the suspension is poured onto 500 ml of water, the mixture is extracted with 600 ml of methylene chloride, the organic phase is extracted with 1 liter of water in each case, and the solvent is distilled off. The oily residue is taken up in 300 ml of diethyl ether, the other phase is filtered and the solvent is distilled off. 14 g (30.6% of theory) of 1-(4-chlorophenyl)-4-(dioxolan-2-yl)-2-(imidazol-1-yl)-4-methyl-pentan-3-one of refractive index nD20 =1.5490 are obtained.