Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12](F)[N:11]=1.[H-].[Na+].O>O1CCCC1>[CH2:1]([O:8][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([F:9])[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: Fc1cccc(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1cccc(OCc2ccccc2)n1
Temperature: 50 °C
Yield: 100 %

Procedure:
An oven-dried 3-neck 2 L round bottom flask under nitrogen was charged with benzyl alcohol (9.04 ml, 87 mmol) and tetrahydrofuran (75 ml). Attached an addition funnel containing a solution of 2,6-difluoropyridine (10.00 g, 87 mmol) in tetrahydrofuran (30 ml). Sodium hydride (3.82 g, 96 mmol) was added in small portions with stirring. Heated in a 50° C. oil bath for 45 minutes; cooled to room temperature. Added contents of addition funnel dropwise. After 18 hours poured into water. Extracted three times with ethyl acetate, washed combined organic portions with brine, dried with anhydrous magnesium sulfate, filtered and rotary evaporated filtrate. The crude product was subjected to flash column chromatography eluting with hexane. Evaporation of fractions gave the title compound as a colorless oil. (17.70 g, 87 mmol, 100% yield). LCMS (ES+) m/z 204.3 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:6](OCC)([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:8]([O:7][CH:6]([O:10][CH2:11][CH3:12])[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[CH3:9]
Reactant: c1c[nH]cn1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(OCC)n1ccnc1
Temperature: 130 °C
Reaction time: 16 h

Procedure:
A mixture of imidazole (12.81 g), triethyl orthoformate (133 ml) and 4-toluenesulphonic acid (1 g) was stirred and heated to 130° C. for 3 hours. The mixture was stored at ambient temperature for 16 hours. The triethyl orthoformate was evaporated and the residue was distilled under vacuum to give imidazole-l-carboxaldehyde diethyl acetal (3.44 g).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29](CO)[CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34]>C1COCC1>[Br:5][CH2:1][C:29]1[CH:30]=[CH:31][C:32]([N+:33]([O-:35])=[O:34])=[C:27]([O:26][CH3:25])[CH:28]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1cc(CO)ccc1[N+](=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(CBr)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.5 %

Procedure:
Carbon tetrabromide (1.63 g, 4.9 mmol) and triphenylphosphine (1.29 g, 4.9 mmol) were added to a solution of (3-methoxy-4-nitrophenyl)methanol (0.6 g, 3.3 mmol) in THF (15 mL). The reaction mixture was stirred at room temperature for 24 hours before being concentrated under reduced pressure and purified on silica gel column chromatography eluting with 20% ethyl acetate in hexane to afford the title compound (0.67 g, 95%). 1H-NMR (500 MHz, CDCl3): δ 4.00 (s, 3H), 4.48 (s, 2H), 7.04 (dd, J=8.3 Hz, 1.7 Hz, 1H), 7.12 (d, J=1.7 Hz, 1H), 7.83 (d, J=8.3 Hz, 1H).
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1.O>N1C=CC=CC=1>[C:1]([NH:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCC(=O)Nc1ccc(C(=O)O)cc1
Reaction time: 3 h
Yield: 86.2 %

Procedure:
n-Dodecanoyl chloride (8.74 g.; 40 mmoles) is added dropwise to a solution of p-aminobenzoic acid (40 mmoles) dissolved in pyridine (100 ml.). The mixture is stirred for 3 hours and poured into water (3 l.). The precipitate which forms is filtered and dried in vacuo to give N-(n-dodecanoyl)-p-aminobenzoic acid (11.01 g.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:14][CH3:15])(=[O:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10].F[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25].Cl>C1(C)C=CC=CC=1.C(#N)C>[F:23][C:21]1[CH:20]=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[C:17]([CH:8]([C:7]([O:14][CH3:15])=[O:13])[C:9]([O:11][CH3:12])=[O:10])[CH:22]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: COC(=O)CC(=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: COC(=O)C(C(=O)OC)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 81.2 %

Procedure:
In a flask made of glass equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel and having an inner volume of 100 ml were charged 8.29 g (60.0 mmol) of potassium carbonate, 30 ml of acetonitrile, 8.09 g (60.0 mmol) of dimethyl malonate with a purity of 99% and 5.00 g (30.0 mmol) of 2,4-difluoronitrobenzene with a purity of 98% under argon atmosphere, and under stirring, the mixture was reacted at 70° C. for 10 hours. After completion of the reaction, the mixture was cooled to room temperature, 50 ml of toluene was added to the mixture, and 7.5 ml (90 mmol) of 12 mol/l hydrochloric acid was gradually added dropwise to the mixture while stirring. Then, the organic layer was separated, and washed successively with 20 ml of water and 20 ml of a saturated saline solution in this order, and dried over anhydrous magnesium sulfate. After filtration, this organic layer was analyzed (absolute quantitative method) by high performance liquid chromatography, it was found that 6.61 g (reaction yield: 81%) of dimethyl 2-(5-fluoro-2-nitrophenyl)malonate was formed.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:20]=[C:19](F)[C:18]([F:22])=[CH:17][C:9]=1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[Cl:23][C:24]1[CH:25]=[C:26]([CH2:31][OH:32])[CH:27]=[N:28][C:29]=1[Cl:30]>CS(C)=O>[Cl:23][C:24]1[CH:25]=[C:26]([CH2:31][O:32][C:19]2[C:18]([F:22])=[CH:17][C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[C:8]([F:7])[CH:20]=2)[CH:27]=[N:28][C:29]=1[Cl:30]
Reactant: OCc1cnc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)c1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1cc(F)c(OCc2cnc(Cl)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.3 %

Procedure:
Potassium carbonate (535 mg, 3.88 mmol) was added to a solution of tert-butyl 2,4,5-trifluorobenzoate (Preparation 10, 275 mg, 1.29 mmol) and (5,6-dichloropyridin-3-yl)methanol (241 mg, 1.36 mmol) in DMSO (5 mL). The reaction mixture was stirred at RT for 18 hours. After cooling the reaction mixture was quenched with water (25 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water (2×100 mL) and dried over MgSO4, filtered and concentrated in vacuo to give 490 mg of the title compound in a quantitative yield. The crude compound was used without further purification.
Reaction SMILES: N[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.N([O-])=[O:12].[Na+].C([O-])([O-])=O.[Na+].[Na+]>Cl.O>[OH:12][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1ccc2cn[nH]c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Oc1ccc2cn[nH]c2c1
Temperature: 2.5 °C
Reaction time: 0.75 h

Procedure:
To a stirred suspension of 6-aminoindazole (20 mmol) in concentrated HCl (6 mL) at 0° C. was added a solution of NaNO2 (22 mmol) in water (12 mL) in portions. During the addition, the temperature of the reaction mixture was maintained at 0-5° C., and the stirring continued for additional 45 min. The contents were then added into a flask containing 1% aqueous HCl (200 mL), and heated at 100° C. The reaction mixture was then stirred at 100° C. for 5 h. The contents were cooled to RT, neutralized to pH 7 using 5% aqueous Na2CO3, and extracted with EtOAc (2×70 mL). Combined organic layers were washed with brine and dried over anhydrous Na2SO4. Removal of solvent under vacuum provided 6-hydroxyindazole as dark brown solid, which was used for further transformation without any purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][CH:3]=1.[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: CCOP(OCC)OCC
Reactant: BrCc1ccc(Br)cc1
Product: CCOP(=O)(Cc1ccc(Br)cc1)OCC
Temperature: 90 °C
Yield: 98 %

Procedure:
1-bromo-4-(bromomethyl)benzene (5.0 g, 20 mmol) and triethyl phosphite (51 mL, 300 mmol) were mixed in a round bottom flask and refluxed at 90° C. for 19 hours. Excess triethyl phosphite was removed under reduced pressure and the product purified by flash chromatography (1:1 Hexane/EtOAc) to give compound 16. 16: 98% yield; colorless liquid; 1H NMR (400 MHz, CDCl3) δ 7.30 (d, 2H, J=7.5 Hz), 7.05 (d, 2H, J=7.6 Hz), 3.99-3.88 (m, 4H), 2.99 (s, 1H), 2.94 (s, 1H), 1.12 (t, 6H, J=106.9 Hz); 13C NMR (100 MHz, CDCl3) δ 131.7, 131.6, 131.5, 121.0, 62.3, 34.0, 32.0, 16.5; HRMS Calc for C11H16BrO3P (M+H)+ 307.0097 found 307.0093.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[CH:5]([CH2:7][OH:8])[NH2:6].CCN(CC)CC.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>ClCCl.CN(C)C1C=CN=CC=1>[OH:8][CH2:7][CH:5]([NH:6][S:25]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=1)(=[O:27])=[O:26])[C:4]([O:3][CH3:2])=[O:9]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C(N)CO
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(CO)NS(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 97.7 %

Procedure:
DL-serine methylester HCl (14,6 g, 93,8 mmol) of the Chemical Formula 5 was suspended in 400 mL of dichloromethane, and Et3N (29 Ml, 206 mmol). and a catalytic amount of 4-dimethylaminopyridine were introduced therein while maintaining the temperature at 0° C., and 4-methoxybenzene-sulfonyl chloride (19.2 g 94 mmol) was add dropwise. They were stirred at room temperature for 20 hours, washed with 200 mL of distilled water, dried, and concentrated under reduced pressure to obtain a yellow solid title compound (26.5 g, yield 97%).
Reaction SMILES: [O-2].[Ca+2:2].O.[C:4]([OH:16])(=[O:15])[CH2:5][C:6]([CH2:11][C:12]([OH:14])=[O:13])([C:8]([OH:10])=[O:9])[OH:7]>O>[C:4]([O-:16])(=[O:15])[CH2:5][C:6]([CH2:11][C:12]([O-:14])=[O:13])([C:8]([O-:10])=[O:9])[OH:7].[Ca+2:2].[C:4]([O-:16])(=[O:15])[CH2:5][C:6]([CH2:11][C:12]([O-:14])=[O:13])([C:8]([O-:10])=[O:9])[OH:7].[Ca+2:2].[Ca+2:2]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Ca+2]
Agent: [O-2]
Solvent: O
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
An aqueous solution of calcium citrate was prepared by combining 56.1 grams of calcium oxide with 210 grams of citric acid monohydrate in 532 grams of water. The mixture immediately gelled and later solidified rendering it impossible to add the acetaldehyde/diacetyl flavorant, or to spray dry the mixture.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(=[O:14])[O:13][C:11](=[O:12])[CH2:10][CH2:9]1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC1C=CC=CC=1Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:14])=[CH:4][CH:3]=1
Reactant: Fc1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: O=C(O)CCC(=O)c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 89.9 %

Procedure:
A mixture of fluorobenzene (104.4 g, 1.09 mol, Aldrich) and succinic anhydride (93.5 g, 0.93 mol) in 1,2-dichlorobenzene (530 mL) was heated to 50° C. Aluminum chloride (245 g, 1.84 mol) was added portionwise keeping the temperature below 60° C. After 4 h at 60° C. followed by 5 h at 80° C., the reaction mixture was poured into a mixture of concentrated HCl (200 mL) and ice water (2 L). The organic layer was separated and the aqueous phase was extracted with dichloromethane. The combined organic phase was dried and concentrated in vacuo. The residue was poured into hexane (2 L) and the resulting solid was filtered and washed with pentane to give 164.1 g (89%) of 3-(4-fluorobenzoyl)propionic acid as a white solid. m.p., 102-104.5° C. (lit J. Org. Chem. 26, 2667, 1961; m.p., 102.5-103.5° C.).
Reaction SMILES: N1C=CC=CC=1.Cl.[CH3:8][NH:9][O:10][CH3:11].[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>C(Cl)Cl>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([N:9]([O:10][CH3:11])[CH3:8])=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CNOC
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Pyridine (27.6 mL, 343 mmol) was added to N,O-dimethylhydroxylamine hydrochloride (16.7 g, 172 mmol) in DCM (400 mL). 4-Chlorobenzoyl chloride (20 mL, 156 mmol) was then added and the mixture was stirred at room temperature for 3 days. Solids were removed by vacuum filtration, washing with DCM. The filtrate was washed with 1 N HCl followed by water. The organic phase was dried (Na2SO4), filtered, and concentrated, affording the crude title compound as a colorless liquid which was used without purification in the next step.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]([O:9]CC)=[O:8])=[CH:5][N:6]=1.[CH3:12][O-:13].[Na+]>CC#N.CO>[CH3:12][O:13][C:2]1[O:3][C:4]([C:7]([OH:9])=[O:8])=[CH:5][N:6]=1
Reactant: C[O-]
Reactant: CCOC(=O)c1cnc(Cl)o1
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: COc1ncc(C(=O)O)o1
Yield: 69.9 %

Procedure:
To a solution of ethyl 2-chlorooxazole-5-carboxylate (510 mg, 2.90 mmol) in anhdryous MeCN (10 mL) and anhydrous MeOH (10 mL) is added NaOMe (628 mg, 11.62 mmol). The crude is stirred at reflux for 2 hrs. To this crude is added additional MeOH. The crude is refluxed for another 4 hrs. The crude is concentrated and is redissolved in MeOH (10 mL). To this crude is added 1 N NaOH (10 ml). The crude is stirred at room temperature for 3 hrs. The crude is quenched with concentrated HCl, PH adjusted to 7 via PH paper indicator. The crude is concentrated and diluted in water. The aq. layer is acidified with concentrated HCl and diluted in EtOAc. The organic layer is washed with water, brine, dried over MgSO4, filtered, and concentrated to give 2-methoxyoxazole-5-carboxylic acid (290 mg). HPLC retention time=0.58 minutes (condition D); MS (m+1)=144.0.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[CH:10](OCC)=[O:11].CC(C)([O-])C.[K+]>>[OH:11]/[CH:10]=[C:4]1/[C:5](=[O:8])[CH2:6][CH2:7][C:2]([CH3:9])([CH3:1])[CH2:3]/1
Reactant: CC1(C)CCC(=O)CC1
Reactant: CCOC=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CC1(C)CCC(=O)/C(=C/O)C1

Procedure:
reacting 4,4-dimethylcyclohexanone, ethyl formate and potassium tert-butoxide at about −10° C. to about 0° C. to provide (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone and isolating or not isolating the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone;
Reaction SMILES: C([O:3][C:4](=[O:22])/[C:5](/[CH3:21])=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:8]=1)C.O[Li].O>CO.O>[CH:16]1([O:15][C:9]2[CH:8]=[C:7](/[CH:6]=[C:5](\[CH3:21])/[C:4]([OH:22])=[O:3])[CH:12]=[CH:11][C:10]=2[O:13][CH3:14])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CCOC(=O)/C(C)=C/c1ccc(OC)c(OC2CCCC2)c1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: COc1ccc(/C=C(\C)C(=O)O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66 %

Procedure:
A suspension of (E)-3-(3-cyclopentoxy-4-methoxyphenyl)-2-methyl-acrylic acid ethyl ester (30 g, 98.6 mmol) and LiOH.H2O (lithium hydroxide hydrate) (5.0 g, 119.2 mmol, 1.2 equiv.) in methanol-water (4:1, 100 mL) was stirred at room temperature for 24 hours. Methanol was removed under reduced pressure and the resulting residue was dissolved in water (100 mL), washed with three 100 mL portions of ethyl acetate, neutralized with 1.0 N HCl (hydrochloric acid) (100 mL), and extracted with two 150 mL portions of ethyl acetate. The extract was washed with brine, dried over anhydrous Na2SO4 (sodium sulfate), and concentrated under reduced pressure to afford the desired product as a light yellow powder (18.2 9, 66% yield). 1H NMR (300 MHz, CDCl3) δ (ppm): 12.4 (br. s, 1H, COOH), 7.56 (s, 1H, olefinic), 7.04 (m, 3H, aromatic), 4.81 (m, 1H), 3.78 (s, 3H, OCH3), 2.06 (s, 3H, CH3), 1.91-1.57 (m, 8H, cyclopentyl).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([OH:10])=[C:5]([Cl:11])[CH:4]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>O>[Cl:9][C:7]1[CH:8]=[C:3]([CH:4]=[C:5]([Cl:11])[C:6]=1[OH:10])[NH:2][C:12](=[O:14])[CH3:13]
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: O
Product: CC(=O)Nc1cc(Cl)c(O)c(Cl)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Into a 500 ml round bottom flask (fitted with a magnetic stirrer), water (200 ml) was mixed with 4-amino-2,6-dichlorophenol hydrochloride (20 g) until the solid was completely dissolved. The resulting solution was warmed to 70° C., and to it was added acetic anhydride (11 g) and the resulting solution was stirred for 1 hour. Upon cooling, crystals of 3', 5'-dichloro-4'-hydroxyacetanilide formed (19.6 g, 95% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: Cc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
1-(tert-Butoxycarbonyl)-4-piperidone (5.00 g) and p-toluidine (2.56 g) was treated in the same manner as described in Preparation Example 37 to give white powder of the title compound.
Reaction SMILES: [Mg].[F:2][C:3]([F:12])([F:11])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.C([O:16][B:17](OC(C)C)[O:18]C(C)C)(C)C.Cl>CCOCC.C1COCC1.CCOCC>[F:2][C:3]([F:12])([F:11])[C:4]1[CH:9]=[CH:8][C:7]([B:17]([OH:18])[OH:16])=[CH:6][CH:5]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.8 %

Procedure:
An oven dried Schlenk tube was charged with magnesium turnings (766 mg, 31.5 mmol), evacuated, and backfilled with argon. To the reaction vessel was added 10 mL of ether followed by 4-(trifluoromethyl)phenyl bromide (4.20 mL, 30.0 mmol). The reaction mixture was stirred without external heating for 1 hour, during which time an exotherm occurred and then subsided. The solution was diluted with ether (10 mL) and transferred via cannula to a flask containing triisopropylborate (13.8 mL, 60.0 mmol) in 1:1 THF/ether (20 mL) at −78° C. The resulting reaction mixture was kept at −78° C. for 15 minutes and then was allowed to warm to room temperature. After stirring at room temperature for 15 minutes, the reaction mixture was poured onto 2.0 M HCl (60 mL). The mixture was transferred to a separatory funnel, extracted with ethyl acetate (60 mL), washed with water (60 mL), and brine (60 mL). The organic solution was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude material was dissolved in 2:1 hexane/ethyl acetate (90 mL) and activated charcoal was added. The mixture was filtered and the product crystallized upon cooling. The crystals were collected by filtration to afford 1.98 g (35%) of pale yellow needles.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[C:3]=1[CH3:9].[OH-:10].[K+].O>CO>[Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([OH:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1Cl
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1c(O)cccc1Cl

Procedure:
8.1 g (0.05 mol) of 2,6-dichlorotoluene and 9.9 g (0.15 mol) of potassium hydroxide (85%) are heated in 40 ml of methanol in an autoclave at 200° C. for 20 hours, which results in a pressure of 30 bar. After cooling, the reaction mixture is poured into 250 ml of water and extracted three times with 70 ml of dichloromethane. The aqueous phase is acidified to pH 1-2 with 30% hydrochloric acid and again extracted three times with 70 ml of dichloromethane each time. The united organic phases are dried over sodium sulphate and evaporated under reduced pressure to give a solid. 3-Chloro-2-methylphenol is obtained as a solid (6.2 g, content by HPLC: 93.5%, 82% of theory).
Reaction SMILES: [ClH:1].O[CH2:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH3:9].Cl.[NH2:11][CH2:12][CH2:13][SH:14]>C(O)(=O)C>[ClH:1].[ClH:1].[CH3:9][C:8]1[N:7]=[CH:6][NH:5][C:4]=1[CH2:3][S:14][CH2:13][CH2:12][NH2:11]
Reactant: Cc1[nH]cnc1CO
Reactant: NCCS
Agent: Cl
Solvent: CC(=O)O
Product: Cc1nc[nH]c1CSCCN
Yield: 184.6 %

Procedure:
(i)(a) A solution of 4-hydroxymethyl-5-methylimidazole hydrochloride (30.0 g.) and cysteamine hydrochloride (23.0 g.) in acetic acid (200 ml.) was heated under reflux for 10 hours. Following cooling to 15°-20°, the solid which crystallised was collected and washed with isopropyl alcohol to give 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole dihydrochloride (45.5 g.), m.p. 189°-192°.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH:11]([N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)[CH:12]([N:15]([CH3:17])[CH3:16])[CH2:13][CH3:14])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:23][O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)=[O:26].C(=O)([O-])[O-].[K+].[K+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:16][N:15]([CH3:17])[CH:12]([CH2:13][CH3:14])[CH:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([C:30]3[CH:31]=[CH:32][C:27]([C:25]([O:24][CH3:23])=[O:26])=[CH:28][CH:29]=3)[S:3][C:4]=2[CH:10]=1)[N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CCC(C(c1ccc2nc(Br)sc2c1)n1ccnc1)N(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCC(C(c1ccc2nc(-c3ccc(C(=O)OC)cc3)sc2c1)n1ccnc1)N(C)C
Temperature: 80 °C

Procedure:
A mixture of 1-(2-bromobenzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethylbutan-2-amine (663 mg, 1.75 mmol), (4-(methoxycarbonyl)phenyl)boronic acid (409 mg, 2.275 mmol), tetrakis(triphenylphosphine)palladium (505 mg, 0.437 mmol), potassium carbonate (725 mg, 5.25 mmol), DME (25 mL) and water (5 mL) was degassed, filled with N2, and heated to 80° C. for 3 h. The reaction mixture was evaporated, dissolved in 10% methanol in DCM, loaded onto a PTLC plate and eluted with 6% methanol in DCM to yield methyl 4-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate. MS ESI: m/z 435.19 [M+1+].
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][NH2:5].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[CH2:13]([NH:5][CH2:4][CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]([CH3:12])[CH3:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)C(CN)c1ccccc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)C(CNCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The title compound is prepared from 3-methyl-2-phenyl-butylamine and benzaldehyde: A solution of 3-methyl-2-phenyl-butylamine (1.3 g, 8 mmol) and benzaldehyde (0.81 mL, 8 mmol) in CH2Cl2 (50 mL) is stirred at RT for 20 min. Sodium triacetoxyborohydride (2.52 g, 11.3 mmol) is then added, followed by acetic acid (0.46 mL, 8 mmol). The reaction mixture is stirred at RT for 16 h, then quenched by the addition of saturated NaHCO3 solution. The organic layer is separated and the aqueous phase is extracted twice with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated. The residue is purified by flash chromatography (hexane/ethyl acetate) to afford benzyl-(3-methyl-2-phenyl-butyl)-amine as a colourless oil. MS: 254.3 [M+H]+; tR (HPLC, C18 column; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.03 min.