Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(N2C3CCCC[C:12]=3[CH:11]=[C:10]2[C:18]2[CH:23]=CC=C[CH:19]=2)=CC=1.[CH:24](O)([CH3:26])[CH3:25]>[Pd]>[C:24]1([CH3:26])[CH:19]=[C:18]([CH3:23])[CH:10]=[C:11]([CH3:12])[CH:25]=1
Reactant: COc1ccc(-n2c(-c3ccccc3)cc3c2CCCC3)cc1
Reactant: CC(C)O
Agent: [Pd]
Product: Cc1cc(C)cc(C)c1

Procedure:
Following a procedure similar to that of Example 1D but using 63 g. of 1-(4-methoxyphenyl)-2-phenyl-4,5,6,7-tetrahydroindole and 18 g. of 10% palladium-on-charcoal in 600 ml. mesitylene (18 hours reflux) there was obtained, on recrystallization first from isopropyl alcohol and then from tetrahydrofuran-hexane, 58.5 g. of 1-(4-methoxyphenyl)-2-phenylindole; m.p. 141°-142°C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[C:11]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:12]C(O)=O.C[Mg]Br.C(N(CC)CC)C>S(Cl)(Cl)=O.O1CCCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8](=[O:10])[CH2:12][C:11]([O:17][CH2:18][CH3:19])=[O:16])=[N:6][CH:7]=1
Reactant: O=C(O)c1cnc(Cl)cn1
Reactant: CCOC(=O)CC(=O)O
Agent: C[Mg]Br
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cnc(Cl)cn1
Temperature: 0 °C
Yield: 53 %

Procedure:
5-Chloropyrazine-2-carboxylic acid (Intermediate 44, 21 g, 0.132 mol) was taken in thionyl chloride (100 mL) which was heated to reflux for 2 h and excess thionyl chloride was distilled off under reduced pressure to obtain a residue, which was dissolved in dry tetrahydrofuran (100 mL). In another round bottom flask ethyl hydrogen malonoate (15.8 g, 0.132 mol) was dissolved in tetrahydrofuran (500 mL) which was cooled to 0° C. To the resulting solution was added methyl magnesium bromide (88 mL, 0.265 M) and stirred the reaction mixture was stirred for 30 min before triethylamine (39.9 g, 0.396 M) was added. To this reaction mixture the above prepared acid chloride mixture was added, stirred for 2 h at room temperature and tetrahydrofuran was evaporated from the reaction mixture and the water (500 mL) was added and extracted with ethyl acetate (2×200 mL). The organic layers were combined and dried over anhydrous sodium sulphate, concentrated under reduced pressure to get obtain crude product which was purified by flash column chromatography (10% ethyl acetate/pet ether) to afford 16.0 g (53.16%) of ethyl 3-(5-chloropyrazin-2-yl)-3-oxopropanoate white solid.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:19][C@@H:20]([C@H:22]4[CH2:26][NH:25][C:24](=[O:27])[CH2:23]4)[CH3:21])=[N:10][C:11](C4C=CN=CC=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.[CH2:28]([O:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH3:29]>>[CH:1]1([N:4]2[C:8]3[C:9]([O:19][C@@H:20]([C@H:22]4[CH2:26][NH:25][C:24](=[O:27])[CH2:23]4)[CH3:21])=[N:10][C:11]([C:33]4[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:31]([O:30][CH2:28][CH3:29])[CH:32]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOc1cc(B(O)O)ccc1OC
Reactant: C[C@@H](Oc1nc(-c2ccncc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Product: CCOc1cc(-c2cc3ncn(C4CC4)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)ccc1OC
Yield: 32.5 %

Procedure:
Prepared by Suzuki coupling reaction procedure, as previously described for the synthesis of (R)-4-((R)-1-((3-cyclopropyl-6-(pyridin-4-yl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one:, using instead (3-ethoxy-4-methoxyphenyl)boronic acid (80.5 mg, 0.41 mmol) as a starting material to afford 38.8 mg (32.5%) of (R)-4-((R)-1-((3-cyclopropyl-6-(3-ethoxy-4-methoxyphenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one:. 1H NMR (300 MHz, DMSO-d6) δ 8.232 (s, 1H), 7.723 (s, 1H), 7.61 (d, J=8.7 Hz 2H), 7.545 (s, 1H), 7.00 (d, J=8.4 Hz, 1H). 5.51 (t, J=5.6 Hz, 1H), 4.1 (q, J=6.9 Hz, 2H), 3.77 (s, 3H), 3.65 (d, J=3.3 Hz, 1H), 3.39 (t, J=9 Hz, 1H), 3.29 (s, 2H) 3.20 (t, J=8 Hz, 1H), 2.84 (d, J=6 Hz, 1H), 2.32 (d, J=8.7 Hz, 2H), 1.414-1.342 (m, 6H), 1.088-1.032 (m, 4H). LCMS-ESI+ (m/z): [M+H]+ calcd for C24H28N4O4:436.21; found 437.18.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([O:7][CH2:18][CH3:19])=[O:6]
Reactant: COc1ccc(C(=O)O)cc1N
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(OC)c(N)c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
3-Amino-4-methoxybenzoic acid (3.34 g) was dissolved in ethanol (100 ml). Concentrated sulfuric acid (3 ml) was added to the solution, and the mixture was stirred at 65° C. overnight. The solvent was removed from the reaction solution by distillation under the reduced pressure, and the residue was adjusted to pH 7 by the addition of a saturated aqueous sodium carbonate solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give 3.50 g (89.4%) of ethyl 3-amino-4-methoxybenzoate.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH:15]([C@:18]1([C:24]([N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][C:30]([C:36]([F:39])([F:38])[F:37])=[CH:31][CH:32]=3)[CH2:27]2)=[O:25])[CH2:22][CH2:21][C@@H:20]([NH2:23])[CH2:19]1)([CH3:17])[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:15]([C@:18]1([C:24]([N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][C:30]([C:36]([F:39])([F:37])[F:38])=[CH:31][CH:32]=3)[CH2:27]2)=[O:25])[CH2:22][CH2:21][C@@H:20]([NH:23][CH:5]2[CH2:6][CH2:7][C:2]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)([OH:1])[CH2:3][CH2:4]2)[CH2:19]1)([CH3:17])[CH3:16]
Reactant: CC(C)[C@]1(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)CC[C@@H](N)C1
Reactant: O=C1CCC(O)(c2ccccn2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)[C@]1(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)CC[C@@H](NC2CCC(O)(c3ccccn3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-hydroxy-4-pyridin-2-yl-cyclohexanone (42.3 mg, 0.221 mmol) of step D-2 and (1R,3S)-3-isopropyl-3-{[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}cyclopentanamine (103 mg, 0.221 mmol) of Step C-2 in CH2Cl2(8 mL) was added sodium triacetoxyborohydride (200 mg, 1.0 mmol). After being stirred at room temperature overnight, the reaction was quenched with aqueous NaOH. The solution was extracted with CH2Cl2. The organic layer was concentrated in vacuo. The residue was purified via HPLC to provide two diastereomers. Isomer 1: LCMS calculated for C30H38F3N3O2: (M+H)+530; found 530.1. Isomer 2: MS found 530.1.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[NH:4][C:5](=[S:13])[N:6]([CH2:9][CH2:10][O:11][CH3:12])[C:7]=1[NH2:8].[CH:15](O)=O>>[CH3:12][O:11][CH2:10][CH2:9][N:6]1[C:7]2[N:8]=[CH:15][NH:1][C:2]=2[C:3](=[O:14])[NH:4][C:5]1=[S:13]
Reactant: O=CO
Reactant: COCCn1c(N)c(N)c(=O)[nH]c1=S
Product: COCCn1c(=S)[nH]c(=O)c2[nH]cnc21
Temperature: 90 °C

Procedure:
5,6-Diamino-1-(2-methoxy-ethyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.27 g, 1.3 mmol) was suspended in formic acid (2 mL) and this solution was heated at 90° C. for 1.5 h. Excess formic acid was evaporated off under reduced pressure. 10% Sodium hydroxide solution (5 mL) was added to the orange solid and the resulting solution was heated at 90° C. for 2 h. The reaction mixture was neutralized with dilute acetic acid. The resulting solution was put in the fridge for several days, then the orange needle-like crystals that had formed were collected by filtration and washed with water. Yield: (0.11 g, 40%).
Reaction SMILES: F[C:2]([C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]=1[C:15]([O:17][CH3:18])=[O:16])=[O:3].O/[N:20]=[C:21](/[C:23]1[CH:40]=[CH:39][C:26]([CH2:27][N:28]2[CH2:31][CH:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]2)=[CH:25][CH:24]=1)\[NH2:22].C(N(C(C)C)CC)(C)C>C(#N)C>[C:35]([O:34][C:32]([CH:30]1[CH2:31][N:28]([CH2:27][C:26]2[CH:39]=[CH:40][C:23]([C:21]3[N:22]=[C:2]([C:4]4[O:8][N:7]=[C:6]([C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=5)[C:5]=4[C:15]([O:17][CH3:18])=[O:16])[O:3][N:20]=3)=[CH:24][CH:25]=2)[CH2:29]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: COC(=O)c1c(-c2ccccc2)noc1C(=O)F
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2)C1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(-c2ccccc2)noc1-c1nc(-c2ccc(CN3CC(C(=O)OC(C)(C)C)C3)cc2)no1
Temperature: 25 °C
Yield: 62.5 %

Procedure:
To a mixture of methyl 5-(fluorocarbonyl)-3-phenylisoxazole-4-carboxylate (99 mg, 0.397 mmol) and (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (121 mg, 0.397 mmol) in acetonitrile (2 mL) at rt was added diisopropylethylamine (0.083 mL, 0.477 mmol) and the reaction mixture was allowed to stir at rt over the weekend. The reaction mixture was partitioned between EtOAc (30 mL) and water (30 mL). The organic layer was washed with brine (20 mL), dried (MgSO4) and concentrated to afford a white solid that was chromatographed on a 12 gm Isco silica gel cartridge, eluting with a 0-100% EtOAc/Hex gradient. The essentially pure fractions containing product were concentrated to afford methyl 5-(3-(4-((3-(tert-butoxycarbonyl)azetidin-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)-3-phenylisoxazole-4-carboxylate (128 mg, 0.248 mmol, 62.4% yield) as a white solid. HPLC retention time=1.78 minutes (YMC Combi 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1 TFA a 2 minute gradient. MS: (M+H)=517.22. 1H NMR (400 MHz, chloroform-d) d ppm 1.45 (s, 9H) 3.23-3.32 (m, 3H) 3.51-3.58 (m, 2H) 3.68 (s, 2H) 3.95 (s, 3H) 7.44 (d, J=8.0 Hz, 2H) 7.48-7.56 (m, 3H) 7.75 (dd, J=7.91, 1.63 Hz, 2H) 8.11 (d, J=8.3 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][NH:11]2)=[CH:4][C:3]=1[CH:15]=[CH:16][CH:17]=[CH:18][C:19]([CH3:22])([CH3:21])[CH3:20].C=O.[C:25]([BH3-])#N.[Na+].C(O)(=O)C>CCO>[ClH:1].[ClH:1].[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:25])=[CH:4][C:3]=1[CH:15]=[CH:16][CH:17]=[CH:18][C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: [BH3-]C#N
Reactant: CC(C)(C)C=CC=Cc1cc(OC[C@@H]2CCCN2)cnc1Cl
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CN1CCC[C@H]1COc1cnc(Cl)c(C=CC=CC(C)(C)C)c1
Product: Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 276.8 %

Procedure:
To a solution of 6-chloro-5-(5,5-dimethyl-1,3-hexadienyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine from Example 148a (150 mg, 0.38 mmol) in EtOH (3.0 mL) was added formalin (37%, 5 mL), sodium cyanoborohydride (120 mg, 1.9 mmol) and acetic acid (0.1 mL), and the mixture was stirred at 25° C. for 16 h. The solvent was concentrated, and solid NaHCO3 was added to the residue. At pH 8 the mixture was extracted with EtOAc, which was dried (MgSO4) and concentrated. The residue was converted to the salt by treatment with hydrogen chloride in Et2O/THF to afford the title compound (143 mg, 100%): mp 220-220° C.;. 1H NMR (CD3OD) δ 1.10 (s, 9H), 2.08-2.18 (m, 2H), 2.23 (m, 1H), 2.41 (m, 1H), 3.08 (s, 3H), 3.23 (m, 111), 3.75 (m, 1H), 3.92 (m, 1H), 4.35 (dd, 1H, J=5.5, 11.5 Hz), 4.53 (dd, 1H, J=3.5, 10.5 Hz), 6.05 (d, 1H, J=15.5 Hz), 6.28 (dd, 1H, J=9.5, 15.5 Hz), 6.73 (d, 1H, J=16.0 Hz), 7.00 (dd, 1H, J=10, 15.5 Hz), 7.75 (d, 1H, J=3.0 Hz), 8.00 (d, 1H, J=3.0 Hz); MS (CI/NH3) m/z 335 (M+H+), 669 (2M+H)+. Anal. Calcd for C19H27ClN2O.1.1 HCl.0.5 H2O: C, 59.43; H, 7.64; N, 7.30. Found: C, 59.55; H, 7.69; N, 7.36. [α]25D −4.5 (c 0.44, MeOH).
Reaction SMILES: [CH3:1][CH:2]1[NH:6][C:5](=O)[CH2:4][CH2:3]1.[F:8][C:9]([F:25])([F:24])[C:10]1[CH:23]=[CH:22][C:21]2[S:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH:11]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>CCOCC.C1(C)C(C)=CC=CC=1>[CH3:1][CH:2]1[N:6]([C:5]2[CH2:4][CH2:3][CH:2]([CH3:1])[N:6]=2)[C:5]([N:13]2[C:12]3[CH:11]=[C:10]([C:9]([F:8])([F:24])[F:25])[CH:23]=[CH:22][C:21]=3[S:20][C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:4][CH2:3]1
Reactant: FC(F)(F)c1ccc2c(c1)Nc1ccccc1S2
Reactant: CC1CCC(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: Cc1ccccc1C
Solvent: O=P(Cl)(Cl)Cl
Product: CC1CCC(N2C(N3c4ccccc4Sc4ccc(C(F)(F)F)cc43)=CCC2C)=N1
Reaction time: 1.5 h

Procedure:
A solution of 5-methyl-2-pyrrolidinone (19.8 g., 0.2 mole) in 25 ml. of xylene is added drop-wise to a mixture of 2-trifluoromethylphenothiazine (26.7 g., 0.1 mole) and phosphorus oxychloride (15.3 g., 0.1 mole) in 125 ml. of refluxing xylene in a two hour period. When the addition is complete, refluxing is continued for an additional 1.5 hr., the reaction mixture poured into 75 ml. of 5 N sodium hydroxide and 75 g. of crushed ice, and, after mixing well, the xylene fraction is separated. The xylene fraction is seqentially extracted with 100 ml. of 1.5 HCl followed by 100 ml. of water and then made basic by stirring with 5 N sodium hydroxide solution. Separation of the basified xylene fraction which is dried over magnesium sulfate and concentrated under reduced pressure provides a residue which is taken up in 50 ml. of benzene and the solution then concentrated. An additional 100 ml. portion of benzene is added to the residue thus obtained and the solution partially concentrated until crystals begin to form. After cooling and standing, the mixture is filtered to remove recovered 2-trifluoromethylphenothiazine starting material. Concentration of the filtrate affords a residual material which is taken up in ether, extracted with 1.5 N hydrochloric acid and then with 50 ml. of water. The combined acid-aqueous extracts are made basic with sodium hydroxide and the mixture extracted with ether. The ethereal extract is dried over magnesium sulfate, filtered, anc concentrated. Distillation of the residual oil through a 6 cm. column provides 10-[5-methyl-1-(5-methyl-1-pyrrolin-2-yl)-2-pyrrolin-2-yl]-2-(trifluoromethyl)phenothiazine free base, b.p. 175°-185° C./0.15 mm. Hg. The bis-pyrrolinyl phenothiazine free base is taken up in ethanol and acidified with ethanolic hydrogen chloride. Addition of ether provides the hydrochloride salt which crystallized from ethanol affords analytically pure 10-[5-METHYL-1-(5-METHYL-1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]-2-(TRIFLUOROMETHYL)PHENOTHIAZINE HYDROCHLORIDE, m.p. 250°-253° C. (dec.)(corr.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C@@H:6]([NH:13][C:14]1[C:19]([NH2:20])=[CH:18][N:17]=[C:16]([CH3:21])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].C1N=CN([C:28](N2C=NC=C2)=[O:29])C=1>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C@@H:6]([N:13]1[C:14]2[CH:15]=[C:16]([CH3:21])[N:17]=[CH:18][C:19]=2[NH:20][C:28]1=[O:29])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)C[C@@H](Nc1cc(C)ncc1N)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H](c1ccccc1)n1c(=O)[nH]c2cnc(C)cc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.1 %

Procedure:
To a solution of (R)-3-(5-amino-2-methyl-pyridin-4-ylamino)-3-phenyl-propionic acid ethyl ester (594 mg, 1.98 mmol) in THF (20 mL) was added CDI (483 mg, 2.98 mmol). The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 95:5 CH2Cl2:MeOH as an eluent to afford 484 mg (75%) of the title compound as light brown solid. LCMS, M++1, m/z: 326.85.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](C#C)([F:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=1.[CH2:25](NCC)[CH3:26]>[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([F:14])[CH2:12][CH:13]1[C:25]#[C:26][C:21]1[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C#CC1(F)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCNCC
Reactant: Fc1ccc(I)cc1
Agent: [Cu]I
Product: CC(C)(C)OC(=O)N1CCC(F)CC1C#Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A mixture of 1-tert-butoxycarbonyl-4-ethynyl-4-fluoropiperidine (1 g, 4.4 mmol) and 4-fluoroiodobenzene (610 μl, 5.3 mmol) in N,N-diethylamine (20 ml) was flushed with nitrogen for 15 mins, then palladium bis(tiphenylphosphine)chloride (150 mg, 0.2 mmol) and copper (I) iodide (42 mg, 0.2 mmol) added. The mixture was stirred at room temperature under an atmosphere of nitrogen for 2 hours, then evaporated. The residue was treated with water (50 ml) and extracted with diethyl ether (3×25 ml). The combined organic solutions were washed with water (1×50 ml), brine (1×20 ml), dried (MgSO4) and concentrated. Flash chromatography of the residue (silica gel, ethyl acetate-hexane 1:9) gave 1.3 g (80%) of the title compound: δH (360 MHz, CDCl3) 1.47 (9H, s), 2.01-2.08 (4H, m), 3.51-3.64 (4H, m), 7.00-7.05 (2H, m), 7.42-7.46 (2H, m).
Reaction SMILES: B(C1CCCCC1)C1CCCCC1.[CH3:14][C:15]([CH3:19])([CH3:18])[C:16]#[CH:17].[Zn](CC)CC.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:33]=[CH:32][C:29]([C@@H:30]([OH:31])[CH:17]=[CH:16][C:15]([CH3:19])([CH3:18])[CH3:14])=[CH:28][CH:27]=1
Reactant: C#CC(C)(C)C
Reactant: O=Cc1ccc(F)cc1
Agent: B(C1CCCCC1)C1CCCCC1
Agent: CC[Zn]CC
Product: CC(C)(C)C=C[C@H](O)c1ccc(F)cc1
Yield: 82 %

Procedure:
The product was prepared by General procedure S using 98 mg (0.55 mmol) Cy2BH, 68 μL (0.55 mmol) 3,3-dimethyl-1-butyne, 0.55 mL (1.1 mmol, 2.0 M in hexanes) Et2Zn, 4.8 mg (0.02 mmol) (−)-MIB, and 54 μL (0.50 mmol) p-fluorobenzaldehyde. The crude product was purified by column chromatography (5% ethyl acetate in hexanes) to afford the title compound as a white solid in 82% yield (85 mg, 0.41 mmol). m.p.: 38-40° C.; [α]D20=+21.3 (c=1.2, CHCl3, 93% ee); 1H NMR (CDCl3, 500 MHz): δ 1.01 (s, 9H), 1.84 (br s, 1H), 5.13 (d, 1H, J=6.9 Hz), 5.52 (dd, 1H, J=15.6, 6.9 Hz), 5.77 (d, 1H, J=15.6 Hz), 7.01 (t, 2H, J=8.7 Hz), and 7.31 (dd, 2H, J=8.3, 5.6 Hz) ppm; 13C{1H} NMR (CDCl3, 125 MHz): δ 29.4, 32.9, 74.7, 115.1, 115.3, 127.1, 127.77, 127.83, 139.18, 139.20, 143.7, 161.1, and 163.1 ppm; IR (film): 3344, 3025, 2959, 2866, 1725, 1661, 1604, 1509, 1463, 1363, 1294, 1225, and 1156 cm−1; HRMS-CI m/z 208.1267 [M+; calcd for C13H17FO: 208.1263].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12](=[O:23])OC2C=CC([N+]([O-])=O)=CC=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:24][C@H:25]([C:29]([OH:31])=[O:30])[CH:26]([CH3:28])[CH3:27].C(N(CC)CC)C.C(O)C>O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][O:11][C:12]([NH:24][C@H:25]([C:29]([OH:31])=[O:30])[CH:26]([CH3:28])[CH3:27])=[O:23])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)[C@H](NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)O
Yield: 35.7 %

Procedure:
The title compound is prepared by the procedure of Example 255 using 14.73 g of product from Example 254, 5.42 g of L-valine, 12.75 ml of triethylamine and 556 ml of 4:1 ethyl alcohol:water to give 4.89 g of the desired product after chromatography.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.C([Li])CCC.[CH2:13]1[O:15][CH2:14]1>O1CCCC1>[CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:13][CH2:14][OH:15])[O:4][N:3]=1
Reactant: C1CO1
Reactant: Cc1cc(C)on1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(CCCO)on1
Temperature: -75 °C
Yield: 45.9 %

Procedure:
3,5-Dimethylisoxazole (220 g, 2.27 moles) in 2.2 L tetrahydrofuran under nitrogen was cooled with stirring to -75° C. and 908 mL of 2.5M n-butyllithium (2.27 moles) in hexanes were added over 1 hour keeping the temperature at or less than 65° C. The chilled solution was stirred for thirty minutes after addition was complete and was then treated at about -70° C. with a solution of 112 g (2.54 moles) of ethylene oxide in 390 ml tetrahydrofuran over a period of 1.5 hours, keeping the temperature at about -65° C. and stirred overnight. The mixture at 8° C. was quenched with continued cooling in an 8° C. bath by adding 1.2 L of 2.5M hydrochloric acid over a period of 20 minutes, during which time the temperature rose to 23° C., and was stirred for 10 minutes. The organic phase was separated, washed with 500 ml of water and concentrated to give 147 g of title compound as a brown oil. The combined aqueous phases (original+wash phase) were extracted with methyl tert-butyl ether (3×200 ml) and the combined organic extracts were concentrated to give an additional 125 g of title compound as a brown oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)[C:13]1=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)[Cl:33].Cl.O1CCOCC1>CO>[ClH:33].[O:31]=[C:13]1[C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16][CH2:15][N:14]1[CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H](NC(=O)OCc3ccccc3)C2=O)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(N[C@H]1CCCN(C2CCNCC2)C1=O)OCc1ccccc1
Reaction time: 8 h
Yield: 100 %

Procedure:
A flask was charged with (S)-tert-butyl 3-(benzyloxycarbonylamino)-2-oxo-1,4′-bipiperidine-1′-carboxylate (Example 39, Steps A-B; 5.0 g, 12 mmol), CH2Cl2 (50 mL), and methanol (5 mL), 4N HCl in dioxane (29 mL, 116 mmol) was added and the reaction stirred overnight. The reaction was concentrated to afford crude (S)-benzyl 2-oxo-1,4′-bipiperidin-3-ylcarbamate hydrochloride (4.3 g, 100%) which was taken forward without further purification.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1>C([O-])(O)=O.[Na+].C(OCC)C.O>[Cl:11][C:12]1[CH:13]=[C:14]([S:18]([O:5][C:4]2[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=2)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(O)cc(OS(=O)(=O)c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
Orcinol monohydrate (1.42 g, 10.0 mmol) and 3-chlorobenzenesulfonyl chloride (2.21 g, 10.0 mmol) were mixed in saturated aqueous NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 2% ethyl acetate in dichloromethane) to give the title compound as a pale yellow oil (2.08 g, 69%). 1H-NMR (300 MHz, CDCl3) δ 7.86 (s, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.48 (t, J=8.0 Hz, 1H), 6.57 (s, 1H), 6.40 (s, 1H), 6.33 (s, 1H), 5.32 (s, 1H), 2.24 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[CH3:12].[CH3:13]OC(N(C)C)OC>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]2[C:3]=1[CH:12]=[CH:13][NH:9]2
Reactant: Cc1c(Br)cc(F)cc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Fc1cc(Br)c2cc[nH]c2c1
Yield: 36.1 %

Procedure:
1-Bromo-5-fluoro-2-methyl-3-nitrobenzene (2.00 g, 8.55 mmol) and (dimethoxymethyl)dimethylamine (5.66 mL, 42.7 mmol) in dry DMF (20 mL) was refluxed under N2 for 8 h, then rt. over night. The mixture was diluted with DCM and extracted 5 times with water. The organic layer was dried, filtered and concentrated under reduced pressure. The residue was dissolved in AcOH (10 mL) and added drop wise to a boiling mixture of Fe(s, fine powder) in AcOH (10 mL). The mixture was refluxed for 40 min., partitioned between DCM and saturated aq. Na2CO3/brine (the mixture was filtered through celite before phase separation). The water layer was extracted once more with DCM. The organic layers were combined, dried and concentrated. Purification was performed by flash column chromatography (DCM/hexane 1:3) and afforded the title compound (660 mg, 39%) as a yellow oil. MS (ESI+) for C8H5BrFN m/z 214 (M+H)+.