Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[C@H:4]([OH:5])[CH:3]=[CH:2]1.[C:11](OC=C)(=[O:13])[CH3:12].[C:17](OCC)(=[O:19])[CH3:18]>>[C:11]([O:5][C@H:4]1[C@H:6]([OH:7])[C@@H:8]([CH2:9][O:10][C:17](=[O:19])[CH3:18])[O:1][CH:2]=[CH:3]1)(=[O:13])[CH3:12]
Reactant: C=COC(C)=O
Reactant: CCOC(C)=O
Reactant: OC[C@H]1OC=C[C@@H](O)[C@@H]1O
Product: CC(=O)OC[C@H]1OC=C[C@@H](OC(C)=O)[C@@H]1O
Yield: 90 %

Procedure:
7.3 g (50 mmol) of glucal are taken up in 50 ml of ethyl acetate and 150 ml of vinyl acetate and stirred at room temperature with 2 g of lipase from Pseudomonas spec. (Lipase P, from Amano Pharmaceutical Co., Ltd., Nagoya, Japan). After the reaction is complete (TLC check, about 48 h) the reusable enzyme is filtered off, and the solvent is evaporated, The 3,6-di-O-acetylglucal which results in more than 90% yield can be used without further purification for synthetic purposes.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[C:22]([CH3:24])[C:21]([C:25]2[NH:33][C:28]3[CH2:29][NH:30][CH2:31][CH2:32][C:27]=3[N:26]=2)=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].Br[CH2:35][CH2:36][F:37].[I-].[K+].C(N(CC)CC)C>CN(C=O)C.ClCCl>[F:37][CH2:36][CH2:35][N:30]1[CH2:31][CH2:32][C:27]2[NH:26][C:25]([C:21]3[C:22]([CH3:24])=[CH:23][C:2]([CH3:1])=[C:3]([CH:20]=3)[C:4]([N:6]3[CH2:7][CH2:8][CH:9]([C:12]4[CH:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=4)[CH2:10][CH2:11]3)=[O:5])=[N:33][C:28]=2[CH2:29]1
Reactant: Cc1cc(C)c(-c2nc3c([nH]2)CNCC3)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reactant: FCCBr
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(C)c(-c2nc3c([nH]2)CCN(CCF)C3)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reaction time: 48 h
Yield: 52 %

Procedure:
A mixture of 4-(1-(2,4-dimethyl-5-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 2.9, 88 mg), 1-bromo-2-fluoroethane (150 μl), potassium iodide (50 mg), and triethyl amine (140 μl) in DMF (2 ml) was stirred for 48 hours. The reaction mixture was then diluted with dichloromethane and washed with brine. The organic layer was dried (MgSO4) and concentrated. The residue was purified by prep. TLC using 8% MeOH in DCM to give 51 mg of a white solid (52%). m/z (ES+) 486 (M+H)+. 1H NMR (400 MHz, Chloroform-d) 7.63 (d, 2H), 7.32 (d, 2H), 7.28 and 7.20 (2 singlets, amide rotamers, 1H), 7.00 (s, 1H), 4.93 (m, 1H), 4.67 (dt, J1=47.6 Hz, J2=4.9 Hz, 2H), 3.71 (d, 2H), 3.62 (d, 1H), 3.03-2.71 (m, 8H), 2.43 (d, 3H), 2.29 and 2.19 (2 singlets, amide rotamers, 3H), 2.08-1.89 (m, 2H), 1.85-1.49 (m, 2H), 3.18-3.05 (m, 1H).
Reaction SMILES: [CH:1](=O)[CH3:2].C=O.[C:6]1([S:12]([CH2:15][C@@H:16]2[CH2:21][C@H:20]([NH:22][CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18][C@@H:17]2[N:26]2[CH2:31][CH2:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=3)=[CH:28][C:27]2=[O:42])(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[C:6]1([S:12]([CH2:15][C@@H:16]2[CH2:21][C@H:20]([N:22]([CH:23]([CH3:25])[CH3:24])[CH2:1][CH3:2])[CH2:19][CH2:18][C@@H:17]2[N:26]2[CH2:31][CH2:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:39])[F:40])[CH:33]=3)=[CH:28][C:27]2=[O:42])(=[O:13])=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC=O
Reactant: CC(C)N[C@@H]1CC[C@H](N2CCC(c3cccc(C(F)(F)F)c3)=CC2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Agent: C=O
Product: CCN(C(C)C)[C@@H]1CC[C@H](N2CCC(c3cccc(C(F)(F)F)c3)=CC2=O)[C@H](CS(=O)(=O)c2ccccc2)C1

Procedure:
Following the procedure of Example 104 but substituting acetaldehyde for aqueous formaldehyde, 1-([(1S,2R,4R)-2-benzenesulfonylmethyl-4-isopropylamino-cyclohexyl)-4-(3-trifluoromethylphenyl)-5,6-dihydro-1H-pyridin-2-one (43 mg, 0.08 mmol) was converted to the title product (45 mg) as a white glassy solid. MS found: (M+H)+=563.29.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16]S(C3C=CC(C)=CC=3)(=O)=O)=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:37]([CH:39]([CH2:42][CH2:43][CH2:44]C)[CH2:40]O)C>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH:43]([CH2:42][CH:39]([CH3:40])[CH3:37])[CH3:44])=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:29][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)c(F)c3)c2=O)cc1
Reactant: CCCCC(CC)CO
Product: CC(C)CC(C)Oc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 178, starting with 2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 4-methyl-2-pentanol for 2-ethyl-1-hexanol (yield: 115 mg, 50%). mp 132-133° C. 1H NMR (300 MHz, DMSO-d6) δ 0.80 (d, J=7 Hz, 3H), 0.87 (d, J=7 Hz, 3H), 1.10 (d, J=7 Hz, 3H), 1.26 (m, 1H), 1.50 (m, 1H), 1.63 (m, 1H), 3.30 (s, 3H), 5.31 (m, 1H), 7.52 (m, 1H), 7.62 (m, 1H), 7.81 (m, 1H), 7.90 (d, J=9 Hz, 2H), 8.08 (d, J=9 Hz, 2H), 8.22 (s, 1H). MS (APCI+) m/z 463 (M+H)+; (APCI−) m/z 497 (M+Cl)−. Anal. calc. for C23H24F2N2O4S: C, 59.72; H, 5.23; N, 6.05. Found: C, 59.44; H, 5.26; N, 5.99.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:4][CH2:3]1.[C:17]([O:20][CH2:21][CH2:22][Br:23])(=[O:19])[CH3:18]>CN(C=O)C>[Br-:23].[CH2:21]([O:20][C:17]([CH2:18][N+:2]1([CH3:1])[CH2:3][CH2:4][N:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:6][CH2:7]1)=[O:19])[CH3:22]
Reactant: CC(=O)OCCBr
Reactant: CN1CCN(c2nc3ccccc3o2)CC1
Solvent: CN(C)C=O
Product: CCOC(=O)C[N+]1(C)CCN(c2nc3ccccc3o2)CC1
Product: [Br-]
Reaction time: 1 h

Procedure:
A 110 mg portion of 2-(4-methyl-1-piperazinyl)-benzoxazole was dissolved in 3 ml of DMF. Under cooling with ice, 101 mg of bromoethyl acetate was added to the thus prepared solution, and the reaction was carried out for 1 hour at the same temperature and then for 84 hours at room temperature. The reaction solution was concentrated under a reduced pressure, and 5 ml of acetone was added to the resulting residue. The precipitate thus formed was collected by filtration, washed with acetone and then dried to obtain 167 mg of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([SH:15])=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.Cl[CH2:18][C:19]1[CH:20]=[C:21]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[CH:22]=[CH:23][CH:24]=1>>[F:32][C:31]([F:33])([F:34])[C:28]1[CH:29]=[CH:30][C:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([CH2:18][S:15][C:12]3[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:2])=[O:16])=[C:7]4[C:11]=3[CH2:10][CH2:9][CH2:8]4)[CH:20]=2)=[CH:26][CH:27]=1
Reactant: FC(F)(F)c1ccc(-c2cccc(CCl)c2)cc1
Reactant: COC(=O)COc1ccc(S)c2c1CCC2
Product: O=C(O)COc1ccc(SCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 12C and 48B. MS m/z 473 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:13])(O)[CH3:11])=[CH:4][CH:3]=1.[Br:14][CH2:15][C:16]1([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])OCC[O:17]1.CC1C=CC(S(O)(=O)=O)=CC=1.CC1C=CC=CC=1>O.C(O)CCC>[Br:14][CH2:15][C:16]1([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[O:13][CH:10]([CH2:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH2:11][O:17]1
Reactant: Cc1ccc(CCC(C)(O)O)cc1
Reactant: Clc1ccc(C2(CBr)OCCO2)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCO
Product: Cc1ccc(CCC2COC(CBr)(c3ccc(Cl)cc3Cl)O2)cc1

Procedure:
A mixture of 14.4 parts of 1-[2-(4-methylphenyl)ethyl]-ethanediol, 15.6 parts of 2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolane, 5 parts of 4-methylbenzenesulfonic acid, 225 parts of methylbenzene and 40 parts of butanol is stirred and refluxed for 3 days with water-separator. The reaction mixture is evaporated and the residue is dissolved in 2,2'-oxybispropane: The solution is stirred for 30 minutes with silica gel. The latter is filtered off and the filtrate is evaporated, yielding 2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-[2-(4-methylphenyl)ethyl]-1,3-dioxolane as a residue.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH2:27]([O:34][C:35]1[C:36]([C:46](Cl)=[O:47])=[CH:37][N:38]2[CH2:43][CH2:42][N:41]([CH3:44])[C:40](=[O:45])[C:39]=12)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(Cl)(=O)C(Cl)=O>ClCCl.CN(C=O)C>[F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]([C:46]([C:36]2[C:35]([O:34][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:39]3[C:40](=[O:45])[N:41]([CH3:44])[CH2:42][CH2:43][N:38]3[CH:37]=2)=[O:47])[NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])=[CH:4][CH:3]=1
Reactant: CN1CCn2cc(C(=O)Cl)c(OCc3ccccc3)c2C1=O
Reactant: CC(C)(C)OC(=O)NNCc1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCn2cc(C(=O)N(Cc3ccc(F)cc3)NC(=O)OC(C)(C)C)c(OCc3ccccc3)c2C1=O

Procedure:
To a cold (0° C.) solution of tert-butyl 2-(4-fluorobenzyl)hydrazinecarboxylate (7.30 g, 30.37 mmol; see Fassler et al., J. Med Chem. 1996, 3203) and diisopropylethylamine (10.70 g, 82.82 mmol) in dichloromethane (200 mL), a solution of 8-(benzyloxy)-2-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carbonyl chloride (8.80 g, 27.61 mmol; derived from treatment of the corresponding acid with oxalyl chloride in dichloromethane in the presence of catalytic amount of DMF at room temperature) in dichloromethane was added. The resultant mixture was stirred at room temperature overnight. The resultant mixture was washed with aqueous ammonium chloride, and brine. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the titled amide. This was used with no further purification.
Reaction SMILES: [CH2:1]([CH:3]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[C:8]([OH:15])[CH:7]=1)[CH3:2].C(OC(=O)C)(=O)C.Cl.C(Cl)Cl.[N:31]1C=CC=[CH:33][CH:32]=1>>[CH2:32]([NH:31][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:6]([O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:7][C:8]=1[OH:15])[CH3:33]
Reactant: CCCCC(CC)COc1ccc(C(=O)O)c(O)c1
Reactant: c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CCCCC(CC)COc1ccc(C(=O)NCC)c(O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 62 %

Procedure:
In 30 ml of pyridine was dissolved 3.00 g (11.3 mmol) of 4-(2-ethylhexyloxy)-2-hydroxybenzoic acid (compound 14), and 2.89 g (28.4 mmol) of acetic anhydride was added to the solution dropwise on an ice-water bath. After the dropwise addition, the mixture was stirred for 20 minutes, poured into 120 ml of a 12% aqueous solution of hydrochloric acid, and extracted with 150 ml of ethyl acetate. The organic layer was washed successively with three 150 ml portions of dilute hydrochloric acid, three 150 ml portions of water, and three 100 ml portions of a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, followed by concentration. The resulting crude product was dissolved in 10 ml of methylene chloride, and a few drops of DMF were added thereto. To the mixture was further added dropwise 1.57 g (13.2 mmol) of methylene chloride at room temperature, followed by stirring for 15 minutes. The solvent was removed by distillation under reduced pressure, and the oily residue was dissolved in methylene chloride. The solution was added to 10 ml of a 70% aqueous solution of ethylamine on an ice bath. After the inner temperature was raised to room temperature, 300 ml of dilute hydrochloric acid was added thereto, and the mixture was extracted with 300 ml of ethyl acetate. The organic layer was washed successively with three 300 ml portions of water and two 300 ml portions of a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was recrystallized from hexane to obtain 2.06 g (62%) of N-ethyl-4-(2-ethylhexyloxy)-2-hydroxybenzamide represented by the following chemical formula (hereinafter referred to as compound 28) as white crystals. The analytical results are shown below. ##STR49##
Reaction SMILES: [N:1]1([C:7]2[N:16]=[C:15]([NH2:17])[C:14]3[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=3)[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1.C(N(CC)CC)C>C(O)CCC>[S:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:16]=[C:15]([NH2:17])[C:14]3[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=3)[N:8]=2)[CH2:2][CH2:3]1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: Clc1nc2ccccc2s1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: COc1cc2nc(N3CCN(c4nc5ccccc5s4)CC3)nc(N)c2cc1OC

Procedure:
A suspension of 2-(1-piperazinyl)-4-amino-6,7-dimethoxy-quinazoline (1.96 g), 2-chlorobenzthiazole (1.02 g), triethylamine (1.82 g) in butanol (100 ml) was refluxed for 72 hr and filtered. The precipitate was taken up in a solution of methanol and dimethyl sulfoxide, and IN sodium hydroxide was added until the mixture was alkaline. The precipitate was collected, washed with water, dried (1.3 g) and crystallized from methanol to give the title compound: mp 242°-245° C.; ir (nujol) 3460 and 3370 cm-1 : uv max (MeOH) 227 (ε=4130), 250 (ε=5280), 276 (ε=3649) and 340 nm (ε=690); nmr (DMSO-d6) δ 3.65 (m, 4H), 3.9 (m, 4H), 3.85 (s, 3H), 3.93 (s, 3H), 5.2 (s, 2H) and 7.2 (m, 6H); and Anal. Calcd for C21H22N6O2S.CH3OH: C, 58.14% H, 5.72% N, 18.50% and Found: C, 57.88% H, 5.90% N, 18.47%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:23](OC(=O)C)(=[O:25])[CH3:24].C(=O)(O)[O-].[Na+]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:23](=[O:25])[CH3:24])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-(4-Nitrophenyl)piperazine (2.5 g, 12.1 mmol) was dissolved in dichloromethane (100 ml). Triethylamine (2.0 ml, 14.5 mmol) was added and the reaction was cooled to 0° C. Acetic anhydride (1.25 ml, 13.3 mmol) was added dropwise and the reaction was stirred at 0° C. for 1 h. Saturated sodium bicarbonate was added and the reaction was extracted (×3) with dichloromethane, dried (MgSO4), filtered and concentrated in vacuo to give 4-(4-nitrophenyl)-1-acetylpiperazine as a yellow solid (3.01 g,).GC/MS (EI, M+) m/z=249.
Reaction SMILES: C[Li].[CH2:3]([C:10]1([C:20]#[CH:21])[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:22][Si:23](Cl)([CH3:25])[CH3:24]>C1COCC1>[CH2:3]([C:10]1([C:20]#[C:21][Si:23]([CH3:25])([CH3:24])[CH3:22])[CH2:19][CH2:18][C:13]2([O:14][CH2:15][CH2:16][O:17]2)[CH2:12][CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C#CC1(Cc2ccccc2)CCC2(CC1)OCCO2
Reactant: C[Si](C)(C)Cl
Agent: [Li]C
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CC1(Cc2ccccc2)CCC2(CC1)OCCO2
Temperature: 0 °C
Yield: 89.3 %

Procedure:
Under nitrogen atmosphere and with stirring at 0° C., methyllithium (1.6 M in hexanes, 4.78 mL, 7.65 mmol, 9.2 eq) was added dropwise to a solution of 28 (212.6 mg, 0.829 mmol) in dry THF (9.56 mL). The ice bath was then removed and the mixture was stirred at room temperature for 25 minutes. To the mixture was added dropwise a solution of trimethylsilyl chloride (3.24 mL, 24.87 mmol, 30 eq) in dry THF (3.9 mL) and the resulting mixture was stirred at room temperature for 45 minutes. During this time the solution became opaque and pale yellow. The reaction was then quenched with water (15 mL) and the aqueous layer was extracted with methylene chloride/ethyl ether (1:2, 3×15 mL). The organic layers were combined and washed with saturated aqueous sodium bicarbonate solution (1×15 mL) and brine (1×15 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give 29 (243.1 mg, 0.74 mmol, 89%) as pale yellow crystals. The product was used in the next reaction without further purification: 1H NMR (CDCl3) δ 7.32-7.30 (5H, m), 3.95 (4H, dd, J=2.5, 3.5 Hz), 2.72 (2H, s), 2.00-1.90, 1.71-1.50 (8H, m), 0.14 (9H, s); 13C NMR (CDCl3) δ 137.8, 130.9, 127.7, 126.5, 110.6, 109.1, 88.2, 64.5, 64.4, 48.2, 38.0, 35.2, 31.9, 0.36. MS (EI) m/z 328.1 [M+], 284.2, 237.2, 193.1, 99.1 (100%), 73.1, 59.0; HRMS (EI) calcd for C20H28O2Si 328.1859. found 328.1856.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18](O)[C:17]3[C:12](=[C:13]([CH3:21])[C:14]([OH:20])=[CH:15][CH:16]=3)[O:11][C:10]=2[CH3:22])=[CH:5][CH:4]=1.O.[NH2:24][NH2:25]>CCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:17]3[CH:16]=[CH:15][C:14]([OH:20])=[C:13]([CH3:21])[C:12]=3[OH:11])=[N:24][NH:25][C:10]=2[CH3:22])=[CH:5][CH:4]=1
Reactant: NN
Reactant: COc1ccc(C2=C(C)Oc3c(ccc(O)c3C)C2O)cc1
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2c(-c3ccc(O)c(C)c3O)n[nH]c2C)cc1

Procedure:
3-(4-Methoxy-phenyl)-2,8-dimethyl-4H-chromene-4,7-diol (1 eq) was taken up in a 1:1 solution of EtOH:Hydrazine hydrate and heated under microwave conditions (120° C., 300 sec). The solution was concentrated in vacuo, residue quenched with cold water, extracted with ethyl acetate and purified by flash chromatography (1% MeOH-DCM). The yellow oil was then triturated with ether:hexane to give 4-[4-(4-methoxy-phenyl)-5-methyl-1H-pyrazol-3-yl]-2-methyl-benzene-1,3-diol as a solid.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)=[CH2:2].Br[C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(N(CC)CC)C.O>C(#N)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1/[CH:1]=[CH:2]/[C:21]1[CH:22]=[CH:23][CH:24]=[CH:14][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)c1ccccc1Br
Reactant: C=Cc1ccc2ccccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccccc1/C=C/c1ccc2ccccc2c1
Yield: 86.5 %

Procedure:
29.7 g (0.13 mol) of 2-vinylnaphthalene, 25 g (0.16 mol) of ethyl 2-bromobenzoate, 22.5 ml (0.16 mol) of triethylamine, 0.54 g of palladium diacetate and 1.44 g of triphenylphosphine in 200 ml of acetonitrile were heated to 100° C. for 20 h. The reaction mixture was then poured into water and the mixture was extracted repeatedly with ethyl acetate. The organic phase was concentrated under reduced pressure and the residue was purified chromatographically on silica gel. 34 g (71%) of the product were obtained.
Reaction SMILES: [CH3:1][Si:2]([CH3:5])(Cl)Cl.[C:6]1(C)[CH:11]=CC=C[CH:7]=1.[Cl:13][C:14]1[CH:19]=[CH:18]C([Mg]Cl)=[CH:16][CH:15]=1.C([Mg]Cl)=C>O1CCCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:1]([SiH2:2][CH:5]=[C:6]([CH3:11])[CH3:7])=[CH:18][CH:19]=1
Reactant: C[Si](C)(Cl)Cl
Reactant: Cl[Mg]c1ccc(Cl)cc1
Reactant: Cc1ccccc1
Agent: C=C[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)=C[SiH2]c1ccc(Cl)cc1
Yield: 51.3 %

Procedure:
Forty cubic centimeters (0.33 mol) of dimethyldichloro silane at 20° C. were placed in a 3-neck balloon-flask swept by a flow of nitrogen. Eighty cubic centimeters of toluene were added while shaking the mixture. The temperature was reduced to 5° C., then 0.33 mol of p-chlorophenylmagnesium chloride in 30 mn in the form of a solution in tetrahydrofurane (140 cubic centimeters) were added. Twenty cubic centimeters of toluene were added and the mixture was shaken for 2 hours 30 minutes. Then, 0.36 mol of vinylmagnesium chloride at 20 mn in the form of a solution in tetrahydrofurane (120 cubic centimeters) were added, the temperature being 25° C. at that time. Then the temperature of the reactive environment was changed and maintained for 2 hours. The reactive environment was cooled, the mixture was washed twice with 100 cubic centimeters of water, acidified with 5 cubic centimeters of HCl. Then, after decantation, the mixture was neutralized by means of sodium bicarbonate, dried, and 42 grams of a product containing (chromatography in the gaseous phase) 80 percent in terms of weight of p-chlorophenyldimethylvinylsilane (yield of 51.3 percent as compared to dimethylchlorosilane) was collected.
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.[Cl:9][C:10]1[C:11]2[N:12]([C:16]([CH:19]3[CH2:22][CH:21]([CH2:23][OH:24])[CH2:20]3)=[N:17][CH:18]=2)[CH:13]=[CH:14][N:15]=1>CN(C=O)C.C(Cl)Cl>[Cl:9][C:10]1[C:11]2[N:12]([C:16]([CH:19]3[CH2:20][CH:21]([CH2:23][OH:24])[CH2:22]3)=[N:17][C:18]=2[I:8])[CH:13]=[CH:14][N:15]=1
Reactant: OCC1CC(c2ncc3c(Cl)nccn23)C1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Solvent: CN(C)C=O
Product: OCC1CC(c2nc(I)c3c(Cl)nccn23)C1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of NIS (6.31 g, 28.0 mmol) in anh DMF (100 mL) under Ar was added dry [3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutyl]methanol (6.67 g) dissolved in anh DMF (30 mL). The flask containing [3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutyl]methanol was rinsed with another portion of anh DMF (20 mL) and the rinse was added to the reaction mixture. The reaction was heated to 60° C. (rt→60° C.˜30 min) and the stirred at this temperature for 3 h. The mixture was then cooled to rt, partitioned between 1 M aq Na2S2O3 (60 mL), brine (60 mL) and DCM (160 mL). The aq layer was extracted with DCM (3×100 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and purified by flash chromatography on SiO2 (0-8% MeOH in DCM) to provide a material, homogenous by UV on both TLC and HPLC, still containing DMF. The material was dissolved in DCM (200 mL) and washed with water (3×40 mL), dried (Na2SO4) and concentrated under reduced pressure to provide the title compound as a pale yellow solid; HPLC (polar5 min) 2.52 min; MS (ES+): m/z (rel. int.) 364.0 (100, M++1); 1H NMR (400 MHz,CDCl3) δ 7.59 (d, J=4.8 Hz, 1H), 7.49 (d, J=4.8 Hz, 0.22 H, minor isomer), 7.29 (d, J=4.8 Hz, 1H), 7.28 (d, J=5.2 Hz, 0.23 H, minor isomer), 3.83-3.80 (m, 0.7H), 3.72-3.62 (m, 3H), 2.75-2.55 (m, 4H), 2.42-2.32 (m, 1-2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:19])([O-])=O.[H][H]>C(O)C.[Ni]>[NH2:1][C:4]1[CH:9]=[C:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:19]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)c2ccccc2)ccc1O
Agent: [Ni]
Solvent: CCO
Product: Nc1cc(S(=O)(=O)c2ccccc2)ccc1O

Procedure:
In 120 ml of dehydrated ethanol was suspended 11.05 g of 2-nitro-4-phenylsulfonylphenol followed by addition of a catalytic amount of Raney nickel for reduction in a hydrogen stream at atmospheric temperature and pressure. After completion of the reduction reaction, the catalyst was filtered off and the solvent was distilled off. The residue was dried under reduced pressure to give 9.73 g-of crude 2-amino-4-phenylsulfonylphenol. This product was dissolved in 19 ml of N,N-dimethylformamide and the solution was added dropwise to a mixture of 5.89 g of potassium fluoride, 7.61 g of ethyl 2-bromoisobutyrate and 11 ml of N,N-dimethylformamide. The mixture was then stirred at 60° C. overnight. The reaction mixture was poured in ice-water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was chromatographed on a silica gel column and elution was carried out with hexane-ethyl acetate (2:1). The crude crystals from the eluate were recrystallized from 15 ml of ethanol to recover 4.706 g of 3,4-dihydro-2,2-dimethyl-3-oxo-6-phenylsulfonul-2H-1,4-benzoxazine.