Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[OH:9].Br[CH2:11][C:12]#[N:13].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[I:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[O:9][CH2:11][C:12]#[N:13]
Reactant: Oc1cc(I)ccc1I
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N#CCOc1cc(I)ccc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
A mixture of 2,5-diiodo-phenol (3.9 g, 11.28 mmol), bromoacetonitrile (2.03 g, 16.91 mmol) and potassium carbonate (3.11 g, 22.55 mmol) in 7 mL acetonitrile was sealed in a stoppered flask and stirred at room temperature for 18 hours. The reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chomatographed on silica gel (30%-70% CH2Cl2/hexanes) to give 2.78 g of (2,5-Diiodo-phenoxy)-acetonitrile.
Reaction SMILES: Cl[Si](C)(C)C.Br[C:7]([F:14])([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:15]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[O:35][CH2:34][CH2:33][N:32]([CH2:36]N3C4C=CC=CC=4N=N3)[CH2:31]2)=[CH:26][CH:25]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C1COCC1.[Zn]>[CH2:11]([O:10][C:8](=[O:9])[C:7]([F:14])([F:13])[CH2:36][N:32]1[CH2:33][CH2:34][O:35][CH:30]([C:27]2[CH:28]=[CH:29][C:24]([O:23][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:25][CH:26]=2)[CH2:31]1)[CH3:12]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: CCCCCCCCOc1ccc(C2CN(Cn3nnc4ccccc43)CCO2)cc1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(C2CN(CC(F)(F)C(=O)OCC)CCO2)cc1
Temperature: 25 °C

Procedure:
To a suspension of zinc dust (0.34 g; 5.2 mmol) in dry THF (10 mL) was added chlorotrimethylsilane (0.33 mL; 2.6 mmol) and ethyl bromodifluoroacetate (0.50 ml; 3.9 mmol), this mixture was heated under reflux for 10 min. and then cooled to RT. To the resulting mixture was added drop-wise a solution of 1-[2-(4-octyloxy-phenyl)-morpholin-4-ylmethyl]-1H-benzotriazole in THF (5 mL). After the addition is complete the resulting mixture is heated under efflux for 2 hours. After cooling to RT the reaction mixture was filtered over Kieselguhr and the filter-cake was washed with ethanol. The solvents were removed in vacuo and the residue was purified by column chromatography (SiO2, Et2O:hexanes 1:1) to afford 2,2-difluoro-3-(2-(4-octyloxy-phenyl)-morpholin-4-yl)-propionic acid ethyl ester (0.58 g).
Reaction SMILES: [Na].[N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3]=1[NH:11][C:12]([O:14][CH3:15])=[O:13].[CH2:16]([Si:18]([CH2:22][CH3:23])([CH2:20][CH3:21])Cl)[CH3:17]>CN(C)C=O>[CH2:16]([Si:18]([CH2:22][CH3:23])([CH2:20][CH3:21])[N:11]([C:3]1[NH:2][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=1)[C:12]([O:14][CH3:15])=[O:13])[CH3:17]
Reactant: CC[Si](Cl)(CC)CC
Reactant: COC(=O)Nc1nc2ccccc2[nH]1
Agent: [Na]
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)N(C(=O)OC)c1nc2ccccc2[nH]1
Reaction time: 12 h

Procedure:
5 parts of the resulting sodium salt of methyl benzimidazolecarbamate are suspended in 15 parts of dimethylformamide and 3.9 parts of triethylchlorosilane are added, in portions, at room temperature. After stirring the mixture for 12 hours under nitrogen, the solvent is distilled off under reduced pressure, tetrahydrofuran is added to the residue, and the solution is filtered. The solvent is then distilled off, giving 2.7 parts of methyl N-triethylsilyl-benzimidazole-2-carbamate; decomposition point >120° C. (active ingredient No. 1).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3](C1C=CC(OCC)=CC=1)([OH:21])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1.N1C=CC=CC=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>O>[F:32][C:2]([F:1])([F:31])[CH:3]([O:21][C:39](=[O:41])[CH3:40])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=1
Reactant: CCOc1ccc(C(O)(COCc2ccc(F)c(Oc3ccccc3)c2)C(F)(F)F)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OC(COCc1ccc(F)c(Oc2ccccc2)c1)C(F)(F)F
Reaction time: 8 h

Procedure:
1,1,1-Trifluoro-2-(4-ethoxyphenyl)-3-(3-phenoxy-4-fluorobenzyloxy)propan-2-ol (0.3 g), pyridine (1 cm3), acetic anhydride (10 cm3) and a catalytic amount of 4-N,N-dimethylaminopyridine (ca. 0.015 g) were mixed at the ambient temperature (ca. 22° C.), then heated at the reflux temperature for 6 hours. The mixture was allowed to stand overnight at the ambient temperature, and was then heated at reflux for a further 6 hours. Analysis by gas liquid chromatography showed 94% conversion to the product. Water was added and the product was extracted into diethyl ether (5×50 cm3). The combined ether layers were dried over anhydrous sodium sulphate and concentrated by evaporation under reduced pressure. The residual oil was purified by column chromatography on a silica gel support, eluted with n-hexane containing 12% by volume ethyl acetate, to give 1,1,1-trifluoro-2-acetoxy-3-(3-phenoxy-4-fluorobenzyloxy)propane (0.29 g) as a viscous oil.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:42][C@H:43]1[CH2:49][CH2:48][CH2:47][CH2:46][N:45]([C:50]2[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][CH:51]=2)[C:44]1=[O:57]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:42][C@H:43]1[CH2:49][CH2:48][CH2:47][CH2:46][N:45]([C:50]2[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][CH:51]=2)[C:44]1=[O:57])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Reactant: N[C@H]1CCCCN(c2ccc(Cl)cc2)C1=O
Agent: Cl
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCCCN(c4ccc(Cl)cc4)C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-((S)-1-(4-chlorophenyl)-2-oxoazepan-3-ylamino)-6-oxohexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (7.0 mg, 0.012 mmol) and Intermediate 50 (3.4 mg, 0.012 mmol) to give a white solid (6.8 mg, 69% yield). Anal. Calcd. for C43H51ClN4O6S m/z 786.4. found: 787.4 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.33 (d, J=8.25 Hz, 2H), 7.22 (q, J=7.15 Hz, 4H), 7.19-7.10 (m, 6H), 7.11-7.04 (m, 2H), 6.89 (br. s., 1H), 6.85-6.73 (m, 1H), 5.31 (br. s., 1H), 5.14 (br. s., 1H), 4.98 (br. s., 1H), 4.78 (br. s., 1H), 3.92 (br. s., 1H), 3.68 (s, 3H), 3.61-3.52 (m, 1H), 3.24-3.08 (m, 1H), 2.92-2.75 (m, 3H), 2.76-2.65 (m, 2H), 2.46-2.26 (m, 3H), 2.09-1.43 (m, 17H).
Reaction SMILES: [CH:1]([C:4]1[O:5][CH:6]=[C:7]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16](OC(C)(C)C)=O)[CH2:12][CH2:11]2)[N:8]=1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.[Br:30][C:31]1C(Cl)=[C:33]([N+:38]([O-:40])=[O:39])[C:34]([NH2:37])=[N:35][CH:36]=1>C(Cl)Cl>[Br:30][C:31]1[C:16]([N:13]2[CH2:12][CH2:11][N:10]([CH2:9][C:7]3[N:8]=[C:4]([CH:1]([CH3:2])[CH3:3])[O:5][CH:6]=3)[CH2:15][CH2:14]2)=[C:33]([N+:38]([O-:40])=[O:39])[C:34]([NH2:37])=[N:35][CH:36]=1
Reactant: CC(C)c1nc(CN2CCN(C(=O)OC(C)(C)C)CC2)co1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)co1
Reaction time: 1 h
Yield: 58.3 %

Procedure:
tert-Butyl 4-((2-isopropyloxazol-4-yl)methyl)piperazine-1-carboxylate (0.400 g, 1.29 mmol, 1.1 eq) was dissolved in DCM (5 mL) and the mixture cooled in a ice-water bath before the dropwise addition of TFA (5 mL). Stirring was continued at this temperature for 1 h and the solvents were removed in vacuo. The resulting crude material was azeotroped with toluene and dried. The resulting 2-isopropyl-4-(piperazin-1-ylmethyl)oxazole (supposedly 0.270 g, 1.29 mmol, 1 eq) was suspended in iPrOH (2.5 mL) and DIPEA (1.0 mL). To this solution, the 5-bromo-4-chloro-3-nitropyridin-2-amine (0.300 g, 1.17 mmol, 0.91 eq) was added, and the mixture heated and stirred for 17 h at 60° C. The mixture was filtered, washed with iPrOH (3×3 mL), cold H2O (3×3 mL), Et2O (2×3 mL) and dried to give the title compound as a bright yellow solid (0.290 g, 53%); 1H-NMR (500 MHz, DMSO-d6): δ 1.26 (d, J=7.0 Hz, 6H, iPr—CH3), 2.52-2.64 (br s, 4H, piperazine N(CH2)2), 2.98-3.12 (m, 5H, piperazine N(CH2)2 and iPr—CH), 3.40 (s, 2H, NCH2), 6.98 (s, 2H, NH2), 7.84 (s, 1H, oxazole 5-H), 8.16 (s, 1H, pyridine 6-H); LC (Method B)-MS (ESI, m/z): R=2.46 min—425/427 [(M+H)+, Br isotopic pattern, 100%].
Reaction SMILES: C1([CH:7]([SH:23])[CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[C:20]3[C:15]([CH2:16][CH2:17][C:18](=[O:22])[NH:19]3)=[CH:14][CH:13]=2)C=CC=CC=1.Cl[C:25]1[C:26](=O)[C:27](C#N)=[C:28](C#N)[C:29](=O)[C:30]=1Cl>>[C:25]1([S:23][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[C:20]3[C:15]([CH:16]=[CH:17][C:18](=[O:22])[NH:19]3)=[CH:14][CH:13]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: O=C1CCc2ccc(OCCCC(S)c3ccccc3)cc2N1
Product: O=c1ccc2ccc(OCCCCSc3ccccc3)cc2[nH]1

Procedure:
Prepared analogous to Example 86 from 7-(4-phenyl-mercapto-butoxy)-3,4-dihydro-carbostyril and 2,3-dichloro-5,6-dicyano-benzoquinone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[C:12]([C:14](=[O:20])[CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:11]=[C:10]([O:21][CH3:22])[C:4]=1[N:5]([CH3:9])[C:6](=[O:8])[CH3:7].[BH4-].[Na+]>C(O)C>[OH:20][CH:14]([C:12]1[CH:13]=[C:3]([O:2][CH3:1])[C:4]([N:5]([CH3:9])[C:6](=[O:8])[CH3:7])=[C:10]([O:21][CH3:22])[CH:11]=1)[CH2:15][S:16]([CH3:19])(=[O:17])=[O:18]
Reactant: COc1cc(C(=O)CS(C)(=O)=O)cc(OC)c1N(C)C(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(C(O)CS(C)(=O)=O)cc(OC)c1N(C)C(C)=O

Procedure:
A suspension of 20.9 g. of 2',6'-dimethoxy-N-methyl-4'-[(methylsulfonyl)acetyl]-acetanilide and 9.5 g. of sodium borohydride in 300 ml. of ethanol was stirred at room temperature for 20 hours. The solution was diluted with 300 ml. of water and the alcohol removed under vacuum. The resulting suspension was extracted with two 1 liter portions of ethyl acetate. The ethyl acetate extracts were washed with two 200 ml. portions of water, combined, dried over magnesium sulfate and evaporated under vacuum. Recrystallization of the residue from ethyl acetate gave 4'-[1-hydroxy-2-(methylsulfonyl)-ethyl]-2',6'-dimethoxy-N-methyl-acetanilide having a melting point of 175°-177° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:17]([NH2:19])[CH3:18])[C:8]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[NH:23][CH:24]=[N:25]2.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:17]([NH:19][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:18])[C:8]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1cc2ccc(F)cc2nc1-c1cccs1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2ccc(F)cc2nc1-c1cccs1

Procedure:
Prepared according to Procedure H using (1S)-1-(7-fluoro-2-(thiophen-2-yl)-quinolin-3-yl)ethanamine (0.078 g, 0.286 mmol), 6-chloropurine (0.053 g, 0.344 mmol, 1.2 eq) and DIEA (0.58 mmol, 2.0 eq) in n-butanol (3 mL). N-((S)-1-(7-fluoro-2-(thiophen-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine [PI3Kδ IC50=8 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.62 (s, 1H), 8.43 (s, 1H), 8.37 (s, 1H), 8.00-8.07 (m, 1H), 7.62-7.73 (m, 3 H), 7.43-7.51 (m, 1H), 7.18 (m 1H), 1.78 (d, J=7.04 Hz, 3H), 1H), Mass Spectrum (ESI) m/e=391 (M+1).
Reaction SMILES: CN1CCOCC1.[O:8]=[C:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH2:14][CH2:15][C:16]([OH:18])=O.[CH:19]1([Mg]Br)[CH2:23][CH2:22][CH2:21][CH2:20]1>C1COCC1.[Cu](I)I>[CH:19]1([C:16](=[O:18])[CH2:15][CH2:14][N:10]2[CH2:11][CH2:12][CH2:13][C:9]2=[O:8])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Br[Mg]C1CCCC1
Reactant: O=C(O)CCN1CCCC1=O
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C(CCN1CCCC1=O)C1CCCC1
Temperature: 0 °C
Yield: 15 %

Procedure:
2-Chloro-4-6-dimethoxy-1,3,5-triazine (2.68 g, 15.2 mmol) and N-methylmorpholine (4.2 mL, 38.1 mmol) were added to a solution of 3-(2-Oxo-pyrrolidin-1-yl)-propionic acid (2 g, 12.7 mmol, from Step 1) in THF (35 mL). After 1 h the reaction mixture was filtered through a glass frit to remove a white precipitate. The filtrate was treated with copper iodide (2.4 g, 12.7 mmol), cooled to 0° C. and then cyclopentyl magnesium bromide (6.35 mL, 12.7 mmol, 2M in ether) was added. After 4 h the resulting black mixture was quenched with saturated NH4Cl and extracted with CH2Cl2. The organic layers were washed with 1 N HCl, saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was purifed by silica gel chromatography (75% EtOAc in hexanes then 5% MeOH in CH2Cl2) to give the title compound as a yellow oil. (0.4 g, 15% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+].[Cl:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][C:43]=1[Cl:44])[CH:39]=O>C(Cl)(Cl)Cl>[Cl:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][C:43]=1[Cl:44])[CH2:39][NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCNCc1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 69.8 %

Procedure:
tert-Butyl N-(2-aminoethyl)carbamate (1.51 g) was dissolved in chloroform (20 ml) and 3,4-dichlorobenzaldehyde (1.65 g), acetic acid (0.54 ml) and sodium triacetoxyborohydride (2.6 g) were added at room temperature. The mixture was stirred overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the obtained reaction mixture and the mixture was stirred and extracted three times with chloroform. The combined organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to give tert-butyl [2-(3,4-dichlorobenzylamino)ethyl]carbamate (2.1 g).
Reaction SMILES: [C:1]([CH:5]1[CH2:9][CH2:8][CH2:7][NH:6]1)([O:3][CH3:4])=[O:2].N1C=CC=CC=1.[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17]>C(Cl)Cl>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([N:6]2[CH2:7][CH2:8][CH2:9][CH:5]2[C:1]([O:3][CH3:4])=[O:2])=[O:24])=[CH:26][CH:27]=1)([O-:18])=[O:17]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)C1CCCN1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1CCCN1C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.8 %

Procedure:
To 2-carbomethoxypyrrolidine (d,1-proline methylester, 1.64 g, 12.7 mmol) with pyridine (10.1 g, 12.7 mmol) in CH2Cl2 (100 mL) at 0° C. was added 4-nitrobenzoyl chloride (2.36 g, 12.7 mmol) in CH2Cl2 (25 mL) dropwise. The reaction was allowed to warm to ambient temperature and stirred 18 h. The reaction was evaporated and applied to a silica gel flash column and eluted with a gradient of 2:1 Hexane:EtOAc to 1:2 Hexane:EtOAc. There was isolated 1.3 g of the title compound; LRMS (M+H)+ m/z=279.
Reaction SMILES: O[C:2]1([C:16]([OH:18])=[O:17])[CH2:7][C:6](=[O:8])[CH2:5][CH2:4][C:3]1([CH3:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:15][C:3]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:5][C:6](=[O:8])[CH:7]=[C:2]1[C:16]([OH:18])=[O:17]
Reactant: CC1(c2ccccc2)CCC(=O)CC1(O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(c2ccccc2)CCC(=O)C=C1C(=O)O
Temperature: 0 °C
Yield: 69.1 %

Procedure:
4.4 g (17.6 mmol) of (1 RS,2RS)-1-hydroxy-2-methyl-5-oxo-2-phenylcyclohexane-1-carboxylic acid were heated at reflux for one hour in 100 cm3 of toluene in the presence of 0.34 g of para-toluenesulphonic acid. The reaction mixture was cooled to 0° C. and the precipitate formed was filtered off, washed with ethyl ether and then dried at 50° C. 2.8 g (69%) of (RS)-2-methyl-5-oxo-2-phenylcyclohexene-1-carboxylic acid were thus obtained in the form of a pink solid, the characteristics of which were as follows:
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].N1C=CC=CC=1.Cl[C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30].Cl>C(Cl)Cl>[CH2:32]([O:31][C:29](=[O:30])[C:28]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:15][CH:16]=1)=[O:34])[CH3:33]
Reactant: CCCCCCCCCCCCOc1ccc(N)cc1
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCOc1ccc(NC(=O)C(=O)OCC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
In a 1 L jacketed flask under a nitrogen atmosphere is added 60 g (0.2425 mols) of p-dodecyloxyaniline, 650 mL of CH2Cl2 and 56.6 g of pyridine (0.716 mols) and the resulting solution is cooled to 0° C. Maintaining an internal temperature below 5° C., 46.3 g (0.339 mols) of ethyl chlorooxoacetate is then added dropwise over a period of one hour. After the addition is complete, the internal temperature is maintained at 10° C. overnight. To the resultant reaction mixture is added rapidly 400 mL of 1N HCl and the resultant mixture is allowed to warm to RT. The reaction mixture is stirred for one hour than the organic phase separated. The organic phase is dried over anhydrous sodium sulphate and isolubles removed by filtration. The volatiles are removed in vacuo and the residue is recrystallized from ethanol (250 mL). The solid is washed twice with ethanol (50 mL) at 0° C. to give 64.1 g of a white solid, mp. 70.5–72° C. The NMR, MS and IR spectra are consistent with the product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C@H:13]([NH:24][C:25]3[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([Cl:33])[C:26]=3[CH3:34])[C@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH3:15])=[N:10][N:9]=2)=[CH:4][CH:3]=1.[C:35](Cl)(=[O:39])[CH2:36][CH2:37][CH3:38]>C(Cl)Cl.N1C=CC=CC=1>[Si:17]([O:16][C@H:14]([CH3:15])[C@H:13]([C:11]1[O:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])=[CH:7][CH:6]=2)=[N:9][N:10]=1)[NH:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([Cl:33])[C:26]=1[CH3:34])([C:20]([CH3:22])([CH3:23])[CH3:21])([CH3:19])[CH3:18]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(N)cc3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=O)Nc1ccc(-c2nnc([C@H](Nc3ccc(C#N)c(Cl)c3C)[C@@H](C)O[Si](C)(C)C(C)(C)C)o2)cc1
Yield: 99.9 %

Procedure:
To a solution of 4-((1R,2R)-1-(5-(4-aminophenyl)-1,3,4-oxadiazol-2-yl)-2-(tert-butyldimethylsilyloxy)propylamino)-2-chloro-3-methylbenzonitrile (intermediate 69d) (308 mg, 0.62 mmol) in CH2Cl2 (10 mL) and pyridine (1.5 mL) was added butyrylchloride (90 μL, 0.87 mmol) at room temperature. The resultant solution stirred for 90 hours and quenched with 2N aq. HCl (15 mL). The mixture was further partitioned between H2O (40 mL) and CH2Cl2 (35 mL). The aqueous layer was extracted with CH2Cl2 (35 mL). The combined organic extracts were washed with sat. aq. NaHCO3 (2×45 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a colourless oil (352 mg, 100%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 9.42 (s 1H), 7.93 (dm, 0.7=8.8 Hz, 2H), 7.85 (dm, J=8.8 Hz, 2H), 7.51 (d, J=8.6 Hz, 1H), 6.94 (d, 8.6 Hz, 1H), 5.74 (d, J=9.2 Hz, 1H), 5.03 (dd, J=6.5, 9.0 Hz, 1H), 4.66 (pentet, 6.3 Hz, 1H), 2.38 (t, J=7.2 Hz, 2H), 2.35 (s, 1.70 (sextet, J=7.4 Hz, 2H), 1.44 (d, J=6.1 Hz, 3H), 0.95 (t, J=7.4 Hz, 3H), 0.81 (s, 9H), 009 (s, 3H), −0.01 (s, 3H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]=[C:10]=[S:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[NH2:12][C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1.C(OCC)(=O)C>CN(C)C=O>[C:1]1([CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]2[S:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[S:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: Nc1nc2ccccc2s1
Reactant: S=C=NCCC1=CCCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: S=C(NCCC1=CCCCC1)Nc1nc2ccccc2s1
Temperature: 25 °C
Yield: 40.5 %

Procedure:
A solution of 2-(1-cyclohexenyl)ethyl isothiocyanate (3.3 g, 20 mmol) and 2-aminobenzothiazole (3.0 g, 20 mmol) in N,N-dimethylformamide (50 mL) was heated at 100° C. for 17.5 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 2.57 g (40%) of the title product:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][S:16](=[O:19])[CH2:15][CH2:14]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([SH:12])[C:6]=2[N:7]=1.[CH:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21]>>[CH:20]([N:22]1[CH2:27][CH2:26][N:25]([C:2]2[N:3]=[C:4]([N:13]3[CH2:18][CH2:17][S:16](=[O:19])[CH2:15][CH2:14]3)[C:5]3[N:11]=[CH:10][N:9]=[C:8]([SH:12])[C:6]=3[N:7]=2)[CH2:24][CH2:23]1)=[O:21]
Reactant: O=S1CCN(c2nc(Cl)nc3c(S)ncnc23)CC1
Reactant: O=CN1CCNCC1
Product: O=CN1CCN(c2nc(N3CCS(=O)CC3)c3ncnc(S)c3n2)CC1

Procedure:
This compound was prepared analagous to Example 93 from 2-chloro-8-mercapto-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: >280° C., decomp.) and N-formyl-piperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]([CH3:28])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])[C:5](O)=[O:6].[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:33]2[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]2)=[O:6])[CH:8]=[CH:9][C:10]=1[N:11]([CH3:28])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13]
Reactant: CN1CCNCC1
Reactant: CN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccc(C(=O)O)cc1Cl
Product: CN1CCN(C(=O)c2ccc(N(C)C(=O)c3cc4c(s3)-c3ccccc3OCC4)c(Cl)c2)CC1

Procedure:
3-Chloro-4-(N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoic acid and N-methylpiperazine were reacted by a procedure similar to Example 47 to give 252. MS: (ESI+) 496.2
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1.[C:13]([NH:18][C@H:19]([C:28]([O:30][CH3:31])=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1)(=[O:17])[CH:14]([CH3:16])[CH3:15].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:13]([NH:18][C@H:19]([C:28]([O:30][CH3:31])=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:12][CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][O:2][CH3:1])=[CH:5][CH:6]=2)=[CH:23][CH:22]=1)(=[O:17])[CH:14]([CH3:15])[CH3:16]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C(C)C
Reactant: COCc1ccc(CCO)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCc1ccc(CCOc2ccc(C[C@H](NC(=O)C(C)C)C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.6 %

Procedure:
2-[4-(Methoxymethyl)phenyl]ethanol (0.6 g, 3.61 mmol) and methyl N-isobutyryltyrosinate (1.15 g, 4.34 mmol) were mixed in dichloromethane (20 ml, dry). 1,1′-(Azodicarbonyl)dipiperidine (1.1 g, 4.36 mmol) and triphenylphosphine (1.14 g, 4.35 mmol) were then added respectively. The mixture was stirred at room temperature overnight and filtered. The filtrate was evaporated in vacuum to dry. Column chromatography of the residue on silica gel using ethyl acetate/heptane (gradient 5:95 to 50:50) as eluant gave 0.71 g desired product, yield 48%.