Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5](I)[C:6]([NH2:9])=[N:7][CH:8]=1.[CH3:13][N:14](C)C=O>C(OCC)(=O)C>[NH2:9][C:6]1[C:5]([C:13]#[N:14])=[CH:4][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:8][N:7]=1
Reactant: CN(C)C=O
Reactant: Nc1ncc(C(F)(F)F)cc1I
Solvent: CCOC(C)=O
Product: N#Cc1cc(C(F)(F)F)cnc1N
Temperature: 25 °C

Procedure:
A solution of 5-(trifluoromethyl)pyridin-2-amine (3-a with R4=CF3, 1.6 g, 9.87 mmol) (Maybridge Chemical company, Cornwall, England) in N,N-dimethylformamide (30 mL) was treated at room temperature with silver sulfate (3.1 g, 9.87 mmol) and iodine (2.5 g, 9.87 mol). The reaction mixture was stirred for 14 h and filtered. The filtrated solution was concentrated in vacuo. The residue was chromatographed (SiO2, 25% ethyl acetate in hexanes) to give 5-(trifluoromethyl)-3-iodopyridin-2-amine (3-b, with R4=CF3). The iodide (3-b, with R4=CF3, 1.0 g, 3.47 mmol) and cuprous cyanide (CuCN, 78 g, 8.68 mmol) was dissolved in N,N-dimethylformamide (6 mL) and heated under the microwave at 100 C for 30 min, cooled to ambient temperature, and diluted with ethyl acetate. The precipitates were removed by filtration. The filtrated solution was partitioned between ethyl acetate and water. The organic layer was washed with brine, separated, dried (MgSO4) and concentrated in vacuo. Trituration of the residue with hexanes afforded the desired product, 2-amino-5-(trifluoromethyl)pyridine-3-carbonitrile (3-c, with R4=CF3). 2-amino-5-(trifluoromethyl)pyridine-3-carbonitrile (3-c, with R4=CF3, 545 mg, 29.2 mmol) was stirred in methanol (10 mL, saturated with ammonia) under hydrogen atmosphere in the presence of Pd/C (200 mg) overnight. The reaction mixture was filtered and the filtrate solution was concentrated in vacuo to afford the crude amine (3-d, with R4=CF3). A solution of (S)-2-phenylbutanoic acid (300 mg, 18.3 mmol) and diisopropylethylamine (888 uL, 52.4 mmol) in N,N-dimethylformamide (5 mL) was treated at room temperature with benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBop, 953 mg, 18.3 mmol). After 15 min, 3-(aminomethyl)-5-(trifluoromethyl)pyridin-2-amine (500 mg, 26.2 mmol) was added. The reaction mixture was stirred for 2 h, partitioned between ethyl acetate and 0.5N—NaOH. The aqueous layer was removed and the organic layer was washed with brine. The organic layer was separated, dried (MgSO4) and concentrated in vacuo to give the desired product (3-g); HRMS (M+1)=338.1405.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O>CO.N1CCCCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[CH:16][C:15]3[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[CH:14]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(F)c1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1Nc2cc(Cl)ccc2C1=Cc1cccc(F)c1
Temperature: 75 °C

Procedure:
6-Chloro-1,3-dihydro-indol-2-one (Aldrich, 7.5 g, 44.92 mmol) was treated with 3-fluoro-benzaldehyde (Aldrich, 5.57 g, 44.92 mmol) in methanol (50 mL) and piperdine (0.2 mL). The mixture was heated at 75° C. overnight and then cooled to room temperature. The solid was filtered and dried to give a yellow solid. 8.8 g.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].C(N(CC)CC)C.[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33]>ClCCl>[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([NH:2][CH2:3][C:4](=[O:5])[NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:33]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CNC(=O)c1cccc(Cl)c1)NC(c1ccccc1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A suspension of 0.32 mmol rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) in 5 ml of dichloromethane was treated with 1.61 mmol of triethylamine. The resulting slurry was cooled to 0° C. and 0.35 mmol of 3-chlorobenzoyl chloride was added. The mixture was stirred for 1 hour at room temperature, concentrated and hydrolysed. The organic phase was dried over magnesium sulfate and concentrated. The residue was triturated with diethyl ether to give the title compound as a colorless solid. Yield=97%.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([CH3:15])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl[C:17]1[C:18]2[N:19](C=NN=2)[C:20]2C(N=1)=CC=C[CH:21]=2.C(NCC)C.C(NCCC)CC>>[CH2:18]([N:19]([CH2:20][CH3:21])[C:2]1[C:3]2[N:4]([C:12]([CH3:15])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:17]
Reactant: Clc1nc2ccccc2n2cnnc12
Reactant: Cc1nnc2c(Cl)nc3ccccc3n12
Solvent: CCCNCCC
Solvent: CCNCC
Product: CCN(CC)c1nc2ccccc2n2c(C)nnc12
Yield: 54 %

Procedure:
This compound was prepared by the method of Example 11, utilizing 4-chloro-1-methyl-[1,2,4]triazolo[4,3-a]quinoxaline (the product of Example 3) as starting material in place of 4-chloro-[1,2,4]triazolo[4,3-a]quinoxaline (the product of Example 2) and diethylamine as reagent in place of di-n-propylamine. The crude product obtained was recrystallized from chloroform and then from cyclohexane to afford 7.2 g. (54% yield) of pure 4-diethylamino-1-methyl-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 123°-125° C.
Reaction SMILES: C1(C(C2C=CC=CC=2)([C@H]2CCCN2)O)C=CC=CC=1.B(OC)(OC)OC.B.C(N(CC)C1C=CC=CC=1)C.[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([C:46](=[O:61])[CH2:47][CH2:48][C:49]([C:51]2[CH:56]=[CH:55][C:54]([Cl:57])=[C:53]([N+:58]([O-:60])=[O:59])[CH:52]=2)=[O:50])=[CH:42][C:41]=1[N+:62]([O-:64])=[O:63]>C1COCC1>[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([C@@H:46]([OH:61])[CH2:47][CH2:48][C@@H:49]([C:51]2[CH:56]=[CH:55][C:54]([Cl:57])=[C:53]([N+:58]([O-:60])=[O:59])[CH:52]=2)[OH:50])=[CH:42][C:41]=1[N+:62]([O-:64])=[O:63]
Reactant: O=C(CCC(=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: B
Agent: COB(OC)OC
Agent: OC(c1ccccc1)(c1ccccc1)[C@H]1CCCN1
Solvent: C1CCOC1
Solvent: CCN(CC)c1ccccc1
Product: O=[N+]([O-])c1cc([C@@H](O)CC[C@H](O)c2ccc(Cl)c([N+](=O)[O-])c2)ccc1Cl
Temperature: 10 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
(R)-(+)-alpha,alpha-diphenyl-2-pyrrolidinemethanol (1.08 g, 4.28 mmol) was dissolved in 70 mL of THF at ambient temperature in a dry flask under nitrogen and the trimethyl borate (650 uL, 5.54 mmol) was added dropwise. The resulting solution was stirred for 1 hr. The solution was cooled in a cold bath to ˜10° C. and the N,N-diethylaniline borane (9.18 mL, 51.6 mmol) was added dropwise with some bubbling. After 15 min, this solution was transferred to an addition funnel and added dropwise to 1,4-bis(4-chloro-3-nitrophenyl)butane-1,4-dione (Example 109B) (10.0 g, 25.2 mmol) suspended in 200 mL of THF and cooled to ˜10° C. Bubbling was observed. After the addition, mixture was stirred at ambient temperature for 4 hours. The mixture was cooled in an ice bath and 30 mL MeOH was added dropwise till bubbling stopped, then the mixture was let stir at ambient temperature for 30 min. The mixture was filtered to get rid of a trace of insoluble unreacted SM. The filtrate was concentrated, poured into 1 M HCl and extracted into ethyl acetate, dried over sodium sulfate; concentrated to give the title compound (9.9 g, 99%) as a yellow waxy solid. Chiral HPLC e.e. >99.9% (RR diol was undetectable). 1H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J=1.9 Hz, 2H), 7.69 (d, J=8.4 Hz, 2H), 7.60 (dd, J=8.4, 1.9 Hz, 2H), 4.65 (m, 2H), 1.62 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][C:13]1=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][C:13]1=[O:18]
Reactant: O=C1COCCN1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: O=C1COCCN1c1ccc([N+](=O)[O-])cc1F
Temperature: 120 °C
Reaction time: 6 h
Yield: 53.4 %

Procedure:
3,4-Difluoro-1-nitrobenzene (0.50 mL, 4.52 mmol) was dissolved in 8 mL NMP. To it was added morpholin-3-one (0.91 g, 9.04 mmol) and cesium carbonate (2.95 g, 9.04 mmol). The mixture was stirred at 120° C. for 6 h. It was cooled to RT, diluted with 200 mL EtOAc, washed with brine three times, dried, concentrated in vacuo and subjected to silica flash column (0-30% EtOAc in DCM) to isolate 4-(2-fluoro-4-nitrophenyl)morpholin-3-one (580 mg, 53%). It was dissolved in 200 mL EtOAc and 100 mL MeOH. To it was added 500 mg 10% Pd/C. The mixture was stirred under a hydrogen balloon for overnight. The mixture was filtered through celite, and the solid cake was thoroughly washed with MeOH. The filtrate was concentrated in vacuo to afford 4-(4-amino-2-fluorophenyl)morpholin-3-one in quantitative yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:15][CH2:16][C:17](Cl)=[O:18]>ClCCl>[Br:15][CH2:16][C:17]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[NH:8][CH:9]=1)=[O:18]
Reactant: O=C(Cl)CBr
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CBr)c1c[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
5-Bromo-1H-pyrrolo[2,3-b]pyridine (5 g, 25.2 mmol) was added to aluminum chloride (16.8 g, 126.2 mmol) in dichloromethane (200 ml) under nitrogen. The mixture was allowed to stir at room temperature for 1 hour. Then bromoacetyl chloride (11 ml, 126.2 mmol) in dichloromethane was added drop wise and the reaction was allowed to proceed at room temperature overnight. The next day the reaction was cooled to 0° C. and was quenched with methanol (˜30 ml) until the reaction turned clear. The reaction was concentrated under vacuum and resuspended in water (300 ml). The pH was adjusted to 7 with 7N sodium hydroxide solution and then extracted with ethyl acetate (300 ml×3). The combined organic layers were extracted with saturated sodium potassium tartrate, brine, dried with Na2SO4. Silica chromatography of the crude using a gradient of ethyl acetate and hexane afforded 2-bromo-1-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-ethanone (7.4 g, 92% yield). 1H NMR (500 MHz, DMSO-d6) δ 4.76 (s, 2H), 8.45 (s, 1H), 8.61 (s, 1H), 8.75 (s, 1H), 12.98 (s, 1H). MS: m/z 318.8 (M+H+).
Reaction SMILES: C(O[C:4]1([O:10]CC)[CH2:9][CH2:8][CH2:7][NH:6][CH2:5]1)C.C(Cl)(Cl)Cl.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(N(CC)CC)C>[C:18]([N:6]1[CH2:7][CH2:8][CH2:9][C:4](=[O:10])[CH2:5]1)([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)Cl
Reactant: CCOC1(OCC)CCCNC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCCC(=O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 8.7 g. of 3,3-diethoxypiperidine in 100 ml. of dry chloroform is treated at 0° C. with 5 g. of triethylamine followed by 5.4 g. of ethyl chloroformate. After stirring at 25° C. for two hours, the solvent is removed in vacuo. The residue is extracted with ether and the extract concentrated in vacuo. This residue is treated with dilute hydrochloric acid for two hours. The solution is then saturated with sodium chloride and extracted with chloroform. The chloroform extract is washed with 5% aqueous sodium bicarbonate solution, dried and concentrated in vacuo to give 1-carbethoxy-3-piperidone.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O.C(N(CC)CC)C.C(=O)=O>CCOCC>[C:2]1([C:9]2[S:8][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: OB(O)c1cccs1
Agent: O=C=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: c1ccc(-c2cccs2)cc1
Reaction time: 64 h
Yield: 49 %

Procedure:
Bis{di(1H,1H,2H,2H-perfluorooctyl)phenylphosphino}palladium dichloride (89 mg, 0.05 mmol), iodobenzene (0.11 ml, 1 mmol), thiophene-2-boronic acid (128 mg, 1 mmol) and triethylamine (0.15 ml, 1.1 mmol) were placed in a 10 ml stainless steel cell. The cell was sealed and pressurised to approximately 5520 kPa (800 psi) (i.e. full of carbon dioxide). The cell was then heated to 100 C. for 64 hrs and then allowed to cool. When the pressure had dropped below 13800 kPa (2000 psi) the cell was vented into ether (100 ml), the cell was opened once atmospheric pressure was reached and washed out with dichloromethane (20 ml). The organic fractions were combined and concentrated in vacuo to give the crude product. The product was purified by flash column chromatography on silica gel, eluting with hexane to give a white crystalline solid (78 mg, 0.49 mmol, 49%); δH (250 MHz; CDCl3) 7.09-7.66 (8H, m, aryl and thienyl).
Reaction SMILES: [CH3:1][C:2]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[CH2:13][CH2:12]1)([CH3:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[F:35][C:36]1[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:43][CH2:44][C:45]1[N:50]([CH2:51][C:52](O)=[O:53])[C:49]2[N:55]=[CH:56][CH:57]=[CH:58][C:48]=2[C:47](=[O:59])[N:46]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:35][C:36]1[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:43][CH2:44][C:45]1[N:50]([CH2:51][C:52]([N:17]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:34])[F:33])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[CH:14]2[CH2:13][CH2:12][N:11]([C:2]([CH3:1])([CH3:10])[C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])[CH2:16][CH2:15]2)=[O:53])[C:49]2[N:55]=[CH:56][CH:57]=[CH:58][C:48]=2[C:47](=[O:59])[N:46]=1
Reactant: O=C(O)Cn1c(CCc2cccc(F)c2F)nc(=O)c2cccnc21
Reactant: CC(C)(C)OC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)N1CCC(N(Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C(=O)Cn2c(CCc3cccc(F)c3F)nc(=O)c3cccnc32)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 1,1-dimethylethyl 2-methyl-2-[4-({[4′-(trifluoromethyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]propanoate (Int. B7) (150 mg, 1 equiv), [2-[2-(2,3-difluorophenyl)ethyl]-4-oxopyrido[2,3-d]pyrimidin-1(4H)-yl]acetic acid (Int. D1) (130 mg, 1.2 equiv), DIPEA (0.164 ml, 3 equiv) and DMF (1.0 ml) was stirred at room temperature for 5 min. HATU (180 mg, 1.5 equiv) was added in 1 portion and stirred an additional 5 min. The crude reaction mixture was concentrated, filtered through a plug of silica eluted with acetone and evaporated to obtain crude 1,1-dimethylethyl 2-[4-({[2-[2-(2,3-difluorophenyl)ethyl]-4-oxopyrido[2,3-d]pyrimidin-1(4H)-yl]acetyl}{[4′-(trifluoromethyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]-2-methylpropanoate.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]([OH:5])[CH3:4].[Br:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[N:11]=[C:12](Cl)[C:13]([CH3:19])=[N:14]2.[H-].[Na+]>C1COCC1.CN(C=O)C>[Br:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[N:11]=[C:12]([O:5][CH:3]([CH3:4])[C:2]([F:7])([F:6])[F:1])[C:13]([CH3:19])=[N:14]2
Reactant: Cc1nc2cccc(Br)c2nc1Cl
Reactant: CC(O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1nc2cccc(Br)c2nc1OC(C)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 88.5 %

Procedure:
To a suspension of 1,1,1,-trifluoro-2-propanol (0.85 mL, 9.38 mmol) and 5-bromo-3-chloro-2-methylquinoxaline (126e) (1.21 g, 4.69 mmol) in 5 mL of THF and 3 mL of DMF at 0° C. was added NaH (60% wt. in mineral oil) (0.31 g, 7.74 mmol). The resulting dark purple homogeneous solution was stirred at 0° C. for 5 min then RT for 1 h. It was quenched with 15 mL of sat. NH4Cl aq. solution, and extracted with 2×75 mL of EtOAc. The organic extracts were concentrated and the residue was purified on a silica gel column (1-35% EtOAc in hexanes) to give 5-bromo-2-methyl-3-((1,1,1-trifluoropropan-2-yl)oxy)quinoxaline (452a) (1.39 g, 4.15 mmol, 88% yield) as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.09 (1H, m), 8.00 (1H, dd, J=8.2, 1.0 Hz), 7.60 (1H, t, J=7.9 Hz), 6.02 (1H, dt, J=13.4, 6.7 Hz), 2.62 (3H, s), 1.64 (3H, d, J=6.7 Hz). 19F NMR (376 MHz, DMSO-d6) δ ppm −77.20 (1F, s). m/z (ESI, +ve) 335.0/337.0 (M+H)+. A mixture of Pd(dppf)Cl2 (51 mg, 0.06 mmol), (BPin)2 (637 mg, 2.50 mmol), KOAc (492 mg, 5.01 mmol), 5-bromo-2-methyl-3-((1,1,1-trifluoropropan-2-yl)oxy)quinoxaline (452a) (420 mg, 1.25 mmol) in THF (5 mL) was heated in a microwave at 90° C. for 90 min. It was diluted with 50 mL of EtOAc and filtered through a pad of Celite. The filtrate was concentrated and the residue was purified on a silica gel column (25-75% EtOAc in hexanes) to give 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-((1,1,1-trifluoropropan-2-yl)oxy)quinoxaline (452b) (400 mg, 84% yield) as a brown solid. m/z (ESI, +ve) 383.0 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][C:7]=2[N:6]([CH3:23])[C:5]1=[O:24])[C:14](=[O:17])[CH:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12][CH2:11]3.Br[CH2:26][CH2:27][CH2:28][Cl:29].O>CN(C)C=O>[Cl:29][CH2:28][CH2:27][CH2:26][C:13]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12][CH2:11][C:10]2[C:15](=[CH:16][C:7]3[N:6]([CH3:23])[C:5](=[O:24])[N:4]([CH3:3])[C:8]=3[CH:9]=2)[C:14]1=[O:17]
Reactant: ClCCCBr
Reactant: CCOC(=O)C1CCc2cc3c(cc2C1=O)n(C)c(=O)n3C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(CCCCl)CCc2cc3c(cc2C1=O)n(C)c(=O)n3C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
60% Oily sodium hydride (832 mg) was added to a solution of ethyl (±)-1,3-dimethyl-2,5-dioxo-2,3,5,6,7,8-hexahydro-1H-naphtho[2,3-d]imidazole-6-carboxylate (5.0 g) obtained in Reference Example 138 in dimethylformamide, and the mixture was stirred at 60° C. for 1 hour. 1-Bromo-3-chloropropane was added thereto, and the mixture was stirred at 60° C. for 4 hours. The reaction mixture was allowed to cool, and water was added to decompose excessive sodium hydride. Then, the mixture was extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[C:20]([F:27])=[C:21]([OH:26])[C:22]([F:25])=[CH:23][CH:24]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[C:28]([O:33][CH3:34])(=[O:32])[C@H:29]([CH3:31])O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[C:20]([F:27])=[C:21]([C:22]([F:25])=[CH:23][CH:24]=2)[O:26][C@H:29]([CH3:31])[C:28]([O:33][CH3:34])=[O:32])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: Oc1c(F)ccc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)c1F
Reactant: COC(=O)[C@H](C)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccccc1
Product: COC(=O)[C@@H](C)Oc1c(F)ccc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)c1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 86 %

Procedure:
To a solution of 3-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-2,6 difluoro-phenol (0.570 g, 1.29 mmol), commercially available (S)-lactic acid, methyl ester. (0.246 mL, 2.58 mmol) and triphenylphosphine (0.677g, 2.58 mmol) in dry benzene (7 mL) was added diethylazodicarboxylate (0.406 mL, 2.58 mmol) dropwise at room temperature under a dry nitrogen atmosphere. The reaction mixture was sealed in a pressure bottle and immersed in a pre-heated oil bath at 105° C. After heating for 2.5 hours the mixture was stirred at ambient temperature for about 14 hours. The reaction mixture was then diluted with methylene chloride and combined with silica gel. The solvents were removed and the adsorbate was flash chromatographed (90/10 petroleum ether/ethyl acetate) to give (R)-2-[3-(6-bromo-benzo[b]naphtho[2,3-d ]thiophen-11-yl)-2,6-difluoro-phenoxy]-propionic acid, methyl ester as a white solid (0.59 g, 86%). To a solution of this methyl ester (0.46 g, 0.929 mmol) in tetrahydrofuran (18 mL) and methanol (6 mL) was added a 1 N aqueous solution of potassuim hydroxide (1.39 mL, 1.39 mmol) dropwise at room temperature. After stirring for 2 hours the solvents were removed and the residue was combined with water (50 mL) and acidified with 10% HCl. The solid was extracted into ether. The layers were shaken together well, separated, and the organic layer was washed with water and concentrated to give the title compound as a white solid (0.396 g, 88%): [a]D25=+13.22 (9.383 mg/mL methanol); NMR (400 MHz, DMSO-d6): δ13.11 (s, 1 H), 8.31 (d, J=8 Hz, 1H), 8.10-8.08 (m, 1H), 7.83-7.78 (m, 1H), 7.65-7.46 (m, 4 H), 7.32-7.19 (m, 2 H), 6.82-6.75 (m, 1 H), 4.98-4.93 (m, 1 H), 1.53-1.50 (m, 3 H); MS (-FAB): (M-H): one bromine pattern observed: 511/513 (2%); Anal. Calc. for C25H15BrF2O3S: C, 58.49, H, 2.95, N, 0.00. Found: C, 58.41, H, 3.44, N, 0.02.
Reaction SMILES: N1C=CN=C1.[C:6]([O:10][C:11](=[O:22])[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20]O)[CH:15]=1)([CH3:9])([CH3:8])[CH3:7].[I:23]I.C(OCC)(=O)C.ClCCl>ClCCl>[C:6]([O:10][C:11](=[O:22])[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][I:23])[CH:15]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)NCc1cccc(CO)c1
Reactant: II
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1cccc(CI)c1
Reaction time: 16 h
Yield: 119.7 %

Procedure:
Stir polystyrene-bound triphenylphosphine (4.27 g, 12.8 mmol) and imidazole (0.86 g, 12.7 mmol) in dichloromethane (45 mL). Add a solution of (3-hydroxymethyl-benzyl)-carbamic acid tert-butyl ester (1.70 g, 6.1 mmol) in dichloromethane (45 mL). Add iodine (3.22 g, 12.7 mmol) in 3 portions. Stir 16 hrs. Filter through a pad of diatomaceous earth. Wash with aqueous sodium thiosulfate. Dry the organic portion over sodium sulfate. Filter and concentrate. Chromatograph the residue on silica eluting with 25% ethyl acetate/dichloromethane to provide the title compound (2.53 g, 7.3 mmol).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:26][CH3:27])[C:9]3[CH:14]=[C:13]([CH2:15][C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19]([OH:21])=O)[N:12]=[CH:11][C:10]=3[N:25]=2)=[N:4][O:5][N:6]=1.[N:28]1([CH2:34][CH2:35][NH2:36])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:26][CH3:27])[C:9]3[CH:14]=[C:13]([CH2:15][C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19]([NH:36][CH2:35][CH2:34][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:21])[N:12]=[CH:11][C:10]=3[N:25]=2)=[N:4][O:5][N:6]=1
Reactant: CCn1c(-c2nonc2N)nc2cnc(Cc3cccc(C(=O)O)c3)cc21
Reactant: NCCN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCn1c(-c2nonc2N)nc2cnc(Cc3cccc(C(=O)NCCN4CCOCC4)c3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 130.8 %

Procedure:
Under nitrogen, to a solution of the product of Step 2 (31 mg, 85 μmol) in DMF (2 mL), was added [2-(4-morpholinyl)ethyl]amine (23 mg, 170 mmol), HOBT (35 mg, 0.26 mmol), HBTU (49 mg, 0.13 mmol), followed with 4-methylmorpholine (30 μL, 0.26 mmol). This mixture was then stirred at rt for overnight. The reaction mixture was concentrated, residue was purified with reverse phase HPLC (10% MeCN/H2O→80% MeCN/H2O, containing 0.1% TFA), to afford the title compound as a pale yellow solid (53 mg, 90%). %). 1H NMR (400 MHz, DMSO) δ ppm 9.74 (t, 1H, 4.4 Hz), 9.28 (s, 1H), 8.73 (t, 1H, 5.2 Hz), 8.16 (s, 1H), 7.87 (s, 1H), 7.73 (d, 1H, 8.0 Hz), 7.56 (d, 1H, 7.2 Hz), 7.49 (d, 1H, 7.6 Hz), 6.96 (s, 2H), 4.72 (q, 2H, 7.2 Hz), 4.41 (s, 2H), 4.00 (d, 2H, 11.2 Hz), 3.53-3.68 (m, 6H), 3.30 (bs, 2H), 3.14-3.17 (m, 2H), 1.42 (t, 3H, 7.2 Hz). MS (ES+) m/e 477 [M+H]+.