Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:5](=[O:19])[O:6][C:7]2[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=[CH:11][C:8]=2[C:9]=1[CH3:10].Cl.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C(O)(C)C.CC(OC)(C)C>[CH3:18][O:17][C:13]1[CH:12]=[CH:11][C:8]2[C:9]([CH3:10])=[C:4]([CH2:3][CH2:2][N:32]3[CH2:31][CH2:30][N:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[O:22][CH3:21])[CH2:34][CH2:33]3)[C:5](=[O:19])[O:6][C:7]=2[C:14]=1[O:15][CH3:16]
Reactant: COc1ccc2c(C)c(CCCl)c(=O)oc2c1OC
Reactant: COc1ccccc1N1CCNCC1
Agent: Cl
Solvent: CC(C)O
Solvent: COC(C)(C)C
Product: COc1ccccc1N1CCN(CCc2c(C)c3ccc(OC)c(OC)c3oc2=O)CC1
Yield: 6 %

Procedure:
Process A; starting materials: 3-(2-chloroethyl)-7,8-dimethoxy-4-methyl-2H-1-benzopyran-2-one (Example 32) and 1-(2-methoxyphenyl)piperazine hydrochloride; yield 6%; m.p. 146°-148° C. (from isopropanol/TBME).
Reaction SMILES: [CH2:1]([NH:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([O:14][CH:15]([CH3:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]([CH3:24])([CH3:23])[CH2:7]1)[CH2:2][CH2:3][CH3:4].Cl[P:26]1[O:31][CH2:30][C:29]([CH3:33])([CH3:32])[CH2:28][O:27]1>>[CH3:22][CH:15]([O:14][N:9]1[C:8]([CH3:23])([CH3:24])[CH2:7][CH:6]([N:5]([P:26]2[O:31][CH2:30][C:29]([CH3:33])([CH3:32])[CH2:28][O:27]2)[CH2:1][CH2:2][CH2:3][CH3:4])[CH2:11][C:10]1([CH3:13])[CH3:12])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC1(C)COP(Cl)OC1
Reactant: CCCCNC1CC(C)(C)N(OC(C)c2ccccc2)C(C)(C)C1
Product: CCCCN(C1CC(C)(C)N(OC(C)c2ccccc2)C(C)(C)C1)P1OCC(C)(C)CO1

Procedure:
The title compound is prepared as a colorless glass from 4-n-butylamino-1-alpha-methylbenzyloxy-2,2,6,6-tetramethylpiperidine and 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphorinane according to the procedure of Example 11C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31]>>[F:1][C:2]1[CH:7]=[C:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1
Reactant: Cc1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Cc1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 2-bromotoluene. MS (ESI): mass calcd. for C17H14FN3, 279.12; m/z found, 280.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.12 (s, 1H), 7.95 (m, 1H), 7.28-7.12 (m, 6H), 4.66 (s, 2H), 2.32 (s, 3H).
Reaction SMILES: C[O-].[CH3:3][O:4][C:5](=O)[CH:6]=[O:7].[CH:9]1([NH:15][C:16]([NH2:18])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(O)(=O)C>CO>[CH3:3][O:4][CH:5]1[NH:18][C:16](=[O:17])[N:15]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]1=[O:7]
Reactant: NC(=O)NC1CCCCC1
Reactant: COC(=O)C=O
Agent: C[O-]
Solvent: CC(=O)O
Solvent: CO
Product: COC1NC(=O)N(C2CCCCC2)C1=O
Yield: 31.4 %

Procedure:
750 mg of glyoxylic acid methyl ester methyl alcoholate and 920 mg of N-cyclohexylurea were refluxed in 50 ml of a mixture of acetic acid and methanol (4:1) for 1 hour. After cooling, the solvent was removed by distillation and the residue was purified by column chromatography on silica gel. The obtained crude product was recrystallized from benzene to give 420 mg of 5-methoxy-3-cyclohexylhydantoin (compound 20) in the form of colorless needle crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[Br:14]C1C=C(CC(O)=O)C=CC=1>>[Br:14][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:7][CH:2]=1
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Reactant: O=C(O)Cc1cccc(Br)c1
Product: CCOC(=O)Cc1cccc(Br)c1

Procedure:
Employing the same general procedure as for the preparation of ethyl (4-bromophenyl)acetate (Compound A), 100 g (463 mmol) of 3-bromophenylacetic acid was converted into the title compound (yellow oil) using 2 g of conc. H2SO4 and 500 ml of ethanol. PMR (CDCl3): δ 1.26 (3H, t, J =7.0 Hz), 3.56 (2H, s), 4.16 (2H, q, J=7.0 Hz), 7.16-7.26 (2H, m), 7.38-7.46 (2H, m).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([OH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]([O:25][CH3:26])[N:17]=1>C1COCC1.O.[OH-].[Na+]>[CH2:7]([O:14][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]([O:25][CH3:26])[N:17]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCc1ccccc1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49.4 %

Procedure:
Potassium tert-butoxide (4.28 g, 38.2 mmol) was added to a solution of benzyl alcohol (3.29 mL, 31.8 mmol) in 66 mL anhydrous THF. The mixture was stirred at room temperature for 20 minutes. 2-Chloro-6-methoxy-3-nitropyridine (5.00 g, 26.5 mmol) was added and the reaction was stirred at vigorous reflux for 18 h. TLC analysis (silica, 1:1 CH2Cl2-hexanes) indicated no unreacted starting material. The reaction mix was diluted with 200 mL H2O and 20 mL 10% aqueous NaOH. The dilution was extracted with ethyl acetate (75 mL) and then with CH2Cl2 (50 mL). The organic extractions were combined, washed with brine (100 mL), dried over Na2SO4, filtered through celite, and concentrated. The crude product was purified by flash chromatography (SiO2, 1:1.5 CH2Cl2-hexanes) to give 3.41 g (13.1 mmol, 49%) of 2-benzyloxy-6-methoxy-3 nitro-pyridine. MS (APCI) m/z 261.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[NH:5][CH2:6][CH2:7][C:8]1[O:9][C:10]([CH3:13])=[CH:11][CH:12]=1)[CH3:2].[H-].[Na+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].O>CN(C=O)C>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][N:5]([C:4]([O:3][CH2:1][CH3:2])=[O:14])[CH2:6][CH2:7][C:8]1[O:9][C:10]([CH3:13])=[CH:11][CH:12]=1)[CH3:23]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)NCCc1ccc(C)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN(CCc1ccc(C)o1)C(=O)OCC
Yield: 95.8 %

Procedure:
Ethyl[2-(5-methylfuran-2-yl)ethyl]carbamate (0.60 g) prepared in the step 3 was dissolved in 6 mL of DMF, 0.15 g of 60% sodium hydride was slowly added thereto with stirring and ice-cooling and the mixture was stirred at room temperature for 1 hour more. Ethyl bromoacetate (0.40 g) was slowly dropped into the reaction solution under cooling with ice and the mixture was made back to room temperature followed by stirring overnight. The reaction solution was poured over 20 mL of water followed by extracting with diethyl ether. The organic layer was washed with water and a saturated solution of sodium chloride successively and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom in vacuo. The residue was purified by silica gel column chromatography to give 0.65 g of the objective compound as pale yellow liquid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([Br:8])[CH3:7].[C:9]1(=[O:19])[NH:13][C:12](=[O:14])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.[K]>CC(C)=O>[Br:8][CH:6]([CH3:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:13]1[C:12](=[O:14])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]2[C:9]1=[O:19]
Reactant: CC(Br)CCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CC(C)=O
Product: CC(Br)CCCCN1C(=O)c2ccccc2C1=O

Procedure:
A mixture of 1,5-dibromohexane (21.6 g, 0.09 mole) in acetone (75 ml) containing potassium phthalimide (12.3 g, 0.066 mole) was heated at reflux for 24 hr. The mixture was cooled, filtered and concentrated. The excess dibromide was recovered (6.3 g) via distillation at 1.5 mm, 130° internal temperature, and recycled. The total yield of crude product was 20.6 g (74%), mp 48°-51°. This material was used as such in the next step.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]2[C:18]([F:19])=[CH:17][N:16]=[C:15]([NH:20][C:21]3[CH:33]=[CH:32][C:24]([O:25][CH2:26][C:27]([O:29]CC)=[O:28])=[CH:23][CH:22]=3)[N:14]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])[CH:2]=[CH2:3].O[Li].O.C(Cl)(Cl)Cl.CO>CO.O>[C:1]([NH:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]2[C:18]([F:19])=[CH:17][N:16]=[C:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:32][CH:33]=3)[N:14]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc(OCC(=O)OCC)cc3)ncc2F)c1
Agent: [Li]O
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc(OCC(=O)O)cc3)ncc2F)c1
Reaction time: 2 h
Yield: 40.9 %

Procedure:
A solution of ethyl 2-(4-((4-((3-acrylamidophenyl)amino)-5-fluoropyrimidin-2-yl)amino)phenoxy)acetate (0.300 g) in methanol was cooled to 0° C. and a solution of LiOH.H2O (0.056 g) in water was added. The reaction mixture was stirred at room temperate for 2 hr. The reaction was monitored on TLC using CHCl3:methanol (8:2) as mobile phase. After completion of the reaction, methanol was removed under reduced pressure and water was added. The aqueous layer was washed with ethyl acetate, acidified with acetic acid and the solid precipitate was filtered and washed with water. Solid material was dried under vacuumed at 45° C. to give 0.115 g of 2-(4-((4-((3-acrylamidophenyl)amino)-5-fluoropyrimidin-2-yl)amino)phenoxy)acetic acid. 1H NMR: DMSO-d6 (400 MHz): 4.492 (s, 2H), 5.740-5.767 (d, 1H, J=10.8), 6.238-6.280 (d, 1H, J=16.8), 6.446-6.513 (dd, 1H, J=6.8, 10), 6.717-6.739 (d, 2H, J=8.8), 7.252-7.292 (t, 1H, J=8), 7.377-7.396 (d, 1H, J=7.6), 7.502-7.523 (d, 3H, J=7.6), 7.961 (s, 1H), 8.060-8.068 (d, 1H, J=3.2), 8.988 (s, 1H), 9.386 (s, 1H), 10.191 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][NH2:8])=[C:5]([N+:9]([O-:11])=[O:10])[C:4]([CH3:12])=[N:3]1.[CH3:13][O:14][C:15]1[C:16]([O:28][CH3:29])=[CH:17][C:18]2[NH:24][C:23](=[O:25])[CH2:22][CH2:21][C:20](=O)[C:19]=2[CH:27]=1.O>C(O)(=O)C>[CH3:1][N:2]1[C:6]([NH:7][N:8]=[C:20]2[CH2:21][CH2:22][C:23](=[O:25])[NH:24][C:18]3[CH:17]=[C:16]([O:28][CH3:29])[C:15]([O:14][CH3:13])=[CH:27][C:19]2=3)=[C:5]([N+:9]([O-:11])=[O:10])[C:4]([CH3:12])=[N:3]1
Reactant: COc1cc2c(cc1OC)C(=O)CCC(=O)N2
Reactant: Cc1nn(C)c(NN)c1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2c(cc1OC)C(=NNc1c([N+](=O)[O-])c(C)nn1C)CCC(=O)N2
Temperature: 70 °C
Yield: 12.2 %

Procedure:
1,3-Dimethyl-4-nitro-1H-pyrazol-5-yl-hydrazine (0.073 g, 0.4 mmol) was added to a suspension of 7,8-dimethoxy-1H-[1]benzazepin-2,5(3H, 4H)-dione (0.100 g, 0.4 mmol) in acetic acid (5 ml) with stirring under argon. The mixture was heated at 70° C. for 2 days, cooled and water (5 ml) added. The precipitate was then filtered off to give the title compound as a yellow solid (0.019 g, yield 11.5%); 1H-NMR (DMSO-d6, 300 MHz): δ (ppm)=12.8 (v br s; 1 H), 9.59 (s; 1H), 7.2 (s; 1H), 6.63 (s; 1H), 3.96 (s; 3H), 3.75-3.77 (s, 6H), 3.05 (br t, 2H), 2.57 (br t, 2H), 2.35 (s, 3H).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][NH:5][CH:4]([CH2:7][N:8]([CH2:24][C:25]([CH3:33])=[CH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]([C:11]2[CH:21]=[C:20]([O:22][CH3:23])[C:14]3[O:15][C:16]([CH3:19])([CH3:18])[O:17][C:13]=3[CH:12]=2)=[O:10])[CH2:3]1.[O:34]1[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1.C(O)(=O)C.C([BH3-])#N.[Na+].Cl>>[OH:1][CH:2]1[CH2:6][N:5]([CH:37]2[CH2:38][CH2:39][O:34][CH2:35][CH2:36]2)[CH:4]([CH2:7][N:8]([CH2:24][C:25]([CH3:33])=[CH:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:9]([C:11]2[CH:21]=[C:20]([O:22][CH3:23])[C:14]3[O:15][C:16]([CH3:19])([CH3:18])[O:17][C:13]=3[CH:12]=2)=[O:10])[CH2:3]1
Reactant: O=C1CCOCC1
Reactant: COc1cc(C(=O)N(CC(C)=Cc2ccccc2)CC2CC(O)CN2)cc2c1OC(C)(C)O2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(C(=O)N(CC(C)=Cc2ccccc2)CC2CC(O)CN2C2CCOCC2)cc2c1OC(C)(C)O2
Yield: 69.2 %

Procedure:
Experimental condition analogous to Example 14 were used with 7-methoxy-2,2-dimethyl-benzo[1,3]dioxole-5-carboxylic acid (4-hydroxy-pyrrolidin-2-ylmethyl)-(2-methyl-3-phenyl-allyl)-amide 0.16 g (0.35 mmol), tetrahydro-4H-pyrane-4-one 0.042 g (0.42 mmol), acetic acid 0.03 ml (0.53 mmol) and sodium cyanoborohydride 0.026 g (0. 42 mmol). After transforming the free base to HCl salt, 130 mg of white solid was obtained. Yield: 65%.
Reaction SMILES: [CH3:1][NH:2]/[C:3](/[NH:8][CH2:9][CH2:10][S:11][CH2:12][C:13]1[O:17][C:16]([CH2:18][N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=1)=[CH:4]\[N+:5]([O-:7])=[O:6].[ClH:22]>C(O)(C)C>[CH3:1][NH:2][C:3]([NH:8][CH2:9][CH2:10][S:11][CH2:12][C:13]1[O:17][C:16]([CH2:18][N:19]([CH3:20])[CH3:21])=[CH:15][CH:14]=1)=[CH:4][N+:5]([O-:7])=[O:6].[ClH:22]
Reactant: CN/C(=C\[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Agent: Cl
Solvent: CC(C)O
Product: CNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Temperature: 30 °C

Procedure:
Ranitidine base (31.44 g, 0.1 mol) was dissolved in anhydrous isopropyl alcohol (isopropanol) (160 mL) by warming to 30° C., filtering through celite and washing the cake with anhydrous isopropyl alcohol (68 mL). The solution was warmed to 43° C., seeds (Form #1, 0.2 g) were added and anhydrous hydrogen chloride in anhydrous isopropyl alcohol (15.19 g, 24%, 1 equivalent) was added all at once. The temperature rose to 51° C. and the temperature was maintained at 45°-50° C. for 5 hours while the product crystallized. The mixture was allowed to cool to 25° C. The precipitate was filtered and washed with anhydrous isopropyl alcohol (2×30 mL) to yield damp Ranitidine Hydrochloride. Vacuum drying at 40° C. overnight yields 34.26 g (0.0977 mol, 97.7%) of pure Ranitidine Hydrochloride (Form #1). The I. R. in KBr of the crystals conformed to Form #1.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH:9]1[CH2:13][CH:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]([CH2:19][CH3:20])[CH2:10]1)C1C=CC=CC=1.[H][H]>CCO.[OH-].[OH-].[Pd+2]>[NH2:8][CH:9]1[CH2:13][CH:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]([CH2:19][CH3:20])[CH2:10]1
Reactant: [H][H]
Reactant: CCOC(=O)C1CC(N(Cc2ccccc2)Cc2ccccc2)CC1CC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1CC(N)CC1CC
Yield: 98.9 %

Procedure:
To a vessel containing a slurry of 20 wt % Pd(OH)2 on C (12.9 g, 18.4 mmol) in EtOH (1.0 L) was added ethyl 4-(dibenzylamino)-2-ethylcyclopentanecarboxylate (129 g, 352 mmol). The reaction was shaken for about 90 min at about 50° C. under about 30 psi of hydrogen. After removal of the hydrogen source, a nitrogen atmosphere was introduced and the resulting mixture was filtered through a pad of Celite® and the filtrate was coned under reduced pressure to give ethyl 4-amino-2-ethylcyclopentanecarboxylate (64.5 g, 99%) as a yellow syrup: 1H NMR (CDCl3) δ 4.03-3.88 (m, 2H), 3.17 (m, 1H), 2.68 (m, 1H), 2.09-2.02 (m, 2H), 2.02-1.94 (m, 2H), 1.84 (m, 1H), 1.58-1.48 (m, 1H), 1.32-1.18 (m, 1H), 1.09 (m, 3H), 1.03 (m, 2H), 0.78-0.69 (m, 3H).
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:27]2[CH2:29][CH2:28]2)[C:10]([C:12]2[CH:13]=[N:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]#[N:26])=[CH:20][CH:19]=3)=[N:16][CH:17]=2)=[O:11])[CH2:5][CH2:4]1)#[N:2].[OH:30][NH:31][C:32](=N)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH:27]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:30][N:31]=[C:32]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:2]=3)[CH2:8][CH2:7]2)[C:10]([C:12]2[CH:17]=[N:16][C:15]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][C:25]#[N:26])=[CH:22][CH:23]=3)=[N:14][CH:13]=2)=[O:11])[CH2:28][CH2:29]1
Reactant: N#CCc1ccc(-c2ncc(C(=O)N(C3CC3)C3CCN(C#N)CC3)cn2)cc1
Reactant: N=C(NO)c1ccccc1
Product: N#CCc1ccc(-c2ncc(C(=O)N(C3CC3)C3CCN(c4nc(-c5ccccc5)no4)CC3)cn2)cc1

Procedure:
The title compound is prepared from 2-(4-cyanomethyl-phenyl)-pyrimidine-5-carboxylic acid (1-cyano-piperidin-4-yl)-cyclopropyl-amide and N-hydroxy-benzamidine following a procedure analogous to that described in Example 6. LC (method 3): tR=2.05 min; Mass spectrum (ESI+): m/z=506 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH2:8][CH2:9][N:10]([CH3:24])[C:11]3([CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:6]2=[CH:5][CH:4]=1)#[N:2].[ClH:25]>O1CCOCC1>[ClH:25].[ClH:25].[CH3:24][N:10]1[C:11]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:6]2=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[N:7]2[CH2:8][CH2:9]1
Reactant: CN1CCn2c(C#N)ccc2C12CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCn2c(C#N)ccc2C12CCNCC2
Reaction time: 0.5 h
Yield: 99 %

Procedure:
tert-Butyl 6-cyano-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (280 mg, 0.8474 mmol) was dissolved in a mixture of hydrochloric acid in dioxane (8 mL of 4 M, 32.00 mmol) and dioxane (8 mL). The reaction mixture was allowed to stir for 30 minutes and then evaporated to dryness to yield 2-methylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-carbonitrile dihydrochloride (258 mg, 99%) as a white solid. ESI-MS m/z calc. 230.2, found 231.5 (M+1)+; Retention time: 0.50 minutes (3 min run). 1H NMR (400 MHz, D2O) δ 7.10 (d, J=4.2 Hz, 1H), 6.59 (d, J=4.3 Hz, 1H), 4.51 (t, J=6.4 Hz, 2H), 4.02 (t, J=6.3 Hz, 2H), 3.66-3.56 (m, 2H), 3.49-3.36 (m, 2H), 2.95 (s, 3H), 2.69-2.59 (m, 2H), 2.54-2.40 (m, 2H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])[CH:5]=[CH:4][CH:3]=1.[NH2:13][C:14]1[S:15][C:16]([C:22]2[C:27]([F:28])=[CH:26][C:25]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:24][C:23]=2[F:33])=[CH:17][C:18]=1[C:19]([NH2:21])=[O:20]>>[C:9]([C:8]([C:6]1[N:7]=[C:2]([NH:13][C:14]2[S:15][C:16]([C:22]3[C:23]([F:33])=[CH:24][C:25]([C:29]([OH:32])([CH3:30])[CH3:31])=[CH:26][C:27]=3[F:28])=[CH:17][C:18]=2[C:19]([NH2:21])=[O:20])[CH:3]=[CH:4][CH:5]=1)([CH3:12])[CH3:11])#[N:10]
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: CC(C)(C#N)c1cccc(Br)n1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(C(C)(C)C#N)n3)s2)c(F)c1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 2-(6-bromopyridin-2-yl)-2-methylpropanenitrile (108 mg, 0.48 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol) as the starting materials.
Reaction SMILES: [CH2:1]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[O-2].[Zn+2:29].[C:30](=[S:32])=[S:31]>>[CH2:15]([N:14]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:30](=[S:31])[S-:32])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[Zn+2:29].[CH2:15]([N:14]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:30](=[S:31])[S-:32])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: S=C=S
Reactant: CCCCCCCCCCCCCNCCCCCCCCCCCCC
Agent: [O-2]
Agent: [Zn+2]
Product: CCCCCCCCCCCCCN(CCCCCCCCCCCCC)C(=S)[S-]
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a 250 mL round bottomed flask was placed 76.5 g of ditridecylamine and 8.10 g of zinc oxide. Carbon disulfide, 16.0 g, was then added dropwise, and the mixture was stirred for 30 minutes. The flask was then stirred and heated for 2 hours at 70° C., and then stirred for an addition 2 hours at 90° C. A vacuum was then applied to remove water of reaction and the temperature was increased to 130° C., and the reaction was maintained in this state for 3 hours. The pale yellow material was then filtered through Celite at 120° C., to give a pale yellow liquid with a Zn content of 6.0%.
Reaction SMILES: [CH2:1]([N:8]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N+:39]([O-:41])=[O:40])[C:34]=1[CH3:42])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][O:26]C3CCCCO3)[CH:18]=2)=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CCO.C(OCC)(=O)C>[CH2:1]([N:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17]2[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=2)[O:23][CH2:24][CH2:25][OH:26])=[CH:14][CH:15]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N+:39]([O-:41])=[O:40])[C:34]=1[CH3:42])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(OCCOC4CCCCO4)c3)cc2)cccc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(OCCO)c3)cc2)cccc1[N+](=O)[O-]
Temperature: 55 °C

Procedure:
The product from Example 92A (0.480 g, 0.845 mmoles) in EtOH (2.0 mL) was treated with pyridinium p-toluenesulfonate (0.0106 g, 0.0422 mmoles) and heated at 55° C. for four hours. The reaction was diluted with ethyl acetate, washed with H2O, brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by chromatography on a pre-packed Biotage silica gel column (hexanes to 50% ethyl acetate:hexanes) to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[C:11]1([CH3:21])[CH:16]=CC(S(Cl)(=O)=O)=C[CH:12]=1.C(=O)([O-])O.[Na+].C1(C)C=CC=CC=1>C(O)(C)(C)C.N1C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][C:11]([CH3:21])([CH3:16])[CH3:12])=[O:9])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
A suspension of 5-bromo-2-pyridinecarboxylic acid (may be prepared as described in Description 11) (68.0 g) in tert-butanol (680 ml) and pyridine (190 ml) was stirred vigorously at rt for 0.5 h under argon. 4-Toluenesulfonyl chloride (153.7 g) was then added portionwise over 10 min to give a thick white mixture which gradually dissolved over 2 h to give a dark brown solution. After 4.5 h at rt the reaction mixture was poured slowly with stirring onto a saturated aqueous solution of sodium hydrogen carbonate (136 g) in water (1 l). Stirring was continued for 18 h at rt. The product was then extracted into diethyl ether (2×1 l) and the combined extracts were dried (MgSO4), filtered and concentrated to give a solid. This was treated with toluene (1 l) and the mixture was evaporated to dryness. This was repeated twice more with toluene (2×1 l) to give a pink solid which was dried in vacuo overnight to give 80.0 g of product. Recrystallisation from acetone/water gave the pure title compound (D12) (66.8 g). MS electrospray (+ve ion) 281 (MNa+). 1H NMR δ CDCl3: 8.79 (1H, s), 7.90 (2H, s), 1.64 (9H, s).
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1)#[N:2].Cl.[NH2:25][OH:26]>N1C=CC=CC=1>[C:1]([C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[CH2:8][CH2:7][C:6](=[N:25][OH:26])[CH2:5][CH2:4]1)#[N:2]
Reactant: NO
Reactant: COc1ccc(C2(C#N)CCC(=O)CC2)cc1OC1CCCC1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(C2(C#N)CCC(=NO)CC2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.2 %

Procedure:
To a solution of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one (0.125 g, 0.4 mmol) in pyridine (2 mL) was added hydroxylamine hydrochloride (0.031 g, 0.44 mmol), the mixture was stirred at room temperature under an argon atmosphere for 4 h and the solvent was evaporated. The mixture was partitioned between water and ethyl acetate, was extracted twice with ethyl acetate, the organic extract was dried (potassium carbonate) and the solvent was removed in vacuo. Purification by flash chromatography, eluting with 25% ethyl acetate/hexanes, followed by trituration of the product with ether/hexanes provided a white solid (0.125 g, 95%): m.p. 50°-53° C.