Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14](F)=[CH:13][C:12]=2F)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:20]([CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([N:30]3[CH2:31][CH2:32][CH:27]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:28][CH2:29]3)=[CH:13][C:12]=2[N:4]2[CH2:9][CH2:8][CH:7]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:6][CH2:5]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Reactant: c1ccc(CC2CCNCC2)cc1
Product: CC(=O)N1CCC(C(=O)c2ccc(N3CCC(Cc4ccccc4)CC3)cc2N2CCC(Cc3ccccc3)CC2)CC1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture consisting of 2.67 g of 1-acetyl-4-(2,4-difluorobenzoyl)piperidine and 8.8 ml of 4-benzylpiperidine was stirred at 100° C. for 24 hours and the reaction mixture was then worked up in the same manner as Example 2 to give 4.1 g of the title compound as oil.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][C:9]([C:11]1[S:12][C:13]2[C:19]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:18][CH:17]=[C:16]([O:26][CH3:27])[C:14]=2[N:15]=1)=O.FC(F)(F)C([O-])=O.[NH4+:35]>O>[CH3:27][O:26][C:16]1[C:14]2[N:15]=[C:11]([C:9]3[NH:35][C:2]4[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=4[N:8]=3)[S:12][C:13]=2[C:19]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)=[CH:18][CH:17]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)NC3CCCCC3=O)nc12
Reactant: [NH4+]
Agent: O=C([O-])C(F)(F)F
Solvent: O
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCCC4)nc12
Temperature: 25 °C
Yield: 42.1 %

Procedure:
A mixture of 0.10 g 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid (2-oxo-cyclohexyl)-amide and 0.34 g ammonium triflouroacetate was melted at 165° C. for 50 minutes and, after cooling to room temperature, suspended in water. Extraction with dichloromethane and chromatography on silicagel with ethylacetate/hexane 6:4 gave 0.04 g (39%) 4-methoxy-7-morpholin-4-yl-2-(4,5,6,7-tetrahydro-1H-benzoimidazol-2-yl)-benzothiazole as light brown solid; MS (ISP): m/e=371 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:21](N=C(N(C)C)N(C)C)([CH3:24])([CH3:23])[CH3:22].BrCC(C)C>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:22][CH:21]([CH3:24])[CH3:23])[C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Reactant: CC(C)c1ccc(NS(=O)(=O)c2ccc(F)cc2)nc1
Solvent: CC(C)CBr
Solvent: CC#N
Product: CC(C)CN(c1ccc(C(C)C)cn1)S(=O)(=O)c1ccc(F)cc1
Temperature: 150 °C
Reaction time: 0.33 h
Yield: 24.6 %

Procedure:
4-fluoro-N-(5-isopropylpyridin-2-yl)benzenesulfonamide (400 mg, 1.359 mmol) was dissolved in acetonitrile (4 mL), 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (284 μL, 1.36 mmol) added and the mixture stirred for 20 minutes. 1-Bromo-2-methylpropane (296 μL, 2.72 mmol) was then added and the reaction vessel sealed and heated by microwaves to 150° C. for 1 hour. The reaction was cooled and concentrated in vacuo, then the crude product was extracted to the organic phase of an aqueous work up between ethyl acetate and water. The organic phase was passed through a hydrophobic frit, concentrated in vacuo and purified by mass directed autoprep (formic acid modifier) to give the title compound (117 mg). LCMS (2 min, formic) Rt 1.38 min, m/z (ES+) 351 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[N+:10]([O-])([O-:12])=[O:11].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:10]([C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=1[OH:9])([O-:12])=[O:11]
Reactant: O=[N+]([O-])[O-]
Reactant: CCc1cccc(O)c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1ccc([N+](=O)[O-])c(O)c1
Reaction time: 24 h
Yield: 24.8 %

Procedure:
3-ethylphenol (5.00 g, 41 mmol) was dissolved in methylene chloride(40 mL) followed by the addition of sodium nitrate (3.83 g, 45 mmol). The addition of sulfuric acid (50 mL/3 M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2Cl2) gave the desired product(1.7 g, 25%). 1H NMR (CD3COCD3): δ 8.02 (d,1H), 6.99 (s,1H), 6.85 (d, 1H), 2.69 (q, 2H), 1.30 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[NH2:22][C:23]1([CH3:28])[CH2:27][CH2:26][NH:25][CH2:24]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:25]2[CH2:26][CH2:27][C:23]([NH2:22])([CH3:28])[CH2:24]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CC1(N)CCNC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(N)CCN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Yield: 60.4 %

Procedure:
A mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.5 g), 3-amino-3-methylpyrrolidine (0.76 g), DBU (0.77 g), and acetonitrile (30 ml) was refluxed for 7 hours. The precipitated crystals were collected by filtration after cooling, and washed with acetonitrile. The crystals were suspended in water (50 ml) and dissolved by addition of a 10% aqueous solution of acetic acid. The solution was treated with activated carbon, and adjusted to pH 7-8 with 10% aqueous ammonia. The precipitated crystals were collected by filtration, washed with water and then with ethanol, and dried to give 5-amino-7-(3-amino-3-methyl1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro4-oxoquinoline-3-carboxylic acid (1.15 g), m.p. 271°-273° C. (decomp.).
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([CH:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH3:9])=[CH:4][C:3]=1[C:16]1[N:24]=[C:23]([CH3:25])[N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][N:20]2[CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1.[NH2:32][C:33]1[CH:34]=[C:35]([NH:40][S:41]([N:44]([CH3:46])[CH3:45])(=[O:43])=[O:42])[C:36]([Cl:39])=[N:37][CH:38]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Cl:39][C:36]1[C:35]([NH:40][S:41]([N:44]([CH3:45])[CH3:46])(=[O:43])=[O:42])=[CH:34][C:33]([NH:32][C:2]2[C:3]([C:16]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:4][C:5]([CH:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[CH3:9])=[CH:6][N:7]=2)=[CH:38][N:37]=1
Reactant: Cc1nc(-c2cc(C(C)N3CCOCC3)cnc2F)c2ncn(C3CCCCO3)c2n1
Reactant: CN(C)S(=O)(=O)Nc1cc(N)cnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(-c2cc(C(C)N3CCOCC3)cnc2Nc2cnc(Cl)c(NS(=O)(=O)N(C)C)c2)c2ncn(C3CCCCO3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
To a stirred solution of 4-(1-(6-fluoro-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethyl)morpholine (Example 339 step 4, 0.0475 g, 0.111 mmol) and N′-(5-amino-2-chloro-3-pyridinyl)-N,N-dimethylsulfamide (Example 384, Step 2 0.0380 g, 0.152 mmol) in THF (1 mL) in 20 mL scintillation vial, NaHMDS (Aldrich, 1 M in THF, 0.445 mL, 0.445 mmol) was added dropwise at 0° C. The dark red mixture was stirred at 0° C. for 30 min. The reaction mixture was partitioned between buffer (pH 5.0, citric acid/NaOH) (20 mL) and EtOAc (20 mL) resulted in having insoluble materials. The biphase mixture was filtered and the solid was collected and washed with water to afford N′-(2-chloro-5-((3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)-5-(1-(4-morpholinyl)ethyl)-2-pyridinyl)amino)-3-pyridinyl)-N,N-dimethylsulfamide (0.0472 g, 65% yield) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 13.12 (s, 1H) 9.76 (s, 1H) 8.86 (d, J=2.35 Hz, 1H) 8.50 (d, J=1.96 Hz, 1H) 8.32 (s, 2H) 6.79 (br. s., 1H) 5.87 (d, J=8.22 Hz, 1H) 4.16-4.26 (m, 1H) 3.79-3.90 (m, 1H) 3.73 (br. s., 4H) 3.55 (br. s., 1H) 2.87-3.04 (m, 9H) 2.50 (br. s., 4H) 1.98-2.21 (m, 3H) 1.69-1.92 (m, 3H) 1.48 (d, J=6.46 Hz, 3H). m/z (ESI, positive ion): 657.0 (M+H)+.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([CH3:12])([CH3:11])[CH2:6][S:7]([NH2:10])(=[O:9])=[O:8].Cl[C:14]1[C:15]([CH3:23])=[CH:16][C:17]2[N:18]([CH:20]=[CH:21][N:22]=2)[N:19]=1>CN(C)C=O>[CH3:11][C:5]([CH3:12])([CH2:6][S:7](=[O:9])(=[O:8])[NH2:10])[CH2:4][O:3][C:14]1[C:15]([CH3:23])=[CH:16][C:17]2[N:18]([CH:20]=[CH:21][N:22]=2)[N:19]=1
Reactant: CC(C)(CO)CS(N)(=O)=O
Reactant: Cc1cc2nccn2nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2nccn2nc1OCC(C)(C)CS(N)(=O)=O
Temperature: 25 °C

Procedure:
1.12 g of 60% oily sodium hydride was suspended in 25 ml of dimethylformamide. To this suspension, 1.51 g of 3-hydroxy-2,2-dimethyl-1-propanesulfonamide was added, followed by stirring at room temperature (15° to 20° C.) under reduced pressure for i hour. To this mixture was added 1.51 g of 6-chloro-7-methylimidazo[1,2-b]pyridazine, followed by stirring at 60° C. for 2 hours. After dimethylformamide was distilled off underreduced pressure, ice water was added to the residue, which was subsequently adjusted to pH 6 by the addition of 5 N hydrochloric acid andthen extracted with tetrahydrofuran. The extract was washed with 20 ml of saturated saline and then dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with dichloromethane-ethyl acetate-methanol (5:5:1). The fraction containing the desired product was concentrated and recrystallized by the addition of ethyl ether-ethyl acetate (5:1). The resulting crystal was collected by filtration, to yield0.522 g of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])[NH2:8])([CH3:4])([CH3:3])[CH3:2].ClC[C:17]([N:19]=C=O)=[O:18].N12CCCN=C1CCCCC2>O1CCOCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:8][C:17]([NH2:19])=[O:18])[CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(I)cc(N)cc1C(C)(C)C
Reactant: O=C=NC(=O)CCl
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1c(I)cc(NC(N)=O)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-tert-butyl-5-iodo-4-methoxyaniline (915 mg, 3.0 mmol) in dioxane (20 mL) at 0° C. was added chloroacetyl isocyanate (0.256 mL, 3.00 mmol) dropwise to give a solution that was stirred at room temperature for 3 hours. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.904 mL, 6.00 mmol) was added and the solution was stirred for 18 hours and partitioned between ethyl acetate and 1 M HCl. The ethyl acetate was washed with H2O, brine and dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified on an Isco 40 g silica cartridge eluting with methanol/dichloromethane (0% to 5%) to give the title compound.
Reaction SMILES: NC1C([N+]([O-])=O)=C(N)C([N+]([O-])=O)=C(N)C=1[N+]([O-])=O.[Cl:19][C:20]1[C:21]([N+:35]([O-:37])=[O:36])=[C:22](OC)[C:23]([N+:30]([O-:32])=[O:31])=[C:24]([Cl:29])[C:25]=1[N+:26]([O-:28])=[O:27].S(Cl)([Cl:40])=O>CN(C)C=O>[Cl:19][C:20]1[C:21]([N+:35]([O-:37])=[O:36])=[C:22]([Cl:40])[C:23]([N+:30]([O-:32])=[O:31])=[C:24]([Cl:29])[C:25]=1[N+:26]([O-:28])=[O:27]
Reactant: O=S(Cl)Cl
Reactant: COc1c([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c(Cl)c1[N+](=O)[O-]
Agent: Nc1c([N+](=O)[O-])c(N)c([N+](=O)[O-])c(N)c1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(Cl)c([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1Cl

Procedure:
Preparation of 1,3,5-triamino-2,4,6-trinitrobenzene (TATB) from 3,5-dichloroanisole. Nitration of 3,5-dichloroanisole under relatively mild conditions gave 3,5-dichloro-2,4,6-trinitroanisole in high yield and purity. Ammonolysis of this latter compound gave the desired TATB. Another route to TATB was through the treatment of the 3,5-dichloro-2,4,6-trinitroanisole with thionyl chloride and dimethylformamide to yield 1,3,5-trichloro-2,4,6-trinitrobenzene. Ammonolysis of this product produced TATB.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([S:15][C:16]4[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=4[C:18](O)=[O:19])=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:3][CH2:2]1.CN.O1CCCC1.F[P-](F)(F)(F)(F)F.[N:40]1(OC(N(C)C)=[N+](C)C)[C:44]2N=CC=CC=2N=N1>CN(C)C=O>[CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([S:15][C:16]4[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=4[C:18]([NH:40][CH3:44])=[O:19])=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:2][CH2:3]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccccc1Sc1ccc2nc(NC(=O)C3CC3)cn2n1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)c1ccccc1Sc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 35 %

Procedure:
A mixture of 2-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)benzoic acid (120 mg, 0.35 mmol), a solution of methylamine in tetrahydrofuran (2M, 1 mL, 2.0 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (200 mg, 0.53 mmol) and N,N-dimethylformamide (4 mL) was stirred at room temperature for 5 hr. The mixture was evaporated under reduced pressure, ethyl acetate/tetrahydrofuran and water were added to the residue, and the aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×4). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=40/60→90/10) to give the title compound (45 mg, 41%) as a pale-yellow solid.
Reaction SMILES: [CH2:1]([N:9]=[C:10]=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:12][NH:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1>>[CH2:1]([NH:9][C:10](=[O:11])[N:13]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1)[CH3:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCOC(=O)CCc1ccc(-c2cccc(NC)c2)cc1
Reactant: CCCCCCCCN=C=O
Product: CCCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OCC)cc2)c1
Temperature: 100 °C
Yield: 101.3 %

Procedure:
464 μl (2.55 mmol, 1.5 eq) of octyl isocyanate are added to 482 mg (1.7 mmol, 1 eq) of ethyl 3-(3′-methylaminobiphenyl-4-yl)propanoate (prepared in Example 7c). The reaction mixture is heated at 100° C. by microwave for 30 minutes. The residue is chromatographed on silica gel (50 g FlashSmart Pack column) eluted with 70/30 heptane/ethyl acetate. 755 mg of ethyl 3-[3′-(3-octyl-1-methylureido)biphenyl-4-yl]propanoate are obtained in the form of a yellowish oil. Yield=100%
Reaction SMILES: [Li]CCCC.[C:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)#[N:7].Br[CH2:22][CH2:23][CH2:24][Cl:25].[NH4+].[Cl-]>O.C1COCC1>[Cl:25][CH2:24][CH2:23][CH2:22][C:8]1([C:6]#[N:7])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Reactant: ClCCCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C#N)(CCCCl)CC1
Temperature: 2.5 °C
Reaction time: 0.75 h
Yield: 86.5 %

Procedure:
Charge 1780 g of THF and 86.6 g of diisopropylanmine to R1. Cool the mixture in R1 to −40° C.˜−60° C. Add drop-wise 210.5 g of n-BuLi (1.6 eq) into R1 and stir the mixture for 0.5-1 hour. Charge 890 g of THF then 100.0 g of tert-butyl 4-cyanopiperidine-1-carboxylate into R2. Add the solution of tert-butyl 4-cyanopiperidine-1-carboxylate in R2 drop-wise to R1, controling the temperature at −40° C.˜−60° C. Stir the mixture in R1 for 1˜2 hour. Charge 890 g of THF and 130.5 g of 1-bromo-3-chloro-propane into R2. Add the solution of 1-bromo-3-chloro-propane in R2 drop-wise to R1, control the temperature at −40˜−60° C. Stir the mixture in R1 for 3 hours at −40˜−60° C. then slowly warm the mixture to 20˜25° C. and stir for 13˜16 hours. Cool the mixture to 0˜5° C. Add drop-wise 525 g of NH4Cl (saturated aqueous solution) then 500 g of water into R1. Concentrate the mixture to total weight 1000˜1100 g below 40° C. then add 380 g of MTBE. Stir the mixture at 10˜20° C. for 20-40 minutes then allow to stand for 30˜60 mins Separate the aqueous layer and wash the organic layer with 2×500 g of H2O. Concentrate the mixture to 300 g total weight below 50° C. Add 136 g of n-heptane then concentrate the mixture to 300 g total weight below 50° C. Cool the mixture 0-5° C., then add drop-wise 340 g of n-heptane. Stir the mixture in for 5˜10 hours, then filter the suspension. Rinse the flask with 68.0 g of n-heptane, then wash the cake to provide of tert-butyl 4-(3-chloropropyl)-4-cyano-piperidine-1-carboxylate (118 g, 87.2% Assay, 75.4% yield): mass spectrum (m/z): 231 (M+H-tBu). Transfer the cake to a flask and add 610.0 g of Toluene. Concentrate mixture to 500 g total weight below 50° C. The product is stored as a toluene solution until required.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[CH:12](O)=[O:13]>>[CH:12]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6])=[O:13]
Reactant: Cc1ccc(C(=O)O)cc1N
Reactant: O=CO
Product: Cc1ccc(C(=O)O)cc1NC=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3-amino-4-methylbenzoic acid (13) (22.139 g, 146.5 mmol) and 90% aqueous formic acid (200 mL) is heated at reflux for about 2 hours. The mixture is cooled to ambient temperature, added to ice water (400 mL) and stirred for about 15 minutes. The solids obtained are filtered and dried to obtain 3-(formylamino)-4-methylbenzoic acid (17), as a light flaky purple-pink solid (23.213 g, 88% yield).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:16])=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.C(OC([NH:24][C@@H:25]([CH2:29][O:30][CH3:31])[C:26](O)=O)=O)(C)(C)C.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:26]([C@@H:25]([NH2:24])[CH2:29][O:30][CH3:31])[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[C:3]=1[CH3:16]
Reactant: COC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1c(F)ccc(N)c1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC[C@H](N)c1nc2ccc(F)c(C)c2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
A mixture of 4-fluoro-3-methyl-N2-phenylbenzene-1,2-diamine (560 mg, 2.59 mmol), (S)-2-tertbutoxycarbonylamino-3-methoxypropionic acid (624 mg, 2.85 mmol), HOAt (388 mg, 2.85 mmol), 4-methylmorpholine (626 μL, 5.69 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (547 mg, 2.85 mmol) in DCM (10 mL) was stirred at RT for 1 h. The reaction mixture was partitioned between DCM and water. The aqueous phase was further extracted with DCM and the combined organic fractions washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was dissolved in 4N HCl in dioxane (5 mL) and the mixture heated at 70° C. for 2 h. The volatiles were removed in vacuo and the resulting residue partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The aqueous phase was further extracted with EtOAc and the combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford the title compound (545 mg, 70%). LCMS (Method C): RT 3.95 min [M+H]+ 300.2.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[C:8](=[O:24])[N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:10]([CH3:13])=[CH:11][CH:12]=1)=[O:6])[C:2]#[CH:3].[OH:25][N:26]=[C:27](Cl)[CH3:28].O>CCOC(C)=O>[CH3:28][C:27]1[CH:3]=[C:2]([CH2:1][NH:4][C:5]([C:7]2[C:8](=[O:24])[N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=3)[C:10]([CH3:13])=[CH:11][CH:12]=2)=[O:6])[O:25][N:26]=1
Reactant: C#CCNC(=O)c1ccc(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: CC(Cl)=NO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(CNC(=O)c2ccc(C)n(-c3cccc(C(F)(F)F)c3)c2=O)on1
Reaction time: 48 h
Yield: 52.8 %

Procedure:
The compound obtained in step (a) (0.050 g, 0.15 mmol) was dissolved in EtOAc (15 ml) under magnetic stirring. To this solution was added N-hydroxyacetimidoyl chloride (0.15 g, 1.6 mmol), water (0.3 ml) and KHCO3 (0.16 g, 1.6 mmol). The mixture was stirred for 2 days at which time LC-MS showed 90% conversion. The reaction was stopped and the mixture was partitioned between EtOAc (25 ml) and water (25 ml). The organic phase was washed (water, brine) and dried. Filtration and evaporation gave a crude mixture which was purified by chromatography on silica. Freeze-drying the pure fractions afforded the subtitle compound (0.031 g, 53%) as a white powder.
Reaction SMILES: [CH2:1]([O:7][C:8]([NH:10][C@@H:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:12]([OH:14])=O)=[O:9])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].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.[Cl:52][C:53]1[CH:54]=[CH:55][C:56]([CH:76]=[CH2:77])=[C:57]([C:59]2[CH:64]=[CH:63][C:62]([C@@:65]3([O:74][CH3:75])[CH2:69][NH:68][C@H:67]([C:70]([O:72][CH3:73])=[O:71])[CH2:66]3)=[CH:61][CH:60]=2)[CH:58]=1>C(Cl)Cl>[Cl:52][C:53]1[CH:54]=[CH:55][C:56]([CH:76]=[CH2:77])=[C:57]([C:59]2[CH:64]=[CH:63][C:62]([C@@:65]3([O:74][CH3:75])[CH2:69][N:68]([C:12](=[O:14])[C@@H:11]([NH:10][C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6])=[O:9])[C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:67]([C:70]([O:72][CH3:73])=[O:71])[CH2:66]3)=[CH:61][CH:60]=2)[CH:58]=1
Reactant: C=CCCCCOC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: C=Cc1ccc(Cl)cc1-c1ccc([C@@]2(OC)CN[C@H](C(=O)OC)C2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCCCOC(=O)N[C@H](C(=O)N1C[C@](OC)(c2ccc(-c3cc(Cl)ccc3C=C)cc2)C[C@H]1C(=O)OC)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
(S)-2-((hex-5-enyloxy)carbonylamino)-3,3-dimethylbutanoic acid (186 mg, 0.723 mmol), DIEA (0.303 mL, 1.735 mmol) and HATU (242 mg, 0.636 mmol) were added to a solution of (2S,4R)-methyl 4-(5′-chloro-2′-vinylbiphenyl-4-yl)-4-methoxypyrrolidine-2-carboxylate (215 mg, 0.578 mmol) in DCM (7 mL). The reaction was stirred at r.t. overnight. The reaction was evaporated and purified on the Biotage (10-50% EtOAc:Hex) to give (2S,4R)-methyl 4-(5′-chloro-2′-vinylbiphenyl-4-yl)-1-((S)-2-((hex-5-enyloxy)carbonylamino)-3,3-dimethylbutanoyl)-4-methoxypyrrolidine-2-carboxylate (13 mg, 0.201 mmol, 35% yield) as a colorless oil. LCMS: rt=2.58 min. [M+H]+=612; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25](O)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:28][C@@H:29]1[CH2:33][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@@H:31]([CH3:41])[CH2:30]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:28][C@@H:29]4[CH2:33][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@@H:31]([CH3:41])[CH2:30]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: C[C@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)O
Product: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1C[C@H](C)N(C(=O)OC(C)(C)C)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.g1) and commercially available tert-butyl (2S,4S)-4-amino-2-methylpyrrolidine-1-carboxylate the title compound is obtained as pale yellow foam.