Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[Br:13]Br>C(Cl)Cl.C1COCC1>[Br:13][C:3]1[C:2]([CH3:1])=[CH:12][C:6]2[NH:7][C:8](=[O:11])[CH2:9][O:10][C:5]=2[CH:4]=1
Reactant: Cc1ccc2c(c1)NC(=O)CO2
Reactant: BrBr
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc2c(cc1Br)OCC(=O)N2
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
To a suspension of 6-methyl-2H-1,4-benzoxazin-3(4H)-one (10.0 g, 61.3 mmol) in DCM (200 mL) and THF (200 mL) at 0° C. was added bromine (15.0 g, 93.7 mmol) dropwise. The reaction mixture was stirred at this temperature for 30 minutes, then filtered. The solid was washed with Et2O (200 mL) to give the title compound (11.95 g, 80%) as a white solid that was used without further purification. δH (CDCl3) 8.95 (1H, s), 7.16 (1H, s), 6.70 (1H, s), 4.59 (2H, s), 2.31 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH2:18]OC)[NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:10]([O:12]C)=[O:11].[N:21]1([CH2:25]CC2NC(C3C=C(C=CC=3C)C(OC)=O)=CN=2)[CH2:24][CH2:23][CH2:22]1.COCC1NC(C2C=C(C=CC=2C)C(OC)=O)=CN=1>>[N:21]1([CH2:25][CH2:18][C:4]2[NH:5][C:6]([C:7]3[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=3[CH3:17])[C:10]([OH:12])=[O:11])=[C:2]([Cl:1])[N:3]=2)[CH2:24][CH2:23][CH2:22]1
Reactant: COC(=O)c1ccc(C)c(-c2cnc(CCN3CCC3)[nH]2)c1
Reactant: COCc1nc(Cl)c(-c2cc(C(=O)OC)ccc2C)[nH]1
Agent: COCc1ncc(-c2cc(C(=O)OC)ccc2C)[nH]1
Product: Cc1ccc(C(=O)O)cc1-c1[nH]c(CCN2CCC2)nc1Cl

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compounds 27.4 and 27.5, except methyl 3-(2-(2-(azetidin-1-yl)ethyl)-1H-imidazol-5-yl)-4-methylbenzoate (compound 157.2) was used in place of methyl 3-(2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoate (compound 27.3).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:9][C:10]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=1[CH:12]=[O:13]>CCOCC.C1COCC1.CCOC(C)=O>[Br:9][C:10]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=1[CH:12]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:13]
Reactant: Br[Mg]c1ccccc1
Reactant: O=Cc1cc(F)ccc1Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: OC(c1ccccc1)c1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.4 %

Procedure:
A solution of PhMgBr (1M in THF, 2.60 mL, 2.60 mmol) was added dropwise to a −78° C. solution of 2-bromo-5-fluorobenzaldehyde (0.4742 g, 2.336 mmol) in Et2O (5 mL) and THF (1.3 mL), stirred for 15 minutes, allowed to warm to room temperature, stirred for 30 minutes, diluted with EtOAc, washed with water and saturated NH4Cl, dried (Na2SO4), and filtered. The residue was chromatographed on SiO2 (0-10% Et2O/hexanes) to give 561.0 mg of the title compound as a clear gum. 1H NMR (300 MHz, DMSO-d6) δ 7.60 (dd, 1H), 7.46 (dd, 1H), 7.21-7.36 (m, 5H), 7.10 (ddd, 1H), 6.21 (s, 1H), 5.88 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19]CC)=[O:18])=[CH:5]2.[OH:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33]C)=[O:32])=[CH:25][CH:24]=1>>[C:31]([CH2:30][CH2:29][C:26]1[CH:25]=[CH:24][C:23]([O:22][C:11]2[CH:10]=[C:9]3[C:4]([CH:5]=[C:6]([C:17]([OH:19])=[O:18])[CH:7]([C:13]([F:16])([F:14])[F:15])[O:8]3)=[CH:3][C:2]=2[Cl:1])=[CH:28][CH:27]=1)([OH:33])=[O:32]
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Product: O=C(O)CCc1ccc(Oc2cc3c(cc2Cl)C=C(C(=O)O)C(C(F)(F)F)O3)cc1
Yield: 27.6 %

Procedure:
Using the two step parallel synthesis route from ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate and methyl 3-(4-hydroxyphenyl)propionate, a mixture of two components was obtained. The two products were separated by reverse phase chromatography (C18, 4 cm i.d.×10 cm, 5% to 95% gradient CH3CN/H2O/0.1%TFA). The less retained component (analytical LC retention time=3.40 min, ELS purity >99%) was concd in vacuo to afford 61.1 mg (27.6%) of a white solid: 1H NMR (d6-acetone/400 MHz) 2.59 (t, 2H, J=7.6 Hz), 2.92 (t, 2H, J=7.6 Hz), 5.78 (q, 1H, J=7.1 Hz), 7.04 (d, 2H, J=8.6 Hz), 7.36 (d, 2H, J=8.6 Hz), 7.66 (s, 1H), 7.82 (s, 1H); 19F NMR (d6-acetone/100 MHz) −79.2 (d, 3F, J=6.8 Hz); MS(ES+) 443 (75%, M+1), 465 (100%, M+Na); MS(ES−) 441 (M−1, 100); HRMS (ES−) m/z calcd for (M−1; C20H13O6ClF3) 441.0347, found 441.0347.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:13](C(C)(C)C)[O:14][SiH](C)C)[CH:6]=[C:7]([C:9]([SH:12])([CH3:11])[CH3:10])[CH:8]=1>C(O)(=O)C.C1COCC1.O>[OH:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([SH:12])([CH3:10])[CH3:11])[CH:6]=[C:5]([CH2:13][OH:14])[CH:4]=1
Reactant: C[SiH](C)OC(c1cc(CO)cc(C(C)(C)S)c1)C(C)(C)C
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(S)c1cc(CO)cc(CO)c1
Yield: 64.4 %

Procedure:
A solution of 43 mg of 5-hydroxymethyl-1-(1-mercapto-1-methylethyl)-3-[(tert-butyl)dimethylsilanyloxymethyl]benzene in 1 ml of an acetic acid/THF/water (3/1/1) mixture is stirred at AT for 4.5 h and concentrated under RP, and then the residue is taken up in 3 ml of water. The pH of the aqueous phase is brought to 7 by addition of a 10% aqueous Na2CO3 solution and then the aqueous phase is extracted with AcOEt. The organic phase is dried over MgSO4 and concentrated under RP. 18 mg of 3,5-bis(hydroxymethyl)-1-(1-mercapto-1-methylethyl)benzene are thus obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:5][C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:3]1.[C:24]([C:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1)#[CH:25]>CCCCCCC.C(Cl)Cl>[C:26]1([C:24]#[C:25][C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:5]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1
Reactant: C#CC1=CCCCC1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(-c3ccccc3)nn2C)cc1
Solvent: CCCCCCC
Solvent: ClCCl
Product: Cn1nc(-c2ccccc2)cc1C#CC1=CCCCC1

Procedure:
This product was prepared from toluene-4-sulfonic acid 2-methyl-5-phenyl-2H-pyrazol-3-yl ester and 1-ethynyl-cyclohexene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/DCM 1:1; yield (110 mg, 84%); 1H NMR δ (CDCl3): 7.78 (d, J=8.09 Hz, 2H), 7.42-7.33 (t, J=8.11 Hz, 2H), 7.32 (m, 1H), 6.62 (s, 1H), 6.31-6.27 (m, 1H), 3.94 (s, 3H), 2.14-2.22 (m, 4H), 1.58-1.73 (m, 4H); LCMS m/z: 246.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:13])=[CH:4][C:3]=1[O:14][CH3:15].[Br:16]Br>C(O)(=O)C>[Br:16][CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[C:11]([Cl:12])[C:2]([Cl:1])=[C:3]([O:14][CH3:15])[CH:4]=2)[C:9]1=[O:13]
Reactant: BrBr
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)CCC2
Solvent: CC(=O)O
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(Br)CC2
Temperature: 0 °C

Procedure:
7,8-Dichloro-6-methoxy-1-tetralone (2.7 g, 0.011 mole) was suspended in acetic acid (45 ml) warmed slightly with stirring, and 0.57 ml of bromine in 5 ml of acetic acid was added over a 20 minute time period. The reaction mixture was stirred for 10 minutes, and then poured into 200 ml of stirred ice water. A white solid was filtered from the reaction mixture, dissolved in ether (75 ml), washed with brine, dried over MgSO4, evaporated in vacuo and directly used in the next step.
Reaction SMILES: Br[CH2:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][O:8][Si:9]([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([CH3:28])[CH:4]=1.C([Li])(CC)C.C(N1CCCCC1)=[O:35]>O1CCCC1>[Si:9]([O:8][CH2:7][C:6]1[CH:26]=[CH:27][C:3]([CH:2]=[O:35])=[CH:4][C:5]=1[CH3:28])([C:22]([CH3:25])([CH3:24])[CH3:23])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=CN1CCCCC1
Reactant: Cc1cc(CBr)ccc1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: Cc1cc(C=O)ccc1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 113 %

Procedure:
To a stirred solution of (4-bromomethyl-2-methyl-benzyloxy)-tert-butyl-diphenyl-silane (3 g, 6.83 mmol) in tetrahydrofuran is added sec-butyl lithium at −78° C. under nitrogen atmosphere. The reaction mixture is warmed to 0° C. and stirred for 30 min. The reaction mixture is cooled to −78° C., N-formyl piperidine (1.13 mL, 10.24 mmol) is added, and the reaction mixture is stirred for 3 hours at room temperature. The reaction mixture is quenched with water at 0° C. and extracted with EtOAc (50 mL×3). The combined organic layer is washed with brine solution, dried over magnesium sulphate, and concentrated under vacuum to give the title compound (3 g, 46%). ESI/MS m/z 389.1 (M+H)+.
Reaction SMILES: [Na].[Cl:2][C:3]1[C:15]([Cl:16])=[C:14]([O:17][CH2:18][C:19]#[N:20])[CH:13]=[C:12]2[C:4]=1[C:5]1[C:10]([CH2:21][CH2:22][O:23]C(=O)C(F)(F)F)([CH2:11]2)[CH2:9][CH2:8][C:7](=[O:30])[CH:6]=1.[Cl-].[NH4+:32]>CO>[ClH:2].[Cl:2][C:3]1[C:15]([Cl:16])=[C:14]([O:17][CH2:18][C:19](=[NH:32])[NH2:20])[CH:13]=[C:12]2[C:4]=1[C:5]1[C:10]([CH2:21][CH2:22][OH:23])([CH2:11]2)[CH2:9][CH2:8][C:7](=[O:30])[CH:6]=1
Reactant: N#CCOc1cc2c(c(Cl)c1Cl)C1=CC(=O)CCC1(CCOC(=O)C(F)(F)F)C2
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Na]
Solvent: CO
Product: Cl
Product: N=C(N)COc1cc2c(c(Cl)c1Cl)C1=CC(=O)CCC1(CCO)C2
Reaction time: 4 h

Procedure:
To a mixture of sodium metal (0.116 gm, 0.005 mole) in methanol (180 ml) was added {[5,6-dichloro-3-oxo-2,3,9,9a-tetrahydro-9a-(2-trifluoroacetoxyethyl)-1H-fluoren-7-yl)oxy}acetonitrile (8.20 g, 0.0183 mole). The reaction mixture was stirred for 11/4 hours in a nitrogen atmosphere then treated with ammonium chloride (2.0 g, 37 mMole) and stirring was continued for 21/2 hours. The methanol was evaporated in vacuo, the residue dissolved in water, allowed to stand for one hour, treated with 10N NaOH (10 ml), extracted with diethyl ether (100 ml) and then CH2Cl2 (3×50 ml), washed with water, dried over potassium carbonate and evaporated in vacuo. The residue was dissolved in diethyl ether, treated with a slight excess of ethanolic HCl, filtered under nitrogen, and washed with diethyl ether to give the {[5,6-dichloro-9a-(2-hydroxyethyl)-3-oxo-2,3,9,9a-tetrahydro-1H-fluoren-7-yl]oxy}ethanimidamide hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.O.Cl.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([NH2:1])=[CH:16][CH:15]=2)=[CH:13][CH:12]=1
Reactant: Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(Cc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 75.6 %

Procedure:
A suspension of 4.27 g (18.4 mmols) of 4-amino-4' chloro-benzophenone and 8.54 g of zinc amalgam in 80 ml of toluene containing 4 ml of water was heated to reflux. 1 ml of concentrated hydrochloric acid were added over 90 minutes. After 22 hours, the mixture was allowed to cool to room temperature and 100 ml of ethyl acetate and 2×100 ml of water were added. The layers were separated and the aqueous phase was extracted with 50 ml of ethyl acetate. The combined organics were washed twice with 100 ml of water and 50 ml of brine, dried over MgSO4, filtered and evaporated to obtain 3.03 g of orange oil. Flash chromatography (20-35% ethyl acetate/pet ether eluent) yielded the above mentioned product as an orange liquid 915 mg (24.6% yield). 1H nmr (CDCl3) δ3.58 (2H, br s) , 3.82 (2H, s), 6.62 (2H, d), 6.94 (2H, d), 7.08 (2H, d), 7.22 (2H, d)
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[F:12].C(=O)(O)[O-].[Na+].[C:23](Cl)(Cl)=[S:24]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:23]=[S:24])=[CH:7][C:6]=1[F:12]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(Oc2cc(Cl)ccc2Cl)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Fc1cc(N=C=S)ccc1Oc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
4-(2,5-Dichloro-phenoxy)-3-fluoro-phenylamine (1.36 g, 5 mmol) was dissolved in 150 ml of chloroform and 100 ml of saturated aqueous sodium bicarbonate was added. To this biphasic mixture was added dropwise a solution of thiophosgene (0.39 ml, 5 mmol) in 30 ml of chloroform at room temperature with vigorous stirring. The mixture was stirred vigorously for 1 hour at room temperature. The bottom layer of the mixture was separated, and the aqueous layer was extracted twice with CHCl3. The combined organic solution was washed with water, dried over Mg2SO4 and evaporated to give 1.53 g (97.4%) of crude product used for next step without further purification.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=3)[CH:16]=2)[N:13]=[C:12]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])[CH2:11]1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH2:22][CH2:23][N:24]([S:42]([CH3:41])(=[O:44])=[O:43])[CH2:25][CH:26]=3)[CH:16]=2)[N:13]=[C:12]([C:27]([F:32])([F:33])[C:28]([F:31])([F:30])[F:29])[CH2:11]1
Reactant: CS(=O)(=O)Cl
Reactant: Fc1ccc(C2CC(C(F)(F)C(F)(F)F)=NN2c2cccc(C3=CCNCC3)c2)c(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CC=C(c2cccc(N3N=C(C(F)(F)C(F)(F)F)CC3c3ccc(F)cc3F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.7 %

Procedure:
5-(2,4-Difluoro-phenyl)-1-[3-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (20.0 mg, 0.04 mmol) prepared in Example 213, triethylamine (28.0 uL, 0.20 mmol) and methanesulfonyl chloride (5.0 uL, 0.06 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 18 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 10.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:9]=2[S:8][CH:7]=1)[CH3:2].C(N(CC)CC)C.[O:24](S(C(F)(F)F)(=O)=O)[S:25]([C:28]([F:31])([F:30])[F:29])(=O)=[O:26].O>CC#N>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:26])=[O:24])=[CH:14][C:9]=2[S:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1csc2cc(O)ccc12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)Cc1csc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl(6-hydroxy-1-benzothiophen-3-yl)acetate (500 mg) and triethylamine (0.592 mL) in CH3CN (20 mL) was added Tf2O (0.417 mL). The mixture was stirred at 0° C. for 10 min. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with 1N HCl and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (745 mg).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[S:16])[NH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)[CH3:2].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O>CO>[CH2:1]([N:3]1[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:18][S:16]/[C:4]/1=[N:5]\[C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)[CH3:2]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCNC(=S)Nc1ccc(C(=O)OC)cc1
Solvent: CO
Product: CCn1c(-c2ccccc2)cs/c1=N\c1ccc(C(=O)OC)cc1
Temperature: 25 °C

Procedure:
A solution of methyl 4-(3-ethylthioureido)benzoate (2-3) (50 mg, 0.19 mmol) and 2-bromoacetophenone (39.8 mg, 0.20 mmol) in MeOH (1 mL) is heated to 80° C. for 2 hours and then cooled to room temperature and concentrated to provide (Z)-methyl 4-(3-ethyl-4-phenylthiazol-2(3H)-ylideneamino)benzoate (2-4).
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:16][C:17](=[O:22])[CH2:18][CH2:19][CH2:20]Br)C>CCCCCC>[CH:1]1([C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=2)[O:13][CH2:20][CH2:19][CH2:18][C:17]([OH:22])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Oc1cccc(C2CCCCC2)c1
Reactant: CCOC(=O)CCCBr
Solvent: CCCCCC
Product: O=C(O)CCCOc1cccc(C2CCCCC2)c1

Procedure:
Following an analogous procedure to that described in Examples 1 and 2, m-cyclohexylphenol and 4-bromobutyric acid ethyl ester give 4-(m-cyclohexylphenoxy)-butyric acid of melting point 83° -84° C (from hexane).
Reaction SMILES: [NH2:1][CH:2]1[C:6]2[CH:7]=[N:8][CH:9]=[C:10]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[N:17]([CH3:21])[C:16](=[O:22])[CH2:15][CH2:14]4)[C:5]=2[CH2:4][CH2:3]1.[CH2:23]([S:25](Cl)(=[O:27])=[O:26])[CH3:24]>>[CH3:21][N:17]1[C:18]2[C:13](=[CH:12][C:11]([C:10]3[C:5]4[CH2:4][CH2:3][CH:2]([NH:1][S:25]([CH2:23][CH3:24])(=[O:27])=[O:26])[C:6]=4[CH:7]=[N:8][CH:9]=3)=[CH:20][CH:19]=2)[CH2:14][CH2:15][C:16]1=[O:22]
Reactant: CCS(=O)(=O)Cl
Reactant: CN1C(=O)CCc2cc(-c3cncc4c3CCC4N)ccc21
Product: CCS(=O)(=O)NC1CCc2c(-c3ccc4c(c3)CCC(=O)N4C)cncc21
Yield: 39 %

Procedure:
In analogy to the procedure described for the preparation of example 4, (rac)-6-(7-amino-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (intermediate A-4) and ethanesulfonyl chloride gave the title compound as an off-white powder in 39% yield. MS: 386.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=O)[C:3]=1[C:10]#[N:11].P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:4]1[N:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]=1[C:10]#[N:11]
Reactant: Cc1cc(C)c(C#N)c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(C)c(C#N)c(Cl)n1
Yield: 90 %

Procedure:
4,6-Dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (5 g, 34 mmol) was added to phosphorus oxychloride (20 ml). The reaction was stirred at reflux for 2 h, after which it was seen complete. Volatiles were removed and the residue triturated with petrol. The resultant solid was filtered off and washed with hexane, and dried to give a pure white solid (5.1 g, 90%). δH (250 MHz, CDCl3) 2.55 (3 H, s, CH3), 2.57 (3 H, s, CH3), 7.09 (1 H, s, ArH); δC (250 MHz, CDCl3) 162.64 (C), 154.39 (C), 152.26 (C), 123.22 (CH), 114.28 (C), 108.31 (C), 24.5 (CH3), 20.54 (CH3); m/z 189 (M+Na)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][CH3:12].[K+].[Br-].Br[CH2:16][CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1>C(#N)C>[Br-:10].[CH2:16]([N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N:5]([C:18]2([CH2:17][CH3:16])[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)[CH:4]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:11][CH3:12]
Reactant: BrCCc1ccc2ccccc2c1
Reactant: CCBr
Reactant: Clc1nc[nH]c1Cl
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCCCCCCCCCC[n+]1cn(C2(CC)C=Cc3ccccc3C2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4,5-Dichloroimidazole (1.23 g, 9 mmol) will be dissolved into acetonitrile. Potassium hydroxide (0.61 g, 9.9 mmol) will be added and the mixture will be allowed to stir for 0.5 h. 1-bromethane (9 mmol) will be added and the solution will be allowed to reflux overnight. The solution will be filtered hot to remove a white precipitate (presumed to be KBr) and 2-(2-bromoethyl)naphthalene (9 mmol) will be added and the mixture will be returned to reflux overnight. The mixture will be allowed to cool to room temperature, and the volatiles will be removed en vacuo resulting in the product.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:13])([F:12])[C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.[I:14]I.Cl>CCCCCC.C1(C)C=CC=CC=1.CCOCC>[I:14][C:8]1[CH:9]=[CH:10][C:5]([C:4]([F:12])([F:13])[F:3])=[CH:6][C:7]=1[OH:11]
Reactant: II
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Oc1cc(C(F)(F)F)ccc1I
Reaction time: 8 h
Yield: 102.1 %

Procedure:
To a round bottom flask under N2 was added 14.2 g (0.296 mole) of sodium hydride, 50% in oil. The NaH was washed twice with hexane, and 33.15 g (0.205 mole) of m-trifluoromethylphenol in 1 liter of toluene was added. After five minutes 51.9 g (0.205 mole) of iodine was added all at once, and the solution allowed to stir overnight. The reaction was poured into 3N HCl, ether added, and the separated organic layer washed with water, brine and dried with MgSo4. The solvent was evaporated in vacuo to give 60.3 g (100% yield) of 2-iodo-5-trifluoromethylphenol, mp 36°-38° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH2:10]=[C:11]1[O:15][C:13](=[O:14])[CH2:12]1>C1C=CC=CC=1>[O:15]=[C:11]([CH3:10])[CH2:12][C:13]([NH:1][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[O:14]
Reactant: C=C1CC(=O)O1
Reactant: CC(C)(C)OC(=O)CN
Solvent: c1ccccc1
Product: CC(=O)CC(=O)NCC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
3.93 g (50 mmol) of t-butyl 2-aminoacetate was dissolved in 65 ml of benzene. To the above mixture, 4.41 g (52.5 mmol) of diketene was added dropwise and the reaction mixture was stirred for one hour. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with water, and dried over anhydrous sodium sulfate. The solvent was distilled away from the reaction mixture under reduced pressure, whereby 9.821 g (91.2%) of the captioned compound was obtained. NMR (δ, CDCl3) 1.47 (9H, s), 2.28 (3H, s), 3.46 (2H, s), 3.96 (2H, d, J=5 Hz), 7.33 (1H, s)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:30]C)=[C:6]([C:8]([CH3:29])([CH3:28])[CH2:9][C:10]([C:24]([F:27])([F:26])[F:25])([OH:23])[CH2:11][NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][N:14]=2)[CH:7]=1.B(Br)(Br)Br.C(Cl)Cl>CCCCCC.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:30])=[C:6]([C:8]([CH3:28])([CH3:29])[CH2:9][C:10]([C:24]([F:25])([F:26])[F:27])([OH:23])[CH2:11][NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][N:14]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1nccc2ccccc12)C(F)(F)F
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)(CC(O)(CNc1nccc2ccccc12)C(F)(F)F)c1cc(F)ccc1O
Yield: 52.1 %

Procedure:
Analogously to Example 2, 65 mg (0.15 mmol) of 4-(5-fluoro-2-methoxyphenyl)-1-(isoquinolin-1-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol is reacted with 2.7 ml of 1 M boron tribromide-CH2Cl2 solution. After chromatography on silica gel with hexane-ethyl acetate (0–80%), 33 mg of the product is obtained.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.CC1C=CC=CC=1S(O[CH2:21][C@H:22]1[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]1)(=O)=O.CCOCC>CN(C)C=O.[Cl-].[Na+].O>[CH:3]1([CH2:8][O:9][CH2:21][C@H:22]2[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: Cc1ccccc1S(=O)(=O)OC[C@H]1COC(C)(C)O1
Reactant: OCC1CCCC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](COCC2CCCC2)O1
Reaction time: 18 h

Procedure:
Sodium hydride (0.63 g, 26.3 mmol) and cyclopentanemethanol (2.8 ml, 25.9 mmol) in dimethylformamide were heated at 50° for 30 min. The reaction mixture was cooled to 20° and (R)-2,2-dimethyl-1,3-dioxolane-4-methanol 4-methylbenzenesulphonate (5.0 g, 17.5 mmol) added. The reaction mixture was heated at 50° for 30 min and left at 20° for 18 h. Ether and brine were added, the organic layer dried (Na2SO4) and the solvent evaporated to give the sub-title ether (3.0 g).