Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:21])[C@H:4]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH:5][C:6](=[O:13])[C@H:7]([CH2:9][C:10](=[O:12])[OH:11])[NH2:8].N[C@H](C(O)=O)CC1C=CC=CC=1>>[NH2:8][C@H:7]([C:6]([NH:5][C@H:4]([C:3]([OH:21])=[O:2])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:13])[CH2:9][C:10](=[O:11])[OH:12]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Product: N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
A regioselective process for the preparation of α-L-aspartyl-L-phenylalanine methyl ester is disclosed. A controlled aqueous coupling reaction between β-methyl-L-aspartate-N-carboxyanhydride and L-phenylalanine produces the aspartyl methyl ester of α-L-aspartyl-L-phenylalanine which is subsequently hydrolyzed and selectively esterified without isolation. The hydrochloride salt of α-L-aspartyl-L-phenylalanine methyl ester, which is selectively precipitated from the esterification mixture, can be neutralized to α-L-aspartyl-L-phenylalanine methyl ester.
Reaction SMILES: [NH2:1][C@H:2]1[C:11]2[C:6](=[C:7]([Br:16])[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][C@@H:4]([CH:17]2[CH2:19][CH2:18]2)[CH2:3]1.C(O)(=O)C.[F:24][C:25]([F:39])([F:38])[C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH:29]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:24][C:25]([F:38])([F:39])[C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:33]=1)[CH2:29][NH:1][C@H:2]1[C:11]2[C:6](=[C:7]([Br:16])[CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=2)[NH:5][C@@H:4]([CH:17]2[CH2:18][CH2:19]2)[CH2:3]1
Reactant: N[C@@H]1C[C@H](C2CC2)Nc2c(Br)cc(C(F)(F)F)cc21
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: FC(F)(F)c1cc(CN[C@@H]2C[C@H](C3CC3)Nc3c(Br)cc(C(F)(F)F)cc32)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.8 %

Procedure:
To a solution of cis-4-amino-8-bromo-2-cyclopropyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinoline (Example 100A) (250 mg, 0.75 mmol) in anhydrous dichloromethane (10 mL) was added acetic acid (112 mg, 1.90 mmol), followed by 3,5-bis(trifluoromethyl)benzaldehyde (180 mg, 0.75 mmol) and sodium triacetoxyborohydride (791 mg, 3.73 mmol). The reaction was stirred at room temperature for 5 h. The reaction mixture was then diluted with dichloromethane and washed with 1N NaOH. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to afford the title crude product (420 mg) which was used without further purification. 1H NMR (CDCl3) δ 0.3 (m, 2H), 0.6 (m, 2H), 1.0 (m, 1H), 7.5 (s, 1H), 7.8 (s, 2H), 7.9 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][CH2:17][C:18]#[N:19])[C:10]([CH:20]=[N:21][O:22][CH3:23])=[CH:9]2.[N:29]([Si](C)(C)C)=[N+:30]=[N-:31].C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:23][O:22][N:21]=[CH:20][C:10]1[N:11]([CH2:15][CH2:16][CH2:17][C:18]2[NH:31][N:30]=[N:29][N:19]=2)[C:12]2[C:8]([CH:9]=1)=[CH:7][C:6]([O:5][CH2:4][C:3]1[C:24]([Cl:28])=[CH:25][CH:26]=[CH:27][C:2]=1[Cl:1])=[CH:14][CH:13]=2
Reactant: CON=Cc1cc2cc(OCc3c(Cl)cccc3Cl)ccc2n1CCCC#N
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CON=Cc1cc2cc(OCc3c(Cl)cccc3Cl)ccc2n1CCCc1nnn[nH]1
Yield: 57.6 %

Procedure:
To a solution of 4-[5-(2,6-dichlorobenzyloxy)-2-(methoxyiminomethyl)indol-1-yl]butyronitrile (0.07 g, 0.17 mmol) in toluene (3 mL) was added azidotrimethylsilane (0.067 mL, 0.55 mmol) and dibutyltin oxide (0.014 g, 0.055 mmol). The reaction was refluxed for 16 h. The solvent was removed under reduced pressure and the crude product was purified by HPLC to yield a yellow foaming solid (0.045 g, 58%). MS(ES) m/e 459.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:19](=[O:20])[N:18]2[C:12]([CH2:13][S:14][CH2:15][CH2:16][CH2:17]2)=[N:11][C:10]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.IC.[Li+].[CH3:29][Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH2:1]([O:8][C:9]1[C:19](=[O:20])[N:18]2[C:12]([CH:13]([CH3:29])[S:14][CH2:15][CH2:16][CH2:17]2)=[N:11][C:10]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCCSC2
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCCSC2C
Reaction time: 1.5 h
Yield: 11.2 %

Procedure:
To a stirred solution of ethyl 3-(benzyloxy)-4-oxo-6,7,8,10-tetrahydro-4H-pyrimido[2,1-c][1,4]thiazepine-2-carboxylate (0.180 g, 0.5 mmol) and iodomethane (0.62 mL, 10 mmol) in THF (5 mL) at −78 C was added 1M solution of LiHMDS (1 mL, 1 mmol) over 2 minutes. After 1.5 h, the reaction mixture was quenched with saturated aq. NH4Cl, diluted with EtOAc (50 mL), dried (Na2SO4), filtered, concentrated and the residue was purified by Prep-HPLC to afford the desired product as orange solid (0.021 g, 11%). 1H NMR (500 MHz, CDCl3) δ: 7.48-7.46 (2H, m), 7.37-7.29 (3H, m), 5.24 (2H, s), 5.15 (1H, dd, J=13.9, 4.4 Hz), 4.33 (2H, q, J=7.0 Hz), 4.18 (1H, q, J=7.0 Hz), 3.62 (1H, dd, J=13.6, 12.1 Hz), 3.14-3.09 (1H, m), 2.77 (1H, dt, J=14.4, 4.2 Hz), 2.34-2.27 (1H, m), 1.91-1.82 (1H, m), 1.62 (3H, d, J=7.0 Hz), 1.30 (3H, t, J=7.0 Hz). HRMS (M+H) calcd for C19H23N2O4S: 375.1379; found: 375.1375.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]([N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1)=O)=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC.O>[NH2:1][CH2:4][CH2:5][CH2:6][CH2:7][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: [N-]=[N+]=NCCCC(=O)N1CCCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: NCCCCN1CCCc2ccccc21

Procedure:
The 1-(4-azidobutanoyl)-1,2,3,4-tetrahydroquinoline (3.9 g) was refluxed in ether containing lithium aluminium hydride (1.8 g) for 5 hours. The solution was cooled and diluted cautiously with water. The organic phase was washed, dried and evaporated to afford the title compound as an oil, which was then converted to the dimaleate mp 79°-81°.
Reaction SMILES: [CH3:1][N:2]([C:9]1[CH:14]=[N:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=1)[C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH2:8].[N:19]1[N:20]([C:24]2[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=2[C:26](O)=[O:27])[N:21]=[CH:22][CH:23]=1.C(Cl)CCl.N1C2C(=NC=CC=2)N(O)N=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][N:2]([C:9]1[CH:14]=[N:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][N:10]=1)[C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=1[N:20]1[N:21]=[CH:22][CH:23]=[N:19]1
Reactant: O=C(O)c1ccccc1-n1nccn1
Reactant: CN(c1cnc(C(F)(F)F)cn1)[C@H]1CCC[C@@H]1N
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN(c1cnc(C(F)(F)F)cn1)[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-n1nccn1

Procedure:
A solution of (1S,2S)-1-N-methyl-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine (Intermediate 22; 59 mg, 0.23 mmol), 2-(2H-1,2,3-triazol-2-yl)benzoic acid (CAS number 1001401-62-2; 51.5 mg, 0.27 mmol), EDC (65.2 mg, 0.34 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (52.4 mg, 0.34 mmol) and triethylamine (0.095 ml, 0.68 mmol) in DCM (2 ml) was stirred at room temperature for 18 hours. The reaction mixture was diluted with DCM (3 ml) and washed with HCl (aq, 1M, 2 ml) then a saturated solution of sodium bicarbonate (2 ml). The organics were filtered through a hydrophobic frit and concentrated in vacuo. The resulting residue was purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[NH:6][CH3:7].C(O[CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[N:6]([CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:7]
Reactant: CNc1cccc(OC)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(=CN(C)c1cccc(OC)c1)C(=O)OCC
Temperature: 25 °C

Procedure:
A mixture of 3-methoxy-N-methylaniline (44 g) and diethyl ethoxymethylenemalonate (69 ml) was heated on a steam bath for 2 hours, the ethanol formed being removed by distillation. The residue was cooled to ambient temperature to give the novel compound diethyl (3-methoxy-N-methylanilino)methylenemalonate as an oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([P:17]([C:25]2[CH:30]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:28]([O:35][CH3:36])=[C:27]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:26]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2Br)[CH:8]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].Cl[P:42]([O:46][CH2:47][CH3:48])[O:43][CH2:44][CH3:45]>O1CCCC1>[C:1]([C:5]1[CH:6]=[C:7]([P:17]([C:25]2[CH:30]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:28]([O:35][CH3:36])=[C:27]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:26]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[P:42]([O:46][CH2:47][CH3:48])[O:43][CH2:44][CH3:45])[CH:8]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(C(C)(C)C)cc(P(c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)c2ccccc2Br)cc1C(C)(C)C
Reactant: CCOP(Cl)OCC
Solvent: C1CCOC1
Product: CCOP(OCC)c1ccccc1P(c1cc(C(C)(C)C)c(OC)c(C(C)(C)C)c1)c1cc(C(C)(C)C)c(OC)c(C(C)(C)C)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
Into a four-neck flask was weighed 15.00 g (24.0 mmol) of the bis(3,5-di-t-butyl-4-methoxyphenyl)(2-bromophenyl)phosphine (7). The atmosphere of the reaction vessel which was fitted with a thermometer, a condenser tube, and a dropping funnel with a pressure-equalizing tube was completely replaced with nitrogen, and 150 mL of anhydrous tetrahydrofuran (hereinafter referred to as THF) was added thereto. Thereto was added dropwise 16.2 mL (25.2 mmol) of n-butyllithium-hexane (1.6 M) solution at −78° C. over a period of 30 minutes, followed by 1 hour of stirring at the same temperature. The resulting mixed solution was cooled to −78° C. and thereto was added dropwise a 10 mL THF solution of 4.15 g (25.2 mmol) of diethyl chlorophosphonite (manufactured by Aldrich) over a period of 30 minutes. After the dropwise addition, a cooling bath was removed and the whole was further stirred at room temperature for 15 hours. After the completion of the reaction, THF was removed by evaporation, the residue was dissolved in 50 mL of diethyl ether, and insoluble matter was removed by filtration. The solvent was removed by evaporation and the residue was purified by active alumina column chromatography (eluent: hexane/ethyl acetate 4/1) to obtain the title compound (14.03 g, a pale yellow solid) Yield 91.5%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([F:9])[C:3]=1[OH:10].[F:11][C:12]1[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:13]=1[C:14](O)=O.[OH-].[Na+]>CCOC(C)=O.O>[Br:8][C:6]1[CH:5]=[C:4]([F:9])[C:3]2[O:10][C:14]([C:13]3[CH:17]=[CH:18][C:19]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:20][C:12]=3[F:11])=[N:1][C:2]=2[CH:7]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(F)c1
Reactant: Nc1cc(Br)cc(F)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2nc3cc(Br)cc(F)c3o2)c(F)c1
Temperature: 195 °C

Procedure:
2-Amino-4-bromo-6-fluorophenol (2.6 g, 9.7 mmol) and 2-fluoro-4-(methylsulfonyl)benzoic acid (2.1 g, 9.7 mmol) were dissolved in polyposphoric acid (63.5 g). This mixture was heated at 195° C. for three and half hours. Reaction mixture cooled to rt and diluted with ice water (100 ml). Aqueous layer basified with sodium hydroxide pellets to pH 9. Work up (EtOAc/H2O) followed by evaporation of EtOAc afforded the crude. Crude (3.1 g) was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]1[CH2:8][N:7]([C:9](=[O:19])[C@@H:10]([NH:14][C:15](=[O:18])[O:16][CH3:17])[CH:11]([CH3:13])[CH3:12])[C@H:6]([C:20]2[NH:24][C:23]3[C:25]4[C:30]([CH:31]=[CH:32][C:22]=3[N:21]=2)=[CH:29][C:28]2[C:33]3[C:38]([CH2:39][O:40][C:27]=2[CH:26]=4)=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=3)[CH2:5]1)[CH3:2].Br[C:51]1[NH:55][C:54]([C@@H:56]2[CH2:60][CH2:59][CH2:58][N:57]2[C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])=[N:53][CH:52]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CN(C=O)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C@@H:4]1[CH2:8][N:7]([C:9](=[O:19])[C@H:10]([CH:11]([CH3:13])[CH3:12])[NH:14][C:15]([O:16][CH3:17])=[O:18])[C@H:6]([C:20]2[NH:24][C:23]3[C:25]4[C:30]([CH:31]=[CH:32][C:22]=3[N:21]=2)=[CH:29][C:28]2[C:33]3[C:38]([CH2:39][O:40][C:27]=2[CH:26]=4)=[CH:37][C:36]([C:51]2[NH:55][C:54]([C@@H:56]4[CH2:60][CH2:59][CH2:58][N:57]4[C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])=[N:53][CH:52]=2)=[CH:35][CH:34]=3)[CH2:5]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(Br)[nH]1
Reactant: CCO[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2-5)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCO[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(-c3cnc([C@@H]4CCCN4C(=O)OC(C)(C)C)[nH]3)ccc2-5)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Temperature: 85 °C
Reaction time: 6 h
Yield: 33.7 %

Procedure:
To a solution of methyl [(2S)-1-{(2S,4S)-4-ethoxy-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate (0.41 g, 0.61 mmol) in a mixture of DME (6.1 mL) and DMF (1.0 mL) was added (S)-tert-butyl 2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (0.39 g, 1.2 mmol), tetrakis(triphenylphosphine)palladium (0.021 g, 0.018 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.030 g, 0.041 mmol), and aqueous potassium carbonate (2M, 1.0 mL, 2.0 mmol). The solution was degasses with argon for 5 min and heated, with stirring, to 85° C. for 6 h. The solution was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water and brine. The aqueous layers were back extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (20% to 100% EtOAc (w/5% MeOH)/Hexanes to 80% MeOH/EtOAc) to afford tert-butyl (2S)-2-[5-(2-{(2S,4S)-4-ethoxy-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate (0.16 g, 33%).
Reaction SMILES: C(O[C@H:5]1[C@H:10]([N:11]=[C:12]=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=O)C.Cl.[F:28][CH2:29][CH2:30][NH2:31].C(N(CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[C:19]([O:18][C@@H:8]1[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6][C@H:5]2[C@H:10]([N:11]=[C:12]([NH:31][CH2:30][CH2:29][F:28])[S:13]2)[C@H:9]1[O:14][C:15](=[O:17])[CH3:16])(=[O:21])[CH3:20]
Reactant: NCCF
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OC[C@H]1O[C@@H]2SC(NCCF)=N[C@@H]2[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
A solution of (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-isothiocyanato-tetrahydro-2H-pyran-2,4,5-triyl triacetate (30 g, 77 mmol) in dichloromethane (100 mL) was added 2-fluoroethylamine hydrochloride (8.4 g, 84 mmol) and triethylamine (11.7 mL, 115 mmol). The resulting solution was stirred for 1 hour at room temperature, and then condensed to give a light yellow foam, which was dissolved into dichloromethane (100 mL) and treated with 2,2,2-trifluoroacetic acid (75.6 g, 663 mmol) overnight at room temperature. The reaction mixture was quenched by saturated aqueous sodium carbonate (500 mL), washed with sodium chloride (3×50 mL), dried over anhydrous magnesium sulfate, and concentrated under vacuum to give a residue, which was purified by a silica gel column, eluting with 50% ethyl acetate in petroleum ether to provide compound 66 as a light yellow oil (24 g, 70%). (ES, m/z) [M+H]+ 393.0; 1H NMR (300 MHz, CDCl3) δ 6.27-6.29 (d, J=6.60 Hz, 1H), 5.42-5.44 (1, J=2.7 Hz, 1H), 4.95-4.99 (dd, J=1.8 Hz, 9.5 Hz, 1H), 4.70-4.73 (m, 1H), 4.54-4.65 (m, 1H), 4.37-4.39 (t, J=0.9 Hz, 1H), 4.16-4.17 (m, 2H), 3.81-3.87 (m, 1H), 3.56-3.71 (m, 2H), 2.09 (s, 3H), 2.11 (s, 3H), 2.14 (s, 3H),
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([NH2:8])=[N:5][CH:4]=1)[CH3:2].[C:9]1([CH:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16](Cl)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:1]([C:3]1[O:7][C:6]([NH:8][C:16](=[O:17])[CH:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:5][CH:4]=1)[CH3:2]
Reactant: CCc1cnc(N)o1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: CCc1cnc(NC(=O)C(c2ccccc2)c2ccccc2)o1

Procedure:
The title compound, white solid, m.p. 148-149° C. and MS: m/e=307.3 (M+H+) was prepared in accordance with the general method of example 44a from 5-ethyl-oxazol-2-ylamine and 2,2-diphenylacetic acid chloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1F)[CH3:2].[NH:13]1[CH:17]=[CH:16][N:15]=[C:14]1[CH2:18][N:19]([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.CC(=O)OCC>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:13]1[CH:17]=[CH:16][N:15]=[C:14]1[CH2:18][N:19]([CH3:21])[CH3:20])[CH3:2]
Reactant: CCOC(=O)c1ccccc1F
Reactant: CN(C)Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccccc1-n1ccnc1CN(C)C
Temperature: 120 °C
Reaction time: 16 h
Yield: 17.8 %

Procedure:
A mixture of 2-fluoro-benzoic acid ethyl ester (200 mg; 1.19 mmol; 10 eq.), (1H-imidazol-2-ylmethyl)-dimethyl-amine (149 mg; 1.19 mmol; 1 eq.) and cesium carbonate (775 mg; 2.38 mmol; 2 eq.) in DMSO (3 mL) was stirred at 120° C. for 16 hours. The mixture was diluted with EA, washed with water (3×), dried over magnesium sulfate and concentrated in vacuo to afford the title compound (58 mg, 18%) as a white solid. HPLC (max plot) 95.7%; Rt 1.80 min.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:22][CH2:23][CH3:24])[N:10]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.C1CCCCC=1>>[CH2:22]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[C:9]([C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)=[N:10]1)[CH2:23][CH3:24]
Reactant: CCCn1nc(-c2ccc(OC)cc2)c2cccc(C(F)(F)F)c21
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: CCCn1nc(-c2ccc(O)cc2)c2cccc(C(F)(F)F)c21
Yield: 86.3 %

Procedure:
Prepared according to Method D step C from 3-(4-methoxyphenyl)-1-propyl-7-trifluoromethyl-1H-indazole (0.058 g, 0.17 mmol), boron tribromide (0.094 mL, 1.0 mmol) and 0.3 mL of cyclohexene to give the product (0.047 g) as an off-white solid.
Reaction SMILES: [C:1]([C@H:5]1[C@@H:16]2[C:17]3[C:8](=[CH:9][C:10]([O:24][CH3:25])=[CH:11][C:12]=3[CH2:13][C@@H:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15]2)[CH2:7][CH2:6]1)([O:3]C)=[O:2].[OH-].[Na+]>CO>[CH3:25][O:24][C:10]1[CH:9]=[C:8]2[C:17]3[C@H:16]([CH2:15][C@H:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:13][C:12]=3[CH:11]=1)[C@H:5]([C:1]([OH:3])=[O:2])[CH2:6][CH2:7]2
Reactant: COC(=O)[C@@H]1CCc2cc(OC)cc3c2[C@@H]1C[C@H](c1ccccc1)C3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2c3c(c1)C[C@@H](c1ccccc1)C[C@@H]3[C@H](C(=O)O)CC2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Crude [1R,8S,9aR] 1-carbomethoxy-5-methoxy-8-phenyl-2,3,7,8,9,9a-hexahydrophenalene (0.8 g., 2.1 mmol), from Step 4, is dissolved in 100 mL of methanol and 8 mL of 1N aqueous sodium hydroxide is added. After stirring for 3 days at ambient temperature, the methanol is removed under reduced pressure. The residue is partitioned between 50 mL of diethyl ether and 75 mL of water. The aqueous phase is acidified to pH 2 with 6M aqueous hydrochloric acid solution and the product is extracted with 3×25 mL of 1:1 ethyl acetate:diethyl ether. The combined organic layers are washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:7][C:4]=1[CH:5]=O.[C:18]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([OH:26])=[O:25])(=[O:20])[CH3:19]>>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:7][C:4]=1/[CH:5]=[CH:19]/[C:18]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([OH:26])=[O:25])=[O:20]
Reactant: COc1cc(OC)c(-c2cccs2)cc1C=O
Reactant: CC(=O)c1cccc(C(=O)O)c1
Product: COc1cc(OC)c(-c2cccs2)cc1/C=C/C(=O)c1cccc(C(=O)O)c1
Yield: 65 %

Procedure:
The title compound was prepared by condensing 2,4-dimethoxy-5-(thiophen-2-yl)-benzaldehyde (Ex-6A) and 3-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, 65% yield, mp 179–182° C. 1H-NMR (DMSO-d6) δ 8.54 (s, 1H), 8.39 (d, 1H), 8.25 (s, 1H), 8.15 (d, 1H), 8.04 (d, 1H), 7.90 (d, 1H), 7.67 (m, 2H), 7.48 (d, 1H), 7.09 (t, 1H), 6.81 (s, 1H), 3.98 (s, 3H), 3.97 (s, 3H). MS m/z=394 ([M]+, 72%), 363 (100%). Anal. calculated for C22H18O5S: C, 66.99; H, 4.60; S, 8.13; found C, 66.80; H, 4.60; S, 8.07.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([NH:9][NH2:10])=[O:8])=[CH:2]1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[C:19](O)=O.N>P(Cl)(Cl)(Cl)=O>[S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]2[O:8][C:19]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[C:12]([F:23])([F:11])[F:22])=[N:10][N:9]=2)=[CH:2]1
Reactant: NNC(=O)Cc1ccsc1
Reactant: O=C(O)c1cnccc1C(F)(F)F
Agent: N
Solvent: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1ccncc1-c1nnc(Cc2ccsc2)o1
Temperature: 0 °C
Yield: 39.9 %

Procedure:
880 mg of thiophene-3-acetic hydrazide were added to a solution of 960 mg of 4-trifluoromethylpyridine-3-carboxylic acid in 5 ml of phosphorus oxychloride, and the mixture was heated at reflux for 2 hours. The reaction mixture was subsequently added dropwise to ice-water, made neutral using concentrated ammonia solution and extracted with ethyl acetate. Drying (Na2SO4), concentration and chromatographic purification gave 624 mg of the desired product as a slightly brown oil.
Reaction SMILES: ClC1C=C(Cl)C=CC=1OC[C:6]1[NH:7][C:8]2[CH:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][C:9]=2[N:10]=1.[CH2:23]([NH2:29])[C:24]1[O:28][CH:27]=[CH:26][CH:25]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C>[O:28]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH2:23][NH:29][C:15]([C:13]1[CH:12]=[CH:11][C:9]2[N:10]=[CH:6][NH:7][C:8]=2[CH:14]=1)=[O:17]
Reactant: O=C(O)c1ccc2nc(COc3ccc(Cl)cc3Cl)[nH]c2c1
Reactant: NCc1ccco1
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccco1)c1ccc2nc[nH]c2c1
Temperature: 25 °C
Yield: 87 %

Procedure:
To solution of 2-(2,4-dichloro-phenoxymethyl)-3H-benzoimidazole-5-carboxylic acid (22.2 mg, 0.07 mmol), furfuryl amine (10.7 mg, 0.11 mmol, 0.01 ml), EDC (21.1 mg, 0.11 mmol) and HOBt (14.9 mg, 0.11 mmol) in DMF 3.0 mL was added DIPEA (14.2 mg, 0.11 mmol, 0.02 ml). After stirring at room temperature, the mixture was partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by Prep-TLC (n-Hexane:EtoAc:MeOH=6:3:1) to give 2-2,4-dichloro-phenoxymethyl)-3H-benzoimidazole-5-carboxylic acid (furan-2-ylmethyl)-amide as a white solid (14.7 mg, yield: 37.92%).