Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1([CH3:23])[CH2:13][CH2:12]OS(=O)(=O)[N:9]1C(OC(C)(C)C)=O.[C:24]1([CH:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:31]#[N:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[NH3:9].[NH2:9][C:8]([CH3:7])([CH3:23])[CH2:13][CH2:12][C:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:31]#[N:32]
Reactant: CC(C)(C)OC(=O)N1C(C)(C)CCOS1(=O)=O
Reactant: N#CC(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(N)CCC(C#N)(c1ccccc1)c1ccccc1
Product: N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Potassium tert-butoxide (203 mg, 1.81 mmol) and tert-butyl 4,4-dimethyl-1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide [(400 mg, 1.51 mmol), WO2003037327, p 83] were added to a solution of diphenylacetonitrile (349 mg, 1.81 mmol) in N,N-dimethylformamide (5 mL) and the mixture was stirred for 18 hours at room temperature. The reaction mixture was then concentrated in vacuo and the residue was treated with hydrochloric acid (4M in dioxane, 10 mL) and heated at 40° C. for 2.5 hours. The reaction mixture was concentrated in vacuo and the residue was basified with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate (2×30 mL). The combined organic solution was dried over magnesium sulfate, concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 90:10:1, to afford the title compound as a colourless oil in 77% yield, 324 mg.
Reaction SMILES: [CH2:1]([S:3][C:4](=[O:10])[CH2:5][C:6](=O)[CH2:7]Br)[CH3:2].[NH2:11][C:12]([NH2:14])=[S:13].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>CN(C)C(=O)C.O>[CH2:1]([S:3][C:4](=[O:10])[CH2:5][C:6]1[N:11]=[C:12]([NH2:14])[S:13][CH:7]=1)[CH3:2]
Reactant: NC(N)=S
Reactant: CCSC(=O)CC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CCSC(=O)Cc1csc(N)n1
Yield: 65.3 %

Procedure:
In 7.0 ml of N,N-dimethylacetamide was dissolved 2.25 g of the 4-bromo-3-oxothiobutyric acid-S-ethyl ester obtained in Referential Example 4-(1), and 1.14 g of thiourea was added to the resulting solution with ice-cooling, after which the resulting mixture was subjected to reaction at room temperature for 1 hour. The reaction mixture was introduced into a mixed solvent of 50 ml of ethyl acetate and 50 ml of water, and the pH was adjusted to 6.0 with sodium hydrogencarbonate. Then, the organic layer was separated, washed with two 50-ml portions of water and with 50 ml of saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. Then the solvent was removed by distillation under reduced pressure. The residue obtained was recrystallized from 20 ml of ethyl acetate to obtain 1.32 g (yield, 65.5%) of 2-(2-aminothiazol-4-yl)thioacetic acid-S-ethyl ester having a melting point of 76°-77° C.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[CH:24]([OH:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=O)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1>C1(C)C(C)=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][CH:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24](=[O:25])[N:16]2[CH2:15][CH2:14][CH2:13][N:10]2[CH2:11][CH:12]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]2)=[CH:30][CH:29]=1
Reactant: O=C1c2ccccc2C(O)N1CCCN1CC=C(c2ccccc2)CC1
Reactant: Nc1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: O=C1c2ccccc2C(Nc2ccc(Cl)cc2)N1CCCN1CC=C(c2ccccc2)CC1
Reaction time: 6 h
Yield: 54 %

Procedure:
Para-toluenesulphonic acid (50 mg) is added to an agitated solution of 2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-3-hydroxy-1-isoindolinone (10 g) and 4-chlorophenylamine (4.6 g) in xylene (230 cc) at a temperature close to 20° C. in a Dean Stark apparatus. Agitation is continued for 6 hours at a temperature close to 135° C. After cooling to a temperature close to 20° C., the precipitate formed is filtered, washed with xylene (2×50 cc), dried under reduced pressure (20 mm Hg; 2.7 kPa) and recrystallized from boiling acetonitrile (360 cc). 7.1 g of 3-(4-chlorophenylamino)-2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1-isoindolinone are obtained, melting at 188° C.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:8][CH2:9][CH2:10][C:11]([CH3:14])([OH:13])[CH3:12])/[CH:3]=[CH:4]\[CH2:5][CH2:6][OH:7].[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][C@@H:2]([CH2:8][CH2:9][CH2:10][C:11]([CH3:14])([OH:13])[CH3:12])[CH2:3][CH2:4][CH2:5][CH2:6][OH:7]
Reactant: C[C@H](/C=C\CCO)CCCC(C)(C)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@H](CCCCO)CCCC(C)(C)O
Yield: 100.7 %

Procedure:
To a solution of diol 13 (55 mg, 0.27 mmol) in ethyl acetate (10 mL) was added Pd/C (10%, 50 mg). The reaction mixture was stirred for 18 hours under a continuous stream of hydrogen at room temperature. The mixture was then filtered, and the solvent was evaporated under reduced pressure. The crude oily product was chromatographed on silica Sep-Pak cartridge eluted with hexane/EtOAc (8:2) to give an oily diol 14 (55 mg, 45%).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].Cl.[CH2:23]([N:25]([CH2:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[CH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)[CH3:24].C(NC(C)C)(C)C>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:37]3[CH2:36][CH2:35][CH:34]([CH2:33][N:25]([CH2:23][CH3:24])[CH2:26][C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)[CH2:39][CH2:38]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CCN(Cc1ccncc1)CC1CCNCC1
Agent: Cl
Solvent: CC(C)NC(C)C
Product: CCN(Cc1ccncc1)CC1CCN(C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)CC1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and ethyl-piperidin-4-ylmethyl-pyridin-4-ylmethyl-amine, hydrochloride, 5 equivalent of diisopropylamine was added, preparative HPLC (Method C) (25%, off-white crystals). HPLC-MS m/z=515.2 (M+1), Rt: 2.77 min.
Reaction SMILES: [CH2:1]([C@@H:8]1[C@@H:16]([O:17][CH2:18][CH:19](O)[CH3:20])[C@H:15]([CH3:22])[O:14][C:13](=[O:23])[C@@H:12]([NH:24][C:25](=[O:35])[C:26]2[C:31]([OH:32])=[C:30]([O:33][CH3:34])[CH:29]=[CH:28][N:27]=2)[CH2:11][O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38].[CH2:43](Cl)Cl>CN(C1C=CN=CC=1)C>[C:37](=[O:38])([O:39][CH:40]([CH3:42])[CH3:41])[O:32][C:31]1[C:26]([C:25](=[O:35])[NH:24][C@H:12]2[CH2:11][O:10][CH2:9][C@H:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@@H:16]([O:17][CH2:18][CH:19]([CH3:20])[CH3:43])[C@H:15]([CH3:22])[O:14][C:13]2=[O:23])=[N:27][CH:28]=[CH:29][C:30]=1[O:33][CH3:34]
Reactant: ClCCl
Reactant: COc1ccnc(C(=O)N[C@H]2COC[C@H](Cc3ccccc3)[C@@H](OCC(C)O)[C@H](C)OC2=O)c1O
Reactant: CC(C)OC(=O)Cl
Agent: CN(C)c1ccncc1
Product: COc1ccnc(C(=O)N[C@H]2COC[C@H](Cc3ccccc3)[C@@H](OCC(C)C)[C@H](C)OC2=O)c1OC(=O)OC(C)C
Temperature: 25 °C
Yield: 44 %

Procedure:
To a solution of N-((3S,7S,8R,9S)-7-benzyl-8-(2-hydroxypropoxy)-9-methyl-2-oxo-1,5-dioxonan-3-yl)-3-hydroxy-4-methoxypicolinamide (160 mg, 0.33 mmol) in CH2Cl2 (2 mL) were added isopropyl chloroformate (44 mg, 0.36 mmol) and DMAP (44 mg, 0.36 mmol) at 0° C., and the solution was allowed to warm to room temperature overnight. The crude reaction mixture was concentrated and the residue purified via flash chromatography (SiO2, 50% EtOAc/hexanes) to furnish the product (83 mg, 44%) as white foam: IR (film) 3375, 2956, 2874, 1762, 1680 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J=8.4 Hz, 1H), 8.32 (d, J=5.4 Hz, 1H), 7.33-7.24 (m, 2H), 7.20 (dd, J=7.2, 5.3 Hz, 3H), 7.00 (d, J=5.5 Hz, 1H), 5.08-4.91 (m, 3H), 4.01 (dd, J=11.7, 7.4 Hz, 1H), 3.92 (s, 3H), 3.50-3.42 (m, 3H), 3.37-3.30 (m, 2H), 3.17-3.11 (m, 2H), 2.37-2.29 (m, 1H), 2.00-1.83 (m, 2H), 1.49 (d, J=6.4 Hz, 3H), 1.41 (d, J=6.3 Hz, 6H), 0.97-0.93 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 171.79, 162.53, 159.38, 152.03, 146.81, 141.44, 140.03, 137.78, 129.20 (2), 128.43 (2), 126.09, 110.03, 84.53, 79.27, 75.68, 73.76, 72.31, 71.92, 56.32, 51.44, 47.43, 35.09, 29.19, 21.71 (2), 19.50 (2), 18.79; ESIMS m/z 574.39 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C[Si]([C:25]#[N:26])(C)C>C(Cl)Cl.[Al+3].[Cl-].[Cl-].[Cl-]>[C:12]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]1[C:25]#[N:26])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[Si](C)(C)C#N
Reactant: Clc1ccc2ncccc2c1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: N#CC1C=Cc2cc(Cl)ccc2N1C(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 6-chloroquinoline (9.5 g), benzoyl chloride (13.2 g) in methylene chloride (50 mL) was treated with AlCl3 (0.10 g) followed by dropwise addition of trimethyl silyl cyanide (12.5 mL). After 0.5 hour, the mixture was diluted with 150 mL of methylene chloride and washed with water, 1N HCl, saturated sodium bicarbonate (aq.), and brine. The organic phase was dried over magnesium sulfate then evaporated to dryness. The residue was purified by column chromatography on silica gel using ethyl acetate/hexane (3:7) as the eluting solvent. The title compound (13 g) was obtained as a white solid, m.p. 141-143° C. This product was used for the preparation of the title compound described in step 2.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[C:8]3[NH:16][N:15]=[N:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)=[CH:4][CH:3]=1.[Br:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25]Br)[N:20]=1>CCCCCC.CCOC(C)=O>[Br:17][CH2:18][C:19]1[N:20]=[C:21]([CH2:25][N:14]2[C:9]3[N:10]=[C:11]([NH2:13])[N:12]=[C:7]([C:5]4[O:6][C:2]([CH3:1])=[CH:3][CH:4]=4)[C:8]=3[N:16]=[N:15]2)[CH:22]=[CH:23][CH:24]=1
Reactant: Cc1ccc(-c2nc(N)nc3nn[nH]c23)o1
Reactant: BrCc1cccc(CBr)n1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nc(N)nc3c2nnn3Cc2cccc(CBr)n2)o1

Procedure:
Prepared from 7-(5-methyl-2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine and 2,6-bis(bromomethyl)pyridine by the alkylation method described in Example 36; NMR δH (400 MHz, DMSO) 2.46 (3H, s), 4.64 (2H, s), 5.75 (2H, s), 6.50 (1H, d, J 3.5 Hz), 7.04 (1H, d, J 8.0 Hz), 7.31 (2H, s), 7.49 (1H, d, J 7.5 Hz), 7.80 (1H, t, J 7.5 Hz), 7.88 (1H, d, J 3.5 Hz). TLC (Hexane:EtOAc (1:1)) Rf=0.28**
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10]C=C2)(=[O:4])=[O:3].O.[N:15]([O-])=O.[Na+].Cl.[O:20]1[CH2:25][CH2:24]OCC1>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:15]=[C:24]2[CH:25]=[O:20])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc2[nH]ccc2c1
Reactant: C1COCCO1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1ccc2[nH]nc(C=O)c2c1
Temperature: 25 °C
Yield: 25 %

Procedure:
A solution of 5-(methylsulfonyl)-1H-indole (0.150 g, 0.768 mmol) in 1,4-dioxane (8 mL) was added with water (96 mL), and the mixture was stirred at room temperature. The reaction mixture was added with sodium nitrite (0.530 g, 7.68 mmol), and the mixture was cooled to 0° C. The reaction mixture was added dropwise with 3 N hydrochloric acid (1.54 mL, 4.62 mmol) at 0° C., and then the mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted three times with ethyl acetate, and then the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 5-(methylsulfonyl)-1H-indazole-3-carboxaldehyde (0.0433 g, 25%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:27](=S)[N:28]=[C:22]4[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:28][C:27]([N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[O:26])[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Reactant: C1CCNC1
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(NC(=O)N4CCCC4)c3)C(C)(C)C2=O)cc1

Procedure:
This compound may be prepared as obtained in stage c) of Example 9, but starting with 200 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazolidine-2,4-dione obtained in stage b) of Example 9, 4 mL of dioxane and 40.2 mg of pyrrolidine. After chromatography on a column of silica, eluting with a mixture of heptane/ethyl acetate (gradient from 100/0 to 0/100 by volume), 64.3 mg of N-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyridin-2-yl)pyrrolidine-1-carboxamide are obtained in the form of a beige-coloured powder, the characteristics of which are as follows:
Reaction SMILES: C([N:4]1[C:12]2C[CH2:10][C:9]3[C:13]4[C:14](=[N:16][CH:17]=[N:18][C:19]=4[NH:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=5)=[C:23]([Cl:36])[CH:22]=4)[S:15][C:8]=3[C:7]=2C=N1)C=C.O.C[N+:39]1([O-])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.S([O-])([O-])=O.[Na+].[Na+].C[C:53](C)=[O:54]>O.[Os](=O)(=O)(=O)=O>[Cl:36][C:23]1[CH:22]=[C:21]([NH:20][C:19]2[C:13]3[C:9]4[CH2:10][CH2:43][C:44]5[N:39]([CH2:40][CH:41]([OH:42])[CH2:53][OH:54])[N:4]=[CH:12][C:7]=5[C:8]=4[S:15][C:14]=3[N:16]=[CH:17][N:18]=2)[CH:26]=[CH:25][C:24]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1
Reactant: C=CCn1ncc2c1CCc1c-2sc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(C)=O
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: OCC(O)Cn1ncc2c1CCc1c-2sc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.9 %

Procedure:
To a solution of 3-allyl-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-4,5-dihydro-3H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-6-amine (300 mg, 0.52 mmol) and 4-methylmorpholine N-oxide monohydrate (133 mg, 1.14 mmol, 2.2 eq) in acetone (5 mL) and water (0.5 mL) was added a catalytic amount of osmium (VIII) tetraoxide (10 mg, 2.5 w % in t-BuOH). The reaction mixture was stirred at rt for 16 h. Sodium sulfite (1 g) was added to the stirred solution and the mixture was stirred for an additional 1 h. The mixture was passed through a pad of silicon gel and Celite mixture. The pad was washed with EtOAc (2×10 mL). The combined EtOAc layers were dried over sodium sulfate and then concentrated in vacuo. The residue was then purified by preparative-HPLC to give 3-[6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-4,5-dihydro-3H pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-3-yl]propane-1,2-diol (25.5 mg, 8.9%) as a white solid. 1H NMR (CD3CN) δ 8.31 (s, 1H), 7.82 (d, J=2.6 Hz, 1H), 7.59 (s, 1H), 7.45 (dd, J=2.3, 8.9 Hz, 1H), 7.45 (m, 1H), 7.33 (t, 1H), 7.28 (d, J=10 Hz, 1H), 7.14 (d, J=9 Hz, 1H), 7.12 (m, 1H), 5.23 (s, 2H), 4.25 (m, 1H), 3.67 (m, 4H), 3.43 (t, 2H), 3.15 (t, 2H); LCMS RT=3.17 min, [M+H]+=552.0
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:16][O:17][C:18](=[O:22])[CH2:19][CH2:20][NH2:21].C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.CN(C1C=CC=CN=1)C>ClCCl.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([C:12](=[O:14])[NH:21][CH2:20][CH2:19][C:18]([O:17][CH3:16])=[O:22])[CH2:11]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: COC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)CCNC(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 50 h
Yield: 97.2 %

Procedure:
A solution of azetidine-1,3-dicarboxylic acid mono-tert-butyl ester (0.4 g, 1.98 mmol) and 3-amino-propionic acid methyl ester hydrochloride (0.277 g, 1.98 mmol) in dichloromethane (16 mL) and THF (6 mL) was treated with diisopropylethylamine (0.256 g, 1.98 mmol); it was then added EDCI (0.42 g, 2.18 mmol) and dimethylaminopyridine (0.073 g, 0.59 mmol). The reaction mixture was stirred at room temperature for 50 hours and rotavapored to dryness. The residue was dissolved in dichloromethane. The dichloromethane layer was then successively washed with aqueous 5% citric acid, aqueous saturated hydrogenocarbonate solution, brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield the title compound as a gum (551 mg, 97%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([NH2:21])=[CH:19][N:18]=[C:17]3[N:22]([S:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:27])=[O:26])[CH:23]=[CH:24][C:16]=23)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:34](Cl)(=[O:38])[CH:35]([CH3:37])[CH3:36].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[C:20]([NH:21][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])=[CH:19][N:18]=[C:17]3[N:22]([S:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:26])=[O:27])[CH:23]=[CH:24][C:16]=23)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
4-(5-Amino-1-benzenesulfonyl 1H-pyrrolo[2,3-b]pyridine-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.00 g, 2.12 mmol), isobutyryl chloride (225 mg, 2.12 mmol) and triethylamine (590 μL, 4.24 mmol) in DCM (15 mL) were stirred at ambient temperature for 2 hours. The mixture was diluted with DCM, washed with a saturated sodium hydrogen carbonate solution, water and brine, dried through a phase separator and concentrated under vacuum affording 4-(1-benzenesulfonyl-5-isobutyrylamino-1H-pyrrolo[2,3-b]pyridine-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester as a brown residue which was used for the next step without further purification. LCMS (Method B, ESI): RT=3.77 min, m+H=542.36.
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[OH:27][C:28]1[C:29]([CH:37]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]([CH2:46][CH2:47][CH2:48][N:49]3[C:57](=[O:58])[C:56]4[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=4)[C:50]3=[O:59])[C:38]2=[O:60])=[CH:30][C:31]2[O:35][CH2:34][O:33][C:32]=2[CH:36]=1>>[OH:27][C:28]1[C:29]([C:37]2([CH2:5][OH:16])[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]([CH2:46][CH2:47][CH2:48][N:49]3[C:57](=[O:58])[C:56]4[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=4)[C:50]3=[O:59])[C:38]2=[O:60])=[CH:30][C:31]2[O:35][CH2:34][O:33][C:32]=2[CH:36]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2ccccc21
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: O=C1c2ccccc2C(=O)N1CCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 2-{3-[3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]propyl}-1H-isoindole-1,3(2H)-dione, the title compound was obtained (94%) as a foam solid: 1H NMR (300 MHz, CDCl3) δ 9.20 (s, 1H), 7.81-7.79 (m, 2H), 7.68-7.61 (m, 2H), 7.35-7.25 (m, 2H), 7.16-7.14 (m, 1H), 6.90 (d, 1H), 6.80 (s, 1H), 6.48 (s, 1H), 5.86 (dd, 2H), 4.64 (d, 1H), 3.67-4.13 (m, 5H), 2.18-2.05-(m, 2H);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[CH2:5][C:6]1[C:7]([CH2:15][CH3:16])=[N:8][N:9]([CH2:13][OH:14])[C:10]=1[CH2:11][CH3:12].ClC(Cl)(Cl)[C:23]([N:25]=C=O)=[O:24]>ClCCl>[C:23](=[O:24])([O:14][CH2:13][N:9]1[C:10]([CH2:11][CH3:12])=[C:6]([CH2:5][C:4]2[CH:17]=[C:18]([Cl:20])[CH:19]=[C:2]([Cl:1])[CH:3]=2)[C:7]([CH2:15][CH3:16])=[N:8]1)[NH2:25]
Reactant: CCc1nn(CO)c(CC)c1Cc1cc(Cl)cc(Cl)c1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCc1nn(COC(N)=O)c(CC)c1Cc1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
A solution of the alcohol of Example 41 (280 mg, 0.90 mmol) in dichloromethane (5 ml) was cooled to 0° C., treated with trichloroacetyl isocyanate (128 l, 1.1 mmol) and stirred at 0° C. for 30 minutes. The solution was soaked into a pad of alumina (neutral, activity II, Brockmann), washed with dichloromethane and then extracted with ethyl acetate. The organic extract was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with a solvent gradient of cyclohexane:ethyl acetate (2:1, by volume) gradually changing to cyclohexane:ethyl acetate (1:1, by volume) to afford the title compound (238 mg) as a solid, m.p. 153-155° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][NH:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])O.[Na+].Cl[C:40]([O:42][C:43]1[CH:52]=[CH:51][C:46]([C:47]([O:49][CH3:50])=[O:48])=[CH:45][CH:44]=1)=[O:41]>C1COCC1.O>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:13][CH2:12][N:11]([C:40]([O:42][C:43]2[CH:44]=[CH:45][C:46]([C:47]([O:49][CH3:50])=[O:48])=[CH:51][CH:52]=2)=[O:41])[CH2:10]1)[C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(OC(=O)Cl)cc1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCCC1c1ccccc1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(=O)N2CCC(c3ccccc3)C(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.9 %

Procedure:
To a solution of 238 mg of the crude tert-butyl[(1R)-1-(1-naphthyl)ethyl][(4-phenylpiperidin-3-yl)methyl]carbamate in 3 mL of THF was added 200 mg of sodium hydrogen carbonate while suspending it in 2 mL of water. The reaction mixture was added 170 mg of methyl 4-[(chlorocarbonyl)oxy]benzoate (Fluka). After stirring at room temperature overnight, the mixed solution was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 4-(methoxycarbonyl)phenyl 3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpiperidine-1-carboxylate (353 mg, colorless foamy substance) as a crude product. ESI+: 623