Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:9][CH2:8]1.[CH2:27]([NH:29][CH2:30][CH2:31][OH:32])[CH3:28].C([O-])(O)=O.[Na+]>CCO>[CH2:27]([N:29]([CH2:30][CH2:31][OH:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:9][CH2:8]1)[CH3:28]
Reactant: CCNCCO
Reactant: O=S(=O)(N[C@H]1CC[C@H](CCCCCBr)CC1)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCN(CCO)CCCCC[C@H]1CC[C@H](NS(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 90 °C

Procedure:
A solution of 2.4 mg (5.26 mmol) of trans-N-[4-(5-Bromo-pentyl)-cyclohexyl]-4-trifluoromethyl-benzenesulfonamide in 36 ml of EtOH was treated with 2.1 ml (21.53 mmol) of ethyl-(2-hydroxy-ethyl)-amine, 1.8 g (21.43 mmol) of NaHCO3 and stirred over night at 90° C. The reaction cooled, filtered, evaporated and the residue extracted with aqueous saturated NaHCO3/EtOAc (3×). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4), filtered and evaporated. Purification by flash column chromatography on silica gel (EtOAc/EtOH/NH3 25% 98:2:1) gave 1.96 g (80%) of trans-N-(4-{5-[Ethyl-(2-hydroxy-ethyl)-amino]-pentyl}-cyclohexyl)-4-trifluoromethyl-benzenesulfonamide, MS: 463 (M−H−).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH2:5][CH2:4][C@H:3]1[OH:15].C(N(CC)CC)C.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[Cl:33])[C:27](Cl)=[O:28]>C1COCC1>[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[Cl:33])[C:27]([NH:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH2:5][CH2:4][C@H:3]1[OH:15])=[O:28]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: N[C@@H]1c2cc([N+](=O)[O-])ccc2CC[C@H]1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1c2cc([N+](=O)[O-])ccc2CC[C@H]1O)c1ccc(Cl)c(Cl)c1
Yield: 103.3 %

Procedure:
A solution of 112 (2.1 g) in warm THF (300 mL) was treated with triethylamine (5 mL) and the solution allowed to come to room temperature. A solution of 3,4-dichlorobenzoyl chloride (2.3 g) in THF (50 mL) was added dropwise over 20 min. After stirring over night, the solvent was evaporated to give a solid (3.97 g) that had the appropriate nmr spectrum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:43][O:44][C:45]1[C:46]2[N:59]=[C:58]([NH2:60])[S:57][C:47]=2[C:48]([CH:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)=[N:49][CH:50]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:60][C:58]1[S:57][C:47]2[C:48]([CH:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[N:49][CH:50]=[C:45]([O:44][CH3:43])[C:46]=2[N:59]=1)=[O:8]
Reactant: COc1cnc(C2CCOCC2)c2sc(N)nc12
Reactant: COc1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cccc(C(=O)Nc2nc3c(OC)cnc(C4CCOCC4)c3s2)c1

Procedure:
From 3-methoxybenzoic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-(tetrahydro-pyran-4-yl)-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 400 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=O)[C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[O:7])=[CH:4][CH:3]=1.[NH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30]>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20]([NH:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:22])[C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1cccc(C)c1N(CCCC(=O)O)C(=O)c1ccc(Cl)cc1
Reactant: COC(=O)CCCN
Product: COC(=O)CCCNC(=O)CCCN(C(=O)c1ccc(Cl)cc1)c1c(C)cccc1C

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyric acid and methyl 4-aminobutyrate and suitable processing produces methyl N-[N-(p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyryl]-4-aminobutyrate (oil), saponification of which and processing of the reaction product yields N-[N-(p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyryl]-4-aminobutyric acid (M.P. 141° to 142°).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](Br)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:32]1[N:37]=[CH:36][CH:35]=[CH:34][N:33]=1)CCC>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:32]4[N:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: c1ccc(COc2ccc(Nc3ncnc4ccc(-c5ncccn5)cc34)cc2)cc1
Yield: 40.3 %

Procedure:
The (4-benzyloxy-phenyl)-(6-bromoquinazolin-4-yl)amine (200 mg, 0.49 mmol), 2-(tributylstannyl)pyrimidine (200 mg, 0.54 mmol) and bis(triphenylphosphine)palladium(II) chloride (catalytic) were dissolved in dioxan (3 ml) and heated at reflux under nitrogen for 27 hr (Procedure B). The solvent was removed from the cooled reaction under vacuum, and the residue was purified by flash column chromatography (silica gel, eluting with an ethyl acetate/iso-hexane gradient). The resulting oily solid was triturated with iso-hexane/ethyl acetate to give the product (80 mg, 40%) as a pale yellow solid; δH [2H6]-DMSO 10.30 (1H, b, NH), 9.61 (1H, s, 5-H), 9.07 (2H, d, pyrimidine 4-H, pyrimidine 6-H), 8.86 (1H, d, 7-H), 8.51 (1H, s, 2-H), 7.93 (1H, d, 8-H), 7.78 (2H, d, 2′-H, 6′-H), 7.65-7.36 (6H, m, 5×Ph-H, pyrimidine 5-H), 7.11 (2H, d, 3′-H, 5′-H), 5.18 (2H, s, CH2); m/z 406 (M+1)+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[N:9]2)=[CH:6][CH:7]=1.O.[NH2:16][NH2:17].O1CCOCC1>O>[NH:16]([C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[N:9]2)=[CH:6][CH:7]=1)[NH2:17]
Reactant: NN
Reactant: Cc1cc(C)n(-c2ccc(Cl)nn2)n1
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)n(-c2ccc(NN)nn2)n1

Procedure:
A mixture of 34.2 g. of 3-chloro-6-(3,5-dimethyl-1-pyrazolyl)-pyridazine, 100 ml of 72% hydrazine hydrate and 200 ml of dioxane is stirred at 90°-95° C. for 14 hours, then the mixture is poured into 1 liter of water, extracted three times with 150 ml of chloroform each, and the combined organic phases are dried over magnesium sulphate. After evaporation of the solvent, the residue is recrystallized from isopropanol. Yield: 27 g /80%/; m.p.: 142°-143° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([O:9][CH2:10][C@H:11]2[CH2:14][CH2:13][N:12]2C(OCC2C=CC=CC=2)=O)=[CH:5][CH:4]=1>CCO.[Pd]>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([O:9][CH2:10][C@H:11]2[CH2:14][CH2:13][NH:12]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(OC[C@H]2CCN2C(=O)OCc2ccccc2)cn1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(OC[C@H]2CCN2)cn1
Reaction time: 16 h
Yield: 94.5 %

Procedure:
6-methoxy-3-(1-Cbz-2-(R)-azetidinylmethoxy)pyridine from Example 119c (300 mg, 0.91 mmol) was combined with 10% Pd/C (50 mg) in 30 mL of EtOH, and the mixture was stirred under an H2 atmosphere for 16 hours. The mixture was filtered and concentrated. The crude free base was converted to the salt by treatment with p toluenesulfonic acid in ethyl acetate. The mixture was concentrated, the residue was triturated with ether, and the product was recrystalized from ethyl acetate/ether to give 167 mg (33.9%) of the title compound: mp 139-142° C.; 1H NMR (D2O 300 MHz) δ2.39 (s, 6H), 2.60-2.70 (m, 2H), 2.98 (s, 3H), 4.04-4.15 (m, 2H), 4.36 (d, J=4.5, 2H), 4.95 (m, 1H), 7.08 (d, J=9.0, 1H), 7.36 (d, J=8.0, 4H), 7.68 (d, J=8.0, 4H), 7.75 (dd, J=3.5, 9.5, 1H), 7.91 (d, J=3.0, 1H); MS (DCI/NH3) m/e 195 (M+H)+. Anal. calcd. for C10H14N2O2.2C7H8O3S: C, 53.52; H, 5.61; N, 5.20. Found: C, 53.24; H, 5.68; N, 5.07. [α]D +3.55(c 1, MeOH).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Cl:4][C:5]1[N:6]=[C:7](Cl)[C:8]2[CH2:14][O:13][CH2:12][CH:11]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=3)[C:9]=2[N:10]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:4][C:5]1[N:6]=[C:7]([NH:3][CH2:1][CH3:2])[C:8]2[CH2:14][O:13][CH2:12][CH:11]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=3)[C:9]=2[N:10]=1
Reactant: Fc1cc(F)cc(C2COCc3c(Cl)nc(Cl)nc32)c1
Reactant: CCN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCNc1nc(Cl)nc2c1COCC2c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
The mixture of ethanamine (406 μL, 0.812 mmol), 2,4-dichloro-8-(3,5-difluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (Preparation X)(117 mg, 0.369 mmol) and DIEA (161 μL, 0.922 mmol) in THF (1845 μL) was stirred at RT for 2 h. The mixture was concentrated and purified by column chromatography on silica gel to give 2-chloro-8-(3,5-difluorophenyl)-N-ethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (104 mg, 0.319 mmol, 87% yield). LC-MS (M+H)+=326.1.
Reaction SMILES: [CH3:1][C:2]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH2:3][C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[N:29]1[C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([NH2:38])[C:32]=2[CH:31]=[N:30]1>>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[N:29]1[C:37]2[C:32](=[C:33]([NH:38][CH2:6][C:4]([OH:5])([CH2:3][C:2]([C:12]3[C:20]4[O:19][CH2:18][CH2:17][C:16]=4[CH:15]=[CH:14][CH:13]=3)([CH3:11])[CH3:1])[C:7]([F:8])([F:9])[F:10])[CH:34]=[CH:35][CH:36]=2)[CH:31]=[N:30]1
Reactant: Nc1cccc2c1cnn2-c1ccc(F)cc1F
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cccc2c1OCC2
Product: CC(C)(CC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1F)C(F)(F)F)c1cccc2c1OCC2

Procedure:
Prepared similarly to Example 1 from racemic 7-{1,1-dimethyl-2-[2-(trifluoromethyl)-2-oxiranyl]ethyl}-2,3-dihydro-1-benzofuran (which may be prepared according to WO 04/063163) and 1-(2,4-difluorophenyl)-1H-indazol-4-amine (Intermediate 4).
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6]/[C:7]/2=[CH:12]\[C:13]([O:15][CH2:16][CH3:17])=[O:14].C([O-])=O.[NH4+]>CCO>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][CH:7]1[C:8]2[C:4](=[C:3]([OH:2])[CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)[CH3:17]
Reactant: CCOC(=O)/C=C1\CCc2c(OC)cccc21
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)CC1CCc2c(O)cccc21
Temperature: 65 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
A round bottomed flask was flushed with argon and then charged with Pd(OH)2 (316 mg, 10 wt %). The flask was evacuated and back-filled with argon, and then EtOH (5 mL) was added to the catalyst. Ethyl(2E)-(4-methoxy-2,3-dihydro-1H-inden-1-ylidene)ethanoate (Example 8, 3.2 g, 13.6 mmol) was added as a solution in EtOH (63 mL). Ammonium formate (4.3 g, 68 mmol) was added, and the reaction mixture was heated to 65° C. After 2 h, the reaction mixture was cooled and filtered through a pad of Celite®, and concentrated under reduced pressure. The reaction mixture was used without further purification according to the method outlined in Example 6 to give the title compound (2.3 g, 78%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.14 (t, 1H), 6.76 (d, 1H), 6.67 (d, 1H), 4.91 (br s, 1H), 4.19 (q, 2H), 3.60 (m, 1H), 2.85-2.88 (m, 1H), 2.76-2.80 (m, 2H), 2.19-2.26 (m, 2H), 1.76-1.82 (m, 1H), 1.26 (t, 3H); GC-MS m/z [M+H]+ 221.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[C:9]([N:14]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:10][N:11](C)[CH3:12])[CH:5]=[CH:6][CH:7]=1.C[NH:27]N>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([NH2:14])=[CH:10][N:11]([CH3:12])[N:27]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=C(C(=O)c1cccc(Cl)c1)N1C(=O)c2ccccc2C1=O
Reactant: CNN
Solvent: CCO
Product: Cn1cc(N)c(-c2cccc(Cl)c2)n1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(3-(3-chlorophenyl)-1-(dimethylamino)-3-oxoprop-1-en-2-yl)isoindoline-1,3-dione (2.30 g, 6.48 mmol, 1 eq) in 50 mL ethanol was added N-methylhydrazine (1.4 mL, 26 mmol, 4.0 eq). The reaction mixture was stirred at 80° C. for 2 hours and then concentrated onto silica gel. The crude mixture of regioisomers was separated and purified by flash chromatography on silica gel (0 to 80% ethyl acetate in dichloromethane) to yield: 715 mg (53%) of 3-(3-chlorophenyl)-1-methyl-1H-pyrazol-4-amine LCMS (ESI) m+H=208.2; 1H NMR (400 MHz, CDCl3) δ: 7.78 (s, 1H), 7.63 (d, 1H), 7.33 (t, 1H), 7.25 (overlapping with CDCl3, 1H), 7.04 (s, 1H), 3.84 (s, 3H), and 274.6 mg (20%) of 5-(3-chlorophenyl)-1-methyl-1H-pyrazol-4-amine. LCMS (ESI) m+H=208.2; 1H NMR (400 MHz, CDCl3) δ: 7.43 (t, 1H), 7.38 (overlapping d and s, 2H), 7.27 (d, 1H), 7.23 (s, 1H), 3.76 (s, 3H).
Reaction SMILES: CN([CH2:4][C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1)C.[CH2:20]=[CH:21][CH:22]=[CH2:23]>C1(C)C=CC=CC=1>[C:16]([C:7]1[C:8](=[O:15])[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]2([CH2:23][CH2:22][CH:21]=[CH:20][CH2:4]2)[CH:6]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: C=CC=C
Reactant: CN(C)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Product: CC(C)(C)C1=CC2(C=C(C(C)(C)C)C1=O)CC=CCC2
Temperature: 205 °C
Yield: 93.7 %

Procedure:
A 300 mL Parr autoclave was charged with a solution of 10.52 g (40 mmols) of N,N-dimethyl-4-aminomethyl-2,6-di-t-butylphenol in 90 g of toluene, sealed and evacuated by a water aspirator, and then charged with 4.38 g (80 mmols) of 1,3-butadiene. The reaction mixture was heated to approximately 205° C. for 10 hours. A maximum pressure of 120 psig was obtained. After cooling, the reaction mixture was poured into a 500 mL separatory funnel, washed with approximately 2N HCl (1×50 mLs), water (1×50 mLs), and brine (1×50 mLs), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford 10.21 g (94% yield) of 2,4-di-t-butylspiro[5.5]undeca-1,4,8-trien-3-one as a brown solid. The brown solid was recrystallized from 80% ethanol to give the product as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7]Cl)=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[S:4][N:3]=1.[OH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[C:20]([F:31])[C:19]=1[F:32]>>[Cl:1][C:2]1[C:6]([CH2:7][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([F:31])[C:19]=2[F:32])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[S:4][N:3]=1
Reactant: CCOC(=O)CCc1ccc(O)c(F)c1F
Reactant: CCc1ccc(-c2snc(Cl)c2CCl)cc1
Product: CCc1ccc(-c2snc(Cl)c2COc2ccc(CCC(=O)O)c(F)c2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 127 following Steps 6 and 7 by coupling 3-chloro-4-(chloromethyl)-5-(4-ethylphenyl)isothiazole and ethyl 3-(4-hydroxy-2,3-difluorophenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ 7.36 (d, J=8.1 Hz, 2H), 7.26 (d, J=8.1 Hz, 2H), 6.87 (t, J=8.4 Hz, 1H), 6.76 (t, J=8.7 Hz, 1H), 4.96 (s, 2H), 2.82 (t, J=7.5 Hz, 2H), 2.61 (q, J=7.5, 15.2 Hz, 2H), 2.49 (t, J=7.5 Hz, 2H), 1.15 (t, J=7.5 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C21H18ClF2NO3S, 438.1 (M+H). found 438.1.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:17][C:18]2[C:23]([C:24]([O:27][CH3:28])([CH3:26])[CH3:25])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[O:29]([C:36]([NH:38][OH:39])=O)C1C=CC=CC=1>C1COCC1>[OH:39][NH:38][C:36]([N:14]1[CH2:13][CH2:12][CH:11]([N:10]([CH2:9][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=2)[CH2:17][C:18]2[C:23]([C:24]([O:27][CH3:28])([CH3:25])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:16][CH2:15]1)=[O:29]
Reactant: COC(C)(C)c1cccnc1CN(Cc1ncc(C)cc1C)C1CCNCC1
Reactant: O=C(NO)Oc1ccccc1
Solvent: C1CCOC1
Product: COC(C)(C)c1cccnc1CN(Cc1ncc(C)cc1C)C1CCN(C(=O)NO)CC1
Temperature: 25 °C
Yield: 62.6 %

Procedure:
To a solution of (3,5-Dimethyl-pyridin-2-ylmethyl)-[3-(1-methoxy-1-methyl-ethyl)-pyridin-2-ylmethyl]-piperidin-4-yl-amine (0.245 g, 0.64 mmol) in dry THF (4 mL) was added N-(phenoxycarbonyl)hydroxylamine (0.193 g, 1.26 mmol) and the resultant solution was stirred at 60° C. overnight. The mixture was cooled to room temperature and concentrated. Purification of the crude material by column chromatography on silica gel (10:1:1 CH2Cl2-MeOH—NH4OH) provided 177 mg (54%) of COMPOUND 263 as a white solid. 1H NMR (CDCl3) δ 1.52-1.74 (m, 8H), 1.94-1.98 (m, 2H), 2.10 (s, 3H), 2.25 (s, 3H), 2.67 (t, 2H, J=12.6 Hz), 2.77-2.95 (m, 4H), 3.93-4.02 (m, 4H), 4.16 (s, 2H), 6.80 (s, 1H), 7.13-7.18 (m, 2H), 7.62 (d, 1H, J=8.1 Hz), 8.14 (s, 1H), 8.49 (dd, 1H, J=4.5, 1.5 Hz); 13C NMR (CDCl3) δ 18.31, 18.54, 27.87, 28.29, 44.05, 50.79, 54.01, 54.53, 54.86, 58.20, 122.10, 131.99, 133.18, 135.73, 139.25, 139.97, 146.56, 147.36, 161.04; ES-MS m/z 442 (M+H). Anal. Calcd. For C24H35N5O3.0.8CH2Cl2: C, 58.46; H, 7.24; N, 13.75. Found: C, 58.40; H, 7.20; N, 13.89.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([NH:11][C:12]2[O:13][C:14]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)=[N:15][N:16]=2)=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)[CH3:23]>>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]([NH:11][C:12]2[O:13][C:14]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)=[N:15][N:16]=2)=[O:10])[CH:3]=[C:2]([C:33]2[CH:34]=[CH:35][C:30]([C:27]3[CH:26]=[CH:25][C:24]([CH2:22][CH3:23])=[CH:29][CH:28]=3)=[CH:31][CH:32]=2)[CH:7]=1
Reactant: O=C(Nc1nnc(-c2ccco2)o1)c1cc(Cl)cc(Br)c1
Reactant: CCc1ccc(-c2ccc(B(O)O)cc2)cc1
Product: CCc1ccc(-c2ccc(-c3cc(Cl)cc(C(=O)Nc4nnc(-c5ccco5)o4)c3)cc2)cc1

Procedure:
The title compound was synthesized in accordance with the synthesis method of compound Ia-50, using 3-bromo-5-chloro-N-[5-(2-furyl)-1,3,4-oxadiazol-2-yl]benzenecarboxamide prepared in Reference Example 36 instead of compound Ia-50 and using commercially available 4′-ethyl-4-biphenylboronic acid instead of 1-methyl-5-indoleboronic acid pinacol ester.
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:41])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([N:26]1[CH2:30][CH2:29][CH2:28][C@@H:27]1[C:31]([O:33]CC1C=CC=CC=1)=[O:32])=[O:25])=[O:10])C1C=CC=CC=1>C(O)C.[Pd]>[C:31]([C@H:27]1[CH2:28][CH2:29][CH2:30][N:26]1[C:24](=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[C:9]([OH:10])=[O:8])=[O:41])([OH:33])=[O:32]
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)CCCCCCCC(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)[C@H]1CCCN1C(=O)CCCCCCCC(=O)N1CCC[C@@H]1C(=O)O
Yield: 87.2 %

Procedure:
100 mg (0.18 mmol) (R)-1-[9-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-9-oxo-nonanoyl]-pyrrolidine-2-carboxylic acid benzyl ester in 20 ml ethanol were hydrogenated in the presence of 20 mg 5% Pd on carbon for two hours at room temperature. Filtration and evaporation gave 60 mg (R)-1-[9-[(R)-2-carboxy-pyrrolidin-1-yl]-9-oxo-nonanoyl]pyrrolidine-2-carboxylic acid, as a colorless oil.
Reaction SMILES: O=[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[N:4][NH:3]1.P(Cl)(Cl)([Cl:20])=O>C(Cl)(Cl)Cl>[Cl:20][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: COC(=O)c1ccc(-c2cnc(=O)[nH]n2)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(-c2cnc(Cl)nn2)cc1
Temperature: 100 °C
Yield: 17.3 %

Procedure:
A mixture of methyl 4-(3-oxo-2,3-dihydro-1,2,4-triazin-6-yl)benzoate (13.4 g, 0.0580 mol), phosphoryl chloride (30 mL, 0.3 mol) in chloroform (50 mL) was refluxed (oil-bath temperature about 100° C.) for 2 h. After cooling to RT, the mixture was concentrated to remove excess phosphoryl chloride. The residue was dissolved in methylene chloride and poured into ice-water, and carefully neutralized with K2CO3. The organic layer was separated and the aqueous solution was extracted with methylene chloride. The combined organic phases were dried over Na2SO4, concentrated, and further purified by chromatography to afford the desired product (2.5 g, 17%). LCMS: (M+H)=249.9. 1H NMR (300 MHz, CDCl3): in ppm, 3.98 (s, 3H), 8.18 (d, 2H), 8.24 (d, 2H), 8.96 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[CH:16][CH:17]=[C:18](I)[C:9]=2[C:8]1=[O:20].[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O>>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[CH:16][CH:17]=[C:18]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[Cl:30])[C:9]=2[C:8]1=[O:20]
Reactant: OB(O)c1ccccc1Cl
Reactant: O=C1c2c(I)ccnc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C1c2c(-c3ccccc3Cl)ccnc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 87.2 %

Procedure:
In a similar manner to Reference Example 4, 5-[3,5-bis(trifluoromethyl)benzyl]-7-iodo-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (300 mg) was reacted with 2-chlorophenylboronic acid (133 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-chlorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (254 mg, 87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([OH:14])[C:11]([OH:13])=[O:12].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24]O.Cl>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([OH:14])[C:11]([O:13][CH2:24][C:23]1[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=1[O:21][CH3:20])=[O:12]
Reactant: COc1ccc(CCNCC(O)C(=O)O)cc1OC
Reactant: COc1ccccc1CO
Agent: Cl
Solvent: c1ccccc1
Product: COc1ccccc1COC(=O)C(O)CNCCc1ccc(OC)c(OC)c1
Yield: 23 %

Procedure:
To 3 g of the 3-(3,4-dimethoxyphenethyl)amino-2-hydroxypropionic acid prepared in Example I was added 200 ml of benzene and 20 ml of 2-methoxybenzyl alcohol. About 0.5 ml of concentrated HCl was added to catalyze the reaction. The reaction mixture was heated to reflux for 6 hours and the water was collected by a moisture trap. The reaction mixture was extracted with 200 ml of 0.5% HCl in water. The aqueous layer was basified with NaHCO3 and extracted with CHCl3. Evaporation of the CHCl3 gave an oily residue which after chromotography on a column (silica gel/Et2O:EtOH=5:1) gave 1 g (23%) of white solid: m.p. 79.5°-82.5° C. The NMR, IR and mass spectra were consistent with the assigned structure and the elemental analysis was consistent with the empirical formula C21H27O6N.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([NH2:20])=[O:19])[CH:13]=2)=[CH:8][C:7]=1[C:21]([F:24])([F:23])[F:22].CC(O)=O.C([O-])(O)=O.[Na+]>O>[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([NH2:20])=[O:19])[CH:13]=2)=[CH:8][C:7]=1[C:21]([F:22])([F:23])[F:24])=[O:1]
Reactant: NC(=O)c1cccc(-c2ccc(C3OCCO3)c(C(F)(F)F)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)c1cccc(-c2ccc(C=O)c(C(F)(F)F)c2)c1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
4′-(1,3-Dioxolan-2-yl)-3′-(trifluoromethyl)-1,1′-biphenyl-3-carboxamide (0.177 g; 0.525 mmol) was added to a solution of HOAc (4 mL) and water (1 mL) and the mixture was stirred at 65° C. in a sealed vial for 1 h. Upon cooling, the mixture was poured into satd NaHCO3 and extracted with EtOAc (×3). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo affording the title compound, which was used without further purification.