Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:13]>[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[OH:13]
Reactant: COc1cccc2c1CCCC2=O
Agent: [Pd]
Product: COc1cccc2c(O)cccc12
Temperature: 25 °C

Procedure:
In a 2000 ml flask a mixtuere of 5-methoxy-1-tetralone (30.0 g, 170.2 mmol) and 10% Pd/C (40 g) in 1000 ml p-cymenewas brought to reflux and monitored by LC-MS until no more starting material was present (approx. 24 h). The mixture was then cooled to room temperature and passed through a silica gel/celite plug and concentrated under vacuum to 26.6 g (90%) of an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ 3.90 (3H, s), 6.83 (1H, appd, J=7.5 Hz), 6.89 (1H, appd, J=7.7 Hz), 7.24 (1H, appt), 7.30 (1H, appt), 7.54 (1H, appd, J=8.5 Hz), 7.65 (1H, d, J=8.5 Hz), 9.98 (1H, s).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[CH3:14]O>>[NH2:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[C:5]([O:7][CH3:14])=[O:6]
Reactant: CO
Reactant: COc1ccc(N)c(C(=O)O)c1
Agent: Cl
Product: COC(=O)c1cc(OC)ccc1N
Temperature: 60 °C

Procedure:
Hydrogen chloride gas was bubbled through a solution of 2-amino-5-methoxybenzoic acid (5.0 g, 30 mmol) in MeOH (200 mL) for 30 minutes. The solution was heated at 60° C. overnight. The reaction was cooled and the solvent removed in vacuo. The residue was dissolved in water, basified with 5M NaOH and extracted twice with ether. The ether extracts were washed with 5M NaOH and water, dried (MgSO4), filtered and concentrated in vacuo to give i-e (4.25 g, 78%): MS m/z=182 (M+H).
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1)=[O:11])(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH:22][N:23]=[C:24]([C:31]#[N:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C.O>C(Cl)Cl>[C:1]([O:6][CH2:7][CH2:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([S:18]([O:22][N:23]=[C:24]([C:31]#[N:32])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1)=[O:11])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCCOC(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: N#CC(=NO)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C=C(C)C(=O)OCCOC(=O)c1cccc(S(=O)(=O)ON=C(C#N)c2ccccc2)c1
Temperature: 0 °C
Yield: 65.5 %

Procedure:
With cooling to 0° C. and with stirring, a solution of 16.6 g (0.05 mole) of 3-[2-(methacryloxy)ethoxycarbonyl]benzenesulfonyl chloride (1b) in 50 ml of CH2Cl2 is added dropwise to a solution of 7.3 g (0.05 mole) of α-hydroxyiminobenzyl cyanide (1c) and 5.05 (0.05 mole) of triethylamine in 100 ml of methylene chloride. The reaction mixture is subsequently stirred for 18 hours at room temperature. Water is then added to the reaction mixture, and the organic phase is separated, washed with water and dried over MgSO4. The solution is concentrated by evaporation, and the oily residue is dried under high vacuum, affording 14.5 g of the title compound as a viscous colourless mass.
Reaction SMILES: FC(F)(F)C(O)=O.COC1C=CC(C[N:15](CC2C=CC(OC)=CC=2)[C:16]2[C:25]3[N:26]=[C:27]([NH:33][CH3:34])[N:28]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:24]=3[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=2)=CC=1>[OH-].[Na+]>[CH3:34][NH:33][C:27]1[N:28]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[C:16]([NH2:15])[C:25]=2[N:26]=1
Reactant: CNc1nc2c(N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)nc3ccccc3c2n1CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CNc1nc2c(N)nc3ccccc3c2n1CC(C)C
Temperature: 70 °C
Yield: 37.8 %

Procedure:
Trifluoroacetic acid (150 mL) was added to N4,N4-bis(4-methoxybenzyl)-N2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2,4-diamine (15 g, 29.5 mmol), and the reaction was heated at 70° C. overnight and allowed to cool to ambient temperature. Aqueous sodium hydroxide (170 mL of 12 M) was added to adjust the solution to pH 9. The resulting mixture was extracted with chloroform (3×), and the combined extracts were washed with brine (3×), dried over magnesium sulfate, filtered through a layer of CELITE filter agent, and concentrated under reduced pressure. The residue was purified by automated flash chromagraphy (silica cartridge, eluting with 0-25% methanol in ethyl acetate). The resulting product was further purified twice by flash chromatography on silica gel (eluting first with 5-10% methanol in dichloromethane and then 5-7.5% methanol in dichloromethane) to provide 3 g of N2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2,4-diamine.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)([CH3:17])[CH2:15][OH:16]
Reactant: CC(C)(C)OC(=O)N1CCN(C(C)(C)CO)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CO)N1CCNCC1
Reaction time: 3 h

Procedure:
To a solution of 4-(2-hydroxy-1,1-dimethylethyl)piperazine-1-carboxylic acid tert-butyl ester (110 mg, 0.43 mmol) in DCM (3 mL) was added TFA (1 mL) and the resulting mixture stirred for 3 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording the title compound as an off-white solid (62 mg, 91%). 1H NMR (CDCl3, 400 MHz): δ 3.32 (2H, s), 2.90 (5H, t, J=4.78 Hz), 2.38-2.13 (4H, m), 1.03 (6H, s)
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[NH:9][C:10](=[O:19])[C:11]([OH:18])=[C:12]([C:14]([O:16]C)=O)[N:13]=1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([NH:33][C:14]([C:12]1[N:13]=[C:8]([CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:9][C:10](=[O:19])[C:11]=1[OH:18])=[O:16])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)c1nc(Cc2ccccc2-c2ccccc2)[nH]c(=O)c1O
Reactant: NCc1ccccc1
Product: O=C(NCc1ccccc1)c1nc(Cc2ccccc2-c2ccccc2)[nH]c(=O)c1O
Yield: 64.3 %

Procedure:
The synthesis was performed as in Example 21 using methyl 2-(biphenyl-2-ylmethyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate (0.070 g, 208 μmol) and benzylamine (0.5 ml; 4.58 mmol) to provide the title compound as an off-white solid (0.055 g; 64%). LCMS: m/z=412 (MH+).
Reaction SMILES: N1(C(N)=O)CCOCC1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]([C:23](O)=[O:24])[CH:20]=[N:21][CH:22]=2)=[CH:13][CH:12]=1.S(=O)(=O)(O)O>C1COCC1>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:18]=[C:19]([CH:23]=[O:24])[CH:20]=[N:21][CH:22]=2)=[CH:15][CH:16]=1
Reactant: O=C(O)c1cncc(-c2ccc(F)cc2)c1
Agent: NC(=O)N1CCOCC1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: O=Cc1cncc(-c2ccc(F)cc2)c1
Reaction time: 1 h
Yield: 98 %

Procedure:
6.0 g of 5-(4-fluorophenyl)pyridine-3-carboxylic acid morpholinamide from Example 1(b) are dissolved in 30 ml of THF, and 57 g of a 13.6% LiAlH—(OEt)3 solution in THF are added over the course of 10 minutes at 30° C. to 35° C. After 1 hour, 30 ml of 12.5% sulfuric acid are added, and the organic phase is separated off. The aqueous phase is adjusted to pH 1 using sulfuric acid and extracted a number of times with methyl tert-butyl ether. The organic phases are then combined, extracted once with water and then evaporated, leaving a residue of 4.3 g having a content of 97% by weight of 5-(4-fluorophenyl)pyridine-3-carbaldehyde (yield=98% of theory).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[C:8](Cl)=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)[CH3:2].[CH3:19][O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[C:8]([C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([O:20][CH3:19])[CH:26]=2)=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(C(F)(F)F)nc1Cl
Reactant: COc1cccc(B(O)O)c1
Product: CCOC(=O)C=Cc1ccc(C(F)(F)F)nc1-c1cccc(OC)c1
Yield: 54 %

Procedure:
3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid ethyl ester (103 mg, 0.368 mmol) was reacted with 3-methoxy phenyl boronic acid (2 eq) to give 3-[2-(3-methoxy-phenyl)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid ethyl ester (70 mg, 54%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([F:19])[C:10]=1[C:20]1[N:25]=[C:24]2[NH:26][N:27]=[C:28](I)[C:23]2=[CH:22][N:21]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[C:40]3[C:45](=[CH:46][CH:47]=2)[C:44](=[O:48])[NH:43][CH2:42][CH2:41]3)O1>>[F:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([F:19])[C:10]=1[C:20]1[N:25]=[C:24]2[NH:26][N:27]=[C:28]([C:38]3[CH:39]=[C:40]4[C:45](=[CH:46][CH:47]=3)[C:44](=[O:48])[NH:43][CH2:42][CH2:41]4)[C:23]2=[CH:22][N:21]=1
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Reactant: CC1(C)OB(c2ccc3c(c2)CCNC3=O)OC1(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5c(c4)CCNC5=O)n[nH]c3n2)c1F

Procedure:
This compound was prepared as a TFA salt by using procedures analogous to those described for the synthesis of Example 7, Step 3 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one. LCMS (M+H)+=438.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15](C)=[C:16](C)[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@@:10]3([CH2:25][C@H:24]3COC)[N:9]=2)=[CH:4][CH:3]=1.ClC1C=CC(C2C3C(C)=NSC=3[NH:39]C(=O)C3(CC3)N=2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[C:15]([CH3:16])=[N:39][S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C:10]3([CH2:25][CH2:24]3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: COC[C@@H]1C[C@]12N=C(c1ccc(Cl)cc1)c1c(sc(C)c1C)-n1c(C)nnc12
Reactant: Cc1nsc2c1C(c1ccc(Cl)cc1)=NC1(CC1)C(=O)N2
Product: Cc1nsc2c1C(c1ccc(Cl)cc1)=NC1(CC1)c1nnc(C)n1-2

Procedure:
A procedure analogous to that set forth for Compound 202 was followed, with the exception that 4′-(4-chlorophenyl)-3′-methylspiro[cyclopropane-1,6′-isothiazolo[5,4-e][1,4]diazepin]-7′(8′H)-one was used as starting material. LRMS (M+H)+: 356 m/z. 1H NMR (400 MHz, DMSO-d6) δ 7.25-7.65 (m, 4H), 2.62 (br. s., 3H), 1.91 (s, 3H), 1.85-1.89 (m, 2H), 1.78-1.82 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:18]O>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([O:14][CH3:18])=[O:13])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(-c2ccc(O)cc2)cc1

Procedure:
A solution of 4-(4′-hydroxyphenyl)benzoic acid (25.6 g) in 10% hydrochloric acid-methanol was stirred for 3 days at room temperature. Then the solvent was evaporated in vacuo and the residue was triturated with toluene-ethyl acetate (20:1) to afford methyl 4-(4′-hydroxyphenyl)benzoate (26.5 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:20]2[S:24][C:23]([C:25]([OH:28])([CH3:27])[CH3:26])=[N:22][CH:21]=2)[CH:6]=[C:7]([NH:9][C:10]2[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][N:11]=2)[CH:8]=1)#[CH:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([C:3]1[CH:4]=[C:5]([C:20]2[S:24][C:23]([C:25]([OH:28])([CH3:27])[CH3:26])=[N:22][CH:21]=2)[CH:6]=[C:7]([NH:9][C:10]2[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][N:11]=2)[CH:8]=1)[CH3:2]
Reactant: C#Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(C)(C)O)s2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(C)(C)O)s2)c1
Reaction time: 8 h
Yield: 61.7 %

Procedure:
To a solution of 2-[5-(3-ethynyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]propan-2-ol (19 mg, 0.047 mmol) in ethyl acetate (1 mL) was added Pd/C (10 wt %, 10.0 mg, 9.4 μmol), and the reaction vessel was then purged with H2 and stirred under an atmosphere of H2 (balloon) overnight. The catalyst was deactivated by addition of dichloromethane, then the mixture was filtered through Celite (ethyl acetate rinse) and concentrated in vacuo. The residue was then purified by preparative HPLC (50-90% CH3CN in 15 mM NH4HCO3(aq)) which provided 12 mg (0.029 mmol, 63%) of 2-[5-(3-ethyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]propan-2-ol as a white solid. MS ESI: [M+H]+ m/z 409.1. 1H NMR (400 MHz, (CD3)2CO): δ 9.20 (s, 1H); 8.82 (d, J=4.9 Hz, 1H); 8.12 (s, 1H); 7.94 (s, 1H); 7.67 (s, 1H); 7.25-7.20 (m, 2H); 5.02 (s, 1H); 2.70 (q, J=7.6 Hz, 2H); 1.63 (s, 6H); 1.28 (t, J=7.6 Hz, 3H). rhSYK activity=+++
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:25])[CH2:14][CH:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16](O)=[O:17])=[CH:8][CH:7]=1)=[O:5])[CH3:2].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:48][C:49]1[CH:54]=[CH:53][C:52]([NH:55][C:56]([NH:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[CH3:65])=[O:57])=[CH:51][CH:50]=1>CC#N>[CH3:65][C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][C:59]=1[NH:58][C:56]([NH:55][C:52]1[CH:51]=[CH:50][C:49]([NH:48][C:16](=[O:17])[CH:15]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:14][C:13]([NH:12][C:9]2[CH:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=2)=[O:25])=[CH:54][CH:53]=1)=[O:57]
Reactant: CCOC(=O)c1ccc(NC(=O)CC(C(=O)O)c2ccccc2)cc1
Reactant: Cc1ccccc1NC(=O)Nc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: CCOC(=O)c1ccc(NC(=O)CC(C(=O)Nc2ccc(NC(=O)Nc3ccccc3C)cc2)c2ccccc2)cc1
Reaction time: 24 h
Yield: 29.1 %

Procedure:
4-{[4-(Ethoxycarbonyl)phenyl]amino}-4-oxo-2-phenylbutanoic acid (400 mg, 1.17 mmol) was dissolved in MeCN (10 mL), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimidhydrochlorid (247 mg, 1.29 mmol), 1-hydroxy-1H-benzotriazol (158 mg, 1.17 mmol) followed by N-(4-aminophenyl)-N′-(2-methylphenyl)urea (282 mg, 5 1.17 mmol) was added at r.t and the reaction mixture was stirred for 24 h. Ethyl 4-[(4- {[4-({[(2-methylphenyl)amino]carbonyl} amino)phenyl]amino}-4-oxo-3-phenyl-butanoyl)amino]benzoate (194 mg, 0.34 mmol) was isolated by filtration as a colorless solid. M.p.>220° C.; TLC (DCM/MeOH 9/1) Rf 0.21; 1H NMR (400 MHz, D6-DMSO) δ 1.30 (t, J=7.1 Hz, 3H); 2.23 (s, 3H); 2.80 (mc, 1H); 3.25 (mc, 1H); 4.25–4.30 (m, 3H); 3.74 (s, 3H); 6.00 (bs, 1H); 6.65 (d, J=6.6 Hz, 2H); 6.90–6.96 (m, 2H); 7.10–7.19 (m, 4H); 7.34–7.38 (m, 2H); 7.43–7.51 (m, 2H); 7.69–7.71 (m, 1H); 7.79–7.90 (m, 2H); 8.70 (s, 1H); 8.97 (s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1(=[C:14]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([O:25]C(C)(C)C)=[O:24])=[CH:17][C:16]=2[F:30])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C(Cl)Cl>[C:8]1(=[C:14]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[CH:17][C:16]=2[F:30])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)cc2)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.1 %

Procedure:
Trifluoroacetic acid (2.0 mL) was added dropwise to 78 (210 mg, 0.514 mmol) dissolved in CH2Cl2 (2 mL) at 0° C. The reaction mixture was stirred at RT for 3 h and the volatiles were removed under reduced pressure. The residue was recrystallized (EtOAc:hexanes) to afford 98.0 mg (54%) of 79 as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 1.52 (br s, 6H), 1.98 (br s, 2H), 2.19 (br s, 2H), 6.52 (d, J=16.0 Hz, 1H), 6.66 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H), 7.11 (t, J=7.9 Hz, 1H), 7.42 (d, J=7.9 Hz, 1H), 7.52 (m, 2H), 9.33 (s, 1H), 12.40 (br s, 1H). LRMS (ESI): m/z 353 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:19][CH2:20][O:21][CH3:22].[I-].[Na+]>CN(C=O)C>[CH3:22][O:21][CH2:20][CH2:19][N:7]([C:3]([CH3:6])([CH3:4])[CH3:5])[S:8]([C:11]1[CH:12]=[CH:13][C:14]([I:17])=[CH:15][CH:16]=1)(=[O:9])=[O:10]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(I)cc1
Reactant: COCCBr
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCN(C(C)(C)C)S(=O)(=O)c1ccc(I)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25.2 %

Procedure:
Sodium hydride (71 mg, 1.77 mg) was added to a solution of N-t-butyl-4-iodobenzenesulphonamide (Method 73; 500 mg, 1.47 mmol), in anhydrous DMF (15 ml), under nitrogen at 0° C. The resulting suspension was stirred at 0° C. for 30 minutes. A solution of 1-bromo-2-methoxyethane (167 μl, 1.77 mmol), and sodium iodide (265 mg, 1.77 mmol) in DMF (15 ml) (which had been pre-stirred at ambient temperature for 1 hour), was then added dropwise to the mixture so that the reaction temperature was maintained at 0° C. and the mixture then stirred for 10 minutes. The mixture was allowed to warm to ambient temperature, and then heated at 60° C. for 20 hours and then allowed to cool to ambient temperature. A further solution of 1-bromo-2-methoxyethane (167 μl, 1.77 mmol), and sodium iodide (265 mg, 1.77 mmol), in DMF (15 ml), (pre-stirred at ambient temperature for 1 hour), was then added dropwise and the reaction mixture was heated at 60° C. for a further 20 hours. The mixture was then cooled and solvent removed by evaporation. The residue was dissolved in ether (25 ml), washed with 10% aqueous sodium hydroxide solution (20 ml), water (3×25 ml), and dried. The volatiles were removed by evaporation and the residue purified by flash chromatography on silica gel eluting with DCM to yield the title compound (147 mg, 25%), as a clear oil that crystallised on standing. NMR: 1.23 (s, 9H), 3.24 (s, 3H), 3.48 (s, 4H), 7.57 (d, 2H), 7.94 (d, 2H).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C@H:11]([C:15]([OH:17])=[O:16])[CH2:12][O:13][CH3:14])=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH:18]1(NC2CCCCC2)CCCCC1.O.COS(OC)(=O)=O.[OH-].[NH4+].Cl>CCCC(C)C.O1CCCC1>[C:3]([O:7][C:8]([N:10]([CH3:18])[C@H:11]([C:15]([OH:17])=[O:16])[CH2:12][O:13][CH3:14])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C1CCC(NC2CCCCC2)CC1
Agent: Cl
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: COS(=O)(=O)OC
Product: COC[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 56 %

Procedure:
Sodium hydride (2.1 g, 52.4 mmol) was washed with iso-hexane under a nitrogen atmosphere. Tetrahydrofuran (20 ml) was added and the suspension cooled in an ice/water bath. A mixture of N-(tert-butoxycarbonyl)-O-methyl-L-serine (starting material obtained by converting the dicyclohexylamine salt to the free base as described above in the pre-amble to the Examples) (2.5 g, 11.4 mmol) and water (41 μl, 2.28 mmol) in tetrahydrofuran (15 ml) was slowly added. The resulting mixture was allowed to stir for 20 minutes and dimethylsulfate (3.3 ml, 35.3 mmol) was slowly added. The mixture was stirred for 2 hours and treated with concentrated ammonium hydroxide (15 ml). The resulting mixture was stirred for a further 2 hours, then acidified with 2M hydrochloric acid, extracted with ethyl acetate, dried (MgSO4) and concentrated under reduced pressure. The residues were dissolved in methanol, absorbed onto an NH2 column, washed with methanol and eluted with 7N ammonia in methanol. Appropriate fractions were combined and evaporated under reduced pressure to give N-(tert-butoxycarbonyl)-N,O-dimethyl-L-serine (1.5 g, 56%) as a viscous, colourless oil; 1H NMR spectrum: (DMSO d6, 100° C.) 1.40 (s, 9H), 2.77 (s, 3H), 3.26 (s, 3H), 3.67 (m, 2H), 4.51 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[CH:4][CH:3]=1.BrC[CH:29]1[CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH2:18][CH:29]3[CH2:31][CH2:30]3)[CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: BrCC1CC1
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)n(CC2CC2)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 161, step 1, 5-[3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-1-methyl-1H-pyridin-2-one (example 162, step 3) was reacted with (bromomethyl)cyclopropane in the presence of potassium carbonate to give the title compound as a colorless foam, MS (ESI+): m/z=450.2 [M+H]+.
Reaction SMILES: [NH:1]([C:65]([O:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)=[O:66])[C@@H:2]([C:15]([NH:17][C@H:18]([C:26]([NH:28][C@@H:29]([C:37]([NH:39][C@H:40]([C:51]([N:53]1[CH2:64][CH2:63][CH2:62][C@H:54]1[C:55]([O:57]C(C)(C)C)=[O:56])=[O:52])[CH2:41][C:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[NH:44][CH:43]=1)=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[NH:25])[NH2:24])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7]C(OC(C)(C)C)=O>FC(F)(F)C(O)=O.C(S)C>[NH:1]([C:65]([O:67][CH2:68][C:69]1[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=1)=[O:66])[C@@H:2]([C:15]([NH:17][C@H:18]([C:26]([NH:28][C@@H:29]([C:37]([NH:39][C@H:40]([C:51]([N:53]1[CH2:64][CH2:63][CH2:62][C@H:54]1[C:55]([OH:57])=[O:56])=[O:52])[CH2:41][C:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[NH:44][CH:43]=1)=[O:38])[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:27])[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[NH:24])[NH2:25])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7]
Reactant: CC(C)(C)OC(=O)NCCCC[C@@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: CCS
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)NCCC[C@H](NC(=O)[C@@H](CCCCN)NC(=O)OCc1ccccc1)C(=O)N[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
1.55 g of Z-D-Lys(Boc)-Arg-D-Phe-Trp-Pro-OBut are dissolved in 14.5 ml of 90 percent strength trifluoroacetic acid and 1.5 ml of ethyl mercaptan. The solution is left to stand for 1 hour at room temperature and is concentrated. The residue is dissolved in water and chromatographed over a weakly basic ion exchanger (acetate form). The eluate is freeze-dried. Yield 883 mg. The peptide is purified by being chromatographed in 90 percent strength methanol over a crosslinked, hydroxypropylated dextran gel. Yield 570 mg, [α]D22 =-24.6° (c=1, methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:25])[CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=2[F:24])[C:19]#[N:20])=[CH:9][CH:8]=1>C1(C)C=CC=CC=1.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([OH:25])[CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=2[F:24])[C:19]#[N:20])=[CH:9][CH:8]=1
Reactant: N#Cc1ccc(F)c(OCC(=O)c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)c1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(F)c(OC[C@H](O)c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)c1
Reaction time: 0.5 h

Procedure:
100 mL dry THF, 75 mL of 1M (R)-CBS reagent in toluene, and 26.7 mL borane-diethylaniline complex were stirred together 20 min at room temperature. 3-{2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-ethoxy}-4-fluoro-benzonitrile (31.7 g) in 700 mL dry THF was then added through an addition funnel at rt over 30 minutes. The mixture stirred for 30 min, then was quenched by slow addition of 100 mL MeOH. After gas evolution ceased the mixture was evaporated to a yellow oil. The oil was dissolved in 200 mL ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated. The residue was stirred with hexanes and the hexanes layer removed. The resulting residue was purified over silica gel (DCM). 1H NMR (400 MHz, CDCl3): 7.54 (d, 1H), 7.46 (d, 1H), 7.38 (m, 2H), 7.3-7.15 (m, 4H), 6.97 (m, 2H), 5.13 (m, 1H), 5.03 (s, 2H), 4.10 (m, 2H), 2.64 (d, 1H).