Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([CH3:16])[CH2:3][C:4]([NH:6][CH2:7][CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5].[C:17]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)#[N:18].N1CCCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.O>[C:2]([C:3](=[CH:23][C:22]1[CH:25]=[CH:26][C:19]([C:17]#[N:18])=[CH:20][CH:21]=1)[C:4]([NH:6][CH2:7][CH:8]=[CH:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:5])(=[O:1])[CH3:16]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CC(=O)CC(=O)NCC=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCNCC1
Solvent: c1ccccc1
Solvent: O
Product: CC(=O)C(=Cc1ccc(C#N)cc1)C(=O)NCC=Cc1ccccc1

Procedure:
600 mg (2.76 mmol) of 3-oxo-N-(3-phenyl-2-propene-1-yl)butyramide, 362 mg (2.76 mmol) of 4-cyanobenzaldehyde and 23.5 mg (0.276 mmol) of piperidine were heated under reflux in the presence of a catalytic amount of p-toluenesulfonic acid in 30 ml of benzene for 6 hours while water was removed. Benzene was evaporated under reduced pressure. Ethyl acetate was added to the reaction mixture. After washing with 1 N hydrochloric acid and then with a saturated aqueous sodium hydrogencarbonate solution, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=5/1) to obtain the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[CH:10]=[CH:11]/[CH2:12][C@H:13]([C:40]1[CH:45]=[CH:44][C:43]2[O:46][CH2:47][O:48][C:42]=2[CH:41]=1)[C@H:14]([N:16]([CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)[C:17]([C@@H:19]([OH:28])[C@@H:20]([C:25]([OH:27])=[O:26])[CH2:21][C:22]([O-:24])=[O:23])=[O:18])[CH3:15].[Na+].[Na+].O1[C:55]2C=CC=[CH:59][C:54]=2N=C1/C=C/C[C@H](C1C=CC2OCOC=2C=1)[C@H](N(CC1C=CC2C(=CC=CC=2)C=1)C([C@@H](O)[C@@H](C(O)=O)CC([O-])=O)=O)C.C(Br)C=C.O>CN(C)C=O>[CH2:59]([O:26][C:25]([C:20](=[C:19]([C:17](=[O:18])[N:16]([C@H:14]([CH3:15])[C@@H:13]([C:40]1[CH:45]=[CH:44][C:43]2[O:46][CH2:47][O:48][C:42]=2[CH:41]=1)[CH2:12]/[CH:11]=[CH:10]/[C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)[CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)[OH:28])[CH2:21][C:22]([OH:24])=[O:23])=[O:27])[CH:54]=[CH2:55]
Reactant: C[C@H]([C@H](C/C=C/c1nc2ccccc2o1)c1ccc2c(c1)OCO2)N(Cc1ccc2ccccc2c1)C(=O)[C@@H](O)[C@H](CC(=O)[O-])C(=O)O
Agent: [Na+]
Solvent: C=CCBr
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)C(CC(=O)O)=C(O)C(=O)N(Cc1ccc2ccccc2c1)[C@H](C)[C@H](C/C=C/c1nc2ccccc2o1)c1ccc2c(c1)OCO2
Reaction time: 6 h
Yield: 48.1 %

Procedure:
69 mg of disodium (3S,4S)-4-[N-{(1R,2R,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-methylenedioxyphenyl)-4-pentenyl}-N-(2-naphthylmethyl)carbamoyl]-3-carboxy-4-hydroxybutanoate obtained in Example 67, was dissolved in 3 ml of dimethylformamide, and 19 μl of allyl bromide was added thereto, followed by stirring for 6 hours. Then, 19 μl of allyl bromide was additionally added, followed by further stirring for 15 hours. The reaction solution was poured into water, extracted with ethyl ether and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/2). The obtained diallyl ester was treated in the same manner as in Example 69(2) and (3) to obtain 17 mg (yield: 25%) of the above-identified compound as colorless oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[C:5]([OH:8])=[N:6][CH:7]=1.[CH3:10][CH2:11][CH2:12]C[N+](CCCC)(CCCC)CCCC.[F-].C(N(CC)CC)C>[Pd].C1(C)C=CC=CC=1.ClCCl.[Cu](I)I>[Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:11]([CH3:12])[O:8][C:5]2=[N:6][CH:7]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: Oc1ncc(Br)cc1I
Agent: I[Cu]I
Agent: [Pd]
Agent: [F-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc2cc(Br)cnc2o1
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-3-iodopyridin-2-ol (1 equiv), copper iodide (3 equiv), palladium catalyst (0.05 equiv), TBAF (1 equiv), triethylamine (3.3 equiv) and alkyne (1 equiv) in toluene was stirred at room temperature until the reaction was deemed complete by TLC analysis. The reaction mixture was diluted with dichloromethane, washed with water, saturated sodium bicarbonate, and brine, dried over sodium bicarbonate, filtered through celite, concentrated, and purified on silica gel to give the product, 5-bromo-2-methylfuro[2,3-b]pyridine.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].[Cl:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.C(OC(=O)C)(=O)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[CH:2][C:1]([OH:4])=[O:3]
Reactant: CC(=O)[O-]
Reactant: O=Cc1ccccc1Cl
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: O=C(O)C=Cc1ccccc1Cl
Temperature: 145 °C
Reaction time: 18 h

Procedure:
A mixture of 18.4 g (0.19 mol) of potassium acetate in 70.3 g (0.5 mol) 2-chlorobenzaldehyde is heated to 145° C. Next 76.5 g (0.75 mol) of acetic anhydride is added in 1 hour. After dosing of 0.50 mol of acetic anhydride the mixture became clear. The mixture is stirred at 145° C. during 18 hours. The hot reaction mixture is poured into a mixture of 670 g of 6.4 w/w % aqueous NaOH (1.1 mol, 2.1 eq based on 2-chlorobenzaldehyde) and 200 mL toluene at 80° C. The final pH was 7.4. After separation of the organic phase, the water layer is again extracted with 100 mL of toluene at 80° C. The combined water phases are acidified with 380 g of 25 w/w % H2SO4 to pH 4.6. Crystallization starts at pH 6.4. The mixture is cooled to 25° C. and the product is isolated by filtration, washed with 100 mL of water and dried (vacuo, 50° C.). 3-(2-chloro-phenyl)-acrylic acid was obtained as an off white solid (100.2 g, 0.55 mol, yield 55%).
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][CH:7]=1.C[O:14][C:15]([C@@H:17]1[CH2:21][C@@H:20](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:19][N:18]1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=O.[OH-].[Na+]>CCO>[CH3:3][CH2:2][O:1][C:15]([C@@H:17]1[CH2:21][C@H:20]([S:12][C:9]2[CH:10]=[CH:11][C:6]([Br:5])=[CH:7][CH:8]=2)[CH2:19][N:18]1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:14]
Reactant: COC(=O)[C@@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OC(C)(C)C
Reactant: Sc1ccc(Br)cc1
Reactant: CC[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)[C@@H]1C[C@H](Sc2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
Reaction time: 48 h
Yield: 40 %

Procedure:
Sodium ethoxide (112 mg, 1.65 mmol) was added slowly to a stirred solution of 4-bromothiophenol (302 mg, 1.65 mmol) in EtOH (6 ml) at room temperature under a nitrogen atmosphere. A solution of (2S,4R)-4-(toluene-4-sulfonyloxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (CAS Reg. No. 88043-21-4) (300 mg, 0.75 mmol) in 1 ml EtOH was added after 30 minutes and the solution was stirred for 48 h. The reaction mixture was poured into 0.5M NaOH (50 ml) and extracted with CH2Cl2 (2×50 ml). The combined organics were dried (magnesium sulphate) and concentrated under vacuum. Flash column chromatography yielded the product as a pink solid (120 mg, 40%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:17]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][CH:9]=[C:8]([Cl:11])[CH:7]=3)[N:1]=2)[CH:19]=[CH:20][CH:21]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:17]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][CH:9]=[C:8]([Cl:11])[CH:7]=3)[NH:1]2)[CH:19]=[CH:20][CH:21]=1
Reactant: NC(=O)c1cc(Cl)ccc1N
Reactant: COc1cccc(C=O)c1
Product: COc1cccc(-c2nc3ccc(Cl)cc3c(=O)[nH]2)c1
Product: COc1cccc(C2NC(=O)c3cc(Cl)ccc3N2)c1
Yield: 95 %
Yield: 1.1 %

Procedure:
According to the preparation of 61 (Method B), 2-amino-5-chlorobenzamide (31) (1.0 g, 5.9 mmol) and 3-methoxybenzaldehyde (34) (0.8 g, 5.9 mmol) were used to afford 50 (20.0 mg, 1.1%) and 68 (1.6 g, 95.0%) as colorless powder.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:9][CH2:10][C:11]#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:19].[Na+].C[OH:22]>O>[C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:9][CH2:10][C:11]([OH:22])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [OH-]
Reactant: CO
Reactant: N#CCCCC(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: O
Product: O=C(O)CCCC(c1ccccc1)c1ccccc1
Yield: 86 %

Procedure:
To a solution of 5,5-diphenylvaleronitrile (6.5 g) in methanol (30 mL), 80 mL of water and 10 g of sodium hydroxide were added, and the mixture was refluxed for 72 hours. After the reaction mixture was allowed to cool, it was washed with diethyl ether and adjusted to pH 1 with concentrated hydrochloric acid. This acidic solution was extracted with diethyl ether and the extract was washed with saturated aqueous NaCl, dried over MgSO4, and concentrated. The residue was recrystallized to provide 5.5 g of the title compound.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:22]=[CH:21][C:14]3[N:15]([CH3:20])[C:16](=[O:19])[CH2:17][S:18][C:13]=3[CH:12]=2)[CH2:6]1)=O.[NH3:23]>CO>[CH3:20][N:15]1[C:14]2[CH:21]=[CH:22][C:11]([N:7]3[CH2:6][C@H:5]([C:3]([NH2:23])=[O:2])[O:9][C:8]3=[O:10])=[CH:12][C:13]=2[S:18][CH2:17][C:16]1=[O:19]
Reactant: N
Reactant: COC(=O)[C@H]1CN(c2ccc3c(c2)SCC(=O)N3C)C(=O)O1
Solvent: CO
Product: CN1C(=O)CSc2cc(N3C[C@H](C(N)=O)OC3=O)ccc21
Reaction time: 3 h
Yield: 57 %

Procedure:
To a stirred suspension of the (5R)-3-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazin-7-yl)-2-oxo-5-oxazolidinecarboxylic acid methyl ester (Step 5, 200 mg, 0.6205 mmol) in MeOH (3 mL) is added a 2.0 M solution of ammonia in MeOH (2.0 mL). This mixture is stirred for 3 h at which time the reaction is concentrated under reduced pressure, washed with ethyl ether (6 mL) and filtered to give the title compound as a white solid (108 mg, 57%), 1H NMR (300 MHz, DMSO) δ 7.86 (s, 1H), 7.63 (d, 2H), 7.47 (dd, 1H), 7.27 (d, 1H), 5.01 (dd, 1H), 4.26 (t, 1H), 4.00 (dd, 1H), 3.52 (s, 2H), 3.32 (s, 3H); MS for C13H13N3O4SMS m/z 308.5 (M+H)+.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15]([O:17][CH3:18])=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li+].[CH3:20]C([N-]C(C)C)C.IC.[Cl-].[NH4+]>C1COCC1>[CH3:20][C:13]1([C:15]([O:17][CH3:18])=[O:16])[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C1c2ccccc2Oc2ccccc21
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)c2ccccc2Oc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
3.25 g (13.53 mmol) of methyl 9H-xanthene-9-carboxylate are dissolved in 70 ml THF, the solution is cooled with an ice bath and 10.15 ml (20.29 mmol) of a 2M solution of LDA are added drop wise whilst keeping the temperature at 0° C. After stirring at room temperature for 1 hr, 1.68 ml (27.06 mmol) of iodomethane are added drop wise and the system is stirred at rt overnight. The solution is poured over excess of saturated solution of ammonium chloride and is extracted thrice with ethyl ether. After washing with brine, the solution is dried and concentrated to give a reddish residue which is purified by column chromatography (Cl3CH/hexane from 1:3 to 1:1) to give 2.6 g of the title compound (75% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1C2C(=O)N[C@H]3CN(C(OC(C)(C)C)=O)C[C@@H]3C=2C(CC)=CC=1.[Cl:25][C:26]1[C:35]2[C:34](=[O:36])[NH:33][C@@H:32]3[CH2:37][N:38](C(OC(C)(C)C)=O)[CH2:39][C@H:31]3[C:30]=2[C:29]([CH2:47][CH3:48])=[CH:28][CH:27]=1>>[ClH:1].[Cl:25][C:26]1[C:35]2[C:34](=[O:36])[N:33]([CH3:2])[C@H:32]3[CH2:37][NH:38][CH2:39][C@@H:31]3[C:30]=2[C:29]([CH2:47][CH3:48])=[CH:28][CH:27]=1
Reactant: CCc1ccc(Cl)c2c1[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1NC2=O
Reactant: CCc1ccc(Cl)c2c1[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1NC2=O
Product: CCc1ccc(Cl)c2c1[C@H]1CNC[C@@H]1N(C)C2=O
Product: Cl

Procedure:
Following the procedures described in Example 15, Part A and Example 45, Part I, (3aR,9bS)-tert-butyl 6-chloro-9-ethyl-5-oxo-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate, the first eluting compound from Example 56, Part B, was converted into the title compound of Example 58 as an pale yellow solid. 1H NMR (DMSO-D6): δ 9.84 (broad s, 1H), 9.79 (broad s, 1H), 7.33 (d, 1H, J=8.2 Hz), 7.26 (d, 1H, J=8.2 Hz), 3.98-3.92 (m, 1H), 3.78-3.71 (m, 1H), 3.62-3.48 (m, 2H), 3.35-3.20 (m, 2H), 2.93 (s, 3H), 2.47 (q, 2H, J=7.4 Hz), 1.05 (t, 3H, J=7.5 Hz). LRMS (ESI): 265.1/267.1 (M+H)+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([CH2:8][OH:9])[CH2:3]1.[OH-].[Na+].[C:12](Cl)(=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15].CCOCC>O.C1COCC1>[OH:9][CH2:8][C@H:4]1[CH2:5][CH2:6][CH2:7][N:2]([C:12](=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:3]1
Reactant: CC(C)CC(=O)Cl
Reactant: OC[C@H]1CCCNC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC(=O)N1CCC[C@H](CO)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 125.3 %

Procedure:
(S)-piperidin-3-ylmethanol hydrochloride (10 g, 65.95 mmol) in water (25 mL) was treated dropwise at 0° C. with a solution of NaOH (13.2 g, 330 mmol, 5 eq.) in water (25 mL). The mixture was stirred for 15 min and a solution of isovaleryl chloride (15.90 g, 131.9 mmol, 2 eq.) in anhydrous THF (25 mL) was added dropwise while stirring vigorously. After 30 minutes at 0° C. the reaction was slowly warmed up to room temperature and stirred overnight. Et2O (500 mL) was added to the reaction mixture with vigorous stirring. The organic layer was separed and washed with brine, dried over Na2SO4 and concentrated to give a residue that was purified by chromatography on silica (Hex/EtOAc 0-100 to yield the desired compound as a colorless oil (16.27 g, 82.62 mmol, 94%). 1H NMR (400 MHz, DMSO-d6, 20° C.) δ0.88 (pseudo d, J=6.4 Hz, 6H), 1.06-1.75 (m, 5H), 1.88-2.05 (m, 1H), 2.07-2.23 (m, 2H), 2.30 (dd, J=10.8, 12.8 Hz, 0.5H), 2.64 (ddd, J=3.2, 10.8, 13.2 Hz, 0.5H), 2.78 (dd, J=10.4, 13.2 Hz, 0.5H), 2.93 (ddd, J=2.4, 11.6, 13.6 Hz, 0.5H), 3.14-3.35 (m, 2H), 3.70-3.85 (m, 1H), 4.08-4.18 (dm, 0.5H), 4.31-4.40 (dm, 0.5H), 4.49 (t, J=5.2 Hz, 0.5H), 4.58 (t, J=5.2 Hz, 0.5H). MS 200 (MH+).
Reaction SMILES: [F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]O.[ClH:12]>>[F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][Cl:12]
Reactant: COc1cccc(CO)c1F
Reactant: Cl
Product: COc1cccc(CCl)c1F
Temperature: 25 °C
Reaction time: 21 h
Yield: 76 %

Procedure:
2-Fluoro-3-methoxybenzyl alcohol from Step 2 (12.16 g, 78 mmol) was dissolved in concentrated hydrochloric acid (60 mL) and hydrochloric acid gas was bubbled through the solution for 3 minutes. The reaction was stirred at room temperature (21 hours). The reaction mixture was extracted with ether, dried over MgSO4 and concentrated in vacuo to give 2-fluoro-3-methoxybenzyl chloride (10.36 g, 76%) as a green oil: 1H NNR (acetone-d6) 300 MHz 7.12 (m, 2H) 7.05 (m, 1H) 4.73 (s, 2H) 3.89 (s, 3H); 19F NMR (acetone-d6) 300 MHz -142.07(m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.C([Li])CCC.[B:14](OC(C)C)([O:19]C(C)C)[O:15]C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([B:14]([OH:19])[OH:15])[CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cc(Cl)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 30.0 g (23 mmol) of 1-chloro-4-fluorobenzene in THF at −78° C. was added 14.4 mL (23 mmol) of a n-butyllithium solution (1.6M in hexanes). After stirring for 2.5 h at that temperature, 10.6 mL (46 mmol) of triisopropyl borate was added dropwise, and the reaction was allowed to slowly warm to room temperature and stir overnight. The reaction was carefully quenched with 1M HCl and then extracted three times with Et2O. The combined organic phase was washed with water, dried over MgSO4, and concentrated to provide 20-1 as a white powder. Data for 20-1: 1HNMR (500 MHz, CDCl3) δ 7.8 (m, 1H), 7.4 (m, 1H), 7.0 (m, 1H), 5.2 (m, 2H) ppm.
Reaction SMILES: [N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([CH3:5])=[CH:3][CH:2]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](OCC)=[O:19].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>O1CCCC1.C1(C)C=CC=CC=1>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=[O:19])[CH2:5][C:4]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:1]=[CH:2][CH:3]=1
Reactant: Cc1ccnc2ccccc12
Reactant: CCOC(=O)c1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(Cc1ccnc2ccccc12)c1ccccn1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 81.5 %

Procedure:
In a 3-neck 3-liter round bottom flask equipped with two addition funnels is dissolved lepidine (10.0 mL, 75.63 mmol) in tetrahydrofuran (200 mL). One addition funnel is charged with ethyl picolinate (20.43 mL, 151.26 mmol) and the other with 0.5 M potassium bis(trimethylsilyl)amide (166.4 mL, 83.19 mmol) in toluene. The solution is cooled to −78° C. and the base added to the reaction mixture dropwise over 40 min. The reaction mixture is stirred an additional 1.5 h and ethyl picolinate is added rapidly. The ice bath is removed and the reaction mixture stirred at ambient temperature for 3 h. The reaction is quenched with water (20 mL) and after 5 min formic acid added until the pH is slightly less than 7. The mixture is concentrated in vacuo and partitioned between ethyl acetate (300 mL) and brine-sodium bicarbonate (300 mL) mixture. The organic layer is washed with brine and sodium bicarbonate, dried over sodium sulfate, and concentrated. The product is chromatographed on SiO2 (27-30% acetone in hexane) to yield 15.31 g (82%) of a yellow-brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].I[CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24].Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: FC(F)(F)CCI
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(CCC(F)(F)F)c1cccc(Cl)c1
Temperature: 25 °C

Procedure:
To a stirred solution of m-chlorophenylacetic acid (2.38 g, 14 mmol) in tetrahydrofuran (85 ml) was added at −78° C. lithium diisopropylamide solution (31 ml 1M in THF, 31 mmol). After stirring the mixture for 20 min 1-iodo-3,3,3-trifluoropropane (4.38 g, 20 mmol) was added and the mixture was allowed to warm to room temperature overnight. Water (5 ml) was added followed by 2N hydrochloric acid (10 ml). The reaction mixture was extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4 and evaporated and the residue was purified by column chromatography (SiO2, heptane/EtOAc=9:1) to yield a colourless oil, (1.75 g, 47%); MS (EI): 264.9 (M+.).
Reaction SMILES: [C:1]([N:5]1[CH2:10][C:9]2[CH:11]=[C:12]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:13]=[C:14]([C:15]3[CH:16]=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=3)[C:8]=2[O:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH:29]1([Mg][Cl:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(OCC)C.C(O)C>C1COCC1.Cl>[ClH:36].[C:25]([C:12]1[CH:13]=[C:14]([C:15]2[CH:16]=[N:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=2)[C:8]([OH:7])=[C:9]([CH2:10][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:11]=1)([CH3:27])([CH3:26])[CH3:28]
Reactant: Cl[Mg]C1CCCCC1
Reactant: CC(C)(C)c1cc2c(c(-c3ccc(C(F)(F)F)nc3)c1)OCN(C(C)(C)C)C2
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)c1cc(CN(CC2CCCCC2)C(C)(C)C)c(O)c(-c2ccc(C(F)(F)F)nc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
To a solution of 3,6-di-tert-butyl-8-(6-(trifluoromethyl)pyridin-3-yl)-3,4-dihydro-2H-benzo[e][1,3]oxazine (Example 75) (250 mg, 0.63 mmol) in THF (10 mL) under argon was added dropwise a 2.0 M solution of cyclohexylmagnesium chloride in diethyl ether (0.41 mL, 0.82 mmol). The reaction mixture was stirred at room temperature for 16 hours, and then partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried (Na2SO4), filtered, and the crude product purified using flash chromatography on silica eluting with a solvent gradient of 0 to 100% ethyl acetate in hexanes. The product was dissolved in a 1.25 M solution of hydrochloric acid in ethanol (5 mL, 6.3 mmol), the mixture stirred for 30 minutes then concentrated under reduced pressure and the product triturated with hexane to give 4-(tert-butyl)-2-((tert-butyl(cyclohexylmethyl)amino)methyl)-6-(6-(trifluoromethyl)pyridin-3-yl)phenol hydrochloride (162 mg, 50% yield) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[C:5]([CH:17]2[CH2:22][C:21]([CH3:24])([CH3:23])[CH2:20][C:19]([CH3:26])([CH3:25])[CH2:18]2)[CH:4]=1.[CH:27](=O)[CH:28]([CH3:30])[CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([N:11]2[CH2:12][CH2:13][N:14]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:15][CH2:16]2)=[C:5]([CH:17]2[CH2:22][C:21]([CH3:24])([CH3:23])[CH2:20][C:19]([CH3:26])([CH3:25])[CH2:18]2)[CH:4]=1
Reactant: COc1cc(C2CC(C)(C)CC(C)(C)C2)c(N2CCNCC2)cc1OC
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc(C2CC(C)(C)CC(C)(C)C2)c(N2CCN(CC(C)C)CC2)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the 1-[4,5-dimethoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (10 mg, 0.028 mmol) produced in Example (87d) in tetrahydrofuran (1 mL) were added isobutyraldehyde (3.0 mg, 0.042 mmol), sodium triacetoxyborohydride (12 mg, 0.057 mmol) and acetic acid (1.7 mg, 0.028 mmol) in that order, followed by stirring for 60 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, extraction was performed with ethyl acetate, and the organic layer was concentrated. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 1-[4,5-dimethoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-isobutylpiperazine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9](Br)=[CH:8]2)=[O:4].[CH3:25][Sn](C)(C)C>CN(C=O)C.[Cl-].[Na+].O.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([CH3:25])=[CH:8]2)=[O:4]
Reactant: C[Sn](C)(C)C
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2Cc2ccccc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ncc2c(cc(C)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 74.1 %

Procedure:
A mixture of 1-benzyl-3-bromo-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (204 mg, 0.52 mmol), tetramethyltin (0.22 mL, 1.57 mmol), and PdCl2(PPh3)2 (74 mg, 0.10 mmol) in 5 mL of DMF was heated at 120° C. for 1 h under N2 atmosphere. Additional tetramethyltin (0.22 mL, 1.57 mmol) was added and the mixture was heated for 1 h at the same temperature. The mixture was cooled to r.t. and diluted with brine (10 mL) and EtOAc (40 mL). The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. After the solvent was evaporated in vacuo, the crude residue was chromatographed (0-60% EtOAc/hexanes+2% AcOH) to give 125 mg of the title compound as a pale yellow solid. MS: (+) m/z 325.05 (M+1).