Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)=[CH:5][C:6]=1[C:7](OCC)=[O:8].[CH3:22][N:23](C=O)C.C(O)=O>C(N)=O.C(O)(C)C>[CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:12]=1[C:4]1[NH:3][C:2]2[N:1]=[CH:22][N:23]=[C:7]([OH:8])[C:6]=2[CH:5]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cc(-c2ccc3ccccc3c2)[nH]c1N
Solvent: CC(C)O
Solvent: NC=O
Solvent: O=CO
Product: Oc1ncnc2[nH]c(-c3ccc4ccccc4c3)cc12

Procedure:
420 mg (1.5 mmol) of 2-amino-3-ethoxycarbonyl-5-(naphth-2-yl)-1H-pyrrole are stirred in 3 ml of formamide, 1.5 ml of DMF and 0.75 ml of formic acid at 150° C. for 22 hours. The reaction mixture is diluted with approximately 1 ml of isopropanol and filtered. Washing with ethanol, isopropanol and hexane yields the title compound; m.p.>300° C.; 1H-NMR (200 MHz, DMSO-d6): 12.2 (sb), 8.39 (s, 1H), 8.0 (m, 2H), 7.9 (m, 3H), 7.53 (m, 2H), 7.11 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2ccc(Cl)cc2)nc1
Temperature: 100 °C
Yield: 103.8 %

Procedure:
A flask was charged with 2-bromo-5-nitropyridine (4 g, 19.71 mmol), 4-chlorophenylboronic acid (4.54 g, 27.6 mmol), Pd(PPh3)4 (1.139 g, 0.985 mmol), potassium carbonate (8.16 g, 59.1 mmol), dioxane (40 ml) and water (20 ml) at room temperature. The flask was sealed, flushed with nitrogen for three times and heated at 100° C. for 3 hours. The reaction mixture was diluted with EtOAc (100 ml) and filtered. The filtrate was concentrated. The residue was washed with water by filtration. The afforded solid was dissolved in EtOAc (200 ml) and washed with saturated aqueous sodium bicarbonate solution and brine, dried over Na2SO4, concentrated, and dried under vacuum to afford crude 2-(4-chlorophenyl)-5-nitropyridine (4.8 g, 75% purity, 78% yield) as yellow solid. 1H NMR (400 MHz, DMSO-d6) ppm 7.27-7.36 (m, 4H) 7.51-7.61 (m, 3H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]3[O:20][C:19]([C:21]4[CH:29]=[CH:28][C:24]5=[CH:25][O:26][CH:27]=[C:23]5[CH:22]=4)=[N:18][C:17]=13)=[O:11])[CH2:2]2.[H][H]>[Pd].CO>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]3[O:20][C:19]([C:21]4[CH:22]=[CH:23][C:27]5[O:26][CH2:25][CH2:24][C:28]=5[CH:29]=4)=[N:18][C:17]=13)=[O:11])[CH2:2]2
Reactant: [H][H]
Reactant: O=C(NC1CN2CCC1CC2)c1cccc2oc(-c3ccc4cocc4c3)nc12
Agent: [Pd]
Solvent: CO
Product: O=C(NC1CN2CCC1CC2)c1cccc2oc(-c3ccc4c(c3)CCO4)nc12
Yield: 26.7 %

Procedure:
A mixture of N-(1-azabicyclo[2.2.2]oct-3-yl)-2-benzofuran-5-ylbenzoxazole-4-carboxamide (30 mg, 0.077 mmol), 10% palladium on carbon (10 mg), and methanol (1 mL) was treated with hydrogen (50 psi) for 24 h on a parr-shaker apparatus, and then the mixture was filtered through a microfilter and washed with methanol. The filtrate was concentrated and the crude material was purified by semi-preparative HPLC to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(2,3-dihydrobenzofuran-5-yl)benzoxazole-4-carboxamide (8 mg, 26%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.60 (d, J=7.0 Hz, 1H), 8.15 (dd, J=7.5, 1.5 Hz, 1H), 8.05 (s, 1H), 8.04 (dd, J=8.5, 1.5 Hz, 1H), 7.66 (dd, J=8.5, 1.0 Hz, 1H), 7.42 (t, J=8.0 Hz, 1H), 6.94 (d, J=8.5 Hz, 1H), 4.72 (t, J=8.5 Hz, 2H), 4.36-4.30 (m, 1H), 3.54 (ddd, J=14.0, 9.5, 2.0 Hz, 1H), 3.34 (t, J=8.5 Hz, 2H), 3.16-2.86 (m, 5H), 2.22-2.09 (m, 2H), 1.83-1.65 (m, 3H); MS (ESI+) m/z 390 (M+H); HPLC>99% (AUC), tR=12.67 min.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)=[N:8]1.Cl.[CH3:48][N:49]([CH3:54])[CH2:50][C:51](O)=[O:52].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:51](=[O:52])[CH2:50][N:49]([CH3:54])[CH3:48])=[CH:42][CH:41]=2)=[N:17]1
Reactant: CN(C)CC(=O)O
Reactant: Nc1ccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN(C)CC(=O)Nc1ccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)cc1
Yield: 16 %

Procedure:
The title compound was prepared as described in Example 379, using 4-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.304 g, 0.50 mmol) in methylene chloride (3 mL) was added N,N-dimethylglycine hydrochloride (0.137 g, 0.98 mmol), 1-hydroxybenzotriazole (0.081 g, 0.60 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.115 g, 0.60 mmol). The final crude product was purified by preparative HPLC (10–70% acetonitrile in H2O, 20 min.) (0.029 g, 16% yield): 1H NMR (DMSO-d6) δ 14.3 (br s, 1H), 13.38 (br s, 1H), 9.91 (s, 1H), 8.69 (s, 1H), 8.08 (d, 1H), 7.95 (d, 2H), 7.87 (d, 2H), 7.68 (d, 1H), 3.12 (s, 2H), 2.30 (s, 6H); ES-MS (m/z) 362 [M+1]+.
Reaction SMILES: [CH:1]1([C:4]2[C:9]([F:10])=[CH:8][N:7]=[C:6]([NH:11][C:12]3[CH:13]=[C:14]([C:19]4[S:23][C:22]([C:24]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:25](OCC)=[O:26])=[N:21][CH:20]=4)[CH:15]=[C:16]([CH3:18])[CH:17]=3)[N:5]=2)[CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C>O1CCCC1>[CH:1]1([C:4]2[C:9]([F:10])=[CH:8][N:7]=[C:6]([NH:11][C:12]3[CH:13]=[C:14]([C:19]4[S:23][C:22]([C:24]([OH:34])([C:30]([F:33])([F:32])[F:31])[CH2:25][OH:26])=[N:21][CH:20]=4)[CH:15]=[C:16]([CH3:18])[CH:17]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)C(O)(c1ncc(-c2cc(C)cc(Nc3ncc(F)c(C4CC4)n3)c2)s1)C(F)(F)F
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: Cc1cc(Nc2ncc(F)c(C3CC3)n2)cc(-c2cnc(C(O)(CO)C(F)(F)F)s2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 1.4 %

Procedure:
To a solution of ethyl 2-(5-{3-[(4-cyclopropyl-5-fluoropyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)-3,3,3-trifluoro-2-hydroxypropanoate (36 mg, 0.073 mmol) in tetrahydrofuran (10 mL) at −78° C. was added DIBAL-H (0.160 mL 0.160 mmol). After 30 minutes, the reaction mixture was warmed to 0° C. After 2 hours, the reaction mixture was quenched with saturated ammonium chloride solution, then diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.05% TFA to give 2-(5-{3-[(4-cyclopropyl-5-fluoropyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)-3,3,3-trifluoropropane-1,2-diol (3.5 mg, 0.001 mmol, 10%). MS ESI: [M+H]+ m/z 455.1. 1H NMR (500 MHz, DMSO-d6) δ 9.58 (bs, 1H); 8.38 (m, 1H); 8.06 (s, 1H); 7.89 (s, 1H); 7.43 (s, 1H); 7.07 (s, 1H); 3.99 (s, 2H); 2.29 (s, 3H); 2.28-2.23 (m, 1H); 1.18-1.14 (m, 4H). rhSYK activity=+++
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[OH:26][CH2:27][CH2:28][N:29]([CH2:40][CH2:41][OH:42])[S:30]([C:33]1[CH:34]=[N:35][CH:36]=[C:37](Br)[CH:38]=1)(=[O:32])=[O:31]>>[OH:26][CH2:27][CH2:28][N:29]([CH2:40][CH2:41][OH:42])[S:30]([C:33]1[CH:34]=[N:35][CH:36]=[C:37]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:38]=1)(=[O:32])=[O:31]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: O=S(=O)(c1cncc(Br)c1)N(CCO)CCO
Product: O=S(=O)(c1cncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1)N(CCO)CCO

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (388 mg, 1.1 mmol) and 5-bromo-pyridine-3-sulfonic acid bis-(2-hydroxy-ethyl)-amide (example B.5) (325 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (160 mg, 29%). MS (ISP) 600.2 [(M+H)+]; mp 173–178° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][N:11](C)[CH2:12][CH2:13][C@H:14]([O:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1)[C:15]1[S:16][CH:17]=[CH:18][CH:19]=1.[ClH:32].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C1(OC(Cl)=O)C=CC=CC=1.C(C(C)=O)C.O>[CH3:10][NH:11][CH2:12][CH2:13][C@H:14]([O:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=12)[C:15]1[S:16][CH:17]=[CH:18][CH:19]=1.[ClH:32]
Reactant: CN(C)CC[C@H](Oc1cccc2ccccc12)c1cccs1
Agent: Cl
Agent: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC(C)=O
Solvent: Cc1ccccc1
Product: CNCC[C@H](Oc1cccc2ccccc12)c1cccs1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Diisopropylethylamine (210 ml) is added to a solution of (S)-N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)-propanamine (311 g; 99.6% ee) in toluene (1200 ml) and phenylchloroformate (150 ml) is then added at 60° C. After two hours of stirring at 80° C., the mixture is cooled down, shaken with a diluted solution of hydrochloric acid, water and a 2% solution of sodium hydrogencarbonate. The organic phase is dried with sodium sulfate and evaporated. The evaporation residue is dissolved in ethanol (300 ml) and a 5M solution of potassium hydroxide (400 ml) is added drop-wise under reflux. After two hours of refluxing, the mixture is evaporated to half the volume, diluted with water (1000 ml) and extracted with toluene (300 ml). The organic phase is dried with sodium sulfate and evaporated. The evaporation residue is dissolved in ethylmethylketone (300 ml) and concentrated HCl (1 mole), diluted with ethylmethylketone (300 ml), is added drop-wise at 0° C.; then the mixture is stirred for two hours. The precipitated crystals are then sucked off. Yield: 250 g (75%), m.p.: 167-169° C. Recrystallization from ethylmethylketone affords colorless crystalline duloxetine hydrochloride, m.p. 170.5-171.5° C. Optical purity: 99.9% ee (CE), chemical purity: 99.9% (HPLC).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][CH:6]([CH3:10])[C:7](Cl)=[O:8].[NH:11]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][C:12]1=[O:13]>C(=S)=S>[Br:5][CH:6]([CH3:10])[C:7]([C:18]1[CH:17]=[C:16]2[C:21](=[CH:20][CH:19]=1)[NH:11][C:12](=[O:13])[CH2:14][CH2:15]2)=[O:8]
Reactant: CC(Br)C(=O)Cl
Reactant: O=C1CCc2ccccc2N1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(Br)C(=O)c1ccc2c(c1)CCC(=O)N2
Temperature: 0 °C
Yield: 92.6 %

Procedure:
To a solution of aluminum chloride (44 g) and α-bromopropionyl chloride (43 g) in carbon disulfide (150 ml) was added portionwise 3,4-dihydrocarbostyril (8 g) while refluxing with stirring. After completion of addition, the mixture was refluxed with stirring for 2 hours. After cooling, the mixture was poured into ice water and crystals which precipitated were collected by filtration and washed with water. Recrystallization from ethanol gave 14.2 g of 6-(α-bromopropionyl)-3,4-dihydrocarbostyril.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[Si:15]([O:22][CH:23]1[CH2:28][CH2:27][C:26](=[CH:29][C:30]#[N:31])[CH2:25][CH2:24]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].N12CCCN=C1CCCCC2>C(#N)C>[Si:15]([O:22][CH:23]1[CH2:24][CH2:25][C:26]([CH2:29][C:30]#[N:31])([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:27][CH2:28]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(=CC#N)CC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC1(C)OB(c2cnn(C3(CC#N)CCC(O[Si](C)(C)C(C)(C)C)CC3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.09 g, 0.0159 mol) in acetonitrile (39.8 mL) was added (4-(tert-butyl(dimethyl)silyl)oxycyclohexylidene)acetonitrile (4.80 g, 0.0191 mol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (1.19 mL, 0.00797 mol). The resulting mixture was stirred at room temperature overnight, then evaporated to dryness. The mixture was purified on silica gel, eluting with 0 to 20% EtOAc in hexanes, to give the desired product as cis- and trans-mixture (2.33 g, 33%). LCMS (M+H) 446.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.[C:16]1([C@@H:22]([CH2:24]O)[NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]23[O:15][CH2:24][C@H:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:23]2[C:12](=[O:14])[CH2:11][CH2:10][CH2:9]3)=[CH:6][CH:7]=1
Reactant: O=C(O)CCCC(=O)c1ccc(F)cc1
Reactant: N[C@H](CO)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C1CCC[C@@]2(c3ccc(F)cc3)OC[C@H](c3ccccc3)N12
Yield: 68 %

Procedure:
5-(4-Fluoro-phenyl)-5-oxo-pentanoic acid (1 g, 5.10 mmol) and (S)-(+)-2-phenylglycinol (0.839 g, 6.12 mmol) in toluene (15 mL) together with 4 Å molecular sieves was heated at 140° C. under Dean-Stark conditions for 20 hours. The reaction mixture was filtered through Celite®, evaporated and the residue dissolved in ethyl acetate then re-evaporated. The crude material was purified by column chromatography eluting with 20-40% ethyl acetate in cyclohexane to afford (3S,8aS)-8a-(4-fluoro-phenyl)-3-phenyl-hexahydro-oxazolo[3,2-a]pyridin-5-one (1.08 g).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6])#[N:2].[CH3:12][N:13]([C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[S:16])[NH2:14].N1C=CC=CC=1.O>C(COC)OC>[NH:2]=[C:1]1[C:3]2[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=[O:6])[N:14]1[N:13]([CH3:12])[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[S:16]
Reactant: N#Cc1ccccc1C(=O)Cl
Reactant: CN(N)C(=S)Nc1ccccc1
Solvent: c1ccncc1
Solvent: O
Solvent: COCCOC
Product: CN(C(=S)Nc1ccccc1)N1C(=N)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 166.9 %

Procedure:
A solution of crude 2-cyanobenzoylchloride (2.2 g; 0.013 mole) in 20 ml of dimethoxyethane was added dropwise to a solution of 2-methyl-4-phenylthiosemicarbazide 0.35 g; 0.013 mole) and pyridine (1.1 g; 0.013 mole) in 35 ml of dimethoxyethane. The resulting red solution was allowed to stir at room temperature overnight. The reaction mixture was poured into a large volume of water to give a reddish gummy precipitate. The water was decanted and the gummy material dissolved in a small amount of ethyl acetate. Upon standing a solid crystallized from solution. Filtration gave 1 g of the desired product, mp: 165-167. The IR and NMR spectra were consistent with the cyclic tautomer structure, as illustrated in the foregoing reaction scheme. Under basic conditions, as in the exemplified synthesis procedure, existence of the tautomeric ortho-cyanobenzoyl compound is probably negligible. It is conceivable, however, that in some chemical environments the tautomeric form can be detected, or that reaction products derived from the tautomeric form will be produced when identification by preparation of chemical derivatives is attempted.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([S:9][CH3:10])=[C:4]([Cl:11])[N:3]=1.[CH2:12]([NH2:14])[CH3:13].[OH-].[Na+]>CC(CC)=O>[CH2:12]([NH:14][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([S:9][CH3:10])=[C:4]([Cl:11])[N:3]=1)[CH3:13]
Reactant: CSc1c(Cl)nc(Cl)nc1Cl
Reactant: CCN
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(C)=O
Product: CCNc1nc(Cl)c(SC)c(Cl)n1
Reaction time: 6 h

Procedure:
230 parts of 2,4,6-trichloro-5-methylthio-pyrimidine are dissolved in 740 parts of methylethylketone, 650 parts of ice are added, and 120 parts of an aqueous 38% solution of ethylamine are run in over 30 minutes while cooling in order that the temperature should not exceed 5° C. 129.5 parts of a 31% solution of caustic soda are added in a period of an hour at 20° C. and the mixture is stirred for 6 hours. The desired isomer is then precipitated while the 4-ethylamino-2,6-dichloro-5-methylthiopyrimidine remains in solution. After cooling for 15 hours, the product is filtered off and washed with methylethylketone. 73 parts of the desired product are obtained, which is recrystallised from ethanol. M.p. 147° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:11][NH:12][CH3:13].O>CCO>[CH3:11][N:12]([CH3:13])[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CNC
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CCO
Solvent: O
Product: CN(C)c1ncccc1[N+](=O)[O-]
Yield: 99.5 %

Procedure:
A stirred mixture of 2-chloro-3-nitropyridine (1.00 g, 0.00631 mol) in absolute EtOH (17 ml), under nitrogen, was treated, dropwise during 10 minutes, with 3.86 g (0.0214 mol) of 25% aqueous dimethylamine and kept at ambient temperature (25° C.) for 30 minutes. The mixture was mixed with water and extracted with EtOAc. The extract was washed with water, dried (MgSO4) and concentrated to give 1.05 g of the titled product, a yellow oil.
Reaction SMILES: [NH2:1][C:2]1([C:9]#[N:10])[CH2:7][CH:6]2[CH2:8][CH:3]1[CH2:4][CH2:5]2.[CH2:11]([O:13]CC)[CH3:12]>C(OC(=O)C)(=O)C>[C:11]([NH:1][C:2]1([C:9]#[N:10])[CH2:7][CH:6]2[CH2:8][CH:3]1[CH2:4][CH2:5]2)(=[O:13])[CH3:12]
Reactant: CCOCC
Reactant: N#CC1(N)CC2CCC1C2
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NC1(C#N)CC2CCC1C2

Procedure:
The procedure is as in Example 3, but starting from 2-amino-2-cyano-bicyclo[2.2.1]heptane (6.33 g), in the form of the mixture of the exo and endo racemates in a ratio of (8/1), in diethyl ether (100 cc) and acetic anhydride (4.7 cc); after recrystallization from a mixture of ethanol and water (15/85 by volume) (300 cc), 2-acetylamino-2-cyano-bicyclo[2.2.1]heptane (7.14 g) is obtained in the form of fine white crystals which melt at 164° C.
Reaction SMILES: C([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.I[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].[BrH:34].C(O)(=O)C>C(OCC)C>[BrH:34].[CH2:25]([C:22]1[CH:23]=[N:24][C:19]([N:18]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:27])[S:12][CH:13]=2)=[N:20][CH:21]=1)[CH3:26]
Reactant: CCCCCI
Reactant: CCc1cnc(NCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)nc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncc(CC)cn1

Procedure:
A compound obtained using 2-[(4-{2-[(5-Ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 265-1 and 1-iodopentane as starting materials, and by an operation similar to that of Example 326 was dissolved in diethyl ether, and reacted with 30% hydrobromic acid-acetic acid to give the title compound.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)[CH2:2][CH2:3][CH3:4].Cl.[NH2:19][OH:20]>>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14](=[N:19][OH:20])[CH2:13][CH2:12]1)[CH2:2][CH2:3][CH3:4]
Reactant: NO
Reactant: CCCCOCCCCCN1CCC(=O)CC1
Agent: Cl
Product: CCCCOCCCCCN1CCC(=NO)CC1

Procedure:
1-(5-Butoxypentyl)-4-piperidone oxime is prepared from 1-(5-butoxypentyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>>[C:34]([NH:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23](=[O:31])[C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[CH2:19][CH2:18]2)[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2cccnc2)cc1
Product: CC(=O)Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2cccnc2)cc1
Yield: 92.3 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(3-pyridyl)benzamide (150.0 mg, 0.335 mmol) and acetic anhydride (0.038 ml, 0.40 mmol), the procedure of Inventive Example 94 was repeated to obtain 151.0 mg (95.6%) of the title compound in a colorless amorphous form.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[N:24]=[C:23]([NH:25][C:26]3[CH:27]=[C:28]([NH:32][C:33](=[O:38])[CH:34]([OH:37])[CH2:35][OH:36])[CH:29]=[CH:30][CH:31]=3)[C:22]([F:39])=[CH:21][N:20]=2)=[CH:14][CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:40][S:41](Cl)(=[O:43])=[O:42].C(Cl)(Cl)Cl.CO.C([O-])(O)=O.[Na+]>C1COCC1.O>[CH3:40][S:41]([O:36][CH2:35][CH:34]([OH:37])[C:33]([NH:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([NH:25][C:23]2[C:22]([F:39])=[CH:21][N:20]=[C:19]([NH:18][C:15]3[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])=[CH:17][CH:16]=3)[N:24]=2)[CH:27]=1)=[O:38])(=[O:43])=[O:42]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(Nc2ncc(F)c(Nc3cccc(NC(=O)C(O)CO)c3)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(Nc2ncc(F)c(Nc3cccc(NC(=O)C(O)COS(C)(=O)=O)c3)n2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 10.5 %

Procedure:
In a 25 mL 3-neck RBF equipped with a calcium chloride guard tube, N-(3-((2-((4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)phenyl)-2,3-dihydroxypropanamide (2.0 g), in THF (25 mL), was added TEA (0.724 g). The reaction mixture was cooled to 0° C. and a solution of CH3SO2Cl (0.491 g) in THF was added dropwise. The reaction mixture was stirred at room temperature for 3 hr. The reaction was monitored on TLC using CHCl3:methanol (9:1) as mobile phase. After completion of reaction, water and saturated NaHCO3 solution were added. The mixture was extracted into ethyl acetate. The organic layer was washed dried over sodium sulfate and concentrated under reduced pressure at 40° C. The crude material was purified by Combiflash eluted with 2.2% methanol in CHCl3 to give 0.24 g of 3-((3-((2-((4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)phenyl)amino)-2-hydroxy-3-oxopropyl methanesulfonate.
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][N:12]=2)[CH:7]=[C:3]1C(O)=O.CCOCC>N1C2C(=CC=CC=2)C=CC=1>[N:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:7]=[CH:3][C:2](=[O:1])[NH:10][CH:9]=2)=[N:12][CH:13]=1
Reactant: O=C(O)c1cc(-c2ccncn2)c[nH]c1=O
Solvent: CCOCC
Solvent: c1ccc2ncccc2c1
Product: O=c1ccc(-c2ccncn2)c[nH]1
Reaction time: 0.5 h

Procedure:
A solution of 90.8 g of 1,2-dihydro-2-oxo-5-(4-pyrimidinyl) nicotinic acid in 900 ml of quinoline is refluxed overnight. The reaction mixture is cooled, poured into 1800 ml of anhydrous ether, stirred for 30 minutes, filtered and the filtered solid washed with 2 l of ether. The solid is dried, recrystallized from 100 ml of hot dimethylformamide and dried to yield 5-(4-pyrimidyl)-2(1H)-pyridone, M.P. >250° C.