Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([O-])=O.[Na+].[C:5]([C:7]1[CH:15]=[C:14]2[C:10](C=C[NH:13]2)=[CH:9][CH:8]=1)#[N:6].Cl.CCO[C:20]([CH3:22])=[O:21]>O>[CH:20]([C:22]1[C:10]2[C:14](=[CH:15][C:7]([C:5]#[N:6])=[CH:8][CH:9]=2)[NH:13][N:1]=1)=[O:21]
Reactant: CCOC(C)=O
Reactant: N#Cc1ccc2cc[nH]c2c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc2c(C=O)n[nH]c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
To a solution of NaNO2 (11.04 g, 160 mmol) in H2O (200 mL) was added 6-cyanoindole (5.68 g, 40 mmol) in one portion slowly. The resulting suspension was stirred for 5 min at rt. HCl (32 mL, 192 mmol 6N) was added dropwise via a dropping funnel over 30 min and the pH was about 1. The resulting suspension was stirred for 4.5 h at rt before of EtOAc (400 mL) was added. After stirring for additional 10 min to dissolve the precipitate, the two layers were separated and the aqueous layer was extracted with EtOAc (150 mL). Combined extracts were dried over Na2SO4. Removal of solvents afforded 6.864 g (100%) of title compound as brown (coffee color) solid. 1H NMR (400 MHz, DMSO-d6) δ 14.70 (s, 1H, NH), 10.22 (s, 1H, CHO), 8.38 (s, 1H), 8.28 (d, J=8.4 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H). MS ESI 172.0 [M+H]+, calcd for [C9H5N3O+H]+ 172.0.
Reaction SMILES: [CH2:1]=O.[O:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5][CH2:4]1.[NH2:19][C:20]1[N:21]([CH3:32])[N:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23](=[O:25])[CH:24]=1>C(O)C>[NH2:19][C:20]1[N:21]([CH3:32])[N:22]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:23](=[O:25])[C:24]=1[CH2:1][N:16]1[CH2:17][CH2:18][N:13]([C:12]2[C:7]3[O:6][CH2:5][CH2:4][O:3][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH2:14][CH2:15]1
Reactant: C=O
Reactant: c1cc2c(c(N3CCNCC3)c1)OCCO2
Reactant: Cn1c(N)cc(=O)n1-c1ccccc1
Solvent: CCO
Product: Cn1c(N)c(CN2CCN(c3cccc4c3OCCO4)CC2)c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
37-40% Aqueous formaldehyde solution (12.4 ml) was added to a solution of 1-(1,4-benzodioxan-5-yl)piperazine (33.1 g; prepared in a similar manner to that described in Example 2 above) in absolute ethanol (250 ml) and the mixture stirred at ambient temperature for 3 hours. The mixture was diluted with absolute ethanol (500 ml) and the resulting solution stirred at ambient temperature for 19 hours. A solution of 3-amino-2-methyl-1-phenyl-3-pyrazolin-5-one (31.7 g) in absolute ethanol (1000 ml) was added and the solution stirred at ambient temperature for 23 hours. The resulting solid was collected by filtration, dried in vacuo at ambient temperature, and suspended in ethyl acetate (1200 ml). The mixture was stirred and heated under reflux for 66 hours, and the resulting solid was collected by hot filtration, dried in vacuo at ambient temperature, ground with a mortar and pestle then again stirred and heated under reflux with ethyl acetate (1700 ml) for 46 hours. The product was collected by hot filtration, then dried in vacuo at ambient temperature to give 3-amino-4-[4-(1,4-benzodioxan-5-yl)piperazin-1-ylmethyl]-2-methyl-1-phenyl-3-pyrazolin-5-one as a white solid (50.4 g), m.p. 223-224° C.
Reaction SMILES: C1(O)C=CC=CC=1.C(O)C=CCCCCCCC.CCOC(/N=N/C(OCC)=O)=O.[CH3:31][O:32][C:33](=[O:59])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]CCCCCCCC)=[CH:36][CH:35]=1>CCOCC>[CH3:31][O:32][C:33](=[O:59])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41]/[CH:42]=[CH:43]/[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:36][CH:35]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: CCCCCCCC=CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: Oc1ccccc1
Solvent: CCOCC
Product: CCCCCCC/C=C/COc1ccc(C(=O)OC)cc1
Yield: 65 %

Procedure:
Phenol 34 (486 mg, 3.2 mmol), 2-decenol 26 g (500 mg, 3.2 mmol), TPP (965 mg, 3.68 mmol), and DEAD (641 mg, 3.68 mmol) in 32 ml ether were reacted according to the procedure for compound 35a. The crude product was purified via flash chromatography over silica gel with gradual elutions from 95/5-90/10 (v/v, Hex/EtOAc). Evaporation of solvent yielded 603 mg (65%) of colorless needles.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[Cl-].[Al+3].[Cl-].[Cl-].Cl.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:1]([C:17]1[CH:18]=[CH:19][C:14]([Br:13])=[CH:15][CH:16]=1)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)Cl
Reactant: Brc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCC(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Pentanoyl chloride (50 g) is added dropwise to a stirred, cooled 0° C.) mixture of bromobenzene (150 ml) and aluminum chloride (0.2 g). The mixture is stirred at 0° C. for 1 h, heated at 80° C. for 2 h, cooled and poured into 18% hydrochloric acid. The product is extracted into CHCl3 twice, the combined organic extracts are washed with water and steam distilled to remove chloroform and the excess of bromobenzene. The product is extracted into chloroform twice, the combined organic phases are washed with water and dried (MgSO4). The solvent is removed in vacuo and the residue is distilled (bp 180°-184° C. at 20 mm Hg) to yield a colourless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[OH:18][CH2:19][C:20]([N+:25]([O-:27])=[O:26])([CH2:23]O)[CH2:21][OH:22].Cl.CN(C)CCCN=C=NCC.N(C(C)C)(C(C)C)CC>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:23][C:20]([CH2:21][OH:22])([N+:25]([O-:27])=[O:26])[CH2:19][OH:18])=[O:15])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: O=[N+]([O-])C(CO)(CO)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: COc1ccc2cc([C@H](C)C(=O)OCC(CO)(CO)[N+](=O)[O-])ccc2c1
Yield: 36.9 %

Procedure:
A solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 4.27 g, 18.5 mmol), 2-hydroxymethyl-2-nitro-1,3-propanediol (2.89 g, 19.1 mmol), N,N-dimethylaminopyridine (DMAP, 0.88 g, 7.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.86 g, 25.4 mmol) and NEt(i-Pr)2 (11 mL, 63.2 mmol) in acetone (100 mL) was stirred at ambient temperature overnight. The reaction mixture was evaporated to dryness and the residue was partitioned between 3N HCl (100 mL) and CH2Cl2 (200 mL×2). The combined organic layer was back washed with water and brine, dried over Na2SO4, filtered, concentrated and dried under vacuum. The product was separated by silica gel column chromatography eluting with ethyl acetate/hexane (gradient from 1:2 to 1:1, Rf=0.1 in 1:2) to give the title compound as a white solid (2.48 g, 39% yield). Mp 124-126° C. 1H NMR (300 MHz, 10% CD3OD/CDCl3) δ 7.73-7.64 (m, 3H), 7.37-7.33 (m, 1H), 7.17-7.12 (m, 2H), 4.44 (d, J=2.6 Hz, 2H), 3.92 (s, 3H), 3.9-3.7 (m, 5H), 3.4 (br, 2H), 1.58 (d, J=7.2 Hz, 3H). 13C NMR (75 MHz, 10% CD3OD/CDCl3) δ 174.1, 157.4, 134.5, 133.5, 129.0, 128.6, 127.0, 125.7, 118.8, 105.4, 92.4, 61.2, 60.1, 55.0, 45.0, 17.7.
Reaction SMILES: [O:1]=[C:2]([CH3:16])[CH2:3][C:4]([NH:6][CH2:7][CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5].[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O.N1CCCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.O>[C:2]([C:3](=[CH:21][C:20]1[CH:23]=[CH:24][CH:25]=[C:18]([Cl:17])[CH:19]=1)[C:4]([NH:6][CH2:7][CH:8]=[CH:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:5])(=[O:1])[CH3:16]
Reactant: CC(=O)CC(=O)NCC=Cc1ccccc1
Reactant: O=Cc1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CC(=O)C(=Cc1cccc(Cl)c1)C(=O)NCC=Cc1ccccc1

Procedure:
569 mg (2.62 mmol) of 3-oxo-N-(3-phenyl-2-propene-1-yl)butyramide, 0.3 ml (2.65 mmol) of 3-chlorobenzaldehyde and 0.03 ml (0.34 mmol) of piperidine were heated under reflux in the presence of a catalytic amount of p-toluenesulfonic acid in 30 ml of benzene overnight while water was removed. Ethyl acetate was added to the reaction mixture, and the product was washed with 1 N hydrochloric acid and then with a saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 2-acetyl-3-(3-chlorophenyl)-N-(3-phenyl-2-propene-1-yl)acrylamide. 20 ml of 2-propanol and 260 mg (2.62 mmol) of 4-amino-3-pentene-2-on were added to the product, and they were heated at 80° C. under stirring for 3 days. 2-Propanol was evaporated under reduced pressure, and the residue was purified by the silica gel chromatography (ethyl acetate) to obtain the title compound.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5](Cl)(=[O:10])/[C:6](=[CH:8]/[CH3:9])/[CH3:7].[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>C(=S)=S.CCCCCC.O>[CH3:7][CH:6]1[CH:8]([CH3:9])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:5]1=[O:10]
Reactant: C/C=C(\C)C(=O)Cl
Reactant: c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCCCCC
Solvent: S=C=S
Product: CC1C(=O)c2ccccc2C1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
Aluminum trichloride in an amount of 30.7 g (250 mmol) was suspended in 150 mL of dried carbon disulfide (dried and distilled on calcium hydride) and was brought to an ice-cooling temperature. Then, 25.1 g (212 mmol) of tigloyl chloride was mixed with 16.6 g (212 mmol) of benzene, and to the resultant mixture was added dropwise the above-produced carbon disulfide solution, followed by continuous stirring at room temperature. As the result, a yellow solution was gradually produced. The solution was allowed to stand overnight, with the result that the solution was separated into two phases including a brown phase and a colorless phase. The solution was allowed to react for another 5 hours under refluxing. The resultant reaction mixture was brought back to room temperature and thereafter, was poured onto the mixture of 250 g of water and 250 mL of concentrated hydrochloric acid, followed by stirring for about one hour. Then, the resultant product was subjected to extraction and separation four times repeatedly with 200 mL each of ether. The ether phases thus produced were combined together, and dried with calcium chloride anhydride as the drying agent. After filtering away the used drying agent, the ether was distilled away and the brown viscous oil was obtained. Because of its being readily soluble in hexane, the oil was again dissolved in hexane, and the resultant solution was washed twice with 150 mL each of saturated aqueous solution of sodium carbonate and twice with 150 mL each of saturated aqueous solution of sodium chloride, and dried with magnesium sulfate anhydride. By distilling away the hexane, there was obtained 19.9 g of 2,3-dimethylindane-1-one.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.Cl[C:31]1[CH:32]=[N:33][C:34]2[C:35](=[O:44])[NH:36][CH:37]([O:42][CH3:43])[CH:38]([F:41])[C:39]=2[CH:40]=1.[CH3:45][N:46](C=O)C>[C-]#N.[Zn+2].[C-]#N>[F:41][CH:38]1[CH:37]([O:42][CH3:43])[NH:36][C:35](=[O:44])[C:34]2[N:33]=[CH:32][C:31]([C:45]#[N:46])=[CH:40][C:39]1=2
Reactant: COC1NC(=O)c2ncc(Cl)cc2C1F
Reactant: CN(C)C=O
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC1NC(=O)c2ncc(C#N)cc2C1F
Temperature: 110 °C
Yield: 72.8 %

Procedure:
A pressure bottle was charged with Pd(dba)3 (Strem, 1.032 g, 1.127 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (Strem 1.157 g, 2.82 mmol), zinc cyanide (Alfa Aesar, 2.482 g, 21.14 mmol), 3-chloro-5-fluoro-6-methoxy-6,7-dihydro-1,7-naphthyridin-8(5H)-one (step 1, 3.25 g, 14.09 mmol) and DMF (70 ml). The bottle was purged with Argon and the reaction mixture was heated to 110° C. for 1 h. The crude reaction mixture was filtered through a pad of Celite and the filtercake was washed with MeOH. The combined filtrates were concentrated under reduced pressure. The residue was triturated with DCM. The solid was filtered off and washed with DCM. The title compound (2.27 g, 10.26 mmol, 72.8% yield) was obtained as an off white solid. MS m/z=222 [M+H]+. Calculated for C10H8FN3O2: 221.1
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([C:7]2[CH:11]=[CH:10][O:9][CH:8]=2)=[CH:3][CH:2]=1.BrC1C=CC(C2C=CC([C:31]#[N:32])=CC=2)=CC=1.O1C=CC(B(O)O)=C1>CO>[O:9]1[CH:10]=[CH:11][C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:12]3[CH:17]=[CH:16][C:15]([C:31]#[N:32])=[CH:14][CH:13]=3)=[CH:2][CH:3]=2)=[CH:8]1
Reactant: N#Cc1ccc(-c2ccc(Br)cc2)cc1
Reactant: c1ccc(-c2ccc(-c3ccoc3)cc2)cc1
Agent: OB(O)c1ccoc1
Solvent: CO
Product: N#Cc1ccc(-c2ccc(-c3ccoc3)cc2)cc1
Yield: 53 %

Procedure:
As described in Example 1(a) for the preparation of 3-biphenyl-4-yl-furan, crude 4'-bromo-biphenyl-4-carbonitrile (200 mg, 0.775 mmol) and 3-furanboronic acid (see Thompson, W. J.; Gaudino, G. J. Org. Chem. 1984, 49, 5237-5243; 105 mg, 0.937 mmol) in MeOH (2 mL) were coupled to give a yellow solid, which was purified via preparative TLC. Elution with EtOAc:benzene (1:99) provided 100 mg (53%) of 4'-furan-3-yl-biphenyl-4-carbonitrile as a grey powder, mp 199-203° C. 1H NMR (CDCl3): δ 7.81 (bs, 1H), 7.72 (d, 4H, J=1.9 Hz), 7.61 (s, 4H), 7.51 (bs, 1H), 6.75 (s, 1H). IR (KBr): 2225, 1604, 1503, 1396, 1162, 1102, 1058 cm-1. Anal. Calculated for C17H11NO.0.3 EtOAc.0.2 C6H6 : C, 80.78; H, 5.05; N, 5.01. Found: C, 80.96; H, 4.88; N, 5.00.
Reaction SMILES: [ClH:1].[CH2:2]1[O:10][C:9]2[CH:8]=[CH:7][C:6]([CH3:11])=[CH:5][C:4]=2[O:3]1.[CH2:12]=O>C(OCC)C>[CH2:2]1[O:10][C:9]2[CH:8]=[C:7]([CH3:12])[C:6]([CH2:11][Cl:1])=[CH:5][C:4]=2[O:3]1
Reactant: Cl
Reactant: C=O
Reactant: Cc1ccc2c(c1)OCO2
Solvent: CCOCC
Product: Cc1cc2c(cc1CCl)OCO2
Temperature: 0 °C
Reaction time: 10 h
Yield: 63 %

Procedure:
To a 1:1 mixture of ethyl ether (100 ml) and conc. HCl (100 ml) at 0° C. was added (3,4-methylenedioxy)toluene (10 ml). Formaldehyde (20 ml, 37% in water) was then added dropwise. The reaction was stirred at 0° C. for 2 hours and at room temperature for an additional 10 hours. The reaction mixture was then diluted with ethyl ether (100 ml) and the two layers were separated. The organic layer was dried (MgSO4), the solid was filtered and the filtrate was concentrated. The residue was then heated with hexane (200 ml) and the insolubles were filtered off the hot solution. The filtrate was concentrated to give a mixture of (3,4-methylenedioxy)-6-methylbenzyl chloride (9.4 g, 63% yield) and bis[(3,4-methylenedioxy)-6-methyl]phenylmethane (3.6 g) as a white solid. This mixture was carried on to the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[NH:21][C:20]3[C:19](=[O:22])[N:18]([CH2:23][CH2:24][CH3:25])[C:17](Cl)=[N:16][C:15]=3[N:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]([N:30](C(C)C)CC)(C)C.FC(F)(F)C1C=CC(CN)=CC=1>CN1C(=O)CCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[NH:21][C:20]3[C:19](=[O:22])[N:18]([CH2:23][CH2:24][CH3:25])[C:17]([NH:30][CH3:27])=[N:16][C:15]=3[N:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCn1c(Cl)nc2nc(-c3cnn(Cc4ccccc4)c3)[nH]c2c1=O
Reactant: CCN(C(C)C)C(C)C
Agent: NCc1ccc(C(F)(F)F)cc1
Solvent: CN1CCCC1=O
Product: CCCn1c(NC)nc2nc(-c3cnn(Cc4ccccc4)c3)[nH]c2c1=O
Temperature: 110 °C
Yield: 44.5 %

Procedure:
To a solution of 8-(1-Benzyl-1H-pyrazol-4-yl)-2-chloro-1-propyl-1,7-dihydro-purin-6-one (0.05 g, 0.136 mmol) in NMP (1 ml) under argon was added Diisopropyl ethyl amine (0.035 g, 0.27 mmol) and 4-Trifluoromethyl-benzylamine (0.035 g, 0.203 mmol). The reaction mixture was heated at 110° C. for overnight. The reaction mixture concentrated under reduced pressure. The residue was obtained was purified by preparative HPLC to obtain 8-(1-Benzyl-1H-pyrazol-4-yl)-2-methylamino-1-propyl-1,7-dihydro-purin-6-one (0.022 g, 32%) as a white solid.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[O:13][C:14]([CH3:17])(C)C)(C)(C)C.[C]=O.[CH2:20]([OH:22])C>[Ru](Cl)(Cl)Cl.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[C:1]1([CH2:7][C:20]([O:13][CH2:14][CH3:17])=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1
Reactant: CC(C)(C)OOC(C)(C)C
Reactant: CCO
Agent: Cl[Ru](Cl)Cl
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [C]=O
Product: CCOC(=O)Cc1ccccc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 15.9 %

Procedure:
Toluene (1.38 g), ethanol (46 mg), di-tert-butyl peroxide (73 mg, 1 equivalent), ruthenium trichloride (1.1 mg, 1 mol %), and Xantphos (2.9 mg) were added into a reaction kettle, into which 10 atm carbon monoxide was introduced. The reaction was heated to 120° C., and stirred at this constant temperature for 16 h. After the reaction was completed, carbon monoxide was discharged, and 13 mg ethyl phenylacetate was obtained by column chromatography, in a yield of 16%. The ethyl phenylacetate obtained was dissolved in 1,4-dioxane. 6 N sodium hydroxide solution was added, and the reaction was heated to 60° C. After 2 h of reaction, the pH value was adjusted to 1 by adding 2 N hydrochloric acid. After removing the organic solvent under reduced pressure, 10 mg product phenylacetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 92%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[S:18](Cl)(=[O:20])=[O:19].C(N(C(C)C)CC)(C)C>ClCCl>[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[S:18]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)(=[O:19])=[O:20]
Reactant: O=C1CNCCN1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(S(=O)(=O)c2ccc3ccccc3c2)CCN1
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
To a stirred solution of piperazine-2-one (353.3 mg, 3.5 mmol) and naphthalene-2-sulfonyl chloride (800 mg, 3.5 mmol) in anhydrous dichloromethane (15 mL) was added diisopropylethylamine (1.54 mL, 8.8 mmol). The mixture was stirred for 30 min. Reaction was complete as determined by TLC. The reaction mixture was filtered, washed with hexane to give a first batch. The mother liquor washed with saturated ammonium chloride, then washed with saturated brine, separated, dried over sodium sulphate. Then hexane was added, lots of precipitate formed. The was filtered, washed with hexane to give a second batch. The two batches were combined to yield 4-(naphthalene-2-sulfonyl)-piperazin-2-one in 92.5% yield (947 mg) as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 3.35-3.40 (m, 2H) 3.42-3.48 (m, 2H) 3.79 (s, 2H) 6.11 (s, 1H) 7.63-7.73 (m, 2H) 7.77 (dd, J=8.72, 1.89 Hz, 1 H) 7.94 (d, J=7.83 Hz, 1H) 7.98-8.05 (m, 2H) 8.38 (s, 1H).
Reaction SMILES: [CH:1]1([N:6]([C:13]2[C:18]([N+:19]([O-])=O)=[CH:17][N:16]=[C:15]([Cl:22])[N:14]=2)[CH2:7][CH2:8][C:9](OC)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH4+].[Cl-]>[Fe].CCO.O>[Cl:22][C:15]1[N:16]=[CH:17][C:18]2[NH:19][C:9](=[O:10])[CH2:8][CH2:7][N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:13]=2[N:14]=1
Reactant: COC(=O)CCN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: O=C1CCN(C2CCCC2)c2nc(Cl)ncc2N1
Yield: 43.7 %

Procedure:
Methyl 3-[cyclopentyl(2-chloro-5-nitropyrimidin-4-yl)amino]propanoate (1.0 g, 0.003 mol, 1 eq) and NH4Cl (1.38 g, 0.025 mol, 8.5 eq) were added to EtOH/H2O (4:1, 10 mL) and the mixture heated to reflux. Iron powder (1.36 g, 0.024 mol, 8 eq) was added portionwise and after 2 h the RM was hot filtered through celite washing through with EtOAc (10 mL) and EtOH (10 mL) [both hot]. The solvent was evaporated under reduced pressure to give the product as a brown solid (0.35 g, 43%); 1H (DMSO-d6): δ 1.55 (4H, m, 2CH2), 1.7 (2H, m, CH2), 1.83 (2H, m, CH2), 2.66 (2H, t, J=5 Hz, CH2), 3.57 (2H, t, J=5 Hz, CH2), 5.01 (1H, m, CH), 7.83 (1H, s, CH), 9.71 (1H, s, NH); MS+ve: 267.2; Rt=2.87 min (Analytical—1).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=O.[CH3:17][N:18]1[N:22]=[N:21][C:20]([NH2:23])=[N:19]1.C(O)C.[BH4-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6][NH:23][C:20]1[N:21]=[N:22][N:18]([CH3:17])[N:19]=1
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cn1nnc(N)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cn1nnc(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
A mixture of 3,5-bis(trifluoromethyl)benzaldehyde (4 g, 16.5 mmol), 2-methyl-2H-tetrazol-5-amine (1.96 g, 19.8 mmol) and molecular sieves (5-10 Å beads) in toluene (50 mL) was heated at reflux for 4 hours, after which time the solvent was removed. Ethanol (50 mL) and sodium borohydride (1.25 g, 33 mmol) were added. The resulting mixture was stirred at room temperature for 30 minutes and then partitioned between saturated NH4Cl (50 mL) and ethyl acetate (2×50 mL). The combined organic layers were washed with saturated NaCl (50 mL), dried (MgSO4), filtered and concentrated to yield the title compound as a white solid (4.7 g). 1H NMR (400 MHz, CDCl3) δ 4.2 (s, 3 H) 4.7 (s, 1 H) 4.7 (s, 1 H) 5.0 (t, J=6.0 Hz, 1 H) 7.8 (s, 1 H) 7.9 (s, 2 H). MS (ES+) Calc: 325.08, Found: 325.8 (M+1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:9])[CH:5]=[C:6]([CH3:8])[N:7]=1.Br[CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>>[CH3:1][C:2]1[N:3]([CH2:11][CH2:12][O:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=2)[C:4](=[O:9])[CH:5]=[C:6]([CH3:8])[N:7]=1
Reactant: Cc1cc(=O)[nH]c(C)n1
Reactant: O=Cc1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(=O)n(CCOc2ccc(C=O)cc2)c(C)n1
Yield: 28 %

Procedure:
The title compound (0.8 g, 30%) was prepared from 2,4-dimethyl-1,6-dihydro-6-pyrimidone (1,3 g, 10.48 mmol) and 4-[2-bromoethoxy]benzaldehyde (2.4 g, 10.48 mmol) in the presence of a base K2CO3 (2.89 g, 20.96 mmol) by a similar procedure as described in preparation 1.
Reaction SMILES: C([C:5]1[CH:9]=[C:8]([CH3:10])[S:7][C:6]=1[NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])(OC)=O.O.O.[I-].[Li+].CCOCC.Cl>N1C(C)=CC(C)=CC=1C>[CH3:10][C:8]1[S:7][C:6]([NH:11][C:12](=[O:16])[CH:13]([CH3:14])[CH3:15])=[CH:5][CH:9]=1
Reactant: COC(=O)c1cc(C)sc1NC(=O)C(C)C
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Solvent: CCOCC
Product: Cc1ccc(NC(=O)C(C)C)s1
Yield: 86.7 %

Procedure:
N-(3-Carbomethoxy-5-methyl-2-thienyl)-2-methylpropanamide (4.1 g, 0.017 mol), prepared by the method of Example 48, was dissolved in hot collidine (10 ml) and added to a mixture of lithium iodide dihydrate (10.1 g, 0.06 mol) in collidine (20 ml) kept under nitrogen. The reaction mixture was stirred under reflux for 48 hours, cooled and equilibrated between ether (3× 50 ml) and 5N-hydrochloric acid (50 ml). The ethereal solution was washed with water (25 ml), dried (Na2SO4) and evaporated to yield the required product as an off-white solid (2.7 g, 47%) m.p. 96°-97° C. The product was identical to the product described in Example 38.