Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[C:10]1([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)(Cl)(Cl)Cl>[N+:1]([C:13]1[CH:14]=[CH:15][C:10]([C@H:16]2[CH2:17][CH2:18][C@H:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:20][CH2:21]2)=[CH:11][CH:12]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccccc2)CC1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C[C@H]1CC[C@H](c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 65% nitric acid (3.95 mL) and 95% sulphuric acid (4.97 mL) was added dropwise to a stirred solution of methyl (trans-4-phenylcyclohexyl)acetate (4710 mg) in CCl4 (20 mL) at 5° C. and the solution was allowed to warm to ambient temperature and stirred for 16 hours. Ice/water (50 mL) was added and the mixture was extracted with DCM (2×40 mL). The organic extracts were combined, washed with brine (50 mL), dried, and concentrated in vacuo to give an oil. This oil was purified by flash chromatography on a 80 g Biotage™ silica column, using a gradient of 0-20% EtOAc in hexane as the eluent to give crude methyl [trans-4-(4-nitrophenyl)cyclohexyl]acetate which was dissolved in ethyl acetate (30 mL). 10% palladium on carbon (0.400 g) was added and the resulting suspension was stirred at ambient temperature for 16 hours under an atmosphere of hydrogen. The suspension was filtered through diatomaceous earth and concentrated in vacuo to give a solid. This was purified by flash chromatography on a 40 g Biotage™ silica column using a gradient of 20-45% EtOAc/hexane as eluent to give the title compound (1740 mg) as a solid; 1H NMR δ 6.83 (2H, d), 6.46 (2H, d), 4.72 (2H, s), 3.59 (3H, s), 2.23 (3H, m), 1.72 (5H, m), 1.35 (2H, m), 1.09 (2H, m); MS m/e MH+ 248.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11]O)[CH:5]=[CH:6][C:7]=1[CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(CCCO)cc1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(CCCBr)cc1C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
Compound 37-2 (1.95 g) was dissolved in methylene chloride (50 ml), triphenylphosphine (3.46 g) and N-bromosuccinimide (2.33 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and at room temperature for 2 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.20 g) as a colorless oil.
Reaction SMILES: [CH2:1]([S:4]([NH:7][C@@H:8]([C:13]([NH:15][C@H:16]([C:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1)=[O:21])[CH2:17][NH:18][CH3:19])=[O:14])[C@@H:9]([CH2:11][CH3:12])[CH3:10])(=[O:6])=[O:5])[CH2:2][CH3:3].O1CCCC1.[O-:37][C:38]#[N:39].[K+]>O>[CH2:1]([S:4]([NH:7][C@@H:8]([C:13]([NH:15][C@H:16]([C:20]([NH:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=1)=[O:21])[CH2:17][N:18]([C:38]([NH2:39])=[O:37])[CH3:19])=[O:14])[C@@H:9]([CH2:11][CH3:12])[CH3:10])(=[O:6])=[O:5])[CH2:2][CH3:3]
Reactant: CCCS(=O)(=O)N[C@@H](C(=O)N[C@@H](CNC)C(=O)NCc1ccc(C#N)cc1)[C@H](C)CC
Reactant: N#C[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCCS(=O)(=O)N[C@@H](C(=O)N[C@@H](CN(C)C(N)=O)C(=O)NCc1ccc(C#N)cc1)[C@H](C)CC
Temperature: 50 °C
Yield: 87 %

Procedure:
To a solution of N-(propylsulfonyl)-D-isoleucyl-3-(methylamino)-N1-(4-cyanobenzyl)-L-alaninamide (500 mg, 1.0 mmol) in water (1.3 ml)/tetrahydrofuran (3 ml), potassium cyanate (243 mg, 3 mmol) was added under stirring at 50° C. and then further stirred under the same conditions. After stirring for 3 hours, water was added to the reaction mixture, which was then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off and the filtrate was concentrated under reduced pressure to give N-(propylsulfonyl)-D-isoleucyl-3-[(aminocarbonyl)(methyl)amino]-N1-(4-cyanobenzyl)-L-alaninamide (430 mg, 0.87 mmol; yield 87%).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][C:13]3[CH:18]=[N:17][CH:16]=[CH:15][N:14]=3)[CH:9]=[C:10]([OH:11])[C:5]=2[CH:4]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[O:3]1.I[CH:26]([CH3:28])[CH3:27].[H-].[Na+]>CN(C=O)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][CH:4]1[O:3][B:2]([OH:1])[C:6]2[CH:7]=[C:8]([O:12][C:13]3[CH:18]=[N:17][CH:16]=[CH:15][N:14]=3)[CH:9]=[C:10]([O:11][CH:26]([CH3:28])[CH3:27])[C:5]1=2)[CH3:24]
Reactant: CC(C)I
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(O)c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(OC(C)C)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a mixture of ethyl 2-(1,4-dihydroxy-6-(pyrazin-2-yloxy)-1,3-dihydrobenzo[c][1,2]oxa-borol-3-yl)acetate (100 mg, 0.30 mmol) and 2-iodopropane (154 mg, 0.91 mmol) in DMF (5 mL) was added 60% NaH (4.85 mg, 1.21 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h and quenched by slow addition of water (3 mL). The resulting mixture was acidified with 1 N HCl to pH=4 and extracted with EtOAc (2×15 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a yellow oil (96 mg, yield: 86%).
Reaction SMILES: [CH2:1]([N:9]1[CH:13]=[C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:24]=[C:25]([CH:40]=[CH:41][CH:42]=4)[O:26][CH:27]4[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]4)[CH:21]=3)[NH:16][CH:15]=2)[CH:11]=[N:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>Cl.CO>[CH2:1]([N:9]1[CH:13]=[C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:42]=[CH:41][CH:40]=[C:25]([O:26][CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH:11]=[N:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(-c3cnc4[nH]cc(-c5cnn(CCc6ccccc6)c5)c4c3)c2)CC1
Agent: Cl
Solvent: CO
Product: c1ccc(CCn2cc(-c3c[nH]c4ncc(-c5cccc(OC6CCNCC6)c5)cc34)cn2)cc1
Yield: 47.1 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(3-(3-(1-phenethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenoxy)piperidine-1-carboxylate (80 mg, 0.142 mmol) was deprotected in HCl in methanol (5 ml). This afforded 31 mg (37.7% yield) of the titled compound after purification by preparative HPLC. 1H NMR (CD3OD, 400 MHz): δ 8.70-8.50 (bs, 1H), 8.32 (s, 1H), 7.89 (s, 1H), 7.79 (s, 1H), 7.65 (s, 1H), 7.52-7.45 (t, 1H), 7.39-7.30 (m, 2H), 7.29-7.20 (t, 2H), 7.19-7.09 (m, 4H), 4.85-4.75 (m, 1H), 4.49-4.45 (t, 2H), 3.51-3.49 (m, 2H), 3.30-3.10 (m, 4H), 2.30-2.10 (m, 4H). MS: m/z=464.3 (M+1), HPLC: 95.43% in method A.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.ClC1C=C(C=CC=1)C(OO)=O>[Br:12][C:3]1[C:2]([CH3:1])=[CH:11][C:6]2=[N:7][C:8](=[O:10])[N:9]=[C:5]2[CH:4]=1
Reactant: Cc1ccc2[nH]c(=O)[nH]c2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc2c(cc1Br)=NC(=O)N=2
Temperature: 25 °C
Yield: 52.6 %

Procedure:
A mixture of 6-methyl-1,3-dihydro-benzoimidazol-2-one (1.00 g, 6.76 mmol) as prepared in Example 1, N-bromosuccinimide (1.30 g, 7.30 mmol) and 3-chloroperoxybenzoic acid (0.05 g, 0.29 mmol) in carbon tetrachloride (15 ml) was heated under reflux for 4 h. When cooled to room temperature, the mixture was filtered and the solid was recrystallised from methanol to give (17) as a beige solid (0.80 g). Furthermore, the solid insoluble in methanol was collected to give more (17) (0.50 g) and the solids were combined (1.30 g, 85%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=O)[CH:9]=2)[NH:4][N:3]=1.[C:13](/[CH:15]=[C:16](\[O-:18])/[CH3:17])#[N:14].[Na+].C(O)(=O)C.N1CCCCC1>ClCCl>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](/[CH:11]=[C:15](/[C:16](=[O:18])[CH3:17])\[C:13]#[N:14])[CH:9]=2)[NH:4][N:3]=1
Reactant: C/C([O-])=C/C#N
Reactant: Cc1n[nH]c2ccc(C=O)cc12
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CC(=O)/C(C#N)=C/c1ccc2[nH]nc(C)c2c1
Yield: 49.8 %

Procedure:
A mixture of 5.0 g (31.2 mmol) 3-methyl-1H-indazole-5-carbaldehyde (Example 1A), 3.61 g (34.3 mmol) sodium (1Z)-1-cyanoprop-1-en-2-olate, 2.23 ml (39 mmol) acetic acid and 0.31 ml (3.12 mmol) piperidine in dry dichloromethane (250 ml) containing 4 Å molecular sieve was stirred under reflux for 12 h. Upon cooling, a precipitate was formed which was collected by filtration and washed with saturated aqueous sodium bicarbonate solution and water. The solid was dissolved in ethanol, and the molecular sieve was filtered off. The filtrate was concentrated under reduced pressure, and the residue was treated with ethyl acetate and saturated aqueous sodium carbonate solution. The organic layer was washed with water, dried, and concentrated under reduced pressure to afford the title compound (3.5 g, 50% of th.) as a pale yellow solid which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[CH:8][NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:10]=[O:11].C(N(CC)CC)C>CC(C)=O>[C:1]([C:5]1[CH:9]=[CH:8][N:7]([CH2:10][OH:11])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=O
Reactant: CC(C)(C)c1cc[nH]n1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccn(CO)n1
Temperature: 130 °C
Reaction time: 7 h
Yield: 67.3 %

Procedure:
The mixture of 1.28 g of 3-t-butyl-1H-pyrazole, 0.66 g of paraformaldehyde and 0.3 g of triethylamine was stirred at 130° C. for 7 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. The mixture was filtered. The filterate was concentrated under reduced pressure. Hexane was added to the residue, and then crystalline was formed. The crystalline was collected to obtain 1.07 g of 3-t-butyl-1H-pyrazole-1-ylmethanol.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18]C)[CH:13]=3)[C:4]([CH3:20])([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3]1.Br.[OH-].[Na+]>C(O)(=O)C>[CH3:1][N:2]1[CH2:11][CH2:10][C:9]2([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)[C:4]([CH3:20])([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3]1
Reactant: COc1cccc(C23CCCCC2(C)CN(C)CC3)c1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN1CCC2(c3cccc(O)c3)CCCCC2(C)C1
Temperature: 25 °C
Yield: 83 %

Procedure:
To a 25 mL single-necked flask was added 180 mg (0.65 mmol) of 9 and 5 mL of glacial acetic acid and 5 mL of 48% HBr. This mixture was heated under reflux for 18 h and then cooled to room temperature. The pH was then adjusted to 10 with cooling with 50% NaOH. This mixture was extracted 3× with methylene chloride. The organic extracts were dried (Na2SO4), and concentrated under reduced pressure to give 0.17 g (99%) of crude product as a white solid. Purification by chromatography on alumina using 15% ethyl acetate/hexane gave 0.140 g (83%) of desired product as a crystalline white solid.
Reaction SMILES: [CH3:1][CH:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3]1.[CH3:19][N:20]([CH3:24])[C:21](Cl)=[O:22].C1(C)C=CC=CC=1.C(N(CC)C(Cl)=O)C>N1C=CC=CC=1.C(OCC)(=O)C.O>[CH3:19][N:20]([CH3:24])[C:21]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:9]2[CH:8]=[CH:7][C:6]3[CH:2]([CH3:1])[CH2:3][O:4][C:5]=3[CH:10]=2)=[N:13][CH:14]=1)=[O:22]
Reactant: CC1COc2cc(Oc3ccc(N)cn3)ccc21
Reactant: CN(C)C(=O)Cl
Agent: CCN(CC)C(=O)Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC1COc2cc(Oc3ccc(NC(=O)N(C)C)cn3)ccc21
Temperature: 25 °C
Reaction time: 9 h
Yield: 97.4 %

Procedure:
2-(3-Methyl-2,3-dihydro-6-benzofuryloxy)-5-aminopyridine (0.5 g) was dissolved in 2.5 ml of pyridine, and a solution of composed 0.27 g of dimethylcarbamoyl chloride and 2.5 ml of toluene was added. A solution composed of 0.27 g of diethylcarbamoyl chloride and 2.5 ml of toluene was added, and the mixture was stirred at room temperature for 9 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. Ethyl acetate was evaporated under reduced pressure, and the precipitated crystals were washed with n-hexane to give 0.63 g (yield 96%) of the desired product as pale brown crystals.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([CH:22]=[O:23])[N:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:24]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].CN(C)C=[O:28].OOS([O-])=O.[K+]>>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([C:22]([OH:28])=[O:23])[N:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:24]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(C=O)ncc1OCC2
Reactant: CN(C)C=O
Agent: O=S([O-])OO
Agent: [K+]
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(C(=O)O)ncc1OCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine-10-carbaldehyde (0.250 g, 0.771 mmol) was dissolved in N,N-Dimethylformamide (2 mL, 0.02 mol). Oxone® (0.569 g, 0.925 mmol) was added and the reaction mixture was stirred overnight at room temperature. A light-brown precipitate formed and was collected by filtration. LC-MS analysis verified precipitate as desired product, 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine-10-carboxylic acid which was carried on without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]=[CH2:24])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].N1C=CC=N1.[OH:30]O.O>ClCCl.C[Re](=O)(=O)=O>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]2[CH2:24][O:30]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5]
Reactant: OO
Reactant: C=CCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: C[Re](=O)(=O)=O
Agent: c1cn[nH]c1
Solvent: O
Solvent: ClCCl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CC2CO2)ccc1Cl

Procedure:
2-Chloro-5-(2-propenyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 5a) (9.4 g), pyrazole (0.45 g) and methyltrioxorhenium(VII) (0.40 g) were stirred together in dichloromethane (40 mL) under nitrogen, and hydrogen peroxide (27.5% wt. solution in water, 13 mL) was added dropwise. The reaction was then monitored by HPLC/MS and further portions of pyrazole, methyltrioxorhenium(VII) and hydrogen peroxide were added over a period of 2 days until the reaction mixture consisted of a 1:1 mixture of starting material and product. The mixture was then poured into water (500 mL), extracted into dichloromethane (3×300 mL), washed with 2M aqueous hydrochloric acid (300 mL), brine (300 mL), saturated aqueous sodium thiosulfate (300 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to give an oil. This was purified by column chromatography eluting with 2:1 isohexane/ethyl acetate to give the sub-titled compound (4.71 g).
Reaction SMILES: [Br:1]Br.[CH2:3]([C:7]12[CH2:19][C:18](=[O:20])[CH:17]=[C:8]1[C:9]1[CH:10]=[CH:11][C:12]([OH:16])=[CH:13][C:14]=1[CH2:15]2)[CH2:4][CH2:5][CH3:6].C([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][C:17]1[C:18](=[O:20])[CH2:19][C:7]2([CH2:3][CH2:4][CH2:5][CH3:6])[CH2:15][C:14]3[CH:13]=[C:12]([OH:16])[CH:11]=[CH:10][C:9]=3[C:8]=12
Reactant: BrBr
Reactant: CCCCC12CC(=O)C=C1c1ccc(O)cc1C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCC12CC(=O)C(Br)=C1c1ccc(O)cc1C2
Temperature: 2.5 °C
Reaction time: 0.75 h

Procedure:
Bromine (0.005 mL, 0.095 mmol) was added to an ice-cold mixture of 8a-butyl-6-hydroxy-8,8a-dihydrocyclopenta[a]inden-2(1H)-one (23 mg, 0.095 mmol) and NaHCO3 (40 mg, 0.48 mmol) in CCl4 (0.3 mL). The resulting mixture was stirred at 0-5° C. for 45 minutes, then diluted with CH2Cl2 (30 mL) and washed with water (30 mL). The aqueous phase was back-extracted with CH2Cl2 (2×10 mL). The combined organics were washed with saturated aqueous Na2S2O3, dried over MgSO4, filtered, and evaporated under vacuum to provide an off-white solid. Recrystallization from hexane/CH2Cl2 afforded 3-bromo-8a-butyl-6-hydroxy-8,8a-dihydrocyclopenta[a]inden-2(1H)-one as small, white needles.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]2[S:6][C:7]([C:9]([O:11]CC)=[O:10])=[CH:8][C:4]=2[CH:3]=1.[Li+].[OH-].CO.Cl>C1COCC1.O>[F:1][C:2]1[CH:15]=[CH:14][C:5]2[S:6][C:7]([C:9]([OH:11])=[O:10])=[CH:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1cc2cc(F)ccc2s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2cc(F)ccc2s1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of 8 (246.68 mg, 1.1 mmol) and LiOH (75.9 mg, 3.3 mmol) in THF (9 mL) was added MeOH (1 mL) and H2O (3 mL), stirred at room temperature for 6 h. Then HCl (1 M) was added to the reaction mixture to pH=4, and extracted with EtOAc (3×15 mL), wash with H2O (3×20 mL). The organic extracts were dried with Na2SO4 and concentrated under reduced pressure. Purified by flash chromatography on silica gel, using ethyl acetate/hexane (4:1) as eluent, give 8-acid as white powder; (212.79 mg, 98.6%). 1H-NMR (300 MHz, acetone-d6): δ 8.14 (s, 1H), 8.10-8.05 (m, 1H), 7.80-7.76 (m, 1H), 7.41-7.34 (m, 1H). 13C NMR (300 MHz, acetone-d6): δ 162.52, 159.31, 140.12, 137.78, 130.11, 124.65, 116.10, 110.66.
Reaction SMILES: [CH:1]1([C:7]2[C:8]([CH2:13][O:14]C(=O)C)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+]>CO>[CH:1]1([C:7]2[C:8]([CH2:13][OH:14])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(=O)OCc1ncccc1C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: OCc1ncccc1C1CCCCC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 78.4 %

Procedure:
A solution of the above ester (0.23 g, 1.0 mmol) in anhydrous MeOH (5 mL) was treated with K2CO3 (0.27 g, 2.0 mmol) and stirred at room temperature for 3.5 h. The mixture was concentrated under reduced pressure and water (5 ml) was added. The aqueous solution was then extracted with CH2Cl2 (3×10 mL) and the combined organic phases dried (Na2SO4), filtered, and concentrated under reduced pressure. This gave the desired (3-cyclohexyl-pyridin-2-yl)-methanol as a brown liquid (0.15 g, 79%) that was used immediately in the next reaction.
Reaction SMILES: [NH2:1][C:2]1[NH:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:5]2=[C:16]([CH3:22])[N:17]=[C:18]([CH2:19][CH2:20][CH3:21])[N:4]2[N:3]=1.Cl>>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:5]2=[C:16]([CH3:22])[N:17]=[C:18]([CH2:19][CH2:20][CH3:21])[N:4]2[N:3]=1
Reactant: CCCc1nc(C)c2n1N=C(N)NC2c1ccc(OC)cc1
Agent: Cl
Product: CCCc1nc(C)c2c(-c3ccc(OC)cc3)nc(N)nn12

Procedure:
2-Amino-4(p-methoxyphenyl)-5-methyl-7-propylimidazo[5,1-f]-as-triazine was prepared from 2-amino-3,4-dihydro-4(p-methoxyphenyl)-5-methyl-7-propylimidazo[5,1-f]-as-triazine (Example 14b). It was converted to its hydrochloride, which was crystallised from a mixture of ethanol and ether and had m.p. 224°-226° (21%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12]Br)[C:5]([O:7][CH3:8])=[O:6].[C:14]([O-:17])(=[O:16])[CH3:15].[K+].O.C(OCC)(=O)C>CN(C)C=O>[C:14]([O:17][CH2:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[Br:1])(=[O:16])[CH3:15]
Reactant: COC(=O)c1ccc(CBr)c(Br)c1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(COC(C)=O)c(Br)c1
Reaction time: 17.5 h
Yield: 63.6 %

Procedure:
10.85 g of methyl 3-bromo-4-(bromomethyl)benzoate was dissolved in 108 mL of N,N-dimethylformamide, to which 3.46 g of potassium acetate was added at room temperature, and this solution was stirred for 17.5 hours at the same temperature. The reaction mixture was added to a mixture of water and ethyl acetate, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=10:1] to yield 6.43 g of methyl 4-[(acetyloxy)methyl]-3-bromobenzoate as white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@@H:19]([NH2:23])[CH2:20][CH2:21][CH3:22])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C1COCC1.C(N(CC)CC)C.[C:42](Cl)(=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C@@H:19]([NH:23][C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:20][CH2:21][CH3:22])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCC[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC[C@H](NC(=O)C(C)(C)C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
To a stirred solution of (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-phenylpentan-2-amine (91a, 13 mg, 0.03 mmol) dissolved in dry THF (150 μmol) were added, at r.t., triethylamine (27.8 μl, 0.20 mmol) and pivaloyl chloride (12.3 ul, 0.1 mmo). The reaction was stirred over night. The solvent was removed under reduced pressure, and the product purified by preparative HPLC.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([OH:10])=[O:9].[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]#[C:38]/[CH:39]=[CH:40]/[CH2:41]O)=[CH:33][CH:32]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([O:10][CH2:41]/[CH:40]=[CH:39]/[C:38]#[C:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:26]2[NH:27][CH:28]=[CH:29][N:25]=2)=[CH:32][CH:33]=1)=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: OC/C=C/C#Cc1ccc(Cc2ncc[nH]2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC/C=C/C#Cc2ccc(Cc3ncc[nH]3)cc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
30 mg (0.089 mM) of 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid together with 21 mg (0.089 mM) of (E)-5-[4-(1-imidazolylmethyl)phenyl)-pent-2-en-4-yn-1-ol, 22 mg (0.107 mM) of dicyclohexylcarbodiimide and 12 mg (0.098 mM) of 4-N,N-dimethylaminopyridine were dissolved in 3 ml of toluene, while heating, and refluxed for six hours. The solution was cooled to room temperature, and the crystals produced were filtered off. The filtrate was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled away, the residue was purified by chromatography on a silica gel column, whereby the captioned compound was obtained. The yield was 49 mg (87%).