Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:20]([OH:22])=O)=[CH:11][C:12]3[N:16]([CH3:17])[CH:15]=[N:14][C:13]=3[C:18]=2[F:19])=[C:4]([Cl:23])[CH:3]=1.[CH:24]([O:26][CH2:27][CH2:28][O:29][NH2:30])=[CH2:25].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.C(OCC)(=O)C>[CH:24]([O:26][CH2:27][CH2:28][O:29][NH:30][C:20]([C:10]1[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[Cl:23])=[C:18]([F:19])[C:13]2[N:14]=[CH:15][N:16]([CH3:17])[C:12]=2[CH:11]=1)=[O:22])=[CH2:25]
Reactant: Cn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(=O)O)cc21
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=COCCONC(=O)c1cc2c(ncn2C)c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 90.1 %

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid 10c (2.00 g, 5.0 mmol), O-(2-vinyloxy-ethyl)-hydroxylamine (0.776 g, 7.5 mmol), HOBt (0.88 g, 6.5 mmol), triethylamine (1.61 mL, 2.3 mmol) and EDCl (1.3 g, 6.5 mmol) are dissolved in dimethylformamide (52 mL) and stirred at room temperature for 48 hours. The reaction mixture is diluted with ethyl acetate, washed with water (3×), saturated potassium carbonate (2×), saturated ammonium chloride (2×), brine, dried (Na2SO4) and concentrated under reduced pressure to an off-white solid. Trituration of the solid with diethyl ether provides 2.18 g (90%) desired product as an off-white solid. MS ESI (+) m/z 483, 485 (M+ Br pattern) detected.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:41])[C@@H:14]([NH:22][C:23](=[O:40])[C@H:24]([CH2:36][C:37](=[O:39])[NH2:38])[NH:25][C:26]([O:28]CC1C=CC=CC=1)=O)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].[C:43]1(C)C=CC(S(O)(=O)=O)=CC=1.C(OC(=O)C)(=O)C.C(N(CC)CC)C>C(O)(C)C.[Pd].N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:42])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:41])[C@@H:14]([NH:22][C:23](=[O:40])[C@H:24]([CH2:36][C:37](=[O:39])[NH2:38])[NH:25][C:26](=[O:28])[CH3:43])[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CC(C)O
Product: CC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN1CCC[C@H]1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.1 %

Procedure:
0.275 g (0.473 mmol) of N-[3(S)-[[N-(benzyloxycarbonyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester was taken up in 10 ml of isopropanol and hydrogenated for 18 hours over 50 mg of 5% palladium-on-carbon in the presence of 0.18 g (0.94 mmol) of toluene-4-sulphonic acid. The catalyst was filtered off and the filtrate was evaporated. The resulting solid was dissolved in 10 ml of dichloromethane and the solution was cooled in an ice-bath. 50 mg (0.49 mmol) of acetic anhydride were added, followed by 0.10 g (0.99 mmol) of triethylamine and 0.2 ml of pyridine. The mixture was stirred at room temperature for 1 hour. The solvent was removed by evaporation and the residue was partitioned between ethyl acetate and water. The organic phase was washed with 5% sodium bicarbonate solution and with saturated sodium chloride solution and then dried over anhydrous sodium sulphate. The solvent was removed by evaporation to give 35 mg of N-[3(S)-[(N-acetyl-L-asparaginyl)amino]-2(R)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester; Rf (System E): 0.28; MS: m/e 491 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24]CC4C=CC=CC=4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:32])[NH:6]2.C([O-])=O.[NH4+]>CN(C)C=O.[OH-].[Pd+2].[OH-]>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([OH:24])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:32])[NH:6]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCc1ccccc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-7-(benzyloxy)-6-methoxyquinazoline (Compound 2, 0.46 g, 1.1 mmol) was dissolved in N,N-dimethylformamide (10 mL). Palladium hydroxide catalyst (250 mg, 10% on carbon) was added, followed by ammonium formate (0.67 g, 10.6 mmol). The reaction solution was stirred for 2 hours at room temperature. The catalyst was filtered through a CELITE pad, then the solution was evaporated, then dried in high vacuum overnight to generate Compound 3 as a brown solid (0.36 g, 100%) m/z: 340 (M+H, 100%) (positive ionization mode).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34]>>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:34]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=C=Nc1ccccc1Cl
Product: O=C1CC(=O)N(c2ccc(NC(=O)Nc3ccccc3Cl)cc2)c2ccc3ccccc3c2N1
Yield: 40.3 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32 mg, 0.10 mmol) obtained in Example 1, (3), and 2-chlorophenyl isocyanate (30 μL, 0.25 mmol), the title compound (19 mg, yield 40%) was obtained in the same manner as that of Example 20.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH3:13])[C:6]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)=[N:5]1)[CH:2]=[CH2:3].B(Br)(Br)Br.C1CCCCC=1>>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH3:13])[C:6]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)=[N:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1nc(-c2ccc(OC)cc2)c2cccc(C)c21
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: C=CCn1nc(-c2ccc(O)cc2)c2cccc(C)c21
Yield: 32.9 %

Procedure:
Prepared according to Method D step C from 1-allyl-3-(4-methoxyphenyl)-7-methyl-1H-indazole (0.027 g, 0.23 mmol), boron tribromide (0.10 mL, 1.05 mmol) and 0.3 mL of cyclohexene to give the product (0.020 g) as a tan solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[C:14]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:15][C:16]([CH3:20])=[C:17]([CH3:19])[CH:18]=1>>[Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:24]1[CH2:25][CH2:26][N:21]([C:14]2[C:13]([CH3:12])=[CH:18][C:17]([CH3:19])=[C:16]([CH3:20])[N:15]=2)[CH2:22][CH2:23]1)=[O:6]
Reactant: Cc1cc(C)c(N2CCNCC2)nc1C
Reactant: O=C(O)c1ccc(Cl)cc1Br
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Cl)cc3Br)CC2)nc1C
Yield: 103.3 %

Procedure:
Using 2-bromo-4-chlorobenzoic acid (1 g) and 1-(3,5,6-trimethylpyridin-2-yl)piperazine (0.87 g) described in Preparation Example 92 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (1.85 g) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:14]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[CH:15]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:14]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)[CH:15]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: Fc1ccc(N2CCN(Cc3cccc(-c4ccccc4)c3)CC2)cc1

Procedure:
74.7 mg of the target compound (0.22 mmol, 26.8%) was obtained using 1-(4-fluorophenyl)piperazine (296 mg, 1.64 mmol), biphenyl-3-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [NH2:1]/[C:2](=[N:19]\[OH:20])/[CH:3]([N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:4][CH2:5][CH2:6][CH:7]([OH:9])[CH3:8].[CH3:21][O:22][C:23]([C:25]#[C:26][C:27]([O:29][CH3:30])=[O:28])=[O:24]>CO>[NH2:1]/[C:2](=[N:19]\[O:20]/[C:25](=[CH:26]/[C:27]([O:29][CH3:30])=[O:28])/[C:23]([O:22][CH3:21])=[O:24])/[CH:3]([N:10]([C:11]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:17])[CH3:18])[CH2:4][CH2:5][CH2:6][CH:7]([OH:9])[CH3:8]
Reactant: COC(=O)C#CC(=O)OC
Reactant: CC(O)CCCC(/C(N)=N/O)N(C)C(=O)OC(C)(C)C
Solvent: CO
Product: COC(=O)/C=C(/O/N=C(\N)C(CCCC(C)O)N(C)C(=O)OC(C)(C)C)C(=O)OC
Temperature: -10 °C
Reaction time: 48 h

Procedure:
The tert-butyl {1-[(Z)-amino(hydroxyimino)methyl]-5-hydroxyhexyl}methylcarbamate (161 g, overweight) was dissolved in methanol (250 mL) and cooled to −10° C. DMAD (65 mL) was added dropwise without allowing the reaction temperature to rise above −5° C. then the reaction mixture was stored in a freezer at −10° C. for 2 days. The reaction mixture was then concentrated to dryness. It was azeotropically dried twice with toluene and dried in vacuo at 30° C. to constant weight to afford the title product: ES MS M+1=431.9.
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][NH:19][C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[CH2:35]([O:42][CH2:43][C:44](Cl)=[O:45])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([O:42][CH2:43][C:44]([N:19]([CH2:18][C:17]1[CH:33]=[CH:34][C:14]([C:13]#[C:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:2][CH2:3][CH2:4][CH3:5])=[CH:11][CH:10]=2)=[CH:15][CH:16]=1)[C:20]1[CH:32]=[CH:31][C:23]2[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=2[CH:21]=1)=[O:45])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Agent: Cl
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)COCc3ccccc3)c3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1

Procedure:
The titled compound was prepared following the procedure K using 6-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one hydrochloride and (benzyloxy)acetyl chloride as a yellow oil (88%). M+ (ESI): 588.5. HPLC, Rt: 5.76 min (Purity: 100%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[BH4-].[Na+].[CH2:7]([CH:11]1[S:15][C:14]2[C:16]([Cl:23])=[C:17]([Cl:22])[C:18]([O:20][CH3:21])=[CH:19][C:13]=2[C:12]1=[O:24])[CH2:8][CH2:9][CH3:10]>ClCCl.C(O)C>[CH2:7]([CH:11]1[S:15][C:14]2[C:16]([Cl:23])=[C:17]([Cl:22])[C:18]([O:20][CH3:21])=[CH:19][C:13]=2[CH:12]1[OH:24])[CH2:8][CH2:9][CH3:10]
Reactant: CCCCC1Sc2c(cc(OC)c(Cl)c2Cl)C1=O
Agent: [Al+3]
Agent: [BH4-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCO
Product: CCCCC1Sc2c(cc(OC)c(Cl)c2Cl)C1O
Reaction time: 2 h

Procedure:
A mixture of 1.62 g of α-[(2,3-dichloro-4-methoxy)phenylthio]hexanoic acid and 8 ml of thionyl chloride in 50 ml dichloromethane is refluxed for 30 minutes. The cooled solution is concentrated in vacuo to dryness at 60°, leaving the acid chloride as a yellow solid. The residue is dissolved in 100 ml dichloromethane, cooled to -70° and the solution is treated with 0.73 g of aluminum chloride in small portions. The cooling bath is removed after the addition is complete and the reaction mixture is stirred for 11/2-2 hours. The mixture is decomposed with water and the aqueous solution is extracted with 3×100 ml portions of dichloromethane. The organic layers are combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate is concentrated under reduced pressure to give a dark oil. The oil is dissolved in 100 ml of 100% ethanol and stirred under a nitrogen atmosphere. To this mixture is slowly added 1.0 g of sodium borohydride. Stirring is continued until the disappearance of the ketone intermediate, 2-n-butyl-6,7-dichloro-5-methoxybenzo[b]thiophen-3(2H)-one, is shown by a thin layer chromatography. The reaction mixture is quenched with 100 g ice-water and extracted with 3×100 ml-portions of diethyl ether. The organic layers are combined and washed with 1×100 ml-portions of water. The organic layer is dried, filtered, and the solvent removed in vacuo. The residue is chromatographed on 60 g of silica gel using dichloromethane as the eluant to give 0.76 g of 2-n-butyl-6,7-dichloro-2,3-dihydro-3-hydroxy-5-methoxybenzo[b]thiophene as an oily epimeric mixture. Upon standing, crystals form from the isolated oil. Recrystallization from ether-hexane gives an isomer which melts at 95°-96°.
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([C@@H:10]2[C@@H:14]3[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]3[C@H:12]([N:20]3[CH:28]=[N:27][C:26]4[C:21]3=[N:22][CH:23]=[N:24][C:25]=4ON3C4C=CC=CC=4N=N3)[O:11]2)[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:39][C:40]1[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][C:41]=1[NH2:42]>>[C:1]([C:5]1[N:9]=[C:8]([C@@H:10]2[C@@H:14]3[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]3[C@H:12]([N:20]3[CH:28]=[N:27][C:26]4[C:21]3=[N:22][CH:23]=[N:24][C:25]=4[NH:42][C:41]3[CH:43]=[CH:44][C:45]([F:47])=[CH:46][C:40]=3[F:39])[O:11]2)[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)O[C@@H]2[C@@H](O1)[C@H](n1cnc3c(On4nnc5ccccc54)ncnc31)O[C@@H]2c1nc(C(C)(C)C)no1
Reactant: Nc1ccc(F)cc1F
Product: CC1(C)O[C@@H]2[C@@H](O1)[C@H](n1cnc3c(Nc4ccc(F)cc4F)ncnc31)O[C@@H]2c1nc(C(C)(C)C)no1
Temperature: 80 °C

Procedure:
9-{(3aR,4R,6S,6aR)-6-[3-(tert-butyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl}-6-(1H-1,2,3-benzotriazol-1-yloxy)-9H-purine (50 mg) was dissolved in 2,4-difluoroaniline (0.4 ml) and the mixture heated at 80° C. for 96 h. The mixture was then cooled to 20° C. and partitioned between dichloromethane (25 ml) and 1 M hydrochloric acid (15 ml). The separated aqueous phase was further extracted with dichloromethane (1×25 ml) and the combined organic extracts were evaporated to dryness in vacuo. Purification by automated preparative HPLC afforded the title compound (18.3 mg) as a dark purple gum.
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].[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>C(Cl)Cl>[C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](/[C:17](=[CH:18]\[N:36]4[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]4)/[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[CH:8]2[C@@:7]([CH3:31])([C@@H:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: CN1CCNCC1
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
Solvent: ClCCl
Product: COC[C@H]1OC(=O)/C(=C/N2CCN(C)CC2)C2=C(O)C(=O)C3=C([C@H](OC(C)=O)C[C@@]4(C)C3CC[C@@H]4O)[C@]21C
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
To a solution of 50 mg (0.12 mmol) 17-hydroxywortmannin in 0.5 mL CH2Cl2 is added 24 mg (0.24 mmol) 1-methylpiperazine. The reaction mixture is stirred at room temperature overnight. CH2Cl2 is removed in vacuo. The residue is triturated with Et2O to give 19 mg (29.8%) product as an orange powder. MS (ESI) m/z 531.2 (M+1).
Reaction SMILES: FC(F)C1C(C(F)(F)F)=C(C(O)=O)N(C)N=1.[CH:17]1([CH:20]([OH:36])[C:21]2[C:25]([C:26]([F:29])([F:28])[F:27])=[C:24]([C:30]([O:32]CC)=[O:31])[N:23]([CH3:35])[N:22]=2)[CH2:19][CH2:18]1>>[CH:17]1([CH:20]([OH:36])[C:21]2[C:25]([C:26]([F:28])([F:29])[F:27])=[C:24]([C:30]([OH:32])=[O:31])[N:23]([CH3:35])[N:22]=2)[CH2:19][CH2:18]1
Reactant: CCOC(=O)c1c(C(F)(F)F)c(C(O)C2CC2)nn1C
Agent: Cn1nc(C(F)F)c(C(F)(F)F)c1C(=O)O
Product: Cn1nc(C(O)C2CC2)c(C(F)(F)F)c1C(=O)O

Procedure:
This compound is prepared analogously to the preparation of 3-(difluoromethyl)-1-methyl-4-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid from ethyl 3-[cyclopropyl(hydroxy)methyl]-1-methyl-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate.
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1.[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccco1
Reactant: CCOC(=O)C1=Cc2ccc(I)cc2OC1C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)C1=Cc2ccc(-c3ccco3)cc2OC1C(F)(F)F
Temperature: 80 °C
Yield: 20.6 %

Procedure:
The ethyl 7-iodo-2-(trifluoromethyl)-2H-chromene-3-carboxylate from Example 9a, Step 2 (2.0 g, 5.02 mmol), 2-furylboronic acid (0.62 g, 5.52 mmol), K2CO3 (2.08 g, 15.06 mmol), and PdCl2(PPh3)2 (106 mg, 0.15 mmol) were mixed in dioxane (20 mL) in a sterling bomb. Carbon monoxide was bubbling to 40 psi. The reaction was heated to 80° C. for 12 h. After filtration, the reaction was quenched with NH4Cl and extracted with EtOAc. The organic layer was washed and dried over MgSO4. The filtrate was evaporated and dried in vacuo to afford crude which was purified Biotage Chromatography with 10 to 20% ethyl acetate in hexane to give yellow solid (350 mg, 21%): LCMS m/z 339.05 (M+H). 1H NMR (CDCl3/300 MHz) 7.74 (s, 1H), 7.51 (s, 1H), 8.97 (m, 3H), 6.76 (d, 1H, J=3.3 Hz), 6.51 (m, 1H), 5.73 (q, 1H, J=6.9 Hz), 4.34 (m,2H), 1.36 (t, 3H, J=7.2 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH2:22][CH2:23][NH:24][OH:25])[CH:17]=3)[C:12]2=[O:26])=[CH:4][CH:3]=1.C[Si]([N:31]=[C:32]=[O:33])(C)C.O>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH2:22][CH2:23][N:24]([C:32]([NH2:31])=[O:33])[OH:25])[CH:17]=3)[C:12]2=[O:26])=[CH:6][CH:7]=1
Reactant: O=C1c2ccc(OCCNO)cc2CCN1CCCc1ccc(F)cc1
Reactant: C[Si](C)(C)N=C=O
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)N(O)CCOc1ccc2c(c1)CCN(CCCc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 2-[3-(4-fluorophenyl)-propyl]-6-[2-(N-hydroxyamino)ethoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline (3.0 g, 8.4 mmol) in dioxane (100 mL) is added trimethylsilyl isocyanate (1.06 g, 9.2 mmol). The reaction is stirred at room temperature for 24 hours and subsequently poured into H2O (350 mL). The resulting suspension is extracted with EtOAc (1×500 mL) and the organic phase washed with 2M HCl (1×250 mL), H2O (5×500 mL), saturated NaCl solution (2×500 mL), dried over MgSO4 and concentrated in vacuo. The resulting material is triturated with hexanes, and recrystallized from EtOAc to give 2-[3-(4-fluorophenyl)-propyl]-6-[2-(N-aminocarbonyl-N-hydroxyamino)ethoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline, m.p. 138°-140°.
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[F:28][C@H:29]1[CH2:33][NH:32][C@H:31]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:30]1>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([N:32]1[CH2:33][C@H:29]([F:28])[CH2:30][C@H:31]1[C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](F)CN1
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(N2C[C@H](F)C[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 3.78 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 6-3 (13.5 mmol) as starting materials, respectively 2.06 g (Isomer A: colorless powder) and 2.74 g (Isomer B: colorless powder) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][N:6]([CH3:10])[C:7]=1[CH2:8][NH2:9].[O-]S([O-])(=O)=O.[Na+].[Na+].[OH-].[K+].Br[CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25].[H-].[Na+]>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][O:2][C:3]1[N:4]=[CH:5][N:6]([CH3:10])[C:7]=1[CH2:8][N:9]1[CH2:21][CH2:22][CH2:23][C:24]1=[O:25]
Reactant: O=C(Cl)CCCBr
Reactant: COc1ncn(C)c1CN
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])[O-]
Agent: [Br-]
Solvent: ClCCl
Product: COc1ncn(C)c1CN1CCCC1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 27.4 %

Procedure:
In a 50 ml, three-necked flask fitted with a magnetic stirrer, under inert atmosphere, 1-(4-methoxy-1-methyl-1H-imidazol-5-yl)methanamine x94 (0.37 g, 2.62 mmol), Na2SO4 (0.37 g, 2.62 mmol) and powdered molecular sieves are stirred in CH2Cl2 (25 ml) at 0° C. At this temperature, powdered KOH (0.53 g, 9.44 mmol) and a solution of tetra-n-butyl ammonium bromide (48 mg, 0.13 mmol) in CH2Cl2 (5 ml) are added. The mixture is stirred for 0.25 h at 0° C. and 4-bromobutanoyl chloride (366 μl, 3.14 mmol) is added dropwise. Stirring is continued for 2 h. The mixture is filtered on Celite and evaporated in vacuo. The residue is dissolved in DMF (25 ml) and NaH (60% dispersion in oil, 0.12 g, 3.14 mmol) is added. The mixture is stirred at room temperature for 16 h. An additional portion of NaH (0.52 mmol) is added and the mixture is stirred for 4 more hours at room temperature. The mixture is then diluted with 30 ml of CH2Cl2, filtered on Celite and concentrated to dryness. The residue is purified by chromatography on silicagel (CH2Cl2/MeOH/NH4OH: 95/4.5/0.5 (v/v/v)) and recrystallized from diisopropyl ether to afford 150 mg of 1-[(4-methoxy-1-methyl-1H-imidazol-5-yl)methyl]pyrrolidin-2-one 120.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([S:13]([CH:16]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:17]([CH3:23])([CH3:22])[C:18]([O:20]C)=[O:19])(=[O:15])=[O:14])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]>O.CO>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([S:13]([CH:16]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:17]([CH3:22])([CH3:23])[C:18]([OH:20])=[O:19])(=[O:14])=[O:15])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COC(=O)C(C)(C)C(CCCCc1ccccc1)S(=O)(=O)c1ccc(OC)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(S(=O)(=O)C(CCCCc2ccccc2)C(C)(C)C(=O)O)cc1OC
Yield: 73.1 %

Procedure:
A solution of sodium hydroxide (0.31 g, 7.7 mmol) in water (4 mL) is added to a solution of methyl 3-(3,4-dimethoxybenzenesulfonyl)-2,2-dimethyl-7-phenylheptanoate (0.78 g, 1.7 mmol) in MeOH (6 mL). The reaction is heated at reflux 24 hours. The solvent is then removed in vacuo, CH2Cl2 (20 mL) added and the solution washed with 1 N HCl (2×40 mL). The organic layer is dried over MgSO4 and the solvent removed in vacuo to afford 3-(3,4-dimethoxyphenylsulfonyl)-2,2-dimethyl-7-phenylheptanoic acid (0.54 g, 73%) 1H NMR (300 MHz, CDCl3) δ 7.47 (dd, J=8.5, 2.1 Hz, 1H), 7.36 (d, J=2.1 Hz, 1H), 7.26-7.16 (m, 3H), 7.02 (d, J=7.0 Hz, 2H), 6.90 (d, J=8.4 Hz, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.76-3.73 (m, 1H), 2.46-2.41 (m, 2H), 2.06-2.00 (m, 1H), 1.65-1.60 (m, 2H), 1.48 (s, 3H), 1.45-1.35 (m, 3H), 1.29 (s, 3H); MS (FAB) m/e 434 (M+).