Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([NH:13][CH2:14][CH3:15])[CH3:12])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:22]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([C:38](Cl)=[O:39])[CH2:34][CH2:33]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([N:13]([C:38]([CH:35]2[CH2:36][CH2:37][N:32]([C:30]([O:29][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:31])[CH2:33][CH2:34]2)=[O:39])[CH2:14][CH3:15])[CH3:12])=[CH:6][CH:5]=1
Reactant: CCNC(C)Cc1ccc(OC)cc1
Reactant: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCN(C(=O)C1CCN(C(=O)OCc2ccccc2)CC1)C(C)Cc1ccc(OC)cc1
Temperature: 22 °C
Reaction time: 16 h

Procedure:
To a mixture of N-[2-(4-methoxyphenyl)-1-methylethyl]ethylamine hydrochloride (2.0 grams, 8.71 mole) and sodium carbonate (3.2 grams, 30 mole) in toluene (75 ml) and water (50 ml) was added dropwise to a solution of 1-benzyloxycarbonylpiperidine-4-carbonyl chloride (2.67 grams, 9.5 mmole) in toluene (25 ml). The reaction mixture was stirred at 22° C. for 16 hours.The mixture was diluted with ethyl acetate (100 ml), the organic phase was dried (anhydrous magnesium sulfate) and concentrated under reduced pressure. The residue was subjected to flash column chromatography over silica gel eluting with 30% ethyl acetate in hexane. The N-[2-(4-methoxyphenyl)-1-methylethyl]-N-ethyl-[1-(benzyloxycarbonyl)piperidin-4-ylcarbonyl]amine was obtained as an oil, (3.5 grams, 95%), M+H 439.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[C:9]([C:12]12[CH2:21][CH:16]([C:17]([CH3:20])=[CH:18][CH2:19]1)[C:15](=[O:22])[CH2:14][CH:13]2[CH3:23])([CH3:11])=[CH2:10].CI.Cl>C1COCC1.CCCCCC.CC(OC)(C)C>[C:9]([C:12]12[CH2:21][CH:16]([C:17]([CH3:20])=[CH:18][CH2:19]1)[C:15](=[O:22])[CH:14]([CH3:2])[CH:13]2[CH3:23])([CH3:11])=[CH2:10]
Reactant: CC(C)[N-]C(C)C
Reactant: C=C(C)C12CC=C(C)C(C1)C(=O)CC2C
Agent: Cl
Agent: [Li+]
Solvent: CI
Solvent: CCCCCC
Solvent: COC(C)(C)C
Product: C=C(C)C12CC=C(C)C(C1)C(=O)C(C)C2C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 21.4 %

Procedure:
At 0° C., 15.3 ml of a soln. of LDA (2M in THF/heptane/ethylbenzene, 31 mmol, 2.5 eq.) was treated dropwise with a soln. of 2.5 g of 5-Isopropenyl-4,8-dimethylbicyclo[3.3.1]non-7-en-2-one (12 mmol) in 25 ml THF. The reaction mixture was stirred 1.5 h at 0° C., treated with 2.6 ml methyl iodide (41.7 mmol, 3.4 eq.), stirred at 25° C. for 3 h, and poured into 1M aq. HCl soln. Extraction with MTBE (2×80 ml), washing of the org. phase with H2O, aq. sat. NaCl soln., drying (MgSO4) gave 3.6 g crude. FC (hexane/MTBE 24:1) gave 0.56 g (21%) of compound 3. The boiling point of the end product is 120° C. at 0.08 mbar. Rf (hexane/MTBE 24:1) 0.26.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)=[O:3].[CH:21]1([CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:23][CH2:22]1>>[CH:14]1([CH2:13][C:12]([NH:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:28]3[CH2:29][CH2:30][N:25]([CH2:24][CH:21]4[CH2:23][CH2:22]4)[CH2:26][CH2:27]3)=[O:3])=[CH:6][CH:7]=2)=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CN(CC2CC2)CCN1
Reactant: O=C(CC1CCCCC1)Nc1ccc(OC(=O)Cl)cc1
Product: O=C(CC1CCCCC1)Nc1ccc(OC(=O)N2CCN(CC3CC3)CC2)cc1

Procedure:
The title compound was prepared from 4-(2-cyclohexyl-acetylamino)-phenyl chloroformate and 1-cyclopropylmethyl-piperazine, preparative HPLC (methode C (60%, off-white crystals). HPLC-MS m/z=400.3 (M+1), Rt: 2.42 min.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[CH:11][C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2/[C:14](/[NH:17][OH:18])=[N:15]\[H])=[N:2]1.N1C=CC=CC=1.[CH2:29]([O:31]C(Cl)=O)C.CC(C)([O-])C.[K+].C(O)(=O)/C=C/C(O)=O>CN(C=O)C.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2[C:14]2[NH:15][C:29](=[O:31])[O:18][N:17]=2)=[N:2]1
Reactant: CCOC(=O)Cl
Reactant: [H]/N=C(/NO)c1ccccc1C=Cc1n[nH]c2ccccc12
Agent: CC(C)(C)[O-]
Agent: O=C(O)/C=C/C(=O)O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=c1[nH]c(-c2ccccc2/C=C/c2n[nH]c3ccccc23)no1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 26.9 %

Procedure:
(E)-2-[2-(1H-indazol-3-yl)vinyl]-N-hydroxybenzamidine (0.06 g, 0.22 mmol) obtained in Step 1 of Example 175 was dissolved in DMF (1.0 mL), and pyridine (35 μL, 0.43 mmol) and ethylchloroformate (0.12 mL, 1.1 mmol) were added thereto, followed by stirring at 0° C. for 30 minutes. The mixture was added with water and the precipitated solid was collected by filtration and the solid was dried. The obtained solid was dissolved in toluene (2.0 mL) at 0° C. and added with potassium tert-butoxide (85 mg, 0.76 mmol), followed by stirring at 60° C. for 2 hours. Then, the mixture was neutralized using aqueous fumaric acid solution. The reaction mixture was extracted with ethyl acetate and the organic layer was concentrated. The residue was triturated in a mixed solvent of ethyl acetate/hexane to obtain Compound 178 (18 mg, 23%).
Reaction SMILES: BrC1C2C(=CC=C(C(=O)NCC3CCCC3)C=2)N(CC(=O)N)N=1.BrCC1C=CC(C(OC)=O)=CC=1OC.[CH:38]1([CH2:43][NH:44][C:45]([C:47]2[CH:48]=[C:49]3[C:53](=[CH:54][CH:55]=2)[N:52]([CH2:56][C:57](=[O:59])[NH2:58])[N:51]=[C:50]3[CH2:60][C:61]2[CH:70]=[CH:69][C:64]([C:65]([O:67]C)=[O:66])=[CH:63][C:62]=2[O:71][CH3:72])=[O:46])[CH2:42][CH2:41][CH2:40][CH2:39]1>[Zn].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]>[CH:38]1([CH2:43][NH:44][C:45]([C:47]2[CH:48]=[C:49]3[C:53](=[CH:54][CH:55]=2)[N:52]([CH2:56][C:57](=[O:59])[NH2:58])[N:51]=[C:50]3[CH2:60][C:61]2[CH:70]=[CH:69][C:64]([C:65]([OH:67])=[O:66])=[CH:63][C:62]=2[O:71][CH3:72])=[O:46])[CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: COC(=O)c1ccc(Cc2nn(CC(N)=O)c3ccc(C(=O)NCC4CCCC4)cc23)c(OC)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: COC(=O)c1ccc(CBr)c(OC)c1
Product: COc1cc(C(=O)O)ccc1Cc1nn(CC(N)=O)c2ccc(C(=O)NCC3CCCC3)cc12

Procedure:
The cross coupling process may be carried out, for example, using a stoichiometric amount of activated zinc dust and a catalytic quantity of a transition metal catalyst, such as, for example, dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) or dichlorobis(triphenylphosphine)nickel-(II) to couple, for example, 3-bromo-5-(N-cyclopentylmethylcarbamoyl)-1-(carbamoylmethyl)indazole with, for example, methyl 4-bromomethyl-3-methoxybenzoate to afford methyl 4-[5-(N-cyclopentylmethylcarbamoyl)-1-(carbamoylmethyl)indazol-3-ylmethyl]-3-methoxybenzoate; followed by decomposition of the ester to afford 4-[5-(N-cyclopentylmethylcarbamoyl)-1-(carbamoylmethyl)indazol-3-ylmethyl]-3-methoxybenzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]3[CH:14]=[C:15]([C:18]4[C:19]([C:42]5[CH:47]=[CH:46][C:45]([C:48]6[C:49]([C:54]([O:56]C)=[O:55])=[CH:50][CH:51]=[CH:52][CH:53]=6)=[CH:44][CH:43]=5)=[N:20][N:21](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:22]=4)[CH:16]=[CH:17][C:12]3=[N:11][CH:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+].CO.[Cl-].[NH4+]>O.O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]3[CH:14]=[C:15]([C:18]4[C:19]([C:42]5[CH:47]=[CH:46][C:45]([C:48]6[C:49]([C:54]([OH:56])=[O:55])=[CH:50][CH:51]=[CH:52][CH:53]=6)=[CH:44][CH:43]=5)=[N:20][NH:21][CH:22]=4)[CH:16]=[CH:17][C:12]3=[N:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccccc1-c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccc(OC)cc4)n3c2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(-c2cnc3ccc(-c4c[nH]nc4-c4ccc(-c5ccccc5C(=O)O)cc4)cn23)cc1
Temperature: 60 °C
Yield: 38.5 %

Procedure:
A mixture of 119 mg methyl 4′-{4-[3-(4-methoxyphenyl)-imidazo[1,2-a]pyridin-6-yl]-1-trityl-1H-pyrazol-3-yl}biphenyl-2-carboxylate (compound in Example 387), 0.5 mL of 1 N aqueous sodium hydroxide and 3 mL methanol was heated at 60° C. overnight under reflux. An aqueous saturated ammonium chloride solution, ethyl acetate, tetrahydrofuran and water were added to the reaction solution, and the organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was evaporated. 134 mg crude product of 4′-{4-[3-(4-methoxyphenyl)imidazo[1,2-a]pyridin-6-yl]-1-trityl-1H-pyrazol-3-yl}biphenyl-2-carboxylic acid was obtained as a colorless amorphous. From this compound, 30 mg of the title compound was obtained as white crystals by the same method as in Example 84.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[N:3]=1.S(=O)(O)[O-].[Na+].C(=O)(O)[O-].[Na+].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[N:3]=1
Reactant: Cc1nc(COc2ccc([N+](=O)[O-])cc2)no1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: O=S([O-])O
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(COc2ccc(N)cc2)no1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
O-(5-Methyl-1,2,4-oxadiazol-3-yl)methyl-4-nitrophenol (1 g) was dissolved in THF (40 mL) and water (40 mL). Sodium bisulfite (3.8 g), sodium bicarbonate (1.4 g), K2CO3 (1.8 g) were added to the solution. It was stirred at rt for 30 min, then diluted with water (80 mL). The aq. solution was extracted with EtOAc (2×100 mL). The organic layers were combined, dried, evaporated to give 4-(5-methyl-1,2,4-oxadiazol-3-yl)methoxyaniline.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[O:12][C:13]2[C:19]([N:20]3[C:25](=[O:26])[CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[N:22]([CH3:31])[C:21]3=[O:32])=[C:18]([F:33])[CH:17]=[C:16]([Cl:34])[C:14]=2[N:15]=1>CN(C)C=O>[Cl:34][C:16]1[C:14]2[N:15]=[C:11]([O:9][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[O:12][C:13]=2[C:19]([N:20]2[C:25](=[O:26])[CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[N:22]([CH3:31])[C:21]2=[O:32])=[C:18]([F:33])[CH:17]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3nc(Cl)oc23)c1=O
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3nc(Oc4ccccc4)oc23)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under a nitrogen atmosphere, a stirred solution of 2.0 grams (51 mmole) of 60% sodium hydride (in mineral oil) in 25 mL of N,N-dimethylformamide is cooled in an ice bath, and a solution of 5.3 grams (56.3 mmoles) of phenol in 25 mL of N,N-dimethylformamide is added dropwise during a five minute period. To this is added a solution of 20.3 grams (51 mmole) of 3-(2,4-dichloro-6-fluorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione (as prepared in Example 24) in 25 mL of N,N-dimethylformamide. Upon completion of the addition the reaction mixture is allowed to warm to ambient temperature, where it stirs for about 18 hours. After this time the reaction mixture is concentrated under reduced pressure, yielding 3-(4-chloro-6-fluoro-2-phenoxybenzoxazol-7-yl]-1-methyl-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6](I)=[CH:7][CH:8]=2)[N:3]=1.[SH:14][C:15]1[CH:16]=[C:17]([C:21]2([C:27]#[N:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CCN(C(C)C)C(C)C>O1CCOCC1.CCOC(C)=O.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6]([S:14][C:15]3[CH:16]=[C:17]([C:21]4([C:27]#[N:28])[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[CH:18]=[CH:19][CH:20]=3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1cc(Cl)c2ccc(I)cc2n1
Reactant: N#CC1(c2cccc(S)c2)CCOCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: N#CC1(c2cccc(Sc3ccc4c(Cl)cc(Cl)nc4c3)c2)CCOCC1
Temperature: 70 °C

Procedure:
2,4-Dichloro-7-iodo-quinoline (1.7 g, 5.26 mmol) and 4-(3-mercapto-phenyl)-tetrahydro-pyran-4-carbonitrile (1p, 1.27 g, 5.79 mmol) were dissolved in 1,4-dioxane (50 mL) and degassed with N2 for 10 minutes. Pd2dba3 (120 mg, 0.13 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (150 mg, 0.27 mmol) were added, followed by iPr2NEt (1.4 mL, 7.9 mmol), and the reaction was heated to 70° C. for 2 hours. The mixture was diluted with EtOAc and water, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography to give the desired product, 1q.
Reaction SMILES: C[O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][CH3:12])=[N:6][C:5]=1[NH2:13].O1CCCC1.O.[OH-].[Na+].C(O)(=O)C>O.CO>[NH2:13][C:5]1[N:6]=[C:7]([CH2:10][O:11][CH3:12])[CH:8]=[CH:9][C:4]=1[C:3]([OH:14])=[O:2]
Reactant: COCc1ccc(C(=O)OC)c(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: COCc1ccc(C(=O)O)c(N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a mixture of 2-amino-6-methoxymethyl-nicotinic acid methyl ester (2.9 g, 15 mmol) described in Production Example 4-1-4, tetrahydrofuran (30 mL), methanol (7.5 mL) and water (7.5 ml) was added sodium hydroxide monohydrate (1.2 g, 29 mmol), which was stirred overnight at room temperature. To the reaction mixture was added acetic acid (1.7 mL, 29 mmol), followed by distilling off the solvent under a reduced pressure. The residue was dissolved in methanol/ethyl acetate (1/3) and filtered using silica gel. The filtrate was collected, concentrated under a reduced pressure and the residue was washed with water to obtain the title compound (2.1 g, 12 mmol, 80%) as a pale yellow solid.
Reaction SMILES: [N+:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]CC)=[O:11])([O-:3])=[O:2].[OH-].[Li+]>CO.C1COCC1.O>[N+:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])([O-:3])=[O:2]
Reactant: CCOC(=O)CCCCCO[N+](=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCCCCO[N+](=O)[O-]
Temperature: 50 °C

Procedure:
19.1 mmol Ethyl 6-nitrooxy-hexanoate were dissolved in 222 ml Methanol/THF 1:1. 37.5 ml 1M Lithiumhydroxide in Water were added to the reaction and the cloudy solution was heated for 18 hours at 50° C. After cooling to room temperature the solution was concentrated in vacuo. The pH level of the solution was brought down to 1 with HCl 25% and extracted two times with TMBE. The organic phases were combined, washed with brine, dried over Na2SO4 and the solvent was removed in vacuo leaving 3.43 g.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]#[N:10])=[N:6][CH:7]=1.B.O1CCCC1.Cl.O>C1COCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][NH2:10])=[N:6][CH:7]=1
Reactant: Cc1ccc(CC#N)nc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(CCN)nc1
Temperature: 60 °C
Yield: 41 %

Procedure:
To a solution of 18 g of crude 2-(5-methylpyridin-2-yl)acetonitrile in dry THF (100 mL) was added dropwise Borane-tetrahydrofuran complex (1.0 M in THF, 232 mL, 232.5 mmol, 4 eq) at 0° C. under N2 atmosphere. The reaction mixture was then heated to 60° C. overnight. The reaction was cooled to room temperature, aq.HCl (6 N, 40 mL) was added carefully and the reaction mixture was then heated at 70° C. for 2 hrs. After cooling, water was added and the resulting solution was washed with ether. The aqueous layer was basified with aq. NaOH (10 N) at 0° C. and saturated with K2CO3 then extracted with ether (5×100 mL). The organic layer was dried over MgSO4, filtered and evaporated to give 7.6 g of crude 2-(5-methylpyridin-2-yl)ethanamine. (96% crude yield)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[C:15]([Br:17])[CH:14]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:12]=2[O:22][CH3:23])[CH:6]=[CH:5][C:4]=1[NH:24][S:25]([CH3:28])(=[O:27])=[O:26].N1C=CC=CC=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>C(Cl)Cl>[Br:17][C:15]1[CH:14]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:12]([O:22][CH3:23])=[C:11](/[CH:10]=[CH:9]/[C:7]2[CH:6]=[CH:5][C:4]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[C:3]([CH:8]=2)[CH2:2][NH:1][C:35](=[O:37])[CH3:36])[CH:16]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1c(/C=C/c2ccc(NS(C)(=O)=O)c(CN)c2)cc(Br)cc1C(C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1c(/C=C/c2ccc(NS(C)(=O)=O)c(CNC(C)=O)c2)cc(Br)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
step 2—To a solution of 210 (0.150 g, 0.321 mmol), pyridine (100 L) and DCM (10 mL) cooled to 0° C. was added acetic anhydride (70 μL). The reaction mixture was allowed to warm to RT and stirred overnight. The reaction mixture was diluted with DCM, washed with sat'd. CuSO4 and twice with 1N HCl, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with a EtOAc/hexane gradient (50 to 75% EtOAc) to afford 45 mg of N-{5-[(E)-2-(5-bromo-3-tert-butyl-2-methoxy-phenyl)-vinyl]-2-methanesulfonylamino-benzyl}-acetamide (212).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[C:21]4[C:16](=[CH:17][C:18]([OH:24])=[C:19]([O:22][CH3:23])[CH:20]=4)[N:15]=[CH:14][CH:13]=3)=[CH:10][C:2]1=2.[CH3:25][C:26]1[O:30][N:29]=[C:28]([NH:31][C:32](=O)[O:33]C2C=CC([N+]([O-])=O)=CC=2)[CH:27]=1.C(N(CC)CC)C>C1COCC1>[OH:24][C:18]1[CH:17]=[C:16]2[C:21]([C:12]([O:11][C:9]3[CH:8]=[CH:7][C:3]4[N:4]([C:32]([NH:31][C:28]5[CH:27]=[C:26]([CH3:25])[O:30][N:29]=5)=[O:33])[CH2:5][CH2:6][O:1][C:2]=4[CH:10]=3)=[CH:13][CH:14]=[N:15]2)=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: Cc1cc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)no1
Reactant: COc1cc2c(Oc3ccc4c(c3)OCCN4)ccnc2cc1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc2c(Oc3ccc4c(c3)OCCN4C(=O)Nc3cc(C)on3)ccnc2cc1O
Temperature: 50 °C
Reaction time: 16 h
Yield: 15.3 %

Procedure:
A 25-mL round bottomed flask was charged with 4-(3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yloxy)-6-methoxyquinolin-7-ol (0.124 g, 0.38 mmol), 4-nitrophenyl 5-methylisoxazol-3-ylcarbamate (0.11 g, 0.40 mmol), and THF (5.0 mL). Triethylamine (0.160 mL, 1.1 mmol) was added, the system was purged with argon, and the tube was sealed. The mixture stirred at 50° C. for 16 h. The reaction mixture was concentrated and the residue was purified via column chromatography on silica gel (RediSep 40 g column, 100% ethyl acetate for 10 min, followed by 5% methanol/dichloromethane for 20 min) to afford 7-(7-hydroxy-6-methoxyquinolin-4-yloxy)-N-(5-methylisoxazol-3-yl)-2,3-dihydrobenzo[b][1,4]oxazine-4-carboxamide (0.026 g, 15% yield) as a yellow solid.
Reaction SMILES: CN(C=O)C.[NH2:6][C@H:7]([C:11]([OH:13])=[O:12])[CH:8]([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].Br[CH:21](Br)[C:22]1[C:23]([CH3:28])=[CH:24][CH:25]=[CH:26][CH:27]=1>O.CCOCC>[CH2:28]1[C:23]2[C:22](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][N:6]1[CH:7]([CH:8]([CH3:10])[CH3:9])[C:11]([OH:13])=[O:12]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: Cc1ccccc1C(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C(C(=O)O)N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To 20 ml DMF is added valine (1.17 g, 10 mmol) and potassium carbonate (5.5 g, 40 mmol) followed by α,α-dibromo-o-xylene (2.63 g, 10 mmol). The reaction mixture is stirred for about 20 hours at RT under nitrogen and then poured into ether and water. The aqueous layer is separated, acidified to about pH 3 with aqueous HCl and extracted thoroughly with ether. The organic layer is washed with water and brine, dried and solvent removed under vacuum to give 2-(2-isoindolinyl)-3-methylbutanoic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[NH2:18])[CH2:3]1.N1C=CC=CC=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>ClCCl.O>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:13])([F:15])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[NH:18][S:37]([C:34]2[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=2)(=[O:39])=[O:38])[CH2:3]1
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(C(F)(F)F)cc21
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC1(C)CC(c2ccccc2NS(=O)(=O)c2ccc(F)cc2)Nc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4,4-dimethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-yl)aniline (100 mg, 0.36 mmol) and pyridine (114 mg, 1.44 mmol) in anhydrous dichloromethane (5 mL) was added 4-fluorobenzene-1-sulfonyl chloride (70.1 mg, 0.36 mmol) at ice-bath. After addition, the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water, and extracted with dichloromethane. The combined organic layer was dried over anhydrous Sodium sulfate, concentrated. The residue was purified by HPLC to give N-[2-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-4-fluoro-benzenesulfonamide LC/MS m/e obsd. (ESI+) [(M+H)+] 478.9.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C@@H:8]1[C@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:11][C:10](=[O:19])[N:9]1C(=O)[C@H](C)CC(F)(F)F.O.[OH-].[Na+]>C(OCC)C>[CH3:7][C@@H:8]1[C@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:11][C:10](=[O:19])[NH:9]1
Reactant: C[C@H](CC(F)(F)F)C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Lithium aluminum hydride (10.26 g) was added to a stirred solution of (4R,5S)-4-methyl-3-((2R)-2-methyl-4,4,4-trifluorobutyryl)-5-phenyl-2-oxazolidinone (28 g) in dry diethyl ether (200 mL) at -20° C. under an inert atmosphere, then the mixture was warmed to 0° C. After 2 h at 0° C., water (10.27 mL), 10% w/v sodium hydroxide(10.27 mL) and water (31 mL) were added, and the mixture was stirred 20 min. The salts were filtered and washed with distilled diethyl ether. The diethyl ether solution was dried (K2CO3) and diluted with pentane. This resulted in precipitation of recovered (4R,5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone which was isolated by filtration. Concentration of the filtrate by distillation afforded several fractions. The first fractions (bath temperature to 60° C.) were pentane and diethyl ether; a second set of fractions (bath temperature 60° C. to 100° C.) was 12 g of a oil that was a 40:60 mixture of (R)-2-methyl-4,4,4-trifluorobutan-1-ol (calculated as 4.8 g alcohol) and diethyl ether by NMR. Warming the remaining tarry residue (bath temperature 85° C.) under vacuum (13,330 Pa) afforded an additional 7.2 g of (R)-2-methyl-4,4,4-trifluorobutan-1-ol (total yield, 12.0 g, 94%); partial NMR (300 MHz, CDCl3 -D2O shake): 1.06 (d, 3H, CH3), 1.41 (br t, 1H, OH), 1.86-2.07 (m, 2H, CH(CH3) plus one CF3CH2), 2.31-2.42 (m, 1H, one CF3CH2), 3.49 (dd, 1H, one CH2OH), 3.58 (dd, 1H, one CH2OH).