Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:21][CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH2:32][CH2:33][NH:34][C:35](=[O:45])[CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[CH:30]=2)[NH:25][CH:24]=1.C(Br)(Br)(Br)[Br:47]>C(Cl)Cl>[Br:47][CH2:21][CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH2:32][CH2:33][NH:34][C:35](=[O:45])[CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[CH:30]=2)[NH:25][CH:24]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc(CC(=O)NCCc2ccc3[nH]cc(CCO)c3c2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CC(=O)NCCc2ccc3[nH]cc(CCBr)c3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
Triphenylphosphine (149 mg) in dry CH2Cl2 (0.5 ml) was added dropwise at -10° to -5° under nitrogen to a stirred solution of the compound of section (a) (155 mg) and CBr4 (139 mg) in dry CH2Cl2 (10 ml). After stirring at room temperature for 20 h (overnight) the solution was evaporated in the presence of silica gel and the resultant fine powder was chromatographed [elution with EA:hexane (1:1)] to give the title compound as a pale yellow viscous oil (117 mg). T.l.c. EA, Rf 0.51 (major).
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:20][F:21])[CH:8]=[C:7]([C:9]([NH:11][CH3:12])=O)[C:6]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:5]=2[O:4]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1C=CC=CC=1>[F:1][CH2:2][C:3]1([CH2:20][F:21])[CH:8]=[C:7]([C:9](=[S:31])[NH:11][CH3:12])[C:6]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:5]=2[O:4]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CNC(=O)C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Solvent: c1ccccc1
Product: CNC(=S)C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Yield: 152.3 %

Procedure:
A mixture of 0.08 g of 2,2-bis(fluoromethyl)-N-methyl-6-nitro-2H-1-benzopyran-4-carboxamide, 0.06 g of a Lawesson's reagent and 2 ml of benzene was refluxed with heating for 1 hour. The solvent was distilled. The resultant residue was purified according to silica gel column chromatography (developing solution:CH2Cl2) and further recrystallized by a mixed solvent of ethyl acetate and hexane to obtain 71 mg of 2,2-bis(fluoromethyl)-N-methyl-6-nitro-2H-1-benzopyran-4-carbothioamide with a melting point of 134°-135° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[C:4]([NH:10][CH3:11])[CH:3]=1.C[O:13][C:14](=O)[CH2:15][C:16]1[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:17]=1[CH3:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:22][C:20]1[CH:19]=[CH:18][C:17]([CH3:23])=[C:16]([C:15]2[C:14](=[O:13])[N:10]([CH3:11])[C:4]3[C:5]([CH:8]=2)=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=3)[CH:21]=1
Reactant: COC(=O)Cc1cc(N)ccc1C
Reactant: CNc1cc(Cl)ncc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(N)cc1-c1cc2cnc(Cl)cc2n(C)c1=O
Temperature: 100 °C

Procedure:
6-Chloro-4-methylamino-pyridine-3-carbaldehyde 6 (19.8 g, 116 mmol) is mixed with 2-(5-amino-2-methyl-phenyl)acetic acid methyl ester 7 (27 g, 151 mmol) and potassium carbonate (48.1 g, 348 mmol) in DMF (1 L). The mixture is heated to 100° C. for 16 h. After cooling to rt and removing solvent in vacuo, the crude product is purified using flash chromatography (ethyl acetate:petroleum ether=1:1). The title compound 8 is obtained as a pale solid. 1H NMR (300 MHz, CDCl3) δ 8.56 (s, 1H), 7.63 (s, 1H), 7.27 (s, 1H), 7.06 (d, J=8.1 Hz, 1H), 6.74 (dd, J=2.4, 8.1 Hz, 1H), 6.58 (d, J=2.4 Hz, 1H), 3.71 (s, 2H), 2.10 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: C1CCNC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)cc1C(F)(F)F)N1CCCC1
Yield: 96.1 %

Procedure:
According to general procedure C, 4-Bromo-2-trifluoromethyl-benzenesulfonyl chloride (0.50 g, 1.54 mmol) and pyrrolidine (0.32 mL, 3.85 mmol) were stirred together in dry dichloromethane (2 mL) for 16 hours. 1-{[4-bromo-2-(trifluoromethyl)phenyl]sulfonyl}pyrrolidine (0.53 g, 96%) was provided after purification. MS (ESI) m/z 358. HPLC purity 100.0% at 210-370 nm, 9.8 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][N:4]=[C:5]=[S:6].[CH3:9][S:10]([NH2:13])(=[O:12])=[O:11].[OH-].[Na+]>CC(C)=O.O>[CH3:9][S:10]([NH:13][C:5]([NH:4][CH2:3][C:2]([F:8])([F:7])[F:1])=[S:6])(=[O:12])=[O:11]
Reactant: FC(F)(F)CN=C=S
Reactant: CS(N)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CS(=O)(=O)NC(=S)NCC(F)(F)F
Yield: 19.2 %

Procedure:
A solution of 2,2,2-trifluoroethylisothiocyanate (1.4 g.) in acetone (20 ml.) was added to a solution of methanesulphonamide (0.95 g.) and sodium hydroxide (0.44 g.) in water (10 ml.) and the mixture stirred and heated under reflux for 18 hours, and then evaporated to dryness. The residue was dissolved in water and the solution washed with ethyl acetate and then acidified with concentrated hydrochloric acid. The mixture was extracted three times with ethyl acetate and the combined extracts dried and evaporated to dryness. The residue was triturated with acetonitrile and filtered and the filtrate evaporated to dryness. The residue was dissolved in ether, and the solution extracted with aqueous sodium bicarbonate solution. The extract was neutralised with N hydrochloric acid and the mixture extracted with ethyl acetate. The ethyl acetate extract was dried and evaporated to dryness to give 1-methanesulphonyl-3-(2,2,2-trifluoroethyl)thiourea (0.45 g.) which was used without further purification.
Reaction SMILES: [NH:1]([CH3:20])[C@H:2]([C:15]([NH:17][O:18][CH3:19])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.[C:21]([N:31]([CH3:39])[C@H:32]([C:36]([OH:38])=O)[CH:33]([CH3:35])[CH3:34])([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].O>C1COCC1>[C:21]([N:31]([CH3:39])[C@H:32]([C:36]([N:1]([CH3:20])[C@H:2]([C:15]([NH:17][O:18][CH3:19])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:12])[CH3:13])[CH:5]=1)=[O:38])[CH:33]([CH3:34])[CH3:35])([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22]
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Reactant: CN[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(=O)NOC
Solvent: C1CCOC1
Solvent: O
Product: CONC(=O)[C@H](Cc1ccc(O)c(C(C)(C)C)c1)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 56.6 %

Procedure:
To a solution of N-Me-Tyr(3-tBu)-NHOMe (1.24 g, 4.42 mmol), Z-N-Me-Val-OH (1.76 g, 6.63 mmol) and CMPI (1.7 g, 6.63 mmol) in THF (30 ml), TEA (1.23 ml, 8.84 mmol) was added and stirred overnight. The mixture was mixed with water, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated to remove the solvent under reduced pressure. The thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:1) to give the titled compound (1.32 g, 57%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH:21][C:22]([C:24]2[C:33]([NH:34][C:35](=[O:44])[O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:32][C:31]3[C:26](=[CH:27][C:28]([CH:45]=C)=[CH:29][CH:30]=3)[N:25]=2)=[O:23])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C[O:50]CC1.I([O-])(=O)(=O)=O.[Na+]>O.[Os](=O)(=O)(=O)=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH:21][C:22]([C:24]2[C:33]([NH:34][C:35](=[O:44])[O:36][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[CH:32][C:31]3[C:26](=[CH:27][C:28]([CH:45]=[O:50])=[CH:29][CH:30]=3)[N:25]=2)=[O:23])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=Cc1ccc2cc(NC(=O)OCc3ccccc3)c(C(=O)Nc3cnccc3N3CCC[C@H](NC(=O)OC(C)(C)C)C3)nc2c1
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2NC(=O)c2nc3cc(C=O)ccc3cc2NC(=O)OCc2ccccc2)C1
Temperature: 70 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
Benzyl (2-{[(4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}pyridin-3-yl)amino]carbonyl}-7-vinylquinolin-3-yl)carbamate (520 mg, 0.84 mmol) was mixed with THF (20 mL), 0.25 M osmium tetroxide in water (1.0 mL, 0.3 mmol) and sodium metaperiodate (840 mg, 3.9 mmol) in water (2 mL). The reaction mixture was stirred at 70° C. for 2 h, then allowed to cool. After cooling, the mixture was filtered through a diatomaceous earth plug, which was rinsed with fresh THF. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column eluting with EtOAc in hexanes (0-100%) to give the sub-title compound (320 mg, 61%) as yellow powder. LCMS calc. for C34H37N6O6 (M+H)+: m/z=625.2. Found: 625.1.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.[Cl:13]N1C(=O)CCC1=O>CN1C(=O)CCC1.C(=O)(O)[O-].[Na+]>[Cl:13][C:11]1[C:5]2[S:4][C:3]([S:2][CH3:1])=[N:7][C:6]=2[CH:8]=[CH:9][C:10]=1[OH:12]
Reactant: CSc1nc2ccc(O)cc2s1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CSc1nc2ccc(O)c(Cl)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.3 %

Procedure:
To the solution of 2-(methylthio)benzo[d]thiazol-6-ol (500 mg, 2.53 mmol, 1.0 eq) in 10 mL of NMP was added N-chlorosuccinimide (507 mg, 3.80 mmol, 1.5 eq) at room temperature. The reaction mixture was stirred at room temperature for 1 hour thereafter the mixture was diluted with saturated sodium bicarbonate solution (ca. 100 mL) and aqueous layer extracted with DCM (ca. 150 mL×3). Combined organic layers were dried over sodium sulfate, filtered and condensed under reduced pressure. Purification on ISCO using gradient 0%-100% ethyl acetate-hexane gave 283.39 mg of product in 48% yields structure of which was confirmed by H+NMR. LC/MS (m/z) [232.0] (MH+)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([NH:17]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OC)(C)(C)C.C(O)(C)C>[NH2:17][C:10]1([C:14]([OH:16])=[O:15])[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCC(NC(=O)OCC2c3ccccc3-c3ccccc32)(C(=O)O)C1
Solvent: CC(C)O
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CCCC(N)(C(=O)O)C1

Procedure:
1-(tert-butoxycarbonyl)-3-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}piperidine-3-carboxylic acid was resolved by chiral HPLC resolution {Merck 50 mm 16 μm Kromasil Chirose 2 No. CT9014, tert-butylmethylether/iso-propanol (90/10). The second eluted enantiomer (800 mg, 1.71 mmol) 1-(tert-butoxycarbonyl)-3-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}piperidine-3-carboxylic acid (Isomer 2) was deprotected using an analogous procedure to that described for the equivalent step in Example 89 to give 3-amino-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (Isomer 2); 1H NMR Spectrum: (D2O) 1.44 (s, 9H); 1.63 (m, 1H); 1.79 (d, 1H); 1.97 (d, 1H); 2.10 (m, 1H); 2.88 (t, 1H); 3.33 (d, 1H); 4.09 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C@@H:15]([CH:16]=O)[CH2:14][C:13]([CH3:19])([CH3:18])[C:12]1=[O:20])[CH3:2].COP([CH2:28][C:29](=[O:39])[C:30]1[O:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=1)(=O)OC.[Cl-].[Li+].C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C@@H:15](/[CH:16]=[CH:28]/[C:29](=[O:39])[C:30]2[O:31][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:33][CH:34]=2)[CH2:14][C:13]([CH3:19])([CH3:18])[C:12]1=[O:20])[CH3:2]
Reactant: COP(=O)(CC(=O)c1ccc(C(F)(F)F)o1)OC
Reactant: CCOC(=O)CCCCCCN1C(=O)C(C)(C)C[C@@H]1C=O
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCCCCN1C(=O)C(C)(C)C[C@@H]1/C=C/C(=O)c1ccc(C(F)(F)F)o1
Temperature: 25 °C

Procedure:
To a stirred solution of 7-((R)-5-formyl-3,3-dimethyl-2-oxo-pyrrolidin-1-yl)-heptanoic acid ethyl ester. (360 mg, 1.21 mmol) and [2-oxo-2-(5-trifluoromethyl-furan-2-yl)-ethyl]-phosphonic acid dimethyl ester (344 mg, 1.21 mmol)(prepared from 5-trifluoromethyl-furan-2-carboxylic acid as described herein) in acetonitrile (14 mL), were added lithium chloride (62 mg, 1.21 mmol) and diisopropylethyl amine (0.214 mL, 1.21 mmol). The reaction flask was left stirring at room temperature over the weekend. The reaction was then quenched with a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic phase was then washed with brine and dried over magnesium sulfate, and the crude was purified on silicagel column using hexane:ethyl acetate 2:1. Evaporation of the solvent gave 280 mg of 7-{(R)-3,3-dimethyl-2-oxo-5-[(E)-3-oxo-3-(5-trifluoromethyl-furan-2-yl)-propenyl]-pyrrolidin-1-yl}-heptanoic acid ethyl ester.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]3=[O:23])=[CH:9][CH:8]=2)=[CH:3][CH2:2]1.[C:24]([CH:28]1[CH2:33][CH2:32][CH:31]([C:34](O)=[O:35])[CH2:30][CH2:29]1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([CH:28]1[CH2:29][CH2:30][CH:31]([C:34]([N:1]2[CH2:6][CH2:5][C:4]([C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]4=[O:23])=[CH:9][CH:8]=3)=[CH:3][CH2:2]2)=[O:35])[CH2:32][CH2:33]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CCNCC3)cc2)C(=O)O1
Reactant: CC(C)(C)C1CCC(C(=O)O)CC1
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(C(=O)C4CCC(C(C)(C)C)CC4)CC3)cc2)C(=O)O1

Procedure:
Using an analogous procedure to that described in Example 20, the TFA salt of Example 2 was reacted with 4-tert-butylcyclohexanecarboxylic acid in place of Acetylglycine, to give the title compound. Yield=208 mg, 58%.
Reaction SMILES: [C:1]([Cl:4])(=[O:3])[NH2:2].[C:5]1([S:11]([N:14]2[CH2:19][CH2:18][CH2:17]N[C:15]2=[O:20])(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(Cl)(Cl)=O>>[Cl:4][C:1]([N:2]1[CH2:17][CH2:18][CH2:19][N:14]([S:11]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)(=[O:13])=[O:12])[C:15]1=[O:20])=[O:3]
Reactant: NC(=O)Cl
Reactant: O=C1NCCCN1S(=O)(=O)c1ccccc1
Agent: O=C(Cl)Cl
Product: O=C(Cl)N1CCCN(S(=O)(=O)c2ccccc2)C1=O

Procedure:
This carbamic acid chloride was produced as described in Example 27 A from 6 parts by weight of 1-phenylsulfonyl-1,3-diaza-cyclohexane-2-one and 5 parts by weight of phosgene. The product was recrystallized from acetone/petrolether.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:11][CH3:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[C:19]1([CH:26]=[CH:25][CH:24]=[C:22]([OH:23])[CH:21]=1)[OH:20]>CN(C=O)C>[CH2:11]([N:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][CH2:2][O:20][C:19]1[CH:21]=[C:22]([OH:23])[CH:24]=[CH:25][CH:26]=1)[CH3:12]
Reactant: CCN(CCCl)c1ccccc1
Reactant: Oc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CCOc1cccc(O)c1)c1ccccc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 54.8 %

Procedure:
A mixture of compound 3a (500 mg, 2.7 mmol), K2CO3 (750 mg, 5.4 mmol), KI (90 mg, 0.54 mmol) in DMF (50 mL) was bubbled with argon for 10 min Resorcinol (600 mg, 5.4 mmol) was added to the mixture under argon. The reaction mixture was heated and stirred at 80° C. for 6 hr. After cooling to room temperature, the solvent was evaporated and the residue was quenched with 100 mL water. The mixture was adjusted pH to ˜7 with diluted hydrochloric acid. The mixture was then extracted with EtOAc and the combined organic layer was washed with water and then brine and dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatography with CH2Cl2 to provide the compound 18 (380 mg, 1.48 mmol, 55%) as a light-yellow oil. 1H NMR (DMSO-d6, 400 MHz) δ 9.38 (s, 1H), 7.15 (t, J=8 Hz, 2H), 7.04 (t, J=8 Hz, 1H), 6.70 (d, J=8 Hz, 2H), 6.57 (t, J=7.2 Hz, 1H), 6.32 (m, 3H), 4.02 (t, J=5.8 Hz, 2H), 3.64 (t, J=5.8 Hz, 2H), 3.44 (q, J=7 Hz, 2H), 1.10 (t, J=7 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 155.14, 151.95, 142.80, 125.44, 124.66, 111.56, 107.52, 103.46, 102.10, 97.43, 60.60, 44.77, 40.83, 7.34; HRMS (ESI, positive) m/z calcd. for C16H20NO2 [M+H]+: 258.1494, found: 258.1534.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH:12]([CH3:14])[CH3:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH:15](O)=[O:16]>C1(C)C=CC=CC=1>[CH:15]([NH:1][CH2:2][C:3]([N:5]([CH:12]([CH3:14])[CH3:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4])=[O:16]
Reactant: CC(C)N(C(=O)CN)c1ccccc1
Reactant: O=CO
Solvent: Cc1ccccc1
Product: CC(C)N(C(=O)CNC=O)c1ccccc1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
α-amino-N-isopropylacetanilide (76.8 g.) was mixed with 97% formic acid, boiling chips added and the mixture refluxed for 2 hours. After cooling to 110° C. and adding toluene, the temperature was again raised to reflux and held for 24 hours. The solvent was then removed and the residue recrystallized from benzene to give α-formamido-N-isopropylacetanilide. To a flask equipped with drying tube was added 55 g. of α-formamido-N-isopropylacetanilide. Triethylamine (126.0 g.) and 400 ml. methylene chloride were then added. The resulting clear solution was cooled to -10° and dropwise addition of POCl3 started (57.5 g.). The temperature was lowered to -10° and continuous addition of sodium carbonate solution (1.0 mole, 106 g.) was commenced, keeping the temperature at 0° or lower. After addition, more water was added and the mixture allowed to stir at room temperature for 30 minutes. The organic layer was separated off, and filtered through MgSO4. The organic layer was then washed with salt water, and again filtered through MgSO4. The material was dried over MgSO4, filtered, and vacuum treated to remove methylene chloride. The residue was recrystallized from ether to give α-isocyano-N-isopropylacetanilide melting at 80°-82° C.
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:12]4.[F:18][C:19]1[CH:20]=[C:21](/[CH:25]=[CH:26]/B(O)O)[CH:22]=[CH:23][CH:24]=1>>[F:18][C:19]1[CH:20]=[C:21](/[CH:25]=[CH:26]/[C:2]2[C:10]3[NH:9][C:8]4[CH:11]5[CH2:17][CH2:16][N:14]([CH2:15][C:7]=4[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]5)[CH:22]=[CH:23][CH:24]=1
Reactant: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Reactant: OB(O)/C=C/c1cccc(F)c1
Product: Fc1cccc(/C=C/c2cccc3c4c([nH]c23)C2CCN(CC2)C4)c1

Procedure:
The product of Example 1B (120 mg, 0.41 mmol) and (E)-2-(3-fluorophenyl)vinylboronic acid (82 mg, 0.50 mmol; Aldrich) were processed as described in Example 4 to provide the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.93-2.01 (m, 4H), 2.88-3.02 (m, 2 H), 3.04-3.10 (m, 1 H), 3.11-3.22 (m, 2 H), 4.12 (s, 2 H), 6.98 (t, J=7.6 Hz, 1 H), 7.06-7.14 (m, 1 H), 7.22 (d, J=7.6 Hz, 1 H), 7.30 (d, J=16.2 Hz, 1 H), 7.38-7.42 (m, 1 H), 7.42-7.50 (m, 2 H), 7.52-7.58 (m, 1 H), 7.77 (d, J=16.5 Hz, 1 H); MS (DCI) m/z 333 (M+H)+.
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:10][C:6]=2[CH:5]=[C:4](Br)[N:3]=1.C([Sn](CCCC)(CCCC)[C:23]1[CH:28]=[N:27][CH:26]=[CH:25][N:24]=1)CCC.O>CN(C=O)C.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>[N:24]1[CH:25]=[CH:26][N:27]=[CH:28][C:23]=1[C:2]1[C:7]2[S:8][C:9]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:10][C:6]=2[CH:5]=[C:4]([C:28]2[CH:23]=[N:24][CH:25]=[CH:26][N:27]=2)[N:3]=1
Reactant: CCNC(=O)Nc1nc2cc(Br)nc(Br)c2s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3cnccn3)nc(-c3cnccn3)c2s1
Temperature: 95 °C
Yield: 6.6 %

Procedure:
To a solution of 1-(4,6-dibromo-thiazolo[5,4-c]pyridin-2-yl)-3-ethyl-urea (0.06 g, 0.16 mmol) in DMF (3 mL) was added 2-(tributylstannyl)pyrazine (0.10 mL, 0.32 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was degassed by bubbling nitrogen for 10-15 min followed by addition of Pd(PPh3)4 (0.018 g, 0.015 mmol). The resulting solution was again degassed for 15-20 min followed by heating up to 95° C. overnight. After completion of reaction (TLC monitoring), the reaction mixture was cooled, added water (30 mL) and extracted with ethyl acetate (3×20 mL). The combined organics was dried over Na2SO4 and evaporated to dryness under high vacuum. The crude residue was purified over silica-gel (100-200 M, 2% MeOH-DCM) to get the desired product (0.004 g, 7%).
Reaction SMILES: [C:1]([N:5]1[CH2:26][CH2:25][CH2:24][CH2:23][C:8]2[CH:9]=[C:10]3[C:19]4[CH:18]=[C:17]([F:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:27])([CH3:4])([CH3:3])[CH3:2].[Br:28]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:28][C:9]1[C:8]2[CH2:23][CH2:24][CH2:25][CH2:26][N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6](=[O:27])[C:7]=2[N:11]2[CH2:12][CH2:13][C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([F:20])=[CH:18][C:19]=3[C:10]=12
Reactant: COc1cc2c(cc1F)-c1cc3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1F)-c1c(Br)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To a solution of 250 mg 27a in 7 mL dimethylformamide was added 120 mg N-bromosuccinimide. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with 2×ethyl acetate. The combined organic phases were washed with water and brine, dried and concentrated. The crude product was triturated with heptane/diisopropyl ethyl ether (1:1) to afford 230 mg of 27b as a white solid.
Reaction SMILES: [CH2:1]([N:4]1[C:11]([NH2:12])=[C:10]([NH2:13])[C:8](=[O:9])[N:7]([CH2:14][CH:15]=[CH2:16])[C:5]1=[O:6])[CH:2]=[CH2:3].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH:22]=[CH:23][C:24](O)=O>>[CH2:14]([N:7]1[C:8](=[O:9])[C:10]2[NH:13][C:24](/[CH:23]=[CH:22]/[C:21]3[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:19]([O:18][CH3:17])[CH:20]=3)=[N:12][C:11]=2[N:4]([CH2:1][CH:2]=[CH2:3])[C:5]1=[O:6])[CH:15]=[CH2:16]
Reactant: C=CCn1c(N)c(N)c(=O)n(CC=C)c1=O
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Product: C=CCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c(OC)c3)nc2n(CC=C)c1=O
Yield: 54.2 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 2.9 g (13.1 mmol) of 1,3-diallyl-5,6-diaminouracil and 2.99 g (14.4 mmol) of 3,4-dimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 2.80 g (yield 54%) of Compound 190 as pale yellow flocculent precipitates.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.[Br:12]NC(=O)CCC(N)=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][Br:12])=[N:7][C:6]=2[CH:11]=1
Reactant: Cc1nc2cc(Br)ccc2s1
Reactant: NC(=O)CCC(=O)NBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1nc2cc(Br)ccc2s1
Temperature: 75 °C
Yield: 63.1 %

Procedure:
To a solution of 5-Bromo-2-methyl-benzothiazole (1.0 g, 4.385 mmol) in CCl4 (15 mL) is added N-bromosuccinamide (1.1 g, 6.140 mmol) and azobisisobutyronitrile (0.029 g, 0.175 mmol) at room temperature reaction. The reaction mixture is heated to 75° C. for 16 hours. Reaction mixture is cooled to room temperature, filtered and the solvent evaporated in vacuo to give the crude material, which is then purified by flash chromatography using 3.5% ethyl acetate in hexane as an eluent to afford the title compound (0.85 g). 1H NMR (400 MHz, DMSO-d6) δ: 5.12 (s, 2H), 7.68-7.71 (dd, J1=1.92 Hz, J2=8.76 Hz, 1H), 7.95 (d, J=8.6 Hz, 1H), 8.43 (d, J=1.92 Hz, 1H). LC-MS (m/z): [M+H]=308.2.