Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.O.Cl[C:11]([F:16])([F:15])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:7]([O:8][CH:11]([F:16])[F:15])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccnc1Cl
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)Oc1cccnc1Cl
Temperature: 100 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
As shown in step 3-i of Scheme 3, 2-chloro-3-hydroxypyridine (Compound 1005, 2.0 g, 15.4 mmol, obtained from Aldrich Chemical Co.) was dissolved in 40 mL of DMF and 5.0 mL of water along with sodium chlorodifluoroacetate (4.71 g, 30.9 mmol, obtained from Lancaster Synthesis, Inc.) and anhydrous potassium carbonate (2.56 g; 18.5 mmol). The reaction mixture was heated in an oil bath at 100° C. for 2 hours. Another equivalent of sodium chlorodifluoroacetate and 1.2 equiv. of potassium carbonate were added and heating continued for an additional 2.0 hours. After this time, the reaction was cooled and the volatiles removed under reduced pressure. The residue was partitioned between brine and ethyl acetate and the organics washed once more with brine, dried over Na2SO4, filtered, and the volatiles removed under reduced pressure. The product was purified by silica gel chromatography, eluting with a hexanes/DCM to DCM gradient, to produce 2-chloro-3-(difluoromethoxy)pyridine as a white solid (Compound 1006, 2.0 g, 72% yield): ESMS (M+H) 180; 1H NMR (CDCl3) δ 8.05 (m, 1H), 7.45 (m, 1H), 6.90 (m, 1H), 6.60 (t, 1H; J=75 Hz), 4.01 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]([C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([Cl:27])[CH:18]=1)=[N:5][NH:6]S(C1C=CC(C)=CC=1)(=O)=O.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3](=[O:28])[C:4]([C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([Cl:27])[CH:18]=1)=[N+:5]=[N-:6]
Reactant: COC(=O)C(=NNS(=O)(=O)c1ccc(C)cc1)c1ccc(S(C)(=O)=O)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(=[N+]=[N-])c1ccc(S(C)(=O)=O)c(Cl)c1
Reaction time: 1 h
Yield: 39.9 %

Procedure:
A solution of (3-chloro-4-methanesulfonyl-phenyl)-(4-toluenesulfonyl-hydrazono)-acetic acid methyl ester (3.82 g, 8.5 mmol) and triethylamine (1.3 mL, 9.35 mmol) in dichloromethane (40 mL) was stirred at 25° C. After 1 h, the reaction was evaporated under reduced pressure and the resulting residue was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) to give (3-chloro-4-methanesulfonyl-phenyl)-diazo-acetic acid methyl ester (978 mg, 40% yield) as a bright yellowish orange solid, mp 102.7-106.5° C.; EI-HRMS m/e calcd for C10H9N2ClSO4 (M+) 287.9972, found 287.9979.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].[Cl-].[NH4+]>ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCCCCCCCCCCCCCCBr
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCCCCCCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
16-Bromohexadecan-1-ol (1 g) was dissolved in 20 ml of dichloromethane, and imidazole (317.9 mg) and t-butyldimethylsilyl chloride (701.4 mg) were added to this solution. The reaction mixture was stirred at room temperature for four hours. Saturated ammonium chloride solution was added to the reaction mixture, which was then extracted three times with dichloromethane. The organic layer was washed with saline solution and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by silica gel flash chromatography (heptane:ethyl acetate=7:3) gave (16-bromohexadecyloxy)-t-butyldimethylsilane as a colorless oil at an 81% yield.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]([O:10][C:11]3[C:12]([CH3:23])=[C:13]([O:21][CH3:22])[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[C:16]=3[O:17][C:6]=2[C:5]([CH:24]=[O:25])=[C:4](O)[CH:3]=1)=[O:9].[C:27](O)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([C:4]1[CH:3]=[C:2]([CH3:1])[C:7]2[C:8](=[O:9])[O:10][C:11]3[C:12]([CH3:23])=[C:13]([O:21][CH3:22])[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[C:16]=3[O:17][C:6]=2[C:5]=1[CH:24]=[O:25])(=[O:29])[CH3:28]
Reactant: COc1cc(C(=O)O)c2c(c1C)OC(=O)c1c(C)cc(O)c(C=O)c1O2
Reactant: CC(=O)O
Solvent: c1ccncc1
Product: COc1cc(C(=O)O)c2c(c1C)OC(=O)c1c(C)cc(C(C)=O)c(C=O)c1O2
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Psoromic acid (1 mmol) was dissolved in pyridine (2 ml) and glacial acetic acid (1 ml). The reaction was stirred for 14 hours at room temperature. Most of the solvent was removed by rotatory evaporation. The residue was taken up in methylene chloride, washed with water and saturated brine, dried with anhydrous MgSO4, evaporated by a rotatory evaporator and purified by column chromatography.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[S:9][CH:10]=1)=[O:5])[CH3:2].Br.[Cl:20][C:21]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:21]=2[Cl:20])[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)c1csc(Nc2ccc(Cl)cc2)n1
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1csc(N(C(=O)c2ccc(Cl)cc2Cl)c2ccc(Cl)cc2)n1

Procedure:
A mixture of 2.58 g (7.1 mmol) 2-(4-Chloro-phenylamino)-thiazole-4-carboxylic acid ethyl ester; hydrobromide, 2.24 g (10.7 mmol) 2,4-Dichlorobenzoyl chloride and 2.96 ml (21.4 mmol) NEt3 in 30 ml DCM was stirred at room temperature for 24 h. After evaporation of the volatiles the residue was taken up in MeOH and purified with flash column chromatography on silica eluting with a gradient of heptane/ethyl acetate to yield after evaporation of the product fractions 2.81 g (87%) of the title compound. MS (m/e): 457.1 (MH+, 100%)
Reaction SMILES: [H-].[Na+].C(=O)=O.CO.[Br:8][C:9]1[CH:10]=[C:11]([CH2:15][C:16]#[N:17])[CH:12]=[N:13][CH:14]=1.Br[CH2:19][CH2:20][O:21][CH2:22][CH2:23]Br>C1COCC1>[Br:8][C:9]1[CH:10]=[C:11]([C:15]2([C:16]#[N:17])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:12]=[N:13][CH:14]=1
Reactant: N#CCc1cncc(Br)c1
Reactant: BrCCOCCBr
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: N#CC1(c2cncc(Br)c2)CCOCC1
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
Under argon, NaH (60% in mineral oil, 0.497 g, 12.4 mmol) is added into THF (10 mL). The reaction mixture is cooled on a bath of dry ice/CH3OH. A solution of (5-bromo-pyridin-3-yl)-acetonitrile (1.0 g, 5.0 mmol) and 2-bromoethyl ether (0.719 mL, 5.15 mmol) in THF (4.5 mL) is added dropwise. The reaction is stirred for 30 min. The dry ice/MeOH bath is removed and the mixture is stirred at room temperature for 14 hrs. The reaction is quenched by slow addition of MeOH (5 mL). The mixture is then concentrated. The resulting crude product is purified by normal phase chromatography using 0-3% MeOH in DCM as the gradient to afford 4-(5-bromo-pyridin-3-yl)-tetrahydro-pyran-4-carbonitrile (1.07 g, 79% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[C:4]([CH3:21])[CH:3]=1.C1(N)CCCCC1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[C:4]([CH3:21])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1-c1ccc(C(=O)CCC(=O)O)cc1
Solvent: NC1CCCCC1
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)ccc1-c1ccc(CCCC(=O)O)cc1
Yield: 76 %

Procedure:
Prepared analogous to Example 1 by reduction of 4-(4'-chloro-2'-methyl-4-biphenylyl)-4-oxo-butyric acid. Yield: 76%. Melting point of the cyclohexylamine salt: 145.5°-147° C. (from ethyl acetate).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH2:31][CH3:32])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C([Sn](CCCC)(CCCC)/[CH:60]=[CH:61]\[O:62][CH2:63][CH3:64])CCC.C(N(CC)CC)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C)C=O>[CH2:63]([O:62]/[CH:61]=[CH:60]\[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH2:31][CH3:32])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1)[CH3:64]
Reactant: CCCC[Sn](/C=C\OCC)(CCCC)CCCC
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(Br)ccn34)c12
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCO/C=C\c1ccn2c(C(=O)Nc3cccc4c3c(CC)nn4Cc3cccc(C)n3)cnc2c1
Temperature: 100 °C
Reaction time: 10 h
Yield: 75.9 %

Procedure:
A round bottom flask was charged with 7-Bromo-N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (330 mg, 0.674 mmol), trio-tolylphosphine (41 mg, 0.135 mmol), tris(dibenzylideneacetone)dipalladium (62 mg, 0.067 mmol) To the flask were added 10 mL of anhydrous dimethylformamide, followed by (Z)-tributyl(2-ethoxyvinyl)stannane (0.34 ml, 1.01 mmol), and triethylamine (0.11 mL, 0.81 mmol). The reaction mixture was degassed under nitrogen, and stirred at 100° C. for 10 hours. The reaction mixture was cooled, diluted with water, and extracted thoroughly with DCM and EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate, and concentrated. The crude product was subjected to preparative thin-layer chromatography on silica with 5% MeOH-DCM as eluent to afford 246 mg of product as a yellow, foamy solid.
Reaction SMILES: [CH3:1][C:2]([NH:6][C:7]([C:9]1[CH:24]=[CH:23][C:12]2[O:13][CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17](=[O:18])[C:11]=2[CH:10]=1)=O)([CH3:5])[CH2:3][OH:4].S(Cl)(Cl)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:5])[CH2:3][O:4][C:7]([C:9]2[CH:24]=[CH:23][C:12]3[O:13][CH2:14][C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[C:17](=[O:18])[C:11]=3[CH:10]=2)=[N:6]1
Reactant: CC(C)(CO)NC(=O)c1ccc2c(c1)C(=O)c1ccccc1CO2
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC1(C)COC(c2ccc3c(c2)C(=O)c2ccccc2CO3)=N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
In this process, 8.0 g of N-(1,1-dimethyl-2-hydroxyethyl)-11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-carboxamide is suspended in 100 ml of methylene chloride. To the suspension is added 3.6 g of thionyl chloride under a nitrogen atmosphere and ice-cooling and the mixture is stirred at room temperature for one hour. To the mixture is added 300 ml of methylene chloride, and the mixture is washed with saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate. The solvent is distilled away under reduced pressure and the residue is purified by column chromatography on silica gel (eluent: hexane:ethyl acetate=2:1 ). The resultant crude product is recrystallized from hexane to obtain 6.3 g of the desired product as a white crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([CH3:25])[C:5]([O:6][C:7]2[C:12]([O:13]C)=[C:11]([C:15](=[O:21])[CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[CH:10]=[C:9]([CH3:22])[N:8]=2)=[C:4]([CH3:26])[CH:3]=1.B(Br)(Br)Br.B(Cl)(Cl)Cl>C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:24]=[C:23]([CH3:25])[C:5]([O:6][C:7]2[C:12]([OH:13])=[C:11]([C:15](=[O:21])[CH:16]([CH2:17][CH3:18])[CH2:19][CH3:20])[CH:10]=[C:9]([CH3:22])[N:8]=2)=[C:4]([CH3:26])[CH:3]=1
Reactant: CCC(CC)C(=O)c1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1OC
Agent: BrB(Br)Br
Agent: ClB(Cl)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCC(CC)C(=O)c1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1O

Procedure:
The title compound was prepared by reacting 1-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-2-ethyl-butan-1-one with BBr3 or BCl3 in THF or methylene chloride. 1H NMR (CDCl3) d 7.04(s,2H), 7.01(s,1H), 3.26(m,1H), 2.24(s,3H), 2.08(s,6H), 1.80(m,2H), 1.63(m,2H), 0.91(t,6H) ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[N:15][N:14]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])[C:13]=2[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:28]([O-])([O-])=O.[K+].[K+]>CO.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[N:15][N:14]([CH:17]([CH3:21])[C:18]([O:20][CH3:28])=[O:19])[C:13]=2[CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C(=O)O)n1nnc2ccc(OCc3ccccc3)cc21
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C(C)n1nnc2ccc(OCc3ccccc3)cc21

Procedure:
A mixture of 6-(benzyloxy)-α-methyl-1H-benzotriazole-1-acetic acid (36.6 g, 0.123 mole) and concentrated sulfuric acid (2.7 ml) in methanol is stirred at reflux temperature for 6 hours, cooled in an ice bath and treated with K2CO3 (25 g). The resulting mixture is stirred vigorously until a thick slurry results, diluted with methylene chloride and filtered. The filtrate is concentrated in vacuo to give a solid residue. Recrystallization of the residue from methanol affords the title product as a white solid, 27 g, mp 88°-91.5° C., identified by NMR and elemental analyses. Another 4.2 g (81.7% total yield) of the title product is obtained from the mother liquor.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:12]=[C:11]([CH3:13])[C:9]([NH2:10])=[C:8]([CH3:14])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[Br:15][CH:16]([CH3:20])[C:17](Br)=[O:18].C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[Br:15][CH:16]([CH3:20])[C:17]([NH:10][C:9]1[C:11]([CH3:13])=[CH:12][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][C:8]=1[CH3:14])=[O:18]
Reactant: CCCCOc1cc(C)c(N)c(C)c1
Reactant: CC(Br)C(=O)Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCOc1cc(C)c(NC(=O)C(C)Br)c(C)c1

Procedure:
To a chilled (ca 10°) solution of 50.7 g (0.263 mole) of 4-butoxy-2,6-dimethylaniline [Buchi et al., Helv. Chim. Acta, 34, 278 (1951)] in 224 ml glacial acetic acid was added rapidly 62.4 g (.289 mole) of 2-bromo-propionyl bromide and immediately thereafter a chilled (ca 5°) solution of 87.2 g sodium acetate thihydrate in 362 ml water. This mixture was shaken for one-half hour, filtered, washed with water until the washes were neutral, and dried in vacuo over silica gel and KOH; yield 68.9 g (71.6%); m.p. 132.5° - 133.5°. The product was recrystallized from 95% ethanol; m.p. 135.5° - 136°.
Reaction SMILES: C([CH:4]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:12]2[C:11](=[O:23])[CH2:10][CH2:9][CH2:8][C:7]=2[NH:6][C:5]1([C:25]([F:28])([F:27])[F:26])O)(O)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:28][C:25]([F:26])([F:27])[C:5]1[NH:6][C:7]2[CH2:8][CH2:9][CH2:10][C:11](=[O:23])[C:12]=2[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[CH:4]=1
Reactant: O=C1CCCC2=C1C(c1cccc([N+](=O)[O-])c1)C(C(=O)O)C(O)(C(F)(F)F)N2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CCCC2=C1C(c1cccc([N+](=O)[O-])c1)C=C(C(F)(F)F)N2
Yield: 31 %

Procedure:
A suspension of 3-carboxy-2-trifluoromethyl-2-hydroxy-4-(3-nitrophenyl)-4,6,7,8-tetrahydro-5(1H)-quinolone (3.17 g) in toluene (150 mL) was treated with p-toluenesulfonic acid monohydrate (0.32g), the mixture refluxed vigorously under Dean-Stark conditions for 4 hours and then partitioned between water and ethyl acetate. The organic phase was washed (water and brine) and evaporated. The residue was purified by chromatography (hexane/ethyl acetate, 1:1 and methylene chloride/acetonitrile 95:5) to yield the title compound (0.83 g) as a pale yellow solid; mp 215°-216° C.; NMR: 1.77-2.00 (m,2, CH2), 2.16-2.36 (m,2, CH2), 2.50-2.71 (m,2, CH2), 4.79 (d,1, J=4.1 , CH), 5.67 (d,1, J=5.4, CH), 7.57-7.67 (m,2, Ar), 8.04 (m,2, Ar), 9.48 (s,1, NH); MS: m/z=338(M). Analysis for C16H13F3N2O3 : Calculated: C, 56.81; H, 3.87; N, 8.28; Found: C, 56.74; H, 4.02; N, 8.28.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[C:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[C:4](=[O:15])[C:3]=1[F:16].[F:17][C:18]1[CH:24]=[C:23]([I:25])[CH:22]=[CH:21][C:19]=1[NH2:20].C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>C1COCC1>[F:16][C:3]1[C:4](=[O:15])[N:5]2[C:10](=[C:11]([C:12]([OH:14])=[O:13])[C:2]=1[NH:20][C:19]1[CH:21]=[CH:22][C:23]([I:25])=[CH:24][C:18]=1[F:17])[CH2:9][CH2:8][CH2:7][CH2:6]2
Reactant: O=C(O)c1c(Cl)c(F)c(=O)n2c1CCCC2
Reactant: Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1c(Nc2ccc(I)cc2F)c(F)c(=O)n2c1CCCC2
Reaction time: 4 h
Yield: 27.8 %

Procedure:
8-Chloro-7-fluoro-6-oxo-2,3,4,6-tetrahydro-1H-quinolizine-9-carboxylic acid (7d, 426 mg, 1.74 mmol, 1 eq) and 2-fluoro-4-iodoaniline (827 mg, 3.49 mmol, 2 eq) were mixed in anhydrous THF (10 ml) at 0° C. under N2. 1N lithium hexamethyldisilazide in THF (5.23 ml, 5.23 mmol, 3 eq) was added drop wise and the mixture stirred for 4 hours while allowing the temperature to return to RT. The solution was evaporated and purified by flash chromatography using 10-16% MeOH in DCM as eluent. This afforded the title compound as a tan solid (216 mg, 28%). [M+H] calc'd for C16H13F2IN2O3, 447. found, 447.
Reaction SMILES: Cl.[F:2][C:3]([F:16])([F:15])[CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1.[NH2:17][C:18]1[CH:19]=[C:20]([C:24]([Cl:27])=[CH:25][N:26]=1)[C:21](O)=[O:22]>>[NH2:17][C:18]1[CH:19]=[C:20]([C:24]([Cl:27])=[CH:25][N:26]=1)[C:21]([NH:14][CH:12]([C:9]1[CH:10]=[N:11][C:6]([O:5][CH2:4][C:3]([F:2])([F:15])[F:16])=[CH:7][CH:8]=1)[CH3:13])=[O:22]
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Reactant: Nc1cc(C(=O)O)c(Cl)cn1
Agent: Cl
Product: CC(NC(=O)c1cc(N)ncc1Cl)c1ccc(OCC(F)(F)F)nc1
Yield: 39 %

Procedure:
The title compound is prepared in 39% yield (213 mg, a white solid) from (−)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (379 mg, 1.48 mmol, Amine-1, single enantiomer) and 2-amino-5-chloroisonicotinic acid (280 mg, 1.62 mmol) by the similar manner in Step-1 of Example-8.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:10]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH2:9][N:8]([CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[CH2:7]1)=[O:5])C.C1NCC2C1CC1C(C#N)=CSC=12>>[C:18]1([CH:16]([N:8]2[CH2:9][CH:10]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)[CH:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH3:17])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C1CN(C(C)c2ccccc2)CC1c1cccs1
Agent: N#Cc1csc2c1CC1CNCC21
Product: CC(c1ccccc1)N1CC(C(=O)O)C(c2cccs2)C1

Procedure:
The product from step b), diastereomer 1 (5.8 g, 0.019 mol) was treated by the method outlined in Example 34, step c) to afford the subtitle compound that was used in the next step without further purification. MS calculated for C17H19NO2S+H: 302, observed: 302.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[OH:7][C:8]([CH3:41])([CH3:40])[CH2:9][C@@:10]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:15][C:14](=[O:16])[N:13]([C@H:17]([C:19]2[CH:24]=[CH:23][C:22](B3OC(C)(C)C(C)(C)O3)=[CH:21][CH:20]=2)[CH3:18])[CH2:12][CH2:11]1.Cl[C:43]1[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[CH:45][N:44]=1>CN(C)C=O>[OH:7][C:8]([CH3:40])([CH3:41])[CH2:9][C@@:10]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:15][C:14](=[O:16])[N:13]([C@H:17]([C:19]2[CH:20]=[CH:21][C:22]([C:43]3[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[CH:45][N:44]=3)=[CH:23][CH:24]=2)[CH3:18])[CH2:12][CH2:11]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](c1ccc(-c2ccc(C#N)cn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 105.2 %

Procedure:
2 M aqueous Na2CO3 solution (1.04 mL) was added to a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one (0.50 g) and 6-chloro-nicotinonitrile (0.22 g) in dimethylformamide (3 mL). The resulting mixture was sparged with argon for 5 min, before [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane complex (51 mg) is added. The mixture was heated to 100° C. and stirred at this temperature overnight. After cooling to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. The residue was purified by chromatography on silica gel (CH2Cl2/MeOH 98:2->80:20) to afford (S)-6-(4-{(S)-1-[6-(2-Hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-nicotinonitrile as an oil (0.50 g) which was crystallized from a mixture of EtOAc (15 mL) and iPr2O (5 mL) by scratching to yield a solid, mp 160-162° C. Yield: 0.32 g (67% of theory). Mass spectrum (ESI+): m/z=456 [M+H]+. mp=160-162° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[S:12]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:14])=[O:13].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(O)(C)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([N:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)[CH:5]=[CH:4][C:3]=1[S:12]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:14])=[O:13]
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1c(Cl)ccc(S(=O)(=O)Oc2ccccc2)c1Cl
Solvent: CC(C)O
Product: CN1CCN(c2ccc(S(=O)(=O)Oc3ccccc3)c(Cl)c2[N+](=O)[O-])CC1

Procedure:
Phenyl 2,4-dichloro-3-nitrobenzenesulfonate (17.4 g, 0.05 mol) and 25 ml of methylpiperazine in 100 ml of isopropanol were refluxed for 10 minutes and subsequently concentrated. The residue was stirred with 50 ml of 50% methanol, filtered off with suction, and washed with 50% methanol and finally with water. Melting point 94-95° C. (after recrystallization from cyclohexane).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:13]1[NH:14][C:15]([CH2:22][CH2:23][C:24](O)=O)=[C:16]2[C:21]=1[CH2:20][CH2:19][CH2:18]C2.ClC1C=CC(C2CCNCC2)=CC=1>>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:24][CH2:23][CH2:22][C:15]3[NH:14][N:13]=[C:21]4[CH2:20][CH2:19][CH2:18][C:16]=34)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(O)CCc1[nH]nc2c1CCCC2
Agent: Clc1ccc(C2CCNCC2)cc1
Product: c1ccc(N2CCN(CCCc3[nH]nc4c3CCC4)CC2)cc1

Procedure:
In the same manner as in Example 102 except that 3-(2,4,5,6-tetrahydrocyclopentapyrazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 4 and 1-phenylpiperazine are used instead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine, 2,4,5,6-tetrahydro-3-(3-(4-phenylpiperazin-1-yl)propyl)cyclopentapyrazole is obtained.