Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.[NH2:19][CH2:20][CH2:21][NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:19][CH2:20][CH2:21][NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCCNS(=O)(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(NCCNS(=O)(=O)c2ccc(Cl)cc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, N-(2-aminoethyl)-p-chlorobenzenesulfonamide hydrochloride and DBU in DME. ES-MS m/e (%): 419 (M+H+, 100).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH3:7])[CH2:5][OH:6].[Br:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11](F)[CH:10]=1>CN(C)C=O>[Br:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([O:6][CH2:5][CH:4]([CH3:7])[CH3:3])[CH:10]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: CC(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)COc1cc(Br)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a suspension of sodium hydride (60% w/w, 20.5 g) in N,N-dimethylformamide (365 ml) was added 2-methyl-1-propanol (48.7 ml) dropwise below 30° C. over 2 hours under nitrogen atmosphere. To the mixture was added 4-bromo-2-fluorobenzoic acid (50.0 g) slowly below 35° C. To the reaction mixture was added N,N-dimethylformamide (600 ml) and the mixture was stirred at room temperature for 4 days. The reaction mixture was partitioned between water (2000 ml) and hexane (1000 ml). The water layer was separated and acidified with 37% hydrochloric acid. The precipitate was collected by filtration, washed with water and dried at 55° C. to give 4-bromo-2-isobutoxybenzoic acid (62.4 g) as a white solid.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[Br:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13](Cl)[CH:12]=1>C1COCC1>[Br:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([O:3][CH:4]2[CH2:9][CH2:8][O:7][CH2:6][CH2:5]2)[CH:12]=1
Reactant: Clc1cc(Br)ccn1
Reactant: OC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1ccnc(OC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of NaH (0.4 g, 10 mmol) in THF (20 ml) at 0° C. was added 4-hydroxytetrahydropyran (1.02 ml, 10 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 30 mins before 4-bromo-2-chloropyridine (0.89 ml, 8.0 mmol) was added dropwise. The reaction mixture was stirred for 18 h before being quenched with EtOH (1 ml), partitioned between CH2Cl2 and H2O and extracted CH2Cl2 (×2). The organics were combined, dried (MgSO4) and the solvent removed in vacuo. Purified by column chromatography to afford 4-bromo-2-(tetrahydro-pyran-4-yloxy)-pyridine MS: [MH]+ 258, 260
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:26])[CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([C:22]([F:25])([F:24])[F:23])=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)=[O:10]>C1COCC1.CO.O>[C:16]1([N:14]2[CH:15]=[C:11]([C:9]([NH:8][CH2:7][CH2:6][C:5]([OH:26])=[O:4])=[O:10])[C:12]([C:22]([F:24])([F:25])[F:23])=[N:13]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)CCNC(=O)c1cn(-c2ccccc2)nc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCNC(=O)c1cn(-c2ccccc2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 98 %

Procedure:
NaOH (212.1 mg, 5.3 mmol) was added to 3-[(1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)amino]propionic acid methyl ester (181 mg, 0.53 mmol) dissolved in THF/MeOH/water (25 mL, 4:2:1). The reaction mixture was stirred at 25° C. for 5 hours and concentrated under vacuum. The residue was acidified with 1M HCl up to pH 2 and extracted with ethyl acetate. The extract was washed with brine and dried with anhydrous sodium sulfate and concentrated under vacuum to obtain the desired compound (170 mg, 98%) as a white solid.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[C:20]([OH:22])=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl[CH2:27][C:28]1[N:29]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:31][C:32]=1[CH3:33]>O1CCOCC1>[CH3:33][C:32]1[O:31][C:30]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[N:29][C:28]=1[CH2:27][S:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[C:20]([OH:22])=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: O=C(O)[C@H]1Cc2ccccc2N1S(=O)(=O)c1ccc(S)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1CSc1ccc(S(=O)(=O)N2c3ccccc3C[C@@H]2C(=O)O)cc1
Reaction time: 1.5 h
Yield: 80.4 %

Procedure:
To a solution of the title D compound, (R)-1-(4-mercapto-benzenesulfonyl)-2,3-dihydro-1H-indole-2-carboxylic acid (0.56 g, 1.67 mmol) in dioxane (8 mL) is added 1N aqueous sodium hydroxide (3.4 mL) and water (2 mL) at room temperature. The resulting solution is treated dropwise with a solution of 4-chloromethyl-5-methyl-2-phenyl-oxazole (0.423 g, 2.04 mmol) in dioxane (4 mL). After stirring 1.5 hours, the reaction mixture is concentrated to near dryness in vacua. The residue is taken into water, the aqueous phase is washed with ether, acidified with 2N aqueous hydrochloric acid and extracted into ethyl acetate. The combined organic phases are washed with water, brine and dried over sodium sulfate. The organic phase is concentrated in vacuo and dried overnight at high vacuum to give 0.68 g of (R)-1-[4-(5-methyl-2-phenyl-oxazol-4-ylmethylsulfanyl)-benzenesulfonyl]-2,3-dihydro-1H-indole-2-carboxylic acid as gum: [M−1]−=504.9.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=1.C([Li])CCC.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1)[CH:23]=[O:24].COC1C=C(C(C2C=CC=C(OC)C=2)=CC#N)C=C(OC)C=1>>[CH3:29][O:28][C:26]1[CH:25]=[C:22]([CH:23]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=2)[OH:24])[CH:21]=[C:20]([O:19][CH3:18])[CH:27]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: CCOc1cc(Br)ccc1OC
Agent: COc1cccc(C(=CC#N)c2cc(OC)cc(OC)c2)c1
Agent: [Li]CCCC
Product: CCOc1cc(C(O)c2cc(OC)cc(OC)c2)ccc1OC
Yield: 79.7 %

Procedure:
4-bromo-2-ethoxy-1-methoxybenzene (0.66 g, 2.86 mmol), n-butyl lithium (1.14 ml, 2.86 mmol), and 3,5-dimethoxybenzaldehyde (0.43 g, 2.60 mmol) were treated in the same manner as described above for the synthesis of 3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The crude was purified via flash colurn chromatography (20% EtOAc in hexane gradient to 50% EtOAc in hexane in about 40 min.) to give (3,5-dimethoxy-phenyl)-(3-ethoxy-4-methoxy-phenyl)-methanol as an off-white solid (0.66 g, 80%): 1HNMR (CDCl3) δ 6.92-6.80 (m, 3H, Ar), 6.54 (d, J=2 Hz, 2H, Ar), 6.36 (t, J=2 Hz, 1H, Ar), 5.70 (d, J=3 Hz, 1H, CHOH), 4.07 (q, J=6 Hz, 2H, CH2CH3), 3.85 (s, 3H, OCH3), 3.76 (s, 6H, 2OCH3), 2.19 (d, J=3 Hz, 1H, OH), 1.44 (t, J=7 Hz, 3H, CH2CH3). The product was carried over to the next step.
Reaction SMILES: N#N.[Br:3][C:4]1[C:11]([F:12])=[CH:10][C:7]([CH2:8][OH:9])=[C:6]([F:13])[CH:5]=1.CCN(CC)CC.[S:21](Cl)([CH3:24])(=[O:23])=[O:22]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:24][S:21]([O:9][CH2:8][C:7]1[CH:10]=[C:11]([F:12])[C:4]([Br:3])=[CH:5][C:6]=1[F:13])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cc(F)c(Br)cc1F
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cc(F)c(Br)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-bromo-2,5-difluorobenzyl alcohol (160 mg, 0.72 mmol) in dry CH2Cl2 (4 mL) was treated at 0° C. with Et3N (0.13 mL, 0.93 mmol) followed by DMAP (9 mg, 0.07 mmol) and Ms-Cl (0.06 mL, 0.75 mmol). After stirring at 0° C. for 0.5 h and at rt for 1 h, the reaction was quenched with water (3 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude (4-bromo-2,5-difluorophenyl)methyl methanesulfonate as a yellow oil. This material was dissolved in dry DMF (3 mL) and treated with NaN3 (51 mg, 0.78 mmol) at 80° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 1-(azidomethyl)-4-bromo-2,5-difluorobenzene as a yellow oil. LC-MS-conditions 07: tR=0.89 min.
Reaction SMILES: C([O:5][C:6](=[O:13])[C@H:7]([CH2:9][CH2:10][CH2:11][CH3:12])[NH2:8])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl.C1C=CC=CC=1>[NH2:8][C@H:7]([C:6]([OH:13])=[O:5])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCC[C@H](N)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccccc1
Solvent: ClCCl
Product: CCCC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
358 mg of the isomer having a high Rf value of L-N-[(2S or R)-2-ethylsulfonylmethyl-4-methylpentanoyl]norleucine tert-butyl ester was dissolved in dry dichloromethane, and 1.5 ml of TFA was added thereto. The reaction solution was stirred at room temperature for 1.5 hours, and then concentrated under reduced pressure to obtain a syrup. The syrup was dissolved in benzene, and the solution was concentrated under reduced pressure. This operation was repeated. The syrup was crystallized from diethyl ether/n-hexane, and evaporated under reduced pressure to dryness to obtain 312 mg of L-N-[(2S or R)-2-ethylsulfonylmethyl-4-methylpentanoyl]norleucine as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:12][NH2:13].[CH3:14][C@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)[CH2:16]1>>[Br:8][C:6]1[CH:5]=[N:4][C:3]2[C:9](=[O:11])[N:13]([CH3:12])[C:29]([C:28]3[CH:31]=[CH:32][C:25]([O:24][CH2:23][CH2:22][CH2:21][N:17]4[CH2:18][CH2:19][CH2:20][C@H:15]([CH3:14])[CH2:16]4)=[CH:26][CH:27]=3)=[N:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Br)cnc1C(=O)O
Reactant: CN
Reactant: C[C@H]1CCCN(CCCOc2ccc(C=O)cc2)C1
Product: C[C@H]1CCCN(CCCOc2ccc(-c3nc4cc(Br)cnc4c(=O)n3C)cc2)C1

Procedure:
The entitled compound was obtained according to the method of Example 15 but starting from 3-amino-5-bromopyridine-2-carboxylic acid, methylamine and 4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}benzaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:17]=[C:16]([NH2:18])[S:15][C:5]=2[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.Cl[CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.C(N(C(C)C)C(C)C)C.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>ClCCCl.C1COCC1>[CH3:1][O:2][C:3]1[C:4]2[N:17]=[C:16]([NH:18][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][C:21]([CH2:20][N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[CH:22][CH:23]=3)[S:15][C:5]=2[C:6]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[N:7][CH:8]=1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Reactant: C1COCCN1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)c3ccc(CN4CCOCC4)cc3)nc12

Procedure:
From 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine with 4-(chloromethyl)benzoyl chloride and N-ethyldiisopropylamine in 1,2-dichloroethane and THF; then subsequent treatment with morpholine. ES-MS m/e (%): 470 (M+H+, 100).
Reaction SMILES: [CH2:1]([NH:4][CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7])[CH:2]=[CH2:3].[Br:10][C:11]1[C:12](Cl)=[N:13][C:14]([Cl:17])=[N:15][CH:16]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[CH2:1]([N:4]([C:12]1[C:11]([Br:10])=[CH:16][N:15]=[C:14]([Cl:17])[N:13]=1)[CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7])[CH:2]=[CH2:3]
Reactant: C=CCNC(CC)CC
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCN(c1nc(Cl)ncc1Br)C(CC)CC
Reaction time: 8 h
Yield: 173.2 %

Procedure:
To a solution of allyl-(1-ethyl-propyl)-amine (1.27 g, 10 mmol) is added anhydrous isopropanol (50 mL) and 5-bromo-2,4-dichloropyrimidine (3.0 g, 5 mmol) and diisopropylethylamine (2.61 mL, 15 mmol) at ambient temperature. The reaction mixture is stirred overnight and concentrated in vacuo. The residue is purified with column chromatography (SiO2, EtOAC/hexane 1:5) to give 2.76 g of allyl-(5-bromo-2-chloro-pyrimidin-4-yl)-(1-ethyl-propyl)-amine.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[S:12])=[CH:6][CH:5]=1)(O)=[O:2].S(Cl)([Cl:15])=O>>[N:10]([C:7]1[CH:8]=[CH:9][C:4]([C:1]([Cl:15])=[O:2])=[CH:5][CH:6]=1)=[C:11]=[S:12]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(N=C=S)cc1
Product: O=C(Cl)c1ccc(N=C=S)cc1
Yield: 93 %

Procedure:
A mixture of 500 mg (2.79 mmol) of 4-carboxyphenyl-isothiocyanate and 5 mL of thionyl chloride was refluxed for 6 hours. The reaction mixture was concentrated at reduced pressure and the resulting tan solid was pumped at high vacuum overnight. The solid was triturated with a small amount of hexane and collected by suction filtration to yield 516 mg (93%) of 6 as an off-white solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[OH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH:17][C:14]2[CH:15]=[C:16]3[C:11]([CH:10]=[N:9][N:8]3[CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:12][CH:13]=2)=[O:27])=[CH:21][CH:20]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: Nc1ccc2cnn(CCN3CCCC3)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccc(O)cc1)Nc1ccc2cnn(CCN3CCCC3)c2c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-ylamine (0.620 g, 2.69 mmol), (4-hydroxy-phenyl)-acetic acid (0.242 g, 5.15 mmol), HATU (1.23 g, 3.23 mmol) and diisopropylethylamine (0.939 mL, 5.39 mmol) in 9 mL of DMF was stirred at room temperature for 6 hours, concentrated under reduced pressure and the residue dissolved in ethyl acetate and washed with aqueous NaHCO3 (×3), brine (×2), and water. The organic layer was dried (Na2SO4), filtered, concentrated under reduced pressure and the residue purified by flash chromatography (60–90% ethyl acetate (1% triethylamine) in hexanes) to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.62 (m, 4 H), 2.45 (m, 4 H), 2.83 (t, J=6.78 Hz, 2 H), 3.53 (d, J=5.76 Hz, 2 H), 4.38 (t, J=6.78 Hz, 2 H), 6.71 (m, 2 H), 7.13 (m, 3 H), 7.64 (m, 1 H), 7.94 (s, 1 H), 8.13 (m, 1 H), 9.25 (s, 1 H), 10.24 (s, 1 H); MS (ESI) m/z 365 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]([C:11](O)=[O:12])[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22].[CH:23]([O:25][CH2:26][CH2:27][O:28][NH2:29])=[CH2:24]>>[F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([NH:29][O:28][CH2:27][CH2:26][O:25][CH:23]=[CH2:24])=[O:12])[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22]
Reactant: C=COCCON
Reactant: O=C(O)c1cc2snnc2c(F)c1Nc1ccc(I)cc1F
Product: C=COCCONC(=O)c1cc2snnc2c(F)c1Nc1ccc(I)cc1F

Procedure:
4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylic acid can be reacted with O-(2-(vinyloxy)ethyl)hydroxylamine in the presence of coupling reagent in appropriate solvent. The reaction is generally carried out at ambient temperature and normally complete within several hours (1-12 h, prefer 3-10 h). 4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide is obtained after conventional workup.
Reaction SMILES: [CH2:1]([C:5]1[O:9][N:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:6]=1)[CH:2]([CH3:4])[CH3:3].[I:14]N1C(=O)CCC1=O>FC(F)(F)C(O)=O>[I:14][C:6]1[C:7]([C:10]([O:12][CH3:13])=[O:11])=[N:8][O:9][C:5]=1[CH2:1][CH:2]([CH3:4])[CH3:3]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1cc(CC(C)C)on1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1noc(CC(C)C)c1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
A mixture of methyl 5-isobutylisoxazole-3-carboxylate (0.923 g, 5.04 mmol) and N-iodosuccinimide (1.247 g, 5.54 mmol) in trifluoroacetic acid (25 mL) was stirred at room temperature overnight. By HPLC, the reaction was complete. The trifluoroacetic acid was removed under reduced pressure, and the residue was diluted with dichloromethane (100 mL), washed with a saturated aqueous solution of sodium bicarbonate (2×25 mL), washed with a 2.5% aqueous solution of sodium bisulfate (25 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by flash silica gel chromatography using a 5% mixture of ethyl acetate in hexane afforded methyl 4-iodo-5-isobutylisoxazole-3-carboxylate (1.21 g, 3.91 mmol, 78% yield) as a pale yellow oil. The product had an HPLC ret. time=2.40 min.-Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=310.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[C:26]([F:33])[CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[C:4]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=3)[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[C:26]([F:33])[CH:25]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: O=C(Nc1cnc(OCC(F)(F)F)c(Br)c1)c1cccnc1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2F)c1)c1cccnc1

Procedure:
The title compound was synthesized in analogy to Example 39, using N45-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-nicotinamide (example G) and B-(4-chloro-2-fluorophenyl)-boronic acid (CAN 160591-91-3) as starting materials; LC-MS (UV peak area/ESI) 97.2%, 424.0483 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15]C(NC3C=CC(CC)=CC=3)=O)=[CH:11][CH:10]=2)[CH:3]=1.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]=[C:36]=[O:37])[CH:30]=1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:36]([NH:35][C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([C:28]([F:38])([F:39])[F:27])[CH:30]=3)=[O:37])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CCc1ccc(NC(=O)Nc2ccc(Cc3cc(N)ncn3)cc2)cc1
Solvent: CN(C)C=O
Product: Nc1cc(Cc2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)ncn1
Reaction time: 4 h

Procedure:
The title compound is prepared as described in Example 102 but using 6-(4-aminobenzyl)-pyrimidin-4-ylamine (see Example 157), α,α,α-trifluoro-m-tolyl-isocyanate, and DMF as the solvent. The reaction mixture is stirred for 4 h. The crude product is washed with a CH2Cl2/MeOH (99/1) solution. The title compound is obtained as a white solid: ES-MS: 387.9 [M+H]+; single peak at tR=7.12 min (System 2); Rf=0.23 (CH2Cl2/MeOH, 90/10).
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[CH3:15][CH2:16][C@H:17]([OH:49])[C@H:18]([C@H:20]1[O:22][C@@H:21]1[CH2:23][C@@H:24](/[CH:26]=[CH:27]/[CH:28]=[C:29](/[C@H:31]1[O:43][C:41](=[O:42])[CH2:40][C@H:39]([OH:44])[CH2:38][CH2:37][C@:36]([OH:46])([CH3:45])[C@@H:35]([OH:47])[CH2:34][CH2:33][C@@H:32]1[CH3:48])\[CH3:30])[CH3:25])[CH3:19].C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:15][CH2:16][C@H:17]([OH:49])[C@H:18]([C@H:20]1[O:22][C@@H:21]1[CH2:23][C@@H:24](/[CH:26]=[CH:27]/[CH:28]=[C:29](/[C@H:31]1[O:43][C:41](=[O:42])[CH2:40][C@H:39]([OH:44])[CH2:38][CH2:37][C@:36]([OH:46])([CH3:45])[C@@H:35]([O:47][C:8]([CH3:9])=[O:10])[CH2:34][CH2:33][C@@H:32]1[CH3:48])\[CH3:30])[CH3:25])[CH3:19]
Reactant: CC[C@H](O)[C@@H](C)[C@H]1O[C@@H]1C[C@H](C)/C=C/C=C(\C)[C@H]1OC(=O)C[C@H](O)CC[C@@](C)(O)[C@@H](O)CC[C@@H]1C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](O)[C@@H](C)[C@H]1O[C@@H]1C[C@H](C)/C=C/C=C(\C)[C@H]1OC(=O)C[C@H](O)CC[C@@](C)(O)[C@@H](OC(C)=O)CC[C@@H]1C
Temperature: 0 °C
Yield: 82 %

Procedure:
Triethylamine (17.2 μl, 123 μmol), acetic anhydride (5.83 μl, 616 μmol) and 4-dimethylaminopyridine (1.50 mg, 12.3 μmol) were added to anhydrous dichloromethane (2.00 ml) solution of pladienolide A (30.5 mg, 61.6 μmol) under stirring at 0° C. After the reaction solution was stirred at 0° C. for one hour, it was poured into a saturated sodium hydrogen carbonate aqueous solution, which was then extracted with ethyl acetate. After the organic layer was washed with brine, it was dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Kanto Chemical, commercial name Silica gel 60N, granular, neutral, 0.040 mm-0.100 mm; n-heptane:acetone=3:1→2:1) to obtain the title compound (27.2 mg) as a colorless oil. This was obtained as a white amorphous by purifying by HPLC (Shiseido, commercial name CAPCELL PAK C18SG120; acetonitrile:water=45:55) followed by performing lyophilization.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH2:16])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[B-](F)(F)(F)F.[CH3:26][CH2:27][O+](CC)CC>C(Cl)Cl>[CH2:1]([O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](=[NH:16])[O:15][CH2:26][CH3:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1ccccc1C(N)=O
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCOc1ccccc1C(=N)OCC
Reaction time: 8 h

Procedure:
2-Decyloxybenzamide (38.4 g.) was added to a solution of triethyloxonium borofluoride (30 g.) in anhydrous methylene chloride (90 ml.), and the mixture allowed to stand at room temperature overnight. The solution was concentrated to about 30 ml., diluted with anhydrous diethyl ether (150 ml.), and filtered to give ethyl 2-decyloxybenzimidate borofluoride (45.5 g.), m.p. 93°-96° C., pure enough for use in the next stage. An aliquot was recrystallised from a mixture of anhydrous methylene chloride and anhydrous diethyl ether to give pure ethyl 2-decyloxybenzimidate borofluoride, m.p. 96.5°-98.5° C.
Reaction SMILES: C([Si](C(C)C)(C(C)C)[N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)(C)C.C1COCC1.O.C([O-])([O-])=O.[K+].[K+]>CCO>[CH:23]([Si:16]([CH:17]([CH3:19])[CH3:18])([CH:20]([CH3:22])[CH3:21])[O:15][CH2:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[NH:5][CH:6]=[CH:7]2)([CH3:25])[CH3:24]
Reactant: CC(C)[Si](OCc1ccc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1)(C(C)C)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(C)[Si](OCc1ccc2[nH]ccc2c1)(C(C)C)C(C)C
Temperature: 85 °C

Procedure:
To a suspension of 1-triisopropylsilanyl-5-triisopropylsilanyloxymethyl-1H-indole (2.80 g, 6.09 mmol) in EtOH (30 mL)/THF (10 mL)/water (10 mL) was added K2CO3 (4.21 g, 30.4 mmol), and the reaction mixture was heated at 85° C. for 16 h. The reaction was quenched with 1N HCl at 0° C. The aqueous layer was extracted with CH2Cl2 (2×) and the combined organic layers were washed with brine, dried (phase separator) and concentrated under reduced pressure. The oily residue was purified by flash column chromatography on silica gel (eluent gradient: c-hexane to c-hexane/EtOAc 9:1) to afford the title compound as a yellow oil. TLC, Rf (c-hexane/EtOAc 9:1)=0.29. tR (HPLC conditions k): 5.02 min. MS (LC/MS): 304 [M+H]+.