Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[CH2:15][CH2:14][CH2:13]2)O.S(Cl)([Cl:21])=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[CH2:15][CH2:14][CH2:13]2)[Cl:21]
Reactant: O=S(Cl)Cl
Reactant: OC(c1ccc2c(c1)CCC2)c1ccccc1Cl
Solvent: c1ccccc1
Product: Clc1ccccc1C(Cl)c1ccc2c(c1)CCC2
Yield: 98.5 %

Procedure:
79.3 g (0.26 mol) of 2-chlorophenyl-indan-5-yl-carbinol, dissolved in 150 ml of benzene, are added dropwise to a mixture of 21.5 ml (0.26 mol) of thionyl chloride and 150 ml of benzene at 70° C. After heating the reaction mixture under reflux for five hours, it is evaporated. 71 g (98% of theory) of 2-chlorophenyl-indan-5-yl-chloromethane of refractive index nD20 =1.6050 are obtained. ##STR11##
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[C:13]([NH:15]OC)=[O:14])[CH2:8][CH2:7]1)[CH3:5].[CH3:24]CN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[C:45]([C:47]1[CH:55]=[C:54]([CH3:56])[C:50]([C:51](O)=[O:52])=[C:49]([CH3:57])[N:48]=1)#[N:46].CCN(C(C)C)C(C)C>CN(C=O)C>[C:45]([C:47]1[CH:55]=[C:54]([CH3:56])[C:50]([C:51]([NH:1][CH2:2][CH2:3][CH:4]([N:6]2[CH2:7][CH2:8][CH:9]([N:12]([CH2:18][C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)[C:13]([NH:15][CH3:24])=[O:14])[CH2:10][CH2:11]2)[CH3:5])=[O:52])=[C:49]([CH3:57])[N:48]=1)#[N:46]
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1cc(C#N)nc(C)c1C(=O)O
Reactant: CONC(=O)N(Cc1ccsc1)C1CCN(C(C)CCN)CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)N(Cc1ccsc1)C1CCN(C(C)CCNC(=O)c2c(C)cc(C#N)nc2C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.1 %

Procedure:
1-[1-(3-Amino-1-methyl-propyl)-piperidin-4-yl]-3-methoxy-1-thiophen-3-ylmethyl-urea (0.150 g, 0.44 mmol), EDCI (0.093 g, 0.48 mmol) and HOBt (0.066 g, 0.48 mmol) were combined in DMF (8 ml) to give a pale yellow solution. To this solution was added 6-cyano-2,4-dimethyl-nicotinic acid (0.091 g, 0.48 mmol) followed by DIPEA (126 μL, 0.66 mmol) and the resulting mixture was stirred at 25° C. for 16 h. Standard workup according to general procedure E gave the crude product as a tan oil. Purification by column chromatography on silica gel (Et2O:MeOH:NH4OH, 90:8:2, v/v/v) afforded 6-cyano-2,4-dimethyl-N-{3-[4-(3-methyl-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-nicotinamide (0.170 g, 77%) as a white foam. 1H NMR (CDCl3) δ 0.95 (m, 1H), 1.03 (d+m, 4H), 1.48 (m, 1H), 1.56-1.73 (m, 5H), 2.22 (br t, 1H), 2.32 (s, 3H), 2.54 (s, 3H), 2.58 (br t, 1H), 2.71-2.85 (m, 3H), 3.31 (m, 1H), 3.62 (s, 1H), 3.66 (m, 1H), 3.75 (s, 2H), 3.86 (m, 1H), 4.21 (m, 1H), 7.00 (m, 2H), 7.14 (s, 1H), 7.21 (s, 1H), 7.41 (m, 1H), 8.75 (br d, 1H); ES-MS m/z 499 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH:7]([NH2:15])[CH2:6]1.Cl[C:22]1[N:27]=[C:26]([NH2:28])[N:25]=[C:24]2[NH:29][N:30]=[CH:31][C:23]=12.C(N(C(C)C)CC)(C)C.O>CC(N(C)C)=O>[F:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH:7]([NH:15][C:22]2[N:27]=[C:26]([NH2:28])[N:25]=[C:24]3[NH:29][N:30]=[CH:31][C:23]=23)[CH2:6]1
Reactant: Nc1nc(Cl)c2cn[nH]c2n1
Reactant: NC1Cc2ccccc2N(Cc2ccc(F)cc2F)C1
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(NC2Cc3ccccc3N(Cc3ccc(F)cc3F)C2)c2cn[nH]c2n1
Temperature: 25 °C

Procedure:
1-(2,4-difluorobenzyl)-1,2,3,4-tetrahydroquinolin-3-amine, 4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-amine (200 mg, 1.2 mmol) and diisopropylethylamine (1 mL) in dimethylacetamide (6 mL) was stirred at 126° C. for 20 hours. After cooling to room temperature, water (15 mL) was added and the mixture extracted with ethyl acetate (3×15 mL). The combined organics were dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (100% ethyl acetate) to provide N4-(1-(2,4-difluorobenzyl)-1,2,3,4-tetrahydroquinolin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine as a light yellow solid (160 mg). M.p.=110-114° C. 1H NMR (DMSO-d6, 400 MHz) δ 12.43 (s, 1H), 7.83 (s, 1H), 7.62 (d, J=6.0 Hz, 1H), 7.34-7.21 (m, 2H), 7.03-6.95 (m, 3H), 6.58-6.54 (m, 2H), 6.00 (s, 2H), 4.66 (br, 1H), 4.54 (m, 2H), 3.55-3.51 (m, 1H), 3.39-3.29 (m, 1H), 3.09-3.04 (m, 1H), 2.89-2.81 (m, 1H). LCMS m/e 408 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.C(O[C:17](=O)[NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([C:25](=[O:30])N(OC)C)[CH2:21][CH2:20]1)(C)(C)C.[O:32]=[C:33]1[NH:38][C:37]2[CH:39]=[C:40](C=O)[CH:41]=[CH:42][C:36]=2[S:35][CH2:34]1>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:25]([C@H:22]3[CH2:21][CH2:20][C@H:19]([NH:18][CH2:17][C:40]4[CH:41]=[CH:42][C:36]5[S:35][CH2:34][C:33](=[O:32])[NH:38][C:37]=5[CH:39]=4)[CH2:24][CH2:23]3)=[O:30])[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2scnc12
Reactant: O=Cc1ccc2c(c1)NC(=O)CS2
Reactant: CON(C)C(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Product: COc1cccc2sc(C(=O)[C@H]3CC[C@H](NCc4ccc5c(c4)NC(=O)CS5)CC3)nc12

Procedure:
Using 4-methoxy-benzothiazole (5 mmol), [trans-4-(methoxy-methyl-carbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester (2.5 mmol) and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbaldehyde (0.3 mmol) according to the same protocol as that described for example 1, steps 1.a to 1.c, the title compound was obtained as a yellow solid (45 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:18]([CH2:19][CH3:20])[CH2:16][CH3:17])=[O:15]
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Reactant: CCNCC
Product: CCN(CC)C(=O)c1cnoc1-c1ccccc1Cl

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and diethylamine (4.4 mg, 0.060 mmol) as described in synthetic method A and thereafter purified by preparative HPLC method A to give a solid (3.8 mg). MS (pos) m/z 279.1 (M+1).
Reaction SMILES: CC(C)=O.[Br:5][C:6]1[N:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.Cl.Cl[CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>C(#N)C>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:10][N:11]=1
Reactant: Oc1ccc(Br)nc1
Reactant: ClCCN1CCCC1
Agent: Cl
Solvent: CC(C)=O
Solvent: CC#N
Product: Brc1ccc(OCCN2CCCC2)cn1

Procedure:
The product is obtained analogously to Example 3.1 e (1:1 mixture of acetone:acetonitrile instead of DMF) from 3.90 g (22.4 mmol) 6-bromo-pyridin-3-ol and 4.25 g (25.0 mmol) N-(2-chloroethyl)-pyrrolidine hydrochloride.
Reaction SMILES: C(Cl)(=O)C(Cl)=[O:3].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:22]([CH2:23][C:24]([OH:26])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:10][CH:9]=1.[NH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1.C(N(CC)CC)C>CN(C)C=O>[OH2:3].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:22]([CH2:23][C:24]([NH:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[O:26])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:12][CH:13]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Nc1cccnc1
Reactant: O=C(O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O
Product: O=C(Cn1c(-c2ccc(Br)cc2)nc2cccnc21)Nc1cccnc1
Temperature: 25 °C
Yield: 53 %

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (3.4 g, 0.0267 mole) was added dropwise (slowly) to a stirred and chilled (10° C.) solution of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (8.4 g, 0.0254 mole) in anhydrous dimethylformamide (50 ml). The reaction was heated at 55°-60° C. for 4 hrs, cooled to room temperature, and added dropwise to a stirred and chilled (10° C.) solution of 3-aminopyridine (2.6 g, 0.0279 mole) and triethylamine (5.4 g, 0.0534 mole) in anhydrous dimethylformamide (100 ml). The reaction mixture was stirred at room temperature overnight and then 100 ml of dimethylformamide was distilled off at 100 mm Hg. The residue was cooled and triturated in potassium bicarbonate solution (2×50 ml) and filtered. The filter cake was rinsed with water (2×50 ml) and recrystallized from isopropyl alcohol-isopropyl ether, giving 5.64 g, (53%) of solids. Recrystallization from isopropyl alcohol-isopropyl ether gave 2.3 g of an off-white solid, mp. 215°-217° C.
Reaction SMILES: C([O:4][C@H:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][C@@H:15]3[CH3:27])[C:8]=2[C@H:7]([CH3:28])[CH2:6]1)(=O)C.[Li+].[OH-]>C1COCC1>[OH:4][C@H:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][C@@H:15]3[CH3:27])[C:8]=2[C@H:7]([CH3:28])[CH2:6]1
Reactant: CC(=O)O[C@@H]1C[C@@H](C)c2c1ncnc2N1CCN(C(=O)OC(C)(C)C)C[C@@H]1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)C[C@@H]3C)c21
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.1 %

Procedure:
To a solution of the (S)-tert-butyl 4-((5R,7R)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (0.281 g, 0.72 mmol) in THF (5 mL) was added LiOH (3M, 2 mL). The mixture was stirred at room temperature for 6 hours and then quenched with 2N HCl (3 mL). The solvent was removed and the residue was purified by silica gel chromatography, eluting with ethyl acetate to give (S)-tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (0.206 g, 82%). 1H NMR (CDCl3, 400 MHz) δ 8.52 (s, 1H), 5.12 (m, 1H), 4.76 (br, 1H), 4.30-3.80 (m, 3H), 3.52 (m, 1H), 3.26 (m, 1H), 3.03 (br, 1H), 2.20 (m, 1H), 1.49 (s, 9H), 1.30-1.10 (m, 6H). MS (APCI+) [M+H]+349.
Reaction SMILES: [I:1]I.[NH2:3][C:4]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]>S([O-])([O-])(=O)=O.[Ag+2].C(O)C>[NH2:3][C:4]1[C:13]([I:1])=[CH:12][C:11]([F:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: II
Reactant: COC(=O)c1cc(F)ccc1N
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: COC(=O)c1cc(F)cc(I)c1N
Reaction time: 1 h
Yield: 93.1 %

Procedure:
Iodine (3.6 g, 14.2 mmol) was added to a mixture of methyl 2-amino-5-fluorobenzoate (2.4 g, 14.2 mmol), silver sulfate (4.42 g, 14.2 mmol) and ethanol (30 mL) at room temperature. The mixture was stirred under nitrogen for 1 h, and then quenched with a saturated solution of sodium bicarbonate, extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:10 hexanes/ethyl acetate) to afford methyl 2-amino-5-fluoro-3-iodobenzoate (3.9 g, 93%) as a light yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.66-7.58 (m, 2H), 6.21 (br s, 2H), 3.89 (s, 3H); 19F NMR (282 MHz, CDCl3) δ 127.87; MS (ESI+) m/z 296 (M+H).
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][N:11]([CH2:15][CH2:16][OH:17])[CH2:12][CH2:13][OH:14].[OH-:18].[Na+].O>C(Cl)Cl>[CH:1]1([C:7]([O:14][CH2:13][CH2:12][N:11]([CH3:10])[CH2:15][CH2:16][O:17][C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:18])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [OH-]
Reactant: CN(CCO)CCO
Reactant: O=C(Cl)C1CCCCC1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CN(CCOC(=O)C1CCCCC1)CCOC(=O)C1CCCCC1
Reaction time: 0.75 h

Procedure:
A solution of 73.31 g (0.50 mol) cyclohexanecarbonyl chloride in 200 ml of methylene chloride was added to a solution of 29.79 g (0.25 mol) of N-methyldiethanolamine, 20.0 g (0.50 mol) of sodium hydroxide and 200 ml of water over approximately 1 minute. The reaction was exothermic requiring the use of a reflux condenser. The reaction mixture was stirred for another 45 minutes after which the organic layer was separated, washed with water, dried over MgSO4 and concentrated. The residue was distilled to give product, bp=192°-9° C./0.30 mm.
Reaction SMILES: O.NN.[CH2:4]([C:8]1[O:12][N:11]=[C:10]([CH2:13][N:14]2C(=O)C3C(=CC=CC=3)C2=O)[CH:9]=1)[CH2:5][CH2:6][CH3:7].C(O)C>C1COCC1>[CH2:4]([C:8]1[O:12][N:11]=[C:10]([CH2:13][NH2:14])[CH:9]=1)[CH2:5][CH2:6][CH3:7]
Reactant: CCCCc1cc(CN2C(=O)c3ccccc3C2=O)no1
Agent: NN
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCc1cc(CN)no1
Yield: 86.1 %

Procedure:
A solution of hydrazine hydrate (888 mg, 15.1 mmol) in THF (5 mL) was added to a solution of 2-[(5-butylisoxazol-3-yl)methyl]-1H-isoindole-1,3(2H)-dione (2.14 g, 7.53 mmol) in 2:1 ethanol:THF (60 mL), and the solution was heated at reflux gently for four hours. A precipitate formed and was removed by filtration and washed with THF. The filtrate was concentrated under reduced pressure to provide 1.0 g of (5-butylisoxazol-3-yl)methylamine as a pale yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[N:9]1([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[C:23](=[O:27])[CH2:22][CH2:21][CH2:20]3)[CH:13]=[CH:12][N:11]=[CH:10]1.Cl.C([O-])(O)=O.[Na+]>N1CCCCC1.C(O)(=O)C>[N:9]1([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[C:23](=[O:27])[C:22](=[CH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:21][CH2:20]3)[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: O=Cc1ccccn1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: O=C1C(=Cc2ccccn2)CCc2cc(OCCn3ccnc3)ccc21
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 18.1 %

Procedure:
2-Pyridine carboxaldehyde (0.202 g, 1.9 mmol) was added to a mixture of 6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (1) (0.322 g, 1.2 mmol) in piperidine:acetic acid (30 μL:24 μL). The reaction mixture was heated in a 130° C. oil bath with efficient stirring for 1.5 hours. After cooling to room temperature, 2 mL of 1N HCl was added and the mixture stirred overnight. The mixture was made neutral with the addition of a saturated solution of NaHCO3 and then extracted into DCM (3×50 mL). The pooled extracts were washed sequentially several times with water, then brine, dried, filtered, and concentrated in vacuo to leave a dark brown oil. Purification by flash chromatography (silica gel, 135 g, 7% MeOH in DCM) afforded 0.075 g of the title compound as a light tan solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[C@H:5]([CH3:14])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.CN1CC[O:43][CH2:42]C1>ClCCl.C(O)=O>[CH3:2][O:3][C:4](=[O:15])[C@H:5]([CH3:14])[N:6]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[CH:42]=[O:43]
Reactant: COC(=O)[C@H](C)Nc1ccc(Cl)cc1
Reactant: CN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O=CO
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@H](C)N(C=O)c1ccc(Cl)cc1
Reaction time: 0.25 h

Procedure:
(±)-(4-Chlorophenyl)alanine methyl ester hydrochloride (2.00 g) was suspended in dichloromethane (20 ml), and 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide hydrochloride (1.60 g), 1-hydroxybenzotriazole monohydrate (1.23 g), N-methylmorpholine (1.90 ml) and formic acid (0.30 ml) were added to stir the mixture for 15 minutes. After a process in which formic acid (0.30 ml) was additionally added to stir the mixture for 15 minutes was repeated 3 times, the reaction mixture was diluted with dichloromethane. After an ogranic layer was washed with water and then dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane methanol=40:1) to obtain the title compound (1.21 g) as a yellow oil.
Reaction SMILES: [NH2:1][C@@H:2]([C:66]([CH3:69])([CH3:68])[CH3:67])[C:3]([N:5]1[C@H:9]([C:10](=[O:22])[NH:11][C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][CH2:13]2)[CH2:8][C@H:7]([C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][C@@H:28]([C:53](=[O:65])[NH:54][C@H:55]4[C:64]5[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=5)[CH2:58][CH2:57][CH2:56]4)[N:29]([C:33](=[O:52])[C@@H:34]([NH:44]C(OC(C)(C)C)=O)[C:35]([S:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])([CH3:37])[CH3:36])[CH2:30]3)=[CH:25][CH:24]=2)[CH2:6]1)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:44][C@H:34]([C:33]([N:29]1[C@H:28]([C:53](=[O:65])[NH:54][C@H:55]2[C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[CH2:58][CH2:57][CH2:56]2)[CH2:27][C:26]2[C:31](=[CH:32][C:23]([C@H:7]3[CH2:8][C@@H:9]([C:10](=[O:22])[NH:11][C@H:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[CH2:15][CH2:14][CH2:13]4)[N:5]([C:3](=[O:4])[C@@H:2]([NH2:1])[C:66]([CH3:69])([CH3:68])[CH3:67])[CH2:6]3)=[CH:24][CH:25]=2)[CH2:30]1)=[O:52])[C:35]([S:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])([CH3:37])[CH3:36]
Reactant: COC(=O)CSC(C)(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1Cc2cc([C@H]3C[C@@H](C(=O)N[C@@H]4CCCc5ccccc54)N(C(=O)[C@@H](N)C(C)(C)C)C3)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CSC(C)(C)[C@H](N)C(=O)N1Cc2cc([C@H]3C[C@@H](C(=O)N[C@@H]4CCCc5ccccc54)N(C(=O)[C@@H](N)C(C)(C)C)C3)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99.1 %

Procedure:
To a solution of methyl 2-(((R)-4-((S)-7-((3R,5S)-1-((S)-2-amino-3,3-dimethylbutanoyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-((tert-butoxycarbonyl)amino)-2-methyl-4-oxobutan-2-yl)thio)acetate (0.34 g, 0.35 mmol) in DCM (6 mL) was added TFA (1.2 mL, 15.6 mmol) slowly. The reaction mixture was stirred at rt for 40 min and concentrated in vacuo. The residue was basified with sat. aq. NaHCO3 solution to adjust the pH to 8-9. The resulting mixture was extracted with EtOAc (2×). The organic layers were combined and washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to afford the title compound as a white solid (0.30 g, 100%). MS (ESI+) m/z 865.5 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.[CH3:20][C:21]1([CH3:30])[CH2:26][C:25](=O)[CH2:24][C:23]([CH3:29])([CH3:28])[O:22]1>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:25]2[CH2:24][C:23]([CH3:29])([CH3:28])[O:22][C:21]([CH3:30])([CH3:20])[CH2:26]2)[C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C(=O)c2ccc(O)cc2)cc1
Reactant: CC1(C)CC(=O)CC(C)(C)O1
Product: COC(=O)c1ccc(C(=C2CC(C)(C)OC(C)(C)C2)c2ccc(O)cc2)cc1
Yield: 93 %

Procedure:
The general McMurry protocol, described for 14 was followed. Thus, methyl 4-[(4-hydroxyphenyl)carbonyl]benzoate (24 (0.196 g, 0.765 mmol) and 2,2,6,6-tetramethyltetrahydro-4H-pyran-4-one (52) (0.370 g, 2.37 mmol) were subjected for McMurry coupling reaction conditions. Standard work-up followed by purification by column chromatography gave 0.272 g (93%) of the title compound 101 as a white foam. 1H NMR (300 MHz, CDCl3): δ 7.98 (d, J=8.1 Hz, 2H), 7.26 (d, J=8.7 Hz, 2H), 7.05 (d, J=8.7 Hz, 2H), 6.78 (d, J=8.4 Hz, 2H), 3.92 (s, 3H), 2.27 (s, 2H), 2.21 (s, 2H), 1.28 (s, 6H), 1.25 (s, 6H). LCMS (ESI): m/z 379 (M−H)−.
Reaction SMILES: [CH2:1]([P:8]([NH:17][C@H:18]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24](O)=[O:25])=[O:21])[CH3:19])([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.Cl.[CH2:41]([O:48][C:49](=[O:55])[C@H:50]1[CH2:54][CH2:53][CH2:52][NH:51]1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:41]([O:48][C:49](=[O:55])[C@H:50]1[CH2:54][CH2:53][CH2:52][N:51]1[C:24](=[O:25])[C@@H:23]1[CH2:27][CH2:28][CH2:29][N:22]1[C:20](=[O:21])[C@H:18]([CH3:19])[NH:17][P:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9])[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 3 h

Procedure:
Dibenzylphosphoryl-L-alanyl-L-proline (1.4 g, 3.2 m mole), HOBt (476 mg, 3.5 m mole) and oily D-proline benzylester hydrochloride (968 mg, 4 m mole) were dissolved in DMF (5 ml) and WSC (0.64 ml, 3.5 m mole) were added thereto while cooling to -15° C. The reaction was carried out for 3 hours under cooling and then overnight at room temperature, and ethyl acetate (100 ml) was added to the reaction solution. The mixture was washed with 1N hydrochloric acid, 5% sodium bicarbonate and water in order, and then dried with anhydrous sodium sulfate. The solution was distilled under reduced pressure leaving an oily dibenzylphosphoryl-L-alanyl-L-prolyl-D-proline benzylester material.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]=[C:9]([NH2:12])[S:10][CH:11]=2)=[CH:4][CH:3]=1.[C:13]1([C:19]2[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]=[C:9]([NH:12][S:25]([C:22]3[CH:21]=[CH:20][C:19]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:24][CH:23]=3)(=[O:27])=[O:26])[S:10][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Nc1nc(-c2ccc(Cl)s2)cs1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Product: O=S(=O)(Nc1nc(-c2ccc(Cl)s2)cs1)c1ccc(-c2ccccc2)cc1

Procedure:
The title compound was prepared from 4-(5-chloro-2-thieny)-1,3-thiazol-2-amine and 4-phenylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (4.3 mg) with purity >80%. MS (pos) m/z 433.1, 435.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][N:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=1)[CH2:6][C:7]([O:9][CH3:10])=[O:8].[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>>[CH3:10][O:9][C:7](=[O:8])[CH2:6][N:5]([CH2:4][C:3]([O:2][CH3:1])=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:12]=1
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCBr
Reactant: COC(=O)CN(CC(=O)OC)c1cccc(O)c1
Product: CCCCC/C=C\C/C=C\CCCCCCCCOc1cccc(N(CC(=O)OC)CC(=O)OC)c1

Procedure:
Using this procedure, the reaction of N-(3-hydroxyphenyl-N-(2-methoxy-2-oxoethyl)glycine methyl ester with linoleyl bromide gave N-(2-methoxy-2-oxoethyl)-N-[3-[(9Z,12Z)-(9,12-octadecadienyl]oxy]phenyl]glycine methyl ester as an oil. The structure was confirmed by nmr and mass spectra.
Reaction SMILES: Br[CH:2]([CH3:10])[C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1>COCCOC>[CH3:10][C:2]1[N:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]2=[N:11][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: Nc1ccccn1
Reactant: CCOC(=O)C(=O)C(C)Br
Solvent: COCCOC
Product: CCOC(=O)c1nc2ccccn2c1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 115.5 %

Procedure:
To a solution of compound 1-B (1.25 g, 5.98 mmol) in DME (5 mL) was added 2-aminopyridine (0.563 g, 5.98 mmol) and the reaction mixture was allowed to warm to room temperature and stir for 18 h. The precipitate was filtered, washed with DME and dried in vacuo to afford 1.41 g of a white solid. The solid was dissolved in MeOH (20 mL) and refluxed for 18 h. The reaction mixture was cooled and the solvent evaporated under reduced pressure. The crude residue was partitioned between EtOAc and 10% NaHCO3, the layers separated and the organic phase washed with 10% NaHCO3, H2O, brine, dried over Na2SO4, filtered and the solvent evaporated under reduced pressure to afford 0.902 g of a white solid. The crude solid was purified by flash column chromatography (SiO2) eluting with a heptanes-EtOAc gradient to afford compound 1-C as a white solid (0.842 g, 69%). 1H-NMR (CDCl3): δ 7.90-7.92 (d, 1H), 7.65-7.68 (d, 1H), 7.21-7.25 (q, 1H), 6.88-6.92 (t, 1H), 4.44-4.50 (q, 2H), 2.80 (s, 3H), 1.44-1.48 (t, 3H); MS: m/z 205.2 (MH+).