Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH2:11][CH2:12]Br)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C1(C)C=CC=CC=1.CCOCC>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH2:11][CH2:12][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: BrCCCc1ccc2c(c1)CCC2
Reactant: C1CCNCC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: c1cc2c(cc1CCCN1CCCCC1)CCC2

Procedure:
The crude 3-(5-Indanyl)-1-bromopropane (13.0 g, 0.054 M) is dissolved in 200 ml toluene and treated with 50 g of piperidine. The mixture is heated under reflux overnight, then cooled and diluted with ether to precipitate salts. The salts are removed by filtration and the solvent removed from the filtrate in vacuo. The residue is distilled collecting 8.4 g (64%) of desired product boiling at 135°-140° (0.15 mm).
Reaction SMILES: [CH2:1]([CH:5]([CH2:8][OH:9])[CH2:6][OH:7])[CH2:2][CH2:3][CH3:4].C(O[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH2:1]([CH:5]1[CH2:8][O:9][CH:13]([CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[O:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCCCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCC1COC(C(C(=O)OCC)C(=O)OCC)OC1
Yield: 89.4 %

Procedure:
A mixture of 17.45 g of 2-butyl-1,3-propanediol, 26.4 g of diethyl (ethoxymethylidene)-malonate, 250 ml of toluene and 0.285 g of p-toluenesulfonic acid monohydrate was heated to boiling for 1 hour, with moist toluene being distilled off and replaced by the addition of fresh toluene. The reaction mixture was neutralized with triethylamine and, after cooling, washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated. The crude product (42.35 g) was chromatographed on 520 g of silica gel with hexane/ethyl acetate (4:1). 33.0 g of oily diethyl (5-butyl-1,3-dioxan-2-yl)-malonate were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>CN(C=O)C.C(Cl)Cl>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]2)=[CH:19][CH:18]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(Cn2cc([N+](=O)[O-])cn2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-nitro-1H-pyrazole (500 mg, 4.42 mmol; Bionet Research, Cornwall, UK) in DMF (5 mL) was treated with potassium carbonate (400 μL, 6.63 mmol) and 4-methoxybenzyl chloride (600 μL, 4.42 mmol). The reaction was stirred at room temperature for 2 h, then diluted with DCM (200 mL) and washed with water (4×40 mL). The organic layer was then dried (MgSO4), filtered and concentrated in vacuo to give the crude product, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH2:13][O:14][C:8]=2[CH:7]=1)[C:3]([NH2:5])=[O:4].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CS(O)(=O)=O.C1(C)C=CC=CC=1>O>[CH3:1][N:2]1[C:6]2[C:11](=[CH:10][C:9]3[O:12][CH2:13][O:14][C:8]=3[CH:7]=2)[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:5][C:3]1=[O:4]
Reactant: CN(C(N)=O)c1ccc2c(c1)OCO2
Reactant: O=Cc1ccccc1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CN1C(=O)NC(c2ccccc2)c2cc3c(cc21)OCO3
Yield: 20 %

Procedure:
A mixture of N-methyl-N-[3,4-(methylenedioxy)phenyl]urea (240 mg), benzaldehyde (140 μL) and methanesulfonic acid (50 μL) and toluene (60 mL) was refluxed for 2 h in a flask equipped with a Dean-Stark water separator. After cooling, the solution was washed with water thoroughly, dried over Na2SO4 and concentrated in vacuo. The resulting solid was recrystallized from chloroform/hexane to provided the title compound as a tan solid (70 mg, 20%), mp: 228-230° C. 1H NMR (CDCl3): 7.37-7.30 (m, 5H), 6.53 (s, 1H), 6.28 (s, 1H), 5.91 (d, 1H, J=1.4), 5.89 (d, 1H, J=1.4), 5.46 (s, 1H), 5.11 (br s, 1H), 3.33 (s, 3H). Anal. calcd. for C16H14N2O3: C, 68.08: H, 5.00; N, 9.92. Found: C, 68.06; H, 4.91; N, 9.71.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]([S:10][C:11]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:12]=1[C:13](O)=[O:14])([CH3:9])[CH3:8].Cl.CN.[N:26]1C=CC=C[CH:27]=1>C(Cl)Cl.CN(C=O)C>[CH:7]([S:10][C:11]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:12]=1[C:13]([NH:26][CH3:27])=[O:14])([CH3:9])[CH3:8]
Reactant: CC(C)Sc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: c1ccncc1
Agent: CN
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)c1cc([N+](=O)[O-])ccc1SC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
Oxalyl chloride (1.75 mL, 19.6 mmol) was added dropwise to a suspension of 16A (2.41 g, 10 mmol) in DCM (20 mL) containing DMF (2 drops) at 0° C. The reaction mixture was warmed to rt and stirred overnight. The reaction mixture was concentrated in vacuo and coevaporated twice with toluene. The residue was dissolved in DCM (25 mL) and added portionwise to a solution of methylamine hydrochloride (2.03 g, 30.1 mmol) and pyridine (8.1 mL, 100 mmol) in DCM (25 mL) at 0° C. The reaction mixture was stirred overnight at rt. The reaction mixture was concentrated in vacuo and the residue was triturated with water to give 16B (2.08 g, 82%) as a yellow solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:33])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17]([OH:19])=O)[C:9]2=[O:14])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1.O>O1CCCC1>[F:28][CH:27]([F:29])[O:26][C:23]1[CH:24]=[CH:25][C:20]([CH:15]([N:8]2[C:7](=[O:33])[C:6]3[C:10](=[CH:11][CH:12]=[CH:13][C:5]=3[NH:4][C:1](=[O:3])[CH3:2])[C:9]2=[O:14])[CH2:16][C:17]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)=[O:19])=[CH:21][C:22]=1[O:30][CH2:31][CH3:32]
Reactant: C1COCCN1
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)N2CCOCC2)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.5 %

Procedure:
To a solution of 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (400 mg, 0.86 μmmol) in tetrahydrofurane was added carbonyldiimidazole (160 mg, 1 mmol) at room temperature. The solution was stirred for 2 hours at room temperature. To the mixture was added morpholine (0.12 ml, 1.3 mmol). The resulted mixture was stirred at room temperature for 2 hours. Water (5 ml) was added to the reaction mixture. THF was removed in vacuo and the resulted mixture was taken up in ethyl acetate (20 ml). The organic layer was washed with saturated sodium bicarbonate solution (3×10 ml), water (10 ml), brine (10 ml) and was dried over magnesium sulfate. The solvent was removed in vacuo. The resulted oil was purified by HPLC (acetonitrile:water=45:55) to give N-{2-[1-(4-difluoromethoxy-3-ethoxy-phenyl)-3-morpholin-4-yl-3-oxo-propyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide as a white solid (200 mg, 44%): mp, 109-111° C.; 1H NMR (CDCl3): 1.44 (t, J=7.5 Hz, 3H, OCH2CH3), 2.26 (s, 3H, CH3CO), 3.02 (dd, J=5, 17.5 Hz, 1H, CHHCO), 3.49-3.68 (m, 8H, morpholine ring), 3.9 (dd, J=7.5, 17.5 Hz, 1H, CHHCO), 4.09 (q, J=7.5 Hz, 2H, OCH2CH3), 5.84 (dd, J=5, 10 Hz, 1H, CHN), 6.54 (t, JH-F=75 Hz, 1H, OCF2H), 7.11-7.16 (m, 3H, Ar), 7.45 (d, J=7.5 Hz, 1H, Ar), 7.63 (t, J=7.5 Hz, 1H, Ar), 8.75 (d, J=7.5 Hz, 1H, Ar), 9.50 (s, 1H, NHCO). 13C NMR (CDCl3): 15.3, 25.6, 35.1, 42.7, 46.6, 51.9, 65.5, 67.2, 67.5, 112.6, 114.4, 115.9, 116.7, 118.6, 120.8, 120.9, 123.5, 125.5, 131.9, 136.6, 138.2, 138.5, 140.6, 151.3, 168.6, 168.7, 169.9, 170.6; Anal. Calcd. for C26H27F2N3O7: C, 58.75; H, 5.12; N, 7.91; Found: C, 58.48; H, 5.09; N, 7.79;
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][C:32]=1[NH:33][C:34](=[O:38])[CH2:35][O:36][CH3:37])[NH:29][C:28](=[O:39])[CH2:27]2>>[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][C:32]=1[NH:33][C:34](=[O:38])[CH2:35][O:36][CH3:37])[NH:29][C:28](=[O:39])/[C:27]/2=[CH:21]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]3)[C:7](=[O:20])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Reactant: COCC(=O)Nc1cc2c(cc1F)CC(=O)N2
Product: COCC(=O)Nc1cc2c(cc1F)/C(=C/c1[nH]c3c(c1C)C(=O)N(CCN1CCCCC1)CCC3)C(=O)N2
Yield: 75 %

Procedure:
The title compound was prepared under the same conditions as described in step 5 of Example 32 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d obtained from step 4 of Example 32 and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-methoxy-acetamide 7a obtained from step 1 of Example 7 as starting materials to obtain (Z)—N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-methoxy-acetamide 37 (59 mg, yield 75%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[OH:63][CH2:64][C@H:65]1[CH2:69][CH2:68][CH2:67][NH:66]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:66]1[CH2:67][CH2:68][CH2:69][C@@H:65]1[CH2:64][OH:63])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: OC[C@H]1CCCN1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCC[C@@H]3CO)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and (2R)-2-hydroxymethyl-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: ClN1C(=O)C[CH2:4][C:3]1=O.Cl[C:10]1[C:14]([Cl:15])=[C:13]([CH3:16])[NH:12][C:11]=1[C:17]([OH:19])=[O:18].[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:15][C:14]1[CH:10]=[C:11]([C:17]([O:19][CH2:3][CH3:4])=[O:18])[NH:12][C:13]=1[CH3:16]
Reactant: Cc1[nH]c(C(=O)O)c(Cl)c1Cl
Reactant: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(Cl)c(C)[nH]1
Temperature: 40 °C
Reaction time: 4 h
Yield: 37.8 %

Procedure:
N-Chlorosuccinimide (0.67 g, 5.08 mmol) was added to a solution of ethyl 5 -methyl-1H-pyrrole-2-carboxylate (Intermediate 3; 0.65 g, 4.23 mmol) in chloroform (20 ml). The reaction was warmed to 40° C. and stirred for 4 h, then poured to a beaker containing 2 N NaOH (20 ml) at 0° C. The layers were separated and the aqueous layer was extracted with chloroform (×3). The combined organic extracts were dried over magnesium sulfate and concentrated. The resultant off-white solid was purified by flash chromatography (hexanes/EtOAc, 16:1) to give the title product as a white solid (0.3 g, 38%). MS (ES): 188 (M+1) for C8H10ClNO2; NMR (CDCl3): 1.34 (t, 3H), 2.27 (s, 3H), 4.30 (q, 2H), 6.76 (s, 1H), 9.07 (brs, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][OH:14])[CH2:11][C@H:10]([O:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[NH:23][C:24]2[C:25]3[C:32]([CH3:33])=[C:31]([C:34]([NH2:36])=[O:35])[S:30][C:26]=3[N:27]=[CH:28][N:29]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:37](OC(=O)C)(=[O:39])[CH3:38]>CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([O:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[NH:23][C:24]2[C:25]3[C:32]([CH3:33])=[C:31]([C:34](=[O:35])[NH2:36])[S:30][C:26]=3[N:27]=[CH:28][N:29]=2)[CH2:11][C@H:12]1[CH2:13][O:14][C:37](=[O:39])[CH3:38])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3C[C@@H](CO)N(C(=O)OC(C)(C)C)C3)c12
Agent: CN(C)c1ccncc1
Product: CC(=O)OC[C@@H]1C[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(N)=O)c(C)c23)CN1C(=O)OC(C)(C)C

Procedure:
Prepared analogously to example 96.4 from 4-[2-((3S,5S)-1-tert-butoxycarbonyl-5-hydroxymethyl-pyrrolidin-3-yloxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid amide and acetic anhydride. The acetic anhydride was added at 0° C. and a catalytic amount of DMAP was used.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.[C:27]1(C)C=CC=CC=1.C(OC(OCC)OCC)C>C(O)(C)C.[Pt]>[N:14]1([CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:1]=[CH:27]1
Reactant: Cc1ccccc1
Reactant: O=C(NCCCNc1c([N+](=O)[O-])cnc2ccccc12)c1ccccc1
Agent: [Pt]
Solvent: CC(C)O
Solvent: CCOC(OCC)OCC
Product: O=C(NCCCn1cnc2cnc3ccccc3c21)c1ccccc1
Temperature: 25 °C

Procedure:
A suspension of N1-{3-[(3-nitroquinolin-4-yl)amino]propyl}benzamide (1.0 g, 2.8 mmol) in isopropyl alcohol (120 mL) was warmed to dissolve some of the material. A catalytic amount of platinum on carbon was added and the reaction mixture was placed under a hydrogen atmosphere at 50 psi (3.4×104 pascals) on a Parr apparatus. After 3 hours the reaction mixture was filtered to remove catalyst. The filtrate was concentrated under vacuum to provide crude N1-{3-[(3-aminoquinolin-4-yl)amino]propyl}benzamide as an oil. Toluene (100 mL) was added to the oil followed by the addition of triethylorthoformate (0.8 g, 5.6 mmol). The reaction mixture was heated on a steam bath overnight. The reaction mixture was allowed to cool to ambient temperature. The resulting precipitate was isolated by filtration to provide 0.53 g of N1-[3-(1H-imidazo[4,5-c]quinolin-1-yl)propyl]benzamide as an off white solid, m.p. 188-190° C. 1H NMR (500 MHz, DMSO-d6) δ 8.67 (t, J=5.5 Hz, 1H), 8.50 (s, 1H), 8.37 (d, J=7.5 Hz, 1H), 8.17 (dd, J=8.0, 1.5 Hz, 1H), 7.87 (d, J=7.0 Hz, 2H), 7.71 (dt, J=7.5, 1.5 Hz, 1H), 7.56 (dt, J=7.5, 1.0 Hz, 1H), 7.54 (d, J=8.0 Hz, 2H), 7.48 (t, J=7.0 Hz, 2H), 4.78 (t, J=7.0 Hz, 2H), 3.38 (q, J=6.0 Hz, 2H), 2.18 (quintet, J=7.0 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH3:8][N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH3:26])[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[C:6](=[O:25])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: Cc1ccccc1B(O)O
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: COCCOC
Solvent: O
Product: Cc1ccccc1-c1cc(CN(C)C(=O)OC(C)(C)C)cn1S(=O)(=O)c1cccnc1
Temperature: 105 °C
Reaction time: 18 h
Yield: 68.2 %

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (2-methylphenyl)boronic acid (190 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-yellow oil (yield 210 mg, 68%). More specifically, a suspension of tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (2-methylphenyl)boronic acid (190 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg) in 1,2-dimethoxyethane (10 mL) and water (7.5 mL) was stirred at 105° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:1→3:1) to give the title compound as a pale-yellow oil (yield 210 mg, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:26])([F:25])[F:24])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(Cl)([Cl:29])=O>C1C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:25])([F:24])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([Cl:29])=[O:19])=[CH:21][CH:22]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=C(Cl)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Yield: 173.1 %

Procedure:
In a suspension of 1.00 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]benzoic acid in 10 ml of benzene, 0.44 g of thionyl chloride and a catalytic amount (2 to 3 drops) of N,N-dimethylformamide were added, and stirred under reflux with heat for 2.5 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure to obtain 1.81 g of crude 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]benzoic acid chloride as pale yellow oily substance.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].O1C=C[CH2:12][C:11]1=O>>[C:3]([CH:2]1[CH2:9][CH:8]([CH2:11][CH3:12])[O:7][C:1]1=[O:6])(=[O:4])[CH3:5]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C1CC=CO1
Product: CCC1CC(C(C)=O)C(=O)O1
Temperature: 60 °C
Yield: 92.5 %

Procedure:
The organic layer was stripped using an aspirator vacuum (60 mm) and heating the flask to 60° C. leaving a net residue of 618 g. The residue was distilled using a packed column and Perkins Triangle Head. The product obtained by distillation comprised three fractions, 164 g, 130 g, and 114 g, respectively, comprising mostly ethyl acetoacetate. The pot material was filtered and the distillation continued to obtain 16.1 g of a fourth fraction boiling below 105° C. at 5 torr that comprised 8% lactone and 887 g of a fifth fraction having a boiling point of 110-120° C. at 5 torr that comprised 92.5% of the desired product when analyzed by gas chromatography. Yield of lactone (fifth fraction) was 42%.
Reaction SMILES: C(O[C:4]([C:6]1[NH:7][N:8]=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=1)=O)C.C(OC(=O)[NH:25][CH2:26][C:27](O)([CH3:29])[CH3:28])(C)(C)C.C(OC(C1N(CC(NC(OC(C)(C)C)=O)C)N=C(COC2C=CC=CC=2)C=1)=O)C.CC1CN2N=C(COC3C=CC=CC=3)C=C2C(=O)N1.CC1CN2N=C(COC3C=CC=CC=3)C=C2CN1>>[CH3:28][C:27]1([CH3:29])[N:7]2[N:8]=[C:9]([CH2:11][O:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:10]=[C:6]2[CH2:4][NH:25][CH2:26]1
Reactant: CC(C)(O)CNC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cc(COc2ccccc2)n[nH]1
Agent: CC1Cn2nc(COc3ccccc3)cc2C(=O)N1
Agent: CC1Cn2nc(COc3ccccc3)cc2CN1
Agent: CCOC(=O)c1cc(COc2ccccc2)nn1CC(C)NC(=O)OC(C)(C)C
Product: CC1(C)CNCc2cc(COc3ccccc3)nn21

Procedure:
The compound was prepared from 5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester and 2-hydroxy-2-methyl-propyl-carbamic acid tert-butyl ester using the methods described in the preceding examples 11 (rac-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester), 12 (rac-6-methyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one), and 13 (rac-6-methyl-2-phenoxymethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:3]=12.[CH3:18][NH:19][CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(N(C(C)C)CC)(C)C>CC#N>[CH2:16]([N:13]1[C:4]2=[N:5][CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]([N:19]([CH3:18])[CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[C:3]2[CH:15]=[N:14]1)[CH3:17]
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Reactant: CNC1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)c1cnc2c(cnn2CC)c1N(C)C1CCOCC1
Yield: 76.5 %

Procedure:
Intermediate 1 (1.2 g, 4.76 mmol), Intermediate 50 (0.79 g, 5.2 mmol) and diisopropylethylamine (4 ml, 24 mmol) in MeCN (8 ml) was heated at 70° C. for 24 hours. The solvent was removed in vacuo and the residue partitioned between DCM and water. The organic phase was concentrated in vacuo and the residue chromatographed on silica (50 g) eluting with cyclohexane:ethyl acetate (2:1 followed by 1:1 then 1:2). Appropriate fractions were combined and evaporated to give Intermediate 51 as a brown oil (1.21 g). LCMS showed MH+=334; TRET=2.61 min.
Reaction SMILES: CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.[CH3:19][C:20]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22].[C:28]([O:32][C:33]([N:35]1[CH2:48][CH2:47][C@@H:46]2[C@@H:38]([N:39]([CH2:51][C:52](O)=[O:53])[C:40]3[CH:41]=[CH:42][C:43]([Cl:50])=[C:44]([Cl:49])[C:45]=32)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>C1COCC1>[Cl:50][C:43]1[CH:42]=[CH:41][C:40]2[N:39]([CH2:51][C:52]([NH:22][C:21]3[CH:23]=[CH:24][CH:25]=[C:26]([CH3:27])[C:20]=3[CH3:19])=[O:53])[C@H:38]3[CH2:37][CH2:36][N:35]([C:33]([O:32][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:34])[CH2:48][CH2:47][C@H:46]3[C:45]=2[C:44]=1[Cl:49]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2c3c(ccc(Cl)c3Cl)N(CC(=O)O)[C@H]2CC1
Reactant: Cc1cccc(N)c1C
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)CN2c3ccc(Cl)c(Cl)c3[C@@H]3CCN(C(=O)OC(C)(C)C)CC[C@@H]32)c1C
Temperature: 50 °C

Procedure:
EEDQ (0.57 g, 2.3 mmol) and 2,3-dimethylaniline (0.28 g, 2.3 mmol) were added to a solution of [3-(tert-butoxycarbonyl) (5aS*,10bS*)-9,10-dichloro-2,3,4,5,5a,10b-hexahydroazepino[4,5-b]indol-6(1H)-yl]acetic acid (0.80 g, 1.9 mmol) in THF (20 mL). The reaction was heated to 50° C., cooled to rt after 6 h, and concentrated. The crude product was purified via column chromatography (Biotage, 40 M) with CH2Cl2/MeOH (99: 1) followed by crystallization from EtOAc/heptane to give a white solid: mp 145.5-146.0° C.; 1H NMR (CDCl3, 300 MHz) δ 68.49 (br s, 1H), 7.31 (m, 1H), 7.21 (d, J=8.3Hz, 1H), 7.13 (m, 1H), 7.00 (d, J=7.5 Hz, 1H), 6.37 (d, J=8.4Hz, 1H), 3.89 (m, 2H), 3.78 (m, 2H), 3.66 (m, 1H), 3.58 (m, 1H), 3.33 (m, 2H), 2.34 (m, 1H), 2.27(s, 3H), 2.17 (m, 1H), 2.02 (s, 3H), 1.90 (m, 2H), 1.45 (s, 9H); IR (diffuse reflectance) 1692, 1661, 1596, 1517, 1499, 1465, 1428, 1365, 1329, 1265, 1252, 1241, 1177, 1142, 795 cm−1; MS (EI) m/z 517 (M+), 519, 315, 313, 269, 228, 226, 57, 56, 55; Anal. Calcd for C27H33Cl2N3O3: C, 62.55; H, 6.41; N, 8.10; found: C, 62.53; H, 6.43; N, 8.08.