Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].CC([O-])(C)C.[K+].Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=3)[CH:21]=2)[C:16]([Cl:31])=[CH:15][N:14]=1>COCCOC.CN1C(=O)CCC1>[Cl:31][C:16]1[C:17]2[C:22](=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=3)=[CH:19][CH:18]=2)[C:13]([NH:4][C:3]([NH2:5])=[NH:2])=[N:14][CH:15]=1
Reactant: N#Cc1cccc(-c2ccc3c(Cl)cnc(Cl)c3c2)c1
Reactant: N=C(N)N
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: COCCOC
Solvent: CN1CCCC1=O
Product: N#Cc1cccc(-c2ccc3c(Cl)cnc(NC(=N)N)c3c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
A stirred suspension of guanidine hydrochloride (3.8 kg, 39.8 mol) and KOtBu (4.28 kg, 38.1 mol) in DME (17.6 L) was heated to reflux under N2 for 1 hour. The gum containing solution was cooled to room temperature, diluted with NMP (8.8 L) and 1,4-dichloro-7-(3-cyanophenyl)isoquinoline (4.4 kg, 14.7 mol) was added as a solid. The mixture was heated at reflux overnight, cooled to room temperature, filtered through a pad of celite and the pad washed with DME (4.4 L). Water (35.2 L) was added to the filtrate. The resultant slurry was stirred for 2 hour and the solid collected by filtration. The solid was washed with water (4.4 L) and dried in vacuo at 50° C. to give (4-chloro-7-(3-cyanophenyl)isoquinolin-1-yl)guanidine (4.55 kg, 14.1 mol, 96%) as a green solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[O:11][CH:12]([CH2:24][OH:25])[CH2:13][O:14][CH2:15][P:16]([O:21]CC)([O:18]CC)=[O:17])=[C:4]([NH2:26])[N:3]=1.Br[Si](C)(C)C>ClCCl>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[O:11][CH:12]([CH2:13][O:14][CH2:15][P:16]([OH:21])([OH:18])=[O:17])[CH2:24][OH:25])=[C:4]([NH2:26])[N:3]=1
Reactant: CCOP(=O)(COCC(CO)On1cnc2c(N)nc(N)nc21)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: Nc1nc(N)c2ncn(OC(CO)COCP(=O)(O)O)c2n1
Temperature: 20 °C
Reaction time: 4 h
Yield: 63.3 %

Procedure:
To a solution of 2,6-diamino-9-[1-(diethoxyphosphorylmethoxy)-3-hydroxyprop-2-oxy]purine (100 mg, 0.26 mmol) in dichloromethane, was added bromotrimethylsilane (0.34 ml, 2.6 mmol) and the solution stirred under nitrogen for 4 h at 20° C. The solution was evaporated in vacuo and co-distilled with methanol and toluene. Recrystallisation of the residue with ethanol-water afforded 2,6-diamino-9-[1-hydroxy-3-(phosphonomethoxy)prop-2-oxy]purine (55 mg, 65%) as a white solid m.p. >300° C. decomp. λmax (H2O), 280 (ε10,100), 255 (ε8,400), 212 (ε26,100); νmax (KBr) 3360, 1700, 1660 and 1410 cm-1 ; δH (D2O+NH3) 3.55 (2H, m, CH2OH), 3.89 (4H, m, CH2OCH2P), 4.62 (1H, m, CHON), 8.10 (1 H, s, H-8). Found: C, 32.49; H, 4.63; N, 24.86%; C9H15N6O6P requires C, 32.34; H, 4.52; N, 25.14%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14].N1C=CC=CC=1>O1CCCC1>[C:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:7][CH:8]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc(-c2cccs2)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc(-c2cccs2)cc1
Reaction time: 1 h
Yield: 79.5 %

Procedure:
To a mixture of 4-(2-thienyl)phenol (1.00 g) and acetic anhydride (869 mg) in tetrahydrofuran (10 ml) was added pyridine (494 mg) with ice-cooling. The mixture was stirred for 1 hour at said temperature and 1 hour at ambient temperature. After concentration, the mixture was partitioned between AcOEt and H2O. The separated organic layer was washed with 1% aqueous citric acid, 3% aqueous NaHCO3 solution and brine, dried over sodium sulfate and concentrated. The residue was triturated with hexane to give 985 mg of 2-(4-acetoxyphenyl)thiophene as a powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:14]([OH:16])=O)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C(Cl)(=O)C(Cl)=O.[C:23]([O:31][CH2:32][CH3:33])(=[O:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].[Mg+2].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:14]([CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:23]([O:31][CH2:32][CH3:33])=[O:30])=[O:16])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(O)C1(c2ccccc2F)CCOCC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C(C(=O)OCC)C(=O)C1(c2ccccc2F)CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 4-(2-fluorophenyl)-tetrahydro-2H-pyran-4-carboxylic acid (1.9 g, 8.5 mmol) in DCM (50 mL) and DMF (5 mL) was carefully added oxalyl chloride (0.79 mL, 8.9 mmol). Gas evolution was observed. The reaction was stirred at room temperature for 3 hours. In a separate flask was combined IPAc (1.0 mL, 8.7 mmol), diethyl malonate (1.6 mL, 11 mmol). and anhydrous MgCl2 (1.0 g, 11 mmol). The resulting white slurry was stirred for 30 minutes, and then TEA (4.0 mL, 29 mmol) was added and the reaction was stirred for 2.5 hours. The reaction was chilled in an ice water bath for 10 minutes, and then the concentrated acid chloride oil was added via syringe over 10 minutes. The ice bath was removed, and the reaction was stirred for 16 hours at 50° C. After cooling to room temperature, the reaction was acidified with 5N HCl solution (100 mL). The aqueous layer was removed, and the organic layer was washed with saturated NaHCO3 solution (150 mL). The aqueous layer was removed, and the organic extract was washed with water. The organic layer was dried (Na2SO4), filtered and concentrated to afford a dark colored oil. The crude reaction mixture was used in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:17]([C:18]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[N:19]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>C(O)(C(F)(F)F)=O.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:17]([C:18]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH2:25])[N:19]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc(OC)c(OC)c3)n2)cc1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncccc2-c2nc(C)nc(N)n2)cc1OC
Temperature: 25 °C
Yield: 11.1 %

Procedure:
A solution of 4-(2-(3,4-dimethoxyphenylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.255 g, 0.441 mmol) in TFA (8.0 mL) (Aldrich) was heated at 80° C. overnight. The solution was cooled to room temperature, the mixture was concentrated, the crude residue was treated with 2M NH3 in MeOH and dry-packed with silica gel. Purification using an ISCO Combiflash Companion (12 g column; 1-25% MeOH in DCM over 30 min; product eluted with 11% MeOH) gave material of insufficient purity for testing. The residue was suspended in MeOH and the solid was removed by filtration to give 4-(2-(3,4-dimethoxyphenylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.017 g, 0.049 mmol, 11.12% yield) as a brown amorphous solid. 1H NMR (400 MHz, d6-DMSO) δ 11.77 (s, 1H); 8.75 (dd, J=7.7, 1.9 Hz, 1H); 8.31 (dd, J=4.5, 2.0 Hz, 1H); 7.79 (br. s., 1H); 7.70 (br. s., 1H); 7.47 (d, J=2.3 Hz, 1H); 7.30 (dd, J=8.7, 2.4 Hz, 1H); 6.91 (d, J=8.8 Hz, 1H); 6.84 (dd, J=7.8, 4.7 Hz, 1H); 3.79 (s, 3H); 3.74 (s, 3H); 2.44 (s, 3H). m/z (ESI, +ve ion) 339.0 (M+H)+.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[CH3:11][O:12][C:13]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:28])(=[O:27])[NH2:26])=[CH:21][CH:20]=2)=[CH:17][C:16]([C:29]2[N:33]([CH3:34])[C:32]([C:35](O)=[O:36])=[CH:31][C:30]=2[CH3:38])=[CH:15][CH:14]=1.Cl.[CH3:40][NH:41][O:42][CH3:43].C(Cl)CCl.C(N(CC)CC)C>CN(C=O)C>[CH3:43][O:42][N:41]([CH3:40])[C:35]([C:32]1[N:33]([CH3:34])[C:29]([C:16]2[CH:17]=[C:18]([C:19]3[CH:20]=[CH:21][C:22]([S:25](=[O:27])(=[O:28])[NH2:26])=[CH:23][CH:24]=3)[C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[C:30]([CH3:38])[CH:31]=1)=[O:36]
Reactant: COc1ccc(-c2c(C)cc(C(=O)O)n2C)cc1-c1ccc(S(N)(=O)=O)cc1
Reactant: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2c(C)cc(C(=O)N(C)OC)n2C)cc1-c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Yield: 86.3 %

Procedure:
HOBT (0.29 g, 1.92 mmol) was added to a solution of 5-(6-methoxy-4′-sulfamoyl-[1,1′-biphenyl]-3-yl)-1,4-dimethyl-1H-pyrrole-2-carboxylic acid (10c, 0.70 g, 1.75 mmol) in DMF (15 ml) under stirring at room temperature. N,O-dimethylhydroxylamine hydrochloride (0.33 g, 3.5 mmol) was then added to the reaction mixture. The reaction mixture was cooled to 0° C. and EDC (0.50 g, 2.60 mmol) and triethylamine (0.70 g, 0.97 ml, 7.00 mmol) were added to it. The reaction mixture was stirred at room temperature for 15 hours. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. The residue obtained after concentration was mixed with ethyl acetate (50 ml) and the resultant mixture was washed with saturated sodium bicarbonate solution (10 ml) followed by washing with brine (10 ml). The organic layer separated was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain a crude product. The crude product was further purified by flash column chromatography using 4% methanol in DCM as an eluent to obtain the title compound 10d (0.67 g, 87%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][NH2:5].[C:6]([CH:9]([O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)[C:10](=O)[CH3:11])(=O)[CH3:7].O>C(O)(=O)C>[OH:1][CH2:2][CH2:3][N:4]1[C:10]([CH3:11])=[C:9]([O:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]#[N:19])=[CH:20][CH:21]=2)[C:6]([CH3:7])=[N:5]1
Reactant: CC(=O)C(Oc1ccc(C#N)cc1)C(C)=O
Reactant: NNCCO
Solvent: O
Solvent: CC(=O)O
Product: Cc1nn(CCO)c(C)c1Oc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 26 %

Procedure:
A mixture of commercially available 3-chloro-2,4-pentanedione (1.2 ml, 10 mmol), 4-cyanophenol (1.19 g, 10 mmol), caesium carbonate (3.25 g, 10 mmol) and acetone (50 ml) was heated at 60° C. for 4 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The resulting oil was diluted with dichloromethane (25 ml) and washed with 1M hydrochloric acid (30 ml). The aqueous layer, at pH 1, was extracted with dichloromethane (20 ml). The combined organic extracts were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure to provide 4-(1-acetyl-2-oxopropoxy)benzonitrile (2.06 g, 9.4 mmol) which was used crude in the next step. 2-Hydroxyethyl hydrazine (169 μL, 2.5 mmol) was added to a stirred solution of a portion of the crude 4-(1-acetyl-2-oxopropoxy)benzonitrile (500 mg, 2.3 mmol) in acetic acid (5 ml) at room temperature under nitrogen, and the mixture was stirred at room temperature for 5 hours. Water (20 ml) was then added, and a solid triturated out and filtered off. This was recrystallised from ethyl acetate to provide the title compound (154 mg, 6%).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[F:15][CH:16]([F:30])[CH2:17][O:18][C:19]1[N:24]=[C:23]([O:25][CH3:26])[C:22]([CH:27]([NH2:29])[CH3:28])=[CH:21][CH:20]=1>>[Cl:13][C:12]1[C:3]2[CH2:2][N:29]([CH:27]([C:22]3[C:23]([O:25][CH3:26])=[N:24][C:19]([O:18][CH2:17][CH:16]([F:15])[F:30])=[CH:20][CH:21]=3)[CH3:28])[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Reactant: COc1nc(OCC(F)F)ccc1C(C)N
Agent: Cl
Product: COc1nc(OCC(F)F)ccc1C(C)N1Cc2c(ccnc2Cl)C1=O
Yield: 91 %

Procedure:
The title compound is prepared in 91% yield (198 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(6-(2,2-difluoroethoxy)-2-methoxypyridin-3-yl)ethanamine hydrochloride (152 mg, 0.57 mmol, Amine-21, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].Br[CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:26][C:25]([CH3:27])=[CH:24][CH2:23][N:14]([C:7]([O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:8])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CC(C)=CCBr
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)=CCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 0.08 h

Procedure:
Potassium tert-butoxide (52 mg, 0.46 mmol) was added to a solution of di-tert-butyl imidodicarbonate (100 mg, 0.46 mmol) in tetrahydrofuran (1 mL). After 5 min, 1-bromo-3-methylbut-2-ene (54 μL, 0.46 mmol) was added. After 3 h, saturated aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. MS 286.2 (M+1).
Reaction SMILES: C1(O)C=CC=CC=1.[Al].[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])([CH3:12])([CH3:11])[CH3:10].[CH3:20][C:21](=[CH2:23])[CH3:22]>>[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:21]([CH3:23])([CH3:22])[CH3:20])[C:14]=1[OH:19])([CH3:12])([CH3:10])[CH3:11]
Reactant: C=C(C)C
Reactant: CC(C)(C)c1ccccc1O
Agent: [Al]
Solvent: Oc1ccccc1
Product: CC(C)(C)c1cccc(C(C)(C)C)c1O
Yield: 98.5 %

Procedure:
The heterogeneous catalyst of the invention provides a new route to ortho-alkylphenols, especially commercially valuable phenols such as 2,6-di-tert-butylphenol, ortho-sec-butylphenol, and the like. Furthermore, the heterogeneous catalyst process of the invention is well suited to a fixed bed embodiment for a continuous process when the bed is properly sized to provide the reactivity required by the reaction conditions, the phenol being alkylated, and the olefin being used. Use of the heterogeneous catalyst of the invention reduces pollution control problems by greatly reducing the amount of phenol-bearing aluminum waste encountered in homogeneous aluminum aryloxide catalyst systems thereby greatly reducing the operating costs for alkylating phenols. Use of the heterogeneous catalyst systems of the invention has resulted in very high yields suitable for commercial operation. For example, ortho-tert-butylphenol and isobutylene may be reacted to form 2,6-di-tert-butylphenol in a yield as high as 98.5%.
Reaction SMILES: [C:1](=[O:12])([O:3][CH2:4][CH:5]([CH2:10][CH3:11])[CH2:6][CH2:7][CH2:8][CH3:9])[NH2:2].[C:13](Cl)(Cl)=[O:14]>CCCCCCCCCCCCCCCCCCCNC=O.ClC1C=CC=CC=1>[CH2:10]([CH:5]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][O:3][C:1]([N:2]=[C:13]=[O:14])=[O:12])[CH3:11]
Reactant: CCCCC(CC)COC(N)=O
Reactant: O=C(Cl)Cl
Agent: CCCCCCCCCCCCCCCCCCCNC=O
Solvent: Clc1ccccc1
Product: CCCCC(CC)COC(=O)N=C=O
Temperature: -78 °C
Reaction time: 3.25 h
Yield: 85 %

Procedure:
138.6 g of 2-ethylhexyl carbamate were initially introduced in melted form and 93 g of phosgene were passed into the melt at 80° C. within 3.25 hours, the gas outlet stream being passed through a reflux condenser cooled to -78° C. 800 g of chlorobenzene and 5.0 g of methylstearylformamide were then added, the mixture was heaLed to 120° C., and 48 g of phosgene were passed into the mixture within 3 hours. The mixture was stirred for a further 1 hour at 130° C. and excess phosgene was subsequently blown out using nitrogen. Subsequent distillation produced 135.5 g (=85% of theory) of 2-ethylhexyloxycarbonyl isocyanate having a boiling point of 45°-60° C. at 0.13-0.4 mbar.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH:19]([CH:23]([OH:25])[CH3:24])[C:20]([OH:22])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.OS(O)(=O)=O.[CH3:31]O>>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH:19]([CH:23]([OH:25])[CH3:24])[C:20]([O:22][CH3:31])=[O:21])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CO
Reactant: CC(O)C(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)C(NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)O
Temperature: 25 °C

Procedure:
To a solution of 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-hydroxybutanoic acid (5 g, 14.65 mmol) in MeOH (50 mL) was added H2SO4 (0.781 mL, 14.65 mmol). The reaction mixture was stirred at reflux overnight. The resulting mixture was cooled to room temperature and the solvent removed under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography using a gradient of 0-100% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: [CH3:1][SiH:2]1[O:9][SiH:8]([CH3:10])[O:7][SiH:6]([CH3:11])[O:5][SiH:4]([CH3:12])[O:3]1.[C:13]([O:17][CH2:18][CH2:19][OH:20])(=[O:16])[CH:14]=[CH2:15].C1C=CC=CC=1>O>[C:13]([O:17][CH2:18][CH2:19][O:20][Si:8]1([CH3:10])[O:9][SiH:2]([CH3:1])[O:3][SiH:4]([CH3:12])[O:5][SiH:6]([CH3:11])[O:7]1)(=[O:16])[CH:14]=[CH2:15]
Reactant: C[SiH]1O[SiH](C)O[SiH](C)O[SiH](C)O1
Reactant: C=CC(=O)OCCO
Solvent: O
Solvent: c1ccccc1
Product: C=CC(=O)OCCO[Si]1(C)O[SiH](C)O[SiH](C)O[SiH](C)O1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixed solution containing 1 M of 2,4,6,8-tetramethylcyclotetrasiloxane and 0.01 g of Zn(CH3CO2)2 was slowly added 1 M of 2-hydroxyethyl acrylate. The resulting mixture was stirred for 12 hours at a room temperature. Thereafter, 200 mL of benzene and 200 mL of cold water were added. The organic layer was separated, washed with 200 mL of cold water, dried over MgSO4, filtered, and concentrated by distillation to provide the title compound of Formula 1A (yield: 97%).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25](Br)=[CH:24][N:23]=[C:22]([N:27]4[CH2:30][CH:29]([F:31])[CH2:28]4)[N:21]=3)[C@H:14]2[CH3:32])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:35]([C:38]1[CH:39]=[C:40](B(O)O)[C:41]([O:44][CH3:45])=[N:42][CH:43]=1)([CH3:37])[CH3:36].C([O-])([O-])=O.[K+].[K+]>[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:40]4[C:41]([O:44][CH3:45])=[N:42][CH:43]=[C:38]([CH:35]([CH3:37])[CH3:36])[CH:39]=4)=[CH:24][N:23]=[C:22]([N:27]4[CH2:30][CH:29]([F:31])[CH2:28]4)[N:21]=3)[C@H:14]2[CH3:32])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1ncc(C(C)C)cc1B(O)O
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(N2CC(F)C2)ncc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Product: COc1ncc(C(C)C)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 50 °C

Procedure:
(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[5-bromo-2-(3-fluoroazetidin-1-yl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 14, 1.2 g, 2.153 mmol), 5-isopropyl-2-methoxypyridin-3-ylboronic acid (0.716 g, 2.58 mmol), 1,1′-Bis(di-tert-butylphosphino)ferrocene palladium dichloride (211 mg, 0.323 mmol) and K2CO3 (893 mg, 6.46 mmol) were added to a reaction vial that was evacuated and charged with nitrogen three times. The solid reactants were then mixed with THF (15 mL) and water (3 mL), degassed and refilled with nitrogen, capped and heated for 1 hour at 50° C. in a BIOTAGE microwave reactor, after which LCMS showed complete conversion to product. The reaction was diluted with 50 mL ethyl acetate and poured into 100 mL sat′d NH4Cl soln. The ethyl acetate layer was washed with brine (100 mL) filtered through a 20 g plug of sodium sulfate, eluting with 50 mL ethyl acetate. The filtrate was concentrated prior to RP Prep purification on a X-Bridge 30×300 mm RP column. After loading the column was eluted with a 10-100% acetonitrile/water (0.1% NH4OH) linear gradient over 20 minutes. The product of interest eluted in 80% portion of above gradient. Pure fractions were concentrated and lyophilized to give a white solid. LCMS (M+H)+: 628.5 1H NMR (CDCl3, 500 MHz): δ 8.16 (s, 1H), 8.11 (d, J=2.2 Hz, 1H), 7.91 (s, 1H), 7.76 (s, 2H), 7.36 (d, J=2.2 Hz, 1H), 5.68 (d, J=8.6 Hz, 1H), 5.54 (m, 0.5H) 5.43 (m, 0.5H), 4.70 (d, J=17.2 Hz, 1H), 4.51 (m, 2H), 4.33 (m, 2H), 4.02 (d, J=17.4 Hz, 1H), 3.94 (s, 3H), 2.96 (m, 1H), 1.30 (d, J=6.9 Hz, 6H), 0.74 (d, J=6.7 Hz, 3H). SPA IC50: 11 nM.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:20][O:21][CH:22]2[CH2:24][CH2:23]2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=1.C(OC(C)C)(C)C>C(O)=O>[CH:22]1([O:21][N:20]=[C:14]([C:12]2[N:13]=[C:9]([NH:8][CH:1]=[O:3])[S:10][CH:11]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:24][CH2:23]1
Reactant: CCOC(=O)C(=NOC1CC1)c1csc(N)n1
Reactant: CC(=O)OC(C)=O
Solvent: CC(C)OC(C)C
Solvent: O=CO
Product: CCOC(=O)C(=NOC1CC1)c1csc(NC=O)n1
Temperature: 45 °C

Procedure:
A mixture of formic acid (13.1 ml) and acetic anhydride (32.6 ml) was warmed at 45° C. for 45 minutes. After the mixture was cooled until ambient temperature, ethyl 2-(2-aminothiazol-4-yl)-2-cyclopropyloxyiminoacetate (syn isomer)(22 g) was added thereto. The suspension was turned to a clear solution and soon a precipitate was appeared. To the suspension was added diisopropyl ether (50 ml) and the mixture was stirred at ambient temperature for additional an hour. The mixture was cooled in ice-bath and the precipitate was collected and washed with diisopropyl ether to give ethyl 2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetate (syn isomer)(20.5 g).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:5]=2[N:6]=1.[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[S:3][C:4]3[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:5]=3[N:6]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc2sc(Br)nc2c1
Reactant: Nc1ccc(Br)cc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2sc(Nc3ccc(Br)cc3)nc2c1

Procedure:
The mixture containing 2-bromo-5-methoxybenzthiazole (1 eq), 4-Bromoaniline (2 eq) and diisopropylethylamine was subjected to microwave in NMP at 220° C. The resultant mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was washed with brine and dried. Purification on silica gel gave the desired product. MS: MH+=335
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12](=[S:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[F:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[C:26]([F:28])[CH:27]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:23]=[C:22]([F:21])[CH:27]=[C:26]([F:28])[CH:25]=3)[CH2:34][CH2:33]2)=[S:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: Fc1cc(F)cc(N2CCNCC2)c1
Reactant: COc1nc(C)c(C)cc1NC(=S)Oc1ccccc1
Product: COc1nc(C)c(C)cc1NC(=S)N1CCN(c2cc(F)cc(F)c2)CC1
Yield: 47 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyridin-3-yl)thiocarbamate and 1-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound.
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([CH:7]=[C:8]2[S:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:5][CH:4]=1)=O.[Cl:17][C:18]1[CH:19]=[C:20]([C:26]([F:29])([F:28])[F:27])[C:21]([NH2:25])=[C:22]([NH2:24])[CH:23]=1>>[Cl:17][C:18]1[CH:19]=[C:20]([C:26]([F:27])([F:28])[F:29])[C:21]2[NH:25][C:1]([C:3]3[CH:16]=[CH:15][C:6]([CH:7]=[C:8]4[S:12][C:11](=[O:13])[NH:10][C:9]4=[O:14])=[CH:5][CH:4]=3)=[N:24][C:22]=2[CH:23]=1
Reactant: Nc1cc(Cl)cc(C(F)(F)F)c1N
Reactant: O=Cc1ccc(C=C2SC(=O)NC2=O)cc1
Product: O=C1NC(=O)C(=Cc2ccc(-c3nc4cc(Cl)cc(C(F)(F)F)c4[nH]3)cc2)S1

Procedure:
6-Chloro-2-[4-[(2,4-dioxothiazolidin-5-ylidene)methyl]phenyl]-4-(trifluoromethyl)benzimidazole was prepared from 5-(4-formylbenzylidene)-2,4-thiazolidinedione and 5-chloro-3-trifluoromethyl-1,2-phenylenediamine by following General Procedure 2.