Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].[NH2:20][C:21](=[N:35]O)[C:22]1[C:31]([O:32][CH3:33])=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([F:34])[CH:23]=1>>[F:34][C:24]1[CH:23]=[C:22]([C:21]2[N:20]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[CH3:19])=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=3)[O:12][N:35]=2)[C:31]([O:32][CH3:33])=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Reactant: COC(=O)c1cc(OC)c(C(N)=NO)cc1F
Product: COCc1cc(-c2nc(-c3cc(F)c(C(=O)OC)cc3OC)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 28 (78.31 mg; 0.31 mmol) and Intermediate 57 (74 mg; 0.31 mmol). The reaction mixture was filtered through a SPE NH2 column (2 g) and rinsed with ACN. The filtrate was passed through a SPE SCX column (2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/(DCM/EtOAc 1:1) gradient from 1:0 to 1:1). The white solid was washed with MeOH affording the title compound as an off-white powder. LC/MS (Method B): 463.2 (M+H)+. HPLC (Method A) Rt 6.16 min (Purity: 97.9%).
Reaction SMILES: [C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]#[N:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27]([O:35][C@H:36]1[C@@H:40]([O:41][C:42](=[O:49])[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:39](OC(=O)C)[O:38][C@@H:37]1[C:54]([NH:56][CH2:57][CH3:58])=[O:55])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O[C@H]1[C@@H](OC(=O)C2C=CC=CC=2)[C@H](OC(=O)C)O[C@@H]1C(NCC)=O)(=O)C1C=CC=CC=1.II>>[C:27]([O:35][C@H:36]1[C@@H:40]([O:41][C:42](=[O:49])[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@H:39]([N:14]2[CH:13]=[N:12][C:11]3[C:15]2=[N:16][C:17]([C:19]#[N:20])=[N:18][C:10]=3[NH:9][CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:38][C@@H:37]1[C:54]([NH:56][CH2:57][CH3:58])=[O:55])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCNC(=O)[C@H]1O[C@H](OC(C)=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Reactant: N#Cc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Agent: CCNC(=O)[C@H]1O[C@@H](OC(C)=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: II
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C#N)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 150 °C
Reaction time: 18 h

Procedure:
A mixture of 6-[(2,2-diphenylethyl)amino]-9H-purine-2-carbonitrile (Preparation 24) (5.00 g, 14.7 mmol), (2S,3S,4R,5R)-5-(acetyloxy)-4-(benzoyloxy)-2-[(ethylamino)carbonyl]tetrahydro-3-furanyl benzoate and (2S,3S,4R,5S)-5-(acetyloxy)-4-(benzoyloxy)-2-[(ethylamino)carbonyl]tetrahydro-3-furanyl benzoate (Preparation 18) (6.50 g, 14.7 mmol) and iodine (0.38 g, 15.0 mmol) were heated together at 150° C. under reduced pressure (7 kPa, 1 psi) for 2.5 hours. The reaction was then allowed to stand at room temperature for 18 hours. The residue was purified by column chromatography on silica gel eluting with a gradient system of ethyl acetate:pentane (40:60 by volume) increasing in polarity to neat ethyl acetate to afford the title compound as a foam (4.95 g).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[O:32]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33]1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:37]([C:34]1[CH:35]=[CH:36][O:32][CH:33]=1)(=[O:39])=[O:38]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: O=S(=O)(Cl)c1ccoc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccoc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. furan-3-sulfonyl chloride (12 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 23 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)furan-3-sulfonamide (percentage yield: 89%), was obtained.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1([CH3:20])[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([CH3:19])[C:10]([CH3:18])=[C:11]([OH:17])[C:12]=2[CH3:16])[O:7]1)=[O:5])[CH3:2].[O:21]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[CH2:1]([NH:3][C:4](=[O:5])[C:6]([OH:21])([CH3:20])[CH2:15][CH2:14][C:13]1[C:8](=[O:7])[C:9]([CH3:19])=[C:10]([CH3:18])[C:11](=[O:17])[C:12]=1[CH3:16])[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CCNC(=O)C1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Agent: [Ce+4]
Agent: [NH4+]
Product: CCNC(=O)C(C)(O)CCC1=C(C)C(=O)C(C)=C(C)C1=O
Yield: 91.1 %

Procedure:
Oxidation as described in protocol B, using 100 mg (0.360 mmol) of N-ethyl-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide and 415 mg CAN (0.757 mmol) yielded 96.2 mg of N-ethyl-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)=[O:18].[Cl:26][C:27]([Cl:32])([Cl:31])[C:28](Cl)=[O:29].C(N(CC)CC)C>C(Cl)Cl>[Cl:26][C:27]([Cl:32])([Cl:31])[C:28]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[C:9]2[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:17](=[O:18])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)=[O:29]
Reactant: Cc1ccc(C(=O)c2ccc(N)c(C(=O)c3cccc(Cl)c3)c2)cc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2ccc(NC(=O)C(Cl)(Cl)Cl)c(C(=O)c3cccc(Cl)c3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
Intermediate 20 (0.0085 mol) was added at 5° C. to DCM (30 ml) under N2 flow, trichloro-acetyl chloride (0.01 mol) then triethylamine (0.01 mol) were added dropwise. The mixture was brought to room temperature, stirred at room temperature for 3 hours, poured out into ice water and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated, yielding 4.2 g (quantitative) of 2,2,2-trichloro-N-[2-(3-chlorobenzoyl)-4-(4-methylbenzoyl)phenyl]-acetamide (intermediate 21).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](O)=[O:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:15][C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH:14][CH2:13][CH2:12][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:8][CH:7]=1)=[O:24]
Reactant: O=C(O)c1cccc(Cc2cccc(F)c2)c1
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2[nH]cc(CCNC(=O)c3cccc(Cc4cccc(F)c4)c3)c2c1
Yield: 51.3 %

Procedure:
3-(3-Fluorobenzyl)-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)benzamide was prepared according to method A with 2-(5-methoxy-1H-indol-3-yl)ethanamine (0.060 g; 0.315 mmol), 3-(3-fluorobenzyl)benzoic acid (0.073 g; 0.316 mmol), HATU (0.120 g; 0.316 mmol) and N,N-diisopropylethylamine (0.135 mL; 0.788 mmol) in DMF (5 mL). Flash chromatography on silica gel (eluent 1 to 20% ethyl acetate in dichloromethane) furnished 0.065 g (51%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH:22]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:23]([O:25]C)=[O:24].[OH-].[Na+]>CO>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH:22]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:23]([OH:25])=[O:24]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)c(C)nc3sc4c(c23)CCCC4)cc1
Temperature: 60 °C
Yield: 28.9 %

Procedure:
To a solution of methyl 2-[2-methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate (0.043 g; 0.098 mmol) in methanol (1 mL) was added a solution of sodium hydroxide 10 N (0.100 mL; 1 mmol) and the mixture was heated to 60° C. for 18 h. The volatiles were removed under reduced pressure and the residue was dissolved in water, the mixture was then acidified by adding 1N HCl until a precipitate was formed. The solid was filtered, washed with water and dried under reduced pressure. The crude product was suspended in a mixture of acetonitrile and methanol, filtered, washed with acetonitrile and dried under reduced pressure to furnish 0.012 g (28%) of the title compound as a white solid.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH:13]1([S:16](Cl)(=[O:18])=[O:17])[CH2:15][CH2:14]1.C(N(CC)CC)C>ClCCl.Cl.O>[CH:13]1([S:16]([NH:10][CH2:9][C:8]2[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:12][CH:11]=2)(=[O:18])=[O:17])[CH2:15][CH2:14]1
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: O=S(=O)(Cl)C1CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CNS(=O)(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Nitrobenzylamine HCl (1.5 g), cyclopropanesulfonyl chloride (1 g) and triethylamine (3 mL) were dissolved in dichloromethane (20 mL). The reaction solution was stirred at rt overnight. The reaction mixture was diluted with 1N HCl aq. solution (50 mL) and water (100 mL). The solution was extracted with ethyl acetate (2×100 mL). The organic solution was evaporated to give N-cyclopropylsulfonyl-4-nitrobenzylamine. 1H NMR (DMSO-d6): δ 0.89 (d, J=7.8 Hz, 4H), 4.33 (d, J=6.6 Hz, 2H), 7.61 (d, J=8.7 Hz, 2H), 7.83 (t, J=6.6 Hz, 1H), 8.20 (d, J=8.7 Hz, 2H).
Reaction SMILES: N1C2C(=CC=CC=2)C(C2CCC(=O)CC2)=C1.O1[C:21]2([CH2:26][CH2:25][CH:24]([C:27]3[C:35]4[C:30](=[CH:31][CH:32]=[C:33]([Cl:36])[CH:34]=4)[NH:29][CH:28]=3)[CH2:23][CH2:22]2)[O:20]CC1>>[Cl:36][C:33]1[CH:34]=[C:35]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[C:27]2[CH:24]1[CH2:23][CH2:22][C:21](=[O:20])[CH2:26][CH2:25]1
Reactant: Clc1ccc2[nH]cc(C3CCC4(CC3)OCCO4)c2c1
Agent: O=C1CCC(c2c[nH]c3ccccc23)CC1
Product: O=C1CCC(c2c[nH]c3ccc(Cl)cc23)CC1
Yield: 62.8 %

Procedure:
This compound was prepared in the manner described above for intermediate 3a by replacing 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-1H-indole with 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-5-chloro-1H-indole (2.12 g) to afford 1.13 g (60%) of the title compound as a clear oil: MS FAB m/e 248 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][N:12]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([S:22][CH3:23])[N:14]=[C:13]2[CH2:24][CH2:25][CH3:26])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH2:11][N:12]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([S:22]([CH3:23])=[O:35])[N:14]=[C:13]2[CH2:24][CH2:25][CH3:26])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCc1nc(SC)c(C(=O)OCC)n1Cc1cc2c(cc1Cl)OCO2
Solvent: ClCCl
Product: CCCc1nc(S(C)=O)c(C(=O)OCC)n1Cc1cc2c(cc1Cl)OCO2
Reaction time: 1 h
Yield: 91.3 %

Procedure:
9.26 g of the product obtained in Stage 4 above is introduced into 400 ml of methylene chloride at 0° C. and 5.8 g of metachloroperbenzoic acid is added. Agitation is carried out for one hour at ambient temperature and the reaction medium is washed with sodium and potassium hydride, extraction is carried out with methylene chloride, the extracts are washed with water, dried, and the solvent is evaporated off. After chromatography, 8.8 g of expected product is obtained. M.p.=187° C.
Reaction SMILES: [OH:1][C:2]1[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:15]N(C=O)C.CI>O>[CH3:15][O:1][C:2]1[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc2c1oc1ccccc12
Reactant: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1cccc2c1oc1ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
To a solution of 4-hydroxydibenzo[b,d]furan (2 g, 0.0109 mol) in DMF (5 mL) potassium carbonate (3.2 g, 0.0232 mol) and methyl iodide (1.35 mL, 0.0217 mol) was added. The reaction slurry was stirred at room temperature for 3 h. Subsequently the reaction mixture was poured into the cold water (100 mL) and extracted with hexane (3×100 mL). The organic layer was dried over anhydrous sodium sulphate and filtered. The filtrate was evaporated at reduced pressure to, give the desired product in 66% yield, Rf 0.74 (Ethyl acetate:Hexane (3:7); MS m/z: 199.1 (M+1).
Reaction SMILES: [ClH:1].[OH:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[C:10]([O:18][CH3:19])[CH:11]=[CH:12][CH:13]=3)[O:8][C:7]=2[CH:6]=[C:5]([O:20][CH2:21][CH:22]2[CH2:24][S:23]2)[CH:4]=1>C(OCC)(=O)C>[Cl:1][CH2:24][CH:22]([SH:23])[CH2:21][O:20][C:5]1[CH:4]=[C:3]([OH:2])[C:16]2[C:15](=[O:17])[C:14]3[C:9]([O:8][C:7]=2[CH:6]=1)=[C:10]([O:18][CH3:19])[CH:11]=[CH:12][CH:13]=3
Reactant: Cl
Reactant: COc1cccc2c(=O)c3c(O)cc(OCC4CS4)cc3oc12
Solvent: CCOC(C)=O
Product: COc1cccc2c(=O)c3c(O)cc(OCC(S)CCl)cc3oc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
Aqueous ethyl acetate 1M-HCl (3 mL) was added to 1-hydroxy-5-methoxy-3-(thiiran-2-ylmethoxy)-9H-xanthen-9-one (30 mg, 0.09 mmol) prepared in Example 3, followed by stirring at room temperature for 3 hours, and the reaction solvent was removed under reduced pressure. Ether was added to the residue, followed by sonication, and the solvent was removed to give the title compound (30 mg, 90.1%) as a light brown solid.
Reaction SMILES: Br[CH:2]([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[S:10]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)([OH:13])(=[O:12])=[O:11].[CH3:21][NH:22]CCCCC=C>>[S:10]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)([OH:13])(=[O:12])=[O:11].[CH3:21][NH:22][CH2:9][CH2:2][CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH3:8]
Reactant: C=CCCCCC(C)Br
Reactant: C=CCCCCNC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCC=CCCCCNC

Procedure:
Compound 32c was synthesized from 7-bromo-octene as a white powder in quantitative yield, following the procedure as described for compound 32a.
Reaction SMILES: ClC[CH2:3][O:4][CH2:5][CH3:6].[CH2:7]([OH:11])[CH2:8][CH2:9][OH:10].C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:5]([O:4][CH2:3][O:10][CH2:9][CH2:8][CH2:7][OH:11])[CH3:6]
Reactant: CCOCCCl
Reactant: OCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOCOCCCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
A solution of chloroethylethyl ether (50 mmol) in dry tetrahydrofuran (10 ml) was added dropwise at 0°-5° C. to a stirred solution of 1,3-propanediol (150 mmol) in dry tetrahydrofuran (100 ml) and N,N-diisopropylethylamine (75 mmol). The mixture was stirred for 2 hours at room temperature, the solvent was evaporated in vacuo and the residue was purified by column chromatography on silica, eluting with dichloromethane:methanol (98:2) to give the title compound as a colourless oil (5.6 g, 83%); νmax (Film) 3420, 2980, 2940, 2880, 1480, 1445, 1390 and 1180 cm-1 ; δH (CDCl3) 1.20 (3H, t, J=6.5 Hz, CH3CH2), 1.8 (2H, m, CH2CH2CH2), 3.2 (1H, s, OH), 3.6 (6H, m, CH2OH, CH2O and CH3CH2), 4.8 (2H, s, OCH 2 O).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C(C(C(C)C)(C(C)C)CN)(C)C.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH2:40][S:41](Cl)(=[O:43])=[O:42])[CH:37]=[CH:38][CH:39]=1>ClCCl>[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:37]=[CH:38][CH:39]=1)[CH2:40][S:41]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)=[O:10])=[CH:6][CH:7]=1)(=[O:42])=[O:43]
Reactant: Nc1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Reactant: COc1cccc(CS(=O)(=O)Cl)c1
Agent: CC(C)C(CN)(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cccc(CS(=O)(=O)Nc2ccc(NC(=O)N3Cc4ccccc4C3)cc2)c1

Procedure:
N-(4-aminophenyl)isoindoline-2-carboxamide (0.0585 g, 0.231 mmol) was suspended in dichloromethane (2 ml) followed by addition of triisopropylethylamine (0.081 ml, 0.462 mmol). (3-Methoxyphenyl)methanesulfonyl chloride (0.061 g, 0.277 mmol) was dissolved in 1 ml dichloromethane and added to the mixture via syringe slowly. The mixture was quenched with water and the separated aqueous layer was extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated. Reverse-phase HPLC provided the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.65 (s, 1H), 8.61 (s, 1H), 8.50 (d, J=5.0 Hz, 1H), 8.34 (t, J=5.6 Hz, 1H), 7.80-7.73 (m, 2H), 7.69-7.61 (m, 2H), 7.44 (d, J=5.0 Hz, 1H), 4.86-4.79 (m, 4H), 3.20 (t, J=6.2 Hz, 2H), 2.46-2.25 (m, 3H), 2.20 (d, J=7.9 Hz, 3H), 2.06-1.78 (m, 1H), 1.52-1.37 (m, 1H); MS (ESI(+)) m/e 438 (M+H)+.
Reaction SMILES: CS(Cl)(=O)=O.C1CCNCC1.[CH2:12]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]O)=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F:27][C:28]([F:50])([F:49])[C:29]1[CH:30]=[C:31]([CH:46]=[CH:47][CH:48]=1)[C:32]([NH:34][CH2:35][C:36]([NH:38][CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:37])=[O:33].C1(N=C=O)C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:12]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:43]2[CH2:44][CH2:45][CH:40]([CH2:39][NH:38][C:36](=[O:37])[CH2:35][NH:34][C:32](=[O:33])[C:31]3[CH:46]=[CH:47][CH:48]=[C:29]([C:28]([F:50])([F:49])[F:27])[CH:30]=3)[CH2:41][CH2:42]2)=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCc1ccc(Cc2ccccc2)cc1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCNCC1
Agent: CS(=O)(=O)Cl
Solvent: C1CCNCC1
Solvent: O=C=Nc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCN(Cc2ccc(Cc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A chloroform (1.0 mL) solution of methanesulfonyl chloride (4.2 mg, 0.037 mmol) and a (piperidinomethyl)polystyrene (54 mg, 2.7 mmol base/g resin) were added to a chloroform (1.0 mL) solution of 4-(benzyl)benzyl alcohol (8.7 mg, 0.044 mmol), and the resulting mixture was stirred at 25° C. for 15 hours. 4-[[N-(3-(Trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine (15.1 mg, 0.044 mmol) and KI (2 mg) were then added to the reaction mixture, and the resulting mixture solution was further stirred at 65° C. for 5 hours. Phenyl isocyanate (5.2 mg) was added to the cooled reaction mixture, and the obtained mixture was stirred at 25° C. for 1 hour. The resulting reaction mixture was loaded onto a Varian™ SCX column and washed with methanol (20 mL). The obtained crude product was eluted with a 2 M methanol solution of NH3 (5 mL) and concentrated to thereby afford 1-(4-benzylbenzyl)-4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine (Compd. No. 926) as an off-white oil (5.6 mg, 29%). The purity was determined by RPLC/MS (94%). ESI/MS m/e 524.1 (M++H, C30H32F3N3O2).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[OH:13])=[CH:6][CH:5]=1.[CH2:20]([O:27][C:28]1[CH:29]=[CH:30][C:31]([C@@H:39]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[CH2:40]Br)=[C:32]2[C:37]=1[NH:36][C:35](=[O:38])[CH:34]=[CH:33]2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CS(C)=O>[OH:13][C@@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:11][NH:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][NH:1][CH2:40][C@@H:39]([C:31]2[CH:30]=[CH:29][C:28]([O:27][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:37]3[C:32]=2[CH:33]=[CH:34][C:35](=[O:38])[NH:36]3)[O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])=[CH:5][CH:6]=1
Reactant: NCCc1ccc(NC[C@@H](O)c2ccccc2)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCc1ccc(NC[C@@H](O)c2ccccc2)cc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 120 °C

Procedure:
Under nitrogen, (S)-2-[4-(2-aminoethyl)-phenylamino]-1-phenylethanol (1.7 g, 6.6 mmol) and 8-benzyloxy-5-[(R)-2-bromo-1-(tert-butyldimethylsilanyloxy)ethyl]-1H-quinolin-2-one (1.5 g, 3.1 mmol) were treated with dimethyl sulfoxide (4.0 mL) and heated to 120° C. for 40 minutes. The mixture was cooled slowly to room temperature and partitioned between water and ethyl acetate (after removal of some insoluble gummy residue by decantation). The organics were washed with 0.9 M sodium acetate/acetic acid, saturated sodium hydrogen carbonate and saturated sodium chloride, dried over sodium sulfate and evaporated to dryness. The title intermediate was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22]([NH:25][C:26]2[CH:35]=[CH:34][C:33]3[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=3[C:27]=2[C:36]([OH:38])=[O:37])(=[O:24])=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si](C=[N+]=[N-])(C)(C)[CH3:40]>C1C=CC=CC=1.CO>[CH3:40][O:37][C:36]([C:27]1[C:28]2[CH2:29][CH2:30][CH2:31][CH2:32][C:33]=2[CH:34]=[CH:35][C:26]=1[NH:25][S:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[NH:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)(=[O:24])=[O:23])=[O:38]
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2ccccc2S(=O)(=O)Nc2ccc3c(c2C(=O)O)CCCC3)CC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1c(NS(=O)(=O)c2ccccc2NCC2CCN(C(=O)OC(C)(C)C)CC2)ccc2c1CCCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of Example 396 (2.69 g, 5.0 mmol) in benzene (40 mL) and methanol (10 mL) was treated with TMSCHN2 (3.0 mL, 6.0 mmol, 2.0M solution in hexanes). The reaction was stirred at room temperature for 1 hour, then quenched with acetic acid, and diluted with ethyl acetate. The organic layer was washed with aqueous NaHCO3, dried (MgSO4), filtered, concentrated, and purified by column chromatography (25% ethyl acetate/hexanes) to provide the desired product. MS (ESI(+)) m/e 528 (M+H)+.