Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:13][C:14]([NH:16][CH3:17])=[O:15])=[CH:9][CH:10]=2)[NH:5][N:4]=1.N1C2C(=CC=CC=2C(C2C=CC=CC=2)CC(NC)=O)C=C1>>[CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([CH:12]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH2:13][C:14]([NH:16][CH3:17])=[O:15])=[CH:9][CH:10]=2)[NH:5][N:4]=1
Reactant: CNC(=O)C=C(c1cccnc1)c1ccc2c(OC)n[nH]c2c1
Agent: CNC(=O)CC(c1ccccc1)c1cccc2cc[nH]c12
Product: CNC(=O)CC(c1cccnc1)c1ccc2c(OC)n[nH]c2c1

Procedure:
3-(3-Methoxy-1H-indazol-6-yl)-N-methyl-3-pyridin-3-yl-propionamide CCL was prepared from 3-(3-methoxy-1H-indazol-6-yl)-N-methyl-3-pyridin-3-yl-acrylamide using the procedure described for preparation of 3-(1H-Indol-7-yl)-N-methyl-3-phenyl-propionamide XIX (Example 4).
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]2[CH:9]=[N:10][C:11]([N+:14]([O-])=O)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1>[Pd].C(O)C>[NH2:14][C:11]1[N:10]=[CH:9][C:8]([N:7]2[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3][C@@H:2]2[CH3:1])=[CH:13][CH:12]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc([N+](=O)[O-])nc1
Agent: [Pd]
Solvent: CCO
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(N)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.1 %

Procedure:
A 500-mL bottle was purged with nitrogen and charged with 105a (5.8 g, 18 mmol), 10% palladium on carbon (50% wet, 2.0 g) and ethanol (200 mL). It was evacuated, charged with hydrogen gas, and stirred for 16 h at room temperature. The hydrogen was then removed in vacuo and replaced with nitrogen. The catalyst was removed by filtration through a pad of CELITE® and the filtrate concentrated under reduced pressure to afford 105b as a brown solid (4.9 g, 96%). LCMS: [M+H]+ 293
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:18][O:19][CH3:20])[C:15]([OH:17])=O)[N:13]=1)=[O:7].[NH2:21][CH:22]1[C:33](=[O:34])[N:24]2[CH:25]([C:30]([OH:32])=[O:31])[CH:26]([OH:29])[CH2:27][S:28][C@H:23]12.C[Si](CC(N)=O)(C)C.C(=O)(O)[O-].[Na+:47]>C(OCC)(=O)C.O.CN(C)C=O>[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:18][O:19][CH3:20])[C:15]([NH:21][CH:22]2[C:33](=[O:34])[N:24]3[CH:25]([C:30]([O-:32])=[O:31])[CH:26]([OH:29])[CH2:27][S:28][C@H:23]23)=[O:17])[N:13]=1)=[O:7].[Na+:47]
Reactant: NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Reactant: CON=C(C(=O)O)c1csc(NC=O)n1
Agent: C[Si](C)(C)CC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])C(O)CS[C@H]12)c1csc(NC=O)n1
Reaction time: 0.5 h

Procedure:
Phosphoryl chloride (704 mg.) was added dropwise to a solution of N,N-dimethylformamide (336 mg.) in ethyl acetate (8 ml.) below 5° C. and stirred at the same temperature for 30 minutes. 2-(2-Formamidothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 1 g.) was added to the solution and stirred at 5° to 10° C. for an hour. The solution was added dropwise to a solution of 7-amino-3-hydroxycepham-4-carboxylic acid (872 mg.) and trimethylsilylacetamide (1.05 g.) in ethyl acetate (20 ml.) at -20° C. over 5 minutes, and stirred at -20° to -25° C. for an hour. Water (50 ml.) was added to the resultant solution and adjusted to pH 7.0 with sodium bicarbonate. The aqueous layer was separated, and the ethyl acetate layer was extracted again with water (10 ml.). The aqueous extracts were combined, adjusted to pH 6 and absorbed on macroporous nonionic adsorption resin Diaion HP-20 (50 ml., Trademark, manufactured by Mitsubishi Chemical Industries). The column was washed with water (50 ml.) and eluted with 30% aqueous isopropyl alcohol. The eluate containing the object compound was adjusted to pH 6.5 and concentrated under reduced pressure. The residue was lyophilized to give sodium 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-hydroxycepham-4-carboxylate (syn isomer, 1.1 g.)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]=[C:10]([O:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:9]([NH:19][C:20]3[C:21]4[C:28]([CH3:29])=[C:27]([C:30]([O:32]C)=O)[S:26][C:22]=4[N:23]=[CH:24][N:25]=3)=[CH:8][CH:7]=2)=[CH:2]1.[OH-].[Na+].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:69][N:70]([CH3:75])[CH2:71][CH2:72][CH2:73][NH2:74]>CCO.C1COCC1.C(Cl)Cl.OS([O-])(=O)=O.[K+]>[CH3:69][N:70]([CH3:75])[CH2:71][CH2:72][CH2:73][NH:74][C:30]([C:27]1[S:26][C:22]2[N:23]=[CH:24][N:25]=[C:20]([NH:19][C:9]3[C:10]([O:12][CH:13]4[CH2:14][CH2:15][O:16][CH2:17][CH2:18]4)=[N:11][C:6]([C:3]4[CH:4]=[CH:5][O:1][CH:2]=4)=[CH:7][CH:8]=3)[C:21]=2[C:28]=1[CH3:29])=[O:32]
Reactant: CN(C)CCCN
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(-c4ccoc4)nc3OC3CCOCC3)c2c1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1c(C(=O)NCCCN(C)C)sc2ncnc(Nc3ccc(-c4ccoc4)nc3OC3CCOCC3)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 11.3 %

Procedure:
To a suspension of methyl 4-(6-(furan-3-yl)-2-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-ylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (0.155 g, 0.33 mmol) in EtOH/THF (5 mL, 3:2) was added aqueous sodium hydroxide (2M, 0.714 mL, 1.43 mmol) and the reaction mixture stirred at ambient temperature for 24 hours. The mixture was diluted with DCM and 10% aqueous KHSO4 and the organic layer separated. The organic phase was washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residue was diluted with DMF (2.0 mL) and cooled in ice-water. Hünig's base (32 L, 0.18 mmol) and HATU (0.076 g, 0.20 mmol) were added and the mixture was stirred at this temperature for 20 minutes when 3-(dimethylamino)-propylamine (0.100 mL, 0.91 mmol) was added. The coolant was removed and the reaction stirred at ambient temperature for 18 hours. The mixture was diluted with EtOAc, washed with water and brine (×2). The organic phase was dried (MgSO4), filtered and the solvent was removed in vacuo. The residue was purified by SCX-2 ion exchange chromatography to afford the title compound as an off-white solid (0.02 g, 11%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:36])[C:5]([CH3:35])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:31]C(=O)C)=[C:17]([CH:30]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:36])[C:5]([CH3:35])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:31])=[C:17]([CH:30]=2)[C:18]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27](=[O:29])[CH3:28])=[CH:25][CH:26]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(C(C)=O)cc3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(C(C)=O)cc3)c2)=C(C)C1=O
Yield: 65.2 %

Procedure:
N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-acetylaniline (0.100 g, 0.204 mmol) was dissolved in methanol (6 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:2) and then recrystallized from ether to obtain the titled compound (0.060 g, 0.133 mmol, 65%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]([CH2:11]Cl)=[CH:9][CH:10]=1)=[O:5])[CH3:2].[I-].[K+].[CH:15]([OH:17])=[O:16]>C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Rh].[Rh]>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]([CH2:11][C:15]([OH:17])=[O:16])=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: O=CO
Reactant: CCOC(=O)c1ccc(CCl)o1
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: [Cl-]
Solvent: C1=CCCC=CCC1
Product: CCOC(=O)c1ccc(CC(=O)O)o1
Temperature: 75 °C
Reaction time: 6 h

Procedure:
5-Chloromethyl-2-furancarboxylic acid ethyl ester (1.0 g, 5.3 mmol), potassium iodide (0.044 g, 0.27 mmol), and chloro(1,5-cyclooctadiene)rhodium(I) dimer (0.26 g, 0.53 mmol) were dissolved in formic acid (25 mL), and the mixture was stirred at 75° C. for 6 hours under a carbon monoxide atmosphere. The solvent was evaporated, and the residue was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate solution. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The drying agent was filtered off, the solvent was evaporated, and the residue was purified by silica gel column chromatography to give the title compound (0.61 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:3]=1[NH2:16].[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>CC(N(C)C)=O>[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:16][C:3]1[C:2]([Cl:1])=[N:7][C:6]([CH3:8])=[N:5][C:4]=1[NH:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:21]
Reactant: Cc1nc(Cl)c(N)c(NC2CCOCC2)n1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: CC(=O)N(C)C
Product: Cc1nc(Cl)c(NC(=O)c2ccccc2Cl)c(NC2CCOCC2)n1
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
Dissolve 6-chloro-2-methyl-N*4*-(tetrahydro-2H-pyran-4-yl)-pyrimidine-4,5-diamine (24.4 g, 100.4 mmol) in dimethylacetamide (175 mL) in a 500 mL 3-necked flask under a nitrogen atmosphere. Cool the resulting solution to 0-5° C. Via addition funnel, add 2-chlorobenzoyl chloride (15.5 mL, 122.4 mmol) over 20 minutes, maintaining the internal temperature below 10° C. Rinse the addition funnel with dimethylacetamide (1.0 mL). Allow the resulting mixture to stir overnight while self-warming to ambient temperature. Charge ice cold de-ionized water (250 mL) to a second 500 mL flask and then transfer the reaction mixture into the cold water over 20 minutes. Stir the resulting slurry for 2 hours. Filter the solids, wash with cold water (120 mL)) and vacuum dry overnight at 50° C. to afford 2-chloro-N-(4-chloro-2-methyl-6-(tetrahydro-2H-pyran-4-ylamino)-pyrimidin-5-yl) benzamide as an off-white solid (33.1 g). MS (m/z): 381/382 (M+1).
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[C:13]([O:15][CH3:16])[N:14]=2)[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([C:19]1[CH:20]=[C:21]([CH:26]=[C:27]([CH3:34])[C:28]=1[NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:22]([NH:24]O)=[NH:23])[CH3:18]>>[CH:1]1([C:6]2[CH:7]=[C:8]([C:9]3[O:11][N:24]=[C:22]([C:21]4[CH:26]=[C:27]([CH3:34])[C:28]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[C:19]([CH2:17][CH3:18])[CH:20]=4)[N:23]=3)[CH:12]=[C:13]([O:15][CH3:16])[N:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1cc(C(=N)NO)cc(C)c1NS(C)(=O)=O
Reactant: COc1cc(C(=O)O)cc(C2CCCC2)n1
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1NS(C)(=O)=O
Yield: 48.4 %

Procedure:
The title compound (48 mg) is prepared in analogy to Example 11 starting from 2-cyclopentyl-6-methoxy-isonicotinic acid (48 mg, 217 μmol) and 3-ethyl-N-hydroxy-4-methanesulfonylamino-5-methyl-benzamidine (62 mg, 228 mmol); LC-MS**: tR=0.91 min, [M+H]+=457.05; 1H NMR (CDCl3): δ1.35 (t, J=7.5 Hz, 3H), 1.71-1.80 (m, 2H), 1.84-1.95 (m, 4H), 2.06-2.16 (m, 2H), 2.56 (s, 3H), 2.93 (q, J=7.5 Hz, 2H), 3.18 (s, 3H), 3.21-3.30 (m, 1H), 4.02 (s, 3H), 5.88 (s, 1H), 7.31 (s, 1H), 7.51 (s, 1H), 7.97 (s, 1H), 7.99 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[Br:20]Br>C(Cl)Cl.C(O)(=O)C>[Br:20][C:10]1[S:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:11]=1
Reactant: Fc1ccc(-c2ccsc2-c2ccc(F)cc2)cc1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClCCl
Product: Fc1ccc(-c2cc(Br)sc2-c2ccc(F)cc2)cc1
Reaction time: 4 h
Yield: 83.7 %

Procedure:
A solution of 2,3-bis(4-fluorophenyl)thiophene (13.6 g, 50 mmole) in 120 ml methylene chloride and 150 ml acetic acid was cooled to ~5° and treated with bromine (2.8 ml, 55 mmole). After 4 hours, the reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine, dried and concentrated in vacuo. Recrystallization from ethanol gave the title compound (14.7 g), m.p. 91°-93°.
Reaction SMILES: [C:1]1(O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]=1.COC.[Cl:12][C:13]1[CH:14]=[C:15]([NH:19][NH2:20])[CH:16]=[CH:17][CH:18]=1>C(O)(=O)C>[Cl:12][C:13]1[CH:14]=[C:15]([NH:19][N:20]=[C:1]2[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:16]=[CH:17][CH:18]=1
Reactant: OC1=NCCCCC1
Reactant: NNc1cccc(Cl)c1
Agent: COC
Solvent: CC(=O)O
Product: Clc1cccc(NN=C2CCCCCN2)c1
Reaction time: 2 h
Yield: 94.2 %

Procedure:
35 G (0.28 mole) of caprolactim-methyl-ether were added dropwise over the course of 15 minutes at 5°C, while stirring and cooling, to a solution of 36 g (0.25 mole) of 3-chlorophenylhydrazine in 250 ml of glacial acetic acid; the red-brown clear solution was kept at 0° to 5°C for a further 2 hours and then for 2 hours at 20°C and excess glacial acetic acid was distilled off in a water-pump vacuum. On fractional distillation in vacuo of the residue which remained, 56 g (94.3% of theory) of caprolactam-(3-chlorophenylhydrazone) were obtained; it was a light viscous oil of boiling point 215° to 220°C/3 mmHg, which solidified to crystals.
Reaction SMILES: B#B.[F:3][C:4]([F:18])([F:17])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:12]([CH3:16])[C:13](O)=[O:14])=[CH:7][CH:6]=1>O1CCCC1>[F:3][C:4]([F:17])([F:18])[C:5]1[CH:6]=[CH:7][C:8]([O:11][CH:12]([CH3:16])[CH2:13][OH:14])=[CH:9][CH:10]=1
Reactant: CC(Oc1ccc(C(F)(F)F)cc1)C(=O)O
Agent: B#B
Solvent: C1CCOC1
Product: CC(CO)Oc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 115 %

Procedure:
To 150 ml of 1M diborane in tetrahydrofuran is added 13.5 g of 2-(α,α,α-trifluoro-p-tolyloxy)propionic acid. The mixture is stirred at room temperature for 6 hrs and poured onto 400 g of ice-water. The mixture is extracted with ether and the extract dried (MgSO4) and concentrated to give 14.6 g of colorless liquid. Distillation gives 8.1 g of liquid which crystallizes to give product, mp 29°-32° C.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[CH2:24]([N:27]=[C:28]=[O:29])[CH2:25][CH3:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:27]([CH2:24][CH2:25][CH3:26])[C:28]2=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCCN=C=O
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: CCCn1c(=O)c2cnc3c(OC)cccc3c2n(C2CCCC2)c1=O
Yield: 39.6 %

Procedure:
1-Cyclopentyl-7-methoxy-3-propyl-1H-pyrimido[5,4-c]quinoline-2,4-dione (14 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.10 mmol) and propyl isocyanate (0.4 mmol) following general procedure C. LCMS: m/z 354 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 9.49 (s, 1H), 7.82 (d, 1H), 7.59 (t, 1H), 7.24 (d, 1H), 5.01 (m, 1H), 4.15 (s, 3H), 4.03 (t, 2H), 2.40 (m, 2H), 2.09 (m, 4H), 1.76 (m, 2H), 1.63 (m, 2H), and 1.16 (t, 3H) ppm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]#[N:9].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:10][CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:8]#[N:9]
Reactant: N#CCc1ccccn1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: N#CC(Br)c1ccccn1
Yield: 94.4 %

Procedure:
To a solution of (2-pyridyl)acetonitrile (12.0 g, 0.10 mole) in 150 ml of carbon tetrachloride, was added 18.1 g of N-bromosuccinimide (0.10 mole) at room temperature. The mixture was refluxed for 1.5 h. The resulting precipitate was removed by filtration and the solvent was removed under reduced pressure to give the crude product, which was recrystallized from hexane to yield 18.6 g (94%) of the title compound as red crystals:
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][CH2:9][CH2:10][CH3:11])[N:6]=[C:5]([C:12]#[N:13])[C:4]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20]C(=O)C(C)(C)C)[CH3:2].[O-]CC.[Na+]>C(O)C>[CH2:1]([C:3]1[N:7]([CH2:8][CH2:9][CH2:10][CH3:11])[N:6]=[C:5]2[C:4]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]=[C:12]2[NH2:13])[CH3:2]
Reactant: CCCCn1nc(C#N)c(-c2ccccc2NC(=O)C(C)(C)C)c1CC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCn1nc2c(N)nc3ccccc3c2c1CC
Temperature: 25 °C
Yield: 40.8 %

Procedure:
To a solution of N-[2-(5-ethyl-1-butyl-3-cyano-1H-pyrazol-4-yl)phenyl]-2,2-dimethylpropanamide (0.45 g, 1.28 mmol) in ethanol (8 mL) was added sodium ethoxide in ethanol (21 wt % solution in ethanol, 1.03 g, 3.19 mmol). The solution was heated at reflux overnight, then was allowed to cool to ambient temperature. The solvent was removed under reduced pressure and the residue was triturated with water. A precipitate formed that was isolated by filtration and washed with water, then was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 0-35% CMA in chloroform) to yield 0.14 g of 1-ethyl-2-butyl-2H-pyrazolo[3,4-c]quinolin-4-amine as a white crystalline solid, mp 215-216° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:12][C@H:13]([C:19]([NH:21][C:22]2([C:25]#[N:26])[CH2:24][CH2:23]2)=[O:20])[CH2:14][C:15]([F:18])([CH3:17])[CH3:16])[CH:9]([F:11])[F:10])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:40]=[CH:39][C:38]([C:41]3([C:44]([NH2:46])=[O:45])[CH2:43][CH2:42]3)=[CH:37][CH:36]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(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]>[NH2:46][C:44]([C:41]1([C:38]2[CH:39]=[CH:40][C:35]([C:2]3[CH:7]=[CH:6][C:5]([C@H:8]([NH:12][C@H:13]([C:19]([NH:21][C:22]4([C:25]#[N:26])[CH2:23][CH2:24]4)=[O:20])[CH2:14][C:15]([F:18])([CH3:16])[CH3:17])[CH:9]([F:11])[F:10])=[CH:4][CH:3]=3)=[CH:36][CH:37]=2)[CH2:42][CH2:43]1)=[O:45]
Reactant: CC(C)(F)C[C@H](N[C@@H](c1ccc(Br)cc1)C(F)F)C(=O)NC1(C#N)CC1
Reactant: CC1(C)OB(c2ccc(C3(C(N)=O)CC3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(F)C[C@H](N[C@@H](c1ccc(-c2ccc(C3(C(N)=O)CC3)cc2)cc1)C(F)F)C(=O)NC1(C#N)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
N2-[(1S)-1-(4-bromophenyl)-2,2-difluoroethyl]-N1-(1-cyanocyclopropyl)-4-fluoro-L-leucinamide (11.2 g, 25.9 mmol), 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarboxamide (8.2 g, 28.5 mmol, 1:1 equiv) and 2M sodium carbonate solution (35.4 mL, 70.8 mmol, 2.7 equiv) were mixed in 225 mL N,N-dimethylformamide. The mixture was degassed 3 times with nitrogen, then [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) chloride, 1:1 complex with dichloromethane (838 mg, 1.15 mmol, 0.044 equiv) was added and mixture degassed again 3 times with nitrogen, heated at 80° C. for 6 hours. The reaction mixture was poured into H2O (900 mL), extracted with ethyl acetate (2×250 mL) and dichloromethane (250 mL). Combined organic fractions were washed with brine, dried over sodium sulphate and evaporated. The residue was purified by flash chromatography, eluting first with 1:1 ethyl acetate/hexane, then with 9:1 ethyl acetate/dichloromethane. The light pink recovered solid was stirred in 150 mL of 1:1 ethyl acetate/dichloromethane for 2 hours and filtered to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5].COC(=O)[C@H](CC1C=CC=CC=1)NC(=O)[C@H](CC(=O)O)NC(OCC1C=CC=CC=1)=O>>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5]
Reactant: COC(=O)C(N)Cc1ccccc1
Agent: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)OCc1ccccc1
Product: COC(=O)[C@H](N)Cc1ccccc1
Yield: 62.3 %

Procedure:
Example 17 was repeated except for using DL-phenylalanine methyl ester instead of L-phenylalanine methyl ester to obtain 756 mg of an addition compound of N-benzyloxycarbonyl-L-aspartyl L-phenylalanine methyl ester and D-phenyl alanine methyl ester (1:1) (melting point: 105 to 111° C; yield: 62.3% based on N-benzyloxycarbonyl L-aspartic acid).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:13][C:14]1[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20](Cl)=[O:21])=[CH:16][CH:15]=1.ClCCl.C(N(CC)CC)C>C1COCC1>[Br:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][C:20](=[O:21])[CH2:19][O:18][C:17]2[CH:23]=[CH:24][C:14]([Cl:13])=[CH:15][CH:16]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Reactant: COC(=O)c1cc(Br)ccc1N
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Br)ccc1NC(=O)COc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 2-amino-5-bromobenzoate (3.03 mL, 17.4 mmol) in THF (28 mL) was added 2-(4-chlorophenoxy)acetyl chloride (3.92 g, 19.1 mmol) to form a suspension. An additional 30 mL of dichloromethane was added. The reaction was then cooled to 0° C. and triethylamine (5.32 mL, 38.3 mmol) was added dropwise. The cold bath was removed and the reaction was stirred at room temperature for 2 hours. Analysis showed the reaction to be incomplete, so additional 2-(4-chlorophenoxy)acetyl chloride (0.5 mL, 3.22 mmol) was added and reaction solution was stirred for 1 hour then transferred to a reparatory funnel with dichloromethane dilution. The organic phase was washed with water and saturated aqueous NH4Cl solution, then dried (MgSO4), filtered, and concentrated to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH:15]([Si](C)(C)C)[CH2:14][CH2:13][CH:12]1[Si](C)(C)C>C(#N)C>[CH3:10][N:11]1[CH:15]2[CH:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][CH:6]=3)[CH2:9][CH:12]1[CH2:13][CH2:14]2
Reactant: C=Cc1ccc(Cl)nc1
Reactant: CN1C([Si](C)(C)C)CCC1[Si](C)(C)C
Solvent: CC#N
Product: CN1C2CCC1C(c1ccc(Cl)nc1)C2
Reaction time: 2.25 h
Yield: 80 %

Procedure:
To a acetonitrile solution containing 3 gms of Ag (1)F. 1.2 gms of dipolarophile (6-chloro-3-vinyl pyridine) was added to 2 gms of N-methyl-2,5-di(trimethyl silyl) pyrrolidine at 25° C. After stirring the reaction mixture for 2 to 2.5 hours, the reaction mixture was filtered through a plug of celite. The solvent was evaporated to give N-methyl Epibatidine in 80% yield which was further purified by column chromatography. Hydrogenation of N-methyl Epibatidine with pd/c for 22 hours gave 70% yield of Epibatidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH:13]=O)[C@H:10]([CH2:15][N:16]([C:20](=[O:34])[C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH3:33])[CH:22]=2)[CH:17]([CH3:19])[CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:35]1([NH2:38])[CH2:37][CH2:36]1>CCOC(C)=O.CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:38][CH:35]2[CH2:37][CH2:36]2)[C@H:10]([CH2:15][N:16]([C:20](=[O:34])[C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH3:33])[CH:22]=2)[CH:17]([CH3:18])[CH3:19])[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: NC1CC1
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C=O)C(C)C)ccc1C
Solvent: CCOC(C)=O
Solvent: CO
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CNC2CC2)C(C)C)ccc1C

Procedure:
From (3R,4S)-3-({[4-methyl-3-(3-methoxy-propoxy)-benzoyl]-isopropyl-amino}-methyl)-4-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (3 g, 6.29 mmol), cyclopropyl amine (0.395 mL, 6.92 mmol) and NaBHOAc3 (1.87 g, 8.81 mmol) and purification by flash chromatography on silica gel (AcOEt/MeOH 100:0 to 85:15) to give the title compound as colorless oil. TLC, Rf (AcOEt)=0.63. MS (LC-MS): 518.3 [M+H]+; tR (HPLC, Nucleosil C-18HD (4×70 mm, 3 μm), 20-100% CH3CN/H2O/6 min, 100% CH3CN/1.5 min; flow: 1 mL/min): 5.37 min.