Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@H:7]([NH2:10])[CH2:8][OH:9])=[CH:3][CH:2]=1.Br[CH2:12][C:13]([C:15]1[CH:26]=[CH:25][C:18]2[O:19][C:20]([CH3:24])([CH3:23])[O:21][CH2:22][C:17]=2[CH:16]=1)=[O:14].C(N(CC)C(C)C)(C)C.C(#N)C>C1COCC1>[CH3:23][C:20]1([CH3:24])[O:19][C:18]2[CH:25]=[CH:26][C:15]([C:13](=[O:14])[CH2:12][NH:10][C@@H:7]([C:4]3[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=3)[CH2:8][OH:9])=[CH:16][C:17]=2[CH2:22][O:21]1
Reactant: N[C@H](CO)c1ccccc1
Reactant: CC1(C)OCc2cc(C(=O)CBr)ccc2O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CC#N
Product: CC1(C)OCc2cc(C(=O)CN[C@H](CO)c3ccccc3)ccc2O1

Procedure:
(S)-Phenylglycinol (28.9 g) was added in two portions to a solution of 2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone (40g) and N,N-di-iso-propylethylamine (48.9 ml) in THF (500 ml) under nitrogen. After 4h the resulting white precipitate was removed by filtration and the mother liquor concentrated in vacuo to give an orange oil. Acetonitrile (40 ml) was added and then removed in vacuo to give a light orange solid which was pulverised and triturated with cold acetonitrile (50 ml). The resulting solid was collected by filtration and washed with acetonitrile (2×30 ml) to give the title compound (38.5 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.[BH4-].[Na+].C(=O)([O-])O.[K+]>CO.O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(F)ccc1C=O
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1cc(F)ccc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
An ice-cold solution of 5.6 g of 4-fluoro-2-methoxy-benzaldehyde in 75 ml of methanol was treated portionwise (5 portions within 50 minutes) with 1.51 g (40mmol) of sodium borohydride and the reaction mixture was stirred for another 1 hour at room temperature. A dispersion of 7 g of potassium hydrogencarbonate in 20 ml of water was added and the mixture stirred for 30 minutes at room temperature. Thereupon, most of the methanol was evaporated under reduced pressure and the residue extracted with dichloromethane. The organic phase was separated, dried and concentrated under reduced pressure to yield 5.15 g (91% of theory) of (4-fluoro-2-methoxy-phenyl)-methanol as a white solid; MS: 156 (M)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH2:22][C:23]([OH:25])=[O:24])[CH:14]=1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:28]=[N+:29]([O-:52])[CH:30]=[C:31]([Cl:51])[C:32]=1[CH2:33][C@@H:34]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH:43]([F:45])[F:44])=[C:38]([O:46][CH2:47][CH:48]2[CH2:50][CH2:49]2)[CH:37]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH2:22][C:23]([O:25][C@H:34]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH:43]([F:44])[F:45])=[C:38]([O:46][CH2:47][CH:48]3[CH2:49][CH2:50]3)[CH:37]=2)[CH2:33][C:32]2[C:31]([Cl:51])=[CH:30][N+:29]([O-:52])=[CH:28][C:27]=2[Cl:26])=[O:24])[CH:14]=1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N(c1cn(CC(=O)O)c2ccccc12)S(C)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(c1cn(CC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c2ccccc12)S(C)(=O)=O
Yield: 70.9 %

Procedure:
A solution of 2-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-1H-indol-1-yl)acetic acid (220 mg, 0.597 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (228 mg, 0.543 mmol), EDC (312 mg, 1.629 mmol) and DMAP (66.3 mg, 0.543 mmol) in dry DCM (10 ml), under nitrogen, was stirred at room temperature for 24 hours. The mixture was washed with aqueous 5% citric acid, with water and then with brine; the organic phase was dried over Na2SO4 and evaporated to dryness. The crude was purified by flash chromatography on silica gel (DCM:ethyl acetate=6:4) to give (S)-4-(2-(2-(3-(N-(tert-butoxycarbonyl)-methylsulfonamido)-1H-indol-1-yl)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (297 mg, 0.385 mmol, 71% yield). MS/ESI+ 770.0 [MH]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[SH:12][CH2:13][CH2:14][OH:15].[OH-].[K+]>>[CH3:8][C:6]1[N:7]=[C:2]([S:12][CH2:13][CH2:14][OH:15])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: OCCS
Agent: [K+]
Agent: [OH-]
Product: Cc1nc(SCCO)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-cooled solution of 6-chloro-2-methyl-3-nitropyridine (2.17 g, 13 mmol) in 2-mercaptoethanol (5 mL, 71 mmol), potassium hydroxide (1.52 g, 27 mmol) was added. Mixture was stirred at room temperature for 2 h and then extracted with NaOH solution and CH2Cl2. Organic phases were dried over MgSO4, filtered, and concentrated to give 2-(6-methyl-5-nitro-pyridin-2-ylsulfanyl)-ethanol as a brown oil (60% pure, 3.25 g, 72%). 1HNMR (CDCl3, 400 MHz) δ 2.87-2.90 (m, 6H), 3.43-3.46 (t, J=5.6 Hz, 2H), 7.22-7.24 (d, J=8.7 Hz, 1H), 8.15-8.17 (d, J=8.7 Hz, 1H). Exact mass calculated for C8H10N2O3S 214.04 found 215.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH2:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[N:3]=1.Cl.[CH2:17]([O:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:31])[C@H:25]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH2:26])[CH3:18].C(N(CC)C(C)C)(C)C>CS(C)=O.C(OCC)(=O)C>[CH2:17]([O:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:31])[CH:25]([NH:26][C:6]1[CH:5]=[C:4]([CH2:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[N:3]=[C:2]([Cl:1])[N:7]=1)[CH2:27][CH:28]([CH3:29])[CH3:30])[CH3:18]
Reactant: C[Si](C)(C)CCCc1cc(Cl)nc(Cl)n1
Reactant: CCOCCCNC(=O)[C@@H](N)CC(C)C
Agent: Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCCNC(=O)C(CC(C)C)Nc1cc(CCC[Si](C)(C)C)nc(Cl)n1
Temperature: 25 °C
Yield: 58.1 %

Procedure:
2,4-dichloro-6-[3-(trimethylsilyl)-propyl]pyrimidine (1 gram), L-leucine-3-ethoxypropylamide hydrochloride (1 gram) and N,N-diisopropylethylamine (2.3 mL) were stirred for 17 h in 20 mL dimethyl sulfoxide at 55° C. The solution was cooled to room temperature and diluted with ethyl acetate (100 mL), then washed 4 times with 100 mL aliquots of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered, and the solvents were removed in vacuo. Silica gel chromatography (heptane/ethyl acetate 3/1) provided 978 mg of 2-(2-chloro-6-[3-trimethylsilylpropyl]pyrimidin-4-ylamino)-4-methyl-pentanoic acid (3-ethoxypropyl)amide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])/[CH:5]=[CH:6]\[C:7]([OH:9])=[O:8])[CH3:2].[CH3:11][N:12]([CH3:17])[CH2:13][CH2:14][CH2:15][NH2:16].N[C@H](C(O)=O)CC(O)=O>C(N(CC)CC)C>[CH2:1]([O:3][C:4](=[O:10])[CH2:5][C@@H:6]([C:7]([OH:9])=[O:8])[NH:16][CH2:15][CH2:14][CH2:13][N:12]([CH3:17])[CH3:11])[CH3:2]
Reactant: CCOC(=O)/C=C\C(=O)O
Reactant: CN(C)CCCN
Agent: N[C@@H](CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Product: CCOC(=O)C[C@H](NCCCN(C)C)C(=O)O

Procedure:
In a manner analogous to that of Example 1, 360.3 g (2.5 mols) of maleic acid monoethyl ester are placed into the glass flask and, with cooling, 500 ml of triethylamine are added dropwise. 306.5 g (2.5 mols+20% excess) of 3-dimethylaminopropylamine are subsequently added, and the reaction mixture is reacted at 64°-90° C. for 50 minutes. The crude product is processed according to Example 1, and the yield is 568.2 g (92.3% of theory) of a white crystalline aspartic acid derivative having a melting point of 168°-169° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[NH:18][C:19](=O)[C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>C(#N)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:7]([C:19]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)=[N:18][C@@H:13]3[C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc([C@H]2CCCC[C@H]2NC(=O)c2ccc(C#N)cc2)ccc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CCOc1cc2c(cc1OC)C(c1ccc(C#N)cc1)=N[C@H]1CCCC[C@@H]21
Yield: 88.5 %

Procedure:
5.1 g of (+/−)-cis-N-[2-(3-ethoxy-4-methoxyphenyl)-cyclohexyl]-4-cyanobenzamide (compound A5) are dissolved in 100 ml of acetonitrile and 3 ml of phosphorus oxychloride and the solution is stirred at 50° C. for 8 h. The reaction mixture is added to 100 ml of saturated sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic phase is washed with sodium hydrogencarbonate solution and water, dried using sodium sulfate and concentrated. 4.3 g of the title compound are obtained as solidified oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[C:10]([CH3:16])([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.CO.[BH4-].[Na+].[NH3:25]>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:25])[C:10]([CH3:16])([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: CC1(C)CN(Cc2ccccc2)CCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC1(C)CN(Cc2ccccc2)CCC1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-benzyl-3,3-dimethylpiperidin-4-one (900 mg, 4.14 mmol) and acetic acid (474 μl, 8.28 mmol) in 7 M NH3 in MeOH (35.5 ml, 249 mmol) was first stirred for 30 min at RT. Then NaBH4 (1.57 g, 41.4 mmol) was added at RT. The reaction batch was stirred for 30 min at RT, concentrated and then diluted with DCM (100 ml). The organic phase was washed with saturated aqueous NaHCO3, dried and concentrated to dryness.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:11])[C:5]2[C:6](=[CH:8][S:9][CH:10]=2)[N:7]=1.Cl.[NH2:13][C@H:14]1[CH2:18][CH2:17][N:16]([C:19](=[O:32])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=2)[CH2:15]1.O1CCOCC1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.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]>[CH3:11][C:4]1[C:5]2[C:6](=[CH:8][S:9][CH:10]=2)[N:7]=[C:2]([NH:13][C@H:14]2[CH2:18][CH2:17][N:16]([C:19](=[O:32])[CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:25][CH:26]=3)[CH2:15]2)[CH:3]=1
Reactant: Cc1cc(Cl)nc2cscc12
Reactant: N[C@H]1CCN(C(=O)Cc2ccc(OC(F)(F)F)cc2)C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(N[C@H]2CCN(C(=O)Cc3ccc(OC(F)(F)F)cc3)C2)nc2cscc12
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 26.8 %

Procedure:
To a mixture of 2-chloro-4-methylthieno[3,4-b]pyridine (0.022 g), Pd2(dba)3 (0.005 g), (±)-BINAP (0.011 g), 1-((S)-3-aminopyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone mono hydrochloride (0.046 g), and 1,4-dioxane (0.5 mL) was added sodium t-butoxide (0.045 g) under nitrogen atmosphere, and the mixture was stirred at 70° C. for 30 min. The reaction mixture was diluted with ethyl acetate and water, then the interlayer was removed by Celite filtration, and the organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate/methanol=20:1, and silica gel, chloroform/methanol=20:1) to obtain light yellow oily (S)-1-(3-(4-methylthieno[3,4-b]pyridin-2-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.014 g).
Reaction SMILES: [C:1]12([C:13]([O:15]C)=[O:14])[CH2:8][CH2:7][C:4]([C:9]([O:11][CH3:12])=[O:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Li+].[OH-]>CO.O>[CH3:12][O:11][C:9]([C:4]12[CH2:7][CH2:8][C:1]([C:13]([OH:15])=[O:14])([CH2:6][CH2:5]1)[CH2:2][CH2:3]2)=[O:10]
Reactant: COC(=O)C12CCC(C(=O)OC)(CC1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)C12CCC(C(=O)O)(CC1)CC2
Temperature: 65 °C

Procedure:
To a solution of dimethyl bicyclo[2.2.2]octane-1,4-dicarboxylate (0.92 g, 4.07 mmol) in MeOH (5 mL) was added LiOH (0.102 g, 4.27 mmol) in water (4 mL) at RT. The reaction mixture was heated at 65° C. for 6 h. It was then cooled to RT and concentrated. The residue was acidified with 1N HCl to pH ˜2. The solid (presumed side product diacid) was removed by filtration. The filtrate was extracted with EtOAc, and the combined organic layer was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated to afford Intermediate A51A as a white solid, which was used for the next step without further purification. MS(ES): m/z=213 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 12.11 (s, 1H), 3.66 (s, 3H), 1.78-1.58 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CO.O.CCOC(C)=O.O.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>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=2)=[CH:12][CH:11]=1
Reactant: Nc1ncc(Br)cn1
Reactant: OB(O)c1ccc(Br)cc1
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: [Cs+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ncc(-c2ccc(Br)cc2)cn1
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-pyrimidin-2-ylamine (0.8 g, 4.59 mmol), 4-bromophenyl boronic acid (1 g, 4.97 mmol), tetrakis(triphenylphosphine)palladium(0) (300 mg, 0.259 mmol), cesium carbonate (1.15 g, 3.03 mmol) was stirred in MeOH/H2O (20 ml, 1/1) at reflux temperature overnight. The reaction was cooled to room temperature and diluted with EtOAc (200 ml) and water (50 ml). The organic layer was separated, dried over MgSO4, filtered and solvent evaporated yielding a residue which was purified on silica gel eluting with 85% v/vEtOAc/hexanes yielding product 81 as white solid. (0.7 g, 63%). ESMS (MH, 250).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([F:9])[CH:3]=1.[F:10][C:11]1[CH:16]=[C:15](B(O)O)[CH:14]=[CH:13][N:12]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>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.C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:15]2[CH:14]=[CH:13][N:12]=[C:11]([F:10])[CH:16]=2)=[C:4]([F:9])[CH:3]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: Fc1cc(Br)ccc1I
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: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Fc1cc(-c2ccc(Br)cc2F)ccn1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a sealed tube were added 4-bromo-2-fluoro-1-iodobenzene 207-1 (600 mg, 2.0 mmol), 2-fluoropyridin-4-ylboronic acid 205-4 (282 mg, 2.0 mmol), Pd(PPh3)4 (116 mg, 0.1 mmol), Na2CO3 (636 mg, 6.0 mmol), toluene (2 mL), H2O (2 mL) and ethanol (0.5 mL). The reaction mixture was stirred at 120° C. overnight. After cooling to room temperature, the solvents were evaporated and the residue was redissolved in water (5 ml) and extracted with ethyl acetate (8 mL×3). The combined organic phases were dried over Na2SO4, and concentrated. The residue was purified by silica gel flash chromatography and eluted with 15% ethyl acetate in hexane to give 4-(4-bromo-2-fluorophenyl)-2-fluoropyridine 207-3. MS m/z 270.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(O)(C)C>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:11]=1[CH3:12]
Reactant: C1CCNCC1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Solvent: CC(C)O
Product: Cc1c(N2CCCCC2)nc2cc(F)cc(F)c2c1Cl
Temperature: 85 °C
Reaction time: 8 h

Procedure:
The 2,4-dichloro-5,7-difluoro-3-methylquinoline (300 mg, 1.21 mmol) was dissolved in isopropanol (3 mL) and piperidine (0.120 mL, 1.21 mmol) was added to the sealed tube. The mixture was heated to 85° C. and stirred overnight. The reaction was then cooled and concentrated to dryness. The residue was then purified by medium pressure chromatography (silica, 0 to 40% DCM:hexane) to give 4-chloro-5,7-difluoro-3-methyl-2-(piperidin-1-yl)quinoline. Mass Spectrum (ESI) m/e=297.1 (M+1).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([NH2:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=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>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:3]=[CH:4][C:5]([NH2:11])=[C:6]([CH:10]=2)[C:7]([OH:9])=[O:8])[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: COc1cccc(B(O)O)c1
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: COc1cccc(-c2ccc(N)c(C(=O)O)c2)c1
Temperature: 80 °C

Procedure:
To a solution of 5-iodo-2-aminobenzoic acid (2.6 g; 10 mmol) in ethylene glycol dimethyl ether (DME, 20 mL) add tetrakis(triphenylphosphine)palladium(0) (150 mg) under argon. After the catalyst dissolved completely, add successively 3-methoxybenzeneboronic acid (1.65 g; 11 mmol) and sodium carbonate (1M in water, 30 mL). Heat the mixture at 80° C. for 1 hour. Cool the reaction mixture then wash with 50% EtOAc in hexane. Filter the aqueous layer through a short pad of celite to remove palladium black and carefully pour the filtrate into cold 3N hydrochloric acid (25 mL) under stirring. Collect the precipitate by filtration and air-dry to obtain 5-(3-methoxyphenyl)-2-aminobenzoic acid as a white solid. B. 5-(3-Methoxyphenyl)benzimidazolidin-2-one
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:10][CH:9]1[CH2:11][CH2:12][C:13]([O:15]C)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH:9]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCC1CN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1 mmol of 3 5 mL of ethanol is added 2 mL of 1 N NaOH and the mixture is stirred for 2 hours at ambient temperature. The mixture is partitioned between 25 mL of water and 25 mI. of ether. The aqueous layer is acidified to pH 2 and extracted with 2×25 mL of ether. The combined either extracts are washed with brine, dried with anhydrous MgSO4, filtered and concentrated to yield 4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([S:22](Cl)(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]1=2.[CH3:26][O:27][C:28]1[CH:40]=[CH:39][C:31]([CH2:32][NH:33][C:34]2[S:35][CH:36]=[CH:37][N:38]=2)=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([S:22]([N:33]([CH2:32][C:31]3[CH:39]=[CH:40][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)[C:34]3[S:35][CH:36]=[CH:37][N:38]=3)(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]1=2
Reactant: COc1ccc(CNc2nccs2)cc1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Cl
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccc(C(F)(F)F)cc2Cl)cc1

Procedure:
4-(2-chloro-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (INTERMEDIATE X) was prepared in the same manner as INTERMEDIATE D, STEP 3, except employing INTERMEDIATE E and INTERMEDIATE W (N-(4-methoxybenzyl)thiazol-2-amine) m/z (ESI) 595.8 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[CH2:10][NH:11][C:12](=[O:22])[CH2:13][NH:14]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:24].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:24].[CH2:1]([O:8][C:9](=[O:23])[CH2:10][NH:11][C:12](=[O:22])[CH2:13][NH2:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCC(=O)NCC(=O)OCc1ccccc1
Reaction time: 4 h
Yield: 100 %

Procedure:
In 80 ml of chloroform were dissolved 14.8 g (42 mmol) of t-butyloxycarbonylglycine-dicyclohexylamine and 14.0 g (41.5 mmol) of glycine benzyl ester p-toluenesulfonic acid salt. To this solution, 70 ml of a chloroform solution containing 8.75 g (45.7 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC) were added at -5° C. with stirring. The resulting mixture was stirred for 24 hours. The resulting chloroform solution was successively washed twice with a 10% by weight aqueous citric acid solution, then twice with water, then twice with a 4% by weight aqueous sodium hydrogen carbonate solution and finally twice with water. Thereafter, the organic phase was dried over anhydrous sodium sulfate. The solvent was then completely removed in vacuo to obtain a white oily material. This was crystallized from hexane to obtain 12.8 g (yield: 96%) of t-butyloxycarbonyl-glycylglycine benzyl ester as a white solid. In 10 ml of ethyl acetate were dissolved 8.0 g (24.8 mmol) of t-butyl oxycarbonyl-glycylglycine benzyl ester, to which 120 ml of 4N HCl/ethyl acetate were added. The mixture was stirred for 4 hours and then the solvent was removed in vacuo to obtain white precipitates. The precipitates were washed well with diethyl ether to obtain 6.4 g (yield: 100%) of glycylglycine benzyl ester hydrochloride as a white solid having the following physical properties:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[NH2:45][CH:46]([C:51]([CH3:54])([CH3:53])[CH3:52])[C:47]([NH:49][CH3:50])=[O:48]>CN(C=O)C>[CH3:52][C:51]([CH3:54])([CH3:53])[CH:46]([NH:45][C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:3]2[CH:4]=[C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:19][CH:18]=1)=[O:21])[C:47]([NH:49][CH3:50])=[O:48]
Reactant: CNC(=O)C(N)C(C)(C)C
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CNC(=O)C(NC(=O)c1ccc(-c2cc(-c3nnc(C)o3)ccc2C)cc1)C(C)(C)C
Reaction time: 18 h

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg, 0.042 mmol) and 2-amino-N,3,3-trimethylbutanamide (0.34 mmol) were mixed in DMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (0.4 ml) and water (0.4 ml). The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue was purified by mass directed HPLC to give N-[2,2-dimethyl-1-(methylaminocarbonyl)propyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide.