Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9](O)=[O:10])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[CH2:9][OH:10])=[CH:6][CH:7]=1
Reactant: CC(C)(C(=O)O)c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CO)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.7 %

Procedure:
A solution of 2-(4-fluorophenyl)-2-methylpropanoic acid (1, 5.49 mmol) in dry THF (10 mL) was carefully added over 2 min to a solution of 2M LAH (10.98 mL, 10.98 mmol) in dry THF (20 mL) at 0° C. The reaction mixture was allowed to warm to rt and was stirred for 6 h. The reaction was quenched with 0.5 mL of water (stir for 10 min), 0.5 mL of 15% NaOH/water (stir for 10 min), and then 1.0 mL of water. After stirring for 18 h, the mixture was filtered through celite. The filtrate was concentrated in vacuum. The residue was dried under high vacuum for 16 h to afford 2-(4-fluorophenyl)-2-methylpropan-1-ol (875 mg, 5.20 mmol, 95% yield) as clear viscous oil. 1H NMR (500 MHz, CDCl3) δ 7.42-7.32 (m, 2H), 7.08-6.98 (m, 2H), 3.61 (s, 2H), 1.34 (s, 6H).
Reaction SMILES: NC1C=CC(C[N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)=CC=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1.N1(C(OC(C)(C)C)=O)CCNCC1>>[N+:30]([C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]2)=[CH:25][CH:26]=1)([O-:32])=[O:31]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(N)cc2)CC1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1

Procedure:
tert-Butyl 4-(4-aminobenzyl)piperazine-1-carboxylate (G32) can be prepared by the nucleophilic displacement of commercially available 1-(bromomethyl)-4-nitrobenzene (G30) with tert-butyl piperazine-1-carboxylate (G7) to give tert-butyl 4-(4-nitrobenzyl)piperazine-1-carboxylate (G31). Subsequent reduction with hydrogen in the presence of a catalyst, for example 10% % palladium on charcoal, gives tert-butyl 4-(4-aminobenzyl)piperazine-1-carboxylate (G32).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:7])[C:3]([CH3:6])([OH:5])[CH3:4].[Cl:8][C:9]([Cl:14])([Cl:13])[C:10](Cl)=[O:11]>N1C=CC=CC=1>[OH:5][C:3]([CH3:6])([CH3:4])[C@@H:2]([NH:1][C:10](=[O:11])[C:9]([Cl:14])([Cl:13])[Cl:8])[CH3:7]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C[C@H](N)C(C)(C)O
Solvent: c1ccncc1
Product: C[C@H](NC(=O)C(Cl)(Cl)Cl)C(C)(C)O
Reaction time: 0.17 h
Yield: 93.6 %

Procedure:
To a solution of (3) (1.193 g, 8.56 mmol) at 0° C. in pyridine (24 ml) was added trichloroacetyl chloride (1.05 ml, 9.41 mmol). After stirring at this temperature for 10 minutes, the reaction mixture was stirred overnight at room temperature. The reaction was quenched by the addition of saturated aqueous sodium chloride solution, after which the product was extracted with dichloromethane and the combined organic extracts were washed with hydrochloric acid (1M). Concentration in vacuo and purification by flash column chromatography using 30% ethyl acetate/40-60 petroleum ether as eluant furnished the title compound (4) (1.992 g, 94%) as an oil; νmax (CH2Cl2) 1713 cm-1 ; [α]D24 (c 1.2 in CHCl3)=+6.3; (Found: C, 33.71; H, 5.12; N, 5.72. C7H12Cl3NO2 requires C, 33.83; H, 4.87; N, 5.64%); δH (200 MHz; CDCl3) 1.21 (3H, d, J=3.4, CH3CH), 1.25 (3H, s, C(CH3)2), 1.26 (3H, s, C(CH3)2), 2.31 (1H, s, OH), 3.82 (1H, dq, J=6.7 and 8.8, CHCH3NH), 7.1 (1H, s, NH); δC (125 MHz; CDCl3) 14.89 (CH3), 26.68 (CH3), 27.56 (CH3), 55.19 (CH), 72.01 (C), 92.82 (CCl3), 161.56 (CO); m/z (CI+, NH3) 248 (M+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22]([OH:24])=O)=[CH:19][C:18]=2[CH:25]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C@H:27]1[CH2:32][CH2:31][C@H:30]([N:33]([CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29][CH2:28]1>>[CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22]([NH:26][C@H:27]3[CH2:28][CH2:29][C@H:30]([N:33]([CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[CH2:31][CH2:32]3)=[O:24])=[CH:19][C:18]=2[CH:25]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](N)CC1
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc2oc(C(=O)O)cc2c1
Product: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](NC(=O)c2cc3cc(C(=N)NC(=O)OCc4ccccc4)ccc3o2)CC1

Procedure:
In the same manner as in Example 15 (3), 5-(benzyloxycarbonylamidino)-2-benzofurancarboxylic acid (690 mg, 2.04 mmol) and t-butyl trans -[4-aminocyclohexyl-N-(t-butoxycarbonyl)amino]acetate (670 mg, 2.04 mmol) were condensed and purified by silica gel column chromatography (n-hexane/ethyl acetate=2/3) to give 493 mg of t-butyl trans-[4-[[5-(benzyloxycarbonylamidino)-2-benzofuranyl]carbonylamino]cyclohexyl-N-(t-butoxycarbonyl)amino]acetate as a colorless solid (37%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[O:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Br:29])[CH:23]=1.CN([CH:33]=[O:34])C>CCCCCC.C1COCC1>[Br:29][C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([Cl:28])[CH:25]=1)[O:21][C:15]1[C:14]([Cl:13])=[CH:19][CH:18]=[C:17]([F:20])[C:16]=1[CH:33]=[O:34]
Reactant: CN(C)C=O
Reactant: Fc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1c(F)ccc(Cl)c1Oc1cc(Cl)cc(Br)c1
Temperature: -16 °C
Reaction time: 0.33 h

Procedure:
A round bottom flask was charged with diisopropylamine (1.336 kg, 13.20 moles; 1.2 eqs.) and THF (25 L), and the mixture cooled to −16° C. in a dry ice/acetone bath. A solution of n-butyl lithium (2.5 M; 12.65 moles; 1.17 eqs.) in hexane was added over 25 minutes, while keeping the temperature below 1° C., after which the mixture was aged 20 minutes and then cooled to below −70° C. 3-Bromo-5-chlorophenyl 2-chloro-5-fluorophenyl ether (3.638 kg; 10.8 moles; 1.0 eq.) in THF (4 L) was then added over 35 minutes. The reaction mixture was kept below −60° C. and aged for 1.5 hours, after which DMF (3.683 kg; 50.4 moles; 1.2 eq.) was added over 15 minutes. After aging the mixture a further 50 minutes, the reaction mixture was warmed to −20° C. and quenched with water (5 L). The mixture was then warmed to 15° C., transferred to an extractor (100 L) filled with water (20 L), and extracted with EtOAc (28 L). The organic layer was washed with water (22 L), 1N HCl (25 L), and brine (18 L), and then concentrated to 15 L. Heptane (25 L) was added to the concentrate, and the resulting solution was heated to 60° C. and then concentrated to 18 L as it was cooled to 11° C. The dark yellow suspension was filtered and washed with heptane (5 L), and dried overnight to provide the title product as a solid.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][C:9]1[C:18]2[C:12]([CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:11][CH:10]=1.[S:19](=O)(=[O:22])([OH:21])[OH:20].[OH-].[Na+:25]>>[CH3:8][C:9]1[CH:10]=[C:11]([S:19]([O-:22])(=[O:21])=[O:20])[C:12]2[C:18]=1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2.[Na+:25]
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc2cccccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: Cc1cc(S(=O)(=O)[O-])c2cccccc1-2
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Acetic anhydride in an amount of 10 ml is added to 1.0 g. of 1-methylazulene under cooling with ice-water, sulfuric acid in an amount of 3.4 g. is added dropwise and the reaction mixture is stirred for 4 hours at 0° C. Then, the reaction mixture is alkalized to pH8-9 by adding 40% of sodium hydroxide solution and the generated solid is collected and dried. The product is recrystalized from 95% ethanol to give 1.1 g. of the objective compound.
Reaction SMILES: Br[CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[CH3:6])=[O:4].C(=O)([O-])[O-].[K+].[K+].[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CC(C)=O>[N:22]1([CH2:2][C:3]([N:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[CH3:6])=[O:4])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CN(C(=O)CBr)c1ccc([N+](=O)[O-])cc1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C(=O)CN1CCCCC1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5.4 g (20 mmol) of 4-(N-bromomethylcarbonyl-N-methyl-amino)-nitrobenzene are dissolved in 100 ml of acetone and combined with 5.5 g (40 mmol) of potassium carbonate. 3 ml (30 mmol) of piperidine are slowly added dropwise and the mixture is stirred for 18 hours at ambient temperature. The reaction solution is filtered, and the filtrate is evaporated to dryness. The residue is dissolved in ethyl acetate, washed with water, dried over magnesium sulphate and evaporated to dryness.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)[CH:5]=[CH:6][CH:7]=1.[C:16]1([CH:22]2[CH2:26][CH2:25][NH:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:24]2[CH2:25][CH2:26][CH:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23]2)=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(-c2oncc2C(=O)O)c1
Reactant: c1ccc(C2CCNC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(-c2oncc2C(=O)N2CCC(c3ccccc3)C2)c1
Temperature: 25 °C

Procedure:
5-(3-methylphenyl)-isoxazole-4-carboxylic acid (46.9 mg, 0.231 mmol), 3-phenylpyrrolidine (40 mg, 0.271 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (92.6 mg, 0.288 mmol) and diisopropylethylamine (49.7 mg, 0.384 mmol) were mixed in dimethylformamide (1.5 mL) and stirred at room temperature over night. Solvent was evaporated in vacuo (0.5-1.0 mL) and the residue was taken up in dichloromethane (1 mL), filtered and purified by normal-phase chromatography (20-50% EtOAc:petroleum ether). The combined fractions were partitioned between H2O/acetic acid (pH 4) and ethyl acetate. The organic fractions were washed with H2O/brine and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C21H20N2O2: 332.1525, found 332.1531.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:5][CH:4]([CH:6]([NH:16][C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][C:23]([F:27])=[CH:22][CH:21]=3)[C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.Cl.[CH2:30]([O:32][C:33](=[O:37])[CH2:34][CH2:35][NH2:36])[CH3:31].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][C:2]1([CH3:28])[CH2:3][CH:4]([CH:6]([NH:16][C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][C:23]([F:27])=[CH:22][CH:21]=3)[C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:36][CH2:35][CH2:34][C:33]([O:32][CH2:30][CH3:31])=[O:37])=[O:12])=[CH:9][CH:8]=2)[CH2:5]1
Reactant: CCOC(=O)CCN
Reactant: CC1(C)CC(C(Nc2cnc3ccc(F)cc3c2)c2ccc(C(=O)O)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)c1ccc(C(Nc2cnc3ccc(F)cc3c2)C2CC(C)(C)C2)cc1
Reaction time: 18 h
Yield: 53.4 %

Procedure:
To a vial containing 4-((3,3-dimethylcyclobutyl)(6-fluoroquinolin-3-ylamino)methyl)benzoic acid (11.0 mg, 0.0290 mmol), was added 3-aminopropionic acid ethyl ester hydrochloride (4.90 mg, 0.0320 mmol), 1-Hydroxy-7-azabenzotriazole (4.80 mg, 0.0350 mmol) and 1-ethyl-3-(3-dimethylamino propyl)carbodiimide hydrochloride (6.70 mg, 0.0350 mmol). Anhydrous methylene chloride (0.290 mL) was added followed by triethylamine (0.005 mL, 0.0380 mmol). After 18 h, the reaction was diluted with methylene chloride and quenched with a saturated solution of ammonium chloride. The aqueous layer was extracted three times with methylene chloride. The combined organic layers were dried with sodium sulfate, filtered, and concentrated to give 28.6 mg of crude material. Purification by silica gel flash chromatography (0-70% ethyl acetate in heptane) provided ethyl 3-(4-((3,3-dimethylcyclobutyl)(6-fluoroquinolin-3-ylamino)methyl)benzamido)propanoate (7.40 mg, 54% yield) as an oil. 1H NMR (400 MHz, CDCl3, δ): 7.86 (s, 1H), 7.72 (d, J=8.2 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.14-7.06 (m, 1H), 7.05-6.96 (m, 1H), 6.80 (t, J=5.9 Hz, 1H), 6.60 (s, 1H), 4.45 (s, 1H), 4.24 (dd, J=9.3, 4.4 Hz, 1H), 4.19-4.08 (m, 2H), 3.70 (q, J=6.0 Hz, 2H), 2.62 (t, J=6.0 Hz, 2H), 2.58-2.44 (m, 1H), 2.06-1.96 (m, 1H), 1.75-1.67 (m, 2H), 1.67-1.55 (m, 2H), 1.28-1.22 (m, 3H), 1.13 (s, 3H), 1.09 (s, 3H). (M+1): 478.3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:29])[NH:21][C:22]([CH3:28])=[CH:23][C:24]=2[CH2:25][CH2:26][CH3:27])=[O:16])[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:30][N:31]([CH3:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1>>[CH3:30][N:31]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]3[C:20](=[O:29])[NH:21][C:22]([CH3:28])=[CH:23][C:24]=3[CH2:25][CH2:26][CH3:27])=[O:16])[C:5]3[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=3[CH:10]=2)=[CH:35][CH:34]=1)[CH3:48]
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1c(C)nn2C(C)C
Reactant: CN(C)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(CN(C)C)cc2)cc2c1c(C)nn2C(C)C

Procedure:
The title compound was prepared in the same manner as described for example 67 from 6-bromo-3-methyl-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (0.090 g, 0.196 mmol) and N,N-dimethyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanamine (0.070 g, 0.235 mmol). The product was collected as a white solid (72 mg, 70%); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.33 Hz, 3H), 1.45 (d, J=6.57 Hz, 6H), 1.56 (sxt, J=7.53 Hz, 2H), 2.07-2.23 (m, 9H), 2.44 (s, 3H), 2.52-2.59 (m, 2H), 3.43 (s, 2H), 4.38 (d, J=5.05 Hz, 2H), 5.06 (quin, J=6.63 Hz, 1H), 5.90 (s, 1H), 7.33-7.45 (m, 3H), 7.75 (d, J=8.08 Hz, 2H), 7.93 (d, J=1.26 Hz, 1H), 8.45 (t, J=4.93 Hz, 1H), 11.50 (s, 1H); LCMS (ES+) m/z: 514.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][S:10][CH2:11][C:12]([O:14]C)=[O:13])=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][S:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17]
Reactant: COC(=O)CSCc1cnc(OC)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1ncc(CSCC(=O)O)cc1[N+](=O)[O-]
Temperature: 75 °C
Yield: 90 %

Procedure:
A mixture of methyl 2-((6-methoxy-5-nitropyridin-3-yl)methylthio)acetate (1.0 mmol, 0.27 g) and sodium carbonate (0.3 g) in 150 mL of distilled water was heated at 75° C. for 6 hrs. The mixture was evaporated in vacuo to give 2-((6-methoxy-5-nitropyridin-3-yl)methylthio)acetic acid. Yield 90%; m.p. 249-251° C. (dec.) 1H-NMR (D2O) δ: 3.04 (s, 2H, CH2), 3.74 (s, 2H, CH2), 4.01 (s, 3H, OCH3), 8.28 (d, J=1.0 Hz, 1H, Ar—H), 8.43 (d, J=1.0 Hz, 1H, Ar—H); 13C-NMR (D2O) 6; 31.50, 35.93, 55.02, 128.19, 133.18, 136.76, 151.83, 155.53, 177.29; DEPT-135 (O2O): δ 31.50 (CH2), 35.93 (CH2), 55.02 (CH3) 136.76 (CH), 151.83 (CH); HR-MS (ESI+) m/z 257.0206 [M+H]+, C9H10N2O6S requires 258.0310.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:23])([F:22])[C:5]1[CH:6]=[C:7]([C@H:15]2[O:19][C:18](=[O:20])[NH:17][C@H:16]2[CH3:21])[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1.Br[CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[C:36]1[CH:41]=[C:40]([CH:42]([CH3:44])[CH3:43])[C:39]([F:45])=[C:38]([OH:46])[C:37]=1[O:47][CH3:48].[NH4+].[Cl-]>C1COCC1>[F:23][C:4]([F:3])([F:22])[C:5]1[CH:6]=[C:7]([C@H:15]2[O:19][C:18](=[O:20])[N:17]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:28][C:27]=3[C:36]3[CH:41]=[C:40]([CH:42]([CH3:44])[CH3:43])[C:39]([F:45])=[C:38]([OH:46])[C:37]=3[O:47][CH3:48])[C@H:16]2[CH3:21])[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1
Reactant: COc1c(-c2ccc(C(F)(F)F)cc2CBr)cc(C(C)C)c(F)c1O
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)cc(C(C)C)c(F)c1O
Reaction time: 8 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 14.7 mg, 0.368 mmol) was added to a stirred solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (57.7 mg, 0.184 mmol) in dry THF (2 mL) at room temperature. After 30 min a solution of 2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl-3-ol (62.0 mg, 0.123 mmol) in dry THF (2 mL) was added by cannula and the reaction mixture was stirred overnight. Saturated NH4Cl (10 mL) was added and the mixture was extracted with EtOAc (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-40% EtOAc in hexanes gradient) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-3′-hydroxy-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. Rf=0.25 (20% EtOAc in hexanes). LCMS calc.=654.2; found=654.2 (M+1)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers) δ 7.86 (m, 1H), 7.73-7.63 (m, 4H) 7.44 (m, 1H), 6.55 (d, J=7.6 Hz, 0.5H), 6.52 (d, J=7.7 Hz, 0.5H), 5.71 (br s, 1H), 5.60 (d, J=8.0 Hz, 0.5H), 5.54 (d, J=8.0 Hz, 0.5H), 4.87 (d, J=16.0 Hz, 0.5H), 4.72 (d, J=16.1 Hz, 0.5H), 4.23 (d, J=16.1 Hz, 0.5H), 3.98 (d, J=15.9 Hz, 0.5H), 3.93-3.85 (m, 0.5H), 3.77-3.71 (m, 0.5H), 3.51 (s, 1.5H), 3.47 (s, 1.5H), 3.25-3.17 (m, 1H), 1.26-1.18 (m, 6H), 0.58 (d, J=6.5 Hz, 1.5H), 0.38 (d, J=6.6 Hz, 1.5H).
Reaction SMILES: N.C1N2CN3CN(C2)CN1C3.[N:12]12[CH2:21][N:16]3[CH2:17][P:18]([CH2:20][N:14]([CH2:15]3)[S:13]1(=O)=O)[CH2:19]2.OCP(CO)CO.C=O.[OH-].[NH4+].S(N)(N)(=O)=O>O>[N:12]12[CH2:21][N:16]3[CH2:17][P:18]([CH2:20][N:14]([CH2:15]3)[S:13]1)[CH2:19]2
Reactant: O=S1(=O)N2CN3CN1CP(C3)C2
Agent: C1N2CN3CN1CN(C2)C3
Agent: C=O
Agent: N
Solvent: O
Product: C1N2CN3CP(C2)CN1S3
Yield: 19.3 %

Procedure:
A solution of ammonia may be used in place of hexamethylenetetramine to prepare 2-thia-1,3,5-triaza-7-phosphaadamantane 2,2-dioxide. Tris(hydroxymethyl)phosphine (3.9 g, 80%, 0.025 moles) was dissolved in formalin (20 ml, 40%, 0.267 moles) and water (20 ml). Ammonium hydroxide (29% NH3, 1.7 ml, 0.025 moles) was added to the solution at room temperature. Sulfamide (2.4 g, 0.025 mole) was then added and dissolved in the solution at room temperature. The solution heated up slightly and over the next twenty-four hours a precipitate formed. Filtration, dissolution of the solid in 4 successive 30 ml acetone washes and evaporation of the acetone yielded 1.0 g of crude 2-thia-1,3,5-triaza-7-phosphaadamantane (19.3% yield).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([Cl:13])[N:5]=1.[CH2:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[Cl:13][C:6]1[N:5]=[C:4]([O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=1
Reactant: OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Cl)nc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 82.6 %

Procedure:
2.0 g of sodium hydride was added to a mixture of 9.65 g of 2,6-dichloro-3-nitropyridine, 5.41 g of benzyl alcohol and 30 ml of tetrahydrofuran 0° C. The mixture was stirred at 0° C. for 1.5 hours, then at room temperature for 1.5 hours. The reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 10.93 g of 6-chloro-2-benzyloxy-3-nitropyridine.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][O:12][CH2:13][CH2:14]Br.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[I:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(I)cc1
Reactant: BrCCOCCBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Ic1ccc(N2CCOCC2)cc1
Temperature: 60 °C

Procedure:
Methyl 2-N-boc-amino-5-(4-morpholinophenyl)-pent-4-ynoate: 4-Iodoaniline (6.2 g, 28.4 mmol) is taken in 50 mL of DMF in the presence of 8 mL of bromoethyl ether and 10 mL of Et3N and heated to 60° C. for 24 hr. The mixture is then diluted with EtOAc, and washed 3x with dil. NaHCO3, 1x with brine, dried over MgSO4, filtered and evaporated. The residue is then recrystallized from MeOH to give 4.21 g of 4-iodophenylmorpholine as a pale brown solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[C:21]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[O:29][C:28]([CH3:34])([CH3:33])[CH2:27][CH2:26]2)#[N:22]>C(Cl)(Cl)(Cl)Cl>[Br:1][CH:26]1[C:25]2[C:30](=[CH:31][CH:32]=[C:23]([C:21]#[N:22])[CH:24]=2)[O:29][C:28]([CH3:34])([CH3:33])[CH2:27]1
Reactant: CC1(C)CCc2cc(C#N)ccc2O1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)CC(Br)c2cc(C#N)ccc2O1
Reaction time: 3 h

Procedure:
11 mmol of N-bromosuccinimide and 0.22 g of azobisisobutyronitrile (Aldrich) are added to a solution of 10 mmol of 6-cyano-2,2-dimethyl-chroman in 30 ml of carbon tetrachloride and the suspension thus obtained is heated to boiling under a reflux condenser for 3 hours. Insoluble succinimide is then filtered off, the solvent is distilled off and the residue is crystallized under a mixture of n-hexane and diisopropyl ether.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10]N.CS[C:14]1[NH:15][S:16](=[O:21])(=[O:20])[CH2:17][CH2:18][N:19]=1>>[CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][C:14]1[NH:15][S:16](=[O:21])(=[O:20])[CH2:17][CH2:18][N:19]=1
Reactant: CSC1=NCCS(=O)(=O)N1
Reactant: Cc1nc[nH]c1CSCCN
Product: Cc1nc[nH]c1CSCCC1=NCCS(=O)(=O)N1
Yield: 32.7 %

Procedure:
A mixture of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (4.0 g.) and 3-methylthio-5,6-dihydro-1,2,4-thiadiazine-1,1-dioxide (4.2 g.) was heated in an oil bath at 140° for 4 hours. The product was chromatographed on a column of silica gel with ethyl acetate-ethanol (3:2) as eluant and finally recrystallised from ethanol-ether to give 3-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-5,6-dihydro-1,2,4-thiadiazine-1,1-dioxide (2.2 g.) m.p. 146°-147°.
Reaction SMILES: [OH-].[K+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1.Cl>CCO.O.O>[CH2:3]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(OCc2ccccc2)cc1
Yield: 62.3 %

Procedure:
KOH (6.16 g, 109.78 mmol) and benzyl bromide (9.42 g, 55.08 mmol) were added to a stirred solution of 4-hydroxy benzoic acid (6.9 g, 49.96 mmol) in EtOH:H2O (9:1, 176 mL) and the resulting mixture was heated to reflux for 20 hrs. 20% KOH solution (60 mL) was then added the mixture maintained at reflux for 4 hours. The reaction mixture was diluted with water (200 mL) and acidified with 20% HCl. The resulting white precipitate was filtered and washed with water followed by hexane to afford 7.1 g (62.2% yield) of 4-benzyloxy benzoic acid. 1H NMR (DMSO-d6): δ 12.6 (s, 1H), 7.9 (d, 2H), 7.4 (m, 5H), 7.1 (d, 2H), 5.2 (s, 2H).