Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:9][N:8]2[C:4](=[N:5][C:6]3[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:7]=32)[CH2:3]1.[ClH:17].[H][H]>C(O)C.[Pd]>[ClH:17].[NH2:14][C:12]1[CH:11]=[CH:10][C:7]2[N:8]3[CH2:9][CH:2]([OH:1])[CH2:3][C:4]3=[N:5][C:6]=2[CH:13]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)nc1n2CC(O)C1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1ccc2c(c1)nc1n2CC(O)C1

Procedure:
A mixture of 0.3 g (1.36 mmol) of the 2,3-dihydro-2-hydroxy-6-nitro-1H-pyrrolo[1,2-a]benzimidazole obtained in step IX-2 and of 100 mg of palladium-on-charcoal at 10% in 15 ml of ethanol and 2 ml of 1N hydrochloric acid is stirred for 5 hours at 20° C. under 4 bar of hydrogen. After this period of time, the reaction mixture is filtered over a celite buffer, the filtrate is concentrated under reduced pressure, and 0.35 g of the expected product is obtained in the form of a solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][C:18]1[O:22][CH:21]=[CH:20][CH:19]=1)[CH:8]1[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N+:23]([O-])([N+]([O-])=O)=[O:24]>>[Cl:1][CH2:2][CH2:3][N:4]([N:23]=[O:24])[C:5]([N:7]([CH2:17][C:18]1[O:22][CH:21]=[CH:20][CH:19]=1)[CH:8]1[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: O=C(NCCCl)N(Cc1ccco1)C1O[C@H](CO)[C@@H](O)[C@H]1O
Product: O=NN(CCCl)C(=O)N(Cc1ccco1)C1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
3.3 g of 1-(2-chloroethyl)-3-furfuryl-3-(D-ribofuranosyl)urea and 5.0 of nitrogen tetroxide gas are treated in the same manner as described in Example 31-(2). 2.2 g of 1-(2-chloroethyl)-1-nitroso-3-furfuryl-3-(D-ribofuranosyl)urea are thereby obtained as yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]([CH3:41])([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][NH:13][C:14]([C:16]1[CH:17]=[C:18]([CH:24]=[C:25]([C:27]2([C:32]#[N:33])[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:26]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>ClC(Cl)C>[C:1]([O:5][C:6]([NH:8][C@:9]([C:10]1[O:15][C:14]([C:16]2[CH:17]=[C:18]([CH:24]=[C:25]([C:27]3([C:32]#[N:33])[CH2:28][CH2:29][CH2:30][CH2:31]3)[CH:26]=2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:13][N:12]=1)([CH3:41])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1cc(C(=O)NNC(=O)[C@@](C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(C2(C#N)CCCC2)c1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cc(-c2nnc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)cc(C2(C#N)CCCC2)c1

Procedure:
A solution of ethyl 3-({2-[(R)-2-tert-butoxycarbonylamino-2-methyl-3-phenylpropanoyl]hydrazino}carbonyl)-5-(1-cyanocyclopentyl)benzoate (0.10 g, 0.18 mmol) and (methoxycarbonylsulfamoyl)triethylammonium hydroxide, inner salt (0.13 g, 0.54 mmol) in 1.5 mL dichloroethane was heated in the microwave at 120° C. for 8 min. Concentration and flash chromatography (silica gel, 0-45% EtOAc/hexanes) gave ethyl 3-(5-((R)-2-tert-butoxycarbonylamino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(1-cyanocyclopentyl)benzoate. 1H NMR (400 MHz, CDCl3) δ 8.57 (app t, J=1.5 Hz, 1H), 8.30 (d, J=1.5 Hz, 2H), 7.29 (m, 3H), 7.08 (m, 2H), 5.11 (br s, 1H), 4.46 (q, J=7.1 Hz, 2H), 3.60 (d, J=13.6 Hz, 1H), 3.44 (d, J=13.6 Hz, 1H), 2.59 (m, 2H), 2.19-1.99 (m, 6H), 1.74 (s, 3H), 1.45 (t, J=7.1 Hz, 3H), 1.43 (s, 9H).
Reaction SMILES: [N+:1]([CH2:4][CH:5]1[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][CH2:11][C:6]21[O:10][CH2:9][CH2:8][O:7]2)([O-])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[NH2:1][CH2:4][CH:5]1[C:14]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:13][CH2:12][CH2:11][C:6]21[O:7][CH2:8][CH2:9][O:10]2
Reactant: O=[N+]([O-])CC1C2(CCCC1(c1ccccc1)c1ccccc1)OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCC1C2(CCCC1(c1ccccc1)c1ccccc1)OCCO2
Yield: 28.6 %

Procedure:
A solution of (RS)-6-nitromethyl-7,7-diphenyl-1,4-dioxaspiro[4.5]decane (63 g) in anhydrous tetrahydrofuran (300 cc) is added dropwise in the course of 1 hour to a suspension, cooled to +5° C., of lithium aluminium hydride (8.13 g) in anhydrous tetrahydrofuran (250 cc) while the temperature of the reaction mixture is maintained at +5° C., and the mixture is then brought to reflux for 2 hours. The reaction mixture is then cooled to +5° C., treated with distilled water (8.93 cc), then with 5N aqueous sodium hydroxide solution (8 cc) and then with distilled water (25 cc), filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel with a slight excess pressure of nitrogen (0.04-0.063 mm, diameter 6.5 cm, height 45 cm), eluting with a mixture of dichloromethane and methanol (90:10) by volume) and collecting 120-cc fractions. Fractions 10 to 31 are combined and concentrated to dryness under reduced pressure (2.7 kPa). (RS)-6-Aminomethyl-7,7-diphenyl-1,4-dioxaspiro[4.5]decane (16.5 g) is obtained in the form of an orange-colored oil.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][CH:14]([OH:15])[C:7]2=[N:6][C:5]=1[CH3:16].Cl.[F:18][C:19]1[CH:33]=[CH:32][C:22]2[C:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[N:24][O:25][C:21]=2[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(#N)C>[CH3:16][C:5]1[N:6]=[C:7]2[N:8]([CH2:11][CH2:12][CH2:13][CH:14]2[OH:15])[C:9](=[O:10])[C:4]=1[CH2:3][CH2:2][N:29]1[CH2:28][CH2:27][CH:26]([C:23]2[C:22]3[CH:32]=[CH:33][C:19]([F:18])=[CH:20][C:21]=3[O:25][N:24]=2)[CH2:31][CH2:30]1
Reactant: Cc1nc2n(c(=O)c1CCCl)CCCC2O
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2O
Temperature: 85 °C
Reaction time: 1.5 h

Procedure:
A mixture of 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (formula-8) (170.1 grams), 6-fluoro-3-(4-piperidinyl)-1,2-benzoisoxazole monohydrochloride (formula-6) (150 grams), sodium carbonate (113.3 grams), and potassium iodide (9.7 grams) in acetonitrile (1.5 L) was heated to 85° C. The reaction mixture was heated at 85° C. for 6 hrs. The reaction mixture was then cooled to −10° C. and stirred for 1.5 hrs. The solid obtained was filtered, washed with cold acetonitrile. The wet solid was taken in water, and acetic acid was added to the mixture to adjust the pH to 4.0. The reaction mixture was treated with acidic carbon and filtered through hyflow bed. The filtrate was treated with sodium hydrosulphite (hydrose). The pH of the reaction mixture was adjusted to 12 by adding aqueous sodium hydroxide solution and stirred for 45 min. The solid obtained was filtered, washed with water and dried to provide the title compound.
Reaction SMILES: [CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14](B(O)O)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:21]([C@H:26]1[CH2:31][CH2:30][C@H:29]([C:32]2[CH:37]=[CH:36][C:35](Br)=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)[CH2:22][CH2:23][CH2:24][CH3:25].C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC=CC=1>[CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:35]3[CH:34]=[CH:33][C:32]([C@H:29]4[CH2:30][CH2:31][C@H:26]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:27][CH2:28]4)=[CH:37][CH:36]=3)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCC1Cc2ccc(B(O)O)cc2C1
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(Br)cc2)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: CCCCCCCCC1Cc2ccc(-c3ccc([C@H]4CC[C@H](CCCCC)CC4)cc3)cc2C1
Temperature: 0 °C

Procedure:
1.78 g (6.5 mM) of 2-octylindan-5-boronic acid, 2.0 g (6.5 mM) of 4-(trans-4-pentylcyclohexy)phenyl bromide, 4 ml of ethanol, 8 ml of benzene, 8 ml of 2M-sodium carbonate aqueous solution and 0.24 g of tetrakis (triphenylphosphine) palladium (O) were mixed and heat-refluxed for 5 hours under stirring. After the reaction, the reaction mixture was poured into ice water, followed by extraction with toluene, washing with water and drying with anhydrous sodium sulfate. Then, the sodium sulfate was removed from the mixture and the resultant mixture was evaporated to obtain a residue. The residue was purified by silica gel column chromatography (eluent: hexane) and recrystallized from a mixture solvent (toluene/methanol) to obtain 1.52 g of 2-octyl-5-[4-(trans-4-pentylcyclohexyl)phenyl]indan (Yield: 51.0%). ##STR310##
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][NH:5][C:6](=[NH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([Li])CCC.Cl[P:21]([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23]>>[CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][NH:5][C:6](=[N:13][P:21]([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)CCNC(=N)c1ccccc1
Reactant: CC(C)P(Cl)C(C)C
Agent: [Li]CCCC
Product: CC(C)P(N=C(NCCN(C)C)c1ccccc1)C(C)C

Procedure:
Procedure as described for NP Amidine I using the following amounts and modifications: 0.956 g of N1-(2-(dimethylamino)ethyl)benzamidine (Amidine XII, 5.0 mmol), 2.50 mL of 2.0 M butyllithium (5.0 mmol), 0.80 mL chlorodiisopropylphosphine (5.0 mmol). After filtration to remove lithium chloride and removal of solvent, a yellow oil was isolated (1.52 g, 99%).
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][CH:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:36][CH2:37][CH2:38][C:39]1[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[CH:41][CH:40]=1>>[C:1]([Si:5]([CH3:24])([CH3:23])[O:6][CH:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH:10]1[CH2:11][CH2:12][C:13](=[O:15])[N:14]1[CH2:36][CH2:37][CH2:38][C:39]1[CH:40]=[CH:41][C:42]([C:43]#[N:44])=[CH:45][CH:46]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: N#Cc1ccc(CCCBr)cc1
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1CCCc1ccc(C#N)cc1)Cc1ccccc1
Yield: 69.4 %

Procedure:
Analogous to the procedure described for Example 1A, Step D, the anion derived from 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-pyrrolidin-2-one (262.8 mg, 0.756 mmol) and NaHMDS (0.83 mL, 0.83 mmol) was reacted with 4-(3-bromo-propyl)-benzonitrile (186 mg, 0.832 mmol) at 70° C. for 24 h. Purification by medium pressure chromatography (5:1 hexanes:EtOAc to 1:1 hexanes:EtOAc to 1% MeOH in CH2Cl2 to 5% MeOH in CH2Cl2) provided 4-(3-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-5-oxo-pyrrolidin-1-yl}-propyl)-benzonitrile (257.6 mg). 1H NMR (CDCl3) δ7.56 (m, 2H), 7.26 (m, 5H), 7.13 (m, 2H), 3.85 (m, 1H), 3.62 (m, 1H), 3.48 (m, 1H), 2.93 (m, 1H), 2.82–2.60 (m, 4H), 2.29 (m, 2H), 1.88–1.25 (m, 7H); MS 491.5 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]3[C:24](=[O:28])[NH:25][C:26](=[O:27])[C:13]=3[C:12]=2[C:11]2[CH:10]=[C:9]([OH:29])[CH:8]=[CH:7][C:6]1=2.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[NH:30]([CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]3[C:24](=[O:28])[NH:25][C:26](=[O:27])[C:13]=3[C:12]=2[C:11]2[CH:10]=[C:9]([OH:29])[CH:8]=[CH:7][C:6]1=2)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1ccccc1
Reactant: O=C1NC(=O)c2c1c(-c1ccccc1)cc1c2c2cc(O)ccc2n1CCCBr
Product: O=C1NC(=O)c2c1c(-c1ccccc1)cc1c2c2cc(O)ccc2n1CCCNc1ccccc1
Reaction time: 20 h
Yield: 38 %

Procedure:
Bromide (204) (75 mg, 0.17 mmol) prepared as described in example 173 was reacted with aniline according to the procedure described in example 179 except that the reaction was performed at room temperature for 20 h, to give aniline (217) (30 mg, 38%) as a yellow powder, mp 240° C. (dec). 1H NMR δ [(CD3)2SO] 11.04 (br s, 1H), 9.33 (s, 1H), 8.40 (d, J=2.4 Hz, 1H), 7.78 (s, 1H), 7.59 (d, J=8.9 Hz, 1H), 7.48 (m, 2H), 7.42 (m, 3H), 7.10 (dd, J=8.8, 2.4 Hz, 1H), 7.05 (m, 2H), 6.52 (m, 3H), 5.70 (t, J=5.3 Hz, 1H), 4.59 (t, J=6.8 Hz, 2H), 2.98 (t, J=6.3 Hz, 2H), 2.07 (m, 2H). Found: C, 74.00; H, 5.22; N, 8.76. C29H23N3O3.1/2H2O requires: C, 74.03; H, 5.14; N, 8.93.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[CH3:10][PH:11](=[O:13])[CH3:12].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:10][P:11]([C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1)([CH3:12])=[O:13]
Reactant: C[PH](C)=O
Reactant: Nc1ccc(Br)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN(C)C=O
Product: CP(C)(=O)c1ccc(N)c(F)c1
Reaction time: 0.33 h
Yield: 19.6 %

Procedure:
To a solution of 4-bromo-2-fluoroaniline (0.380 g, 2.00 mmol) in 8 mL DMF was added dimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassium phosphate (0.467 g, 2.20 mmol). The mixture was purged with nitrogen, and subjected to microwaves at 150° C. for 20 minutes. The reaction mixture was concentrated and purified by silica gel chromatography (0-20% 7N ammonia in methanol:dichloromethane) to afford the desired product (73.5 mg, 20% yield).
Reaction SMILES: CC1(C(=O)C)CC1.[CH:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH:9]1[NH:18][C:19](=[O:27])[CH2:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:15]2>>[CH:8]12[CH2:15][CH:14]3[CH2:13][CH:12]([CH2:11][CH:10]([CH2:16]3)[CH:9]1[NH:18][C:19](=[O:27])[CH2:20][C:21]([C:22]1([CH3:23])[CH2:24][CH2:25]1)=[O:26])[CH2:17]2
Reactant: CC(C)(C)C(=O)CC(=O)NC1C2CC3CC(C2)CC1C3
Agent: CC(=O)C1(C)CC1
Product: CC1(C(=O)CC(=O)NC2C3CC4CC(C3)CC2C4)CC1

Procedure:
Prepared from 1-(1-methylcyclopropyl)ethanone by the same process as used for Intermediate #60
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:15][C:16]([F:27])([F:26])[C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=O.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[O:5]=[C:4]1[O:6][C:20]([C:19]2[CH:23]=[CH:24][CH:25]=[C:17]([C:16]([F:15])([F:26])[F:27])[CH:18]=2)=[N:1][C:2]2[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]1=2
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1cccc(C(=O)O)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COC(=O)c1cccc2c(=O)oc(-c3cccc(C(F)(F)F)c3)nc12
Reaction time: 16 h
Yield: 69.9 %

Procedure:
To a solution of 2-amino-3-(methoxycarbonyl)benzoic acid 20 (1.16 g, 5.94 mmol) in pyridine (10 mL) was added 3-trifluoromethylbenzoyl chloride 2 (0.90 mL, 5.94 mmol). The reaction was stirred for 16 h, poured into sat. aq NaHCO3 (50 mL), extracted with dichloromethane (3×50 mL) and the combined organic layers were dried (MgSO4) and concentrated. Toluene (10 mL) was added and the solution was concentrated in vacuo. The crude residue was purified by MPLC eluting with pentane/EtOAc (10-50%) to give 42 (1.45 g, 70% yield).
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=1)[CH3:2]>CO.[Pd]>[NH2:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[O:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:17][CH3:18]
Reactant: CCN(CC)CCCOc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CCN(CC)CCCOc1cccc(N)c1

Procedure:
The N,N-diethyl-N-[3-(3-nitrophenoxy)propyl]amine (1 mmol) was dissolved in MeOH (5 mL) and hydrogenated in the presence of 10% Pd/C (50 mg) until completion as indicated by TLC or HPLC, according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired N-[3-(3-aminophenoxy)propyl]-N,N-diethylamine, which was used directly for further transformation without further purification.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:22][S:23](O)(=[O:25])=[O:24]>>[O:21]=[C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19](=[O:20])[N:11]1[CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][C:4]([S:23]([Cl:22])(=[O:25])=[O:24])=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCc1ccccc1
Reactant: O=S(=O)(O)Cl
Product: O=C1c2ccccc2C(=O)N1CCCCc1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
2-(4-Phenylbutyl)isoindole-1,3-dione 12 (1.9 g, 6.8 mmol) was added to chlorosulfonic acid (10 mL, 138 mmol) at 0° C. and the mixture was stirred for 1 h at the temperature. After storing in refrigerator at −5° C. overnight, the reaction mixture was poured onto crushed ice (100 g) and precipitates were collected by a suction filtration and dried under high vacuum to afford the desired product 13 (2.48 g, 99% yield). 1H NMR (300 MHz, CDCl3) δ 1.70 (m, 4H), 2.78 (m, 2H), 3.70 (m, 2H), 7.40 (d, 2H) 7.70 (d, 2H), 7.85 (d, 2H), 7.95 (d, 2H).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([O:10]CC)=O.[NH2:13][CH:14]([C:16]([N:18]1[CH2:22][C:21](=[O:23])[NH:20][C:19]1([CH3:25])[CH3:24])=[O:17])[CH3:15]>CC(O)C>[CH3:25][C:19]1([CH3:24])[NH:20][C:21](=[O:23])[CH2:22][N:18]1[C:16](=[O:17])[CH:14]([NH:13][C:8](=[O:10])[CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])[CH3:15]
Reactant: CCOC(=O)CN1CCCC1=O
Reactant: CC(N)C(=O)N1CC(=O)NC1(C)C
Solvent: CC(C)O
Product: CC(NC(=O)CN1CCCC1=O)C(=O)N1CC(=O)NC1(C)C

Procedure:
The same procedure of Example 25, starting from ethyl 2-oxo-1-pyrrolidineacetate and 1-(D,L-alanyl)-2,2-dimethyl-4-imidazolidinone, afforded the title compound, m.p. 198°-200° C. (2-propanol).
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:16][O:17]C(Cl)Cl>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([C:9]1[CH:10]=[C:11]([CH:16]=[O:17])[C:12]([OH:15])=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(O)cc1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCCCCCCc1ccc(O)c(C=O)c1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
5-octylsalicylaldehyde was prepared as follows: p-octyl phenol (20.6 g) was dissolved in dry methylene chloride (400 cm3). The solution was cooled in an ice bath, stirred and treated carefully with titanium tetrachloride (44 cm3). 1,1-Dichloromethyl methyl ether (30 cm3) was then added dropwise to the cooled stirred solution. After the addition was complete, the temperature was raised to 40° C. and stirring continued for a further 15 minutes. The mixture was then poured into crushed ice (500 g) and the organic layer extracted with ether. The ethereal solution was washed several times with water, dried over anhydrous sodium sulpate and evaporated. The oily residue was purified by fractional distillation under vacuum to give 5-octylsalicylaldehyde as a colourless liquid which solidified at 30° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:27](OCC)[O:28]CC)=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].Cl>CC(C)=O>[CH3:1][C:2]1[NH:3][C:4]([CH:27]=[O:28])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(C(OCC)OCC)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
To a solution of diethyl 2-methyl-4-(2-nitrophenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.1563 g) in acetone (10 ml) was added 6N-hydrochloric acid (2.5 ml) and stirred at room temperature for 30 minutes. After removing acetone, water was added to the residue and neutralized with aqueous solution of sodium bicarbonate. The precipitated solid was collected by filtration, washed with water and then dried to give yellowish powder of diethyl 2-methyl-4-(2-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (0.9407 g). The product was recrystallized from a mixture of ethanol and n-hexane to give the pure product, m.p. 101° to 103° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[NH:4][C:5]1[S:6][C:7]2[C:13]([C:14]3[O:15][CH2:16][CH2:17][CH2:18][CH:19]=3)=[CH:12][CH:11]=[C:10]([O:20][CH3:21])[C:8]=2[N:9]=1>[Pd].ClCCl.CO.C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:22])[NH:4][C:5]1[S:6][C:7]2[C:13]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)=[CH:12][CH:11]=[C:10]([O:20][CH3:21])[C:8]=2[N:9]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc(C3=CCCCO3)c2s1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: COC(=O)Nc1nc2c(OC)ccc(C3CCCCO3)c2s1

Procedure:
From [7-(5,6-dihydro-4H-pyran-2-yl)-4-methoxy-benzothiazol-2-yl]-carbamic acid methyl ester by hydrogenation with palladium on charcoal in dichloromethane, methanol and triethylamine. ES-MS m/e (%): 323 (M+H+, 100).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15](=[O:32])[C@@H:16]([NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:17][CH2:18]SC)[C@H:10]([CH2:33][CH2:34][CH3:35])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CCOC(C)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:25]([O:24][C:22](=[O:23])[NH:21][C@H:16]1[CH2:17][CH2:18][N:14]([C@H:11]2[CH2:12][CH2:13][C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:36])[CH2:9][C@H:10]2[CH2:33][CH2:34][CH3:35])[C:15]1=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)[C@H](CCSC)NC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 54.3 %

Procedure:
The compound (1R,3R,4S)-[4-((2S)-2-benzyloxycarbonylamino-4-methylsulfanyl-butyrylamino)-3-propyl-cyclohexyl]-carbamic acid tert-butyl ester (375 mg) was “wetted” with EtOAc, and then the majority of EtOAc was removed under nitrogen stream. The residue was dissolved in iodomethane (6 mL), and the resulting solution was stirred at RT for 48 h before being concentrated in vacuo. The residue was dissolved in methylene chloride, and the resulting solution was concentrated; this was repeated to afford the salt. MS found: (M+H)+=536.3. This material was dissolved in DMF (12 mL) and the solution was charged with Cs2CO3 (470 mg, 1.4 mmol) and stirred for 12 h at RT before being partitioned between EtOAc and brine. The organic phase was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford {(3S)-1-[(1S,2R,4R)-4-tert-butoxycarbonylamino-2-propyl-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-carbamic acid benzyl ester (185 mg). MS found: (M+H)+=474.3.