Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([S:14]C(C)(C)C)=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[CH:5]=[N:6]O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CCC>[Br:1][C:2]1[C:3]2[S:14][N:6]=[CH:5][C:4]=2[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1
Reactant: CC(C)(C)Sc1c(Br)cc([N+](=O)[O-])cc1C=NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Product: O=[N+]([O-])c1cc(Br)c2sncc2c1
Yield: 64.7 %

Procedure:
A mixture of 3-bromo-2-tert-butylsulfanyl-5-nitro-benzaldehyde oxime (1.98 g, 5.97 mmol) and p-toluenesulfonic acid (567 mg, 2.98 mmol) in n-butanol (20 mL) was heated to reflux for 16 h. The reaction mixture was cooled and concentrated. The residue was treated with water followed by saturated sodium bicarbonate solution and then was extracted with dichloromethane (3×20 mL). The combined organic fractions were washed with water, dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (20% ethyl acetate:hexanes) afforded 1.0 g (65%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 9.21 (s, 1H), 8.95 (s, 1H), 8.59 (s, 1H).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[NH:6][C:5]=2[CH:4]=[C:3]([C:14]#[N:15])[CH:2]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[CH2:17]([CH:10]1[C:8]2[C:9]3[CH:1]=[CH:2][C:3]([C:14]#[N:15])=[CH:4][C:5]=3[NH:6][C:7]=2[CH2:13][CH2:12][CH2:11]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCBr
Reactant: N#Cc1ccc2c3c([nH]c2c1)CCCC3
Product: CCCCCCCCC1CCCc2[nH]c3cc(C#N)ccc3c21
Yield: 71.7 %

Procedure:
Using the procedure described in Example 9, 10.2 g of the carbonitrile from Example 2 was alkylated with 12.8 g of 1-bromooctane to give 11.5 g (68.5%) of 5,6,7,8-tetrahydro-9-octyl-9H-dibenzo[b,d]pyrrole-3-carbonitrile as a white solid.
Reaction SMILES: [C:1]([OH:5])(=[O:4])C=C.[CH2:6]([O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH2:7][CH:8]=[CH2:9]>Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl.ClCCl>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[O:10][CH2:6][CH2:7][CH:8]=[CH:9][C:1]([OH:5])=[O:4]
Reactant: C=CCCOC1CCCCO1
Reactant: C=CC(=O)O
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Product: O=C(O)C=CCCOC1CCCCO1
Yield: 84 %

Procedure:
In a 500 ml rb flask were placed acrylic acid (2.85 g, 39.6 mmol) and Grubbs catalyst (1.68 g, 1.98 mmol) in anhydrous dichloromethane (200 ml). To this solution was added 2-but-3-enyloxy-tetrahydro-pyran (7.73 g, 49.50 mmol) and heated at refluxing for 12 hrs. The solvent was removed and the residue was purified on the column with Hexane/Ethyl acetate=100/5 to remove unchanged 2-but-3-enyloxy-tetrahydro-pyran. Then the column was eluted with Ethyl acetate/Methanol=100/1 to provide 6.66 g of a black oil (84%). 1H-NMR (DMSO-d6) δ 12.190 (s, 1H), 6.845-6.771 (m, 1H), 5.846-5.800 (d, 1H), 4.565-4.548 (t, 1H), 3.739-3.674 (m, 2H), 3.468-3.398 (m, 2H), 2.481-2.395 (m, 2H), 1.689-1.609 (m, 2H), 1.501-1.259 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](=[O:17])(=[O:16])[NH:12][CH:13]2[CH2:15][CH2:14]2)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:19](Cl)=[O:20]>C(Cl)CCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](=[O:17])(=[O:16])[NH:12][CH:13]2[CH2:14][CH2:15]2)=[CH:7][C:3]=1[C:4]([N:6]=[C:19]=[O:20])=[O:5]
Reactant: NC(=O)c1cc(S(=O)(=O)NC2CC2)ccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: O=C=NC(=O)c1cc(S(=O)(=O)NC2CC2)ccc1Cl
Yield: 91.4 %

Procedure:
To a solution of 2-chloro-5-(N-cyclopropylsulfamoyl)benzamide (1.50 g, 5.46 mmol) in EDC (20 mL) was added oxalyl chloride (0.59 mL, 6.55 mmol). The reaction mass was refluxed for 1-2 h. Excess of solvent was removed under vacuum to afford 1.5 g of desired product.
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].[CH:7]([NH:10][CH:11]([CH3:13])[CH3:12])([CH3:9])[CH3:8].[C:14](#[N:18])[CH:15]([CH3:17])O>C(OCC)C>[CH:7]([N:10]([CH:11]([CH3:13])[CH3:12])[CH:15]([CH3:17])[C:14]#[N:18])([CH3:9])[CH3:8]
Reactant: CC(C)NC(C)C
Reactant: CC(O)C#N
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CC(C)N(C(C)C)C(C)C#N
Temperature: 51 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
Anhydrous magnesium sulfate (12.04 g, 0.1 mol) was added to diisopropylamine (12.14 g, 0.12 mol), followed by lactonitrile (7.73 g of 92% aqueous solution, 0.1 mol) added all at once with stirring. The reaction mixture spontaneously warmed up to 51° C. It was left overnight at room temperature. Diethyl ether (50 ml) was added, and magnesium sulfate was filtered off and washed with ether (50 ml). The product was isolated by distillation, 11.57 g, 75% yield, bp 49°-50° C./0.1 mm Hg. 1H NMR CDCl3 δ ppm, 1.02 (d, J=6.5 Hz, 6H, CH3), 1.17 (d, J=6.5 Hz, 6H, CH3), 1.41 (d, J=6.5 Hz, 3H, CH3, 3.21 (sep, J=6.5 Hz, 2H,=CH) , 3.89 (q, J=6.5 Hz, 1H, CH) .
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:22])[C:10](=[O:21])[NH:11][C:12]=2[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[C:7]1=[O:23].Br[CH2:29][C:30]#[N:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:22])[C:10](=[O:21])[N:11]([CH2:29][C:30]#[N:31])[C:12]=2[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[C:7]1=[O:23]
Reactant: N#CCBr
Reactant: CN(C)C(=O)c1[nH]c(=O)c(O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Product: CN(C)C(=O)c1c2c(c(O)c(=O)n1CC#N)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2

Procedure:
The title compound was prepared in a manner similar to that described for 6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide (Example 13, step 6), wherein bromoacetonitrile was employed in place of 2-iodopropane.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[N+:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)([O-:27])=[O:26]>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:9]=[C:4]([C:3]([OH:2])=[O:24])[C:5]([C:31]4[CH:32]=[CH:33][C:28]([N+:25]([O-:27])=[O:26])=[CH:29][CH:30]=4)=[CH:6][CH:7]=3)[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc([N+](=O)[O-])cc1
Yield: 18 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 4-nitrophenylboronic acid (available from Combi-Blocks Inc.; 67 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-nitro-biphenyl-2-carboxylic acid (17 mg, 18%). 1H NMR (400 MHz, DMSO-d6) δ 13.35 (br s, 3H), 8.50 (s, 1H) 8.47 (s, 1H), 8.34 (s, 1H), 8.27-8.32 (m, 2H), 8.10 (d, J=8.5 Hz, 1H), 7.77 (d, J=6.8 Hz, 1H), 7.68 (d, J=7.0 Hz, 2H), 7.61 (d, J=6.5 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[CH3:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>COCCOC>[CH:22]([N:12]([C:10](=[O:11])[CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:36]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:31])[CH:37]=1)[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:24])[CH3:23]
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Reactant: Cc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cccc(-c2ccccc2CCC(=O)N(NC(=O)c2ccccc2)C(C)C)c1
Yield: 92.2 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (50 mg, 0.13 mmol) in DME (4 ml)/2M Na2CO3 (225 μL, 0.45 mmol) was treated with 3-methyl-phenylboronic acid (26 mg, 0.19 mmol) and Pd[PPh3]4 (15 mg, 0.013 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product as a solid (48 mg, 93%). LC-MS m/e 401.37 (M+H+)
Reaction SMILES: C(OC([NH:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=[O:22])[NH:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)[CH:11]=1)=O)(C)(C)C.Cl.C(OCC)(=O)C.N>C(OCC)(=O)C>[CH:19]1([CH2:18][NH:17][C:16]([C:12]2[CH:11]=[C:10]([NH:9][NH2:8])[CH:15]=[CH:14][CH:13]=2)=[O:22])[CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)NNc1cccc(C(=O)NCC2CC2)c1
Agent: Cl
Agent: N
Solvent: CCOC(C)=O
Product: NNc1cccc(C(=O)NCC2CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
In 5 ml of ethyl acetate, 1.92 g of 1-tert-butoxycarbonyl-2-[3-(N-cyclopropylmethylcarbamoyl)phenyl]hydrazine was dissolved and about 12 ml of 2N hydrochloric acid/ethyl acetate solution was added to the solution. The resulting suspension was stirred at room temperature for 4 hours. To the reaction mixture, 15 ml of aqueous 2N ammonia solution was added and the resultant was extracted with 20 ml of ethyl acetate. The extract was dried and concentrated to obtain 1.28 g of crude crystals. The crude crystals were recrystallized from ethyl acetate-hexane to obtain 1.20 g (yield 93%) of the captioned compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([CH:19]=O)[CH:15]=[CH:14][C:13]=2[C:12]2[N:21]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[N:22]=[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:27][CH2:26]3)[C:11]=2[N:10]=1.Cl.[NH2:44][OH:45]>N1C=CC=CC=1.CCOC(C)=O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([CH:19]=[N:44][OH:45])[CH:15]=[CH:14][C:13]=2[C:12]2[N:21]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:41])([CH3:42])[CH3:40])[N:22]=[C:23]([NH:24][CH:25]3[CH2:26][CH2:27][N:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:29][CH2:30]3)[C:11]=2[N:10]=1
Reactant: C[Si](C)(C)CCOCn1nc(NC2CCN(S(C)(=O)=O)CC2)c2nc(-c3c(F)cccc3F)c3cc(C=O)ccc3c21
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1nc(NC2CCN(S(C)(=O)=O)CC2)c2nc(-c3c(F)cccc3F)c3cc(C=NO)ccc3c21
Temperature: 25 °C
Reaction time: 64 h
Yield: 85.1 %

Procedure:
A 100 ml round-bottomed flask equipped with a magnetic stirrer and with a septum having a top-mounted argon intake is charged with 211 mg of 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline-7-carbaldehyde in 8.5 ml of pyridine, 36 mg of hydroxylamine hydrochloride are added, and the mixture is stirred at RT for 64 h. It is concentrated under RP and the solid obtained is taken up in AcOEt, washed with a 1M aqueous solution of potassium phosphate and then with saturated aqueous NaCl solution, dried over MgSO4, filtered and concentrated under RP. Purification is carried out by flash chromatography on silica gel (20-45 μm), eluting with a mixture of DCM and AcOEt (75/25 by vol.), to give 184 mg of 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline-7-carbaldehyde oxime (yellow solid). MS (E/I): m/z=630 (M+); 1H NMR: 0.04 (s, 9H); 0.89 (m, 2H); 1.61 (m, 2H); 2.11 (m, 2H); 2.74 (m, 2H); 2.85 (s, 3H); 3.58 (m, 2H); 3.67 (m, 2H); 4.46 (m, 1H); 5.65 (s, 2H); 6.50 (d, J=8.3 Hz, 1H); 7.33 (broad t, J=8.1 Hz, 2H); 7.65 (m, 1H); 7.72 (broad s, 1H); 8.01 (dd, J=8.4, 17 Hz, 1H); 8.27 (s, 1H); 8.35 (d, J=8.4 Hz, 1H); 11.39 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH:2]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:15][CH:14]=2)[CH:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=C(O)c1ccc(-c2cccnc2)cc1
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)c1ccc(-c2cccnc2)cc1

Procedure:
In the same manner as in Referential Example 12, a reaction was conducted using 4-(3-pyridyl)benzoic acid and 1-tert-butoxycarbonyl-3-ethoxycarbonylpiperazine as starting materials, whereby the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:24][CH3:25])[C:5]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12].Br[CH:27]([CH3:42])[CH2:28][CH2:29][CH2:30][N:31]1[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]2[C:32]1=[O:41]>CCN(CC)CC>[CH3:25][O:24][C:4]1[C:5]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[C:6]2[C:11](=[C:2]([NH:1][CH:27]([CH3:42])[CH2:28][CH2:29][CH2:30][N:31]3[C:35](=[O:36])[C:34]4=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]4[C:32]3=[O:41])[CH:3]=1)[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12]
Reactant: CC(Br)CCCN1C(=O)c2ccccc2C1=O
Reactant: COc1cc(N)c2nccc(C)c2c1OCCCCCc1cccs1
Solvent: CCN(CC)CC
Product: COc1cc(NC(C)CCCN2C(=O)c3ccccc3C2=O)c2nccc(C)c2c1OCCCCCc1cccs1
Reaction time: 4 h

Procedure:
A stirred mixture of 8-amino-6-methoxy-4-methyl-5-[5-(2-thienyl) pentoxy] quinoline (4.00 g, 0.0108 mol) and 4-bromo-1-phthalimidopentane (BPP) (6.40 g, 0.0216 mol) was heated at 110°-115° C. while Et3N (4 ml) was slowly added during 25 min. After 4 h at 115°-120° C., more BPP (6.4 g, 0.0216 mol) and Et3N (2 ml during 10 min) were added and heating was continued for 4 h. A final batch of BPP (1.60 g, 0.0054 mol) and Et3N (1 ml during 5 min) were added and heating was continued for 2 h. On cooling, the mixture was extracted with Et2O (200 ml) leaving behind a gray residue. The extract was washed with H2O (2×75 ml), dried (Na2SO4) and concentrated to a black oil. The oil was dissolved in CHCl3 (12 ml), applied to a silica gel column and eluted with 5% EtOAc in hexane. After recovering the unreacted BPP, the eluting solvent was changed to 10% EtOAc in hexane. Product eluates were combined and concentrated to give 6-methoxy-4-methyl-8-(1-methyl-4-phthalimidobutylamino)-5-[5-(2-thienyl) pentoxy] quinoline as a thick orange-yellow oil, 5.57 g (87%). This material was used without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:13][C:12]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:8][N:7]=1)=O)C.CO.[CH2:39]([NH2:41])[CH3:40]>>[CH2:39]([NH:41][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([CH2:17][CH:18]([CH3:19])[CH3:20])[C:14]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:13][C:12]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:8][N:7]=1)=[O:3])[CH3:40]
Reactant: CCOC(=O)c1cc(-c2cc(CC(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Reactant: CCN
Solvent: CO
Product: CCNC(=O)c1cc(-c2cc(CC(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Temperature: 120 °C

Procedure:
5-(2,4-Bis-benzyloxy-5-isobutyl-phenyl)-isoxazole-3-carboxylic acid ethyl ester was dissolved in 2M ethylamine in methanol (10 eq) and heated in the Smith Synthesiser microwave at 120° C. for 600 seconds. The solution was concentrated in vacuo to give 5-(2,4-bis-benzyloxy-5-isobutyl-phenyl)-isoxazole-3-carboxylic acid ethylamide as a white solid which was used without additional purification.
Reaction SMILES: [CH3:1]N(N=O)C(N[N+]([O-])=O)=N.[OH-].[K+].C(OCC)C.[CH2:18]=[C:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]1[C:19]2([CH2:24][CH2:23][N:22]([C:25]3[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)[CH2:18]1
Reactant: CN(N=O)C(=N)N[N+](=O)[O-]
Reactant: C=C1CCN(c2ccc(C(=O)OCC)cc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)c1ccc(N2CCC3(CC2)CC3)cc1
Reaction time: 0.17 h

Procedure:
A mixture of methyl-3-nitro-1-nitrosoguanidine (1.18 g, 8.1 mmol), 40% KOH (3.4 mL), and diethyl ether (12 mL) at 0° C. was stirred for 10 minutes. The organic phase was added slowly to a −25° C. solution of Example 158C and Pd(OAc)2 (18 Mg, 0.11 mmol) in THF (8.8 mL). The mixture was stirred for 1 hour at −20° C. and concentrated. The concentrate was purified by flash column chromatography on silica gel with 9:1 hexanes/ethyl acetate to provide the desired product. MS (DCI) m/e 260 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][C:3]=1[Cl:10].Cl.[CH2:12]([O:14][C:15](=[O:18])[CH2:16][NH2:17])[CH3:13].C(=O)([O-])O.[Na+]>>[CH2:12]([O:14][C:15]([C:16]1[NH:17][C:2]2[C:3]([Cl:10])=[CH:4][N:5]=[CH:6][C:7]=2[C:8]=1[NH2:9])=[O:18])[CH3:13]
Reactant: N#Cc1cncc(Cl)c1Cl
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1[nH]c2c(Cl)cncc2c1N

Procedure:
A mixture of 4,5-dichloronicotinonitrile (3.0 g, 17.3 mmol), glycine ethyl ester hydrochloride (7.2 g, 52.0 mmol) and sodium hydrogen carbonate (9.06 g, 104 mmol) in IMS (50 ml) was heated at reflux for 16 hours. The cooled reaction mixture was then partitioned between ethyl acetate and water, the organic layer washed with water then brine, dried (MgSO4) filtered and concentrated in vacuo. The resultant residue was triturated in diethyl ether to give the title compound as a buff solid (3.58 g, 86%). 1H NMR (CDCl3) 8.80 (1H, s), 8.36 (1H, s), 4.97 (2H, s, br), 4.44 (2H, q, J=7.0 Hz), 1.44 (3H, t, J=7.0 Hz).
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: CCCCI
Solvent: O
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: [CH3:1][NH:2][C:3]([CH3:6])([CH3:5])[CH3:4].[CH2:7]1[CH2:13][S:10](=[O:12])(=[O:11])[O:9][CH2:8]1>CC(C)=O>[CH3:1][N:2]([CH2:8][CH2:7][CH2:13][S:10]([OH:12])(=[O:11])=[O:9])[C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: CNC(C)(C)C
Reactant: O=S1(=O)CCCO1
Solvent: CC(C)=O
Product: CN(CCCS(=O)(=O)O)C(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of N-methyl-tert-butylamine (2.0 g, 22.9 mmol) in acetone (25 mL) was slowly added 1,3-propane sultone (2.72 g, 21.8 mmol). The mixture was stirred at reflux for 3 h. The reaction mixture was cooled to room temperature. The solid material was collected by filtration, washed with acetone (2×25 mL). The crude product was suspended in 80% Acetone/EtOH. The suspension was stirred at reflux for 30 seconds. The solid product was collected by filtration, and dried in a vacuum oven (50° C.), to afford compound EN (2.9 g, 65%). 1H NMR (DMSO, 500 MHz) δ ppm 9.40 (s (broad), 1H), 3.45 (m, 1H), 2.85 (m, 1H), 2.59 (m, 5H), 1.99 (m, 2H), 1.28 (s, 9H). 13C NMR (DMSO, 125 MHz) δ ppm 63.23, 51.12, 49.73, 34.79, 25.50, 21.72. ES-MS 208 (M−1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[N:23]1[C:32]2[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[C:27]=2[CH:26]=[CH:25][CH:24]=1>>[F:18][C:17]1[C:12]2[N:13]([C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:28]4[CH:29]=[CH:30][CH:31]=[C:32]5[C:27]=4[CH:26]=[CH:25][CH:24]=[N:23]5)[CH:3]=3)=[CH:10][N:11]=2)[CH:14]=[CH:15][C:16]=1[C:19]([OH:22])([CH3:21])[CH3:20]
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: OB(O)c1cccc2ncccc12
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cccc5ncccc45)c3)cnc2c1F
Yield: 5 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and quinoline-5-boronic acid were coupled in the same way as in Example 30 to give 2-{8-fluoro-3-[4-fluoro-3-(quinolin-5-yl)phenyl]-imidazo[1,2-α]pyridin-7-yl}propan-2-ol as an off-white solid (7 mg, 5%): m/z (ES+) 416 [MH+].
Reaction SMILES: [N+](=[C:3]([C:17](=[O:28])[C@@H:18]([C@@H:20]1[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[NH:21]1)[CH3:19])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])=[N-]>ClCCCl.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[OH:26][C@@H:24]([C@H:23]1[C:22](=[O:27])[N:21]2[C@H:20]1[C@@H:18]([CH3:19])[C:17](=[O:28])[CH:3]2[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])[CH3:25]
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@@H]12

Procedure:
To a solution of 4-nitrobenzyl (4R)-2-diazo-4-[(2R,3S)-3-{(1R)-1-hydroxyethyl}-4-oxoazetidin-2-yl]-3-oxopentanoate (0.60 g) in 1,2-dichloroethane (15 ml) was added rhodium(II) acetate (2 mg) under reflux. The mixture was refluxed for 30 minutes under nitrogen atmosphere and concentrated under reduced pressure to give 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2carboxylate. The compound obtained above was dissolved in acetonitrile (15 ml) and N,N-diisopropyl-N-ethylamine (0.32 ml). Diphenyl phosphorochloridate (0.33 ml) was added thereto at -10°~-5° C. in a nitrogen stream, followed by stirring at the same temperature for 30 minutes. To the solution were added N,N-diisopropyl-N-ethylamine (0.32 ml) and a solution of a mixture of (2S,4S)-4-mercapto-2-(1-methyl-1H-tetrazol-5-yl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine and (2S, 4S)-4-mercapto-2-(2-methyl-2H-tetrazol-5-yl)-1-(4nitrobenzyloxycarbonyl)pyrrolidine (0.55 g) in acetonitrile (2 ml) successively at -20° C. The mixture was stirred at the same temperature for 30 minutes and at 0°-10° C. for 3 hours. The mixture was poured into ethyl acetate (150 ml) and water (100 ml). The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of acetone and dichloromethane (10:90,V/V) to give 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[(2S,4S)-2-{1(or 2)-methyl-1H(or 2H)-tetrazol-5-yl}-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]thio-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (isomer A) (0.32 g).