Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[Al+3].[Br-].[Br-].[CH:5]1[C:17]2[CH:16]([CH2:18][O:19][C:20]([NH:22][C:23]([CH2:34][CH2:35][CH2:36][CH:37]=[CH2:38])([CH2:29][CH2:30][CH2:31][CH:32]=[CH2:33])[C:24]([O:26]CC)=[O:25])=[O:21])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1.O.Cl>CSC.ClCCl>[CH:14]1[C:15]2[CH:16]([CH2:18][O:19][C:20]([NH:22][C:23]([CH2:34][CH2:35][CH2:36][CH:37]=[CH2:38])([CH2:29][CH2:30][CH2:31][CH:32]=[CH2:33])[C:24]([OH:26])=[O:25])=[O:21])[C:17]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]=2[CH:11]=[CH:12][CH:13]=1
Reactant: C=CCCCC(CCCC=C)(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCC
Agent: Cl
Agent: [Al+3]
Agent: [Br-]
Solvent: CSC
Solvent: ClCCl
Solvent: O
Product: C=CCCCC(CCCC=C)(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A procedure previously described for dealkylation of esters was used after modifications (see Node et al., J. Org. Chem. 1981, 46, 1991): To a stirred solution of aluminum bromide (22.4 g, 84.0 mmol, 3.0 equiv.) in methyl sulfide (90 mL) was slowly added a solution of ethyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-2-(pent-4-enyl)hept-6-enoate 12 (12.7 g, 27.5 mmol) in dichloromethane (90 mL) at 0° C. over 15 min. The resulting mixture was allowed to warm to room temperature and stirred for 24 h. The reaction mixture was poured into water and acidified with a diluted HCl. The product was extracted with dichloromethane (2×100 mL) and the combined organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residual yellowish solid was purified by silica gel column chromatography (eluting with 7% methanol in dichloromethane) to give B5 as a white solid: 1H-NMR (400 MHz, CDCl3) δ 9.94 (bs, 1H), 7.78 (d, J=7.6 Hz, 2H), 7.61 (d, J=7.6 Hz, 2H), 7.41 (t, J=7.6 Hz, 2H), 7.33 (dt, J=7.6, 0.8 Hz, 2H), 5.75 (m, 2H), 5.00 (d, J=18.8 Hz, 2H), 4.96 (d, J=11.6 Hz, 2H), 4.42 (d, J=6.8 Hz, 2H), 4.23 (t, J=6.8 Hz, 1H), 2.34 (dt, J=12.8, 3.6 Hz, 2H), 2.04 (m, 4H), 1.82 (dt, J=12.8, 3.6 Hz, 2H) 1.40 (m, 2H), 1.17 (m, 2H); 13C-NMR (100 MHz, CDCl3) δ 179.2, 154.2, 144.1, 141.6, 138.3, 128.0, 127.3, 125.2, 120.3, 115.2, 66.5, 64.1, 47.5, 35.2, 33.6, 23.5; HRMS (ESI) m/z for C27H31NO4 [M+H]+ calcd 434.2331. found 434.2334.
Reaction SMILES: FC(F)(F)C1C=C(C2C3C(=CC(OC)=CC=3)C(=O)CC2)C=CC=1.[F:24][C:25]([F:48])([F:47])[C:26]1[CH:27]=[C:28]([CH:32]2[C:41]3[C:36](=[CH:37][C:38]([O:42][CH3:43])=[CH:39][CH:40]=3)[C:35](=[O:44])[C:34]([CH3:46])([CH3:45])[CH2:33]2)[CH:29]=[CH:30][CH:31]=1.CI.CC(C)([O-])C.[K+].[CH3:57][N:58]([CH2:60]CCl)[CH3:59]>C(O)(C)(C)C>[F:24][C:25]([F:47])([F:48])[C:26]1[CH:27]=[C:28]([CH:32]2[C:41]3[C:36](=[CH:37][C:38]([O:42][CH2:43][CH2:57][N:58]([CH3:60])[CH3:59])=[CH:39][CH:40]=3)[C:35](=[O:44])[C:34]([CH3:45])([CH3:46])[CH2:33]2)[CH:29]=[CH:30][CH:31]=1
Reactant: CN(C)CCCl
Reactant: COc1ccc2c(c1)C(=O)C(C)(C)CC2c1cccc(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: COc1ccc2c(c1)C(=O)CCC2c1cccc(C(F)(F)F)c1
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CI
Product: CN(C)CCOc1ccc2c(c1)C(=O)C(C)(C)CC2c1cccc(C(F)(F)F)c1

Procedure:
4-(3-Trifluoromethylphenyl)-7-methoxy-1-tetralone was converted to 4-(3-trifluoromethylphenyl)-7-methoxy-2,2-dimethyl-1-tetralone using methyl iodide-potassium t-butoxide in t-butanol (88%). Dimethylation and alkylation with dimethylaminoethylchloride, as described above, gave 4-(3-trifluoromethylphenyl)-2,2-dimethyl-7-(2-dimethylaminoethoxy)-1-tetralone, obtained, after purification by chromatography on alumina with ether-light petrol (b.p. 60°-80°), as a brown oil (40%). A portion was converted to the hydrochloride salt (92%) which formed white prisms from ethanol-ether, m.p. 208°-209°.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:12](=[O:22])[NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[CH:8][C:9]=1[C:10]#[N:11])=[O:4].O.[OH-].[Li+].C1COCC1.Cl>O>[C:10]([C:9]1[CH:8]=[C:7]([C:12](=[O:22])[NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)[S:6][C:5]=1[C:3]([OH:4])=[O:2])#[N:11]
Reactant: COC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1C#N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(C(=O)NCc2cccc(O)c2)sc1C(=O)O
Reaction time: 15 h

Procedure:
A mixture of 3-Cyano-5-(3-hydroxy-benzylcarbamoyl)-thiophene-2-carboxylic acid methyl ester (33 mg, 0.104 mmol), lithium hydroxide monohydrate (44 mg, 1.04 mmol), THF (2 mL) and water (3 mL) was stirred 15 h, acidified with 1N HCl and extracted with EtOAc (×3). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to give the title compound, 31.4 mg (100%). MS m/e 302.8 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([N:22]([CH2:45][CH2:46][CH2:47][CH3:48])[CH2:23][CH2:24][CH2:25][CH2:26][O:27][Si:28]([C:41]([CH3:44])([CH3:43])[CH3:42])([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:12]=[CH:13][C:14]=1[CH:15]=[CH:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:56]=[O:57].II>O1CCCC1.CCOCC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([N:22]([CH2:45][CH2:46][CH2:47][CH3:48])[CH2:23][CH2:24][CH2:25][CH2:26][O:27][Si:28]([C:41]([CH3:42])([CH3:43])[CH3:44])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:12]=[CH:13][C:14]=1[CH:15]=[CH:16][C:17]1[S:18][C:19]([CH:56]=[O:57])=[CH:20][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCN(CCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ccc(C=Cc2cccs2)c(OCc2ccccc2)c1
Reactant: CN(C)C=O
Agent: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCN(CCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ccc(C=Cc2ccc(C=O)s2)c(OCc2ccccc2)c1
Temperature: -69 °C
Reaction time: 0.58 h
Yield: 57.6 %

Procedure:
In a stream of argon, in 20 ml of tetrahydrofuran was dissolved 2.02 g (3.0 mmol) of [3-benzyloxy-4-(2-thiophene-2-ylvinyl)phenyl]butyl[4-(tert-butyldiphenylsiloxy) butyl]amine, and 2.8 ml of n-butyllithium (1.6 mol solution in hexane) (4.48 mmol) was added dropwise thereto under cooling at −66 to −72° C. After the mixture was stirred for 35 minutes, 0.3 ml (3.9 mmol) of N,N-dimethylformamide was added dropwise thereto. After the mixture was stirred for 1.5 hours, the bath was removed and the temperature was allowed to rise. At −10° C., 10 ml of water was added dropwise. After the reaction mixture was poured into 100 ml of water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residual liquid was purified by silica gel column chromatography to give a reddish orange oily matter. Next, 1.43 g of the oily matter was dissolved in 150 ml of ether and 50 mg of iodine was added thereto. After stirred at room temperature for 30 minutes, the mixture was washed with a 5% sodium bisulfite solution and then with a saturated saline solution. Drying over anhydrous magnesium sulfate and concentration were performed. The residue was purified by silica gel column chromatography to give 1.21 g of a red oily matter (yield: 57.6%).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:13]2[O:14][CH2:15][C@@:10]1([CH2:27][O:28]S(C)(=O)=O)[O:11][C@H:12]2[N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][C:19]([NH2:26])=[N:20][C:21]=2[Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](O[Na])([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:34].CCOC(C)=O.C([O-])(O)=O.[Na+]>CS(C)=O.[Cl-].[Na+].O>[CH2:1]([O:8][C@@H:9]1[C@@H:13]2[O:14][CH2:15][C@@:10]1([CH2:27][O:28][C:33](=[O:34])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[O:11][C@H:12]2[N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][C:19]([NH2:26])=[N:20][C:21]=2[Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OC[C@]12CO[C@H]([C@H](n3cnc4c(Cl)nc(N)nc43)O1)[C@H]2OCc1ccccc1
Reactant: O=C(O[Na])c1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Nc1nc(Cl)c2ncn([C@@H]3O[C@]4(COC(=O)c5ccccc5)CO[C@H]3[C@H]4OCc3ccccc3)c2n1
Temperature: 100 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
Compound 84 (4.49 g, 9.32 mmol) was dissolved in DMSO (200 mL) and BzONa (6.76g, 46.6 mmol) was added. The reaction was stirred at 100° C. for 16 h. The reaction allowed to cool to room temperature and EtOAc (200 mL) and brine:sat. aq NaHCO3 (1:1, 400 mL) was added. The mixture was transferred to a separatory funnel. The phases were separated and the aq-phase was extracted with EtOAc (3×200 mL). The combined organic phase was washed with brine (half-sat., 2×200 mL), dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by DCVC (Ø=6 cm, 50-100% EtOAc in n-heptane v/v, 5% increments, 2×100 mL fractions, 0-10% MeOH in EtOAc v/v, 10% increments, 100 mL) yielding nucleoside 85 (3.30 g, 70%) as a white powder. Rf=0.40 (35% n-heptane in EtOAc (v/v)). ESI-MS m/z found 508.2.; 510.1 ([MH]+, calcd. 508.1). 1H NMR (DMSO-d6, 400 MHz): δ 8.05 (s, 1H, H8), 7.98 (d, 2H, J=7.3 Hz, Bz), 7.68 (t, 1H, J=7.3 Hz, Bz), 7.53 (t, 2H, J=7.7 Hz, Bz), 7.25-7.15 (m, 3H, Bn), 7.05-7.00 (m, 4H, Bn, NH2), 5.98 (s, 1H, H1′), 4.85 (s, 2H, H5″), 4.67 (d, 1H, J=1.8 Hz, H2′), 4.50 (d, 1H, J=12.1 Hz, CH2), 4.35 (d, 1H, J=2.0 Hz, H3′), 4.34 (d, 1H, J=11.7 Hz, CH2), 4.16 (d, 1H, J=8.4 Hz, CH2), 3.98 (d, 1H, J=8.1 Hz, CH2). 13C NMR (DMSO-d6, 100 MHz): δ 165.1 (PhCO), 159.6, 152.9, 149.0 (C2, C4, C6), 140.6 (C8), 136.7, 133.5, 129.2, 128.9, 128.7, 128.0, 127.9, 127.7,127.6 (Ph), 123.2 (C5), 86.7 (C4′), 85.9 (C1′), 79.9 (C3′), 75.8 (C2′), 72.5, 72.1 (5′, CH2Ph), 60.4 (C5″).
Reaction SMILES: CCN=C=NCCCN(C)C.[F:12][C:13]1[CH:14]=[C:15]([NH:20][CH:21]([C:23]2[CH:24]=[C:25]([C:40](O)=[O:41])[CH:26]=[C:27]3[C:32]=2[O:31][C:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[CH:29][C:28]3=[O:39])[CH3:22])[CH:16]=[C:17]([F:19])[CH:18]=1.[NH:43]1[CH2:47][CH2:46][C@H:45]([OH:48])[CH2:44]1.OP=O>C(Cl)Cl>[F:12][C:13]1[CH:14]=[C:15]([NH:20][CH:21]([C:23]2[CH:24]=[C:25]([C:40]([N:43]3[CH2:47][CH2:46][C@H:45]([OH:48])[CH2:44]3)=[O:41])[CH:26]=[C:27]3[C:32]=2[O:31][C:30]([N:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)=[CH:29][C:28]3=[O:39])[CH3:22])[CH:16]=[C:17]([F:19])[CH:18]=1
Reactant: CC(Nc1cc(F)cc(F)c1)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: O[C@H]1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: O=PO
Solvent: ClCCl
Product: CC(Nc1cc(F)cc(F)c1)c1cc(C(=O)N2CC[C@H](O)C2)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95 %

Procedure:
EDCI (102 mg, 0.53 mmol) was added in one portion to 8-(1-(3,5-difluorophenylamino) ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (200 mg, 0.35 mmol, enantiomer 2 ([α]D20°−102°, described as a starting material in Example 7.0a), (S)-pyrrolidin-3-ol (0.043 mL, 0.53 mmol) and HOPO (47.1 mg, 0.42 mmol) dissolved in DCM (2 mL) in a screwcap vial. The resulting solution was stirred at RT for 5 min then 50° C. for 30 min. More EDCI (˜50 mg) was added to complete the reaction. The solution was washed with a 10% aq. citric acid solution, water, brine and dried over magnesium sulfate. The solvent was evaporated and the crude product purified by flash chromatography on silica gel (40 g) eluting with 0 to 10% MeOH in DCM. The solvent was evaporated to dryness to afford 8-(1-(3,5-difluorophenylamino)ethyl)-6-((S)-3-hydroxypyrrolidine-1-carbonyl)-2-morpholino-4H-chromen-4-one (95%) as a off-white foam. Mass Spectrum: M+H+ 500. NMR Spectrum (CDCl3): 1.60 (d, 3H), 1.89-2.11 (m, 1H), 2.54 (bs, 0.5H), 2.81 (bs, 0.5H), 3.29-3.43 (m, 2H), 3.51 (bs, 4H), 3.64-3.78 (m, 2H), 3.79-3.91 (m, 5H), 4.42 (bs, 0.5H), 4.54 (bs, 0.5H), 4.59 (bs, 0.5H), 4.70 (bs, 0.5H), 4.87-4.95 (m, 1H), 5.54 (bs, 1H), 5.89-6.01 (m, 2H), 6.09 (dd, 1H), 7.85 (s, 0.5H), 7.87 (s, 0.5H), 8.18 (bs, 0.5H), 8.25 (bs, 0.5H).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.IC.[CH3:26][Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[C@H:15]([C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=C(Cc1ccc(F)cc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: C[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 48.7 %

Procedure:
To a room-temperature solution of (S)-4-benzyl-3-(2-(4-fluorophenyl)acetyl)oxazolidin-2-one (5.1 g, 16.3 mmol, 1.0 equiv) in dry THF (100 mL) was added iodomethane (1.0 mL, 16.2 mmol, 1.0 equiv) by syringe. The resulting mixture was cooled to −78° C., and NaHMDS (8.15 mL, 2M in THF, 16.3 mmol, 1.0 equiv) was added dropwise by syringe. After stirring for 15 minutes at −78° C., the reaction mixture was allowed to warm to room temperature. The reaction was quenched with saturated. aq. NH4Cl, and diluted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (7-20% EtOAc/hexanes) provided the title compound (2.6 g, 49%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:10][CH:9]=1)(=[O:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(OCC)(=O)C>CN(C=O)C.O>[OH:1][CH2:2][CH2:3][N:4]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: CCCCOc1ccc(S(=O)(=O)NCCO)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCOc1ccc(S(=O)(=O)N(CCO)Cc2ccccc2)cc1
Reaction time: 16 h
Yield: 69 %

Procedure:
Part A: To a solution of 15.11 g (55 mmol) of N-(2-hydroxyethyl)-4-(n-butoxy)benzenesulfonamide from Example 2 in 100 mL of anhydrous DMF, was added 22.9 g (165 mmol) of powdered potassium carbonate and then 10.3 g (60 mmol) of benzyl bromide. After 16 hours, ethyl acetate and water was added, the organic layer separated and washed 3×s with brine, dried with sodium sulfate, filtered and stripped to afford 20.7 g of crude product. This was recrystallized from ethyl acetate/hexane to afford 13.8 g of the desired N-(hydroxyethyl)-N-(phenylmethyl)-4-(n-butoxy)benzenesulfonamide.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][O:5][C:6]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16]Br)[CH:11]=[CH:10][C:7]=1[CH:8]=[O:9].C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CC(C)=O>[Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][O:5][C:6]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:11]=[CH:10][C:7]=1[CH:8]=[O:9]
Reactant: O=Cc1ccc(OCCBr)cc1OCc1ccccc1Br
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1ccc(OCCN2CCOCC2)cc1OCc1ccccc1Br

Procedure:
2-(2-Bromobenzyloxy)-4-(2-bromoethoxy)benzaldehyde (100 mg, 0.241 mmol) synthesized in step 3 was dissolved in acetone, and K2CO3 (66.6 mg, 0.482 mmol), NaI (3.6 mg, 0.024 mmol), and morpholine (0.032 ml, 0.362 mmol) were added to the solution, followed by flux with stirring. After stirring for 24 hours, the solution was cooled, filtered, washed with brine, and extracted with CH2Cl2. Then, the extract was dried over anhydrous MgSO4 and filtered and the filtrate was concentrated in a vacuum. The residue was subjected to column chromatography (50% EA/Hx) to afford the object compound (yellowish oil, 52 mg, 51%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)=O.C(N(CC)CC)C.[NH:21]1[CH2:29][CH2:28][CH2:27][C@H:22]1[C:23](OC)=[O:24]>O.CN(C)C=O>[N:4]1[C:3]2[C:8](=[O:10])[N:21]3[CH2:29][CH2:28][CH2:27][CH:22]3[C:23](=[O:24])[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccnc1C(=O)O
Reactant: COC(=O)[C@@H]1CCCN1
Agent: O=C=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2cccnc2C(=O)N2CCCC12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
36 g (0.26 mol) of 3-aminopyridine-2-carboxylic acid, 46.6 g (0.29 mol) of N,N'-carbonyldiimidazole and 200 ml of dimethylformamide are stirred at room temperature until the carbon dioxide evolution has finished, then the mixture is treated with 26.3 g (0.26 mol) of triethylamine and 43.1 g (0.26 mol) of methyl L-prolinate and stirred at room temperature for a further 1.5 hours. Subsequently, the solution is poured into water, extracted four times with chloroform, the combined chloroform extracts are dried over magnesium sulphate and then evaporated in vacuo. The oily residue is treated with 500 ml of glacial acetic acid, heated to boiling under reflux for 1 hour and then evaporated to dryness. By recrystallization from ethanol there is obtained 6a,7,8,9-tetrahydro-6H-pyrido[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11(5H)-dione of melting point 249°-250°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].C(O)(=O)C.[C:14]([CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])(=O)[CH3:15]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:14]([CH3:15])=[C:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: COc1ccccc1N
Reactant: CCOC(=O)C(C)C(C)=O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(C)=C(C)Nc1ccccc1OC

Procedure:
A mixture of 2-methoxyaniline (10 g), acetic acid (1 ml) and ethyl 2-acetylpropionate (12.3 g) in benzene (30 ml) was refluxed for 24 hours, and then the solvent was removed to give crude ethyl 3-(2-methoxyanilino)-2-methyl-2-butenoate, which was used as a starting compound at the following example without further purification.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][C@@H:29]4[CH2:34][CH2:33][NH:32][CH2:31][C@H:30]4[OH:35])=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][C@@H:29]4[CH2:34][CH2:33][N:32]([C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:31][C@H:30]4[OH:35])=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: COc1cc(-c2ccnc3c(C(=O)N[C@@H]4CCNC[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ccnc23)[C@H](O)C1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f25) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C@H:2]([CH3:17])[C:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[OH:18][C:19]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:20]=1[CH:21]=O>CO>[N+:27]([C:24]1[CH:23]=[C:20]([CH:21]=[N:1][C@H:2]([CH3:17])[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[OH:4])[C:19]([OH:18])=[CH:26][CH:25]=1)([O-:29])=[O:28]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Reactant: C[C@@H](N)C(O)(c1ccccc1)c1ccccc1
Solvent: CO
Product: C[C@@H](N=Cc1cc([N+](=O)[O-])ccc1O)C(O)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
2.0 g of (R)-2-amino-1,1-diphenyl-1-propanol, 1.47 g of 2-hydroxy-5-nitrobenzaldehyde and 30 ml of methanol were mixed, and the mixture was stirred at 80° C. for 1 hour. Thereafter, the mixture was cooled to 20° C. and the deposited crystals were collected by filtration. The collected crystals were washed with methanol and dried to give 3.22 g of (R)-N-(5-nitrosalicylidene)-2-amino-1,1-diphenyl-1-propanol. Yield 97.2%
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][NH:4][CH2:5][C:6]([CH3:16])([N:8]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[N:10]=[CH:9]1)[CH3:7].[CH2:19]=O>C(O)=O>[CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][N:4]([CH3:19])[CH2:5][C:6]([CH3:16])([N:8]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[N:10]=[CH:9]1)[CH3:7]
Reactant: CC(C)(C)CNCC(C)(C)n1cnc([N+](=O)[O-])c1
Reactant: C=O
Solvent: O=CO
Product: CN(CC(C)(C)C)CC(C)(C)n1cnc([N+](=O)[O-])c1

Procedure:
(2,2-Dimethyl-propyl)-[2-methyl-2-(4-nitro-imidazol-1-yl)-propyl]-amine was treated with formalin and formic acid at 85° C. for 5 h, quenched with aqueous sodium bicarbonate, extracted with methylene chloride, dried, concentrated, and the resultant residue purified by chromatography to afford the title compound: H1 NMR (400 MHz, CDCl3) 0.74 (s, 9H), 1.52 (s, 6H), 2.2 (s, 2H), 2.8 (s, 2H), 7.6 (s, 1H), 7.9 (s, 1H); MS m/z 255.3 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][C:13](O)=O)=[CH:2]1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[OH:37][C:38]1[CH:39]=[CH:40][C:41]2[O:46][CH2:45][CH:44]([CH2:47][NH2:48])[O:43][C:42]=2[CH:49]=1>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][CH2:13][NH:48][CH2:47][CH:44]2[CH2:45][O:46][C:41]3[CH:40]=[CH:39][C:38]([OH:37])=[CH:49][C:42]=3[O:43]2)=[CH:2]1
Reactant: NCC1COc2ccc(O)cc2O1
Reactant: O=C(O)CCCc1c[nH]c2ccccc12
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccc2c(c1)OC(CNCCCCc1c[nH]c3ccccc13)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 17 %

Procedure:
3-Indolebutyric acid (1.0 g, 5.0 mmole), 1-hydroxybenzotriazole hydrate (0.8 g, 6.0 mmole) and 1,3-diisopropylcarbodiimide (1.9 ml, 12.0 mmole) were combined in 100 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 7-hydroxy-2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.1 g, 5.0 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and replaced with dichloromethane. The mixture was then washed with H2O. The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. Chromatography on silica gel using first dichloromethane and then 2.5% methanol in dichloromethane as eluants gave 0.3 g (16%) of the desired product, (7-hydroxy-2,3-dihydro-benzo[1,4]dioxin-2-methyl)-4-(1H-indol-3-yl)-butanamide, as an oil.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:13][C:14]1[C:15]([OH:31])=[C:16]([NH:24][C:25](=O)[C:26]([CH3:29])([CH3:28])[CH3:27])[C:17]([C:22]#[N:23])=[C:18]([CH3:21])[C:19]=1[I:20].O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Br:13][C:14]1[C:19]([I:20])=[C:18]([CH3:21])[C:17]([C:22]#[N:23])=[C:16]2[C:15]=1[O:31][C:25]([C:26]([CH3:27])([CH3:28])[CH3:29])=[N:24]2
Reactant: Cc1c(I)c(Br)c(O)c(NC(=O)C(C)(C)C)c1C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(I)c(Br)c2oc(C(C)(C)C)nc2c1C#N
Yield: 93.9 %

Procedure:
Toluene (25 ml), p-toluenesulfonic acid monohydrate (10.9 mg, 57.2 μmol) were added to N-(3-bromo-6-cyano-2-hydroxy-4-iodo-5-methylphenyl)-2,2-dimethylpropionamide (I-7) (250 mg, 572 μmol), followed by refluxing with a Dean-Stark condenser for 3 hours. After cooling, saturated sodium bicarbonate water (30 ml) was added to the reaction liquid, the product was extracted with ethyl acetate (50 ml×2). The organic layer was washed with saturated brine (50 ml), dried over anhydrous magnesium sulfate, concentrated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1) to obtain the entitled compound (225 mg, 94%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[S:17][C:11]=2[CH2:10][CH2:9]1)[C:2]1C=CC=CC=1>[Ni].C(O)C>[CH2:1]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[S:17][C:11]=2[CH2:10][CH2:9]1)[CH3:2]
Reactant: CCOC(=O)c1cc2c(s1)CCN(Cc1ccccc1)CC2
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)c1cc2c(s1)CCN(CC)CC2

Procedure:
3.15 gm (0.01 mol) of ethyl 6-benzyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine-2-carboxylate were refluxed with the same amount of Raney nickel in 50 ml of ethyl alcohol for 6 hours. The catalyst was then removed by suction filtering, and the filtrate was concentrated by evaporation.