Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][CH2:24][CH3:25])=[C:6]([C:8]2[NH:9][C:10](=[O:21])[C:11]3[C:16]([CH3:17])=[N:15][N:14]([CH2:18][CH2:19][CH3:20])[C:12]=3[N:13]=2)[CH:7]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:55]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])(=[O:58])[CH:56]=[CH2:57]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:60]([O:59][C:55](=[O:58])/[CH:56]=[CH:57]/[C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][CH2:24][CH3:25])=[C:6]([C:8]2[NH:9][C:10](=[O:21])[C:11]3[C:16]([CH3:17])=[N:15][N:14]([CH2:18][CH2:19][CH3:20])[C:12]=3[N:13]=2)[CH:7]=1)([CH3:63])([CH3:62])[CH3:61]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CCCOc1ccc(Br)cc1-c1nc2c(c(C)nn2CCC)c(=O)[nH]1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCOc1ccc(/C=C/C(=O)OC(C)(C)C)cc1-c1nc2c(c(C)nn2CCC)c(=O)[nH]1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
To a solution of 6-(5-bromo-2-n-propoxyphenyl)-3-methyl-1-n-propyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 11; 2.14 g, 0.0053 mol) and triethylamine (0.81 g, 0.008 mol) in acetonitrile (4 ml), was added palladium(II) acetate (0.06 g, 0.00027 mol), tri-o-tolylphosphine (0.16 g, 0.00053 mol) and t-butyl acrylate (1.03 g, 0.008 mol). The mixture was heated under reflux for 4 hours, cooled to room temperature and then partitioned between water (30 ml) and dichloromethane (30 ml). The organic phase was removed and the aqueous phase extracted with dichloromethane (2×30 ml). The combined organic solutions were dried (Na2SO4) and the solvent removed by evaporation under vacuum to give a greenish brown solid. Purification by column chromatography (SiO2, CH2Cl2 then 2% MeOH in CH2Cl2) and crystallisation from ethyl acetate-hexane afforded the title compound as white crystals (1.48 g, 58%), m.p. 181-182° C. Found: C, 66.50; H, 6.75; N, 12.27. C25H32N4O4 requires C, 66.35; H, 7.12; N, 12.38%.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:9][CH2:10][C:11]#[CH:12])=[N:5][CH2:6][CH2:7][SH:8])#[N:2].Cl.[CH3:14][N:15]([CH2:17][C:18]1[N:23]=[C:22]([CH2:24]Cl)[CH:21]=[CH:20][CH:19]=1)[CH3:16]>>[C:1]([NH:3][C:4]([NH:9][CH2:10][C:11]#[CH:12])=[N:5][CH2:6][CH2:7][S:8][CH2:24][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:17][N:15]([CH3:14])[CH3:16])[N:23]=1)#[N:2]
Reactant: C#CCNC(=NCCS)NC#N
Reactant: CN(C)Cc1cccc(CCl)n1
Agent: Cl
Product: C#CCNC(=NCCSCc1cccc(CN(C)C)n1)NC#N

Procedure:
A ethanolic solution of the product of Step A of Example 6 is reacted with about an equimolar amount of 6-dimethylaminomethyl-2-chloromethylpyridine hydrochloride and about three equivalents of base, and the title compound is produced.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[NH:23]([CH2:27][CH2:28][OH:29])[CH2:24][CH2:25][OH:26]>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:23]([CH2:27][CH2:28][OH:29])[CH2:24][CH2:25][OH:26])=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: OCCNCCO
Product: OCCN(CCO)CCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
According to the method in example 5, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and diethanolamine were converted to yield 2-[[4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl]-(2-hydroxy-ethyl)-amino]-ethanol as white semisolid, MS: 465 (MH+, 1Br).
Reaction SMILES: Cl.OC(COC1C=CC([Cl:26])=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl.[OH:28][CH:29]([CH2:44][O:45][C:46]1[C:55]2C(=[CH:51][CH:52]=[CH:53][CH:54]=2)C=[CH:48][CH:47]=1)[CH2:30][NH:31][C:32]([CH3:43])([CH3:42])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1.Cl.OC(COC1C=CC(OC)=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:26].[OH:28][CH:29]([CH2:44][O:45][C:46]1[CH:55]=[CH:54][C:53]([CH2:52][CH3:51])=[CH:48][CH:47]=1)[CH2:30][NH:31][C:32]([CH3:43])([CH3:42])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(Cl)cc2)cc1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2cccc3ccccc23)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccc(OC)cc2)cc1
Agent: Cl
Product: CCc1ccc(OCC(O)CNC(C)(C)Cc2ccc(OC)cc2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 342 (M−15,0.1), 237 (15), 236 (100), 163 (5), 121 (19), 114 (7).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[Cl:13]>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:13][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:3]=1[CH2:2][C:7]([O:9][CH3:10])=[O:8])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(CBr)c(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Product: COC(=O)Cc1ccc(C(=O)OC)cc1Cl
Temperature: 60 °C
Yield: 58.6 %

Procedure:
To a solution of methyl 4-(bromomethyl)-3-chlorobenzoate (10 g, 37.95 mmol) in MeOH (300 mL) was added TEA (4.2 mL, 30.36 mmol) and Pd(dppf)Cl2 (2.8 g, 3.8 mmol). The reaction was heated under 0.4 MPa CO pressure at 60° C. for 3 h, filtered and concentrated. The residue was purified by Combi-Flash (120 g silica gel, start PE/EA=10:0 to 5:1 by gradient, 60 mL/min, 60 min, 3.6 L total solvent volume) to afford product as a white solid (2.7 g, 29%). MS (ESI): m/z 243.0 [M+1]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]2[CH:11]=[CH:10][CH:9]=[N:8][C:6]=2[N:7]=1.[NH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C.[CH3:37][C:38]1[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[C:39]=1[NH2:40].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(O)CCC>[CH3:37][C:38]1[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[C:39]=1[NH:40][C:23](=[O:25])[C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:2]2[N:3]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]3[CH:11]=[CH:10][CH:9]=[N:8][C:6]=3[N:7]=2)=[CH:27][CH:26]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: Cc1cccc(C)c1N
Reactant: Clc1nc(-c2ccccc2)c2cccnc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3cccnc3n2)cc1
Temperature: 138 °C
Yield: 9.1 %

Procedure:
A mixture of 2-chloro-4-phenylpyrido[2,3-d]pyrimidine (233 mg, 0.965 mmol), 4-aminobenzoic acid (133 mg, 0.965 mmol), Hunig's base (300 μL, 1.72 mmol) and n-butanol (5 mL) was heated to 138° C. for 30 min. The solvent was removed on a rotary evaporator to give the intermediate acid as a black oil that was treated with 2,6-dimethylaniline (88 mg, 0.73 mmol), Hunig's base (100 μL, 0.57 mmol) and HATU (137 mg, 0.36 mmol) in DMF (1 mL) The mixture was heated to 60° C. overnight. The reaction was cooled to rt and purified by preparative reverse phase HPLC to give N-(2,6-dimethylphenyl)-4-[(4-phenylpyrido[2,3-d]pyrimidin-2-yl)amino]benzamide (29.6 mg, 18%) as a yellow solid. 1H NMR (400 MHz, CD3OD): δ 8.96 (d, 1H), 8.61-8.58 (m, 1H), 8.20 (d, 2H), 8.05 (d, 2H), 7.86-7.84 (m, 2H), 7.67-7.61 (m, 3H), 7.51 (dd, 1H), 7.13 (s, 3H), 2.27 (s, 6H). MS (EI) for C28H23N5O: 446.0 (MH+).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[Cl:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]([N:18]2[CH2:23][CH2:22][N:21]([S:24]([CH2:27][CH:28]([NH:37][OH:38])[CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:26])=[O:25])[CH2:20][CH2:19]2)[CH:13]=1>O1CCCC1>[Cl:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]([N:18]2[CH2:19][CH2:20][N:21]([S:24]([CH2:27][CH:28]([N:37]([OH:38])[CH:5]=[O:7])[CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:26])=[O:25])[CH2:22][CH2:23]2)[CH:13]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=S(=O)(CC(CCc1ccccc1)NO)N1CCN(c2cc(Cl)ncn2)CC1
Solvent: C1CCOC1
Solvent: O=CO
Product: O=CN(O)C(CCc1ccccc1)CS(=O)(=O)N1CCN(c2cc(Cl)ncn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (19 ml) was added directly to formic acid (76 ml). The solution was stirred at room temperature for 30 minutes. A solution of 1-(6-chloropyrimidin-4-yl)-4-{[2-(hydroxyamino)-4-phenylbutyl]sulphonyl}piperazine (17.2 g) in tetrahydrofuran (85 ml) was added in portions, to the above solution at 27° C. over 25 minutes. The solution was stirred at room temperature for 1 hour. The solution was evaporated (water-bath temperature 30° C.) and the residual gum was dissolved in ethyl acetate (500 ml). This solution was treated with saturated aqueous sodium hydrogen carbonate solution (200 ml) and the mixture (pH8) was stirred at room temperature for 16 hours. The ethyl acetate layer was separated, washed with saturated brine (100 ml), dried (Na2SO4), and evaporated to dryness. The residual foam was dissolved in ethanol, a solid separated and the miixture was stirred for 2 days. The solid was collected by filtration, slurry washed with diethyl ether (100 ml), and dried to give N-[1-({[4-(6-chloropyrimidin-4-yl)piperazino]sulphonyl}methyl)-3-phenylpropyl]-N-hydroxyformamide as a colourless solid (12.8 g). mp 155-157° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](OCC)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[Li]CCCC.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C.[O:33]1CC[CH2:35][CH2:34]1>>[CH2:34]([O:33][C:2]1[CH:7]=[CH:6][C:5]([B:20]([OH:25])[OH:21])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14])[CH3:35]
Reactant: C1CCOC1
Reactant: CCOc1ccc(Br)c(C(F)(F)F)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Product: CCOc1ccc(B(O)O)cc1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-bromo-1-ethoxy-3-trifluoromethyl-benzene (21.25 g, 90.8 mmol) in dry tetrahydrofuran (120 ml) was purged with nitrogen, cooled to −78° C. and BuLi (2.5 M solution in hexanes, 39.96 ml, 99.9 mmol) added dropwise maintaining a temperature below −70° C. The mixture was stirred for 5 minutes before addition of triisopropyl borate (17.9 g, 95.36 mmol) in one portion. Stirring was continued at −78° C. for 30 minutes before allowing to come to room temperature. The reaction was quenched by addition of 10 ml of acetic acid dissolved in 150 ml water before concentration under reduced pressure to remove tetrahydrofuran. The precipitate was collected by filtration, dissolved in ethyl acetate and dried over sodium sulfate. Purification was achieved by recrystalisation from ethyl acetate/hexane mixtures to afford 4-ethoxy-3-trifluoromethylphenylboronic acid (10 g). 1H NMR (DMSOd6): δ 8.08 (s, 1H) 8.01 (d, 1H) 7.2 (d, 1H) 4.18 (q, 2H) 1.34 (t, 3H).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([CH2:12][CH2:13][C:14]([OH:16])=O)=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:22]1[C:30]2[N:29]=[CH:28][NH:27][C:26]=2[C:25](=[O:31])[NH:24]/[C:23]/1=[N:32]\[NH2:33])[CH2:18][CH2:19][CH2:20][CH3:21].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.CN(C=O)C>[O:31]=[C:25]1[NH:24]/[C:23](=[N:32]\[NH:33][C:14](=[O:16])[CH2:13][CH2:12][C:10]2[O:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][N:9]=2)/[N:22]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:30]2[N:29]=[CH:28][NH:27][C:26]1=2
Reactant: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]cnc21
Reactant: O=C(O)CCc1nnc(-c2ccccc2)o1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCn1/c(=N/NC(=O)CCc2nnc(-c3ccccc3)o2)[nH]c(=O)c2[nH]cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
The mixture of 3-(5-phenyl-1,3,4-oxadiazol-2-yl)propanoic acid (500 mg, 20 mmol), (2E)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone (480 mg, 0.0020 mol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (980 mg, 22 mmol), 4-dimethylaminopyridine (100 mg, 10 mmol), and N,N-diisopropylethylamine (0.73 mL, 42 mmol) in DMF (30 mL) was stirred at room temperature overnight. The mixture was quenched with water and extracted with ethyl acetate three times. The combined organic layers were washed by brine, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by flash column chromatography to yield the desired product (485 mg, 48.5%). LCMS calculated for C21H25N8O3(M+H): 437.2; found 437.2.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([S:30][CH3:31])=[CH:26][N:25]=4)=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[Li+].[OH-]>C1COCC1.CO>[CH3:31][S:30][C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([C:14]3[CH:15]=[CH:16][C:11]([CH:8]4[CH2:7][CH2:6][CH:5]([CH2:4][C:3]([OH:32])=[O:2])[CH2:10][CH2:9]4)=[CH:12][CH:13]=3)=[N:18][CH:19]=2)=[N:25][CH:26]=1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ccc(Nc4ccc(SC)cn4)cn3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CSc1ccc(Nc2ccc(-c3ccc(C4CCC(CC(=O)O)CC4)cc3)nc2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The crude (4-{4-[5-(5-Methylsulfanyl-pyridin-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid methyl ester was dissolved in THF/MeOH (4:1, 2.5 mL) and to it was added aqueous LiOH (4M, 0.5 mL). The mixture was stirred at room temperature for 18 hours, then was immediately purified via reverse-phase HPLC to yield the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08-1.20 (m, 2H) 1.44-1.57 (m, 2H) 1.84 (m, 5H) 2.16 (d, J=6.82 Hz, 2H) 2.50 (m, 1H) 6.91 (d, J=8.59 Hz, 1H) 7.36 (d, J=8.34 Hz, 2H) 7.70 (dd, J=8.59, 2.53 Hz, 1H) 7.91 (d, J=8.34 Hz, 2H) 7.95 (d, J=8.84 Hz, 1H) 8.21 (d, J=2.27 Hz, 1H) 8.33 (dd, J=9.09, 2.53 Hz, 1H) 8.98 (br. s., 1H) 9.64 (br. s., 1H); MS (M+H)+434.2.
Reaction SMILES: [SH:1][CH:2]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:3]([NH:5][C:6]1([C:11]([NH:13][CH:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28](SC)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[C:15]([OH:17])=[O:16])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4].CS[C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1>>[SH:1][CH:2]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:3]([NH:5][C:6]1([C:11]([NH:13][CH:14]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:26]=[CH:27][C:28]([C:41]4[C:42]5[C:43](=[CH:3][CH:2]=[CH:33][CH:34]=5)[CH:44]=[CH:39][CH:40]=4)=[CH:29][CH:30]=3)=[CH:23][CH:24]=2)[C:15]([OH:17])=[O:16])=[O:12])[CH2:7][CH2:8][CH2:9][CH2:10]1)=[O:4]
Reactant: CSc1ccc(B(O)O)cc1
Reactant: CSc1ccc(-c2ccc(CC(NC(=O)C3(NC(=O)C(S)CC(C)C)CCCC3)C(=O)O)cc2)cc1
Product: CC(C)CC(S)C(=O)NC1(C(=O)NC(Cc2ccc(-c3ccc(-c4cccc5ccccc45)cc3)cc2)C(=O)O)CCCC1

Procedure:
2-{[1-(2-mercapto4-methyl-pentanoylamino)-cyclopentanecarbonyl]-amino}-3-(4′-methylthio-biphenyl-4-yl)-propionic acid (from 4-methylthiophenyl-boronic acid; mp 187-189° C.
Reaction SMILES: [C:1]1([C:7]2[C:8](=O)[O:9][C:10](C)(C)[O:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=[N:17][C:18]([CH3:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19].[C:27]1(C)C(C)=CC=CC=1>>[CH3:27][C:8]1[O:9][CH2:10][N:17]([C:18]([CH3:26])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:19])[C:12](=[O:11])[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1C
Reactant: CC1(C)OC=C(c2ccccc2)C(=O)O1
Reactant: C=NC(C)(C)c1ccccc1
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)c2ccccc2)CO1

Procedure:
Xylene (2 ml) was added to a mixture of 5-phenyl-2,2-dimethyl-2H,4H-1,3-dioxin-4-one (0.82 g) and N-methylene-1-methyl-1-phenylethylamine (0.59 g), and the resulting mixture was heated at reflux for 20 minutes for reaction. The reaction mixture was purified by silica gel chromatography to obtain the captioned compound (0.9 g).
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH2:10]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:14][C:13]=1[CH:24]1[CH2:33][C:32]([CH3:35])([CH3:34])[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:36](O)=[O:37])[CH:30]=2)[NH:25]1)[CH3:11].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH2:10]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)=[CH:14][C:13]=1[CH:24]1[CH2:33][C:32]([CH3:34])([CH3:35])[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:36]([NH:9][S:6]([CH:3]3[CH2:5][CH2:4]3)(=[O:8])=[O:7])=[O:37])[CH:30]=2)[NH:25]1)[CH3:11]
Reactant: NS(=O)(=O)C1CC1
Reactant: CCc1ccc(N2CCOCC2)cc1C1CC(C)(C)c2cc(C(=O)O)ccc2N1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(N2CCOCC2)cc1C1CC(C)(C)c2cc(C(=O)NS(=O)(=O)C3CC3)ccc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.8 %

Procedure:
To a suspension of 60% sodium hydride (356 mg, 8.9 mmol) in N,N-dimethylformamide (4 mL) was added cyclopropanesulfonic acid amide (1 g, 8.9 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A47. A solution of 2-(2-ethyl-5-morpholin-4-yl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (500 mg, 1.27 mmol) and 1,1′-carbonyldiimidazole (412 mg, 2.54 mmol) in N,N-dimethylformamide (2 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B47. Solution B47 was added to Solution A47 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [2-(2-ethyl-5-morpholin-4-yl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (100 mg, 15%) as a white solid: MS (ESI) M+1=498.1.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:17]([CH3:21])[C:18](N)=[O:19].C(O)(=[O:24])C.Cl>O>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:17]([CH3:21])[C:18]([OH:24])=[O:19]
Reactant: CC(C(N)=O)c1ccc2c(=O)c3ccccc3ccc2c1
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1
Yield: 90 %

Procedure:
3.0 Gm. of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionamide is refluxed in a mixture of 20 ml. of acetic acid and 30 ml. of concentrated hydrochloric acid for 3 hours. The solution is cooled and poured into water. The mixture is extracted with ethyl acetate and the extract is washed, dried and evaporated to yield 90% of 2-(5H-dibenzo[a,d] cyclohepten-5-on-2-yl)propionic acid., m.p. (chloroform-hexane) 138°-139°C.; m.p. (acetone-hexane) 113°-115°C. Use of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetamide gives a similar yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetic acid, m.p. (acetone-hexane) 148°-149.5°C.
Reaction SMILES: CC1[N:3]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=2[NH:19][C:20]2[N:28]=[C:27]3[C:23]([NH:24][C:25](=[O:35])[N:26]3[CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:22]([C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)[N:21]=2)C(C)=CC=1.Cl.NO>C(O)C.O>[NH2:3][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:16])[F:17])=[CH:10][C:9]=1[NH:19][C:20]1[N:28]=[C:27]2[C:23]([NH:24][C:25](=[O:35])[N:26]2[CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[C:22]([C:36]2[CH:37]=[CH:38][N:39]=[CH:40][CH:41]=2)[N:21]=1
Reactant: Cc1ccc(C)n1-c1ccc(OC(F)(F)F)cc1Nc1nc(-c2ccncc2)c2[nH]c(=O)n(C3CCOCC3)c2n1
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: O
Product: Nc1ccc(OC(F)(F)F)cc1Nc1nc(-c2ccncc2)c2[nH]c(=O)n(C3CCOCC3)c2n1

Procedure:
2-(2-(2,5-dimethyl-1H-pyrrol-1-yl)-5-(trifluoromethoxy)phenylamino)-6-(pyridin-4-yl)-9-(tetrahydro-2H-pyran-4-yl)-7H-purin-8(9H)-one (0.018 mmol) was reacted with hydroxylamine hydrochloride (5 equiv.) in a mixture of ethanol and water (1.6 mL/0.6 mL) at reflux for 20 h. Upon completion of the reaction (monitoring by HPLC and MS), the solvent was removed in vacuo, the material thoroughly dried and used in the next step without further purification. MS (EI) m/z 488.4 (MH)+.
Reaction SMILES: CS(O[C@@:6]1([CH3:44])[CH2:10][C@H:9]([S:11][C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][N:7]1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)=[O:32])(=O)=O.[C:45]([C@@H:48]1[CH2:52][CH2:51][CH2:50][NH:49]1)(=[O:47])[NH2:46]>CN(C)C=O>[C:45]([C@@H:48]1[CH2:52][CH2:51][CH2:50][N:49]1[CH2:44][C@@H:6]1[CH2:10][C@H:9]([S:11][C:12]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:8][N:7]1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)=[O:32])(=[O:47])[NH2:46]
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: C[C@]1(OS(C)(=O)=O)C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: NC(=O)[C@@H]1CCCN1C[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 25.3 %

Procedure:
To a solution of (2S,4S)-2-(methanesulfonyloxy)-methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (3.0 g) in dimethylformamide (30 ml) was added (2S)-2-carbamoylpyrrolidine (10.76 g) and the mixture was stirred at 100°-110° C. for 5 hours. The reaction mixture was poured into ice-water (100 ml). The resulting precipitates were collected by filtration and washed with water (100 ml). The precipitates were dissolved in ethyl acetate (80 ml) and the solution was washed with aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (100 g) eluting with a mixture of dichloro-methane and acetone (9:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S ,4S )-2-[(2S)-2-carbamoylpyrrolidin-1-yl]methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (0.78 g).
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:8](=[N:9][C:10]3[C:15]([C:16]=2[NH2:18])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:7]=[CH:6][CH:5]=1)([O-])=O.C(OCC)(=O)C.C([O-])=O.[NH4+]>CO>[NH2:1][C:4]1[C:17]2[C:8](=[N:9][C:10]3[C:15]([C:16]=2[NH2:18])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1c2ccccc2nc2cccc([N+](=O)[O-])c12
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cccc2nc3ccccc3c(N)c12
Yield: 40.1 %

Procedure:
To a 50 mL rbf equipped with a nitrogen bubbler were charged 1-nitro-9-aminoacridine (162 mg, 0.68 mmol) and ethyl acetate (3.4 mL). Methanol (1.7 mL) and Pd/Alumina 10% (22 mg) were added and the reaction mixture was stirred to a fine suspension. Ammonium formate (85 mg, 1.35 mmol) was added and the mixture was stirred for 20 min at room temperature. A further portion of ammonium formate (128 mg, 2.03 mmol) was then added. Stirring was maintained overnight. The reaction mixture was filtered to remove catalyst and concentrated to dryness. The residue was purified by flashmaster column eluting with a gradient elution (DCM→DCM:MeOH 98:2) to afford pure 1,9-diaminoacridine as a brown-yellow solid (57 mg, 40%). 1H NMR and LCMS analyses conformed to structure.
Reaction SMILES: [CH2:1]([CH2:5][C:6](=O)[CH3:7])[C:2]([CH3:4])=O.[NH2:9][CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17]>CO>[CH3:4][C:2]1[N:9]([CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[C:6]([CH3:7])=[CH:5][CH:1]=1
Reactant: NCCN1CCCC1=O
Reactant: CC(=O)CCC(C)=O
Solvent: CO
Product: Cc1ccc(C)n1CCN1CCCC1=O

Procedure:
5.7 g (0.05 mmol) of acetonylacetone and 6.4 g (0.05 mmol) of 1-(2-aminoethyl)-2-pyrrolidinone are heated under reflux in 70 ml of methanol for 2 h. The reaction mixture is then concentrated and, after the concentration, the crude reaction product is then precipitated by addition of petroleum ether. The crude product is recrystallized from diethyl ether. Yield: 3.2 g (31% of theory), Melting point: 66°-68° C. Elemental analysis: C12H18N2O (206.29) calculated: C 69.9 H 8.8 N 13.6 0 7.8 found: C 69.4 H 8.7 N 13.7 0 8.11