Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[C:3]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)([O:5][CH2:6][CH3:7])=[O:4].Br>O.C1COCC1>[CH2:6]([O:5][C:3]([N:8]1[CH2:9][CH2:10][C:11](=[O:14])[CH:12]([Br:1])[CH2:13]1)=[O:4])[CH3:7]
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: BrBr
Agent: Br
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(=O)C(Br)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 108 %

Procedure:
Bromine (2.83 mL, 55 mmol) was added dropwise to a stirred solution of N-carbethoxy-4-piperidone (7.54 mL, 50 mmol) and a 48% solution of HBr in H2O (1.41 mL) in THF (88 mL) at 0° C. The mixture was stirred at room temperature for 15 minutes and then quenched with a saturated solution of Na2S2O3, basified with a saturated solution of Na2CO3 and extracted with diethyl ether. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo to yield 3-bromo-4-oxo-1-piperidinecarboxylic acid ethyl ester (13.5 g, 54% yield, 50% pure) as a dark brown oil that was used in the next step without further purification. C8H12BrNO3 GCMS (EI): Rt 3.77, MW (theor) 249; m/z [M]+ 249 (using method, GC-MS Method 2).
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[C@H:3]([NH:10][C:11]([C:13]1[N:14]=[C:15]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][C:17]=12)=[O:12])[C:4]1[O:8][N:7]=[C:6]([CH3:9])[N:5]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]([CH3:36])([CH3:35])[C@H:3]([NH:10][C:11]([C:13]1[N:14]=[C:15]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:16]2[CH2:21][CH2:20][NH:19][CH2:18][C:17]=12)=[O:12])[C:4]1[O:8][N:7]=[C:6]([CH3:9])[N:5]=1
Reactant: Cc1noc([C@@H](NC(=O)c2nc(-c3ccccc3)n3c2CN(C(=O)OC(C)(C)C)CC3)C(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc([C@@H](NC(=O)c2nc(-c3ccccc3)n3c2CNCC3)C(C)(C)C)n1
Reaction time: 2 h
Yield: 93.2 %

Procedure:
Intermediate 22D (170 mg, 0.34 mmol) was dissolved in DCM (2 mL) and TFA (0.5 mL) was added. The resulting mixture was stirred for 2 h. The mixture was concentrated, neutralized with NaHCO3 saturated solution and extracted several times with EtOAc. The combined organic extracts were washed successively with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to give of Compound 282 (125 mg, 87%). 1H-NMR (400 MHz, CDCl3-d) δ: 1.09 (s, 9H), 2.40 (s, 3H), 3.78 (m, 2H), 4.11 (m, 2H), 5.01 (m, 2H), 5.37 (d, 1H), 7.35 (m, 3H), 7.64 (m, 2H), 7.78 (d, 1H), LCMS (+ESI) m/z 395.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:11]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Cl:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cccc(O)c1Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cccc(C=O)c1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-chloro-3-hydroxybenzaldehyde (4.55 g, 29 mmol) in DMF (30 mL) was added K2CO3 (4.8 g, 34.9 mmol) followed by MeI (2.7 mL, 43.6 mmol), and the mixture was stirred at room temperature for 16 hours. Following concentration in vacuo, the residual was taken up in ethyl acetate, washed with H2O, brine, dried over Na2SO4, and concentrated. Purification by column chromatography on silica gel with ethyl acetate/hexanes 1/5 afforded 2-chloro-3-methoxybenzaldehyde 7a (4.68 g, 94%) as a colorless oil, which solidified upon standing. GCMS (EI) m/z 170, 172 (M+).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:48][CH:49]1[C:53]2[C:54]([O:58][C:59]3[N:64]=[CH:63][C:62]([NH2:65])=[CH:61][CH:60]=3)=[CH:55][CH:56]=[CH:57][C:52]=2[CH2:51][O:50]1>CN(C)C=O>[CH3:48][CH:49]1[C:53]2[C:54]([O:58][C:59]3[N:64]=[CH:63][C:62]([NH:65][C:10]([C@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:13][CH3:14])=[O:12])=[CH:61][CH:60]=3)=[CH:55][CH:56]=[CH:57][C:52]=2[CH2:51][O:50]1
Reactant: CC1OCc2cccc(Oc3ccc(N)cn3)c21
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2cccc3c2C(C)OC3)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 8 ml vial (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (32.2 mg, 0.158 mmol) was dissolved in N,N-dimethylformamide (0.5 ml) to give a colourless solution. DIPEA (0.035 ml, 0.198 mmol) and HATU (60.3 mg, 0.158 mmol) were added. The reaction mixture was stirred at room temperature for 30 minutes. 6-[(3-methyl-1,3-dihydro-2-benzofuran-4-yl)oxy]-3-pyridinamine (Intermediate 100, 32 mg) was dissolved in 1.5 ml of DMF and the obtained solution was added to the reaction mixture. It was shaken at 60° C. After 2 hours, no reaction occurred. Additional 0.5 ml of a solution [obtained dissolving in 0.5 ml of DMF (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (32.2 mg, 0.158 mmol), DIPEA (0.035 mL, 0.198 mmol) and HATU (60.3 mg, 0.158 mmol)] was added to the reaction mixture. It was shaken at 60° C. over weekend. After that time, only traces of the title compound along with the Intermediate 100 was detected. The reaction mixture was evaporated under vacuum using the Vaportec V10 to give the crude product which was purified by silica gel chromatography (Biotage SP1 system, 10 g-SNAP Silica column) with Cyclohexane/EtOAc as eluents (from 3/1 to 1/1 in 10 CV; then 1/1 for 10 CV). The collected fractions afforded 4.9 mg of the title compound mixed with the amino acid and 61 mg of a mixture of starting material (Intermediate 100) and the amino acid.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8](=[O:13])O[C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[CH:4][C:3]=1[F:14].[NH:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1C(O)=O>CN(C)C=O.C(O)(=O)C>[F:1][C:2]1[C:7]2[C:8](=[O:13])[N:15]3[CH2:22][CH2:21][CH2:20][C@H:16]3[C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[CH:4][C:3]=1[F:14]
Reactant: O=c1[nH]c2ccc(F)c(F)c2c(=O)o1
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1Nc2ccc(F)c(F)c2C(=O)N2CCC[C@@H]12
Yield: 82.3 %

Procedure:
A solution of 28.8 g (144.6 mmol) of 5,6-difluoro-2,4-dihydro-1H-3,1-benzoxazine-2,4-dione and 16.7 g (144.6 mmol) of L-proline in 110 ml of dimethylformamide and 20 ml of acetic acid was stirred at 120° for 16 hours. The brown solution was evaporated and the brown residue obtained was crystallized from ethanol. There were obtained 30 g (82%) of (S)-6,7-difluoro-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione as colourless crystals of m.p. >250°.
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][CH2:8][C@@H:9]([CH2:25][O:26][S:27]([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH2:10][C@H:11]1[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[N:12]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])(C)(C)C.CC(C[AlH]CC(C)C)C.[BH4-].[Na+]>C(Cl)Cl>[OH:5][CH2:6][CH2:7][CH2:8][C@@H:9]([CH2:25][O:26][S:27]([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:28])=[O:29])[CH2:10][C@H:11]1[CH2:15][O:14][C:13]([CH3:16])([CH3:17])[N:12]1[C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](CCC(=O)OC(C)(C)C)C[C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H](CCCO)C[C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
To a solution of (S)-tert-butyl 4-((R)-5-tert-butoxy-5-oxo-2-(tosyloxymethyl)pentyl)-2,2-dimethyloxazolidine-3-carboxylate (317 mg, 0.58 mmol) in anhydrous DCM (8 mL) at −78° C. under N2 was added DiBAlH (1M in hexane, 1.75 mL, 1.75 mmol) dropwise. After the addition, the reaction mixture was stirred for another 30 min. The reaction was quenched with MeOH (2 mL), followed by 50% Rochelle's salt aq solution and stirred 2 hr. The resulting solution was extracted with DCM (3×20 mL), the combined organic phases were concentrated and dissolved in THF/MeOH (10 mL, 4/1, v/v), and chilled to 0° C., NaBH4 (11 mg, 0.29 mmol) was added and stirred at this temperature for 30 min. The reaction was quenched by aqueous NH4Cl, then extracted with EtOAc (3×20 mL), the combined organic phases were washed with H2O, brine, and dried over Na2SO4, and filtered, and concentrated to give crude product (S)-tert-butyl 4-((R)-5-hydroxy-2-(tosyloxymethyl)pentyl)-2,2-dimethyloxazolidine-3-carboxylate (255 mg, 92%). It was used without further purification.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:39][C:40]1[N:41]=[C:42]([CH2:45][CH3:46])[S:43][CH:44]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[N:41]=[C:42]([CH2:45][CH3:46])[S:43][CH:44]=2)[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCc1nc(CCl)cs1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: CCc1nc(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)cccc43)c3ccc(C(C)C)nc3)cn2)cs1
Yield: 72.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 4-chloromethyl-2-ethylthiazole (0.49 g) as starting materials, 5-benzyloxy-N-({1-[(2-ethylthiazol-4-yl}methyl]pyrazol-4-yl)methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.66 g) was obtained.
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][N:5]([CH:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][CH:17]=C)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7].[BH4-].[Na+]>CO>[OH:1][CH2:17][CH2:16][CH:15]([N:5]([CH3:4])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=[O+][O-]
Reactant: C=CCC(c1ccccc1)N(C)S(=O)(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(C(CCO)c1ccccc1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93 %

Procedure:
Ozone was bubbled through a solution of the product of Step 1 (1.0 g, 3.3 mmol) in MeOH (50 mL) at −78° C. for 30 min, then after appearance of a pale blue colour, the reaction was purged with N2 for several minutes and NaBH4 (245 mg, 6.6 mmol) was added. The resulting solution was allowed to warm to RT and stirred for a further 15 min at RT. The reaction was quenched by the addition of NH4Cl solution (10 mL) and then concentrated under reduced pressure. H2O (50 mL) was added and then extracted with EtOAc (100 ml and 50 mL). The combined organic extracts were dried (MgSO4) and then concentrated under reduced pressure to yield the alcohol (0.94 g, 93%). 1H NMR (CDCl3, 400 MHz) δ 7.81 (2H, d, J=7.2 Hz), 7.65–7.45 (3H, m), 7.20–7.13 (3H, m), 6.93 (2H, d, J=7.5 Hz), 5.25 (1H, dd, J=9.1, 6.3 Hz), 3.90–3.80 (1H, m), 3.74–3.59 (1H, m), 2.63 (3H, s), 2.13–1.98 (2H, m).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7](Cl)=[O:8])=[C:5]([CH3:10])[O:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[N:24][C:25]=3[NH2:27])[N:20]([C@H:28]3[CH2:33][CH2:32][C@@H:31]([N:34]4[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]4)[CH2:30][CH2:29]3)[N:19]=2)=[CH:14][C:13]=1[O:41][CH3:42]>N1C=CC=CC=1>[NH2:27][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[N:20]([C@H:28]3[CH2:33][CH2:32][C@@H:31]([N:34]4[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]4)[CH2:30][CH2:29]3)[N:19]=[C:18]([C:15]3[CH:16]=[CH:17][C:12]([NH:11][C:7]([C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH3:10])=[O:8])=[C:13]([O:41][CH3:42])[CH:14]=3)[C:26]=12
Reactant: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Reactant: Cc1noc(C)c1C(=O)Cl
Solvent: c1ccncc1
Product: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)c1c(C)noc1C
Reaction time: 5 h

Procedure:
3,5-dimethyl-4-isoxazolecarbonyl chloride (22 mg, 0.137 mmol) was added to a solution of cis-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.067 mmol) in pyridine (0.5 mL). After 5 hours, the solvent was evaporated and the residue was re-crystallized from DMSO to give cis-N4-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-3,5-dimethyl-4-isoxazolecarboxamide (33 mg, 87%). 1H NMR (DMSO-d6) δ 1.91 (m, 2H), 2.24 (m, 2H), 2.36 (m, 2H), 2.41 (s, 3H), 2.63 (s, 3H), 2.77 (m, 3H), 3.17 (s, 3H), 3.37 (bm, 8H), 3.95 (s, 3H), 4.95 (m, 1H), 7.37 (m, 2H), 8.17 (d, J=8.17, 1H), 8.30 (s, 1H), 9.26 (s, 1H). LC/MS (Micromass-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 3.5 mL/min.), MH+=560.2, Rt=2.44 min.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:19][P:20]([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])=[O:21])([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11](=[O:16])[CH2:10][C:9]2([CH3:18])[CH3:17])=[O:5])[CH3:2].[OH-:28].[K+]>CO>[OH:12][C:13]1[CH:14]=[CH:15][C:6]([P:4]([O:3][CH2:1][CH3:2])([CH2:19][P:20]([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])=[O:21])=[O:5])=[CH:7][C:8]=1[C:9]([CH3:18])([CH3:17])[CH2:10][C:11]([OH:16])=[O:28]
Reactant: CCOP(=O)(CP(=O)(OCC)c1ccc2c(c1)C(C)(C)CC(=O)O2)OCC
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Product: CCOP(=O)(CP(=O)(OCC)c1ccc(O)c(C(C)(C)CC(=O)O)c1)OCC
Yield: 105 %

Procedure:
A solution of 120 (0.99 g, 2.4 mmol) and KOH (0.095 g, 2.4 mmol) in methanol was stirred at room temperature for 2 hr. The solvent was removed removed under reduced pressure and the product was resuspended in water, the pH was adjusted to 4 by the addition of HCl, and the product was extracted with CH2Cl2. The organics were dried over Na2SO4, filtered and concentrated, resulting in 121 as a pale yellow oil (1.1 g, 105%) which was used without purification. 1H NMR (400 MHz, CDCl3) δ 1.26 (t, J=7.2, 3H), 1.29-1.37 (m, 6H), 1.45 (s, 3H), 1.48 (s, 3H), 2.63 (dd, J=17.7, 20.9, 2H), 2.93 (AB q, J=14.2, 2H), 4.00-4.20 (m, 6H), 6.74 (bs, 1H), 7.56 (ddd, J=1.6, 8.5, 12.2, 2H), 7.63 (d, J=13.3, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:14][C:13](=[O:15])[C:12]([C:16]([OH:18])=[O:17])=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1.[CH3:26]O>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:14][C:13](=[O:15])[C:12]([C:16]([O:18][CH3:26])=[O:17])=[CH:11][C:10]=1[C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1
Reactant: CO
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)[nH]c1=O
Product: COC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)[nH]c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Into a suspension of 6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (3.5 g, 8.7 mmol) from Example 32, Step A in methanol (350 mL) was bubbled HCl gas until the resulting solution was saturated. The mixture was stirred at rt for 72 h. The reaction was concentrated in vacuo, made basic with saturated sodium carbonate solution, and extracted twice with methylene chloride. The organic layers were washed with a portion of brine and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude methyl 6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (3.8 g) which was purified by flash column chromatography on silica gel eluted with 100% methylene chloride, then a gradient of 1 to 3% methanol in methylene chloride to give methyl 6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate as an off-white solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](O)=[O:4].C(Cl)(=O)C(Cl)=O.[Br:13][C:14]1[N:15]=[C:16]2[C:22]([NH2:23])=[CH:21][NH:20][C:17]2=[N:18][CH:19]=1.C(O)C(N)(CO)CO.C(=O)([O-])[O-]>O1CCOCC1.CN(C=O)C>[Br:13][C:14]1[N:15]=[C:16]2[C:22]([NH:23][C:3](=[O:4])[CH:2]([CH3:6])[CH3:1])=[CH:21][NH:20][C:17]2=[N:18][CH:19]=1
Reactant: Nc1c[nH]c2ncc(Br)nc12
Reactant: CC(C)C(=O)O
Agent: NC(CO)(CO)CO
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CC(C)C(=O)Nc1c[nH]c2ncc(Br)nc12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-methyl propanoic acid (62.06 mg, 65.46 μL, 0.7044 mmol) in dioxane (1 mL) with DMF was added oxalyl chloride (87.9 mg, 60.43 μL, 0.6927 mmol) at ambient temperature. The resulting solution was stirred for 30 minutes at this temperature. To this solution was added 2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-amine (50 mg, 0.2347 mmol) and this was stirred for a further 4 hours at ambient temperature. The reaction mixture was then heated to 50° C. for 1 hour. After this time trisamine resin and carbonate resin were added and the sample filtered. This crude solution was taken onto the next step as is.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[N:4][C:3]=1[CH:26]=O.[CH3:28][N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38](=[O:40])[CH3:39])=[CH:30]1.[OH-].[K+]>C(O)C.O>[CH3:28][N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38](=[O:40])/[CH:39]=[CH:26]/[C:3]2[N:4]=[CH:5][N:6]([C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:2]=2[CH3:1])=[CH:30]1
Reactant: CC(=O)c1cn(C)c2ccccc12
Reactant: Cc1c(C=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(/C=C/C(=O)c2cn(C)c3ccccc23)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 133.1 %

Procedure:
A mixture of 5-methyl-1-(triphenylmethyl)-1H-imidazole-4-carboxaldehyde (2.5 g), 1-(1-methyl-1H-indol-3-yl)-1-ethanone (1.0 g) and potassium hydroxide (3.1 g) in absolute ethanol (50 ml) and water (25 ml) was stirred at room temperature for 72 h, then at 50° for 18 h. The mixture was partitioned between 2N sodium carbonate (200 ml) and ethyl acetate (2×200 ml) and the combined organic layers were washed with brine (150 ml), dried and evaporated in vacuo to leave a foam (3.9 g) which was purified by FCC eluting with ethyl acetate:hexane (1:1) to give the title compound (1.76 g) as a solid, m.p. 216°-219°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:24]([OH:26])=O.Cl.[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH2:36][CH2:37][NH:38][CH2:39][CH:40]=2)=[CH:31][CH:30]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:24]([N:38]1[CH2:37][CH:36]=[C:35]([C:32]2[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=2)[CH2:40][CH2:39]1)=[O:26]
Reactant: Fc1ccc(C2=CCNCC2)cc1
Reactant: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)O)cnc12
Agent: Cl
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)N3CC=C(c4ccc(F)cc4)CC3)cnc12
Yield: 74.7 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-(2,5-dimethylphenylamino)-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (110 mg, 0.31 mmol) obtained in Example 88, step 2 and 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (79 mg, 0.37 mmol), the title compound (119 mg, 75%) was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([OH:23])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1.[CH2:34](I)[CH3:35].[H-].[Na+]>CN(C)C=O>[CH3:1][N:2]([CH3:33])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:24]2[CH:25]=[CH:26][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:29]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:34][CH3:35])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1
Reactant: CCI
Reactant: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3ccc(O)cc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc2c(c1)C(C(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(C(C)C)cc1)CCC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
N-[(4-Dimethylaminophenyl)methyl]-7-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.5 g) and ethyl iodide (0.14 mL) were dissolved in dimethylformamide (5 mL), and sodium hydride (0.07 g) was added under ice-cooling. The mixture was stirred at room temperature for 24 hr. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give N-[(4-dimethylaminophenyl)methyl]-7-ethoxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.27 g).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:30]([C:41]([F:44])([F:43])[F:42])[CH:29]=1>CN(C=O)C>[CH:35]1([CH2:34][C:31]2[CH:32]=[CH:33][C:28]([CH2:27][O:1][C:2]3[CH:10]=[CH:9][C:8]4[NH:7][C:6]5[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=5[C:4]=4[CH:3]=3)=[CH:29][C:30]=2[C:41]([F:42])([F:43])[F:44])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Reactant: FC(F)(F)c1cc(CBr)ccc1CC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(CC4CCCCC4)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.9 %

Procedure:
To a stirred reaction mixture of ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (40 mg, 0.15 mmol) and cesium carbonate (75 mg, 0.23 mmol) in DMF (1 mL) was added 4-(bromomethyl)-1-(cyclohexylmethyl)-2-(trifluoromethyl)benzene (78 mg, 0.23 mmol). The reaction mixture was stirred at room temperature for 1 h. The solid was filtered and washed with ethyl acetate. The combined filtrate was concentrated, and the residue was purified by preparative TLC to give the title compound (40 mg) as an oil. LCMS m/z=514.5 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 0.96-1.06 (m, 2H), 1.14-1.22 (m, 3H), 1.30 (t, J=7.2 Hz, 3H), 1.55-1.72 (m, 6H), 2.07-2.15 (m, 1H), 2.50 (dd, J=16.7 and 11.2 Hz, 1H), 2.66 (d, J=6.8 Hz, 2H), 2.70-2.86 (m, 4H), 3.52-3.58 (m, 1H), 4.18-4.25 (m, 2H), 5.08 (s, 2H), 6.85 (dd, J=8.8 and 2.4 Hz, 1H), 7.00 (d, J=2.4 Hz, 1H), 7.21 (d, J=8.8 Hz, 1H), 7.31 (d, J=7.9 Hz and 1.6 Hz, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.72 (d, J=1.6 Hz, 1H), 8.46 (s, 1H).