Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[CH3:12].C([O:16][C@@H:17]1[C@@H:30]([O:31]C(=O)C)[C@H:29]([O:35]C(=O)C)[CH2:28][S:27][C@H:18]1[O:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24](Br)[CH:25]=1)(=O)C>>[O:19]([C:20]1[CH:21]=[N:22][CH:23]=[C:24]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:12])[CH:5]=2)[CH:25]=1)[C@@H:18]1[S:27][CH2:28][C@@H:29]([OH:35])[C@H:30]([OH:31])[C@H:17]1[OH:16]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Reactant: COc1ccc(B(O)O)cc1C
Product: COc1ccc(-c2cncc(O[C@@H]3SC[C@@H](O)[C@H](O)[C@H]3O)c2)cc1C

Procedure:
By following a procedure analogous to Example 122 starting from 4-methoxy-3-methylphenylboronic acid and 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, 5-(4-methoxy-3-methylphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=21%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH:9]([N:11]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:12]([NH:14][C@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])=[O:13])[CH3:10])=[CH:4][N:3]=1.CC(C)([O-])C.[K+]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[N:14]([C@H:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH3:16])[C:12](=[O:13])[N:11]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[CH:9]([CH3:10])[C:5]2=[CH:4][N:3]=1
Reactant: COc1ccc(N(C(=O)N[C@@H](C)c2ccccc2)C(C)c2cnc(Cl)nc2Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(N2C(=O)N([C@@H](C)c3ccccc3)c3nc(Cl)ncc3C2C)cc1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
A solution of 1-[1-(2,4-dichloro-pyrimidin-5-yl)-ethyl]-1-(4-methoxy-phenyl)-3-[1-(S)-phenyl-ethyl]-urea (less polar diastereomer, 250 mg, 0.56 mmol) (from Example 16 supra) in tetrahydrofuran (5 mL). cooled to 5° C. was treated with potassium tert-butoxide (1.0 M solution in tetrahydrofuran, 0.62 mL, 0.62 mmol). After stirring at 5° C. for 15 minutes and then at room temperature for another 15 minutes, reaction mixture was diluted with ethyl acetate (20 mL) and was washed with water (2×10 mL) and dried over MgSO4. Solvent was evaporated under reduced pressure to give crude 7-chloro-3-(4-methoxy-phenyl)-4-methyl-1-[1-(S)-phenyl-ethyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one which was used directly in the following step. (308 mg, contains some solvent).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:13]2[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[N:17]=2)=[C:9]([CH:12]=1)[CH:10]=[O:11])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH2:37](O)[CH2:38][CH2:39][OH:40]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:13]2[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[N:17]=2)=[C:9]([CH:10]2[O:40][CH2:39][CH2:38][CH2:37][O:11]2)[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)COC(c2ccc(C(C)(C)C)cc2C=O)=N1
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CC1(C)COC(c2ccc(C(C)(C)C)cc2C2OCCCO2)=N1
Temperature: 25 °C
Yield: 21.7 %

Procedure:
A mixture of 101d (60 g, 0.23 mol), pyridinium p-toluenesulfonate (4 g, 0.02 mol) and 1,3-propanediol (60 mL) in toluene (500 mL) was heated to reflux overnight and cooled to room temperature upon the completion of reaction determined by LCMS. The reaction mixture was washed with 200 mL of 50 percent aqueous NaHCO3, 200 mL of water, and 200 mL of brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give a residue which was purified by silica gel chromatography using EtOAc/petroleum ether=1:5 as eluent to provide 101e (16 g, 21.7%) as a clear yellow gum. LCMS (ESI) 318 (M+H)+. 1HNMR (300 MHz, CDCl3) δ 7.79 (s, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.36 (dd, J=1.6, 8.4 Hz, 1H), 6.32 (s, 1H), 4.23 (dd, J=5.2, 11.2 Hz, 2H), 4.06 (s, 2H), 4.04-3.98 (m, 2H), 2.27-2.21 (m, 1H), 1.48-1.38 (m, 1H), 1.38 (s, 6H), 1.32 (s, 9H).
Reaction SMILES: Br[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH:15]1[CH2:23][CH2:22][CH:18]([C:19]([NH2:21])=[O:20])[CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:3]1([CH:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:15]2[CH2:23][CH2:22][CH:18]([C:19]([NH2:21])=[O:20])[CH2:17][CH2:16]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: NC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)C1CCN(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 2 h
Yield: 66 %

Procedure:
Step 1): Bromodiphenylmethane (2.5 g, 0.01 mol) in DMF (10 ml) was added dropwise at 0°-5° C. to a mixture of isonipecotamide (1.3 g, 0.01 mol) and K2CO3 (1.4 g) in DMF (25 ml). The reaction mixture was stirred for 2 hours at 0°-5° C., then poured into water. The mixture was extracted with ethylether, then the extract was washed with brine, dried (MgSO4) and evaporated to give 1-diphenylmethylpiperidine-4-carboxamide (66%): mp 150° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12]([C:14]1[CH:15]=[CH:16][N:17]2[CH:21]=[CH:20][S:19][C:18]=12)=[O:13])[CH3:10].O>C(Cl)Cl>[CH2:9]([O:11][C:12]([C:14]1[C:15]([Br:1])=[CH:16][N:17]2[CH:21]=[CH:20][S:19][C:18]=12)=[O:13])[CH3:10]
Reactant: CCOC(=O)c1ccn2ccsc12
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1c(Br)cn2ccsc12

Procedure:
N-Bromosuccinimide (0.56 mmol) is added to a solution of pyrrolo[2,1-b]thiazole-7-carboxylic acid ethyl ester (0.56 mmol) in DCM (6.0 mL). After 30 min water (5.0 mL) is added, the layers are separated and the aqueous layer is extracted with DCM (5.0 mL). The combined organic layers are dried over Na SO and the solvents are removed in vacuo to give the desired product which is used without further purification. LC-MS: tR=1.02 min; [M+H]+=273.9.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]=[C:16]=S)=[CH:11][CH:10]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[C:18]1([NH2:25])[C:19]([NH2:24])=[CH:20][CH:21]=[CH:22][CH:23]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[NH:25][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N:24]=3)=[CH:11][CH:10]=2)=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: S=C=Nc1ccc(Oc2nccnc2Cl)cc1
Reactant: Nc1ccccc1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Clc1nccnc1Oc1ccc(Nc2nc3ccccc3[nH]2)cc1
Temperature: 75 °C

Procedure:
The mixture of 2-chloro-3-(4-isothiocyanatophenoxy)pyrazine (190 mg, 721 mmol), benzene-1,2-diamine (93.5 mg, 865 μmol) and N,N′-dicyclohexylcarbodiimide (223 mg, 1081 μmol) in THF (1.5 ml) was heated at 75° C. for 1.5 hrs. The mixture was cooled to room temperature, diluted with DCM and absorbed onto silica for purification using a 20-100% EtOAc/hexanes gradient to give the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[N:16][C:11]3=[N:10][C:9]=2[CH3:17])=[CH:4][CH:3]=1.[CH3:18][Sn](C)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[CH3:17][C:9]1[N:10]=[C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]2[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([CH3:18])=[CH:3][CH:4]=1
Reactant: C[Sn](C)(C)C
Reactant: Cc1nc2ncccn2c1-c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(C)nc3ncccn23)cc1
Temperature: 130 °C
Yield: 64.5 %

Procedure:
Add 3-(4-bromophenyl)-2-methyl-imidazo[1,2-a]pyrimidine (1.00 g, 3.470 mmol) and DMF (17 mL) to a 50 mL screw-cap vial (fitted with stir bar). Degas the solution with nitrogen for 3 min. Add tetramethylstannane (1.91 mL, 13.88 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.36 g, 520.57 μmol) to the vial, and close the vial. Heat the mixture in an oil bath to 130° C. for 2 hours. Cool the reaction to room temperature, and quench with an excess of water. Extract the mixture with EtOAc. Wash the combined organic extracts with brine. Dry the organic extracts over potassium carbonate; filter; collect the filtrate; and concentrate the filtrate under reduced pressure. Purify the crude mixture by silica gel chromatography with a gradient of 50-100% hexane/EtOAc to give the title compound as a white solid (0.50 g, 64% yield). LCMS (m/z) 224.2 (M+1). 1H NMR (399.83 MHz, d6-DMSO) δ 8.81-8.79 (m, 1H), 8.51-8.49 (m, 1H), 7.73 (d, J=7.9 Hz, 2H), 7.31 (d, J=7.9 Hz, 2H), 7.09-7.06 (m, 1H), 2.64 (s, 3H), 2.36 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:11]1[CH:10]=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([Cl:1])[CH:12]=1
Reactant: CCOC(=O)c1ccc(C)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(CBr)cc1Cl

Procedure:
A mixture of ethyl 2-chloro-4-methylbenzoate (2.34 g, 0.0118 mol), N-bromosuccinimide (2.05 g, 0.0115 mol), and benzoyl peroxide (0.5 g) in carbon tetrachloride (50 ml) was heated under reflux for 90 minutes. The resulting solution was filtered and the solvent was evaporated off under reduced pressure to yield ethyl 4-(bromomethyl)-2-chlorobenzoate as a yellow crystalline solid having the following structural characteristics:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH2:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23])([O-:15])=[O:14]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH:12][S:22]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N+:13]([O-:15])=[O:14])(=[O:23])=[O:24])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Nc1cc(F)cc2cccnc12
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1cc(F)cc2cccnc12
Yield: 76 %

Procedure:
In a similar fashion using route 14 general procedure 26, 6-fluoroquinolin-8-ylamine (Intermediate 48) (320 mg, 1.97 mmol), 2-nitro-benzenesulfonyl chloride (523 mg, 2.37 mmol), pyridine (2 ml) for 16 h gave the title compound (520 mg, 76%) which was used in the next step without further purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Cl:13][O-].[Na+].O>C(O)(=O)C>[C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[Cl:13])(=[O:3])[CH3:2]
Reactant: [O-]Cl
Reactant: CC(=O)Nc1ccc(C=O)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(C=O)cc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 32 %

Procedure:
To a solution of 6.43 g (0.039 mole) 4-acetamidobenzaldehyde (14) (Aldrich, A180-0) in 55 mL of glacial acetic acid, was added 100 mL of 5.25% solution of sodium hypochlorite (Clorox, Pathmark brand) and the reaction mixture was stirred at room temperature for 48 hours. A white precipitate developed in the reaction mixture when a sample of the reaction mixture was taken off for TLC. The mixture was poured into 100 mL water and filtered to give 2.5 g (32%) of 24 as white powder, mp 110-113°. Infrared (IR) and NMR analysis gave the following results:
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[C:15]2[CH:34]=[CH:33][CH:32]=[CH:31][C:16]=2[C:17]2[CH2:18][N:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:20](=[O:23])[C:21]=2[CH:22]=1.IC.[Cl-].[NH4+]>O1CCCC1>[Br:13][C:14]1[C:15]2[CH:34]=[CH:33][CH:32]=[CH:31][C:16]=2[C:17]2[CH:18]([CH3:1])[N:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:20](=[O:23])[C:21]=2[CH:22]=1
Reactant: CC(C)NC(C)C
Reactant: O=C1c2cc(Br)c3ccccc3c2CN1c1ccccc1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1c2c(cc(Br)c3ccccc23)C(=O)N1c1ccccc1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (0.30 mL, 2.1 mmol) in 1 mL of tetrahydrofuran cooled to 0° C. was added n-butyllithium (2.5 M tetrahydrofuran solution, 0.93 mL, 2.3 mmol) dropwise. After 30 min, the mixture was added to a −78° C. solution of 5-bromo-2-(2-fluorophenyl)-1,2-dihydro-3H-benzo[e]isoindol-3-one (0.150 g, 0.421 mmol) in 2 mL of tetrahydrofuran. After stirring for 30 min at −78° C., iodomethane (0.026 mL, 0.42 mmol) was added dropwise and after an additional 1 hr, the mixture was warmed to ambient temperature, treated with saturated aqueous ammonium chloride, and extracted 2× with ethyl acetate. The combined organic extracts were washed with water and brine, dried with magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the 5-bromo-2-(2-fluorophenyl)-1-methyl-1,2-dihydro-3H-benzo[e]isoindol-3-one that gave a proton NMR spectra consistent with theory.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][OH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:19](Cl)(=[O:31])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C1C=CC=CC=1>[C:19]([O:12][CH2:11][CH2:10][O:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:31])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: O=C(OCCO)c1ccccc1
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCCCCCCCCCC(=O)OCCOC(=O)c1ccccc1

Procedure:
To 16 grams (0.1 mole) of ethylene glycol monobenzoate containing 20 gms (0.25 mole) of pyridine was added 22 gms (0.1 mole) of lauroyl chloride with stirring. With the final addition of lauroyl chloride approximately 50 ml of benzene was added and the mixture stirred for 1 hour. The pyridine hydrochloride was filtered off and the product water washed to remove residual pyridine. The benzene solution was dried over anhydrous sodium sulfate and percolated through a column filled with activated alumina to removal residual free acid. The solvent was removed at reduced pressure. The product, 2-benzoyloxyethyl laurate, was characterized on the basis of the chemical shifts in the NMR spectrum and the absence of OH-stretching and other bands associated with reaction byproducts or impurities.
Reaction SMILES: [Na].[SH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.Br[CH:15]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH2:19]([O:18][C:16]([CH:15]([S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1)[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)=[O:17])[CH3:20]
Reactant: Sc1ccccc1-n1cccc1
Reactant: CCOC(=O)C(Br)c1ccc(OC)cc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(Sc1ccccc1-n1cccc1)c1ccc(OC)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
To a solution of sodium (0.46 g, 0.02 g-atom) in 25 mL of anhydrous ethanol, a solution of 1-(2-mercaptophenyl)pyrrole (3.5 g, 0.02 mol) in 8 mL of anhydrous ethanol was added dropwise and the mixture was allowed to stirr for 1 h. After evaporation of the solvent the residue was dissolved in anhydrous tetrahydrofuran (25 mL) and ethyl α-bromo-p-methoxyphenylacetate (5.5 g, 0.02 mol) was slowly added. The reaction mixture was heated at 60° C. for 5 h and then was cooled and poured onto crushed ice, extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated. The residue was purified by flash chromatography (dichloromethane as eluant) giving 5.05 g (69%) of the desired product. IR (neat) 1735 cm−1; 1HNMR (CDCl3) δ 1.06 (t, 3 H), 3.76 (s, 3 H), 4.07 (q, 2 H), 4.30 (s, 1 H), 6.35 (t, 2 H), 6.70-7.70 (m, 10 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13](=[O:15])[CH3:14])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C[Si](C)(C)[O:30][CH2:31][CH2:32]O[Si](C)(C)C>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2([CH3:14])[O:30][CH2:31][CH2:32][O:15]2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1
Reactant: CC(=O)c1ccc(OCC2CC2)c(Br)c1
Reactant: C[Si](C)(C)OCCO[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CC1(c2ccc(OCC3CC3)c(Br)c2)OCCO1
Reaction time: 2 h

Procedure:
A solution of 1-(3-bromo-4-cyclopropylmethoxy-phenyl)-ethanone from example B.b13 (14.0 g; 52.0 mmol) in dry dichloromethane (250 mL) was cooled in an ice-bath before addition of trimethylsilyl trifluoro-methane sulfonate (0.23 g; 1.04 mmol) and dropwise addition of 1,2-bis-(trimethylsilyloxy)-ethane (13.15 g; 62.4 mmol). The reaction mixture was stirred for two hours, extracted with 1M aqueous NaHCO3 (100 mL) and dried over MgSO4. The crude is purified by column chromatography on silica gel (ethyl acetate/cyclohexane—9:1) to yield the title compound as pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10]Br)=[CH:4][CH:3]=1.CC([O-])(C)C.[K+]>C1COCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]=[CH2:10])=[CH:4][CH:3]=1
Reactant: BrCCOc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=COc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.8 %

Procedure:
To a solution of 1-bromo-4-(2-bromoethoxy)benzene (19.9 g, 100 mmol; see step (a) above) in THF (120 mL) was portion-wise added t-BuOK (14.0 g, 125 mmol) over 10 min at 0° C. After stirring at room temperature for 16 h, the mixture was diluted with water (400 mL) and the product was extracted with light petrol (4×100 mL). The combined organic extracts were washed with brine, dried (Na2SO4), concentrated and distilled under vacuum to yield the sub-title compound (11.5 g, 58%).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][O:18][CH3:19])[C:10]=1[CH3:20])C1C=CC=CC=1.[ClH:21]>C(O)(C)C>[ClH:21].[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][O:18][CH3:19])[C:10]=1[CH3:20]
Reactant: COCCn1ccc(=O)c(OCc2ccccc2)c1C
Agent: Cl
Solvent: CC(C)O
Product: COCCn1ccc(=O)c(O)c1C

Procedure:
A mixture of 18.0 g of the 3-benzyloxy-1-(2-methoxyethyl)-2-methyl-4(1H)-pyridinone so obtained and 100 ml of fuming aqueous hydrochloric acid is refluxed for 2 minutes, cooled, diluted with isopropanol, and concentrated by evaporation under reduced pressure. The 3-hydroxy-1-(2-methoxyethyl)-2-methyl-4(1H)-pyridinone hydrochloride obtained as crystalline residue is further purified by recrystallisation from ethyl acetate and isopropanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14](=[N:16][NH2:17])[CH3:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[OH:18][C:19]1[C:26]([CH3:27])=[CH:25][C:22]([CH:23]=O)=[CH:21][C:20]=1[CH3:28]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([C:14](=[N:16][N:17]=[CH:23][C:22]3[CH:25]=[C:26]([CH3:27])[C:19]([OH:18])=[C:20]([CH3:28])[CH:21]=3)[CH3:15])=[C:11]([CH3:13])[N:12]=2)=[CH:6][CH:7]=1
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: CC(=NN)c1sc(-c2ccc(Cl)cc2)nc1C
Solvent: CCO
Product: CC(=NN=Cc1cc(C)c(O)c(C)c1)c1sc(-c2ccc(Cl)cc2)nc1C
Yield: 38.4 %

Procedure:
In ethanol (3 ml), {1-[2-(4-chlorophenyl)-4-methylthiazol-5-yl]ethylidene}-hydrazine (40 mg) prepared in the Step 30-1-2 and 4-hydroxy-3,5-dimethylbenzaldehyde (29 mg) was heated under reflux for 20 hours. After the mixture was allowed to cool, the precipitated crystal was separated by filtration to give the title compound (23 mg, 38%).
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1>C1COCC1>[Br:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:18])([CH3:1])[CH3:17])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1
Reactant: CC(=O)c1ccc(Oc2ccc(Br)cc2)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(Oc2ccc(Br)cc2)cc1
Reaction time: 3 h

Procedure:
A 1.4 M solution of methylmagnesium bromide in THF (7.36 ml; 10.304 mmol) was added to a stirred solution of 4′-(4-bromophenoxy)acetophenone (1 g, 3.435 mmol; [CAS: 54916-27-7]) in THF (40 ml) at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred for 3 hours. The reaction was quenched by the addition of an aqueous solution of saturated ammonium chloride and extracted with EtOAc. The combined organic extracts were dried (Na2SO4) and the solvent was evaporated to dryness. The crude residue was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate D28 (0.8 g, 75%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[N:6][CH:7]=1.[CH3:12][Si](C=[N+]=[N-])(C)C>C(OCC)C.CO>[CH3:12][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: O=C(O)Cc1cncc(Br)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)Cc1cncc(Br)c1
Temperature: 25 °C

Procedure:
To a cooled (0° C.) solution of (5-bromo-3-pyridinyl)acetic acid (1.00 g, 4.63 mmol) in diethyl ether (17 mL) and methanol (11 mL) was added a solution of (trimethylsilyl)diazomethane in diethyl ether (2.0 M, 4.6 ml, 9.3 mmol). The reaction was warmed to room temperature and then quenched by the dropwise addition of acetic acid. Once gas evolution ceased, the solution was concentrated under reduced pressure. The resulting material was diluted with ethyl acetate and washed with water and saturated aqueous sodium chloride solution. The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel (20-80% ethyl acetate in hexanes) provided the title compound: LCMS m/z 231.66 [M+2+H]+; 1H NMR (500 MHz, CD3OD) δ 7.01 (s, 1H), 6.88 (s, 1H), 6.45 (s, 1H), 2.21 (s, 2H), 2.17 (s, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:11])=[O:10])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[F:16]C1C=C(C(F)(F)F)C=C(C=1)N>>[F:16][C:7]1[CH:6]=[C:5]([NH:8][C:9]([NH2:11])=[O:10])[CH:4]=[C:3]([C:12]([F:15])([F:14])[F:13])[CH:2]=1
Reactant: NC(=O)Nc1ccc(F)c(C(F)(F)F)c1
Reactant: Nc1cc(F)cc(C(F)(F)F)c1
Product: NC(=O)Nc1cc(F)cc(C(F)(F)F)c1

Procedure:
The title compound is prepared in analogy to 1-(4-fluoro-3-(trifluoromethyl)phenyl)urea (intermediate 42), using 5-fluoro-3-(trifluoromethyl)aniline (1.00 g, 5.58 mmol) as starting material. Yield: 630 mg; ESI mass spectrum [M+H]+=223; Retention time HPLC: 0.91 min (Z018_S04).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[NH:13][CH:14]=[CH:15][N:16]=2)=[O:9])[CH:5]=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.[H-].[Na+].[CH3:24]I.O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[N:13]([CH3:24])[CH:14]=[CH:15][N:16]=2)=[O:9])[CH:5]=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1
Reactant: CI
Reactant: Nc1nc(C(=O)NCc2ncc[nH]2)cc(-c2ccco2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccnc1CNC(=O)c1cc(-c2ccco2)nc(N)n1
Reaction time: 0.33 h
Yield: 56.9 %

Procedure:
A solution of 2-amino-6-(2-furyl)-N-(1H-imidazol-2-ylmethyl)pyrimidine-4-carboxamide (300 mg, 1.06 mmol) in DMF (15 mL) at room temperature was treated with NaH (44 mg, 1.11 mmol), stirred for 20 min, treated with MeI (99 μl, 1.58 mmol) and stirred at room temperature for 16 h. The mixture was poured into water (30 mL), extracted with EtOAc (3×10 mL) and the combined organic phase was dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; EtOAc] to give the title compound (180 mg, 57%) as a yellow solid.
Reaction SMILES: C[O-].[Na+].[SH:4][C:5]1[NH:6][CH:7]=[CH:8][N:9]=1.F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1>C(O)C>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([S:4][C:5]2[NH:6][CH:7]=[CH:8][N:9]=2)=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: Sc1ncc[nH]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Sc2ncc[nH]2)cc1
Reaction time: 0.5 h
Yield: 39 %

Procedure:
To a mixture of 6.2 g (0.12 mmoles) of sodium methoxide and 90 ml of ethyl alcohol was added 5.8 g (0 058 mmoles) of 2-mercaptoimidazole. After stirring for 0.5 hour, 8.2 g (0.058 mole) of 1-fluoro-4-nitrobenzene was added and the mixture refluxed for 4 hours. The mixture was allowed to cool and filtered to give 5.0 g (39%) of the product. An additional 2.0 g (16%) of product was recovered from the filtrates. Recrystallization from dichloromethane/methanol gave the product as yellow rods. mp 207°-209° C.