Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:24][C:25]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([Br:37])=[CH:29][CH:28]=1)=[O:26]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15][CH2:24][C:25]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([Br:37])=[CH:29][CH:28]=1)=[O:26])=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Reactant: O=C(CBr)c1ccc(Br)c2ccccc12
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)OCC(=O)c1ccc(Br)c2ccccc12
Reaction time: 1.5 h
Yield: 96.2 %

Procedure:
Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (4.85 g) was dissolved in acetonitrile (65 mL), and triethylamine (3.09 mL) was added. A solution of 2-bromo-1-(4-bromonaphthalen-1-yl)-ethanone (6.60 g) in acetonitrile (35 mL) was added. Reaction mixture was stirred 90 minutes and evaporated under vacuum. Oil was dissolved in DCM (50 mL), extracted once with water (20 mL) and once with NaHCO3 solution (20 mL), and evaporated under vacuum to a concentrated liquid. Solution was purified by chromatography (0-50% ethyl acetate:hexane) and evaporated under vacuum, giving pyrrolidine-1,2-dicarboxylic acid 2-[2-(4-bromonaphthalen-1-yl)-2-oxo-ethyl]ester 1-tert-butyl ester (8.95 g, 95%) as a tan solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([Cl:14])([Cl:13])[Cl:12])[O:8][CH:7]([C:15]([Cl:18])([Cl:17])[Cl:16])[C:6]=2[CH:19]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>O>[C:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([Cl:12])([Cl:13])[Cl:14])[O:8][CH:7]([C:15]([Cl:18])([Cl:17])[Cl:16])[C:6]=2[CH:19]=1)(=[O:22])[CH3:21]
Reactant: Oc1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Oc1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 6-hydroxy-2,4-bis(trichloromethyl)benzo[1,3]dioxin (1.0 g.) and acetic anhydride (10 ml.) was warmed on the steam bath for 15 minutes, and then cooled to ambient temperature. Water (40 ml.) was added, and the mixture stirred for 1 hour. The product was removed by filtration, washed with water, dried and crystallised from ethanol to give 6-acetoxy-2,4-bis(trichloromethyl)benzo[1,3]dioxin, m.p. 142°-144° C.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][S@:12](=[O:45])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[N:13][C:14](=[O:38])[C:15]1[CH:20]=[C:19]([C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30]([C:32]3[O:33][CH:34]=[CH:35][C:36]=3[CH3:37])=[O:31])[CH:24]=2)[CH:18]=[N:17][CH:16]=1)(C(C)(C)C)(C)C.[F-].C([NH3+])(C)(C)C>C1COCC1.CCOC(C)=O>[OH:8][CH2:9][CH2:10][CH2:11][S@:12](=[O:45])([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[N:13][C:14](=[O:38])[C:15]1[CH:20]=[C:19]([C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30]([C:32]3[O:33][CH:34]=[CH:35][C:36]=3[CH3:37])=[O:31])[CH:24]=2)[CH:18]=[N:17][CH:16]=1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=[S@](=O)(CCCO[Si](C)(C)C(C)(C)C)c3ccccc3)c2)c1
Agent: CC(C)(C)[NH3+]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=[S@](=O)(CCCO)c3ccccc3)c2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To the solution of (S)-N-[(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide (2.2 g, 3.43 mmol) in anhydrous THF (60 mL) at 0° C. was added dropwise tert-butylammonium fluoride (7.2 mL, 1 M in THF) and the reaction was stirred at 0° C. for 1 hour. The yellow reaction solution was then concentrated at room temperature to give a red oil. The oily residue was diluted with EtOAc, which was washed with saturated aqueous NaHCO3 (2×), brine (1×), and then dried (anhydrous Na2SO4). The organic layer was decanted, concentrated, and the resulting oily residue was chromatographed (MeOH—CH2Cl2: from 1:100 to 1:50) yielding the title compound as a clear oil which turned into white foam in-vacuo (1.72 g, 95%).
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][NH:5][C:6](=[O:19])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]=[CH2:17])=[C:10]([Cl:18])[CH:9]=1.[OH-].[Na+].Cl>CC(C)=O>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C:6]([NH:5][CH2:4][C:3]([OH:20])=[O:2])=[O:19])=[CH:9][C:10]=1[Cl:18])[CH:16]=[CH2:17]
Reactant: C=CCOc1ccc(CC(=O)NCC(=O)OC)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: C=CCOc1ccc(CC(=O)NCC(=O)O)cc1Cl
Temperature: 40 °C
Yield: 79.5 %

Procedure:
4-Allyloxy-3-chloro-phenylacetyl-glycine methyl ester (0.594 g) was suspended in acetone (8.0 ml) to which was added aqueous sodium hydroxide solution (1 M, 4.0 ml) and the whole was warmed to 40° C. for 30 min. After the solution had been cooled to 0° C., the pH was adjusted to 2-3 using dilute hydrochloric acid (3 M) and quickly extracted with ethyl acetate (20 ml). The extract was dried (anhydrous sodium sulphate). The solvent was evaporated at reduced pressure to leave a solid residue (450 mg), m.p. 115°-119° C. After recrystallisation from ethyl acetate/light petroleum (b.p. 60°-80° C.) the above-named product, m.p. 117°-119° C., was obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:17])=[C:4]([NH:9]C(=O)OC(C)(C)C)[CH:5]=[C:6]([Cl:8])[CH:7]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Br:1][C:2]1[C:3]([F:17])=[C:4]([CH:5]=[C:6]([Cl:8])[CH:7]=1)[NH2:9]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)cc(Br)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(Cl)cc(Br)c1F
Yield: 117.9 %

Procedure:
A solution of tert-butyl 3-bromo-5-chloro-2-fluorophenylcarbamate (900 mg, 2.78 mmol) in DCM/TFA (1:1, 20 mL) was stirred at rt for 1 h. The reaction mixture was concentrated, then the residue was taken up in ethyl acetate and washed with aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to provide the crude title compound (736 mg). MS m/z 223.9 (M+1).
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([CH2:13][C:14]([F:17])([F:16])[F:15])[CH2:10][C:9]1=[O:18])C1C=CC=CC=1.N.[Na].[Cl-].[NH4+]>C(OCC)C.C(O)C.C(O)(C)(C)C>[F:17][C:14]([F:15])([F:16])[CH2:13][CH:11]1[CH2:12][NH:8][C:9](=[O:18])[CH2:10]1
Reactant: O=C1CC(CC(F)(F)F)CN1Cc1ccccc1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: O=C1CC(CC(F)(F)F)CN1
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
1-Benzyl-4-(2,2,2-trifluoroethyl)pyrrolidin-2-one x102 (1.67 g, 6.5 mmol) is dissolved in diethyl ether (17 ml) and anhydrous tert-butanol (7 ml). The solution is cooled to −78° C. and ammonia (33 ml) is condensed into the flask. Sodium (0.373 g, 16.2 mmol) is added to the solution portionwise at −78° C., followed by the anhydrous tert-butanol (7 ml). The reaction mixture is stirred at −78° C. for 2-3 h. Ethanol (50 ml) is slowly added. The mixture is warmed to room temperature and stirred overnight. Saturated ammonium chloride is added and the mixture is extracted with ether (3 times). The organic layers are combined, dried over magnesium sulphate, filtered and concentrated in vacuo to obtain 4-(2,2,2-trifluoroethyl)pyrrolidin-2-one x103 as an orange solid (0.61 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([NH:19][CH2:20][CH2:21][OH:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)CCC>[CH2:12]([N:19]([C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[CH2:20][CH2:21][OH:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCCNCc1ccccc1
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Solvent: CCCCO
Product: O=[N+]([O-])c1cc(Br)ccc1N(CCO)Cc1ccccc1

Procedure:
A mixture of 2,5-dibromonitrobenzene (40 g) and N-benzylethanolamine (40.4 ml) in 1-butanol (160 ml) was heated at reflux for 18 hours then a further portion (20.2 ml) of N-benzylethanolamine was added and refluxing was continued for a further hour. The reaction mixture was evaporated under reduced pressure (2.7 kPa) at 40° C. and the residue was treated with water (500 ml) and the mixture was then extracted three times with diethyl ether (250 ml). The combined organic extracts were washed with hydrochloric acid (180 ml, 1N), then with an aqueous sodium hydrogen carbonate solution (20 ml, 5%), then twice with distilled water (50 ml), then dried over magnesium sulphate and then evaporated under reduced pressure (2.7 kPa) at 40° C. The resulting brown oil (47.1 g) was subjected to flash chromatography on silica (0,040-0,063 mm) eluting with dichloromethane to give the title compound (19.66 g) as a red oil. 1H NMR, 400 MHz, (CD3)2SO: δ3.1 (t, 2H); 3.5 (q, 2H); 4.5 (s, 2H); 4.6 (t, 1H); 7.3 (m, 6H); 7.6 (dd, J=8 Hz and J=1.5 Hz, 1H); 8 (d, J=1.5 Hz, 1H). MS (EI): M+ 352 and 350 (5%), 321 and 319 (20%), 91 (100%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH2:18]([N:20]=[C:21]=[S:22])[CH3:19]>>[CH2:18]([NH:20][C:21]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[S:22])[CH3:19]
Reactant: CCN=C=S
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CCNC(=S)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Yield: 15.5 %

Procedure:
Beginning with 0.15 gm (0.65 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.068 mL (0.78 mMol) ethyl isothiocyanate, 0.032 gm (10%) of the title compound were recovered essentially by the procedure of Example 122. An analytical sample was crystallized from aqueous ethanol. MS(m/e): 317(M+)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][O:11][C:12](=[O:14])[CH3:13])=[CH:4][CH:3]=1.[CH2:16]([SH:19])[CH2:17][SH:18].[OH-].[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:9][CH2:10][O:11][C:12](=[O:14])[CH3:13])[S:19][CH2:16][CH2:17][S:18]2)=[CH:4][CH:3]=1
Reactant: CC(=O)OCCC(=O)c1ccc(F)cc1
Reactant: SCCS
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)OCCC1(c2ccc(F)cc2)SCCS1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.1 %

Procedure:
To a solution of acetic acid [3-(4-fluorophenyl)-3-oxo-propyl]ester (2.0 g, 9.52 mmol) in dry dichloromethane (40 ml) are added 1,2-ethanedithiol (1.79 g, 19.0 mmol) and boron trifluoride diethyl ether complex (0.68 g, 4.76 mmol) at 0° C. The resulting reaction mixture is stirred at RT for 16 h. After completion of reaction, the mixture is neutralized with 10M aqueous sodium hydroxide and extracted with DCM (3×100 ml). The combined organic layers are washed with water (100 ml), brine (100 ml), dried over anhydrous sodium sulfate and evaporated in vacuo to get the crude, which is purified by column chromatography (silica gel, 5% ethyl acetate/hexane) to yield acetic acid 2-[2-(4-fluorophenyl)-[1,3]dithiolan-2-yl]-ethyl ester (1.80 g, 6.29 mmol, 66%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=2[F:30])=[C:4]([CH:12]=[C:13]([CH2:16][NH:17][O:18][CH2:19][CH2:20][OH:21])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)[C:33](=[O:34])C1.CCN(CC)CC>C(Cl)Cl.C1COCC1>[F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=2[F:30])=[C:4]([CH:12]=[C:13]([CH2:16][N:17]2[C:33](=[O:34])[O:21][CH2:20][CH2:19][O:18]2)[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: O=C(NOCCO)c1cc(CNOCCO)c(F)c(F)c1Nc1ccc(I)cc1F
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(NOCCO)c1cc(CN2OCCOC2=O)c(F)c(F)c1Nc1ccc(I)cc1F
Yield: 11.9 %

Procedure:
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyamino)-methyl]-benzamide (100 mg, 0.185 mmol) obtained in Example 6, N,N′-disuccinimidyl carbonate (59 mg, 0.231 mmol) and NEt3 (113 mg, 1.12 mmol) were stirred in a mixed solvent of CH2Cl2/THF (1 mL/1 mL) at room temperature for 10 hours. The reaction mixture was purified by silica gel column chromatography (CH2Cl2/MeOH as a developing solvent) to give the title compound (12.5 mg).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[CH2:20][CH2:21][CH2:22][O:23][C:24]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[F:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][CH:38]=[C:37]2[C:43]1[CH2:44][CH2:45][NH:46][CH2:47][CH:48]=1>O1CCCC1.CN(C)C=O>[F:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][CH:38]=[C:37]2[C:43]1[CH2:44][CH2:45][N:46]([CH2:12][CH:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[CH2:20][CH2:21][CH2:22][O:23][C:24]=4[C:15]=3[O:14]2)[CH2:47][CH:48]=1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)OCCC4)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Fc1ccc2[nH]cc(C3=CCN(CC4COc5ccc6c(c5O4)OCCC6)CC3)c2c1

Procedure:
To a mixture of (2R)-2,3,8,9-tetrahydro-7H-[1,4]dioxino[2,3-h]chromen-2-ylmethyl 4-methylbenzenesulfonate (0.25 g, 0.66 mmole) and potassium carbonate (0.22 g, 1.55 mmole) in 1:1 tetrahydrofuran/dimethylformamide (20 mL) was added 0.45 g (2.08 mmole) of 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole. The reaction mixture was refluxed under nitrogen for six hours. After completion, the mixture was evaporated to dryness under reduced pressure and the residue was column chromatographed on silica gel with methylene chloride to remove impurities and 4% methanol/methylene chloride to elute the desired product as an oil, which was crystallized from isopropanol with the addition of a solution of oxalic acid in hot isopropanol to give 0.040 g (6%) of the (S)-enantiomer of the title compound as a dark yellow solid, m.p. 146-148° C.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]1[N:9]=[CH:8][N:7]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1.[F-:29].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[F:29][CH2:2]/[CH:3]=[CH:4]/[C:5]1[N:9]=[CH:8][N:7]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1
Reactant: BrC/C=C/c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: FC/C=C/c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
A stirred solution of E-1-bromo-3(1-trityl-1,2,4-triazol-3-yl)prop-2-ene) (34.47 g, prepared as described in Example 12) in dry dichloromethane (150 ml) was treated, under nitrogen, with tetrabutylammonium fluoride (160 ml, 1M in tetrahydrofuran). The mixture was heated under reflux for thirty minutes, cooled, washed with water (3×100 ml), dried over magnesium sulphate and evaporated under reduced pressure. The residue was chromatographed on silica, using dichloromethane-ether (25:2) as eluant, to give E-1-fluoro-3(1-trityl-1,2,4-triazol-3-yl)prop-2-ene (19.37 g, m.p. 149° C). NMR (CDCl3): δ 4.95, 5.15(2H,dd), 6.7-6.9(2H,m), 7.1-7.3(15H,m), 7.9(1H,s). JCH=CH 16.1 Hz, JHF 46.8 Hz. 19F NMR (CDCl3): -216.4 ppm vs. CFCl3.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]([OH:17])[C:13]([NH:15][CH3:16])=O)[CH2:3][CH2:2]1.B.Cl>O1CCCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]([OH:17])[CH2:13][NH:15][CH3:16])[CH2:3][CH2:2]1
Reactant: CNC(=O)C(O)C(c1ccccc1)N1CCOc2ccccc21
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CNCC(O)C(c1ccccc1)N1CCOc2ccccc21
Temperature: 70 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
A solution of (2RS,3RS)-3-(2,3-dihydro-4H-1,4-benzoxazin-4-yl)-2-hydroxy-N-methyl-3 phenylpropanamide (216 mg, 0.692 mmol) in dry tetrahydrofuran (3 mL) under nitrogen was treated dropwise with a solution of borane (1.0 M in tetrahydrofuran, 3.50 mL, 3.50 mmol), and the resulting solution was stirred at 70° C. for 2 hours. After cooling in an ice bath, the reaction mixture was treated with a 2N aqueous solution of hydrochloric acid (1 mL), and the resulting mixture was heated at 50° C. for 30 minutes. Tetrahydrofuran was removed under reduced pressure, and the aqueous residue was dissolved in water (5 mL) and washed with diethyl ether (10 mL). The aqueous layer was made alkaline with solid potassium carbonate and extracted with ethyl acetate (2×10 mL). The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated under reduced pressure to yield 202 mg (98%) (1RS,2SR)-1-(2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-phenylpropan-2-ol as a colorless oil. This oil was dissolved in ethanol (1 mL) and treated with a solution of hydrochloric acid (0.5 mL, 4M in 1,4-dioxane). All volatiles were again removed under reduced pressure. The resulting white solid was recrystallized (minimal warm ethanol/ethyl ether/−20° C.) to yield 105 mg (41%) (1RS,2SR)-1-(2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-phenylpropan-2-ol dihydrochloride as a white solid. MS (ESI) m/z 299.0 ([M+H]+);
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10]CC)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].N1C=CC=CC=1.[Cl:19][C:20]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:21]=1[NH2:22]>>[Cl:19][C:20]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:21]=1[NH:22][C:8](=[O:10])[CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: Nc1cc(F)ccc1Cl
Solvent: c1ccncc1
Product: CCOC(=O)C(C)C(=O)Nc1cc(F)ccc1Cl

Procedure:
The ester was prepared according to Procedure A using diethyl 2-methylmalonate (7.09 mL, 41.2 mmol), pyridine (4.45 mL, 55.0 mmol) and 2-chloro-5-fluoroaniline (4.0 g, 27.5 mmol) over 6 days. The residue was purified by column chromatography on silica gel (0-30% EtOAc/hexanes) to give ethyl 3-(2-chloro-5-fluorophenylamino)-2-methyl-3-oxopropanoate as a red oil. Mass Spectrum (ESI) m/e=274.0 (M+1).
Reaction SMILES: [Br:1][C:2]1([N+:25]([O-:27])=[O:26])[CH:7]=[C:6]([C:8]2[C:20]3[C:19]([CH3:21])=[C:18]([CH3:22])[S:17][C:16]=3[C:15]([Br:23])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[CH:4][CH:3]1[OH:24].O[C@@H:29]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:30]([O:32]C)=[O:31].BrBr>>[Br:1][C:2]1([N+:25]([O-:27])=[O:26])[CH:7]=[C:6]([C:8]2[C:20]3[C:19]([CH3:21])=[C:18]([CH3:22])[S:17][C:16]=3[C:15]([Br:23])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[CH:4][CH:3]1[O:24][CH:29]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:30]([OH:32])=[O:31]
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Reactant: Cc1sc2c(Br)c3ccccc3c(C3=CC(Br)([N+](=O)[O-])C(O)C=C3)c2c1C
Agent: BrBr
Product: Cc1sc2c(Br)c3ccccc3c(C3=CC(Br)([N+](=O)[O-])C(OC(Cc4ccccc4)C(=O)O)C=C3)c2c1C

Procedure:
Prepared from of 2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenol (Example 21) and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (Example 25) according to the procedure of Example 30. White solid: mp 243-245° C.: NMR (DMSO-d6); δ11.30 (broad s, 1H), 8.23, 8.22 (2d, J=3 Hz, 1H), 8.06, 8.04 (2d, J=3 Hz, 1H), 7.95 (t, J=2, 1H), 7.68 (m, 1H), 7.56-7.50 (m, 1H), 7.45 (d, J=8 Hz, 1H),7.34-7.24 (m, 6H), 5.28 5.22 (2t, J=6 Hz, 1H), 3.40-3.23 (m, 2H), 4.82 (d, J=6 Hz, 1H), 2.46 (s, 3H), 1.59 1.57 (2s, 3H); MS (+FAB): 2 bromine isotope pattern 653, 655 , 657; Anal. Calc. for C29H21Br2NO5S: C, 53.15; H, 3.23; N, 2.14. Found: C, 53.77; H, 3.73; N, 2.04.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][CH2:17][CH3:18])[C:13](O)=[S:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][CH2:17][CH3:18])[C:13]([NH:19][C:20]2[CH:30]=[CH:29][CH:28]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:21]=2)=[S:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: CCC[C@H](NS(=O)(=O)c1ccc(Cl)cc1)C(O)=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCC[C@H](NS(=O)(=O)c1ccc(Cl)cc1)C(=S)Nc1cccc(C(=O)OCC)c1
Yield: 18.9 %

Procedure:
The procedure described in Example 180 was repeated, except that (S)-2-(4-chlorobenzenesulfonylamino)-4-methylthiobutanoic acid (10 g) and ethyl 3-aminobenzoate (4.1 g) were condensed in dichloromethane (80 ml) in the presence of N,N'-dicyclohexylcarbodiimide (7.65 g). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from methanol-ethyl acetate to obtain (S)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-4-methylthiobutanamide (2.13 g).
Reaction SMILES: [Br:1][C:2]1[NH:6][N:5]=[C:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[N:3]=1.[N+](=[CH:22][Si](C)(C)C)=[N-].CCCCCC>C1(C)C=CC=CC=1.CO>[Br:1][C:2]1[N:6]([CH3:22])[N:5]=[C:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[N:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c(Br)n2)CC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CO
Product: Cn1nc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
To a stirred suspension of tert-butyl 4-(5-bromo-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (26 g, 78.50 mmol) in toluene (200 mL) and methanol (50 mL) was added dropwise (diazomethyl)trimethylsilane 2M solution in hexane (43.2 mL, 86.35 mmol) under N2, keeping temperature around 20° C.: gas evolution and a small exotherm were observed. The yellow solution obtained was stirred at room temperature for 1 h. The solvent were evaporated and the resulting oil was purified on silica, eluting with 40% EtOAc in petroleum ether to afford tert-butyl 4-(5-bromo-1-methyl-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (15.00 g, 55.3%) as an oil: 1H NMR Spectrum; (CDCl3) 1.46 (9H, s), 1.65-1.78 (2H, m), 1.90-2.01 (2H, m), 2.68-3.02 (3H, m), 3.83 (3H, s), 3.94-4.31 (2H, m); Mass Spectrum [M+H]+=no mass ion.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]([N:15]([CH2:24][CH:25]=O)[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:14])=[CH:4][CH:3]=1.Cl.[NH2:28][CH2:29][CH2:30][C:31]1[C:39]2[S:38][C:37](=[O:40])[NH:36][C:35]=2[C:34]([OH:41])=[CH:33][CH:32]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]([N:15]([CH2:24][CH2:25][NH:28][CH2:29][CH2:30][C:31]2[C:39]3[S:38][C:37](=[O:40])[NH:36][C:35]=3[C:34]([OH:41])=[CH:33][CH:32]=2)[CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:14])=[CH:6][CH:7]=1
Reactant: NCCc1ccc(O)c2[nH]c(=O)sc12
Reactant: O=CCN(CCc1ccccc1)C(=O)CCOCCc1ccc(Br)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: O=C(CCOCCc1ccc(Br)cc1)N(CCNCCc1ccc(O)c2[nH]c(=O)sc12)CCc1ccccc1
Reaction time: 8 h

Procedure:
3-[2-(4-Bromophenyl)ethoxy]-N-(2-oxoethyl)-N-phenethyl-propanamide (Example 10d), 0.54 g) was dissolved in methanol (25 mL) and treated with 7-(2-aminoethyl)-4-hydroxy-3H-benzothiazol-2-one hydrochloride (0.32 g), acetic acid (0.5 mL) and water (1.5 mL). The resultant mixture was stirred at room temperature for 2 hours and then sodium cyanoborohydride (0.05 g) was added and the reaction mixture was stirred overnight. The mixture was concentrated in vacuo and the residue was taken up in methanol (25 mL) and adsorbed onto silica gel. The adsorbed mixture was purified by flash chromatography to yield the titled compound (0.51 g) as a crystalline yellow solid.