Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:20])=[C:7]([C:16]([O:18]C)=O)[C:8]([C:12]([O:14]C)=O)=[N:9]2)=[CH:4][CH:3]=1.Cl.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:20])[C:7]3[C:16]([OH:18])=[N:30][N:29]([C:26]4[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][CH:25]=4)[C:12](=[O:14])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: COC(=O)c1nc2cc(Cl)ccc2c(O)c1C(=O)OC
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc(-n2nc(O)c3c(=O)c4ccc(Cl)cc4[nH]c3c2=O)cc1
Temperature: 25 °C
Yield: 49.3 %

Procedure:
To a stirred suspension of dimethyl 7-chloro-4-hydroxyquinoline-2,3-dicarboxylate (3.90 g, 13.3 mM) and 4-methylphenyl hydrazine hydrochloride (14.8 g, 93.2 mM) in ethanol (140 mL) was added triethylamine (14.8 mL, 106.4 mM). The resulting brown solution was refluxed for 16 hours during which time a precipitate formed. The resulting suspension was cooled to room temperature and filtered to give the 4-methylphenyl hydrazine salt of the title compound as a grey powder (2.30 g). This material was refluxed in glacial acetic acid (45 mL) for 2 hours and cooled to room temperature. The resulting brown suspension was filtered to give the title compound (1.60 g, 34%) as a tan powder, mp 380-382° C.; MS(CI): 354 (M+H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C(N(CC)C(C)C)(C)C.C([O:23][C:24](=O)/[CH:25]=[C:26](/[O:29][C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=1[F:37])\[CH2:27]Br)C>C(#N)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([N:6]1[CH2:27][C:26]([O:29][C:30]2[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=2[F:37])=[CH:25][C:24]1=[O:23])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: CCOC(=O)/C=C(\CBr)Oc1cc(C)ccc1F
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC(C)C)N1CC(Oc2cc(C)ccc2F)=CC1=O
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 43.2 %

Procedure:
A mixture of (L)-leucine methyl ester hydrochloride (0.82 g, 4.56 mmol) in acetonitrile (11.4 mL) was treated with N,N-diisopropylethylamine (0.74 mL, 4.48 mmol). After addition was complete, the mixture was stirred at 60° C. for 45 min. At this time, the reaction was cooled to 25° C., treated with N,N-diisopropylethylamine (0.74 mL, 4.48 mmol) and acetonitrile (11.4 mL) and then heated to 80° C. Upon reaching 80° C., the reaction was treated with a solution of (E)-4-bromo-3-(2-fluoro-5-methyl-phenoxy)-but-2-enoic acid ethyl ester (1.31 g, 4.14 mmol) in acetonitrile (10.4 mL). After the addition was complete, the reaction mixture was heated to 100° C. where it stirred for 24 h. At this time, the reaction mixture was cooled to 25° C. and was stirred at 25° C. for 2 d. The reaction was then concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 10-50% ethyl acetate/hexanes) afforded (S)-2-[4-(2-fluoro-5-methyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (0.60 g, 43%) as an orange oil: HR-ES-MS m/z calculated for C18H22NO4F [M+H]+ 336.1606, observed 336.1607; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.87 (d, J=6.6 Hz, 3H), 0.92 (d, J=6.6 Hz, 3H), 1.34-1.53 (m, 1H), 1.53-1.69 (m, 1H), 1.72-1.89 (m, 1H), 2.31 (s, 3H), 3.66 (s, 3H), 4.18 (d, J=18.4 Hz, 1H), 4.25 (d, J=18.4 Hz, 1H), 4.73 (dd, J=11.3, 4.4 Hz, 1H), 4.90 (s, 1H), 7.11-7.20 (m, 1H), 7.26-7.38 (m, 2H).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CC(N=NC(C#N)(C)C)(C#N)C.[CH2:21]([SnH:25]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH3:24]>C1(C)C=CC=CC=1>[CH2:30]([Sn:25]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:26][CH2:27][CH2:28][CH3:29])/[CH:1]=[CH:2]/[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:31][CH2:32][CH3:33]
Reactant: C#CCCCCCC
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Cc1ccccc1
Product: CCCCCC/C=C/[Sn](CCCC)(CCCC)CCCC
Temperature: 25 °C

Procedure:
A solution of 10.0 g (0.0908 mol) of 1-octyne, 60 ml of anhydrous toluene, 230 mg of azobisisobutylonitrile (AIBN), and 25 (0.0943 mol) of tri-n-butyltin hydride is refluxed under an argon atomosphere for 3 hours. The reaction mixture is cooled to ambient temperature and concentrated in vacuo. The resulting yellow liquid is distilled (bulb to bulb) to give 36.29 (99%) of the stannyl octene as a pale yellow liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]=[C:18]=S)=[C:6]([CH:16]=1)[CH2:7][O:8][Si](C(C)(C)C)(C)C.[CH3:20][O:21][C:22]1[C:27]2[CH:28]([NH2:31])[CH2:29][O:30][C:26]=2[CH:25]=[CH:24][CH:23]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:17]=[C:18]([NH:31][CH:28]3[C:27]4[C:22]([O:21][CH3:20])=[CH:23][CH:24]=[CH:25][C:26]=4[O:30][CH2:29]3)[O:8][CH2:7][C:6]=2[CH:16]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(Br)ccc1N=C=S
Reactant: COc1cccc2c1C(N)CO2
Product: COc1cccc2c1C(NC1=Nc3ccc(Br)cc3CO1)CO2
Yield: 49.7 %

Procedure:
Prepared from (5-bromo-2-isothiocyanato-benzyloxy)-tert-butyl-dimethyl-silane (Example 32, step B) (4.0 g, 11.2 mmol) and rac-4-methoxy-2,3-dihydro-benzofuran-3-ylamine (Example 5, step B) (1.84 g, 11.2 mmol) according to the procedure described for Example 1. Obtained the title compound as a white solid (2.09 g, 50%), m.p. 132.5° C.; MS (ISP) m/e=375.1 [(M+H)+].
Reaction SMILES: [CH2:1]([C:5]1[S:21][C:8]2[N:9]=[C:10]3[CH:17]=[CH:16][C:15]([C:18]([OH:20])=O)=[CH:14][N:11]3[C:12](=[O:13])[C:7]=2[CH:6]=1)[CH2:2][CH2:3][CH3:4].C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:35][C:36]1[NH:40][N:39]=[N:38][N:37]=1>CN(C)C=O>[CH2:1]([C:5]1[S:21][C:8]2[N:9]=[C:10]3[CH:17]=[CH:16][C:15]([C:18]([NH:35][C:36]4[NH:40][N:39]=[N:38][N:37]=4)=[O:20])=[CH:14][N:11]3[C:12](=[O:13])[C:7]=2[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Nc1nnn[nH]1
Reactant: CCCCc1cc2c(=O)n3cc(C(=O)O)ccc3nc2s1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1cc2c(=O)n3cc(C(=O)Nc4nnn[nH]4)ccc3nc2s1
Temperature: 105 °C

Procedure:
1.6 g (0.0053 mol) of 2-butyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid (Example 4) and 1.75 g (0.0108 mol) of 1,1'carbonyldiimidazole (Aldrich Chemical Company) in 50 ml of dimethylformamide are stirred under a nitrogen atmosphere at 105° C. for seventy minutes. The mixture is allowed to stand at room temperature for thirty minutes and then 0.545 g (0.00529 mol) of 5-aminotetrazole monohydrate (Aldrich Chemical Company) is added and the mixture heated at 105° C. for one hundred minutes. The solvent is evaporated and the residue is dissolved in dimethylformamide and filtered. The filtrate is cooled and 1.1 g of 2-butyl-4-oxo-N-1H-tetrazol-5-yl-4H-pyrido[1,2-a]thieno[2,3-d]-pyrimidine-7-carboxamide is collected; mp 290° (dec).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.O/[N:33]=[C:34](\[NH2:44])/[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1>CN(C=O)C.CCOC(C)=O>[CH3:43][O:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][C:34]2[N:33]=[C:14]([CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]3)[O:16][N:44]=2)=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: COc1ccc(C/C(N)=N/O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Cc2noc(C3CCN(C(=O)OC(C)(C)C)CC3)n2)cc1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
1-(tert-Butoxycarbonyl)piperidine-4-carboxylic acid (2.29 g, 10.0 mmoles) in 10 mL DMF was treated with 1,1′-carbonyldiimidazole (1.62 g, 10 mmoles, 1 eq.) at ambient temperature for 30 min until CO2 evolution ceased. (1Z)-N′-hydroxy-2-(4-methoxyphenyl)ethanimidamide [J. Med. Chem., 36(11), 1529 (1993)] (10.0 mmoles, 1 eq.) was dissolved in 5 mL DMF and added to the reaction mixture. The reaction mixture was heated at 70° C. for 6 h then at 120° C. for an additional 6 h. The reaction mixture was diluted with EtOAc and washed successively with water, 1N citric acid, saturated aqueous NaHCO3, and brine. The organic phase was isolated, dried over MgSO4, filtered and concentrated to give the title compound as an amber oil. 1H NMR (300 MHz, CDCl3) δ 7.26 (d, 2H, J=8.5 Hz), 6.88 (d, 2H, J=8.5 Hz), 4.10 (m, 2H), 4.00 (s, 2H), 3.80 (s, 3H), 3.08 (m, 1H), 2.97-2.90 (m, 2H), 2.04 (m, 2H), 1.87-1.73 (m, 2H), 1.47 (s, 9H). ES-LCMS m/z 395.99 (M+Na).
Reaction SMILES: Br[CH:2]([CH:5]=[O:6])[CH:3]=O.[Br:7][C:8]1[CH:9]=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1>C(#N)C>[Br:7][C:8]1[CH:9]=[N:10][C:11]2[N:12]([C:2]([CH:5]=[O:6])=[CH:3][N:14]=2)[CH:13]=1
Reactant: Nc1ncc(Br)cn1
Reactant: O=CC(Br)C=O
Solvent: CC#N
Product: O=Cc1cnc2ncc(Br)cn12
Yield: 40 %

Procedure:
Bromomalonaldehyde (500 mg, 2.90 mmol) was added to a solution of 5-bromopyrimidin-2-amine (526 mg, 3.49 mmol) in acetonitrile. The reaction mixture was refluxed for 2 hours. After completion of the reaction, the reaction mixture was quenched with sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The organic layer was concentrated and the product was purified by column chromatography using up to 2% methanol in chloroform gradient to obtain the title compound. Yield: 40%; 1H NMR (DMSO-d6; 300 MHz): δ 9.98(s, 1H), 9.75-9.76 (d, 1H, J=2.4 Hz), 8.97-8.98 (d, 1H, 2.4 Hz), 8.70 (s, 1H); MS (m/z): 226 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH2:20][CH:21]=C)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].CC([OH:26])C>O.O=[Os](=O)(=O)=O>[CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH2:20][CH:21]=[O:26])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)O
Reactant: C=CCCC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: CCOC(=O)C1(CCC=O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 6 h

Procedure:
4-But-3-enyl-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (13.5 g, 43.48 mmol, 1 eq) was dissolved in i-PrOH (217 mL) and a solution of NaIO4 (20.23 g, 94.6 mmol, 2.18 eq) in 217 mL of water was added followed by OsO4 (37 mg, 0.144 mmol, 0.003 eq). The reaction mixture was vigorously stirred for 6 h. The reaction mixture was then quenched with 1500 mL of water, transferred to a separatory funnel and extracted with ethyl acetate (3×200 mL). The combined organics were dried over Na2SO4 and purified by column chromatography on silica gel (300 g column, 30% EtOAc in heptanes; 50 mL/min). This gave 8.5 g (63%) of the title compound as a beige oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][N:12]2[CH:15]([CH3:17])[CH3:16])=[C:8]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:7]=1.[Br:26]Br>C(Cl)(Cl)Cl>[OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([Br:26])[N:12]2[CH:15]([CH3:17])[CH3:16])=[C:8]([NH:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:7]=1
Reactant: CC(C)n1cnc2c(NCc3ccccc3)nc(NCCCO)nc21
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CC(C)n1c(Br)nc2c(NCc3ccccc3)nc(NCCCO)nc21
Yield: 90 %

Procedure:
1 mmol of 2-(3-hydroxypropylamino)-6-benzylamino-9-isopropylpurine was dissolved in chloroform and 1.1 mmol of bromine was added. The 8-bromo derivative hydrobromide was removed by filtration and crystallized from n-propanol-ether. M.p. 156-161° C. Yield 90%. TLC: chloroform-methanol (96:4), single spot. MS-ESI(+)m/z: 420, 422 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12](O)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][OH:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC(=O)O)cc1OC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CCO)cc1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3,4-dimethoxyphenylacetic acid (2 g) in anhydrous THF (40 ml) at 0° C. under N2 was added dropwise borane-methyl sulfide complex (10 M, 1.5 ml). The mixture was stirred at room temperature for further 4 hrs. Cold water (5 ml) was added to destroy any excess of borane followed by the addition of H2SO4 (1 M, 50 ml). The mixture was extracted three time with ethyl acetate (50 ml). The organic layer was separated and evaporated off to give a colourless liquid which was then purified by column chromatography to afford a colourless solid in quantitative yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]([O:10][CH3:11])=[CH:8][C:6]([NH2:7])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.[CH3:15][C:16](=O)[CH:17]=[CH:18][CH3:19]>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:11][O:10][C:9]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]2[C:8]=1[C:16]([CH3:15])=[CH:17][C:18]([CH3:19])=[N:7]2
Reactant: CC=CC(C)=O
Reactant: COc1cc(N)c([N+](=O)[O-])cc1OC
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc([N+](=O)[O-])c2nc(C)cc(C)c2c1OC
Yield: 14 %

Procedure:
4,5-Dimethoxy-2-nitroaniline and 3-penten-2-one were subjected to a Skraup reaction. A black, tarry substance was obtained, from which an orange solid could be isolated by chromatography over silica gel using benzene-ethyl acetate (19:1) to elute the product. That material was thrice crystallized from 2-propanol, re-chromatographed, and again crystallized to afford 14% yield of golden 5,6-dimethoxy-2,4-dimethyl-8-nitroquinoline. Although it melted 85°-108°, it showed a single spot on two tlc systems.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.[OH-].[NH4+]>C1COCC1>[CH3:22][O:11][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][C:14]1[CH:15]=[C:16]([F:21])[CH:17]=[C:18]([F:20])[CH:19]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)C(=O)O
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: COS(=O)(=O)OC
Product: COC(=O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
(2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propanoic acid (1,5.0 g, 0.017 moles, 1.0 equivalent) and potassium carbonate (2.5 g, 0.018 moles, 1.1 equivalent) are mixed in THF (100 mL). To this heterogeneous mixture is then added dimethyl sulfate (1.6 mL, 2.1 g, 0.017 moles, 1.0 equivalent) and the contents were then stirred at 20-25° overnight. Once the reaction is complete as measured by HPLC, ammonium hydroxide (10%, 20 mL) is added and allowed to stir for 1 hr at which time the contents are extracted with ethyl acetate (3×50 mL). The combined organic phases are washed with water (50 mL) and saline (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:11]1[O:15][C:14]([CH:16]=[O:17])=[CH:13][CH:12]=1>>[OH:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][N:4]([C:13]2[CH:12]=[CH:11][O:15][C:14]=2[CH:16]=[O:17])[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(Br)o1
Reactant: OCCN1CCNCC1
Product: O=Cc1occc1N1CCN(CCO)CC1
Yield: 61.1 %

Procedure:
Through the procedure as employed in Production step 1, an amine moiety derived from 1-piperazineethanol (3.91 g) was introduced into 5-bromo-2-furaldehyde (1.75 g), to thereby yield 5-[(4-(2-hydroxy-ethyl)-piperazin-1-yl)-furan-2-carbaldehyde (yield: 1.37 g, 61%). The produced 5-[(4-(2-hydroxy-ethyl)-piperazin-1-yl)-furan-2-carbaldehyde (1.12 g) was condensed with 3,4-dimethoxybenzyl cyanide (888 mg) through Method A (production step 2), to thereby yield the target product (yield: 1.32 g, 69%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([NH:12][CH:13]=[O:14])[CH:6](O)[C:7]([CH2:9][CH3:10])=[CH2:8])[CH3:2].S(Br)(Br)=O.[P:20]([O:25]C)([O:23][CH3:24])[O:21][CH3:22]>>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([NH:12][CH:13]=[O:14])/[CH:6]=[C:7](\[CH2:9][CH3:10])/[CH2:8][P:20]([O:23][CH3:24])([O:21][CH3:22])=[O:25])[CH3:2]
Reactant: C=C(CC)C(O)C(NC=O)C(=O)OCC
Reactant: COP(OC)OC
Agent: O=S(Br)Br
Product: CCOC(=O)C(/C=C(\CC)CP(=O)(OC)OC)NC=O

Procedure:
Reaction of the 2-formylamino-3-hydroxy-4-ethyl-4-pentenoic acid ethyl ester with thionyl bromide and subsequent treatment with trimethyl phosphite in a manner analogous to that described in Example 1 yields E-2-formylamino-4-ethyl-5-dimethylphosphono-3-pentenoic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1.[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1)([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]2[N:6]([CH2:19][C:18]3[CH:21]=[CH:22][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: Cc1cc2nc[nH]c2cc1C
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2ncn(Cc3ccc([N+](=O)[O-])cc3)c2cc1C
Temperature: 60 °C
Reaction time: 14 h
Yield: 32.4 %

Procedure:
A mixture of 5,6-dimethyl-1H-benzimidazole (5.0 g), 4-nitrobenzyl bromide (6.16 g), potassium carbonate (7.88 g) and N,N-dimethylformamide (60 ml) was stirred at 60° C. for 14 hrs. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to give 5,6-dimethyl-1-(4-nitrobenzyl)-1H-benzimidazole (2.6 g, 32%) as crystals from a fraction eluted with methanol-ethyl acetate (1:20, v/v). Recrystallization thereof from ethyl acetate-hexane gave pale-red prism crystals. melting point: 175-177° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=2)=[N:4][C:5]([Cl:18])=[C:6]([C:13](OCC)=[O:14])[C:7]=1[C:8](OCC)=[O:9].O.[NH2:27][NH2:28]>C(O)(=O)C>[NH2:1][C:2]1[C:7]2[C:8](=[O:9])[NH:28][NH:27][C:13](=[O:14])[C:6]=2[C:5]([Cl:18])=[N:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=1
Reactant: NN
Reactant: CCOC(=O)c1c(Cl)nc(-c2cccc(N)c2)c(N)c1C(=O)OCC
Solvent: CC(=O)O
Solvent: O
Product: Nc1cccc(-c2nc(Cl)c3c(=O)[nH][nH]c(=O)c3c2N)c1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To 0.35 g of 3-amino-6-chloro-4,5-diethoxycarbonyl-2-(3-aminophenyl)pyridine was added 7.5 ml of hydrazine monohydrate, and the mixture was stirred at 90° C. for 30 minutes. The reaction mixture was poured into ice water (100 ml), and the mixture was adjusted to pH 6 by adding acetic acid. The resulting precipitate was collected by filtration and washed with water, followed by reprecipitation from DMSO-H2O, to give 0.23 g of the title compound as orange powder.
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])O.[Na+]>O.CC(O)C>[CH:12]1([NH:20][C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: NC1CCCCCCC1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Nc1ccc(NC2CCCCCCC2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A mixture of 3.12 g (0.020 mol) of 4-fluoro-3-nitroaniline, 2.57 g (0.022 mol) of cyclooctylamine and 1.7 g (0.020 mol) of sodium hydrogen carbonate was refluxed for 3 hours in 5 ml of water and 5 ml of 2-propanol. After cooling to room temperature, the residues were filtered off and the filtrate was extracted with chloroform. The solvent was removed in vacuo and the residue was recrystallized from 20% hydrochloric acid. A yellow-green solid melting at 161° C. was obtained.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:10]=[CH:9][C:7]([NH2:8])=[N:6][C:4]1=[O:5].Cl[CH2:12][O:13][CH2:14][O:15][CH2:16][P:17]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C>[CH2:23]([O:22][P:17]([CH2:16][O:15][CH2:14][O:13][CH2:12][N:3]1[CH:10]=[CH:9][C:7]([NH2:8])=[N:6][C:4]1=[O:5])([O:19][CH2:20][CH3:21])=[O:18])[CH3:24]
Reactant: Nc1cc[nH]c(=O)n1
Reactant: CCOP(=O)(COCOCCl)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOP(=O)(COCOCn1ccc(N)nc1=O)OCC
Temperature: 80 °C
Reaction time: 15 h

Procedure:
To a suspension of 60% sodium hydride in mineral oil (700 mg, 17 mmol) in DMF (50 mL) was added cytosine (1.9 g, 17 mmol) and the mixture was heated at 80° C. for 2 hr under nitrogen. To the resulting yellow solution was added dropwise a solution of chloromethoxy(diethylphosphonomethoxy)methane [prepared from diethylphosphate (2.4 g, 17 mmol) and bis-(chloromethoxy)methane (12.5 g, 86 mmol)] in DMF (10 mL) under nitrogen. After stirring 15 hr at 25° C., the volatiles were removed in vacuo. The residue was dissolved in ethyl acetate (120 mL) and water (30 mL). The organic phase was washed with brine and dried (MgSO4). After removal of the solvent in vacuo, the residual oil was chromatographed on silica gel using CH2Cl2 /10% MeOH as eluent to give the title compound as a white oil: yield 1.2 g (22%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH:31]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N+:28]([O-])=O)(=[O:21])=[O:20])[CH2:15][CH2:14]2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[Cl-].[Ca+2].[Cl-]>C(O)C.O.[Zn]>[C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH:31]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH2:28])(=[O:21])=[O:20])[CH2:15][CH2:14]2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(N(C(=O)NC2CCN(S(=O)(=O)c3ccccc3[N+](=O)[O-])CC2)C2CCCCCC2)c1
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: N#Cc1cccc(N(C(=O)NC2CCN(S(=O)(=O)c3ccccc3N)CC2)C2CCCCCC2)c1
Yield: 81 %

Procedure:
N-(3-cyanophenyl)-N′-(1-(2-nitrophenyl)sulfonylpiperidin-4-yl)cycloheptylurea (0.71 g, 1.47 mmol) in ethanol (90 ml) and water (10 ml) was stirred with zinc dust (3.2 g, 48.6 mmol) and calcium chloride (0.11 g, 0.95 mmol). This mixture was heated at reflux for 3 h then filtered hot through a Celite® pad and evaporated; 0.59 g of N-(3-cyanophenyl)-N′-(1-(2-aminophenyl)sulfonylpiperidin-4-yl)cycloheptylurea was obtained; LRMS (M+H)+ m/z 454.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:25][O:26][C:27](=[O:37])[CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([NH2:36])[CH:31]=1>ClCCl>[CH3:25][O:26][C:27](=[O:37])[CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([NH:36][C:2]2[C:3]3[C:10]([C:11]4[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=4)=[C:9]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[O:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:31]=1
Reactant: COC(=O)COc1cccc(N)c1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Solvent: ClCCl
Product: COC(=O)COc1cccc(Nc2ncnc3oc(-c4ccccc4)c(-c4ccc(OC)cc4)c23)c1

Procedure:
Heat 4.7 g (14 mmol) of 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine and 3.03 g (16.7 mmol) of 3-aminophenoxyacetic acid methyl ester to 150° C. in an oil bath for 1.5 h. After cooling, add dichloromethane to the residue and purify by means of silica gel (eluent: cyclohexane/ethyl acetate 2:1). 2.29 g (34.1% of theory) of the target compound are obtained as a pale yellowish solid.
Reaction SMILES: CS[C:3]1[N:8]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][CH:11]=[C:7]2[CH:6]=[C:5]([S:18][CH3:19])[N:4]=1.C[O-:21].[Na+]>>[CH3:19][S:18][C:5]1[CH:6]=[C:7]2[CH:11]=[N:10][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]2[C:3](=[O:21])[N:4]=1
Reactant: C[O-]
Reactant: CSc1cc2cnc(-c3ccccc3)n2c(SC)n1
Agent: [Na+]
Product: CSc1cc2n(c(=O)n1)C(c1ccccc1)N=C2

Procedure:
Using the method of Part H, Example 1, 5,7-bis(methylthio)-3-phenylimidazo[1,5-c]pyrimidine was reacted with aqueous sodium methoxide to provide 7-methylthio-3-phenylimidazo[1,5-c]pyrimidin-5-one, m.p. 198°-199° C. Analysis: Calculated for C13H11N3OS: %C, 60.7; %H, 4.3; %N, 16.3; Found: %C, 60.7; %H, 4.1; %N, 16.7.