Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:17]=[C:18]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=3)[C:19]3[CH2:25][NH:24][CH2:23][CH2:22][C:20]=3[N:21]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:17]=[C:18]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=3)[C:19]3[CH2:25][N:24]([C:35](=[O:37])[CH3:36])[CH2:23][CH2:22][C:20]=3[N:21]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc(Cc2nc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)nc3c2CNCC3)c1
Solvent: ClCCl
Product: COc1cccc(Cc2nc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)nc3c2CN(C(C)=O)CC3)c1
Yield: 16.7 %

Procedure:
N-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4-(3-methoxybenzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (137 mg, 0.3 mmol, example 95a) was dissolved in DCM (3 mL) and acetic anhydride (0.028 mL, 0.30 mmol) was added. The crude product was purified by preparative HPLC yielding 1-(2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-4-(3-methoxybenzyl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (25.00 mg, 16.7%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)[CH3:2].C(N(CC)C(C)C)(C)C.Br[CH2:21][CH2:22][OH:23]>O>[CH2:1]([N:3]([CH2:21][CH2:22][OH:23])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCNc1ccc(Br)cc1
Reactant: OCCBr
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CCO)c1ccc(Br)cc1
Temperature: 125 °C
Yield: 69.5 %

Procedure:
17.3 g (86.7 mmols) of N-ethyl-4-bromoaniline, 22.7 ml (1.5-fold equivalent weight) of N,N-diisopropylethylamine and 9.64 ml (1.5-fold equivalent weight) of 2-bromoethanol were mixed, and the mixture obtained was heated at 125° C. for 2 hours in an atmosphere of argon. Next, to the reaction solution obtained, 1.5 ml (0.1-fold equivalent weight) of diisopropylethylamine and 0.64 ml (0.1-fold equivalent weight) of 2-bromoethanol were added, and the mixture obtained was heated at 125° C. for 3 hours in an atmosphere of argon. Water was added to the reaction solution obtained, which was then extracted with ethyl acetate. The organic layer obtained was dried with anhydrous magnesium sulfate and then concentrated. The residue thus obtained was purified by silica gel column chromatography developing system (chloroform) to obtain 14.7 g of N-ethyl-N-(2-hydroxyethyl)-4-bromoaniline (yield: 69.5%; a colorless oily liquid).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:13]([CH3:14])[CH:12]=[CH:11][C:5]2=[N:6][C:7]=1[C@@H:8]([NH2:10])[CH3:9].C(N(CC)CC)C.[C:22](Cl)([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[N:13]([CH3:14])[CH:12]=[CH:11][C:5]2=[N:6][C:7]=1[C@@H:8]([NH:10][C:22](=[O:23])[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:9]
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1Br
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)OCc1ccccc1)c1nc2ccn(C)c2cc1Br
Temperature: 13 °C
Reaction time: 1.5 h
Yield: 94.4 %

Procedure:
To a stirred solution of (S)-1-(6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethan-1-amine (1.0 g, 3.93 mmol) in DCM (20 mL) was added triethylamine (796 mg, 7.87 mmol) followed by CbzCl (808 mg, 4.72 mmol) at 0° C. The reaction mixture was stirred at about 0 to 26° C. for 1.5 hours. After the solvent was removed, the residue was purified by silica gel column chromatography (PE/EtOAc=10:1) to give the title compound as a yellow oil (1.44 g, 94.7%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([NH2:12])[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=[O:8].I[C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]>CO.O>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([NH:12][C:16]2[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([O:20][CH3:21])=[O:19])[CH:4]=1
Reactant: COC(=O)c1ccccc1I
Reactant: Nc1cc(C(F)(F)F)ccc1C(=O)O
Solvent: O
Solvent: CO
Product: COC(=O)c1ccccc1Nc1cc(C(F)(F)F)ccc1C(=O)O
Yield: 43 %

Procedure:
Reaction of 4-trifluoromethylanthranilic acid and methyl 2-iodobenzoate by the reported method [Rewcastle and Denny, Synth, Comm 1987, 17, 309 gave 4-trifluoromethyl-2-(2-methoxycarbonylphenyamino)benzoic acid (43%), mp (MeOH/H2O) 206-207° C. 1H NMR [(CD3)2SO] δ 3.87 (s, 3 H, CO2CH3), 7.12 (ddd, J=8.0, 6.1, 2.1 Hz, 1 H., H-5'), 7.23 (dd, J=8.3, 1.0 Hz, 1 H, ArH), 7.55-7.62 (m, 3 H, 3×ArH), 7.95 (dd, J=8.0, 1.3 Hz, 1 H, ArH), 8.12 (d, J=8.2 Hz, 1 H, ArH). Formation of the corresponding imidazolide and immediate reduction of this as above gave methyl-2-[N-(5'-trifluoromethyl-2'-hydroxymethyl)phenyl-amino]benzoate (86%), mp (hexane) 86-87° C. 1H NMR (CDCl3) δ 2.00 (t, J=5.6 Hz, 1 H, OH), 3.92 (s, 3 H, CO2CH3), 4.78(d, J=5.3 Hz, 2 H, CH2), 6.84 (td, J=7.6, 1.1 Hz, 1 H, ArH), 7.15 (dd, J=8.6, 0.8 Hz, 1 H, ArH), 7.31-7.39 (m, 2 H, 2×ArH), 7.52 (d, J=7.7 Hz, 1 H, ArH), 7.70 (s, 1 H, H-6'), 8.76 (dd, J=8.0, 1.6 Hz, 1 H, ArH), 9.72 (s, 1 H, NH).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.CON(C)[C:17](=[O:27])[CH2:18][O:19][CH:20]([CH:25]=[CH2:26])[C:21]([F:24])([F:23])[F:22]>C1COCC1>[F:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:17](=[O:27])[CH2:18][O:19][CH:20]([CH:25]=[CH2:26])[C:21]([F:23])([F:22])[F:24]
Reactant: Fc1ccccc1Br
Reactant: C=CC(OCC(=O)N(C)OC)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CC(OCC(=O)c1ccccc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.9 %

Procedure:
To a solution 1-bromo-2-fluorobenzene (0.967 kg, 5.527 mol) in THF (6.2 L) at −75° C., was added n-butyllithium (2.50 M in hexane, 2.09 L, 5.22 mol) while maintaining temperature below −65° C. (ca. 100 min.). After 15 mins, a solution of N-methoxy-N-methyl-2-(1,1,1-trifluorobut-3-en-2-yloxy)acetamide (0.949 kg, 4.178 mol) in THF (1.6 L) was added while maintaining temperature below −65° C. (ca. 70 min.). After 2.5 h at −78° C., the reaction was quenched by addition of sat. aq. NH4Cl (3.0 L) and methyl tert-butyl ether (9.0 L). The reaction mixture was warmed to rt, the aq. phase was extracted again with methyl tert-butyl ether (2.5 L). The organic phases were combined, washed with sat. aq. NaCl (2×0.3 L) and concentrated under vacuum to afford the title compound as an oil (1.007 kg, 80.0%). 1H NMR (500 MHz, CDCl3) δ ppm 7.96 (td, J=7.6, 1.8 Hz, 1H), 7.62-7.54 (m, 1H), 7.33-7.25 (m, 1H), 7.20-7.12 (m, 1H), 5.86 (ddd, J=17.5, 10.4, 7.3 Hz, 1H), 5.60 (dd, J=20.5, 13.8 Hz, 2H), 4.91-4.76 (m, 2H), 4.39 (dq, J=12.8, 6.4 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ ppm 193.55, 162.14 (d, JCF=254.1 Hz), 135.36 (d, JCF=9.2 Hz), 130.62 (d, JCF=3.2 Hz), 128.49, 124.85 (d, JCF=3.3 Hz), 123.89, 122.93, 122.72 (d, JCF=24.5 Hz), 116.50 (d, JCF=23.7 Hz), 78.97 (q, JCF=31.4 Hz), 74.56 (d, JCF=12.4 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S([CH2:40][C@@H:41]2[NH:45][C:44](=[O:46])[CH2:43][CH2:42]2)(=O)=O)=CC=1.CCOCC>CN(C=O)C>[CH3:24][O:23][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:40][C@@H:41]1[NH:45][C:44](=[O:46])[CH2:43][CH2:42]1)[N:9]=[CH:8][N:7]=[C:6]2[O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:22])=[CH:16]2
Reactant: Cc1ccc(S(=O)(=O)C[C@H]2CCC(=O)N2)cc1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OC[C@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 0.3 %

Procedure:
To a suspension of 7-hydroxy-6-methoxy-4-(2-methyl-1H-indol-5-yloxy)quinazoline (1.36 g, 4.24 mmol), (prepared as described in Example 49), in DMF (70 ml), was added potassium carbonate (2.34 g, 17.0 mmol, 4 eq.) followed by (5R)-5-(p-toluenesulphonylmethyl)-2-pyrrolidinone (1.25 g, 4.66 mmol, 1.1 eq.), (prepared as described for the starting material in Example 317), and the resulting yellow suspension heated at reflux. After 4 hours, some starting material remained, and a further addition of (5R)-5-(p-toluenesulphonylmethyl)-2-pyrrolidinone (0.57 g, 2.12 mmol, 0.5 eq.) was made. The reaction was heated at reflux for a further 2 hours resulting in consumption of starting material. The reaction was cooled to ambient temperature, the inorganic residue filtered off and the filtrate evaporated in vacuo to leave a brown oil which was purified by column chromatography (methylene chloride/methanol, (100/0 to 90/10)) to give a light brown oil. Trituration with ether afforded a thick oil, which upon chromatography eluting as above gave a yellow oil. Trituration of this oil with ether gave an initial crop of (5R)-6-methoxy-4-(2-methyl-1H-indol-5-yloxy)-7-(2-oxopyrrolidin-5-ylmethoxy)quinazoline (5 mg) as an off-white solid (ca. 90% pure by nmr). Chromatography of the residues (eluting as above) followed by ether trituration gave further crops of (5R)-6-methoxy-4-(2-methyl-1H-indol-5-yloxy)-7-(2-oxopyrrolidin-5-ylmethoxy)quinazoline as a white solid (180 mg, >95% pure by nmr), as an off-white solid (800 mg, ca. 95% pure by nmr).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH3:19])[C:6]([O:17][CH3:18])=[C:7]([CH:9]([O:12][Si](C)(C)C)[C:10]#[N:11])[CH:8]=1.[CH2:20]([OH:22])[CH3:21]>>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([CH3:19])[C:6]([O:17][CH3:18])=[C:7]([CH:9]([OH:12])[C:10](=[NH:11])[O:22][CH2:20][CH3:21])[CH:8]=1
Reactant: CCO
Reactant: COc1c(C)cc(Cl)cc1C(C#N)O[Si](C)(C)C
Agent: Cl
Product: CCOC(=N)C(O)c1cc(Cl)cc(C)c1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
Ethanol (100 ml.) was saturated with hydrogen chloride at 0° C. 2-(5-Chloro-2-methoxy-3-methylphenyl)-2-trimethylsiloxyethanenitrile (2.9 g.) in 5 ml. of ethanol was added dropwise, keeping the temperature less than 10° C. The reaction mixture was stirred at 0° C. for about 1 hour, evaporated to dryness and the residue triturated with ether to yield ethyl 1-(5-chloro-2-methoxy-3-methylphenyl)-1-hydroxymethanecarboximidate hydrochloride [2.67 g., 89%; m.p. 131°-133° C. (dec); ir (KBr) 1653, 1538, 1488, 1227, 1093 cm-1 ].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:10][C:11]([C:17]([F:20])([F:19])[F:18])=[C:12]([C:14]([OH:16])=O)[N:13]=1.[CH3:21][O:22][CH2:23][CH2:24][N:25]([CH3:33])[C:26]1[N:31]=[CH:30][C:29]([NH2:32])=[CH:28][N:27]=1>>[CH3:21][O:22][CH2:23][CH2:24][N:25]([CH3:33])[C:26]1[N:27]=[CH:28][C:29]([NH:32][C:14]([C:12]2[N:13]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[O:10][C:11]=2[C:17]([F:20])([F:19])[F:18])=[O:16])=[CH:30][N:31]=1
Reactant: COCCN(C)c1ncc(N)cn1
Reactant: COc1ccccc1-c1nc(C(=O)O)c(C(F)(F)F)o1
Product: COCCN(C)c1ncc(NC(=O)c2nc(-c3ccccc3OC)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-(2-methoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide was prepared from 2-(2-methoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and N-(2-methoxy-ethyl)-N-methyl-pyrimidine-2,5-diamine. LCMS calcd for C20H20F3N5O4 (m/e) 451. obsd 452 (M+H).
Reaction SMILES: [C:1]1([C@H:11]([NH:13][CH2:14][CH:15]2[CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][CH2:18][NH:17][CH2:16]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[N:34]([C:37]1[CH:46]=[CH:45][CH:44]=[CH:43][C:38]=1[C:39]([O:41][CH3:42])=[O:40])=[C:35]=[O:36]>C1(C)C=CC=CC=1>[C:1]1([C@H:11]([NH:13][CH2:14][CH:15]2[CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][CH2:18][N:17]([C:35]([NH:34][C:37]3[CH:46]=[CH:45][CH:44]=[CH:43][C:38]=3[C:39]([O:41][CH3:42])=[O:40])=[O:36])[CH2:16]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](NCC1CNCCC1c1ccccc1)c1cccc2ccccc12
Reactant: COC(=O)c1ccccc1N=C=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1NC(=O)N1CCC(c2ccccc2)C(CN[C@H](C)c2cccc3ccccc23)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 11.4 %

Procedure:
To a solution of 158 mg of (1R)-1-(1-naphthyl)-N-[(4-phenylpiperidin-3-yl)methyl]ethaneamine and 0.100 mL of triethylamine in 3.0 mL of toluene was added 83 mg of methyl 2-isocyanatobenzoate at room temperature. It was stirred at 90° C. overnight, and then cooled to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 27.3 mg of methyl 2-({[3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpiperidin-1-yl]carbonyl}amino)benzoate as a colorless foamy substance.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[OH-].[Na+].[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1>C1COCC1.O>[CH:16]1([C:19]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=2)=[O:20])[CH2:18][CH2:17]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NC(=O)C2CC2)cc1[N+](=O)[O-]

Procedure:
6 g (0.033 mol) of 4-amino-2-nitrobenzoic acid were dissolved in a mixture (100 ml) of THF and water (1:1). The solution was adjusted to pH 8.5 with 2 N NaOH and reacted at room temperature with 3.78 g (0.0363 mol) of cyclopropanecarboxylic acid chloride in 25 ml of THF. The pH value of the reaction solution was kept at 8.0 - 8.5 to the end by further addition of 2 N sodium hydroxide solution. After a reaction time of 3.5 hours, the solvent was next distilled off. The residue was diluted with water and the aqueous solution was extracted by shaking once with ethyl acetate and was finally acidified with 2 N HCl to pH 2.0. The oil which precipitated was isolated by extraction with ethyl acetate. After washing and drying the ethyl acetate phase, the solution was concentrated to dryness. The product was crystallized from ethyl acetate/petroleum ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:13][N:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(O)(=O)C.[H][H]>C(OCC)(=O)C.[Pd]>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][CH2:17][C:14]2[CH:15]=[CH:16][C:11]([S:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)(=[O:10])=[O:9])=[N:12][CH:13]=2)=[CH:24][CH:23]=1
Reactant: [H][H]
Reactant: O=S(=O)(c1ccc(F)cc1)c1ccc(/C=C/c2ccc(F)cc2)cn1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(F)cc1)c1ccc(CCc2ccc(F)cc2)cn1
Reaction time: 240 h
Yield: 17.2 %

Procedure:
2-[(4-Fluorophenyl)sulfonyl]-5-[(E)-2-(4-fluorophenyl)vinyl]pyridine (Example 37, 0.11 g, 0.308 mmol) and palladium (10% wt. on activated carbon, 32 mg) were suspended in ethyl acetate (5 mL) and acetic acid (5 mL) and shaken in a Parr apparatus at 50 psi hydrogen for 2 days. The catalyst was removed by filtration, fresh catalyst (80 mg) added and shaking at 50 psi hydrogen continued for 10 days. The catalyst was removed by filtration and the solvent removed in vacuo. The residue was partitioned between saturated sodium carbonate solution and ethyl acetate. The aqueous phase was extracted with further portions of ethyl acetate and the combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by mass-triggered preparative HPLC (Nebula) to give the title compound as a beige solid (19 mg, 17%). δH (500 MHz, d6 DMSO): 8.52 (1H, s), 8.10 (1H, d, J=8.0 Hz), 8.02-7.99 (2H, m), 7.95 (1H, dd, J=1.9, 8.0 Hz), 7.46 (2H, t, J=8.8 Hz), 7.21 (2H, dd, J=5.7, 8.4 Hz), 7.05 (2H, t, J=8.9 Hz), 2.97-2.94 (2H, m), 2.89-2.85 (2H, m); m/z (ES+) 360 [MH+].
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:4]=1[C:5]#[N:6].[CH3:13][C:14]([O-:16])=[O:15].[Na+]>CC(O)=O>[C:14]([O:16][CH2:2][C:3]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:4]=1[C:5]#[N:6])(=[O:15])[CH3:13]
Reactant: CC(=O)[O-]
Reactant: N#Cc1c(Cl)cc(Cl)cc1CBr
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OCc1cc(Cl)cc(Cl)c1C#N
Temperature: 100 °C

Procedure:
To a solution of 2-(bromomethyl)-4,6-dichlorobenzonitrile (15.1 mmol) in 30 mL AcOH was added NaOAc (75.7 mmol). The suspension was heated to 100° C. for 2 h. The solvent was evaporated off and the residue partitioned between DCM and water. The organic phase was washed with water, dried over MgSO4 and concentrated in vacuo. Purification with CC (KP-SIL™ from Biotage) using Hept/EtOAc (95/5 to 30/70) gives the desired compound as white solid.
Reaction SMILES: FC(F)(F)C(O)=O.C([NH:12][C:13](=[O:26])[C@@H:14]1[CH2:18][C@H:17](OC2C=CC=CC=2)[CH2:16][NH:15]1)(C)(C)C.[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[OH:37].C1(O)C=CC=CC=1>>[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[O:37][N:15]1[CH2:16][CH2:17][CH2:18][C@H:14]1[C:13]([NH2:12])=[O:26]
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@H](Oc2ccccc2)CN1
Reactant: Oc1ccc2ccccc2c1
Solvent: Oc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)[C@@H]1CCCN1Oc1ccc2ccccc2c1

Procedure:
Following substantially the same procedure for synthesizing N-t-butyl-4(S)-phenoxy-L-prolineamide trifluoroacetic acid salt as outlined in Example 1, Steps 6 through 8, but substituting 2-naphthol for the phenol used therein, the 2-naphthyloxy proline amide was produced.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([O:12][C:13]1[CH:14]=[CH:15][C:16]([OH:22])=[C:17]([C:19](=[O:21])[CH3:20])[CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)(=O)C>[CH2:5]([O:12][C:13]1[CH:14]=[C:15]([N+:1]([O-:4])=[O:2])[C:16]([OH:22])=[C:17]([C:19](=[O:21])[CH3:20])[CH:18]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(=O)c1cc(OCc2ccccc2)ccc1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC(=O)c1cc(OCc2ccccc2)cc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
18 mL fuming nitric acid are added dropwise to a solution of 81.5 g (0.34 mol) 1-(5-benzyloxy-2-hydroxyphenyl)-ethanone in 700 mL acetic acid while cooling with the ice bath, so that the temperature does not exceed 20° C. Then the reaction mixture is stirred for two hours at ambient temperature, poured onto ice water and filtered. The product is recrystallized from isopropanol, suction filtered and washed with isopropanol and diisopropylether. Yield: 69.6 g (72%); mass spectroscopy [M+H]+=288.
Reaction SMILES: C1(C)C=CC(S([C:10]([OH:31])([OH:30])[CH2:11][CH:12]([CH2:14][CH2:15][CH2:16][CH:17]([CH2:19][CH2:20][CH2:21][CH:22]([CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH3:23])[CH3:18])[CH3:13])(=O)=O)=CC=1.[N-:33]=[N+:34]=[N-:35].[Na+].[N-]=[N+]=[N-]>CN(C)C=O>[N:33]([C:10]([OH:31])([OH:30])[CH2:11][CH:12]([CH2:14][CH2:15][CH2:16][CH:17]([CH2:19][CH2:20][CH2:21][CH:22]([CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH3:23])[CH3:18])[CH3:13])=[N+:34]=[N-:35]
Reactant: Cc1ccc(S(=O)(=O)C(O)(O)CC(C)CCCC(C)CCCC(C)CCCC(C)C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CC(O)(O)N=[N+]=[N-]
Yield: 81.6 %

Procedure:
The yielded phytandiol derivative (0.48 g) was dissolved in 25 ml of dimethyl formamide and 0.06 g (1.00 mmol) of sodium azide was added, followed by reflux for 5 hr in order to substitute azide for para-toluene sulfonyl group. The reaction mixture was extracted with 50 ml of methylene chloride solution and washed with saline. Following drying over anhydrous magnesium sulfate, filtration and concentration, 0.29 g of azido phytandiol derivative was yielded.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[Cl:5][C:6]1[N:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.BrBr.O>C(O)(=O)C>[Cl:5][C:6]1[N:11]=[C:10]2[S:1][C:2]([NH2:3])=[N:12][C:9]2=[CH:8][CH:7]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(Cl)nc1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc2ccc(Cl)nc2s1
Reaction time: 2 h
Yield: 53.3 %

Procedure:
Potassium thiocyanate (16.0 g, 165 mmol) and 6-chloropyridin-3-amine (2.6 g, 20.2 mmol) were dissolved in acetic acid (52 mL). To this solution was added dropwise a solution of bromine (3.2 mL, 62.5 mmol) in acetic acid (12 mL) under cooling in a water bath, and the mixture was stirred for 2 hr. The mixture was warmed to, stirred for 10 hr, and water (30 mL) was added. This reaction mixture was filtered at 85° C., and the insoluble material was suspended in acetic acid (50 mL) and the suspension was filtered. The obtained filtrate was neutralized with aqueous ammonia solution, and the precipitated solid was collected by filtration and recrystallized from methanol to give the title compound (2.0 g, 54%) as a colorless powder.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[C:12]([N+:25]([O-])=O)[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[NH2:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: [H][H]
Reactant: CCCCCCCCOc1ccc([N+](=O)[O-])cc1OCCCCCCCC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCOc1ccc(N)cc1OCCCCCCCC
Yield: 97 %

Procedure:
3,4-Dioctyloxynitrobenzene (25.25 g, 0.067 mol) was dissolved in ethyl acetate (250 mL) in a Parr bottle. 10% Pd on charcoal (3.5 g) was added and the mixture was hydrogenated (5–6 hr) at 50 psi until the hydrogen uptake ceased. The reaction mixture was filtered and evaporated. The aniline was obtained as a dark syrup. (22.5 g, 0.064 mol, 97% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:29]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH2:45]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:41][CH2:40]1)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C.O>[C:1]([O:5][C:6]([NH:7][C@@H:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=1)[O:21][CH2:45][CH:42]1[CH2:43][CH2:44][N:39]([C:37]([O:36][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:38])[CH2:40][CH2:41]1)=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](c1ccccc1)c1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](c1ccccc1)c1cccc(OCC2CCN(C(=O)OCc3ccccc3)CC2)c1
Temperature: 50 °C
Reaction time: 17 h
Yield: 96.7 %

Procedure:
To a mixture of (S)-tert-butyl((3-hydroxyphenyl)(phenyl)methyl)carbamate (8.0 g, 26.7 mmol) and cesium carbonate (13.1 g, 37.4 mmol) in DMF (130 ml) was added 4-(toluene-4-sulfonyloxymethyl)-piperidine-1-carboxylic acid benzyl ester (12.94 g, 32.1 mmol). The resulting reaction mixture was stirred at 50° C. for 17 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic extracts were washed with brine (×3), dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The residue was purified by flash column chromatography eluting with 0 to 50% ethyl acetate/iso-hexane to afford the title compound (13.7 g, 93%).