Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[NH:2][C:3]([C:5]1[CH:29]=[CH:28][C:8]([O:9][CH:10]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1)=[NH:4].C(OC(=O)C)(=O)C.[H][H]>C(O)(=O)C.[Pd]>[C:11]([OH:13])(=[O:12])[CH3:10].[C:3]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH:10]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:23])[CH3:24])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:28][CH:29]=1)(=[NH:2])[NH2:4]
Reactant: [H][H]
Reactant: CCOc1cc(C(Oc2ccc(C(=N)NO)cc2)C(=O)OC)ccc1OC(C)C
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCOc1cc(C(Oc2ccc(C(=N)N)cc2)C(=O)OC)ccc1OC(C)C
Yield: 181.7 %

Procedure:
To 9B (575 mg, 1.43 mmol) in acetic acid (14 mL) was added acetic anhydride (0.155 mL, 1.64 mmol) and 10% Pd/C (90 mg). The mixture was hydrogenated with a hydrogen balloon at rt for 3.0 h. After removal of solvent, 9C (580 mg, 100% yield) was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.24 (d, J=6.16 Hz, 6H) 1.30 (t, J=7.03 Hz, 3H) 1.69 (s, 3H) 3.66 (s, 3H) 4.00 (q, J=7.03 Hz, 2H) 4.46-4.50 (m, 1H) 6.09 (s, 1H) 6.90 (d, J=8.35 Hz, 1H) 6.97-7.14 (m, 4H) 7.72 (d, J=9.23 Hz, 2H). LC-MS 387 (M+H)+.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Cl[C:37]1[N:42]=[N:41][C:40]([C:43]2([C:46]#[N:47])[CH2:45][CH2:44]2)=[CH:39][CH:38]=1>>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[N:42]=[N:41][C:40]([C:43]4([C:46]#[N:47])[CH2:44][CH2:45]4)=[CH:39][CH:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: N#CC1(c2ccc(Cl)nn2)CC1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(C3(C#N)CC3)nn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 51 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 1-(6-chloro-pyridazin-3-yl)-cyclopropanecarbonitrile following a procedure analogous to that described in Example 1. Yield: 51% of theory; LC (method 2): tR=3.42 min; Mass spectrum (ESI+): m/z=497 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][N:14]([CH3:15])[C:12]1[C:11]([C:17]([F:18])([F:20])[F:19])=[CH:10][C:9]2[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2cccc(C3=Nc4cc(N(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from (5-dimethylamino-2-{3-[3-(6-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M7) (350 mg, 0.63 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (207 mg).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][Cl:21]>CC(C)=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:19][CH2:20][Cl:21]
Reactant: Oc1ccc2ccccc2c1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCCOc1ccc2ccccc2c1

Procedure:
A mixture of β-naphthol (1 gm, 0.006 mole), anhydrous K2CO3 (10 gm, in excess) and 1-bromo-2-chloroethane (0.6 ml, 0.006 mole) was refluxed in dry acetone (50 ml) for 6 hours. Reaction mixture was filtered and filtrate was concentrated to get oily compound, which was crystallized with benzene-hexane to give the colorless crystals of pure desired compound. m.p. 94° C., (yield 1.36 gm, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=1[F:32].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:12]([CH2:16][CH2:17][C:18]([F:21])([F:19])[F:20])[C:13]([NH2:15])=[O:14])[CH2:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=2[F:32])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NC(=O)[C@@H](CCC(F)(F)F)NS(=O)(=O)c1ccc(Cl)cc1
Reactant: N#Cc1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(CN([C@H](CCC(F)(F)F)C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of (R)-2-(4-chlorophenylsulfonamido)-5,5,5-trifluoropentanamide (6.88 g, 20.0 mmol) and 4-(bromomethyl)-3-fluorobenzonitrile (6.43 g, 30 mmol) in DMF (35 mL) was added anhydrous Cs2CO3 (19.56 g, 60 mmol). The resulting mixture was stirred at room temperature for 45 min. and then diluted with EtOAc (200 mL), washed with water (100 mL×4) and dried over Na2SO4. The product was purified by Biotage (40+M column, 3% to 80% EtOAc in hexanes, 651 mL). The title compound was obtained as a white solid (6.50 g, 68.1% yield). 1H NMR (DMSO-d6, 400 MHz) δ 7.80-7.88 (m, 3H), 7.70-7.75 (m, 2H), 7.67 (d, 2H, J=8), 7.60 (s, 1H), 7.26 (s, 1H), 4.99 (d, 1H, J=16), 4.68 (d, 1H, J=16), 4.14 (t, 1H, J=8), 1.99-2.17 (m, 2H), 1.80-1.94 (m, 1H), 1.40-1.56 (m, 1H). LC/MS M+H 478.14, 94%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[C@H:4]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[NH:5][C:6](=[O:30])[C@H:7]([CH2:26][C:27](=[O:29])[OH:28])[NH:8][C:9](=[O:25])[C@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1C(OCC1C=CC=CC=1)=O.[H][H]>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:38])[C@H:4]([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[NH:5][C:6](=[O:30])[C@H:7]([CH2:26][C:27](=[O:28])[OH:29])[NH:8][C:9](=[O:25])[C@H:10]1[CH2:14][CH2:13][CH2:12][NH:11]1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H]1CCCN1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H]1CCCN1
Yield: 87.8 %

Procedure:
N-Benzyloxycarbonyl-D-prolyl-α-L-aspartyl-L-phenylalanine methyl ester (2.6 g) was dissolved in 100 ml of 80% aqueous acetic acid, and the solution was subjected to catalytic reduction in a hydrogen gas stream at room temerature for four hours using palladium/carbon as catalyst. After filtering off the catalyst, the filtrate was concentrated to dryness under reduced pressure, affording 1.7 g of white powder. M.p.: 238°-241.5° C.
Reaction SMILES: [O-]CC.[K+].[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8]CC)=O.[CH3:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1>C(OCC)C.C(O)C>[CH2:13]([O:12][C:5](=[O:11])[C:6](=[O:8])[CH2:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1)[CH3:14]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1ncccc1[N+](=O)[O-]
Agent: CC[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(=O)Cc1ncccc1[N+](=O)[O-]
Reaction time: 0.08 h

Procedure:
To a solution of potassium ethoxide (2.44 g, 27.7 mmol) in diethyl ether (90 mL) and ethanol (8 mL) was added diethyl oxalate (3.79 mL, 27.7 mmol) resulting in a yellow suspension. The reaction mixture was stirred for 5 min prior to the addition of 2-methyl-3-nitropyridine (Preparation 29, 3.40 g, 24.6 mmol) in one portion. The resulting red suspension was stirred at rt, under argon, for 20 h. The mixture was filtered, washed thoroughly with diethyl ether and dried. The red solid was dissolved in water and the mixture adjusted to pH 4 by addition of glacial acetic acid. The resulting precipitate was collected by filtration, dissolved in dichloromethane, washed with brine, dried (MgSO4), and then filtered and concentrated in vacuo to give the title compound as an orange solid. δH (CDCl3): 1.40 (3H, t), 4.39 (2H, q), 7.34 (1H, s), 7.36 (1H, dd), 8.43 (1H, dd), 8.66 (1H, dd).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([S:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH:8]=[CH:7][C:6]=1[NH:16][C:17](=[N:23][C:24](=[O:27])[O:25][CH3:26])[NH:18][C:19]([O:21][CH3:22])=[O:20])(=[O:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:33]>C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([S:11]([CH2:12][CH:13]([CH3:15])[CH3:14])=[O:33])[CH:8]=[CH:7][C:6]=1[NH:16][C:17](=[N:18][C:19](=[O:20])[O:21][CH3:22])[NH:23][C:24]([O:25][CH3:26])=[O:27])(=[O:3])[CH3:2]
Reactant: COC(=O)N=C(NC(=O)OC)Nc1ccc(SCC(C)C)cc1NC(C)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COC(=O)N=C(NC(=O)OC)Nc1ccc(S(=O)CC(C)C)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3.9 g (0.01 mole) of [[[2-(acetylamino)-4-[(2-methylpropyl)thio]phenyl]amino][(methoxycarbonyl)amino]methylene carbamic acid, methyl ester in 250 ml of chloroform there is added 2.0 g (0.01 mole of 85% m-chloroperoxybenzoic acid in 10 ml of chloroform with ice bath cooling. The reaction mixture is allowed to warm to room temperature and then stirred for 3 hours. The reaction mixture is washed with aqueous potassium carbonate and then with water until the pH is 7. The organic layer is dried (MgSO4), filtered, and evaporated in vacuo. The residue is crystallized from ethanol to yield 1.8 g, m.p. 178°-180° C. dec.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][CH:6]([C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([CH3:9])=O)C.[C:19]1([NH:25][NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>C(O)CCC>[CH3:9][C:7]1[C:6]([CH2:5][C:4]([OH:3])=[O:18])=[C:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:26]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)CC(C(C)=O)C(=O)c1ccccc1
Agent: Cl
Solvent: CCCCO
Product: Cc1nn(-c2ccccc2)c(-c2ccccc2)c1CC(=O)O
Yield: 93.9 %

Procedure:
3.0 grams 3-benzoyl-levulinic acid-ethyl ester, 1.3 gram phenyl-hydrazine, 0.15 milliliter 2n aqueous hydrochloric acid and 25 milliliters n-butanol were mixed and the mixture heated to boiling temperature under reflux for 1.5 hour. The reaction mixture was evaporated in vacuo and benzene added to the residue. The benzene solution was adjusted to a pH of 4 and extracted with water. The benzene was evaporated from the solution, and 15 milliliters ethanol and 20 milliliters 1n aqueous sodium hydroxide were added to the residue and the mixture heated to the boiling temperature. The mixture was then worked up and the free acid recovered in accordance with the procedure set out in Example (1b). 3,3 grams 3-methyl-1,5-diphenyl-pyrazol-4-acetic acid, melting at 159°-161° C., were obtained representing a yield of 93%.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[N:26]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27]1.C(N(CC)CC)C>ClCCl>[CH3:1][N:2]([CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1)[C:31]([N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:32]
Reactant: CNC1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Reactant: O=C(Cl)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1C2CCC3C4CC=C5CC(N(C)C(=O)N6CCCC6)CCC5(C)C4CCC32CN1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A mixture of compound 7B (10.7 mg, 0.031 mmol), 1-pyrrolidinecarbonyl chloride (13 μL, 3.0 eq), triethylamine (26 μL, 6.0 eq) and dichloromethane (1 mL) was stirred at room temperature overnight. The clear solution was directly loaded on silica gel column and eluted with 0.5% ammonium hydroxide and 5% methanol in dichloromethane to give the desired product (12 mg, 87% yield).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:12][C:13](=[O:15])[CH3:14])=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[BH4-].[Na+].Cl>CO>[F:1][C:2]1[C:3]([CH2:12][CH:13]([OH:15])[CH3:14])=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(=O)Cc1c([N+](=O)[O-])ccc(F)c1F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)Cc1c([N+](=O)[O-])ccc(F)c1F
Reaction time: 0.5 h
Yield: 88 %

Procedure:
31.2 g (145 mmol) of the compound (148) obtained above was added to 500 ml of methanol, and while cooling on ice, 6.04 g (160 mmol) of sodium borohydride was added to the solution through 5 minutes. After the solution was stirred for 30 minutes as was, the solution was stirred overnight at room temperature. 100 ml of 4N hydrochloric acid was added slowly to the solution and the solution was stirred for 30 minutes at room temperature. Then, the solvent was removed by distillation. The solution was extracted with 400 ml of chloroform, and after drying over magnesium sulfate, the solvent was removed by distillation to obtain 27.7 g of the subject compound (149) in a 89% yield.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[S:8](Cl)(Cl)=[O:9].O>C(OCC)C>[CH3:1][C:2]1([CH3:7])[CH2:5][O:6][S:8](=[O:9])[O:4][CH2:3]1
Reactant: CC(C)(CO)CO
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: CCOCC
Product: CC1(C)COS(=O)OC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
Step A A mixture of 2,2-dimethyl-propane-1,3-diol (Aldrich) (5 g, 48 mmol) in anhydrous ethyl ether (100 mL) at 0° C. was added thionyl chloride (8.7 mL, 120 mmol). The reaction mixture was stirred at 0° C. for 2 h. Water was added. The organic layer was separated, the aqueous layer was then extracted with ethyl ether. The combined organic layers were washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, concentrated to give 5,5-dimethyl-[1,3,2]dioxathiane 2-oxide as a light pink oil (4.8 g, 82%).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.[C:15]([N:23]1[CH:27]([CH3:28])[C:26](=[O:29])[O:25][CH:24]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Br[CH2:37][N:38]1[C:42](=[O:43])[C:41]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:40]2[C:39]1=[O:48]>C1COCC1>[C:15]([N:23]1[C:27]([CH2:37][N:38]2[C:42](=[O:43])[C:41]3[C:40](=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:39]2=[O:48])([CH3:28])[C:26](=[O:29])[O:25][CH:24]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC1C(=O)OC(c2ccccc2)N1C(=O)c1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1CBr
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(CN2C(=O)c3ccccc3C2=O)C(=O)OC(c2ccccc2)N1C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 73.5 %

Procedure:
Into a solution of hexamethyldisilazane (17.5 g, 106 mmol) in THF (100 mL) was added n-butyllithium (1.58 M in hexane, 50 mL, 78.5 mmol) at −78° C. After 5 min at −78° C., the solution was allowed to warm to 0° C. for 30 min and then cooled to −78° C. again. A solution of 3-benzoyl-4-methyl-2-phenyl-1,3-oxazolidin-5-one (dried overnight in vacuo before using, 20 g, 71 mmol) in THF (250 mL) was added slowly under argon, and the dark red brown solution was stirred at this temperature for 3 h. A solution of N-(bromomethyl)phthalimide (22.2 g, 92.5 mmol) in THF (200 mL) was then added dropwise. The reaction mixture was allowed to warm to 20° C. in 4 h and stirred at this temperature overnight. The solvent was evaporated. The residue was dissolved in 10% NH4Cl (250 mL) and extracted with CH2Cl2. The organic phase was dried over Na2SO4 and evaporated. Recrystallization from CH2Cl2 and ether (1:4) gave white crystals of 2-((3-benzoyl-4-methyl-5-oxo-2-phenyloxazolidin-4-yl)methyl)isoindoline-1,3-dione (23 g, 74%). LC-MS (ES, m/z): 441 [M+H]+.
Reaction SMILES: [C:1]1(O)C2C(=CC=CC=2)C=CC=1.[Br:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[OH:23].BrNC(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[O:23][CH3:1]
Reactant: Oc1cccc2ccccc12
Reactant: Oc1c(Br)ccc2ccccc12
Agent: CC(C)(C)NBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1c(Br)ccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-naphthol was converted into 2-bromo-1-naphthol by reaction with a slurry of N-bromo-t-butylamine at -78° C. according to the procedure described in Pearson, Wysong, Breder, J. Org. Chem. 32, 2358 (1967). To a solution of 1 mole (crude) of the bromonaphthol in 750 mL of acetone was added 175 g of potassium carbonate. Over a 2-hous period, 95 mL of dimethylsulate was added dropwise to the mechanically stirred reaction mixture. The resulting slurry was stirred at 25° C. overnight. The solids were filtered and the solution was stripped to yield a dark brown oil. Initial purification was accomplished by vacuum distillation (80°-120° C., 0.2 Torr) followed by further purification by HPLC with hexane to yield 145 g of 2-bromo-1-methoxynaphthalene as a pale yellow oil. NMR confirmed the structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH2:10][CH:11]([OH:16])[CH2:12][CH2:13][CH:14]=[CH2:15].[Br:17]N1C(=O)CCC1=O>C(Cl)Cl>[Br:17][CH2:15][CH:14]1[CH2:13][CH2:12][CH:11]([CH2:10][C:4]2[CH:5]=[C:6]([F:9])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[O:16]1
Reactant: C=CCCC(O)Cc1cc(F)ccc1OC
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COc1ccc(F)cc1CC1CCC(CBr)O1
Temperature: 25 °C

Procedure:
To a solution of 1-(2′-methoxy-5′-fluorophenyl)hex-5-en-2-ol (1.35 g, 6.0 mmol) in dry CH2Cl2 (30 mL) at 0° C. was added N-bromosuccinimide (NBS, 1.30 g, 7.2 mmol) portionwise and the reaction was warmed to room temperature for 12 h. Solvent was then removed in vacuo and the residue was purified by flash column chromatography (5% EtOAc in Hexane, Rf=0.12) to give in the trans isomer (663 mg, 36%) as an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[C@H:24]([CH3:25])[CH2:23][CH2:22][C@H:21]3[CH3:26])=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH3:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:26][C@@H:21]1[CH2:22][CH2:23][C@@H:24]([CH3:25])[N:20]1[C:18]([C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:31]3[CH2:32][CH2:33][CH:28]([CH3:27])[CH2:29][CH2:30]3)=[CH:7][CH:8]=2)=[CH:13][CH:14]=1)=[O:19]
Reactant: C[C@@H]1CC[C@@H](C)N1C(=O)c1ccc(-c2ccc(OCCCCl)cc2)cc1
Reactant: CC1CCNCC1
Product: CC1CCN(CCCOc2ccc(-c3ccc(C(=O)N4[C@H](C)CC[C@H]4C)cc3)cc2)CC1

Procedure:
The product from Example 4A and 4-methylpiperidine were processed as described in Example 10F to provide the title compound.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25](O)=[O:26])=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH3:31][O:32][CH2:33][CH2:34][NH:35][CH3:36]>>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([N:35]([CH2:34][CH2:33][O:32][CH3:31])[CH3:36])=[O:26])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1
Reactant: CNCCOC
Agent: Cl
Product: COCCN(C)C(=O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1

Procedure:
50 mg (0.12 mmol) of 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzofuran-7-yl)benzoic acid hydrochloride (Example 149) and 20.9 mg (0.23 mmol) of N-(2-methoxyethyl)-N-methylamine are reacted together by general method E. 20.4 mg (31.3% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([Mg]I)[CH3:2].[Br:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=O)=[C:8]([F:16])[CH:7]=1.[NH4+].[Cl-]>C(OCC)C.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[Br:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]2([OH:12])[CH2:2][CH2:1]2)=[C:8]([F:16])[CH:7]=1
Reactant: CC[Mg]I
Reactant: COC(=O)c1ccc(Br)cc1F
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: OC1(c2ccc(Br)cc2F)CC1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 27.5 %

Procedure:
To a stirred solution of Ti(OiPr)4 (44.68 mL, 141.63 mmol, 1 eq) in diethyl ether (250 mL) was added freshly prepared ethyl magnesium iodide (212.44 mL, 424.89 mmol, 3 eq) in diethyl ether (220 mL) at −78° C. for 45 min. The reaction mixture was stirred for 90 min at −78° C., then methyl 4-bromo-2-fluorobenzoate (33.0 g, 141.63 mmol, 1.0 eq) was added and the mixture allowed to stir at RT for 16 h. Saturated aqueous NH4Cl (30 mL) was added and the mixture passed through celite pad. The ether layer was separated, washed with 1 N HCl (250 mL), brine (500 mL), water (750 mL), dried over MgSO4 and the solvent evaporated. The resulting residue was purified by CC using PE/EtOAc (19:1) as eluent to get 1-(4-bromo-2-fluorophenyl)cyclopropanol (9.01 g, 28%; TLC system: PE/EtOAc (9:1), Rf: 0.3).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH:22]2[CH2:24][CH2:23]2)[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[N:8]=1.[F:25][C:26]1[C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=[CH:29][C:27]=1[NH2:28].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>[NH4+].[Cl-].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:13][C:9]1[N:8]=[C:7]([C:6]2[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:4]([CH:22]3[CH2:24][CH2:23]3)=[N:3][C:2]=2[C:32]2[C:26]([F:25])=[C:27]([CH:29]=[CH:30][CH:31]=2)[NH2:28])[CH:12]=[CH:11][N:10]=1
Reactant: CC1(C)OB(c2cccc(N)c2F)OC1(C)C
Reactant: C[Si](C)(C)CCOCn1c(C2CC2)nc(Br)c1-c1ccnc(Cl)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1c(C2CC2)nc(-c2cccc(N)c2F)c1-c1ccnc(Cl)n1
Yield: 36.9 %

Procedure:
To a microwave vial with stir bar was added 4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine (I-1a, step 5, 0.55 g, 1.3 mmol), 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.61 g, 2.6 mmol), 2.0 M aqueous sodium carbonate solution (3.2 mL, 6.4 mmol) and DME (6.4 mL). The resulting mixture was sparged with nitrogen followed by the addition of PdCl2(dppf)•DCM adduct (0.052 g, 0.06 mmol). The reaction was sealed and irradiated in microwave reactor for 20 minutes at 120° C. The reaction mixture was diluted with a saturated aqueous NH4Cl solution and extracted with EtOAc. The organic phase was washed with water, brine, dried (Na2SO4), filtered, concentrated, and adsorbed onto silica gel. Purification by flash chromatography (SiO2, 0-100% EtOAc in heptane) yielded 3-(5-(2-chloropyrimidin-4-yl)-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-2-fluoroaniline (223 mg, 0.48 mmol, 38%) as a viscous yellow oil: LCMS(m/z) 460.1 (MH+), tR=0.95 minute.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CCN(CC)CC.[C:13]([O:17][C:18](=[O:24])[NH:19][CH2:20][CH2:21][CH2:22][OH:23])([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl>[C:13]([O:17][C:18]([NH:19][CH2:20][CH2:21][CH2:22][O:23][S:2]([CH3:1])(=[O:4])=[O:3])=[O:24])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
MsCl (6.5 mL, 84 mmol) was added slowly to a solution of Et3N (16.0 mL, 114 mmol) and (3-hydroxy-propyl)-carbamic acid tert-butyl ester (13.4 g, 76.5 mmol) in CH2Cl2 (200 mL) at 0° C. (bath temp). The reaction mixture was stirred at rt for 2 h and then quenched with H2O (100 mL). The aqueous layer was extracted with CH2Cl2 and the organic fractions were then dried (MgSO4) and concentrated in vacuo. The title compound was isolated as a colorless oil: yield 18.9 g (98%).