Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][O:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([CH3:41])([CH3:40])[CH2:23][CH2:24][C:25]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:26]#[N:27])[CH2:18][CH2:17]3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH-:42].[K+]>CC(C(O)C)CC>[NH3:19].[OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][O:15][CH:16]3[CH2:17][CH2:18][N:19]([C:22]([CH3:41])([CH3:40])[CH2:23][CH2:24][C:25]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:26]([NH2:27])=[O:42])[CH2:20][CH2:21]3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: CC(C)(CCC(C#N)(c1ccccc1)c1ccccc1)N1CCC(OCc2cccc(-c3cccc(O)c3)c2)CC1
Agent: CCC(C)C(C)O
Agent: [K+]
Product: CC(C)(CCC(C(N)=O)(c1ccccc1)c1ccccc1)N1CCC(OCc2cccc(-c3cccc(O)c3)c2)CC1
Product: N
Temperature: 25 °C

Procedure:
A suspension of the product of example 97 (70 mg, 0.13 mmol) and powdered potassium hydroxide (144 mg, 2.57 mmol) in 3-methyl-4-pentanol (4 mL) was heated under reflux for 36 hours. The reaction mixture was allowed to cool to room temperature and the solvent removed under reduced pressure. The residue was partitioned between ethyl acetate (30 mL) and water (20 mL). The organic layer was separated, dried over magnesium sulphate and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 95:5:0.5 to 90:10:1. Appropriate fractions were concentrated in vacuo and the residue further purified by chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 98:2:0.2 to 95:5:0.5, to afford the title compound as a gum in 21% yield.
Reaction SMILES: [Li+].[BH4-].C([O:5][C:6](=O)[C@@H:7]([O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH3:8])C.CO>C1COCC1.C(OCC)C>[C:13]([Si:10]([CH3:12])([CH3:11])[O:9][C@@H:7]([CH3:8])[CH2:6][OH:5])([CH3:15])([CH3:16])[CH3:14]
Reactant: CCOC(=O)[C@H](C)O[Si](C)(C)C(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](CO)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
A 2M solution of LiBH4 (2.77 g, 0.13 mol) in THF (60 mL) was added dropwise to a solution of (S)-2-(tert-butyl-dimethyl-silanyloxy)-propionic acid ethyl ester (22.75 g, 0.10 mol) and methanol (5.15 mL, 0.13 mol) in diethyl ether (500 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and then at room temperature for 1.5 hours before cooling to 0° C. and carefully quenching with water. The reaction mixture was filtered and the filtrate extracted with diethyl ether (2×50 mL), the combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to give the title product as a colourless oil (18.2 g, 97%). 1H NMR (CDCl3, 400 MHz) 3.86-3.77 (1H, m), 3.45-3.37 (1H, m), 3.31-3.22 (1H, m), 1.96-1.85 (1H, m), 1.03 (3H, d, J=6.23 Hz), 0.81 (9H, s), 0.00 (6H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[O:6][CH2:7][CH2:8][NH2:9])[CH3:2].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](=O)[CH3:24])=[CH:18][C:17]=1[S:26]([NH2:29])(=[O:28])=[O:27].[H][H]>CO.[Pt]>[CH3:2][CH2:1][O:3][C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[O:6][CH2:7][CH2:8][NH:9][C@@H:23]([CH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[C:17]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:18]=1)[CH3:24]
Reactant: COc1ccc(CC(C)=O)cc1S(N)(=O)=O
Reactant: CCOc1ccccc1OCCN
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Product: CCOc1ccccc1OCCN[C@H](C)Cc1ccc(OC)c(S(N)(=O)=O)c1
Temperature: 25 °C

Procedure:
2-(o-Ethoxyphenoxy)ethylamine (45 gm) was dissolved in methanol (250 mL). To this 2-methoxy-5-(2-oxopropyl)-benzene sulfonamide (55 gm), catalyst 5% platinum on carbon (12.1 gm) and methanol (330 mL) were added. The mixture was hydrogenated in autocalve at 55° C. at hydrogen pressure of 13 kg/cm2 for 5 hrs. The reaction mixture was cooled and the catalyst was filtered off. To the filtrate containing racemic tamsulosin, oxalic acid (14.3 gm) was added and the solvent was distilled off. To the residue, acetone (700 mL) was added and stirred at reflux temperature for 30 mins. The mixture was cooled, filtered, and the filter cake washed with acetone (50 mL). The salt was further purified by suspending the material in 2-propanol at reflux temperature, cooling to ambient temperature and filtering the solid. The pure oxalate salt of racemic tamsulosin shows a melting range of: 178-182° C. and HPLC purity: 97.24 (area %). The chiral HPLC showed it to be a mixture R and S isomers in the ratio of 50.1 to 49.9. The infrared spectrum of the oxalate salt of racemic tamsulosin as shown in FIG. 1 of the drawing accompanying this specification, exhibited peaks at cm−1: 1154 & 1332 (SO2), 3408 (—NH2), 2983 (NH2+), 1591 (COO—). The 1H-NMR spectrum in CD3SOCD3 gave signals at δ values: 1.06-1.08 (3H, d, >CH—CH3), 1.30-1.33 (3H, t, —CH2—CH3), 3.89 (3H, s, —OCH3), 4.15-4.36 (10 H, 4-CH2, —CH, —NH), 7.61 (2H, s, —NH2), 6.8-7.5 (7H, m, Ar—H).
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2.C(N(CC)CC)C.[CH2:25]([OH:29])[CH2:26][C:27]#[CH:28]>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:17][C:3]1[C:2]([C:28]#[C:27][CH2:26][CH2:25][OH:29])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][N:7]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1
Reactant: C#CCCO
Reactant: Fc1c(Br)ccc2c1cnn2C1CCCCO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: OCCC#Cc1ccc2c(cnn2C2CCCCO2)c1F
Temperature: 60 °C
Reaction time: 16 h
Yield: 74.1 %

Procedure:
To a mixture of 5-bromo-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (2.80 g, 9.36 mmol, Intermediate 18), Pd(PPh3)2Cl2 (660 mg, 0.94 mmol), CuI (180 mg, 0.94 mmol), and triethylamine (50 mL) was added but-3-yn-1-ol (2.0 g, 28.1 mmol) under N2 atmosphere. The resulting mixture was stirred at 60° C. for 16 hours. Upon completion, the reaction mixture was diluted with EtOAc, and washed with water (3×10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified on silica gel column (0˜20% EtOAc in petroleum ether) affording the title compound (2.0 g). 1H NMR (300 MHz, DMSO-d6): δ 8.33 (s, 1H), 7.64 (d, 1H), 7.49 (dd, 1H), 5.94 (dd, 1H), 4.99 (t, 1H), 3.98-3.92 (m, 1H), 3.85-3.77 (m, 1H), 3.68 (t, 2H), 2.67 (t, 2H), 2.48-2.35 (m, 1H), 2.12-2.02 (m, 2H), 1.84-1.78 (m, 1H), 1.68-1.62 (m, 2H).
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:22][C:23]1[O:27][C:26](=[O:28])[O:25][C:24]=1[CH2:29][O:30][C:31](=[O:52])[C@H:32]([OH:51])[CH2:33][N:34]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:44]=2[F:50])=[CH:39][CH:38]=1)[NH2:35].[F:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[C:60]1[CH:64]=[C:63]([C:65](O)=[O:66])[O:62][N:61]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:22][C:23]1[O:27][C:26](=[O:28])[O:25][C:24]=1[CH2:29][O:30][C:31](=[O:52])[C@H:32]([OH:51])[CH2:33][N:34]([CH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]2[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:44]=2[F:50])=[CH:41][CH:42]=1)[NH:35][C:65]([C:63]1[O:62][N:61]=[C:60]([C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=2[F:53])[CH:64]=1)=[O:66]
Reactant: O=C(O)c1cc(-c2ccccc2F)no1
Reactant: Cc1oc(=O)oc1COC(=O)[C@H](O)CN(N)Cc1ccc(-c2cc(Cl)ccc2F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1oc(=O)oc1COC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(-c2ccccc2F)no1
Temperature: 25 °C
Reaction time: 5 h
Yield: 37.8 %

Procedure:
EDCI (92 mg, 480 μmol) and HOBT (65 mg, 480 μmol) were added to a solution of (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester (108 mg, 240 μmol) and 3-(2-fluorophenyl)isoxazole-5-carboxylic acid (50 mg, 240 μmol) in DMF (20 mL). DIPEA (62 mg, 480 μmol) was added and the mixture was stirred for 5 hours at room temperature. The mixture was washed with saturated aqueous NaCl (2×30 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (hexanes/EtOAc=1:1) to yield the title compound as a white solid (58 mg). LC-MS: 640.2 [M+H]+. 1H-NMR: (CDCl3) 2.07 (s, 3H), 3.43 (br, 2H), 4.4-4.2 (m, 2H), 4.3 (br, 1H), 4.94-4.86 (m, 2H), 7.24-6.85 (m, 5H), 7.97-7.27 (m, 8H).
Reaction SMILES: N1C=CC=CC=1.C(OC(=O)C)(=O)C.[CH2:14]([O:16][C:17]([C:19]([C:30]([O:32][CH2:33][CH3:34])=[O:31])([CH2:25][CH2:26][C:27]([OH:29])=O)[CH2:20][CH2:21]C(O)=O)=[O:18])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>O>[O:29]=[C:27]1[CH2:21][CH2:20][C:19]([C:17]([O:16][CH2:14][CH3:15])=[O:18])([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:25][CH2:26]1
Reactant: CCOC(=O)C(CCC(=O)O)(CCC(=O)O)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C1(C(=O)OCC)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.6 %

Procedure:
(Kutsuma, T., Sugasawa, S., Tetrahedron, 3, 175 (1958).) To 100 mL of a pre-mixed solution of 10% (v/v) pyridine and acetic anhydride was added 4,4-bis(ethoxycarbonyl)heptanedioic acid (23.6 g, 78 mmol), and the resulting mixture heated at reflux in a pre-heated oil bath. The reaction was stirred for 3 hrs then cooled to room temperature and concentrated under reduced pressure. The resulting oil was azeotroped twice with CH2Cl2, then dissolved in 95% EtOH (300 mL) and water (300 mL) and treated with solid potassium carbonate (12.9 g, 93.6 mmol). The mixture was stirred for 16 hrs. The reaction was concentrated under reduced pressure to remove EtOH, and the remaining water layer was diluted to re-dissolve the solids, then extracted with Et2O (2×150 mL). The combined extracts were dried (MgSO4), filtered, and concentrated under reduced pressure, to afford the title compound (11.82 g, 48.8 mmol, 62.9% yield), as an amber oil. HPLC: 2.00 min (AP 74%); 1H NMR (500 MHz, CDCl3) δ ppm 4.24 (4H, q, J=7.12 Hz), 2.44 (4H, t, J=6.56 Hz), 2.37 (4H, t, J=6.41 Hz), 1.27 (6H, t, J=7.17 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:16](N(CC)CC)[CH3:17].ICC>O1CCCC1.CO>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][N:11]([CH2:16][CH3:17])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCN(CC)CC
Reactant: COC1(c2cc(F)cc(F)c2)CCNC1
Solvent: C1CCOC1
Solvent: CO
Solvent: CCI
Product: CCN1CCC(OC)(c2cc(F)cc(F)c2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (+)-3-(3,5-difluorophenyl)-3-methoxypyrrolidine (0.01 g, 0.047 mmol) and triethylamine (13.1 μL, 0.0938 mmol) in tetrahydrofuran (3 ml), was added iodoethane (5.6 μL, 0.070 mmol). The resulting mixture was stirred at ambient temperature for 24 h and then diluted with methanol and analyzed by GCMS and LCMS. Analysis show 64% conversion. MS m/z (relative intensity, 70 eV) 241 (M+, 10), 226 (86), 211 (33), 141 (49), 71 (bp).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([O:17][CH3:18])=[O:16])=[CH:5][CH:4]=1.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C>[N:19]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([O:17][CH3:18])=[O:16])=[CH:5][CH:4]=1)=[N+:20]=[N-:21]
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1-c1ccc(CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
To a stirred solution of 4-bromomethyl-2'-methoxycarbonylbiphenyl (150 g, 0.49 mol) in dry DMF (500 ml) was added NaN3 (80 g, 1.23 mol, 2.5 eq). The mixture was stirred at room temperature overnight (ca. 18 hours), filtered, and the filtrate was partitioned between ethyl acetate and H2O (500 ml each). The organic phase was washed twice more with H2O, once with saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate before being filtered and concentrated to leave 111.3 g (85%) of a yellow oil, used in the following step without further purification. NMR (CDCl3, TMS, δ) 7.9-7.1 (m, 8H); 4.35 (s, 2H); 3.55 (s, 3H) IR Vmax 2487 cm-1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([OH:17])[CH3:16])(Cl)[CH2:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[Cl:25]C(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C1[CH2:41][O:40]CC1>>[CH2:18]([C:15]1([CH3:16])[O:17][C:41](=[O:40])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([Cl:25])[CH:9]=3)=[CH:4][C:3]1=2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(O)(Cc1ccccc1)C1(Cl)CC(c2ccccc2)=CC=C1N
Reactant: C1CCOC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: CC1(Cc2ccccc2)OC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Reaction time: 0.17 h
Yield: 30 %

Procedure:
A mixture of 1-(4-amino-3-chloro-biphenyl-3-yl)-1-benzyl-ethanol (prepared using 1-(4-amino-3′-chloro-biphenyl-3-yl)-ethanone and benzylmagnesium bromide according to Procedure C, 0.14 g, 0.42 mmol) and triphosgene (0.04 g, 0.14 mmol) in dry THF (10 mL) was stirred under a blanket of nitrogen for 10 minutes. Upon completion of the reaction, the THF was removed and the residue purified via flash chromatography (silica gel, 35% ethyl acetate/hexane) to give 4-benzyl-6-(3-chlorophenyl)-4-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (0.045 g, 30%) as an off-white solid: mp 187-188° C.; 1H-NMR (DMSO-d6) δ10.1 (s, 1H), 7.70 (t, 1H, J=2.3 Hz), 7.6 (d, 1H, J=8.0 Hz), 7.58-7.53 (m, 2H), 7.46 (t, 1H, J=8.0 Hz), 7.38 (d, 1H, J=8.0 Hz), 7.22-7.17 (m, 3H), 7.06-7.0 (m, 2H), 6.84 (d, 1H, J=9.14 Hz), 3.24 (d, 1H, J=14.3 Hz), 3.06 (d, 1H, J=14.3 Hz), 1.68 (s, 3H); MS (ESI) m/z 364 ([M+H]+, 100%); Anal. Calc. For C22H18ClNO2: C,72.63; H, 4.99; N, 3.85. Found: C, 71.82; H,5.09; N,3.58.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:28](=[O:34])[C:29]([O:31]CC)=[O:30])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:28](=[O:34])[C:29]([OH:31])=[O:30])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 72.1 %

Procedure:
A mixture of ethyl 2-{1-benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}-2-oxoacetate(0.463 g, 0.991 mmol), potassium hydroxide (0.224 g, 3.99 mmol) in THF (5 mL) and water (5 mL) was stirred for 40 minutes at room temperature then poured into excess water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated to dryness. The residue was dried for 15 hours at 80° C. to yield the title compound as a light yellow solid (0.314 g, 78%), mp 169–171° C. A sample was crystallized from acetonitrile for analysis. Mass spectrum (+APCI, [M+H]+) m/z 440; 1HNMR (400 MHz, DMSO-d6): δ13.8–14.2 (br,1H), 8.75 (s, 1H), 8.45 (d, 1H, J=1.5 Hz), 7.75–7.8 (m, 2H), 7.7 (d, 1H, J=8.5 Hz), 7.6 (dd, 1H, J=8.7 Hz), 7.45 (d, 2H, J=8.8 Hz), 7.25–7.35 (m, 5H), and 5.65 ppm (s, 2H).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([F:23])([F:22])[F:21])[C:3]1=[O:24].C1C([N+]([O-])=O)=CC=C([Cl-][C:35]([O-])=[O:36])C=1.C(N(CC)CC)C.OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[NH:59]1[CH2:64][CH2:63][CH:62]([N:65]2[CH2:70][C:69]3[CH:71]=[CH:72][N:73]=[CH:74][C:68]=3[NH:67][C:66]2=[O:75])[CH2:61][CH2:60]1>O1CCCC1>[O:75]=[C:66]1[NH:67][C:68]2[CH:74]=[N:73][CH:72]=[CH:71][C:69]=2[CH2:70][N:65]1[CH:62]1[CH2:61][CH2:60][N:59]([C:35]([NH:1][C@@H:2]2[N:8]=[C:7]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[N:4]([CH2:19][C:20]([F:21])([F:23])[F:22])[C:3]2=[O:24])=[O:36])[CH2:64][CH2:63]1
Reactant: NC1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O
Reactant: O=C1Nc2cnccc2CN1C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O)N1CCC(N2Cc3ccncc3NC2=O)CC1
Reaction time: 1 h
Yield: 26.3 %

Procedure:
A solution of (3R) 3-amino-2-oxo-5-phenyl-1-(2,2,2-trifluorethyl)-2,3-dihydro-1H-1,4-benzodiazepine (0.030 g, 0.090 mmol) and 4-nitrophenylchloroformate (0.018 g, 0.090 mmol) in dry tetrahydrofuran (2 mL) was cooled to 0° C. under argon. Triethylamine (0.013 mL, 0.090 mmol) was added and the reaction stirred for 1 h. Solid 3-piperidin4-yl-3,4-dihydropyrido[3,4-d]pyrimidin-2(1H)-one bisTFA salt (0.90 mmol) followed by triethylamine (0.065 mL) were added. The reaction was allowed to come to room temperature and stirred for 1 h. The reaction was quenched with 1N NaOH and concentrated. The crude product was purified by chromatography (silica gel, 0 to 10% methanol in methylene chloride gradient elution), to give the title compound (0.014 g, 27% yield). MS 592.2276 (M+1).
Reaction SMILES: [H][H].[N:3]([CH2:6][C@@H:7]1[C@@H:11]([F:12])[CH2:10][N:9]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:8]1)=[N+]=[N-].N(CC1CN(C(OCC2C=CC=CC=2)=O)CC=1)=[N+]=[N-]>C(O)C.[Pt](=O)=O>[NH2:3][CH2:6][C@@H:7]1[C@@H:11]([F:12])[CH2:10][N:9]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:8]1
Reactant: [H][H]
Reactant: [N-]=[N+]=NC[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F
Agent: O=[Pt]=O
Agent: [N-]=[N+]=NCC1=CCN(C(=O)OCc2ccccc2)C1
Solvent: CCO
Product: NC[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F
Yield: 62.7 %

Procedure:
Platinum (IV) oxide (50.0 mg) was suspended in ethanol (7 mL) and the suspension was stirred at room temperature under a stream of hydrogen gas (blown by a balloon) for 30 min. Subsequently, a mixture (551 mg) of (3R,4R)-3-azidomethyl-1-benzyloxycarbonyl-4-fluoropyrrolidine and 3-azidomethyl-1-benzyloxycarbonyl-3-pyrroline in ethanol (3 mL) was added and the mixture was stirred at room temperature under a stream of hydrogen gas (blown by a balloon) for 5 hours. The catalyst in the reaction mixture was filtered and was washed with ethanol. The filtrate and the washings were combined and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: ethyl acetate->ethyl acetate: methanol=10:1) to give a mixture (313 mg) of (3S,4R)-3-aminomethyl-1-benzyloxycarbonyl-4-fluoropyrrolidine and 3-aminomethyl-1-benzyloxycarbonyl-3-pyrroline.
Reaction SMILES: [CH3:1]NC.[CH3:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.N[CH:14]([CH:17]1CCC2(OCCO2)[CH2:19][CH2:18]1)[C:15]#[N:16]>>[CH3:4][N:5]([CH3:1])[CH:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:17]1[CH2:18][CH2:19][NH:16][CH2:15][CH2:14]1
Reactant: CNC
Reactant: CNCc1ccccc1
Reactant: N#CC(N)C1CCC2(CC1)OCCO2
Product: CN(C)C(c1ccccc1)C1CCNCC1

Procedure:
Amine units AM 19 and 21 were prepared by the same process using dimethylamine and, respectively, N-methyl(phenyl)methanamine in the preparation of the amino-(1,4-dioxa-spiro[4.5]dec-8-yl)-acetonitrile intermediate.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:20])[C@@H:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])=[CH:5][CH:4]=1)[CH3:2].[Al](C(C)C)(C(C)C)C(C)C.CC(O)C>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]([OH:20])[C@@H:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C(=O)[C@H](C)NC(=O)OC(C)(C)C)cc1
Agent: CC(C)[Al](C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CCc1ccc([C@@H](O)[C@H](C)NC(=O)OC(C)(C)C)cc1
Temperature: 50 °C

Procedure:
The procedure described by J. Yin et al., J. Org. Chem. 2006, 71, 840-843) was used. A mixture of tert-butyl [(1S)-2-(4-ethylphenyl)-1-methyl-2-oxoethyl]carbamate (555 mg, 2 mmol), Al(iPr)3 (81 mg, 0.4 mmol), 2-propanol (1.32 g, 22 mmol), and toluene (2.6 ml, 1.3 ml/mmol) was heated in a sealed vial at 50° C. overnight. Then the reaction mixture was cooled to r.t., quenched with aqueous HCl (1 N, 10 ml), and diluted with ethyl acetate (10 ml). The layers were separated, the organic layer was washed with water (80 ml), dried with Na2SO4, and concentrated. Trituration with n-heptane (30 ml) afforded the subtitle compound as colourless precipitate, 137 mg. n-Heptane solution was concentrated under reduced pressure, and the residue purified by flash chromatography in silica gel to give the second crop of the subtitle compound, 318 mg. Overall yield 455 mg (81%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][N:11]=[C:10]([CH3:19])[N:9]=1.[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:19][C:10]1[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][N:11]=1
Reactant: CCOC(=O)c1cnc(C)nc1-c1ccccc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc(CBr)nc1-c1ccccc1Cl
Temperature: 25 °C

Procedure:
An amount of 820 mg (2.96 mmol) of ethyl 4-(2-chlorophenyl)-2-methylpyrimidine-5-carboxylate and 633 mg (3.55 mmol) of N-bromosuccinimide were dissolved in 18 ml of carbon tetrachloride and heated with stirring to boiling. At the heat of boiling, in portions, 49 mg (0.29 mmol) of 2,2′-azobis-2-methylpropanenitrile were added over 5 hours, followed by refluxing for a further hour. After cooling to room temperature, the reaction solution was filtered and the mother liquor was freed from the solvent under reduced pressure. The desired product was isolated by chromatographic purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C:12]([F:15])([F:14])[CH2:11][CH:10]([C:16]([OH:18])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19](N1C=CN=C1)([N:21]1C=CN=[CH:22]1)=O.Cl.CNC.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[CH3:19][N:21]([CH3:22])[C:16]([CH:10]1[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][C:12]([F:15])([F:14])[CH2:11]1)=[O:18]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)CC(F)(F)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C(=O)C1CN(C(=O)OC(C)(C)C)CC(F)(F)C1
Reaction time: 16 h
Yield: 60.5 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-5,5-difluoropiperidine-3-carboxylic acid (2.1 g, 7.92 mmol) in N,N-dimethylformamide (100 mL) were added 1,1′-carbonyldiimidazole (CDI, 2.56 g, 15.82 mmol), dimethylamine hydrochloride (1.29 g, 15.82 mmol) and triethylamine (2.4 g, 23.71 mmol). After 16 h, the mixture was diluted with ethyl acetate, then was washed sequentially with cold water (×2) and brine, The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to afford tert-butyl 5-(dimethylcarbamoyl)-3,3-difluoropiperidine-1-carboxylate (1.4 g, 60% over two steps) as a pale yellow solid.