Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([F:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].CC(C)([O-])C.[K+].[OH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.O>CN(C)C=O>[NH2:7][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]([F:12])=[C:2]([O:19][C:20]2[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=2)[CH:8]=1
Reactant: Nc1cc(Cl)c(F)cc1[N+](=O)[O-]
Reactant: O=Cc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc(C=O)cc2)c(F)cc1[N+](=O)[O-]
Yield: 85.1 %

Procedure:
A solution of 5-chloro-4-fluoro-2-nitroaniline (0.380 g, 1.99 mmol), potassium t-butoxide (0.269 g, 2.39 mmol), and 4-hydroxybenzaldehyde (0.292 g, 2.39 mmol) in dimethylformamide (5 mL) was heated to 80 degrees Centigrade for 6 hours and then cooled. Water was added and the organics extracted using ethyl acetate (2×50 mL). The combined organics were then washed one time in brine and then dried (Na2SO4), filtered and concentrated. Chromatography on silica gel using a gradient of 20%-30% ethyl acetate/hexanes eluted the product to give 0.468 g of 4-[(5-amino-2-fluoro-4-nitrophenyl)oxy]benzaldehyde as an orange solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.C1C(=O)N([Br:30])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[C:12]([O:11][C:9]([N:8]([C:5]1[CH:6]=[N:7][C:2]([CH2:1][Br:30])=[CH:3][CH:4]=1)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cn1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ccc(CBr)nc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 26.3 %

Procedure:
A mixture of di-tert-butyl (6-methylpyridin-3-yl)imidodicarbonate (Compound 260D, 15 g, 49 mmol), NBS (8.2 g, 49 mmol) and AIBN (1.0 g) in CCl4 (200 mL) was stirred at 100° C. overnight. TLC showed the reaction was complete. The reaction mixture was concentrated and residue was purified by column chromatography to afford the desired compound (5.0 g, yield: 26%) as a yellow solid. 1H NMR (CDCl3, 400 MHz): δ=1.41 (s, 18H), 4.53 (s, 2H), 7.44 (dd, J=2.4, 8.0 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 8.33 (dd, J=2.4, 8.0 Hz, 1H).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH2:7]([O:14][C:15](=[O:23])[CH2:16][CH2:17][CH2:18]CC(O)=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)(Cl)Cl>[Cl:4][C:2](=[O:3])[CH2:1][CH2:18][CH2:17][CH2:16][C:15]([O:14][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:23]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCCCC(=O)OCc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(Cl)CCCCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Next, oxalyl chloride (52.2 g; 0.41 mol) was dissolved in CHCl3 (1000 ml), and cooled to 0° C. To this was slowly added a solution of 6(benzyloxy)-6-oxohexanoic acid, (81.0 g; 0.34 mol) in CHCl3 (250 ml), and stirring was continued for 18 hr at room temperature. The reaction mixture was concentrated, coevaporated with CHCl3 (2 times 250 ml), and dried in vacuo, to yield benzyl 6-chloro-6-oxohexanoate as a colourless liquid (87 g; 100%).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([CH:6]=O)=O.[NH2:8][CH:9]([C:13]([NH2:15])=[O:14])[C:10]([NH2:12])=[O:11].Cl>O>[OH:11][C:10]1[C:9]([C:13]([NH2:15])=[O:14])=[N:8][C:4]([CH3:6])=[CH:3][N:12]=1
Reactant: CC(=O)C=O
Reactant: NC(=O)C(N)C(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cnc(O)c(C(N)=O)n1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
An aqueous solution of NaOH (10.6 mL, 12.5N, 0.133mol) is added dropwise to a 40% water solution of pyruvic aldehyde (24 g, 9.6 g, 0.133mol) and 2-amino-malonamide (16 g, 0.136mol) at −20° C., keeping the temperature bellow 0° C. The reaction mixture is mechanically stirred overnight at r.t and then the reaction mixture is cooled to −20° C. and HCl conc. (16 mL, 0.16 mol) is slowly added keeping the temperature bellow 0° C. and stirred at r.t. for 48 h. The reaction mixture is cooled in an ice bath and the crystals formed filtered off, washed with a little water and dried with air, to give 3-hydroxy-6-methyl-pyrazine-2-carboxylic acid amide as a brown solid, (5.7 g, 28%).
Reaction SMILES: C1(C[N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][CH:15]([CH3:17])[CH3:16])[CH2:9]2)C=CC=CC=1.[H][H]>[Pd].CO>[CH3:16][CH:15]([NH:14][CH2:13][CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH3:17]
Reactant: CC(C)NCC1CCN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)NCC1CCNC1
Yield: 76.4 %

Procedure:
A mixture of 13.4 g (58.0 mmol) of 1-phenylmethyl-N-(2-propyl)-3-pyrrolidinemethanamine, 1.0 g of 20% palladium on carbon and 130 ml of methanol was shaken in an atmosphere of hydrogen at about 50 psi and room temperature for 24 hours. The catalyst was removed by filtration through Celite; the filtrate concentrated and distilled in vacuo to give 6.3 g of N-(2-propyl)-3-pyrrolidinemethanamine, bp 58°-60° C./3.5 mm.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[C:14]([Br:15])=[CH:13][CH:12]=[C:11]([CH3:16])[N:10]=1>O1CCOCC1>[Br:15][C:14]1[C:9]([NH:8][C:5](=[O:7])[CH3:6])=[N:10][C:11]([CH3:16])=[CH:12][CH:13]=1
Reactant: Cc1ccc(Br)c(N)n1
Reactant: CC(=O)OC(C)=O
Solvent: C1COCCO1
Product: CC(=O)Nc1nc(C)ccc1Br
Temperature: 50 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
Acetic anhydride (21 mL, 223 mmol) was added to a solution of 2-amino-3-bromo-6-picoline (10 g, 53.46 mmol) in dioxan (50 mL) and the mixture was stirred at 50° C. for 18 hours. The solvent was then evaporated under reduced pressure and the residue was diluted with saturated sodium hydrogen carbonate solution (150 mL). The precipitate was filtered off, washed with water and re-dissolved in dichloromethane, and the filtrate was neutralised to pH7 with saturated sodium hydrogen carbonate solution and extracted with dichloromethane (3×100 mL). The organic solutions were combined, washed with water, dried over magnesium sulfate and concentrated in vacuo to give a white solid. Purification of the solid by column chromatography on silica gel, eluting with ethyl acetate:heptane, 75:25, afforded the title compound as a white solid in 75% yield, 9.2 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]([OH:15])=O)[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1.C(Cl)(=O)C([Cl:19])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]([Cl:19])=[O:15])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc2c(c(C(=O)O)c1)CCCC2
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2c(c(C(=O)Cl)c1)CCCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-methoxy-5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid (0.20 g, 0.97 mmol) in DCM (5 mL) was added oxalyl chloride (0.11 mL, 1.21 mmol) and 1 drop of DMF. The mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo and 3-methoxy-5,6,7,8-tetrahydro-1-naphthalenecarbonyl chloride was used without purification.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5].[CH2:19]([O:26][C:27](Cl)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O.Cl>[OH-].[Na+]>[CH2:19]([O:26][C:27]([NH:2][C@@H:3]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]([F:16])([F:17])[F:18])=[CH:12][CH:13]=1)[C:4]([OH:6])=[O:5])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H](Cc1ccc(OC(F)(F)F)cc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(N[C@@H](Cc1ccc(OC(F)(F)F)cc1)C(=O)O)OCc1ccccc1

Procedure:
(2S)-2-Amino-3-[4-(trifluoromethoxy)phenyl]propanoic acid hydrochloride (3 mg) prepared in Reference Example 3 (3b) was dissolved in 0.5 N sodium hydroxide (100 μL), and then (benzyloxy)carbonyl chloride (ZCl, 5 μL) was added thereto. The resulting mixture was stirred, and then water (100 μL) was added thereto. The resulting mixture was changed to acidic with 1 N hydrochloric acid (50 μL) and extracted with ethyl acetate (300 μL) to obtain the corresponding (2S)-2-{[(benzyloxy)carbonyl]amino}-3-[4-(trifluoromethoxy)phenyl]propanoic acid. The optical purity was determined by HPLC under the following conditions.
Reaction SMILES: [OH:1][C:2]([CH:11]=[CH2:12])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3]/[CH:4]=[CH:5]/[I:6].N1C=CN=C1.Cl[Si:19]([CH3:22])([CH3:21])[CH3:20]>CN(C)C=O>[CH3:20][Si:19]([CH3:22])([CH3:21])[O:1][C:2]([CH:11]=[CH2:12])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3]/[CH:4]=[CH:5]/[I:6]
Reactant: C[Si](C)(C)Cl
Reactant: C=CC(O)(C/C=C/I)CCCC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=CC(C/C=C/I)(CCCC)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a stirred solution of 456 mg of 4-hydroxy-4-vinyl-1-iodo-trans-1-octene and 320 mg of imidazole in 1.0 ml of dimethylformamide is added 0.23 ml of chlorotrimethylsilane during 3 minutes. The mixture is stirred at room temperature for 22 hours and partitioned with a mixture of cold hexane and water. The hexane layer is washed repeatedly with water and then brine, dried over magnesium sulfate, and concentrated to give an oil, pmr spectrum (CDCl3): 0.13 (s, trimethylsiloxy group) and 2.32 (d, =CHCH2).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[N:8]/[OH:9].[Cl:10]NC(=O)CCC(N)=O>CN(C=O)C.C(OCC)C>[OH:9]/[N:8]=[C:7](\[Cl:10])/[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: NC(=O)CCC(=O)NCl
Reactant: O/N=C/c1ccccn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O/N=C(\Cl)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
To a solution of (E)-picolinaldehyde oxime (10.0 g, 82.0 mmol) in DMF (30 mL) at room temperature was slowly added over 30 minutes N-chlorosuccinamide (10.9 g, 82.0 mmol). An exotherm was noted during the addition. The reaction mixture was stirred overnight at room temperature, diluted with diethyl ether (300 mL), washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was triturated with dichloromethane, and the resulting solid was collected by vacuum filtration and dried to give (Z)—N-hydroxypicolinimidoyl chloride (12.8 g, 51.1 mmol, 62% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.49 (ddd, 1H), 7.83-7.95 (m, 2H), 8.66 (ddd, J=4.73, 1.43, 1.32 Hz, 1H), and 12.64 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])([CH2:6][CH3:7])[C:4]#[CH:5])[CH3:2].[OH-].[K+]>C(O)C>[CH2:4]([C:3]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([CH2:6][CH3:7])[C:1]#[CH:2])[CH3:5]
Reactant: C#CC(CC)(CC)NCCCC(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C#CC(CC)(CC)NCCCC(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl-4-[(1-ethynylcyclohexyl-1)-amino]butyric acid and ethyl 4-[(3-ethyl-1-pentyn3-yl)amino]butyrate and suitable processing, dissolving the evaporation residue in ethanol, adding an ethanolic solution of potassium hydroxide, stirring for 12 hours at room temperature and further processing yields N-[p-chlorobenzoyl)-4-(1-ethynylcyclohexyl-1-amino)butyryl]-4-(3-ethyl-1-pentyn-3-ylamino)butyric acid.
Reaction SMILES: [CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([CH2:23][C:24]([OH:26])=[O:25])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(=O)=O.[CH2:30](O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1>[CH2:30]([O:25][C:24](=[O:26])[CH2:23][C:21]([C:19]1[O:20][C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:17][CH:18]=1)=[O:22])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)CC(=O)O)o1
Reactant: OCc1ccccc1
Agent: O=C=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)CC(=O)OCc2ccccc2)o1
Temperature: 25 °C

Procedure:
A mixture of 10.0 g (0.027 mole) of 2-[5-(tetradecyloxy)-2-furoyl]acetic acid, 4.4 g (0.027 mole) of N,N'-carbonyldiimidazole, and anhydrous tetrahydrofuran is stirred until the evolution of carbon dioxide stops. The mixture is cooled on an ice bath and 3.0 g (0.027 mole) of benzyl alcohol is added. The reaction is allowed to warm to room temperature and evaporated to dryness. The residue is extracted with ether-H2O. The ether layer is washed with 10% aqueous HCl, water, saturated sodium chloride, dried with sodium sulfate and evaporated to dryness affording 2-[5-(tetradecyloxy)-2-furoyl]acetic acid benzyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([O:16][CH3:17])=[O:15])=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1.[C:18](Cl)(=[O:21])[CH2:19][CH3:20]>C(=O)(O)[O-].[Na+].ClCCl>[NH2:1][C:2]1[C:3]([C:14]([O:16][CH3:17])=[O:15])=[N:4][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([C:18](=[O:21])[CH2:19][CH3:20])[CH2:12][CH2:13]2)=[CH:6][N:7]=1
Reactant: COC(=O)c1nc(C2CCNCC2)cnc1N
Reactant: CCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCC(=O)N1CCC(c2cnc(N)c(C(=O)OC)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
To a rapidly stirring biphasic solution of methyl 3-amino-6-(4-piperidyl)pyrazine-2-carboxylate (135 mg, 0.57 mmol) in 50% saturated sodium bicarbonate and dichloromethane (20 mL) at 25° C. was added propanoyl chloride (79 mg, 75 μL, 0.86 mmol) dropwise. The reaction was stirred at room temperature for 30 minutes. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to provide methyl 3-amino-6-(1-propionylpiperidin-4-yl)pyrazine-2-carboxylate (111 mg, 66%). 1H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 7.19 (s, 2H), 4.51 (d, J=12.9 Hz, 1H), 3.95 (d, J=13.6 Hz, 1H), 3.84 (s, 3H), 3.08 (t, J=12.2 Hz, 1H), 2.88 (ddd, J=15.5, 7.9, 3.7 Hz, 1H), 2.61 (t, J=11.7 Hz, 1H), 2.34 (q, J=7.5 Hz, 2H), 1.80 (t, J=13.7 Hz, 2H), 1.69-1.39 (m, 2H), 1.00 (t, J=7.4 Hz, 3H). LC/MS m/z 293.5 [M+H]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[C:6]([CH3:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].C([O-])([O-])=O.[K+].[K+].Cl.[CH3:21][S:22]([CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(=[O:24])=[O:23].O>CS(C)=O>[CH3:10][C:6]1[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[N:30]1[CH2:29][CH2:28][N:27]([CH2:26][CH2:25][S:22]([CH3:21])(=[O:23])=[O:24])[CH2:32][CH2:31]1
Reactant: COc1cc(F)c(C)cc1[N+](=O)[O-]
Reactant: CS(=O)(=O)CCN1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 68.5 %

Procedure:
5-fluoro-4-methyl-2-nitrophenyl methyl ether (Example 113, step B) (5.0 g, 27 mmol), K2CO3 (11.2 g, 81 mmol), and 1-[2-(methylsulfonyl)ethyl]piperazine hydrochloride (8.0 g, 35 mmol) were weighed into a 150 mL sealed tube, taken up in 85 mL of DMSO and heated to 100° C. for 24 h. The mixture was poured into 500 mL of H2O, filtered, washed with H2O, air dried for 15 min, washed with hexanes (200 mL), washed with 20% Ether/Hexanes (200 mL), and air dried for 2 h to give the title compound of step C (6.6 g, 18.5 mmol, 68%). An additional (540 mg, 5.5%) of product was obtained by extraction of the H2O layer, followed by flash chromatography. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (s, 1H), 6.70 (s, 1H), 3.90 (s, 3H), 3.31-3.35 (m, 2H), 3.04 (s, 3H), 2.99-3.03 (m, 4H), 2.77 (t, J=6.60 Hz, 2H), 2.56-2.63 (m, 4H), 2.19 (s, 3H).
Reaction SMILES: [C:1]([CH:4]([C:11](=O)[CH3:12])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=O)[CH3:2].O.[NH2:15][NH2:16]>C(O)C>[CH3:2][C:1]1[C:4]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:11]([CH3:12])[NH:16][N:15]=1
Reactant: NN
Reactant: CCOC(=O)CC(C(C)=O)C(C)=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1c(C)n[nH]c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of ethyl 3-acetyl-4-oxopentanoate (synthesized as described D. P. Shrout and D. A. Lightner, Synth. Commun. 20 (1990), 2075) (9.676 g, 51.96 mmol) in ethanol, at 0° C., was added slowly a solution of hydrazine hydrate (2.990 g, 59.75 g) in absolute ethanol. The reaction mixture was warmed to room temperature and stirred for 2 hours. After removing ethanol under vacuum, dichloromethane and water were added to the crude product and the organic layer was separated. The aqueous layer was extracted further with dichloromethane and the combined organic extracts were washed with water. After drying over MgSO4 and evaporation of the solvent under reduced pressure, the pyrazole was isolated as a yellow oil. Yield: 72% (6.777 g, 37.2 mmol).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([O:14][CH3:15])=[O:13])[NH:5][C:4]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO>[CH:22](=[N:2][C:3]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([O:14][CH3:15])=[O:13])[NH:5][C:4]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1[nH]c(-c2ccccc2)c(N)c1C(=O)OC
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CO
Product: COC(=O)c1[nH]c(-c2ccccc2)c(N=Cc2ccccc2)c1C(=O)OC

Procedure:
From the compound of Example 41 and benzaldehyde, yeild, 78% m.p. 218°-20° C. (from methanol).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:28])[C@@H:13]2[CH2:17][C@@H:16]([N:18]=[N+]=[N-])[CH2:15][N:14]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:2]=1>[Pd].CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:28])[C@@H:13]2[CH2:17][C@@H:16]([NH2:18])[CH2:15][N:14]2[C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH:2]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N=[N+]=[N-])C[C@H]1C(=O)Nc1cnc2ccccc2c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@H](N)C[C@H]1C(=O)Nc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.3 %

Procedure:
A mixture of trans-4-azido-N-tert-butoxycarbonyl-L-proline 3-quinolylamide (D, 526 mg) and 10% palladium on activated carbon (102 mg) in methanol (15 mL) was stirred at room temperature for 4 hr under hydrogen. The catalysts were removed by filtration and washed with methanol. The combined organic layers were evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1 to 5: 1, v/v) to afford the title compound (477 mg) as a colorless sticky oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@:9]1([CH3:16])[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si](C=[N+]=[N-])(C)(C)[CH3:18]>CO.CCOCC>[CH3:16][C@@:9]1([C:13]([O:15][CH3:18])=[O:14])[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@]1(C)C(=O)O
Solvent: CCOCC
Solvent: CO
Product: COC(=O)[C@]1(C)CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a stirred solution of (S)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid 106A in methanol (100 ml) and ether (100 ml) was added TMS-Diazomethane (80 ml) (2.0 M ether solution) dropwise at 0° C. The reaction mixture was stirred at room temperature for 2 h and the reaction mixture was concentrated. The residue was purified by flash chromatography (10% EtOAc/Hexane) to give (S)-1-tent-butyl 2-methyl 2-methylpyrrolidine-1,2-dicarboxylate 106B (28.5 g, 76% overall yield) as an oil. 1H NMR (CDCl3, 400 MHz) δ 3.69 (s, 3H), 3.42-3.56 (m, 2H), 2.13-2.17 (m, 1H), 1.83-1.93 (m, 3H), 1.49 (s, 3H), 1.39 (s, 9H).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[NH:10][CH:11]=[CH:12][N:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(C1C=CC(C)=CC=1)(O[CH2:18][C@@H:19]1[CH2:33][C@H:32]2[C@@H:22]([CH2:23][C:24]3[C:34]4[C:27](=[CH:28][CH:29]=[CH:30][C:31]2=4)[NH:26][CH:25]=3)[N:21]([CH3:35])[CH2:20]1)(=O)=O.C>ClCCl.CN(C)C=O>[CH3:35][N:21]1[C@H:22]2[C@@H:32]([C:31]3[CH:30]=[CH:29][CH:28]=[C:27]4[C:34]=3[C:24]([CH2:23]2)=[CH:25][NH:26]4)[CH2:33][C@@H:19]([CH2:18][N:13]2[CH:12]=[CH:11][N:10]=[C:9]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:20]1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1C[C@H](Cn2ccnc2-c2ccccc2)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reaction time: 0.5 h
Yield: 30.7 %

Procedure:
1.0 g of 50% sodium hydride in an oil was added in small portions to a mixture of 10.5 g of 2-phenylimidazole and 60 ml of dimethylformamide, and the resulting mixture was stirred for 30 minutes. 3.5 g of 6-methylergolin-8β-ylmethyl tosylate was added to the mixture which was then heated on a water bath for 2 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with acetone). The product thus obtained was treated with charcoal in dichloromethane, and recrystallized from dichloromethaneisopropyl acetate to obtain 1.0 g of the titled compound as colorless prisms having a melting point of 193°-195° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1OC)([O-:3])=[O:2].[CH3:15][NH2:16].Cl>>[CH3:15][NH:16][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2])[C:8]([OH:10])=[O:9]
Reactant: CN
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: Cl
Product: CNc1cc(C(=O)O)ccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 73 %

Procedure:
A mixture comprising 4-nitro-3-methoxybenzoic acid (5.0 g, 25.4 mmol) and aqueous methylamine (40%, 15 mL) is a sealed tube was heated in an oil bath at 100° C. for 12 hours, allowed to cool to room temperature, and then poured into a stirring slurry of 1M aqueous hydrochloric acid and ice to give an orange precipitate. The precipitate was collected by filtration, rinsed with water and recrystallized from hot ethanol to provide 3-methylamino-4-nitrobenzoic acid as a bright red crystalline solid (3.6 g, 73% yield); 1H-NMR (300 MHz, DMSO-d6): 13.5 (s), 8.3 (q), 8.2 (d), 7.4 (s), 7.1 (d), 3.0 (d).
Reaction SMILES: [CH3:1][C:2]1([CH3:42])[C:6]2=[N:7][CH:8]=[C:9](B3OC(C)(C)C(C)(C)O3)[CH:10]=[C:5]2[N:4]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=3)[N:23]=[C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[S:37]([CH3:40])(=[O:39])=[O:38])[C:21]=2[CH3:41])[CH2:3]1.[NH2:43][C:44]1[N:49]=[C:48](Cl)[CH:47]=[CH:46][N:45]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[F:30][C:26]1[CH:25]=[C:24]2[C:29]([C:20]([N:4]3[C:5]4[C:6](=[N:7][CH:8]=[C:9]([C:46]5[CH:47]=[CH:48][N:49]=[C:44]([NH2:43])[N:45]=5)[CH:10]=4)[C:2]([CH3:1])([CH3:42])[CH2:3]3)=[C:21]([CH3:41])[C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[S:37]([CH3:40])(=[O:38])=[O:39])=[N:23]2)=[CH:28][CH:27]=1
Reactant: Nc1nccc(Cl)n1
Reactant: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(-c3ccnc(N)n3)cc21
Temperature: 120 °C

Procedure:
Prepared according to procedure P using 4-(3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)quinoline (131 mg, 0.22 mmol) (described herein), 2-amino-4-chloropyrimidine (28.9 mg, 0.22 mmol), bis(triphenylphosphine)palladium(ii) chloride (15.7 mg, 0.022 mmol), and sodium carbonate (70.9 mg, 0.67 mmol) in 1,4-dioxane (4.8 mL) and water (1.2 mL). The reaction mixture was heated in a microwave at 120° C. for 60 min. Purification afforded 4-(1-(7-fluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)-4-quinolinyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-2-pyrimidinamine as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.55 (1H, m), 8.11-8.35 (2H, m), 8.04 (1H, m), 7.64-7.91 (3H, m), 7.44-7.57 (1H, m), 7.20-7.44 (2H, m), 6.70-7.05 (1H, m), 4.9-5.35 (2H, m), 3.35-3.96 (2H, m), 2.97-3.22 (3H, m), 1.87-2.05 (3H, m), 1.44-1.73 (6H, m). Mass Spectrum (ESI) m/e=555 (M+1).