Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)/[CH:15]=[CH:16]\[O:17][CH2:18][CH3:19])CCC>C1(C)C=CC=CC=1.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>[Cl:8][C:5]1[N:4]=[C:3]([NH2:9])[C:2](/[CH:15]=[CH:16]/[O:17][CH2:18][CH3:19])=[CH:7][N:6]=1
Reactant: CCCC[Sn](/C=C\OCC)(CCCC)CCCC
Reactant: Nc1nc(Cl)ncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCO/C=C/c1cnc(Cl)nc1N
Yield: 31.8 %

Procedure:
To a degassed suspension of 5-bromo-2-chloropyrimidin-4-amine (preparation 37a, 2.50 g, 11.03 mmol) and (Z)-tributyl(2-ethoxyvinyl)stannane (4.76 g, 11.20 mmol) in toluene (40 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.42 g, 0.36 mmol) and the mixture was subjected to several vacuum-argon cycles and then heated to reflux for 24 hours. Further catalyst (0.42 g, 0.36 mmol) was added and the mixture was refluxed an additional 24 hours. Further (Z)-tributyl(2-ethoxyvinyl)stannane (1.20 g, 2.82 mmol) was added and the reaction was refluxed overnight. The mixture was cooled and concentrated in vacuo and the oily residue was treated with hexanes to give a solid which was purified by flash chromatography (4:1 hexanes/ethyl acetate) to give the title compound (0.70 g, 32%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[O:9][CH2:8][CH2:7][N:6]3[C:10](=[O:24])[C:11]([CH:16](C#N)[C:17](OCC)=[O:18])([C:14]#[N:15])[C:12]([CH:13]=1)=[C:5]23.C(O)(=[O:27])C>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]2[O:9][CH2:8][CH2:7][N:6]3[C:10](=[O:24])[C:11]4([CH2:16][C:17](=[O:18])[NH:15][C:14]4=[O:27])[C:12]([CH:13]=1)=[C:5]23
Reactant: CCOC(=O)C(C#N)C1(C#N)C(=O)N2CCOc3cc(Cl)cc1c32
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Product: O=C1CC2(C(=O)N1)C(=O)N1CCOc3cc(Cl)cc2c31
Temperature: 0 °C

Procedure:
A solution of ethyl 2-(8-chloro-6-cyano-2,3-dihydro-5-oxopyrrolo[1,2,3-de]-1,4-benzoxazine-6-yl)-2-cyanoacetate (1 g) in sulfuric acid (0.5 ml)-acetic acid (10 ml) was heated under reflux for 2 hours. The reaction mixture was poured into ice water, and the resulting precipitate was collected by filtration. Recrystallization from acetic acid afforded colorless crystals (0.48 g, 57%), mp 271° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:34]([CH3:35])=[CH:33][C:13]2[N:14]=[C:15]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([CH3:26])[N:21]=[C:20]4[C:27]3[CH:28]=NC=C[CH:32]=3)[S:16][C:12]=2[C:11]=1[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].BrC1C=CC(F)=C(C(O)C(C)C)C=1>>[C:1]([O:5][C@@H:6]([C:10]1[C:34]([CH3:35])=[CH:33][C:13]2[N:14]=[C:15]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([CH3:26])[N:21]=[C:20]4[CH:27]([CH3:28])[CH3:32])[S:16][C:12]=2[C:11]=1[C:36]1[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1cc2nc(-c3ccc4c(c3)c(-c3cccnc3)nn4C)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Agent: CC(C)C(O)c1cc(Br)ccc1F
Product: Cc1cc2nc(-c3ccc4c(c3)c(C(C)C)nn4C)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(3-isopropyl-1-methyl-1H-indazol-5-yl)-5-methylbenzo[d]thiazol-6-yl)acetic acid was prepared in a similar manner as (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-3-(pyridin-3-yl)-1H-indazol-5-yl)benzo[d]thiazol-6-yl)acetic acid except 1-(5-bromo-2-fluorophenyl)-2-methylpropan-1-ol was used instead of (5-bromo-2-fluorophenyl)(pyridin-3-yl)methanol. LCMS-ESI+: calc'd for C31H33ClN3O3S: 562.2 (M+H+); Found 562.3 (M+H+). 1H NMR (400 MHz, CD3OD) δ 8.44 (s, 1H), 8.03 (dd, J=8.9, 1.6 Hz, 1H), 7.81 (s, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.58 (dd, J=9.4, 6.9 Hz, 4H), 5.26 (s, 1H), 4.01 (s, 3H), 3.45 (hept, J=7.0 Hz, 1H), 2.61 (s, 3H), 1.46 (d, J=7.0 Hz, 6H), 0.98 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:6]([CH:7]=[O:8])=[C:5]([Br:9])[NH:4][N:3]=1.[CH:10]([O:12][CH2:13][CH3:14])=[CH2:11]>Cl.C1(C)C=CC=CC=1>[Br:1][C:2]1[C:6]([CH:7]=[O:8])=[C:5]([Br:9])[N:4]([CH:10]([O:12][CH2:13][CH3:14])[CH3:11])[N:3]=1
Reactant: C=COCC
Reactant: O=Cc1c(Br)n[nH]c1Br
Agent: Cl
Solvent: Cc1ccccc1
Product: CCOC(C)n1nc(Br)c(C=O)c1Br
Reaction time: 15 h
Yield: 92.7 %

Procedure:
1 g (3.94 mmol) of 3,5-dibromo-1H-pyrazole-4-carboxaldehyde, 1.5 cm3 (16 mmol) of ethyl vinyl ether and 3 drops of 12N concentrated hydrochloric acid are introduced with stirring into 30 cm3 of toluene at a temperature in the region of 20° C. The reaction mixture is stirred for 15 hours at a temperature in the region of 20° C., 1.5 cm3 (16 mmol) of ethyl vinyl ether are then run in and stirring is continued for 15 hours at a temperature in the region of 20° C. The reaction mixture is then diluted with 20 cm3 of toluene and washed with twice 30 cm3 of saturated sodium hydrogen carbonate solution. The organic phase is dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) to give 1.19 g of 3,5-dibromo-1-(1-ethoxyethyl)-1H-pyrazole-4-carboxaldehyde in the form of a yellow oil. 1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 1.10 (t, J=7.5 Hz: 3H); 1.64 (d, J=6.5 Hz: 3H); 3.31 (mt: 1H); 3.51 (mt: 1H); 5.88 (q, J=6.5 Hz: 1H); 9.73 (s: 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([O:9][CH:10]([CH2:15][CH3:16])[C:11]([O:13]C)=[O:12])[CH:6]=[N:7][CH:8]=1)#[N:2].[OH-].[Na+].O>CC(O)C>[C:1]([C:3]1[CH:4]=[C:5]([O:9][CH:10]([CH2:15][CH3:16])[C:11]([OH:13])=[O:12])[CH:6]=[N:7][CH:8]=1)#[N:2]
Reactant: CCC(Oc1cncc(C#N)c1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCC(Oc1cncc(C#N)c1)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The product from Step 1 (0.29 g) was dissolved in propan-2-ol (5 ml) containing sodium hydroxide (0.053 g) and water (2 ml). The mixture was stirred at ambient temperature for 20 minutes, evaporated under reduced pressure to a small volume and diluted with water. The solution was acidified with dilute aqueous hydrochloric acid and extracted with ethyl acetate (three times). The extracts were combined, washed with water (three times), dried over magnesium sulphate and evaporated under reduced pressure to give the required product, 0.25 g, as a gum.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+].C(O)C>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.C1(C)C=CC=CC=1>[C:12]1([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1cccc(Br)c1
Reactant: OB(O)c1ccccc1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1cccc(-c2ccccc2)c1
Yield: 9853.7 %

Procedure:
Using Preparation Method 2, Methyl 3-bromobenzoate (3.86 g, 18.6 mmol) was reacted with phenyl boronic acid (2.4 g, 20.5 mmol) in the presence of 5 mol % Pd(PPh3)4, 18 mL of 2N Na2CO3, 9.4 mL of Ethanol and 37 mL of toluene. The resulting reaction mixture was purified using SiO2 with hexane/diethyl ether 98:2 to give a colourless thick oil (389 g, 96%). NMR 1H (ppm, CDCl3): 8.29 (s, 1H), 8.03 (d, J3=7.8 Hz, 1H), 7.79 (d, J3=7.8 Hz, 1H), 7.63 (d, J3=7.2 Hz, 2H), 7.54-7.26 (m, 4H), 3.96 (s, 3H). MS: M+1 463.2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([OH:7])=[O:6].Cl.[CH2:13](O)[CH3:14]>>[CH2:13]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([I:11])=[C:2]([OH:1])[CH:3]=1)[CH3:14]
Reactant: CCO
Reactant: O=C(O)c1ccc(I)c(O)c1
Agent: Cl
Product: CCOC(=O)c1ccc(I)c(O)c1
Yield: 99 %

Procedure:
Reflux 3-hydroxy-4-iodo-benzoic acid (38 g, 144 mmol) and saturated solution of HCl in ethanol (600 mL) overnight. Evaporate the solvent yielding 42 g, 99% of 3-hydroxy -4-iodo-benzoic acid ethyl ester. 1H NMR (300 MHz, CDCl3): δ 1.39 (t, J=7.1 Hz, 3H), 4.36 (q, J=7.1 Hz, 2H), 7.33 (dd, J=8.3 and 2.0 Hz, 1H), 7.64 (d, J=2.0 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H). Add ethyl iodide (33.8 g, 216 mmol) to a solution of 3-hydroxy -4-iodo-benzoic acid ethyl ester (42 g, 144 mmol) and K2CO3 (39.9 g, 288 mmol) in acetonitrile (400 mL) under magnetic stirring. Heat the reaction mixture at 65° C. for 2 hours, allow the mixture to cool and maintain at RT overnight. Evaporate the solvent and add ethyl acetate to the crude. Filter the solid through Celite® and evaporate the solvent. Yield 42 g, 96%. 1H NMR (300 MHz, CDCl3): δ 1.39 (t, J=7.1 Hz, 3H), 1.50 (t, J=7.0 Hz, 3H), 4.16 (q, J=7.0 Hz, 2H), 4.37 (q, J=7.1 Hz, 2H), 7.36 (dd, J=8.1 and 1.8 Hz, 1H), 7.42 (d, J=1.8 Hz, 1H), 7.84 (d, J=8.1 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:34])[C:8]4[CH:20]=[CH:19][C:18]([O:21][CH:22]5[CH2:27][CH2:26][N:25](C(=O)C(F)(F)F)[CH2:24][CH2:23]5)=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[OH-].[K+].O>C1COCC1.CO>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:34])[C:8]4[CH:20]=[CH:19][C:18]([O:21][CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: CC1(C)c2cc(OC3CCN(C(=O)C(F)(F)F)CC3)ccc2C(=O)c2c1[nH]c1cc(Br)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)c2cc(OC3CCNCC3)ccc2C(=O)c2c1[nH]c1cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Bromo-6,6-dimethyl-8-[1-(2,2,2-trifluoro-acetyl)-piperidin-4-yloxy]-5,6-dihydro-benzo[b]carbazol-11-one (Compound T6-1, 28.0 mg, 52.3 μmol) was dissolved in THF (1.00 mL) and methanol (0.50 mL), added with aqueous solution of potassium hydroxide (1.00 mL, 20 wt %), and stirred at room temperature for 1 hr. The reaction solution was added to water, and extracted with mixture solution of chloroform and methanol, and dried over sodium sulfate. Then, after filtering and concentration under reduced pressure, 3-bromo-6,6-dimethyl-8-(piperidin-4-yloxy)-5,6-dihydro-benzo[b]carbazol-11-one was obtained as a crude product.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[C:7]#[CH:8].Cl[Si:17]([CH3:25])([CH3:24])[CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21]>C1COCC1>[CH3:24][Si:17]([CH3:25])([C:8]#[C:7][CH2:6][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21]
Reactant: C#CCOC1CCCCO1
Reactant: C[Si](C)(Cl)CCC(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C#CCOC1CCCCO1)CCC(F)(F)F
Temperature: -78 °C

Procedure:
A solution of n-butyllithium (12.0 ml, 30.0 mmol, 2.5 mol dm−3 in hexanes) was added dropwise to a stirred, cooled (−78° C.) solution of compound 1 (4.20 g, 30.0 mmol) in THF (80 ml) under an atmosphere of dry nitrogen. The reaction mixture was maintained at −78° C. for 1.5 h and a solution of chlorodimethyl-3,3,3-trifluoropropylsilane (5.72 g, 30.0 mmol) in THF (20 ml) added dropwise. The reaction mixture was allowed to warm to room temperature, washed with water and the organic layer extracted into ethyl acetate/hexane (3 times). The combined extracts were washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield an amber oil. The crude product was purified by column chromatography [silica gel, eluted with hexane/ethyl acetate (4:1), Rf: 0.58] to yield a colorless oil.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15](Br)=[CH:16][CH:17]=1)=[O:12])[CH2:3]2.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(O)C>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>[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:16][CH:17]=1)=[O:12])[CH2:3]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Br)o1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(-c2ccccc2)o1
Yield: 71.3 %

Procedure:
(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-bromofuran-2-carboxamide) hydrochloride (100 mg), phenylboronic acid (45 mg), tetrakis(triphenylphosphine)palladium(0) (20 mg), cesium carbonate (547 mg), in a mixture of 1,2-dimethoxyethane (6 mL), ethanol (1.5 mL) and water (1 mL) were stirred under reflux under a nitrogen atmosphere for 17 h. The solution was evaporated and the residue was dissolved in chloroform. The solution was washed with aqueous sodium carbonate and the organic layer was then dried (Mg2SO4), filtered, and evaporated. HPLC purification using a gradient of 1:1 ammoniated methanol in chloroform, and chloroform gave the title compound as a colourless solid (63 mg); MS (ES+) 297 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:24])[CH:3]=1.[O:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:27]4[CH2:28][CH2:29][O:25][C:26]4=[O:30])=[CH:3][C:4]=3[CH3:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Reactant: O=C1NCCO1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3C)CC2)c(C)c1
Yield: 49.4 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (777 mg) described in Preparation Example 67 and oxazolidin-2-one (209 mg), the title compound (390 mg) was obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:8]=2[N:7]([C:15]([CH3:17])=[CH2:16])[C:6]1=[O:18].Cl.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[O:28])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([CH:29]2[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:8]=4[N:7]([C:15]([CH3:17])=[CH2:16])[C:6]3=[O:18])[CH2:31][CH2:30]2)=[O:28])=[CH:25][CH:26]=1
Reactant: C=C(C)n1c(=O)n(CCCCl)c2cc(C)ccc21
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: C=C(C)n1c(=O)n(CCCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2cc(C)ccc21
Yield: 52 %

Procedure:
A mixture of 5.3 parts of 3-(3-chloropropyl)-1,3-dihydro-5-methyl-1-(1-methylethenyl)-2H-benzimidazol-2-one, 4.9 parts of (4-fluorophenyl)(4-piperidinyl)methanone hydrochloride, 8.5 parts of sodium carbonate, 0.2 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. The reaction mixture is cooled, water is added and the layers are separated. The 4-methyl-2-pentanone phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 4.5 parts (52%) of 3-{3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl}-1,3-dihydro-5-methyl-1-(1-methylethenyl)-2H-benzimidazol-2-one as an oily residue.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[Cl:38])[NH:33][CH3:34]>>[Cl:29][C:30]1[CH:31]=[C:32]([N:33]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:27])([F:26])[F:28])(=[O:17])=[O:18])=[N:11][CH:12]=[CH:13][N:14]=3)=[CH:5][CH:4]=2)[CH3:34])[CH:35]=[CH:36][C:37]=1[Cl:38]
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Reactant: CNc1ccc(Cl)c(Cl)c1
Product: CN(Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2C(F)(F)F)cc1)c1ccc(Cl)c(Cl)c1
Yield: 63 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and 3,4-dichloro-N-methylaniline, the title compound was isolated as a yellow solid in 63% yield (91% purity by HPLC).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[CH:6][C:7]=1[CH3:8].Cl([O-])(=O)(=O)=O.[Li+].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])O.[Na+]>[N+](C)([O-])=O.FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:24])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1ccc(C)c(C)c1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: C[N+](=O)[O-]
Product: COc1cc(C)c(C)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 92.4 %

Procedure:
Commercially available 3,4-dimethylanisole (409 mg) was dissolved in nitromethane (6 ml) to prepare a solution. Lithium perchlorate (1.9 g) and benzoyl chloride (843 mg) were added to the solution, scandium trifluoromethanesulfonate (148 mg) was then added thereto, and the mixture was stirred at room temperature for 3 days. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate and was concentrated. The residue was subjected to separation and purification by column chromatography on silica gel using hexane/ethyl acetate as a solvent to give (4,5-dimethyl-2-methoxyphenyl)(phenyl)methanone (667 mg, yield 93%).
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:33]=2[N:34]=[CH:35][N:36]=1)[C@@H:15]1[O:32][C@H:22]([CH2:23][O:24][Si](C(C)(C)C)(C)C)[C@@H:17]([O:18][CH2:19]SC)[CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCCCC=1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)C1.[N-:61]=[N+:62]=[N-:63].[Na+].[NH4+].[F-]>C(Cl)Cl>[C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:33]=2[N:34]=[CH:35][N:36]=1)[C@@H:15]1[O:32][C@H:22]([CH2:23][OH:24])[C@@H:17]([O:18][CH2:19][N:61]=[N+:62]=[N-:63])[CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CSCO[C@H]1C[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Agent: [F-]
Agent: [NH4+]
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: [N-]=[N+]=NCO[C@H]1C[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1CO
Reaction time: 0.17 h
Yield: 48.1 %

Procedure:
To 0.4 g N6-benzoyl-3′-O-(methylthiomethyl)-5′-O-(tert-butyldimethylsilyl)-2′-deoxyadenosine (0.76 mmol) dissolved in 7 mL dry CH2Cl2 was treated with 0.4 mL cyclohexene and 155 μL SO2Cl2 (1.91 mmol) at 0° C. for 2 h. During this time the starting material completely converted to 7a which was shown by disappearance of the starting material and appearance of 3′-OH analog (5a) in TLC (EtOAC:Hex/7:3, Rf˜0.3; the 3-CH2Cl (7a) could not detected in TLC due to decomposition in TLC plate to 5a). Then solvent was removed by rotary evaporation and kept about 10 minutes in high vacuum pump. Then dissolved in 5 mL dry DMF and treated with 400 mg NaN3 (6.6 mmol) at room temperature for 3 h. Then the reaction mixture was partitioned in H2O/CH2Cl2, the combined organic part was dried over Na2SO4 and concentrated by rotary evaporation. The crude sample was then dissolved in 5 mL MeOH and treated with 300 mg NH4F (8.1 mmol) more than 38 h. Then MeOH was removed by rotary evaporation. After partitioning in H2O/EtOAc, the combined organic part was dried over Na2SO4, concentrated, and purified by silica gel column chromatography (100% EtOAc to 98:2, EtOAc/MeOH) resulting 150 mg of 9a as white powder (48% yield in three steps). HR-MS: Obs. m/z 411.1530, calcd for C18H19O4N8 411.1529 [M+H]+. 1H-NMR (CDC3): δH 8.84 (brs, 1H), 8.70 (brs, 1H), 8.08 (m, 1H), 7.76-7.54 (m, 5H), 6.47 (t, J=5.6 Hz, 1H), 4.83 (m, 2H), 4.78 (m, 1H), 4.39 (m, 1H), 4.09 (d, J=12.78 Hz, H5′, 1H), 3.88 (d, J=12.78 Hz, H5″, 1H), 3.09 (m, H2′, 1H), and 2.65 (m, H2″, 1H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]([OH:8])[CH2:6][C:4](=[O:5])[C:3]=1[CH2:9][CH:10]=[CH2:11].[CH:12]([OH:14])=[O:13]>C(Cl)(Cl)Cl>[CH:12]([O-:14])=[O:13].[CH3:1][C:2]1[CH:7]([OH:8])[CH2:6][C:4](=[O:5])[C:3]=1[CH2:9][CH:10]=[CH2:11]
Reactant: O=CO
Agent: C=CCC1=C(C)C(O)CC1=O
Solvent: ClC(Cl)Cl
Product: O=C[O-]
Temperature: 102 °C
Reaction time: 26 h

Procedure:
38 kg of a mixture of 60% (R) allethrolone and 40% of (S) allethrolone resulting from the industrial resolution of racemic allethrolone and having a specific rotation [α]D20 = -7.5° C (c = 10% in chloroform) and the proportion of which is shown by its circular dichroism, were added to 190 liters of formic acid and the mixture refluxed with stirring under nitrogen at a temperature of about 102° C for 26 hours. The mixture was cooled and residual formic acid was distilled under reduced pressure to obtain raw formate of racemic (R,S) allethrolone which was used as is for the next step.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]([CH2:42][CH3:43])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[C:19]([NH:27][C:28]([C:30]2[CH:31]=[N:32][CH:33]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:35]=2)=[O:29])[CH:18]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(Cl)(Cl)Cl>CO.O1CCOCC1>[C:3]([O:7][C:8]([N:10]([CH2:42][CH3:43])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[C:19]([NH:27][C:28]([C:30]2[CH:31]=[N:32][CH:33]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:35]=2)=[O:29])[CH:18]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CCN(C(=O)OC(C)(C)C)c1ccccc1-c1ccc(C(=O)OC)c(NC(=O)c2cncc(-c3ccccc3)c2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCN(C(=O)OC(C)(C)C)c1ccccc1-c1ccc(C(=O)O)c(NC(=O)c2cncc(-c3ccccc3)c2)c1
Reaction time: 0.17 h
Yield: 97.7 %

Procedure:
A 2 mol/L aqueous solution of sodium hydroxide (3.8 mL) was added to a solution mixture of methyl 4-(2-((tert-butoxycarbonyl)(ethyl)amino)phenyl)-2-(5-phenylpyridine-3-carboxamido)benzoate (0.84 g) in methanol (4.2 mL) and dioxane (4.2 mL) at room temperature, followed by stirring at the same temperature for 3 hours and 10 minutes. After adjusting the pH to 4.9 with a 10% aqueous solution of citric acid, chloroform was added thereto. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride sequentially, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.80 g of 4-(2-((tert-butoxycarbonyl)(ethyl)amino)phenyl)-2-(5-phenylpyridine-3-carboxamido)benzoic acid as a white solid.