Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6]2.[C:12](OC(=O)C)(=[O:14])[CH3:13]>CN(C)C1C=CN=CC=1.ClCCl>[C:12]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1)(=[O:14])[CH3:13]
Reactant: COc1ccc2c(c1)CCN2
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc2c(c1)CCN2C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A 4-neck 22L round bottom flask equipped with a reflux condenser, mechanical stirrer and thermowell was charged with 5-methoxyindoline (1520 g, ca. 10.2 mol) produced in accordance with Step A, immediately above and dichloromethane (15 L). To the solution was added 4-dimethylaminopyridine (50 g, 0.446 mol), followed by slow addition of acetic anhydride (1051 mL, 11.22 mol, 1.1 equiv, maintaining gentle reflux of the solvent). The reaction mixture was stirred at room temperature overnight. After completion, the reaction mixture was diluted with dichloromethane (10 L), then washed with water (15 L) and saturated sodium bicarbonate solution (15 L). The organic layer was dried over sodium sulfate and evaporated in vacuo to a crude solid, which was triturated from heptane (4 L) to afford 1-acetyl-5-(methyloxy)-2,3-dihydro-1H-indole (1800 g, 92% yield over two steps). 1H-NMR (CDCl3, 300 MHz) δ 8.13 (d, J=6.3 Hz, 1H), 6.74-6.71 (m, 2 H), 4.05 (t, 2 H), 3.78 (s, 3 H), 3.17 (t, 2 H), 2.21 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:19]=[CH:18][C:11]3[C:12](O)=[N:13][S:14](=[O:16])(=[O:15])[C:10]=3[CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:20]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[CH:26][C:27]([CH2:28][NH:29][C:12]2[C:11]3[CH:18]=[CH:19][C:8]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=4)=[CH:9][C:10]=3[S:14](=[O:16])(=[O:15])[N:13]=2)=[CH:30][CH:31]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: O=S1(=O)N=C(O)c2ccc(-c3ncccc3Cl)cc21
Reactant: CC(C)(C)c1ccc(CN)cc1
Product: CC(C)(C)c1ccc(CNC2=NS(=O)(=O)c3cc(-c4ncccc4Cl)ccc32)cc1

Procedure:
The title compound was prepared by reacting the product of Example 1B (0.1507 g, 0.51 mmol) with 4-tert-butylbenzylamine (0.1070 g, 0.66 mmol) using the procedure as described in Example 1C. MS (ESI+) m/z 440 (M+H)+; (ESI−) m/z 438 (M−H)−; 1H NMR (300 MHz, CDCl3) δ 1.33 (s, 9H), 4.79 (d, J=5.4 Hz, 2H), 6.14 (t, J=5.3 Hz, 1H), 7.32 (dd, J=8.0, 4.6 Hz, 1H), 7.37 (m, 2H), 7.44 (m, 2H), 7.57 (d, J=8.1 Hz, 1H), 7.85 (dd, J=8.1, 1.4 Hz, 1H), 8.03 (dd, J=8.1, 1.4 Hz, 1H), 8.34 (d, J=1.0 Hz, 1H), 8.62 (dd, J=4.4, 1.4 Hz, 1H).
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].C(O)C>[CH2:9]1[C@H:10]2[CH2:15][CH2:14][C@H:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C@H:11]2[CH2:12][NH:8]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21

Procedure:
tert-Butyl(3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-ylcarbamate (1.06 g, 3.35 mmol) from Step A and ethanol (20 mL) were added to 20% Pd(OH)2 on carbon, wet (212.0 mg, 1.51 mmol) in a 250 mL stainless steel pressure bottle. The reaction mixture was stirred for 16 hours under 30 psi hydrogen at room temperature. The mixture was filtered through a nylon membrane and the solvent was removed in vacuo to give tert-butyl(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-ylcarbamate: 1H NMR (500 MHz, pyridine-d5) δ ppm 4.02-3.99 (m, 1H), 3.03 (d, J=10.4, 1H), 2.98-2.89 (m, 1H), 2.84 (dd, J=10.1, 6.4, 1H), 2.61-2.50 (m, 3H), 2.06-1.98 (m, 1H), 1.91 (td, J=12.9, 6.7, 1H), 1.63 (dt, J=19.5, 7.6, 1H), 1.53 (s, 9H), 1.29-1.23 (m, 1H); MS (ESI+) m/z 227 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].Br[C:19]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2.CCN(CC)CC>C(Cl)Cl>[C:32]1([C:19]2([NH:1][C@@H:2]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:3]([O:5][CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[O:4])[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:25]3[C:20]2=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: BrC1(c2ccccc2)c2ccccc2-c2ccccc21
Reactant: COC(=O)C[C@H](N)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C[C@H](NC1(c2ccccc2)c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1

Procedure:
Pb(NO3)2 (6.06 g, 18.3 mmol) was added over 1 min to a CH2Cl2 (80 mL) solution of (S)-1-benzyl 4-methyl 2-aminosuccinate (4.50 g, 19.0 mmol), 9-bromo-9-phenyl-9H-fluorene (6.44 g, 20.0 mmol) and Et3N (3.0 mL, 21.5 mmol), and the heterogeneous mixture was stirred at ambient condition for 48 Hr. The mixture was filtered and the filtrate was treated with MgSO4 and filtered again, and the final filtrate was concentrated. The resulting crude material was submitted to a Biotage purification (350 g silica gel, CH2Cl2 elution) to afford (S)-1-benzyl 4-methyl 2-(9-phenyl-9H-fluoren-9-ylamino)succinate as highly viscous colorless oil (7.93 g). 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz): δ 7.82 (m, 2H), 7.39-7.13 (m, 16H), 4.71 (d, J=12.4, 1H), 4.51 (d, J=12.6, 1H), 3.78 (d, J=9.1, NH), 3.50 (s, 3H), 2.99 (m, 1H), 2.50-2.41 (m, 2H, partially overlapped with solvent). LC (Cond. 1): RT=2.16 min; LC/MS: Anal. Calcd. for [M+H]+ C31H28NO4: 478.20. found 478.19.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].Br[CH2:19][CH:20]=[C:21]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH2:25][CH2:24][C:23]2[CH:32]=[CH:33][CH:34]=[CH:35][C:22]1=2.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C1C=CC=CC=1>[CH:32]1[C:23]2[CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:21](=[CH:20][CH2:19][O:17][C:14]3[CH:13]=[CH:12][C:11]([CH2:10][CH:4]([O:3][CH2:1][CH3:2])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:16][CH:15]=3)[C:22]=2[CH:35]=[CH:34][CH:33]=1
Reactant: BrCC=C1c2ccccc2CCc2ccccc21
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCC=C2c3ccccc3CCc3ccccc32)cc1)OCC
Temperature: 100 °C

Procedure:
A mixture of ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (2.38 g, 0.01 mol), 5-(2-bromo-1-ethylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (2.75 g, 0.01 mol) and potassium carbonate (5.14 g, 0.03 mol) in dimethylformamide (30 ml) was heated at 100° C. for 20 h. The reaction mixture was diluted with benzene (80 ml), washed with 5% aqueous citric acid (3×25 ml) and with saturated NaHCO3 (25 ml), dried (MgSO4) and evaporated. The residue (4.88 g) was purified by column chromatography on silica gel (benzene eluent) to yield the title compound; 2.3 g (53.7%).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=2[CH3:20])[CH2:6][CH2:5]1)(=O)C.[ClH:21].C(O)C>O>[ClH:21].[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([O:10][CH:7]2[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]2)=[C:12]([CH3:20])[CH:13]=1)([O-:19])=[O:18]
Reactant: CC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2C)CC1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc([N+](=O)[O-])ccc1OC1CCNCC1

Procedure:
To 1-acetyl-4-(4-nitro-2-methylphenyloxy)piperidine (11.8 g) were added conc. hydrochloric acid (15 ml), ethanol (15 ml) and water (15 ml) and the mixture was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, the residue thus obtained was washed with ethyl ether and crystals were filtered off to obtain 4-(4-nitro-2-methylphenyloxy)piperidine hydrochloride (8.3 g) as white crystals, m.p. 204°-226° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][NH2:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:12]([O-])(=[O:15])[CH2:13][CH3:14].CC(C)([O-])C.[K+]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:14]=[CH:13][C:12]([OH:15])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NNc1ccc(Cl)c(Cl)c1
Reactant: CCC(=O)[O-]
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: Oc1ccn(-c2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
N′-(3,4-Dichlorophenyl)hydrazine was liberated from its hydrochloride (8.7 g, 40.6 mmol) by partitioning the solid between dilutes Na2CO3 solution and ethyl acetate. The aqueous layer was extracted 2 more times with AcOEt, dried over Na2SO4 and the solvent removed in vacuo. The residue is taken up in t-butyl alcohol (60 ml) and, in a dry nitrogen atmosphere, the ethyle propionate (4.6 ml, 44.66 mmol) was dropwise added. The mixture was ice-cooled and potassium t-butoxide (10.5 g, 81.2 mmol) was slowly added over the time of 1 hr. The resulting mixture was stirred overnight at room temperature. The solvent was evaporated in vacuo and ice-water was added. The resulting aqueous solution is extracted with dichloromethane and acidified to pH 6 with acetic acid. The solid precipitated was filtered off, dried and crystallized from ethyl acetate yielding 2.4 g of brown solid. The mother liquors were evaporated to dryness and the crude residue was column chromatographied on silica gel (petroleum ether/AcOEt 9:1) another fraction of 1 g was obtained (total yield 37%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:6]([CH:14]=1)[CH2:7]NC(C)(C)CO.ClN1C(=[O:29])CCC1=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:6]([CH:14]=1)[CH:7]=[O:29]
Reactant: CC(C)(CO)NCc1cc(Br)ccc1CCc1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: O=Cc1cc(Br)ccc1CCc1ccccc1
Reaction time: 4 h
Yield: 48.6 %

Procedure:
A mixture of 2-(N-(5-bromo-2-(phenethyl)benzyl)amino)-2-methylpropan-1-ol (9.13 g), N-chlorosuccinimide (3.38 g) and dichloromethane (50mi) was stirred for 4 hours. Alumina (10 g) was added and the mixture stirred for 6 days, filtered and the solvent evaporated. The residue was dissolved in dichloromethane (200 ml) and alumina (60 g) added in 6 portions over 8 hours. The mixture was filtered, the filtrate evaporated and the residue purified by MPLC eluting with dichloromethane/hexane (1: 1) to give 5-bromo-2-(phenethyl)benzaldehyde (3.54 g).
Reaction SMILES: [CH:1]1([CH:6]([NH:14][C:15](=O)OC)[C:7]([N:9]2[CH2:12][CH:11]([OH:13])[CH2:10]2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.CCOCC>[CH:1]1([CH:6]([NH:14][CH3:15])[CH2:7][N:9]2[CH2:12][CH:11]([OH:13])[CH2:10]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)NC(C(=O)N1CC(O)C1)C1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CNC(CN1CC(O)C1)C1CCCC1
Temperature: 45 °C
Yield: 102.6 %

Procedure:
To a solution of methyl 1-cyclopentyl-2-(3-hydroxyazetidin-1-yl)-2-oxoethylcarbamate (Compound K2.1) (1.89 g, 7.37 mmol) in THF (50 mL) was a 1M solution of LAH in THF (30 mL, 30.0 mmol) dropwise added (over approximately 5 min) at rt under a nitrogen atmosphere. The resultant mixture was stirred at rt for 30 min and heated at 45° C. over night. Additional LAH in THF (1M solution, 10 mL) was added and the mixture was heated at 65° C. for 1 day. The mixture was diluted with Et2O (150 mL) and the reaction was quenched with Na2SO4×10H2O. The mixture was filtered and a HCl solution in EtOH was added (1.25N, 15 mL) to the filtrate. The filtrate was concentrated under reduced pressure and the residue was co-evaporated with MeOH to give the title compound (1.5 g, 75.0%). The obtained crude product was used without further purification. LCMS (M+H)+: 199.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:14])/[CH:11]=[CH:12]/[CH3:13].[CH3:15][C:16]1[NH:20][CH2:19][CH2:18][N:17]=1.CS(O)(=O)=O>C(O)C>[CH3:15][C:16]1[N:20]([CH:12]([CH3:13])[CH2:11][C:10](=[O:14])[NH:9][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:8])[CH2:19][CH2:18][N:17]=1
Reactant: CC1=NCCN1
Reactant: C/C=C/C(=O)Nc1c(C)cccc1C
Agent: CS(=O)(=O)O
Solvent: CCO
Product: CC1=NCCN1C(C)CC(=O)Nc1c(C)cccc1C

Procedure:
Combine 1.89 gm. (0.01 M) N-(2,6-dimethylphenyl)crotonamide, 0.90 gm. (0.0107 M) lysidine, 0.01 gm. (~0.001 M) methanesulphonic acid and about 40 ml. of ethanol in a pressure bottle and heat (bath temp. 100°-110° C.) for about 100 hours. Remove the solvent in vacuo, add about 50 ml. of water. Adjust the pH to 8.0 with concentrated HCl, and extract the aqueous phase with 2×25 ml. methylene chloride. Then adjust the aqueous phase to pH 13 with 50% sodium hydroxide and extract with 3×30 ml. of methylene chloride. Wash the combined methylene chloride extracts with 2×5 ml. of water. Dry the methylene chloride extracts over sodium sulfate. Evaporate off the solvents to obtain the title compound.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([N:14]([S:37]([C:40]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=1)(=[O:39])=[O:38])[C:15](=[CH2:36])[C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[CH:21]=1)=[O:17])[CH3:13].O.C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl>[CH2:12]([N:14]([S:37]([C:40]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=1)(=[O:39])=[O:38])[C:15](=[CH2:36])[C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][N+:23]([O-:9])=[C:22]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:31]=2)[CH:21]=1)=[O:17])[CH3:13]
Reactant: C=C(C(=O)NCc1ccnc(-c2ccc(C(F)(F)F)cc2)c1)N(CC)S(=O)(=O)c1ccc(F)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=C(C(=O)NCc1cc[n+]([O-])c(-c2ccc(C(F)(F)F)cc2)c1)N(CC)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 29 %

Procedure:
3-Chloro perbenzoic acid (1.5 mol eq, 100 mg) was added to a solution of Example 1 (200 mg, 0.39 mmol) in CHCl3 (10 mL) and the mixture was stirred at r.t. for 24 hours. Then 10% water solution of K2CO3 was added to wash the organic phase that was then dried over Na2SO4 and evaporated under reduced pressure. The resulting residue was purified by flash chromatography (EtOAc 6/petroleum ether 4) to obtain a white solid (60 mg, 29% yield). 1HNMR (DMSO, 200 MHz) δ 1.09 (3H, t, J=7.2 Hz), 3.40 (2H, q, J=6.8 Hz), 4.40 (2H, d, J=6 Hz), 5.14 (1H, s), 6.10 (1H, s), 7.36 (1H, dd, J=4.8 Hz, J′=1.2 Hz), 7.46 (2H, t, J=8.8 Hz), 7.63 (1H, d, J=2.2 Hz), 7.83 (4H, m), 8.05 (2H, d, J=8 Hz), 8.34 (1H, d, J=6.8 Hz), 8.82 (1H, bt) [M+1] 524.6 (C24H21F4N3O4S requires 523.50).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[C:4]([N:14]2[CH:18]=[CH:17][C:16]([CH3:19])=[N:15]2)[CH:3]=1.[NH2:20][C:21]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][C@H:34]([NH:38]C(OC(C)(C)C)=O)[C:35]([OH:37])=[O:36])=[CH:29][CH:28]=2)[CH:24]=[C:23](Cl)[N:22]=1.O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[NH2:38][C@@H:34]([CH2:33][C:30]1[CH:31]=[CH:32][C:27]([C:25]2[CH:24]=[C:23]([O:13][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[N:14]3[CH:18]=[CH:17][C:16]([CH3:19])=[N:15]3)[C:9]([F:12])([F:11])[F:10])[N:22]=[C:21]([NH2:20])[N:26]=2)=[CH:28][CH:29]=1)[C:35]([OH:37])=[O:36]
Reactant: Cc1ccn(-c2cc(Cl)ccc2C(O)C(F)(F)F)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(Cl)nc(N)n2)cc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Cc1ccn(-c2cc(Cl)ccc2C(Oc2cc(-c3ccc(C[C@H](N)C(=O)O)cc3)nc(N)n2)C(F)(F)F)n1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
1-[4-Chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-2,2,2-trifluoro-ethanol (0.120 g, 0.41 mmol), (S)-3-[4-(2-amino-6-chloro-pyrimidine-4-yl)-phenyl]-2-tert-butoxycarbonylamino-propionic acid (0.176 g, 0.45 mmol), 1,4-dioxane (4 ml), and Cs2CO3 (0.533 g, 1.64 mmol) were combined in a 20 ml sealed tube, and the mixture was heated at 100° C. for 12 h. The mixture was concentrated. To the residue, 10% methanol in DCM (50 ml) was added and the mixture was filtered. The filtrate was concentrated to give a crude product, which was taken in THF/3N HCl (30 ml/15 ml) and the resulting mixture was stirred at 40-45° C. for 12 h. LCMS indicated the completion of reaction with desired product. The mixture was concentrated to give a crude product, which was dissolved in MeOH and H2O (1:1) and purified by preparative HPLC using MeOH/H2O/TFA as solvent system to give (S)-2-amino-3-[4-(2-amino-6-{1-[4-chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-2,2,2-trifluoro-ethoxy}-pyrimidine-4-yl)-phenyl]-propionic acid as a TFA salt. LCMS: M+1=547. 1H-NMR (400 MHz, CD3OD): δ (ppm) 2.30 (s, 3H), 3.10-3.30 (m, 2H), 4.20 (t, 1H), 6.32 (d, 1H), 6.74 (s, 1H), 7.0 (q, 1H), 7.38 (d, 2H), 7.50 (m, 2H), 7.72 (m, 1H), 7.90 (m, 3H).
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1>C(N)CN.C(O)(C)C>[NH:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:3][CH2:4][CH2:5][NH2:6]
Reactant: Clc1nc2ccccc2[nH]1
Solvent: NCCN
Solvent: CC(C)O
Product: NCCNc1nc2ccccc2[nH]1
Temperature: 10 °C
Yield: 37.4 %

Procedure:
A mixture of 2-chloro-1H-benzoimidazole (1 g) in 4 mL of ethane-1,2-diamine was heated to 10° C. for several hours until complete by HPLC. The reaction was allowed to cool and diluted with a mixture of chlororform and isopropanol (3:1). The organic phase was washed with water then dried and concentrated to give 216 mg of product as a solid which was used in the next step without further purification. MS(ES): m/e (EI*) 177.1 [M+H]
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([N+:10]([O-])=O)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].C(OCC)(=O)C>[Pd].CO>[NH2:10][C:5]1[C:4]([NH:3][CH2:1][CH3:2])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: CCNc1cccnc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCNc1cccnc1N

Procedure:
A mixture of 3-ethylamino-2-nitro-pyridine (400 mg), 10% palladium on carbon (40 mg) and 1:1 ethyl acetate:methanol (30 mL) were placed in a Parr apparatus under hydrogen (50 psi) for 50 min. The mixture was filtered through Celite, concentrated, and the product triturated with hexane to give 2-Amino-3-ethylaminopyridine as a brown solid. More material was recovered from the filtrate. 1H NMR (CDCl3): δ 7.59 (d, J=4.94 Hz, 1H), 6.81 (d, J=6.32 Hz, 1H), 6.71 (dd, J=4.94, 7.69 Hz, 1H), 3.12 (q, J=7.14 Hz, 2 h), 1.31 (t, J=7.14 Hz, 3H).
Reaction SMILES: CS[C:3](=[NH:8])[NH:4][N+:5]([O-:7])=[O:6].[CH2:9]([NH:11][CH2:12][CH3:13])[CH3:10]>C(#N)C>[CH2:9]([N:11]([CH2:12][CH3:13])[C:3]([NH:4][N+:5]([O-:7])=[O:6])=[NH:8])[CH3:10]
Reactant: CCNCC
Reactant: CSC(=N)N[N+](=O)[O-]
Solvent: CC#N
Product: CCN(CC)C(=N)N[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 6 h
Yield: 53.1 %

Procedure:
To a mixture of 1.35 g of S-methyl-N-nitroisothiourea and 5 ml of acetonitrile was added 0.88 g of diethylamine, followed by stirring for 6 hours in an oil bath of 60° C. The reaction mixture was concentrated and the residue was purified by a column chromatography [developing solvent: dichloromethanemethanol (20:1)] to afford 0.85 g of N,N-diethyl-N'-nitroguanidine as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:11](=[O:12])[N:10]2[C:5]([C:6]([CH3:14])([CH3:13])[O:7][CH2:8][CH2:9]2)=[N:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOCC>[CH2:20]([O:1][C:2]1[C:11](=[O:12])[N:10]2[C:5]([C:6]([CH3:13])([CH3:14])[O:7][CH2:8][CH2:9]2)=[N:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CCOC2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.8 %

Procedure:
To a stirred solution of intermediate 25, ethyl 3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate, (2.68 g, 10 mmol) and benzyl bromide (1.43 mL, 12 mmol) in DMF (40 mL) was added K2CO3 (2.07 g, 20 mmol). After stirring 48 h at ambient temperature, the reaction mixture was diluted with ether (100 mL), then washed with water (3×30 mL) and brine (20 mL). The organic layer was dried (Na2SO4/activated carbon), filtered and concentrated to give a yellow solid. Trituration with hexanes/ether (9: 1) afforded the title compound as an off-white solid (2.79 g, 78% yield). 1H NMR (500 MHz, CDCl3) δ ppm: 7.48-7.45 (2H, m), 7.37-7.30 (3H, m), 5.25 (2H, s), 4.33 (2H, q, J=7.3 Hz), 4.05-3.99 (4H, m), 1.62 (6H, s), 1.29 (3H, t, J=7.3 Hz). HRMS (M+H) calcd for C19H23N2O5: 359.1607; found: 359.1611. Anal calcd for C19H22N2O5: C, 63.67; H, 6.18; N, 7.81; found: C, 63.63; H, 6.16; N, 7.78.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][P:6]([O-:9])([O-:8])=[O:7])#N.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C[O:23][C:24](=[O:56])[C@H:25]([CH2:48][C:49]1C=CC(O)=[CH:51][CH:50]=1)[NH:26][C:27](=[O:47])[CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46].C1(N=C=NC2CCCCC2)CCCCC1.Cl>C(#N)C.O>[C:27]([NH:26][C@H:25]([C:24]([OH:56])=[O:23])[CH2:48][C:49]1[CH:50]=[CH:51][C:4]([O:5][P:6]([OH:9])([OH:8])=[O:7])=[CH:3][CH:1]=1)(=[O:47])[CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH:34]=[CH:35][CH2:36][CH:37]=[CH:38][CH2:39][CH:40]=[CH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OC
Reactant: N#CCCOP(=O)([O-])[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CC#N
Solvent: O
Product: CCCCCC=CCC=CCC=CC/C=C\CCCC(=O)N[C@@H](Cc1ccc(OP(=O)(O)O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 120 h
Yield: 23 %

Procedure:
A solution of pyridinium cyanoethylphosphate (2 mmol) in anhydrous acetonitrile (3 ml) was added to dry N-arachidonoyl-L-tyrosine methyl ester. N,N′-Dicyclohexylcarbodiimide (413 mg, 2 mmol) was then added and the mixture was stirred at room temperature. After 5 days, the mixture was cooled to 0° C., water (0.5ml) was added and, after stirring for 30 min at room temperature, the precipitated N,N′-dicyclohexylurea was separated by filtration. The filtrate was evaporated in vacuo and the residue obtained was fractionated by short column chromatography on silica gel. The desired phosphorylated N-acyl-L-tyrosine methyl ester was eluted from column with chloroform-methanol (70-60:30-40, v/v). The composition of the eluates was controlled by TLC on Silica gel 60 plates (system B) using a molybdate spray for detecting the spots. The appropriate fractions were combined, evaporated to dryness in vacuo and residue was dissolved in 1 ml tetrahydrofuran. The solution obtained was added, dropwise over a period of 5 min, to a cooled (ice-bath), stirred 1.5 M NaOHaq (4 ml). After a further 25 min, the mixture was acidified with 1 N HCl to pH 2-3 and extracted with chloroform-methanol (2:1, v/v). The extract was washed with methanol-water (10:9, v/v), concentrated in vacuo and applied to a column of silica gel. The desired products was eluted from column with chloroform-methanol (30-20:70-80, v/v), the fractions containing pure substance stained on the TLC plates with molybdate spray were combined and evaporated to dryness to give 63 mg (23%) of (8): Rf 0.05-0.10 (system B); 1H-NMR (CD3SOCD3, 200 MHz) δ0.9-1.0 (t, 3H, ω-CH3); 1.3 (s, 8H, 4CH2); 2.0-2.4 (m, 6H, 2CH2CH═CH and CH2CO); 2.7-2.9 (br s, 6H, 3HC═CHCH2CH═CH); 2.9-3.1 (m, 2H, CH2Ar); 4.3-4.4 (m, 1H, NHCHCO); 5.2-5.4 (br s, 8H, 4HC═CH); 7.0-7.2 (q, 4H, Ar); 8.2-8.4 (m, 3H, NH and 2POH)