Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[N:15]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:29][C:30]1[CH:51]=[CH:50][C:33]([CH2:34][O:35][C:36]2[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])=[C:38]([F:49])[CH:37]=2)=[CH:32][CH:31]=1.Cl>CN(C)C=O.C(O)C.O1CCCC1.[OH-].[Na+]>[F:49][C:38]1[CH:37]=[C:36]([O:35][CH2:34][C:33]2[CH:50]=[CH:51][C:30]([CH2:29][N:10]([CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:11]3[S:12][CH:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:18][CH:17]=4)[N:15]=3)=[CH:31][CH:32]=2)[CH:41]=[CH:40][C:39]=1[CH2:42][CH2:43][C:44]([OH:46])=[O:45]
Reactant: Fc1ccc(CCNc2nc(-c3ccc(C(F)(F)F)cc3)cs2)cc1
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C(O)CCc1ccc(OCc2ccc(CN(CCc3ccc(F)cc3)c3nc(-c4ccc(C(F)(F)F)cc4)cs3)cc2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.3 %

Procedure:
To a solution of N-[2-(4-fluorophenyl)ethyl]-4-[4-(trifluoromethyl)phenyl]-1,3-thiazole-2-amine (500 mg, 1.36 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (40 mg, in oil, 1.0 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hr. Ethyl 3-(4-{[4-(chloromethyl)benzyl]oxy}-2-fluorophenyl)propanoate (350 mg, 1.0 mmol) was added, and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19-1:1 in volume ratio) give a yellow oil. The oil was dissolved in a mixed solvent of ethanol (5 mL) and tetrahydrofuran (5 mL), and 2N aqueous sodium hydroxide solution (2 mL) was added. The mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by preparative HPLC. The obtained fraction was concentrated, neutralized with 10% aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The ethyl acetate layer was filtered with a Presep Dehydration tube (manufactured by Wako Pure Chemical Industries, Ltd.) and concentrated to give the title compound (139 mg, yield 21%, 2 steps) as a yellow oil.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH:31][CH:32]([CH2:37][CH:38]3[O:40][CH2:39]3)[C:33]([O:35]C)=[O:34])(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:23]=[CH:24][C:25]([S:28]([NH:31][CH:32]([CH2:37][CH:38]([OH:40])[CH2:39][S:1][C:2]3[CH:11]=[C:10]4[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[O:9]4)=[CH:4][CH:3]=3)[C:33]([OH:35])=[O:34])(=[O:29])=[O:30])=[CH:26][CH:27]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Reactant: Cc1cc(=O)oc2cc(S)ccc12
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3ccc4c(C)cc(=O)oc4c3)C(=O)O)cc2)cc1

Procedure:
Example 49 is prepared from 7-mercapto-4-methylcoumarin and 1d using the procedure described for compound 20.
Reaction SMILES: [N:1]1[C:6]([CH2:7][OH:8])=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:9][OH:10]>O1CCOCC1>[N:1]1[C:6]([CH:7]=[O:8])=[CH:5][CH:4]=[CH:3][C:2]=1[CH:9]=[O:10]
Reactant: OCc1cccc(CO)n1
Solvent: C1COCCO1
Product: O=Cc1cccc(C=O)n1
Yield: 858.1 %

Procedure:
This preparation procedure followed the literature procedure (J. Chem. Soc., Dalton Trans. 1984-1937). To the mixture of 11.51 g of 2,6-pyridine-dimethanol (8.28 mmol) and 9.99 g of SeO2, was added 200 mL of 1,4-dioxane. The mixture was then refluxed for 4 h and filtered. The filtrate was concentrated under reduced pressure. The solid was dissolved in CH2Cl2 and passed through a silica gel plug. The solution was concentrated, and the solid was recrystallized from 60 mL of acetone and 100 mL of hexanes to afford 9.6 g of white crystal (71%), which was kept under N2. 1H NMR (CDCl3) δ 8.02-8.12 (m, 3H), 10.08 (s, 2H), 13C NMR δ 125.7, 138.8, 153.3, 192.7.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:14][C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2].CC(C)([O-])C.[K+].[C:21]([O:25][C:26]([N:28]1[CH2:32][C@H:31]([CH3:33])OS1(=O)=O)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[CH2:1]([O:3][C:4]([C:6]1[N:14]([C@H:31]([CH3:33])[CH2:32][NH:28][C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reactant: CCOC(=O)c1cc2cccnc2[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCOC(=O)c1cc2cccnc2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
This compound was prepared in analogy to Example 1 intermediate a), from 1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester, potassium tert-butoxide and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[N:13]=[CH:14][C:15]2[N:16]([CH2:25][CH3:26])[C:17]3[C:22]([C:23]=2[CH:24]=1)=[CH:21][CH:20]=[CH:19][CH:18]=3)=O)C>O1CCCC1>[CH2:25]([N:16]1[C:15]2[CH:14]=[N:13][C:12]([CH:10]=[O:9])=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:26]
Reactant: CCOC(=O)c1cc2c3ccccc3n(CC)c2cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCn1c2ccccc2c2cc(C=O)ncc21
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a suspension of lithium aluminium hydride (116 mg, 3.06 mmol, 1 eq) in anhydrous tetrahydrofuran (15 mL) was added at 0° C. under nitrogen a solution of 9-ethyl-9H-β-carboline-3-carboxylic acid ethyl ester (820 mg, 3.06 mmol, 1 eq) in anhydrous tetrahydrofuran (25 mL). The reaction mixture was stirred at 0° C. for 6 h then quenched with a 5% aqueous solution of sodium hydroxide (2.88 mL). The solid formed was filtered, washed with ethyl acetate and dried to afford the title compound, which is used without further purification. Mass Spec m/z=227 [M+H+].
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([CH3:16])=[C:9]([CH3:17])[C:8]=1[N+:18]([O-:20])=[O:19])[CH2:4][CH3:5])[CH3:2].CO[CH:23](OC)[N:24]([CH3:26])[CH3:25]>>[CH2:1]([CH:3]([NH:6][C:7]1[C:8]([N+:18]([O-:20])=[O:19])=[C:9]([C:10]([CH3:16])=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[CH:17]=[CH:23][N:24]([CH3:26])[CH3:25])[CH2:4][CH3:5])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: CCC(CC)Nc1c([N+](=O)[O-])cc(C)c(C)c1[N+](=O)[O-]
Product: CCC(CC)Nc1c([N+](=O)[O-])cc(C)c(C=CN(C)C)c1[N+](=O)[O-]
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A mixture of N-(1-ethylpropyl)-2,6-dinitro-3,4-xylidine (50.0 g; 0.18 mol) and dimethylformamide dimethyl acetal (125 ml) is stirred at 85° C. overnight. The temperature of the reaction mixture is then raised to 90°-100° C. and methanol distilled off until approximately 12.5 ml methanol is collected. The reaction mixture is then cooled down, poured into hexane (400 ml) and chilled. The crystallized red solid (45.6 g; 75.3%) is collected and air dried. A sample is purified for analysis, melting point 100°-102° C.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][N:2]1[C:12]1[CH:21]=[C:20](/[CH:22]=[CH:23]/[C:24]([O:26][CH3:27])=[O:25])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1>CO.[Pd]>[CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][N:2]1[C:12]1[CH:21]=[C:20]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: COC(=O)/C=C/c1cc(N2CCCc3ccccc3C2)nc2ccccc12
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1cc(N2CCCc3ccccc3C2)nc2ccccc12
Reaction time: 3 h
Yield: 99.3 %

Procedure:
To a solution of methyl (2E)-3-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]prop-2-enoate (1.4 g, 3.91 mmol) in 30 mL of methanol was added 10% palladium on carbon (70 mg). After being vigorously stirred under hydrogen (balloon) for 3 hours, the reaction was filtered and the filtrate was concentrated in vacuo to give 1.4 g of product as a white solid (yield was 98%). MS obsd. (ESI+) [(M+H)+] 361.
Reaction SMILES: [NH2:1][C@H:2]1[C:5](=[O:6])[NH:4][C@@H:3]1[CH2:7][C:8]([O:14][CH3:15])=[CH:9][C:10]([O:12][CH3:13])=[O:11].[CH:16](OC(=O)C)=[O:17]>>[CH:16]([NH:1][C@H:2]1[C:5](=[O:6])[NH:4][C@@H:3]1[CH2:7][C:8]([O:14][CH3:15])=[CH:9][C:10]([O:12][CH3:13])=[O:11])=[O:17]
Reactant: COC(=O)C=C(C[C@H]1NC(=O)[C@@H]1N)OC
Reactant: CC(=O)OC=O
Product: COC(=O)C=C(C[C@H]1NC(=O)[C@@H]1NC=O)OC

Procedure:
A solution of methyl 4-[(2R,3R)-3-amino-4-oxoazetidin-2-yl]-3-methoxybut-2-enoate[(E,Z)-isomeric mixture](145 mg) in acetic formic anhydride (1 ml) was stirred at 5° C. for one hour. The resultant solution was evaporated in vacuo, and the residue was chromatographed on silica gel (2.5 g) eluting with 3 to 5% methanol in dichloromethane to give methyl 4-[(2R,3R)-3-formamido-4-oxoazetidin-2-yl]-3-methoxybut-2-enoate[(E,Z)-isomeric mixture](133 mg) as an amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:15]([OH:17])=O.C1N=C[N:20](C(N2C=NC=C2)=O)C=1.[NH4+].[OH-].CCCCCC>C1COCC1>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:15]([NH2:20])=[O:17]
Reactant: COc1ccc2ccc(C(=O)O)c(OC)c2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc2ccc(C(N)=O)c(OC)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 49 %

Procedure:
To a room temperature solution of 1,7-dimethoxy-2-naphthalenecarboxylic acid (131 mg, 0.56 mmol) in 3 mL of THF is added N,N-carbonyldiimidazole (105 mg, 0.65 mmol). The solution is heated at reflux for 2.5 hours and cooled slightly. Aqueous NH4OH (1 mL) is added and the reaction mixture is stirred at room temperature for 1.5 hours, then poured into 1:1 hexane:ethyl acetate and washed with brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. The crude product is chromatographed on silica gel eluting with hexane:ethyl acetate (1:1) to provide 1,7-dimethoxy-2-naphthalenecarboxamide in 49% yield; mp 134°-136° C.
Reaction SMILES: [CH2:1]([C:3]1[S:43][C:6]2[N:7]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]4[NH:41][C:40](=[O:42])[O:39][N:38]=4)=[CH:27][CH:26]=3)[C:8](=[O:23])[N:9]([CH2:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=O)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Cl.[NH2:45][O:46][CH3:47].N1C=CC=CC=1.Cl>O.C(Cl)(Cl)Cl.C(O)C>[CH2:1]([C:3]1[S:43][C:6]2[N:7]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]4[NH:41][C:40](=[O:42])[O:39][N:38]=4)=[CH:29][CH:30]=3)[C:8](=[O:23])[N:9]([CH2:12][C:13](=[N:45][O:46][CH3:47])[C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Reactant: CON
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCc1cc2c(=O)n(CC(=NOC)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 6-ethyl-3-[2-(4-methoxyphenyl)-2-oxoethyl]-1-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.13 g), (aminooxy)methane hydrochloride (0.06 g), pyridine (5 mL) and ethanol (5 mL) was stirred at 100° C. for 16 hr. To the reaction mixture were added chloroform and water, and the mixture was adjusted to pH 4 with 1N hydrochloric acid. The chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a stereoisomer mixture (0.06 g, 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]([N:19]([C:26]3[C:27]4[CH:34]=[CH:33][N:32](S(C5C=CC(C)=CC=5)(=O)=O)[C:28]=4[N:29]=[CH:30][N:31]=3)[CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[CH2:14]2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+]>CO>[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]([N:19]([C:26]3[C:27]4[CH:34]=[CH:33][NH:32][C:28]=4[N:29]=[CH:30][N:31]=3)[CH2:20][C:21]([N:23]([CH3:24])[CH3:25])=[O:22])[CH2:14]2)=[O:12])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N(CC(=O)N(C)C)[C@@H]4CCCN(C(=O)CNc5cc(Cl)cc(Cl)c5)C4)ncnc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CN(C)C(=O)CN(c1ncnc2[nH]ccc12)[C@@H]1CCCN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1
Yield: 40.8 %

Procedure:
A solution of (R)-2-((1-(2-(3,5-dichlorophenylamino) acetyl) piperidin-3-yl) (7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N, N-dimethylacetamide (45 mg, 0.068 mmol) and K2CO3 (37 mg, 0.27 mmol) in MeOH (5 mL) was heated at 70° C. for 2 h. The solvent was then evaporated in vacuo to give a solid, which was purified by column chromatography (silica gel, gradient 0-3% methanol in chloroform) to afford the titled compound (14 mg, 41%). 1H NMR (400 MHz, CDCl3): δ 10.19 (s, 1H), 8.32 and 8.23 (2s, 1H), 7.04 (s, 1H), 6.66 (s, 1H), 6.48 (s, 1H), 6.18 (s, 1H), 5.21 (s, 1H), 4.65-4.64 (m, 2H), 4.41-4.20 (m, 3H), 3.80-3.76 (m, 1H), 3.20 (s, 3H), 3.05 (s, 3H), 3.02-2.88 (m, 2H), 2.60 (t, J=11.6 Hz, 1H), 2.36 (t, J=11.6 Hz, 1H), 1.99-1.67 (m, 4H). LCMS [M+1]: 504, [M+23]: 526.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:24]2[CH2:28][CH2:27][CH2:26][S:25]2(=[O:30])=[O:29])[CH:3]=1.[CH3:31][C:32]1([CH3:38])[O:36][C:35](=[O:37])[NH:34][CH2:33]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:34]4[CH2:33][C:32]([CH3:38])([CH3:31])[O:36][C:35]4=[O:37])=[CH:3][C:4]=3[N:24]3[CH2:28][CH2:27][CH2:26][S:25]3(=[O:30])=[O:29])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CC1(C)CNC(=O)O1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CC(C)(C)OC4=O)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Yield: 32.8 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (247 mg) described in Preparation Example 118 and 5,5-dimethyloxazolidin-2-one (57.6 mg) described in Preparation Example 43, the title compound (86.6 mg) was obtained.
Reaction SMILES: [Si:1](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:19][C:20]1[S:24][C:23]([CH2:25][OH:26])=[CH:22][CH:21]=1.CN(C)C=O.N1C=CN=C1>CCOCC>[Si:1]([O:26][CH2:25][C:23]1[S:24][C:20]([Br:19])=[CH:21][CH:22]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccc(Br)s1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCc1ccc(Br)s1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tert-butyldiphenylsilyl chloride (7.8 mL, 30.1 mmol) was added to a solution of 5-bromo(thiophen-2-yl)methyl alcohol (4.9 g, 25.1 mmol) and 9.7 mL of dimethylformamide. The solution was treated with imidazole (4.29 g, 62.8 mmol) and stirred overnight at room temperature. The solution was diluted with ether and washed with 2% aqueous HCl. The layers were separated and the aqueous layer was extracted with ether. The combined organic extracts were washed with brine, and dried (MgSO4), and filtered, and the solvents were removed in vacuo. The residue was purified by silica gel chromatography (hexane) to produce the title compound.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][C:11]=1[C:12](F)([C:17]([F:20])([F:19])[F:18])[C:13]([F:16])([F:15])[F:14])[NH2:8])[CH:2]([CH3:4])[CH3:3].[CH3:22][OH:23]>C[O-].[Na+]>[CH2:1]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][C:11]=1[C:12]([O:23][CH3:22])([C:17]([F:20])([F:19])[F:18])[C:13]([F:16])([F:15])[F:14])[NH2:8])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1cc(N)ccc1C(F)(C(F)(F)F)C(F)(F)F
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Product: COC(c1ccc(N)cc1CC(C)C)(C(F)(F)F)C(F)(F)F
Temperature: 0 °C
Yield: 79.6 %

Procedure:
3-Isobutyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline (1.6 g, 5 mmol) was dissolved in a 28% by weight methanol solution (9.6 g) of sodium methoxide and stirred under heating for 3 hours. After cooling, the reaction solution was poured into ice water, followed by extracting with ethyl acetate and washing with water. The solution was dried over magnesium sulfate and concentrated under reduced pressure, and then the residue was purified by using silica gel chromatography (hexane:ethyl acetate=5:1) to obtain 1.31 g of the desired compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH2:22][OH:23])[N:19]=[CH:18]3)=[C:13]([O:24][CH3:25])[CH:12]=2)[N:3]=1.[Cl:26][C:27]1[C:32]([OH:33])=[CH:31][CH:30]=[CH:29][N:28]=1>>[Cl:26][C:27]1[C:32]([O:33][C:2]2[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:21]=[C:20]([CH2:22][OH:23])[N:19]=[CH:18]4)=[C:13]([O:24][CH3:25])[CH:12]=3)[N:3]=2)=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: COc1nc(Cl)nc(Nc2ccc(-n3cnc(CO)c3)c(OC)c2)n1
Reactant: Oc1cccnc1Cl
Product: COc1nc(Nc2ccc(-n3cnc(CO)c3)c(OC)c2)nc(Oc2cccnc2Cl)n1
Yield: 43 %

Procedure:
This compound was prepared in analogy to example 3 from {1-[4-(4-chloro-6-methoxy-[1,3,5]triazin-2-ylamino)-2-methoxy-phenyl]-1H-imidazol-4-yl}-methanol and 2-chloro-3-hydroxypyridine. The title compound was isolated as a slightly brownish solid in 43% yield.
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].[N:32]1([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>C(Cl)Cl>[N:32]1([CH:38]2[CH2:43][CH2:42][N:41]([CH:18]=[C:17]3[C:16]4[C:15]([CH3:30])([C:14]5[CH:5]([O:4][C:2](=[O:3])[CH3:1])[CH2:6][C:7]6([CH3:31])[CH:8]([C:13]=5[C:21](=[O:22])[C:20]=4[OH:19])[CH2:9][CH2:10][CH:11]6[OH:12])[CH:26]([CH2:27][O:28][CH3:29])[O:25][C:23]3=[O:24])[CH2:40][CH2:39]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]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: C1CCN(C2CCNCC2)CC1
Solvent: ClCCl
Product: COCC1OC(=O)C(=CN2CCC(N3CCCCC3)CC2)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
17-Hydroxywortmannin (30 mg, 0.069 mmol) is dissolved in 2 ml methylene chloride and stirred at room temperature under nitrogen atmosphere as 4-piperidinopiperidine (0.069 mmol, 11.6 mg) is added. The reaction solution turns orange immediately. After 30 min, the solvent is evaporated and the solid is recrystallized from ethyl acetate/hexane (2:1). After filtration, the solid is washed with hexane and dried under vacuum to yield about 30 mg the title compound as an orange powder. UV λmax (CH3CN/H2O): 250 nm, 320 nm, 397 nm; Positive ESI-MS: m/z 599 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:17])([CH2:12][C@@H:13]([CH3:16])[CH2:14][CH3:15])[C:3](=[O:11])[CH2:4]P(=O)(OC)OC.O.[OH-].[Li+].[C:21]([O:24][C@@H:25]1[C@H:29]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[C@@H:28]([CH:40]=O)[C@H:27]([O:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][O:44]2)[CH2:26]1)(=[O:23])[CH3:22]>COC(C)(C)C.O>[C:21]([O:24][C@@H:25]1[C@H:29]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[C@@H:28](/[CH:40]=[CH:4]/[C:3](=[O:11])[C:2]([F:1])([F:17])[CH2:12][C@@H:13]([CH3:16])[CH2:14][CH3:15])[C@H:27]([O:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][O:44]2)[CH2:26]1)(=[O:23])[CH3:22]
Reactant: COC(=O)CCCCCC[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Reactant: CC[C@H](C)CC(F)(F)C(=O)CP(=O)(OC)OC
Agent: [Li+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: O
Product: CC[C@H](C)CC(F)(F)C(=O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
To a solution of dimethyl ((5S)-3,3-difluoro-5-methyl-2-oxoheptyl)phosphonate (A) (74.7 g, 274 mmol) in t-butyl methyl ether (1120 ml), lithium hydroxide monohydrate (11.5 g, 273 mmol) was added and the mixture was stirred for one hour at room temperature. A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyl-oxy)cyclopentyl]heptanate (B) (64.02 g, 160.6=1) in t-butyl methyl ether (278 ml) and water (21.7 ml) were added thereto, and the mixed solution was heat refluxed for approximately 31 hours (internal temperature: approximately 53° C.). After cooling to room temperature, water (351 ml) was added to the solution and the mixture was stirred, let to stand and then separated into two layers. The aqueous layer was extracted twice with ethyl acetate (234 ml). The organic layers were combined, washed twice with saturated aqueous sodium chloride (351 ml), and dried with anhydrous magnesium sulfate (55 g). After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300: 2110 g; ethyl acetate:hexane=1:4 to 1:2). The fractions containing impurities were re-purified by silica gel column chromatography (Fuji Silysia BW-300: 850 g; ethyl acetate:hexane=1:4 to 1:2) to give methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-(6S)-4,4-difluoro-6-methyl-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (C) (75.03 g; 137.8 mmol; yield: 85.8%) as a pale yellow oil.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C@H:5]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:6]([OH:8])=[O:7])[CH3:3].[NH2:20][C@H:21]([C:26]([OH:28])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24].CN(OC)[C:31](=[O:37])[C@H:32]([CH2:34][CH2:35][CH3:36])[NH2:33].[H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)[O-].[K+]>O1CCCC1.O>[CH3:3][CH:2]([CH2:4][C@H:5]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])[C:6]([OH:8])=[O:7])[CH3:1].[NH2:20][C@H:21]([C:26]([OH:28])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24].[NH2:33][C@H:32]([CH:31]=[O:37])[CH2:34][CH2:35][CH3:36]
Reactant: CCC[C@H](N)C(=O)N(C)OC
Agent: CC(C)C[C@H](N)C(=O)O
Agent: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: O=S(=O)([O-])O
Solvent: C1CCOC1
Solvent: O
Product: CCC[C@H](N)C=O
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
A solution of Z-L-leucine-L-leucine-L-norvaline N,O-dimethylhydroxylamide (1.09 g) was dissolved in 20 mL dry tetrahydrofuran (THF) and cooled to 0° C. Lithium aluminum hydride (1 M solution in THF, 3.05 mL) was added and the mixture was stirred at 0° C. for 25 minutes. Potassium bisulfate (465 mg) in 20 mL water was added and the mixture was extracted with EtOAc (3×80 mL). The combined organic layers were washed with aqueous 5% HCl, saturated NaHCO3, and brine, then dried over anhydrous MgSO4, filtered, and evaporated to afford the product (430 mg) as a white solid.