Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].O.CO.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][C:18]2[C:26]3[C:21](=[CH:22][C:23]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:34][O:35][CH3:36])=[C:29]([O:37][CH3:38])[CH:28]=4)=[CH:24][CH:25]=3)[N:20](S(C3C(C)=CC(C)=CC=3C)(=O)=O)[N:19]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:6][O:7][C:8]1[CH:9]=[C:10](/[CH:16]=[CH:17]/[C:18]2[C:26]3[C:21](=[CH:22][C:23]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:34][O:35][CH3:36])=[C:29]([O:37][CH3:38])[CH:28]=4)=[CH:24][CH:25]=3)[NH:20][N:19]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COCOc1ccc(-c2ccc3c(C=Cc4ccc(OC)c(OC)c4)nn(S(=O)(=O)c4c(C)cc(C)cc4C)c3c2)cc1OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COCOc1ccc(-c2ccc3c(/C=C/c4ccc(OC)c(OC)c4)n[nH]c3c2)cc1OC
Temperature: 30 °C
Reaction time: 7 h

Procedure:
A 1M solution of KOH (1.0 g, 17.8 mmol) in 1:1 water/MeOH (18 mL total) was prepared under argon and was degassed by vacuum/purge cycles with argon (5 times). In a separate flask, 3-[2-(3,4-dimethoxy-phenyl)-vinyl]-6-(3-methoxy-4-methoxymethoxy-phenyl)-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole (289 mg, 0.461 mmol, 1.0 equiv) was dissolved in THF (8 mL) under argon. To this solution was added the above 1M KOH solution (10 mL, 1:1 water/MeOH). The reaction was warmed to 30° C. and was allowed to stir for 7 h. The reaction mix was neutralized by the addition of 20% citric acid (7 mL). The resulting mix was partitioned between ethyl acetate (150 mL) and water (100 mL). The organic material was separated, dried over sodium sulfate, decanted, and concentrated under reduced pressure to give cis and trans 3-[2-(3,4-dimethoxy-phenyl)-vinyl]-6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazole (used crude): Rfsm 0.46, p1 0.17, p2 0.23 (ethyl acetate-hexane 1:1); 1H NMR cis isomer (CDCl3) δ 7.55 (s, 1H), 7.3-7.1 (m, 6H), 7.02 (dd, 1H, J=1.9, 8.3 Hz), 6.85 (d, 1H, J=12.5 Hz), 6.78 (d, 1H, J=12.5 Hz), 6.74 (d, 1H, J=8.3 Hz), 5.21 (s, 2H), 3.88 (s, 3H), 3.70 (s, 3H), 3.43 (s, 3H), 3.42 (s, 3H). MS (ES) [m+H]/z Calc'd 447, found 447, [m−H]/z Calc'd 445, found 445.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:34])[NH:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=3)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:35]([O:37]C)=[O:36])#[N:2].O.[OH-].[Li+].O.Cl.O1CCOCC1>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:34])[NH:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][N:25]=3)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:35]([OH:37])=[O:36])#[N:2]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(C(F)(F)F)cn4)cc3)c(C#N)cc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cc2c(cc1Oc1ccc(C(=O)NCCc3ccc(C(F)(F)F)cn3)cc1)OCCC2C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.9 %

Procedure:
Methyl 6-cyano-7-(4-(2-(5-(trifluoromethyl)-pyridin-2-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylate (14.2 mg, 0.0270 mmol) was dissolved in THF (3 mL) and 1M solution of lithium hydroxide monohydrate in water (54.0 μl, 0.0540 mmol) was added. The mixture was stirred overnight at ambient temperature, then quenched with 4.0 M HCl solution in 1,4-dioxane (20.3 μl, 0.0811 mmol). The reaction mixture was purified on silica gel (MeOH in dichloromethane with 1% acetic acid gradient) to provide 5.1 mg of the title compound as a thin film (37%). MS (apci) m/z=509.7 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[C:20]1[C:24](=O)[CH2:23][CH2:22][C:21]=1[CH3:26]>[Pt](=O)=O.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[CH:20]1[CH2:24][CH2:23][CH2:22][CH:21]1[CH3:26]
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2=C(C)CCC2=O)c1
Agent: O=[Pt]=O
Solvent: CO
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2CCCC2C)c1
Reaction time: 8 h
Yield: 13.4 %

Procedure:
A screw-cap pressure tube was charged with 66.56B (0.31 g, 0.87 mmol), MeOH (10 mL), and platinum(IV) oxide (0.040 g, 0.17 mmol). The tube was purged three times with H2 at 45 psi and sealed, and the contents were stirred overnight. The mixture was diluted with EtOAc, filtered through silica gel (EtOAc), and concentrated. The crude product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford 69.33A (1:1 d.r.) (0.040 g) as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH:7]([N:11]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](Br)[N:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:8]([CH3:10])[CH3:9])[CH2:4][CH3:5])[CH3:2].[NH4+:27].[OH-]>O>[NH2:27][C:22]1[N:21]=[C:20]([CH2:19][N:11]([CH:7]([CH2:6][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH:8]([CH3:10])[CH3:9])[C:12](=[O:13])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:25]=[CH:24][CH:23]=1
Reactant: CCN(CC)CC(C(C)C)N(Cc1cccc(Br)n1)C(=O)OC(C)(C)C
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Product: CCN(CC)CC(C(C)C)N(Cc1cccc(N)n1)C(=O)OC(C)(C)C
Temperature: 90 °C

Procedure:
To a stirred solution of N-{1-[(diethylamino)-methyl]-2-methylpropyl}(tert-butoxy)-N-[(6-bromo(2-pyridyl))methyl]carboxamide (5 mg, 0.012 mmol) in IpOH (5 ML) in a sealed tube, was added NH4OH (28–30% 6 mL) followed by excess Cu. The resulting solution was heated under pressure at 90° C. for 24 h. The mixture was brought to RT, diluted with H2O (10 mL) and extracted with CHCl3 (3×20 mL) The organic layers were combined, dried over MgSO4, filtered and concentrated by rotary evaporation to afford the title compound as a green oil. No purification was required. EI-MS m/z 365 (M+H).
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5]1.C(N(CC)CC)C.[S:18](Cl)([CH3:21])(=[O:20])=[O:19]>>[CH3:21][S:18]([CH2:2][CH2:3][CH:4]1[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)OCC(CCO)O1
Solvent: CCN(CC)CC
Product: CC1(C)OCC(CCS(C)(=O)=O)O1
Temperature: -5 °C
Reaction time: 1.5 h

Procedure:
4-(2-Hydroxylethyl)-2,2-dimethyl-1,3-dioxolane (25 g, 170 mmol), triethylamine (55.9 mL, 400 mmol), and a stir bar were added to a 1000 mL round bottom flask. The flask was sealed and flushed with nitrogen. Anhydrous DCM (600 mL) was added, and the mixture cooled to approx −5° C. (ice and NaCl). Mesyl chloride (19.9 mL, 255 mmol, 1.5 eq) was added slowly via syringe over a 60 minute period, and the reaction stirred at −5° C. for a further 1.5 hours. At this point TLC showed that the starting material had been consumed. The solution was diluted with DCM (350 mL), divided into two (˜500 mL) portions, and each portion worked up as follows: the solution was transferred to a 1000-mL separating funnel and washed with saturated NaHCO3 (2×200 mL). The organic phase was then dried (MgSO4), filtered, and concentrated (rotovap). The crude product was purified by column chromatography. Final yield: 32.0 g, 84.1%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])=[N:6][CH:7]=1.Br[C:26]1C=C(C=C[CH:33]=1)C#N>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:19]=[CH:33][CH:26]=[C:22]([C:21]#[N:20])[CH:23]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])=[N:6][CH:7]=1
Reactant: N#Cc1cccc(Br)c1
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccc(F)cn2)n1
Product: Cc1ccc(Nc2cccc(C#N)c2)c(C(=O)Nc2ccc(F)cn2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (5-fluoro-pyridin-2-yl)-amide (example 8) in accordance with the general method of example 20 using 3-Bromobenzonitrile instead of 3-Bromo-4-methylpyridine to yield the final compound as a yellow crystalline solid, MS (ISP): m/e=348.0 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][O:11][N:12]2C(=O)C3=CC=CC=C3C2=O)[CH2:4][CH2:3]1.[ClH:23]>C(O)C>[ClH:23].[ClH:23].[ClH:23].[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][CH2:10][O:11][NH2:12])[CH2:6][CH2:7]1
Reactant: CN1CCN(CCCON2C(=O)c3ccccc3C2=O)CC1
Agent: Cl
Solvent: CCO
Product: CN1CCN(CCCON)CC1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
3-(4-Methyl-1-piperazinyl)propoxyamine trihydrochloride may be obtained in the following manner: a solution of N-[3-(4-methyl-1-piperazinyl)propoxy]phthalimide (5.7 g) in 6 N hydrochloric acid (30 cc) is heated to reflux for 3 hours. After 18 hours' stirring at a temperature in the region of 20° C., the suspension obtained is filtered and the filtrate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the region of 60° C. A crude product (6 g) is thereby obtained, which is resuspended in ethanol (30 cc). The crystals which appear are separated by filtration, washed 3 times with ethanol (45 cc in total) and then 3 times with ethyl ether (75 cc in total) and finally dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the region of 20° C. 3-(4-Methyl-1-piperazinyl)propoxyamine trihydrochloride (3.4 g) is thereby obtained in the form of cream-coloured crystals, m.p. 240° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.Br[C:13]1[C:18]([CH2:19][O:20][CH3:21])=[CH:17][CH:16]=[CH:15][N:14]=1>>[CH3:21][O:20][CH2:19][C:18]1[C:13]([N:4]2[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]([CH3:1])=[N:3]2)=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1c[nH]nc1C
Reactant: COCc1cccnc1Br
Product: CCOC(=O)c1cn(-c2ncccc2COC)nc1C
Yield: 83 %

Procedure:
This compound is prepared essentially as described in Preparation 12 by using ethyl 3-methyl-1H-pyrazole-4-carboxylate and 2-bromo-3-(methoxymethyl)pyridine in a 83% yield. MS (m/z): 276 (M+1).
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([CH2:25][O:26][CH2:27][CH3:28])[CH:22]=[N:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(O)C.CC(C)=O.Cl>[CH2:27]([O:26][CH2:25][C:23]1[CH:24]=[N:20][NH:21][CH:22]=1)[CH3:28]
Reactant: CCOCc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCO
Product: CCOCc1cn[nH]c1
Temperature: 80 °C
Yield: 44 %

Procedure:
1-trityl-4-ethoxymethylpyrazole (1.800 g, 4.88 mmol) was dissolved in a mixture of ethanol/acetone (15 ml/5 ml) and 30 mL of 2N HCl was added to the resulting solution. The mixture was heated at 80° C. for 2 h. After cooling to room temperature, the reaction mixture was filtered and washed with dichloromethane. The aqueous layer was basified with 2N NaOH and extracted with dichloromethane. The organic layers were combined, dried over MgSO4 and the solvent was evaporated under vacuum yielding compound 4-ethoxymethylpyrazole as a white oil. Yield: 44% (270 mg, 2.14 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2].[F:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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]>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:45]3[CH:44]=[CH:43][CH:42]=[C:41]([F:40])[CH:46]=3)[CH:25]=[C:26]([O:28][CH2:29][CH3:30])[CH:27]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2]
Reactant: OB(O)c1cccc(F)c1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(OCC)c2)c1CCC(=O)OCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCC)cc(-c3cccc(F)c3)c2)c1CCC(=O)OCC
Yield: 70.7 %

Procedure:
A similar procedure as described in Example 44, step 3 was used, starting from 4-[3-[6-(3-bromo-5-ethoxy-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (305 mg, 0.5 mmol), 3-fluoro-phenylboronic acid (142 mg, 1.0 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (55 mg, 0.075 mmol), and cesium carbonate (331 mg, 1.0 mmol) to obtain 4-[2-(2-ethoxycarbonyl-ethyl)-3-[6-(5-ethoxy-3′-fluoro-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid ethyl ester (220 mg, 70%) as a colorless viscous oil: ES(+)-HRMS m/e calcd for C37H47FO7 (M+Na)+ 645.3198. found 645.3198.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:15]([C:16](=O)/[CH:17]=[CH:18]/N(C)C)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+]([O-])([O-])=O.[C:35]([C:43]1[CH:44]=[C:45]([NH:49][C:50]([NH2:52])=[NH2+:51])[CH:46]=[CH:47][CH:48]=1)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+].CCOCC>CN(C)C=O.O>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:15]([C:16]4[CH:17]=[CH:18][N:52]=[C:50]([NH:49][C:45]5[CH:44]=[C:43]([C:35]([C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)=[O:42])[CH:48]=[CH:47][CH:46]=5)[N:51]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(-c2nn3c(NC4CCCC4)cccc3c2C(=O)/C=C/N(C)C)cc1
Reactant: NC(=[NH2+])Nc1cccc(C(=O)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: COc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(Nc3cccc(C(=O)c4ccccc4)c3)n2)cc1
Temperature: 140 °C
Yield: 62 %

Procedure:
To a solution of (2E)-1-[7-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (100 mg, 0.25 mmol) in N,N-dimethylformamide (5 mL) was added N-(3-benzoylphenyl)guanidinium nitrat (223 mg, 0.74 mmol) and potassium carbonate (102 mg, 0.74 mmol). The suspension was heated at 140° C. (bath temperature) for 18 hours. The mixture was cooled to room temperature, ether was added followed by water. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics were dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (4:1 to 2:1 hexanes-ethyl acetate) provided [3-({4-[7-(Cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}amino)phenyl](phenyl)methanone (90 mg, 76%) as a yellow solid. 1H NMR (CDCl3): δ 8.10 (d, 1 H), 8.04 (s, 1 H), 7.95 (d, 1 H), 7.81 (d, 2 H), 7.64 (d, 1 H), 7.57 (d, 2 H), 7.53-7.38 (m, 6 H), 7.22 (t, 1 H), 6.98 (d, 2 H), 6.53 (d, 1 H), 6.04-5.99 (m, 2 H); 4.00 (m, 1 H), 3.86 (s, 3 H), 2.12 (m, 2 H), 1.81-1.67 (m, 6 H); MS m/z 581 (M+1).
Reaction SMILES: [CH3:1][NH2:2].[C:3]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH:4]=[CH2:5].CCOC(C)=O.CO>CCO>[C:8]([O:7][C:3](=[O:6])[CH2:4][CH2:5][NH:2][CH3:1])([CH3:11])([CH3:10])[CH3:9]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CN
Solvent: CO
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCCC(=O)OC(C)(C)C

Procedure:
A 33% solution of methylamine in EtOH (62 ml) is cooled to 0°. A solution of tert-butyl acrylate (12.8 g) in EtOH (50 ml) is added dropwise over 2.5 hours. This mixture is allowed to reach room temperature over night. All volatiles are removed under reduced pressure and the residue chromatographed on silicagel using first EtOAc and then EtOAc/MeOH 1:1 as eluent. 7.81 g of a slightly yellow oil are obtained. TLC (silicagel, EtOAc/MeOH 1:1): rf 0.13.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:34][CH2:33][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:22][C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26]([OH:28])=[O:27])[C:12]2=[O:32])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(N=[C:42]=[N:43][CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46]C2)CCCCC1.C[C@H](O)CC>CN(C)C1C=CN=CC=1.ClCCl>[CH3:42][N:43]1[CH2:44][CH2:49][CH:48]([O:27][C:26]([C:25]2[CH:24]=[C:23]([CH:31]=[CH:30][CH:29]=2)[CH2:22][N:13]2[C:12](=[O:32])[C:11]3([CH2:33][CH2:34][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]3)[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14]2)=[O:28])[CH2:47][CH2:46]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(Cc1cccc(C(=O)O)c1)CN2c1ccccc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC[C@H](C)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN1CCC(OC(=O)c2cccc(CN3CN(c4ccccc4)C4(CCN(C(=O)OC(C)(C)C)CC4)C3=O)c2)CC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 55.5 %

Procedure:
To a solution of 3-((8-(tert-butoxycarbonyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid (0.15 g, 0.32 mmol), dicyclohexylcarbodiimide (0.079 g, 0.38 mmol) and 4-(dimethylamino)pyridine (0.005 g, 0.038 mmol) in dichloromethane (5 mL), was added (S)-2-butanol (0.037 g, 0.32 mmol). After stirring at room temperature for 60 hours, the reaction mixture was filtered, concentrated in vacuo and isolated by preparatory TLC (10% methanol/dichloromethane) to obtain the title compound (0.1 g, 56%); 1H NMR (DMSO-d6): δ 1.45 (s, 9H), 1.63-1.66 (m, 4H), 1.89 (br, 2H), 2.15-2.23 (m, 5H), 2.43-2.48 (m, 4H), 3.43 (br, 2H), 3.89 (br, 2H), 4.60-4.65 (m, 4H), 4.95-5.00 (m, 1H), 6.67 (d, 2H, J=8.4 Hz), 6.76 (t, 1H, J=7.6 Hz), 7.17 (t, 2H, J=8.4 Hz), 7.52-7.60 (m, 2H), 7.86-7.91 (m, 2H); MS for C32H42N4O5 m/z 563.06(M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([C:9]1[CH:14]=[C:13]([C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=3)[N:19]=2)[CH:12]=[CH:11][N:10]=1)[CH2:7][CH3:8].N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH2:6]([C:9]1[CH:14]=[C:13]([C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:21]=[CH:22][C:23]([NH:26][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:24][CH:25]=3)[N:19]=2)[CH:12]=[CH:11][N:10]=1)[CH2:7][CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: CCCc1cc(-c2nc(-c3ccc(N)cc3)cs2)ccn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCc1cc(-c2nc(-c3ccc(NS(C)(=O)=O)cc3)cs2)ccn1
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
In reaction (d) methanesulfonyl chloride (0.23 mL, 2.97 mmol) was added to a stirred solution of 16 (800 mg, 2.71 mmol) and pyridine (0.66 mL, 8.1 mmol) in CH2Cl2 (20 mL) at 0° C. After being stirred for 0.5 h, the mixture was poured into 2 M citric acid solution and extracted with EtOAc. The combined extracts were washed with saturated NaHCO3 solution and brine, dried over Na2SO4, and concentrated to produce N-(4-(2-(2-propylpyridin-4-yl)thiazol-4-yl)phenyl)methanesulfonamide 19 (880 mg, 87%) as a yellow foam.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH:21]=[CH:20][C:19]3[C:11]2=[N:12][CH:13]=[C:14]2[C:18]=3[N:17]([CH:22]3[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]3)[N:16]=[N:15]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br].[CH3:30][Mg].O>O1CCCC1>[C:1]1([S:7]([N:10]2[CH:21]=[CH:20][C:19]3[C:11]2=[N:12][CH:13]=[C:14]2[C:18]=3[N:17]([CH:22]3[CH2:23][CH2:24][C:25]([CH3:30])([OH:28])[CH2:26][CH2:27]3)[N:16]=[N:15]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Mg]
Reactant: O=C1CCC(n2nnc3cnc4c(ccn4S(=O)(=O)c4ccccc4)c32)CC1
Agent: [Br]
Solvent: C1CCOC1
Solvent: O
Product: CC1(O)CCC(n2nnc3cnc4c(ccn4S(=O)(=O)c4ccccc4)c32)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(6-Benzenesulfonyl-6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclohexanone (400 mg, 1.01 mmol) in anhydrous tetrahydrofuran (20 mL) was added dropwise methylmagnesium bromine (3 M in diethyl ether, 2.3 mL, 7.07 mmol), followed by stirring at 0° C. for 30 minutes under nitrogen. The reaction was warmed to room temperature and stirred for another 90 minutes. The resulting mixture was poured into water and extracted with ethyl acetate. The organic solution was used for the next step. LCMS (Method K, ESI): RT=1.318 min and 1.359, m+H=411.8.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:56])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33](=[O:49])[NH:34][C:35]3([C:39]([O:41]CC4C=CC=CC=4)=[O:40])[CH2:38][CH2:37][CH2:36]3)[N:28]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:56])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33](=[O:49])[NH:34][C:35]3([C:39]([OH:41])=[O:40])[CH2:38][CH2:37][CH2:36]3)[N:28]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)NC3(C(=O)OCc4ccccc4)CCC3)n(-c3ccccc3)n2)CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)NC3(C(=O)O)CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 24 h

Procedure:
To a solution of 4.7 g 4-[(S)-2-({5-[(1-Benzyloxycarbonyl-cyclobutylcarbamoyl)-methoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-4-tert-butoxycarbonyl-butyryl]-piperazine-1-carboxylic acid ethyl ester in 100 ml ethyl acetate were added under argon 0.5 g Pd/C (10%) and the suspension was stirred under an atmosphere of hydrogen (3 bar) for 24 h. The suspension was filtered over a plug of Celite® and washed with ethyl acetate. The crude product obtained after evaporation of the solvent was used in the subsequent reaction. Yield: 3.7 g
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[NH:7][CH:8]=[CH:9][C:2]=12.[F:10][C:11]1[C:16]([CH:17]=[O:18])=[C:15]([F:19])[CH:14]=[CH:13][C:12]=1[NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22].[OH-].[K+].[Cl-].[NH4+]>O.CO>[F:10][C:11]1[C:16]([CH:17]([OH:18])[C:9]2[C:2]3[C:3](=[N:4][CH:5]=[CH:6][N:1]=3)[NH:7][CH:8]=2)=[C:15]([F:19])[CH:14]=[CH:13][C:12]=1[NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22]
Reactant: c1cnc2[nH]ccc2n1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C=O)c1F
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(O)c2c[nH]c3nccnc23)c1F
Reaction time: 0.17 h
Yield: 50.4 %

Procedure:
To 5H-pyrrolo[2,3-b]pyrazine (3, 0.150 g, 1.26 mmol) and propane-1-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide (8, 0.388 g, 1.47 mmol), 2.2 mL of methanol was added. This suspension was allowed to stir for 10 minutes, followed by the addition of potassium hydroxide (0.230 g, 4.10 mmol). The reaction was allowed to stir at room temperature for 7 hours, then poured into 5 mL of water and 5 mL of saturated ammonium chloride and extracted with 5 mL of ethyl acetate. The organic layer was separated and concentrated under vacuum, and the resulting residue was purified by silica gel column chromatography eluting with a gradient of 10 to 100% ethyl acetate in hexanes. Appropriate fractions were combined and concentrated under vacuum to give the desired compound (9, 243 mg). MS (ESI)[(M-18)+H+]+=365.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([CH2:13][PH:14]([CH2:16][OH:17])=[O:15])([O:10][CH2:11][CH3:12])[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:18])[C:5]([CH2:13][PH:14]([CH2:16][O:17][S:20]([CH3:19])(=[O:22])=[O:21])=[O:15])([O:10][CH2:11][CH3:12])[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C(CC(C)C)(C[PH](=O)CO)OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CC(C)C)(C[PH](=O)COS(C)(=O)=O)OCC
Temperature: -20 °C
Reaction time: 2 h

Procedure:
2-(Ethoxy)(hydroxymethyl)phosphinoylmethyl-4-methylpentanoic acid ethyl ester (5 g) was dissolved in 20 mL of CH2Cl2 and cooled to -20° C. (in duplicate). Methanesulfonyl chloride (1.5 mL) and triethylamine (3.0 mL) were added to solution dropwise. After 15 minutes the bath was removed and the reaction left at room temperature for 31/2 hours. Each solution was then washed with 10 mL cold 2% HCl, 10 mL NaHCO3 (sat), 10 mL brine, dried with MgSO4, filtered and evaporated to yield 12.8 g (combined yield) of 2-(ethoxy)(methane-sulfonyloxymethyl)phosphinoylmethyl-4-methylpentanoic acid ethyl ester.