Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][N:11]=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(O)=[O:16]>>[C:2]1([C:1]([C:8]2[CH:13]=[CH:12][N:11]=[N:10][CH:9]=2)=[O:16])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cc2ccnnc2)cc1
Reactant: CC(=O)O
Product: O=C(c1ccccc1)c1ccnnc1
Temperature: 100 °C
Yield: 91 %

Procedure:
A solution of 4-benzylpyridazine (1.0 g, 5.9 mmol) in AcOH (28 mL) was added dropwise to a stirring suspension of SeO2 (3.2 g, 29.5 mmol) in AcOH (28 mL), the resulting mixture was heated to 100° C. for 1 h. TLC showed the starting material had disappeared, then the reaction solution was filtrated, the filtration was concentrated under reduced pressure, and Sat.aq Na2CO3 was added to adjust PH=9-10, then, extracted with DCM (50 mL×3), washed by brine, dried over Na2SO4 and concentrated to get the phenyl(pyridazin-4-yl)methanone (1.0 g, yield: 91%). 1H NMR (CDCl3 400 MHz): δ9.50-9.45 (m, 2H), 7.83 (d, J=7.6 Hz, 2H), 7.78-7.74 (dd, J=5.2, 2.4 Hz, 1H), 7.74-7.68 (m, 1H), 7.57 (t, J=7.2 Hz, 2H).
Reaction SMILES: [C:1]([O:9][N:10]=[C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:12]1[CH2:16][CH2:15][CH2:14][N:13]1C(OC(C)(C)C)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.ClCCl>[CH2:1]([O:9][N:10]=[C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:12]1[CH2:16][CH2:15][CH2:14][NH:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=NOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(CON=C(c2ccccc2)C2CCCN2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
8 g (20 mmol) of tert-butyl 2-[[(benzoyloxy)imino](phenyl)methyl]-1-pyrrolidinecarboxylate dissolved in 400 ml of a mixture of 30% trifluoroacetic acid in dichloromethane are introduced into a 500 ml round-bottomed flask equipped with a magnetic stirrer, and the mixture is stirred for 4 hours at room temperature. After evaporating the reaction medium to dryness under reduced pressure, the residue is diluted with aqueous ammonia and dichloromethane, and the aqueous phase is separated out and extracted with dichloromethane. After washing the combined organic phases, drying over sodium sulfate and evaporating the solvent under reduced pressure, the residue is purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:12](OCC)=[O:13])[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[C:1]1([C:7]2[CH:8]=[C:9]([CH2:12][OH:13])[NH:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)c[nH]1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cc(-c2ccccc2)c[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.8 %

Procedure:
A solution of ethyl 4-phenyl-1H-pyrrole-2-carboxylate (1 g, 5.58 mmol) in tetrahydrofuran (10 mL) was added to a suspension of lithium aluminum hydride (300 mg, 8.10 mmol) in tetrahydrofuran (20 mL) at 0° C. The reaction mixture was slowly warmed to ambient temperature and stirred for 5 h. The mixture was slowly added to saturated sodium sulphate followed by extraction with ethyl acetate (2×25 mL). The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford (4-phenyl-1H-pyrrol-2-yl)methanol (800 mg, 84%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][OH:12].N[C:14](N)=[O:15].Cl>O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:14](=[O:15])[N:9]([CH2:10][CH2:11][OH:12])[C:3]=2[CH:4]=1
Reactant: Nc1ccc(Cl)cc1NCCO
Reactant: NC(N)=O
Agent: Cl
Solvent: O
Product: O=c1[nH]c2ccc(Cl)cc2n1CCO
Temperature: 190 °C
Yield: 57.1 %

Procedure:
A mixture of 20 parts of 2-[(2-amino-5-chlorophenyl)-amino]ethanol and 18 parts of urea is stirred and heated for 4 hours in an oil-bath at about 190° C. The reaction mixture is cooled and dissolved in alkaline water. The solution is acidified with a concentrated hydrochloric acid solution. The precipitated product is filtered off, washed with water and dried, yielding 13 parts (57.1%) of 6-chloro-1,3-dihydro-1-(2-hydroxyethyl)-2H-benzimidazol-2-one; mp. 160° C.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][CH2:14][C@H:15]1[C:19](=[O:20])[O:18][CH2:17][C@@H:16]1[CH2:21][C:22]1[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=1.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.Cl>CCCCCC.O1CCCC1>[CH3:13][CH2:14][C@@H:15]1[C:19](=[O:20])[O:18][CH2:17][C@@H:16]1[CH2:21][C:22]1[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=1
Reactant: CC[C@H]1C(=O)OC[C@@H]1Cc1cncn1C
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC[C@@H]1C(=O)OC[C@@H]1Cc1cncn1C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
0.97 ml of a 15% solution of n-butyllithium in hexane is added at 0° C. to a solution of 0.21 ml of diisopropylamine in tetrahydrofuran. After stirring for 15 minutes and cooling to -78° C., 100 mg of (+)-isopilocarpine dissolved in 1 ml of tetrahydrofuran are added, and the mixture is stirred at -78° C. for 10 hours. After the addition of 1 g of 2,6-di-tert.-butyl-4-methylphenol, warming to room temperature and addition of 15 ml of hydrochloric acid (0.5 N), the layers are separated. The aqueous layer is washed twice with 25 ml of chloroform. Concentration of the organic layer and preparative separation on an HPLC column gives optically pure (+)-pilocarpine which is converted into the pilocarpine nitrate, m.p. 174° C., αD =+81° (c=1.618, water) with nitric acid (65%) in ethanol. Reference1 : R. S. Compagnone, H. Rapoport, J. Org. Chem. 51, 1713-1719 (1986)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1([C:14](=[O:15])NC(=O)[NH:11]1)[CH2:6][CH2:5]2.O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].C(=O)=[O:30]>O>[NH2:11][C:7]1([C:14]([OH:15])=[O:30])[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: O=C=O
Reactant: O=C1NC(=O)C2(CCc3cc(Cl)ccc32)N1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Product: NC1(C(=O)O)CCc2cc(Cl)ccc21
Temperature: 120 °C

Procedure:
A mixture of (+/−)-5′-chloro-spiro[imidazolidine-4,1′indan]-2,5-dione (473 mg, 2 mmol) in water (55 mL) containing barium hydroxide nonahydrate (3.06 gm, 10 mmol) was sealed in a screw-top vessel and heated at 120° C. for 22 hours. The reaction suspension was cooled, the vessel opened and the mixture diluted to ˜200 mL with water. This suspension was brought to boil and small pieces of solid carbon dioxide were added over a 1-2 hour period. The heat was removed and the suspension was filtered while still very warm. The aqueous filtrate was concentrated under vacuum and the residue redissolved in water (30 mL). A few drops of sulfuric acid were added and any suspended material removed by filtration before concentrating the aqueous solution to dryness. This residue was triturated with methanol and several crops of the crude title compound were obtained. This material was used as is.
Reaction SMILES: [C:1]([NH:5][C:6](=[NH:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].Br[C:10](=[CH:14]OC)[C:11](=[O:13])[CH3:12].C(N(CC)CC)C>S(=O)(=O)(O)O>[C:11]([C:10]1[N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([CH3:7])=[N:8][CH:14]=1)(=[O:13])[CH3:12]
Reactant: COC=C(Br)C(C)=O
Reactant: CC(=N)NC(C)(C)C
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Product: CC(=O)c1cnc(C)n1C(C)(C)C
Temperature: 120 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
In a 300 mL-volume glass vessel equipped with a stirrer, a thermometer and a dropping funnel, 18.5 g (0.162 mol) of N-tert-butylacetamidine (which was prepared in the above-mentioned Reference Example 3), 19.3 g (0.108 mol) of 3-bromo-4-methoxy-3-buten-2-one and 16.4 g (0.162 mol) of triethylamine were placed. The mixture was heated to 120° C. under stirring for 8 hours for carrying out reaction. After the reaction was complete, 80 mL of sulfuric acid (2 mol/L) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The concentrate was washed with methyl isobutyl ketone, and the aqueous portion was taken out. The aqueous portion was made basic by adding an aqueous 48% sodium hydroxide, while the mixture was kept at a temperature of not higher than 40° C. The aqueous basic portion was subjected to extraction with methyl isobutyl ketone, and the extracted portion was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluant: ethyl acetate) to give 4.86 g (yield: 25%) of 5-acetyl-1-tert-butyl-2-methyl-imidazole.
Reaction SMILES: FC(F)(F)C(O)=O.COC(=O)CC1CC2C(=CC(OCCCCNC(N)=N)=CC=2)NC1=O.C[O:34][C:35](=[O:62])[CH2:36][C:37]1[C:38](=[O:61])[N:39]([CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:40]2[C:45]([CH:46]=1)=[CH:44][CH:43]=[C:42]([O:47][CH2:48][CH2:49][NH:50][C:51]([NH2:53])=[NH:52])[CH:41]=2>>[CH2:54]([N:39]1[C:40]2[C:45](=[CH:44][CH:43]=[C:42]([O:47][CH2:48][CH2:49][NH:50][C:51]([NH2:53])=[NH:52])[CH:41]=2)[CH:46]=[C:37]([CH2:36][C:35]([OH:62])=[O:34])[C:38]1=[O:61])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: COC(=O)Cc1cc2ccc(OCCNC(=N)N)cc2n(Cc2ccccc2)c1=O
Agent: COC(=O)CC1Cc2ccc(OCCCCNC(=N)N)cc2NC1=O
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)NCCOc1ccc2cc(CC(=O)O)c(=O)n(Cc3ccccc3)c2c1

Procedure:
The title compound is prepared according to the procedure of Example 84 except that [7-(4-guanidino-butoxy)-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]acetic acid methyl ester trifluoroacetate is replaced with [1-benzyl-7-(2-guanidino-ethoxy)-2-oxo-1,2-dihydro-quinolin-3-yl]acetic acid methyl ester.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][N:23]4[CH2:26][CH:25]([C:27]5[N:31]=[C:30]([C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=6)[NH:29][N:28]=5)[CH2:24]4)=[CH:18][CH:17]=3)=[N:9][C:10]3[N:11]([CH:13]=[CH:14][N:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:38]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:38][C:13]1[N:11]2[CH:12]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][N:23]4[CH2:24][CH:25]([C:27]5[N:31]=[C:30]([C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=6)[NH:29][N:28]=5)[CH2:26]4)=[CH:18][CH:17]=3)=[N:9][C:10]2=[N:15][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(-c2cn3ccnc3nc2-c2ccc(CN3CC(c4n[nH]c(-c5ccccn5)n4)C3)cc2)cc1
Solvent: ClC(Cl)Cl
Product: Brc1cnc2nc(-c3ccc(CN4CC(c5n[nH]c(-c6ccccn6)n5)C4)cc3)c(-c3ccccc3)cn12
Yield: 11.3 %

Procedure:
143 mg (0.3 mmol) 6-Phenyl-7-{4-{3-[5-(pyridine-2-yl)-1H-[1,2,4]triazole-3-yl)azetidine-1-ylmethyl]-phenyl}-imidazo[1,2-a]pyrimidine are dissolved in 11.8 mL chloroform. 57.8 mg (0.3 mmol) N-bromosuccinimide are added and the reaction mixture is heated for one hour at reflux. The solvent is evaporated and the residue is purified by chromatography (silicagel, eluents: dichloromethane/methanol). 19.1 mg (10%) pure compound and 75.8 mg (41%) slightly contaminated product are obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[F:15][C:16]([F:26])([F:25])[O:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>>[F:15][C:16]([F:25])([F:26])[O:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH:21][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Reactant: Nc1cccc(OC(F)(F)F)c1
Product: Cc1cc(Nc2cccc(OC(F)(F)F)c2)nc(-c2ccccn2)n1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and 3-(trifluoromethoxy)aniline (65 μl, 0.243 mmol) similar to Example 11 and isolated as a pale white solid (78 mg, 93%). 1H NMR (DMSO-d6): 9.95 (s, 1H), 8.74 (s, 1H), 8.31 (d, J=9.3 Hz, 2H), 7.95 (t, J=7.7 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.53-7.43 (m, 2H), 6.98 (d, J=8.4 Hz, 1H), 6.71 (s, 1H), 2.44 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[NH:9][N:8]=[C:7]([C:10]([NH2:12])=[O:11])[C:6]=1[N+:13]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[NH2:13][C:6]1[C:7]([C:10]([NH2:12])=[O:11])=[N:8][NH:9][C:5]=1[C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1[nH]nc(C(N)=O)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)c1[nH]nc(C(N)=O)c1N
Yield: 77.4 %

Procedure:
5-tert-Butyl-4-nitro-1H-pyrazol-3-carboxylic acid amide (4.6 g, 21 mmol) and 10% palladium on carbon (300 mg) in ethanol (80 ml) was stirred under hydrogen (60 psi) at room temperature for 18 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was pre-absorbed onto silica gel and purified by flash column chromatography eluting with a solvent gradient of dichloromethane: methanol (100:0 changing to 95:5 then 90:10, by volume) to give 4-amino-5-tert-butyl-1H-pyrazol-3-carboxylic acid amide (2.96 g) as an off-white solid, which was a mixture of rotamers. 1H NMR (400 MHz, DMSO-D6): δ=12.10-12.20 (0.75H, brs), 11.75-11.85 (0.25H, brs), 7.04-7.16 (1.5H, brs), 6.88-6.96 (0.5H, brs), 4.27-4.59 (2H, 2×brs), 1.12 (9H, s) ppm. LRMS (electrospray): m/z [M+H]+ 183, [M+Na]+ 205, [M−H]+ 181. Anal. Found C, 52.45; H, 7.84; N, 30.62. C8H14N4O requires C, 52.73; H, 7.74; N, 30.75%.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH2:7][O:8][C:9]2[C:10]3[N:14]=[CH:13][NH:12][C:11]=3[N:15]=[C:16](N)[N:17]=2)=[CH:5][CH:6]=1.[H+].[B-](F)(F)(F)[F:21].N([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH:1]1[CH:2]=[CH:3][C:4]([CH2:7][O:8][C:9]2[C:10]3[NH:14][CH:13]=[N:12][C:11]=3[N:15]=[C:16]([F:21])[N:17]=2)=[CH:5][CH:6]=1
Reactant: F[B-](F)(F)F
Reactant: Nc1nc(OCc2ccccc2)c2nc[nH]c2n1
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [H+]
Solvent: O
Product: Fc1nc(OCc2ccccc2)c2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
O6 -Benzylguanine (1.21 g, 5 mmol) was added to 100 mL of 48% fluoboric acid at -20° C.. Sodium nitrite (1.23 g, 35 mmole) was dissolved in water (5 mL) and 2.5 mL of this sodium nitrite solution was added slowly to the cold fluoboric acid solution. The resulting mixture was stirred for 1 h at or below -15° C. Additional fluoboric acid (25 mL) was added followed by an additional 2.5 mL of the aqueous sodium nitrite solution. After stirring for an additional 1 h below -15° C., fluoboric acid (25 mL) was again added and stirring was continued for 1 h. The resulting solution was neutralized with saturated aqueous sodium carbonate solution at -20° C. and was allowed to warm to room temperature. A white precipitate that formed was collected by filtration and was washed with water and dried under vacuum to afford crude 4c: yield, 0.52 g, 43%. An analytical sample was prepared by chromatography on a Sephadex LH-20 column (3×80 cm) eluted with methanol/water (1:1) at 1 mL/min. The desired 4c eluted in fractions 66-77: mp 182°-183° C. (184°-185° C.; Robins and Robins, J. Org. Chem., 34, 2160-2163 (1969)); UV (pH 1) λmax 256 nm (ε=1.117×104) ; (pH 6.9) 257 (1.078×104) (pH 13) 264 (1.063×104); 1H NMR δ5.60 (s, 2H, ArCH2), 7.37-7.57 (m, 5H, ArH), 8.40 (s, 1H, H-8), 13.60 (s, 1H, NH, exchanges with D2O), 19F NMR δ23.54 downfield from trifluoroacetic acid standard; MS (EI) calcd. m/z for C12H9 FN4O 244.0760, found 244.0756; Anal. (C12H9FN4 O.2/3 H2O) C, H, N.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:5]([O:14]C)=[CH:4][CH:3]=1.[CH3:16][S-:17].[Na+]>CN(C)C=O>[CH3:16][S:17][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:5]([OH:14])=[CH:4][CH:3]=1
Reactant: COc1ccc(F)nc1-c1cccnc1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(O)c(-c2cccnc2)n1
Temperature: 160 °C
Reaction time: 4 h
Yield: 40.5 %

Procedure:
6-Fluoro-3-methoxy-[2,3′]bipyridine (30 mg) and sodium thiomethoxide (103 mg) were suspended in N,N-dimethylformamide (1.5 ml), and the suspension was stirred at 160° C. for 4 hr. The reaction solution was cooled to room temperature, the reaction solution was filtered, and the solvent was removed from the filtrate by distillation under the reduced pressure. The residue was purified by thin layer chromatography using chloroform-methanol to give 6-methylsulfanyl-[2,3′]bipyridin-3-ol (13 mg, yield 45%).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[N:6][C:7]3[C:12]([C:13]=2[CH2:14][N:15]2[C:21](=[O:22])[C@@H:20]([NH:23][C:24](=[O:36])[C@@H:25]([N:27](C)[C:28](=O)OC(C)(C)C)[CH3:26])[C@H:19]([CH3:37])[N:18]([C:38]([CH:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)=[O:39])[C:17]4[CH:46]=[CH:47][CH:48]=[CH:49][C:16]2=4)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:3][CH2:2]1.[ClH:50]>O1CCOCC1.CCOCC>[ClH:50].[CH:1]1([C:4]2[CH:5]=[N:6][C:7]3[C:12]([C:13]=2[CH2:14][N:15]2[C:21](=[O:22])[C@@H:20]([NH:23][C:24](=[O:36])[C@@H:25]([NH:27][CH3:28])[CH3:26])[C@H:19]([CH3:37])[N:18]([C:38]([CH:40]4[CH2:41][CH2:42][O:43][CH2:44][CH2:45]4)=[O:39])[C:17]4[CH:46]=[CH:47][CH:48]=[CH:49][C:16]2=4)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:2][CH2:3]1
Reactant: C[C@@H](C(=O)N[C@@H]1C(=O)N(Cc2c(C3CC3)cnc3ccccc23)c2ccccc2N(C(=O)C2CCOCC2)[C@H]1C)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(C3CC3)cnc3ccccc23)c2ccccc2N(C(=O)C2CCOCC2)[C@H]1C
Yield: 95 %

Procedure:
A rt solution of tert-butyl(S)-1-((3S,4S)-1-((3-cyclopropylquinolin-4-yl)methyl)-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (78 mg, 116 μmol) in 4 M HCl in dioxane (582 μl) was stirred for 2 h. The reaction was diluted with Et2O and the solids were collected by vacuum filtration, taken up in MeCN—H2O, and lyophilized to provide (S)-N-((3S,4S)-1-((3-cyclopropylquinolin-4-yl)methyl)-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride (66.8 mg, 95%) as an off-white solid. MS m/z 570 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[C:12]([O:17][CH2:18][CH3:19])(=[O:16])[C:13]([O-])=[O:14].N12CCCN=C1CCCCC2.C(OCC)(=O)C>C(O)(=O)C.O>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:13](=[O:14])[C:12]([O:17][CH2:18][CH3:19])=[O:16])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Cc1cc(F)ncc1[N+](=O)[O-]
Reactant: CCOC(=O)C(=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C(=O)Cc1cc(F)ncc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 46.6 %

Procedure:
2 g (12.81 mmol) of 2-fluoro-4-methyl-5-nitropyridine and 9.36 g (32.03 mmol) of ethyl oxalate are placed in a 100 ml three-necked flask equipped with a magnetic stirrer and maintained under a flush of nitrogen. 2.11 ml (14.09 mmol) of 1,8-diazabicyclo-[5.4.0]undec-7-ene are then added to the reaction medium stirred at room temperature. The reaction mixture is then stirred at room temperature for 4 hours. A mixture of ethyl acetate (100 ml), water (40 ml) and acetic acid (2 ml) is then added. The mixture is extracted twice with ethyl acetate. The combined organic phases are washed with 100 ml of water and with 100 ml of saturated aqueous sodium chloride solution, dried over sodium sulfate and then concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of heptane and ethyl acetate. 1.53 g of product are thus isolated, and are used without further purification in the following step.
Reaction SMILES: [CH2:1]([CH:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C.[Br:46][CH2:47][CH2:48][C:49](Cl)=[O:50]>C(Cl)Cl>[Br:46][CH2:47][CH2:48][C:49]([O:20][CH:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:50]
Reactant: O=C(Cl)CCBr
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(O)CCCCCCCC/C=C\C/C=C\CCCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC/C=C\C/C=C\CCCCCCCCC(CCCCCCCC/C=C\C/C=C\CCCCC)OC(=O)CCBr
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of dilinoleylmethanol (II, 560 mg, 1 mmol) and dry triethylamine (0.44 g, 4.2 mmol) in 50 mL of anhydrous CH2Cl2 was added dropwise 3-bromopropionyl chloride (technical grade, 0.34 mL) under nitrogen. The resulting mixture was stirred at room temperature for 3 days. The organic phase was diluted with 50 mL of dichloromethane and washed with water (3×50 mL), brine (50 mL), and dried over anhydrous Na2SO4. The solvent was evaporated to afford 610 mg of brownish oil as a crude product. The crude product was purified by column chromatography on silica gel (230-400 mesh, 100 mL) with 0-3% ethyl acetate gradient in hexanes as eluent. This resulted in 540 g of a mixture of III as a major product and a by-product. The mixture was used in the following step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:14]([C:15]([O:17]N2C3C=CC=CC=3N=N2)=O)=[C:5]2[N:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][C:29]=1[NH2:34]>CN1C(=O)CCC1>[NH2:1][C:2]1[C:14]([C:15]([NH:34][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][C:28]=2[CH3:27])=[O:17])=[C:5]2[N:6]=[C:7]([C:10]([F:11])([F:12])[F:13])[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: Cc1ccncc1N
Reactant: Nc1nn2ccc(C(F)(F)F)nc2c1C(=O)On1nnc2ccccc21
Solvent: CN1CCCC1=O
Product: Cc1ccncc1NC(=O)c1c(N)nn2ccc(C(F)(F)F)nc12
Temperature: 100 °C
Reaction time: 17 h

Procedure:
To a solution of benzotriazol-1-yl 2-amino-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate 6a (150 mg, 0.4129 mmol) in NMP (1.666 mL) was added 4-methylpyridin-3-amine (44.65 mg, 0.4129 mmol) and the reaction mixture was stirred at 100° C. for 17 hours in a sealed tube. The solid precipitate was filtered and dried under vacuum to afford the desired Compound I-C-1 as a yellow powder (60.4 mg, 42%). LC-MS (M+H)+ 337.2; 1H NMR (500 MHz, DMSO-d6) δ 9.45 (s, 1H), 9.40 (s, 1H), 9.30 (dd, J=6.9, 0.6 Hz, 1H), 8.22 (d, J=4.7 Hz, 1H), 7.52 (d, J=6.9 Hz, 1H), 7.33 (d, J=4.8 Hz, 1H), 7.01 (s, 2H), 2.42 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11](=[O:12])[CH:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:9][C:8]2=[O:20])[CH2:3][CH2:2]1.[CH3:21][C:22]([CH3:34])([O:24][C:25]([N:27]1[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1)=[O:26])[CH3:23].C(O)C.C([BH3-])#N.[Na+]>[Ti+4].CC(C)[O-].O.C(O)(=O)C>[CH3:23][C:22]([CH3:34])([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[C:11](=[O:12])[CH:10]([CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[NH:9][C:8]3=[O:20])[CH2:3][CH2:2]2)[CH2:29][CH2:28]1)=[O:26])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=C1NC(Cc2ccccc2)C(=O)N1C1CCNCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(N3C(=O)NC(Cc4ccccc4)C3=O)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 5.5 g (20.2 mmol) of 3-(4-piperidinyl)-5-(phenylmethyl)-imidazolidin-2,4-dione, 4.0 g (20.1 mmol) of 1-(1,1-dimethylethoxycarbonyl)-4-piperidinone, 8 ml (20 mmol) of titanium(IV)-isopropoxide and 100 ml of anhydrous ethanol was stirred for 1 hour at ambient temperature. Then 0.89 g (13.45 mmol) of 95% sodium cyanoborohydride was added, the mixture was adjusted to pH 5 by the dropwise addition of glacial acetic acid and stirred overnight at ambient temperature. The mixture was stirred into 200 ml of water and freed from the precipitate formed. The filtrate was evaporated down in vacuo until no more ethanol passed over, the aqueous phase remaining was made alkaline with sodium hydroxide and extracted exhaustively with dichloromethane. Conventional working up of the extracts yielded 5.0 g (54% of theoretical) of colourless crystals.