Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OP(CC(CC(C)C)C(O)=O)(C[N:7]1[C:11](=[O:12])[C:10]2=CC=[CH:15][CH:16]=[C:9]2C1=O)=O)C.N[CH:28]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][C:30](=[O:41])[NH:29]1>>[O:41]=[C:30]1[CH:31]([CH:10]([CH2:9][CH2:16][CH3:15])[C:11]([NH2:7])=[O:12])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:28][NH:29]1
Reactant: CCOP(=O)(CC(CC(C)C)C(=O)O)CN1C(=O)c2ccccc2C1=O
Reactant: NC1CCCCCCCCCCC(=O)N1
Product: CCCC(C(N)=O)C1CCCCCCCCCCNC1=O

Procedure:
In a manner analogous to that described in Example 1(A)(iv), from 1.9 g of 2(RS)-[[(RS)-(ethoxy)(phthalimidomethyl)phosphinyl]methyl]-4-methylvaleric acid and 1.0 g of (-)-3-amino-2-azacyclotridecanone, there were obtained 2.1 g of 2(RS)-[[(RS)-(ethoxy)(phthalimidomethyl)phosphinyl]methyl]-4-methyl-N(R or S)-(2-oxoazacyclotridecan-3-yl)valeramide in the form of a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]=[C:3]2[C:7](=[O:10])[S:8][CH2:9][CH:2]12.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C1(C=CC(O)=CC=1)O.O=O>C1C=CC=CC=1.O>[O:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:7](=[O:10])[S:8][CH2:9][CH:2]12
Reactant: O=C1SCC2OCCC=C12
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=O
Agent: Oc1ccc(O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=C1SCC2OC=CC=C12

Procedure:
A magnetically-stirred solution of 3,5,6,7-tetrahydro-1H-thieno[3,4-b]pyran-5-one (14.32 g, 0.09168 mol) in benzene (150 mL) was treated, in portions, with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (21.29 g, 0.09378 mol). The DDQ dissolved exothermically, giving a dark brown solution which gradually faded to orange, as the crystalline hydroquinone separated. The solids were removed by filtration and rinsed with CH2Cl2. The filtrates were concentrated in vacuo, and the residue was twice distilled (Kugelrohr) to give a mobile light orange oil. (bp>141° C./1.8 Torr or 126°-145° C./0.55 Torr, external temperature). Yield: 11.98 g (84.7%). The product solidified upon storage under N2 at -20° C. NMR and GC/MS data were in agreement with the proposed structure. The compound is sensitive to water, oxygen and light.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[CH2:5]([O:12][C:13](Cl)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>N1C=CC=CC=1.C(Cl)Cl>[CH2:5]([O:12][C:13](=[O:14])[NH:4][CH2:1][C:2]#[CH:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C#CCN
Solvent: c1ccncc1
Solvent: ClCCl
Product: C#CCNC(=O)OCc1ccccc1
Reaction time: 16 h
Yield: 32.9 %

Procedure:
To a solution of propargylamine (6.4 g, 71.2 mmol) in pyridine (100 mL) was added benzylchloroformate (13.37 g, 78.2 mmol) in 100 mL CH2Cl2 over 0.5 h. The reaction was stirred for 16 h and the volatiles were removed in vacuo. The residue was dissolved in EtOAc and the organic solution was washed with water (2×). The organic solution was washed with dilute aqueous HCl followed by saturated NaHCO3. The organic solution was dried over MgSO4, filtered, and concentrated in vacuo to provide the title compound of Step A(4.43 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:21]3[C:20](=[O:30])[N:19](COC(=O)C(C)(C)C)[C:18](=[O:39])[N:17]([CH2:40][C:41]([O:43][CH3:44])=[O:42])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl>O1CCCC1.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:21]3[C:20](=[O:30])[NH:19][C:18](=[O:39])[N:17]([CH2:40][C:41]([O:43][CH3:44])=[O:42])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)Cn1c(=O)n(COC(=O)C(C)(C)C)c(=O)c2c1nc(N1CCN(C(=O)OC(C)(C)C)CC1)n2-c1ccccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)Cn1c(=O)[nH]c(=O)c2c1nc(N1CCN(C(=O)OC(C)(C)C)CC1)n2-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
4-[7-(2-Chlorophenyl)-1-(2,2-dimethylpropionyloxymethyl)-3-methoxycarbonylmethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (139 mg) was dissolved in tetrahydrofuran (1 ml) and methanol (1 ml), and sodium hydride (10 mg) was added to the solution. Then, the mixture was stirred at room temperature for 1 hour. The mixture was neutralized by adding 1N Hydrochloric acid, and was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and filtered. The solvent was removed by distillation to give 100 mg of 4-[7-(2-chlorophenyl)-3-methoxycarbonylmethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester. This compound was dissolved in N,N-dimethylformamide (2 ml) and potassium carbonate (20 mg) and methyl iodide (0.02 ml) were added to the solution. The mixture was stirred at room temperature for 3 days. The mixture was diluted with ethyl acetate, and washed with water and 1N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate, and filtered. The solvent was removed by distillation to give 108 mg of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[OH:17])(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:24](Br)[CH:25]=[CH2:26].CCOCC>CN(C=O)C>[C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:7]=[CH:6][C:5]=1[O:17][CH2:26][CH:25]=[CH2:24])(=[O:3])[CH3:2]
Reactant: C=CCBr
Reactant: CC(=O)c1cc(Oc2ccccc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=CCOc1ccc(Oc2ccccc2)cc1C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Acetyl-4-phenoxyphenol (4.22 g, 18.5 mmol) and cesium carbonate (15.0 g, 46.0 mmol) are taken in DMF (50 mL) and treated with allyl bromide (2.24 g, 18.5 mmol). The mixture is stirred overnight at room temperature. Ether is added and the mixture is washed with saturated aqueous ammonium chloride solution. The organic phase is dried over magnesium sulfate and evaporated to give 2-acetyl-1-allyloxy-4-phenoxybenzene as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O[NH:38][C:39]([C:41]1[C:42]2[CH:43]=[CH:44][NH:45][C:46]=2[CH:47]=[CH:48][CH:49]=1)=[NH:40]>CN(C=O)C.CCOC(C)=O>[NH:45]1[C:46]2[C:42](=[C:41]([C:39]3[N:38]=[C:6]([C:5]4[CH:9]=[CH:10][C:11]([O:12][CH:13]([CH3:15])[CH3:14])=[C:3]([CH:4]=4)[C:1]#[N:2])[O:8][N:40]=3)[CH:49]=[CH:48][CH:47]=2)[CH:43]=[CH:44]1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Reactant: N=C(NO)c1cccc2[nH]ccc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1C#N
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
To 3-cyano-4-[(1-methylethyl)oxy]benzoic acid (can be prepared as described in WO2005/58848) (500 mg, 2.44 mmol) in DMF (15 ml) was added EDAC (514 mg, 2.67 mmol) and HOBt (367 mg, 2.67 mmol) and the solution left standing for 30 minutes. Added N-hydroxy-1H-indole-4-carboximidamide (D9) (427 mg, 2.44 mmol) and left standing for 1 hour. To the solution were added EDAC (117 mg, 0.61 mmol) and HOBt (84 mg, 0.61 mmol) and left standing for 2 hours. To the solution were added EDAC (234.9 mg, 1.22 mmol) and HOBt (167.7 mg, 1.22 mmol) and left standing overnight. Heated at 80° C. overnight, cooled and added EtOAc (30 ml). Washed with water (30 ml), sat. sodium hydrogen carbonate (30 ml) and water (30 ml). Dried over MgSO4 and evaporated off the solvent. The residue was triturated with diethyl ether to give 353 mg of the title compound as a pale brown solid. δH (400 MHz, d6-DMSO) 1.39 (6H, d), 4.94-5.03 (1H, m), 7.09-7.10 (1H, m), 7.30 (1H, t), 7.56-7.59 (2H, m), 7.67 (1H, d), 7.92 (1H, dd), 8.45 (1H, dd), 8.55 (1H, d), 11.52 (1H, broad s). MS (ES) C20H16N4O2 requires 344; found 345 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10](Cl)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]1[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[CH:17]=[CH:16]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]1[CH2:9][N:15]1[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[CH:17]=[CH:16]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: ClC1CCCN(Cc2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc(CN2CCCC2Cn2ccc3cccnc32)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
A mixture of 1-benzyl-3-chloropiperidine (3.83 g, 18.3 mmol), 1H-pyrrolo[2,3-b]pyridine (4.4 g, 36.5 mmol) and cesium carbonate (17.8 g, 54.8 mmol) in DMSO is stirred at 80° C. under a nitrogen atmosphere for 24 h. The reaction is monitored by thin layer chromatography. Two additional amounts of 1-benzyl-3-chloro-piperidine (3.83 g and 1.91 g) are added at 12 h intervals. After 48 h, the mixture is cooled, treated with water and extracted with ethyl acetate. The extracts are combined, washed sequentially with water and brine and concentrated in vacuo. The resultant residue is purified by flash chromatography (4–5% methanol in CH2Cl2 as eluent) to afford the title compound as an oil, 6.5 g (60% yield), identified by HNMR and mass spectral analyses.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[CH3:19][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI.S(=O)(=O)(O)O>COCCOCCOC>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:7](=[O:9])[N:8]([CH3:19])[C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2cc(Br)ccc2n1-c1ccc(F)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)(O)O
Agent: [Li+]
Solvent: CI
Solvent: COCCOCCOC
Product: Cn1c(=O)n(-c2ccc(F)cc2)c2ccc(Br)cc21
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
To a stirred room temperature suspension of 5-bromo-1-(4-fluorophenyl)-1,3-dihydro-benzimidazol-2-one (160 mg, 0.52 mmol) in anhydrous bis(2-methoxyethyl)ether (5 mL) was added lithium bis(trimethylsilyl)amide (0.55 mL of 1.06 M solution in THF, 0.58 mmol). After 30 minutes, methyl iodide (125 μL, 2 mmol) was added. After 2 hours, the mixture was poured into 1 N sulfuric acid containing ice. The resulting precipitate was filtered, washed with water, and dried to afford 160 mg of 5-bromo-1-(4-fluorophenyl)-3-methyl-1,3-dihydro-benzimidazol-2-one as an off-white solid. MS m/z 321/323 (MH+).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2].C1C=CC2N(O)N=[N:38]C=2C=1.N.C(Cl)CCl.C(N1CCOCC1)C.CCN=C=NCCCN(C)C>ClCCl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([NH2:38])=[O:19])=[CH:21][CH:22]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](Nc2ccc(Cl)cc2)C[C@@H]1C
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(=O)N1c2ccc(-c3ccc(C(N)=O)cc3)cc2[C@H](Nc2ccc(Cl)cc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
A flask was charged with 4-{(2S,4R)-1-acetyl-4-[(4-chlorophenyl)amino]-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl}benzoic acid (for a preparation see example 6) (109 mg, 0.251 mmol), HOBT.NH3 (85 mg, 0.501 mmol) and EDC (57.7 mg, 0.301 mmol) then filled with dichloromethane (DCM) (5 mL) and the resulting mixture was treated with N-ethylmorpholine (NEM) (0.095 mL, 0.752 mmol) then stirred a room temperature. After 4 h, 50% of the previous quantities of EDAC, HOBT and NEM were added and the resulting mixture was stirred at room temperature for 16 h. Most of the DCM was removed in vacuo and the residue was partitioned between AcOEt and water. The layers were separated and the aqueous phase was extracted with AcOEt. The combined organic phases were washed twice with a saturated NaHCO3 aqueous solution then brine, dried over MgSO4 and concentrated in vacuo. The residue was triturated with Et2O then filtered off and dried under house vacuum to give 4-{(2S,4R)-1-acetyl-4-[(4-chlorophenyl)amino]-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl}benzamide (75 mg, 0.173 mmol, 69.0% yield) as a very pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:16][N:15]([CH2:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[C@H:14](/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][C:29]([O:31]C)=[O:30])[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[C:29]([CH2:28][CH2:27][CH2:26]/[CH:25]=[CH:24]\[C@@H:14]1[CH2:13][C@@H:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])[CH2:16][N:15]1[CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)([OH:31])=[O:30]
Reactant: COC(=O)CCC/C=C\[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1Cc1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCC/C=C\[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1Cc1cccnc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.7 %

Procedure:
A solution of (2S,4R)-4-[4-chlorophenylsulfonylamino)-2-[(Z)-5-methoxycarbonyl-1-pentenyl]-1-(3-pyridylmethyl)pyrrolidine (670 mg) in a mixture of methanol (5 ml) and 1N-aqueous sodium hydroxide (3 ml) was stirred at room temperature for 4 hours. The solution was adjusted to pH 5 with 10% hydrochloric acid and extracted with chloroform, and the organic solution was washed with brine. The solution was dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was chromatographed on a silica gel (20 g) column with a mixture of chloroform and methanol (20:1) as an eluent to give (2S,4R)-2-[(Z)-5-carboxy-1-pentenyl]-4-(4-chlorophenylsulfonylamino)-1-(3-pyridylmethyl)pyrrolidine (408 mg) as a pale yellow amorphous.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[N+:8]([O-:22])([O:10][CH2:11][C@H:12]([O:18][N+:19]([O-:21])=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[O:9].C(N(CC)CC)C>C(Cl)Cl>[C:2](=[O:3])([O:4][CH:5]([Cl:7])[CH3:6])[O:17][CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]([O:18][N+:19]([O-:21])=[O:20])[CH2:11][O:10][N+:8]([O-:22])=[O:9]
Reactant: O=[N+]([O-])OC[C@@H](CCCCO)O[N+](=O)[O-]
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Cl)OC(=O)OCCCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-]
Reaction time: 2 h

Procedure:
1-Chloroethyl chloroformate (6.42 mL, 58.9 mmol) was added dropwise to a stirred solution of (2R)-6-hydroxyhexane-1,2-diyl dinitrate (12 g, 53.5 mmol) and triethylamine (8.95 mL, 64.2 mmol) in DCM (268 mL) at 0° C. After 2 h, the solution was washed with water, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 5-40% EtOAc/hexanes to give the title compound as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 6.40 (q, J=6.0 Hz, 1H), 5.28 (ddd, J=13.0, 6.2, 3.0 Hz, 1H), 4.74 (dd, J=13.0, 3.0 Hz, 1H), 4.47 (dd, J=13.0, 6.5 Hz, 1H), 4.25-4.16 (m, 2H), 1.82 (d, J=6.0 Hz, 3H), 1.82-1.71 (m, 4H), 1.63-1.46 (m, 2H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[C:15](Br)=[CH:14][C:13]2[C:12]([CH3:18])([CH3:17])[CH2:11][CH2:10][C:9]([CH3:20])([CH3:19])[C:8]=2[CH:7]=1.[Cl-].[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1[CH2:25][Zn+]>O1CCCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[C:15]([CH2:25][C:24]2[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:23]=2[F:22])=[CH:14][C:13]2[C:12]([CH3:18])([CH3:17])[CH2:11][CH2:10][C:9]([CH3:20])([CH3:19])[C:8]=2[CH:7]=1
Reactant: CC1(C)CCC(C)(C)c2cc(C3OCCO3)c(Br)cc21
Reactant: Fc1ccc(C[Zn+])c(F)c1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(C3OCCO3)c(Cc3ccc(F)cc3F)cc21
Yield: 85.7 %

Procedure:
To a mixture of 2-(1,3-dioxolan-2-yl)-3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (250 mg, 0.74 mmol) and tetrakis(triphenylphospine)palladium(0) (21 mg, 0.018 mmol) under an argon atmosphere was added a 0.5 M tetrahydrofuran solution of 2,4-difluorobenzylzinc chloride (7.3 mL, 3.68 mmol). The reaction was stirred at reflux overnight and partitioned between saturated ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was purified by preparative thin layer chromatography on silica gel (5% ethyl acetate/hexane) to give 2-(1,3-dioxolan-2-yl)-3-(2,4-difluorobenzyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene as a white crystalline solid (245 mg, 96%).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:9]([CH3:19])=[C:10]3[C:15](=[O:16])[NH:14][CH2:13][CH2:12][N:11]3[C:17]=2[CH3:18])[CH:5]=[CH:4][N:3]=1.[NH:20]1[C:24]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)=[N:23][N:22]=[N:21]1>>[CH3:18][C:17]1[N:11]2[CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:10]2=[C:9]([CH3:19])[C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([C:24]3[NH:23][N:22]=[N:21][N:20]=3)=[CH:26][CH:27]=2)[N:7]=1
Reactant: Nc1ccc(-c2nnn[nH]2)cc1
Reactant: Cc1c(-c2ccnc(F)n2)c(C)n2c1C(=O)NCC2
Product: Cc1c(-c2ccnc(Nc3ccc(-c4nnn[nH]4)cc3)n2)c(C)n2c1C(=O)NCC2

Procedure:
Prepared by reaction of 7-(2-fluoropyrimidin-4-yl)-6,8-dimethyl-3,4-dihydro-2H-pyrrolo[1,2-a]pyrazin-1-one with 4-(1H-tetrazol-5-yl)-phenylamine.
Reaction SMILES: C[Si](C)(C)Cl.Br[CH2:7][C:8]([O:10][CH3:11])=[O:9].[CH2:12]1[O:20][CH:13]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>C(OC(C)C)(=O)C.[Zn]>[OH:20][CH:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:12][CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: c1ccc(C2CO2)cc1
Reactant: COC(=O)CBr
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)OC(C)C
Product: COC(=O)CCC(O)c1ccccc1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
At room temperature, a three-neck flask equipped with a reflux condenser, internal thermometer, dropping funnel and stirrer under nitrogen protective gas was initially charged with 15.1 g of zinc powder (231 mmol) in 90 ml of isopropyl acetate. After 3.7 ml of trimethylchlorosilane (29 mmol) had been added, the mixture was heated to 60° C. for 20 min, then allowed to cool to 55° C. and 32.6 g of undiluted methyl bromoacetate (213 mmol) were subsequently added dropwise within 10 min, and the temperature was maintained at 60° C. by external cooling. The mixture was then stirred at 50° C. for 15 min. After cooling to 5° C., 21.3 g of undiluted styrene oxide (178 mmol) were added, and the temperature was maintained at 5° C. by external cooling. After stirring had been continued at 5° C. for 30 min, the mixture was heated to 25° C. within 20 min and stirred at this temperature for a further 30 min. After cooling to 0° C., the mixture was acidified using 33 ml of 20% hydrochloric acid to a pH of 1 and stirred for 30 min. Excess zinc was then filtered off and the organic phase removed. The organic phase was then stirred at 0° C. with 40 ml of 1 N hydrochloric acid and finally washed with 20 ml of concentrated ammonia solution. After the phase separation, drying was effected over sodium sulfate and the solvent was distilled off under reduced pressure (>90% of the solvent isopropyl acetate was recovered). After distillation, methyl 4-hydroxy-4-phenylbutyrate was obtained in a yield of 30.9 g (90% of theory) and had a boiling point of 128° C. (4 mbar).
Reaction SMILES: [N:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][C:16]([C:19]4[C:20]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[N:21][O:22][C:23]=4[CH3:24])=[N:17][N:18]=3)=[CH:10][CH:9]=2)=[O:7])C=CN=[CH:2]1.NC[CH:33]1[CH2:35][CH2:34]1>>[CH:33]1([CH2:2][NH:1][C:6](=[O:7])[C:8]2[CH:9]=[CH:10][C:11]([C:14]3[O:15][C:16]([C:19]4[C:20]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)=[N:21][O:22][C:23]=4[CH3:24])=[N:17][N:18]=3)=[CH:12][CH:13]=2)[CH2:35][CH2:34]1
Reactant: NCC1CC1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(C(=O)n3ccnc3)cc2)o1
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(C(=O)NCC3CC3)cc2)o1
Yield: 44 %

Procedure:
As described for example 78c, imidazol-1-yl-{4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-methanone (200 mg, 0.50 mmol) was converted using aminomethylcyclopropane instead of cyclopropylamine to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=60:20:20 to 0:80:20, 88 mg, 44%) which was obtained as a white solid. MS: m/e=433.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]2[N:7]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:6]=[CH:5][C:4]=2[C:3]=1[CH:22]=[O:23].[CH:24]([Mg]Br)=[CH2:25].[NH4+].[Cl-].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C1COCC1.O>[CH3:1][C:2]1[C:3]([C:22](=[O:23])[CH:24]=[CH2:25])=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([S:12]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C=O)c(C)cc(C)c32)cc1
Reactant: C=C[Mg]Br
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC(=O)c1c(C)cc(C)c2c1ccn2S(=O)(=O)c1ccc(C)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 5,7-dimethyl-1-tosyl-1H-indole-4-carbaldehyde (Example 46-D) (500 mg, 1.53 mmol) in THF (15 mL) at −78° C., vinylmagnesium bromide (2.29 mL, 2.29 mmol) was added and the reaction was stirred for 15 minutes. At this point a saturated water solution of NH4Cl was added. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organics were dried over MgSO4 and evaporated. The resulting residue was dissolved in DCM (4 mL), and Dess-Martin Periodinane (1.19 g, 2.81 mmol) was added. After 15 minutes the reaction was complete. The reaction was quenched with a sat. aq. solution of NaHCO3 and sodium thiosulfate. The layers were separated and the aqueous layer was extracted with DCM. It was purified using FCC eluting with heptane/EtOAc 1:1 to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J=3.79 Hz, 1H), 7.50-7.66 (m, J=8.34 Hz, 2H), 7.30-7.45 (m, J=8.34 Hz, 2H), 7.01 (s, 1H), 6.71 (dd, J=10.48, 17.56 Hz, 1H), 6.59 (d, J=4.04 Hz, 1H), 6.14 (d, J=10.86 Hz, 1H), 5.88 (d, J=17.43 Hz, 1H), 2.35 (s, 3H), 2.21 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>>[Br:1][C:2]1[S:6][C:5]([C:7]([Cl:12])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Br)s1
Product: O=C(Cl)c1ccc(Br)s1

Procedure:
Following the procedure of Example 32, 2.07 g (10.0 mmoles) of commercially available 5-bromo-2-thiophenecarboxylic acid was reacted with 10 ml of thionyl chloride to give 2.35 g of crude 5-bromo-2-thiophenecarbonyl chloride as a red oil. The total crude acid chloride was coupled to 1.76 g (8.33 mmoles) of 5-chloro-2-oxindole-1-carboxamide by the procedure in Example 32 using 3.05 g (25.0 mmoles) of 4-(N,N-dimethylamino)pyridine and 50 ml of N,N-dimethylformamide. Acidic workup gave a solid which was recrystallized to give 1.77 g (4.43 mmoles, 53% yield) of title compound as reddish-brown crystals, m.p. 228°-229° C (tetrahydrofuran).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH2:19])[CH:13]([CH3:15])[CH3:14]>>[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH:19][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)COC(=O)[C@H](C)N
Reactant: Cc1ccc(CC(=O)O)cc1
Product: Cc1ccc(CC(=O)N[C@@H](C)C(=O)OCC(C)C)cc1

Procedure:
Following General Procedure I′ above, and using 4-methylphenylacetic acid (Aldrich) and L-alanine iso-butyl ester (prepared following General Procedure J′ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.