Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[S:34])=[CH:28][C:27]=1[C:35]([F:38])([F:37])[F:36]>>[C:19]1([C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([S:8][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:33]([NH:32][C:29]4[CH:30]=[CH:31][C:26]([Cl:25])=[C:27]([C:35]([F:38])([F:36])[F:37])[CH:28]=4)=[S:34])=[CH:7][CH:6]=3)[CH:18]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ccc(Sc2cc(-c3ccccc3)c3ccccc3n2)cc1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Product: FC(F)(F)c1cc(NC(=S)Nc2ccc(Sc3cc(-c4ccccc4)c4ccccc4n3)cc2)ccc1Cl
Yield: 55.1 %

Procedure:
2-(4-aminophenylthio)-4-phenylquinoline (3.0 moles, 1.0 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate (3.3 mmoles, 0.79 g) were reacted according to procedure C to yield the title compound 1.03 g, 61%. Mass Spec (FD) 565. Calculated for C29H19ClF3N3S2 : C, 61.53; H, 3.38; N, 7.42. Found: C, 61.82; H, 3.63; N, 7.43.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH:12]=1.[CH3:17][C:18]1([CH3:35])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([CH2:27][CH2:28]OS(C)(=O)=O)[C:19]1=[O:34].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:35][C:18]1([CH3:17])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([CH2:27][CH2:28][N:14]2[CH2:15][CH2:16][C:11]([C:7]3[C:6]4[C:10](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=4)[NH:9][CH:8]=3)=[CH:12][CH2:13]2)[C:19]1=[O:34]
Reactant: CC1(C)C(=O)N(CCOS(C)(=O)=O)c2ccccc21
Reactant: Fc1cccc2c(C3=CCNCC3)c[nH]c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC1(C)C(=O)N(CCN2CC=C(c3c[nH]c4c(F)cccc34)CC2)c2ccccc21
Reaction time: 3 h

Procedure:
4-(7-Fluoroindol-3-yl)-1,2,5,6-tetrahydropyridine (2.0 g, 9.26 mmols), 3,3-dimethyl-1-(2-methanesulfonyloxy-1-ethyl)-1,3-dihydro-2H-indol-2-one (2.623 g, 9.26 mmols), sodium carbonate (2.947 g,27.8 mmols),water (20 mls) combined and heated to 90 deg C. for 3 hours. Extracted into ethyl acetate (2×50 ml). Dried (MgSO4),filtered and concentrated in vacuo. The resultant solid was recrystallised from ethyl acetate and then converted to the hydrochloride salt (0.85 g).m.p 235-236 deg. C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]([S:18][C:19]([F:22])([F:21])[F:20])[C:15]([CH:23]([OH:25])[CH3:24])=[N:14]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC>ClCCl>[C:23]([C:15]1[C:16]([S:18][C:19]([F:20])([F:21])[F:22])=[CH:17][N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][C:4]=2[Cl:12])[N:14]=1)(=[O:25])[CH3:24]
Reactant: CC(O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1SC(F)(F)F
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1SC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
To a solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-(1-hydroxyethyl)-4-trifluoromethylthiopyrazole (1.1 g) in dichloromethane (40 ml) was added pyridinium chlorochromate (0.62 g), and the mixture stirred at room temperature overnight. Ether (50 ml) was added and the mixture filtered on diatomaceous earth. Evaporation of the filtrate in vacuo gave a brown solid, which was triturated with hexane and filtered. The filtrate was evaporated in vacuo to give a yellow solid, which recrystallised from cyclohexane to give 3-acetyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazole (0.4 g) in the form of a yellow solid, m.p. 89-91° C.
Reaction SMILES: [CH:1]1([N:4]([CH3:16])[CH:5]2[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]2)[CH2:3][CH2:2]1.O1CCOCC1>C(Cl)Cl.Cl>[CH:1]1([N:4]([CH3:16])[CH:5]2[CH2:8][NH:7][CH2:6]2)[CH2:3][CH2:2]1
Reactant: CN(C1CC1)C1CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN(C1CC1)C1CNC1
Temperature: 20 °C
Reaction time: 21 h

Procedure:
Combine a solution of tert-butyl 3-(cyclopropyl(methyl)amino)azetidine-1-carboxylate (73 mg, 0.323 mmol) in methylene chloride (3 mL) and 4 M HCl in dioxane (0.323 mL, 1.290 mmol) and the solution stirred at 20° C. for 4 hours then added 4 M HCl in dioxane (0.323 mL, 1.290 mmol) and stirred at 20° C. for 21 h. The solution was then concentrated in vacuo to give the title compound as a hydrochloride salt which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10]=[CH2:11])[CH:7]=[C:6]([F:12])[C:3]=1[C:4]#[N:5].C1C=C(Cl)C=C(C(OO)=[O:21])C=1.FC1C(C2CO2)=CC(OC)=C(C=1)C#N>>[F:1][C:2]1[CH:9]=[C:8]([CH:10]2[CH2:11][O:21]2)[CH:7]=[C:6]([F:12])[C:3]=1[C:4]#[N:5]
Reactant: C=Cc1cc(F)c(C#N)c(F)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: COc1cc(C2CO2)c(F)cc1C#N
Product: N#Cc1c(F)cc(C2CO2)cc1F

Procedure:
2,6-Difluoro-4-(oxiran-2-yl)benzonitrile was prepared from 2,6-Difluoro-4-vinylbenzonitrile using m-CPBA in an analagous fashion to that described for 5-fluoro-2-methoxy-4-(oxiran-2-yl)benzonitrile (Step H) above: 1H NMR (500 MHz, CDCl3) δ 7.02 (d, J=8.0 Hz, 2H), 3.92 (dd, J=3.6, 2.4 Hz, 1H), 3.24 (dd, J=5.4, 4.0 Hz, 1H), 2.74 (dd, J=5.4, 2.4 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5](O)=[O:6])[C:3]=1[NH2:11].[NH2:12][C:13](N)=[O:14].C1(O)C=CC=CC=1>C(O)C>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]2[C:3]=1[NH:11][C:13](=[O:14])[NH:12][C:5]2=[O:6]
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: NC(N)=O
Solvent: CCO
Solvent: Oc1ccccc1
Product: Cc1cccc2c(=O)[nH]c(=O)[nH]c12
Temperature: 100 °C
Yield: 75 %

Procedure:
3-Methylanthranilic acid (15 g., 0.1 mole), urea (36 g., 0.6 mole) and phenol (86 g.) were mixed together and heated to reflux for three hours. The reaction was then allowed to cool to 100° C. and ethanol (75 ml.) added dropwise. The resulting solid was filtered and washed twice with cold ethanol to afford 13.2 g. (75% yield); m.p. 170° C.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].Br[CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C.O>[C:16]([Si:13]([CH3:15])([CH3:14])[O:12][CH2:11][CH2:10][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: Oc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(O)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a stirred solution of hydroquinone (Aldrich, 11.01 g, 100 mmol) in DMF (300 mL), (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (Aldrich, 12.0 g, 50 mmol), cesium carbonate (40.7 g, 125 mol) were added and the mixture was stirred at 60° C. overnight. The mixture was poured into water (300 mL) and 6N HCl was added to adjust the “pH” to 6. The mixture was extracted with EtOAc (3×60 mL) and the extracts were combined and dried. Removal of solvent gave the crude, which was chromatographied on a ISCO machine eluting with EtOAc/hexane (0-30%) to give a light brown solid. 5.71 g.
Reaction SMILES: CS([Cl:5])(=O)=O.[CH2:6]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14]O)=[CH:12][CH:11]=1)[CH2:7][CH2:8][CH3:9].C(N(CC)CC)C>ClCCl>[CH2:6]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14][Cl:5])=[CH:12][CH:11]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCc1ccc(CO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
Methanesulfonyl chloride (3.069 g, 26.791 mmol) was added to a solution of 4-butylbenzyl alcohol (4.000 g, 24.355 mmol) in dichloromethane (120 mL) at 0° under argon atmosphere. Triethylamine (2.711 g, 26.791 mmol) was added dropwise at a slow speed to this mixture, and stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane) to give the title compound (3.64 g, 82%) as a colorless oil.
Reaction SMILES: Br[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[F:29][C:30]([F:39])([F:38])[C:31]1[N:36]=[N:35][C:34]([NH2:37])=[CH:33][CH:32]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[C:23]1([C:2]2[N:35]3[N:36]=[C:31]([C:30]([F:38])([F:29])[F:39])[CH:32]=[CH:33][C:34]3=[N:37][C:3]=2[C:5]2[CH:10]=[CH:9][C:8]([C:11]3([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]3)=[CH:7][CH:6]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccc(C(F)(F)F)nn1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(C(F)(F)F)nn4c3-c3ccccc3)cc2)CCC1
Yield: 34 %

Procedure:
A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-1-A (1.85 g, ˜80% purity, 3.45 mmol, 1.0 eq), 6-(trifluoromethyl)pyridazin-3-amine (CAS-Nr. 935777-24-5, 0.674 g, 4.14 mmol, 1.2 eq), N,N-diisopropylethylamine (0.60 mL, 6.89 mmol, 1.0 eq) and activated 3 Å molecular sieves in isopropanol (10.5 mL) was heated for 7 hours under reflux. On cooling, the mixture was partitioned between DCM and water, stirred vigorously and filtered through a silicone coated filter paper. The filtrate was concentrated in vacuo. The crude mixture was purified via MPLC (Biotage Isolera; 100 g SNAP cartridge: hexane→hexane/ethyl acetate 2/1) to give 680 mg (34% yield) of the title compound.
Reaction SMILES: ClCCC1NC2C=CC=CC=2N=1.C(N)CN.[N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:19][C:18]=1[CH2:26][CH2:27][NH:28][CH2:29][CH2:30][NH2:31].[C:32]([NH:34][C:35](=[N:38][CH3:39])SC)#[N:33]>>[N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:19][C:18]=1[CH2:26][CH2:27][NH:28][CH2:29][CH2:30][NH:31][C:35]([NH:34][C:32]#[N:33])=[N:38][CH3:39]
Reactant: NCCNCCc1nc2ccccc2[nH]1
Reactant: CN=C(NC#N)SC
Agent: ClCCc1nc2ccccc2[nH]1
Solvent: NCCN
Product: CN=C(NC#N)NCCNCCc1nc2ccccc2[nH]1

Procedure:
Reacting 2-(2-chloroethyl)benzimidazole with ethylenediamine by the procedure of Example 34, then reacting the resulting N-[2-(2-benzimidazolyl)ethyl]-ethylenediamine with N-cyano N',S-dimethylisothiourea by the procedure of Example 3(a) give the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[C:9]([F:17])[CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[C:5]=1[F:18])=[CH:2][CH3:3].C(O)C>[C].[Pd].C1(C)C=CC=CC=1>[CH2:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[C:9]([F:17])[CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[C:5]=1[F:18])[CH2:2][CH3:3]
Reactant: CC=Cc1ccc2c(c1F)Cc1c(F)cccc1-2
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCc1ccc2c(c1F)Cc1c(F)cccc1-2
Reaction time: 8 h
Yield: 43.7 %

Procedure:
A mixture of 19.3 g of 2-(propen-1-yl)-1,8-difluorofluorene (K-3) (crude product), 1.5 g of 5% palladium-carbon, 80 ml of ethanol and 80 ml of toluene was hydrogenated over an 8 hour period at room temperature and under atmospheric pressure, with constant stirring. The palladium-carbon was removed by filtration, the solvent was removed from the filtrate by evaporation under reduced pressure, and the residue was then purified by silica gel column chromatography (hexane) to yield 8.5 g of 2-propyl-1,8-difluorofluorene (K-4).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:2]1.C1C(=O)N([Br:23])C(=O)C1>ClCCl>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]=1[Br:23])[CH3:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cc1c[nH]c2ccccc12
Solvent: ClCCl
Product: CCOC(=O)Cc1c(Br)[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 50.4 %

Procedure:
To a solution of 15.0 g (73.8 mmol) of ethyl (indol-3-yl)acetate in 75 ml of anhydrous dichloromethane at 0° C. was added 13.1 g (73.8 mmol) of NBS in small portions. The mixture was stirred at 0° C. for 3 h and then quickly concentrated under reduced pressure (argon was used to normalize the pressure after concentration to avoid decomposition due to the product's instability). Column chromatography with 99:1 toluene/ethanol afforded 10.5 g (50%) of the 2-bromoindole as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CCC[C@H]1CO)=O)(C)(C)C.[CH3:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][SH:40])=[CH:37][CH:36]=1.[H-].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][S:40][CH2:39][C:38]1[CH:41]=[CH:42][C:35]([O:34][CH3:33])=[CH:36][CH:37]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COS(C)(=O)=O
Reactant: COc1ccc(CS)cc1
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CSC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1

Procedure:
The procedure described in Preparation 5-(2) was repeated, but using 12.16 g of (2S)-1-t-butoxycarbonyl-2-methanesulfonyloxymethylpyrrolidine [prepared by the methanesulfonylation of (2S)-1-t-butoxycarbonyl-2-hydroxymethylpyrrolidine], 7.3 ml of 4-methoxybenzyl mercaptan and 2.3 g of sodium hydride (as a 55% w/w suspension in mineral oil) in 100 ml of dry dimethylformamide, to afford 13.93 g of the title compound as an oil.
Reaction SMILES: [H-].[Na+].[CH:3]([NH:5][CH2:6][C:7]([C:9]1[N:10]=[CH:11][N:12]2[CH:16]=[CH:15][S:14][C:13]=12)=[O:8])=[O:4].CI.Cl[CH2:20]Cl>CN(C=O)C>[CH:3]([NH:5][CH:6]([CH3:20])[C:7]([C:9]1[N:10]=[CH:11][N:12]2[CH:16]=[CH:15][S:14][C:13]=12)=[O:8])=[O:4]
Reactant: O=CNCC(=O)c1ncn2ccsc12
Reactant: ClCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(NC=O)C(=O)c1ncn2ccsc12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (31 mg) was added to a solution of 0.24 g of 7-formylaminoacetylimidazo[5,1-b]thiazole in 4 ml of DMF. The mixture was stirred at 60° C. for 30 min, and cooled to room temperature. Thereafter, 176 mg of methyl iodide was added thereto. The mixture was stirred for one hr. Dichloromethane was added to the reaction mixture. The mixture was washed with water and saturated brine in that order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=20:1) to give 0.12 g of 7-(2-formylaminopropionyl)imidazo[5,1-b]thiazole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.Cl[C:22]1[CH:23]=[C:24]2[N:31]([CH3:32])[C:30]([CH3:34])([CH3:33])[CH2:29][N:25]2[C:26](=[O:28])[N:27]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1)[CH2:19][O:20][C:22]1[CH:23]=[C:24]2[N:31]([CH3:32])[C:30]([CH3:34])([CH3:33])[CH2:29][N:25]2[C:26](=[O:28])[N:27]=1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCc1ccc(Oc2cncc(C(F)(F)F)c2)c(F)c1
Product: CN1c2cc(OCc3ccc(Oc4cncc(C(F)(F)F)c4)c(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3-fluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol and 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][C:8]([C:10]3[N:11]=[C:12]4[N:16]([CH:17]=3)[N:15]=[C:14]([O:18][CH3:19])[S:13]4)=[CH:7][C:6]2=[C:20]([OH:22])[CH:21]=1.[CH2:23](O)[C:24]#[CH:25].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.ClCCl>[CH3:19][O:18][C:14]1[S:13][C:12]2=[N:11][C:10]([C:8]3[O:9][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:21]=[C:20]([O:22][CH2:25][C:24]#[CH:23])[C:6]=4[CH:7]=3)=[CH:17][N:16]2[N:15]=1
Reactant: C#CCO
Reactant: COc1cc(O)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: C#CCOc1cc(OC)cc2oc(-c3cn4nc(OC)sc4n3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
A solution of 6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol (Example 1H, 205 mgs, 0.646 mmol) in THF (10 mL) was treated at r.t. and under a nitrogen atmosphere, with propargyl alcohol (0.096 mL, 1.615 mmol), tri-n-butylphosphine (0.398 mL, 1.615 mmol) and dropwise, over a 25 min period with a solution of 1,1′-(azodicarbonyl)dipiperidine (408 mgs, 1.615 mmol) in THF (10 mL). The mixture was sonicated in a bath for 30 min and stirred at r.t. for another 30 min. The mixture was then dissolved in dichloromethane (50 mL) and washed with sat. aqueous NaHCO3, brine and dried (MgSO4). Evaporation of the solvent gave a solid that was purified by silica gel column chromatography ISCO to give the title material (180 mg, 0.507 mmol, 78% yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm: 8.38 (s, 1H), 6.92 (s, 1H), 6.86 (dd, J=1.8, 1.0 Hz, 1H), 6.53 (d, J=1.6 Hz, 1H), 4.94 (d, J=2.7 Hz, 2H), 4.21 (s, 3H), 3.77-3.84 (m, 3H), 3.60-3.66 (m, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:14][NH2:15].O>C1COCC1>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:15][CH3:14])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(C(C)=O)cc1
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
Ex-29A: To a solution of 4-acetylbenzenesulfonyl chloride (1.1 g, 5.0 mmol) in 25 ml of THF, methylamine (0.44 ml of 40% solution in H2O, 5 mmol) was added dropwise, and the mixture was stirred for 30 min. The reaction mixture was poured into water, and the precipitate was filtered. Recrystallization from EtOAc/hexanes gave 0.67 g (62.6%) of 4-acetyl-N-methyl-benzenesulfonamide as a white solid. 1H-NMR (300 MHz, CDCl3) δ 8.09 (d, J=8 Hz, 2H), 7.96 (d, J=8 Hz, 2H), 4.48 (br, 1H), 2.70 (d, J=4 Hz, 1H), 2.66 (s, 3H).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:4]=1[OH:5].C(O[C:14](OCC)(OCC)[CH2:15][CH3:16])C.O>C(O)C>[CH2:15]([C:16]1[O:5][C:4]2[CH:6]=[CH:7][CH:8]=[C:9]([OH:10])[C:3]=2[N:2]=1)[CH3:14]
Reactant: Nc1c(O)cccc1O
Reactant: CCOC(CC)(OCC)OCC
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCc1nc2c(O)cccc2o1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-aminoresorcinol hydrochloride (5.0 g) and triethylorthopropionate (13.7 ml) was heated to 150° C. for 2 h before being poured into a mixture of water (140 ml) and ethanol (35 ml). The mixture was stirred vigorously for 30 minutes at room temperature. The resulting precipitate was removed by filtration and dried to give the title compound as a beige solid (4.11 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:19])[CH:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4].[CH2:20]([O:27][CH2:28][CH2:29]Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[CH2:11]([O:10][C:8](=[O:9])[C:7]([CH2:29][CH2:28][O:27][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]([O:5][CH2:3][CH3:4])=[O:19])[CH3:12]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Reactant: BrCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCOCc1ccccc1)(C(=O)OCC)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38.3 %

Procedure:
Sodium hydride (406 mg) was dissolved in dimethylformamide (20 mL) and the solution was cooled to 0° C. To this solution was added phenylmalonic acid diethyl ester (2.0 g), and the mixture was stirred at room temperature for 30 minutes. Bromoethyl benzyl ether (2.0 g) was further added thereto, stirred at 60° C. for 4 hours, and water was added thereto. The reaction mixture was concentrated, diluted with ethyl acetate, washed with water, dried over sodium sulfate and purified by column chromatography on silica gel with ethyl acetate:hexane=1:9 to give the title compound (1.2 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[C:19]([Cl:28])[CH:18]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9]C(C)(C)C)=[O:8].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:25])([F:26])[F:27])=[C:19]([Cl:28])[CH:18]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([OH:9])=[O:8]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(Oc2ccc(OC(F)(F)F)c(Cl)c2)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(Cl)c(Oc2ccc(OC(F)(F)F)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 50 h

Procedure:
Tert-butyl 5-chloro-4-[3-chloro-4-(trifluoromethoxy)phenoxy]-2-fluorobenzoate (Preparation 161, 41.88 g, 0.0868 mol) was dissolved in dichloromethane (75 mL), then trifluoroacetic acid (21.2 mL, 0.285 mol) was added and the mixture was stirred at room temperature for 50 hours. Trifluoroacetic acid was added again (1.2 mL, 0.017 mol) and the reaction left to stir for 4 hours. A solid was observed in the flask, so it was collected by filtration. The filtrate was concentrated in vacuo and dichloromethane (5 mL) was added to the crude, which was stirred for 5 minutes at room temperature. The resulting solid was collected by filtration and set aside. The crops were combined and title compound was isolated as a white solid (29.6 g, 81%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[C:4]([CH2:10][CH3:11])[C:3]=1[CH2:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=1.N1C=CN=C1.[C:26]([Si:30]([CH3:33])([CH3:32])Cl)([CH3:29])([CH3:28])[CH3:27]>CN(C)C=O>[Si:30]([O:9][CH2:8][CH2:7][N:6]1[C:2]([NH2:1])=[C:3]([CH2:12][C:13]2[CH:14]=[C:15]([Cl:20])[CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:4]([CH2:10][CH3:11])=[N:5]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:33])[CH3:32]
Reactant: CCc1nn(CCO)c(N)c1Cc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCc1nn(CCO[Si](C)(C)C(C)(C)C)c(N)c1Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.2 %

Procedure:
To a solution of the pyrazole of Example 89 (3.0 g, 9.6 mmol) in dimethylformamide (20 ml) was added imidazole (850 mg, 12.5 mmol), followed by tert-butyldimethylchlorosilane (1.58 g, 10.6 mmol). The solution was stirred at room temperature for 20 hours. The reaction mixture was partitioned between diethyl ether and aqueous sodium carbonate and the aqueous phase was separated and further extracted with diethyl ether. The combined organic phases were washed with water, washed with brine, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5, by volume) to afford the title compound (4.0 g) as a colourless oil.