Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:6](=[O:7])[O:5][CH2:4][C:3]=1[N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[C:9]1=[O:25].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:6](=[O:7])[O:5][CH2:4][C:3]=1[N:8]1[CH2:12][CH2:11][C:10]2([CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)[C:9]1=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1=C(Cl)C(=O)OC1)C2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1OCC(N2CCC3(CCNCC3)C2=O)=C1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-(4-chloro-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (2.26 g, 6.09 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid (9.39 mL, 122 mmol) and the resulting solution was stirred at rt for 1 h. After removing the volatiles, the residue was partitioned between methylene chloride (100 mL) and 1N sodium hydroxide (100 mL). The alkaline phase was extracted with methylene chloride (2×100 mL). The combined organic phase was dried over sodium sulfate and concentrated to give 2-(4-chloro-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one. LCMS: (M+1)+: 271.07, 272.96.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[C:20]([C:24]1[CH:25]=[C:26]([NH2:37])[N:27]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=2[CH3:36])[N:28]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[C:26]([NH:37][C:17](=[O:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:15][CH:14]=2)[N:27]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=2[CH3:36])[N:28]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)c(C)c1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Cc2ccc(-n3cnc4cccnc43)cc2)c(C)c1

Procedure:
The title compound is prepared as described in Example 28 but using 2-(4-imidazo[4,5-b]pyridine-3-yl-phenyl)-acetic acid and 5-tert-butyl-2-(2,4-dimethyl-phenyl)-2H-pyrazol-3-ylamine. Title compound: ES-MS: 479.11 [M+H]+; tR=3.24 min (System 3).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[C:18]1[C:22]([CH3:23])=[CH:21][S:20][CH:19]=1)[C:12]([OH:14])=O.[NH2:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([C:34](=[N:36]O)[NH2:35])=[CH:30][CH:29]=1)(=[O:27])=[O:26].C(C1C=CC(S(N)(=O)=O)=CC=1)#N.CCN(C(C)C)C(C)C>>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:12]2[O:14][N:36]=[C:34]([C:31]3[CH:30]=[CH:29][C:28]([S:25]([NH2:24])(=[O:26])=[O:27])=[CH:33][CH:32]=3)[N:35]=2)[CH:15]=[CH:16][C:17]=1[C:18]1[C:22]([CH3:23])=[CH:21][S:20][CH:19]=1
Reactant: NC(=NO)c1ccc(S(N)(=O)=O)cc1
Reactant: COc1cc(C(=O)O)ccc1-c1cscc1C
Agent: N#Cc1ccc(S(N)(=O)=O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2nc(-c3ccc(S(N)(=O)=O)cc3)no2)ccc1-c1cscc1C

Procedure:
Oxalyl chloride (123 mL; 1.45 mmol), Intermediate 8 (120 mg; 0.48 mmol), 4-(aminosulfonyl)-N′-hydroxybenzenecarboximidamide, prepared as described in WO 2006/013104 A1 from 4-cyanobenzene-1-sulfonamide (ABCR; CD10716), (104 mg; 05 mmol, 1 eq.) and DIEA (250 mL; 1.45 mmol) were reacted according to the procedure described for Example 38. Purification by recrystallisation from DCM/n-pentane afforded the title compound as a white solid. LC/MS (Method A): 426.3 (M−H)−. HPLC (Method A) Rt 4.93 min (purity 89.2%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[C:17]([N:6]2[C:7]3[C:3](=[CH:2][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:5]2)[CH:16]=[CH:15][CH:14]=1
Reactant: Brc1cccc2[nH]ccc12
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: FC(F)(F)c1cccc(-n2ccc3ccccc32)c1
Temperature: 75 °C
Reaction time: 16 h
Yield: 88.8 %

Procedure:
To a mixture of 4-bromoindole (3.00 g, 15.3 mmol), and 3-trifluoromethylphenylboronic acid (2.91 g, 15.3 mmol) in THF (52 mL)) were added Palladium catalyst Pd(PPh3)4 (530 mg, 0.46 mmol) and the freshly prepared sodium hydroxide solution (1.84 g, 45.9 mmol in 21 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 75° C. oil bath for 16 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 3.55 g (89%) of the product 4-(3-trifluoromethyl-phenyl)-1H-indole.
Reaction SMILES: C(N1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)C1C=CC=CC=1.[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][CH:39]=3)[C:33]2=[O:49])[S:27][C:28]=1[C:29](O)=[O:30].[NH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>>[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:39]=[CH:40][C:41]([O:44][C:45]([F:47])([F:46])[F:48])=[CH:42][CH:43]=3)[C:33]2=[O:49])[S:27][C:28]=1[C:29]([NH:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:30]
Reactant: Cc1nc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)O
Reactant: Nc1ccccc1
Agent: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)Nc1ccccc1
Yield: 67 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-(4-(trifluoromethoxy)benzyl)imidazolidin-1-yl)thiazole-5-carboxylic acid to react with aniline, the title compound was obtained as a white powder in 67% yield: mp 187-188° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.54 (d, J=6.0 Hz, 2H), 7.42 (br s, 1H), 7.36-7.28 (m, 4H), 7.19 (d, J=6.0 Hz, 2H), 7.15-7.08 (m, 1H), 4.47 (s, 2H), 4.12-4.07 (m, 2H), 3.50-3.44 (m, 2H), 2.63 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.6, 157.3, 155.4, 154.1, 149.0, 137.8, 134.3, 129.7, 129.0, 124.4, 121.4, 120.3, 120.2, 117.5, 47.3, 42.0, 41.8, 17.3; MS (ES+) m/z 477.3 (M+1).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]([F:14])[C:7]=1[F:15])[CH2:2][CH2:3][CH3:4].C([Li])CCC.CCCCCC.[C:27](=[O:29])=[O:28].Cl>O1CCCC1>[CH2:1]([O:5][C:6]1[C:7]([F:15])=[C:8]([F:14])[C:9]([C:27]([OH:29])=[O:28])=[C:10]([F:13])[C:11]=1[F:12])[CH2:2][CH2:3][CH3:4]
Reactant: O=C=O
Reactant: CCCCOc1c(F)c(F)cc(F)c1F
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCOc1c(F)c(F)c(C(=O)O)c(F)c1F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
24.4 g of the compound (2) dissolved in 250 mL of tetrahydrofuran (THF) were cooled at −78° C. in an argon atmosphere; thereto were then dripped 82 mL of a 1.6 M/L n-butyllithium/hexane solution, with stirring for 2 hours at the same temperature. After addition of a suitable amount of crushed dry ice, the temperature was raised to room temperature, followed by stirring overnight. 200 mL of 3N hydrochloric acid were then added under ice cooling, the organic layer was separated, and the aqueous layer was extracted with diethyl ether. The organic layers were combined, were washed with saturated brine, and were then dried over anhydrous magnesium sulfate. After evaporating the solvent, the organic layer was recrystallized from hexane to yield 14.6 g (54.8 mmol) of 4-butoxy-2,3,5,6-tetrafluorobenzoic acid (3).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([CH:13]3[CH2:15][CH2:14]3)(O)[CH3:11])=[CH:9][C:4]=2[O:3][CH2:2]1.FC(F)(F)C(O)=O.[CH3:23][S:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:34]=1[NH:33][CH:32]=[CH:31]2>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([C:31]3[C:30]4[C:34](=[C:26]([CH2:25][S:24][CH3:23])[CH:27]=[CH:28][CH:29]=4)[NH:33][CH:32]=3)([CH:13]3[CH2:15][CH2:14]3)[CH3:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: CC(O)(c1ccc2c(c1)OCO2)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCc1cccc2c(C(C)(c3ccc4c(c3)OCO4)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
600 mg (2.91 mmol) of the compound from Example 143A and 0.27 ml (3.49 mmol) of trifluoroacetic acid were added to 516 mg (2.91 mmol) of the compound from Example 8A in 4 ml of dichloromethane. The reaction mixture was stirred at RT for 30 min, and the crude product was then purified twice by preparative HPLC (mobile phase: acetonitrile/water gradient). 377 mg (35% of theory) of the title compound were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][NH:20][CH2:19][C@H:18]2[C:23]([O:25][CH3:26])=[O:24])[C:13]1=[O:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:42][C:43]([CH3:45])=O.[OH-].[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([CH:17]2[CH2:22][CH2:21][N:20]([CH:43]([CH3:45])[CH3:42])[CH2:19][CH:18]2[C:23]([O:25][CH3:26])=[O:24])[C:13]1=[O:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: COC(=O)[C@@H]1CNCC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)C1CN(C(C)C)CCC1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.1 %

Procedure:
(3R,4S)-Methyl 4-((3S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)piperidine-3-carboxylate (1.00 g, 2.66 mmol, 1 eq.), sodium triacetoxyborohydride (0.85 g, 4.00 mmol, 1.5 eq.) and acetone (0.59 mL, 7.99 mmol, 3 eq.) were mixed in methylene chloride (15 mL) and stirred for 20 hours at room temperature. Worked up by adding 20 mL of 1.000 N NaOH. Stirred 10 minutes then extracted 3 times with methylene chloride. The organic layers were combined, dried over sodium sulfate and stripped to give methyl 4-((3S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-1-isopropyl-piperidine-3-carboxylate (1.10 g) of a white glass. Yield=99%. LCMS detects (M+H)+=418.41.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][CH2:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]#N.C(O)=[O:19]>[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][CH2:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[O:19]
Reactant: O=CO
Reactant: N#Cc1ccccc1COc1cccc(Cl)c1
Agent: [Ni]
Product: O=Cc1ccccc1COc1cccc(Cl)c1
Temperature: 150 °C
Reaction time: 17 h

Procedure:
Raney nickel alloy (9.72 g) was added to a solution of part of the crude (2-(3-chlorophenoxymethyl)benzonitrile (9.72 g) in 75% formic acid (150 ml). The resulting mixture was heated at 150° C. for about 5 hours, further Raney nickel alloy (3 g) was added, and heating at 150° C. was continued for a further 17 hours. The mixture was filtered and the solid was washed with a little methanol. The combined filtrate and washings were diluted with water and extracted with ether. The extracts was washed successively with water, aqueous potassium carbonate and brine, then dried and concentrated to give 2-(3-chlorophenoxymethyl)benzaldehyde (5.80 g) as a yellow-brown oil, 1H NMR delta 5.51 (2H, s), 10.18 (1H, s) ppm. A mixture of this crude benzaldehyde, methyl(methylthiomethyl)sulphoxide (1.73 g) and Triton B [(40 weight % solution of benzyltrimethylammonium hydroxide in methanol) 1.21 ml] in THF (6 ml) was heated at 110° C. for 3 hours. Further Triton B (2 ml) was added and the mixture was heated for a further 4 hours at 110° C. Further Triton B (2 ml) and methyl (methylthiomethyl)sulphoxide (1.5 ml ) were then added and the mixture was heated for a further 6 hours at 110° C. After cooling, the mixture was poured into water and extracted with ether. The extracts were washed with water and brine, dried, concentrated and chromatographed using ether as eluant to give a single stereoisomer of the sulphoxide (A) [1.10 g, 7% yield from 2-(bromomethyl)benzonitrile] as a viscous oil, 1H NMR delta 2.18 (3H, s), 2.74 (3H, s), 5.04 and 5.12 (each 1H, d J 12 Hz), 7.85 (1H, s) ppm. ##STR53##
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][C:5]([NH:14][C:15](=O)[O:16]CC)=[C:4]([F:20])[CH:3]=1.[OH:21][CH:22]([C:27]([CH3:29])=[CH2:28])[C:23]([O:25]C)=O.Cl>C(N(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][C:5]([N:14]2[C:23](=[O:25])[C:22](=[C:27]([CH3:29])[CH3:28])[O:21][C:15]2=[O:16])=[C:4]([F:20])[CH:3]=1
Reactant: CCOC(=O)Nc1cc(OC2CCCC2)c(Cl)cc1F
Reactant: C=C(C)C(O)C(=O)OC
Agent: Cl
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)=C1OC(=O)N(c2cc(OC3CCCC3)c(Cl)cc2F)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
Ethyl N-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)carbamate (3.01 g, 10 mmol), methyl 2-hydroxy-3-methyl-3-butenoate (3.09 g, 30 mmol), ferric chloride (162 mg, 1.0 mmol) and tributylamine (92.7 mg, 0.5 mmol) were introduced into a flask (25 cc) equipped with a distillation unit, and the reaction was conducted at 200° C. for 3 hours. After the reaction solution was cooled to room temperature, toluene (30 mL) was added, and then the reaction solution was washed with 1N sodium hydroxide (20 mL×2) and 1N hydrochloric acid (20 mL×2). The organic layer was dried over magnesium sulfate. After the drying agent was filtered off, the filtrate was concentrated under reduced pressure. To the resulting oily crude product, acidic methanol (5.0 mL) was added to form a homogeneous solution. Then, 6N hydrochloric acid (0.25 mL) was further added, and the solution was left to stand at room temperature. The precipitated crystals were collected by filtration, washed with a 20:1 mixed solvent consisting of methanol and 6N hydrochloric acid and dried to obtain 3-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)-5-isopropylidene-1,3-oxazolidine-2,4-dione (2.36 g, yield 66.8%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:14](Cl)(Cl)=[S:15].O1CCOCC1>O>[C:3]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]([N:1]=[C:14]=[S:15])=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Nc1ccccc1-c1ccccc1
Reactant: S=C(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: S=C=Nc1ccccc1-c1ccccc1
Temperature: 30 °C
Reaction time: 3 h

Procedure:
A mixture of 2-aminobiphenyl (10.2 g), thiophosgene (10.4 g), dioxane (50 ml) and water (100 ml) was prepared with cooling in an ice bath. The temperature was raised to 30° C. and stirred for 3 hours at 30° C. to yield 2-biphenylylisothiocyanate as a yellow oil.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=O)=O.[NH2:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1>CN(C)P(N(C)C)(N(C)C)=O>[O:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:29][CH:30]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CS(=O)(=O)OCCCCCCOc1ccccc1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCCCCCOc2ccccc2)cc1

Procedure:
A solution of 13.6 g of 6-(phenoxy)-1-hexanol O-methanesulfonate and 16.5 g of ethyl p-aminobenzoate in 75 ml of hexamethylphosphoramide is heated at 110° C. for 16 hours. The product is isolated as described in Example 3 to give crystals. Recrystallization from ethanol gives crystals, mp 105°-108° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17]>>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[CH:3]=1
Reactant: O=C1CCCN1
Reactant: Brc1cnc2ccccc2c1
Product: O=C1CCCN1c1cnc2ccccc2c1
Yield: 99 %

Procedure:
Using general procedure C, 3-bromoquinoline was coupled with 2-pyrrolidinone with the reaction time of 15 h. Chromatography gave 210 mg (99%) of the title compound as a solid. 1H NMR (CDCl3, 300 MHz): δ 9.24 (d, 1H, J=2.7 Hz), 8.45 (d, 1H, J=2.4 Hz), 8.08 (d, 1H, J=8.4 Hz), 7.82 (d, 1H, J=8.1 Hz), 7.66 (t, 1H, J=7.7 Hz), 7.55 (t, 1H, J=7.5 Hz), 4.04 (t, 2H, J=7.2 Hz), 2.69 (t, 2H, J-8.1 Hz), 2.28 (p, 2H, J=7.8 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:19][CH:18]=1)[C:5](=[O:16])[N:6]2[C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1.Cl.[CH:31]1([N:35]([CH3:42])[CH2:36]/[CH:37]=[CH:38]/[C:39](O)=[O:40])[CH2:34][CH2:33][CH2:32]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([C:17]1[CH:18]=[CH:19][C:20]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:21][CH:22]=1)[C:5](=[O:16])[N:6]2[C@@H:11]1[CH2:15][CH2:14][N:13]([C:39](=[O:40])/[CH:38]=[CH:37]/[CH2:36][N:35]([CH:31]2[CH2:34][CH2:33][CH2:32]2)[CH3:42])[CH2:12]1
Reactant: Nc1ncnc2c1n(-c1ccc(Oc3ccccc3)cc1)c(=O)n2[C@@H]1CCNC1
Reactant: CN(C/C=C/C(=O)O)C1CCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C/C=C/C(=O)N1CC[C@@H](n2c(=O)n(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1)C1CCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
In mixture of (R)-6-amino-7-(4-phenoxyphenyl)-9-(pyrrolidin-3-yl)-7H-purin-8(9H)-one (62) (95 mg, 0.24 mmol), (E)-4-(cyclobutyl(methyl)amino)but-2-enoic acid hydrochloride (76 mg, 0.37 mmol) and DIPEA (213 μL, 1.2 mmol) in 5 mL dry DMF was cooled to 0° C., HBTU (190 mg, 0.49 mmol) was added in one portion. The reaction mixture was allowed to warm up to rt, and stirred for 2 hrs under N2, and purified directly by preparative-HPLC (RP C18, 10 to 95% acetonitrile in water (0.2% NH3.H2O)) to give (R,E)-6-amino-9-(1-(4-(cyclobutyl(methyl)amino)but-2-enoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one (64) (36 mg, 25.9%) as a light yellow solid. LC-MS (ESI): m/z (M/M+2) 518/520. 1H NMR (400 MHz, DMSO) δ 8.11 (d, J=6.0 Hz, 1H), 7.48-7.36 (m, 4H), 7.23-7.07 (m, 5H), 6.69-6.55 (m, 1H), 6.34 (dd, J=35.9, 15.1 Hz, 1H), 5.89-5.67 (m, 2H), 5.18-4.95 (m, 1H), 4.15-3.42 (m, 4H), 2.97 (dd, J=18.6, 6.2 Hz, 2H), 2.85-2.73 (m, 1H), 2.73-2.58 (m, 1H), 2.33-2.10 (m, 1H), 1.98 (d, J=12.6 Hz, 3H), 1.95-1.87 (m, 2H), 1.80-1.67 (m, 2H), 1.63-1.48 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([OH:9])[C:5]([Cl:8])=[CH:6][CH:7]=1.Cl[C:12]([F:17])([F:16])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH:12]([F:17])[F:16])[C:3]=1[F:10]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: Oc1c(Cl)ccc(Br)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1c(Br)ccc(Cl)c1OC(F)F
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 3-bromo-6-chloro-2-fluorophenol (1.00 g, 4.44 mmol) and sodium chlorodifluoroacetate in dimethylformamide (DMF; 9 mL) was added potassium carbonate (1.22 g, 5.32 mmol) and water (1.77 mL) and the resulting mixture heated to 100° C. for 4 hours. The solution was cooled to ambient temperature and concentrated hyrdrochlroric acid (2.5 mL) and water (4 mL) were added and stirred at ambient temperature overnight. The solution was cooled in an ice bath and neutralized with 2N sodium hydroxide and then extracted with ethyl ether (2×25 mL). The combined extracts were washed with brine, dried (sodium sulfate), and concentrated to give 1-bromo-4-chloro-2-fluoro-3-difluoromethoxybenzene (1.20 g, 4.2 mmol). This material was used without further purification.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[C:22]([F:25])([F:24])[F:23].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C(OC(=O)C)C.C1(C)C=CC=CC=1>[C:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][N:4]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[C:22]([F:23])([F:25])[F:24])[CH2:3][CH2:2]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: Fc1ccc(Br)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(F)cc2C(F)(F)F)CC1

Procedure:
A mixture of tert-butyl piperazine-1-carboxylate 1.04 g, (5.6 mmol), 2-bromo-5-fluoro benzotrifluoride (1.21 g, 5.0 mmol), tris(dibenzylidineacetone)dipalladium (0) (45.8 mg, 0.05 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (93.4 mg, 0.15 mmol) and sodium tert-butoxide (600 mg, 6.25 mmol) were charged to a microwave vial. Toluene (10.0 mL) was introduced under nitrogen atmosphere and the reaction mixture was irradiated at 110° C. for 30 minutes. Reaction was complete as determined by TLC. The reaction was repeated four times. Reaction mixtures were combined, diluted with ethylacetate, washed with water, saturated brine then dried over MgSO4 and concentrated. The crude product was purified via flash column chromatography to yield tert-butyl-4-(4-fluoro-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate in quantitative yield (6.8 g) as yellow oil.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].[F:19][C:20]([F:32])([F:31])[C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.C(N(CC)CC)C.Cl>O1CCCC1>[F:18][C:2]([F:1])([F:17])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([NH:16][S:27]([C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:31])[F:32])=[CH:26][CH:25]=3)(=[O:29])=[O:28])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: Nc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(N1CCc2ccc(NS(=O)(=O)c3ccc(C(F)(F)F)cc3)cc2CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1 g (2.68 mmol) of 3-(trifluoroacetyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-7-amine and 947 mg (3.87 mmol) of 4-(trifluoromethyl)benzenesulfonyl chloride were dissolved in 20 ml of tetrahydrofuran at room temperature, and 1.62 ml (11.62 mmol) of triethylamine were added dropwise to the solution, which was stirred at room temperature overnight. After evaporation of the solvent, 20 ml of water were added and acidified with 1 mol of hydrochloric acid, and the aqueous phase was extracted with 50 ml of diethyl ether. The residue obtained after drying with sodium sulfate and after removal of the solvent was separated by column chromatography (cyclohexane/ethyl acetate 6:1).
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:14])[CH3:13])[CH2:8][CH2:7]1)=O.Cl.[NH2:21][OH:22].C([O-])(=O)C.[Na+]>CCO>[F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[C:4](=[N:21][OH:22])[CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:14])[CH3:13])[CH2:8][CH2:7]1
Reactant: NO
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=O)N1CCC(C(=NO)c2ccc(F)cc2F)CC1

Procedure:
The title compound was prepared from 1-(4-(2,4-difluoro-benzoyl)piperidin-1-yl)ethanone, hydroxylamine hydrochloride and sodium acetate in refluxing EtOH.