Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:10]=3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20](=[O:32])[C@H:21]([N:29]=[C:30]=[O:31])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.COC(=O)C(N=C=O)CC1C=CC=CC=1>C1COCC1>[CH3:18][O:19][C:20](=[O:32])[C@H:21]([NH:29][C:30]([O:17][CH2:16][C:13]1[CH:14]=[CH:15][C:9]2[O:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:11][C:10]=2[CH:12]=1)=[O:31])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)[C@@H](Cc1ccccc1)N=C=O
Reactant: OCc1ccc2oc(-c3ccccc3)cc2c1
Agent: COC(=O)C(Cc1ccccc1)N=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccc2oc(-c3ccccc3)cc2c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
To a solution of 2-phenyl-benzofuran-5-carboxylic acid methyl ester 27 (0.7 g, 2.8 mmol) in THF (15 ml) was added dropwise a solution of lithium aluminum hydride (1M in THF) (3.6 ml, 3.6 mmol) at 0° C. After the addition, the reaction mixture was allowed to warm to room temperature and stirred for 2 hrs. The mixture was cooled to 0° C., diluted with ether and sodium sulfate decahydrate was added. After filtration the solids were washed with ether, and the organic layer was washed and dried. Evaporation of the solvent and purification by chromatography yielded (2-phenyl-benzofuran-5-yl)-methanol (0.55 g). A mixture of (2-phenyl-benzofuran-5-yl)-methanol (0.5 g, 2.23 mmol), (R)-2-isocyanato-3-phenyl-propionic acid methyl ester 5 (0.55 g, 2.68 mmol), triethylamine (0.74 ml, 5.35 mmol) and THF (15 ml) was heated at 50° C. for 6 hrs. Additional (R) 2-isocyanato-3-phenyl-propionic acid methyl ester 5 (0.15 g) was added, and the mixture was stirred at 50° C. overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. After extraction and evaporation of the solvent, the residue was purified by chromatography to give about 0.76 g of (R)-3-phenyl-2-(2-phenyl-benzofuran-5-ylmethoxycarbonylamino)-propionic acid methyl ester 28.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:11])[CH3:10])[S:7][CH:8]=1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl>[CH:9]([C:6]1[S:7][CH:8]=[C:4]([CH2:3][NH:15][CH:12]2[CH2:14][CH2:13]2)[N:5]=1)([CH3:11])[CH3:10]
Reactant: NC1CC1
Reactant: CC(C)c1nc(CCl)cs1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC(C)c1nc(CNC2CC2)cs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
A solution of 1.8 g (10.2 mmol) of 4-(chloromethyl)-2-isopropylthiazole hydrochloride in 10 ml of chloroform was added dropwise with stirring to 10 ml of cyclopropylamine. The resulting solution was stirred at ambient temperature for 16 h, concentrated in vacuo, and purified by silica gel chromatography using 5% methanol in chloroform to provide 0.39 g (19%) of the desired compound. 1 H NMR (DMSO-d6) δ 0.24 (m, 2 H), 0.35 (m, 2H), 1.30 (d, J=7 Hz, 6 H), 2.10 (tt, J=12,3 Hz. 1 H), 3.23 (heptet, J=7 Hz, 1 H), 3.77 (s, 2 H), 7.21 (s, 1 H). Mass spectrum: (M+H)+=197.
Reaction SMILES: [C:1]([O:7][CH2:8][CH:9]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:10]1[C:25]([CH3:26])=[CH:24][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](Cl)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:39]([O:45][CH2:46][C@H:47]([C:53]1[C:62]([CH3:63])=[CH:61][C:56]2[N:57]=[C:58](Br)[S:59][C:55]=2[C:54]=1[C:64]1[CH:69]=[CH:68][C:67]([Cl:70])=[CH:66][CH:65]=1)[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])(=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41].[CH3:71][N:72]1[C:80]2[C:75](=[CH:76][C:77](B(O)O)=[CH:78][CH:79]=2)[CH:74]=[N:73]1>>[C:1]([O:7][CH2:8][C@@H:9]([O:34][C:35]([CH3:37])([CH3:38])[CH3:36])[C:10]1[C:25]([CH3:26])=[CH:24][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:77]4[CH:76]=[C:75]5[C:80](=[CH:79][CH:78]=4)[N:72]([CH3:71])[N:73]=[CH:74]5)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)(=[O:6])[C:2]([CH3:5])([CH3:3])[CH3:4].[C:39]([O:45][CH2:46][C@@H:47]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[C:53]1[C:62]([CH3:63])=[CH:61][C:56]2[N:57]=[C:58]([C:77]3[CH:76]=[C:75]4[C:80](=[CH:79][CH:78]=3)[N:72]([CH3:71])[N:73]=[CH:74]4)[S:59][C:55]=2[C:54]=1[C:64]1[CH:69]=[CH:68][C:67]([Cl:70])=[CH:66][CH:65]=1)(=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41]
Reactant: Cc1cc2nc(Br)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: Cc1cc2nc(-c3ccnc(Cl)c3)sc2c(-c2ccc(Cl)cc2)c1C(COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: Cn1ncc2cc(B(O)O)ccc21
Product: Cc1cc2nc(-c3ccc4c(cnn4C)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Product: Cc1cc2nc(-c3ccnc(-c4ccc5c(cnn5C)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 120 °C

Procedure:
One-half of above reaction mixture containing S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)ethyl pivalate to (S)-2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (1.5:1 ratio) was telescoped into the subsequent reaction. 1-Methyl-1H-indazol-5-ylboronic acid was added to the previous reaction mixture and reaction continued was heated at 120° C. for 30 minutes to give (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(1-methyl-1H-indazol-5-yl)pyridin-4-yl)benzo[d]thiazol-6-yl)ethyl pivalate and (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-1H-indazol-5-yl)benzo[d]thiazol-6-yl)ethyl pivalate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH3:20])[C:13]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)=[C:12]2[CH3:28])([CH3:7])[CH3:6])[CH3:2].C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38].O>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:29])[C:5]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH3:20])[C:13]([C:21]1[CH:22]=[CH:23][C:24]([NH:27][C:37](=[O:39])[CH3:38])=[CH:25][CH:26]=1)=[C:12]2[CH3:28])([CH3:6])[CH3:7])[CH3:2]
Reactant: CCCn1c(-c2ccc(N)cc2)c(C)c2cc(OC(C)(C)C(=O)OCC)ccc21
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCn1c(-c2ccc(NC(C)=O)cc2)c(C)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
One gram (2.53 m mole) of 2-[2-(4-amino-phenyl)-3-methyl-1-propyl-1H-indole-5-yloxy]-2-methyl-propanoic acid ethylester and 0.25 g (2.5 m mole) of triethylamine were dissolved in 15 ml of chloroform and 0.2 g (2.55 m mole) of acetyl chloride were added dropwise while ice-cooling. After a few hours at room temperature the reaction mixture was mixed with water and extracted with chloroform. The chloroform extracts were dried and evaporated, and the residue was purified by chromatography on silicagel (solvent: toluene/acetone (5:1)).
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=1[O:17][CH3:18])([CH3:3])[CH3:2]>CO.[C].[Pd]>[CH:1]([NH:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[O:17][CH3:18])([CH3:3])[CH3:2]
Reactant: COc1cc([N+](=O)[O-])ccc1OCCNC(C)C
Agent: [Pd]
Solvent: CO
Product: COc1cc(N)ccc1OCCNC(C)C
Yield: 99.5 %

Procedure:
N-isopropyl-2-(2-methoxy-4-nitrophenoxy)ethylamine (9.29 g) solution in methanol (100 ml) was added with 10% palladium carbon catalyst and subjected to hydrogenation reaction at ambient pressure. After completion of hydrogenation reaction, catalyst was removed by filtration. Filtrate was concentrated under vacuum to obtain 4-[2-(isopropylamino)ethoxy]-3-methoxyaniline (8.15 g) as yellowish oily substance.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:26][C:27]=1[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:28][C:27]1[O:26][C:25]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[N:24][C:23]=1[CH2:22][S:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: O=C(O)c1ccccc1NS(=O)(=O)c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1CSc1ccc(S(=O)(=O)Nc2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of the title B compound, 2-(4-mercaptobenzene-sulfonylamino)-benzoic acid (200 mg, 0.65 mmol), 4-chloromethyl-5-methyl-2-phenyl-oxazole (134 mg, 0.65 mmol) and cesium carbonate (1.05 g, 3.24 mmol) in DMF is stirred at RT for 3 h. The mixture is then partitioned between EtOAc and 1 N aqueous HCl. The organic phase is dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue is chromatographed on silica gel using 15% EtOAc in hexane (containing 0.5% formic acid) as the eluent to afford 2-[4-(5-methyl-2-phenyl-oxazol-4-ylmethylsulfanyl)-benzenesulfonyl-amino]-benzoic acid as a white foam: m.p. 182-184° C.; ESI-MS 481 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:36])=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([NH:24][C@@H:25]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:26][NH:27][CH3:28])=[O:23])[CH2:17]2)(O)[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1.[C:37](#[N:41])[CH:38]([CH3:40])[CH3:39].C([O-])([O-])=[O:43].[K+].[K+]>OS(O)(=O)=O.O>[Cl:1][C:2]1[C:3]([F:36])=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([NH:24][C@@H:25]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:26][NH:27][CH3:28])=[O:23])[CH2:17]2)([NH:41][C:37](=[O:43])[CH:38]([CH3:40])[CH3:39])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CNC[C@H](CC1CCCCC1)NC(=O)N1CCC[C@@H]([C@@](O)(CCCCOC)c2cccc(Cl)c2F)C1
Reactant: O=C([O-])[O-]
Reactant: CC(C)C#N
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: CNC[C@H](CC1CCCCC1)NC(=O)N1CCC[C@@H]([C@](CCCCOC)(NC(=O)C(C)C)c2cccc(Cl)c2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14 %

Procedure:
(3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide (70 mg, 0.133 mmol) was mixed with isobutyronitrile (8 mL) and conc H2SO4 (23 drops). After stirring vigorously overnight at rt, the mixture was neutralized with K2CO3 (ca. 100 mg). A few drops of water were added and the mixture was filtered. The filtrate was concentrated and the residue was purified by preparative HPLC to afford (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-(isobutyramido)-5-methoxypentyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide (11.4 mg, 14%) as a TFA salt. 1H NMR (400 MHz, CDCl3): 7.94 (s, 1H), 7.41 (td, 1H), 7.27 (td, 1H), 7.15 (t, 1H), 4.25 (d, 1H), 4.11 (m, 1H), 3.92 (d, 1H), 3.37 (t, 1H), 3.28 (s, 3H), 3.07 (dd, 1H), 2.96 (dd, 1H), 2.71 (s, 3H), 2.66 (m, 1H), 2.54 (td, 1H), 1.14 (dd, 6H). 3 min. LC-MS: R/T 1.59 min., m/z 596 (M+H+). In addition, (3R)-3-((R)-1-(3-chloro-2-fluorophenyl)-1-(isobutyramido)-5-methoxypentyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide and (S)-3-(1-(3-chloro-2-fluorophenyl)-1-(isobutyramido)-5-methoxypentyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide and (S)-3-(1-(3-chloro-2-fluorophenyl)-5-methoxypent-1-enyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide were isolated.
Reaction SMILES: [CH:1]([O:14][CH2:15][CH2:16][C:17]1[CH2:18][CH2:19][NH:20][CH2:21][CH:22]=1)([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.[CH2:23](O)[CH3:24].[C:26]([O:29][C:30](=[O:32])[CH3:31])(=O)[CH3:27]>N1C=CC=CC=1>[C:30]([O:29][C@@H:26]([C:24]1[CH:23]=[CH:3][CH:2]=[CH:1][CH:8]=1)[CH2:27][N:20]1[CH2:19][CH2:18][C:17]([CH2:16][CH2:15][O:14][CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:22][CH2:21]1)(=[O:32])[CH3:31]
Reactant: CCO
Reactant: CC(=O)OC(C)=O
Reactant: C1=C(CCOC(c2ccccc2)c2ccccc2)CCNC1
Solvent: c1ccncc1
Product: CC(=O)O[C@H](CN1CC=C(CCOC(c2ccccc2)c2ccccc2)CC1)c1ccccc1

Procedure:
With reference to FIG. 8, 4-(2-(benzhydryloxy)ethyl)-1,2,3,6-tetrahydropyridine 5 (0.5 g, 1.704 mmol), S-styrene oxide 6b (0.205 g, 1.704 mmol), ethanol (20 ml). Yield (after purification)=0.65 g. For acetylation, the mixture of regioisomers (0.5 g, 1.209 mmol), pyridine (10 ml) and acetic anhydride (0.148 ml, 1.571 mmol, 1.3 equiv). Yield (after purification)=0.2 g. 1H-NMR (CDCl3; 400 MHz): 2.03-2.07 (brs, 5H, H-3, COCH3), 2.31-2.34 (t, 2H, J=6.4 Hz, OCH2CH2), 2.59-2.74 (m, 3H, H-2, NCHHCHOAc), 2.95-2.30 (dd, 1H, J=9.2 Hz, NCHHCHOAc), 3.04 (brs, 2H, H-6), 3.51-3.54 (t, 2H, OCH2CH2), 5.33 (s, 1H, PhCH(O)Ph), 5.39 (brs, 1H, CH═C), 5.96-6.00 (dd, 1H, CHOAc), 7.21-7.37 (m, 15H, ArH). [a]25D=+21.17° (c=1.02, CHCl3).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:19][N:18]([OH:20])[C:17](=[O:21])[CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:24](=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CN1CCCC1=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:19][N:18]([O:20][CH3:24])[C:17](=[O:21])[CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1CC(c2ccc(OCc3ccccc3)cc2)CN1O
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CI
Product: CON1CC(c2ccc(OCc3ccccc3)cc2)CC1=O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture containing 0.7 g 4-(4-benzyloxyphenyl)1-hydroxy2-pyrrolidone (Example 2), 5.0 ml methyl iodide and 2.0 g potassium carbonate in 5.0 ml N-methylpyrrolidone was stirred for 2 h at 50° C. 20 ml 1N sodium hydroxide solution was then added and the solution was extracted with a mixture of 20 ml cyclohexane and 10 ml of ether. The extract was washed with water and concentrated in vacuo whereupon the product crystallized. yield 0.31 g (41%), mp 92°-97° C.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([NH:11][S:12]([C:15]2[C:16]3[N:17]=[CH:18][CH:19]=[N:20][C:21]=3[CH:22]=[CH:23][CH:24]=2)(=[O:14])=[O:13])[CH:3]=1.Cl.[CH3:26][O:27][C:28](=[O:40])[C@@H:29]([NH2:39])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[C:33]([Br:38])[CH:32]=1>>[CH3:26][O:27][C:28](=[O:40])[C@@H:29]([NH:39][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[CH:3][C:4]=1[NH:11][S:12]([C:15]1[C:16]2[N:17]=[CH:18][CH:19]=[N:20][C:21]=2[CH:22]=[CH:23][CH:24]=1)(=[O:14])=[O:13])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[C:33]([Br:38])[CH:32]=1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: COC(=O)[C@@H](N)Cc1ccc(F)c(Br)c1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(F)c(Br)c1)NC(=O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
4-Iodo-2-(quinoxaline-5-sulfonylamino)-benzoic acid was coupled to (S)-2-amino-3-(3-bromo-4-fluoro-phenyl)-propionic acid methyl ester hydrochloride as in EXAMPLE 1, Part C, to afford the title compound. HPLC: RT=10.30 min. MS (ESI+): mass calcd. for C25H19BrFIN4O5S, 713.32; m/z found, 713/715 [M+H]+. 1H NMR (500 MHz, CDCl3): 11.09 (s, 1H), 8.99 (d, J=1.7, 1H), 8.92 (d, J=1.7, 1H), 8.58 (dd, J=7.3, 1.3, 1H), 8.33 (dd, J=8.5, 1.3, 1H), 8.09 (d, J=1.5, 1H), 7.90 (dd, J=8.3, 7.5, 1H), 7.30 (dd, J=8.2, 1.5, 1H), 7.25-7.23 (m, 1H), 7.05-6.98 (m, 1H), 6.98-6.90 (m, 2H), 6.43 (d, J=7.1, 1H), 4.90 (q, J=5.5, 1H), 3.81 (s, 3H), 3.20-3.08 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:9]12[CH2:16][CH2:15][C:12]([C:17](OC)=[O:18])([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+].O>C1COCC1.CCOC(C)=O>[CH2:1]([N:8]([C:9]12[CH2:14][CH2:13][C:12]([CH2:17][OH:18])([CH2:11][CH2:10]1)[CH2:15][CH2:16]2)[C:21](=[O:22])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C12CCC(N(Cc3ccccc3)C(=O)OC(C)(C)C)(CC1)CC2
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)C12CCC(CO)(CC1)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.5 %

Procedure:
To a solution of methyl 4-(benzyl(tert-butoxycarbonyl)amino)bicyclo[2.2.2]octane-1-carboxylate (2.70 g, 7.23 mmol) in THF (24 mL) at about 0° C. was added lithium borohydride (0.350 g, 14.46 mmol). The reaction mixture was warmed to ambient temperature and stirred for about 16 h. The reaction was cooled to about 0° C. and water (15 mL) was carefully added. The reaction mixture was warmed to ambient temperature and was diluted with EtOAc (20 mL). The layers were separated and the organic layer was washed with brine (2×20 mL), dried over anhydrous Na2SO4, filtered and concd under reduced pressure to provide tert-butyl benzyl(4-(hydroxymethyl)bicyclo[2.2.2]octan-1-yl)carbamate (2.31 g, 92%) as an off white sticky foam: LC/MS (Table 1, Method b) Rt=2.67 min; MS m/z: 346 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:17])([C:13]([F:16])([F:15])[F:14])[O:8][C:7](=[O:18])[CH2:6]2.[BH4-].[Na+].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:17])([C:13]([F:14])([F:15])[F:16])[O:8][CH:7]([OH:18])[CH2:6]2
Reactant: COc1ccc2c(c1)CC(=O)OC2(C)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CC(O)OC2(C)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution 6-methoxy-1-methyl-1-trifluoromethyl-isochroman-3-one (1.50 g, 5.76 mmol) in tetrahydrofuran (30 mL) at 0° C. was added sodium borohydride (0.240 g, 6.34 mmol) followed by boron trifluoride diethyl ether complex (0.992 g, 8.07 mmol). The reaction mixture was warmed to room temperature and was stirred overnight. The reaction mixture was added to water (75 mL) and extracted with methyl-tert-butyl ether (75 mL). The layers were separated and the organic layer was washed with 1N aqueous hydrochloric acid (50 mL), dried over magnesium sulfate, filtered, and concentrated to afford 6-methoxy-1-methyl-1-trifluoromethyl-isochroman-3-ol as an oil and a mixture of a and b anomers (1.19 g, 79%). Data reported for the major diastereoisomer. 1H NMR (400 MHz, CDCl3) δ1.74 (s, 3), 2.85 (dd, 1, J=15.7, 4.3), 2.88-2.99 (m, 1), 3.11 (dd, 1, J=15.7, 3.2), 3.80 (s, 3), 5.63 (t, 1, J=3.7), 6.69 (d, 1, J=2.7), 6.82 (dd, 1, J=8.7, 2.7), 7.22-7.27 (m, 1). 13C NMR (100 MHz, CDCl3, data reported for identifiable signals of the major diastereoisomer) δ24.52, 35.46, 55.16, 90.71, 113.11, 113.98, 125.22, 127.57, 132.98, 159.59. IR 3439, 2949,1735, 1613, 1506, 1166, 1141, 1070cm−1
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14]N2C3C=CC=CC=3N=N2)=[CH:10][CH:9]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]=NC2C=CC=CC=2)=[CH:27][CH:26]=1>CN(C=O)C>[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[C:14][C:11]2[CH:10]=[CH:9][C:8]([F:7])=[CH:13][CH:12]=2)=[CH:27][CH:26]=1
Reactant: Fc1ccc(Cn2nnc3ccccc32)cc1
Reactant: Fc1ccc(C=Nc2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(C#Cc2ccc(F)cc2)cc1
Temperature: 0 °C

Procedure:
To potassium t-butoxide (1.5 g, 13.4 mmol) in DMF (15 mL) at 75° C. was added as quickly as possible and all at once [(4-fluorophenyl)methyl]-1-H-benzotriazole (1.14 g, 5 mmol) and (4-fluorophenyl)methylenebenzenamine (1.00 g, 5 mmol) dissolved in DMF (10 mL). Within a minute the solution is poured into ice-cold water (75 mL) crystallizing the title compound which was filtered and then chromatographed (PE). The acetylene 0.54 g (50%) recrystallizes as needles: mp 95°-96° C. (MeOH); (lit.1 94°-95° C.).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[NH2:29][C:30]1([CH2:35][OH:36])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH3:28][N:4]1[C:3]([CH2:2][NH:29][C:30]2([CH2:35][OH:36])[CH2:34][CH2:33][CH2:32][CH2:31]2)=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])=[N:8][C:9]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: NC1(CO)CCCC1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CNC3(CO)CCCC3)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with (1-aminocyclopentyl)methanol via General Procedure E to give 10.2 mg of 274 following reverse phase purification. MS (Q1) 477.2 (M)+
Reaction SMILES: COC(=O)NC(C(N1CCCC1C1NC(C2C=CC(C3C=CC(C4NC(C5CCCN5[C:46](=[O:56])[CH:47]([NH:51][C:52]([O:54][CH3:55])=[O:53])[CH:48]([CH3:50])[CH3:49])=NC=4)=CC=3)=CC=2)=CN=1)=O)CCC(F)(F)F.[CH3:58][O:59][C:60](=[O:105])[NH:61][CH:62]([C:71]([N:73]1[CH2:77][CH2:76][CH2:75][CH:74]1[C:78]1[NH:79][C:80]([C:83]2[CH:88]=[CH:87][C:86]([C:89]3[CH:94]=[CH:93][C:92]([C:95]4[NH:96][C:97]([CH:100]5[CH2:104][CH2:103][CH2:102][NH:101]5)=[N:98][CH:99]=4)=[CH:91][CH:90]=3)=[CH:85][CH:84]=2)=[CH:81][N:82]=1)=[O:72])[CH2:63][CH2:64][O:65][CH2:66][C:67]([F:70])([F:69])[F:68]>>[CH3:55][O:54][C:52](=[O:53])[NH:51][CH:47]([C:46]([N:101]1[CH2:102][CH2:103][CH2:104][CH:100]1[C:97]1[NH:96][C:95]([C:92]2[CH:93]=[CH:94][C:89]([C:86]3[CH:87]=[CH:88][C:83]([C:80]4[NH:79][C:78]([CH:74]5[CH2:75][CH2:76][CH2:77][N:73]5[C:71](=[O:72])[CH:62]([NH:61][C:60]([O:59][CH3:58])=[O:105])[CH2:63][CH2:64][O:65][CH2:66][C:67]([F:70])([F:68])[F:69])=[N:82][CH:81]=4)=[CH:84][CH:85]=3)=[CH:90][CH:91]=2)=[CH:99][N:98]=1)=[O:56])[CH:48]([CH3:50])[CH3:49]
Reactant: COC(=O)NC(CCOCC(F)(F)F)C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5)[nH]4)cc3)cc2)[nH]1
Reactant: COC(=O)NC(CCC(F)(F)F)C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1
Product: COC(=O)NC(CCOCC(F)(F)F)C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1
Yield: 45 %

Procedure:
This compound was made in 45% yield by the same procedure as (4,4,4-Trifluoro-1-{2-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-butyl)-carbamic acid methyl ester, using [1-(2-{5-[4′-(2-Pyrrolidin-2-yl-3H-imidazol-4-yl)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-3-(2,2,2-trifluoroethoxy)-propyl]-carbamic acid methyl ester as the starting material. LCMS-ESI+: calculated for C41H49F3N8O7: 822.87; observed [M+1]+: 823.45. 1H-NMR: 400 MHz, (CD3OD) δ: 7.82-7.72 (m, 4H), 7.69-7.65 (m, 4H), 7.38-7.32 (m, 2H), 5.22-5.16 (m, 2H), 4.65-4.61 (m, 1H), 4.26-4.21 (m, 1H), 4.04-3.84 (m, 6H), 3.72-3.48 (m, 8H), 2.39-1.98 (m, 10H), 1.88-1.78 (m, 1H), 1.01-0.89 (m, 6H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][C@@H:11]3[C@@H:16]([C:7]=2[CH:6]=[CH:5][CH:4]=1)[CH2:15][CH2:14][CH2:13][N:12]3C.[Cl:18]C(OC1C=CC=CC=1)=O>C1(C)C=CC=CC=1>[ClH:18].[CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][C@@H:11]3[C@@H:16]([C:7]=2[CH:6]=[CH:5][CH:4]=1)[CH2:15][CH2:14][CH2:13][NH:12]3
Reactant: COc1cccc2c1OC[C@@H]1[C@@H]2CCCN1C
Reactant: O=C(Cl)Oc1ccccc1
Solvent: Cc1ccccc1
Product: COc1cccc2c1OC[C@H]1NCCC[C@H]21
Product: Cl

Procedure:
A solution of 628 mg of trans-7-methoxy-4-methyl-1,2,3,4a,5,10b-hexahydro-4H-[1]-benzopyrano[3,4-b]pyridine and 1 g of phenyl chloroformate in 20 ml of toluene is refluxed for 3 hours. After dilution with ether and washing with aqueous hydrochloric acid, the solvent is removed and 1 g of potassium hydroxide and 20 ml of dioxane is added. After refluxing for 2 hours, the reaction is diluted with water and the product extracted with ether. After drying and removal of solvent, the hydrochloride salt is prepared from ethanolic hydrogen chloride to afford trans-7-methoxy-1,2,3,4a,5,10b-hexahydro-4H-[1]-benzopyrano[3,4-b]pyridine hydrochloride, m.p. 207°-210°.