Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH2:14])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([CH:34]=O)=[CH:26]1.S([O-])([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>C1(C)C=CC=CC=1.CO>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:34][C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[NH:25][CH:26]=2)[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(c1cc(Cl)cc(Cl)c1)N1CC[C@H](NCc2c[nH]c3ccccc23)C[C@H]1Cc1ccccc1

Procedure:
200 mg (0.551 mmol) of (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine are reacted in analogy to Example 2g with 80 mg (0.551 mmol) of indole-3-carboxaldehyde and 90 mg of magnesium sulfate in 2 ml of toluene and subsequently reduced with 22 mg (0.584 mmol) of sodium borohydride in 2 ml of methanol. The title compound ##STR96## is obtained (75 mg, 28%) as while foam. TLC:methylene chloride/methanol/cone. ammonia (400:50:1) Rf =0.49, FD-MS:M+ =491, 493. IR:3460, 1630 cm-1 .
Reaction SMILES: O[C:2]1[N:3]=[C:4]2[CH:17]=[CH:16][C:15]([NH:18][NH:19][C:20](=O)[C:21]3[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=3)=[N:14][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O=P(Cl)(Cl)[Cl:30]>C(#N)C>[Cl:30][C:2]1[N:3]=[C:4]2[CH:17]=[CH:16][C:15]3=[N:18][N:19]=[C:20]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[N:14]3[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(NNc1ccc2nc(O)c(-c3ccccc3)nc2n1)c1cccnc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Clc1nc2ccc3nnc(-c4cccnc4)n3c2nc1-c1ccccc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a mixture of N′-(2-hydroxy-3-phenylpyrido[2,3-b]pyrazin-6-yl)nicotinohydrazide (3-4) (5.8 g, 16.2 mmol) in acetonitrile (1.3 mL) was added POCl3 (7.5 mL, 81 mmol), and stirred at 100° C. for overnight. The solvent was removed under reduced pressure, and to the residue was added CHCl3 and water. The organic layer was separated, dried (Na2SO4), filtered, and evaporated in vacuo. To the residue was added CHCl3, and the resulting solid was collected by filtration to yield 3-chloro-2-phenyl-9-(3-pyridinyl)[1,2,4]triazolo[4′,3′:1,6]pyrido[2,3-b]pyrazine (3-5) as an orange solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5](O)=[O:6].O.[NH2:13][NH2:14].ON1C=CC=CC1=O.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([NH:13][NH2:14])=[O:6]
Reactant: NN
Reactant: O=C(O)c1ccc(O)c(O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=c1ccccn1O
Solvent: C1CCOC1
Solvent: O
Product: NNC(=O)c1ccc(O)c(O)c1
Reaction time: 16 h

Procedure:
16.9 g (0.11 mol) of 3,4-dihydroxybenzoic acid in 170 ml of tetrahydrofuran are treated with 5 g (0.1 mol) of hydrazine hydrate and 1.1 g (0.01 mol) of 1-hydroxy-2-(1H)-pyridone. A solution of 22.7 g (0.11 mol) of dicyclohexylcarbodiimide in 200 ml of tetrahydrofuran is added to the reaction mixture at 20° within 15 minutes. The reaction mixture is stirred at 20° for 16 hours. The resulting dicyclohexylurea is filtered off and the filtrate is evaporated. The residue is stirred with 60 ml of ethanol at 20° for 2 hours and the crystalline crude product is subsequently filtered off under suction and dried firstly in a water-jet vacuum and then in a high vacuum at 40°, whereby 3,4-dihydroxybenzoic acid hydrazide is obtained as a beige powder.
Reaction SMILES: [CH3:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[N:4][C:3]2[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:2]=2[CH3:1])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Cc1c(N)cccc1Cl
Product: Cc1c(Cl)cccc1N=Cc1ccc(Cl)cc1
Reaction time: 1.5 h

Procedure:
2-methyl-3-chloroaniline (0.25 mole) and 4-chlorobenzaldehyde (0.25 mole) are ground in a mortar. The mixture is heated, with stirring in a water bath for 1.5 hours. Distillation at reduced pressure gives N-(p-chlorobenzylidene)-2-methyl-3-chloroaniline; Bp. 139° C./0/020 mm.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([S:14](Cl)(=[O:16])=[O:15])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].[CH3:18][NH2:19]>>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([S:14](=[O:16])(=[O:15])[NH:19][CH3:18])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CN
Reactant: CC(=O)N1CCc2ccc(S(=O)(=O)Cl)cc2C1
Product: CNS(=O)(=O)c1ccc2c(c1)CN(C(C)=O)CC2

Procedure:
2-Acetyl-7-chlorosulfonyl-1,2,3,4-tetrahydroisoquinoline was reacted with a concentrated aqueous solution of methylamine with cooling. The resulting solid was filtered and washed with water to give 2-acetyl-7-methylsulfamoyl-1,2,3,4-tetrahydroisoquinoline. Hydrolyzing in refluxing 10% hydrochloric acid by the procedure of Example 15 and then recrystallizing from methanol/ether gave 7-methylsulfamoyl-1,2,3,4-tetrahydroisoquinoline hydrochloride, m.p. 238°-240° C.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][C:28]=1[Cl:29])[N:25](COCC[Si](C)(C)C)[N:24]=[C:23]2[NH:38][C:39](=[O:43])[CH2:40][CH2:41][CH3:42].C(OCC)(=O)C>O1CCCC1>[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][C:28]=1[Cl:29])[NH:25][N:24]=[C:23]2[NH:38][C:39](=[O:43])[CH2:40][CH2:41][CH3:42]
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(Br)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1n[nH]c2cc(Cl)c(Br)cc12
Temperature: 67 °C

Procedure:
12.6 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 940 mg of N-[5-bromo-6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 30 cm3 of tetrahydrofuran. The medium is then maintained at 67° C. for 19 hours and is then allowed to return to room temperature and 50 cm3 of ethyl acetate are added. The organic phase is washed with 2×50 cm3 of saturated aqueous sodium hydrogen carbonate solution and then with 50 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2 kPa; 45° C.). The residue is purified by chromatography under an argon pressure of 50-kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with a cyclohexane/ethyl acetate mixture (70/30 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.) and the residue is taken up in 15 cm3 of diisopropyl ether, filtered off on a sinter funnel and washed successively with 5 cm3 of ethyl acetate and then with 2×10 cm3 of diisopropyl ether. After drying (90 Pa; 50° C.), 460 mg of N-(5-bromo-6-chloro-1H-indazol-3-yl)butanamide are obtained in the form of a white solid melting at 250° C.
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH:13]([CH3:15])[CH3:14])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:16])=[N:9]2)=[CH:4][CH:3]=1.[C:17]([Zn]C#N)#[N:18].O.C(OCC)(=O)C>CC(N(C)C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.[Zn]>[CH:13]([O:12][C:11]1[C:2]([C:17]#[N:18])=[CH:3][CH:4]=[C:5]2[C:10]=1[N:9]=[C:8]([CH3:16])[CH:7]=[CH:6]2)([CH3:15])[CH3:14]
Reactant: N#C[Zn]C#N
Reactant: Cc1ccc2ccc(Br)c(OC(C)C)c2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: Cc1ccc2ccc(C#N)c(OC(C)C)c2n1
Temperature: 25 °C
Yield: 140 %

Procedure:
A solution of 7-bromo-8-isopropoxy-2-methylquinoline (1.13 g, 4.03 mmol), PdCl2(dppf) dichloromethane adduct (0.165 g, 0.202 mmol), zinc (0.063 g, 0.97 mmol) and dicyanozinc (0.31 g, 2.62 mmol) in DMA (5 mL) was stirred at 100° C. for 18 hours. After cooling to ambient temperature, water (10 mL) and ethyl acetate (20 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (DCM) to give 8-isopropoxy-2-methylquinoline-7-carbonitrile (0.83 g, 91.1%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2[C:14]3[S:21][CH:20]=[CH:19][C:15]=3[CH2:16][CH2:17][CH2:18][C:12]=2[C:11]([C:22]([O:24]CC)=[O:23])=[N:10]1.[OH-].[Li+].O.Cl>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2[C:14]3[S:21][CH:20]=[CH:19][C:15]=3[CH2:16][CH2:17][CH2:18][C:12]=2[C:11]([C:22]([OH:24])=[O:23])=[N:10]1
Reactant: CCOC(=O)c1nn(-c2ccc(Cl)cc2Cl)c2c1CCCc1ccsc1-2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nn(-c2ccc(Cl)cc2Cl)c2c1CCCc1ccsc1-2
Temperature: 60 °C
Yield: 71.6 %

Procedure:
300 mg of ethyl 1-(2′,4′-dichlorophenyl)-1,4,5,6-tetrahydro-thieno[3′,2′:6,7]cyclohepta[1,2-c]pyrazol-3-carboxylate prepared in example 9e are solubilized in THF/H2O 4:1 (7 mL). Lithium hydroxide (72 mg; 2.7 mmoles) is added and the mixture is heated to 60° C. for 5 hours. After cooling at room temperature, it is diluted first by adding water (5 mL) and then a HCl 1N solution to lower the pH to 1-2. A precipitate is formed which is recovered by filtration and then washed with ethyl ether (2×10 mL). 200 mg of 1-(2′,4′-dichlorophenyl)-1,4,5,6-tetrahydro-thieno[3′,2′:6,7]cyclohepta[1,2-c]pyrazol-3-carboxylic acid are obtained (white solid; yield 72%). Rf=0.76 (chloroform/methanol 9/1 volume/volume); 1H NMR (CDCl3) δ (ppm): 7.58 (d, 1H, ArH), 7.45 (m, 2H, ArH), 7.04 (d, 1H, ArH), 6.80 (d, 1H, ArH), 3.30 (m, 2H, CH2), 3.00 (m, 2H, CH2), 2.07 (m, 2H, CH2); 13C NMR (CDCl3) δ (ppm): 163.4, 143.6, 141.3, 139.3, 137.5, 136.0, 135.0, 131.6, 130.5, 130.2, 128.2, 125.1, 123.8, 122.4, 31.0, 25.9, 24.1; FT-IR (film) νmax: 3078.0, 2929.3, 2854.1, 2715.1, 1683.4, 1450.3, 1386.6, 1251.4, 1204.2, 705.8, 665.3 cm−1.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:12]2[CH2:14][O:13]2)=[CH:4][C:5]2[CH2:9][O:8][C:7](=[O:10])[C:6]=2[CH:11]=1.[O:15]=[C:16]1[CH2:21][NH:20][CH2:19][CH2:18][N:17]1[CH:22]1[CH2:31][CH2:30][C:29]2[CH:28]=[C:27]([C:32]#[N:33])[CH:26]=[CH:25][C:24]=2[CH2:23]1>CCO>[OH:13][CH:12]([C:3]1[C:2]([CH3:1])=[CH:11][C:6]2[C:7](=[O:10])[O:8][CH2:9][C:5]=2[CH:4]=1)[CH2:14][N:20]1[CH2:19][CH2:18][N:17]([CH:22]2[CH2:31][CH2:30][C:29]3[CH:28]=[C:27]([C:32]#[N:33])[CH:26]=[CH:25][C:24]=3[CH2:23]2)[C:16](=[O:15])[CH2:21]1
Reactant: Cc1cc2c(cc1C1CO1)COC2=O
Reactant: N#Cc1ccc2c(c1)CCC(N1CCNCC1=O)C2
Solvent: CCO
Product: Cc1cc2c(cc1C(O)CN1CCN(C3CCc4cc(C#N)ccc4C3)C(=O)C1)COC2=O
Temperature: 140 °C

Procedure:
A mixture of 6-methyl-5-(oxiran-2-yl)-2-benzofuran-1 (3H)-one (22 mg, 0.12 mmol) and 6-(2-Oxopiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (30 mg, 0.12 mmol) in EtOH (2 mL) was heated to 140° C. for 1 hour. The reaction mixture was concentrated to dryness, and dissolved in MeOH, filtered and shot into Mass-directed HPLC for separation to give the title product. LC-MS (IE, m/z): 446 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][CH2:7][C:8]#[C:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[CH:13]=1)[OH:11])[CH3:5])[CH3:2]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:3][CH:4]([O:6][CH2:7][C:8]#[C:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[CH:13]=1)=[O:11])[CH3:5])[CH3:2]
Reactant: CCOC(C)OCC#CC(O)c1ccc2c(c1)OCO2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCOC(C)OCC#CC(=O)c1ccc2c(c1)OCO2
Reaction time: 0.17 h

Procedure:
A solution of 10.9 g 39.2 mmol) of 4-(1-ethoxyethoxy)-1-[3,4-(methylenedioxy)phenyl]-2-butyn-1-ol in 63 ml of methylene chloride was added dropwise at 0° to a suspension of 101 g (1.16 mol) of manganese dioxide in 150 ml of methylene chloride. The reaction mixture was stirred at 0° for 10 minutes, filtered over magnesium sulphate and concentrated. Chromatography of the residue on 300 g of silica gel (elution agent ether/hexane 1:1) yielded 4-(1-ethoxyethoxy)-1-[3,4 -(methylenedioxy)phenyl]2-butyn-1-one as an oil.
Reaction SMILES: [H][H].C([O:8][CH:9]([CH2:17][CH3:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=O)C(C)=C.C(OC(CC)CCCCCCC)(=O)C=C.C1C2C3C=CC(C2C=C1)C3>O>[CH2:13]1[CH:12]2[CH:11]3[CH2:10][CH:9]([OH:8])[CH:17]([CH:16]2[CH:15]=[CH:14]1)[CH2:18]3
Reactant: [H][H]
Reactant: C=C(C)C(=O)OC(CC)CCCCCCC
Agent: C=CC(=O)OC(CC)CCCCCCC
Solvent: C1=CC2C3C=CC(C3)C2C1
Solvent: O
Product: OC1CC2CC1C1C=CCC21

Procedure:
The compound of the formula: ##STR3## wherein Rl is hydrogen or a methyl group, that is, tricyclo-[5.2.1.02,6 ]deca-8-yl methacrylate or tricyclo[5.2.1.02,6 ]-deca-8-yl acrylate, can be prepared by a conventional process for synthesizing a methacrylic or acrylic acid ester. For example, the compound of the formula (I) can be prepared by adding H2O to dicyclopentadiene to give dicyclopentenyl alcohol, which is changed to tricyclo[5.2.1.02,6 ]deca-8-ol by catalytic hydrogenation reaction, followed by ester exchange reaction with methyl methacrylate or methyl acrylate, or condensation reaction with methacrylic acid, acrylic acid, methacrylic acid chloride or acrylic acid chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([N:28]([CH3:38])[C:29]([CH2:31][CH2:32][NH:33]C(=O)C=C)=[O:30])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.NCCC(N(C1C=C2C(=CC=1)N=CN=C2NC1C=CC(OCC2C=CC=C(F)C=2)=C(Cl)C=1)CC)=O>>[NH2:33][CH2:32][CH2:31][C:29]([N:28]([C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][N:19]=[C:18]2[NH:17][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[C:2]([Cl:1])[CH:3]=1)[CH3:38])=[O:30]
Reactant: C=CC(=O)NCCC(=O)N(C)c1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Agent: CCN(C(=O)CCN)c1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Product: CN(C(=O)CCN)c1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1

Procedure:
The procedure of (139-5) of Example 139 was repeated except for using 3-amino-N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-N-ethyl-propionamide instead of the compound obtained in (139-4) of Example 139 to obtain the title compound (15 mg, 5%).
Reaction SMILES: Cl[C:2]1[NH:3][C:4](=[O:12])[C:5]2[CH:10]=[CH:9][N:8]([CH3:11])[C:6]=2[N:7]=1.[N:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C>C(O)C.CO.C(Cl)Cl>[CH3:11][N:8]1[C:6]2[N:7]=[C:2]([N:22]3[CH2:23][CH2:24][N:19]([C:16]4[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=4)[CH2:20][CH2:21]3)[NH:3][C:4](=[O:12])[C:5]=2[CH:10]=[CH:9]1
Reactant: Cn1ccc2c(=O)[nH]c(Cl)nc21
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccc2c(=O)[nH]c(N3CCN(c4ccncc4)CC3)nc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
A solution of 2-chloro-7-methyl-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (Intermediate A) (50.1 mg, 273 μmol) in ethanol (730 μL) was treated with 1-(pyridin-4-yl)piperazine (51.8 mg, 317 μmol) and N,N-diisopropylethylamine (46.7 mg, 63.10 μL, 361 μmol). The reaction stirred at 100° C. overnight. At this time, the reaction was diluted with methanol and methylene chloride and concentrated in vacuo onto Celite®. Flash chromatography (4 g silica gel column, 10% methanol/methylene chloride) afforded 7-methyl-2-(4-pyridin-4-yl-piperazin-1-yl)-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (43 mg, 50.8%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.48 (d, J=4.33 Hz, 4H) 3.57 (s, 3H) 3.69 (d, J=6.03 Hz, 4H) 6.25 (d, J=3.39 Hz, 1H) 6.78 (d, J=3.20 Hz, 1H) 6.91 (d, J=6.97 Hz, 2H) 8.19 (d, J=6.40 Hz, 2H) 10.90 (s, 1H). LC-MS calcd. for C16H19N6O [(M+H)+] 311, obsd. 311.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9](=O)[CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([CH3:4])([CH3:3])[CH3:2].[C:21]([CH:26]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:23][CH2:24][CH3:25])=[O:22]>C1C=CC=CC=1>[CH2:24]([O:23][C:21](=[O:22])[CH:26]=[C:9]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:20])[CH3:25]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)CNC(=O)OC(C)(C)C
Solvent: c1ccccc1
Product: CCOC(=O)C=C(CNC(=O)OC(C)(C)C)CNC(=O)OC(C)(C)C
Temperature: 45 °C
Reaction time: 16 h
Yield: 74.8 %

Procedure:
To a solution of (3-tert-Butoxycarbonylamino-2-oxo-propyl)-carbamic acid tert-butyl ester (28 g, 97.0 mmol) dissolved in benzene (350 ml) was added (carbethoxymethylene)-triphenyl phosphorane (89 g, 0.26 mol) and the reaction mixture stirred for 16 hours at 45° C., under a N2 atmosphere. The mixture was concentrated and purified by column chromatography on silica gel (ethyl acetate:hexane, 1:3, v/v) to afford the product as a yellowish solid (26 g, 75%). 1H NMR (CDCl3) δ 1.43 (s, 18H), 1.59 (s, 3H), 3.90 (d, 2H, J=4.75 Hz), 4.11 (m, 4H), 5.35 (m, 2H), 5.87 (s, 1H).
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:42]1[N:43]=[C:44]([NH:47][CH:48]=[O:49])[S:45][CH:46]=1)[C:12]([NH:14][CH:15]1[C:40](=[O:41])[N:17]2[C:18]([C:24]([O:26]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:25])=[C:19]([CH:22]=[CH2:23])[CH2:20][S:21][C@H:16]12)=[O:13])=[O:7])(C)(C)C.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>C1(OC)C=CC=CC=1.C(Cl)Cl>[C:6]([CH2:8][O:9][N:10]=[C:11]([C:42]1[N:43]=[C:44]([NH:47][CH:48]=[O:49])[S:45][CH:46]=1)[C:12]([NH:14][CH:15]1[C:40](=[O:41])[N:17]2[C:18]([C:24]([OH:26])=[O:25])=[C:19]([CH:22]=[CH2:23])[CH2:20][S:21][C@H:16]12)=[O:13])([OH:7])=[O:5]
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(NC=O)n3)[C@H]2SC1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(NC=O)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
To a solution of benzhydryl 7-[2-tert-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (2.5 g) in anisole (2.5 ml) and methylene chloride (5.0 ml) was added trifluoroacetic acid (10.0 ml) under ice-cooling, and the mixture was stirred at ambient temperature for 2 hours. To the reaction mixture was added dropwise diisopropyl ether, and the precipitated crystals were collected by filtration, washed with diisopropyl ether to obtain 7-[2-carboxymethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (1.57 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]([C:37](=[O:40])[NH:38][OH:39])[CH:16]([OH:36])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=[C:27]([CH3:35])[CH:26]=3)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:36][CH:16]([C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=[C:27]([CH3:35])[CH:26]=2)=[CH:21][CH:22]=1)[CH:15]([CH2:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:37]([NH:38][OH:39])=[O:40]
Reactant: Cc1cc(COc2ccc(C(O)C(CC3CCN(C(=O)OC(C)(C)C)CC3)C(=O)NO)cc2)c2ccccc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(COc2ccc(C(O)C(CC3CCNCC3)C(=O)NO)cc2)c2ccccc2n1
Reaction time: 2 h
Yield: 133.5 %

Procedure:
4-{3-Hydroxy-2-hydroxycarbamoyl-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-propyl}-piperidine-1-carboxylic acid tert-butyl ester (0.05 g, 0.075 mmol) from Example 17 was taken up in methylene chloride (3 mL) and TFA (2 mL) under nitrogen atmosphere at room temperature. The reaction was complete after 2 h, was concentrated, taken up in water (5 mL), and freeze-dried to give the title compound (0.045 g, 88%) as a white solid. MS found: (M+H)+=450.
Reaction SMILES: [F:1][C:2]1[C:3]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[O:26][CH3:27])=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:12][CH:13]4[CH2:17][NH:16][CH2:15][CH:14]4[CH:18]=3)[NH:8][C:5]2=[N:6][CH:7]=1.Br[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].C(N(CC)CC)C.O>CN(C)C=O.[Cl-].[Na+].O>[F:1][C:2]1[C:3]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[O:26][CH3:27])=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:12][CH:13]4[CH2:17][N:16]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:15][CH:14]4[CH:18]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(F)cc1-c1c(F)cnc2[nH]c(C3=CC4CNCC4C3)cc12
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1-c1c(F)cnc2[nH]c(C3=CC4CN(CC(=O)OC(C)(C)C)CC4C3)cc12

Procedure:
A mixture of Example 282A (400 mg, 0.908 mmol), tert-butyl 2-bromoacetate (0.157 mL, 1.090 mmol), and triethylamine (0.633 mL, 4.54 mmol) in N,N-dimethylformamide (7 mL) was heated at 85° C. for 30 minutes in a Biotage Initiator microwave reactor. The mixture was treated with water and brine and extracted with ethyl acetate (twice). The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, concentrated, and purified on silica gel using the ISCO Companion eluting with ethyl acetate/heptanes (7:3 to 8:2) to give the title compound. MS (ESI+) m/z 481.9 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].[CH3:27][O:28][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:38]=1[N:37]=[CH:36][C:35]([NH2:39])=[CH:34]2.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([C:18](=[O:19])[NH:39][C:35]3[CH:36]=[N:37][C:38]4[C:33]([CH:34]=3)=[CH:32][CH:31]=[CH:30][C:29]=4[O:28][CH3:27])=[CH:21][CH:22]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Reactant: COc1cccc2cc(N)cnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cnc5c(OC)cccc5c4)cc3)c(C#N)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
Dissolved 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (0.10 g, 0.29 mmol), 8-methoxyquinolin-3-amine (0.050 g, 0.29 mmol), and HOAT (0.039 g, 0.29 mmol) in dry DMF (1 mL) at ambient temperature. EDCI (0.049 g, 0.32 mmol) was added and the mixture stirred at ambient temperature overnight. The reaction was diluted with excess water, acidified with 10% HCl and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel column chromatography eluting with 2-5% methanol/dichloromethane to provide the desired product (0.061 g, 42%) as a colorless foam.