Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Li+].CC([N-]C(C)C)C.Br[CH2:28][CH2:29][C:30]#[N:31]>C1COCC1>[C:30]([CH2:29][CH2:28][C:11]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]1)#[N:31]
Reactant: N#CCCBr
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CCC#N)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
To a solution of ethyl N-Boc-piperidine-4-carboxylate (10.0 g, 38.86 mmol) in THF (200 mL) was added LDA (2 M solution in Hexane, 38.86 mL, 77.72 mmol) at −78° C. and stirred for 30 min. 3-bromo propionitrile (6.25 g, 46.63 mmol) was then added at −78° C. The resulting reaction mixture was stirred at −60° C. for 4 h and quenched with saturated NH4Cl solution. Ethyl acetate was added and the organic layer was extracted with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography using 10% ethyl acetate in hexane to yield the title compound as a pale yellow liquid (5.0 g, 40%). [1H-NMR (DMSO-d6, 300 MHz): δ 4.15 (q, 2H), 3.78-3.54 (m, 2H), 2.93-2.72 (m, 2H), 2.43 (t, 2H), 2.02-1.78 (m, 4H), 1.45-1.29 (m, 11H), 1.22 (t, 3H); HPLC RtA=4.703 min (93%); LCMS RtA=1.881, [M+H-Boc]+=211.1].
Reaction SMILES: [CH2:1]([NH:5][C:6]1[NH:11][C:10](=O)[CH:9]=[C:8]([CH3:13])[N:7]=1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:16])=O.[OH-].[Na+]>O>[CH2:1]([NH:5][C:6]1[N:11]=[C:10]([Cl:16])[CH:9]=[C:8]([CH3:13])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCNc1nc(C)cc(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCNc1nc(C)cc(Cl)n1
Yield: 88 %

Procedure:
2-Butylamino-6-methylpyrimidin-4-one (8.4 g, 0.046M) was treated with phosphorus oxychloride (5 ml). A vigorous reaction ensued. When this had subsided, the resultant mixture was heated at 90° C. for 30 minutes. This gave an orange coloured syrup which was cooled and added to water to decompose the excess phosphorus oxychloride. The aqueous solution was adjusted to pH 7 using 2M sodium hydroxide solution. The resultant white precipitate was extracted with methylene chloride. The extracts were dried (MgSO4) and the solvent evaporated to give 2-butylamino-4-chloro-6-methylpyrimidine (8.1 g) as a solid, m.p. 35°-36° C., in 88% yield.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:20]([NH:24][CH2:25][C:26]#[N:27])[CH2:21][CH2:22][CH3:23]>>[CH2:20]([N:24]([CH2:25][C:26]#[N:27])[C:15](=[O:16])[C:14]1[CH:18]=[CH:19][C:11]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[CH:12][CH:13]=1)[CH2:21][CH2:22][CH3:23]
Reactant: O=C(O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Reactant: CCCCNCC#N
Product: CCCCN(CC#N)C(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1

Procedure:
The title compound was prepared from 4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-benzoic acid (which was obtained in Example 150) (0.37 g, 1.4 mmol) and (n-butylamino)acetonitrile (0.48 g, 4.2 mmol) according to the procedure shown for Example 154 to give 0.52 g of an amber gum; MS (ES) m/z: 358.3 (MH+); HRMS (ES) Calcd. for C20H28N3O3 (MH+): 358.2125. Found: 358.2120.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:11])[NH:4][C:3]1=[O:12].Cl[CH2:15][CH2:16][O:17]C1CCCCO1>>[OH:17][CH2:16][CH2:15][N:4]1[C:5]2[C:10](=[C:9]([CH3:11])[CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:13])([CH3:1])[C:3]1=[O:12]
Reactant: Cc1cccc2c1C(C)(C)C(=O)N2
Reactant: ClCCOC1CCCCO1
Product: Cc1cccc2c1C(C)(C)C(=O)N2CCO

Procedure:
Prepared from 3,3,4-trimethyl-1,3-dihydro-2H-indol-2-one (prepared by the method of Endler and Becker; Organic Syntheses Coll. vol.4, page 657) and 2-(2-chloroethoxy)tetrahydro-2H-pyran as described above.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[Cl-:9].[Cl-].[Cl-].[Al+3].ClCl>>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][C:7]=1[Cl:9]
Reactant: [Cl-]
Reactant: Clc1ccc(Cl)nn1
Agent: ClCl
Agent: [Al+3]
Product: Clc1cc(Cl)c(Cl)nn1
Yield: 145.7 %

Procedure:
44 g 3,6-dichloropyridazine and 22 g aluminium trichloride are heated to 140° C. At this temperature 10.6 l chlorine are piped into the reaction mixture over a period of 4 hours. After cooling the product is extracted with toluene, washed with a 10% sodium chloride solution and distilled (bp=127-129° C.). 44.1 g of product are obtained.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2([CH3:39])[CH2:38][O:37]2)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[N:9]([CH2:39][C:36]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)([OH:37])[CH3:38])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CC1(c2ccc(F)cc2)CO1
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CC(C)(O)c3ccc(F)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 80 °C
Reaction time: 16 h
Yield: 64.6 %

Procedure:
A mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (2 g), 2-(4-fluorophenyl)-2-methyloxirane (1.2 g), potassium carbonate (1.4 g) and DMF (20 mL) was stirred at 80° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (1.8 g, 66%).
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1.[NH:17]1[CH2:20][CH2:19][CH2:18]1>CCO>[CH3:16][S:13]([C:10]1[CH:11]=[CH:12][C:6]2[CH2:5][O:4][CH:3]([CH2:2][N:17]3[CH2:20][CH2:19][CH2:18]3)[O:8][C:7]=2[CH:9]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc2c(c1)OC(CBr)OC2
Reactant: C1CNC1
Solvent: CCO
Product: CS(=O)(=O)c1ccc2c(c1)OC(CN1CCC1)OC2

Procedure:
Preparation according to Example 22 using 2-(bromomethyl)-7-(methylsulfonyl)-4H-1,3-benzodioxine (30 mg, 0.10 mmol), azetidine (0.10 ml, 1.5 mmol) and EtOH (1.0 ml). MS m/z (rel. intensity, 70 eV) 283 (M+, 1), 123 (4), 77 (6), 71 (5), 70 (bp).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]2[C:17](=O)[O:18][C:19](=[O:31])[C:20]=2[C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH3:30])[CH:22]=2)=[CH:8]1)=[N+:2]=[N-:3].C[N:34](C=O)C>N>[N:1]([CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]2[C:17](=[O:18])[NH:34][C:19](=[O:31])[C:20]=2[C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH3:30])[CH:22]=2)=[CH:8]1)=[N+:2]=[N-:3]
Reactant: Cn1cc(C2=C(c3cn(CCCN=[N+]=[N-])c4ccccc34)C(=O)OC2=O)c2ccccc21
Reactant: CN(C)C=O
Agent: N
Product: Cn1cc(C2=C(c3cn(CCCN=[N+]=[N-])c4ccccc34)C(=O)NC2=O)c2ccccc21

Procedure:
A solution of 2.50 g of 3-[1-(3-azidopropyl)-3-indolyl]-4-(1-methyl-3-indolyl)furan-2,5-dione in 13 ml of DMF and 18 ml of 33% aqueous ammonia was heated to 140° C. for 4 hours. The product was filtered off from the cooled mixture to give 2.27 g of 3-[1-(3-azidopropyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 222°-224° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]=[C:8]=[O:9])=[O:5])[CH3:2].[NH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:5])[CH2:6][NH:7][C:8]([NH:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)=[O:9])[CH3:2]
Reactant: N#Cc1ccc(N)cc1
Reactant: CCOC(=O)CN=C=O
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)Nc1ccc(C#N)cc1
Reaction time: 168 h
Yield: 74.6 %

Procedure:
To a solution of ethoxycarbonylmethyl isocyanate (24.5 ml, 0.212 mol) in DMF (100 ml) a solution of 4-aminobenzonitrile (25 g, 0.212 mol) in DMF (100 ml) was added within 30 min at 0° C. Stirring was continued for 7 d and additional ethoxycarbonylmethyl isocyanate was added periodically (18.5 ml, 0.156 mol). The solvent was removed in vacuo and the residue was stirred in ethyl acetate/diethyl ether. The mixture was filtered to give the title compound (39.12 g, 74%; white solid of m.p. 140-144° C.) which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([C:8]2[N:16]3[C:11]([CH:12]=[CH:13][CH:14]=[CH:15]3)=[C:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:27]([C:31]1[CH:36]=[CH:35][C:34]([CH:37]([C:39]2[CH:44]=[CH:43][C:42]([CH2:45][CH:46]([CH3:48])[CH3:47])=[CH:41][CH:40]=2)Cl)=[CH:33][CH:32]=1)[CH:28]([CH3:30])[CH3:29].C(N(C(C)C)CC)(C)C>ClCCl>[CH2:45]([C:42]1[CH:43]=[CH:44][C:39]([CH:37]([C:34]2[CH:35]=[CH:36][C:31]([CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:32][CH:33]=2)[O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([C:8]3[N:16]4[C:11]([CH:12]=[CH:13][CH:14]=[CH:15]4)=[C:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=3)=[O:7])=[CH:25][CH:26]=2)=[CH:40][CH:41]=1)[CH:46]([CH3:48])[CH3:47]
Reactant: CCOC(=O)CCCc1cc(C(=O)c2ccc(O)cc2)n2ccccc12
Reactant: CC(C)Cc1ccc(C(Cl)c2ccc(CC(C)C)cc2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCc1cc(C(=O)c2ccc(OC(c3ccc(CC(C)C)cc3)c3ccc(CC(C)C)cc3)cc2)n2ccccc12
Yield: 22 %

Procedure:
A mixture of ethyl 4-[3-(4-hydroxybenzoyl]indolizin-1-yl]butyrate (400 mg), bis(4-isobutylphenyl)chloromethane (430 mg) and diisopropylethylamine (736 mg) in dichloromethane (20 ml) was refluxed for 14 hours and evaporated. The residue was dissolved in ethyl acetate. The solution was washed with water and brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel eluting with n-hexane and ethyl acetate (4:1) to give ethyl 4-[3-[4-[bis(4-isobutylphenyl)methoxy]benzoyl]indolizin-1-yl]butyrate (158 mg) as an oil.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH3:18][O:19][CH:20]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][O:33][CH:34]1CCCC[O:35]1)C(OCC)=O.O>CO>[CH3:18][O:19][CH:20]1[C:26]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:32][O:33][C:34]1=[O:35]
Reactant: CCOC(=O)C(OC)c1ccccc1COC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CO
Product: COC1C(=O)OCc2ccccc21
Temperature: 25 °C
Yield: 74.2 %

Procedure:
Pyridinium p-toluenesulfonate (0.30 g) was added to a solution of ethyl α-methoxy-2-(tetrahydropyran-2-yloxy-methyl)phenylacetate (14.00 g, 45.4 mmol) in methanol (50 ml), and the mixture was heated under reflux for 1 hour. The mixture was cooled to room temperature, and water (50 ml) was added. The mixture was extracted with methylene chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by recrystallization from n-hexane/ethyl acetate (=1/1) to give the desired compound 4-methoxy-3-isochromanone (6.00 g, 74.2%) as white crystals.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][N:6]([CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:7](=[O:19])[CH2:8][CH2:9][N:10]1[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[NH:13][C:11]1=[O:12])C.[OH-].[Na+]>CO>[C:23]([NH:22][CH2:21][CH2:20][N:6]([C:7](=[O:19])[CH2:8][CH2:9][N:10]1[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[NH:13][C:11]1=[O:12])[CH2:5][C:4]([OH:30])=[O:3])([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24]
Reactant: CCOC(=O)CN(CCNC(=O)OC(C)(C)C)C(=O)CCn1cc(C)c(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cn(CCC(=O)N(CCNC(=O)OC(C)(C)C)CC(=O)O)c(=O)[nH]c1=O
Reaction time: 1 h

Procedure:
N—(N′—BOC-aminoethyl)-N-[(1-thyminyl)propanoyl]glycine ethyl ester (0.83 g, 0.00195 mol) was dissolved in methanol (25 mL). Sodium hydroxide (2 M, 25 mL) was added. The solution was stirred for 1 h. The methanol was removed by evaporation in vacuo, and the pH adjusted to 2 with 4 M hydrochloric acid at 0° C. The product was isolated by filtration, washed with ether (3×15 mL), and dried over sicapent, in vacuo. Yield: 0.769 g, 99%). M.p. 213° C. (decomp.).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:8][CH2:9][NH2:10])[CH:4]=[C:5]([CH3:7])[N:6]=1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH:19]=O)=[CH:13][CH:12]=1>>[CH3:7][C:5]1[N:6]=[C:2]([CH3:1])[N:3]2[CH2:8][CH2:9][NH:10][CH:19]([CH2:18][CH2:17][C:14]3[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=3)[C:4]=12
Reactant: Cc1cn(CCN)c(C)n1
Reactant: Cc1ccc(CCC=O)cc1
Product: Cc1ccc(CCC2NCCn3c(C)nc(C)c32)cc1

Procedure:
Prepared according to the previously described general procedure (GP11) by reaction of 2-(2,4-dimethyl-imidazol-1-yl)-ethylamine with 3-p-tolyl-propionaldehyde. LC-MS: tR=0.57 min.; [M+H]+=270 g/mol.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].[I-:13].[K+].CC(C)=O>O>[I:13][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4]
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(C(=O)CI)cc1
Yield: 94 %

Procedure:
A mixture of 2-bromo-1-(4'-methoxy-phenyl)-ethanone (22.9 g, 0.1 mol), potassium iodide (66.4 g, 0.4 mol) and acetone (200 ml) is heated at reflux for 3 h. The reaction mixture is cooled, poured into water (0.25 l) and extracted with ethyl ether (3×100 ml) The combined organic extract is washed with water and dried (Na2SO4). Evaporation of the solvent in vacuo leaves a residue which by crystallization from petroleum ether gives 2-iodo-1-(4'-methoxy-phenyl)-ethanone (22 g, 0.094 mol, yield 80%), m.p. 63°-65° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7](Cl)=[O:8])[O:5][CH:6]=1.Cl.[CH3:11][NH:12][O:13][CH3:14].C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:14][O:13][N:12]([CH3:11])[C:7]([C:4]1[O:5][CH:6]=[C:2]([Br:1])[CH:3]=1)=[O:8]
Reactant: CNOC
Reactant: O=C(Cl)c1cc(Br)co1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(Br)co1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.9 %

Procedure:
The crude 4-bromofuran-2-carbonyl chloride (157 mmol theoretical) was dissolved in CH2Cl2 (500 mL) in a 1 L round bottomed flask. The flask was immersed in an ice bath and N,O-dimethyl-hydroxylamine hydrochloride (19.5 g, 200 mmol) was added. The cold suspension was then treated with N,N-diisopropylethylamine (75 mL, 430 mmol), and a small amount of 4-(N,N-dimethylamino)pyridine (catalytic). Several minutes after the addition of the 4-(N,N-dimethylamino)pyridine the ice bath was removed and the pale orange solution was allowed to warm to ambient temperature. After standing at ambient temperature for ˜16 hours the pale brown reaction mixture was quenched with water (100 mL) and diluted with CH2Cl2 (500 mL). The layers were separated and the organic layer was washed with 1N HCl (2×100 mL), H2O (100 mL), and saturated NaHCO3 (50 mL). The organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 4-bromo-furan-2-carboxylic acid methoxy-methyl-amide (25.7 g, 70% yield from crude acid) as a pale brown solid. 1H NMR of the material showed it to be very clean. 1H-NMR (400 MHz, CDCl3): δ 7.60 (1H, d, J=0.8 Hz), 7.14 (1H, d, J=0.8 Hz), 3.77 (3H, s), 3.35 (3H, s).
Reaction SMILES: [C:1]1([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=2[N+:23]([O-])=O)[C:17]([NH2:19])=[O:18])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H][H]>O1CCCC1.[Ni]>[NH2:23][C:22]1[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][C:14]=1[O:13][CH2:12][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: NC(=O)c1ccc([N+](=O)[O-])c(OCCc2cccc3ccccc23)c1
Agent: [Ni]
Solvent: C1CCOC1
Product: NC(=O)c1ccc(N)c(OCCc2cccc3ccccc23)c1
Yield: 100.4 %

Procedure:
To a solution of 3-(2-naphthalen-1-yl-ethoxy)-4-nitro-benzamide (0.500 g, 1.48 mmol) in 75 mL of tetrahydrofuran at room temperature was added Raney Nickel (0.50 g). The reaction was pressurized to 50 psi of hydrogen for 18 hours. The reaction was then filtered through celite and washed with tetrahydrofuran. The filtrate was then concentrated in vacuo to dryness to yield 4-amino-3-(2-naphthalen-1-yl-ethoxy)-benzamide 455 mg (100%) of a white solid. 1HNMR(300 MHz, DMSO) 8.26 (d, 1H), 7.99 (d, 1H), 7.98 (d,1H), 7.68(m, 5H), 7.33 (m, 2H), 6.93 (bs, 1H), 6.62 (d, 1H), 4.89 (s, 2H), 5.16 (s, 2H), 4.34 (t, 2H), 3.63 (t, 2H). MS(APCI) m/z 307.1 (M+H).
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:9]2[O:10][C:11]3[C:12](=[O:19])[N:13]([CH2:17][CH3:18])[N:14]=[CH:15][C:16]=3[C:8]=2[C:7]([C:20]([OH:22])=[O:21])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH:31]1[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=[C:33](O)[CH:32]=1.CCN=C=NCCCN(C)C>O1CCCC1>[F:23][CH:2]([F:1])[O:3][C:4]1[C:9]2[O:10][C:11]3[C:12](=[O:19])[N:13]([CH2:17][CH3:18])[N:14]=[CH:15][C:16]=3[C:8]=2[C:7]([C:20]([O:22][C:33]2[CH:32]=[CH:31][C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=2)=[O:21])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCn1ncc2c(oc3c(OC(F)F)ccc(C(=O)O)c32)c1=O
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCn1ncc2c(oc3c(OC(F)F)ccc(C(=O)Oc4ccc([N+](=O)[O-])cc4)c32)c1=O
Temperature: 25 °C
Reaction time: 16.5 h

Procedure:
A mixture of 6-difluoromethoxy-3-ethyl-4-oxo-3,4-dihydrobenzo[4,5]furo[2,3-d]pyridazine-9-carboxylic acid (form step II) (90 mg, 0.276 mmol), triethyl amine (41 mg, 0.415 mmol), p-nitro phenol (43 mg, 0.304 mmol) and EDCI (79 mg, 0.415 mmol) in tetrahydrofuran (3 ml) was stirred at room temp for 16-17 hrs. Progress of reaction was monitored by TLC. At the end, reaction mixture was concentrated under vacuum. Then water (50 ml) was added to reaction mixture and acidified with dilute HCl. The precipitate obtained was filtered and dried in oven. 87 mg buff colored solid was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C@H:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.CS[C:18]1[NH:24][C:22](=[O:23])[CH:21]=[CH:20][N:19]=1>N1C=CC=CC=1>[O:23]=[C:22]1[CH:21]=[CH:20][NH:19][C:18]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[C@H:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:4][CH:3]=2)=[N:24]1
Reactant: C[C@@H]1CC(=O)NN=C1c1ccc(N)cc1
Reactant: CSc1nccc(=O)[nH]1
Solvent: c1ccncc1
Product: C[C@@H]1CC(=O)NN=C1c1ccc(Nc2nc(=O)cc[nH]2)cc1

Procedure:
A stirred mixture of (R)-6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone and 2-methylthiouracil in dry pyridine are heated together to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH2:15][N:16](CC3C=CC=CC=3)[C:17]3[CH:18]=[N:19][C:20]4[C:25]([C:26]=3[CH:27]=2)=[N:24][C:23]([O:28][CH3:29])=[CH:22][CH:21]=4)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[C:1]([O:5][C:6](=[O:37])[NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([CH:14]2[CH2:27][C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:28][CH3:29])[N:24]=4)[N:19]=[CH:18][C:17]=3[NH:16][CH2:15]2)[CH2:12][CH2:13]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc2ncc3c(c2n1)C=C([C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)CN3Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2ncc3c(c2n1)CC([C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)CN3
Temperature: 60 °C
Reaction time: 3 h

Procedure:
10% Palladium on activated carbon (1.20 g, 1.13 mmol, 0.94 eq) is added at room temperature to a stirred solution of [trans-4-(1-benzyl-6-methoxy-1,2-dihydro-1,5,9-triaza-phenanthren-3-yl)-cyclohexyl]-carbamic acid tert-butyl ester (600 mg, 1.20 mmol, 1.0 eq) in ethanol (60 mL). The resulting mixture is stirred under hydrogen flow (1 bar) at 60° C. for 3 hours. The catalyst is then removed by filtration and the solution is concentrated to give the crude product that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate: dichloromethane, 1:3:1, v/v/v) to afford [trans-4-(6-methoxy-1,2,3,4-tetrahydro-1,5,9-triaza-phenanthren-3-yl)-cyclohexyl]-carbamic acid tert-butyl ester as an off-white solid (292 mg, 59% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:25].C1C(=O)N([Br:33])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>ClCCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:15])([F:14])[F:16])[O:10][N:9]=2)=[CH:4][C:3]=1[CH2:25][Br:33]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(Br)c(CBr)c2)=NO1
Yield: 42.5 %

Procedure:
A mixture of 3-(4-bromo-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (100 mg, 0.221 mmol), NBS (62.8 mg, 0.35 mmol) and AIBN (cat.) in 1,2-dichloroethane (10 mL) was refluxed for 3.5 h and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel to give crude 3-(4-bromo-3-(bromomethyl)phenyl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (50 mg, yield 42%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=2[C:34]#[N:35])=[CH:4][C:5](=[O:26])[N:6]([CH:8]([CH3:25])[C:9]([NH:11][C:12]2[CH:24]=[CH:23][C:15]([C:16]([O:18]C(C)(C)C)=[O:17])=[CH:14][CH:13]=2)=[O:10])[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[C:3]([C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=2[C:34]#[N:35])=[CH:4][C:5](=[O:26])[N:6]([CH:8]([CH3:25])[C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:23][CH:24]=2)=[O:10])[CH:7]=1
Reactant: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)Nc1ccc(C(=O)O)cc1)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
281 mg (purity 58%, 0.32 mmol) of tert-butyl 4-({2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate (racemate) (Example 12.1E) were hydrolysed with TFA according to General Method 2. Yield: 97 mg (67% of theory)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:40](=[O:41])[N:12]2[C:13]([C:24]([O:26][CH:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])=[C:14]([CH:18]([O:20][C:21](=[O:23])[CH3:22])[CH3:19])[CH2:15][S:16](=O)[C@H:11]12)=[O:8].P(Cl)(Cl)Cl>CN(C)C=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:40](=[O:41])[N:12]2[C:13]([C:24]([O:26][CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:25])=[C:14]([CH:18]([O:20][C:21](=[O:23])[CH3:22])[CH3:19])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: CC(=O)OC(C)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S(=O)C1
Solvent: ClP(Cl)Cl
Solvent: CN(C)C=O
Product: CC(=O)OC(C)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
To a cooled solution of 0.514 g. of benzhydryl 7-(2-thienylacetamido)-3-(1-acetoxyethyl)-3-cephem-4-carboxylate 1-oxide (isomer II from the previous example) in 15 ml. of dimethylformamide was added 0.190 ml. of phosphorous trichloride. The reaction mixture was removed from the ice-bath and allowed to warm to room temperature at which temperature it was stirred for one hour. The reaction mixture was then transferred with the aid of ethyl acetate to a separatory funnel and was then washed with aqueous sodium bicarbonate solution (2X), and brine (2X) and then dried over anhydrous sodium sulfate. Evaporation in vacuo provided a product which was chromatographed on a silica gel column using a toluene-ethyl acetate gradient to give 0.328 g. (65.5 percent) of the title product as a froth: