Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]2[N:15](C(OC(C)(C)C)=O)[C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1.F[C:32]1[CH:33]=[CH:34][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[N:36][CH:37]=1.O>CN(C)C=O>[CH3:12][O:11][CH2:10][C@H:9]([CH3:13])[O:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([C:14]2[NH:15][C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=1)[O:1][C:32]1[CH:33]=[CH:34][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[N:36][CH:37]=1
Reactant: CS(=O)(=O)c1ccc(F)cn1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Solvent: O
Solvent: CN(C)C=O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(-c3nccs3)[nH]2)c1
Reaction time: 72 h
Yield: 36 %

Procedure:
t-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (70.0 mg, 0.16 mmol) synthesized in Example (38d) and 5-fluoro-2-(methylsulfonyl)pyridine (35.0 mg, 0.20 mmol) synthesized in Example (65b) were dissolved in N,N-dimethylformamide (5 mL), and stirring was carried out at 90° C. for 3 days under nitrogen atmosphere. To the reaction solution, water (15 mL) was added, followed by extraction with ethyl acetate (30 mL), and washing was carried out with saturated brine (30 ml), followed by drying over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-40%) to afford the desired compound (28 mg, yield 35%) as a pale yellow solid.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[F:12][C:13]([F:41])([F:40])[O:14][C:15]1[CH:16]=[C:17]([C:21]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]([F:39])([F:38])[F:37])[CH:30]=2)=[N:22][S@@:23]([C:25]([CH3:28])([CH3:27])[CH3:26])=[O:24])[CH:18]=[CH:19][CH:20]=1.[NH4+].[Cl-]>CCOCC.CCOC(C)=O>[F:39][C:36]([F:37])([F:38])[O:35][C:31]1[CH:30]=[C:29]([C:21]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([O:14][C:13]([F:41])([F:40])[F:12])[CH:16]=2)=[N:22][S@@:23]([C:25]([CH3:28])([CH3:27])[CH3:26])=[O:24])[CH:34]=[CH:33][CH:32]=1.[C:1]([CH2:2][C:21]([NH:22][S@@:23]([C:25]([CH3:28])([CH3:27])[CH3:26])=[O:24])([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]([F:37])([F:38])[F:39])[CH:30]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][C:13]([F:40])([F:41])[F:12])[CH:16]=1)#[N:3]
Reactant: CC#N
Agent: CC(C)(C)[S@@](=O)N=C(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)(C)[S@@](=O)NC(CC#N)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
(R)—N-(bis(3-(trifluoromethoxy)phenyl)methylene)-2-methylpropane-2-sulfinamide was prepared as described for Procedure 11. Under an argon atmosphere, acetonitrile (0.46 mL, 8.84 mmol, 2.0 eq) was stirred in anhydrous Et2O (40 mL) in an oven-dried round bottomed flask at −78° C. LDA (2.0 M, 4.42 mL, 8.84 mmol, 2.0 eq) was added dropwise. The resulting mixture was stirred at −78° C. for 30 min. (R)—N-(bis(3-(trifluoromethoxy)phenyl)methylene)-2-methylpropane-2-sulfinamide (2.0 g, 4.42 mmol) in Et2O (10 mL) was added dropwise to the above stirred solution. The reaction mixture was stirred at −78° C. for 4 h. Sat'd NH4Cl was added, followed by the addition of EtOAc. The organic layer was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, EtOAc/Hexanes=0 to 100%) to give (R)—N-(2-cyano-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide as light tan oil (1.15 g, yield: 52.7% with 0.85 g recovery of the starting material). LC-MS (ESI) 495.26 (M+H), retention time=3.84 min (10-90% MeOH in H2O with 0.1% TFA in a 4-min run); 1H NMR (400 MHz, CDCl3) δ ppm 7.40-7.35 (m, 2H), 7.29 (d, J=8 Hz, 1H), 7.21-7.16 (m, 4H), 7.08 (m, 1H), 4.53 (s, 1H), 3.75 (d, J=16 Hz, 1H) 3.56 (d, J=16 Hz, 1H), 1.21 (s, 9H).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[CH:6][CH2:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH3:16])[CH2:11][CH2:10]1)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CO.C1COCC1.[Pd]>[C:20]([O:19][C:17](=[O:18])[N:15]([C@H:12]1[CH2:11][CH2:10][C@H:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][OH:3])[CH2:14][CH2:13]1)[CH3:16])([CH3:21])([CH3:23])[CH3:22]
Reactant: CCOC(=O)C=CCC[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Agent: [Al+3]
Agent: [H-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](CCCCCO)CC1

Procedure:
A solution of 2.45 g (7.2 mmol) trans-5-[4-(tert-Butoxycarbonyl-methyl-amino)-cyclohexyl]-pent-2-enoic acid ethyl ester and 200 mg of Pd/C (10%) in 40 ml MeOH was stirred for 20 h under H2-atmosphere. After filtration and evaporation of the methanol under vacuo, 2.39 g 5-[4-(tert-Butoxy carbonyl-methyl-amino)-cyclohexyl]-pentanoic acid ethyl ester could be isolated. 2.05 g (6.0 mmol) of this ester and 470 mg (12 mmol) of LiAlH4 were stirred in 20 ml of THF at RT for 5 h. Exess of LiAlH4 was destroyed by adding 10 ml of EtOAc and by carefully dropping brine to the reaction-mixture. The solution was dissolved in ether and washed with 1N HCl and water. The organic phase was concentrated under reduced pressure yielding 1.75 g (97%) of clean trans-[4-(5-Hydroxy pentyl)-cyclohexyl)-methyl-carbamic acid tert-butyl ester, MS: 300 (MH+).
Reaction SMILES: [OH-].[K+].[CH:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][C:4]=1[OH:13].Br[CH2:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1>C(O)C>[CH:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][C:4]=1[O:13][CH2:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1
Reactant: Oc1ccc2c(c1)CCCC2
Reactant: O=Cc1ccc(OCCBr)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=Cc1ccc(OCCOc2ccc3c(c2)CCCC3)cc1
Temperature: -5 °C
Yield: 47.9 %

Procedure:
To a solution of potassium hydroxide (0.67 g, 9.80 mmol) in ethanol (30 ml) is added 5,6,7,8-tetrahydro-2-naphthol (1.45 g, 9.80 mmol) and 4-(2-bromoethoxy)benzaldehyde (2.25 g, 9.80 mmol). Then the mixture is heated to reflux for 8 hours. After cooled to −5° C., the precipitate is collected by filtration, washed with water, and dried under vacuum to give the title product (1.39 g, 48.0%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[CH:9]=2)[N:4]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:3]=1.[F:40][C:41]1[CH:42]=[C:43]([CH:61]=[CH:62][CH:63]=1)[CH2:44][N:45]1[C:49]([CH3:50])=[C:48](B2OC(C)(C)C(C)(C)O2)[C:47]([CH3:60])=[N:46]1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].COCCOC.O>[F:40][C:41]1[CH:42]=[C:43]([CH:61]=[CH:62][CH:63]=1)[CH2:44][N:45]1[C:49]([CH3:50])=[C:48]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)=[CH:13][CH:12]=4)[CH:9]=3)[N:4]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:3]=2)[C:47]([CH3:60])=[N:46]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (intermediate 41) (130 mg, 0.19 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (71 mg, 0.21 mmol) in sodium carbonate (40 mg, 0.38 mmol), PdCl2(dppf) (6.94 mg, 0.0095 mmol), 1,2-Dimethoxyethane/water (15/1.5 ml) to give titled compound quantity and yield as off white solid. MS: m/z=735.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[Cl:12][CH2:13][CH2:14][C:15](Cl)=[O:16].N1C=CC=CC=1>C(#N)C>[Cl:12][CH2:13][CH2:14][C:15]([NH:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7])=[O:16]
Reactant: Nc1ccc(C(=O)O)c(O)c1
Reactant: O=C(Cl)CCCl
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(CCCl)Nc1ccc(C(=O)O)c(O)c1
Reaction time: 0.33 h

Procedure:
7.5 g of 4-Aminosalicyclic acid was dissolved in 300 ml of acetonitrile at about 60° C. 12 ml of 3-chloropropionyl chloride was added dropwise and followed by addition of 5 ml of pyridine, the resulting mixture was refluxed for three hours. The mixture, which became clear after approximately 20 minutes of refluxing, was cooled and evaporated to dryness under reduced pressure. A gummy oil was dissolved in isopropanol-water and refrigerated for several days. A small amount of solid thus produced was filtered off. The filtrate was evaporated to dryness and approximately 16.8 g of crude 4-(3-chloropropionamido) salicyclic acid was produced. A lens treated with this compound was found to be clear with excellent UV blockage up to about 320 nm. ##STR9##
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])O[C:4](=[O:9])[CH:3]=1.[F:10][C:11]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:12]=1[NH2:13]>O>[F:10][C:11]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:12]=1[N:13]1[C:6]([CH3:8])=[CH:7][C:2]([OH:1])=[CH:3][C:4]1=[O:9]
Reactant: Cc1cc(O)cc(=O)o1
Reactant: Nc1c(F)cccc1F
Solvent: O
Product: Cc1cc(O)cc(=O)n1-c1c(F)cccc1F
Temperature: 170 °C
Yield: 37.5 %

Procedure:
A mixture of 4-hydroxy-6-methyl-2-pyrone (10.0 g, 0.079 mol) and 2,6 difluoroaniline (9.5 g, 0.073 mol) was heated at 170° C. under argon atmosphere for 20 min. The water formed was removed using a Dean-stark apparatus. The melt was cooled, the dark solid was tritutrated with EtOAc., and filtered. This material was washed thoroughly with EtOAc to afford the desired product 1-(2,6-difluorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one 6.5 g (35%) as a light brown solid: 1H NMR (CD3OD/400 MHz) δ 7.56 (m, 1H), 7.19 (m, 2H), 6.09 (m, 1H), 5.77 (d, 1H, J=2.4 Hz), and 1.99 (s, 3H); ES-HRMS m/z 238.0679 (M+H C12H10NO2F2 requires 238.0674).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:12](Cl)=[N:13][C:14]([N:17]([CH3:19])[CH3:18])=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH2:21].[Na]>>[CH2:1]([NH:8][C:9]([C:11]1[C:12]([SH:21])=[N:13][C:14]([N:17]([CH3:19])[CH3:18])=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)c1ncc(C(=O)NCc2ccccc2)c(Cl)n1
Reactant: S
Agent: [Na]
Product: CN(C)c1ncc(C(=O)NCc2ccccc2)c(S)n1
Yield: 43.9 %

Procedure:
Using the procedure of Preparation 34, 14.3 g (0.045 mol) of 4-chloro-2-dimethylamino-pyrimidine-5-carboxylic acid benzylamide and 12 g (0.21 mol) of sodium hydrogen sulfide were reacted to give 5.7 g of the title compound, mp 175°-178° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[C:10]([CH3:16])[CH:9]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH2:42])[CH:28]=[CH:29][C:30]=1[O:31][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34].CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:42][C:13]([C:11]2[S:12][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:9][C:10]=2[CH3:16])=[O:15])[CH:28]=[CH:29][C:30]=1[O:31][Si:32]([CH:36]([CH3:38])[CH3:37])([CH:39]([CH3:41])[CH3:40])[CH:33]([CH3:35])[CH3:34]
Reactant: COc1cc(N)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Reactant: Cc1cc(-c2ccc(Cl)cc2)sc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(NC(=O)c2sc(-c3ccc(Cl)cc3)cc2C)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
Suspend 5-(4-chloro-phenyl)-3-methyl-thiophene-2-carboxylic acid (2.13 g, 8.44 mmol) in CH2Cl2 (15 mL) and treat with oxalyl chloride (1.5 mL, 16.87 mmol), followed by the addition of DMF (2 drops). Stir the mixture at RT for 2 h and then evaporate down in vacuo. Dissolve the resulting solid material in CH2Cl2 (30 mL) and cool to 0° C. Add 3-methoxy-4-triisopropylsilanyloxy-phenylamine (2.62 g, 8.86 mmol) and Et3N (1.8 mL, 12.66 mol) in CH2Cl2 (10 mL) dropwise at 0° C. Stir the reaction at 0° C. for 10 min and at RT for 30 min. Dilute the reaction with CH2Cl2 (100 mL), wash with 0.1 M HCl (2×30 mL), 1.0 M NaOH (2×30 mL), dry over Na2SO4, filter, and concentrate. Purify the crude material by chromatography, eluting with 20% EtOAc/hexane to give 3.53 g (79%) of the title compound. LC-MS/ES m/z (37Cl) 531.2 [M+].
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:6][B:5]([OH:7])[C:4]2[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:3]1=2.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C(=O)N([Br:39])C(=O)C1.O>C(Cl)(Cl)(Cl)Cl>[Br:39][CH2:12][C:10]1[CH:9]=[CH:8][C:4]2[B:5]([OH:7])[O:6][C:2]([CH3:13])([CH3:1])[C:3]=2[CH:11]=1
Reactant: Cc1ccc2c(c1)C(C)(C)OB2O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)OB(O)c2ccc(CBr)cc21
Temperature: 25 °C
Yield: 62.2 %

Procedure:
To a solution of 3,3,5-trimethylbenzo[c][1,2]oxaborol-1(3H)-ol (5.0 g, 28.4 mmol) in CCl4 (50 mL) at rt was added benzoyl peroxide (0.7 g, 2.8 mmol) following by NBS (5.0 g, 28.4 mmol). The reaction mixture was refluxed overnight, cooled to rt and treated with water. The aqueous layer was extracted with EA (20 mL×3). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give the product (4.5 g, yield 62%) as yellow oil. MS: 255 & 257 [M+H]+.
Reaction SMILES: [C:1]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17]2[O:21][N:20]=[C:19]([CH:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[N:18]=2)=[O:8])=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[O:21][N:20]=[C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:18]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: CON=C1C[C@@H](c2nc(C3CCN(C(=O)OC(C)(C)C)CC3)no2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CON=C1C[C@@H](c2nc(C3CCNCC3)no2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 80 %

Procedure:
tert-butyl 4-{5-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-3-yl}-1-piperidinecarboxylate) (100 mg, 1.80 mmol) was treated with a 25% TFA/DCM solution at 0° C. for 1 hour. The reaction was then made basic with a sodium carbonate solution (10%) and extracted with DCM. The organic phases were combined and dried over magnesium sulfate and solvent removal afforded a residue which was purified by flash-chromatography using cyclohexane/ethylacetate (2/8) as eluent to give (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(4-piperidinyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinone O-methyloxime as a mixture of E-/Z-isomers in 80% yield (96.1% purity by HPLC).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.NN.[NH:16]([C:18]1N=CC(C2C=NC=CC=2)=CC=1)[NH2:17]>N1C=CC=CC=1.C(OCC)(OCC)OCC.C(O)(=O)C>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]3[N:7]([CH:18]=[N:16][N:17]=3)[CH:6]=2)[CH:9]=1
Reactant: NNc1ccc(-c2cccnc2)cn1
Reactant: Clc1ccc(-c2cccnc2)cn1
Agent: NN
Solvent: CCOC(OCC)OCC
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: c1cncc(-c2ccc3nncn3c2)c1

Procedure:
As described in Example 5, 2.2 g of 6-chloro-3,3'-bipyridine was treated with 3.6 ml of anhydrous hydrazine in pyridine at 115° C. for 48 hours. The resulting crude 6-hydrazino-3,3'-bipyridine was dissolved in 25 ml of triethyl orthoformate and 2 drops of acetic acid and heated to 130° C. for 10 hours. The volatiles were removed at reduced pressure and the residue purified by chromatography on silica gel, eluting with ethyl acetate:methanol (9:2). The obtained solid was recrystallized from ethyl acetate-methanol, giving the desired product, mp 200°-202.5° C.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[CH:30][CH:29]=1.O>C1COCC1>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:32]([C:31]1[CH:34]=[CH:35][C:28]([Cl:27])=[CH:29][CH:30]=1)[OH:33])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Brc1ccccc1OCc1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1ccc(Cl)cc1)c1ccccc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (2.44 M, 10.3 mL) was added dropwise to a solution of 1-benzyloxy-2-bromobenzene (6.0 g, 22.8 mmol) in THF (228 mL) at −78° C. and the mixture was stirred at the same temperature for 30 minutes. To this solution, a solution of 4-chlorobenzaldehyde (2.67 g, 19.0 mmol) in THF (76 mL) was added dropwise at −78° C. The reaction mixture was stirred at the same temperature for two hour and further more at 0° C. for one hour. Water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate: n-hexane (1:5)] to obtain the title compound (4.76 g, 77%).
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:20])=[N:4][C:5]2[CH:6]=[CH:7][C:8]3[C:15]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]=2[N:11]=1.[N+:21]([O-])([OH:23])=[O:22]>S(=O)(=O)(O)O>[OH:1][C:2]1[C:3]([OH:20])=[N:4][C:5]2[CH:6]=[C:7]([N+:21]([O-:23])=[O:22])[C:8]3[C:15]([S:16](=[O:18])(=[O:19])[NH2:17])=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]=2[N:11]=1
Reactant: O=[N+]([O-])O
Reactant: NS(=O)(=O)c1cccc2c1ccc1nc(O)c(O)nc12
Agent: O=S(=O)(O)O
Product: NS(=O)(=O)c1cccc2c1c([N+](=O)[O-])cc1nc(O)c(O)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a solution of 1,0 g (3,4 mmol) 2,3-dihydroxy-7-sulphamoylbenzo[f]quinoxaline in 25 ml concentrated sulfuric acid was added at 0° C. 0,15 ml 100% nitric acid. Stirring was continued at 0° C. for 30 min, and then the mixture was poured into 100 ml ice-water to give a precipitate. The crude product was recrystallized (dimethylformamide-water) to give 0,7 g (61%) 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo[f]quinoxaline.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.CC1(C)C(C)(C)OB([C:17]2[CH:21]=[CH:20][N:19](C(OC(C)(C)C)=O)[N:18]=2)O1.C([O-])([O-])=O.[Na+].[Na+].CO.C(Cl)Cl>C1(C)C=CC=CC=1.CCO.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>[NH:18]1[CH:17]=[CH:21][C:20]([C:2]2[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=2)=[N:19]1
Reactant: O=Cc1cnc(Br)s1
Reactant: CC(C)(C)OC(=O)n1ccc(B2OC(C)(C)C(C)(C)O2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: O=Cc1cnc(-c2cc[nH]n2)s1
Temperature: 100 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
To a solution of 2-bromothiazole-5-carbaldehyde (0.8 g, 4.16 mmol) in toluene (6 mL) and EtOH (5 mL), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (1.8 g, 6.2 mmol), 2M Na2CO3 (6.2 mL, 12.4 mmol) and Pd(PPh3)4 (0.45 mg, 0.4 mmol) were added under argon. The mixture was degassed, heated to 100° C., stirred for 1 h. After completion of the reaction, by monitoring with TLC (5% MeOH\DCM), the resulting mixture was filtered with Celite® reagent and the filtrate was separated. This filtrate was concentrated, extracted with EtOAc (2×100 mL), washed with water (100 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by Biotage Isolera® One column purifier (silica gel 100-200 microns) using 3% methanol in dichloromethane and isolated as yellow color solid (0.25 g, 33% yield). 1H NMR (400 MHz, DMSO-d6): δ 13.49 (brs, 1H), 10.03 (s, 1H), 8.60 (s, 1H), 8.55 (s, 1H), 8.09 (s, 1H); LC-MS m/z calcd for [M+H]+, 180.02. found, 180.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:21](N1C=CN=C1)([N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)=O.CN(C)CCN>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:25][CH2:26][CH2:27][N:23]([CH3:24])[CH3:21])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: CN(C)CCN
Solvent: ClCCl
Product: CN(C)CCNC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stream of nitrogen was bubbled through a stirred suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.50 g, 0.0157 mole), 1,1'-carbonyldiimidazole (2.54 g, 0.0157 mole) and anhydrous methylene chloride (100 ml) for 2 hrs at room temperature. A solution of N,N-dimethylethylenediamine (1.50 g, 0.0170 mole) in 10 ml of methylene chloride was added dropwise and the reaction mixture was stirred overnight at room temperature. The methylene chloride was washed with water (2×30 ml), 5% sodium hydroxide (2×30 ml), water (30 ml), dried over sodium sulfate and concentrated. The residue (4.5 g) was recrystallized from isopropyl alcohol to give 3.5 g (62%) of white flakes, mp 195°-196.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.C([Li])CCC.C([Li])(C)(C)C.CN(C)[CH:29]=[O:30]>O1CCCC1.O>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:5]2[N:6]=[CH:7][C:2]([CH:29]=[O:30])=[CH:3][CH:4]=2)=[CH:11][CH:12]=1
Reactant: Clc1ccc(CNc2ccc(Br)cn2)cc1
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(NCc2ccc(Cl)cc2)nc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To (5-Bromo-pyridin-2-yl)-(4-chloro-benzyl)-amine (41, 10.00 g, 0.03360 mol) in tetrahydrofuran (400.0 mL) under an atmosphere of nitrogen at −78° C. was added n-butyllithium (17.5 mL, 2.00 M in cyclohexane). After 90 minutes, tert-butyllithium (42.00 mL, 1.70 M in hexane) was added to the reaction. After 80 minutes, N,N-dimethylformamide (6.9 mL, 0.089 mol) was added to the reaction. The reaction mixture was stirred at −78° C. for 2 hours, then allowed to warm to room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give the crude compound, which was crystallized from tert-butoxyl methyl ether to provide compound (42, 7.66 g, 92.2%).