Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][C:6]=1[NH2:8])([O-:11])=[O:10]
Reactant: C1CNCCN1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 18 h
Yield: 70.2 %

Procedure:
A mixture of 5-chloro-2-nitrophenylamine (4.3 g, 25 mmol), piperazine (12.5 g, 145 mmol), and K2CO3 (4.0 g, 29 mmol) in DMF (50 mL) was stirred at 150° C. for 18 h. The reaction mixture was cooled to room temperature, solids were removed by filtration, and the filtrate was concentrated to a red residue. The residue was dissolved in EtOAc (100 mL), washed with water (50 mL), dried with Na2SO4, and concentrated in vacuo to afford the product as a yellow solid (3.9 g, 70%). See, Pharmazie, 39:747 (1984).
Reaction SMILES: N[C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[CH2:15][OH:16].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C(Cl)Cl>[CH2:27]([O:26][C:24]([C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@@H:3]1[CH2:15][OH:16])=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](CO)C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](C(=O)OCc2ccccc2)[C@@H](CO)C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A sample of (3R,4S)-tert-butyl 4-amino-3-(hydroxymethyl)piperidine-1-carboxylate (113.6 mMol) was dissolved in CH2Cl2 prior to the addition of saturated sodium carbonate (180 mL). This mixture was cooled to 0° C. and then benzyl chloroformate (21.76 mL, 136.32 mMol) was added slowly. The cooling was removed and stirring continued overnight. Partitioned the mixture between water and CH2Cl2. Aqueous layer was re-extracted with CH2Cl2. Combined organic layer was washed with brine and dried (MgSO4). Filtered, concentrated and dried in vacuo to get the desired product, (3R,4S)-tert-butyl 4-(benzyloxycarbonyl)-3-(hydroxymethyl)piperidine-1-carboxylate as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:3]=1[NH:4][C:5](=[O:16])[C:6]([F:15])([C:11]([F:14])([F:13])[F:12])[C:7]([F:10])([F:9])[F:8].CI.[C:26](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:26][N:4]([C:5](=[O:16])[C:6]([F:15])([C:11]([F:12])([F:13])[F:14])[C:7]([F:8])([F:9])[F:10])[C:3]1[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:2]=1[Br:1]
Reactant: O=C([O-])[O-]
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1Br)C(F)(C(F)(F)F)C(F)(F)F
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CN(C(=O)C(F)(C(F)(F)F)C(F)(F)F)c1ccc([N+](=O)[O-])cc1Br
Yield: 70 %

Procedure:
2'-Bromo-4'-nitro-2,3,3,3-tetrafluoro-2-(trifluoromethyl)propionanilide was reacted with methyl iodide, in acetone and in the presence of potassium carbonate, yielding N-methyl-2'-bromo-4'-nitro-2,3,3,3-tetrafluoro-2-(trifluoromethyl)propionanilide, an oil, yield 70% (>99% branched isomer).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)=[CH:4][CH:3]=1.C(O)(=O)C.[Cl:31]Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:17][CH:18]=3)[N:11]=[C:10]([C:23]([F:24])([F:25])[F:26])[C:9]=2[Cl:31])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(Cl)cc2)cc1
Reactant: ClCl
Solvent: CC(=O)O
Solvent: O
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(Cl)c2-c2ccc(Cl)cc2)cc1
Yield: 75 %

Procedure:
A 100 mL three-necked round-bottomed flask equipped with reflux condenser, gas dispersion tube and provisions for magnetic stirring was charged with 4-[5-(4-chlorophenyl)-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide (Example 1) (500 mg, 1.2 mmol) and 50 mL of glacial acetic acid. The solution was stirred at room temperature and treated with a stream of chlorine gas for a period of 15 minutes. The solution was then stirred at room temperature for 1.25 hours and then diluted with 100 mL of water. The solution was then extracted three times with ether and the combined ethereal phase washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give a white solid that was recrystallized from ether/petroleum ether to provide 390 mg (75%) of 4-[5-(4-chlorophenyl)-4-chloro-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide: mp 180°-182° C.; 1H NMR (CDCl3/300 MHz) 7.97 (d, J=6.6Hz, 2H, 7.49 (d, 2H), 7.45 (d, J=6.3Hz, 2H), 7.25 (d, J=6.6Hz, 2H), 5.78 (brs, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Br)ccc1Br
Product: O=C(Cl)c1cc(Br)ccc1Br
Yield: 75.1 %

Procedure:
Into a 2 L flask fitted with a reflux condenser and magnetic stir-bar was introduced 2,5-dibromobenzoic acid (50.0 g, 0.1786 mol) and thionyl chloride (150 mL, 2.04 mol). The mixture was refluxed for 8 hours. Most of the thionyl chloride was distilled off followed by removal of the remainder by rotary evaporation. Distillation gave 40 g of 2,5-dibromobenzoyl chloride. (pot temperature 110° C.; distillation temp 70° C./0.70 mm Hg).
Reaction SMILES: C[C:2]1[N:3]2[C:9]([C:10](=[O:12])[CH3:11])=[CH:8][N:7]=[C:4]2[S:5][CH:6]=1.[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.C[O-].[Na+]>C1COCC1>[Br:13][C:14]1[CH:21]=[CH:20][C:17](/[CH:18]=[CH:11]/[C:10]([C:9]2[N:3]3[C:4]([S:5][CH:6]=[CH:2]3)=[N:7][CH:8]=2)=[O:12])=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC(=O)c1cnc2scc(C)n12
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccc(Br)cc1)c1cnc2sccn12
Yield: 81 %

Procedure:
A solution of 1-(3-methylimidazo[2,1-b]thiazol-5-yl)ethanone (Formula B-1) (1.8 g) in THF (25 mL) was treated with 4-bromobenzaldehyde (3.05 mL) and sodium methoxide (0.27 g) at 25°. Within 5 minutes a heavy precipitate formed and additional THF (65 mL) was added to maintain fluididy. After 20 minutes the reaction was concentrated in vacuo and the concentrate was diluted with water and precipitated 2-(4-Bromophenyl)-E-ethenylimidazo[2,1-b]thiazole-5-yl methanone (Formula B-9) (2.9 g) was filtered. The precipitate was recrystallized from ethanol to yield pure 2-(4-Bromophenyl)-E-ethenylimidazo[2,1-b]thiazol-5-yl methanone (Formula B-9) (2.8 g, 81%), m.p. 213-215°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.Cl[CH2:10][C:11](=O)[CH3:12]>C(O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([CH3:12])[N:1]=2)[CH:4]=1
Reactant: CC(=O)CCl
Reactant: Nc1ccc(Br)cn1
Solvent: CCO
Product: Cc1cn2cc(Br)ccc2n1
Temperature: 90 °C
Yield: 73.8 %

Procedure:
2-Amino-5-bromopyridine (10 g, 57.8 mmol) was dissolved in ethanol (100 mL) and chloroacetone (9.3 mL, 115.59 mmol) was added. The mixture was heated to reflux at 90° C. for 16 h. The reaction mixture was concentrated under vacuum and the residue was purified by flash chromatography, eluting with a gradient of 0-20% methanol in DCM, to afford the title compound (9 g, 66.4%) as a yellow solid. δH (500 MHz, CD3OD) 9.03 (s, 1H), 8.02 (m, 1H), 7.93 (s, 1H), 7.79 (d, J 9.4 Hz, 1H), 2.56 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([C:24]4[CH:29]=[CH:28][C:27]([CH2:30]O)=[CH:26][CH:25]=4)[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3].[BrH:32].O.[OH-].[Na+]>CC(O)=O>[Br:32][CH2:30][C:27]1[CH:28]=[CH:29][C:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:16]3[CH:17]=[C:8]([C:5]([S:2]([CH3:1])(=[O:4])=[O:3])([CH3:7])[CH3:6])[CH:9]=[C:10]4[C:15]=3[N:14]=[CH:13][CH:12]=[CH:11]4)[CH:19]=2)=[CH:25][CH:26]=1
Reactant: Br
Reactant: CC(C)(c1cc(-c2cccc(-c3ccc(CO)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(c1cc(-c2cccc(-c3ccc(CBr)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of {3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl}-methanol from Step 1 (1.0 eq.) in AcOH (0.3M) was added HBr (48%; 9.5 eq.). The mixture was stirred at 80° C. for 12 h, cooled to rt, poured in cold water containing 10 eq. of NaOH and extracted with EtOAc. The organic extract was washed with saturated aqueous NaHCO3 (3×), brine, dried over Na2SO4, filtered and concentrated to afford the title compound as a yellow solid.
Reaction SMILES: [O:1]=[C:2]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]2)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[H][H]>C(O)C.[C].[Pd]>[OH:1][CH:2]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]2)[CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:9][CH2:10]1
Reactant: O=C1CCc2cc(C(=O)CCN3CCN(c4ccccc4)CC3)ccc2N1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C1CCc2cc(C(O)CCN3CCN(c4ccccc4)CC3)ccc2N1

Procedure:
2.0 Grams of 6-[1-oxo-3-(4-phenylpiperazinyl)-propyl]-3,4-dihydrocarbostyril and 0.6 g of 5%-palladium carbon were dispersed in 80 ml of ethanol and stirred at a room temperature under 2 atmospheric pressure of hydrogen gas for 5 hours. The reaction mixture was filtered for removing the palladium carbon and the mother liquor was concentrated under a reduced pressure and the residue thus obtained was recrystallized from isopropanol to obtain 1.4 g of 6-[1-hydroxy-3-(4-phenyl-1-piperazinyl)propyl]-3,4-dihydrocarbostyril in colorless needle-like crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:25]=[CH:24][C:23]3[C:22](=O)[C:21]4[C:16](=[CH:17][C:18]([S:27]([NH:30][C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=5)(=[O:29])=[O:28])=[CH:19][CH:20]=4)[C:15](=[O:38])[C:14]=3[CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:40][OH:41]>CO>[OH:41][N:40]=[C:22]1[C:23]2[C:14](=[CH:13][C:12]([S:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=3)(=[O:11])=[O:10])=[CH:25][CH:24]=2)[C:15](=[O:38])[C:16]2[CH:17]=[C:18]([S:27]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=3)(=[O:29])=[O:28])[CH:19]=[CH:20][C:21]1=2
Reactant: O=C1c2ccc(S(=O)(=O)Nc3cccc(O)c3)cc2C(=O)c2cc(S(=O)(=O)Nc3cccc(O)c3)ccc21
Reactant: NO
Agent: Cl
Solvent: CO
Product: O=C1c2cc(S(=O)(=O)Nc3cccc(O)c3)ccc2C(=NO)c2ccc(S(=O)(=O)Nc3cccc(O)c3)cc21
Temperature: 25 °C
Yield: 17.7 %

Procedure:
The product from Example 10B (110 mg, 0.2 mmol) and hydroxylamine hydrochloride (0.69 g, 10 mmol) were dissolved in methanol (6 ml) and heated at reflux for 18 hours. The mixture was allowed to cool to room temperature and the methanol was removed under reduced pressure. The residue was taken up in water, extracted with 10% methanol in methylene chloride, the aqueous layer was brought to pH 7 with aqueous sodium bicarbonate, and extracted again with ethyl acetate. All the organic layers were combined, dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 5% methanol in methylene chloride, followed by preparative thin-layer chromatography eluting with 10% methanol in methylene chloride to provide the title compound (20 mg, 18% yield) and the bis(oxime) (28 mg, 24% yield). 1H NMR (CD3OD) δ 9.37 (d, 1H, J=7 Hz), 8.73 (d, 1H, J=2 Hz), 8.61 (d, 1H, J=2 Hz), 8.41 (d, 1H), J=7 Hz), 8.08 (dd, 1H, J1=7 Hz, J2=2 Hz), 7.96 (dd, 1H, J1=7 Hz, J2=2 Hz), 7.00-6.95 (m, 2H), 6.63 (narrow m, 2H), 8.10-8.05 (m, 2H), 7.98-7.94 (m, 2H); MS (ESI+) 566 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:6]2[CH:7]=[CH:8][C:9]3=[N:10][NH:11][C:12]4[C:13](=[CH:14][N:15]([CH3:29])[CH2:16][C:17]=4[C:18]4[CH2:19][CH2:20][N:21]([CH2:25][C:26](O)=[O:27])[CH2:22][CH2:23][CH:24]=4)[C:4](=[C:5]23)[CH:3]=1.[NH:31]1[CH2:34][CH:33]([OH:35])[CH2:32]1.Cl.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O>[F:1][C:2]1[CH:30]=[C:6]2[CH:7]=[CH:8][C:9]3=[N:10][NH:11][C:12]4[C:13](=[CH:14][N:15]([CH3:29])[CH2:16][C:17]=4[C:18]4[CH2:19][CH2:20][N:21]([CH2:25][C:26]([N:31]5[CH2:34][CH:33]([OH:35])[CH2:32]5)=[O:27])[CH2:22][CH2:23][CH:24]=4)[C:4](=[C:5]23)[CH:3]=1
Reactant: OC1CNC1
Reactant: CN1C=C2C(=C(C3=CCCN(CC(=O)O)CC3)C1)NN=C1C=Cc3cc(F)cc2c31
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1C=C2C(=C(C3=CCCN(CC(=O)N4CC(O)C4)CC3)C1)NN=C1C=Cc3cc(F)cc2c31

Procedure:
A mixture of Example 90B (60 mg, 0.125 mmol), azetidin-3-ol, hydrochloric acid (20.57 mg, 0.188 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (57.1 mg, 0.150 mmol) and triethylamine (87 μL, 0.626 mmol) in 2 mL N,N-dimethylformamide was stirred at room temperature overnight. The mixture was extracted with dichloromethane and purified by flash chromatography on silica using an Analogix system (0-10% methanol/dichloromethane) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 2.46-2.90 (m, 10H), 3.17 (d, J=5.1 Hz, 2H), 3.62 (dd, J=10.3, 4.4 Hz, 1H), 3.89-4.14 (m, 5H), 4.33-4.61 (m, 2H), 5.72 (d, J=5.9 Hz, 1H), 5.92 (t, J=6.3 Hz, 1H), 7.18-7.35 (m, 3H), 7.69 (dd, J=10.4, 3.0 Hz, 1H), 8.22 (d, J=5.2 Hz, 1H), 11.51 (s, 1H). MS (ESI+) m/z 462 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[S:20])[CH2:10][N:9]=1.[H-].[Na+].[CH3:23][N:24]([CH2:26][CH2:27][CH2:28]Cl)[CH3:25].O>CN(C)C=O>[CH3:23][N:24]([CH3:25])[CH2:26][CH2:27][CH2:28][S:20][C:11]1[CH2:10][N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[N:12]=1
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCCSC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 6.4 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-1,4-benzodiazepine-2-thione in 50 ml of anhydrous dimethylformamide is added under cooling with stirring 1,2 g of sodium hydride (50% oily suspension), and the resulting mixture is stirred at room temperature for 20 minutes. To the mixture is added dropwise 7.6 g of N,N-dimethyl-3-chloropropylamine and the mixture is stirred at room temperature for 1.5 hours. The reaction mixture is poured into iced water and extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate and, thereafter, the solvent is distilled off under reduced pressure. An oily product obtained as the residue is subjected to column chromatography on alumina and eluted from the column with a benzenechloroform mixture. The eluate is treated according to usual procedure to obtain an oily 2-(3-dimethylaminopropylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine. The oily product thus obtained is treated, according to usual procedure, with fumaric acid and recrystallized from anhydrous ethanol and acetone to obtain 4.3 g of 2-(3-dimethylaminopropylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine fumarate, m.p. 154°- 156° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][N:14]([CH3:15])[C:12]1[C:11]([C:17]([F:18])([F:20])[F:19])=[CH:10][C:9]2[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccccn3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccccn3)c1)=N2

Procedure:
The title compound was prepared from {5-dimethylamino-2-[3-oxo-3-(3-pyridin-2-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M3) (253 mg, 0.466 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (66 mg).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.C(Cl)Cl.CS(Cl)(=O)=O.[NH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1>>[N:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][NH:27][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1
Reactant: NCc1ccccn1
Reactant: OCCCSc1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: c1ccc(CNCCCSc2ccncc2)nc1
Temperature: 80 °C
Yield: 24.4 %

Procedure:
To a solution of 5.26 g (31.1 mmol) of 4-(3-hydroxypropylthio)pyridine and 5.20 ml (37.3 mmol) of triethylamine in150 ml of methylene chloride, 2.90 ml (37.3 mmol) of methanesulfonyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. To 6.33 g of the residue was added 2.64 ml (25.6 mmol) of 2-aminomethylpyridine. The resulting mixture was heated at 80° C. for 3 hours. After cooling, the mixture was purified by column chromatography (eluent: chloroform/methanol=25:1) to obtain 1.62 g of the desired compound (yield: 25.4%, yellow oil).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9]C(=O)[N:7]([CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[C:6]=2[CH:16]=1.O.[K]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([SH:9])=[C:6]([NH:7][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[CH:16]=1
Reactant: CN(C)CCn1c(=O)sc2ccc(Cl)cc21
Agent: [K]
Solvent: O
Solvent: CCO
Product: CN(C)CCNc1cc(Cl)ccc1S
Reaction time: 2 h
Yield: 79 %

Procedure:
After removal of the solvent under reduced pressure, the residue was dissolved in ethylacetate, and the solution was washed with aqueous sodium hydroxide. The ethylacetate extract was acidified with dilute hydrochloric acid and the aqueous layer was neutralized with saturated aqueous sodium bicarbonate and then the resulting oily substance was extracted with ethylacetate. The extract was washed with water, dried (Na2SO4) and evaporated to give 5-chloro-3-(2-dimethylaminoethyl)-2-benzothiazolinone (74.5 g) as prisms. m.p. 62.5-65.5° C. 5-Chloro-3-(2-dimethylaminoethyl)-2-benzothiazolinone (74.5 g) was added to a mixture of water (110 ml), ethanol (350 ml) and potassium hydroide (75.0 g). The solution was refluxed with stirring for two hours. After removal of the solvent under reduced pressure, the residual oil was dissolved in water, then the aqueous solution was washed with ether. The aqueous layer was washed and neutralized with 2N-acetic acid with weak stirring. The resulting light yellow precipitates were collected on a filter, washed with water and air-dried to give 4-chloro-2-(2 -dimethylaminoethylamino)-thiophenol (52.9 g) as prisms. m.p. 126-130° C.
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].CC(=CC)C.[C:16]([O:20][C:21]([N:23]1[CH2:27][CH2:26][C:25]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH:39]=[O:40])([C:28]([F:31])([F:30])[F:29])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>O.O1CCOCC1>[C:16]([O:20][C:21]([N:23]1[CH2:27][CH2:26][C:25]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([OH:6])=[O:40])([C:28]([F:29])([F:30])[F:31])[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2C=O)(C(F)(F)F)C1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2C(=O)O)(C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.5 %

Procedure:
A solution of sodium chlorite (120 mg; 1.32 mmol; 5 eq.) and sodium dihydrogenphosphate (127 mg; 1.06 mmol; 4 eq.) in water (2 mL) was added dropwise to a mixture of 2-methyl-2-butene (0.25 mL) and 3-(2-formyl-phenoxy)-3-trifluoromethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (95 mg; 0.26 mmol; 1 eq.) in 1,4-dioxane (2 mL). The reaction mixture was stirred at room temperature for 3 hours and the 1,4-dioxane concentrated in vacuo. The aqueous solution was diluted with water and the pH made acidic with 0.1M HCl. The mixture was extracted with EA (2×) and the combined organic phase was dried over magnesium sulfate and concentrated in vacuo to afford the title compound (100 mg, quantitative) as a colourless oil. HPLC (max plot) 93.5%, Rt 4.22 min. UPLC/MS: (MS−) 374.3 ([M−H]−).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:12][N:11]([CH3:13])[C:10](=[O:14])[CH2:9]2)=[CH:4][C:3]=1Br.[Cl:16][C:17]1[CH:18]=[C:19]([C@H:23]([NH:26][C:27](=[O:44])[C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][C:29]=2[F:43])[CH2:24][OH:25])[CH:20]=[CH:21][CH:22]=1>>[NH2:1][C:2]1[C:3]([C:31]2[CH:32]=[CH:33][C:28]([C:27]([NH:26][C@@H:23]([C:19]3[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[CH:18]=3)[CH2:24][OH:25])=[O:44])=[C:29]([F:43])[CH:30]=2)=[CH:4][C:5]([CH:8]2[CH2:9][C:10](=[O:14])[N:11]([CH3:13])[CH2:12]2)=[CH:6][N:7]=1
Reactant: CC1(C)OB(c2ccc(C(=O)N[C@H](CO)c3cccc(Cl)c3)c(F)c2)OC1(C)C
Reactant: CN1CC(c2cnc(N)c(Br)c2)CC1=O
Product: CN1CC(c2cnc(N)c(-c3ccc(C(=O)N[C@H](CO)c4cccc(Cl)c4)c(F)c3)c2)CC1=O

Procedure:
Following Step 6 in Scheme 50, using 4-(6-amino-5-bromopyridin-3-yl)-1-methylpyrrolidin-2-one and (S)—N-(1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide, 4-(2-amino-5-(1-methyl-5-oxopyrrolidin-3-yl)pyridin-3-yl)-N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide was obtained as a diastereomeric mixture (33.3%). LCMS (m/z): 483.3 (MH+), 0.59 min; 1H NMR (400 MHz, CD3OD) δ ppm 8.79-8.61 (m, 1H) 7.97 (d, J=1.96 Hz, 1H) 7.93-7.82 (m, 2H) 7.48-7.39 (m, 3H) 7.39-7.25 (m, 3H) 5.25-5.14 (m, 1H) 3.95-3.76 (m, 3H) 3.69 (quin, J=8.22 Hz, 1H) 3.50 (dd, J=9.78, 7.43 Hz, 1H) 2.89 (s, 3H) 2.80 (dd, J=16.82, 9.00 Hz, 1H) 2.56 (dd, J=16.82, 8.22 Hz, 1H). The diastereomeric mixture was separated by chiral SFC (ChiralPak 5mic AD column, 4.6×100 (mm), IPA+0.1% DEA=40%, 5 mL/min). The polar diastereomer, 4-(2-amino-5-((R)-1-methyl-5-oxopyrrolidin-3-yl)pyridin-3-yl)-N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide, was obtained at Rt=1.41 min. LCMS (m/z): 483.3 (MH+), 0.586 min; 1H NMR (400 MHz, CD3OD) δ ppm 7.82 (d, J=1.56 Hz, 1H) 7.74 (t, J=7.83 Hz, 1H) 7.35 (d, J=2.35 Hz, 2H) 7.33-7.15 (m, 5H) 5.09 (t, J=5.87 Hz, 1H) 4.48 (s, 1H)) 3.83-3.63 (m, 3H) 3.50 (quint, J=8.22 Hz, 1H) 3.36 (dd, J=9.39, 7.43 Hz, 1H) 2.78 (s, 3H) 2.67 (dd, J=16.82, 9.00 Hz, 1H) 2.42 (dd, J=16.63, 8.41 Hz, 1H). The less polar diastereomer, 4-(2-amino-5-((S)-1-methyl-5-oxopyrrolidin-3-yl)pyridin-3-yl)-N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide, was obtained at Rt=2.16 min. LCMS (m/z): 483.3 (MH+), 0.585 min; 1H NMR (400 MHz, CD3OD) δ ppm 7.92 (d, J=2.35 Hz, 1H) 7.84 (t, J=8.02 Hz, 1H) 7.51-7.21 (m, 7H) 5.18 (t, J=5.87 Hz, 1H) 3.94-3.72 (m, 3H) 3.59 (quin, J=8.22 Hz, 1H) 3.50-3.42 (m, 1H) 2.88 (s, 3H) 2.82-2.70 (m, 1H) 2.51 (dd, J=16.82, 8.61 Hz, 1H).