Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH3:6][C:7]1([CH3:31])[C:11](=[O:12])[C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[N:22]=[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]4[CH:30]=3)=[CH:15][CH:14]=2)=[CH:9][O:8]1>C(Cl)Cl.C(OCC)C>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:9]2[O:8][C:7]([CH3:31])([CH3:6])[C:11](=[O:12])[C:10]=2[C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]3[N:22]=[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]4[CH:30]=3)=[CH:17][CH:18]=2)=[CH:14][CH:15]=1
Reactant: Cc1cccc2nc(COc3ccc(C4=COC(C)(C)C4=O)cc3)cn12
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(C2=C(c3ccc(OCc4cn5c(C)cccc5n4)cc3)C(=O)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 174.3 %

Procedure:
Methanesulfonic acid (53.1 mg, 0.5 mmol) was added to a solution of 544-methoxyphenyl)-2,2-dimethyl-4-(4-((5-methylimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)furan-3(2H)-one (250 g, 0.5 mmol) in DCM (2.5 ml) and diethyl ether (50 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 4 h upon which, the solids were collected by filtration, washed with 20% DCM in diethyl ether, dried in vacuo to afford 5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-((5-methylimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)furan-3(2H)-one methanesulfonate (240 mg, 82.7%) as white solid: 1H NMR: 500 MHz, DMSO-d6: δ 7.95 (s, 1H), 7.6 (d, 2H), 7.4 (d, 1H), 7.25 (t, 1H), 7.2 (d, 3H), 7.15 (d, 2H), 7.0 (d, 2H), 6.8 (d, 1H), 5.2 (s, 2H), 3.85 (s, 3H), 2.6 (s, 3H), 2.5 (s, 3H), 1.25 (s, 6H), HPLC: (98.4%, Condition-A).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH3:5].[OH:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[I:17])[C:10]([O:12][CH3:13])=[O:11].C(=O)([O-])[O-].[K+].[K+].O>CC(=O)CC>[CH2:2]([O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[I:17])[C:10]([O:12][CH3:13])=[O:11])[CH2:3][CH2:4][CH3:5]
Reactant: COC(=O)c1ccc(I)c(O)c1
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCCCOc1cc(C(=O)OC)ccc1I
Temperature: 60 °C
Yield: 49.5 %

Procedure:
14.7 ml (130 mmol) of iodobutane is added to a solution of 30 g (110 mmol) of methyl 3-hydroxy-4-iodobenzoate and 17.9 g (130 mmol) of potassium carbonate in 300 ml of 2-butanone. The reaction mixture is heated at 60° C. for 16 hours. After adding 100 ml of water and then extraction with ethyl acetate, the organic phases are combined, dried over sodium sulfate, and filtered. The solvents are evaporated and then the residue is taken up in heptane and filtered. 18.2 g of methyl 3-butoxy-4-iodobenzoate is obtained in the form of white crystals. The filtrate is concentrated and the residue is purified by silica column chromatography, eluted with a heptane/ethyl acetate mixture 8/2, obtaining 11.6 g of methyl 3-butoxy-4-iodobenzoate. 29.8 g (82%) of methyl 3-butoxy-4-iodobenzoate is thus obtained.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CS(C)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CN1CCNCC1
Solvent: CS(C)=O
Product: COc1c(N2CCN(C)CC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reaction time: 5 h
Yield: 19.7 %

Procedure:
A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (200 mg), N-methylpiperazine (140 mg) and anhydrous DMSO (3 ml) was stirred for 5 hours at 70° to 95° C. on an oil bath. The reacting mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with chloroform-methanol-concentrated aqueous ammonia (20:6:1), the residue was recrystallized from methanol to give the title compound (50 mg) as colorless needles, mp 221°-222° C. (decompd.).
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[CH3:16][S:17]([N:6]1[CH2:5][CH2:4][NH:3][C:2]([CH3:8])([CH3:1])[CH2:7]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)CNCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)CN(S(C)(=O)=O)CCN1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
To a solution of 2,2-dimethylpiperazine (400 mg) and triethylamine (0.59 mL) in dichloromethane (10 mL) at 0° C. was added dropwise methanesulfonyl chloride (0.30 mL). The reaction mixture was stirred at room temperature for 16 h and then quenched with water (10 mL) and extracted into dichloromethane (2×20 mL). The combined organic layers were washed with saturated aqueous brine solution (2×20 mL), dried (MgSO4) and concentrated to afford 1-methanesulfonyl-3,3-dimethyl-piperazine as a white solid (412 mg, 61%).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([OH:17])=O)=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2].[C:25]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)(=[O:27])[CH3:26]>>[CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([N:31]3[CH2:32][CH2:33][N:28]([C:25](=[O:27])[CH3:26])[CH2:29][CH2:30]3)=[O:17])=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(Nc2cc3cc(C(=O)O)ccc3c(OC(C)C)n2)n[nH]1
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(C(=O)c2ccc3c(OC(C)C)nc(Nc4cc(C)[nH]n4)cc3c2)CC1

Procedure:
Similar procedure as described in example 384 was used, starting from 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-6-carboxylic acid and 1-acetylpiperazine to give 1-{4-[1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-6-carbonyl]-piperazin-1-yl}-ethanone. LC-MS: m/e 437 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[Br:16]Br.C1C=CC=CC=1>C(OCC)C>[Br:16][CH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: O=C(c1ccccc1)c1ccc(CBr)cc1
Temperature: 70 °C

Procedure:
30 g (0.153 mol) of 4-methylbenzophenone are introduced into a 250 ml three-necked flask equipped with a reflux condenser and a dropping funnel containing 8.7 ml (0.168 mol) of bromine. In a first step, the reaction medium is heated to 70° C. and then, after complete dissolution of the solid, to 150° C. The bromine is then added dropwise over a period of 3 hours. The reaction is exothermic. The initially colorless solution becomes orange-yellow. Heating is maintained at 150° C. for 15 hours. At the end of the reaction, the temperature of the reaction medium is allowed to return to room temperature. The solution is brown in color. 75 ml of benzene and 35 ml of diethyl ether are added. Washing is carried out with a saturated Na2CO3 solution, then with a saturated Na2S2O3 solution and finally with a saturated NaCl solution, in order to remove the salts formed and to bring the solution to a pH of the order of 6-7. The organic phase is recovered and the solvents are evaporated. A caramel-colored paste is obtained. It is recrystallized from 100 ml of ethanol. The cream-colored crystals are collected and dried under vacuum. The mother liquors are collected and a second crystallization is carried out. The crystals obtained are dried under vacuum. The yield of expected product is 50%, m=20.81 g.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@@H:11]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:12]([OH:14])=O.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][CH2:31][CH2:32][NH2:33])=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@@H:11]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:12]([NH:33][CH2:32][CH2:31][NH:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1)=[O:14]
Reactant: O=C(O)[C@H](CC1CCCCC1)Nc1nc2ccccc2o1
Reactant: COc1ccc(NCCN)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(NCCNC(=O)[C@H](CC2CCCCC2)Nc2nc3ccccc3o2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56 %

Procedure:
A slurry of L-cyclohexylalanine (2.44 g, 14.3 mmol) and powdered NaOH (1.14 g, 28.6 mmol) in DMSO (20 mL) was heated to 100° C. for 20 min until the mixture viscosity decreased and stirring was enabled. 2-Chlorobenzoxazole (1.99 g, 13.0 mmol) was added, and the solution was stirred at 100° C. for 4 h. Upon cooling to room temperature, the solution was poured into 1 M HCl. The precipitate was filtered and dried to afford 2-(S)-(benzooxazol-2-ylamino)-3-cyclohexyl propionic acid was isolated as a white powder (1.69 g, 41%). Step B. To a stirring solution of 2-(S)-(benzooxazol-2-ylamino)-3-cyclohexyl propionic acid (288 mg, 1.0 mmol), N1-(4-methoxy-phenyl)-ethane-1,2-diamine.2HCl (239 mg, 1.0 mmol), and iPr2NEt (0.87 mL, 5.0 mmol) in dichloromethane (4 mL) was added HATU (418 mg, 1.1 mmol). The solution was stirred at room temperature for 4 hours and then evaporated to dryness. The crude material was chromatographed over silica gel (Hexanes/EtOAc) to afford the title compound as a white powder (243 mg, 56%). HPLC-MS calcd. for C25H32N4O3 (M+H+) 437.25. found 437.5.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]2([C:12]([CH3:16])([CH3:15])[CH:13]=[CH2:14])[CH2:11][O:10]2)=[CH:3][CH:2]=1.[Na].[NH:24]1[CH:28]=[N:27][CH:26]=[N:25]1>C(O)CC>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]([OH:10])([CH2:11][N:27]2[CH:26]=[N:25][N:24]=[CH:28]2)[C:12]([CH3:16])([CH3:15])[CH:13]=[CH2:14])=[CH:3][CH:2]=1
Reactant: c1nc[nH]n1
Reactant: C=CC(C)(C)C1(COc2ccc(-c3ccccc3)cc2)CO1
Agent: [Na]
Solvent: CCCO
Product: C=CC(C)(C)C(O)(COc1ccc(-c2ccccc2)cc1)Cn1cnnc1
Yield: 15.1 %

Procedure:
35.3 g (0.120 mol) of 2-(biphenyl-4-yloxymethyl)-2-(3,3-dimethylprop-1-en-3-yl)-oxirane, dissolved in 80 ml of n-propanol, were added to a boiling solution of 1 g (0.012 mol) of sodium propylate and 9.1 g (0.132 mol) of 1,2,4-triazole in 50 ml of n-propanol. After the solution had been boiled under reflux for two days, it was evaporated down under reduced pressure, the oily residue was taken up in 200 ml of ethyl acetate, and the solution was washed with three times 50 ml of water. After the organic phase had been dried over anhydrous sodium sulphate, the solution was concentrated under reduced pressure. After the residue had been triturated with 150 ml of ethyl acetate,, 6.6 g (15.1% of theory) of 4-(biphenyl-4-yloxymethyl)-3,3-dimethyl-4-hydroxy-5-(1,2,4-triazol-4-yl)-pent-1-ene were obtained as colorless crystals of melting point 171° to 173° C. The oil (37.1 g) which remained after the filtrate had been evaporated down was taken up in 200 ml of acetone, and a solution of 34.6 g of naphthalene-1,5-disulphonic acid in 100 ml of acetone was added. The salt which crystallized out was filtered off under suction, washed with acetone, and taken up in a mixture of 250 ml of water and 250 ml of dichloromethane. The solution was rendered alkaline by stirring in 10% strength sodium carbonate solution. After the organic phase had been concentrated, 24 g of an oil were obtained, which was dissolved in ethyl acetate and the solution then filtered over silica gel. After the filtrate had been concentrated, 17.8 g (40.8% of theory) of 4-(biphenyl-4-yloxymethyl)-3,3-dimethyl-4-hydroxy-5-(1,2,4-triazol-1-yl)-pent-1-ene were obtained in the form of colorless crystals of melting point 85° to 87° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH:16]([OH:18])[CH2:15][C@H:9]1[C:10](OCC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+].O.Cl>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH:16]([OH:18])[CH2:15][C@H:9]1[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H]1CC(O)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(O)C[C@H]1CO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice cold solution of 50.0 g (190 mmol) of 6 in 600 mL of tetrahydrofuran was added 15.0 g (690 mmol) of lithium borohydride in one portion. The mixture was stirred at 0° C. for 1 h followed by 15 h at room temperature. The solution was cooled to 0° C. with stirring and 255 mL of water and 100 mL of 1:1 water:concentrated hydrochloric acid were added carefully. The solution was warmed until an organic phase separated. The organic phase was withdrawn and the aqueous layer was extracted with three 150 mL portions of ethyl acetate. The combined organic layers were washed with 100 mL each of 2 N sodium hydroxide, 2 N hydrochloric acid, and brine. The organic layers were dried over magnesium sulfate and evaporated under reduced pressure to an oil. The oil was kept at 0.05 mm for 24 h and then used without further purification. The yield of 7 was 33.9 g (81%). 1H NMR (CDCl3) δ1.1-2.0 (m), 1.48 (s, 9H), 3.3-4.2 (m), 4.4 (s). 13C NMR (CDCl3) δ28.4, 37.2, 54.9, 55.4, 57.7, 58.4, 63.5, 65.9, 68.6, 80.2, 154.8, 156.5; IR (neat) 3400, 1670, 1420 cm-1.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[N:4]=[C:3]1[C:10]([OH:12])=O.C(Cl)(=O)C([Cl:16])=O>C1COCC1>[CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[N:4]=[C:3]1[C:10]([Cl:16])=[O:12]
Reactant: Cn1cc([N+](=O)[O-])nc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: Cn1cc([N+](=O)[O-])nc1C(=O)Cl

Procedure:
To a solution of 1-methyl-4-nitroimidazole-2-carboxylic acid (2.0 g, 0.012 mol) in dry THF (20 mL) was slowly added oxalyl chloride (6 mL). The solution was heated to reflux for 45 minutes, and the solvent and excess oxalyl chloride were removed under reduced pressure to give 1-methyl-4-nitroimidazole-2-carbonyl chloride as a yellow powder which was coevaporated with dry CH2Cl2 (15 mL).
Reaction SMILES: [Br-].[O:2]=[C:3]1[N:8]2[CH:9]=[N+:10]([CH2:12][CH2:13][CH3:14])[CH:11]=[C:7]2[CH2:6][CH2:5][NH:4]1.[F:15][C:16]1[CH:17]=[C:18]([C:26]2[S:30][C:29]([NH2:31])=[N:28][C:27]=2[CH3:32])[CH:19]=[CH:20][C:21]=1[S:22]([CH3:25])(=[O:24])=[O:23].CCN(CC)CC>CCOC(C)=O>[F:15][C:16]1[CH:17]=[C:18]([C:26]2[S:30][C:29]([NH:31][C:3]([NH:4][CH2:5][CH2:6][C:7]3[N:8]=[CH:9][N:10]([CH2:12][CH2:13][CH3:14])[CH:11]=3)=[O:2])=[N:28][C:27]=2[CH3:32])[CH:19]=[CH:20][C:21]=1[S:22]([CH3:25])(=[O:23])=[O:24]
Reactant: CCC[n+]1cc2n(c1)C(=O)NCC2
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCn1cnc(CCNC(=O)Nc2nc(C)c(-c3ccc(S(C)(=O)=O)c(F)c3)s2)c1
Temperature: 120 °C
Yield: 23.4 %

Procedure:
A stirred mixture of 5-oxo-2-propyl-5,6,7,8-tetrahydro-imidazo[1,5-c]pyrimidin-2-ium bromide (Intermediate DA) (0.214 g, 0.83 mmol) and 5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Intermediate AA) (0.15 g, 0.55 mmol) and Et3N (0.48 ml, 3.3 mmol) is heated at 120° C. for 2 days. After cooling to room temperature the mixture is diluted with EtOAc (50 ml) and washed water followed by brine. The organic extract is dried (MgSO4) and the solvent is removed to give a solid. Purification by chromatography oh silica eluting with DCM:MeOH (95:5) affords the titled compound (0.06 g, 25%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[CH2:16][C:15]23[CH:17]=[CH:18][CH:19]=[CH:20][C:14]2=[CH:13][C:12]([CH2:21][N:22]2[CH2:27][CH2:26][C:25]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=4)([C:28]#[N:29])[CH2:24][CH2:23]2)=[CH:11][CH:10]3[C:9]1=[O:37].[CH3:38]B(O)O>>[CH:36]([C:32]1[N:31]=[C:30]([C:25]2([C:28]#[N:29])[CH2:24][CH2:23][N:22]([CH2:21][C:12]3[CH:13]=[C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]54[CH:10]([CH:11]=3)[C:9](=[O:37])[N:8]([C@H:3]3[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]3[OH:1])[CH2:16]5)[CH2:27][CH2:26]2)[CH:35]=[CH:34][CH:33]=1)=[CH2:38]
Reactant: CB(O)O
Reactant: Cc1cccc(C2(C#N)CCN(CC3=CC4C(=O)N([C@H]5CCCC[C@@H]5O)CC45C=CC=CC5=C3)CC2)n1
Product: C=Cc1cccc(C2(C#N)CCN(CC3=CC4C(=O)N([C@H]5CCCC[C@@H]5O)CC45C=CC=CC5=C3)CC2)n1

Procedure:
4-(6-Ethenylpyridin-2-yl)-1-({2-[(1S,2S)-2-hydroxycyclohexyl]-3-oxo-2,3-dihydro-1H-benzo[d]isoindol-5-yl}methyl)piperidine-4-carbonitrile was prepared employing the procedures described for the construction of 1-({2-[(1S,2S)-2-hydroxycyclohexyl]-3-oxo-2,3-dihydro-1H-benzo[d]isoindol-5-yl}methyl)-4-(6-methylpyridin-2-yl)piperidine-4-carbonitrile in Example 4, substituting potassium vinyltrifluoroborate for methylboronic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.C(OC([NH:18][CH2:19][CH2:20][NH:21][CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=1)[C:23](O)=[O:24])=O)(C)(C)C>>[NH2:18][CH2:19][CH2:20][NH:21][CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=1)[C:23]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2)=[O:24]
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: COc1cccc(C(NCCNC(=O)OC(C)(C)C)C(=O)O)c1
Product: COc1cccc(C(NCCN)C(=O)Nc2ccc3[nH]ncc3c2)c1

Procedure:
5-Aminoindazole was coupled with (2-tert-butoxycarbonylamino-ethylamino)-(3-methoxy-phenyl)-acetic acid according to the method described in Example 1. The BOC protecting group was then removed according to the method described in Example 8 to afford compound I-1017. 1H NMR (400 MHz, DMSO-d6) δ 3.02–3.14 (4H, m), 3.80 (3H,s), 4–5 (1H, vbr s), 5.11 (1H, brs), 7.05 (1H,d), 7.20 (2H,m), 7.40 (2H,m), 7.52 (1H,d), 7.5–8 (2H, brs), 8.05 (1H,s), 8.07 (1H,s), 8.2–10.1 (1H, brs), 10.68 (1H,brs), 13.15 (1H,brs); MS (ES+): m/e=340.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33]>C(Cl)Cl.C(OCC)(=O)C>[C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](/[C:17](=[CH:18]\[N:34]([CH2:35][CH3:36])[CH2:32][CH3:33])/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[C@H:8]2[C@@:7]([CH3:31])([C@@H:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: CCNCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCN(/C=C1/C(=O)O[C@H](COC)[C@@]2(C)C1=C(O)C(=O)C1=C2[C@H](OC(C)=O)C[C@]2(C)[C@@H](O)CC[C@@H]12)CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a solution of 50 mg (0.116 mmol) 17-hydroxywortmannin in 1 mL CH2Cl2 is added 22.5 mL (0.217 mmol) diethylamine. The reaction mixture is stirred at room temperature for 2 hours 30 minutes and then concentrated in vacuo to give an orange paste. The residue is dissolved in ethyl actate (EtOAc) and precipitated with hexane. The precipitate is washed two times with hexane to give 45 mg (77%) product as an orange solid. HRMS (ESI) m/z calcd for C27 H37NO8 503.25206, found: 504.25747 (M+H)+1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]1([C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)Cl)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>CN(C)C=O>[C:7]1([C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C1CNCCN1
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(C(c2ccccc2)(c2ccccc2)N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
Piperazine (1.00 g, 11.6 mmol) (Wako Pure Chemical Industries, Ltd.) was dissolved in N,N-dimethylformamide (25 mL) (Wako Pure Chemical Industries, Ltd.), and triphenylchloromethane (0.65 g, 2.33 mmol) (Wako Pure Chemical Industries, Ltd.) was added little by little, and the mixture was stirred at room temperature overnight. Water was poured into the reaction solution, and mixture was extracted with ethyl acetate (Wako Pure Chemical Industries, Ltd.). The organic layer was dried with anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform (Wako Pure Chemical Industries, Ltd.):methanol (Wako Pure Chemical Industries, Ltd.)=9:1 as an eluent). The residue was dissolved in ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate (Wako Pure Chemical Industries, Ltd.), and the mixture was shaken, followed by separation of the organic layer. The organic layer was dried with anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and then the solvent was distilled off under reduced pressure, to thereby obtain the title compound (0.76 g, 99% yield).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7](=[O:9])[CH3:8])=[C:5]([CH3:10])[O:4][N:3]=1.[BrH:11].BrBr.C([O-])(O)=O.[Na+]>C(O)(=O)C.O>[Br:11][CH2:8][C:7]([C:6]1[C:2]([CH3:1])=[N:3][O:4][C:5]=1[CH3:10])=[O:9]
Reactant: CC(=O)c1c(C)noc1C
Reactant: Br
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1noc(C)c1C(=O)CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
400 mg (2.87 mmol) of 1-(3,5-dimethylisoxazol-4-yl)ethanone are dissolved in 20 mL of glacial acetic acid. 1.42 mL (8.62 mmol) of hydrobromic acid and 163 μl (3.16 mmol) of bromine are added to the medium. The reaction mixture is placed under magnetic stirring at room temperature for 2 hours. The solution is diluted with water, basified with saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness to give 540 mg of 2-bromo-1-(3,5-dimethylisoxazol-4-yl)ethanone, corresponding to the following characteristics:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:17])[C:7]=2[C:6]([NH:18][CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1>C(Cl)(Cl)Cl>[CH2:22]([N:21]([CH2:24][CH3:25])[CH2:20][CH2:19][NH:18][C:6]1[C:7]2[C:8](=[O:17])[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[S:15][C:16]=2[C:3]([CH2:2][NH:1][S:41]([C:38]2[CH:37]=[CH:36][C:35]([O:34][CH3:33])=[CH:40][CH:39]=2)(=[O:43])=[O:42])=[CH:4][CH:5]=1)[CH3:23]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(CC)CCNc1ccc(CN)c2sc3ccccc3c(=O)c12
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCNc1ccc(CNS(=O)(=O)c2ccc(OC)cc2)c2sc3ccccc3c(=O)c12
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
A solution of 1.40 g (3.94 mmol) of 4-(aminomethyl)-1-[[2-(diethylamino)ethyl]amino]-thioxanthen-9-one (prepared by the method described in Example 4) in 30 mL of chloroform containing 1.5 mL of triethylamine was cooled to 0° C. and treated with p-methoxybenzenesulfonyl chloride (0.83 g, 4.02 mmol). After 10 min at 0° C. the reaction mixture was stirred at room temperature for 2 h. Chloroform was removed in vacuo, the residue dissolved in 100 mL of methylene chloride containing 1 mL of triethylamine and treated with additional p-methoxybenzenesulfonyl chloride (0.85 g) with stirring at room temperature. The mixture was concentrated in vacuo, the residue was purified by passing through a pad of silica gel (1% triethylamine/chloroform) affording 1.57 g of N-[[1-[[2-(diethylamino)ethyl]amino]-9-oxothioxanthen-4-yl]methyl]-p-methoxy-benzenesulfonamide. The sulfonamide was treated with methanesulfonic acid (0.3 g) in isopropanol/isopropyl acetate/methanol to afford 1.07 g of the methanesulfonate salt, m.p. 133°-137° C.