Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14]Cl)=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39].[CH3:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.O>CN(C)C(=O)C>[Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][N:44]2[CH2:45][CH2:46][N:41]([CH3:40])[CH2:42][CH2:43]2)=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39]
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(OCCCCl)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: CN1CCNCC1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN1CCN(CCCOc2cc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c(c2Cl)CNC3=O)CC1
Yield: 61.5 %

Procedure:
In a similar manner to Step 2 of Example 440, 4-chloro-5-(3-chloropropoxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (87.1 mg, 0.152 mmol) was dissolved in N,N-dimethylacetoamide (0.9 mL), and the solution was treated with N-methylpiperazine (0.138 mL, 1.58 mmol). The reaction mixture was added with water. The obtained solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 4-chloro-5-[3-(4-methylpyperazin-1-yl)propoxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (59.5 mg, yield 68%).
Reaction SMILES: B(Br)(Br)Br.C([N:12]1[C:17](=[O:18])[C:16]2=[C:19]3[NH:24][CH2:23][CH2:22][N:20]3[N:21]=[C:15]2[N:14]([CH2:25][CH2:26][CH2:27][CH3:28])[C:13]1=[O:29])C1C=CC=CC=1>CO>[CH2:25]([N:14]1[C:15]2=[N:21][N:20]3[CH2:22][CH2:23][NH:24][C:19]3=[C:16]2[C:17](=[O:18])[NH:12][C:13]1=[O:29])[CH2:26][CH2:27][CH3:28]
Reactant: CCCCn1c(=O)n(Cc2ccccc2)c(=O)c2c3n(nc21)CCN3
Agent: BrB(Br)Br
Solvent: CO
Product: CCCCn1c(=O)[nH]c(=O)c2c3n(nc21)CCN3
Temperature: 25 °C
Yield: 27.2 %

Procedure:
Boron tribromide (0.35 ml) was added to a stirred suspension of 3-benzyl-1-butyl-1,2,3,4,6,7-hexahydroimidazo[2',1':5,1]pyrazolo[3,4-d]pyrimidine2,4-dione (0.5 g) at room temperature. The reaction mixture was refluxed for 19 hours and there was cooled to room temperature, followed by addition of methanol (5 ml). The mixture was stirred for a while, then concentrated to dryness. The residue was dissolved in ethyl acetate, washed with water, dried and concentrated to give crude crystals, followed by recrystallization from ethyl acetate/hexane to afford colorless crystals (0.1 g, 27%), m.p. 239°-240° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][C:8]=2[CH:15]([CH3:17])[CH3:16])[CH2:6][CH2:5]1)[CH3:2].[CH3:18][O:19][C:20](=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:18][O:19][C:20](=[O:29])[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:14]#[C:13][C:10]2[CH:11]=[CH:12][C:7]([C:4]3([O:3][CH2:1][CH3:2])[CH2:6][CH2:5]3)=[C:8]([CH:15]([CH3:16])[CH3:17])[CH:9]=2)=[CH:26][CH:27]=1
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: C#Cc1ccc(C2(OCC)CC2)c(C(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC1(c2ccc(C#Cc3ccc(CC(=O)OC)cc3)cc2C(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
Using General Procedure F; 1-(1-ethoxycyclopropyl)-4-ethynyl-2-isopropylbenzene (Intermediate 103, 120.0 mg, 0.52 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 150.0 mg, 0.52 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (32.0 mg, 0.17 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (121 mg, 0.17 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-5% EtOAc-hexanes) afforded 140.0 mg (71%) of the title compound as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:29])=[C:23]([S:25](Cl)(=[O:27])=[O:26])[CH:24]=1>>[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:29])=[C:23]([S:25]([NH:15][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][O:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=3)[N:14]=2)(=[O:27])=[O:26])[CH:24]=1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Reactant: Nc1cccc(COCc2ccc(F)cc2)n1
Product: Cc1ccc(F)cc1S(=O)(=O)Nc1cccc(COCc2ccc(F)cc2)n1

Procedure:
This material was prepared in analogy to example 1 from 6-(4-fluoro-benzyloxymethyl)-pyridin-2-ylamine (0.058 g) and 5-fluoro-2-methyl-benzenesulfonyl chloride (0.057 g) as a light yellow gum (0.0476 g). MS (ESI−): 403.2 ([M−H]−)
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[CH3:24][N:25]([CH3:35])[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:34][C:31]2[CH:30]=[CH:29][C:28]([CH2:27][CH2:26][N:25]([CH3:24])[CH3:35])=[CH:33][CH:32]=2)=[N:3][CH:4]=1
Reactant: CN(C)CCc1ccc(O)cc1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2ccc(CCN(C)C)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 4-[2-(dimethylamino)ethyl]phenol: 1H-NMR (CDCl3) δ 8.53 (1H, d, J=2.6 Hz), 8.23 (1H, d, J=7.5 Hz), 8.13 (1H, d, J=2.8 Hz), 8.02–7.98 (2H, m), 7.43 (2H, d, J=8.3 Hz), 7.33–7.30 (2H, m), 7.11–7.06 (2H, m), 5.39–5.30 (1H, m), 3.90 (3H, s), 2.87–2.82 (2H, m), 2.63–2.58 (2H, m), 2.33 (6H, s), 1.59 (3H, d, J=7.0 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([N:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)=[N:41][CH:42]=2)O1>>[CH:11]1([N:8]2[C:9]3[CH:10]=[C:2]([C:37]4[CH:42]=[N:41][C:40]([N:43]5[CH2:44][CH2:45][NH:46][CH2:47][CH2:48]5)=[CH:39][CH:38]=4)[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]4[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=4[CH3:26])=[O:17])[C:5]=3[CH:6]=[N:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC1(C)OB(c2ccc(N3CCNCC3)nc2)OC1(C)C
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N4CCNCC4)nc3)cc3c2cnn3C2CCCC2)c(=O)[nH]1

Procedure:
The title compound was prepared in a similar manner as described for example 8 from 6-bromo-1-cyclopentyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (200 mg, 0.451 mmol) and 1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (196 mg, 0.677 mmol). The product was collected as a white solid (92 mg, 37%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (br. s., 1H) 8.64-8.67 (m, 1H) 8.60 (t, J=4.80 Hz, 1H) 8.35 (s, 1H) 8.03-8.09 (m, 2H) 7.84 (d, J=1.26 Hz, 1H) 6.89-6.99 (m, 1H) 5.89 (s, 1H) 5.27-5.35 (m, 1H) 4.39 (br. s., 1H) 4.38 (br. s., 1H) 3.41-3.56 (m, 4H) 2.69-2.91 (m, 4H) 2.22 (s, 3H) 2.07-2.20 (m, 6H) 1.97-2.06 (m, 2H) 1.85-1.93 (m, 2H) 1.65-1.74 (m, 2H). LC-MS (ES) m/z=526.3 [M+H]+
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:15].[OH-].[Ba+2].[OH-]>S(=O)(=O)(O)O.O.[O-2].[O-2].[Cr+4]>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=[O:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CCN(Cc2ccccc2)C1
Reactant: O
Agent: [Cr+4]
Agent: O=S(=O)(O)O
Agent: [Ba+2]
Product: O=C(O)C1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 6916.1 %

Procedure:
A suspension of lithium aluminum hydride (7.50 g) in 150 ml THF was cooled to -5° C. A solution of methyl 1-benzyl-5-oxo-3-pyrrolidine carboxylate (0.064 moles, 15.0 g) in THF was added dropwise. The mixture was heated to 40° C. for 16 hours. Water (25 ml) was added. The mixture was filtered and extracted with ether. The organic phase was washed with water, dried over sodium sulfate and concentrated to yield 11.65 g of N-benzyl-3-hydroxymethylpyrrolidine. (MS) The alcohol (0.06 moles, 11.5 g) in 75 ml 2N sulfuric acid was added dropwise to a stirred solution of chromium dioxide (0.15 moles, 15.0 g) in 100 ml 2N sulfuric acid. The solution was stirred at room temperature for 16 hours. The solution was treated with barium hydroxide hydrate (0.317 mmoles, 100 g) in 250 ml hot water. The solid was filtered and washed with water. The aqueous solution was extracted with ether. Carbon dioxide was bubbled through the solution until the pH was 7.0. The solution was filtered and concentrated to yield 4.5 g of N-benzyl-3-pyrrolidinecarboxylic acid. (MS) The oil was dissolved in 50 ml methanol. Dry HC1 gas was bubbled through the solution. The solution was heated to near reflux for 4 hours and concentrated. The residue was neutralized with aqueous sodium bicarbonate. The product was extracted with ether, dried and concentrated to yield 3.0 g of methyl N-benzyl-3-pyrrolidinecarboxylate.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[OH-].[Na+].[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13].[Cl-].[Na+]>C1(C)C=CC=CC=1.O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:14]([CH2:15][CH3:16])[CH2:12][CH3:13])[N:7]=1
Reactant: CCNCC
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCN(CC)c1nc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
A mixture of 50.0 g (271 mmol) of cyanuric chloride, 22.0 g of 50% aqueous sodium hydroxide, 22 ml of water, and 150 ml of toluene, cooled to 0° C., is admixed with a solution of 19.8 g (271 mmol) of diethylamine in 25 ml of toluene over a 45 minute interval. The reaction temperature is maintained at 0°-5° C. throughout the addition. After the addition is complete, the reaction mixture is stirred for two hours at ambient temperature. Water is added to the mixture to dissolve the sodium chloride, and the phases are separated. The organic phase is dried over magnesium sulfate and concentrated to give an oil which is crystallized from heptane to give 42.0 g (70% yield) of 2,4-dichloro-6-diethylamino-1,3,5-triazine, a white crystalline material, m.p. 77°-9° C.
Reaction SMILES: C(N(CC)CC)C.[OH:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19].[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[C:20]1([S:26]([O:8][N:9]2[C:10](=[O:19])[C:11]3=[CH:18][CH:17]=[CH:16][CH:15]=[C:12]3[C:13]2=[O:14])(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1OS(=O)(=O)c1ccccc1
Reaction time: 24 h
Yield: 86.2 %

Procedure:
A dichloromethane (50 ml) solution of triethylamine (3.1 g, 0.0306 mole) was slowly added to a stirred dichloromethane (50 ml) suspension of N-hydroxyphthalimide (5.0 g, 0.0306 mole) and benzenesulfonyl chloride (5.4 g, 0.0306 mole) at ice-bath temperature. The stirred reaction mixture was kept at ambient temperature for about 24 hours. The product was partitioned between dichloromethane and distilled water and the dichloromethane extract was dried with magnesium sulfate. Solvent was removed under reduced pressure and the residue was crystallized with ethyl acetate-n-pentane (2:1 v/v) to give 8.0 g (87%) of colorless crystals; mp 186°; mass spectrum M+ 303 (calcd. M+ 303).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Cl[C:6]([CH3:20])([CH3:19])[C:7]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=[O:8]>ClCCl.CCCCCCC>[CH3:19][CH:6]1[C:7](=[O:8])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH:12]=[CH:11][C:10]=2[CH2:20]1
Reactant: CC(C)(Cl)C(=O)c1cccc2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCCCCCC
Product: CC1Cc2ccc3ccccc3c2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
Aluminium chloride (35 g, 0.26 mole) was suspended in 200 ml of anhydrous dichioromethane. 2-Chloro-2-methyl-1-(1-naphthalenyl)-1-propanone (30.0 g, 0.13 mole) in 30 ml of heptane was slowly added to this suspension. During the addition (30 min) the temperature was kept at room temperature. After the addition was completed, the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was poured onto 400 g of ice water, and the organic layer was separated. The organic layer was successively washed twice with a 5 wt % aqueous hydrochloric acid solution (150 ml) and once with a 2 wt % aqueous sodium bicarbonate solution (150 ml). After drying over anhydrous magnesium sulfate the solution was concentrated under reduced pressure. The yield of crude 2,3-dihydro-2-methyl-1H-benz[e]inden-1-one was 23.4 g or 93%. Distillation of the crude product under reduced pressure (b.p. 130° C., 0.5 mbar) gave 18.7 g (75%) of 2,3-dihydro-2-methyl-1H-benz[e]inden-1-one, which crystallized upon standing at room temperature.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:9][C:10]([F:17])([F:16])[C:11]1[CH:15]=[CH:14][NH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:8][C:7]1[C:2]([N:13]2[CH:14]=[CH:15][C:11]([C:10]([F:17])([F:16])[F:9])=[N:12]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cccnc1Cl
Reactant: FC(F)(F)c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccn(-c2ncccc2Cl)n1
Temperature: 117.5 °C
Yield: 75.1 %

Procedure:
To a mixture of 2,3-dichloropyridine (99.0 g, 0.67 mol) and 3-(trifluoromethyl)-pyrazole (83 g, 0.61 mol) in dry N,N-dimethylformamide (300 mL) was added potassium carbonate (166.0 g, 1.2 mol) and the reaction was then heated to 110-125° C. over 48 hours. The reaction was cooled to 100° C. and filtered through Celite® diatomaceous filter aid to remove solids. N,N-Dimethylformamide and excess dichloropyridine were removed by distillation at atomospheric pressure. Distillation of the product at reduced pressure (b.p. 139-141° C., 7 mm) afforded the desired intermediate as a clear yellow oil (113.4 g).
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.Br[C@@H:15]1[C@@H:20]([OH:21])[CH2:19][CH2:18][CH2:17][C@H:16]1[N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32]>C1(C)C=CC=CC=1.CO.N(C(C)(C)C#N)=NC(C)(C)C#N>[OH:21][C@@H:20]1[CH2:19][CH2:18][CH2:17][C@H:16]([N:22]2[C:23](=[O:32])[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]2=[O:31])[CH2:15]1
Reactant: O=C1c2ccccc2C(=O)N1[C@@H]1CCC[C@H](O)[C@H]1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C1c2ccccc2C(=O)N1[C@H]1CCC[C@@H](O)C1
Yield: 87.9 %

Procedure:
Tributyltin hydride (1.99 ml, 7.40 mmol) and 2,2′-azobis(isobutyronitrile) (8 mg) were added to a solution of 2-[(1R, 2S, 3S)-2-bromo-3-hydroxycyclohexyl]-1H-isoindole-1,3(2H)-dione (2.0 g, 6.17 mmol) in a mixture of toluene (40 ml) and methanol (4 ml) at room temperature, and the resulting mixture was refluxed for 3 hours. Tributyltin hydride (1.99 ml, 7.40 mmol) and 2,2′-azobis(isobutyronitrile) (8 mg) were further added thereto, and the resulting mixture was refluxed for 1 hour. The reaction solution was concentrated and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=2/1) to obtain cis-2-(3-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione (1.33 g, 88%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:18])[C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[NH:11][C:12](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21]I.O>CN(C)C=O>[NH2:1][C:2]1[C:7]2[C:8](=[O:18])[C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[N:11]([CH3:21])[C:12](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: Nc1cccc2c(=O)[nH]c3ccccc3c(=O)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2cccc(N)c2c(=O)c2ccccc21

Procedure:
To 5 g 10-amino-5,6-dihydro-11H-dibenzo(b,e)azepine-6,11-dione in 25 ml dimethylformamide are added 0.8 g 60% sodium hydride in mineral oil and then 1.5 ml methyl iodide. After leaving for 24 hours at ambient temperature, with stirring, the mixture is poured into water, filtered and dried: melting point 171°-3° C. (water).
Reaction SMILES: CS(O[C@H:6]([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=O)=O.[C:13]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:25])[CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].[F-].[Cs+].O>CN(C=O)C>[CH:14]([C:13]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@H:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:12]
Reactant: CCOC(=O)[C@@H](C)OS(C)(=O)=O
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@H](C)C(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 50 °C

Procedure:
To a solution of (R)-ethyl 2-(methylsulfonyloxy)propanoate (15 g, 0.076 mol) in DMF (300 ml) was added dibenzyl malonate (21.5 g, 0.076 mol) and CsF (11.5 g, 0.076 mol). The mixture was heated to 50° C. for 2 days. After cooled to room temperature, the mixture was poured into water and then extracted with EtOAc. The organic phase was washed with brine, water and dried. Concentrated to afford (R)-1,1-dibenzyl 2-ethyl propane-1,1,2-tricarboxylate, which was purified by silica gel chromatography (11 g, 40%).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([NH2:10])=[O:9])[C:3]1=[O:11].[C:12](Cl)(=[O:14])[CH3:13]>C(Cl)(Cl)Cl>[C:12]([O:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([NH2:10])=[O:9])[C:3]1=[O:11])(=[O:14])[CH3:13]
Reactant: CC(=O)Cl
Reactant: NC(=O)CN1CCC(O)C1=O
Solvent: ClC(Cl)Cl
Product: CC(=O)OC1CCN(CC(N)=O)C1=O

Procedure:
1.5 g of (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide are heated to reflux for 20 minutes with 13.5 ml of acetyl chloride and 25 ml of chloroform. The mixture is evaporated. The residue is treated four times with toluene and in each case again evaporated. There is obtained (R/S)-2-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetamide which melts at 116°-117° after crystallization from diethyl ether.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[NH2:26])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][N:28]1[C:32]([C:33]2[CH:34]=[C:35]([NH:39][C:40](=O)[O:41]C3C=CC=CC=3)[CH:36]=[CH:37][CH:38]=2)=[N:31][N:30]=[N:29]1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH2:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[NH:26][C:40]([NH:39][C:35]1[CH:36]=[CH:37][CH:38]=[C:33]([C:32]2[N:28]([CH3:27])[N:29]=[N:30][N:31]=2)[CH:34]=1)=[O:41])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCCc1ccc(F)cc1)C[C@@H]1CCCC[C@H]1N
Reactant: Cn1nnnc1-c1cccc(NC(=O)Oc2ccccc2)c1
Solvent: CN(C)C=O
Product: Cn1nnnc1-c1cccc(NC(=O)N[C@@H]2CCCC[C@H]2CN(CCCc2ccc(F)cc2)C(=O)OC(C)(C)C)c1
Reaction time: 8 h
Yield: 25.1 %

Procedure:
The product of Step i (0.26 g, 0.69 mmol, 1 eq.), and phenyl 3-(1-methyl-1H-tetraazol-5-yl)phenylcarbamate (Example 1a, see below)(0.20 g, 0.69 mmol, 1 eq.) were dissolved in DMF (2 mL) at room temperature and stirred under N2 overnight. The DMF was stripped on the rotary evaporator and EtOAc was added (50 mL). This mixture was washed with water (3×50 mL), dried (MgSO4), stripped, and flash chromatographed in 3:1 Hexanes/EtOAc to 1:1 Hexanes/EtOAc to 100% EtOAc to yield 98 mg of a white glass. MS (AP+) detects (M+H)+=566.6.
Reaction SMILES: [CH3:1][O:2][CH:3]([NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16])[C:4]([Cl:7])([Cl:6])[Cl:5].N1C=CC=CC=1.[C:24](Cl)(=[O:26])[CH3:25]>O>[CH3:1][O:2][CH:3]([NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][C:24](=[O:26])[CH3:25])[C:4]([Cl:7])([Cl:6])[Cl:5]
Reactant: COC(NC(=O)c1ccccc1O)C(Cl)(Cl)Cl
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: COC(NC(=O)c1ccccc1OC(C)=O)C(Cl)(Cl)Cl
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
To 2.5 g of N-(1'-methoxy-2',2',2'-trichloroethyl)-2-hydroxy benzamide was added 20 g of pyridine and maintained at below -10° C., 1.5 g of acetyl chloride was added dropwise and then allowed at room temperature for about 30 minutes, and poured into water to give a crystal which was recrystalized by using methanol to obtain 2.2 g white crystal of N-(1'-methoxy-2',2',2'-trichloroethyl)-2-acetoxy benzamide.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:35]([CH3:36])=[CH:34][C:13]2[N:14]=[C:15]([N:17]3[CH2:22][CH2:21][NH:20][CH:19]([C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[N:28]([CH3:32])[N:27]=[CH:26]5)[C:18]3=[O:33])[S:16][C:12]=2[C:11]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].C=O.[C:46](O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:1]([O:5][C@@H:6]([C:10]1[C:35]([CH3:36])=[CH:34][C:13]2[N:14]=[C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH3:46])[CH:19]([C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[N:28]([CH3:32])[N:27]=[CH:26]5)[C:18]3=[O:33])[S:16][C:12]=2[C:11]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2nc(N3CCNC(c4ccc5c(cnn5C)c4)C3=O)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1cc2nc(N3CCN(C)C(c4ccc5c(cnn5C)c4)C3=O)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reaction time: 1 h

Procedure:
To the solution of: (2S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)-2-oxopiperazin-1-yl)benzo[d]thiazol-6-yl)acetic acid (3 mg) in methanol (0.5 mL) was added formaldehyde solution (20 μL, 37%), followed by acetic acid (10 μL) and sodium cyanoborohydride (12 mg). The mixture was stirred for 1 hour, and solvents were removed under reduced pressure. The remaining solid was dissolved with DMF/water (1 mL/0.5 mL), and was purified with reverse phase HPLC to give (2S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(4-methyl-3-(1-methyl-1H-indazol-5-yl)-2-oxopiperazin-1-yl)benzo[d]thiazol-6-yl)acetic acid. LCMS-ESI+: calc'd for C33H35ClN5O4S: 632.2 (M+H+); Found: 632.2 (M+H+). 1H-NMR 400 MHz, (CD3OD) δ 8.0 (m, 1H), 7.82 (m, 1H), 7.68 (s, 1H), 7.62-7.40 (m, 6H), 5.21 (m, 1H), 4.70 (m, 1H), 4.6-4.3 (m, 2H), 4.08/4.05 (s, 3H), 3.5 (m, 2H), 2.57 (s, 3H), 2.40 (m, 3H), 0.93 (s, 9H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Br:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](Cl)=[O:11]>O1CCCC1>[Br:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([N:2]([CH3:3])[CH3:1])=[O:11]
Reactant: CNC
Reactant: O=C(Cl)CCCCCBr
Solvent: C1CCOC1
Product: CN(C)C(=O)CCCCCBr
Yield: 89.7 %

Procedure:
A solution of 27.5 g (0.610 mole) of dimethylamine in 100 ml of cold tetrahydrofuran was added dropwise to a solution of 25.0 g (0.117 mole) of 6-bromohexanoyl chloride in 100 ml of tetrahydrofuran. The reaction mixture was stirred mechanically and the temperature maintained between 5° and 15° C. throughout the addition. After the final addition, the solution was filtered to remove the solid precipitate and the filtrate was concentrated under reduced pressure to yield 23.3 g (90%) of light-yellow oil. An analytical sample was prepared by filtering the oil through a small bed of silica gel and eluting with ethyl acetate. The fractions containing the desired product were combined and concentrated under reduced pressure to give the title compound as a colorless oil.