Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH:6]=[C:5]([C:7]2[N:8]=[C:9]([SH:12])[S:10][CH:11]=2)[CH2:4][N:3]1[C:13](OCC=C)=O.ClCC(C1CN(C(OCC=C)=O)[C@@H](C)C=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].CO>C1COCC1>[CH3:13][N:3]1[C@@H:2]([CH3:1])[CH:6]=[C:5]([C:7]2[N:8]=[C:9]([SH:12])[S:10][CH:11]=2)[CH2:4]1
Reactant: C=CCOC(=O)N1CC(c2csc(S)n2)=C[C@@H]1C
Agent: C=CCOC(=O)N1CC(C(=O)CCl)=C[C@@H]1C
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H]1C=C(c2csc(S)n2)CN1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77 %

Procedure:
Allyl (2S)-2-methyl-4-(2-sulfanyl-1,3-thiazol-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate prepared from allyl (2S)-4-(chloroacetyl)-2-methyl-2,5-dihydro-1H-pyrrole-1-carboxylate (331 mg, 1.36 mmol) in the same manner as Reference example 2.e) was dissolved in THF (3 ml). The solution was dropped into a suspension of LiAlH4 (103 mg, 2.71 mmol) in THF (3 ml) at 0° C. and the mixture was stirred at room temperature for 10 minutes. Thereto was added methanol and the mixture was filtered through a pad of silica gel. The solvent was removed in vacuo and the residue was purified with silica gel chromatography to give 4-[((5S)-1,5-dimethyl-2,5-dihydro-1H-pyrrol-3-yl]-1,3-thiazole-2-thiol (224 mg, 77%).
Reaction SMILES: [CH3:1]I.[CH2:3]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C@H:25]([OH:53])[CH2:26][O:27][CH2:28][C:29]([O:32][C:33]([F:52])([F:51])[C:34]([F:50])([F:49])[O:35][C:36]([F:48])([F:47])[C:37]([F:46])([F:45])[C:38]([F:44])([F:43])[C:39]([F:42])([F:41])[F:40])([F:31])[F:30])=[CH:19][CH:18]=2)=[N:15][CH:16]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[H-].[Na+]>CN(C)C=O.O>[CH2:3]([C:11]1[CH:16]=[N:15][C:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][C@H:25]([O:53][CH3:1])[CH2:26][O:27][CH2:28][C:29]([O:32][C:33]([F:52])([F:51])[C:34]([F:49])([F:50])[O:35][C:36]([F:47])([F:48])[C:37]([F:45])([F:46])[C:38]([F:43])([F:44])[C:39]([F:40])([F:41])[F:42])([F:30])[F:31])=[CH:21][CH:22]=2)=[N:13][CH:12]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CI
Reactant: CCCCCCCCc1cnc(-c2ccc(OC[C@H](O)COCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCc1cnc(-c2ccc(OC[C@@H](COCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)OC)cc2)nc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Methyl iodide (1.1 g, 7.76 mmol) was added to a solution of 5-octyl-2-[4-((R)-2-hydroxy-3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2,-difluoroethoxy)propoxy)phenyl]pyrimidine (Example 4, 1.5 g, 1.94 mmol) and sodium hydride (116 mg, 60 weight percent in oil, 2.91 mmol) in dimethyl formamide (10 ml). The resulting mixture was stirred at room temperature for 10 hours, was diluted with 50 ml of water, and was extracted with three 50 ml aliquots of diethyl ether. The organic extracts were dried (over MgSO4), filtered, and concentrated. The resulting product was then recrystallized from methanol at -30° C. to give a white smectic material.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][O:9][N:10]=[C:11]([C:18]2[N:22]([CH3:23])[N:21]=[N:20][N:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:4][CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>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.C1(C)C=CC=CC=1.C(O)C.O>[CH3:23][N:22]1[C:18]([C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][O:9][CH2:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:7]=2)=[N:19][N:20]=[N:21]1
Reactant: OB(O)c1ccccc1
Reactant: Cn1nnnc1C(=NOCc1cccc(Br)n1)c1ccccc1
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: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cn1nnnc1C(=NOCc1cccc(-c2ccccc2)n1)c1ccccc1
Temperature: 90 °C
Yield: 96.7 %

Procedure:
In a dried and purged vessel were added N-[(6-bromopyridin-2-yl)methoxy]-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.2 g, 0.536 mmol, 1 eq.), phenylboronic acid (0.072 g, 0.58 mmol, 1.1 eq.), Na2CO3 (0.119 g, 1.12 mmol, 2.1 eq.) and Tetrakis(triphenylphosphine)palladium (0.030 g, 0.027 mmol, 0.05 eq.). A mixture of solvent was added toluene/ethanol/water (4/1/1) was added and the vessel purged with argon and sealed. The reaction was heated to 90° C. for 6 hrs. After cooling, 10 ml of EtOAc were added and the solids were filtered through a “Celite” plug and washed with EtOAc. The organics were separated, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel to give 1-(1-methyl-1H-tetrazol-5-yl)-1-phenyl-N-[(6-phenylpyridin-2-yl)methoxy]methanimine (0.192 g, 91% yield) as a colorless gum.
Reaction SMILES: [OH:1][C:2]1[C:7]2=[N:8][C:9]3[CH2:15][CH2:14][CH2:13][C:10]=3[C:11](=[O:12])[N:6]2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Na].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O.[Cu]>[C:20]1([CH2:19][O:1][C:2]2[C:7]3=[N:8][C:9]4[CH2:15][CH2:14][CH2:13][C:10]=4[C:11](=[O:12])[N:6]3[CH:5]=[CH:4][CH:3]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=c1c2c(nc3c(O)cccn13)CCC2
Agent: [Cu]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2c(nc3c(OCc4ccccc4)cccn13)CCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6.1 g. of 2,3-dihydro-5-hydroxycyclopenta[d]pyrido[1,2-a]pyrimidin-10(1H)-one in 100 ml of N,N-dimethylformamide is added, portionwise, a total of 1.6 g of a 50% dispersion of sodium hydride in mineral oil. A yellow precipitate of the sodium salt separates. The mixture is allowed to stir for 0.5 hour at room temperature, and then 6.2 g. of benzyl bromide dissolved in 25 ml of N,N-dimethylformamide is added, dropwise, followed by 100 mg. of copper bronze powder. The mixture is stirred and heated to 100°-110° and kept at that temperature for 2 hours. The hot solution is filtered, concentrated in vacuo, and the solid residue recrystallized from cyclohexane to give 7.2 g. of product, m.p. 150°-152°.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C@@H:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([N:33](C)[C:34](NCCCCCCC)=O)[CH:28]=2)=[CH:23][CH:22]=1)[C:17]([OH:19])=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1C=CC=CC=1N[C@@H](CC1C=CC(C2C=CC=C(NC)C=2)=CC=1)C(OCC)=O)(=O)C1C=CC=CC=1.[OH-].[Li+]>>[C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C@@H:16]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][CH3:34])[CH:28]=2)=[CH:25][CH:26]=1)[C:17]([OH:19])=[O:18])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C[C@H](Nc3ccccc3C(=O)c3ccccc3)C(=O)O)cc2)c1
Agent: CCOC(=O)[C@H](Cc1ccc(-c2cccc(NC)c2)cc1)Nc1ccccc1C(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Product: CNc1cccc(-c2ccc(C[C@H](Nc3ccccc3C(=O)c3ccccc3)C(=O)O)cc2)c1
Yield: 80 %

Procedure:
In a manner similar to the preparation of the (S)-2-(2-benzoylphenylamino)-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propionic acid (Example 2), using 1.2 g (1.06 mmol) of ethyl (S)-2-(2-benzoylphenyl-amino)-3-(3′-methylaminobiphenyl-4-yl)propionate (Example 1g) and 120 mg (2.85 mmol) of lithium hydroxide, 0.90 g of acid is obtained with an 80% yield.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][N:13]=1)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6].[CH3:14][O:15][C:16]1[CH:32]=[CH:31][C:19]([CH2:20][NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1.CC(C)([O-])C.[Na+]>CC(C1C=CC=C(C(C)C)C=1N1C(=[Pd])N(C2C(C(C)C)=CC=CC=2C(C)C)C=C1)C.CC(C1C=CC=C(C(C)C)C=1N1C(=[Pd])N(C2C(C(C)C)=CC=CC=2C(C)C)C=C1)C.C1C=C2C(C(C=CC2=O)=O)=CC=1.C1C=C2C(C(C=CC2=O)=O)=CC=1.O1CCOCC1>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:21]([CH2:20][C:19]2[CH:31]=[CH:32][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[C:2]2[CH:3]=[C:4]([CH:11]=[CH:12][N:13]=2)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6])=[CH:28][CH:27]=1
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Reactant: CON(C)C(=O)c1ccnc(Cl)c1
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd]
Agent: CC(C)(C)[O-]
Agent: O=C1C=CC(=O)c2ccccc21
Solvent: C1COCCO1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(C(=O)N(C)OC)ccn2)cc1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A 40 mL vial was charged with 2-chloro-N-methoxy-N-methyl-isonicotinamide (800 mg, 3.86 mmol), bis-(4-methoxy-benzyl)-amine (1.49 g, 5.80 mmol), 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene-(1,4-naphthoquinone)palladium (0) dimer (126 mg, 0.097 mmol), sodium tert-butoxide (519 mg, 5.41 mmol), and dioxane (12 mL). The vial was sealed, warmed to 110° C., and stirred overnight. The next day, the reaction was filtered through Celite, dry loaded onto silica gel, and purified via automated silica gel chromatography to generate 795 mg (47%) of the protected aminopyridine.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[CH3:19][N:20]([CH3:23])[CH:21]=O>ClCCl>[CH3:19][N:20]([CH:23]=[N:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])[CH3:21]
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccccc1N=CN(C)C

Procedure:
To a stirred solution of 7.56 g of methyl anthranilate in 50 ml of dimethylformamide at 0° C. was added 5.6 ml of phosphorous oxychloride during 15 m. The mixture was heated at 55 for 45 m, cooled to 0, and diluted with dichloromethane. The mixture was basified at 0° C. by slow addition of cold 1N NaOH to pH 9. The dichloromethane layer was separated, washed with water, dried and concentrated to an oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:12])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1.Cl.[N:14]([O-])=O.[Na+].[OH-].[K+]>O>[CH3:1][N:2]1[C:3]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[N:12]=[N:14]1
Reactant: O=N[O-]
Reactant: CNc1ccc([N+](=O)[O-])cc1N
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: Cn1nnc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
A stirred suspension of diamine 248 (1.13 g, 6.76 mmol) and concentrated HCl (5.6 mL, 67 mmol) in water (22 mL) at 0° C., was treated with a solution of NaNO2 (586 mg, 8.5 mmol) in water (10 mL). The mixture was stirred at the same conditions for 3 h, warmed to room temperature, neutralized with a 5% w/v solution of KOH in water and filtered. The solid was washed with cold water and dried to afford title compound 264 (975 mg, 81% yield). 1H NMR: (DMSO) δ (ppm): 9.00 (d, J=1.3 Hz, 1H), 8.39 (dd, J=1.3, 8.8 Hz, 1H), 8.09 (d, J=8.8 Hz, 1H), 4.40 (s, 3H).
Reaction SMILES: C([Li])CCC.[CH2:6]([OH:9])[CH2:7][OH:8].Br[CH2:11][CH:12]=[C:13]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]>C1(C)C=CC=CC=1>[CH3:28][O:27][C:23]1[CH:22]=[C:21]([C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[CH:12][CH2:11][O:8][CH2:7][CH2:6][OH:9])[CH:26]=[CH:25][CH:24]=1
Reactant: OCCO
Reactant: COc1cccc(C(=CCBr)c2ccccc2C)c1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: COc1cccc(C(=CCOCCO)c2ccccc2C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
A solution of n-butyllithium in hexanes (32.2 ml, 2.5 M) was added dropwise under a nitrogen atmosphere to ethylene glycol (60 ml) at 10° C. When addition was complete the mixture was stirred for 0.5 h at room temperature. A solution of 3-bromo-1-(3-methoxyphenyl)-1-(2-methylphenyl)-1-propene (24.4 g, 77 mmol) in toluene (50 ml) was added and the reaction mixture was stirred at room temperature for 4 days and at 65° C. for 6 h. The solvent was evaporated in vacuo, water (250 ml) was added and the mixture was extracted with ethyl acetate (2×200+100 ml). The combined organic phases was dried over magnesium sulphate and the solvent was evaporated in vacuo. Flash chromatography of the residue on silica gel (320 g) using a mixture of cyclohexane and ethyl acetate gradient as eluent provided 16.6 g (72%) of 2-(3-(3-methoxyphenyl)-3-(2-methylphenyl)-2-propen-1-yloxy)ethanol.
Reaction SMILES: [Br:1][C:2]1[N:6]([CH2:7][CH3:8])[C:5]([CH:9]([NH:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[CH3:25])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[C:4]([C:26](O)=[O:27])[CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>O>[Br:1][C:2]1[N:6]([CH2:7][CH3:8])[C:5]2[CH:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[N:17]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[CH3:25])[C:26](=[O:27])[C:4]=2[CH:3]=1
Reactant: CCn1c(Br)cc(C(=O)O)c1C(Nc1cc(Cl)ccc1C)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCn1c(Br)cc2c1C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C)C2=O

Procedure:
A solution of 5-bromo-2-[(5-chloro-2-methyl-phenylamino)-(4-chloro-phenyl)-methyl]-1-ethyl-1H-pyrrole-3-carboxylic acid (Step K1) (3.11 mmol), TBTU (4.36 mmol) and DIEA (9.33 mmol) was stirred at 80° C. for 1 h. The reaction mixture was diluted with H2O and extracted with EtOAc (2×). The combined organic layers were washed successively with H2O and brine, dried (MgSO4), filtered and concentrated. The product was purified by chromatography column to afford the title compound as a colorless oil. tR: 5.90 min (HPLC 4); ESI-MS: tR=1.35 min, [M+H]+ not ionized (LC-MS 1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:9]1[C:10]([C:22]2[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[C:24]([F:35])[CH:23]=2)=[N:11][C:12]([C:15]2[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH:16]=2)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.C(Cl)Cl.[Pd]>[C:1]([O:5][C:6]([N:8]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:9]1[C:10]([C:22]2[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])=[C:24]([F:35])[CH:23]=2)=[N:11][C:12]([CH:15]2[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]2)=[CH:13][N:14]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2nc(C3=CC(=O)CCC3)cnc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1F
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(-c2nc(C3CCCC(=O)C3)cnc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 49.3 %

Procedure:
To a solution of tert-butyl 4-(3-(bis(tert-butoxycarbonyl)amino)-6-(3-oxocyclohex-1-en-1-yl)pyrazin-2-yl)-2-fluorobenzoate (3 g, 5.14 mmol) in MeOH (15 mL) and DCM (10 mL) at RT was added Pd—C (10%, degauss, 1.094 g, 1.028 mmol). The resultant mixture was flushed with hydrogen for 10 min, then stirred at RT for 5 hours under hydrogen atmosphere. The suspension was filtered and the solution was concentrated. ISCO silica column separation (80 g silica, 30 min, 5 to 60% EtOAc in Heptane) afforded the desired product as a light yellow sticky liquid, which solidified upon standing over night. (1.485 g, 2.54 mmol, 49.3% yield). LC-MS (m/z): (MH+) 586.3, 1.17 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH3:11].C1C(=O)N([Br:19])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:11][C:3]1[C:4]([N+:8]([O-:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Cc1c(Cl)cccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc(Cl)c1CBr
Temperature: 25 °C

Procedure:
To a solution of the 1-chloro-2-methyl-3-nitrobenzene (2.0 g, 11.66 mmol) in anhydrous carbon tetrachloride 50 mL, NBS (2.07 g, 11.66 mmol) and benzoyl peroxide (0.141 g, 0.583 mmol) was added. The reaction mixture was heated to reflux overnight. Then, the reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated to provide crude 2-(bromomethyl)-1-chloro-3-nitrobenzene, which was used for the next step without any further purification (2.93 g); 1H NMR (400 MHz, DMSO-d6): δ 4.77 (s, 2H), 7.60 (t, J=6.2, 8.2 Hz, 1H), 7.90 (d, J=8.2 Hz, 1H), 8.00 (d, J=8.2 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:12][C:13]([NH2:15])=[O:14])=[CH:8][NH:9]2)=[CH:5][CH:4]=1.C[O:17][C:18](=O)[C:19]([C:21]1[C:31]2=[C:32]3[C:27](=[CH:28][C:29]([F:33])=[CH:30]2)[C:26]([CH3:35])([CH3:34])[CH2:25][CH2:24][N:23]3[CH:22]=1)=O>>[CH3:34][C:26]1([CH3:35])[C:27]2[C:32]3=[C:31]([C:21]([C:19]4[C:18](=[O:17])[NH:15][C:13](=[O:14])[C:12]=4[C:7]4[C:6]5[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)[NH:9][CH:8]=4)=[CH:22][N:23]3[CH2:24][CH2:25]1)[CH:30]=[C:29]([F:33])[CH:28]=2
Reactant: COc1ccc2c(CC(N)=O)c[nH]c2c1
Reactant: COC(=O)C(=O)c1cn2c3c(cc(F)cc13)C(C)(C)CC2
Product: COc1ccc2c(C3=C(c4cn5c6c(cc(F)cc46)C(C)(C)CC5)C(=O)NC3=O)c[nH]c2c1

Procedure:
Beginning with (6-methoxyindol-3-yl)acetamide and (6,6-dimethyl-8-fluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:11]([C:16]([OH:18])=O)=[CH:12][CH:13]=[CH:14][CH:15]=1.CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O>[Cl:1][C:2]1[C:3]2[C:10]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:16](=[O:18])[C:4]=2[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1ccc(-c2ccccc2C(=O)O)c(Cl)c1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: COc1cc(Cl)c2c(c1)C(=O)c1ccccc1-2
Temperature: 100 °C
Reaction time: 1 h
Yield: 151 %

Procedure:
Under an argon atmosphere, to 2′-chloro-4′-methoxybiphenyl-2-carboxylic acid (65.4 g) was added an Eaton reagent (phosphorus pentoxide-methanesulfonic acid (weight ratio 1:10) solution, 330 ml), and the mixture was stirred at an oil bath temperature of 100° C. for 1 hr. The reaction mixture was ice-cooled, water (650 ml) was slowly added dropwise, and the mixture was stirred at room temperature for 1 hr. The precipitated solid was collected by filtration, and washed with water (500 ml). The obtained solid was air-dried overnight to give the title compound (92.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10](S(C3C=CC=CC=3)(=O)=O)[CH:9]=2)[CH:5]=[C:4]([Cl:28])[N:3]=1.[OH-].[K+]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=3)[NH:10][CH:9]=2)[CH:5]=[C:4]([Cl:28])[N:3]=1
Reactant: COc1cnc2c(c1)c(-c1cc(Cl)nc(Cl)c1)cn2S(=O)(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cnc2[nH]cc(-c3cc(Cl)nc(Cl)c3)c2c1
Temperature: 50 °C
Yield: 85.9 %

Procedure:
A suspension of Example 149d (88.0 mg, 0.203 mmol) in ethanol (2 mL) was treated with a solution of potassium hydroxide (45.5 mg, 0.811 mmol) in water (0.5 mL). The reaction mixture was heated at 50° C. for 1.5 hours. After concentration, water was added to the residue and the mixture was sonicated. The solid was filtered, washed with water, and oven-dried to give 51.3 mg of the title compound.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7](C(OC(C)(C)C)=O)[CH2:6][C@@H:5]1[CH3:21])(=[O:3])[CH3:2].Cl>O1CCOCC1>[CH3:21][C@H:5]1[CH2:6][NH:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]1[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2N(C(=O)OC(C)(C)C)C[C@@H]1C
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)N1c2ccccc2NC[C@@H]1C
Temperature: 50 °C
Yield: 86.8 %

Procedure:
A 40 mL reaction vial was charged with (S)-tert-butyl 4-acetyl-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.35 g, 1.21 mmol) and 1,4-dioxane (6 mL). HCl (4 M solution in 1,4-dioxane, 3.0 mL, 12.1 mmol) was then added, and the reaction mixture was heated to 50° C. for 2 hrs on a heater shaker. The reaction concentrated under reduced pressure and the residue was dissolved in ethyl acetate (20 mL) and washed with saturated aqueous sodium bicarbonate (20 mL). The organic layer was removed and set aside. The aqueous layer was washed with another portion of ethyl acetate (20 mL) and the organic layers were combined and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient elution with 2:1 hexanes-ethyl acetate to 1:1 hexanes-ethyl acetate) to afford ((S)-1-(2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (0.2 g, 1.05 mmol, 87% yield) as a colorless oil. MS poor ionization (ESI, -acetate fragment) m/z 149 [M+1]+.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:27]=[CH:26][C:18]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([O:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH2:43][C@H:44]2[O:46][CH2:45]2)=[CH:38][C:37]=1[N:47](C(OC(C)(C)C)=O)[S:48]([CH3:51])(=[O:50])=[O:49])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl>C(O)C>[CH2:1]([N:8]([CH2:45][C@H:44]([OH:46])[CH2:43][O:42][C:39]1[CH:40]=[CH:41][C:36]([O:35][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:37]([NH:47][S:48]([CH3:51])(=[O:50])=[O:49])[CH:38]=1)[C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]2[CH:27]=[CH:26][C:18]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=2)[CH2:13][CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(c1cc(OC[C@@H]2CO2)ccc1OCc1ccccc1)S(C)(=O)=O
Reactant: CCOC(=O)COc1ccc([C@H]2CC[C@H](NCc3ccccc3)CC2)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)COc1ccc([C@H]2CC[C@H](N(Cc3ccccc3)C[C@H](O)COc3ccc(OCc4ccccc4)c(NS(C)(=O)=O)c3)CC2)cc1
Temperature: 50 °C

Procedure:
A mixture of 3.22 g of ethyl trans-{4-[4-(benzylamino)cyclohexyl]phenoxy}acetate (8.7 mmol) and 5 g of 4-benzyloxy-3-(N-(tert-butoxycarbonyl)-N-(methylsulfonyl)amino)-1-((2S)-2,3-epoxypropoxy)benzene (11.2 mmol) in ethanol (72 ml) is brought to reflux for 40 h. A 3N solution of hydrochloric acid in ethanol is added and the reaction medium is heated at 50° C. for 19 h. The solvents are evaporated under reduced pressure and then water, dichloromethane and a saturated aqueous sodium carbonate solution are added. The aqueous phase is extracted once with dichloromethane. The organic phases are combined, washed with water and then dried over magnesium sulfate. The solvents are evaporated under reduced pressure and ethyl trans-(4-{4-[Benzyl((2S)-3-{4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy}-2-hydroxypropyl)amino]cyclohexyl}phenoxy)acetate is obtained in the form of an oil (2.7 g, 43%) after purification on silica gel (eluent: ethyl acetate/heptane 30/70 to 50/50 gradient in 40 min). [M+H+]=717.6
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH3:8])[N:4]=[CH:3]1.[Li]CCCC.CN([CH:17]=[O:18])C>O1CCCC1>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH3:8])[N:4]=[C:3]1[CH:17]=[O:18]
Reactant: Cc1ncn(C)c1C
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc(C=O)n(C)c1C
Reaction time: 2 h
Yield: 49.2 %

Procedure:
To a solution of 1,4,5-trimethyl-1H-imidazole (550 mg, 5 mmol) in dry tetrahydrofuran (15 mL) was added dropwise n-BuLi (3 mL, 2.5 M in hexane) at −40° C. After stirring for 2 h at this temperature, to the solution was added dried DMF (840 mg, 11.5 mmol) at −70° C. The resulting yellow suspension was stirred at −70° C. for 1 h, then at 0° C. for 0.5 h and quenched with ice-water. The mixture was extracted with ethyl acetate, and the organic extracts were dried with Na2SO4 before evaporation to afford an oily residue. The residue was purified by silica column (petroleum ether:ethyl acetate=3:1) to obtain 340 mg of white solid, yield: 50%. 1H-NMR (400 MHz, CDCl3) δ (ppm): 2.21 (s, 1H), 2.25 (s, 1H), 3.90 (s, 1H), 9.66 (s, 1H). LC-MS (ESI) m/z: 138 (M+1)+.