Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[C:3]=1[NH:4][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1B1OC(C)(C)C(C)(C)O1.Br[C:32]1[N:37]=[C:36]([C:38]([NH:41][C:42]2[C:47]([CH3:48])=[CH:46][C:45]([CH3:49])=[CH:44][C:43]=2[CH3:50])([CH3:40])[CH3:39])[CH:35]=[CH:34][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+].O>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.C1(C)C=CC=CC=1.CO>[C:43]1([CH3:50])[CH:44]=[C:45]([CH3:49])[CH:46]=[C:47]([CH3:48])[C:42]=1[NH:41][C:38]([C:36]1[N:37]=[C:32]([C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[CH:15][C:6]=2[CH2:5][NH:4][C:3]2[C:2]([CH3:1])=[CH:28][C:27]([CH3:29])=[CH:26][C:25]=2[CH3:30])[CH:33]=[CH:34][CH:35]=1)([CH3:40])[CH3:39]
Reactant: Cc1cc(C)c(NCc2ccc3ccccc3c2B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: Cc1cc(C)c(NC(C)(C)c2cccc(Br)n2)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: Cc1cc(C)c(NCc2ccc3ccccc3c2-c2cccc(C(C)(C)Nc3c(C)cc(C)cc3C)n2)c(C)c1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of 1.70 g (4.20 mmol) of 2,4,6-trimethyl-N-{[1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthyl]methyl}aniline, 1.40 g (4.20 mmol) of N-[1-(6-bromopyridin-2-yl)-1-methylethyl]-2,4,6-trimethylaniline, 3.00 g (10.50 mmol) of Na2CO3×10H2O, 48 ml of water, 13 ml of methanol, and 56 ml of toluene was purged with argon for 30 min. To this solution 0.24 g (0.21 mmol) of Pd(PPh3)4 was added. The resulting mixture was stirred for 12 h at 80° C. and then cooled to room temperature. The organic layer was separated, the aqueous layer was extracted with 3×200 ml of ethyl acetate. The combined organic extract was washed with brine, dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel 60 (40-63 um, eluent: dichloromethane-ethyl acetate=20:1, vol.). Yield 1.25 g (56%) of yellow oil. Anal. calc. for C37H41N3: C, 84.21; H, 7.83; N, 7.96. Found: C, 84.38; H, 7.69; N, 8.02. 1H NMR (CDCl3): δ 7.90 (m, 1H, 8-H in naphthalene), 7.86 (d, J=8.4 Hz, 1H, 4-H in naphthalene), 7.77-7.82 (m, 2H, 4, 5-H in pyridine), 7.37-7.50 (m, 4H, 3, 5, 6, 7-H in naphthalene), 7.23 (dd, J=6.1 Hz, J=2.3 Hz, 1H, 3-H in pyridine), 6.79 (s, 2H, 3, 5-H in mesityl), 6.78 (s, 2H, 3, 5-H in mesityl), 3.99 (m, 2H, CH2N), 3.66 (br.s, 2H, NH), 2.24 (s, 3H, 4-Me in mesityl), 2.23 (s, 3H, 4-Me in mesityl), 2.06 (s, 6H, 2, 6-Me in mesityl), 2.05 (s, 6H, 2, 6-Me in mesityl), 1.57 (s, 3H, CMeMe′), 1.54 (s, 3H, CMeMe′).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[C:11]([F:21])[CH:10]=2)[CH2:4]1.[C:22](OC(=O)C)(=[O:24])[CH3:23].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:23][C:22]([NH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[C:11]([F:21])[CH:10]=2)[CH2:4]1)=[O:24]
Reactant: NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
(S)-5-(aminomethyl)-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one (0.3 g, 1 mmol), acetic anhydride (0.12 g, 1.2 mmol) and triethylamine (0.5 g, 5 mmol) were added to 10 mL ethyl acetate and the reaction mixture was stirred at room temperature for 2 hours. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, most part of the solvent was evaporated, frozen crystallized and filtered to yield the crude product. The crude product was recrystallized with ethyl acetate to provide 0.30 g of linezolid in 88% yield.
Reaction SMILES: [CH2:1]1[C:6]2([C:15](=[O:16])[NH:14][C:8]3([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([N:19]=[C:20]=[O:21])[CH3:18].N12CCN(CC1)CC2>C1C=CC=CC=1>[CH2:17]([NH:19][C:20]([N:14]1[C:15](=[O:16])[C:6]2([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5]2)[NH:7][C:8]21[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:21])[CH3:18]
Reactant: O=C1NC2(CCCCC2)NC12CCCCC2
Reactant: CCN=C=O
Agent: C1CN2CCN1CC2
Solvent: c1ccccc1
Product: CCNC(=O)N1C(=O)C2(CCCCC2)NC12CCCCC2
Reaction time: 6 h

Procedure:
5.5 Parts of 7,14-diazadispiro[5.1.5.2]pentadecan-15-one, 1.76 parts of ethyl isocyanate and a trace of 1,4-diaza bicyclo[2.2.2]octane in 100 parts of dry benzene were heated at reflux for 18 hours. The solvent was evaporated in vacuo and the residue was stirred in 100 of water for 6 hours. 6.4 Parts of a solid were separated by filtration and crystallised twice from ethanol to yield 14-ethylcarbamoyl-7,14-diazadispiro[5.1.5.2]pentadecan-15-one as colourless crystals of melting point 185° to 188°C. This material gave the following elemental analysis by weight:
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[NH:6][CH:7]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[Cl:24])[CH2:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[CH:10]=1.C([O-])(C)(C)C.[K+].Br[CH2:32][CH2:33][CH2:34][O:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1>O1CCCC1>[O:37]1[CH2:38][CH2:39][CH2:40][CH2:41][CH:36]1[O:35][CH2:34][CH2:33][CH2:32][N:3]1[CH2:4][CH2:5][S:1][C:2]1=[N:6][CH:7]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[Cl:24])[CH2:8][C:9]1[CH:10]=[C:11]([CH3:16])[CH:12]=[C:13]([CH3:15])[CH:14]=1
Reactant: BrCCCOC1CCCCO1
Reactant: Cc1cc(C)cc(CC(NC2=NCCS2)c2cccc(Cl)c2Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(CC(N=C2SCCN2CCCOC2CCCCO2)c2cccc(Cl)c2Cl)c1
Yield: 48.5 %

Procedure:
A mixture of 1-(4,5-dihydrothiazol-2-yl)amino-1-(2,3-dichlorophenyl)-2-(3,5-dimethylphenyl)-ethane (300 mg), potassium tert.-butanolate and tetrahydrofuran (THF, 10 ml) was treated at room temperature with 2-(3-bromo-propoxy)-tetrahydropyran (210 mg) for 3 days. Aqueous work-up by dilution in ethyl acetate, washing with an aqueous potassium carbonate solution (5% strength) and water and drying over sodium sulphate yielded a crude product that was purified by column chromatography over silica gel to give 200 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5](=[O:8])[C:4]([OH:9])=[C:3]1[CH3:10].Cl.[CH3:12][O:13][C:14](=[O:23])[C@@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[C:20](Cl)=[O:21].Cl.COC(=O)[C@@H]1CCCN1.C(Cl)(Cl)=O>N1C=CC=CC=1.C(#N)C.C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:1][N:2]1[CH:7]=[CH:6][C:5](=[O:8])[C:4]([O:9][C:20]([N:16]2[CH2:17][CH2:18][CH2:19][C@H:15]2[C:14]([O:13][CH3:12])=[O:23])=[O:21])=[C:3]1[CH3:10]
Reactant: Cc1c(O)c(=O)ccn1C
Reactant: COC(=O)[C@@H]1CCCN1C(=O)Cl
Agent: COC(=O)[C@@H]1CCCN1
Agent: Cl
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: CC#N
Product: COC(=O)[C@@H]1CCCN1C(=O)Oc1c(C)n(C)ccc1=O
Temperature: 110 °C
Reaction time: 6 h

Procedure:
2.80 ml of triethylamine are added to a suspension of 2.78 g of 1,2-dimethyl-3-hydroxy-4(1H)-pyridinone in 100 ml of pyridine and 100 ml of acetonitrile, and then a hot solution of 1-chlorocarbonyl-L-proline methyl ester hydrochloride (prepared by reacting a solution of 0.99 g of L-proline methyl ester hydrochloride (dry) in 150 ml of toluene with 245 ml of a 20% solution of phosgene in toluene after stirring for 6 hours at 110° C.) is added dropwise. The reaction mixture becomes reddish in hue and a solution forms, whereupon a precipitate forms again immediately. After a reaction time of 20 hours the solid is removed by filtration and the filtrate is concentrated by evaporation under reduced pressure. The residue, which contains the desired product in the form of the hydrochloride, is dissolved in 50 ml of water. The solution is adjusted to pH 2.5 by addition of phosphoric acid and extracted with methylene chloride. The aqueous phase is subsequently saturated with sodium chloride and extracted once more with methylene chloride. The residue of the second extract is crystallised from 10 ml of isopropanol and 50 ml of ethyl acetate at 4° C., affording 1,2-dimethyl-3-[(2(S)-methoxycarbonylpyrrolidino)carbonyloxy]-4(1H)-pyridinone which melts at 198°-200° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[CH2:3][C:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:15]2[NH:16][CH:17]=[C:18]([C:20](=[O:25])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:19]=2)=[O:14])=[CH:9][C:8]=1[CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5].[H-].[Na+].[CH2:36](I)[CH2:37][CH:38]([CH3:40])[CH3:39].Cl>CN(C)C=O.O.C(OCC)(=O)C>[CH3:1][CH:2]([CH3:33])[CH2:3][C:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:15]2[N:16]([CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])[CH:17]=[C:18]([C:20](=[O:25])[CH2:21][CH:22]([CH3:23])[CH3:24])[CH:19]=2)=[O:14])=[CH:9][C:8]=1[CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5]
Reactant: CCOC(=O)CCc1cc(C(=O)c2cc(C(=O)CC(C)C)c[nH]2)ccc1OC(=O)CC(C)C
Reactant: CC(C)CCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cc(C(=O)c2cc(C(=O)CC(C)C)cn2CCC(C)C)ccc1OC(=O)CC(C)C
Temperature: 55 °C
Reaction time: 1 h

Procedure:
To a solution of 0.9 g of 2-(3-ethoxy-3-oxopropyl)-4-{[4-(3-methylbutanoyl)-1H-pyrrol-2-yl]carbonyl}phenyl 3-methylbutanoate in 18 ml N,N-dimethylformamide are added 0.12 g of 60% sodium hydride and 0.4 ml of isopentyl iodide successively, and the mixture thus obtained is stirred at 50-60° C. for one hour. The reaction mixture is added to a mixture of ethyl acetate and water, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Thus, 0.7 g of 2-(3-ethoxy-3-oxopropyl)-4-{[1-isopentyl-4-(3-methylbutanoyl)-1H-pyrrol-2-yl]carbonyl}phenyl 3-methylbutanoate is obtained as a white solid product.
Reaction SMILES: [NH3:1].[CH2:2]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([OH:22])=[C:15]([C:18](OC)=[O:19])[CH:16]=2)[NH:11][N:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl-].[Mg+2].[Cl-]>>[NH2:1][C:18]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][C:14]=1[OH:22])[NH:11][N:10]=[C:9]2[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:19]
Reactant: N
Reactant: COC(=O)c1cc2c(Cc3ccccc3)n[nH]c2cc1O
Agent: [Cl-]
Agent: [Mg+2]
Product: NC(=O)c1cc2c(Cc3ccccc3)n[nH]c2cc1O
Reaction time: 0.67 h

Procedure:
2.1 1.5 ml of ammonia (7 M in methanol) are added under argon to 30 mg of “A1”, and the mixture is stirred in the microwave at 100°/10 bar for 40 minutes. 0.5 ml of ammonia solution (32%) and 5.06 mg of magnesium chloride are added, and the mixture is stirred at 120°/17 bar for a further 40 minutes. The mixture is subjected to conventional work-up, and the residue is chromatographed over an RP18 silica-gel column, giving 2.7 mg of 5-aminocarbonyl-3-benzyl-6-hydroxy-1H-indazole (“A3”).
Reaction SMILES: [CH2:1]([N:8]([CH2:12][Si](C)(C)C)[CH2:9]OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][O:18][C:19](=[O:25])/[CH:20]=[CH:21]/[CH:22]1[CH2:24][CH2:23]1.C(O)(C(F)(F)F)=O.C1CCCCC1>C(Cl)Cl.C1CCCCC1.CCOC(C)=O>[CH3:17][O:18][C:19]([CH:20]1[CH:21]([CH:22]2[CH2:24][CH2:23]2)[CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12]1)=[O:25]
Reactant: COC(=O)/C=C/C1CC1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCCCC1
Product: COC(=O)C1CN(Cc2ccccc2)CC1C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.8 %

Procedure:
101.1 To a stirred, cooled (0° C.) solution of 3.18 g N-benzyl-N-(methoxymethyl)trimethyl-silylmethylamine (CAS 93102-05-7) in 30 ml CH2Cl2 under an argon atmosphere was added dropwise a solution of 1.69 g (E)-3-cyclopropyl-acrylic acid methyl ester (CAS 59939-11-6; J. Org. Chem. 1990, 55(10), 3097) in 15 ml CH2Cl2 over a period of 20 min. Then a solution of 0.1 ml TFA in 5 ml CH2Cl2 was added dropwise within 10 min. When addition was complete, the mixture (slowly warming up to room temperature) was stirred overnight. Then, the mixture was diluted with CH2Cl2, washed with sat. aq. NaHCO3 and brine, dried over MgSO4, filtered and concentrated. The crude product was isolated by chromatography (silica gel; (gradient: cyclohexane->cyclohexane/EtOAc 7:3) to give 1.14 g (3RS,4RS)-1-benzyl-4-cyclopropyl-pyrrolidine-3-carboxylic acid methyl ester as light yellow oil. MS 260.3 ([M+H]+)
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[N:19]=[C:18]([N:20]2[C@H:25]([CH3:26])[CH2:24][O:23][C@H:22]([CH2:27][OH:28])[CH2:21]2)[CH:17]=[C:16]([Cl:29])[N:15]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:8][S:9]([O:28][CH2:27][C@H:22]1[O:23][CH2:24][C@@H:25]([CH3:26])[N:20]([C:18]2[CH:17]=[C:16]([Cl:29])[N:15]=[C:14]([NH2:13])[N:19]=2)[CH2:21]1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H]1CO[C@H](CO)CN1c1cc(Cl)nc(N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CO[C@H](COS(C)(=O)=O)CN1c1cc(Cl)nc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 117.1 %

Procedure:
Triethylamine (0.65 mL, 4.69 mmol) and methanesulfonyl chloride (0.34 mL, 4.36 mmol) were added dropwise to a solution of [(2S,5R)-4-(2-amino-6-chloro-4-pyrimidinyl)-5-methyl-2-morpholinyl]methanol (1.00 g, 3.88 mmol) in CH2Cl2 (35 mL), and the mixture was stirred at room temperature under nitrogen. After 75 minutes another portion each of triethylamine (0.16 mL, 1.16 mmol) and methanesulfonyl chloride (0.076 mL, 0.97 mmol) were added dropwise and stirring continued for an additional 30 minutes. The reaction mixture was then poured into saturated aqueous NaHCO3 (100 mL) and extracted with CH2Cl2 (3×75 mL). The extracts were dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound (1.53 g, about 85% purity) as a white foam. LC-MS (ES) m/z=337, 339 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)=[O:5].[OH:18][CH2:19][CH2:20][O:21][C:22]1[C:29]([CH3:30])=[CH:28][C:25]([CH:26]=O)=[CH:24][C:23]=1[CH3:31]>C(O)C.[Cu](Cl)Cl>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:1]=[C:26]2[C:25]2[CH:28]=[C:29]([CH3:30])[C:22]([O:21][CH2:20][CH2:19][OH:18])=[C:23]([CH3:31])[CH:24]=2)=[CH:8][CH:9]=1
Reactant: Nc1ccccc1C(=O)Nc1ccc(Br)cc1
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Agent: Cl[Cu]Cl
Solvent: CCO
Product: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(Br)cc2)cc(C)c1OCCO
Temperature: 25 °C

Procedure:
To a solution of 2-amino-N-(4-bromo-phenyl)-benzamide (3.75 g, 12.9 mmol) and 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (D) (2.50 g, 12.9 mmol) in anhydrous ethanol (75 mL) was added anhydrous copper (II) chloride (5.19 g, 38.6 mmol). The reaction mixture was stirred under reflux for 16 hours under nitrogen, then cooled to room temperature. The ethanol was evaporated under reduced pressure. The residue was taken in dichloromethane (300 mL) and the organic phase was washed with water (200 mL). The aqueous phase was then extracted with CH2Cl2 (2×200 mL). The combined organic phase was washed with brine (200 mL) and dried over anhydrous Na2SO4. The solvent was evaporated. The crude compound was purified by column chromatography (silica gel 230-400 mesh; 30-50% ethyl acetate in hexanes as eluent) to give the title compound (K) as white solid. Yield: 3.84 g (64%). MP 164-165° C. 1H-NMR (400 MHz, DMSO-d6): δ 8.33 (d, J=7.80 Hz, 1H), 7.82-7.80 (m, 2H), 7.55-7.45 (m, 3H), 7.04 (d, J=8.58 Hz, 2H), 6.98 (s, 2H), 3.94-3.90 (m, 2H), 3.82 (t, J=4.68 Hz, 2H), 2.17 (s, 6H), 2.13 (t, J=3.51 Hz, 1H). MS (ES+) m/z: 465.42 (97%) (M+1), 467.43 (100%) (M+3).
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:16]=[CH:15][C:9]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:8]([S:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])[CH:7]=1)(=[O:5])[CH3:4].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:1][CH2:4][C:3]([C:6]1[CH:16]=[CH:15][C:9]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:8]([S:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])[CH:7]=1)=[O:5]
Reactant: BrBr
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)c(Sc2ccc(F)cc2F)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)Nc1ccc(C(=O)CBr)cc1Sc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of bromine (0.81 g) in chloroform (5 ml) was added dropwise to a stirred solution of 4'-acetyl2'-(2,4-difluorophenylthio)methanesulfonanilide (1.8 g) and benzoyl peroxide (8 mg) in chloroform (20 ml). After stirring for 1 hour at room temperature, the mixture was washed with water and an aqueous solution of sodium bisulfite successively. The organic layer was dried and concentrated to give 4'-bromoacetyl-2'(2,4-difluorophenylthio)methanesulfonanilide.
Reaction SMILES: [F-].[K+].[CH2:3]([O:7][C:8]1[C:13]([C:14]2[NH:15][C:16](=[O:29])[C:17]3[C:18](=[C:20]([CH2:27][CH3:28])[N:21]([CH2:23][CH2:24][O:25][CH3:26])[N:22]=3)[N:19]=2)=[CH:12][C:11]([C:30]#[C:31][Si](C)(C)C)=[CH:10][N:9]=1)[CH2:4][CH2:5][CH3:6]>CN(C)C=O.C(OCC)(=O)C>[CH2:3]([O:7][C:8]1[C:13]([C:14]2[NH:15][C:16](=[O:29])[C:17]3[C:18](=[C:20]([CH2:27][CH3:28])[N:21]([CH2:23][CH2:24][O:25][CH3:26])[N:22]=3)[N:19]=2)=[CH:12][C:11]([C:30]#[CH:31])=[CH:10][N:9]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCOc1ncc(C#C[Si](C)(C)C)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#Cc1cnc(OCCCC)c(-c2nc3c(CC)n(CCOC)nc3c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.8 %

Procedure:
Potassium fluoride (22 mg, 0.38 mmol) was added to a stirred solution of the title compound from Example 14 (90 mg, 0.19 mmol) in aqueous N,N-dimethylformamide (2 mL N,N-dimethylformamide/0.2 mL water) at 0° C. After 10 min the reaction was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was diluted with ethyl acetate and washed with water, 1 N hydrochloric acid (3 times) and brine. The organic layer was dried (MgSO4) and concentrated to give the title compound as a white solid (75 mg).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH3:7])=[N:4][C:3]=1[C:8]([OH:10])=[O:9].Cl.[CH3:12]O>CCOCC>[CH3:12][O:9][C:8]([C:3]1[N:4]=[C:5]([CH3:7])[S:6][C:2]=1[Br:1])=[O:10]
Reactant: Cc1nc(C(=O)O)c(Br)s1
Reactant: CO
Agent: Cl
Solvent: CCOCC
Product: COC(=O)c1nc(C)sc1Br
Yield: 82 %

Procedure:
A solution of 5-bromo-2-methyl-thiazole-4-carboxylic acid (1.50 g, 6.75 mmol) in methanol (80.00 ml) was treated with a saturated solution of HCl in ether (3.00 ml). The reaction mixture was heated at reflux for 3 h then the volatiles were removed. The residue was purified by flash chromatography (methylene chloride/methanol) yielding 5-bromo-2-methyl-thiazole-4-carboxylic acid methyl ester (1.30 g, 82%) as a white solid, MS (ISP): m/e=235.9, 237.9 (M+H+).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2].[N+:14]([O-])([OH:16])=[O:15]>>[C:1]([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)NC1Cc2ccccc2C1
Product: CC(=O)NC1Cc2ccc([N+](=O)[O-])cc2C1
Temperature: 0 °C

Procedure:
20.5 g of 2-acetylaminoindan is added gradually into 200 ml of fuming nitric acid under cooling. After the reaction, the reaction mixture is poured onto 100 g of ice, and the solvent is evaporated from the chloroform extract, and the residue is recrystallized from isopropyl alcohol to give 18.6 g of 2-acetylamino-5-nitroindan.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.[NH2:17][CH2:18][CH2:19][OH:20]>O1CCOCC1>[CH3:16][O:15][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([NH:17][CH2:18][CH2:19][OH:20])=[N:3]2)=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: NCCO
Reactant: COc1cc2nc(Cl)ccc2cc1[N+](=O)[O-]
Solvent: C1COCCO1
Product: COc1cc2nc(NCCO)ccc2cc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 63.3 %

Procedure:
A mixture of 2-chloro-7-methoxy-6-nitro-quinoline (0.1 g, 0.42 mmol) and 2-aminoethanol (38 μL, 0.63 mmol) in anhydrous 1,4-dioxane (5 mL) was heated at 90° C. overnight. A second aliquot of 2-aminoethanol (38 μL, 0.63 mmol) was added and the resulting mixture was heated at 90° C. overnight. The reaction mixture was then concentrated under reduced pressure, the residue was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 70 mg of 2-(7-methoxy-6-nitro-quinolin-2-ylamino)-ethanol as a solid without further purifications. MS=264 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:20])([CH2:16][CH2:17][CH:18]=C)[CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.I([O-])(=O)(=O)=[O:22].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[F:1][C:2]([F:20])([CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:16][CH2:17][CH:18]=[O:22]
Reactant: C=CCCC(F)(F)CCOCCCCc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=CCCC(F)(F)CCOCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.3 %

Procedure:
Intermediate 16 (110 mg, 0.39 mmol) was dissolved in a mixture of THF (3 mL) and water (1 mL). To this solution was added sodium metaperiodate (272 mg, 1.27 mmol) and osmium tetroxide (4% water solution, 0.15 ml). The suspension was stirred 12 hours at room temperature, filtered and concentrated. The residue was purified by column chromatography on silica gel using methylene chloride/acetone (10:1) as eluent, to afford the title compound (89 mg, 81%) as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:22])[CH:11]=[CH:12][C:13]=1[O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1.[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][C:25]=1[CH3:33].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:22][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([F:23])=[C:25]([CH3:33])[CH:26]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1
Reactant: Cc1cc(C(=O)Cl)ccc1F
Reactant: CN1CCC(Oc2ccc(N)cc2-c2c(Cl)cnn2C)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(=O)Nc2ccc(OC3CCN(C)CC3)c(-c3c(Cl)cnn3C)c2)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A mixture of 3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(I-methyl-piperidin-4-yloxy)-phenylamine (0.040 g, 0.12 mmol), 4-fluoro-3-methylbenzoyl chloride (0.026 g, 0.12 mmol) and triethylamine (0.016 mL, 0.13 mmol)) in methylene chloride (1.5 mL) was stirred at room temperature overnight and concentrated to give a crude product that was subjected to a purification by prep HPLC. The corresponding fractions were collected and lyophilized to give a TFA-salt of Compound 745 as a white solid in 57.0% yield. LCMS m/z (%)=457.4 (+H, 100).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([NH2:7])=[N:4][N:3]=1.[C:8]1([CH:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15](Cl)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH3:1][C:2]1[O:6][C:5]([NH:7][C:15](=[O:16])[CH:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:4][N:3]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: Cc1nnc(N)o1
Product: Cc1nnc(NC(=O)C(c2ccccc2)c2ccccc2)o1

Procedure:
The title compound, white solid, m.p. 160-161° C. and MS: m/e=293.1 (M+) was prepared in accordance with the general method of example 44a from 5-methyl[1,3,4]oxadiazol-2-ylamine and 2,2-diphenylacetic acid chloride.