Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([CH3:16])[CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[Br:17]Br.OS(O)(=O)=O>CO>[Br:17][CH2:16][C:2](=[O:1])[CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15]
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Reactant: BrBr
Agent: O=S(=O)(O)O
Solvent: CO
Product: O=C(CBr)CCN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
To an ice-cooled and well-stirred suspension of 2-(3-oxo-butyl)-isoindole-1,3-dione (30.0 g, 138 mmol, 1 eq.) in MeOH (180 mL), bromine (14.3 mL, 276 mmol, 2 eq.) was added in one portion. The resulting red heterogeneous mixture was stirred at 0° C. for 5 min., and further at r.t. for 3.5 hours. The orange homogeneous reaction mixture was then treated with 10M aq. H2SO4 soln. (26.2 mL). The resulting heterogeneous mixture was further stirred at r.t. for 2 hours. The resulting heterogeneous reaction mixture was filtered in order to isolate the target product as a white-off solid which was further dried under high vacuum. The product was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C(OC(C)(C)C)=O)[C:9]1[S:10][C:11]([CH3:20])=[C:12]([CH3:19])[C:13]=1[C:14]([O:16]CC)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[K+].C(O)(=O)C>O>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([CH3:20])=[C:12]([CH3:19])[C:13]=1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)sc(C)c1C
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: Cc1sc(NC(=O)OC(C)(C)C)c(C(=O)O)c1C
Reaction time: 8 h

Procedure:
Ethyl 2-bis(t-butoxycarbonyl)amino-4,5-dimethylthiophene3-carboxylate (13.6 g, 34 mmol) was hydrolysed by refluxing in 70 ml of water and 140 ml of methanol with 7.63 g of potassium hydroxide. Addition of 8.1 ml of acetic acid and stirring overnight precipitated 8.27 g (90%) of 2-t-butoxycarbonylamino-4,5-dimethylthiophene-3-carboxylic acid. M.p. 185° C. (dec.). 1H-NMR (DMSO-d6, δ): 1.5 (s, 9H), 2.15 (s, 3H), 2.2 (s, 3H), 10.4 (s, 1H), 13.1 (br.s, 1H).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[O:7][CH:8]=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[C:19](Cl)(=[O:23])[CH:20]([CH3:22])[CH3:21].O>C1C=CC=CC=1>[CH2:1]([N:5]([C:6]1[O:7][CH:8]=[C:9]([CH3:11])[N:10]=1)[C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)C(=O)Cl
Reactant: CCCCNc1nc(C)co1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: O
Product: CCCCN(C(=O)C(C)C)c1nc(C)co1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76 %

Procedure:
2-(N-butylamino)-4-methyloxazole (106.7 g., 0.69 m.) and triethylamine (110 g., 0.77 m.) were stirred together in dry benzene (1500 c.c.) during the addition of isobutyryl chloride (81.0 g., 0.76 m.). The mixture was stirred at room temperature for 15 hours and then water (1 liter) was added. After stirring for a further hour the organic phase was separated, and the aqueous phase extracted twice in ether. The combined extract was washed successively with 2N hydrochloric acid (2 × 500 c.c.), 10% sodium carbonate solution (2 × 500 c.c.), and saturated brine (2 × 500 c.c.). Evaporation of the dried organic phase gave an oil, which was distilled to give 2-(N-butyl isobutyramido)-4-methyloxazole, (118 g., 80%), b.p. 75°-76° C/0.15 mm., which existed as an oil at room temperature but crystallised on cooling to 0° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]#[N:25])=[CH:18][CH:17]=1.[N-:26]=[N+:27]=[N-:28].[Na+].[Cl-].[NH4+].CN(C)C=O>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]2[NH:28][N:27]=[N:26][N:25]=2)=[CH:18][CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCc2nnn[nH]2)cc1
Temperature: 120 °C
Reaction time: 24 h
Yield: 48.1 %

Procedure:
A mixture of 3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propionitrile (0.7 g), sodium azide (0.411 g), ammonium chloride (0.337 g) and N,N-dimethylformamide (15 ml) was stirred for 24 hours at 120° C. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried, then the solvent was distilled off to leave 5-[2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]ethyl]tetrazole (0.38 g, 48%), which was recrystallized from ethyl acetate--hexane to give colorless prisms, m.p.143°-144° C.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]2[C:11]=1[CH:12]=[CH:13][NH:14]2.[CH3:20][CH:21]([N:23]1[C:27]([C:28]([NH:30][C:31]2[C:32]3[C:36]([CH:37]=[C:38](B4OC(C)(C)CC(C)(C)O4)[CH:39]=2)=[N:35][N:34](C2CCCCO2)[CH:33]=3)=[O:29])=[CH:26][CH:25]=[N:24]1)[CH3:22].O>O1CCOCC1.CO>[F:19][C:17]1[CH:16]=[C:15]2[C:11]([CH:12]=[CH:13][NH:14]2)=[C:10]([C:38]2[CH:37]=[C:36]3[C:32]([CH:33]=[N:34][NH:35]3)=[C:31]([NH:30][C:28]([C:27]3[N:23]([CH:21]([CH3:22])[CH3:20])[N:24]=[CH:25][CH:26]=3)=[O:29])[CH:39]=2)[CH:18]=1
Reactant: CC(C)n1nccc1C(=O)Nc1cc(B2OC(C)(C)CC(C)(C)O2)cc2nn(C3CCCCO3)cc12
Reactant: Fc1cc(Br)c2cc[nH]c2c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)n1nccc1C(=O)Nc1cc(-c2cc(F)cc3[nH]ccc23)cc2[nH]ncc12
Temperature: 120 °C

Procedure:
A microwave vial was charged with Solvias catalyst (8 mg), tripotassium phosphate (90 mg) and 4-bromo-6-fluoro-1H-indole (available from Sinova, 33 mg). 1-(1-Methylethyl)-N-[2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-4-yl]-1H-pyrazole-5-carboxamide (70 mg) in 1,4-dioxane (0.5 ml) was added followed by water (0.1 ml). The mixture was heated under microwave irradiation at 120° C. for 10 min. The mixture was passed through a silica cartridge which had been preconditioned with methanol, washed through with methanol, then dried under a stream of nitrogen. The residue was subjected to a DCM/water wash and then dried under a stream of nitrogen. The residue was dissolved in DMSO:methanol (1 ml, 1:1, v/v) and purified by MDAP (method A). Appropriate fractions were evaporated under a stream of nitrogen. The residues were dissolved in a minimum amount of methanol, a few drops of 2M HCl (aq) were added and the reactions were left to stand briefly at room temperature. The reactions were combined then passed through an aminopropyl cartridge preconditioned with methanol and dried. Purification was carried out using the following system:
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:15].[CH:16]1([CH2:22][C:23](Cl)=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>N1C=CC=CC=1>[CH:16]1([CH2:22][C:23]([NH:15][C:2]2[CH:3]=[CH:4][C:5]3[O:6][C:7]4[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:8]=4[C:9]=3[CH:1]=2)=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Nc1ccc2oc3c(c2c1)CCCCC3
Reactant: O=C(Cl)CC1CCCCC1
Solvent: c1ccncc1
Product: O=C(CC1CCCCC1)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 36.2 %

Procedure:
Following the procedure of Example 1, 7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-ylamine (0.91 g, 4.5 mmol) and cyclohexylacetyl chloride (0.80 g, 5.0 mmol) in pyridine (10 mL) provided 2-cyclohexyl-N-[7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-yl]acetamide (0.53 g). Mp 188-189° C.; Anal. Calcd. for C21H27NO2: C, 77.50; H, 8.36; N, 4.30; Found: C, 77.51; H, 8.43; N, 4.32.
Reaction SMILES: [CH2:1]([N:4]1[C:18](=[O:19])[C:17]2[C:11]3([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:10][C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=3[C:7]=2[NH:6][C:5]1=[S:24])[CH:2]=[CH2:3].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1.[OH-].[K+].O>C(O)C>[CH2:1]([N:4]1[C:18](=[O:19])[C:17]2[C:11]3([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)[CH2:10][C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=3[C:7]=2[N:6]=[C:5]1[S:24][CH2:31][C:30]1[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=1)[CH:2]=[CH2:3]
Reactant: COc1ccc(CBr)cc1
Reactant: C=CCn1c(=S)[nH]c2c(c1=O)C1(CCCCC1)Cc1ccccc1-2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCn1c(SCc2ccc(OC)cc2)nc2c(c1=O)C1(CCCCC1)Cc1ccccc1-2

Procedure:
A mixture of 3-allyl-2-thioxo-2,3-dihydro-1H-spiro[benzo[h]quinazoline-5,1′-cyclohexan]-4(6H)-one (5, 0.100 g, 0.295 mmol), paramethoxybenzyl bromide (0.047 ml, 0.325 mmol), potassium hydroxide (0.025 g, 0.443 mmol) in Ethanol (1.738 ml) was refluxed overnight. 1 ml of water was added to the cooled reaction and the mixture was extracted with EtOAc 2×. The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. 1H NMR (500 MHz, CDCl3) δ ppm 8.17, 7.39-7.24, 6.88, 5.93, 5.31-5.26, 4.68, 4.57, 3.82, 3.07, 2.61, 1.75-1.72, 1.60-1.53, 1.43-1.37; MS (EI) m/z 459 (M+1)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[C:11](=[O:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O>C(#N)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]([C:19]#[N:20])=[CH:21][CH:22]=2)[C:11](=[O:23])[C:10]=1[Br:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc(-n2ccc(OCc3ccccc3)cc2=O)cc1
Solvent: CC#N
Product: N#Cc1ccc(-n2ccc(OCc3ccccc3)c(Br)c2=O)cc1
Reaction time: 0.75 h
Yield: 89.9 %

Procedure:
4-[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]benzonitrile (Step 1) (2.76 g, 9.13 mmol) was suspended in acetonitrile (50 mL) and cooled in an ice-bath. N-bromosuccinimide (1.71 g, 9.54 mmol) was added. Once the addition was complete the cooling bath was removed. After stirring for 45 minutes the reaction was diluted with acetonitrile and solids were collected by filtration to give a white solid (3.13 g, 90%). 1H NMR (300 MHz, DMSO-d6) δ 8.00 (d, J=8.5 Hz, 2H), 7.84 (d, J=7.9 Hz, 1H), 7.66 (d, J=8.5, 2H), 7.50-7.37 (m, 5H), 6.63 (d, J=7.9 Hz, 1H), 5.41 (s, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][C:24](=[O:26])[NH:23][S:22]3(=[O:28])=[O:27])=[C:17]([OH:29])[CH:16]=2)[CH2:9]1)=O)(C)(C)C.Cl>CCOCC.O1CCOCC1>[OH:29][C:17]1[CH:16]=[C:15]([CH2:14][CH:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH:20]=[CH:19][C:18]=1[N:21]1[S:22](=[O:28])(=[O:27])[NH:23][C:24](=[O:26])[CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCCC(Cc2ccc(N3CC(=O)NS3(=O)=O)c(O)c2)C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C1CN(c2ccc(CC3CCCNC3)cc2O)S(=O)(=O)N1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 3-[3-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-benzyl]-piperidine-1-carboxylic acid tert-butyl ester (24 mg, 0.052 mmol) in ether (1.5 mL) is added 2 mL of HCl in dioxane (4 M) and the mixture is stirred at RT for 18 h. The solvent is removed under reduced pressure to give the hydrochloride salt of the title compound: (M−1)−=324.
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH:11]=[CH2:12])[N:9]=1.[Cl-:13].[NH4+:14]>CO>[ClH:13].[CH2:10]([CH:8]1[NH:9][C:3](=[NH:14])[CH2:4][CH2:5][CH2:6][CH2:7]1)[CH:11]=[CH2:12]
Reactant: [Cl-]
Reactant: C=CCC1CCCCC(OC)=N1
Reactant: [NH4+]
Solvent: CO
Product: C=CCC1CCCCC(=N)N1
Product: Cl
Yield: 79.5 %

Procedure:
The product of EXAMPLE 106 (70 mg, 0.42 mmol) in 3 mL of MeOH was reacted with ammonium chloride (21.4 mg, 0.4 mmol) by the method of EXAMPLE 27 to yield 60 mg (76%) of the title material.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[O-:7].[Na+].F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([N:1]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]2=[O:7])=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: [O-]c1cnccn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cnccn1-c1ccc([N+](=O)[O-])cc1
Temperature: 35 °C

Procedure:
A mixture of 632 mg Sodium pyrazin-2-olate and 720 mg 1-Fluoro-4-nitro-benzene and 3.3 g Cs2CO3 in 13 mL DMF was heated to 35° C. for 6 h. This solution was poured on to 300 mL of water and the resulting precipitate was collected by filtration to yield a bright yellow crystalline product, which was dried under reduced pressure. Yield: 545 mg.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][C:7]([CH2:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CN=C1.[C:17]1(=[O:22])[CH2:21][CH2:20][CH:19]=[CH:18]1>CO.O>[Cl:1][C:2]1[C:3]([CH:4]([OH:5])[C:18]2[C:17](=[O:22])[CH2:21][CH2:20][CH:19]=2)=[CH:6][C:7]([CH2:10][CH3:11])=[CH:8][N:9]=1
Reactant: CCc1cnc(Cl)c(C=O)c1
Reactant: O=C1C=CCC1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CO
Product: CCc1cnc(Cl)c(C(O)C2=CCCC2=O)c1
Yield: 97 %

Procedure:
The clear solution of 2-Chloro-5-ethylnicotinaldehyde (10 mmol, 1.69) and imidazole (10 mmol, 0.68 g) in 50 ml. of MeOH was slowly charged with 50 ml. of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclopenten-1-one (10.2 mmol., 0.88 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl3 thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 97% yield (2.47 g).
Reaction SMILES: C(O)(=O)C[C:3]1[C:4](=CC=C(C=1)O)[OH:5].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.C(Cl)(=O)C.[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:3][C:4]([C:19]1[CH:20]=[C:15]([O:14][CH3:13])[CH:16]=[CH:17][C:18]=1[O:21][CH3:22])=[O:5]
Reactant: COc1ccc(OC)cc1
Reactant: O=C(O)Cc1cc(O)ccc1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(=O)Cl
Product: COc1ccc(OC)c(C(C)=O)c1

Procedure:
The best method known for preparing homogentisic acid appears to be that described in J. Biol. Chem. 179, 365 (1949), in which 1,4-dimethoxybenzene is reacted with acetyl chloride in the presence of aluminum chloride to give 2,5-dimethoxyacetophenone, the latter is reacted with sulphur in morpholine to give 2,5-dimethoxyphenylacetic acid, which on demethylation with hydrobromic acid gives homogentisic lactone, ring-opening of which gives the desired acid.
Reaction SMILES: C[N:2]([CH:4]=[C:5]([C:8]1[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:10][N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=12)[CH:6]=O)C.O.[NH2:24]N.C(O)C>O>[NH:2]1[CH:4]=[C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:6]=[N:24]1
Reactant: CN(C)C=C(C=O)c1c(-c2ccccc2)nn2ccccc12
Reactant: NN
Solvent: O
Solvent: CCO
Product: c1ccc(-c2nn3ccccc3c2-c2cn[nH]c2)cc1
Yield: 81.5 %

Procedure:
A mixture of 3-(N,N-dimethylamino)-2-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylaldehyde (0.70 g), hydrazine mono hydrate (0.18 g) and ethanol (7 ml) was refluxed for 4 hours. To the reaction mixture was added water (12 ml), and stirred under ice-cooling. The precipitates were collected and recrystallized from a mixture of ethanol and water to give 3-(4-pyrazolyl)-2-phenylpyrazolo[1,5-a]pyridine (0.51 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH3:12].CN(C(OC)OC)C.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.O1CCO[CH2:28][CH2:27]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH:12]=[C:27]([N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[CH3:28]
Reactant: C1CCNC1
Reactant: C1COCCO1
Reactant: Cc1c(Br)cc(F)cc1[N+](=O)[O-]
Agent: COC(OC)N(C)C
Product: CC(=Cc1c(Br)cc(F)cc1[N+](=O)[O-])N1CCCC1
Temperature: 100 °C

Procedure:
To a solution of 1-bromo-5-fluoro-2-methyl-3-nitro-benzene (7.49 g, 31.8 mmol) in dioxane (40 mL) were added DMF-DMA (21.0 mL, 158 mmol) and pyrrolidine (2.6 mL, 31.1 mmol). The reaction mixture was heated at 100° C. for 3 h. The mixture was cooled to RT and concentrated in vacuo to give 1-[2-(2-bromo-4-fluoro-6-nitro-phenyl)-1-methyl vinyl]-pyrrolidine as a dark red residue. To a suspension of the pyrrolidine (10.0 g, 31.7 mmol) and Raney®-Nickel (suspension in H2O, 15 mL) in MeOH:THF (1:1, 150 mL) was added hydrazine monohydrate (2.3 mL, 47.4 mmol) at 0° C. and the mixture stirred at RT for 5 hours. The reaction mixture was then filtered through Celite and the filter cake washed with EtOAc. The filtrate was concentrated in vacuo and the resulting residue was purified by column chromatography (silica gel, pentane:EtOAc 75:25) to provide the title compound as a pale oil (2.57 g, 37%).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[N:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7](Cl)[N:6]=1>CO>[Cl:4][C:5]1[N:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]([O:2][CH3:1])[N:6]=1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(OC)nc(Cl)n1
Reaction time: 0.25 h

Procedure:
A 0.5 M solution of sodium methoxide in MeOH was added slowly to a solution of methyl 2,6-dichloropyrimidine-4-carboxylate (0.30 g, 1.45 mmol) in MeOH (2 ml). A white precipitate formed which was stirred for further 15 minutes. The product was collected by filtration (0.20 g).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][NH:9][CH2:10][C:11]([OH:13])=O.O[N:15]1[C:36](=[O:37])[NH:35][C@H:34]2[C@@H:16]1[CH2:17][S:18][C@H:19]2[CH2:20][CH2:21][CH2:22][CH:23](N1C(=O)CCC1=O)[C:24](=[O:26])[OH:25]>CN(C=O)C>[CH3:8][NH:9][CH2:10][C:11]([CH:23]([CH2:22][CH2:21][CH2:20][C@H:19]1[C@@H:34]2[C@@H:16]([NH:15][C:36]([NH:35]2)=[O:37])[CH2:17][S:18]1)[C:24](=[O:25])[OH:26])=[O:13]
Reactant: CNCC(=O)O
Reactant: O=C(O)C(CCC[C@@H]1SC[C@H]2[C@@H]1NC(=O)N2O)N1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNCC(=O)C(CCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)C(=O)O
Temperature: 85 °C
Yield: 83.2 %

Procedure:
DMF (8.0 ml) and triethylamine (0.61 ml, 4.35 mmol) were added to solids N-methyl glycine (182 mg, 2.05 mmol) and N-hydroxy-succinimidyl biotin (500 mg, 1.46 mmol). The mixture was heated for 1 hour in an oil bath at 85° C. during which time the solids dissolved producing a clear and colorless solution. The solvents were then evaporated. The yellow oil residue was acidified with glacial acetic acid, evaporated and chromatographed on a 27 mm column packed with 50 g silica, eluting with 30% MeOH/EtOAc 1% HOAc to give the product as a white solid (383 mg) in 66% yield.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[C:7](Cl)=[O:8].[C:10]1([CH2:16][O:17][C:18]([C:20]2([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:10]1([CH2:16][O:17][C:18]([C:20]2([NH:26][C:7]([N:3]3[CH2:4][CH2:5][NH:6][C:2]3=[O:1])=[O:8])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[O:19])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NC1(C(=O)OCc2ccccc2)CCCCC1
Reactant: O=C(Cl)N1CCNC1=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C1NCCN1C(=O)NC1(C(=O)OCc2ccccc2)CCCCC1
Temperature: 60 °C
Reaction time: 96 h
Yield: 82.2 %

Procedure:
1.38 g (9.3 mmol) of 2-oxo-1-imidazolidinecarbonyl chloride was added to a solution of 2.17 g (9.3 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester and 1.04 g (10 mmol) of triethylamine in 100 ml of chloroform, and the mixture was stirred at 60° C. for four days. The reaction solution was successively washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and it was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained crystal was washed with diethyl ether to obtain 2.64 g (82%) of the title compound.
Reaction SMILES: CN(C)[N:3]=[CH:4]/[CH:5]=[CH:6]/[CH2:7][CH3:8].Br[C:11]1[C:12](=[O:22])[C:13]2[C:18]([C:19](=[O:21])[CH:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.CC1C=CN=C2C(=O)C3C=CC=CC=3C(=O)C=12>C1(C)C(C)=CC=CC=1>[CH3:8][CH2:7][C:6]1[CH:5]=[CH:4][N:3]=[C:11]2[C:12]([C:13]3[C:18]([C:19](=[O:21])[C:20]=12)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:22]
Reactant: CC/C=C/C=NN(C)C
Reactant: O=C1C=C(Br)C(=O)c2ccccc21
Agent: Cc1ccnc2c1C(=O)c1ccccc1C2=O
Solvent: Cc1ccccc1C
Product: CCc1ccnc2c1C(=O)c1ccccc1C2=O
Yield: 15.3 %

Procedure:
A solution of trans-2-pentenal N,N-dimethylhydrazone (49.15 g, 0.39 mol) in xylene (100 mL) was quickly added to a xylene (600 mL) solution of 2-bromo-1,4-naphthoquinone (71.12 g, 0.30 mol) and the dark reaction heated at reflux for 6 h. Workup followed the procedure described above for cleistopholine. Chromatography provided pure homocleistopholine (13) (10.90 g, 14%). An analytical sample was obtained by crystallization from EtOAc: mp 157°-158° C.; IR (KBr) 1680, 1665, 1590, 1575, 1450, 1340, 1300, 1280, 1260, 1225, 1200, 1000, 955, 870, 850, 800, 790, 730 cm-1 ; 1H NMR (CDCl3) δ 1.29 (t, 3H, J=7.4 Hz), 3.28 (q, 2H, J=7.4 Hz), 7.48 (d, 1H, J=5.0 Hz), 7.71-7.78 (m, 2H), 8.14-8.18 (m, 1H), 8.25-8.28 (m, 1H), 8.87 (d, 1H, J=5.0 Hz); 13C NMR (CDCl3) 14.1 (3), 28.0 (2), 127.1 (1), 127.2 (1), 128.5 (0), 129.3 (1), 132.4 (0), 133.9 (0), 134.0 (1), 134.5 (1), 150.2 (0), 153.6 (1), 157.2 (0), 181.8 (0), 184.5 (0) ppm; Anal. calcd for C15H11NO2 : C 75.94, H 4.67, N 5.90; found C 75.85, H, 4.68, N 5.91.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:8][CH2:7][C:6](=O)[NH:5][C:4]2[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:3]1=2.CO>C1COCC1>[CH3:1][C:2]1([CH3:17])[CH2:8][CH2:7][CH2:6][NH:5][C:4]2[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:3]1=2
Reactant: CC1(C)CCC(=O)Nc2ccc([N+](=O)[O-])cc21
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)CCCNc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Yield: 71.7 %

Procedure:
Combined 5,5-Dimethyl-7-nitro-1,3,4,5-tetrahydrobenzo[b]azepin-2-one (89 mg, 0.38 mmol), Borane-THF complex, 1M in THF (1.9 mL, 1.9 mmol) and 3 mL anhydrous THF. Heated reaction to reflux for 1 hour. Let reaction cool to room temperature, added methanol and concentrated under reduced pressure. Dissolved residue in methylene chloride and washed with saturated sodium bicarbonate solution. Purified with normal phase chromatography eluting with 10% ethyl acetate in hexane to yield a yellow solid, 5,5-Dimethyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (60 mg, 72%). mp 99° C.; LCMS: m/z=221.06 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.26 (d, 1H, J=2.3 Hz), 7.91 (dd, 1H, J=8.6, 2.5 Hz), 6.68 (d, 1H, J=8.8 Hz), 4.28 (br s, 1H), 3.16 (m, 2H), 1.91 (m, 2H), 1.72 (m, 2H), 1.41 (s, 6H).
Reaction SMILES: C(OC([N:8]([C:16]1[C:21]([C:22]2[O:26][N:25]=[C:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][O:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)=[CH:30][CH:29]=3)[CH:23]=2)=[CH:20][CH:19]=[CH:18][N:17]=1)C(OC(C)(C)C)=O)=O)(C)(C)C.FC(F)(F)C(O)=O.O.C(=O)(O)[O-].[Na+]>ClCCl>[N:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[O:35][CH2:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][C:24]2[CH:23]=[C:22]([C:21]3[C:16]([NH2:8])=[N:17][CH:18]=[CH:19][CH:20]=3)[O:26][N:25]=2)=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Reaction time: 14 h

Procedure:
To a solution of di-tert-butyl(3-(3-(4-((pyridin-2-yloxy)methyl)benzyl)isoxazol-5-yl)pyridin-2-yl)imidodicarbonate described in Preparation Example 3-1-2 (11.8 g, purity approximately 70%) and dichloromethane (120 mL) was added trifluoroacetic acid (40 mL) at 0° C. Stirring was carried out at room temperature for 14 hours. To the reaction solution was added saturated sodium bicarbonate water at 20° C or lower, extracted with ethyl acetate, and then purified by NH-silica gel column chromatography (heptane:ethyl acetate=1:1). The solvent was concentrated under a reduced pressure, tert-butyl methyl ether was added to the resulting residue, and solids were filtered to obtain the title compound (7.29 g).