Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:16][C:6]2[N:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[S:9][C:5]=2[C:4](=[O:17])[CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1([CH3:18])[CH2:16][C:6]2[N:7]=[C:8]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)[S:9][C:5]=2[CH:4]([OH:17])[CH2:3]1
Reactant: CC1(C)CC(=O)c2sc(N3CCOCC3)nc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)Cc2nc(N3CCOCC3)sc2C(O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
To a stirred solution of Example 48 (0.13 g, 0.5 mmol) in THF (10 mL) at r.t. was added LiAlH4 (0.5 mL, 1M solution in THF, 0.5 mmol) dropwise. The reaction mixture was stirred at r.t. for 2 h and then poured into 10% NaOH solution (20 mL) and extracted with DCM (2×20 mL). The combined organic fractions were dried over MgSO4, filtered and the solvent removed by evaporation in vacuo. Purification by column chromatography gave the title compound (0.07 g, 52%) as a solid. δH (DMSO-d6) 5.23 (1H, d, J 6.5 Hz), 4.65 (1H, dt, J 8.1 and 6.7 Hz), 3.77-3.70 (4H, m), 3.39 (4H, m), 2.40-2.24 (2H, m), 1.84 (1H, dd, J 5.9 and 11.3 Hz), 1.48 (1H, dd, J 8.8 and 12.6 Hz), 1.09 (3H, s), 0.94 (3H, s). LCMS (ES+) 269.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](I)=[CH:9][N:10]=2)[CH:7]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:16]3[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=3)=[CH:9][N:10]=2)[CH:7]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1ccc2ncc(I)n2c1
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: O
Solvent: COCCOC
Product: Fc1ccc(-c2cnc3ccc(Br)cn23)cc1
Temperature: 25 °C
Yield: 47.5 %

Procedure:
To a mixture of commercially available 6-bromo-3-iodoimidazo[1,2-a]pyridine (0.7 g, 2.17 mmol) and commercially available 4-fluoro-phenylboronic acid (0.3 g, 2.17 mmol) in 1,2-dimethoxyethane (14 ml), 2M sodium carbonate solution (2.71 ml, 5.42 mmol) was added, and the reaction mixture was purged with argon for 5 min in an ultrasonic bath. Afterwards tetrakis(triphenylphosphine)palladium(0) (125 mg, 108 μmol) was added, and the stirred reaction mixture was heated under reflux conditions for 17 h. The reaction mixture was cooled to room temperature, poured into water (30 ml) and extracted with ethyl acetate (2×40 ml). The combined organic layers were washed with brine (30 ml), dried (MgSO4) and evaporated. The crude material (0.74 g) was further purified by flash chromatography on silica gel (dichloromethane/MeOH 98:2) and trituration (diethyl ether) to yield the title compound as a light yellow solid (0.3 g, 48%), MS (ISP) m/z=291.3 [(M+H)+], mp 102° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].[CH3:16][CH:17]([CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:22]=1)=[O:19]>>[CH3:16][CH:17]([CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:9])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:29][CH2:28]2)[CH:22]=1)=[O:19]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCCCl)c1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCC(=O)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 7-chloro-1-phenyl-1-heptanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 435.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl[CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: ClCc1cccc2ccccc12
Product: O=[N+]([O-])c1cc(OCc2cccc3ccccc23)ccc1Cl

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 1-Chloromethyl-naphthalene using the conditions described in Example 10C to provide 1-(4-Chloro-3-nitro-phenoxymethyl)-naphthalene which was treated sequentially using the procedures from Examples 10D and 10E to provide the title product.
Reaction SMILES: Br.[NH:2]=[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][N:4]1[CH2:10][C:11](OCC)=O.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:11]1[N:2]=[C:3]2[CH:8]=[CH:7][C:6]([F:9])=[CH:5][N:4]2[CH:10]=1
Reactant: CCOC(=O)Cn1cc(F)ccc1=N
Reactant: O=P(Cl)(Cl)Cl
Agent: Br
Product: Fc1ccc2nc(Cl)cn2c1
Temperature: 105 °C

Procedure:
A mixture of ethyl 2-imino-5-fluoro-1,2-dihydropyridine-1-yl-acetate hydrobromide (4.12 g, 14.76 mmol) in phosphorus oxychloride (68.8 mL, 738 mmol) was heated at 105° C. for 2 hours. The mixture was then cooled to room temperature and concentrated under reduced pressure. To the resulting residue were added ice water and ammonium hydroxide until the pH of the solution was 8. The solution was then extracted with dichloromethane. The organic extracts were combined, dried over MgSO4, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel (30% ethyl acetate in hexanes) provided the title compound: LCMS m/z 170.96 [M+H]+, 172.79 [M+2+H]+; 1H NMR (500 MHz, CDCl3) δ 8.00 (s, 1H), 7.53-7.50 (m, 2H), 7.18-7.13 (m, 1H).
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]([CH:10]([Cl:12])[F:11])([F:9])[F:8])([F:4])([F:3])[F:2].[Br:13]Br.C(=O)=O>>[C:1]([CH:5]([O:6][C:7]([CH:10]([Cl:12])[F:11])([F:8])[F:9])[Br:13])([F:4])([F:3])[F:2]
Reactant: FC(Cl)C(F)(F)OCC(F)(F)F
Reactant: BrBr
Agent: O=C=O
Product: FC(Cl)C(F)(F)OC(Br)C(F)(F)F

Procedure:
CF3CH2OCF2CHFCl (104 g.) and bromine (85 g.) were vaporized in a stream of nitrogen at 15-20 l/hr. The gaseous mixture was then passed through a 1 × 12 inch glass tube at 475° C. The crude product (137 g.) was condensed in a "Dry Ice" trap and purified by fractional distillation and preparative gas chromatography. The product CF3CHBrOCF2CHFCl had b.p. 109° C., nD20 1.3525 and analyzed as follows:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:12][C:13](=[O:25])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16](Br)[CH:15]=2)[CH2:10][CH2:9][CH:8]([CH3:11])[CH2:7][CH2:6]1)=[O:4].[F:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([F:35])[C:28]=1B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2OC2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O=O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(=O)OCC.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1([NH:12][C:13]([C:14]2[CH:15]=[C:16]([C:28]3[C:27]([F:26])=[CH:32][C:31]([O:33][CH3:34])=[CH:30][C:29]=3[F:35])[C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)=[O:25])[CH2:10][CH2:9][CH:8]([CH3:11])[CH2:7][CH2:6]1)=[O:4]
Reactant: COc1cc(F)c(B(O)O)c(F)c1
Reactant: COC(=O)C1(NC(=O)c2ccc(C(F)(F)F)c(Br)c2)CCC(C)CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)C1(NC(=O)c2ccc(C(F)(F)F)c(-c3c(F)cc(OC)cc3F)c2)CCC(C)CC1
Temperature: 25 °C
Yield: 4.6 %

Procedure:
300 mg of 1-(3-Bromo-4-trifluoromethyl-benzoylamino)-4-methyl-cyclohexanecarboxylic acid methyl ester, 267 mg of 2,6-difluoro-4-methoxyphenylboronic acid, 65 mg of tris(dibenzylideneacetone)di-palladium(0), 96 mg of bis(2-dicyclohexylphosphinophenyl)ether, 453 mg of K3PO4, and 1 g of molecular sieve 4 Å were added to 10 ml of toluene. The mixture was made oxygen-free by passing argon through it. Then, the mixture was kept at 160° C. under microwave irradiation for 2 h. Then, 267 mg of 2,6-difluoro-4-methoxyphenylboronic acid, 65 mg of tris(dibenzylideneacetone)di-palladium(0), 96 mg of bis(2-dicyclohexylphosphinophenyl)ether were added and the mixture was kept at 160° C. under microwave irradiation for 2 h. The mixture was cooled to room temperature and 100 ml of EA added. The mixture was then washed twice using 20 ml of a saturated aqueous Na2CO3-solution each. The organic layer was dried using MgSO4 and the solvent evaporated. Chromatography on silica gel using EA/HEP 1:5 yielded 16 mg of the title compound, viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10].Cl.[C:14](O)(=[O:16])[CH3:15]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:14](=[O:16])[CH3:15])=[CH:5][C:4]=1[C:9]([F:10])([F:11])[F:12]
Reactant: COc1ccccc1C(F)(F)F
Reactant: CC(=O)O
Agent: Cl
Product: COc1ccc(C(C)=O)cc1C(F)(F)F
Temperature: 0 °C

Procedure:
A solution 1-methoxy-2-(trifluoromethyl)benzene (3.52 g) was dissolved in glacial acetic acid (30 ml) and treated with boron trifluoride acetic acid complex (30 ml) and the resulting solution maintained at 55° for 48 hours. The solution was poured into dilute hydrochloric acid (100 ml) and ice (100 g) added and the mixture extracted with chloroform (2×200 ml). The combined organic extracts were washed with sodium bicarbonate solution (3×100 ml), then water (100 ml), dried and evaporated to dryness to give an oily black solid. This was chromatographed on silica (40 g) eluting with ether:light petroleum (bp.60°-80°) (1:4) to give a solid which was crystallised from light petroleum (bp.60°-80°) to give the title compound (0.3 g), m.p.56°-57°
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6].[CH3:13][C:14]1[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([CH3:23])[C:15]=1[CH:16]=O>CS(C)=O.O>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]2[N:12]=[C:16]([C:15]3[C:14]([CH3:13])=[CH:21][C:20]([OH:22])=[CH:19][C:18]=3[CH3:23])[NH:1][C:2]=2[CH:3]=1)=[O:6]
Reactant: Cc1cc(O)cc(C)c1C=O
Reactant: COC(=O)c1ccc(N)c(N)c1
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc2nc(-c3c(C)cc(O)cc3C)[nH]c2c1
Reaction time: 120 h

Procedure:
3.65 g of methyl 3,4-diaminobenzoate and 3.3 g of 2,6-dimethyl-4-hydroxybenzaldehyde were stirred in 25 ml of DMSO at room temperature. A solution of 170 mg of FeCl3 in 5 ml of DMSO was added by pipet and the reaction was stirred at the same temperature for 5 days. The reaction was then diluted with water and the resulting precipitates were collected by filtration. The filter cake was washed with water and heptane, and dried by air in the suction funnel to afford the title compound. LCMS retention T=1.01 min. (M+H)+=297.01, Method 10.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[C:7](=[CH:18][NH:19][C:20]=3[CH3:21])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.[CH3:24]C(C)([O-])C.[K+].CI>CN(C)C=O.O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[C:7](=[CH:18][N:19]([CH3:24])[C:20]=3[CH3:21])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: Cc1[nH]cc2c1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c2c(cn1C)CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In one portion, 2.0 g (5.8) mmol) of 8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine were added to an ice-cooled solution of 0.8 g (7.1 mmol) of potassium t-butoxide in 20 ml of dry dimethylformamide. After stirring at 0° C. for 10 minutes, 0.8 ml (12.8 mmol) of methyl iodide was added and the resulting solution was stirred for 20 minutes. The mixture was diluted with water, and the resulting precipitate was collected by filtration. The solid was dissolved in methylene chloride, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to give 8-chloro-6-(2-chlorophenyl)-1,2-dimethyl-2H,4H-pyrrolo[3,4-d][2]benzazepine as orange prisms, mp 200°-202° C. A sample was recrystallized from a mixture of ether and methylene chloride to give pale yellow prisms, mp 203°-204° C.
Reaction SMILES: CON(C)[C:4](=[O:18])[C@@H:5]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:6].C([Mg]Cl)(C)C.[F:25][C:26]1[CH:27]=[C:28]([Mg]Br)[CH:29]=[C:30]([F:32])[CH:31]=1.[NH4+].[Cl-]>C1COCC1.CCOCC>[F:25][C:26]1[CH:27]=[C:28]([C:4](=[O:18])[C@@H:5]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:6])[CH:29]=[C:30]([F:32])[CH:31]=1
Reactant: Fc1cc(F)cc([Mg]Br)c1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OCc1ccccc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)c1cc(F)cc(F)c1
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
To a −15° C. solution of benzyl {(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (1.96 g, 7.36 mmol) in THF (9.4 mL) was added i-propyl magnesium chloride (3.6 mL of a 2M solution in Et2O, 7.2 mmol). The reaction was stirred at −15° C. for 15 minutes and then 3,5-difluorophenylmagnesium bromide (29.44 mL of a 0.5 M solution in THF, 14.72 mmol) was added. The reaction was warmed to room temperature and stirred for 24 hours. The reaction was then poured into saturated NH4Cl (100 mL) and extracted with EtOAc (3×100 mL). The organic extracts were washed with water and brine (100 mL each), dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (15% EtOAc/hexanes) afforded benzyl [(1S)-2-(3,5-difluorophenyl)-1-methyl-2-oxoethyl]carbamate. Rf=0.34 (15% EtOAc/hexanes). LCMS=342.3 (M+Na)+.
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([O:20][C:21]1[CH:22]=[C:23]([CH:37]=[CH:38][C:39]=1[N+:40]([O-:42])=[O:41])[C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](=[O:36])(=[O:35])[NH2:34])=[O:25])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[CH2:13]([O:20][C:21]1[CH:22]=[C:23]([CH:37]=[CH:38][C:39]=1[N+:40]([O-:42])=[O:41])[C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([NH:34][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:36])=[O:35])=[O:25])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Reactant: CCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
In a stream of nitrogen and at 0° C., 0.24 ml (1.16 mmol) of decanoyl chloride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 435 mg (1.02 mmol) of 3-benzyloxy-4-nitro-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 3 and 274 mg (2.23 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 490 mg (yield: 83.0%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][C:11]([CH:21](O)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C(N(CC)CC)C.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.[Cl-].[NH4+]>ClCCl.C(OCC)(=O)C>[CH2:1]([O:8][CH:9]1[CH2:12][C:11](/[CH:21]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])([NH:13][C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(O)C1(NC(=O)OC(C)(C)C)CC(OCc2ccccc2)C1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/C1(NC(=O)OC(C)(C)C)CC(OCc2ccccc2)C1
Temperature: 0 °C
Yield: 91.4 %

Procedure:
A 35.61 g (90.50 mmol) portion of ethyl 3-[1-benzyloxy-3-(tert-butoxycarbonylamino)cyclobutan-3-yl]-3-hydroxypropionate was dissolved in 200 ml of dichloromethane to which, while cooling in an ice bath with stirring, were subsequently added 9.050 ml (116.9 mmol) of methanesulfonyl chloride and 37.24 ml (267.2 mmol) of triethylamine in that order. After 2 hours of stirring, to this was added 30.60 ml (204.6 mmol) of diazabicycloundecene. After 1 hour of stirring, the ice bath was detached and the reaction mixture was stirred at room temperature for 2 hours. While cooling in an ice bath with stirring, this was mixed with saturated ammonium chloride aqueous solution and then with ethyl acetate to effect separation of layers. The resulting organic layer was washed with 10% citric acid aqueous solution and then with saturated brine. After extraction of the aqueous layer with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under a reduced pressure and the resulting residue was purified by a silica gel column chromatography to give 31.07 g (91.4%) of the title compound.
Reaction SMILES: ClC1C=CC(C(N)C(N)CCCCC)=CC=1.Cl.C(OC1C=C(OC)C=CC=1C(=N)OCC)C.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([CH:41]2[NH:45][C:44]([C:46]3[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][C:47]=3[O:54][CH2:55][CH3:56])=[N:43][CH:42]2[CH2:57][CH:58]2C[CH2:61][CH2:60][CH2:59]2)=[CH:37][CH:36]=1>>[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([CH:41]2[NH:45][C:44]([C:46]3[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][C:47]=3[O:54][CH2:55][CH3:56])=[N:43][CH:42]2[CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])=[CH:39][CH:40]=1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1
Agent: CCCCCC(N)C(N)c1ccc(Cl)cc1
Agent: CCOC(=N)c1ccc(OC)cc1OCC
Agent: Cl
Product: CCCCCC1N=C(c2ccc(OC)cc2OCC)NC1c1ccc(Cl)cc1

Procedure:
5-(4-Chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-pentyl-4,5-dihydro-1H-imidazole was prepared from 1-(4-chloro-phenyl)-heptane-1,2-diamine and ethyl 2-ethoxy-4-methoxy-benzimidate hydrochloride in an analogous manner as described for the preparation of 5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole (Example 9). HR-MS (ES, m/z) observed 401.1993, calculated for C23H30N2O2Cl [(M+H)+]401.1991.
Reaction SMILES: [CH3:1][C@:2]12[C:8]([CH3:10])([CH3:9])[C@H:5]([CH2:6][CH2:7]1)[CH:4]([C:11](Cl)=[O:12])[C:3]2=O.C(=[N:17][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C.N1C=CC=CC=1.Cl>ClCCCl.O1CCOCC1.C(O)(=O)C>[C:19]1([N:18]2[C:11](=[O:12])[C:4]3[C@@H:5]4[C:8]([CH3:10])([CH3:9])[C@@:2]([CH3:1])([CH2:7][CH2:6]4)[C:3]=3[NH:17]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Reactant: CC=NNc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
A solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 4.36 g, 20.3 mmol) in 1,2-dichloroethane (40 mL) was added over a period of one minute to a cooled (˜0° C.) solution of N-ethylidene-N′-phenyl-hydrazine (prepared according to A. R. Maguire et al. Bioorg. Med. Chem. 2001, 9, 745-762; 2.60 g, 19.4 mmol) and pyridine (2.5 mL, 30.9 mmol) in 1,2-dichloroethane (20 mL). The reaction mixture was stirred at room temperature for 15 min and then at 50° C. for 25 min. It was then cooled to room temperature and 4M HCl in dioxane (12 mL) was added. The reaction mixture was stirred for 5 min at room temperature, then glacial acetic acid (20 mL) was added and the mixture was heated in an oil bath at 100° C. for 20 min. The reaction mixture was cooled to room temperature and then evaporated. Dichloromethane (200 mL) was added, the solution was washed with 50% saturated brine (2×50 mL), and the combined aqueous layers were back-extracted with dichloromethane (2×100 mL). The combined organic layers were washed with brine (150 mL), dried (magnesium sulfate), filtered, evaporated and eluted through a plug of silica gel with 30% ethyl acetate/hexanes to give (4S,7R)-2-phenyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (5.04 g, 97%) as an orange foam.
Reaction SMILES: P(Br)(Br)[Br:2].O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]#[N:15])=[CH:9][CH:8]=1.O>CC(OC)(C)C>[Br:2][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]#[N:15])=[CH:9][CH:8]=1
Reactant: BrP(Br)Br
Reactant: N#CCc1ccc(CO)cc1
Solvent: COC(C)(C)C
Solvent: O
Product: N#CCc1ccc(CBr)cc1

Procedure:
0.86 mL (9 mmol) of phosphorus tribromide are added dropwise to a solution of 2.6 g (17.66 mmol) of (4-hydroxymethyl-phenyl)-acetonitrile in 25 mL MTBE at 0° C. After the reaction has ended the reaction mixture is combined with water at RT, the organic phase is separated off and these are extracted successively with sodium hydrogen carbonate solution and water. The organic phase is dried over magnesium sulphate and the solvent is distilled off using the rotary evaporator.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:36])=[C:23]([C:25]4[N:26]=[CH:27][C:28]5[C:33]([CH:34]=4)=[CH:32][CH:31]=[CH:30][C:29]=5[Cl:35])[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.O1CCOCC1.[ClH:43]>>[ClH:35].[ClH:43].[ClH:35].[Cl:35][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:28]=1[CH:27]=[N:26][C:25]([C:23]1[C:22]([NH2:36])=[N:21][CH:20]=[C:19]([C:17]3[CH:16]=[N:15][N:14]([CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:18]=3)[CH:24]=1)=[CH:34]2
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4cc5cccc(Cl)c5cn4)c3)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2cccc(Cl)c2cn1
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
To a solution of 4-{4-[6-amino-5-(8-chloroisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (64.2 mg, 0.127 mmol) in 1,4-dioxane (1.5 mL, 19 mmol) was added HCl (4.0 M in 1,4-dioxane; 1.2 mL, 4.8 mmol), and the mixture was stirred at ambient temperature for 70 min. Almost immediately an off-white solid precipitated. The solid was filtered off, washed with MTBE, and dried in vacuo overnight to give the title compound as yellow solid. It appeared to be slightly hygroscopic during the filtration; however, after the washing and initial drying it appeared to be non-hygroscopic. 1H NMR (400 MHz, DMSO-d6): δ=14.7 (very brs, 1H), 9.68 (s, 1H), 9.23-9.14 (brm, 1H), 9.12-8.99 (brm, 1H), 8.89 (d, J=2.0 Hz, 1H), 8.82 (s, 1H), 8.76 (brs, 2H), 8.52 (s, 1H), 8.49 (d, J=2.0 Hz, 1H), 8.16 (s, 1H), 8.12 (d, J=8.0 Hz, 1H), 7.95 (dd, J=1.2, 7.6 Hz, 1H), 7.90 (t, J=7.8 Hz, 1H), 4.58-4.49 (mc, 1H), 3.40 (brd, J=12.0 Hz, 2H), 3.07 (brq, J=11.2 Hz, 2H), 2.30-2.12 (m, 4H). MS(ES+): m/z=405.13/407.13 (88/60) [MH+], 322.07/324.05 (90/64) [MH+-piperidine]. HPLC: tR=1.98 min (polar—5 min, ZQ3). UV: λmax=210, 244, 352 nm.