Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:38]4[C:39]([C:44]([O:46]C)=[O:45])=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:33]=[CH:34][C:35]=3[O:36][CH3:37])[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[K+].O.Cl>C(O)C>[F:50][C:2]([F:1])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:38]4[C:39]([C:44]([OH:46])=[O:45])=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:33]=[CH:34][C:35]=3[O:36][CH3:37])[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: COC(=O)c1ccccc1-c1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2ccccc2C(=O)O)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
Methyl 2″-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4′ methoxy-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-2-carboxylate (50 mg, 0.07 mmol), aqueous potassium hydroxide (1.1 mL, 3M, 3.3 mmol), water (1.5 mL) and ethanol (3.6 mL) were stirred at 20° C. for 23 hours. The reaction mixture was acidified by HCl (aq., 1N). Volatiles were removed under reduced pressure. The resulting mixture was worked up with ethyl acetate, washed with brine. The combined organic extracts were dried over Na2SO4, filtered, and concentrated to an oil. This oil was purified by a reverse-phase preparative HPLC (column: Kromasil 100-5C18, 100×21.1 mm) eluting with a MeCN (0.1% v/v TFA buffered)/H2O (0.1% v/v TFA buffered) gradient mixture to afford 2″-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4′-methoxy-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-2-carboxylic acid. LCMS calc.=697.15; found=698.16 (M+1)+. 1H NMR signals are doubled because of atropisomerism 1H NMR (CDCl3, 500 MHz) δ 7.94 (t, J=7.0 Hz, 1H), 7.85 (d, J=7.0 Hz, 1H), 7.68-7.63 (m, 2.5H), 7.63-7.59 (m, 1.5H), 7.59-7.54 (m, 1H), 7.47-7.35 (m, 4H), 7.14 (dd, J=8.0, 2.0 Hz, 1H), 7.04 (d, J=8.5 Hz, 1H), 5.53 (d, J=8.0 Hz, 0.4H), 5.42 (d, J=8.0 Hz, 0.6H), 5.02 (d, J=15.5 Hz, 0.6H), 4.85 (d, J=15.5 Hz, 0.4H), 4.11-4.02 (m, 0.4H), 3.87-3.77 (m, 3.6H), 0.99 (d, J=6.5 Hz, 0.6H), 0.93 (d, J=7.0 Hz, 0.4H), 0.58 (d, J=7.0 Hz, 1.2H), 0.54 (d, J=6.5 Hz, 1.8H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:17]O>>[NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: CO
Reactant: Nc1c(Br)cccc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(Br)c1N

Procedure:
2-amino-3-bromobenzoic acid (1.00 g) was mixed with methanol (10 ml) and concentrated sulfuric acid (1 ml). The mixture was stirred at reflux for 31 hours. The solvent were evaporated, and saturated aqueous sodium bicarbonate was carefully added. The solid was extracted with CH2Cl2 (3×). The combined extracts were dried over Na2SO4 and the solvents removed in vacuo to afford methyl 2-amino-3-bromobenzoate as a semi-crystalline solid (976 mg, 91% yield). LCMS (ES): >85% pure, m/z 230 [M+1]+.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:8][C:7]=1[C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)=[O:4].[NH4+:32].C([O-])(=O)C>CS(C)=O>[Cl:28][C:24]1[CH:23]=[C:22]([C:21]2[C:7]3[C:6](=[CH:11][CH:10]=[C:9]([C:12](=[O:20])[C:13]4[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=4)[CH:8]=3)[NH:5][C:3](=[O:4])[N:32]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: Cc1ccc(C(=O)c2ccc(NC(=O)C(Cl)(Cl)Cl)c(C(=O)c3cccc(Cl)c3)c2)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Product: Cc1ccc(C(=O)c2ccc3[nH]c(=O)nc(-c4cccc(Cl)c4)c3c2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 63.4 %

Procedure:
A mixture of intermediate 21 (0.0085 mol) and acetic acid, ammonium salt (0.0169 mol) in DMSO (42 ml) was stirred at 60° C. for 4 hours then cooled and poured out into ice water. The precipitate was filtered, washed with water, taken up in warm CH3CN, filtered off and dried under a vacuo, yielding 2.02 g (63%) of 4-(3-chlorophenyl)-6-(4-methylbenzoyl)-2(1H)-quinazolinone (intermediate 22), mp.>260° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[C:16]([CH3:18])[C:15]([CH2:19]O)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1>CN(C)C=O>[Cl:3][CH2:19][C:15]1[C:16]([CH3:18])=[N:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=2)=[CH:13][CH:14]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1nc(-c2ccc(F)cc2)ccc1CO
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(F)cc2)ccc1CCl
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.6 %

Procedure:
10.1 g (6.2 ml, 85 mmol) thionyl chloride is added drop by drop within 15 min. at 0° C. to a solution of 0.2 ml N,N-dimethylformamide (DMF) and 9.24 g (42.5 mmol) [6-(4-Fluor-phenyl)-2-methyl-pyridin-3-yl]-methanol, and stirred for 3 h at room temperature (r.t.) The mixture is poured on ice/sodium bicarbonate solution, the organic phase separated, washed with water, dried (sodium sulphate), and evaporated. 9.78 g (97%) of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(N)cc1
Solvent: ClCCl
Product: COc1ccc(NC(C)=O)cc1
Yield: 95.3 %

Procedure:
To a stirring suspension of p-anisidine (6.036 g, 49 mmol) in dichloromethane (20 ml) was added acetic anhydride (5 ml, 53 mmol, 1.1 equ) over one hour. The reaction was stirred for a further hour then poured onto hexane (60 ml) and stirred for another hour. The solid was collected and washed with hexane to give N-(4-methoxy-phenyl)-acetamide 51 (7.717 g, 95%) as a pale grey solid.
Reaction SMILES: [C:1]([C@H:4]([NH:6][C:7]([C@@H:9]([NH:11][C:12]([C:14]1[N:18]2[C@@:19]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=3)([CH3:31])[C:20](=[O:30])[N:21]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)[C:17]2=[N:16][CH:15]=1)=[O:13])[CH3:10])=[O:8])[CH3:5])(=[S:3])[NH2:2].[CH2:41](OC(OCC)CBr)[CH3:42].Cl>CC(C)=O.O1CCOCC1>[S:3]1[CH:42]=[CH:41][N:2]=[C:1]1[CH:4]([NH:6][C:7]([C@@H:9]([NH:11][C:12]([C:14]1[N:18]2[C@@:19]([CH2:32][C:33]3[CH:34]=[CH:35][C:36]([C:39]#[N:40])=[CH:37][CH:38]=3)([CH3:31])[C:20](=[O:30])[N:21]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)[C:17]2=[N:16][CH:15]=1)=[O:13])[CH3:10])=[O:8])[CH3:5]
Reactant: CCOC(CBr)OCC
Reactant: C[C@H](NC(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)N[C@H](C)C(N)=S
Agent: Cl
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: CC(NC(=O)[C@H](C)NC(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)c1nccs1
Temperature: 25 °C
Yield: 89.1 %

Procedure:
To a solution of (R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid [(S)-1-((R)-1-thiocarbamoyl-ethylcarbamoyl)-ethyl]-amide (132 mg, 0.22 mmol) in 1 mL of acetone was added bromoacetaldehyde diethyl acetal (0.166 mL, 1.10 mmol) and HCl in dioxane (4 M, 0.003 mL, 0.01 mmol). The reaction mixture was heated at reflux for 5 h, and then cooled to room temperature and concentrated in vacuo. The residue was dissolved in 25 mL of ethyl acetate and washed with 10 mL of saturated NaHCO3 solution. The organic phase was washed with water and brine (10 mL each), dried over Na2SO4, filtered, and concentrated in vacuo to a pale brown oil. The crude product was purified by flash chromatography on silica gel, eluting with 0-5% MeOH in CH2Cl2, to furnish 122 mg (89%) of the title compound as a pale brown foam, obtained as a 1:1 mixture of thiazole α-methyl diastereomers, m/z 622.3 [M+1]+.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[CH:6](=O)[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)C>O>[CH:6](=[N:1][NH:2][C:3]([NH2:5])=[S:4])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NNC(N)=S
Reactant: O=CC=Cc1ccccc1
Solvent: CCO
Solvent: O
Product: NC(=S)NN=CC=Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 18.2 g (0.20 m) of thiosemicarbazide in 250 ml of hot water was gradually added to a solution of 26.4 g (0.20 m) of cinnamaldehyde in 250 ml of hot 2B ethanol. Small, colorless crystals began to ppt from the homogeneous mixture after several minutes of heating on a steam bath. Heating was continued for a half an hour, after which the mixture was cooled to room temperature and the product was collected by filtration, washed with cold ethanol, and air-dried to yield 25.5 g of small, pale yellow crystals. An additional 18.3 g of product was recovered by concentrating the mother liquors. Recrystallization from ethanol gave 29.3 g (0.14 m) of small, pale yellow crystals, m.p. 137°-139° C.
Reaction SMILES: C(N(CC)CC)C.[NH:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[NH2:9].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C1C=CC=CC=1>[CH3:14][C:13]([CH3:16])([O:12][C:10]([NH:8][NH:9][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:11])[CH3:15]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)NN
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNNC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Triethylamine (13.94 ml., 0.1 mol.) was added to a solution of hydrazine carboxylic acid, 1,1-dimethylethyl ester (13.216 g., 0.1 mole) in benzene (100 ml.), followed by the addition of ethyl bromoacetate (11.09 ml., 0.1 mol.). The reaction mixture was refluxed (oil bath, 95°-100° C.) for 14 hours, after which triethylamine (1.4 ml., 0.01 mol.) was added followed by ethyl bromoacetate (1.1 ml., 0.01 mole). After refluxing for an additional 8 hours, triethylamine (2 ml., 0.015 mol.) and ethyl bromoacetate (1.4 ml., 0.013 mole) were added. The mixture was allowed to reflux for another 14 hours (total 36 hours). After cooling to room temperature, the reaction mixture was filtered and the solid triethylamine, hydrochloride salt was washed with ethyl acetate/hexane (1:1). The combined filtrate was diluted with ethyl acetate, washed with saturated sodium bicarbonate, water, brine, dried (sodium sulfate) and filtered. The filtrate was concentrated in vacuo to afford 19.38 g. of crude product as a yellow syrup which was used for the next reaction without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:21])[C:6]=1[N:7]1[CH2:11][CH2:10][C@@H:9]([CH2:12][NH:13]C(=O)OC(C)(C)C)[CH2:8]1.C(OC([NH:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43](O)=[O:44])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:21])[C:6]=1[N:7]1[CH2:11][CH2:10][C@@H:9]([CH2:12][NH2:13])[CH2:8]1)=[O:44]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Cn1ncc(N)c1N1CC[C@@H](CNC(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CC[C@@H](CN)C1
Yield: 33 %

Procedure:
Following the procedures as described in Example 113, (S)-tert-butyl (1-(4-amino-1-methyl-1H-pyrazol-5-yl)pyrrolidin-3-yl)methylcarbamate, 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid, and HATU were reacted to give 137 as a white solid (56 mg, 33%) over two steps. 1H NMR (400 MHz, DMSO) δ 8.79 (s, 1H), 7.61-7.45 (m, 3H), 7.41 (d, J=5.1, 1H), 7.28 (t, J=8.6, 2H), 3.62 (s, 3H), 3.31-3.20 (m, 4H), 2.98 (dt, J=19.0, 9.5, 1H), 2.61 (d, J=6.9, 1H), 2.34-2.19 (m, 1H), 1.96 (tt, J=29.5, 14.8, 1H), 1.60 (dq, J=14.3, 7.2, 1H). ESIMS m/z=434.1 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O.S(Cl)(Cl)=O.[C:18]([O:26][CH2:27][CH3:28])(=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].[Mg+2].[Cl-].[Cl-]>C(#N)C.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:13])([CH3:12])[C:9]([CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:18]([O:26][CH2:27][CH3:28])=[O:25])=[O:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C(=O)O)c1ccccc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
A solution of 2-(2-chlorophenyl)-2-methylpropanoic acid (2.55 g, 12.8 mmol) in thionyl chloride (50.0 mL, 685 mmol) was heated at 95° C. for 2 hours. The solution was concentrated in vacuo, azeotroped using toluene (2×100 mL), and dried in vacuo to give the crude acid chloride. A mixture of diethyl malonate (1.94 mL, 12.8 mmol) and MgCl2 (1.22 g, 12.8 mmol) in ACN (50 mL) was cooled to 0° C. TEA (3.75 mL, 27.0 mmol) was added slowly, and the mixture was stirred at 25° C. for 2 hours. A solution of the acid chloride in ACN (50 mL) was added, and the mixture was heated at 50° C. for 2 days. The solution was diluted with 10% HCl (aq) (200 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with 2N NaOH (aq) (3×200 mL) and then with brine (75 mL). The organic layer was dried over MgSO4, concentrated, and purified by flash column chromatography (silica, 0-100% DCM in hexane) to give diethyl 2-(2-(2-chlorophenyl)-2-methylpropanoyl)malonate (3.25 g). MS m/e=341 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[NH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26]>CN(C=O)C>[Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:4]=2[N:3]=1
Reactant: CC(C)CCBr
Reactant: C=CCn1c(Cl)nc2[nH]c(=O)[nH]c(=O)c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCC(C)C
Temperature: 50 °C

Procedure:
A solution of 8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (1.5 g, 6.6 mmol) in DMF (40 ml) was treated with sodium carbonate (0.9 g, 8.5 mmol) and 1-bromo-3-methylbutane (1.04 g, 6.9 mmol). The stirred mixture was heated at 50° C. for 18 hours then cooled and evaporated to dryness. The residue was treated with water (60 ml) and extracted with ethyl acetate (3×80 ml). The organic fractions were combined, dried over magnesium sulfate, filtered and evaporated. The residue was triturated with a mixture of diethyl ether and cyclohexane to reveal the product as a white solid which was filtered off and dried. This gave the title compound as a white solid m/z 297 [MH+].
Reaction SMILES: CO.C([O:6][C@@H:7]1[CH2:42][N:10]2[C:11]3[C:16]([N:17]([C:19](=[O:41])[C:20]4[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:40])[C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[CH:22][CH:21]=4)[CH2:18][C@@H:9]2[CH2:8]1)=[CH:15][CH:14]=[CH:13][CH:12]=3)(=O)C.C(=O)([O-])[O-].[K+].[K+]>O>[OH:6][C@@H:7]1[CH2:42][N:10]2[C:11]3[C:16]([N:17]([C:19](=[O:41])[C:20]4[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:40])[C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)=[CH:24][CH:25]=4)[CH2:18][C@@H:9]2[CH2:8]1)=[CH:15][CH:14]=[CH:13][CH:12]=3
Reactant: CC(=O)O[C@H]1C[C@H]2CN(C(=O)c3ccc(NC(=O)c4ccccc4-c4ccccc4)cc3)c3ccccc3N2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(Nc1ccc(C(=O)N2C[C@@H]3C[C@H](O)CN3c3ccccc32)cc1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.1 %

Procedure:
To 20 ml of methanol, there were added 0.57 g of (2S, 3aS)-2-acetoxy-5-[4-[(2-phenylbenzoyl)amino]benzoyl]-1,2,3,3a,4,5-hexahydro-pyrrolo [1,2-a]quinoxaline prepared in Example 5 and 0.2 g of anhydrous potassium carbonate and the reaction solution was stirred at room temperature for 15 hours. After concentration of the reaction solution, the resulting residue was diluted with water and then extracted with ethyl acetate. The resulting organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated. The resulting residue was recrystallized from ethyl acetate-hexane to give 0.52 g (yield 88.0%) of the title compound.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[CH:9]=2)[N:4](S(C2C=CC(C)=CC=2)(=O)=O)[CH:3]=1.CC1(C)C(C)(C)OB([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[NH:48][CH:49]=[CH:50][N:51]=3)=[CH:43][CH:42]=2)O1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:48]1[CH:49]=[CH:50][N:51]=[C:47]1[C:44]1[CH:45]=[CH:46][C:41]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=4)[CH:9]=3)[NH:4][CH:3]=2)=[CH:42][CH:43]=1
Reactant: COc1cc(-c2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)cc(OC)c1OC
Reactant: CC1(C)OB(c2ccc(-c3ncc[nH]3)cc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(-c2cnc3[nH]cc(-c4ccc(-c5ncc[nH]5)cc4)c3c2)cc(OC)c1OC
Yield: 22.1 %

Procedure:
3-Iodo-1-(toluene-4-sulfonyl)-5-(3,4,5-trimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine (Intermediate CJ, 30 mg, 0.053 mmol), 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazole (Intermediate CG, 18 mg, 0.064 mmol) and dichlorobis(triphenylphosphine)palladium (II) (2 mg, 0.003 mmol) were combined in CH3CN (1 ml) and 1 M Na2CO3 (1 ml) and stirred at 60° C. for 2 d. Additional Intermediate CG (18 mg, 0.064 mmol) was added and stirring was continued for another day. EtOAc was added and the mixture was washed with water, dried, evaporated and purified by silica gel chromatography using 0-5% MeOH:DCM to yield 5 mg (22%) of the title compound. MS ESI (m/z): 427.2 (M+1)+, calc. 426.
Reaction SMILES: C([O:5][C:6](=[O:53])[CH2:7][CH2:8][S:9][CH2:10][CH:11]([O:33][C:34](=[O:52])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:12][O:13][C:14](=[O:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:46]1([CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][C:34]([O:33][CH:11]([CH2:12][O:13][C:14](=[O:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:10][S:9][CH2:8][CH2:7][C:6]([OH:53])=[O:5])=[O:52])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CC(C)(C)OC(=O)CCSCC(COC(=O)CCCCCCCCCCCc1ccccc1)OC(=O)CCCCCCCCCCCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCSCC(COC(=O)CCCCCCCCCCCc1ccccc1)OC(=O)CCCCCCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
A solution of 6,7-bis(12-phenyldodecanoyloxy)-4-thiaheptanoic acid t-butyl ester as obtained in Reference Example 33 (1.22 g) in dichloromethane (2 ml)-trifluoroacetic acid (6 ml) was stirred at room temperature for 2 hours, after which the solvent was distilled off under reduced pressure, to yield the title compound (1.12 g, yield 99%) as a colorless oily substance.
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([O:25][CH2:26][CH3:27])[C:22](O)=[O:23])=[CH:16][CH:15]=2)[CH2:3][CH2:2]1.[CH2:28]([N:30](CC)CC)C.C(Cl)(=O)C(C)(C)C.CN>ClC.O>[CH3:28][NH:30][C:22](=[O:23])[CH:21]([O:25][CH2:26][CH3:27])[CH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][N:4]2[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[S:1][CH2:2][CH2:3]2)=[CH:15][CH:16]=1
Reactant: CCOC(Cc1ccc(OCCN2CCSc3ccccc32)cc1)C(=O)O
Reactant: CCN(CC)CC
Agent: CC(C)(C)C(=O)Cl
Agent: CCl
Agent: CN
Solvent: O
Product: CCOC(Cc1ccc(OCCN2CCSc3ccccc32)cc1)C(=O)NC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice cooled solution of 3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (0.3 g, 0.78 mmol) obtained in example 29 and triethylamine (0.162 g, 1.6 mmol) in dry chloromethane (10 mL) was added pivaloyl chloride (0.10 g, 0.86 mmol) and stirring was continued for 30 min at 0° C. To the above reaction mixture, methyl amine (40% solution) (0.124 mL) was added at 25° C. and stirring was continued for 1 h at 25° C. Water (20 mL) was added and extracted with ethyl acetate (2×20 mL). The combined organic extract was washed with water (10 mL), brine (10 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was chromatographed over silica gel using a mixture of ethyl acetate and pet. ether (1:1) to afford the title compound as a colorless solid. mp: 80-82° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:13]2[C:8](=[C:9]([O:16]C)[C:10]([O:14]C)=[CH:11][CH:12]=2)[CH2:7][CH:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=1.B(Cl)(Cl)[Cl:25].CO>ClCCCl>[ClH:25].[NH2:2][CH2:3][C:4]1[C:13]2[C:8](=[C:9]([OH:16])[C:10]([OH:14])=[CH:11][CH:12]=2)[CH2:7][CH:6]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:5]=1
Reactant: ClB(Cl)Cl
Reactant: COc1ccc2c(c1OC)CC(c1ccccc1)C=C2CN
Agent: Cl
Solvent: ClCCCl
Solvent: CO
Product: NCC1=CC(c2ccccc2)Cc2c1ccc(O)c2O
Temperature: 25 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
A slurry of 10 g (25 mmol) of 1-aminomethyl-5,6-dimethoxy-3-phenyl-3,4-dihydronaphthalene hydrochloride, from Step 2, in 150 mL of 1,2-dichloroethane was cooled to 10° C. under a nitrogen atmosphere. Boron trichloride was passed through the reaction mixture until 27 g (230 mmol) had been added. The reaction mixture was allowed to warm to ambient temperature and stirred for 18 h. The reaction mixture was then cooled in ice and 100 mL of methanol was added dropwise. The reaction mixture was again allowed to warm to ambient temperature and concentrated in vacuo. Twice, 500 mL portions of methanol were added to the residue and it was reconcentrated. The resultant foam was dissolved in 40 mL of ethanol, filtered and the solution was treated with 40 mL of methylene chloride and 80 mL of heptane. Off-white crystals of 1-aminomethyl-5,6-dihydroxy-3-phenyl-3,4-dihydronaphthalene hydrochloride (5.1 g, 56% yield) were collected by filtration, m.p. 204°-205° C. The 1H NMR spectrum was identical to the spectrum for the product of Example 2A.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH:13]([O:15][CH3:16])[CH2:12][CH2:11][NH:10]1.CO[CH2:19][CH:20]1CCC(C2C=CC=CC=2OC)[NH:21]1.COCC1CCC(C2C=CC=CC=2OC)N1CCN>>[NH2:21][CH2:20][CH2:19][N:10]1[CH2:11][CH2:12][CH:13]([O:15][CH3:16])[CH2:14][CH:9]1[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COCC1CCC(c2ccccc2OC)N1
Reactant: COc1ccccc1C1CC(OC)CCN1
Agent: COCC1CCC(c2ccccc2OC)N1CCN
Product: COc1ccccc1C1CC(OC)CCN1CCN

Procedure:
2-(2-Methoxyphenyl)-4-methoxypiperidine was converted to the title compound in two steps by the same procedures as the transformation of 2-methoxymethyl-5-(2-methoxyphenyl)-tetrahydropyrrole to 2-methoxymethyl-5-(2-methoxyphenyl)-1-(2-aminoethyl)-tetrahydropyrrole as described above in Preparations 23 and 24. 1H NMR (CDCl3, 400 MHz) δ:3.80 (3H, S, OMe), 3.31 (3H, s, OMe).