Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[N:10][C:5]2=[C:4](Cl)[CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[Cl:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[N:10][C:5]2=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1
Reactant: Nc1ccccc1
Reactant: Clc1cc(Cl)c2nc[nH]c2n1
Solvent: CO
Product: Clc1cc(Nc2ccccc2)c2nc[nH]c2n1

Procedure:
5,7-Dichloro-3H-imidazo[4,5-b]pyridine (4.4 g, 23.3 mMol) was heated with 50 mL of aniline at 135° C. under a nitrogen atmosphere. After 48 hours the reaction mixture was cooled and diluted with 50 mL methanol. The 5-chloro-7-anilino-3H-imidazo[4,5-b]pyridine was isolated and washed with methanol. The dried solid weighed 4.8 g. Yield 19.6 mMol, 84%; m.p. >300° C.; NMR (DMSO-d6): 9.23 δ (s, 1H, NH-anilino); 8.24 (s, 1H, H2); 7.44-7.37 (m, 5H, aromatic); 6.69 (s, 1H, H5).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([C:11](=O)[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:9]([CH3:21])[O:8][N:7]=1)=O)C.O.[NH2:23][NH2:24]>C(O)C>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[C:10]3[C:6](=[N:7][O:8][C:9]=3[CH3:21])[C:4](=[O:3])[NH:23][N:24]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1noc(C)c1C(=O)c1ccc(OC)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2n[nH]c(=O)c3noc(C)c23)cc1
Yield: 93.8 %

Procedure:
A solution of 2.47 g of 4-(4-methoxybenzoyl)-5-methylisoxazole-3-carboxylic acid ethyl ester (8.54 mmol) and 0.598 mL of hydrazine monohydrate (12.0 mmol) in 18.4 mL ethanol was stirred at room temperature for 19 hours. The heterogeneous reaction was cooled in an ice bath then filtered off the white solid, washing with cold ethanol then diethyl ether. Dried on under high vacuum to give 2.06 g (92%) of 4-(4-methoxyphenyl)-3-methyl-6h-isoxazolo[3,4-d]pyridazin-7-one.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:21]1([O:27][C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>ClCCl>[C:21]1([O:27][C:28]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Oc2ccccc2)CC1
Reaction time: 12 h

Procedure:
To a solution of 1.0 g tert-butyl 1-piperazinecarboxylate and 1.5 ml triethylamine in 5 ml dichloromethane were added at 0° C. 0.8 ml phenylchloroformate. After stirring for 12 h, 2 ml of water were added and the mixture loaded on a chem Elute® cartridge. Elution with dichloromethane yielded the crude product which was used in the subsequent reaction.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][C:14](=[O:16])[CH3:15])=[C:7]([CH3:17])[C:6]=1[CH2:18][CH:19]=O)(=[O:3])[CH3:2].[C:21]([CH:26]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:23][CH2:24][CH3:25])=[O:22]>>[C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][C:14](=[O:16])[CH3:15])=[C:7]([CH3:17])[C:6]=1[CH2:18]/[CH:19]=[CH:26]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C)c(C)c(OC(C)=O)c(CC=O)c1C
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)/C=C/Cc1c(C)c(OC(C)=O)c(C)c(C)c1OC(C)=O

Procedure:
In the first step a condensation according to Wittig is carried out between 2,5-diacetyloxy-3,4,6-trimethylphenylacetaldehyde and carboethoxymethylentriphenylphosphorane, dissolving the two compounds in a suitable organic solvent under stirring, bringing then the solution to boil and refluxing it for a sufficiently long time. By evaporation of the solvent, ethyl trans-4-(2,5-diacetyloxy-3,4,6-trimethylphenyl)-2-butenoate is obtained, which is crystallized by a suitable solvent.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:11]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:19])[CH:7]=3)=[CH:4][C:3]=1[F:20].BrC1C(=O)C(Br)=C(Br)C(C)([N+:29]([O-:31])=[O:30])C=1Br>FC(F)(F)C(O)=O.CCOC(C)=O>[NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:11]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:19])[C:7]=3[N+:29]([O-:31])=[O:30])=[CH:4][C:3]=1[F:20]
Reactant: CC1([N+](=O)[O-])C(Br)=C(Br)C(=O)C(Br)=C1Br
Reactant: CCCCC12CCC(=O)C=C1c1cc(F)c(N)cc1C2
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCC12CCC(=O)C([N+](=O)[O-])=C1c1cc(F)c(N)cc1C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 7-amino-9a-butyl-6-fluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (34.6 mg, 0.126 mmol) in trifluoroacetic acid (0.25 mL) was treated with 2,3,5,6-tetrabromo-4-methyl-4-nitro-2,5-cyclohexadien-1-one (59 mg, 0.126 mmol). The resulting mixture was placed under a N2 atmosphere, sonicated briefly, and stirred at room temperature for one hour. The mixture was diluted with EtOAc (15 mL), washed successively with water, 5% NaHCO3 and brine, dried over MgSO4, filtered, and evaporated under vacuum to a brown oil (86 mg). The crude product was purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate, developing with 2:1 hexanes-EtOAc. The major UV visible band was eluted with 5% MeOH in CH2Cl2, the eluant was concentrated under vacuum to an orange oil (16 mg, 40%), and the oil was lyophilized from benzene to afford 7-amino-9a-butyl-6-fluoro-4-nitro-1,2,9,9a-tetrahydro-3H-fluoren-3-one as an amorphous solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:6][O:7][C:8]2[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[CH:10][C:9]=2[C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH2:20][CH2:21][C:22]3=[O:27])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:35](Cl)(=[O:40])[O:36][CH:37]([CH3:39])[CH3:38]>ClCCl>[CH:37]([O:36][C:35](=[O:40])[NH:1][CH2:2][C:3]1([CH2:6][O:7][C:8]2[C:9]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C:22]4=[O:27])=[CH:10][CH:11]=[C:12]([O:16][CH3:17])[C:13]=2[O:14][CH3:15])[CH2:4][CH2:5]1)([CH3:39])[CH3:38]
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CN)CC2)c1OC
Reactant: CC(C)OC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CNC(=O)OC(C)C)CC2)c1OC

Procedure:
To a stirring solution of 4-[2-(1-Aminomethyl-cyclopropylmethoxy)-3,4-dimethoxy-phenyl]-indan-1-one (Compound 182) (150 mg, 0.272 mmol) in dichloromethane (10 mL), were added triethylamine (0.082 g, 0.811 mmol) and isopropyl carbonochloridate (66 mg, 0.544 mmol) and the resultant reaction mixture was subjected to the conditions used in the preparation of Compound 183 to afford the title compound as a solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][NH:6][CH2:7][CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1.N1CC[CH2:21]NN1.ClNCC1C=CC=CC=1>O.CN(C)C=O>[ClH:2].[Cl:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:7][CH2:8][C:9]2[S:10][CH:11]=[CH:12][C:13]=2[CH2:21]1
Reactant: C1CNNNC1
Reactant: Clc1ccccc1CNCCc1cccs1
Agent: Cl
Agent: ClNCc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccccc1CN1CCc2sccc2C1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To 42 ml dimethylformamide in which are dissolved 0.25 mole gaseous hydrochloric acid and heated at 40° C. is added, over 2 minutes, a mixture of 25.15 g (0.1 M) N-(2-chloro-benzyl)-2-(2-thienyl)ethylamine and 15.3 g (0.033 M) s.hexahydrotriazine of o.chlorobenzylamine. The reaction is exothermal and, during the addition, the reaction must be cooled with water to maintain the temperature of the reaction medium below 70° C. After completion of the addition, stirring is continued for a further 30 minutes and the material is then cooled. The desired product is filtered off and washed twice with acetone, to give 17.3 g 5-(2-chloro-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine hydrochloride. Treatment of the filtrates provides another 20 g of the desired product (Overall yield: 90%).
Reaction SMILES: [Cl:1][C:2]1[C:13]([Cl:14])=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[C:4]([F:15])[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>C1COCC1.O>[Cl:1][C:2]1[C:13]([Cl:14])=[CH:12][C:5]([CH:6]=[O:7])=[C:4]([F:15])[CH:3]=1
Reactant: CON(C)C(=O)c1cc(Cl)c(Cl)cc1F
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc(Cl)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirring solution of 4,5-dichloro-2-fluoro-N-methoxy-N-methyl-benzamide (5.1 g, 20.23 mmol) in THF (100 mL) at −78° was added a solution of lithium aluminum hydride in THF (12.14 mL of 2 M, 24.28 mmol). After 3 h at −78° C., 50 mL water was added followed by 50 mL of 1N HCl. The reaction was allowed to warm to 25° C. and stirred for 1 h. The reaction was diluted with water and extracted with diethyl ether. The ether was dried over Na2SO4, filtered, and concentrated to provide crude 4,5-dichloro-2-fluoro-benzaldehyde that was taken directly into the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][C:13](=[O:19])[NH:14]3)=[CH:6][CH:5]=1.[CH3:22][C:23]1[C:27]([C:28]([N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[O:29])=[C:26]([CH3:37])[NH:25][C:24]=1[CH:38]=O>C(O)C.N1CCCCC1>[CH3:22][C:23]1[C:27]([C:28]([N:30]2[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]2)=[O:29])=[C:26]([CH3:37])[NH:25][C:24]=1[CH:38]=[C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[CH:18][C:10]=2[C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:9][CH:8]=2)[NH:14][C:13]1=[O:19]
Reactant: O=C1Cc2c(cccc2-c2ccc(OC(F)(F)F)cc2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(OC(F)(F)F)cc4)c32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 60.9 %

Procedure:
To a solution of 4-(4-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one (73.3 mg, 0.25 mmol) and 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The solvent was evaporated and the solid was washed by ether for three times to provide pure product 3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(4-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one (79.9 mg, 61%).
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[CH2:12]([O:19][C:20]([N:22]1[CH2:26][C@H:25]([O:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][C@H:23]1[C:32](O)=[O:33])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)(=O)C>O1CCCC1>[CH2:12]([O:19][C:20]([N:22]1[CH2:26][C@H:25]([O:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][C@H:23]1[CH2:32][OH:33])=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CS(=O)(=O)O[C@@H]1C[C@@H](CO)N(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Yield: 89.6 %

Procedure:
To a suspension of sodium borohydride (10.7 g) in tetrahydrofuran (600 ml) was added boron trifluoride etherate (43.4 ml) with stirring at 0°-10° C. After stirring for 30 minutes, a solution of (2S,4R)-1-benzyloxycarbonyl-2-carboxy-4-methanesulfonyloxypyrrolidine (66.2 g) in tetrahydrofuran (80 ml) was added to the mixture at 0°-10° C. The mixture was stirred at the same condition for 2 hours. Glacial acetic acid (20 ml) was added to the mixture at 0°-5° C. The reaction mixture was stirred at ambient temperature overnight, poured into ice-water (1 l), extracted with ethyl acetate (400 ml). The organic layer was washed with brine (400 ml), dried over magnesium sulfate and evaporated under reduced pressure to give (2S,4R)-1-benzyloxycarbonyl-2-hydroxymethyl-4-methanesulfonyloxypyrrolidine (56.90 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Br)[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH3:15][N:16](Cl)[CH3:17]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([N:16]([CH3:17])[CH3:15])[CH:5]=[N:4][CH:3]=1
Reactant: Brc1cncc(Br)c1
Reactant: CN(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)c1cncc(Br)c1
Temperature: 200 °C
Yield: 88.5 %

Procedure:
To a solution of 3,5-dibromopyridine (XLII) (2.37 g, 10.0 mmol) in dry DMF (20.0 mL) was added K2CO3 (4.5 g, 33 mmol) and dimethylamino hydrochloride (1.79 g, 22 mmol). The mixture was heated overnight at 200° C. in a sealed tube. The solution was cooled to room temperature and excess DMF was removed under vacuum. The residue was partitioned between EtOAc and water. The organic phase was separated. The aqueous phase was washed with EtOAc and the combined organic phases were dried over MgSO4, and concentrated to afford 5-bromo-N,N-dimethylpyridin-3-amine (XLIII) as an off-white solid (1.78 g, 8.85 mmol, 88% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.94 (s, 6H), 7.25 (t, J=2 Hz, 1H), 7.91 (d, J=2 Hz, 1H), 8.07 (d, J=2 Hz, 1H); ESIMS found C7H9BrN2 m/z 201.1 (M+H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]>[O-2].[O-2].[Ti+4]>[C:9](=[O:10])([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Oc1ccccc1
Agent: [Ti+4]
Agent: [O-2]
Product: O=C(Oc1ccccc1)Oc1ccccc1

Procedure:
Example 1 was repeated at 140° C. with 14.1 g of a granular (4 to 5 mm diameter) titanium dioxide, Calsicat 20503, from the Calsicat company. After 2 h reaction time, the phenol conversion was 7.2%, whereby 0.8 g phenyl chloroformate and 11.0 g diphenyl carbonate were formed. The selectivity to carbonate esters was >99%.
Reaction SMILES: C[O:2][C:3](=O)[N:4]=[C:5](SC)[C:6]([C:20]1[CH:21]=[C:22]([CH2:30][CH3:31])[C:23]2[O:28][CH2:27][O:26][CH2:25][C:24]=2[CH:29]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.[NH:35]([C:37]1[N:42]=[CH:41][CH:40]=[CH:39][N:38]=1)[NH2:36].C(N(CC)CC)C>CN(C=O)C>[CH2:30]([C:22]1[C:23]2[O:28][CH2:27][O:26][CH2:25][C:24]=2[CH:29]=[C:20]([CH:6]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:18]=[C:17]([CH3:19])[O:16][N:15]=3)=[CH:12][CH:13]=2)[C:5]2[NH:4][C:3](=[O:2])[N:35]([C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:36]=2)[CH:21]=1)[CH3:31]
Reactant: CCc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)cc2c1OCOC2
Reactant: NNc1ncccn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)cc2c1OCOC2
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a solution of 101 mg of [2-(8-ethyl-4H-benzo[1,3]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester in 2 ml of DMF there were added 21 mg of 2-hydrazinopyrimidine and 50 μl of triethylamine, and the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 200 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 5-{(8-ethyl-4H-benzo[1,3]dioxin-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH2:8][CH:7]=[C:6]2[C:11]2[CH:16]=[CH:15][N:14]=[N:13][C:12]=2[NH2:17])[O:4]CC1.Cl>C1COCC1>[NH2:17][C:12]1[N:13]=[N:14][CH:15]=[CH:16][C:11]=1[C:6]1[C:5](=[O:4])[CH2:10][CH2:9][CH2:8][CH:7]=1
Reactant: Nc1nnccc1C1=CCCCC12OCCO2
Agent: Cl
Solvent: C1CCOC1
Product: Nc1nnccc1C1=CCCCC1=O
Yield: 99 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 67c by using the crude 4-(1,4-dioxaspiro[4.5]dec-6-en-6-yl)pyridazin-3-amine prepared in Example 82c, 2 M hydrochloric acid (0.37 mL) and THF (0.92 mL), to yield the title compound (69 mg, 99%, 2 steps) as a colorless oil.
Reaction SMILES: [OH:1][C@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:43](O)(=[O:47])[CH:44]([CH3:46])[CH3:45]>O1CCCC1>[C:43]([O:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1)(=[O:47])[CH:44]([CH3:46])[CH3:45]
Reactant: CC(C)C(=O)O
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC(=O)C(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 8 h

Procedure:
To a stirred solution of 3β-hydroxy-5α-pregnan-20-one (8g, 318.5 g/m, 25 mmol) in 200 mL of freshly distilled tetrahydrofuran (THF), triphenylphosphine (9.88 g, 262.3 g/m, 38 mmol), and isobutyric acid (3.5 mL) were added. To this stirred reaction mixture at room temperature was added solution of diisopropylazidodicarboxylate (DIAD, 7.42 mL, 1.027 g/mL, 202.2 g/m, 38 mmol) in 75 mL of THF dropwise over a period of 10 minutes. The solution was stirred overnight. TLC indicated that the reaction was not complete. Triphenylphosphine (6.58 g), DIAD (4.94 mL), and isobutyric acid (2.33 mL) were added to the reaction and allowed to stir at room temperature for an additional 3 hours. TLC indicated complete reaction. The excess THF was evaporated and the residue was purified by column chromatography on silica gel with 90:10 hexane:ethyl acetate elution to give 7.3 g (346.5 g/m, 83.9%).
Reaction SMILES: [OH:1][NH:2]/[C:3](/[C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[N:10][CH:11]=1)=[N:4]\[H].[O:20]=[C:21]1[C:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:24][CH2:23][N:22]1[CH2:38][C:39](O)=O.Cl.C(N=C=NCCCN(C)C)C>ClC(Cl)C>[O:20]=[C:21]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:24][CH2:23][N:22]1[CH2:38][C:39]1[O:1][N:2]=[C:3]([C:6]2[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[N:10][CH:11]=2)[N:4]=1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: [H]/N=C(\NO)c1ccc(NC(=O)OC(C)(C)C)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1ccc(-c2noc(CN3CCC(c4ccccc4)(c4ccccc4)C3=O)n2)cn1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A solution of (Z)-tert-butyl 5-(N-hydroxycarbamimidoyl)pyridin-2-ylcarbamate (0.131 g, 0.5 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (0.153 g, 0.5 mmol; Example 1C) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.199 g, 1.0 mmol) were stirred together in dichloroethane (7.0 mL) at room temperature for 2 hours. The reaction was then heated to 85° C. and stirred overnight. The reaction was cooled, loaded onto a SF25-40 column (Analogix®) and the product eluted using a gradient of 10% ethyl acetate/hexanes to 70% ethyl acetate over 30 minutes (Flow=30 mL/minute) to supply the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]([OH:21])=O)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[N:51]1([C:56]2[CH:61]=[CH:60][C:59]([NH2:62])=[CH:58][CH:57]=2)[CH:55]=[N:54][N:53]=[N:52]1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19](=[O:21])[NH:62][C:59]3[CH:60]=[CH:61][C:56]([N:51]4[CH:55]=[N:54][N:53]=[N:52]4)=[CH:57][CH:58]=3)[N:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Nc1ccc(-n2cnnn2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)Nc3ccc(-n4cnnn4)cc3)cs2)CC1
Reaction time: 8 h

Procedure:
4-(4-Carboxy-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.28 mmol) was dissolved in anhydrous DMF (20 mL). To the solution was added triethylamine (4 eq.) and O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (1.5 eq.). The reaction was allowed to stir at room temperature for 5 minutes before 4-tetrazol-1-yl-phenylamine (1.2 eq.) was added. The reaction was stirred overnight, quenched with water, extracted with ethylacetate, washed with brine, dried over sodium sulfate and filtered. The organic filtrate was concentrated in vacuo and the residual oil was purified by column chromatography (EtOAC/Hex) furnishing the expected product. 1H NMR (CDCl3): δ 9.37 (1H, s), 9.02 (1H, s), 8.14 (1H, s), 7.96 (2H, d), 7.72 (2H, d), 4.23 (2H, m), 3.20 (1H, m), 2.91 (2H, m), 2.14 (2H, m), 1.79 (2H, m), 1.45 (9H, s).
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[CH:11][N:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:13]=[C:9]2[C:8](=[O:23])[N:7]([CH3:24])[C:6]1=[O:25])[CH:2]([CH3:4])[CH3:3].[Cl:26]C(Cl)(Cl)C(Cl)(Cl)Cl.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:26][C:13]1[N:12]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH:11]=[C:10]2[C:9]=1[C:8](=[O:23])[N:7]([CH3:24])[C:6](=[O:25])[N:5]2[CH2:1][CH:2]([CH3:4])[CH3:3]
Reactant: COc1ccc(Cn2cc3c(=O)n(C)c(=O)n(CC(C)C)c3c2)cc1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc3c(c2Cl)c(=O)n(C)c(=O)n3CC(C)C)cc1
Temperature: 25 °C
Yield: 120.9 %

Procedure:
1-isobutyl-6-(4-methoxybenzyl)-3-methyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (1.88 g, 5.5 mmol) and hexachloroethane (6.5 g, 26.5 mmol) are dissolved in anhydrous THF (3 mL), and then 1.0 M LiHMDS in THF (11 mL, 11 mmol) is added dropwise over 2 hours. The reaction mixture is stirred at room temperature for an hour, and then quenched with saturated ammonium chloride aqueous solution. The mixture is poured into cold water (100 mL), and then extracted with ethyl acetate three times. The combined organic phase is dried with anhydrous sodium sulfate. After filtration, the filtrate is evaporated to dryness to give 2.5 g of crude product as light brown solids, which is used in the next step without further purification. MS (ESI) m/z 376.1 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14]CC(=O)NCCCCCCCC)[N:10]=[C:9]1[NH2:27])=O)(C)(C)C.[N:28]#CN.C(O)C.[ClH:34]>O.CO>[ClH:34].[ClH:34].[NH2:28][CH2:14][CH2:13][C:11]1[N:10]=[C:9]([NH2:27])[NH:8][CH:12]=1
Reactant: N#CN
Reactant: CCCCCCCCNC(=O)CCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Agent: Cl
Solvent: CO
Solvent: O
Solvent: CCO
Product: NCCc1c[nH]c(N)n1
Yield: 62 %

Procedure:
1,4-diamino-2-butanone dihydrochloride 25 (0.300 g, 1.71 mmol) and cyanamide (0.753 g, 17.9 mmol) were dissolved in water (10 mL). The pH of the solution was adjusted to pH=4.3 before heating the reaction at 95° C. for 3.5 h while open to the atmosphere. After cooling to ambient temperature ethanol (10 mL) was added to the flask and the solution was evaporated to dryness. Purification of the residue by column chromatography (MeOH sat. with NH3/CH2Cl2 90:10) yielded the product as its corresponding free base. Addition of methanol (10 mL) and concentrated hydrochloric acid followed by evaporation in vacuo afforded the target compound 26 (0.211 g, 62%) as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 6.21 (s, 1H), 5.14 (br s, 2H), 2.81 (m, 2H), 2.47 (m, 2H); HRMS (ESI) calcd for C5H11N4 (MH+) 127.0978, found 127.0977.