Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11](Cl)=[N:12][C:13]([Cl:15])=[N:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:17][CH2:18][O-:19].[Na+]>C(O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]([O:19][CH2:18][CH3:17])=[N:12][C:13]([Cl:15])=[N:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: Clc1nc(Cl)c2[nH]c3ccc(Br)cc3c2n1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(Cl)nc2c1[nH]c1ccc(Br)cc12
Temperature: 25 °C
Yield: 97.1 %

Procedure:
930 mg (2.9 mmol) 8-bromo-2,4-dichloro-5H-pyrimido[5,4-b]indole was suspended in 20 ml ethanol and mixed with 592 mg (8.7 mmol) sodium ethylate. The mixture was refluxed for 8 h. Having cooled down to room temperature, the solvent was concentrated and water was added. The resulting precipitate was sucked off and washed with water. 920 mg (97%) 8-bromo-2-chloro-4-ethoxy-5H-pyrimido[5,4-b]indole was obtained. ESI-MS [m/z]: 324, 326 [M−H]−
Reaction SMILES: [CH2:1]1[C:6]2=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=[CH:9][CH:10]=[CH:11][C:5]2=C(C#N)[CH:3]=[CH:2]1.[OH-:18].[K+].[CH2:20]([OH:23])[CH2:21]O>O>[CH:1]1[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][CH2:11][C:5]=2[C:21]([C:20]([OH:23])=[O:18])=[CH:3][CH:2]=1
Reactant: OCCO
Reactant: N#CC1=C2C=CC=c3ccccc3=C2CC=C1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1cccc2c1CCCc1ccccc1-2

Procedure:
Under a dry nitrogen atmosphere a solution of 6,7-dihydro-5e,uns/H/ -dibenzo[a,c]cycloheptene-4-carbonitrile (2.95 grams, 0.0134 mole), potassium hydroxide (4 grams, 0.085 mole), ethylene glycol (40 ml) and water (3 ml) was heated at reflux for approximately 24 hours. The mixture was cooled, diluted with water, and the solution was washed with diethyl ether. The aqueous solution was acidified and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated to give a white solid. The solid was combined with similar material prepared in a separate experiment, and the combined solids were recrystallized from n-hexane to give 6,7-dihydro-5H-dibenzo[a,c]cycloheptene-4-carboxylic acid (mp 137°-139°) as nearly white crystals.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[S:16][C:15]3[N:17]=[CH:18][CH:19]=[N:20][C:14]=3[N:13](COC)[C:12]=2[CH:24]=1)(=O)=O.[NH:25]1[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][CH:33]([CH3:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:27][CH2:26]1.CC(CC)C([O-])=O>>[N:20]1[C:14]2[NH:13][C:12]3[CH:24]=[C:8]([CH2:7][CH2:6][N:25]4[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][CH:33]([CH3:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:27][CH2:26]4)[CH:9]=[CH:10][C:11]=3[S:16][C:15]=2[N:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)C(C)CCC1CCNCC1
Reactant: COCN1c2cc(CCOS(C)(=O)=O)ccc2Sc2nccnc21
Agent: CCC(C)C(=O)[O-]
Product: CCOC(=O)C(C)CCC1CCN(CCc2ccc3c(c2)Nc2nccnc2S3)CC1

Procedure:
Starting with 2-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl]ethyl methanesulfonate and ethyl 4-(piperidin-4-yl)-2-methylbutanoate, ethyl 4-[1-[2-10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-ethyl]piperidin-4-yl]-2-methylbutanoate was obtained by the same method as the one of Example 63. Next, this product was treated by the same method as the one of Example 8 to thereby give the title compound.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][C:13]3([C:19]([NH:21][CH3:22])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[O:23]=[C:24]1[CH:33]=[N:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]1[CH2:34][CH:35]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][C:13]3([C:19]([NH:21][CH3:22])=[O:20])[CH2:14][CH2:15][N:16]([CH2:35][CH2:34][N:25]4[C:26]5[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=5)[N:32]=[CH:33][C:24]4=[O:23])[CH2:17][CH2:18]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=CCn1c(=O)cnc2ccccc21
Reactant: CNC(=O)C1(NCc2ccc3c(c2)OCCO3)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CNC(=O)C1(NCc2ccc3c(c2)OCCO3)CCN(CCn2c(=O)cnc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.7 %

Procedure:
To 3 mL of dichloromethane solution containing 0.11 g of 4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)-N-methylpiperidine-4-carboxamide, 65 mg of (2-oxoquinoxalin-1(2H)-yl)acetaldehyde and 20 μl of acetic acid were added and stirred at room temperature for 3 hours. To the reaction mixture, 0.11 g of sodium triacetoxyborohydride was added and stirred at the same temperature for 30 min. Chloroform and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=10:1] to give 0.12 g of 4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)-N-methyl-1-(2-(2-oxoquinoxalin-1(2H)-yl)ethyl)piperidine-4-carboxamide as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[Al+3].[Cl-].[Cl-].O>C(OCC)(=O)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([C:18]1[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=1)=[O:5]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl
Reactant: Clc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1Cl
Temperature: 40 °C
Yield: 77.3 %

Procedure:
2-Chloro-4-nitrobenzoyl chloride (23.1 g) was added dropwise to a mixture composed of 11.8 g of monochlorobenzene and 13.3 g of aluminum chloride. The mixed solution was stirred with heating at 40° C. for 6 hr and was then added dropwise to 45 mL of warm water. Further, toluene and ethyl acetate were added to the mixed solution followed by separation and washing with sodium bicarbonate water and brine. The organic layer was concentrated under the reduced is pressure. n-Hexane was added to the residue, and the precipitated crystals were collected by filtration to give 24.0 g of (2-chloro-4-nitrophenyl)-(4′-chlorophenyl)methanone (yield 81%).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:8]([C:15](C)(C)[C:16]#[N:17])=N[C:10](C)(C)C#N>CO>[CH:1]([C:7]1[NH:8][CH2:15][CH2:16][N:17]=1)=[CH2:6].[CH2:10]=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Reactant: Cc1ccccc1
Solvent: CO
Product: C=CC1=NCCN1
Product: C=Cc1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of 17.0 parts 2-vinyl-2-imidazoline, 43.0 parts of styrene and 140.0 parts of toluene is prepared in a suitable polymerization vessel equipped with means for stirring and deaeration and temperature controls. After deaeration for 1 hour with a stream of nitrogen, the temperature is raised to 60° C. and polymerization is initiated by the addition of 100 ppm (based on total weight of imidazoline) of azobisisobutyronitrile as a 1.0% solution in methanol. After allowing the polymerization to proceed overnight at a temperature of 60°-70° C., the polymer is precipitated from the resulting viscous solution by pouring it into an excess of methanol with vigorous stirring. The resultant yellowish colored polymer is redissolved in toluene and then reprecipitated once more by pouring into methanol. IR and NMR analysis of dried polymer show about 75 mole percent styrene and 25 mole percent 2-vinyl-2-imidazoline incorporated into the copolymer. A sample of the polymer is an effective sizing agent for 50/50 Albacel-Astracel pulp (bleached hardwood-softwood Kraft pulp).
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](=[O:19])([O-])[O-].[K+].[K+].[CH:22](O)([CH3:24])[CH3:23]>>[C:1]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:23][CH2:22][C:24]2[CH:6]=[CH:7][C:2]([O:19][CH3:16])=[CH:3][CH:4]=2)[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)O
Reactant: O=C([O-])[O-]
Reactant: O=C(NC1CCNCC1)c1ccccc1
Agent: [K+]
Product: COc1ccc(CCN2CCC(NC(=O)c3ccccc3)CC2)cc1

Procedure:
2-(p-Methoxyphenyl)ethanol p-toluenesulphonate ester (1.53 g.), 4-benzamidopiperidine (1.02 g.) and anhydrous potassium carbonate (1.10 g.) were refluxed in isopropanol (50 ml.) for 8 hours and the mixture worked up as in Example 48 to provide the title compound, which was further recrystallized from ethyl acetate as colourless needles (0.78 g.), m.p. 178° C. (Found: C, 74.7; H, 7.9; N, 8.45. C21H26N2O2 requires C, 74.5; H, 7.7; N, 8.3%).
Reaction SMILES: [Br:1][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:3](OCC)=[O:4].[OH-].[NH4+:16].[NH3:17]>C(O)C>[BrH:1].[NH2:16][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:3]([NH2:17])=[O:4]
Reactant: N
Reactant: [NH4+]
Reactant: CCOC(=O)C(Br)c1ccc(Cl)cc1
Agent: [OH-]
Solvent: CCO
Product: Br
Product: NC(=O)C(N)c1ccc(Cl)cc1

Procedure:
By the method of T. Naito, et al., Chem. Pharm. Bull. 16, 544 (1968), incorporated herein by reference, 50.0 g (0.18 mole) of ethyl alpha-bromo-(4-chlorophenyl)acetate, 110 ml of concentrated ammonium hydroxide solution, and ammonia gas in 125 ml of ethanol were reacted to produce 20.0 g of alpha-amino(4-chlorophenyl)acetamide hydrobromide (m.p. 273°-280° C. dec.).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[OH-].[Na+].[CH3:15][C:16]([CH3:18])=[O:17].Cl>CCCCCCC.C(O)(C)C.O>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:15][C:16](=[O:17])[CH:18]=[CH:7][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:11])[F:12])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCCC
Solvent: CC(C)O
Solvent: O
Product: O=C(C=Cc1ccc(C(F)(F)F)cc1)C=Cc1ccc(C(F)(F)F)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
A solution of 4-trifluoromethylbenzaldehyde (64.2 g; 0.369 mol) in heptane (70 ml) is stirred under a nitrogen atmosphere, then sodium hydroxide (15 g; 10% aq), water (30 g), and bis(2-hydroxyethyl)tallowamine N-oxide (6 g) are added. Next a solution of acetone (10.7 g; 0.184 mol) in heptane (30 ml) is added at 25° C. to 35° C. over a period of two hours. The resulting slurry is then stirred for two hours at 25° C. to 30° C. Concentrated hydrochloric acid (9.4 ml) and isopropyl alcohol (48 ml) are then added and the mixture heated at reflux for 1.5 hours, and is then cooled to 20° C. The solid is filtered, washed with heptane (40 ml) and water, and is dried to afford 54.5 g of 99.9% pure title product (yield: 79.1%), mp 153° C. to 155° C.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11].[C:19](O)(=[O:24])[CH2:20][C:21](O)=[O:22]>C(O)(=O)C>[CH3:8][N:9]1[C:21](=[O:22])[CH2:20][C:19](=[O:24])[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]1=[O:11]
Reactant: CNC(=O)Nc1ccccc1
Reactant: O=C(O)CC(=O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CN1C(=O)CC(=O)N(c2ccccc2)C1=O
Temperature: 90 °C

Procedure:
Acetic anhydride (16 ml, 0.17 mole) was added dropwise over three hours to a solution of 1-methyl-3-phenylurea (6 g, 0.04 mole) and malonic acid (4.6 g, 0.04 mole) in acetic acid (40 ml) at 60° C. After the addition was completed, the temperature was raised to 90° C. and maintained for four hours. The solvent was evaporated and the resulting residue treated with 0.1N NaOH (50 ml). After filtration, the solution was acidified with 0.2N HCl (120 ml). The solution was evaporated to dryness under reduced pressure, leaving solid 1-methyl-3-phenyl-2,4,6-(1H,3H,5H)- pyrimidinetrione upon cooling. It was recrystallized from ethanol to yield colorless crystals, m.p. 122.5°-123° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([C:10]2[C:15]([F:16])=[CH:14][CH:13]=[C:12]([F:17])[C:11]=2[F:18])O)=[C:4]([CH3:19])[CH:3]=1.S(Cl)([Cl:22])=O.CN(C)C=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH3:19])[C:5]([CH:8]([Cl:22])[C:10]2[C:15]([F:16])=[CH:14][CH:13]=[C:12]([F:17])[C:11]=2[F:18])=[CH:6][N:7]=1
Reactant: Cc1cc(Br)ncc1C(O)c1c(F)ccc(F)c1F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(Br)ncc1C(Cl)c1c(F)ccc(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a solution of (6-bromo-4-methylpyridin-3-yl)(2,3,6-trifluorophenyl)methanol (4.60 g, 13.9 mmol) in methylene chloride (70 ml), thionyl chloride (10.1 ml, 139 mmol) and N,N-dimethylformamide (0.60 ml) were added at 0° C., and the resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the resulting residue, and subsequently water and then saturated aqueous sodium hydrogencarbonate were added thereto at 0° C. After the organic layer was separated, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure, to obtain the title compound (4.65 g, 13.3 mmol, 96%) as a pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br.Br[CH2:26][C:27]([C:29]1[S:33][CH:32]=[N:31][CH:30]=1)=[O:28]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:26]=1[C:27]([C:29]1[S:33][CH:32]=[N:31][CH:30]=1)=[O:28]
Reactant: O=C(CBr)c1cncs1
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Agent: Br
Product: COC(=O)Cc1c(C(=O)c2cncs2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and 5-bromoacetylthiazole hydrobromide*.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C@H:14]([C:19]([OH:21])=O)[CH2:15][C:16](=[O:18])[NH2:17])=[O:12].[NH2:22][C@@H:23]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C@H:24]([OH:43])[CH2:25][N:26]1[C@H:35]([C:36]([NH:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][C@H:33]2[C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32]2)[CH2:27]1.ON1C(=O)C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(OCC)(=O)C>[C:39]([NH:38][C:36]([C@@H:35]1[CH2:34][C@H:33]2[C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32]2)[CH2:27][N:26]1[CH2:25][C@@H:24]([OH:43])[C@@H:23]([NH:22][C:19](=[O:21])[C@H:14]([CH2:15][C:16](=[O:18])[NH2:17])[NH:13][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:12])[CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:37])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@@H](N)Cc1ccccc1
Reactant: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=c1c2ccccc2nnn1O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1
Temperature: 20 °C
Reaction time: 16 h
Yield: 80.2 %

Procedure:
A solution of 287 mg of N-(2-quinolylcarbonyl)-L-asparagine and 401 mg of 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide [prepared as described in Example 1 (i)-(vii)] in 3 ml of tetrahydrofuran was cooled to -10° C. and 163 mg of 3-hydroxy-1,2,3-benzotriazin-4(3H)-one and 220 mg of dicyclohexylcarbodiimide were added. The mixture was stirred at -10° C. for 2 hours and at 20° C. for 16 hours, then diluted with ethyl acetate and filtered. The filtrate was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution and then evaporated. The residue was chromatographed on silica gel using 4% (by volume) methanol in dichloromethane for the elution to give 537 mg of N-tert.butyl-decahydro-2[2(R)-hydroxy-4-phenyl-3-(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide which was identical with the product obtained in the first paragraph of Example 2.
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:47])[CH2:7][C:8]1[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][C:9]=1[CH2:10][CH2:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)=[CH:25][CH:24]=2)[N:13]=1>C1COCC1.O.CO>[C:38]([O:37][C:35]([N:32]1[CH2:33][CH2:34][CH:29]([C:26]2[CH:27]=[CH:28][C:23]([NH:22][C:14]3[N:13]=[C:12]([CH2:11][CH2:10][C:9]4[CH:42]=[C:43]([CH3:46])[CH:44]=[CH:45][C:8]=4[CH2:7][C:6]([OH:47])=[O:5])[C:17]([C:18]([F:20])([F:19])[F:21])=[CH:16][N:15]=3)=[CH:24][CH:25]=2)[CH2:30][CH2:31]1)=[O:36])([CH3:41])([CH3:39])[CH3:40]
Reactant: COC(=O)Cc1ccc(C)cc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(CC(=O)O)c(CCc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 27 h

Procedure:
LiOH.H2O (0.028 g, 0.65 mmol) was added to a solution of tert-butyl 4-(4-((4-(2-(2-methoxy-2-oxoethyl)-5-methylphenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A88) (0.133 g, 0.217 mmol) in THF (7 mL), water (1.5 mL) and MeOH (1 mL) and the resulting mixture stirred at room temperature for 27 hours. The volatiles were removed in vacuo and the residue was partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4 and the volatiles removed in vacuo to give the title compound A89 as a white solid (0.124 g, 95%); 1H NMR (400 MHz, d4-MeOH) δ 8.49 (s, 1H), 7.61 (d, J=8.5 Hz, 2H), 7.15 (d, J=8.5 Hz, 2H), 7.09 (d, J=7.7 Hz, 1H), 7.00 (s, 1H), 6.96 (d, J=7.7 Hz, 1H), 4.18 (d, J=13.1 Hz, 2H), 3.65 (s, 2H), 3.13-2.90 (m, 4H), 2.92-2.71 (m, 2H), 2.64 (tt, J=12.0, 3.1 Hz, 1H), 2.26 (s, 3H), 1.78 (d, J=12.5 Hz, 2H), 1.61-1.49 (m, 2H), 1.47 (s, 9H). LCMS-A: rt 6.736 min; m/z 599.3 [M+H]+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[O:10][C:11]1[CH:12]=[C:13]([C@@H:19]([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)[CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18].[CH2:34]([N:36]=[C:37]=[O:38])[CH3:35].C(OCC)(=O)C.[Cl:45]CCl>CN(C1C=CN=CC=1)C>[ClH:45].[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[O:10][C:11]1[CH:12]=[C:13]([C@@H:19]([C:27]2[CH:33]=[CH:32][C:30]([NH:31][C:37]([NH:36][CH2:34][CH3:35])=[O:38])=[CH:29][CH:28]=2)[CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: CCN=C=O
Reactant: COc1ccc([C@H](Cc2ccncc2)c2ccc(N)cc2)cc1OC1Cc2ccccc2C1
Reactant: ClCCl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CCNC(=O)Nc1ccc([C@@H](Cc2ccncc2)c2ccc(OC)c(OC3Cc4ccccc4C3)c2)cc1
Product: Cl
Reaction time: 8 h
Yield: 77 %

Procedure:
To a solution of the aniline of Example 1 (50 mg, 1.15 mmol) in dichloromethane (5 ml) at RT was added DMAP (cat.) and ethyl isocyanate (100 μl, 1.1 eq) and the mixture stirred at this temperature overnight. The reaction mixture was concentrated in vacuo to yield a yellow foam, which was subjected to column chromatography (SiO2 ; ethyl acetate) to afford the free base of the title compound (445 mg, 77%) as a white foam. The material was converted to its hydrochloride salt (Found: C, 68.89, H, 6.38; N, 7.81. C32H33N3O3. HCl. 0.75 H2O requires C, 68.93; H, 6.42; N, 7.54%). δH (d4MeOH) 1.12 (3H, m), 2.96-3.30 (8H, m), 3.71 (3H, s), 4.36 (1H, t, J 8.0 Hz), 5.13 (1H, m), 6.87 (4H, m), 7.02 (1H, d, J 7.5 Hz), 7.11-7.16 (5H, m), 7.52 (1H, s), 7.83 (2H, br), and 8.58 (2H, br). m/z ESI 508 (MH+, 100%), 530 (MNa+, 3).
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[C:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)#[N:20].C(N(CC)CC)C.O1CCCC1>O>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:25]([C:24]2[CH:28]=[CH:29][C:21]([C:19]#[N:20])=[CH:22][CH:23]=2)=[O:26])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (1.0 g), 4-cyanobenzoyl chloride (662 mg), triethylamine (1.67 mL), and tetrahydrofuran (30 mL) was stirred at room temperature for 16 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography (NH-silica gel, ethyl acetate) to provide the title compound (1200 mg, quant.) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](C)=[CH:8][CH2:9][CH2:10]2)=[CH:5][CH:4]=1.[Mg+2].C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=O.O.[C:29]([O-:32])(O)=O.[Na+]>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:29](=[O:32])[CH:10]2[CH3:9])=[CH:5][CH:4]=1
Reactant: O=C([O-])O
Reactant: COc1ccc2c(c1)CCC=C2C
Agent: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: COc1ccc2c(c1)C(C)C(=O)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dihydro-7-methoxy-4-methylnaphthalene (20.87 g) was dissolved in isopropanol (100 ml) and cooled in an ice bath. Monoperoxyphthalic acid magnesium salt (mmpp) (17 g) was added, then water (50 ml) was added and the mixture was stirred at room temperature for 2 hours. When oxidation was complete, the product mixture was hydrolyzed with aqueous NaHCO3, partially evaporated and extracted with ethylacetate. The latter extract was washed with brine and evaporated. The residue was dissolved in a mixture of ethanol (156 ml), water (121 ml) and conc. H2SO4 (24.3 ml), and heated to reflux under N2 atmosphere for 3 hours, cooled and neutralized with NaHCO3. After partial evaporation, the residue was extracted with ethylacetate, washed with brine, dried over MgSO4 and evaporated. The product was purified on a silica gel column using a mixture of hexanes and ethylacetate (100:1, 50:1, 50:1.5). The yield of the product was 16.2 g (71%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.Cl.[NH2:18][CH2:19][C:20]1[CH:21]=[C:22]([O:31][CH2:32][CH2:33][CH3:34])[C:23]([O:27][CH2:28][CH2:29][CH3:30])=[C:24]([OH:26])[CH:25]=1.CCN(CC)CC.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:18][CH2:19][C:20]1[CH:21]=[C:22]([O:31][CH2:32][CH2:33][CH3:34])[C:23]([O:27][CH2:28][CH2:29][CH3:30])=[C:24]([OH:26])[CH:25]=1
Reactant: CCCOc1cc(CN)cc(O)c1OCCC
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCOc1cc(CN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc(O)c1OCCC
Yield: 89.1 %

Procedure:
6-Bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (110 mg, 0.39 mmol), 5-aminomethyl-2,3-dipropoxy-phenol hydrochloride salt (93 mg, 0.39 mmol) and Et3N (112 μL, 0.8 mmol) in N,N-dimethylformamide (DMF) (2 mL) is stirred at 25° C. for 24 hours. H2O (10 mL) is added to the reaction mixture. The resulting precipitate is filtered, washed with H2O and dried in vacuo to give 170 mg (91%) of the title compound as a tan powder. HRMS (ESI) m/z calcd for C23H25BrN2O5 (M+H)+1 489.10196. found: 489.10078.