Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=CC=CC=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13](S(C)(=O)=O)=[N:14][CH:15]=2)[N:10](C2C=CC=C(CCN3C(=O)C4=CC=CC=C4C3=O)C=2)[C:9]1=[O:41].[CH3:42][O:43][C:44]1[CH:50]=[CH:49][C:47]([NH2:48])=[CH:46][CH:45]=1>Cl>[CH3:42][O:43][C:44]1[CH:50]=[CH:49][C:47]([NH:48][N:10]2[C:11]3=[N:12][CH:13]=[N:14][CH:15]=[C:16]3[CH2:17][NH:8][C:9]2=[O:41])=[CH:46][CH:45]=1
Reactant: CS(=O)(=O)c1ncc2c(n1)N(c1cccc(CCN3C(=O)c4ccccc4C3=O)c1)C(=O)N(c1ccccc1Br)C2
Reactant: COc1ccc(N)cc1
Agent: Cl
Product: COc1ccc(NN2C(=O)NCc3cncnc32)cc1
Temperature: 120 °C

Procedure:
A solution of 130 mg (0.31 mmol) of 3-(2-bromophenyl)-7-methanesulfonyl-3,4-dihydro-1-[3-(2-phthalimidoethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one from Example 50 was treated with 1 g (8 mmol) of 4-methoxyaniline. The mixture was heated to 120° C. for 2 hours. The mixture was cooled and treated with 30 ml of 2M aqueous hydrochloric acid. The suspended solid was filtered, washed with water and dried. The solid was dissolved in 20 ml of ethanol and treated with 0.2 ml of hydrazine hydrate. After 18 hours the mixture was evaporated and the product purified by column chromatography on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined, evaporated and the residue evaporated with toluene. The residue was then dissolved in 50 ml of dichloromethane, washed with 50 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to give 35 mg (31%) of 1-[3-(2-aminoethyl)phenyl]-3-(2-bromophenyl)-7-(4-methoxyanilino-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 132-133° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:28]([O:29][CH3:30])=[CH:27][C:6]2[CH2:7][C:8](=[O:26])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:25])[CH2:16][CH2:17][S:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[OH:31]O>>[CH3:1][O:2][C:3]1[C:28]([O:29][CH3:30])=[CH:27][C:6]2[CH2:7][C:8](=[O:26])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:25])[CH2:16][CH2:17][S:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCSc1ccccc1)CC2
Reactant: OO
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCS(=O)c1ccccc1)CC2

Procedure:
The title compound is prepared from N-[3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-N-(2-phenylthioethyl)-methylamine and hydrogen peroxide analogously to Example 4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[CH:29][N:28]=[C:27](Cl)[N:26]=3)[CH:20]=2)[S:14]([CH3:17])(=[O:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:32][CH2:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=4)[N:26]=3)[CH:20]=2)[S:14]([CH3:17])(=[O:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(-c3ccnc(Cl)n3)c2)S(C)(=O)=O)C1
Product: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(-c3ccnc(NCCc4ccc(O)cc4)n3)c2)S(C)(=O)=O)C1

Procedure:
Intermediate 36 was coupled with tyramine following procedure F. The resulting product was deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 468. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.2 (d, 2H), 8.0 (d, 1H) 7.6 (d, 1H) 7.5 (t, 1H), 7.2 (d, 1H), 7.1 (d, 2H), 6.7 (d, 2H), δ 4.6 (s, 2H), 3.5-3.4 (m, 6H), δ 3.2-3.1 (m, 1H), 3.0 (s, 3H), δ 2.9 (t, 2H), δ 2.2-2.0 (m, 2H).
Reaction SMILES: C[O:2][C:3]1[C:8]([CH2:9][NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[CH:7][C:6]([CH2:21][CH3:22])=[C:5]([CH3:23])[N:4]=1.Cl.N1C=CC=CC=1.Cl>O>[C:11]1([NH:10][CH2:9][C:8]2[C:3](=[O:2])[NH:4][C:5]([CH3:23])=[C:6]([CH2:21][CH3:22])[CH:7]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CCc1cc(CNc2cccc3ccccc23)c(OC)nc1C
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCc1cc(CNc2cccc3ccccc23)c(=O)[nH]c1C
Yield: 15.8 %

Procedure:
A mixture of 2-methoxy-3-{[1-naphthylamino]-methyl}-5-ethyl-6-methylpyridine (125 mg, 0.41 mmol) and pyridine hydrochloride (500 mg, 4.3 mmol) was warmed at 145°-160° C. for 20 minutes. The reaction mixture was then cooled, water added, and the mixture made acidic with dilute aqueous hydrochloride acid. The product was then extracted into chloroform. Chloroform extracts were concentrated and the residue flash chromatographed on silica gel eluting with 5% methanol/95% chloroform. Appropriate fractions were combined and evaporated. The residue was triturated with diethyl ether to give 18.9 mg (15%) of product, m.p. 165°-167° C.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH2:6]([S:8][C:9]1[CH:16]=[C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C@H:18]2[CH3:23])[CH:14]=[C:13]([CH3:24])[C:10]=1[C:11]#[N:12])[CH3:7]>>[CH2:6]([S:8][C:9]1[CH:16]=[C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C@H:18]2[CH3:23])[CH:14]=[C:13]([CH3:24])[C:10]=1[C:11]([NH2:12])=[O:2])[CH3:7]
Reactant: O=S(=O)(O)O
Reactant: CCSc1cc(N2CCOC[C@H]2C)cc(C)c1C#N
Product: CCSc1cc(N2CCOC[C@H]2C)cc(C)c1C(N)=O
Temperature: 100 °C

Procedure:
Concentrated sulfuric acid (5 ml) is added to 2-ethylsulfanyl-6-methyl-4-[(3R)-3-methyl-morpholin-4-yl]-benzonitrile (0.11 g, 0.40 mmol) at RT and the resulting mixture is heated at 100° C. for 4 h. Upon completion (monitored by TLC), the reaction is slowly quenched with ice at 0° C. The mixture is basified with aqueous ammonia (pH=10). The aqueous part is extracted with ethyl acetate (3×10 ml). The combined organic layers are washed with water (10 ml), brine (10 ml), dried over anhydrous sodium sulfate and evaporated to get 2-ethylsulfanyl-6-methyl-4-[(3R)-3-methyl-morpholin-4-yl]-benzamide which is used in the next step without further purification (0.075 g, 0.26 mmol, 55%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[I-:13].[Cs+].B(F)(F)F.CCOCC>C(#N)C>[C:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][I:13])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: [I-]
Reactant: CC(=O)Oc1ccc(CO)cc1
Agent: FB(F)F
Agent: [Cs+]
Solvent: CCOCC
Solvent: CC#N
Product: CC(=O)Oc1ccc(CI)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 4-acetoxybenzyl alcohol (0.332 g, 2 mmol), and cesium iodide (0.571 g, 2.2 mmol) in anhyd. acetonitrile (10 mL) under nitrogen, boron trifluoride etherate (0.28 mL, 2.2 mmol) in acetonitrile (5 mL) was introduced. After stirring overnight, the reaction mixture was poured into ice-cold water (20 mL) and the solid separated was filtered, washed with water and later with hexanes. The product was dried under high vacuum. Yield, 0.39 g, 71%; TLC, hexanes:EtOAC (4:1). 1H NMR (CDCl3): δ 2.3 (s, 3H), 4.35 (s, 2H), 7.05 (d, 2H), 7.5 (d, 2H).
Reaction SMILES: N1C=CN=C1.Cl.Cl[CH2:8][CH2:9][CH2:10][CH:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([F:26])([F:25])[F:24])[C:12](=[NH:16])OCC.Cl.Cl.[CH3:29][O:30][C:31]1[N:36]=[C:35](/[CH:37]=[CH:38]/[C:39]([NH:41][NH2:42])=O)[CH:34]=[CH:33][C:32]=1[N:43]1[CH:47]=[C:46]([CH3:48])[N:45]=[CH:44]1.Cl>CO>[CH3:29][O:30][C:31]1[N:36]=[C:35](/[CH:37]=[CH:38]/[C:39]2[N:16]=[C:12]3[CH:11]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:23]([F:24])([F:25])[F:26])[CH2:10][CH2:9][CH2:8][N:42]3[N:41]=2)[CH:34]=[CH:33][C:32]=1[N:43]1[CH:47]=[C:46]([CH3:48])[N:45]=[CH:44]1
Reactant: COc1nc(/C=C/C(=O)NN)ccc1-n1cnc(C)c1
Reactant: CCOC(=N)C(CCCCl)c1ccccc1C(F)(F)F
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CO
Product: COc1nc(/C=C/c2nc3n(n2)CCCC3c2ccccc2C(F)(F)F)ccc1-n1cnc(C)c1
Temperature: 30 °C
Reaction time: 40 h
Yield: 86 %

Procedure:
Imidazole (4.75 g, 69.7 mmol) and Ethyl 5-chloro-2-(2-trifluoromethylphenyl)pentanimidoate hydrochloride (2.00 g, 5.81 mmol) were added the solution of (2E)-3-[6-Methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylohydrazide dihydrochloride in methanol (10 mL) at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at 30° C. for 40 hours. The reaction mixture was adjusted to the pH6.5 with 5N HCl aq., and extracted with ethyl acetate (22 mL). The organic layer was washed with water (4 mL), concentrated under the reduced pressure and azeotroped with 2-propanol under the reduced pressure to obtain the title compound (2.4 g, 86% yield). Traces of seed crystal of the title compound which was obtained by the method similar to this step was added to the solution of the crude title compound in 2-propanol (10 mL), and the mixture was stirred at room temperature for 13.5 hours. The suspension was stirred for 2 hours with an ice-bath cooling. The solids were collected by filtration and washed with 2-propanol and dried under the reduced pressure to obtain the title compound (1.55 g, 56% yield).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[C-:25]#[N:26].[K+]>CN(C)C=O>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:5]2[N:6]([C:8]3[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][CH:13]=3)[CH:7]=[C:3]([CH2:2][C:25]#[N:26])[N:4]=2)=[CH:19][CH:20]=1
Reactant: [C-]#N
Reactant: CS(=O)(=O)c1ccc(-n2cc(CCl)nc2-c2ccc(Cl)cc2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-n2cc(CC#N)nc2-c2ccc(Cl)cc2)cc1
Temperature: 85 °C
Reaction time: 24 h

Procedure:
A mixture of 250 mg (0.656 mmole) of 4-chloromethyl-2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole (Example 159, Step 1) and 86 mg (1.3 mmol) of potassium cyanide in 4 ml of dimethylformamide was stirred at 85° C. for 24 hours. An additional 86 mg of potassium cyanide was added, and stirring continued for 8 hours. After cooling, the mixture was partitioned between dichloromethane and water and the aqueous layer further extracted with dichloromethane. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and evaporated. Chromatography of the residue over silica gel using 60% ethyl acetate in toluene, followed by trituration with ethyl acetate gave the title compound, 59 mg, as a very pale yellow crystalline solid: mp (DSC) 197° C. Anal. Calc'd. for C18H14ClN3O2S (MW 371.85): C, 58.14; H, 3.80; N, 11.30. Found: C, 57.92; H, 3.57; N, 11.01.
Reaction SMILES: [CH2:1]([C@@:4]1([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22](=[O:25])[N:21]([CH3:26])[CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=C.C1C[O:37]CC1.O>CCOC(C)=O.O=[Os](=O)(=O)=O>[F:33][C:30]1[CH:31]=[CH:32][C:27]([C@:4]2([CH2:1][CH2:2][OH:37])[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]3[CH:14]=[CH:15][C:16]([C:19]4[CH:24]=[CH:23][C:22](=[O:25])[N:21]([CH3:26])[CH:20]=4)=[CH:17][CH:18]=3)[CH3:12])[CH2:6][CH2:5]2)=[CH:28][CH:29]=1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(=O)n(C)c3)cc2)C(=O)O1
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (0.064 g, 0.144 mmol, 1.0 equiv) in THF-H2O (1:1, 6 mL) were added NalO4 (0.145 g, 0.678 mmol, 4.7 equiv) and OsO4 (2.5 wt. % solution in t-BuOH, 0.048 g, 0.0047 mmol, 0.033 equiv), and the mixture was stirred at rt for 1 h. The mixture was diluted with EtOAc, dried over Na2SO4, and concentrated under reduced pressure. The residue was dissolved in MeOH (3 mL) and NaBH4 (0.100 g) was added. After the mixture was stirred for 0.5 h at rt, acetone was added. The solvents were removed in vacuo, the residue was treated with saturated brine, extracted with CH2Cl2, and dried over Na2SO4. After the solvent was evaporated, the residue was purified by reversed-phase HPLC (SunFire™ Prep O18 OBD™ 5 μm 19×50 mm column, 10%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 2 min, flow rate 20 mL/min) to afford (S)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one. LC-MS Method 1 tR=1.21 min, m/Z=451 (M+1); 1H NMR (400 MHz, CD3OD) δ 7.80 (m, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.22-7.19 (m, 4H), 7.00-6.92 (m, 4H), 6.52 (d, J=9.4 Hz, 1H), 5.45 (q, J=7.0 Hz, 1H), 3.60-3.52 (m, 1H), 3.52 (s, 3H), 3.24-3.18 (m, 1H), 3.02-2.98 (m, 1H), 2.39-2.35 (m, 1H), 2.23-2.12 (m, 2H), 2.01 (t, J=7.3 Hz, 2H), 1.43 (d, J=7.0 Hz, 3H); 19F NMR (376 MHz, CD3OD) 8-117.19 (m).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19]>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][C:10]=1[O:11][C:18](=[O:19])[C:17]([CH3:22])([CH3:21])[CH3:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1ccc(O)c(C(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(OC(=O)C(C)(C)C)c(C(C)(C)C)c1
Reaction time: 0.5 h
Yield: 72 %

Procedure:
5.00 g of 3-t-butyl-4-hydroxyanisole was dissolved in 30 ml of dimethylformamide and the solution was added dropwise into a suspension of 1.33 g of oily sodium hydride in 30 ml of dimethylformamide at 0° C. under a nitrogen stream. After stirring for 30 minutes, 3.76 ml of trimethylacetyl chloride was added dropwise and the solution was stirred overnight and allowed to attain room temperature. After the reaction was quenched with a saturated aqueous ammonium chloride solution, the reaction solution was extracted with water and ethyl acetate. The organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 3%-5% ethyl acetate) to give 5.25 g of 3-t-butyl-4-trimethylacetoxyanisole as a white solid (yield 72%).
Reaction SMILES: [CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:17])[F:16])=[CH:10][CH:9]=1)[C:5](Cl)=[O:6])([CH3:3])[CH3:2].[C:18]([CH:20]([OH:34])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1)#[N:19].N1C=CC=CC=1>CCOCC>[CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:17])[F:16])=[CH:10][CH:9]=1)[C:5]([O:34][CH:20]([C:18]#[N:19])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:22]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Reactant: CC(C)C(C(=O)Cl)c1ccc(OC(F)F)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)C(C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1)c1ccc(OC(F)F)cc1
Reaction time: 8 h

Procedure:
A solution of α-isopropyl-4-difluoromethoxyphenylacetyl chloride (4.58 mmol) in ether (5 ml) is added to an ether (20 ml) solution of α-cyano-m-phenoxybenzyl alcohol (4.58 mmol) and pyridine (0.5 ml). The mixture is stirred overnight and filtered. The filtrate and the washings are evaporated and the residual oil is purified on 5×20 cm silica gel plates using 1:1 methylenechloride-hexane as eluent. The band in the silica gel plate is extracted with ether and evaporated to give the desired ester as an oil.
Reaction SMILES: [Na].S(O)(O)(=O)=[O:3].[CH2:7]([NH:14][C:15](N)=N)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]C>>[CH2:7]([N:14]=[C:15]=[O:3])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=S(=O)(O)O
Reactant: CCCCCCCNC(=N)N
Agent: [Na]
Product: CCCCCCN=C=O

Procedure:
Proceeding in a manner similar to that described above in part A of Example 18, and using 3.44 g. of sodium, 30.9 g. of n-heptylguanidine sulfate, and 19.1 g. of n-hexyl isocyanate, there was obtained 26.2 g. of 1-n-heptylamidino-3-n-hexylurea having the structural formula ##STR63## as a white crystalline solid which melted at 68°-72° C. The solubility of this base in a dilute acidic solution (prepared by mixing 0.36 ml. of N/2 hydrochloric acid and 9.64 ml. of water) at 25° C. was less than 0.25 percent. In 95 percent ethyl alcohol at 25° C. it was soluble to the extent of 5 percent (w/v); a precipitate formed when the 5 percent alcoholic solution was diluted with four volumes of water.
Reaction SMILES: OC[C:3]1[S:4][S:5][C:6]([CH2:9][O:10][Si](C(C)(C)C)(C)C)=[CH:7][CH:8]=1.O[C:19]1[CH:20]=[C:21]([C:25]#[CH:26])[CH:22]=[CH:23][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:25]([C:21]1[CH:20]=[C:19]([O:10][CH2:9][C:6]2[S:5][S:4][CH:3]=[CH:8][CH:7]=2)[CH:24]=[CH:23][CH:22]=1)#[CH:26]
Reactant: C#Cc1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)OCC1=CC=C(CO)SS1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C#Cc1cccc(OCC2=CC=CSS2)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 56 %

Procedure:
To a stirred solution of 3-(hydroxymethyl)-6-[(tert-butyldimethylsilyloxy)methyl]-1,2-dithiin (U.S. Ser. No. 08/212,096) (235 mg, 0.802 mmol) in 1 mL of dry THF was added a solution of 3-hydroxyphenylacetylene (142 mg, 1.20 mmol) in 1 mL THF, followed by the addition of triphenylphosphine (315 mg, 0.977 mmol). The resulting solution was cooled to 0° C., then 190 μL (210 mg, 1.037 mmol) of diethylazodicarboxylate was added, and the reaction mixture was kept at 0°-5° C. for 1.5 h until TLC analysis showed the reaction to be complete. For 5 isolation of the products, the reaction mixture was chromatographed directly on a silica gel column, using ethyl acetate-hexane, 1:20, to yield 3-[tert-butyldimethylsilyloxy)methyl]-6-[(3-ethynylphenyloxy)methyl]-1,2-dithiin (175 mg, 56.0%); 1H-NMR (CDCl3) δ7.23 (t, J=8.0, 1 H), 7.12 (d, J=8.0, 1 H), 7.05 (s, 1 H), 6.93 (dd, J=6.0, 2.4, 1 H), 6.44 (d, J=6.0, 1 H), 6.37 (d, J=6.0, 1 H), 4.66 (s, 2 H), 4.30 (s, 2 H), 3.07 (bs, 1 H), 0.92 (s, 9 H), 0.10 (s, 6 H); 13C--NMR (CDCl3) δ157.79, 136.21, 132.54, 129.46, 128.74, 127.03, 125.43, 123.45, 118.29, 116.22, 83.28, 77.21, 69.73, 64.79, 25.76, 18.31, -5.41. MS (EI) 390.1 (M+).
Reaction SMILES: C1(C)C(S([CH2:10][N+:11]#[C-:12])(=O)=O)=CC=CC=1.[CH:14]1([CH:18]=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:17][CH2:16][CH2:15]1.[H-].[Na+]>CS(C)=O.C(OCC)C>[CH:14]1([C:18]2[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:10][NH:11][CH:12]=2)[CH2:15][CH2:16][CH2:17]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Reactant: CCOC(=O)C=CC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CCOC(=O)c1c[nH]cc1C1CCC1
Reaction time: 0.75 h
Yield: 67.7 %

Procedure:
Toluenesulfonylmethyl isocyanide (3.04 g, 15.59 mmol) was added to the stirred solution of ethyl 3-cyclobutylprop-2-enoate (2.00 g, 12.99 mmol) in a mixture of dimethylsulfoxide (2 mL) and diethyl ether (30 mL) and stirred for 45 min. The resulting mixture was added to a slurry of sodium hydride (675 mg, 38.14 mmol, 60% in mineral oil) in diethyl ether (10 mL) over a period of 30 min then stirred for a further 1 h. The reaction mixture was quenched with saturated ammonium chloride solution, the organics were separated and the aqueous layer was extracted with diethyl ether (4×10 mL). The combined organic layer was washed with water, brine, dried over anhydrous sodium sulphate, filtered and concentrated. The residue was subjected to column chromatography over silica gel (100-200 mesh) using 0% to 15% of ethyl acetate in pet-ether as eluent, concentrated and dried under reduced pressure to afford ethyl 4-cyclobutyl-1H-pyrrole-3-carboxylate (1.70 g, 67%) as a liquid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[CH3:26])[CH2:9]/[C:10](/[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[N:28]\[OH:29])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1cc(C(=O)CC(c2ccc(Br)cc2)c2ccc(Cl)cc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(CC(c2ccc(Br)cc2)c2ccc(Cl)cc2C)=N/O)ccn1

Procedure:
In analogy to example 74, step 7, from 3-(4-bromophenyl)-3-(4-chloro-2-methylphenyl)-1-(2-methylpyridin-4-yl)propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound which contains less than 10% of the Z isomer as a white foam, MS (ESI+): m/z=445.05 [M+H]+.
Reaction SMILES: C(OC([N:11]1[CH2:16][C@@H:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14][C@H:13]([NH:21][CH2:22][C:23]2[CH:28]=[C:27]([O:29][C:30]([F:33])([F:32])[F:31])[CH:26]=[CH:25][C:24]=2[O:34][CH3:35])[C@@H:12]1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=O)C1C=CC=CC=1.C1COCC1>[OH-].[OH-].[Pd+2].CO>[CH3:20][O:19][C:17]([C@@H:15]1[CH2:16][NH:11][C@@H:12]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C@@H:13]([NH:21][CH2:22][C:23]2[CH:28]=[C:27]([O:29][C:30]([F:33])([F:31])[F:32])[CH:26]=[CH:25][C:24]=2[O:34][CH3:35])[CH2:14]1)=[O:18]
Reactant: COC(=O)[C@H]1C[C@H](NCc2cc(OC(F)(F)F)ccc2OC)[C@H](c2ccccc2)N(C(=O)OCc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)[C@@H]1CN[C@@H](c2ccccc2)[C@@H](NCc2cc(OC(F)(F)F)ccc2OC)C1
Temperature: 25 °C

Procedure:
A mixture of (2S*,3S*,5S*)-1-benzyloxycarbonyl-5-methoxycarbonyl-3-[N-(2-methoxy-5-trifluoromethoxybenzyl)amino]-2-phenylpiperidine (1.007 g, 1.758 mmol) and 20% Pd(OH)2 /C (0.258 g), THF (5.0 ml), and MeOH (30.0 ml) was stirred under an atmosphere of H2 (baloon) at room temperature for an hour. The catalyst was filtered off by the aid of Celite, and washed with THF. The combined filtrate and THF washings were concentrated in vacuo to give title compound (0.789 g, quantitatively) as a pale yellow oil. IRmax (film): 3340(s), 1735(s), 1718(s), 1608(m), 1250(br., s), 1150(br., s), 1033(s), 810(m), 750(m), 700(m) cm-1 ; 1H-NMR δ: 7.36-7.18(m, 5H), 7.00(dd, J=9.2, 2.2 Hz, 1H), 6.84(d, J=2.2 Hz, 1H), 6.62(d, J=9.2 Hz, 1H), 3.89(d, J=2.2 Hz, 1H), 3.71(s, 3H), 3.68(d, J=14.3 Hz, 1H), 3.51(ddd, J=11.9, 3.7, 1.8 Hz, 1H), 3.47(s, 3H), 3.40(d, J=14.3 Hz, 1H), 3.05(dddd, J=12.3, 11.9, 3.7, 3.7 Hz, 1H), 2.92-2.82(m, 1H), 2.88(dd, J=11.9, 11.9 Hz, 1H), 2.37(dm, J=13.6 Hz, 1H), 1.78(ddd, J=13.6, 12.3, 2.9 Hz, 1H), 1.68(br.s, 2H, NH×2) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[N:17]=[C:16]([NH:18][O:19]C3CCCCO3)[C:15]3[C:14]([CH3:26])=[N:13][C:12]([NH2:27])=[N:11][C:10]=3[CH2:9]2)=[C:4]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[N:29]=2)[CH:3]=1.Cl>O1CCOCC1>[NH2:27][C:12]1[N:13]=[C:14]([CH3:26])[C:15]2=[C:10]([CH2:9][C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[N:29]=3)[NH:17]/[C:16]/2=[N:18]\[OH:19])[N:11]=1
Reactant: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3C(NOC3CCCCO3)=N2)n1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/O)N2)n1
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
(7R)-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-5-(tetrahydro-2H-pyran-2-yloxyamino)-7,8-dihydropyrido[4,3-d]pyrimidin-2-amine (0.891 g, 1.86 mmol) was dissolved in 10 mL of dioxane. 4M of HCl in dioxane (1.86 mL, 7.45 mmol) was then added slowly to the above stirred solution. After all the HCl was added, a yellow solid was formed at the bottom of the reaction flask. The deprotection was allowed to go for 30 minutes, then the supernatant was decanted. Dichloromethane was added to wash the solid, then it was decanted. This process was repeated a few times. No product was found in the dioxane and dichloromethane washes. The solid product was then purified on flash column chromatography, SiO2, gradient 2-15% methanol/chloroform to give 0.404 g of product, 63.5% yield over 2 steps. MS (ES) [M+H] calc'd for C20H19FN6O2, 395; found, 395.3. 1H NMR (400 MHz, METHANOL-d4) δ 2.60 (s, 3H), 3.09-3.19 (m, 1H), 3.29-3.34 (m, 1H), 3.91 (s, 3H), 5.45 (br. s., 1H), 6.82 (d, J=8.34 Hz, 1H), 7.16 (d, J=6.57 Hz, 1H), 7.19-7.30 (m, 2H), 7.55 (dd, J=8.59, 5.56 Hz, 1H), 7.79 (dd, J=8.34, 7.33 Hz, 1H).