Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C:5](=[O:17])[C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=1)=CC.[CH2:18]([Li])CCC.CI.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:18][C:11]1[CH:10]=[C:9]([O:12][C:13]([F:14])([F:15])[F:16])[CH:8]=[CH:7][C:6]=1[C:5]([NH2:4])=[O:17]
Reactant: CC=CNC(=O)c1ccc(OC(F)(F)F)cc1
Reactant: [Li]CCCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc(OC(F)(F)F)ccc1C(N)=O
Temperature: -30 °C
Yield: 75 %

Procedure:
To a solution of N-Propenyl-4-trifluoromethoxy-benzamide 12 (8.0 g, 33 mmol) in THF (100 mL) at −78° C. was added n-butyllithium (29 mL, 72 mmol of a 2.5 M solution in hexanes). The reaction mixture was warmed to −30° C. for 10 min and cooled back to −78° C. A solution of MeI (2.24 mL, 33 mmol) in THF (5 mL) was slowly added to the reaction mixture. The cooling bath was removed and once the reaction temperature warmed to 0° C., 3 N HCl (10 mL) was added and the resulting two phase mixture heated to 60° C. for 1 h. Upon completion of reaction, the solution was neutralized with aqueous sodium bicarbonate and extracted with ether. The combined organic layers were dried (sodium sulfate) and concentrated. The residue was purified by ether/hexane triturated to provide the title compound (colorless solid 75%). 1H NMR (400 MHz,CDCl3) δ7.50 (d, J=8.4 Hz, 1 H, Ar), 7.09 (m, 2 H, Ar), 5.74 (broad s, 2 H, NH2), 2.52 (s, 3 H, CH3)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Cl:21])[CH:19]=2)[NH:14][C:13](=[O:22])[C@@H:12]1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:24]([O-])([OH:26])=[O:25]>C(O)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[C:16]([N+:24]([O-:26])=[O:25])[CH:17]=[C:18]([Cl:21])[CH:19]=2)[NH:14][C:13](=[O:22])[C@@H:12]1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: C[C@H]1C(=O)Nc2ccc(Cl)cc2N1C(=O)OCc1ccccc1
Solvent: CC(=O)O
Product: C[C@H]1C(=O)Nc2c(cc(Cl)cc2[N+](=O)[O-])N1C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
The compound of Example III (1.5 g, 4.5 mmol) was nitrated in glacial acetic acid (15 ml). A total of 5 ml (124.3 mmol) of fuming nitric acid were added dropwise in the course of 4 hours at 0° C. to room temperature. The mixture was subsequently poured into 100 ml of ice-water, and the product, which was obtained in the form of a yellow solid, was filtered off, washed thoroughly with water, and dried. Melting point 85° C. (subl.).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH:9]=[C:10](Br)[C:5]=2[NH:4][N:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([CH2:33][C:34]#[N:35])[S:31][CH:32]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)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.O>[NH2:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH:9]=[C:10]([C:28]3[CH:29]=[C:30]([CH2:33][C:34]#[N:35])[S:31][CH:32]=3)[C:5]=2[NH:4][N:3]=1
Reactant: CC1(C)OB(c2csc(CC#N)c2)OC1(C)C
Reactant: Nc1n[nH]c2c(Br)cn(-c3ccccc3Cl)c(=O)c12
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: O
Solvent: CN(C)C=O
Product: N#CCc1cc(-c2cn(-c3ccccc3Cl)c(=O)c3c(N)n[nH]c23)cs1
Temperature: 120 °C
Reaction time: 8 h
Yield: 37.2 %

Procedure:
A mixture of 3-amino-7-bromo-5-(2-chlorophenyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in Step B of Example 18 (200 mg), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)acetonitrile (220 mg), tetrakis(triphenylphosphine)palladium(0) (68.1 mg), aqueous sodium carbonate solution (2 M, 0.589 mL) and N,N-dimethylformamide (3.0 mL) was stirred overnight at 120° C. under argon atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, methanol/ethyl acetate) to give the title compound (83.6 mg).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]([C:12]([OH:14])=O)[CH2:3]1.C1N=CN(C(N2C=NC=C2)=O)C=1.[C:27]1([C@H:37]([NH2:39])[CH3:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[C:27]1([C@H:37]([NH:39][C:12]([CH:4]2[CH2:3][C:2](=[O:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5]2)=[O:14])[CH3:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: O=C1CC(C(=O)O)Cc2ccccc21
Reactant: C[C@@H](N)c1cccc2ccccc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)C1CC(=O)c2ccccc2C1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
To a mixture of 4-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (4.6 g, 24.19 mmol) (Tetrahedron: Asymmetry 14, 2003, 3689; Journal of Medicinal Chemistry 25, 1982, 535), in DMF (20 mL), CDI (3.92 g, 24.19 mmol) was added. The reaction mixture was stirred at room temperature (RT) for 2 h. Then (R)-1-(naphthalen-1-yl)ethanamine (5.40 g, 31.5 mmol) was added and the reaction mixture was stirred at RT overnight. After completion of reaction, ice was added to the reaction mixture, solid precipitated out was filtered on Buchner funnel, washed with DM water (50 mL) and dried to get crude compound. Compound was further purified by flash chromatography (biotage) using eluent 15% ethyl acetate:hexane to yield the title compound (8 g, 96%); m/z 344.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1([CH2:22][CH2:23]OS(C)(=O)=O)[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]1)(=O)=O.[NH3:29]>CO>[CH2:7]1[C:8]2([CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)[CH2:22][CH2:23][NH:29][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCCC(CCOS(C)(=O)=O)(CCOS(C)(=O)=O)CC1
Reactant: N
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC2(CCNCC2)CC1
Temperature: 50 °C

Procedure:
A mixture of tert-butyl 4,4-bis(2-(methylsulfonyloxy)ethyl)azepane-1-carboxylate (500 mg, 1.12 mmol), MeOH (2 ml) and NH3 solution (1.5 ml) was heated at 50° C. in a sealed tube for 16 h. The reaction mixture was concentrated under reduced pressure and the crude material was washed with hexanes and dried to afford the desired compound as a yellowish semi-solid which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:11]([CH:19]([CH3:21])[CH3:20])[C:12](=[O:18])[N:13]([CH3:17])[C:14]=2[CH2:15]O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:22]1([OH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:11]([CH:19]([CH3:21])[CH3:20])[C:12](=[O:18])[N:13]([CH3:17])[C:14]=2[CH2:15][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[OH:28])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)n1c(Sc2cc(Cl)cc(Cl)c2)c(CO)n(C)c1=O
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)n1c(Sc2cc(Cl)cc(Cl)c2)c(Cc2ccccc2O)n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.1 %

Procedure:
To a solution of 100 mg of 4-(3,5-dichlorophenylthio)-5-(hydroxymethyl)-3-isopropyl-1-methyl-1,3-dihydro-2-imidazolone, 30 mg of phenol and 100 mg of triphenylphosphine in 5 mL of tetrahydrofuran at 0° C. was added 70 μL of diisopropylazodicarboxylate in 5 mL of tetrahydrofuran over 20 min. The reaction was stirred overnight warming to room temperature. The mixture was then diluted with ethyl acetate and washed with 0.5N hydrochloric acid solution then 0.5N sodium hydroxide solution, dried, concentrated and purified by flash chromatography eluting with 3:1 hexane: ethyl acetate to give 16 mg of a colourless oil. Mass spectrum (ES) m/z 423 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19]Br)[CH2:11][CH2:10]1.[Cl:22][C:23]1[CH:31]=[C:30]2[C:26]([C:27]([C:32]3[CH2:33][CH2:34][NH:35][CH2:36][CH:37]=3)=[CH:28][NH:29]2)=[CH:25][CH:24]=1.C(N(CC)CC)C>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][N:35]2[CH2:36][CH:37]=[C:32]([C:27]3[C:26]4[C:30](=[CH:31][C:23]([Cl:22])=[CH:24][CH:25]=4)[NH:29][CH:28]=3)[CH2:33][CH2:34]2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCN(C(=O)CCCCBr)CC1
Reactant: Clc1ccc2c(C3=CCNCC3)c[nH]c2c1
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(C(=O)CCCCN2CC=C(c3c[nH]c4cc(Cl)ccc34)CC2)CC1
Yield: 39.8 %

Procedure:
Following the same procedure reported in the Step 2 of EXAMPLE 13, the reaction of 1-(2-methoxyphenyl)-4-(5-bromovaleryl)piperazine (3.54 mmol) with 6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (3.54 mmol) and triethylamine (4.23 mmol) gave the alkylation product (715 mg, 40%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[Li]>N>[CH2:3]1[C:4]2[CH2:5][CH:6]=[CH:7][CH2:8][C:9]=2[CH2:10][CH:2]1[NH2:1]
Reactant: NC1Cc2ccccc2C1
Agent: N
Agent: [Li]
Product: NC1CC2=C(CC=CC2)C1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Liquid ammonia (80 ml) is condensed at −78° C. and 2-aminoindane (2 g, 15 mmol) is added, followed by lithium wire (2 g, 300 mmol) portionwise over 5 minutes. The reaction is stirred at −78° C. for 2 hours, then cautiously quenched with ethanol (100 ml) and warmed to ambient temperature overnight. Water is added, the mixture is extracted with ether and the combined organic extracts are washed with brine, dried (MgSO4) and evaporated to afford 2,3,4,7-tetrahydro-1H-inden-2-ylamine. [M+CH3CN] 177.
Reaction SMILES: [OH-].[Li+].[CH2:3]([C:5]1[NH:6][C:7]([C:11]([O:13]CC)=[O:12])=[C:8]([CH3:10])[N:9]=1)[CH3:4].CO>C1COCC1>[CH2:3]([C:5]1[NH:6][C:7]([C:11]([OH:13])=[O:12])=[C:8]([CH3:10])[N:9]=1)[CH3:4]
Reactant: CCOC(=O)c1[nH]c(CC)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1nc(C)c(C(=O)O)[nH]1
Temperature: 70 °C
Yield: 102.5 %

Procedure:
Lithium hydroxide (2 mL, 2 mmol, 1 M in H2O) was added to a solution of ethyl 2-ethyl-4-methyl-1H-imidazole-5-carboxylate (72 mg, 0.39 mmol) in THF:MeOH (6 mL/2 mL). The reaction mixture was heated at 70° C. for 4 h. The solvent was evaporated and dried in vacuo to give the title compound (61.6 mg, >99%) as a white solid which was directly used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:26](=[CH:27][CH:28]=1)[O:25][C:11]1([CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20]C(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:29].[C:31](Cl)(=O)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:30])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:26](=[CH:27][CH:28]=1)[O:25][C:11]1([CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:20])[CH3:31])[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:29]
Reactant: CC(=O)Cl
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C(=O)OC(C)(C)C)CC1)O2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C(C)=O)CC1)O2
Temperature: 25 °C
Yield: 98.4 %

Procedure:
A suspension of (±)-(E)-3-[4-oxo-spiro(chromane-2,4′-azepane)-6-yl]acrylic acid methyl ester hydrochloride salt (500 mg, 1.43 mmol, Intermediate 3) in DCM (15 ml) was treated with acetyl chloride (0.121 ml, 1.72 mmol) and DIPEA (0.507 ml, 2.86 mmol) and was stirred at RT for 1. The solution was evaporated under vacuum and the crude product was purified by chromatography column (eluent: DCM/MeOH 95:5) to give (±)-(E)-3-[1′-acetyl-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-acrylic acid methyl ester (503 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:29])[C:22]([O:24]C(C)(C)C)=[O:23])[C:17]1=[O:30])(=[O:14])=[O:13])[CH:6]=[CH:5]2.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:29])[C:22]([OH:24])=[O:23])[C:17]1=[O:30])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: C[C@@H](C(=O)OC(C)(C)C)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](C(=O)O)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.4 %

Procedure:
tert-Butyl (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate (0.643 g) was dissolved in DCM (19 ml), and trifluoroacetic acid (19 ml) was added. The mixture was stirred at room temperature for 2.5 h and then concentrated under reduced pressure. Anhydrous DCM (4 ml) was added and the solution concentrated under reduced pressure. Repetitive addition of DCM and concentration under reduced pressure provided the title compound (0.56 g) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])C(F)(F)F)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[OH-:17].[Na+]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:16])=[O:17])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)C(F)(F)F
Agent: [Na+]
Product: O=C(O)c1c[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Yield: 78 %

Procedure:
A mixture of 1.3 g (5.3 mmol) 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone and 26.5 ml of a 4 M aqueous solution of sodium hydroxide was heated at reflux for 4.5 h. The mixture was cooled to room temperature and washed with two 100-ml portions of tert-butyl methyl ether. The aqueous layer was acidified to pH 2-3 by addition of concentrated hydrochloric acid solution at 0° C. Extraction with three 100-ml portions of tert-butyl methyl ether, drying over sodium sulfate, filtration and concentration in vacuo gave 0.80 g (78%) of the crude title compound as a brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:7]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([O-:3])=[O:2].Br[CH:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH:25]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:8]1[C:13]([O:15][CH2:16][CH3:17])=[O:14])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1[nH]c2ccc([N+](=O)[O-])cc2c1-c1ccccc1
Product: CCOC(=O)c1c(-c2ccccc2)c2cc([N+](=O)[O-])ccc2n1C(c1ccccc1)c1ccccc1

Procedure:
Ethyl 1-benzhydryl-5-nitro-3-phenyl-1H-indole-2-carboxylate was prepared from ethyl 5-nitro-3-phenyl-1H-indole-2-carboxylate and bromodiphenylmethane according to the procedure of Example 1 Step 1 as a yellowish solid: 1H NMR (CDCl3) δ 0.92 (t, J=7.1 Hz, 3H, 4.08 (q, J=7.1 Hz, 2H, 6.86 (d, J=9.4 Hz, 1H, 7.20-7.50 (m, 15H, 7.89 (dd, J=9.3, 2.3 Hz, 1H, 7.97 (s, 1H, 8.47 (d, J=2.3 Hz, 1H, MS (ESI) m/z 477 (MH+); HRMS calcd for C30H25N2O4: 477.1812; found (ESI+): 477.1808.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[C:40]([N:43]([CH3:73])[NH:44][C:45](=[O:72])[C@H:46]([N:54]([CH3:71])[C:55](=[O:70])[C@H:56]([NH:68][CH3:69])[CH2:57][C:58]1[CH:67]=[CH:66][C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[CH:59]=1)[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)(=[O:42])[CH3:41].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](=[O:15])[N:68]([C@@H:56]([C:55](=[O:70])[N:54]([C@H:46]([CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[C:45]([NH:44][N:43]([C:40](=[O:42])[CH3:41])[CH3:73])=[O:72])[CH3:71])[CH2:57][C:58]1[CH:67]=[CH:66][C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[CH:59]=1)[CH3:69])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)NN(C)C(C)=O
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N(C)NC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
To a solution of (2E)-5-(tert-butyloxycarbonylamino)-5-methylhex-2-enoic acid (0.1 g, 0.42 mmol) in methylene chloride (5 ml) was added 1-hydroxy-7-azabenzotriazole (0.06 g, 0.42 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.08 g, 0.42 mmol) and the mixture was cooled to 0° C. Then (2R)-N-[(1R)-2-(N'-acetyl-N'-methylhydrazino)-1-benzyl-2-oxoethyl]-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide (0.13 g, 0.28 mmol) and diisopropylethylamine (0.062 ml, 0.36 mmol) were added and the mixture was stirred at room temperature overnight. Then methylene chloride (50 ml) was added and the mixture was washed with water (10 ml), saturated sodium bicarbonate (10 ml), brine (10 ml), dried (MgSO4), filtered and concentrated in vacuo. The product was chromatographed on silica (40 g) with heptane:ethyl acetate (1:1) to give 0.12 g (63%) of ((3E)-4-[N-((1R)-1-(N-[(1R)-2-(N'-acetyl-N'-methylhydrazino)-1-benzyl-2-oxoethyl]-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl]-1,1-dimethylbut-3-enyl)carbamic acid tert-butyl ester as a colourless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[NH:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([CH2:16][CH2:17][NH:18]C(OCC3C=CC=CC=3)=O)=[CH:11][CH:12]=2)[CH:7]1[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=1)[CH3:2].Br>C(O)(=O)C.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:37])[NH:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([CH2:16][CH2:17][NH2:18])=[CH:11][CH:12]=2)[CH:7]1[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=1)[CH3:2]
Reactant: CCOC(=O)NC1CCc2ccc(CCNC(=O)OCc3ccccc3)cc2C1Cc1cccc(Cl)c1
Agent: Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)NC1CCc2ccc(CCN)cc2C1Cc1cccc(Cl)c1
Yield: 105.5 %

Procedure:
To [7-(2-benzyloxycarbonylamino-ethyl)-1-(3-chloro-benzyl)-1,2,3,4-tetrahydronaphthalen-2-yl]-carbamic acid ethyl ester (500 mg, 0.960 mmol) was added at room temperature 8 ml of 33% HBr in acetic acid. After 2 h the mixture was diluted with CH2Cl2, washed twice with NaHCO3, dried and filtered. The solvent was evaporated to obtain the product as a yellow oil (392 mg), which was used without further purification.
Reaction SMILES: C(OC([NH:8][C:9]([NH:25]C(OC(C)(C)C)=O)=[N:10][C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=2)[CH:14]=[CH:13][C:12]=1[CH3:24])=O)(C)(C)C.[ClH:33]>ClCCl.O1CCOCC1>[ClH:33].[ClH:33].[CH3:24][C:12]1[CH:13]=[CH:14][C:15]([C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=2)=[CH:16][C:11]=1[NH:10][C:9]([NH2:25])=[NH:8]
Reactant: Cc1ccnc(-c2ccc(C)c(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccnc(-c2ccc(C)c(NC(=N)N)c2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(2-methyl-5-(4-methylpyridin-2-yl)phenyl)guanidine (200 mg) in dichloromethane (2 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 4 ml), and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure. To the residue were added ethanol (2 ml) and ethyl acetate (10 ml), and the precipitate was collected by filtration and dried under reduced pressure to give (2-methyl-5-(4-methylpyridin-2-yl)phenyl)guanidine dihydrochloride (127 mg).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[CH2:17][C@H:18]1[O:22][C:21](=[O:23])[CH2:20][CH2:19]1.N1C(C)=CC=CC=1C>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][CH2:17][C@@H:18]1[CH2:19][CH2:20][C:21](=[O:23])[O:22]1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C1CC[C@@H](CO)O1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: O=C1CC[C@@H](COS(=O)(=O)C(F)(F)F)O1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Trifluoromethanesulfonic anhydride (0.97 g, 3.4 mmol) was added dropwise to a 0° C. solution of (S)-5-(hydroxymethyl)-dihydrofuran-2(3H)-one (0.20 g, 1.7 mmol) and lutidine (0.41 g, 3.8 mmol) in CH2Cl2 (2 mL). The reaction was stirred at 0° C. for 1.5 hours, then diluted with 1:4 EtOAc/hexanes and passed through a plug of silica gel. The volatiles were removed under reduced pressure to yield a yellow oil which was used immediately without purification (0.38 g, 89%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:13][C:12]([C:22](=[O:24])[CH3:23])=[CH:11][C:10]=1[C:25]([CH3:28])([CH3:27])[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1)([OH:31])=[O:30].[OH-].[K+].Cl>CO>[CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)=[CH:13][C:12]([C:22](=[O:24])/[CH:23]=[CH:36]/[C:35]2[CH:38]=[CH:39][C:32]([C:29]([OH:31])=[O:30])=[CH:33][CH:34]=2)=[CH:11][C:10]=1[C:25]([CH3:28])([CH3:27])[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1cc(-c2ccc(C)cc2)c(OCc2ccccc2)c(C(C)(C)C)c1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2cc(C(=O)/C=C/c3ccc(C(=O)O)cc3)cc(C(C)(C)C)c2OCc2ccccc2)cc1
Reaction time: 36 h
Yield: 38 %

Procedure:
970 mg (2.6 mmol) of 1-(6-benzyloxy-5-tert-butyl-4′-methyl-3-biphenylyl)ethanone are dissolved in 40 mL of methanol. 350 mg (2.3 mmol) of 4-carboxybenzaldehyde are added, followed by 1.23 mL (10 mmol) of 47% KOH. The reaction medium is stirred for 36 hours and then acidified with concentrated hydrochloric acid. The medium is extracted with ethyl acetate, and the residue obtained is purified by chromatography on a column of silica. The solid obtained is recrystallized from an ethyl ether/heptane mixture. A yellow powder is obtained (m=500 mg; yield=38%; m.p.=208° C.).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:9]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[N:28])[CH:22]=2)=[N:10][C:11]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:12][CH:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[C:9]([O:20][C:21]2[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=2)[C:27]#[N:28])=[N:10][C:11]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(-c2cccnc2)nc1Oc1cccc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(Oc2nc(-c3cccnc3)ncc2N)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of Compound 14g (0.78 g; 2.0 mmol) in CH2Cl2 (20 mL) was added TFA (4 mL). The mixture was stirred at room temperature for 4 h. The solvent was evaporated under reduced pressure to afford Compound 14h. The crude product was used in the next reaction without further purification. MS: m/z 290.3 (M+H)+.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[F:23])=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.[F:24][C:25]1[CH:26]=[C:27]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[CH:28]=[C:29]([F:32])[C:30]=1O>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:8]2[C:7]([CH2:6][O:5][C:30]3[C:29]([F:32])=[CH:28][C:27]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[CH:26][C:25]=3[F:24])=[C:11]([C:12]([F:15])([F:14])[F:13])[S:10][N:9]=2)=[C:17]([F:23])[CH:18]=1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Reactant: CS(=O)(=O)OCc1c(-c2ccc(Cl)cc2F)nsc1C(F)(F)F
Product: O=C(O)CCc1cc(F)c(OCc2c(-c3ccc(Cl)cc3F)nsc2C(F)(F)F)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (3-(2-fluoro-4-chlorophenyl)-5-(trifluoromethyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ 7.30-7.44 (m, 3H), 6.73-6.81 (m, 2H), 5.16 (s, 2H), 2.84 (t, J=7.5 Hz, 2H), 2.58 (t, J=7.5 Hz, 2H) Mass spectrum (ESI, m/z): Calcd. for C20H12ClF6NO3S, 496.0 (M+H). found 496.0.