Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[NH:34]1[CH2:38][CH2:37][C@@H:36]([CH2:39][OH:40])[CH2:35]1>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:34]4[CH2:38][CH2:37][C@@H:36]([CH2:39][OH:40])[CH2:35]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: OC[C@@H]1CCNC1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(N3CC[C@@H](CO)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, DIPEA and (R)-pyrrolidin-3-ylmethanol. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (1H), 7.48 (2H), 6.69 (1H), 4.72 (1H), 3.66 (m, 2H), 3.49 (m, 2H), 3.32 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.30 (m, 2H). m/z: 438 [M+H]
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=O)[CH:8]=O.[CH2:11]([NH2:14])[CH2:12][NH2:13].[BH4-].[Na+].O>C(O)C>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:8][NH:14][CH2:11][CH2:12][NH:13]1
Reactant: Cc1ccsc1C(=O)C=O
Reactant: NCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccsc1C1CNCCN1
Reaction time: 3 h

Procedure:
A 5 g portion of the above aldehyde was dissolved in 100 ml of ethanol, cooled to 0°-5° C. and a solution of 2.14 g of ethylenediamine in 10 ml of ethanol was added dropwise with stirring. The mixture was allowed to come to room temperature over 3 hours, then 2.4 g of sodium borohydride was added and the mixture was stirred for 18 hours. Water was added, then the mixture was concentrated. The residue was dissolved in dichloromethane, cooled, extracted with water, dried, filtered and evaporated to an oil which crystallized, giving 4.6 g of 2-(3-methyl-2-thienyl)piperazine.
Reaction SMILES: N1N=C[N:4]([C:6]2[CH:11]=[CH:10][C:9](NN)=[CH:8][CH:7]=2)[CH:5]=1.[CH3:14]OC(OC)CCCCN1CCN(C(OC(C)(C)C)=O)CC1.C([O-])([O-])=O.[K+].[K+]>S(=O)(=O)(O)O>[NH:4]1[C:6]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:14]=[CH:5]1
Reactant: COC(CCCCN1CCN(C(=O)OC(C)(C)C)CC1)OC
Reactant: NNc1ccc(-n2cnnc2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: c1ccc2[nH]ccc2c1
Yield: 116.4 %

Procedure:
A mixture of 4-(1,2,4-triazol-4-yl)phenylhydrazine (5.0 g, 28.6 mmol) and 5-[4-(tert-butyloxycarbonyl)piperazin-1-yl]pentanal dimethyl acetal (9.03 g, 28.6 mmol) in 4% sulphuric acid (150 ml) was heated at reflux for 48 h. The solution was cooled in an ice-bath, basified with solid K2CO3 and extracted with butan-1-ol (×3). The solvent was removed under vacuum and azeotroped with hexane (×2). The crude product was purified by chromatography on silica gel eluting with CH2Cl2 /MeOH/NH3 (30:8:1) to give the title-indole (3.9 g, 44%). δ(360 MHz, oxalate salt in D2O) 2.12-2.24 (2H, m, CH2); 2.93 (2H, t, J=7 Hz, CH2); 3.46-3.76 (8H, m, 4 of CH2) 7.37 (1H, dd, J=1.9 and 8.7 Hz, Ar-H); 7.39 (1H, s, Ar-H); 7.66 (1H, d, J=8.7, Ar-H); 7.82 (1H, d, J=1.9 Hz, Ar-H); 9.13 (2H, s, Triazole-H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[C:5](=[O:17])[NH:4][C:3]=1[C:18]1[N:22]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[N:21]=[CH:20][CH:19]=1.CC(C)([O-])C.[K+].[CH2:37]1[CH2:41]O[CH2:39][CH2:38]1.ICCCC>O>[CH2:41]([N:4]1[C:3]([C:18]2[N:22]([C:23]3[CH:24]=[CH:25][C:26]([C:27]#[N:28])=[CH:29][CH:30]=3)[N:21]=[CH:20][CH:19]=2)=[C:2]([CH3:1])[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[C:5]1=[O:17])[CH2:37][CH2:38][CH3:39]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)[nH]c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCI
Product: CCCCn1c(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reaction time: 7 h

Procedure:
4-(5-{5-Methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazol-4-yl}-1H-pyrazol-1-yl)benzonitrile (Example 1) (102 mg, 0.25 mmol) was added to a stirred mixture of potassium tert-butoxide (42 mg, 0.375 mmol) and THF (2.0 mL) under a nitrogen atmosphere. This resulted in the formation of a yellow solution. 1-Iodo-butane (0.057 mL, 0.5 mmol) was added and the mixture was stirred for 7 h then left to stand for 16 h. Water (10 mL) was added and the mixture was extracted with DCM (3×10 mL). The combined organic phase was dried (sodium sulfate) and concentrated in vacuo. The residue was purified by flash column chromatography (2 g Si II SPE eluted with DCM). The crude product thus obtained was further purified by flash column chromatography (2 g Si II SPE eluted with 20% EtOAc in cyclohexane). Concentration of the appropriate fractions in vacuo gave the title compound which was freeze-dried from acetonitrile/water to afford a white solid (25 mg).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Br[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([N:18]2[CH2:22][CH2:21][CH2:20][S:19]2(=[O:24])=[O:23])[CH:9]=1>>[O:23]=[S:19]1(=[O:24])[CH2:20][CH2:21][CH2:22][N:18]1[C:10]1[CH:9]=[C:8]([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ccc(Br)cc1N1CCCS1(=O)=O
Reactant: O=C1CCCN1
Product: COC(=O)c1ccc(N2CCCC2=O)cc1N1CCCS1(=O)=O
Yield: 71.8 %

Procedure:
Using pyrrolidin-2-one (432 mg) and methyl 4-bromo-2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoate (1.54 g) described in Preparation Example 13 and by the reaction and treatment in the same manner as in Example 1, methyl 2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-4-(2-oxopyrrolidin-1-yl)benzoate (1.12 g) was obtained. The obtained methyl 2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-4-(2-oxopyrrolidin-1-yl)benzoate (1.12 g) was dissolved in a solution of methanol (5 mL) and tetrahydrofuran (5 mL), 1N aqueous sodium hydroxide solution (5 mL) was added, and the mixture was stirred at room temperature for 4 hr. The solvent was evaporated from the reaction mixture, and the mixture was neutralized with 1N hydrochloric acid, and extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated to give 2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-4-(2-oxopyrrolidin-1-yl)benzoic acid (720 mg). A mixture of the obtained 2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-4-(2-oxopyrrolidin-1-yl)benzoic acid (250 mg), 1-(2,4-dimethylphenyl)piperazine (154 mg) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM) (242 mg) was dissolved in ethanol (3 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated from the reaction mixture, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give the title compound (330 mg).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[C:4]([CH3:10])[C:3]=1[O:11][CH3:12].C([Li])CCC.[C:18]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])[CH:19]([CH3:21])[CH3:20]>O1CCCC1.O>[CH3:12][O:11][C:3]1[C:4]([CH3:10])=[C:5]([CH3:9])[CH:6]=[C:7]([CH3:8])[C:2]=1[C:18]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([OH:22])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)C(=O)c1ccccc1
Reactant: COc1c(C)c(C)cc(C)c1Br
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C)c(C)cc(C)c1C(O)(c1ccccc1)C(C)C
Reaction time: 0.25 h
Yield: 80.1 %

Procedure:
A solution of 2-bromo-3,5,6-trimethylanisole (3.0 g, 13.1 mmol) in tetrahydrofuran (20 ml) was cooled to -78° C. and n-butyllithium (1.6M solution in hexane, 8.2 ml, 13.1 mmol) was added dropwise. The reaction mixture was stirred at the same temperature for 15 minutes. Then a solution of isobutyrylbenzene (1.94 g, 13.1 mmol) in tetrahydrofuran (5 ml) was added dropwise and the resulting mixture was stirred at room temperature for additional 30 minutes. The reaction mixture was diluted with water and the product was extracted with isopropyl ether. The extract was washed with water, dried and then concentrated. The residue was crystallized from hexane to obtain the desired compound (3.13 g, yield: 80.2%), m.p. 80°-81° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[S:18](Cl)(=[O:20])=[O:19]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([N:9]([S:18]([C:12]2[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=2[F:10])(=[O:20])=[O:19])[S:18]([C:12]2[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=2[F:10])(=[O:20])=[O:19])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Reactant: Nc1cc(Br)cnc1Cl
Solvent: c1ccncc1
Product: O=S(=O)(c1ccc(F)cc1F)N(c1cc(Br)cnc1Cl)S(=O)(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a solution of 5-bromo-2-chloropyridin-3-amine (7.93 g, 38.2 mmol) in pyridine (76 mL) was drop wise added 2,4-difluorobenzene-1-sulfonyl chloride (20.3 g, 96.0 mmol) at 0° C. The mixture was stirred for 1 h at room temperature. The resulting solid was filtered, and washed with water, and dried under vacuum oven to give the N-(5-bromo-2-chloropyridin-3-yl)-N-(2,4-difluorophenylsulfonyl)-2,4-difluorobenzenesulfonamide (19.6 g, 90%) as a white solid, which was used for the next step without further purification.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:8]([NH:10][C@H:11]([C:22]([NH:24][C@H:25]([C:37]([NH:39][C@H:40]([C:44]([NH:46][CH2:47][C:48]([NH:50][C@H:51]([C:53]([NH:55][CH2:56][C:57]([NH:59][C@H:60]([C:71]([N:73]1[CH2:80][CH2:79][CH2:78][C@H:74]1[C:75]([NH2:77])=[O:76])=[O:72])[C@@H:61]([CH3:70])[O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)=[O:58])=[O:54])[CH3:52])=[O:49])=[O:45])[CH:41]([CH3:43])[CH3:42])=[O:38])[CH2:26][C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:23])[C@@H:12]([CH3:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[NH:88]([C:110]([O:112][C:113]([CH3:116])([CH3:115])[CH3:114])=[O:111])[C@H:89]([C:100]([N:102]1[CH2:109][CH2:108][CH2:107][C@H:103]1[C:104]([OH:106])=O)=[O:101])[C@@H:90]([CH3:99])[O:91][CH2:92][C:93]1[CH:98]=[CH:97][CH:96]=[CH:95][CH:94]=1>>[NH:88]([C:110]([O:112][C:113]([CH3:114])([CH3:115])[CH3:116])=[O:111])[C@H:89]([C:100]([N:102]1[CH2:109][CH2:108][CH2:107][C@H:103]1[C:104]([NH:1][C@H:2]([C:8]([NH:10][C@H:11]([C:22]([NH:24][C@H:25]([C:37]([NH:39][C@H:40]([C:44]([NH:46][CH2:47][C:48]([NH:50][C@H:51]([C:53]([NH:55][CH2:56][C:57]([NH:59][C@H:60]([C:71]([N:73]1[CH2:80][CH2:79][CH2:78][C@H:74]1[C:75]([NH2:77])=[O:76])=[O:72])[C@@H:61]([CH3:70])[O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)=[O:58])=[O:54])[CH3:52])=[O:49])=[O:45])[CH:41]([CH3:43])[CH3:42])=[O:38])[CH2:26][C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:23])[C@@H:12]([CH3:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6])=[O:106])=[O:101])[C@@H:90]([CH3:99])[O:91][CH2:92][C:93]1[CH:98]=[CH:97][CH:96]=[CH:95][CH:94]=1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(C)[C@H](NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C)[C@@H](C)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](C)C(=O)NCC(=O)N[C@H](C(=O)N1CCC[C@H]1C(N)=O)[C@@H](C)OCc1ccccc1
Product: CC(C)[C@H](NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)OCc1ccccc1)[C@@H](C)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](C)C(=O)NCC(=O)N[C@H](C(=O)N1CCC[C@H]1C(N)=O)[C@@H](C)OCc1ccccc1
Yield: 84.2 %

Procedure:
By using 3.08 g of Boc-Gln-Thr(Bzl)-Asp(OBzl)-Val-Gly-Ala-Gly-Thr(Bzl)-Pro-NH2 and 1.52 g of Boc-Thr(Bzl)-Pro-OH, and the same procedure as in Reference Example 15 was repeated to obtain 3.21 g (yield: 85.4%) of the above-mentioned objective product.
Reaction SMILES: [CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=3)[O:20][C:19]=2[CH3:34])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:35][NH:36][CH2:37][CH2:38][C:39]([O:41]CC)=[O:40]>>[CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:24]=[CH:25][C:26]([O:29][C:30]([F:31])([F:33])[F:32])=[CH:27][CH:28]=3)[O:20][C:19]=2[CH3:34])[O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([N:36]([CH3:35])[CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:15])=[CH:16][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1oc(-c2ccc(OC(F)(F)F)cc2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CCOC(=O)CCNC
Product: Cc1oc(-c2ccc(OC(F)(F)F)cc2)cc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 95.5 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-(cyclohexyl{2-methyl-5-[4-(trifluoromethoxy)phenyl]-3-furyl}methoxy)benzoic acid (119 mg) as well as ethyl 3-(methylamino)propanoate (39 mg) to give the title compound (134 mg, 96%) as an amorphous compound.
Reaction SMILES: C(Cl)Cl.[CH3:4][O:5][C:6]1[C@@:7]2([CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])[CH2:13][CH:11]3[O:12][C@@:8]2([O:29][CH3:30])[C@H:9]([C:21](=[O:28])[C:22]=1[CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C@:10]3([CH3:20])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18].BrB(C)C.CCCCCC.CC[O:48]C(C)=O>>[OH:12][C@@H:11]1[C@@:10]([CH3:20])([CH2:14][CH2:15][CH:16]=[C:17]([CH3:18])[CH3:19])[C@@H:9]2[C@:8]([OH:48])([O:29][CH3:30])[C@@:7]([CH2:31][CH:32]=[C:33]([CH3:34])[CH3:35])([C:6]([O:5][CH3:4])=[C:22]([CH2:23][CH:24]=[C:25]([CH3:26])[CH3:27])[C:21]2=[O:28])[CH2:13]1
Reactant: COC1=C(CC=C(C)C)C(=O)[C@H]2[C@]3(OC)OC(C[C@]13CC=C(C)C)[C@@]2(C)CCC=C(C)C
Reactant: CCOC(C)=O
Agent: CB(C)Br
Solvent: ClCCl
Solvent: CCCCCC
Product: COC1=C(CC=C(C)C)C(=O)[C@@H]2[C@](C)(CCC=C(C)C)[C@@H](O)C[C@@]1(CC=C(C)C)[C@@]2(O)OC
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
A DCM (2 mL) solution of 15 (29 mg, 6.6 μmol, 1 equiv.) was cooled to −78° C. in a 10-mL teardrop-shaped flask, and a DCM solution of bromodimethylborane (2.65 M, 0.25 mL, 0.66 mmol, 10 equiv.) was added dropwise. After stirring the bright yellow solution at −78° C. for 10 min, it was quenched sequentially at −78° C. with 1.25 mL NEt3 and saturated aqueous NaHCO3. The mixture was warmed to room temperature and extracted thrice with EtOAc. The organic extracts were combined, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield a yellow residue. Flash column chromatography (30 mL SiO2, 9:1 hexane:EtOAc) afforded 26.7 mg (58 μmol, 88% yield) of 17 as a yellow oil. TLC Rf 0.38 (7:3 hexane:EtOAc). 1H NMR (600 MHz; C6D6): δ 5.55 (dq, J=11.5, 1.3 Hz, 1H), 5.35 (t, J=7.3 Hz, 1H), 5.28 (t, J=6.6 Hz, 1H), 3.71 (s, 1H), 3.67 (dd, J=11.8, 5.3 Hz, 1H), 3.53 (s, 3H), 3.34 (dd, J=15.2, 6.4 Hz, 1H), 3.16 (m, 1H), 3.14 (s, 1H), 3.06 (s, 3H), 2.92 (dd, J=14.1, 11.5 Hz, 1H), 2.86 (tdd, J=12.8, 7.7, 5.0 Hz, 1H), 2.26 (d, J=14.1 Hz, 1H), 2.08 (tt, J=12.5, 6.1 Hz, 1H), 2.00 (dd, J=12.8, 12.0 Hz, 1H), 1.84 (s, 3H), 1.72 (s, 3H), 1.72-1.68 (m, 1H), 1.62 (s, 6H), 1.60-1.58 (m, 1H), 1.56 (s, 3H), 1.42 (s, 3H), 1.27 (td, J=12.7, 4.4 Hz, 1H), 1.12 (s, 3H). 13C NMR (126 MHz; C6D6): δ 197.3, 171.2, 136.5, 131.8, 131.1, 125.8, 124.5, 123.36, 123.23, 100.2, 73.4, 61.8, 57.5, 52.4, 48.2, 40.9, 39.7, 37.5, 30.8, 26.0, 25.76, 25.72, 23.7, 22.2, 18.01, 17.90, 17.7, 17.3. FTIR (thin film) νmax: 3464 (br), 2969, 2928, 2859, 1665, 1615, 1450, 1376, 1329, 1235, 1087, 1040, 986, 928, 907, 858, 737 cm-1. HRMS-ESI (m/z): [M+H]+ calculated for C28H44O5, 461.3262. found, 461.3254.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][CH:17]([CH2:19][N:20]=[N+]=[N-])[O:16][C:15]2=[O:23])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[N:11][C:10](C)=[N:9]1.N[CH2:25][C@@H]1OC(=O)N(C2C=CC(N3C=C(C)N=N3)=C(F)C=2)C1.CO>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][CH:17]([CH2:19][NH2:20])[O:16][C:15]2=[O:23])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:12][N:11]([CH3:25])[CH:10]=[N:9]1
Reactant: Cc1ncn(-c2ccc(N3CC(CN=[N+]=[N-])OC3=O)cc2F)n1
Reactant: Cc1cn(-c2ccc(N3C[C@H](CN)OC3=O)cc2F)nn1
Solvent: CO
Solvent: ClCCl
Product: CN1C=NN(c2ccc(N3CC(CN)OC3=O)cc2F)C1

Procedure:
3-[3-Fluoro-4-(3-methyl-1,2,4-triazol-1-yl)phenyl]-5-(azidomethyl)oxazolidin-2-one (Intermediate 24) (1.8 g, 5.67 mmol) was hydrogenated as described for Intermediate 16. Chromatography on silica gel with 3-7% methanol in dichloromethane gave the title compound (1.28 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][CH:10]=[C:9]2[CH3:23])=[CH:4][C:3]=1[Cl:24].[O:25]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26]1>>[Cl:24][C:3]1[CH:4]=[C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][CH:10]=[C:9]2[CH3:23])[CH:6]=[CH:7][C:2]=1[C:27]1[CH:28]=[CH:29][O:25][CH:26]=1
Reactant: OB(O)c1ccoc1
Reactant: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(Br)c(Cl)c1
Product: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(-c2ccoc2)c(Cl)c1

Procedure:
The title compound was prepared according to the procedure of Example 35 using 1-(4-bromo-3-chlorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole instead of 1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-1H-pyrrole and 3-furanboronic acid instead of 2-furanboronic acid in step 4.
Reaction SMILES: [O:1]([CH2:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][C:13]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH:21]([NH2:26])[CH2:20]1)=[O:18])([CH3:15])[CH3:14].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:15][C:13]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH:21]([NH:26][C:9](=[O:10])[CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:20]1)=[O:18])([CH3:12])[CH3:14]
Reactant: O=C(Cl)COc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(N)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(O)C(NC(=O)COc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.9 %

Procedure:
Phenoxyacetyl chloride (0.15 mL, 1.06 mmol) was added dropwise to a stirred solution of 3-amino-4-hydroxy-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (0.23 g, 1.06 mmol) and TEA (0.18 mL, 1.27 mmol) in DCM (3 mL) at 0° C. The reaction mixture was stirred at room temperature for 15 minutes and a saturated solution of NaHCO3 was added. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo to yield 4-hydroxy-3-[(phenoxyacetyl)amino]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (0.36 g, 98% yield) that was used in the next step without further purification. C18H26N2O5 LCMS: Rt 2.03, m/z 351 [M+H]+ (using method, LC-MS Method 6).
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH3:4].Br[CH:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:25]=2)[C:20]1=[O:37]>CN(C=O)C>[CH2:11]([O:10][C:8](=[O:9])[C:7]([NH:6][C:3](=[O:5])[CH3:4])([CH:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:25]=2)[C:20]1=[O:37])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:12]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CCCCCCCCc1ccc2c(c1)CCC(Br)C2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc2c(c1)CCC(C(NC(C)=O)(C(=O)OCC)C(=O)OCC)C2=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 74.6 %

Procedure:
Sodium hydride (720 mg, 18.0 mmol) 60% in mineral oil was suspended in dry DMF (10 mL) and a solution of diethyl acetamidomalonate (3.26 g, 15 mmol) in dry DMF (10 mL) was added. The solution was stirred at 0° C. for 3 hours until the anion had formed. A solution of 4 (2.02 g, 6.0 mmol) in dry DMF (10 mL) was added and the solution warmed to room temperature and stirred overnight. The mixture was poured into distilled water (50 mL), in an ice-bath, acidified to pH 3 with 1M hydrochloric acid and extracted with ethyl acetate (3×50 mL). The organic phases were washed with brine (2×30 mL) and dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography (Silica gel, 40% EtOAc in hexanes) to provide 2.12 g of compound 5 (75%).
Reaction SMILES: [CH3:1][C:2]([CH3:23])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:18]=[CH:17][N:16]=[C:15](Cl)[C:14]=2[N+:20]([O-])=O)[CH2:9][CH2:8]1)=[O:6])[CH3:3].C(N(CC)CC)C.[H][H]>[Pd].C(O)C>[CH3:3][C:2]([CH3:23])([O:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([C:13]2[N:18]=[CH:17][N:16]=[CH:15][C:14]=2[NH2:20])[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc(Cl)c2[N+](=O)[O-])CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ncncc2N)CC1

Procedure:
A mixture of 1-[1,1-dimethylethoxycarbonyl]-4-[4chloro-5-nitro-6-pyrimidyl]piperazine and triethylamine (0.3 ml) and palladium on carbon (5%, 0.13 g) in ethanol (100 ml) is charged with hydrogen gas (30 psi). After the theoretical amount of hydrogen gas is consumed, the catalyst is removed under reduced pressure. The filtrate is concentrated under reduced pressure to a foam which is diluted with an aqueous saturated solution of potassium carbonate and dichloromethane. The phases are separated and the organic phase is dried over sodium sulfate and concentrated to give to give the title compound, NMR (CDCl3) 1.49, 3.49, 3.29, 3.56, 7.98, and 8.39 δ.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15](=O)[CH:16]=[C:17]([C:19]([OH:21])=[O:20])[N:18]=2)=[CH:9][CH:8]=1.C(#[N:25])C>O>[NH2:25][C:15]1[N:14]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=2)[N:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=1
Reactant: CC#N
Reactant: O=C(O)c1cc(=O)[nH]c(-c2ccc(Cl)cc2)n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Nc1cc(C(=O)O)nc(-c2ccc(Cl)cc2)n1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To phosphorus oxychloride (180 mL) was added 2-(4-chlorophenyl)-1,6-dihydro-6-oxo-4-pyrimidinecarboxylic acid (i.e. the product of Step A) (81.81 g, 326 mmol). The mixture was heated to 90° C. for 2.5 h. After cooling to room temperature the reaction mixture was slowly added to 1:2 acetonitrile:water (1.5 L) while keeping the temperature between 35 and 45° C. After the reaction mixture was stirred at room temperature for 30 minutes the resulting solid was isolated by filtration and washed with water. The solid was then combined with aqueous ammonia (5%, 2.1 L) and heated to 80° C. for 18 h. After 2 days at room temperature the solid was isolated by filtration and washed with water. A second crop was obtained by cooling the filtrate and refiltering. The combined solids were dried to afford the title compound (58.8 g).
Reaction SMILES: C([O:3][C:4](=[O:38])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)C.O.[OH-].[Li+].O>O1CCOCC1>[Cl:37][C:34]1[CH:33]=[CH:32][C:31]([C:21]2[N:20]([CH:13]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:12][O:11][C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:38])=[O:3])=[CH:6][CH:7]=3)[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=2)=[CH:36][CH:35]=1
Reactant: CCOC(=O)c1ccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To the solution of 0.22 g (0.4 mmol) 4-{2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethoxy}-benzoic acid ethyl ester in 3 mL dioxane, 50 mg (1.2 mmol) lithium hydroxide monohydrate and 3 mL water were added and the solution was stirred for 2 h at 100° C. After cooling to room temperature dioxane was evaporated and 7.6 mL 1N hydrochloric acid was added under stirring. The resulting suspension was filtered, thoroughly washed with water and the filter cake dried under high vacuum to give the product as a white solid (94%). MS (Turbo Spray): m/z=509.2 [M+H].