Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH:18]3[CH2:20][CH2:19]3)=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[SH:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([CH:31]2[CH2:33][CH2:32]2)=[O:30])=[CH:24][CH:23]=1>>[CH:18]1([C:13]2=[N:14][NH:15][C:16](=[O:17])/[C:12]/2=[C:4]2\[NH:5][C:6]3[C:11]([C:2]([S:21][C:22]4[CH:23]=[CH:24][C:25]([NH:28][C:29]([CH:31]5[CH2:32][CH2:33]5)=[O:30])=[CH:26][CH:27]=4)=[CH:3]\2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:20][CH2:19]1
Reactant: O=C(Nc1ccc(S)cc1)C1CC1
Reactant: O=C1NN=C(C2CC2)/C1=C1\C=C(Cl)c2ccccc2N1
Product: O=C1NN=C(C2CC2)/C1=C1\C=C(Sc2ccc(NC(=O)C3CC3)cc2)c2ccccc2N1

Procedure:
The title compound was prepared from (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-cyclopropyl-1H-pyrazol-5(4H)-one and N-(4-mercaptophenyl)cyclopropanecarboxamide under conditions similar to those described in Example 6. The final compound was purified by precipitating it from methanol. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.17-0.29 (m, 2H) 0.47-0.59 (m, 2H) 0.77-0.87 (m, 4H) 1.05-1.17 (m, 1H) 1.74-1.84 (m, 1H) 6.96 (s, 1H) 7.49-7.60 (m, 1H) 7.68 (d, J=8.59 Hz, 2H) 7.77-7.81 (m, 4H) 8.06 (d, J=7.07 Hz, 1H) 10.52 (s, 1H) 11.03 (s, 1H) 11.82 (s, 1H); ESI-MS: m/z calc'd for C25H22N4O2S 442.15. found 443.3 (M+H)+.
Reaction SMILES: [CH:1]12[O:8][CH:7]1[CH2:6][O:5][CH:4]([C:9]1[N:13]([CH3:14])[N:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])[CH2:3][CH2:2]2.[Cl-].[NH4+].[N-:20]=[N+:21]=[N-:22].[Na+]>CO.O>[N:20]([C@@H:1]1[CH2:2][CH2:3][C@@H:4]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[O:5][CH2:6][C@H:7]1[OH:8])=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: Cn1ncc([N+](=O)[O-])c1C1CCC2OC2CO1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](N=[N+]=[N-])[C@H](O)CO1
Temperature: 70 °C

Procedure:
To a solution of 5-(5,8-dioxabicyclo[5.1.0]octan-4-yl)-1-methyl-4-nitro-pyrazole (2.7 g, 11.3 mmol, intermediate 19) in MeOH/water (60 mL/15 mL) was added ammonium chloride (1.51 g, 28.3 mmol) and sodium azide (3.67 g, 56.5 mmol). The mixture was heated at 70° C. behind a blast shield for 4 hr. The MeOH was removed under reduced pressure and the aqueous residue extracted with EtOAc (100 mL). The organic layer was washed with aqueous NaHCO3 (3×20 mL), passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) followed by chiral SFC chromatography gave (3S,4R,7S)-4-azido-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-3-ol as the second eluting isomer as a clear gum (1.4 g, 41%). 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 5.43-5.37 (m, 1H), 4.18 (dd, J=13.9, 2.1 Hz, 1H), 4.06 (s, 3H), 3.97-3.77 (m, 3H), 2.45 (d, J=3.9 Hz, 1H), 2.32-2.09 (m, 2H), 2.10-1.85 (m, 2H).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:15][C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:14][CH2:13][CH2:12][C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([CH3:2])[CH:4]=3)[NH:8][CH:7]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(O)c1ccc(Cc2cccc(F)c2)cc1
Reactant: Cc1ccc2[nH]cc(CCN)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2[nH]cc(CCNC(=O)c3ccc(Cc4cccc(F)c4)cc3)c2c1
Yield: 41.9 %

Procedure:
4-(3-Fluorobenzyl)-N-(2-(5-methyl-1H-indol-3-yl)ethyl)benzamide was prepared according to method A with 2-(5-methyl-1H-indol-3-yl)ethanamine hydrochloride (0.060 g; 0.284 mmol), 4-(3-fluorobenzyl)benzoic acid (0.079 g; 0.341 mmol), HATU (0.141 g; 0.370 mmol) and N,N-diisopropylethylamine 0.123 mL; 0.711 mmol) in DMF (5 mL). Flash chromatography on silica gel (eluent 20 to 100% ethyl acetate in heptane) furnished 0.046 g (42%) of the title compound as a white solid.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:34])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11](CC1C=CC=CC=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39].C[O-].[Na+]>>[CH2:9]([N:14]1[CH:13]=[C:12]2[C:7](=[CH:8][CH:9]([C:23]3[CH:24]=[CH:25][C:26]([O:29][C:30]([F:32])([F:33])[F:31])=[CH:27][CH:28]=3)[C:10](=[O:22])[NH:11]2)[C:6]([OH:34])=[C:5]1[C:3]([NH:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:4])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3ccc(OC(F)(F)F)cc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)C1=C(O)C2=CC(c3ccc(OC(F)(F)F)cc3)C(=O)NC2=CN1Cc1ccccc1
Temperature: 25 °C
Yield: 103 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-(4-trifluoromethoxy-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (36 mg, 0.077 mmol), β-alanine (682 mg, 7.7 mmol) and NaOMe solution (12 mL, 6.1 mmol, 0.5 M in MeOH) was refluxed for 16 h. After cooling to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stilling until pH was about 2. The organic layer was washed with brine, dried over MgSO4 and concentrated. The crude solid was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 21 mg of the title compound as a yellow solid. MS: (+) m/z 528.27 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[CH3:18].Br[C:20]1[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([CH3:27])[CH:21]=1>>[Cl:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([C:20]2[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([CH3:27])[CH:21]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(Br)cc(C)n1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1Cl
Product: Cc1cc(-c2cc(C)c(Cl)c(C)c2)cc(C)n1

Procedure:
The title compound is prepared from 2-chloro-1,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene and 4-bromo-2,6-dimethyl-pyridine following a procedure analogous to that described in Step 1 of Intermediate 56. Mass spectrum (ESI+): m/z=246/248 (Cl) [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]2[C:7]([N:8]=[C:9]3[CH2:15][CH2:14][CH2:13]CC[C:10]=13)=[CH:6][CH:5]=[N:4]2.N1N2C(N=C3C(=C2O)CCC3)=CC=1.P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[N:3]2[C:7](=[CH:6][CH:5]=[N:4]2)[N:8]=[C:9]2[C:10]=1[CH2:13][CH2:14][CH2:15]2
Reactant: Clc1c2c(nc3ccnn13)CCCCC2
Agent: Oc1c2c(nc3ccnn13)CCC2
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1c2c(nc3ccnn13)CCC2

Procedure:
Using the method described for the preparation of 10-chloro-6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]indene, the reaction of 6,7-dihydro-5H-1,4,8a-triaza-s-indacen-8-ol and phosphorus oxychloride provided the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].Br[CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH3:21])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CCOCCOCCBr
Reactant: COC(=O)c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOCCOCCOc1ccc(C(=O)OC)cc1F
Yield: 89.1 %

Procedure:
Into a 500-ml, round-bottom flask equipped with a magnetic stirrer, heating mantle and condenser were placed 5.7 g (33.5 mmol) methyl 3-fluoro-4-hydroxybenzoate, 8.5 g (43.2 mmol) 1-bromo-2-(2-ethoxyethoxy)-ethane, 23.2 g of powdered anhydrous potassium carbonate and 350 ml acetonitrile. After stirring the reaction mixture under reflux for four hours, TLC analysis showed that none of the phenolic starting material remained. Three hundred ml of the acetonitrile was then distilled off and 300 ml dichloromethane was added. The reaction mixture was filtered through Celite and the solids were washed thoroughly with dichloromethane. Evaporation of the filtrate yielded product in the form of a yellow oil. Purification by flash chromatography on silica gel with 4% ethyl ether in dichloromethane, followed by low temperature recrystallization from pentane, yielded 8.55 g of white crystals, 89%, m.p. 33°-36.5° C. The structure was confirmed by infrared, nuclear magnetic resonance and mass spectral analyses. ##STR32##
Reaction SMILES: [Mg+2].[Cl-].[Cl-].[Cl-].[K+].C=C(OP(O)(O)=O)C(O)=O.P(OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.C([O-])(=O)C(C)=O.[O:53]=[C:54]1[O:60][C@H:59]([C@H:61]([CH2:63][OH:64])[OH:62])[C:57]([OH:58])=[C:55]1[OH:56]>O1CCN(CCS(O)(=O)=O)CC1>[O:53]=[CH:54][C@@H:55]([C@H:57]([C@@H:59]([C@@H:61]([CH2:63][OH:64])[OH:62])[OH:60])[OH:58])[OH:56]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: C=C(OP(=O)(O)O)C(=O)O
Agent: CC(=O)C(=O)[O-]
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
In 10.0 mM 2-morpholinoethanesulfonic acid (MES) buffer, 17.6 mM MgCl2, 17.6 mM KCl, 175.7 mM phosphoenolpyruvic acid (PEP), 17.6 mM ATP, 123 U/mL pyruvate kinase (PK), 97 U/mL hexokinase, and 20 U/mL ascorbic acid oxidase were dissolved in this composition, and the pH was adjusted to 7.0 to obtain a glucose converting reagent.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]=O)=[CH:8][CH:7]=[CH:6][C:5]=12.[C:12]([O:18][CH3:19])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15]>C(OC(C)C)(C)C.N1CCCCC1>[CH:4]([O:15][CH:14]([CH3:16])[CH3:13])([CH3:9])[CH3:5].[CH3:19][O:18][C:12](=[O:17])[C:13]([C:14](=[O:15])[CH3:16])=[CH:10][C:9]1[C:4]2=[N:3][O:2][N:1]=[C:5]2[CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1cccc2nonc12
Reactant: COC(=O)CC(C)=O
Solvent: CC(C)OC(C)C
Solvent: C1CCNCC1
Product: COC(=O)C(=Cc1cccc2nonc12)C(C)=O
Temperature: 70 °C
Yield: 177.7 %

Procedure:
Suspended 2,1,3-benzoxadiazole-4-carboxaldehyde (50 g, 0.33 mote) in diisopropyl ether (1300 ml) and added methyl acetoacetate (38 g, 0.32 mole), piperidine (2 g) glacial acetic acid (6 g) in to the suspension one after another. Refluxed the reaction mixture at 70° C. with continuous water separation. Removed sample from the reaction mixture and analysed the samples by qualitative HPLC. Washed the reaction mixture with hydrochloric acid (˜3.5 wt %, 250 ml, sodium bicarbonate solution (˜10 wt %, 250 ml and water (250 ml, 100 ml. Dried the organic layer over sodium sulphate (25 g) and then distilled diisopropyl ether under vacuum to get crude 2-acetyl-3-benzofurazan-4-yl-acrylic acid methyl ester (yield 70 g, HPLC purity 93.4%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([OH:13])[C:7](O)=[N:6]2.O=S(Cl)[Cl:17].Cl>CN(C=O)C>[Cl:17][C:7]1[C:8]([OH:13])=[N:9][C:10]2[C:5]([N:6]=1)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2nc(O)c(O)nc2c1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc2nc(O)c(Cl)nc2c1
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
A solution (1.53 M) of 6-methoxyquinoxaline-2,3-diol in DMF was treated with SOCl2 (1 eq) and heated at 110° C. After 1.5 h, the reaction mixture was cooled and poured into aqueous HCl (1 N). The resulting precipitate was filtered and washed with H2O and Et2O. The dried solid contained predominantly the title compound as a mixture with 6-methoxyquinoxaline-2,3-diol and 2,3-dichloro-6-methoxyquinoxaline. This material was used directly in the subsequent step. MS (ES+) m/z 211 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20](=[O:28])[NH:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1.[H-].[Na+].[F:31][CH:32]([F:44])[O:33][C:34]1[CH:35]=[C:36]([S:40](Cl)(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=1>>[F:44][CH:32]([F:31])[O:33][C:34]1[CH:35]=[C:36]([S:40]([N:19]2[CH2:18][CH:17]([C:15]([N:12]3[CH2:13][CH2:14][N:9]([C:3]4[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=4[CH3:1])[CH2:10][CH2:11]3)=[O:16])[N:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:20]2=[O:28])(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CNC(=O)N3c3ccccc3)CC2)c1
Reactant: O=S(=O)(Cl)c1cccc(OC(F)F)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4cccc(OC(F)F)c4)C(=O)N3c3ccccc3)CC2)c1

Procedure:
In analogy to example 33, (RS)-5-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-1-phenyl-imidazolidin-2-one (example 33, step 1) was reacted with sodium hydride and 3-(difluoromethoxy)benzenesulfonyl chloride to give the title compound as a colorless solid. MS: 584.7 ([M]+)
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[C:4]#[N:5].[NH3:11]>C(O)C>[NH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[C:3]=1[C:4]#[N:5]
Reactant: N
Reactant: N#Cc1c(F)cccc1F
Solvent: CCO
Product: N#Cc1c(N)cccc1F

Procedure:
2,6-Difluorobenzonitrile, 19 g (0.14 mol) in 200 ml of ethanol saturated with NH3 at 0° C. is heated in a sealed vessel at 140° C. for 6 hrs. The mixture is evaporated to dryness, water is added and the product is collected and recrystallized from benzene, m.p. 128°-130° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)[CH:12]([C:15]1[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][N:17]2[N:16]=1)[CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NCCCN(C(C1N(CC2C=CC(F)=CC=2)C(=O)C2=CC=CN2N=1)CC)C(=O)C1C=CC(C)=CC=1)(C)(C)C.[F:77][C:78]1[CH:79]=[C:80]([CH:83]=[CH:84][CH:85]=1)[CH2:81]Br>>[C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:12]([C:15]1[N:20]([CH2:81][C:80]2[CH:83]=[CH:84][CH:85]=[C:78]([F:77])[CH:79]=2)[C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][N:17]2[N:16]=1)[CH2:13][CH3:14])[C:25](=[O:33])[C:26]1[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCC(c1nn2cccc2c(=O)[nH]1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Reactant: Fc1cccc(CBr)c1
Agent: CCC(c1nn2cccc2c(=O)n1Cc1ccc(F)cc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Product: CCC(c1nn2cccc2c(=O)n1Cc1cccc(F)c1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Yield: 13.5 %

Procedure:
(±)-(3-{(4-Methylbenzoyl)-[1-(4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4] triazin-2-yl)-propyl]amino}propyl)carbamic acid tert-butyl ester (Example 3 A, 42 mg, 0.09 mmol) was converted to the title compound (7 mg, 13%) in a manner similar to the preparation of (±)-{3-[{1-[3-(4-fluorobenzyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl]-propyl}-(4-methylbenzoyl)-amino]-propyl}-carbamic acid tert-butyl ester, except that 3-fluorobenzyl bromide (22 mg, 0.12 mmol) was used instead of 4-fluorobenzyl bromide: 1H NMR (CDCl3) δ 7.45–6.96 (m, 10H), 6.62 (m, 1H), 5.95 (m, 1H), 5.86 (m, 1H), 4.90 (m, 1H), 3.86 (m, 1H), 3.33 (m, 2H), 2.71 (m, 2H), 2.39 (s, 3H), 2.05 (m, 1H), 1.85 (m, 1H), 1.60 (m, 1H), 1.40 (s, 9H), 1.05 (m, 1H), 0.72 (m, 3H).
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[C:6]2=[N:5][CH:4]=1)#[CH:2].[OH:26][CH2:27][C:28]([NH:31][S:32]([C:35]1[S:39][C:38](Cl)=[N:37][CH:36]=1)(=[O:34])=[O:33])([CH3:30])[CH3:29]>>[OH:26][CH2:27][C:28]([NH:31][S:32]([C:35]1[S:39][C:38]([C:2]#[C:1][C:3]2[N:7]3[CH:8]=[C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)[CH:10]=[C:11]([C:12]([F:14])([F:13])[F:15])[C:6]3=[N:5][CH:4]=2)=[N:37][CH:36]=1)(=[O:34])=[O:33])([CH3:30])[CH3:29]
Reactant: C#Cc1cnc2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)cn12
Reactant: CC(C)(CO)NS(=O)(=O)c1cnc(Cl)s1
Product: CC(C)(CO)NS(=O)(=O)c1cnc(C#Cc2cnc3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)cn23)s1

Procedure:
The title compound was prepared from 3-ethynyl-8-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.18) (354 mg, 1 mmol) and 2-chloro-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.19) (244 mg, 0.9 mmol) according to general procedure II. Obtained as a yellow solid (77 mg, 13%). MS (ISP) 589.3 [(M+H)+]; mp 202-203° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.[CH2:17](O)[CH2:18][OH:19]>C1C=CC=CC=1.CCOC(C)=O.CC1C=CC(S(O)(=O)=O)=CC=1.O>[O:19]1[C:2]2([CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:8])[CH2:3]2)[O:1][CH2:17][CH2:18]1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCC2(C1)OCCO2
Reaction time: 20 h
Yield: 101.4 %

Procedure:
A solution of benzyl 3-oxopyrrolidine-1-carboxylate (11.2 g, 51.09 mmol), ethylene glycol (2.4 g, 38.67 mmol) and TsOH.H2O (10 mg) in benzene (100 mL) was heated at reflux using Dean-Stork condenser. After 20 h, the reaction mixture was cooled, diluted with EtOAc (100 mL), washed with water (2×25 mL), brine (25 mL), dried (MgSO4), filtered and concentrated to give yellow oil. Flash column chromatography purification on silica gel column with 1:4 followed by 3:7 EtOAc:hexanes provided desired product (10.32 g, 100%) as colorless liquid. 1H NMR (500 MHz, CDCl3) δ: 7.38-7.28 (5H, m), 5.13 (2H, s), 3.99-3.92 (4H, m), 3.58-3.54 (2H, m), 3.45 (2H, d, J=10.7 Hz), 2.07-2.02 (2H, m).
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[CH3:12]OC(OC)(C)C.Cl>CO>[C:1]([O:11][CH3:12])(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: O=C(O)[C@H](O)c1ccccc1
Reactant: COC(C)(C)OC
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](O)c1ccccc1
Reaction time: 20 h

Procedure:
(R)-Mandelic acid (2.568 g, 16.87 mmol) and 2,2-dimethoxypropane (5.1 mL, 41.48 mmol) were dissolved in MeOH (100 mL) and 12M HCl (100 mL) was added. The resulting solution was stirred for 20 hr under a CaCl2 tube and evaporated to dryness under reduced pressure. EtOAc (100 mL) and saturated aqueous NaHCO3 (100 mL) were added, and the aqueous phase was extracted with EtOAc (3×100 mL). The organic fractions were dried with MgSO4, and evaporated under reduced pressure to give (R)-methyl mandelate, (R)-4, quantitatively (2.78 g) as a white solid which was of sufficient purity for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10]CC)=[O:9])=[N:6][CH:7]=1>Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(Cl)cn1
Agent: Cl
Product: O=C(O)c1ccc(Cl)cn1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
250 mg (1.35 mmol) of ethyl 5-chloropyridin-2-carboxylate was dissolved in 6 N hydrochloric acid, and the obtained solution was stirred at 70° C. for 2 hours. The solvent was evaporated to obtain the crude product.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19](Br)[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)[CH:9]=[N:10][CH:11]=1)=[O:6])([CH3:3])[CH3:2].[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:1]([O:4][C:5]([C:7]1[N:8]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:24]4[S:23][CH:27]=[CH:26][CH:25]=4)[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)[CH:9]=[N:10][CH:11]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)c1cncn1C1CCCc2ccc(Br)cc21
Reactant: OB(O)c1cccs1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)c1cncn1C1CCCc2ccc(-c3cccs3)cc21
Temperature: 150 °C

Procedure:
A flask is charged with 3-(7-bromo-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester (0.225 g, 0.520 mmol), which can be prepared as described in Example 5, 2-thienylboronic acid (0.145 g, 1.041 mmol), aqueous sodium carbonate (2M, 1.30 mL, 2.60 mmol) and DMF (35 mL). Tetrakis(triphenylphosphine) palladium (0.060 g, 0.052 mmol) is added and the mixture is heated to 150° C. in a sealed tube under microwave irradiation conditions for 12 minutes. The reaction is then cooled to room temperature, diluted with water and extracted with dichloromethane. The organic phase is dried over sodium sulfate, filtered, and concentrated to give a residue, which is purified by silica gel chromatography (hexanes-ethyl acetate mixtures) to give 3-[7-thiophen-2-yl-1,2,3,4-tetrahydro-naphthalen-1-yl]-3H-imidazole-4-carboxylic acid isopropyl ester. MS: (ESI) m/z 367.2 (M+H)+. The HCl salt of the title compound can be prepared by dissolution in diethyl ether followed by treatment with an excess of 1N HCl in diethyl ether. The resulting heterogeneous solution is concentrated to furnish the HCl salt of 3-[7-thiophen-2-yl-1,2,3,4-tetrahydro-naphthalen-1-yl]-3H-imidazole-4-carboxylic acid isopropyl ester; 1H NMR (400 MHz, MeOD) δ ppm 1.38 (d, J=6.3 Hz, 3 H), 1.41 (d, J=6.3 Hz, 3 H), 1.80-1.97 (m, 2 H), 2.22-2.34 (m, 2 H), 2.86-2.94 (m, 1 H), 3.04 (dt, J=17.2, 6.0 Hz, 1 H), 5.26 (d, J=6.3 Hz, 1 H), 6.36 (t, J=5.6 Hz, 1 H), 7.06 (dd, J=5.2, 3.7 Hz, 1 H), 7.18 (br. s, 1 H), 7.28 (dd, J=3.7, 1.1 Hz, 1 H), 7.30 (d, J=8.1 Hz, 1 H), 7.34 (dd, J=5.2, 1.1 Hz, 1 H), 7.48 (s, 1 H), 7.58 (dd, J=8.1, 2.0 Hz, 1 H), 7.77 (d, J=1.0 Hz, 1 H).
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[NH:23][C:24]([C:26]2[CH:27]=[C:28]([CH:40]=[CH:41][CH:42]=2)[CH2:29][S:30][CH2:31][CH2:32][C:33]([O:35]C(C)(C)C)=[O:34])=[O:25])[CH:11]=1)=[O:9].FC(F)(F)C(O)=O>ClCCl>[F:46][C:2]([F:1])([F:47])[C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[NH:23][C:24]([C:26]2[CH:27]=[C:28]([CH:40]=[CH:41][CH:42]=2)[CH2:29][S:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:25])[CH:11]=1)=[O:9]
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(F)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(F)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.7 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-fluorophenyl)carbamoyl)benzylthio)propanoate (100 mg, 0.15 mmol, 1.00 equiv) in dichloromethane (5 mL), and trifluoroacetic acid (1 mL). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 22.7 mg (25%) of a yellow solid. 1H-NMR (300 MHz, DMSO, ppm): δ 12.78 (s, 1H), 9.55-9.54 (m, 1H), 9.00-8.99 (m, 1H), 8.58-8.53 (m, 1H), 8.43 (s, 1H), 7.94-7.39 (m, 11H), 4.65-4.63 (t, J=3 Hz, 2H), 3.89 (s, 2H), 2.63-2.59 (m, 2H). MS (ES, m/z): 612 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][N:5]=[C:6]1[C:10](=O)[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[O:7]1.Cl.[NH2:17][OH:18].O>CN1CCCC1=O>[OH:1][CH2:2][CH2:3][O:4][N:5]=[C:6]1[C:10](=[N:17][OH:18])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[O:7]1
Reactant: NO
Reactant: O=C1C(=NOCCO)Oc2ccccc21
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: OCCON=C1Oc2ccccc2C1=NO
Yield: 37.8 %

Procedure:
At 80° C., 10.1 g (0.05 mol) of benzofuran-2,3-dione2-[O-(2-hydroxy-ethyl)-oxime] (VII-1) in 50 ml of N-methyl-2-pyrrolidinone are stirred with 3.5 g of hydroxylamine hydrochloride for 2 hours. The reaction mixture is poured into water and the resulting mixture is extracted with ethyl acetate, the organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. The residue is then chromatographed over silica gel using tert-butyl methyl ether/petroleum ether (1:1). The eluent is distilled off under reduced pressure, affording 4.2 g (29.6% of theory) of benzofuran-2,3-dione2-[O-(2-hydroxy-ethyl)-oxime]3-oxime consisting of 62.4% of isomer A and 15.8% of isomer B (HPLC).