Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[C:6]([O:13][CH3:14])[CH:5]=[C:4]([O:15][CH3:16])[C:3]=1[C:17](=[O:32])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=1.[H-].[Na+].Br[CH2:36][C:37]([O:39][CH3:40])=[O:38]>CN(C)C=O>[CH3:14][O:13][C:6]1[CH:5]=[C:4]([O:15][CH3:16])[C:3]([C:17](=[O:32])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=2)=[C:2]([O:1][CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:7]=1[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: COC(=O)CBr
Reactant: COCOc1ccc(CCC(=O)c2c(OC)cc(OC)c(CCC(C)C)c2O)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccc(CCC(=O)c2c(OC)cc(OC)c(CCC(C)C)c2OCC(=O)OC)cc1OC
Reaction time: 1 h

Procedure:
Then, 10 ml of dimethylformamide was dropped into a mixture of 2.0 g of 1-(2-hydroxy-4,6-dimethoxy-3-isopentylphenyl)-3-(3-methoxy-4-methoxymethoxyphenyl)-1-propanone and 0.2 g of sodium hydride, and the mixture was stirred for 60 minutes. Then, 0.5 ml of methyl α-bromoacetate was added to the mixture at 0° C., and the mixture was stirred for 45 minutes. After the reaction, the solvent was removed from the reaction liquid mixture by distillation, and the residue was dried under reduced pressure to obtain substantially quantitatively 1-(4,6-dimethoxy- 2-methoxycarbonylmethoxy-3-isopentylphenyl)-3-(3-methoxy-4-methoxymethoxyphenyl)-1-propanone in the form of a colorless transparent oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([CH:21]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:22]([O:24]CC)=[O:23])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([CH:21]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[C:22]([OH:24])=[O:23])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:33][CH:34]=1
Reactant: CCOC(=O)C(c1ccccc1)N1CCc2c(cnc3c2cnn3Cc2ccc(OC)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(C(=O)O)c2ccccc2)CC4)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 2-(3-(4-methoxybenzyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7(6H)-yl)-2-phenylacetate (0.116 g, 0.25 mmol) in methanol (3 mL) was added 1.5 M NaOH (1.67 mL, 2.5 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction was then acidified to pH 2-3 using 1N HCl. The mixture was then extracted with dichloromethane (3×20 mL). The organic extracts were combined, dried (Na2SO4), filtered and concentrated under reduced pressure to afford the pure desired product 2-(3-(4-methoxybenzyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7(6H)-yl)-2-phenylacetic acid as an off-white solid; (0.095 g, 87%). M.p. 130-145° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.17 (s, 1H), 7.53 (m, 5H), 7.18 (m, 2H), 6.84 (m, 2H), 5.57 (s, 2H), 4.85 (m, 1H), 4.05 (m, 2H), 3.68 (s, 3H), 3.21 (m, 4H); LCMS [M+H]: 429.
Reaction SMILES: [ClH:1].[NH:2]1[CH2:7][CH2:6]C[CH2:4][CH2:3]1.[CH2:8]([N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C-]#N.[Na+]>CO.O.O>[ClH:1].[ClH:1].[C:9]1([C:8]2([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:6][CH2:7][NH:2][CH2:3][CH2:4]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C1CCNCC1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: c1ccc(C2(N3CCCCC3)CCNCC2)cc1
Reaction time: 48 h
Yield: 170.2 %

Procedure:
12.16 g of piperidine hydrochloride and 18.9 g of 1-benzylpiperid-4-one are dissolved in 50 ml of an MeOH/H2O mixture (50/50; v/v). 5.3 g of NaCN dissolved in 20 ml of water are added dropwise. After stirring for 48 hours, the precipitate formed is filtered, rinsed with water and dried to give 27 g of the expected product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:17])=[CH:4][C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:8][N:9]=2.[C:18](O)([CH3:21])([CH3:20])[CH3:19].[N+](C)([O-])=O.[F:27][B-:28]([F:31])([F:30])[F:29].[H+]>C(OCC)C>[F:27][B-:28]([F:31])([F:30])[F:29].[C:18]([N+:9]1[O:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]2[CH:16]=[C:2]([Cl:1])[C:3]([CH3:17])=[CH:4][C:5]=12)([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1cc2noc(-c3ccccc3)c2cc1Cl
Reactant: CC(C)(C)O
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: C[N+](=O)[O-]
Solvent: CCOCC
Product: Cc1cc2c(cc1Cl)c(-c1ccccc1)o[n+]2C(C)(C)C
Temperature: 25 °C
Reaction time: 85 h

Procedure:
To a suspension of 59 g. of 5-chloro-6-methyl-3-phenyl-2,1-benzisoxazole, 26.6 ml. of tert.-butanol and 740 ml. of nitromethane, is added dropwise 45.7 g. of a 50% aqueous solution of tetrafluoroboric acid. The resulting suspension is stirred at room temperature for 85 hours. The reaction mixture is diluted with approximately 10 liters of diethyl ether and the crystalline precipitate formed is isolated by filtration to yield 1-tert.-butyl-5-chloro-6-methyl-3-phenyl-2,1-benzisoxazolium tetrafluoroborate, m.p. 164°-166°C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8]C)=[CH:6][C:5]([Cl:10])=[CH:4][C:3]=1[C:11](=[O:16])[C:12]([F:15])([F:14])[F:13].B(Br)(Br)Br.O>C(Cl)Cl>[NH2:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([Cl:10])=[CH:4][C:3]=1[C:11](=[O:16])[C:12]([F:15])([F:13])[F:14]
Reactant: COc1cc(Cl)cc(C(=O)C(F)(F)F)c1N
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Nc1c(O)cc(Cl)cc1C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 17 h
Yield: 102.1 %

Procedure:
To a stirred, cooled (0° C.) solution of 31.2 g (123 mmol) of 2′-amino-5′-chloro-3′-methoxy-2,2,2-trifluoroacetophenone in 150 mL of CH2Cl2 was added 550 mL (550 mmol) of 1 M BBr3 in CH2Cl2 over 20 min. The dark solution was stirred 17 h at ambient temperature, re-cooled to 0° C., and fitted with a pressure-equalizing dropping addition funnel and a Claisen adapter connected by rubber tubing to a large water scrubber. The reaction was carefully quenched by dropwise addition of aqueous Na2CO3 until a pH of 7-8 was reached. The phases were separated, and the aqueous phase was extracted with 1 liter of 1:1 ether-hexanes. The combined organic phases were washed with water then brine, dried (MgSO4), and concentrated under reduced pressure to afford 30.1 g (100%) of 2′-amino-5′-chloro-3′-hydroxy-2,2,2-trifluoroacetophenone as a chalky brown solid, mp 120-122° C. 1H NMR (300 MHz, CDCl3) δ7.33-7.36(m, 1H); 6.88(d, 1H, J=1.8 Hz); 6.75(br. s, 2H); 5.78(br. s, 1H). High resolution mass spec: calculated for C8H6NO2ClF3(M+H)+: 240.0039, found: 240.0029.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([OH:11])=[C:4]([CH3:12])[CH:3]=1.[C:13]([O-])([O-])=O.[K+].[K+].CI>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([O:11][CH3:13])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])c(F)cc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.9 %

Procedure:
4-Fluoro-2-methyl-5-nitrophenol (D16) (0.85 mmol, 145 mg) in dimethylformamide (5 mL) under argon was treated with K2CO3 (0.85 mmol, 117 mg, 1 eq) then methyl iodide (1.7 mmol, 242 mg, 2 eq). The mixture was allowed to stir at room temperature for 1.5 h, concentrated under reduced pressure, treated with 10% Na2CO3 aqueous solution and extracted 3 times with ethyl acetate. Organics were combined, dried on MgSO4 and concentrated under reduced pressure to give the title compound as a bright yellow solid (0.79 mmol, 146 mg, 93% yield). Rt=2.84 min.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].Br[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][N:12]=1>CN(C=O)C>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[N:12][CH:13]=1
Reactant: CCCCCCO
Reactant: Brc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCOc1ccc(Br)cn1
Temperature: 80 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
A solution of 300 mmol of 1-hexanol in 100 ml of DMF is added dropwise at 50° C. under a protective gas to a suspension of 300 mmol of sodium hydride (80 percent in mineral oil) in 100 ml of dry DMF. The mixture is stirred at 80° C. for 1 hour, and a solution of 200 mmol of 2,5-dibromopyridine in 150 ml of warm DMF is subsequently slowly added dropwise. The mixture is then stirred at 80° C. for 3-4 hours. For hydrolysis, the cooled reaction mixture is introduced into 1 l of ice/water, the mixture is extracted a number of times with dichloromethane, and the combined organic extracts are washed with sat. sodium chloride solution and dried using sodium sulfate. After the solvent has been removed in vacuo, the residue is chromatographed on silica gel 60 using dichloromethane as eluent, giving 52 g (quant. yield) of a viscous liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30]4[CH:38]=[C:37]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:36]=[C:35]5[C:31]=4[CH:32]=[N:33][NH:34]5)=[CH:28][N:27](COCC[Si](C)(C)C)[C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2.FC(F)(F)C(O)=O.N>>[CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30]4[CH:38]=[C:37]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:36]=[C:35]5[C:31]=4[CH:32]=[N:33][NH:34]5)=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(NS(C)(=O)=O)cc5[nH]ncc35)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cc(NS(C)(=O)=O)cc6[nH]ncc56)c34)n(-c3ccccc3)c(=O)c12
Yield: 58.9 %

Procedure:
(S)—N-(4-(4-((1-(5-Methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1H-indazol-6-yl)methanesulfonamide (13 mg, 0.02 mmol) was treated with trifluoroacetic acid (2 ml, 26 mmol) and a solution of ammonia (7N in methanol, 2 ml, 117 mmol) according to the method described in Example 27 to give 7 mg (66% yield) of the title compound. Purity 100%.
Reaction SMILES: [I-].CN1C2C(=CC=CC=2)C([C@H]([C@H:14]2[NH:19][C:18](=[O:20])[C@@H:17]([CH2:21][CH2+:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]3[CH3:28])[NH:16][C:15]2=[O:29])C)=C1.CO.[BH4-].[Na+]>O>[CH3:28][N:23]1[CH:22]([CH2:21][CH:17]2[NH:16][C:15](=[O:29])[CH2:14][NH:19][C:18]2=[O:20])[CH:27]=[CH:26][CH2:25][CH2:24]1
Reactant: C[C@H](c1cn(C)c2ccccc12)[C@H]1NC(=O)[C@@H](C[CH2+]2C=CC=CN2C)NC1=O
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CCC=CC1CC1NC(=O)CNC1=O
Reaction time: 1 h
Yield: 56.7 %

Procedure:
To a mixture of (3R,6R)-3-[(R)-1-(1-methylindol-3-yl)ethyl]-6-(1-methyl-2-pyridiniomethyl)piperazine-2,5-dione iodide (0.12 g), methanol (1.2 ml), and water (1.2 ml) was added sodium borohydride (0.12 g). The mixture was stirred on an ice bath for 1 hour, diluted with water (10 ml), and set aside in a refrigerator overnight. A precipitated solid was filtered, washed with water, and dried in vacuo to afford (3R,6R)-3-[(R)-1-methylindol-3-yl)ethyl]-6-[(RS)-1-methyl-1,2,3,6-tetrahydropyridin-6-yl-methyl]piperazine-2,5-dione (0.03 g).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:8](O)([OH:13])[C:9]([F:12])([F:11])[F:10]>>[F:10][C:9]([F:12])([F:11])[CH:8]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7])[OH:13]
Reactant: OC(O)C(F)(F)F
Reactant: Oc1ccccc1
Product: Oc1ccccc1C(O)C(F)(F)F
Temperature: 50 °C

Procedure:
9.3 g (100 mmol) of phenol and 3.9 g (25 mmol) of 75% fluoral hydrate are introduced into a 100 ml reactor. 5.0 g of a catalyst are added and the mixture is heated at 50° C. for 5 hours. The nature of the catalyst employed and the yields of monocondensed products obtained, with their ortho/para ratio, are reported in Table I below.
Reaction SMILES: C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:12][NH:13][C:14]([NH:16][OH:17])=[NH:15].[ClH:18].[CH:19]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([NH2:26])=[NH:25])=O>O.Cl.CO>[ClH:18].[ClH:18].[OH:17][NH:16][C:14]([NH:13][N:12]=[CH:19][C:21]1[CH:29]=[CH:28][CH:27]=[C:23]([C:24](=[NH:25])[NH2:26])[CH:22]=1)=[NH:15]
Reactant: N=C(NN)NO
Reactant: N=C(N)c1cccc(C=O)c1
Agent: Cc1ccccc1S(=O)(=O)O
Agent: Cl
Solvent: CO
Solvent: O
Product: N=C(NO)NN=Cc1cccc(C(=N)N)c1

Procedure:
A solution of 7.3 g (0.028 mol) of 1-amino-3-hydroxyguanidine toluenesulfonate in 14 ml of water and 14.5 ml of 2N hydrochloric acid is added to a solution of 6.9 g (0.028 mol) of crude 3-formylbenzamidine hydrochloride (prepared as described in Example 1b) in 28 ml of methanol, and the reaction mixture is heated at 70° for 1 hour. It is then cooled and concentrated by evaporation, and the crude product is recrystallised from water/ethanol; m.p. 248°-250°.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[OH:18][C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[CH:24][NH:25]2)=[CH:21][CH:20]=1.[OH-].[Na+]>O1CCOCC1>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([O:18][C:19]3[CH:27]=[C:26]4[C:22]([CH:23]=[CH:24][NH:25]4)=[CH:21][CH:20]=3)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Reactant: Oc1ccc2cc[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(-c2cc(Oc3ccc4cc[nH]c4c3)ncn2)cc1
Temperature: 25 °C

Procedure:
To a 100-mL, round-bottomed flask containing 4-chloro-6-(4-trifluoromethyl-phenyl)pyrimidine, (Example 2(a), Method A), (0.20 g, 0.77 mmol) and 6-hydroxyindole (0.21 g, 1.5 mmol, Aldrich) in 1,4-dioxane (10 mL), was added NaOH (8.0 mL, 8.0 mmol, 1.0 N). The mixture was heated at reflux for 8 h, and after cooling to room temperature, the reaction mixture was concentrated in vacuum. EtOAc (30 mL) was added, and the organic layer was washed with brine (10 mL), water (15 mL), dried over Na2SO4, filtered, and concentrated in vacuum. After the product was purified by silica gel chromatography (5:1 hexanes/EtOAc), the residue was dissolved in acetone (3 mL). Water (4 mL) was then added dropwise to afford a white precipitate, which was collected by filtration, washed with water (0.5 mL), and dried under vacuum at 50° C. for 48 h to furnish the title compound. Mp: 206–209° C. MS (ESI, pos. ion) m/z: 356 (M+1); Anal. Calcd for C19H12F3N3O.(H2O)0.2: C, 63.58; H, 3.48; N, 11.71. Found: C, 63.82; H, 3.37; N, 11.61.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:26])[C@@H:15]([NH:18]C(OC(C)(C)C)=O)[CH2:16][F:17])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:26])[C@@H:15]([NH2:18])[CH2:16][F:17])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CF)NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CF)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 230 mg 4-((R)-2-tert-Butoxycarbonylamino-3-fluoro-propionyl)-piperazine-1-carboxylic acid butyl ester in 5 ml dichloromethane was added 1.0 ml TFA. After 12 h stirring at RT the solvents were removed and the residue was codistilled twice with toluene. Yield: 307 mg.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[Cl:27][C:28]1[C:38]([Cl:39])=[CH:37][C:31]2[C:32](=O)O[C:34](=O)[C:30]=2[CH:29]=1>>[Cl:27][C:28]1[CH:29]=[C:30]2[C:31](=[CH:37][C:38]=1[Cl:39])[CH2:32][N:23]([C:22]1[CH:24]=[CH:25][CH:26]=[C:20]([CH2:19][CH2:18][N:15]3[CH2:14][CH2:13][N:12]([C:8]4[CH:7]=[CH:6][CH:5]=[C:4]5[C:9]=4[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]5)[CH2:17][CH2:16]3)[CH:21]=1)[CH2:34]2
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5Cc6cc(Cl)c(Cl)cc6C5)c4)CC3)cccc2n1

Procedure:
Prepared from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 5,6-dichloro-2-benzofuran-1,3-dione according to Method I.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:18]([NH:26][CH2:27][CH:28]([C:30]2[CH:31]=[CH:32][C:33]([O:41]CC3C=CC=CC=3)=[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:35]=2)[OH:29])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].[H][H]>[Pd].CO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:18]([NH:26][CH2:27][CH:28]([C:30]2[CH:31]=[CH:32][C:33]([OH:41])=[C:34]([NH:36][S:37]([CH3:40])(=[O:38])=[O:39])[CH:35]=2)[OH:29])[CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: COc1ccc(C(Cc2ccccc2)NCC(O)c2ccc(OCc3ccccc3)c(NS(C)(=O)=O)c2)cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1ccc(C(Cc2ccccc2)NCC(O)c2ccc(O)c(NS(C)(=O)=O)c2)cc1OC
Yield: 97.4 %

Procedure:
N-[5-[2-[[1-(3,4-Dimethoxyphenyl)-2-phenylethyl]amino]-1-hydroxyethyl]-2-(phenylmethoxy)phenyl]methanesulfonamide, trifluoroacetate salt (220 mg, 0.38 mmol) was hydrogenated using 10% Pd/C (120 mg) and MeOH (25 mL, AR grade) at 40 psi of hydrogen in a Parr apparatus for one hour at room temperature. The catalyst was filtered through Celite and washed with MeOH. The filtrate and MeOH washings were combined and concentrated to afford 178 mg (0.37 mmol, 96% yield) of the title compound as a pale yellow crystalline powder. The title compound is a racemic mixture of diastereomers.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[CH:11][NH:12][CH:13]=[C:9]2[C:8](=[O:14])[N:7]([CH3:15])[C:6]1=[O:16])[CH:2]([CH3:4])[CH3:3].Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[N:26]=2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[F:31][C:27]1[N:26]=[C:25]([C:22]2[CH:21]=[CH:20][C:19]([CH2:18][N:12]3[CH:13]=[C:9]4[C:10]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:6](=[O:16])[N:7]([CH3:15])[C:8]4=[O:14])=[CH:11]3)=[CH:24][CH:23]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: Fc1cccc(-c2ccc(CCl)cc2)n1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c[nH]cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cn(Cc3ccc(-c4cccc(F)n4)cc3)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.5 %

Procedure:
A suspension of 1-isobutyl-3-methyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (540 mg, 2.46 mmol), 2-(4-(chloromethyl)phenyl)-6-fluoropyridine (0.60 g, 2.7 mmol) and cesium carbonate (1.6 g, 4.9 mmol) in anhydrous DMF is stirred at room temperature for 10 minutes. The mixture is diluted with 200 mL of water, and then extracted with CH2Cl2 three times. The combined organic phase is washed with brine, and then dried with anhydrous Na2SO4. After filtration, the filtrate is concentrated under vacuum. The residue is purified by silica gel chromatography to give product as pale yellow solids (705 mg, yield: 71%). MS (ESI) m/z 407.2 [M+H]+.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].[Br:27][C:28]1[N:29]=[CH:30][C:31]([NH:34][C:35]2[CH:39]=[C:38]([C:40]3[C:45]([O:46][CH3:47])=[CH:44][CH:43]=[CH:42][C:41]=3O)[NH:37][N:36]=2)=[N:32][CH:33]=1>C1COCC1>[Br:27][C:28]1[N:29]=[CH:30][C:31]([NH:34][C:35]2[CH:39]=[C:38]([C:40]3[C:45]([O:46][CH3:47])=[CH:44][CH:43]=[CH:42][C:41]=3[O:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[NH:37][N:36]=2)=[N:32][CH:33]=1
Reactant: COc1cccc(O)c1-c1cc(Nc2cnc(Br)cn2)n[nH]1
Reactant: CC(C)(C)OC(=O)NCCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Product: COc1cccc(OCCCNC(=O)OC(C)(C)C)c1-c1cc(Nc2cnc(Br)cn2)n[nH]1
Reaction time: 0.75 h
Yield: 54 %

Procedure:
Diisopropyl azodicarboxylate (1.73 mL, 8.76 mmol) is added to a stirred solution of tert-butyl 3-hydroxypropylcarbamate (0.83 mL, 4.83 mmol), 2-(3-(5-bromopyrazin-2-ylamino)-1H-pyrazol-5-yl)-3-methoxyphenol) (1.59 g, 4.38 mmol) and polystyrene triphenylphosphine (5.91 g, 8.76 mmol) in THF (50 mL) at room temperature. After stirring for 45 min, the reaction is filtered, and the solvent is removed under reduced pressure. The resulting residue is chromatographed (methanol/CH2Cl2) to afford 1.27 g (54%) of a yellow solid.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].S(Cl)([Cl:15])=O.CN(C)C=O>C(Cl)Cl>[CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([Cl:15])=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)c1ccc(C(=O)O)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)c1ccc(C(=O)Cl)cc1
Reaction time: 1 h

Procedure:
In 5 ml of methylene chloride was suspended 0.25 g of 4-isopropylbenzoic acid. Then, at ambient temperature, 0.12 ml of thionyl chloride and 0.03 ml of N,N-dimethylformamide were added. After stirring the mixture at the same temperature as above for one hour, the solvent was distilled off under reduced pressure, and an azeotropic distillation treatment using toluene was carried out to obtain 0.25 g of 4-isopropylbenzoic acid chloride. To a suspension of 0.50 g of trifluoroacetic acid salt of 2-(4-benzyl-3-oxo-1-thia-4,8-diazaspiro[4.5]decan-2-yl]-acetic acid in 5 ml methylene chloride were successively added dropwise at 0-5° C. 0.64 ml of triethylamine and a solution of 0.25 g of 4-isopropylbenzoic acid chloride in 5 ml methylene chloride. The resulting mixture was stirred at ambient temperature for 24 hours. The reaction mixture was poured into ice water, pH was adjusted to 1.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluents: toluene:ethyl acetate=1:1, followed by chloroform] gave 0.30 g of 2-[4-benzyl-8-(4-isopropylbenzoyl)-3-oxo-1-thia-4,8-diazaspiro[4.5]-decan-2-yl]-acetic acid as a light yellow solid product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[CH:3][CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Brc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Yield: 59.5 %

Procedure:
Under an argon atmosphere, p-dibromobenzene (9.99 g), 4-methoxyphenylboronic acid (2.03 g) and tetrakistriphenylphosphine palladium (497 mg) were dissolved in dimethoxyethane (20 ml). A 2M aqueous sodium carbonate solution (20 ml) was added and the mixture was heated under reflux for 14 h. The reaction mixture was cooled to room temperature and the precipitated crystals were collected by filtration. The obtained crystals were dissolved in ethyl acetate and insoluble materials were filtered off. The solvent was evaporated and the obtained solid was washed with hexane to give the title compound (2.09 g) as a colorless solid.