Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][N:10]=[C:9]([C:12](F)=[O:13])[C:8]=1[C:15]([F:18])([F:17])[F:16].O[N:20]=[C:21]([C:23]1[CH:40]=[CH:39][C:26]([CH2:27][N:28]2[CH2:31][CH:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]2)=[CH:25][CH:24]=1)[NH2:22].N1C=CC=CC=1C1C(C(F)(F)F)=C(C2ON=C(C3C=CC(CN4CC(C(O)=O)C4)=CC=3)N=2)ON=1.N1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>ClCCl.C(#N)C.C(OCC)(=O)C>[C:35]([O:34][C:32]([CH:30]1[CH2:31][N:28]([CH2:27][C:26]2[CH:39]=[CH:40][C:23]([C:21]3[N:22]=[C:12]([C:9]4[C:8]([C:15]([F:18])([F:17])[F:16])=[C:7]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)[O:11][N:10]=4)[O:13][N:20]=3)=[CH:24][CH:25]=2)[CH2:29]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(C(N)=NO)cc2)C1
Reactant: O=C(F)c1noc(-c2ccccn2)c1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)C1CN(Cc2ccc(-c3noc(-c4onc(-c5ccccn5)c4C(F)(F)F)n3)cc2)C1
Agent: [F-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(-c4noc(-c5ccccn5)c4C(F)(F)F)n3)cc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(pyridin-2-yl)-4-(trifluoromethyl)isoxazole-3-carbonyl fluoride (48 mg, 0.185 mmol) and tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate, Int. 1 (56.3 mg, 0.185 mmol) in dichloromethane (2 mL) was added pyridine (37.3 μL, 0.461 mmol). The reaction mixture was stirred at room temperature for 16 hrs. The reaction mixture was then concentrated under reduced pressure, and the residue was diluted with ethyl acetate (3 mL), washed with water (1 mL), washed with a saturated aqueous solution of sodium bicarbonate (1 mL), washed with brine (1 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure resulted in the crude mixture which was dissolved in acetonitrile (2 mL). A 1.0M solution of tetrabutylammonium fluoride in tetrahydrofuran (369 μL, 0.369 mmol) was added, and the solution was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate (30 mL), washed with water (10 mL), washed with a saturated aqueous solution of sodium bicarbonate (10 mL), washed with brine (10 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by preparative HPLC afforded tert-butyl-1-(4-(5-(5-(pyridin-2-yl)-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate, which was used in the next step without any further purification. The product had an HPLC retention time=2.97 min.—Column: YMC S5 COMBISCREEN® 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=528.3.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:29](O)(=[O:39])[C:30]1[CH:38]=[CH:37][CH:36]=[C:32]([C:33]([OH:35])=[O:34])[CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:28])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:10][N:9]2[C:29]([C:30]2[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33]([OH:35])=[O:34])=[O:39])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: O=C(O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1CN(C(=O)c2cccc(C(=O)O)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.1 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (42.3 mg, 0.10 mmol), isophthalic acid (33.2 mg, 0.20 mmol), HATU (72.0 mg, 0.20 mmol) and iPr2NEt (0.1 mL) in CH2Cl2 (2 mL) was stirred at rt 2 hrs. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and the residue was purified by RP-HPLC to give rac-3-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-benzoic acid (19.5 mg, 34.2%). HRMS (ES+) m/z Calcd for C30H26Cl2F2N2O3+H [(M+H): 571.1362; Found: 571.1364.
Reaction SMILES: [CH:1]12[CH2:10][CH:7]([CH2:8][CH2:9]1)[CH:6]1[CH:2]2[C:3](=[O:12])[CH2:4][C:5]1=[O:11].[N+:13]([O-])([OH:15])=[O:14]>CCOCC>[N+:13]([CH:4]1[C:3](=[O:12])[CH:2]2[CH:6]([CH:7]3[CH2:10][CH:1]2[CH2:9][CH2:8]3)[C:5]1=[O:11])([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: O=C1CC(=O)C2C3CCC(C3)C12
Solvent: CCOCC
Product: O=C1C2C3CCC(C3)C2C(=O)C1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
To a stirred suspension of tricyclo [5,2,1,02,6 ] decane-3,5-dione (0.82g; 0.05 mole) in dry ether (8ml.) was added fuming nitric acid (1ml.) at -20° C. After stirring for 1hr. at 20° C the solid was filtered, washed with cold, dry ether and recrystallised from methanol, m.p. 167° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[C:8]2[C:3]=1[CH:4]=[N:5][C:6](Cl)=[N:7]2.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[C:30]([Cl:40])[CH:29]=1>C(O)(C)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:17][CH2:18]2)=[C:8]2[C:3]=1[CH:4]=[N:5][C:6]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[C:30]([Cl:40])[CH:29]=1)=[N:7]2
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)c3cnc(Cl)nc23)CC1
Reactant: Nc1ccc(N2CCOCC2)c(Cl)c1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)c3cnc(Nc4ccc(N5CCOCC5)c(Cl)c4)nc23)CC1
Temperature: 110 °C

Procedure:
A mixture of tert-butyl 4-(5-bromo-2-chloroquinazolin-8-yloxy)piperidine-1-carboxylate (1 eq) and N-(4-amino-2-chlorophenyl) morpholine (1 eq) in isopropanol was heated in a sealed tube at 110° C. for overnight. The reaction mixture was concentrated and proceeds for next step. ES/MS m/z 618.0 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][CH2:13][NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[C:3]([CH2:12][CH:13]=[N:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:23])([F:24])[F:25])=[N:4][CH:5]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:7]=1
Reactant: O=C(NCCc1ncc(C(F)(F)F)cc1Cl)c1ccccc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(N=CCc1ncc(C(F)(F)F)cc1Cl)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.1 %

Procedure:
2.00 g of N-{2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]ethyl}-2-(trifluoromethyl)benzamide (Int-5), (known from WO 2004/016088), were dissolved in 20 mL of methanol. 1 mL of concentrated bleach was added to the reaction mixture at room temperature. The reaction mixture was stirred for 24 hours at room temperature. 20 mL of a 1N aqueous solution of sodium hydroxide were added to the reaction mixture which was then extracted twice with diethyl ether. The combined organic phases were dried over magnesium sulphate, concentrated in vacuo to yield 1.41 g of crude product which was purified by chromatography on silica gel with ethyl acetate/heptane (3/7 v/v) as eluting phase. 340 mg (17%) of desired N-{2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]ethylidene}-2-(trifluoromethyl)benzamide (Int-6) were obtained, [M+1]=395.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[NH2:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([Br:15])=[CH:10][N:9]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1CCCC1.[Br:31][C:32]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][C:33]=1[O:34][C:35]([CH3:40])([CH3:39])[C:36](Cl)=[O:37].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(=O)([O-])O.[Na+]>ClCCl.O1CCCC1.C(=O)=O.CC(C)=O.CN(C)C=O>[Br:15][C:11]1[CH:12]=[C:13]([CH3:14])[C:8]([NH:7][C:36](=[O:37])[C:35]([O:34][C:33]2[CH:41]=[C:42]([N+:45]([O-:47])=[O:46])[CH:43]=[CH:44][C:32]=2[Br:31])([CH3:40])[CH3:39])=[N:9][CH:10]=1
Reactant: CC(C)(Oc1cc([N+](=O)[O-])ccc1Br)C(=O)Cl
Reactant: Cc1cc(Br)cnc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(Br)cnc1NC(=O)C(C)(C)Oc1cc([N+](=O)[O-])ccc1Br
Reaction time: 0.08 h

Procedure:
To a solution of the compound obtained in Reference Example 63(1) (295 mg) in dichloromethane (10 mL) were added oxalyl chloride (253 μL) and a drop of N,N-dimethylformamide, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to give crude 2-(2-bromo-5-nitrophenoxy)-2-methylpropionyl chloride. To a solution of 2-amino-5-bromo-3-methylpyridine (727 mg) in tetrahydrofuran (20 mL) was added dropwise 1M lithium bis(trimethylsilyl)amide-tetrahydrofuran solution (3.88 mL) over a period of one minute under cooling in dry ice-acetone bath under argon atmosphere. The mixture was stirred at the same temperature for 5 minutes. Thereto was added quickly a solution of 2-(2-bromo-5-nitrophenoxy)-2-methylpropionyl chloride in tetrahydrofuran (10 mL), and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added an aqueous citric acid solution, and the mixture was basified with an aqueous saturated sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on NH-silica gel (Chromatorex NH-silica gel; solvent; n-hexane/ethyl acetate=19/1→3/1) to give N-(5-bromo-3-methylpyridin-2-yl)-2-(2-bromo-5-nitrophenoxy)-2-methylpropionamide (599 mg) as a colorless powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Cl:21])[CH:19]=2)[NH:14][C:13](=[O:22])[C@@H:12]1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:24]([O-])([OH:26])=[O:25]>C(O)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[C:16]([N+:24]([O-:26])=[O:25])[CH:17]=[C:18]([Cl:21])[CH:19]=2)[NH:14][C:13](=[O:22])[C@@H:12]1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H]1C(=O)Nc2ccc(Cl)cc2N1C(=O)OCc1ccccc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: C[C@H]1C(=O)Nc2c(cc(Cl)cc2[N+](=O)[O-])N1C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
The compound of Example III (1.5 g, 4.5 mmol) was nitrated in glacial acetic acid (15 ml). A total of 5 ml (124.3 mmol) of fuming nitric acid were added dropwise in the course of 4 hours at 0° C. to room temperature. The mixture was subsequently poured into 100 ml of ice-water, and the product, which was obtained in the form of a yellow solid, was filtered off, washed thoroughly with water, and dried. Melting point 85° C. (subl.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=1)[CH3:2].C(=O)(O)[O-].[Na+].[CH2:21](I)[CH3:22].O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[C:11]([C:12]([O:14][CH2:21][CH3:22])=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=1)[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)Cc1ncccc1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ncccc1C(=O)OCC
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a mixture of 54 g (0.26 mole) of 3-carboxy-2-pyridineacetic acid ethyl ester* and 24.4 g (0.29 mole) of sodium bicarbonate in 300 ml of dimethylformamide was added 60.8 g (0.39 mole) of ethyliodide. The mixture was stirred at 50° C. for 24 hr; cooled to 25° C. and treated with 300 ml of water. The aqueous solution was extracted 3 times with isopropyl ether. The isopropyl ether solution was extracted with dilute hydrochloric acid. The acid layer was made basic with sodium hydroxide and extracted with isopropyl ether. The ether layer was dried over anhydrous sodium sulfate, concentrated and the residue was distilled to give 47 g (76%), b.p. 128°-130° C./0.5 mm.
Reaction SMILES: C([C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[C:5]([NH:7][CH:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:11][NH:10][CH2:9]1)=[O:6])C.[N:28]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1)=[C:29]=[O:30].C(N(CC)CC)C>C1COCC1>[C:4]1([C:5]([NH:7][CH:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:15]=3)[CH2:11][N:10]([C:29]([NH:28][C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)=[O:30])[CH2:9]2)=[O:6])[CH:3]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C=Nc1ccncc1
Reactant: CCc1ccccc1C(=O)NC1CNCC(c2ccc(C(F)(F)F)cc2)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)Nc2ccncc2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
80 mg (0.23 mmol) of ethyl-N-{5-[4-(trifluoromethyl)phenyl]piperidin-3-yl}benzamide were initially charged in 2 ml of THF, and 28 mg (0.23 mmol) of 4-isocyanatopyridine and 35 μl (0.25 mmol) of triethylamine were added. The mixture was stirred at RT overnight. The reaction mixture was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 75 mg (70% of theory)
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:11]=[C:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[C@H:21]2[CH2:25][CH2:24][CH2:23][N:22]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[NH:13]1.Cl.[CH2:34]([N:41]([CH2:45][CH2:46]Cl)[CH2:42][CH2:43]Cl)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[CH2:34]([N:41]1[CH2:45][CH2:46][C:20]2([C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[C@H:21]3[CH2:25][CH2:24][CH2:23][N:22]3[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[NH:13][C:12]2=[O:11])[CH2:43][CH2:42]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: ClCCN(CCCl)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1cccc2c1CC(=O)N2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1c1cccc2c1C1(CCN(Cc3ccccc3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 32.8 %

Procedure:
NaHMDS (5.0 mL, 5.0 mmol) was added into a solution of (R)-tert-butyl 2-(2-oxoindolin-4-yl)pyrrolidine-1-carboxylate (300 mg, 0.992 mmol) in THF (10 mL) at −78° C. The mixture was stirred for 20 minutes at that temperature. N-benzyl-2-chloro-N-(2-chloroethyl)ethanamine HCl salt (300 mg, 1.12 mmol) was added into the solution at −78° C. The reaction mixture was allowed to warm up to room temperature and was heated to reflux for 12 hours. The reaction was quenched by pouring the reaction mixture into water (10 mL) and was extracted with EtOAc (100 mL). The organic layer was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified with flash chromatography to afford the product (R)-tert-butyl 2-(1′-benzyl-2-oxospiro[indoline-3,4′-piperidine]-4-yl)pyrrolidine-1-carboxylate (150 mg, 0.325 mmol, 32.8%) as a solid. 1H NMR (CDCl3, 400 MHz) δ 7.20-7.45 (m, 6H), 7.10 (t, 1H), 6.80 (d, 1H), 6.60-6.70 (m, 1H), 5.40-5.80 (m, 1H), 3.50-3.80 (m, 4H), 3.00-3.20 (m, 2H), 2.90-3.00 (m, 2H), 2.75-2.85 (m, 2H), 2.60-2.70 (m, 1H), 2.20-2.50 (m, 2H), 1.90-2.00 (m, 1H), 1.80-1.90 (m, 1H), 1.70-1.80 (m, 1H), 1.60-1.70 (m, 1H), 1.50-1.60 (m, 1H), 1.00-1.50 (m, 9H). MS (APCI+) [M+H]+ 462.
Reaction SMILES: BrC1C=CC(S([O:11][C@@H:12]2[CH2:37][CH2:36][C@H:15]3[C:16](=[O:35])[N:17]([CH3:34])[CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[CH:23][C@@H:24]4[CH2:29][C@@:25]4([C:30]([O:32][CH3:33])=[O:31])[NH:26][C:27](=[O:28])[C@@H:14]3[CH2:13]2)(=O)=O)=CC=1.[C:38]([C:40]1[N:41]=[C:42]([C:45]2[CH:54]=[C:53](O)[C:52]3[C:47](=[C:48]([CH3:58])[C:49]([O:56][CH3:57])=[CH:50][CH:51]=3)[N:46]=2)[S:43][CH:44]=1)#[CH:39].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[C:38]([C:40]1[N:41]=[C:42]([C:45]2[CH:54]=[C:53]([O:11][C@H:12]3[CH2:37][CH2:36][C@H:15]4[C:16](=[O:35])[N:17]([CH3:34])[CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[CH:23][C@@H:24]5[CH2:29][C@@:25]5([C:30]([O:32][CH3:33])=[O:31])[NH:26][C:27](=[O:28])[C@@H:14]4[CH2:13]3)[C:52]3[C:47](=[C:48]([CH3:58])[C:49]([O:56][CH3:57])=[CH:50][CH:51]=3)[N:46]=2)[S:43][CH:44]=1)#[CH:39]
Reactant: C#Cc1csc(-c2cc(O)c3ccc(OC)c(C)c3n2)n1
Reactant: COC(=O)[C@@]12C[C@H]1C=CCCCCN(C)C(=O)[C@@H]1CC[C@@H](OS(=O)(=O)c3ccc(Br)cc3)C[C@H]1C(=O)N2
Agent: C#Cc1csc(-c2cc(O[C@H]3CC[C@H]4C(=O)N(C)CCCC/C=C\[C@@H]5C[C@@]5(C(=O)OC)NC(=O)[C@@H]4C3)c3ccc(OC)c(C)c3n2)n1
Agent: COC(=O)[C@@]12C[C@H]1/C=C\CCCCN(C)C(=O)[C@@H]1CC[C@@H](OS(=O)(=O)c3ccc(Br)cc3)C[C@H]1C(=O)N2
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: C#Cc1csc(-c2cc(O[C@H]3CC[C@H]4C(=O)N(C)CCCCC=C[C@@H]5C[C@@]5(C(=O)OC)NC(=O)[C@@H]4C3)c3ccc(OC)c(C)c3n2)n1
Temperature: 70 °C

Procedure:
Compound 44 (0.13 mmol) and 2-(4-ethynyl-thiazol-2-yl)-7-methoxy-8-methyl-quinolin-4-ol (0.14 mmol) 209b were dissolved in NMP (0.5 mL). K2CO3 (0.19 mmol) was added and the reaction mixture was heated at 70° C. for 2 days. The crude material was purified by silica gel chromatography (PE/EtOAc) to yield compound 45 as a beige solid. MS (ESI, EI+): m/z=657 (MH+).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([Cl:13])=[O:12])=[CH:6][CH:5]=1>>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([Br:1])[C:11]([Cl:13])=[O:12])=[CH:8][CH:9]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: BrBr
Product: O=C(Cl)C(Br)c1ccc(Cl)cc1
Temperature: 90 °C
Yield: 85 %

Procedure:
16 g (0.2 moles) of elemental bromine were added dropwise to 18.9 g (0.1 moles) of 4-chlorophenylacetic acid chloride at 95° C. while stirring. The reaction mixture was maintained for a further 2.5 hours at a temperature of 90° C. and then excess bromine was distilled off. The crude product was finally distilled under 16 mb in a temperature range of from 90° C. to 96° C. 22.9 g (0.085 moles) of 4-chlorophenyl-alpha-bromoacetic acid chloride, corresponding to 85% of the theoretical yield, were obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[C:40]([O:41][CH3:42])=[CH:39][C:24]2[CH2:25][CH2:26][N:27]([CH2:30][C:31]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[O:32])[CH2:28][CH2:29][C:23]=2[CH:22]=1>>[Cl:19][C:5]1[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])=[N:7][C:2]([NH:20][C:21]2[C:40]([O:41][CH3:42])=[CH:39][C:24]3[CH2:25][CH2:26][N:27]([CH2:30][C:31]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[O:32])[CH2:28][CH2:29][C:23]=3[CH:22]=2)=[N:3][CH:4]=1
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N1CCOCC1)CC2
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n1)CCN(CC(=O)N1CCOCC1)CC2
Yield: 20 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-1-morpholin-4-yl-ethanone. Product was isolated as a white solid (20 mg, 20%). mp: 163° C. (125 soft), MS (ESI+): 582.5 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.21 (s, 1H), 7.91 (s, 1H), 7.42 (s, 1H), 6.65 (s, 1H), 6.57 (d, J=8 Hz, 1H), 6.33 (s, 2H), 5.56 (s, 1H), 5.28 (s, 1H), 4.46 (t, J=8 Hz, 1H), 3.89 (s, 3H), 3.74-3.67 (m, 9H), 3.30 (s, 2H), 3.09 (s, 1H), 2.89 (m, 6H), 2.69 (m, 5H), 2.53 (d, J=7 Hz, 1H), 2.28 (d, J=7 Hz, 1H), 1.67 (d, J=7 Hz, 1H).
Reaction SMILES: C(OC([N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:20]3[C:29]([O:30][CH3:31])=[C:28]4[C:23]([C:24](=[O:38])[C:25]([C:35]([OH:37])=[O:36])=[CH:26][N:27]4[CH:32]4[CH2:34][CH2:33]4)=[CH:22][CH:21]=3)[CH:17]=2)[CH2:12]1)=O)C1C=CC=CC=1>C(O)(=O)C.[C].[Pd]>[CH:32]1([N:27]2[C:28]3[C:23](=[CH:22][CH:21]=[C:20]([C:16]4[CH:17]=[C:18]5[C:13](=[CH:14][CH:15]=4)[CH2:12][NH:11][CH2:19]5)[C:29]=3[O:30][CH3:31])[C:24](=[O:38])[C:25]([C:35]([OH:37])=[O:36])=[CH:26]2)[CH2:33][CH2:34]1
Reactant: COc1c(-c2ccc3c(c2)CN(C(=O)OCc2ccccc2)C3)ccc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1c(-c2ccc3c(c2)CNC3)ccc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
In 14 ml of acetic acid and 140 mg of 5% palladium-carbon was suspended 140 mg of 7-[2-(benzyl-oxycarbonyl)isoindolin-5-yl]-1-cyclopropyl-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, and the suspension was stirred at room temperature for 2 hours under a hydrogen atomsphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Ethanol and diethyl ether were added to the resulting residue and the crystals were collected by filtration. To the crystals collected were added 0.8 ml of ethanol, 0.8 ml of a 1N aqueous sodium hydroxide solution and 0.8 ml of water to dissolve the crystals, after which carbon dioxide was bubbled into the resulting solution and the crystals were collected by filtration to obtain 74 mg of colorless 1-cyclopropyl-7-(isoindolin-5-yl)-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Cl[CH:9]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1>CC#N>[CH3:1][C@H:2]1[NH:3][CH2:4][CH2:5][N:6]([CH:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH2:7]1
Reactant: C[C@@H]1CNCCN1
Reactant: FC(F)(F)c1cccc(C(Cl)c2ccccc2)c1
Solvent: CC#N
Product: C[C@@H]1CN(C(c2ccccc2)c2cccc(C(F)(F)F)c2)CCN1
Temperature: 100 °C
Yield: 80.8 %

Procedure:
To a solution of (R)-(−)-2-methylpiperazine (2.2 g, 22 mmol) in CH3CN (20 mL) was added 1-(chloro(phenyl)methyl)-3-(trifluoromethyl)benzene (2.0 g, 7.4 mmol) and heated to 100° C. for 12 h and concentrated under vacuum. The residue was dissolved in CH2Cl2 (150 mL) and washed with 1N NaOH (150 mL). The organic layer was dried with K2CO3 or Na2SO4, filtered, and concentrated. The crude product was purified by ISCO using 0-20% 2N NH3/MeOH solution in CH2Cl2 to give the title compound (2.00 g, 81% yield) as oil. MS (ESI, pos. ion) m/z: 335.1 (M+1).
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:12]([N+:22]([O-])=O)[CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].CO.[H][H]>[Pd]>[OH:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:12]([NH2:22])[CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(O)CCc1ccc(C2CCCCC2)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C(O)CCc1ccc(C2CCCCC2)c(N)c1

Procedure:
A mixture of 0.05 moles of ethyl α-hydroxy-γ-(3-nitro-4-cyclohexylphenyl)butyrate in 100 ml. methanol containing 0.05 mole citric acid and 1.5 g. of 5% palladium-on-carbon is shaken with hydrogen at 2 atm. pressure and 27°C until 3 moles of hydrogen are absorbed. The mixture is filtered, washed with methanol and the filtrate concentrated in vacuo to obtain ethyl α-hydroxy-γ-(3-amino-4-cyclohexylphenyl)butyrate, isolated as the citrate salt.