Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH:18]=3)=[CH:9][CH:8]=2)[CH2:5][C@H:4]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:3]1.[O:24]=[C:25]1N(C2C=CC(C3CCNCC3)=C(F)C=2)C[C@H:27](CNC(=O)C)[O:26]1>>[CH3:27][O:26][C:25]([N:16]1[CH2:15][CH:14]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([N:6]3[CH2:5][C@H:4]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:3][C:2]3=[O:1])=[CH:8][CH:9]=2)[CH2:18][CH2:17]1)=[O:24]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CCNCC3)cc2)C(=O)O1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCNCC3)c(F)c2)C(=O)O1
Product: COC(=O)N1CC=C(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2)CC1

Procedure:
Following the general procedure of EXAMPLE 26, and making non-critical variations but substituting (S)-(-)-N-[[2-oxo-3-[4-(3,6-dihydro-2H-pyridin-4-yl)phenyl]-5-oxazolidinyl]methyl]acetamide EXAMPLE 58) for (S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-5-oxazolidinyl]methyl]acetamide, the title compound is obtained, mp 142-145° C.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][C:9]([P:17](=[O:22])([O:20]C)[O:18]C)([P:11](=[O:16])([O:14]C)[O:12]C)[OH:10])C(=O)C2=CC=CC=C12.Cl>>[NH2:5][CH2:6][CH2:7][CH2:8][C:9]([P:17](=[O:18])([OH:20])[OH:22])([P:11](=[O:12])([OH:14])[OH:16])[OH:10]
Reactant: COP(=O)(OC)C(O)(CCCN1C(=O)c2ccccc2C1=O)P(=O)(OC)OC
Agent: Cl
Product: NCCCC(O)(P(=O)(O)O)P(=O)(O)O

Procedure:
contacting tetramethyl phthalimido-1-hydroxybutylidene-bisphosphonate from Step (b) with aqueous hydrochloric acid at a temperature in the range of 80° C. to reflux to form 4-amino-1-hydroxybutylidene-bisphosphonic acid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[C:18]3[N:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[Mg].[H-].C([Al+]CC(C)C)C(C)C.BrC1C=CC(C(F)(F)F)=CC=1.[N:44]1C2C(=O)CCCC=2C=CC=1>C1COCC1>[F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([NH2:44])[C:18]3[N:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: OC1(c2ccc(C(F)(F)F)cc2)CCCc2cccnc21
Reactant: O=C1CCCc2cccnc21
Agent: CC(C)C[Al+]CC(C)C
Agent: FC(F)(F)c1ccc(Br)cc1
Agent: [H-]
Solvent: C1CCOC1
Product: NC1(c2ccc(C(F)(F)F)cc2)CCCc2cccnc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroquinolin-8-ol. To a solution of magnesium (515 mg, 21.19 mmol) in THF (50 mL) was added 1M diisobutylaluminum hydride in hexanes (0.14 mL, 0.140 mmol). The solution was stirred at room temperature. After 20 min., the reaction was treated with a 20% portion of 1-bromo-4-(trifluoromethyl)benzene (1.9 mL, 13.57 mmol). After stirring for 20 min., the solution went from clear to light brown. The remaining 1-bromo-4-(trifluoromethyl)benzene was added dropwise. The solution was stirred for 0.5 h and then cooled in a dry ice/acetone bath. After cooling for 1 h, the reaction was treated with a solution of 6,7-dihydroquinolin-8(5H)-one (1.0 g, 6.79 mmol) in THF (7 mL) dropwise over 10 min. The solution was allowed to warm to room temperature as the cooling bath expires. After stirring for 16 h, the reaction was quenched with sat'd NH4Cl. The reaction was poured into water and EtOAc. The aqueous layer was extracted with EtOAc (25 mL). The combined EtOAc layers were concentrated in vacuo and adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with 0-20% EtOAc in hexane, to provide the title compound as a colorless oil. MS (ESI pos. ion) m/z: 293.9 (MH+). 1H NMR (CDCl3) δ: 8.36-8.51 (m, 1H), 7.44-7.60 (m, 3H), 7.27 (s, 1H), 7.15-7.26 (m, 2H), 4.19 (s, 1H), 2.82-3.01 (m, 2H), 2.14-2.36 (m, 2H), 1.90 (dt, J=14.2, 4.5 Hz, 1H), 1.57-1.78 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][CH2:14][NH:13][C:12](=O)[C@H:11]([CH3:17])[C:7]=3[NH:8][C:9]=2[CH:10]=1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][CH2:14][NH:13][CH2:12][C@@H:11]([CH3:17])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: C[C@H]1C(=O)NCCc2c1[nH]c1cc(F)ccc21
Solvent: C1CCOC1
Product: C[C@@H]1CNCCc2c1[nH]c1cc(F)ccc21
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To an oven dried flask containing dry THF (10 mL) under argon at −78° C. was added a 1 M solution of (iBu)2AlH in CH2Cl2 (16.3 mL). This mixture was stirred at −78° C. for 5 min. To this was (R)-8-fluoro-5-methyl-2,3,5,6tetrahydroazepino[4,5-b]indol-4(1H)-one (0.236 g, 1.02 mmol) in dry THF (16 mL). The reaction mixture was stirred at rt for 72 h, cooled to 0° C., then quenched by the addition of MeOH (4.5 mL). The mixture was partitioned between CH2Cl2 and 1 M aq NaO2CCH(OH)CH(OH)CO2K. The CH2Cl2 extracts were washed with brine, and dried, filtered and concentrated to give an oil. The oil was purified by silica chromatography to give the amine. To a solution of this amine (0.105 g, 0.48 mmol) in dry MeOH (4 mL) was added fumaric acid (0.028 g, 0.24 mmol) in MeOH (2.2 mL). The mixture was stirred overnight, concentrated, and the residue was dissolved in hot MeOH from which crystalline product was recovered: mp 256-258° C.; MS (ESI+) m/z 219.1; 1H NMR (CD3SOCD3, 300 MHz) δ 10.83 (1H), 9.3-8.5 (2H), 7.35 (1H), 7.01 (1H), 6.78 (1H), 6.43 (1H), 3.22-2.70 (8H), 1.30 (3H); Anal. C 64.94, H 6.27, N 10.07.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C@H:3]([N:26]1[CH2:30][CH2:29][C@H:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10]/[N:11]=[CH:12]/[C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][C:17]([O:24][CH3:25])=[C:18]([F:23])[CH:19]=3)[N:14]=2)=[CH:8][CH:9]=1.C(O)(=O)C.I(C1C=CC=CC=1)=O>C(Cl)Cl>[F:40][C:2]([F:1])([F:39])[C@H:3]([N:26]1[CH2:30][CH2:29][C@H:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:35])[CH3:36])[CH2:27]1)[C:4]1[CH:9]=[CH:8][C:7]2[N:6]([C:12]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:24][CH3:25])=[C:18]([F:23])[CH:19]=4)[N:14]=3)=[N:11][N:10]=2)[CH:5]=1
Reactant: COc1cc2nc(/C=N/Nc3ccc([C@@H](N4CC[C@H](NC(=O)OC(C)(C)C)C4)C(F)(F)F)cn3)ccc2cc1F
Agent: O=Ic1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc2nc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)ccc2cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
To tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-((E)-2-((6-fluoro-7-methoxyquinolin-2-yl)methylene)hydrazinyl)pyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (150 mg, 0.267 mmol) in DCM (5 mL) was added iodosobenzene acetate (112 mg, 0.347 mmol), and the reaction was stirred at ambient temperature for 2 hours. After concentration, the residue was purified by reverse phase chromatography (SP4, 12M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(3-(6-fluoro-7-methoxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (109 mg, 72.9% yield) as beige solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([O:15][CH2:16][CH:17]([CH2:19][OH:20])[OH:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]([NH:28][C@H:29]([C:33](O)=[O:34])[CH:30]([CH3:32])[CH3:31])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([O:15][CH2:16][CH:17]([CH2:19][O:20][C:33](=[O:34])[C@H:29]([CH:30]([CH3:31])[CH3:32])[NH:28][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[OH:18])=[O:14])[CH:10]([CH3:11])[CH3:12])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(O)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(O)COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Yield: 49 %

Procedure:
1-O-(N-tert-butoxycarbonyl-L-valyl)glycerol (17.95 g. 61.6 mmol), Boc-L-valine (6.69 g, 30.8 mmol), DMAP (0.38 g, 3.1 mmol), and DCC (7.10 g, 34.4 mmol) in 240 mL CH2Cl2 and 60 mL DMF were stirred at rt under N2 for 18 h. The reaction mixture was filtered, concentrated under vacuum, and redissolved in 200 mL EtOAc. The organic solution was washed with 50 mL saturated NH4Cl. The aqueous phase was reextracted with 50 mL EtOAc. The organic phases were combined, washed successively with 50 mL saturated NaHCO3 and 50 mL brine, dried over NA2SO4 and concentrated under vacuum. Flash column chromatography of the crude material on silica gel (eluent 2/1 petroleum ether-EtOAc, and then EtOAc) gave 7.41 g (49%) of the title compound (alternative nomenclature: 1,3-bis(N-tert-butoxycarbonyl-L-valyloxy)-2-propanol).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[C:10](Cl)[CH:9]=1)=[O:7].[CH3:30][O-:31].[Na+]>CO.C(OCC)(=O)C>[CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[C:10]([O:31][CH3:30])[CH:9]=1)=[O:7]
Reactant: C[O-]
Reactant: COc1cccc2c1ccc1nc3cc(Cl)cc(C(=O)NCCN(C)C)c3nc12
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(C(=O)NCCN(C)C)c2nc3c(ccc4c(OC)cccc43)nc2c1

Procedure:
A mixture of 9-chloro-4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide (85 mg) and a 25% solution of sodium methoxide in methanol (4 mL) was heated to reflux for 6 hours. The reaction mixture was then cooled, diluted with ethyl acetate, washed with water, dried (MgSO4) and the solvent removed in vacuo to yield a yellow solid which was purified using flash chromatography to yield the desired title compound (42 mg).
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:14]1[C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:15]1>C(O)C>[CH2:1]([N:8]([CH2:15][C:16]1([OH:14])[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]1)[C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(CO)NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(O)(CN(Cc2ccccc2)C(C)(C)CO)CC1
Temperature: 100 °C
Yield: 59.9 %

Procedure:
2-(Benzylamino)-2-methyl-propan-1-ol hydrochloride (539 mg, 2.50 mmol) was treated with aqueous sodium hydroxide (50 mL of 2 M, 100 mmol), then diethyl ether (50 mL) was added to the solution and stirred for 3 min. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to provide the 2-(benzylamino)-2-methyl-propan-1-ol free base as a white powder. The 2-(benzylamino)-2-methyl-propan-1-ol (2.50 mmol) and tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (500 mg, 2.344 mmol) were dissolved in ethanol (2 mL) and the reaction mixture was heated in a sealed tube at 100° C. for 48 h. The ethanol was evaporated and the crude material purified by silica gel column chromatography (1-100% ethyl acetate/hexanes) to provide tert-butyl 4-((benzyl(1-hydroxy-2-methylpropan-2-yl)amino)methyl)-4-hydroxypiperidine-1-carboxylate as white powder (551 mg, 60%). ESI-MS m/z calc. 392.5. Found 373.3 (M+1)+; Retention time: 1.14 minutes (3 min run). 1H NMR (400 MHz, DMSO-d6) δ 7.43 (d, J=7.4 Hz, 2H), 7.24 (t, J=7.6 Hz, 2H), 7.13 (t, J=7.3 Hz, 1H), 4.66 (t, J=5.1 Hz, 1H), 4.43 (s, 1H), 3.91 (s, 2H), 3.62 (s, 2H), 3.22 (d, J=4.8 Hz, 2H), 2.97 (s, 2H), 2.58 (s, 2H), 1.44-1.27 (m, 13H), 0.88 (s, 6H).
Reaction SMILES: CN1C(C)=[C:9]2[C:4]([N:5]([CH3:15])[C:6](=[O:14])[N:7]([CH3:13])[C:8]2=[O:12])=N1.Br[CH2:17][C:18]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[C:28]([Cl:38])[CH:27]=2)[N:25]=1)=[O:19].[H-].[Na+]>CN(C=O)C>[Cl:38][C:28]1[CH:27]=[C:26]([C:24]2[N:25]=[C:21]([NH:20][C:18](=[O:19])[CH2:17][N:25]3[C:9]4[C:8](=[O:12])[N:7]([CH3:13])[C:6](=[O:14])[N:5]([CH3:15])[C:4]=4[CH:23]=[C:24]3[CH3:26])[S:22][CH:23]=2)[CH:31]=[CH:30][C:29]=1[O:32][CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)COc1ccc(-c2csc(NC(=O)CBr)n2)cc1Cl
Reactant: Cc1c2c(=O)n(C)c(=O)n(C)c2nn1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(c(=O)n(C)c(=O)n2C)n1CC(=O)Nc1nc(-c2ccc(OCC(C)(C)C)c(Cl)c2)cs1

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 2 (50 mg, 0.258 mmol) with 2-bromo-N-{4-[3-chloro-4-(2,2-dimethylpropoxy)phenyl]-1,3-thiazol-2-yl}acetamide (129 mg, 0.308 mmol) in the presence of NaH (15 mg, 0.375 mmol) in dry DMF (5.0 mL) to give 85 mg of the product as a white solid; 1H-NMR (δ ppm, DMSO-d6, 300 MHz): 1.04 (s, 9H), 2.27 (s, 3H), 3.17 (s, 3H), 3.36 (s, 3H), 3.76 (s, 2H), 5.32 (s, 2H), 6.07 (s, 1H), 7.19 (d, J=8.7 Hz, 1H), 7.62 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.96 (s, 1H), 12.69 (br s, 1H, exchangeable with D2O); APCI-MS (m/z) 530.26 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:16])[CH:14]=[O:15])[CH:7]=[CH:6]2.C(O)(=[O:19])C.N(CCO)(CCO)CCO.C(OO)(=O)C>C(O)C.C(OCC)(=O)C.O>[CH3:16][C@H:13]([C:14]([OH:19])=[O:15])[C:8]1[CH:7]=[CH:6][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:10]=2[CH:9]=1
Reactant: COc1ccc2cc([C@H](C)C=O)ccc2c1
Reactant: CC(=O)O
Agent: CC(=O)OO
Solvent: O
Solvent: CCOC(C)=O
Solvent: OCCN(CCO)CCO
Product: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Temperature: 2 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
To a stirred solution of 1.0 g (4.67 mmol) of (S)-2-(6-methoxy-2-naphthyl)propionaldehyde in absolute ethanol (5.0 mL) cooled in a wet-ice bath (ca. 2° C.) was added 0.27 mL (0.28 g, 4.67 mmol) of glacial acetic acid followed by 0.62 mL (0.70 g, 4.67 mmol) of triethanolamine. To this solution was then added slowly dropwise 2.25 mL (7.0 mmol) of a 23.0 weight percent solution of peracetic acid in ethyl acetate, at a rate slow enough such that the reaction temperature did not exceed 10° C. The reaction mixture was stirred at 2° C. for 2 hours, then an additional 2.25 mL (7.0 mmol) of the peracetic acid solution was added to complete the conversion of the aldehyde (4 hours total). The solution was transferred into a larger flask with the aid of ethanol (5 mL), heated to 50° C., and was diluted with water (40 mL). The solution was cooled in a wet-ice bath causing precipitation, and was vacuum filtered through a #2 Whatman filter. The light purple solid thus obtained was washed with 20 mL water and was dried in a vacuum oven 14 hours at 55° C. (25 mm Hg), giving 0.79 g (73.5%) of naproxen. Chiral phase HPLC analysis indicated a ratio of S:R naproxen of 95.8: 4.2, the same as that obtained by an independent oxidation method.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][NH:5][CH:6]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.N1C=CC=CC=1>CN(C)C(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:5]2[CH:6]=[C:2]([CH3:1])[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4]2)=[CH:16][CH:15]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1n[nH]cc1C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1nn(-c2ccc(OC)cc2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
Ethyl 4-methyl-1H-pyrazole-3-carboxylate (2.58 g) was dissolved in N,N-dimethylacetamide (50 mL), 4-methoxyphenylboronic acid (5.0 g), copper acetate (6.0°g) and pyridine (5.3 mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1N hydrochloric acid (50 mL) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (2.7 g, 66%) as a pale-yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[O:36][N:35]=[C:34]([CH3:37])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]5[O:36][N:35]=[C:34]([CH3:37])[CH:33]=5)[CH:27]=4)[CH2:23][C:22](=[O:38])[NH:21][C:9]=3[CH:10]=2)=[CH:15][CH:16]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(-c4ccc(F)cc4)ccc3NC(=O)OC(C)(C)C)c2)on1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4ccc(-c5ccc(F)cc5)cc4NC(=O)C3)c2)on1

Procedure:
Prepared from (4′-fluoro-3-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example K84) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (33 mg).
Reaction SMILES: [CH3:1][C:2]([C:6]1([OH:18])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)([CH3:5])[CH:3]=[CH2:4].C(O)(=[O:21])C.O>[O-2].[Cr+6].[O-2].[O-2].C(Cl)Cl>[CH3:5][C:2]1([CH3:1])[C:6]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]2)[O:18][C:4](=[O:21])[CH2:3]1
Reactant: C=CC(C)(C)C1(O)CCN(C(=O)OC(C)(C)C)C1
Reactant: CC(=O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(C1)OC(=O)CC2(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of borane-dimethyl sulfide complex (0.409 mL, 0.00460 mol) in methylene chloride (6.00 mL, 0.0936 mol) was slowly added a solution of tert-butyl 3-(1,1-dimethylprop-2-en-1-yl)-3-hydroxypyrrolidine-1-carboxylate (3.20 g, 0.0125 mol) in methylene chloride (6.00 mL, 0.0936 mol) with stirring at rt. After 2 h, the reaction mixture was slowly added to a solution of chromium(VI) oxide (7.52 g, 0.0752 mol)in acetic acid (45.00 mL, 0.7915 mol), and water (5.00 mL, 0.278 mol) at 5° C. After stirring the reaction mixture at rt for 12 h, water (60 mL) and methylene chloride (30 mL) were added. The organic layer was separated and the aqueous layer was further extracted with methylene chloride (2×30 mL). The organic layers were combined, washed with brine (2×30 mL), dried and concentrated. The residue was purified on silica gel, eluting with 0 to 50% EtOAc in hexane, to give the product. LCMS (M+Na) 292.2.
Reaction SMILES: N[C:2]1[C:11]2[N:10]=[CH:9][C:8](=[O:12])[NH:7][C:6]=2[N:5]=[C:4]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])[N:3]=1.C(Br)(Br)[Br:24].C(ON=O)CC(C)C>CS(C)=O>[Br:24][C:2]1[C:11]2[N:10]=[CH:9][C:8](=[O:12])[NH:7][C:6]=2[N:5]=[C:4]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])[N:3]=1
Reactant: BrC(Br)Br
Reactant: Nc1nc(SCc2cccc(F)c2F)nc2[nH]c(=O)cnc12
Agent: CC(C)CCON=O
Solvent: CS(C)=O
Product: O=c1cnc2c(Br)nc(SCc3cccc(F)c3F)nc2[nH]1
Temperature: 125 °C
Reaction time: 0.08 h

Procedure:
The product of step (a) (0.5 g) was suspended in DMSO (10 ml) and bromoform (10 ml) and the mixture was heated to 125° C. Isoamylnitrite (2 ml) was added and the mixture was stirred at 125° C. for 5 minutes before being cooled in an ice bath. Solvent was removed by evaporation under high vacuum and the residue suspended in dichloromethane (100 ml). This suspension was washed with saturated aqueous ammonium chloride (50 ml) and then filtered through a plug of celite. The filtrate was evaporated and purified by column chromatography, eluting with 10% ethyl acetate in dichloromethane to give the subtitled compound as a white solid (0.22 g).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=3)=[O:26])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: COc1cccc(-c2oc(C)nc2C(=O)O)c1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: COc1cccc(-c2oc(C)nc2C(=O)Nc2ccn(Cc3ccc(C(C)=O)o3)n2)c1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 2-methyl-5-(3-methoxy-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.01 min; [M+H]+=421.41.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][C:8]2[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=2[C:10]([O:12]C)=[O:11])=[CH:5][CH:4]=1.[OH-].[K+]>CO>[NH2:1][CH2:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][C:8]2[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=2[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccccc1Cc1ccc(CN)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: NCc1ccc(Cc2ccccc2C(=O)O)cc1
Yield: 53.9 %

Procedure:
Methyl 2-(4-aminomethylbenzyl)benzoate (2.41 g, 0.01 moles) is dissolved in 50 mL methanol and 10 mL of 50% KOH is added. The mixture is heated at reflux for 6 hours, concentrated in vacuo and then acidified to yield 1.3 g (57%) of title compound as a precipitate. Mass Spec (DCI) m/z 228. Further purification is achieved by forming the HCI salt in isopropanol/saturated with HCI gas.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH:19][CH2:20][CH:21]([CH3:23])[CH3:22])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].[F:26][C:27]([F:37])([F:36])[C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30]Br>CC(N(C)C)=O.CCOC(C)=O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([S:16]([N:19]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=3[C:27]([F:37])([F:36])[F:26])(=[O:18])=[O:17])=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: CC(=O)N1CCN(c2ccc(S(=O)(=O)NCC(C)C)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(=O)N1CCN(c2ccc(S(=O)(=O)N(Cc3ccccc3C(F)(F)F)CC(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
A solution of 4-(4-acetyl-piperazin-1-yl)-N-isobutyl-benzenesulfonamide (100 mg, 0.295 mmol) in DMA (2 mL) was treated with NaH (60% dispersion in mineral oil, 18 mg, 0.443 mmol) and stirred at room temperature for 30 minutes. 2-(Trifluoromethyl)benzyl bromide (141 mg, 0.590 mmol) was added and the mixture heated at 90° C. for 1 hour. The cooled mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-100% EtOAc in DCM) gave the title compound (110 mg, 75%). 1H NMR (400 MHz, DMSO) δ 7.81 (d, J=7.9 Hz, 1H), 7.69-7.71 (m, 4H), 7.50 (t, J=7.6 Hz, 1H), 7.08 (d, J=8.8 Hz, 2H), 4.36 (s, 2H), 3.59 (d, J=5.26 Hz, 4H), 3.38 (dd, J=26.2, 5.0 Hz, 4H), 2.86 (d, J=7.2 Hz, 2H), 2.05 (s, 3H), 1.36 (t, J=6.7 Hz, 1H), 0.70 (d, J=6.6 Hz, 6H). LCMS (m/z Method B) ES+ 498.1 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([CH:12]2[CH2:14][CH2:13]2)O)=[CH:4][CH:3]=1.P(Br)(Br)[Br:16].[Br-].[Li+]>[Br-].[Zn+2].[Br-]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]=[CH:12][CH2:13][CH2:14][Br:16])=[CH:4][CH:3]=1
Reactant: OC(CCc1ccc(Cl)cc1)C1CC1
Reactant: BrP(Br)Br
Agent: [Br-]
Agent: [Li+]
Agent: [Zn+2]
Product: Clc1ccc(CCC=CCCBr)cc1

Procedure:
6-(4-Chlorophenyl)-3-hexenyl bromide [V; Ar is 4-ClC6H4, R is H] was prepared from 21 g. of 2-(4-chlorophenyl)ethyl cyclopropyl carbinol (Preparation B7), 23 g. of phosphorus tribromide, 18.85 g. of lithium bromide and 22.5 g. of zinc bromide according to the procedure given above in Preparation C1, affording 25.5 g. of product as an oil.