Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[C:17](=O)[NH:18][CH:19]=[N:20]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:46]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[C:17]([Cl:46])=[N:18][CH:19]=[N:20]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc3nc[nH]c(=O)c23)CC1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc3ncnc(Cl)c23)CC1

Procedure:
5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-3,4-dihydroquinazolin-4-one (0.31 g) was reacted with triphenylphosphine and carbon tetrachloride to give 5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-chloroquinazoline (0.156 g); NM Spectrum: (CDCl3) 1.5 (s, 9H), 1.9–2.1 (m, 4H), 3.5–3.8 (m, 4H), 4.8 (m, 1H), 7.05 (d, 1H), 7.65 (d, 1H), 7.82 (m, 1H), 8.95 (s, 1H); Mass Spectrum: M+H+ 364 and 366; and
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].C(O)=O.S(=O)(=O)(O)O.[CH2:17]=[CH:18][CH2:19][CH3:20].C=C(C)C>CCCCCCC>[C:1]([O:8][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5]
Reactant: CC(=O)CCC(=O)O
Reactant: C=CCC
Agent: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: CCCCCCC
Solvent: O=CO
Product: CCCCOC(=O)CCC(C)=O
Temperature: 150 °C

Procedure:
A 5 cc autoclave is charged with 1 cc of heptane and 1 cc of an aqueous solution containing 2 mmoles of levulinic acid and 2 mmoles of formic acid. 5 wt. % sulfuric acid is added as a catalyst. The reactor is pressurized to 0.69 MPa with 1-butene and heated to 150° C. for 0.5 hours while maintaining a constant pressure of isobutene. After cooling, the organic phase is separated. A mixture of butyl formate and butyl levulinate is formed as product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]([C:13]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][CH3:22])[C:14]=2[NH2:15])=[O:12])[N:4]=1.O1CCCC1.B.[Na]>O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([CH:11]([OH:12])[C:13]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][CH3:22])[C:14]=2[NH2:15])[N:6]=1
Reactant: COCc1cccc(C(=O)c2nc(OC)cc(OC)n2)c1N
Agent: B
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Product: COCc1cccc(C(O)c2nc(OC)cc(OC)n2)c1N
Temperature: 25 °C
Yield: 89.7 %

Procedure:
3.1 g (10 mM) of the 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-6-methoxymethylaniline obtained in the above (4) was dissolved in 50 ml of a 1:1 (by volume ratio) mixed solvent of tetrahydrofuran and water. While the solution was stirred at room temperature, thereto was added 0.6 g (16 mM) of sodium boron hydride. The mixture was stirred at room temperature for 2 hours. 50 ml of ice water was added, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried, and subjected to vacuum distillation to remove the solvent. The residual crystals were washed with diisopropyl ether to obtain 2.8 g (yield: 92%) of 2-[(4,6-dimethoxypyrimidine-2-yl)hydroxymethyl]-6-methoxymethylaniline as a white powder (melting point: 40 to 42° C.).
Reaction SMILES: [C:1]([Si:5]([CH3:50])([CH3:49])[O:6][C:7]1[CH:8]=[CH:9][C:10]([C:14]2[CH2:15][O:16][C:17]3[C:22]([C:23]=2[C:24]([OH:40])([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:28][CH:27]=2)[CH3:25])=[CH:21][CH:20]=[C:19]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[CH:18]=3)=[C:11](O)[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].Cl>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[C:45]([Si:42]([CH3:44])([CH3:43])[O:41][C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[C:24]([C:26]4[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH2:34][N:35]5[CH2:36][CH2:37][CH2:38][CH2:39]5)=[CH:30][CH:31]=4)([CH3:25])[O:40][C:9]4[CH:8]=[C:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:49])[CH3:50])[CH:12]=[CH:11][C:10]=4[C:14]=3[CH2:15][O:16][C:17]=2[CH:18]=1)([CH3:46])([CH3:48])[CH3:47]
Reactant: CC(O)(C1=C(c2ccc(O[Si](C)(C)C(C)(C)C)cc2O)COc2cc(O[Si](C)(C)C(C)(C)C)ccc21)c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC1(c2ccc(OCCN3CCCC3)cc2)Oc2cc(O[Si](C)(C)C(C)(C)C)ccc2C2=C1c1ccc(O[Si](C)(C)C(C)(C)C)cc1OC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
5-(Tert-butyl-dimethyl-silyloxy)-2-(7-(tert-butyl-dimethyl-silyloxy)-4-{1-hydroxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-ethyl}-2H-chromen-3-yl)phenol, prepared as in STEP A above, was dissolved in toluene (8 mL) and treated with diluted HCl (0.4 mL of concentrated HCl:H2O=1:2 v/v). The reaction mixture was vigorously stirred at room temperature for 1.5 h. The mixture was then diluted with water and ethyl acetate. The layers were separated and the organic layer washed successively with saturated NaHCO3, brine and dried over MgSO4. The desiccant was filtered off, and the filtrate concentrated. Flash chromatography with ethyl acetate:hexane:CH3OH (containing 1% NH4OH)=49:49:2 as the eluent to yield the title compound as a light oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[C:12]1([NH2:19])[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([NH2:19])[CH:13]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: Nc1cccc(N)c1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cccc(Nc2ccc(Br)cc2[N+](=O)[O-])c1
Temperature: 120 °C
Yield: 63.2 %

Procedure:
A mixture of 4-bromo-1-fluoro-2-nitro-benzene (1.14 ml, 9.25 mmol), benzene-1,3-diamine (1.96 g, 18.1 mmol) and DIPEA (1.93 ml, 11.1 mmol) in dry NMP (5 ml) was deoxygenated by evacuate/fill N2 (×3), then stirred and heated at 120° C. under N2 for 18 hours. After cooling to RT the mixture was partitioned between EtOAc and 0.5N HCl. The organic layer was washed with H2O (×1), brine (×1) then dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica (10→40% EtOAc/petrol) to give the title compound (1.8 g) as a red solid. 1H NMR (400 MHz, DMSO-d6): 9.28 (1H, s), 8.20 (1H, d), 7.63 (1H, dd), 7.14 (1H, d), 7.07 (1H, t), 6.49 (1H, s), 6.48-6.39 (2H, m), 5.24 (2H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[F:22][C:23]([F:34])([F:33])[O:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH2:28]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[C:6]([CH:10]=1)[C:7]([NH:28][CH2:27][C:26]1[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=1[O:24][C:23]([F:22])([F:33])[F:34])=[O:8]
Reactant: O=C(Cl)c1cc(Br)ccc1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: NCc1ccccc1OC(F)(F)F
Product: O=C(NCc1ccccc1OC(F)(F)F)c1cc(Br)ccc1NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
This compound was prepared using the procedure described in Example 70, using 5-bromo-2-(4-chloro-benzenesulfonylamino)-benzoyl chloride instead of 5-bromo-2-(4-trifluoromethoxy-benzenesulfonylamino)-benzoyl chloride, and 2-trifluoromethoxybenzyl amine instead of 2-methoxy benzyl amine. M/Z of [M−H]−=563.8. 1H NMR (DMSO) δ=4.4 (sd, 2H), 7.3–7.4 (5H), 7.5 (2H), 7.65–7.7 (3H), 7.9–8.0 (1H), 9.4 (br, 1H), 11.5 (br, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH:11]([N:12]([CH3:23])[S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:24][CH3:25])=[CH:7][CH:8]=2)[C:3]1=[CH:26][CH2:27][OH:28].C(N(CC)CC)C.[H][H]>CO.[Pd]>[CH3:1][C:2]1([CH3:29])[CH:11]([N:12]([CH3:23])[S:13]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:24][CH3:25])=[CH:7][CH:8]=2)[CH:3]1[CH2:26][CH2:27][OH:28]
Reactant: COc1ccc2c(c1)C(=CCO)C(C)(C)C(N(C)S(=O)(=O)c1ccc(C)cc1)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc2c(c1)C(CCO)C(C)(C)C(N(C)S(=O)(=O)c1ccc(C)cc1)C2

Procedure:
2,2-Dimethyl-1-(2-hydroxyethylidene)-7-methoxy-3-(N-methyl-p-toluenesulphonamido)-1,2,3,4-tetrahydronaphthalene (15.5 g), dissolved in 250 ml of methanol, containing 2.2 ml of triethylamine, is submitted to catalytic hydrogenation, at atmosphere pressure and room temperature, the catalyst being 2.3 g 5% palladium on charcoal. The calculated amount of hydrogen is taken up within one hour. The catalyst is removed by filtration and the solvent by evaporation in vacuo. The residue is dissolved in chloroform and the solution is freed from basic material by means of washing with dilute hydrochloric acid and water, respectively. The dried solution is then concentrated in vacuo leaving a mixture containing two stereoisomers of the desired product. This mixture is suitable for further elaboration as described in example 13.
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH2:18][CH2:17][CH:16]([NH:19]C(=O)OC(C)(C)C)[CH2:15][CH:14]=3)=[CH:10][CH:11]=2)[N:6]([CH3:27])[C:5]1=[O:28].C(Cl)Cl.Cl.CCOC(C)=O>CO>[NH2:19][CH:16]1[CH2:17][CH2:18][C:13]([C:9]2[N:8]=[C:7]3[N:6]([CH3:27])[C:5](=[O:28])[N:4]([CH2:3][C:2]([CH3:1])([CH3:30])[CH3:29])[C:12]3=[CH:11][CH:10]=2)=[CH:14][CH2:15]1
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CCC(NC(=O)OC(C)(C)C)CC3)nc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CCC(N)CC3)nc21
Temperature: 25 °C

Procedure:
To a round bottom flask was added tert-butyl {-4-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]cyclohex-3-en-1-yl}carbamate (17-1) (338 mg, 0.815 mmol), DCM (2 mL), MeOH (2 mL), and a 4N solution of HCl in EtOAc (2.038 ml, 8.15 mmol). The reaction mixture was then capped & stirred at room temperature for several hours. The reaction was then concentrated to yield 5-(4-Aminocyclohex-1-en-1-yl)-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (17-2) as a tan solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[C:7]([C:8]([NH:10][CH3:11])=O)[CH:6]=1)[CH3:2].S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[N-:34]=[N+:35]=[N-:36].[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[C:7]([C:8]2[N:10]([CH3:11])[N:36]=[N:35][N:34]=2)[CH:6]=1)[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1cc(C(=O)NC)cc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cc(-c2nnnn2C)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
To a 2M solution of N-methyl-5-nitro-isophthalamic acid ethyl ester (10 g) in dichloroethane (200 ml) at −20° C. was added pre-cooled triflic anhydride (10 ml) dropwise. This was stirred for 30 min and then sodium azide (4.6 g) was added. This was allowed to warm to room temperature and stirred overnight. The reaction was neutralised with 5% NaHCO3(aq) solution and the organic and aqueous layers were separated and the organic layer dried and concentrated in vacuum. Flash chromatography (100:0 to 50:50 gradient cyclohexane:EtOAc) afforded the title compound (6.5 g). Rt=1.52 min (method D).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[F:23][C:24]([F:29])([F:28])[CH2:25][CH2:26]O>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:26][CH2:25][C:24]([F:29])([F:28])[F:23])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Reactant: OCCC(F)(F)F
Product: FC(F)(F)CCn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21

Procedure:
Compound IId was synthesized from 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine and 3,3,3-trifluoropropan-1-ol following the general procedure for the Mitsunobu reaction as described above.
Reaction SMILES: [C:1]1([C:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.S(=O)(=O)(O)O.[CH3:19]O>>[C:1]1([C:11]([O:13][CH3:19])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: O=C(O)c1nccc2ccccc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1nccc2ccccc12
Temperature: 65 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
To a solution of isoquinoline-1-carboxylic acid (10 g, 57.74 mmol) in MeOH (150 mL) was added concentrated sulfuric acid (15 mL) at 0° C. The mixture was warmed to 65° C. and stirred at 65° C. for 24 hours. After cooling to RT, the reaction mixture was partitioned between DCM and saturated aqueous NaHCO3. The organic layer was separated and dried over Na2SO4, and the solvent was evaporated under reduced pressure to give the title compound as a yellow oil (11.2 g, 100%). ESI-MS m/z [M+H]+ 188.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)=[C:18]([Cl:33])[CH:17]=3)=[N:12][CH:11]=[N:10][C:9]=2[CH:8]=[CH:7]1.[OH:34][C:35]([CH3:41])([CH3:40])[CH2:36][C:37](O)=[O:38].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O.C(N(CC)CC)C>[Cl:33][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[C:14]3[N:6]([CH2:5][CH2:4][NH:3][C:37](=[O:38])[CH2:36][C:35]([OH:34])([CH3:41])[CH3:40])[CH:7]=[CH:8][C:9]=3[N:10]=[CH:11][N:12]=2)[CH:21]=[CH:20][C:19]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1
Reactant: CC(C)(O)CC(=O)O
Reactant: NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(O)CC(=O)NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 120 h
Yield: 77.3 %

Procedure:
A mixture of 5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (150 mg), 3-hydroxy-3-methylbutyric acid (68 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (166 mg), 1-hydroxybenzotriazole monohydrate (133 mg), triethylamine (0.40 mL) and N,N-dimethylformamide (5.0 mL) was stirred at room temperature for 5 days. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate→ethyl acetate:methanol=9:1). Crystallization from ethyl acetate-diisopropyl ether gave the title compound (122 mg) as colorless crystals.
Reaction SMILES: [Cl:1]C(OCC)=O.CCN(C(C)C)C(C)C.[CH3:16][C:17]1[CH:18]=[CH:19][C:20]2[CH:21]([CH3:29])[CH:22]3[CH2:26][NH:25][CH2:24][CH:23]3[C:27]=2[CH:28]=1>C(Cl)Cl>[CH3:16][C:17]1[C:18]([Cl:1])=[CH:19][C:20]2[CH:21]([CH3:29])[CH:22]3[CH2:26][NH:25][CH2:24][CH:23]3[C:27]=2[CH:28]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1ccc2c(c1)C1CNCC1C2C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc2c(cc1Cl)C(C)C1CNCC21
Reaction time: 2 h
Yield: 54.1 %

Procedure:
Ethyl chloroformate (0.29 mL, 3.0 mmol) and DIEA (1.6 mL, 9.0 mmol) were added to a solution of 5-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 13, Step F) (0.56 g, 3.0 mmol) in CH2Cl2 (15 mL) at 0° C. The reaction was stirred for 2 hours from 0° C. to room temperature. The reaction was quenched with aqueous HCl (15 mL, 1M). The desired product was extracted with CH2Cl2 (3×15 mL). The organic extracts were washed with brine, dried over MgSO4, and concentrated. The crude product was purified by column chromatography (SiO2) using a 10-60% EtOAc-hexanes gradient to afford 0.36 g (46%) of the subtitle compound. MS calculated for C16H21NO2+H: 260, observed: 260.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:35]2[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=2)[CH2:9][NH:10][C:11]2[N:19]=[C:18]([Cl:20])[N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[C@@H:21]2[CH2:25][C@H:24]([N:26]3[N:30]=[N:29][C:28]([CH2:31][CH3:32])=[N:27]3)[C@@H:23]([OH:33])[C@H:22]2[OH:34])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C1(C(C2C=CC=CC=2)CN[C:58]2[N:66]=[C:65](NCCN3CCCCC3)N=[C:63]3[C:59]=2N=C[N:62]3[C@@H:76]2[CH2:80][C@H:79](N3C=C(CO)C=N3)[C@@H:78](O)[C@H]2O)C=CC=CC=1.N1([C@@H]2CCNC2)CCCC1>>[ClH:20].[N:62]1([C@@H:63]2[CH2:59][CH2:58][N:66]([C:18]3[N:17]=[C:16]4[C:12]([N:13]=[CH:14][N:15]4[C@@H:21]4[CH2:25][C@H:24]([N:26]5[N:30]=[N:29][C:28]([CH2:31][CH3:32])=[N:27]5)[C@@H:23]([OH:33])[C@H:22]4[OH:34])=[C:11]([NH:10][CH2:9][CH:8]([C:35]4[CH:36]=[CH:37][C:38]([OH:41])=[CH:39][CH:40]=4)[C:5]4[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=4)[N:19]=3)[CH2:65]2)[CH2:76][CH2:80][CH2:79][CH2:78]1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccc(O)cc5)c5ccc(O)cc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)n1
Reactant: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)c1
Agent: C1CCN([C@@H]2CCNC2)C1
Solvent: O=C(O)C(F)(F)F
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccc(O)cc5)c5ccc(O)cc5)nc(N5CC[C@@H](N6CCCC6)C5)nc43)[C@H](O)[C@@H]2O)n1
Product: Cl

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-{6-[2,2-bis-(4-hydroxy-phenyl)-ethylamino]-2-chloro-purin-9-yl}-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (Intermediate BF1) using a procedure analogous to that of (1R,2S,3R,5S)-3-[6-(2,2-diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoroacetate (Example 46) by replacing 1-(2-amino-ethyl)piperidine with (R)-[1,3′]bipyrrolidinyl (intermediate EB). MS (ES+) m/e 650.42 (MH+).
Reaction SMILES: [Cl-].[Cl:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](=[O:28])[CH2:8][P+:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[Na+]>O>[Cl:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH:8]=[P:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:28]
Reactant: O=C(CCCCCl)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)CCCCCl

Procedure:
A solution of 20 parts of (6-chloro-2-oxo-hexyl)-triphenylphosphonium chloride in 200 parts of water is made alkaline by the addition of a 50% aqueous sodium hydroxide solution and extracted with benzene. The combined organic extracts are dried over anhydrous sodium sulfate, then stripped of solvent under reduced pressure to afford (5-chloropentanoylmethylene) triphenylphosphorane.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([OH:14])=[C:6]([CH:9]=[C:10]([CH:12]=O)[CH:11]=1)[C:7]#[N:8])[CH3:2].[C:15]1([C:21](=O)[CH2:22][C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH2:29][C:30]([NH2:32])=[O:31].Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:5]([OH:14])=[C:6]([CH:9]=[C:10]([CH:12]2[C:22]([C:23]3[CH:27]=[CH:26][S:25][CH:24]=3)=[C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:32][C:30](=[O:31])[NH:29]2)[CH:11]=1)[C:7]#[N:8])[CH3:2]
Reactant: NC(N)=O
Reactant: CCOc1cc(C=O)cc(C#N)c1O
Reactant: O=C(Cc1ccsc1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccsc2)cc(C#N)c1O
Yield: 15.4 %

Procedure:
To a solution of 3-ethoxy-5-formyl-2-hydroxybenzonitrile (Intermediate 51) (70 mg, 0.37 mmol), 1-phenyl-2-(thiophen-3-yl)ethanone (Intermediate 2) (50 mg, 0.28 mmol) and urea (71 mg, 1.1 mmol) in 3 mL of ethanol was added 0.2 mL of concentrated HCl. Refluxed for 2 days. Solvent removed and resulting residue was purified by prep-HPLC (0.1% TFA as additive) to give Compound 105 (18 mg, yield 12%). 1H NMR (DMSO-d6 300 MHz): δ 10.33 (s, 1H), 8.70 (s, 1H), 7.51 (s, 1H), 7.37-7.10 (m, 8H), 6.84 (s, 1H), 6.22 (d, J=4.8 Hz, 1H), 5.16 (d, J=2.4 Hz, 1H), 4.07 (q, J=6.9 Hz, 2H), 1.35 (t, J=6.9 Hz, 3H). MS (ESI): m/z 418.0 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:9]([O:10][C:11](=[O:13])[CH3:12])[CH:8]=[CH:7][S:6]1)=[O:4].S(Cl)(Cl)(=O)=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[O:10][C:11](=[O:13])[CH3:12])=[O:4]
Reactant: COC(=O)C1SC=CC1OC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: O=S(=O)(Cl)Cl
Product: COC(=O)c1sccc1OC(C)=O
Yield: 79 %

Procedure:
20.2 parts of 3-acetoxydihydrothiophene-2-carboxylic acid methyl ester are reacted with 6.75 parts by volume of sulfuryl chloride in 150 parts by volume of CCl4 at 0° C. for one hour. The end product is isolated from the reaction mixture by the method described in Example 14(c). 15.8 parts (79% of theory) of 3-acetoxythiophene-2-carboxylic acid methyl ester of boiling point 84°-86° C./0.04 mbar are obtained.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8](O)=[C:7]([O:13][CH3:14])[C:6]=1[O:15][CH3:16])(=[O:3])[CH3:2].[CH2:17](Cl)[C:18](=[CH2:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH2:19][C:18]([CH3:20])=[CH2:17])=[C:7]([O:13][CH3:14])[C:6]=1[O:15][CH3:16])(=[O:3])[CH3:2]
Reactant: C=C(C)CCl
Reactant: COc1c(O)cc(C)c(OC(C)=O)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)Cc1cc(C)c(OC(C)=O)c(OC)c1OC
Yield: 84 %

Procedure:
A suspension (200 ml) of 4-acetoxy-2,3-dimethoxy-5-methylphenol (26 g), methallyl chloride (13 ml) and potassium carbonate (18 g) in N,N-dimethylformamide was stirred under an atmosphere of argon at 65° C. for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1) to obtain the title compound (27 g, 84%) as an oil.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([OH:43])=O)=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[Cl-].[N:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH:52]=[C:51]([CH2:59][NH3+:60])[CH:50]=1>>[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([NH:60][CH2:59][C:51]4[CH:50]=[N:49][C:58]5[C:53]([CH:52]=4)=[CH:54][CH:55]=[CH:56][CH:57]=5)=[O:43])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1
Reactant: [NH3+]Cc1cnc2ccccc2c1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Agent: [Cl-]
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cnc2ccccc2c1
Yield: 50 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with quinolin-3-ylmethanaminium chloride, the title compound was obtained as a colorless solid in 50% yield: 1H NMR (300 MHz, CDCl3) δ 8.91 (s, 1H), 8.15-8.08 (m, 2H), 7.81 (d, J=8.2 Hz, 1H), 7.74-7.66 (m, 1H), 7.58-7.51 (m, 1H), 7.30-7.22 (m, 2H), 7.07-6.98 (m, 2H), 6.22 (t, J=5.6 Hz, 1H), 6.09 (s, 1H), 4.74 (d, J=5.6 Hz, 2H), 4.42 (s, 2H), 3.83-3.74 (m, 2H), 3.47-3.38 (m, 2H), 2.50 (s, 3H); MS (ES+) m/z 475.2 (M+1).