Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[CH:6][C:5]([N+:20]([O-:22])=[O:21])=[C:4]([Cl:23])[CH:3]=1.[CH:24]([Sn](CCCC)(CCCC)CCCC)=[CH2:25]>C1(C)C=CC=CC=1>[Cl:23][C:4]1[CH:3]=[C:2]([CH:24]=[CH2:25])[C:7]([O:8][CH2:9][C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[CH:6][C:5]=1[N+:20]([O-:22])=[O:21]
Reactant: COc1ccc(F)c(F)c1COc1cc([N+](=O)[O-])c(Cl)cc1Br
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=Cc1cc(Cl)c([N+](=O)[O-])cc1OCc1c(OC)ccc(F)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-1-nitrobenzene (3.06 g) in toluene (120 mL) were added vinyltri(n-butyl)tin (2.4 mL) and tetrakis-(triphenylphosphine)palladium(0) (0.87 g), and the reaction mixture was heated at reflux under an argon atmosphere overnight. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. To the residue were added tetrahydrofuran (30 mL), water (30 mL) and 0.5 mol/L aqueous potassium fluoride solution (30 mL), and the mixture was stirred at room temperature for 1 hour. The insoluble material was removed by filtration, and the insoluble material was washed with ethyl acetate. The filtrate and washing were combined, and the organic layer was separated. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residual crystals were suspended in a mixed solvent (n-hexane/ethyl acetate=5/1), and collected by filtration. The collected crystals were dried under reduced pressure to give 2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-1-nitro-4-vinylbenzene (2.32 g). This material was dissolved in tetrahydrofuran (65 mL). To the solution was added borane-tetrahydrofuran complex (1.2 mol/L tetrahydrofuran solution, 9 mL) in a dropwise manner under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature overnight. To the reaction mixture were added 1 mol/L aqueous sodium hydroxide solution (30 mL) and 30% aqueous hydrogen peroxide solution (30 mL) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was stirred at room temperature for 1 hour, and then stirred at 90° C. for 1 hour. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1−1/1) to give the title compound (0.38 g).
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]3[N:34]=[CH:33][CH:32]=[CH:31][C:25]=3[N:26]3[C:30]=2[CH2:29][CH2:28][CH2:27]3)=[CH:19][CH:18]=1.Cl.C([O-])(O)=O.[Na+]>CCO>[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]3[N:34]=[CH:33][CH:32]=[CH:31][C:25]=3[N:26]3[C:30]=2[CH2:29][CH2:28][CH2:27]3)=[CH:19][CH:18]=1
Reactant: C[Si](C)(C)CCOCn1c(Oc2ccc(-c3c4n(c5cccnc35)CCC4)cc2)nc2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: c1ccc2[nH]c(Oc3ccc(-c4c5n(c6cccnc46)CCC5)cc3)nc2c1
Temperature: 70 °C
Yield: 92 %

Procedure:
To a solution of 9-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzo[d]imidazol-2-yloxy)phenyl]-7,8-dihydro-6H-pyrido[2,3-b]pyrrolizine (199 mg) in EtOH (2 mL) was added 6 M HCl aqueous solution (2 mL) and the mixture was heated at 70° C. for 2 h. The mixture was neutralized with saturated NaHCO3 aqueous solution and extracted with AcOEt. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was collected by filtration and washed with AcOEt to give the title compound (135 mg).
Reaction SMILES: [I:1][C:2]#[C:3][CH2:4][N:5]([CH2:10][C:11]#[C:12][I:13])[CH2:6][C:7]#[C:8][I:9].[F:14][C:15]([F:27])([F:26])[C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[CH2:19][N:20]=[N+:21]=[N-:22]>>[I:1][C:2]1[N:20]([CH2:19][C:18]2[CH:23]=[CH:24][CH:25]=[C:16]([C:15]([F:26])([F:27])[F:14])[CH:17]=2)[N:21]=[N:22][C:3]=1[CH2:4][N:5]([CH2:10][C:11]1[N:22]=[N:21][N:20]([CH2:19][C:18]2[CH:23]=[CH:24][CH:25]=[C:16]([C:15]([F:14])([F:27])[F:26])[CH:17]=2)[C:12]=1[I:13])[CH2:6][C:7]1[N:22]=[N:21][N:20]([CH2:19][C:18]2[CH:23]=[CH:24][CH:25]=[C:16]([C:15]([F:26])([F:27])[F:14])[CH:17]=2)[C:8]=1[I:9]
Reactant: IC#CCN(CC#CI)CC#CI
Reactant: [N-]=[N+]=NCc1cccc(C(F)(F)F)c1
Product: FC(F)(F)c1cccc(Cn2nnc(CN(Cc3nnn(Cc4cccc(C(F)(F)F)c4)c3I)Cc3nnn(Cc4cccc(C(F)(F)F)c4)c3I)c2I)c1

Procedure:
Synthesized from tris(3-iodoprop-2-ynyl)amine and 3-trifluoromethyl-benzylazide using general procedure, sample triturated with MeCN; 0.391 g, 0.352 mmol, 81%; mp=171-173° C. (dec.); IR (υ[cm−1]) 3072, 1445, 1328, 1162, 1123, 1095, 756; 1H NMR (600 MHz, CDCl3) δ=7.62 (s, 3H), 7.59 (d, J=7.7, 3H), 7.51 (d, J=7.6, 3H), 7.44 (t, J=7.7, 3H), 5.48 (s, 6H), 3.64 (s, 6H); 13C NMR (151 MHz, CDCl3) δ=149.4, 135.4, 132.3, 131.6 (q, J=32.7), 129.8, 125.9 (q, J=3.6), 125.8 (q, J=3.5), 123.8 (q, J=272.5), 81.2, 53.6, 48.2; HRMS (ESI-TOF) (m/z): [M+H]+ calcd for C33H25F9I3N10, 1112.9249; found 1112.9249.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16]N)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH2:25][C:26](=O)[CH3:27])[CH:22]=[CH:23][CH:24]=1.S(=O)(=O)(O)O>C(O)C>[CH2:2]([O:9][C:10]1[CH:15]=[C:14]2[C:13](=[CH:12][CH:11]=1)[NH:16][C:26]([CH3:27])=[C:25]2[C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[CH:20]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)Cc1cccc(Cl)c1
Reactant: NNc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Cc1[nH]c2ccc(OCc3ccccc3)cc2c1-c1cccc(Cl)c1

Procedure:
An amount of 11.7 g (47 m mole) of 4-benzyloxyphenylhydrazine-hydrochloride and 6.39 g (38 m mole) of (3-chlorophenyl)-acetone was dissolved in 35 ml of absolute ethanol, and after addition of 2.7 ml of concentrated sulfuric acid the mixture was refluxed for five hours. After the ethanol was distilled off, the residue was mixed with water and extracted with chloroform. The extracts were dried over sodium sulfate and evaporated. The evaporation residue was purified by chromatography on silicagel by using toluene as solvent.
Reaction SMILES: [C:1]1(=O)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.[O:14]=[C:15]1[N:19]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:18]2[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=2[NH:16]1.[Na].O>O1CCCC1.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[CH:1]1([N:23]2[CH2:22][CH2:21][CH:20]([N:19]3[C:18]4[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=4[NH:16][C:15]3=[O:14])[CH2:25][CH2:24]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: O=C1Cc2cccc3cccc1c23
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Na]
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]c2ccccc2n1C1CCN(C2Cc3cccc4cccc2c34)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 18.4 %

Procedure:
Acenaphthen-1-one (1.68 g, 10 mmol) was dissolved in tetrahydrofuran (THF, 15 ml). 4-(2-Keto-1-benzoimidazolinyl)piperidine (2.17 g, 10 mmol) and tetraisopropyl orthotitanate (3.4 g, 12 mmol) were added and the mixture was stirred at room temperature for 20 hr. The solvent was evaporated and a mixed solvent (15 ml) of THF/ethanol (1:2) was added to the obtained residue for dissolution. Sodium cyanoborohydrate (2.1 mmol) was added to this solution, and the mixture was stirred at stirred at room temperature for one day. Water was added, and the precipitate was removed by celite filtration and washed with ethanol. The filtrate was extracted with chloroform and washed with water and saturated brine. The extract was dried over sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (0.68 g) as yellow crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:37]=[CH:36][C:9]2[N:10]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:17]=[C:16]4Cl)=[N:12][C:8]=2[CH:7]=1)=[O:5])C.[C:38]([O:42][C:43](=[O:48])[NH:44][CH2:45][CH2:46][NH2:47])([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42][C:43]([NH:44][CH2:45][CH2:46][NH:47][C:16]1[C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:11]3[N:10]([CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[C:9]4[CH:36]=[CH:37][C:6]([C:4]([OH:5])=[O:3])=[CH:7][C:8]=4[N:12]=3)[CH:14]=2)[N:19]=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)=[O:48])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cc(Cl)c3c1)n2C1CCCCC1
Product: CC(C)(C)OC(=O)NCCNc1cc(-c2ccccc2)nc2ccc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)cc12

Procedure:
In this reaction 51 mg (0.1 mmol) of crude 2-(4-chloro-2-phenyl-quinolin-6-yl)-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid ethyl ester were used. The nucleophile used was (2-amino-ethyl)-carbamic acid tert-butyl ester. Yield: 21 mg.
Reaction SMILES: Cl.C(O[C:7]([N:9]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[CH3:10])=[O:8])(C)(C)C.[CH2:19]([O:26][C:27](=[O:37])[C@H:28]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH2:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.ClC(OC(Cl)=O)(Cl)Cl>C(OCC)(=O)C>[CH2:19]([O:26][C:27](=[O:37])[C@H:28]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH:29][C:7]([N:9]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[CH3:10])=[O:8])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CN(CCc1ccccn1)C(=O)OC(C)(C)C
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: Cl
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CN(CCc1ccccn1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 4N-hydrogen chloride in ethyl acetate (5 ml) was added to 2-[2-(N-t-butoxycarbonyl-N-methylamino)ethyl]pyridine at 0° C. The solution was stirred at 0° C. for 1 hour and concentrated under reduced pressure. The residue was dissolved in methylene chloride (10 ml). Triethylamine (304 mg) and (1S)-1-benzyloxycarbonyl-2-phenylethyl isocyanate (281 mg) prepared by reacting L-phenylalanine benzyl ester with trichloromethylchloroformate was added to this solution at 0° C. The solution was stirred at the same temperature for 1 hour and the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate and the solution was washed with 10% citric acid aqueous solution, saturated sodium bicarbonate solution, and saturated sodium chloride solution successively, dried over magnesium sulfate, and concentrated under reduced pressure to give N-[N-(2-pyridyl)ethyl-N-methylaminocarbonyl]-L-phenylalanine benzyl ester (400 mg) as an oil. Rf: 0.50 ( chloroform:methanol, 20: 1, V/V)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:32])[CH2:10][C:11]1([C:20]2[S:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)CC)C.[CH3:40][O:41][CH2:42][CH2:43][NH:44][S:45](ON1C(=O)CCC1=O)(=[O:47])=[O:46]>C(#N)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:32])[CH2:10][C@@:11]1([C:20]2[S:21][C:22]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)=[CH:23][CH:24]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][N:14]([S:45]([NH:44][CH2:43][CH2:42][O:41][CH3:40])(=[O:47])=[O:46])[CH2:13][CH2:12]1
Reactant: O=C(CC1(c2ccc(-c3ccc(Cl)cc3)s2)CCNCCS1(=O)=O)NOC1CCCCO1
Reactant: COCCNS(=O)(=O)ON1C(=O)CCC1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COCCNS(=O)(=O)N1CC[C@](CC(=O)NOC2CCCCO2)(c2ccc(-c3ccc(Cl)cc3)s2)S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
To a solution of N-(2-tetrahydropyranyloxy)-2-[7-(5-(4-chlorophenyl)-2-thienyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (100 mg) and triethylamine (22.3 mg) in acetonitrile (2 ml) was added N-(2-methoxyethylaminosulfonyloxy)succinimide (55.6 mg) and the mixture was stirred at ambient temperature for 1 hour. The mixture was partitioned with ethyl acetate and water. The organic layer was separated, washed with 5% citric acid solution, water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of chloroform and methanol (200:1, 100:1, 200:3) to give N-(2-tetrahydropyranyloxy)-2-[(S)-7-(5-(4-chlorophenyl)-2-thienyl)-4-(2-methoxyethylaminosulfonyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (80.0 mg) as a colorless amorphous powder.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]([O:18]CC)=O)[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[NH4+:22]>O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]([NH2:22])=[O:18])[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: CCOC(=O)c1cc(-c2ccc(C(C)(C)C)cc2)on1
Agent: [OH-]
Solvent: O
Product: CC(C)(C)c1ccc(-c2cc(C(N)=O)no2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl 5-(4-tert-butylphenyl)-3-isoxazolecarboxylate (25 grams) was mixed with 1 liter of concentrated ammonium hydroxide, and the reaction mixture stirred overnight (about 18 hours) at room temperature. The reaction mixture was then poured into 1 liter of water. The product precipitated and was separated by filtration, yield, 34 grams. The structure of the product was confirmed by NMR.
Reaction SMILES: N[C:2]1[CH:9]=[C:8]([F:10])[C:7]([Br:11])=[CH:6][C:3]=1[CH:4]=[O:5].S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:21].[K+]>O>[Br:11][C:7]1[C:8]([F:10])=[CH:9][C:2]([I:21])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: Nc1cc(F)c(Br)cc1C=O
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: O=Cc1cc(Br)c(F)cc1I
Reaction time: 1 h
Yield: 15.7 %

Procedure:
To a solution of Example 115A (1.0 g, 4.0 mmol) in 1: 1 ethanol-water (50 mL), was added iron-powder (0.6 g) then 6 N hydrochloric acid (1 mL). The reaction mixture was heated to reflux overnight, cooled, neutralized with I N sodium hydroxide, filtered, and the filtrate extracted with ethyl acetate (3x). The organic extracts were dried over magnesium sulfate, filtered and solvent evaporated to provide 0.68 g of 5-bromo-4-fluoro-2-aminobenzaldehyde. To a solution of 2-amino-5-bromo-4-fluorobenzaldehyde (0.68 g, 3.1 mmol) in water (10 mL) at 0 ° C. was added sulfuric acid (2 mL) then slowly a solution of sodium nitrite (0.23 g, 3.4 mmol) in water (10 mL) keeping the temperature below 10 ° C.. After stirring at this temperature for 1 hour this suspension was added to a solution of potassium iodide (0.50 g, 3.1 mmol) in water (20 mL), the reaction mixture stirred at room temperature overnight, extracted with ethyl acetate (3x). The organic extracts were washed with aqueous sodium thiosulfate, 5% sodium bicarbonate solution and water, then dried over magnesium sulfate, filtered and solvent evaporated. The crude residue was purified by flash chromatography over silica gel eluting with ethyl acetate:hexane (1:9) to provide 0.16 g of the title compound as a tan solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(O)(=O)C.C(OC(=O)C)(=O)C.[OH:16][C:17]1[CH2:22][CH:21]([C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[CH2:20][C:19](=[O:32])[C:18]=1[C:33](=[O:36])[CH2:34][CH3:35]>O>[OH:32][C:19]1[CH2:20][CH:21]([C:23]2[CH:24]=[C:25]3[O:31][CH2:30][O:29][C:26]3=[CH:27][C:28]=2[N+:1]([O-:4])=[O:2])[CH2:22][C:17](=[O:16])[C:18]=1[C:33](=[O:36])[CH2:34][CH3:35]
Reactant: O=[N+]([O-])O
Reactant: CCC(=O)C1=C(O)CC(c2ccc3c(c2)OCO3)CC1=O
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCC(=O)C1=C(O)CC(c2cc3c(cc2[N+](=O)[O-])OCO3)CC1=O

Procedure:
A solution consisting of fuming nitric acid (0.84 g), glacial acetic acid (0.54 g) and acetic anhydride (0.54 g) was added to a mixture of 3-hydroxy-5-(3,4-methylenedioxyphenyl)-2-propionylcyclohex-2-en-1-one (2.60 g) and acetic anhydride (1.62 g) at 0° C. The mixture was stirred at 0°-3° C. for 1.5 hours with addition of extra portions of acetic anhydride when necessary to aid the stirring. The mixture was poured into water and the precipitate was collected and dried giving 3-hydroxy-5-(2-nitro-4,5-methylenedioxyphenyl)-2-propionylcyclohex-2-en-1-one as a yellow solid, mp 139° C.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:11][C@H:10]([N:12]2[C:16]3=[N:17][CH:18]=[C:19]([Br:21])[N:20]=[C:15]3[N:14]([CH:22]3[CH2:24][CH2:23]3)[C:13]2=[O:25])[CH2:9]1)(C)(C)C.[ClH:27]>O1CCOCC1>[ClH:27].[NH2:7][C@H:8]1[CH2:11][C@H:10]([N:12]2[C:16]3=[N:17][CH:18]=[C:19]([Br:21])[N:20]=[C:15]3[N:14]([CH:22]3[CH2:23][CH2:24]3)[C:13]2=[O:25])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](n2c(=O)n(C3CC3)c3nc(Br)cnc32)C1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1C[C@H](n2c(=O)n(C3CC3)c3nc(Br)cnc32)C1
Reaction time: 8 h

Procedure:
To a room temperature slurry of tert-butyl(trans-3-(5-bromo-3-cyclopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclobutyl)carbamate (0.556 g, 1.31 mmol) in dioxane (10 mL) was added hydrogen chloride, 4.0M solution in 1,4-dioxane (5.0 mL, 20.00 mmol). After stirring overnight the reaction was filtered and the precipitate was washed with Et2O to give 430 mg of a white amorphous solid. ESI MS 323.9, 325.9 [M+1].
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9](NC1CCN(C2SC(C#N)=C(O)N=2)CC1)=[O:10].Cl.[NH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]2[S:35][C:36]([C:51]([O:53][CH2:54][CH3:55])=[O:52])=[C:37]([CH2:39][N:40]3[C:48](=[O:49])[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[C:41]3=[O:50])[N:38]=2)[CH2:30][CH2:29]1>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]2[S:35][C:36]([C:51]([O:53][CH2:54][CH3:55])=[O:52])=[C:37]([CH2:39][N:40]3[C:41](=[O:50])[C:42]4[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=4)[C:48]3=[O:49])[N:38]=2)[CH2:30][CH2:29]1)=[O:10]
Reactant: CCOC(=O)c1sc(N2CCC(N)CC2)nc1CN1C(=O)c2ccccc2C1=O
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3nc(O)c(C#N)s3)CC2)c(Cl)c1Cl
Agent: Cl
Product: CCOC(=O)c1sc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc1CN1C(=O)c2ccccc2C1=O

Procedure:
The title compound was prepared from 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 3) and ethyl 2-(4-aminopiperidin-1-yl)-4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1,3-thiazole-5-carboxylate hydrochloride (Intermediate 77) in a manner analogous to Example 29.
Reaction SMILES: [OH-].[K+].[CH2:3]([C:7]1([CH2:23][CH2:24][CH2:25][CH3:26])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][Si](C)(C)C)[CH:15]=2)[S:10][CH2:9][CH2:8]1)[CH2:4][CH2:5][CH3:6]>O.C(O)C>[CH2:3]([C:7]1([CH2:23][CH2:24][CH2:25][CH3:26])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[CH:18])[CH:15]=2)[S:10][CH2:9][CH2:8]1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCC1(CCCC)CCSc2ccc(C#C[Si](C)(C)C)cc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C#Cc1ccc2c(c1)C(CCCC)(CCCC)CCS2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1.41 g (25 mmol) of potassium hydroxide in 1.4 mL of water and 10.0 mL of ethanol was added to 1.44 g (4.00 mmol) of (4,4-dibutylthiochroman-6-yl)(trimethylsilyl)acetylene (Compound 34) and the resulting mixture stirred at room temperature for 16 hours during which time it became homogeneous. The solvent was removed in-vacuo and the residue was acidified with 5% aqueous H2SO4. The product was extracted with 2×50 mL of ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH:13]([OH:15])[CH3:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[C:16]1(=O)[CH2:20][CH2:19][C:18](=[O:21])[CH2:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([CH:13]([O:15][C:16]3[CH2:20][CH2:19][C:18](=[O:21])[CH:17]=3)[CH3:14])=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(O)c1cnc(-c2ccc(Cl)cc2)s1
Reactant: O=C1CCC(=O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(OC1=CC(=O)CC1)c1cnc(-c2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.9 %

Procedure:
To a solution of 1-[2-(4-Chloro-phenyl)-thiazol-5-yl]-ethanol (4.1 g, 17.1 mmol) in anhydrous THF (100 ml), at 0° C. under an atmosphere of nitrogen was added cyclopentane-1,3-dione (2.18 g, 22.23 mmol), followed by triphenylphosphine (5.83 g, 22.23 mmol). Diisopropylazodicarboxylate (4.31 ml, 22.23 mmol) was then added dropwise over a period of 5 minutes and the reaction allowed to warm to room temperature and stirred for 2 hours. The crude reaction mixture was dry loaded onto silica and purified by flash chromatography to give 3-{1-[2-(4-Chloro-phenyl)-thiazol-5-yl]-ethoxy}-cyclopent-2-enone (2.29 g).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.OS(O)(=O)=O.[C:16]([O-])([O-])=O.[Na+].[Na+]>CO>[OH:1][C:2]1[C:3]([C:8]([O:10][CH3:16])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ncccc1O
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ncccc1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
A solution of 3-hydroxypicolinic acid (30 g, 0.22 mol) in CH3OH (300 mL) was stirred at RT and conc. H2SO4 (30 mL) was added dropwise. The resulting mixture was stirred at 80° C. overnight. After the pH was adjusted to 7 with solid Na2CO3, the mixture was filtrated and the precipitate was thoroughly washed with EtOAc several times. The filtrate was concentrated to give crude methyl 3-hydroxypicolinate (27 g, yield: 82.8%). 1H-NMR (CDCl3, 400 MHz) δ 10.57 (s, 1H), 8.22˜8.20 (m, 1H), 7.32˜7.29 (m, 1H), 3.93 (s, 3H). MS (M+H)+: 154.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3=[N:12][N:13]([CH3:15])[CH:14]=[C:9]3[C:8]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:7][C:6]=2[CH:22]=1.Br[CH2:24][CH:25]1[CH2:27][CH2:26]1.C(N(CC)CC)C.O>C(#N)C>[CH:25]1([CH2:24][N:19]2[CH2:20][CH2:21][N:16]([C:8]3[C:9]4[C:10](=[N:12][N:13]([CH3:15])[CH:14]=4)[NH:11][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:22][C:6]=4[N:7]=3)[CH2:17][CH2:18]2)[CH2:27][CH2:26]1
Reactant: BrCC1CC1
Reactant: Cn1cc2c(n1)Nc1ccc(F)cc1N=C2N1CCNCC1
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cn1cc2c(n1)Nc1ccc(F)cc1N=C2N1CCN(CC2CC2)CC1

Procedure:
A solution of 7-fluoro-2,10-dihydro-2-methyl-4-(1-piperazinyl)pyrazolo[3,4-b][1,5]benzodiazepine (1.0 g), bromomethylcyclopropane (0.5 g) and triethylamine (0.0375 g) in acetonitrile (30 ml) was stirred at ambient temperature for 20 hours. The solution was poured into water and the product extracted with chloroform (3X). The organic extract was washed with saturated brine and water, dried over magnesium sulphate, the solvent removed and the residue crystallised from ethyl acetate to give the title compound m.p. 188°-189° C. 4-(4-Benzyl-1-piperazinyl)-7-fluoro-2,10-dihydro-2-methyl-pyrazolo[3,4-b][1,5]benzodiazepine was similarly prepared, m.p. 241°-245° C. (ethyl acetate-diethyl ether)