Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:17]([OH:19])=O)=[N:11][CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.CN(C=O)C.[O:37]([C:44]1[CH:50]=[CH:49][C:47]([NH2:48])=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O>[CH2:1]([O:8][C:9]1[C:10]([C:17]([NH:48][C:47]2[CH:46]=[CH:45][C:44]([O:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:50][CH:49]=2)=[O:19])=[N:11][CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: COc1ccnc(C(=O)O)c1OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccnc(C(=O)Nc2ccc(Oc3ccccc3)cc2)c1OCc1ccccc1
Reaction time: 8 h
Yield: 71.3 %

Procedure:
3-Benzyloxy-4-methoxypicolinic acid (0.65 g, 2.5 mmol) and 0.50 g (3.0 mmol) of carbonyldiimidazole were mixed into anhydrous DMF to prepare a suspension (8 ml). An anhydrous DMF solution (2 ml) of 0.56 g (3.0 mmol) of 4-phenoxyaniline was added dropwise to this suspension, and a reaction was allowed to proceed at room temperature overnight. Water (10 ml) was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the dried organic layer was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate-n-hexane) to give 0.76 g (yield 71%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[CH2:7]([CH2:22][C:23](Cl)=[O:24])[CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH3:15])[CH3:10].[OH-].[Na+]>CCOCC>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:23](=[O:24])[CH2:22][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH3:15])[CH3:10]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(=O)Cl
Reactant: CN(C)CCN
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(=O)NCCN(C)C
Yield: 88 %

Procedure:
A solution of 12.3 g of N,N-dimethylethylenediamine in 50 cc of ether was placed in a three-necked flask equipped with a stirrer, a dropping funnel and a thermometer. Then 37 g of the above-mentioned farnesylacetyl chloride was added dropwise at 5° to 10° C. After completion of the dropping, the reaction was continued at room temperature for an hour. After the reaction, 70 g of a 10% aqueous solution of sodium hydroxide was added, the aqueous layer was separated from the ether layer and extracted with ether, and the ether extract was combined with the ether layer. The ether was distilled off from the ether solution. The residue was subjected to preparative liquid chromatography (Waters Associates, Prep LC/System 500), which gave 38.5 g of N,N-dimethyl-N'-farnesylacetylethylenediamine (1). The structure was identified by proton NMR and mass spectrometry (M.S.). The NMR data are shown below.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:14])([CH3:13])[C:9]([O:11]C)=[O:10])[CH:5]=[N:6][CH:7]=1.C[Si](C)(C)[O-].[K+:20]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:14])([CH3:13])[C:9]([O-:11])=[O:10])[CH:5]=[N:6][CH:7]=1.[K+:20]
Reactant: COC(=O)C(C)(C)c1cncc(Br)c1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Product: CC(C)(C(=O)[O-])c1cncc(Br)c1

Procedure:
In analogy to the procedure described for the preparation of example 59 [B], methyl 2-(5-bromopyridin-3-yl)-2-methylpropanoate (example 72 [A]) was reacted with 90% potassium trimethylsilanolate to give the title compound as a light brown solid. MS: 244.3 (M+H+).
Reaction SMILES: [C:1]([C:4](=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=1)[C:5]([O:7][CH:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:6])(=O)[CH3:2].[N+](C1C=C(C=CC=1)C=O)([O-])=O.C(OC(C1C=CC=CC=1)CN1CCCCC1)(=O)CC(C)=O.[NH2:64][C:65]1[CH:69]=[CH:68][NH:67][N:66]=1>C(O)C>[CH3:2][C:1]1[NH:64][C:65]2[N:66]([N:67]=[CH:68][CH:69]=2)[CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[C:4]=1[C:5]([O:7][CH:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:6]
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OC(CN1CCCCC1)c1ccccc1
Reactant: Nc1cc[nH]n1
Agent: CC(=O)CC(=O)OC(CN1CCCCC1)c1ccccc1
Agent: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: CC1=C(C(=O)OC(CN2CCCCC2)c2ccccc2)C(c2cccc([N+](=O)[O-])c2)n2nccc2N1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To 1-phenyl-2-piperidinoethyl α-acetyl-3-nitrocinnamate prepared from 7.5 g of 3-nitrobenzaldehyde and 14.5 g of 1-phenyl-2-piperidinoethyl acetoacetate is added a solution of 4.2 g of 3-aminopyrazole in ethanol, and then stirred at 50° C. for 3 hours. The mixture is concentrated at reduced pressure, and the residue is purified by column chromatography on silica gel with chloroform-ethyl acetate-ethanol eluents to give two forms of diastereromers. The initally eluated solution is concentrated and the residue is recrystallized from ethanol to give one form (α-form) of diastereomer of 1-phenyl-2-piperidinoethyl 5-methyl-7-(3-nitrophenyl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylate, melting at 92°-93° C. Then, the subsequently eluated solution is concentrated and the residue is recrystallized from ethanol to give the other form (β-form) of diastereomer of 1-phenyl-2-piperidinoethyl 5-methyl-7-(3-nitrophenyl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylate, melting at 191°-192° C.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[C:7]([F:13])[C:5]=2[N:6]=1>C1COCC1.[O-2].[Mn+4].[O-2]>[Br:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH:11]=[O:12])[CH:8]=[C:7]([F:13])[C:5]=2[N:6]=1
Reactant: OCc1cc(F)c2nc(Br)sc2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: O=Cc1cc(F)c2nc(Br)sc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.8 %

Procedure:
A mixture of (2-bromo-4-fluorobenzo[d]thiazol-6-yl)methanol (0.269 g, 1.03 mmol) and manganese (IV) oxide (activated, 85%, 1.47 g, 14.4 mmol) in THF (15 mL) was stirred at rt for 16 hr. Solid material was removed by filtration through Celite® 545, and the filtrate was concentrated under vacuum. The residue was diluted with AcOEt, washed with brine, and dried over anhydrous MgSO4. Evaporation of solvent under vacuum gave the title compound (0.136 g, 61% yield) as a white solid.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[CH:5][C:6]([N:18]2[C:22]([CH2:23]O)=[N:21][N:20]=[C:19]2[CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])=[C:7]([CH:17]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16])=[O:9].[C:32]1(=[O:42])[NH:36][C:35](=[O:37])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>COCCOC>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[CH:5][C:6]([N:18]2[C:22]([CH2:23][N:36]3[C:32](=[O:42])[C:33]4=[CH:41][CH:40]=[CH:39][CH:38]=[C:34]4[C:35]3=[O:37])=[N:21][N:20]=[C:19]2[CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])=[C:7]([CH:17]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16])=[O:9]
Reactant: CN(C)CCc1nnc(CO)n1-c1ccc(C(F)(F)F)cc1C(=O)c1ccccc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CN(C)CCc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(C(F)(F)F)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 1B, 5-(trifluoromethyl)-2'-chloro-2-[3-[2-(dimethylamino)ethyl]-5-(hydroxymethyl)-4H-1,2,4-triazol-4-yl]benzophenone in 1,2-dimethoxyethane is treated with phthalimide, triphenylphosphine and diethyl azodicarboxylate to give 5-(trifluoromethyl)-2'-chloro-2-[3-[2-(dimethylamino)ethyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][S:6][CH:7]=1.[C:12](Cl)(Cl)=[S:13].C(=O)(O)[O-].[Na+]>O.ClCCl>[N:2]([C:3]1[C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][S:6][CH:7]=1)=[C:12]=[S:13]
Reactant: COC(=O)c1cscc1N
Reactant: S=C(Cl)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cscc1N=C=S
Reaction time: 1 h

Procedure:
19.4 g of methyl 4-aminothiophen-3-carboxylate hydrochloride were added to a suspension of 7.7 ml of thiophosgene and 18.5 g of sodium bicarbonate in 70 ml of water and 200 ml of dichloromethane at room temperature in the course of 30 minutes, and stirring was carried out for 1 hour at room temperature. After separation of the phases, the aqueous phase was extracted once with dichloromethane and the combined organic phases were washed once with water, dried over sodium sulfate and evaporated down.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH:13]3[O:17][CH2:16][CH2:15][O:14]3)[C:6]=2[N:18]=1.[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1.[H-].[Na+].Cl>CN(C)C=O.O.C(OCC)(=O)C>[O:14]1[CH2:15][CH2:16][O:17][CH:13]1[CH2:12][N:7]1[C:8](=[O:11])[CH:9]=[N:10][C:5]2[CH:4]=[CH:3][C:2]([N:19]3[CH:23]=[N:22][CH:21]=[N:20]3)=[N:18][C:6]1=2
Reactant: c1nc[nH]n1
Reactant: O=c1cnc2ccc(Cl)nc2n1CC1OCCO1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cnc2ccc(-n3cncn3)nc2n1CC1OCCO1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 22.9 %

Procedure:
To a solution of 0.30 g of 6-chloro-4-(1,3-dioxolan-2-ylmethyl)pyrido(2,3-b)pyrazin-3(4H)-one and 78 mg of 1,2,4-triazole in 9 mL of N,N-dimethylformamide, 48 mg of 60% sodium hydride was added, and the mixture was stirred at 40 to 50° C. for 1 hour 30 minutes. Thereto was further added 78 mg of 1,2,4-triazole and 48 mg of 60% sodium hydride, and the mixture was stirred at 40 to 50° C. for 1 hour 30 minutes, and stirred at 60 to 70° C. for 20 minutes. The reaction mixture was charged with a mixed solution of ethyl acetate and water and neutralized with 2.0 mol/L hydrochloric acid, and the insoluble substance was filtered off. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed sequentially with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by flash silica gel column chromatography using gradient elution with hexane:ethyl acetate=80:20 to 30:70 and washed with diisopropyl ether to obtain 77 mg of 4-(1,3-dioxolan-2-ylmethyl)-6-(1H-1,2,4-triazole-1-yl)pyrido(2,3-b)pyrazin-3(4H)-one as a light red solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[N:10]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH:19]4[CH2:22][O:21][CH2:20]4)[CH2:15][C:14]3([CH3:24])[CH3:23])=[O:12])[S:8][C:6]=2[N:7]=1.[CH2:31]([C:33]1[NH:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1)[CH3:32].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:23][C:14]1([CH3:24])[CH2:15][N:16]([CH:19]2[CH2:22][O:21][CH2:20]2)[CH2:17][CH2:18][N:13]1[C:11]([C:9]1[S:8][C:6]2[N:7]=[C:2]([N:34]3[C:35]4[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=4[N:37]=[C:33]3[CH2:31][CH3:32])[N:3]=[C:4]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:5]=2[N:10]=1)=[O:12]
Reactant: CCc1nc2ccccc2[nH]1
Reactant: CC1(C)CN(C2COC2)CCN1C(=O)c1nc2c(N3CCOCC3)nc(Cl)nc2s1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)N3CCN(C4COC4)CC3(C)C)sc2n1
Temperature: 150 °C

Procedure:
A mixture of (5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-yl)-(2,2-dimethyl-4-oxetan-3-ylpiperazin-1-yl)methanone (137 mg, 0.30 mmol), 2-ethylbenzimidazole (47 mg, 0.32 mmol), tris(dibenzylideneacetone)dipalladium (8 mg, 2.5 mol %), XPhos (13 mg, 10 mol %) and Cs2CO3 (140 mg, 0.43 mmol) in DMF (4 mL) was purged with argon then heated at 150° C. for 30 min in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 1-2%) followed by triturating with EtOAc affording 793 (22 mg, 13%). LCMS (method I): RT 3.79 min [M+H]+ 563.3. 1H NMR (CDCl3, 400 MHz): δ 8.07-8.03 (1 H, m), 7.76-7.75 (1 H, m), 7.30-7.29 (2 H, m), 4.72 (2 H, t, J=6.51 Hz), 4.62 (2 H, t, J=6.07 Hz), 4.40 (4 H, brd s), 4.07-4.06 (2 H, m), 3.89 (4 H, t, J=4.72 Hz), 3.53-3.52 (1 H, m), 3.36 (2 H, q, J=7.46 Hz), 2.47 (2 H, t, J=5.08 Hz), 2.25 (2 H, s), 1.56 (6 H, s), 1.44 (3 H, t, J=7.45 Hz)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([OH:15])=[C:13]([C:16]([OH:18])=O)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].Cl.[NH:20]1[CH2:25][CH2:24][C:23]2([C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26]2)[CH2:22][CH2:21]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([OH:15])=[C:13]([C:16]([N:20]3[CH2:25][CH2:24][C:23]4([C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH2:27][CH2:26]4)[CH2:22][CH2:21]3)=[O:18])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn2c(O)c(C(=O)O)cnc12
Reactant: c1ccc2c(c1)CCC21CCNCC1
Agent: Cl
Product: CCOC(=O)c1cnn2c(O)c(C(=O)N3CCC4(CCc5ccccc54)CC3)cnc12
Yield: 65.1 %

Procedure:
In the same manner as in Example 1, step 2 and using 3-ethoxycarbonyl-7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.27 g, 1.06 mmol) obtained in Example 19, step 2 and spiro[indane-1,4′-piperidine]hydrochloride (0.3 g, 1.32 mmol), the title compound (0.29 g, 64%) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][NH:15][C:16](=[O:26])[CH2:17][NH:18][C:19]1[S:20][C:21]([CH:24]=[O:25])=[CH:22][N:23]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].FC(F)(F)C(O)=O>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][NH:15][C:16](=[O:26])[CH2:17][NH:18][C:19]1[S:20][C:21]([CH2:24][OH:25])=[CH:22][N:23]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](CNC(=O)CNc1ncc(C=O)s1)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](CNC(=O)CNc1ncc(CO)s1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
To a solution of material from Example 106 (10 mg, 0.026 mmol) in methanol (1.5 mL) is added sodium borohydride (3.5 mg, 0.093 mmol). The reaction is allowed to stir at room temp for 1 min, cooled to 0° C., quenched with trifluoroacetic acid (26.5 μL, 0.344 mmol) and the solvent removed in vacuo. The resulting residue is used immediately in the next reaction. LC/MS (Condition A): ret, T=2.54 min, (M+Na) 411.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:25])[C:11](C(OCC)=O)=[C:12]([C:16]([F:19])([F:18])[F:17])[N:13]([CH3:15])[CH:14]=1.B(Br)(Br)Br.N1C2C(=CC=CC=2)C=CC=1.O>ClCCl.[Cu]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:25])[CH:11]=[C:12]([C:16]([F:19])([F:17])[F:18])[N:13]([CH3:15])[CH:14]=1
Reactant: CCOC(=O)c1c(C(F)(F)F)n(C)cc(-c2ccc(Cl)cc2Cl)c1=O
Agent: [Cu]
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Solvent: c1ccc2ncccc2c1
Product: Cn1cc(-c2ccc(Cl)cc2Cl)c(=O)cc1C(F)(F)F
Temperature: -60 °C
Reaction time: 3 h
Yield: 26.9 %

Procedure:
4.1 g (10.4 mmol) of 5-(2,4-dichlorophenyl)-3-ethoxycarbonyl-1-methyl-2-trifluoromethyl-4(1H)-pyridone was dissolved in 100 ml of dichloromethane, and 10 ml of a dichloromethane solution of 3N boron tribromide was dropwise added thereto under cooling to −60° C. After stirring at room temperature for 3 hours, the reaction solution was poured into ice water, and precipitated crystals were collected by filtration and washed with water. They were dried under reduced pressure to obtain crude crystals. To 50 ml of quinoline, the crude crystals and 0.04 g (0.6 mmol) of copper were added, followed by stirring at 170° C. for 1 hour. This reaction solution was poured into water, and precipitated crude crystals were collected by filtration. The crude crystals were dissolved in a small amount of DMF, and insoluble matters were filtered off. Then, the filtrate was poured into water, and precipitated crystals were collected by filtration. The crystals were washed with water and then dried to obtain 0.9 g (yield: 26%) of the desired product. Melting point: 205-206° C.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]#[N:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CCOCC>C1COCC1>[NH2:17][CH2:16][CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][CH:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]1
Reactant: N#CCCN1CCC(Cc2ccccc2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: NCCCN1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a stirred solution of 3-(4-benzylpiperidin-1-yl)propionitrile (8.20 g, 35.9 mmol, 1.0 equiv) in anhydrous THF (20 mL) under argon was added a solution of BH3 in THF (1.0 M, 126 mL, 3.5 equiv) at room temperature. The mixture was refluxed for 4.5 hours, then cooled to room temperature and concentrated to a volume of about 30 mL. Aqueous HCl (6 N, 80 mL) was added and stirring was continued for 2 hours at 55-60° C. The mixture was basified to pH 9 by addition of 6 N aq. NaOH and extracted with CH2Cl2 (3×150 mL). The combined organic solutions were dried over MgSO4 and concentrated. The residue was dissolved in CH2Cl2 (20 mL) and treated with HCl in ether (1.0 M, 75 mL, 2.1 equiv). The solvents were removed, ether (60 mL) was added, the mixture was filtered, and the filter cake was washed with ether (2×30 mL). Water (40 mL) was added to the resulting white solid, the pH was adjusted to 10 with 1 M NaOH, and the aqueous phase was extracted with CH2Cl2 (3×80 mL). The combined organic solutions were dried over MgSO4 and concentrated to give 7.59 g (91%) of colorless oil, which was characterized spectroscopically.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:40]=[CH:39][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:34][CH2:35][CH2:36][CH:37]=[O:38])[C:24](=[O:33])[C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].CC(=CC)C.Cl([O-])=[O:47].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.O>[CH2:1]([O:8][C:9]1[CH:40]=[CH:39][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:34][CH2:35][CH2:36][C:37]([OH:47])=[O:38])[C:24](=[O:33])[C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: [O-][Cl+][O-]
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CCCC=O)C(=O)c3ccc(OC)cc3)cc2)cc1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CCCC(=O)O)C(=O)c3ccc(OC)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a stirring solution of 4-((4-methoxy-N-(4-oxobutyl)benzamido)methyl)phenyl 4-(heptyloxy)benzoate INT-8 (264 mg, 0.484 mmol) in tert-butanol (12 mL) was added 2-methylbut-2-ene (4.7 ml, 44.4 mmol). A solution of sodium chlorite (400 mg, 4.42 mmol) and sodium dihydrogen phosphate (400 mg, 3.33 mmol) in H2O (2.5 mL) were added and the reaction stirred for 1 h at room temperature. The reaction was quenched with aq. Na2S2O5 (10 mL) and brine (10 mL). The aqueous phase was extracted with DCM and the combined organic phases were dried over MgSO4 and concentrated. The crude product was purified by chromatography (EA/hexanes) to provide 150 mg (55%) of 4-(N-(4-((4-(heptyloxy)benzoyl)oxy)benzyl)-4-methoxybenzamido)butanoic acid 88. LCMS-ESI (m/z) calculated for C33H39NO7: 561; found 560 [M−H]−, tR=9.53 min (Method 4).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10](O)=[O:11])[CH:5]=[C:6]([Br:8])[CH:7]=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][OH:11])[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: O=C(O)Cc1cc(Br)cc(Br)c1
Solvent: C1CCOC1
Product: OCCc1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (3,5-dibromo-phenyl)acetic acid (1.543 g, 5.2 mmol) in tetrahydrofuran (40 mL) was cooled to 0° C. Within 30 minutes borane tetrahydrofuran complex (1 M, 9.19 mL) was added. After complete addition the ice bath was removed and the reaction mixture warmed to room temperature within 25 minutes. After 3 hours, the mixture was cooled to −2° C., quenched by addition of methanol (10 mL) and evaporated under reduced pressure. The residue was dissolved in dichloromethane, the resulting solution was washed with hydrochloric acid (1 N, 50 mL), a saturated solution of sodium hydrogencarbonate (50 mL), and brine. The organic layer was dried over sodium sulfate and evaporated under reduced pressure and yielded. The residue was chromatographed on silica gel using a gradient of heptane/ethyl acetate=100/0 to 2/1 as the eluent. There were obtained 1.29 g (88% of theory) of the title compound as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:19])[CH2:9][C:10]1[NH:14][C:13]2[CH2:15][CH2:16][CH2:17][CH2:18][C:12]=2[N:11]=1.C[O-].[Na+].[C:23](OC)(=[O:26])[C:24]#[CH:25]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:9]1[CH:25]=[CH:24][C:23](=[O:26])[N:14]2[C:13]3[CH2:15][CH2:16][CH2:17][CH2:18][C:12]=3[NH:11][C:10]=12)=[O:19]
Reactant: Cc1ccccc1C(=O)Cc1nc2c([nH]1)CCCC2
Reactant: C#CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Product: Cc1ccccc1C(=O)c1ccc(=O)n2c3c([nH]c12)CCCC3

Procedure:
The compound is prepared as described in example 20 with 1450 mg (5.90 mmol) of 1-(2-Methylphenyl)-2-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)ethanone (example XXXX), 637.2 mg (11.80 mmol) of sodium methylate and 495.8 mg (5.90 mmol) methyl propiolate.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH3:31])[C:10]([N:13]2[CH2:30][CH2:29][C:16]3([C:20](=[O:21])[N:19]([C@H:22]4[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)[CH2:15][CH2:14]2)=[N:11][CH:12]=1.C(N(CC)C(C)C)(C)C>C(#N)C.CO>[OH:28][C@@H:25]1[CH2:26][CH2:27][C@H:22]([N:19]2[CH2:18][CH2:17][C:16]3([CH2:29][CH2:30][N:13]([C:10]4[N:11]=[CH:12][C:7]([NH:6][C:2](=[O:3])[O:4][CH3:5])=[CH:8][C:9]=4[CH3:31])[CH2:14][CH2:15]3)[C:20]2=[O:21])[CH2:23][CH2:24]1
Reactant: COC(=O)Cl
Reactant: Cc1cc(N)cnc1N1CCC2(CC1)CCN([C@H]1CC[C@@H](O)CC1)C2=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)Nc1cnc(N2CCC3(CC2)CCN([C@H]2CC[C@@H](O)CC2)C3=O)c(C)c1
Reaction time: 2 h

Procedure:
Methyl chloroformate (6.0 μL) was added to a mixture of 8-(5-amino-3-methylpyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,8-diazaspiro[4.5]decan-1-one (18.0 mg) and N,N-diisopropylethylamine (20.0 μL) in acetonitrile (1.0 mL). The mixture was stirred for 2 h, and was diluted with methanol. The resulting solution was purified by prep-HPLC under basic condition to afford methyl {6-[2-(cis-4-hydroxycyclohexyl)-1-oxo-2,8-diazaspiro[4.5]dec-8-yl]-5-methylpyridin-3-yl}carbamate. LCMS: (M+H)+=416.2.
Reaction SMILES: C[O-].[Na+].[Na].Cl.[NH2:6][OH:7].[Cl:8][C:9]1[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=1[Cl:22])[NH:12][CH2:13][C:14](OCC)=[O:15]>CO>[Cl:8][C:9]1[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=1[Cl:22])[NH:12][CH2:13][C:14]([NH:6][OH:7])=[O:15]
Reactant: CCOC(=O)CNc1ccc(Cl)c(Cl)c1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(CNc1ccc(Cl)c(Cl)c1)NO
Reaction time: 8 h
Yield: 36 %

Procedure:
A solution of sodium methylate, that is to say 3.22 g (0.14 gram atom) of sodium in 75 ml of methanol is mixed in the cold with 4.9 g (0.07 mol) of hydroxylamine hydrochloride in solution in 100 ml of methanol, the sodium chloride is filtered off and 16.1 g (0.065 mol) of ethyl 3,4-dichloroanilinoacetate are added to the filtrate. The reactants are left in contact overnight, the mixture is evaporated to dryness in vacuo, the residue is taken up with water, the solution is filtered over charcoal and the product is precipitated with 3 N HCl and filtered off. Recrystallisation from ethyl acetate gives CRL 40,500. Melting point = 138°-140° C. (with decomposition). Yield: 36%.