Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:5]2[N:4]=[C:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1SC.Cl[C:24]1C=CC=C(C(OO)=O)C=1.C(=O)([O-])O.[Na+].[S:39]([O-:43])([O-])(=[O:41])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:24][S:39]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:3]1[N:2]([CH3:1])[C:6]2=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:12])[F:13])[CH:10]=[C:5]2[N:4]=1)(=[O:43])=[O:41]
Reactant: CSc1ccccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cn1c(-c2ccccc2S(C)(=O)=O)nc2cc(C(F)(F)F)cnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-methyl-2-(2-methylsulfanylphenyl)-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (0.30 g) and chloroform (9 ml), 69% of 3-chloroperbenzoic acid (0.70 g) was added under ice-cooling, and then heated to room temperature, and stirred for 2 hours. Then, into the mixture, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium thiosulfate solution were poured, and extracted with chloroform 2 times. The combined organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.32 g of 2-(2-methylsulfonylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 3).
Reaction SMILES: [CH3:1][N:2]1N=[N:10][C:9]2[N:5]([CH:6]=[N:7][C:8]=2[C:12]([NH2:14])=[O:13])[C:3]1=[O:4].C(C(N=C(C1C=CC=CC=1)C1C=CC=CC=1)C(N[C:21]([CH3:24])([CH3:23])[CH3:22])=O)#N.Cl.NC(C#N)C(NC(C)(C)C)=O>>[NH2:10][C:9]1[N:5]([C:3]([NH:2][CH3:1])=[O:4])[CH:6]=[N:7][C:8]=1[C:12]([NH:14][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:13]
Reactant: Cn1nnc2c(C(N)=O)ncn2c1=O
Reactant: CC(C)(C)NC(=O)C(C#N)N=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)NC(=O)C(N)C#N
Agent: Cl
Product: CNC(=O)n1cnc(C(=O)NC(C)(C)C)c1N

Procedure:
Another process for preparing Temozolomide is described in U.S. patent application having the Publication No. 2002/0095036 (see Scheme 4 below). In this process, the imine (V) is converted to 2-cyano-N-(1,1-dimethylethyl)-2-[(diphenyl-methylene)amino]-acetamide, which is converted to 2-amino-2-cyano-N-(1,1-dimethyl-ethyl)-acetamide hydrochloride. The latter is reacted with compound (VI) to obtain 5-amino-N4-(1,1-dimethylethyl)-N1-methyl-1H-imidazole-1,4-dicarboxamide, which is converted to 3,4-dihydro-N-(1,1-dimethylethyl)-3-methyl-imidazo-[5,1-d]-1,2,3,5-tetrazine-8-carboxamide (tert-butyl-Temozolomide), which yields Temozolomide under acidic treatment with concentrated sulfuric acid.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.ClCCl>[CH2:9]([NH:16][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCc1ccccc1
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: Clc1cncc(NCc2ccccc2)n1
Temperature: 85 °C
Yield: 80.2 %

Procedure:
A mixture of 2,6-dichloropyrazine (1.31 g, 8.8 mmol), benzylamine (1.15 g, 10.7 mmol) and K2CO3 (1.65 g, 11.9 mmol) in acetonitrile (6 mL) was heated at 85° C. for 13 h in a sealed pyrex flask. The reaction mixture was diluted with dichloromethane, filtered and concentrated in vacuo. The yellow solid residue was dissolved in a small volume of methanol and purified by silica gel chromatography (18×4 cm) using CHCl3/MeOH (98:2) as eluent. A second purification (SiO2;16×4 cm) using CHCl3 as eluent furnished 1.55 g (81%) of the title compound as a light yellow solid. HRMS m/z calcd for C11H10ClN3 (M)+ 219.0563, found 219.0568. Anal. (C11H10ClN3) C, H, N.
Reaction SMILES: [Cl:1][CH:2]([CH3:15])[CH2:3][NH:4][C:5]1[C:10]([CH2:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:13][CH3:14].[CH2:16]([C:18]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH3:26])[C:19]=1[NH2:20])[CH3:17].[I-].[K+]>C(O)(C)C>[ClH:1].[ClH:1].[CH2:13]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][CH3:12])[C:5]=1[NH:4][CH2:3][CH:2]([NH:20][C:19]1[C:21]([CH2:25][CH3:26])=[CH:22][CH:23]=[CH:24][C:18]=1[CH2:16][CH3:17])[CH3:15])[CH3:14]
Reactant: CCc1cccc(CC)c1NCC(C)Cl
Reactant: CCc1cccc(CC)c1N
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Product: CCc1cccc(CC)c1NCC(C)Nc1c(CC)cccc1CC
Product: Cl
Reaction time: 4 h
Yield: 69.7 %

Procedure:
A mixture of 46.3 g (0.205 moles) of N-(β-chloropropyl)-2,6-diethyl-aniline, obtained as indicated in point (b) above, 61.2 g (0.41 moles) of 2,6-diethylaniline and 1.66 g (10 mmoles) of potassium iodide is stirred at 140° to 145° C. for 4 hours under nitrogen atmosphere. The mixture is allowed to cool, 150 ml of isopropanol are added, and the resulting mixture is stirred at 0° to +5° C. for 2 hours. The separated 2,6-diethylaniline hydrochloride (19.2 g, 25.2%) is filtered off, washed with cold isopropanol and dried. The filtrate is acidified with isopropanolic hydrochloric acid (acid content: about 15 g/100 ml), the separated precipitate is filtered off, washed with cold isopropanol and dried. The resulting crude substance, weighing 72 g, is recrystallized from methanol to obtain 29.4 g (34.8%) of 1,2-bis(2',6'-diethylphenyl-amino)-propane dihydrochloride as a uniform substance; m.p.: 161°-167° C. The base is liberated from this salt as described in point (c) of Example 16 and isolated from the reaction mixture by extraction with chloroform.
Reaction SMILES: [CH2:1]1[CH:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][N:2]1[CH2:20][CH2:21][O:22][CH2:23][C:24](O)=[O:25].[CH:27]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>O.O1CCCC1>[CH:27]1([NH:33][C:24](=[O:25])[CH2:23][O:22][CH2:21][CH2:20][N:2]2[CH2:3][CH2:4][N:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[CH2:9][C:8]4[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=4[CH:6]3[CH2:1]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NC1CCCCC1
Reactant: O=C(O)COCCN1CCN2c3ccccc3Cc3ccccc3C2C1
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(COCCN1CCN2c3ccccc3Cc3ccccc3C2C1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.5 %

Procedure:
0.358 g of 2-(1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepin-2-yl)ethoxyacetic acid (prepared as described in Example 2), 0.1 g of cyclohexylamine and 0.11 g of triethylamine were added to 10 m of tetrahydrofuran, and 0.17 g of diethyl cyanophosphonate was added dropwise to the mixture, whilst ice-cooling. The mixture was then stirred at room temperature for 5 hours, after which it was mixed with water and then extracted with methylene chloride. The extract was concentrated by evaporation under reduced pressure, and the residue was subjected to column chromatography through silica gel, using 10% by volume ethanol in ethyl acetate as the eluent, to afford 0.4 g (yield 91%) of the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1.[CH:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:29]([NH:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1c(N)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1c(NCc2ccccc2)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reaction time: 0.33 h

Procedure:
6-Amino-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile hydrochloride (10 mg, 0.026 mmol), benzaldehyde (2.8 mg, 0.026 mmol) and acetic acid (0.5 ml) in 1,2-dichloroethane (1.0 ml) were stirred at RT. After 20 minutes, NaBH(OAc)3 was added and the reaction mixture was stirred for additional 15 minutes, quenched with saturated NH4OH (4.0 ml), extracted with dichloromethane (3×3 ml), dried over Na2SO4, concentrated and purified by silica gel flash chromatography to isolate 376 as a yellow film (1.3 mg, 11%). [M+H]+=446.2.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:12][CH2:13][NH2:14].[CH2:20]([O:22][CH:23]([O:26][CH2:27][CH3:28])[CH2:24]Br)[CH3:21].O>CN(C)C=O>[CH2:20]([O:22][CH:23]([O:26][CH2:27][CH3:28])[CH2:24][NH:14][CH2:13][CH2:12][C:11]1[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:9]([O:8][CH3:7])[CH:10]=1)[CH3:21]
Reactant: CCOC(CBr)OCC
Reactant: COc1ccc(CCN)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(CNCCc1ccc(OC)c(OC)c1)OCC
Reaction time: 1 h
Yield: 71 %

Procedure:
To a stirred suspension of anhydrous potassium carbonate (300 g) and 3,4-dimethoxyphenethylamine (148 g, 0.818 m) in dimethylformamide (750 ml) under N2 at 110° C. was added dropwise over 30 min bromoacetaldehyde diethylacetal (167.5 g, 0.850 m). During the addition, the temperature was allowed to rise to 130° C., maintained at 125°-130° C. for 1.5 hrs, then cooled. At ca 40° C., 70 ml of water was added, stirred for 1 hr, then the salts removed by filtration and the solvent evaporated to a volume of ca 300 ml. Ether (750 ml) was added, the precipitated solid was filtered and the filtrate evaporated to an oil, 247 g. This material was vacuum-distilled to give three fractions: (1) b.p. 30°-154° C./0.1 mm, 17.0 g; (2) b.p. 154°-157° C./0.1 mm, 171.6 g; (3) b.p. 157°-174° C./ 0.1 mm, 37.3 g. Fraction (2) contained the product in 71% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:16])[NH:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O-])([O-])=O.[K+].[K+].IC.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10](=[O:16])[N:11]([CH3:17])[CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]cc(Br)cc1OCc1ccccc1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(Br)cc(OCc2ccccc2)c1=O
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a suspension of 2.51 g (8.96 mmol) 3-benzyloxy-5-bromo-1H-pyridin-2-one and 2.48 g (17.9 mmol) K2CO3 in 45 mL DMF was added 1.12 mL (17.9 mmol) iodomethane at room temperature. After stirring overnight, 150 mL water was added with vigorous stirring causing precipitation of the product which was collected by filtration and dried in vacuo affording 2.3 g (87%) 3-benzyloxy-5-bromo-1-methyl-1H-pyridin-2-one
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[C:13]1[N:18]=[C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:16]=[C:15]([S:25][CH3:26])[C:14]=1[C:27]#[N:28])=[O:4]>CO.ClCCl>[OH:4][CH2:3][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[C:13]1[N:18]=[C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:16]=[C:15]([S:25][CH3:26])[C:14]=1[C:27]#[N:28]
Reactant: COc1ccc(-c2nc(-c3cccnc3)cc(SC)c2C#N)c(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(-c2nc(-c3cccnc3)cc(SC)c2C#N)c(CO)c1
Reaction time: 0.33 h
Yield: 64.2 %

Procedure:
Sodium borohydride (2.2 mg, 0.058 mmol) was added to a solution of 6-(2-formyl-4-methoxyphenyl)-4-(methylthio)-2,3′-bipyridine-5-carbonitrile (4.3 mg, 0.012 mmol) in methanol (0.45 mL) and dichloromethane (0.450 mL) at room temperature. After 20 min at ambient temperature, the mixture was quenched with TEA (10 μL) and concentrated. Silica gel chromatography, eluting with 0-10% methanol in dichloromethane, gave 6-(2-(hydroxymethyl)-4-methoxyphenyl)-4-(methylthio)-2,3′-bipyridine-5-carbonitrile as white solid (2.8 mg, 65% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.12 (1H, δ, J=2.01 Hz), 8.72-8.77 (1H, m), 822-8.28 (1H, m), 7.60-7.65 (1H, m), 7.43-7.49 (2H, m), 7.11 (1H, δ, J=2.76 Hz), 6.97-7.02 (1H, m), 4.44 (2H, s), 3.90 (3H, s), 2.72 (3H, s); MS (ES+) 111/Z: 364 (M+H); LC retention time: 3.061 min (analytical HPLC Method A).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3]1.[C:14](OCI)(=O)C(C)(C)C.[OH:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([C:36]#[C:37][CH3:38])[CH2:31][C:32]([O:34]C)=[O:33])=[CH:26][CH:25]=1>>[CH3:1][C:2]1([CH3:13])[C:7](=[O:8])[N:6]([CH2:14][O:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]([C:36]#[C:37][CH3:38])[CH2:31][C:32]([OH:34])=[O:33])=[CH:26][CH:25]=2)[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: CC(C)(C)C(=O)OCI
Reactant: CC1(C)Oc2ccccc2NC1=O
Reactant: CC#CC(CC(=O)OC)c1ccc(O)cc1
Product: CC#CC(CC(=O)O)c1ccc(OCN2C(=O)C(C)(C)Oc3ccccc32)cc1

Procedure:
Analogously to example 6, 2,2-dimethyl-4H-benzo[1,4]oxazin-3-one, iodomethyl pivalate and methyl 3-(4-hydroxyphenyl)hex-4-ynoate were used to obtain 3-[4-(2,2-dimethyl-3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-ylmethoxy)phenyl]hex-4-ynoic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]([O:12][CH:13]2[CH:17]([OH:18])[CH2:16][O:15][CH2:14]2)=[O:11])=[CH:6][C:5]([N:19]2[C:23](=[O:24])[C:22]3[CH2:25][CH2:26][CH2:27][CH2:28][C:21]=3[C:20]2=[O:29])=[C:4]([F:30])[CH:3]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39]>C1C=CC=CC=1>[C:38]([O:18][CH:17]1[CH2:16][O:15][CH2:14][CH:13]1[O:12][C:10]([CH2:9][O:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:30])=[C:5]([N:19]2[C:20](=[O:29])[C:21]3[CH2:28][CH2:27][CH2:26][CH2:25][C:22]=3[C:23]2=[O:24])[CH:6]=1)=[O:11])(=[O:40])[CH3:39]
Reactant: O=C(COc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl)OC1COCC1O
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(=O)OC1COCC1OC(=O)COc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.1 %

Procedure:
In 15 ml of benzene were dissolved 0.66 g of N-(4-chloro-2-fluoro-5-(4-hydroxytetrahydrofuran-3-yloxycarbonylmethoxy)phenyl)-3,4,5,6tetrahydrophthalimide and 0.20 g of triethylamine, followed by dropwise addition of a solution of 0.14 g of acetyl chloride in benzene. After stirring at room temperature for 4 hours, the reaction mixture was washed with water and subsequently with aqueous saturated sodium chloride solution, and 'dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by chromatography on a silica gel column (eluted with ethyl acetate/hexane=2/3), to obtain 0.55 g of a compound described in Table 1 (No.3) (76%).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)=O.[CH3:28][O:29][C:30]([C:32]1[CH:36]=[C:35]([NH2:37])[NH:34][N:33]=1)=[O:31].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:28][O:29][C:30]([C:32]1[CH:36]=[C:35]2[NH:37][C:5]([C:7]3[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:11][CH:12]=3)=[C:4]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:3](=[O:2])[N:34]2[N:33]=1)=[O:31]
Reactant: COC(=O)c1cc(N)[nH]n1
Reactant: COC(=O)C(C(=O)c1ccc(OCc2ccccc2)cc1)C1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3)c(C3CCCCC3)c(=O)n2n1
Yield: 16.1 %

Procedure:
A mixture of 274 mg (0.747 mmol) of 3-(4-benzyloxy-phenyl)-2-cyclohexyl-3-oxo-propionic acid methyl ester, 106 mg (0.747 mmol) of 5-amino-1H-pyrazole-3-carboxylic acid methyl ester, 15 mg (10 mol %) of p-toluenesulfonic acid monohydrate (PTSA), and 10 mL of toluene was heated at reflux for 88 h. The reaction mixture was then concentrated to a residue which was chromatographed on silica gel (Biotage; gradient elution 2% to 20% ethyl acetate in dichloromethane) to afford 55 mg (16% yield) of desired 5-(4-benzyloxy-phenyl)-6-cyclohexyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester as a solid as indicated by 1H NMR; LC-MS—calcd for C27H27N3O4 [M++H]+: 458.2, found: 458.2.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[CH:12](O)([CH3:14])[CH3:13]>>[Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH:12]([CH3:14])[CH3:13])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(CCl)cc1
Reactant: CC(C)O
Product: CC(C)OC(=O)c1ccc(CCl)cc1

Procedure:
Isopropyl 4-(chloromethyl)benzoate 13d was prepared by reacting 4-(chloromethyl)benzoic acid 24 with isopropanol according to the procedure described for the compound 13a in Example 16 (scheme 7). The benzoate 13d was isolated as colorless oil in 89% yield (1.90 g). 1H NMR (400 MHz, CDCl3): δ 1.35 (6H, m); 4.59 (2H, s); 5.25 (2H, m); 7.42 (1H, m); 7.44 (1H, broad s); 8.00 (1H, broad s); 8.02 (1H, s).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[Li]CCCC.CN(CCN(C)C)C.[Sn:20](Cl)([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24]>O1CCCC1>[CH3:1][N:2]1[C:6]([Sn:20]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:21][CH2:22][CH2:23][CH3:24])=[CH:5][N:4]=[CH:3]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cn1ccnc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cncn1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
To a dehydrated tetrahydrofuran solution (10 mL) of 1-methylimidazole (1.6 mL, 18.8 mmol), there was added dropwise a mixture of n-BuLi (18 mL, 45 mmol) and TMEDA (6.7 mL, 44.6 mmol) at −20° C. under nitrogen atmosphere. After stirring for 30 minutes, the mixture was raised to room temperature and stirred for another hour. After again cooling to −20° C., a solution of n-Bu3SnCl (12.5 mL, 46.4 mmol) in tetrahydrofuran (10 mL) was added dropwise thereto, the mixture was raised to room temperature and stirred for 17 hours. The reaction was terminated with water (15 mL), and then extraction was performed twice with ethyl acetate (20 mL). The mixture was then purified by silica gel chromatography (ethyl acetate:methanol=96:4) to yield the title compound (2.2 g, 32%).
Reaction SMILES: C[C@@H]1O[C@@H]([O:8][C@H:9]2[C@H:14]([O:15]C3C4OC5=C(Cl)C=C(C=C5)[C@@H](O)[C@@H]5NC(=O)[C@@H](C6C=CC(O)=C(C7C(O)=CC(O)=CC=7[C@@H](C(O)=O)NC5=O)C=6)NC(=O)[C@H]5C(=CC=3OC3C=CC([C@@H](O)[C@@H](NC([C@H](NC)CC(C)C)=O)C(N[C@@H](CC(N)=O)C(N5)=O)=O)=CC=3Cl)C=4)[O:13][C@H:12]([CH2:95][OH:96])[C@@H:11]([OH:97])[C@@H:10]2[OH:98])C[C@@](N)(C)[C@@H]1O>Cl>[O:15]=[CH:14][C@H:9]([C@H:10]([C@@H:11]([C@@H:12]([CH2:95][OH:96])[OH:13])[OH:97])[OH:98])[OH:8]
Reactant: CN[C@H](CC(C)C)C(=O)N[C@H]1C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H]2C(=O)N[C@H]3C(=O)N[C@H](C(=O)N[C@H](C(=O)O)c4cc(O)cc(O)c4-c4cc3ccc4O)[C@H](O)c3ccc(c(Cl)c3)Oc3cc2cc(c3O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O[C@H]2C[C@](C)(N)[C@H](O)[C@H](C)O2)Oc2ccc(cc2Cl)[C@H]1O
Agent: Cl
Product: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Total hydrolysis of AAD 216A, AAD 216B and AAD 216C, individually, in 6N hydrochloric acid at reflux for 18 hours yielded no common amino acids which could be detected in a standard amino acid analysis. The presence of actinoidinic acid, which is common in the vancomycin class of antibiotics, was confirmed in the hydrolysis products by high pressure liquid chromatography and FAB mass spectrum when compared to an authentic sample. Further, hydrolysis of AAD 216A, AAD 216B and AAD 216C, individually, in 1N hydrochloric acid at reflux for 4 hours yielded mannose but not ristosamine, glucosamine or vancosamine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2(O)[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:35])CC)C.[ClH:38]>>[ClH:38].[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2([F:35])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(OCc3ccccc3)c2)CC1
Agent: Cl
Product: FC1(c2cccc(OCc3ccccc3)c2)CCNCC1

Procedure:
This material was prepared from the reaction of tert-butyl 4-(3-benzyloxyphenyl)-4-hydroxypiperidine-1-carboxylate with diethylaminosulfur trifluoride followed by direct deprotection of the crude product with methanolic hydrogen chloride as described in Step 2 of Example 1 in 75% overall yield.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH2:29][CH3:30])[C:27]=4[CH3:28])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1>C1COCC1>[CH3:32][N:33]1[CH2:34][CH2:35][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[CH:24]=[N:25][N:26]([CH2:29][CH3:30])[C:27]=6[CH3:28])=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:31])=[CH:41][CH:40]=2)[CH2:37][CH2:38]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CCn1ncc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)c1C
Solvent: C1CCOC1
Product: CCn1ncc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCN(C)CC4)cc3)c2)c1C
Temperature: 65 °C
Reaction time: 24 h
Yield: 16 %

Procedure:
A small screw cap test tube was charged with 1-Ethyl-5-methyl-1H-pyrazole-4-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 192 mg, 0.4611 mmol) and THF (4.6 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (87.9 mg, 0.46 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was purified by flash silica gel chromatography (CHCl3:MeOH mix eluant with gradient of 1% MeOH to 15% MeOH) to afford the title compound in 16% yield (0.041 g, 0.072 mmol).
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(N(CC)CC)C.[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>C(Cl)Cl>[OH:1][C:2]1[C:9]([O:10][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cccc(O)c1O
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Oc1cccc(C=O)c1O
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A suspension of 2,3-dihydroxybenzaldehyde (15 g, 109 mmole) in CH2Cl2 (70 ml) was cooled to -10° C. Triethyl amine (5.49 g, 54.3 mmol) was added followed by pivaloyl chloride (6.49 g, 53.9 mmol). The reaction was allowed to stir for 1 hour at -10° C. and then warmed to ambient temperature. The reaction mixture was stirred at ambient temperature overnight, then washed with water, 1N aqueous HCl, saturated aqueous NaHCO3 and water. The organic phase was dried (MgSO4) and evaporated. The residue was purified by chromatography (eluant: ethyl acetate/hexane) to give 2-hydroxy-3-pivaloyloxybenzaldehyde: (10.15 g, 84%).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]([C:26]([C:28]2[CH:38]=[C:37]([CH3:39])[C:31]3[N:32]([CH3:36])[C:33](=[O:35])[O:34][C:30]=3[CH:29]=2)=[O:27])[CH:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:36][N:32]1[C:31]2[C:37]([CH3:39])=[CH:38][C:28]([C:26]([C:22]3[N:23]=[CH:24][N:25]=[C:20]([N:3]4[CH2:4][CH2:5][CH:6]([N:9]5[C:17]6[C:12](=[N:13][CH:14]=[CH:15][CH:16]=6)[NH:11][C:10]5=[O:18])[CH2:7][CH2:8]4)[CH:21]=3)=[O:27])=[CH:29][C:30]=2[O:34][C:33]1=[O:35]
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)cc2oc(=O)n(C)c12

Procedure:
72.8 mg (0.25 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one-dihydrochloride, 75 mg (0.25 mmol) 6-(6-chloropyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.22 mL (1.25 mmol) DIPEA were stirred in 2 mL DMF for 2 h at RT. The mixture was purified by preparative HPLC-MS. The fractions containing the product were combined, the organic solvent was eliminated i. vac. and the aqueous phase remaining was neutralised with a 4N aqueous NaOH solution. The precipitate was suction filtered, washed with water and dried in the CAD.