Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[CH:20][C:19](F)=[CH:18][CH:17]=1)(=[O:15])=[O:14])[C:8]1[S:9][CH:10]=[CH:11][N:12]=1)(C)(C)C.C([Li])CCC.[O:29]1[CH:33]=[CH:32][C:31]([C:34]2[N:41]=[CH:40][CH:39]=[CH:38][C:35]=2[CH:36]=[O:37])=[CH:30]1.Cl>O1CCCC1.O.C(OCC)(=O)C>[O:29]1[CH:33]=[CH:32][C:31]([C:34]2[C:35]([CH:36]([OH:37])[C:19]3[CH:18]=[CH:17][C:16]([S:13]([NH:7][C:8]4[S:9][CH:10]=[CH:11][N:12]=4)(=[O:14])=[O:15])=[CH:21][CH:20]=3)=[CH:38][CH:39]=[CH:40][N:41]=2)=[CH:30]1
Reactant: CC(C)(C)OC(=O)N(c1nccs1)S(=O)(=O)c1ccc(F)cc1
Reactant: O=Cc1cccnc1-c1ccoc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=S(=O)(Nc1nccs1)c1ccc(C(O)c2cccnc2-c2ccoc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 11.2 %

Procedure:
100 mg (0.28 mmol) of tert-butyl((4-fluorophenyl)sulfonyl)(thiazol-2-yl)carbamate was dissolved in 5 mL of tetrahydrofuran under nitrogen gas, and cooled to −78° C. After adding 0.26 mL (0.42 mmol) of n-butyllithium (1.6 M in tetrahydrofuran) slowly, the mixture was stirred for 30 minutes as maintaining −78° C. 23 mg (0.13 mmol) of 2-(furan-3-yl)nicotinaldehyde was dissolved in 0.5 mL of tetrahydrofuran, and added to the above reacting solution. As warming from −78° C. to room temperature, the reacting solution was stirred for 24 hours. Ethyl acetate and water/1 N-hydrochloride were added to the reacting solution, and it was stirred. After separating layers, the organic layer only was collected and concentrated under reduced pressure. The obtained residue was separated by column chromatography (developing solvent, hexane:ethyl acetate=1:1) to obtain 6 mg (5.2% yield) of the title compound.
Reaction SMILES: [CH:1]1([CH2:4][C:5](=O)[CH:6]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:7]([CH3:12])([N+:9]([O-])=O)[CH3:8])[CH2:3][CH2:2]1>CO.[Ni]>[ClH:19].[CH:1]1([CH:4]2[CH2:5][CH:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]([CH3:12])([CH3:8])[NH:9]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C(C(=O)CC1CC1)c1ccc(Cl)cc1)[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: CC1(C)NC(C2CC2)CC1c1ccccc1
Product: Cl

Procedure:
15.2 G of 1-cyclopropyl-3-(p-chlorophenyl)-4-methyl-4-nitropentanone in 250 ml of methanol are hydrogenated for 7 hours 30 minutes under 100 atmospheres at 120° C in the presence of 10 g of Raney Nickel. Filtration, evaporation of the methanolic filtrate under reduced pressure and recrystallisation from isopropanol give 9 g of 2-cyclopropyl-4-phenyl-5,5-dimethylpyrrolidine hydrochloride as white crystals. Melting point = 271°-273° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:16]#[N:17])[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Br:18][Si](C)(C)C.O.[OH-].[Na+]>C(#N)CCC>[Br:18][C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:16]#[N:17])[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: N#CC1(c2ccc(Cl)nc2)CCC(F)(F)CC1
Reactant: C[Si](C)(C)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCCC#N
Solvent: O
Product: N#CC1(c2ccc(Br)nc2)CCC(F)(F)CC1
Temperature: 120 °C
Yield: 65.1 %

Procedure:
To a stirred solution of 1-(6-chloro-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile (1.3 g, 5.1 mmol) in butyronitrile (100 mL) at room temperature under nitrogen atmosphere was added bromotrimethylsilane (1.55 g, 10.2 mmol). The reaction mixture was heated at 120° C. for 24 hours. The reaction mixture was then cooled to room temperature and poured into water (25 mL) and 10% aqueous NaOH solution (25 mL). The aqueous layer was extracted with diethyl ether (3×250 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was then purified by column chromatography on silica gel to afford 1-(6-bromo-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile as a white solid (1.0 g, 65%). LC-MS (m/z) 301.0 (MH+). 1H NMR (400 MHz, CDCl3) δ ppm 8.55 (d, J=2.7 Hz, 1 H), 7.69 (dd, J=8.4, 2.8 Hz, 1 H), 7.57 (d, J=8.4 Hz, 1 H), 2.09-2.41 (m, 8 H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.Cl.N[CH:31]1[CH2:36][CH2:35][O:34][CH:33](C)[CH2:32]1.[CH3:38][N:39](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[O:34]1[CH2:33][CH2:32][CH:31]([CH2:38][NH:39][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:14][C:15]4[S:16][C:17]5[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=5[N:19]=4)=[N:4][C:5]=3[CH:10]=2)=[O:13])[CH2:36][CH2:35]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC1CC(N)CCO1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC3CCOCC3)ccc21
Yield: 73.5 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide (91 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzo-thiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), 4-amino-methyltetrahydropyran hydrochloride (41 mg), HBTU (111 mg), and DIEA (64 uL). LC/MS: m/z 507.0. 1H NMR (DMSO-d6, 400 MHz): δ 8.47 (s, 1H), 8.08 (s, 1H), 7.91 (s, 1H), 7.77 (d, 1H), 7.73 (d, 1H), 7.48 (d, 1H), 7.35 (d, 1H), 3.86 (d, 2H), 3.63 (bs, 3H), 3.28 (t, 2H), 3.18 (t, 2H), 1.91-1.62 (m, 1H), 3.28 (d, 2H), 1.30-1.14 (m, 2H), —NH proton signal was not observed.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[CH:6]([C:9]1[O:13][N:12]=[C:11]([CH3:14])[CH:10]=1)[O:7][CH3:8].CN(C)C=O.[CH3:24][CH:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[H-].[Na+]>CCOCC>[CH3:8][O:7][CH:6]([C:9]1[O:13][N:12]=[C:11]([CH3:14])[CH:10]=1)[C:5]1[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=1[CH:3]=[N:2][O:1][CH:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:24]
Reactant: CC(Br)c1ccccc1
Reactant: COC(c1cc(C)no1)c1ccccc1C=NO
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(c1cc(C)no1)c1ccccc1C=NOC(C)c1ccccc1
Reaction time: 3 h
Yield: 91.3 %

Procedure:
To a mixture of 0.25 g (1 mmol) of 5-(2-hydroxyiminomethyl-α-methoxybenzyl)-3-methylisoxazole, 3 ml of N,N-dimethylformamide and 0.24 g (1.3 mmol) of α-methylbenzyl bromide was added 0.05 g (1.3 mmol) of 60% sodium hydride under ice-cooling and stirred at the same temperature for 3 hours. After completion of the reaction, 100 ml of ether was added and washed twice with 80 ml of brine. The ether layer was dried over anhydrous magnesium and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 5-[α-methoxy-2-(4-phenyl-2-aza-3-oxa-1-pentenyl)benzyl]-3-methylisoxazole (0.32 g, 91.3%) as colorless oil.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[Br:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1>CC(C)=O>[BrH:5].[C:2]([S:3][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)(=[NH:4])[NH2:1]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: NC(N)=S
Solvent: CC(C)=O
Product: Br
Product: N=C(N)SCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
To a solution of thiourea (3.87 g, 50.92 mmol) in acetone (15 mL) was added a solution of 1-(bromomethyl)-4-nitrobenzene (10 g, 46.29 mmol) in acetone (15 mL) and the mixture stirred at rt for 2 h upon which a white precipitate formed. After completion of reaction (by TLC), the mixture was filtered and solid washed with EtOAc and acetone respectively to afford the desired product as off-white solid (12.0 g, 89%). 1H NMR (DMSO-d6): δ 9.17 (br s, 4H), 8.24 (d, J=8.40 Hz, 2H), 7.70 (d, J=8.40 Hz, 2H) and 4.66 (s, 2H). MS: 212.08 [M+H]+
Reaction SMILES: [N:1]([CH2:4][C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:6])=[N+:2]=[N-:3].[Cl:13][C:14]1[C:21]([F:22])=[CH:20][C:17]([C:18]#[N:19])=[C:16](F)[CH:15]=1.[H-].[Na+].O>CN(C=O)C>[N:1]([CH2:4][C@@H:5]([O:6][C:16]1[CH:15]=[C:14]([Cl:13])[C:21]([F:22])=[CH:20][C:17]=1[C:18]#[N:19])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC[C@@H](O)c1ccccc1
Reactant: N#Cc1cc(F)c(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(F)c(Cl)cc1O[C@H](CN=[N+]=[N-])c1ccccc1
Yield: 69.8 %

Procedure:
The product from step (a) (1.75 g) and 4-chloro-2,5-difluorobenzonitrile (1.86 g) in dry DMF (40 ml) were treated with 60% sodium hydride in mineral oil (470 mg) with stirring under nitrogen. The reaction mixture was stirred for 2.5 h, poured into water, and extracted with ethyl acetate. The extract was washed with water (5×) then brine and dried (MgSO4). The solvent was evaporated and the residue purified by chromatography (silica, 10% ether/isohexane as eluent) to give the sub-title compound (2.37 g) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][C:11]([OH:13])=O.[OH-].[Na+]>Cl>[NH2:8][C:6]1[C:5]([F:9])=[CH:4][C:3]2[C:2]([CH:7]=1)=[N:1][C:11](=[O:13])[CH:10]=2.[F:9][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][C:6]=1[NH2:8])[NH:1][C:11](=[O:13])[CH2:10]2
Reactant: Nc1cc(N)c(CC(=O)O)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc2c(cc1F)=CC(=O)N=2
Product: Nc1cc2c(cc1F)CC(=O)N2
Temperature: 25 °C
Yield: 164.8 %

Procedure:
(2,4-Diamino-5-fluoro-phenyl)-acetic acid 9c (7.12 g, 38.7 mmol) was dissolved in 100 mL of hydrochloric acid (1 M) under stirring at room temperature, and the reaction solution was heated to reflux for 1 hour. The reaction was completed until TLC showed the disappearance of starting materials. The reaction mixture was naturally cooled down to room temperature, followed by an ice-water bath cooling, and 100 mL of sodium hydroxide solution (1M) was then added dropwise to neutralize the reaction solution. The mixture was extracted with ethyl acetate (125 mL ×4). The combined organic extracts were washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound 5-fluoro-6-amino-1,3-dihydro-indol-2-one 9d (5.3 g, yield 82.8%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][C@@H:19]([CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C:20]([O:22][CH3:23])=[O:21]>CO.C(Cl)(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][C@@H:19]([CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](CC1CCCCC1)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl (S)-2-amino-3-cyclohexylpropionate (Novabiochem), the title compound was prepared as a solid (mp=116-119° C.). The reaction was monitored by tlc (Rf=0.4 in 4% MeOH/CHCl3) and the product was purified by silica gel chromatography using 4% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-chlorobutane/hexanes.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[N:19][C:20]([N:22]5[CH2:27][CH2:26][N:25]([CH2:28][C:29](O)=[O:30])[CH2:24][CH2:23]5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:32]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C[N:34](C)C=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[N:19][C:20]([N:22]5[CH2:23][CH2:24][N:25]([CH2:28][C:29]([NH2:34])=[O:30])[CH2:26][CH2:27]5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:32]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCN(CC(=O)O)CC3)cc1OCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCN(CC(N)=O)CC3)cc1OCC2
Temperature: 25 °C

Procedure:
2-(4-(2-(1-Isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)piperazin-1-yl)acetic acid from Example 331 (0.050 g, 0.11 mmol) dissolved in N,N-Dimethylformamide (1.79 mL, 0.0231 mol) and treated sequentially with N,N-Diisopropylethylamine (0.119 mL, 0.686 mmol) Ammonium chloride (0.0244 g, 0.457 mmol) then N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (0.0521 g, 0.137 mmol;). Stir at r.t. 2 h. Add sat. sodium bicarbonate, extract with ethyl acetate. Dry organics over sodium sulfate and concentrate to give 332, analyzed by rHPLC. MS: (ESI+)=466.2. 1H NMR (400 MHz, DMSO) δ 9.11 (s, 1H), 7.89 (s, 1H), 7.85 (s, 1H), 7.20 (s, 2H), 6.35 (s, 1H), 5.93 (dt, J=13.7, 7.0 Hz, 1H), 4.50 (d, J=10.4 Hz, 4H), 3.57 (s, 5H), 2.91 (s, 2H), 1.47 (d, J=6.5 Hz, 6H).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:15]C)[C:9]=2[O:13]C)[C:4]1=[O:17].[BrH:18]>>[BrH:18].[NH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:15])[C:9]=2[OH:13])[C:4]1=[O:17]
Reactant: COc1ccc2c(c1OC)CCC(N)C2=O
Agent: Br
Agent: Cl
Product: NC1CCc2c(ccc(O)c2O)C1=O

Procedure:
30 parts of 2-amino-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride is subjected to boiling reflux in 500 volume parts of a 47 % aqueous solution of hydrogen bromide for 3 hours and, then, concentrated to dryness under reduced pressure. The residue is dissolved in methanol, followed by the addition of ethyl acetate, whereupon crystals separate. Filtrative recovery yields 31 parts of 2-amino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide.
Reaction SMILES: [NH2:1][N:2]1[CH2:6][C@@H:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:4]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:3]1=[O:25].N1C=CC=CC=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[CH3:32][S:33]([NH:1][N:2]1[CH2:6][C@@H:5]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)[N:4]([CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[C:3]1=[O:25])(=[O:35])=[O:34]
Reactant: COc1ccc(CCN2C(=O)N(N)C[C@H]2c2ccc(OC)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(CCN2C(=O)N(NS(C)(=O)=O)C[C@H]2c2ccc(OC)cc2)cc1
Reaction time: 2.5 h
Yield: 75 %

Procedure:
A solution of 1-amino-3-[2-(4-methoxyphenyl)-ethyl]-4-(R)-(4-methoxyphenyl)-2-imidazolidinone (247 g, 0.72 mol) in dichloromethane (2.35 L) and pyridine (174 mL, 2.15 mol) is cooled in an ice bath to 18° C. Methanesulfonyl chloride (73 mL, 0.94 mol) is added dropwise. The reaction is stirred cold for 2.5 hours then washed with 0.5 N HCl (2×1.5 L), brine (2×1.5 L) and dried (Na2SO4). The solvent is then removed in vacuo to afford a mixture of the desired product (75%) and unreacted starting material (25%) which is separated by liquid chromatography. [α]20D−39.83 (c 0.89, CHCl3) 1H NMR (300 MHz, CDCl3) δ 7.16 (d, J=8.81, 2H, ArH), 7.02 (d, J=8.51, 2H, ArH), 6.91 (d, J=8.81, 2H, ArH), 6.80 (d, J=8.81, 2H, ArH), 4.41 (m, 1H), 3.92 (m, 1H), 3.82 (s, 3H, CH3), 3.77 (s, 3H, CH3), 3.60-3.72 (m, 1H), 3.30 (m, 1H), 3.03 (s, 3H, CH3), 2.87-2.98 (m, 1H), 2.53-2.79 (m, 3H). MS 418 (MH+). Anal. Calcd. for C21H27N3O4S ¼H2O: C, 59.77; H, 6.57; N, 9.96. Found: C, 59.82; H, 6.06; N, 9.85. FAB-HRMS: anal. calcd for C21H27N3O4S: 418.18005. Found: 418.17960.
Reaction SMILES: [NH:1]([C:11]([O:13][CH2:14][CH:15]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].Cl.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH:35]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[C:51]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])(=[O:54])[CH:52]=O>ClCCCl.O>[CH:17]1[C:16]2[CH:15]([CH2:14][O:13][C:11](=[O:12])[NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]([CH2:35][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=3)[CH2:52][C:51](=[O:54])[O:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=Cc1ccccn1
Reactant: CC(C)(C)OC(=O)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)CN(CCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)Cc1ccccn1
Temperature: 0 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
A suspension of Fmoc-Lys-OH.HCl (4.859 g, 12 mmol) and 2-pyridinecarboxaldehyde (1.285 g, 12 mmol) in DCE (100 mL) was refluxed for 30 min under nitrogen. The reaction mixture was cooled to 0° C., and treated sequentially with NaBH(OAc)3 (6.36 g, 30 mmol) and crude tert-butyl glyoxalate (2.34 g, 18 mmol) The reaction mixture was stirred at room temperature for overnight and decomposed with water. The reaction mixture was extracted with DCM. The organic layer was dried and concentrated under reduced pressure. The residue was purified by flash chromatography over silica gel to afford ((S)-1-(9H-fluoren-9-yl)-14,14-dimethyl-3,12-dioxo-10-(pyridin-2-ylmethyl)-2,13-dioxa-4,10-diazapentadecane-5-carboxylic acid (1.924 g, 28%). 1H NMR (400 MHz, CDCl3) 8.89 (d, J=4.4 Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 8.02 (d, J=7.6 Hz, 2H), 7.88 (t, J=5.8 Hz, 2H), 7.81 (d, J=7.6 Hz, 1H), 7.66 (t, J=7.4 Hz, 2H), 7.60-7.53 (m, 4H), 6.03 (d, J=7.2 Hz, 1H), 4.67-4.22 (m, 8H), 3.64-3.53 (m, 2H), 3.12 (t, J=6.8 Hz, 2H), 2.19-2.08 (m, 2H), 1.92-1.79 (m, 2H), 1.73 (s, 9H); MS (ESI), 564 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=2[CH3:19])=[CH:8][CH:7]=1.[CH3:54][C:55]1[O:56][C:57]([C:61](Cl)=[O:62])=[C:58]([CH3:60])[N:59]=1>>[Cl:52][C:47]1[CH:46]=[C:45]([CH:50]=[CH:49][C:48]=1[Cl:51])[CH2:44][O:43][C:40]1[CH:41]=[CH:42][C:37]([C@H:35]2[CH2:34][O:33][C:29]3=[CH:30][C:31]4[CH2:32][C@@H:23]([C:21]([NH:20][C@@H:4]([CH2:5][C:6]5[CH:11]=[CH:10][C:9]([C:12]6[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=6[CH3:19])=[CH:8][CH:7]=5)[C:3]([OH:2])=[O:53])=[O:22])[N:24]([C:61]([C:57]5[O:56][C:55]([CH3:54])=[N:59][C:58]=5[CH3:60])=[O:62])[CH2:25][C:26]=4[CH:27]=[C:28]3[O:36]2)=[CH:38][CH:39]=1
Reactant: Cc1nc(C)c(C(=O)Cl)o1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Product: Cc1nc(C)c(C(=O)N2Cc3cc4c(cc3C[C@H]2C(=O)N[C@@H](Cc2ccc(-c3ccnc(C)c3C)cc2)C(=O)O)OC[C@H](c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)O4)o1

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (30 mg) was reacted with 2,4-dimethyl-oxazole-5-carbonyl chloride (prepared above) according to General Procedure F and purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (9 mg). LCMS (m/z) 862.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27]C)=[O:26])C(=O)C2=CC=CC=C12.O.NN.Cl>C(O)C>[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26]
Reactant: COC(=O)CCCCCCCCCCCCCCCCCCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCCCCCCCCCCCCCCCCCC(=O)O
Yield: 72 %

Procedure:
A mixture of methyl 20-phthalimidoeicosanoate (5.0 g, 10.6 mmoles), 100 ml of ethanol, 80% hydrazine hydrate (1.0 ml, 15.9 mmoles) was refluxed for 9 hours. After the addition of 26.5 ml of 6N aqueous hydrochloric acid, the reaction mixture was further refluxed for 1 hour. The insoluble matter that formed was removed by filtration. The filtrate was concentrated under reduced pressure. To the residue were added 70 ml of ethanol and 42.4 ml of 1N aqueous sodium hydroxide solution, and the obtained reaction mixture was refluxed for 16 hours. The reaction mixture was neutralized by adding 6N aqueous hydrochloric acid solution under ice-cooled condition. The precipitates that formed were collected by filtration and recrystallized from ethanolacetic acid-water, to give 20-aminoeicosanoic acid (2.50 g, 72%) having the following properties.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[O:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][O:20][CH:21]2[CH2:25][CH2:24][NH:23][CH2:22]2)[CH2:14][CH2:13]1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([N:23]2[CH2:24][CH2:25][CH:21]([O:20][CH2:19][CH2:18][N:15]3[CH2:14][CH2:13][O:12][CH2:17][CH2:16]3)[CH2:22]2)=[O:11])=[CH:7][CH:8]=1
Reactant: C1CC(OCCN2CCOCC2)CN1
Reactant: COc1ccc(N=C=O)cc1
Solvent: c1ccccc1
Product: COc1ccc(NC(=O)N2CCC(OCCN3CCOCC3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under anhydrous conditions 2.2 g. p-methoxyphenyl isocyanate in 10 ml. of reagent grade benzene was added dropwise to a stirring solution of 3.0 g. (0.15 mole) of 3-(2-morpholinoethoxy) pyrrolidine in 40 ml. of reagent grade benzene. After the addition was complete the reaction mixture was stirred overnight at room temperature and then concentrated at reduced pressure to give the theoretical yield of crude product, which would not crystallize nor form addition salts. The crude product was chromatographed on a column of magnesium silicate to give 1.4 g. of oily product. The nuclear magnetic resonance spectrum and mass spectrum analysis agreed with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:14])=O>ClCCl.CN(C)C=O>[ClH:14].[CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ncccc1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ncccc1C(=O)Cl
Product: Cl
Reaction time: 1 h
Yield: 169.9 %

Procedure:
To a solution of 2-methylnicotinic acid (470 mg) in dichloromethane (6 ml) were dropwise added oxalyl chloride (522 mg) and dimethylformamide (1 drop) at 0° C. under nitrogen atmosphere, and the mixture was stirred for 1 hour at the same condition. The mixture was concentrated and the residue was pulverized with diethyl ether to give 2-methylnicotinoyl chloride hydrochloride (671 mg) as a solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH:13]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][O:25][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])=[CH:20][CH:19]=1)[C:14]([O:16]C)=[O:15].[OH:36][Li].O>C1COCC1.O>[C:14]([CH:13]([C:18]1[CH:19]=[CH:20][C:21]([CH2:24][O:25][Si:26]([CH:30]([CH3:32])[CH3:31])([CH:33]([CH3:34])[CH3:35])[CH:27]([CH3:29])[CH3:28])=[CH:22][CH:23]=1)[CH2:12][NH:3][C:2]([C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:4]([OH:11])=[O:36])=[O:1])([OH:16])=[O:15]
Reactant: [Li]O
Reactant: COC(=O)C(CN1C(=O)c2ccccc2C1=O)c1ccc(CO[Si](C(C)C)(C(C)C)C(C)C)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](OCc1ccc(C(CNC(=O)c2ccccc2C(=O)O)C(=O)O)cc1)(C(C)C)C(C)C
Reaction time: 1.5 h

Procedure:
To methyl 3-(1,3-dioxoisoindolin-2-yl)-2-(4-((triisopropylsilyloxy)methyl)phenyl)propanoate (E134) in THF/H2O was added LiOH.H2O, and the solution was stirred for 1.5 h or until conversion to product was visible by LC-MS. The solution was then poured into EtOAc/NH4Cl(sat)/1 N HCl (3:1) and the aqueous layer was further extracted with EtOAc. The organics were dried (MgSO4), filtered, and evaporated to give crude 2-(2-carboxy-2-(4-((triisopropylsilyloxy)methyl)phenyl)ethylcarbamoyl)benzoic acid (E135).