Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N:11][C:12]2[CH2:13][CH2:14][NH:15][C:16](=[O:19])[C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:22]I>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[N:11][C:12]2[CH2:13][CH2:14][N:15]([CH3:22])[C:16](=[O:19])[C:17]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: O=C1NCCc2ncc(OCc3ccccc3)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2ncc(OCc3ccccc3)cc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
3-(Benzyloxy)-7,8-dihydro-1,6-naphthyridin-5(6H)-one (10.0 mg, 0.04 mmol) was dissolved in DMF (0.5 mL). NaH (2.0 mg, 0.08 mmol) was added into the solution and stirred at room temperature. After 30 min, MeI (5.0 μL) was added into the mixture and allowed to stir for another hour. Reaction was then quenched with H2O (2.0 mL) and extracted with EtOAc (3.0 mL×3). The organic layers were combined and concentrated to afford pure product as a white solid (9.2 mg, 87%). LC-MS (M+H)=267.1.
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([N:12]2[CH2:15][CH:14]([OH:16])[CH2:13]2)=[O:11])[CH2:5][CH2:4]1)[CH3:2].F[C:18]1[CH:19]=[CH:20][C:21]([C:24]([OH:27])([CH3:26])[CH3:25])=[N:22][CH:23]=1>>[CH2:1]([N:3]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([N:12]2[CH2:15][CH:14]([O:16][C:18]3[CH:19]=[CH:20][C:21]([C:24]([OH:27])([CH3:26])[CH3:25])=[N:22][CH:23]=3)[CH2:13]2)=[O:11])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCCN(C(=O)N2CC(O)C2)CC1
Reactant: CC(C)(O)c1ccc(F)cn1
Product: CCN1CCCN(C(=O)N2CC(Oc3ccc(C(C)(C)O)nc3)C2)CC1

Procedure:
In a similar fashion (Route 20, GP I), 1-[(4-ethyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-ol (90 mg, 0.40 mmol) and 2-(5-fluoropyridin-2-yl)propan-2-ol (95 mg, 0.44 mmol) were used to give the title compound. Crude material (53 mg) after workup gave the title compound as colourless oil (35.6 mg) after purification by preparative HPLC.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=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](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33](O)=O>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=3)[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: O=C(O)c1ccccn1
Product: CON=C1C[C@@H](c2noc(-c3ccccn3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and 2-pyridinecarboxylic acid, the title compound was obtained in 82% purity by HPLC. MS(ESI+): m/z=440.2.
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5](=[O:24])[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH:10]=1)=[O:8])C.[OH-].[Na+]>CO.CC(O)=O.C(Cl)Cl>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[CH2:15][C:11]1[CH:10]=[C:9]([C:7](=[O:8])[CH2:6][C:5](=[O:24])[C:4]([OH:25])=[O:3])[CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)C(=O)CC(=O)c1cccc(Cc2ccc(F)cc2F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: O=C(O)C(=O)CC(=O)c1cccc(Cc2ccc(F)cc2F)c1

Procedure:
In a manner similar to example AIV-2-1, 4-[3-(2,4-difluoro-benzyl)-phenyl]-2,4-dioxo-butyric acid ethyl ester was formed and the crude material was hydrolyzed in a manner similar to example AIV-3-1 using 1N NaOH to afford L2 as a yellow solid. Rf=0.60 (6:6:94 MeOH/AcOH/CH2Cl2). 1H NMR (400 MHz, CDCl3) δ7.85 (m, 2H), 7.45 (m, 2H), 7.13 (m, 2H), 6.82 (m, 2H), 4.03 (s, 2H). mass spec (FAB, M+1) 319 m/e.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24]5=[N:34][NH:35][C:36]([N:37]6[CH2:42][CH2:41][O:40][CH2:39][CH2:38]6)=[C:23]5[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C>C(O)(C(F)(F)F)=O>[O:40]1[CH2:39][CH2:38][N:37]([C:36]2[NH:35][N:34]=[C:24]3[C:23]=2[CH2:22][CH2:21][C:20]2[N:19]=[C:18]([C:15]4[CH:14]=[CH:13][C:12]([C:8]5([NH2:7])[CH2:11][CH2:10][CH2:9]5)=[CH:17][CH:16]=4)[C:27]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][C:25]3=2)[CH2:42][CH2:41]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-c3n[nH]c(N5CCOCC5)c3CC4)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-c3n[nH]c(N5CCOCC5)c3CC4)cc2)CCC1
Reaction time: 0.01 h
Yield: 92.6 %

Procedure:
tert-butyl(1-(4-(3-morpholino-8-phenyl-4,5-dihydro-2H-pyrazolo[3,4-f]quinolin-7-yl)phenyl)cyclobutyl)carbamate (30 mg, 0.052 mmol) was dissolved in TFA (2 mL) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 mL) and concentrated to dryness under reduced pressure three times. The residue was then slurried in diethyl ether (2 mL) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and freeze-dried to give the desired product as an off-white solid (23 mg, 63% yield). 1H-NMR (500 MHz, CD3OD) δ 8.08 (1H, s), 7.49 (2H, d), 7.44 (2H, d), 7.29-7.33 (3H, m), 7.22-7.27 (2H, m), 3.86 (4H, t), 3.26 (2H, t), 3.22 (4H, t), 2.98 (2H, t), 2.73-2.82 (2H, m), 2.54-2.64 (2H, m), 2.19-2.30 (1H, m), 1.92-2.03 (1H, m). LCMS (Method A) RT=3.74 min, M+H+=478.23.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Br-:16].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C1COCC1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH2:14][Br:16])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: [Br-]
Reactant: CC(=O)c1ccc2c(c1)CCN2C(C)=O
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: CC(=O)N1CCc2cc(C(=O)CBr)ccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.9 %

Procedure:
To a suspension of 1,5-diacetylindoline (10.0 g, 49.2 mmol) in 90 mL of THF at rt was added pyridinium tribromide (16.52 g, 51.7 mmol, 1 equiv) as solids portionwise over a period of 10 min. When there was still about 1.5 g of pyridinium tribromide left, the mixture solidified. Added another 30 mL of THF to make the mixture stirrable again. The remaining 1.5 g tribromide was added in one portion. The mixture was stirred at rt (no exotherm as checked by a thermometer). After 1.5 h, LCMS showed conversion complete. The suspension was filtered. The cake was washed with THF (2×30 mL), and then water (2×50 mL). The wet cake was sucked under house vacuum at rt for 2 days to give 1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-2-bromoethanone (12.89 g) as light grey solids. LC-MS (ES) m/z=281.9, 283.9.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([CH3:11])=[O:10])[CH:3]=1.[CH2:12]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][C:21]=1[N+:28]([O-:30])=[O:29])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:19][C:20]1[CH:27]=[CH:26][C:23](/[CH:24]=[CH:11]/[C:9]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=2[OH:8])=[O:10])=[CH:22][C:21]=1[N+:28]([O-:30])=[O:29])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Reactant: CC(=O)c1cc(C)ccc1O
Product: Cc1ccc(O)c(C(=O)/C=C/c2ccc(OCc3ccccc3)c([N+](=O)[O-])c2)c1
Yield: 32.1 %

Procedure:
2-Hydroxy-5-methylacetophenone (200 mg, 1.33 mol) and 4-benzyloxy-3-nitrobenzaldehyde (350 mg, 1.36 mmol) were reacted according to the same procedure as Preparation 1 to give 170 mg (Yield 29%) of the title compound.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[N:12]1(C(OC(C)(C)C)=O)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].FC(F)(F)C(O)=O>ClCCl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[N:12]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[N:4][CH:3]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Brc1cncc2ccccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: c1ccc2c(N3CCNCC3)cncc2c1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
4.51 g (21.7 mmol) of 4-bromoisoquinoline, 4.65 g (25.0 mmol) of t-butyl piperazine-N-carboxylate, 0.1 g (0.11 mmol) of tris(dibenzylideneacetone)dipalladium, 0.11 g (0.18 mmol) of 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and 2.92 g (30.4 mmol) of sodium t-butoxide were together added to 50 ml of toluene and the mixture was stirred at 75° C. for 2 h. The reaction mixture was added to ice/sodium chloride and the latter mixture was extracted with ethyl acetate; the organic phase was dried over sodium sulfate and the solvent was removed on a rotary evaporator. The product crystallized out and was filtered off with suction and washed with pentane. This resulted in 5.5 g (81%) of the Boc-protected piperazine (m.p.: 111° C.). 5.2 g (16.6 mmol) of this substance were taken up in 17 ml of dichloromethane, after which 17 ml (0.22 mmol) of trifluoroacetic acid were slowly added at 0° C. The mixture was left to stir at 0° C. for 4 h and was then poured onto ice water and this latter mixture was extracted with dichloromethane. The aqueous phase was filtered, rendered alkaline and extracted with dichloromethane. After drying over sodium sulfate and to a large extent removing the solvent, dilution was carried out with diethyl ether, and the hydrochloride was precipitated with ethereal hydrochloric acid. This afforded 3.2 g (67%) of the product having a m.p. of 293-294° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[C:9]([O:13][C:14]([N:16]1[CH2:19][CH2:18][C@H:17]1[CH2:20]O)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1C(COC(/N=N\C(OCC2C=CC(Cl)=CC=2)=O)=O)=CC=C(Cl)C=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:9]([O:13][C:14]([N:16]1[CH2:19][CH2:18][C@H:17]1[CH2:20][O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Oc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CO
Agent: O=C(/N=N\C(=O)OCc1ccc(Cl)cc1)OCc1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Br)c1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-7, 5-bromopyridin-3-ol was reacted with (S)-2-hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester in presence of di-(4-chlorobenzyl)azodicarboxylate and triphenylphosphine to give the title compound as an amorphous colorless solid. MS: 343.1 and 345.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:29][CH3:30])=[C:16]([CH2:19][N:20]([CH3:28])[C:21]4([C:25]([NH2:27])=[O:26])[CH2:24][NH:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:41][O:42][CH2:43][CH2:44]Cl.[I-].[K+]>C(#N)C>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:29][CH3:30])=[C:16]([CH2:19][N:20]([CH3:28])[C:21]4([C:25]([NH2:27])=[O:26])[CH2:24][N:23]([CH2:44][CH2:43][O:42][CH3:41])[CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COCCCl
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CNC1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COCCN1CC(C(N)=O)(N(C)Cc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)C1
Yield: 36.1 %

Procedure:
A solution of the hydrochloride salt of 3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]azetidine-3-carboxamide (55 mg, 0.11 mmol Example 74), diisopropylethylamine (84 μl, 0.48 mmol), 2-chloroethyl methyl ether (29 μl, 0.32 mmol) and potassium iodide (18 mg, 0.11 mmol) in acetonitrile (0.5 ml) was heated in a microwave at 145° C. for 30 minutes. Purification of the crude product on preparative HPLC (standard basic condition) gave the title product (20 mg, 36%) as a white solid; 1H NMR Spectrum: (CDCl3) 2.41 (s, 3H), 2.76 (t, 2H), 3.34 (s, 3H), 3.36 (d, 2H), 3.44 (t, 2H), 3.66 (d, 2H), 3.96 (s, 3H), 4.00 (s, 2H), 5.38 (brs, 1H), 7.16 (m, 2H), 7.24 (s, 1H), 7.21 (s, 1H), 7.42 (brs, 1H), 7.87 (brs, 1H), 8.01 (s, 1H), 8.75 (m, 1H); Mass Spectrum: (M+H)+ 503.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][C@:10]2([CH2:12][O:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)[C@@H:8]([CH2:9]2)[N:7]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:5])C.[OH-].[K+]>CO.C1COCC1.O.CCOC(C)=O>[C:23]([O:22][C:20]([N:7]1[C@H:6]([C:4]([OH:5])=[O:3])[CH2:11][C@:10]2([CH2:12][O:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)[C@H:8]1[CH2:9]2)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CCOC(=O)[C@@H]1C[C@@]2(COC3CCCCO3)C[C@H]2N1C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@H](C(=O)O)C[C@@]2(COC3CCCCO3)C[C@@H]12
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
To a solution of (1R,3S,5S)-5-(tetrahydro-pyran-2-yloxymethyl)-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester 3-ethyl ester (510 mg, 1.38 mmol) in MeOH (2.3 mL), THF (2.3 mL) and water (2.3 mL) was added KOH (155 mg, 2.76 mmol). The reaction was stirred at 60° C. for 45 min. Then allowed to cool to RT and diluted with EtOAc. The layers were separated, the aqueous layer was acidified by addition of HCl (0.1N, until pH 1) and extracted with EtOAc (×2). The organics were dried (Na2SO4), filtered and concentrated. MS (UPLC/MS): 359.4 [M+NH4]+, 340.4 [M−H]−, 386.4 [M+HCOO]−, 681.5 [2M−H]−; tR (HPLC conditions f): 1.84 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10](=[O:18])[C:9]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[H-].[Na+].[CH3:26]I.O>CN(C)C=O>[CH3:26][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][N:13]=2)[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:10]1=[O:18]
Reactant: CI
Reactant: CCOC(=O)c1c(-c2ccccc2Cl)c2cccnc2[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccccc2Cl)c2cccnc2n(C)c1=O
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
To a solution of ethyl 4-(2-chlorophenyl)-1,2-dihydro-2-oxo-1,8-naphthyridine-3-carboxylate (4.50 g, 13.7 mmol) in N,N-dimethylformamide (50 ml) was added sodium hydride (60% oily, 547 mg, 13.7 mg) at room temperature, and the mixture was stirred for 0.5 hour. To the mixture was added methyl iodide (1.9 g, 13.7 mmol) at 0° C. to 5° C., and the mixture was stirred at the same temperature for 0.5 hour, and then stirred at room temperature for five hours. The mixture was poured into water, and extracted with ethyl acetate. The extract was washed with water, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (4.60 g, 13.4 mmol), which was used without further isolation in the subsequent reaction.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:12]([O-:14])=[O:13])[N:3]=1.[C:15]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:16]=1.C(C([Sn])=C(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[N+:12]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([CH:15]=[CH2:16])=[N:3]2)([O-:14])=[O:13]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Agent: CCCCC([Sn])=C(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=Cc1ccc2c([N+](=O)[O-])cccc2n1

Procedure:
5.06 g (24.5 mmol) of 2-chloro-5-nitroquinoline, 1.26 g (4.9 mmol) of triphenylphosphine and 8.0 g (25.2 mmol) of tri-n-butylvinyltin are dissolved in 60 ml of toluene. After adding 2.75 g (2.5 mmol) of tris(dibenzylidenacetone)dipalladium, the reaction mixture is allowed to reflux for 20 hours. Then, it is filtered on Celite and washed with ethyl acetate. The filtrate is mixed with saturated ammonium chloride solution. It is extracted with ethyl acetate, and the combined organic phases are dried on sodium sulfate. After the solvent is removed in a vacuum and after subsequent chromatography on silica gel with hexane-ethyl acetate (5–20%), 3.05 g (62% of theory) of the product is obtained.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:8][C:9](N)=[O:10]>O>[CH:1]1([NH:7][C:9]([NH2:8])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(N)=O
Reactant: NC1CCCCC1
Solvent: O
Product: NC(=O)NC1CCCCC1
Yield: 91.7 %

Procedure:
730 ml of mother liquor from Example 3, 50 ml of water, 495 g (5 mols) of cyclohexylamine and 312 g (5.2 mols) of urea are reacted and worked up as in Example 3. 652 g of N-cyclohexylurea (92% of theory) are obtained.
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[Si:12]([O:19][CH2:20][C:21]1[S:25][C:24]([NH2:26])=[N:23][CH:22]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>>[Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:26][C:24]2[S:25][C:21]([CH2:20][O:19][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:14])=[CH:22][N:23]=2)=[N:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cnc(N)s1
Reactant: Brc1ncc(Br)n2ccnc12
Product: CC(C)(C)[Si](C)(C)OCc1cnc(Nc2ncc(Br)n3ccnc23)s1

Procedure:
Prepared from Intermediate 2 and Intermediate 7 using the procedure described in Example 1, Step1. MS (MH+, m/z) 440.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[K+].[CH2:10](Br)[C:11]#[CH:12]>CN(C)C=O>[CH2:12]([O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[C:11]#[CH:10]
Reactant: C#CCBr
Reactant: Oc1cccnc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: C#CCOc1cccnc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 3-hydroxypyridine (5.0 g, 52 mmol) and potassium hydroxide (8.8 g, 158 mmol) in N,N-dimethylformamide (30 mL) was added propargyl bromide (7.5 g, 63 mmol) dropwise at about 5-10 C and the mixture was stirred at room temperature for about 15 min. The reaction was quenched by addition of water and the product was extracted with dichloromethane. The combined organic extracts were washed with water and then stirred with activated charcoal for 30 min. The mixture was filtered through Celite and the filtrate was concentrated under vacuum to provide Example 638. 1H NMR (300 MHz, CDCl3): δ 2.57 (t, J=3.0 Hz, 1H), 4.77 (d, J=3.0 Hz, 2H), 7.30 (m, 2H), 8.27 (dd, J=3.0, 7.6 Hz, 1H), 8.40 (d, J=3.0 Hz, 1H).
Reaction SMILES: [C:1]1([CH:7]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([NH:27]C(=O)C(F)(F)F)[CH2:23][CH2:22]3)=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@@H:34]2[O:38][C@H:37]([C:39]([NH:41][CH2:42][CH3:43])=[O:40])[C@@H:36]([OH:44])[C@H:35]2[OH:45])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.N>[NH2:27][CH:24]1[CH2:25][CH2:26][N:21]([C:19]([C:17]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[C@@H:34]3[O:38][C@H:37]([C:39]([NH:41][CH2:42][CH3:43])=[O:40])[C@@H:36]([OH:44])[C@H:35]3[OH:45])=[C:10]([NH:9][CH2:8][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[N:18]=2)=[O:20])[CH2:22][CH2:23]1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)N4CCC(NC(=O)C(F)(F)F)CC4)nc32)[C@H](O)[C@@H]1O
Agent: N
Solvent: CO
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)N4CCC(N)CC4)nc32)[C@H](O)[C@@H]1O
Yield: 101.7 %

Procedure:
A solution of (2S,3S,4R,5R)-5-[6-[(2,2-diphenylethyl)amino]-2-({4-[(trifluoroacetyl)amino]-1-piperidinyl}carbonyl)-9H-purin-9-yl]-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide (Preparation 40) (40 mg, 0.056 mmol) in methanol (1 ml) and concentrated aqueous ammonia solution (0.5 ml) was stirred at room temperature for 48 hours. Solvent was removed by evaporation under reduced pressure to give the target compound as a white solid, (35 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([C:18]2[NH:23][C:22](=[O:24])[C:21]([C:25]([O:27]C)=[O:26])=[C:20]([OH:29])[C:19]=2[CH2:30][CH3:31])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[I-].Cl>CCOC(C)=O>[CH2:1]([O:8][C:9]1[C:17]([C:18]2[NH:23][C:22](=[O:24])[C:21]([C:25]([OH:27])=[O:26])=[C:20]([OH:29])[C:19]=2[CH2:30][CH3:31])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1c(-c2ccc3c(ccn3C)c2OCc2ccccc2)[nH]c(=O)c(C(=O)OC)c1O
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: CCc1c(-c2ccc3c(ccn3C)c2OCc2ccccc2)[nH]c(=O)c(C(=O)O)c1O
Temperature: 60 °C
Yield: 93.5 %

Procedure:
To a solution of methyl 6-(4-(benzyloxy)-1-methyl-1H-indol-5-yl)-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate (0.0387 g, 0.09 mmol) in EtOAc (0.5 mL) was added LiI (0.0360 g, 0.27 mmol). The reaction mixture was stirred and heated at 60° C. for 1 h until complete consumption of starting material was observed. The mixture was then cooled to room temperature and acidified with aqueous HCl (1M, 1.0 mL) to pH˜2. The product was extracted with EtOAc (3×3 mL). The organic phase was dried over Na2SO4. Upon removal of the solvent 6-(4-(benzyloxy)-1-methyl-1H-indol-5-yl)-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid was obtained as a yellow foam (0.0352 g, 94%).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:16]=[N:17][NH:18][CH:19]=4)[C:11]=3[CH:20]=2)=[N:5][N:6]=1.[F:21][C:22]([F:32])([F:31])[C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Br>>[CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:19]=[N:18][N:17]([CH2:25][C:24]5[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=5[C:22]([F:21])([F:31])[F:32])[CH:16]=4)[C:11]=3[CH:20]=2)=[N:5][N:6]=1
Reactant: Cc1nnc(-c2ccc3occ(-c4cn[nH]c4)c3c2)o1
Reactant: FC(F)(F)c1ccccc1CBr
Product: Cc1nnc(-c2ccc3occ(-c4cnn(Cc5ccccc5C(F)(F)F)c4)c3c2)o1
Yield: 92 %

Procedure:
In the same manner as in Example 1 and using 2-methyl-5-[3-(1H-pyrazol-4-yl)-1-benzofuran-5-yl]-1,3,4-oxadiazole instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and using 2-(trifluoromethyl)benzyl bromide instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 92%) was obtained as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].O>O1CCCC1>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(S(C)(=O)=O)CC1
Reaction time: 1 h

Procedure:
A solution of piperidin-4-yl-carbamic acid tert-butyl ester (1.0 g, 5.0 mmol, Astratech, Inc.) and diisopropylethylamine (4 mL) in tetrahydrofuran (40 mL) was stirred at +5° C. To this was added methanesulfonyl chloride (1.0 g, 8.8 mmol) in a bolus. The reaction was brought to room temperature for 1 hour, poured into water and extracted into methylene chloride (2×50 mL). The combined organic extracts were washed with 5% aqueous sodium bicarbonate. The organic solution was dried (Na2SO4) and solvent was removed under vacuum to give a crude solid. Purification was by trituration with ether/hexane to give (1-methanesulfonyl-piperidin-4-yl)-carbamic acid tert-butyl ester as a white solid. Mass spectrum (ES) H+: 278 B) A suspension of (1-methanesulfonyl-piperidin-4-yl)-carbamic acid tert-butyl ester (1.14 g, 4.1 mmol, from Example 162, Step A) in methylene chloride (15 mL) was treated at room temperature with trifluoroacetic acid (5.3 mL). After stirring for 2 hours, all solvent was removed and the residue was triturated with ether. This was filtered, washed with ether and dried in vacuum to give 1.20 g of 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoro-acetic acid (100% yield). HRMS, observed: 177.0692; Calcd for M+: 177.0698