Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][CH3:12])=[N:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[C:5]([NH:11][CH3:12])=[N:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CNc1ncc(Br)n2ccnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNc1ncc(-c2ccc(F)cc2)n2ccnc12
Temperature: 170 °C

Procedure:
To a solution of (5-bromo-imidazo[1,2-a]pyrazin-8-yl)-methyl-amine (intermediate O) (68 mg, 0.3 mmol) in DMF (4 ml) and water (2 ml) was added 4-fluorobenzene boronic acid (84 mg, 0.6 mmol), K2CO3 (165 mg 1.2 mmol), and Pd(PPh3)4 (35 mg, 0.1 eq). The mixture was heated at 170° C. in microwave for 6 min. The mixture was purified on a silica gel column to give the title compound.
Reaction SMILES: [C:1]([NH:3][C:4](=[NH:12])OC1C=CC=CC=1)#[N:2].[CH:13]1([NH2:23])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1.NC(=N)O.C1(C)C=CC=CC=1>C(Cl)(Cl)Cl>[C:1]([NH:3][C:4](=[NH:12])[NH:23][CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1)#[N:2]
Reactant: NC1CCCc2ccccc21
Reactant: N#CNC(=N)Oc1ccccc1
Agent: N=C(N)O
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: N#CNC(=N)NC1CCCc2ccccc21
Reaction time: 30 h

Procedure:
A mixture of 1.3 g of N-cyano-O-phenylisourea and 1.2 g of 1,2,3,4-tetrahydro-1-naphthylamine in 5 ml of chloroform was heated at reflux in an oil bath. Disappearance of the isourea was monitored by thin layer chromatography analysis. After 30 hours, the resulting thick solution was treated with 5 ml of toluene and allowed to stand at room temperature which resulted in the crystallization of the desired product. The supernatant solution was withdrawn and the product washed with toluene (10 ml). Upon drying under vacuum, 0.91 g of the desired compound was obtained. A second crop of crystals was collected after concentrating the mother liquor slightly. Total yield of N'-cyano-N-(1,2,3,4-tetrahydro-1-naphthyl)guanidine was 1.29 g, mp 153°-155° C.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].CC(C)([O-])C.[K+].Br[C:13]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:18])[C:14]([O:16][CH3:17])=[O:15].C(=O)=O.CO>C1COCC1>[C:3]([CH:2]([C:1]#[N:5])[C:13]([CH3:18])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])#[N:4]
Reactant: N#CCC#N
Reactant: COC(=O)C(C)(Br)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=C=O
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C(C)(c1ccccc1)C(C#N)C#N
Temperature: 25 °C

Procedure:
Malononitrile (4.29 g, 65 mmol) and potassium t-butoxide (7.29 g, 65 mmol) were added to a THF (100 mL) solution containing the intermediate from Step B (15.8 g, 65 mmol). The reaction solution was then placed in an 85° C. oil bath for 4 hours. The solution was then cooled to room temperature and partitioned between saturated aqueous ammonium chloride and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated racemic product. 1H NMR (500 MHz, CHCl3-d): δ 7.44-7.42 (m, 3H); 7.38-7.36 (m, 2H); 4.50 (s, 1H); 3.80 (s, 3H); 2.00 (s 3H). The racemic material was resolved on a Berger SFC II preparative instrument using a ChiralPak AD-H, 250×30 mm I.D. column and a SFC CO2/Methanol eluent.
Reaction SMILES: Cl.[CH3:2][CH:3]([O:5][C:6]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]4[CH2:28][NH:27][CH2:26][CH2:25][CH2:24][C:23]=4[CH:29]=3)[N:15]=2)=[CH:10][C:7]=1[C:8]#[N:9])[CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41].CCOC(C)=O>CN(C=O)C>[C:8]([C:7]1[CH:10]=[C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]4[CH2:28][N:27]([CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:26][CH2:25][CH2:24][C:23]=4[CH:29]=3)[N:15]=2)[CH:12]=[CH:13][C:6]=1[O:5][CH:3]([CH3:2])[CH3:4])#[N:9]
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCCNC4)no2)cc1C#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN1CCCc2cc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)ccc2C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 108.4 %

Procedure:
2-[(1-Methylethyl)oxy]-5-[3-(2,3,4,5-tetrahydro-1H-2-benzazepin-7-yl)-1,2,4-oxadiazol-5-yl]benzonitrile hydrochloride (Example 3) (70 mg, 0.170 mmol) and caesium carbonate (167 mg, 0.511 mmol) in dry DMF (5 ml) were treated with ethyl 4-bromobutyrate (0.037 ml, 0.256 mmol) and stirred at 60° C. for 2 hours. Additional quantities of ethyl 4-bromobutyrate (37 ul) were added and the reaction heated at 60° C. for 3 hours. The reaction was left standing overnight. EtOAc (50 ml) was added and the mixture washed with water (2×60 ml), dried over anhydrous MgSO4 and evaporated to yield the title compound (90 mg) as a clear, colourless oil. MS (ES) C28H32N4O4 requires 488; found 489.0 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:19][CH2:20][CH3:21])[C:17]#[N:18])=[CH:11][C:10]=1[N+:22]([O-])=O)C1C=CC=CC=1>C(O)C.C(O)(=O)C.[Pd]>[NH2:22][C:10]1[CH:11]=[C:12]([CH2:15][CH:16]([O:19][CH2:20][CH3:21])[C:17]#[N:18])[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: CCOC(C#N)Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(C#N)Cc1ccc(O)c(N)c1
Reaction time: 1 h
Yield: 57 %

Procedure:
A solution of 3-(4-benzyloxy-3-nitrophenyl)-2-ethoxypropanenitrile (0.54 g, 1.7 mmol) in ethanol (25 ml) and acetic acid (75 ml) containing 10% palladium on carbon (0.40 g) was hydrogenated at 45 psi for 1 hour. The catalyst was filtered and the solution concentrated. The residue was treated with 5% sodium bicarbonate (100 ml) and extracted with ethyl acetate (3×100 ml). The combined extracts were washed with water (2×100 ml) and brine (100 ml), dried over sodium sulfate and concentrated. The product was isolated by column chromatography (silica gel, 2% methanol in chloroform) as a solid (0.20 g, m.p. 114°-115° C.)
Reaction SMILES: C([N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=O)=C.C([N-]C(C)C)(C)C.[Li+].[Br:17][C:18]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:19]=1C(OC)=O.Cl>C1COCC1.O>[Br:17][C:18]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:19]=1[C:4]1[CH2:5][CH2:6][CH2:7][N:3]=1
Reactant: COC(=O)c1ccc(F)cc1Br
Reactant: C=CN1CCCC1=O
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(C2=NCCC2)c(Br)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 20.2 %

Procedure:
Treat a solution of 1-vinylpyrrolidin-2-one (2 g, 8.58 mmol) in dry THF (30 mL) with lithium diisopropylamide (LDA) (13 mL, 31.45 mmol) at −20° C. under N2 atmosphere and stir at the same temperature for 30 min. Then add methyl 2-bromo-4-fluorobenzoate (2 g, 8.58 mmol) and stir it over the weekend. Add an HCl (12 N, 9 mL) solution and water (12 mL). Remove the THF and add HCl (12 N, 12 mL) and water (15 mL). Heat it to 100° C. for 15 h. Cool the mixture to RT and add a 5% NaOH solution. Extract the solution with ether, dry over magnesium sulfate, and remove the solvent. Purify the residue by column chromatography (hexane to ethyl acetate) to give the title compound (0.42 g, 27%). MS (ES) m/z 244 [M+1]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:20])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=2)=[N:5]1.[C:21]([C:24]1[CH:28]=[C:27]([C:29](O)=[O:30])[NH:26][N:25]=1)(=[O:23])[CH3:22]>>[C:21]([C:24]1[CH:28]=[C:27]([C:29]([NH:1][C@@H:2]([CH3:20])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=3)=[N:5]2)=[O:30])[NH:26][N:25]=1)(=[O:23])[CH3:22]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c([N+](=O)[O-])c2)n1
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Product: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c([N+](=O)[O-])c3)n2)[nH]n1
Yield: 48.9 %

Procedure:
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-nitrobenzonitrile (400 mg, 1.48 mmol) was coupled with 3-acetyl-1H-pyrazole-5-carboxylic acid (250 mg, 1.62 mmol) using the method of Example 34(d). Crude product was purified by CombiFlash (column: silica, eluent: 0-10% MeOH in DCM) to yield 295 mg (49%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.18 (d, 3H), 2.49 (s, 3H), 4.26-4.55 (m, 3H), 7.04 (d, 1H), 7.30 (s, 1H), 7.86 (d, 1H), 8.18 (d, 1H), 8.31 (d, 1H), 8.50 (d, 1H), 8.63 (s, 1H), 14.1 (bs, 1H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1[N:12]=[C:11]([CH2:13][CH2:14][OH:15])[CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][S:2]([O:15][CH2:14][CH2:13][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:6])[N:12]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cccc(CCO)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cccc(CCOS(C)(=O)=O)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
MsCl (6.7 mmol, 0.52 mL) was added to a solution of 6-methyl-2-pyridineethanol (6.7 mmol, 0.92 g) and triethyl amine (13.4 mmol, 1.88 mL) in toluene (6 mL) at 0° C. dropwise. The resulting mixture was stirred at 0° C. for 30 min. The precipitate generated from reaction was filtered off. The filtrate was concentrated in vacuo to give crude 2-(6-methylpyridin-2-yl)ethyl methanesulfonate which was used for next step without further purification. A mixture of above described 2-(6-methylpyridin-2-yl)ethyl methanesulfonate, PhOH (13.4 mmol, 1.26 g) and NaOH (13.4 mmol, 0.54 g) in isopropanol (20 mL) was refluxed at 90° C. for 3 h. The reaction mixture was concentrated in vacuo and dissolved in EtOAc which was washed with water. The organic layer was separated, dried with MgSO4 and concentrated in vacuo. The crude product was purified by chromatography to give desired 2-methyl-6-(2-phenoxyethyl)pyridine as a colorless oil in 26% yield.
Reaction SMILES: N1C=CC=C[C:2]=1C(C1C=CC=CN=1)=O.[Br-].[C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:18])=[O:17].CC([O-])(C)C.[K+]>C1COCC1>[C:16]([OH:18])(=[O:17])/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][CH3:2]
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(c1ccccn1)c1ccccn1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC/C=C\C(=O)O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 59.1 %

Procedure:
To a cooled (0° C.) solution of 293.6 mg (0.74 mmol) of the pyridyl ketone and 670.4 mg (1.48 mmol) of (5-carboxypentyl)-triphenylphosphonium bromide in 2.5 mL of THF was added dropwise 2.95 mL (2.95 mmol) of 1.0 M t-BuOK in THF over 10 min period. The dark brown solution was stirred at 0° C. for 1.5 h, and then the reaction was quenched with 20 mL of saturated aqueous NH4Cl. The mixture was extracted with 3× 50 ML of CH2Cl2. The combined extract was dried over MgSO4, concentrated and purified by preparative HPLC with MeOH--AcOH--CH2Cl2 (2:1:97) as the eluent to afford 56.1 mg (8.4%) of the less polar (Z)-heptenoic acid and 434.9 mg of the (E)-isomer containing a byproduct from the Wittig salt. In order to purify it, the (E)-isomer was therefore esterified with CH2N2 which was generated by a standard method from MNNG and aqueous NaOH in Et2O. The ester was isolated cleanly by flash chromatography with EtOAc-hexanes-CH2Cl2 (2:1:1) as the eluent. The ester (102.5 mg) was then hydrolyzed with 1 N NaOH in THF--MeOH (1:1). Flash chromatography with EtOAc--MeOH--AcOH--CH2Cl2 (50:1:1:48) yielded 92.5 mg (25%) of the pure (E)-heptenoic acid: mp 56-61° C.; 1H NMR (CDCl3) δ8.58 (s, 1H), 8.47 (d, J=4.1 Hz, 1H), 8.26 (s, 1H), 8.02 (d, J=8.2 Hz, 2H), 7.44 (dt, J=8.0, 1.5 Hz, 1H), 7.35-7.16 (m, 9H), 6.19 (t, J=7.4 Hz, 1H), 3.70 (dt, J=6.9, 6.7 Hz, 2H), 2.94 (t, J=7.2 Hz, 2H), 2.32 (t, J=7.8 Hz, 2H), 2.20 (ddd, J=7.3, 7.2, 7.0 Hz, 2H), 1.68-1.51 (m, 4H); FDMS 496 (M+1). Anal. (C30H29N3O4.0.1C2H4O2) C, H, N.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[CH:6][CH:5]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.O>[Si:15]([O:14][CH2:13][CH2:12][O:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][CH:6]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: COC(=O)c1ccc(COCCO[Si](C)(C)C(C)(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCOCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
To a solution of the product of Example 5B (670 mg, 2.18 mmol) dissolved in anhydrous THF (22 mL) was added a solution of LAH (1.0 M solution in THF, 2.18 mL, 2.18 mmol) dropwise. After completion of addition the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water. The aqueous layer was extracted with ethyl acetate (3×). All combined organic layers were dried over Na2SO4, filtered, and concentrated to provide an oil (587 mg, 1.98 mmol), which was used in the next step without any further purification (91% yield).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1I>[Cu](I)I.O1CCOCC1>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:9]1[CH:10]=[CH:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8]1
Reactant: c1ccc(-c2cc[nH]n2)cc1
Reactant: Fc1ccccc1I
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Fc1ccccc1-n1ccc(-c2ccccc2)n1
Temperature: 110 °C
Yield: 36 %

Procedure:
Add dioxane (7 mL) to a mixture of 3-phenyl-1H-pyrazole (2 g, 13.9 mmol), copper iodide (132 mg, 0.05 mmol) and potassium carbonate (555 mg, 4.2 mmol). Add 2-fluoroiodobenzene (1.94 mL, 16.6 mmol), trans-cyclohexyldiamine (0.35 mL, 2.78 mmol). Heat at 110° C. for about 18 hours. Cool to RT and filter through a silica gel pad eluting with ethyl acetate. Concentrate and purify (silica gel chromatography, eluting with hexane:ethyl acetate 84:16) to give the desired compound (36%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.Br[CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([OH:16])=[O:15].C(=O)([O-])[O-].[K+].[K+].CN(P(N(C)C)(N(C)C)=O)C>O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][C@H:13]([C:14]([OH:16])=[O:15])[CH:17]([CH3:19])[CH3:18])=[CH:5][CH:4]=1
Reactant: CC(C)C(Br)C(=O)O
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CC(C)[C@H](Nc1ccc(C(F)(F)F)cc1)C(=O)O
Reaction time: 1.5 h

Procedure:
A mixture of 5 g of p-trifluoromethylaniline, 2.25 g of α-bromoisovaleric acid and 2.0 g of potassium carbonate is heated at 100° for 1 hour. After 1.5 hour, 5 ml of HMPT is added and the mixture heated at 100° for 15 hr. The mixture is then poured into water and potassium carbonate added to about pH 11. The mixture is washed with ether, methylene chloride and the aqueous phase acidified to about pH 3 and washed with ether and concentrated. The residue is recrystallized from hexane/ether to yield N-(4-trifluoromethylphenyl)valine, which is reacted with m-phenoxybenzyl bromide to yield the m-phenoxybenzyl ester of N-(4-trifluoromethylphenyl)valine. MS m/e 443 (M+, 5.9).
Reaction SMILES: C(O[CH:4]=[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]3[N:16]=[CH:15][S:14][C:12]3=2)[NH:7][C:6]1=[O:17])C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(O)C>O>[O:17]=[C:6]1[C:5](=[CH:4][NH:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]3[N:16]=[CH:15][S:14][C:12]3=2)[NH:7]1
Reactant: Nc1ccc(S(=O)(=O)NCc2ccncc2)cc1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Solvent: CCO
Solvent: O
Product: O=C1Nc2ccc3ncsc3c2C1=CNc1ccc(S(=O)(=O)NCc2ccncc2)cc1
Yield: 74.6 %

Procedure:
To a 250-ml round bottom flask was added a magnetic stir bar, 8-[ethoxymethylidene]-6H-[1,3]thiazolo[5,4-e]indol-7-one (1.98 grams, 8.05 mmol), 4-amino-N-(4-pyridinylmethyl)benzenesulfonamide (2.16 grams, 8.2 mmol) and 95% ethanol (80 ml). The round bottom reaction flask was fitted with a water cooled reflux condenser. The reaction vessel was placed in an oil bath at room temperature with stirring and the temperature of the oil bath was then raised to a gentle reflux and maintained at that temperature for approximately 36 hours. The reaction vessel was removed from the oil bath and the hot mixture was filtered with the solids being collected by suction filtration. The resultant solid was washed with excess 95% ethanol and collected by suction filtration. The solid was then dried under vacuum for two days at room temperature to yield 2.785 grams (74.7%) of the thiazolindolinone compound. MS (M+H)=464.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14]Br)[CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[F:16][C:17]([F:26])([F:25])[C@H:18]1[CH2:23][CH2:22][C@H:21]([O-:24])[CH2:20][CH2:19]1.[Na+]>C1COCC1>[F:16][C:17]([F:25])([F:26])[C@H:18]1[CH2:19][CH2:20][C@H:21]([O:24][CH2:14][C@H:11]2[CH2:12][CH2:13][C@H:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:9][CH2:10]2)[CH2:22][CH2:23]1
Reactant: CCCCCCC[C@H]1CC[C@H](CBr)CC1
Reactant: [O-][C@H]1CC[C@H](C(F)(F)F)CC1
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCC[C@H]1CC[C@H](CO[C@H]2CC[C@H](C(F)(F)F)CC2)CC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 0.11 mol of trans-4-heptylcyclohexylmethyl bromide and 80 ml of THF is added at 0° C. to a mixture of 0.1 mol of sodium (trans-4-trifluoromethylcyclohexanolate) (prepared from 0.1 mol of trans-4-trifluoromethylcyclohexanol and 0.1 mol of sodium hydride) and 200 ml of THF. The mixture is stirred at 60° C. for 3 hours, and customary work-up gives the product as a colourless solid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.[O:27]1C[CH:28]1[C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:40]=[C:39]([C:41]3[O:45][N:44]=[C:43]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:42]=3[C:52]([F:55])([F:54])[F:53])[O:38][N:37]=2)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[OH:27][CH:28]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:40]=[C:39]([C:41]3[O:45][N:44]=[C:43]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:42]=3[C:52]([F:55])([F:54])[F:53])[O:38][N:37]=2)=[CH:32][CH:31]=1)[CH2:6][N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1
Reactant: FC(F)(F)c1c(-c2ccccc2)noc1-c1nc(-c2ccc(C3CO3)cc2)no1
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C1CN(CC(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)CCO1
Temperature: 80 °C

Procedure:
4-(tert-Butoxycarbonyl)morpholine-2-carboxylic acid (69.5 mg, 0.301 mmol) was treated with TFA/DCM for 1 hour. Solvents were removed in vacuo and the resulting material was dried. The solids were dissolved in 2-propanol (2 mL) and DMSO (1 mL). 3-(4-(oxiran-2-yl)phenyl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazole (30 mg, 0.075 mmol) and cesium carbonate (98 mg, 0.301 mmol) were added. The reaction mixture was heated at 80° C. overnight. LCMS indicated almost complete conversion to desired product and no starting material. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30 mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 21 mg of 4-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)morpholine-2-carboxylic acid as a TFA salt. 1H NMR (400 MHz, MeOH-d3) δ ppm 8.23 (2H, d, J=7.91 Hz), 7.69 (4H, dd, J=12.08, 7.69 Hz), 7.54-7.65 (3H, m), 5.29 (1H, td, J=6.81, 4.39 Hz), 4.41-4.65 (1H, m), 4.08-4.37 (1H, m), 3.92-4.05 (2H, m), 3.56-3.91 (1H, m), 3.44 (3H, t, J=6.81 Hz), 3.12-3.38 (1H, m). MS (m+1)=531. HPLC Peak RT=3.24 minutes (Analytical Method A). Purity=85%.
Reaction SMILES: C1(C=CC=C(O)C=1)[OH:2].[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1.[O-]Cl=O.[Na+]>C(O)(C)(C)C.O>[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([OH:2])=[O:26])=[CH:27][CH:28]=1
Reactant: O=Cc1ccc(OCCCCCCCCCCBr)cc1
Reactant: Oc1cccc(O)c1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)c1ccc(OCCCCCCCCCCBr)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Resorcinol (4.16 g, 38 mmol) and 5 (10.0 g, 29 mmol) were dissolved in t-butanol (600 mL) through gentle heating to 70° C. The solution was cooled to room temperature, and a solution of NaH2PO4·H2O (13.7 g, 88 mmol) and NaClO2 (15.3 g, 170 mmol) in deionized H2O (100 mL) was added dropwise to the flask over a period of 10 minutes. The purple-red mixture was stirred overnight, following which it faded to a pale yellow colour. Volatile components were removed, and the residue was taken in hexane (200 mL) and 1 M HCl (200 mL). The white precipitate was filtered and washed profusely with distilled H2and hexane. Yield 10.5 g (quant.). 1H NMR: δH (CDCl3; 300 MHz): 1.26-1.55 (12 H, m, CH2), 1.86 (4 H, m, O—CH2—CH2/Br—CH2—CH2), 3.44 (2 H, t, 3J=6.8 Hz, Br—CH2), 4.04 (2 H, t, 3J=6.5 Hz, O—CH2), 6.95 (2 H, d, 3J=8.9 Hz, Ar—H), 8.07 (2 H, d, 3J=8.9 Hz, Ar—H). 13C NMR: δC (CDCl3; 75 MHz): 26.0, 28.1, 28.7, 29.0, 29.3, 29.4, 32.8, 34.0, 68.3, 114.2, 121.4, 132.3, 163.7, 171.5.
Reaction SMILES: [CH2:1]([NH:20][CH2:21][CH:22]([OH:32])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][CH2:8][CH:9]([OH:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:33]([OH:37])(=[O:36])[CH2:34][OH:35].C[OH:39]>>[C:33]([OH:37])(=[O:36])[CH2:34][O:35][CH2:23][C:22]([OH:32])=[O:39].[CH2:1]([NH:20][CH2:21][CH:22]([OH:32])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][CH2:8][CH:9]([OH:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C(O)CO
Reactant: CO
Agent: CCCCCCCCCC(O)CNCCCCCCNCC(O)CCCCCCCCC
Product: O=C(O)COCC(=O)O

Procedure:
A solution of N,N'-(1,6-hexylene-bis[2-hydroxyundecylamine] (5 g.), glycolic acid (1.66 g.) and methanol was heated until the solids dissolved, then evaporated to dryness. Recrystallization of the solid from acetone afforded N,N'-(1,6-hexylene)bis[2-hydroxyundecylamine] diglycolate (4.6 g., m.p. 88.2°-94.6° C.).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([C:9]#[N:10])=[N:6][NH:7][CH:8]=1.[CH3:11]I>CN(C=O)C>[Br:3][C:4]1[C:5]([C:9]#[N:10])=[N:6][N:7]([CH3:11])[CH:8]=1
Reactant: N#Cc1n[nH]cc1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(Br)c(C#N)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
Add sodium hydride (60 wt % oil dispersion, 700 mg, 17.5 mmol) in several portions under a nitrogen purge to a solution of 4-bromo-1H-pyrazole-3-carbonitrile (2.0 g, 11.6 mmol) in 15 mL of anhydrous DMF at 0° C. Stir the reaction at 0° C. for one hour. Add methyl iodide (0.9 mL, 14.5 mmol) to the mixture and allow to stir and come to room temperature over 1 hour. Pour into 100 mL of ice-water and stir for 15 minutes. Filter off the resulting solid and rinse with 20 mL of water. Dry the solid overnight. Chromatograph (1/9-1/3 EtOAc/hexanes) over silica gel to give the title compound as a white solid (1.38 g, 63%), along with a small amount (100 mg) of the regioisomeric bromide.