Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)[C:2]([Cl:4])=O.[CH3:7][O:8][C:9]([CH:11]1[O:15][CH:14]([C:16]([OH:18])=O)[CH2:13][CH2:12]1)=[O:10]>ClCCl.CN(C)C=O>[Cl:4][CH2:2][C:16]([CH:14]1[O:15][CH:11]([C:9]([O:8][CH3:7])=[O:10])[CH2:12][CH2:13]1)=[O:18]
Reactant: COC(=O)C1CCC(C(=O)O)O1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C1CCC(C(=O)CCl)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (1.55 ml) was added to a stirred solution of (2RS, 5SR) -5-methoxycarbonyltetrahydrofuran-2-ylcarboxylic acid (2.00 g) in dichloromethane (30 ml). Dimethylformamide (1 drop) was added and the mixture stirred at room temperature for 1 h, and then heated to reflux for 10 min. The mixture was cooled and the solvent removed on a rotary evaporator. Chloroform was then evaporated from the residue twice. The residue was dissolved in dichloromethane (100 ml) and the solution cooled in an ice bath, then excess diazomethane was passed into the solution. The mixture was stirred at 0° C. for 15min and then excess hydrogen chloride was passed into the solution. The solution was washed with brine, dried over magnesium sulphate and evaporated. The title compound (2.02 g) was isolated by column chromatography of the residue using gradient elution (silica gel, 4:1 going to 1:1 hexane:ethyl acetate); νmax (CHCl3) 1740 cm-1 ; δH (CDCl3) 1.9-2.5 (4 H, m), 3.71 (3 H, s), 4.45-4.8 (2 H, m), 4.54 (1 H, d, J 18 Hz) and 4.89 (1 H, d, J 18 Hz).
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]#[C:17][C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=3)=[C:14]([CH3:25])[N:13]=[CH:12][N:11]=2)=[CH:6][C:5]=1[F:26].[Li+].[OH-]>O.C1COCC1>[NH2:24][C:21]1[N:20]=[CH:19][C:18]([C:17]#[C:16][C:15]2[C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:27])=[O:2])=[C:5]([F:26])[CH:6]=3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:25])=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(-c2ncnc(C)c2C#Cc2ccc(N)nc2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ncnc(-c2ccc(C(=O)O)c(F)c2)c1C#Cc1ccc(N)nc1
Temperature: 50 °C

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 2.28 g (6.29 mmol) 4-[5-(6-amino-pyridin-3-ylethynyl)-6-methyl-pyrimidin-4-yl]-2-fluoro benzoic acid methyl ester using 1.32 g (31.5 mmoL) LiOH in 5 mL water and 50 mL THF. The reaction mixture is stirred over night at 50° C. The solvent is removed under reduced pressure and the residue is taken up in water. Aqueous 1 M HCl is added until pH 5 is reached. The precipitated product is filtered off and taken up in water. After freeze drying 2.7 g of crude product is obtained which is used for the next step without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH:5]([O:8][CH3:9])[CH2:6][OH:7].Cl[C:11]1[N:16]=[C:15]([O:17][CH2:18][CH3:19])[CH:14]=[CH:13][N:12]=1.CC(O)=O>CN(C=O)C>[CH3:3][O:4][CH:5]([O:8][CH3:9])[CH2:6][O:7][C:11]1[N:16]=[C:15]([O:17][CH2:18][CH3:19])[CH:14]=[CH:13][N:12]=1
Reactant: CCOc1ccnc(Cl)n1
Reactant: COC(CO)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOc1ccnc(OCC(OC)OC)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
To a suspension of 60% NaH/mineral oil (2.55 g, 63.96 mmol) in anhydrous DMF (70 mL) at 0° C. under nitrogen atmosphere was slowly added glycolaldehyde dimethyl acetal (Aldrich, 5.65 g, 53.3 mmol). The mixture was stirred at ambient temperature for 1 hour and then transferred to a solution of the product from step (a) (8.05 g, 50.76 mmol) in anhydrous DMF (70 mL) at -55° C. over 15 minutes. The mixture was allowed to warm to -20° C. over 2 hours and then neutralized with AcOH. Solvent was evaporated in vacuo and the residue partitioned between H2O and CH2Cl2. The aqueous phase was extracted with CH2Cl2 and the combined organic phase was dried (Na2SO4) and evaporated in vacuo. The residue was flash chromatographed (EtOAc/hexanes, 1:4) to give the desired product (7.92 g, 69%) as a colourless oil: 1H NMR (CDCl3): δ1.37 (t, J=7.0 Hz, 3H), 3.44 (s, 6H), 4.36-4.43 (m, 4H), 4.78 (t, J=5.0 Hz, 1H), 6.34 (d, J=6.0 Hz, 1H), 8.15 (d, J=6.0 Hz, 1H); MS m/z 229 (M=1, 13%), 197 (100%). Anal Calcd. for C10H16N2O4 : C, 52.62; H, 7.07; N, 12.27. Found: C, 52.45; H, 7.01; N, 12.26.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[O:15][C:14]([NH2:16])=[N:13][N:12]=1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N:17]1[CH:22]=[CH:21][C:20]([C:23]2[NH:27][C:26]3[CH:28]=[CH:29][C:30]([C:32](O)=[O:33])=[CH:31][C:25]=3[N:24]=2)=[CH:19][CH:18]=1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.C(NC(C)C)(C)C>CN(C)C=O>[NH2:16][C:14]1[O:15][C:11]([CH:2]([NH:1][C:32]([C:30]2[CH:29]=[CH:28][C:26]3[NH:27][C:23]([C:20]4[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=4)=[N:24][C:25]=3[CH:31]=2)=[O:33])[CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[N:12][N:13]=1
Reactant: Nc1nnc(C(N)CCc2ccccc2)o1
Reactant: O=C(O)c1ccc2[nH]c(-c3ccncc3)nc2c1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: Nc1nnc(C(CCc2ccccc2)NC(=O)c2ccc3[nH]c(-c4ccncc4)nc3c2)o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.18 g of 5-(1-amino-3-phenylpropyl)-[1,3,4]oxadiazol-2-ylamine was dissolved in 10 ml of dry dimethylformamide at RT, treated with 200 mg of 2-pyridin-4-yl-1H-benzimidazole-5-carboxylic acid, 270 mg of TOTU, and 0.12 ml of diisopropylamine, and stirred at RT for 4 h. The reaction mixture was concentrated, and the residue was taken up in ethyl acetate and washed successively with water, saturated sodium hydrogencarbonate solution, water, and saturated sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered, and concentrated. The residue was stirred with methyl tert-butyl ether, filtered off, and dried under high vacuum. 2-Pyridin4-yl-1H-benzimidazole-5-carboxylic acid [1-(5-amino-[1,3,4]oxadiazol-2-yl)-3-phenylpropyl]amide, which melts at 160° C. with decomposition, is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([S:8]([N:11]2[C:16]3[CH:17]=[C:18]([C:21]([OH:23])=O)[CH:19]=[CH:20][C:15]=3[O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.C(N(CC)CC)C.[Cl-].[CH2:34]([O:36][C:37](=[O:45])[C:38]1[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=1)[CH3:35]>CC(C)=O.O1CCCC1>[CH2:34]([O:36][C:37](=[O:45])[C:38]1[CH:43]=[CH:42][C:41]([NH:44][C:21]([C:18]2[CH:19]=[CH:20][C:15]3[O:14][CH2:13][CH2:12][N:11]([S:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:24][CH3:25])(=[O:9])=[O:10])[C:16]=3[CH:17]=2)=[O:23])=[CH:40][CH:39]=1)[CH3:35]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCOc2ccc(C(=O)O)cc21
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCO3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid (1.0 g, 2.6 mmol) in acetone (130 mL) and tetrahydrofuran (30 mL) was treated with triethylamine (0.5 g, 0.68 mL, 1.9 equiv.) and stirred at room temperature overnight. A solution of cianuric chloride (596 mg, 3.2 mmol, 1.24 equiv.) in acetone (20 mL) was added dropwise over a period of 1 hour. The reaction mixture was stirred at room temperature for 4 hours, 4-amino-benzoic acid ethyl ester (775 mg, 4.7 mmol, 1.8 equiv.) was then added. The reaction mixture was stirred at room temperature overnight, the solvents were then removed. The residue was purified by flash chromatography, to yield 4-{[4-(5-chloro-2-methoxy-benzene-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester as a white solid, 0.91 g (66%). OH (300 MHz; CDCl3) 8.10 (1H, d), 8.03-8.07 (3H, m), 7.92 (1H, bs), 7.73 (2H, d), 7.70 (1H, d), 7.67 (1H, d), 7.53(1H, d), 7.50 (1H, d), 4.37 (2H, q), 4.03 (2H, m), 3.88 (2H, m), 3.56 (3H, s), 1.40 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:9]2[CH:10]([C:13]([O:15][CH3:16])=[O:14])[CH2:11][O:12][C:8]=2[CH:7]=1.[CH2:24]=[O:25].C[O-].[Na+]>CS(C)=O>[Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:9]2[C:10]([CH2:24][OH:25])([C:13]([O:15][CH3:16])=[O:14])[CH2:11][O:12][C:8]=2[CH:7]=1
Reactant: C=O
Reactant: COC(=O)C1COc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C1(CO)COc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
To a mixture of methyl 6-((2,4-dichlorobenzyl)oxy)-2,3-dihydro-1-benzofuran-3-carboxylate (400 mg) and DMSO (11 mL) were added paraformaldehyde (37.4 mg) and sodium methoxide (6.8 mg). The mixture was stirred at room temperature for 2 h. The mixture was quenched with water and 1N HCl at 0° C. and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (332.6 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]#[N:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][OH:15])[CH:9]=2)=[CH:6][N:7]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([NH:25][NH2:26])=O.C[O-].[Na+]>CO>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=2)=[N:4][C:3]=1[C:16]1[NH:26][N:25]=[C:23]([C:19]2[S:18][CH:22]=[CH:21][CH:20]=2)[N:17]=1
Reactant: NNC(=O)c1cccs1
Reactant: N#Cc1nc(-c2cccc(CO)c2)cnc1N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1ncc(-c2cccc(CO)c2)nc1-c1nc(-c2cccs2)n[nH]1
Yield: 6.1 %

Procedure:
To a solution of 3-amino-6-[3-(hydroxymethyl)phenyl]pyrazine-2-carbonitrile (149 mg, 0.74 mmol) was added thiophene-2-carboxylic acid hydrazide (94 mg, 0.66 mmol), sodium methoxide (53 mg, 0.996 mmol) in MeOH (5 mL). After reflux for 4 days, the reaction mixture was extracted with ethyl acetate (10 mL×3) and dried over MgSO4. Filteraction and concentration in vacuo gave a crude product, which was purified by preparative HPLC (0.1% TFA in water/0.1% TFA in CH3CN). The product fractions were neutralized by aqueous saturated sodium bicarbonate solution and partitioned with ethyl acetate. The aqueous phase was extracted once with additional ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride then dried over anhydrous magnesium sulfate. Filtration and concentration in vacuo gave the (3-{5-amino-6-[3-(2-thienyl)-1H-1,2,4-triazol-5-yl]pyrazin-2-yl } phenyl)methanol (14 mg, yield): 1H NMR (400 MHz, CD3OD): δ 8.65 (s, 1H), 8.14 (s, 1H), 8.02 (d, 1H), 7.77 (m, 1H), 7.53 (m, 1H), 7.47 (m, 1H), 7.38 (m, 1H), 7.17 (m, 1H), 4.72 (s, 2H); MS (EI) for C17H14N6O: 351.10 (MH+).
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@@H:8]([C:20](=[O:35])[N:21]([CH3:34])[C@@H:22]([C:30](=[O:33])[NH:31][CH3:32])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O.O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:34][N:21]([C@@H:22]([C:30](=[O:33])[NH:31][CH3:32])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:20](=[O:35])[C@H:8]([NH:7][CH3:6])[CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1cccc2ccccc12)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1cccc2ccccc12)NC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.3 %

Procedure:
Methyl-((1R)-1-(methyl-((1R)-1-methylcarbamoyl-2-phenylethyl)carbamoyl)-2-(1-naphthyl)ethyl)carbamic acid tert butyl ester (0.77 g; 1.52 mmol) was dissolved in methylene chloride (4 mL) and trifluoroacetic acid (4 mL) was added. The reaction mixture was stirred for 30 min at room temperature. Water (5 mL) and methylene chloride (5 mL) were added. An aqueous solution of sodium hydrogen carbonate was added until pH 8. The organic phase was extracted with methylene chloride (3×10 mL) and dried (magnesium sulfate). The solvent was removed in vacuo to afford 0.64 g of (2R)-N-methyl-2-methylamino-N-((1R)-1-methylcarbamoyl-2-phenylethyl)-3-(1-naphthyl)propionamide.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:44])[C@@H:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:43])[CH2:9][CH2:10][C@@:11]3([C:27]([NH:29][C@@H:30]4[CH2:34][CH2:33][C@H:32]([CH2:35][N:36]5[CH2:41][CH2:40][CH2:39][CH:38]([CH3:42])[CH2:37]5)[CH2:31]4)=[O:28])[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]32)[C:3]1([CH3:46])[CH3:45].N1C=CC=CC=1.[CH3:53][C:54]1([CH3:61])[CH2:58][C:57](=[O:59])[O:56][C:55]1=[O:60]>C(OCC)(=O)C>[CH3:53][C:54]([CH3:61])([CH2:58][C:57](=[O:59])[O:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:44])[C@@H:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:43])[CH2:9][CH2:10][C@@:11]3([C:27](=[O:28])[NH:29][C@@H:30]4[CH2:34][CH2:33][C@H:32]([CH2:35][N:36]5[CH2:41][CH2:40][CH2:39][CH:38]([CH3:42])[CH2:37]5)[CH2:31]4)[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]32)[C:3]1([CH3:45])[CH3:46])[C:55]([OH:60])=[O:56]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCCC(C)C4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC1(C)CC(=O)OC1=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCCC(C)C4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-N-((1R,3S)-3-((3-methylpiperidin-1-yl)methyl)cyclopentyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxamide (Example −50, 0.24 mmol) in pyridine (5 ml) dimethyl amino pyridine (0.32 g, 0.48 mmol) and 3,3-dimethyldihydrofuran-2,5-dione (1.3 ml) were added and the contents were refluxed for about 16 hours and completion of the reaction monitored by TLC. The reaction mixture was diluted with ethyl acetate (30 ml). The organic layer was washed with 5% aqueous HCl, washed with water followed by brine solution, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% MeOH in DCM as eluent to furnish the title compound (0.1 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.80-0.95 (m, 16H) 1.23-1.90 (m, 41H); 2.03-3.08 (m, 16H), 4.13-4.18 (m, 1H), 4.46 (s, 1H), 4.58 (s, 1H), 4.72 (s, 1H); 5.61-5.63 (m, 1H); ES Mass: [M+1] 778 (100%); HPLC: 78.4%.
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl-].[NH4+:5].[F:6][C:7]([F:13])([F:12])[CH2:8][CH2:9][CH2:10]O>O.CO>[NH2:5][CH:10]([CH2:9][CH2:8][C:7]([F:13])([F:12])[F:6])[C:1]#[N:2]
Reactant: [C-]#N
Reactant: [NH4+]
Reactant: OCCCC(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#CC(N)CCC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.8 %

Procedure:
To a solution of sodium cyanide (10 g, 0.20 mol, 1 eq) in water (50 ml) at room temperature are added successively ammonium chloride (12 g, 0.22 mol, 1.1 eq.) and 4,4,4-trifluorobutanol a4 (25 g, 0.20 mol, 1 eq) dissolved in methanol (50 ml). The mixture is stirred overnight at room temperature. The reaction mixture is quenched with water and extracted with ethyl acetate (3 times). The organic layers are dried over MgSO4, filtered and evaporated under reduced pressure to afford 34 g of 2-amino-5,5,5-trifluoropentanenitrile a5.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][N:6]([CH2:8][CH2:9][C@H:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:7])[CH3:2].[C:19]1([C:25]2[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][N:6]([CH2:8][CH2:9][C@H:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[O:17][C:28]1[CH:29]=[CH:30][C:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:26][CH:27]=1)[CH3:7])[CH3:2]
Reactant: CCOC(=O)CN(C)CC[C@H](O)c1ccccc1
Reactant: Oc1ccc(-c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CN(C)CC[C@@H](Oc1ccc(-c2ccccc2)cc1)c1ccccc1
Yield: 22 %

Procedure:
prepared by Mitzunobu reaction (analogously to Example 8C, Step 1) of [S]-(−)-N-(3-hydroxy-3-phenylpropyl)sarcosine ethyl ester (from step 1) with 4-phenylphenol (Aldrich)—yield 22%; [α]D25+22.3° (c 8.1, CHCl3). See Reaction 26, FIG. 3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[CH:5]=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[SH:18].C([O-])(=O)C.[Pb+4].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[S:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=2)[CH:7]=[C:8]([Br:10])[CH:9]=1
Reactant: Nc1ccccc1S
Reactant: O=Cc1cc(Br)cc(Br)c1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: O
Solvent: CC(=O)O
Product: Brc1cc(Br)cc(-c2nc3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.03 g (19.1 mmol) of 3,5-dibromobenzaldehyde and 3.1 mL (28.6 mmol) of 2-aminothiophenol were dissolved in 60 mL of acetic acid. The solution was agitated at room temperature for 30 minutes. 9.78 g (21.0 mmol) of lead(IV) acetate was added thereto. The resulting mixture was agitated at 50° C. for 1 hour. Then, water was poured into the reactant. It was extracted with ethyl acetate. The extract was separated through a column and dried, obtaining 4.74 g (Y=67%) of a white solid.
Reaction SMILES: F[C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=1)=[O:5].[OH-:25].[Li+].[CH3:27][OH:28]>>[F:22][C:21]([F:24])([F:23])[O:25][C:2]1[CH:20]=[CH:19][C:27]([O:28][C:2]2[CH:20]=[C:19]([C:21]([F:22])([F:24])[F:23])[CH:18]=[CH:17][C:3]=2[C:4]([NH:6][C:7]2[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)=[O:5])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(NC(=O)c2ccc(C(F)(F)F)cc2F)cc1
Reactant: CO
Reactant: [OH-]
Agent: [Li+]
Product: O=C(O)c1ccc(NC(=O)c2ccc(C(F)(F)F)cc2Oc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
To the ester from the previous step were added lithium hydroxide (2M, 450 μL, 0.9 mmol) and methanol (300 μL) and the reaction was stirred at 50° C. for 3 hours. The reaction was filtered and purified by reverse phase preparative chromatography utilizing a gradient of 3 0-99% acetonitrile in water containing HCl as a modifier to yield 4-(2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamido)benzoic acid (7) (53.8 mg, 37%). ESI-MS m/z calc. 485.07. found 486.3 (M+1)+; Retention time: 2.05 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 10.85 (s, 1H), 7.96-7.86 (m, 3H), 7.78-7.67 (m, 3H), 7.45-7.35 (m, 3H), 7.24-7.17 (m, 2H) ppm.
Reaction SMILES: C(N(C(C)C)CC)(C)C.N1([C:15]2[CH2:19][CH2:18][CH2:17][CH:16]=2)CCCC1.Cl[CH2:21][C:22]1[C:27]([CH2:28]Cl)=[CH:26][CH:25]=[CH:24][N:23]=1.[OH-:30].[Na+]>C(#N)C>[N:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[CH2:28][CH:15]3[C:16](=[O:30])[CH:17]([CH2:21][C:22]=12)[CH2:18][CH2:19]3
Reactant: ClCc1cccnc1CCl
Reactant: [OH-]
Reactant: C1=C(N2CCCC2)CCC1
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1C2CCC1Cc1ncccc1C2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Diisopropylethylamine (6.6 mL, 38 mmol) and 1-pyrrolidinocyclopentene (2.8 mL, 19 mmol) were added to a stirred solution of freshly prepared 2,3-bis(chloromethyl)pyridine [K. Tsuda et al; Pharm. Bull. 1, 1953, 142 ] (2.6 g, 15 mmol) in dry acetonitrile (50 mL) at 0° C. under nitrogen. The reaction was stirred for 15 minutes at this temperature, then 1 hour at room temperature. The mixture was then stirred and heated at reflux for 2 hours. The reaction was allowed to cool, the volatiles removed in vacuo, and the residue taken up in water (40 mL). Concentrated hydrochloric acid was added to give pH 1, and the mixture heated at reflux for 24 hours. The reaction was cooled to 0° C. and basified with 4N aqueous sodium hydroxide, and the dark mixture extracted with dichloromethane (×4). The combined extracts were dried (Na2SO4), filtered and evaporated, and the residue purified by chromatography on silica gel, eluting with 80% ethyl acetate/hexanes to 100% ethyl acetate to give (6S/R,9R/S)-5,6,7,8,9,10-hexahydro-6,9-methanocycloocta[b]pyridin-11-one (700 mg) as a dark oil (˜75% pure); MS (ES+) 188 ([MH]+). This material was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7]2[N:8]=[C:9]([S:11][CH2:12][C:13]([OH:15])=O)[S:10][C:6]=2[CH:5]=1)[CH3:2].C(N(CC)CC)C.N1(OC(=[N+](C)C)N(C)C)C2C=CC=CC=2N=N1.[B-](F)(F)(F)F.CCCC[P+](C1SC(C(OC)=O)=C(C(OC)=O)S1)(CCCC)CCCC.[Cl:73][C:74]1[CH:75]=[C:76]([CH:84]=[CH:85][C:86]=1[Cl:87])[CH2:77][N:78]1[CH2:81][CH:80]([CH2:82][NH2:83])[CH2:79]1>ClCCl>[Cl:73][C:74]1[CH:75]=[C:76]([CH:84]=[CH:85][C:86]=1[Cl:87])[CH2:77][N:78]1[CH2:81][CH:80]([CH2:82][NH:83][C:13](=[O:15])[CH2:12][S:11][C:9]2[S:10][C:6]3[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:17]=[CH:16][C:7]=3[N:8]=2)[CH2:79]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)C1
Reactant: CCOc1ccc2nc(SCC(=O)O)sc2c1
Agent: CCCC[P+](CCCC)(CCCC)C1SC(C(=O)OC)=C(C(=O)OC)S1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccc2nc(SCC(=O)NCC3CN(Cc4ccc(Cl)c(Cl)c4)C3)sc2c1
Reaction time: 3 h

Procedure:
A solution of (6-Ethoxy-benzothiazol-2-ylsulfanyl)-acetic acid (0.087 g, 0.326 mmol) in dichloromethane (3 ml) is treated with triethylamine (0.041 ml, 0.326 mmol) and [(Benzotriazol-1-yloxy)-dimethylamino-methylene]-dimethyl-ammonium; tetrafluoro borate (0.104 g, 0.326 mmol) and stirred at ambient temperature for 3 minutes. To the reaction mixture is added a solution of C-[1-(3,4-Dichloro-benzyl)-azetidin-3-yl]-methylamine (0.08 g, 3.26 mmol) in dichloromethane (1 ml), with stirred for a further 3 hours. The reaction mixture is partitioned between ethyl acetate and sodium bicarbonate solution. The organic phase is dried over magnesium sulphate and evaporated. The crude product is purified by flash silica chromatography using 95:5 dichloromethane:methanol as eluent to afford N-[1-(3,4-Dichloro-benzyl)-azetidin-3-ylmethyl]-2-(6-ethoxy-benzothiazol-2-ylsulfanyl)-acetamide. [MH]+ 495.8.
Reaction SMILES: [C:1]([NH:24][CH2:25][CH2:26][NH:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[OH:35])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\CC.[F:37][C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=1C1C=CC(O)=C(C(O)=O)C=1>>[F:37][C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=1[C:33]1[CH:32]=[CH:31][C:30]([OH:35])=[C:29]([C:28]([NH:27][CH2:26][CH2:25][NH:24][C:1](=[O:23])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20])=[O:36])[CH:34]=1
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCNC(=O)c1ccccc1O
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)NCCNC(=O)c1cc(-c2ccc(F)cc2F)ccc1O

Procedure:
2′,4′-Difluoro-4-hydroxy-N-(2-(5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamidoethyl)biphenyl-3-carboxamide was prepared in a similar fashion as N-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)-2-hydroxybenzamide, using the appropriate 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylic acid and EPA starting materials. Mass calculated for C35H42F2N2O3=576.72; found: [M+H]+=577.3.