Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27])=[N+:2]=[N-:3].[H-].[Na+].[CH2:30](Br)[C:31]#[CH:32].CO.C(Cl)Cl>CN(C=O)C.C(Cl)Cl>[N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:32][C:31]#[CH:30])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCOCCOCCOCCOCCOCCOCCOCCO
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: C#CCOCCOCCOCCOCCOCCOCCOCCOCCN=[N+]=[N-]
Reaction time: 4 h
Yield: 69.9 %

Procedure:
23-Azido-3,6,9,12,15,18,21-heptaoxatricosan-1-ol (azido-PEG8-ol) (1.1 g, 3.17 mmol, 1.0 equiv.) was dissolved in N,N′-dimethylformamide (6 mL), and sodium hydride (152 mg, 6.34 mmol, 2.0 equiv.) was added, followed by propargyl bromide (80% in PhMe, 683 μL 6.34 mmol, 2.0 equiv.). The reaction ran for 4 h at rt, at which time it was found complete by NMR aliquot. The reaction was taken up in CH2Cl2 (25 mL) and washed with a saturated aqueous ammonium chloride solution (25 mL). The aqueous solution was back-extracted with dichloromethane (2×10 mL), and combined organics were dried over MgSO4 and concentrated to a brown oil. Chromatography (3 cm×20 cm Silica gel, 3% MeOH/CH2Cl2) yielded azido-PEG8-yne (960 mg, 78% yield). IR (thin film/NaCl) 2874 (m), 2110 (m), 1160 (s), 1105 (s) cm−1; 1HNMR (400 MHz, CDCl3) δ 4.20 (d, J=2.4 Hz, 2H), 3.58 (m, 30H), 3.39 (t, J=5.1 Hz, 2H), 2.43 (t, J=2.4 Hz, 1H), 1.82 (s, 1H); 13CNMR (125 MHz, CDCl3) δ 79.82, 74.72, 70.75, 7022, 68.27, 58.62, 50.84; HRMS (ES+) calc'd for C19H35N3O8 (M+Na) m/z 456.231637. Found 456.23182.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:32]=[CH:33][C:34]=1[CH3:35])[C:12]([NH:14][C:15]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:18]=[C:17]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[C:16]=1[O:30][CH3:31])=[O:13])C1C=CC=CC=1.[H][H]>CO.O1CCCC1.[Pd]>[C:21]([C:19]1[CH:18]=[C:17]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[C:16]([O:30][CH3:31])=[C:15]([NH:14][C:12](=[O:13])[C:11]2[CH:32]=[CH:33][C:34]([CH3:35])=[C:9]([OH:8])[CH:10]=2)[CH:20]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: [H][H]
Reactant: COc1c(NC(=O)c2ccc(C)c(OCc3ccccc3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1c(NC(=O)c2ccc(C)c(O)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
7.10 g 3-benzyloxy-N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-4-methyl-benzamide are hydrogenated in a mixture of 70 ml of methanol and 40 ml of tetrahydrofuran in the presence of 800 mg palladium on activated charcoal (10% Pd) at ambient temperature and 50 psi partial hydrogen pressure. Then the catalyst is suction filtered and the filtrate is evaporated down using the rotary evaporator. A white solid remains, which is reacted further without any further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][C@H:34]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:46][C:47]1[NH:48][C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=1.N1C=CC=CC=1>C(Cl)Cl.O>[NH:48]1[C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=[C:47]1[NH:46][C:35](=[O:37])[C@@H:34]([C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=1)[CH2:33][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Nc1nc2ccccc2[nH]1
Reactant: O=C(O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1nc2ccccc2[nH]1)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 63.2 %

Procedure:
A solution of triphenylphosphine (274 mg, 1.04 mmol) in methylene chloride (6 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (211 mg, 1.18 mmol). The resulting brownish-purple mixture was stirred at 0° C. for 5 min until the reaction mixture became homogeneous. The reaction mixture was then treated with 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionic acid (prepared as in Example 3, 200 mg, 0.70 mmol). The reaction mixture was stirred at 0° C. for 20 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminobenzimidazole (139 mg, 1.04 mmol) and pyridine (0.17 mL, 2.09 mmol), and the reaction mixture was allowed to stir at 25° C. for 20 h. The resulting reaction mixture was diluted with water (15 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 75/25 hexanes/ethyl acetate) afforded N-(1H-benzoimidazol-2-yl)-3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionamide (178 mg, 64%) as an of-white foam: [α]23589=−26.7° (c=0.105, chloroform); EI-HRMS m/e calcd for C21H21Cl2N3O (M+) 401.1062, found 401.1062.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([CH:14]=[N:15][OH:16])[N:2]=1.[Br:17]N1C(=O)CCC1=O.C[Si]([C:29]#[CH:30])(C)C.C(N(CC)CC)C>C1COCC1>[Br:17][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[NH:12][C:13]1[CH:1]=[N:2][C:3]([C:14]3[CH:30]=[CH:29][O:16][N:15]=3)=[CH:4][C:5]2=1
Reactant: C#C[Si](C)(C)C
Reactant: O=C1CCC(=O)N1Br
Reactant: ON=Cc1cc2c(cn1)[nH]c1ccccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Brc1ccc2[nH]c3cnc(-c4ccon4)cc3c2c1
Temperature: 25 °C
Reaction time: 95 h

Procedure:
1.05 g (5 mmol) of β-carboline-3-carbaldehyde oxime is suspended in 50 ml of dry THF and combined at 0° C. with 1.8 g of N-bromosuccinimide in 20 ml of dry THF. The reaction mixture is heated to room temperature, stirred for 95 hours, and combined with 1.5 eq. of trimethylsilylacetylene and 2 ml of triethylamine. The mixture is further stirred overnight, poured on ice water, and extracted with ether. The organic phase is dried over magnesium sulfate, filtered, and the solvent drawn off. The remaining oil is dissolved in 10 ml of DMF and combined with 10 ml of sodium hydroxide solution (1-molar). The reaction mixture is stirred overnight at room temperature, poured on water, and extracted with ethyl acetate. The resultant product is purified by column chromatography with ethyl acetate as the eluent. Melting point: 292°-293° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:38])=[C:9]([CH2:11][O:12][C:13]2[CH:35]=[CH:34][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[CH:26]=O)=[CH:22][N:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:20]=3)=[CH:15][C:14]=2[O:36][CH3:37])[N:10]=1.[CH2:39]([P:48](=[O:55])([O:52][CH2:53][CH3:54])[O:49][CH2:50][CH3:51])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:38])=[C:9]([CH2:11][O:12][C:13]2[CH:35]=[CH:34][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[CH:26]=[CH:39]/[P:48](=[O:55])([O:49][CH2:50][CH3:51])[O:52][CH2:53][CH3:54])=[CH:22][N:21]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:20]=3)=[CH:15][C:14]=2[O:36][CH3:37])[N:10]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 82.3 %

Procedure:
To a mixture of (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenaldehyde (0.51 g), tetraethyl methylenediphosphonate (0.32 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.050 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (1E,3E)-4-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-1,3-butadienylphosphonate as colorless crystals (0.53 g, yield 82%) from a fraction eluted with ethyl acetate-hexane (8:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 143-144° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.[CH3:57][N:58]1[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:61]1[CH2:62][CH2:63][N:58]([CH3:57])[CH2:59][CH2:60]1)=[O:13])=[CH:5]2
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-chloroindole-2-carboxylic acid (0.234 g), HATU (0.569 g), HOAT (0.203 g) and N,N-diisopropylethylamine (0.191 mL) in DMF (0.6 mL) was treated with N-methylpiperazine (0.1 mL) stirred at ambient temperature for 48 h then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate solution and then brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (3-10% 2 M ammonia in methanol/dichloromethane) to give the title compound (0.18 g). 1H NMR (400 MHz, CDCl3): δ 9.60 (br s, 1H), 7.65 (d, J=1.5 Hz, 1H), 7.40 (d, J=8.6 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H), 7.26 (d, 1.8 Hz, 1H), 6.76 (d, J=1.5 Hz, 1H), 4.0 (br m, 4H), 2.56 (t, J=5.1 Hz, 4H), 2.41 (s, 3H). Analysis: Calc'd for C14H16ClN3O; C, 60.54; H, 5.81; N, 15.13; Found: C, 59.99; H, 5.94; N, 18.87.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][C@H:34]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:46][C:47]1[O:48][C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=1.N1C=CC=CC=1>C(Cl)Cl.O>[O:48]1[C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=[C:47]1[NH:46][C:35](=[O:37])[C@@H:34]([C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=1)[CH2:33][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Nc1nc2ccccc2o1
Reactant: O=C(O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1nc2ccccc2o1)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 82.9 %

Procedure:
A solution of triphenylphosphine (274 mg, 1.04 mmol) in methylene chloride (6 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (211 mg, 1.18 mmol). The resulting brownish-purple mixture was stirred at 0° C. for 5 min until the reaction mixture became homogeneous. The reaction mixture was then treated with 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionic acid (prepared as in Example 3, 200 mg, 0.70 mmol). The reaction mixture was stirred at 0° C. for 20 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminobenzoxazole (140 mg, 1.04 mmol) and pyridine (0.17 mL, 2.09 mmol), and the reaction mixture was allowed to stir at 25° C. for 20 h. The resulting reaction mixture was diluted with water (15 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 80/20 hexanes/ethyl acetate) afforded N-benzooxazol-2-yl-3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionamide (234 mg, 83%) as a light yellow foam: [α]23589=−33.1° (c=0.169, chloroform); EI-HRMS m/e calcd for C21H20Cl2N2O2 (M+) 402.0902, found 402.0901.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[N:8]1[C:13]([CH3:16])=[N:14][N:15]=[C:7]1[CH2:6][CH2:5]2.[Li]CCCC.CCCCCC.[B:28](OC(C)C)([O:33]C(C)C)[O:29]C(C)C>C1COCC1>[F:12][C:10]1[CH:11]=[C:2]([B:28]([OH:33])[OH:29])[CH:3]=[C:4]2[C:9]=1[N:8]1[C:13]([CH3:16])=[N:14][N:15]=[C:7]1[CH2:6][CH2:5]2
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1nnc2n1-c1c(F)cc(Br)cc1CC2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1nnc2n1-c1c(F)cc(B(O)O)cc1CC2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
7-Bromo-9-fluoro-4,5-dihydro-1-methyl[1,2,4]triazolo[4,3-a]quinoline (1-5, 3.90 g, 13.8 mmol) was dissolved under nitrogen atmosphere in dry THF and cooled to −78° C. A 2.5 M n-BuLi solution in hexane (V=6.60 ml, 16.6 mmol) was added dropwise and stirred at −78° C. for 30 min. Triisopropyl borate (V=4.5 ml, 19.3 mmol) was added in one portion and the temperature raised to −50° C. for additional 30 min. The mixture was allowed to warm up to 0° C. and quenched with a 1M KHSO4 solution in order to reach pH 3. The solution was basified with a 2M NaOH solution and washed twice with ethyl acetate. The water layer was neutralized with conc. HCl and the precipitate was successively washed with water and ether and dried under reduced pressure to obtain the title compound as a white solid; MS (ESI): m/z=248.04 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)[N:11]([CH2:22][C:23](O)=[O:24])[C:10](=[O:26])[C@H:9]1[CH2:27][CH:28]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=O)(C)(C)C.[NH2:35][C:36]1[CH:37]=[C:38]2[C:51](=[CH:52][CH:53]=1)[CH2:50][C@:40]1([C:48]3[C:43](=[N:44][CH:45]=[CH:46][CH:47]=3)[NH:42][C:41]1=[O:49])[CH2:39]2.Cl.C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH:28]1([CH2:27][C@H:9]2[NH:8][CH2:13][CH:12]([C:14]3[CH:15]=[C:16]([F:21])[CH:17]=[C:18]([F:20])[CH:19]=3)[N:11]([CH2:22][C:23]([NH:35][C:36]3[CH:37]=[C:38]4[C:51](=[CH:52][CH:53]=3)[CH2:50][C@:40]3([C:48]5[C:43](=[N:44][CH:45]=[CH:46][CH:47]=5)[NH:42][C:41]3=[O:49])[CH2:39]4)=[O:24])[C:10]2=[O:26])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(F)cc(F)c2)N(CC(=O)O)C(=O)[C@H]1CC1CCCCCC1
Reactant: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)[C@@H](CC2CCCCCC2)NCC1c1cc(F)cc(F)c1)Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Temperature: 50 °C
Reaction time: 1 h

Procedure:
0.20 g (0.42 mmol) 2-((3R)-4-(tert-butoxycarbonyl)-3-(cycloheptylmethyl)-6-(3,5-difluorophenyl)-2-oxopiperazin-1-yl)ethanoic acid (isomer 4.1.1.1), 0.11 g (0.45 mmol) (R)-5-amino-1,3-dihydrospiro[inden-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, 0.11 g (0.55 mmol) 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, 74 mg (0.55 mmol) HOBT, 0.06 ml (0.45 mmol) TEA and 2.0 ml DMF were stirred overnight at RT. The reaction mixture was concentrated by rotary evaporation. The residue was stirred with 15 ml of a 1.25M methanolic hydrochloric acid for 1 h at 50° C. The mixture was concentrated by rotary evaporation and the residue was purified by HPLC. The product-containing fractions were combined and lyophilised.
Reaction SMILES: [CH2:1]([O:19][P:20]([CH2:41][C:42]1[CH:47]=[C:46]([C:48]([CH3:51])([CH3:50])[CH3:49])[C:45]([OH:52])=[C:44](C(C)(C)C)[CH:43]=1)(=[O:40])[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[ClH:57]>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:19][P:20]([CH2:41][C:42]1[CH:47]=[C:46]([C:48]([CH3:51])([CH3:50])[CH3:49])[C:45]([OH:52])=[C:44]([Cl:57])[CH:43]=1)(=[O:40])[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Cl
Reactant: CCCCCCCCCCCCCCCCCCOP(=O)(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)OCCCCCCCCCCCCCCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOP(=O)(Cc1cc(Cl)c(O)c(C(C)(C)C)c1)OCCCCCCCCCCCCCCCCCC
Reaction time: 3 h

Procedure:
80.5 g of 3,5-di-tert. butyl-4-hydroxybenzyl-phosphonic acid di-n-octadecyl ester are dissolved in 250 ml of carbon tetrachloride and the solution is treated briefly with hydrogen chloride gas. The chlorination is effected by carefully bubbling in 10.5 g of chlorine gas for 3 hours at -5° C. The reaction mixture is allowed to come to room temperature and after stirring for a further 3 hours the solvent is removed in vacuo. The oily residue is digested with acetonitrile to purify the reaction product and the cyrstalline precipitate is isolated. The product is further purified by recrystallisation from aqueous ethylene glycol monomethyl ether. The resultant 3-chloro-5-tert. butyl-4-hydroxybenzyl-phosphonic acid di-n-octadecyl ester (stabiliser 3) forms white crystals with a melting point of 55° C.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[C:25]1([C:31]2[O:32][C:33]([CH3:49])=[C:34]([CH2:36][CH2:37][O:38]S(C3C=CC(C)=CC=3)(=O)=O)[N:35]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:23][O:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:38][CH2:37][CH2:36][C:34]2[N:35]=[C:31]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[O:32][C:33]=2[CH3:49])=[CH:11][CH:12]=1)[C:4]([OH:24])=[O:3]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1cccc(OC)c1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Product: COc1cccc(OC(C)(Cc2ccc(OCCc3nc(-c4ccccc4)oc3C)cc2)C(=O)O)c1

Procedure:
Standard Procedure (B) was utilized to prepare the title compound from 3-(4-hydroxy-phenyl)-2-(3-methoxy-phenoxy)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester. 1H NMR (400 MHz, CDCl3) δ 7.97-7.95 (m, 2H), 7.42-7.39 (m, 3H), 7.18-7.12 (m, 3H), 6.83 (d, 2H, J=8.99 Hz), 6.61-6.58 (m, 1H), 6.52-6.46 (m, 2H), 4.21 (t, 2H, J=6.65 Hz), 3.74 (s, 3H), 3.25 (d, 1H, J=13.69 Hz), 3.15 (d, 1H, J=13.69 Hz), 2.98 (t, 2H, J=6.65 Hz), 2.37 (s, 3H), 1.45 (s, 3H); HRMS (ES+) m/z exact mass calcd for C29H30NO6 488.2073, found 488.2083.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11](Cl)=[O:12].[NH2:14][CH2:15][C:16]1([C:27]2([OH:32])[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:19]2[C:20]3[O:24][CH:23]=[CH:22][C:21]=3[CH:25]=[CH:26][C:18]=2[CH2:17]1>ClCCl.C(N(C(C)C)CC)(C)C.O>[OH:32][C:27]1([C:16]2([CH2:15][NH:14][C:11]([C@@H:2]3[O:1][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][CH2:3]3)=[O:12])[C:19]3[C:20]4[O:24][CH:23]=[CH:22][C:21]=4[CH:25]=[CH:26][C:18]=3[CH2:17]2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NCC1(C2(O)CCCC2)Cc2ccc3ccoc3c21
Reactant: O=C(Cl)[C@H]1COc2ccccc2O1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCC1(C2(O)CCCC2)Cc2ccc3ccoc3c21)[C@H]1COc2ccccc2O1
Reaction time: 48 h

Procedure:
A solution of 762 mg of (2R)-2,3-dihydrobenzo[1,4]dioxin-2-ylcarboxylic acid chloride is added, at 0° C., to 900 mg of the compound obtained in Step A in 30 ml of dichloromethane and 1.2 ml of diisopropylethylamine. After 48 hours at room temperature, the reaction mixture is diluted with water and extracted with dichloromethane. Conventional treatment of the organic phases enables, after evaporation under reduced pressure, the expected product to be isolated in the form of a meringue.
Reaction SMILES: Cl.NC1C2C(=CC(CC(NC(=O)CNS(C3C(C)=C(C)C4OC(C)(C)CCC=4C=3C)(=O)=O)C(=O)N3CCCCC3)=CC=2)C=CN=1.[NH2:46][C:47]1[C:56]2[C:51](=[CH:52][C:53]([CH2:57][CH:58]([NH:67][C:68](=[O:74])OC(C)(C)C)[C:59](=[O:66])[N:60]3[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]3)=[CH:54][CH:55]=2)[CH:50]=[CH:49][N:48]=1.[CH3:75][C:76]([O:79][C:80](=[O:101])[CH2:81][C@H:82]([NH:86][S:87]([C:90]1[C:95]([CH3:96])=[CH:94][C:93]([O:97][CH3:98])=[C:92]([CH3:99])[C:91]=1[CH3:100])(=[O:89])=[O:88])C(O)=O)([CH3:78])[CH3:77].N[C@H](C(O)=O)CC(=O)OC(C)(C)C.COC1C=C(C)C(S([Cl:127])(=O)=O)=C(C)C=1C>>[ClH:127].[CH3:78][C:76]([O:79][C:80](=[O:101])[CH2:81][C@H:82]([NH:86][S:87]([C:90]1[C:95]([CH3:96])=[CH:94][C:93]([O:97][CH3:98])=[C:92]([CH3:99])[C:91]=1[CH3:100])(=[O:89])=[O:88])[C:68]([NH:67][CH:58]([CH2:57][C:53]1[CH:54]=[C:55]2[C:56](=[CH:51][CH:52]=1)[C:47]([NH2:46])=[N:48][CH:49]=[CH:50]2)[C:59](=[O:66])[N:60]1[CH2:61][CH2:62][CH2:63][CH2:64][CH2:65]1)=[O:74])([CH3:75])[CH3:77]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc2c(N)nccc2c1)C(=O)N1CCCCC1
Reactant: COc1cc(C)c(S(=O)(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)O)c(C)c1C
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1C
Agent: CC(C)(C)OC(=O)C[C@H](N)C(=O)O
Agent: Cc1c(C)c(S(=O)(=O)NCC(=O)NC(Cc2ccc3c(N)nccc3c2)C(=O)N2CCCCC2)c(C)c2c1OC(C)(C)CC2
Agent: Cl
Product: COc1cc(C)c(S(=O)(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)NC(Cc2ccc3c(N)nccc3c2)C(=O)N2CCCCC2)c(C)c1C

Procedure:
The procedure described for 5c was used. Deprotection of 5a and coupling with 121 mg of (2S)-2-[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]butanedioic acid 4-(1,1-dimethyl-ethyl)ester (prepared from Asp(OtBu)—OH and (4-methoxy-2,3,6-trimethylphenyl)-sulfonylchloride using the procedure described for 5b) yielded after purification 8 as a mixture of diastereomers (1:1). 1H-NMR 200 MHz (CD3OD) δ: 1.30 and 1.35 (9H, 2× s), 1.38-1.70 (6H, m), 2.12 and 2.14 (3H, 2× s) 2.18-2.51 (2H, m), 2.53 and 2.54, (3H, 2× s), 2.63 (3H, s) 2.85-3.54 (6H, m), 3.81 and 3.86 (3H, 2× s), 3.95-4.11 (1H, m), 5.03-5.21 (1H, 6.73 and 6.75 (1H, 2× s), 7.17-7.24 (1H, m), 7.52-7.78 (3H, m), 8.30-8.38 (1H, m).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH3:17])[CH3:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:49])[CH2:27][C:28](=O)[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[S:36][CH:37]=[C:38]([CH2:40][O:41]C3CCCCO3)[N:39]=2)[CH:30]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:11]1[C:12]([N:14]([CH2:16][CH3:17])[CH3:15])=[CH:13][C:8]2[N:7]=[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]4[S:36][CH:37]=[C:38]([CH2:40][OH:41])[N:39]=4)[CH:30]=3)[CH2:27][C:26](=[O:49])[NH:19][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nc(COC3CCCCO3)cs2)c1
Reactant: CCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nc(CO)cs3)c1)=N2

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(ethyl-methyl-amino)-phenyl]-carbamic acid tert-butyl ester (0.15 g) (Example J7) and 3-oxo-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl)-thiazol-2-yl]-phenyl]-propionic acid tert-butyl ester (0.23 g) (Example K27) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (0.14 g).