Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[NH:8][C:7]1=[O:14])=[CH2:2].[C:15](#[N:18])[CH:16]=[CH2:17].C1(C=CC(O)=CC=1)O.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>CO.CN(C)C=O>[C:15]([CH2:16][CH2:17][N:8]1[C:9]([CH3:13])([CH3:12])[C:10](=[O:11])[N:6]([CH2:5][CH2:4][O:3][CH:1]=[CH2:2])[C:7]1=[O:14])#[N:18]
Reactant: C=COCCN1C(=O)NC(C)(C)C1=O
Reactant: C=CC#N
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Oc1ccc(O)cc1
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: C=COCCN1C(=O)N(CCC#N)C(C)(C)C1=O

Procedure:
A mixture of 237.8 g (1.2 mols) of 3-(2-vinyloxyethyl)-5,5-dimethylhydantoin, prepared as described in Example 1, 79.6 g (1.2 mols+20% excess) of acrylonitrile, 0.5 g of hydroquinone, 2.4 ml of a 40% solution of benzyltrimethylammonium hydroxide in methanol and 360 ml of dimethylformamide is allowed to react for 27 hours at 81°-85° C. The solution is then concentrated on a rotary evaporator at 90° C. under vacuum from a waterpump and the residue is dried to constant weight at 90° C. and 13.3 Pa. 300.4 g (99.6% of theory) of a dark brown, crystalline crude product are obtained and are purified by distillation. 260.8 g (86.5% of theory) of a crystalline distillate boiling at 147°-150° C. are obtained. After recrystallisation from ether, the product melts at 54.8°-55.5° C.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:25](=[O:28])[NH:26][N:27]=4)[N:24]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[C:38]([CH3:45])([CH3:44])[C:39]([O:41][CH2:42][CH3:43])=[O:40]>CN(C)C=O>[C:29]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:25](=[O:28])[N:26]([C:38]([CH3:45])([CH3:44])[C:39]([O:41][CH2:42][CH3:43])=[O:40])[N:27]=4)[N:24]=3)[CH2:13][CH2:14]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=c1[nH]nc2ccc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)n1nc2ccc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.459 g of 6-[3-[4-(diphenylmethoxy)piperidino]propoxy][1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one was suspended in 6 ml of N,N-dimethylformamide; 0.048 g of 60% oily sodium hydride was added, followed by stirring at room temperature for 30 minutes. 0.294 ml of ethyl 2-bromoisobutyrate was added, followed by stirring in an oil bath (bath temperature 110° C.) for 4 hours. After cooling, 0.048 g of 60% oily sodium hydride and 0.294 ml of ethyl 2-bromoisobutyrate were added, followed.by stirring in an oil bath (bath temperature 110° C.) for 10 hours. After cooling, ice water was added; the reaction mixture was extracted with ethyl acetate; the extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (185:15:2). The desired fraction was collected and concentrated to yield 0.401 g of ethyl 2-[6-[3-[4-(diphenylmethoxy)piperidino]propoxy]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionate as an oily substance. This oily substance was dissolved in 5 ml of ethyl acetate; 0.5 ml of a 4 N solution of hydrogen chloride in ethyl acetate was added, followed by concentration; the residue was powdered from diethyl ether; the powder was collected by filtration and dried to yield 0.300 g of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([F:12])[CH:6]=1)C.[O:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[CH2:19]OS(C)(=O)=O>>[F:12][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[O:11][CH2:19][C@@H:15]1[CH2:16][CH2:17][CH2:18][O:14]1)[C:4]([OH:3])=[O:13]
Reactant: CCOC(=O)c1ccc(O)c(F)c1
Reactant: CS(=O)(=O)OC[C@@H]1CCCO1
Product: O=C(O)c1ccc(OC[C@@H]2CCCO2)c(F)c1

Procedure:
According to method F, 3-fluoro-4-hydroxybenzoic acid ethyl ester was alkylated with methanesulfonic acid (S)-1-(tetrahydrofuran-2-yl)methyl ester, and the reaction product was hydrolyzed by method E. The product was thus obtained with the molecular weight of 240.23 (C12H13FO4); MS (ESI): 241 (M+H+).
Reaction SMILES: [O:1]=[Si]=O.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1>>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:1])=[CH:7][CH:6]=1
Reactant: O=[Si]=O
Reactant: Cc1ccc(Cl)cc1
Product: O=Cc1ccc(Cl)cc1
Temperature: -70 °C

Procedure:
To carry out the oxidation, 20 g of the catalyst is mixed with 20 g of broken quartz glass of the same screening fraction and this mixture is placed in a quartz glass tube having an inner diameter of 1.5 cm. For thermostating, the reactor is immersed in a fluidized sand bath which is heated externally. The starting material gas comprising 1% by volume of 4-chlorotoluene and 99% by volume of air is passed through the heated reactor at a total volumetric flow rate of 2.5 ml/s (STP) and the product is collected in a trap cooled to -70° C. Carbon monoxide and carbon dioxide are quantitatively determined by gas chromatography. The unreacted 4-chlorotoluene collected in the cold trap and the 4-chlorobenzaldehyde formed are taken up in acetonitrile and analyzed by HPLC. The results of the reaction are given in Table 1.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C1COCC1>[CH3:13][S:14]([O:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: COCCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCOS(C)(=O)=O

Procedure:
The 2-methoxyethanol (Aldrich, 94 mg, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:18]([OH:20])=[O:19])[CH2:16][CH2:15][C:14](=[O:17])[O:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:23]I.O>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C:12]1([C:18]([O:20][CH3:23])=[O:19])[CH2:16][CH2:15][C:14](=[O:17])[O:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(NC(=O)OCc2ccccc2)(C(=O)O)O1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1(NC(=O)OCc2ccccc2)CCC(=O)O1
Reaction time: 4 h

Procedure:
In 100 ml of N,N-dimethylformamide was dissolved 27.93 g of 2-benzyloxycarbonylamino-5-oxo-2-tetrahydrofurancarboxylic acid obtained by the method described in Journal of Organic Chemistry, 6 878 (1941). To the solution was added 4.0 g of sodium hydride (60% oil), to which was further added 28.4 of methyl iodide, and the reaction was allowed to proceed at room temperature for 4 hours. The reaction mixture was supplemented with 14.2 g of methyl iodide, which was stirred for further 3 hours. The reaction solution was poured into water, which was subjected to extraction with ethyl acetate. The organic layer was washed with sodium hydrogen carbonate and a saturated saline solution, successively, followed by drying (MgSO4). The solvent was evaporated off, and the crystals which separated out were collected by filtration, followed by washing with ether to give 27.25 g of methyl 2-benzyloxycarbonylamino-5-oxo-2-tetrahydrofurancarboxylate as colorless crystals, m.p. 134-134.5° C.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=1[N:27]=[C:28]=[O:29]>C(N(CC)CC)C>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:28](=[O:29])[NH:27][C:21]3[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:20]=3[CH3:19])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(N=C=O)c(C)c1
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)OC2CCN(C)C(=O)N2c2nnc(C(C)(C)C)s2)c(C)c1
Reaction time: 1 h

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole) and 2,4-dimethylphenyl isocyanate (3.5 ml; 0.06 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer. The mixture is stirred and triethylamine (1 drop) is added thereto. After the addition is completed the reaction mixture is allowed to stand for a period of about 1 hour. The mixture is then washed with hexane and is dried to yield the desired product tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-[N-(2,4-dimethylphenyl)carbamoyloxy]-2(1H)-pyrimidinone.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[NH2:18][C:19]1[CH:20]=[N:21][N:22]([CH2:24][C@H:25]2[O:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]2)[CH:23]=1>O1CCOCC1>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:18][C:19]2[CH:20]=[N:21][N:22]([CH2:24][C@H:25]3[O:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]3)[CH:23]=2)[N:7]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(N)cn2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(Nc3ncnc(Cl)n3)cn2)C1
Temperature: 110 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a solution of 2,4-dichloro-1,3,5-triazine (1.8 g, 6.4 mmol) in dioxane (20 mL) was added diisopropylethylamine (4 mL), followed by the addition of (S)-tert-butyl 2-((4-amino-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate (1.2 g, 7.2 mmol). The reaction mixture was stirred at 110° C. for 1 hour, and LCMS (liquid chromatography-mass spectrometry) showed the reaction was completed. The solvents were removed under reduced pressure, and the residue was purified by silica gel chromatography, eluting with petroleum ether:ethyl acetate=5:1, to afford (S)-tert-butyl 2-((4-(4-chloro-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate as a yellow solid (1.8 g, 70%). MS (ES+) C16H22ClN7O3 requires: 395, 396, found: 396, 397 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH3:11][C:10]1[C:2]2[NH:1][C:13](=[O:15])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: Cc1cccc2c(=O)oc(=O)[nH]c12

Procedure:
The compounds of this invention can be prepared as illustrated by the exemplary reaction in Scheme 3. Reaction of 2-amino-3-methylbenzoic acid with triphosgene in THF produced 8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione, which was treated with tert-butylamine and DMAP in DMF to produce 2-amino-N-tert-butyl-3-methylbenzamide. Reaction of the benzamide with CDI in THF produced 3-tert-butyl-8-methylquinazoline-2,4(1H,3H)-dione, which was reacted with methyl 3-(bromomethyl)benzoate and MeONa in DMF, followed by treatment with hydrochloric acid aqueous solution, to produce 8-methyl-1-(3-carboxybenzyl)quinazoline-2,4(1H,3H)-dione. Coupling of the acid with 2-(piperazin-1-yl)pyrimidine in the presence of coupling agents, such as HATU and DIPEA in DMF, produced the targeted compound 8-methyl-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione.
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:11][CH2:10][C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+]>O>[CH2:1]([NH:8][C:9]([C:10]1[NH:11][C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:13]2[C:14]=1[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18]2)=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccccc1)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of 36.1 g. of 1-benzyl-7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one in 300 ml. of dimethylformamide is treated under an atmosphere of argon at room temperature with 0.11 mol. of sodium hydride (4.8 g of a 55% dispersion in mineral oil). The mixture is first heated to 60° C. over a period of about 30 minutes, and then stirred for 1 hour at this temperature for an additional 1 hour at 70° C. After cooling, 10 ml. of water are added dropwise and the mixture is poured into 3 liters of ice-water. After the addition of 100 g. of sodium chloride, the separated product is extracted with methylene chloride. The organic phase is washed with a saturated solution of sodium chloride, dried over sodium sulfate and concentrated to dryness. The resulting oily residue is chromatographed on 1000 g. of silica gel with methylene chloride/ethyl acetate (4:1) as the eluant. The homogeneous fractions are combined, evaporated and triturated with a small amount of ether, and there is obtained 5-chloro-3-phenylisoindole-1-carboxylic acid benzylamide in the form of fibrous, greenish crystals; melting point 202°-204° C. (decomposition). Recrystallization from chloroform does not increase the melting point.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1([C:16]#[N:17])[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1.[C-:18]#[N:19].[Na+]>CN(C)C=O.O>[C:18]([CH2:2][CH2:3][CH2:4][C:5]1([C:16]#[N:17])[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1)#[N:19]
Reactant: [C-]#N
Reactant: CCOC(=O)N1CCC(C#N)(CCCCl)CC1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(C#N)(CCCC#N)CC1
Temperature: 140 °C
Yield: 88.3 %

Procedure:
To a solution of ethyl 4-(3-chloropropyl)-4-cyano-1-piperidinecarboxylate (12.7 g) in dimethylformamide (250 ml) was added sodium cyanide (24 g) under nitrogen, with stirring. The mixture was warmed at 140° C. overnight and then cooled to ambient temperature, diluted with water and extracted with ethyl acetate. The organic extracts were washed with saturated, sodium chloride solution and water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was chromatographed, eluting with 2:1 heptane/ethyl acetate. The appropriate fractions were collected and concentrated to give 10.8 g (88.5%) of product. A portion was distilled to give the analytical sample, bp 196-201° C. (4 mm of mercury).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]1.[C:10]([O:14][C:15](OC([O-])=O)=[O:16])([CH3:13])([CH3:12])[CH3:11]>C(#N)C.CN(C1C=CN=CC=1)C>[C:7]([CH:4]1[CH2:5][CH2:6][N:1]([C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])[CH2:2][CH2:3]1)(=[O:8])[NH2:9]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: NC(=O)C1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To a solution of piperidine-4-carboxamide (2 g, 15.6 mmol) in acetonitrile (30 mL), tert-butyldicarbonate (4.4 g, 20.2 mmol, 1.3 eq) and DMAP (190 mg, 1.56 mmol, 0.1 eq) were added and the mixture was stirred at r.t. overnight. It was then concentrated under reduced pressure, taken up with DCM and washed with saturated aqueous NaHCO3, saturated aqueous NH4Cl, brine and water. The organic phase was dried over Na2SO4 and evaporated to dryness. The residue was triturated with diethyl ether and the white solid was filtered and dried to give 2.65 g (74%) of the title product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH3:25][N:26]([CH3:32])[CH:27]1[CH2:31][CH2:30][NH:29][CH2:28]1>C(OCC)(=O)C.CO>[CH3:25][N:26]([CH3:32])[CH:27]1[CH2:31][CH2:30][N:29]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]3[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:28]1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Reactant: CN(C)C1CCNC1
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nc2ccc(N3CCC(N(C)C)C3)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 37 %

Procedure:
The title compound was prepared from 1-(6-Bromo-2-methyl-4-phenyl-quinolin-3-yl)-2,2,2-trifluoro-ethanone [example 3] and 3-(dimethylamino)pyrrolidine according to the procedure of example 25, except that the reaction time was of 16 h and that ethyl acetate/methanol (9:1) was used. Yield: 37%; MS: m/z=428 (M+H).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=1[NH2:6]>C(O)(=O)C>[Br:1][C:9]1[CH:8]=[C:7]([CH3:11])[C:5]([NH2:6])=[C:4]([CH3:3])[CH:10]=1
Reactant: BrBr
Reactant: Cc1cccc(C)c1N
Solvent: CC(=O)O
Product: Cc1cc(Br)cc(C)c1N
Temperature: 40 °C
Reaction time: 2 h

Procedure:
21.3 ml (66.1 g, 0.413 mol) of bromine were added dropwise, while vigorously stirring, over ca. 20 minutes to a solution of 50.0 g (0.413 mol) of 2,6-dimethylaniline in 1200 cm3 of glacial acetic acid. This mixture was stirred for 2 hours at 40° C. The precipitate formed was filtered off, washed with 50 ml of acetic acid, and dried in air. Then, this white solid was added to a solution of 100 g of sodium hydroxide in 600 ml of water. This mixture was stirred for 30 minutes. The crude product was extracted with 3×100 ml of dichloromethane. The combined organic fractions were dried over Na2SO4 and evaporated to dryness. Fractional distillation gave a yellow liquid, bp 82-85° C./1 mm Hg. Yield 61.7 g (75%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.[Br:14]Br>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH2:11][Br:14])=[CH:6][CH:5]=1
Reactant: BrBr
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C(=O)CBr)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a solution of 4-acetyl-benzoic acid methyl ester (8.4 mmol) in acetic acid (20 mL) was added bromine (8.4 mmol). The reaction was stirred at RT for 2 h over which time the red colour disappeared and an off white precipitate formed. The product was collected by filtration and washed with cold methanol/water (200 mL 1:1) to yield a white powder (55%). 1H NMR (400 MHz, CDCl3) 3.98 (3H, s), 4.20 (2H, s), 8.02 (2H, d, J=8 Hz), 8.18 (2H, d, J=8 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>O1CCCC1>[CH3:18][S:19]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc2[nH]ccc2c1
Yield: 94.5 %

Procedure:
To a solution of 2.0 gm (15.1 mMol) 5-amino-1H-indole in 25 mL tetrahydrofuran were added 2.4 mL (17.2 mMol) triethylamine. The reaction mixture was cooled in an ice bath as 1.23 mL (15.9 mMol) methanesulfonyl chloride were added dropwise. After 3.5 hours the reaction mixture was partitioned between 1N sodium hydroxide and ethyl acetate. The organic phase was extracted twice with 1N sodium hydroxide. All sodium hydroxide phases were combined, adjusted to pH=5 with acid and extracted well with ethyl acetate. These organic phases were combined, washed sequentially with water and saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure to give 3.0 gm of a purple solid. This solid was crystallized from cyclohexane/ethyl acetate to give 2.5 gm (78.6%) of the title compound as light purple crystals.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N:11]([S:25]([C:28]3[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=3)(=[O:27])=[O:26])[CH2:12][CH2:13][NH:14]C(=O)OCC3C=CC=CC=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.C1COCC1.[H][H]>CO.[Pd]>[NH2:14][CH2:13][CH2:12][N:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[CH:3]=[CH:4]2)[S:25]([C:28]1[CH:29]=[C:30]([O:38][CH3:39])[C:31]([O:36][CH3:37])=[C:32]([O:34][CH3:35])[CH:33]=1)(=[O:27])=[O:26]
Reactant: [H][H]
Reactant: COc1cc(S(=O)(=O)N(CCNC(=O)OCc2ccccc2)c2ccc3c(ccn3C)c2)cc(OC)c1OC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(S(=O)(=O)N(CCN)c2ccc3c(ccn3C)c2)cc(OC)c1OC

Procedure:
A solution of Example 51A in methanol:THF (1 mL:1 mL) was treated with 10% palladium on carbon (30 mg), stirred under with hydrogen (1 atm) for 2 hours, filtered through diatomaceous earth (Celite®), and concentrated to provide the desired compound.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH:42]([S:45](Cl)(=[O:47])=[O:46])([CH3:44])[CH3:43]>C(#N)C>[CH:42]([S:45]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:47])=[O:46])([CH3:44])[CH3:43]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)S(=O)(=O)Oc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 38.9 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0303 g, 0.0656 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0550 mL, 0.394 mmol) and isopropanesulfonyl chloride (0.0220 mL, 0.197 mmol) to obtain 4-isopropanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0145 g, yield 39%).
Reaction SMILES: C(C(CCCCCCCCCCCC)CN=[C:14]([C:16]1[C:25]2[C:24]([C:26]([OH:28])=[O:27])=[C:23]([Br:29])[C:22]([Br:30])=[C:21]([C:31]([OH:33])=[O:32])[C:20]=2[C:19]([C:34](=[N:36][CH2:37][CH:38](CCCCCCCCCC)CCCCCCCCCCCC)[OH:35])=[C:18]([Br:61])[C:17]=1[Br:62])[OH:15])CCCCCCCCC.[CH2:75]([CH:81]([CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH3:92])[CH2:82][CH2:83][NH2:84])[CH2:76][CH2:77][CH2:78][CH2:79][CH3:80]>>[CH2:75]([CH:81]([CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH3:92])[CH2:82][CH2:83][N:84]=[C:14]([C:16]1[C:25]2[C:24]([C:26]([OH:28])=[O:27])=[C:23]([Br:29])[C:22]([Br:30])=[C:21]([C:31]([OH:33])=[O:32])[C:20]=2[C:19]([C:34](=[N:36][CH2:37][CH2:38][CH:81]([CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH3:80])[CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH3:92])[OH:35])=[C:18]([Br:61])[C:17]=1[Br:62])[OH:15])[CH2:76][CH2:77][CH2:78][CH2:79][CH3:80]
Reactant: CCCCCCCCCCCCC(CCCCCCCCCC)CN=C(O)c1c(Br)c(Br)c(C(O)=NCC(CCCCCCCCCC)CCCCCCCCCCCC)c2c(C(=O)O)c(Br)c(Br)c(C(=O)O)c12
Reactant: CCCCCCCCC(CCN)CCCCCC
Product: CCCCCCCCC(CCCCCC)CCN=C(O)c1c(Br)c(Br)c(C(O)=NCCC(CCCCCC)CCCCCCCC)c2c(C(=O)O)c(Br)c(Br)c(C(=O)O)c12
Yield: 31 %

Procedure:
The same synthetic method for compound 22 was used except using 3-hexylundecyl amine instead of 2-decyltetradecyl amine, and the yield was 31% (calculated based on TBNDA as a starting material).