Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[Br:9][C:10](=[CH2:13])[CH2:11]Br>>[Br:9][C:10](=[CH2:11])[CH2:13][O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4]
Reactant: C=C(Br)CBr
Reactant: Oc1ccccc1O
Product: C=C(Br)COc1ccccc1O
Yield: 52 %

Procedure:
This compound was prepared in 52% yield from catechol and 2-bromoallyl bromide according to the procedure for 2p in Example IX. Yellow oil; 1H NMR (CDCl3): δ 4.70 (s, 2H), 5.68 (s, 1H), 5.70-5.71 (m, 1H), 5.95-5.96 (m, 1H), 6.81-6.97 (m, 4H); 13C NMR (CDCl3): δ 73.10, 113.09, 115.33, 119.17, 120.28, 122.82, 127.06, 144.83, 146.12; HRMS (FAB): 243.95575 calcd for C9H9BrOS [M]+. found 243.9557 (−0.2 ppm, 0.0 mmu).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[CH3:4][C:5]1[N:6]=[C:7]([NH:17][C:18](=[NH:22])SCC)[S:8][C:9]=1[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]=1>C(O)C>[CH2:1]([NH:3][C:18]([NH:17][C:7]1[S:8][C:9]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]=2)=[C:5]([CH3:4])[N:6]=1)=[NH:22])[CH3:2]
Reactant: CCSC(=N)Nc1nc(C)c(-c2cc(C)ccn2)s1
Reactant: CCN
Solvent: CCO
Product: CCNC(=N)Nc1nc(C)c(-c2cc(C)ccn2)s1

Procedure:
To a solution of ethylamine in ethanol (20% w/w, 10 ml) was added N-(4-methyl-5-(4-methylpyridin-2-yl)thiazol-2-yl)-S-ethylisothiourea (292 mg), and the mixture was heated in a steel autoclave at 110° C. for 17 hours. The mixture was evaporated under reduced pressure and crystallized from ethanol. The precipitate was collected by filtration to give N-ethyl-N′-(4-methyl-5-(4-methylpyridin-2-yl)-thiazol-2-yl)guanidine (124 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([C:26]([F:29])([F:28])[F:27])([C:22]([F:25])([F:24])[F:23])[OH:21])[CH2:9]2)=[CH:4][CH:3]=1.[C:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O)(=[O:32])[CH3:31].C(=O)([O-])[O-].[Na+].[Na+]>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.CN(C)C=O>[C:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([C:26]([F:28])([F:29])[F:27])([C:22]([F:23])([F:24])[F:25])[OH:21])[CH2:9]2)=[CH:4][CH:3]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)c1ccccc1B(O)O
Reactant: OC(C1=NN(c2ccccc2Cl)C(c2ccc(Br)cc2)C1)(C(F)(F)F)C(F)(F)F
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: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccccc1-c1ccc(C2CC(C(O)(C(F)(F)F)C(F)(F)F)=NN2c2ccccc2Cl)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 18.5 %

Procedure:
5-(4-Bromo-phenyl)-1-(2-chloro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (50.0 mg, 0.10 mmol) prepared in Step 4 of Preparation 17, 2-acetylphenylboronic acid (21.0 mg, 0.13 mmol), Pd(PPh3)4 (4.0 mg, cat.) and a 2N sodium carbonate solution (0.5 mL) were added to N,N-dimethylformamide (0.5 mL). The reaction mixture was stirred at 80° C. for 2 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3) to give 10.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH3:14])=[CH:12][C:11](=[O:15])[C:10]([C:16]([OH:18])=[O:17])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].[Br:21]Br.Cl>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH3:14])=[C:12]([Br:21])[C:11](=[O:15])[C:10]([C:16]([OH:18])=[O:17])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cc(=O)c(C(=O)O)nn1-c1ccc(F)cc1
Reactant: BrBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(Br)c(=O)c(C(=O)O)nn1-c1ccc(F)cc1
Yield: 70.8 %

Procedure:
1-(4-Fluorophenyl)-1,4-dihydro-4-oxo-6-methylpyridazine-3-carboxylic acid (1.5 g) is suspended in 100 ml of dry methanol, and 0.242 g of sodium hydroxide is added. To the solution is added dropwise 1.038 g of bromine dissolved in 50 ml of methanol. The solvent is removed leaving a white solid, which is taken up in dilute base and the solution acidified with hydrochloric acid. The resulting precipitate is filtered and recrystallized from chloroform/ether to yield 1.4 g of 1-(4-fluorophenyl)-5-bromo-1,4-dihydro-4-oxo-6-methylpyridazine-3-carboxylic acid. (mp-219°-20°).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[CH3:14][O:15][C:16]([C:18]1[CH:19]=[CH:20][C:21]2[O:26][CH2:25][CH2:24][NH:23][C:22]=2[CH:27]=1)=[O:17]>ClCCl.N1C=CC=CC=1>[CH3:14][O:15][C:16]([C:18]1[CH:19]=[CH:20][C:21]2[O:26][CH2:25][CH2:24][N:23]([S:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:12][CH3:13])(=[O:10])=[O:9])[C:22]=2[CH:27]=1)=[O:17]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Reactant: COC(=O)c1ccc2c(c1)NCCO2
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-chloro-2-methoxy-benzenesulfonyl chloride (4.7 g, 19.7 mmol, 1.05 equiv.) in dichloromethane (60 mL) and pyridine (25 mL) was added a solution of 3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester (3.6 g, 18.8 mmol, 1 equiv.) in dichloro-methane (60 mL). The mixture was stirred at room temperature overnight then the solvent was removed. The residue was purified by flash chromatography to yield 4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester as a pink solid, 7.12 g (95%), MS (ISP): m/e=398.0 (M+H+.); δH (300 MHz; CDCl3) 8.24 (1H, s), 8.07 (1H, s), 7.72 (1H, dd), 7.48 (1H, dd), 6.91 (1H, d), 6.89 (1H, d), 4.10 (2H, m), 3.91 (2H, m), 3.88 (3H, s), 3.63 (3H, s).
Reaction SMILES: Cl.[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][NH2:13])[CH:3]=1.[CH3:14][C:15]([CH3:22])([CH3:21])[C:16](=O)[CH2:17][C:18]#[N:19]>CCO.Cl>[C:15]([C:16]1[CH:17]=[C:18]([NH2:19])[N:12]([C:4]2[CH:3]=[N:2][C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:13]=1)([CH3:22])([CH3:21])[CH3:14]
Reactant: NNc1cnc2ccccc2c1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(-c2cnc3ccccc3c2)n1
Yield: 54.9 %

Procedure:
A mixture of 1-(quinolin-3-yl)hydrazine hydrochloride (4 g, 20.5 mmol) and 4,4-dimethyl-3-oxo-pentanenitrile (3.6 g, 30 mol) in EtOH (50 mL) and conc. HCl (5 mL) was heated at reflux overnight. After removal of the solvent, the residue was purified by column chromatography to yield 3-t-butyl-1-(quinolin-3-yl)-1H-pyrazol-5-amine (3.0 g, 55% yield). 1H NMR (300 MHz, DMSO-d6): δ 9.16 (d, J=2.4 Hz, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.03 (s, 1H), 8.00 (s, 1H), 7.72 (t, J=7.2 Hz, 1H), 7.64 (t, J=7.2 Hz, 1H), 5.72 (s, 1H), 5.45 (s, 3H), 1.23 (s, 9H).
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]2([C:12]([CH3:16])([CH3:15])[CH:13]=[CH2:14])[CH2:11][O:10]2)=[CH:3][CH:2]=1.[Na].[NH:24]1[CH:28]=[N:27][CH:26]=[N:25]1>C(O)CC>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]([OH:10])([CH2:11][N:27]2[CH:26]=[N:25][N:24]=[CH:28]2)[C:12]([CH3:16])([CH3:15])[CH:13]=[CH2:14])=[CH:3][CH:2]=1
Reactant: C=CC(C)(C)C1(COc2ccc(-c3ccccc3)cc2)CO1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CCCO
Product: C=CC(C)(C)C(O)(COc1ccc(-c2ccccc2)cc1)Cn1cnnc1
Yield: 15.1 %

Procedure:
35.3 g (0.120 mol) of 2-(biphenyl-4-yloxymethyl)-2-(3,3-dimethylprop-1-en-3-yl)-oxirane, dissolved in 80 ml of n-propanol, were added to a boiling solution of 1 g (0.012 mol) of sodium propylate and 9.1 g (0.132 mol) of 1,2,4-triazole in 50 ml of n-propanol. After the solution had been boiled under reflux for two days, it was evaporated down under reduced pressure, the oily residue was taken up in 200 ml of ethyl acetate, and the solution was washed with three times 50 ml of water. After the organic phase had been dried over anhydrous sodium sulphate, the solution was concentrated under reduced pressure. After the residue had been triturated with 150 ml of ethyl acetate,, 6.6 g (15.1% of theory) of 4-(biphenyl-4-yloxymethyl)-3,3-dimethyl-4-hydroxy-5-(1,2,4-triazol-4-yl)-pent-1-ene were obtained as colorless crystals of melting point 171° to 173° C. The oil (37.1 g) which remained after the filtrate had been evaporated down was taken up in 200 ml of acetone, and a solution of 34.6 g of naphthalene-1,5-disulphonic acid in 100 ml of acetone was added. The salt which crystallized out was filtered off under suction, washed with acetone, and taken up in a mixture of 250 ml of water and 250 ml of dichloromethane. The solution was rendered alkaline by stirring in 10% strength sodium carbonate solution. After the organic phase had been concentrated, 24 g of an oil were obtained, which was dissolved in ethyl acetate and the solution then filtered over silica gel. After the filtrate had been concentrated, 17.8 g (40.8% of theory) of 4-(biphenyl-4-yloxymethyl)-3,3-dimethyl-4-hydroxy-5-(1,2,4-triazol-1-yl)-pent-1-ene were obtained in the form of colorless crystals of melting point 85° to 87° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[CH2:26][CH2:25]3)=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.C(O)C>Cl>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[CH2:26][CH2:25]3)=[CH:21][CH:22]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OC3CCN(c4ccccn4)CC3)cc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1nn(Cc2ccc(OC3CCN(c4ccccn4)CC3)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.5 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-[4-[1-(2-pyridyl)piperidine-4-yloxy]benzyl]-1H-pyrazole-4-yl]propionate (598 mg), 1 N aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for 3 hours, diluted with 1 N hydrochloric acid (2.5 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained crystals were collected by filtration, and 3-[3-ethoxy-1-[4-[1-(2-pyridyl)piperidine-4-yloxy]benzyl]-1H-pyrazol-4-yl]propionic acid (408 mg, yield: 72%) was obtained. This was recrystallized from ethanol-hexane. Melting point: 142–143° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:25][CH2:26][CH2:27][CH2:28][N:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>CN(C)C=O>[N:29]1([CH2:28][CH2:27][CH2:26][NH:25][C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[O:12])[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: NCCCn1ccnc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(NCCCn1ccnc1)c1n[nH]c2ccccc12
Temperature: 60 °C

Procedure:
Indazole-3-carboxylic acid (810 mg, 5 mmol) is heated at 60° C. in the presence of carbonyldiimidazole (891 mg, 5.5 mmol) in N,N-dimethylformamide (DMF) (14 ml) under argon for 3 h. 1-(3-Aminopropyl)-imidazole (597 μl, 5 mmol) in solution in DMF (2 ml) is added and the mixture is heated for 2 h and 20 min at 60° C. After cooling, the DMF is evaporated under vacuum to give a yellow oil which is chromatographed on 54 g of silica. The compound obtained is eluted with an ethyl acetate (AcOEt)/methanol (MeOH) (9/1) mixture.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]([N:21]3[CH2:27][C:26]4([CH3:29])[CH2:28][CH:22]3[CH2:23][C:24]([CH3:31])([CH3:30])[CH2:25]4)=[O:20])[CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]([N:21]3[CH2:27][C:26]4([CH3:29])[CH2:28][CH:22]3[CH2:23][C:24]([CH3:31])([CH3:30])[CH2:25]4)=[O:20])[CH:18]=2)[CH2:10][CH2:9]1
Reactant: CC1(C)CC2CC(C)(CN2C(=O)c2csc(C3CCN(C(=O)OC(C)(C)C)CC3)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CC2CC(C)(CN2C(=O)c2csc(C3CCNCC3)c2)C1
Yield: 81.6 %

Procedure:
4-[4-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-thiophen-2-yl]-piperidine-1 carboxylic acid tert-butyl ester [Enantiomer E] (0.06 g) was dissolved in DCM (2 mL) and TFA (1 mL) and the reaction stirred at room temperature for 2 hours. The solvent was evaporated and the residue product was purified by flash chromatography on a SCX-2 cartridge, washing with acetonitrile and then eluting with 2 M ammonia in methanol. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.038 g). LCMS m/z 347.17 [M+H]+ RT=6.63 min (Analytical Method 2).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3](=O)[CH2:4][CH2:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)(=O)C.CO>[CH3:28][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]([C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:17][CH2:18]2)=[CH:11][CH:12]=1)[OH:26]
Reactant: CN(C)C(=O)CCC(=O)c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)CCCC(O)c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Yield: 61 %

Procedure:
Prepared analogously to example A51 from N,N-dimethyl-γ-oxo-4-[4-(phenylmethyl)-1-piperazinyl]-benzenebutanoic acid amide by reduction with lithium aluminium hydride in a yield of 61% of theory. Colourless, amorphous substance of Rf=0.62 (eluant:ethyl acetate/methanol 1/1 v/v).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[O:11][C:12]1[C:13]2[N:14]([C:18]([N:22]=O)=[C:19]([CH3:21])[N:20]=2)[CH:15]=[CH:16][CH:17]=1.C(O)(=O)C.C(=O)([O-])O.[Na+]>[Zn].O>[NH2:22][C:18]1[N:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][C@@H:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH2:10][C@H:2]3[OH:1])[C:13]2=[N:20][C:19]=1[CH3:21]
Reactant: Cc1nc2c(O[C@@H]3c4ccccc4C[C@H]3O)cccn2c1N=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc2c(O[C@@H]3c4ccccc4C[C@H]3O)cccn2c1N

Procedure:
0.5 g of 8-(2-(trans)-hydroxy-2,3-dihydro-1-indenyloxy)-2-methyl-3-nitroso-imidazo[1,2-a]pyridine is dissolved in a mixture consisting of 10 ml glacial acetic acid and 3 ml water and 0.5 g commercial zinc powder is added at 0° C. waterbath temperature. After one hour the solution is diluted with 100 ml icewater adjusted to pH 8 with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The combined extracts are dried over potassium carbonate. After removal of the solvent in vacuo, the mixture is purified over silica gel (methylene chloride/methanol=98/02). After recrystallization from ethanol the title compound of 125°-127° C. is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][C@@H:6]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]3[N:22]([N:24]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=4)[N:26]=3)[CH:23]=2)=[CH:12][CH:11]=1)[C:7]#[C:8][CH3:9])[CH3:2].Br[CH2:36][CH2:37][C:38]([CH3:41])([OH:40])[CH3:39].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][C@@H:6]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]3[N:22]([N:24]=[C:25]([C:27]4[CH:28]=[CH:29][C:30]([O:33][CH2:36][CH2:37][C:38]([OH:40])([CH3:41])[CH3:39])=[CH:31][CH:32]=4)[N:26]=3)[CH:23]=2)=[CH:12][CH:11]=1)[C:7]#[C:8][CH3:9])[CH3:2]
Reactant: CC(C)(O)CCBr
Reactant: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc3nc(-c4ccc(O)cc4)nn3c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc3nc(-c4ccc(OCCC(C)(C)O)cc4)nn3c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
To a stirred solution of (S)-3-{4-[2-(4-hydroxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-ylmethoxy]-phenyl}-hex-4-ynoic acid ethyl ester (0.2 g, 0.43 mmol) in acetonitrile (20 mL) is added 4-bromo-2-methyl-butan-2-ol (0.14 g, 0.87 mmol) and cesium carbonate (0.41 g, 1.2 mmol) and the reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is filtered and evaporated to dryness. The crude material is purified by silica gel chromatography (combiflash purifier 24 g redisep column) and is eluted with 15-20% EtOAc in hexane to give the title compound (0.23 g, 100%). LCMS m/z 542 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].Cl[CH2:11][CH:12]([OH:16])[CH2:13][CH2:14][Cl:15].[OH-].[Na+].O>C(O)(C)(C)C>[Cl:15][CH2:14][CH2:13][CH:12]([OH:16])[CH2:11][O:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[CH3:1]
Reactant: OC(CCl)CCCl
Reactant: Cc1cc(Cl)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1cc(Cl)ccc1OCC(O)CCCl

Procedure:
4-Chloro-1-(4-chloro-2-methylphenoxy)-2-butanol was prepared according to the procedure of Preparation 4 using 105 g. (0.74 mole) of 2-methyl-4-chlorophenol, 171.5 g. (1.2 mole) of 1,4-dichloro-2-butanol, 50.3 g. of sodium hydroxide, 300 ml. of water and 300 ml. of tertiary butanol. There was obtained 84 g. (45.5%) of product which distilled at 135° C./0.01 mm.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[CH3:14])=[C:4]([CH3:15])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH3:24]>C(#N)C>[CH3:14][C:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:23][CH3:24])=[CH:3][C:4]=2[CH3:15])[C:12]([CH3:13])=[CH:11][CH:10]=1
Reactant: Cc1cc(O)ccc1-n1c(C)ccc1C
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1ccc(-n2c(C)ccc2C)c(C)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(4-hydroxy-2-methylphenyl)-2,5-dimethylpyrrole (˜50 mmol) in acetonitrile (300 mL) was added potassium carbonate (55 mmol) and an excess of bromoethane (>100 mmol). The reaction mixture was stirred at 50° C. overnight, cooled to room temperature, and partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, filtered, concentrated in vacuo, and purified by column chromatography (15% EtOAc/hexanes) to give 2,5-dimethyl-1-(4-ethoxy-2-methylphenyl)pyrrole as a colorless oil: 1H NMR (CDCl3, 500 MHz) δ 7.07 (d, 1H), 6.84 (d, 1H), 6.79 (dd, 1H), 5.90 (s, 2H), 4.07 (q, 2H), 1.92 (s, 6H), 1.90 (s, 3H), 1.45 (t, 3H; MS (ESI) 230 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:12]2[CH:13]=[C:14]([O:17][C@H:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C@@H:21]([NH2:28])[CH2:20][CH2:19]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.C1([O:35][C:36](=O)[NH:37][C:38]2[N:39]([C:47]3[CH:52]=[CH:51][N:50]=[C:49]([N:53]([CH2:55][CH2:56][N:57]([CH3:59])[CH3:58])[CH3:54])[N:48]=3)[N:40]=[C:41]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:42]=2)C=CC=CC=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:43]([C:41]1[CH:42]=[C:38]([NH:37][C:36]([NH:28][C@@H:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([N:3]5[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]5[CH3:1])=[N:9][N:10]=4)[CH:13]=3)[CH2:19][CH2:20]2)=[O:35])[N:39]([C:47]2[CH:52]=[CH:51][N:50]=[C:49]([N:53]([CH2:55][CH2:56][N:57]([CH3:58])[CH3:59])[CH3:54])[N:48]=2)[N:40]=1)([CH3:46])([CH3:44])[CH3:45]
Reactant: CN(C)CCN(C)c1nccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)n1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccnc(N(C)CCN(C)C)n4)c4ccccc43)cn12
Temperature: 70 °C
Reaction time: 18 h
Yield: 56.7 %

Procedure:
A solution of Intermediate 81d (25 mg, 0.066 mmol) in 1,4-dioxane (0.7 mL) was treated with Intermediate 140c (32 mg, 0.073 mmol) and DIPEA (0.014 mL, 0.083 mmol) and the mixture was stirred at 70° C. for 18 h. The cooled solution was concentrated in vacuo, and the residue was partitioned between DCM and water. The phases were separated and the aqueous layer was extracted with DCM (×2). The combined organic phase was washed with brine, dried (Na2SO4) and concentrated in vacuo to a brown gum. FCC, using 0-8% MeOH in DCM, gave a colourless glass (27 mg). The glass was purified further by HPLC (Phenomenex Gemini C18 column, 5-95% MeCN in H2O, 0.1% HCO2H) over 30 mins. Concentration of the fractions in vacuo gave a colourless glass that was dissolved in ether. A solid was precipitated out of solution by addition of cyclohexane. The solid was filtered off to give the title compound as a white solid (8 mg, 17%). LCMS (Method 5): Rt 4.07 min, m/z 721.6 [MH+]. 1H NMR (400 MHz, d6-DMSO, 353K): 0.92 (3H, d, J=6.4 Hz), 1.29 (9H, s), 1.49-1.58 (2H, m), 1.65-1.72 (2H, m), 1.77-1.86 (2H, m), 1.99 (6H, s), 2.00-2.14 (4H, m), 2.20-2.29 (1H, m), 3.12-3.19 (5H, m), 3.30-3.39 (1H, m), 3.58-3.72 (2H, m), 4.94-5.02 (1H, m), 5.42 (1H, t, J=3.9 Hz), 6.55 (1H, s), 7.03 (1H, d, J=5.5 Hz), 7.15 (1H, dd, J=9.8, 2.3 Hz), 7.22-7.27 (1H, m), 7.31-7.37 (2H, m), 7.41-7.45 (1H, m), 7.56-7.61 (2H, m), 7.70 (1H, br s), 8.35 (1H, d, J=5.5 Hz), 10.18 (1H, br s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CN(C)C=O.[NH:19]1[CH2:23][CH2:22][C:21]2([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[S:25](=[O:33])(=[O:32])[NH:24]2)[CH2:20]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([N:19]3[CH2:23][CH2:22][C:21]4([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[S:25](=[O:33])(=[O:32])[NH:24]4)[CH2:20]3)=[O:13])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=S1(=O)NC2(CCNC2)c2ccccc21
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N1CCC2(C1)NS(=O)(=O)c1ccccc12)C1(c2ccc(Cl)cc2)CC1
Reaction time: 0.05 h

Procedure:
To a solution of 1-(4-chlorophenyl)cyclopropanecarboxylic acid (40.0 mg, 0.000203 mol) in N,N-dimethylformamide (0.5 mL, 0.006 mol) at 0 Celsius were added spiro[1,2-benzisothiazole-3,3′-pyrrolidine]1,1-dioxide (45.6 mg, 0.000203 mol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (99.0 mg, 0.000224 mol). The reaction mixture was stirred for 3 minutes, then N,N-Diisopropylethylamine (88.6 μL, 0.000508 mol) was added. The solution was then stirred at r.t. overnight. The crude material was purified by prep-HPLC to give the desired compound. MS (ESI): 404.0 (M+H+).