Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]2[C@H:10]([CH2:11]2)[C@H:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:16]1[CH:17]=[C:18]([C:25](O)=[O:26])[N:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=12>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]2[C@H:10]([CH2:11]2)[C@H:9]1[CH2:14][NH:15][C:25]([C:18]1[N:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]2=[N:16][CH:17]=1)=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1cnc2ccccn12
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1CN
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1CNC(=O)c1cnc2ccccn12

Procedure:
prepared by reaction of (1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester with Imidazo[1,2-a]pyridine-3-carboxylic acid.
Reaction SMILES: C(=[N:8][N:9]([CH:16]=[C:17]([C:27]#[N:28])[C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)C1C=CC=CC=1.Cl>C(O)C>[NH2:28][C:27]1[C:17]([C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:25])[CH3:26])=[O:19])=[CH:16][N:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:8]=1
Reactant: C[Si](C)(C)CCOC(=O)C(C#N)=CN(N=Cc1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: C[Si](C)(C)CCOC(=O)c1cn(-c2ccccc2)nc1N
Yield: 46.8 %

Procedure:
To a solution of 2-(trimethylsilyl)ethyl 3-(N′-benzylidene-N-phenylhydrazino)-2-cyanoacrylate (2.69 g, 6.87 mmol) in 10 mL ethanol was added, 2.1 mL conc. HCl solution and the mixture was heated under Nitrogen at reflux for 2 hrs. The ethanol was evaporated under reduced pressure. The residue was taken up in ethyl acetate and slowly treated with 30 mL cold 1N NaOH solution. The ethyl acetate layer was separated, washed with sat. brine, and dried over MgSO4. Evaporation of the solvent afforded 1.68 g of crude material, which was purified by chromatography to afford 976 mg (47%) of 2-(trimethylsilyl)ethyl 3-amino-1-phenylpyrazol-4-carboxylate as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:23]#[N:24])=[CH:5][CH:4]=1.NN>[Pd]>[NH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]([C:23]#[N:24])=[C:10]2[NH:9][C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:25])[CH3:1])=[CH:4][CH:5]=1
Reactant: CN(C)c1ccc(Nc2c(C#N)cnc3ccc([N+](=O)[O-])cc23)cc1
Agent: [Pd]
Agent: NN
Product: CN(C)c1ccc(Nc2c(C#N)cnc3ccc(N)cc23)cc1

Procedure:
Prepared from 4-(4-dimethylaminophenylamino)-6-nitroquinoline-3-carbonitrile (5.00 g), 1.20 g of anhyd hydrazine and 0.500 g of 10% Pd/C in the same manner as Example 388 155179. After washing first with MeOH (discarded), the product was eluted with DMF. The latter solvent was collected separately, evaporated and the residue was dried in vacuo (50° C.). The yield of 6-amino-4-(4-dimethylaminophenylamino)quinoline-3-carbonitrile was 4.00 g as a yellow solid: mass spectrum (electrospray, m/e): M+H 303.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[O:12]=[C:13]1[CH2:17][S:16][CH2:15][NH:14]1.C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:14]2[C:13](=[O:12])[CH2:17][S:16][CH2:15]2)=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: O=C1CSCN1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2CSCC2=O)cc1
Reaction time: 8 h
Yield: 62.9 %

Procedure:
A solution of 4-methoxybenzoyl chloride (20.7 g) in tetrahydrofuran (50 ml) was added dropwise to a mixture of 4-oxo-thiazolidine (12.5 g) and triethylamine (16.9 ml) in tetrahydrofuran (200 ml) at -5° C. with stirring. The mixture was stirred at that temperature for 3 hours and at room temperature for 4 hours, and allowed to stand overnight. After the solvent was evaporated in vacuo, the residue was mixed with water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate and then with water, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and n-hexane to give 3-(4-methoxybenzoyl)-4-oxothiazolidine (18.1 g) as slightly brown prisms.
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]2[C:22]2[CH:27]=[C:26]([CH3:28])[C:25]([OH:29])=[C:24]([CH3:30])[CH:23]=2)=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:38][CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]>CN(C=O)C>[Si:41]([O:40][CH2:39][CH2:38][O:29][C:25]1[C:24]([CH3:30])=[CH:23][C:22]([C:12]2[N:11]([C:8]3[CH:7]=[CH:6][C:5]([CH:1]([CH2:3][CH3:4])[CH3:2])=[CH:10][CH:9]=3)[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:27][C:26]=1[CH3:28])([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CCC(C)c1ccc(-n2c(-c3cc(C)c(O)c(C)c3)nc3ccccc3c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCC(C)c1ccc(-n2c(-c3cc(C)c(OCCO[Si](C)(C)C(C)(C)C)c(C)c3)nc3ccccc3c2=O)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
To a solution of 3-(4-sec-butylphenyl)-2-(4-hydroxy-3,5-dimethylphenyl)quinazolin-4(3H)-one in anhydrous DMF were added cesium carbonate and (2-bromo-ethoxy)-tert-butyl-dimethyl-silane at room temperature. The reaction mixture was stirred at 80° C. under nitrogen for 15 hours. The reaction mixture was cooled to room temperature and compound 2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylphenyl)-3-(4-sec-butylphenyl)quinazolin-4(3H)-one (G) was isolated and optionally purified.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:13]2[C:8](=[C:9](C)[CH:10]=[C:11](C(C3C=NN(CC)C=3OS(CCC)(=O)=O)=O)[C:12]=2[CH3:14])[S:7](=O)(=O)[CH2:6][CH2:5]1.[Mg].C([Br:37])C.CON=C1C2C(=CC=C(C3C=NN(CC)C=3OS(CCC)(=O)=O)C=2C)S(=O)(=O)C(=C=O)C1>C1COCC1>[CH3:1][O:2][N:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Br:37])[C:12]=2[CH3:14])[S:7][CH2:6][CH2:5]1
Reactant: CCBr
Reactant: CCCS(=O)(=O)Oc1c(C(=O)c2cc(C)c3c(c2C)C(=NOC)CCS3(=O)=O)cnn1CC
Agent: CCCS(=O)(=O)Oc1c(-c2ccc3c(c2C)C(=NOC)CC(=C=O)S3(=O)=O)cnn1CC
Agent: [Mg]
Solvent: C1CCOC1
Product: CON=C1CCSc2ccc(Br)c(C)c21

Procedure:
3.0 Grams (12 mmol) of 5-methyl-6-bromothiochroman-4-one and 1.9 g (23 mmol) of O-methylhydroxylamine hydrochloride were refluxed in a solvent mixture of 10 ml of ethanol and 10 ml of pyridine under heat for 30 minutes. The solvents were distilled off under reduced pressure, 50 ml of 5% hydrochloric acid was added, and a formed solid was recovered by filtration, washed with water and then dried to give 3.2 g (yield 93%) of 4-methoxyimino-5-methyl-6-bromothiochroman. (2) 1.1 Grams (46 mmol) of magnesium was dispersed in 10 ml of THF, and 2.2 g (20 mmol) of ethyl bromide was dropwise added under nitrogen current. The mixture was allowed to react for 10 minutes, and then a THF solution of 2.9 g (10 mmol) of the 4-methoxyimino-5-methyl-6-bromothiochroman obtained in the above (1) was gradually added at room temperature. The mixture was refluxed for 3 hours and then cooled to room temperature, and carbon dioxide gas was bubbled in for 1 hour. To the reaction mixture was added 5% hydrochloric acid, and the mixture was extracted with ether. An ether layer was extracted with a 5% potassium carbonate aqueous solution, and an aqueous layer was neutralized with concentrated hydrochloric acid. The neutralization product was extracted with ethyl acetate, and the extract was washed with a saturated sodium chloride aqueous solution. The washed extract was dried over sodium sulfate, and then the solvent was distilled off to give 1.6 g (yield 63%) of 4-methoxyimino-5-methylthiochroman-6-carboxylic acid.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([O:11][CH3:12])=[N:6][CH:5]=1.Cl.[CH3:15][O:16][C:17]([C:19]1([NH2:28])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18]>>[CH3:15][O:16][C:17]([C:19]1([NH:28][C:3]([C:4]2[CH:5]=[N:6][C:7]([O:11][CH3:12])=[C:8]([Br:10])[CH:9]=2)=[O:13])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18]
Reactant: COC(=O)c1cnc(OC)c(Br)c1
Reactant: COC(=O)C1(N)Cc2ccccc2C1
Agent: Cl
Product: COC(=O)C1(NC(=O)c2cnc(OC)c(Br)c2)Cc2ccccc2C1

Procedure:
5-Bromo-6-methoxy-nicotinic acid methyl ester (W. J. Thompson and J. Gaudino, J. Org. Chem. 49 (1984), 5237-5243) (2.00 g, 8.13 mmol) was hydrolyzed in analogy to example 2. The obtained acid was reacted with 2-amino-indane-2-carboxylic acid methyl ester hydrochloride in analogy to step 2 of example 13.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[NH:11][C:10]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C:9]=3[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[C:12]2[NH:11][C:10]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C:9]=3[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3c([N+](=O)[O-])cccc3c2C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2[nH]c3c(N)cccc3c2C1
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 6-nitro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (15.6 g, 49.15 mmol) in ethanol (250 mL) was added a spatula tip of 10% Pd/C. The reaction mixture was shaken under a hydrogen atmosphere (15 psi, Parr apparatus) for 2 h. Upon removal from the Parr apparatus, the reaction mixture was filtered through Celite. The Celite was washed with ethanol and the combined filtrates were concentrated in vacuo to give tert-butyl 6-amino-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate, quantitatively as a white solid: 1H NMR (CDCl3, 500 MHz) δ 1.42-1.67 (m, 9H), 2.74-2.85 (m, 2H), 3.58 (brs, 2H), 3.79 (brs, 2H), 4.60 (brs, 2H), 6.53-6.56 (m, 1H), 6.89-6.99 (m, 2H), 7.77 (brs, 1H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:16][CH:17]=O)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8].O.[NH2:20][NH2:21]>CO>[NH2:20][N:21]1[C:7]([OH:8])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:15]=2)[N:16]=[CH:17]1
Reactant: NN
Reactant: O=CNc1ccc(Br)cc1C(=O)c1ccccn1
Solvent: CO
Solvent: O
Product: NN1C=Nc2ccc(Br)cc2C1(O)c1ccccn1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a solution of 11.2 g. of the 2-(5-bromo-2-formamidobenzoyl)pyridine prepared in the experiment (a) in 50 ml. of methanol is added 10 ml. of hydrazine hydrate (100 %). The resulting mixture is heated at 60° C for several minutes and thereafter left to stand at room temperature for 5 hours. The resulting precipitate is collected by filtration and washed with methanol and ether and dried to give 3-amino-6-bromo-4-hydroxy-4-(2-pyridyl)-3,4-dihydroquinazoline as colorless granules melting at 185° to 187° C. (decomposition).
Reaction SMILES: [O:1]=[C:2]([CH3:17])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:11]([C:14]([O-:16])=[O:15])=[CH:12][N:13]=2)[CH:10]=1.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO>[O:1]=[C:2]([CH3:17])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:11]([C:14]([OH:16])=[O:15])=[CH:12][N:13]=2)[CH:10]=1
Reactant: CC(=O)CCc1ccc2ncc(C(=O)[O-])n2c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)CCc1ccc2ncc(C(=O)O)n2c1
Temperature: 50 °C

Procedure:
A stirring mixture of ethyl 6-(3-oxobutyl)imidazo[1,2-a]pyridine-3-carboxylate (77) (190 mg, 0.730 mmol) and 2N LiOH (0.2 mL) in THF:MeOH (4:1, 3 mL) was heated at 50° C. for 45 minutes. The reaction was cooled to room temperature and the pH was adjusted between 3-5 with 10% citric acid. The solvent was partially reduced. The resulting solid was collected by vacuum filtration and washed with excess water. Crude 6-(3-oxobutyl)imidazo[1,2-a]pyridine-3-carboxylic acid (78) was dried and used in the next step without further purification. MS m/z 233.08 (M+1)+.
Reaction SMILES: [CH3:1][C@@:2]([S:20]([CH3:23])(=[O:22])=[O:21])([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH3:19])=[N:9]1)[C:3]([OH:5])=O.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[O:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH:44]1[O:49][NH2:50].CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:1][C@@:2]([S:20]([CH3:23])(=[O:22])=[O:21])([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH3:19])=[N:9]1)[C:3]([NH:50][O:49][CH:44]1[CH2:45][CH2:46][CH2:47][CH2:48][O:43]1)=[O:5]
Reactant: NOC1CCCCO1
Reactant: Cc1nn(CC[C@](C)(C(=O)O)S(C)(=O)=O)cc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nn(CC[C@](C)(C(=O)NOC2CCCCO2)S(C)(=O)=O)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
To a solution of (2R)-2-methyl-4-(3-methyl-4-phenyl-1H-pyrazol-1-yl)-2-(methylsulfonyl)butanoic acid (129 mg, 0.38 mmol, 1 eq) in anhydrous DCM (7 mL) was added DIPEA (140 uL, 0.804 mmol, 2.1 eq), followed by HOBt (120 mg, 0.784 mmol, 2.05 eq) and the solution was stirred at RT for 30 minutes. The mixture was then treated with O-tetrahydro-2H-pyran-2-yl-hydroxylamine (70 mg, 0.60 mmol, 1.6 eq) followed by EDCI (110 mg, 0.574 mmol, 1.5 eq) and the reaction was allowed to stir at RT. The reaction mixture was concentrated in vacuo to give a crude white solid. The crude mixture was purified via flash chromatography using an Analogix SF15-12 g silica column eluting with ethyl acetate in heptane (0-80%) to give (2R)-2-methyl-4-(3-methyl-4-phenyl-1H-pyrazol-1-yl)-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (110 mg, 66% yield). LC-MS M+H+436.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])[CH:5]=[CH:4][CH:3]=1.CCN([CH:21]([CH3:23])[CH3:22])C(C)C.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>C(Cl)Cl>[CH2:28]([O:27][C:25](/[N:1]=[C:2]1/[N:7]([C:25]([O:27][CH2:28][C:22]2[CH:21]=[CH:23][CH:34]=[CH:29][CH:30]=2)=[O:26])[C:6]([CH2:8][C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])=[CH:5][CH:4]=[CH:3]/1)=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CON(C)C(=O)Cc1cccc(N)n1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: CON(C)C(=O)Cc1ccc/c(=N\C(=O)OCc2ccccc2)n1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 122.6 %

Procedure:
To a solution of 2-(6-aminopyridin-2-yl) N-methoxy-N-methylacetamide (84.4 mg, 0.43 mmol) in DCM (15 ml) was added DIEA (0.114 ml, 0.65 mmol) and the resulting mixture cooled via ice/water bath to 0° C. Benzyl chloroformate (0.08 ml, 0.60 mmol) was added after 5 minutes and the resulting solution stirred for 1 hour allowing to warm to room temperature. The major product was observed to be the di-Cbz protected intermediate via LC-MS and TLC. Therefore, an additional 1 eq of benzyl chloroformate was added to ensure that all the product was converted to the di-CBz product. The reaction was quenched with water (10 ml) and extracted with DCM (2×10 mL). The organics were combined, washed with water (5 mL) and brine (5 mL), dried over sodium sulfated, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC plate (1000 μM) eluting with 25% ethyl acetate in hexane to afforded the title compound (170.4 mg, 85%). LC-MS: C25H25N3O6 calculated 463.48 found m/z (ES) 464 (MH)+ and 330 (M-Cbz)+.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH:20]1([CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]2)[CH2:22][CH2:21]1>>[ClH:19].[CH:20]1([CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([NH:30][S:16]([C:14]3[S:15][C:11]([C:5]4[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=4[CH3:10])=[CH:12][CH:13]=3)(=[O:18])=[O:17])[CH2:26][CH2:25]2)[CH2:21][CH2:22]1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: NC1CCN(CC2CC2)CC1
Product: CCc1cc(-c2ccc(S(=O)(=O)NC3CCN(CC4CC4)CC3)s2)c(C)[nH]c1=O
Product: Cl
Yield: 58 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with (1-cyclopropylmethylpiperidin-4-yl)amine as described in Steps 5 and 6, Example 24 to give the title compound as a white solid (58% yield). LC/MS: RT 2.07 min; m/e 436; 1H NMR (δ, ppm): 11.85 (1H, br), 10.18 (1H, br), 8.30 (1H, d), 7.57 (1H, d), 7.34 (1H, s), 7.17 (1H, d), 3.30-3.58 (2H, m), 2.80-3.08 (2H, m), 2.40 (2H, q), 2.33 (3H, s), 1.72-2.18 (4H, m), 1.00-1.20 (4H, m), 0.60 (2H, m), 0.35 (2H, m).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[NH:3]1.[CH3:20][O:21][C:22](=[O:46])[C@H:23]([CH2:44]O)[NH:24][C:25]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:20][O:21][C:22]([C@@H:23]([NH:24][C:25]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:44][N:6]1[C:5](=[O:7])[C:4]2([CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]2)[NH:3][C:2]1=[O:1])=[O:46]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=O)NC2=O
Reactant: COC(=O)[C@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](CN1C(=O)NC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A solution of 3.6 g (13.37 mmol) of (34.2) in 15 ml of absolute THF is added to a solution of 3.72 g (10.3 mmol) of (34.3) and 3.5 g (13.34 mmol) of triphenylphosphine in 20 ml of absolute THF. 2.11 ml (13.37 mmol) of diethyl azodicarboxylate (DEAD) are added to this solution and the reaction mixture is stirred at room temperature until the reaction has come to an end. The solvent is removed in vacuo and the residue is chromatographed through silica gel using heptane/ethyl acetate. 6 g (95%) of (34.4) are obtained after concentrating the product fractions.
Reaction SMILES: [C:1]([CH2:6][NH:7][CH2:8][CH2:9][N:10]1[C:14]([S:15]CC2C=CC(OC)=CC=2)=[N:13][N:12]=[N:11]1)([O:3]CC)=[O:2].CO.S>O>[C:1]([CH2:6][NH:7][CH2:8][CH2:9][N:10]1[C:14](=[S:15])[NH:13][N:12]=[N:11]1)([OH:3])=[O:2]
Reactant: CCOC(=O)CNCCn1nnnc1SCc1ccc(OC)cc1
Agent: S
Solvent: O
Solvent: CO
Product: O=C(O)CNCCn1nn[nH]c1=S
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.8 %

Procedure:
To a solution of 12.5 g. (35.6 mmol) 1-[2-[[(carbethoxy)methyl]amino]ethyl]-5-[(4-methoxybenzyl)thio]-1H-tetrazole in 250 ml. of methanol and 65 ml. of water was added a solution of 25.5 g. (80 mmol) of mercuric acetate in 80 ml. of water. The mixture was stirred at room temperature for 15 hours and at reflux for 1 hour. After thorough cooling, the mixture was treated with hydrogen sulfide gas for 1.5 hours. The dark mixture was heated over a steam bath for 1.5 hours and filtered. The filtrate was evaporated in vacuo to dryness. The residue was recrystallized from ethyl acetate to give 5.9 g. of 1-[2-[(carboxymethyl)amino]ethyl]-1,4-dihydro-5H-tetrazole-5-thione (82.8% yield) mp 215°-220° dec.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11](Cl)=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.CN(C=O)C>O>[CH2:1]([C:8]1[S:12][C:11]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: COc1ccc(-c2nc(Cl)sc2Cc2ccccc2)cc1
Agent: [Li]O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2nc(N3CCOCC3)sc2Cc2ccccc2)cc1
Temperature: 100 °C
Yield: 62.8 %

Procedure:
To 25 ml eggplant-shaped bottle were added 1.00 g (3.17 mmol) 5-benzyl-2-chloro-4-(4-methoxy-phenyl)-thiazole prepared in the step 1, 0.27 g (6.34 mmol) LiOH.H2O, 20 mg KI, 0.55 g (6.34 mmol) morpholine, 5 ml DMF and 0.5 ml water. The mixture was stirred until homogeneous, heated to 100° C., stirred for 20 hours, added 20 ml water, and extracted with ethyl acetate 3×10 ml. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a thick crude product, which was purified under a reduced pressure by silica gel column chromatography eluted with petroleum ether and ethyl acetate at a ratio 4:1-3:1 (V:V) to give a 0.73 g product as a white solid in a yield of 62.9%, mp: 88-89 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.47 (4H, m, 2×CH2), 3.80 (4H, t, J=5.2 Hz, 2×CH2), 3.82 (3H, s, OCH3), 4.12 (2H, s, CH2), 6.92 (2H, d, J=8.40 Hz, ArH), 7.18˜7.32 (5H, m, ArH), 7.53 (2H, d, J=8.40 Hz, ArH); EI-MS m/e (%): 366.1 (M+, 100), 309.1 (23); HREI-MS Calcd. for C21H22N2O2S: 366.1402. found: 366.1404. Anal. Calcd. for C21H22N2O2S: C, 68.83; H, 6.05; N, 7.64. found: C, 68.73; H, 6.26; N, 7.83.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:10][CH2:11][C:12](OC)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[BH4-]>C1COCC1.CO>[Si:18]([O:17][CH2:16][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:11][CH2:12][OH:13])([C:21]([CH3:23])([CH3:24])[CH3:22])([CH3:20])[CH3:19]
Reactant: COC(=O)CC[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CCCO)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.7 %

Procedure:
To a solution of (S)-methyl 4-(tert-butoxycarbonylamino)-5-(tert-butyldimethylsilyloxy)pentanoate (40 g, 0.111 mol) in THF (100 mL) and MeOH (5.0 mL) was added LiBH4 (2M in THF, 56.0 mL, 0.112 mol) at 0° C. The reaction mixture was stirred at RT for 2 h. The reaction mixture was cooled to 0° C. and slowly quenched with saturated NaHCO3 solution. The resulting mixture was stirred RT overnight and filtered. The solid was washed with EtOAc. The combined filtrate was diluted with an additional EtOAc (200 mL). The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated to give (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)-5-hydroxypentan-2-ylcarbamate (39.5 g), which was used without further purification. LRMS (M+Na+) m/z 356.4.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[NH:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].S(OC)(O[CH3:27])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>O.CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[N:12]([CH3:27])[CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C1NCN(c2cccc([N+](=O)[O-])c2)c2ncccc21
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CN(c2cccc([N+](=O)[O-])c2)c2ncccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a solution of 2.7 g of 1-(m-nitrophenyl)-4-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine and 20 ml of dry dimethylformamide was added 0.48 g of approximately 55% sodium hydride and the mixture was stirred at room temperature for 30 minutes. To this was added dropwise 2.52 g of dimethyl sulfate and the whole was stirred at room temperature for 3 hours. The reaction mixture was neutralized with sodium carbonate and concentrated under reduced pressure to leave a residue, to which was added water to precipitate a crude product. This product was collected by filtration and recrystallized from a mixture of dimethylformamide and methanol to give 1.96 g of 1-(m-nitrophenyl)-3-methyl-4-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine as yellow needles, melting at 247° - 248° C.