Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[CH2:5]([O:12][C:13]([N:15]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[O:18][CH:17]([CH:25]=O)[CH2:16]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>N1C=CC=CC=1>[CH2:5]([O:12][C:13]([N:15]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[O:18][CH:17]([CH:25]=[N:4][O:3][CH3:2])[CH2:16]1)=[O:14])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CON
Reactant: O=CC1CN(C(=O)OCc2ccccc2)c2ccccc2O1
Agent: Cl
Solvent: c1ccncc1
Product: CON=CC1CN(C(=O)OCc2ccccc2)c2ccccc2O1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
3.42 g of O-methylhydroxylamine hydrochloride are added to a solution of 600 mg of N-benzyloxycarbonyl-2(R,S)-formyl-3,4-dihydro-2H-1,4-benzoxazine (Rf =0.31; prepared by means of Swern oxidation (Example 1g) from Example 87c) in 30 ml of pyridine and the reaction mixture is then stirred at room temperature for 36 h and subsequently concentrated. The crude product is dissolved in ethyl acetate and the solution is washed with a 1N sodium bicarbonate solution, water and saturated sodium chloride solution. N-Benzyloxycarbonyl-2(R,S)-methoxyiminomethyl-3,4-dihydro-2H-1,4-benzoxazine is obtained (540 mg): Rf (A)=0.61. A further reaction analogously to Example 87a) and purification of the crude product by means of FC over 50 g of silica gel (mobile phase N) gives 2(R,S)-methoxyiminomethyl-3,4-dihydro-2H-1,4-benzoxazine: Rf (A)=0.51.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[OH:13][C:14]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].[CH2:27](O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C1C=CN=CC=1.C(#N)C>[CH2:27]([O:17][C:16](=[O:18])[C:15]1[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:14]=1[OH:13])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: OCc1ccccc1
Reactant: CS(=O)(=O)c1ccc(O)c(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(O)c(C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5 mmol of N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimid-hydrochloride was slowly added to a stirred suspension of 5 mmol 2-hydroxy-5-methanesulfonyl-benzoic acid, 5 mmol of benzyl alcohol and 0.5 mmol of 4-dimethylaminopyridine in 10 ml acetonitrile. The mixture was stirred overnight at room temperature, concentrated and treated with 10 ml of water. A few drops of diluted hydrochloric acid were added to acidify the solution. The resulting solid was filtered and then purified by chromatography (SiO2; ethyl acetate/cyclohexane 3:7) to yield the title compound as a colorless solid. MS (m/e): 305.0 (M−H, 100%)
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C:3]([NH:5][O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:4].[CH3:28][N:29]([CH3:34])[S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl.N1C=CC=CC=1>[C:7]([O:6][NH:5][C:3](=[O:4])[C@@H:2]([NH:1][S:30]([N:29]([CH3:34])[CH3:28])(=[O:32])=[O:31])[CH2:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:19][CH:20]=1)(=[O:13])=[O:14])([CH3:8])([CH3:9])[CH3:10]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CC(C)(C)ONC(=O)[C@@H](N)CS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)S(=O)(=O)N[C@@H](CS(=O)(=O)c1ccc(Oc2ccccc2)cc1)C(=O)NOC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-2-amino-N-tert-butoxy-3-(4-phenoxyphenylsulfonyl)-propionamide (1.5 g) in methylene chloride (20 ml) and pyridine (1.2 ml) was added dimethylsulfamoyl chloride (1 ml), and the mixture stirred overnight at room temperature. The mixture was partitioned between methylene chloride and water, and after the organic layer was dried over magnesium sulfate, solvent was removed under reduced pressure. The residue was chromatographed on silica gel, eluting with 0-45% ethyl acetate/hexane, to give (R)-N-tert-butoxy-2-dimethylaminosulfonamido-3-(4-phenoxyphenylsulfonyl)-propionamide (1.6 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)[CH2:9][CH2:10][NH:11][C:12]1[N:17]2[N:18]=[C:19]([CH3:34])[C:20]([C:21]3[C:26]([Cl:27])=[CH:25][C:24](OS(C)(=O)=O)=[CH:23][C:22]=3[Cl:33])=[C:16]2[N:15]=[C:14]([CH3:35])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:49][Si:50]([C:53]#[CH:54])([CH3:52])[CH3:51]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][NH:11][C:12]1[N:17]2[N:18]=[C:19]([CH3:34])[C:20]([C:21]3[C:22]([Cl:33])=[CH:23][C:24]([C:54]#[C:53][Si:50]([CH3:52])([CH3:51])[CH3:49])=[CH:25][C:26]=3[Cl:27])=[C:16]2[N:15]=[C:14]([CH3:35])[CH:13]=1)[CH:36]1[CH2:37][CH2:38][O:39][CH2:40][CH2:41]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(NCCN(C(=O)OC(C)(C)C)C2CCOCC2)n2nc(C)c(-c3c(Cl)cc(OS(C)(=O)=O)cc3Cl)c2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(NCCN(C(=O)OC(C)(C)C)C2CCOCC2)n2nc(C)c(-c3c(Cl)cc(C#C[Si](C)(C)C)cc3Cl)c2n1
Temperature: 65 °C
Reaction time: 4 h
Yield: 86.5 %

Procedure:
A suspension of methanesulfonic acid 4-(7-{2-[tert-butoxycarbonyl-(tetrahydro-pyran-4-yl)-amino]-ethylamino}-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-3-yl)-3,5-dichloro-phenyl ester (1.5 g, 2.2 mmol) in acetonitrile (5 mL)/triethylamine (1.9 mL) was degassed (3×) by alternately pulling a vacuum followed by repressurization with nitrogen. Trimethylsilylacetylene (0.50 mL, 3.6 mmol), dichlorobis(triphenylphosphine)palladium (65 mg, 0.093 mmol), and copper(I) iodide (42 mg, 0.22 mmol) were added, and the mixture was degassed (3×) again. The mixture was stirred for 4 hours at 65° C., the black mixture was extracted from saturated aqueous sodium bicarbonate with methylene chloride, dried (Na2SO4), filtered through Celite, concentrated under reduced pressure, and then chromatographed (7:3 hexanes/ethyl acetate) to give the product as a light brown foam (1.2 g, 89%): +APcI MS (M+1)+630; 1H NMR (CDCl3) δ: 7.51 (s, 2H), 5.82 (s, 1H), 2.44 (s, 3H), 2.23 (s, 3H), 1.53 (s, 9H), 0.24 (s, 9H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5]([C:7]2[CH:11]=[CH:10][N:9]([CH3:12])[N:8]=2)[C:4](=[O:13])[CH2:3]1.[H-].[Na+].I[CH3:17]>C1COCC1.O>[CH3:17][O:1][C@@H:2]1[CH2:6][N:5]([C:7]2[CH:11]=[CH:10][N:9]([CH3:12])[N:8]=2)[C:4](=[O:13])[CH2:3]1
Reactant: Cn1ccc(N2C[C@@H](O)CC2=O)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CO[C@H]1CC(=O)N(c2ccn(C)n2)C1

Procedure:
To a solution of (4S)-4-hydroxy-1-(1-methyl-1H-pyrazol-3-yl)pyrrolidin-2-one (97 mg) in THF (3.0 mL) was added a sodium hydride 60% dispersion in mineral oil (24 mg) under ice-cooling, and the mixture was stirred under ice-cooling for 10 min. Iodomethane (50 μL) was added to the reaction mixture under ice-cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (30 mg).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:25])[NH:13][C:14]1[CH:19]=[C:18]([Cl:20])[N:17]=[C:16]([Cl:21])[C:15]=1[N+:22]([O-:24])=[O:23])[CH3:10]>C(#N)C>[CH2:9]([O:11][C:12](=[O:25])[N:13]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:14]1[CH:19]=[C:18]([Cl:20])[N:17]=[C:16]([Cl:21])[C:15]=1[N+:22]([O-:24])=[O:23])[CH3:10]
Reactant: CCOC(=O)Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Solvent: CC#N
Product: CCOC(=O)N(Cc1ccccc1)c1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Benzyl bromide (2.33 ml) was added drop-wise to a stirred suspension of (2,6-dichloro-3-nitro-pyridin-4-yl)-carbamic acid ethyl ester (4.57 g) in acetonitrile (40 ml). The mixture was left to stir at RT under nitrogen for 16 h. The mixture was concentrated in vacuo then partitioned between EtOAc (50 ml) and water (50 ml). The layers were separated and the organics were washed with saturated NH4Cl (50 ml), water (50 ml) and brine (50 ml). The organics were dried (MgSO4) and evaporated to a yellow oil. This material was pre-absorbed onto silica then columned on Isco Companion on a silica column (330 g, Redisep) eluting with EtOAc:heptane, isocratic at 10:90 for 1 column volume (CV) then increasing the gradient from 10:90 to 30:70 over 6 CVs. The desired fractions were combined and evaporated to provide the title compound as a yellow oil (6.05 g).
Reaction SMILES: [OH-].[Na+].[CH:3]([C:5]1[C:14]2[O:15][C:16]3([C:26]([CH3:28])([CH3:27])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]3[CH3:29])[CH:17]=[N:18][C:13]=2[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=O.[CH3:30][C:31]1[CH:39]=[CH:38][C:34]([CH2:35][C:36]#[N:37])=[CH:33][CH:32]=1>C1(C)C=CC=CC=1>[C:36]([C:35]([C:34]1[CH:38]=[CH:39][C:31]([CH3:30])=[CH:32][CH:33]=1)=[CH:3][C:5]1[C:14]2[O:15][C:16]3([C:26]([CH3:27])([CH3:28])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]3[CH3:29])[CH:17]=[N:18][C:13]=2[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)#[N:37]
Reactant: CN1c2ccccc2C(C)(C)C12C=Nc1c(c(C=O)cc3ccccc13)O2
Reactant: Cc1ccc(CC#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1ccc(C(C#N)=Cc2cc3ccccc3c3c2OC2(C=N3)N(C)c3ccccc3C2(C)C)cc1
Reaction time: 2 h

Procedure:
5 ml of a 50% strength sodium hydroxide solution are added to a solution of 0.36 g (1 mmol) of the compound of Example 1, of 0.13 g (1 mmol) of 4-methylbenzyl cyanide and of 0.05 g of polyethylene glycol 400 in 15 ml of toluene. The mixture is left at ambient temperature for 2 hours. The organic phase is separated off, washed with water, dried and evaporated. The product is purified by chromatography on a silica column (CH2Cl2 eluent)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][CH3:18])=[N:15][CH:16]=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([F:27])[C:24]([Cl:28])=[C:23]([F:29])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:30]N1C(=O)CCC1=O>CC#N.CC(=O)OCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][CH3:18])=[N:15][C:16]([Cl:30])=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([F:29])[C:24]([Cl:28])=[C:25]([F:27])[CH:26]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1ncc2n1CCN(C(=O)OC(C)(C)C)C2CCc1cc(F)c(Cl)c(F)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCc1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1cc(F)c(Cl)c(F)c1
Temperature: 70 °C

Procedure:
To a yellow homogeneous solution of 8-[2-(4-chloro-3,5-difluoro-phenyl)-ethyl]-3-ethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (1.150 g; 2.700 mmol) in anhydrous MeCN (40 ml) was added dropwise, at rt, a solution of N-chlorosuccinimide (0.367 g; 2.700 mmol; 1 eq.) in anhydrous MeCN (10 ml). The resulting solution was then heated to 70° C., under nitrogen, for 3 h30. Concentration to dryness afforded a yellow oily residue which was dissolved in EA (80 ml), and this organic layer was washed with aq. sat. NaHCO3 (2×120 ml), was then dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/EA=2/3) gave the expected 1-chloro-8-[2-(4-chloro-3,5-difluoro-phenyl)-ethyl]-3-ethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow solid (0.724 g; 58%). LC-MS: tR=1.08 min.; [M+H]+=461.94 g/mol.
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)=[CH:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(OCC)=O.[CH2:27]([NH2:37])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C(Cl)Cl.C(N(CC)CC)C>[CH2:27]([NH:37][C:9](=[O:11])[CH:8]=[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: O=C(O)C=C(c1ccccc1)c1cccc([N+](=O)[O-])c1
Reactant: CCCCCCCCCCN
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCNC(=O)C=C(c1ccccc1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 8.0 g. of 3-phenyl-3-(3-nitrophenyl)propenoic acid in 260 ml. of methylene chloride was added 3.3 g. of triethylamine. The mixture was stirred for 20 minutes and then it was cooled in an ice-bath. To the cooled solution was added, dropwise, during 15 minutes, a solution of 3.6 g. of ethyl chloroformate in 30 ml. of methylene chloride. Stirring was continued for 20 minutes, and then a solution of 5.2 g. of decylamine in 30 ml. of methylene chloride was added, dropwise, during 10 minutes. The reaction mixture was allowed to warm to room temperature, and then it was washed successively with 1 N potassium hydroxide, 1 N hydrochloric acid, water, and saturated sodium chloride solution. The resulting solution was dried (Na2SO4) and evaporated in vacuo to give the 10.7 g. of the title compound as a oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:12]2[N:17]=[C:16]([N:18]3[C@@H:22]([CH:23]([CH3:25])[CH3:24])[CH2:21][O:20][C:19]3=[O:26])[CH:15]=[CH:14][N:13]=2)[CH3:10])=[CH:5][CH:4]=1.[N:27]1[CH:28]=[CH:29][N:30]2[CH2:35][CH2:34][NH:33][CH2:32][C:31]=12>CS(C)=O.CCOC(C)=O>[N:27]1[CH:28]=[CH:29][N:30]2[CH2:35][CH2:34][N:33]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:12]4[N:17]=[C:16]([N:18]5[C@@H:22]([CH:23]([CH3:25])[CH3:24])[CH2:21][O:20][C:19]5=[O:26])[CH:15]=[CH:14][N:13]=4)[CH3:10])=[CH:5][CH:4]=3)[CH2:32][C:31]=12
Reactant: c1cn2c(n1)CNCC2
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(CCl)cc2)n1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(CN3CCn4ccnc4C3)cc2)n1
Yield: 62.8 %

Procedure:
A solution of (S)-3-(2-((S)-1-(4-(chloromethyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one (75 mg, 0.2 mmol) and 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (25 mg, 0.2 mmol) in DMSO (2 mL) was heated at 80° C. for 16 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (20 mL). After separation, the aqueous phase was washed with EtOAc (2×15 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (MeOH in CH2Cl2 0 to 10%) provided (S)-3-(2-((S)-1-(4-((5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)methyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one (58 mg, white solid) in 62.8% yield.
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(O)(=O)C(O)=O.[CH2:19]([NH:23][NH2:24])[CH2:20][CH2:21][CH3:22]>C(O)(=O)C>[CH2:10]([C:9]1[N:23]([CH2:19][CH2:20][CH2:21][CH3:22])[N:24]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:8]=1)[CH3:11]
Reactant: CCOC(=O)C(=O)CC(=O)CC
Reactant: CCCCNN
Agent: O=C(O)C(=O)O
Solvent: CC(=O)O
Product: CCCCn1nc(C(=O)OCC)cc1CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.6 %

Procedure:
A solution of ethyl 2,4-dioxohexanoate (approximately 60% pure, 45.0 g, 0.232 mol), prepared as described in Part A of Example 10, in glacial acetic acid (150 mL) was cooled to 0° C. Butylhydrazine oxalate (25.0 g, 0.139 mol) was added slowly. The reaction was allowed to warm to ambient temperature, stirred overnight, and concentrated under reduced pressure. The residue was adjusted to pH 10 with the addition of 2 M aqueous sodium carbonate. The mixture was extracted with chloroform and an emulsion that contained solid material formed. The solid was isolated by filtration, and the filtrate was transferred to the separatory funnel. The organic layer was separated. The aqueous layer was extracted with chloroform three times. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide an oil that was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with CMA in chloroform) to yield 13.27 g of ethyl 5-ethyl-1-butyl-1H-pyrazole-3-carboxylate as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[O:9][CH:10]=1)[CH3:2].Br.Br[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:13][CH:12]=2)[O:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)Cc1coc(-c2ccc(O)cc2)n1
Reactant: BrCc1ccccn1
Agent: Br
Product: CCOC(=O)Cc1coc(-c2ccc(OCc3ccccn3)cc2)n1

Procedure:
The title compound is prepared in a manner substantially similar to Intermediate 16 from [2-(4-Hydroxy-phenyl)-oxazol-4-yl]-acetic acid ethyl ester (See Intermediate 64) and 2-(bromomethyl)pyridine hydrobromide. MS (m/e): 339.2 (M+1)
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[S:5].[N-:9]=[N+:10]=[N-:11].[Na+].CN(C)C=O>CCOCC>[N:9]([CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[S:5])=[N+:10]=[N-:11]
Reactant: CCOC(=S)CCCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=S)CCN=[N+]=[N-]

Procedure:
After stirring a mixture of 6.7 g. of ethyl chloromethylthioacetate, 5 g. of sodium azide and 15 ml. of dimethylformamide for 17 hours at 45° C., the reaction mixture was diluted with 150 ml. of ether, followed by washing with water for three times. By drying the ether layer over magnesium sulfate and then distilling it under reduced pressure, 6.1 g. of ethyl azidomethylthioacetate was obtained as a liquid having a boiling point of 77° - 80° C. (3 mm Hg.).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])[N:5]=[C:4]([CH:15]([CH3:17])[CH3:16])[C:3]=1[C:18]([NH2:20])=[O:19].[OH:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](OCC)=O)=[CH:24][CH:23]=1.CC[O-].[Na+].CC(O)=O>CCO>[Cl:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([Cl:13])[C:7]=1[N:6]1[C:2]2[N:1]=[C:29]([CH2:28][C:25]3[CH:26]=[CH:27][C:22]([OH:21])=[CH:23][CH:24]=3)[NH:20][C:18](=[O:19])[C:3]=2[C:4]([CH:15]([CH3:16])[CH3:17])=[N:5]1
Reactant: CC(C)c1nn(-c2c(Cl)cccc2Cl)c(N)c1C(N)=O
Reactant: CCOC(=O)Cc1ccc(O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)c1nn(-c2c(Cl)cccc2Cl)c2nc(Cc3ccc(O)cc3)[nH]c(=O)c12
Temperature: 25 °C
Yield: 75.7 %

Procedure:
To a suspension of 5-amino-1-(2,6-dichlorophenyl)-3-isopropyl-1H-pyrazole-4-carboxylic acid amide (5.0 g, 16 mmol) in EtOH (20 mL) was added ethyl 4-hydroxyphenylacetate (8.6 g, 48 mmol) followed by NaOEt (2.66M in EtOH, 36 mL, 96 mmol). The reaction was then heated to reflux for 3 h. The reaction was then cooled to room temp and poured onto 10% aq. HOAc (100 mL). The resulting suspension was then cooled to 0° C. and filtered. The precipitate was then washed with 1:1 MeOH/H2O (100 mL) and 1:1 Et2O/hexane (75 mL). The solid was then dried under vacuum to yield the desired product (5.2 g, 76%).
Reaction SMILES: Cl.[CH3:2][NH2:3].[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>CO.[Pt]=O>[NH2:3][CH2:2][CH:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:10])[CH2:12][CH2:13]1
Reactant: CN
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CN)CC1
Yield: 93.9 %

Procedure:
A solution of methylamine hydrochloride (1.01 g, Wako Pure Chemical Industries) and 1-(tert-butoxycarbonyl)-4-oxopiperidine (1.99 g, Aldrich) in methanol (13 ml) was stirred in the presence of platinum oxide (69 mg, Wako Pure Chemical Industries) at room temperature for 3 hours under hydrogen atmosphere of ordinary pressure. The hydrogen was purged with a nitrogen gas, and the platinum catalyst was removed by filtration. Then, the reaction mixture was adjusted to pH of from 10 to 11 with 1 N aqueous sodium hydroxide. The reaction mixture was added with water (10 ml), and the product was extracted three times with ethyl acetate (15 ml for each time). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=20:1) to obtain the title compound (2.01 g).
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[N:13]=[C:12](Cl)[C:11]2[C:6](=[C:7]([CH3:17])[C:8]([O:15][CH3:16])=[CH:9][CH:10]=2)[N:5]=1>O.C1COCC1>[Cl:3][C:4]1[N:13]=[C:12]([OH:1])[C:11]2[C:6](=[C:7]([CH3:17])[C:8]([O:15][CH3:16])=[CH:9][CH:10]=2)[N:5]=1
Reactant: [OH-]
Reactant: COc1ccc2c(Cl)nc(Cl)nc2c1C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(O)nc(Cl)nc2c1C
Temperature: 40 °C
Yield: 99.3 %

Procedure:
A solution of NaOH (1.58 g, 39.6 mmol) in water (40 mL) was added to 2,4-dichloro-7-methoxy-8-methylquinazoline (139) (3.2 g, 13.05 mmol) in THF (20 mL). The resulting mixture was heated at 40° C. for 24 h. Then, the reaction mixture was cooled to room temperature, THF was evaporated and additional water (30 mL) was added. The precipitate was filtered off. Then, the pH of the filtrate was adjusted to 5 with AcOH to give a solid which was subsequently filtered off and successively washed with water and isopropylether to give the title compound (2.91 g, 99%) as a yellowish powder: m/z=225 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:15]([O-:17])=[O:16])=[C:7]([CH:9]([OH:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:8]=1.[C@:18]12([CH3:30])[C:24]([CH3:26])([CH3:25])[CH:21]([CH2:22][CH2:23]1)[CH2:20][CH:19]2[C:27](Cl)=[O:28]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C@:18]12([CH3:30])[C:24]([CH3:25])([CH3:26])[CH:21]([CH2:22][CH2:23]1)[CH2:20][CH:19]2[C:27]([O:14][CH:9]([C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[N+:15]([O-:17])=[O:16])[C:10]([CH3:13])([CH3:12])[CH3:11])=[O:28]
Reactant: CC1(C)C2CC[C@@]1(C)C(C(=O)Cl)C2
Reactant: COc1ccc([N+](=O)[O-])c(C(O)C(C)(C)C)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc([N+](=O)[O-])c(C(OC(=O)C2CC3CC[C@]2(C)C3(C)C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of racemic (R/S)-1-(5-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propanol (1.75 g, 7.3 mmol) and DMAP (2.92 g, 23.9 mmol) in anhydrous CH2Cl2 (10 mL), (1S)-camphanic chloride (Corrie et al., 1992), which is incorporated by reference) (2.6 g, 12 mmol) was added, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was diluted with CH2Cl2 (50 mL) and washed with saturated NaHCO3 solution (50 mL). The organic phase was dried over Na2SO4, concentrated in vacuo, and the residue was purified by silica gel column chromatography to yield (R/S)-1-(5-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propyl (1S)-camphanate (2.5 g, 85%, 1:1 mixture of diastereomers). The camphanate was dissolved in ethyl acetate (30 mL) followed by slow addition of hexane (120 mL) with stirring. Needle crystals formed gradually from the solution over a two-hour period. The crystals were collected by filtration to yield pure single diastereomer (S)-1-(5-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propyl (1S)-camphanate. The filtrate was concentrated in vacuo, and the crystallization process was repeated twice to provide additional (S)-1-(5-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propyl (1S)-camphanate (total 1.08 g, 43%). 1H NMR (400 MHz, CDCl3): δ 8.04 (d, 1H, J=9.2 Hz, Ph-H), 7.27 (d, 1H, J=2.8 Hz, Ph-H), 6.88 (dd, 1H, J=2.8 and 8.8 Hz, Ph-H), 6.81 (3, 1H, Ph-CH), 3.87 (s, 3H, OCH3), 2.36 (m, 1H, CH), 1.92 (m, 2H, CH2), 1.66 (m, 1H, CH), 1.12 (s, 3H, CH3), 1.06 (s, 3H, CH3), 1.02 (s, 3H, CH3), 0.95 (s, 9H, C(CH3)3).