Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][C:7]1([CH3:13])[CH2:10][C:9]([F:12])([F:11])[CH2:8]1)(=O)=O.[C-:14]#[N:15].[Na+]>CS(C)=O.O>[F:11][C:9]1([F:12])[CH2:10][C:7]([CH2:6][C:14]#[N:15])([CH3:13])[CH2:8]1
Reactant: CC1(COS(C)(=O)=O)CC(F)(F)C1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(CC#N)CC(F)(F)C1
Temperature: 80 °C
Reaction time: 12 h
Yield: 73.8 %

Procedure:
To a solution of Intermediate 229B (200 mg, 0.934 mmol) in DMSO (3 mL) was added NaCN (114 mg, 2.334 mmol) at RT and the reaction mixture was heated to 80° C. and stirred for 12 h. The reaction mixture was cooled to RT, was diluted with water and was extracted with EtOAc (3×10 mL) To the combined organic layer was washed with water and brine, dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography (12 g REDISEP® column, eluting with 30% EtOAc in petroleum ether). Fractions containing the product were combined and evaporated to afford Intermediate 229C as a brown oil (100 mg, 74%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.56-2.42 (m, 6H), 1.17 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[CH3:12][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=1[CH3:1]
Reactant: Cc1ccc(C)c(C(=O)O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)ccc1C
Temperature: 25 °C
Yield: 97.6 %

Procedure:
Into a suspension of 75 g (499 mmol) 2,5-dimethylbenzoic acid, 103 g (748 mmol) potassium carbonate in 500 mL of DMF was added dropwise 77.9 g (549 mmol) of iodomethane with stirring at ambient temperature. After addition, the suspension was stirred for additional 5 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. All solids were removed by filtration and the filtrate was concentrated to 80 g of colorless oil as product in 97.6% yield. 1H NMR (CDCl3) (300 MHz) δ 2.7 (s, 3H), 2.8 (s, 3H), 3.95 (s, 3H), 7.45 (s 1H), 7.51 (d, 3JHCCH=7.9 Hz, 1H), 7.42 (d, 3JHCCH=7.9 Hz, 1H)
Reaction SMILES: C(O[CH:5]([CH2:11][CH:12]([CH3:24])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:23])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[CH:6]([N+:8]([O-:10])=[O:9])[CH3:7])(=O)C.CC(C)([O-])C.[K+].CCOCC.O>C(O)(C)(C)C>[CH3:24][CH:12]([CH2:13][CH2:14][CH:15]=[C:16]([CH3:23])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[CH2:11][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH3:7]
Reactant: CC(=O)OC(CC(C)CCC=C(C)CCC=C(C)C)C(C)[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)=CCCC(C)=CCCC(C)CC=C(C)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.4 %

Procedure:
A solution of 1.30 g of 5 in 25 mL of t-butyl alcohol was added to a solution of 30 mL of t-butyl alcohol containing 0.53 g of potassium t-butoxide. The reaction mixture was stirred at room temperature for 1 h, whereupon it was added to 150 mL of ether and 20 mL of H2O. The organic layer was separated and dried over MgSO4, and the solvent was removed by rotary evaporation to afford 0.40 g of racemic RG-4, predominantly the (E)-isomer. 1H NMR δ (ppm) 7.18 (t, CH═CNO2), 5.2 (t, CH3C(CH3)═CH and CH2C(CH3)═CH), 2.19 (s, C═C(CH3)NO2), 2.0 (m, C═CHCH2CH2C(CH3)═CHCH2), 2.2-2.3 (m, CH2C═CNO2), (CH3C═(CH3), 1.6-1.7 (all s, CH3C(CH3)═CHCH2CH2CCH3), 1.2-1.5 (m, CH2CH(CH3)CH2), 0.95 (d, CH2CH(CH3)CH2).
Reaction SMILES: Cl[C:2]([O:4][C@@H:5]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])=[O:3].[CH:20]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>O1CCCC1>[CH:20]1([NH:26][C:2]([O:4][C@@H:5]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[O:3])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NC1CCCCC1
Reactant: CC(C)C[C@H](OC(=O)Cl)C(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: CC(C)C[C@H](OC(=O)NC1CCCCC1)C(=O)OCc1ccccc1
Reaction time: 0.17 h
Yield: 65.9 %

Procedure:
To a solution of benzyl (2S)-2-chlorocarbonyloxy-4-methylvalerate (0.56 g) in tetrahydrofuran (11 ml) was added cyclohexylamine (0.40 g) at room temperature. After being stirred for 10 minutes, the solvent was removed by evaporation under reduced pressure, and the residue was dissolved in ethyl acetate (30 ml). The solution was washed with 1N HCl, water and brine successively. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residual solid was triturated with hexane to give benzyl (2S)-2-cyclohexylcarbamoyloxy-4-methylvalerate (0.45 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.[C:19](OCC)(=[O:21])[CH3:20].S([O-])([O-])(=O)=O.[Mg+2].C(O)(=O)CO>Cl.[Pt]>[CH3:17][CH:16]([CH3:18])[CH2:15][N:14]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:1]=[C:20]1[CH2:19][OH:21]
Reactant: CC(C)CNc1c([N+](=O)[O-])cnc2ccccc12
Reactant: CCOC(C)=O
Agent: [Pt]
Agent: Cl
Agent: O=C(O)CO
Product: CC(C)Cn1c(CO)nc2cnc3ccccc3c21
Temperature: 155 °C
Yield: 89.6 %

Procedure:
3-Nitro-4-(2-methylpropylamino)quinoline (36.8 g; 0.15 mol) was added to a mixture of ethyl acetate (300 mL), 5% Pt/C (about 1 g), and magnesium sulfate (30 g). The mixture was hydrogenated at about 50 psi initial pressure. When hydrogenation was complete the solids were filtered from the mixture and the ethyl acetate was evaporated. The resulting intermediate diamine was mixed with glycolic acid (26.9 g; 0.35 mol) and the mixture was heated at 150-160° C. for about 3 hr with occasional manual stirring. The reaction mixture was then dissolved in dilute hydrochloric acid and treated with decolorizing carbon, and the solids were filtered from the mixture. The filtrate was made basic with ammonium hydroxide to precipitate the product as a greenish solid. The solid was filtered and dried to give 34.3 g (89.6%) of crude product. The solid was reprecipitated a second time as above and the product recrystallized from ethyl acetate to give greenish crystals, m.p. 165-168° C. Analysis: Calculated: C, 70.6; H, 6.7; N, 16.5. Found: C, 70.4, H, 6.7; N, 16.3.
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][O:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11]#[N:12].C(=O)([O-])[O-].[K+].[K+].[C:19]1([CH:25]([CH2:29][CH3:30])[C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OCC)C>[C:11]([C:3]1[C:4]2[CH2:9][CH2:8][O:7][CH2:6][C:5]=2[S:10][C:2]=1[NH:1][C:26](=[O:27])[CH:25]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:29][CH3:30])#[N:12]
Reactant: N#Cc1c(N)sc2c1CCOC2
Reactant: CCC(C(=O)Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCC(C(=O)Nc1sc2c(c1C#N)CCOC2)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66 %

Procedure:
To a stirred suspension of 2-Amino-3-cyano-4,7-dihydro-5H-thieno[2,3-c]pyran (361 mg; 2.0 mmol; prepared as described in Example 2, Step 1) and potassium carbonate (1.40 g; 10.1 mmol) in diethylether (6.0 mL) was added 2-phenylbutyryl chloride dropwise. The resulting mixture was stirred at room temperature for 24 h. The solvent was then removed in vacuo, the residue taken up into methylene chloride and washed with water. The organic layer was dried (sodium sulfate) filtered and concentrated in vacuo to give crude product which was triturated with diethyl ether to provide 428 mg (66%) of N-(3-Cyano-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-2-phenyl-butyramide as a beige colored solid. EI-HRMS m/e calcd for C18H18N2O2S (M+) 326.1809, found 326.1809.
Reaction SMILES: [NH2:1][CH:2]([C:10]([OH:12])=[O:11])[CH2:3][CH:4]=[CH:5][CH2:6][C:7]([OH:9])=[O:8].[OH-].[Na+]>C(O)C>[NH2:1][CH:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH:5]=[CH:6][C:7]([OH:9])=[O:8]
Reactant: NC(CC=CCC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(CCC=CC(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1 g of the product of Step D were dissolved in 10 ml of ethanol and 5.1 ml of a 2N solution of sodium hydroxide were added. The mixture was stirred for 16 hours at ambient temperature and the mixture was evaporated to dryness under reduced pressure. The product obtained was neutralized with resin Dowex 50 W×8 and the fractions containing the desired product were evaporated to dryness. A product was obtained which was lyophilized in 150 ml of filtered, double distilled water to obtain 660 mg of the expected product with a Rf=0.5 in a BuOH--AcOH--H2O mixture (4-2-2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C[O:16][C:17](=O)[CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[F:31])[C:19](=O)[CH2:20][CH3:21].O1CCOCC1.C([O-])(=O)C.[Na+]>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:17](=[O:16])[C:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[F:31])=[C:19]([CH2:20][CH3:21])[NH:13]2
Reactant: COC(=O)COc1ccc(F)c(N)c1
Reactant: CCC(=O)C(Cc1ccc(F)cc1F)C(=O)OC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(F)cc1F
Temperature: 130 °C

Procedure:
A mixture of (3-amino-4-fluorophenoxy)acetic acid methyl ester (0.5 g), 2-(2,4-difluorobenzyl)-3-oxopentanoic acid methyl ester (0.64 g), polyphosphoric acid (2.5 mL) and dioxane (10 mL) was heated at 130° C. for 17 hours. The mixture was diluted with water and the pH adjusted to 4 by the addition of sodium acetate. The resulting precipitate was collected by filtration, washed with water and dried to give title compound as a creamy solid, 0.84 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:29]([O-])=O)[C:5]([CH:8](C(OCC2C=CC=CC=2)=O)[C:9](OCC2C=CC=CC=2)=[O:10])=[N:6][CH:7]=1>C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]2[NH:29][C:9](=[O:10])[CH2:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)C(C(=O)OCc1ccccc1)c1ncc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: O=C1Cc2ncc(Br)cc2N1
Temperature: 120 °C
Reaction time: 7 h
Yield: 53.3 %

Procedure:
Iron dust (0.82 g, 14.60 mmol) was added to a solution of dibenzyl 2-(5-bromo-3-nitropyridin-2-yl)malonate (preparation 16b, 1.78 g, 3.70 mmol) in glacial acetic acid (50 mL) and the mixture was heated with stirring to 120° C. After 7 hours, the mixture was cooled and left to stand overnight. The reaction was poured onto ice-water and extracted first with ethyl acetate and then with chloroform. The combined organic extract was washed with brine, dried (MgSO4) and evaporated in vacuo. Purification of the residue by flash chromatography (98:2 dichloromethane/methanol) gave the title compound (0.42 g, 54%) as a pink solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1)(=O)=O.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>COCCOC.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C(OCC)(=O)C>[N:20]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[CH2:12][CH2:11][CH2:10]3)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CCCc2cc(N3CCOCC3)ccc21
Yield: 95.8 %

Procedure:
A solution of 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (3.40 g), morpholine (5.18 g), tripotassium phosphate (3.79 g), tris(dibenzylideneacetone) dipalladium (0) (109 mg) and 2-(di-tert-butylphosphino)biphenyl (71 mg) in 1,2-dimethoxyethane (24 mL) was stirred in a nitrogen atmosphere at 80° C. for one and a half hours. The reaction solution was returned to room temperature, and water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (elution solvent:heptane-ethyl acetate system) to obtain 2.56 g of the title compound. Properties data of the compound are as follows.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[C:16]([C@H:20]2[CH2:25][C@@H:24]([CH2:26][CH:27]=[CH2:28])[S:23][N:22]([CH:29]([CH3:31])[CH3:30])[C@@H:21]2[C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[CH:17]=[CH:18][CH:19]=1.CI.[Li+].CC([N-]C(C)C)C>C1COCC1>[Cl:13][C:14]1[CH:15]=[C:16]([C@H:20]2[CH2:25][C@:24]([CH3:1])([CH2:26][CH:27]=[CH2:28])[S:23][N:22]([CH:29]([CH3:31])[CH3:30])[C@@H:21]2[C:32]2[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(C)C)S1
Reactant: CC(C)NC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(C)C)S1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a degassed solution of diisopropylamine (300 μL, 2.123 mmol) in THF (1.0 ml) was added dropwise at −78° C. n-butyllithium, 2.5 M in hexanes (800 μL, 2.000 mmol). After stirring the solution at −78° C. for 10 min, the reaction was warmed to room temperature. In a separate flask, a degassed solution of 111.9 mg (0.255 mmol) of (3S,4R,6R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-2-(2-propanyl)-6-(2-propen-1-yl)-1,2-thiazinan (Example 117, Step E) and methyl iodide (0.6 ml, 9.62 mmol) in THF (1.0 ml) was heated to 50° C. After five minutes, the LDA solution was added dropwise to the other flask, and stirring continued for 14 hours at 50° C. Upon cooling to room temperature, the reaction was quenched with water (3 mL), then concentrated under reduced pressure. Purification by reverse-phase preparative HPLC using an Agilent Eclipse Plus C18 column (Agilent Technologies, Santa, Clara, Calif.), 0.1% TFA in CH3CN/H2O, gradient 60% to 80% over 25 minutes provided the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([NH:5][CH2:6][C:7]#[CH:8])=[O:4].Br[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.C(N(CC)CC)C>[F:1][C:2]([F:10])([F:9])[C:3]([NH:5][CH2:6][C:7]#[C:8][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)=[O:4]
Reactant: O=[N+]([O-])c1cccc(Br)c1
Reactant: C#CCNC(=O)C(F)(F)F
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=C(NCC#Cc1cccc([N+](=O)[O-])c1)C(F)(F)F
Temperature: 90 °C
Reaction time: 16 h

Procedure:
2,2,2-Trifluoro-N-(prop-2-ynyl)acetamide (3.4 g, 22.2 mmol), 1-bromo-3-nitrobenzene (14) (3.0 g, 14.85 mmol), Pd(Ph3P)4 (0.85 g, 0.74 mmol) and CuI (0.14 g, 0.74 mmol) was added to triethylamine (30 mL) and the mixture was flushed with argon for 15 min. The reaction mixture was stirred at 90° C. for 16 h, cooled and diluted with ethyl acetate. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. Purification by column chromatography (100-200 silica mesh, 15% to 20% EtOAc in hexane) gave 2,2,2-trifluoro-N-(3-(3-nitrophenyl)prop-2-ynyl)acetamide as a brown semi-solid. Yield (1.95 g, 48%); 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 8.16 (d, J=8.0 Hz, 1H), 1.79 (d, J=7.6 Hz, 1H), 7.66 (t, J=8.0 Hz, 1H), 7.34 (s, 1H), 4.38 (s, 2H).
Reaction SMILES: O=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[NH3:10]>C(O)C>[NH2:10][C:2]([CH2:8][CH3:9])=[CH:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: CCC(=O)CC(=O)OC
Reactant: N
Solvent: CCO
Product: CCC(N)=CC(=O)OC
Temperature: 80 °C

Procedure:
Methyl 3-oxopentanoate (10 g, 77 mmol) was treated with 2M ammonia in ethanol (200 mL), heated at 80° C. in a sealed tube for 16 hours and concentrated to dryness to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[F:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]2[C:59]3[O:58][C:57]([NH2:60])=[N:56][C:55]=3[C:54]([O:61][CH3:62])=[CH:53][CH:52]=2)=[CH:47][CH:46]=1>C1COCC1.O1CCOCC1.CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:60][C:57]1[O:58][C:59]2[C:51]([C:48]3[CH:49]=[CH:50][C:45]([F:44])=[CH:46][CH:47]=3)=[CH:52][CH:53]=[C:54]([O:61][CH3:62])[C:55]=2[N:56]=1)=[O:7]
Reactant: O=C(O)c1ccnc(Br)c1
Reactant: COc1ccc(-c2ccc(F)cc2)c2oc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc(F)cc2)c2oc(NC(=O)c3ccnc(Br)c3)nc12
Reaction time: 5 h
Yield: 68.4 %

Procedure:
To a stirred solution of 203 mg (1.00 mmol) 2-bromo-isonicotinic acid in 5 ml THF were added 442 mg (1.16 mmol) HATU and 0.20 ml (1.16 mmol) N-ethyldiisopropylamine and stirring continued at room temperature for 5 h. A solution of 200 mg (0.77 mmol) 7-(4-fluoro-phenyl)-4-methoxy-benzooxazol-2-yl-amine in 5 ml dioxane and 1 ml DMF was then added and stirring continued at 40° C. for 16 h. The reaction mixture was then poured into 100 ml water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Trituration in ether/ethyl acetate (4/1) afforded 233 mg (68%) 2-bromo-N-[7-(4-fluoro-phenyl)-4-methoxy-benzooxazol-2-yl]-isonicotinamide as an off-white crystalline solid. ES-MS m/e (%): 444 (M{81Br}+H+, 90), 442 (M{79Br}+H+, 100).
Reaction SMILES: C(OC(=O)[N:7]([C:15](=[O:26])[CH2:16][CH2:17][C:18]#[C:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.O>[F:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:15](=[O:26])[CH2:16][CH2:17][C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)CCC#Cc1ccccn1)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=C(CCC#Cc1ccccn1)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
tert-Butyl-5-(pyridin-2-yl)pent-4-ynoyl-4-fluorophenylcarbamate (299 mg, 0.81 mmol) was dissolved in DCM (4 mL) with 0.01% w/w of water. 4mL of trifluoroacetic acid was added at room temperature to the solution. The resulting mixture was stirred at R.T. for 2h. The solvent was removed under reduced pressure. The brown oil was dissolved in saturated NaHCO3 until pH=8. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and the solvent was removed under reduced pressure. The brownish solid was tritureted in a mixture Et2O/Pentane:50/50. The solid was collected by filtration and washed with a mixture Et2O/Pentane:50/50. The solid was dried by lyophilisation to afford 181 mg of N-(4-fluorophenyl)-5-(pyridine-2-yl)pent-4-ynamide (Yield: 83%) as a colorless solid (M.P.=189.9-190.2° C.).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](CCC=O)=[CH:8]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:1]([C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH3:6])[CH:8]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: Cn1cc(CCC=O)c2ccccc21
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=CCCc1cn(C)c2ccccc12
Temperature: -78 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
Methyltriphenylphosphonium bromide (2.06 g, 5.77 mmol) was dried in vacuo for 2 hours then suspended with stirring in tetrahydrofuran (15 ml) under nitrogen. The mixture was cooled to −78° C. and n-butyllithium in tetrahydrofuran (3.75 ml, 5.77 mmol) was added dropwise. After stirring for 2 hours being allowed to warm to room temperature, the mixture was again cooled to −78° C. and 3-(1-methylindol-3-yl)propionaldehyde (90° mg, 4.81 mmol) in tetrahydrofuran (6 ml) was added dropwise. After 2 hours stirring at room temperature, the reaction was quenched by addition of aqueous ammonium chloride. This mixture was extracted with ethyl acetate, and the extracts were washed with brine, dried (magnesium sulfate) and evaporated in vacuo. The residue was purified by silica gel (36 g) chromatography eluting with hexane/ethyl acetate (20:1) to give 3-(3-butenyl)-1-methylindole (539 mg, 60.5%) as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[CH3:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:20][C:19]([NH2:21])=[N:18][C:17]=2[CH3:22])=[CH:12][CH:11]=1)(=[O:9])=[O:8]>CN(C)C=O>[CH2:1]([NH:3][C:4]([NH:21][C:19]1[S:20][C:16]([C:13]2[CH:12]=[CH:11][C:10]([S:7]([CH3:6])(=[O:9])=[O:8])=[CH:15][CH:14]=2)=[C:17]([CH3:22])[N:18]=1)=[O:5])[CH3:2]
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)cc1
Reactant: CCN=C=O
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)cc2)s1
Temperature: 85 °C

Procedure:
Ethyl isocyanate (0.09 ml, 1.1 mmol) is added to a stirred solution of 5-(4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 58) (0.10 g, 0.37 mmol) in dimethylformamide (1.0 ml). The mixture is heated at 85° C. for 90 minutes followed by removal of the solvent. The residue is crystallised from ethyl acetate—methanol to afford the title compound. MH+ 340.0.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[Cs+].[Cs+].[C:18]([N:21]1[CH2:25][CH:24]([CH3:26])[CH2:23][CH:22]1[C:27]1[C:32](F)=[CH:31][C:30]([NH:34][C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)=O)=[C:29]([N+:43]([O-])=O)[CH:28]=1)(=[O:20])[CH3:19].O.O.[Sn](Cl)(Cl)(Cl)Cl>C(OCC)(=O)C.CN1CCCC1=O>[C:18]([N:21]1[CH2:25][CH:24]([CH3:26])[CH2:23][CH:22]1[C:27]1[C:32]([O:11][C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:31][C:30]2[N:34]=[C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[NH:43][C:29]=2[CH:28]=1)(=[O:20])[CH3:19]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: CC(=O)N1CC(C)CC1c1cc([N+](=O)[O-])c(NC(=O)c2ccccn2)cc1F
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(=O)N1CC(C)CC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(S(C)(=O)=O)cc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
13.4 mg of 4-(methanesulfonyl)phenol and 44.9 mg of cesium carbonate were added in order to an N-methyl-pyrrolidinone (2 ml) solution of 15 mg of N-(4-(1-acetyl-4-methylpyrrolidin-2-yl)-5-fluoro-2-nitrophenyl)pyridine-2-carboxamide, and the reaction liquid was stirred at 90° C. for 1 hour. 43.8 mg of tin chloride dihydrate was added to the reaction liquid, then heated up to 100° C. and stirred for 2 hours. The reaction liquid was dissolved in ethyl acetate, washed with aqueous saturated sodium bicarbonate, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=9/1) to obtain the entitled compound as a white solid.