Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:16])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13]>C(O)(=O)C.[Zn]>[CH3:16][CH:4]([CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH:3]=[CH2:2]
Reactant: CC(=CCBr)CCCC(C)CCCC(C)C
Agent: [Zn]
Solvent: CC(=O)O
Product: C=CC(C)CCCC(C)CCCC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.3 %

Procedure:
In 300 ml of hexane were dissolved 50 g of 3,7,11-trimethyl-1-dodecen-3-ol and 0.87 g of pyridine, and 30.8 g of phosphorus tribromide was added dropwise to the solution at 0° to -10° C. After 2 hours of stirring at 0° C., the reaction mixture was poured into water and extracted with hexane. The hexane layer was successively washed with aqueous sodium hydrogen carbonate and aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off to give 62.5 g of crude 1-bromo-3,7,11-trimethyl-2-dodecene. To a suspension of 14.2 g of zinc in 26 ml of acetic acid was added dropwise 62.5 g of the crude 1-bromo-3,7,11 -trimethyl-2-dodecene and the mixture was stirred at room temperature for 1 hour. Thereafter, the zinc was filtered off and the filtrate was poured into water and extracted with hexane. The hexane layer was washed with aqueous sodium hydrogen carbonate and aqueous sodium chloride in that order and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was further distilled under reduced pressure to give 10.6 g (yield 25%) of 3,7,11-trimethyl-1-dodecene. The physical constants of the compound are as follows.
Reaction SMILES: [C@H]1(C[N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([C:21]3[NH:22][C:23]4[C:28]([CH:29]=3)=[C:27]([O:30][CH2:31][C:32]3[C:36]5[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:35]=5[O:34][CH:33]=3)[CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:14][CH2:13]2)[C@@H]2N(CCCC2)CCC1.[ClH:42].Cl.Cl.NC1CCN([CH2:52][CH2:53][N:54]2[CH2:59][CH2:58][CH:57]([OH:60])[CH2:56][CH2:55]2)CC1>>[ClH:42].[ClH:42].[OH:60][CH:57]1[CH2:58][CH2:59][N:54]([CH2:53][CH2:52][N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([C:21]3[NH:22][C:23]4[C:28]([CH:29]=3)=[C:27]([O:30][CH2:31][C:32]3[C:36]5[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:35]=5[O:34][CH:33]=3)[CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:14][CH2:13]2)[CH2:55][CH2:56]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4ccc(F)cc34)cccc2[nH]1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCC(O)CC2)CC1)c1cc2c(OCc3coc4ccc(F)cc34)cccc2[nH]1

Procedure:
This compound is synthesized from 4-(5-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (113, see example 60) and amine 21 analogously to the method described in example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[C:16]([CH:17]=O)=[CH:15][CH:14]=[CH:13][N:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:19][O:20][C:21](=[O:34])[CH2:22][N:23]1[C:31]2[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=2)[CH:25]=[C:24]1[CH3:33]>>[CH3:19][O:20][C:21](=[O:34])[CH2:22][N:23]1[C:31]2[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=2)[C:25]([CH2:17][C:16]2[C:11]([S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:9])=[O:10])=[N:12][CH:13]=[CH:14][CH:15]=2)=[C:24]1[CH3:33]
Reactant: O=Cc1cccnc1S(=O)(=O)c1cccc(Cl)c1
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Product: COC(=O)Cn1c(C)c(Cc2cccnc2S(=O)(=O)c2cccc(Cl)c2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 1c using 2-(3-chlorobenzenesulfonyl)pyridine-3-carbaldehyde and (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][CH2:7][C:8]#[CH:9])[CH3:5])[CH3:2].C([Li])CCC.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:3][CH:4]([O:6][CH2:7][C:8]#[C:9][CH:21]([C:20]1[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)[OH:22])[CH3:5])[CH3:2]
Reactant: C#CCOC(C)OCC
Reactant: COc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(C)OCC#CC(O)c1ccc(OC)cc1
Reaction time: 0.5 h

Procedure:
A solution of 6 g (47 mmol) of 1-(1-ethoxyethoxy)-2-propyne in 100 ml of tetrahydrofuran was treated at -78° under argon with 29.2 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -40° for 30 minutes and then a solution of 5.7 ml (47 mmol) of 4-methoxybenzaldehyde in 41 ml of tetrahydrofuran was added within 10 minutes. The reaction mixture was warmed to 0°, stirred at 0° for a further 1 hour and then treated with 80 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed in succession with saturated sodium chloride solution and with water dried over magnesium sulphate and concentrated. The residue was purified by flash chromatography on 500 g of silica gel (elution agent ether/hexane 1:1). There was obtained 4-(1-ethoxyethoxy)-1-(4-methoxyphenyl)-2-butyn-1-ol as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].[C:11]([O:15][C:16](=[O:19])[CH2:17]Br)([CH3:14])([CH3:13])[CH3:12]>CN(C)C=O>[C:11]([O:15][C:16](=[O:19])[CH2:17][N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1ccc([N+](=O)[O-])n1
Yield: 77.2 %

Procedure:
To a solution of 3-Nitro-1H-pyrazole (1.00 g, 8.84 mmol) in anhydrous N,N-dimethylformamide (20 mL), a 60% dispersion of sodium hydride in mineral oil (390 mg, 9.73 mmol) was added while stirring under nitrogen. After the effervescence ceased and the mixture was stirred for additional 1 h, tert-butyl-bromoacetate (1.44 mL, 9.73 mmol) was added. The mixture was continued to stir under nitrogen for an additional 2 h. The solvent was removed in vacuo and purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% ethyl acetate/hexanes to 50% ethyl acetate/hexanes, 30 min) afforded (3-nitro-pyrazol-1-yl)-acetic acid tert-butyl ester (1.55 g, 77%) as a white powder. H1-NMR (400 MHz, CDCl3) δ: 1.42 (9H, s), 4.86 (2H, s), 6.87 (1H, d, J=2.4 Hz), 7.54 (1H, d, J=2.3 Hz).
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22](O)=O)[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26](=[N:32][OH:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22]3[O:33][N:32]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=3)[CH2:9]2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)C3CCCC3)C2)cc1
Reactant: CCOC(=O)C(N)=NO
Product: CCOC(=O)c1noc(C2CC(c3ccc(CC)cc3)CN(C(=O)C3CCCC3)C2)n1

Procedure:
198 mg (0.60 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 7A) and 87 mg (0.66 mmol, 1.1 eq.) of ethyl 2-amino(hydroxyimino)ethanoate were reacted according to the General Method 1. Yield: 73 mg (27% of theory)
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([C:8]2[S:9][C:10]([CH2:22][CH3:23])=[CH:11][C:12]=2[C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[CH:5]=[CH:6][N:7]=1.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>C(O)C>[CH2:24]([N:26]([CH2:2][C:3]1[N:4]([C:8]2[S:9][C:10]([CH2:22][CH3:23])=[CH:11][C:12]=2[C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[CH:5]=[CH:6][N:7]=1)[CH2:27][CH3:28])[CH3:25]
Reactant: CCNCC
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2ccnc2CCl)s1
Solvent: CCO
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2ccnc2CN(CC)CC)s1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 5.6 g of 2-chloromethyl-1-(3o-chlorobenzoyl-5-ethyl-2-thienyl)imidazole in 50 ml of ethanol is added 4 g of diethylamine, and the mixture is stirred at 50°C for 2 hours. After allowing the mixture to stand overnight, the solvent is distilled off under reduced pressure. The residue to which a water is added is extracted with ethyl acetate. The extract is washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residual brown oil is chromatographed on 150 g of 70 - 325 mesh silica gel with chloroform as eluent. The eluates are combined and concentrated in vacuo to give 2-diethylaminomethyl-1-(3-o-chlorobenzoyl-5-ethyl-2-thienyl)imidazole as yellowish transparent oil (nD21 = 1.5813).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:33])=[C:5]([C:24]([O:31][CH3:32])=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:16]CC2C=CC=CC=2)=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[C:4]([CH3:33])=[C:5]([C:24]([O:31][CH3:32])=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:16])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13]
Reactant: COc1c(C)c(Cc2ccc(OCc3ccccc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1c(C)c(Cc2ccc(O)c(C(=O)O)c2)c(OC)c(OC)c1OC
Yield: 150.5 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-benzyloxybenzoic acid (159.53 g, 1.156 mmol) was dissolved in ethanol (20 ml) and after adding thereto an ethanol suspension (3 ml) of 5% Pd—C (0.250 g), the solution was stirred at room temperature for 16 hours in a hydrogen stream. The reaction solution was filtered, the filtrate was concentrated, and the obtained residue was recrystallized from ether to obtain the titled compound (0.630 g, 1.74 mmol, 79%).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[CH:10]=[CH:11][C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[OH:19]C1(C)CC(O)CC(C)(C)C1C=CC(O)C>>[OH:19][C:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[CH:3]1[CH:10]=[CH:11][CH:12]([OH:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CC(O)C=CC1C(C)(C)CC(O)CC1(C)O
Reactant: CCCCCC(=O)C=CC1=C(C)CCCC1(C)C
Product: CCCCCC(O)C=CC1C(C)(C)CCCC1(C)O

Procedure:
The entitled compound was obtained from 1-(2,6,6-trimethylcyclohex-1-enyl)oct-1-en-3-one in the same manner as in Example 1-(4), (5), and (6).
Reaction SMILES: [C:1](/[C:4](/[CH2:13][CH2:14]/[CH:15]=[C:16](\[CH3:23])/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:5]/[CH2:6][CH2:7]/[C:8](/[CH3:12])=[CH:9]/[CH2:10][OH:11])([OH:3])=O.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:39]([NH2:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.O>ClCCl>[CH2:39]([NH:46][C:1](/[C:4](/[CH2:13][CH2:14]/[CH:15]=[C:16](\[CH3:23])/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:5]/[CH2:6][CH2:7]/[C:8](/[CH3:12])=[CH:9]/[CH2:10][OH:11])=[O:3])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: NCc1ccccc1
Reactant: CC(C)=CCC/C(C)=C/CC/C(=C\CC/C(C)=C/CO)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: O
Product: CC(C)=CCC/C(C)=C/CC/C(=C\CC/C(C)=C/CO)C(=O)NCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
660 mg of (E,Z,E) and (E,E,E)-7-carboxy-3,11,15-trimethyl-2,6,10,14-hexadecatetraen-1-ol was dissolved in 10 ml of dichloromethane. The solution was cooled to 0° C., 440 mg of dicyclohexylcarbodiimide was added and the mixture was stirred for 1 hour. Then, 0.5 ml of benzylamine was added and stirring was continued for 1 hour. The reaction mixture was left at room temperature overnight and water was added followed by extraction with ethyl ether. The oily substance derived from the extract was purified by a thin-layer chromatography to afford 315 mg of the end product.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[NH:9][C:8](=[O:10])[C:7]([C:11]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:16]2)=[O:12])=[CH:6][C:5]=1[Cl:25].[H-].[Na+].I[CH3:29].O>CN(C)C=O>[NH2:3][C:4]1[N:9]([CH3:29])[C:8](=[O:10])[C:7]([C:11]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:16]2)=[O:12])=[CH:6][C:5]=1[Cl:25]
Reactant: CCCCN1CCC(CNC(=O)c2cc(Cl)c(N)[nH]c2=O)CC1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCN1CCC(CNC(=O)c2cc(Cl)c(N)n(C)c2=O)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 5.9 %

Procedure:
To a solution of 6-amino-N-[(1-butyl-4-piperidinyl)methyl]-5-chloro-2-oxo-1,2-dihydro-3-pyridinecarboxamide dihydrochloride (step 2 in example 3, 80 mg, 0.19 mmol) in N,N-dimethylformamide (3 ml), sodium hydride (60% dispersion in mineral oil, 39 mg, 0.97 mmol) was added at 0° C. and the mixture was stirred for 15 min at room temperature. The mixture was cooled to 0° C. and iodomethane (1.0 M in N,N-dimethylformamide, 0.19 ml, 0.19 mmol) was added. After stirring for 18 h at room temperature, the mixture was poured into water, extracted with ethyl acetate (50 ml×2), washed with water (50 ml) and brine (50 ml) and dried over magnesium sulfate. Removal of solvent gave pale yellow oil, which was chromatographed on a column of silica gel eluting with 25% ammonium hydroxide/methanol/dichloromethane (0.2:1:12) to give 4 mg (6%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[C:9](\[CH3:15])/[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[ClH:16]>CC(O)=O>[ClH:16].[NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[C:9](\[CH3:15])/[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C(C)=C/c1ccc(N)nc1
Agent: Cl
Solvent: CC(=O)O
Product: C/C(=C\c1ccc(N)nc1)C(=O)O
Temperature: 100 °C

Procedure:
To ethyl (E)-3-(6-aminopyridin-3-yl)-2-methylacrylate (5.0 g, 24.2 mmole) was added HOAc (25 mL) and cone. HCl (25 mL). The reaction was stirred and heated at 100° C. for 6 hr, cooled to RT and concentrated to dryness. The remaining residue was triturated with Et2O, filtered and dried under vacuum to give the title compound (5.5 g, quantitative) as a white solid: LCMS (ES) m/e 179.0 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.47 (br s, 2H), 8.16 (d, J=1.7 Hz, 1H), 8.08 (dd, 1H), 7.42 (s, 1H), 7.08 (d, J=9.3 Hz, 1H), 2.01 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[NH2:12][C:13]([CH3:29])([CH2:16][N:17]1[N:21]=[C:20]2[C:22]([Cl:28])=[CH:23][C:24]([Cl:27])=[C:25]([Cl:26])[C:19]2=[N:18]1)[C:14]#[N:15]>C1COCC1>[C:14]([C:13]([NH:12][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)([CH3:29])[CH2:16][N:17]1[N:21]=[C:20]2[C:22]([Cl:28])=[CH:23][C:24]([Cl:27])=[C:25]([Cl:26])[C:19]2=[N:18]1)#[N:15]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CC(N)(C#N)Cn1nc2c(Cl)cc(Cl)c(Cl)c2n1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1nc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=O)c1ccc(C#N)cc1

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 4-cyanobenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-2-methyl-3-(4,5,7-trichloro-2H-benzotriazol-2-yl)-propionitrile (0.075 mmole, described in Example 39) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (4.2 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=433, RT=0.64 min.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].C([O-])([O-])=O.[K+].[K+].[O:17]1[CH2:21][CH2:20]OC1=O>CN(C=O)C>[CH3:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[O:1][CH2:20][CH2:21][OH:17])[CH:6]=[O:7]
Reactant: Cc1cc(C=O)ccc1O
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C=O)ccc1OCCO
Temperature: 110 °C
Reaction time: 60 h

Procedure:
To a solution of 4-hydroxy-3-methylbenzaldehyde (0.50 g, 3.67 mmol) in anhydrous DMF (8 mL) was added K2CO3 (1.01 g, 7.34 mmol) and 1,3-dioxolan-2-one (0.65 g, 7.34 mmol), and the mixture was stirred at 110° C. for 60 hours under nitrogen. DMF was removed under vacuum, the residue was diluted with water (50 mL) and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and concentrate under vacuum to give 3-methyl-4-hydroxylethoxybenzaldehyde as a yellow oil. Yield: 0.60 g (91%).
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9](O)=[O:10])=[CH:5][CH:4]=1)#[N:2].C(Cl)(=O)C([Cl:17])=O.CN(C)C=O>ClCCl>[C:1]([C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([Cl:17])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(OCC(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCC(=O)Cl)cc1
Reaction time: 2 h

Procedure:
To a suspension of commercially available 2-(4-cyanophenoxy)acetic acid (4.0 g, 22.6 mmol) in dichloromethane (80 mL) was added oxalyl dichloride (2.17 mL, 24.8 mmol). To this mixture was added N,N-dimethylformamide (30 μL) dropwise and stirred for 2 hours during which cessation of evolution of gas was observed. The resulting solution was diluted with dichloromethane (50 mL) and the solvent was removed under reduced pressure to provide the title compound as an oil which became a solid upon storing in the refrigerator.
Reaction SMILES: C(O[CH2:5][C:6]1[N:7]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:31][CH:30]=2)[C:8]2[C:13]([C:14]=1[C:15](=[O:19])[C:16]([OH:18])=[O:17])=[CH:12][C:11]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:10][CH:9]=2)(=O)C.[OH-].[K+].Cl>>[CH2:21]([O:20][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]([CH3:36])([CH3:38])[CH3:37])=[CH:33][CH:34]=1)[C:6]1[CH2:5][O:18][C:16](=[O:17])[C:15](=[O:19])[C:14]2=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(=O)OCc1c(C(=O)C(=O)O)c2cc(OCc3ccccc3)ccc2n1Cc1ccc(C(C)(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C)c1ccc(Cn2c3c(c4cc(OCc5ccccc5)ccc42)C(=O)C(=O)OC3)cc1

Procedure:
The title compound was prepared from [2-[(acetyloxy)methyl]-5-(benzyloxy)-1-(4-tert-butylbenzyl)-1H-indol-3-yl](oxo)acetic acid and aqueous potassium hydroxide in substantially the same manner, as described in step 6 of Example 1, followed by the treatment with aqueous HCl, as described in step 7 of Example 1. The product was obtained as an off-white solid; mp: 233–234° C. Mass spectrum (ESI, [M+H]+) m/z 454. 1H NMR (400 MHz, DMSO-d6) δ 7.59–7.56 (m, 2H), 7.47 (d, 1H, J=7.33 Hz), 7.39 (t, 2H, J=7.33 Hz), 7.35–7.30 (m, 3H), 7.15 (d, 2H, J=8.40 Hz), 7.07 (dd, 1H, J=9.05 and 2.45 Hz), 5.87 (s, 2H), 5.42 (s, 2H), 5.16 (s, 2H), and 1.22 ppm (s, 9H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:13]([C:24]([O:26][CH3:27])=[O:25])[C:12]2=[O:28])=[CH:2]1.[CH:29]1(CO)[CH2:31][CH2:30]1>CN(C)C(=O)C.[Zn]>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[C:13]([C:24]([O:26][CH2:27][CH:29]3[CH2:31][CH2:30]3)=[O:25])[C:12]2=[O:28])=[CH:2]1
Reactant: OCC1CC1
Reactant: COC(=O)C1=C(Nc2ccc(F)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Agent: [Zn]
Solvent: CC(=O)N(C)C
Product: O=C(OCC1CC1)C1=C(Nc2ccc(F)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 19.1 %

Procedure:
Under a nitrogen atmosphere, a solution of the compound (0.038 g, 0.10 mmol) of Example 51, cyclopropyl carbinol (0.10 mL, 1.3 mmol) and zinc cluster catalyst (Zn4(OCOCF3)6O) (0.0019 g, 0.0020 mmol) in N,N-dimethylacetamide (0.9 mL) was stirred with the microwave synthesizer (Biotage Initiator™) at 150° C. for 30 min. Cooled to ambient temperature, the precipitate was removed by filtration. The filtrate was purified by preparative HPLC to afford the titled compound as solid (0.0080 g, y. 19%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[NH:14][C:15]([NH2:24])=[C:16]2[C:20]([N:21]=1)=[N:19][C:18]([O:22][CH3:23])=[N:17]2)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][O:33][C:32]([CH3:37])([CH3:36])[CH2:31]1>>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][O:33][C:32]([CH3:36])([CH3:37])[CH2:31]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CC1(C)CC(CCCCBr)CCO1
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCOC(C)(C)C3)c2n1

Procedure:
Prepared similarly to Intermediate 224 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 4-(4-bromobutyl)-2,2-dimethyltetrahydro-2H-pyran but conducting the alkylation over 1.5 hours at 60° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=2[O:16][CH2:17][CH:18]2[CH2:20][O:19]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:25][NH:26][CH3:27]>O1CCCC1>[CH3:25][N:26]([CH3:27])[CH2:20][CH:18]([OH:19])[CH2:17][O:16][C:15]1[CH:21]=[CH:22][CH:23]=[CH:24][C:14]=1[CH2:13][CH2:12][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: CC(C)c1ccc(CCCCc2ccccc2OCC2CO2)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: CC(C)c1ccc(CCCCc2ccccc2OCC(O)CN(C)C)cc1
Yield: 95 %

Procedure:
Following a procedure similar to that described in Example 1(b), a solution of 648 mg of 2-{2-[4-(4-isopropylphenyl)butyl]phenoxymethyl}oxirane [prepared as described in step (a) above] in 13 ml of tetrahydrofuran was treated with 2.6 ml of 50% by volume aqueous dimethylamine. The reaction mixture was worked up and purified as described in Example 1(b), to give 703 mg (yield 95%) the title compound as a colorless oil.
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:11]=[C:10]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:8][C:7]=1[C:16]1[C:21]([F:22])=[CH:20][C:19]([O:23]C)=[CH:18][C:17]=1[F:25].[CH3:26]O>ClCCl>[Cl:5][C:6]1[CH:11]=[C:10]([CH2:12][C:13]([O:15][CH3:26])=[O:14])[CH:9]=[CH:8][C:7]=1[C:16]1[C:21]([F:22])=[CH:20][C:19]([OH:23])=[CH:18][C:17]=1[F:25]
Reactant: COc1cc(F)c(-c2ccc(CC(=O)O)cc2Cl)c(F)c1
Reactant: CO
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)Cc1ccc(-c2c(F)cc(O)cc2F)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
Boron tribromide (1.494 mL, 15.80 mmol) was added dropwise to 2-(2-chloro-2′,6′-difluoro-4′-methoxybiphenyl-4-yl)acetic acid (Intermediate 2-5; 822 mg, 2.63 mmol) in dichloromethane (30 mL) at ambient temperature under nitrogen. The resulting solution was stirred at ambient temperature for 90 minutes. The reaction mixture was cautiously added to ice water cooled methanol (50 mL) and the mixture was stirred for a further 20 minutes. The reaction mixture was evaporated to dryness and redissolved in EtOAc (150 mL), and washed sequentially with 2M HCl (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford methyl 2-(2-chloro-2′,6′-difluoro-4′-hydroxybiphenyl-4-yl)acetate (822 mg, 100%) as a yellow gum.