Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:7]=[N:8][CH:9]=[N:10][CH:11]=1)CCC.CC(N)CC1C=CC=CC=1.OP(O)(O)=O.FC(F)(F)S(O[C:41]1[CH:54]=[C:53]2[C:44]([O:45][C:46]3[CH:47]=[CH:48][C:49]([C:60]4[CH2:61][CH2:62][O:63][CH2:64][CH:65]=4)=[CH:50][C:51]=3[C@@:52]32[CH2:58][O:57][C:56]([NH2:59])=[N:55]3)=[CH:43][C:42]=1[F:66])(=O)=O>CN(C=O)C>[O:63]1[CH2:64][CH:65]=[C:60]([C:49]2[CH:50]=[C:51]3[C:46]([O:45][C:44]4[CH:43]=[C:42]([F:66])[C:41]([C:6]5[CH:11]=[N:10][CH:9]=[N:8][CH:7]=5)=[CH:54][C:53]=4[C@:52]43[CH2:58][O:57][C:56]([NH2:59])=[N:55]4)=[CH:47][CH:48]=2)[CH2:61][CH2:62]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncnc1
Reactant: NC1=N[C@]2(CO1)c1cc(C3=CCOCC3)ccc1Oc1cc(F)c(OS(=O)(=O)C(F)(F)F)cc12
Agent: CC(N)Cc1ccccc1
Agent: O=P(O)(O)O
Solvent: CN(C)C=O
Product: NC1=N[C@]2(CO1)c1cc(C3=CCOCC3)ccc1Oc1cc(F)c(-c3cncnc3)cc12
Temperature: 130 °C

Procedure:
A mixture of 5-(tributylstannyl)pyrimidine (73.8 mg, 0.200 mmol), AmPhos (4.24 mg, 5.99 μmol) and (R)-2-amino-2′-(3,6-dihydro-2H-pyran-4-yl)-6′-fluoro-5H-spiro[oxazole-4,9′-xanthene]-7′-yl trifluoromethanesulfonate (50 mg, 0.100 mmol) in 0.3 mL of DMF was heated at 130° C. for 1 hour. After cooling and evaporation of the solvent under high vacuum, the mixture was purified by silica gel chromatography (DCM to DCM/EA=1:1 to 1:2 to pure EA to EA/MeOH=100:5 to 100:10) to provide (R)-7′-(3,6-dihydro-2H-pyran-4-yl)-3′-fluoro-2′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:26]=[CH:25][C:16]4[C:17]([C:21]([NH:23][CH3:24])=[O:22])=[C:18]([CH3:20])[O:19][C:15]=4[CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.Br[CH2:28][CH2:29][CH2:30][C:31]([O:33]C)=[O:32].C([O-])([O-])=O.[Cs+].[Cs+].CC#N>CN(C=O)C>[CH3:20][C:18]1[O:19][C:15]2[CH:14]=[C:13]([O:12][C:6]3[C:5]4[C:10](=[CH:11][C:2]([O:1][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:3][CH:4]=4)[N:9]=[CH:8][CH:7]=3)[CH:26]=[CH:25][C:16]=2[C:17]=1[C:21]([NH:23][CH3:24])=[O:22]
Reactant: COC(=O)CCCBr
Reactant: CNC(=O)c1c(C)oc2cc(Oc3ccnc4cc(O)ccc34)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CNC(=O)c1c(C)oc2cc(Oc3ccnc4cc(OCCCC(=O)O)ccc34)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 6-[(7-hydroxyquinolin-4-yl)oxy]-N,2-dimethyl-1-benzofuran-3-carboxamide 119-A (200mg, 0.57 mmol), methyl 4-bromobutanoate (155mg, 0.85 mmol), and Cs2CO3 (433 mg, 1.14 mmol) in a mixed solvent of CH3CN (4 mL)/DMF(1 mL) was heated to 65° C. overnight. The reaction mixture was extracted with EtOAc, concentrated and dissolved in 5 mL of MeOH. To the solution was added 1 N NaOH (1 mL). The solution was stirred at room temperature for 2 hours and then heated to 60° C. for 2 hours. The solution was acidified with AcOH to a pH of about 6 and extracted with EtOAc. The concentrated residue was purified by HPLC using 20-60% CH3CN/H2O over 30 min. to give 4-{[4-({2-methyl-3-[(methylamino)carbonyl]-1-benzofuran-6-yl}oxy)quinolin-7-yl]oxy}butanoic acid 119.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12](Cl)=[O:13])[C:3]1=[O:15].CN1C2C(=CC=CC=2)C=C(C(O)=O)C1=O.C(Cl)(=O)C(Cl)=O.Cl.[NH2:38][CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([NH:38][CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[O:13])[C:3]1=[O:15]
Reactant: CC(C)(C)OC(=O)CN
Reactant: Cn1c(=O)c(C(=O)Cl)cc2ccccc21
Agent: Cl
Agent: Cn1c(=O)c(C(=O)O)cc2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1c(=O)c(C(=O)NCC(=O)OC(C)(C)C)cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonyl chloride, prepared from 1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (Archiv der Pharmazie (1990), 323(2), 67-72) and oxalyl chloride, was added dropwise to a solution of tert-butyl 2-aminoacetate hydrochloride (0.041 g, 0.25 mmol), diisopropylethyl amine (0.086 ml, 0.49 mmol), in dichloromethane (1.00 ml), stirred at room temperature for 1 hr. The reaction mixture was diluted with dichloromethane, washed with water and dried over MgSO4 to afford tert-butyl 2-(1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetate in a 27% yield.
Reaction SMILES: [CH:1]([Li])([CH2:3][CH3:4])[CH3:2].CO[N-:8][C:9](=O)[CH2:10][CH3:11].C(O)(C(F)(F)F)=O.[CH2:20]1[CH2:24][O:23][CH2:22][CH2:21]1>C(Cl)Cl>[CH2:24]([O:23][C:22]1[CH:21]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:1]([CH3:2])=[CH:3]2)[CH3:20]
Reactant: [Li]C(C)CC
Reactant: CCC(=O)[N-]OC
Reactant: C1CCOC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc2[nH]c(C)cc2c1
Temperature: -40 °C
Reaction time: 48 h
Yield: 53 %

Procedure:
Compound 506a (900 mg, 3.58 mmol) was dissolved in THF (15 mL) under an atmosphere of Argon. The solution was cooled to −40° C. over 10 min and secbutyllithium (1.4 M, 5.37 mL) was added slowly as to maintain an internal temperature of <−25° C. After reaching 1 equiv of sec-butyllithium (2.7 mL) the reaction mixture turned a bright yellow signifying deprotonation of the amide nitrogen. The reaction mixture was then cooled to −50° C. and a solution of N-methoxy-N-methylacetylamide 407 (442.8 mg, 4.78 mmol) in THF (3 mL) was added over 5 min. The reaction mixture was warmed to −10° C. over 30 min. The mixture was partitioned between Et2O (75 mL) and 0.5 N HCl (75 mL). The aqueous layer was separated and extracted an additional two times with Et2O (50 mL). The Et2O phases were combined and washed with brine (75 mL) and then dried over Na2SO4 to yield a dark-brown oil. The crude intermediate was dissolved in DCM (20 mL). TFA (3 mL) was added to the mixture which was then stirred at rt for 48 h. Upon completion, the reaction mixture was added to a separatory funnel and washed with NaHCO3 (50 mL) followed by brine (50 mL). The organic layer was separated and then dried over Na2SO4 to provide a crude black oil (1 g) which was purified by chromatography (0% to 20% EtOAc/hexanes) to yield a brown solid (335 mg, 53%): mp 88-90° C. TLC Rf 0.48 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 7.72 (s, 1H), 7.16-7.14 (d, 1H, J=8.64 Hz), 6.99 (d, 1H, J=2.4 Hz), 6.77-6.75 (dd, 1H, J1=8.7 Hz, J2=2.4 Hz), 6.13 (s, 1H), 4.07-4.04 (q, 2H, J=6.96 Hz), 2.41 (s, 3H), 1.43-1.40 (t, 3H, J=6.96 Hz). 13C NMR (150 MHz, CDCl3) δ 153.3, 135.8, 131.2, 129.5, 111.33, 110.75, 103.1, 100.3, 64.2, 15.1, 13.8. Elemental analysis calculated for C11H13NO: C, 75.40; H, 7.48; N, 7.99. Found: C, 75.11; H, 7.64; N, 7.46.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][C@@H:9]([N:12]([CH3:14])[CH3:13])[CH2:8]2)=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[I:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25](Cl)=[O:26].IC1C=C(C=CC=1C)C(O)=O.O=S(Cl)Cl.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:13][N:12]([CH3:14])[C@@H:9]1[CH2:10][CH2:11][N:7]([CH2:6][C:5]2[CH:15]=[CH:16][C:2]([NH:1][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][C:30]([CH3:31])=[C:22]([I:21])[CH:23]=3)=[CH:3][C:4]=2[C:17]([F:20])([F:18])[F:19])[CH2:8]1
Reactant: CN(C)[C@@H]1CCN(Cc2ccc(N)cc2C(F)(F)F)C1
Reactant: Cc1ccc(C(=O)Cl)cc1I
Agent: Cc1ccc(C(=O)O)cc1I
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2ccc(CN3CC[C@@H](N(C)C)C3)c(C(F)(F)F)c2)cc1I
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a cooled (0° C.) solution of (R)-1-(4-amino-2-(trifluoronnethyl)benzyl)-N,N-dimethylpyrrolidin-3-amine (3.79 mmol) in 14 mL DCM, under an atmosphere of N2, was added 3-Iodo-4-methylbenzoyl chloride (1.17 g, 4.17 mmol; CAS#52107-98-9, prepared from the reaction of 3-iodo-4-methylbenzoic acid and SOCl2) followed by dropwise addition of N,N-diisopropylethylamine (2.64 mL, 15.2 mmol). After stirring to ambient temperature over 1.5 h, the reaction mixture was concentrated and the crude product was purified by silica gel chromatography (eluted with 0-8% MeOH/DCM; MeOH was pre-saturated with ammonia gas), to provide 0.71 g of product as a thick yellow oil.
Reaction SMILES: [CH:1]1([C:6]2([CH3:19])[CH:14](O)[C:13]3[C:8](=[C:9]([Cl:17])[C:10]([Cl:16])=[CH:11][CH:12]=3)[C:7]2=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-:21].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32]>CN(C)C=O>[Cl:16][C:10]1[C:9]([Cl:17])=[C:8]2[C:13]([CH2:14][C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)([CH3:19])[C:7]2=[O:18])=[CH:12][C:11]=1[O:21][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32]
Reactant: CC1(C2CCCC2)C(=O)c2c(ccc(Cl)c2Cl)C1O
Reactant: COC(=O)CCCCBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCOc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Cyclopentyl-6,7-dichloro-2,3-dihydro-2-methyl-hydroxy-1H-inden-1-one (12 g., 0.04 mole) is dissolved in dimethylformamide (30 ml.) and treated with potassium carbonate (5.5 g., 0.04 mole). Methyl 5-bromopentanoate (8.5 g., 0.04 mole) is added dropwise with good stirring over a period of 30 minutes. Then, the mixture is stirred and heated in a steam bath for two hours. The mixture is cooled and poured in to ice water (300 ml.). The product which solidifies upon standing is removed by filtration. The yield is 15.1 g., m.p. 83°-86° C. Upon recrystallization from petroleum ether the methyl 5-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]pentanoate melts at 85°-88° C.
Reaction SMILES: [C:1]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1/[CH:20]=[CH:21]/[P:22](=[O:29])([O:26]CC)[O:23]CC)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].Br[Si](C)(C)C.CC(C)=O.O>C(Cl)Cl.[2H]C([2H])(Cl)Cl>[C:1]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]=[CH:21][P:22](=[O:23])([OH:29])[OH:26])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCC#Cc1ccccc1/C=C/P(=O)(OCC)OCC
Agent: C[Si](C)(C)Br
Agent: [2H]C([2H])(Cl)Cl
Solvent: CC(C)=O
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCCCC#Cc1ccccc1C=CP(=O)(O)O
Reaction time: 30 h
Yield: 76.8 %

Procedure:
Diethyl E-2-[2-(1-tridecynyl)phenyl]ethenylphosphonate (0.521 g, 1.25 mmol) prepared according to Example 13 was dissolved in CH2Cl2 : CD2Cl2 (1:1, 9 ml) and stirred while bromotrimethylsilane (0.38 g, 2.48 mmol) was added. The reaction was monitored by 1H and 31P NMR. Additional bromotrimethylsilane (0.1 ml, 0.76 mmol) was added after 6.5 hours. After stirring for 30 hours, the solvent was removed under reduced pressure. Acetone (5 ml) was added, along with water (0.15 ml, 8.3 mmol). The reaction mixture was stirred for about 42 hours, then stripped. NMR indicated that the reaction was incomplete. Acetone (3 ml) and water (0.2 ml, 11.1 mmol) were added back and the reaction was stirred overnight. The solvent was then removed, and the residue was recrystallized from heptane, as a white crystalline solid, 0.348 g, 0.96 mmol, 76.8% yield; mp 82°-83° C.; 1H NMR (CDCl3) ∂ 0.85 (t, J=6.7 Hz, 3H), 1.10 to 1.45 (m, 16H), 1.59 (m, 2H), 2.43 (t, J=7.1 Hz, 2H), 6.44 (t, J=18.5 Hz, 1H), 7.26 (m, 2H), 7.41 (m, 1H), 7.54 (m, 1H), 8.04 (dd, J=24.2, 17.6 Hz, 1H), 10.46 (br s, 2H); FAB mass spectrum m/z 363 (M+H)+.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH:25]([O:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][C:30]=1[O:37][CH3:38])([CH3:27])[CH3:26]>C(Cl)Cl.[Zn]>[Br:2][C:1]([Br:5])=[CH:33][C:32]1[CH:35]=[CH:36][C:29]([O:28][CH:25]([CH3:27])[CH3:26])=[C:30]([O:37][CH3:38])[CH:31]=1
Reactant: COc1cc(C=O)ccc1OC(C)C
Reactant: BrC(Br)(Br)Br
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(C=C(Br)Br)ccc1OC(C)C
Temperature: 0 °C
Reaction time: 22 h
Yield: 100.5 %

Procedure:
Carbon tetrabromide (51.3 g, 154.7 mmol) was added portion-wise to a magnetically stirred mixture of zinc dust (10.1 g, 154.5 mmol) and PPh3 (40.5 g, 159.4 mmol) in CH2Cl2 (350 ml) maintained at 0° C. on an ice-salt bath. This suspension was allowed to warm to room temperature and then stirred at for a further 22 h. After this time the reaction mixture was re-cooled to 0° C. and vanillin isopropyl ether (15.0 g, 77.3 mmol) was added dropwise over 2 min. and allowed to stir at room temperature for 1 h. After dilution with hexane (200 ml) the resulting mixture was filtered through a sintered glass funnel and the filtrate concentrated on to silica gel (30 g). The resulting solid was added to the top of a flash chromatography column (silica gel: 20 cm long×10 cm wide) which was subjected to gradient elution (2:1, 1:1 and then 1:2 hexane/CH2Cl2). Concentration of the appropriate fractions (Rf 0.5 in 1:1 hexane/CH2Cl2) then afforded the title compound (27.2 g, 99.8%) as white crystalline masses, m.p. 36–38° C. IR (KBr disc, cm−1) 2976, 2973, 1599, 1510, 1464, 1418, 1383, 1373, 1267, 1235, 1141, 1110, 1036. 1H NMR (300 MHz, CDCl3) δ 7.41 (s, 1H), 7.21 (d, J=2.1 Hz, 1H), 7.07 (dd, J=2.1, 8.4 Hz, 1H), 6.87 (d, J=8.4 Hz), 4.58 (septet, J=6.0 Hz, 1H), 3.87 (s, 3H), 1.39 (d, J=6.0 Hz, 6H). 13C NMR+APT (75.5 MHz, CDCl3) δ 149.7 (C), 147.7 (C), 136.5 (CH), 127.9 (C), 121.9 (CH), 114.4 (CH), 111.8 (CH), 87.1 (CH), 71.1 (CH), 56.0 (CH3), 22.1 (CH3). MS (70 eV) m/z (%): 352 (28), 350 (49), 448 (31) (M+•), 310 (51), 308 (100), 306 (54) (M+•-CH2CHCH3), 295 (34), 293 (38), 291 (36) (M+•-CH2CHCH3—CH3). Anal. Calcd for C12H14O2Br2, 41.17; H, 4.03; Br, 45.65. Found: C, 41.21; H, 3.92; Br, 45.47.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:25]([C:27]1[CH:36]=[N:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1)[NH2:26].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CCOC(C)=O>[F:23][C:2]([F:1])([F:24])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:26][NH:25][C:27]3[CH:36]=[N:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=3)=[O:22])[N:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: NNc1cnc2ccccc2n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NNc1cnc2ccccc2n1
Reaction time: 2 h
Yield: 17.1 %

Procedure:
A 50-mL, 3-necked, round-bottomed flask was charged with a solution of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.25 g) and 2-hydrazinylquinoxaline (0.14 g, 1.2 eq.) in EtOAc. T3P (50% in EtOAc; 0.83 mL, 2.0 eq.) and DIPEA (0.5 mL, 4.0 eq.) were added under nitrogen atmosphere at −55 to −60° C. and the reaction mixture was stirred for 2 hr before being concentrated under reduced pressure (25° C., 20 mmHg) to afford 0.150 g of crude solid. Purification using Combi-Flash column chromatography (eluting with MeOH:CH2Cl2; desired compound started eluting at 5% MeOH in CH2Cl2) afforded 60 mg (yield: 20%) (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(quinoxalin-2-yl)acrylohydrazide. 1H NMR (400 MHz, DMSO-d6) δ=10.851 (s, 1H), 9.89-9.87 (s, 1H), 9.67 (s, 1H), 8.49-8.54 (m, 3H), 8.26 (s, 1H), 8.28 (s, 1H), 7.86-7.88 (d, J=8 Hz, 1H), 7.45-7.66 (m, 4H), 6.17-6.20 (d, J=10.4 Hz, 1H); LCMS for C21H14F6N7O [M+H]+ 494.37; found 494.19 (RT 2.88 min, purity: 100%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])[C@@H:14]([CH3:26])[CH2:13]2)=[N:4][N:3]=1.[NH:27]1[CH:31]=[CH:30][N:29]=[CH:28]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I.O1CCOCC1>[N:27]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:19])[C@@H:14]([CH3:26])[CH2:13]3)=[N:4][N:3]=2)[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: C[C@H]1CN(c2nnc(Cl)c3ccccc23)CCN1C(=O)c1ccccc1
Reactant: c1c[nH]cn1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@H]1CN(c2nnc(-n3ccnc3)c3ccccc23)CCN1C(=O)c1ccccc1
Temperature: 110 °C

Procedure:
Compound 77 was prepared as described in general Method I. A 15 mL Schlenk tube was charged with (S)-(4-(4-chlorophthalazin-1-yl)-2-methylpiperazin-1-yl)(phenyl)methanone JK-4 (100 mg, 0.273 mmol), 1H-imidazole (22.3 mg, 0.328 mmol), copper (I) iodide (2.6 mg, 0.0136 mmol), potassium phosphate (122 mg, 0.573 mmol), trans-cyclohexanediamine (3.3 μl, 0.0273 mmol), and dioxane (0.75 mL). The vessel was evacuated, backfilled with argon 5 times, and then heated at 110° C. for 22 hours. After cooling, the reaction was then taken up in ethyl acetate (80 mL) and washed with aqueous K2CO3 (10%), water, and saturated sodium chloride. The organics were dried (MgSO4) and evaporated to give a yellow oil. Chromatography over silica gel with a gradient of hexanes/0-100% ethyl acetate gave a white solid, compound 77. MS (M+H)+=399.2.
Reaction SMILES: [Cl:1][C:2]([Cl:8])([Cl:7])[C:3]([CH3:6])([OH:5])[CH3:4].[Cl:9][C:10]([CH3:16])([CH3:15])[C:11](OC)=[O:12]>>[C:11]([O:5][C:3]([CH3:6])([CH3:4])[C:2]([Cl:8])([Cl:7])[Cl:1])(=[O:12])[C:10]([CH3:16])=[CH2:15].[Cl:9][C:10]([CH3:16])([CH3:15])[C:11]([O:5][C:3]([CH3:6])([CH3:4])[C:2]([Cl:8])([Cl:7])[Cl:1])=[O:12]
Reactant: CC(C)(O)C(Cl)(Cl)Cl
Reactant: COC(=O)C(C)(C)Cl
Product: C=C(C)C(=O)OC(C)(C)C(Cl)(Cl)Cl
Product: CC(C)(Cl)C(=O)OC(C)(C)C(Cl)(Cl)Cl

Procedure:
An analysis of the crude reaction solution by gas chromatography revealed that the conversion of 1,1,1-trichloro-2-methyl-2-propanol was 67.7% and the yield of methyl 2-chloro-2-methylpropanoate was 36.5%. As to other products, it was obtained (1,1,1-trichloro-2-methyl-2-propyl) methacrylate in a 10.5% yield, and (1,1,1-trichloro-2-methyl-2-propyl) 2-chloro-2-methylpropanoate in a 13.5% yield. The crude reaction solution obtained was distilled under a reduced pressure, thereby obtaining methyl 2-chloro-2-methylpropanoate at a purity of 85%.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8](O)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:11]([O-:14])([O-])=O.[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[CH2:17]([O:1][C:2]1[CH:9]=[C:8]([O:14][CH2:11][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:3]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(O)cc1O
Reactant: O=C([O-])[O-]
Reactant: BrCc1ccccc1
Agent: [K+]
Solvent: CC#N
Product: O=Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 20.1 %

Procedure:
To a 250 mL RB flask fitted with magnetic stirrer was charged 100 mL of acetonitrile. To the stirred solvent was added 2,4-dihydroxybenzaldehyde (10.0 g, 72.0 mmol) and K2CO3 (19.87 g, 144.0 mmol). Then it was stirred for 15 min, slowly was added benzylbromide (12.38 g, 72.0 mmol), the RM was heated to 80° C. for 3 h. Then, the solvent was removed under reduced pressure and the compound was extracted with ethyl acetate (50 mL×3). The organic layer washed with water and saturated brine solution and dried over anhydrous Na2SO4 and evaporated to dryness to get the crude product. The crude material was purified by silica gel column chromatography using ethyl acetate and petroleum ether as elutants to obtain the product (2.3 g, yield: 10.03%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].BrC[C:35]1[CH:44]=[CH:43][C:38]2[N:39]([CH3:42])[N:40]=[N:41][C:37]=2[CH:36]=1.[CH:45](N(C(C)C)CC)(C)C.CN(C=O)C>CC#N.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:45][C:44]3[CH:35]=[CH:36][C:37]4[N:41]=[N:40][N:39]([CH3:42])[C:38]=4[CH:43]=3)[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cn1nnc2cc(CBr)ccc21
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(Cc3ccc4nnn(C)c4c3)C2)c1
Reaction time: 0.17 h
Yield: 95.8 %

Procedure:
To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (52.6 mg, 0.118 mmol) in CH3CN (5 ml) was added 5-(Bromomethyl)-1-methyl-1H-1,2,3-benzotriazole (40.0 mg, 0.18 mmol), diisopropylethylamine (41 μl, 0.24 mmol) and DMF)(0.3 ml) to solubolize. The reaction was microwaved at 130° C. for 40 minutes, then at 150° C. for 1 hour 10 min. The reaction was diluted with EtOAc and washed with brine, sat. NaHCO3, and brine, dried and filtered. Purification by silica gel chromatography (Isco) gave the desired product, (67 mg, 96%). Calcd for C33H39F3NO4 (M+H) 592.69, Found 593.4.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:19][NH2:20]>C(O)CCC.COC(C)(C)C>[F:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][C:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[NH:20][N:19]=1
Reactant: O=C(Cc1ccccc1F)c1cccnc1Cl
Reactant: NN
Solvent: CCCCO
Solvent: O
Solvent: COC(C)(C)C
Product: Fc1ccccc1Cc1n[nH]c2ncccc12

Procedure:
A solution of 2.00 g (8.01 mmol) of 1-(2-chloropyridin-3-yl)-2-(2-fluorophenyl)ethanone from example 11A and 560 mg (11.2 mmol) of hydrazine hydrate in 6 ml of 1-butanol is heated in a microwave at 200° C. for 10 min. It is then diluted with tert-butyl methyl ether, washed with saturated sodium bicarbonate solution and dried over sodium sulfate. The solution is concentrated in vacuo. The crystalline residue is stirred with a little tert-butyl methyl ether and filtered off with suction. The mother liquor is concentrated and purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 2:1). In total, 1.40 g (77% of theory) of the desired product are obtained as yellow crystals.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH3:24]>C1COCC1>[CH3:24][N:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]([C:14]=23)=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(-c2ccccc2)c2c3c(cccc31)C(=O)NCC2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of compound 12 (51.3 mg, 0.20 mmol) in THF (1 mL) and 0.1 mL 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H1)-pyrimidinone (DMPU) was cooled with an ice/water bath and treated dropwise with a suspension of NaH (0.45 mmol) in THF (0.5 mL). The yellow mixture was allowed to stir at 0° C. for 10 min., and was treated dropwise with a 1M solution of iodomethane in THF (0.22 mL, 0.22 mmol). The mixture was allowed to warm to ambient temperature and stirred for 30 min. The reaction was quenched at 0° C. with saturated aqueous NH4Cl, and extracted with EtOAc (5 mL×3). The organic solution was washed with water and brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by radial chromatography (2 mm SiO2; 1-5% MeOH in CH2Cl2) to yield 18 as a white solid, 44.9 mg (81%). mp 254-256° C. (dec.); 1H NMR (DMSO-d6) δ2.88 (m, 2H), 3.40 (m, 2H), 3.74 (s, 3H), 7.34 (t, 1H, J=7.7 Hz), 7.56 (m, 5H), 7.73 (d, 1H, J=7.7 Hz), 7.80 (d, 1H, J=7.7 Hz), 8.15 (bt, 1H); Anal. (C18H16N2O.0.75 H2O) C, H, N.