Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH:17]([NH2:19])[CH3:18])=[N:9][C:10]3[C:15]([CH:16]=2)=[N:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25](Cl)[N:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>CCCCO>[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25]([NH:19][CH:17]([C:8]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH3:18])[N:24]=[CH:23][N:22]=1
Reactant: CC(N)c1nc2cccnc2cc1-c1ccccc1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Nc1ncnc(N)c1C#N)c1nc2cccnc2cc1-c1ccccc1
Temperature: 25 °C

Procedure:
1-(3-Phenyl-1,5-naphthyridin-2-yl)ethanamine (46 mg, 0.19 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (28.5 mg, 1.0 eq) and Hunig's base (39 μL, 1.2 eq) in n-BuOH (2 mL) was heated to 130° C. for 4 h. The mixture was cooled to rt, filtered and washed with small amount of EtOH to give a white solid as 4-amino-6-(1-(3-phenyl-1,5-naphthyridin-2-yl)ethylamino)pyrimidine-5-carbonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.04 (1H, dd, J=8.0, 4.0 Hz), 8.44 (1H, dd, J=8.0, 4.0 Hz), 8.21 (1H, s), 7.97 (1H, s), 7.84 (1H, dd, J=8.0, 4.0 Hz), 7.61-7.47 (6H, m), 7.30 (1H, br, s), 5.63 (1H, t, J=8.0 Hz)), 1.31 (3H, d, J=8.0 Hz); LC-MS (ESI) m/z 368 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].[CH3:23][NH:24][CH2:25][CH2:26][CH3:27].C(N(CC)CC)C>CS(C)=O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:24]([CH3:23])[CH2:25][CH2:26][CH3:27])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CCCNC
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F

Procedure:
The title compound was prepared from (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example B5) (4.00 g, 11.7 mmol), N-methyl-propyl-amine (1.89 ml, 17.6 mmol) and triethylamine (5.73 ml, 41.1 mmol) in DMSO (30 mL) at RT according to the general procedure C.
Reaction SMILES: C(O[C:4](=[O:51])[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](=[O:50])[C@@H:15]([NH:17][C:18]([C:20]2[N:24]3[C@:25]([CH3:49])([CH2:37][C:38]4[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][CH:39]=4)[C:26](=[O:36])[N:27]([C:28]4[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=4)[C:23]3=[N:22][CH:21]=2)=[O:19])[CH3:16])[CH2:9]1)=O)C.[NH2:52][NH2:53]>C(O)C>[Cl:34][C:32]1[CH:33]=[C:28]([N:27]2[C:26](=[O:36])[C@@:25]([CH3:49])([CH2:37][C:38]3[CH:39]=[CH:40][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:42][CH:43]=3)[N:24]3[C:20]([C:18]([NH:17][CH:15]([CH3:16])[C:14]([N:10]4[CH2:11][CH2:12][CH2:13][C@@H:8]([C:6]5[NH:53][N:52]=[C:4]([OH:51])[CH:5]=5)[CH2:9]4)=[O:50])=[O:19])=[CH:21][N:22]=[C:23]23)[CH:29]=[C:30]([Cl:35])[CH:31]=1
Reactant: NN
Reactant: CCOC(=O)CC(=O)[C@@H]1CCCN(C(=O)[C@H](C)NC(=O)c2cnc3n2[C@](C)(Cc2ccc(OC(F)(F)F)cc2)C(=O)N3c2cc(Cl)cc(Cl)c2)C1
Solvent: CCO
Product: CC(NC(=O)c1cnc2n1[C@](C)(Cc1ccc(OC(F)(F)F)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)N1CCC[C@@H](c2cc(O)n[nH]2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.9 %

Procedure:
To a solution of 3-[(R)-1-((S)-2-{[(R)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-5-(4-trifluoromethoxy-benzyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-propionyl)-piperidin-3-yl]-3-oxo-propionic acid ethyl ester (40 mg, 0.05 mmol) in ethanol (2 mL) was added hydrazine (8.5 μL, 0.26 mmol). The reaction mixture was stirred at room temperature for 1.5 h. The solvent was evaporated in vacuo, and the residue was purified using reverse phase HPLC to afford the title compound (27 mg, 71%) as a white solid, m/z 720.6 [M+1]+.
Reaction SMILES: [CH:1]([N:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[C:7](Cl)[C:6]1=[O:13])([CH2:3][CH3:4])[CH3:2].Cl.[Br:15][C:16]1[CH:17]=[C:18]([O:25][CH3:26])[CH:19]=[C:20]2[C:24]=1[NH:23][CH2:22][CH2:21]2>>[Br:15][C:16]1[CH:17]=[C:18]([O:25][CH3:26])[CH:19]=[C:20]2[C:24]=1[N:23]([C:7]1[C:6](=[O:13])[N:5]([CH:1]([CH3:2])[CH2:3][CH3:4])[CH:10]=[C:9]([Cl:11])[N:8]=1)[CH2:22][CH2:21]2
Reactant: COc1cc(Br)c2c(c1)CCN2
Reactant: CCC(C)n1cc(Cl)nc(Cl)c1=O
Agent: Cl
Product: CCC(C)n1cc(Cl)nc(N2CCc3cc(OC)cc(Br)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 1-sec-butyl-3,5-dichloro-2(1H)-pyrazinone and 7-bromo-5-methoxyindoline hydrochloride as the starting materials. mp 155–157° C.; 1H NMR (300 MHz, CDCl3): δ 6.90 (d, J=2.6 Hz, 1 H), 6.78 (s, 1 H), 6.76 (d, J=2.1 Hz, 1 H), 4.99–4.87 (m, 1 H), 4.34 (t, J=7.7 Hz, 2 H), 3.76 (s, 3 H), 3.08 (t, J=7.7 Hz, 2 H), 1.74–1.65 (m, 2 H), 1.34 (d, J=7.0 Hz, 3 H), 0.89 (t, J=7.5 Hz, 3 H); HRMS (ESI) calcd for C20H22N3O2BrCl (M+H)+: 412.0427; found m/z 412.0448.
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].Cl.[C:7]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(=[NH:9])[NH2:8]>>[C:7]([C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[C:14]([S:1]([OH:3])(=[O:5])=[O:2])[CH:15]=1)(=[NH:8])[NH2:9]
Reactant: O=S(=O)(O)O
Reactant: N=C(N)c1ccc(O)cc1
Agent: Cl
Product: N=C(N)c1ccc(O)c(S(=O)(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 15 ml of 60% fuming sulfuric acid, while being cooled in ice, was added slowly 10.0 g of 4-amidinophenol hydrochloride. After the addition, the mixture was stirred at room temperature for 4 hours, then poured slowly into 200 ml of ice water, and stirred for a while. The colorless solid which was precipitated was collected by filtration, washed with water, then with acetone, and dried to obtain 10.2 g of 5-amidino-2-hydroxybenzenesulfonic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([OH:22])[C@@H:9]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH2:36]([O:38][C:39](=[O:43])[CH2:40][CH2:41][NH2:42])[CH3:37]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([OH:22])[C@@H:9]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:42][CH2:41][CH2:40][C:39]([O:38][CH2:36][CH3:37])=[O:43])=[O:18])=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCC[C@H](c1ccc(C(=O)O)cc1)[C@@H](O)c1ccc(Cl)cc1
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)OCC)cc1)[C@@H](O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product of Step C (5.00 g, 15.7 mmol) in THF (100 mL) was added CDI (3.05 g, 18.82 mmol). After stirring at room temperature for one hour, β-alanine ethyl ester hydrochloride (3.61 mg, 23.53 mmol) was added, then the mixture was stirred at room temperature for two days. The mixture was diluted with EtOAc then washed with 1N NaOH, then water, then brine. The organic layer was dried over MgSO4, filtered, then concentrated to provide the title compound which was used without further purification. 1H NMR (499 MHz, CDCl3): δ 7.74 (d, J=7.9 Hz, 2H); 7.32 (d, =8.2 Hz, 2H); 7.28 (t, J=4.0 Hz, 2H); 7.25-7.15 (m, 2H); 6.88 (brs, 1H); 4.77 (d, 0.1=7.7 Hz, 1H); 4.20 (q, J=7.1 Hz, 2H); 3.75 (q, J=5.9 Hz, 2H); 2.89 (ddd, J=11.1, 7.7, 4.1 Hz, 1H); 2.66 (1, J=5.8 Hz, 2H); 1.47-1.37 (m, 2H); 1.30 (t, J=7.1 Hz, 3H); 1.11 (m, 2H); 0.76 (t, J=7.3 Hz, 3H). LC-MS: LC1 1.14 min. (M+H)+ 418.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]1([C:17]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:25]3[CH2:24][CH2:23][NH:22][CH2:21][C:20]=3[C:19](=[O:26])[O:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl>[CH2:1]([NH:8][C:9]([N:22]1[CH2:23][CH2:24][C:25]2[C:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:18][C:19](=[O:26])[C:20]=2[CH2:21]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2=C1CNCC2
Reactant: O=C=NCc1ccccc1
Solvent: ClCCl
Product: O=C1OC(c2ccccc2)(c2ccccc2)C2=C1CN(C(=O)NCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.7 %

Procedure:
The title compound was synthesized in a manner analogous to R06039-222 except 3-diisopropylamidopyridine was coupled to benzophenone to provide intermediate 1,1-diphenylfuro[3,4-c]pyridin-3-one. 1,1-diphenylfuro[3,4-c]pyridin-3-one was reduced in a manner analogous to 3,3-diphenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (compound 2) to afford 1,1-diphenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-3-one. Benzyl isocyanate (0.023 g, 0.17 mmol) was then added to a solution of 1,1-diphenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-3-one (0.05 g, 0.17 mmol) in dichloromethane (10 mL) and was stirred at room temperature for 1 h. The solvent was removed and the resulting residue was purified on silica to give the desired product (0.038 g, 50%). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.66-3.70 (dd, 2H, J=6 Hz), 4.10-4.15 (m, 2H), 4.34-4.42 (dd, 2H, J=6 Hz), 5.09 (t, 1H, J=6 Hz), 7.20-7.38 (m, 15H).
Reaction SMILES: Cl.[C:2]([NH:6][OH:7])([CH3:5])([CH3:4])[CH3:3].C[O-].[Na+].[Cl:11][C:12]1[C:13]([OH:21])=[C:14]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[CH:15]=O>CO.Cl>[Cl:11][C:12]1[C:13]([OH:21])=[C:14]([CH:15]=[N+:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[O-:7])[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: O=Cc1cc(Cl)cc(Cl)c1O
Reactant: CC(C)(C)NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[N+]([O-])=Cc1cc(Cl)cc(Cl)c1O
Yield: 97.1 %

Procedure:
To a solution of tert-butylhyroxylamine hydrochloride (1.5 eq.) and sodium methoxide (1.2 eq.) in MeOH was added 3,5-dichloro-2-hydroxybenzaldehyde (1 eq.) and 5 drops of 37% HCl. The resulting solution was refluxed over molecular sieves (40 g) until no more aldehyde was detected by TLC. The mixture was then cold filtered to remove molecular sieves and sodium chloride, and rinsed with CH2Cl2. The solvent was removed in vacuo and the title compound was isolated in 97.1% yield as a yellow crystalline solid, m.p. 102.9° C. (Rf=0.33 on a silica gel plate using 7:3 hexanes/EtOAc as an eluant).
Reaction SMILES: Br.Br[CH2:3][C:4]1[N:5]=[C:6]2[C:11](=[N:12][CH:13]=1)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]2[NH2:15].Cl.[C:17]([O:21][C:22](=[O:37])[CH:23]([NH2:36])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][CH:26]=1)([CH3:20])([CH3:19])[CH3:18].C(N(C(C)C)C(C)C)C.C(=O)(O)[O-]>CN(C)C(=O)C>[C:17]([O:21][C:22](=[O:37])[CH:23]([NH:36][CH2:3][C:4]1[N:5]=[C:6]2[C:11](=[N:12][CH:13]=1)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]2[NH2:15])[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:29][CH:30]=1)([CH3:18])([CH3:20])[CH3:19]
Reactant: Nc1nc(N)c2nc(CBr)cnc2n1
Reactant: CC(C)(C)OC(=O)C(N)Cc1ccc(OC(C)(C)C)cc1
Agent: Br
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C(Cc1ccc(OC(C)(C)C)cc1)NCc1cnc2nc(N)nc(N)c2n1
Temperature: 50 °C
Reaction time: 4 h
Yield: 37.8 %

Procedure:
To a solution of 6-bromomethyl-2,4-pteridinediamine hydrobromide (53.7 mg, 0.1598 mmol) in anhydrous N,N dimethylacetamide was added 2-amino-3-(4-tert-butoxy-phenyl)-propionic acid tert-butyl ester hydrochloride (51.58 mg, 0.1758 m mol). Under positive pressure of Argon, iPr2EtN (33.69 ul) was added. The reaction mixture was stirred at 50° C. for 4 hrs and then at room temperature overnight. The crude product was poured into saturated bicarbonate solution. The resulted precipitate was collected and purified by preparative HPLC. 27.6 mg product was obtained. Yield: 41%; 1H NMR (500 MHz, DMSO-d6): δ 1.22491(s, 9H), 1.26835 (s, 9H), 2.921–2.971 (m, 2H), 4.130 (b, 1H), 4.427(s, 2H), 6.91485–6.93165(d, J=8.4 Hz, 2H), 7.16037–7.17723(d, J=8.43 Hz, 2H), 8.89353 (s, 1H); 9.13119 (s, 2H), 9.30829 (s, 2H); ESI-MS: m/z 468 (M++1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12][C:13]#[N:14].[CH2:15](N)[CH2:16][NH2:17]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:11])[F:9])=[CH:4][C:3]=1[CH2:12][C:13]1[NH:17][CH2:16][CH2:15][N:14]=1
Reactant: NCCN
Reactant: N#CCc1cc(C(F)(F)F)ccc1F
Product: Fc1ccc(C(F)(F)F)cc1CC1=NCCN1

Procedure:
2-(2-Fluoro-5-trifluoromethyl-benzyl)-4,5-dihydro-1H-imidazole was prepared from (2-fluoro-5-trifluoromethyl-phenyl)-acetonitrile and ethylene diamine in analogy to Example 19 b): brown solid; MS (ISP): 247.3 ((M+H)+.).
Reaction SMILES: CCOCC.[C:6]([C:9]1[C:10]([O:29]C)=[CH:11][C:12]([O:27]C)=[C:13]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[N:18]=[CH:17][CH:16]=2)[CH:14]=1)([OH:8])=[O:7].B(Br)(Br)Br>ClCCl>[C:6]([C:9]1[C:10]([OH:29])=[CH:11][C:12]([OH:27])=[C:13]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[N:18]=[CH:17][CH:16]=2)[CH:14]=1)([OH:8])=[O:7]
Reactant: COc1cc(OC)c(-c2ccnn2-c2ccccc2C)cc1C(=O)O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccccc1-n1nccc1-c1cc(C(=O)O)c(O)cc1O

Procedure:
1.6 Ether hydrolysis of “1d” using boron tribromide in dichloromethane under standard conditions gives the compound 5-(5-carboxy-2,4-dihydroxyphenyl)-1-(2-methylphenyl)-1H-pyrazole (“1e”).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13](=[O:20])[C:7]=3[C:8](=O)[NH:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:8]1[C:7]2[C:13](=[O:20])[C:14]3[C:19]([C:6]=2[C:5]2[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=2)[N:9]=1)=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: Cc1ccc2c3c(c(=O)[nH]c2c1)C(=O)c1ccccc1-3
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccc2c3c(c(Cl)nc2c1)C(=O)c1ccccc1-3
Yield: 73.4 %

Procedure:
A mixture of 3-methyl-5H-indeno[2,1-c]quinoline-6,7-dion obtained in reference example 5 (700 mg, 2.7 mmol) and phosphorous oxychloride (10 ml, 107 mmol) was refluxed with heat for 1.5 hours. The reaction mixture was distilled to dryness. To the residue was added water to obtain a crystal precipitated by filtration. The crystal obtained was washed with water and dissolved in chloroform to filter off undissolved substances. Recrystallization from benzene to give 550 mg (yield 73.4%) of the title compound.
Reaction SMILES: CO[C:3]1[CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH:4]=1.[CH2:10]([Mg]Br)[CH3:11].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH2:10]1[C:3]2([CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH2:4]2)[CH2:11]1
Reactant: COC1=CC(=O)CCC1
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Product: O=C1CCCC2(CC2)C1
Temperature: 25 °C
Yield: 32.6 %

Procedure:
3-Methoxy-cyclohex-2-enone (7.8 g, 61.83 mmol) was dissolved in Et2O (100 mL) and titanium tetraisopropoxide (20.1 mL, 68.01 mmol) was added. To the resulting brown solution ethylmagnesium bromide solution (3M, 60 mL, 180 mmol) was added dropwise over 70 minutes. A precipitate formed over the course of the addition. After 2 hours at RT the now dark brown/black reaction mixture was carefully quenched with saturated aqueous NH4Cl. A dark gray precipitate formed and was filtered off over Celite. The aqueous layer was extracted twice with Et2O. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and evaporated. The residue was taken up in Et2O (100 mL) and p-toluenesulfonic acid monohydrate (0.588 g, 3.091 mmol) was added. The resulting brown solution was stirred at RT over the weekend before being evaporated. The remaining brown oil was purified by SiO2 chromatography (330 g SiO2, hexanes/EtOAc 0 to 7% EtOAc) to give 2.5 g of spiro[2.5]octan-5-one as a light yellow liquid (32% yield).
Reaction SMILES: C(OC(=O)[N:7]([CH2:15][CH2:16][CH2:17][O:18][C:19]1[C:24]2[C:25]([CH3:36])=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])[O:27][C:23]=2[CH:22]=[CH:21][CH:20]=1)[CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[CH3:35][O:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:26]1[O:27][C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([O:18][CH2:17][CH2:16][CH2:15][NH:7][CH2:8][C:9]3[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=3)[C:24]=2[C:25]=1[CH3:36]
Reactant: COc1ccccc1-c1oc2cccc(OCCCN(Cc3cccnc3)C(=O)OC(C)(C)C)c2c1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1-c1oc2cccc(OCCCNCc3cccnc3)c2c1C
Yield: 88.5 %

Procedure:
{3-[2-(2-Methoxy-phenyl)-3-methyl-benzofuran-4-yloxy]-propyl}-pyridin-3-ylmethyl-carbamic acid tert-butyl ester (24 mg) was treated in 10% trifluoroacetic acid in dichloromethane at room temperature for 18 hours. The mixture was washed with saturated sodium bicarbonate solution and the organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the residue was purified by silica gel TLC (dichloromethane-methanol=10:1) to give a pale yellow oil (17 mg, 88%). FAB-MS: m/z 402 (MH+); 1H-NMR (CDCl3) δ: 2.07 (2H, tt, J=6.6 Hz, 5.9 Hz), 2.28 (3H, s), 2.90 (2H, t, 6.6 Hz), 3.84 (3H, s), 3.85 (2H, s), 4.17 (2H, t, J=5.9 Hz), 6.61 (1H, d, J=7.6 Hz), 6.95-7.23 (5H, m), 7.40 (1H, dt, J=7.6 Hz, 1.7 Hz), 7.46 (1H, dd, J=7.6, 1.7 Hz), 7.67 (1H, d, J=7.4 Hz), 8.48 (1H, d, J=3.0 Hz), 8.56 (1H, s).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[C:7]([OH:21])=[N:8][C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:10][C:11]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:9]2[N:8]=[C:7]([OH:21])[C:6]3[N:5]=[C:1]([SH:2])[O:12][C:11]=3[N:10]=2)=[CH:15][CH:16]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1c(O)nc(Cc2ccc(Cl)cc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Oc1nc(Cc2ccc(Cl)cc2)nc2oc(S)nc12
Temperature: 5 °C
Reaction time: 2 h

Procedure:
3 ml of thiophosgene were added slowly to a suspension of 9.65 g of 5-amino-2-(4-chloro-benzyl)-pyrimidine-4,6-diol and 5.3 g of potassium carbonate in 75 ml of N-methyl-pyrrolidin-2-one (NMP) while maintaining the temperature below 10° C. The reaction mixture was stirred for 2 h at 0-10° C. Then 300 ml of water were added and the resulting solution was extracted three times with 200 ml of dichloromethane and three times with 200 ml of a mixture of dichloromethane and isopropanol (3:1). The combined organic phases were dried over sodium sulfate and filtered. The solvents were removed in vacuo to yield approximately 7 g of 5-(4-chloro-benzyl)-2-mercapto-oxazolo[5,4-d]pyrimidin-7-ol as a solution in NMP. 45 ml of NMP and a solution of 2.38 g of sodium hydroxide in 64 ml of water were added at 0° C., and the mixture was stirred for 30 min at 0° C. while the color changed to brown. Then a solution of 1.5 ml of iodomethane in 1.5 ml of NMP was added dropwise. After stirring at 0° C. for 90 min the reaction was complete. The solution was extracted twice with 80 ml of ethyl acetate, and the combined organic phases were dried over sodium sulfate and filtered. The solvents were removed in vacuo to yield 2.2 g of the title compound as a brown solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]3[O:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][CH2:20][CH2:21][CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:33]=[CH:34][C:35](=[O:38])[NH:36][N:37]=2)=[CH:28][CH:27]=1)(=[O:25])=[O:24]>>[CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][CH2:22][S:23]([C:26]3[CH:27]=[CH:28][C:29]([C:32]4[CH2:33][CH2:34][C:35](=[O:38])[NH:36][N:37]=4)=[CH:30][CH:31]=3)(=[O:24])=[O:25])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: NCCCS(=O)(=O)c1ccc(-c2ccc(=O)[nH]n2)cc1
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CC1
Product: O=C1CCC(c2ccc(S(=O)(=O)CCCNCC(O)COc3ccc(CCOCC4CC4)cc3)cc2)=NN1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-cyclopropylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[4-(3-aminopropylsulphonyl)phenyl]-3(2H)-pyridazinone.
Reaction SMILES: [C:1]([CH2:4][CH:5]([CH3:11])[S:6][C:7](=[N:9][OH:10])[CH3:8])(=[O:3])[NH2:2].[CH3:12][N:13]=[C:14]=[O:15]>C(N(CC)CC)C.CC(C)=O>[CH3:12][NH:13][C:14]([O:10][N:9]=[C:7]([S:6][CH:5]([CH3:11])[CH2:4][C:1](=[O:3])[NH2:2])[CH3:8])=[O:15]
Reactant: CN=C=O
Reactant: CC(=NO)SC(C)CC(N)=O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CNC(=O)ON=C(C)SC(C)CC(N)=O
Reaction time: 48 h
Yield: 75 %

Procedure:
A mixture of 3.0 g (0.017 m) of 1-(2-carbamoyl-1-methylethylthio)acetaldoxime, 200 ml. of dry acetone, 3.0 g. (0.053 m) of methyl isocyanate, and two drops of triethylamine was allowed to stand at room temperature, with occasional shaking, for two days. The acetone and excess methyl isocyanate was removed from the product under reduced pressure. The white solid residue was recrystallized from isopropanol and dried at room temperature to give 3.0 g (75% yield) of 1-(2-carbamoyl-1-methylethylthio)acetaldehyde O-(methylcarbamoyl)oxime; melting point=119-121. The nmr spectra confirmed the structure.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:22])[CH3:21])=[N:17][CH:18]=1.[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:20]([NH:19][C:16]1[CH:15]=[CH:14][C:13]([CH3:12])=[CH:18][N+:17]=1[O-:9])(=[O:22])[CH3:21]
Reactant: CC(=O)Nc1ccc(C)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
m-CPBA (75% in H2O, 89.6 g, 390 mmol) was added portion wise to a stirred solution of N-(5-methylpyridin-2-yl)acetamide (45.0 g, 300 mmol) in DCM (2.7 L) at rt, and the mixture stirred at rt for 4 h. 5% aqueous Na2SO3 (200 mL) was added slowly, the phases were separated and the organic layer washed with saturated NaHCO3, brine (100 mL), dried (MgSO4) and filtered. After concentration in vacuo purification by gradient column chromatography eluting with 2-5% MeOH in DCM yielded the title compound (37.5 g, 243 mmol) as a pale yellow solid.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3].[NH2:25][CH:26]([CH2:29][OH:30])[CH2:27][OH:28]>>[OH:28][CH2:27][CH:26]([NH:25][CH2:12][C:9]1[C:10](=[O:11])[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[N:6]=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:8]=1)[CH2:29][OH:30]
Reactant: NC(CO)CO
Reactant: Cc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1
Product: Cc1ccc(-c2cc(CNC(CO)CO)c(=O)n(CC(C)C)n2)cc1
Yield: 83.7 %

Procedure:
Following the procedure of Example 1(10), 2-isobutyl-4-methanesulfonyloxymethyl-6-(4-methylphenyl)-2H-pyridazin-3-one and 2-amino-1,3-propanediol were reacted to yield the title compound as colorless needles (yield: 83.7%).
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH:7]([CH2:9][CH2:10][CH2:11][CH3:12])[O:6][C:5]1=[O:13])(=O)[CH3:2].[OH-].[Na+].C(=O)[C:17]1[CH:22]=[CH:21]C=[CH:19][CH:18]=1>>[C:2]1([CH:1]=[C:4]2[CH2:8][CH:7]([CH2:9][CH2:10][CH2:11][CH3:12])[O:6][C:5]2=[O:13])[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: CCCCC1CC(C(C)=O)C(=O)O1
Agent: [Na+]
Agent: [OH-]
Product: CCCCC1CC(=Cc2ccccc2)C(=O)O1

Procedure:
3-Phenylmethylene-5-butyldihydro-2(3H)-furanone was prepared by reacting 3-acetyl-5-butyldihydro-2(3H)-furanone with sodium hydroxide and benzaldehyde in accordance with the procedure described in Example I. The crude product (64.5% yield) was recovered by distillation of the reaction mixture at 25°-147° C. (0.04 mm/Hg) to remove light ends. The structure was confirmed by proton nuclear magnetic resonance spectroscopy. 1HNMR (CDCl3) δ7.5 (m,6H), 4.56 (pentet,1H),3.3 (ddd,1H) 2.8 (ddd,1H) 1.9-1.2 (m,6H), 0.86(t,3H)