Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[OH:33])/[C:27]([O:29]CC)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:35][CH2:36][Cl:37]>>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][CH2:35][CH2:36][Cl:37])/[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: ClCCBr
Product: O=C(O)/C(=N\OCCCl)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
The starting material was prepared by reaction of ethyl 2-(2-tritylaminothiazol-4-yl)-2-((Z)-hydroxyimino)acetate with 1-bromo-2-chloroethane followed by hydrolysis of the ester to give 2-(2-tritylaminothiazol-4-yl)-2-[(Z)-(2-chloroethoxy)imino]acetic acid; n.m.r. in solvent C: 3.75(t, 2H); 4.36(t, 2H); 6.64(s, 1H); 7.35(s, 15H).
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[F:11][C:12]([F:42])([F:41])[C:13]1[CH:14]=[C:15]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][C@H:19]1[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)=[O:17].[I-].[K+].C(N(C(C)C)CC)(C)C>C(#N)C>[F:40][C:37]([F:38])([F:39])[C:35]1[CH:34]=[C:15]([CH:14]=[C:13]([C:12]([F:11])([F:41])[F:42])[CH:36]=1)[C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:1][C:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:3])[CH2:20][C@H:19]1[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)=[O:17]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Reactant: O=C(CBr)c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
A mixture of phenacyl bromide (0.88 g), (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine (2 g), potassium iodide (catalytical), diisopropyl-ethylamine (0.77 mL), and acetonitrile (20 mL) was stirred at room temperature overnight. After cooling to room temperature the solvent was removed in vacuo, and the residue treated with dichloromethane and NaOH (2N). The layers were separated, the organic layer was dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, CH2Cl2/MeOH 97/3) to afford (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(2-phenyl-2-ethanon-1-yl)piperazine 2.16 g (85%). MH+ 574, Rf 0.44 (CH2Cl2/MeOH 97/3).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH2:4][C:5]([CH3:9])([CH2:7]O)[N:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:29]N1C(=O)CCC1=O>ClCCl>[CH3:1][C:2]1[O:3][CH2:4][C:5]([CH3:9])([CH2:7][Br:29])[N:6]=1
Reactant: CC1=NC(C)(CO)CO1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1=NC(C)(CBr)CO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 40.1 g (310 mmol) of 2,4-dimethyl-4-hydroxymethyl-2-oxazoline (J. Nys and J. Libeer, Bull. Soco Chim. Belg., 65, 377 (1956)) and 85.5 g (326 mmol) of triphenylphosphine in 400 ml of dichloromethane is mixed at 0° C. in portions with 58.0 g (326 mmol) of N-bromosuccinimide and then stirred overnight at room temperature. The solution is concentrated by evaporation and the residue is pulverized with tert-butyl methyl ether. A precipitate develops, which is separated and washed with tert-butyl methyl ether. The combined filtrates are subjected to a fractionated distillation at normal pressure, and first the solvent is drawn off and then the title compound is distilled at an oil bath temperature of 200° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([C:13](Br)([CH3:19])[CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16])=[CH:8][N:7]=1>C(Cl)(Cl)(Cl)Cl>[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([C:13](=[CH2:19])[CH2:14][C:15]([Cl:18])([Cl:16])[Cl:17])=[CH:8][N:7]=1
Reactant: CC(Br)(CC(Cl)(Cl)Cl)c1cnc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(CC(Cl)(Cl)Cl)c1cnc(Cl)c(Cl)c1
Yield: 80 %

Procedure:
To a slurry of 5 g of neutral alumina in 300 ml of carbon tetrachloride was added 0.5 g of anhydrous aluminum chloride and the mixture was heated at reflux for 20 minutes. To the slurry was added 20 g (0.052 mole) of 2,3-dichloro-5-(1-bromo-3,3,3-trichloro-1-methylpropyl)pyridine, and the resulting mixture was heated at reflux for 48 hours. The mixture was cooled and filtered. The filtrate was concentrated in vacuo yielding the crude product. Recrystallization from pentane yielded 12.7 g (80%) of product, m.p. 76°-77° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH2:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([CH3:15])[CH:9]=2)[CH:3]1[C:16]([O:18][CH3:19])=[O:17].[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C(Cl)(Cl)Cl.[BH3-]C#N.[Na+]>Cl.CO>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[CH:3]([C:16]([O:18][CH3:19])=[O:17])[C:2]([CH3:20])([CH3:1])[CH2:7][CH:6]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:5]=2)=[CH:9][C:10]=1[CH3:15]
Reactant: COC(=O)C1C(c2ccc(F)c(C)c2)=CCCC1(C)C
Reactant: C1CCNC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)C1C(c2ccc(F)c(C)c2)=CC(N2CCCC2)CC1(C)C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
A solution of 4a (11.05 g, 38.1 mmol) and pyrrolidine (8.13 g, 0.114 mol) in 11.5 mL of 5N HCl in methanol (57.1 mmol) and 100 mL chloroform was stirred at ambient temperature overnight and the volatiles were removed in vacuo. The residue was dissolved in 100 mL methanol and 5N HCl methanol was added until the mixture became acidic (bromocresol green). To the solution was added NaCNBH3 (2.40 g, 38.7 mmol) and the reaction was maintained at pH 3-5 by the dropwise addition of 5N HCl in methanol. After stirring overnight the volatiles were removed in vacuo. The residue was diluted with ether and 1N NaOH. The organic layer was washed with H2O and brine and dried (MgSO4). Removal of the volatiles in vacuo and purification of the residue by HPLC using 1% Et3N in 1:1 hexanes:EtOAc as the eluent provided 8.75 g of the oily product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:21][CH:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[O:1][CH2:17][C:18]2[N:19]=[C:20]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[O:21][CH:22]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: ClCc1coc(-c2ccccc2)n1
Reactant: Oc1cccc(CCCn2ccnc2)c1
Product: c1ccc(-c2nc(COc3cccc(CCCn4ccnc4)c3)co2)cc1
Yield: 78 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(3-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-phenyloxazole to give 4-[3-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-phenyloxazole. The yield was 78%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 62-63° C.
Reaction SMILES: [CH2:1]([CH:8]([C:12]([OH:14])=[O:13])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=1O.O=P(Cl)(Cl)Cl>>[CH2:1]([CH:8]([C:9]([O:11][C:17]1[C:16]([Cl:15])=[CH:21][C:20]([Cl:22])=[CH:19][C:18]=1[Cl:23])=[O:10])[C:12]([O:14][C:21]1[C:16]([Cl:15])=[CH:17][C:18]([Cl:23])=[CH:19][C:20]=1[Cl:22])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(Cc1ccccc1)C(=O)O
Reactant: Oc1c(Cl)cc(Cl)cc1Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(Oc1c(Cl)cc(Cl)cc1Cl)C(Cc1ccccc1)C(=O)Oc1c(Cl)cc(Cl)cc1Cl
Temperature: 105 °C
Reaction time: 2 h

Procedure:
A mixture of 2-benzylmalonic acid (10.0 g, 51.5 mmol), 2,4,6-trichlorophenol (20.3 g, 103 mmol), and POCl3 (12.0 mL, 129 mmol) was stirred under air at 105° C. for 2 hours. The reaction was then cooled to room temperature, poured on 150 mL ice, and extracted with 4:1 ether/DCM (3×150 mL). The combined organic layers were washed with water (1×400 mL) and 4 M aqueous NaCl (1×100 mL), and the yellow organic layer was dried (Na2SO4), filtered, and concentrated by rotary evaporation at <40° C. to provide the title compound as a tan thick oil that became a beige solid upon standing.
Reaction SMILES: [I-].[CH2:2]([N+:4]1(C)[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1)[CH3:3].[CH2:12]([O:14][C@H:15]1[CH2:20]C[C@H](N)[CH2:17][CH2:16]1)[CH3:13].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[CH2:12]([O:14][C@H:15]1[CH2:20][CH2:3][C@H:2]([N:4]2[CH2:5][CH2:6][C:7](=[O:10])[CH2:8][CH2:9]2)[CH2:17][CH2:16]1)[CH3:13]
Reactant: CCO[C@H]1CC[C@H](N)CC1
Reactant: CC[N+]1(C)CCC(=O)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCO[C@H]1CC[C@H](N2CCC(=O)CC2)CC1
Temperature: 80 °C

Procedure:
A mixture of 1-ethyl-4-piperidone methiodide (D9, 27 g), trans-4-ethoxycyclohexylamine (D65, 8.16 g, 0.065 mol), potassium carbonate (13.5 g), water (100 mL), and ethanol (200 mL) was heated for 3 hours at 80° C., then cooled overnight. The mixture was partitioned with aqueous sodium bicarbonate and dichloromethane. The dichloromethane layer was separated, washed with brine and solvent removed to give the title compound as an amber coloured oil (13.2 g).
Reaction SMILES: C(O)(C(F)(F)F)=O.[O:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:43]=[CH:42][C:17]3[NH:18][C:19]([C:21]4[C:29]5[C:24](=[CH:25][CH:26]=[C:27]([NH:30][C:31]([CH:33]6[CH2:35][CH2:34]6)=[O:32])[CH:28]=5)[N:23](C5CCCCO5)[N:22]=4)=[N:20][C:16]=3[CH:15]=2)[CH2:10][CH2:9]1>C(Cl)Cl>[O:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:43]=[CH:42][C:17]3[NH:18][C:19]([C:21]4[C:29]5[C:24](=[CH:25][CH:26]=[C:27]([NH:30][C:31]([CH:33]6[CH2:34][CH2:35]6)=[O:32])[CH:28]=5)[NH:23][N:22]=4)=[N:20][C:16]=3[CH:15]=2)[CH2:12][CH2:13]1
Reactant: O=C(Nc1ccc2c(c1)c(-c1nc3cc(N4CCOCC4)ccc3[nH]1)nn2C1CCCCO1)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc2[nH]nc(-c3nc4cc(N5CCOCC5)ccc4[nH]3)c2c1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
TFA (0.238 mL, 3.08 mmol) was added to solution of N-(3-(5-morpholino-1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropanecarboxamide (15 mg, 0.031 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred overnight at room temperature, and then the solvent was removed in vacuum. Purification by flash column chromatography (5% CH3OH/CH2Cl2) afforded the title compound (10 mg) as a solid. 1H NMR: (400 MHz, CD3OD): δ 8.59 (d, 1H, J=1.2 Hz), 7.66 (m, 2H), 7.47 (dd, 1H, J=1.6 and 9.2 Hz), 7.31 (dd, 1H, J=2.0 and 9.2 Hz), 7.16 (s, 1H), 3.87 (m, 4H), 3.23 (m, 4H), 1.85 (m, 1H), 1.03 (m, 2H), 0.93 (m, 2H); ESI-MS [M+H]+: 403.19.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26]([OH:28])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36]([C:40]2([NH2:43])[CH2:42][CH2:41]2)[N:35]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:28])[NH:43][C:40]5([C:36]6[N:35]=[C:34]([CH3:33])[CH:39]=[CH:38][N:37]=6)[CH2:41][CH2:42]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Reactant: Cc1ccnc(C2(N)CC2)n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5nccc(C)n5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.04 g, 0.092 mmol, 1 eq), 1-(4-methylpyrimidin-2-yl)cyclopropanamine (130 mg, crude), Py-Bop (0.062 g, 0.12 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.028 g, 0.3 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.028 g (53%). 1H NMR (400 MHz, CD3OD): δ 8.49 (d, J=5.3 Hz, 1H), 8.07-7.95 (m, 2H), 7.92 (s, 1H), 7.69-7.51 (m, 2H), 7.39-7.23 (m, 3H), 7.16 (d, J=5.3 Hz, 2H), 4.08 (s, 3H), 2.95 (s, 3H), 2.49 (s, 3H), 2.37 (s, 3H), 1.87-1.76 (m, 2H), 1.57-1.45 (m, 2H). 19F NMR (376.47 MHz, CD3OD): δ−78.09 (TFA), −113.44 LCMS: (ES+) m/z=565.2 (M+H)+
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.C(OC(=O)[N:34]([CH2:50][CH3:51])[C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][N:36]=1)(C)(C)C>>[CH2:50]([NH:34][C:35]1[CH:40]=[CH:39][C:38]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[CH:10]=[C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)[S:8][C:6]=3[N:7]=2)=[CH:37][N:36]=1)[CH3:51]
Reactant: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: CCN(C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CCNc1ccc(-c2nc(N3CCOCC3)c3cc(CN4CCN(S(C)(=O)=O)CC4)sc3n2)cn1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine was reacted with ethyl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-carbamic acid tert-butyl ester in General Procedure A. Purification on silica yielded 365. NMR: (CDCl3): 1.31 (3H, t, J 7.2, Me), 2.65-2.68 (4H, m), 2.82 (3H, s, Me), 3.28-3.31 (4H, m), 3.38-3.44 (2H, m, CH2), 3.81 (2H, s, CH2), 3.88-3.90 (4H, m), 3.94-3.97 (4H, m), 4.71-4.74 (1H, m, NH), 6.45 (1H, d, J 8.7, Ar), 7.12 (1H, s, Ar), 8.46 (1H, dd, J 8.7 and 2.3, Ar) and 9.19 (1H, d, J 2.3, Ar). MS: (ESI+): MH+=518.22
Reaction SMILES: [CH2:1]([C:9]1[N:13]=[C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)[O:11][N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl.[F:23][C:24]([F:37])([F:36])[S:25]([C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1)(=[O:27])=[O:26]>>[F:36][C:24]([F:23])([F:37])[S:25]([C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH:33][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([C:12]3[O:11][N:10]=[C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[N:13]=3)=[CH:15][CH:16]=2)=[CH:30][CH:29]=1)(=[O:26])=[O:27]
Reactant: NCc1ccc(S(=O)(=O)C(F)(F)F)cc1
Reactant: CCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Agent: Cl
Product: CCCCCCCCc1noc(-c2ccc(CNCc3ccc(S(=O)(=O)C(F)(F)F)cc3)cc2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 4-(3-octyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 4-[(trifluoromethyl)sulfonyl]benzylamine hydrochloride gave the title compound as an oil. HPLC (Condition A), Rt: 4.36 min (HPLC purity: 43.4%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[C@@H:10]([N:16]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.[CH2:45](O)[CH2:46][OH:47]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CO.C(Cl)Cl>[CH:27]1[C:28]2[N:16]([C@@H:10]([CH2:11][CH2:12][C:13]([O:15][CH2:45][CH2:46][OH:47])=[O:14])[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:29])[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]=2[CH:24]=[CH:25][CH:26]=1
Reactant: OCCO
Reactant: O=C(O)CC[C@@H](C(=O)OCc1ccccc1)n1c2ccccc2c2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: O=C(CC[C@@H](C(=O)OCc1ccccc1)n1c2ccccc2c2ccccc21)OCCO
Temperature: 0 °C
Reaction time: 12 h
Yield: 71 %

Procedure:
To a solution of 22 (1.2 g, 3.10 mmol) in CH2Cl2 (20 mL) were added DCC (0.703 g, 3.40 mmol) and catalytic amount of DMAP (0.057 g, 0.46 mmol) under nitrogen atmosphere. The reaction mixture was cooled to 0° C. and ethylene glycol (0.770 g, 0.680 mL, 12.4 mmol) in CH2Cl2 (5 mL) was added dropwise. The reaction mixture was allowed to warm up to room temperature and stirred for 12 h. The solid DCU was removed by filtration and the filtrate was evaporated under reduced pressure. The crude residue obtained was dissolved in CH2Cl2 (100 mL), washed with water (40 mL×2), brine (40 mL×2), dried over Na2SO4, filtrated and then concentrated to get a yellow residue. A flash chromatography using CH3OH:CH2Cl2 (1:99) as eluent afforded (S)-1-benzyl 5-(2-hydroxyethyl) 2-(9H-carbazol-9-yl)pentanedioate 23 (0.950 g, 71%) as a yellow gummy liquid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:25])[CH:3]=1.[CH3:26][C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[NH:28]1>>[CH2:23]([C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:28]4[C@H:27]([CH3:26])[CH2:31][O:30][C:29]4=[O:32])=[CH:3][C:4]=3[F:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)[CH3:24]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Reactant: C[C@@H]1COC(=O)N1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3F)CC2)c(C)c1
Yield: 58.2 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-fluorophenyl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (630 mg) described in Preparation Example 100 and (R)-4-methyloxazolidin-2-one (243 mg) described in Preparation Example 25, the title compound (385 mg) was obtained.
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[N:14]=[C:13]([O:15]C)[C:12]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[CH:18]=3)=[CH:11][N:10]=2)[CH2:3]1.C(O)(=O)C>Br.CO>[CH3:8][C@H:6]1[O:7][C@@H:2]([CH3:1])[CH2:3][N:4]([C:9]2[NH:10][CH:11]=[C:12]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[CH:18]=3)[C:13](=[O:15])[N:14]=2)[CH2:5]1
Reactant: COc1nc(N2CC(C)OC(C)C2)ncc1-c1ccnc(C)c1
Agent: Br
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(-c2c[nH]c(N3C[C@@H](C)O[C@@H](C)C3)nc2=O)ccn1
Temperature: 80 °C
Yield: 56 %

Procedure:
2,6-Dimethyl-4-[4-(methyloxy)-5-(2-methyl-4-pyridinyl)-2-pyrimidinyl]morpholine (1.42 g, 4.52 mmol) was dissolved in 33% hydrobromic acid in acetic acid (45.4 ml, 836 mmol) and heated at 80° C. for 18 hours. It was confirmed reaction had progressed to completion by LC/MS. The reaction mixture was allowed to cool to room temperature. The product was then diluted with methanol and passed down a 50 g SCX column. The impurities were eluted with methanol, followed by elution of the product with 2M ammonia/methanol. The fractions containing product were combined and evaporated under reduced pressure to give the title compound as a white solid (760 mg, 2.53 mmol, 56.0 yield). LC/MS [M+H]+=301.
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[CH:5][S:4][CH:3]=1.C([Li])CCC.CN(OC)[C:15](=[O:18])[CH2:16][CH3:17]>CCOCC>[Br:7][C:6]1[C:2]([C:15](=[O:18])[CH2:16][CH3:17])=[CH:3][S:4][CH:5]=1
Reactant: CCC(=O)N(C)OC
Reactant: Brc1cscc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCC(=O)c1cscc1Br
Reaction time: 0.25 h
Yield: 38.3 %

Procedure:
A solution of 3,4-dibromothiophene (6.0 g, 24.8 mmol) in 10 mL of ether was cooled to -78° C. and trated with n-butyllithium (9.92 mL, 2.5M solution in hexanes, 24.8 mmol). While holding the temperature at -78° C., the reaction was stirred for 15 minutes, then 2.9 g (24.8 mmol) of N-methyl-N-methoxypropionamide was added and the reaction was stirred for 1 hour. The reaction was quenched with satd NH4Cl, and the mixture was diluted with ether. The ether layer was separated, washed with water and brine, dried over MgSO4 and concentrated. The residue was triturated with hexanes, and the mixture was filtered. The solvent was removed to give 2.08 g of a tan solid. MS 236, 238 (M+NH4)+. NMR (CDCl3) δ:7.99 (d, J=3 Hz, 1H), 7.32 (d, J=3 Hz, 1H), 2.98 (q, J=7 Hz, 2H), 1.21 (t, J=7 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([CH3:10])[CH:3]=1.[CH:11]([Sn](CCCC)(CCCC)CCCC)=[CH2:12].[F-].[K+]>C1(C)C=CC=CC=1.CCOC(C)=O.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>[CH3:10][C:4]1[CH:3]=[C:2]([CH:11]=[CH2:12])[CH:9]=[CH:8][C:5]=1[CH2:6][OH:7]
Reactant: Cc1cc(Br)ccc1CO
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=Cc1ccc(CO)c(C)c1
Temperature: 110 °C
Reaction time: 12 h
Yield: 91.1 %

Procedure:
A solution of 4-bromo-2-methylbenzyl alcohol (M. I. Dawson, et al., J. Med. Chem. 1984, 27, 1516-1531; 0.81 g, 4.0 mmol) in toluene (10 mL) was charged successively with Pd(PPh3)4 (0.13 g, 0.11 mmol), BHT (few crystals, catalytic), and vinyltributyltin (1.3 mL, 4.4 mmol). The mixture was heated at 110° C. for 3.5 h, cooled, charged with aqueous KF and stirred for 12 h at RT. The mixture was diluted with EtOAc and the resultant white precipitate was removed via filtration. The organic phase was separated, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified via flash chromatography to afford 2-methyl-4-vinylbenzyl alcohol (0.54 g). A portion (0.27 g) of this product in methylene chloride (5 mL) was added to a precooled (−78 ° C.) mixture of oxalyl chloride (1.3 mL, 2.6 mmol) and DMSO (0.3 mL, 4.3 mmol) in methylene chloride (10 mL). The reactoin was charged with triethylamine (1.0 mL, 7.2 mmol) and stirred in the cold bath for 2 h, at which point the bath was at RT. The reaction was stirred for an additional hour at RT and then quenched with sat.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:17][C:18]1[C:23](O)=[C:22]([F:25])[C:21]([F:26])=[C:20]([F:27])[C:19]=1[F:28].C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[F:17][C:18]1[C:23]([O:11][C:10](=[O:12])[C@@H:9]2[CH2:13][C@@H:14]([OH:16])[CH2:15][N:8]2[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])=[C:22]([F:25])[C:21]([F:26])=[C:20]([F:27])[C:19]=1[F:28]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Boc-trans-4-hydroxy-L-proline (3.5 kg) (prepared as described in Step 1) and pentafluorophenol (3.06 kg) were dissolved in ethyl acetate (52 L). The solution was treated with a solution of dicyclohexylcarbodiimide (3.43 kg) in ethyl acetate (8 L) and the mixture was stirred at room temperature for 2 hours. The resulting slurry was cooled to 0° C., filtered and the solids washed with ethyl acetate (15 L). The filtrate was evaporated at atmospheric pressure to a volume of 10 L and diluted with hexane (100 L). The resulting mixture was stirred at room temperature overnight and then cooled to 0° C. for 1 hour. The solid was collected by filtration, washed with cold (° C.) 10:1 hexane/ethyl acetate (15 L) and dried at 45° C. in vacuo to afford the title compound as a white crystalline solid.
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][NH:8][CH2:7][CH2:6][NH:5]1)([CH3:3])[CH3:2].[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1>C(#N)C>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:8]2[CH2:7][CH2:6][NH:5][CH:4]([CH:1]([CH3:3])[CH3:2])[CH2:9]2)=[CH:13][CH:12]=1
Reactant: CC(C)C1CNCCN1
Reactant: BrCc1ccc(Br)cc1
Solvent: CC#N
Product: CC(C)C1CN(Cc2ccc(Br)cc2)CCN1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
0.7 g of 2-isopropyl-piperazine could be dissolved in acetonitrile and cooled to 0° C. A solution of 0.5 quiv. 4-bromobenzylbromide in acetonitrile could be added dropwise over 1 h. The reaction would be stirred at room temperature for 2 h. The reaction mixture could be concentrated and the residue could be purified by column chromatography (silica, eluent dichloromethane, 0-5% methanol, 0-0.5% dimethylethylamine) to afford 1-(4-bromo-benzyl)-3-isopropyl-piperazine.