Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:15][CH2:16][CH2:17][N:18]1[C:22]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:21][S:20][C:19]1=[N:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=1[O:38][CH3:39])[CH2:9][C:10](OCC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+].O>O1CCCC1>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([N:30]=[C:19]2[N:18]([CH2:17][CH2:16][CH2:15][N:8]([CH2:9][CH2:10][OH:11])[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:22]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)=[CH:21][S:20]2)=[C:32]([O:38][CH3:39])[CH:33]=1
Reactant: CCOC(=O)CN(CCCn1c(-c2ccc(F)cc2)csc1=Nc1ccc(Cl)cc1OC)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Cl)ccc1N=c1scc(-c2ccc(F)cc2)n1CCCN(CCO)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the compound (3 g) obtained in the above (1) in tetrahydrofuran (20 ml) was added lithium borohydride (170 mg), and the mixture was stirred at room temperature overnight. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [n-hexane:ethyl acetate (1:1)] to give the title compound (2.14 g) as amorphous.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([NH2:17])=[O:16].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15](=[O:16])[NH2:17])=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(N)=O
Temperature: 0 °C
Yield: 96 %

Procedure:
N-tert-butyloxycarbonyl glycine 1a (5 g, 28.56 mmol) and L-prolinamide (3.25 g, 28.50 mmol) were dissolved in 75 mL of N,N-dimethylformamide and the mixture was cooled to 0° C. Then 1-hydroxybenzotriazole (11.8 g, 87.3 mmol), N-ethyl-N′-(dimethylaminopropyl)-carbodiimide (11.3 g, 59 mmol) and triethylamine (12.1 mL, 87.3 mmol) were added with stirring. The reaction mixture was warmed up to room temperature and stirred overnight. The reaction was monitored by thin layer chromatography (TLC) until the disappearance of the starting materials. N,N-dimethylformamide was evaporated below 50° C. The resulting mixture was extracted with ethyl acetate (200 mL×3). The combined organic extracts were washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to obtain the title compound (S)-[2-(2-carbamoyl-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester 1b (7.42 g, yield 95.8%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]3[CH2:12][CH2:13][S:14][C:7]3=[N:6][C:5]=2[N:4]([CH3:15])[N:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>N1C=CC=CC=1>[C:16]([NH:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]3[CH2:12][CH2:13][S:14][C:7]3=[N:6][C:5]=2[N:4]([CH3:15])[N:3]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: Cn1nc(N)c2c(=O)n3c(nc21)SCC3
Solvent: c1ccncc1
Product: CC(=O)Nc1nn(C)c2nc3n(c(=O)c12)CCS3
Temperature: 50 °C
Reaction time: 6 h
Yield: 61.4 %

Procedure:
In 20 ml of pyridine was dissolved 2.00 g (8.96 mmol) of Compound 13 prepared in Example 10, and 1.23 ml (13.0 mmol) of acetic anhydride was added to the solution, followed by stirring at 50° C. for 6 hours. After evaporation of the solvent, the residue was subjected to partition between chloroform and water. The chloroform layer was washed with a dilute aqueous solution of hydrochloric acid and water, and concentrated to dryness under reduced pressure. The residue was recrystallized from chloroform/ethanol to give 1.46 g (62%) of Compound 20 in pure form.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.[NH2:16][C@H:17]([CH:25]([CH3:27])[CH3:26])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].[F:28][C:29]1[C:30]([CH:51]=O)=[C:31]2[C:37]([C:38]([O-:40])=[O:39])=[CH:36][N:35]([S:41]([C:44]3[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=3)(=[O:43])=[O:42])[C:32]2=[N:33][CH:34]=1>C(Cl)Cl>[C:21]([O:20][C:18](=[O:19])[C@H:17]([NH:16][CH2:51][C:30]1[C:29]([F:28])=[CH:34][N:33]=[C:32]2[N:35]([S:41]([C:44]3[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=3)(=[O:43])=[O:42])[CH:36]=[C:37]([C:38]([OH:40])=[O:39])[C:31]=12)[CH:25]([CH3:27])[CH3:26])([CH3:22])([CH3:24])[CH3:23]
Reactant: Cc1ccc(S(=O)(=O)n2cc(C(=O)[O-])c3c(C=O)c(F)cnc32)cc1
Reactant: CC(C)[C@@H](N)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(C(=O)O)c3c(CN[C@@H](C(=O)OC(C)(C)C)C(C)C)c(F)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of sodium triacetoxyborohydride (1.143 g, 5.39 mmol), (R)-tert-butyl 2-amino-3-methylbutanoate hydrochloride (1.131 g, 5.39 mmol) and DCM (20 mL) was stirred at room temperature for 10 min. The reaction mixture was cooled to 0° C. 5-fluoro-4-formyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (1.299 g, 3.60 mmol) was added and the reaction was stirred at 0° C. for 20 min to afford the title compound. [M+H] calc'd for C25H30FN3O6S, 520; found, 520.2.
Reaction SMILES: FC(F)(F)S(N1CCC(/C=C/C(O)=O)CC1)(=O)=O.[F:19][C:20]1[CH:21]=[C:22]([C@@H:27]([CH:31]2[CH2:36][CH2:35][N:34]([S:37]([C:40](F)(F)F)(=[O:39])=[O:38])[CH2:33][CH2:32]2)[CH2:28][CH:29]=[O:30])[CH:23]=[C:24]([F:26])[CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([C@@H:27]([CH:31]2[CH2:32][CH2:33][N:34]([S:37]([CH3:40])(=[O:39])=[O:38])[CH2:35][CH2:36]2)[CH2:28][CH:29]=[O:30])[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: O=CC[C@@H](c1cc(F)cc(F)c1)C1CCN(S(=O)(=O)C(F)(F)F)CC1
Agent: O=C(O)/C=C/C1CCN(S(=O)(=O)C(F)(F)F)CC1
Product: CS(=O)(=O)N1CCC([C@@H](CC=O)c2cc(F)cc(F)c2)CC1

Procedure:
In a similar manner but starting from (2E)-3-[1-(trifluoromethylsulfonyl)piperidin-4-yl]acrylic acid in step 1 was prepared (3R)-3-(3,5-difluorophenyl)-3-[1-(trifluoromethylsulfonyl)piperidin-4-yl]propanal.
Reaction SMILES: [CH:1]([OH:3])=O.OO.[C:6]1([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])C[CH2:9][CH2:8][CH:7]=1>>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[CH:6]1[CH2:7][CH2:8][CH2:9][C:1]1=[O:3]
Reactant: Fc1ccc(C2=CCCC2)c(F)c1
Reactant: O=CO
Agent: OO
Product: O=C1CCCC1c1ccc(F)cc1F
Temperature: 40 °C
Yield: 45.5 %

Procedure:
A mixture of 90% formic acid (26.4 mL, 689 mmol) and 30% hydrogen peroxide (6.0 mL, 39.2 mmol) was warmed at 40° C. for 10 min. The resulting solution was carefully added to 1-cyclopentenyl-2,4-difluorobenzene (7.064 g, 39.2 mmol) under stirring. The two-phase system was initially stirred at room temperature. After a certain period of time, a spontaneous exothermic reaction took place, and the temperature rose to about 50° C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched by careful addition of a saturated sodium bicarbonate solution. Ether was added and the content of the separatory funnel was vigorously shaken. The organic layer was separated and the aqueous layer was extracted with ether. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuum and the residue was purified by column chromatography on silica gel to give 2-(2,4-difluorophenyl)cyclopentanone (3.503 g, 17.85 mmol, 45.5% yield) as colorless oil. LC-MS (M+H)+=195.2. 1H NMR (500 MHz, CDCl3) δ ppm 7.08 (1H, td, J=8.4, 6.4 Hz), 6.76-6.86 (2H, m), 3.42 (1H, dd, J=12.2, 8.9 Hz), 2.42-2.53 (2H, m), 2.28-2.39 (1H, m), 2.13-2.23 (1H, m), 1.86-2.10 (2H, m).
Reaction SMILES: Br[C:2]1[C:3]([CH3:11])=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.[Cu][C:13]#[N:14]>CN(C=O)C>[C:13]([C:2]1[C:3]([CH3:11])=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2)#[N:14]
Reactant: N#C[Cu]
Reactant: Cc1c(Br)cnc2c1CCN2
Solvent: CN(C)C=O
Product: Cc1c(C#N)cnc2c1CCN2
Temperature: 180 °C

Procedure:
A stirred mixture of 5-bromo-4-methyl-7-azaindoline (270 mg, 1.27 mmol) and copper (I) cyanide (135 mg, 1.5 mmol) in DMF (0.3 mL) was heated to 180° C. for 4 h. The reaction mixture was cooled and partitioned between 5% potassium cyanide solution and ethyl acetate. The organic layer was dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash column chromatography (50% ethyl acetate/hexanes) to give the title compound:
Reaction SMILES: Cl.[C:2]1([CH:8]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:9]([NH:11][C@@H:12]([C:17]([NH:19][C@H:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH2:21][OH:22])=[O:18])[CH2:13][CH2:14][CH2:15][NH2:16])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37]([NH:47][C:48](=[N:51][C:52]([O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)=[O:53])SC)([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38].C(N(CC)CC)C.CCN(C(C)C)C(C)C>CN(C)C=O>[C:52]([NH:51][C:48](=[N:47][C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])[NH:16][CH2:15][CH2:14][CH2:13][C@@H:12]([C:17]([NH:19][C@H:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[CH2:21][OH:22])=[O:18])[NH:11][C:9](=[O:10])[CH:8]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([O:54][CH2:55][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)=[O:53]
Reactant: CSC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reactant: COc1ccc([C@H](CO)NC(=O)[C@@H](CCCN)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc([C@H](CO)NC(=O)[C@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Yield: 55 %

Procedure:
Prepared according to the method described in Example 4(f) above from (R)-N2 -(diphenylacetyl)-(R)-N-[2-hydroxy-1-(4-methoxyphenyl) ethyl]ornithine amide hydrochloride (0.57 g; 1.11 mmol; from step (d) above), N,N'-bis(Cbz)-S-methylisothiourea (0.44 g; 1.22 mmol), triethylamine (0.17 g; 1.67 mmol; instead of DiPEA) and dimethyl formamide (10 mL), 60 hours reaction time. Concentration under vacuum gave the crude product which was chromatographed on silica eluting with CH2Cl2 :EtOAc (3:1), then CH2Cl2 :EtOAc (1:1), to give pure sub-title compound as a solid (0.48 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][CH2:9][C:10](OCC)=[O:11])=[CH:6][CH:5]=[C:4]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[N:3]=1>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][O:15][C:4]2[CH:5]=[CH:6][C:7]3[N:8]=[CH:9][C:10](=[O:11])[NH:1][C:2]=3[N:3]=2)=[CH:18][CH:19]=1
Reactant: CCOC(=O)CNc1ccc(OCc2ccc(OC)cc2)nc1N
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: COc1ccc(COc2ccc3ncc(=O)[nH]c3n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
Ethyl N-[2-amino-6-({[4-(methyloxy)phenyl]methyl}oxy)-3-pyridinyl]glycinate (5 g, 15.1 mmol) was dissolved in toluene (500 mL) and heated at reflux for 2.5 days, the reaction was cooled to rt and manganese dioxide (2.4 g, 27.5 mmol) was added. After stirring for 5 h at room temperature 0.8 g of manganese dioxide were added and the reaction was stirred at room temperature overnight. The reaction was filtered through celite and the celite was washed with plenty of 20% methanol/DCM. The solvent were removed and the solid was triturated with diethyl ether, filtered off and washed with more diethyl ether to afford the title compound as a black solid (2.1 g, 50%).
Reaction SMILES: Cl.Cl.[I:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[N:10][C:11]=2[NH2:13])[N:6]([CH:14]2[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]2)[N:5]=1.[CH:20]1[C:32]2[CH:31]([CH2:33][O:34][C:35]([N:37]([CH3:44])[C:38]([CH3:43])([CH3:42])[C:39](O)=[O:40])=[O:36])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2N=CC=CC=2N=N1>ClCCl>[NH2:13][C:11]1[N:10]=[CH:9][N:8]=[C:7]2[N:6]([CH:14]3[CH2:19][CH2:18][CH2:17][N:16]([C:39](=[O:40])[C:38]([N:37]([CH3:44])[C:35](=[O:36])[O:34][CH2:33][CH:31]4[C:30]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:24]5[C:32]4=[CH:20][CH:21]=[CH:22][CH:23]=5)([CH3:43])[CH3:42])[CH2:15]3)[N:5]=[C:4]([I:3])[C:12]=12
Reactant: CN(C(=O)OCC1c2ccccc2-c2ccccc21)C(C)(C)C(=O)O
Reactant: Nc1ncnc2c1c(I)nn2C1CCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)OCC1c2ccccc2-c2ccccc21)C(C)(C)C(=O)N1CCCC(n2nc(I)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 11.9 %

Procedure:
A mixture of 3-iodo-1-(3-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (0.17 g, 0.00042 mol), 2-[[(9H-9-fluorenylmethoxy)carbonyl]-(methyl)amino]-2-methylpropanoic acid (0.175 g, 0.00052 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.1 g, 0.00052 mol), N,N-diisopropylethylamine (0.23 g, 0.0018 mol) and 1-hydroxy-7-azabenzotriazole (0.057 g, 0.00042 mol) in anhydrous dichloromethane (7 mL) was stirred for 18 hours at room temperature. Additional 2-[[(9H-9-fluorenylmethoxy)carbonyl](methyl)amino]-2-methylpropanoic acid (0.044 g, 0.00013 mol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.025 g, 0.00013 mol) were added to the reaction and stirred for 16 hours. The solvent was removed under reduced pressure. The residue was partitioned between brine and ethyl acetate. The aqueous layer was extracted with ethyl acetate, and the combined organic solvent was removed under reduced pressure, and the residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 20 min with 0.1 M ammonium acetate, 21 mL/min) to yield 9H-9-fluorenylmethyl N-{2-[3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidino]-1,1-dimethyl-2-oxoethyl}-N-methylcarbamate (0.030 g, 0.00005 mol). RP-HPLC (Delta Pak C18, 5 μm, 300A, 15 cm; 5%-85% acetonitrile—0.1M ammonium acetate over 10 min, 1 mL/min) Rt 11.2 min. MS: MH+ 666
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[Br:22].N([O-])=O.[Na+].[I-:27].[K+]>Cl.O>[Br:22][C:3]1[CH:4]=[C:5]([CH2:8][C@H:9]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][C:2]=1[I:27]
Reactant: COC(=O)[C@H](Cc1ccc(N)c(Br)c1)NC(=O)OC(C)(C)C
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(I)c(Br)c1)NC(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 72.9 %

Procedure:
Methyl (2S)-3-(4-amino-3-bromophenyl)-2-[(tert-butoxycarbonyl)amino]-propanoate (19.8 g, 53.0 mmol) suspended in 1 N aqueous hydrogen chloride (500 mL) was treated sequentially at 0° C. with sodium nitrite (3.66 g, 53.0 mmol) in water (75 mL) dropwise. After 15 minutes at 0° C., potassium iodide (8.81 g, 53.1 mmol) in water (75 mL) was added and the solution was heated at 40° C. for 15 minutes. The solution was quenched with saturated aqueous sodium thiosulfate solution (100 mL), and extracted with ethyl acetate (500 mL). The organic phase was washed with 0.1 N Hydrochloric acid solution (500 mL), saturated aqueous sodium bicarbonate solution (500 mL), and dried over sodium sulfate. Purification by silica gel chromatography (10–40% ethyl acetate/hexanes) afforded product as slightly yellow solid (18.7 g, 73%). 1H NMR (400 MHz, CD3OD): δ 7.80 (d, J=8.0 Hz, 1H), 7.55 (d, J=1.8 Hz, 1H), 6.92 (dd, J=8.0, 1.9 Hz), 4.36–4.29 (m, 1H), 3.71 (s, 3H), 3.10–2.79 (m, 1H), 1.37 (s, 9H); LCMS found for C15H19BrINO4Na (M+Na)+: m/z=506.
Reaction SMILES: [C:1]([N:3]=[C:4]([O-])[NH:5][C:6]1[CH:7]=[C:8]2[CH2:24][CH2:23][C:15]3([O:20][CH2:19][C:18]([CH3:22])([CH3:21])[CH2:17][O:16]3)[CH2:14][CH2:13][CH2:12][C:9]2=[N:10][CH:11]=1)#[N:2].[N:26]1[C:31]2[C:32]3[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=3[CH2:34][CH2:35][CH2:36][C:30]=2[CH:29]=[C:28]([NH:41][NH2:42])[N:27]=1>C(O)(C)C>[N:26]1[C:31]2[C:32]3[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=3[CH2:34][CH2:35][CH2:36][C:30]=2[CH:29]=[C:28]([N:41]2[C:1]([NH2:2])=[N:3][C:4]([NH:5][C:6]3[CH:7]=[C:8]4[CH2:24][CH2:23][C:15]5([O:20][CH2:19][C:18]([CH3:21])([CH3:22])[CH2:17][O:16]5)[CH2:14][CH2:13][CH2:12][C:9]4=[N:10][CH:11]=3)=[N:42]2)[N:27]=1
Reactant: CC1(C)COC2(CCCc3ncc(NC([O-])=NC#N)cc3CC2)OC1
Reactant: NNc1cc2c(nn1)-c1ccccc1CCC2
Solvent: CC(C)O
Product: CC1(C)COC2(CCCc3ncc(Nc4nc(N)n(-c5cc6c(nn5)-c5ccccc5CCC6)n4)cc3CC2)OC1
Temperature: 150 °C

Procedure:
A mixture of N′-cyano-N-(5′,5′-dimethyl-6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxane]-3-yl)carbamimidate (120 mg, 0.286 mmol) and (6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)hydrazine (65 mg, 0.286 mmol) in isopropyl alcohol (2 mL) was heated in microwave at 150° C. for 20 min, filtered, and washed with isopropanol to give 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N3-(5′,5′-dimethyl-6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxane]-3-yl)-1H-1,2,4-triazole-3,5-diamine, compound #247 (55 mg, 35%); 1H NMR (DMSO-d6, 300 MHz) 9.22 (s, 1H), 8.72 (d, 1H), 7.94 (s, 1H), 7.88 (s, 2H), 7.13 (m, 1H), 7.62 (d, 1H), 7.44 (m, 2H), 7.36 (m, 1H), 3.42 (s, 4H), 2.82 (t, 2H), 2.71 (m, 2H), 2.25 (m, 2H), 1.97 (d, 2H), 1.69 (m, 2H), 1.52 (m, 2H), 1.02 (d, 4H), 0.88 (d, 6H) ppm; MS (ES) 553.28 (M+H).
Reaction SMILES: O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].O.[C:15]([C:17]([C:28]1[CH:32]=[CH:31][S:30][CH:29]=1)([CH:25]([CH3:27])[CH3:26])[CH2:18][CH2:19][C:20](OCC)=[O:21])#[N:16]>>[C:15]([C:17]([C:28]1[CH:32]=[CH:31][S:30][CH:29]=1)([CH:25]([CH3:27])[CH3:26])[CH2:18][CH2:19][CH2:20][OH:21])#[N:16]
Reactant: CCOC(=O)CCC(C#N)(c1ccsc1)C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(C#N)(CCCO)c1ccsc1
Reaction time: 2 h
Yield: 94.6 %

Procedure:
A tetrahydrofuran solution (35 ml) in which ethyl 4-cyano-5-methyl-4-(3-thienyl)hexanoate (6.66 g) was dissolved was added dropwise to a tetrahydrofuran solution (50 ml) of lithium aluminum hydride (686 mg). After stirring for 2 hours, 2N aqueous NaOH and water were added to treat the mixture, and the resulting precipitates were filtered. The resulting filtrate was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a yellow oil (5.30 g, 95%).
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C.[C:32]([O:36][C:37](=[O:42])[NH:38][CH2:39][CH2:40]Br)([CH3:35])([CH3:34])[CH3:33]>CC#N.CCOC(C)=O>[C:32]([O:36][C:37]([NH:38][CH2:39][CH2:40][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=2)=[O:8])[CH2:2][CH2:3]1)=[O:42])([CH3:35])([CH3:34])[CH3:33]
Reactant: O=C(OCc1cc(Cl)cc(Cl)c1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCN1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
3,5-Dichlorobenzyl piperazine-1-carboxylate (Example 26, step 2) (3.466 mg, 11.99 mmol), potassium carbonate (4.97 g, 36 mmol) and triethlyamine (5.01 ml, 36 mmol) were suspended in MeCN (60 ml). tert-Butyl(2-bromoethyl)carbamate (3.49 g, 15.58 mmol) was added and the reaction mixture was refluxed for 18 hrs at 80° C. A further portion of tert-butyl(2-bromoethyl)carbamate (1.05 g, 4.69 mmol) was added and heating continued at 80° C. for 3 hrs. After cooling to RT, the reaction mixture was diluted with EtOAc and filtered. The organic portion was evaporated under reduced pressure. The crude product was solubilised in EtOAc and washed with 2M NaOH. The organic portion was dried over MgSO4 (anh) filtered and evaporated under reduced pressure. Purification by chromatography on silica using a gradient solvent system of DCM to 10% MeOH with ammonia in DCM afforded product fractions that were concentrated to give the title compound;
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:27]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([O:24][CH2:25][CH3:26])[CH:18]=2)[CH2:12][CH2:11]1)=[O:8].[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1>>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:13]2[CH2:14][CH2:15][CH:10]([NH:9][C:7](=[O:8])[C:6]3[CH:27]=[C:2]([NH:1][C:31]([CH:28]4[CH2:30][CH2:29]4)=[O:32])[CH:3]=[N:4][CH:5]=3)[CH2:11][CH2:12]2)=[CH:18][C:19]=1[O:24][CH2:25][CH3:26]
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cncc(N)c3)CC2)ccc1Cl
Reactant: O=C(Cl)C1CC1
Product: CCOc1cc(CN2CCC(NC(=O)c3cncc(NC(=O)C4CC4)c3)CC2)ccc1Cl
Yield: 26 %

Procedure:
The title compound (12 mg, 26%) was prepared analogously to example 7 by coupling of 5-amino-N-[1-(4-chloro-3-ethoxy-benzyl)piperidin-4-yl]-nicotinamide with cyclopropanecarbonyl chloride. MS: 457.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:18]=[CH:17][N:16]([S:19]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)(=[O:21])=[O:20])[C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)=[C:4]([O:29][CH2:30][CH:31]2[CH2:33][CH2:32]2)[C:3]=1[N+:34]([O-])=O.[Cl-].[NH4+]>C(OCC)(=O)C.CO.ClCCl.[Zn]>[NH2:34][C:3]1[C:4]([O:29][CH2:30][CH:31]2[CH2:33][CH2:32]2)=[C:5]([C:8]2[C:9]3[CH:18]=[CH:17][N:16]([S:19]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)(=[O:21])=[O:20])[C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc(N)c([N+](=O)[O-])c4OCC4CC4)cn(C)c(=O)c32)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc(N)c(N)c4OCC4CC4)cn(C)c(=O)c32)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 4-[4-amino-2-(cyclopropylmethoxy)-3-nitrophenyl]-6-methyl-1-[(4-methylphenyl)sulfonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (0.119 g, 0.234 mmol) in ethyl acetate (1.2 mL) and methanol (1.2 mL) was treated with saturated aqueous ammonium chloride solution (0.274 mL, 4.09 mmol). The mixture was cooled to 0° C., treated with zinc (0.122 g, 1.87 mmol) in two portions over 5 min, stirred at RT for 30 min and heated at 55° C. for 1 h. The reaction mixture was diluted with dichloromethane, filtered through a Celite pad, and the solids were washed with dichloromethane. The filtrate was concentrated to give a residue. The residue was dissolved in dichloromethane (30 mL), washed with saturated sodium bicarbonate solution (20 mL), dried with sodium sulfate, filtered, and concentrated to give the desired product that was used without further purification. LCMS calculated for C25H27N4O4S (M+H)+: m/z=479.2. found: 479.1.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:16]4[CH:30]=[CH:29][C:19]([CH2:20][N:21]5[CH2:25][C:24](=[O:26])[N:23]([CH3:27])[C:22]5=[O:28])=[CH:18][CH:17]=4)=[C:13]([CH:14]=[CH2:15])[C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1>CCO.[Pd]>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:16]4[CH:30]=[CH:29][C:19]([CH2:20][N:21]5[CH2:25][C:24](=[O:26])[N:23]([CH3:27])[C:22]5=[O:28])=[CH:18][CH:17]=4)=[C:13]([CH2:14][CH3:15])[C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1
Reactant: C=Cc1c(-c2ccc(CN3CC(=O)N(C)C3=O)cc2)ccc2c1nnn2CC1CC1
Agent: [Pd]
Solvent: CCO
Product: CCc1c(-c2ccc(CN3CC(=O)N(C)C3=O)cc2)ccc2c1nnn2CC1CC1
Reaction time: 18 h

Procedure:
To a solution of 1-{4-[1-(cyclopropylmethyl)-4-ethenyl-1H-benzotriazol-5-yl]benzyl}-3-methylimidazolidine-2,4-dione (68 mg, 0.17 mmol) in EtOH (1.7 mL) was added palladium on carbon (10 wt %, 9 mg). The mixture was sparged under an atmosphere of hydrogen (1 atm) and stirred for 18 hours. The mixture was filtered through Celite and washed with ethanol. The filtrate was concentrated in vacuo and purified via reverse phase HPLC (5-95% MeCN/water+0.1% TFA) to provide the title compound: 1H NMR (400 MHz, CDCl3) 7.31-7.43 (m, 6H), 4.65 (s, 2H), 4.53 (d, 2H, J=6.8 Hz), 3.83 (s, 2H), 3.13 (q, 2H, J=7.6 Hz), 3.09 (s, 3H), 1.40-1.48 (m, 1H), 1.26 (t, 3H, J=7.2 Hz), 0.66-0.71 (m, 2H), 0.50-0.54 (m, 2H) ppm. LRMS m/z (M+H) 404.3 found, 404.2 required.