Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].I[CH:20]([CH3:22])[CH3:21]>CN(C=O)C.CCOCC>[F:1][C:2]1[CH:11]=[C:10]([O:12][CH:20]([CH3:22])[CH3:21])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(O)cc1F
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(C)C)cc1F
Temperature: 60 °C
Yield: 83.6 %

Procedure:
To a mixture of methyl 2-fluoro-4-hydroxy-benzoate (2.1 g, 12.4 mmol), potassium carbonate (6.8 g, 49.5 mmol) in dry DMF (13 mL) was added 2-iodopropane (2.5 mL, 24.8 mmol) and the reaction mixture was heated at 60° C. for 2 hours. The reaction was cooled and diluted with ether (50 mL) and filtered over Celite®. The filtrate was washed sequentially with water (3×25 mL) and brine solution (25 mL). The organic layer was separated and dried over MgSO4 and solvent was concentrated in vacuo to give a residue which was purified by silica gel column chromatography using 5-45% EtOAc/hexanes to give methyl 2-fluoro-4-isopropoxybenzoate as a colorless oil (2.2 g, 83%). To a solution of methyl 2-fluoro-4-isopropoxybenzoate (2.2 g, 10.3 mmol) in THF (5.5 mL) was added a suspension of lithium hydroxide (0.9 g, 37.1 mmol) in water (5.5 mL). The reaction mixture was stirred at 70° C. for 2 hours. The reaction mixture was cooled to room temperature and the excess LiOH was removed by filtration. The filtrate was diluted with water (9 ml), and washed with ether (2×5 mL). The aqueous layer was separated and cooled to 0° C. and the pH was adjusted to pH 2 by addition of 6 M HCl solution. The aqueous layer was extracted with EtOAc (3×30 mL). The organics were separated and washed sequentially with water and brine. The organic layer was separated, dried and concentrated in vacuo to give 2-fluoro-4-isopropoxy-benzoic acid (2.45 g, 67%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.98 (t, J=8.8 Hz, 1H), 6.69 (ddd, J=15.1, 10.9, 2.0 Hz, 2H), 4.63 (dt, J=12.1, 6.0 Hz, 1H), 1.39 (d, J=6.1 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([C:10]#N)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C1(C)C=CC=CC=1.[H-].C([NH2+]CC(C)C)C(C)C.Cl.[OH2:31]>ClCCl>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:10]=[O:31])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Cl)c(C)c1C#N
Reactant: O
Agent: CC(C)C[NH2+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ncc(Cl)c(C)c1C=O
Temperature: -78 °C
Reaction time: 72 h

Procedure:
2.47 g (13.5 mmol) of 5-chloro-3-cyano-4-methyl-2-methoxypyridine was dissolved in 50 ml of anhydrous dichloromethane, the solution was cooled to −78° C., and 20.3 ml (20.3 mmol) of a toluene solution of 1M diisobutylammonium hydride was dropwise added slowly. After stirring at −78° C. for two and a half hours, the temperature was gradually increased to room temperature, and stirring was carried out at the same temperature for three days. The obtained solution was cooled in an ice bath, and 30 ml of water was slowly added to terminate the reaction. The reaction mixture was poured into 150 ml of 1N hydrochloric acid, followed by extraction with 100 ml of dichloromethane twice. The dichloromethane solution was washed with 100 ml of a saturated sodium chloride solution and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain crude 5-chloro-3-formyl-4-methyl-2-methoxypyridine.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:15]([O:16]CC2C=CC=CC=2)[C@H:14]([O:24]CC2C=CC=CC=2)[C@@H:13]([CH2:32][O:33]CC2C=CC=CC=2)[O:12][C@@:10]1([C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[C:43]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([C:55]#[C:56][Si:57]([CH3:60])([CH3:59])[CH3:58])=[CH:51][CH:50]=2)[CH:42]=1)[OH:11])C1C=CC=CC=1>C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[OH:11][C@:10]1([C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[C:43]([CH2:48][C:49]3[CH:50]=[CH:51][C:52]([CH2:55][CH2:56][Si:57]([CH3:60])([CH3:58])[CH3:59])=[CH:53][CH:54]=3)[CH:42]=2)[O:12][C@H:13]([CH2:32][OH:33])[C@@H:14]([OH:24])[C@H:15]([OH:16])[C@H:9]1[OH:8]
Reactant: Cc1ccc([C@@]2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(C#C[Si](C)(C)C)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1ccc([C@@]2(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc(CC[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 0.29 g 1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranos-1-yl)4-methyl-3-[4-(trimethylsilylethynyl)-benzyl]-benzene and 0.25 g of 10% palladium hydroxide on charcoal in 3 ml of ethyl acetate is shaken for 24 h at ambient temperature under a hydrogen pressure of 1 atm. Then another 0.2 g of catalyst are added and the solution is shaken for a further 20 h under a hydrogen atmosphere. Then the catalyst is filtered off, the filtrate is evaporated down and the residue is chromatographed through silica gel (dichloromethane/methanol 1:0->5:1).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Br:15][C:16]1[C:21](=[O:22])[N:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[NH:19][C:18](=[O:32])[CH:17]=1.[CH3:33][O:34][C:35]1[CH:36]=[CH:37][C:38]([C@H:41]2[CH2:43][C@@H:42]2[CH2:44]O)=[N:39][CH:40]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[Br:15][C:16]1[C:21](=[O:22])[N:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[N:19]=[C:18]([O:32][CH2:44][C@H:42]2[CH2:43][C@@H:41]2[C:38]2[CH:37]=[CH:36][C:35]([O:34][CH3:33])=[CH:40][N:39]=2)[CH:17]=1
Reactant: COc1ccc(Cn2[nH]c(=O)cc(Br)c2=O)cc1
Reactant: COc1ccc([C@H]2C[C@@H]2CO)nc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(OC[C@H]3C[C@@H]3c3ccc(OC)cn3)cc(Br)c2=O)cc1

Procedure:
DIAD (0.625 ml, 3.21 mmol) was added to a mixture of 5-bromo-1-(4-methoxybenzyl)-1,2-dihydropyridazine-3,6-dione (500 mg, 1.607 mmol), ((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methanol (288 mg, 1.607 mmol) and PPh3 (843 mg, 3.21 mmol) in THF (15 ml) at 0° C.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1.C(OCC)(=O)C>ClCCl.C(#N)C.CCCCCC.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[I:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: OCc1ccc(I)cc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.1 %

Procedure:
A solution of 4-iodobenzyl alcohol (9 g, 38.29 mmol) in dichloromethane (90 mL) and acetonitrile (10 mL) was treated sequentially with 4 A molecular sieves powder (9 g), tetra-n-propyl ammoniumperruthenate (0.13 g) and N-methyl morpholine-N-oxide (9 g, 76.6 mmol). After stirring at ambient temperature for 2 h, the reaction mixture was diluted with hexane and subjected to flash column chromatography over-silica-gel-(230–400 mesh) using-6–1% ethyl acetate in hexane as the eluent to afford the title compound (2.5 g pure and 4 g˜95% pure, 73%).
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[O:20]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[N:21]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1>[O:20]1[CH:24]=[C:23]([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:22]=[N:21]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: CC1(C)OB(c2cnoc2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2cnoc2)C1
Temperature: 85 °C
Reaction time: 12 h
Yield: 62.7 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), 4-isooxazolylboronic acid pinacol ester (119 mg, 0.609 mmol), tripotassium phosphate (194 mg, 0.914 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (24.9 mg, 0.0305 mmol) in dioxane (2 ml) was stirred at 85° C. for 12 hr under a nitrogen atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (120 mg, 62.2%) as an oil.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:46])[C:10]([O:12][C:13]1([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[C:32](=[O:33])[C:31]4[S:34][C:35]([C:37]5[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=5)=[CH:36][C:30]=4[N:29]=[CH:28]3)=[CH:23][C:22]=2[O:44][CH3:45])[CH2:16][C:15]([F:18])([F:17])[CH2:14]1)=[O:11])=O)(C)(C)C.Cl.CO>C(O)(C(F)(F)F)=O.C(Cl)Cl.C(Cl)Cl>[NH2:8][C@@H:9]([CH3:46])[C:10]([O:12][C:13]1([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[C:32](=[O:33])[C:31]4[S:34][C:35]([C:37]5[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=5)=[CH:36][C:30]=4[N:29]=[CH:28]3)=[CH:23][C:22]=2[O:44][CH3:45])[CH2:14][C:15]([F:17])([F:18])[CH2:16]1)=[O:11]
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC1(OC(=O)[C@H](C)NC(=O)OC(C)(C)C)CC(F)(F)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC1(OC(=O)[C@H](C)N)CC(F)(F)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A mixture of (S)-1-((4-(6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-methoxyphenoxy)methyl)-3,3-difluorocyclobutyl 2-(tert-butoxycarbonylamino)-propanoate from Part A (59 mg, 0.087 mmol) in 25% TFA/CH2Cl2 (4 mL) was stirred at RT for 30 min. After removal of the volatiles under vacuum, the crude product was purified by prep-HPLC (PHENOMENEX® Axia, Luna 5 micron 30×100 mm, flow rate=40 ml/min., gradient 0% A to 100% B in 10 min., A=90% H2O/10% MeOH/0.1% TFA, B=10% H2O/90% MeOH/0.1% TFA). The desired fractions were concentrated and dried under high vacao prior to addition of aq. saturated NaHCO3 (6 ml) and extraction with CH2Cl2 (2×10 ml). The combined CH2Cl2 layers were dried over Na2SO4 and concentrated prior to conversion of the free base (42 mg, 0.073 mmol) to the HCl salt by dissolution in CH2Cl2 (2 ml) and addition of 1.0 M HCl (0.079 mL, 0.079 mmol)/MeOH (2 ml) at −30° C. The HCl salt was then concentrated and was dried under high vacuum to yield (S)-1-((4-(6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-methoxyphenoxy)methyl)-3,3-difluorocyclobutyl 2-aminopropanoate (41.94 mg, 0.073 mmol, 83% yield) as white solid. 1H NMR (400 MHz, MeOD) δ ppm 8.27 (1H, s), 7.73 (2 H, d)3 7.63 (1 H, s), 7.43 (2 H, d), 7.02-7.15 (2 H, m), 6.94 (1 H, dd, J=8.56, 2.52 Hz), 4.41 (2 H, d, J=3.02 Hz), 3.91-4.02 (1 H, m), 3.78 (3 H, s), 2.87-3.18 (4 H, m), 1.44 (3 H, d, J=7.30 Hz). LC-MS: 2.33 min 576 (M+H). Luna 5 u C18 30×4.6 mm ID, flow rate=4 ml/min., gradient=0% A to 100% B in 2 min., A=90% H2O/10% MeOH/0.1% TFA, B=10% H2O/90% MeOH/0.1% TFA).
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1[C:12](=[O:22])[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([F:21])[CH:14]=1)C.[Li+].[OH-].O.Cl>O1CCCC1>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:23])=[O:3])=[C:6]([C:12](=[O:22])[C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([F:21])[CH:14]=2)[CH:7]=1
Reactant: CCOC(=O)c1ccc(Br)cc1C(=O)c1cc(F)cc(OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(F)cc(C(=O)c2cc(Br)ccc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-Bromo-2-(3-fluoro-5-methoxy-benzoyl)-benzoic acid ethyl ester (165 mg; 0.43 mmol) in 900 μl tetrahydrofuran is added a 1 M solution of LiOH in water (866 μl; 0.87 mmol). It is stirred at ambient temperature for 2 hours. The reaction mixture is acidified with 1 N HCl and washed with methylene dichloride several times. The organic layers are pooled, dried over MgSO4 and evaporated to dryness.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[Cl:20][C:21]1[C:27]([O:28][C:29]2[C:30]([O:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[N:31][CH:32]=[CH:33][CH:34]=2)=[CH:26][C:24]([NH2:25])=[C:23]([F:41])[CH:22]=1>C(OCC)(=O)C>[Cl:20][C:21]1[C:27]([O:28][C:29]2[C:30]([O:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[N:31][CH:32]=[CH:33][CH:34]=2)=[CH:26][C:24]([N:25]=[C:2]=[O:4])=[C:23]([F:41])[CH:22]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)COc1ncccc1Oc1cc(N)c(F)cc1Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)COc1ncccc1Oc1cc(N=C=O)c(F)cc1Cl
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
Into a solution of 227 mg of triphosgene in 8 ml of ethyl acetate, a solution of 155 mg of triethylamine and 250 mg of 4-chloro-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}aniline in 8 ml of ethyl acetate was added at 0° C. The mixture was stirred for 30 minutes at the same temperature, then for 2 hours at reflux temperature. The reaction solution was filterated while it was hot, and the solvent was distilled off under reduced pressure to obtain 266 mg of 4-chloro-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}phenyl isocyanate.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[NH4+:12].[OH-]>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:12])=[O:7]
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: NC(=O)c1cccc(CCl)c1
Yield: 81.4 %

Procedure:
To a solution of 66.50 g (0.352 mol, 1.0 mol-equiv) 3-chloromethylbenzoylchloride in 400 mL CH2Cl2 at 0°-5° C. under argon was added 47.6 mL (0.704, 2.0 mol-equiv) concentrated aqueous NH4OH over 25 min. The resulting slurry was filtered, washed with water and the product was dried overnight at 50° C. under vacuum to provide 48.59 g (81%) of 3-chloromethylbenzamide.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:3][CH:2]=1.[Li+].[CH3:15]C([N-]C(C)C)C.CI.CN1C(=O)N(C)CCC1>C1COCC1.O>[CH2:11]([O:10][C:8](=[O:9])[CH:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:13])=[CH:6][CH:5]=1)[CH3:15])[CH3:12]
Reactant: CCOC(=O)Cc1ccc(C)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: O
Solvent: CI
Product: CCOC(=O)C(C)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
Under N2 atmosphere, a solution of ethyl p-tolyl-acetate (2.72 g, 15.2 mmol) in anhydrous THF (70 mL) was cooled to −40° C. and a solution of LDA (7.6 mL, 15.25 mmol) was added drop-wise over 30 minutes. The reaction mixture was stirred for 1 h, and methyl iodide (3.03 g, 21.30 mmol) was added drop-wise, followed by the addition of DMPU (1 mL). The reaction mixture was allowed to warm to rt, after 1 h and stirred overnight. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with saturated NH4Cl solution (10 mL), 1 M HCl (10 mL), saturated NaHCO3 solution (10 mL), and brine (10 mL), then dried over MgSO4, and concentrated in vacuo. The residue was distilled in high vacuo (bp. 59-63° C./0.2 mmHg) to furnish 2-p-tolyl-propionic acid ethyl ester (2.5 g, 86.0%) as an oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm) 7.18 (d, 2H, J=8.1), 7.10 (d, 2H, J=8.1), 4.09 (m, 2H), 3.67 (q, 1H, J=7.2), 2.29 (s, 3H), 1.47 (d, J=7.2 Hz, 3H), 1.20 (t, J=5.7 Hz, 3H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm) 174.71, 137.80, 136.63, 129.33, 129.14, 127.36, 60.66, 45.18, 21.05, 18.70, 14.15. [Lit. ref.: Ghosh, S.; Pardo, S. N.; Salomon, R. G. J. Org. Chem. 1982, 47, 4692-4702.].
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CON(C)[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[CH:3]1([CH2:2][C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:19])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: BrCC1CCCCC1
Reactant: CON(C)C(=O)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CC1CCCCC1)c1ccccc1
Temperature: 25 °C
Yield: 64.8 %

Procedure:
To a suspension of Mg (735 mg, 30.5 mmol) in anhydrous THF (20 mL) was added (bromomethyl)cyclohexane (5.4 g, 30.5 mmol) at 10° C. under N2 atmosphere. The resulting mixture was stirred at reflux until all of Mg was consumed. Then the resulting mixture was cooled to ambient temperature and N-methoxy-N-methylbenzamide (1.0 g, 6.1 mmol) was added and the mixture was stirred at 10° C. for 2 hours. The mixture was quenched with aqueous saturated NH4Cl (50 mL). Followed a standard aqueous/EtOAc workup and the residue was purified by column chromatography on silica gel (PE:EtOAc=20:1) to give Intermediate 96 as colorless oil (800 mg, yield 67%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:28])C(=O)C1.CCOC(C)=O>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][C:3]=1[Br:28]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)cc2)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)c(Br)c2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 101.7 %

Procedure:
To a stirred solution of tert-butyl (RS)-2-(4-aminophenyl)morpholine-4-carboxylate (3.07 g, CAS-1002726-96-6) in DMF (30 ml) was added NBS (1.96 g) and the mixture was stirred at room temperature for 15 min. The reaction mixture was then poured into EtOAc and extracted sequentially with water and with saturated brine. The organic layer was dried over Na2SO4 and then concentrated in vacuo to afford tert-butyl (RS)-2-(4-amino-3-bromophenyl)morpholine-4-carboxylate (4.0 g, quant.) as a light brown solid which was used in the next step without further purification. MS (ISP): 359.0 ([{81Br}M+H]+), 357.0 ([{79Br}M+H]+), 303.0 ([{81Br}M+H—C4H8]+), 301.0 ([{79Br}M+H—C4H8]+).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])[CH:2]=[CH2:3].[F-].[K+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[N+](C1C=C(S(O[CH2:45][C@@H:46]2[O:48][CH2:47]2)(=O)=O)C=CC=1)([O-])=O>C1COCC1.O>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:45][C@@H:46]1[O:48][CH2:47]1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccccc1O
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOc1ccccc1OC[C@H]1CO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
o-Allyloxyphenol (1.0 g) was dissolved in THF (10 ml) under nitrogen atmosphere and the solution was cooled to 0° C. Potassium fluoride (1.55 g) and tetrabutyl ammonium fluoride (0.2 g) were added thereto and the mixture was stirred for 1 hour. Then, (R)-glycidyl m-nitrobenzenesulfonate (1.73 g, 99.3% e.e.) was added thereto and the mixture was stirred for 40 hours at the same temperature. After the reaction, water was added to the mixture, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, condensed and the residue was subjected to silica gel chromatography (hexane/ethyl acetate; 3:2) to give 0.96 g of (R)-3-(o-allyloxyphenoxy)-1,2-epoxypropane (yield 70%, optical purity 95.9% e.e.) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[NH:7][C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[CH3:21][CH:22]([N:24]([CH:37]([CH3:39])[CH3:38])[CH2:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][NH2:36])[CH2:30][CH2:29]1)[CH3:23]>C(#N)C>[CH3:39][CH:37]([N:24]([CH:22]([CH3:23])[CH3:21])[CH2:25][CH2:26][CH2:27][CH:28]1[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][NH:36][C:11]([N:10]2[C:4]3[CH:3]=[C:2]([Cl:1])[CH:20]=[CH:19][C:5]=3[C:6](=[O:18])[NH:7][C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]2=3)=[O:12])[CH2:32][CH2:33]1)[CH3:38]
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2cc(Cl)ccc21
Reactant: CC(C)N(CCCC1CCN(CCN)CC1)C(C)C
Solvent: CC#N
Product: CC(C)N(CCCC1CCN(CCNC(=O)N2c3cc(Cl)ccc3C(=O)Nc3cccnc32)CC1)C(C)C
Yield: 44 %

Procedure:
Prepared analogously to Example 1 from 9-chloro-11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[4-[3-[bis(methylethyl)amino]propyl]-piperidin-l-yl]ethanamine in a yield of 44% of theory. Colourless crystals, m.p. 175°-176° C. (acetonitrile).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([N:12]([CH3:14])[CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].O[CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:25]([O:24][C:22]([N:19]1[CH2:20][CH2:21][CH:16]([O:1][C:2]2[CH:11]=[C:10]([N:12]([CH3:13])[CH3:14])[CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH2:17][CH2:18]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: COC(=O)c1ccc(N(C)C)cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(N(C)C)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.7 %

Procedure:
To a mixture of methyl 2-hydroxy-4-(N,N-dimethylamino)benzoate (7.809 g, 40 mmol), 4-hydroxy-1-tert-butoxycarbonylpiperidine (8.048 g, 40 mmol), triphenylphosphine (11.02 g, 42 mmol), and THF (250 mL) at 0° C. was added diethyl azodicarboxylate (7.1 mL, 45.1 mmol), dropwise. The reaction was warmed to room temperature and stirred overnight. The reaction was concentrated, chromatographed (hexane to 30% EtOAc/hexane), and triturated with ether/hexane to give the desired product as a white solid (5.55 g, 37%).
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]([CH2:23][C:24]([NH:26][CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:25])[CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])C1C=CC=CC=1>C(O)C.[Pd]>[C:19]([O:18][C:16](=[O:17])[NH:15][CH2:14][CH2:13][CH2:12][C@H:11]([NH2:10])[CH2:23][C:24]([NH:26][CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:25])([CH3:20])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CC(=O)NCCNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCC[C@H](N)CC(=O)NCCNC(=O)OC(C)(C)C
Reaction time: 15 h

Procedure:
400 mg (0.765 mmol) of benzyl{(1S)-4-[(tert-butoxycarbonyl)amino]-1-[2-({2-[(tert-butoxycarbonyl)amino]ethyl}amino)-2-oxoethyl]butyl}carbamate (Example 114A) are dissolved in 50 ml of ethanol. 80 mg of palladium on activated carbon (10%) are added thereto, and the mixture is then hydrogenated under atmospheric pressure for 15 h. The reaction mixture is filtered through prewashed kieselguhr, and the filtrate is concentrated on a rotary evaporator in vacuo. The crude product is reacted without further purification.