Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[O:11])[CH2:8]2.Br[C:13]1[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][C:14]=1[Cl:26].[Cl-].[Li+].C([Mg]Cl)(C)C>O1CCCC1>[Cl:26][C:14]1[CH:15]=[C:16]([CH:24]=[CH:25][C:13]=1[C:2]1([OH:11])[CH:3]2[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][CH:1]1[CH2:8]3)[CH2:4]2)[C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)c(Cl)c1
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(C2(O)C3CC4CC(C3)CC2C4)c(Cl)c1
Temperature: 25 °C

Procedure:
To a cold (−40° C.) solution of 2-adamantanone (1.50 g, 10.00 mmol) and tert-butyl 4-bromo-3-chlorobenzoate (2.45 g, 10.00 mmol) in anhydrous tetrahydrofuran (120 mL) was added isopropylmagnesium chloride lithium chloride complex (1.3 M solution in tetrahydrofuran, 10 mL, 13 mmol). The reaction mixture was warm to ambient temperature over 2 hours and heated to reflux for 1 hour. After cooling to ambient temperature, the mixture was quenched with saturated aqueous ammonium chloride (10 mL), diluted with ethyl acetate (200 mL), washed with saturated aqueous ammonium chloride
Reaction SMILES: [Cl:1][C:2]1[S:9][C:8]2[CH:7]=[CH:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:4]=2[CH:3]=1.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.[Li+].CC([N-]C(C)C)C>C1COCC1>[C:13]([O:12][C:10]([N:5]1[C:6]([B:17]([OH:22])[OH:18])=[CH:7][C:8]2[S:9][C:2]([Cl:1])=[CH:3][C:4]1=2)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)n1ccc2sc(Cl)cc21
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(B(O)O)cc2sc(Cl)cc21
Temperature: 0 °C
Reaction time: 6 h
Yield: 49.7 %

Procedure:
To a solution of tert-butyl 2-chloro-4H-thieno[3,2-b]pyrrole-4-carboxylate (0.52 g, 2 mmol) and B(OiPr)3 (0.7 mL, 3 mmol) in 10 mL of THF cooled at 0° C. was added a LDA solution (4 mmol, prepared from 0.56 mL of iPr2NH, 5.84 mL of THF and 1.6 mL of 2.5 M n-BuLi solution in hexane) by a syringe pump over a period of 2 h. The reaction mixture was stirred for additional 6 h at 0° C. before being quenched by addition of 20 mL of saturated NH4Cl solution. The product was extracted with 2×20 mL of EtOAc, dried over Na2SO4, filtered and concentrated. The residue was purified by Combiflash on a silica gel column eluted with a gradient of up to 60% EtOAc/hexanes to give 0.3 g of the title compound as a solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[C:15]([CH:17]=[C:18](OCC)[NH:19][C:20]#[C:21][CH3:22])#[N:16].C(N)C#C.C(C=C(OCC)OCC)#N>>[C:15]([CH:17]=[C:18]([NH:19][CH2:20][C:21]#[CH:22])[NH:14][CH2:13][CH2:12][S:11][CH2:10][C:8]1[O:9][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:6][CH:7]=1)#[N:16]
Reactant: CC#CNC(=CC#N)OCC
Reactant: CN(C)Cc1ccc(CSCCN)o1
Agent: C#CCN
Agent: CCOC(=CC#N)OCC
Product: C#CCNC(=CC#N)NCCSCc1ccc(CN(C)C)o1

Procedure:
When 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine is reacted with 1-cyano-2-ethoxy-2-propynylaminoethylene [prepared from propargylamine and 1-cyano-2,2-bis(ethoxy)ethylene, which itself is prepared by the procedure described in J. Am. Chem. Soc., 71, 47 (1949)], the title product is produced.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Cl)[CH:3]=1.Cl.[CH3:11][O:12][C:13]([CH:15]1[CH2:19][CH:18]([OH:20])[CH2:17][NH:16]1)=[O:14].C(N(CC)CC)C.[OH-].[Na+]>ClCCl>[CH3:11][O:12][C:13]([C@@H:15]1[CH2:19][C@@H:18]([OH:20])[CH2:17][N:16]1[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:14]
Reactant: COC(=O)C1CC(O)CN1
Reactant: ClCc1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@@H](O)CN1Cc1cccc(Cl)c1
Yield: 64.9 %

Procedure:
Chloro-3-chloromethyl-benzene (15.2 ml, 120 mmol) was added to the mixture of 4-hydroxy-pyrrolidine-2-carboxylic acid methyl ester hydrochloride (14.5 g, 80 mmol) and triethylamine (18.6 g, 180 mmol) in dichloromethane (120 ml). The reaction mixture was refluxed overnight. After cooling, 1M aqueous sodium hydroxide was added, and the mixture was extracted with dichloromethane. The extract was washed with brine, dried over sodium sulfate, concentrated and purified by chromatography on silica gel (hex/EA=5:1 to hex/EA=31) to give 14 g title product as yellow oil in 65% yield.
Reaction SMILES: B#B.[CH:3]1([C:12]([NH2:14])=O)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.Cl>C1COCC1>[CH:3]1([CH2:12][NH2:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1
Reactant: NC(=O)C1CCc2ccccc21
Agent: B#B
Agent: Cl
Solvent: C1CCOC1
Product: NCC1CCc2ccccc21
Temperature: 25 °C
Yield: 71 %

Procedure:
To a solution of 150 ml of diborane (1M in THF) in 250 ml of dry THF. Ten g of 1-indane carboxamide is slowly added. Reaction mixture is stirred at reflux for three hours, cooled to room temperature, and worked up by slowly adding 150 ml of 1N HCl. THF is distilled off under reduced pressure, the aqueous solution is brought to pH~13 by addition of NaOH. It is extracted with ethyl acetate (2×300 ml). The organic extract is washed with water (1×100 ml), dried over MgSO4, filtered, and evaporated to dryness affording 6.5 g (71%) of 1-indanylmethylamine. It was used as is in the next reaction.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][C:5]([Cl:9])=[C:6](Cl)[N:7]=1.[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.[Cl-].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH3:14])[N:7]=1
Reactant: COC(=O)c1nc(Cl)c(Cl)nc1N
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1nc(Cl)c(-c2ccccc2C)nc1N
Temperature: 110 °C
Reaction time: 48 h
Yield: 32 %

Procedure:
Put 5 g (22.5 mmol) of methyl 3-amino-5,6-dichloropyrazine-2-carboxylate, 3.2 g (23.65 mmol) of 2-methylphenyl boronic acid in 45 mL of anhydrous toluene in a screw-top bottle. After dissolution, add 34 mL (67.6 mmol) of a 2N aqueous solution of sodium carbonate and degas the two-phase mixture for 30 min by bubbling with argon. Then add 1.3 g (1.13 mmol) of Pd(PPh3)4 and stir the reaction mixture vigorously at 110° C. for 48 h. After cooling, distribute the solution in 500 mL of EtOAc/brine 1:1 mixture and extract the aqueous phase again with 4×50 mL of EtOAc. Combine the organic phases, dry over Na2SO4 and concentrate under reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a cyclohexane/EtOAc gradient from 0 to 20% of EtOAc. After concentration under reduced pressure, we obtain 2 g of methyl 3-amino-6-chloro-5-(2-methylphenyl)pyrazine-2-carboxylate in the form of yellow wax.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=[CH:4][CH:3]=1.[S:24](Cl)([C:27]1[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=1)(=[O:26])=[O:25]>CN(C)C1C=CN=CC=1.ClCCl>[S:24]([C:27]1[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=1)([O:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=1)(=[O:26])=[O:25]
Reactant: OCCCCCCCCCCCCCCCc1ccc(I)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCCCCCCCCCCCCCc2ccc(I)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.3 %

Procedure:
A mixture of 15-(p-iodophenyl)pentadecanol (Compound II) (200 mg; 0.47 mmol), tosyl chloride (102 mg; 0.53 mmol) and 4-dimethylaminopyridine (66 mg; 0.53 mmol) in dichloromethane (3 ml) was stirred at room temperature for 12 h. The reaction mixture was then partitioned between chloroform (40 ml), methanol (40 ml) and 0.1 N hydrochloric acid (36 ml). The chloroform layer was separated and extraction was repeated (2×40 ml of chloroform). Extracts were combined, dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel in hexane-chloroform (from 95:5 to 40:60) to give Compound III, 15-(p-Iodophenyl)pentadecyl tosylate (259 mg; 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([C:29]([C:31]2[CH:40]=[C:39]([CH3:41])[C:34]3[NH:35][C:36](=[O:38])[O:37][C:33]=3[CH:32]=2)=[O:30])[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([C:29]([C:31]5[CH:40]=[C:39]([CH3:41])[C:34]6[NH:35][C:36](=[O:38])[O:37][C:33]=6[CH:32]=5)=[O:30])[N:25]=[C:26]([CH3:28])[N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: Cc1nc(Cl)cc(C(=O)c2cc(C)c3[nH]c(=O)oc3c2)n1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5[nH]c(=O)oc5c4)nc(C)n3)CC1)C(=O)N2

Procedure:
83 mg (0.30 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 91 mg (0.30 mmol) 6-(6-chloro-2-methyl-pyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one and 0.11 mL (0.60 mmol) DIPEA were stirred together in 3 mL DMF overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and the organic solvent was evaporated down. The residue was neutralised with 4N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried i. vac.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[O:11][C:12]([C:14]2[C:19]([CH:20]=1)=[C:18]([N+:21]([O-])=O)[CH:17]=[CH:16][CH:15]=2)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>CO.[Cl-].[Cl-].[Cl-].[Ti+3]>[CH2:1]([O:8][CH2:9][C:10]1[O:11][C:12]([C:14]2[C:19]([CH:20]=1)=[C:18]([NH2:21])[CH:17]=[CH:16][CH:15]=2)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1oc(COCc2ccccc2)cc2c([N+](=O)[O-])cccc12
Agent: [Ti+3]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Nc1cccc2c(=O)oc(COCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.9 %

Procedure:
A solution of 3-benzyloxymethyl-5-nitroisocoumarin (850 mg) in methanol (40.0 ml) was treated with aqueous titanium trichloride (11.2 ml), added as a single portion. After stirring 2 hours at ambient temperature, water (100 ml) and chloroform (120 ml) were added. The whole was carefully basified with saturated sodium bicarbonate aqueous solution and the organic layer was separated. The aqueous layer was further extracted with chloroform (120 ml) and the combined extract was washed with water, dried over magnesium sulfate, and concentrated to afford 3-benzyloxymethyl-5-aminoisocoumarin (806 mg).
Reaction SMILES: [Na].Cl.[NH2:3][OH:4].[F:5][C:6]([F:27])([F:26])[C:7]1[C:12]2[C:13](=[O:25])[N:14]3[CH2:24][CH2:23][C@H:15]3[C:16]3[N:17]([CH:18]=[N:19][C:20]=3[C:21]#[N:22])[C:11]=2[CH:10]=[CH:9][CH:8]=1>CO>[F:27][C:6]([F:5])([F:26])[C:7]1[C:12]2[C:13](=[O:25])[N:14]3[CH2:24][CH2:23][C@H:15]3[C:16]3[N:17]([CH:18]=[N:19][C:20]=3[C:21](=[N:3][OH:4])[NH2:22])[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: N#Cc1ncn2c1[C@@H]1CCN1C(=O)c1c-2cccc1C(F)(F)F
Reactant: NO
Agent: Cl
Agent: [Na]
Solvent: CO
Product: NC(=NO)c1ncn2c1[C@@H]1CCN1C(=O)c1c-2cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
730 mg (31.8 mmol) of sodium were dissolved in 40 ml of methanol. 2.37 g (34.1 mmol) of hydroxylamine hydrochloride and 7.1 g (22.3 mmol) of (S)-8-trifluoromethyl-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carbonitrile were added in succession at room temperature and the mixture was stirred at room temperature overnight. By evaporating the solvent there were obtained 7.8 g (100%) of (S)-8-trifluoromethyl-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamidoxime, which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[CH2:6][CH2:7][CH:8]([C:10]([O:12][CH3:13])=[O:11])[O:9][C:4]=2[C:3]=1[CH2:16][CH2:17][CH3:18].Br[CH2:20][CH2:21][CH2:22][Cl:23].C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>C(OCC)(=O)C>[Cl:23][CH2:22][CH2:21][CH2:20][O:1][C:2]1[CH:15]=[CH:14][C:5]2[CH2:6][CH2:7][CH:8]([C:10]([O:12][CH3:13])=[O:11])[O:9][C:4]=2[C:3]=1[CH2:16][CH2:17][CH3:18]
Reactant: CCCc1c(O)ccc2c1OC(C(=O)OC)CC2
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: CCCc1c(OCCCCl)ccc2c1OC(C(=O)OC)CC2
Reaction time: 8 h

Procedure:
Methyl 3,4-dihydro-7-hydroxy-8-propyl-2H- l-benzopyran-2-carboxylate (10 g, 40 mmol), 1-bromo-3-chloropropane (75 g, 48 mmol), and potassium carbonate (828g, 60 mmol) were added to 100 ml of methyl ethyl ketone, and the reaction mixture was heated to reflux and stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate, concentrated, and the crude product was chromatographed on silica gel using 20% ethyl acetate/80% hexane as eluant to give the product.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])[N:14]([CH:25]([NH:36][CH:37]=O)[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:13]1=[O:39])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.P(Cl)(Cl)(Cl)=O>C(Cl)Cl.C1C=CC=CC=1.C(OCC)(=O)C>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])[N:14]([CH:25]([N+:36]#[C-:37])[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:13]1=[O:39])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CNC(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SC(=O)OCC(Cl)(Cl)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: [C-]#[N+]C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SC(=O)OCC(Cl)(Cl)Cl
Reaction time: 4.8 h

Procedure:
To a solution of benzyl 2-[3-phenoxyacetamido-4-(2,2,2-trichloroethoxycarbonylthio)-2-oxo-1-azetidinyl]-2-formamidoacetate (2.70 g.) and 2,6-lutidine (11.4 ml.) in methylene chloride (16 ml.) was added dropwise phosphorus oxychloride (1.12 ml.) at 0° C. After stirring at the same temperature for 4.8 hours, the mixture was diluted with a mixture of benzene and ethyl acetate (120 ml.) (6:4 by volume), and washed successively with a chilled dilute aqueous solution of sodium chloride, a mixture of 10% phosphoric acid (75 ml.) and a saturated aqueous solution of sodium chloride, a dilute aqueous solution of sodium chloride, ice-water and a saturated aqueous solution of sodium chloride. Drying over magnesium sulfate and removal of the solvent left an oil (2.5 g.), which was chromatographed on silica gel (30 g.) with a mixed solvent of benzene and ethyl acetate (5:1 by volume) as an eluent to give an amorphous solid of benzyl 2-[3-phenoxyacetamido-4-(2,2,2-trichloroethoxycarbonylthio)-2-oxo-1 -azetidinyl]-2-isocyanoacetate.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][C:12]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)[C:13](OCC)=[O:14]>C1COCC1.C(OCC)(=O)C>[CH3:11][C:12]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)[CH2:13][OH:14]
Reactant: CCOC(=O)C(C)(Cc1ccc(C)cc1)c1cccnc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(CC(C)(CO)c2cccnc2)cc1
Reaction time: 1 h

Procedure:
A solution of diisobutylaluminum hydride 120 ml. 120 mmol, 1.0M in THF) was added to a solution of the product of STEP 2 (11.6 g, 38.7 mmol) in 100 ml THF at 0° C. over 20 min. After 1 h, the reaction was diluted with 25 ml ethyl acetate and quenched with 75 ml H2O. The resulting mixture was filtered through a short column of Celite®, and washed with ethyl acetate. Filtrate was extracted with ethyl acetate (3×100 ml). The combined organic layer was washed with brine, dried with MgSO4, and concentrated. The residue was purified by chromatography (on silica gel, ethyl acetate) to give a pale brown liquid in 4.1 g. NMR spectra of the product were consistent for the proposed structure.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([OH:9])=O)=[N+:2]=[N-:3].[NH2:14][C:15]1[C:16]([CH3:30])=[C:17]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:18]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:20]=1.N(C1C=C(C=CC=1C)C(NC1C=C(C(C)(C)C)C=C(NS(C)(=O)=O)C=1OC)=O)=[N+]=[N-]>>[N:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([NH:14][C:15]1[CH:20]=[C:19]([C:21]([CH3:23])([CH3:24])[CH3:22])[CH:18]=[C:17]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[C:16]=1[CH3:30])=[O:9])=[N+:2]=[N-:3]
Reactant: Cc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: Cc1ccc(C(=O)O)cc1N=[N+]=[N-]
Agent: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Product: Cc1ccc(C(=O)Nc2cc(C(C)(C)C)cc(NS(C)(=O)=O)c2C)cc1N=[N+]=[N-]

Procedure:
3-Azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methyl-phenyl)-4-methyl-benzamide was prepared from 3-azido-4-methyl benzoic acid (U.S. Ser. No. 04/102,492) and N-(3-Amino-5-tert-butyl-2-methyl-phenyl)-methanesulfonamide in the same manner as 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide (Example 15).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][CH:13]([C:20]1[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][CH:21]=1)[CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1>C(Cl)(Cl)Cl>[Cl:12][CH:13]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:27])=[O:9])=[CH:22][CH:21]=1)[CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(C(Cl)Cn2ccnc2)cc1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1ccc(C(Cl)Cn2ccnc2)cc1
Reaction time: 6 h

Procedure:
A solution of 85% m-chloroperbenzoic acid in chloroform (2 g/100 ml.) is added dropwise, over a period of one hour, to a stirred solution of 2.53 g. of 1-[β-chloro-4-methylthiophenethyl]imidazole in 150 ml. of chloroform at 0° C. After 6 hours, the resultant solution is washed with aqueous potassium carbonate and with water. The organic phase is separated and dried over magnesium sulfate. Evaporation of the solvent yields 1-[β-chloro-4-methylsulfinylphenethyl]imidazole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:41])[CH2:10][NH:11][C:12]([C:14]2[N:15]=[C:16]3[N:31]([CH2:32][C:33](=[O:40])[N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)[CH:30]=[CH:29][N:17]3[C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=O)=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[CH2:21]([O:20][C:19]1[C:18](=[O:28])[N:17]2[CH:29]=[CH:30][N:31]([CH2:32][C:33](=[O:40])[N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[C:16]2=[N:15][C:14]=1[C:12]1[O:41][C:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:10][N:11]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(CNC(=O)c1nc2n(CC(=O)N3CCCCC3)ccn2c(=O)c1OCc1ccccc1)Cc1ccc(F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Cn1ccn2c(=O)c(OCc3ccccc3)c(-c3ncc(Cc4ccc(F)cc4)o3)nc12)N1CCCCC1
Reaction time: 3 h
Yield: 20.7 %

Procedure:
To a solution of the product of example 5 (200 mg, 0.357 mmol) in acetonitrile (3 ml), carbon tetrachloride (330 mg, 2.1 mmol), triethylamine (180 mg, 1.78 mmol) and triphenylphosphine (470 mg, 1.79 mmol) were added successively at room temperature. The mixture was stirred for 3 hours. The product was purified by column chromatography (CH2Cl2/MeOH=150/1) to give the titled product (40 mg, 21% yield).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.[CH2:25]([O:27][CH2:28][C:29](O)=[O:30])[CH3:26].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C1COCC1.C(N(CC)CC)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4][C@H:3]2[CH2:2][NH:1][C:29](=[O:30])[CH2:28][O:27][CH2:25][CH3:26])=[CH:11][C:12]=1[F:17]
Reactant: CCOCC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOCC(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(F)c1
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate (150 mg), ethoxyacetic acid (35 mg), 1H-benzotriazol-1-ol (67.8 mg) and triethylamine (0.146 ml) in THF (2.1 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (96 mg), and the mixture was stirred overnight. To the reaction mixture was added distilled water, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (125 mg).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:11]=[C:10]([CH:12]3[CH2:18][C:17](=[O:19])[O:16][C:14](=O)[CH2:13]3)[CH:9]=[CH:8][C:5]=2[C:6]=1[CH3:7].[CH:20]1([NH2:23])[CH2:22][CH2:21]1.C(O)(=O)C.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:20]1([N:23]2[C:14](=[O:16])[CH2:13][CH:12]([C:10]3[CH:9]=[CH:8][C:5]4[C:6]([CH3:7])=[C:2]([CH3:1])[O:3][C:4]=4[CH:11]=3)[CH2:18][C:17]2=[O:19])[CH2:22][CH2:21]1
Reactant: NC1CC1
Reactant: Cc1oc2cc(C3CC(=O)OC(=O)C3)ccc2c1C
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cc1oc2cc(C3CC(=O)N(C4CC4)C(=O)C3)ccc2c1C
Temperature: 25 °C

Procedure:
2.58 g (0.01 mol) of 3-(2,3-dimethyl-6-benzofuranyl)-glutaric anhydride (c.f. Example (4c), 0.855 g, corresponding to about 1.04 ml (1.5 molar equivalents) of cyclopropylamine and 11 ml of glacial acetic acid are dissolved in 11 ml of toluene and the solution is refluxed for 2 days using a water separator. The reaction mixture is then cooled to room temperature, diluted with 50 ml of ethyl acetate and washed twice with 25 ml of water. Thereafter, the organic phase is extracted with 2 N aqueous sodium carbonate solution to remove the acid constituents, then washed again with water and with saturated sodium chloride solution (25 ml of each) and dried over sodium sulfate and the ethyl acetate is evaporated off under a waterpump vacuum. A sand-coloured crude product of melting point 180°-182° is thereby obtained. This is recrystallised from warm methylene chloride and hexane, whereupon N-cyclopropyl-3-(2,3-dimethyl-6-benzofuranyl)-glutarimide is obtained as white flakes of melting point 183°-184° .
Reaction SMILES: [CH:1]1([CH2:7][O:8][N:9]2C(=O)C3=CC=CC=C3[C:10]2=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][O:21][C:22](=[O:38])[C:23]1[CH:28]=[CH:27][C:26](C=O)=[CH:25][C:24]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH3:37]>>[CH3:20][O:21][C:22](=[O:38])[C:23]1[CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])[C:25](=[CH:10][NH:9][O:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:26]=[CH:27][CH:28]=1
Reactant: O=C1c2ccccc2C(=O)N1OCC1CCCCC1
Reactant: COC(=O)c1ccc(C=O)cc1-c1ccccc1C
Product: COC(=O)C1=CC=CC(=CNOCC2CCCCC2)C1c1ccccc1C

Procedure:
The desired product was prepared using the method described in Example 1176B starting with the compound from Example 1185A and N-[4-Formyl-2-(2-methylphenyl)benzoic acid methyl ester, prepared using the method of Example 403G and starting with the alcohol prepared in Example 1178C.