Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH:9]1[O:14]CCCO1.[Li][CH2:16]CCC.CI>C1COCC1>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:16])[C:3]=1[CH:9]=[O:14]
Reactant: Brc1cccc(Br)c1C1OCCCO1
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cccc(Br)c1C=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96 %

Procedure:
1H NMR (500 MHz, CDCl3) δ [ppm] 7.55 (d, 3J=8.0 Hz 2 H, ar), 7.00 (t, 3J=8.0 Hz 1 H, ar), 6.19 (s, 1 H, CH), 4.33-4.29 (m, 2 H, CH2), 4.02-3.97 (m, 2 H, CH2), 2.44-2.34 (m, 1 H, CH2), 1.44-1.40 (m, 1 H, CH2); 13C{1} NMR (125.77 MHz, CDCl3) δ [ppm] 133.9, 132.5, 129.8, 122.9, 101.6, 66.7, 24.1. The acetal (10.1 g, 31.25 mmol) was dissolved in THF, abs. (200 ml). At −78° C. n-BuLi (15.1 ml, 2.5 M in hexane, 37.8 mmol) was added within 25 min, followed by 90 min additional stirring at that temperature. Then the reaction mixture was treated with methyliodide (5.99 g, 42.2 mmol) and stirred for 25 min at −78° C. Next the reaction mixture was allowed to warm to ambient temperature within 1.5 h. The resulting solution was quenched with HCl (290 ml of a 5 N solution) and stirred for 1.5 h at ambient temperature. The complete deprotection of the aldehyde was checked via GC analysis. Then the reaction mixture was subsequently extracted with diethylether (4×100 ml), the combined organic layers were washed with a 10% solution of sodium thiosulfate (100 ml), water (100 ml), dried over MgSO4, filtered and the volatiles removed in vacuo. The resulting slightly yellow solid was purified via Kugelrohr distillation to afford 50 (5.97 g, 96%) as white crystals. Rf 0.56 (cyclohexane:ethylacetate 10:1).
Reaction SMILES: [OH:1][C:2]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([CH3:14])[C:3]=1[C:4]#[N:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:5][CH2:4][C:3]1[C:2]([OH:1])=[N:9][C:8]([C:10]([F:11])([F:12])[F:13])=[CH:7][C:6]=1[CH3:14]
Reactant: Cc1cc(C(F)(F)F)nc(O)c1C#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)nc(O)c1CN
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.6 %

Procedure:
To a solution of 2-hydroxy-4-methyl-6-(trifluoromethyl)nicotinonitrile (1 g, 5 mmol) in tetrahydrofuran (100 mL) was added lithium aluminum hydride (0.3 g, 7.9 mmol). The mixture was stirred at room temperature for 24 hours. The mixture was filtered, acidified and concentrated. To the residue, water (50 mL) was added and then extracted with dichloromethane (2*50 mL). The combined organic phase was separated, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, methanol/dichloromethane=1:5, 1% NH3) to give 3-(aminomethyl)-4-methyl-6-(trifluoromethyl)pyridin-2-ol as a yellow oil (0.8 g, 78%).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][CH:6]1[OH:7])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:22](Cl)(=[O:38])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>CN(C)C=O>[C:1]([NH:4][C@@H:5]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][O:15][C:22](=[O:38])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[O:8][C@@H:6]1[OH:7])(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCC(=O)OC[C@H]1O[C@H](O)[C@H](NC(C)=O)[C@@H](O)[C@@H]1O
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To 1 g of N-acetylglucosamine, 5 mL of pyridine and 15 mL of N,N-dimethylformamide were added, and the mixture was heated to 70° C. under stirring and 1.37 mL of palmitoyl chloride was dropwise added, and the reaction was carried out for 4 hours. On completion of the reaction, after extracting with ethyl acetate and washing with 2 mol/L hydrochloric acid, the ethyl acetate layer was dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent; chloroform:methanol=15:1) to obtain 710 mg of 2-acetamido-2-deoxy-6-O-palmitoyl-α-D-glucopyranose as a white crystal.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH:12][CH2:13][C:14](=O)[CH2:15][C:16]([CH3:20])([CH3:19])[CH2:17][CH3:18])=O)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:26].[OH-].[NH4+]>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[NH:12][CH:13]=[C:14]([CH2:15][C:16]([CH3:20])([CH3:19])[CH2:17][CH3:18])[N:26]=2)=[CH:4][CH:3]=1
Reactant: CCC(C)(C)CC(=O)CNC(=O)CCc1ccc(Br)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCC(C)(C)Cc1c[nH]c(CCc2ccc(Br)cc2)n1
Temperature: 160 °C

Procedure:
A mixture of 3-(4-bromophenyl)-N-(4,4-dimethyl-2-oxohexyl)propionamide (71.5 g, 202 mmol), ammonium acetate (770 g, 10 mol) and acetic acid (700 mL) was heated at 160° C. for 20 h. Upon cooling, the reaction mixture was poured onto ice (600 mL), and the pH was adjusted to ˜10 with concentrated ammonium hydroxide. The product was extracted with ethyl acetate, and the extracts were dried over sodium sulfate and concentrated to provide 2-[2-(4-bromophenyl)ethyl]-4-(2,2-dimethylbutyl)-1H-imidazole, which was used without purification.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)=O.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([NH2:27])[CH:21]=1>[N+](C1C=CC=CC=1)([O-])=O>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]2[N:26]=[C:1]([C:3]3[CH:4]=[C:5]4[C:9](=[CH:10][CH:11]=3)[NH:8][CH:7]=[C:6]4[CH:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[NH:27][C:22]=2[CH:21]=1
Reactant: Nc1ccc(Cl)cc1N
Reactant: CN1CCC(c2c[nH]c3ccc(C=O)cc23)CC1
Solvent: O=[N+]([O-])c1ccccc1
Product: CN1CCC(c2c[nH]c3ccc(-c4nc5ccc(Cl)cc5[nH]4)cc23)CC1
Temperature: 155 °C
Reaction time: 24 h
Yield: 65.5 %

Procedure:
A solution of 5-formyl-3-(1-methylpiperidin-4-yl)-1H-indole (0.210 g, 0.90 mmol), and 4-chloro-o-phenylenediamine (0.197 g, 1.38 mmol), in 15 mL of nitrobenzene was heated, with stirring, at 150-160° C. for 24 hours. The solution was allowed to cool to room temperature, the solvent was removed in vacuo, and the residue was purified by silica gel chromatography (dichloromethane:methanol 10:1.5) to give the title compound (0.215 g, 68%) as an amorphous tan solid. FDMS m/e=365 (M+). EA calculated for C21H21N4Cl.¼ H2O C, 68.28; H, 5.87; N, 15.17. Found: C, 68.32; H, 6.17; N, 14.51.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8](=[O:20])[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][CH:13]=3)=[CH:10][O:11][C:6]=2[CH:5]=[C:4]([O:21]C)[CH:3]=1.Cl.N1C=CC=CC=1.Cl>>[F:1][C:2]1[C:7]2[C:8](=[O:20])[C:9]([C:12]3[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=3)=[CH:10][O:11][C:6]=2[CH:5]=[C:4]([OH:21])[CH:3]=1
Reactant: COc1ccc(-c2coc3cc(OC)cc(F)c3c2=O)cc1
Agent: Cl
Solvent: c1ccncc1
Product: O=c1c(-c2ccc(O)cc2)coc2cc(O)cc(F)c12
Temperature: 200 °C
Reaction time: 0.67 h
Yield: 68.5 %

Procedure:
A mixture of 5-fluoro-7-methoxy-3-(4-methoxyphenyl)-4-oxo-4H-1-benzopyran (132 mg) and pyridine hydrochloride (2 g) in a test tube was heated in an oil bath (preheated at 200° C.). The mixture melted, was stirred at 200° C. for 40 min and cooled. The residue was poured into 1N hydrochloric acid. The solids were filtered, washed with water and ether, and dried under high vacuum to give the title compound as a beige powder (82 mg). 1H NMR (DMSO-d6): 11.19 (s br, 1H), 9.55 (s br, 1H); 8.22 (s, 1H), 7.33 (d, 2H, J=7.8 Hz), 6.80 (d, 2H, J=7.8 Hz), 6.71 (s br, 1H), 6.65 (d br, 1H, J=12.9 Hz); MS: 273 (MH+); HPLC tR: 1.66 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[N:8][O:9][CH2:10][CH2:11][CH3:12])[C:5]([CH3:7])=[O:6].S(Cl)([Cl:17])(=O)=O>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[N:8][O:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:7][Cl:17])=[O:6]
Reactant: CCCON=C(C(C)=O)C(=O)OC
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: CCCON=C(C(=O)CCl)C(=O)OC
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 93.6 %

Procedure:
To a solution of 7.4 g of 2-(n-propoxyimino)acetoacetic acid methyl ester in 7.4 ml of acetic acid is added 5.5 g of sulfuryl chloride, and the mixture is stirred for 10 minutes at 40° C., then for 6 hours at room temperature. The reaction solution is poured into 100 ml of ice-water, and subjected to extraction twice with chloroform. The extract is washed with an aqueous solution of sodium chloride, and aqueous solution of sodium bicarbonate and water in this order, and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure to yield 8.2 g (94%) of 4-chloro-2-(n-propoxyimino)acetoacetic acid methyl ester as a pale yellow oily product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@H:18]2[CH2:22][CH2:21][O:20][CH2:19]2)[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].[N:23]1([C:27]([C:29]2[CH:34]=[CH:33][C:32](Br)=[CH:31][N:30]=2)=[O:28])[CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]Br>[N:23]1([C:27]([C:29]2[N:30]=[CH:31][C:32]([O:1][C:2]3[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@H:18]4[CH2:22][CH2:21][O:20][CH2:19]4)[CH:16]=3)[C:5]([NH:7][C:8]3[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=3)=[O:6])=[CH:33][CH:34]=2)=[O:28])[CH2:26][CH2:25][CH2:24]1
Reactant: O=C(c1ccc(Br)cn1)N1CCC1
Reactant: Cn1ccc(NC(=O)c2cc(O)cc(O[C@H]3CCOC3)c2)n1
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(O[C@H]3CCOC3)c2)n1
Temperature: 160 °C
Reaction time: 6 h
Yield: 48.1 %

Procedure:
A mixture of 3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide (80 mg, 0.26 mmol), 2-(azetidin-1-ylcarbonyl)-5-bromopyridine (64 mg, 0.26 mmol), bromotris(triphenylphosphine)copper(I) (49 mg, 0.05 mmol) and caesium carbonate (257 mg, 0.78 mmol) in acetonitrile (3 mL) was stirred in a Smith Creator microwave at 160° C. for 6 hours. The solid was filtered off and the solvent was removed in vacuo and ethyl acetate (50 mL) added to the residue. The organic phase was washed with water (20 mL), brine (50 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give a yellow oil which was chromatographed on silica, eluting with a gradient of 0-10% methanol in DCM, to give the title compound as a colourless solid (58 mg). This compound was crystallised from ethyl acetate and isohexane using vapour diffusion techniques. 1H NMR δ (CDCl3): 2.11-2.17 (1H, m), 2.20-2.29 (1H, m), 2.32-2.39 (2H, m), 3.78 (3H, s), 3.88-3.93 (1H, m), 3.96-4.02 (3H, m), 4.25 (2H, t), 4.71 (2H, t), 4.97 (1H, t), 6.73 (1H, t), 6.79 (1H, s), 7.11 (1H, s), 7.22 (1H, s), 7.27-7.30 (1H, m), 7.36-7.39 (1H, m), 8.12 (1H, d), 8.32 (1H, d), 8.73 (1H, s); m/z 464 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][CH3:10])[C:6]([N+:11]([O-:13])=[O:12])=[C:5]([NH:14][CH3:15])[N:4]=1.ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)Cl.CO>[CH3:1][S:2]([C:3]1[N:4]=[C:5]([NH:14][CH3:15])[C:6]([N+:11]([O-:13])=[O:12])=[C:7]([NH:9][CH3:10])[N:8]=1)=[O:24]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CNc1nc(SC)nc(NC)c1[N+](=O)[O-]
Solvent: CO
Solvent: ClCCl
Product: CNc1nc(S(C)=O)nc(NC)c1[N+](=O)[O-]

Procedure:
Prepared from 2-methylsulphenyl-4,6-bis(methylamino)-5-nitro-pyrimidine by reacting with m-chloroperbenzoic acid, Rf value: 0.36 (silica gel; methylene chloride/methanol=3:1)
Reaction SMILES: Cl.N[C@@H](CC(C)C)C(C1C=CC=CC=1)(C1C=CC=CC=1)O.[BH4-].[Na+].[Cl:24][C:25]1[CH:30]=[CH:29][C:28](/[CH:31]=[C:32](/[N:39]2[CH:43]=[N:42][CH:41]=[N:40]2)\[C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:27][CH:26]=1.Cl>ClCCCl.CN(C)C=O>[Cl:24][C:25]1[CH:30]=[CH:29][C:28](/[CH:31]=[C:32](/[N:39]2[CH:43]=[N:42][CH:41]=[N:40]2)\[CH:33]([OH:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:27][CH:26]=1
Reactant: CC(C)(C)C(=O)/C(=C\c1ccc(Cl)cc1)n1cncn1
Agent: CC(C)C[C@H](N)C(O)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [BH4-]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)C(O)/C(=C\c1ccc(Cl)cc1)n1cncn1
Temperature: -20 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
In a nitrogen atmosphere, 0.551 g (1.8 moles) of (S)-2-amino-1,1-diphenyl-4-methylpentan-1-ol hydrochloride was suspended in 5 ml of 1,2-dichloroethane, and after cooling to -20° C., a solution of 0.0681 g (1.8 mmoles) of sodium borohydride in 1 ml of dimethylformamide was added. The temperature of the suspension was raised from -20° C. to room temperature over 2 hours. Thereafter, a solution of 0.348 g (1.2 mmoles) of (E)-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one in 4 ml of 1,2-dichloroethane was added to this suspension at room temperature, and stirring was carried out for 48 hours. Thereafter, 6 ml of 2N hydrochloric acid was added and stirring was carried out for 2 hours. After removing the intermediate layer by filtration, the organic layer was washed with water and concentrated under reduced pressure, and the residue was purified on a column packed with 2 g of silica gel with chloroform as a developing solvent to obtain 0.35 g of (+)-(E)-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol as a crystal. By gas-chromatographic analysis, it was found that the conversion was 96.3%, and the composition of the product was: E-form alcohol, 78.9%; Z-form alcohol, 20.3%; and saturated alcohol, 0.8% (said alcohol means a product obtained by hydrogenation of both the carbonyl group and the double bond contained in the α,β-unsaturated ketone used as a material). By high-performance liquid-chromatographic analysis using an optically active column, it was found that the enantiomer ratio of the produced E-form alcohol was: (+)-isomer, 86.1% and (-)-isomer, 13.9%. The optical yield was 72.2%.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[CH:22])=[N:19][CH:20]=2)=[CH:11][CH:10]=1.Br[C:24]1[CH:37]=[CH:36][C:27]([O:28][CH2:29][CH2:30][N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:26][C:25]=1[CH3:38]>CN(C=O)C.CCOC(C)=O.[Cu]I>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[C:22][C:24]3[CH:37]=[CH:36][C:27]([O:28][CH2:29][CH2:30][N:31]4[CH2:32][CH2:33][CH2:34][CH2:35]4)=[CH:26][C:25]=3[CH3:38])=[N:19][CH:20]=2)=[CH:13][CH:14]=1
Reactant: Cc1cc(OCCN2CCCC2)ccc1Br
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cc(OCCN2CCCC2)ccc1C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
0.13 mL (1.00 mmol) triethylamine, 22 mg (0.02 mmol) tetrakis-triphenylphosphane-palladium and 3.7 mg (0.02 mmol) CuI are added successively to a solution of 80 mg (0.37 mmol) 5-(4-chloro-phenyl)-2-ethynyl-pyridine and 106 mg (0.37 mmol) 1-[2-(4-bromo-3-methyl-phenoxy)-ethyl]-pyrrolidine in 3.0 mL DMF in an argon atmosphere. The mixture is stirred for 15 min at 100° C. and at 200 Watt in the microwave. The reaction solution is diluted with 30 mL EtOAc, washed with semisaturated NaHCO3 solution and the organic phase is dried over MgSO4. The solvent is eliminated i.vac. and the residue is triturated with tert-butylmethylether. The solvent is eliminated i.vac. and further purified by HPLC-MS.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[CH2:7][NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][NH:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl[CH2:26]OCC1C=CC=CC=1>O1CCCC1>[CH3:3][O:4][C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[CH2:7][N:8]1[CH2:26][N:11]2[CH:10]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:9]1[CH2:14][CH2:13][CH2:12]2
Reactant: ClCOCc1ccccc1
Reactant: COc1ccccc1CN[C@H]1CCCN[C@H]1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1CN1CN2CCCC1C2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (1.47 g, 36.8 mmol of a 60% dispersion in oil) was added to a round-bottomed flask fitted with an N2 inlet, condensor, stirrer and washed with hexane to remove the oil. Anhydrous tetrahydrofuran (THF), 50 mL, was added followed by 6.30 grams (18.9 mmol) of (2S, 3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine in 50 mL of tetrahydrofuran. After heating to reflux for two hours, the mixture was allowed to cool to room temperature and was treated dropwise with benzyl chloromethyl ether (5.1 mL, 36.8 mmol). The mixture was stirred overnight and the excess sodium hydride quenched with water. After being stirred an additional hour, the organic layer was separated and the aqueous layer was extracted with methylene chloride. The organic layers were combined and washed with saturated aqueous sodium chloride before drying over magnesium sulfate. Concentration in vacuo gave a solid which recrystallized from methanol/methylene chloride to a white solid, 2.36 grams (40%), mp 105°-107° C. Mass Spectrum (m/e): 309 (M+1, 100%), 159 (12%). 1H-NMR (CDCl3) δ1.45-2.20 (m, 5H), 3.15 (m, 2H), 3.5 (d, 1H), 3.65-3.85 (m, 2H), 3.75 (s, 3H), 3.95 (d, 1H), 4.10 (d, 1H), 6.8 (d, 1H), 6.95 (t, 1H), 7.15-7.6 (m, 7H). Anal. Calc'd for C20 H24N2O: C, 77.88; H, 7.83, N, 9.08. Found: C, 77.72; H, 7.75; N, 9.04.
Reaction SMILES: C([O:5][C:6](=[O:47])[C@@H:7]([NH:37][S:38]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)(=[O:40])=[O:39])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][C:18](=[O:20])[N:17]([CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[S:16]2(=[O:28])=[O:27])=[C:11]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:10]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:41]1([S:38]([NH:37][C@@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C:18](=[O:20])[N:17]([CH2:21][CH2:22][Si:23]([CH3:25])([CH3:26])[CH3:24])[S:16]3(=[O:28])=[O:27])=[C:11]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:10]=2)[C:6]([OH:47])=[O:5])(=[O:40])=[O:39])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1)NS(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc2OCc2ccccc2)S1(=O)=O

Procedure:
A solution of (S)-2-benzenesulfonylamino-3-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid tert-butyl ester (80 mg, 0.114 mmol) in 12 mL of TFA/CH2Cl2 (5:1) is stirred at RT for 1 h. The solution is concentrated, then four times redissolved in CH2Cl2 and reconcentrated to give the title compound: (M−1)−=644.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][N:17]1[C:22]2=[C:23]3[C:28](=O)[CH2:27][CH2:26][NH:25][N:24]3[C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:21]2[C:20](=[O:37])[N:19]([CH3:38])[C:18]1=[O:39].N1C(C)=CC=CC=1C>C(Cl)Cl>[CH3:16][N:17]1[C:18](=[O:39])[N:19]([CH3:38])[C:20](=[O:37])[C:21]2[C:22]1=[C:23]1[N:24]([C:30]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[NH:25][CH2:26][CH:27]=[C:28]1[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cn1c(=O)c2c(-c3ccccc3)n3c(c2n(C)c1=O)C(=O)CCN3
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: Cn1c(=O)c2c(-c3ccccc3)n3c(c2n(C)c1=O)C(OS(=O)(=O)C(F)(F)F)=CCN3
Reaction time: 1.75 h

Procedure:
Trifluoromethanesulfonic anhydride (0.254 ml, 1.506 mmol) was added slowly to a solution of 1,3-dimethyl-5-phenyl-8,9-dihydropyrimido[4′,5′:3,4]pyrrolo[1,2-b]pyridazine-2,4,10(1H,3H,7H)-trione (step 4) (222 mg, 0.684 mmol) and 2,6-lutidine (commercial) (0.159 ml, 1.369 mmol) in DCM (10 ml) at 0° C. and the mixture stirred for 1.75 hours. The reaction mixture was quenched with sat. NaHCO3(aq) and extracted with DCM. The organic phase was passed through a hydrophobic frit and evaporated under reduced pressure. Purification of the residue by chromatography on silica, eluting with 20% EtOAc/hexane then 40% EtOAc/hexane afforded the title compound as a yellow solid.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>C1(C)C=CC=CC=1>[O:18]1[CH2:19][CH2:20][N:15]([C:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]=2)[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC=C(N2CCOCC2)CC1
Yield: 99.5 %

Procedure:
tert-Butyl 4-oxopiperidine-1-carboxylate (5 g, 25.09 mmol) was dissolved in toluene (25 mL). Morpholine (2.186 mL, 25.09 mmol) was added and the reaction mixture was heated overnight in a atmosphere of argon in a Dean-Stark reflux apparatus. The mixture was allowed to reach room temperature and it was evaporated to dryness yielding tert-butyl 4-morpholino-5,6-dihydropyridine-1(2H)-carboxylate (6.70 g, 99%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[CH3:30][N:31]1[C:35](=[O:36])[C:34](=[CH:37][C:38]2[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=2)[S:33][C:32]1=[S:46]>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:42][C:41]3[CH:40]=[CH:39][C:38]([CH:37]=[C:34]4[S:33][C:32](=[S:46])[N:31]([CH3:30])[C:35]4=[O:36])=[CH:45][CH:44]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CN1C(=O)C(=Cc2ccc(C=O)cc2)SC1=S
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: CN1C(=O)C(=Cc2ccc(CNc3cccc(-c4c(C(=O)c5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)cc2)SC1=S

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and 4-(3-methyl-4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-benzaldehyde according to the procedure of Example 66. MS (ES) m/z 637.9.
Reaction SMILES: Cl[CH2:2][C@H:3]1[O:8][CH2:7][C@H:6]([CH3:9])[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4]1.[CH3:17][NH:18][CH3:19]>C(O)C>[CH3:17][N:18]([CH2:2][C@@H:3]1[O:8][CH2:7][C@H:6]([CH3:9])[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4]1)[CH3:19]
Reactant: C[C@H]1CO[C@H](CCl)CN1Cc1ccccc1
Reactant: CNC
Solvent: CCO
Product: C[C@H]1CO[C@@H](CN(C)C)CN1Cc1ccccc1
Temperature: 150 °C

Procedure:
A mixture of (2S,5S)-2-(chloromethyl)-5-methyl-4-benzylmorpholine (1 equivalent) and dimethylamine (5 equivalents) in ethanol, was heated at 150° C. for 36 hours in a sealed high pressure vessel. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was taken up in 1 N HCl, and the solution was washed with CH2Cl2. The water phase was made basic with a 30% aq. NaOH solution (pH=12) and extracted with CH2Cl2. The organic extracts were collected and dried over Na2SO4. Evaporation of the solvent under reduced pressure afforded (2S,5S)-2-[dimethylamino(methyl)]-5-methyl-4-benzylmorpholine as a yellow oil. GC/MS: 247 (2%, M-H), 204 (55%, M-NMe2), Rt=15.5 min; LC/MS (m/z): 249.2 (MH+), Rt 0.72 minutes.
Reaction SMILES: [CH3:1][C@@H:2]1[N:8]([C:9]([CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])[C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]=2[NH:5][C:4](=[O:21])[C@H:3]1[NH:22]C(=O)OC(C)(C)C.[ClH:30]>O1CCOCC1>[ClH:30].[NH2:22][C@@H:3]1[C:4](=[O:21])[NH:5][C:6]2[CH:20]=[CH:19][CH:18]=[CH:17][C:7]=2[N:8]([C:9]([CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])[C@H:2]1[CH3:1]
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)Nc2ccccc2N1C(=O)C1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H]1[C@H](N)C(=O)Nc2ccccc2N1C(=O)C1CCOCC1

Procedure:
A room temperature solution of tert-butyl(2S,3S)-2-methyl-4-oxo-1-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (205 mg, 0.51 mmol) in a 4 M solution of hydrochloric acid in dioxane (2.5 mL) was stirred for 1.5 h. After this time, the reaction mixture was concentrated in vacuo to afford (3S,4S)-3-amino-4-methyl-5-(tetrahydro-2H-pyran-4-carbonyl)-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one hydrochloride (theo. yield 173 mg) which was used without purification.