Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([CH2:14][CH2:15][CH:16]([OH:18])[CH3:17])[CH:3]=1.[C:19](Cl)(=[O:21])[CH3:20]>N1C=CC=CC=1>[C:19]([O:18][CH:16]([CH2:15][CH2:14][C:4]1[CH:3]=[C:2]([F:1])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=1)[CH3:17])(=[O:21])[CH3:20]
Reactant: COc1ccc2cc(CCC(C)O)cc(F)c2c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: COc1ccc2cc(CCC(C)OC(C)=O)cc(F)c2c1
Temperature: 0 °C
Yield: 85 %

Procedure:
4-(4-Fluoro-6-methoxy-2-naphthyl)-butan-2-ol (2.8 g) was dissolved in pyridine (22 ml) and cooled in an ice-bath. Acetyl chloride (2.9 ml) was added dropwise with stirring. The solution was then stirred for 30 minutes at 0° and 1 hour at room temperature. The suspension produced was poured into ice-water (250 ml) and the product was extracted into ether. The ether was washed with dilute hydrochloric acid and sodium hydrogen carbonate solution. After drying over anhydrous sodium sulphate and solvent was removed under reduced pressure to give the title compound as a pale yellow oil (2.8 g., 85%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:36]2[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][CH:37]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([F:25])[C:18]=1[N:9]1[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=2[C:7]([C:36]2[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][CH:37]=2)=[N:8]1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2-c1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nn(-c3c(F)cccc3F)c3ccnc(OC)c23)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of 1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (3.20 g) obtained in Step C of Example 35 in DMF (20 mL)/water (2.0 mL) were added methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (2.87 g), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (319 mg) and potassium carbonate (2.16 g). The reaction mixture was stirred overnight at 90° C. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.75 g).
Reaction SMILES: COC(=O)[NH:4][CH2:5][C@H:6]([CH2:11][C:12](=[O:22])N[C@H](C1C=CC=CC=1)C)[CH2:7][CH:8]([CH3:10])[CH3:9].[OH-:24].[Na+]>>[CH3:10][CH:8]([CH2:7][C@H:6]([CH2:5][NH2:4])[CH2:11][C:12]([OH:22])=[O:24])[CH3:9]
Reactant: [OH-]
Reactant: COC(=O)NC[C@H](CC(=O)N[C@@H](C)c1ccccc1)CC(C)C
Agent: [Na+]
Product: CC(C)C[C@H](CN)CC(=O)O
Temperature: 117.5 °C
Yield: 50.4 %

Procedure:
A 0.2 1 reactor was loaded with 70% sulfiric acid (200 g) containing compound 26 (10 g, 0.031 mole), and was heated to 115-120° C. for 5-10 hours, and then cooled to room temperature, i.e., about 20° to about 25° C. An aqueous 40% sodium hydroxide solution was added in an amount sufficient to provide a pH of 1. The solution was then extracted with 50 ml of isopropanol, the organic layer was separated, and NH4OH was added in an amount sufficient to provide a pH of 4. The (S)-Pregabalin was precipitated, filtered, and washed with 10 ml of isobutanol. After drying at 55° C. under vacuum, (S)-Pregabalin was obtained as white crystals in a 50.4% yield. Purity: 99.05% area by HPLC.
Reaction SMILES: [ClH:1].[CH2:2]1[C:9]2([C:10]([OH:12])=O)[N:5]([CH2:6][CH2:7][CH2:8]2)[CH2:4][CH2:3]1.S(Cl)([Cl:15])=O>>[ClH:15].[CH2:2]1[C:9]2([C:10]([Cl:1])=[O:12])[N:5]([CH2:6][CH2:7][CH2:8]2)[CH2:4][CH2:3]1
Reactant: O=C(O)C12CCCN1CCC2
Reactant: O=S(Cl)Cl
Agent: Cl
Product: O=C(Cl)C12CCCN1CCC2
Reaction time: 17 h
Yield: 95.6 %

Procedure:
A mixture of pyrrolizidine-7a-carboxylic acid hydrochloride (24.6 g, 0.128 mol, prepared as described in Reference Example 2) and thionylchloride (280 ml, 3.89 mol) was stirred for 17 hours at 20° to 25° C. and the excess of thionylchloride was evaporated in vacuo to give 25.7g (95.9%) of the desired compound, as yellowish solids.
Reaction SMILES: C(OC[N:10]1[C:14]2=[N:15][CH:16]=[CH:17][C:18]([O:19][C:20]3[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=3)=[C:13]2[CH:12]=[N:11]1)C1C=CC=CC=1>CO.Cl.[C].[Pd]>[NH:10]1[C:14]2=[N:15][CH:16]=[CH:17][C:18]([O:19][C:20]3[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=3)=[C:13]2[CH:12]=[N:11]1
Reactant: Nc1ccc(Oc2ccnc3c2cnn3COCc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1ccc(Oc2ccnc3[nH]ncc23)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 25.4 %

Procedure:
4-(1-Benzyloxymethyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)aniline (140 mg, 0.40 mmol) was dissolved in methanol (5 mL) and 5 N hydrochloric acid (0.2 mL), and palladium carbon (10%, 10 mg) was added thereto. The resulting mixture was stirred at 50° C. for 4 hours under a hydrogen atmosphere. The catalyst was removed by filtration, and the methanol solution was concentrated. The residue was neutralized with a 5 N sodium hydroxide aqueous solution (0.2 mL) and partitioned between saturated brine (3 mL) and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated. The residue was purified by amino-silica gel (Fuji Silysia, 5 g, ethyl acetate) to give 4-(1H-pyrazolo[3,4-b]pyridin-4-yloxy)aniline (23 mg, yield: 25%).
Reaction SMILES: [C:1]([N:4]1[C@H:12]([C:13]([O-:15])=O)[CH2:11][C:10](=[O:16])[C:9]2[CH:17]=[CH:18][CH:19]=[CH:20][C:8]=2[N:7]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[C:6](=[O:29])[C@H:5]1[CH2:30][C:31]12[CH2:40][CH:35]3[CH2:36][CH:37]([CH2:39][CH:33]([CH2:34]3)[CH2:32]1)[CH2:38]2)(=[O:3])[CH3:2].C([N:44]1[C@H:52]([C:53]([O-:55])=[O:54])CC(=O)C2C=CC=CC=2N(CC2C=CC=CC=2)C(=O)[C@H]1CC12CC3CC(CC(C3)C1)C2)(=O)C>>[C:1]([N:4]1[C@H:12]([C:13]([NH:44][CH2:52][C:53]([OH:55])=[O:54])=[O:15])[CH2:11][C:10](=[O:16])[C:9]2[CH:17]=[CH:18][CH:19]=[CH:20][C:8]=2[N:7]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[C:6](=[O:29])[C@H:5]1[CH2:30][C:31]12[CH2:38][CH:37]3[CH2:39][CH:33]([CH2:34][CH:35]([CH2:36]3)[CH2:40]1)[CH2:32]2)(=[O:3])[CH3:2]
Reactant: CC(=O)N1[C@H](CC23CC4CC(CC(C4)C2)C3)C(=O)N(Cc2ccccc2)c2ccccc2C(=O)C[C@H]1C(=O)[O-]
Reactant: CC(=O)N1[C@H](CC23CC4CC(CC(C4)C2)C3)C(=O)N(Cc2cccc(Cl)c2)c2ccccc2C(=O)C[C@H]1C(=O)[O-]
Product: CC(=O)N1[C@H](CC23CC4CC(CC(C4)C2)C3)C(=O)N(Cc2cccc(Cl)c2)c2ccccc2C(=O)C[C@H]1C(=O)NCC(=O)O

Procedure:
The compound was prepared by an identical route to that used to prepare example 22 except that (3R,5S)-4-acetyl-3-(1-adamantyl)methyl-1-(3-chlorobenzyl)-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine-5-carboxylate was used in step a in place of (3R,5S)-4-acetyl-3-(1-adamantyl)methyl-1-benzyl-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine-5-carboxylate
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[CH:15]([OH:19])([CH2:17][CH3:18])[CH3:16]>>[CH:15]([O:19][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([CH2:17][CH3:18])[CH3:16]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CCC(C)O
Product: CCC(C)Oc1cccc([N+](=O)[O-])c1C#N

Procedure:
Prepared in a similar manner as example 161c from 2,6-dinitrobenzonitrile and sec-butanol to provide 2-sec-butoxy-6-nitrobenzonitrile. 1H NMR (400 MHz, DMSO-d6) δ 0.98 (t, J=7.5 Hz, 3H), 1.33 (d, J=5.9 Hz, 3H), 1.73 (m, 2H), 4.76 (sext, J=5.9 Hz, 1H), 7.78 (dd, J=6.8, 2.8 Hz, 1H), 7.90 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[I:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1>>[I:22][C:23]1[N:24]=[CH:25][N:26]([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:3]=2)[CH:27]=1
Reactant: Ic1c[nH]cn1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)cc1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(4-trifluoromethylphenyl)-pyrimidine (example A.2) (1.31 g, 4.0 mmol) and commercially available 4-iodo-imidazole (0.85 g, 4.4 mmol) according to the general procedure IVa. Obtained as a pink solid (1.88 g, 97%). MS (ISP) 485.3 [(M+H)+]; mp 194° C.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([Cl:10])[C:7]([Cl:11])=[C:6](Cl)[C:3]=1[C:4]#[N:5].[NH4+].[Cl-]>CO.C1COCC1.[Zn]>[Cl:1][C:2]1[N:9]=[C:8]([Cl:10])[C:7]([Cl:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(Cl)nc(Cl)c(Cl)c1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cc(Cl)c(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
To a solution of 2,4,5,6-tetrachloronicotinonitrile (7.6 g, 31.4 mmol) in MeOH/THF (230 ml/230 ml) was added zinc dust (4.0 g, 62.8 mmol) slowly at 0° C. and the saturated NH4Cl solution (105 ml) and the mixture was stirred for 30 minutes. TLC indicated that the reaction is complete. Saturated NH4OAc solution (180 ml) was added to the mixture and the mixture was allowed to stir at room temperature for 30 minutes. The mixture was filtered and was washed with EtOAc (500 ml). The filtrate was washed with brine and dried and concentrated to give a solid. ISCO column purification gave the title compound (4.63 g, 71%). 1H NMR (CDCl3): δ 8.97 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:15]=[CH:16][C:17]4[O:21][CH2:20][CH2:19][C:18]=4[CH:22]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:23].[CH3:24][O:25][C:26]1[C:31](B(O)O)=[CH:30][CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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:21]1[C:17]2[CH:16]=[CH:15][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:31]5[C:26]([O:25][CH3:24])=[N:27][CH:28]=[CH:29][CH:30]=5)[C:3]([CH3:23])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:22][C:18]=2[CH2:19][CH2:20]1
Reactant: COc1ncccc1B(O)O
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc1Cl
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: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ncccc1-c1nc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)ccc1C
Yield: 72.2 %

Procedure:
To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide (95 mg, 0.3 mmol) in 1,2-dimethoxyethane (3 mL) was added 2-methoxypyridin-3-ylboronic acid (66 mg, 0.4 mmol), tetrakis(triphenylphosphine)palladium (0) (33 mg, 0.03 mmol), and 2 M sodium carbonate (0.45 mL, 0.9 mmol). The reaction mixture was irradiated in the microwave at 120° C. for twenty minutes. The reaction mixture was diluted with ethyl acetate (5 mL) and washed with water (5 mL). The organics were dried over sodium sulfate and evaporated to dryness. The crude reaction mixture was purified by silica gel chromatography (eluting with 0-50% ethyl acetate in hexanes) to yield the product (87 mg, 75%). ESI-MS m/z calc. 401.17. found 402.1 (M+1)+. Retention time 1.79 minutes.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].CO[CH:14](OC)[CH2:15][CH:16](OC)OC>C(O)(=O)C>[N:5]1[N:6]2[CH:14]=[CH:15][CH:16]=[N:1][C:2]2=[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:4]=1
Reactant: CCOC(=O)c1cn[nH]c1N
Reactant: COC(CC(OC)OC)OC
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2cccnc12
Yield: 58.2 %

Procedure:
A stirred mixture of 10.88 g of 5-amino-4-pyrazolecarboxylic acid, ethyl ester, 11.51 g of malonaldehyde bis(dimethyl acetal) and 100 ml of glacial acetic acid was heated at reflux for 16 hours, then worked up as described in Example 50 to give 7.8 g of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid, ethyl ester.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH3:14])=[CH:8][C:7]=1[CH:15]([NH:21][C:22]1[CH:27]=[CH:26][C:25](/[C:28](=[N:31]/[H])/[NH:29]O)=[CH:24][CH:23]=1)[C:16]([O:18][CH2:19]C)=[O:17])(=[O:3])[NH2:2]>CO.C(O)(=O)C.[Ni]>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([NH:21][CH:15]([C:7]2[CH:8]=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=[CH:11][C:6]=2[O:5][CH2:4][C:1](=[O:3])[NH2:2])[C:16]([O:18][CH3:19])=[O:17])=[CH:27][CH:26]=1)(=[NH:29])[NH2:31]
Reactant: [H]/N=C(\NO)c1ccc(NC(C(=O)OCC)c2cc(OCC)ccc2OCC(N)=O)cc1
Agent: [Ni]
Solvent: CC(=O)O
Solvent: CO
Product: CCOc1ccc(OCC(N)=O)c(C(Nc2ccc(C(=N)N)cc2)C(=O)OC)c1
Yield: 93.4 %

Procedure:
305 mg of ethyl (Z)-(RS)-(2-carbamoylmethoxy-5-ethoxy-phenyl)-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetate were treated in 8 ml of methanol-acetic acid (1:1) with Raney-nickel and stirred under hydrogen. The reaction mixture was filtered, evaporated in a vacuum and, for purification, the residue was triturated in acetonitrile. There were obtained 265 mg of methyl (RS)-(4-carbamimidoyl-phenylamino)-(2-carbamoylmethoxy-5-ethoxyphenyl)-acetate; m.p. 200° C. (dec.), MS: 401 (M+H)+.
Reaction SMILES: Cl.[F:2][CH2:3][C:4]1([OH:10])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.[C:20](Cl)([Cl:22])=[O:21]>ClCCl>[F:2][CH2:3][C:4]1([OH:10])[CH2:9][CH2:8][N:7]([C:20]([Cl:22])=[O:21])[CH2:6][CH2:5]1
Reactant: O=C(Cl)Cl
Reactant: OC1(CF)CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Cl)N1CCC(O)(CF)CC1
Reaction time: 0.25 h
Yield: 37 %

Procedure:
4-(Fluoromethyl)piperidin-4-ol hydrochloride (233 mg, 1.37 mmol) was suspended in dichloromethane (3 mL) followed by addition of DIPEA (0.6 mL, 3.4 mmol) and the slurry obtained added in portions over several minutes to a solution of phosgene (20W % in toluene, 0.75 mL) diluted into dichloromethane (5 mL) and the mixture was allowed to stir at this temperature for 15 minutes. The mixture was then concentrated and the residue partitioned with ethyl acetate and water. The organic solution was washed 0.5M hydrochloric acid, brine then dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (3:1 ethyl ether:hexanes) to give 4-(fluoromethyl)-4-hydroxypiperidine-1-carbonyl chloride (100 mg, 37% yield) as a colorless amorphous residue. GC-MS (EI) for C7H11FNO2Cl: 196 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)[CH:5]=[CH:6][CH:7]=1.[F:16][C:17]([F:28])([F:27])[O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([NH:24][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([O:18][C:17]([F:16])([F:27])[F:28])=[CH:20][CH:21]=2)=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnoc1-c1cccc(Cl)c1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)c1cnoc1-c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-(3-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and 4-(trifluoromethoxy)benzylamine (11.5 mg, 0.060 mmol) as described in synthetic method A and thereafter purified by preparative HPLC method B to give a solid (4.5 mg). MS (pos) m/z 397.0 (M+H).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[CH:3]1.[C:17](OC=C)(=[O:19])[CH3:18]>CC(CC(C)C)=O>[C:17]([O:1][C@@H:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[CH:3]1)(=[O:19])[CH3:18]
Reactant: COc1cccc(CC2=CC(O)CC2=O)c1
Reactant: C=COC(C)=O
Solvent: CC(=O)CC(C)C
Product: COc1cccc(CC2=C[C@H](OC(C)=O)CC2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Hydroxy-2-(3-methoxybenzyl)cyclopent-2-enone (9 g, 41.26 mmol) was dissolved in isobutyl methyl ketone (90 mL), and vinyl acetate (8.4 g, 97.57 mmol) and Lipase derived from Alcaligenese spp. (0.9 g) were added to the solution, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered to remove Lipase and the filtrate was evaporated. The resulting residue was purified by chromatography on a silica gel column using hexane-EtOAc as eluent to give (R)-3-(3-methoxybenzyl)-4-oxocyclopent-2-enyl acetate as yellow oil: 4.29 g (95% ee by HPLC using a chiral column) and (S)-4-hydroxy-2-(3-methoxybenzyl)cyclopent-2-enone as yellow oil: 4.05 g (100% ee by HPLC using a chiral column)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH2:8].C(=O)([O-])O.[Na+].[CH3:14][C:15]1[O:19][N:18]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]=1[C:26](Cl)=[O:27]>O.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:26]([C:16]1[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:18][O:19][C:15]=1[CH3:14])=[O:27]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)Cl
Reactant: NCc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1onc(-c2ccccc2)c1C(=O)NCc1ccccn1
Yield: 92.5 %

Procedure:
A mixture of 5-methyl-3-phenyl-isoxazole-4-carboxylic acid (4.06 g, 20 mmol, commercially available) and thionyl chloride (5 mL) was heated under reflux for 3 h. Evaporation of all volatiles afforded 5-methyl-3-phenyl-isoxazole-4-carboxylic acid chloride (4.4 g, 93%) as yellow oil, which was used without further purification in the next reaction. To a mixture of an aqueous solution of 2-picolylamine (0.182 g, 1.68 mmol) in water (2 mL) and ethyl acetate (4 mL) were added sodium hydrogen carbonate (362 mg, 4.2 mmol) in one portion. Then, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid chloride (0.31 g, 1.4 mmol) in ethyl acetate (2 mL) was added dropwise with vigorous stirring under ice-bath cooling keeping the temperature at 0° C. After addition, the reaction mixture was stirred at room temperature for 18 h. The resulting solution was then diluted with ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined extracts were then washed with brine, dried over sodium sulphate) and concentrated to afford the title compound (0.38 g, 93%) as a white solid. MS: m/e: 294.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[N:12]=[CH:11][NH:10][N:9]=1)=[O:7])[CH3:4].[CH3:13][O:14][C:15](=[O:30])[C:16]1[CH:21]=[C:20](F)[C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][C:17]=1[N+:27]([O-:29])=[O:28].O>CN1CCCC1=O>[CH2:3]([O:5][C:6]([C:8]1[N:12]=[CH:11][N:10]([C:20]2[CH:21]=[C:16]([C:15]([O:14][CH3:13])=[O:30])[C:17]([N+:27]([O-:29])=[O:28])=[CH:18][C:19]=2[C:23]([F:24])([F:26])[F:25])[N:9]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1nc[nH]n1
Reactant: COC(=O)c1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)c1ncn(-c2cc(C(=O)OC)c([N+](=O)[O-])cc2C(F)(F)F)n1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
A solution of 613 mg (14.0 mmol) of sodium hydride in 10 ml of 1-methyl-2-pyrrolidinone is cooled to 0-5° C. and treated dropwise with a solution of 1.74 g (12.4 mmol) of 1H-[1,2,4]triazole-3-carboxylic acid ethyl ester in 10 ml of 1-methyl-2-pyrrolidinone over 8 minutes. The mixture is stirred for 1 hour at 0-5° C. and a solution of 3.00 g (11.2 mmol) of 5-fluoro-2-nitro4-trifluoromethyl-benzoic acid methyl ester in 10 ml of 1-methyl-2-pyrrolidinone is added. The mixture is allowed to warm slowly to room temperature and stirred for 18 hours under N2. It is poured into water and extracted with ethyl acetate. The organic phase is separated and dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by flash chromatography (SiO2, hexane/ethyl acetate 1:1) and the mixed fractions are recrystallized in toluene to provide overall 3.12 g (71%) of 1-(5-methoxycarbonyl-4-nitro-2-trifluoromethyl-phenyl)-1H-[1,2,4]triazole-3-carboxylic acid ethyl ester, m.p. 190-192° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH2:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[S:13][C:14]([CH2:22][CH2:23][CH2:24][CH3:25])=[CH:15][C:16]=1[C:17](OCC)=[O:18]>>[CH2:22]([C:14]1[S:13][C:12]2[N:11]=[C:2]3[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[O:9])=[CH:6][N:7]3[C:17](=[O:18])[C:16]=2[CH:15]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCc1cc(C(=O)OCC)c(N)s1
Reactant: NC(=O)c1ccc(Cl)nc1
Product: CCCCc1cc2c(=O)n3cc(C(N)=O)ccc3nc2s1
Yield: 15.8 %

Procedure:
From 6.2 g (0.040 mol) of 6-chloro-3-pyridinecarboxamide (Aldrich Chemical Company) and 9.0 g (0.040 mol) of 2-amino-5-butyl-3-thiophenecarboxylic acid, ethyl ester and heating in a wax bath at 180°-195° C. for one hundred forty-five minutes and then at 185°-200° C. for ninety minutes, following the procedure of Example 22 there is obtained 1.9 g of 2-butyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide; mp 266°-267° C. after recrystallization from glacial acetic acid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C(O)C>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([O-:10])=[O:9]
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCO
Product: O=[N+]([O-])c1cnccc1N1CCCCC1
Yield: 95 %

Procedure:
A solution of 4-chloro-3-nitropyridine (1.0 equiv.) and piperidine (2.0 equiv.) in ethanol, at a concentration of 0.5 M, was stirred at rt for 48 hours at which time the ethanol was removed in vacuo. The residue was partitioned between EtOAc (300 mL) and Na2CO3 (sat.) (75 mL), was washed further with H2O (50 mL), NaCl(sat.) (50 mL), was dried over MgSO4, was filtered and the volatiles were removed in vacuo yielding 3-nitro-4-(piperidin-1-yl)pyridine (95%). LCMS (m/z): 207.7 (MH+); LC Rt=1.60 min. 1H NMR (CDCl3): δ 8.80 (s, 1H), 8.31 (d, J=5.7, 1H), 6.84 (d, J=6.3, 1H), 3.18-3.21 (m, 4H), 1.64-1.78 (m, 6H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[N:27]1([C:34]2[S:35][C:36]3[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=3[N:38]=2)[CH2:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:30]2[CH2:31][CH2:32][CH2:33][N:27]([C:34]3[S:35][C:36]4[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=4[N:38]=3)[CH2:28][CH2:29]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: c1ccc2sc(N3CCCNCC3)nc2c1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCCN(c3nc4ccccc4s3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-[1.4] diazepan-1-yl-benzothiazole.
Reaction SMILES: [OH-].[K+].[C:3]([C:5]1[CH:6]=[C:7]([CH2:11][N:12]2[C:16]3=[N:17][C:18]([C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)=[N:19][C:20](=[O:21])[C:15]3=[C:14]([CH3:28])[NH:13]2)[CH:8]=[CH:9][CH:10]=1)#[N:4].OO.C(O)(=[O:33])C>O>[C:3]([C:5]1[CH:6]=[C:7]([CH2:11][N:12]2[C:16]3=[N:17][C:18]([C:22]4[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=4)=[N:19][C:20](=[O:21])[C:15]3=[C:14]([CH3:28])[NH:13]2)[CH:8]=[CH:9][CH:10]=1)(=[O:33])[NH2:4]
Reactant: Cc1[nH]n(Cc2cccc(C#N)c2)c2nc(-c3ccncc3)nc(=O)c1-2
Reactant: CC(=O)O
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1[nH]n(Cc2cccc(C(N)=O)c2)c2nc(-c3ccncc3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
A mixture of potassium hydroxide (0.7 g, 9.9 mmol) in water (75 ml) was stirred in an ice-bath for 30 minutes and 1-(3-cyanophenylmethyl)-3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]-pyrimidin-4-one (1.1 g, 3.3 mmol), followed by 30% hydrogen peroxide (1.7 ml, 16.5 mmol) were added. The mixture was slowly warmed to room temperature and stirred for 24 hours. The mixture was chilled in an ice-bath and neutralized with acetic acid. The product was collected by filtration and washed with water, ethanol and ether. The product was recrystallized from DMF to afford 0.87 g (73%) of 1-(3-carbamoylphenylmethyl)-3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one as an off-white powder, m.p. >300° C. when dried at 120° C. for 24 hours in high vacuum.