Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:32]=[CH:31][C:12]([O:13][CH2:14][CH2:15][C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([O:29][CH3:30])[C:26]([OH:28])=[O:27])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][OH:34]>C(O)C>[OH:34][N:33]=[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:32]=[CH:31][C:12]([O:13][CH2:14][CH2:15][C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([O:29][CH3:30])[C:26]([OH:28])=[O:27])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1
Reactant: NO
Reactant: CO[C@@H](Cc1ccc(C#CCCOc2ccc(C(=O)c3ccccc3)cc2)cc1)C(=O)O
Solvent: CCO
Product: CO[C@@H](Cc1ccc(C#CCCOc2ccc(C(=NO)c3ccccc3)cc2)cc1)C(=O)O
Reaction time: 8 h

Procedure:
(2S)-3-{4-[4-(4-Benzoyl-phenoxy)-but-1-ynyl]-phenyl}-2-methoxy-propionic acid from Example 42, (1 eq) was mixed with Hydroxylamine chlorydrate (4 eq), pyrydine (10 eq) and Ethanol (2 ml) and the mixture reaction was stirred overnight. The ethanol was evaporated under vacuo and HCl 0.5% was added to the residue to pH=3. Extracted with Ethyl Acetate and concentrated to give the title product as a mixture of two oximes. MS (ES) for C27H25NO5 [M+H]+: 444.2.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]2=[C:9]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=4)[CH:10]=[C:11]([C:12]([CH:14]3[CH2:18][CH2:17][NH:16][CH2:15]3)=[O:13])[N:7]2[N:6]=[CH:5][N:4]=1.C([O-])([O-])=O.[Na+].[Na+].[C:41](Cl)(=[O:43])[CH3:42]>CC#N.CO>[NH2:2][C:3]1[C:8]2=[C:9]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:23]=4)[CH:10]=[C:11]([C:12]([CH:14]3[CH2:18][CH2:17][N:16]([C:41](=[O:43])[CH3:42])[CH2:15]3)=[O:13])[N:7]2[N:6]=[CH:5][N:4]=1
Reactant: CC(=O)Cl
Reactant: Nc1ncnn2c(C(=O)C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CC(=O)N1CCC(C(=O)c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 47.8 %

Procedure:
[4-Amino-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-pyrrolidin-3-yl-methanone hydrochloride salt (80 mg, 0.17 mmol) was dissolved in CH3CN/MeOH (1:1, 2 mL) and 2N Na2CO3 (0.84 mL, 1.68 mmol) was added, followed by acetyl chloride (0.013 mL, 0.19 mmol). The resulting mixture was stirred at rt for 12 h. The mixture was concentrated, diluted with EtOAc and layers were separated. The organic layer was washed with brine and concentrated. The residue was purified by short silica-gel column eluting with EtOAc, then 10% MeOH in EtOAc to give 39 mg (48%) of the desired product. 1H-NMR (CD3OD-d4) 8.39-8.35 (m, 1H), 8.03 (d, 1H), 7.81 (dt, 1H), 7.69-7.67 (m, 1 H), 7.47 (d, 1H), 7.37-7.27, (m, 5 H), 7.19 (fit, 1 H), 5.64 (s, 1 H), 4.53-4.38 (m, 1 H), 3.92-3.72 (m, 2 H), 3.62 (t, 1H), 3.52 (t, 1 H), 2.38-2.07 (m, 2 H), 2.10 (d, 3 H); LC-MS [M+H]+=480.1, RT=2.64 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:15])[C:7]3[N:8]([CH:12]=[CH:13][CH:14]=3)[NH:9][C:10]=2[CH:11]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH2:24][CH3:25].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:15])[C:7]3[N:8]([CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:23][CH2:24][CH3:25])[C:10]=2[CH:11]=1
Reactant: O=c1c2ccc(Cl)cc2[nH]n2cccc12
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1c2cc(Cl)ccc2c(=O)c2cccn21
Temperature: 25 °C
Reaction time: 48 h
Yield: 59 %

Procedure:
7-Chloropyrrolo[1,2-b]cinnolin-10(5H)-one (9.0 g) was taken up in 100 ml of DMF and milled K2CO3 (11.33 g) was added. 1-Bromopropane (10.09 g) was then added dropwise and the solution was stirred at room temperature for 48 h. Water was added and the solution was extracted into dichloromethane and washed several times with H2O and dilute hydrochloric acid. The organics were then dried (MgSO4), charcoaled, filtered and concentrated to an orange oil. The oil was purified by HPLC (silica, dichloromethane) and concentrated to give 6.33 g of an orange powder which was recrystallized from ether to yield 3.4 g of yellow-orange microcrystals, mp 107°-108°.
Reaction SMILES: C(OC([N:8]1[CH2:58][CH2:57][CH2:56][C@H:9]1[C:10]([NH:12][C@H:13]([C:15]([O:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:32]([C:33]#[N:34])=[C:31]([N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[N:30]=[C:29]([S:40][CH2:41][C:42]3[N:43]=[C:44]([C:47]4[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=4)[S:45][CH:46]=3)[C:28]=2[C:54]#[N:55])=[CH:23][CH:22]=1)=[O:16])[CH3:14])=[O:11])=O)(C)(C)C.Cl>ClCCl.C(OCC)C>[ClH:53].[NH:8]1[CH2:58][CH2:57][CH2:56][C@H:9]1[C:10]([NH:12][C@H:13]([C:15]([O:17][CH2:18][CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[C:32]([C:33]#[N:34])=[C:31]([N:35]3[CH2:36][CH2:37][CH2:38][CH2:39]3)[N:30]=[C:29]([S:40][CH2:41][C:42]3[N:43]=[C:44]([C:47]4[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=4)[S:45][CH:46]=3)[C:28]=2[C:54]#[N:55])=[CH:25][CH:26]=1)=[O:16])[CH3:14])=[O:11]
Reactant: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@H](NC(=O)[C@@H]1CCCN1)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Reaction time: 6 h

Procedure:
495 mg (0.588 mmol) of 2-{4-(2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl)phenoxy}ethyl 1-(tert-butoxycarbonyl)-L-prolyl-L-alaninate were dissolved in 3 ml dichloromethane, and 5.876 ml of a 1N solution of hydrogen chloride in diethyl ether were added. After 6 hours of stirring, the precipitated solid was filtered off with suction, washed with diethyl ether and dried under reduced pressure. 410 mg (90% of theory) of the target compound were obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:12][CH2:11][CH:10](O)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].COCCN(S(F)(F)[F:25])CCOC>C(Cl)Cl>[F:25][C@@H:10]1[CH2:11][CH2:12][C@H:8]([NH:7][C:6](=[O:14])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:9]1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1CCC(O)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](F)C1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of (3-hydroxycyclopentyl)-carbamic acid tert-butyl ester (prepared as described in Tetrahedron 1999, 55, 10815-10834) (1 eq) in DCM (1 M) at −10° C. was added [bis(2-methoxyethyl)amino]sulfur trifluoride (1 eq). The reaction mixture was stirred at −10° C. for 15 min, then the reaction mixture was diluted with DCM, washed with sat. aq. NaHCO3 solution, and back-extracted with DCM (3×). The collected organic phases were dried (Na2SO4), and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford tert-butyl cis-3-fluorocyclopentylcarbamate, MS (ES) C10H18FNO2 requires: 203 found: 204 (M+H)+. A solution of this intermediate in DCM/TFA (1:1, 0.24 M) was stirred at RT for 30 min and then concentrated under reduced pressure. The resulting crude was used as such in the next step without further purification. MS (ES) C5H10FN requires: 103 found: 104 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[CH3:9])=[O:7].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:37]=O)[C:23]2[C:28]([C:29]=1[O:30][CH2:31][O:32][CH3:33])=[C:27]([CH2:34][CH2:35][CH3:36])[CH:26]=[CH:25][CH:24]=2>CN(C)C=O.[Cl-].[Na+].O>[CH3:18][O:19][C:20]1[CH:21]=[C:22](/[CH:37]=[C:8](\[CH3:9])/[C:6]([O:5][CH2:4][CH3:3])=[O:7])[C:23]2[C:28]([C:29]=1[O:30][CH2:31][O:32][CH3:33])=[C:27]([CH2:34][CH2:35][CH3:36])[CH:26]=[CH:25][CH:24]=2
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: CCCc1cccc2c(C=O)cc(OC)c(OCOC)c12
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1cccc2c(/C=C(\C)C(=O)OCC)cc(OC)c(OCOC)c12
Temperature: 10 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
45 g of 60% sodium hydride was suspended in 650 ml of N,N-dimethylformamide and cooled to 10° C. 355 g of triethyl 2-phosphonopropionate was added to the solution to make a clear solution. A solution of 270 g of 3-methoxy-4-methoxymethoxy-5-propyl-1-naphthalenecarbaldehyde in N,N-dimethylformamide (250 ml) was dropped in the solution and stirred at room temperature for 1 hour. The reaction mixture was poured into brine and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (8% ethyl acetate/hexane) to obtain 325.3 g of the titled compound as a pale yellow oil (containing a small amount of Z isomer).
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[S: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)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][C:39]([NH2:42])=[N:40][CH:41]=2)O1>>[O:25]1[CH2:26][CH2:27][N:22]([C:4]2[C:5]3[S: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)=[CH:8][C:6]=3[N:7]=[C:2]([C:36]3[CH:37]=[N:38][C:39]([NH2:42])=[N:40][CH:41]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
(2-Chloro-6-((4-methylsulfonylpiperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidine was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure B to give, after purification by reverse HPLC, 10 mg of 221. MS (Q1) 491 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:17][N:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][C:24]#[N:25].Cl>ClCCCl>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([C:22]2[N:18]([CH3:17])[C:19]([CH2:23][C:24]#[N:25])=[CH:20][CH:21]=2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Cn1cccc1CC#N
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cn1c(CC#N)ccc1C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
A solution of 46.4 g. (0.25 mole) of p-nitrobenzoyl chloride in 100 ml. 1,2-dichloroethane is added portionwise to a suspension of 32.2 g. (0.25 mole) aluminum cloride in 100 ml. 1,2-dichloroethane. This mixture is added dropwise to a chilled solution of 30.0 g. (0.25 mole) 1-methylpyrrole-2-acetonitrile in 100 ml. 1,2-dichloroethane. After the addition is complete, the mixture is stirred for twenty minutes at room temperature and then refluxed for four minutes. It is poured into ice acidified with 2N hydrochloric acid. The organic phase is separated and washed successively with N,N-dimethyl-1,3-propanediamine, 3N hydrochloric acid and saturated sodium chloride solution. It is then dried over magnesium sulfate and the solvent evaporated in vacuo. The resulting semi-solid residue is triturated with cold methanol from which the product, 5-(p-nitrobenzoyl)-1-methylpyrrole-2-acetonitrile, crystallizes. It is removed by filtration and purified by recrystallization from acetone, m.p. 167-169° C.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C@@H:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][OH:11])=[O:7])=[C:4](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:3]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>O1CCCC1>[C:29]([NH:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C@@H:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][OH:11])=[O:7])=[C:4](/[CH:21]=[CH:22]/[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:3]=1)(=[O:31])[CH3:30]
Reactant: Nc1ccc(C(=O)N[C@H](CO)Cc2ccccc2)c(/C=C/c2ccccc2)c1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C(=O)N[C@H](CO)Cc2ccccc2)c(/C=C/c2ccccc2)c1
Reaction time: 16 h
Yield: 69.7 %

Procedure:
1 g (2.7 mmol) of (S)-4-amino-2(E-2-phenylethen-1-yl)-N-(3-phenylpropan-1-ol-2-yl)benzamide (intermediate 43f) was suspended in 50 ml of tetrahydrofuran and mixed with 0.25 ml (2.7 mmol) of acetic anhydride at 100° C. The mixture was stirred for 16 h. The reaction was then concentrated under reduced pressure and the residue was recrystallized from ethanol. 0.78 g (71%) of the product was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:22][CH2:23][C:24]([CH3:27])([OH:26])[CH3:25])=[C:14]([N+:19]([O-])=O)[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl>CO.[Pt]>[NH2:19][C:14]1[CH:15]=[N:16][C:17]2[C:12]([C:13]=1[NH:22][CH2:23][C:24]([CH3:27])([OH:26])[CH3:25])=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:18]=2
Reactant: CC(C)(O)CNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Agent: [Pt]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(O)CNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Temperature: 40 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
A solution of 1-[(7-benzyloxy-3-nitroquinolin-4-yl)amino]-2-methylpropan-2-ol (245.0 g, 0.667 mol) in methanol (3 L) was added to a pressure vessel containing 5% platinum on carbon (7.35 g). The vessel was placed under hydrogen pressure (30 psi, 2.1×105 Pa) at 55° C. for five hours. The reaction was allowed to cool to 40° C., and dichloromethane (2.5 L) was added. The reaction mixture was then filtered through CLARCEL filter aid at 30-40° C., and the filter cake was washed with methanol. The filtrate was concentrated to a volume of 1.5 L, cooled to 5-10° C., and stirred for two hours. A solid formed and was isolated by filtration, washed with a small amount of methanol, and dried under vacuum at 50° C. to provide 199.4 g of 1-{[3-amino-7-(benzyloxy)quinolin-4-yl]amino}-2-methylpropan-2-ol.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]3[N:13]([CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC=CC=1.[C:22](Cl)(=[O:26])[C:23]([Cl:25])=[O:24]>C1COCC1>[CH:1]1([C:6]2[CH:7]=[C:8]3[N:13]([C:14]=2[C:22](=[O:26])[C:23]([Cl:25])=[O:24])[CH2:12][CH2:11][CH2:10][CH2:9]3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1c(C2CCCC2)cn2c1CCCC2
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(Cl)C(=O)c1c(C2CCCC2)cc2n1CCCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
2-Cyclopentyl-5,6,7,8-tetrahydro-indolizine (0.24 g, 1.27 mmol) was dissolved in THF (1 mL) and toluene (1.5 mL) and cooled to 0° C. Oxalyl chloride (0.14 mL, 1.52 mmol) was added dropwise and the mixture was stirred at 0° C. for 30 min, then at room temperature for 1 hour. Concentration in vacuo afforded (2-cyclopentyl-5,6,7,8-tetrahydro-indolizin-3-yl)-oxo-acetyl chloride (0.31 g, 88%) as a semi-solid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH2:8][C:7]([C:18]3[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=3)([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[CH2:6]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:32](Cl)(=[O:35])[CH2:33][CH3:34]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH2:8][C:7]([C:18]3[CH:19]=[C:20]([O:24][C:32](=[O:35])[CH2:33][CH3:34])[CH:21]=[CH:22][CH:23]=3)([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[CH2:6]2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C2(c3cccc(O)c3)CCCN(CC3CC3)C2)cc1
Reactant: CCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Oc1cccc(C2(c3ccc(C)cc3)CCCN(CC3CC3)C2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 102.4 %

Procedure:
To a solution of 3-(1-cyclopropylmethyl-3-p-tolyl-piperidin-3-yl)-phenol (65 mg, 0.15 mmol) in CH2Cl2 (2 ml) at room temperature were added DMAP (18 mg, 0.15 mmol), triethylamine (0.071 mL, 0.52 mmol) and propionyl chloride (0.038 mL, 0.45 mmol). The reaction mixture was stirred at room temperature for 12 hours. The reaction was partitioned between 5 mL CH2Cl2 and 5 mL of aqueous saturated NaHCO3. The aqueous layer was washed with CH2Cl2 (3×5 mL), dried over Na2SO4 and concentrated. Purification by flash chromatography with hexanes/EtOAc (1:1) afforded 58 mg of propionic acid 3-(1-cyclopropylmethyl-3-p-tolyl-piperidin-3-yl)-phenyl ester. 1HNMR (400 MHz, CDCl3) δ 7.33 (d, 2H), 7.26-7.19 (comp, 3H), 7.16-7.03 (comp, 2H), 6.89-6.86 (m, 1H), 3.59-3.43 (comp, 2H), 3.35-3.19 (comp, 2H), 2.59-2.53 (q, 2H), 2.52-2.41 (comp, 2H), 2.27-2.18 (comp, 4H), 1.57-1.44 (comp, 2H), 1.31-1.19 (t, 3H), 1.18-1.09 (comp, 3H), 1.08-1.01 (comp, 3H), 100-0.91 (m, 1H), 0.59-0.49 (comp, 2H), 0.19-0.11 (comp, 1H); MS (M+1) 463.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([F:23])[CH:14]=3)[C@H:11]([CH2:24][N:25]3[CH:29]=[C:28]([C:30]([OH:32])=O)[N:27]=[N:26]3)[O:10][C:9]2=[O:33])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:67][N:68]1[CH2:73][CH2:72][CH2:71][CH2:70][CH2:69]1>CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:16]=[C:15]([F:23])[CH:14]=3)[C@H:11]([CH2:24][N:25]3[CH:29]=[C:28]([C:30]([NH:67][N:68]4[CH2:73][CH2:72][CH2:71][CH2:70][CH2:69]4)=[O:32])[N:27]=[N:26]3)[O:10][C:9]2=[O:33])=[CH:4][CH:3]=1
Reactant: NN1CCCCC1
Reactant: O=C(O)c1cn(C[C@@H]2OC(=O)N(c3ccc(Cl)cc3)[C@H]2c2cc(F)cc(C(F)(F)F)c2)nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NN1CCCCC1)c1cn(C[C@@H]2OC(=O)N(c3ccc(Cl)cc3)[C@H]2c2cc(F)cc(C(F)(F)F)c2)nn1
Reaction time: 0.08 h
Yield: 36.6 %

Procedure:
(4S,5S)-1-((3-(4-Chlorophenyl)-4-(3-fluoro-5-(trifluoromethyl)phenyl)-2-oxooxazolidin-5-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (40 mg, 0.082 mmol) is dissolved in CH3CN (2 mL) and is successively treated with DIEA (14 μL, 0.082 mmol) and HATU (31 mg, 0.082 mmol) at ambient temperature. After 5 minutes, 1-aminopiperidine (10 μL, 0.097 mmol) is added and the reaction stirred for 2 h as judged complete by LC-MS. The reaction is quenched with 1 mL 1M HCl and diluted with water and ethyl acetate. The organic layer is washed successively with NaHCO3, brine, dried over MgSO4, filtered and concentrated. Purification by flash chromatography on silica gel (0-5% methanol/dichloromethane) gives the title compound (17 mg, 37%) as a white film. 1H NMR (acetone-d6, 400 MHz) δ 8.49 (s, 1H), 8.39 (s, 1H), 7.72 (s, 1H), 7.66 (d, 1H, J=9.2 Hz), 7.52 (d, 1H, J=8.5 Hz), 7.45-7.49 (m, 2H), 7.30-7.33 (m, 2H), 5.85 (d, 1H, J=5.5 Hz), 5.21 (d, 2H, J=5.6 Hz), 5.11 (q, 1H, J=5.6 Hz), 2.89 (t, 4H, J=5.3 Hz), 1.65 (pentet, 4H, J=6.0 Hz), 1.48-1.51 (m, 1H), 1.39-1.45 (m, 1H). HPLC-MS calculated C25H23ClF4N6O3 (M+H+): 567.2, found: 567.2.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=O)[C:7](=[O:13])[NH:8]2)([O-:3])=[O:2].[CH:15]1[C:20]([NH:21][NH2:22])=[CH:19][CH:18]=[C:17]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:16]=1.Cl>>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[N:22][NH:21][C:20]1[CH:19]=[CH:18][C:17]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:16][CH:15]=1)[C:7](=[O:13])[NH:8]2)([O-:3])=[O:2]
Reactant: O=C1Nc2cccc([N+](=O)[O-])c2C1=O
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3cccc([N+](=O)[O-])c32)cc1
Yield: 33 %

Procedure:
The title compound was prepared from 4-nitro-1H-indole-2,3-dione (Gassman, et al., Journal of Organic Chemistry 1977, 42,1344–8) and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G in 33% yield: 1H NMR (DMSO-d6): δ 7.23 (d, J=7.7 Hz, 1H), 7.31 (s, 2H), 7.47 (t, J=7.9 Hz, 1H), 7.56 (d, J=7.9 Hz, 2H), 7.59 (d, J=7.2 Hz, 1H), 7.83 (d, J=7.7 Hz, 2H), 11.59 (s, 1H), 13.20 (s, 1H); APCI-MS m/z 361 (M). Anal. Calcd for C14H11N5O5S: C, 46.54, H, 3.07; N, 19.38; S, 8.87. Found C, 46.62, H, 3.09; N, 19.46; S, 8.81.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:8][C:6]1[CH:5]=[C:4]([CH3:9])[C:3]([O:10][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=2)=[C:2]([Cl:1])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Cc1cc(Br)cc(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(Cl)c1Oc1ccc([N+](=O)[O-])cn1
Temperature: 50 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a DMF (30 mL) solution of 2-chloro-4-bromo-6-methylphenol (4.90 g) were added 2-chloro-5-nitropyridine (3.58 g) and K2CO3 (3.12 g) at room temperature. After stirring at 50° C. for 3 hours, the solvent was removed under reduced pressure. To the residue was added water, and extracted with AcOEt. The organic layer was washed with water, saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 2-(4-bromo-2-chloro-6-methylphenoxy)-5-nitropyridine as a brown solid (7.59 g).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([O:17][CH3:18])[CH:11]=[CH:10]2.[C:19](=[O:21])=[O:20]>CCCCCC.C1COCC1>[CH3:18][O:17][C:12]1[CH:11]=[CH:10][C:9]2[C:14](=[CH:15][CH:16]=[C:7]([C:19]([OH:21])=[O:20])[CH:8]=2)[N:13]=1
Reactant: COc1ccc2cc(Br)ccc2n1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc2cc(C(=O)O)ccc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (63 cm3 of a 1.6M solution in hexane) was added dropwise to a stirred solution of 6-bromo-2-methoxyquinoline (20 g) in THF (250 cm3) at -70° under nitrogen. After 0.5 hours, solid carbon dioxide (50 g) was added, the solution was allowed to warm to room temperature, and volatile material was removed in vacuo. The residue was partitioned between dichloromethane (100 cm3) and water (100 cm3), the aqueous phase was separated and acidified to pH 3.5 with 5M hydrochloric acid. The precipitated solid was filtered and dried (14.2 g). Recrystallisation of a small portion from isopropanol afforded 2-methoxyquinoline-6-carboxylic acid, m.p. 220°-222°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[C:10]([CH2:16][CH2:17][NH:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:11]([C:13](O)=[O:14])[N:12]=2)=[CH:4][CH:3]=1.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[C:10]3[CH2:16][CH2:17][N:18]([CH:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[C:13](=[O:14])[C:11]=3[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1nc(-c2ccc(Cl)cc2)n(-c2ccccc2Cl)c1CCNC1CCCC1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C1c2nc(-c3ccc(Cl)cc3)n(-c3ccccc3Cl)c2CCN1C1CCCC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 2-(4-chloro-phenyl)-1-(2-chloro-phenyl)-5-(2-cyclopentylamino-ethyl)-1H-imidazole-4-carboxylic acid I-5j (20 mg, 0.046 mmol), EDC (19 mg, 0.1 mmol), HOAt (13 mg, 0.1 mmol), and triethylamine (14 μl, 0.1 mmol) in 1,2-dichloroethane (20 ml) was stirred for 17 hours at room temperature. The reaction mixture was washed with sat'd aq NaHCO3 and the aqueous bicarbonate solution was back extracted once with CH2Cl2. The combined CH2Cl2 extracts were dried and concentrated in vacuo. The residue was dissolved in diethyl ether (1 ml) and several drops of 4M HCl in dioxane were added. The organic solution was decanted and additional ether was added. The mixture was stirred for several minutes and the solvent decanted again. The residue was dried under vacuum to give the desired produce 5A-1 as a colorless solid: +APCl MS (M+1) 426.3; 1H NMR (CDCl3): δ 7.62-7.57 (m, 1H), 7.53-7.47 (m, 1H), 7.44-7.39 (m, 1H), 7.37-7.33 (m, 2H), 7.32-7.28 (m, 1H), 7.24-7.19 (m, 2H), 5.16-5.06 (m, 1H), 3.56-3.50 (m, 2H) 3.2-3.17 (m, 2H), 2.71-2.56 (m, 2H), 1.92-1.83 (m, 2H), 1.76-1.46 (m, 4H).