Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[F-].[Cs+].O.[CH3:12][C:13]1[N:18]=[CH:17][C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][N:14]=1>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([C:16]2[CH:15]=[N:14][C:13]([CH3:12])=[N:18][CH:17]=2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Product: Cc1ncc(-c2cc(Cl)ncn2)cn1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
As shown in step 9-i of Scheme 9, to 4,6-dichloropyrimidine (265.3 g, 1.781 mol) in 1.68 L DME was added CsF (241.5 g, 1.59 mol) and 700 mL water. The mixture was flushed with nitrogen gas for 30 minutes and Pd(PPh3)4 (22.05 g 19.08 mmol) was added. The resulting light yellow solution was flushed with nitrogen gas for an additional 40 minutes, heated to reflux, and a nitrogen-flushed solution of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (140 g, 636.1 mmol in 420 mL DME) was added dropwise over 1.6 hours. The resulting dark red solution was refluxed under an atmosphere of nitrogen for 16 hours. After this time the mixture was cooled to RT and 300 mL of water was added. The mixture was then cooled to 5° C. and stirred for 40 minutes. The resulting precipitate (6-chloro-2′-methyl-4,5′-bipyrimidine, compound 2039) was collected by filtration, washed with 50 mL water, followed by washing with 150 mL EtOAc. The filtrate was separated into two layers and the aqueous layer extracted with EtOAc (2×1 L). The combined organics were dried over Na2SO4, concentrated under reduced pressure, diluted with 300 mL of DCM, and purified by medium pressure silica gel chromatography (0-100% EtOAc/DCM). Fractions containing pure product were concentrated under reduced pressure and the concentrate treated with 400 mL of hexanes to produce compound 2039 as a solid. This material was combined with the solid product previously collected and treated with 400 mL of 1:1 THF/DCM. The resulting suspension was heated and transferred to a filtration funnel containing a plug of Florisil®. The plug was washed with additional 1:1 THF/DCM to dissolve any remaining solid material and then washed with 4:1 EtOAc/DCM (2×1 L). The combined filtrates were concentrated under reduced pressure to produce a pink solid which was triturated with 500 mL hexanes, collected by filtration, and dried under reduced pressure to provide 6-chloro-2′-methyl-4,5′-bipyrimidine (compound 2039, 88.8 g, 68% yield): LC-MS=207.01 (M+H); 1H NMR (300 MHz, CDCl3) δ 9.30 (s, 2H), 9.10 (d, J=1.2 Hz, 1H), 7.78 (d, J=1.2 Hz, 1H), 2.85 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[OH:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:12]=1[CH:13]=O.C(N(CC)CC)C>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]=[CH:13][C:12]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:11]=2[OH:10])=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: Cc1cccc(O)c1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cccc(O)c1C=Nc1ccc(Br)cc1F
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A solution of 4-bromo-2-fluoroaniline (19.6 g, 103.16 mmol), 2-hydroxy-6-methyl-benzaldehyde (14.03 g, 103.16 mmol) and p-toluenesulfonic acid (188 mg, 0.99 mmol) in toluene (300 mL) was heated to reflux in a Dean-Stark apparatus for 1 h and then allowed to cool to ambient temperature. After adding triethylamine (0.8 mL) the reaction mixture was concentrated to give the crude title compound (31.7 g, 99%) which was used without further purification. Data: 1H-NMR (400 MHz, CDCl3) δ 2.52 (s, 3H), 6.72 (d, J=7.6 Hz, 1H), 6.88 (d, J=8.6 Hz, 1H), 5.15 (t, J=7.8 Hz, 1H), 7.26-7.38 (m, 3H), 9.03 (s, 1H), 13.63 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:14])([CH3:13])[C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([Br:15])[C:9]([CH3:14])([CH3:13])[C:10](=[O:12])[CH3:11])=[CH:6][CH:7]=1
Reactant: CC(=O)C(C)(C)Cc1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)C(C)(C)C(Br)c1ccc(Cl)cc1
Yield: 82 %

Procedure:
50 g (0.237 mol) of 1-(4-chlorophenyl)-2,2-dimethyl-3-butanone are dissolved in 500 ml of tetrachloromethane, and 44.5 g (0.25 mol) of N-bromosuccinimide and 0.5 g of azobisisobutyronitrile are added. The reaction mixture is heated to boiling under reflux until solid material no longer sinks to the bottom on switching off the stirrer. After cooling down, the succinimide is filtered off with suction, the solvent is distilled off from the filtrate under waterpump vacuum and the residue is distilled under high vacuum. 56.3 g (82% of theory) of 1-(4-chlorophenyl)-1-bromo-2,2-dimethyl-3-butanone of boiling point 112°-118° C./0.2 mbar are obtained.
Reaction SMILES: F[B-](F)(F)F.[C:6]1([OH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(O[CH2:17][CH:18]=[CH2:19])(=O)C>C1(C)C=CC=CC=1>[CH2:19]([O:12][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:18]=[CH2:17].[C:6]1([OH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=CCOC(C)=O
Agent: F[B-](F)(F)F
Solvent: Oc1ccccc1
Solvent: Cc1ccccc1
Product: C=CCOc1ccccc1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
A mixture of bis(1,5-cyclooctadiene)iridium tetrafluoroborate [Ir(cod)2]+BF4− (0.01 mmol) and toluene (1.0 ml) was treated with phenol (1 mmol) and allyl acetate (5 mmol) with stirring at 100° C. The reaction mixtures after 5 hours and after 15 hours of the reaction were analyzed by gas chromatography. In the reaction mixture after 5 hours, phenyl allyl ether was formed in a yield of 21% with a conversion from phenol of 23%. In the reaction mixture after 15 hours, phenyl allyl ether was formed in a yield of 51% with a conversion from phenol of 51%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([OH:14])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:15]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28]O)[CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][C:11]([O:14][CH2:28][CH:25]3[CH2:26][CH2:27][N:22]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:23][CH2:24]3)=[CH:12][N:13]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Oc1cnc(-c2ccc(Br)cc2)nc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2cnc(-c3ccc(Br)cc3)nc2)CC1

Procedure:
1,1-Dimethylethyl 4-({[2-(4-bromophenyl)-5-pyrimidinyl]oxy}methyl)-1-piperidinecarboxylate was prepared (0.387 g, 76%) as a white solid from 2-(4-bromophenyl)-pyrimidine-5-ol (0.30 g, 1.19 mmol), N-Boc-4-piperidinemethanol (0.27 g, 1.19 mmol) and Ph3P (0.32 g, 1.19 mmol) in THF (8 mL) followed by diisopropyl azodicarboxylate (0.26 g, 94%, 1.19 mmol) in THF (3 mL) in a manner similar to Example 1, Step 2. 1H NMR (400 MHz, CDCl3): δ 8.44 (s, 2H), 8.22 (d, 2H, J=8.3 Hz), 7.59 (d, 2H, J=8.3 Hz), 4.25-4.10 (m, 2H), 3.94 (d, 2H, J=6.1 Hz), 2.85-2.70 (m, 2H), 2.10-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.46 (s, 9H), 1.35-1.20 (m, 2H); LRMS (ESI), m/z 448/450 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[S:10][C:11]=2[C:12](O)=[O:13])=[CH:4][CH:3]=1.C1C=[CH:25][C:26]2N(O)N=[N:29][C:27]=2C=1.CCN=C=NCCCN(C)C.C(N)C=C>C(Cl)Cl>[CH2:27]([NH:29][C:12]([C:11]1[S:10][C:9]([C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)=[N:8][C:7]=1[CH2:6][C:5]1[CH:21]=[CH:22][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:13])[CH:26]=[CH2:25]
Reactant: O=C(O)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: C=CCN
Product: C=CCNC(=O)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a stirred solution of 4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole-5-carboxylic acid (220 mg, 0.665 mmol) in DCM (4.05 mL) was added HOBT (98.8 mg, 0.732 mmol) and EDCI (204 mg, 1.06 mmol) at room temperature and the mixture was stirred for 30 min. To the solution was added 2-propen-1-amine (0.200 mL, 2.66 mmol) then the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (10 mL) and washed with water (3 mL) and brine (2 mL), then dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/DCM=0/100→75/25) to give 150 mg of the title compound as a yellow solid (61% yield). LC/MS (FA) ES+ 370. 1H NMR (400 MHz, CDCl3) δ: 8.74-8.72 (m, 2H), 7.79-7.77 (m, 2H), 7.35-7.32 (m, 2H), 7.27-7.25 (m, 2H), 5.94-5.80 (m+bs, 2H), 5.25-5.20 (m, 2H), 4.48 (s, 2H), 4.06-4.02 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([N:19]([CH2:23][CH2:24][CH2:25][CH2:26]O)[CH:20]([CH3:22])[CH3:21])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:48]>ClCCl>[Br:48][CH2:26][CH2:25][CH2:24][CH2:23][N:19]([C:10]1[CH:9]=[N:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:11]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)N(CCCCO)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)N(CCCCBr)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reaction time: 1 h
Yield: 67 %

Procedure:
A solution of 1.50 g of 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1-butanol and 1.18 g of triphenylphosphine in 20 ml of dichloromethane was ice-cooled and 1.49 g of carbon tetrabromide was added. After stirring for one hour, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.18 g of the desired compound as a yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=O.[CH2:12]([NH2:16])[CH2:13][CH2:14][CH3:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:12](/[N:16]=[CH:4]/[C:3]1[C:6]([F:11])=[CH:7][CH:8]=[C:9]([F:10])[C:2]=1[Cl:1])[CH2:13][CH2:14][CH3:15]
Reactant: O=Cc1c(F)ccc(F)c1Cl
Reactant: CCCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCC/N=C/c1c(F)ccc(F)c1Cl

Procedure:
Butyl-[1-(2-chloro-3,6-difluoro-phenyl)-meth-(E)-ylidene]-amine was prepared from 2-chloro-3,6-difluorobenzaldehyde, N-butylamine and p-toluenesulphonic acid in analogy to Example 191a): yellow oil; MS (ISP): 234.1 ([M+H]+, 30%), 232.3 ([M+H]+, 100%).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1>O1CCCC1>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:34])=[CH:28][CH:27]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)cc1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a solvent of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 4-chlorophenyl isocyanate (0.188 mg, 1.22 mmol), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 310 mg (95.4%) of the desired product as a solid.
Reaction SMILES: [CH3:1][SH:2].C[O-].[Na+].Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]/[CH:12]=[C:13](\[NH:17][C:18]([CH:20]1[CH2:22][C:21]1([CH3:24])[CH3:23])=[O:19])/[C:14]([OH:16])=[O:15].N#N>CO>[CH3:23][C:21]1([CH3:24])[CH2:22][CH:20]1[C:18]([NH:17]/[C:13](=[CH:12]\[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][S:2][CH3:1])/[C:14]([OH:16])=[O:15])=[O:19]
Reactant: CS
Reactant: CC1(C)CC1C(=O)N/C(=C\CCCCCBr)C(=O)O
Agent: C[O-]
Agent: N#N
Agent: [Na+]
Solvent: CO
Product: CSCCCCC/C=C(\NC(=O)C1CC1(C)C)C(=O)O
Temperature: 25 °C

Procedure:
A stream of CH3SH gas was bubbled through a solution of 162 mg (3 mmoles) of sodium methoxide in 5 ml of methanol for 10 min. with cooling in an ice bath. The solution was allowed to warm to room temperature and 332 mg (1 mmole) of Z-8-bromo-2-(2,2-dimethylcyclopropanecarboxamido)-2-octenoic acid was added. The solution was heated under reflux for 30 min. in a N2 atmosphere. Most of the methanol was evaporated under reduced pressure, the residue 2.5 N HCl. The precipitated oil was extracted with ether (3×). The ether extracts were washed with water, saturated brine and dried over MgSO4. Removal of the ether under reduced pressure gave a colorless oil that crystallized upon standing. It was recrystallized from ether-hexane to give 178 mg of Z-2-(2,2-dimethylcyclopropanecarboxamido)-8-methylthio-2-octenoic acid, m.p. 82°-84° C. Homogeneous by TLC (toluene-acetic acid, 4:1). The NMR spectrum was in accord with the desired structure.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Br:20])[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].[CH:22](=[O:26])[CH:23]([CH3:25])[CH3:24].O>O1CCCC1.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][CH:12]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Br:20])[CH:14]=1)[C:23]([CH3:25])([CH3:24])[CH:22]2[OH:26])=[O:21])[CH3:2]
Reactant: CC(C)C=O
Reactant: CCOC(=O)c1ccc(N=Cc2ccc(F)c(Br)c2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1ccc(F)c(Br)c1)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
To a mixture of 4-{[1-(3-bromo-4-fluoro-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (1.6 g, 4.57 mmol) and ytterbium(III) triflate hydrate (0.28 g, 0.457 mmol) in dry tetrahydrofuran (10 mL) at 25° C. was added isobutyraldehyde (0.42 mL, 4.57 mmol) and water (82 mg, 4.57 mmol) dropwise. The reaction mixture was stirred at 25° C. for 5 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-4-fluoro-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.93 g, 100%) as a light yellow oil: LC/MS m/e calcd for C20H21BrFNO3 M+: 422.3, observed: 404.2.
Reaction SMILES: B1C2CCCC1CCC2.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][CH:19]=2)=[CH:13][C:12]=1[C:26]([F:29])([F:28])[F:27].[OH-:30].[Na+].OO>C1COCC1.O>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][OH:30])=[CH:22][CH:23]=2)=[CH:13][C:12]=1[C:26]([F:27])([F:28])[F:29]
Reactant: C=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
9-BBN (158 mL, 79 mmol) was added to a solution of 1-chloro-2-(trifluoromethyl)-4-(4-vinylphenoxyl)benzene (15.75 g, 52.7 mmol) in THF (160 mL) at 0° C. The resultant reaction mixture was stirred at room temperature overnight. To the mixture was added water (16 mL), 3M NaOH solution (80 mL) and 30% hydrogen peroxide (80 mL). It was stirred at 50° C. for 2 h, concentrated in vacuo, and diluted with ethyl acetate (200 mL). The organic phase was collected, washed with water (100 mL×2) & brine (100 mL), dried over sodium sulfate, and concentrated. Purification via a column chromatography then provided the title compound as a colorless oil (12.13 g, 71.7% yield). LCMS: rt=2.08 min, [M+H+]=299
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(N(CC)CC)C>C(O)(C)C>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([N:19]2[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]2)[C:11]=1[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cc(F)cc(F)c2c1Cl
Temperature: 120 °C

Procedure:
2,4-dichloro-5,7-difluoro-3-methylquinoline (4.90 g, 10.0 mmol), tert-butyl piperazine-1-carboxylate (3.70 g, 20.0 mmol) and triethylamine (2.80 mL, 20.0 mmol) were slurried in isopropyl alcohol (40 mL) and heated at 120° C. for 12 h. The reaction was then allowed to cool to rt and concentrated to dryness. The crude product was then purified by column chromatography (silica gel, 0 to 20% EtOAc:hexane) to give tert-butyl 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)piperazine-1-carboxylate. Mass Spectrum (ESI) m/e=398.2 (M+1).
Reaction SMILES: [Na].[CH3:2][O:3][C:4](=[O:17])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=1)[CH3:6].O.[CH:19]1(CO)[CH2:21][CH2:20]1>>[CH:19]1([CH2:2][O:3][C:4](=[O:17])[CH:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:11][CH:12]=2)[CH3:6])[CH2:21][CH2:20]1
Reactant: OCC1CC1
Reactant: COC(=O)C(C)c1ccc(CC(C)C)cc1
Agent: [Na]
Solvent: O
Product: CC(C)Cc1ccc(C(C)C(=O)OCC2CC2)cc1
Temperature: 50 °C

Procedure:
A mixture of 0.05 g of sodium in 20 ml of cyclopropylmethyl alcohol was heated at 50° C. for 5 hours. To the mixture was added 2.2 g of 2-(p-isobutylphenyl)propionic acid methyl ester and the whole was refluxed for 10 hours. After the reaction was completed, the solvent was removed by distillation under reduced pressure to leave a residue, to which was added water. The resulting mixture was extracted with ether, and the extract was washed sufficiently with water and then dehydrated. The ether was removed by distillation to leave a residual oily product. This product was then distilled under reduced pressure to yield 1.38 g of 2-(p-isobutylphenyl)propionic acid cyclopropylmethyl ester as a colorless oil, boiling at 109°-111° C./1 mmHg. Analysis-Calculated for C17H24O2 : C, 78.42; H, 9.29. Found: C, 78.19; H, 9.22.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:8][C:9](=[O:19])[C@@H:10]1[CH2:14][CH:13]([OH:15])[CH2:12][N:11]1[C:16](=[O:18])[CH3:17])[CH3:7].C(N(CC)CC)C.Cl>C(Cl)(Cl)Cl>[CH2:6]([O:8][C:9](=[O:19])[C@@H:10]1[CH2:14][CH:13]([O:15][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:12][N:11]1[C:16](=[O:18])[CH3:17])[CH3:7]
Reactant: CCOC(=O)[C@@H]1CC(O)CN1C(C)=O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CC(OS(C)(=O)=O)CN1C(C)=O
Reaction time: 0.5 h
Yield: 72 %

Procedure:
457 g of methanesulfonyl chloride was added dropwise to a solution of 1020 g of N-acetyl-4-hydroxy-L-proline ethyl ester, 435 g of triethylamine and 1.9 L of chloroform at not higher than 15° C. while cooling. After stirring for 30 minutes, 1N hydrochloric acid (0.6 L) was added, and the layers were separated. The organic layer was washed with 5% aqueous sodium bicarbonate (600 g), washed with water (0.6 L), dried over magnesium sulfate, and concentrated under reduced pressure to obtain 802 g of N-acetyl-4-mesyloxy-L-proline ethyl ester as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>C(Cl)Cl>[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:21]
Reactant: Cc1ccc(CN)cc1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(CNC(=O)c2ccccc2C)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 84.6 %

Procedure:
A solution of 4-methylbenzylamine (2.0 mL, 15.7 mmol), and triethylamine (4.4 mL, 31.6 mmol) in CH2Cl2 (50 mL) was cooled in an ice bath and treated dropwise with 2-methylbenzoyl chloride (2.5 mL, 19.2 mmol). After the end of the addition the ice bath was removed and the reaction mixture was allowed to warm to ambient temperature. After stirring at ambient temperature for 14 hours the resulting white suspension was diluted with CH2Cl2 (100 mL), and quenched by the addition of water (20 mL) and saturated aqueous sodium bicarbonate (20 mL). The aqueous layer was extracted with CH2Cl2 (3×30 mL), and the combined organics were dried over Na2SO4, filtered and concentrated to afford a white solid. The crude solid was recrystallized from ethyl acetate/hexane to afford 2-methyl-N-(4-methylbenzyl)benzamide (3.18 g, 85% yield) as a white crystalline solid: 1H-NMR (400 MHz, CDCl3): δ 7.36 (1H, dd, J=7.6, 1.3 Hz), 7.32-7.14 (7H, m), 5.98 (1H, br s), 4.59 (2H, d, J=5.6 Hz), 2.47 (3H, s), 2.35 (3H, s) ppm.
Reaction SMILES: [C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:8]([NH:10][C:11]2[C:12]([OH:20])=[N:13][C:14]([C:17](O)=[O:18])=[N:15][CH:16]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CS(C)=O>[C:1]1([CH:7]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:8]([NH:10][C:11]2[C:12]([OH:20])=[N:13][C:14]([C:17]([NH:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:18])=[N:15][CH:16]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ncc(NC(=O)C(c2ccccc2)c2ccccc2)c(O)n1
Reactant: COC(=O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)CNC(=O)c1ncc(NC(=O)C(c2ccccc2)c2ccccc2)c(O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of Step A product, 3-1-a, (300 mg, 0.86 mmol), methyl 2-aminoacetate (129 mg, 1.03 mmol) and DIEA (222 mg, 1.7 mmol) in DMSO (10 mL) was added with TBTU (330 mg, 1.03 mmol) and stirred at room temperature for overnight. The reaction mixture was poured into ice water (100 mL). The solids were filtered and purified by pre-HPLC to afford the product as a white solid, 3-1-b, (60 mg, 17%). LC-MS (M+H)+ 421.0
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH: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].O>C(#N)C>[F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([CH2:25][CH2:26][CH3:27])[CH2:14][CH2:13]1
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1F
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCN1CCC(c2cccc(S(C)(=O)=O)c2F)CC1
Temperature: 25 °C
Yield: 79.7 %

Procedure:
To a solution of 4-[2-fluoro-3-(methylsulfonyl)phenyl]piperidine (0.4 g, 1.55 mmol) in acetonitrile (40 ml) was added potassium carbonate (0.3 g, 2.17 mmol) and 1-iodopropane (0.151 ml, 1.55 mmol) and the mixture was heated at reflux for 15 h. The mixture was cooled to ambient temperature and water (50 ml) was added. The aqueous residue was extracted with ethylacetate (3×50 ml) and the combined organic phases was dried, concentrated, and purified by flash column chromatography (ethylacetate/methanol, 1:1) to give the title compound (0.37 g, 79%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 255-257° C. MS m/z (relative intensity, 70 eV) 299 (M+, 2), 271 (16), 270 (bp), 147 (9) 133 (10).