Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[C:25]([F:26])=[CH:24][C:23]([F:27])=[C:22]([NH2:28])[C:18]=3[C:19](=[O:21])[CH:20]=2)=[CH:11][C:10]=1[F:29])[CH2:5][CH2:6][CH2:7][Cl:8])(=O)C.Cl.O>O1CCOCC1>[NH2:28][C:22]1[C:18]2[C:19](=[O:21])[CH:20]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([NH:4][CH2:5][CH2:6][CH2:7][Cl:8])=[C:10]([F:29])[CH:11]=3)[O:16][C:17]=2[C:25]([F:26])=[CH:24][C:23]=1[F:27]
Reactant: CC(=O)N(CCCCl)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Nc1c(F)cc(F)c2oc(-c3ccc(NCCCCl)c(F)c3)cc(=O)c12
Reaction time: 3 h
Yield: 48.8 %

Procedure:
508 mg (1.20 mmol) of the resulting 2-[4-[N-acetyl-N-(3-chloropropyl)amino]-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one was dissolved in 30 ml of dioxane, 30 ml of concentrated hydrochloric acid was added and the mixture was stirred for 3 hours under heating at reflux. The reaction solution was cooled on ice and adjusted to pH 8 by addition of water thereto, and the precipitated crystals were collected by filtration. The crystals were purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give 224 mg (49%) of 5-amino-2-[4-(3-chloropropylamino)-3-fluorophenyl]-6,8-difluoro-4H-1-benzopyran-4-one.
Reaction SMILES: C[O-].[Na+:3].[SH:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]([OH:8])=[O:7].C[O-].Cl.[N:18]1[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=1>C(O)C>[C:9]1([CH:5]([S:4][CH2:24][C:21]2[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=2)[C:6]([O-:8])=[O:7])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Na+:3]
Reactant: ClCc1ccncc1
Reactant: O=C(O)C(S)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C([O-])C(SCc1ccncc1)c1ccccc1
Reaction time: 0.08 h
Yield: 99.9 %

Procedure:
Sodium methoxide (6.8 g., 0.124 mole) was dissolved in 150 ml. of ethanol and cooled to 0° C. A solution of alpha-mercaptophenylacetic acid (7.0 g., 0.042 moles) in 50 ml. of ethanol was added over a period of 5 minutes to the cold methoxide solution. After 5 minutes, a slurry of 4-picolylchloride hydrochloride (6.83 g., 0.042 moles) slurried in 50 ml. of ethanol was then added over 5 minutes. The reaction was removed from the ice bath and left to stir for approximately 60 hours. The reaction mixture was filtered and evaporated to yield sodium phenyl(4-picolylthio)acetate (11.8 g.; waxy solid; ir: 3.0, 6.1, 6.25, 7.3, 13.6μ) used directly in the next step.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[N:9]1[CH:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:11][CH:10]=1>CC#N>[CH2:17]([O:16][C:14]([C:12]1[NH:11][CH:10]=[N:9][C:13]=1[Br:8])=[O:15])[CH3:18].[N:9]1[CH:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:11][CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Agent: CCOC(=O)c1cnc[nH]1
Solvent: CC#N
Product: CCOC(=O)c1[nH]cnc1Br
Reaction time: 12 h

Procedure:
NBS (25 g, 140 mmol) is added to a stirred solution of ethyl 3H-imidazole-4-carboxylate (I-17) in 1.4 L of MeCN. The reaction mixture is stirred for 12 h in the dark, then is concentrated and purified by silica chromatography (0-70% EtOAc in heptane) to provide 17 g (65 mmol) of ethyl 3H-imidazole-4-carboxylate ethyl 4-bromo-1H-imidazole-5-carboxylate (I-18) as a white solid. This material is stirred with 11 g (78 mmol) of K2CO3 and 8.5 mL (71 mmol) of benzyl bromide in 200 mL of DMF for 12 h. The reaction is diluted with water and extracted with three times with EtOAc. Extracts are combined, washed with brine, dried over Na2SO4, filtered, concentrated and purified via silica chromatography (0-50% EtOAc in heptane) to provide 9.6 g (31 mmol) of ethyl 3-benzyl-5-bromo-imidazole-4-carboxylate (I-19) as a colorless oil that solidified upon standing.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.[CH2:11]=[O:12]>>[OH:12][CH2:11][C:3]1[N:2]([CH3:1])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=1
Reactant: Cn1cnc2ccccc21
Reactant: C=O
Product: Cn1c(CO)nc2ccccc21
Reaction time: 2 h
Yield: 43.5 %

Procedure:
A solution of 1-methylbenzimidazole (2.5 g, 19 mmol), (J. Chem. Soc. 1929, 2820-2828), and paraformaldehyde (2 g) was heated at 165° C. for 30 minutes. Further paraformaldehyde (1 g) was added and heating continued for 2 hours. The mixture was allowed to cool and was purified by column chromatography eluting with methylene chloride, followed by methylene chloride/methanol (95/5) to give 2-hydroxymethyl-1-methylbenzimidazole (1.34 g, 45%).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH3:17][N:18]=[C:19]=[O:20]>C(Cl)Cl>[Br:16][C:13]1[CH:12]=[C:3]2[C:2](=[CH:15][CH:14]=1)[NH:1][C:19](=[O:20])[N:18]([CH3:17])[C:4]2([OH:5])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1
Reactant: CN=C=O
Solvent: ClCCl
Product: CN1C(=O)Nc2ccc(Br)cc2C1(O)c1ccccc1
Yield: 91.6 %

Procedure:
A solution of 14.70 g (0.053 mole) of 2-amino-5-bromobenzophenone and 6.0 g (0.21 mole) of methyl isocyanate in 75 ml of methylene chloride was refluxed for two days and then cooled. The solid portion of the reaction mixture was collected on a filter and washed with methylene chloride to give 16.18 g (90% yield) of 6-bromo-3,4-dihydro-4-hydroxy-3-methyl-4-phenyl-2(1H)-quinazolinone as a white crystalline powder: mp 293°-294° (dec.).
Reaction SMILES: CS(O[CH2:6][C:7]1[C:11]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=3)[C:15](=[O:25])[O:14][N:13]=2)=[N:10][O:9][N:8]=1)(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C=O)C>[N:26]([CH2:6][C:7]1[C:11]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=3)[C:15](=[O:25])[O:14][N:13]=2)=[N:10][O:9][N:8]=1)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Reaction time: 3 h
Yield: 65.3 %

Procedure:
4-[4-(3-Chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-ylmethyl methanesulfonate (400 mg, 1.02 mmol) was dissolved in anhydrous DMF (10 mL) followed by addition of sodium azide (133 mg, 2.04 mmol). Reaction was stirred for 3 hrs. Consumption of starting material was monitored by TLC and HPLC. The reaction mixture was added to a mixture of (400 μL) bromine/water and stirred for 10 min. DCM was added and the layers were separated. The combined organics were dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (225 mg, 65%). MF═C11H5ClFN7O3; LCMS calculated for C11H6ClFN7O3(M+H)+: m/z=338.020.
Reaction SMILES: [Cl:1][C:2]([Cl:45])([Cl:44])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:43])[C@@H:14]([NH:35][C:36](OC(C)(C)C)=[O:37])[C@H:15]([O:17][Si:18]([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:16])[NH:8]1)=[O:6].FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(N(CC)C(C)C)(C)C.[C:67]([O:71][C:72]([NH:74][C@@H:75]([CH:79]([CH3:81])[CH3:80])C(O)=O)=[O:73])([CH3:70])([CH3:69])[CH3:68].C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>ClCCl.C(#N)C>[Cl:44][C:2]([Cl:1])([Cl:45])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:43])[C@@H:14]([NH:35][C:36](=[O:37])[C@@H:75]([NH:74][C:72]([O:71][C:67]([CH3:69])([CH3:68])[CH3:70])=[O:73])[CH:79]([CH3:81])[CH3:80])[C@H:15]([O:17][Si:18]([C:31]([CH3:34])([CH3:32])[CH3:33])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:16])[NH:8]1)=[O:6]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1)[C@@H](C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.7 %

Procedure:
(S)-1-[(2S,3R)-2-tert-Butoxycarbonylamino-3-(tert-butyl-diphenyl-silanyloxy)-butyryl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (1.95 g, 2.79 mmol) was dissolved in dichloromethane (10 mL), under an atmosphere of nitrogen and cooled using an ice bath before adding trimethylsilyl trifluoromethanesulfonate (379 μL, 4.19 mmol). The reaction mixture was stirred for 1 h before adding N,N-diisopropylethylamine (1.95 mL, 11.2 mmol) and removing all volatiles. The residue was redissolved, along with (S)-2-tert-butoxycarbonylamino-3-methyl-butyric acid (728 mg, 3.35 mmol) in anhydrous acetonitrile (10 mL). The solution was cooled using an ice bath, before adding 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (1.49 g, 3.91 mmol) and N,N-diisopropylethylamine (1.95 mL, 11.2 mmol). The reaction mixture was allowed to slowly warm to room temperature and left to stir overnight. The solvent was evaporated and the remaining residue was purified by silica gel chromatography using a stepwise gradient of iso-hexanes/ethyl acetate 1:0 to 1:1 to afford the title compound (1.02 g, 46%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.03 (d, J=6.9 Hz, 6H), 1.12 (d, J=6.3 Hz, 3H), 1.49 (s, 9H), 1.21-1.25 (m, 1H), 1.74-1.94 (m, 2H), 2.12-2.24 (m, 1H), 2.66-2.86 (m, 2H), 3.48 (d, J=11.1 Hz, 1H), 4.06-4.29 (m, 4H), 4.76 (ABq, Δδ=0.24, JAB=11.8 Hz, 2H), 5.16 (d, J=9.3 Hz, 1H), 5.25 (d, J=9.0 Hz, 1H), 6.72 (d, J=8.7 Hz, 1H), 7.34-7.47 (m, 6H), 7.57-7.65 (m, 2H), 7.66-7.74 (m, 2H). LCMS (m/z) 801.2 [M+H], Tr=4.31 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([OH:13])=O)=[C:4]2[CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:47][O:48][C:49]1[CH:65]=[CH:64][C:52]([CH2:53][NH:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([O:62][CH3:63])=[CH:58][CH:57]=2)=[CH:51][CH:50]=1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([N:54]([CH2:53][C:52]3[CH:51]=[CH:50][C:49]([O:48][CH3:47])=[CH:65][CH:64]=3)[CH2:55][C:56]3[CH:57]=[CH:58][C:59]([O:62][CH3:63])=[CH:60][CH:61]=3)=[O:13])=[C:4]2[CH:3]=1
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Reactant: O=C(O)c1cnn2ccc(Br)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)C(=O)c2cnn3ccc(Br)cc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid (I-25) (66 mg, 0.27 mmol) in DMF (3 mL) was added DIEA (0.14 mL) and HATU (0.10 g, 0.27 mmol). The reaction was stirred for 30 minutes at room temperature then bis(4-methoxybenzyl)amine (70 mg, 0.27 mmol) was added. Stirring was continued at room temperature for 12 hours. The reaction was diluted with EtOAc, washed with brine, dried over magnesium sulfate, filtered and reduced to dryness. The crude product was purified by flash column chromatography on silica with hexanes/EtOAc gradient as eluant to yield 5-bromo-N,N-bis(4-methoxybenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (I-26). 1H NMR (400 MHz, CDCl3) δ 8.50 (d, J=2.4 Hz, 1 H), 8.26 (dd, J=0.4, 7.2 Hz, 1 H), 7.88 (s, 1 H), 7.22 (d, J=8.0 Hz, 4 H), 7.00 (dd, J=2.0, 7.2 Hz, 1 H), 6.91 (d, J=8.4 Hz, 4 H), 4.67 (s, 4 H), 3.82 (s, 6 H). MS m/z 480.1, 482.1 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3([OH:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.[O-:31][C:32]#[N:33].[K+].Cl>C1COCC1.O.C([O-])(O)=O.[Na+]>[OH:30][C:24]1([C:22]2[S:23][C:19]([C:4]3[CH:5]=[C:6]([NH:8][C:9]4[N:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:11][N:10]=4)[CH:7]=[C:2]([CH3:1])[CH:3]=3)=[CH:20][N:21]=2)[CH2:25][CH2:26][N:27]([C:32]([NH2:33])=[O:31])[CH2:28][CH2:29]1
Reactant: N#C[O-]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCNCC3)s2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCN(C(N)=O)CC3)s2)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
To 15 mg (0.034 mmol) of 4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol-2-yl]piperidin-4-ol in THF/Water (3:1, 1 mL) was added 4.2 mg (0.052 mmol, 1.5 eq) of potassium cyanate and 2N hydrochloric acid (22 μL, 1.3 eq). The mixture was heated at 50° C. for 6 h and then another 1.5 eq of potassium cyanate and 1.5 eq HCl added and the mixture stirred at 50° C. overnight. The reaction was diluted with saturated aqueous NaHCO3 and was partitioned with ethyl acetate. The organic layer was washed with water and dried, filtered and solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate in hexanes) to give 12 mg (0.025 mmol, 73%) of 4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-1-carboxamide as off-white solid. MS ESI: [M+H]+ m/z 479.2. 1H NMR (600 MHz, CD3OD): δ 8.68 (d, J=4.8 Hz, 1H); 7.99 (s, 1H); 7.87 (s, 1H); 7.40 (s, 1H); 7.10 (m, 2H); 3.91 (m, \2H); 3.28 (m, 2H); 2.34 (s, 3H); 2.16 (m, 2H); 1.83 (m, 2H). rhSYK activity=+++
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH3:10])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[Sn](Cl)(Cl)Cl.[CH3:17][O:18]C(Cl)Cl>ClCCl>[CH3:1][C:2]([CH3:11])([CH3:10])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:17]=[O:18])=[CH:6][CH:5]=1
Reactant: CC(C)(C)Cc1ccccc1
Reactant: COC(Cl)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)Cc1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
(2,2-Dimethylpropyl)benzene (9.33 g, 63 mmol) was dissolved in dichloromethane (50 mL) and cooled to 0° C. on an ice bath. With vigorous stirring, SnCl4 (28.66 g, 110 mmol) was added all at once via syringe, followed by dropwise addition of dichloromethyl methyl ether (7.24 g, 63 mmol) over 10 min. After 20 min, the ice bath was removed, and the mixture was quenched by the addition of ice-water (100 mL). The aqueous layer was discarded and the organic phase was washed with water (3×25 mL), 3 N hydrochloric acid (3×25 mL), and aqueous saturated sodium chloride (2×25 mL). The organic phase was then treated with activated carbon, dried (magnesium sulphate), filtered and concentrated in vacuo. This afforded the title compound. Yield 7.49 g (62%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[C:7]([CH3:19])[N:8]2[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])([O-])=O.[H][H]>C(OCC)(=O)C.[Pt]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[C:7]([CH3:19])[N:8]2[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: [H][H]
Reactant: CCOC(=O)Cn1c(C)cc2c([N+](=O)[O-])cccc21
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1c(C)cc2c(N)cccc21

Procedure:
A solution of (4-nitro-2-methyl-1H-indol-1-yl)-acetic acid, ethyl ester (5.0 g, 19 mmol) in ethyl acetate (75 ml) was hydrogenated under 3 bar hydrogen pressure in the presence of a wet 1% Pt/C catalyst paste (38 w/w, 0.7 g) until hydrogen uptake ceased (3 hours). The reaction mixture was filtered through kieselguhr and the solids washed with ethyl acetate (75 ml). The filtrate and wash were combined with solutions obtained from 2 previous experiments which had been carried out in a similar maimer, each on a 2 g scale, and evaporated to dryness to provide (4-amino-2-methyl-1H-indol-1-yl)-acetic acid, ethyl ester, 8.59 g, >100% as a brown oil which solidified on standing.
Reaction SMILES: C([NH:8][C:9](=[O:42])[C@@H:10]([N:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:30][CH:29]=2)[C:18]1=[O:41])[CH2:11][CH2:12][C:13](OC)=[O:14])C1C=CC=CC=1.[C:43]1([CH3:49])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[CH2:49]([N:8]1[C:13](=[O:14])[CH2:12][CH2:11][C@H:10]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[CH:30][CH:29]=3)[C:18]2=[O:41])[C:9]1=[O:42])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: COC(=O)CC[C@@H](C(=O)NCc1ccccc1)N1Cc2c(OCc3ccc(CN4CCOCC4)cc3)cccc2C1=O
Reactant: Cc1ccccc1
Product: O=C1CC[C@H](N2Cc3c(OCc4ccc(CN5CCOCC5)cc4)cccc3C2=O)C(=O)N1Cc1ccccc1

Procedure:
A mixture of (S)-methyl 5-(benzylamino)-4-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate (2.5 mmol) and p-TsOH monohydrate (1.25 mmol) in toluene, under argon, is refluxed for 8 hours. The solvent is evaporated. The crude is taken up in ether (50 mL) and washed with saturated aqueous NaHCO3 (2×20 mL). The organic layer is dried and purified by silica gel chromatography to afford (S)-1-benzyl-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C@H:11]1[CH2:15][O:14][C:13](C)(C)[O:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](O)(=O)C>>[CH2:1]([NH:8][C:9](=[O:10])[C@H:11]([O:12][CH3:18])[CH2:15][O:14][CH3:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: CC1(C)OC[C@H](C(=O)NCc2ccccc2)O1
Product: COC[C@@H](OC)C(=O)NCc1ccccc1
Yield: 85 %

Procedure:
A 50% aqueous acetic acid solution (30 mL) containing (R)-N-benzyl-2,2-dimethyl-1,3-dioxolane-4-carboxamide (1.22 g, 5.19 mmol) was heated at reflux (30 min). The solvents were evaporated in vacuo and the resulting residue was purified by silica gel column chromatography (10% MeOH-CHCl3) to obtain the desired product as a white solid (0.86 g, 85%); mp 83°-84° C., Rf 0.35 (10% MeOH-CHCl3); [α]23D=+35.4° (c=0.19, MeOH); IR (KBr) 3336, 1649, 1623, 1542, 1400, 1319, 1110, 1049, 972, 739, 697 cm-1 ; 1H NMR (DMSO-d6) δ 3.42-3.55 (m, CHH'OH), 3.53-3.64 (m, CHH'OH), 3.89-3.95 (m, CHOH), 4.28 (d, J=6.0 Hz, CH2Ph), 4.74 (t, J=5.7 Hz, CH2OH), 5.57 (d, J=5.4Hz, CHOH) 7.19-7.35 (m, PhH), 8.24 (t, J=6.0 Hz, NH); 13C NMR (DMSO-d6) 41.7 (CH2Ph), 64.0 (CH2OH), 73.1 (CHOH), 126.6 (C4 '), 127.2 (2C2 ' or 2C3 '), 128.2 (2C2 ' or 2C3 '), 139.6 (C1 '), 172.2 (C(O)NH) ppm; MS(+Cl) (rel. intensity) 196 (M+ +1, 100); Mr (+Cl) 196.098 03 [M+ +1] (calcd. for C10H14NO3 196.097 37); Anal. (C10H13NO3) C, H, N.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)(=O)=O.[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C)C=O>[N:32]([CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 70 °C
Reaction time: 17 h
Yield: 80.9 %

Procedure:
A suspension of 60.0 g of (N-triphenylmethyl-4-piperidyl)methyl methanesulfonate and 17.9 g of sodium azide in 300 ml of dried N,N-dimethyl-formamide was stirred at 70° C. for 17 hours. After the reaction, an insoluble matter was filtered off and the filtrate was concentrated. The resulting residue was added with water and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried, and then the solvent was evaporated. The resulting solid was washed successively with ethanol and n-hexane to give 42.6 g of colorless crystals. Recrystallization from a mixture of methanol and diethyl ether gave colorless crystals having the melting point of from 103.5 to 105.5° C.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[F:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][N:20]2[C:28]3[C:23](=[CH:24][C:25]([C:29](O)=[O:30])=[CH:26][CH:27]=3)[C:22]([CH3:32])=[C:21]2[CH3:33])=[CH:17][C:16]=1[O:36][C@@H:37]([CH3:42])[C:38]([O:40]C)=[O:39]>>[F:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][N:20]2[C:28]3[C:23](=[CH:24][C:25]([C:29](=[O:30])[NH:13][C@H:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=4)[CH3:12])=[CH:26][CH:27]=3)[C:22]([CH3:32])=[C:21]2[CH3:33])=[CH:17][C:16]=1[O:36][C@@H:37]([CH3:42])[C:38]([OH:40])=[O:39]
Reactant: CC(C)c1cccc([C@H](C)N)c1
Reactant: COC(=O)[C@H](C)Oc1cc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)ccc1F
Agent: Cl
Product: Cc1c(C)n(Cc2ccc(F)c(O[C@@H](C)C(=O)O)c2)c2ccc(C(=O)N[C@@H](C)c3cccc(C(C)C)c3)cc12

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and (S)-1-(4-fluoro-3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid, followed by an ester hydrolysis step as outlined in Step 6, example 36.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]([NH:23][S:24]([C@H:27]([CH2:29][CH3:30])[CH3:28])(=[O:26])=[O:25])[CH:14]([C:19](=[O:22])[CH2:20][CH3:21])[CH2:15][C:16]([OH:18])=[O:17])=[CH:9][CH:8]=2)=[CH:3][CH2:2]1>CO.[Pd]>[NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[CH:9][C:10]([N:13]([NH:23][S:24]([C@H:27]([CH2:29][CH3:30])[CH3:28])(=[O:26])=[O:25])[CH:14]([C:19](=[O:22])[CH2:20][CH3:21])[CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CCC(=O)C(CC(=O)O)N(NS(=O)(=O)[C@@H](C)CC)c1ccc(C2=CCNCC2)cc1
Agent: [Pd]
Solvent: CO
Product: CCC(=O)C(CC(=O)O)N(NS(=O)(=O)[C@@H](C)CC)c1ccc(C2CCNCC2)cc1
Reaction time: 2 h

Procedure:
A solution of 10-14 (0.05 g, 0.114 mmoles) in CH3OH (1 ml) was treated with 10% Pd/C (25 mg) and then hydrogenated for 2 hours at 1 atom H2. The catalyst was then removed by filtration. The solution concentrated to give pure 10-15. Rf 0.3 (silica, EtOH(10)/H2O(1)/NH4OH(1).
Reaction SMILES: [C:1]([O-:7])([O-])([O:3][CH2:4][CH3:5])[CH3:2].[CH3:8][C:9]([CH3:18])=[CH:10][CH2:11][CH2:12][C:13](O)([C:15]#[CH:16])[CH3:14].C(O)(=O)C(C)C>>[CH3:14][C:13]([CH2:12][CH2:11][CH:10]=[C:9]([CH3:18])[CH3:8])=[C:15]=[CH:16][CH2:2][C:1]([O:3][CH2:4][CH3:5])=[O:7]
Reactant: C#CC(C)(O)CCC=C(C)C
Reactant: CCOC(C)([O-])[O-]
Solvent: CC(C)C(=O)O
Product: CCOC(=O)CC=C=C(C)CCC=C(C)C
Yield: 96 %

Procedure:
A mixture of 65.6 g of ethyl ortho-acetate, 30.4 g of dehydrolinalool and 1.5 g of isobutyric acid was reacted at 130° to 140°C. for 8 hours. Distillation was conducted after the reaction in the same manner as in the preceeding Examples, and a fraction boiling at 92 to 94°C. under 0.5 mm Hg was collected. Ethyl 5,9-dimethyl-3,4,8-decatrienoate was obtained in a yield of 96%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12]1[N:17]=[C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:15]([C:24]([O:26]CC)=[O:25])=[CH:14][N:13]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12]1[N:17]=[C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:15]([C:24]([OH:26])=[O:25])=[CH:14][N:13]=1
Reactant: CCOC(=O)c1cnc(Nc2cc([N+](=O)[O-])ccc2C)nc1-c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc([N+](=O)[O-])cc1Nc1ncc(C(=O)O)c(-c2cccnc2)n1
Temperature: 50 °C

Procedure:
23 g ethyl 2-[(2-methyl-5-nitrophenyl)amino]-4-(3-pyridinyl)pyrimidine-5-carboxylate and 19 g sodium carbonate in a mixture composed by 150 mL water and 150 mL ethanol is suspended. It is refluxed for three hours distilling the ethanol, and compensating with water the volume loss. Once completed the conversion, it is cooled to 50° C. and adjusted to pH 6 with acetic acid. The suspension is filtrated, yielding, upon drying, 20 g of product with HPLC purity of 95% (A %), which is identified through 1H-NMR.