Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4]CC1.CN(C=O)C.Cl>O>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH:8]2[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]2)=[CH:12]1
Reactant: c1ccc2c(C3CCC4(CC3)OCCO4)c[nH]c2c1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCC(c2c[nH]c3ccccc23)CC1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a 3-L, four-neck round bottom flask equipped with an overhead stirrer, temperature probe, addition funnel, was added 3-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-indole (as prepared in the previous step, 143.2 g, 0.56 mol) and DMF (190 mL). The suspension was heated to 50° C., and aqueous HCl (2M, 290 mL) was charged to the addition funnel and added dropwise and after about 5 mins, a precipitate formed. The reaction was stirred at 30° C. for 24 h. HPLC showed there was <2% of the acetal remaining. The suspension was chilled in an ice bath to 6° C., water (1.2 L) was added, and the suspension stirred at ambient temperature for 15 mins. The solid was filtered, washed with water (250 mL), and dried in a vacuum oven at 50° C. overnight. 1H NMR (400 MHz, CHLOROFORM-d) δ: 8.16 (br. s., 1H), 7.65 (d, J=7.6 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H), 7.15-7.26 (m, 1H), 7.08-7.16 (m, 1H), 6.95 (d, J=2.0 Hz, 1H), 3.33 (tt, J=3.3, 11.6 Hz, 1H), 2.28-2.66 (m, 6H), 1.88-2.06 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH3:12].C([Li])CCC.[C:18](=[O:20])=[O:19].O>O1CCCC1>[CH3:12][C:3]1[C:4]2[O:9][CH2:8][CH2:7][O:6][C:5]=2[CH:10]=[CH:11][C:2]=1[C:18]([OH:20])=[O:19]
Reactant: O=C=O
Reactant: Cc1c(Br)ccc2c1OCCO2
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)ccc2c1OCCO2
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 77 %

Procedure:
In 300 ml of dry tetrahydrofuran, was dissolved 32.0 g of 6-bromo-5-methyl-1,4-benzodioxane and after cooling the solution to -78° C., 96.7 ml of n-butyl lithium (n-hexane solution) was added dropwise over 20 minutes or more. After stirring at the same temperature for 1.5 hours, the reaction mixture was poured onto crushed dry ice and dry ice was sublimated while stirring. Water was added to the mixture and the tetrahydrofuran was removed under reduced pressure. The resulting alkaline aqueous solution was washed with methylene chloride and adjusted to pH 3 with a 5% hydrochloric acid, and the precipitated crystals were collected by filtration and dried to obtain 20.9 g of 5-methyl-1, 4-benzodioxan-6-carboxylic acid (yield: 77%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([CH:12]=[CH2:13])=[C:10]([S:14][CH3:15])[N:9]=[C:8]([NH2:16])[N:7]=1.[H][H]>C(O)C.[Pd]>[CH2:12]([C:11]1[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[N:7][C:8]([NH2:16])=[N:9][C:10]=1[S:14][CH3:15])[CH3:13]
Reactant: C=Cc1c(SC)nc(N)nc1-c1ccco1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCc1c(SC)nc(N)nc1-c1ccco1
Yield: 29.6 %

Procedure:
A solution of 200 mg (0.86 mmol) 4-furan-2-yl-6-methylsulfanyl-5-vinyl-pyrimidin-2-ylamine in 30 ml ethanol was stirred with a spatula end of 10% palladium on charcoal under 1 atm of hydrogen for 16 h at room temperature. After filtration to remove the catalyst, the reaction mixture was concentrated in vacuo and the residue triturated in ether/hexane to afford 60 mg (30%) 5-ethyl-4-furan-2-yl-6-methylsulfanyl-pyrimidin-2-ylamine as an off-white crystalline solid. ES-MS rn/e (%): 236 (M+H+, 100).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[C:11]=1[Cl:12].[CH3:13][C:14]1[N:19]=[C:18]([SH:20])[N:17]=[C:16]([OH:21])[CH:15]=1.C(N(CC)CC)C>C(O)C>[Cl:12][C:11]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[CH2:2][S:20][C:18]1[N:17]=[C:16]([OH:21])[CH:15]=[C:14]([CH3:13])[N:19]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Clc1c(CBr)nc2ccccn12
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2nc3ccccn3c2Cl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-(bromomethyl)-3-chloroimidazo[1,2-a]pyridine (1.07 g, 5.87 mmol) and 6-methyl-2-sulfanylpyrimidin-4-ol (0.539 g, 3.82 mmol) in anhydrous ethanol (30 mL) at 0° C. was added triethylamine (2.08 g, 2.86 mL, 20.57 mmol), and the reaction mixture was stirred overnight at room temperature. The solvent was evaporated to dryness, and water was added to precipitate the product. The crude product was purified by column chromatography using dichloromethane and methanol (0-10%) to provide 2-[({3-chloroimidazo[1,2-a]pyridin-2-yl}methyl)sulfanyl]-6-methylpyrimidin-4-ol; 1H NMR (400 MHz, DMSO-d6): δ 2.18 (s, 3H), 4.52 (s, 2H), 6.03 (bs, 1H), 7.07 (t, 1H), 7.35 (t, 1H), 7.59 (d, 1H), 8.30 (d, 1H); M+1 279.3.
Reaction SMILES: O=[C:2]1[C@@:19]2([CH3:20])[C:6]([NH:7][CH2:8][C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][CH2:13]2)=[CH:5][C:4](=[O:21])[CH:3]1CCC1CCCCC1.CC[O:32][CH2:33][CH3:34]>>[O:32]=[C:33]([C@H:13]1[CH2:12][CH2:11][C@H:10]2[C@H:9]3[C@H:18]([CH2:17][CH2:16][C@:14]12[CH3:15])[C@:19]1([CH3:20])[C:6](=[CH:5][C:4](=[O:21])[CH2:3][CH2:2]1)[NH:7][CH2:8]3)[CH2:34][CH:2]1[CH2:19][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C[C@@]12CCC[C@H]1[C@@H]1CNC3=CC(=O)C(CCC4CCCCC4)C(=O)[C@]3(C)[C@H]1CC2
Reactant: CCOCC
Product: C[C@]12CC[C@H]3[C@@H](CNC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)CC1CCCCC1

Procedure:
A solution of 17β-carboxy-6-t-butoxycarbonyl-6-azaandrost-4-en-3-one (260 mg, 0.62 mmol), example 1, part F, is dissolved in toluene (10 mL) and treated with pyridine (3 eq) and catalytic dimethylformamide, cooled to 0° C., and thionyl chloride added (80 mL, 1.10 mmol). The reaction is then allowed to warm to room temperature and stir for 1 hr. The solids are then removed by filtration, the solution concentrated, the resulting crude acrid chloride dissolved in THF (6 mL), Cul added (120 mg, 0.62 mmol), cooled to -78° C. and treated with methylenecyclo-hexylmagnesium bromide (2.0M in diethyl ether, 0.5 mL, 1 mmol). The reaction is allowed to warm to room temperature, stir for 30 min, is quenched with saturated NaHSO4, extracted with ethyl acetate (2×25 mL), dried over MgSO4, concentrated and chromatographed on silica gel (25% ethyl acetate/hexane) to give 17β-(1-oxo-2-(cyclohexylethyl))-6-t-butoxycarbonyl-6-azaan-drost-4-en-3-one; yield: 302 mg (98%). This material may be deprotected as described in example 1, part G above to give, on crystallization from ether, 17β-(1-oxo-2-(cyclohexylethyl)-6-azaandrost-4-en-3-one; yield: 121 mg (50%); m.p. 214°-216° C. Anal. Calcd. for C26H39 NO2. 1/2H2O; C, 76.80; H, 9.92; N, 3.44. Found: C, 76.61; H, 9.89; N, 3.49.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C@@H:5]1[NH:10][CH2:9][CH2:8][N:7]([C:11]2[C:20]3[N:19]=[C:18]([CH:21]([CH3:23])[CH3:22])[S:17][C:16]=3[NH:15][C:14]3[CH:24]=[CH:25][CH:26]=[CH:27][C:13]=3[N:12]=2)[CH2:6]1.C=O.[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(=O)(O)[O-].[Na+]>[CH3:1][O:2][CH2:3][CH2:4][C@@H:5]1[N:10]([CH3:30])[CH2:9][CH2:8][N:7]([C:11]2[C:20]3[N:19]=[C:18]([CH:21]([CH3:23])[CH3:22])[S:17][C:16]=3[NH:15][C:14]3[CH:24]=[CH:25][CH:26]=[CH:27][C:13]=3[N:12]=2)[CH2:6]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(C)C)nc32)CCN1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(C)C)nc32)CCN1C
Yield: 89.6 %

Procedure:
Combine (S)-10-[3-(2-methoxy-ethyl)-piperazin-1-yl]-2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.181 g, 0.469 mmol), formaldehyde (50 μL, 0.610 mmol, 37%), and sodium triacetoxyborohydride (0.149 g, 0.704 mmol) in dichloroethane (12 mL) and stir at room temperature for 2 hours. Dilute the mixture with saturated sodium bicarbonate and extract three times with methylene chloride. Combine the organic layers, dry over sodium sulfate and concentrate under reduced pressure to give the crude product. Purification by flash chromatography, eluting with a step gradient starting with dichloromethane going to 5% 2N ammonia-methanol in dichloromethane gives (S)-10-[3-(2-methoxy-ethyl)-4-methyl-piperazin-1-yl]-2 isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.168 g, 0.420 mmol, 90%) as a yellow oil: mass spectrum (APCI): m/z=400.3 (M+1). Isolate clean product as the corresponding dihydrochloride in the following manner: dissolve the yellow foam in ethanol (5 mL) and add a solution of about 5 equivalents of HCl in ethanol (5 mL). Evaporate the mixture to obtain the title compound as a brown foam. Exact Mass, Calc: 400.2171; Found: 400.2171.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].[Mg+2].[Br-].[Br-].C(N(CC)CC)C.[N:26]1[CH:31]=[CH:30][CH:29]=[N:28][C:27]=1[C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1>C1COCC1>[CH2:2]([O:3][C:4](=[O:5])/[C:6](/[F:7])=[CH:36]/[C:35]1[CH:34]=[CH:33][C:32]([C:27]2[N:26]=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:39][CH:38]=1)[CH3:1]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: O=Cc1ccc(-c2ncccn2)cc1
Agent: [Br-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)/C(F)=C/c1ccc(-c2ncccn2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
Triethyl 2-fluoro-2-phosphonoacetate (1.55 mL, 7.64 mmol) was added to a suspension of MgBr2 (1.68 g, 9.12 mmol) in THF (20 mL). The resulting mixture was cooled to 0° C., triethylamine (1.20 mL, 8.61 mmol) was added, and stirring was continued for 1 h at 0° C. A solution of 4-(2-pyrimidinyl)-benzaldehyde (1.00 g, 5.43 mmol, prepared as described in WO 9828264) in THF (10 mL) was aded via cannula and an additional amount of THF (5 mL) was used to rinse the transfer flask and cannula. The resulting mixture was stirred for 3 h at 0° C., quenched with 10% aq. ammonium chloride (5 mL), and concentrated to a small volume. The concentrate was diluted with ethyl acetate (50 mL), washed with 10% aq. ammonium chloride, sat. aq. NaHCO3, and brine (50 mL each), dried (MgSO4), and concentrated. Purification by chromatography (SiO2, 3:1 hexane/ethyl acetate) provided 1.27 g of the title compound as a 3:1 mixture with its E isomer. Recrystallization from 2-propanol provided 0.76 g (51%) of the title compound containing ca. 1% of the E isomer. MS 273 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[S:3]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][C:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH2:26][C:27]4[S:28][C:29]5[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:30]=5[N:31]=4)[CH:21]=3)[O:16][C:15]=2[CH3:37])[CH:8]=1)(=[O:5])=[O:4].CO>O1CCCC1.ClCCl>[F:39][C:2]([F:1])([F:38])[S:3]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][C@@H:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH2:26][C:27]4[S:28][C:29]5[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:30]=5[N:31]=4)[CH:21]=3)[O:16][C@H:15]2[CH3:37])[CH:8]=1)(=[O:5])=[O:4]
Reactant: Cc1oc2ccc(OCc3nc4cc(F)ccc4s3)cc2c(=O)c1Cc1cccc(NS(=O)(=O)C(F)(F)F)c1
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@@H]1Oc2ccc(OCc3nc4cc(F)ccc4s3)cc2C(=O)[C@H]1Cc1cccc(NS(=O)(=O)C(F)(F)F)c1
Reaction time: 2 h
Yield: 53.8 %

Procedure:
To a stirred suspension of 2.59 g (4.48 mmole) product from Example 127 in 100 mL tetrahydrofuran was added dropwise 9 mL (9.40 mmole) UB(sec-butyl)3H (1M in THF, L-Selectride®) at -78° C. The mixture was stirred for 2 hours, then quenched with 5% ammonium chloride. The mixture was poured into water, acidified to ph 1-4 with 1N HCl, and extracted with ethyl acetate. The ethyl acetate extract was washed with water and brine and dried (MgSO4) and concentrated to give an oil. Flash chromatography on silica gel eluting with 2.5% methanol in dichloromethane afforded 1.4 g (54%) of the title product as a solid, mp 183°-185° C. Analysis calculated for C26H20N2S2O5F4 : C, 53.79; H, 3.47; N, 4.83. Found: C, 53.25; H, 3.23; N, 4.45.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10](N)=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.N(OC(C)(C)C)=O.C(Br)(Br)[Br:20]>>[Br:20][C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=2)[NH:8][N:9]=1
Reactant: Nc1n[nH]c2ncc(F)cc12
Reactant: BrC(Br)Br
Agent: CC(C)(C)ON=O
Product: Fc1cnc2[nH]nc(Br)c2c1
Temperature: 61 °C

Procedure:
To the miture of 5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine, 3, (0.88 g, 5.79 mmol) in bromoform (8.8 mL) was added tert-butyl nitrite (1.38 mL, 11.57 mmol). This mixture was heated to 61° C. for 1 h and then heated to 90° C. for an additional hour. The mixture was cooled to room temperature and bromoform was removed under reduced pressure. The resulting crude residue was purified by silica gel chromatography (5-50% ethyl acetate/hexanes) to afford 970 mg of the desired product as a white solid: 1H NMR (300 MHz, DMSO) δ 14.22 (s, 1H), 8.67 (dd, J=2.7, 1.9 Hz, 1H), 8.07 (dd, J=8.2, 2.7 Hz, 1H); LC/MS Gradient 10-90%, 0.1% formic 5 min, C18/ACN, Retention Time=2.42 min, (M+H) 216.11.
Reaction SMILES: C(=O)(O)O.[NH2:5][NH:6][C:7]([NH2:9])=[NH:8].Cl.[OH:11][C@H:12]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@H:14]([CH2:15][CH2:16][C@@H:17]3[C@@H:29]2[CH2:28][CH2:27][C@@:26]2([CH3:34])[C@:18]3([OH:35])[CH2:19][CH2:20][C@@H:21]2/[CH:22]=[CH:23]/[CH:24]=O)[CH2:13]1>O.O1CCOCC1>[NH:6](/[N:5]=[CH:24]/[CH:23]=[CH:22]/[C@H:21]1[CH2:20][CH2:19][C@:18]2([OH:35])[C@H:17]3[C@H:29]([CH2:28][CH2:27][C@:26]12[CH3:34])[C@:30]1([CH3:33])[C@@H:14]([CH2:13][C@@H:12]([OH:11])[CH2:32][CH2:31]1)[CH2:15][CH2:16]3)[C:7]([NH2:9])=[NH:8]
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](/C=C/C=O)CC[C@]12O
Reactant: N=C(N)NN
Agent: Cl
Agent: O=C(O)O
Solvent: C1COCCO1
Solvent: O
Product: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](/C=C/C=N/NC(=N)N)CC[C@]12O
Yield: 65.4 %

Procedure:
A mixture of 1.05 g of aminoguanidine hydrogencarbonate in 23 ml of water and 70 ml of dioxane was made acid to pH 3 with 3N HCl. A solution of 2.08 g of (E)-3β,14β-dihydroxy-5β-pregn-20-ene-21-carboxaldehyde (Fullerton D. S. et al., J. Med. Chem., 1976, 19, 1330) in 20 ml of dioxane was added at room temperature. After 3 days the mixture was evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (SiO2) using chloroform/methanol/28% ammonium hydroxide 80/20/3 as the eluant; the fractions containing the title compound were collected and evaporated to dryness. The residue was ground with diethyl ether and ethanol to give 1.58 g of the title compound (I-aa) as a white solid.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[CH:16][C:17]4[C:23](=[O:24])[NH:22][C:21]5[CH:25]=[C:26]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:28][C:20]=5[NH:19][C:18]=4[CH:34]=3)=[CH:10][C:9]=2[O:35][CH3:36])=[CH:4][CH:3]=1.C(O)(=[O:39])C>O.C(OCC)(=O)C>[CH3:36][O:35][C:9]1[CH:10]=[C:11]([C:14]2[CH:15]=[CH:16][C:17]3[C:23](=[O:24])[NH:22][C:21]4[CH:25]=[C:26]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:28][C:20]=4[NH:19][C:18]=3[CH:34]=2)[CH:12]=[CH:13][C:8]=1[C:5]1[CH:4]=[CH:3][C:2](=[O:39])[NH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc2c(c1)NC(=O)c1ccc(-c3ccc(-c4ccc(F)nc4)c(OC)c3)cc1N2
Reactant: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)Cc1ccc2c(c1)NC(=O)c1ccc(-c3ccc(-c4ccc(=O)[nH]c4)c(OC)c3)cc1N2
Temperature: 25 °C
Yield: 13 %

Procedure:
A mixture of Example 656A (20 mg, 0.04 mmol) in acetic acid (1 mL) and water (200 μL) was heated at 100° C. overnight, cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered and concentrated. The concentrate was purified by preparative HPLC (2.5 mg, 13% yield). MS (ESI) m/e 482 (M+H)+; 1H NMR (400 MHz, DMSO-d.6 □ 11.67 (br s, 1H), 9.83 (s, 1H), 7.95 (s, 1H), 7.77 (d, J=8.1 Hz, 1H), 7.69 (dd, J=9.7, 2.5 Hz, 1H), 7.56 (m, 1H), 7.24-7.43 (m, 5H), 6.96 (d, J=8.1 Hz, 1H), 6.82-6.87 (m, 2H), 6.39 (d, J=9.2 Hz, 1H), 3.90 (s, 3H), 3.60 (s, 3H), 3.54 (s, 2H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]23[CH2:23][CH:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.F[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.[F-].[K+]>CN1CCCC1=O>[CH:21]1[C:22]2[C:9]3([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)[CH2:3][CH2:4]4)[CH2:23][CH:16]([C:15]4[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: Fc1ccccn1
Reactant: NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: c1ccc(NC2CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)nc1
Yield: 50 %

Procedure:
4-amino-1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-piperidine (0.305 g, 1.0 mmol, prepared as described in Example 8b), 2-fluoropyridine (0.117 g, 1.2 mmol), and anhydrous potassium fluoride (0.174 g, 3.0 mmol) were heated to 150° C. in 3 mL N-methylpyrrolidinone for 52 hours. The warm reaction mixture was added slowly to a rapidly stirring mixture of aqueous NaOH/ice/methanol to give a tan precipitate. The solid was collected and washed with water. The solid was dissolved in methanolic hydrogen chloride and concentrated to dryness several times from methanol to give the hydrochloride salt of the title compound as a white solid (0.239 g, 0.5 mmol, 50%), mp 270° C. (decomp); MS(CI): 382 (M+H); NMR (300 MHz, DMSO-d6): 10.27(br s, 1H), 7.95-7.85(m, 2H), 7.39-7.33(m, 5H), 7.04-6.96(m, 5H), 6.85(br m, 1H), 4.47(s, 1H), 4.41(s, 2H), 4.20-4.00(br m, 1H), 3.66-3.30(m, 4H), 2.76(s, 2H), 2.20-2.04(m, 4H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][CH:15]([C:19]([OH:21])=[O:20])[CH2:16]3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH:31][CH3:32])=[CH:26][CH:25]=1.[OH-].[Na+]>CN1C(=O)CCC1.O.Cl>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH3:32])[C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:18]=[C:17]4[C:12]([CH2:13][CH2:14][CH:15]([C:19]([OH:21])=[O:20])[CH2:16]4)=[CH:11][CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:26][CH:25]=1
Reactant: O=C(O)C1CCc2ccc(Oc3ccnc(Cl)c3)cc2C1
Reactant: CNCc1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(CN(C)c2cc(Oc3ccc4c(c3)CC(C(=O)O)CC4)ccn2)cc1
Temperature: 25 °C
Yield: 28.1 %

Procedure:
A solution of 7-[(2-chloropyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (1.50 g, 4.94 mmol) and 1-(4-methoxyphenyl)-N-methylmethanamine (2.24 g, 14.8 mmol) in NMP (9 mL) was heated in a sealed tube at 150° C. for 40 hr. The reaction mixture was allowed to cool to rt and diluted with water and 1N HCl solution. The pH was adjusted to 4 by the addition of 1N NaOH solution. The mixture was extracted with EtOAc (3×) and the organic solutions were combined, washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography to give 7-({2-[(4-methoxybenzyl)(methyl)amino]pyridin-4-yl}oxy)-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid as an off-white solid (581 mg, 28.1%). LCMS: (FA) ES+ 419.2, ES− 417.2.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([O:23][CH3:24])=[C:16]([O:25][CH3:26])[C:15]=2[O:27][CH3:28])=[CH:9][CH:8]=1)C.Cl>[OH-].[Na+].O1CCOCC1>[CH3:28][O:27][C:15]1[C:16]([O:25][CH3:26])=[C:17]([O:23][CH3:24])[C:18]([O:21][CH3:22])=[C:19]([CH3:20])[C:14]=1[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([OH:29])=[O:3])=[CH:8][CH:9]=1
Reactant: CCOC(=O)CCc1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1c(C)c(Cc2ccc(CCC(=O)O)cc2)c(OC)c(OC)c1OC
Temperature: 70 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
The compound (914 mg, 2.27 mmol) obtained in Step 5 was dissolved in a mixture of an aqueous solution of 2 N sodium hydroxide (30 ml) and 1,4-dioxane (15 ml) and the mixture was stirred at 70° C. for 3 hours. The reaction mixture was acidified by adding concentrated hydrochloric acid and then was extracted with ethyl acetate. The extract was washed with water, dried, and then the solvent was distilled off to yield the title compound (731 mg, 1.95 mmol, yield 86%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:13](=[O:33])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[C:25]([C:27]3[O:28][CH:29]=[CH:30][N:31]=3)[CH:24]=[CH:23][C:22]=2[CH3:32])=[CH:17][CH:16]=1)[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.FC(F)(F)C(O)=O.C(Cl)Cl.CO>C(Cl)Cl>[CH3:32][C:22]1[CH:23]=[CH:24][C:25]([C:27]2[O:28][CH:29]=[CH:30][N:31]=2)=[CH:26][C:21]=1[C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:13](=[O:33])[CH:8]([NH2:7])[CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:20][CH:19]=1
Reactant: Cc1ccc(-c2ncco2)cc1-c1ccc(NC(=O)C(CC(C)C)NC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cc1ccc(-c2ncco2)cc1-c1ccc(NC(=O)C(N)CC(C)C)cc1
Yield: 10.3 %

Procedure:
Into a 50 ml round bottom flask, was placed [3-Methyl-1-(2′-methyl-5′-oxazol-2-yl-biphenyl-4-ylcarbamoyl)-butyl]-carbamic acid tert-butyl ester (370 mg, 0.80 mmol) followed by the slow addition of a solution of 2,2,2-trifluoroacetic acid (3 ml) in DCM (7 ml) with stirring. The resulting solution was allowed to stir at rt for 4 hours. The reaction progress was monitored by TLC (CH2Cl2/MeOH=10:1). The mixture was then concentrated by evaporation under vacuum using a rotary evaporator. Adjustment of the pH to 7-8 was accomplished by the addition of aq NaHCO3 (sat.). The resulting solution was extracted three times with 10 ml of EtOAc and the organic layers combined and dried over Na2SO4 and concentrated by evaporation under vacuum using a rotary evaporator. The residue was triturated with 10 ml of n-Hexane to provide 30 mg (21%) of 2-Amino-4-methyl-pentanoic acid (2′-methyl-5′-oxazol-2-yl-biphenyl-4-yl)-amide as a white solid.
Reaction SMILES: [Br:1][CH2:2][C@@H:3]1[C@@H:7](O)[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.C(N(S(F)(F)[F:22])CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][CH2:2][C@@H:3]1[C@H:7]([F:22])[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](CBr)[C@@H](O)C1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](CBr)[C@H](F)C1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Process A: (3S,4R)-3-Bromomethyl-1-tert-butoxycarbonyl-4-hydroxypyrrolidine (1.97 g) was dissolved in dichloromethane (50 mL). While this solution was chilled in an ice water bath, diethylaminosulfur trifluoride (1.90 mL) was added dropwise and the mixture was stirred at room temperature for 19 hours. Subsequently, while the reaction mixture was chilled in an ice water bath, a saturated aqueous solution of sodium bicarbonate (40 mL) was added and the dichloromethane layer was separated. The dichloromethane layer was then washed sequentially with a saturated aqueous solution of sodium bicarbonate (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: hexane: ethyl acetate=2:1) to give (3S,4S)-3-bromomethyl-1-tert-butoxycarbonyl-4-fluoropyrrolidine as a yellow-brown tar (1.64 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pt]=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2ccc(Cl)c(Cl)c2)CC1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc(Cl)c(Cl)c2)CC1
Reaction time: 8 h
Yield: 102.9 %

Procedure:
Platinum oxide (0.3 g) was added to a solution of 1-(tert-butoxycarbonyl)-4-(3,4-dichlorobenzylidene)piperidine (29 g, 84.7 mmol) in ethyl acetate (500 ml) and the reaction mixture was stirred under a hydrogen atmosphere overnight. The reaction mixture was filtered through celite and the filtrate was concentrated to give 1-(tert-butoxycarbonyl)-4-(3,4-dichlorobenzyl)piperidine (30 g) as a tan oil.