Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([NH:15][C:16](=[O:18])[CH3:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)=O.[NH2:19][C:20]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[C:21]=1[C:22]([NH2:24])=[O:23].CC1C=CC(S(O)(=O)=O)=CC=1.OS([O-])=O.[Na+].C([O-])(O)=O.[Na+]>CC(N(C)C)=O.O>[CH3:32][O:31][C:25]1[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=[C:20]2[C:21]=1[C:22](=[O:23])[NH:24][C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]3[CH2:14][CH2:13][CH:12]([NH:15][C:16](=[O:18])[CH3:17])[CH2:11][CH2:10]3)=[CH:5][CH:4]=1)=[N:19]2
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: CC(=O)NC1CCN(c2ccc(C=O)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: O=S([O-])O
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCC(NC(C)=O)CC4)cc3)nc2c1
Temperature: 155 °C
Yield: 29.1 %

Procedure:
A mixture of N-(1-(4-formylphenyl)piperidin-4-yl)acetamide (0.280 g, 1.14 mmol), 2-amino-4,6-dimethoxybenzamide (0.224 g, 1.14 mmol), p-TsOH (0.022 g, 0.114 mmol), and NaHSO3 (0.125 g, 1.21 mmol) in DMA was heated at 155° C. for 6 hours. The reaction mixture was cooled, diluted with water (100 mL), basified with saturated NaHCO3, and extracted with ethyl acetate (3×150 mL). The organic phase was concentrated and purified by flash chromatography on silica gel, eluting with 1:1 CH2Cl2/(92:7:1 CHCl3/MeOH/concentrated NH4OH) to 100% 92:7:1 CHCl3/MeOH/concentrated NH4OH. Further purification by reverse-phase HPLC, eluting with 10% to 90% CH3CN in H2O with 0.1% TFA, afforded the title compound as a yellow solid (0.140 g, 29%): 1H NMR (300 MHz, DMSO-d6): δ 11.74 (s, 1H), 8.08 (d, J=9.0 Hz, 2H), 7.83 (d, J=7.7 Hz, 1H), 7.01 (d, J=9.0 Hz, 2H), 6.68 (d, J=2.3 Hz, 1H), 6.46 (d, J=2.3 Hz, 1H), 3.7-3.89 (m, 9H), 2.92-3.00 (m, 2H), 1.76-1.85 (m, 5H), 1.36-1.48 (m, 2H); APCI MS m/z 423 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=[O:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[Br:16][CH2:17][CH2:18]Br.[OH-].[Na+].C1(=O)C2C(C3C(N=2)=CC=CC=3)=CC=C1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:18][CH2:17][Br:16])[C:10]1[C:9](=[O:15])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCCC3=O
Reactant: BrCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C1C=CC=C2C1=Nc1ccccc12
Agent: O=S(=O)([O-])O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CCBr)C(=O)CCC1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
199 g. (1 mole) of 6-methyl-1,2,3,4-tetrahydrocarbazol-1-one (m.p.: 199° C., as given in literature: 194°-195° C., 195°-196° C., 195° C., cf. Bloink and Pausacker loc. cit. page 1330), 1520 g. (8.1 moles), 1,2-dibromoethane and 1000 ml. (7.5 moles) of aqueous sodium hydroxide solution (30% strength) are taken initially and admixed, while stirring at room temperature, with 4.25 g. (12.5 m mole) of tetrabutylammoniumhydrogensulfate dissolved in 25 ml of water. With a slight temperature rise, the reaction sets in and while continuously stirring, comes to an end after some seven hours' time. For working up, the aqueous alkaline layer is separated, the organic layer washed with water and the excess dibromoethane distilled off in vacuo. The residue is recrystallized from 200 ml. of ethanol. 281 g. (92% of the theoretical) of 6-methyl-9-(2-ethylbromide)-1,2,3,4-tetrahydrocarbazol-1-one (melting at 103° C.). The amount of the tetrabutylammoniumhydrogensulfate used as catalyst can be reduced to 5 m moles per 1 mole of the carbazolone employed, but the reaction takes twice as long when this change is made.
Reaction SMILES: Br[C:2]1[O:23][C:5]2[N:6]([CH3:22])[CH:7]=[C:8]([C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[O:12])[C:9](=[O:10])[C:4]=2[CH:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:30]([OH:34])[CH2:31][C:32]#[CH:33]>>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][NH:13][C:11]([C:8]2[C:9](=[O:10])[C:4]3[CH:3]=[C:2]([C:33]#[C:32][CH2:31][CH:30]([OH:34])[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)[O:23][C:5]=3[N:6]([CH3:22])[CH:7]=2)=[O:12])=[CH:16][CH:17]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(Br)oc21
Reactant: C#CCC(O)c1ccccn1
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCC(O)c3ccccn3)oc21

Procedure:
Analogous to the procedures described in Example 88, 2-bromo-N-(4-chlorobenzyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 79) is treated with 1-(pyridin-2-yl)but-3-yn-1-ol (Preparation 76) to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[OH-].[Na+].[CH2:27](Br)[CH2:28][CH2:29][CH2:30][CH3:31]>C(Cl)Cl.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:27]([O:1][C:2]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])[CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCc1ccc(O)c(C(=O)c2ccccc2)c1
Reactant: CCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCc1ccc(OCCCCC)c(C(=O)c2ccccc2)c1
Yield: 82 %

Procedure:
A solution of 2-hydroxy-5-nonyl benzophenone, 15 g, in 100 mL methylene chloride was mixed with a solution of 9.25 g NaOH in 100 mL water. To this mixture was added 6.9 g n-pentyl bromide and 1.48 g tetra-n-butylammonium bromide. The whole mixture was then vigorously agitated overnight at 40° C. After cooling to room temperature with 50 mL CH2Cl2. The combined methylene chloride layers were concentrated to an oil, which was taken up in 100 mL petroleum ether and washed with 100 mL water. Finally, the organic layer was dried over anhydrous magnesium sulfate and the volatiles removed under vacuum to give 15 g (82% yield) of 2-n-pentoxy-5-nonyl benzophenone.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=2)[C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5]1)([CH3:3])[CH3:2].Br[C:26]1[S:30][C:29]([C:31]2[N:35]([CH3:36])[N:34]=[N:33][N:32]=2)=[CH:28][CH:27]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C(OCC)(=O)C.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>[CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=2)[C:6]([C:26]2[S:30][C:29]([C:31]3[N:35]([CH3:36])[N:34]=[N:33][N:32]=3)=[CH:28][CH:27]=2)=[CH:5]1)([CH3:2])[CH3:3]
Reactant: Cn1nnnc1-c1ccc(Br)s1
Reactant: CC(C)n1cc(B2OC(C)(C)C(C)(C)O2)c2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)n1cc(-c2ccc(-c3nnnn3C)s2)c2ccc([N+](=O)[O-])cc21
Temperature: 100 °C
Yield: 42.9 %

Procedure:
Method CC In a 501 mL flask fitted with a reflux condenser, combine 1-isopropyl-6-nitro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (4, R1=i-Pr) (700 mg, 2.1 mmol), 5-(5-Bromo-thiophen-2-yl)-1-methyl-1H-tetrazole (466 mg, 1.9 mmol), tris-(dibenzylideneacetone) di-palladium (0) (17 mg, 0.019 mmol), and tricyclohexylphosphine (13 mg, 0.0047 mmol) in dioxane (5.5 mL). Degas under nitrogen atmosphere three times; then add 1.3M aqueous potassium phosphate (2.5 mL, 3.2 mmol) in a 50 mL flask fitted with a reflux condenser. Heat the reaction mixture to 100° C. for 4 hours. Cool the reaction mixture to room temperature and dilute with water (20 mL) and ethyl acetate (20 mL); then separate layers. Extract the aqueous layer three times with ethyl acetate (10 mL). Combine the organics; dry over MgSO4; remove the solids by filtration; and concentrate the filtrate in vacuo. Purify by silica gel column chromatograph eluting with ethyl acetate in hexanes to afford 0.3 g (39%) of the title material. 1H NMR (CDCl3) δ 8.39 (s, 1H), 8.09 (d, 1H, J=9.1 Hz), 8.02 (d, 1H, J=9.1 Hz), 7.78 (d, 1H, J=3.9 Hz), 7.75 (s, 1H), 7.28 (d, 1H, J=3.9 Hz), 4.79 (quin., 1H, J=6.5 Hz), 4.37 (s, 3H), 1.62 (d, 6H, J=6.5 Hz).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](O)=[O:41])=[CH:33][C:32]=2[CH3:43])=[C:28]([CH:44]([CH3:46])[CH3:45])[NH:27][N:26]=1)(=[O:3])[CH3:2].[NH2:47][C:48]([CH3:53])([CH3:52])[C:49]([NH2:51])=[O:50].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](=[O:41])[NH:47][C:48]([C:49](=[O:50])[NH2:51])([CH3:53])[CH3:52])=[CH:33][C:32]=2[CH3:43])=[C:28]([CH:44]([CH3:46])[CH3:45])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)(N)C(N)=O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)NC(C)(C)C(N)=O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole (0.2 g) in N,N-dimethyl-formamide (3 mL) were added 2-amino-2-methylpropionamide (47 mg), 1-hydroxybenzotriazole (50 mg), 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride (118 mg) and triethylamine (0.13 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over an hydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1-10/1) to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carbamoyl-1-(methyl)ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole (0.12 g). This material was dissolved in methanol (3 mL). To the solution was added sodium methoxide (28% methanol solution, 0.06 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added acetic acid (0.1 mL), and the resulting mixture was concentrated under reduced pressure. The residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (80 mg).
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([OH:16])=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:24]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([O:16][CH3:24])=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
Boc-Asp(OBn)-OH 2.4 g (1 equiv, 7.45 mmol) was dissolved in 17 mL of dry DMF in a 100 mL round-bottom flask. Finely ground K2CO3 (1.5 g, 11 mmol) was added to the solution to form a suspension. The mixture was cooled to 0° C. in an ice-bath over five minutes. MeI (1 mL, 15 mmol) was then added to the mixture over 20 seconds under a positive flow of nitrogen. A yellow color developed within 30 min. The resulting mixture was stirred for 3 hours. The ice-bath was removed and 25 mL of water were added and the mixture left standing at room temperature 2 hours. The mixture was then treated with 30 mL of water and extracted with 3×25 mL AcOEt. The organics were washed with saturated NaHCO3 1×, brine 3×, dried over Na2SO4 filtered and concentrated to yield a yellow oil. This material was passed through a short silica column (eluting w/ AcOEt), after concentration of the pure fractions 2.42 g of Boc-Asp(OBn)-OMe as a yellow oil was obtained (98% yield). 1H NMR (DMSO d6, 500 mHz): δ 7.36 (m, 5H), 5.10 (s, 2H), 4.40 (q, 1H), 3.6 (s, 3H), 2.80 (dd, 1H), 2.72 (dd, 1H), 1.38 (s, 9H). LCMS (C18, 2-98% CH3CN in 0.1% TFA/H2O over 6 min); Calculated mass for C17H23NO6 (M+H)+ 338.23. found by LC-MS 338.2.
Reaction SMILES: C(O)C.[H-].[Na+].[N:6]1[CH:11]=[CH:10][C:9]([C:12]([O:14]CC)=O)=[N:8][CH:7]=1.[C:17]([O:20][CH2:21][CH3:22])(=[O:19])[CH3:18].Cl.C(=O)(O)[O-].[Na+]>C(OCC)C.C1(C)C=CC=CC=1>[O:14]=[C:12]([C:9]1[CH:10]=[CH:11][N:6]=[CH:7][N:8]=1)[CH2:18][C:17]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)c1ccncn1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)CC(=O)c1ccncn1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
A solution of ethanol (16.18 g, 0.351 mol) in diethyl ether (15 ml) was added to a solution of sodium hydride (13.71 g, 0.343 mol, 60% in paraffin, paraffin was removed by washing with hexane) in diethyl ether (100 ml). After stirring the mixture for 30 minutes, the solvent was evaporated under reduced pressure, and toluene (100 ml) was added to the residue. The solution was added with a solution of ethyl pyrimidine-4-carboxylate (intermediate 5, 30.86 g, 0.203 mol) and ethyl acetate (30.48 g, 0.346 mol) in toluene (100 ml), and the mixture was heated at 80° C. for 3 hours. The mixture was added with hydrochloric acid and then sodium bicarbonate to be adjusted to pH 4. The solution was partitioned between water and ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give ethyl 3-oxo-3-(pyrimidin-4-yl)propionate (intermediate 6, 36.10 g, 92%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12]([NH:14][CH:15]([CH2:22][C:23]#[C:24][CH3:25])[C:16](N(OC)C)=[O:17])=[O:13])([CH3:10])([CH3:9])[CH3:8].S([O-])(O)(=O)=O.[K+]>CCOCC.O>[C:7]([O:11][C:12]([NH:14][CH:15]([CH2:22][C:23]#[C:24][CH3:25])[CH:16]=[O:17])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC#CCC(NC(=O)OC(C)(C)C)C(=O)N(C)OC
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: CC#CCC(C=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of lithium aluminum hydride (1.56 g, 41.1 mmol) in ether (150 mL) was stirred at room temperature for 30 minutes. The solution was cooled to -55° C. under nitrogen, and a solution of the product from Step J (11.10 g, 41.1 mmol) in ether (150 mL) was added over 15 min, maintaining the temperature below -50° C. When the addition was complete, the reaction was warmed to 5° C., then recooled to -40° C. A solution of potassium hydrogen sulfate (21.8 g) in 25 mL water was slowly added, maintaining the temperature below -35° C. The mixture was warmed to room temperature and stirred for one hour, filtered through Celite, and concentrated in vacuo to provide the title aldehyde.
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([NH:9][C:10]2[S:11][C:12]([CH2:15][OH:16])=[CH:13][N:14]=2)=[O:8])[CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1CCCCC1C(OCC)=O.[Cl:34][C:35]1[CH:40]=[C:39](I)[CH:38]=[C:37]([Cl:42])[CH:36]=1.[OH-].[NH4+]>CS(C)=O.[Cu](I)I>[Cl:34][C:35]1[CH:40]=[C:39]([N:14]2[CH:13]=[C:12]([CH2:15][OH:16])[S:11]/[C:10]/2=[N:9]\[C:7]([N:4]2[CH2:5][CH2:6][C@@H:2]([F:1])[CH2:3]2)=[O:8])[CH:38]=[C:37]([Cl:42])[CH:36]=1
Reactant: Clc1cc(Cl)cc(I)c1
Reactant: O=C(Nc1ncc(CO)s1)N1CC[C@@H](F)C1
Agent: I[Cu]I
Agent: CCOC(=O)C1CCCCC1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: O=C(/N=c1\sc(CO)cn1-c1cc(Cl)cc(Cl)c1)N1CC[C@@H](F)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 4 mL vial charged with a stir bar, (3R)-3-fluoro-N-[5-(hydroxymethyl)-1,3-thiazol-2-yl]pyrrolidine-1-carboxamide (43 mg, 0.18 mmol, Example 36B) was added followed by copper iodide (8 mg, 0.04 mmol) and cesium carbonate (88 mg, 0.27 mmol). A loose cap with septum was placed on the vial and then the vial was placed under vacuum for 30 minutes. The solid mixture was purged with nitrogen gas a couple of times. Then ethyl 2-cyclohexanecarboxylate (12 mg, 0.07 mmol) dissolved in dry dimethyl sulfoxide (0.4 mL) was added to the mixture followed by 1,3-dichloro-5-iodobenzene (60 mg, 0.22 mmol) dissolved in dry dimethyl sulfoxide (0.7 mL). The vial was capped and the resulting mixture was shaken at room temperature for 1 hour followed by shaking at 95° C. overnight. Then 1 mL of concentrated ammonium hydroxide solution was added. The reaction was filtered and concentrated to dryness. The residue was purified by reverse phase HPLC (C18, gradient 10-95% acetonitrile/water/0.1% trifluoroacetic acid) to provide the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[CH2:4][C@H:3]1[C:9]1[N:13]2[CH:14]=[C:15]([O:18][C@H:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:22]([NH2:29])[CH2:21][CH2:20]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1.ClC(Cl)(Cl)C[O:33][C:34](=O)[NH:35][C:36]1[N:37]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=2)[N:38]=[C:39]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:40]=1.CCN(C(C)C)C(C)C.N>CN(C=O)C.CO.C(Cl)Cl.C(OCC)C>[C:41]([C:39]1[CH:40]=[C:36]([NH:35][C:34]([NH:29][C@@H:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@H:19]([O:18][C:15]3[CH:16]=[CH:17][C:12]4[N:13]([C:9]([C@@H:3]5[CH2:4][C:5]([CH3:8])([CH3:7])[CH2:6][N:2]5[CH3:1])=[N:10][N:11]=4)[CH:14]=3)[CH2:20][CH2:21]2)=[O:33])[N:37]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=2)[N:38]=1)([CH3:44])([CH3:42])[CH3:43]
Reactant: CN1CC(C)(C)C[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Agent: N
Solvent: CCOCC
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc([C@@H]5CC(C)(C)CN5C)n4c3)c3ccccc32)cc1
Yield: 68 %

Procedure:
A solution of Intermediate 87d (150 mg, 0.383 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 232 mg, 0.575 mmol) and DIPEA (198 mg, 1.53 mmol) in DMF (4 mL) was stirred at 50° C. for 1 h. The cooled reaction mixture was applied to an SCX-2 cartridge (10 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-6% [2M NH3 in MeOH] in DCM, then trituration with diethyl ether gave the title compound as an off-white powder (170 mg, 68%). LCMS (Method 5): Rt 3.80 min, m/z 647.5 [MH+]. 1H NMR (400 MHz, d4-MeOH): 1.15 (3H, s), 1.24 (3H, s), 1.30 (9H, s), 1.85-2.05 (4H, m), 2.14 (3H, s), 2.19-2.31 (2H, m), 2.38 (3H, s), 2.97 (1H, d, J 10.3), 3.45 (1H, dd, J 7.5, 6.1), 4.06 (1H, t, J 9.3), 4.90 (1H, m), 5.30 (1H, t, J 4.2), 6.33 (1H, s), 7.20-7.36 (9H, m), 7.65 (1H, d, J 10.8), 8.46 (1H, d, J 1.1).
Reaction SMILES: [I:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][CH2:7][CH2:8][C:9]3[N:10]([N:11]=[C:12]([C:14](OCC)=[O:15])[CH:13]=3)[C:4]=2[CH:3]=1.[NH3:21]>>[I:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][CH2:7][CH2:8][C:9]3[N:10]([N:11]=[C:12]([C:14]([NH2:21])=[O:15])[CH:13]=3)[C:4]=2[CH:3]=1
Reactant: N
Reactant: CCOC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2
Product: NC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2
Temperature: 130 °C
Yield: 36 %

Procedure:
A suspension of ethyl 9-iodo-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxylate (300 mg, 0.78 mmol) in 7 M ammonia solution (in methanol, 3 ml) was heated in a microwave apparatus to 130° C. for 70 minutes. After cooling the volatiles were removed in vacuo and the residue was purified by FCC (silica, 20-100% ethyl acetate in heptane) to give 99 mg (36%) of the title compound as an off-white solid. 1H NMR (DMSO, 500 MHz) δ 3.17 (2H, t, J=5.8 Hz), 4.47 (2H, t, J=5.9 Hz), 6.71 (1H, s), 7.03 (1H, d, J=8.5 Hz), 7.36 (1H, s), 7.66 (1H, dd, J=8.5, 2.2 Hz), 7.81 (1H, s), 8.29 (1H, d, J=2.2 Hz); M+1=356
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1.[Br:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br.[Cl-].[NH4+]>C1COCC1>[Br:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][C:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)C1CC1
Reactant: BrCc1cccc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)C1(Cc2cccc(Br)c2)CC1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Under argon, 14.8 ml (105.48 mmol) of diisopropylamine were initially charged in 66 ml of dry THF, and the mixture was cooled to −40° C. 42.2 ml (105.48 mmol) of n-butyllithium solution (2.5 M in hexane) were slowly added dropwise, and the mixture was stirred for 30 min. The reaction solution was then cooled to −78° C., and a solution of 10.0 g (70.32 mmol) of tert-butyl cyclopropanecarboxylate in 17 ml of THF were added. After 4 h of stirring at −78° C., a solution of 19.34 g (77.36 mmol) of 3-bromobenzyl bromide in 17 ml of THF was added. Slowly, the reaction mixture was warmed to RT overnight, ammonium chloride solution was then added carefully and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by chromatography on 750 g of silica gel (mobile phase cyclohexane/dichloromethane 50:1, then 5:1). This gave 13.3 g (60.7% of theory) of the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)=[O:2].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH:42]1([C:45]([N:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)=[O:46])[CH2:44][CH2:43]1>ClCCl>[CH:42]1([C:45]([N:47]2[CH2:52][CH2:51][N:50]([C:7]([C:6]3[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:11][CH:10]=3)=[O:9])[CH2:49][CH2:48]2)=[O:46])[CH2:43][CH2:44]1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: O=C(C1CC1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=Cc1ccc(C(=O)N2CCN(C(=O)C3CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 47.1 %

Procedure:
To a stirred mixture of 4-formylbenzoic acid (900 mg, 6 mmol) in anhydrous dichloromethane (30 mL) was added triethylamine (1.52 mg, 15 mmol), 1-hydroxybenzotriazole (891 mg, 6.6 mmol), followed by 1-ethyl-3-(3-dimethylamino propyl) carbodiimide hydrochloride (1.254 g, 6.6 mmol). After the addition, the mixture was stirred at room temperature for 40 mins. Then the mixture was cooled to 0° C. and cyclopropyl(piperazin-1-yl)methanone hydrochloride (1.259 g, 6.6 mmol) was added in portion-wise. After the addition, the mixture was allowed to stir at room temperature overnight. The mixture was diluted with dichloromethane (50 mL), washed with saturated citric acid (100 mL×2), followed by saturated sodium bicarbonate (100 mL×2), brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give 4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzaldehyde (810 mg, yield 80%) as a light yellow oil. 1H-NMR (400 MHz, CDCl3) δ (ppm): 0.79-0.85 (m, 2H), 1.00-1.04 (m, 2H), 1.72-1.80 (m, 1H), 3.41-3.81 (m, 8H), 7.58-7.60 (d, J=8.0 Hz, 1H), 7.95-7.97 (d, J=8.0 Hz, 1H), 10.07 (s, 1H); LC-MS (ESI) m/z: 287 (M+1)+.