Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1[CH:50]=[CH:49][C:12]([C:13]([N:15]([CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[O:27][N:26]=[C:25]([C:28]4[CH:33]=[CH:32][C:31]([C:34]5[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=5)=[CH:30][CH:29]=4)[N:24]=3)=[CH:19][CH:18]=2)=[O:14])=[CH:11][CH:10]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[NH2:8][C:9]1[CH:50]=[CH:49][C:12]([C:13]([N:15]([CH2:41][C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[O:27][N:26]=[C:25]([C:28]4[CH:33]=[CH:32][C:31]([C:34]5[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=5)=[CH:30][CH:29]=4)[N:24]=3)=[CH:21][CH:22]=2)=[O:14])=[CH:11][CH:10]=1
Reactant: Cc1ccc(-c2ccc(-c3noc(-c4ccc(CN(CC(=O)OC(C)(C)C)C(=O)c5ccc(NC(=O)OC(C)(C)C)cc5)cc4)n3)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(-c3noc(-c4ccc(CN(CC(=O)OC(C)(C)C)C(=O)c5ccc(N)cc5)cc4)n3)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
Prepared using General Procedure 8. To a stirred solution of tert-butyl 2-(4-((tert-butoxycarbonyl)amino)-N-(4-(3-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetate INT-63 (659 mg, 0.977 mmol) in DCM (15 mL) was added TFA (752 μL, 9.77 mmol) at room temperature. After 2 h additional TFA (752 μL, 9.77 mmol) was added and the reaction mixture stirred for a further 3 h at room temperature. The reaction mixture was diluted with toluene (20 mL) and the solvent removed in vacuo. The residue was diluted with EA (100 mL) and washed with NaHCO3 (30 mL). The organics were concentrated in vacuo and the crude product was purified by chromatography (EA/hexanes) to afford 284 mg (50%) of tert-butyl 2-(4-amino-N-(4-(3-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetate INT-64 as an off-white powder. LCMS-ESI (m/z) calculated for C35H34N4O4: 574; found 519 [M-t-Bu+H]+, 573 [M−H]−, tR=3.12 min (Method 10).
Reaction SMILES: O1CCCCC1[O:7][C:8]1[CH:33]=[CH:32][C:11]([CH2:12][NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:31]=[CH:30][C:29]4[O:28][CH2:27][O:26][C:25]=4[CH:24]=3)[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:7][C:8]1[CH:33]=[CH:32][C:11]([CH2:12][NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:31]=[CH:30][C:29]4[O:28][CH2:27][O:26][C:25]=4[CH:24]=3)[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1
Reactant: O=C(NCc1ccc(OC2CCCCO2)cc1)N1CCN(Cc2ccc3c(c2)OCO3)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: O=C(NCc1ccc(O)cc1)N1CCN(Cc2ccc3c(c2)OCO3)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-piperonylpiperazine-1-carboxylic acid 4-(tetrahydropyran-2-yloxy)benzylamide (1.1 g, 2.43 mmol) in methanol (50 mL) was added p-toluenesulfonic acid monohydrate (1.0 g, 5.26 mmol), and the resulting solution was stirred for 1 hour at room temperature. The resulting reaction solution was concentrated under reduced pressure. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated, to thereby yield 330 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:23])[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH2:15][N:16]2[CH2:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=[N:3]1.CCN(C(C)C)C(C)C.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38](Cl)=[O:39]>CC(N(C)C)=O.CS(C)=O>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH:23][C:38](=[O:39])[C:37]3[CH:41]=[CH:42][CH:43]=[C:35]([C:34]([F:33])([F:44])[F:45])[CH:36]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH2:15][N:16]2[CH2:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CCCOCC1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cn1nccc1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1OCCN1CCCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenylamine (0.07 g, 0.2215 mmol) in 2.0 mL of DMA was added DIEA (0.057 g, 0.443 mmol), followed by m-trifluoromethyl benzoyl chloride (0.056 g, 0.266 mmol), and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted to 5.0 mL with DMSO and purified by RP-HPLC. The proper fractions were collected and lyophilized to afford N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-3-trifluoromethyl-benzamide as an off-white semisolid in 87% yield. LCMS m/z (%)=489 (M+H, 100). 1H NMR (400 MHz, DMSO-d6) δ: 10.5 (bs, 1H), 8.29 (s, 1H), 8.26 (d, J=7.94 Hz, 1H), 7.98 (d, J=7.83 Hz, 1H), 7.89 (dd, J=8.93 and 2.55 Hz, 1H), 7.79 (t, J=7.82 Hz, 1H), 7.72 (d, J=2.53 Hz, 1H), 7.49 (s, 1H), 7.26 (d, J=9.14 Hz, 1H), 6.31 (d, J=1.79 Hz, 1H), 4.29-4.43 (m, 2H), 3.69 (s, 3H), 3.55-3.64 (m, 5H), 3.01-3.18 (m, 5H), 1.8-2.1 (m, 2H).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[C:8]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].N12CCCN=C1CCCCC2.CCOC(C)=O>C1COCC1>[O:7]=[C:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:8]([O:16][CH2:17][CH3:18])=[O:15])[CH2:2]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C1C=CCCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)OCC)C1CCCC(=O)C1
Temperature: 50 °C
Yield: 104 %

Procedure:
A solution of cyclohex-2-enone (3.05 mL, 30 mmol) and diethyl malonate (4.58 mL, 30.0 mmol) in THF (30 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (4.52 mL, 30.0 mmol) and heated at 50° C. for 16 h. The cooled mixture was poured into EtOAc and washed sequentially with 1M aqueous HCl and brine. The combined aqueous layers were extracted with EtOAc, and the combined organic phases were dried and concentrated to give diethyl 2-(3-oxocyclohexyl)malonate as an oil (8.0 g), used without further purification. Mass spectrum m/z 257 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:13][C:14]1[N:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].CS(C)=O>CC(O)=O>[Cl:13][C:14]1[N:19]=[CH:18][C:17]([S:20]([NH:23][C:2]2[C:11]([Cl:12])=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)(=[O:21])=[O:22])=[CH:16][CH:15]=1
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: NS(=O)(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: O=S(=O)(Nc1nc2ccccc2nc1Cl)c1ccc(Cl)nc1
Temperature: 150 °C
Reaction time: 3.5 h
Yield: 96.6 %

Procedure:
2,3-dichloroquinoxaline (1.09 g, 5.48 mmol), 6-chloropyridine-3-sulfonamide (1.05 g, 5.45 mmol), K2CO3 (753 mg, 5.45 mmol) and dry DMSO (30 mL) were combined and heated to 150° C. with vigorous stirring for 3-4 hr. The reaction mixture was allowed to cool to room temperature, then poured into 1% AcOH in ice water (300 mL) with vigorous stirring. The resulting solids were filtered, washed with H2O and dried under high vacuum to give 6-chloro-N-(3-chloroquinoxalin-2-yl)pyridine-3-sulfonamide (1.87 g, 96%). MS (EI) m/z for C13H8Cl2N4O2S: 354.99 (MH+).
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:20]=[C:19]([CH2:21][NH:22][CH3:23])[S:18][CH:17]=2)=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:2].[C:24](Cl)(=[O:28])[CH2:25][CH2:26][CH3:27]>>[C:24]([CH2:23][NH:22][CH2:21][C:19]1[S:18][CH:17]=[C:16]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][C@H:4]([O:3][CH2:1][CH3:2])[C:5]([O:7][CH3:8])=[O:6])=[CH:11][CH:12]=2)[CH:20]=1)(=[O:28])[CH2:25][CH2:26][CH3:27]
Reactant: CCO[C@@H](Cc1ccc(-c2csc(CNC)c2)cc1)C(=O)OC
Reactant: CCCC(=O)Cl
Product: CCCC(=O)CNCc1cc(-c2ccc(C[C@H](OCC)C(=O)OC)cc2)cs1
Yield: 99.1 %

Procedure:
In a manner similar to that of Example 16(e), starting with 0.1 g (0.3 mmol) of methyl 2(S)-ethoxy-3-[4-(5-methylaminomethylthiophen-3-yl)phenyl]propanoate and 40 μl (0.33 mmol) of butanoyl chloride, 0.12 g (75%) of methyl 3-(4-{5-[(butyrylmethylamino)methyl]thiophen-3-yl}phenyl)-2(S)-ethoxypropanoate is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:6]([CH3:17])[C:5](=[O:18])[N:4]2[CH2:19][CH2:20][S:21][C:3]=12.[CH2:22]([O:29][CH:30]1[CH2:33][CH:32]([S:34](Cl)(=[O:36])=[O:35])[CH2:31]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[F:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:7]1[C:2]([NH:1][S:34]([CH:32]2[CH2:33][CH:30]([O:29][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:31]2)(=[O:36])=[O:35])=[C:3]2[S:21][CH2:20][CH2:19][N:4]2[C:5](=[O:18])[C:6]=1[CH3:17]
Reactant: O=S(=O)(Cl)C1CC(OCc2ccccc2)C1
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCS2
Solvent: c1ccncc1
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC(OCc3ccccc3)C2)c2n(c1=O)CCS2
Yield: 44.5 %

Procedure:
Using the same reaction conditions and workup as described for the preparation of Example 19A, 8-amino-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (I-19f: 0.15 g, 0.35 mmol) in pyridine (2 mL) was reacted with 3-benzyloxy-cyclobutanesulfonyl chloride (0.1 g, 0.39 mmol) to afford the crude product. Purification by column chromatography on silica gel (50% ethylacetate in hexane) afforded 0.1 g of the product (43% yield).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:18])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[CH:9][CH:8]=1.[OH-:19].[Na+].O1C(C[C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][O:33][CH3:34])=[CH:27][CH:26]=2)C1>CO.O>[OH:19][CH:7]([CH2:6][O:18][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][O:33][CH3:34])=[CH:29][CH:30]=1)[CH2:8][NH:2][CH2:3][CH2:4][NH:5][C:6](=[O:18])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[CH:9][CH:8]=1
Reactant: [OH-]
Reactant: NCCNC(=O)c1ccc(-n2ccnc2)cc1
Reactant: COCCc1ccc(CC2CO2)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCCc1ccc(OCC(O)CNCCNC(=O)c2ccc(-n3ccnc3)cc2)cc1
Temperature: 60 °C

Procedure:
To a solution of 10 g (37.5 mmol) N-(2-aminoethyl)-4-(1H-imidazol-1-yl)benzamide hydrochloride in 50 mL methanol and 5 mL water with 1.69 g (42 mmol) sodium hydroxide, add 8.59 g(41.2 mmol) 1,2-epoxy-3-[4-(2-methoxyethyl)phenyl]propane. Heat the mixtureto 60° C. for about 18 h. Cool the reaction mixture to room temperature and remove the solvents in vacuo. The resulting oil is chromatographed on alumina (activity III) using CH2Cl2 :MeOH, 98:2. Combine the appropriate fractions and remove the solvents to give the title compound which can be recrystallized from ethyl acetate.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:23])=[C:7]([CH:22]=1)[C:8]([NH:10][CH2:11][C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2)=[O:9].[NH:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1>>[Cl:23][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][N:24]2[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]2)=[CH:22][C:7]=1[C:8]([NH:10][CH2:11][C:12]12[CH2:21][CH:16]3[CH2:15][CH:14]([CH2:20][CH:18]([CH2:17]3)[CH2:19]1)[CH2:13]2)=[O:9]
Reactant: O=C1CCNCC1
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CBr)ccc1Cl
Product: O=C1CCN(Cc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1

Procedure:
Prepared according to the method described in Example 8c from 5-bromomethyl-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 8b) and 4-piperidinone.
Reaction SMILES: [OH:1][N:2]=[C:3]1[S:7][C:6](=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:9]#[N:10])[CH:5]=[CH:4]1.[C:18]1([P:24](Cl)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.O>C1COCC1>[C:18]1([P:24]([O:1][N:2]=[C:3]2[S:7][C:6](=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:17])[C:9]#[N:10])[CH:5]=[CH:4]2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1ccccc1C(C#N)=C1C=CC(=NO)S1
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(C#N)=C1C=CC(=NOP(=O)(c2ccccc2)c2ccccc2)S1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
4.7 g (20 mmol) of (5-Hydroxyimino-5H-thiophen-2-ylidene)-(2-methylphenyl)-acetonitrile, prepared as described in example 7.1, are dissolved in 50 ml of THF and cooled in an ice bath. After adding 5.1 g (21 mmol) of diphenylphosphinic chloride to the solution, 3.0 g (29 mmol) of triethylamine are added dropwise, keeping the temperature below 5° C. The reaction mixture is stirred at 5° C. for 30 min. The reaction mixture is poured into 50 ml of water, and filtered off. The yellow solid is washed with 50 ml of water and 50 ml of a mixture of water and CH3OH (10:1). The product is purified by the recrystallization from 2-PrOH to afford a yellow solid, mp 165-167° C.(Dec). The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ [ppm]: 2.31 (s, 3H), 6.09 (d, 1H), 6.82 (d, 1H), 7.12-7.35 (m, 4H), 7.48-7.65 (m, 6H), 7.95-8.04 (m, 4H).
Reaction SMILES: [SH:1][C:2]1[N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6](=[O:12])[N:5]([CH3:13])[C:4](=[O:14])[CH:3]=1.Br[CH2:16][C:17](=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:13][N:5]1[C:4](=[O:14])[C:3]2[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][S:1][C:2]=2[N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6]1=[O:12]
Reactant: CC(C)Cn1c(S)cc(=O)n(C)c1=O
Reactant: CCOC(=O)C(=O)CBr
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc2c1c(=O)n(C)c(=O)n2CC(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
6-Mercapto-3-methyl-1-(isobutyl)-pyrimidine-2,4(1H,3H)-dione (49.5 g) was dissolved in dry DMF (900 ml) and ethyl bromopyruvate (30 ml) was added, and then with stirring anhydrous potassium carbonate (15.95 g) was also added. The mixture was stirred at room temperature for 5 h, and then poured into water (5 L). The aqueous solution was acidified with dil hydrochloric acid, and then extracted thoroughly with ethyl acetate. The organic extract was dried (MgSO4) and evaporated at high vacuum to leave a semisolid mass. A portion of this semisolid mass (24 g) was dissolved in methylene chloride (500 ml) and cooled in an ice-bath under an atmosphere of nitrogen. With efficient stirring titanium tetrachloride (13.5 ml) was slowly added. The reaction mixture was stirred 1 hr in the ice-bath and then 3 hr at room temperature. The reaction mixture was poured slowly into vigorously stirred ice-water (1.5 L), and then the resulting suspension was extracted into methylene chloride. After drying the organic solvent was removed in vacuo, and the residue was chromatographed (SiO2/1:1 ethyl acetate-isohexane) to afford the sub-title compound as a pale yellow solid 15 g. δ 1HCDCl3 1.0 (6H, d), 1.4 (3H, t), 2.31-2.45 (1H, m), 3.4 (3H, s), 3.8 (2H, d), 4.4 (2H, q), 7.28 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[N:7]=[C:6]([C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: OB(O)c1ccc(Cl)cc1
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: COCCOC
Product: Clc1ccc(-c2ccnc(Cl)n2)cc1
Temperature: 0 °C
Yield: 40.4 %

Procedure:
A mixture of 2,4-dichloropyrimidine (3.1 g, 20 mmol), 4-chlorophenylboronic acid (3.0 g, 20 mmol), and tetrakis(triphenylphosphine)palladium (0.69 g, 0.6 mmol) in dimethoxyethane (200 mL)/sat. Na2CO3 solution (34 mL) was heated to 80° C. for 20 h. The cooled mixture was poured into ice-water and the product was extracted with ethyl acetate. The organic layer was washed with brine, dried and evaporated. The crude product was purified by chromatography on silica gel using ethyl acetate/cyclohexane (1:2, v/v) as eluent to give the title compound (1.82 g, 40%) as white solid. NMR (DMSO-d6) δ 7.67 (d, 2H, J=7 Hz), 8.19 (d, 2H, J=5 Hz), 8.23 (d, 2H, J=7 Hz), 8.86 (d, 2H, J=5 Hz) ppm; mp 290-292° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][C:11]([OH:17])=[CH:10][C:9]=2[Br:18])=[O:5])[CH3:2].S(OCC)(O[CH2:23][CH3:24])(=O)=O.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][C:11]([O:17][CH2:23][CH3:24])=[CH:10][C:9]=2[Br:18])=[O:5])[CH3:2]
Reactant: CCOS(=O)(=O)OCC
Reactant: CCOC(=O)c1cc(=O)c2cc(O)cc(Br)c2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(=O)c2cc(OCC)cc(Br)c2o1
Yield: 65.6 %

Procedure:
Into a 100 mL 3 neck round bottom flask equipped with a reflux condenser, nitrogen inlet and magnetic stirrer is added 700 mg (2.24 mg, 1.0 equiv.) of 8-Bromo-6-hydroxy-4-oxo-4H-chromene-carboxylic acid ethyl ester (Reference Example 23a). This material is dissolved in 50 mL of toluene, then 689 mg, 586 μL (4.47 mmol, 2.0.equiv.) of diethyl sulfate and 309 mg (2.24 mmol, 1.0 equiv.) of K2CO3 were added. The reaction was then heated to reflux for 24 hr. At the end of this time, monitoring by LC/MS reveals that the reaction is >than 95% complete. The reaction is then cooled, 100 mL of ethyl acetate is added and the organic layer is washed with 0.5N HCl solution, dried over Na2SO4, filtered and concentrated. The residues were subjected to flash chromatography, using 40% ethyl acetate in hexane as eluent. The purified fractions were concentrated to yield 500 mg (65%) of a colorless solid.
Reaction SMILES: [OH:1]C1C2C(=CC=CC=2)C(=O)N1CC1SC=CC=1.[O:18]=[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]([S:28][CH2:29][C:30]([NH:32][C:33]2[S:34][CH:35]=[CH:36][N:37]=2)=[O:31])[N:20]1[CH2:38][C:39]1S[CH:41]=[CH:42][CH:43]=1>>[O:1]1[CH:41]=[CH:42][CH:43]=[C:39]1[CH2:38][N:20]1[C:19](=[O:18])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]1[S:28][CH2:29][C:30]([NH:32][C:33]1[S:34][CH:35]=[CH:36][N:37]=1)=[O:31]
Reactant: O=C1c2ccccc2C(O)N1Cc1cccs1
Reactant: O=C(CSC1c2ccccc2C(=O)N1Cc1cccs1)Nc1nccs1
Product: O=C(CSC1c2ccccc2C(=O)N1Cc1ccco1)Nc1nccs1

Procedure:
Compound 32 was prepared using the synthetic sequence in a manner analogous to the method described for the conversion of compound 12 to compound 14 and illustrated in Scheme 1b. 1H NMR (300 MHz, DMSO): δ 11.96 (s, 1H), 7.71 (d, J=8 Hz, 1H), 7.59 (m, 4H), 7.48 (m, 2H), 7.42 (d, J=4 Hz, 1H), 7.19 (d, J=4 Hz, 1H), 5.76 (s, 1H), 4.97 (d, J=16 Hz, 1H), 4.44 (d, J=16 Hz, 1H), 3.09 (d, J=15 Hz, 1H), 2.95 (d, J=15 Hz, 1H). MS: m/z (MH+) 386.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.C1(CN2CCN(C3SC(C(O)=O)=C(C)N=3)C2=O)CCCC1.[NH2:44][CH2:45][C:46]1[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=1>>[CH:2]1([CH2:1][N:8]2[CH2:12][CH2:11][N:10]([C:13]3[S:14][C:15]([C:19]([NH:44][CH2:45][C:46]4[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=4)=[O:21])=[C:16]([CH3:18])[N:17]=3)[C:9]2=[O:22])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: NCc1cccnc1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(CC3CCCC3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(CC3CCCC3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 61 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(cyclopentylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a white powder in 61% yield: nip 142-143° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.54-8.43 (m, 2H), 7.63 (d, J=7.2 Hz, 1H), 7.27-7.18 (m, 1H), 6.45 (br s, 1H), 4.53 (d, J=5.7 Hz, 2H), 4.09-4.00 (m, 2H), 3.58-3.52 (m, 2H), 3.17 (d, J=7.2 Hz, 2H), 2.54 (s, 3H), 2.16-1.98 (m, 1H), 1.68-1.49 (m, 6H), 1.19-1.17 (m, 2H): 13C NMR (75 MHz, CDCl3) δ 162.7, 157.5, 155.5, 153.6, 149.2, 148.8, 135.5, 134.0, 123.5, 116.6, 48.9, 42.6, 42.0, 41.3, 37.9, 30.3, 25.6, 17.2; MS (ES+) m/z 400.3 (M+1).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[CH:4][C:3]=1[CH3:9].C([Li])CCC.CN([CH:18]=[O:19])C>CCOCC.CCCCCC>[CH3:9][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH:18]=[O:19]
Reactant: CN(C)C=O
Reactant: Cc1cncc(C)c1Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1cncc(C)c1C=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 4-bromo-3,5-dimethylpyridine (0.70 g, 3.76 mmol) in ether (10 mL) was cooled to −78° C. and then 2.50 M n-butyllithium in hexane (1.50 mL) was added to the reaction flask dropwise. After stirring at −78° C. for 1 h, DMF (1.75 mL, 22.6 mmol) was added to the reaction flask slowly. The reaction solution was allowed to warm to room temperature overnight. The reaction was quenched with 10 mL saturated NH4Cl solution and diluted with ethyl acetate. The aqueous layer was extracted with ethyl acetate once. The combined organic solutions were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (40% to 50% ethyl acetate/hexanes) to afford the desired product as a solid. (280 mg, 55%). 1H NMR (400 MHz, CDCl3): δ 10.62 (s, 1H), 8.43 (s, 2H), 2.57 (s, 6H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:25])([F:24])[F:23])[CH:16]=1)=O)(C)(C)C.[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]>C(Cl)Cl>[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:23])([F:24])[F:25])[CH:16]=1.[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1cccc(OC(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)Oc1cccc(NC[C@@H]2CCCN2)c1

Procedure:
A solution of (S)-2-[(3-trifluoromethoxy-phenylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 0.277 mmol) and TFA (1 mLl) in CH2Cl2 (2 mL) was stirred at RT for 2 h. Solvent was concentrated and the residue was co-evaporated twice with CH2Cl2 and dried under high vacuum overnight to give the crude title compound as a TFA salt. MS: 261.1 [MH−Boc]+, tR (HPLC conditions a): 2.61 min.