Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[N:7]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[N:17]=3)[C:6]=2[CH:23]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[N:26][C:25]=1[C:30]([OH:34])([C:32]#[CH:33])[CH3:31].C(N(CC)CC)C>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:22][C:18]1[N:17]=[C:16]([N:7]2[C:6]3[CH:23]=[C:2]([C:33]#[C:32][C:30]([C:25]4[N:24]=[CH:29][CH:28]=[CH:27][N:26]=4)([OH:34])[CH3:31])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:21]=[CH:20][N:19]=1
Reactant: Nc1nccc(-n2c(OCC(F)(F)F)nc3ccc(Br)cc32)n1
Reactant: C#CC(C)(O)c1ncccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(O)(C#Cc1ccc2nc(OCC(F)(F)F)n(-c3ccnc(N)n3)c2c1)c1ncccn1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 12.8 %

Procedure:
A mixture of 4-[6-bromo-2-(2,2,2-trifluoroethoxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (150 mg, 0.31 mmol, 80% purity), 2-(pyrimidin-2-yl)but-3-yn-2-ol (300 mg, 2.02 mmol), bis(triphenylphosphine)palladium(II) dichloride (220 mg, 0.31 mmol) and triethylamine (2 mL) in dimethylsulfoxide (3 mL) was stirred for 1.5 hr at 90° C. under nitrogen. The reaction mixture was cooled to room temperature then filtered through a frit filter to remove the catalyst. The filtrate was purified by preparative HPLC to afford 18 mg (13%) of 4-[1-(2-aminopyrimidin-4-yl)-2-(2,2,2-trifluoroethoxy)-1H-1,3-benzodiazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-ol as a light brown solid: 1H NMR (400 MHz, DMSO) delta 8.89 (d, J=4.8 Hz, 2H), 8.44 (d, J=5.6 Hz, 1H), 8.12 (s, 1H), 7.51-7.48 (m, 2H), 7.28 (d, J=8.0 Hz, 1H), 7.16 (s, 2H), 6.85 (d, J=5.2 Hz, 1H), 6.13 (s, 1H), 5.36-5.29 (m, 2H), 1.89 (s, 3H); LC-MS: m/z=+456 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])=[CH:7]2.C(O[C@H]([C@@H](OC(=O)C1C=CC=CC=1)C(O)=O)C(O)=O)(=O)C1C=CC=CC=1.[NH:47]1[CH2:51][CH2:50][C@H:49]2[CH2:52][N:53]([C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:54][C@@H:48]12.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[Na+].[Cl-]>[C:15]1([S:12]([C:8]2[CH:9]=[N:10][C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[N:47]2[CH2:51][CH2:50][C@H:49]3[CH2:52][N:53]([C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:54][C@@H:48]23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(c1ccccc1)c1cnc2c(F)cccc2c1
Reactant: CCOC(=O)N1C[C@@H]2CCN[C@@H]2C1
Agent: O=C(O[C@@H](C(=O)O)[C@@H](OC(=O)c1ccccc1)C(=O)O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCOC(=O)N1C[C@@H]2CCN(c3cccc4cc(S(=O)(=O)c5ccccc5)cnc34)[C@@H]2C1
Temperature: 100 °C

Procedure:
A solution of 8-fluoro-3-(phenylsulfonyl)quinoline (100 mg, 0.348 mmol), (3aS,6aS)-ethyl hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (2R,3R)-2,3-bis(benzoyloxy)succinate (944 mg, 1.74 mmol) and K2CO3 (577 mg) in DMF (3 mL) was stirred under nitrogen and heated at 100° C. for 7 h. The cooled mixture was diluted with 10 mL of saturated NaCl and the resultant precipitate collected and dried to give the title compound.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][CH2:13][C@@H:14]1[C@H:19]([CH2:20][CH2:21][CH:22]([OH:35])[C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17][N:16]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:15]1.C(N(CC)CC)C>ClCCl>[O:35]=[C:22]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][CH:24]=1)[CH2:21][CH2:20][C@@H:19]1[CH2:18][CH2:17][N:16]([C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])[CH2:15][C@@H:14]1[CH2:13][CH:12]=[O:11]
Reactant: COc1ccc2nccc(C(O)CC[C@@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3CCO)c2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2nccc(C(=O)CC[C@@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3CC=O)c2c1
Temperature: 0 °C
Yield: 100.4 %

Procedure:
A mixture of 13.7 g of dimethyl sulfoxide in 65 cm3 of dichloromethane was slowly added, with stirring and under an inert atmosphere, to a solution, cooled to a temperature in the region of −60° C., of 8.3 cm3 of oxalyl chloride in 65 cm3 of dichloromethane. After stirring the mixture for 15 minutes, 10 g of (3R,4R)-3-(2-hydroxyethyl)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine, dissolved in 65 cm3 of dichloromethane, were slowly added. After stirring the mixture for 30 minutes, 61.7 cm3 of triethylamine, dissolved in 65 cm3 of dichloromethane, were finally added dropwise. The mixture was stirred for a further 3 hours at approximately −60° C. and then poured onto 400 cm3 of ice-cold water. After separating the mixture by settling, the organic phase was washed with 400 cm3 of a 10% (by mass) aqueous citric acid solution and then dried over magnesium sulfate, filtered, and evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 9.95 g of (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine-3-acetaldehyde were obtained in the form of an. oil with a brown color.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:3]=1[O:4][CH2:5][C:6]([NH2:8])=O.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:3]=1[O:4][CH2:5][C:6]#[N:8]
Reactant: Cc1cccc(C)c1OCC(N)=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cccc(C)c1OCC#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
500 Milligrams of benzyltriethyl ammonium chloride and 13.4 g of 2,6-dimethylphenoxyacetamide was added to a heterogeneously mixed solution of 182 ml of chloroform and 60 g of 50% sodium hydroxide aqueous solution, and the solution was stirred vigorously at room temperature for two hours. After completion of reaction, the chloroform phase was separated, and the reaction solution was washed with water, dried over anhydrous magnesium sulfate, and freed from the solvent to obtain an oily substance. The distillation under reduced pressure of the reaction mixture gave 9.7 g of a distillate, 2,6-dimethylphenoxyacetonitrile, b.p. 86°-88° C./0.6 mmHg.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].I[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([N:1]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[CH:3]=[C:2]2[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:17]=1
Reactant: CCOC(=O)c1cc2cccnc2[nH]1
Reactant: Ic1cccnc1
Product: CCOC(=O)c1cc2cccnc2n1-c1cccnc1

Procedure:
This compound was prepared according to the experimental protocol described in Example 6.1, starting with ethyl 1H-pyrrolo[2,3-b]pyridine-2-carboxylate obtained according to the protocol described in step 3.2 and 3-iodopyridine. A yellow solid is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([CH2:16][CH3:17])[CH2:14][N:13]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:12]3)=[C:8]([C:28](=[O:30])[NH2:29])[CH:7]=[N:6][N:5]2[CH:31]=1.BrC1C=C2C(Cl)=C(C(N)=O)C=NN2C=1.N[C@H]1[C@@H](CC)CN(C(OCC2C=CC=CC=2)=O)C1.[O:64]=[C:65]1[C:73]2[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=2)[C:67](=[O:74])[N:66]1[CH2:75][C:76]1[N:81]=[CH:80][C:79](B(O)O)=[CH:78][CH:77]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC(N(C)C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:28]([C:8]1[CH:7]=[N:6][N:5]2[CH:31]=[C:2]([C:79]3[CH:80]=[N:81][C:76]([CH2:75][N:66]4[C:65](=[O:64])[C:73]5[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=5)[C:67]4=[O:74])=[CH:77][CH:78]=3)[CH:3]=[C:4]2[C:9]=1[NH:10][C@H:11]1[C@@H:15]([CH2:16][CH3:17])[CH2:14][N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:12]1)(=[O:30])[NH2:29]
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(B(O)O)cn1
Reactant: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N
Solvent: CC(=O)N(C)C
Product: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(CN4C(=O)c5ccccc5C4=O)nc3)cc12
Temperature: 90 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
A mixture of 100 mg (0.206 mmol) of (3S,4S)-benzyl 3-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate (prepared by coupling Intermediate 2 and Intermediate 9 using the method described in Step 1 of Example 52), (6-((1,3-dioxoisoindolin-2-yl)methyl)pyridin-3-yl)boronic acid (174 mg, 0.617 mmol), potassium phosphate, tribasic, 2M (0.514 mL, 1.028 mmol) and PdCl2(dppf) (30.1 mg, 0.041 mmol) in DMA (2 mL) was stirred at 90° C. for 1 hr. After cooling to rt, the reaction mixture was filtered through celite and the filtrate was partitioned between EtOAc (30 ml) and water (30 ml). The organic layer was washed with 10% LiCl solution (2×30 ml) and brine (30 ml). After drying (MgSO4) and filtration, the organic layer was concentrated to a brown oil that was chromatographed on a 40 gm ISCO silica gel cartridge, eluting with a 0-100% EtOAc/Hex gradient. The pure fractions were concentrated to afford (3S,4S)-benzyl 3-((3-carbamoyl-6-(6-((1,3-dioxoisoindolin-2-yl)methyl)pyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate (59 mg, 0.092 mmol, 44.6% yield) as a tan solid. The material was used as is in the next step. MS (ES+) m/z: 644.3 (M+H); LC retention time: 2.916 min (analytical HPLC Method O).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].Cl[CH2:7][C:8](=[O:38])[C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([C:24](=[O:28])[CH2:25]2)[C@:21]2([CH3:22])[C@H:16]([CH2:17][C@H:18]([OH:37])[C@@H:19]([N:29]4[CH2:34][CH2:33][O:32][C:31]([CH3:36])([CH3:35])[CH2:30]4)[CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1.[I-].[K+].C(=O)([O-])[O-].[Na+].[Na+]>O.CN(C)C=O.C(O)(=O)C>[C:1]([O:4][CH2:7][C:8](=[O:38])[C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([C:24](=[O:28])[CH2:25]2)[C@:21]2([CH3:22])[C@H:16]([CH2:17][C@H:18]([OH:37])[C@@H:19]([N:29]4[CH2:34][CH2:33][O:32][C:31]([CH3:36])([CH3:35])[CH2:30]4)[CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CC1(C)CN([C@H]2C[C@@]3(C)[C@@H](CC[C@H]4[C@@H]5CC[C@H](C(=O)CCl)[C@@]5(C)CC(=O)[C@@H]43)C[C@@H]2O)CCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](N5CCOC(C)(C)C5)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Temperature: 65 °C
Yield: 62.9 %

Procedure:
Potassium acetate (0.83 g) was added to a solution of the 21-chloro compound of Example 2 (0.5 g), potassium iodide (0.04 g), glacial acetic acid (1.05 ml) and N,N-dimethylformamide (20 ml) and the mixture was heated at 65° C. in an atmosphere of nitrogen for 1.5 h. The mixture was then poured into water (200 ml) and aqueous sodium carbonate was added until the pH exceeded 9. The precipitated solid was filtered off, washed with water and dissolved in dichloromethane. After drying over sodium sulfate, the solvent was removed under reduced pressure and the residue was crystallised from methanol to give (2β,3α,5α)-21-(acetyloxy)-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)pregnane-11,20-dione (0.33 g). m.p. 158°-160° C.; [α]D +123° (c 0.68).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([CH:10]=[O:11])=[CH:2]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: O=Cc1c[nH]c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=Cc1cn(S(=O)(=O)c2ccc(Cl)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
A solution of 1H-indole-3-carboxaldehyde (0.290 g, 2.00 mmol) in methylene chloride (4 mL) was added with 4-chlorophenylsulfonyl chloride (0.507 g, 2.40 mmol) and diisopropylethylamine (0.310 g, 2.40 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate to terminate the reaction, and then extracted three times with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain 1-(4-chlorophenylsulfonyl)-1H-indole-3-carboxaldehyde (0.575 g, 89%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:10]([CH3:11])=[CH:9][CH2:8][N:7]1S(C1C=CC(C)=CC=1)(=O)=O)=[O:5])[CH3:2].C1CCN2C(=NCCC2)CC1>C1COCC1.CCOCC>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C(C)=CCN1S(=O)(=O)c1ccc(C)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]ccc1C
Temperature: 25 °C
Yield: 98.6 %

Procedure:
Pyrroline 83 (8.80 g, 28.48 mmol) was dissolved in THF (70 mL). DBU (9.78 mL, 65.50 mmol) was added dropwise and the resulting solution stirred under reflux overnight. The mixture was cooled to room temperature, diluted with ether and washed with 5% aq. HCl, 5% sodium bicarbonate solution and water. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure to give the crude solid 84 (4.30 g, 98%). 1H-NMR (400 MHz, CDCl3): δ 1.37 (t, 3H), 2.35 (s, 3H), 4.31 (q, 2H), 6.08 (d, 1H), 6.81 (d, 1H), 8.90 (s broad, 1H) ppm. 13C-NMR (100 MHz, CDCl3): δ 12.76, 14.53, 59.96, 112.58, 119.35, 121.53, 127.96, 162.01 ppm. DEPT (100 MHz, CDCl3): CH3 carbons: 12.76, 14.53; CH2 carbons: 59.96; CH carbons: 112.58, 121.53 ppm. LC/MS: 90.74%, m/z=153.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8](F)[C:5]=1[CH:6]=O.[SH:13][CH2:14][C:15]([OH:17])=[O:16]>CN(C)C=O>[Br:3][C:4]1[C:5]2[CH:6]=[C:14]([C:15]([OH:17])=[O:16])[S:13][C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: O=Cc1c(F)cccc1Br
Reactant: O=C(O)CS
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(O)c1cc2c(Br)cccc2s1
Temperature: 136 °C
Reaction time: 1 h
Yield: 78.1 %

Procedure:
Potassium hydroxide (415.1 g, 7.40 mol) is added to a stirred solution of 2-bromo-6-fluorobenzaldehyde (1.00 Kg, 4.93 mol) and mercaptoacetic acid (453.8 g, 4.93 mol) in dimethylformamide (5.0 L). The resultant solution is brought to and maintained at reflux (136° C.) for 90 min. The reaction mixture is allowed to cool to room temperature and is quenched by the slow addition of hydrochloric acid (2.25 M, 5.90 L) over 5 min. The mixture is cooled to 10° C., stirred for 1 h and the observed solid material is collected by filtration. The filter cake is washed with water (1.00 L) and hexanes (2.00 L) and dried in vacuo at 40 to 45° C. to constant weight to yield the title compound (990.0 g, 78.2%). 1H NMR (DMSO, d6): δ 13.8 (bs, 1H), 8.10 (d, 1H, J=8.2 Hz), 7.97 (s, 1H), 7.72 (d, 1H, J=7.6 Hz), 7.45 (t, 1H, J=8.0 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C([O-])([O-])=O.[K+].[K+].Cl.[CH:19]12[NH:25][CH:22]([CH2:23][CH2:24]1)[CH2:21][CH2:20]2>CS(C)=O.O>[Br:1][C:2]1[CH:7]=[C:6]([N:25]2[CH:19]3[CH2:24][CH2:23][CH:22]2[CH2:21][CH2:20]3)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: C1CC2CCC1N2
Reactant: O=[N+]([O-])c1ccc(F)cc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N2C3CCC2CC3)cc1Br
Temperature: 80 °C
Reaction time: 24 h
Yield: 77.1 %

Procedure:
To a solution of 2-bromo-4-fluoro-1-nitro-benzene 24 (1.1 g, 4.8 mmol) and K2CO3 (2.0 g, 14.3 mmol) in DMSO (8.400 mL) was added 7-azabicyclo[2.2.1]heptane 7a (765.4 mg, 5.7 mmol) portion-wise. The reaction was stirred at 80° C. for 24 h. The reaction was diluted with water to precipitate the product. The solid was redissolved in dichloromethane, washed with 1.0 N HCl, dried over MgSO4, filtered and concentrated to provide 7-(3-bromo-4-nitrophenyl)-7-azabicyclo[2.2.1]heptane 25 (1.1 g, 78% yield). The crude product was used directly in the next step. LC/MS m/z 299.1 [M+H]+, retention time 1.97 min (RP-C18, 10-99% CH3CN/0.05% TFA over 3 min).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:28])[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].O=O.[C:31](=O)([O-:33])[O-:32].[K+].[K+]>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:12]([O:11][C:10]([NH:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[C:31]([OH:33])=[O:32])=[O:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: O=C([O-])[O-]
Reactant: CCCCCCCCCCCCCCCCOC(=O)Nc1ccc(C)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=O
Agent: [K+]
Solvent: O
Product: CCCCCCCCCCCCCCCCOC(=O)Nc1ccc(C)cc1C(=O)O
Temperature: 115 °C
Yield: 77.2 %

Procedure:
217.5 g (478.5 mmol) of hexadecyl (2-bromo-4-methylphenyl)carbamate, 0.5 g (0.7 mmol) of bis(triphenylphosphine)palladium dichloride and 2.5 g (9.3 mmol) of triphenylphosphine were introduced into an autoclave. The autoclave was closed, flushed with nitrogen and an oxygen-free solution of 78.1 g (565.3 mmol) of potassium carbonate in 400 ml of water is added. The autoclave is evacuated and then 2 bar of carbon monoxide are injected and heated to 115° C. The pressure is subsequently adjusted to 8 bar. After CO uptake ceases, the mixture is cooled to RT and 200 ml of toluene are added. The pH is adjusted to 2 with 2M aqueous HCl solution, and the organic phase is separated off. The aqueous phase is extracted anew with 100 ml of toluene, the organic phase is separated off, and the two toluene extracts are combined. Removal of the solvent in vacuo results in 154.9 g (369.2 mmol, 77%) of 2-hexadecyloxycarbonylamino-5-methylbenzoic acid in the form of a pale yellow-coloured solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](O)=[O:32])=[O:22])[C:16]=1[CH3:34].Cl.C(N=C=NCCCN(C)C)C.O[C:48]1[C:56]2[N:55]=N[NH:53][C:52]=2[CH:51]=[CH:50][CH:49]=1.C(N(CC)CC)C.C1(N)C=CC=CC=1N>[Cl-].[Na+].O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([NH:53][C:52]2[CH:51]=[CH:50][CH:49]=[CH:48][C:56]=2[NH2:55])=[O:32])=[O:22])[C:16]=1[CH3:34]
Reactant: Oc1cccc2[nH]nnc12
Reactant: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCCCCCC(=O)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.8 %

Procedure:
8-(5-(((5-fluoro-2-oxoindolin-3-ylidene)hydrazono)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamido)-octanoic acid (469 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxy-benzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and o-phenylenediamine (432 mg, 4 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (402 mg, 72% yield) as a red solid. LC-MS (m/z) 560 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[N:17]1([C:22]2[CH:30]=[CH:29][C:25]([C:26]([O-])=[O:27])=[CH:24][CH:23]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1>>[C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:23][CH:24]=2)=[CH:10][CH:9]=1)([C:5]1[CH:15]=[CH:16][C:2]([NH:1][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:23][CH:24]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: Nc1ccc(C(=O)c2ccc(N)cc2)cc1
Reactant: O=C([O-])c1ccc(N2CCCC2)cc1
Product: O=C(Nc1ccc(C(=O)c2ccc(NC(=O)c3ccc(N4CCCC4)cc3)cc2)cc1)c1ccc(N2CCCC2)cc1

Procedure:
Compound 324 was prepared according to the procedure described in Scheme IV from 4,4′-diaminobenzophenone and 4-pyrrolidinobenzoate. [M+H]+ calcd for C35H34N4O3: 559.27; found: 559.00.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.F[C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][C:17]=1[N+:26]([O-:28])=[O:27].C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][C:17]=2[N+:26]([O-:28])=[O:27])[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(NC2CCN(Cc3ccccc3)CC2)c([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 12 h
Yield: 98.5 %

Procedure:
4-Amino-1-benzylpiperidine (87 g) was added slowly during 20 minutes to a stirred mixture of 2-fluoro-5-methylsulphonyl-nitrobenzene (100 g) and anhydrous sodium carbonate (35 g) in 500 mL DMSO, the internal temperature rose from 20° C. to 50° C. The mixture was stirred at 90° C. for 12 hours, then poured into ice/water and the yellow solid was filtered off, redissolved in dichloromethane, dried and evaporated to give 175 g N-(1-benzylpiperidin-4-yl)-2-nitro-4-methylsulphonylaniline.
Reaction SMILES: C[O-].[Na+].[CH:4]([C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[CH:15]=O)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].[N:17]([CH2:20][C:21]([O:23][CH2:24]C)=[O:22])=[N+:18]=[N-:19]>CO>[N:17](/[C:20](=[CH:15]\[CH:14]=[CH:13]\[C:10]1[CH:9]=[CH:8][C:7]([CH:4]([CH3:5])[CH3:6])=[CH:12][CH:11]=1)/[C:21]([O:23][CH3:24])=[O:22])=[N+:18]=[N-:19]
Reactant: CC(C)c1ccc(/C=C/C=O)cc1
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)/C(=C/C=C/c1ccc(C(C)C)cc1)N=[N+]=[N-]

Procedure:
Following General Procedure I, a 1.34 M solution of NaOMe in methanol (30 ml), (E)-3-(4-isopropylphenyl)acrylaldehyde (Compound 110, 1.4 g, 8.0 mmol) and ethyl azidoacetate (12 ml, 40.2 mmol) in MeOH (20 ml) were reacted to produce the title compound as a solid.