Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)=[CH2:2].C(C1C=CC(O)=CC=1)C.C1(O)C=CC=CC=1.C1C(O)=CC=C(C)C=1.C(O)(=O)C(O)=O>O>[CH:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1
Reactant: C=Cc1ccc(O)cc1
Agent: CCc1ccc(O)cc1
Agent: Cc1ccc(O)cc1
Agent: O=C(O)C(=O)O
Solvent: Oc1ccccc1
Solvent: O
Product: C#Cc1ccc(O)cc1
Temperature: 180 °C

Procedure:
409.8 g of a mixture consisting of 21.4% of p-vinylphenol, 59.8% of p-ethylphenol, 1.5% of phenol, 7.7% of p-cresol and 9.6% of water was introduced, over 30 minutes, into a rotary evaporator heated at 180° C. under a vacuum of 6 mmHg, and vacuum flash distillation was conducted. 364.2 g of a distillate was obtained and its composition was 21.3% of p-vinylphenol, 61.6% of p-ethylphenol, 1.5% of phenol, 7.8% of p-cresol and 7.8% of water. 132.4 g of this p-vinylphenol fraction was mixed, without being dehydrated, with 0.12 ml of a 0.5 M aqueous oxalic acid solution. The -resulting mixture was polymerized at 45° C. for 6 hours. The reaction mixture was treated in the same manner as in Example 1 to obtain 26.2 of a poly(p-vinylphenol). The polymer had a Mw of 10,470, Mn of 7,180, a light transmittance at 248 nm, of 70.5% and glass transition temperature of 173° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][CH:8]=[N:9]2)=[C:4]([O:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:3]=1.P(Cl)(Cl)([Cl:22])=O.C(N(C(C)C)CC)(C)C>ClCCCl>[Cl:22][C:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[CH:3][C:4]=2[O:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:9]=[CH:8][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2cc(F)cc(OC3CCOCC3)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Fc1cc(OC2CCOCC2)c2c(Cl)ncnc2c1
Temperature: 80 °C

Procedure:
A mixture of 7-fluoro-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (1 g), phosphoryl chloride (4 ml), diisopropylethylamine (1.5 ml) and 1,2-dichloroethane (15 ml) was stirred and heated to 80° C. for 3 hours. The mixture was evaporated to give 4-chloro-7-fluoro-5-tetrahydropyran-4-yloxyquinazoline which was used without further purification.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1([CH3:18])[CH:14]=[CH:13][CH:12]=[C:11]([C:15](Cl)=[O:16])[CH:10]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(=S)=S>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([CH3:18])[CH:10]=2)=[O:16])=[CH:3][CH:2]=1
Reactant: COc1ccccc1
Reactant: Cc1cccc(C(=O)Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COc1ccc(C(=O)c2cccc(C)c2)cc1
Temperature: 10 °C
Reaction time: 3 h
Yield: 87.8 %

Procedure:
In sequence, 1,000 mL of carbon disulfide, 384 g (3.55 mole; 10% excess) of anisole, and 500 g (3.23 mole) of m-toluoyl chloride were placed in a 5 L flask, and the contents were cooled to about 10° C. Then 500 g AlCl3 was added in small increments with stirring over a 3 hr period. The stirred mixture was kept at room temperature for 2 days during which 500 mL more of carbon disulfide was added by maintain fluidity. After adding ice-water to decompose the complex, carbon disulfide was removed by steam distillation and the product was extracted with methylene chloride. The extract was washed with water and then distilled at 170° C./1.2 mm Hg to yield 642 g of 4-methoxy-3'-methylbenzophenone. Half of the product (1.42 mole) was mixed with 1500 mL of pyridine and a solution of 75 g sodium hydroxide in 1500 mL of water. This mixture was heated to 80°-90° C. and 500 g potassium permanganate was added stepwise over a 4 hr period. Refluxing continued one more hour. Sludge was filtered out and washed well with hot water. Acidification of the filtrate yielded a precipitate of 4-methoxy-3'-carboxybenzophenone. After recrystallization from ethanol, melting temperature was 183°-186° C. A total of 392 g (1.53 mole) of so prepared 4-methoxy-3'-carboxybenzophenone was added to a premixture of 1150 mL of 48% HBr/575 mL acetic anhydride/575 mL acetic acid, and the mixture was refluxed for 15 hr. Pouring the contents into water precipitated 4-hydroxy-3'-carboxybenzophenone which, after filtration and drying, yielded 350 g (1.45 mole) of crude product. Mixing this product with 1050 mL of acetic anhydride containing 1.5 mL of concentrated sulfuric acid and heating for 30 min at 100° C. yielded 4-acetoxy-3'-carboxybenzophenone which was isolated by precipitation in excess ice-water, filtration, and drying. Recrystallization first from dioxane and then chloroform provided 4-acetoxy-3'-carboxybenzophenone melting at 190°-193° C.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C@H:4]1[C:6]([CH3:8])([CH3:7])[C@H:5]1[C:9]([OH:11])=[O:10].C(S)CCC>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:12])=[CH:3][CH:4]1[C:6]([CH3:7])([CH3:8])[CH:5]1[C:9]([OH:11])=[O:10]
Reactant: CC(C)=C[C@@H]1[C@H](C(=O)O)C1(C)C
Solvent: CCCCS
Solvent: Cc1ccccc1
Product: CC(C)=CC1C(C(=O)O)C1(C)C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of cis chrysanthemic acid (1.0 g) in toluene (9 g) was added butanethiol (107 mg). Irradiation with a high pressure mercury lamp (100 W) was made for one hour. After the reaction was over, similar after-treatment as in Example 1 was applied to obtain chrysanthemic acid (0.9 g). A part of the product was converted to ethyl ester in a usual manner. Gas chromatography assay of the product gave the following isomer ratio: cis, 5.2%; and trans, 94.8%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C@@:8]2([CH3:15])[NH:13][C:12](=O)[CH2:11][O:10][CH2:9]2)[CH:7]=1.F[B-](F)(F)F.C[O+](C)C.[Cl-].[NH4+:27]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C@:8]2([CH3:15])[CH2:9][O:10][CH2:11][C:12]([NH2:27])=[N:13]2)[CH:7]=1
Reactant: [NH4+]
Reactant: C[C@@]1(c2cc(Br)ccc2F)COCC(=O)N1
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Product: C[C@@]1(c2cc(Br)ccc2F)COCC(N)=N1

Procedure:
In analogy to step a) in the synthesis of building block D, the treatment of (R)-5-(5-bromo-2-fluoro-phenyl)-5-methyl-morpholin-3-one with trimethyloxonium tetrafluoroborate followed by the nucleophilic substitution with ammonium chloride yielded the title compound; its hydrochloride was obtained as a white solid (74%). Mass (calculated) C11H12BrFN2O [287.13]; (found) [M+H]+=287, [M+2+H]+=289.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]([F:10])[C:7]=1[CH2:8][OH:9].Cl[C:13]([F:18])([F:17])C([O-])=O.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.C(OCC)(=O)C>[F:17][CH:13]([F:18])[O:11][C:4]1[CH:3]=[C:2]([F:1])[C:7]([CH2:8][OH:9])=[C:6]([F:10])[CH:5]=1
Reactant: OCc1c(F)cc(O)cc1F
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: OCc1c(F)cc(OC(F)F)cc1F
Temperature: 100 °C
Yield: 56 %

Procedure:
500 mg 3,5-difluoro-4-(hydroxymethyl)phenol (3.12 mmol, 1.0 eq.) were dissolved in DMF. 523 mg sodium chloro(difluoro)acetate (3.44 mmol, 1.1 eq.), 1.22 g cesium carbonate (3.75 mmo, 1.2 eq) and 0.20 mL water (10.9 mmol, 3.5 eq.) were added. The reaction mixture was stirred at 100° C. over night. The reaction mixture was divided between water and ethyl acetate. The aqueous layer was washed twice with ethyl acetate. The combined organic layers were washed with brine, dried over a silicon filter and concentrated in vacuo. The crude product was purified by flash chromatography to provide 161 mg (0.69 mmol, 22%) of the 56% pure target compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9]([S:11]([CH:14]=[CH2:15])(=[O:13])=[O:12])=[CH2:10].C(O)(=O)C>C(O)C>[O:12]=[S:11]1(=[O:13])[CH2:14][CH2:15][N:1]([C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)[CH2:10][CH2:9]1
Reactant: C=CS(=O)(=O)C=C
Reactant: Nc1ccc(O)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: O=S1(=O)CCN(c2ccc(O)cc2)CC1
Temperature: 0 °C

Procedure:
The preparation of stabilizer compounds of formula S of the invention is illustrated by the following synthesis of Stabilizer S-3. ##STR16## A mixture of para-aminophenol (25 g, 229 mmol) and divinylsulfone (32.5 g, 275 mmol) was heated at reflux in ethanol (100 ml) for two days. The reaction mixture was cooled and poured into ice water (1 l). The mixture was made acidic with the addition of acetic acid and the resulting tan solid was isolated by filtration and washed with water. Recrystallization from methanol afforded the desired 4-(1',1'-dioxothiomorpholino)phenol as a light tan crystalline solid (35 g, 67%). Mp. 149-151° C.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].S(=O)(=O)(O)O.[CH3:17]O>>[OH:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[I:1])[C:6]([O:8][CH3:17])=[O:7]
Reactant: O=C(O)c1ccc(I)c(O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(I)c(O)c1

Procedure:
4-Iodo-3-hydroxybenzoic acid (VI) is esterified with methanol in the presence of sulphuric acid in order to provide methyl 3-hydroxy-4-iodobenzoate (VII).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:12])=[C:4]([C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)[CH:5]=O.[C:13](#[N:16])[CH:14]=[CH2:15]>>[C:13]([C:14]1[CH2:15][O:12][C:3]2[C:4]([CH:5]=1)=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:2]=2[F:1])#[N:16]
Reactant: COc1ccc(F)c(O)c1C=O
Reactant: C=CC#N
Product: COc1ccc(F)c2c1C=C(C#N)CO2
Yield: 13.6 %

Procedure:
Crude 3-fluoro-hydroxy-6-methoxybenzaldehyde (8.0 g) from above, acrylonitrile (13 mL; 193 mmol) and 1,4.diazadicyclo[2,2,2]octane (0.66 g; 5.9 mmol) were refluxed in a three-necked round-bottom flask (50 mL) under nitrogen for 4 h. Rotary-evaporation of the volatiles left a thick, red oil which was flash-chromatographed on a silica column eluted with methylene chloride/n-hexane (4:5). Concentration of relevant fractions gave an impure product (91% GC) which was crystallized form EtOAc to give 1.31 g of the title compound as colourless bars. Mp. 133°-135° C.
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[O:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[C:18]([O:22][C:23](=[O:26])[CH2:24]Br)([CH3:21])([CH3:20])[CH3:19].[H-].[Na+]>>[C:18]([O:22][C:23](=[O:26])[CH2:24][N:13]1[C:14]2[C:10](=[CH:9][CH:8]=[C:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:17])[CH3:16])[CH:15]=2)[CH:11]=[CH:12]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc[nH]c2c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)Cn1ccc2ccc(O[Si](C)(C)C(C)(C)C)cc21

Procedure:
In analogy to the procedure described in example 1 b], 6-(tert-butyl-dimethyl-silanyloxy)-1H-indole was reacted with bromo-acetic acid tert-butyl ester in the presence of sodium hydride to obtain [6-(tert-butyl-dimethyl-silanyloxy)-indol-1-yl]-acetic acid tert-butyl ester as colorless liquid.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)=[O:11])[CH2:5][CH2:4]1.[Cl:33][Si](C)(C)C>CC(CC)=O>[ClH:33].[CH3:32][N:2]([CH3:1])[C:3]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:4][CH2:5][C:6](=[CH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)=[O:11])[CH2:7][CH2:8]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccc2)CCC(=CC(=O)NCCCCc2c[nH]c3ccccc23)CC1
Solvent: CCC(C)=O
Product: Cl

Procedure:
2-(4-Dimethylamino-4-phenylcyclohexylidene)-N-[4-(1H-indol-3-yl)butyl]acetamide (184 mg, 0.428 mmol) was dissolved in ethyl methyl ketone (10 ml), and chlorotrimethylsilane (0.08 ml, 0.64 mmol) was added. After 1.5 h the hydrochloride was isolated as a colourless solid with an m.p. of 185-188° C. in a yield of 74% (147 mg).
Reaction SMILES: O.C[Si]([Cl:6])(C)C.[CH3:7][N:8]([CH2:10][CH:11]1[CH:17]2[CH2:18][CH:14]([CH2:15][CH2:16]2)[CH:13]=[C:12]1[C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1)[CH3:9]>CC(=O)CC>[ClH:6].[CH3:9][N:8]([CH2:10][CH:11]1[CH:17]2[CH2:18][CH:14]([CH2:15][CH2:16]2)[CH:13]=[C:12]1[C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1)[CH3:7]
Reactant: C[Si](C)(C)Cl
Agent: CN(C)CC1C(c2cccc(O)c2)=CC2CCC1C2
Solvent: CCC(C)=O
Solvent: O
Product: Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Add H2O (392 mg, 21.8 mmol) and TMSCl (1.4 g, 12.9 mmol) to a solution of 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-phenol (2.8 g, 10.9 mmol) in 2-butanone (200 mL). Stir the reaction mixture at ambient temperature for 12 hours. Collect the precipitate by filter, and wash with EtOAc (30 mL×2), dry under vacuum to give 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-phenol hydrochloride as white solid (2.41 g, Yield: 75.5%). 1H NMR (400 MHz, D2O) δ 7.20-7.24 (t, J=15.6, 1H), 6.76-6.81 (m, 2H), 6.72 (s, 1H), 6.15 (d, J=6.4, 1H), 3.58-3.61 (d, J=12.8, 1H), 3.08-3.14 (t, J=26.0, 1H), 2.89-2.92 (m, 1H), 2.88 (s, 3H), 2.76 (s, 3H), 2.56 (m, 1H), 2.45 (m, 1H), 1.72-1.83 (m, 6H).
Reaction SMILES: C1C2N(C(=O)C[C@@H](CCC)C(O)=O)C3C(=CC=CC=3)C=2C=CC=1.C([O:28][C:29](=[O:59])[CH2:30][CH:31]([NH:36][C:37](=[O:58])[CH:38]([CH2:42][C:43]([N:45]1[C:57]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[C:51]2[C:46]1=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:44])[CH2:39][CH2:40][CH3:41])[C:32](=[O:35])[CH2:33][F:34])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:56]1[C:57]2[N:45]([C:43](=[O:44])[CH2:42][CH:38]([CH2:39][CH2:40][CH3:41])[C:37]([NH:36][CH:31]([C:32](=[O:35])[CH2:33][F:34])[CH2:30][C:29]([OH:59])=[O:28])=[O:58])[C:46]3[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:52]=2[CH:53]=[CH:54][CH:55]=1
Reactant: CCCC(CC(=O)n1c2ccccc2c2ccccc21)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CF
Agent: CCC[C@H](CC(=O)n1c2ccccc2c2ccccc21)C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC(CC(=O)n1c2ccccc2c2ccccc21)C(=O)NC(CC(=O)O)C(=O)CF
Reaction time: 2 h
Yield: 5.6 %

Procedure:
A solution of [3S/R, (2R)]-3-[2-(2-carbazol-9-yl-2-oxo-ethyl)-pentanoylamino]-5-fluoro-4-oxo-pentanoic acid tert-butyl ester (1.43 g, 2.88 mmol) in anhydrous DCM (20 ml) was treated with a solution of TFA (10 ml) in anhydrous DCM (10 ml) with stirring. The mixture was stirred at 0° C. for 2 h then at room temperature for 2 h. The mixture was concentrated under reduced pressure and then the residue was dissolved in dry DCM. This process was repeated several times in order to remove excess trifluoroacetic acid. The off-white solid was recrystallized from Et2O/40/60 hexanes to give the title compound as a white powder (71 mg): IR (solid, cm−1) 1746, 1689, 1641, 1541, 1436, 1374, 1284, 1207, 1160 cm-1; 1H NMR (400 MHz, d6-DMSO) δ 0.80-1.00 (3H, m), 1.20-1.76 (4H, m), 2.30-2.90 (2H, m), 2.95-3.24 (1H, m), 3.26-3.59 (2H, m), 4.25-4.79 (1.5H, m) 5.02-5.43 (1.5H, m), 7.36-7.58 (4H, m), 8.10-8.30 (4H, m), 8.54-8.91 (1H, m); 13C NMR (100 MHz, DMSO) δ 14.31, 20.03, 20.13, 21.92, 22.51, 34.36, 34.77, 41.20, 41.62, 44.06, 51.77, 52.84, 83.45, 85.22, 116.70, 120.54, 123.91, 124.01, 127.85, 126.01, 138.20, 172.15, 172.36, 172.96, 173.00, 175.32, 175.48, 202.60, 203.10; 19F (376 MHz, DMSO) δ −226.68, −226.73, −231.21, −232.95, −233.38, −233.52.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([CH3:14])([CH3:13])[CH2:5]2.[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH:16]=[CH2:17].CCN(C(C)C)C(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:13][C:6]1([CH3:14])[C:7](=[O:12])[NH:8][C:9]2[N:10]=[CH:11][C:2](/[CH:17]=[CH:16]/[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:3][C:4]=2[CH2:5]1
Reactant: CC1(C)Cc2cc(Br)cnc2NC1=O
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)/C=C/c1cnc2c(c1)CC(C)(C)C(=O)N2
Temperature: 125 °C
Yield: 77.8 %

Procedure:
To a stirred solution of 6-bromo-3,3-dimethyl-3,4-dihydro-1,8-naphthyridin-2(1H)-one (Intermediate-7) (1.3 g, 5.10 mmol), tert-butyl acrylate (3.26 g, 25.50 mmol) in DMF/propionitrile (5 mL/20 mL) was added DIPEA (2.7 mL, 15.30 mmol) at 20-35° C. and the mixture was degassed with N2 for 10 minutes. Then Pd(OAc)2 (114 mg, 0.51 mmol), P(o-tolyl)3 (310 mg, 1.02 mmol) were added, again degassed with N2 for another 10 minutes and heated at 125° C. for 16 h. The reaction mixture was cooled to 20-35° C. and filtered through Celite®. The filtrate was rotary evaporated under vacuum to get residue which was purified by column chromatography using a mixture of 80% ethyl acetate/hexane as an eluent to get the desired compound as a pale yellow solid (1.2 g, 78%); 1H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.37 (d, J=2.0 Hz, 1H), 8.02 (d, J=1.0 Hz, 1H), 7.50 (d, J=15.6 Hz, 1H), 6.51 (d, J=16.1 Hz, 1H), 2.78 (s, 2H), 1.48 (s, 9H), 1.07 (s, 6H).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[Cl:5][C:6]1[S:7][C:8]([CH:12]=O)=[C:9]([Cl:11])[N:10]=1>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:5][C:6]1[S:7][C:8]([CH:12]2[O:4][CH2:1][CH2:2][O:3]2)=[C:9]([Cl:11])[N:10]=1
Reactant: OCCO
Reactant: O=Cc1sc(Cl)nc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1nc(Cl)c(C2OCCO2)s1
Yield: 96.2 %

Procedure:
Ethylene glycol (7.0 ml, 125.5 mmol) and p-toluenesulfonic acid monohydrate (0.56 g, 2.94 mmol) are added to a solution of 2,4-dichloro-thiazole-5-carboxaldehyde (7.88 g, 43.3 mmol) in toluene (100 ml). The reaction is heated at reflux and water removed via Dean-Stark for 4 h. The reaction is cooled, poured into 20% Na2CO3 (200 ml), and extracted with ethyl acetate (3×100 ml). The ethyl acetate is washed with aqueous saturated brine solution and dried over anhydrous Na2SO4. The solid is filtered off and the filtrate concentrated. The crude product is purified by flash chromatography on silica gel eluting with 10% ethyl acetate/hexanes to yield (9.42 g, 96%) of 2,4-dichloro-5-([1,3]dioxolan-2-yl)-thiazole: 1H NMR (CDCl3): δ=6.07 (1H, s), 4.18-3.99 (4H, m).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH:13]2[CH2:25]O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[K+]>C(Cl)(Cl)(Cl)Cl.O>[Cl:3][CH2:25][CH:13]1[CH2:14][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:16][CH2:17][N:12]1[CH2:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: O=S(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: ClCC1CN(Cc2ccccc2)CCN1Cc1ccccc1

Procedure:
To a solution of 10.1 ml of thionyl chloride in 50 ml of carbon tetrachloride was added, with stirring, a solution of 22.15 g of 1,4-bis(phenylmethyl)-2-piperazinemethanol in 120 ml of carbon tetrachloride. This mixture was stirred in an oil bath at 70° C. for one hour, then cooled in an ice bath and a solution of 17.1 g of potassium hydroxide in 50 ml of water was added. The mixture was extracted several times with dichloromethane. The extracts were combined, filtered through hydrous magnesium silicate and evaporated. The residual gum was dissolved in warm heptane, filtered and evaporated to an oil which crystallized on standing, giving 17.94 g of 2-chloromethyl-1,4-bis(phenylmethyl)piperazine, mp 54°-56° C.
Reaction SMILES: N1C=CC=CC=1.Cl.[CH3:8][NH:9][O:10][CH3:11].[C:12](Cl)(=[O:16])[CH2:13][CH2:14][CH3:15]>C(Cl)Cl.O>[CH3:11][O:10][N:9]([CH3:8])[C:12](=[O:16])[CH2:13][CH2:14][CH3:15]
Reactant: CNOC
Reactant: CCCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCC(=O)N(C)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
Pyridine (100 mL) was cooled to 0° C., and N,O-dimethylhydroxylamine hydrochloride (20.14 g, 206 mmol) was added with stirring. This solution was stirred for 10 minutes, and then a solution of butyryl chloride (19.5 ml, 20 g, 188 mmol) dissolved in 50 ml methylene chloride was added via addition funnel over 30 minutes. A precipitate formed after 5 minutes. This suspension was stirred and allowed to warm to room temperature. Stirring was continued for 2.0 hours, and the reaction was diluted with water, extracted with methylene chloride twice. The methylene chloride layers were combined and washed with 1 N HCl twice and once with brine. Diethyl ether (100 mL) was added to facilitate emulsion separation, and the organic layer was separated and washed with saturated bicarbonate solution, brine, and dried over magnesium sulfate. The solution was filtered and the solvent removed in vacuo to give N-Methoxy-N-methyl-butyramide as an oil (22.1 g, 89% ).
Reaction SMILES: [O-]CC.[Na+].Cl.[NH2:6][OH:7].C(O)C.[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]#[N:17]>C1CCCCC1.CCCCC>[OH:7][NH:6][C:16]([C:12]1[S:11][CH:15]=[CH:14][CH:13]=1)=[NH:17]
Reactant: N#Cc1cccs1
Reactant: NO
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: CCCCC
Solvent: CCO
Product: N=C(NO)c1cccs1

Procedure:
A solution of sodium ethoxide (21% by weight in ethanol, 64.9 ml, 0.174 mol, 1.1 eq.), hydroxylamine hydrochloride (12.1 g, 0.174 mol, 1.1 eq.) and ethanol (100 ml) was refluxed for 30 minutes. Thiophene-2-carbonitrile (18.8 g; 0.172 mol; 1 eq.) was then added and the solution was refluxed continuously for 18 hours. The reaction was monitored by thin layer chromatography (TLC) (50/50 cyclohexane/pentane). The solution was evaporated under reduced pressure and the residue obtained triturated in water at pH 7. The aqueous phase, saturated beforehand with NaCl, was then extracted with ethyl ether (three times). The organic phases were combined, dried over MgSO4 and concentrated under reduced pressure to give a white powder.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH3:2].[CH3:16][NH2:17].[BH4-].[Na+]>CO>[CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:17][CH3:16])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CN
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(OCC)c1ccc(CNC)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 98.5 %

Procedure:
A mixture of 4-(diethoxymethyl)benzaldehyde (1.04 g, 5 mmol) and methylamine (27-32% solution in methanol, 2.3 g, 20 mmol) in methanol (20 mL) was stirred at room temperature for 40 mins. The mixture was cooled to 0° C., sodium borohydride (0.284 g, 7.5 mmol) was added portionwise. After the addition, the mixture was stirred at room temperature for 4 hr. Methanol was removed under reduced pressure. The residue was partitioned between water (50 mL) and ethyl acetate (50 mL). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude 1-(4-(diethoxymethyl)phenyl)-N-methylmethanamine (1.1 g) as a light yellow oil which was used in the next step without further purification. LC-MS (ESI) m/z: 224 (M+1)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][CH:10]([NH:13]C(=O)OC(C)(C)C)[CH2:9][CH2:8]1.C1COCC1.CO.[ClH:28]>O1CCOCC1>[ClH:28].[ClH:28].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][CH:10]([NH2:13])[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccccn2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CO
Product: NC1CCN(c2ccccn2)CC1
Yield: 85 %

Procedure:
A solution of tert-butyl (1-pyridin-2-ylpiperidin-4-yl)carbamate (0.64 g, 2.31 mmol) in HCl in Dioxane (4M, 3.5 ml), THF (2.5 ml) and MeOH (2 ml) was stirred at rt for 17 h. The reaction mixture was filtered, the residue washed with EtOAc and dried to give the title compound (0.49 mg, 85%) as a solid. 1H NMR (500 MHz, D2O): 7.91 (dd, 1H), 7.78 (d, 1H), 7.22 (d, 1H), 6.88 (t, 1H), 4.12 (d, 2H), 3.56-3.48 (m, 1H), 3.26 (t, 2H), 2.15 (d, 2H), 1.67 (dq, 2H); 13C NMR (D2O): 152.1, 144.7, 135.9, 113.3, 47.6, 44.7, 28.8; Mass Spectrum: M+H 178