Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH2:23].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH:23][C:9](=[O:11])[CH2:8][C:6]1[CH:5]=[CH:4][C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:2]([F:1])[CH:7]=1
Reactant: NCc1cccc(F)c1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)c(F)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(-c2ccccc2)c(F)c1)NCc1cccc(F)c1
Reaction time: 8 h

Procedure:
(2-Fluoro-biphenyl-4-yl)-acetic acid (0.12 gm, 0.5 mmole), 3-fluorobenzylamine (0.0.8 ml, 0.6 mmole), PyBOP (0.34 gm, 0.6 mmole), and DIEA (0.22 ml, 1.3 mmole) was dissolved in DMF stirred overnight, the reaction mixture was then poured into water, solid was collected by filtration, re-crystallized using water-methanol. (0.140 gm, 83%); HL-NMR INOVA-500 (DMSO d6) δ 3.580 (s, 2H), 4.316 (d, J=5.5 Hz, 2H), 7.037-7.110 (m, 3H), 7.210-7.247 (m, 2H), 7.343-7.372 (m, 2H), 7.457-7.501 (m, 3H), 7.544 (d, J=8.0 Hz, 2H), 8.660 (t, J=6.0 Hz, 1H). MS (m/z) 338.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:22])[C:10]([C:13]1[O:14][CH2:15][CH:16]([C:18]([O:20][CH3:21])=[O:19])[N:17]=1)([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N(Br)C(=O)C1>C(Cl)(Cl)(Cl)Cl.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:22])[C:10]([C:13]1[O:14][CH:15]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[N:17]=1)([CH3:12])[CH3:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C1COC(C(C)(C)[C@@H](C)NC(=O)OC(C)(C)C)=N1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1coc(C(C)(C)[C@@H](C)NC(=O)OC(C)(C)C)n1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
To a solution of methyl 2-((R)-3-((tert-butoxycarbonyl)amino)-2-methylbutan-2-yl)-4,5-dihydrooxazole-4-carboxylate (2.0 g, 6.36 mmol) in CCl4 (180 mL) was added NBS (3.96 g, 22.27 mmol) at RT. The reaction mixture was heated to 85° C. and stirred for 30 min. It was then diluted with water and extracted with CCl4 (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4 and the solvent was removed under vacuum. Crude product was purified by ELSD combiflash (120 g silica column, 40% EtOAc: Pet-Ether) to afford a white solid (1.2 g, 60.4%). 1HNMR (400 MHz, CDCl3) δ ppm: 1.12 (d, J=6.8 Hz, 3H), 1.408 (s, 15H), 3.89-3.97 (m, 4H), 4.88-4.91 (d, J=10 Hz, 1H), 8.17 (s, 1H). LC retention time: 1.985 min (analytical HPLC Method N).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([CH2:9][OH:10])[CH:6]=[C:5]([CH2:11][OH:12])[CH:4]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.CO>C(Cl)Cl.CC(C)=O>[CH:9]([C:7]1[CH:6]=[C:5]([CH:11]=[O:12])[CH:4]=[C:3]([CH:2]=[O:1])[CH:8]=1)=[O:10]
Reactant: OCc1cc(CO)cc(CO)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CO
Solvent: CC(C)=O
Product: O=Cc1cc(C=O)cc(C=O)c1
Reaction time: 0.5 h
Yield: 32.8 %

Procedure:
1,3,5-Tris(hydroxymethyl)benzene 15 (927 mg, 5.12 mmol) was suspended in CH2Cl2 (25 mL) and solid PCC (5.94 g, 27.6 mmol) was added. After 30 minutes of stirring, the reaction was diluted with acetone (10 mL) and was allowed to stir for 3 hr at RT. TLC (10% MeOH, 90% CH2Cl2 Rf=0.50) was used to determine if the reaction was complete. After the reaction was complete, the precipitated chromium salts were filtered off and washed with CH2Cl2. The aqueous layer was extracted 3 times in CH2Cl2 and saturated Na2CO3. The organic layers were combined and dried over anhydrous Na2SO4, filtered, and concentrated. Flash column chromatography (100% CH2Cl2 Rf=0.4) gave 16 (272 mg, 1.68 mmol, 33%). 1H NMR (CDCl3): δ 10.21 (s, 3H), 8.63 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[O:16]1CCO[CH:17]1[C:21]1[CH:26]=[CH:25][C:24]([C:27](=[S:29])[NH2:28])=[CH:23][CH:22]=1>CCO>[CH2:4]([C:3]1[N:28]=[C:27]([C:24]2[CH:25]=[CH:26][C:21]([CH:17]=[O:16])=[CH:22][CH:23]=2)[S:29][CH:2]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: NC(=S)c1ccc(C2OCCO2)cc1
Reactant: CCCCCCCCCCCC(=O)CBr
Solvent: CCO
Product: CCCCCCCCCCCc1csc(-c2ccc(C=O)cc2)n1
Yield: 58.9 %

Procedure:
A solution of 1-bromotridecan-2-one (5.54 g, 20 mmol) and 4-(1,3-dioxolan-2-yl)benzenecarbothioamide (4.19 g, 20 mmol) in EtOH (50 mL) was refluxed overnight. After evaporation of the solvent, the residue was taken up in ether, washed with water, brine, dried over MgSO4, filtered. The solvents were evaporated under vacuum to give a yellow oil. Purification on silicagel gave the title product as a yellow solid (4.05 g, 59%). 1H NMR (CDCl3, 300 MHz) δ 10.0 (s, 1H), 8.11 (d, 2H, J=8.3 Hz), 7.93 (d, 2H, J=8.6 Hz), 6.98 (s, 1H), 2.84 (t, 2H, J=7.2 Hz), 1.78-1.72 (m, 2H), 1.50-1.20 (m, 16H), 0.87 (t, 3H, J=6.8 Hz). M+(LC/MS(ESI)): 344.3
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)=[O:5])[CH3:2].N1C=CC=CC=1.B(O)(O)[C:22]1[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[N:8]=[C:9]([C:11]([CH3:13])([CH3:12])[CH3:14])[CH:10]=1)=[O:5])[CH3:2]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1cc(C(C)(C)C)n[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(C)(C)C)nn1-c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 86 %

Procedure:
To a round bottom flask containing 5-tert-Butyl-2H-pyrazole-3-carboxylic acid ethyl ester (0.5 g, 2.6 mmol) stirring in 25 mL DCM was added Pyridine (0.95 mL, 11.7 mmol), p-tolylboronic acid (1.1 g, 8.1 mmol), Cu(OAc)2 (0.75 g, 4.1 mmol) and 4 A molecular sieves (0.75 g). The reaction stirred at room temperature for 14 h under air. The resulting mixture was filtered through a pad of diatomaceous earth and the filtrate concentrated in vacuo to afford a light green solid. The crude material was purified by Flash chromatography to afford (0.64 g, 83%) the desired product as a clear oil (0-50% EtOAc:hexanes on silica gel). Expected mass=286. Observed mass=287.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.[NH3:15].CO>S(Cl)(Cl)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([NH2:15])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(Br)ccc2c1
Reactant: N
Solvent: O=S(Cl)Cl
Solvent: CO
Product: NC(=O)c1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
6-bromo-2-naphthoic acid (2 g, 7.97 mmol) was stirred in thionyl chloride (13.28 ml) at 70° C. for 16 h. After concentration in vacuo, the residue was rediluted in CH2Cl2 and concentrated again. To the acid chloride intermediate was added ammonia in MeOH (7 M, 13.66 ml, 96 mmol) and the mixture was stirred at room temperature for 3 h. The mixture was then concentrated. The residue was taken up in AcOEt, filtered, rinsed with AcOEt and then dried over MgSO4, filtered and concentrated in vacuo. The title compound (1.802 g, 90%) was isolated as a beige solid. LC-MS (M+1) 251.9, t=1.34 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.Cl.CNOC.Cl.CON(C)C(=O)[C@@H](NC(=O)OC(C)(C)C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.O1CCCC1.C(OCC)C>[CH3:13][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=[O:11]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CNOC
Agent: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.2 %

Procedure:
To a solution of 10.7 g (57.0 mmol) of (2S)-2-[(tert-butoxycarbonyl)amino]propanoic acid in 200 mL of dichloromethane at 0° C. was added 12.0 g (74.1 mmol) of carbonyldiimidazole, 10.39 mL (74.1 mmol) of triethylamine, and 7.08 g (74.1 mmol) of N,O-dimethylhydroxylamine hydrochloride. The reaction mixture was warmed to room temperature and left stirring for 16 h. Diethyl ether was then added, followed by the addition of 10% hydrochloric acid. The layers were separated, and the organic layer was then washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated under vacuum to afford 7.05 g of the crude product. Then, 7.05 g (30.4 mmol) of the crude tert-butyl (1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethylcarbamate was dissolved in 109 mL of tetrahydrofuran and cooled to 0° C. A 1.0 M solution of 45.6 mL (45.6 mmol) of lithium aluminum hydride in tetrahydrofuran was then added gradually over 20 min. After stirring for 30 min, 10% citric acid solution was added. and the reaction mixture was stirred for another 5 min. The reaction mixture was diluted with diethyl ether and the layers were separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated under vacuum to afford 5.25 g (>99%) of tert-butyl (1S)-1-methyl-2-oxoethylcarbamate, which was carried into the next step directly. 1H-NMR (300 MHz, CDCl3) δ 9.58 (s, 1H), 5.15 (m, 1H), 4.25 (m, 1H), 1.35 (s, 9H), 1.27 (d, J=7 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)=[C:4]([C:16]2[CH:21]=[CH:20][C:19](F)=[CH:18][CH:17]=2)[CH:3]=1.[C:23]1([SH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:15][S:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:6]=[N:7][C:2]([S:14][C:11]3[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=3)=[CH:3][C:4]=2[C:16]2[CH:21]=[CH:20][C:19]([S:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)=[CH:9][CH:10]=1
Reactant: Sc1ccccc1
Reactant: CSc1ccc(-c2nnc(Cl)cc2-c2ccc(F)cc2)cc1
Product: CSc1ccc(-c2nnc(Sc3ccccc3)cc2-c2ccc(Sc3ccccc3)cc2)cc1

Procedure:
In a similar manner as in Example 2, 6-chloro-4-(4-fluorophenyl)-3-[4-(methylthio)phenyl]pyridazine (198 mg, 0.599 mmol) and thiophenol (165 mg, 1.5 mmol) were reacted as starting materials at 150° C. for 20 hours and post-treatment was then conducted, whereby the title compound was obtained as a yellow oil (217 mg, 73.1%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:35])[CH2:21][NH:22][C:23]([CH3:34])([CH3:33])[CH2:24][C:25]2[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[CH:26]=2)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.Cl>C(O)(C)C>[CH3:32][C:27]1[CH:26]=[C:25]([CH2:24][C:23]([NH:22][CH2:21][CH:20]([C:11]2[C:12]3[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=3[CH:19]=[C:9]([OH:8])[CH:10]=2)[OH:35])([CH3:34])[CH3:33])[CH:30]=[C:29]([CH3:31])[CH:28]=1
Reactant: Cc1cc(C)cc(CC(C)(C)NCC(O)c2cc(OCc3ccccc3)cc3c2OCC(=O)N3)c1
Agent: Cl
Solvent: CC(C)O
Product: Cc1cc(C)cc(CC(C)(C)NCC(O)c2cc(O)cc3c2OCC(=O)N3)c1

Procedure:
The target compound was obtained after hydrogenolysis of 0.90 g (1.71 mmol) of 6-benzyloxy-8-{2-[2-(3,5-dimethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-4H-benzo[1,4]oxazin-3-one and recrystallization of the crude product from isopropanol. White solid. Yield: 0.50 g (69%, hydrochloride); melting point: 235° C.-238° C.; mass spectroscopy: [M+H]+=385.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH:17]C(=O)C)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4]([NH2:21])[N:3]=1.Cl>CO>[NH2:17][C:12]1[C:11]2[C:15](=[CH:16][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH2:21])[CH:5]=3)=[CH:9][CH:10]=2)[NH:14][N:13]=1
Reactant: CC(=O)Nc1n[nH]c2cc(-c3cc(N)nc(N)n3)ccc12
Agent: Cl
Solvent: CO
Product: Nc1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
In a 100 mL flask under argon were combined N-[6-(2,6-diamino-4-pyrimidinyl)-1H-indazol-3-yl]acetamide (0.083 g, 0.29 mmol) and HCl (0.28 mL, 9.4 mmol, 12 M) in CH3OH (20 mL). The reaction mixture was stirred at 60° C. for 8 hours and then cooled to room temperature overnight. The mixture was concentrated and the resulting yellow solid was dissolved in water (3 mL). NaOH (1M) was added to the solution until the pH was 12. The precipitated solid was filtered, washed with water, and dried under vacuum at 40° C. The solid (18 mg) was dissolved in hot DMSO (0.5 mL) and sonicated. The resulting precipitate was filtered. Since HPLC showed the material to be only 90% pure, everything was combined (solids and filtrate) and purified on a Gilson RPHPLC (CH3CN/H2O w/0.1% NH4OH) to afford the title compound (7 mg, 10%) as a white solid. LC-MS (ES) m/z=242 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 5.37 (s, 2H), 5.93 (s, 2H), 6.25 (s, 1H), 6.31 (s, 2H), 7.40 (dd, J=8.3, 1.3 Hz, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.82 (s, 1H), 11.51 (s, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:12])=[CH:5][CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=1.[F:13][C:14]([F:19])([F:18])[C:15](O)=O.C(=O)(O)[O-]>Cl.C(Cl)Cl>[CH3:1][N:2]1[C:3]2[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=2[N:12]=[C:15]1[C:14]([F:19])([F:18])[F:13]
Reactant: O=C(O)C(F)(F)F
Reactant: CNc1cc([N+](=O)[O-])ccc1N
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)nc2ccc([N+](=O)[O-])cc21
Temperature: 70 °C
Yield: 20.4 %

Procedure:
A 250 ml round bottomed flask was charged with N1-methyl-5-nitrobenzene-1,2-diamine (29 g, 0.16 mol), trifluoroacetic acid (22 ml, 0.24 mol) and a few drops of concentrated HCl. A minimum amount of DCM (˜20 ml) was added so that the solid mixture was stirring. The reaction mixture was heated to 70° C. for 12 hours forming a dark brown liquid. The reaction mixture was allowed to cool to room temperature, basified by the slow addition of saturated bicarbonate solution, and extracted into ethyl acetate. The aqueous layer was further extracted twice with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The compound was purified by flash column chromatography (10 to 20% ethyl acetate/petrol) to afford the title compound (8 g, 20% yield). 1H NMR (DMSO D6, 400 MHz) 4.2 (3H, s), 8.05 (1H, d), 8.35 (1H, d), 8.55 (1H, s); MS (ES+) 246.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([CH3:16])([CH3:15])[C:13](=[O:17])[N:12]([CH:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:33])[CH2:25][N:26]4[C:30](=[O:31])[CH2:29][CH2:28][C:27]4=[O:32])[CH2:20][CH2:19]3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[F:34][C:35]([F:39])([F:38])[CH2:36]I>>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[C:14]([CH3:15])([CH3:16])[C:13](=[O:17])[N:12]([CH:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:33])[CH2:25][N:26]4[C:27](=[O:32])[CH2:28][CH2:29][C:30]4=[O:31])[CH2:20][CH2:19]3)[N:11]=2)=[CH:3][C:2]=1[O:1][CH2:36][C:35]([F:39])([F:38])[F:34]
Reactant: FC(F)(F)CI
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)CN4C(=O)CCC4=O)CC3)C(=O)C2(C)C)cc1O
Product: COc1ccc(C2=NN(C3CCN(C(=O)CN4C(=O)CCC4=O)CC3)C(=O)C2(C)C)cc1OCC(F)(F)F

Procedure:
Prepared analogously as described for example 5 using 1-(2-{4-[3-(3-hydroxy-4-methoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)pyrrolidine-2,5-dione (compound A4) and 1,1,1-trifluoro-2-iodoethane as starting compounds.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[C:10]([F:19])=[C:11]([C:15]([F:18])=[CH:16][CH:17]=2)[C:12]([NH2:14])=[O:13])=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.[C:28]([Cu])#[N:29].Cl>N1C=CC=CC=1>[C:28]([C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[C:10]([F:19])=[C:11]([C:15]([F:18])=[CH:16][CH:17]=2)[C:12]([NH2:14])=[O:13])=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)#[N:29]
Reactant: N#C[Cu]
Reactant: COc1ccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)sc2Br)cc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)sc2C#N)cc1
Temperature: 150 °C
Yield: 11.6 %

Procedure:
To a solution of 3-[5-bromo-4-(4-methoxy-phenyl)-thiazol-2-ylmethoxy]-2,6-difluoro-benzamide (0.20 g, 0.43 mmol) in pyridine (4.0 mL) was added CuCN (0.19 g, 2.19 mmol). The reaction mixture was heated to 150° C. in microwave for 2 h. After the completion of the reaction, pH was adjusted to 3-4 with 1N HCl solution and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (60-120 M, 45% EtOAc-Hexane) to get the desired product (0.02 g, 11%) as a brown solid. 1H NMR (DMSO-d6, 400 MHz): δ 3.79 (s, 3H), 5.67 (s, 2H), 7.16 (m, 3H), 7.42 (m, 1H), 7.88 (br s, 1H), 8.03 (d, J=8.80 Hz, 2H) and 8.19 (br s, 1H). MS ES+ (402.07), HPLC (method I) Rt=16.60 min.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C:9]3=2)[NH:4][CH:3]=1.[H-].[Na+].[C:25]([C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1)#[N:26].[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>CN(C=O)C>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[O:15][CH2:14][CH2:13][NH:12][CH2:11][C:9]3=2)[N:4]([S:33]([C:29]2[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=2)[C:25]#[N:26])(=[O:35])=[O:34])[CH:3]=1
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]cc(Cl)c3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(S(=O)(=O)n2cc(Cl)c3c4c(ccc32)OCCNC4)c1
Temperature: 50 °C

Procedure:
tert-Butyl 10-chloro-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 20, 10 mg, 0.031 mmol) was dissolved in DMF (1 mL) and sodium hydride (60% in mineral oil, 2.5 mg, 0.062 mmol) was added. The mixture was stirred for 10 minutes at room temperature before 3-cyanobenzene-1-sulfonyl chloride (13 mg, 0.062 mmol) was added. The reaction mixture was stirred for 20 minutes before TFA (2 mL) was added and the mixture was heated at 50° C. overnight. The reaction mixture was evaporated and the crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH3CN) to give the title compound as an off-white solid (1.3 mg) in the form of the trifluoroacetate salt. MS m/z 388 [M+H]+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]#[N:13].[Cl-].[NH4+].[N-:16]=[N+:17]=[N-:18].[Na+].Cl>CN(C=O)C.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]1[NH:18][N:17]=[N:16][N:13]=1
Reactant: N#CCc1ccc2ccccc2c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2cc(Cc3nnn[nH]3)ccc2c1
Temperature: 125 °C
Reaction time: 15 h
Yield: 53.6 %

Procedure:
A mixture of the above acetonitrile (2.50 g, 15 mmol), ammonium chloride (1.60 g, 30 mmol) and sodium azide (1.94 g, 30 mmol) in N,N'-dimethylformamide (25 ml) was stirred at 125° C. for 15 hours. The cooled reaction mixture was poured into water (300 ml) and acidified with 1N hydrochloric acid, stirred at room temperature for 2 hours. The precipitate was filtered off and washed successively with water, a 1:1 mixture of diethyl ether and heptane and finally with heptane. The solid was dried by suction affording 1.69 g (53%) of the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([NH:32][C:33](=[O:35])[CH3:34])[CH:31]=1)[NH:28][C:27](=[O:36])[CH2:26]2>>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([NH:32][C:33](=[O:35])[CH3:34])[CH:31]=1)[NH:28][C:27](=[O:36])[C:26]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Reactant: CC(=O)Nc1cc(F)cc2c1NC(=O)C2
Product: CC(=O)Nc1cc(F)cc2c1NC(=O)C2=Cc1[nH]c2c(c1C)C(=O)N(CCN1CCOCC1)CC2
Yield: 37 %

Procedure:
The title compound was prepared under the same conditions as described in Example 15 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-7-yl)-acetamide as starting materials to give N-{5-fluoro-3-[3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-7-yl}-acetamide (33 mg, 37%) as an orange solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([NH:12][C:13]([C:15]1[S:19][C:18]([O:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24])=[N:17][CH:16]=1)=[O:14])[CH2:7][CH2:8][CH2:9][C:10]#[CH:11]>N1C=CC=CC=1>[OH:25][CH:22]([CH2:21][O:20][C:18]1[S:19][C:15]([C:13]([NH:12][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[CH:11])=[O:14])=[CH:16][N:17]=1)[CH2:23][O:24][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: C#CCCCCNC(=O)c1cnc(OCC(O)CO)s1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: C#CCCCCNC(=O)c1cnc(OCC(O)COS(C)(=O)=O)s1
Temperature: 25 °C

Procedure:
In this example 0.42 g. of methanesulfonyl chloride is added with rapid stirring to a mixture containing 1.2 g. of (+) 3-[5-(hex-5-ynylaminocarbonyl)thiazol-2-yloxy]propane-1,2-diol in 20 ml. of pyridine at -30° C. The mixture is then allowed to warm to room temperature and evaporated to dryness affording a residue of (+) 2-hydroxy-1-methylsulfonyloxy-3-(5(-hex-5-ynylaminocarbonyl)thiazol-2-yloxy]propane. The residue is then dissolved in 50 ml. of anhydrous methanol and cooled to 0° C. A mixture containing 1 g. of sodium methoxide in 10 ml. of anhydrous methanol is added and the resulting mixture stirred for 2 minutes and then evaporated to remove methanol. 100 Ml. of ethyl acetate is added and the resulting ethyl acetate mixture washed three times with water, dried over magnesium sulfate, and evaporated affording a residue of (+) 1,2-epoxy-3-[5-(hex-5-ynylaminocarbonyl)thiazol-2-yloxy]propane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[F:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[C:32]([CH3:39])=[C:33]([CH:37]=O)[NH:34][C:35]=2[CH3:36])[CH2:26][CH2:25]1>C(O)C.N1CCCCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:37]\[C:33]1[NH:34][C:35]([CH3:36])=[C:31]([CH2:30][N:27]2[CH2:26][CH2:25][CH:24]([F:23])[CH2:29][CH2:28]2)[C:32]=1[CH3:39])(=[O:12])=[O:11]
Reactant: Cc1[nH]c(C=O)c(C)c1CN1CCC(F)CC1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CN1CCC(F)CC1

Procedure:
5-(2,6-Dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one was condensed with 4-(4-fluoro-piperidin-1-ylmethyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde in ethanol and piperidine to give the titled compound as an orange solid.
Reaction SMILES: [C:1]([NH:8][C@H:9]([CH2:14][OH:15])[CH2:10][CH:11]([CH3:13])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>C1COCC1.CN(C1C=CN=CC=1)C>[C:4]([O:3][C:1]([NH:8][C@@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[CH2:14][O:15][S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=1)(=[O:24])=[O:23])=[O:2])([CH3:6])([CH3:5])[CH3:7]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
To a solution of 4.50 g of Boc-L-leucinol in 30 ml of THF were added 4.74 g of p-toluenesulfonylchloride, 7.2 ml of TEA and 0.25 g of DMAP. The reaction was stirred at rt overnight. The pH of the reaction was then adjusted to 6 by the addition of 1 M aqueous hydrochloric acid. The phases were separated and the aqueous phase was extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulphate and concentrated to yield 6.94 g of toluene-4-sulfonic acid (S)-2-tert-butoxycarbonylamino-4-methyl-pentyl ester.