Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[CH:12]=[N:11][C:10]([N:13]3[CH2:18][CH:17]([OH:19])[C:16]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[CH:15][CH2:14]3)=[N:9][C:8]2=[O:27])=[CH:4][CH:3]=1.CO.[H][H]>[Pd].ClCCl>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[CH:12]=[N:11][C:10]([N:13]3[CH2:14][CH2:15][CH:16]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH:17]([OH:19])[CH2:18]3)=[N:9][C:8]2=[O:27])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=c1nc(N2CC=C(c3ccc(F)cc3)C(O)C2)ncn1Cc1ccc(Cl)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: O=c1nc(N2CCC(c3ccc(F)cc3)C(O)C2)ncn1Cc1ccc(Cl)cc1
Yield: 71.5 %

Procedure:
A solution of 1-(4-chlorobenzyl)-4-[4-(4-fluorophenyl)-5-hydroxy-5,6-dihydropyridin-1(2H)-yl]-1,3,5-triazin-2(1H)-one (10 mg, 0.03 mmol) synthesized in Reference Synthesis Example 90 and palladium-activated carbon (3 mg) in a solvent mixture of methanol (5 mL) and dichloromethane (5 mL) was stirred in a hydrogen atmosphere for 3 days. After the completion of the reaction, the reaction solution was filtered through Celite and the filtrate was concentrated under reduced pressure to obtain the title compound (8.9 mg, yield: 90%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[NH:8])=[CH:5][CH:4]=1.[Na].[CH2:13]([O:15][C:16](=[O:25])[C:17]([C:22](=O)[CH3:23])=[CH:18]N(C)C)[CH3:14]>C(O)C>[CH2:13]([O:15][C:16]([C:17]1[C:22]([CH3:23])=[N:8][C:7]([C:6]2[CH:10]=[CH:11][C:3]([F:2])=[CH:4][CH:5]=2)=[N:9][CH:18]=1)=[O:25])[CH3:14]
Reactant: N=C(N)c1ccc(F)cc1
Reactant: CCOC(=O)C(=CN(C)C)C(C)=O
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2ccc(F)cc2)nc1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.5 %

Procedure:
4-Fluorobenzamidine hydrochloride (1.25 g, 7.16 mmol) is added to a solution of sodium metal (0.17 g, 7.39 mmol) in dry ethanol (25 mL) and stirred at room temperature for 20 min. Ethyl-2-acetyl-3-(dimethylamino)acrylate (1.35 g, 7.16 mmol) is added. The mixture is heated to reflux for 3 hours. The solvent is removed in vacuo. The residue is dissolved in EtOAc, washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo to afford ethyl-2-(4-fluorophenyl)-4-methyl-pyrimidine-5-carboxylate (1.65 g, 87%) as a solid. MS: 261 (M+H) 261.
Reaction SMILES: C(OC(C)COC)(=O)C.N(C(C)(C)C#N)=NC(C)(C)C#N.[CH2:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[C:30]([OH:34])(=[O:33])[CH:31]=[CH2:32]>>[CH:22]([CH:32]=[CH:31][C:30]([OH:34])=[O:33])=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C=CC(=O)O
Reactant: C=Cc1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: COCC(C)OC(C)=O
Product: O=C(O)C=CC=Cc1ccccc1
Reaction time: 2 h

Procedure:
432 g of propyleneglycol monomethyl ether acetate and 13 g of azobisisobutyronitrile were poured into a five-necked reaction vessel having a capacity of one litter. Then, while introducing nitrogen gas into the reaction vessel, the resultant mixture was heated to 80° C. Then, a mixed liquid constituted by 96.3 g of styrene and 11.8 g of acrylic acid was added drop-wise to the above mixture taking two hours. 30 minutes after finishing of the dropping of the mixed liquid, 6.5 g of azoisobutyronitrile was added to the resultant mixture and the mixture thus obtained was heated for 5 hours to obtain a styrene-acrylic acid copolymer. The weight average molecular weight of the styrene-acrylic acid copolymer thus obtained was 3000.
Reaction SMILES: CN(C)C=O.P(Cl)(Cl)([Cl:8])=O.[CH3:11][O:12][C:13]1[C:30]([O:31][CH3:32])=[C:29]([O:33][CH3:34])[CH:28]=[C:27]([CH3:35])[C:14]=1[C:15]([C:17]1[C:22]([O:23][CH3:24])=[CH:21][N+:20]([O-])=[CH:19][C:18]=1[Cl:26])=[O:16]>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13]1[C:30]([O:31][CH3:32])=[C:29]([O:33][CH3:34])[CH:28]=[C:27]([CH3:35])[C:14]=1[C:15]([C:17]1[C:22]([O:23][CH3:24])=[CH:21][N:20]=[C:19]([Cl:8])[C:18]=1[Cl:26])=[O:16]
Reactant: COc1cc(C)c(C(=O)c2c(Cl)c[n+]([O-])cc2OC)c(OC)c1OC
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(C)c(C(=O)c2c(OC)cnc(Cl)c2Cl)c(OC)c1OC
Yield: 739.8 %

Procedure:
5 ml of dimethylformamide was added to 2.5 ml of toluene, the mixture was cooled with ice, and 1.3 ml (1.4 mmol) of phosphorus oxychloride was dropwise added thereto. After the mixture was stirred under cooling with ice for 10 minutes, 2.5 g (0.7 mmol) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-3-chloro-5-methoxypyridine-N-oxide was added thereto. After the mixture was stirred under cooling with ice for 30 minutes, the temperature was recovered to room temperature, followed by stirring for 2 hours. 30 ml of water was added to the mixture to terminate the reaction, and ethyl acetate was added thereto for extraction. The organic layer was dried over anhydrous sodium sulfate, subjected to filtration and purified by silica gel column chromatography to obtain 2.0 g (yield 76%) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-2,3-dichloro-5-methoxypyridine (compound No. 193; m.p. 98-99° C.).
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:15]=[CH:14][C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=1.[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([CH:25]=[O:26])=[CH:24][C:19]=2[O:18][CH2:17]1.C(OCC)=O>C1COCC1>[O:11]1[C:10]2[CH:14]=[CH:15][C:7]([CH:25]([C:23]3[CH:22]=[CH:21][C:20]4[O:16][CH2:17][O:18][C:19]=4[CH:24]=3)[OH:26])=[CH:8][C:9]=2[O:13][CH2:12]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: Brc1ccc2c(c1)OCO2
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC=O
Product: OC(c1ccc2c(c1)OCO2)c1ccc2c(c1)OCO2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of tert-butyllithium (1.8 mL, 3.1 mmol, 1.7M in pentane) at −78° C. was added dropwise a solution of 5-bromobenzo-1,3-dioxole (1.5 mmol) in THF (3 mL). After 30 min, benzo-1,3-dioxole-5-carbaldehyde (1.5 mmol) or ethyl formate (0.5 mmol) in THF (1 mL) was added. The mixture was stirred at −78° C. for 1 h and subsequently warmed to room temperature and stirred for an additional 4 h. The reaction was quenched by the addition of a saturated solution of NH4Cl and extracted with EtOAc (3×). The organic layers were combined, dried over Na2SO4 and concentrated under reduced pressure. Purification of the crude oil by flash chromatography (20% EtOAc/hexanes) provided the diphenyl methanol product.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]([C:15]2[N:19]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=3)[N:18]=[CH:17][CH:16]=2)=[C:11]([CH3:28])[N:10]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)[C:9]1=[O:39].C(N(CC)CC)C.[C:47](Cl)(=[O:49])[CH3:48].C(=O)([O-])O.[Na+]>ClCCl>[C:24]([C:23]1[CH:22]=[CH:21][C:20]([N:19]2[C:15]([C:12]3[C:13](=[O:14])[N:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][NH:2][C:47](=[O:49])[CH3:48])[C:9](=[O:39])[N:10]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:38])[F:37])[CH:30]=4)[C:11]=3[CH3:28])=[CH:16][CH:17]=[N:18]2)=[CH:27][CH:26]=1)#[N:25]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n(CCCCCN)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCCCCn1c(=O)c(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reaction time: 0.08 h
Yield: 59.6 %

Procedure:
To a solution of 4-[5-[3-(5-aminopentyl)-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile hydrochloride (prepared in Example 85) (6.4 mg) and triethylamine (10 μl) in dichloromethane (1.0 ml) was added acetyl chloride (0.7 mg) in ice-cooling and the resulting mixture was stirred for five minutes and stirred at room temperature for thirty minutes. To the reaction mixture was added aqueous saturated sodium hydrogen carbonate solution (10 ml) and the resulting mixture was extracted with chloroform (10 ml×2). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford N-[5-[5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]pentyl]acetamide (3.0 mg).
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH3:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:20]#N.C1C[O:29]CC1>>[CH3:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:20]([CH:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)=[O:29]
Reactant: C1CCOC1
Reactant: Cc1ccc(C#N)cc1C
Reactant: c1cnc2c(c1)CCCC2
Agent: [Li]CCCC
Product: Cc1ccc(C(=O)C2CCCc3cccnc32)cc1C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
5,6,7,8-Tetrahydroquinoline (7.2g 0.054M) was dissolved in THF (50ml) and cooled to 0° C. 35ml of a solution of n-butyl lithium (1.6M in hexane) was added. The mixture was left for 20 minutes then a solution of 3,4,-dimethyl-benzonitrile (7g 0.053M) in THF (50ml) was added. The mixture was allowed to stand for 30 minutes them 2MHCl (100ml) was added. The mixture was allowed to stand for 16 hours after which the resulting yellow crystals were filtered off and washed with isopropyl alcohol then ether to give 6.17g of the title compound as the hydrochloride. The mother liquids were diluted with 2M HCl and extracted with hexane. A small quantity of solid was obtained filtered off and washed . with isopropyl alcohol then ether to give a further 2.2g of the title compound hydrochloride dihydrate m.p. 236°-7° C.
Reaction SMILES: [Cl:1]C(OC(Cl)C)=O.C([N:21]1[CH2:24][CH:23]([O:25][C:26]2[CH:31]=[CH:30][C:29]([I:32])=[CH:28][N:27]=2)[CH2:22]1)(C1C=CC=CC=1)C1C=CC=CC=1.CO>ClCCl>[ClH:1].[NH:21]1[CH2:22][CH:23]([O:25][C:26]2[CH:31]=[CH:30][C:29]([I:32])=[CH:28][N:27]=2)[CH2:24]1
Reactant: CC(Cl)OC(=O)Cl
Reactant: Ic1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)nc1
Solvent: ClCCl
Solvent: CO
Product: Cl
Product: Ic1ccc(OC2CNC2)nc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 109.5 %

Procedure:
1-chloroethyl chloroformate (12.8 mL, 0.104 mol) was added drop-wise via syringe to a stirred solution of 2-(1-Benzhydryl-azetidin-3-yloxy)-5-iodo-pyridine (23.03 g, 0.052 mol) in dichloromethane (250 mL) at ambient temperature. The resulting solution was stirred at ambient temperature for 3.5 hr, then methanol (250 mL) was added and the reaction mixture stirred at ambient temperature for 16 hr. The solvents were then removed in vacuo and the resulting solid residue was triturated with diethyl ether, filtered and then dried in vacuo to afford the title product as a cream-coloured solid (17.8 g, >quant yield). The crude product was used directly without further purification.
Reaction SMILES: [Cl:1][C:2](=[CH2:12])[CH2:3][C:4]1([C:9]([OH:11])=O)[CH2:8][CH2:7][CH2:6][CH2:5]1.CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.OC(C(F)(F)F)=O.[NH2:49][C@@H:50]([CH2:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)=[CH:58][CH:57]=1)[C:51]([NH:53][CH3:54])=[O:52]>CN(C=O)C>[C:59]1([C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)[CH:60]=[CH:61][C:56]([CH2:55][C@H:50]([NH:49][C:9]([C:4]2([CH2:3][C:2]([Cl:1])=[CH2:12])[CH2:5][CH2:6][CH2:7][CH2:8]2)=[O:11])[C:51]([NH:53][CH3:54])=[O:52])=[CH:57][CH:58]=1
Reactant: C=C(Cl)CC1(C(=O)O)CCCC1
Reactant: CNC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: C=C(Cl)CC1(C(=O)N[C@@H](Cc2ccc(-c3ccccc3)cc2)C(=O)NC)CCCC1
Temperature: 25 °C
Yield: 49.7 %

Procedure:
To a solution of 1-(2-chloroallyl)cyclopentanecarboxylic acid (50 mg, 0.27 mmol) in DMF (1.2 mL) was added EDC.HCl (51 mg, 0.27 mmol), HOAt (29 mg, 0.21 mmol) and triethylamine (0.04 mL, 0.27 mmol). To the mixture stirred at room temperature was added (S)-2-amino-3-(biphenyl-4-yl)-N-methylpropanamide TFA salt (45 mg, 0.18 mmol). The mixture was stirred at room temperature for 18 hours. The mixture was extracted with EtOAc, and the organic layer was washed with water (8 times), brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by TLC preparation plates using 70% EtOAc/heptane to give (S)—N-(3-(biphenyl-4-yl)-1-(methylamino)-1-oxopropan-2-yl)-1-(2-chloroallyl)cyclopentanecarboxamide (38 mg). HPLC retention time=1.69 minutes (condition B); MS (m+1)=425.0; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.34-1.64 (m, 6H), 1.79-2.02 (m, 2H), 2.59 (d, J=5.8 Hz, 2H), 2.66 (d, J=4.9 Hz, 3H), 3.05 (d, J=7.3 Hz, 2H), 4.66 (q, J=7.5 Hz, 1H), 4.95 (s, 1H), 5.05 (s, 1H), 6.28-6.35 (m, 1H), 6.37 (d, J=7.7 Hz, 1H), 7.20 (d, J=8.2 Hz, 2H), 7.23-7.30 (m, 1H), 7.34 (t, J=7.5 Hz, 2H), 7.45 (dd, J=14.5, 7.8 Hz, 4H).
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40]#[N:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].C([Li])CCC.C[Si]([CH:51]=[N+:52]=[N-:53])(C)C>C1COCC1.CCCCCC.[Cl-].[NH4+]>[NH:9]1[CH:10]=[C:6]([C:2]([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35]([C:40]4[N:41]=[N:53][NH:52][CH:51]=4)[CH:36]=3)[CH:31]=2)([OH:1])[CH:3]([CH3:4])[CH3:5])[N:7]=[CH:8]1
Reactant: CC(C)C(O)(c1ccc2cc(C#N)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)C(O)(c1ccc2cc(-c3c[nH]nn3)ccc2c1)c1c[nH]cn1
Reaction time: 0.33 h

Procedure:
To an solution of 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthonitrile in THF (15 mL) was added a solution of n-butyllithium in hexane (1.6M:2.57 mL) under ice cooling, and the mixture was stirred for 20 min. A solution of trimethylsilyldiazomethane in THF (10% wt.:6.0 g) was added dropwise to the mixture and stirred for 90 min under ice cooling. The reaction mixture was diluted with saturated aq. ammonium chloride and extracted with ethyl acetate. The extract was washed with water and brine, dried and concentrated. The residue was purified by column chromatography (eluent; hexane:THF=1:1) and crystallized from ethyl acetate-hexane (1:1) to give the titled compound (881 mg) as a colorless powder.
Reaction SMILES: [C:1]([C:3]1[C:7]2[CH2:8][CH2:9][C:10](=O)[CH2:11][C:6]=2[S:5][C:4]=1[NH:13][C:14](=[O:20])[CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])#[N:2].[NH2:21][CH:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:23][OH:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl.C([O-])(O)=O.[Na+]>[C:1]([C:3]1[C:7]2[CH2:8][CH2:9][CH:10]([NH:21][CH:22]([CH2:23][OH:24])[C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:11][C:6]=2[S:5][C:4]=1[NH:13][C:14](=[O:20])[CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])#[N:2]
Reactant: CCC(CC)C(=O)Nc1sc2c(c1C#N)CCC(=O)C2
Reactant: CC(C)(C)C(N)CO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCC(CC)C(=O)Nc1sc2c(c1C#N)CCC(NC(CO)C(C)(C)C)C2

Procedure:
To a solution of the intermediate isolated in Example 9, Step C, in 40 mL of dichloromethane was added 0.452 g (3.90 mmol) of 2-amino-3,3-dimethylbutan-1-ol, followed by 1.24 g (5.9 mmol) of sodium triacetoxyborohydride and 0.468 mL (7.80 mmol) of acetic acid. After 16 h at ambient temperature the reaction was diluted with an equal volume of saturated aqueous NaHCO3. The organic layer was dried (Na2SO4) and concentrated in vacuo. Purification by preparative reversed phase HPLC afforded the title compound (TFA salt).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15][CH2:16][C:17]([CH2:24][CH3:25])([CH2:20][CH2:21][CH2:22][CH3:23])[CH:18]=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>COCCOC.[Cl-].[Na+].O.[Zn]>[CH2:20]([C:17]1([CH2:24][CH3:25])[CH:18]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15][CH2:16]1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCC(C=O)(CC)CSc1ccccc1C(=O)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn]
Solvent: O
Solvent: COCCOC
Product: CCCCC1(CC)C=C(c2ccccc2)c2ccccc2SC1
Temperature: 5 °C
Reaction time: 16 h
Yield: 52.7 %

Procedure:
A mixture of 2.6 g (0.04 mole) of zinc dust, 7.2 g (0.047 mole) of TiCl, and 80 mL of anhydrous ethylene glycol dimethyl ether (DME) was held at reflux for 2 h. The reaction mixture was cooled to 5° C. To the reaction mixture was added dropwise a solution of 3.54 g (0.01 mole) of 2 in 30 mL of DME in 40 min. The reaction mixture was stirred at room temperature for 16 h and then was held at reflux for 2 h and cooled before being poured into brine. The organic was extract into methylene chloride. The methylene chloride extract was dried over MgSO4 and concentrated in vacuo. The residue was purified by HPLC (hexane) to give 1.7 g (43%) of 3 as an oil in the first fraction. The second fraction was discarded and the third fraction was further purified by HPLC (hexane) to give 0.07 g (2%) of 4a in the earlier fraction and 0.1 g (3%) of 4b in the later fraction.
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[NH:9][C:8]1=[O:21].[CH2:28](Cl)/[CH:29]=[CH:30]/[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[OH:6][N:7]1[C:12](=[O:13])[C:11]2[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[N:9]([CH2:28][CH:29]=[CH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:8]1=[O:21]
Reactant: COc1ccc(COn2c(=O)[nH]c3c(oc4ccccc43)c2=O)c(OC)c1
Reactant: ClC/C=C/c1ccccc1
Product: O=c1c2oc3ccccc3c2n(CC=Cc2ccccc2)c(=O)n1O

Procedure:
Following general procedure B2 and D1, 3-(2,4-Dimethoxy-benzyloxy)-1H-benzo[4,5]furo[3,2-d]pyrimidine-2,4-dione was alkylated with trans-cinnamyl chloride and subsequently deprotected to provide the title compound as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ 5.09 (s, 1H); 5.11 (s, 1H); 6.49-6.58 (m, 2H); 7.18-7.30 (m, 3H); 7.37-7.47 (m, 3H); 7.64 (dd, J=8 Hz, 1H); 7.82 (d, J=8 Hz, 1H); 8.07 (d, J=8 Hz, 1H), 10.73 (br s, 1H); Ret. time=2.66 min, m/z=333.0.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][NH2:11])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(N(CC)CC)C.C[O:20][C:21](=O)[N:22]=[C:23](SC)[C:24]([C:38]1[CH:43]=[C:42]([CH3:44])[N:41]=[C:40]([O:45][CH3:46])[CH:39]=1)=[N:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]=[C:35]([CH3:37])[O:34][N:33]=2)=[CH:28][CH:27]=1>CN(C=O)C>[N+:1]([C:4]1[C:5]([N:10]2[C:21](=[O:20])[NH:22][C:23]([CH:24]([C:38]3[CH:43]=[C:42]([CH3:44])[N:41]=[C:40]([O:45][CH3:46])[CH:39]=3)[NH:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[N:36]=[C:35]([CH3:37])[O:34][N:33]=4)=[CH:28][CH:27]=3)=[N:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(C)nc(OC)c1
Reactant: NNc1ncccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccc3[N+](=O)[O-])c(=O)[nH]2)cc(C)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 28.4 %

Procedure:
After adding 32 mg of (3-nitropyridin-2-yl)hydrazine [CAS No. 15367-16-5] and 29 μl of triethylamine to a solution of 90 mg of {2-(2-methoxy-6-methylpyridin-4-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 3 ml of DMF, the mixture was stirred at 85° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 2 ml of a methanol:THF=1:1 mixed solvent. After adding 42 μl of acetic acid and 64 mg of sodium cyanotrihydroborate to the reaction mixture, it was stirred at room temperature for 4 hours. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give 2-(3-nitropyridin-2-yl)-5-{(2-methoxy-6-methylpyridin-4-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2,4-dihydro-[1,2,4]triazol-3-one (30 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[CH:25]=[CH:24][C:11]([CH2:12][N:13]3[C:21]4[C:16](=[N:17][C:18](Cl)=[N:19][C:20]=4Cl)[N:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[O-:28][CH2:29][CH3:30].[Na+].[CH2:32]([OH:34])[CH3:33]>O>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][N:13]3[C:21]4[C:16](=[N:17][C:18]([O:34][CH2:32][CH3:33])=[N:19][C:20]=4[O:28][CH2:29][CH3:30])[N:15]=[CH:14]3)=[CH:24][CH:25]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cn2cnc3nc(Cl)nc(Cl)c32)cc1
Reactant: CC[O-]
Reactant: CCO
Agent: [Na+]
Solvent: O
Product: CCOc1nc(OCC)c2c(ncn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)n1
Temperature: 25 °C
Reaction time: 96 h
Yield: 67 %

Procedure:
To a solution of 7-(4-(4-chlorobenzoyl)benzyl)-2,6-dichloropurine (1.12 g) in ethanol (30 ml) was added sodium ethoxide (1.83 g) and the mixture was stirred at room temperature for 96 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was washed with ether and hexane to provide the title compound (0.78 g, 67%) as colorless powder. 1H-NMR (CDCl3) δ: 1.34(3H,t,J=7.OHz), 1.50(3H,t,J=7.OHz), 4.50(2H,q,J=7.OHz), 4.55(2H,q,J=7.OHz), 5.53(2H,s), 7.25-7.80(8H,m), 7.98(1H,s).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13].[CH3:14][N:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1.O>O1CCCC1>[F:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:18]1([OH:21])[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]1
Reactant: CN1CCC(=O)CC1
Reactant: Fc1ccccc1Br
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CN1CCC(O)(c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
46 ml of 2.4M n-butyllithium are added over a 15 minute span to a mixture cooled to -70° C. of 17.5 g of 2-bromofluorobenzene and 50 ml of tetrahydrofuran. After total addition, the reaction mixture is stirred at between -60° to -70° C. for 15 minutes to enable complete lithiation, which results in a tan colored solution. A mixture of 11.3 g of 1-methyl-4-piperidone in 20 ml of tetrahydrofuran is added to the solution at a rate to maintain the reaction medium's temperature below -60° C. After total addition, the reaction mixture is stirred at the same low temperature for one hour before being permitted to warm to ambient temperature. Water is added and the biphasic mixture is permitted to separate into its organic and aqueous phases. The organic phase is collected and the aqueous phase is extracted thrice with ether and the ether extracts are combined with the organic phase. The combined organic solution is extracted with an excess of 2N hydrochloric acid and then discarded. The acidic solution is basified with ammonium hydroxide, producing a heavy oil which is dissolved in a 1:1 ethyl acetate ether mixture. This solution is dried and then concentrated to dryness, leaving a viscous oil which crystallizes with cooling. The solid product is recrystallized from a benzene-hexane mixture to give prisms, mp 127°-129° C. of 4-(2-fluorophenyl)-4-hydroxy-1-methylpiperidine.
Reaction SMILES: [CH:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][OH:11])[N:9]=1)([CH3:3])[CH3:2].C(N(CC)CC)C>CS(C)=O>[CH:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH:10]=[O:11])[N:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Nc1nc(CO)cs1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)Nc1nc(C=O)cs1

Procedure:
The reaction described in Preparation 44 was repeated, but using 4.4 q of 2-isopropylaminothiazol-4-ylmethanol, 12.2 g of pyridine sulfur trioxide complex, 7.7 g of triethylamine and 60 ml of dimethyl sulfoxide, giving the title compound as a pale brown oil.