Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N.[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C1C=CC2N(O)N=[N:24]C=2C=1.CCN=C=NCCCN(C)C.Cl>O1CCCC1>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([NH2:24])=[O:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: C1CCOC1
Product: NC(=O)c1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.2 %

Procedure:
Into a 50-mL round-bottom flask was placed tetrahydrofuran saturated with NH3 (gas) (20 mL), 4′-hydroxybiphenyl-4-carboxylic acid (1 g, 4.67 mmol, 1 equiv), HOBt (900 mg, 6.67 mmol, 1.4 equiv), EDCl (1.34 g, 7.0 mmol, 1.5 equiv). The resulting solution was stirred for 4 hrs at room temperature. The resulting mixture was concentrated under vacuum. The residue was dissolved in 50 mL of ethyl acetate, washed with 2×40 mL of H2O, 1×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The reside was purified by column chromatography on silica gel (eluting with 1:1 ethyl acetate/petroleum ether) to give 500 mg (50%) of 4′-hydroxybiphenyl-4-carboxamide as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][OH:15])[NH:11][CH2:10][C@H:9]1[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:18][C:19](Cl)=[O:20].[F:22][C:23]1[CH:40]=[CH:39][CH:38]=[CH:37][C:24]=1[CH2:25][C:26]1[N:31]=[CH:30][C:29]2[C:32]([CH3:36])([CH3:35])[CH2:33][NH:34][C:28]=2[CH:27]=1.CCN(C(C)C)C(C)C>C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][OH:15])[N:11]([CH2:18][C:19]([N:34]2[C:28]3[CH:27]=[C:26]([CH2:25][C:24]4[CH:37]=[CH:38][CH:39]=[CH:40][C:23]=4[F:22])[N:31]=[CH:30][C:29]=3[C:32]([CH3:36])([CH3:35])[CH2:33]2)=[O:20])[CH2:10][C@H:9]1[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN[C@@H](CO)CN1C(=O)OC(C)(C)C
Reactant: CC1(C)CNc2cc(Cc3ccccc3F)ncc21
Reactant: O=C(Cl)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3cnc(Cc4ccccc4F)cc32)[C@@H](CO)CN1C(=O)OC(C)(C)C

Procedure:
Prepared from (2R,5R)-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester, chloroacetyl chloride and 6-(2-fluoro-benzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine using an analogous method to Preparation 203, but with DIPEA as base instead of triethylamine and heating carried out at 40° C. (See also General Procedure 5, below). MS: [M+H]+=527.
Reaction SMILES: [CH2:1]([C@:3]1([OH:11])[CH2:7][CH2:6][NH:5][C@H:4]1[CH:8]([CH3:10])[CH3:9])[CH3:2].F[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([O:21][CH3:22])[CH:14]=1.C(=O)([O-])[O-].[Li+].[Li+]>>[CH2:1]([C@:3]1([OH:11])[CH2:7][CH2:6][N:5]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([O:21][CH3:22])[CH:14]=2)[C@H:4]1[CH:8]([CH3:10])[CH3:9])[CH3:2]
Reactant: CC[C@]1(O)CCN[C@H]1C(C)C
Reactant: COc1cc(F)ccc1C#N
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@]1(O)CCN(c2ccc(C#N)c(OC)c2)[C@H]1C(C)C

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-3-ethyl-2-isopropylpyrrolidin-3-ol 0.5 oxalate (203 mg), 4-fluoro-2-methoxybenzonitrile (151 mg) and lithium carbonate (163 mg), the title compound was obtained as colorless oil (yield: 22 mg, yield: 7.6%).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:16][C:17]([OH:19])=O)([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.CC(C)(OC([N:38]1[C@H:46]([C:47]([O:49][CH2:50][O:51][C:52](=[O:57])[C:53]([CH3:56])([CH3:55])[CH3:54])=[O:48])[CH2:45][C:40]2([S:44][CH2:43][CH2:42][S:41]2)[CH2:39]1)=O)C.FC(F)(F)C(O)=O>C(#N)C>[CH2:1]([O:3][P:4]([CH2:16][C:17]([CH:43]1[CH2:42][S:41][C:40]2([CH2:45][CH:46]([C:47]([O:49][CH2:50][O:51][C:52](=[O:57])[C:53]([CH3:55])([CH3:54])[CH3:56])=[O:48])[NH:38][CH2:39]2)[S:44]1)=[O:19])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOP(=O)(CCCCc1ccccc1)CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CC2(C[C@H]1C(=O)OCOC(=O)C(C)(C)C)SCCS2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCOP(=O)(CCCCc1ccccc1)CC(=O)C1CSC2(CNC(C(=O)OCOC(=O)C(C)(C)C)C2)S1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
A mixture of 1.7 g of [ethoxy(4-phenylbutyl)phosphinyl]acetic acid, acetonitrile and 0.96 g of carbonyldiimidazole is stirred under argon at 0° C. for 1 hour. (S)-7-[(1,1-Dimethylethoxy)carbonyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid, (2,2-dimethyl-1-oxopropoxy)methyl ester (2.5 g) is treated with trifluoroacetic acid (about 2 ml) and stirred at room temperature for 30 minutes. The trifluoroacetic acid is removed in vacuo, the residue taken up in acetonitrile and added dropwise to the above mixture over a 20 minute period at room temperature. After an additional 2.5 hours, the acetonitrile is stripped and the resulting oil is partitioned between ethyl acetate and water. The layers are separated and the organic portion is washed with 5% potassium sulfate, saturated sodium bicarbonate, brine, dried (MgSO4) and evaporated. The residue (3.4 g) is chromatographed on silica (120 g) eluting with ethyl acetate/dichloromethane (1:1) and yielding 2.7 g of the title compound as a glass.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.CCN(C(C)C)C(C)C.[NH:26]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>CS(C)=O>[N:26]1([C:2]2[C:3](=[O:16])[NH:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Reactant: C1CCCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCCCCC3)nc2c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (500 mg, crude) in DMSO (6 mL) was added DIEA (543 mg, 4.20 mmol) and azepane (208 mg, 2.10 mmol). The solution was stirred overnight at 90° C. Then the reaction was quenched by the addition of water (50 mL), extracted with ethyl acetate (5×20 mL) and the organic layers were concentrated under vacuum to give a residue, which was purified by a silica gel column with 1%-5% ethyl acetate in petroleum ether to afford methyl 3-(azepan-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a yellow solid (165 mg).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[CH:4][C:3]=1[CH3:16].[Br:17]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(OCC)(=O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][Si:7]([C:10]([CH3:11])([CH3:12])[CH3:13])([CH3:8])[CH3:9])=[CH:4][C:3]=1[CH2:16][Br:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(O[Si](C)(C)C(C)(C)C)ccc1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Br)c(CBr)c1
Yield: 30.1 %

Procedure:
To a solution of (4-bromo-3-methylphenoxy)(tert-butyl)dimethylsilane (6.97 g) and N-bromosuccinimide (6.21 g) in ethyl acetate (100 mL) was added 2,2′-azobis(isobutyronitrile) (383 mg), and the mixture was refluxed for 17 hr. The mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.65 g) as a colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:10]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Fc1ccc(CNc2nc(Cl)nc3sc4c(c23)CCCC4)cc1
Reactant: c1c[nH]cn1
Product: Fc1ccc(CNc2nc(-n3ccnc3)nc3sc4c(c23)CCCC4)cc1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5,6,7,8-tetrahydro-4-(4-fluorobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5,6,7,8-tetrahydro-4-(4-fluorobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([C:19]#[N:20])=[CH:10][C:9]=1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1.C[Mg+].[Br-].[Cl:31][CH2:32][C:33](Cl)=[O:34]>C1COCC1.CCOC(C)=O>[Cl:31][CH2:32][C:33]([N:14]([C:12]1[C:11]([C:19]#[N:20])=[CH:10][C:9]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:13]=1)[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:34]
Reactant: O=C(Cl)CCl
Reactant: CC(C)CNc1nc(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)CN(C(=O)CCl)c1nc(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Reaction time: 0.08 h

Procedure:
To the product of Step A EXAMPLE 27 (300 mg) in THF (5.0 mL) was added MeMgBr (0.92 mL, 1.4 M solution in toluene/THF 3:1) at 0° C. The reaction stirred for 5 minutes before adding chloroacetyl chloride (0.08 mL). The reaction stirred about 7 hours and was diluted with EtOAc, washed with 2 M aqueous HCl and brine. The dried solution (Na2SO4) was concentrated and purified via flash chromatography on silica gel gradient eluted with 0-15% EtOAc in hexane affording the title compound. HPLC/MS: 471.9 (M+1), 473.9 (M+3); Rt=4.32 min.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:13]=[CH:12][N:11]([C:14](=[O:18])[N:15]([CH3:17])[CH3:16])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:27])C=1.C(OCC)(=O)C.[OH2:36]>C(Cl)Cl>[CH2:1]([S:8]([C:9]1[N:13]=[CH:12][N:11]([C:14](=[O:18])[N:15]([CH3:16])[CH3:17])[N:10]=1)(=[O:27])=[O:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)n1cnc(SCc2ccccc2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C)C(=O)n1cnc(S(=O)(=O)Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-benzylthio-1-dimethylcarbamoyl-1H-1,2,4-triazole (Example 1) (134 mg) in methylene chloride was added m-chloroperbenzoic acid (185 mg) with cooling it on ice, and the resulting mixture was stirred at room temperature for 4 hours. Ethyl acetate and water were added to the reaction mixture, which in turn was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and purified by a column chromatography (ethyl acetate/hexane=1/2) to yield the titled compound (69 mg) as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(N(CC)C(C)C)(C)C.ClC(Cl)(O[C:37](=[O:43])OC(Cl)(Cl)Cl)Cl.[NH:45]1[C:49]([NH2:50])=[CH:48][CH:47]=[N:46]1.C(=O)([O-])O.[Na+]>ClC1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:37]([NH:50][C:49]2[NH:45][N:46]=[CH:47][CH:48]=2)=[O:43])=[C:18]([F:23])[CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccn[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: Clc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccn[nH]4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (20 mg) was dissolved in chlorobenzene (1.5 ml) and N,N-diisopropylethylamine (0.15 ml) to prepare a solution. A solution of triphosgene (19 mg) in chlorobenzene (0.5 ml) was then added to the solution, and the mixture was stirred at room temperature for 30 min. Next, 1H-5-pyrazolamine (10 mg) was added thereto, and the mixture was further stirred at 100° C. overnight. The reaction solution was developed through diatomaceous earth impregnated with a saturated aqueous sodium hydrogencarbonate solution, followed by extraction with chloroform. The solvent in the extract was removed by distillation. The residue was purified by HPLC using chloroform/methanol for development to give the title compound (3 mg, yield 11%).
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([OH:16])=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:24][C:25]([Cl:29])([Cl:28])[CH2:26]O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([O:16][CH2:26][C:25]([Cl:29])([Cl:28])[Cl:24])=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Reactant: OCC(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)OCC(Cl)(Cl)Cl
Reaction time: 20 h

Procedure:
Synthesis of the peptide segment is started by making the trichloroethanol ester of Boc-Asp(OBzl)-OH (Shioiri et al., 1989). This is achieved by stirring 1 g (3 mmol) of Boc-Asp(OBzl)-OH (Sigma), 0.4 ml of (3 mmol) 2,2,2-trichloroethanol (Aldrich), 100 mg of DMAP (dimethylaminopyridine; Aldrich), and 576 mg (3 mmol) of EDC (Aldrich) in 50 ml of DCM for 3 h at 0° C. and for 20 h at room temperature. The precipitate is filtered out and the filtrate is diluted with 100 ml of ethyl acetate. The ethyl acetate solution is extracted with 10% aqueous citric acid, water, saturated NaHCO3, water and saturated brine. Then, the ethyl acetate layer is dried over anhydrous Na2 SO4, decanted, and concentrated to give an oil. The crude oily product is purified by washing with petroleum ether to give Boc-Asp(OBzl)-OTce (9). 1H-NMR (CDCl3): 1.45 (9H, s), 2.93 and 3.15 (2H, dd, J=17 Hz and 4.5 Hz), 4.67 and 4.75 (2H, dd, J=12.3 Hz), 4.7-4.75 (1H, m), 5.13 (2H, s), 5.56 (1H, d, J=9 Hz), 7.34 -7.38 (5H, m). FABMS: 454 (M+1)
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:18])=[C:7]([CH:12]=[C:13]([N+:15]([O-])=O)[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].[C:19]([OH:23])(=[O:22])[CH:20]=[CH2:21].[C:24]1(C)C=CC=CC=1>>[C:1]([C:5]1[CH:14]=[C:13]([NH:15][CH2:21][CH2:20][C:19]([OH:23])=[O:22])[CH:12]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:6]=1[O:18][CH3:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(C(C)(C)C)c1O
Reactant: Cc1ccccc1
Reactant: C=CC(=O)O
Product: COC(=O)c1cc(NCCC(=O)O)cc(C(C)(C)C)c1OC

Procedure:
The product from Example 5, Part C (16.44 g, 69.3 mmol) was dissolved in toluene (200 mL). This mixture was heated to reflux and acrylic acid added over time (1 mL of acrylic acid added every 3 h, 5.23 mL total, 76.2 mmol). The mixture was then refluxed for 24 h. The mixture was then cooled and concentrated under vacuum to dryness to yield an oil as the crude title compound that was used directly in the next reaction.
Reaction SMILES: ClC[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([O:14][CH3:15])[C:10]([NH:12][CH3:13])=[O:11].[CH3:16][C:17]1[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=1[OH:25].[H-].[Na+].O.[CH3:29]N(C)C=O>>[CH3:15][O:14][C:9]([CH2:29][O:25][C:18]1[CH:19]=[C:20]([CH3:24])[CH:21]=[C:22]([CH3:23])[C:17]=1[CH3:16])([C:4]1[CH:3]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]([NH:12][CH3:13])=[O:11]
Reactant: CNC(=O)C(OC)c1ccccc1CCl
Reactant: CN(C)C=O
Reactant: Cc1cc(C)c(C)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CNC(=O)C(COc1cc(C)cc(C)c1C)(OC)c1ccccc1
Temperature: 0 °C
Reaction time: 1.17 h
Yield: 50 %

Procedure:
A solution of 2-chloromethyl-α-methoxy-N-methyl-phenylacetamide (0.25 g, 1.1 mmol) and 2,3,5-trimethylphenol (0.18 g, 1.3 mmol) in N,N-dimethylformamide (3 ml) was stirred at 0° C., and 60% oily sodium hydride (0.08 g, 2.0 mmol) was added thereto. The mixture was stirred at 0° C. for 70 minutes and then at room temperature for 1 hour, and ice and water were added in this order. The mixture was extracted with ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=7/3) to give the desired compound α-methoxy-N-methyl-(2,3,5-trimethylphenoxymethyl)phenylacetamide (0.17 g, 50%) as an oil.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([C:11]1[O:15][C:14](=O)[NH:13][N:12]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([C:23]2[N:28]=[CH:27][C:26]([C:29]3[CH:30]=[N:31][N:32]4[C:37]([N:38]([CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])[CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])=[CH:36][C:35]([CH:55]5[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]5)=[N:34][C:33]=34)=[CH:25][CH:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[CH2:1]([O:8][C@@H:9]([C:11]1[O:15][C:14]([N:58]2[CH2:57][CH2:56][CH:55]([C:35]3[CH:36]=[C:37]([N:38]([CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])[CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[N:32]4[N:31]=[CH:30][C:29]([C:26]5[CH:27]=[N:28][C:23]([C:17]6[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=6)=[CH:24][CH:25]=5)=[C:33]4[N:34]=3)[CH2:60][CH2:59]2)=[N:13][N:12]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](OCc1ccccc1)c1n[nH]c(=O)o1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCNCC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](OCc1ccccc1)c1nnc(N2CCC(c3cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n4ncc(-c5ccc(-c6ccccc6)nc5)c4n3)CC2)o1
Reaction time: 8 h
Yield: 85.2 %

Procedure:
To a stirred solution of (R)-5-(1-(benzyloxy)ethyl)-1,3,4-oxadiazol-2(3H)-one (44 mg, 0.2 mmol), 3-(6-phenylpyridin-3-yl)-5-(piperidin-4-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (150 mg, 0.24 mmol) and DIEA (70 ul, 0.4 mmol) in DMF (1.4 mL) was added BOP (97 mg, 0.22 mmol) and the resulting solution was allowed to stir overnight. Water was added and was extracted with EtOAc (3×) and combined organic layers were washed with water (3×), brine once and dried (MgSO4). After concentration in vacuo the residue was purified on silica gel. Elution with EtOAc/Hexanes (0-10%) gave the title compound (142 mg, 85%).
Reaction SMILES: [OH:1][C@@:2]12[C:11](=O)[CH2:10][CH2:9][CH2:8][C@H:7]1[CH2:6][CH2:5][CH2:4][CH2:3]2.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC(O)=O>[C:14]1([NH:13][C@H:11]2[C@:2]3([OH:1])[C@H:7]([CH2:6][CH2:5][CH2:4][CH2:3]3)[CH2:8][CH2:9][CH2:10]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCC[C@H]2CCCC[C@]12O
Reactant: Nc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: O[C@]12CCCC[C@@H]1CCC[C@H]2Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (4aR,8aR)-8a-hydroxyoctahydronaphthalen-1(2H)-one (0.339 g, 2.015 mmol) and aniline (0.552 mL, 6.05 mmol) in 2% CH3COOH in ACE (20 mL) was stirred for 1 hr at rt. Sodium triacetoxyborohydride (1.37 g, 6.45 mmol) was then added and the mixture was stirred for several hours. The mixture was then quenched with sat'd. aq. NaHCO3 and extracted 3× with CH2Cl2. The combined organics were dried, filtered, and concentrated. The residue was purified by column chromatography on silica gel to give the title compound. 1H NMR (500 MHz, CDCl3) δ 7.12-7.18 (m, 2H), 6.60-6.69 (m, 3H), 1.96-2.04 (m, 1H), 1.73-1.81 (m, 1H), 1.64-1.70 (m, 2H), 1.18-1.60 (m, 12H). HRMS (ES) m/z M+H calc'd: 246.1852. found: 246.1850.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:14])[NH:9]2)([OH:3])=[O:2].[OH-].[Na+].[H][H]>O.[Pt].[C]>[C:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C:8](=[O:14])[NH:9]2)([OH:3])=[O:2]
Reactant: O=C(O)c1cccc2[nH]c(=O)ccc12
Reactant: [H][H]
Agent: [Pt]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1CCc2c(cccc2C(=O)O)N1

Procedure:
2 Grams of 5-carboxycarbostyril was suspended in 30 ml of water, then 10N-sodium hydroxide aqueous solution was added to dissolve the crystals. To this solution was added 500 mg of 10% platinum-carbon and this mixture was catalytically reduced with hydrogen gas under condition of 3-4 kg/cm2 at 70° C. After the completion of the reaction, the catalyst was removed from the reaction mixture by filtration, then the pH of the filtrate was adjusted to about pH=1 by adding concentrated hydrochloric acid. The precipitated crystals were collected by filtration, recrystallized from methanol to obtain 820 mg of 5-carboxy-3,4-dihydrocarbostyril in the form of colorless needle-like crystals.
Reaction SMILES: [NH2:1][C:2]([C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[F:13])([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.Br[CH:22]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:23](Cl)=[O:24]>C(#N)C>[Br:12][C:10]1[CH:9]=[CH:8][C:7]([F:13])=[C:6]([C:2]([NH:1][C:23](=[O:24])[CH:22]=[CH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([CH3:5])[CH2:3][OH:4])[CH:11]=1
Reactant: CC(N)(CO)c1cc(Br)ccc1F
Reactant: O=C(Cl)C(Br)Cc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(CO)(NC(=O)C=Cc1ccccc1)c1cc(Br)ccc1F
Temperature: 25 °C
Yield: 10.3 %

Procedure:
A solution of (RS)-2-amino-2-(5-bromo-2-fluoro-phenyl)-propan-1-ol (1.5 g, 6 mmol) and triethylamine (1.01 ml, 7.3 mmol) in acetonitrile (31 ml) was cooled to 0° C. A solution of (RS)-2-bromo-3-phenyl-propionyl chloride (CAS 42762-86-7) (1.637 g, 6.6 mmol) in acetonitrile was added dropwise. After complete addition the reaction mixture was left to warm to room temperature. After 1 hour the reaction mixture was evaporated under reduced pressure and directly purified by chromatography on silica gel using a gradient of heptane and ethyl acetate=100/0 to 50/50 as the eluent. Besides the N-[(RS)-1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-3-phenyl-acrylamide (0.233 g, 10% of theory), the (2RS)-bromo-N-[(RS)-1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-3-phenyl-propionamide (mixture of diastereoisomers 3:2) was obtained as a white solid (1.985 g, 71.5% of theory). Mass (calculated) C18H18Br2FNO2 [459.156]; (found) [M+H]+=457, [M+2-H]+=459, [M+4-H]+=461.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][CH2:17][C:18]#[N:19])[C:13]([O-:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:20]=[N+:21]=[N-:22].Cl.[CH2:24](N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][CH2:17][C:18]1[NH:22][N:21]=[N:20][N:19]=1)[C:13]([O:15][CH3:24])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCN(CC)CC
Reactant: N#CCC[C@H](NC(=O)OCc1ccccc1)C(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](CCc1nnn[nH]1)NC(=O)OCc1ccccc1
Yield: 75.8 %

Procedure:
Into the same device as used in Example 1 were placed 77.3 g (0.28 mole) ofmethyl (2S)-2-benzyloxycarbonylamino-4-cyanobutyrate, 27.3 g (0.42 mole) ofsodium azide, 57.7 g (0.42 mole) of triethylamine hydrochloride and 280 ml of toluene. Thereafter, the mixture was heated to a temperature of 82° to 83° C. to undergo a reaction for 24 hours. Subsequently the same procedure as in Example 1 was repeated, and crystalswere collected by filtration. Further, the crystals were recrystallized from methanol and water, filtered and dried, giving 67.7 g (0.21 mole) of methyl (2S)-2-benzyloxycarbonylamino-4-(tetrazole-5-yl)butyrate (yield 75.8% based on methyl (2S)-2-benzyloxycarbonylamino-4-cyanobutyrate). The reaction is illustrated below with chemical formulas: ##STR27##