Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]1OC(C)(C)[O:7][C@@H:6]([CH2:12][C:13]([OH:15])=[O:14])[CH2:5]1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=O)[CH:24]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:25]([C:35](=O)[CH:36]([CH3:38])[CH3:37])[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:27])=[CH:19][CH:18]=1.C(OCC)C.[Cl-].[NH4+]>CS(C)=O.O>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[N:1]([CH2:2][CH2:3][C@H:4]3[CH2:5][C@H:6]([OH:7])[CH2:12][C:13](=[O:14])[O:15]3)[C:35]([CH:36]([CH3:38])[CH3:37])=[C:25]([C:26]([NH:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:27])[C:24]=2[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[CH:21][CH:22]=1
Reactant: CC1(C)O[C@H](CCN)C[C@H](CC(=O)O)O1
Reactant: CC(C)C(=O)C(C(=O)Nc1ccccc1)C(C(=O)c1ccc(F)cc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOCC
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@H]1C[C@H](O)CC(=O)O1
Temperature: 105 °C
Reaction time: 18 h
Yield: 24.7 %

Procedure:
A solution of 0.26 g (1.21 mmol) of (±)-cis-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid and 0.504 g (1.20 mmol) of (±)4-fluoro-α-[2-methyl-1-oxopropyl]-γ-oxo-N,β-diphenylbenzenebutaneamide mixture of [R-(R*,R*)], [R-(R*,S*)], [S-(R*,R*)] and [S-(R*,S*)] isomers in 5 mL of dimethyl sulfoxide is heated at 105° C. for 15 hours. The solution is cooled and poured into 100 mL of diethyl ether and 50 mL of saturated ammonium chloride in water. The layers are separated and the organic layer washed with water (2×50 mL) and 5% sodium hydroxide solution (2×100 mL--to extract the intermediate from unreacted diketone). The aqueous layer is acidified with dilute hydrochloric acid solution and extracted with 30 mL of ethyl acetate. A drop of concentrated hydrochloric acid is added to the ethyl acetate solution and allowed to stand 18 hours. The solution is concentrated in vacuo and the concentrate is redissolved in 30 mL of ethyl acetate and treated with one drop of concentrated hydrochloric acid. The solution is stirred two hours, concentrated in vacuo, and dissolved in 6 mL of toluene. Trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide crystallizes and is isolated by filtration. A total of 0.16 g of trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide is isolated in two crops.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([CH:7]([NH:15][CH3:16])[CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:3][CH:2]=1.[CH3:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[CH3:34])[N:30]([CH2:35][C:36]([OH:38])=O)[C:29](=[O:39])[CH:28]=[N:27]2.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:2]=[CH:3][C:4]([CH:7]([N:15]([CH3:16])[C:36](=[O:38])[CH2:35][N:30]2[C:31]3[C:26](=[CH:25][C:24]([CH3:23])=[C:33]([CH3:34])[CH:32]=3)[N:27]=[CH:28][C:29]2=[O:39])[CH2:8][N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[CH:5][CH:6]=1
Reactant: CNC(CN1CCOCC1)c1ccc(-c2ccccc2)cc1
Reactant: Cc1cc2ncc(=O)n(CC(=O)O)c2cc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc2ncc(=O)n(CC(=O)N(C)C(CN3CCOCC3)c3ccc(-c4ccccc4)cc3)c2cc1C
Reaction time: 0.17 h
Yield: 16.2 %

Procedure:
[1-(4-biphenylyl)-2-(4-morpholinyl)ethyl]methylamine (180 mg, 0.62 mmol) was added to a solution of (6,7-dimethyl-2-oxo-1(2H)-quinoxalinyl)acetic acid (120 mg, 0.52 mmol), (benzotriazol-1-yloxy) tris(dimethylamino) phosphonium-hexafluorophosphate (BOP) (270 mg, 0.62 mmol) and diisopropylethylamine (340 mg, 2.6 mmol) in dimethylformamide (DMF) (5 mL). The reaction mixture was stirred at room temperature for 3h, filtered and washed with DMF. The crude was purified by preparative HPLC (YMC CombiPrep ODS-A, 50×20 mm, 20 mL/min, A: acetonitrile B: water, A: 10 to 90% over 10 min, UV detection at 214 nm) to give the title compound (43 mg, 14% ), MS (ES) m/e 511 [M+H]+.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][CH2:10]C(O)=O)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([O:16][C:17](=[O:25])[N:18]([CH2:22][CH:23]=[CH2:24])[CH2:19][CH:20]=O)[CH3:15]>C1(C)C=CC=CC=1.CO>[C:1]1([C@H:7]([N:9]2[CH:20]3[CH2:19][N:18]([C:17]([O:16][CH2:14][CH3:15])=[O:25])[CH2:22][CH:23]3[CH2:24][CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](NCC(=O)O)c1ccccc1
Reactant: C=CCN(CC=O)C(=O)OCC
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOC(=O)N1CC2CCN([C@H](C)c3ccccc3)C2C1
Temperature: 90 °C
Reaction time: 14 h
Yield: 100 %

Procedure:
A solution of (1-(R)-phenyl-ethylamino)-acetic acid (25.6 g) in 384 mL of toluene was heated to 90° C. To this 170 g (1.1 equivalents) of a 15.84 wt. % solution of allyl-(2-oxo-ethyl)-carbamic acid ethyl ester (U.S. Pat. No. 5,071,999) in toluene, was added over 20 minutes and the mixture was stirred at 90° C. for 14 hours then at 95° C. for 12 hours. After cooling, the product was extracted with 2×115 g of 20% citric acid solution. The citric acid solution was diluted with 205 mL of isopropyl acetate, and the mixture was neutralized with a solution of 51.2 g K2CO3 in 120 g water, and thoroughly shaken. The layers were separated, and the aqueous layer was extracted again with 102 mL of isopropyl acetate. The organic extracts were combined and distilled under reduced pressure to provide an oil which was then diluted with 125 mL of MeOH to provide 140 g (100% yield) of the title compound as a 30% by weight solution in MeOH.
Reaction SMILES: S(O[CH:7]1[CH2:13][CH:12]2[N:14]([CH3:15])[CH:9]([CH2:10][CH2:11]2)[CH2:8]1)(OC)(=O)=O.[H-].[Na+].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1.O>O1CCCC1>[CH3:15][N:14]1[CH:9]2[CH2:10][CH2:11][CH:12]1[CH2:13][CH:7]([S:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)[CH2:8]2
Reactant: COc1ccc(S)cc1
Reactant: COS(=O)(=O)OC1CC2CCC(C1)N2C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(SC2CC3CCC(C2)N3C)cc1
Temperature: 30 °C
Yield: 103.7 %

Procedure:
To a solution of methyl 8-methyl-8-azabicyclo[3.2.1]oct-3-yl sulfate (Preparation 13, 35 g, 0.16 mol) in tetrahydrofuran (300 ml) was added with cooling to 0° C. sodium hydride (60% dispersion in oil, 7 g, 0.17 mol). After complete addition, 4-methoxybenzene thiol (23.8 g, 0.16 mol) was added in tetrahydrofuran (300 ml). The reaction mixture was heated under reflux for 2 h and then cooled to 30° C. and water (250 ml) was added. The tetrahydrofuran was removed in vacuo, dichloromethane was added and the layers separated. The organic layer washed with water, sodium hydroxide (1 M solution), water, and saturated brine before drying (Na2SO4). The organic extracts were concentrated in vacuo to give the title compound (43.7 g, 100%).
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[C:15]2[S:14](=[O:17])(=[O:16])[N:13]=[C:12]([CH2:18][C:19]([OH:21])=O)[NH:11][C:10]=2[S:9][CH:8]=1)(=[O:4])=[O:3].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=C[C:32]=2N=N1.CN1CCOCC1.C(O[C:56](=[O:71])[CH:57]([CH2:61][NH:62][CH2:63][C:64]1[CH:69]=[CH:68][C:67]([F:70])=[CH:66][CH:65]=1)[CH:58]([CH3:60])[CH3:59])C.[O-]CC.[Na+].C(O)C>CN(C)C=O>[C:58]([CH:57]1[CH2:61][N:62]([CH2:63][C:64]2[CH:65]=[CH:66][C:67]([F:70])=[CH:68][CH:69]=2)[C:19](=[O:21])[C:18]([C:12]2[NH:11][C:10]3[S:9][CH:8]=[C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[C:15]=3[S:14](=[O:16])(=[O:17])[N:13]=2)=[C:56]1[OH:71])([CH3:59])([CH3:60])[CH3:32]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)C(CNCc1ccc(F)cc1)C(C)C
Agent: CC[O-]
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)C1CN(Cc2ccc(F)cc2)C(=O)C(C2=NS(=O)(=O)c3c(CNS(C)(=O)=O)csc3N2)=C1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
[7-(Methanesulfonylamino-methyl)-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-acetic acid (prepared as described in Example 2c; 0.164 g, 0.464 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.195 g, 0.513 mmol) and 4-methylmorpholine (0.102 mL, 0.928 mmol) were added sequentially to a solution of rac-2-[(4-fluoro-benzylamino)-methyl]-3-methyl-butyric acid ethyl ester (0.131 g, 0.466 mmol) in N,N-dimethylformamide (5 mL) at 25° C. The reaction mixture was stirred at 25° C. for 16 h, and then was concentrated in vacuo. The residue was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was dissolved in ethanol (10 mL) at 25° C. A 21 wt. % solution of sodium ethoxide in ethanol (1.81 mL, 5.58 mmol) was added and the reaction mixture was heated to 70° C. for 84 h. After cooling to 25° C., the reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash chromatography (Teledyne Isco RediSep column; 60-100% ethyl acetate in hexanes) to afford (after trituration with diethylether) rac-N-{3-[5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}-methanesulfonamide (0.1111 g, 0.195 mmol, 42%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ: 0.92 (9H, s), 2.36 (1H, bs), 2.96 (3H, s), 3.44 (1H, d, J=14.3 Hz), 3.59 (1H, dd, J=5.5 Hz, J2=14.2 Hz), 4.25 (2H, d, J=6.1 Hz), 4.44 (1H, d, J=14.6 Hz), 4.79 (1H, d, J=13.9 Hz), 7.14-7.18 (2H, m), 7.27 (1H, s), 7.39-7.42 (2H, m), 7.65 (1H, t, J=6.2 Hz). LC-MS (ESI) calculated for C23H27FN4O6S3 570.11. found 571.2 [M+H+].
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH3:25][S:26]([O:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([C@H:8]([NH:10][C:11]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:17])[CH3:9])[CH2:4][CH2:3]1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](NC(=O)OC(C)(C)C)[C@H]1CC[C@@H](O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)OC(C)(C)C)[C@H]1CC[C@@H](OS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Cis-(R)-tert-butyl 1-(4-hydroxycyclohexyl)ethylcarbamate (575 mg, 2.363 mmol) was dissolved in dichloromethane (10 mL) and cooled to 0° C. under nitrogen. Triethylamine (478.2 mg, 658.7 μL, 4.726 mmol) followed by methanesulfonylchloride (284.2 mg, 192.0 μL, 2.481 mmol) were added dropwise. The reaction mixture was stirred at room temperature for 30 minutes. The crude mixture was washed with 1M HCl, water and a saturated aqueous solution of sodium bicarbonate. The organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to give the compound as a white solid (706 mg, 93% yield).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C-:4]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH-:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.[Fe+2:16].CCN(CC)CC.[CH3:24][C:25](OC(C)=O)=[O:26]>CN(C1C=CN=CC=1)C.C1COCC1.CCOCC>[C:25]([O:1][CH2:2][C:3]1[C-:4]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1)(=[O:26])[CH3:24].[CH-:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.[Fe+2:16]
Reactant: CN(C)[c-]1cccc1CO
Reactant: CC(=O)OC(C)=O
Agent: [Fe+2]
Agent: CN(C)c1ccncc1
Agent: c1cc[cH-]c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)OCc1ccc[c-]1N(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.3 %

Procedure:
A solution of 61 (407 mg, 1.57 mmol), DMAP (19 mg, 0.16 mmol) and Et3N (0.65 mL, 4.70 mmol) in THF (8 mL) was treated with Ac2O (0.22 mL, 2.35 mmol) and allowed to stir at room temperature for 16 h. The reaction mixture was diluted with Et2O, washed with H2O (2×10 mL), brine (1×10 mL), dried over Na2SO4, filtered, and all volatiles were removed in vacuo. The crude product was taken up in hexanes and filtered through a pad of silica gel, eluting with 60:40 hexane/EtOAc. Evaporation of the filtrate afforded acetate 62 (413 mg, 88%) as a dark orange oil: Rf=0.44 (silica, 50:50 hex/EtOAc); IR (KBr, neat) vmax 3095, 3014, 2947, 2848, 2783, 1736, 1486, 1454 cm−1; 1H NMR (300 MHz, CDCl3) δ 5.03 (AB q, 2H, J=12.0, 12.0 Hz), 4.16 (s, 5H), 4.10 (t, 1H, J=1.8 Hz), 4.02-3.93 (m, 2H), 2.61 (s, 6H), 2.03 (s, 1H), 13C NMR (75 MHz, CDCl3) δ 170.9, 114.4, 68.7, 67.7, 63.5, 61.9, 56.6, 45.2, 21.0; EIMS [m/z (%)] 301 (M+, 33), 121 (100); HRMS (EI) calcd for C15H19NO256Fe: 301.0765. Found 301.0766.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[OH:14][CH:15]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[CH2:16]O.C([O-])([O-])=[O:26].[K+].[K+]>CN(C)C=O>[OH:26][C:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:3][C:4]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[CH:20][CH:19]=1)([OH:14])[CH3:16]
Reactant: OCC(O)c1ccc(O)cc1
Reactant: O=C([O-])[O-]
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(O)(O)c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
A mixture containing 2-(chloromethyl)quinoline hydrochloride (2.68 g), 2-hydroxy-2-(4-hydroxyphenyl)ethanol (1.74 g) and anhydrous K2CO3 (4.70 g) was stirred at room temperature in dry N,N-dimethylformamide (DMF) for 3 days. DMF was removed under reduced pressure and the residue was partitioned between CH2Cl2 and water. The aqueous phase was re-extracted with CH2Cl2 and the combined organic phase was washed with brine, dried and concentrated. The title compound was obtained after recrystallization from methanol/ethyl acetate/hexane.
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCN(C(C)C)C(C)C.[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([CH2:56]O)[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl>[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([CH2:56][N:22]2[C:23]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([C:32]#[N:33])=[CH:30][CH:31]=3)=[CH:24][N:20]=[CH:21]2)[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: N#Cc1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Cn2cncc2Cc2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To 1-trityl-4-(4-Cyanobenzyl)-imidazole (1.99 g, 4.64 mmol) in CH2Cl2 (9.3 mL), Hunigs base (1.62 mL, 9.28 mmol) and the product from step B (1.0 g 4.64 mmol) at -78° C. was added trifluoromethanesulfonic anhydride (0.78 mL, 4.64 mmol). After 45minutes the reaction was allowed to warm to room temperature. The solvent was evaporated and the residue was dissolved in methanol (50 ml) and heated at reflux for 1 hour, cooled and evaporated to dryness. The residue was partitioned between sat. aq. NaHCO3 solution and CH2Cl2. The organic layer was dried, (MgSO4) and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 3% MeOH in CH2Cl2) to afford the title compound.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH3:18])[CH:11]=[O:12])[CH3:6]>ClCCCl>[CH2:17]([O:16][C:15]1[C:8]([O:7][CH2:5][CH3:6])=[CH:9][C:10]([CH:11]=[O:12])=[C:13]([N+:1]([O-:4])=[O:2])[CH:14]=1)[CH3:18]
Reactant: O=[N+]([O-])O
Reactant: CCOc1ccc(C=O)cc1OCC
Solvent: ClCCCl
Product: CCOc1cc(C=O)c([N+](=O)[O-])cc1OCC
Temperature: 0 °C

Procedure:
2.13 ml of fuming nitric acid were added within 30 minutes to a solution, cooled to −30° C. of 10 g of 3,4-diethoxybenzaldehyde in 185 ml of 1,2-dichloroethane. Subsequently, the reaction mixture was left to warm to 0° C. and was poured on to ice. The product was isolated by extraction. There were obtained 12.06 g of 4,5-diethoxy-2-nitro-benzaldehyde.
Reaction SMILES: O[Li].O.[CH3:4][O:5][C:6]1[C:7]([CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH2:40][C:41]([O:43]C)=[O:42])=[N:8][C:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[N:10][CH:11]=1>C1COCC1.O.CO>[C:28]([O:27][C:25]([N:22]1[CH2:23][CH2:24][CH:19]([C:16]2[CH:15]=[CH:14][C:13]([NH:12][C:9]3[N:8]=[C:7]([CH2:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[CH2:40][C:41]([OH:43])=[O:42])[C:6]([O:5][CH3:4])=[CH:11][N:10]=3)=[CH:18][CH:17]=2)[CH2:20][CH2:21]1)=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1OC
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cnc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)nc1CCc1ccccc1CC(=O)O
Temperature: 25 °C
Reaction time: 17 h
Yield: 90.6 %

Procedure:
LiOH.H2O (0.025 g, 0.59 mmol) was added to a solution of tert-butyl 4-(4-((5-methoxy-4-(2-(2-methoxy-2-oxoethyl)phenethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A100) (0.11 g, 0.20 mmol) in THF (7 mL), water (1.5 mL) and MeOH (1 mL) and the resulting mixture stirred at room temperature for 17 hours. The volatiles were removed in vacuo and the residue was partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4 and the volatiles removed in vacuo to give the title compound A101 as a pale yellow oil (0.099 g, 92%); 1H NMR (400 MHz, d4-MeOH) δ 7.98 (s, 1H), 7.52 (d, J=8.5 Hz, 2H), 7.22-7.04 (m, 6H), 4.16 (d, J=13.1 Hz, 2H), 3.76 (s, 3H), 3.71 (s, 2H), 2.96-2.88 (m, 4H), 2.88-2.70 (m, 2H), 2.65-2.55 (m, 1H), 1.76 (d, J=12.3 Hz, 2H), 1.59-1.49 (m, 2H), 1.46 (s, 9H). LCMS-A: rt 6.35 min; m/z 547.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][C:9](=[O:15])[NH:8][C:7]=2[CH:16]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[N+:30]([O-:33])([O-:32])=[O:31].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][C:9](=[O:15])[NH:8][C:7]=2[C:16]=1[N+:30]([O-:32])=[O:31].[CH3:1][O:2][C:3]1[C:4]([N+:30]([O-:33])=[O:31])=[CH:5][C:6]2[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][C:9](=[O:15])[NH:8][C:7]=2[CH:16]=1
Reactant: O=[N+]([O-])[O-]
Reactant: COc1ccc2c(c1)NC(=O)CCC2(C)C
Agent: [K+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: COc1cc2c(cc1[N+](=O)[O-])C(C)(C)CCC(=O)N2
Product: COc1ccc2c(c1[N+](=O)[O-])NC(=O)CCC2(C)C
Temperature: -10 °C
Reaction time: 8 h
Yield: 22 %
Yield: 42 %

Procedure:
8-Methoxy-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (612 mg, 2.79 mmol) was dissolved in Acetonitrile (25 mL) and was cooled at −10° C. Trifluoroacetic anhydride (1.40 mL, 9.91 mmol) was added followed by Potassium nitrate (0.285 g, 2.82 mmol; Acros). After overnight stirring, the reaction was partitioned between aq. sodium hydroxide and DCM. The organic extract was chromatographed to afford two products, 8-Methoxy-5,5-dimethyl-9-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (310 mg, 42%) and 8-Methoxy-5,5-dimethyl-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (160 mg, 22%). 1H-NMR (CDCl3): 7.48 (m, 2H), 6.85 (d, 1H, J=8.8 Hz), 3.91 (s, 3H), 2.36 (t, 2H, J=7.2 Hz), 2.12 (t, 2H, J=7.2H), 1.42 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17](=O)[C:16]3[C:15]([C:19](OCC)=[O:20])=[CH:14][CH:13]=[CH:12][C:11]=3[NH:10][CH:9]2[C:24]2N(C)C=CN=2)=[CH:4][CH:3]=1.O.[NH2:31][NH2:32]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3=[N:31][NH:32][C:19](=[O:20])[C:15]4[CH:14]=[CH:13][CH:12]=[C:11]([C:16]=43)[NH:10][CH:9]2[C:24]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]=[CH:9][CH:8]=[CH:17]3)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(F)cc1)C(c1nccn1C)N2
Solvent: O
Solvent: CO
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccc3ncccc3c1)C2c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 25 %

Procedure:
A mixture of ethyl 3-(4-fluorophenyl)-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (260 mg, 0.59 mmol) in 85% hydrazine monohydrate (1 mL) and methanol (5 mL) was stirred at room temperature for 4 h. The resulting mixture was filtered and washed by water (20 mL) and methanol (5 mL) to obtain the title compound as a white solid (61 mg, yield 25%). LC-MS (ESI) m/z: 409 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 4.52-4.55 (d, J=9.6 Hz, 1H), 4.98-5.01 (d, J=9.6 Hz, 1H), 6.97-7.01 (m, 2H), 7.19-7.22 (m, 3H), 7.41-7.43 (d, J=7.6 Hz, 1H), 7.46-7.50 (m, 1H), 7.54 (s, 1H), 7.59-7.63 (t, J=7.6 Hz, 1H), 7.77-7.79 (m, 1H), 7.84 (s, 1H), 7.91-7.93 (m, 1H), 8.24-8.26 (d, J=7.6 Hz, 1H), 8.85-8.86 (m, 1H), 12.20 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:13][CH2:14][C:15]([OH:18])([CH3:17])[CH3:16])=[CH:8][C:9]=1[N+:10]([O-])=O)=[O:4].CO[CH:21]([N:24]([CH3:26])[CH3:25])OC>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:13][CH2:14][C:15]([OH:18])([CH3:17])[CH3:16])=[CH:8][C:9]=1[N:10]=[CH:21][N:24]([CH3:26])[CH3:25])=[O:4]
Reactant: COC(=O)c1sc(CCC(C)(C)O)cc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Product: COC(=O)c1sc(CCC(C)(C)O)cc1N=CN(C)C

Procedure:
5-(3-Hydroxy-3-methylbutyl)-3-nitrothiophene-2-carboxylic acid methyl ester was reacted with dimethoxymethyldimethylamine by method B. The product with the molecular weight of 298.41 (C14H22N2O3S) was obtained in this way; MS (ESI): 299.1 (M+H+).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:12])[C:10]#[N:11].O.Cl.[O:15]1CCOCC1>C(OCC)(=O)C>[Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:12])[C:10]([NH2:11])=[O:15]
Reactant: C1COCCO1
Reactant: N#CC(=O)c1ccccc1CCl
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: NC(=O)C(=O)c1ccccc1CCl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Crude 2-(2-chloromethylphenyl)-2-oxoacetonitrile (purity: about 72%)(17.6 g), water (1.76 g) and 5N hydrogen chloride/dioxane solution (200 ml) were added into a round-bottom flask. The flask was stoppered, and then the mixture was stirred at room temperature for 3 days. After the reaction mixture was ice-cooled, water (150 ml) was added, and the mixture was stirred at room temperature for 40 minutes. The reaction mixture was diluted with ethyl acetate, and washed successively with a saturated aqueous solution of sodium bicarbonate, water and saturated brine. The ethyl acetate layer obtained was dried over anhydrous sodium sulfate and at the same time decolorized with Norit SX-3. Evaporation of the solvent under reduced pressure gave the crude product (16.6 g). The crude product was crystallized from ethyl acetate-hexane, and the crystallization mother liquor was purified by column chromatography on silica gel to obtain the title compound (11.3 g, total yield in the two steps: 57.3%, pale yellow crystals).
Reaction SMILES: CO.[C:3](O)([CH3:6])([CH3:5])[CH3:4].O.[CH3:9][C:10]([O:13][CH3:14])([CH3:12])[CH3:11]>>[CH3:14][O:13][CH:10]([CH2:11][CH3:3])[CH3:9].[CH3:4][C:3]([CH2:6][C:10]([CH3:12])([CH3:11])[CH3:9])=[CH2:5]
Reactant: COC(C)(C)C
Reactant: CC(C)(C)O
Solvent: O
Solvent: CO
Product: C=C(C)CC(C)(C)C
Product: CCC(C)OC

Procedure:
The bottom product (IV) from the column K1 comprised predominantly unreacted MTBE (about 23% by mass) and methanol (about 75% by mass). In addition, unreacted 2-methoxybutane, tert-butanol, water and diisobutene formed by reaction and also diisobutene originating from the feed MTBE, inter alia, were present. This stream was fed to the column K2.