Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[NH:9][C:8]1=[O:21].[C:28]1([C:34]2[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=2[CH2:36]Br)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:34]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][N:9]1[C:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:11]=2[C:12](=[O:13])[N:7]([OH:6])[C:8]1=[O:21]
Reactant: BrCc1ccccc1-c1ccccc1
Reactant: COc1ccc(COn2c(=O)[nH]c3c(oc4ccccc43)c2=O)c(OC)c1
Product: O=c1c2oc3ccccc3c2n(Cc2ccccc2-c2ccccc2)c(=O)n1O

Procedure:
Following general procedure B2 and D1, 3-(2,4-Dimethoxy-benzyloxy)-1H-benzo[4,5]furo[3,2-d]pyrimidine-2,4-dione was alkylated with 2-phenylbenzyl bromide and subsequently deprotected to provide the title compound as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ 5.39 (s, 2H); 7.11 (d, J=7 Hz, 1H); 7.22-7.63 (m, 11H); 7.76 (d, J=8 Hz, 1H); Ret. time=3.01 min., m/z=383.0.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)=O.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH:29]=O>>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:29]=[N:1][C:2]2[C:3]([C:12]=1[C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)=[CH:4][CH:5]=[CH:6][C:7]=2[C:8]([F:11])([F:10])[F:9]
Reactant: O=CCc1ccccc1Cl
Reactant: Nc1c(C(=O)c2cccc(O)c2)cccc1C(F)(F)F
Product: Oc1cccc(-c2c(-c3ccccc3Cl)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [2-amino-3-(trifluoromethyl)phenyl]-(3-hydroxy-phenyl)methanone and (2-chloro-phenyl)-acetaldehyde following the procedure of Example 457: MS (ES) m/z 397.9; HRMS: calcd for C22H13ClF3NO+H+, 400.07105; found (ESI, [M+H]+), 400.0706.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:10](=[O:17])[CH:9]([CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH2:8]2)([CH3:3])[CH3:2].C=O.[C:26]([BH3-])#N.[Na+]>C1COCC1.CO.CC(O)=O>[CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:10](=[O:17])[CH:9]([CH:18]1[CH2:23][CH2:22][N:21]([CH3:26])[CH2:20][CH2:19]1)[CH2:8]2)([CH3:3])[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(C)Oc1cc2c(cc1[N+](=O)[O-])C(=O)C(C1CCNCC1)C2
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)Oc1cc2c(cc1[N+](=O)[O-])C(=O)C(C1CCN(C)CC1)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-isopropoxy-6-nitro-2-piperidin-4-yl-indan-1-one (Example 1, Step 5) in THF (5 mL) and methanol (5 mL) is added formaldehyde (104.2 uL, 1.39 mmol) and 10 drops of AcOH sequentially. The reaction mixture is stirred at room temperature for 1 h, then sodium cyanoborohydride (175.1 mg, 2.78 mmol) is added in one portion, and the reaction is stirred for an additional 30 min. The reaction is quenched by saturated aqueous NH4Cl and concentrated in vacuo to give an oily residue. This oil is partitioned between EtOAc and brine, the organic extract is dried over Na2SO4, filtered and concentrated under vacuum. Silica gel chromatography (5% MeOH in DCM) affords 5-isopropoxy-2-(1-methyl-piperidin-4-yl)-6-nitro-indan-1-one; MS m/z 333.2 (M+1).
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][O:2]1.[CH2:7]([NH2:11])[CH2:8][CH2:9][CH3:10]>>[CH2:7]([NH:11][C:1](=[O:6])[O:2][CH2:3][CH2:4][OH:5])[CH2:8][CH2:9][CH3:10]
Reactant: CCCCN
Reactant: O=C1OCCO1
Product: CCCCNC(=O)OCCO
Reaction time: 8 h
Yield: 89.5 %

Procedure:
274.8 grams of ethylene carbonate (3.12 moles) were placed in a round bottom flask equipped with stirrer, thermometer, addition funnel and reflux condenser. 228.2 grams (3.12 mole) of butylamine were charged to the addition funnel and added to the flask at a rate sufficient to maintain the flask contents at 50°-80° C. The resultant reaction product was allowed to stand overnight. Thereafter, stripping of the reaction product in a rotary evaporator gave 449.9 g of crude product. A portion of the crude product was distilled at a pressure of 2 mm Hg, and a temperature of from 124° C. to 126° C. to purify same. The HLB value of 2-hydroxyethyl 1 butyl carbamate calculated as previously described is 12.9.
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[N:9]([CH2:10][C:11]#[C:12][CH3:13])[C:8]([C:14]([O:16]C)=O)=[C:7]([CH:18]=O)[N:6]=1.C(O)(=O)C>C(O)C>[Br:4][C:5]1[N:9]([CH2:10][C:11]#[C:12][CH3:13])[C:8]2[C:14](=[O:16])[NH:3][N:2]=[CH:18][C:7]=2[N:6]=1
Reactant: CC#CCn1c(Br)nc(C=O)c1C(=O)OC
Reactant: NN
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC#CCn1c(Br)nc2cn[nH]c(=O)c21

Procedure:
0.31 ml hydrazine hydrate (99%), dissolved in 1 ml of ethanol, is added dropwise at ambient temperature to a solution of 1.80 g of methyl 2-bromo-3-(2-butyn-1-yl)-5-formyl-3H-imidazol-4-carboxylate in 25 ml of ethanol. Five minutes later 1.5 ml of concentrated acetic acid are added and the mixture is refluxed for 30 minutes. After cooling the solid precipitated is suction filtered, washed with 10 ml of ethanol and 20 ml of diethyl ether and dried.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:48])[CH2:16][N:17]1[C:26](=[O:27])[C:25]2[N:24]([CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])[C:23]([N:33]3[CH2:38][CH2:37][CH2:36][CH:35]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:34]3)=[N:22][C:21]=2[N:20]([CH3:47])[C:18]1=[O:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:6]([O:5][C:3]([CH2:2][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:48])[CH2:16][N:17]1[C:26](=[O:27])[C:25]2[N:24]([CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])[C:23]([N:33]3[CH2:38][CH2:37][CH2:36][CH:35]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:34]3)=[N:22][C:21]=2[N:20]([CH3:47])[C:18]1=[O:19])=[O:4])[CH3:7]
Reactant: CCOC(=O)CBr
Reactant: CC(C)=CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(=O)c1ccccc1O)c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccccc1C(=O)Cn1c(=O)c2c(nc(N3CCCC(NC(=O)OC(C)(C)C)C3)n2CC=C(C)C)n(C)c1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
63 mg of ethyl bromoacetate are added to a mixture of 200 mg of 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine and 63 mg of potassium carbonate in 3 ml N,N-dimethylformamide. The reaction mixture is stirred for five hours at ambient temperature. For working up it is combined with water and the precipitate formed is suction filtered, washed with water and dried for three hours at 80° C. in the drying cupboard.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([I:9])[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[Cl:1][C:2]1[C:7]([O:8][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:6][CH:5]=[C:4]([I:9])[N:3]=1
Reactant: Oc1ccc(I)nc1Cl
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Clc1nc(I)ccc1OCc1ccccc1
Temperature: 22 °C
Yield: 61.4 %

Procedure:
To a solution of 2-chloro-6-iodo-3-pyridinol (500 mg, 1.96 mmol), and K2CO3 (690 mg, 5.0 mmol) in methanol (5 mL) was added benzyl bromide (510 mg, 3.0 mmol). The reaction was refluxed for 60 minutes and was allowed to cool to 22° C. The mixture was then concentrated in vacuo. The remaining solids were slurried in ethyl acetate and filtered. The filtrate was dried over MgSO4 and concentrated in vacuo to yield 416 mg (61%) of 2-chloro-3-benzyloxy-6-iodo-pyridine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:13]2[CH2:27][CH2:26][C:16]3([O:21][CH2:20][C:19](=[O:22])[N:18]([CH:23]4[CH2:25][CH2:24]4)[CH2:17]3)[CH2:15][CH2:14]2)[C:9]([NH:11][CH3:12])=[O:10])=[C:4]([F:28])[CH:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:46]=[C:45]3[C:40]([CH:41]=[CH:42][CH:43]=[N:44]3)=[CH:39][CH:38]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:23]1([N:18]2[CH2:17][C:16]3([CH2:26][CH2:27][N:13]([CH:8]([C:5]4[CH:6]=[CH:7][C:2]([C:37]5[CH:46]=[C:45]6[C:40]([CH:41]=[CH:42][CH:43]=[N:44]6)=[CH:39][CH:38]=5)=[CH:3][C:4]=4[F:28])[C:9]([NH:11][CH3:12])=[O:10])[CH2:14][CH2:15]3)[O:21][CH2:20][C:19]2=[O:22])[CH2:25][CH2:24]1
Reactant: CNC(=O)C(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Reactant: CC1(C)OB(c2ccc3cccnc3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNC(=O)C(c1ccc(-c2ccc3cccnc3c2)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Yield: 25 %

Procedure:
A solution of 2-(4-bromo-2-fluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-N-methylacetamide (0.366 mmol) in 1,4-dioxane (2 mL) was treated with 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (0.403 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.018 mmol), and 2M aq potassium carbonate (1.099 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture irradiated in a Biotage Initiator Microwave at 120° C. for 15 min. The resulting black mixture was diluted with water (50 mL) and brine (20 mL), and extracted with dichloromethane four times. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The material was triturated with hexanes and the hexane solution was discarded. Purification of the residue by chiral HPLC (Chromegachiral CC4, methanol) followed by lyophilization from water (w/25% acetonitrile) afforded the title compound as a beige solid in >98% ee (50 mg, 25% yield). MS(ES)+ m/e 503.1 [M+H]+. αD=+34 deg (c=0.04, methanol).
Reaction SMILES: C(C1C(=O)C(Cl)=C(Cl)C(=[O:6])C=1C#N)#N.[CH:15]([C:18]1[CH:19]=[CH:20][C:21]([O:26][CH3:27])=[C:22]([CH:25]=1)[CH:23]=[O:24])([CH3:17])[CH3:16].O.CCOCC>C(Cl)Cl>[OH:6][C:15]([C:18]1[CH:19]=[CH:20][C:21]([O:26][CH3:27])=[C:22]([CH:25]=1)[CH:23]=[O:24])([CH3:17])[CH3:16]
Reactant: COc1ccc(C(C)C)cc1C=O
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(C(C)(C)O)cc1C=O
Reaction time: 24 h
Yield: 16.8 %

Procedure:
DDQ (10.07 g, 44.36 mmol) was added to a solution of 5-isopropyl-2-methoxybenzaldehyde (2.63 g, 15.3 mmol) dissolved in methylene chloride (100 ml) contained water (10 ml) at room temperature, and the resulting mixture was stirred for 24 h. Ether (200 ml) was added to the reaction mixture, and insoluble materials were removed by filtration. The filtrate was washed with aq. sodium thiosulfate solution, aq. sodium carbonate solution, and brine, successively and dried over magnesium sulfate. After evaporation of the solvent the resultant yellow oil was purified by chromatography (silica gel, 2-70% ethyl acetate/hexane) to afford pure 5-(1-hydroxy-1-methylethyl)-2-methoxybenzaldehyde (498 mg, 17%) as a slightly yellow oil and 5-(1-methoxy-1-methylethyl)-2-methoxybenzaldehyde (less polar, 129 mg, 4%) as a solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]([CH2:26][C:27]([O:29]CC)=[O:28])[C:6]([CH3:25])=[C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]=1[CH3:9].[Li+].[OH-]>C1COCC1.CO.O>[OH:1][CH2:2][CH2:3][C:4]1[N:5]([CH2:26][C:27]([OH:29])=[O:28])[C:6]([CH3:25])=[C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)(=[O:18])=[O:19])=[CH:13][CH:12]=2)[C:8]=1[CH3:9]
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccc(S(=O)(=O)N3CCCC3)cc2)c(C)c1CCO
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(S(=O)(=O)N3CCCC3)cc2)c(C)n(CC(=O)O)c1CCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
Ethyl 2-(2-(2-hydroxyethyl)-3,5-dimethyl-4-(4-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (20 mg, 0.045 mmol) in THF (2.0 ml), MeOH (0.500 ml) and water (0.50 ml) was stirred and LiOH (4.27 mg, 0.178 mmol) was added. The resulting mixture was stirred at 25° C. for two hours. The solvent was then removed and water was added, followed by 1 N HCl. The solvent was again removed, MeOH was added, and the resulting solution purified by preparative HPLC to give 12 mg of a light blue solid (12 mg, 0.029 mmol, 64.0% yield). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.63 (d, 2H), 7.19 (d, 2H), 4.57 (s, 2H), 3.76 (s, 2H), 3.66 (t, 2H), 3.18-3.15 (m, 4H), 2.76-2.73 (m, 4H), 2.03 (s, 3H), 1.78 (s, 3H), 1.70-1.66 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:17]=3)[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]O)[N:6]2[N:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:50].O>O1CCCC1>[CH2:23]([O:22][C:18]1[CH:17]=[C:16]([C:8]2[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][Br:50])[N:6]3[C:7]=2[C:2]([NH2:1])=[N:3][CH:4]=[N:5]3)[CH:21]=[CH:20][CH:19]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1ncnn2c(CCCCO)cc(-c3cccc(OCc4ccccc4)c3)c12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncnn2c(CCCCBr)cc(-c3cccc(OCc4ccccc4)c3)c12
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To a cooled (0° C.) solution of 4{4-amino-5-[3-(benzyloxy)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}butan-1-ol (489 mg, 1.26 mmol) and triphenylphosphine (495 mg, 1.89 mmol) in tetrahydrofuran (8 mL) was added carbon tetrabromide (501 mg, 1.51 mmol). The reaction was stirred (0° C.) for 2 h and was then warmed to rt and stirred an additional 17 h. Water (25 mL) was added and the mixture was extracted with ethyl acetate (2×20 mL). The combined organics were washed with brine, dried (Na2SO4) and evaporated. The crude material was purified via ISCO® chromatography using a gradient of 25 to 50% ethyl acetate in hexanes to afford 484 mg (85%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ7.88 (s, 1 H), 7.46-7.42 (m, 2 H), 7.41-7.28 (m, 4 H), 7.08-7.05 (m, 1 H), 7.03-6.97 (m, 2 H), 6.57 (s, 1 H), 5.14 (s, 2 H), 3.57 (t, 2 H), 2.90 (t, 2 H), 1.92-1.77 (m, 4 H); ES-MS m/z 451.1 [M+H]+, HPLC RT (min) 3.22.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14]C)=[O:13])[CH:10]=2)[NH:5][N:4]=1)#[N:2].OO.NC(N)=[O:20].C(#N)C.ClCCl>CO.[OH-].[Na+].O>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[NH:5][N:4]=1)(=[O:20])[NH2:2]
Reactant: NC(N)=O
Reactant: COC(=O)c1ccc2[nH]nc(C#N)c2c1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: NC(=O)c1n[nH]c2ccc(C(=O)O)cc12
Temperature: 10 °C
Reaction time: 16 h
Yield: 77.3 %

Procedure:
A suspension of methyl 3-cyano-1H-indazole-5-carboxylate (50.0 g, 249 mmol) in methanol (1 L) was cooled to 10° C. A solution of urea hydrogen peroxide (241 g, 2.49 mol) in sodium hydroxide (1 L of 2.5 N) and water (100 mL) was added dropwise, maintaining an internal temperature below 25° C. When the addition was complete, the ice bath was removed and the reaction was allowed to stir at room temperature for 16 hours. A small amount of unreacted starting material was observed by HPLC. The reaction was cooled to 15° C. and additional urea hydrogen peroxide (50 g) was added portionwise. Vigorous bubbling was noted. The reaction was allowed to stir for another 2 hours. The crude reaction was filtered to remove the solids present and the filtrate was concentrated to remove the methanol. The remaining solution was cooled in an ice bath and 6 N hydrochloric acid (420 mL) was added dropwise to adjust the pH to 4. The solution was stirred for 20 minutes and the resulting tan solid was collected by filtration and dried to give 57.2 g of crude product. To the crude was added acetonitrile (700 mL) and dichloromethane (700 mL) and the mixture was stirred at room temperature for 1 hour. The solid was collected by filtration, washed with 1:1 acetonitrile:dichloromethane (400 mL) and dried to give the title compound (39.5 g, 77%) as a tan solid. +ESI (M+H) 206.1; 1H NMR (DMSO-d6, δ): 13.81 (s, 1 H), 12.85 (br. s., 1 H), 8.82 (d, J=0.8 Hz, 1 H), 7.93 (dd, J=8.8, 1.6 Hz, 1 H), 7.79-7.85 (m, 1 H), 7.64 (d, J=8.6 Hz, 1 H), 7.44 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([NH:21][C:22](=[O:35])[C@@H:23]([NH:25][C:26](=[O:34])[CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH3:24])[C:11]([O:13]CC2C=CC=CC=2)=[O:12])=[CH:5][CH:4]=1>C1COCC1.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C@H:10]([NH:21][C:22](=[O:35])[C@@H:23]([NH:25][C:26](=[O:34])[CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH3:24])[C:11]([OH:13])=[O:12])=[CH:7][CH:8]=1
Reactant: COc1ccc(C[C@H](NC(=O)[C@H](C)NC(=O)CN2CCOCC2)C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1ccc(C[C@H](NC(=O)[C@H](C)NC(=O)CN2CCOCC2)C(=O)O)cc1
Reaction time: 2 h
Yield: 80.7 %

Procedure:
A mixture of (S)-benzyl 3-(4-methoxyphenyl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propanoate (5.00 g, 10.4 mmol) and Pd/C (10%, 1.0 g) in THF (50 mL) was stirred under a hydrogen atmosphere for 2 h. The mixture was filtered and concentrated to afford (S)-3-(4-methoxyphenyl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propanoic acid (3.3 g, 94% yield) as a colorless solid. 1H NMR (300 MHz, DMSO-d6): δ 8.24 (d, J=8.1 Hz, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.13 (m, 2H), 6.82 (m, 2H), 4.35 (m, 2H), 3.71 (s, 3H), 3.63-3.56 (m, 4H), 2.99-2.65 (m, 4H), 2.41-2.38 (m, 4H), 1.20 (d, J=6.9 Hz, 3H). MS (EI) for C19H27N3O6, found 394.5 (MH+).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:25][CH:24]=3)[C@H:8]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]4)=[CH:25][CH:24]=3)[C@H:8]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)OC[C@@H](c1ccc(C(F)(F)F)cc1)[C@H]2c1ccc(OCCN2CCCCC2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccc2c(c1)OC[C@@H](c1ccc(C(F)(F)F)cc1)[C@H]2c1ccc(OCCN2CCCCC2)cc1

Procedure:
In an manner analogous to that described in step 5 for Example 10, (±)-cis-7-methoxy-4-(4-(2-piperidinoethoxy)phenyl)-3-(4-(trifluoromethyl)phenyl)chromane (0.512 g, 1.0 mmol) was de-methylated by heating with pyridine hydrochloride to give the title compound as an off-white solid.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:7]([NH:9][C@H:10]([C:12]([NH:14][C@H:15]([C:20]([OH:22])=O)[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13])[CH3:11])=[O:8])[CH3:6])(=[O:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:38]([O:40][C:41](=[O:50])[C:42]([C:45](=[O:49])[N:46]([CH3:48])[NH2:47])([CH3:44])[OH:43])[CH3:39]>C(Cl)Cl.O1CCCC1>[CH2:38]([O:40][C:41](=[O:50])[C:42]([C:45](=[O:49])[N:46]([CH3:48])[NH:47][C:20](=[O:22])[C@H:15]([CH2:16][CH:17]([CH3:18])[CH3:19])[NH:14][C:12](=[O:13])[C@H:10]([CH3:11])[NH:9][C:7](=[O:8])[C@H:5]([CH3:6])[NH:4][C:1](=[O:3])[CH3:2])([CH3:44])[OH:43])[CH3:39]
Reactant: CCOC(=O)C(C)(O)C(=O)N(C)N
Reactant: CC(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)C(C)(O)C(=O)N(C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(C)=O
Temperature: 25 °C

Procedure:
Acetylalanylalanylleucine (1.5 mmole) and N-methylmorpholine (3 mmole) are dissolved in methylene chloride (10 ml) and diluted with dry tetrahydrofuran (250 ml) and cooled to -20° to -25°. Isobutyl chloroformate (1.5 mmole) is added with stirring and the mixture is stirred for 10 minutes. A solution of 2-azaalanyl-dl-lactic acid ethyl ester (1.5 mmole, Example 5, Step A) in tetrahydrofuran (3 ml) is added and the mixture is allowed to warm to room temperature over a period of 2 hours and stirred overnight. The precipitate is filtered off and the filtrate is evaporated to dryness. Chromatography on silica gel (25 gm) and elution with 12% methanol in chloroform gives acetylalanylalanylleucyl-2-azaalanyl-dl-lactic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([S:13]C(=O)C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].Cl>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([SH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)SC1CCN(C(=O)OC(C)(C)C)C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(S)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 116.4 %

Procedure:
To a 0° C. solution of (RS)-3-acetylsulfanyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.4 g, 5.07 mmol) in MeOH (15 ml) was added dropwise a suspension of sodium methoxide (0.61 g, 11.3 mmol) in MeOH. After 6 hours stirring at room temperature, the reaction mixture was neutralized with 1N HCl and MeOH was partially evaporated. H2O and ethylacetate were added. The aqueous phase was extracted with ethylacetate, the combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated to provide (RS)-3-mercapto-pyrrolidine-1-carboxylic acid tert-butyl ester (1.2 g, 100%) as a colorless oil, MS: m/e 130.1 (M-OtBu).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][C:6]=1[CH:7]([OH:12])[C:8]([O:10][CH3:11])=[O:9].Cl(O)(=O)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(OC(C)(C)C)(=O)C>[Br:1][C:2]1[S:3][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][C:6]=1[CH:7]([O:12][C:6]([CH3:7])([CH3:5])[CH3:2])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C(O)c1cc(-c2ccccc2)sc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: COC(=O)C(OC(C)(C)C)c1cc(-c2ccccc2)sc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 173.9 %

Procedure:
Methyl 2-(2-bromo-5-phenylthiophen-3-yl)-2-hydroxyacetate (11h) (75 mg, 0.23 mmol) was dissolved in tert-butyl acetate (8.6 mL) at 0° C. and 70% perchloric acid (1.1 mL) was rapidly added. The mixture was stirred at 0° C. for 30 minutes then poured in a saturated solution of potassium carbonate. Layers were separated. The aqueous layer was extracted with ethyl acetate (2×15 mL). The organic layers were washed with brine (8 mL), dried over sodium sulfate and concentrated in vacuo to provide the desired product (11i) (77 mg, 0.20 mmol, 87%) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:19]2[N:23]=[C:22]([C:24]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=3)=[O:25])[O:21][N:20]=2)[CH:5]=[C:6]([Cl:18])[C:7]=1[O:8]CC1C=CC(OC)=CC=1.[F:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][C:37]=1[C:45]([F:48])([F:47])[F:46].N1C=CC=CC=1>ClCCl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Cl:1][C:2]1[CH:3]=[C:4]([C:19]2[N:23]=[C:22]([C:24]([NH:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([O:34][C:39]4[CH:40]=[CH:41][C:36]([F:35])=[C:37]([C:45]([F:48])([F:47])[F:46])[CH:38]=4)=[CH:32][CH:33]=3)=[O:25])[O:21][N:20]=2)[CH:5]=[C:6]([Cl:18])[C:7]=1[OH:8]
Reactant: OB(O)c1ccc(F)c(C(F)(F)F)c1
Reactant: COc1ccc(COc2c(Cl)cc(-c3noc(C(=O)NCc4ccc(O)cc4)n3)cc2Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NCc1ccc(Oc2ccc(F)c(C(F)(F)F)c2)cc1)c1nc(-c2cc(Cl)c(O)c(Cl)c2)no1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.8 %

Procedure:
3-(3,5-Dichloro-4-(4-methoxybenzyloxy)phenyl)-N-(4-hydroxybenzyl)-1,2,4-oxadiazole-5-carboxamide (compound G, 60 mg, 0.12 mmol), 4-fluoro-3-(trifluoromethyl)phenylboronic acid (50 mg, 0.24 mmol), Cu(OAc)2 (44 mg, 0.24 mmol) and 3 Å powdered molecular sieves (70 mg) were stirred in an open tube in dichloromethane (3 mL). Pyridine (57 mg, 0.72 mmol) was added and the dark green suspension stirred vigorously at room temperature in an open tube for 1 d. The molecular sieves were filtered, washed with dichloromethane and the filtrate concentrated in vacuo. The residue was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (0.3 mL) was added. The dark solution was stirred at room temperature for 5 h, then methanol (1 mL) was added and the solution concentrated in vacuo. The residue was purified by preparative HPLC providing the title compound (46 mg, 0.085 mmol, 71%). 1H NMR δ (ppm) (DMSO-d6): 4.53 (2H, d, J=6.20 Hz), 7.06-7.13 (2H, m), 7.36-7.48 (4H, m), 7.53-7.60 (1H, m), 8.01 (2H, s), 10.03 (1H, t, J=6.20 Hz), 11.20 (1H, s). LCMS (10 cm_esci_Bicarb_MeCN) tR 3.48 min; m/z 540/542/544 [M−H]−.