Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:15][CH2:14][C:13](=O)[CH2:12]1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>[OH-].[Na+]>[CH2:17]([NH:24][CH:13]1[CH2:14][CH2:15][CH:11]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][CH:6]=2)[CH2:12]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: O=C1CCC(c2c[nH]c3ccc(F)cc23)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Fc1ccc2[nH]cc(C3CCC(NCc4ccccc4)C3)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 105.5 %

Procedure:
A mixture 3-(5-fluoro-1H-indol-3-yl)-cyclopentanone (1.0 g, 4.61 mmol), benzylamine (0.54 g, 5.05 mmol) and glacial acetic acid (0.7 mL, 1.08 mmol) were stirred at room temperature for 30 minutes. Sodium triacetoxy borohydride (1.5 g; 7.11 mmole) was added portionwise over a 10 minutes period. The reaction was stirred at room temperature for 24 hours. The reaction mixture was poured into 1 N aqueous NaOH (80 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with H2O (100 mL) and brine (100 mL), then were dried over anhydrous sodium sulfate, filtered and concentrated to give 1.5 g of a thick yellow oil. Flash chromatography on silica gel (7% 2 M NH3 in methanol/ethyl acetate) afforded 0.5 g of the cis isomer (first eluting) and 0.5 g of the trans isomer.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14]O>S(=O)(=O)(O)O>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 19.5 h

Procedure:
To a solution of 4-hydroxy-3-nitrobenzoic acid (10.0 g) in methanol (100 ml), concentrated sulfuric acid (1 ml) was added and stirred at 80° C. for 19.5 hours. After the reaction mixture was concentrated, saturated aqueous sodium bicarbonate and ethyl acetate were added to the resulting residue. This mixture was stirred and the aqueous layer was then separated. The separated aqueous layer was diluted with 1M aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed sequentially with water and brine, and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to give methyl 4-hydroxy-3-nitrobenzoate (10.9 g) as a yellow solid. To a solution of methyl 4-hydroxy-3-nitrobenzoate thus obtained (10.9 g) in tetrahydrofuran:methanol (1:1, 100 ml), 10% palladium on activated carbon (550 mg) was added and stirred overnight under a hydrogen atmosphere at room temperature. After the reaction mixture was filtered through celite, the solvent was distilled off under reduced pressure to give methyl 3-amino-4-hydroxybenzoate (9.1 g) as a light-brown solid. To a solution of methyl 3-amino-4-hydroxybenzoate thus obtained (9.1 g) in N,N-dimethylformamide (80 ml), potassium carbonate (37.3 g) and 1,2-dibromoethane (14 ml) were added and stirred at 130° C. for 2 hours and then stirred overnight at room temperature. After insoluble materials were filtered off, the filtrate was diluted with ethyl acetate and washed with water. The organic layer was extracted with 6M aqueous hydrochloric acid, and the resulting aqueous layer was diluted with 8M aqueous sodium hydroxide and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then filtered to remove the desiccant, followed by distilling off the solvent under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=10:1 to 5:1) to give the titled compound, i.e., methyl 3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (7.10 g) as a pink solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].C([O-])(O)=O.[Na+].[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:19](Cl)=[O:20]>C(#N)C.O>[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:19]([NH:1][C:2]1[C:3]([CH3:9])=[CH:4][CH:5]=[CH:6][C:7]=1[OH:8])=[O:20]
Reactant: O=C(Cl)c1ccc(Cl)c(Br)c1
Reactant: Cc1cccc(O)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1cccc(O)c1NC(=O)c1ccc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.9 %

Procedure:
2-Amino-m-cresol (4.9 g, 40 mmol) was dissolved in a mixture of acetonitrile (90 mL) and water (80 mL) containing NaHCO3 (6.7 g, 80 mmol) with vigorous stirring. 3-Bromo-4-chloro-benzoyl chloride (10.1 g, 40 mmol, Step 2A) was added in several portions and the mixture was stirred at room temperature for 3 hrs. The resulting precipitates were filtered, washed with water and tert-butyl methyl ether, then dried to yield 3-bromo-4-chloro-N-(2-hydroxy-6-methyl-phenyl)-benzamide (11.3 g). MS (M+H)+: 339.7/341.7; tR=2.36 min. (method 1)
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:10]2[CH2:22][CH2:21][N:13]3[C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=4[CH:20]=[C:12]3[C:11]2=[O:23])[N:5]=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:56][O:55][CH2:54]4)[CH2:49][CH2:48]3)=[CH:43][N:42]=2)[C:26]1=[O:57]>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].O1CCCC1>[CH3:24][N:25]1[C:26](=[O:57])[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:54][O:55][CH2:56]4)[CH2:49][CH2:48]3)=[CH:43][N:42]=2)=[CH:28][C:29]([C:2]2[C:7]([CH:8]=[O:9])=[C:6]([N:10]3[CH2:22][CH2:21][N:13]4[C:14]5[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=5[CH:20]=[C:12]4[C:11]3=[O:23])[N:5]=[CH:4][CH:3]=2)=[CH:30]1
Reactant: O=Cc1c(Cl)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 25 °C
Yield: 80.3 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 103b (600 mg, 1.0 mmol), 1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)pyridin-2(1H)-one 101l (468 mg, 1.0 mmol), Pd(dppf)Cl2 (81 mg, 0.1 mmol), K3PO4.3H2O (678 mg, 3.0 mmol), and tetrahydrofuran (20 mL). After three cycles of vacuum/argon flush, the mixture was heated at reflux for 4 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (40:1) to afford 103c as yellow solid (510 mg, 73%). MS: [M+H]+ 635.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]([CH3:25])([CH3:24])[CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[C:16]2[CH2:17][C:18]([CH3:25])([CH3:24])[CH2:19][C:20]([CH3:23])([CH3:22])[CH2:21]2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(F)cc2)CC(C)(C)C1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 90.4 %

Procedure:
The o-alkylation procedure described for 10 (example 5, step 2) was used. To a stirred suspension of 4-[(4-fluorophenyl)(3,3,5,5 tetramethylcyclohexylidene) methyl]phenol 9 (0.590 g, 1.74 mmol), K2CO3 (0.482 g, 3.5 mmol), and acetone (50 mL) was added ethyl 4-bromobutyrate (0.62 mL, 4.4 mmol) under a nitrogen atmosphere at RT. The reaction mixture was refluxed for 6 h, cooled to RT and filtered. Standard work-up followed by purification afforded 0.712 g (90%) of compound 12 as a white foam. 1H NMR (300 MHz, CDCl3): δ 7.14 (d, J=5.7 Hz, 1H), 7.11 (d, J=5.7 Hz, 1H), 7.07 (d, J=8.7 Hz, 2H), 6.98 and 6.95 (dd, J=8.7 Hz, J2=8.7 Hz, 2H), 6.81 (d, J=8.4 Hz, 2H), 4.16 (q, J=7.2 Hz, 2H), 3.99 (t, J=6.00 Hz, 2H), 3.49 (t, J=6.3 Hz, 2H), m, 2H), 2.11 (quint., J=6.30 Hz, 2H), 2.00 (s, 2H), 1.96 (s, 2H), 1.31 (br s, 2H), 1.27 (t, J=7.2 Hz, 3H), 0.95 (s, 6H), 0.94 (s, 6H). LCMS (ESI): m/z 475 (M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:16]=[CH:15][N:14]=[C:13]3[C:8]=2[C:9]2[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=2[C:11](=[O:17])[NH:12]3)=[CH:4][C:3]=1[F:24].[Cl:25][C:26]1[N:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:27]=1[C:28](Cl)=[O:29]>>[Cl:25][C:26]1[N:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:27]=1[C:28]([NH:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:16]=[CH:15][N:14]=[C:13]3[C:8]=2[C:9]2[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=2[C:11](=[O:17])[NH:12]3)=[CH:4][C:3]=1[F:24])=[O:29]
Reactant: O=C(Cl)c1cc(Cl)cnc1Cl
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)c4ccccc4c23)cc1F
Product: O=C(Nc1ccc(Oc2ccnc3[nH]c(=O)c4ccccc4c23)cc1F)c1cc(Cl)cnc1Cl
Yield: 46.7 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 180 using Compound 185 (50 mg, 0.16 mmol) and 2,5-dichloro-nicotinoyl chloride (36 mg, 0.17 mmol) to provide 186 (37 mg, 48% yield) as a dark solid. LC-MS (M+H=496, obsd.=496).
Reaction SMILES: P(Br)(Br)[Br:2].[C:5]([C:9]1[CH:10]=[C:11]([CH:38]=[C:39]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:40]=1)[CH:12]=[CH:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([CH:22]=[CH:23][C:24]2[CH:29]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:27]=[C:26]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:25]=2)[CH:21]=1)[CH2:17]O)([CH3:8])([CH3:7])[CH3:6].CC(O)C>ClCCl>[C:5]([C:9]1[CH:10]=[C:11]([CH:38]=[C:39]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:40]=1)[CH:12]=[CH:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([CH:22]=[CH:23][C:24]2[CH:29]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:27]=[C:26]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:25]=2)[CH:21]=1)[CH2:17][Br:2])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)c1cc(C=Cc2cc(C=Cc3cc(C(C)(C)C)cc(C(C)(C)C)c3)cc(CO)c2)cc(C(C)(C)C)c1
Reactant: BrP(Br)Br
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C)(C)c1cc(C=Cc2cc(C=Cc3cc(C(C)(C)C)cc(C(C)(C)C)c3)cc(CBr)c2)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.5 %

Procedure:
Phosphorus tribromide (2.8 cm3, 30 mmol) was added to a solution of 3,5-bis(3′,5′-di-tert-butylstyryl)benzyl alcohol (1.60 g, 3.0 mmol) in dichloromethane (50 cm3) and the mixture stirred at room temperature for 3 h. Propan-2-ol (14 cm3) was added slowly and the solvent was completely removed. The residue was purified by column chromatography over silica, eluting with dichloromethane-light petroleum (40–60) (1:9), giving 3,5-bis(3′,5′-di-tert-butylstyryl)benzyl bromide (1.52 g, 85%). A sample for analysis was recrystallised from a dichloromethane-light petroleum (60–80) mixture, mp 222–223° C. (Found: C, 77.75; H, 8.72. C39H51Br requires C, 78.11; H, 8.57%); vmax(CHCl3)/cm−1 1596s (C═C) and 964s (C═C—H trans); λmax(CHCl3)/nm (log ε) 315 (4.82); δH(400 MHz, CDCl3) 1.38 (36H, s, t-Bu), 4.55 (2H, s, CH2), 712 and 7.24 (4H, d, J 16, 7′, 8′-H), 7.39 (2H, dd, J 1.5, 4′-H), 7.41 (4H, d, J 1.5, 2′, 6′-H), 7.47 (2H, d, J 1, 2, 6-H) and 7.63 (1H, m, 4-H); m/z (APCI+) 521 ((M-Br)+, 100%) and 599 (M+, 40%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C(OCC)(=O)C>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]2[NH:8][C:9]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:15])=[O:24])=[CH:26][CH:27]=1)([O-:18])=[O:17]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@@H]1O
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1OC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
To a solution of tert-butyl (1S,2S)-2-hydroxycyclohexylcarbamate (1.30 g, 6.04 mmol), 4-nitrobenzoic acid (1.11 g, 6.64 mmol), triphenylphosphine (1.74 g, 6.64 mmol) in THF (30 mL) was added diethylazo dicarboxylate (1.05 ml, 6.64 mmol) and the resulting solution was stirred at ambient temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried and concentrated to give an orange oil that was purified by column chromatography (hexanes/ethyl acetate, 8:1) to give (1R,2S)-2-(tert-butoxycarbonylamino)cyclohexyl 4-nitrobenzoate (1.95 g, 89%).
Reaction SMILES: [N+:1]([O-:4])([OH:3])=O.[N+:5]([C:8]1[N:9]=[CH:10][NH:11][CH:12]=1)([O-:7])=[O:6]>C(O)(=O)C.C(OC(=O)C)(=O)C>[N+:1]([N:11]1[CH:12]=[C:8]([N+:5]([O-:7])=[O:6])[N:9]=[CH:10]1)([O-:4])=[O:3]
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cn([N+](=O)[O-])cn1
Yield: 52.1 %

Procedure:
In NON-PATENT DOCUMENT 5, 100 mass % nitric acid is added dropwise to 4-nitroimidazole in glacial acetic acid and acetic anhydride is further added dropwise thereto to perform nitration reaction, and then the reaction solution is added into crushed ice and 1,4-dinitroimidazole is produced at a yield of 52.1% by performing filtration, washing and vacuum drying.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[C:5]=1[F:20]>O.CO>[F:3][C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH:8]([OH:15])[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[C:5]=1[F:20]
Reactant: O=c1c2ccccc2c(F)c(F)c2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC1c2ccccc2C(F)=C(F)c2ccccc21
Reaction time: 1 h

Procedure:
In a similar manner, a solution of 0.20 gram (52 millimoles) of sodium borohydride in 5 milliliters of water was added dropwise with stirring to a boiling refluxing solution of 0.50 gram (21 millimoles) of 10,11-difluoro-5H-dibenzo[a,d]cyclohepten-5-one in 50 milliliters of methanol; the stirring and refluxing were continued for one hour, and the mixture thereafter allowed to cool. Most of methanol then was vaporized from the mixture, water added and stirred to obtain white crystalline 10,11-difluoro-5H-dibenzo[a,d]cyclohepten-5-ol intermediate. The latter was washed with water and dried under reduced pressure at about 75° C.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]2[CH2:6][CH2:7][CH2:8][CH:9]([N:11]([CH2:19][C@H:20]([OH:29])[CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10][C:4]=2[CH:3]=1.Cl[C:33]([O:35][CH3:36])=[O:34].N1C=CC=CC=1.C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:36][O:35][C:33]([NH:1][C:2]1[CH:31]=[CH:30][C:5]2[CH2:6][CH2:7][CH2:8][CH:9]([N:11]([CH2:19][C@H:20]([OH:29])[CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10][C:4]=2[CH:3]=1)=[O:34]
Reactant: Nc1ccc2c(c1)CC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)CCC2
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Nc1ccc2c(c1)CC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)CCC2

Procedure:
Under nitrogen, a solution of (2S)-1-(N-(3-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-benzylamino]-3-phenoxy-2-propanol (150 mg), methyl chloroformate (29 μl), pyridine (25 μl) and catalytic amounts of 4-dimethylaminopyridine in dichloromethane (3 ml) was stirred at room temperature for 1.5 hours. The resulting mixture was poured into saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1) to give (2S)-1-[N-(3-methoxycarbonylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-benzylamino]-3-phenoxy-2-propanol (158 mg).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[CH:31]=[CH:30][C:18]([C:19]([N:21]([CH3:29])[CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=O)=[CH:17][CH:16]=1.[C:32](#[N:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[NH4+].[Cl-]>C1COCC1>[CH3:29][N:21]1[C:22]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[C:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:39]=[C:19]1[C:18]1[CH:30]=[CH:31][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1
Reactant: N#Cc1ccccc1
Reactant: COc1ccc(C(=O)N(C)Cc2ccncc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc(-c2nc(-c3ccccc3)c(-c3ccncc3)n2C)cc1
Temperature: -40 °C
Reaction time: 10 h
Yield: 16.5 %

Procedure:
To a solution of diisopropylamine (0.16 mL, 1.1 mmol) in THF at −78° C. was added n-butyllithium (0.38 mL of 2.5 M solution, 0.95 mmol). To the resulting mixture was added a solution of 4-methoxy-N-methyl-N-(4-picolyl)benzamide (0.16 g, 0.62 mmol) in THF. The resulting dark red solution was warmed to −40° C. and stirred for 15 min, at which time benzonitrile (0.13 mL, 1.2 mmol) was added. The mixture to warmed to rt and stirred for 10 h. Aqueous NH4Cl (0.5 mL) was added, and the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with a solvent gradient of 2-4% MeOH/CHCl3. The material which was isolated was triturated with Et2O and recrystallized from EtOAc to provide the title compound as an off-white solid (35 mg, 17%): mp 193-194° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)[CH2:3][CH2:2]1.[CH:19]12[NH:26][CH:23]([CH2:24][CH2:25]1)[CH2:22][CH:21]([OH:27])[CH2:20]2>>[OH:27][CH:21]1[CH2:20][CH:19]2[N:26]([C:13]([C:12]3[CH:16]=[CH:17][CH:18]=[C:10]([O:9][CH2:8][CH2:7][CH:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[CH:11]=3)=[O:15])[CH:23]([CH2:24][CH2:25]2)[CH2:22]1
Reactant: OC1CC2CCC(C1)N2
Reactant: O=C(O)c1cccc(OCCC2CCOCC2)c1
Product: O=C(c1cccc(OCCC2CCOCC2)c1)N1C2CCC1CC(O)C2

Procedure:
Prepared from 3-(tetrahydro-pyran-4-yl-ethoxy)-benzoic acid and 8-aza-bicyclo[3.2.1]octan-3-ol. LC-MS (m/z): 360 (M).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[C:20]1[O:21][CH:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]([OH:26])[CH2:24][N:25]=1>ClCCCl>[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[C:20]1[O:21][CH:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]([O:26][C:8](=[O:9])[NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:24][N:25]=1
Reactant: O=C=Nc1ccccc1
Reactant: OC1CN=C(c2ccc3ccccc3c2)OC1c1ccccc1
Solvent: ClCCCl
Product: O=C(Nc1ccccc1)OC1CN=C(c2ccc3ccccc3c2)OC1c1ccccc1
Temperature: 80 °C
Yield: 36.3 %

Procedure:
Phenyl isocyanate (0.7 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of (5RS, 6SR)-2-(2-naphthyl)-6-phenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (1.8 g) in 1,2-dichloroethane (21 cc). The solution obtained is heated to 80° C. for 4 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is purified by chromatography on silica (0.063-0.2 mm; 200 g) contained in a column 2.5 cm in diameter, collecting 20-cc fractions. The fractions 12 to 20, eluted with dichloromethane, are concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in acetonitrile, (5RS, 6SR)-2-(2-naphthyl)-6-phenyl-5-phenylcarbamoyloxy-5,6-dihydro-4H-1,3-oxazine (0.9 g), m.p. 163° C., is obtained.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@:10]([CH2:29][O:30][S:31]([CH3:34])(=[O:33])=[O:32])([CH2:20][O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:9][CH:6]1OC)(=[O:3])[CH3:2].[C:35]1([S:41][Si](C)(C)C)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O>ClCCl>[C:1]([O:4][C@@H:5]1[C@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@:10]([CH2:29][O:30][S:31]([CH3:34])(=[O:33])=[O:32])([CH2:20][O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:9][C@H:6]1[S:41][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:3])[CH3:2]
Reactant: COC1O[C@@](COCc2ccccc2)(COS(C)(=O)=O)[C@@H](OCc2ccccc2)[C@H]1OC(C)=O
Reactant: C[Si](C)(C)Sc1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)O[C@H]1[C@H](Sc2ccccc2)O[C@@](COCc2ccccc2)(COS(C)(=O)=O)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 8.8 %

Procedure:
Method a. A stirred solution of 209 (738 mg, 1.49 mmol) in anhydrous dichloromethane (6.4 mL) was added phenylthiotrimethylsilane (2.42 mL, 12.8 mmol) and cooled to 0° C. Trimethylsilyl triflate (0.67 mL, 3.67 mmol) was added dropwise and the solution was stirred at room temperature for 4 h. The reaction was quenched with a saturated aqueous solution of sodium hydrogen carbonate (100 mL) and extracted with dichloromethane (2×200 mL). The combined extract was dried (MgSO4) and the solvent removed by distillation under reduced pressure. The residue was purified by chromatography over silica gel with dichloromethane as eluent to given the product 210 as a clear oil (564 mg, 66%) and unreacted starting material (191 mg, 26%); Method b. A stirred solution of 211 (86 mg, 0.165 mmol) in anhydrous dichloromethane (0.49 mL) was added phenylthiotrimethylsilane (0.16 mL, 0.825 mmol) and cooled to 0° C. Trimethylsilyl triflate (0.037 mL, 0.206 mmol) was added and the solution was stirred at room temperature for 2 h. The reaction was quenched with a saturated aqueous solution of sodium hydrogen carbonate (15 mL) and the resulting mixture was extracted with dichloromethane (2×25 mL). The combined extract was dried (MgSO4) and the solvent removed by distillation under reduced pressure. The residue was purified by chromatography over silica gel with dichloromethane as eluent to give the product 210 as a clear oil (75 mg, 79%); 1H NMR (CDCl3); δ7.47-7.19 (15H, m, Bn, SPh), 5.48 (1H, d, J 3.6 Hz, H-2), 5.34 (1 H, dd, J 3.7, 5.2 Hz, H-1), 4.54-4.36 (7H, m, H-3, H-5′, Bn), 3.66 (1H, d, J 9.7 Hz, H-5), 3.48 (1H, d, J 9.5 Hz, H-5), 2.89 (3H, s, SO2CH3), 2.09 (3H, s, OCCH3); 13C NMR (CDCl3): δ169.93 (C═O), 137.69, 137.08, 132.65, 32.45, 129.15, 128.53, 128.52, 128.18, 128.14, 128.08, 127.91, 127.85 (Bn, SPh), 87.99, 84.35, 80.34, 75.33, 74.20, 73.67, 70.83, 69.34 (C-1, C-2, C-3, C-4, C-5, C-5′, Bn), 37.27 (SO2CH3), 20.68 (OCCH3); MS FAB: 463 (M−Sph, 100%), 595 (M+Na, 24%); Found: C, 61.17; H, 5.55; C29H32O8S2 requires C, 60.82; H, 5.63%.