Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:18]=[C:17]2[C:12]([N:13]=[C:14]([C:20]([F:23])([F:22])[F:21])[C:15](=O)[NH:16]2)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:25].S([O-])([O-])(=O)=O.[Mg+2]>C(OCC)C.C(OCC)(=O)C>[Br:25][C:15]1[C:14]([C:20]([F:23])([F:22])[F:21])=[N:13][C:12]2[C:17]([N:16]=1)=[CH:18][C:9]([C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8])=[CH:10][CH:11]=2
Reactant: O=C(c1ccccc1)c1ccc2nc(C(F)(F)F)c(=O)[nH]c2c1
Reactant: BrP(Br)Br
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)c1ccc2nc(C(F)(F)F)c(Br)nc2c1
Temperature: 0 °C
Yield: 53 %

Procedure:
A mixture of 7-benzoyl-3-trifluoromethylquinoxalin-2(1H)-one (3.0 g, 9.4 mmol) [J. Org. Chem. 57(21), 5630,1992] and 40 ml of phosphorous tribromide was refluxed for 5 hours. The mixture was cooled and poured into ice water and the precipitate was isolated. The crude solid was dissolved in a mixture of diethylether and ethyl acetate (1:1), followed by addition of Norite A and anhydrous magnesium sulfate. The mixture was filtered and the solvent evaporated under reduced pressure. The residue was triturated with hexane, filtered off and dried to yield 1.9 g (53%) of the title compound as a pale yellow solid.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[CH:8][C:7]=1[OH:16])([CH2:4][CH3:5])([CH3:3])[CH3:2].[OH-].[Na+].[C:19]1([OH:25])C=CC=CC=1.C(Cl)(Cl)Cl.S(=O)(=O)(O)O>C(O)C.O>[C:1]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[C:8]([CH:19]=[O:25])[C:7]=1[OH:16])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(C)(C)c1cc(C(C)(C)C)ccc1O
Reactant: Oc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCC(C)(C)c1cc(C(C)(C)C)cc(C=O)c1O
Reaction time: 1 h

Procedure:
2-t-amyl-4-t-butylphenol (53 g, 0.24 mole) is dissolved in 150 ml absolute ethanol in a 1 L round bottom flask equipped with a water-cooled condenser. Sodium hydroxide (96 g, 2.4 moles) is dissolved in 100 ml water, and the hot solution is added to the solution of the phenol. Chloroform (57 g, 0.48 mole) is added in 1 ml portions over a 45-minute period. The resulting yellow-brown mixture is stirred 1 hour as it cools to ambient temperature. The mixture is diluted into 500 ml of 1M sulfuric acid and extracted with 200 ml hexanes. The organic layer is isolated in a separatory funnel and dried over anhydrous magnesium sulfate. The mixture is filtered and rotoevaporated to a thick syrup. A typical yield for this reaction is 30%. The product is used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:10]([C@H:9]1[C:17](=[O:19])[O:18][CH2:20][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)OC(=O)N1COC(=O)[C@@H]1Cc1ccccc1

Procedure:
(4S)-4-Benzyl-N-tert-butyloxycarbonyl-1,3-oxazolidin-5-one (1) was prepared from N-tert-butyloxycarbonyl-(L)-phenylalanine (2.65 g, 10.0 mM) and para-toluene-sulfonic acid (30 mg) following general procedure A and obtained as a white solid after crystallisation from diethyl ether (1.49 g, 54%): [α]D20 +23.5 (c 1.0, CHCl3); mp 84-86° C.; IR (KBr): 1795, 1705 cm-1 ; 1H NMR (500 MHz, d8 -toluene, 90° C.): δ 6.97-7.08 (m, 5H), 4.75 (d, J=4 Hz, 1H), 4.03-4.05 (m, 2H), 3.17 (dd, J=4, 14 Hz, 1H), 2.92 (dd, J=3, 14 Hz, 1H), 1.31 (s, 9H); 13C NMR (50.3 MHz, CDCl3): 6 172.7, 153.2, 135.0, 129.8, 128.9, 127.6, 82.0, 78.0, 56.3, 34.3, 28.6; LRMS (NH3): 295 (MNH4+). Anal. Calcd for C15H19NO4 : C, 64.96; H, 6.90; N, 5.05; found: C, 64.93; H, 6.73; N, 4.83.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[C:10]([C:28]([O:30][CH3:31])=[O:29])=[N:11][C:12]([CH:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[CH:13][N:14]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.C(#N)C>[NH2:8][C:9]1[C:10]([C:28]([O:30][CH3:31])=[O:29])=[N:11][C:12]([CH:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)=[CH:13][N:14]=1
Reactant: COC(=O)c1nc(C2CCN(C(=O)OC(C)(C)C)CC2)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1nc(C2CCNCC2)cnc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-[bis(tert-butoxycarbonyl)amino]-6-(1-tert-butoxycarbonyl-4-piperidyl)pyrazine-2-carboxylate (285 mg) in DCM (7 mL) was added TFA (3 mL) dropwise. The reaction mixture was stirred at room temperature for 1 h, then diluted with acetonitrile and concentrated in vacuo. The reaction mixture was diluted with ethyl acetate, washed with 50% saturated sodium bicarbonate solution (2×20 mL), water, and brine. The product was not able to be extracted from aqueous layer with ethyl acetate, and was taken forward directly to the subsequent acylation step using Schotten-Baumen conditions LC/MS m/z 237.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[C:6]2[C:7]([NH:9][C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1)=O>CC(O)=O.[Zn]>[OH:1][C:2]1[CH:12]=[C:6]2[C:5](=[CH:4][CH:3]=1)[C:10](=[O:11])[NH:9][CH2:7]2
Reactant: O=C1NC(=O)c2cc(O)ccc21
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1NCc2cc(O)ccc21
Reaction time: 0.67 h
Yield: 20.9 %

Procedure:
To a solution of 5-hydroxyphthalimide (19.8 g, 121 mmol) in AcOH (500 mL) was slowly added zinc dust (47.6 g, 729 mmol) in portions, then the mixture was heated at the reflux temp. for 40 min., filtered hot, and concentrated under reduced pressure. The reaction was repeated on the same scale and the combined oily residue was purified by column chromatography (1.1 Kg SiO2; gradient from 60% EtOAc/40% hexane to 25% MeOH/75% EtOAc) to give 5-hydroxyisoindolin-1-one (3.77 g): TLC (100% EtOAc) Rf0.17; HPLC ES-MS m/z 150 ((M+H)+).
Reaction SMILES: C[Mg]Br.[CH2:4](OCC)C.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH3:18])=[CH:13][CH:12]=1.Cl>C(OCC)C>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:18])=[CH2:4])=[CH:13][CH:12]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: CCOCC
Agent: C[Mg]Br
Agent: Cl
Product: C=C(C)c1ccc(OC)cc1
Reaction time: 0.5 h

Procedure:
To a 1000 mL three-necked flask equipped with a mechanical stirrer, methyl magnesium bromide/diethyl ether solution (200 mL, 3.0 mol) is added. A solution of 85.3 g of 4′-methoxyacetophenone dissolved in 80 mL of anhydrous diethyl ether is charged to the Grignard reagent over 90 minutes at ambient temperature. Diethyl ether (200 mL) and 250 mL of 3N hydrochloric acid are added slowly to the reaction mixture. The solution is stirred for another 30 minutes. The aqueous layer is separated and washed twice with 100 mL of diethyl ether. The ethereal layers are combined and vacuum distilled. The desired product is obtained in a yield of 91.7 g as a yellow oil whose structure is verified by 1Hnmr and mass spectroscopy.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([F:13])([F:12])[O:9]C(F)(F)[C:7]=2[CH:16]=1.[C-:17]#[N:18].[Na+]>CS(C)=O>[F:13][C:10]1([F:12])[O:11][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][C:17]#[N:18])=[CH:16][C:7]=2[O:9]1
Reactant: FC1(F)Oc2ccc(CCl)cc2C(F)(F)O1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1ccc2c(c1)OC(F)(F)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
A mixture of 6-chloromethyl-2,2,4,4-tetrafluoro-4H-benzo[1,3]dioxine (6.2 g) and NaCN (2.07 g, 42.3 mmol) in DMSO (50 mL) was stirred at room temperature for 2 h. The reaction mixture was poured into ice and extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4, and evaporated to give a crude product, which was purified by silica gel column (Petroleum Ether/EtOAc 10:1) to give (2,2-difluoro-benzo[1,3]dioxol-5-yl)-acetonitrile (4.5 g, 68% over 3 steps). 1H NMR (CDCl3, 300 MHz) δ 7.57-7.60 (m, 2 H), 7.20 (d, J=8.7 Hz, 1 H), 3.82 (s, 2 H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[C:21]([Cl:22])=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=1[Cl:23].C(N(CC)CC)C>C(Cl)Cl>[CH:12]([C:13]1[C:14]([Cl:23])=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:20][C:21]=1[Cl:22])=[O:11]
Reactant: O=C(O)c1cc(Cl)c(CO)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=Cc1c(Cl)cc(C(=O)O)cc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
In a 1 liter 4-necked round-bottomed flask were place 300 ml of methylene chloride and cooled down to -78° C. 26.0 g (0.20 mole) of oxalyl chloride were added slowly, followed by dropwise addition of 35.4 g (0.452 mole) of dry dimethylsulfoxide in 25 ml of methylene chloride, keeping the temperature below -70° C. After the addition was completed the reaction mixture was stirred at -78° C. for 30 minutes and 50.0 g (0.226 mole) of 4-hydroxymethyl-3,5-dichlorobenzoic acid were added in 1 portion 82.5 g (0.817 mole) of triethylamine in 25 ml of methylene chloride were added dropwise, keeping the temperature below -65° C. The reaction mixture was warmed up slowly to room temperature and stirred during 90 minutes, washed with 2% aqueous sodium hydroxide (3×300 ml). The combined basic layers were washed with hexane (2×250 ml) then acidified with concentrated hydrochloric acid and then extracted with ethyl acetate (4×200 ml). The combined organic layers were washed with water (1×500 ml), and then with brine (1×300 ml) and dried over anhydrous magnesium sulfate. The solvent was then eliminated in a rotavap. The resulted oily product was triturated with hexane and filtered yielding 39.6 g (80% purity) 4-formyl-3,5-dichloro benzoic acid as a tan solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH:5]1[C:14]2[C:9](=[CH:10][C:11]([S:15]([N:18]3[CH2:24][CH:23]4[CH2:25][CH2:26][CH:20]([CH2:21][CH2:22]4)[CH2:19]3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1.CC(C)([O-])C.[K+]>O1CCCC1>[C:1]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([S:15]([N:18]3[CH2:24][CH:23]4[CH2:25][CH2:26][CH:20]([CH2:21][CH2:22]4)[CH2:19]3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: O=S(=O)(c1ccc2c(c1)CCCN2)N1CC2CCC(CC2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)N1CCCc2cc(S(=O)(=O)N3CC4CCC(CC4)C3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was synthesized by addition of acetyl chloride to the compound of Example 41. 3-(1,2,3,4-Tetrahydro-6-quinolinesulfonyl)-3-azabicyclo-[3.2.2]nonane (100 mg, 0.31 mmol) was dissolved in dry tetrahydrofuran. The solution was cooled with an ice bath. Potassium tert-butoxide (76 mg, 0.68 mmol) was added, followed by acetyl chloride (0.03 ml, 0.41 mmol). The mixture was allowed to warm slowly to room temperature as it stirred overnight. The solvent was evaporated and the residue extracted with ethyl acetate. The organics were washed with brine, dried over magnesium sulfate and evaporated to give an orange solid. Purification by chromatotron using chloroform/ethyl acetate (9/1) gave a yellow solid (36 mg, 32% yield): mp 177°-179° C.; 1H NMR (CDCl3): 7.56-7.52 (m, 3 H, aryl H's), 3.80 (t, J=6.3, 2 H, alkyl H's), 3.26 (d, J=4.2, 4 H, N(CH2R)2), 2.82, (t, J=6.6, 2 H, alkyl H's), 2.31 (s, 3 H, CH3), 2.10-1.97 (m, 4 H, N(CH2CHR)2 and alkyl H's), 1.78-1.65 (m, 8 H, alkyl H's).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10]O)=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)([Cl:20])=O>ClCCl>[Cl:20][CH2:10]/[CH:9]=[CH:8]/[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: OC/C=C/c1ccc(F)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Fc1ccc(/C=C/CCl)cc1
Reaction time: 0.5 h

Procedure:
(2E)-3-(4-Fluorophenyl)prop-2-en-1-ol (1.36 g) synthesized in Reference Example 24 was dissolved in dichloromethane (45 mL), pyridine (0.78 g) and thionyl chloride (0.72 mL) were added under ice-cooling, and the mixture was stirred for 30 min. The mixture was diluted with dichloromethane. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane) to give the title compound (1.1 g) as a colorless oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[Cl:11][C:12]1[N:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]=1>CCOCC>[Cl:11][C:12]1[N:17]=[C:16]([CH3:18])[CH:15]=[C:14]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[N:13]=1
Reactant: Cc1ccnc(Cl)n1
Reactant: c1ccsc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1cc(-c2cccs2)nc(Cl)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 12.8 %

Procedure:
Part B: To thiophene (0.66 g) in dry ether (25 mL) at 0° C. was added n-butyl lithium in hexanes (1.6 M, 2.7 mL) and the reaction was stirred at 0° C. for 15 minutes. After cooling to −30° C., a solution of 2-chloro-4-methylpyrimidine (1.0 g) in ether (10 mL) was slowly added and the reaction was stirred at −30° C. for 30 minutes and at 0° C. an additional 30 minutes before quenching with a mixture of acetic acid (glacial, 0.45 mL), water (0.5 mL) and tetrahydrofuran (1.0 mL). 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (1.77 g) in tetrahydrofuran (5 mL) was added and the reaction mixture was stirred at room temperature for 5 minutes, then cooled to 0° C. before aq. sodium hydroxide solution (3 M, 50 mL) was added. The organic layer was separated, washed with water, and dried with magnesium sulfate. The solvent was evaporated and the resultant crude oil was chromatographed on silica gel (30% ethyl acetate in hexanes; Rf 0.55) to yield 2-chloro-4-methyl-6-(2-thienyl)pyrimidine (0.21 g). Anal. Calcd: % C, 51.46; % H, 3.33; % N, 13.33. Found: % C, 51.77; % H, 3.35; % N, 12.97.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10](Cl)[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][C@H:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]1=[O:26].[H][H]>[Pd].CO>[ClH:1].[CH3:13][N:7]1[CH2:6][C@@H:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]2[C:21](=[O:26])[CH2:22][CH2:23][C:24]2=[O:25])[C:4]2[C:9](=[CH:10][CH:11]=[CH:2][CH:3]=2)[CH2:8]1
Reactant: [H][H]
Reactant: CN1Cc2c(Cl)cc(Cl)cc2[C@H](c2ccccc2N2C(=O)CCC2=O)C1
Agent: [Pd]
Solvent: CO
Product: CN1Cc2ccccc2[C@H](c2ccccc2N2C(=O)CCC2=O)C1
Product: Cl
Reaction time: 8 h
Yield: 16 %

Procedure:
In a hydrogenation apparatus, a spatula-tip of palladium on activated carbon (5%) was added to a solution of 1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-2,5-dione (68 mg, example 7) in methanol (15 ml), and, after application of a hydrogen atmosphere, agitated for 2 h. After the hydrogen had been removed, the apparatus was left to stand under argon overnight, and then the catalyst was filtered off and washed with methanol. The filtrate was concentrated to dryness. 10 mg of the crude product were taken up with water and 10% hydrochloric acid and freeze-dried. 10 mg of the title compound were obtained.
Reaction SMILES: [S:1]([OH:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].[N+:12]([O-])(O)=O.N([O-])=O.[Na+]>O>[OH-:2].[S:1]([C:3]1[CH:4]=[CH:5][C:6]([N+:9]#[N:12])=[CH:7][CH:8]=1)([OH:11])(=[O:10])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: N#[N+]c1ccc(S(=O)(=O)O)cc1
Product: [OH-]

Procedure:
Two hundred grams of CB-A is added to a solution of 10.1 g sulfanilic acid and 6.23 g of concentrated nitric acid in 21 g of water. A solution of 4.87 g of NaNO2 in 10 g of water is added to the rapidly stirring mixture. 4Sulfobenzenediazonium hydroxide inner salt is formed in situ, which reacts with the carbon black. After 15 minutes, the dispersion is dried in an oven at 125 C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:32]([OH:34])=O)=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:35]([O:42][CH2:43][CH2:44][NH:45][CH:46]([CH3:48])[CH3:47])([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].[Si](OCCN(C(C)C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2(C3C=C(Cl)C=CC=3Cl)CCCC2)N=1)=O)(C(C)(C)C)(C)C>>[Si:35]([O:42][CH2:43][CH2:44][N:45]([CH:46]([CH3:48])[CH3:47])[C:32]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:26][CH:27]=3)[CH2:18][CH2:19][CH2:20][CH2:21]2)[N:11]=1)=[O:34])([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]
Reactant: CC(C)NCCO[Si](C)(C)C(C)(C)C
Reactant: O=C(O)c1nc(CC2(c3ccc(C(F)(F)F)cc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3cc(Cl)ccc3Cl)CCCC2)nc(O)c1OCc1ccccc1
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccc(C(F)(F)F)cc3)CCCC2)nc(O)c1OCc1ccccc1
Yield: 52.55 %

Procedure:
5-Benzyloxy-6-hydroxy-2-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (245) (187 mg, 52.55%) as a yellow sticky solid was synthesized from 5-benzyloxy-6-hydroxy-2-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-pyrimidine-4-carboxylic acid (244) (250 mg, 0.53 mmol) and 2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamine (8b) following the procedure as described for 5-benzyloxy-2-[1-(2,5-dichlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]isopropylamide (206).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].Cl[C:7]([O:9][CH2:10][Cl:11])=[O:8].N1C=CC=CC=1>C(OCC)C>[C:7](=[O:8])([O:9][CH2:10][Cl:11])[O:5][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Reactant: O=C(Cl)OCCl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCOC(=O)OCCl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
A solution of butyl alcohol (50 mmol) and chloromethyl chloroformate (4.5 mL, 50 mmol) in diethyl ether (200 mL) was cooled to 0° C. under argon. Pyridine (5.7 mL, 50 mmol) was added dropwise with stirring over 5 min. The solution was stirred at 0° C. for 15 min, then allowed to warm to room temperature and stirred for three additional hours. The ether solution was filtered, washed with 1 M HCl, and then twice with water, dried over MgSO4, filtered, and concentrated on a rotary evaporator to give butyl chloromethyl carbonate (7 g, 85%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=O.C(N([CH:16]([CH3:18])[CH3:17])CC)(C)C.[NH2:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1>>[CH:6]([C:17]1[CH:16]=[CH:18][C:5]([C:23]2[N:24]=[C:20]([NH:19][C:7](=[O:9])[CH2:6][C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[S:21][CH:22]=2)=[CH:4][CH:3]=1)([CH3:7])[CH3:2]
Reactant: Nc1nccs1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)Cc1cccs1
Product: CC(C)c1ccc(-c2csc(NC(=O)Cc3cccs3)n2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 159.4 %

Procedure:
To the mixture of fluoro-N,N,N″,N″-tetramethylformamidinium hexafluorophosphate (TFFH) (290 mg, 1.1 mmol) and thiophen-2-acetic acid (156 mg, 1 mmol) at 0° C. was added diisopropylethylamine (0.35 mL, 2 mmol) and stirred at same temperature for 20 min. before adding 2-aminothiazole (261 mg, 1.2 mmol). The reaction mixture was warmed to room temperature and stirred for 12 h. The mixture was concentrated and loaded onto silica gel column to provide N-[4-(4-isopropyl-phenyl)-thiazol-2-yl]-2-thiophen-2-yl-acetamide (273 mg). LCMS m/z: 344 (M+1)+.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14](O)[C:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:16])=[CH:10][CH:9]=1.[CH3:26][C:27]1[CH:28]=[C:29](O)[CH:30]=[CH:31][C:32]=1[CH3:33].[OH-].[Na+]>>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[O:16][C:30]3[CH:31]=[C:32]([CH3:33])[C:27]([CH3:26])=[CH:28][C:29]=3[C:14]=2[C:11]2[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(C(=O)C(O)c2ccc(OC)cc2)cc1
Reactant: Cc1ccc(O)cc1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(-c2oc3cc(C)c(C)cc3c2-c2ccc(OC)cc2)cc1

Procedure:
160 g of 73% strength aqueous sulphuric acid are added dropwise to a mixture of 54.5 g of 1,2-di-(4-methoxyphenyl)-2-oxo-ethanol (p-anisoin) and 73 g of 3,4-dimethylphenol and the mixture is heated at 130°-135° for 20 minutes and then cooled to 20°. The reaction mixture is rendered alkaline by adding an aqueous solution of sodium hydroxide and is heated under reflux and then cooled. It is extracted twice with ethyl acetate; the combined organic extracts are washed with a 2 N aqueous solution of sodium hydroxide and with water, dried over sodium sulphate and filtered and the filtrate is concentrated to half its volume and cooled. The crystalline precipitate is filtered off and recrystallised from ethyl acetate and gives 2,3-di-(4-methoxyphenyl)-5,6-dimethylbenzofurane, melting point 153°.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)=[CH:14][N:13]([CH:29]3[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36][OH:37])[CH2:31][CH2:30]3)[C:9]=2[N:10]=[CH:11][N:12]=1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:37][CH2:36][CH2:35][CH:32]1[CH2:31][CH2:30][CH:29]([N:13]2[C:9]3[N:10]=[CH:11][N:12]=[C:7]([NH2:6])[C:8]=3[C:15]([C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:20][CH:21]=3)=[CH:14]2)[CH2:34][CH2:33]1)(=[O:4])=[O:3]
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(CCO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCC1CCC(n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
Methanesulfonyl chloride (0.036 g, 0.31 mmol) was added into a solution of 2-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl}-1-ethanol (0.11 g, 0.26 mmol) and triethylamine (2.5 mL) in dichloromethane (2.5 mL) at 0° C. The mixture was allowed to warm up to ambient temperature and stirred overnight. Methanesulfonyl chloride (0.036 g, 0.31 mmol) and dichloromethane (2.5 mL) was added. The mixture was stirred at ambient temperature for 17 hours. Methanesulfonyl chloride (0.036 g, 0.31 mmol) and dichloromethane (2.5 mL) was added. The mixture was stirred at ambient temperature for 4 hours. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel using methanol/dichloromethane (5:95) as a mobile phase to yield 2-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl}ethyl methanesulfonate (0.10 g, 0.21 mmol) as a white solid: 1H NMR (CDCl3, 400 MHz) δ 8.31(s, 1H), 7.44 (d, 2H), 7.38(t, 2H), 7.15(t, 1H), 7.08 (m, 5H), 5.31(br, 2H), 4.73(m, 1H), 4.32(t, 2H), 3.03(s, 3H), 1.99-1.61(m, 11H); TLC (methanol/dichloromethane=5:95) Rf 0.37; RP-HPLC (Hypersil C18, 5 μm, 100 A, 250×4.6mm; 25%-100% over 10 min then 100%-25% over 2 min acetonitrile-0.05M ammonium acetate, 1 mL/min) Rt 11.45 min; MS: MH+ 507.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH:14]([CH3:18])[N:15]([CH3:17])[CH3:16])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[I:19][CH3:20]>CCOCC>[I-:19].[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][CH:14]([CH3:18])[N+:15]([CH3:20])([CH3:17])[CH3:16])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(CCC(C)N(C)C)cc1
Reactant: CI
Solvent: CCOCC
Product: CCCCOc1ccc(CCC(C)[N+](C)(C)C)cc1
Product: [I-]
Yield: 31 %

Procedure:
To an ether solution containing 1.0 g of 4-butoxy-N,N,α-trimethylbenzenepropanamine (the free base of the compound prepared in Example 41B) was added 2.5 ml of iodomethane and, over a period of 4 hours an oil separated from the solution. The solvent was evaporated and the residue was crystallized from ethyl acetate to give 0.48 g (31% yield) of the desired titled compound, m.p. 160°-165° C.