Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][C:17]=3[O:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=3[F:30])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9]C.B(Br)(Br)Br.CO.[OH-].[Na+]>ClCCl>[F:30][C:22]1[CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=[CH:26][C:21]=1[O:20][C:17]1[CH:16]=[CH:15][N:14]=[C:13]2[CH:12]=[C:11]([C:5]3[CH:4]=[C:3]([OH:2])[C:8]([OH:9])=[CH:7][CH:6]=3)[S:19][C:18]=12
Reactant: COc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cc1OC
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(O)c(O)c4)sc23)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
To a stirred solution of 331 (172 mg, 0.40 mmol) in anhydrous dichloromethane (20 ml) at −78° C. was slowly added BBr3 (˜4 mL, 1.0 M in CH2Cl2). The temperature was allowed to warm to room temperature over 1.5 hrs, and the reaction mixture was stirred overnight. After cooling to 0° C., MeOH and 1 N NaOH (few mL) were added, respectively. The reaction mixture was stirred for 1 h, concentrated, diluted with MeOH and water, shaken for 30 min, isolated by filtration, and rinsed with MeOH. The mother liquid was concentrated, dissolved in a minimum of MeOH, and diluted with a small amount of water. The pH of the solution was adjusted to 4 with 1N NaOH in order to get a pale brown suspension. After shaking for 15 min, the suspension was filtered off, rinsed with water, air-dried, and dried under high vacuum to afford the title compound 332 (154 mg, 96% yield) as a yellow-green solid. MS (m/z): 399.0 (M+H)+.
Reaction SMILES: [CH:1]1([C@H:5]([NH:13][C:14]([CH2:16][C:17]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[C:18]=2[C:19]([OH:21])=[O:20])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1.[C:28](C1C2C=C(F)C=C(F)C=2C(=O)OC=1N[C@@H](C1CCC1)C1C=CC=C(F)C=1)(=[O:30])[CH3:29].C1([C@H](NC(C2C3C=C(F)C=C(F)C=3C(=O)OC=2C)=O)C2C=CC=C(F)C=2)CCC1.[OH-].[Na+]>C(OC(=O)C)(=O)C.O1CCCC1>[CH:1]1([C@H:5]([NH:13][C:14]([CH:16]([C:17]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[C:18]=2[C:19]([OH:21])=[O:20])[C:28](=[O:30])[CH3:29])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)c1c(N[C@H](c2cccc(F)c2)C2CCC2)oc(=O)c2c(F)cc(F)cc12
Reactant: O=C(Cc1cc(F)cc(F)c1C(=O)O)N[C@H](c1cccc(F)c1)C1CCC1
Agent: Cc1oc(=O)c2c(F)cc(F)cc2c1C(=O)N[C@H](c1cccc(F)c1)C1CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)C(C(=O)N[C@H](c1cccc(F)c1)C1CCC1)c1cc(F)cc(F)c1C(=O)O
Reaction time: 0.5 h
Yield: 42 %

Procedure:
2-({[(S)-Cyclobutyl-(3-fluoro-phenyl)-methyl]-carbamoyl}-methyl)-4,6-difluoro-benzoic acid (3.4 g, 9.0 mmol in acetic anhydride (60 mL) was stirred at 100° C. overnight then evaporated and co-evaporated with toluene twice in vacuo to give a mixture of 4-acetyl-3-{[(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amino}-6,8-difluoro-2-benzopyran-1-one and 6,8-difluoro-3-methyl-1-oxo-1H-2-benzopyran-4-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide. The obtained residue was dissolved in tetrahydrofuran (15 mL), allowed to cool on an ice-water bath and 2M aqueous NaOH (18 mL) was added. The cold bath removed and the reaction mixture was stirred for 30 min. The obtained mixture was diluted with water (20 mL) and extracted with isopropyl acetate (40 mL) which was washed with water (40 mL). The combined aqueous phase was cooled on ice bath and the pH was adjusted to 1 with conc. HCl. The title product was separated by extraction with isopropylacetate (2×40 mL) and purified by flash chromatography (50 g SiO2, the product was eluted with 1:1 ethyl acetate-heptane, 1.58 g, yield 42%). LC-MS (m/z) 420.6 (MH+); tR=1.35.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:24][C:25](=[O:34])[NH:26][O:27]C2CCCCO2)[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)(=O)C.O>[CH:1]1([CH2:6][C@H:7]([CH2:24][C:25]([NH:26][OH:27])=[O:34])[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)Nc1ncccn1)NOC1CCCCO1
Solvent: CC(=O)O
Solvent: O
Product: O=C(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)Nc1ncccn1)NO
Temperature: 25 °C
Reaction time: 72 h
Yield: 36.3 %

Procedure:
A mixture of (5S)-1-{(2R)-2-(cyclopentylmethyl)-4-oxo-4-[(tetrahydro-2H-pyran-2-yloxy)amino]butanoyl}-N-2-pyrimidinyl-4,5-dihydro-1H-pyrazole-5-carboxamide (80 mg, 0.17 mmol) in acetic acid (8 mL) and water (2 mL) was stirred at room temperature for 3 days. The solvent was then removed to provide a residue which was purified by Gilson HPLC (Sunfire Column 19×50 mm, flowrate 25 mL/min, 10 min, 5-70% MeCN:H2O) to afford (5S)-1-[(2R)-2-(cyclopentylmethyl)-4-(hydroxyamino)-4-oxobutanoyl]-N-2-pyrimidinyl-4,5-dihydro-1H-pyrazole-5-carboxamide (24 mg, 35% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.15 (br. s., 2H) 1.37-1.94 (m, 9H) 2.41 (br. s., 1H) 2.64 (br. s., 1H) 3.24 (br. s., 2H) 3.52 (br. s., 1H) 3.83 (br. s., 1H) 5.11 (br. s., 1H) 6.99-7.07 (m, 2H) 8.64 (d, J=4.80 Hz, 2H) 9.21 (br. s., 1H) 10.33 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9](O)[C:10]1[N:14]([CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:13]2[C:26]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[CH:27][CH:28]=[CH:29][C:12]=2[N:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]2=[N:11][C:12]3[CH:29]=[CH:28][CH:27]=[C:26]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])[C:13]=3[N:14]2[CH2:15][CH2:16][CH2:17][N:18]1[C:19]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:25]
Reactant: CCN(CC)c1cccc2nc(C(O)c3ccc(Cl)cc3Cl)n(CCCNC(=O)OC(C)(C)C)c12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCN(CC)c1cccc2nc3n(c12)CCCN(C(=O)OC(C)(C)C)C3c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 28.6 %

Procedure:
To a stirred solution of tert-butyl (3-{2-[(2,4-dichlorophenyl)(hydroxy)methyl]-7-(diethylamino)-1H-benzimidazol-1-yl}propyl)carbamate (Reference example 228, 500 mg, 0.959 mmol) and triphenylphosphine (377 mg, 1.44 mmol) in tetrahydrofuran (30 mL) was added a solution of diethyl azodicarboxylate in toluene (40%, 0.655 mL, 1.44 mmol) at 0° C. The mixture was stirred at 0° C. for 2 h, concentrated in vacuo, and purified by column chromatography on silica gel eluting with a 10-20% ethyl acetate/n-hexane gradient mixture to give a colorless amorphous solid (138 mg, 0.274 mmol, 29%).
Reaction SMILES: [Br:1][C:2]1[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[C:5]2[N:6]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:7]([CH2:9][CH2:10][CH2:11][CH3:12])=[N:8][C:4]=2[CH:3]=1.Cl.[CH:27](Cl)(Cl)Cl.CO.C(O)=O>CO>[Br:1][C:2]1[CH:22]=[C:21]([C:23]([O:25][CH3:27])=[O:24])[C:5]2[N:6]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:7]([CH2:9][CH2:10][CH2:11][CH3:12])=[N:8][C:4]=2[CH:3]=1
Reactant: CCCCc1nc2cc(Br)cc(C(=O)O)c2n1Cc1ccccc1Cl
Reactant: ClC(Cl)Cl
Agent: Cl
Solvent: CO
Solvent: O=CO
Product: CCCCc1nc2cc(Br)cc(C(=O)OC)c2n1Cc1ccccc1Cl

Procedure:
A mixture of 5-bromo-2-n-butyl-1-(2-chlorophenyl)-methyl-1H-benzimidazole-7-carboxylic acid (prepared in Example 1)(1.0 g, 2.4 mmol) in methanol (15 mL) was cooled in ice and then saturated with dry hydrochloric acid. The reaction mixture was refluxed for 14 hours, and TLC on silica with 9:1 chloroform/methanol containing a trace of formic acid gave an Rf 0.87 for the product; the starting material had an Rf 0.65. The methanol was evaporated, the residue was diluted with ice water and the solid was separated, washed with water and dried at 92° C. at high vacuum to provide 0.88 g of methyl 5-bromo-2-n-butyl-1-(2-chlorophenyl)methyl-1H-benzimidazole-7-carboxylate.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)=[O:12])[CH2:7][CH2:6]1.[NH:23]1[CH:27]=[C:26]([CH2:28][C:29](O)=[O:30])[N:25]=[N:24]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][N:2]([CH2:3][CH2:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[C:17]([Cl:22])[CH:18]=[C:19]([Cl:21])[CH:20]=2)=[O:12])[CH2:9][CH2:10]1)[C:29](=[O:30])[CH2:28][C:26]1[N:25]=[N:24][NH:23][CH:27]=1
Reactant: O=C(O)Cc1c[nH]nn1
Reactant: CNCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)C(=O)Cc1c[nH]nn1

Procedure:
A mixture comprising of 3,5-dichlorobenzyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate (Example 1, step 3) (100 mg, 0.290 mmol), 2-(1H-1,2,3-triazol-4-yl)acetic acid (55.2 mg, 0.434 mmol), T3P® (50% solution in DMF) (338 μl, 0.579 mmol) and Huenig's base (101 μl, 0.579 mmol) in DMF was stirred at room temperature for 18 hours. The resulting mixture was concentrated under pressure. The crude residue was diluted with water and extracted with EtOAc. The organic portion was dried over MgSO4, filtered and solvent concentrated under reduced pressure. Further purification was carried out using preparative LC-MS. The resulting product fractions were concentrated under reduced pressure to give an aqueous solution and then extracted with EtOAc. The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:5][CH2:4][CH2:3]1.[OH:16]O.[OH-].[Na+]>CO>[O:1]1[CH:2]2[CH2:3][CH2:4][C:5](=[O:16])[C:6]12[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: OO
Reactant: O=C(O)CCCCCCC1=CCCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCCCCC12OC1CCC2=O
Reaction time: 18 h

Procedure:
A stirred solution of 7-(5-oxocyclopent-1-enyl)heptanoic acid (16.5 g) in methanol (400 ml) was treated slowly with aqueous hydrogen peroxide solution (32 ml; 100 volume strength) and 4N sodium hydroxide solution (28 ml) at 5° to 10° C. and allowed to stand at room temperature for 18 hours. The solution was concentrated in vacuo (to a volume of about 100 ml) and water (100 ml) was then added to the residue. The mixture was washed with chloroform and the chloroform discarded. The aqueous solution was then acidified to pH 3 by means of glacial acetic acid. The mixture was extracted with chloroform and the chloroform extract was washed with water and dried over magnesium sulphate. The solvent was removed in vacuo to give (±)-7-(1,2-epoxy-5-oxocyclopentyl)heptanoic acid (16.0 g), pure enough for use in the preparation of (±)-7-(4-acetoxy-5-oxocyclopent-1-enyl)heptanoic acid without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[NH:14][C:15]([NH2:24])=[C:16]2[C:20]([N:21]=1)=[N:19][C:18]([O:22][CH3:23])=[N:17]2)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][O:31][CH2:30]1>>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][O:31][CH2:30]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: BrCCCC1CCCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCOC3)c2n1

Procedure:
Prepared similarly to Intermediate 213 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 3-(3-bromopropyl)tetrahydro-2H-pyran. LCMS (Method B): tRET=1.13 min; MH+=364
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:7])[C:4](Cl)=[O:5]>C(O)(C)C>[Br:1][CH2:2][C:3](=[O:7])[C:4]([O:7][CH:3]([CH3:4])[CH3:2])=[O:5]
Reactant: O=C(Cl)C(=O)CBr
Solvent: CC(C)O
Product: CC(C)OC(=O)C(=O)CBr
Temperature: 20 °C
Reaction time: 8 h
Yield: 124.2 %

Procedure:
To iso-propanol was added 3-bromopyruvic chloride (5 g) at −5° C. dropwise and the solution was stirred overnight at 20° C. Evaporation of solvent gave iso-propyl 3-bromopyruvate (3.5 g), which was used in the next step without further purification.
Reaction SMILES: CC(=O)CC.Br[CH2:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.[F:23][C:24]1[CH:31]=[C:30]([OH:32])[CH:29]=[CH:28][C:25]=1[C:26]#[N:27].C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[C:26]([C:25]1[CH:28]=[CH:29][C:30]([O:32][CH2:7][CH2:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:31][C:24]=1[F:23])#[N:27]
Reactant: N#Cc1ccc(O)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(CCCBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCCOc2ccc(C#N)c(F)c2)CC1
Temperature: 25 °C
Yield: 54.5 %

Procedure:
A 2-butanone (7.6 mL) solution of 1.12 g of tert-butyl 4-(3-bromopropyl)-1-piperidinecarboxylate was added to a 2-butanone (7.0 mL) mixture of 0.50 g of 2-fluoro-4-hydroxybenzonitrile and 0.56 g of potassium carbonate, which was then heated to reflux for 6 hours and 30 minutes. After cooling down to room temperature, the reaction mixture was added to a mixture of ethyl acetate and water. The organic layer was separated, washed with water, and dried with anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The resultant residue was purified using silica gel column chromatography (eluent; hexane:ethyl acetate=4:1) to provide 0.72 g of tert-butyl 4-[3-(4-cyano-3-fluorophenoxy)propyl]-1-piperidinecarboxylate as colorless oily form.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:12]=3[CH2:11][CH2:10][NH:9][CH2:8][C:7]=2[C:21]=1[O:22][CH3:23].[CH2:24](Br)[CH:25]=[CH2:26].C(=O)(O)[O-].[Na+]>O>[CH2:26]([N:9]1[CH2:10][CH2:11][C:12]2[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:13]=2[CH2:14][CH2:15][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:21]([O:22][CH3:23])[C:7]=2[CH2:8]1)[CH:25]=[CH2:24]
Reactant: COc1ccc2c(c1OC)CNCCc1cc(O)ccc1CC2
Reactant: C=CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: C=CCN1CCc2cc(O)ccc2CCc2ccc(OC)c(OC)c2C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 100 mg of 3,4-dimethoxy-10-hydroxy-5,6,7,8,13,14-hexahydrodibenz[c,g]azecine, 42.6 ml of allyl bromide and 32.3 mg of sodium bicarbonate in 4 ml of dimethylformaide is stirred for 2 hours at 100°C in argon atmosphere. After cooling, 40 ml of water is added to the mixture, and the mixture is extracted with methylene chloride. The extract is washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue is dissolved in benzene, passed through a column of 3.8 g of silica gel, and eluated with benzene - ethyl acetate (10 : 1). The evaporation of the solvent affords 106 mg of 6-allyl-3,4-dimethoxy-10-hydroxy-5,6,7,8,13,14-hexahydrodibenz[c,g]azecine as a colorless oily material. IR: νmaxCHCl 3 3604, 3420 and 1641 cm-1.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[CH:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[O-]CCCC.[K+]>C(O)(C)C>[C:30]1([CH:29]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)O
Product: O=C(O)CCCCC=Cc1ccccc1
Reaction time: 2 h
Yield: 85.1 %

Procedure:
5-Carboxypentyl-triphenylphosphonium bromide (20 g) and benzaldehyde (5.6 g) were suspended in isopropanol (100 ml). To the suspension was added potassium butoxide (10.8 g) in limited amounts at 25° C., then the reaction was allowed to proceed for 2 hours at 70° C. Isopropanol was distilled off under reduced pressure. To the residue was added water (100 ml) to make a solution, which was acidified with hydrochloric acid, followed by extraction with ethyl acetate. The extract was washed with water, dried and concentrated under reduced pressure. The concentrate was subjected to a silica gel column chromatography to afford 7-phenyl-6-heptenoic acid (7.6 g) as a colorless oily product.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH2:8].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>CCOC(C)=O.O>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=2[NH2:8])[CH2:15][CH2:14]1
Reactant: Nc1c(Br)cncc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Solvent: CCOC(C)=O
Solvent: O
Product: CN1CCN(c2cncc([N+](=O)[O-])c2N)CC1
Yield: 56.9 %

Procedure:
A solution of 3-bromo-5-nitropyridin-4-amine (LVIII) (618 mg, 2.83 mmol) in 1-methylpiperazine (1 mL, 8.51 mmol) was heated at 140° C. overnight. The reaction was poured into an EtOAc/H2O mixture; the organic layer was separated, dried over MgSO4 and concentrated under vacuum. The crude product was purified on a silica gel column (100% CHCl3→3:97 MeOH (7N NH3):CHCl3) to give 3-(4-methylpiperazin-1-yl)-5-nitropyridin-4-amine (LXX) as a yellow solid (382 mg, 1.61 mmol, 56.7% yield). 1H NMR (CDCl3, 500 MHz,) δ ppm 2.20 (s, 3H), 2.35-2.37 (m, 4H), 4.52-3.54 (m, 4H), 5.96 (s, 1H), 7.42 (s, 2H), 8.78 (s, 1H); ESIMS found C10H15N5O2 m/z 238 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[N:6][CH:5]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=1B(O)O>C1C=CC=CC=1.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.C(O)C>[NH2:1][C:2]1[C:7]([C:21]2[CH:22]=[C:23]([Cl:27])[CH:24]=[C:25]([Cl:26])[C:20]=2[Cl:19])=[N:6][CH:5]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[N:3]=1
Reactant: CC(=O)Nc1cnc(Br)c(N)n1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1Cl
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: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: CC(=O)Nc1cnc(-c2cc(Cl)cc(Cl)c2Cl)c(N)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-amino-3-bromo-6-acetamidopyrazine (7.00 g, 0.03 mole) in benzene (60.90 ml) and tetrakis(triphenylphosphine)palladium(0) was stirred under nitrogen at room temperature for 10 minutes. 2M aqueous sodium carbonate (30.24 ml) was added to the mixture followed by a solution of 2,3,5-trichlorobenzene boronic acid (6.83 g, 0.03 mole) in absolute ethanol (7.07 ml) and the mixture refluxed under nitrogen for 17 hrs. A further equivalent of 2,3,5-trichlorobenzene boronic acid in absolute ethanol was then added and the mixture refluxed for an additional 7.50 hrs. Finally, another equivalent of 2,3,5-trichlorobenzene boronic acid in absolute ethanol was added to the mixture and continued refluxing for 17 hrs. The cooled mixture was evaporated in vacuo. The residue was dissolved in chloroform (150 ml), washed with aqueous saturated sodium bicarbonate (1×100 ml) and water (1×100 ml), dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated down in vacuo. The residue was purified by ‘flash chromatography’ using chloroform to 98:2 chloroform:methanol as the eluent. Yield 3.02 g (30%), M.p. 200-203° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([OH:18])=[CH:17][C:12]=3[S:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19](Br)[CH:20]=[CH2:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]1([CH2:7][CH2:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([O:18][CH2:21][CH:20]=[CH2:19])=[CH:17][C:12]=3[S:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc2c(CCc3ccccc3)csc2c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc2c(CCc3ccccc3)csc2c1
Reaction time: 2.5 h

Procedure:
A stirred solution of the product from Step E (4.651 grams) in dry DMF (40 mL) was exposed to allyl bromide (1.66 mL) followed by cesium carbonate (6.26 grams). After 2.5 hours at ambient temperature, the reaction was partitioned between isopropyl acetate and pH4 pthalate buffer. The organic was washed twice with water, dried over magnesium sulfate and filtered. Evaporation gave a residue which, when chromatographed over silica gel (3:1 hex/CH2Cl2), gave the title compound, a clear oil.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[N:8]=1.[C:14]1(=[O:18])[CH2:17][CH2:16][CH2:15]1.[NH4+].[Cl-]>ClCCl>[Br:13][C:9]1[N:8]=[C:7]([C:14]2([OH:18])[CH2:17][CH2:16][CH2:15]2)[CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCC1
Reactant: Brc1cccc(Br)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: ClCCl
Product: OC1(c2cccc(Br)n2)CCC1
Reaction time: 0.25 h

Procedure:
n-Butyllithium (6.85 mL, 11.0 mmol) was added to a suspension of 2,6-dibromopyridine (2.36 g, 9.96 mmol) in dichloromethane (60 mL) at −78° C. The reaction mixture was stirred for 15 minutes and cyclobutanone (0.838 g, 12.0 mmol) was added in one portion at −78° C. The reaction was stirred for an additional 30 minutes before pouring the reaction into a mixture of saturated aqueous NH4Cl and dichloromethane. The organic layer was concentrated to dryness and was purified by flash chromatography to yield 1-(6-bromopyridin-2-yl)cyclobutanol as a light yellow oil. MS ESI calc'd. for C9H11BrNO [M+H]+ 228 and 230. found 228 and 230.
Reaction SMILES: C1([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)CCCCC=1.[CH3:13][C:14]1([CH3:21])[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.N1CCOCC1>C1CCCCC1>[CH3:13][C:14]1([CH3:21])[CH2:19][CH2:18][C:17]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[CH:16][CH2:15]1
Reactant: CC1(C)CCC(=O)CC1
Reactant: C1=C(N2CCOCC2)CCCC1
Solvent: C1CCCCC1
Solvent: C1COCCN1
Product: CC1(C)CC=C(N2CCOCC2)CC1

Procedure:
Compound III″ (brown liquid) is obtained quantitatively according to Example 1, from 4,4-dimethylcyclohexanone (350.03 g, 2.76 mol), morpholine (327.01 g, 3.75 mol) and cyclohexane (330 mL).
Reaction SMILES: [CH:1]1[C:6]2[C:7](=O)[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.[OH-].[NH4+]>C1(C)C=CC=CC=1.Cl[Ti](Cl)(Cl)Cl>[N:17]1([C:7]2[C:6]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: O=C1Nc2ccccc2Oc2ccccc21
Reactant: C1CNCCN1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)N=C(N1CCNCC1)c1ccccc1O2
Temperature: 25 °C

Procedure:
To a stirred solution of 10, 11-dihydro-dibenz[b,f][1,4]oxazepin-11-one in dry toluene at room temperature was added piperazine (Aldrich) followed by the dropwise addition of TiCl4. The reaction mixture was refluxed for 2 hours, cooled to room temperature and then poured into an ammonium hydroxide solution. The resulting mixture was extracted with dichloromethane, and the combined organic phases were then dried (K2CO3) and concentrated. Purification of the product was conducted on silica gel using ethyl acetate:hexane (5:1→4:1) as the eluant to give the title compound.