Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:9]=[C:10]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[N:11]2[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]2)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:20]([O:19][C:17]([C:10]1[N:11]2[C:16]([CH:15]=[CH:14][CH:13]=[CH:12]2)=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=1)=[O:18])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)c1cc(C(=O)OCc2ccccc2)n2ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(C(=O)OCc2ccccc2)n2ccccc12

Procedure:
A solution of indolizine-1,3-dicarboxylic acid 3-benzyl ester 1-tert-butyl ester (400 mg, 1.14 mmol) and TFA (872 μl, 11.4 mmol) in CH2Cl2 (10 mL) was stirred at RT overnight. The reaction mixture was concentrated and the crude solid was taken-up in a mixture of MeOH and CH2Cl2, the precipitate was filtered-off and washed with a minimum of MeOH to give the desired compound as a white powder. The filtrate was concentrated and purified by flash column chromatography on silica gel (CH2Cl2 to CH2Cl2/MeOH 95:5) to give again the desired compound. TLC, Rf (CH2Cl2/MeOH 9:1)=0.6; MS (LC/MS): 296.0 [M+H]+ 294.1 [M−H]−; tR (HPLC conditions a): 3.64 min.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[CH:15]=[C:16]([N:22]2[C:27](=[O:28])[C:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4[C:37]([C:42]#[N:43])=[CH:38][CH:39]=[CH:40][CH:41]=4)=[CH:32][CH:31]=3)=[C:25]([CH2:44][CH2:45][CH3:46])[N:24]=[C:23]2[CH3:47])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>O.C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[C:16]([N:22]2[C:27](=[O:28])[C:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[C:42]4[NH:3][C:4](=[O:7])[O:5][N:43]=4)=[CH:32][CH:31]=3)=[C:25]([CH2:44][CH2:45][CH3:46])[N:24]=[C:23]2[CH3:47])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1nc(C)n(-c2ccc(OC)c(F)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC)c(F)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
A mixture of hydroxylammonium chloride (1.74 g), sodium hydrogen carbonate (2.5 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[1-(3-fluoro-4-methoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.24 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.45 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.42 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.04 g, 74%).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:50]([C:57]1[CH:62]=[CH:61][C:60]([C:63]2[CH:68]=[CH:67][CH:66]=[C:65]([NH2:69])[CH:64]=2)=[CH:59][CH:58]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CN(C=O)C>[O:50]([C:57]1[CH:62]=[CH:61][C:60]([C:63]2[CH:68]=[CH:67][CH:66]=[C:65]([NH:69][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:64]=2)=[CH:59][CH:58]=1)[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Nc1cccc(-c2ccc(Oc3ccccc3)cc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc(Oc5ccccc5)cc4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 83.3 %

Procedure:
DIEA (0.011 mL, 0.063 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.013 g, 0.057 mmol) and HATU (0.024 g, 0.063 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-phenoxy-biphenyl-3-ylamine (0.015 g, 0.057 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.022 g of product in 83% yield: LCMS (ESI) m/z 464 (MH+).
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH:16]3[CH:21]([C:22]([OH:24])=[O:23])[NH:20][CH2:19][CH2:18][S:17]3)(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[O:27]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28]1.C(O)C>C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].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>[O:27]1[CH:31]=[CH:30][C:29]([C:2]2[CH:26]=[CH:25][C:5]([O:6][C:7]3[CH:8]=[CH:9][C:10]([S:13]([CH:16]4[CH:21]([C:22]([OH:24])=[O:23])[NH:20][CH2:19][CH2:18][S:17]4)(=[O:15])=[O:14])=[CH:11][CH:12]=3)=[CH:4][CH:3]=2)=[CH:28]1
Reactant: O=C(O)C1NCCSC1S(=O)(=O)c1ccc(Oc2ccc(Br)cc2)cc1
Reactant: OB(O)c1ccoc1
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: c1ccccc1
Solvent: CCO
Product: O=C(O)C1NCCSC1S(=O)(=O)c1ccc(Oc2ccc(-c3ccoc3)cc2)cc1
Temperature: 80 °C
Yield: 67 %

Procedure:
A mixture of 0.45 g (1.0 mmol) of 3(S)-4-(4-(4-bromophenoxy)benzenesulfonyl-tetrahydro-2H-1,4-thiazine-3-carboxylic acid and 0.11 g (1.0 mmol) of 3-furan boronic acid (J. Org. Chem. 1984, 49, 5237-5243) in 2 mL of benzene, 2 mL of 2M aq. sodium carbonate, and 1.5 mL of ethanol was deoxygenated with a stream of argon for 15 minutes, and then 115 mg (0.1 mmol) of tetrakis(triphenylphosphine)palladium was added and the mixture was heated at 80° C. for six days. After cooling to room temperature, the mixture was partitioned between ethyl acetate and pH 4 citrate buffer. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by chromatography on silica gel, eluting with a gradient from dichloromethane to 5% methanol in dichloromethane, to provide 3(S)-4-(4-(4-(furan-3-yl)phenoxy)benzenesulfonyl-tetrahydro-2H-1,4-thiazine-3-carboxylic acid (0.317 g, 67%) as a sticky solid foam. FAB+MS Calcd for M+Cs+ =606.0021. Obs 606.0036; 1H NMR (CDCl3) δ7.72-7.43 (m, 6H), 7.04 (d, 2H, J=8.46 Hz), 7.00 (d, 2H, J=8.82 Hz), 6.67 (s, 1H), 4.51 (s, 1H), 4.1-3.9 (bm, 1H), 3.7-3.6 (bm, 1H), 3.2-3.1 (bm, 1H), 2.42 (bd, 1H, J=12.87 Hz), 1.61 (s, 3H), 1.38 (s, 3H)
Reaction SMILES: C(Cl)(=O)C1C=CC=CC=1.[S-:10][C:11]#[N:12].[NH4+].[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>CC(C)=O>[CH:14]1([NH:20][C:11]([NH2:12])=[S:10])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: NC1CCCCC1
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: O=C(Cl)c1ccccc1
Product: NC(=S)NC1CCCCC1
Temperature: 0 °C

Procedure:
295.5 g (2.1 mol) of benzoyl chloride were added dropwise over the course of 10 minutes to a solution of 165.0 g (2.2 mol) of ammonium thiocyanate in 500 ml of absolute acetone. After refluxing for 10 minutes, 198.9 g (2.0 mol) of cyclohexylamine were added dropwise, and the mixture was refluxed for a further 20 minutes. It was then stirred into 4 1 of ice-water, and the water was decanted off the oily product. The residue was dissolved in a hot mixture of 2 1 of 10% strength sodium hydroxide solution and 500 ml of ethanol and refluxed for 30 minutes. The reaction mixture was then diluted with ice-water, and the pH was adjusted initially to 1 with concentrated hydrochloric acid and then to 9 with solid sodium bicarbonate. The resulting precipitate was filtered off with suction, washed with water and dried at 80° C. under reduced pressure.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][O:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([NH2:23])[CH:16]=1.[Cl:25][C:26]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:27]=1[C:28]#[N:29].C([O-])(O)=O.[Na+].[O-][Cl:41].[Na+]>>[CH3:12][O:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([NH:23][C:28](=[N:29][Cl:41])[C:27]2[CH:30]=[CH:31][C:32]([Cl:34])=[CH:33][C:26]=2[Cl:25])[CH:16]=1
Reactant: COC(=O)c1ccc(OC)c(N)c1
Reactant: N#Cc1ccc(Cl)cc1Cl
Reactant: [O-]Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)c1ccc(OC)c(NC(=NCl)c2ccc(Cl)cc2Cl)c1
Temperature: 180 °C
Reaction time: 6 h
Yield: 50 %

Procedure:
Anhydrous p-toluene sulfonic acid (20.99 g, 110.04 mmol) was melted at 120° C. and 3-amino-4-methoxy benzoic acid methyl ester (10 g, 55.20 mmol) obtained in step 1 of Preparation Example 1 and 2,4-dichlorobenzonitrile (18.99 g, 110.04 mol) were added thereto and stirred at 180° C. for 6 hours. The resulting solution was cooled to room temperature and the reaction was stopped by adding NaHCO3 thereto. The resulting mixture was extracted with ethyl acetate, the extract was dried over MgSO4 and concentrated under a reduced pressure. The concentrate was dissolved in 50% methanol and 5% NaOCl (30 ml, 20.64 mmol) was added dropwise thereto. After 5 min, the resulting mixture was extracted with ethyl acetate, the extract was dried over MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent—MeOH:CDCl3=5:95, Merck, Silicagel 60) to obtain the title compound (18 g, 10.32 mmol) in a yield of 84%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[C:12]([C:20]1[C:21](=[O:31])[N:22]([CH3:30])[C:23](=[O:29])[N:24]([CH3:28])[C:25]=1[CH2:26]Br)(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[N:11]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:20]2[C:25]([N:24]([CH3:28])[C:23](=[O:29])[N:22]([CH3:30])[C:21]2=[O:31])=[CH:26]1
Reactant: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Solvent: CCO
Product: Cn1c(=O)c2c(-c3ccccc3)n(-c3cc([N+](=O)[O-])ccc3N)cc2n(C)c1=O
Yield: 44.3 %

Procedure:
In a 25 mL round bottom flask 4-nitro 1,2-phenylenediamine (300 mg, 1.96 mmol), and 4a (330 mg, 979 mmol) (see Example 2 for synthesis of 4a) were combined in ethanol (10 mL). The stirred mixture was brought to reflux for 3 h during which a yellow precipitate formed. The mixture was then chilled in an ice bath, filtered, and the precipitate washed with cold ethanol to give 5b (340 mg, 88.7%) as a waxy shiny yellow solid; mp>300° C. 1H NMR (600 MHz, DMSO-d6) δ 7.97 (dd, J=2.7, 9.2, 1H), 7.86 (d, J=2.6, 1H), 7.37-7.32 (m, 2H), 7.28-7.24 (m, 4H), 7.05 (s, 1H), 6.75 (d, J=9.2, 1H), 6.65 (s, 2H), 3.35 (s, 3H), 3.21 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 159.06, 151.66, 150.89, 135.01, 133.84, 130.38, 129.34, 129.02; 128.32, 127.38, 126.19, 126.05, 121.34, 114.31, 105.49, 102.98, 31.59, 27.46. MS (ES+) (m/z): [M+1]+ calculated for C20H18N5O4, 392.135880. found 392.03.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[Na+].[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[Cl:15])[CH:10]=[O:11]>S(=O)(=O)(O)O>[Br:6][C:7]1[C:14]([Cl:15])=[CH:13][C:12]([N+:1]([O-:4])=[O:2])=[C:9]([CH:8]=1)[CH:10]=[O:11]
Reactant: O=Cc1ccc(Cl)c(Br)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=Cc1cc(Br)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 7 h
Yield: 47.8 %

Procedure:
To a mixture of sulphuric acid (40 ml) and sodium nitrate (2.66 g, 31.3 mM) at 0°-5° C. was added 3-bromo-4-chlorobenzaldehyde (6.25 g, 28.5 mM). The resulting mixture was stirred at room temperature for 7 h and then diluted with ice water (300 ml). The precipitated solids were filtered, washed with water and dried to give a powder. Recrystallization of this material from the mixture of isopropanol and water (2:1) provided the title 2-nitrobenzaldehyde 1f (3.6 g, 51.5%) as a light yellow powder, m.p. 81°-82° C.
Reaction SMILES: N1C2C=CC=CC=2NC=1CN1C2C=CC=CC=2N=C1C[N:21]([CH3:43])[CH2:22][C:23]([C:25]1[CH:42]=[CH:41][C:28]([O:29][CH2:30][C:31]([O:33][CH2:34]C2C=CC=CC=2)=[O:32])=[CH:27][CH:26]=1)=[O:24]>CCOC(C)=O.CO>[CH3:43][NH:21][CH2:22][CH:23]([C:25]1[CH:26]=[CH:27][C:28]([O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[C:41]([O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:42]=1)[OH:24]
Reactant: CN(CC(=O)c1ccc(OCC(=O)OCc2ccccc2)cc1)Cc1nc2ccccc2n1Cc1nc2ccccc2[nH]1
Solvent: CO
Solvent: CCOC(C)=O
Product: CNCC(O)c1ccc(OCC(=O)OC)c(OCC(=O)OC)c1
Yield: 90 %

Procedure:
Following the procedure of Example 76(e), except substituting dimethyl 4-[2-(Cbz-methylamino)acetyl]-1,2-phenylenedioxydiacetate (2.1 g, 4.57 mmol) for benzyl 4-[2-[[[1-[(benzimidazol-2-yl)methyl]benzimidazol-2-yl]methyl]methylamino]acetyl]phenoxyacetate and using EtOAc (50 mL) and MeOH (20 mL) as solvents, the title compound (1.34 g, 90%) was prepared: MS (ES) m/e 328.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][CH3:11].[Cl:13]N1C(=O)CCC1=O>C(Cl)Cl>[NH2:1][C:2]1[C:7]([Cl:13])=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][CH3:11]
Reactant: CCC(=O)c1cc(Br)ccc1N
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CCC(=O)c1cc(Br)cc(Cl)c1N
Temperature: 45 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
1-(2-Amino-5-bromo-phenyl)-propan-1-one (144.0 mg, 0.63 mmol) was dissolved in CH2Cl2 (10.0 mL), and N-chlorosuccinimide (168.0 mg, 1.26 mmol) was added to this solution. The resulting mixture was stirred at 45° C. overnight. The reaction was cooled to room temperature and concentrated. The residue was purified through column chromatography to afford 1-(2-amino-5-bromo-3-chloro-phenyl)-propan-1-one as a solid (130.0 mg, 76.1%).
Reaction SMILES: [H-].[Na+].[NH2:3][C@H:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)[CH2:5][OH:6].Cl[CH2:15][C:16](OCC)=[O:17]>C1COCC1>[F:13][C:9]1[CH:8]=[C:7]([C@H:4]2[NH:3][C:16](=[O:17])[CH2:15][O:6][CH2:5]2)[CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)CCl
Reactant: N[C@@H](CO)c1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1COC[C@@H](c2cccc(F)c2)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
To a stirring mixture of NaH (900 mg, 37.5 mmol) in THF (25 mL) at room temperature under N2 atmosphere was added dropwise a solution of (R)-2-amino-2-(3-fluoro-phenyl)-ethanol (4.0 g, 26.4 mmol) in THF (25 mL). The reaction mixture was stirred at room temperature for 30 minutes, then cooled to 0° C. A solution of ethyl chloroacetate (3.31 g g, 27 mmol) in THF (10 mL) was added dropwise, and the reaction mixture was stirred for 25 minutes at 0° C., then stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and a 1:1 mixture of brine and water. The organic layer was separated, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was recrystallized from diethyl ether to give 1.73 g (34%) of (R)-5-(3-fluoro-phenyl)-morpholin-3-one, MP=119-121° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[C:4](Cl)[N:3]=1.[OH-:14].[K+].[CH3:16]O>CN(C)C=O>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[C:4]([O:14][CH3:16])[N:3]=1
Reactant: CO
Reactant: Nc1nc(Cl)c(C(F)(F)F)cc1Cl
Reactant: [OH-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1nc(N)c(Cl)cc1C(F)(F)F
Temperature: 130 °C
Reaction time: 89 h

Procedure:
6.7 g (0.029 mol) of 2-amino-3,6-dichloro-5-trifluoromethylpyridine were added to a stirred mixture of 2.4 g (0.0377 mol) of 88% potassium hydroxide powder in 10 ml of methanol and 100 ml of dimethylformamide at 20° C. in the course of 5 minutes. The reaction mixture was now stirred for 89 hours at 130° C., with HPLC monitoring, a further 5 ml of methanol being added to the reaction mixture after 40 hours. After working-up in accordance with Example I.2., 0.3 g (4.6% of theory) of the title compound of ηD24 =1.5143 was obtained in fractions 3 and 4. Fraction 5 contained 0.7 g (10% of theory) of 2-amino-3-chloro-6-dimethylamino-5-trifluoromethylpyridine (NMR 400 MHz, CDCl3 7.58 (pyridine), 2.95 (CH3)2N) and fractions 9-16 contained 1.1 g (16% of theory) of starting material. Other secondary components were found in the fractions which followed.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].S(Cl)([Cl:28])=O>ClCCl>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([Cl:28])=[O:25])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Solvent: ClCCl
Product: CCc1ccc(C2CC(C(=O)Cl)CN(C(=O)N3CCOCC3)C2)cc1
Reaction time: 2 h

Procedure:
150 mg (0.43 mmol) of the compound from Example 38A were initially charged in 3 ml of dichloromethane, and 63 μl (103 mg, 0.87 mmol) of thionyl chloride were added. The reaction mixture was stirred under RF for 2 h, concentrated under reduced pressure, and then three times toluene was added and the mixture was in each case concentrated again under reduced pressure.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH2:16][C:17](OCC)=[O:18])=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:22]([NH2:25])[CH2:23][NH2:24]>>[NH2:24][CH2:23][CH2:22][NH:25][C:17](=[O:18])[CH2:16][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)Cc1c(-c2ccccc2)[nH]c2ccccc12
Reactant: NCCN
Product: NCCNC(=O)Cc1c(-c2ccccc2)[nH]c2ccccc12
Yield: 80 %

Procedure:
A mixture of 1.6 g (5.7 mmol) of ethyl (2-phenylindol-3-yl)acetate and 15 ml of ethylenediamine was heated at reflux overnight. The excess diamine and the formed water were removed by distillation at 90° C. in vacuo, and the crude product was chromatographed with dichloromethane/ethanol 1:1 to afford 1.35 g (80%) of N-(2-aminoethyl)-(2-phenylindol-3-yl)acetamide as a yellow crystalline solid. The amide and 20 ml of HMDS were heated at reflux under argon overnight. The crystals formed upon cooling were collected by filtration, dissolved in ethanol, and traces of HMS were stripped off along with ethanol. The title imidazoline was purified by chromatography with dichloromethane/ethanol 7:3, dissolved in ethanol and treated with ethanolic HCl to form a hydrochloride salt which was recrystallized from EtOH/EtOAc to yield 0.45 g (31%) of colorless crystals along with 0.32 g of the product salt from the mother liquid (54% overall yield).
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2([F:24])[CH2:22][CH:21]2[NH2:23])=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2([F:24])[CH2:22][CH:21]2[NH:23][C:8]([C:7]2[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=2)=[O:9])=[CH:18][CH:19]=1
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: NC1CC1(F)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(C(=O)NC2CC2(F)c2ccc(Cl)cc2)c(C(F)F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (0.105 g; 0.54 mmol) in dichloromethane (2 ml) was added dropwise to a stirred solution of the amine from example P5 (compound Z1.004; 2-(4-chlorophenyl)-2-fluoro-cyclopropylamine; 0.100 g; 0.54 mmol) and triethylamine (0.15 ml; 1.08 mmol) in dichloromethane (3 ml). The reaction mixture was stirred for 1 hr at ambient temperature then allowed to stand for 18 h. The reaction mixture was washed with 2M HCl (5 ml) and with saturated NaHCO3 (5 ml) and then dried over MgSO4. Evaporation of the solvent yielded 0.15 g 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (2-(4-chlorophenyl)-2-fluoro-cyclopropyl)-amide in the form of a yellow solid (81% of theory) as a 7:3 mixture of cis/trans isomers.
Reaction SMILES: [NH2:1][C@H:2]([CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])[OH:4].CCN(C(C)C)C(C)C.[C:28](Cl)(=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>C1COCC1.CCOC(C)=O>[OH:4][C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])[C@H:2]([NH:1][C:28](=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:13][N:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CCCCCCCC(=O)Cl
Reactant: COc1ccccc1[C@@H](O)[C@H](N)CN1CCCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCCCCCCC(=O)N[C@H](CN1CCCC1)[C@H](O)c1ccccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.5 %

Procedure:
To a 0° C. solution of (1R,2R)-2-amino-1-(2-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-1-ol (0.1 g, 0.40 mmol) (compound 6) in THF (5 ml) was added Hunig's Base (0.07 g, 0.52 mmol), followed by the dropwise addition of octanoyl chloride (0.07 g, 0.40 mmol). The resulting mixture was allowed to stir overnight at room temperature, diluted with EtOAc, and washed with satd. aq. NaHCO3, satd. aq. NaCl, and dried over MgSO4. Purified by flash silica chromatography (MeOH/CH2Cl2) to give a yellow oil (0.03 g, 0.09 mmol, 22% yield). HPLC purity 93% (tR=5.3 min) NMR (500 MHz, CDCl3) δ 7.4 (m, 1H), 7.2-7.3 (m, 1H), 6.9-7.0 (m, 1H), 6.8-6.9 (m, 1H), 6.0-6.1 (m, 1H), 5.3 (d, 1H), 4.2-4.3 (m, 1H), 3.8 (s, 3H), 2.9-3.0 (m, 3H), 2.5-2.7 (m, 4H), 2.0-2.1 (m, 2H), 1.7-1.8 (m, 4H), 1.9-2.0 (m, 2H), 1.2-1.4 (m, 6H), 0.8-0.9 (t, 3H). ESI-MS m/z 377.2 (M+H +).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:30])[C:13]([NH:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:14][N:15]3[CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:10][C:9]=2[F:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:40](=[O:49])[CH2:41][CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45].O>C1COCC1>[CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:30])[C:13]([N:23]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:40](=[O:49])[CH2:41][CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])=[CH:14][N:15]3[CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:10][C:9]=2[F:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CNc1cn(C(CC)CC)c2cc(NC3CCCCC3)c(F)cc2c1=O
Reactant: CCOC(=O)CCCC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCC(=O)N(CC(=O)OCC)c1cn(C(CC)CC)c2cc(NC3CCCCC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg of ethyl {[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]amino}acetate was dissolved in 3.0 ml of THF, and 0.060 ml of triethylamine and 0.060 ml of ethyl 5-chloro-5-oxopentanoate were added, followed by overnight stirring at room temperature. Water was added to the reaction mixture, followed by extraction with chloroform. The resulting organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and then concentrated under a reduced pressure. By purifying the resulting residue by silica gel column chromatography, 199 mg of ethyl 5-[[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl](2-ethoxy-2-oxoethyl)amino]-5-oxopentanoate was obtained.