Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](Cl)(C)C.Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:13][O:14][CH2:15][C:16]1[CH:23]=[C:22]([O:24]C2CCCCO2)[CH:21]=[C:20]([B:31]2[O:35][C:34](C)(C)C(C)(C)[O:32]2)[C:17]=1C=O.Cl>C1COCC1.[Zn]>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][CH:34]1[O:35][B:31]([OH:32])[C:20]2[CH:21]=[C:22]([OH:24])[CH:23]=[C:16]([CH2:15][O:14][CH3:13])[C:17]1=2)[CH3:12]
Reactant: CCOC(=O)CBr
Reactant: COCc1cc(OC2CCCCO2)cc(B2OC(C)(C)C(C)(C)O2)c1C=O
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC1OB(O)c2cc(O)cc(COC)c21
Temperature: 55 °C
Reaction time: 0.75 h
Yield: 67.5 %

Procedure:
To a suspension of zinc dust (5.35 g, 82.3 mmol) in THF (10 mL) was added trimethylsilyl chloride (1.1 g, 10.15 mmol) at 40° C. The mixture was heated to 55° C. and stirred for 45 minutes. After cooling down to 37° C., ethyl bromoacetate (7.58 mL, 74.87 mmol) was slowly added to the reaction mixture at 37-40° C. After addition, the resulting mixture was allowed to cool to room temperature over 30 minutes. This solution was added to a solution of 2-methoxymethyl-4-(tetrahydro-pyran-2-yloxy)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (1.99 g, 5.29 mmol) in THF (6 mL) at 0° C. The mixture was stirred for 10 minutes before treating with 3 N HCl and extracting with EtOAc (2×25 mL). The organic extracts were washed with brine, dried and concentrated in vacuo. The residue was purified by silica gel flash column chromatography and lyophilized to give (1,6-dihydroxy-4-methoxymethyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (1.0 g, 68%). 1H NMR (400 MHz, Acetone-d4) δ 8.40 (s, 1H), 8.00 (s, 1H), 7.10 (s, 1H), 6.90 (s, 1H), 5.60 (m, 1H), 4.47 (m, 2H), 4.08 (m, 2H), 3.37 (s, 3H), 3.10 9m, 1H), 2.25 (m, 1H), 1.20 (m, 3H).
Reaction SMILES: [CH:1]([N:14]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][N:16]=[C:15]1[SH:23])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Na+].[CH3:27]I>C(Cl)Cl.CO>[CH:1]([N:14]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][N:16]=[C:15]1[S:23][CH3:27])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1cnc(S)n1C(c1ccccc1)c1ccccc1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cnc(SC)n1C(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
3.2 g (0.01 mol) of 1-benzhydryl-2-mercapto-5-methoxycarbonyl-imidazole (Example 1a) were introduced into a mixture of 30 cc of water, 15 cc of methanol, 15 cc of methylene chloride, 10 cc of 2 N sodium hydroxide solution and 1.3 cc of methyl iodide. Stirring was continued for 30 minutes. During this time the temperature of the reaction mixture rose to 39° C. After cooling, 3 g (90% of the theory) of 1-benzhydryl-5-methoxycarbonyl-2-methylthio-imidazole, m.p. 118° C. were isolated from the organic phase.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[F:33][C:34]([F:45])([F:44])[O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42]N)=[CH:38][CH:37]=1>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:42][C:39]3[C:40]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:41][C:36]([O:35][C:34]([F:45])([F:44])[F:33])=[CH:37][CH:38]=3)=[CH:6][CH:7]=1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(I)cc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(I)cc4)[nH]c4ccc(OC(F)(F)F)cc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS m/e: 690.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8]>C1(C)C=CC=CC=1.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[C:6]([CH:10]=1)[CH:7]=[O:8]
Reactant: Cc1ccccc1Oc1ccc(Cl)cc1C(=O)Cl
Agent: [Pd]
Solvent: Cc1ccccc1
Product: Cc1ccccc1Oc1ccc(Cl)cc1C=O

Procedure:
5-Chloro-2-(2'-methylphenoxy)benzoyl chloride (5.0 g) was dissolved in toluene (50 mls) and the catalyst poison (0.7 mls) followed by the catalyst (0.7 g; 5% palladium on barium carbonate) were added. Hydrogen was then bubbled through the stirred mixture at 100° until no more hydrogen chloride was evolved. The mixture was then cooled to 40°. Animal charcoal (0.2 g) was added and the mixture was filtered through kieselguhr. Evaporation of the solvent from the filtrate gave an oil which was purified by distillation under reduced pressure to give the title compound as a low melting point solid (mp 45°-46°).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1.[OH:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:26])=[C:23]([CH:25]=1)[NH2:24]>>[OH:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:26])=[C:23]([CH:25]=1)[NH:24][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: Cc1ccc(O)cc1N
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccncc2)n1
Product: Cc1ccc(O)cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 5-hydroxy-2-methylaniline (36 mg, 0.290 mmol) similar to Example 117 and isolated as a tan solid (19 mg, 28%). 1H NMR (Acetone-d6): 8.91 (s, 1H), 8.75 (dd, J=1.2, 4.8 Hz, 2H), 8.55 (s, 1H), 8.22 (dd, J=1.8, 4.8 Hz, 2H), 7.23 (s, 1H), 7.18 (d, J=8.1 Hz, 1H), 7.02 (s, 1H), 6.76 (dd, J=3.0, 8.7 Hz, 1H), 2.23 (s, 3H).
Reaction SMILES: CO[Na].Cl.[C:5]([NH2:8])(=[NH:7])[CH3:6].[CH3:9][CH:10]([C:15](OC)=[O:16])[C:11](OC)=[O:12]>CO>[CH3:6][C:5]1[N:8]=[C:11]([OH:12])[C:10]([CH3:9])=[C:15]([OH:16])[N:7]=1
Reactant: COC(=O)C(C)C(=O)OC
Reactant: CC(=N)N
Agent: CO[Na]
Agent: Cl
Solvent: CO
Product: Cc1nc(O)c(C)c(O)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
A solution of CH3ONa (5.02 g, 93 mmol) in CH3OH (31 mL) was cooled to 0° C. Acetamidine hydrochloride (3.21 g, 34 mmol) was added slowly. The reaction mixture was stirred at 0° C. for 30 min. Then dimethyl 2-methylmalonate (4.5 g, 31 mmol) was added. The mixture was stirred at 75° C. for 4 h, during which time a precipitate formed. The solid was filtered and dissolved in water and HCl (conc.) was added until pH 1-2. The white precipitate was filtered, and dried in vacuum to give 2,5-dimethylpyrimidine-4,6-diol as a white solid (3.41 g). MS (ESI): m/z 141 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[S:18][CH:19]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[S:18]1[CH:19]=[C:15]([N:10]2[CH2:11][CH2:12][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:13])[C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]1=2
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: Brc1csc2ccccc12
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2csc3ccccc23)C1=O
Yield: 36.3 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8465 mmol) was reacted with 3-bromo-benzo[b]thiophene (216.3 mg, 1.0158 mmol), 1,4-dioxane (50 mL), copper iodide (10.7 mg, 0.0865 mmol), trans-1,2-diamino cyclohexane (29 mg, 0.2539 mmol) and potassium phosphate (449.1 mg, 2.1162 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3) afforded 95 mg of the product (36.3% yield).
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2=[N:19]C1C=CC=CC=1.[CH:26]1([NH:32]N)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH:26]1([NH:32][N:19]=[C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[C:9]([C:3]4[CH:2]([CH3:1])[S:7][C:6](=[O:8])[NH:5][N:4]=4)[CH:10]=3)[NH:14][C:13]2=[O:18])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: NNC1CCCCC1
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)C(=Nc1ccccc1)C(=O)N2
Product: CC1SC(=O)NN=C1c1ccc2c(c1)C(=NNC1CCCCC1)C(=O)N2
Yield: 54 %

Procedure:
Starting from 1,3-dihydro-5-(3,6-dihydro-6-methyl-2-oxo -2H-1,3,4-thiadiazin-5-yl)-3-phenylimino-2H-indol-2-one, and cyclohexylhydrazine and following the method described in Example 21, the desired compound was obtained.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:23]2[CH:30]=[CH:29][C:26]([CH:27]=O)=[C:25]([CH3:31])[CH:24]=2)([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:14][C:13]=1[CH3:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(CC)CC.Cl.[NH2:45][CH2:46][CH2:47][S:48]([CH3:51])(=[O:50])=[O:49]>CO.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[Si:1]([O:8][CH:9]([C:33]([CH3:34])([CH3:35])[CH3:36])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27][NH:45][CH2:46][CH2:47][S:48]([CH3:51])(=[O:50])=[O:49])=[C:25]([CH3:31])[CH:24]=2)([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:14][C:13]=1[CH3:32])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)CCN
Reactant: CCC(CC)(c1ccc(C=O)c(C)c1)c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCC(CC)(c1ccc(CNCCS(C)(=O)=O)c(C)c1)c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1
Reaction time: 1 h
Yield: 50.5 %

Procedure:
To a mixture of 4-(1-{4-[2-(t-butyldimethylsilanyloxy)-3,3-dimethylbutoxy]-3-methylphenyl}-1-ethylpropyl)-2-methylbenzaldehyde (2.40 g, 4.71 mmol), Et3N (0.9 ml, 6.12 mmol), and 2-aminoethylmethylsulfone hydrochloride (0.78 g, 5.18 mmol) is treated with Ti(OiPr)4 (1.8 ml, 6.12 mmol). The mixture is stirred for 1 h, diluted with CH3OH (20 mL), then NaBCNH3 (0.33 g, 5.18 mmol) is added. The mixture is stirred overnight, quenched with H2O (3 mL), stirred for 1 h., and filtered through SiO2 with EtOAc (100 mL) wash. The filtrate is concentrated and chromatographed (75-80% EtOAc) to give the title compound (1.47 g, 2.38 mmol, 51%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH3:22])[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]3=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[CH3:22][N:18]1[C:19]2[CH:20]=[CH:21][C:9]([C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=3)=[CH:10][C:11]=2[C:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C:17]1=2
Reactant: COc1ccc(-c2ccc3c(c2)c2c(n3C)CCCC2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1c2c(c3cc(-c4ccc(O)cc4)ccc31)CCCC2

Procedure:
The desired product was prepared using a procedure similar to step 4 of example 3. Thus, 6-(4-methoxy-phenyl)-9-methyl-2,3,4,9-tetrahydro-1H-carbazole (1.214 g, 4.166 mmol) was reacted with BBr3 (5.0 ml of a 1M solution in CH2Cl2) to give the product (0.382 g, 1.377 mmol, 33%) as a brown oil. 1H NMR (DMSO-d6) δ 1.76-1.80 (m, 2H), 1.83-1.90 (m, 2H), 2.65 (t, J=5.8 Hz, 2H), 2.71 (t, J=5.8 Hz, 2H), 3.59 (s, 3H), 6.81 (d, J=8.6 Hz, 2H), 7.26 (dd, J=1.2, 8.4 Hz, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.45 (d, J=8.6 Hz, 2H), 7.50 (s, 1H), 9.31 (s, 1H); [ESI(+)], m/z 276 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10](/[C:13](/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:14](\[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)/[CH2:15][CH2:16][Cl:17])=[CH:9][CH:8]=1)[CH3:3].[CH:30]([OH:32])=[O:31]>C(OCC)C>[CH3:1][N:2]([CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10](/[C:13](/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:14](\[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)/[CH2:15][CH2:16][Cl:17])=[CH:11][CH:12]=1)[CH3:3].[CH:30]([O-:32])=[O:31]
Reactant: O=CO
Agent: CN(C)CCOc1ccc(/C(=C(/CCCl)c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: O=C[O-]
Temperature: 25 °C

Procedure:
To a solution of toremifene base (1.00 g, 0.0025 moles) and refluxing diethyl ether (14 ml) was slowly added formic acid (100 μl, 0.0027 moles). The refluxing mixture was stirred for a while and cooled to room temperature. The mixture was stirred additional 30 min at room temperature. The salt was crystallised at −15° C. for 36 hours. After filtration the formate of toremifene was obtained (yield 78%) having melting point of 147° C. 1H-NMR (d6-DMSO) d 8.19 (s, 1H), 7.39 (t, 2H), 7.35-7.27 (m, 3H), 7.27-7.12 (m, 5H), 6.76 (d, 2H), 6.62 (d, 2H), 3.95 (t, 2H), 3.43 (t, 2H 2.85 (t, 2H), 2.70 (t, 2H), 2.28 (s, 6H).
Reaction SMILES: [C:1]1([CH2:7][SH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12](F)[C:11]=1[C:17]([F:20])([F:19])[F:18]>>[CH2:7]([S:8][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([Br:9])[C:11]=1[C:17]([F:18])([F:20])[F:19])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: SCc1ccccc1
Reactant: Fc1cccc(Br)c1C(F)(F)F
Product: FC(F)(F)c1c(Br)cccc1SCc1ccccc1

Procedure:
Phenyl-methanethiol (4.g g, 37.0 mmol) was treated with commercially available 1-bromo-3-fluoro-2-trifluoromethyl-benzene (10.0 g, 41.1 mmol) in close analogy to the procedure described in step 5.3). The crude product (10.5 g) after workup was used as such in the next reaction step without purification by chromatography.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.O>ClCCl.C(OCC)(=O)C.CCCCCC>[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCCCO[Si](C)(C)C(C)(C)C)cc1
Reaction time: 2 h
Yield: 81.4 %

Procedure:
To a solution of 4-(t-butyldimethylsilyloxy)-1-butanol (2.8 g, 13.7 mmol) in dichloromethane (30 ml) were added triethyamine (3.83 ml, 27.4 mmol) and p-toluenesulfonyl chloride (2.88 g, 15.1 mmol) at 0° C., which was then stirred at the same temperature for 2 hours. After the reaction was completed, water was added to the reaction mixture. The resulting mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. This crude product thus obtained was subjected to silica gel column chromatography (n-hexane:ethyl acetate=5:1) to give the title compound (4.0 g, yield: 81%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](O)=[O:10])=[CH:4][CH:3]=1.CSC.B>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: OCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a chilled solution (about 0° C.) of 4-bromophenyl acetic acid (25 g, 0.116 mol) in THF (250 mL), borane methyl sulphide (13.2 g, 0.174 mol) was added, dropwise, under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 3 h. After cooling the mixture to between 0 and 5° C., the reaction was quenched by adding 1.5 N HCl (80 mL), dropwise. After warming for 30 min at about 80° C., the reaction mixture was extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with water and brine and then dried. The product was obtained as colourless liquid after concentration (yield: 23.3 g, 99%).
Reaction SMILES: [CH3:1]OCCOC.C([Zn]CC)C.ICI.[CH:15](/[C:19]1=[CH:20][N:21]([C:36]([CH3:39])([CH3:38])[CH3:37])[S:22]/[C:23]/1=[N:24]\[C:25](=[O:35])[C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[O:33][CH3:34])=[CH:16]/[CH2:17][CH3:18]>C(Cl)Cl>[C:36]([N:21]1[CH:20]=[C:19]([CH:15]2[CH2:1][CH:16]2[CH2:17][CH3:18])/[C:23](=[N:24]/[C:25](=[O:35])[C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=2[O:33][CH3:34])/[S:22]1)([CH3:38])([CH3:37])[CH3:39]
Reactant: CC/C=C\c1cn(C(C)(C)C)s/c1=N\C(=O)c1cc(Cl)ccc1OC
Reactant: COCCOC
Agent: CC[Zn]CC
Solvent: ClCCl
Solvent: ICI
Product: CCC1CC1c1cn(C(C)(C)C)s/c1=N\C(=O)c1cc(Cl)ccc1OC
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 76.3 %

Procedure:
To a solution of CH2Cl2 (10 mL) and 1,2-dimethoxyethane (95 mg, 1.06 mmol) at −10° C. was added diethylzinc (130 mg, 1.06 mmol). To this solution was added dropwise diiodomethane (565 mg, 2.1 mmol). After the addition was complete, the resulting clear solution was stirred for 10 min at −10° C. A solution of Example 25B (200 mg, 0.53 mmol) was added to the reaction mixture, which was allowed to warm to room temperature and stir overnight. The reaction was quenched with NH4Cl then acetone and extracted with EtOAc (2×). The organics were combined, dried (MgSO4), filtered and solvent evaporated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% Hexane in ethyl acetate) to afford 159 mg (77%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 0.59 (q, J=5.52 Hz, 1 H) 0.92 (t, J=7.36, 6.44 Hz, 3 H) 0.94-1.14 (m, 2 H) 1.16-1.29 (m, 2 H) 1.65 (s, 9 H) 2.11-2.33 (m, 1 H) 3.91 (s, 3 H) 6.91 (d, J=8.90 Hz, 1 H) 7.33 (dd, J=8.90, 2.76 Hz, 1 H) 7.81 (s, 1 H) 8.08 (d, J=2.76 Hz, 1 H); MS (DCI/NH4+) m/z 393 (M+H)+.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][C@@H:11]1[C@H:15]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:14][C@@H:13]([OH:25])[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[Cl:26][C:27]1[C:32]([F:33])=[C:31](Cl)[N:30]=[CH:29][N:28]=1>C1COCC1>[Si:3]([O:10][C@@H:11]1[C@H:15]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])[CH2:14][C@@H:13]([O:25][C:31]2[C:32]([F:33])=[C:27]([Cl:26])[N:28]=[CH:29][N:30]=2)[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: Fc1c(Cl)ncnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ncnc(Cl)c2F)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 0.25 h
Yield: 83.4 %

Procedure:
To a stirred suspension of sodium hydride (37.4 mg, 0.93 mmol) in THF (5.00 mL) was added a solution of (1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentanol (285 mg, 0.79 mmol) in THF (2.50 mL) at 0° C. under an atmosphere of Argon, and the mixture was stirred for 15 minutes. To this cooled suspension was added a solution of 4,6-dichloro-5-fluoropyrimidine (120 mg, 0.72 mmol) in THF (2.50 mL) at 0° C., and the resulting mixture was stirred for 19 h at 23° C. After quenching by addition of saturated NH4Cl solution (50.0 mL), the mixture was extracted with ethyl acetate (3×70.0 mL). The organic layers were combined, dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified via silica gel column chromatography eluting with a gradient of 5 to 7% ethyl acetate in hexanes to afford the title compound (295 mg, 79%). 1H-NMR (400 MHz, CDCl3) δ: 8.32 (s, 1H), 5.67-5.61 (m, 1H), 4.41-4.37 (m, 1H), 3.73 (dd, 1H, J=9.8, 7.1 Hz), 3.59 (dd, 1H, J=9.8, 6.6 Hz), 2.33-2.25 (m, 1H), 2.10-1.96 (m, 2H), 1.90 (ddd, 1H, J=13.8, 7.7, 1.8 Hz), 1.55 (s, 18H), 0.89 (s, 6H), 0.88 (s, 6H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[C:24]([Cl:25])=[CH:23][C:22]([O:26][CH2:27][CH:28]=[C:29]([Cl:31])[Cl:30])=[CH:21][C:20]=2[Cl:32])=[CH:10][CH:9]=1)[C:5](=O)[CH3:6].Cl.[CH3:34][O:35][NH2:36]>N1C=CC=CC=1>[CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[C:20]([Cl:32])=[CH:21][C:22]([O:26][CH2:27][CH:28]=[C:29]([Cl:30])[Cl:31])=[CH:23][C:24]=2[Cl:25])=[CH:10][CH:9]=1)[C:5](=[N:36][O:35][CH3:34])[CH3:6]
Reactant: CON
Reactant: CON=C(C(C)=O)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CON=C(C)C(=NOC)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1

Procedure:
0.23 g of 1-(4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-phenyl)-propane-1,2-dione 1-(O-methyl-oxime) and 44 mg of O-methylhydroxylamine hydrochloride are stirred in 5 ml of pyridine at 80° C. for 2 hours. The reaction mixture is concentrated; the residue is taken up in ethyl acetate and washed with water. After concentration of the organic phase and purification over silica gel, the title compound is obtained. 1H-NMR (CDCl3) 300 MHz: 2.12 (s, 3H), 2.30 (m, 2H), 3.88 (s, 3H), 3.94 (s, 3H), 4.17 (t, 2H), 4.29 (t, 2H), 4.59 (d, 2H), 6.11 (t, 1H), 6.83 (s, 2H), 6.91 (d, 2H), 7.29 (d, 2H)
Reaction SMILES: [C:1]1([CH2:11][CH2:12][CH2:13]O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:34]N1C(=O)CCC1=O>C(Cl)Cl>[Br:34][CH2:13][CH2:12][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCCc1cccc2ccccc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCc1cccc2ccccc12
Reaction time: 15 h
Yield: 90.2 %

Procedure:
Compound 73-1 (4.70 g) was dissolved in methylene chloride (50 ml), triphenylphosphine (7.13 g) and N-bromosuccinimide (4.84 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and further at room temperature for 15 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography to give the object product (5.67 g) as a colorless oil.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:11][C:12]([F:18])([F:17])[C:13]#[C:14][CH2:15][OH:16].C(N(CC)CC)C>ClC(Cl)C.ClCCl>[C:4]1([C:3]2[C:13]([C:12]([F:18])([F:17])[F:11])=[C:14]([CH2:15][OH:16])[O:1][N:2]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCC#CC(F)(F)F
Reactant: O/N=C(\Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: OCc1onc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a pale yellow, homogeneous mixture of (Z)—N-hydroxybenzimidoyl chloride (Intermediate I-3B, 5.50 g, 35.4 mmol) and 4,4,4-trifluorobut-2-yn-1-ol (Intermediate I-3A, 5.46 g, 39.6 mmol) in dichloroethane (85 mL) in a 250 mL round bottom flask at 70° C. was added triethylamine (9.85 mL, 70.7 mmol) in 22 mL of dichloroethane over 2.5 h via an addition funnel (the first ˜50% over 2 h and the remaining 50% over 0.5 h). The reaction mixture was stirred at room temperature overnight, diluted with dichloromethane (100 mL), washed with water (100 mL), and the organic layer was collected. The aqueous layer was extracted with dichloromethane (2×50 mL), and the combined organic layers were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. Analysis indicated that the product mixture was composed of a 86:14 mixture of the desired regioisomer, (3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)methanol, and the undesired regioisomer, (3-phenyl-5-(trifluoromethyl)isoxazol-4-yl)methanol. The mixture was purified by silica gel chromatography using a mixture of ethyl acetate and hexane to afford (3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)methanol (5.34 g, 21.96 mmol, 62.1% yield) as a pale yellow oil. The compound had an HPLC ret. time=1.91 min. (condition A); LC/MS M+1=244.2; 1H NMR (500 MHz, CDCl3) δ ppm 2.21 (br. s., 1H), 4.97 (s, 2H), 7.47-7.56 (m, 3H), and 7.65 (d, J=6.60 Hz, 2H).