Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][N+:13]([O-])=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.C[Si]([C:21]#[N:22])(C)C.C(N(CC)CC)C>C(#N)C>[N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:21]#[N:22])[CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCCC(c1cc[n+]([O-])cc1)n1ccnc1
Reactant: C[Si](C)(C)C#N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCC(c1ccnc(C#N)c1)n1ccnc1
Reaction time: 22 h
Yield: 89.9 %

Procedure:
0.109 g of 4-[1-(1-imidazolyl)-butyl]pyridine-N-oxide is dissolved in 2 ml of acetonitrile, 0.150 g of trimethylsilyl cyanide and 0.101 g of triethylamine are added to it. The reaction is left for 22 hours at 110° C. The mixture is concentrated by evaporation in a vacuum and then distilled on a bulb tube, boiling point: 210°-220° C./0.035 mbar. 0.102 g of 4-[1-(1-imidazolyl)-butyl]-2-cyanopyridine is obtained as brownish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.[CH3:17][N:18]([CH3:32])[C:19]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1.C(O)(=O)C>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH:22]2[CH2:21][CH2:20][C:19]([N:18]([CH3:32])[CH3:17])([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:24][CH2:23]2)[CH2:15][CH:16]=1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: Clc1ccc2[nH]cc(C3=CCNCC3)c2c1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(C)C1(c2ccccc2)CCC(N2CC=C(c3c[nH]c4ccc(Cl)cc34)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-chloro-3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole (170 mg, 0.79 mmole) and 4-dimethylamino-4-phenylcyclohexanone (171 mg, 0.79 mmole) were dissolved in dry 1,2-dichloro-ethane (10 ml). Glacial acetic acid (0.79 mmole) and sodium triacetoxy boron hydride (300 mg, 1.4 mmole) were added to this mixture. The reaction mixture was then stirred for 24 hours at RT. The reaction mixture was worked up by distilling off the 1,2-dichloroethane and diluting with water (10 ml). The reaction mixture was adjusted to pH 11 with 5M NaOH and extracted with EE (4×20 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. The diastereoisomer mixture was obtained as a colourless solid in a yield of 340 mg (100%).
Reaction SMILES: [O:1]=[C:2]([CH3:19])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]2[C:11]([C:14]([O:16]CC)=[O:15])=[CH:12][N:13]=[C:7]2[CH:6]=1.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO>[O:1]=[C:2]([CH3:19])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]2[C:11]([C:14]([OH:16])=[O:15])=[CH:12][N:13]=[C:7]2[CH:6]=1
Reactant: CCOC(=O)c1cnc2cc(CCC(C)=O)ccn12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)CCc1ccn2c(C(=O)O)cnc2c1
Temperature: 60 °C

Procedure:
A stirring mixture of ethyl 7-(3-oxobutyl)imidazo[1,2-a]pyridine-3-carboxylate (85) (90 mg, 0.346 mmol) and 2N LiOH (0.5 mL) in THF:MeOH (4:1, 3 mL) was heated at 60° C. for 45 minutes. The reaction was cooled to room temperature and the pH was adjusted between 3-5 with 10% citric acid. The solvent was partially concentrated and the crude product was purified by reverse phase preparative HPLC to yield 7-(3-oxobutyl)imidazo[1,2-a]pyridine-3-carboxylic acid (86). MS m/z 233.08 (M+1)+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:13][C:14]([C:24]1([CH3:29])[CH2:28][CH2:27][CH2:26][CH2:25]1)([OH:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22]>CN(C)C=O>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][C:14]([C:24]1([CH3:29])[CH2:28][CH2:27][CH2:26][CH2:25]1)([OH:23])[CH2:13][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC1(C(O)(CCl)Cc2ccccc2Cl)CCCC1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C(O)(Cc2ccccc2Cl)Cn2cncn2)CCCC1
Temperature: 80 °C
Yield: 35.7 %

Procedure:
13 g (188 mmol) of 1,2,4-triazole and 18 g (130 mmol) of potassium carbonate are initially introduced into 30 ml of absolute dimethylformamide under a nitrogen atmosphere and the mixture is heated to 80° C. At this temperature, a solution of 17.1 g (59.6 mmol) of 1-chloro-3-(2-chlorophenyl)-2-(1-methyl-cyclopent-1-yl)-propan-2-ol in 20 ml of absolute dimethylformamide is added dropwise with stirring. The reaction mixture is then stirred at 80° C. for a further 8 hours. The precipitate is filtered off with suction, and the filtrate is concentrated by stripping off the diluent under reduced pressure. The residue is taken up in ethyl acetate, washed with water and, after drying over sodium sulphate, the solvent is stripped off under reduced pressure. The product which remains is chromatographed through a silica gel column using dichloromethane/ethanol=99:1 as the eluent. 6.8 g (35.7% of theory) of 1-(2-chlorophenyl)-2-(1-methyl-cyclopent- 1-yl)-3-(1,2,4-triazol-1-yl)-propan-2-ol are obtained in this way in the form of a solid substance of melting point 110° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].O.[C:15](Cl)(Cl)=[S:16]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([N:8]=[C:15]=[S:16])[N:7]=1
Reactant: Nc1cccc(Br)n1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: S=C=Nc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.7 %

Procedure:
A mixture of 6-bromopyridin-2-amine (253 mg, 1.46 mmol), chloroform (2 mL), sodium bicarbonate (850 mg, 10.12 mmol) and water (3 mL) was assembled, and to this was added a solution of thiophosgene (190 mg, 1.65 mmol) in chloroform (1 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was transferred to a separatory funnel and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered and the solvent evaporated to give a yellow solid. The solid was purified by column chromatography (5% ethyl acetate/hexanes) to afford 2-bromo-6-isothiocyanatopyridine (281 mg, 1.31 mmol, 89% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 7.50-7.62 (m, 1 H), 7.34-7.43 (m, 1 H), 6.91-7.11 (m, 1H). MS (LC/MS) R.T.=1.92; [M+H]+=216.86.
Reaction SMILES: C([O:5][C:6](=[O:32])[CH2:7][C@H:8]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:9]([N:11]1[C@H:15]([CH3:16])[C@H:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:13][C:12]1=[O:23])=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][C@H:8]([C:9]([N:11]2[C@H:15]([CH3:16])[C@H:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[O:13][C:12]2=[O:23])=[O:10])[CH2:7][C:6]([OH:32])=[O:5])=[CH:30][CH:29]=1
Reactant: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)[C@H](CC(=O)OC(C)(C)C)Cc1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)[C@H](CC(=O)O)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
A solution of (3S)-3-(4-Chlorobenzyl)-4-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-yl)-4-oxo-butyric acid tert-butyl ester (5.1 g, 11 mmol) in DCM (100 mL) was treated with TFA (50 mL) and stirred at room temperature for 1 hour. The solution was concentrated in vacuo, taken up into toluene and then conc. in vacuo. Placed on high vacuum for 6 hours to give (3S)-3-(4-Chlorobenzyl)-4-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-yl)-4-oxo-butyric acid (4.5 g, 100%.) 1H NMR (CDCl3, 400 MHz) δ 7.44-7.37 (3H, m), 7.31-7.21 (6H, m), 5.48 (1H, d, J 6.9 Hz), 4.70-4.63 (1H, m), 4.50-4.42 (1H, m), 3.05 (1H, dd, J 13.3 and 6.2 Hz), 2.89 (1H, dd, J 17.7 and 10.6 Hz), 2.63 (1H, dd, J 13.2 and 9.0 Hz), 2.43 (1H, dd, J 17.6 and 4.4 Hz), 0.86 (3H, d, J 6.6 Hz.)
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1/[CH:11]=N/C(C(C)C)C(C)C)[CH3:2].[OH-:20].[Na+]>C1COCC1.Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[CH:11]=[O:20])[CH3:2]
Reactant: [OH-]
Reactant: CCc1cccc(CC)c1/C=N/C(C(C)C)C(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cccc(CC)c1C=O
Temperature: 25 °C

Procedure:
A solution of 15.6 g (E)-[1-(2,6-diethyl-phenyl)-methylidene]-(1-isopropyl-2-methyl-propyl)-amine in 60 ml THF and 120 ml 4N HCl was heated to reflux for 2 hours then cooled to ambient temperature and poured onto a 1N NaOH solution. The aqueous phase was extracted with ethyl acetate, the combined extracts washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by flash-chromatography on silica gel with a heptane/ethyl acetate gradient as eluent: 8.35 g 2,6-diethyl-benzaldehyde as light yellow oil: MS (EI): 162.1 (M+., 100%).
Reaction SMILES: [C:1]1([C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:8]2[C@@H:11]([S:12]([CH3:15])(=[O:14])=[O:13])[NH:10][C:9]2=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]1(S([O-])=O)[CH:34]=[CH:33]C=[CH:31][CH:30]=1.[Na+].ClCCCl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:23]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:8]2[CH:11]([S:12]([C:15]3[CH:33]=[CH:34][CH:29]=[CH:30][CH:31]=3)(=[O:14])=[O:13])[NH:10][C:9]2=[O:16])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=S([O-])c1ccccc1
Reactant: CS(=O)(=O)[C@H]1NC(=O)[C@H]1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: O=C1NC(S(=O)(=O)c2ccccc2)[C@@H]1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 72.8 %

Procedure:
A mixture of 30 g of (3R-cis)-3-triphenylmethyl-4-methylsulfonyl-2-azetidinone, 40 g of sodium benzenesulfinate, 25 g of tetra-n-butylammonium bromide, 400 ml of 1,2-dichloroethane, and 100 ml of water were refluxed under nitrogen for 30 minutes. The dichloroethane was removed in vacuo and the residue was extracted with 700 ml of ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate solution, then water, then saturated aqueous sodium chloride solution. The extract was dried over sodium sulfate and evaporated. The residue was chromatographed on a 50×280 mm silica gel column eluted with 1000 ml 1:4 ethyl acetate:hexane, then 1000 ml 1:1 ethyl acetate:hexane. (3R)-3-triphenylmethyl-4-phenylsulfonyl-2-azetidinone (25.3 g) was obtained as a mixture of cis and trans isomers.
Reaction SMILES: O.P(=O)(O)(O)O.[C:7]([C:9]1[CH:14]=[C:13]([C:15]([NH:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=O)=[NH:16])[CH:12]=[CH:11][N:10]=1)#[N:8]>CC(O)CC>[N:24]1[CH:25]=[CH:26][C:21]([C:19]2[NH:18][N:17]=[C:15]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([C:7]#[N:8])[CH:14]=3)[N:16]=2)=[CH:22][CH:23]=1
Reactant: N#Cc1cc(C(=N)NNC(=O)c2ccncc2)ccn1
Agent: O=P(O)(O)O
Solvent: O
Solvent: CCC(C)O
Product: N#Cc1cc(-c2n[nH]c(-c3ccncc3)n2)ccn1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Water (82 mL), 2-butanol (8.2 mL), and phosphoric acid (4.00 g) were added to 4-pyridinecarboxylic acid N′-(2-cyanopyridine-4-carbonimidoyl)hydrazide (4) (9.25 g), and the mixture was stirred at 80° C. for 8 hours. The reaction mixture was cooled to room temperature, and precipitated crystals were recovered through filtration. The crystals were washed with a water-2-butanol (10:1) mixture (92.5 mL). The thus-washed crystal were dried at 80° C. for 13 hours under reduced pressure, to thereby yield 7.89 g of 4-[5-(pyridin-4-yl)-1H-1,2,4-triazol-3-yl]pyridine-2-carbonitrile (1).
Reaction SMILES: [ClH:1].[N:2]1([C@@H:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:12]([OH:16])[CH2:13][NH:14][CH3:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[CH3:23]C1C2C(=CC=CC=2)N([C@@H](C2C=CC=CC=2)[C@H](O)COS(C2C=CC(C)=CC=2)(=O)=O)C=1.CN>CO>[ClH:1].[CH3:15][NH:14][CH2:13][C@@H:12]([OH:16])[C@@H:11]([N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:23])=[CH:3]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](O)[C@H](c2ccccc2)n2cc(C)c3ccccc32)cc1
Reactant: CNC[C@@H](O)[C@H](c1ccccc1)n1ccc2ccccc21
Agent: CN
Agent: Cl
Solvent: CO
Product: CNC[C@@H](O)[C@H](c1ccccc1)n1cc(C)c2ccccc21

Procedure:
In an analogous manner to EXAMPLE 5, (1S,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol hydrochloride was prepared from (2S,3S)-toluene-4-sulfonic acid 3-(3-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester and methylamine (2N solution in methanol) as a white solid. [□]D25/MeOH=+116; CD/MeOH=(−); MS (ESI) m/z 295 ([M+H]+); HRMS: calcd for C19H22N20+H+, 295.18049; found (ESI, [M+H]+), 295.1816.
Reaction SMILES: [OH:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[S:14].[Na].[C:16](Cl)(=[O:18])[CH3:17]>C(Cl)Cl>[C:16]([O:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[S:14])(=[O:18])[CH3:17]
Reactant: Cn1c(=O)c2ccccc2n(O)c1=S
Reactant: CC(=O)Cl
Agent: [Na]
Solvent: ClCCl
Product: CC(=O)On1c(=S)n(C)c(=O)c2ccccc21
Reaction time: 0.08 h
Yield: 71 %

Procedure:
A slurry of 6.00 g (0.0260 mole) of 1-hydroxy-3-methyl-2-thioxo-1,2-dihydroquinazoline-4(3H)-one, sodium salt (IIa-Na) in 48 ml of methylene chloride was added to 2.1 g (0.0265 mole) of acetyl chloride at reflux. After 5 minutes, the colorless solution developed a white precipitate. After 1 hour at reflux, the reaction was cooled, filtered and the solvent was removed in vacuo to give 6.50 g of the crude product. The product was then recrystallized from 55 ml of methylene chloride and 150 ml of petroleum ether to give 4.62 g of compound IIi. The yield was 94.6%. Compound IIj-IIl were made in a similiar manner to compound IIi by using the appropriate acid chlorides and compound IIa-Na.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([S:15](=[O:18])(=[O:17])[NH2:16])[CH:9]=[C:10]([C:11]([O:13]C)=O)[C:4]=2[O:3]1.[CH2:19]([N:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[CH2:28][NH2:29])[CH2:20][CH2:21][CH3:22].O>C(O)COCCO>[CH2:19]([N:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[CH2:28][NH:29][C:11]([C:10]1[C:4]2[O:3][CH:2]([CH3:1])[CH2:6][C:5]=2[CH:7]=[C:8]([S:15](=[O:18])(=[O:17])[NH2:16])[CH:9]=1)=[O:13])[CH2:20][CH2:21][CH3:22]
Reactant: COC(=O)c1cc(S(N)(=O)=O)cc2c1OC(C)C2
Reactant: CCCCN1CCCC1CN
Solvent: O
Solvent: OCCOCCO
Product: CCCCN1CCCC1CNC(=O)c1cc(S(N)(=O)=O)cc2c1OC(C)C2
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A suspension of 4.4 g methyl 2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxylate and 3.3 g of 1-butyl-2-aminomethylpyrrolidine in 25 ml of diethylene glycol is heated at 120°-130° C. and stirred for 18-20 hours. The reaction solution is cooled to room temperature and added slowly to 150 ml-200 ml of water while stirring. Under ice-cooling crystals are precipitated thoroughly and collected by suction filtration. The crude crystals are dried and recrystallized from ethyl acetate to give crystals of N-(1-butyl-2-pyrrolidinylmethyl)-2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxamide, m.p. 169.5°-170.5° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)(O)[O-].[Na+]>C(O)(C)C>[I:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:12]=[C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]3[CH:2]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(I)cc1
Reactant: Cc1cccnc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1cccn2cc(-c3ccc(I)cc3)nc12
Temperature: 80 °C
Yield: 70.5 %

Procedure:
A mixture of crude 2-bromo-1-(4-iodophenyl)ethanone (18.2 g), 2-amino-3-picoline (1.1 equiv, 61.6 mmol), and sodium bicarbonate (1.3 equiv, 72.8 mmol) in isopropanol (160 mL) was heated at 80° C. for 16 h. After concentrating the reaction mixture in vacuo, water (100 mL) was added and the resultant tan slurry was filtered, rinsing with water (2×50 mL). The brown solid was recrystallized from hot isopropanol and further dried in vacuo to provide the title product as a brown solid (13.2 g, 71%). ESMS [M+H]+: 335.0.
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[C:13]1([CH2:19][OH:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]([O:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Cl)OCc1ccccc1
Temperature: 5 °C
Reaction time: 5 h
Yield: 95.6 %

Procedure:
Triphosgene (29.8 g, 0.1 mol) and 50 mL of carbon tetrachloride were added into 250 mL of flask in sequence, the mixture was cooled to 5° C. below by ice bath, then the solution of phenylmethanol (10.8 g, 0.1 mol) and 20 mL of carbon tetrachloride were dropwise to the reaction solution followed by stirring for 5 hours at room temperature after removing ice bath. The reaction was monitored by thin-layer chromatography (TLC). Upon completion the mixture was added ethyl acetate, the organic phase was washed by water and then evaporated under reduced pressure to obtain 16.3 g of colorless of oil with yield of 95.6%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[N:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:24][C:25]1[N:30]=[C:29](Cl)[C:28]([F:32])=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:24][C:25]1[N:30]=[C:29]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][C:10]3[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH:13]=[N:14][CH:15]=3)[CH:5]=[CH:6][CH:7]=2)[C:28]([F:32])=[CH:27][N:26]=1
Reactant: CC(C)(C)OC(=O)Nc1cncc(CCc2cccc(N)c2)c1
Reactant: Fc1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cncc(CCc2cccc(Nc3nc(Cl)ncc3F)c2)c1
Yield: 21.1 %

Procedure:
To a solution of tert-butyl {5-[2-(3-aminophenyl)ethyl]pyridin-3-yl}carbamate (0.20 g, 0.64 mmol) (prepared in Example C19, step B) and 2,4-dichloro-5-fluoropyrimidine (200 mg, 1.2 mmol) in N,N-dimethylformamide (4 mL) was added potassium carbonate (0.430 g, 3.1 mmol). The resultant mixture was stirred overnight at room temperature. The reaction was quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc once. The combined organic layers were washed with water and brine, and then dried (Na2SO4), filtered, and concentrated. The crude was purified by silica gel column chromatography to give the desired product as a light yellow oil (60 mg, 20%). LCMS for C22H24ClFN5O2 (M+H)+: m/z=444.0.
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]([NH:21][CH:22]([CH3:27])[CH:23]=[C:24](Cl)Cl)=[O:20])=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.C(OCC)(=[O:31])C>CN1CCCC1=O>[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2[O:20][C:23]([CH2:24][OH:31])=[C:22]([CH3:27])[N:21]=2)=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C=C(Cl)Cl)NC(=O)c1nn(Cc2ccccc2)c2ccccc12
Reactant: CCOC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1nc(-c2nn(Cc3ccccc3)c3ccccc23)oc1CO
Temperature: 55 °C
Yield: 77 %

Procedure:
80 μl of NaOH, 1M, were added to 15 mg of 3-(1-benzylindazole-3-carboxamido)-1,1-dichlorobut-1-ene (40 μmol) in 20 μl of N-methylpyrrolidone under argon and the mixture was heated at 55° C. for 1 hour. It was cooled and 0.8 ml of water and 8 ml of ethyl acetate were added. The organic phase was concentrated and the residue was purified by preparative TLC (SiO2). 9.9 mg (77%) of 2-(1-benzylindazol-3-yl)-5-hydroxymethyl-4-methyl-oxazole were obtained (melting point 127-129° C.).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)[NH2:7])(=[O:3])[CH3:2].Cl[C:15]1[N:20]=[C:19]([NH2:21])[N:18]=[C:17]([NH2:22])[N:16]=1.Cl>O>[C:1]([C:4]1[CH:5]=[C:6]([NH:7][C:15]2[N:20]=[C:19]([NH2:21])[N:18]=[C:17]([NH2:22])[N:16]=2)[CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(N)cc(C(C)=O)c1
Reactant: Nc1nc(N)nc(Cl)n1
Agent: Cl
Solvent: O
Product: CC(=O)c1cc(Nc2nc(N)nc(N)n2)cc(C(C)=O)c1
Yield: 62.5 %

Procedure:
Compound No. 13: A suspension of 3,5-diacetylaniline (1.95 g) in water (10 mL) was treated with 2-chloro-4,6-diamino-1,3,5-triazine (1.455 g) and concentrated HCl (0.1 mL) and heated at reflux for 20 min. After cooling the hydrochloride of Compound No. 13 separated as a white powder. This was filtered out, dissolved in 60 mL of boiling aqueous 75% methanol and treated with triethylamine (1.5 mL). On cooling, off-white flakes separated. Filtration and drying gave 1.79 g of 2-(3,5-diacetylphenyl)amino-4,6-diamino-1,3,5-triazine, mp 271°-2° C.
Reaction SMILES: [Li].[N+:2]([CH:5]([CH3:7])[CH3:6])([O-:4])=[O:3].[N+]([C:11]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][CH2:13][CH2:12]1)([O-])=O>CN(C)P(N(C)C)(N(C)C)=O>[N+:2]([C:5]([C:11]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][CH2:13][CH2:12]1)([CH3:7])[CH3:6])([O-:4])=[O:3]
Reactant: CCOC(=O)C1([N+](=O)[O-])CCC1
Reactant: CC(C)[N+](=O)[O-]
Agent: [Li]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C1(C(C)(C)[N+](=O)[O-])CCC1
Reaction time: 3 h
Yield: 70 %

Procedure:
The lithium salt of 2-nitropropane (9.9 g.) was dissolved in 200 ml. of hexamethylphosphoramide under nitrogen and ethyl 1-nitrocyclobutanecarboxylate was added. The mixture was stirred for three hours under fluorescent lighting. The mixture was then diluted with 400 ml. of water and extracted three times with 200 ml. portions of ether. The combined ether extracts were washed three times with water, dried over magnesium sulfate, and the ethyl 1-(α-nitroisopropyl)cyclobutanecarboxylate (70 percent yield) was recovered by distillation: b.p. (0.1 mm.), 62° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.CN(C)C=O.S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:19])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1ccc(F)cc1
Temperature: 40 °C
Yield: 89.5 %

Procedure:
A solution of 150 g (0.974 mol) of 4-fluorophenylacetic acid an 1 mL of N,N-dimethylformamide in 500 mL of toluene at 40° C. was treated with 20 mL of thionyl chloride and heated to 40° C. An additional 61.2 mL of thionyl chloride was added dropwise over 1.5 hours. After the addition, the solution was heated at 50° C. for 1 hour, the solvent was removed in vacuo and the residual oil was distilled at reduced pressure (1.5 mmHg) to afford 150.4 g (89.5%) of the title compound, bp=68-70° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[S:8][C:9]=1[CH2:10]Cl)[CH2:2][CH2:3][CH3:4].[Cl:22][C:23]1[CH:30]=[C:29]([OH:31])[CH:28]=[CH:27][C:24]=1[CH:25]=[O:26].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([C:5]1[N:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[S:8][C:9]=1[CH2:10][O:31][C:29]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[C:23]([Cl:22])[CH:30]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=Cc1ccc(O)cc1Cl
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
3.2 g 4-Butyl-5-chloromethyl-2-(4-trifluoromethyl-phenyl)-thiazole and 1.5 g 2-Chloro-4-hydroxybenzaldehyde were dissolved in 150 ml dimethylformamide. 4.7 g cesiumcarbonate were added and the reaction mixture stirred at room temperature for four hours. The reaction mixture was then diluted by adding 300 ml ethyl acetate and washed three times with 50 ml water, saturated NaHCO3 solution and brine. The organic layer was dried over MgSO4 and the solvent removed in vacuo to provide 3.0 g 4-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-chloro-benzaldehyde as oil.