Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([OH:30])[C:26]([O:28][CH3:29])=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:32]1[N:37]=[CH:36][N:35]=[C:34]2[N:38]([C:41]3[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][C:42]=3[CH3:48])[N:39]=[CH:40][C:33]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([O:30][C:32]1[N:37]=[CH:36][N:35]=[C:34]2[N:38]([C:41]3[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][C:42]=3[CH3:48])[N:39]=[CH:40][C:33]=12)[C:26]([O:28][CH3:29])=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1ccc(F)cc1-n1ncc2c(Cl)ncnc21
Reactant: COC(=O)[C@@H](O)COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1cc(F)ccc1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 53.3 %

Procedure:
60% Sodium hydride (156 mg, 3.89 mmol) was added to (S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxypropanoate (Intermediate AB3) (1119 mg, 2.78 mmol) in anhydrous THF (15 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(5-fluoro-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate AK3) (730 mg, 2.78 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was neutralised with 1M citric acid and the majority of the THF removed in vacuo. The residue was diluted with water (20 mL) and EtOAc (100 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (100 mL). The combined organics were washed with saturated brine (75 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica (120 g) chromatography, elution gradient 0 to 20% EtOAc in isohexane to afford the product (932 mg, 53.3%). 1H NMR (400 MHz, DMSO) δ 0.94 (9H, s), 2.03 (3H, s), 3.80-3.65 (7H, m), 4.16-4.03 (2H, m), 5.89 (1H, dd), 7.46-7.33 (8H, m), 7.54-7.48 (1H, m), 7.65-7.61 (4H, m), 8.48 (1H, s), 8.59 (1H, s); m/z (ES+) (M+H)+=629; HPLC tR=3.41 min.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].FC(F)(F)C(O)=O.[F:27][C:28]([F:41])([F:40])[C:29]1[S:33][C:32]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[N:31][N:30]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:9]([C:10]([N:37]2[CH2:36][CH2:35][N:34]([C:32]3[S:33][C:29]([C:28]([F:40])([F:27])[F:41])=[N:30][N:31]=3)[CH2:39][CH2:38]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(N2CCOCC2)c(C(=O)O)c1
Reactant: FC(F)(F)c1nnc(N2CCNCC2)s1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(N2CCOCC2)c(C(=O)N2CCN(c3nnc(C(F)(F)F)s3)CC2)c1

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-morpholin-4-yl-benzoic acid (Example A13) and 1-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-piperazine trifluoroacetate (Example 62(b)). The crude material was purified by chromatography (SiO2, dichloromethane/methanol 99:1) to yield the title compound as a colorless solid. MS (m/e): 506.3 (M+H+, 100%).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.NC1C(C)=CC(Br)=CN=1.C(Cl)(=O)C.[I-:23].[Na+].C>BrBr.Br.C(#N)C.CCCCCC>[Br:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([I:23])=[N:3][CH:4]=1
Reactant: Cc1cc(Br)cnc1Br
Reactant: [I-]
Agent: Br
Agent: BrBr
Agent: Cc1cc(Br)cnc1N
Solvent: CCCCCC
Solvent: CC(=O)Cl
Solvent: CC#N
Product: Cc1cc(Br)cnc1I
Yield: 70 %

Procedure:
2,5-Dibromo-3-picoline is commercially available or may be prepared from 2-amino-5-bromo-3-methylpyridine by standard diazotization followed by bromination in Br2/HBr. Acetyl chloride (0.68 mol, 52.7 mL) was added to a stirring solution of 2,5-dibromo-3-picoline (0.45 mol, 113 g) in acetonitrile (600 mL) followed by sodium iodide (1.66 mol, 250 g) and the reaction mixture was gently refluxed for 18 h. The cooled reaction mixture was filtered and the solid was washed with acetonitrile until colorless. It was suspended in methylene chloride and treated with aq. Na2CO3 until the pH was 10-11. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to give a brown oil. It was subjected to iodination a second time as above (reflux time 6 h). A dark brown oil was obtained using the same work-up as above. A solution of this oil in hexane was treated with charcoal, filtered and concentrated to give a light brown oil. It slowly solidified on standing to give 5-bromo-2-iodo-3-methylpyridine as a light brown solid (95.0 g, 0.32 mol). Yield: 70%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[NH2:12][CH:13]1[C:17](=[O:18])[N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH:14]1[C:25]([O:27][CH2:28][CH3:29])=[O:26].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:12][C@H:13]2[C:17](=[O:18])[N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][C@H:14]2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:6])[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)C1CN(c2ccccc2)C(=O)C1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CN(c2ccccc2)C(=O)[C@@H]1NC(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.3 %

Procedure:
To a solution of 3,4-dichlorobenzoyl chloride (295 mg, 1.41 mmol) in CH2Cl2 (4 ml) was added a solution of aminopyrrolidinone of Example S (350 mg, 1.41 mmol) and triethylamine (0.4 ml, 2.82 mmol) in CH2Cl2 (4 ml) and the resulting solution was stirred for 18 h at room temperature. Concentration in vacuo gave an oil which was chromatographed on silica gel eluting with 2% EtOH/CH2Cl2 to give the title compound (400 mg, 67%) as a colorless solid. Anal calcd for C20H18N2O4Cl2 : C, 57.02; H, 4.31; N, 6.65. Found: C, 57.05; H, 4.39; N, 6.50. MS M+1 calcd for C20H18N2O4Cl2 422, found 422. DSC=185.5°-193.1° C. at 82.8 J/g.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][CH2:4][C:3]1=[O:9].OC1CCC(C)CC1=O.CC1CCC(O)C(O)C1>>[CH3:8][C:6]1[CH:7]=[C:2]([OH:1])[C:3](=[CH:4][CH:5]=1)[OH:9]
Reactant: CC1CCC(=O)C(O)C1
Agent: CC1CCC(O)C(=O)C1
Agent: CC1CCC(O)C(O)C1
Product: Cc1ccc(O)c(O)c1

Procedure:
4-Methyl catechol (25 mg, 2×10−4 mol) and wet Raney Ni 4200 (12 mg, 2×10−4 mol, 100 mol %) is weighed into a reaction flask under argon. Degassed i-PrOH (5 mL) is added and the flask is capped with a rubber septa and the mixture is heated (80° C.). The reaction is run for 24 hours and the reaction mixture is cooled. Nickel was removed with a magnet. Concentration gave 20 mg of a reaction mixture which is, according to analysis by HNMR, a complex mixture of mainly, 2-hydroxy-4-methyl-Cyclohexanone; 2-hydroxy-5-methyl-Cyclohexanone; 4-methyl-1,2-Cyclohexanediol. The aromatic ring was saturated.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH:20]=O)[CH:14]=1)[CH2:8][CH:9]1[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH:30]1([NH2:33])[CH2:32][CH2:31]1.[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO>[C:1]([O:5][C:6](=[O:22])[N:7]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH2:20][NH:33][CH:30]2[CH2:32][CH2:31]2)[CH:14]=1)[CH2:8][CH:9]1[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Cl)c(C=O)c1)CC1CC1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1ccc(Cl)c(CNC2CC2)c1)CC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
A mixture of (4-chloro-3-formyl-benzyl)-cyclopropylmethyl-carbamic acid tert-butyl ester (1.00 g, 3.09 mmol), Et3N (0.646 mL, 4.64 mmol) and cyclopropylamine (0.325 mL, 4.64 mmol) in MeOH (10.5 mL) was heated to reflux for 4 h. The mixture was allowed to cool to rt, and NaBH4 (292 mg, 7.71 mmol) was added. The mixture was stirred for 1 h, and aq. sat. NaHCO3 was added. The mixture was extracted with EtOAc (2×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (MeOH/CH2Cl2 1:49) yielded the title compound (535 mg, 48%). LC-MS: tR=0.81 min; ES+: 406.20.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[S:9][CH:10]=1)=[O:5])C.[Li+].[OH-]>>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:8]2[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)=[CH:13][CH:14]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)c1csc(Cc2ccc(C(C)(C)C)cc2)n1
Agent: [Li+]
Agent: [OH-]
Product: CC(C)(C)c1ccc(Cc2nc(C(=O)O)cs2)cc1

Procedure:
2-(4-tert-Butylbenzyl)thiazole-4-carboxylic acid ethyl ester was hydrolysized with 1M LiOH (5 ml). The reaction solvent was removed in vacuo. The residue was diluted with EtOAc and H2O and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4 and then concentrated in vacuo.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:16])[CH2:7]P(OCC)(OCC)=O)[CH3:4].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[CH:25]=[C:26]([CH3:29])[CH:27]=O>C1COCC1>[CH2:3]([O:5][C:6](=[O:16])[CH:7]=[CH:27][C:26]([CH3:29])=[CH:25][C:19]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=1[Cl:17])[CH3:4]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(C=O)=Cc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=CC(C)=Cc1ccc(Cl)cc1Cl
Reaction time: 4 h
Yield: 89.4 %

Procedure:
Sodium hydride (4.88 g of a 60% dispersion in mineral oil, 1.5 eq, 0.122 mol) was suspended in THF (442 mL). To this suspension was added a solution of diethoxyphosphorylactic acid ethyl ester (27.5 g, 0.122 mol, 1.5 eq) in THF (10 mL), dropwise. After 10 minutes a solution of 3-(2,4-dichlorophenyl)-2-methylpropenal (17.56 g, 0.082 mol) in THF (50 mL) was added, dropwise. After stirring for 4 hours the mixture was added to NH4Cl(sat) and extracted with EtOAc. The combined organic extracts were dried (MgSO4), concentrated under reduced pressure to give a residue that was purified by silica gel chromatography (0-2.5-5% EtOAc in hexanes) to give 20.9 g of 5-(2,4-dichlorophenyl)-4-methylpenta-2,4-dienoic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.C1(C)C=CC(S([CH2:28][N+:29]#[C-:30])(=O)=O)=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:18]=[CH:17][C:14]([C:15]4[O:16][CH:30]=[N:29][CH:28]=4)=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: O=Cc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Product: Brc1ccc2nc(-c3ccc(-c4cnco4)cc3)cn2c1
Yield: 78.8 %

Procedure:
The procedure of Example 1 was repeated, except that 4-(6-bromoimidazo[1,2-a]pyridin-2-yl)benzaldehyde (255 mg) and p-toluenesulfonylmethylisocyanide (198 mg) were used, to thereby yield the title compound (227 mg).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][N+:4]=1[O-:10].Cl.[N-:12]=[N+:13]=[N-].[Na+]>O>[N:2]([C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][N+:4]=1[O-:10])=[N+:12]=[N-:13]
Reactant: Nc1ccc(Cl)c[n+]1[O-]
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1ccc(Cl)c[n+]1[O-]
Temperature: 25 °C

Procedure:
In this example, 6.70 grams (0.036 mol) of 2-amino-5-chloropyridine N-oxide hydrochloride was added to and dissolved in 100 ml. of water and 10 ml. of concentrated hydrochloric acid under vigorous stirring and was thus cooled to 0° C. to 5° C. in a salt-ice bath. To the above cold solution, a solution of 2.50 grams (0.036 mol) in 30 ml. of water was added dropwise at such a rate that the temperature of the reaction mixture did not rise above 5° C. Immediately after the above addition was complete a solution of 2.30 grams (0.036 mol) of sodium azide in 30 ml. of water was added to the cold vigorously stirred above solution at such a rate that the temperature did not rise above 5° C. When the above addition was complete the cooling bath was removed and the solution slowly warmed to about 25° C. The reaction mixture was continuously extracted with methylene chloride. From the methylene chloride extract, after evaporation in vacuo was obtained 2-azido-5-chloropyridine N-oxide in a yield of 3.75 grams or 62% of theory having a melting point of 80° C. to 82° C. with decomposition.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19]([C:21]1([CH2:36]I)[CH2:25][CH2:24][N:23]([C:26](=[O:35])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:22]1)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1([CH2:36][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH2:25][CH2:24][N:23]([C:26](=[O:35])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:22]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccccc2OC)C1
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(C#N)cc3)cc2)CCN(C(=O)c2ccccc2OC)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 4′-hydroxy-4-biphenyl carbonitrile and 3-iodomethyl-1-(2-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 15) to afford the racemate as a white solid (157 mg, 66%)
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH3:7][Si:8]([CH2:11][C:12](=[CH2:16])[C:13](O)=[O:14])([CH3:10])[CH3:9]>C1(C)C=CC=CC=1>[CH3:7][Si:8]([CH2:11][C:12](=[CH2:16])[C:13]([Cl:4])=[O:14])([CH3:10])[CH3:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=C(C[Si](C)(C)C)C(=O)O
Solvent: Cc1ccccc1
Product: C=C(C[Si](C)(C)C)C(=O)Cl
Temperature: 50 °C
Reaction time: 2 h

Procedure:
With stirring at 50° C., 60.0 g of oxalyl chloride was slowly added dropwise to a mixture of 69.8 g of 2-(trimethylsilylmethyl)acrylic acid obtained in Example 2 and 300 ml of toluene. Stirring was continued at the temperature. After gas evolution ceased, stirring was continued at 70° C. for 2 hours. After cooling, the product in toluene solution was directly used in the subsequent step.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Br[CH2:24][CH2:25][CH2:26][Cl:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:24][CH2:25][CH2:26][Cl:27])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: ClCCCBr
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCCl
Temperature: 40 °C
Yield: 54.7 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (957 mg, 3 mmol), (prepared as described for the starting material in Example 2), 1-bromo-3-chloropropane (2.36 g, 15 mmol) and potassium carbonate (2.1 g, 15 mmol) in DMF (20 ml) was heated at 40° C. for 1.5 hours. The mixture was allowed to cool, was diluted with water and extracted with ethyl acetate (3×50 ml). The organic extracts were combined, washed with water and brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was triturated with hexanelethyl acetate, collected by filtration and dried under vacuum to give 4-(4-chloro-2-fluoroaniiino)-7-(3-chloropropoxy)-6-methoxyquinazoline (650 mg, 55%).
Reaction SMILES: CC1C(=O)CC(N2CC3C(=CC=CC=3)N(CCNC3N=CN=C4C=3N=CN4COCC[Si](C)(C)C)C2)=C(C=1)[C:7]#[N:8].O[C:42]1[CH:43]=[C:44]([N:48]2[C:57](=[O:58])[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][C:55]=3[CH3:59])[N:50]=[C:49]2[CH:60]([NH:62][C:63]2[N:71]=[CH:70][N:69]=[C:68]3[C:64]=2[N:65]=[CH:66][NH:67]3)[CH3:61])[CH:45]=[CH:46][CH:47]=1>>[CH3:59][C:55]1[CH:54]=[CH:53][CH:52]=[C:51]2[C:56]=1[C:57](=[O:58])[N:48]([C:44]1[CH:45]=[CH:46][CH:47]=[CH:42][C:43]=1[C:7]#[N:8])[C:49]([CH:60]([NH:62][C:63]1[N:71]=[CH:70][N:69]=[C:68]3[C:64]=1[N:65]=[CH:66][NH:67]3)[CH3:61])=[N:50]2
Reactant: CC1=CC(C#N)=C(N2Cc3ccccc3N(CCNc3ncnc4c3ncn4COCC[Si](C)(C)C)C2)CC1=O
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4[nH]cnc34)n(-c3cccc(O)c3)c(=O)c12
Product: Cc1cccc2nc(C(C)Nc3ncnc4[nH]cnc34)n(-c3ccccc3C#N)c(=O)c12

Procedure:
Compound 141 was treated with 4N HCL in NeOH for 1 hour using the procedure described for compound 121 (step B) to provide compound 140. m/z=423 (M+H). The structure of compound 140 is shown below.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=2)[O:5][N:4]=1.[CH3:23][NH:24][CH3:25]>>[CH3:23][N:24]([CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=2)[O:5][N:4]=1)[CH3:25]
Reactant: CC(C)(C)c1cc(-c2nc(CCl)no2)cc(C(C)(C)C)c1O
Reactant: CNC
Product: CN(C)Cc1noc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)n1

Procedure:
In a manner analogous to Example 70, 0.5 g (0.002 mole) of 4-[3-(chloromethyl)-1,2,4-oxadiazol-5-yl]-2,6-bis(1,1-dimethylethyl)phenol is reacted with excess dimethylamine gas to give 0.3 g (59%) of analytically pure 4-[3-[(dimethyamino)methyl]-1,2,4-oxadiazol-5-yl]-2,6-bis(1,1-dimethylethyl)phenol, mp 129°-130° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:16][C:17]1[N:21]=[C:20]([CH3:22])[NH:19][N:18]=1>CN(C=O)C>[Cl:8][C:6]1[CH:7]=[C:2]([N:18]2[C:17]([CH3:16])=[N:21][C:20]([CH3:22])=[N:19]2)[N:3]=[C:4]([CH3:9])[N:5]=1
Reactant: Cc1n[nH]c(C)n1
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nc(Cl)cc(-n2nc(C)nc2C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a slurry of 4,6-dichloro-2-methylpyrimidine (1-1) (5.00 g, 30.7 mmol) and cesium carbonate (15.0 g, 46 mmol) in DMF (250 mL) at 0° C. was added a solution of 3,5-dimethyl-1H-1,2,4-triazole (2.98 g, 30.7 mmol) in DMF (50 mL) via a dropping funnel over 1 h. The reaction was then warmed to room temperature and stirred for 1 h. The reaction was quenched by addition of water (500 mL) and extracted with ethyl acetate (3×400 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (0-30% EtOAc/hexanes) to afford 4-chloro-6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidine (1-2) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.75 (s, 1H), 2.91 (s, 3H), 2.72 (s, 3H), 2.41 (s, 3H); MS m/z=224 (M+H).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C(=O)([O-])[O-].[K+].[K+].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][CH:19]2[CH2:22][N:21](C(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:20]2)=[CH:14][CH:13]=1>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([S:18][CH:19]2[CH2:22][N:21]([C:1]([Cl:4])=[O:2])[CH2:20]2)=[CH:16][CH:17]=1
Reactant: Clc1ccc(SC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Reactant: O=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(Cl)N1CC(Sc2ccc(Cl)cc2)C1
Temperature: 0 °C
Reaction time: 20 h
Yield: 74.7 %

Procedure:
A stirred mixture of 8.5 g (0.086 mole) of phosgene and 12 g (0.086 mole) of potassium carbonate in 200 ml of methylene chloride was cooled in a water bath under nitrogen atmosphere while 26.3 g (0.072 mole) of 3-[(4-chlorophenyl)thio]-1-diphenylmethylazetidine in 100 ml of methylene chloride was added dropwise. After the addition, the reaction mixture was stirred for 20 hr then treated with enough ice to form a thick paste. The methylene chloride solution was decanted, filtered through Whatman phase separating paper and concentrated in vacuo. The residue (40 g) was triturated 3 times at -78° C. with 30/60 petroleum ether and allowed to warm to 0° C. before decanting the petroleum ether. The fine granular solid which remained was collected by filtration to yield 14.1 g (75%) of crude product. A sample was recrystallized from hexanes for analysis, m.p. 47°-48° C.
Reaction SMILES: [CH:1]([C:3]1[S:4][C:5]([CH:13]([CH3:15])[CH3:14])=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1)=O.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:14][CH:13]([C:5]1[S:4][C:3]([CH2:1][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:7][C:6]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:15]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1nc(C=O)sc1C(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1nc(CN2CCOCC2)sc1C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 2-formyl-5-(1-methylethyl)-1,3-thiazole-4-carboxylate (150 mg) was dissolved in anhydrous DCM (10 ml) and morpholine (0.064 ml) was added and the mixture stirred under nitrogen for 2 h at RT. Sodium triacetoxyborohydride (280 mg) was added and the mixture stirred at RT for 18 h. Sodium bicarbonate (20 ml) and DCM (20 ml) were added and separated by hydrophobic frit. The solvent was removed in vacuo and purified by column chromatography on silica gel (10 g silica), eluting with a gradient of 0-100% ethyl acetate in cyclohexane to give the title compound as a yellow oil (77 mg).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])[CH3:4].[H][H]>[Pt].C(C(C)=O)C>[CH:3]([NH:8][C:7]1[CH:9]=[CH:10][CH:11]=[C:5]([CH:3]([O:2][CH3:1])[CH3:4])[CH:6]=1)([CH2:5][CH3:11])[CH3:4]
Reactant: [H][H]
Reactant: COC(C)c1cccc(N)c1
Agent: [Pt]
Solvent: CCC(C)=O
Product: CCC(C)Nc1cccc(C(C)OC)c1
Temperature: 95 °C
Yield: 572.6 %

Procedure:
A 300-cubic centimeter capacity stirred autoclave equipped with a heating mantle and sample port was charged with 3.02 grams (0.02 mole) of the 3-(1-methoxyeth-1-yl)aniline prepared in paragraph (b) of Example IV and 0.6 gram of 5 percent platinum on carbon hydrogenation catalyst in 200 milliliters of methyl ethyl ketone. The autoclave was then sealed, the air driven stirrer turned on, and the temperature was brought up to and maintained at about 95° C. The autoclave was then charged with hydrogen gas to a pressure of 200 psi (the valve to the hydrogen cylinder being left open). After 5 hours' reaction, the autoclave was cooled, broken open, and the contents were removed and filtered. The filtrate was concentrated on a rotary evaporator at 55° C., leaving 11.87 grams of a light yellow liquid identified by NMR spectroscopy as N-sec-butyl-N-3-(1-methyleth-1-yl)aniline.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([C:15]([O:17][CH3:18])=[O:16])[CH:9]=[C:10]([CH:14]=2)[C:11](O)=[O:12])[CH:5]=[CH:4][CH:3]=[CH:2]1.C(N(CC)CC)C.ClC(OCC(C)C)=O>O1CCCC1>[OH:12][CH2:11][C:10]1[CH:9]=[C:8]([CH:7]=[C:6]([N:1]2[CH:5]=[CH:4][CH:3]=[CH:2]2)[CH:14]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1cc(C(=O)O)cc(-n2cccc2)c1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(CO)cc(-n2cccc2)c1
Reaction time: 0.75 h
Yield: 83 %

Procedure:
To a solution of 5-(pyrrol-1-yl)-3-methoxycarbonylbenzoic acid (9.37 g) in tetrahydrofuran (100 ml) was added triethylamine (6.4 ml) followed by slow addition of isobutyl chloroformate (5.9 ml) under nitrogen at -40° C. to -30° C. The reaction mixture was stirred below -20° C. for 45 minutes. Then, triethylamine hydrochloride was filtered off and washed with cold tetrahydrofuran, and the filtrate was added as quickly as possible to a suspension of sodium borohydride (4.35 g) in tetrahydrofuran-water (8:1, 80 ml) at 0° C. with vigorous stirring. The stirring was continued at ambient temperature for 5 hours, followed by acidification of the solution to pH 5. The tetrahydrofuran was removed under reduced pressure, and the product was extracted with ethyl acetate. The ethyl acetate extracts were washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (30:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give methyl 3-hydroxymethyl-5-(pyrrol-1-yl)benzoate (7.33 g).