Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:38][NH:37][CH2:36][CH2:35][NH:34]2)=[CH:29][CH:28]=1)([O-:26])=[O:25]>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:37]4[CH2:36][CH2:35][NH:34][CH:33]([C:30]5[CH:29]=[CH:28][C:27]([N+:24]([O-:26])=[O:25])=[CH:32][CH:31]=5)[CH2:38]4)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(C2CNCCN2)cc1
Reactant: CCOC(=O)c1cn(C)c2nc3cc(F)c(F)cc3cc2c1=O
Product: CCOC(=O)c1cn(C)c2nc3cc(N4CCNC(c5ccc([N+](=O)[O-])cc5)C4)c(F)cc3cc2c1=O

Procedure:
(RS)-3-Ethoxycarbonyl-7-fluoro-1-methyl-8-[3-(4-nitrophenyl)-1-piperazinyl]-4-oxo-1,4 -dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 39, but starting with 3-ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (0.636 g) and (RS)-2-(4-nitrophenyl)piperazine (0.5 g). After recrystallization in dimethylformamide (10 cc), the expected product (0.7 g) is obtained in the form of a yellow solid, decomposing at approximately 300° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[C:27]4[C:22](=[N:23][CH:24]=[C:25](B(O)O)[CH:26]=4)[C:21]([CH3:32])([CH3:31])[CH2:20]3)=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1.Br[C:34]1[CH:35]=[N:36][NH:37][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:32][C:21]1([CH3:31])[C:22]2=[N:23][CH:24]=[C:25]([C:34]3[CH:35]=[N:36][NH:37][CH:38]=3)[CH:26]=[C:27]2[N:19]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([F:1])=[CH:3][CH:4]=3)[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:7]=2[CH3:18])[CH2:20]1
Reactant: Brc1cn[nH]c1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(B(O)O)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(-c3cn[nH]c3)cc21
Temperature: 120 °C

Procedure:
Prepared according to procedure P using 1-(7-fluoro-3-methyl-2-(pyridin-2-yl)-quinolin-4-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-ylboronic acid (60 mg, 0.14 mmol), 4-bromopyrazole (21 mg, 0.14 mmol), PdCl2(PPh3)2 (9.8 mg, 0.014 mmol), sodium carbonate (29.7 mg, 0.28 mmol) and heating in the microwave for 1 h at 120° C. After purification 4-(3,3-dimethyl-6-(1H-pyrazol-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-methyl-2-(2-pyridinyl)quinoline was obtained as a yellow film. 1H NMR (400 MHz, chloroform-d) δ ppm 8.71-8.79 (1H, m), 8.10-8.17 (1H, m), 7.78-7.97 (4H, m), 7.69-7.75 (2H, m), 7.38-7.45 (1H, m), 7.30-7.37 (1H, m), 6.34 (1H, quin, J=2.2 Hz), 3.83-3.93 (2H, m), 2.33-2.46 (3H, m), 1.63-1.70 (3H, m), 1.56-1.62 (3H, m). Mass Spectrum (ESI) m/e=451 (M+1).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=O)[CH2:25][CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:20][CH:19]=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2([CH2:25][CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[O:4][CH2:1][CH2:2][O:3]2)=[CH:22][CH:23]=1
Reactant: OCCO
Reactant: CCN(CC)CCCC(=O)c1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCN(CC)CCCC1(c2ccc(Br)cc2)OCCO1
Temperature: 150 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
Ethylene glycol (10 mL) and p-toluenesulfonic acid monohydrate (128 mg) were added to a solution of 1-(4-bromophenyl)-4-(diethylamino)butan-1-one (2.0 g) in toluene (80 mL), and the mixture was stirred at 150° C. for one hour. The reaction solution was cooled to room temperature and p-toluenesulfonic acid monohydrate (1.28 g) was added, after which the mixture was stirred at 150° C. for further one hour. The reaction solution was cooled to room temperature and neutralized with saturated aqueous sodium bicarbonate, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to give the title compound as a brown oil (2.09 g, 91%).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:6]([CH2:8][Cl:9])=[O:7])[CH:3]([CH3:5])[CH3:4].[ClH:17]>>[NH2:1][C@H:2]([C:6]([CH2:8][Cl:9])=[O:7])[CH:3]([CH3:5])[CH3:4].[ClH:17]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)CCl
Agent: Cl
Product: CC(C)[C@H](N)C(=O)CCl

Procedure:
First, precursor H-ValCH2Cl.HCl was prepared by dissolving Boc-Val-OH (6.5 g, 30 mmol) in 10 mL of THF and treating it with N-methylmorpholine (3.3 mL, 30 mmol) and isobutyl chloroformate (3.9 mL, 30 mmol) for 10 minutes at -20°. The resulting mixture was filtered and the retained material was washed with 40 mL of cold THF. The combined filtrates were added to 200 mL of diazomethane:ether. The resulting solution was stirred for 2 hours at 0°, and then solvent was removed by evaporation to yield an oil. The oil was dissolved in ethyl acetate, washed with 5% sodium bicarbonate followed by saturated aqueous sodium chloride, and then dried over sodium sulfate. Evaporation of solvent left 6.4 g of an oil. The oil was dissolved in 100 mL of ether, and the resulting solution was treated with a 5% excess of ethanolic HCl for 15 minutes at 0°. This solution was washed with cold water followed by saturated aqueous sodium chloride, and then dried over sodium sulfate. After evaporation of solvent, product was washed with hexane to yield 2.7 g of Boc-ValCH2Cl (m.p. 70°-73°). Boc-ValCH2Cl (1.0 g) was deblocked by stirring with 5 mL of 3N ethanolic HCl for 30 minutes at about 23°. Solvent was evaporated and the resulting residue was triturated with ether to yield 0.69 g of H-ValCH2Cl.HCl.
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Br[C:44]1[CH:45]=[CH:46][C:47]([NH:52][C:53]2[C:58]([O:59][CH3:60])=[CH:57][C:56]([C:61]3[CH:66]=[CH:65][C:64]([Cl:67])=[C:63]([CH3:68])[CH:62]=3)=[C:55]([F:69])[CH:54]=2)=[C:48]([CH:51]=1)[CH:49]=[O:50].N#N.[C:72]1([CH2:78][SH:79])[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:78]([S:79][C:44]1[CH:45]=[CH:46][C:47]([NH:52][C:53]2[C:58]([O:59][CH3:60])=[CH:57][C:56]([C:61]3[CH:66]=[CH:65][C:64]([Cl:67])=[C:63]([CH3:68])[CH:62]=3)=[C:55]([F:69])[CH:54]=2)=[C:48]([CH:51]=1)[CH:49]=[O:50])[C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1
Reactant: SCc1ccccc1
Reactant: COc1cc(-c2ccc(Cl)c(C)c2)c(F)cc1Nc1ccc(Br)cc1C=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: N#N
Solvent: C1COCCO1
Product: COc1cc(-c2ccc(Cl)c(C)c2)c(F)cc1Nc1ccc(SCc2ccccc2)cc1C=O
Temperature: 90 °C

Procedure:
A small microwave vial was charged with Pd2(dba)3 (0.064 g, 0.070 mmol), xantphos (0.081 g, 0.140 mmol). The vial was sealed with a septum cap and 0.3 mL dioxane was added. The vial was heated at 90° C. in an oil bath for 3 min. The solution was then cooled to rt. A separate vial was charged with 5-bromo-2-((4′-chloro-2-fluoro-5-methoxy-3′-methyl-[1,1′-biphenyl]-4-yl)amino)benzaldehyde (1.26 g, 2.81 mmol) and sealed with a septum cap. The vial was flushed with N2 and 1,4-dioxane (9.36 ml), phenylmethanethiol (0.399 ml, 3.37 mmol) and dipea (1.471 ml, 8.42 mmol) were added. The pre-activated catalyst solution prepared in the microwave vial was transferred to the vial containing the reactants via syringe and the resulting mixture was heated at 90° C. for 3 h. The reaction mixture was partitioned between 1 N HCl/brine (20 mL) and EtOAc (30 mL). The layers were separated and the aqueous layer was extracted with EtOAc (1×20 mL). The combined organic layers were dried (Na2SO4) and concentrated for purification by MPLC (Biotage Isolera). The crude residue was taken up in minimal DCM and absorbed onto a 25 g loading cartridge and passed through a Redi-Sep® Gold pre-packed silica gel column (80 g) using 100% Heptane to 60:40 Heptane: EtOAc gradient to afford 5-(benzylthio)-2-((4′-chloro-2-fluoro-5-methoxy-3′-methyl-[1,1′-biphenyl]-4-yl)amino)benzaldehyde as a bright yellow foam. (ESI) 490.2 (M−H)−.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[N:11]=[C:10]([CH2:12]O)[CH:9]=[CH:8][CH:7]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:5][C:6]1[N:11]=[C:10]([CH2:12][Cl:3])[CH:9]=[CH:8][CH:7]=1
Reactant: OCc1cccc(Cl)n1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: ClCc1cccc(Cl)n1
Temperature: 25 °C

Procedure:
Thionyl chloride (12.6 mL; 173 mmol) in 100 mL chloroform was added dropwise to a solution of 6-chloro-2-hydroxymethylpyridine (13.0 g; 90.5 mmol), prepared as in step 3, in 100 mL chloroform. Upon complete addition the reaction mixture was heated at reflux for 2 hours. The reaction mixture was cooled to ambient temperature and carefully poured into 250 mL saturated aqueous sodium bicarbonate. The layers were separated and the aqueous was extracted with dichloromethane. The extracts were dried over magnesium sulfate and concentrated. 6-chloro-2-chloromethylpyridine was isolated as a pale yellow solid by flash chromatography (20% diethyl ether in hexane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C=O)C>[CH2:21]([O:20][C:18](=[O:19])[CH:17]([O:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH3:23])[CH3:22]
Reactant: CCOC(=O)C(C)Br
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc(OC)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
4-Methoxyphenol (3.29 g, 26.5 mmol), K2CO3 (7.32 g, 53 mmol), and ethyl 2-bromopropionate (4.8 g, 26.5 mmol) were combined in anhydrous DMF (50 mL) and stirred at 90° C. under an atmosphere of nitrogen. After 16 h, the DMF was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL) and washed twice with water and once with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to produce a golden oil (4.8 g, 81%) 1H NMR (250 MHz, CDCl3): δ 6.76 (d, 2H, J=7.9), 6.73 (d, 2H, J=7.9), 4.58 (q, 1H, J=6.1), 4.14 (q, 2H, J=7.2), 3.69 (s, 3H), 1.52 (d, 3H, J=6.1), 1.19 (t, 3H, J=7.2). MS [EI+] 225 (M+H)+, [EI−] 223 (M−H)+.
Reaction SMILES: [C:1]1([C:7]2[C:8]3([C:14]([O:16]CC)=[O:15])[CH2:13][C:11]([CH:12]=2)=[CH:10][CH2:9]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>CO>[C:1]1([C:7]2[C:8]3([C:14]([OH:16])=[O:15])[CH2:13][C:11]([CH:12]=2)=[CH:10][CH2:9]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C12CC=C(C=C1c1ccccc1)C2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C12CC=C(C=C1c1ccccc1)C2

Procedure:
Next, 2-phenyl-norbornadiene-1-carboxylic acid was synthesized. Ethyl 2-phenyl-norbornadiene-1-carboxylate (5.0 g) was combined with 3.8 g of potassium hydroxide in 50 mL of methanol. This solution was stirred at gentle reflux for 16 hours. All methanol was then removed by rotary evaporation, and the resulting residue was dissolved in 75 mL water. To this solution was added 10% HCl (aq) dropwise until the pH of the solution was acidic. The resulting yellow solid was collected by filtration. Recrystallization of this residue from isopropyl alcohol/water (40/60) gave 2.6 g of colorless needles in two crops (60% of theoretical). This intermediate product was characterized by NMR and by mass spectroscopy. 1H NMR (CDCl3) δ 7.54-7.50 (m, 2H); 7.39-7.32 (m, 3H); 7.02-6.99 (m, 1H); 6.93-6.90 (m, 1H); 4.08 (s, 1H); 3.87 (s, 1H); 2.27 (d, 1H); 2.08 (d, 1H).
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](/[CH:37]=[CH:38]/[C:39](O)=[O:40])=[CH:33][CH:32]=2)=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=[O:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:67][C:68]([CH3:73])([CH3:72])[C:69]([OH:71])=[O:70]>CN(C)C=O.ClCCl.O.C(O)(=O)C.C(N(CC)CC)C>[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:32]=[CH:33][C:34](/[CH:37]=[CH:38]/[C:39](=[O:40])[NH:67][C:68]([C:69]([OH:71])=[O:70])([CH3:73])[CH3:72])=[CH:35][CH:36]=2)=[C:28]([CH:42]([CH3:44])[CH3:43])[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(/C=C/C(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)(N)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/C(=O)NC(C)(C)C(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 32.2 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-2-carboxyvinyl]phenyl}methyl)-5-isopropyl-1H-pyrazole (1.2 g) in N,N-dimethylformamide (15 mL) and dichloromethane (10 mL) was added triethylamine (15 mL). To the mixture were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.56 g), 1-hydroxybenzotriazole (0.4 g), and a solution of 2-amino-2-methylpropionic acid (2.0 g) in water (15 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized by addition of 2 mol/L aqueous acetic acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate-dichloromethane/methanol=7/1-3/1) to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{(1E)-2-[1-carboxy-1-(methyl)-ethylcarbamoyl]vinyl}phenyl)methyl]-5-isopropyl-1H-pyrazole (0.44 g). This material was dissolved in N,N-dimethylformamide (0.3 mL). To the solution were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.18 g), 1-hydroxybenzotriazole (0.13 g) and N,N-dimethylethylenediamine (0.55 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 5 mol/L aqueous sodium hydroxide solution (1.5 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added acetic acid (1 mL), and the mixture was diluted with water (3 mL). The insoluble material was removed by filtration, and the filtrate was purified by preparative reverse phase column chromatography (Shiseido CAPCELL PAK UG120 ODS, 5 μL, 120 Å, 20×50 mm, flow rate 30 mL/minute linear gradient, water/acetonitrile=90/10-10/60) to give the title compound (71 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=3)=[N:11][C:10]=2[C:23](O)=[O:24])=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[NH2:30][C:31]1[S:32][CH:33]=[N:34][N:35]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[NH:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=3)=[N:11][C:10]=2[C:23]([NH:30][C:31]2[S:32][CH:33]=[N:34][N:35]=2)=[O:24])=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2[nH]c(-c3cccc([N+](=O)[O-])c3)nc2C(=O)O)cc1
Reactant: Nc1nncs1
Solvent: O=S(Cl)Cl
Product: COc1ccc(-c2[nH]c(-c3cccc([N+](=O)[O-])c3)nc2C(=O)Nc2nncs2)cc1

Procedure:
5-(4-Methoxyphenyl)-2-(3-nitrophenyl)imidazole-4-carboxylic acid, 1 M hydrochloric acid—ether solution, thionyl chloride and 2-amino-1,3,4-thiadiazole are reacted and treated in the same manner as in Example 1 to give 5-(4-methoxyphenyl)-2-(3-nitrophenyl)-N-(1,3,4-thiadiazol-2-yl)imidazole-4-carboxamide.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=1>>[Br:1][C:2]1[C:3]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH:13][C:17]3[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1Br
Reactant: Nc1ccc(Oc2ncccc2Br)cc1
Product: Cc1cccnc1Nc1ccc(Oc2ncccc2Br)cc1
Temperature: 160 °C
Reaction time: 3 h

Procedure:
To a 35 ml pressure vessel was added 4-(3-bromopyridin-2-yloxy)aniline (0.7095 g, 2.68 mmol) and 2-bromo-3-methylpyridine (0.575 mL, 3.35 mmol) to stir at 160° C. for 3 hours. Upon completion, the crude product was adsorbed onto a plug of silica gel and chromatographed to provide N-(4-(3-bromopyridin-2-yloxy)phenyl)-3-methylpyridin-2-amine. MS (ESI, pos. ion) m/z: 356.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][CH:6]1[C:10]2[NH:11][C:12]([C:14]([O:16]C)=[O:15])=[CH:13][C:9]=2[CH2:8][CH2:7]1.[OH-].[Li+].CO>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][CH:6]1[C:10]2[NH:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:9]=2[CH2:8][CH2:7]1
Reactant: COC(=O)c1cc2c([nH]1)C(Cc1cccc(Br)c1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2c([nH]1)C(Cc1cccc(Br)c1)CC2
Yield: 10 %

Procedure:
The title compound was synthesized from methyl 6-(3-bromobenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.151 g, 0.45 mmol) and lithium hydroxide (0.193 g, 4.6 mmol in 2 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (4 mL) was used. The resulting product was purified by reverse phase HPLC, eluting with a gradient of 40-100% MeOH: water (with 0.1% formic acid) to afford a light pink solid: 0.014 g (10% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.03-2.13 (m, 1H), 2.37-2.46 (m, 4H), 2.68 (dd, J1=13.28 Hz, J2=8.88 Hz, 1H), 3.08 (dd, J1=13.52 Hz, J2=4.73 Hz, 1H), 6.56 (s, 1H), 7.10-7.12 (m, 1H), 7.17 (t, J=7.74 Hz, 1H), 7.32-7.35 (m, 2H); LCMS-MS (ESI−) 318.0 (M−H); HPLC (UV=96.26%), (ELSD=100%).
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[NH:4][N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:17])[CH3:16])[C@H:10]1[CH3:18].[H][H]>CO.[C].[Pd]>[CH3:18][C@H:10]1[C@H:9]([NH:8][C:7]2[CH:6]=[N:5][NH:4][C:3](=[O:19])[CH:2]=2)[CH2:14][C@@H:13]2[CH2:15][C@H:11]1[C:12]2([CH3:16])[CH3:17]
Reactant: [H][H]
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cn[nH]c(=O)c1Br)C2(C)C
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cn[nH]c(=O)c1)C2(C)C
Yield: 100 %

Procedure:
4-Bromo-5-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-3(2H)-one (300 mg, 0.92 mmol) and 10% palladium-carbon (50 wt %, 30 mg) in methanol were stirred in a hydrogen stream at room temperature for 1 day. The reaction solution was filtered through celite, and the filtrate was concentrated to give the desired product (100% yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-])=O)([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]=[N:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccccc1[N+](=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)c1ccccc1N=Nc1ccccc1C(C)(C)C
Yield: 18.4 %

Procedure:
2-t-Butylnitrobenzene (30.0grams, 0.17 mole) in 100 milliliters of ether was added to a suspension of 8.22 grams (0.22 mole) of lithium aluminum hydride in 700 milliliters of ether at a temperature of 5 - 10° C. The mixture was allowed to come to ambient temperature and stirred for an additional 0.5-hour period. Hydrolysis was accomplished by the successive addition of 15 milliliters of water, 15 milliliters of 20 percent aqueous sodium hydroxide, and 30 milliliters of water. After mixing for 2 hours, the inorganic salts were removed by filtration and the ether evaporated. The residue was applied to an activated neutral alumina column (200 grams, 80-200 mesh) and eluted with hexane at a flow rate of 10 drops per minute. The initial fractions (about 700 milliliters) were discarded and the product, a bright red band on the column, was collected. Evaporation of the hexane followed by crysta-lization of the residue from ethanol gave 4.6 grams (18.7 percent) of 2,2'-di-t-butylazobenzene melting point, 90-91° C.
Reaction SMILES: [CH3:1][N:2]1[CH:17]=[C:5]2[N:6](C(OC(C)(C)C)=O)[CH2:7][CH2:8][CH2:9][C:4]2=[N:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[CH:17]=[C:5]2[NH:6][CH2:7][CH2:8][CH2:9][C:4]2=[N:3]1
Reactant: Cn1cc2c(n1)CCCN2C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc2c(n1)CCCN2
Reaction time: 18 h
Yield: 0 %

Procedure:
To a stirred solution of tert-butyl 2-methyl-6,7-dihydro-2H-pyrazolo[4,3-b]pyridine-4(5H)-carboxylate (56 mg, 236 mol) in CH2Cl2 (4.00 mL) was added TFA (740 mg, 500 μL, 6.49 mmol) at room temperature. After 18 h, the reaction mixture was concentrated in vacuo and the residue obtained was purified by chromatography (40 g column, 50 m silica-gel from Analogix, 0 to 5% 9:1 methanol:ammonium hydroxide in CH2Cl2, 20 min) to give 2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridine (25 mg, 77%). 1H NMR (CHLOROFORM-d) δ: 6.81 (s, 1H), 3.75 (s, 3H), 3.11-3.18 (m, 2H), 3.04 (s, 1H), 2.73 (t, J=6.4 Hz, 2H), 1.86-2.00 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:8][CH2:9][NH:10]C(=O)C)[C:4]([CH3:7])=[CH:5][CH:6]=1.[OH-].[K+].O>C(O)C>[NH2:10][CH2:9][CH2:8][N:3]1[C:4]([CH3:7])=[CH:5][CH:6]=[C:2]1[CH3:1]
Reactant: CC(=O)NCCn1c(C)ccc1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C)n1CCN

Procedure:
251.1 g (1.39 mol) of 2,5-dimethyl-1-(2-acetylaminoethyl)-pyrrole, prepared as in Example 5, and 390.8 g (6.97 mol) of potassium hydroxide are heated reflux in 2.8 l of ethanol and 180 ml of water under an atmosphere of nitrogen for 4 h. After the mixture has been concentrated, the aqueous phase is extracted with methylene chloride, and the extract is fractionally distilled. Yield: 150.2 g (78% of theory), Boiling point: 70° C./0.267 mbar
Reaction SMILES: Cl[CH2:2][O:3][C:4]([NH:6][C@@H:7]([CH3:18])[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])=[O:5].N[C@@H](C)C(OCC1C=CC=CC=1)=O.ClC(OCCl)=O.[Cl:38][C:39]1[C:40]([F:79])=[C:41]([C@@H:45]2[C@:49]([C:52]3[CH:57]=[CH:56][C:55]([Cl:58])=[CH:54][C:53]=3[F:59])([C:50]#[N:51])[C@H:48]([CH2:60][C:61]([CH3:64])([CH3:63])[CH3:62])[NH:47][C@H:46]2[C:65]([NH:67][C:68]2[CH:76]=[CH:75][C:71]([C:72]([OH:74])=[O:73])=[CH:70][C:69]=2[O:77][CH3:78])=[O:66])[CH:42]=[CH:43][CH:44]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl.CN(C)C=O.N1C=CC=CC=1>[Cl:38][C:39]1[C:40]([F:79])=[C:41]([C@@H:45]2[C@:49]([C:52]3[CH:57]=[CH:56][C:55]([Cl:58])=[CH:54][C:53]=3[F:59])([C:50]#[N:51])[C@H:48]([CH2:60][C:61]([CH3:63])([CH3:64])[CH3:62])[NH:47][C@H:46]2[C:65]([NH:67][C:68]2[CH:76]=[CH:75][C:71]([C:72]([O:74][CH2:2][O:3][C:4](=[O:5])[NH:6][C@@H:7]([CH3:18])[C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])=[O:73])=[CH:70][C:69]=2[O:77][CH3:78])=[O:66])[CH:42]=[CH:43][CH:44]=1
Reactant: C[C@H](NC(=O)OCCl)C(=O)OCc1ccccc1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: C[C@H](N)C(=O)OCc1ccccc1
Agent: O=C(Cl)OCCl
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C(=O)OCOC(=O)N[C@@H](C)C(=O)OCc2ccccc2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 23, (S)-benzyl 2-((chloromethoxy)-carbonylamino)propanoate was prepared from (S)-benzyl 2-aminopropanoate (Chem-Impex) and 1-chloromethyl chloroformate (Aldrich) in the presence of pyridine in methylene chloride. It was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid and cesium carbonate in dimethylformamide to give chiral ((S)-1-(benzyloxy)-1-oxopropan-2-ylcarbamoyloxy)methyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as a white solid.