Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:3]=1[C:4](OC1C=CC=CC=1)=O.[NH2:21][C:22]1[S:23][CH:24]=[C:25]([C:27]([O:29][CH3:30])=[O:28])[N:26]=1.CO>C1(C)C(C)=CC=CC=1>[CH3:30][O:29][C:27]([C:25]1[N:26]=[C:22]([NH:21][CH2:4][C:3]2[CH:13]=[C:14]([O:19][CH3:20])[C:15]([O:17][CH3:18])=[CH:16][C:2]=2[OH:1])[S:23][CH:24]=1)=[O:28]
Reactant: COC(=O)c1csc(N)n1
Reactant: COc1cc(O)c(C(=O)Oc2ccccc2)cc1OC
Solvent: CO
Solvent: Cc1ccccc1C
Product: COC(=O)c1csc(NCc2cc(OC)c(OC)cc2O)n1
Temperature: 140 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
In 250 mg of xylene were suspended 250 mg of phenyl 2-hydroxy-4,5-dimethoxybenzoate (3a) and 144 mg of methyl 2-amino-1,3-thiazole-4-carboxylate (4a) in a stream of argon, which was then heated to reflux (at 140° C.) for 7 hours. The reaction was not completed. After cooling, methanol was added, followed by stirring for one hour. The precipitated crystal was collected by filtration and dried under reduced pressure at 60° C. to provide 170 mg of the same compound (5a) as that of Example 4 at a yield of 55%.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:28].[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:37])=[C:34]([OH:36])[CH:35]=1>C1COCC1>[OH:36][C:34]1[CH:35]=[C:30]([NH:29][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]5[S:24][CH:25]=[CH:26][CH:27]=5)=[O:22])=[CH:16][CH:15]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:28])[CH:31]=[CH:32][C:33]=1[CH3:37]
Reactant: Cc1ccc(N)cc1O
Reactant: O=C1Nc2cc(C(=O)c3ccc(NC(=O)c4cccs4)cc3)ccc2C1=CO
Solvent: C1CCOC1
Product: Cc1ccc(NC=C2C(=O)Nc3cc(C(=O)c4ccc(NC(=O)c5cccs5)cc4)ccc32)cc1O
Temperature: 65 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
A small screw cap test tube was charged with Thiophene-2-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 20, 100 mg, 0.257 mmol) and THF (2 mL). To the resulting solution was added 5-amino-2-methylphenol (34.7 mg, 0.282 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 70% (89 mg, 0.180 mmol) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[C:9]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=2[Cl:18])=[C:8]([Cl:19])[C:7]([NH2:20])=[N:6][CH:5]=1.Cl[CH:23]([CH:26]=O)[CH:24]=[O:25]>>[CH3:1][O:2][C:3]([C:4]1[C:9]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=2[Cl:18])=[C:8]([Cl:19])[C:7]2[N:6]([C:23]([CH:24]=[O:25])=[CH:26][N:20]=2)[CH:5]=1)=[O:21]
Reactant: COC(=O)c1cnc(N)c(Cl)c1Nc1ccc(Br)cc1Cl
Reactant: O=CC(Cl)C=O
Product: COC(=O)c1cn2c(C=O)cnc2c(Cl)c1Nc1ccc(Br)cc1Cl
Temperature: 80 °C

Procedure:
A suspension of 6-amino-4-(4-bromo-2-chlorophenylamino)-5-chloro-nicotinic acid methyl ester (28) (1.06 g, 2.72 mmol) and 2-chloro-malonaldehyde (587 mg, 5.43 mmol) was heated to 80° C. for 45 minutes. The solution was allowed to cool to room temperature, and then washed with saturated aqueous NaHCO3, and brine. The organic layer was dried over NaSO4, filtered, concentrated in vacuo, and purified by column chromatography (20:1 methylene chloride/methanol) to give the desired product as a dark yellow solid. The solid was triturated with ethyl acetate and isolated by filtration to provide the desired product as a yellow solid (0.436 g, 36%). MS (APCI+) m/z 442, 444, 446 (M+; Cl, Br pattern) detected.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[CH:30])=[N:27][CH:28]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[C:30][C:2]3[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][N:11]4[CH2:15][CH2:14][CH2:13][CH2:12]4)=[CH:4][CH:3]=3)=[N:27][CH:28]=2)=[CH:21][CH:22]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Ic1ccc(NCCN2CCCC2)cc1
Product: Clc1ccc(-c2ccc(C#Cc3ccc(NCCN4CCCC4)cc3)nc2)cc1

Procedure:
Prepared according to general working method I from (4-iodo-phenyl)-(2-pyrrolidin-1-yl-ethyl)-amine (450 mg, 1.42 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (450 mg, 2.11 mmol).
Reaction SMILES: N1C=CN=C1.Cl.[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[C:8]1[CH:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1C)[N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.S(Cl)([Cl:31])=O.O1C2C=CC=CC=2C=C1C(C1C=CC=CC=1)O>C(#N)C>[ClH:31].[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[C:8]1[CH:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: Cc1ccccc1C(c1cc2ccccc2o1)n1ccnc1
Reactant: O=S(Cl)Cl
Agent: Cl
Agent: OC(c1ccccc1)c1cc2ccccc2o1
Agent: c1c[nH]cn1
Solvent: CC#N
Product: c1ccc(C(c2cc3ccccc3o2)n2ccnc2)cc1
Reaction time: 1 h

Procedure:
To 0.08 moles of imidazole in 70 ml of acetonitrile, at the temperature of 10 C., 0.02 moles of thionylchloride are added, followed by 1 hour rest, and then 0.02 moles of (benzofuran-2-yl)phenylmethanol are added in 20 ml of acetonitrile. The reaction admixture is kept 24 hours at ambient temperature and then concentrated to dryness. The residue is taken up with ethylether, washed first with 2% sodium hydrate solution and then with water: the hydrochloride is obtained from the ethereal solutions using 5% hydrochloric acid, then an oil is obtained by alkalinization with 5% NaOH, which is extracted with ethylether. The ethereal extract is washed, made anhydrous and saturated with gaseous HCl: the precipitate thus obtained is crystallized from isopropanol: m.p. 205°-207° C. (dec.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][NH2:16])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[C:27]1([S:37](Cl)(=[O:39])=[O:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][NH:16][S:37]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)(=[O:39])=[O:38])[CH2:13][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CN)CC1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CNS(=O)(=O)c2cccc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of trans-(4-aminomethyl-cyclohexylmethyl) carbamic acid tert-butyl ester (17 g) and ethyldiisopropylamine (14.41 ml) in N,N-dimethylformamide (350 ml) is cooled to 0° C. and treated with a solution of naphthalene-1-sulfonylchloride (15.9 g) in N,N-dimethylformamide (100 ml). The reaction is stirred at ambient temperature for 2 h, concentrated in vacuo. The residue is taken up in dichloromethane, washed with a 0.5 N HCl solution, a saturated aqueous sodium carbonate solution and water, dried and concentrated. Crystallization from hexanes-ethyl acetate gives trans-{4-[(naphthalene-1-sulfonylamino)-methyl]cyclohexylmethyl}-carbamic acid tert-butyl ester as a white powder, melting at 199-200° C. Rf (A1) 0.42.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.O>C1COCC1>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(CN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.9 %

Procedure:
In THF (50 ml) was dissolved 4-nitrobenzylchloride (5.00 g), and piperidine (6.20 g) was added to the mixture. The reaction mixture was stirred at room temperature for 20 hours. To the mixture was added water (500 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1/2) to give 1-(4-nitrobenzyl)piperidine (6.41 g) as pale yellow oil. 1H NMR (200 MHz, CDCl3) δ: 1.38-1.70 (6H, m), 2.30-2.45 (4H, m), 3.55 (2H, s), 7.51 (2H, d, J=8.8 Hz), 8.17 (2H, d, J=8.8 Hz).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([F:29])=[C:25]([CH2:27][OH:28])[CH:26]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:29][C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:16](=[O:18])[CH2:15][C:3]2[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)[N:4]=2)=[CH:26][C:25]=1[CH2:27][OH:28]
Reactant: Nc1ccc(F)c(CO)c1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1c(CC(=O)Nc2ccc(F)c(CO)c2)nc(N2CCOCC2)cc1=O
Yield: 45.9 %

Procedure:
The product is prepared according to the procedure described in example 5, using 250 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of example 68, 184 mg of (5-amino-2-fluorophenyl)methanol, and 285 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 2 ml of pyridine and 2 ml of N,N-dimethylformamide. 157 mg of N-[4-fluoro-3-(hydroxymethyl)phenyl]-2-[1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a grey solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:20]=[C:19]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[NH:31])[NH:29][OH:30])=[C:24](F)[CH:23]=3)[C:13]3[CH2:14][C:15]([CH3:18])([CH3:17])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1.CN1C=CC(NC(C2C=C(OC3C=CC(C#N)=C([Cl:62])C=3)C3CC(C)(C)OC=3C=2)=O)=N1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:20]=[C:19]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[NH:31])[NH:29][OH:30])=[C:24]([Cl:62])[CH:23]=3)[C:13]3[CH2:14][C:15]([CH3:18])([CH3:17])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1
Reactant: Cn1ccc(NC(=O)c2cc(Oc3ccc(C#N)c(Cl)c3)c3c(c2)OC(C)(C)C3)n1
Reactant: Cn1ccc(NC(=O)c2cc(Oc3ccc(C(=N)NO)c(F)c3)c3c(c2)OC(C)(C)C3)n1
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(C(=N)NO)c(Cl)c3)c3c(c2)OC(C)(C)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 185a, from 4-(3-chloro-4-cyano-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (189b) and used without further purification for the next step.
Reaction SMILES: C([O:4][CH:5]([CH2:45][O:46]C(=O)C)[CH2:6][NH:7][C:8]([C:10]1[C:15]([I:16])=[C:14]([N:17]2[C:22](=[O:23])[CH2:21][O:20][CH2:19][CH:18]2[CH2:24][O:25]C(=O)C)[C:13]([I:29])=[C:12]([C:30]([NH:32][CH2:33][CH:34]([O:40]C(=O)C)[CH2:35][O:36]C(=O)C)=[O:31])[C:11]=1[I:44])=[O:9])(=O)C.C[O-].[Na+].[Na]>CO.O>[OH:40][CH:34]([CH2:35][OH:36])[CH2:33][NH:32][C:30]([C:12]1[C:13]([I:29])=[C:14]([N:17]2[C:22](=[O:23])[CH2:21][O:20][CH2:19][CH:18]2[CH2:24][OH:25])[C:15]([I:16])=[C:10]([C:8]([NH:7][CH2:6][CH:5]([OH:4])[CH2:45][OH:46])=[O:9])[C:11]=1[I:44])=[O:31]
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c(I)c(N2C(=O)COCC2COC(C)=O)c1I)OC(C)=O
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CO
Product: O=C(NCC(O)CO)c1c(I)c(C(=O)NCC(O)CO)c(I)c(N2C(=O)COCC2CO)c1I
Reaction time: 3 h
Yield: 60 %

Procedure:
To a solution of N,N'-bis[2,3-bis(acetyloxy)propyl]-5-[3-(Acetyloxy)methyl-5-oxo-4-morpholinyl]-2,4,6-triiodo-1,3-benzenedicarboxamide (5.15 g, 5 mmol) in anhydrous methanol (100 ml), was added a solution of sodium methoxide, prepared from sodium (25 mg) and anhydrous methanol (5 ml), and the mixture was stirred for 3 hours. The solution was adjusted to pH 7 by a slow addition of Dowex-50 (H+) resin and then filtered. The filtrate was concentrated in vacuo to obtain the crude product (3.85 g) as a white solid. The material was dissolved in water (40 ml) and loaded onto a column of CHP-20 diaion resin. The column was first eluted with water (1 L) and then with a stepwise gradient of ethanol in water (1-8%). The fractions containing the pure product were combined and the solvents removed in vacuo to obtain N,N'-Bis(2,3-dihydroxypropyl)-5-[3-(hydroxymethyl)-5-oxo-4-morpholinyl]-2,4,6-triiodo-1,3-benzenedicarboxamide as a white microcrystalline solid (2.45 g, 60% yield, 99% purity). Recrystallization from ethanol/isopropanol (95/5) afforded the analytical sample as a white solid, m.p. 227°-230°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1I.C[Sn](C)(C)[C:22]1[S:26][C:25]([C:27]2[CH2:31][CH:30]([CH2:32][OH:33])[O:29][N:28]=2)=[CH:24][CH:23]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1[C:22]1[S:26][C:25]([C:27]2[CH2:31][CH:30]([CH2:32][OH:33])[O:29][N:28]=2)=[CH:24][CH:23]=1
Reactant: C[Sn](C)(C)c1ccc(C2=NOC(CO)C2)s1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(C4=NOC(CO)C4)s3)c(F)c2)C(=O)O1
Temperature: 90 °C
Yield: 57.5 %

Procedure:
N-{[(5S)-3-(3-Fluoro-4-iodophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide (273 mg, 0.72 mM), {3-[5-(trimethylstannyl)thien-2-yl]-4,5-dihydroisoxazol-5-yl}methanol (250 mg, 0.72 mM), tris(dibenzylideneacetone)dipalladium (0)-chloroform adduct (75 mg, 0.072 mM) and tri-2-furylphosphine (34 mg, 0.145 mM) were placed in a flask. The solids were degassed and placed under nitrogen. Anhydrous dioxane (5 ml) was added and the suspension was heated at 90° C. for 16 hours. The reaction mixture was cooled and the solvent was evaporated. The residue was chromatographed on silica gel eluting with 5% methanol in dichloromethane to give the title compound (180 mg).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:10]=[C:9]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]3[NH:23][C:22]4[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:21]=4[N:20]=3)[CH2:14][C:13]2=[O:29])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[CH2:30]([N:32](CC)CC)C.C(O)(=O)C.N1C=CC=NN=1>C(O)C>[NH2:6][C:5]1[C:4]2[C:3](=[CH:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([CH2:18][C:19]4[NH:23][C:22]5[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:21]=5[N:20]=4)[CH2:14][C:13]3=[O:29])=[CH:8][CH:7]=2)[N:2]=[CH:30][N:32]=1
Reactant: N#Cc1ccc(CN2CCC(Cc3nc4ccc(Cl)cc4[nH]3)CC2=O)cc1N
Reactant: CCN(CC)CC
Agent: Cl
Agent: c1cnnnc1
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ncnc2cc(CN3CCC(Cc4nc5ccc(Cl)cc5[nH]4)CC3=O)ccc12
Yield: 84.9 %

Procedure:
To a solution of 2-Amino-4-[4-(6-chloro-1H-benzoimidazol-2-ylmethyl)-2-oxo-piperidin-1-ylmethyl]-benzonitrile hydrochloric acid salt (143 mg, 0.308 mmol), EXAMPLE 814, Part E, in 2 mL of ethanol is added triethylamine (0.05 mL, 0.366 mmol), glacial acetic acid (0.02 mL, 0.366 mmol) and triazine (15 mg, 0.183 mmol). The resulting mixture is refluxed overnight. The volatile solvents are removed on the rotovap, and the residue is purified by reverse phase HPLC (0-50% Acetonitrile/H2O). The desired product (110 mg, 55% yield) is isolated as a white powder with a melting point of 128-132 ° C. C22H21ClN6O MS m/z: 421, 423. Anal. calcd. for C22H21ClN6O: C, 48.12; H,3.57; N, 12.95. Found: C, 45.79; H, 3.68; N, 11.94. H NMR (CD3OD) δ: 8.67 (s, 1H); 8.31 (d, 1H, J=4.0 Hz); 7.83-7.55 (m, 5H); 4.93-4.73 (m, 2H); 3.48-3.42 (m, 2H); 3.31-3.21 (m, 2H); 2.71-2.58 (m, 2H); 2.43-2.33 (m, 1H); 2.07-2.01 (m, 1H); 1.82-1.69 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=[NH:21])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].Br[CH2:30][C:31](=[O:36])[C:32]([F:35])([F:34])[F:33]>C(O)(C)C>[OH:36][C:31]1([C:32]([F:35])([F:34])[F:33])[CH2:30][N:10]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:22])[F:23])=[CH:8][CH:7]=2)=[N:21]1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(C(F)(F)F)cc2)cc1
Reactant: O=C(CBr)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccc(C(F)(F)F)cc2)cc1

Procedure:
To a mixture of 4-(trifluoromethyl)-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (10 mmol) and sodium bicarbonate (20 mmol) in isopropanol (100 mL), 3-bromo-1,1,1-trifluoroacetone (20 mmol) is added. After heating the reaction mixture at 70–75° C. for 20 hours, the solvent is removed. The residue is redissolved in methylene chloride and washed with water. The organic fractions are combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product is purified by chromatography (silica gel, toluene/ethyl acetate, 7/3) to give 4-hydroxy-1-[4-(methylsulfonyl)phenyl]-2-(4-trifluoromethylphenyl)-4-trifluoromethyl-4,5-dihydro-1H-imidazole.
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[C:7](I)=[C:6]([CH2:11][CH3:12])[N:5]=[C:4]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:2].[F:19][C:20]([F:25])([F:24])C([O-])=O.[Na+].CN1CCCC1=O>CCOCC.[Cu]I>[CH2:1]([N:3]1[C:8](=[O:9])[C:7]([C:20]([F:25])([F:24])[F:19])=[C:6]([CH2:11][CH3:12])[N:5]=[C:4]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:2]
Reactant: CCc1nc(-c2ccccc2)n(CC)c(=O)c1I
Reactant: O=C([O-])C(F)(F)F
Agent: [Cu]I
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: CCc1nc(-c2ccccc2)n(CC)c(=O)c1C(F)(F)F
Temperature: 175 °C
Yield: 47.3 %

Procedure:
A mixture of 1.00 g (2.5 mmol) of 3,6-diethyl-5-iodo-2-phenyl-4(3H)-pyrimidinone, 1.08 g (5.7 mmol) of copper (I) iodide, 1.54 g (11.3 mmol) of sodium trifluoroacetate and 8 mL of anhydrous N-methylpyrrolidinone was heated at 175° C. for 2 h. The mixture was cooled, diluted with 175 mL of ether, washed with four 50 mL portions of water and dried over MgSO4. Removal of the solvent on the rotovap afforded 0.92 g of crude product as a brown oil. This material was purified by flash chromatography on a 25 g column of silica gel eluting with 100 mL portions of 0, 10, 20, 30, 40, 50 and 75% ether in hexanes to afford 0.35 g of 3,6-diethyl-2-phenyl-5-trifluoromethyl-4(3H)-pyrimidinone (compound 185) as a white solid. 1H-NMR (CDCl3) 1.25(3H,t), 1.30(3H,t), 2.8(2H,q), 4.0(2H, q), 7.5(5H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12]([C:25]3[CH:30]=[CH:29][C:28](Cl)=[CH:27][CH:26]=3)[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2nn(Cc3ccccc3)c(-c3ccc(Cl)cc3)c2CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2nn(Cc3ccccc3)c(-c3ccccc3)c2CC1

Procedure:
To a solution of 2-benzyl-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (0.1 mmol) (Example 59, Step D) in THF (25 mL) was added lithium aluminum hydride (100 mg). The mixture was heated at reflux for 4 h. Water (1 mL) was added, the mixture was filtered, and the filtrate was concentrated. After purification (SiO2, EtOAc/hexanes), 2-benzyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester was obtained. The intermediate was diluted with CH2Cl2 (5 mL) and TFA (1 mL) was added. The reaction mixture was stirred at RT for 4 h. The reaction mixture was concentrated to obtain the title compound (0.018 g). MS (ESI): exact mass calculated for C20H21N3, 303.17; found, m/z 304.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.38-7.35 (m, 3H), 7.19-7.18 (m, 3H), 7.12-7.10 (m, 2H), 5.13 (s, 2H), 3.35-3.21 (br m, 6H), 3.34-3.30 (br m, 2H), 2.81-2.79 (br m, 2H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][N+:7]=1[O-:13].C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O>[Cl:5][C:6]1[CH:11]=[C:10]([N+:1]([O-:4])=[O:2])[C:9]([CH3:12])=[CH:8][N+:7]=1[O-:13]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(Cl)[n+]([O-])c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1c[n+]([O-])c(Cl)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a mixture of 165 mL of nitric acid and 209 mL of sulfuric acid was slowly added 56.4 g of 2-chloro-5-methylpyridine-1-oxide. The reaction mixture was stirred at 100° C. for two hours, cooled to room temperature, and added to ice. Sodium carbonate was added to adjust the pH to about pH 2 to pH 3. The resulting yellow solid was separated by filtration and washed with ice-water. The combined filtrates were extracted with hot chloroform. The extracts were combined, dried over sodium sulfate, and concentrated to give 59.1 g of 2-chloro-5-methyl-4-nitropyridine-1-oxide (80%). Mass Spec. M+H=189.
Reaction SMILES: CC(OCC1CS[C@@H]2[C@H](NC(CCC[C@@H](N)C(O)=O)=O)C(=O)N2C=1C(O)=O)=O.[N:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1>[Cl-].[Na+]>[CH:38]1[C:33]2[C:32](=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:31]=[CH:30][N:29]=1
Reactant: c1ccc2ncccc2c1
Agent: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CCC[C@@H](N)C(=O)O)[C@H]2SC1
Agent: [Cl-]
Agent: [Na+]
Product: c1ccc2cnccc2c1

Procedure:
15 ml of the remaining reaction solution were diluted with 5% sodium chloride solution to make 30 ml (corresponds to 0.5% solution calculated as cephalosporin C). After adding 0.22 ml of quinoline to the solution, the mixture was adjusted to pH 3.0 and stirred at 5 - 10° C. Very soon crystals are separated out. The crystals were collected after an hour, washed with ice-water and with ethyl acetate and dried in vacuo. 226 mg of isoquinoline adduct of N-methylthioacetyl-cephalosporin C having 97% purity were obtained.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[F:7][C:8]([F:46])([F:45])[C:9]1[CH:10]=[C:11]([C:19]([CH3:44])([CH3:43])[C:20]([N:22]([CH3:42])[C:23]2[CH:24]=[N:25][C:26]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[CH:27][C:28]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])=[O:21])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1>C(Cl)(Cl)(Cl)Cl.O.O.[Ru](=O)=O>[F:46][C:8]([F:7])([F:45])[C:9]1[CH:10]=[C:11]([C:19]([CH3:44])([CH3:43])[C:20]([N:22]([CH3:42])[C:23]2[CH:24]=[N:25][C:26]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][C:37]3=[O:2])=[CH:27][C:28]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])=[O:21])[CH:12]=[C:13]([C:15]([F:18])([F:16])[F:17])[CH:14]=1
Reactant: Cc1ccccc1-c1cc(N2CCOCC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru]=O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Cc1ccccc1-c1cc(N2CCOCC2=O)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 34.3 %

Procedure:
To an ice-cooled suspension of 1.2 g (7.1 mmol) ruthenium(IV)oxide hydrate in a mixture of 50 ml carbon tetrachloride and 50 ml water were added 9.0 g (42 mmol) sodium periodate. After stirring for 30 min the organic layer was separated and the aqueous layer was extracted twice with 10-ml portions of carbon tetrachloride. The combined organic layers were filtered over celite, cooled to 0° C. and were added slowly to an ice-cooled solution of 2.0 g (3.54 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide in 20 ml carbon tetrachloride. The mixture was stirred for additional 15 min at 0° C., was filtered over celite and was evaporated. The residue was purified by flash-chromatography and gave 704 mg (34%) of the title compound as colourless foam. MS m/e (%): 580 (M+H+, 100).