Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@H:2]1[C@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C@@H:15]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)[C:16]2=[O:28])[CH2:3]1.[C:29]([O:33][C:34]([NH:36][C@@H:37]([CH3:41])[C:38](O)=[O:39])=[O:35])([CH3:32])([CH3:31])[CH3:30].C1CCC(N=C=NC2CCCCC2)CC1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:29]([O:33][C:34]([NH:36][C@@H:37]([CH3:41])[C:38]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C@@H:7]2[CH2:6][CH2:5][N:4]([C@@H:15]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=4)[C:16]3=[O:28])[CH2:3][C@H:2]2[F:1])=[CH:9][CH:10]=1)=[O:39])=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: Cc1ccc(CN2CC[C@@H](N3CC[C@@H](c4ccc(O)cc4)[C@H](F)C3)C2=O)cc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(CN2CC[C@@H](N3CC[C@@H](c4ccc(OC(=O)[C@H](C)NC(=O)OC(C)(C)C)cc4)[C@H](F)C3)C2=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.4 %

Procedure:
To a solution of (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (0.03 g, 0.078 mmol, example 1) in DCM (5 mL) was added (S)-2-((tert-butoxycarbonyl)amino)propanoic acid (0.077 g, 0.408 mmol) followed by DCC (0.049 g, 0.235 mmol) and DMAP (9.58 mg, 0.078 mmol). The reaction mixture was stirred at rt for 18 h. Water (15 mL) was then added, and the layers were separated. The aqueous layer was extracted with DCM (3×15 mL) and the organic layers were combined, dried over Na2SO4, and concentrated to a crude product. The crude product was purified by preparative TLC eluting with 20% ethyl acetate in petroleum ether to provide the purified product (S)-4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl 2-((tert-butoxycarbonyl)amino)propanoate (0.032 g, 0.058 mmol, 74% yield) as off-white semi solid. LC-MS (Method A) RT=2.40 min, (M+H)+=554.2. 1H NMR (400 MHz, DMSO-d6) δ 7.51 (d, J=7.0 Hz, 1H), 7.44-7.32 (m, J=8.5 Hz, 2H), 7.21-7.09 (m, 4H), 7.07-6.98 (m, J=8.5 Hz, 2H), 4.62 (d, J=4.5 Hz, 1H), 4.39 (d, J=15.1 Hz, 1H), 4.30 (d, J=15.1 Hz, 1H), 4.27-4.17 (m, 1H), 3.58 (t, J=8.5 Hz, 1H), 3.50-3.40 (m, 1H), 3.22-3.07 (m, 2H), 2.81-2.64 (m, 3H), 2.39-2.31 (m, 1H), 2.29 (s, 3H), 2.17-2.04 (m, 1H), 1.93 (dd, J=12.8, 8.3 Hz, 1H), 1.78 (br. s., 1H), 1.74-1.59 (m, 1H), 1.41 (s, 9H), 1.39 (d, J=2.5 Hz, 3H). 19F NMR (376 MHz, DMSO-d6) δ −180.172.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:10][CH2:11][C:12]([OH:14])=O)=[N:4][C:5]([F:9])=[C:6]([Cl:8])[CH:7]=1.S(Cl)([Cl:17])=O>>[Cl:1][C:2]1[C:3]([O:10][CH2:11][C:12]([Cl:17])=[O:14])=[N:4][C:5]([F:9])=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)COc1nc(F)c(Cl)cc1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)COc1nc(F)c(Cl)cc1Cl

Procedure:
A solution was prepared by admixing 8.6 grams (0.036 mole) of 3,5-dichloro-6-fluoro-2-pyridyloxy acetic acid in 15 milliliters of thionyl chloride. The mixture was refluxed for about 50 minutes. At the completion of the reaction, the excess thionyl chloride was removed by distillation. The liquid residue was cooled and the crystals which formed were separated. The (3,5-dichloro-6-fluoro-2-pyridyloxy)acetyl chloride product was recovered in a yield of 8.4 grams (92 percent of theoretical). Upon analysis, the product was found to have carbon, hydrogen, chlorine and nitrogen contents of 32.9, 0.9, 41.9 and 5.3 percent, respectively as compared with the theoretical contents of 32.8, 0.4, 41.4 and 5.5 percent, respectively, as calculated for the above-named compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]=[CH:17][N:18](C)C)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].C(O)C.O.[NH2:25]N>C(O)(=O)C>[NH2:25][N:18]1[C:7]([OH:8])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:15]=2)[N:16]=[CH:17]1
Reactant: CN(C)C=Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: NN
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: NN1C=Nc2ccc(Cl)cc2C1(O)c1ccccc1
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of 0.29 part of 5-chloro-2-dimethylaminomethyleneaminobenzophenone in 4 volume parts of ethanol are added 0.2 volume part of hydrazine hydrate and 0.06 volume part of glacial acetic acid. The mixture is shaken and kept standing at room temperature for about 30 minutes. The resulting crystals are recovered by filtration and washed with ethanol and then dried, whereby 3-amino-6-chloro-3,4-dihydro-4-hydroxy-4-phenylquinazoline is obtained as colorless needles melting at 185° (softening) to 192° C. This compound is identical with the product obtained in Example 1. Yield: 95%.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[H-].[Na+].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1>CN(C=O)C>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8])=[CH:16][CH:15]=1
Reactant: C=CCCCCCCO
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCCCCCOCc1ccc(OC)cc1
Temperature: 0 °C
Yield: 48.8 %

Procedure:
A 250 mL round-bottom flask equipped with stir bar was charged with 7-octen-1-ol (1.20 mL, 7.80 mmol). Anhydrous DMF (60 mL) was added, and the solution was allowed to cool to 0° C. (ice-bath). Sodium hydride (2.40 g, 40.0 mmol) was added in portions, and the mixture was allowed to stir until gas evolution ceased. p-Methoxybenzyl chloride (2.1 mL, 16 mmol) was added by a syringe and the mixture was allowed to stir for 24 h. The reaction was quenched by addition of a saturated aqueous solution of sodium bicarbonate (100 mL), and washed with ethyl acetate (5×100 mL). The combined organic layers were washed with water (3×100 mL) to remove dmf, further washed in brine (1×50 mL), dried over MgSO4, filtered, and concentrated in vacuo. The resulting yellow oil was purified by silica gel chromatography (96:4 hexanes:EtOAc), delivering 1-methoxy-4-((oct-7-en1-yloxy)methyl)benzene (946 mg, 3.81 mmol, 49.0% yield) as a colorless oil. IR (neat): 3074 (w), 2998 (m), 2929 (m), 2854 (w), 1640 (m), 1613 (w), 1586 (w), 1511 (m), 1463 (m), 1441 (w), 1361 (w), 1301 (m), 1245 (s), 1208 (w), 1172 (m), 1095 (s), 1036 (s), 995 (w), 909 (m), 819 (s), 755 (w), 727 (w), 707 (w), 637 (w), 571 (w), 513 (w), 418 (w); 1H NMR (400 MHz, CDCl3): δ 7.25 (2H, d, J=8.8 Hz), 6.87 (2H, d, J=8.4 Hz), 5.80 (1H, m), 4.98 (1H, dd, J=17.2, 2.0 Hz), 4.92 (1H, dd, J=10.0, 2.4 Hz), 4.42 (2H, s), 3.79 (3H, s), 3.43 (2H, t, J=6.6 Hz), 2.03 (2H, app q, J=6.9 Hz), 1.63-1.56 (2H, m), 1.41-1.27 (6H, m); 13C NMR (100 MHz, CDCl3): δ 159.2, 139.2, 130.9, 129.3, 114.3, 113.8, 72.6, 70.3, 55.3, 33.8, 29.8, 29.1, 29.0, 26.2; HRMS (ESI+) [M+NH4]+ calcd for C16H28NO2: 266.2120, found: 266.2130.
Reaction SMILES: C(OC([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([O:17][CH:18]3[CH2:23][CH2:22][N:21]([CH:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]3)[CH:16]=[C:11]2[CH:10]=[C:9]1[C:27]([O-])=[O:28])=O)(C)(C)C.[Li+].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]=N1.N1CCCC1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:24]([N:21]1[CH2:22][CH2:23][CH:18]([O:17][C:15]2[CH:16]=[C:11]3[CH:10]=[C:9]([C:27]([N:38]4[CH2:39][CH2:44][CH2:43][CH2:42]4)=[O:28])[NH:8][C:12]3=[N:13][CH:14]=2)[CH2:19][CH2:20]1)([CH3:26])[CH3:25]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)N1CCC(Oc2cnc3c(c2)cc(C(=O)[O-])n3C(=O)OC(C)(C)C)CC1
Agent: F[B-](F)(F)F
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: CC(C)N1CCC(Oc2cnc3[nH]c(C(=O)N4CCCC4)cc3c2)CC1
Yield: 33 %

Procedure:
The title compound was synthesized in analogy to example 9, intermediate a), from lithium 1-tert-butoxycarbonyl-5-(1-isopropyl-piperidin-4-yloxy)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, pyrrolidine and N,N-diisopropylethylamine in DMF to give the desired product as a light yellow solid (33%).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:12]3[N:13]=[CH:14][C:15](=[O:17])[NH:16][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[S:20][CH3:21].[C:22]([C:26]1[CH:30]=[C:29]([N:31]=[C:32]=[O:33])[N:28]([C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[N:38][CH:39]=2)[N:27]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([C:26]1[CH:30]=[C:29]([NH:31][C:32]([NH:1][C:2]2[CH:19]=[CH:18][C:5]([O:6][C:7]3[C:12]4[N:13]=[CH:14][C:15](=[O:17])[NH:16][C:11]=4[N:10]=[CH:9][CH:8]=3)=[CH:4][C:3]=2[S:20][CH3:21])=[O:33])[N:28]([C:34]2[CH:39]=[N:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[N:27]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: COc1ccc(-n2nc(C(C)(C)C)cc2N=C=O)cn1
Reactant: CSc1cc(Oc2ccnc3[nH]c(=O)cnc23)ccc1N
Product: COc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc4[nH]c(=O)cnc34)cc2SC)cn1
Yield: 53 %

Procedure:
Method F2 was used with 8-(4-amino-3-(methylthio)phenoxy)pyrido[3,2-b]pyrazin-3(4H)-one and 5-(3-tert-butyl-5-isocyanato-1H-pyrazol-1-yl)-2-methoxypyridine to afford the title compound (97 mg, 53%) as a white powder.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:11]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:10][C:9]2[N:8]3[CH2:16][CH2:17][N:18]([C:23]4[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[C:26]([C:33](O)=[O:34])=[CH:25][N:24]=4)[CH:19]([CH:20]([CH3:22])[CH3:21])[C:7]3=[CH:6][C:5]=2[CH:4]=1.C[N:37](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH4+].[Cl-].C(N(CC)C(C)C)(C)C>CN(C=O)C.C(Cl)Cl>[OH:1][CH2:2][C:3]1[C:11]([S:12]([CH3:15])(=[O:13])=[O:14])=[CH:10][C:9]2[N:8]3[CH2:16][CH2:17][N:18]([C:23]4[N:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[C:26]([C:33]([NH2:37])=[O:34])=[CH:25][N:24]=4)[CH:19]([CH:20]([CH3:21])[CH3:22])[C:7]3=[CH:6][C:5]=2[CH:4]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)C1c2cc3cc(CO)c(S(C)(=O)=O)cc3n2CCN1c1ncc(C(=O)O)c(C(F)(F)F)n1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C1c2cc3cc(CO)c(S(C)(=O)=O)cc3n2CCN1c1ncc(C(N)=O)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylic acid (55 μmol) in anhydrous DMF (1 mL) was added HATU (42 mg, 0.11 mmol), NH4Cl (30 mg, 0.55 mmol) and N,N-diisopropylethylamine (100 μL, 0.55 mmol). The mixture was stirred at rt for 20 h. It was diluted with CH2Cl2 (10 mL) and washed with H2O. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organic solution was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica chromatography and SFC separation to give isomers of 2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxamide.
Reaction SMILES: CN([CH2:4][N:5]([CH3:7])[CH3:6])C.C(Cl)(=O)C.[CH3:12][O:13][C:14]1[CH:29]=[CH:28][C:17]([O:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][CH:23]=[CH:22]3)=[CH:16][CH:15]=1>C(Cl)Cl>[CH3:7][N:5]([CH2:4][C:22]1[C:21]2[C:25](=[CH:26][CH:27]=[C:19]([O:18][C:17]3[CH:28]=[CH:29][C:14]([O:13][CH3:12])=[CH:15][CH:16]=3)[CH:20]=2)[NH:24][CH:23]=1)[CH3:6]
Reactant: COc1ccc(Oc2ccc3[nH]ccc3c2)cc1
Reactant: CN(C)CN(C)C
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: COc1ccc(Oc2ccc3[nH]cc(CN(C)C)c3c2)cc1
Reaction time: 0.33 h

Procedure:
N,N,N',N'-Tetramethyldiaminomethane (0.29 g, 0.39 mL, 2.82 mmol) was dissolved in CH2Cl2 (dry; 8.5 mL) and the stirred solution cooled in an ice-bath. Acetyl chloride (0.23 g, 0.21 mL, 2.95 mmol) was added dropwise (syringe) over 10 min, to give a white suspension. After stirring for a further 20 min. with cooling maintained, a solution of 5-(4-methoxyphenoxy)indole (0.5 g, 2.09 mmol) in CH2Cl2 (7.2 mL) was added dropwise, over 20 min. The cooling was removed and the resulting clear solution was stirred for 1 hr at room temperature. The solution was then diluted with CH2Cl2, washed with 10% aq. NaOH (2×) followed by saturated aqueous NACl and dried (MgSO4). Evaporation in vacuo gave 3-(N,N-dimethylaminomethyl)-5-(4-methoxyphenoxy)indole as a gum. This material was dissolved in DMF (dry; 7 mL) and potassium cyanide (0.52 g, 8.0 mmol) was added, followed by methyl iodide (1.19 g, 0.52 mL, 8.35 mmol). The mixture became cloudy and eventually opaque. After stirring at room temperature for 36 hr, water was added and the mixture was extracted with Et2O (2×). The combined organic layers were washed with H2O (2×) and then with saturated aqueous NaCl, dried (MgSO4) and evaporated to give an almost colourless gum. This was triturated with Et2O to give: 3-cyanomethyl-5-(4-methoxyphenoxy)indole as a virtually colourless solid, 0.334 g (57%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[C:14]2[C:9](=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][NH:6]1)[CH3:3].[Cl:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26](O)=[O:27])[CH:21]=[CH:22][C:23]=1[Cl:24].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:3][N:2]([CH2:4][C:5]1([C:26](=[O:27])[CH2:25][C:20]2[CH:21]=[CH:22][C:23]([Cl:24])=[C:18]([Cl:17])[CH:19]=2)[C:14]2[C:9](=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][NH:6]1)[CH3:1]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: COc1cccc2c1CCNC2CN(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1cccc2c1CCNC2(CN(C)C)C(=O)Cc1ccc(Cl)c(Cl)c1

Procedure:
Prepared as Ex. No. 1, from 1.2 g (5.45 mmoles) of 1-dimethylaminomethyl-5-methoxy-1,2,3,4-tetrahydroisoquinoline, 1.3 g (6.37 mmoles) of 3,4-dichlorophenylacetic acid and 2.4 g (11.70 mmoles) of dicyclohexylcarbodiimide in 50 ml of dry methylene chloride.
Reaction SMILES: CN(C)C=O.[CH3:6][C:7]1([CH3:24])[C:12](=[CH2:13])[S:11][C:10]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[C:9]([CH:22]=O)[CH2:8]1.C(N(CC)CC)C.CS([Cl:36])(=O)=O>O>[Cl:36]/[CH:22]=[C:9]1/[C:10](=[N:14]/[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)/[S:11][C:12](=[CH2:13])[C:7]([CH3:24])([CH3:6])[CH2:8]/1
Reactant: C=C1SC(Nc2ccc(C)cc2)=C(C=O)CC1(C)C
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=C1SC(=N\c2ccc(C)cc2)/C(=C/Cl)CC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an N,N-dimethylformamide (5 ml) solution of 5,5-dimethyl-6-methylene-2-p-tolylamino-5,6-dihydro-4H-thiopyran-3-carbaldehyde (0.26 g), triethylamine (0.14 g) and methanesulfonyl chloride (0.16 g) were added at 0° C. After raising the temperature to room temperature and further stirring for 1 hour, water was added thereto and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure to obtain a crude product of {3-[1-chloro-(E)-methylidene]-5,5-dimethyl-6-methylene-tetra hydro-thiopyran-(2Z)-ylidene}-p-tolyl-amine.
Reaction SMILES: C([CH:3]([CH2:7][CH2:8][C:9]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:4]([OH:6])=[O:5])C.[OH-].[K+].Cl>O>[CH2:19]([O:18][C:16]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([OH:15])[C:9]=1[CH2:8][CH2:7][CH2:3][C:4]([OH:6])=[O:5])=[O:17])[CH3:20]
Reactant: CCOC(=O)c1cccc(O)c1CCC(CC)C(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)c1cccc(O)c1CCCC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 4-[2-ethoxycarbonyl-6-hydroxyphenyl]butanoic acid (9.06 g, 32.4 mmol) was dissolved in a room temperature solution of potassium hydroxide (3.62 g, 64.6 mmol) in water (68 ml). The solution was stirred at room temperature for 2 hr, and then made acidic with 12 N HCl. The mixture was extracted twice with ethyl acetate. The ethyl acetate extracts were combined and extracted with 10% aqueous potassium carbonate three times. These aqueous extracts were made acidic with 12 N HCl and extracted twice with ethyl acetate. The ethyl acetate extracts were concentrated in vacuo to a white solid (6.4 g, 79%).
Reaction SMILES: BrC[C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:15]CN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[CH3:33][C:34]1([CH3:56])[CH2:43][CH2:42][C:41]2[C:36](=[CH:37][CH:38]=[C:39]([S:44]([NH:47][CH2:48][C:49]([O:51]C(C)(C)C)=[O:50])(=[O:46])=[O:45])[CH:40]=2)[O:35]1>C(#N)C>[C:9]1([C:5]2[CH:4]=[CH:3][CH:8]=[CH:7][CH:6]=2)[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=1[CH2:15][N:47]([CH2:48][C:49]([OH:51])=[O:50])[S:44]([C:39]1[CH:40]=[C:41]2[C:36](=[CH:37][CH:38]=1)[O:35][C:34]([CH3:56])([CH3:33])[CH2:43][CH2:42]2)(=[O:46])=[O:45]
Reactant: BrCc1cccc(-c2ccccc2)c1
Reactant: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Reactant: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc2c(c1)CCC(C)(C)O2
Solvent: CC#N
Product: CC1(C)CCc2cc(S(=O)(=O)N(CC(=O)O)Cc3ccccc3-c3ccccc3)ccc2O1
Temperature: 90 °C
Reaction time: 48 h
Yield: 66 %

Procedure:
To a Wheaton vial containing 3-(bromomethyl)biphenyl (22.2 mg, 0.090 mmol) and resin-supported BEMP (52 mg, 0.095 mmol) was added a solution of tert-butyl 2-(2,2-dimethylchroman-6-sulfonamido)acetate (18 mg, 0.05 mmol) in acetonitrile (1 mL). The mixture was heated to 90° C. and shaken vigorously for two days. The reaction mixture was filtered, and the filtrate was concentrated. The crude product was taken in dichloromethane (0.5 mL) and trifluroacetic acid (0.5 mL) was added. The mixture was shaken for 4 hours at room temperature. It was concentrated and the residue was purified by prep HPLC to obtain the product (15.3 mg, 66% yield in two steps). 1H NMR (600 MHz, DMSO/CDCl3) δ 7.52-7.46 (m, 1H), 7.46-7.41 (m, 2H), 7.41-7.33 (m, 5H), 7.23 (d, J=7.4 Hz, 2H), 7.19-7.14 (m, 1H), 6.77 (d, J=9.1 Hz, 1H), 4.40 (s, 2H), 3.63 (s, 2H), 2.75 (t, J=6.4 Hz, 2H), 1.82 (t, J=6.5 Hz, 2H), 1.34 (s, 6H). LRMS [ESI, MH+] m/z calcd for C26H28NO5S 466.17, found 466.22.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.N1C=CC=CC=1.[F:31][C:32]([F:44])([F:43])[C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][S:39]([C:36]4[CH:35]=[CH:34][C:33]([C:32]([F:31])([F:43])[F:44])=[CH:38][CH:37]=4)(=[O:41])=[O:40])=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ccc(N)cn3)cc2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CC1CCC(c2ccc(-c3ccc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 0.300 g (0.925 mmol) of {4-[4-(5-Amino-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester, and 8 mL of dichloromethane was added 0.112 mL (1.39 mmol) of pyridine, 0.271 g (1.11 mmol) of 4-Trifluoromethyl-benzenesulfonyl chloride and 0.004 g (0.0277 mmol) DMAP. The dark orange solution was stirred at r.t. for 4 h. The mixture was extracted with dichloromethane, then washed with water, 1 N HCl, and brine. Dried with Na2SO4. Purified on silica gel (EtOAc/Heptane, 9:1 to 6:4) to afford the title compound. 1H NMR (400 MHz, CHLOROFORM-d6) 0.99-1.10 (m, 2H) 1.34-1.46 (m, 2H) 1.71-1.82 (m, 5H) 2.14 (d, J=6.82 Hz, 2H) 2.39 (tt, J=−12.16, 3.25 Hz, 1H) 3.57 (s, 3H) 7.16 (d, J=8.34 Hz, 2H) 7.54 (dd, J=2.53, 1.77 Hz, 2H) 7.61 (d, J=8.34 Hz, 2H) 7.73 (d, J=8.34 Hz, 2H) 7.78 (d, J=8.08 Hz, 2H) 8.14 (dd, J=2.27, 1.01 Hz, 1′H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH:12]1[C:16](=[O:17])[O:15][CH:14]2CC=C[CH:13]12.C[N+]1([O-])CC[O:25]CC1.[CH3:29][C:30]([CH3:32])=[O:31]>C(O)(C)(C)C.[Os](=O)(=O)(=O)=O>[OH:31][CH:30]1[CH:32]2[CH:14]([O:15][C:16](=[O:17])[CH:12]2[CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH2:13][CH:29]1[OH:25]
Reactant: O=C1OC2CC=CC2C1Cc1ccc2ccccc2c1
Reactant: CC(C)=O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)(C)O
Product: O=C1OC2CC(O)C(O)C2C1Cc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
200 mg (0.75 mmol) of the compound from Example 7, 0.08 ml of a 2.5% strength osmium tetroxide solution in tert-butanol and 180 mg of N-methylmorpholine N-oxide were dissolved in 2.5 ml of acetone and stirred at RT for 15 h. The mixture was concentrated and the residue was chromatographed over silica gel (mobile phase: dichloromethane/methanol (100:4)). Yield: 161 mg of a diastereomer mixture. Diastereomer ratio: 1:5:5:1 (HPLC). MS (DCI/NH3): m/e=316 (M+NH4)
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH2:16]([O:18][C:19](Cl)=[O:20])[CH3:17]>C(Cl)Cl.O>[O:8]=[C:5]1[CH2:6][CH2:7][N:2]([C:19]([O:18][CH2:16][CH3:17])=[O:20])[CH2:3][CH2:4]1
Reactant: CCOC(=O)Cl
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)N1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To the stirred solution of piperidin-4-one hydrochloride (2.0 g, 14.7 mmol) in DCM (60 mL) cooled at 0° C., was added triethylamine (5.15 mL, 36.75 mmol) and ethylchloroformate (1.59 mL, 16.6 mml). The reaction mixture was stirred at room temperature for 2 hours before being diluted with water. The two layers were separated, the organic layer was dried over anhydrous sodium sulfate and the volatiles were removed under reduced pressure to obtain ethyl 4-oxo-piperidine-1-carboxylate (3.14 grams).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[C:13]1([CH2:19][CH2:20][NH2:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[F:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4][NH:21][CH2:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Reactant: NCCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=[N+]([O-])c1ccc(F)c(CNCCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 24 h
Yield: 81.2 %

Procedure:
2-Fluoro-5-nitro-benzaldehyde (11.9 g, 70 mmol) and 2-phenylethylamine (13 mL, 0.1 mol) were dissolved in methanol (150 mL) and glacial acetic acid (15 mL). The solution was cooled to 0° C., and sodium cyanoborohydride (6.6 g, 0.1 mol) was added portionwise. The reaction was adjusted to pH 6 with acetic acid and stirred at room temperature for 24 h. The reaction mixture was quenched with ice and diluted with water. The pH was adjusted to 11 with sodium hydroxide and the mixture was extracted with EtOAc. The organic extracts were washed with cold dilute HCl solution and a solid precipitated. Filtration yielded the title compound (15.6 g, 82%). Mp 235-6° C.; MS m/e 275 [M+H]+.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[CH3:30][C:31]1[NH:32][C:33]2[CH2:38][CH2:37][NH:36][CH2:35][C:34]=2[N:39]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([N:36]3[CH2:37][CH2:38][C:33]4[NH:32][C:31]([CH3:30])=[N:39][C:34]=4[CH2:35]3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: Cc1nc2c([nH]1)CCNC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N3CCc4[nH]c(C)nc4C3)sc2c1-c1ccc(Cl)cc1
Temperature: 80 °C

Procedure:
A flask was charged with (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (100 mg, 0.20 mmol), 2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine (85 mg, 0.40 mmol), Cs2CO3 (325 mg, 1.0 mmol), and then diluted with ACN (4 mL). The suspension was heated to 80° C. for 24 hours and then allowed to cool to room temperature. The resulting mixture was filtered and concentrated in vacuo. The crude residue was purified by reverse phase column chromatography (5-100% ACN/H2O+0.1% TFA)to afford the desired product. LCMS-ESI+: calc'd for C29H34ClN4O3S: 553.2 (M+H+); Found: 553.2 (M+H+).