Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[CH:12]=[CH2:13].CN(C1CCCCC1)C1CCCCC1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>O1CCOCC1>[CH3:10][C:4]1[CH:3]=[C:2]([CH:13]=[CH:12][C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: Cc1cc(Br)ccc1C#N
Reactant: C=CC(=O)OC(C)(C)C
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: Cc1cc(C=CC(=O)OC(C)(C)C)ccc1C#N
Temperature: 70 °C
Yield: 80.6 %

Procedure:
A solution of 10.0 g (51.0 mmol) of 4-bromo-2-methylbenzonitrile in 80 mL of 1,4-dioxane was treated with 7.19 g (56.1 mmol) of tert-butyl acrylate, 10.96 g (56.1 mol) of N-methyldicyclohexylamine, 228 mg (0.76 mol) of 2-(di-tert-butylphosphino) biphenyl, and 396 mg (0.38 mol) of tris(dibenzylideneacetone)dipalladium(0)-chloroforin adduct. The resulting mixture was heated at 70° C. for 16 h and cooled to rt. The reaction mixture was filtered though a filter paper, and the filtrate was concentrated. The crude product was partitioned into four portions. Chromatography on four Biotage 40M cartridges using 19:1 v/v hexanes/EtOAc as the eluant followed by pooling of product fractions afforded 10.0 g of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.55 (s, 9H), 2.58 (s, 3H), 6.44 (d, J=16.0, 1H), 7.41 (d, J=8.0, 1H), 7.45 (s, 1H), 7.53 (d, J=16.0, 1H), 7.61 (d, J=8.0, 1H).
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.C[C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.[CH3:16][CH:17]=C(C)C>C1CCCCC1>[C:11]1(=[O:12])[C:10]2[C:14](=[CH:15][CH:7]=[CH:8][CH:9]=2)[CH2:17][CH2:16]1
Reactant: CC=C(C)C
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: C1CCCCC1
Product: O=C1CCc2ccccc21
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
100 g Tin (IV) chloride is added at 10° C. to a solution of 79 g p-methyl benzoyl chloride and 40 g trimethyl ethene in 100 ml cyclohexane. The reaction mixture is then stirred at 10° C. during 30 min., subsequently poured out into ice and extracted with ether. The solution in ether is washed neutral, dried and evaporated. The residue is added to a solution of 72 g AlCl3 in 200 ml nitropropane, in the course of which the temperature is kept at 25°-30° C. Then the reaction mixture is stirred during five hours at 20° C. After that it is poured out into ice and extracted with ether. The solution in ether is washed neutral, dried and evaporated. The residue is distilled under diminished pressure yielding 45.4 g of the desire indanone. B.p. 95° C./1 mm Hg.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][N:9]=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([NH:24][CH:25]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH2:26][C:27]([O:29]CC)=[O:28])=[O:23])=[CH:13][CH:12]=1.[Li+].[OH-].Cl>CO>[NH2:8][N:9]=[CH:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([NH:24][CH:25]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH2:26][C:27]([OH:29])=[O:28])=[O:23])=[CH:15][CH:16]=1
Reactant: CCOC(=O)CC(NC(=O)NCCCCc1ccc(C=NN)cc1)c1cccnc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: NN=Cc1ccc(CCCCNC(=O)NC(CC(=O)O)c2cccnc2)cc1
Reaction time: 0.5 h
Yield: 9.1 %

Procedure:
ethyl β-[[[[4-[4-(aminoiminomethyl)phenyl]butyl]amino]carbonyl]amino]-3-pyridinepropanoate TFA (100 mg; 2 mmol), methanol (5ml), and 2N LiOH (5 ml) were stirred for 30 min. The solution was acidified to pH=3 with 3N HCl and reduced to dryness on a rotary evaporator. The residue was dissolved in acetonitrile/water and purified by HPLC on a C-18 HPLC column (30 cm×5 cm). A gradient of 10 to 40% acetonitrile/water/ 0.05% TFA in 30 min. was used and the acid eluted at an acetonitrile concentration of 15%. Fractions containing the desired peak were lyophilized to give 70 mg of white solid.
Reaction SMILES: CC1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1.[CH2:51]([O:58][CH:59]([CH3:68])[CH2:60][CH2:61][C:62]1[C:63](=[O:67])[CH2:64][CH2:65][CH:66]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.CCCCC>C(OCC)C>[CH2:51]([O:58][CH:59]([CH3:68])[CH2:60][CH2:61][CH:62]1[CH2:66][CH2:65][CH2:64][C:63]1=[O:67])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: CC(CCC1=CCCC1=O)OCc1ccccc1
Agent: Cc1ccc(P(c2ccc(C)cc2)c2ccc3ccccc3c2-c2c(P(c3ccc(C)cc3)c3ccc(C)cc3)ccc3ccccc23)cc1
Solvent: CCCCC
Solvent: CCOCC
Product: CC(CCC1CCCC1=O)OCc1ccccc1
Yield: 94 %

Procedure:
General procedure B using (S)-p-tol-BINAP and 3-benzyloxybutyl-cyclopent-2-enone (0.146 g, 0.6 mmol) gave, after 30 h at 0° C. and flash chromatography (1:2 pentane:diethyl ether), the title compound as a clear oil (0.139 g, 94% yield). 1H NMR (300 MHz, CDCl3): δ 7.37-7.23 (m, 5H), 4.50 (s, 2H), 3.47 (t, J=6.3 Hz, 2H), 2.43-2.04 (m, 5H), 1.78 (ddd, J=18.0, 9.6, 1.2 Hz, 1H), 1.70-1.56 (m, 2H), 1.56-1.34 (m, 5H). 13C NMR (75 MHz, CDCl3): δ 219.8, 138.6, 128.4, 127.7, 127.6, 73.1, 70.3, 45.4, 38.7, 37.4, 35.7, 30.0, 29.7, 24.8. IR (neat): 2934, 2860, 1741, 1455, 1405, 1363, 1158, 1100, 737, 699 cm−1. HRMS m/z calcd for C16H22O2 246.1620, obsd 246.1615. [α]D25° C.−89° (c 1.4, CHCl3). Chiral HPLC analysis (Chiracel OD column) indicated that the title compound was obtained in 94% ee.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[N:21]=[C:20]([C:22]5[CH:23]=[N:24][C:25]([O:29]C)=[C:26]([CH3:28])[CH:27]=5)[C:19]([CH3:31])=[CH:18][CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.I[Si](C)(C)C>C(#N)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([CH3:31])=[C:20]([C:22]5[CH:27]=[C:26]([CH3:28])[C:25](=[O:29])[NH:24][CH:23]=5)[N:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: COc1ncc(-c2nc(NC(=O)C3(c4ccc5c(c4)CCO5)CC3)ccc2C)cc1C
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc1-c1c[nH]c(=O)c(C)c1
Yield: 76.8 %

Procedure:
To 1-(2,3-dihydrobenzofuran-5-yl)-N-(6′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (98 mg, 0.24 mmol) in acetonitrile (4 mL) at 50° C. was added iodotrimethylsilane (95 mg, 0.5 mmol). The reaction was heated for one hour before being quenched with methanol (1 mL). The reaction was diluted with dichloromethane (15 mL) and washed with an aqueous saturated sodium bisulfite solution (2×15 mL). The organics were dried over sodium sulfate and evaporated to dryness. The resulting white solid was purified by silica gel chromatography (eluting with 0-10% methanol in ethyl acetate) to yield the product (74 mg, 76%) as a white solid. ESI-MS m/z calc. 401.46. found 402.5 (M+1)+. Retention time 1.47 minutes.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=[O:8].[CH2:10](O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:26])[CH3:27])=[O:8]
Reactant: O=C(O)c1ccccn1
Reactant: CC(C)CCCCCCCCCCCCCCCO
Product: CC(C)CCCCCCCCCCCCCCCOC(=O)c1ccccn1

Procedure:
Isooctadecyl picolinate was prepared using the method of Example 7 from picolinic acid and isooctadecyl alcohol, the commercial material obtained from Farbwerke Hoechst AG and described in Example 8. The light brown, oily product of the reaction had an estimated purity of 93.5%.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].F[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.O>CN(C=O)C.CCCCCC.CCOC(C)=O>[C:1]1([S:7][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=Cc1ccc(Sc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.7 %

Procedure:
Benzenethiol (500 mg, 4.537 mmol) was dissolved in 6 mL of DMF. K2CO3 (940 mg, 6.81 mmol) was then added and the resulting mixture was allowed to stir at room temperature for 10 minutes. 4-Fluorobenzaldehyde (675 mg, 5.4 mmol) was then added and the resulting mixture was allowed to stir at 50° C. for 2 hours. The mixture was then stirred at 80° C. for 3 hours. Water was then added and the product was extracted with EtOAc and washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford a crude product. Purification by column chromatography (using 60-120 mesh silica gel and 5:95: EtOAc:Hexane as the eluent) afforded 940 mg (96% yield) of 4-phenylsulfanyl-benzaldehyde. LC-MS purity: 91.3
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][CH2:7][N:8]1[N:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([C:18](=[O:32])[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[CH:21][C:20]=2[N+:29]([O-])=O)=[N:9]1)=[O:5])[CH3:2].[H][H]>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[NH2:29][C:20]1[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:19]=1[C:18]([C:10]1[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:12][N:8]([CH2:7][O:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:9]=1)=[O:32]
Reactant: CCOC(=O)OCn1nc(C(=O)OCC)c(C(=O)c2cc(OC)c(OC)cc2[N+](=O)[O-])n1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCOC(=O)OCn1nc(C(=O)OCC)c(C(=O)c2cc(OC)c(OC)cc2N)n1
Yield: 95.2 %

Procedure:
Ethyl 2-(ethoxycarbonyloxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (45 mg) prepared in step (3a) was dissolved in ethyl acetate (1 ml). Palladium hydroxide (15 mg) was added to the solution. The mixture was stirred in a hydrogen atmosphere at room temperature for 15 hr. The reaction solution was filtered through Celite. The filtrate was concentrated under reduced pressure to give ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(ethoxycarbonyloxymethyl)-2H-1,2,3-triazole-4-carboxylate as a yellow oil (40 mg, 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=[CH:5][C:4]=1[C:18]1[N:23]=[N:22][C:21]([N:24]([CH3:35])[CH:25]2[CH2:30][C:29]([CH3:32])([CH3:31])[NH:28][C:27]([CH3:34])([CH3:33])[CH2:26]2)=[CH:20][CH:19]=1.Br[C:37]1[N:41]2[CH2:42][CH2:43][NH:44][CH2:45][C:40]2=[N:39][CH:38]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.CCO>[N:39]1[CH:38]=[C:37]([C:7]2[CH:6]=[CH:5][C:4]([C:18]3[N:23]=[N:22][C:21]([N:24]([CH3:35])[CH:25]4[CH2:30][C:29]([CH3:32])([CH3:31])[NH:28][C:27]([CH3:33])([CH3:34])[CH2:26]4)=[CH:20][CH:19]=3)=[C:3]([O:2][CH3:1])[CH:8]=2)[N:41]2[CH:42]=[CH:43][N:44]=[CH:45][C:40]=12
Reactant: Brc1cnc2n1CCNC2
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: COc1cc(-c2cnc3cnccn23)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Temperature: 150 °C
Yield: 103.9 %

Procedure:
To a microwave vial was added 6-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (Intermediate 9-3, 50 mg, 0.1 mmol), 3-bromo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (49.6 mg, 0.21 mmol), Na2CO3 (44 mg, 0.42 mmol), and Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), followed by DME (1 mL)/EtOH 0.25 mL)/(H2O (0.25 mL). The vial was purged with N2 for 10 minutes and the reaction mixture was heated at 150° C. in a microwave reactor for 20 min. The reaction mixture was filtered through celite and the filter cake was washed with EtOAc. The filtrate was concentrated in vacuo to give the crude product which was purified by silica gel chromotography (5%-15% MeOH/DCM) to afford 6-(4-(imidazo[1,2-a]pyrazin-3-yl)-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (49 mg). MS: 476.5 [M+H+]).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:10]1([CH2:16][CH2:17][CH2:18][Mg]Br)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[Br:1][C:2]1[C:7]([CH:8]([OH:9])[CH2:18][CH2:17][CH2:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Br[Mg]CCCc1ccccc1
Reactant: O=Cc1cccnc1Br
Solvent: C1CCOC1
Product: OC(CCCc1ccccc1)c1cccnc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Bromo-pyridine-3-carbaldehyde (1.25 g, 6.72 mmol) was dissolved in THF (10 mL) and cooled to 0° C. 3-phenyl-propyl magnesium bromide (0.5 M in THF, 20.2 mL, 10.08 mmol) was slowly added and the reaction stirred at 0° C. for 1 hour and then at room temperature for 30 minutes. The reaction was monitored by TLC and when complete was quenched with 10 mL of NH4Cl (sat'd, aq.). The volume of THF was reduced and the reaction was submitted to EtOAc/H2O workup. The crude material was purified on silica gel (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[H-].[Na+].[CH3:17][Si:18]([CH2:21][CH2:22][O:23][CH2:24]Cl)([CH3:20])[CH3:19]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:24][O:23][CH2:22][CH2:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cnn(COCC[Si](C)(C)C)c2)OC1(C)C
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 61.7 %

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (348 mg, 1.8 mmol) was dissolved in DMF (5 mL) and sodium hydride (60% dispersion, 86 mg, 2.15 mmol) added and the mixture heated to 60° C. for 5 min. Upon cooling and stirring for an additional 15 min, trimethylsilylethoxymethyl chloride (358 mg, 2.15 mmol, 381 μL) was added dropwise over 5 min and mixture stirred for 16 h. The reaction mixture was diluted with ethyl acetate (25 mL), washed with 5% lithium chloride (5×), dried over sodium sulfate and concentrated. The residue was purified by column chromatography (40 g ISCO column eluting with hexanes and ethyl acetate; gradient 100% hexanes to 50% hexanes over 30 min at 30 mL/min) to provide the SEM-protected pyrazole (360 mg, 61%) as a colorless oil; 1H NMR (500 MHz, CDCl3) δ 7.84 (s, 1H), 7.80 (s, 1H), 5.42 (s, 2H), 3.56-3.53 (t, J=8.3 Hz, 2H), 1.31 (s, 12H), 0.91-0.87 (t, J=8.3 Hz, 2H), −0.03 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[C:22]([CH3:24])[C:21]([C:25]2NC(CC3CCOC3)=N[N:26]=2)=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[NH:36]([C:38](=O)[C:39]([N:41]([CH3:43])[CH3:42])=[O:40])[NH2:37].O1CCC(CC(NN)=O)C1>>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([CH:9]2[CH2:10][CH2:11][N:6]([C:4]([C:3]3[C:2]([CH3:1])=[CH:23][C:22]([CH3:24])=[C:21]([C:25]4[NH:26][C:38]([C:39]([N:41]([CH3:43])[CH3:42])=[O:40])=[N:36][N:37]=4)[CH:20]=3)=[O:5])[CH2:7][CH2:8]2)=[CH:13][CH:14]=1)#[N:17]
Reactant: CN(C)C(=O)C(=O)NN
Reactant: Cc1cc(C)c(-c2nnc(CC3CCOC3)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Agent: NNC(=O)CC1CCOC1
Product: Cc1cc(C)c(-c2nnc(C(=O)N(C)C)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of 4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 130), using 2-hydrazinyl-N,N-dimethyl-2-oxoacetamide (compound 135.1) instead of 2-(tetrahydrofuran-3-yl)acetohydrazide (compound 130.4). m/z (ES+) 457 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:60])([CH3:59])[C@H:3]([N:45]1[CH2:49][CH2:48][N:47]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([CH3:57])[N:52]=2)[C:46]1=[O:58])[C:4]([NH:6][C@@H:7]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@@H:8]([OH:37])[CH2:9][C@@H:10]([NH:26]C(=O)OCC1C=CC=CC=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[N:19]=2)=[CH:14][CH:13]=1)=[O:5].Cl>CO.[Pd]>[NH2:26][C@@H:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[N:19]=2)=[CH:14][CH:13]=1)[CH2:9][C@H:8]([OH:37])[C@@H:7]([NH:6][C:4](=[O:5])[C@@H:3]([N:45]1[CH2:49][CH2:48][N:47]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([CH3:57])[N:52]=2)[C:46]1=[O:58])[C:2]([CH3:1])([CH3:59])[CH3:60])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: COc1cccc(-c2ccc(C[C@@H](C[C@H](O)[C@H](Cc3ccccc3)NC(=O)[C@@H](N3CCN(Cc4cccc(C)n4)C3=O)C(C)(C)C)NC(=O)OCc3ccccc3)cc2)n1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1cccc(-c2ccc(C[C@H](N)C[C@H](O)[C@H](Cc3ccccc3)NC(=O)[C@@H](N3CCN(Cc4cccc(C)n4)C3=O)C(C)(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution containing the product from Example 113E (0.049 mmol) in methanol (1 mL) was treated with Pd on carbon (0.005 g, 10% Pd by wt.) and HCl solution (0.050 ML, 4N in dioxane), stirred under a hydrogen atmosphere (balloon pressure) at 25° C. for 16 hours, filtered through a bed of celite®, rinsed with methanol, and concentrated to give the title compound as the hydrochloride salt.
Reaction SMILES: [N:1]([C@:4]1([CH2:36][O:37]C(=O)C2C=CC=CC=2)[O:8][C@@:7]([CH3:17])([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[C@:6](C(=O)C2C=CC=CC=2)([OH:18])[C@:5]1(C(=O)C1C=CC=CC=1)[OH:27])=[N+:2]=[N-:3]>N>[N:1]([C@:4]1([CH2:36][OH:37])[O:8][C@@:7]([CH3:17])([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[C@H:6]([OH:18])[C@@H:5]1[OH:27])=[N+:2]=[N-:3]
Reactant: C[C@@]1(n2ccc(=O)[nH]c2=O)O[C@@](COC(=O)c2ccccc2)(N=[N+]=[N-])[C@](O)(C(=O)c2ccccc2)[C@]1(O)C(=O)c1ccccc1
Agent: N
Product: C[C@@]1(n2ccc(=O)[nH]c2=O)O[C@@](CO)(N=[N+]=[N-])[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 14 h
Yield: 46.2 %

Procedure:
4′-Azido-1′-methyl-2′,3′,5′-O-tribenzoyluridine (37-7) (0.20 g, 0.34 mmol) was dissolved in saturated methanolic ammonia (50 mL), and the mixture was stirred at R.T. for 14 hours. The solvent was removed, and the residue was purified on a silica gel column (DCM/MeOH=50:1 to 30:1) to give (54) as a white solid (47 mg, 46.0%). 1H NMR (CD3OD, 400 MHz) δ8.15 (d, J=8.4 Hz, 1H), 5.63 (d, J=8.4 Hz, 1H), 4.73 (d, J=5.6 Hz, 1H), 4.17 (d, J=5.2 Hz, 1H), 3.67 (d, J=12.0 Hz, 1H), 3.55 (d, J=12.0 Hz, 1H), 1.76 (s, 3H); ESI-negative-MS: m/z=298.1 [M−H]+, 597.2 [2M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:39]#[N:40])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][C@H:34]([O:36][CH3:37])[CH3:35])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:38])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:39]#[N:40])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][C@H:34]([O:36][CH3:37])[CH3:35])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:38])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(C[C@@H](C)OC)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(C[C@@H](C)OC)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
26 mg (0.05 mmol) of tert-butyl 4-({(4R)-2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxypentanoyl}amino)benzoate (enantiomerically pure diastereomer 1) were hydrolysed with TFA according to General Method 2. Yield: 11 mg (45% of theory)
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[CH3:18]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>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].O.CN(C)C=O>[CH3:18][C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1
Reactant: CB1OB(C)OB(C)O1
Reactant: Brc1ccc2ccc3cccc4ccc1c2c34
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc2ccc3cccc4ccc1c2c34
Temperature: 80 °C
Reaction time: 7 h
Yield: 81.7 %

Procedure:
A mixed solution of 7 g of 1-bromopyrene, 6 g of trimethylboroxin, 12 g of cesium carbonate, 2 g of PdCl2(dppf).CH2Cl2, 80 ml of dimethylformamide and 8 ml of distilled water was heated and stirred under a nitrogen gas stream at 80° C. for 7 hours. The solution was cooled to room temperature and 50 ml of water was poured into the solution, followed by filtration. The resulting solid was purified by silica gel column chromatography and then vacuum-dried to obtain 4.4 g of 1-methylpyrene.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N:10]2[C@@H:15]([CH3:16])[CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:12]([CH3:24])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:25][C:26]([CH3:29])([O-:28])[CH3:27].[K+].[Cl-].[NH4+]>C1COCC1>[C:26]([O:28][C:2]1[CH:3]=[C:4]([N:10]2[C@@H:15]([CH3:16])[CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:12]([CH3:24])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9])([CH3:29])([CH3:27])[CH3:25]
Reactant: C[C@@H]1CN(c2ccc(C#N)c(F)c2)[C@@H](C)CN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2ccc(C#N)c(OC(C)(C)C)c2)[C@@H](C)CN1C(=O)OC(C)(C)C
Yield: 30.6 %

Procedure:
Into 20 ml of THF was dissolved 3.12 g of tert-butyl (2R,5S)-4-(3-fluoro-4-cyanophenyl)-2,5-dimethylpiperazine-1-carboxylate, and then 1.40 g of potassium tert-butoxide was added thereto, followed by heating under refluxing overnight. A saturated ammonium chloride aqueous solution was added to the reaction solution, followed by extraction with chloroform. After the organic layer was dried over anhydrous sodium sulfate, the solvent was removed by evaporation to obtain 1.11 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[C:12]([CH2:13][N:14]3[C:22]4[C:17](=[C:18]([N+:23]([O-])=O)[CH:19]=[CH:20][CH:21]=4)[C:16]([CH:26]=[CH2:27])=[N:15]3)=[CH:11][CH:10]=[N:9]2)=[CH:5][CH:4]=1>CCO.C(Cl)Cl.[OH-].[OH-].[Pd+2]>[CH2:26]([C:16]1[C:17]2[C:18]([NH2:23])=[CH:19][CH:20]=[CH:21][C:22]=2[N:14]([CH2:13][C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:29][CH:28]=3)[N:9]=[CH:10][CH:11]=2)[N:15]=1)[CH3:27]
Reactant: C=Cc1nn(Cc2ccnn2Cc2ccc(OC)cc2)c2cccc([N+](=O)[O-])c12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: CCc1nn(Cc2ccnn2Cc2ccc(OC)cc2)c2cccc(N)c12
Reaction time: 3 h

Procedure:
To 1-((1-(4-methoxybenzyl)-1H-pyrazol-5-yl)methyl)-4-nitro-3-vinyl-1H-indazole (0.86 g, 2.2 mmol) in EtOH/DCM (20 mL/2 mL) was added palladium hydroxide on carbon (400 mg, 20% wt). The reaction mixture was purged with nitrogen and hydrogen three times each. The mixture was then stirred under hydrogen for 3 hours. The reaction mixture was filtered, washed with MeOH/DCM (10:1, 50 mL) and concentrated under reduced pressure to give the crude product 3-ethyl-1-((1-(4-methoxybenzyl)-1H-pyrazol-5-yl)methyl)-1H-indazol-4-amine. To imidazo[1,2-a]pyridine-3-carboxylic acid (0.43 g, 2.7 mmol) in DCE (5 mL) was added thionyl chloride (1.3 g, 11 mmol). The slurry was stirred for one hour. The reaction mixture was then concentrated under reduced pressure and dried under vacuum for 30 minutes. The resulting acid chloride was then resuspended in THF/DCE (5 mL/5 mL), to which the previously prepared 3-ethyl-1-((1-(4-methoxybenzyl)-1H-pyrazol-5-yl)methyl)-1H-indazol-4-amine was added. The reaction mixture was heated to 80° C. for three hours. The mixture was cooled to ambient temperature, diluted with DCM (20 mL), washed with saturated NaHCO3 aqueous solution (20 mL) and brine (10 mL), and then concentrated under reduced pressure. Silica gel chromatography (DCM/MeOH 10:1) provided the product (0.36 g).