Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:11][C:10]2[C:9]([NH:12][C:13](=[O:21])[C:14]3[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=3)=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.CN(C=O)C.[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[F:34].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:27][C:28]1[CH:29]=[C:30]([C:17]2[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:9]3[C:10]4[CH2:11][CH:2]([OH:1])[CH2:3][CH2:4][C:5]=4[CH:6]=[CH:7][CH:8]=3)=[O:21])=[CH:15][CH:16]=2)[CH:31]=[CH:32][C:33]=1[F:34]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: O=C(Nc1cccc2c1CC(O)CC2)c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1cccc2c1CC(O)CC2)c1ccc(-c2ccc(F)c(F)c2)cc1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 54.7 %

Procedure:
Next, to a solution of N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-4-iodobenzamide (100 mg, 0.25 mmol) in a 3 to 1 mixture of DMF and H2O was added 3,4-difluorophenylboronic acid (80.3 mg, 0.51 mmol), tetrakis(triphenylphosphine)palladium(0) (8.82 mg, 0.01 mmol), and sodium carbonate (80.9 mg, 0.76 mmol). The mixture was stirred at 80° C. for 2.5 hours, and after cooled to room temperature, the product was extracted with diethyl ether. The organic layer was washed with water then brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. After triturated with ethylacetate and hexane, the solid was filtered to afford 3′,4′-difluoro-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)biphenyl-4-carboxamide (51.9 mg, 54%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([SH:7])=[N:5][C:4]([N+:8]([O-:10])=[O:9])=[N:3]1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:24][C:25]1[N:29]([CH2:30][CH2:31][CH3:32])[CH:28]=[N:27][CH:26]=1>O>[CH3:1][N:2]1[C:6]([S:7][CH2:24][C:25]2[N:29]([CH2:30][CH2:31][CH3:32])[CH:28]=[N:27][CH:26]=2)=[N:5][C:4]([N+:8]([O-:10])=[O:9])=[N:3]1
Reactant: CCCn1cncc1CCl
Reactant: Cn1nc([N+](=O)[O-])nc1S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1cncc1CSc1nc([N+](=O)[O-])nn1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.3 %

Procedure:
1-methyl-3-nitro-1,2,4-triazol-5-thiol (0.66 g) was dissolved in. DMF (13.2 ml), potassium carbonate (1.7 g) and 5-chloromethyl-1-propylimidazole hydrochloride (1.1 g) were added to the mixture, and the mixture was stirred for 18 hours at room temperature. The reaction solution was added to water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed, to give 1-methyl-3-nitro-5-[[(1-propylimidazol-5-yl)methyl]thio]-1,2,4-triazole (0.55 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[C:10]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:33][C:34]#[N:35]>CC(C)=O>[OH:24][C:21]1[CH:20]=[CH:19][C:18]([C:10](=[C:4]2[CH2:3][C:2]([CH3:25])([CH3:1])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5]2)[C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:33][C:34]#[N:35])=[CH:15][CH:16]=2)=[CH:23][CH:22]=1
Reactant: N#CCBr
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(O)cc2)CC(C)(C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(OCC#N)cc2)CC(C)(C)C1
Temperature: 25 °C
Yield: 29.3 %

Procedure:
The O-alkylation procedure described for 190 was used. To a stirred suspension of 4,4′-[(3,3,5,5-tetramethylcyclohexylidene) methanediyl]diphenol (219) (0.600 g, 1.78 mmol), K2CO3 (0.368 g, 2.67 mmol), and acetone (60 mL) was added bromoacetonitrile (0.200 mL, 2.85 mmol) under a nitrogen atmosphere at RT. The reaction mixture was refluxed for 3 h, cooled to RT and filtered. Standard work-up followed by purification afforded 0.196 g (29%) of the title compound 229 as a white solid along with 0.38 g (52%) of the bis-alkylated compound 2,2′-[[(3,3,5,5-tetramethylcyclohexylidene) methanediyl]bis(benzene-4,1-diyloxy)]diacetonitrile. In addition, 0.10 g of unreacted starting material (219) was recovered. 1H NMR (300 MHz, CDCl3): δ 7.15 (d, J=8.7 Hz, 2H), 7.04 (d, J=8.4 Hz, 2H), 6.90 (d, J=8.7 Hz, 2H), 6.76 (d, J=8.4 Hz, 2H), 4.75 (s, 2H), 2.00 (s, 2H), 1.98 (s, 2H), 1.31 (s, 2H), 0.95 (s, 12H). LCMS (ESI): m/z 374 (M−H)−. Anal. Calcd for C25H29NO2, C, 79.96; H, 7.78; N, 3.73; Found: C, 79.95; H, 7.84; N, 3.73.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
To a solution of 4-benzoylbenzoic acid (2.00 g) in trifluoroacetic acid (30 mL) was added dropwise triethylsilane (3.53 mL), and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and then n-hexane was added to the residue. The precipitate was collected by filtration, washed with n-hexane and dried under reduced pressure at 60° C. to give 4-benzylbenzoic acid (1.66 g). To an ice-cold suspension of lithium aluminium hydride (0.315 g) in tetrahydrofuran (45 mL) was added dropwise a solution of 4-benzylbenzoic acid (1.60 g) in tetrahydrofuran (30 mL), and the resulting mixture was stirred at room temperature for 4.5 hours. The reaction was quenched by sequential addition of water (0.320 mL), 15% aqueous sodium hydroxide (0.320 mL) and water (0.320 mL). The insoluble material was filtered out and the filtrate was concentrated under reduced pressure to give 4-benzylbenzyl alcohol (1.56 g). 4-Benzylbenzylalcohol (1.56 g) was dissolved in tetrahydrofuran (39 mL). After addition of phthalimide (1.39 g) and triphenylphosphine (2.68 g), diisopropylazodicarboxylate (40% toluene solution, 5.17 g) was added dropwise, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to give the title compound (1.87 g).
Reaction SMILES: [CH:1](I)([CH3:3])[CH3:2].[NH:5]1[CH2:10][CH:9]=[C:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:7][CH2:6]1>CC(C)=O.[Ag]=O>[CH2:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:9][CH2:10]1)[CH2:1][CH3:3]
Reactant: CC(C)I
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Agent: O=[Ag]
Solvent: CC(C)=O
Product: CCCN1CC=C(c2c[nH]c3ccccc23)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
3.15 g of silver oxide and 2.25 ml of isopropyl iodide were added to a solution of 4.5 g of 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole in 90 ml of acetone and the mixture was heated at 50° C. for 3 hours and was then cooled. The mixture was filtered and the filtrate was distilled to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 6-3-1 chloroform-acetone-triethylamine mixture. The fractions were distilled to dryness and the residue was dissoved in 200 ml of refluxing ethyl acetate. The mixture was filtered and the filtrate was concentrated to 150 ml and cooled to 20° C. Crystallization was induced and the mixture was iced overnight and vacuum filtered. The recovered product was washed with ethyl acetate and dried to obtain 3.9 g of 3-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole melting at 210° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4](=[N:29][S:30][N:31]=2)[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[N:13]([C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[N:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[O:8][C:7]2=[O:28].[CH:32]([NH2:35])([CH3:34])[CH3:33]>C1COCC1>[CH:32]([NH:35][C:7]([C:6]1[C:11]([NH:10][C:9]([C:12]2[N:13]([C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[N:14]=[C:15]([C:17]([F:19])([F:18])[F:20])[CH:16]=2)=[O:8])=[C:2]([Cl:1])[C:3]2[C:4]([CH:5]=1)=[N:29][S:30][N:31]=2)=[O:28])([CH3:34])[CH3:33]
Reactant: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2c(Cl)c3nsnc3cc12
Reactant: CC(C)N
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1cc2nsnc2c(Cl)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 25 mg (52 mmol) of 4-chloro-6-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-7-oxa-2-thia-1,3,5-triaza-cyclopenta[b]naphthalen-8-one in 0.5 ml of THF, is added dropwise 7 ml (77 mmol) of isopropylamine. The reaction is stirred for 18 hours at ambient temperature. Then, the solvent is evaporated and the residue is suspended in a mixture of hexanes and a minimum of EtOAc. After decantation the solid is washed with a minimum of hexanes and after drying 24.5 mg (45 mmol, 87%) of a slightly brown solid were obtained. LC/MS: 544/546 (M+1)+.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.[OH:26][C:27]1[CH:28]=[C:29](OB(O)O)[CH:30]=[CH:31][CH:32]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:7]([N:5]1[CH:6]=[C:2]([C:31]2[CH:32]=[C:27]([OH:26])[CH:28]=[CH:29][CH:30]=2)[N:3]=[CH:4]1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Brc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: OB(O)Oc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Oc1cccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A solution of 0.389 g of 4-bromo-1-trityl-1H-imidazole, 0.152 g of 3-hydroxyphenylboric acid and 10 ml of toluene is admixed with 3 ml of ethanol and 10 ml of aqueous 2N sodium carbonate solution. The mixture is purged with argon for 15 minutes and then 0.026 g of tetrakis(triphenylphosphine)palladium(0) is added. The reaction mixture is stirred at 100° C. for 48 hours, then cooled and poured onto 75 ml of aqueous saturated sodium hydrogencarbonate solution. The mixture is extracted three times with 75 ml of dichloromethane. The combined organic phases are washed with 75 ml of brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a white solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.13 (1:2 EtOAc-heptane); Rt=4.33.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15](COCCOC)[C:14]3[CH:22]=[CH:23][CH:24]=[C:25]([Cl:26])[C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].Cl.O1CCOCC1>CCO>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:15][C:14]3[CH:22]=[CH:23][CH:24]=[C:25]([Cl:26])[C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2nc3c(Cl)cccc3n2COCCOC)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2nc3c(Cl)cccc3[nH]2)c1
Temperature: 23 °C
Reaction time: 18 h
Yield: 91.3 %

Procedure:
To a mixture of 1-[4-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.370 g, 0.980 mmol) and EtOH (2.5 mL), was added 4M HCl in dioxane (2.5 mL, 10 mmol). The mixture was stirred for 18 h at 23° C. The resulting white precipitate was filtered and washed with EtOH to yield the titled compound (0.260 g, 93%). MS (ESI/CI): mass calcd. for C13H11ClN4O2, 290.1; m/z found, 291.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 13.83 (s, 1H), 8.98 (s, 1H), 8.45-8.29 (m, 1H), 7.46 (s, 1H), 7.38-7.16 (m, 2H), 4.59-4.01 (m, 2H), 1.60-1.01 (m, 3H).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH3:9].Br[CH2:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]>>[CH3:15][C:14]([CH3:17])([CH3:16])[C:13]([C:12]1[S:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]=1[CH3:9])=[O:18]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CC(=O)c1ccccc1S
Product: Cc1c(C(=O)C(C)(C)C)sc2ccccc12

Procedure:
The title compound was prepared from 1-(2-mercaptophenyl)ethanone and 1-bromopinacolone using the procedure in Step B Examples 36˜49. 1H NMR (CDCl3, 500 MHz) 7.82˜7.88 (m, 2H), 7.44˜7.50 (m, 2H), 2.60 (s, 3H), 1.41 (s, 9H). LC-MS: 4.06 min. (m/Z=233.4, 191).
Reaction SMILES: [Li]C(CC)C.Br[C:7]1[C:8]2[C:13]([CH:14]=[C:15]3[C:20]=1[CH:19]=[CH:18][CH:17]=[CH:16]3)=[CH:12][CH:11]=[CH:10][CH:9]=2.C([O:24][B:25](OC(C)C)[O:26]C(C)C)(C)C.Cl>CCOCC.CO>[CH:19]1[C:20]2[C:15](=[CH:14][C:13]3[C:8]([C:7]=2[B:25]([OH:26])[OH:24])=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1c2ccccc2cc2ccccc12
Agent: Cl
Agent: [Li]C(C)CC
Solvent: CO
Solvent: CCOCC
Product: OB(O)c1c2ccccc2cc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.6 %

Procedure:
sec-BuLi (4.3 mL, 6.0 mmol, 1.4M solution in cyclohexane) was added dropwise to a solution of 9-bromoanthracene (1.29 g, 5.0 mmol) in Et2O (20 mL) at 0° C. under N2. The reaction was held at 0° C. for 15 minutes then warmed to rt and stirred an additional 45 minutes. Triisopropylborate (1.5 mL, 6.5 mmol) was added and the reaction was stirred at rt for 18 h. Concentrated HCl (1.0 mL) and MeOH (1.0 mL) was added and the reaction was stirred for 30 minutes. The layers were separated and the aqueous phase was extracted three times with CH2Cl2. The combined organic layers were washed with H2O, sat. NaHCO3 (aq.), brine, and then dried over Na2SO4. Filtration and concentration gave 1.05 g of 9-anthraceneboronic acid.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C1(N2C(S([CH2:25][CH:26]3[CH2:30][CH2:29][O:28][CH2:27]3)(=O)=O)=NN=N2)C=CC=CC=1.[CH:31]1([C:34]2[CH:35]=[CH:36][C:37]([C:42]([C:44]3[CH:49]=[CH:48][C:47]([S:50][CH3:51])=[CH:46][CH:45]=3)=O)=[N:38][C:39]=2[O:40][CH3:41])[CH2:33][CH2:32]1.[Cl-].[NH4+]>O1CCCC1>[CH:31]1([C:34]2[C:39]([O:40][CH3:41])=[N:38][C:37](/[C:42](/[C:44]3[CH:49]=[CH:48][C:47]([S:50][CH3:51])=[CH:46][CH:45]=3)=[CH:25]/[CH:26]3[CH2:30][CH2:29][O:28][CH2:27]3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1
Reactant: COc1nc(C(=O)c2ccc(SC)cc2)ccc1C1CC1
Reactant: O=S(=O)(CC1CCOC1)c1nnnn1-c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1nc(/C(=C/C2CCOC2)c2ccc(SC)cc2)ccc1C1CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 14 %

Procedure:
A 1 M solution of lithium hexamethyldisilazide in tetrahydrofuran (5.14 mL) was added to a solution of 1-phenyl-5-[(tetrahydrofuran-3-ylmethyl)sulfonyl]-1H-tetrazole obtained in Reference Example 3-6 (1.51 g) in tetrahydrofuran (15 mL) in a nitrogen gas stream at −78° C., and the mixture was stirred at −78° C. for one hour. A solution of (5-cyclopropyl-6-methoxypyridin-2-yl)[4-(methylsulfanyl)phenyl]methanone obtained in Reference Example 1-51 (700 mg) in tetrahydrofuran (10 mL) was added, and the mixture was stirred at −78° C. to 0° C. for one hour. The reaction solution was poured into a saturated ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→7:3) to give 3-cyclopropyl-2-methoxy-6-[(E)-1-[4-(methylsulfanyl)phenyl]-2-(tetrahydrofuran-3-yl)ethenyl]pyridine (122 mg, 14%) as a colorless oil.
Reaction SMILES: [CH2:1]=[C:2]1[CH:4]([CH2:5][O:6][C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:3]1[CH2:15][O:16][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-:25].[Na+].OO>O1CCCC1.C(OCC)(=O)C>[OH:25][CH2:1][CH:2]1[CH:3]([CH2:15][O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:4]1[CH2:5][O:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [OH-]
Reactant: C=C1C(COC(=O)c2ccccc2)C1COC(=O)c1ccccc1
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(OCC1C(CO)C1COC(=O)c1ccccc1)c1ccccc1
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 46.3 %

Procedure:
A solution of 8.36 g (26 mmol) of 3-Methylene-1,2-bis(benzoyloxymethyl)cyclopropane (from Step C) in tetrahydrofuran (THF) was cooled in an ice-water bath. To this solution was added 26 mL (26 mmol) of a 1 M THF solution of borane-THF complex, and the resultant solution was stirred at 5° C. for 2 h. 3N Sodium hydroxide solution (8.67 mL, 26 mmol) was then added slowly to the reaction mixture at 5° C., followed by 7.8 mL (78 mmol) of 30% aqueous hydrogen peroxide solution. The reaction mixture was stirred for 20 min at 5° C., allowed to warm to ambient temperature and stirred for 30 min at ambient temperature. The reaction mixture was diluted with ethyl acetate, washed 3 times with brine (until the pH of the aqueous layer was approximately 7) and concentrated in vacuo. The residue was purified by column chromatography on a 3×65 cm silica gel column eluted with 2% methanol in chloroform. Fractions numbered 35-47 were combined and concentrated in vacuo to give 4.1 g (46% yield) of 3-Hydroxymethyl-1,2-bis((benzoyl)oxymethyl)cyclopropane. DCI NH3MS, M/Z: 341 (M+H)+, 358 (M+NH4)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9](I)[C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[Cu](C#N)[C:15]#[N:16]>CN(C=O)C>[C:15]([C:9]1[C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=[C:5]([CH:8]=1)[CH:6]=[O:7])#[N:16]
Reactant: COc1cc(C=O)cc(I)c1OC
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(C#N)c1OC
Temperature: 25 °C
Yield: 99.6 %

Procedure:
3,4-dimethoxy-5-iodobenzaldehyde (41) (FIG. 22) (4.40 g, 15.07 mmole), copper cyanide (13.5 g, 150.7 mmole) and dry DMF (45 ml) were stirred under an argon atmosphere for 18 hours at 140° C. The reaction was cooled to room temperature, filtered through celite, and the filtrate concentrated to an oil in vacuo. The dark brown oil was purified through a short flash silica column using 11 hexane/ethyl acetate as eluent to yield 2.87 g (69%) of a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:10]([NH2:14])[CH:11]([CH3:13])[CH3:12].CCCCCC>CO.CCOC(C)=O>[Br:1][C:2]1[C:3]([NH:14][CH2:10][CH:11]([CH3:13])[CH3:12])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CC(C)CN
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CO
Product: CC(C)CNc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
To a solution of 5-bromo-2,4-dichloropyrimidine (14.0 mmol) in methanol (30 ml) is added isobutylamine (28.0 mmol) at room temperature. The mixture is stirred at room temperature for one day and diluted with AcOEt. The organic layer is washed with water and brine, dried over sodium sulfate and concentrated. Chromatography on silica gel (n-hexane and n-hexane:AcOEt=25:1) gives the product in 78% yield. Rf=0.52 (n-hexane:AcOEt=4:1)
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1([C:16](=[NH:19])[NH:17][OH:18])[CH2:11][CH:10]1[CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].[C:21](C1NC=CN=1)(C1NC=CN=1)=[O:22]>C1COCC1>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1([C:16]2[NH:19][C:21](=[O:22])[O:18][N:17]=2)[CH2:11][CH:10]1[CH2:12][CH:13]([CH3:14])[CH3:15])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CC1CC1(CNC(=O)OC(C)(C)C)C(=N)NO
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CC(C)CC1CC1(CNC(=O)OC(C)(C)C)c1noc(=O)[nH]1
Temperature: 25 °C
Yield: 76.4 %

Procedure:
To a solution of [1-(N-hydroxycarbamimidoyl)-2-isobutyl-cyclopropylmethyl]-carbamic acid tert-butyl ester (5.6 g, 19.6 mmol) in dry THF (190 mL) was added dropwise a solution of carbonyl diimidazole (4.8 g, 29.4 mmol) in dry THF (190 mL). The reaction mixture was heated to reflux for 12 hours and allowed to cool to room temperature. Excess of solvents was removed in vacuo and the residue was partitioned between ether (100 mL) and 1N NaOH (100 mL) solution. The ethereal solution was extracted with 1N NaOH (2×50 mL) and the combined aqueous layers were acidified to pH=3 with 4N HCl solution. The aqueous solution was extracted with EtOAc (3×100 mL) and the combined organic phase was washed with brine and dried over Na2SO4. Removal of excess of solvent, followed by purification of the residue by flash column chromatography using hexanes/EtOAc (1:1) as an eluent gave 4.66 g (76%) of {2-isobutyl-1-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-cyclopropylmethyl}-carbamic acid tert-butyl ester as a colorless foam: 1H NMR (300 MHz, CD3OD) δ 0.89 (t, J=5.7 Hz, 1H), 0.96 (d, J=5.1 Hz, 3H), 0.98 (d, J=5.1 Hz, 3H), 1.26-1.37 (m, 3H), 1.43 (s, 9H), 1.63-1.71 (m, 2H), 3.35 (d, J=14.8 Hz, 1H), 3.53 (d, J=14.8 Hz, 1H); MS (APCI) m/z 210 [M+H-100(Boc)]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[C:12]([OH:13])=[C:11]([C:14](=O)[CH3:15])[C:10]([CH3:17])=[N:9]2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([NH:28][NH2:29])=[O:27])=[CH:24][CH:23]=1)=[O:21]>CS(C)=O>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:14]([NH:29][NH:28][C:26]([C:25]3[CH:30]=[CH:31][C:22]([C:20]([O:19][CH3:18])=[O:21])=[CH:23][CH:24]=3)=[O:27])[CH3:15])[C:10]([CH3:17])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C(=O)NN)cc1
Reactant: CC(=O)c1c(C)nn(-c2ccc(Cl)nn2)c1O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(C(=O)NNC(C)=C2C(=O)N(c3ccc(Cl)nn3)N=C2C)cc1
Temperature: 100 °C
Yield: 64 %

Procedure:
0.2 mmol of 1-[1-(6-chloro-3-pyridazinyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]ethanone and 0.2 mmol of 4-methoxycarbonylbenzhydrazide were dissolved in 2 ml of DMSO and heated at 100° C. for 8 hours with stirring. After the solvent was removed by evaporation, the crude product was dissolved in chloroform and recrystallized from ether to obtain 55 mg of the desired product, methyl 4-[(2-{1-[1-(6-chloro-3-pyridazinyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]-ethyl}hydrazino)carbonyl]benzoate (yield 64%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=1>C(Cl)Cl.C(Cl)Cl.O>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: O
Solvent: ClCCl
Product: CC(C)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-Isopropylpiperazine (1.8 mL, 12.7 mmol, 2 equiv) is added to a cold (5° C.) mixture of 2-chloro-5-nitropyridine (1 g, 6.3 mmol) in DCM (5 mL). The reaction mixture is allowed to warm to RT, stirred for 16 h, diluted with DCM/H2O and extracted with DCM. The organic phase is washed with brine, dried (Na2SO4), filtered and concentrated to provide the title compound as a yellow solid: ES-MS: 251.2 [MH]+; tR=2.20 min (system 1).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:26][CH:25]=3)[N:9]=[C:10]([C@H:11]3[CH2:16][CH2:15][C@H:14]([CH2:17][NH:18][CH2:19][CH2:20]N(C)C)[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.NCC[OH:40]>>[NH2:1][C:2]1[C:7]2=[C:8]([C:24]3[CH:25]=[CH:26][C:27]([O:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[CH:28][CH:29]=3)[N:9]=[C:10]([C@H:11]3[CH2:12][CH2:13][C@H:14]([CH2:17][NH:18][CH2:19][CH2:20][OH:40])[CH2:15][CH2:16]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: NCCO
Reactant: CN(C)CCNC[C@H]1CC[C@H](c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnn32)CC1
Product: Nc1ncnn2c1c(-c1ccc(Oc3ccccc3)cc1)nc2[C@H]1CC[C@H](CNCCO)CC1

Procedure:
Prepared according to the procedure analogous to that described above for trans-N-{4-[4-Amino-5-(4-phenoxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclohexylmethyl}-N′,N′-dimethyl-ethane-1,2-diamine, except using 2-amino-ethanol.