Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1.F[B-](F)(F)F.[CH2:16]([O+](CC)CC)[CH3:17]>C(Cl)Cl>[CH2:16]([O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1)[CH3:17]
Reactant: COC(=O)c1cc(O)no1
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOc1cc(C(=O)OC)on1
Reaction time: 8 h
Yield: 86 %

Procedure:
A stirred suspension of 3.53 g (24.67 mmole) of a commercial sample of methyl 3-hydroxy-5-isoxazolecarboxylate in 50 ml of methylene chloride was treated dropwise with a solution of triethyloxonium tetrafluoroborate (5.62 g, 29.60 mmole) dissolved in 30 ml of methylene chloride at room temperature. After stirring overnight the solution was washed with water (2×30 ml), 5% sodium bicarbonate (2×30 ml) and water once again. The organic layer was dried (magnesium sulfate) and evaporated in vacuo to furnish the title compound (3.61 g, 86% yield) as a light yellow solid, m.p. 77°-9° C. 1H-NMR delta, 6.65 (1H, s), 3.93 (2H, q, J=7.4 Hz), 3.87 (3H, s) and 1.21 (3H, t, J=7.4 Hz); EIMS (m/z): 171 (M+, 48%), 156 (M+ -CH3, 4%), 143 (C5H5NO4 , 31%), 112 (C4H2NO3, 12%) and 69 (C3H3NO, base); ir (potassium bromide): 3105, 1744, 1611, 1441, 1241, 1106, 974 and 797 cm-1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15](Cl)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([C:23]1[N:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>>[CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:29][C:26]3[CH:27]=[N:28][C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:24][CH:25]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2c1CN(Cc1ccccc1)CC2
Reactant: CC(C)(C)c1ccc(N)cn1
Product: CC(C)(C)c1ccc(Nc2ncnc3c2CN(Cc2ccccc2)CC3)cn1

Procedure:
The title compound was prepared substantially according to the procedure given for Compound 1A, using 6-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (Intermediate 2), and 6-tert-butyl-pyridin-3-ylamine to give the desired N-benzyl intermediate as a brown solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[C:20]([C:22]1[CH:23]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:26][CH:27]=1)#[N:21]>CCCCCC.C(OCC)(=O)C>[O:17]1[CH2:18][CH2:19][N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:26]3[CH:27]=[C:22]([CH:23]=[CH:24][CH:25]=3)[C:20]#[N:21])[N:3]=2)[CH2:15][CH2:16]1
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Reactant: CC1(C)OB(c2cccc(C#N)c2)OC1(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: N#Cc1cccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)c1
Yield: 57 %

Procedure:
Following the general procedure A, 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine was coupled with 3-cyanophenylboronic acid pinacol ester with reaction time of 15 h. Column chromatography (hexane/ethyl acetate 1:1) gave 57% of the title compound as an colorless solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:36])[C:20]=3[C:24](=[O:35])[NH:25][CH2:26][CH:27]3[CH2:32][CH2:31][C:30]([F:34])([F:33])[CH2:29][CH2:28]3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.ClCCl.Cl.O1CCOCC1.C(=O)(O)[O-].[Na+]>>[F:34][C:30]1([F:33])[CH2:31][CH2:32][CH:27]([CH2:26][NH:25][C:24]([C:20]2[C:21]3[CH:22]=[CH:23][C:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[N:15][C:16]=3[CH:17]=[CH:18][C:19]=2[Cl:36])=[O:35])[CH2:28][CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3c(C(=O)NCC4CCC(F)(F)CC4)c(Cl)ccc3n2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(C3CCNCC3)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.2 %

Procedure:
To a stirred solution of 4-{6-chloro-5-[(4,4-difluoro-cyclohexylmethyl)-carbamoyl]-quinolin-2-yl}-piperidine-1-carboxylic acid tert-butyl ester (50 mg, 0.09 mmol, 1.00 eq) in dichloromethane (5.00 mL, 77.14 mmol, 100 V) at 0 OC was added 4M HCl in dioxane (2 mL, 8.00 mmol, 89.05 eq) dropwise under nitrogen. The reaction mixture was stirred at RT for 2 h and the solvent was evaporated completely. The crude obtained was basified with 10% sodium bicarbonate solution and was extracted with DCM. The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure. The crude obtained was purified by preparative HPLC to afford the title compound (10 mg, 0.02 mmol, 24.5%) as a pale brown solid. 1H NMR (400 MHz, DMSO-d6): δ 8.79 (t, J=5.91 Hz, 1H), 7.99 (dd, J=9.42, 9.0 Hz, 2H), 7.76 (d, J=9.03 Hz, 1H), 7.58 (d, J=8.72 Hz, 1H), 3.43 (s, 1H), 3.25-3.29 (m, 2H), 3.03-3.06 (m, 2H), 2.91-2.98 (m, 1H), 2.58-2.67 (m, 2H), 2.02-2.04 (m, 2H), 1.64-1.84 (m, 9H), 1.23-1.30 (m, 2H). m/z: 422.0 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:8][CH2:7]1.[O-:22][C:23]#[N:24].[Na+].[OH-].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([CH:12]2[CH2:13][CH2:14][N:15]([C:23]([NH2:24])=[O:22])[CH2:16][CH2:17]2)[CH2:10][CH2:11]1
Reactant: N#C[O-]
Reactant: Clc1ccc(OC2CCN(C3CCNCC3)CC2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)N1CCC(N2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
4-(3,4-Dichlorophenoxy)-1,4′-bipiperidine (2.0 g) was dissolved in glacial acetic acid (0.608 ml), the solution was diluted with water (6 ml) and added with stirring to a solution of sodium cyanate (0.395 g) in warm water (3 ml). The reaction was allowed to stand for 30 mins. 2M Sodium hydroxide solution was added until the solution was alkaline. The resulting precipitate was collected and washed with water followed by dichloromethane and then dried to leave the sub-title compound (1.3 g; ES+ 372/374).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][CH2:20][O:19][CH2:18]4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[N:29]1([C:2]2[N:7]=[C:6]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[C:14]([CH:17]5[CH2:22][CH2:21][CH2:20][O:19][CH2:18]5)[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:4][CH:3]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1
Reactant: Fc1cccc(-c2nn(C3CCCCO3)c3cnc(C4CCCOC4)cc23)n1
Reactant: C1CNCCN1
Product: c1cc(-c2n[nH]c3cnc(C4CCCOC4)cc23)nc(N2CCNCC2)c1
Yield: 20 %

Procedure:
Following the procedure of Example 144, 3-(6-fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-5-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-c]pyridine and piperazine were reacted and consequently deprotected by the procedure of Example 131, to give a racemic mixture purified via reverse phase HPLC using a gradient of MeOH in water with 0.1% NH4OH to afford 30 mg (20%) of 3-(6-(piperazin-1-yl)pyridin-2-yl)-5-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-c]pyridine. ESI MS m/z 365.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O[CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[O:10][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1
Reactant: OC1CCNCC1
Reactant: OC(c1ccccc1)c1ccc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc(C(OC2CCNCC2)c2ccccc2)c(F)c1
Temperature: 25 °C
Yield: 54.9 %

Procedure:
Molecular sieves, (2,4-difluorophenyl)phenylmethanol (3.69 g, 16.8 mmol), and p-toluenesulfonic acid monohydrate (3.84 g, 20.2 mmol) were added to a suspension of 4-hydroxypiperidine (1.7 g, 16.8 mmol) in toluene, and the mixture was refluxed for 3 hours while removing water using a Dean-Stark condenser. After the completion of the reaction was confirmed by HPLC, the reaction mixture was allowed to cool down to a room temperature. From the reaction mixture, the insoluble matter was removed, and then the solvent was distilled off. The resulting residue was dissolved in ethyl acetate and washed with a 2-N sodium hydroxide solution 3 times. The organic layer was dried over magnesium sulfate, and then the solvent was distilled off. Thus the title compound (2.8 g, 54.9%) was obtained as an oily substance.
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:7]([NH:8][C:9]([CH:11]2[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[N:12]2[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][NH:26][C@H:27]([CH2:33][N:34]([CH3:36])[CH3:35])[CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH:20]=2)=[O:10])[CH2:6][C@H:5]2[CH2:37][C@@H:3]1[C:4]2([CH3:39])[CH3:38].[Cl:40][C:41]1[CH:42]=[CH:43][C:44]([OH:49])=[C:45]([CH:48]=1)[CH:46]=O>>[CH3:1][C@@H:2]1[C@@H:7]([NH:8][C:9]([CH:11]2[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[N:12]2[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]([CH2:46][C:45]3[CH:48]=[C:41]([Cl:40])[CH:42]=[CH:43][C:44]=3[OH:49])[C@H:27]([CH2:33][N:34]([CH3:35])[CH3:36])[CH2:28][C:29]([CH3:30])([CH3:31])[CH3:32])[CH:20]=2)=[O:10])[CH2:6][C@H:5]2[CH2:37][C@@H:3]1[C:4]2([CH3:38])[CH3:39]
Reactant: C[C@@H]1[C@@H](NC(=O)C2CCS(=O)(=O)N2Cc2cccc(CN[C@H](CN(C)C)CC(C)(C)C)c2)C[C@H]2C[C@@H]1C2(C)C
Reactant: O=Cc1cc(Cl)ccc1O
Product: C[C@@H]1[C@@H](NC(=O)C2CCS(=O)(=O)N2Cc2cccc(CN(Cc3cc(Cl)ccc3O)[C@H](CN(C)C)CC(C)(C)C)c2)C[C@H]2C[C@@H]1C2(C)C
Yield: 17.8 %

Procedure:
Using Method A, 2-{3-[((S)-1-Dimethylaminomethyl-3,3-dimethyl-butylamino)methyl]-benzyl}-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid((1S,2S,3S,5R)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amide (Intermediate 6, 0.200 g, 0.360 mmol) and 5-chloro-2-hydroxy-benzaldehyde (available from Aldrich; 0.066 g, 0.430 mmol) were reacted to form 2-(3-{[(5-Chloro-2-hydroxy-benzyl)-((S)-1-dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid((1S,2S,3S,5R)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amide (0.0450 g, 18%). Mass spectrum: m/Z: 701.5 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[N:5][C:6]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:7][C:8]=1[C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH:18]=[CH:19][CH2:20][CH2:21][CH3:22])=[CH:15][CH:14]=[CH:13][CH:12]=2>[Pd].C(O)C>[CH3:1][O:2][C:3]1[N:4]=[N:5][C:6]([C:23]2[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=2)=[CH:7][C:8]=1[C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: CCCC=Cc1c(-c2cc(-c3ccncc3)nnc2OC)[nH]c2ccccc12
Agent: [Pd]
Solvent: CCO
Product: CCCCCc1c(-c2cc(-c3ccncc3)nnc2OC)[nH]c2ccccc12
Reaction time: 8 h

Procedure:
20 mg Palladium catalyst (10% on Charcoal) is added to a solution of 145 mg 2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-3-pent-1-enyl-1H-indole in 1 ml ethanol and the suspension is stirred under a hydrogen atmosphere for 8 hours. The crude product is isolated by filtration and removal of the solvent and purified by silicagel chromatography (ethylacetate/n-hepatane)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C:16](=[O:17])[N:15]2[C@@H:10]1[CH2:11][S:12][CH:13]=[C:14]2[C:18]([O:20]CC(Cl)(Cl)Cl)=[O:19])=[O:7])([CH3:4])(C)C.Cl.[C:27](O)(=O)[CH3:28]>CN(C)C=O.O.[Zn]>[CH2:1]([O:5][C:6]([NH:8][C@H:9]1[C:16](=[O:17])[N:15]2[C@@H:10]1[CH2:11][S:12][CH:13]=[C:14]2[C:18]([OH:20])=[O:19])=[O:7])[CH2:4][CH2:27][CH3:28]
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H]1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=CSC[C@H]12
Agent: Cl
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOC(=O)N[C@H]1C(=O)N2C(C(=O)O)=CSC[C@H]12
Reaction time: 3 h

Procedure:
To a solution of 43 mg (0.1 mmole) of trichloroethyl cis-7-t-butoxycarbonylamino-8-oxo-4-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate in 6 ml of dimethylformamide and 6 ml of acetic acid is added over a 1.5 hr period 250 mg (3.8 mmole) zinc dust. The mixture is stirred vigorously for 3 hrs and then diluted with 50 ml of water. The mixture is acidified with dilute HCl, filtered and extracted with ethyl acetate. The organic phase is extracted with 5% NaHCO3 which is acidified and reextracted into ethyl acetate. The final extracts are washed with brine, dried, and evaporated to give cis-7-butoxycarbonylamino-8-oxo-4-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][N:18]([CH3:20])[C:17](=[O:21])[N:16]([CH3:22])[CH2:15]2)=[CH:10][CH:9]=1)(C)(C)C.C1C(=O)N([Br:31])C(=O)C1.C(Cl)Cl.C([O-])(O)=O.[Na+].[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>>[F:43][C:42]([F:45])([F:44])[C:40]([OH:46])=[O:41].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][N:18]([CH3:20])[C:17](=[O:21])[N:16]([CH3:22])[CH2:15]2)=[CH:10][C:9]=1[Br:31]
Reactant: O=C1CCC(=O)N1Br
Reactant: CN1CC(c2ccc(NC(=O)OC(C)(C)C)cc2)CN(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CC(c2ccc(N)c(Br)c2)CN(C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
[4-(1,3-Dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-phenyl]-carbamic acid tert-butyl ester (as prepared in the previous step, 106 mg, 0.333 mmol) was dissolved in TFA (2 mL). The resulting mixture was stirred at RT for 30 min and concentrated. The residue obtained was dried in vacuo for 30 min and redissolved in DCM (5 mL). The resulting solution was cooled to 0° C. and NBS (64 mg, 0.35 mmol) was added. The reaction mixture was stirred at RT for 30 min and treated with DCM (20 mL) and satd aq NaHCO3 (20 mL). The organic layer was separated, dried (Na2SO4) and concentrated to afford the title compound (92 mg, 92%), which was directly used in next step without further purification. Mass spectrum (ESI, m/z): Calcd. for C12H16BrN3O, 298.0 and 300.0 (M+H), found 298.2 and 300.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3([CH3:26])[O:25][CH2:24][CH2:23][O:22]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([F:36])=[C:32]([CH:35]=1)[CH2:33]Br>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH2:33][C:32]2[CH:35]=[C:28]([Cl:27])[CH:29]=[CH:30][C:31]=2[F:36])[C:15]2[CH:20]=[CH:19][C:18]([C:21]3([CH3:26])[O:22][CH2:23][CH2:24][O:25]3)=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(Cl)cc1CBr
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C3(C)OCCO3)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(N(Cc2cc(Cl)ccc2F)c2ccc(C3(C)OCCO3)cc2)CC1
Yield: 64.5 %

Procedure:
Using general procedure H, 4-[4-(2-methyl-[1,3]dioxolan-2-yl)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 173) (350 mg, 0.97 mmol) and 5-chloro-2-fluorobenzyl bromide (324 mg, 1.5 mmol) afforded 4-{(5-chloro-2-fluoro-benzyl)-[4-(2-methyl-[1,3]dioxolan-2-yl)-phenyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester as a beige solid (316 mg, 65%).
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[F:22][C:23]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:24]=1[NH2:25].[Br:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37](O)=[O:38]>CN(C=O)C>[Br:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([NH:25][C:24]1[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:23]=1[F:22])=[O:38]
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(O)CCCCCBr
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CCCCCBr)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 68.6 %

Procedure:
WSC (2.1 g, 11 mmols) and HOBt (1.49 g, 11 mmols) were added to a DMF (30 ml) solution of 2,4-difluoroaniline (1.29 g, 10 mmols) and 6-bromohexanoic acid (2.93 g, 15 mmols), and stirred at room temperature for 15 hours. The reaction mixture was extracted with ether. The organic layer was washed with water, 1 N HCl, an aqueous saturated solution of sodium hydrogencarbonate and saturated saline in that order, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. Then, the residue was purified through silica gel column chromatography (developer: hexane/acetone=5/1), and the resulting crystals were recrystallized from ether-hexane to obtain 2.1 g (yield: 69%) of 6-bromo-N-(2,4-difluorophenyl)hexanamide as colorless needle-like crystals.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH2:7][N:8](C(OC(C)(C)C)=O)[CH2:9][CH2:10][C:5]=2[CH:4]=[N:3]1.Cl.CC(=O)OCC>CC(=O)OCC>[CH3:1][N:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[N:3]1
Reactant: Cn1ncc2c1CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOC(C)=O
Product: Cn1ncc2c1CNCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 28 %

Procedure:
To a stirred mixture of tert-butyl 1-methyl-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (744 mg, 3.14 mmol) in EA (2 mL) was added HCl/EA (3 N, 4 mL). The mixture was stirred at 25° C. for 16 hours. The reaction mixture was then concentrated and the residue purified by Prep-HPLC and SFC to afford the target compound as colorless oil which was used without further purification in the next step. (120 mg; yield 28%). LCMS (m/z): 138.10 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:23][CH3:24])=[CH:11][C:12]([C:17]2[N:21]=[C:20]([CH3:22])[O:19][N:18]=2)=[C:13]([CH:16]=1)[CH:14]=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]1([Mg]Br)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Cl-].[NH4+].Cl>C(OCC)(=O)C.O1CCCC1>[CH2:1]([O:8][C:9]1[C:10]([O:23][CH3:24])=[CH:11][C:12]([C:17]2[N:21]=[C:20]([CH3:22])[O:19][N:18]=2)=[C:13]([CH:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[OH:15])[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Br[Mg]c1ccccc1
Reactant: COc1cc(-c2noc(C)n2)c(C=O)cc1OCc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(-c2noc(C)n2)c(C(O)c2ccccc2)cc1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
To a mixture of 5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)benzaldehyde (reference example 15-1) (450 mg) and tetrahydrofuran (5.6 mL) was added dropwise phenylmagnesium bromide (1.08 mol/L tetrahydrofuran solution, 1.4 mL) in an ice salt bath. After stirring at the same temperature for 30 minutes, an aqueous solution of ammonium chloride, 2 mol/L hydrochloric acid and ethyl acetate were added to the mixture. The separated organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (564 mg).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:10])[CH2:5][CH2:6][C:7]=1[CH:8]=O)[CH3:2].CO[CH2:13][CH2:14][O:15]C>>[O:15]=[C:14]([CH2:2][CH2:1][CH2:3][CH2:7][CH3:6])/[CH:13]=[CH:8]/[C:7]1[CH2:6][CH2:5][C:4](=[O:10])[C:3]=1[CH2:1][CH3:2]
Reactant: COCCOC
Reactant: CCC1=C(C=O)CCC1=O
Product: CCCCCC(=O)/C=C/C1=C(CC)C(=O)CC1
Reaction time: 2 h
Yield: 80 %

Procedure:
1.7 g (0.035 mole) of a 50% NaH dispersion is transferred into a dry 500 ml 3-neck flask equipped with an addition funnel, overhead stirrer and septum. The NaH was covered with 175 ml of DME and a solution of 10.1 g (0.045 mole) dimethyl (2-oxoheptyl) phosphonate in 12 ml of DME is added dropwise over a 10 minute period. The mixture is stirred for 1 hour at room temperature to form the sodium salt of the phosphonate. A solution of the crude aldehyde 5 supra [from oxidation of 7.0 g (0.05 mole) of the vinyl compound 4] in 25 ml of DME was added over a twenty-minute period, and the mixture was stirred an additional two hours. The reaction was terminated by the addition of 2.5 ml glacial acetic acid followed by 175 ml water. The reaction mixture was extracted with CHCl3, and the combined organic extracts washed with water and dried over sodium sulfate. The CHCl3 was removed under reduced pressure to yield 12.6 g of crude product. This material was chromatographed over silicic acid using ethyl acetate-cyclohexane for elution to give 6.7 g (80%) of a yellow liquid Ic. The spectral characteristics of this compound were similar to Ia and Ib with the ##STR6## group evident in the nmr spectrum, --(CH2)4CH3 at δ0.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH:19]([CH3:21])[CH3:20])=[CH:14][C:13]=1[O:22][CH3:23])[C:6](=[O:24])[C:5]2([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:32])[CH3:25].[CH2:33]=O.[BH4-].[Na+].Cl>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]([CH:19]([CH3:21])[CH3:20])[CH3:33])=[CH:14][C:13]=1[O:22][CH3:23])[C:6](=[O:24])[C:5]2([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:32])[CH3:25]
Reactant: COc1cc(NC(C)C)ccc1CN1C(=O)C(C)(c2ccccc2Cl)c2cc(Cl)ccc21
Reactant: C=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Product: COc1cc(N(C)C(C)C)ccc1CN1C(=O)C(C)(c2ccccc2Cl)c2cc(Cl)ccc21

Procedure:
The compound of Example 56 is treated with aqueous formaldehyde and sodium borohydride. The compound obtained is salified with a solution of hydrochloric acid in diethyl ether. The hydrochloride is then isolated after filtration and drying at 45° C. under reduced pressure; M.p.=156° C. (HCl.1.5H2O).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:9][CH2:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=1)[O:1][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27]
Reactant: OCc1cc(O)cc(CO)c1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCCCOc1cc(CO)cc(CO)c1
Yield: 78 %

Procedure:
To a stirred solution of (5-hydroxy-1,3-phenylene)dimethanol (7.27 g, 47 mmol, 1 eq.) in 200 mL of acetonitrile at room temperature, 2-(4-bromobutyl)isoindoline-1,3-dione (1.2 eq.) and potassium carbonate (K2CO3, 2 eq.) were slowly added. The resultant mixture was then heated at reflux for 8 hours, after which the volatiles were removed, and the residue was partitioned between EtOAc and water. The EtOAc layer was washed with brine and dried over MgSO4. Evaporation of EtOAc gave 2-(4-(3,5-bis(hydroxymethyl)phenoxy)butyl)isoindoline-1,3-dione (13 g, 78% yield).