Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[C:3]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=[CH:7][CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:4]=1.[F:21][C:22]([F:46])([F:45])[CH2:23][NH:24][C:25]([C:27]1([CH2:40][CH2:41][CH2:42][CH2:43]Br)[C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:26].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[F:21][C:22]([F:45])([F:46])[CH2:23][NH:24][C:25]([C:27]1([CH2:40][CH2:41][CH2:42][CH2:43][N:12]2[CH2:11][CH2:10][N:9]([C:5]3[CH:4]=[C:3]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:8]=[CH:7][CH:6]=3)[CH2:14][CH2:13]2)[C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:26]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc(-c2cccc(N3CCNCC3)c2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3cccc(-c4ccccc4)c3)CC2)c2ccccc2-c2ccccc21
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A suspension of 0.2 g (0.643 mmol) of 1-biphenyl-3-yl-piperazine-dihydrochloride, 0.256 g (0.6 mmol) of 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide and 0.1 g potassium carbonate in 20 ml of acetonitrile and 0.1 ml of water is stirred for 24 hours at 60° C. The reaction mixture is poured onto water, extracted with ethyl acetate and dried over sodium sulphate. Purification is by column chromatography on silica gel (eluant: dichloromethane/ethanol=30:1).
Reaction SMILES: [F:1][CH:2]([F:19])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([OH:18])[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])[CH3:6].Cl[C:21]1[N:22]=[CH:23][C:24]([C:27]([N:29]([CH3:31])[CH3:30])=[O:28])=[N:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[F:1][CH:2]([F:19])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([O:18][C:21]2[CH:26]=[N:25][C:24]([C:27](=[O:28])[N:29]([CH3:30])[CH3:31])=[CH:23][N:22]=2)[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])[CH3:6]
Reactant: CN(C)C(=O)c1cnc(Cl)cn1
Reactant: COC(=O)c1cc(O)cc(O[C@@H](C)COC(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(O[C@@H](C)COC(F)F)c1
Temperature: 140 °C
Reaction time: 5 h
Yield: 77.5 %

Procedure:
A mixture of methyl 3-[(2S)-1-(difluoromethoxy)propan-2-yl]oxy-5-hydroxy-benzoate (0.25 g, 0.91 mmol), 5-chloro-N,N-dimethyl-pyrazine-2-carboxamide (168 mg, 0.91 mmol) and potassium carbonate (250 mg, 1.81 mmol) in acetonitrile (5 mL) was stirred in a microwave reactor at 140° C. for 5 hours. The mixture was reduced in vacuo and ethyl acetate (50 mL) added. The mixture was washed with water (50 mL), brine (50 mL), dried (MgSO4) and reduced in vacuo. The residue was chromatographed on silica, eluting with 20 to 70% ethyl acetate in isohexane, to give the desired compound (0.3 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][C:13]([NH2:16])=[N:14][CH:15]=1)=[O:8].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25].CCN(CC)CC>C(Cl)Cl>[NH2:16][C:13]1[N:12]=[CH:11][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:17]=[C:2]([NH:1][C:24]([C:23]3[CH:27]=[CH:28][CH:29]=[C:21]([C:20]([F:19])([F:30])[F:31])[CH:22]=3)=[O:25])[CH:3]=[CH:4][C:5]=2[CH3:18])=[CH:15][N:14]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1C(=O)Nc1cnc(N)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1C(=O)Nc1cnc(N)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Amino-N-(2-aminopyrimidin-5-yl)-2-methylbenzamide 9 (86 mg, 0.353 mmol) was taken up in CH2Cl2 (3 mL) and 3-(trifluoromethyl)benzoyl chloride (0.052 mL, 0.353 mmol) was added. The mixture was allowed to stir at rt for 2 h, becoming a thick yellow suspension. NEt3 (0.064 mL, 0.459 mmol) was added. After 0.5 h, a thick yellow suspension remained. Complete consumption of the amine starting material was indicated by LCMS. The crude reaction mixture was concentrated and the title compound was purified using automated medium pressure chromatography (Isco—40 g column; eluting with a linear gradient from 100% CH2Cl2 (A line) to 100% 90/10/1 CH2Cl2/MeOH/NH3 (B line) on silica gel) to afford N-(2-amino-5-pyrimidinyl)-2-methyl-5-(((3-(trifluoromethyl)phenyl)carbonyl)amino)benzamide 10 as an off-white solid. MS: m/z found 416 [MH+] (by ESI, positive ion); MS calculated for C20H16F3N5O2=415.13.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:25])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[OH:24])[N:15]=[CH:14]1>O.CO>[OH:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[N:15]=[CH:14][N:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:25])=[O:4])[CH:17]=1
Reactant: COC(=O)CCCCCCCn1cnc(-c2ccccc2O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCCCn1cnc(-c2ccccc2O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
Add sodium hydroxide (1.32 g, 33 mmol) in water (20 mL) to a suspension of 8-[4-(2-hydroxyphenyl)imidazol-1-yl]octanoic acid methyl ester (2.60 g, 8 mmol) in methanol (50 mL) at 0° C. under nitrogen and warm the mixture to room temperature and stir for 8 hours. Remove the solvent under reduced pressure, dilute the residue with water (200 mL), cool to 0° C., and acidify to pH 1 with 1 N HCl. Collect the precipitate to provide 8-[4-(2-hydroxyphenyl)imidazol-1-yl]octanoic acid (1.70 g, 68%). APCI mass spectrum m/z 301 [C17H22N2O3−H]−.
Reaction SMILES: [OH-].[Na+].Cl.[N:4]1([C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([CH2:17]Cl)[C:11]=2[Cl:19])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[F:20][C:21]([F:36])([O:25][C:26]1[CH:35]=[CH:34][C:29]2[N:30]=[C:31]([SH:33])[NH:32][C:28]=2[CH:27]=1)[CH:22]([F:24])[F:23]>C(O)C>[N:4]1([C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([CH2:17][S:33][C:31]3[NH:30][C:29]4[CH:34]=[CH:35][C:26]([O:25][C:21]([F:36])([F:20])[CH:22]([F:24])[F:23])=[CH:27][C:28]=4[N:32]=3)[C:11]=2[Cl:19])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: FC(F)C(F)(F)Oc1ccc2nc(S)[nH]c2c1
Reactant: Cc1cnc(CCl)c(Cl)c1N1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cnc(CSc2nc3cc(OC(F)(F)C(F)F)ccc3[nH]2)c(Cl)c1N1CCCCC1

Procedure:
5N Sodium hydroxide (2 ml) was added to a stirred suspension of 4-piperidino-3-chloro-5-methyl-2-chloromethylpyridine hydrochloride (1.6 g) and 5-(1,1,2,2-tetrafluoroethoxy)-2-mercaptobenzimidazole (1.5 g) in ethanol at room temperature. After standing over night an additional quantity of sodium hydroxide (1 ml) was added and after a further 1 hour the mixture was evaporated at reduced pressure. The residue was chromatographed (silica gel chloroform/methanol 2%) and crystallised from acetonitrile to give 2-(4-piperidino-3-chloro-5-methyl-2-pyridylmethylthio)-5-(1, 1,2,2-tetrafluoroethoxy)-(1H)-benzimidazole, 1.66 g, m.p. 170°-71°.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:12]=[C:11]([C:13]([N:15]([O:17][CH3:18])[CH3:16])=[O:14])[NH:10][N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.Cl[CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>O>[CH3:1][C:2]1[N:3]([C:8]2[CH:12]=[C:11]([C:13](=[O:14])[N:15]([O:17][CH3:18])[CH3:16])[N:10]([CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: CON(C)C(=O)c1cc(-n2c(C)ccc2C)n[nH]1
Reactant: CC(C)(C)OC(=O)NCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cc(-n2c(C)ccc2C)nn1CCNC(=O)OC(C)(C)C
Temperature: 110 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
A 250-mL round-bottomed flask equipped with a magnetic stirrer was charged with 287c (10.4 g, 1.0 eq., 41.9 mmol), tert-butyl 2-chloroethylcarbamate (37.7 g, 5.0 eq., 210.0 mmol), Na2CO3 (22.3 g, 5.0 eq., 210.0 mmol), and DMF (100 mL). The reaction mixture was stirred at 110° C. overnight. After cooling to room temperature, the resulting mixture was poured into water (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layer was concentrated under reduced pressure. The resulting residue was purified by silica-gel column chromatography eluting with ethyl acetate to afford 287d (10.8 g, 66%) as yellow oil. MS-ESI: [M+H]+ 392.0
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([Cl:13])[C:9](Cl)=[N:10][CH:11]=1.[OH:14][CH2:15][CH:16]1[O:20]C(C2C=CC=CC=2)[N:18]([CH:27]([CH3:29])[CH3:28])[CH2:17]1>COCCOC>[NH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([Cl:13])[C:9]([O:14][CH2:15][CH:16]([OH:20])[CH2:17][NH:18][CH:27]([CH3:29])[CH3:28])=[N:10][CH:11]=1
Reactant: NCCc1cnc(Cl)c(Cl)c1
Reactant: CC(C)N1CC(CO)OC1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)NCC(O)COc1ncc(CCN)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
12 g of sodium hydride dispersion (55% strength) are added in portions to 44 g of 5-(2'-aminoethyl)-2,3-dichloro-pyridine and 55 g of 5-hydroxymethyl-3-isopropyl-2-phenyl-oxazolidine, dissolved in 500 ml of 1,2-dimethoxyethane, whilst cooling with ice at 0°-10° C. The reaction mixture is then stirred for 2 hours at room temperature and 16 hours under reflux. Working up gives crude 5-(2'-aminoethyl)-3-chloro-2-[3'-isopropyl-2'-phenyloxazolidinyl-(5')]-methoxy-pyridine, which is hydrolysed without further purification, analogously to Example 37, to give 5-(2'-aminoethyl)-3-chloro-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyridine (boiling point 165°-185° C./0.06 mm Hg).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1([OH:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]([F:31])([F:30])[CH2:27][CH2:28]I>C(#N)C>[F:1][C:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1([OH:18])[CH2:17][CH2:16][N:15]([CH2:28][CH2:27][C:26]([F:31])([F:30])[F:25])[CH2:14][CH2:13]1
Reactant: FC(F)(F)CCI
Reactant: OC1(c2cccc(C(F)(F)F)c2F)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OC1(c2cccc(C(F)(F)F)c2F)CCN(CCC(F)(F)F)CC1

Procedure:
Preparation according to Example 2: 4-[2-fluoro-3-(trifluoromethyl)phenyl]piperidin-4-ol (0.02 g, 0.076 mmol), acetonitrile (2 ml), potassium carbonate (0.02 g, 0.14 mmol), 1,1,1-trifluoro-3-iodopropane (0.010 ml, 0.082 mmol). MS m/z (relative intensity, 70 eV) 359 (M+, 20), 276 (bp), 258 (39), 191 (21), 152 (19).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[CH:4][C:3]=1[CH:9]=[O:10].[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C=O)C>[N:11]([C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[CH:4][C:3]=1[CH:9]=[O:10])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: O=Cc1cncc(Cl)c1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1c(Cl)cncc1C=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.3 %

Procedure:
A mixture of 4,5-dichloropyridine-3-carbaldehyde (6.78 g, 38.5 mmol) and sodium azide (2.62 g, 40.4 mmol) in DMF (25 mL) was stirred at room temperature for 18 hours. The reaction mixture was quenched with brine (250 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-40% ethyl acetate in pentane) to afford the title compound as a yellow solid (6.7 g, 96% yield). 1H NMR (400 MHz, CDCl3): δ 10.36 (s, 1H), 8.84 (s, 1H), 8.65 (s, 1H).
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[CH2:27])[C:24](=O)[CH3:25])=[CH:19][CH:18]=1.C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C>C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[CH2:27])[C:24]([O:8][S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2])=[CH2:25])=[CH:19][CH:18]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: C=C(C(C)=O)c1ccc(Cl)cc1
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Solvent: ClCCl
Product: C=C(OS(=O)(=O)C(F)(F)F)C(=C)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 41.8 %

Procedure:
Triflic anhydride (0.23 mL, 1.4 mmol) was added to a mixture of 3-(4-chloro-phenyl)-but-3-en-2-one (189 mg, 1.04 mmol) and 2,6-di-t-butyl-4-methylpyridine (0.32 g, 1.6 mmol) in CH2Cl2 (10 mL) and refluxed for 16 h. After cooling to room temperature, the solution washed with 10% HCl solution and saturated NH4Cl aqueous solution, dried (MgSO4), concentrated, and chromatographed (SiO2, hexanes) to give trifluoro-methanesulfonic acid 2-(4-chloro-phenyl)-1-methylene-allyl ester as a clear oil (136 mg, 41%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10].N1C=CC=CC=1.Cl[C:18]([O:20][CH:21]=[CH2:22])=[O:19]>C(Cl)(Cl)Cl>[CH:21]([O:20][C:18]([O:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10])=[O:19])=[CH2:22]
Reactant: C=COC(=O)Cl
Reactant: O=C1CCC(=O)N1CCO
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: C=COC(=O)OCCN1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.2 %

Procedure:
To a 500 mL 3-neck round bottom flask fitted with a mechanical stirrer, condenser, nitrogen blanket, dropping funnel, ice-saltwater bath, and thermometer were added 5.0 (35.0 mmol) of N-(2-hydroxyethyl) succinimide, 2.8 g (35.0 mmol) of pyridine, and 100 mL chloroform. To the reaction mixture was added 3.7 g (35.0 mmol) of vinyl chloroformate so that the temperature remained below 10° C. After stirring at room temperature for 18 hours the reaction mixture was washed with 100 mL 2N HCl and 100 mL 2N NaOH. The organic phase was dried over magnesium sulfate. The solvent was removed on a rotary evaporator and the resulting red liquid chromatographed (silica gel, chloroform). The recovered oil totaled 3.0 g (14.1 mmol, 40.2% yield). FTIR (neat, capillary) 1755.10, 1694.90, 1648.77, 1427.00, 1396.38, 1366.15, 1329.97, 1298.34, 1239.58, 1185.85, 1152.26, 1111.20, 1085.92, 1024.25, 1005.00, 946.53, 894.87, 882.46, 848.52, 818.51, 778.99, 700.00, 661.32. NMR (CDCl3) 6.50-6.83 (1H,q), 4.13- 4.66 (2H,m), 3.93-4.13 (2H,m), 3.33-3.66 (2H,m), 2.41 (4H,S). ##STR17##
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[S:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:17](Cl)=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:32]=1)([CH3:3])[CH3:2].[Br:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1.NC1C=C(O)C(C)=CC=1>>[Br:33][C:34]1[CH:40]=[CH:39][C:37]([NH:38][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:22]([S:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)=[C:14]([NH:13][C:12]3[C:7]4[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[N:32][C:8]=4[N:9]=[CH:10][N:11]=3)[CH:15]=2)=[CH:36][CH:35]=1
Reactant: Nc1ccc(Br)cc1
Reactant: COc1ccc(Sc2ccc(C(=O)Cl)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Agent: Cc1ccc(N)cc1O
Product: COc1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cc3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1

Procedure:
The product from Example 137B was reacted with 4-bromoaniline according to the procedure from Example 137C substituting 4-bromoaniline for 5-amino-o-cresol to provide the title compound as an off white solid after silica gel chromatography (109 mg, 85%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH:12]([C:15]#[N:16])[C:13]#[N:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:20][CH2:21][CH:22]1[O:26][CH2:25][CH2:24][O:23]1>CS(C)=O>[O:23]1[CH2:24][CH2:25][O:26][CH:22]1[CH2:21][CH2:20][C:12]([CH2:11][CH2:10][O:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:13]#[N:14])[C:15]#[N:16]
Reactant: BrCCC1OCCO1
Reactant: N#CC(C#N)CCOCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CC(C#N)(CCOCCc1ccccc1)CCC1OCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
A solution of the compound from step b) (1.53 g) in dry dimethyl sulphoxide (20 ml) was added to a suspension of sodium hydride (prewashed with diethyl ether) in dimethyl sulphoxide (20 ml). The mixture was stirred for 2 hours at room temperature. 2-[2-Bromoethyl]-1,3-dioxolane (0.920 ml) was then added and the whole heated at 60° for a further 2 hours. The cooled mixture was then quenched with water, acidified with dilute aqueous hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried (MgSO4) and evaporated under reduced pressure to yield the crude final product. This material was purified by flash chromatography over silica using ethyl acetate in dichloromethane as eluant to yield a pure sample of the subtitled compound (0.56g, 25%).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C(N(CCCC)CCCC)CCC.[CH:18]([N:21]1[CH2:25][CH2:24][NH:23][C:22]1=[O:26])=[CH:19][CH3:20]>C(OCC)(=O)C>[Cl:4][C:1]([N:23]1[CH2:24][CH2:25][N:21]([CH:18]=[CH:19][CH3:20])[C:22]1=[O:26])=[O:2]
Reactant: O=C(Cl)Cl
Reactant: CC=CN1CCNC1=O
Solvent: CCOC(C)=O
Solvent: CCCCN(CCCC)CCCC
Product: CC=CN1CCN(C(=O)Cl)C1=O
Reaction time: 8 h

Procedure:
First 6.3 pts. by wt. of phosgene and then 11.8 pts. by wt. of tri-n-butylamine are added to a suspension of 8.0 pts. by wt. of 1-propenyl-2-oxo-imidazolidine (prepared according to DAS (German Published Specification) No. 1,057,126) in 100 pts. by vol. of abs. ethyl acetate. The reaction mixture is stirred overnight and concentrated. The 1-chlorocarbonyl-2-oxo-3-propenyl-imidazolidine formed is used for Example 2 in a mixture with tributylammonium chloride. IR (liquid paraffin): 1,800 and 1,710 cm-1.
Reaction SMILES: OS(O)(=O)=O.O=S(=O)=O.[N+:10]([O-:13])(O)=[O:11].[Br:14][C:15]1[C:16]([F:26])=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[C:22]([Cl:25])[CH:21]=[CH:20]2.[N+]([O-])(O)=O>>[Br:14][C:15]1[C:16]([F:26])=[CH:17][C:18]([N+:10]([O-:13])=[O:11])=[C:19]2[C:24]=1[N:23]=[C:22]([Cl:25])[CH:21]=[CH:20]2
Reactant: O=[N+]([O-])O
Reactant: Fc1ccc2ccc(Cl)nc2c1Br
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=[N+]([O-])c1cc(F)c(Br)c2nc(Cl)ccc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
To a solution of 2-bromo-3-fluoroaniline (6.5 g, 34.17 mmol) and pyridine (2.7 g, 34.17 mmol) in 20 ml of CH2Cl2, cinnamoyl chloride (5.95 g, 35.88 mol) in 10 ml CH2Cl2 are added dropwise and mixture was refluxed for 30 min. The reaction mixture is diluted with CH2Cl2, the organic layer washed with diluted HCl, saturated Na2CO3 solution, water, and dried (Na2SO4). The solvent is removed in vacuo to give 10.5 g of N-(2-bromo-3-fluorophenyl)-3-phenylacrylamide. To a solution of N-(2-bromo-3-fluorophenyl)-3-phenylacrylamide (10.5 g, 32.8 mmol) in 70 ml of chlor-benzene at 130° C. AlCl3 (21.9 g, 0.164 mol) is added portionwise, the mixture is stirred at this temperature 2 h and poured in ice-water. The precipitate is filtered off and dried. Yield 6.05 g (76%). 6 g (24.8 mmol) of 8-bromo-7-fluoro-1H-quinolin-2-one are refluxed in 30 mL of POCl3 during 2 h, then poured on ice, extracted with benzene, the benzene extract dried (Na2SO4) to yield 6.1 g 8-bromo-2-chloro-7-fluoroquinoline after solvent removal. To a mixture of 10 ml 10%-oleum and 1.4 g (22.2 mmol) of fuming HNO3 8-bromo-2-chloro-7-fluoroquinoline (4.8 g 18.5 mmol) is added portionwise. The mixture is heated at 100° C. for 2 h. Additional HNO3 (0.17 g) is added and stirred for additional 1 h. The reaction mixture is poured in ice-water, extracted with EtOAc, filtered through silica gel, and crystallized from heptane-toluene to yield 2.3 g (50%) 8-bromo-2-chloro-7-fluoro-5-nitroquinoline. 2.3 g (7.54 mmol) of 8-bromo-2-chloro-7-fluoro-5-nitroquinoline are heated at 100° C. for 5 h in a solution containing 16 ml of CH3COOH, 3.2 ml of H2O and 5 ml of conc. HCl. The mixture is poured in water, the formed precipitate is filtered off, stirred in EtOAc and filtered to yield 1.71 g. 8-bromo-7-fluoro-5-nitro-1H-quinolin-2-one. To a suspension 1.7 g (5.92 mmol) of 8-bromo-7-fluoro-5-nitro-1H-quinolin-2-one and 2.3 g (35.5 mmol) of HCOONH4 in 10 ml of ethanol 0.1 g 10% Pd—C are added, and stirred for 2 h at 60° C. A solid disappeared and then formed again. The precipitate is filtered off, dissolved in 3 ml of DMSO and filtered through silica gel. 15 ml of water are added to the eluate, the precipitate is filtered off and dried to yield 0.5 g (47%) 5-Amino-7-fluoro-1H-quinolin-2-one. 1H-NMR (DMSO-d6); δ=6.14 (dd, 1H), 6.20 (dd, 1H), 6.23 (d, 1H), 6.27 (br, 2H), 8.06 (d, 1H), 11.50 (br., 1H).
Reaction SMILES: [F:1][C:2]([F:51])([F:50])[C:3]1[CH:4]=[C:5]([C:13]([CH3:49])([CH3:48])[C:14]([N:16]([CH3:47])[C:17]2[C:18]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=3[CH3:46])=[CH:19][C:20]([C:23]#[C:24][CH2:25][C@@H:26]([NH:31]C(OC(C)(C)C)=O)[C:27]([O:29][CH3:30])=[O:28])=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:31][C@H:26]([CH2:25][C:24]#[C:23][C:20]1[CH:19]=[C:18]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=2[CH3:46])[C:17]([N:16]([C:14](=[O:15])[C:13]([C:5]2[CH:4]=[C:3]([C:2]([F:50])([F:51])[F:1])[CH:8]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:6]=2)([CH3:48])[CH3:49])[CH3:47])=[CH:22][N:21]=1)[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)[C@@H](CC#Cc1cc(-c2ccc(F)cc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H](N)CC#Cc1cc(-c2ccc(F)cc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl (2R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-pentynoate (Intermediate 12, 1 g, 1.382 mmol) in Dichloromethane (15 ml), TFA (5 ml, 64.9 mmol) was added and the reaction mixture was stirred for 1 h at r.t. The solvent and the excess of TFA were evaporated and the residue purified by SPE-SCX cartridge to obtain Intermediate 13. This residue was dissolved in Acetonitrile (14 ml) and Silver trifluoromethanesulfonate (0.036 g, 0.138 mmol) was added; the reaction mixture was stirred for 6 hours at 60° C. The solvent was evaporated and the residue was dissolved in DCM (15 ml) and the metal catalyst was filtered off.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.CC(N)(C)C[C:22]1[CH:27]=[CH:26][C:25]([NH:28][S:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[CH:24][CH:23]=1>C(O)C>[OH:1][C@@H:2]([CH2:3][N:11]([C:22]1[CH:23]=[CH:24][C:25]([NH:28][S:29]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)(=[O:30])=[O:31])=[CH:26][CH:27]=1)[CH2:10][CH:18]([CH3:6])[CH3:17])[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Reactant: CC(C)(N)Cc1ccc(NS(=O)(=O)c2ccccc2)cc1
Solvent: CCO
Product: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(NS(=O)(=O)c2ccccc2)cc1
Yield: 134.6 %

Procedure:
A solution of (S)-4-(oxiranylmethoxy)-9H-carbazole (1.0 g, 4.18 mmol) and N-(4-[2-methyl-2-aminopropyl]phenyl) benzenesulfonamide (1.9 g, 6.24 mmol) in absolute ethanol (100 mL) was refluxed for 18 h. The solvent was removed under vacuum and the residue was purified by column chromatography eluting with chloroform:methanol (95:5). Concentration of the appropriate fractions provided 1.53 g (69%) of the desired product. MS (FD) m/e 544.3 (MH+); Anal. Calcd. for C31H33N3O4S: C, 68.48; H, 6.12. N, 7.73. Found: C, 68.49; H, 6.02; N, 7.53.