Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH2:26][CH3:27].Cl>C(#N)C>[F:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[N:12]1[CH2:13][CH2:14][N:15]([CH2:25][CH2:26][CH3:27])[CH2:16][CH2:17]1
Reactant: Fc1c(N2CCNCC2)cccc1C(F)(F)F
Reactant: CCCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCN(c2cccc(C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 1: 1-[2-fluoro-3-(trifluoro-methyl)phenyl]piperazine (0.97 g, 3.9 mmol), acetonitrile (50 ml), potassium carbonate (0.81 g, 5.86 mmol) and 1-iodopropane (0.457 ml, 4.6 mmol). Yield: 0.57 g (50%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 180-181° C. MS m/z (relative intensity, 70 eV) 290 (M+, 22), 262 (13), 261 (bp), 218 (18), 190 (22).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:12]1([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])[CH:16]=[CH:15][N:14]=[CH:13]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NCCCCCCCCn1ccnc1
Product: O=S(=O)(NCCCCCCCCn1ccnc1)c1ccc(Cl)cc1

Procedure:
The compound of this Example, mp 54°-56° C., was obtained when 4-chlorobenzenesulfonyl chloride was reacted with 1H-imidazole-1-octanamine by the procedure of Example 20.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[I:6][C:7]1[C:14]([I:15])=[CH:13][C:12]([I:16])=[CH:11][C:8]=1[CH2:9][OH:10].C(N(C(C)C)CC)(C)C.O>ClCCl>[S:1]([O:10][CH2:9][C:8]1[CH:11]=[C:12]([I:16])[CH:13]=[C:14]([I:15])[C:7]=1[I:6])(=[O:3])(=[O:2])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cc(I)cc(I)c1I
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCc1cc(I)cc(I)c1I
Temperature: 0 °C
Yield: 84 %

Procedure:
Mesyl chloride (0.6 ml, 8 mmol) was added dropwise to a suspension of 2,3,5-triiodobenzyl alcohol 1 (1.94 g, 4 mmol) in dry dichloromethane (30 ml) containing diisopropylethylamine (1.4 ml, 8 mmol) at 0° C. under dry nitrogen gas flow. The reaction mixture was stirred 1 h15 at 0° C., then cold H2O (40 ml) was added. The resulting aqueous phase was extracted with dichloromethane (10 ml). The combined organic extracts were washed with H2O (8 ml) then dried (Na2SO4), filtered and concentrated. The pale yellow solid was also washed with cold methanol (35 ml). 1.894 g of 2,3,5-triiodobenzyl mesylate in the form of a white clean solid was obtained in 84% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[N+:11]([O-])([OH:13])=[O:12]>>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc2nc[nH]c2c1
Product: Cc1cc2[nH]cnc2cc1[N+](=O)[O-]
Temperature: -15 °C
Reaction time: 3 h
Yield: 17 %

Procedure:
To a solution of 20 ml of fuming nitric acid was added 5-methylbenzimidazole (1.6 g, 12 mmol) slowly over 0.5 hand reaction mixture was stirred for 3 h at −15° C. During addition of substrate, reaction temperature was kept below −10° C. Sticky reaction mixture was then poured into ice water to form a yellow precipitation, which was collected and dried in vacuo to provide 0.37 g (2.1 mmol, 17%) of 5-methyl-6-nitrobenzimidazole. The nitrobenzimidazole was converted to the corresponding amine (0.32 g, 95%) on hydrogenation (H2, Pd/C).
Reaction SMILES: [Na].[CH3:2][N:3]1[S:7](=[O:9])(=[O:8])[NH:6][C:5](=[O:10])[CH:4]1[CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14].[F:16][C:17]1[N:22]=[C:21]([F:23])[C:20]([F:24])=[C:19](F)[C:18]=1[F:26].C1OCCOCCOCCOCCOC1>C(#N)C>[F:23][C:21]1[C:20]([F:24])=[C:19]([N:6]2[C:5](=[O:10])[CH:4]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[N:3]([CH3:2])[S:7]2(=[O:9])=[O:8])[C:18]([F:26])=[C:17]([F:16])[N:22]=1
Reactant: Fc1nc(F)c(F)c(F)c1F
Reactant: CC(C)CCC1C(=O)NS(=O)(=O)N1C
Agent: C1COCCOCCOCCOCCO1
Agent: [Na]
Solvent: CC#N
Product: CC(C)CCC1C(=O)N(c2c(F)c(F)nc(F)c2F)S(=O)(=O)N1C
Yield: 40.6 %

Procedure:
To a mixture of the sodium salt of 5-methyl-4-(3-methylbutyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (1 g; 4.13 mmol, prepared by treatment with sodium methoxide), pentafluoropyridine (0.54 ml, 4.97 mmol), and 0.91 g (4.13 mmol) of 15-Crown-5 suspended in 30 ml of acetonitrile was refluxed for 17 hours. The mixture was cooled, concentrated in vacuo, and the residue extracted with methylene chloride, and the organic layer was washed with water (3x) and brine. After drying over sodium sulfate, the organic layer was concentrated in vacuo and a crude product was purified by flash chromatography (10% ethyl acetate in hexane) to afford 0.62 g (41%) of 2-(2,3,5,6-tetrafluoro-4-pyridyl)-5-methyl-4-(3-methylbutyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula I: R1 =(CH2)2CH(CH3)2 ; R2 =H; R3 =CH3), as a solid, m.p. 80.5°-81.5° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[N:21]=[CH:20][CH:19]=[C:18]2[O:1][C:2]1[C:3]([C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: Cc1ccc(O)c(C(=O)c2ccccc2)n1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(C)nc3C(=O)c3ccccc3)c2cc1OC
Temperature: 120 °C
Reaction time: 8 h
Yield: 22.3 %

Procedure:
(3-Hydroxy-6-methyl-pyridin-2-yl)-phenyl-methanone (213 mg), 4-chloro-6,7-dimethoxyquinoline (223 mg), and 4-dimethylaminopyridine (366 mg) were suspended in o-dichlorobenzene (3 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (89 mg, yield 22%).
Reaction SMILES: C=C.[C:3]1(C)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[CH2:8]=[CH:3][CH2:4][CH2:5][CH3:6].[CH3:5]/[CH:4]=[CH:3]/[CH2:8][CH3:7]
Reactant: Cc1ccccc1
Agent: C=C
Product: C/C=C/CC
Product: C=CCCC

Procedure:
Addition of 1 atm. ethylene to a photostationary state mixture of IIa,b (1.4:1 a:b at 25°, toluene solution, see Example E) followed by continued photolysis at 25° resulted in slow production of free pentene, primarily trans-2-pentene. Less than 0.1 equiv pentene was evolved after 1 hour irradiation. Pentene formation did not occur thermally at 25°. The isomeric distribution, as measured after 15 and 60 min photolysis, was 85% trans-2-pentene, 10-12% cis-2-pentene, and 3-5% 1-pentene.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](O)=O.C(N1C=CN=C1)(N1C=CN=C1)=O.N1C=CC=CC=1.[CH3:25][NH:26][C:27](=[S:30])[NH:28][NH2:29]>CN(C)C=O>[CH3:25][N:26]1[C:4]([CH2:3][O:2][CH3:1])=[N:29][N:28]=[C:27]1[SH:30]
Reactant: CNC(=S)NN
Reactant: COCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COCc1nnc(S)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 192.4 %

Procedure:
5 g of methoxy-acetic acid (55.5 mmol) were dissolved in 70 ml of dimethylformamide. 11.73 g of 1,1′-carbonyldiimidazol (72.3 mmol) were added in portions within 10 min. After 30 min. at room temperature 23 ml of pyridine were added. Then 5.84 g of 4-methyl-3-thiosemicarbazide (55.5 mmol) were added and the obtained solution was stirred at room temperature overnight, and for an additional 3 h at 100° C. The solvent was evaporated, the residue dissolved in 70 ml of saturated aqueous sodium chloride solution and 30 ml of water. The aqueous layer was extracted six times with 100 ml of ethyl acetate each, and the combined organic layers were dried over magnesium sulfate, filtered, and the solvent was evaporated to dryness to yield 17 g of the crude title compound, which was further purified by silica gel chromatography with ethyl acetate, thereby obtaining 7.1 g of the purified title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:41]=[CH:42][CH:43]=4)[O:24][CH2:25][C:26]([NH:28][C@@H:29]4[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30]4)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:41]=[CH:42][CH:43]=4)[O:24][CH2:25][C:26]([NH:28][C@@H:29]4[CH2:33][CH2:32][NH:31][CH2:30]4)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)COc2cccc(-c3nc(Nc4ccc5[nH]ncc5c4)c4ccccc4n3)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1)N[C@@H]1CCNC1

Procedure:
To (3R)-tert-butyl 3-(2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetamido)pyrrolidine-1-carboxylate was added a solution of 1:1 TFA:CH2Cl2 (3 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the crude product was purified by prep HPLC (method 10-35_90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N—((R)-pyrrolidin-3-yl)acetamide. (45 mg, 0.094 mmol)
Reaction SMILES: [CH2:1]([C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[CH2:13][CH:12]3[CH:10]([CH:11]3[CH2:14][NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:18]([F:28])[CH:17]=3)[CH2:9]2)=[CH:5][CH:4]=1)[CH3:2].CCN(C(C)C)C(C)C.[S:40]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[CH:42]=[C:41]1[C:49](Cl)=[O:50].C([O-])(O)=O.[Na+]>ClCCCl>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:13][CH:12]3[CH:10]([CH:11]3[CH2:14][N:15]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:18]([F:28])[CH:17]=3)[C:49]([C:41]3[S:40][C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=4[CH:42]=3)=[O:50])[CH2:9]2)=[CH:29][CH:30]=1)[CH3:2]
Reactant: O=C(Cl)c1cc2ccccc2s1
Reactant: CCc1ccc(CN2CC3C(CNc4ccc(N5CCOCC5)c(F)c4)C3C2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc(CN2CC3C(C2)C3CN(C(=O)c2cc3ccccc3s2)c2ccc(N3CCOCC3)c(F)c2)cc1
Reaction time: 1 h

Procedure:
To a stirring solution of [3-(4-Ethyl-benzyl)-3-aza-bicyclo[3.1.0]hex-6-ylmethyl]-(3-fluoro-4-morpholin-4-yl-phenyl)-amine prepared above (50 mg, 0.12 mmol) in 2 mL of DCE at room temperature was added DIEA (0.03 mL, 0.18 mmol) and 2-benzthiophenecarbonylchloride (0.02 mL, 0.18 mmol). After 1 hour, saturated NaHCO3 was added, and the mixture was extracted with CH2Cl2. The combined extracts were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The resulting crude material was taken up in 50% EtOAc/hexanes and the white solids were filtered off. The remaining filtrate was concentrated under reduce pressure to yield 58 mg of the desired product. 400 MHz 1H NMR (CDCl3) δ 7.60-7.68 (m, 2H), 7.24-7.31 (m, 2H),7.08-7.18 (m, 5H), 6.99-7.02 (m, 2H), 6.86-6.91 (m, 1H), 3.82-3.88 (m, 4H), 3.68 (d, J=7.47 Hz, 2H), 3.50 (brs, 2H), 3.10-3.12 (m, 4H), 2.88 (brd, J=7.47 Hz, 2H), 2.49 (q, 2H), 2.28, (brs, 2H), 1.49 (brs, 1H), 1.22-1.24 (m, 2H), 1.19 (t, 3H); MS (M+1) 570.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][NH2:14])[CH2:6]2.[C:15]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[OH-].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][NH:14][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[CH2:6]2
Reactant: O=C1CCCC1
Reactant: COc1cc2c(cc1OC)[C@@H](CN)C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)[C@@H](CNC1CCCC1)C2
Reaction time: 4 h

Procedure:
At ambient temperature, 2.9 g (15 mmol) of {[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}amine and 1.3 mL (15 mmol/1 eq.) of cyclopentanone are mixed into 60 mL of dichloromethane. There are then added 4.8 g (22.5 mmol/1.5 eq.) of sodium triacetoxyborohydride and then 0.86 mL (15 mmol/1 eq.) of acetic acid, and stirring is carried out at ambient temperature for 4 hours. 90 mL of 1N sodium hydroxide solution are then poured in; extraction with two 120 mL quantities of ether is then carried out. The combined organic phases are washed with 90 mL of water and then with 90 mL of saturated aqueous sodium chloride solution and are then dried over magnesium sulphate. After filtration and concentration, the desired product is collected.
Reaction SMILES: O1C=CC(C2O[C:8]([C:12]([C:14]3[O:18][C:17](C4C=COC=4)=[N:16][C:15]=3[CH3:24])=[O:13])=[C:9]([CH3:11])N=2)=C1.[CH3:25][Li].[CH2:27]([OH:29])C.[Cl-].[Na+]>C(OCC)C>[O:29]1[CH:11]=[CH:9][C:8]([C:12]([C:14]2[O:18][CH:17]=[N:16][C:15]=2[CH3:24])([OH:13])[CH3:25])=[CH:27]1
Reactant: [Li]C
Reactant: CCO
Reactant: Cc1nc(-c2ccoc2)oc1C(=O)c1oc(-c2ccoc2)nc1C
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Product: Cc1ncoc1C(C)(O)c1ccoc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
3-Furyl-4-methyl-5-oxazolyl ketone (1 g) in dry diethylether (15 ml) at -70° C. under a nitrogen atmosphere was treated dropwise with methyllithium (1.5M solution in diethylether, 4.1 ml). After 45 minutes the reaction mixture was allowed to warm to room temperature and ethanol (2 ml) was added. The mixture was poured into saturated aqueous sodium chloride and extracted with dichloromethane. Chromatography and crystallisation then gave 1-(3-furyl)-1-(4-methyl-5-oxazolyl)ethanol identical to the material obtained in (a) above.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([OH:13])([CH3:12])[CH3:11])=[CH:6][CH:5]=1)C=C.C[N+]1([O-])[CH2:20][CH2:19][O:18]CC1.S(S([O-])=O)([O-])=[O:23].[O-][Si]([O-])=O.[Mg+2]>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[OH:13][C:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:1][CH:19]([OH:18])[CH2:20][OH:23])=[CH:5][CH:6]=1)([CH3:12])[CH3:11]
Reactant: O=S([O-])S(=O)[O-]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCc1ccc(C(C)(C)O)cc1
Agent: O=[Os](=O)(=O)=O
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(O)c1ccc(CC(O)CO)cc1
Reaction time: 24 h

Procedure:
To a biphasic mixture of 2-(4-allylphenyl)propan-2-ol (5.53 g, 31.4 mmol) and N-Methyl morpholine N-oxide (3.86 g, 32.9 mmol) in acetone (11 mL) and water (22 mL) was added osmium tetroxide (3.14 mL, 0.157 mmol) with vigorous stirring. After 24 hours, dithionite (0.15 g), Florisil (1.5 g), and water (8 mL) were added and allowed to stir for an additional 15 minutes before filtering through a pad of Celite. The filter was rinsed with acetone (2×5 mL, then 2×10 mL), and filtrate was concentrated by rotary evaporation to remove the acetone. The remaining liquid was diluted with 9:1 chloroform:isopropanol (20 mL) and aqueous hydrogen chloride (1 M, 20 mL), the layers were separated, and the acidic (pH=1) aqueous layer was extracted with 9:1 chloroform:isopropanol (2×20 mL). The combined organic layers were washed with 3:1 water:brine (12 mL), saturated aqueous sodium bicarbonate (10 mL), and brine (10 mL). The aqueous layers were combined and saturated with solid sodium chloride (50 cc) by stirring for 90 minutes, and then extracted with 9:1 chloroform:isopropanol (3×50 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated, and the crude material was purified by silica gel chromatography (5-20% methanol/dichloromethane) to afford 3-[4-(1-hydroxy-1-methylethyl)phenyl]propane-1,2-diol as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[N:14][C:13]=1[CH2:18][NH2:19].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:19][CH2:18][C:13]2[N:14]=[CH:15][CH:16]=[CH:17][N:12]=2)=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: NCc1ncccn1
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ncccn1)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.3 %

Procedure:
To a flask was charged with 4-bromo-2-fluorobenzoic acid (180 mg, 0.821 mmol), pyrimidin-2-ylmethanamine (89.6 mg, 0.821 mmol), DIEA (0.358 mL, 2.05 mmol) in DMF (3 mL), and to the resulting solution was added PyBOP (513 mg, 0.915 mmol) and the resulting mixture was stirred at room temperature overnight, then was concentrated under reduced pressure and the residue was diluted with EtOAc (20 mL), washed with water (3×10 mL), brine (10 mL) and dried (Na2SO4), concentrated and the residue was purified by flash chromatography on silica gel eluted with gradient EtOAc/heptane (0-100%) and 4-bromo-2-fluoro-N-(pyrimidin-2-ylmethyl)benzamide (74.5 mg, 29.3%) was obtained as light color solid. LCMS (m/z): 310.0/312.0 (MH+), 0.64 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14]2[N:18]=[CH:19][C:20](I)=[CH:21][C:13]1=2)[CH3:11].[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][N:31]=2)[CH2:26][CH2:25]1>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14]2[N:18]=[CH:19][C:20]([C:33]3[CH:32]=[N:31][C:30]([N:27]4[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]4)=[CH:35][CH:34]=3)=[CH:21][C:13]1=2)[CH3:11]
Reactant: CC(c1c(F)ccc(F)c1Cl)N1CCNc2ncc(I)cc21
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Product: CC(c1c(F)ccc(F)c1Cl)N1CCNc2ncc(-c3ccc(N4CCN(C)CC4)nc3)cc21
Yield: 15 %

Procedure:
1-[1-(2-Chloro-3,6-difluorophenyl)ethyl]-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (53 mg) was coupled to 1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine as in General Procedure 4B to give the title compound as an orange solid (15% yield). LCMS: m/z=435.02 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.66 (3H, d, J=7.1 Hz), 2.35 (3H, s), 2.54 (4H, t, J=4.9 Hz), 3.54 (8H, m), 4.89 (1H, bs), 5.31 (1H, m), 6.68 (1H, d, J=8.9 Hz), 6.72 (1H, s), 6.96 (1H, m), 7.05 (1H, m), 7.52 (1H, dd, J=8.8, 2.5 Hz), 7.57 (1H, s), 8.29 (1H, d, J=2.3 Hz).
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][N:5]1[C:13]2[C:8](=[N:9][C:10]([C:21]#[N:22])=[C:11]([N:14]3[CH2:20][C:16]4([CH2:19][O:18][CH2:17]4)[CH2:15]3)[CH:12]=2)[CH:7]=[CH:6]1.[BH4-].[Na+].O>C1COCC1>[CH3:4][N:5]1[C:13]2[C:8](=[N:9][C:10]([CH:21]([NH2:22])[CH3:1])=[C:11]([N:14]3[CH2:20][C:16]4([CH2:19][O:18][CH2:17]4)[CH2:15]3)[CH:12]=2)[CH:7]=[CH:6]1
Reactant: Cn1ccc2nc(C#N)c(N3CC4(COC4)C3)cc21
Reactant: C[Mg]Br
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(N)c1nc2ccn(C)c2cc1N1CC2(COC2)C1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 46.7 %

Procedure:
Methylmagnesium bromide (1.56 mL, 2.18 mmol) was added slowly to a stirred solution of 1-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile (222 mg, 0.873 mmol) in THF (20 mL). The reaction was stirred at 40° C. for 1.5 hours, then cooled to 0° C. and quenched with MeOH (10 mL). After 10 minutes, sodium tetrahydroborate (83 mg, 2.18 mmol) was added. The reaction mixture was stirred for 20 minutes. Water (1 mL) was added and the reaction mixture was stirred for an additional 10 minutes. The reaction mixture was dried over MgSO4, filtered through Celite, and concentrated. The crude product was purified by basic silica column chromatography (3-5% MeOH in DCM) to give the title compound as a clear oil (111 mg, 47%). 1H NMR (500 MHz, CD3OD) δ ppm 7.28 (d, 1H, J=3.5 Hz), 7.14 (s, 1H), 6.47 (d, 1H, J=3.5 Hz), 4.89 (s, 4H), 4.33 (q, 1H, J=7.0 Hz), 4.10 (qAB, 4H, J=35.5, 7.5 Hz), 3.36 (s, 3H), 1.43 (d, 3H, J=7.0 Hz). ESI-MS m/z [M+H]+ calc'd for C15H20F4O, 273; found 273.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[O-:13].[K+].Cl[C:16]1[CH:21]=[C:20](Cl)[CH:19]=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24].[OH2:26]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:11])([F:12])[F:10])[CH:5]=[CH:4][C:3]=1[O:13][C:16]1[CH:21]=[C:20]([O:26][C:3]2[CH:4]=[CH:5][C:6]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:7][C:2]=2[Cl:1])[CH:19]=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24]
Reactant: O
Reactant: [O-]c1ccc(OC(F)(F)F)cc1Cl
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(OC(F)(F)F)cc2Cl)cc1Oc1ccc(OC(F)(F)F)cc1Cl

Procedure:
A solution of 0.1 g of metallic sodium in 8 ml of methanol was added to a solution of 1.2 g (0.002 mole) of 2,4-bis(2-chloro-4-trifluoromethoxy-phenoxy)nitrobenzene in benzene. The mixture was heated with stirring at 40°-50° C. in a water bath for 1.5 hours. The reaction mixture was thoroughly washed with a dilute aqueous sodium hydroxide solution and then with water, dehydrated over anhydrous sodium sulfate, and freed from the benzene by distillation to obtain a crude product. The crude product was purified by chromatography on silica gel to obtain 0.7 g of the intended product (nD20 1.5562; 84% yield). 2,4-Bis(2-chloro-4-trifluoromethoxyphenoxy)-nitrobenzene was synthesized in the following way: 11.0 Grams (0.044 mole) of potassium 2-chloro-4-trifluoromethoxyphenolate and 3.2 g (0.017 mole) of 2,4-dichloronitrobenzene were heated under reflux in 100 ml of dimethylformamide for one hour. After cooling, the reaction mixture was poured into about 500 ml of water and then extracted with benzene. The benzene layer was thoroughly washed successively with dilute aqueous sodium hydroxide solution, dilute hydrochloric acid and water, then dehydrated, and concentrated. The resulting oily substance was distilled under reduced pressure to obtain 5.3 g (57% yield) of the intended product boiling at 170°-185° C./0.1 mmHg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:29][CH2:30][CH2:31][OH:32])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CC(C)=[O:35].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:29][CH2:30][C:31]([OH:35])=[O:32])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:27])([F:26])[F:28])=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: C[C@@H](c1ccc(OCC(F)(F)F)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: C[C@@H](c1ccc(OCC(F)(F)F)cc1)N1CC[C@](CCC(=O)O)(c2ccc(F)cc2)OC1=O
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1,3-oxazinan-2-one (320 mg, 0.7 mmol) in acetone (7 mL) was added Jones reagent (2.5 M□1.05 mL) at 0° C. The mixture was stirred at this temperature for 30 min. The formed mixture was filtered and the filtrate was concentrated. The residue was treated with H2O (10 mL) and CH2Cl2 (10 mL). The mixture was separated, and the organic layer was washed with brine and concentrated. The residue was purified by preparative TLC to give 3-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1,3-oxazinan-6-yl)propanoic acid (290 mg, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[C:17]([OH:25])(=[O:24])[C:18]([CH2:20][C:21](O)=[O:22])=[CH2:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([N:16]3[C:21](=[O:22])[CH2:20][CH:18]([C:17]([OH:25])=[O:24])[CH2:19]3)=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(CCc2cccc(Cl)c2)cc1
Reactant: C=C(CC(=O)O)C(=O)O
Product: O=C(O)C1CC(=O)N(c2ccc(CCc3cccc(Cl)c3)cc2)C1

Procedure:
In an analogous manner to that described in Example 36c), the reaction of 4-[2-(3-chloro-phenyl)-ethyl]-phenylamine with itaconic acid yields the (RS)-1-{4-[2-(3-chloro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid as an off-white solid; MS: m/e=342 (M−H)+.