Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[N:21]=[C:20]([N:22]3[CH2:27][C@@H:26]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][C@@H:24]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:23]3)[N:19]=[C:18]([N:44]3[CH2:49][C@@H:48]([NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][C@@H:46]([NH:58][C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:45]3)[N:17]=2)[CH:12]=[CH:11][C:10]=1[NH:66]C(=O)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CO.O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[N:21]=[C:20]([N:22]3[CH2:27][C@@H:26]([NH:28][C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[CH2:25][C@@H:24]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:23]3)[N:19]=[C:18]([N:44]3[CH2:45][C@@H:46]([NH:58][C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:47][C@@H:48]([NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:49]3)[N:17]=2)[CH:12]=[CH:11][C:10]=1[NH2:66])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc(Nc2nc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)nc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)n2)cc1OCc1ccccc1
Agent: NN
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2nc(Nc3ccc(N)c(OCc4ccccc4)c3)nc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)n2)C1
Temperature: 0 °C
Yield: 67.5 %

Procedure:
N-[2-Benzyloxy-4-(4,6-bis-((3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidin-1-yl)-[1,3,5]triazin-2-ylamino)-phenyl]-acetamide (401) (2.32 g, 2.4 mmol) was dissolved in an mixture of MeOH and dioxane (150 mL, 4:1). Hydrazine monohydrate (100 mL) was added and the mixture was heated to reflux for 10 days. LC-MS indicated complete de-protection at this point. Upon cooling, a white precipitate formed. The mixture was poured into ice water, forcing additional precipitate to form. The solid was collected by filtration under reduced pressure, rinsed with water (100 mL), and dried under high vacuum for 16 h to give the desired product (402) as a white powder (1.48 g, 1.62 mmol, 68% yield). LC-MS (ESI): (exact mass: 919.53) m/e=920.6 [M+1]+ (100%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8](=[O:26])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15][C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][C:21](=[O:25])[NH:22]3)=[CH:18][CH:17]=2)=[CH:5][C:4]([CH3:27])=[N:3]1.[CH:28](OCC)=[O:29].[O-]CC.[Na+].Cl>C(O)C.CCOC(C)=O>[CH3:1][N:2]1[C:6]([NH:7][C:8](=[O:26])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15][C:16]2[CH:24]=[C:23]3[C:19](/[C:20](=[CH:28]/[OH:29])/[C:21](=[O:25])[NH:22]3)=[CH:18][CH:17]=2)=[CH:5][C:4]([CH3:27])=[N:3]1
Reactant: Cc1cc(NC(=O)c2ccccc2Sc2ccc3c(c2)NC(=O)C3)n(C)n1
Reactant: CCOC=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(NC(=O)c2ccccc2Sc2ccc3c(c2)NC(=O)/C3=C\O)n(C)n1
Temperature: 78 °C
Yield: 19 %

Procedure:
N-(2,5-Dimethyl-2H-pyrazol-3-yl)-2-(2-oxo-2,3-dihydro-1H-indol-6-ylsulfanyl)-benzamide (as prepared above in Step 4; 0.300 g, 0.793 mmol) was dissolved in anhydrous ethanol (8 mL) and the resulting solution was treated with ethyl formate (0.058 mL, 0.717 mmol) The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (1.48 mL, 3.97 mmol). This reaction mixture was heated at 78° C. for 0.5 h, which caused the reaction mixture to turn black in color. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH=1 with dropwise addition of 1M HCl(aq). The reaction mixture was diluted with EtOAc (25 mL) and extracted with brine (2×25 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified via flash silica gel chromatography (5% MeOH in CHCl3) affording the title compound in 19% yield (0.061 g, 0.150 mmol).
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.N=C=N.Cl.Cl.[NH:24]1[C:28]2([CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:27][NH:26]/[C:25]/1=[N:34]\[C:35]([C:37]1[C:42]([NH2:43])=[N:41][C:40]([NH2:44])=[C:39]([Cl:45])[N:38]=1)=[O:36].CN1CCOCC1>CN1C(=O)CCC1>[C:1]1([CH3:18])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12]([C:15]([N:31]3[CH2:32][CH2:33][C:28]4([NH:24]/[C:25](=[N:34]/[C:35]([C:37]5[C:42]([NH2:43])=[N:41][C:40]([NH2:44])=[C:39]([Cl:45])[N:38]=5)=[O:36])/[NH:26][CH2:27]4)[CH2:29][CH2:30]3)=[O:17])=[CH:11]2)(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc(C(=O)O)c2)cc1
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCNCC3)N2)nc1Cl
Agent: Cl
Agent: N=C=N
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Product: Cc1ccc(S(=O)(=O)n2ccc(C(=O)N3CCC4(CC3)CN/C(=N\C(=O)c3nc(Cl)c(N)nc3N)N4)c2)cc1
Temperature: 25 °C

Procedure:
A solution of 1-(Toluene-4-sulfonyl)-1H-pyrrole-3-carboxylic acid (0.023 g, 0.085 mmol) in NMP (850 l) is added to PS-carbodiimide (190 mg of 1.3 mmol/g loading, 0.24 mmol), followed by a solution of 3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid [1,3,8-triaza-spiro[4.5]dec-(2E)-ylidene]-amide dihydrochloride (Ex. 38) (0.08 mmol) and N-methyl morpholine (8 l, 0.08 mmol) in NMP (1 ml), and the resulting reaction mixture is shaken at room temperature. The reaction mixture is filtered and the resin is washed with NMP (1 ml). The collected filtrate is concentrated in vacuo and the residues are purified by mass-directed preparative HPLC. The purified fractions are evaporated under vacuum to afford the title compound; [M+H]+ 572.08
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[C:16]3[N:17]([CH2:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]4)[C:18]([N:20]4[CH2:25][CH2:24][O:23][C@@H:22]5[CH2:26][CH2:27][CH2:28][C@@H:21]45)=[N:19][C:15]=3[CH:14]=[C:13]([C:37](=[NH:40])[NH:38][OH:39])[N:12]=2)[C:5]([N:8]([CH3:10])[CH3:9])=[N:6][CH:7]=1.[C:41](N1C=CN=C1)(N1C=CN=C1)=[O:42].N1(C2CCCCCCCCCC2)CCCN=CCCCCC1>C(#N)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[C:16]3[N:17]([CH2:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]4)[C:18]([N:20]4[CH2:25][CH2:24][O:23][C@@H:22]5[CH2:26][CH2:27][CH2:28][C@@H:21]45)=[N:19][C:15]=3[CH:14]=[C:13]([C:37]3[NH:40][C:41](=[O:42])[O:39][N:38]=3)[N:12]=2)[C:5]([N:8]([CH3:9])[CH3:10])=[N:6][CH:7]=1
Reactant: CN(C)c1ncc(Cl)cc1-c1nc(C(=N)NO)cc2nc(N3CCO[C@@H]4CCC[C@H]43)n(C[C@H]3CC[C@H](C)CC3)c12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Solvent: ClCCl
Solvent: CC#N
Product: CN(C)c1ncc(Cl)cc1-c1nc(-c2noc(=O)[nH]2)cc2nc(N3CCO[C@@H]4CCC[C@H]43)n(C[C@H]3CC[C@H](C)CC3)c12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-[5-chloro-2-(dimethylamino)pyridin-3-yl]-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-N-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide (racemic, 22 mg, 0.075 mmol) and 1,1′-carbonyldiimidazole (12 mg, 0.07 mmol) in acetonitrile (1 mL) was added 1,8-diazabicycloundec-7-ene (23 mg, 0.15 mmol). The reaction was stirred at room temperature for 18 hours. The reaction was then diluted with CH2Cl2 and washed with water. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified on a silica gel column (0 to 10% MeOH/CH2Cl2) to afford 3-{4-[5-chloro-2-(dimethylamino)pyridin-3-yl]-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (racemic). NMR shows 8:2 mixture of rotamers, 1H NMR (400 MHz, CD3OD) (for major rotamer) δ 8.27 (d, J=2.8 Hz, 1H), 8.12 (s, 1H), 7.98 (d, J=2.8 Hz, 1H), 3.76-4.04 (m, 3H), 3.35-3.51 (m, 3H), 3.13 (m, 1H), 2.98 (m, 1H), 2.53 (s, 6H), 2.34 (m, 1H), 1.64-1.77 (m, 3H), 1.44-1.56 (m, 3H), 1.12-1.24 (m, 3H), 0.71-0.84 (m, 7H), 0.50-0.62 (m, 2H). MS ES calc'd. for C30H37ClN8O3 [M+H]+ 593. found 593
Reaction SMILES: [BH4-].[Li+].[CH3:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:9](=[O:14])[N:8]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH:7]2[CH2:22][C:23](OCC)=[O:24].O>O1CCCC1>[CH3:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:9](=[O:14])[N:8]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH:7]2[CH2:22][CH2:23][OH:24]
Reactant: CCOC(=O)CC1c2cc(C)c(C)cc2C(=O)N1c1ccc(F)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2c(cc1C)C(CCO)N(c1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 39 h
Yield: 89.7 %

Procedure:
To a solution of lithium borohydride (80 mg, 3.7 mmol) in tetrahydrofuran was added with stirring 5,6-dimethyl-2-(4-fluorophenyl)-3-ethoxycarbonylmethylisoindolin-1-one [IUPAC name: ethyl 2-[2-(4-fluorophenyl)-5,6-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl]acetate] (0.63 g, 1.9 mmol) under ice cooling and stirred at 25° C. for 39 hrs. To the reaction solution was added water, and the precipitated crystals were collected by filtration, washed with water, followed by drying to give 0.51 g of 5,6-dimethyl-2-(4-fluorophenyl)-3-(2-hydroxyethyl)isoindolin-1-one.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([O:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 67.8 %

Procedure:
1-Bromo-4-chloro-2-nitrobenzene (10 g, 42.2 mmol) was added to a solution of 4-methoxyphenol (5.3 g, 42.2 mmol), and K2CO3 (14.5 g, 105 mmol) in DMF (50 mL). The mixture was heated at 80° C. for 16 h. The reaction was poured into water. The aqueous phase was extracted with ethyl acetate and the combined phases were washed with water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the crude title compound. The crude product was purified by silica gel chromatography eluting with (hexanes/ethyl acetate 90:10) to give the title compound (8.0 g, 67%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16]([O:18]/[N:19]=[C:20](/[C:22]3[CH:39]=[CH:38][C:25]([CH2:26][N:27]4[CH2:30][CH:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28]4)=[CH:24][CH:23]=3)\[NH2:21])=O)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O1CCCC1>C(#N)C>[C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:18][N:19]=[C:20]([C:22]4[CH:39]=[CH:38][C:25]([CH2:26][N:27]5[CH2:28][CH:29]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:30]5)=[CH:24][CH:23]=4)[N:21]=3)[S:10][C:11]=2[C:12]([F:13])([F:15])[F:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/OC(=O)c3cc(-c4ccccc4)c(C(F)(F)F)s3)cc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)cc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.3 %

Procedure:
To a solution of (Z)-tert-butyl 1-(4-(N′-(4-phenyl-5-(trifluoromethyl)thiophene-2-carbonyloxy)carbamimidoyl)benzyl)azetidine-3-carboxylate (744 mg, 1.33 mmol) in acetonitrile (30 mL) was added a 1M solution of TBAF in tetrahydrofuran (3.99 mL, 3.99 mmol), and the reaction mixture was allowed to stir at room temperature for 3 days. The volatiles were removed under reduced pressure, and the residue was chromatographed on a 5×12 cm silica gel column, eluting with a 0-50% EtOAc/Hex gradient. The essentially pure fractions containing product were concentrated to afford tert-butyl 1-(4-(5-(4-phenyl-5-(trifluoromethyl)thiophen-2-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (521 mg, 0.962 mmol, 72.4% yield) as a colorless solid. HPLC ret. time=3.63 min. (YMC Combi S-5 4.6×50 mm ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS: (M+H)=542.22. 1H NMR (500 MHz, CDCl3) δ ppm 1.46 (s, 9H), 3.25-3.31 (m, 3H), 3.52-3.58 (m, 2H), 3.69 (s, 2H), 7.43 (d, J=8.25 Hz, 2H), 7.47 (m, 5H), 7.91 (s, d, J=1.65 Hz, 1H), and 8.09 (d, J=8.25 Hz, 2 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[S:8])=[O:5])[CH3:2].[NH2:9][C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([Cl:18])[N:11]=1.CCCCCC>C(Cl)(Cl)Cl>[Cl:18][C:12]1[N:11]=[C:10]([NH:9][C:7]([NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[S:8])[C:15]([O:16][CH3:17])=[CH:14][CH:13]=1
Reactant: CCOC(=O)N=C=S
Reactant: COc1ccc(Cl)nc1N
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: CCOC(=O)NC(=S)Nc1nc(Cl)ccc1OC
Reaction time: 8 h
Yield: 90.9 %

Procedure:
Ethoxycarbonyl isothiocyanate (3.7 mL, 4.1 g, 31.5 mmol) was added slowly with stirring to a solution of 2-amino-6-chloro-3-methoxypyridine (5.0 g, 31.5 mmol) in chloroform (40 mL) and the mixture was stirred overnight. The solvent was removed by evaporation and the residue obtained was mixed with hexane. The resulting slurry was filtered and the solids collected were washed with a small amount of ether and dried to obtain 8.3 g of the title compound as a man powder melting at 184°-185° C. with decomposition.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[ClH:12].[CH3:13][O:14][C:15]1[C:23]2[O:22][C:21]([CH3:25])([CH3:24])[CH2:20][C:19]=2[C:18]([C:26]2[C@@H:35]3[C@@H:30]([CH2:31][CH:32]=[CH:33][CH2:34]3)[C:29](=[O:36])[N:28]([C:37]3[CH:42]=[CH:41][C:40]([C:43](N4CCN(C/C=C/C5C=CC=CC=5)CC4)=[O:44])=[CH:39][CH:38]=3)[N:27]=2)=[CH:17][CH:16]=1>>[ClH:12].[ClH:12].[CH3:1][N:2]([CH3:11])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:43]([C:40]2[CH:41]=[CH:42][C:37]([N:28]3[N:27]=[C:26]([C:18]4[C:19]5[CH2:20][C:21]([CH3:25])([CH3:24])[O:22][C:23]=5[C:15]([O:14][CH3:13])=[CH:16][CH:17]=4)[C@@H:35]4[C@@H:30]([CH2:31][CH:32]=[CH:33][CH2:34]4)[C:29]3=[O:36])=[CH:38][CH:39]=2)=[O:44])[CH2:7][CH2:6]1
Reactant: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(C/C=C/c5ccccc5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)c2c1OC(C)(C)C2
Reactant: CN(C)CCN1CCNCC1
Agent: Cl
Product: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(CCN(C)C)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)c2c1OC(C)(C)C2

Procedure:
Prepared from intermediate product A2 and 1-(2-dimethylaminoethyl)-piperazine as described for compound 8. M.p. 245° C. (with decomposition).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+].Cl>O.CC(C)=O>[C:2]1([NH:1][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(Nc1ccccc1)c1ccccc1
Reaction time: 1.5 h

Procedure:
N-phenylbenzamide (Structure II) is synthesized from aniline and benzoyl chloride using acetone as a reaction media and an aqueous solution of NaOH to neutralize the HCl generated. A 20 ml aqueous solution of NaOH (2.57 grams, 0.064 moles) and 6.0 grams (0.064 moles) of aniline are first added to a stirred 250 ml flask containing 75 ml of acetone. Benzoyl chloride (9.06 grams, 0.064 moles) is next added over a five minute period. This reaction mixture which now contains a white precipitate is stirred for 1.5 hours and then diluted with 50 ml of deionized water. This solution is next filtered and the filter cake obtained is sequentially washed with 50 ml of deionized water (two times) followed by 50 ml of methanol. The washed filter cake is recovered and DCS analysis of this product showed a sharp melting endotherm at 169° C. ##STR10##
Reaction SMILES: O=S(Cl)Cl.[N+:5]([C:8]1[CH:19]=[CH:18][C:11]([CH2:12][C@@H:13]([C:15]([OH:17])=[O:16])[NH2:14])=[CH:10][CH:9]=1)([O-:7])=[O:6].[CH3:20]O>>[CH3:20][O:16][C:15](=[O:17])[C@H:13]([CH2:12][C:11]1[CH:10]=[CH:9][C:8]([N+:5]([O-:7])=[O:6])=[CH:19][CH:18]=1)[NH2:14]
Reactant: CO
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Yield: 97 %

Procedure:
10 mL of SOCl2 and 40 mL of methanol were thoroughly mixed in an ice bath for 30 minutes, followed by mixing with 0.51 g of p-nitrophenylalanine to obtain a reaction solution. The reaction solution was subjected to reflux reaction at 70° C. for 24 hours, followed by evaporating, re-crystallizing in ether, and filtering to obtain a product of 0.53 g (97.0%) of a white solid of NBPDA.
Reaction SMILES: C([N:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C@@H:19]([O:32][Si:33]([CH2:38][CH3:39])([CH2:36][CH3:37])[CH2:34][CH3:35])[CH2:20][N:21](CC2C=CC=CC=2)[CH2:22][CH2:23][OH:24])[CH:14]=1)[S:9]([CH3:12])(=[O:11])=[O:10])C1C=CC=CC=1.CO.O.[H][H]>C1COCC1.[OH-].[OH-].[Pd+2]>[OH:24][CH2:23][CH2:22][NH:21][CH2:20][C@@H:19]([C:15]1[CH:14]=[C:13]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])[CH:18]=[CH:17][CH:16]=1)[O:32][Si:33]([CH2:34][CH3:35])([CH2:36][CH3:37])[CH2:38][CH3:39]
Reactant: [H][H]
Reactant: CC[Si](CC)(CC)O[C@@H](CN(CCO)Cc1ccccc1)c1cccc(N(Cc2ccccc2)S(C)(=O)=O)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC[Si](CC)(CC)O[C@@H](CNCCO)c1cccc(NS(C)(=O)=O)c1
Temperature: 50 °C
Reaction time: 15 h
Yield: 106.6 %

Procedure:
(R)—N-Benzyl-N-(3-(2-(benzyl(2-hydroxyethyl)amino)-1-(triethylsilyloxy)ethyl)phenyl)methanesulfonamide (500 mg; intermediate described in Reference example 1 of International Publication No. WO03/035620) was dissolved in THF (1.76 mL; manufactured by Wako Pure Chemical Industries, Ltd.) and methanol (1.76 mL; manufactured by Wako Pure Chemical Industries, Ltd.) under nitrogen atmosphere, and added with 20% palladium hydroxide on carbon-49.94% wet with Water (102.7 mg; manufactured by N. E. Chemcat Corp.). The reaction system was replaced with hydrogen, and stirred at 50° C. for 15 hours under hydrogen atmosphere. After cooling the reaction solution to room temperature and replacement with nitrogen, filtration was carried out. The filtrate was concentrated under reduced pressure to obtain the title compound (364 mg).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][C:10]#[N:11])[CH:4]=1.Br[CH2:13][C:14]([O:19][CH3:20])([O:17][CH3:18])[CH2:15]Br.O>CN(C=O)C>[CH3:18][O:17][C:14]1([O:19][CH3:20])[CH2:15][C:9]([C:5]2[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=2)([C:10]#[N:11])[CH2:13]1
Reactant: N#CCc1cccnc1
Reactant: COC(CBr)(CBr)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC1(OC)CC(C#N)(c2cccnc2)C1
Temperature: 60 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
To a stirred suspension of NaH (1.466 g, 36.6 mmol, 60% in mineral oil) in DMF (25 mL) was added 2-(pyridin-3-yl)acetonitrile (1.954 mL, 18.32 mmol) followed by 1,3-dibromo-2,2-dimethoxypropane (4 g, 15.27 mmol) and the reaction mixture was warmed to 60° C. and stirred for 12 h. The reaction mixture was cooled to RT, poured into water (250 mL) and extracted with EtOAc (3×50 mL). The organic layer was separated, washed with water, brine, dried over Na2SO4, filtered and the filtrate concentrated. The crude product was purified by silica gel chromatography (40 g REDISEP® column, eluting with 50% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate 311A as a white solid (2 g, 60%). MS(ES): m/z=219.2 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.71 (dd, J=0.8, 2.6 Hz, 1H), 8.58 (dd, J=1.7, 4.7 Hz, 1H), 7.89 (s, 1H), 7.51-7.45 (m, 1H), 3.19 (s, 3H), 3.08 (s, 3H), 2.89 (s, 1H), 2.83 (s, 1H), 2.78 (s, 1H), 2.73 (d, J=0.8 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:39]=[C:40]([F:42])[CH:41]=1)[CH2:5][C@H:6]1[C@@H:10]([C@H:11]2[CH2:20][C:19]3[C:14](=[C:15]([O:21][CH2:22][CH:23]=[CH2:24])[CH:16]=[CH:17][CH:18]=3)[CH2:13][N:12]2[CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:9]C(=O)[NH:7]1.[Li+].[OH-].C(OCC)C>CCO.O>[CH2:22]([O:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[CH2:13][N:12]([CH:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C@@H:11]([C@@H:10]([OH:9])[C@@H:6]([NH2:7])[CH2:5][C:4]1[CH:39]=[C:40]([F:42])[CH:41]=[C:2]([F:1])[CH:3]=1)[CH2:20]2)[CH:23]=[CH2:24]
Reactant: C=CCOc1cccc2c1CN(C(c1ccccc1)c1ccccc1)[C@@H]([C@H]1OC(=O)N[C@H]1Cc1cc(F)cc(F)c1)C2
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: C=CCOc1cccc2c1CN(C(c1ccccc1)c1ccccc1)[C@@H]([C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1)C2
Temperature: 110 °C
Reaction time: 5 h
Yield: 105.7 %

Procedure:
To a solution of (4S,5S)-4-(3,5-difluorobenzyl)-5-((R)-8-(allyloxy)-2-benzhydryl-1,2,3,4-tetrahydroisoquinolin-3-yl)oxazolidin-2-one (Step F (15), 40 mg, 0.07 mmol) in EtOH (3 mL) was added a solution of LiOH (17 mg, 0.7 mmol) in H2O (0.6 mL). This reaction mixture was stirred at 110° C. for 5 h and stirred at 80° C. overnight. Ethyl ether (50 mL) was added to the mixture and washed with 1N HCl (40 mL) twice. The aqueous phase was basified to pH 12 with 50% aqueous NaOH solution. This mixture was extracted with ethyl acetate (120 mL). The organic layer was dried (Na2SO4), and concentrated in vacuo to give 40 mg of the title compound of Preparation F. 1H NMR (CDCl3, 500 MHz) δ 1.87 (3H, brd s), 2.38 (1H, dd, J=10, 15 Hz), 2.79 (1H, d, J=20 Hz), 2.96-2.99 (2H, m), 3.05 (1H, dd, J=5, 15 Hz), 3.62 (1H, m), 3.66 (1H, dd, J=5, 10 Hz), 3.71 (1H, d, J=20 Hz), 4.04 (1H, d, J=15 Hz), 4.33-4.40 (2H, m), 4.77 (1H, s), 5.08-5.15 (2H, m), 5.81 (1H, m), 6.63 (1H, d, J=10 Hz), 6.71-6.75 (1H, m), 6.79 (1H, d, J=10 Hz), 6.88 (2H, m), 7.10-7.21 (5H, m), 7.28-7.31 (2H, m), 7.40 (2H, d, J=10 Hz), 7.44 (2H, d, J=5 Hz). MS (ESI) (M+H)+ 541.22.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][NH:5][C:4](=[O:7])[CH2:3]1.[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.C1(C)C=CC(S([O-])(=O)=[O:21])=CC=1.[NH+]1C=CC=CC=1>ClCCl.C(OCC)C>[O:21]=[C:13]1[CH2:12][CH:11]([O:1][C@@H:2]2[CH2:6][NH:5][C:4](=[O:7])[CH2:3]2)[CH2:10][CH2:9][O:8]1
Reactant: C1=COCCC1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: O=C1C[C@H](O)CN1
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1C[C@H](OC2CCOC(=O)C2)CN1
Temperature: 25 °C
Reaction time: 18 h
Yield: 608.5 %

Procedure:
To a solution of (S)-4-hydroxypyrrolidin-2-one (1.00 g, 9.89 mmol) in anhydrous dichloromethane (40 mL) was added 3,4-dihydro-2H-pyrane (1.35 mL, 14.84 mmol) and pyridinium p-toluenesulfonate (0.25 g, 0.99 mmol). The reaction mixture was stirred at ambient temperature for 18 hours, diluted with diethyl ether (100 mL) and washed with brine (25 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to afford (4S)-4-(2-oxotetrahydro-2H-pyran-4-yloxy)pyrrolidin-2-one as a clear oil (1.20 g, 61%): 1H NMR (300 MHz, CDCl3) δ 6.60 (br s, 1H), 4.98-4.57 (m, 1H), 4.57-4.46 (m, 1H), 3.89-3.70 (m, 1H), 3.68-3.22 (m, 3H), 2.69-2.22 (m, 2H), 1.89-1.50 (m, 6H).
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[C:10]([CH2:13][N:14]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:15]([CH:17]3[O:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]3)=[O:16])[CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][CH2:3]1.[H][H]>[Pd].C(O)C>[CH2:30]([N:14]([CH2:13][C:10]1[CH:11]=[CH:12][C:7]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:8]=2[CH:9]=1)[C:15]([CH:17]1[O:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:18]1)=[O:16])[CH:31]([CH3:33])[CH3:32]
Reactant: [H][H]
Reactant: CC(C)CN(Cc1ccc2c(c1)C(O)CCCC2)C(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Agent: [Pd]
Solvent: CCO
Product: CC(C)CN(Cc1ccc2c(c1)CCCCC2)C(=O)C1CN(C(=O)OC(C)(C)C)CCO1

Procedure:
A mixture of 230 mg 0.50 mmol) of (±)-tert-butyl 2-{[[(9-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)methyl](isobutyl)amino]-carbonyl}morpholine-4-carboxylate, and 60 mg of 10% palladium on carbon catalyst in 5 mL of ethanol was stirred under of hydrogen (1 atmosphere) for four hours. The mixture was filtered and concentrated under reduced pressure. The residue was filtered through a pad of silica gel eluting with 33% ethyl acetate in hexanes. The filtrate was concentrated and the residue dried to give product as a gummy foam. MS (m+1)=445.4; H NMR (400 MHz, CDCl3) 7.04 (m, 1H), 6.89 (m, 2H), 4.7 (m, 1H), 4.45 (d, 1H, J 16 Hz), 4.18-4.02 (m, 2H), 3.90 (m, 2H), 3.51 (m, 1H), 3.22 (m, 2H), 3.03 (m, 2H), 2.77 (m, 4H), 2.00 (m, 1H), 1.82 (m, 2H), 1.63 (m, 4H), 1.45 (d, 9H, J 15 Hz), 0.91 (m, 6H).