Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([N:11]2[CH2:16][C:15]3([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[O:14][CH2:13][CH2:12]2)=[O:10])[N:8]=1)([CH3:3])[CH3:2].FC(F)(F)C([O-])=O.[C:29]([O:32][CH2:33][CH2:34][C:35]1[S:36][CH:37]=[C:38]([CH2:40][CH2:41]OS(C)(=O)=O)[CH:39]=1)(=[O:31])[CH3:30]>>[C:29]([O:32][CH2:33][CH2:34][C:35]1[S:36][CH:37]=[C:38]([CH2:40][CH2:41][N:19]2[CH2:18][CH2:17][C:15]3([O:14][CH2:13][CH2:12][N:11]([C:9]([C:7]4[N:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[S:5][CH:6]=4)=[O:10])[CH2:16]3)[CH2:21][CH2:20]2)[CH:39]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)OCCc1cc(CCOS(C)(=O)=O)cs1
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Agent: O=C([O-])C(F)(F)F
Product: CC(=O)OCCc1cc(CCN2CCC3(CC2)CN(C(=O)c2csc(C(C)C)n2)CCO3)cs1

Procedure:
Prepared by the method of Example 1, step c using the hydrochloride salt of (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone [Example 27, step a] (1 g) in place of its trifluoroacetate salt, and 2-(4-(2-(methylsulfonyloxy)ethyl)thiophen-2-yl)ethyl acetate [Aromatic Intermediate 21] (0.8 g) in place of 4-(2-hydroxyethyl)phenethyl methanesulfonate. Yield 1 g.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].S(=O)(=O)(O)O>>[C:12]([O:11][C:4]1[CH:3]=[C:2]([Br:1])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])(=[O:14])[CH3:13]
Reactant: O=C(O)c1ccc(Br)cc1O
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)Oc1cc(Br)ccc1C(=O)O
Temperature: 100 °C

Procedure:
A mixture of 4-bromo-2-hydroxy-benzoic acid (12.35 g, 56.91 mmol), acetic anhydride (35.6 mL) and conc sulfuric acid (0.93 mL) was heated at 100° C. for 1 h; then cooled, poured into 400 g ice/water, stirred for several minutes, the white precipitates were collected with filtration, washed with water, then the white solids were oven vacuum dried at 50° C. for 3 days to give the desired product (11.62 g). 1H NMR (200 MHz, CDCl3): δ (ppm)=7.95 (d, 1H, J=8.5 Hz), 7.48 (dd, 1H, J=2.0 Hz, 8.5 Hz), 7.32 (d, 1H, J=2.0 Hz).
Reaction SMILES: [CH:1]([CH2:3][O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[CH:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1)=[O:2].[BH4-].[Na+].O>CO>[OH:2][CH2:1][CH2:3][O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[CH:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1
Reactant: C[C@]12CC[C@H](OCC=O)CC1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@]12CC[C@H](OCCO)CC1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 87 %

Procedure:
To a solution of 4.0 g of 3β-formylmethoxy-androstan-17-one in 50 ml of methanol 0.60 g of sodium borohydride were added slowly at -78° C. After 1/2 hr 20 ml of water were added, the methanol was distilled under reduced pressure, and the mixture was extracted with methylene chloride; the organic layer was washed with water, dried over sodium sulfate and evaporated to dryness under reduced pressure. The crude product was purified by flash-chromatography (SiO2) using n-hexane/ethyl acetate 80/20 as eluant to give 3.5 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:14]1[C:23]2[C:22](=[O:24])[N:21]([CH3:25])[CH:20]=[N:19][C:18]=2[CH:17]=[C:16]([Cl:26])[N:15]=1>CN(C=O)C>[Cl:26][C:16]1[N:15]=[C:14]([O:8][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:23]2[C:22](=[O:24])[N:21]([CH3:25])[CH:20]=[N:19][C:18]=2[CH:17]=1
Reactant: COc1ccc(CO)cc1
Reactant: Cn1cnc2cc(Cl)nc(Cl)c2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2nc(Cl)cc3ncn(C)c(=O)c23)cc1
Temperature: 80 °C

Procedure:
To a solution of 4-methoxybenzylalcohol (596 μL, 4.78 mmol) in anhydrous DMF (20 mL) was added NaH (208 mg, 60% dispersion in mineral oil, 5.20 mmol) at 0° C. The mixture was stirred at 0° C. for 10 minutes before 5,7-dichloro-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one (1.00 g, 4.35 mmol) was slowly added. The resulting mixture was heated at 80° C. overnight, cooled down, quenched with H2O (200 mL), and extracted with EtOAc (3×100 mL). The combined organic layer was dried over MgSO4 and evaporated under reduced pressure to afford crude 7-chloro-5-(4-methoxybenzyloxy)-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][Cl:17])=[CH:11][CH:10]=1.[C:26](Cl)(=O)[CH2:27][CH3:28]>>[C:22]([NH:21][S:18]([C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:9]3[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][Cl:17])=[CH:13][CH:14]=3)[C:26]([CH2:27][CH3:28])=[N:1][C:2]=2[CH:3]=1)(=[O:19])=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CCC(=O)Cl
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Nc2ccc(CCCl)cc2)c(N)c1
Product: CCc1nc2cc(S(=O)(=O)NC(C)(C)C)ccc2n1-c1ccc(CCCl)cc1

Procedure:
The title compound was prepared according to the procedure described in step 5 Example 1 from 3-amino-N-(tert-butyl)-4-[4-(2-chloroethyl)anilino]benzenesulfonamide (step 4) and propionyl chloride.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][NH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:20][CH2:21][C@@:22]([CH3:32])([S:28]([CH3:31])(=[O:30])=[O:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C1COCC1>[CH3:32][C@@:22]([S:28]([CH3:31])(=[O:29])=[O:30])([CH2:21][CH2:20][N:4]1[CH:5]=[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:2]([CH3:1])=[N:3]1)[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: Cc1n[nH]cc1-c1ccccc1
Reactant: CCOC(=O)[C@@](C)(CCBr)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@](C)(CCn1cc(-c2ccccc2)c(C)n1)S(C)(=O)=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 19.3 %

Procedure:
To a solution of the 3-methyl-4-phenylpyrazole (400 mg, 2.53 mmol, 1 eq) in THF (25 mL) was added cesium carbonate (2.52 g, 7.70 mmol, 3 eq) and (R)-ethyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate (950 mg, 3.31 mmol, 1.3 eq). The resulting suspension was heated to 70° C. and stirred overnight. The reaction was filtered through celite, and the filter pad was washed with ethyl acetate (2×100 mL). Combined filtrates were concentrated and the crude material was purified on a Analogix SF15-24 g column using an eluant of ethyl acetate in heptane (0-80%) to give ethyl (2R)-2-methyl-4-(3-methyl-4-phenyl-1H-pyrazol-1-yl)-2-(methylsulfonyl)butanoate (178 mg, 19.3%). LC-MS M+H+365.1.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[N:4][CH:5]=[C:6]([CH:17]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[OH:16])=[O:8]>CCCCCCC.C(O)(C)C>[Br:1][C:2]1[C:3]([O:18][CH2:19][C:20]([F:22])([F:23])[F:21])=[N:4][CH:5]=[C:6]([CH:17]=1)[C:7]([NH:9][C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16])=[O:8]
Reactant: O=C(NC1CCCCC1O)c1cnc(OCC(F)(F)F)c(Br)c1
Solvent: CC(C)O
Solvent: CCCCCCC
Product: O=C(N[C@H]1CCCC[C@H]1O)c1cnc(OCC(F)(F)F)c(Br)c1
Yield: 47.7 %

Procedure:
5-Bromo-N-((1SR,2RS)-2-hydroxy-cyclohexyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinamide (91.3 g, 0.23 mol) was submitted to preparative HPLC on ChiralPak AD® (250×110 mm column) using n-heptane/isopropanol 85/15 as mobile phase. Baseline separation was achieved and the title compound (43.6 g) was isolated as colorless solid from the first peak; MS (ISP) 395.2, 397.2 (M−H); ORD (589 nM, 20° C., CHCl3) −21.6°.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([OH:15])=[C:7](C(OCC)=O)[C:6]1=[O:21])[CH2:2][CH2:3][CH3:4].Cl>[OH-].[Na+]>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([OH:15])=[CH:7][C:6]1=[O:21])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(C(=O)OCC)c(O)c2cccnc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCn1c(=O)cc(O)c2cccnc21
Temperature: 11 °C
Yield: 101.4 %

Procedure:
A slurry of the product of Example 89A (3.24 g, 11.16 mmol) in 2 N sodium hydroxide (100 mL) was heated at reflux for 3 hours, cooled to 11° C. and treated dropwise with concentrated hydrochloric acid to a constant pH of 3. The resulting white solid was collected by filtration, washed with water and dried to give the title compound (2.47 g, quantitative). MS (APCI+) m/z 219 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (t, J=7.35 Hz, 3 H) 1.32 (m, 2 H) 1.57 (m, 2 H) 4.31 (m, 2 H) 5.89 (s, 1 H) 7.27 (dd, J=7.72, 4.78 Hz, 1 H) 8.23 (dd, J=7.72, 1.84 Hz, 1 H) 8.64 (dd, J=4.78, 1.84 Hz, 1 H) 11.61 (s, 1 H).
Reaction SMILES: [S:1]([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)([O:4][CH2:5][CH:6]([OH:9])[CH2:7][OH:8])(=[O:3])=[O:2].[CH3:17][O:18][C:19]1[CH:40]=[CH:39][C:22]([C:23](Cl)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[CH:21][CH:20]=1.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[S:1]([O:4][CH2:5][CH:6]([CH2:7][O:8][C:23]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[C:22]1[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:40][CH:39]=1)[OH:9])([C:10]1[CH:11]=[CH:12][C:13]([CH3:14])=[CH:15][CH:16]=1)(=[O:2])=[O:3]
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC(O)CO)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc(C(OCC(O)COS(=O)(=O)c2ccc(C)cc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 65.9 %

Procedure:
(±)-2,3-Dihydroxypropyl tosylate (IV) (525 mg, 2.13 mmol, 1 eq.) was dissolved in pyridine (20 mL, anhydrous) and cooled to 0° C. 4,4′-Dimethoxytrityl chloride (758 mg, 2.24 mmol, 1.05 eq.) was added in 3 portions over 2 h and the reaction solution was allowed to warm up to rt. After 2 h, sat. aq. NaHCO3 (75 mL) was added to the reaction mixture, followed by extraction with CH2Cl2 (3×75 mL). The extract was dried with Na2SO4, filtered, concentrated in vacuo and dried by coevaporation with toluene (3×). Purification by flash column chromatography (SiO2, 1:2:97 NEt3/Et2O/CH2Cl2) gave V as a white powder (770.6 mg, 66%). 1H NMR (300 MHz, CD2Cl2/D2O): δ=7.74 (d, J=8.4 Hz, 2H, arom.), 7.36-7.21 (m, 11H, arom.), 6.82 (d, J=5.1 Hz, 4H, arom.), 4.10-3.98 (m, 2H, CH2OTs), 3.92-3.89 (m, 1H, CHOH), 3.78 (s, 6H, OCH3), 3.13-3.11 (m, 2H, CH2ODMT), 2.44 (s, 3H, C6H4CH3); 13C{1H} NMR (75.5 MHz, CD2Cl2/D2O): δ=159.3, 145.8, 145.3, 136.1, 133.1, 130.6, 129.6, 128.44, 128.41, 127.5, 127.4, 113.7, 86.9, 71.8, 69.3, 64.1, 55.8, 22.0; MS (EI): m/z. calcd for [C31H32O7S]+: 548.1869. found: 548.1867 [M]+. elemental analysis calcd (%) for C31H32O7S: C, 67.86; H, 5.88; found: C, 67.84; H, 5.93.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[C:24](I)[CH:23]=2)[C:10]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:2].[F:41][C:42]1[CH:43]=[C:44](B(O)O)[CH:45]=[CH:46][C:47]=1[F:48].C(=O)([O-])[O-].[Cs+].[Cs+]>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]>[CH2:1]([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:45]3[CH:44]=[CH:43][C:42]([F:41])=[C:47]([F:48])[CH:46]=3)[CH:25]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:27]=2)[C:10]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Reactant: OB(O)c1ccc(F)c(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccc(F)c(F)c3)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Yield: 42 %

Procedure:
A similar procedure as described in Example 41, step 1 was used, starting from 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(3-iodo-5-methanesulfonyl-phenoxy)-hexyl]-phenoxy}-butyric acid ethyl ester (500 mg, 0.73 mmol), 3,4-difluorophenylboronic acid (236 mg, 1.45 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (79.7 mg, 0.109 mmol), and cesium carbonate (477.9 mg, 1.45 mmol) to afford 4-[2-(2-ethoxycarbonyl-ethyl)-3-[6-(5-methanesulfonyl-3′,4′-difluoro-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid ethyl ester (207 mg, 42.2%) as a light yellow viscous oil: ES(+)-HRMS m/e calcd for C36H44F2O8S (M+Na)+ 697.2617, found 697.2611.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([CH3:7])[N:3]=1.[CH2:8]([NH2:12])[CH2:9][CH2:10][CH3:11]>C(O)C>[CH2:8]([NH:12][C:2]1[S:6][N:5]=[C:4]([CH3:7])[N:3]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCN
Reactant: Cc1nsc(Cl)n1
Solvent: CCO
Product: CCCCNc1nc(C)ns1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Chloro-3-methyl-1,2,4-thiadiazole (27 g, 0.20 mol) was dissolved in 200 ml ethanol and, under cooling in an ice bath, added to an ethanolic solution of butylamine (44 g, 0.60 mol), stirred at room temperature overnight and evaporated to small bulk. Upon addition of ether a white precipitate of butylamine hydrochloride formed which was filtered off. The yellow filtrate was washed with water, dried over magnesium sulphate, filtered and evaporated to dryness to yield a yellow oil which was distilled under vacuum to give 5-butylamino-3-methyl-1,2,4-thiadiazole as a pale yellow liquid. Yield 29.9 g, (87.2%), b.p. 101°-102° C./0.14 mmHg.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Si:1]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:22][CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OCc1ccc(O)cc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1

Procedure:
Step A ##STR104## A solution of 4-tert-butyldiphenylsilyloxymethylphenol (see Example 1, Step A) (13 g) and ethyl bromoacetate (4.0 ml) in acetone (50 ml) was refluxed for 40 h in the presence of sodium iodide (5.37 g) and potassium carbonate (4.69 g). The reaction mixture was partitioned between ethyl ether and water, and the dried (MgSO4) organic phase was evaporated. Silica gel chromatography of the residue afforded ethyl 2-(4-tert-butyldiphenylsilyloxymethylphenyl)oxyacetate as a colourless syrup (8 g); IR νmax 1735 cm-1 ; NMR (60 MHz, CDCl3)δ 1.1 (9H, s), 1.3 (3H, t, J=6 Hz), 4.2 (2H, q, J=6 Hz), 4.55 and 4.65 (each 2H, s), 6.8-7.8 (10H, m).
Reaction SMILES: Cl.O.[C:3]([O:11][C:12]1[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[CH:15]=[CH:14][C:13]=1[C:21]1([NH:35][C:36](=[O:43])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[N+:31]([O-])=O)[C:22]1=[O:34])(=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>C(O)C.[Fe]>[C:3]([O:11][C:12]1[CH:17]=[C:16]([CH:18]([CH3:19])[CH3:20])[CH:15]=[CH:14][C:13]=1[C:21]1([NH:35][C:36](=[O:43])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[NH2:31])[C:22]1=[O:34])(=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCC(=O)NC1(c2ccc(C(C)C)cc2OC(=O)CCCCCC)C(=O)c2cccc([N+](=O)[O-])c2C1=O
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCCCCCC(=O)NC1(c2ccc(C(C)C)cc2OC(=O)CCCCCC)C(=O)c2cccc(N)c2C1=O
Yield: 37.4 %

Procedure:
Iron powder (0.03 g, 0.5 mmol), conc. HCl (0.05 ml), and water (0.5 ml) were added in that order to a solution of 2-(2-heptanamido-4nitro-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl heptanoate (60 mg, 0.10 mmol) in ethanol (5 ml). The reaction mixture was heated for 1 hrs under reflux. The reaction mixture was hot filtered off, the filtrate was concentrated in a vacuum and purified by column chromatography (ethylacetate:hexane=1:6 to 1:4) to afford the title compound (20 mg, 36%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([CH:13]([OH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C.I[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1OC>>[O:20]([CH:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)c2ccccc2)C1
Reactant: COc1ccccc1I
Product: c1ccc(OC(c2ccccc2)C2CCNC2)cc1

Procedure:
Following the procedure of Example 2, and, in Preparation 3, substituting the RS/SR mixture of enantiomers with the SS/RR mixture of enantiomers of 3-(hydroxyphenylmethyl)-pyrrolidine-1-carboxylic acid t-butyl ester (47.5 mg, 170 μmol), and substituting 2-iodoanisole with the appropriate aryl iodide, the SS/RR mixture of enantiomers (16-2) of the title compound was prepared (12.4 mg) as a TFA salt. MS m/z: [M+H]+ calcd for C17H19NO, 254.15. found 254.2.
Reaction SMILES: C(O[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1Cl)C.[CH2:13]([O:15][C:16](=[O:19])[CH2:17][SH:18])[CH3:14].[H-].[Na+]>CN(C=O)C>[CH2:13]([O:15][C:16]([C:17]1[S:18][C:6]2=[CH:7][N:8]=[CH:9][CH:10]=[C:5]2[C:4]=1[OH:12])=[O:19])[CH3:14]
Reactant: CCOC(=O)c1ccncc1Cl
Reactant: CCOC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2cnccc2c1O
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 99.3 %

Procedure:
To a cooled (5° C.) stirred solution of 3-chloro-isonicotinic acid ethyl ester (1.11 g, 6.0 mmol) and mercapto-acetic acid ethyl ester (1.8 ml, 16.7 mmol) in anhydrous DMF (20 ml), under an argon atmosphere, was added sodium hydride (15.6 mmol, 60% dispersion in oil, 622 mg) in portions over 20 minutes. Stirring was continued at 5° C. for 20 minutes, followed by 18 hours at room temperature. The reaction mixture was then quenched by the addition of water (5 ml), acidified by the addition of acetic acid (1 ml), and subsequently concentrated to provide a residue. The residue was partitioned between ethyl acetate (150 ml) and water (50 ml). The organic phase was isolated, dried over sodium sulphate, filtered and evaporated to give a yellow oil. The oil was purified by flash chromatography (Si-SPE, pentane:ethyl acetate, gradient 80:20 to 30:70) to afford the title compound as a yellow solid (1.33 g, 99%). LCMS (method B): RT=2.57 min, M+H+=224.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[N:27]1([NH:26][C:3]([C:5]2[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:4])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C)nn1C
Reactant: NN1CCOCC1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)NN2CCOCC2)n(C)n1
Yield: 87 %

Procedure:
As described for example 48c, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.29 mmol) was converted, using 4-aminomorpholine instead of N,N-dimethylhydrazine, to the title compound (104 mg, 87%) which was obtained as a colorless oil. MS: m/e=416.2 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[S:11][CH:10]=[C:9]([CH2:12][N:13]3C(=O)C4C(=CC=CC=4)C3=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NN>CO>[C:1]1([C:7]2[S:11][CH:10]=[C:9]([CH2:12][NH2:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1csc(-c2ccccc2)c1
Agent: NN
Solvent: CO
Product: NCc1csc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
Prepare a solution of 2-(5-phenylthiophen-3-ylmethyl)isoindole-1,3-dione (565 mg, 1.77 mmol) in methanol (57 mL). Add hydrazine (0.35 mL, 11.14 mmol). Heat the mixture to reflux. After stirring for 1 hour, cool the mixture to room temperature and concentrate. Perform flash chromatography on silica gel eluting with 50:40:9:1 methylene chloride/CHCl3/MeOH/concentrated NH4OH to afford 280 mg of the title compound as a yellow solid. MS: m/e=190 [MH+].
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH:10]1[C:15]2[CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH2:20][C:14]=2[CH:13]=[CH:12][CH:11]=1>[N+](C)([O-])=O>[N+:6]([C:12]1[CH:11]=[CH:10][C:15]2[CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH2:20][C:14]=2[CH:13]=1)([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: O=C1CCc2ccccc2CC1
Agent: O=S(=O)(O)O
Solvent: C[N+](=O)[O-]
Product: O=C1CCc2ccc([N+](=O)[O-])cc2CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
To a solution of cold (0° C.) concentrated sulfuric acid (15 mL) was added 70% nitric acid (15 mL) dropwise over 30 min. The addition was controlled to maintain the internal reaction temperature below 5° C. After the addition, the resulting solution was transferred into an addition funnel and was added dropwise to a solution of 8,9-dihydro-5H-benzo[7]annulen-7(6H)-one (14 g, 87.5 mmol) in nitromethane (80 mL) at 0° C. over a period of 40 min. After the addition, the reaction mixture was stirred at 0° C. for 2 h. Then ice water (˜80 mL) was added to the reaction mixture, and the mixture was stirred for additional 30 min. Then the mixture was transferred to a separatory funnel where the layers were separated. The aqueous layer was extracted with ethyl acetate (3×80 mL). The combined layers were washed with cold water, sat. NaHCO3 solution and brine. After being dried (MgSO4), filtered, and concentrated, the residue was purified by flash column chromatography on silica gel (hexanes/EtOAc=3:1 to 2:1) to afford the mixture of nitro regioisomers (˜15 g), which was then purified by recrystallization from MTBE (tert-butyl methyl ether, 180 mL) to yield 7.3 g of 2-nitro-8,9-dihydro-5H-benzo[7]annulen-7(6H)-one (40% yield) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ: 8.10-8.06 (m, 2H), 7.40-7.37 (m, 1H), 3.04-3.00 (m, 4H), 2.67-2.65 (m, 4H); LC-MS: 206 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.N1([NH:28][S:29]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34](Br)[CH:33]=2)(=[O:31])=[O:30])CCCC1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([CH2:16][CH2:15][C@@H:2]([OH:1])[C@@H:3]([O:4][C:5]2[CH:10]=[CH:9][C:8]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([S:29]([N:28]4[CH2:14][CH2:3][CH2:2][CH2:15]4)(=[O:30])=[O:31])[CH:37]=3)=[CH:7][CH:6]=2)[CH3:14])[CH:18]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Reactant: O=S(=O)(NN1CCCC1)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C[C@H](Oc1ccc(-c2cccc(S(=O)(=O)N3CCCC3)c2)cc1)[C@H](O)CCc1cccnc1
Temperature: 90 °C
Yield: 117.9 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.150 g, Example 33), 3-bromobenzenesulfonic acid, pyrrolidinyl amide (0.290 g), 2M aqueous sodium carbonate (0.50 ml) and tetrakis(triphenylphosphine)palladium(0) (0.025 g) in ethanol (3 ml). The reaction mixture was heated at 90° C. for 4 hours. After cooling, the solution was concentrated under reduced pressure, taken up in ethanol and concentrated again (twice). The residue was triturated with acetone and then filtered through silica gel. The filtrate was concentrated under reduced pressure, dissolved in dichloromethane, filtered and purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give a gum, which was further purified by reverse-phase HPLC to give the title compound as a foam (0.137 g).