Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[C:2]([C@@H:4]1[CH2:9][CH2:8][C:7]([CH:10]=[O:11])=[CH:6][CH2:5]1)[CH3:3].[N+:12]([CH:14](S(C1C=CC(C)=CC=1)(=O)=O)[CH3:15])#[C-:13].C([O-])([O-])=O.[K+].[K+]>CO>[CH3:15][C:14]1[N:12]=[CH:13][O:11][C:10]=1[C:7]1[CH2:8][CH2:9][C@@H:4]([C:2]([CH3:3])=[CH2:1])[CH2:5][CH:6]=1
Reactant: C=C(C)[C@H]1CC=C(C=O)CC1
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C=C(C)[C@H]1CC=C(c2ocnc2C)CC1
Temperature: 25 °C
Yield: 69.5 %

Procedure:
A mixture of (R)-4-(prop-1-en-2-yl)cyclohex-1-enecarbaldehyde (0.574 g, 3.82 mmol), 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (0.80 g, 3.82 mmol), and K2CO3 (1.06 g, 7.65 mmol) in MeOH (25 mL) was heated at reflux for 2 h. The reaction mixture was cooled to ambient temperature, concentrated in vacuo, and diluted with EtOAc. The organic solution was washed with water, separated, and concentrated in vacuo. The residue was chromatographed on silica gel with EtOAc/hexanes (0%-35%) to isolate 0.54 g (70%) of the title compound as an oil. 1H NMR (300 MHz, DMSO-d6) δ 8.12 (s, 1H), 6.15-6.06 (m, 1H), 4.74 (s, 2H), 2.47-2.25 (m, 3H), 2.24-2.00 (m, 5H), 1.94-1.82 (m, 1H), 1.74 (s, 3H), 1.59-1.40 (m, 1H). MS (DCI+) m/z 204 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([Br:17])=[CH:16][C:11]=2[N:10]=[C:9]1[CH:18]([NH:22][CH2:23][CH2:24][CH2:25][N:26]1[C:34](=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]1=[O:36])[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:44]1([CH3:53])[CH:49]=[CH:48][C:47]([C:50](Cl)=[O:51])=[CH:46][CH:45]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([Br:17])=[CH:16][C:11]=2[N:10]=[C:9]1[CH:18]([N:22]([CH2:23][CH2:24][CH2:25][N:26]1[C:27](=[O:36])[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]1=[O:35])[C:50](=[O:51])[C:47]1[CH:48]=[CH:49][C:44]([CH3:53])=[CH:45][CH:46]=1)[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(NCCCN1C(=O)c2ccccc2C1=O)c1nc2cc(Br)ccc2n1Cc1ccccc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)N(CCCN2C(=O)c3ccccc3C2=O)C(c2nc3cc(Br)ccc3n2Cc2ccccc2)C(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
To a solution of 2-{3-[1-(1-Benzyl-5-bromo-1H-benzimidazol-2-yl)-2-methyl-propylamino]-propyl}-isoindole-1,3-dione (310 mg, 0.56 mmol) and triethylamine (0.47 ml, 3.36 mmol, 6 eq) in DCM (3 ml) at 0° C., was added p-toluoyl chloride (0.38 ml, 2.8 mmol, 5 eq). The reaction mixture was stirred at 0° C. for 30 minutes. Ethyl acetate and saturated sodium bicarbonate were added. The mixture was extracted with ethyl acetate. The organic layers was combined, dried over MgSO4, filtered, and the filtrate was concentrated in vacuo. The crude material was purified by flash chromatography to give N-[1-(1-Benzyl-5-bromo-1H-benzimidazol-2-yl)-2-methyl-propyl]-N-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-4-methyl-benzamide (242 mg, yield 65%)
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][CH2:6][C:7](=[O:19])[CH:8]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])C#N)C.S(=O)(=O)(O)O.C(OC(C)C)(C)C>O.C(O)(=O)C>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[CH2:8][C:7](=[O:19])[CH2:6][CH2:5][C:4]([OH:20])=[O:3]
Reactant: CCOC(=O)CCC(=O)C(C#N)c1ccc(Cl)cc1Cl
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CC(C)OC(C)C
Solvent: O
Product: O=C(O)CCC(=O)Cc1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 79.8 %

Procedure:
A 1-liter 1-neck R.B. flask was charged with 156.61 g (0.50 Mol) of ethyl-5-(2',4'-dichlorophenyl)-5-cyano-4-ketopentanoate, 153 ml of concentrated sulfuric acid, 153 ml of water, and 440 ml of glacial acetic acid. The reaction mixture was stirred and refluxed for 24 hours. The reaction mixture was cooled to room temperature and 300 ml of water added followed by 200 ml of isopropyl ether. The mixture was refluxed for 1/2 hour, cooled in an ice bath, and filtered. The desired acid (104.13 g, 80% yield) was obtained as a viscous dark-colored oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[C:12]([OH:14])[C:11](=[O:15])[CH:10]=[C:9]2[CH2:16][OH:17])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32]Cl)=[CH:28][CH:27]=1.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[C:12]([O:14][CH2:32][C:29]3[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)[C:11](=[O:15])[CH:10]=[C:9]2[CH2:16][OH:17])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=c1cc(CO)n(-c2cccc(Br)c2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2cn(-c3cccc(Br)c3)c(CO)cc2=O)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a mixture of 1-(3-bromo-phenyl)-5-hydroxy-2-hydroxymethyl-1H-pyridin-4-one and K2CO3 (5.17 g, 37.5 mmol) in 50 mL of DMF was added 2.35 g of PMBCl (15 mmol) dropwise, and the reaction mixture was stirred at 80° C. for 3 h. After cooling to room temperature, the mixture was poured into 200 mL of water and extracted with EtOAc (50 mL) three times. The combined organic layers were washed with water, brine, and dried over anhydrous MgSO4. Most of the volatiies were removed in vacuo and the resulting solid was collected and washed with EtOAc to obtain 1-(3-bromophenyl)-2-hydroxymethyl-5-(4-methoxy-benzyloxy)-1H-pyridin-4-one.
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1[N:8]=[C:9]([SH:12])[S:10][CH:11]=1)=[O:5])C.[OH-].[Na+].Cl>O>[C:4]([CH2:6][C:7]1[N:8]=[C:9]([SH:12])[S:10][CH:11]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)Cc1csc(S)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cc1csc(S)n1
Temperature: 25 °C
Yield: 87.4 %

Procedure:
In 366 ml of water was suspended 185 g (0.91 mol) of 4-ethoxycarbonylmethyl-2-mercaptothiazole and 366 ml (1.84 mols) of an aqueous solution of 5 mol/l sodium hydroxide was added dropwise to the suspension. After heating the mixture for 2 hours in a steam bath with-stirring, the reaction mixture was cooled to room temperature, and 165 ml (1.90 mols) of concentrated hydrochloric acid was added dropwise to the mixture. The crystals formed were collected by filtration under a reduced pressure to provide 139.4 g (yield 87.4%) of 4-carboxymethyl-2-mercaptothiazole.
Reaction SMILES: Cl.[F:2][C:3]([F:28])([F:27])[C:4]1[CH:5]=[C:6]([S:14]([NH:17][C:18]2[S:19][C:20]3[CH2:21][NH2+:22][CH2:23][CH2:24][C:25]=3[N:26]=2)(=[O:16])=[O:15])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.F[C:30]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:31]=1[C:32]([NH2:34])=[O:33].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CO>[F:28][C:3]([F:2])([F:27])[C:4]1[CH:5]=[C:6]([S:14]([NH:17][C:18]2[S:19][C:20]3[CH2:21][N:22]([C:30]4[CH:38]=[C:37]([C:39]([F:40])([F:42])[F:41])[CH:36]=[CH:35][C:31]=4[C:32]([NH2:34])=[O:33])[CH2:23][CH2:24][C:25]=3[N:26]=2)(=[O:15])=[O:16])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: O=S(=O)(Nc1nc2c(s1)C[NH2+]CC2)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NC(=O)c1ccc(C(F)(F)F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CS(C)=O
Product: NC(=O)c1ccc(C(F)(F)F)cc1N1CCc2nc(NS(=O)(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)sc2C1

Procedure:
3.3 g of 2-(3,5-bis-trifluoromethyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-5-ium hydrochloride, 1.545 g of 2-fluoro-4-trifluoromethyl-benzamide and 3.3 g of K2CO3 are heated in DMSO at 150° for 5 hours. From the mixture obtained solvent is evaporated, the evaporation residue obtained is dissolved in EtAc/MeOH (9/1) and the mixture obtained is extracted with 50 ml of 1 M HCl and brine. Two phases are obtained and are separated and the organic layer obtained is concentrated and subjected to chromatography. 2-[2-(3,5-Bis-trifluoromethyl-benzenesulfonylamino)-6,7-dihydro-4H-thiazolo-[5,4-c]pyridin-5-yl]-4-trifluoromethyl-benzamide is obtained and is re-crystallized from EtAc.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([NH:15][C:16]([N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[C:30]1[O:34][N:33]=[C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[CH:31]=1)=[N:17]C(OC(C)(C)C)=O)=O)(C)(C)C>C(Cl)Cl>[N:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[C:32]1[CH:31]=[C:30]([CH:26]2[CH2:27][CH2:28][CH2:29][N:25]2[C:16](=[NH:15])[NH2:17])[O:34][N:33]=1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCCC1c1cc(-c2ccccn2)no1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N=C(N)N1CCCC1c1cc(-c2ccccn2)no1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
TFA (30 ml) was added to a cooled solution of N,N′-di(tert-butyloxycarbonyl)-2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidine-1-carboximidamide (Method 39) in DCM (150 ml) at 0° C. The mixture was stirred 0° C. for one hour, allowed to warm to ambient temperature and stirred for a further 18 hours. The volatiles were removed by evaporation and the residue triturated from DCM/ether/hexane. The product was collected by filtration to give the title compound (2.2 g, >100%).
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:3]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:65][C:66]1[N:71]=[CH:70][C:69]([C:72](O)=[O:73])=[CH:68][CH:67]=1>CN(C=O)C>[CH3:1][C@H:2]1[CH2:3][N:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=2)(=[O:9])=[O:10])[CH2:5][CH2:6][N:7]1[C:72]([C:69]1[CH:70]=[N:71][C:66]([CH3:65])=[CH:67][CH:68]=1)=[O:73]
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Reactant: Cc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]2C)cn1
Yield: 62.1 %

Procedure:
To a solution of (3S)-3-methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (Description 2) (100 mg, 0.324 mmol) in DMF (5 ml) was added DIPEA (0.170 ml, 0.973 mmol), HOBT.H2O (49.7 mg, 0.324 mmol), HBTU (123 mg, 0.324 mmol) and 6-methyl-3-pyridinecarboxylic acid (44.5 mg, 0.324 mmol) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was evaporated in vacuo, DCM (50 ml) was added and the solution was washed with NfaHCO3 (5 ml×2). The organic layer was dried with dried magnesium sulphate which was removed by filtration and the filtrate evaporated to dryness in vacuo. The residual oil was dissolved in 1:1 MeCN/DMSO (1.8 ml) and purified by MDAP in two batches. The fractions containing the desired product were combined and evaporated to dryness in vacuo. The residue was azeotroped with toluene to remove any remaining water to yield the title compound (86 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.C(N(CC)CC)C>C(O)CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:23]3[CH2:22][CH2:21][N:20]([C:17]4[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=4)[CH2:25][CH2:24]3)[N:10]=2)[CH:7]=1
Reactant: ClCc1cn2cc(Br)ccc2n1
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: OCCO
Solvent: CCN(CC)CC
Product: Fc1ccc(N2CCN(Cc3cn4cc(Br)ccc4n3)CC2)cc1
Yield: 62.1 %

Procedure:
Following the general procedure of Example 11 and making noncritical variations, 6-bromo-2-(chloromethyl)imidazo[1,2-a]pyridine (0.253 g), 1-(4-fluorophenyl)piperazine (Aldrich; 0.186 g), triethylamine (Aldrich; 0.104 g), and ethylene glycol (2 mL) give 0.249 g of the title compound after chromatography (silica gel, methanol/dichloromethane, 4/96) and crystallization from dichloromethane/hexane; mp 110-112° C.; MS m/z 388, 390; IR (mineral oil) 1511, 1234, 1219, 1448, 1326 cm-1. 1H NMR (CDCl3) δ2.74, 3.16, 3.77, 6.87-6.98, 7.21, 7.48, 7.53, 8.24.
Reaction SMILES: [OH:1][C:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:3]1[CH2:8][CH2:7][N:6]([CH:9](O)[CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:26])([CH3:25])[C:20]([O:22]CC)=[O:21])=[CH:15][CH:14]=2)[CH2:5][CH2:4]1.[OH-:40].[Na+]>C(O)C>[OH:1][C:2]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:3]1[CH2:4][CH2:5][N:6]([CH2:9][CH2:10][CH2:11][CH:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:25])([CH3:26])[C:20]([OH:22])=[O:21])=[CH:15][CH:14]=2)[OH:40])[CH2:7][CH2:8]1
Reactant: [OH-]
Reactant: CCOC(=O)C(C)(C)c1ccc(CCCC(O)N2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C(=O)O)c1ccc(C(O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
According to the described procedure of Carr et al., U.S. Pat. No. 4,254,129, to a solution of 0.6 g of ethyl 4-[4[4-(hydroxydiphenylmethyl)-1-piperidinyl]-hydroxybutyl]-α,α-dimethylbenzeneacetate in 20 ml of absolute ethanol is added 10 ml of a 50% solution of sodium hydroxide. The mixture is refluxed for 3½ hours and concentrated to a solid after which a minimum amount of methanol to dissolve the residue is added. 10% Aqueous HCl is added until pH 7 is reached, the methanol removed by evaporation and water (25 ml) is added. The resulting precipitate is recrystallized from methanolbutanone to give 4-[4[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid, M.P. 195°-197° C.
Reaction SMILES: [I-].[Na+].C[Si](C)(C)Cl.[C:8]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:9][C:10]([CH3:12])=[O:11].[CH:17]1[C:22]([CH:23]=O)=[CH:21][C:20]2[O:25][CH2:26][O:27][C:19]=2[CH:18]=1>C(#N)C.CCOCC.O>[CH2:15]([O:14][C:8](=[O:13])[CH:9]([CH2:23][C:22]1[CH:17]=[CH:18][C:19]2[O:27][CH2:26][O:25][C:20]=2[CH:21]=1)[C:10](=[O:11])[CH3:12])[CH3:16]
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CCOC(=O)CC(C)=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc2c(c1)OCO2)C(C)=O
Temperature: 2.5 °C
Reaction time: 5 h
Yield: 32.9 %

Procedure:
To a solution of 117.2 g sodium iodide in 700 ml of acetonitrile, first 85.9 g trimethylchlorosilane and then 20.56 g ethyl acetoacetate were dropped in at room temperature. After cooling down to 0-5° C., a solution of 23.65 g Piperonal in 50 ml of acetonitrile was dropped in. Then the mixture was stirred at room temperature for 5 hours and then at 60° C. overnight. After the mixture was cooled down to room temperature it was diluted with ether and water. The organic phase was separated and washed with saturated sodium thiosulfate until the color of the iodine was gone. Then the organic phase was washed with water, dried, filtered and evaporated to dryness. The resulting dark oil was purified by chromatography to yield 13.7 g of a yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH2:18]([O:10][C:6]1[CH:5]=[C:4]([CH2:3][CH2:2][OH:1])[CH:9]=[CH:8][CH:7]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: OCCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCCc1cccc(OCc2ccccc2)c1
Reaction time: 17 h

Procedure:
To a solution of 3-(2-hydroxyethyl)phenol (1.0 g) and K2CO3 (1.5 g) in acetone (20 mL) was added (bromomethyl)benzene (1.49 g) at ambient temperature. The reaction mixture was stirred at the same temperature for 17 hours. The resulting mixture was evaporated in vacuo. The residue was diluted with EtOAc and washed successively with water and brine. The organic layer was dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=90:10-70:30) to give 2-[3-(benzyloxy)phenyl]ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[C:9]([S:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[C:8]2[CH2:22][C:23]([CH3:29])([CH3:28])[C:24]([O:26][CH3:27])=[O:25])=[CH:4][CH:3]=1.Cl.Cl[CH2:34][C:35]1[N:36]=[C:37]([CH3:40])[S:38][CH:39]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:34][C:35]4[N:36]=[C:37]([CH3:40])[S:38][CH:39]=4)=[CH:13][CH:14]=3)[C:9]([S:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[C:8]2[CH2:22][C:23]([CH3:29])([CH3:28])[C:24]([O:26][CH3:27])=[O:25])=[CH:30][CH:31]=1
Reactant: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Reactant: Cc1nc(CCl)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3csc(C)n3)ccc2n1Cc1ccc(Cl)cc1

Procedure:
A solution of methyl 3-[1-(4-chlorobenzyl)-3-(t-butylthio)-5-hydroxyindol-2-yl]-2,2-dimethylpropanoate (Preparation 2) (25 g), 4-chloromethyl-2-methylthiazole hydrochloride (Maybridge Chemical Co., Ltd.) (11.6 g) and Cs2CO3 (68.7 g) in 250 mL of CH3CN were heated at reflux for 24 hours. The mixture was cooled, poured onto water, and extracted (2× EtOAc), washed twice with brine, dried (MgSo4), and evaporated. Chromatography of the residue on silica gel eluting with hexane/EtOAc 4:1 afforded the title compound as a solid.
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[CH:5][S:4][C:3]=1[N+:8]([O-:10])=[O:9].C([Sn](CCCC)(CCCC)[C:16]1[S:17][CH:18]=[CH:19][N:20]=1)CCC.O1CCOCC1>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.CCOC(C)=O>[Br:7][C:6]1[C:2]([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)=[C:3]([N+:8]([O-:10])=[O:9])[S:4][CH:5]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: O=[N+]([O-])c1scc(Br)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1scc(Br)c1-c1nccs1
Temperature: 130 °C
Yield: 85.9 %

Procedure:
A mixture of 3,4-dibromo-2-nitrothiophene (242 mg, 0.85 mmol), 2-(tributylstannyl)thiazole (315 mg, 0.84 mmol), Pd(Ph3P)4 catalyst (194 mg, 0.17 mmol) and dioxane (0.9 mL) was heated in the microwave to 130° C. for 25 min. The reaction mixture was diluted with EtOAc and filtered to remove solids. The remaining organic solution was washed with saturated, aqueous solutions of sodium bicarbonate and salt before drying over sodium sulfate. The organic was concentrated under reduced pressure to give a dark oil. The crude product was purified by column chromatography (30% EtOAc/hexanes) to give 2-(4-bromo-2-nitrothiophen-3-yl)thiazole (210 mg). LCMS m/z of 289.1/291.1 with a retention time of 2.043 min on the [1] method.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:12]=[C:11]([CH3:13])[O:10][N:9]=1)=[O:6].C(N(CC)CC)C.[CH3:21][C:22]1[N:23]=[C:24]([NH:38][C:39](N2C=CN=C2)=[O:40])[S:25][C:26]=1[C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH:37]=[CH:36][CH:35]=[N:34]2)=[CH:29][CH:28]=1.O>CN(C=O)C>[CH3:13][C:11]1[O:10][N:9]=[C:8]([NH:7][C:5](=[O:6])[CH2:4][CH2:3][NH:2][C:39]([NH:38][C:24]2[S:25][C:26]([C:27]3[CH:28]=[CH:29][C:30]([N:33]4[CH:37]=[CH:36][CH:35]=[N:34]4)=[CH:31][CH:32]=3)=[C:22]([CH3:21])[N:23]=2)=[O:40])[CH:12]=1
Reactant: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccc(-n2cccn2)cc1
Reactant: Cc1cc(NC(=O)CCN)no1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(NC(=O)CCNC(=O)Nc2nc(C)c(-c3ccc(-n4cccn4)cc3)s2)no1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3-amino-N-(5-methyl-isoxazol-3-yl)-propionamide hydrochloride (Intermediate B1 produced by HCl deprotection) (0.1 g, 0.49 mmol) and triethylamine (0.164 ml, 1.18 mmol) is stirred in DMF (4 ml). Imidazole-1-carboxylic acid [4-methyl-5-(4-pyrazol-1-yl-phenyl)-thiazol-2-yl]-amide (Intermediate A2) (0.16 g, 0.47 mmol) is added and the mixture stirred at room temperature for 18 h. Water (20 ml) is added and the mixture stirred for 30 min. The solid is filtered off, washed with water and dried in vacuo at 45° C. for 4 h to afford the title compound.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[CH:7][C:6]([C:13]([NH2:15])=[O:14])=[C:5]2[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1.CCN(C(C)C)C(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[SH:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][OH:88]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[OH:88][CH2:87][CH2:86][CH2:85][CH2:84][CH2:83][CH2:82][CH2:81][CH2:80][CH2:79][CH2:78][CH2:77][S:76][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[CH:7][C:6]([C:13]([NH2:15])=[O:14])=[C:5]2[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1
Reactant: OCCCCCCCCCCCS
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(I)cc23)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(SCCCCCCCCCCCO)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described in Org. Lett. 2004, 6(24), 4587-4590. To a round bottom flask were added 6-iodo-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide (1.0 g, 2.31 mmol), dry dioxane (23 mL) and i-Pr2NEt (0.81 mL, 4.62 mmol). Catalytic Pd2(dba)3 (63 mg, 0.07 mmol), Xantphos (80 mg, 0.14 mmol) and 11-mercapto-1-undecanol (494 mg, 2.42 mmol) were then added. The mixture was evacuated and backfilled with nitrogen (3 cycles). The mixture was heated to reflux for 2 h (HPLC confirmed the completion of the reaction). The reaction mixture was then allowed to reach ambient temperature followed by filtration and concentration. The crude product was used without further purification for the next step. ES/MS calcd. for C29H40N3O3S+ 510.3. Found m/z=510.4 (M+H)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][N:8]=1.[C:14]([O:18][C:19]([N:21]1[CH:26]2[CH2:27][CH2:28][CH:22]1[CH2:23][C:24](=[O:29])[CH2:25]2)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(O)(=O)C>C(OCC)C>[C:14]([O:18][C:19]([N:21]1[CH:26]2[CH2:27][CH2:28][CH:22]1[CH2:23][C:24]([C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][N:8]=1)([OH:29])[CH2:25]2)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Reactant: Fc1cccnc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1C2CCC1CC(O)(c1ncccc1F)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.2 %

Procedure:
n-Butyl lithium (2.5M, 1 mL, 2.5 mmol) was added dropwise to a solution of 2-bromo-3-fluoro-pyridine (0.4 g, 2.27 mmol) in diethyl ether (8 mL), under nitrogen at −78° C. and stirred for 1 hour. 3-Oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.51 g, 2.27 mmol) in diethyl ether (5 mL) was added dropwise at −78° C. and the reaction mixture stirred for 0.5 hours before warming to room temperature. The reaction mixture was poured onto ice, acidified with acetic acid and extracted into ethyl acetate. The remaining aqueous solution was basified with 1 M sodium hydroxide, extracted with DCM and the combined organics were dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. Methanol (10 mL) and sodium borohydride (0.14 g) were added to the residues and stirred for 2 hours to reduce any unreacted ketone. The solvent was removed by evaporation under vacuum, DCM added to the residues and the organics washed with water and brine, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 5-10% ethyl acetate/cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.25 g). LCMS m/z 323 [M+H]+. R.T.=4.67 min (Analytical Method 3).