Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].COCCOC.[F:19][C:20]([F:26])([F:25])[S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[F:19][C:20]([F:26])([F:25])[S:21]([O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7])(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: O=C1c2ccccc2C(=O)N1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Yield: 84.2 %

Procedure:
N-Trifluoromethanesulfonyloxyphthalimide was prepared by the following procedure. To a dried flask equipped with a stirrer, under nitrogen, were added N-hydroxyphthalimide (3.04 g, 18.7 mmol), 60 mL of dried DME, and trifluoromethanesulfonyl chloride (2.00 mL, 18.7 mmol). The mixture was cooled to -15° and triethylamine (3.00 mL, 22 mmol) was added dropwise by syringe. After warming to room temperature, 100 mL of methylene chloride was added and the resulting mixture was washed with 100 mL of 2% aqueous sodium bicarbonate and dried. Evaporation of the solvent gave 4.65 g of crude N-trifluoromethanesulfonyloxyphthalimide: mp 90°-93°. Recrystallization from methylene chloride-hexane gave 2.65 g (48%) of product as shiny white flakes: mp 99°-102°; uv (CH3CN) 220 (47,000), 249 (2090), 297 nm (2290); ir (KBr) 1810 (m), 1750 (vs), 1440 (s), 1240 (s), 1230 (s), 1220 (s), 1115 (m), 940 (m), 860 (m), 695 (s), 585 (m); nmr (CDCl3) 8.10-7.85 (m); 19F nmr (CDCl3) -71.42 ppm (s); mass spectrum 294.9782 (calcd for C9H4NO5F3S: 294.9762).
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][C@@H:6]([CH:8]2[CH2:10][N@@:9]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])(=[O:13])=[O:12])[O:5][C:4]1=[O:23])[CH3:2].[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][C:35]([CH3:38])([CH3:37])[NH:34][CH2:33][C:32]1=[O:39]>C1(C)C=CC=CC=1>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[C:32](=[O:39])[CH2:33][N:34]([CH2:10][C@H:8]([NH:9][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])(=[O:13])=[O:12])[C@@H:6]2[CH2:7][C@@H:3]([CH2:1][CH3:2])[C:4](=[O:23])[O:5]2)[C:35]([CH3:38])([CH3:37])[CH2:36]1
Reactant: CC[C@@H]1C[C@@H](C2C[N@@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Reactant: CC1(C)CN(c2ccccc2Cl)C(=O)CN1
Agent: CC[C@@H]1C[C@@H](C2C[N@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Solvent: Cc1ccccc1
Product: CC[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3ccccc3Cl)CC2(C)C)NS(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Yield: 95.7 %

Procedure:
A solution of 916 mg of (3R,5S)-3-ethyl-5-[(S)-1-(2-nitrobenzenesulfonyl)aziridin-2-yl]dihydrofuran-2-one obtained in Example (106g) (2.69 mmol) and 771 mg of 1-(2-chlorophenyl)-5,5-dimethylpiperazin-2-one obtained in Example (1k) (3.23 mmol) in toluene (27 ml) was stirred at 110° C. for two hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/ethyl acetate=3/1-2/1) to obtain 1.49 g of the title compound (yield: 96%).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([CH2:39][C:40]2[S:44][C:43]([CH3:45])=[N:42][C:41]=2[CH3:46])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([CH2:39][C:40]2[S:44][C:43]([CH3:45])=[N:42][C:41]=2[CH3:46])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(C)n(Cc2sc(C)nc2C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2sc(C)nc2C)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 28.1 %

Procedure:
A mixture of hydroxylammonium chloride (2.9 g), sodium hydrogen carbonate (4.7 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-({4-butyl-1-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (1.33 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.49 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.41 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.42 g, 27%).
Reaction SMILES: [OH-].[NH4+:2].Cl.[C:4]([CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH3:20])([CH3:19])[C:11]1=[NH:21])(OCC)=[O:5]>C(O)C>[C:4]([CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH3:20])([CH3:19])[C:11]1=[NH:21])(=[O:5])[NH2:2]
Reactant: [NH4+]
Reactant: CCOC(=O)CN1C(=N)C(C)(C)c2ccccc21
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: CC1(C)C(=N)N(CC(N)=O)c2ccccc21

Procedure:
To a solution of 25 ml. of 32% ammonium hydroxide and 15 ml. of ethanol, 4.5 g. of 1-carbethoxymethyl-3,3-dimethyl-2-iminoindoline hydrochloride are added. After 15 hours the reaction mixture is evaporated to dryness and the residue is crystallized from chloroform giving 3,5 g. of the product of the title, melting at 167°-173° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10]([CH3:16])([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>COC(OC)N(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][C:12](=[CH:6][N:8]([CH3:13])[CH3:9])[C:11](=[O:14])[C:10]([CH3:16])([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C)(C)C1
Agent: COC(OC)N(C)C
Product: CN(C)C=C1CN(C(=O)OC(C)(C)C)CC(C)(C)C1=O
Temperature: 130 °C

Procedure:
3,3-Dimethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (5 g, 22 mmol) was dissolved in dimethyl formamide dimethylacetal (25 mL) and heated at reflux for 2 h. The reaction mixture was then heated to 130° C. for 1 h via microwave, and concentrated to give 6.43 g (quant.) as an oil which used without purification. 1H-NMR (CDCl3, 500 MHz) δ 1.07 (s, 6H), 1.45 (s, 9H), 3.06 (s, 6H), 3.37 (m, 2H), 4.57 (m, 2H), 7.41 (bs, 1H).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9](=[O:15])[CH2:10][C:11]([O:13]C)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)(=O)C.[Cl:32][C:33]1C(=O)C(Cl)=C(Cl)C(=O)C=1Cl.[ClH:44]>C1C=CC=CC=1.CN(C)C=O.O1CCOCC1>[ClH:32].[ClH:44].[C:1]1([C:7]2[N:29]([C:28]3[CH:30]=[CH:31][C:25]([N:22]4[CH2:23][CH2:24][NH:19][CH2:20][CH2:21]4)=[CH:26][CH:27]=3)[CH:33]=[C:10]([C:9](=[O:15])[CH:8]=2)[C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CC(=O)C=Cc1ccccc1
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: c1ccccc1
Product: O=C(O)c1cn(-c2ccc(N3CCNCC3)cc2)c(-c2ccccc2)cc1=O
Temperature: 25 °C

Procedure:
In 5 ml of benzene was dissolved 0.3 g of methyl 5-phenyl-3-oxo-4-pentenoate, and 0.2 g of N,N-dimethylformamidodimethylacetal was added to the solution. They were reacted at 60°-70° C. for 2 hours. The reaction mixture was cooled to room temperature, and 0.3 g of 4-(4-acetylpiperazino)-aniline was added thereto. The mixture was subjected to reaction at room temperature for 4 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the oily substance thus obtained was dissolved in 5 ml of N,N-dimethylformamide, and they were refluxed for 5 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue was purified by a column chromatography (Wako Silica Gel C-200; eluent: chloroform/ethanol (25:1 by volume) mixture). The fraction containing the objective substance was concentrated, and the oily substance thus obtained was dissolved in 4 ml of dioxane, and 0.12 g of 2,3,5,6-tetrachloro-p-benzoquinone was added thereto. They were reacted at 90°-100° C. for 30 minutes. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue was purified by a column chromatography (Wako Silica Gel C-200; eluent: chloroform/ethanol (100:3 by volume) mixture). The fraction containing the objective substance was concentrated, and to the crystals thus formed were added 3 ml of 6N hydrochloric acid, and the resulting mixture was refluxed for 2 hours. Water was removed by distillation under reduced pressure, to obtain 0.12 g of 6-phenyl-1-(4 -piperazinophenyl)-4-oxo-1,4-dihydronicotinic acid dihydrochloride having a melting point of 211°-213° C. (decomp.)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)=[CH:14][CH:13]=1)[C:6]([CH2:23][CH2:24][C:25]([OH:27])=O)=[C:5]2[CH3:28].O=S(Cl)Cl.[NH3:33]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)=[CH:14][CH:13]=1)[C:6]([CH2:23][CH2:24][C:25]([NH2:33])=[O:27])=[C:5]2[CH3:28]
Reactant: N
Reactant: Cc1c(CCC(=O)O)n(Cc2ccc(-n3ccnc3)cc2)c2ccc(F)cc12
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1c(CCC(N)=O)n(Cc2ccc(-n3ccnc3)cc2)c2ccc(F)cc12
Reaction time: 6 h

Procedure:
A suspension of 5-fluoro-1-[[4-(1H-imidazol-1-yl)phenyl]methyl]-3-methyl-1H-indole-2-propanoic acid (1.0 g) in DMF (10 ml) is treated with SOCl2 (0.5 g) and, after cooling a gaseous NH3 is passed through the reaction mixture for 6 hours. The ammonium salt is filtered off and ether is added to the solution. The so obtained precipitated is filtered and dried to give 0.8 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][CH:21]=1)[CH2:11][O:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C([O:25][C@@H:26]([C@@H:29]([C@@H:34]([C@H:39]([CH3:44])[O:40][C:41](=[O:43])[CH3:42])[O:35][C:36](=[O:38])[CH3:37])[O:30][C:31](=[O:33])[CH3:32])[CH:27]=O)(=O)C.B(F)(F)F.CCOCC.O>ClCCCl>[C:41]([O:40][C@H:39]1[C@H:34]([O:35][C:36](=[O:38])[CH3:37])[C@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:26]([CH3:27])[O:25][C@H:44]1[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][CH:21]=1)[CH2:11][O:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:43])[CH3:42]
Reactant: CC(=O)O[C@H]([C@H](OC(C)=O)[C@H](C)OC(C)=O)[C@@H](C=O)OC(C)=O
Reactant: CCOC(=O)COCc1cccc(-c2ccccc2O)c1
Agent: FB(F)F
Solvent: O
Solvent: CCOCC
Solvent: ClCCCl
Product: CCOC(=O)COCc1cccc(-c2ccccc2O[C@@H]2O[C@@H](C)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
Part C: Ethyl 3-(2-hydroxyphenyl)benzyloxyacetate (0.85 g, 2.97 mmol) was dissolved in 1,2-dichloroethane (25 ml) in a dry 50 ml flask. L-Fucose tetraacetate (1.97 g, 5.94 mmol) was added in one portion, then boron trifluoride etherate (1.86 ml, 14.84 mmol) was added slowly. The mixture was stirred under nitrogen overnight at room temperature then mixed with water (50 ml). The organic material was separated and the aqueous portion was extracted with dichloromethane (3×5 ml). The extracts were combined with the original organic fraction, dried (MgSO4) then concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, gradient elution hexane to 3:1 hexane/ethyl acetate) which provided 1.0 g (61%) of ethyl 3-(2-(2,3,4-tri-O acetyl-α-L-fucopyranosyloxy)phenyl)benzyloxyacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](C=C([N+]([O-])=O)C)=[CH:7][NH:8]2)=[CH:4][C:3]=1[F:17].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH:8][CH:9]([CH3:10])[CH3:5])=[CH:7][NH:8]2)=[CH:4][C:3]=1[F:17]
Reactant: CC(=Cc1c[nH]c2cc(Cl)c(F)cc12)[N+](=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)Nc1c[nH]c2cc(Cl)c(F)cc12
Temperature: 0 °C
Yield: 211.3 %

Procedure:
A solution of 6-chloro-5-fluoro-3-(2-nitro-propenyl)-1H-indole (5.0 g, 19.63 mmol) in tetrahydrofuran (10 mL) was added to the suspension of lithium aluminium hydride (2.92 g, 78.54 mmol) in tetrahydrofuran (20 mL) at 0° C. and then refluxed for 3 hours. The reaction mixture was cooled to 0° C., and quenched according to the Fischer method. The reaction mixture was filtered through celite and the filtrate concentrated to give 2-(6-chloro-5-fluoro-1H-indol-3-yl-1-methyl-ethylamine (4.7 g crude) as a viscous brown liquid. The residue was used without further purification. 1H NMR (500 MHz, CDCl3): δ 8.13 (s, 1H), 7.37 (d, 1H, 6.Hz), 7.32 (d, 1H, J=10 Hz), 7.08 (s, 1H), 3.23-3.26 (m, 1H), 2.77-2.81 (m, 1H), 2.58-2.63 (m, 1H), 1.15 (d, 3H, J=6.5 Hz).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](OS(C(F)(F)F)(=O)=O)=[C:5]([O:17][CH3:18])[CH:4]=1)=[O:2].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C)C=O>[CH3:18][O:17][C:5]1[CH:4]=[C:3]([CH:1]=[O:2])[CH:8]=[CH:7][C:6]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:20]([F:31])([F:30])[F:19]
Reactant: COc1cc(C=O)ccc1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)ccc1-c1ccccc1C(F)(F)F
Temperature: 120 °C
Yield: 73.3 %

Procedure:
A stirred solution of trifluoromethanesulfonic acid 4-formyl-2-methoxy-phenyl ester of Step A (6.9 g, 22.1 mmol), 2-trifluoromethyl phenyl boronic acid (5.4 g, 28.6 mmol) and potassium phosphate (13.2 g, 62.2 mmol) in N,N-dimethylformamide (120 mL) was degassed with nitrogen, whereupon a catalytic amount (0.285 g) of [1,4-bis-(diphenylphosphine)butane]palladium (II) dichloride was added. The solution was heated to 120° C. for 5 hours, poured into water and extracted with ethyl acetate. The combined extracts were washed with water, dried over anhydrous magnesium sulfate and filtered through a plug of silica gel. Removal of the solvent provided the crude title compound (4.54 g) as an oil, which was used as such in the next step.
Reaction SMILES: OC1ON=[C:4]([CH3:7])[C:3]=1[C:8]1[O:12][N:11]=[C:10]([CH3:13])[CH:9]=1.C(O)(=[O:16])C.CO.Cl>[Fe].O>[CH2:3]([C:8]1[O:12][N:11]=[C:10]([CH3:13])[CH:9]=1)[C:4]([CH3:7])=[O:16]
Reactant: CC(=O)O
Reactant: Cc1cc(-c2c(C)noc2O)on1
Agent: [Fe]
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(=O)Cc1cc(C)no1
Temperature: 60 °C

Procedure:
9.70 g of 5-hydroxy-3-methyl-4-(3-methylisooxazol-5-yl)isoxazole was added to 18 ml of acetic acid and 30 ml of methanol, and was heated to 60° C. to dissolve. To the resulting solution was added 3.20 g of electrolytic iron powder to stir for an hour at 60° C. 20 ml of 3N hydrochloric acid was further added to the reaction solution to stir for 20 minutes at 60° C. The reaction mixture was cooled to room temperature and water was added. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated salt water, dried over anhydrous magnesium sulfate and concentrated to give 6.00 g of the title compound as a reddish brown liquid.
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:22][NH:23][O:24][CH3:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C=O)C>[CH3:25][O:24][N:23]([CH3:22])[C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:8]=1[NH:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1Nc1ccccc1
Reactant: CNOC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccc(C(F)(F)F)nc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.9 %

Procedure:
In a 1 L pear-shaped flask, 2-phenylamino-6-trifluoromethyl-nicotinic acid (6.2 g, 22.0 mmol) was combined with DMF (120 mL) to give a dark brown solution. N,O-dimethylhydroxyl-amine hydrochloride (2.79 g, 28.6 mmol) and HBTU (13.3 g, 35.2 mmol) were added. N,N-diisopropylethylamine (8.88 g, 12 mL, 68.7 mmol) was added. The reaction mixture was stirred at 25° C. for 4 hr. The reaction mixture was diluted with methylene chloride (400 mL), washed with saturated NH4Cl (1×300 mL), saturated NaHCO3 (1×300 mL), and brine (1×200 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo to give 20.5 g of crude product as a brown oil. The crude material was purified by flash chromatography (silica gel, 250 g, 10% to 35% ethyl acetate-hexanes). Fractions containing the desired product were concentrated, treated with ether and concentrated again to give N-methoxy-N-methyl-2-phenylamino-6-trifluoromethyl-nicotinamide (6.86 g, 96%) as a brown oil which solidified on standing overnight at room temperature. 1H NMR (DMSO-d6) δ ppm 8.85 (s, 1H) 7.93 (d, J=7.5 Hz, 1H) 7.64 (d, J=7.8 Hz, 2H) 7.14-7.48 (m, 3H) 6.78-7.14 (m, 1H) 3.55 (s, 3H) 3.31 (s, 3H). MS calcd. for C15H14F3N3O2 [(M+H)+] 326.0, obsd. 326.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:26])[NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1)[CH3:9].[CH2:27]([O:29][C:30](=[O:48])[CH:31]([C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)[CH3:32])[CH3:28]>>[CH2:27]([O:29][C:30](=[O:48])[CH:31]([C:33]1[CH:38]=[CH:37][C:36]([C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:25])[C:13]=3[NH:12][C:11]([O:10][C@@H:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH3:9])=[O:26])=[CH:19][CH:20]=2)=[CH:35][CH:34]=1)[CH3:32])[CH3:28]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1F
Reactant: CCOC(=O)C(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)C(C)c1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3F)cc2)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-fluoro-phenyl)-ethyl ester and 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic acid ethyl ester were reacted to provide 2-(4′-{4-[(R)-1-(2-Fluoro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-propionic acid ethyl ester, which was hydrolyzed to the acid as described in Example 17, Step 3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH2:18])[CH:17]=1)=[CH:5]2.[C:21]([C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[S:32])[CH:27]=[CH:28][CH:29]=1)([OH:23])=[O:22].C(OCC)(=O)C>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH:18][C:31](=[S:32])[NH:30][C:26]3[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=3)[C:21]([OH:23])=[O:22])[CH:17]=1)=[CH:5]2
Reactant: O=C(O)c1cccc(N=C=S)c1
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NC(=S)Nc1cccc(C(=O)O)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
The product from Example 3, 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine, (0.274 g, 1.0 mmol) was mixed with 3-carboxyphenyl isothiocyanate (0.185 g, 1.0 mmol) in tetrahydrofuran (10 mL) and was heated briefly to 50° C. and then allowed to stand overnight at room temperature. The tetrahydrofuran was boiled off on the rotary evaporator (no vacuum) to give a solid. Ethyl acetate (10 mL) was added, and the mixture was allowed to stand overnight at room temperature. The insoluble material was collected by filtration, washed with ethyl acetate, and air-dried to give the product (0.379 g), mp 221-223° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[CH:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1.C([Li])CCC.[C:20]([C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1)([OH:22])=[O:21].O>C1COCC1>[OH:28][CH:27]([C:26]1[CH:25]=[CH:24][C:23]([C:20]([OH:22])=[O:21])=[CH:30][CH:29]=1)[C:13]#[C:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[S:5][CH2:4][CH2:3][C:2]2([CH3:14])[CH3:1]
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCS2
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CCSc2ccc(C#CC(O)c3ccc(C(=O)O)cc3)cc21
Reaction time: 0.5 h

Procedure:
2 g (9.9 mmol) of (4,4-dimethylthiochroman-6-yl) acetylene and 25 ml of THF were introduced into a three-necked flask under a stream of nitrogen, 4 ml (9.9 mmol) of an n-butyllithium solution (2.5M in hexane) were added dropwise at −50° C. and stirring was carried out for 30 min. A solution of 743 mg (4.9 mmol) of 4-carboxybenzaldehyde in 25 ml of THF was then added and stirring was carried out at room temperature for one hour. The reaction mixture was poured into water and extracted with ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue was recrystallized from diisopropyl ether. After filtration, 730 mg (42%) of the expected acid, with a melting point of 168°-169° C., were obtained.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH3:10]I>>[NH2:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(=O)O)s1
Reactant: CI
Product: COC(=O)c1ccc(N)s1
Yield: 114.5 %

Procedure:
5-Aminothiophene-2-carboxylic acid (1.00 g, 5.78 mmol) instead of 2-formylbenzoic acid and methyl iodide (1.44 mL, 23.1 mmol) instead of benzyl bromide were used to give the title compound (1.04 g; yield, 97%) as a dark brown solid according to the method described in Example 3a.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:17]([OH:20])[C:18]#[CH:19].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.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>[Cl:8][C:5]1[N:4]=[C:3]([NH:9][CH:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:2]([C:19]#[C:18][CH2:17][OH:20])=[CH:7][N:6]=1
Reactant: C#CCO
Reactant: Clc1ncc(Br)c(NC2CCCCCC2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCC#Cc1cnc(Cl)nc1NC1CCCCCC1
Yield: 56 %

Procedure:
To a yellow solution of 5-bromo-2-chloro-N-cycloheptylpyrimidin-4-amine (18.1 g, 55.5 mmol) in THF (200 mL) were added propargyl alcohol (4.5 mL, 1.4 equiv) and a solution of tetrabutylammonium fluoride in THF (1M, 130 mL, 2.3 equiv) and the resulting brown mixture was treated with a stream of nitrogen for 15 min (bubble in the solution). The mixture was then treated with bis(triphenylphosphine)palladium(II) chloride (2.09 g, 0.054 equiv) and heated to reflux for 5 h. After cooling, the reaction mixture was filtered through a pad of celite (rinsed with EtOAc ˜350 mL). The filtrate was concentrated to remove THF, further diluted with EtOAc (total volume 250 mL), washed with sat. NaHCO3 (2×150 mL) and water (150 mL), dried over Na2SO4, filtered and concentrated. Titration of the residue in acetone and CH2Cl2 provided 3-(2-chloro-4-(cycloheptylamino)pyrimidin-5-yl)prop-2-yn-1-ol (8.65 g) in 56% yield. 1H NMR (400 MHz, CD3OD) δ 7.98 (s, 1H), 4.45 (s, 2H), 4.19 (septet, J=4.5 Hz, 1H), 1.95 (m, 2H), 1.77-1.52 (m, 10Hz); MS m/z 280.4 (M+H)+