Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]3[CH:16]=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:14][C:12]1[N:13]=[C:8]([C:4]2[CH:3]=[C:2]([C:29]3[CH:30]=[CH:31][C:26]([NH2:25])=[N:27][CH:28]=3)[CH:7]=[CH:6][CH:5]=2)[CH:9]=[C:10]([C:15]2[CH:16]=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[CH:11]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)nc2)cc(-c2cccc(Br)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(C(F)(F)F)nc2)cc(-c2cccc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 6′-(3-bromo-phenyl)-2′-methyl-6-trifluoromethyl-[3,4′]bipyridinyl (example B.12) (0.098 g, 0.25 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.61 g, 0.275 mmol) according to the general procedure III. Obtained as an off-white solid (0.031 g, 31%). MS (ISP) 407.3 [(M+H)+]; mp 124-125° C.
Reaction SMILES: [CH2:1]([O:3]/[CH:4]=[CH:5]/[C:6]1[C:11]([C:12]([O:14]CC)=O)=[N:10][CH:9]=[C:8]2[N:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH:18]=[CH:19][C:7]=12)[CH3:2].[NH2:28][OH:29].[OH-].[Na+].Cl>CO>[CH2:1]([O:3]/[CH:4]=[CH:5]/[C:6]1[C:11]([C:12]([NH:28][OH:29])=[O:14])=[N:10][CH:9]=[C:8]2[N:17]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH:18]=[CH:19][C:7]=12)[CH3:2]
Reactant: NO
Reactant: CCO/C=C/c1c(C(=O)OCC)ncc2c1ccn2Cc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCO/C=C/c1c(C(=O)NO)ncc2c1ccn2Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.5 %

Procedure:
To ethyl 4-[(E)-2-ethoxyvinyl]-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (0.2 g, 0.54 mmol) in methanol (5 mL) were added hydroxylamine (1 mL, 50% in water, 15.2 mmol) and sodium hydroxide (0.0763 g, 1.9 mmol). The mixture was stirred at room temperature for 5 h, neutralized with 4N aq. HCl solution (0.48 mL, 1.9 mmol), and extracted with ethyl acetate. The organic extract was concentrated and recrystallized from ethyl acetate/ethyl ether/hexane to give the title compound (0.12 g, 62% yield). 1H NMR (DMSO-d6) δ; 11.76 (d, 1H, J=1.9 Hz), 8.88 (d, 1 H, J=1.9 Hz), 8.60 (s, 1 H), 7.83 (d, 1 H, J=3.0 Hz), 7.31 (t, 2H, J=8.9 Hz), 7.22 (d, 1H, J=13.2 Hz), 7.05 (t, 2H, J=8.9 Hz), 6.82 (d, 1H, J=3.0 Hz), 6.66 (d, 1H), J=13.2 Hz), 5.54 (s, 2H), 3.96 (q, 2H, J=7.0 Hz), 1.28 (t, 3H, J=7.0 Hz). LCMS (APCl, M+H+): 356.1. Anal. (C19H18FN3O3) C, H, N. HPLC: 95% purity.
Reaction SMILES: [F:1][C:2]1[CH:44]=[CH:43][C:5]([O:6][C:7]2[C:8]([NH:23][C:24]3[S:28][N:27]=[C:26]([CH2:29][CH:30]4[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]4)[N:25]=3)=[N:9][CH:10]=[C:11]([S:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]4[CH:20]=[CH:21][S:22][C:15]=34)[CH:12]=2)=[CH:4][CH:3]=1.CO.C(Cl)[Cl:48].[ClH:50]>O1CCOCC1>[ClH:48].[ClH:50].[ClH:48].[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[C:8]([NH:23][C:24]3[S:28][N:27]=[C:26]([CH2:29][CH:30]4[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]4)[N:25]=3)=[N:9][CH:10]=[C:11]([S:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]4[CH:20]=[CH:21][S:22][C:15]=34)[CH:12]=2)=[CH:43][CH:44]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2nsc(Nc3ncc(Sc4ccnc5ccsc45)cc3Oc3ccc(F)cc3)n2)CC1
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Fc1ccc(Oc2cc(Sc3ccnc4ccsc34)cnc2Nc2nc(CC3CCNCC3)ns2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
A 10 mL round-bottomed flask was charged with tert-butyl 4-((5-(3-(4-fluorophenoxy)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)methyl)piperidine-1-carboxylate (52.2 mg, 0.0802 mmol) and a 1:1 mix of methanol and CH2Cl2 (4 mL). 4N HCl in dioxane (2 mL) was added and the reaction stirred at room temperature for 10 minutes. The solvent was removed to afford crude 3-(4-fluorophenoxy)-N-(3-(piperidin-4-ylmethyl)-1,2,4-thiadiazol-5-yl)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-amine trihydrochloride (52.9 mg, 100%).
Reaction SMILES: Br[C:2]1[C:3]([Cl:10])=[C:4]([CH3:9])[C:5]([F:8])=[CH:6][CH:7]=1.[CH3:11][N:12](C=O)C>[C-]#N.[Zn+2].[C-]#N.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.C(OCC)C>[Cl:10][C:3]1[C:4]([CH3:9])=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[C:11]#[N:12]
Reactant: CN(C)C=O
Reactant: Cc1c(F)ccc(Br)c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOCC
Product: Cc1c(F)ccc(C#N)c1Cl
Yield: 42 %

Procedure:
3-Bromo-2-chloro-6-fluorotoluene 165RL91 (173 mg, 0.78 mmol), zinc cyanide (91 mg, 0.78 mmol) and tetrakis(triphenylphosphine)palladium(0) (27 mg, 23 μmol) was charged in a vial, DMF (1 mL) added, and the mixture irradiated for 150 sec at 200° C. in a microwave oven. Diethyl ether (30 ml) was added and the reaction mixture washed with magnesium sulphate (4% solution, 3×20 mL) followed by brine (20 mL). The organic layer was dried and evaporated. The product was further purified by column chromatography on silica gel using n-heptane/ethyl acetate (9:1) giving a white solid (55 mg, 42%).
Reaction SMILES: [C:1]([O:4][CH2:5][O:6][C:7]1[C:8]([C:15]([NH:17][C@H:18]2[CH2:26][O:25][C:24](=[O:27])[C@H:23]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@@H:22]([O:35][CH2:36][C:37]([CH3:39])=[CH2:38])[C@H:21]([CH3:40])[O:20][C:19]2=[O:41])=[O:16])=[N:9][CH:10]=[CH:11][C:12]=1[O:13][CH3:14])(=[O:3])[CH3:2].[H][H]>[Pd].C(OCC)(=O)C>[C:1]([O:4][CH2:5][O:6][C:7]1[C:8]([C:15]([NH:17][C@H:18]2[CH2:26][O:25][C:24](=[O:27])[C@H:23]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C@@H:22]([O:35][CH2:36][CH:37]([CH3:38])[CH3:39])[C@H:21]([CH3:40])[O:20][C:19]2=[O:41])=[O:16])=[N:9][CH:10]=[CH:11][C:12]=1[O:13][CH3:14])(=[O:3])[CH3:2]
Reactant: C=C(C)CO[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)c2nccc(OC)c2OCOC(C)=O)COC(=O)[C@@H]1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccnc(C(=O)N[C@H]2COC(=O)[C@H](Cc3ccccc3)[C@@H](OCC(C)C)[C@H](C)OC2=O)c1OCOC(C)=O
Yield: 95 %

Procedure:
Compound 12 was prepared in 95% yield using Compound 6 (6.0 g, 10.5 mmol) with 10% palladium on charcoal (1.2 g) and hydrogen (40 psi) in ethyl acetate (150 mL) for 1.5 hour. Recrystallization from a mixture of hot methylcyclohexane and toluene (4:1) gave 5.7 g of white needles: m.p.134-136° C. Spectral data were consistent with the assigned structure.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([CH:19]=O)[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].CC(O)=O.Cl.[CH3:26][NH:27][CH3:28].[BH3-]C#N.[Na+]>C1COCC1>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([CH2:19][N:27]([CH3:28])[CH3:26])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CC(C)N1CCN(c2nc3ccc(C=O)cc3s2)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)N1CCN(c2nc3ccc(CN(C)C)cc3s2)CC1
Temperature: 63 °C
Yield: 32.4 %

Procedure:
To a solution of 2-(4-isopropylpiperazin-1-yl)benzothiazole-6-carboxaldehyde (0.7 g, 2.42 mmol) and AcOH (291 mg, 4.84 mmol) in THF, dimethylamine hydrochloride (397 mg, 4.84 mmol) and NaCNBH3 (245 mg, 3.88 mmol) were added in turn. The reaction mixture was heated at 63° C. for 12 hours. The solvent was removed and the residue was extracted with ethyl acetate, washed with water and brine and dried (MgSO4). The volatiles were evaporated and the residue was purified by preparative HPLC to yield 250 mg (32%) of [2-(4-isopropylpiperazin-1-yl)benzothiazol-6-ylmethyl]dimethylamine as a trifluoroacetate salt.
Reaction SMILES: [CH3:1][NH: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][CH:10]([CH3:12])[CH3:11])[NH2:8].Br[CH2:23][N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34].[I-].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][NH:2][C:3](=[O:21])[C@H:4]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[NH:5][C:6](=[O:13])[C@H:7]([CH2:9][CH:10]([CH3:12])[CH3:11])[NH:8][CH2:23][N:24]1[C:25](=[O:34])[C:26]2=[CH:33][CH:32]=[CH:31][CH:30]=[C:27]2[C:28]1=[O:29]
Reactant: O=C1c2ccccc2C(=O)N1CBr
Reactant: CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(C)C
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Product: CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.8 %

Procedure:
A solution of L-leucyl-L-phenylalanine N-methylamide (1.3 g) in dichloromethane (13 ml) was treated with N-bromomethylphthalimide (1.17 g) and sodium iodide (0.06 g). The resulting yellow solution was stirred at room temperature for 16 h. The solution was treated with saturated sodium bicarbonate solution (ca. 8 ml) and extracted with dichloromethane. The crude, organic extracts were preadsorbed onto silica gel and purified by flash silica chromatography, eluting with ethyl acetate/heptane (5:1), to furnish the title compound as a white solid (0.74 g).
Reaction SMILES: Br[C:2]1[C:3](=[O:15])[C:4]([CH3:14])([CH3:13])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.O>[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[C:3](=[O:15])[C:4]([CH3:14])([CH3:13])[O:5][C:6]=2[C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC1(C)OC(c2ccncc2)=C(Br)C1=O
Reactant: CC1(C)OB(c2ccc(OCc3ccccc3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)OC(c2ccncc2)=C(c2ccc(OCc3ccccc3)cc2)C1=O
Yield: 60.1 %

Procedure:
A solution of 4-bromo-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one (10.0 g, 37.2 mmol), 2-(4-(benzyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13.8 g, 44.7 mmol), and Cs2CO3 (36.27 g, 111.6 mmol) in toluene (100 mL) and water (50 mL) was degassed. Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(ll) (2.7 g, 3.7 mmol) was added under an inert atmosphere and again degassed. Then the reaction was refluxed for 3 h and monitored by TLC. Upon complete consumption of the starting material, the reaction mixture was filtered through a bed of Celite® washing with ethyl acetate. The organic layer was then washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 20% ethyl acetate in n-hexanes on 230-400 mesh silica gel to afford 4-(4-(benzyloxy)phenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one (8.3 g, 60.2%) as a light orange color solid. 1H NMR, 500 MHz, DMSO-d6: δ 8.2 (d, 2H), 7.85 (d, 2H), 7.6 (d, 4H), 7.4 (t, 1H), 7.15 (d, 2H), 7.05 (d, 2H), 5.1 (s, 2H), 1.45 (s, 6H). MS: [M+H]+: m/z=396.0. HPLC: (97.5%, Column: Eclipse XDB-C18, 150×4.6 mm, 5 um. Mobile Phase: 0.1% TFA in Water. (A). ACN (B), Flow rate: 1.5 ml/min).
Reaction SMILES: C([Li])CCC.[CH:6]([S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10])([CH3:8])[CH3:7].[Br:18][CH2:19][CH2:20][CH2:21]Br>O1CCCC1>[Br:18][CH2:19][CH2:20][CH2:21][C:6]([CH3:8])([S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:10])=[O:11])[CH3:7]
Reactant: BrCCCBr
Reactant: CC(C)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(CCCBr)S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
A solution of n-butyllithium in cyclohexanes (1.82M, 18 ml, 32.8 mmol) was added dropwise to a stirred solution of phenyl i-propyl sulphone (5.55 g, 30.1 mmol) in tetrahydrofuran (60 ml) at −78° C. The mixture was stirred for 30 min. and 1,3-dibromopropane (6 ml, 58.7 mmol) was added via syringe over 30 seconds. The mixture was allowed to warm to 0° C. over 3 hours, then quenched with satd. aqueous NH4Cl and extracted into 1:1 mixture of i-hexane-diethyl ether. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified on silica (i-hexane-diethyl ether) to give the title product (5.7 g, 62%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15](=[O:23])[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)=[O:5].[C:28](OC(=O)C)(=O)[CH3:29]>CC1C=CC=CC=1>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]([CH:12]2[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][N:6]3[C:4](=[O:5])[C:3]4[C:2](=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:1]=[C:28]3[CH3:29])[CH2:14][CH2:13]2)=[O:23])=[CH:21][CH:20]=1
Reactant: Nc1ccccc1C(=O)NCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: Cc1nc2ccccc2c(=O)n1CCN1CCC(C(=O)c2ccc(F)cc2)CC1
Yield: 69 %

Procedure:
A mixture of 6 parts of 2-amino-N-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]benzamide, 10 parts of acetic acid anhydride and 108 parts of methylbenzene is stirred and refluxed overnight. The reaction mixture is evaporated and water is added to the oily residue. The whole is alkalized with a dilute sodium hydroxide solution and extracted with trichloromethane. The extract is dried, filtered and evaporated. The oily residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The product is filtered off and recrystallized from 2-propanol, yielding 4.4 parts (69%) of 3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2-methyl-4(3H)-quinazolinone; mp. 164.9° C.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[F:16][C:17]([F:29])([F:28])[O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1.[CH2:30]([C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=1)[CH2:31][CH3:32].CN(C1C=CC=CN=1)C.C(O)(=O)C(O)=O>C1(C)C=CC=CC=1.O>[F:16][C:17]([F:28])([F:29])[O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([O:25][C:36]2[CH:37]=[CH:38][C:33]([CH2:30][CH2:31][CH3:32])=[CH:34][CH:35]=2)=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(OC(F)(F)F)cc1
Reactant: CCCc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1ccc(OC(=O)c2ccc(OC(F)(F)F)cc2)cc1
Reaction time: 2 h

Procedure:
10.0 g of dicyclohexylcarbodiimide in 20 ml of toluene are added with water cooling to a mixture of 9.1 g of 4-trifluoromethoxybenzoic acid, 6.0 g of 4-propylphenol, 2.7 g of dimethylaminopyridine and 30 ml of toluene. The mixture is stirred for 2 hours, 1 g of oxalic acid is added, and the mixture is stirred for a further hour and filtered with suction. The filtrate is washed by shaking with 1M HCl, the phases are separated, and the organic phase is washed by shaking with 1M NaOH and worked up. After purification by chromatography and/or crystallization, 4-propylphenyl 4-(trifluoromethoxy)-benzoate having C 59° I is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:12][C:13]1[N:14]=[C:15]([CH2:18][CH3:19])[S:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:18]([C:15]1[S:16][CH:17]=[C:13]([CH2:12][O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[N:14]=1)[CH3:19]
Reactant: CCc1nc(CCl)cs1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc(COc2ccc([N+](=O)[O-])cc2)cs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 34.6 %

Procedure:
A mixture of 4-nitrophenol (5.48 g), 4-chloromethyl-2-ethyl-1,3-thiazole (7.40 g), potassium carbonate (5.45 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 2-ethyl-4-[(4-nitrophenoxy)methyl]-1,3-thiazole as colorless crystals (3.60 g, yield 35%) from a fraction eluted with hexane-ethyl acetate (4:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 79-80° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][N:14]=[C:7]1[C:6]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])=[N:5]2.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.COCCOC>[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][N:14]=[C:7]1[C:6]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])=[N:5]2
Reactant: OCCCNc1nc2cc(Br)ccc2n2ccnc12
Reactant: OB(O)c1ccccc1C(F)(F)F
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: [K+]
Solvent: COCCOC
Solvent: O
Product: OCCCNc1nc2cc(-c3ccccc3C(F)(F)F)ccc2n2ccnc12
Yield: 38.7 %

Procedure:
Tetrakis(triphenylphosphine)palladium (11 mg, 0.009 mmol, 0.1 eq), 3-(7-Bromo-imidazo[1,2-a]quinoxalin-4-ylamino)-propan-1-ol (30 mg, 0.093 mmol, 1 eq), 2-(trifluoromethyl)phenylboronic acid (19 mg, 0.102 mmol, 1.1 eq), potassium carbonate (51 mg, 0.372 mmol, 4 eq) are stirred under argon in a mixture of degassed water/1,2-dimethoxyethane (1 mL/1 mL) at 80° C. for 3 days. Evaporation of 1,2-dimethoxyethane, partition (water/ethyl acetate), extraction of the aqueous phase (two times ethyl acetate), reunion of the organic phases, drying over magnesium sulfate and purification over silicagel on prep TLC (eluent: dichloromethane/methanol 90:10) affords the title compound as an off-white solid (14 mg, 0.036 mmol, 39%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[S:8])[NH2:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].Cl[CH2:15][CH:16]=O>C(O)C>[N+:11]([C:3]1[CH:4]=[C:5]([C:6]2[S:8][CH:15]=[CH:16][N:7]=2)[CH:9]=[CH:10][C:2]=1[NH2:1])([O-:13])=[O:12]
Reactant: O=CCCl
Reactant: NC(=S)c1ccc(N)c([N+](=O)[O-])c1
Solvent: CCO
Product: Nc1ccc(-c2nccs2)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 18.6 %

Procedure:
To a stirred suspension of 220 (500 mg, 2.53 mmol) in ethanol (15 mL) was added chloroacetaldehyde (50% solution in water, 0.796 ml, 5.0 mmol). The mixture was heated at 80° C. for 18 hours, evaporated under reduced pressure and the residue was dissolved in DCM, washed with brine, dried with sodium sulfate and concentrated. The crude material was purified by flash chromatography on silica gel, eluents hexane-EtOAc (4:1), then EtOAC (100%), to afford the title compound 221a (104 mg, 19% yield). 1H NMR: (CD3OD) δ (ppm): 8.62 (d, J=2.0 Hz, 1H), 7.91 (dd, J=2.4, 8.8 Hz, 1H), 7.78 (d, J=3.2 Hz, 1H), 7.51 (d, J=3.2 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H). MS: (calc.) 221.2; (obt.) 222.1 (MH)+.
Reaction SMILES: [CH3:1][C@:2]1([NH:17][C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[NH:24]C(=O)OCC2C=CC=CC=2)[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH2:3]1.I[Si](C)(C)C.Cl>C(Cl)Cl.CO>[CH3:1][C@:2]1([NH:17][C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[NH2:24])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[CH2:3]1
Reactant: C[C@]1(N[C@@H]2CCCC[C@H]2NC(=O)OCc2ccccc2)CCCN(c2ccc([N+](=O)[O-])cc2)C1
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: C[C@]1(N[C@@H]2CCCC[C@H]2N)CCCN(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24 %

Procedure:
To a solution of benzyl (1R,2R)-2-((S)-3-methyl-1-(4-nitrophenyl)piperidin-3-ylamino)cyclohexylcarbamate (132 mg, 0.283 mmol) in CH2Cl2 (2 mL) cooled at 0° C. was added iodotrimethylsilane (0.058 mL, 0.424 mmol) dropwise. After addition, the orange colored suspension was stirred at 0° C. for 10 min, then at rt for 40 min. LCMS showed little reaction happened. Then more TMSI (0.060 mL) was added and the reaction was stirred for total 2 h. LCMS showed the reaction was about ˜20% completed. More TMSI (0.070 mL) was added and the reaction was stirred at rt for total 7 h. LCMS showed the reaction was about ˜60% completed. Additional amount of TMSI (0.060 mL, total 0.25 mL, 1.84 mmol) was added and the reaction was stirred at rt for total 9 h. LCMS showed the reaction was completed. The reaction was quenched by addition of 1.70 mmol of HCl (0.45 mL of 4N HCl in dioxane) in MeOH (3 mL), and then the mixture was concentrated. The dark reddish residue was partitioned between ether and water. The ether phase was extracted with 0.2 N aqueous HCl (3×). The combined acidic aqueous was cooled at 0° C. and then basified with 1N aqueous NaOH to pH ˜10. The aqueous phase was extracted with CH2Cl2 (3×). The combined CH2Cl2 extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified using RP prep-HPLC (Method A). The desired fractions was neutralized and concentrated to give the desired product (1R,2R)—N1-((S)-3-methyl-1-(4-nitrophenyl)piperidin-3-yl)cyclohexane-1,2-diamine (23 mg, 0.068 mmol, 24.21% yield) as a yellow oil. Anal. Calcd. for C18H28N4O2 m/z 332.4, found: 333.2 (M +H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.08 (d, J=9.34 Hz, 2H), 6.83 (d, J=9.34 Hz, 2 H), 3.35-3.46 (m, 1 H), 3.23-3.35 (m, 2 H), 3.16 (d, J=12.64 Hz, 1 H), 2.11-2.26 (m, 2 H), 1.88-2.00 (m, 2 H), 1.85 (ddd, J=8.11, 3.99, 3.85 Hz, 1 H), 1.65-1.75 (m, 4 H), 1.56 (ddd, J=17.31, 8.52, 8.25 Hz, 3 H), 1.21-1.33 (m, 3 H), 1.12 (s, 1 H).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]1[CH:9]=[C:10](N)[C:11](=[CH:15][CH:16]=1)[C:12]([OH:14])=[O:13].N([O-])=O.[Na+].[Na+].[I-:23]>O>[I:23][C:10]1[CH:9]=[C:8]([O:7][CH3:6])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]
Reactant: [I-]
Reactant: COc1ccc(C(=O)O)c(N)c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1ccc(C(=O)O)c(I)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.1 %

Procedure:
To a mixture of 50% sulfuric acid (150 ml) and 4-methoxyanthranilic acid (12 g) at 5°-10° C. is added sodium nitrite (5.5 g) in water, followed 10 minutes later by NaI (16.5 g) in water (30-50 ml). The reaction mixture is warmed to room temperature and stirred for 2 hours, then is heated at 60°-70° C. for 10 minutes, followed by stirring at room temperature for 1 hour. The reaction mixture is extracted with ether (4×125 ml) and the combined ether extracts are washed with water (50 ml×2), dried over MgSO4, filtered and evaporated. The residue is purified by column chromatography on silica gel eluting with ether to afford 12 g of 2-iodo-4-methoxybenzoic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([CH3:20])[CH:14]=[C:13]2[OH:21])=[O:5])[CH3:2].[Br:22][CH2:23][CH2:24][CH2:25]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([CH3:20])[CH:14]=[C:13]2[O:21][CH2:25][CH2:24][CH2:23][Br:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)CCCOc1ccc2nc(C)cc(O)c2c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1ccc2nc(C)cc(OCCCBr)c2c1

Procedure:
A reaction between 6-(3-ethoxycarbonylpropoxy)-2-methylquinolin-4-ol (1.157 g, 4 mmol), 1,3-dibromopropane (3.230 g, 16 mmol) and anhydrous potassium carbonate (0.663 g, 4.8 mmol) in acetone was performed similar to that described in Example 5b. The expected compound was obtained as a white solid (0.903 g, 55%). 1H NMR (400 MHz, CDCl3): 1.25 (3H, t, J=7.2 Hz), 2.18 (2H, m), 2.56 (4H, m), 2.65 (3H, s), 3.67 (2H, t, J=6.3 Hz), 4.14 (4H, m), 4.31 (2H, t, J=5.8 Hz), 6.61 (s, 1H), 7.29 (1H, dd, J=9.1, 2.6 Hz), 7.36 (1H, d, J=2.6 Hz), 7.85 (1H, d, J=9.1 Hz).