Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:12][C@H:13]([C:20]([O-:22])=[O:21])[C@H:14]([OH:19])[C:15]([O:17][CH3:18])=[O:16])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23]CN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:10]([NH:12][C@H:13]([C:20]([OH:22])=[O:21])[C@H:14]([OH:19])[C:15]([O:17][CH3:18])=[O:16])=[O:11])[CH3:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](O)[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)[O-]
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](O)[C@H](NC(=O)[C@@H](C)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The compound of example 255A (470 mg, 1.32 mmol) and (2S,3S)-2-amino-3-hydroxy-4-methoxy-4-oxobutyric acid hydrochloride (see example 33A for preparation, 407 mg, 2.04 mmol, 1.6 equivalents) are dissolved in DMF (20 ml) at 0° C., and DIPEA (1.78 ml, 10.20 mmol, 7.7 equivalents) are added. The mixture is stirred at room temperature for about 16 h and then chromatographed according to method 45 and fine purified by method 32. Yield: 200 mg (29% of theory).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH2:8].[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH:23]=[CH:24][CH2:25]Br)=[CH:12][CH:11]=1.O>CN(C)C=O>[F:9][C:10]1[CH:11]=[CH:12][C:13]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH:23]=[CH:24][CH2:25][NH:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:14][CH:15]=1
Reactant: Fc1ccc(Sc2ccccc2C=CCBr)cc1
Reactant: NOC1CCCCO1
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(Sc2ccccc2C=CCNOC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To O-tetrahydropyranyl hydroxylamine (2.77 g; 23.6 mmol) in 10 ml of dry dimethylformamide was added 1-[2-(4-fluorophenylthio)phenyl]-3-bromoprop-1-ene (2.54 g; 7.87 mmol) in 10 ml of dimethylformamide dropwise. The reaction mixture was stirred overnight at room temperature. The mixture was poured into 200 ml of water and extracted twice with diethyl ether. The organics were collected, washed twice with water and then with brine, dried over K2CO3 and concentrated. The crude subtitle compound was chromatographed by HPLC using 3:1 hexane/ethyl acetate and then 2:1 hexane/ethyl acetate to afford the subtitle compound.
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]1=2.[CH:16]1([C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[B][B][B][B][B][B][B][B][B][B]>CO>[CH:16]1([C:22]2[CH:23]=[CH:24][C:25]([NH:26][CH:2]3[CH2:11][CH2:10][CH2:9][C:8]4[CH:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]3=4)=[CH:27][CH:28]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: Nc1ccc(C2CCCCC2)cc1
Reactant: COC(=O)c1ccc2c(c1)CCCC2=O
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: COC(=O)c1ccc2c(c1)CCCC2Nc1ccc(C2CCCCC2)cc1
Reaction time: 4 h

Procedure:
A mixture of methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (1.2 g, 5.9 mmol), 4-cyclohexylaniline (2.1 g, 11.8 mmol), decaborane (0.22 g, 1.8 mmol) in dry MeOH (20 mL) was stirred under nitrogen for 4 h. Solvent evaporation and chromatography (5% to 20% EtOAc in Hexane) gave methyl 5-[(4-cyclohexylphenyl)amino]-5,6,7,8-tetrahydronaphthalene-2-carboxylate as a yellow solid. HPLC/MS: m/z=364.2 (M+1), Rt=2.83 min. 1H NMR (CDCl3): δ 7.86 (1H, s), 7.85 (1H, d, J=7.5 Hz), 7.54 (1H, d, J=7.5 Hz), 7.11 (2H, d, J=8.5 Hz), 6.68 (2H, d, J=8.5 Hz), 4.66 (1H, t, J=5.5 Hz), 3.96 (3H, s), 3.79 (1H, br s), 2.97-2.82 (2H, m), 2.46 (1H, m), 2.10-1.78 (9H, m), 1.44 (4H, m), 1.30 (1H, m).
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH:14]([C:20](OCC)=[O:21])[C:15](OCC)=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:1]1([CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH:14]([CH2:15][OH:16])[CH2:20][OH:21])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(CCOCCOCc1ccccc1)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: O
Product: OCC(CO)CCOCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
C6H5—CH2O—CH2CH2OCH2CH2—CH(COOC2H5)2 (5 g) from Step B was dissolved in 200 ml of toluene and 29.5 ml of LiAlH4 (1 M in THF) was added at 0-5° C. After stirring overnight at room temperature, 1 ml of water was added followed by 1.0 ml of 15% NaOH and 3.0 ml of water. The insoluble material was filtered and the filtrate was evaporated to dryness. The product was purified by flash chromatography on a silica gel column eluted with ethyl acetate. Combined fractions were evaporated to dryness. The final product was dried under vacuum overnight.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH2:2]1.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH2:2]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1cc(NC2CCCNC2)ccn1
Reactant: O=Cc1ccccc1
Product: c1ccc(CN2CCCC(Nc3ccncc3)C2)cc1

Procedure:
Reaction of N-(piperidin-3-yl)pyridin-4-amine with the benzaldehyde using the method of Example 8 affords the title compound.
Reaction SMILES: [F:1][C:2]([F:31])([C:6]([F:30])([F:29])[C:7]([F:28])([F:27])[C:8]([F:26])([F:25])[C:9]([F:24])([F:23])[C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])C(O)=O.[Br:32]Br.FF>>[F:1][C:2]([Br:32])([F:31])[C:6]([F:30])([F:29])[C:7]([F:28])([F:27])[C:8]([F:26])([F:25])[C:9]([F:24])([F:23])[C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14]
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: BrBr
Agent: FF
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)Br
Yield: 149 %

Procedure:
Perfluorodecanoic acid 788 g (1.53 mole), bromine 144 g (0.90 mole) and Freon 113 (200 ml) were treated with fluorine at 30°-38° C. according to the method of Example 3. Approximately 736 g of perfluorononyl bromide (88% yield) was produced. The perfluoroalkyl halide has a boiling point between 95°-6° C./20 mm Hg and a melting point of 30° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:26])[C:4](=[O:25])[C:5]([C:14]2[CH:15]=[C:16]([CH:23]=[O:24])[N:17]([CH2:19][CH2:20][CH2:21][F:22])[CH:18]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9](Br)[CH:8]=2)[N:6]=1.[C:27]1([C:33]#[C:34]B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[NH2:1][C:2]1[N:3]([CH3:26])[C:4](=[O:25])[C:5]([C:14]2[CH:15]=[C:16]([CH:23]=[O:24])[N:17]([CH2:19][CH2:20][CH2:21][F:22])[CH:18]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:34]#[C:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:8]=2)[N:6]=1
Reactant: OB(O)C#Cc1ccccc1
Reactant: CN1C(=O)C(c2cccc(Br)c2)(c2cc(C=O)n(CCCF)c2)N=C1N
Product: CN1C(=O)C(c2cccc(C#Cc3ccccc3)c2)(c2cc(C=O)n(CCCF)c2)N=C1N

Procedure:
Using essentially the same procedure described in Example 200 and employing 4-{2-amino-1-methyl-5-oxo-4-(3-bromophenyl)-4,5-dihydro-1H-imidazol-4-yl}-1-(3-fluoropropyl)-1H-pyrrole-2-carbaldehyde and phenylethyneboronic acid, the title compound was obtained as a white solid, mp 85-90° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [O:1]([CH2:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:20]2([OH:26])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]2)[CH:17]=[CH:18][CH:19]=1>>[OH:26][C:20]1([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)[CH2:25][CH2:24][CH2:23][N:22]([C:9](=[O:10])[CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:21]1
Reactant: O=C(Cl)COc1ccccc1
Reactant: COc1cccc(C2(O)CCCNC2)c1
Product: COc1cccc(C2(O)CCCN(C(=O)COc3ccccc3)C2)c1

Procedure:
The compound of Example 15 was prepared according to the general preparation protocol A from phenoxyacetyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][N:9]=2)[CH2:4][CH2:3]1.C(NC(C)C)(C)C.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[CH2:24]([NH:31][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][C:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[N:9][CH:10]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: CN1CCN(c2ccc(C(=O)O)cn2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(C(=O)NCc3ccccc3)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 6-(4-methyl-piperazin-1-yl)-nicotinic acid (200 mg) in DMF (2 ml) was treated under an argon atmosphere with diisopropylamine (0.50 ml), benzylamine (0.12 ml) and BOP (600 mg). The reaction mixture was stirred at r.t. overnight, then diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2→CH2Cl2/MeOH 9:1) to give N-benzyl-6-(4-methyl-piperazin-1-yl)-nicotinamide (120 mg) as off-white solid. MS (ISP): 311.3 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[C:7]([NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([S:21](=[O:24])(=[O:23])[NH2:22])[CH:19]=2)[O:14][CH2:13][CH2:12]1)=[O:8].[CH2:30]([NH:32][C:33](=[O:38])C(Cl)(Cl)Cl)[CH3:31]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[C:7]([NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([S:21]([NH:22][C:33]([NH:32][CH2:30][CH3:31])=[O:38])(=[O:23])=[O:24])[CH:19]=2)[O:14][CH2:13][CH2:12]1)=[O:8]
Reactant: COc1ccc(Cl)cc1C(=O)NCC1CCOc2cc(OC)c(S(N)(=O)=O)cc21
Reactant: CCNC(=O)C(Cl)(Cl)Cl
Product: CCNC(=O)NS(=O)(=O)c1cc2c(cc1OC)OCCC2CNC(=O)c1cc(Cl)ccc1OC

Procedure:
4-(5-Chloro-2-methoxybenzamidomethyl)-6-(ethylaminocarbonyl-aminosulfonyl)-7-methoxychroman ##STR32## 4-(5-Chloro-2-methoxybenzamidomethyl)-6-(ethylaminocarbonyl-aminosulfonyl)-7-methoxychroman is synthesized analogously to Example 1 from 4-(5-chloro-2-methoxybenzamidomethyl)-6-sulfamoyl-7-methoxychroman and N-ethyltrichloroacetamide. Melting point: 211°-213° C.
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([O:8][P:9]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH:5]([CH3:7])[CH3:6].CO.[OH-].[K+].Cl>O>[CH2:20]([O:19][P:9]([O:8][C@@H:4]([CH:5]([CH3:7])[CH3:6])[C:3]([OH:27])=[O:2])([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)[C@@H](OP(=O)(OCc1ccccc1)OCc1ccccc1)C(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)[C@H](OP(=O)(OCc1ccccc1)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 40 h
Yield: 96.5 %

Procedure:
To a 50 mL flask containing (S)-methyl2-(bis(benzyloxy)phosphoryloxy)-3-methylbutanoate (699 mg, 1.78 mmol, 1.0 eq.) (prepared as in Example 18 or 19) was added methanol (9.2 mL). All starting material dissolved. Then a solution of potassium hydroxide in water (1 N, 3.56 mL, 3.56 mmol, 2.0 eq.) was added at ice-bath temperature. The resulting mixture was stirred at room temperature for 40 hrs. The reaction was monitored by LC-MS, and almost no starting remained. The reaction mixture was diluted with water (15 mL) and neutralized by hydrochloric acid (1 N, 3.6 mL, 3.6 mmol, 2.02 eq.) to reach pH 3 at 0° C. which was extracted by ethyl acetate (3×30 mL). The combined organic phase was washed with water (30 mL), brine (30 mL), and dried over Na2SO4 and concentrated under reduced pressure to afford crude compound 20, (S)-2-(bis(benzyloxy)phosphoryloxy)-3-methylbutanoic acid (650 mg) which was used directly in the next step without further purification. MS: m/z=379.0 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH3:28])[C:22]4=[O:29])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Br>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH3:28])[C:22]4=[O:29])=[CH:19][CH:20]=3)[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: CCCN1CCN(c2ccc(N3CCN(c4ccc(OC)cc4)CC3)cc2)C1=O
Agent: Br
Product: CCCN1CCN(c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)C1=O
Yield: 89 %

Procedure:
A mixture of 7 parts of 1-[4-[4-(4-methoxyphenyl)-1-piperazinyl]-phenyl]-3-propyl-2-imidazolidinone and 225 parts of a hydrobromic acid solution 48% was stirred and refluxed for 5 hours. After cooling, the precipitated product was filtered off, washed with 2-propanol and dissolved in a mixture of methanol and water. The solution was neutralized with a sodium hydrogen carbonate solution. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was triturated in dichloromethane. The product was filtered off and dried, yielding 6 parts (89%) of 1-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-3-propyl-2-imidazolidinone (46).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:11]1[O:15][C:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:13][C:12]=1[C:23]1[CH:24]=[C:25]([O:30][CH3:31])[C:26]([NH2:29])=[N:27][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[O:15][C:11]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[C:12]([C:23]3[CH:24]=[C:25]([O:30][CH3:31])[C:26]([NH2:29])=[N:27][CH:28]=3)[N:13]=2)=[CH:17][CH:18]=1
Reactant: OB(O)c1ccncc1
Reactant: COc1cc(-c2nc(-c3ccc(F)cc3)oc2Br)cnc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(-c2nc(-c3ccc(F)cc3)oc2-c2ccncc2)cnc1N
Yield: 56.6 %

Procedure:
A mixture of 4-pyridineboronic acid (113 mg, 0.9 mmol) and 5-(5-bromo-2-(4-fluorophenyl)oxazol-4-yl)-3-methoxypyridin-2-amine (135 mg, 0.4 mmol), and in DME (1.0 mL) and 2.0 M aqueous Na2CO3 (1.0 mL, 2.0 mmol) was sparged with Ar. Tetrakis(triphenylphosphine)palladium(0) (21 mg, 0.018 mmol) was added and the mixture was again sparged with Ar. The reaction was irradiated at 120° C. for 15 min in a microwave reactor. The reaction mixture was diluted with water and extracted with EtOAc (3×). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography over (SiO2, 100:0-0:100 hexanes-EtOAc). Enriched fractions were concentrated in vacuo and further purified by column chromatography (SiO2, 100:0-80:20 DCM-MeOH) to afford 82 mg of the title compound: LC/MS (m/z): 362.9 (MH+), tR=0.54 min.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.S(Cl)(Cl)=O.[CH2:16](N(CC)CC)C>ClCCCl>[CH3:16][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[CH3:11]
Reactant: CCN(CC)CC
Reactant: Cc1cc(Br)ccc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: COC(=O)c1ccc(Br)cc1C

Procedure:
To a suspension of 4-bromo-2-methylbenzoic acid (10.0 g, 0.0465 mol) in 1,2-dichloroethane (60 mL) was added thionyl chloride (28 g, 0.23 mol) and the mixture heated to reflux for 1 hour. The mixture was concentrated to dryness and vacuum dried. The crude acid chloride was dissolved in methanol (100 mL) and the solution was treated with triethylamine (4.7 g, 0.046 mol). The mixture was heated to reflux for an hour and then concentrated to dryness. The crude ester was dissolved in EtOAc, washed consecutively with sat. sodium bicarbonate solution and water. The organic phase was dried and concentrated to obtain the title ester.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:35]4[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39][CH:40]=4)=[C:28]4[C:32]=3[C:31](=[O:33])[N:30]([CH3:34])[CH2:29]4)[C:20]([C:48]([F:51])([F:50])[F:49])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[CH2:52]([O:54]P(CC1C=CC(NC2N=C(NC3C=CC(Br)=C4C=3C(=O)N(C)C4)C(C(F)(F)F)=CN=2)=C(OC)C=1)(=O)OCC)C.C(OC(N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1)=O)(C)(C)C>>[CH2:7]([O:6][P:4]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:35]4[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])[CH2:39][CH:40]=4)=[C:28]4[C:32]=3[C:31](=[O:33])[N:30]([CH3:34])[CH2:29]4)[C:20]([C:48]([F:50])([F:49])[F:51])=[CH:19][N:18]=2)=[C:14]([O:54][CH3:52])[CH:15]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C4=CCN(C(=O)OC(C)(C)C)CC4)c4c3C(=O)N(C)C4)n2)cc1)OCC
Agent: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C4=CCN(C(=O)OC(C)(C)C)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for Compound 246A using diethyl[4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)-3-methoxybenzyl]phosphonate and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (Tetrahedron Letters, 2000, 44, pp 3705-3708). MS (ES+): m/z 761.33 (100) [MH+]; HPLC: tR=1.56 min (UPLC, analytical).
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14](=[O:26])[C@H:15]([CH3:25])[C@H:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[OH:17])C1C=CC=CC=1.OO.[Li+].[OH-].[O-:31]S([O-])=O.[Na+].[Na+]>O.C1COCC1.O>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C@H:16]([OH:17])[C@@H:15]([CH3:25])[C:14]([OH:26])=[O:31])=[CH:23][CH:22]=1
Reactant: O=S([O-])[O-]
Reactant: C[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)[C@@H](O)c1ccc(Cl)cc1
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](C(=O)O)[C@@H](O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of (4R)-4-benzyl-3-[(2R,3R)-3-(4-chloro-phenyl)-3-hydroxy-2-methyl-propionyl]-oxazolidin-2-one (1.32 g, 3.53 mmol) in 4:1 THF/water (20 mL) was cooled to 0° C. and treated with 30% aq. H2O2 (1.5 mL, 13.2 mmol) and LiOH (1 M in water, 5.6 mL, 5.6 mmol). The reaction mixture was stirred for 1 h at 0° C., and then a solution of Na2SO3 (1.76 g, 14 mmol) in water (10 mL) was added. The mixture was concentrated at a temperature<30° C. The aqueous layer was extracted with DCM (3×), then was acidified with conc. HCl and extracted with EtOAc (4×). The combined EtOAc layers were dried (Na2SO4) and concentrated to give the crude acid, which was used without further purification (0.76 g, quant.). 1H NMR (500 MHz, CDCl3): 7.36-7.32 (m, 2H), 7.32-7.28 (m, 2H), 5.16 (d, J=3.9, 1H), 2.81 (dq, J=7.2, 3.9, 1H), 1.15 (d, J=7.2, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25](=[N:27][OH:28])[NH2:26])[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:37]([O:44]CC(O)=O)[C:38]1C=CC=CC=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C>C(Cl)Cl.CCOC(C)=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]4[N:26]=[C:38]([CH2:37][OH:44])[O:28][N:27]=4)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:35])([F:36])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)COCc1ccccc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C(N)=NO)cc32)cc1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(-c4noc(CO)n4)cc32)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 6-[(4-tert-butylphenyl)sulfonyl]-N′-hydroxy-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine-8-carboximidamide (intermediate 55, 0.20 g, 0.38 mmol), 2-benzyloxyacetic acid (0.064 mg, 0.385 mmol), DIPEA (0.103 mg, 0.800 mmol), HOBt (0.108 g, 0.8 mmol), and DIC (0.073 g, 0.578 mmol) in DCM (3.85 mL) was stirred at rt for 4 h. The reaction mixture was diluted with EtOAc, washed with dilute NaOH, 5% citric acid, dried (MgSO4) and concentrated to afford the desired product, which was used without further purification. LC/MS: m/e 667.5 (M+H)+.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:15].[CH2:17]([CH:22]1[CH2:28][CH:27]2[NH:29][CH:24]([CH2:25][CH2:26]2)[CH2:23]1)[CH2:18][CH2:19][CH2:20][CH3:21]>CC#N>[CH3:16][C@H:3]([CH2:2][N:29]1[CH:24]2[CH2:25][CH2:26][CH:27]1[CH2:28][CH:22]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:23]2)[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:15]
Reactant: C[C@H](CI)CN1C(=O)CCc2ccccc21
Reactant: CCCCCC1CC2CCC(C1)N2
Solvent: CC#N
Product: CCCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)CCc2ccccc21
Reaction time: 20 h
Yield: 35 %

Procedure:
A 4 mL vial was charged with (S)-1-(3-iodo-2-methylpropyl)-3,4-dihydro-1H-quinolin-2-one (122LH18) (0.185 g, 0.56 mmol) and 3-pentyl-8-azabicyclo[3.2.1]octane (0.112 g, 0.62 mmol) in MeCN (0.5 mL) and shaken at 40° for 20 h. The reaction mixture was quenched with water, basified with ammonium hydroxide, and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (SiO2; n-heptane/EtOAc 4:1) to give the title compound (107LH55) (0.075 g, 35%). 1H NMR (CD3OD) δ 7.28-7.18 (m, 3H), 7.01 (t, J=7.2 Hz, 1H), 4.03 (d, J=7.0 Hz, 2H), 3.11-3.04 (m, 2H), 2.90-2.85 (m, 2), 2.64-2.56 (m 2H), 2.28-2.11 (m, 4H), 1.97-1.84 (m, 3H), 1.66-1.54 (m, 3H), 1.42-1.21 (m, 10H), 0.90-0.85 (m, 2 CH3); 13C NMR (CD3OD) δ 173.1, 140.3, 129.1, 128.4, 128.3, 124.3, 117.1, 61.4, 60.2, 58.3, 46.4, 39.5, 37.1, 37.0, 33.1, 32.9, 32.2, 29.5, 29.4, 28.5, 27.9, 26.3, 23.7, 17.1, 14.4.
Reaction SMILES: [H-].[Na+].[C:3]([N:6]1[CH2:11][CH2:10][C:9]([OH:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])[CH3:4].F[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1>CN(C)C=O>[C:3]([N:6]1[CH2:11][CH2:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([O:18][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:8][CH2:7]1)(=[O:5])[CH3:4]
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: CC(=O)N1CCC(O)(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(Oc2ccc(C(F)(F)F)cc2)(c2ccccc2)CC1
Temperature: 70 °C
Reaction time: 25 h
Yield: 32.6 %

Procedure:
A stirred suspension of sodium hydride (60% in oil, 2.0 g) in 50 ml of dimethylformamide was treated with a solution of 9.8 g of 1-acetyl-4-hydroxy-4-phenylpiperidine in 80 ml of dimethylformamide and then heated at 70° C. for 1 hour. After cooling to room temperature a solution of 8.06 g of 4-fluorobenzotrifluoride in 20 ml of dimethylformamide was added dropwise and the reaction allowed to proceed for 25 hours. The reaction mixture was then poured into 400 ml of ice water and the aqueous suspension extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated to an oil. High pressure liquid chromatography of the oil (silica gel; elution with a 10% solution of ethyl acetate in dichloromethane) afforded 5.3 g of 1-acetyl-4-phenyl-4-(4-trifluoromethylphenoxy)piperidine, m.p. 96°-100° C.