Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])[C@H:2]([C:7]([NH:9][C@H:10]([C:19]([NH:21][C@H:22]([C:27]([NH:29][C@H:30]([C:32]([CH2:34][Cl:35])=[O:33])[CH3:31])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH2:11][C:12](=[O:18])[O:13]C(C)(C)C)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].FC(F)(F)C(O)=O>C(Cl)Cl>[NH:1]([C:36]([O:38][CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:37])[C@H:2]([C:7]([NH:9][C@H:10]([C:19]([NH:21][C@H:22]([C:27]([NH:29][C@H:30]([C:32]([CH2:34][Cl:35])=[O:33])[CH3:31])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH2:11][C:12](=[O:13])[OH:18])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)CCl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)CCl
Yield: 78.7 %

Procedure:
The Z-Leu-Asp(OtBu)-Leu-Ala-CH2Cl (0.653 g) in methylene chloride (5 mL) was stirred with trifluoroacetic acid (5 mL) at room temp for 2 h. After removal of the volatile species, the residue was triturated with diethyl ether to yield Z-Leu-Asp-Leu-Ala-CH2Cl as white powder (0.47 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]=[CH2:9])[CH:5]=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([C:18]2[S:22][C:21]([N:23]3[CH2:29][CH2:28][CH2:27][NH:26][C:25](=[O:30])[CH2:24]3)=[N:20][CH:19]=2)[CH:14]=[C:15]([CH3:17])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)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]>[CH:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:10][C:11]2[CH:12]=[C:13]([C:18]3[S:22][C:21]([N:23]4[CH2:29][CH2:28][CH2:27][NH:26][C:25](=[O:30])[CH2:24]4)=[N:20][CH:19]=3)[CH:14]=[C:15]([CH3:17])[CH:16]=2)[N:7]=1)=[CH2:9]
Reactant: C=Cc1ccnc(Cl)n1
Reactant: Cc1cc(N)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: C=Cc1ccnc(Nc2cc(C)cc(-c3cnc(N4CCCNC(=O)C4)s3)c2)n1
Temperature: 90 °C
Yield: 26 %

Procedure:
2-Chloro-4-ethenylpyrimidine (250 mg, 1.78 mmol), 4-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one (Intermediate XX, 538 mg, 1.78 mmol), potassium carbonate (490 mg, 3.56 mmol), Pd2(dba)3 (163 mg, 0.18 mmol), and XPhos (420 mg, 0.89 mmol) were added to an oven-dried vessel which was purged and flushed with argon. t-Amyl alcohol (5 ml) was added and the reaction mixture was heated at 90° C. for 18 h. The mixture was then cooled to room temperature, diluted with water and brine and extracted with ethyl acetate (3×). The organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The residual orange oil was purified via silica gel column chromatography (0-10% methanol/dichloromethane) to provide 188 mg of 4-(5-{3-[(4-ethenylpyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)-1,4-diazepan-2-one as a yellow-orange solid. MS APCI: [M+H]+ m/z 407.1. 1H NMR (500 MHz, CDCl3) δ 8.37 (d, 1H, J=4.9 Hz), 7.77 (s, 1H), 7.50 (s, 1H), 7.42 (s, 1H), 7.24 (s, 1H), 6.89 (s, 1H), 6.68 (d, 1H, J=5.2 Hz), 6.67-6.46 (m, 2H), 5.65 (m, 1H, J=9.1 Hz), 4.26 (m, 2H), 3.85 (m, 2H), 3.32 (m, 2H), 2.33 (s, 3H), 1.99 (m, 2H). rhSyk=+++.
Reaction SMILES: [C@@H:1]1([NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[NH2:7].[CH2:9](O)[CH:10](O)[CH2:11][CH3:12]>C[C-]1C(C)=C(C)C(C)=C1C.C[C-]1C(C)=C(C)C(C)=C1C.[Cl-].[Cl-].[Cl-].[Cl-].[Ir+3].[Ir+3].C(=O)(O)[O-].[Na+]>[CH2:10]([C@@H:11]1[CH2:12][NH:8][C@@H:1]2[C@H:2]([CH2:3][CH2:4][CH2:5][CH2:6]2)[NH:7]1)[CH3:9]
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: CCC(O)CO
Agent: [Ir+3]
Agent: Cc1c(C)c(C)[c-](C)c1C
Agent: O=C([O-])O
Product: CC[C@@H]1CN[C@H]2CCCC[C@@H]2N1
Temperature: 25 °C
Yield: 68.9 %

Procedure:
Dichloro(pentamethylcyclopentadienyl)iridium (III) dimer (70 mg, 0.090 mmol) and sodium bicarbonate (73 mg, 0.87 mmol) were added to an aqueous (20 mL) solution of trans-cyclohexane-1,2-diamine (2.00 g, 17.5 mmol) and (±)-1,2-butanediol (1.69 mL, 18.4 mmol) with stirring at room temperature. Degassing and argon substitution were repeated 3 times, and the mixture was then stirred for 24 hours under reflux. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (methylene chloride/methanol) to obtain (2R*,4aS*,8aS*)-2-ethyldecahydroquinoxaline (2.03 g, yield: 69%) in a yellow solid form.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][Si](C(C)(C)C)(C)C)/[CH:6]=[CH:7]/[C:8]1[CH:12]=[C:11]([OH:13])[N:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:9]=1.[Si](OC(C1C=NN(C2C=CC=CN=2)C=1O)=CC1C=CC=CC=1)(C(C)(C)C)(C)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[OH:23])[CH:6]=[CH:7][C:8]1[CH:12]=[C:11]([OH:13])[N:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:9]=1
Reactant: COc1cc(/C=C/c2cc(O)n(-c3ccccn3)n2)ccc1O[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)[Si](C)(C)OC(=Cc1ccccc1)c1cnn(-c2ccccn2)c1O
Product: COc1cc(C=Cc2cc(O)n(-c3ccccn3)n2)ccc1O
Yield: 95 %

Procedure:
The title compound was prepared in the same manner as in Example C-11, except that an equimolar amount of Compound 9h prepared in Example C-8 was used in place of Compound 9g.
Reaction SMILES: Cl.[C:2]1([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[S:13][CH:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[CH2:30][C:31](O)=[O:32]>>[S:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[CH2:30][C:31]([N:18]1[CH2:19][CH2:20][CH:15]([C:12]2[S:13][CH:14]=[C:10]([CH2:9][CH2:8][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:11]=2)[CH2:16][CH2:17]1)=[O:32]
Reactant: O=C(O)Cc1nc2ccccc2s1
Reactant: c1ccc(CCc2csc(C3CCNCC3)n2)cc1
Agent: Cl
Product: O=C(Cc1nc2ccccc2s1)N1CCC(c2nc(CCc3ccccc3)cs2)CC1

Procedure:
4-[4-(2-Phenylethyl)-1,3-thiazol-2-yl]piperidine hydrochloride (II-1, 308 mg) is reacted analogously to Example I-63 with 1,3-benzothiazol-2-ylacetic acid (252 mg). After chromatographic purification, this gives 2-(1,3-benzothiazol-2-yl)-1-{4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidin-1-yl}ethanone (109 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:22][CH2:23][CH2:24][OH:25])=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:22][CH2:23][CH2:24][O:25][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1NCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OCCNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Temperature: 65 °C
Yield: 80.8 %

Procedure:
A 2-necked 2-liter round bottom flask was charged with 2-{[7-(benzyloxy)-3-nitroquinolin-4-yl]amino}ethanol (95.0 g, 0.28 mol) and pyridine (400 mL). The suspension was heated to 65° C. To the resulting homogenous solution was added in one portion tert-butyldimethylsilyl chloride (46.4 g, 0.31 mol, 1.1 eq) and 4-(N,N-dimethylamino)pyridine (3.42 g, 0.028 mol, 0.1 eq). The reaction temperature rose to 87° C., was slowly cooled to 65° C., and was maintained overnight at this temperature. The reaction was determined to be incomplete. Additional tert-butyldimethylsilyl chloride (20 g, 0.13 mol, 0.5 eq) was added in one portion and the reaction temperature was increased to 70° C. for 8 hours. The reaction was still not complete. Additional tert-butyldimethylsilyl chloride (21.5 g, 0.14 mol, 0.5 eq) was added in one portion and the reaction was maintained at 70° C. overnight. The reaction was now complete. The reaction mixture was poured into a 2-liter flask, followed by an ethyl acetate rinse, and set aside over the weekend. A precipitate, determined to be pyridine hydrochloride, formed and was removed by filtration. The reaction mixture was then concentrated under reduced pressure to a brown/yellow solid. The solid was slurried in ethyl acetate and collected by filtration; this was repeated three times. The combined filtrates were washed with water and then concentrated to approximately one-third of the original volume until solid began to precipitate. The mixture was diluted with hexane (700 mL) and stirred for an additional hour. A light brown solid was collected by vacuum filtration and dried overnight to provide 102.6 g of 7-(benzyloxy)-N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-nitroquinolin-4-amine, which was used without further purification in the next step.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:17]=1)[C:10]([CH3:30])([CH3:29])[CH2:9]2)=[O:5])C.O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[CH:23]1([C:18]2[CH:17]=[C:16]([CH:11]3[C:10]([CH3:29])([CH3:30])[CH2:9][C:8]4[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=4)[NH:12]3)[CH:21]=[C:20]([F:22])[CH:19]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(F)cc(C3CCCCC3)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cc(F)cc(C2CCCCC2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 61.7 %

Procedure:
A mixture of 2-(3-cyclohexyl-5-fluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.21 g, 0.51 mmol), lithium hydroxide hydrate (0.22 g, 5.1 mmol), water (1 mL) in methanol (2 mL) and tetrahydrofuran (10 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-(3-cyclohexyl-5-fluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (120 mg, 62%) as a white solid: LC/MS m/e calcd for C24H28FNO2 (M+H)+: 382.5, observed: 382.2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:11][C@@H:12]([C@H:14]2[CH2:18][N:17]([C@@H](C3C=CC(O)=CC=3)C)[C:16](=[O:28])[CH2:15]2)[CH3:13])[C:5]2[S:9][CH:8]=[N:7][C:6]=2[CH:10]=1.C(O)(C(F)(F)F)=O>>[OH:1][C:2]1[CH:3]=[C:4]([O:11][C@@H:12]([C@H:14]2[CH2:18][NH:17][C:16](=[O:28])[CH2:15]2)[CH3:13])[C:5]2[S:9][CH:8]=[N:7][C:6]=2[CH:10]=1
Reactant: C[C@H](c1ccc(O)cc1)N1C[C@H]([C@@H](C)Oc2cc(O)cc3ncsc23)CC1=O
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](Oc1cc(O)cc2ncsc12)[C@H]1CNC(=O)C1
Temperature: 65 °C
Reaction time: 15 h

Procedure:
The crude (R)-4-((R)-1-(5-hydroxybenz o[d]thiazol-7-yloxy)ethyl)-1-((R)-1-(4-hydroxyphenyl)ethyl)pyrrolidin-2-one (˜1 mmol) from the previous step was dissolved in TFA (10 mL, 130 mmol) and the resulting solution was heated to 65° C. After 15 h, additional TFA (5 mL, 65 mmol) was added and the reaction temperature was increased to 70° C. After an additional 2 h, the reaction mixture was concentrated in vacuo and was diluted with EtOAc (50 mL), saturated aqueous NaHCO3 (30 mL) and brine (20 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (50 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated to afford (R)-4-((R)-1-(5-hydroxybenzo[d]thiazol-7-yloxy)ethyl)pyrrolidin-2-one that was used without further purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C13H15N2O3S: 279.1, found 279.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]([NH2:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]1([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:10]([N:20]2[CH2:29][CH2:28][CH:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:30][CH2:31]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCC(CC)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2)C(N)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2)C(N2CCC(c3ccccc3)CC2)C1

Procedure:
To a solution of amine (from Example 104, Step E) and (±) -1, 5-dibromo, 3-phenyl-pentane in 0.5 mL of isobutylnitrile was added 0.080 mL of DIEA and a catalytic amount of tetrabutyl-ammonium iodide. After warming the reaction to 95° C. for 22 h, the mixture was partitioned between 10 mL of CH2Cl2 and 10 mL 1N NaOH. After separating layers, the aqueous phase was extracted with 10 mL of CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography eluting with 10% EtOAc in hexanes to provide 10 mg of the title compound: 1H NMR (300 MHz, CDCl3): δ1.2-1.9 (m, 16H), 2.1-2.4 (m, 2H), 2.6-3.0 (m, 6H), 4.0-4.4 (m, 2H), 7.0-7.4 (m, 10H). RF : 0.45 (20% EtOAc in hexanes).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][C:11]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.ClC1SC2C=C([F:29])C=CC=2N=1.FC1C=C(Br)C=CC=1N>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[S:10][C:11]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[C:6]([F:29])[CH:7]=1
Reactant: Fc1ccc2nc(Nc3ccc(Br)cc3)sc2c1
Reactant: Fc1ccc2nc(Cl)sc2c1
Agent: Nc1ccc(Br)cc1F
Product: Fc1ccc2nc(Nc3ccc(Br)cc3F)sc2c1

Procedure:
In a similar manner to the procedure described above for the preparation of N-(4-bromophenyl)-6-fluoro-1,3-benzothiazol-2-amine, 2-chloro-6-fluoro-benzothiazole and 2-fluoro-4-bromoaniline were reacted together to provide N-(4-bromo-2-fluoro-phenyl)-6-fluoro-1,3-benzothiazol-2-amine as a solid. 1H NMR (DMSO-d6) δ 10.50 (s, 1H), 8.60 (t, 1H), 7.80 (d, 1H), 7.60 (m, 2H), 7.40 (d, 1H), 7.20 (m, 1H)).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:6]=2[N:7]=1.[BH4-].[Na+]>C(O)C.C(Cl)(Cl)Cl>[Cl:1][C:2]1[NH:3][CH2:4][C:5]2[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:6]=2[N:7]=1
Reactant: Cc1sc2nc(Cl)nc(Cl)c2c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: Cc1sc2c(c1C)CNC(Cl)=N2
Yield: 51.1 %

Procedure:
To a solution of 4.66 g of 2,4-dichloro-5,6-dimethylthieno[2,3-d]pyrimidine in 150 ml of ethanol-chloroform (1:1 by volume) was slowly added 2.32 g of sodium borohydride with stirring. The mixture was stirred at room temperature for 6 hours and the solvent removed in vacuo. To the solid residue was added 50 ml of water and the insoluble material was filtered, washed with water, dried, and recrystallized from benzene to give 2.05 g of 2-chloro-5,6-dimethyl-3,4-dihydrothieno[2,3-d]pyrimidine, mp 170°-172° C.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[F:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9]2.[Cl-].[NH4+]>CCOCC>[CH2:1]([C:11]1([OH:15])[C:12]2[C:8](=[CH:7][C:6]([F:5])=[CH:14][CH:13]=2)[CH2:9][CH2:10]1)[CH3:2]
Reactant: CC[Mg]Br
Reactant: O=C1CCc2cc(F)ccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCC1(O)CCc2cc(F)ccc21
Yield: 92.9 %

Procedure:
Add ethyl magnesium bromide (1.3 ml, 3.90 mmol, 1.30 equivalents, 3.0 M in tetrahydrofuran) drop wise to a solution of 5-fluoroindanone (450 mg, 3.00 mmol) in. anhydrous ether (5 ml) under nitrogen at room temperature and stir overnight. Quench the reaction by drop wise addition of 10% aqueous ammonium chloride, dilute with ether, wash with water (2×), dry over anhydrous sodium sulfate, filter, and concentrate to obtain the'title compound (502 mg, 93%). NMR (400 MHz, CDCl3): δ 0.94 (t, 3H), 1.79 (m, 1H), 1.92 (m, 1H), 2.12 (m, 1H), 2.31 (m, 1H), 2.81 (m, 1H), 2,98 (m, 1H), 6.91 (m, 2H), 7.24 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9]C)=O)[O:4][N:3]=1.[CH3:11][NH:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=2)=[O:22])[CH2:17][CH2:16]1.N1CCCN2CCCN=C12>CN(C=O)C.CCOC(C)=O>[OH:1][C:2]1[CH:6]=[C:5]([C:7]([N:12]([CH2:13][CH2:14][CH:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][C:25]3[CH:26]=[C:27]([Cl:32])[CH:28]=[C:29]([Cl:31])[CH:30]=3)=[O:22])[CH2:19][CH2:20]2)[CH3:11])=[O:9])[O:4][N:3]=1
Reactant: COC(=O)c1cc(O)no1
Reactant: CNCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Agent: C1CN=C2NCCCN2C1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(CCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)C(=O)c1cc(O)no1

Procedure:
A solution comprising of methyl 3-hydroxyisoxazole-5-carboxylate (20.72 mg, 0.145 mmol), 3,5-dichlorobenzyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate (step 3) (50 mg, 0.145 mmol) and 2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine (20.16 mg, 0.145 mmol) in DMF (483 μl) was refluxed for 18 hours. The reaction mixture was diluted with EtOAc and washed with water. The organic portion was separated, dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound;
Reaction SMILES: C([O:5][CH2:6][C@@H:7]([C:26]([OH:28])=[O:27])[NH:8]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)(C)(C)C.N1CCCCC1.[CH:35]1[C:47]2[CH:46]([CH2:48][O:49][C:50]([NH:52][CH2:53][C:54]([OH:56])=O)=[O:51])[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39]=2[CH:38]=[CH:37][CH:36]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH:44]1[C:45]2[CH:46]([CH2:48][O:49][C:50]([NH:52][CH2:53][C:54]([NH:8][C@H:7]([C:26]([OH:28])=[O:27])[CH2:6][OH:5])=[O:56])=[O:51])[C:47]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:40]=2[CH:41]=[CH:42][CH:43]=1
Reactant: CC(C)(C)OC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: O=C(CNC(=O)OCC1c2ccccc2-c2ccccc21)N[C@@H](CO)C(=O)O
Reaction time: 0.5 h

Procedure:
1 g (0.62 mmol) of a Wang resin (Merck Biosciences; loading: 0.62 mmol/g) preloaded with O-tert.-butyl-N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-serine is treated twice in succession with piperidine as follows: the resin is mixed with 10 ml of a 20% piperidine solution in dimethylformamide, shaken for 30 min and collected by suction filtration. The resin obtained in this way is provided in 10 ml of dimethylformamide, and 369 mg (1.24 mmol) of N-[(9H-fluoren-9-ylmethoxy)carbonyl]glycine, 398 mg (1.24 mmol) of N-[(1H-benzotriazol-1-yloxy)(dimethyl-amino)methylene]-N-methylmethanaminium tetrafluoroborate (TBTU) and 240 mg (1.86 mmol) of N-ethyl-N-isopropylpropan-2-amine (DIEA) are added. The mixture is shaken at RT overnight. The solid is collected by suction filtration, washed three times each with 10 ml of dimethylformamide, methanol and dichloromethane and collected by suction filtration. 20 ml of a 50% trifluoroacetic acid solution in dichloromethane are added and left to act for 60 min, the resin is removed by filtration on a frit and the resin is washed three times with 10 ml of dichloromethane. The filtrate is concentrated and the target compound is obtained as crude product.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[N:12]1([S:18](Cl)(=[O:20])=[O:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([S:18]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)(=[O:20])=[O:19])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=S(=O)(Cl)N1CCOCC1
Reactant: CCOC(=O)C1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1CCN(S(=O)(=O)N2CCOCC2)CC1
Yield: 103.4 %

Procedure:
Piperidine-4-carboxylic acid ethyl ester (0.943 g) dissolved in methylene chloride (60 ml) under an argon atmosphere was treated at RT, first with 4-dimethylaminopyridine (1.465 g) then dropwise with morpholine-4-sulfonyl chloride (1.136 g) and the reaction mixture was stirred for 12 h at RT to complete the reaction. The reaction mixture was then partitioned between methylene chloride and aqueous 1N HCL, the layers were separated and the organic layer washed with 2M aqueous KHCO3 then dried over Na2SO4. The solvent was evaporated off, to give 1-(morpholine-4-sulfonyl)-piperidine-4-carboxylic acid ethyl ester (1.9 g) as a light yellow solid which was directly used in the next step.
Reaction SMILES: FC(F)(F)C1C=CC=CC=1[Mg]Br.C(=O)C1C=CC=CC=1.[F:21][C:22]([F:39])([F:38])[C:23]1[CH:36]=[C:35](Cl)[CH:34]=[CH:33][C:24]=1[CH:25]([OH:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[F:21][C:22]([F:38])([F:39])[C:23]1[CH:36]=[CH:35][CH:34]=[CH:33][C:24]=1[CH:25]([OH:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: OC(c1ccccc1)c1ccc(Cl)cc1C(F)(F)F
Agent: FC(F)(F)c1ccccc1[Mg]Br
Solvent: O=Cc1ccccc1
Product: OC(c1ccccc1)c1ccccc1C(F)(F)F

Procedure:
This material was prepared from 2-(trifluoromethyl)phenylmagnesium bromide (16 mmol) and benzaldehyde (15 mmol) using the procedure described for compound (96) (3.7 g, 98%).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][C:21]3[C:26]([Cl:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[Cl:29])=[CH:13][CH:12]=2)[CH2:9][CH2:8][N:7]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:6]1)=[O:4].[OH-].[Na+].Cl>CO>[C:33]([O:32][C:30]([N:7]1[CH2:8][CH2:9][C@H:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][C:21]3[C:26]([Cl:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[Cl:29])=[CH:13][CH:12]=2)[C@@H:5]([C:3]([OH:4])=[O:2])[CH2:6]1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: COC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1ccc(OCCOc2c(Cl)cc(C)cc2Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(Cl)c(OCCOc2ccc([C@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3C(=O)O)cc2)c(Cl)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
A mixture of compound D7 (4.31 g, 8 mmol) in MeOH (50 mL) and aq. 1M NaOH (79 mL) was stirred at 80° C. for 8 h. The mixture was allowed to cool to rt, and aq. 2M HCl (50 mL) was added. The mixture was extracted with EtOAc. The combined org. extracts were washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Drying the residue under high vacuum yielded the crude title compound (4.18 g, quantitative yield). LC-MS: tR=1.12 min, ES+: 524.41.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[C:8]2[N:10]([CH:13]([CH3:15])[CH3:14])[CH:11]=[N:12][C:7]2=[C:6]([N+:16]([O-])=O)[CH:5]=1)([O-:3])=[O:2].CCN(CC)CC.[CH2:26](N)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCOCC>CN(C=O)C>[CH2:26]([NH:16][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[N:9]=[C:8]2[N:10]([CH:13]([CH3:15])[CH3:14])[CH:11]=[N:12][C:7]=12)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)n1cnc2c([N+](=O)[O-])cc([N+](=O)[O-])nc21
Reactant: NCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)n1cnc2c(NCc3ccccc3)cc([N+](=O)[O-])nc21
Temperature: 20 °C
Reaction time: 6 h

Procedure:
To a solution of 5,7-dinitro-3-iso-propylimidazo[4,5-b]pyridine, 5, in DMF was added NEt3 and benzylamine. After 6 h stirring at 20° C., 15 mL Et2O was added and the solid which precipited was filtered and washed with Et2O.