Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[C@H:13]1[C@H:8]([CH2:9][CH2:10][CH2:11][CH2:12]1)[N:7]=[C:6]2[C:19]1[CH:24]=[CH:23][C:22]([C:25]([O:27]C)=O)=[CH:21][CH:20]=1.[C-:29]#[N:30].[Na+]>CN.C(O)C>[CH3:29][NH:30][C:25]([C:22]1[CH:21]=[CH:20][C:19]([C:6]2[C:5]3[C:14](=[CH:15][C:16]([O:17][CH3:18])=[C:3]([O:2][CH3:1])[CH:4]=3)[C@H:13]3[C@H:8]([CH2:9][CH2:10][CH2:11][CH2:12]3)[N:7]=2)=[CH:24][CH:23]=1)=[O:27]
Reactant: [C-]#N
Reactant: COC(=O)c1ccc(C2=N[C@H]3CCCC[C@H]3c3cc(OC)c(OC)cc32)cc1
Agent: CN
Agent: [Na+]
Solvent: CCO
Product: CNC(=O)c1ccc(C2=N[C@H]3CCCC[C@H]3c3cc(OC)c(OC)cc32)cc1

Procedure:
680 mg of (+/−)-cis-8,9-dimethoxy-6-[4-(methoxycarbonyl)phenyl]-1,2,3,4,4a,10b-hexahydrophenanthridine with 25 mg of sodium cyanide in 13 ml of 9 molar methylamine solution in ethanol are heated to 90° C. in an autoclave for 10 h. The solution is concentrated under reduced pressure and the residue is taken up in methylene chloride and extracted with water. The organic phase is dried with sodium sulfate, the solvent is removed under reduced pressure and the residue is treated with diethyl ether, filtered off with suction and dried. This gives 380 mg (56.1 % of Th.) of the title compound of m.p. 209-211° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:4][N:3]1[P:5](Cl)([N:7]1[CH2:9][C:8]1([CH3:11])[CH3:10])=[O:6].[CH3:14][N:15]([CH3:20])[CH2:16][CH2:17][CH2:18][NH2:19]>C1COCC1>[CH3:1][C:2]1([CH3:13])[CH2:4][N:3]1[P:5]([N:7]1[CH2:9][C:8]1([CH3:11])[CH3:10])(=[O:6])[NH:19][CH2:18][CH2:17][CH2:16][N:15]([CH3:20])[CH3:14]
Reactant: CC1(C)CN1P(=O)(Cl)N1CC1(C)C
Reactant: CN(C)CCCN
Solvent: C1CCOC1
Product: CN(C)CCCNP(=O)(N1CC1(C)C)N1CC1(C)C
Temperature: -40 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
A solution containing 0.025 moles of P,P-bis(2,2-dimethyl-1-aziridinyl)phosphinyl chloride in about 170 milliliters of THF was prepared in accordance with Example 1, chilled to -40° C. and treated, by slow dropwise addition, with a solution containing 0.026 moles of 3-dimethylaminopropylamine, in 25 milliliters of THF. The resulting slurry was stirred overnight at ambient temperature, filtered, the filtrate was concentrated by rotary evaporation, and vacuum distilled at 119° C./0.45 millimeter of mercury to produce a 40% yield of P,P-bis(2,2-dimethyl-1-aziridinyl)-N-(3-dimethylaminopropyl)phosphinic amide. NMR characterization confirmed the product was 99% pure. Elemental analysis confirmed the structure contained the following:
Reaction SMILES: [CH3:1][N:2]([CH3:46])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH:16][C:17](=[O:45])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[N:27][C:28]([O:34]CC4C=CC(OC)=CC=4)=[C:29]([O:31][CH2:32][CH3:33])[CH:30]=3)=[CH:21][C:20]=2[F:44])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1>CO.[Pd]>[CH3:46][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH:16][C:17](=[O:45])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[C:29]([O:31][CH2:32][CH3:33])[C:28](=[O:34])[NH:27][CH:26]=3)=[CH:21][C:20]=2[F:44])[CH:9]=[C:10]([C:12]([F:15])([F:13])[F:14])[CH:11]=1
Reactant: CCOc1cc(-c2ccc(CC(=O)Nc3cc(OCCN(C)C)cc(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Agent: [Pd]
Solvent: CO
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cc(OCCN(C)C)cc(C(F)(F)F)c3)c(F)c2)c[nH]c1=O
Reaction time: 3 h
Yield: 50.6 %

Procedure:
To a suspension of N-(3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (100 mg, 0.156 mmol) in MeOH (10 mL) was added Pd/C (16.59 mg, 0.156 mmol). The mixture was hydrogenated at 26° C. for 3 h under a H2 atmosphere. Then the solution was filtered and concentrated to give the residue. The crude material was purified by preparative HPLC (Instrument: Gilson GX281/Column: Gemini 150*25 mm*5 um/Mobile phase A: Water (0.05% ammonia solution)/Mobile phaseB: Acetonitrile/Gradient:52-82(B %)/Flowrate: 25 mL/min/Run time: 10 min) to yield a white solid of N-(3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide (41.16 mg, 0.079 mmol, 50.6% yield). TLC (DCM/MeOH=10:1, Rf=0.4): 1H NMR (400 MHz, CD3OD) δ 7.56-7.47 (m, 2H), 7.46-7.39 (m, 1H), 7.38-7.29 (m, 3H), 7.24 (d, J=2.2 Hz, 1H), 6.96 (s, 1H), 4.19-4.09 (m, 4H), 3.80 (s, 2H), 2.81 (t, J=5.3 Hz, 2H), 2.36 (s, 6H), 1.47 (t, J=6.9 Hz, 3H). ES-LCMS m/z 522 (M+H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([CH2:10]Br)[CH:7]([CH3:9])[CH3:8])(=[O:3])[CH3:2].[S-:12][C:13]#[N:14].[K+].O>CN(C)C=O>[C:1]([O:4][CH2:5][CH:6]([CH2:10][S:12][C:13]#[N:14])[CH:7]([CH3:9])[CH3:8])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(CBr)C(C)C
Reactant: N#C[S-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCC(CSC#N)C(C)C

Procedure:
A mixture of 2-bromomethyl-3-methylbutyl acetate (6 g) and potassium thiocyanate (7.3 g) in dry dimethylformamide (50 ml) was heated at 140° for 2 hours. After cooling, the reaction mixture was poured into water (150 ml) and then extracted with diethylether (3×50 ml). The combined ethereal extracts were washed with water (3×50 ml) before drying over anhydrous magnesium sulphate and evaporation in vacuo. 2-Thiocyanatomethyl-3methylbutyl acetate was obtained and was used without further purification.
Reaction SMILES: [CH:1]([C:4]1[S:8][C:7]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15](I)[CH:14]=2)=[O:11])=[N:6][CH:5]=1)([CH3:3])[CH3:2].CN(C)C(=N)N(C)C.[I-].[OH2:29]>CN(C)C=O>[OH:29][CH:4]([CH3:5])[C:1]#[C:2][C:15]1[CH:14]=[C:13]([NH:12][C:10]([NH:9][C:7]2[S:8][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][N:6]=2)=[O:11])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)c1cnc(NC(=O)Nc2cccc(I)c2)s1
Reactant: O
Agent: CN(C)C(=N)N(C)C
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(O)C#Cc1cccc(NC(=O)Nc2ncc(C(C)C)s2)c1

Procedure:
To a solution of 0.2 g (0.56 mmol) of N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(3-iodophenyl)urea in 3 ml of anhydrous N,N-dimethylformamide 0.6 ml of tetramethylguanidine, 0.088 ml (1.126 mmol) of D,L-1-butyn-3-ol, 19 mg (0.027 mmol) of bis(triphenylphosphine)palladium(II)dihydrochloride and 5.8 mg (0.03 mmol) of rameous iodide under argon were added successively. After 5 hours water was added and the mixture extracted with ethylacetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated, giving 0.116 g of the title compound as a yellowish solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:12](=[O:13])[C@@H:11]([CH2:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@@H:10]2[C:23]2[CH:28]=[CH:27][C:26]([CH:29]=[CH:30][C:31]([O:33][CH3:34])=[O:32])=[CH:25][CH:24]=2)=[CH:5][CH:4]=1>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:12](=[O:13])[C@@H:11]([CH2:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@@H:10]2[C:23]2[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:28]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)C=Cc1ccc([C@H]2[C@H](CCCc3ccccc3)C(=O)N2c2ccc(OC)cc2)cc1
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccc([C@H]2[C@H](CCCc3ccccc3)C(=O)N2c2ccc(OC)cc2)cc1
Reaction time: 3 h
Yield: 99.3 %

Procedure:
Dissolve the product of Example 2 (0.35 g, 0.77 mmol) in EtOAc (6 mL) and purge with N2. Add 10% Pd/C (0.082 g), purge the resulting suspension with H2 and stir under a balloon of H2 for 3 h. Filter the mixture through celite, wash the filter cake with EtOAc and concentrate the filtrate to obtain 0.35 g (100%) of the title compound as a clear oil. MS (EI): 455(M+, 13), 308(31), 217(78), 185(25), 149(52), 129(100).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:32])=[C:4]([CH:29]=[CH:30][CH:31]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([O:16][CH2:17][C@@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[C:23](=[O:26])[CH2:24]Cl)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[Cl:1][C:2]1[C:3]([F:32])=[C:4]([CH:29]=[CH:30][CH:31]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([O:16][CH2:17][C@@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[C:23](=[O:26])[CH2:24][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: C1CCNC1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1C(=O)CCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1C(=O)CN1CCCC1
Yield: 50 %

Procedure:
Using a procedure similar to that described in Example 43, 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(chloroacetyl)pyrrolidin-2-yl]methoxy}quinazoline (0.28 g) was reacted with pyrrolidine (2.5 ml) to give the title product as a foam (0.151 g, 50%); 1H NMR Spectrum: (CDCl3) 1.68-1.75 (m, 4H), 1.90-2.01 (m, 1H), 2.04-2.14 (m, 2H), 2.15-2.23 (m, 1H), 2.51-2.61 (m, 2H), 2.66-2.74 (m, 2H), 3.15-3.21 (d, 1H), 3.38-3.48 (m, 2H), 3.55-3.62 (m, 1H), 4.00-4.08 (m, 4H), 4.52-4.55 (d, 1H), 4.68-4.74 (t, 1H), 7.06-7.27 (m, 3H), 7.90-7.96 (m, 1H), 8.43 (s, 1H), 8.60 (s, 1H), 8.69 (s, 1H); Mass Spectrum: (M−H)− 512.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH:5]([CH2:8][CH2:9][CH:10](OS([O-])(=O)=O)[CH2:11][CH:12]([CH3:14])[CH3:13])CC.[Na+].[OH2:21]>>[CH2:1]([OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([CH3:13])[CH3:14]
Reactant: CCCCC(CC)CCC(CC(C)C)OS(=O)(=O)[O-]
Reactant: O
Agent: [Na+]
Product: CC(C)CCCCCCCCCCCCCCCO
Temperature: 65 °C
Yield: 21.9 %

Procedure:
The reaction mixture was emulsified as follows: 300 g polycarbodiimide solution as prepared above was heated to 65° C. and added to a hot aqueous solution of Ethoquad™ C-12 (2% on solids), Tergitol 15S30 (3% on solids) and Tergitol™ TMN-6 (5.4% solids). 199 g water was added. The mixture was emulsified with 2 stage lab Manton-Gaulin at 220/20 bar (2 passes). The solvent was stripped off with a Büchi evaporator, using water jet vacuum. A stable, milky dispersion of 21.9% solids was obtained.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([N:20]([CH2:25][C:26]([OH:28])=O)[CH2:21][C:22]([OH:24])=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)=O.[NH2:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([O:43][CH3:44])[CH:41]=2)[CH:36]=[CH:35][CH:34]=1>O1CCCC1.C(O)C>[CH3:44][O:43][C:40]1[CH:41]=[C:42]2[C:37]([CH:36]=[CH:35][CH:34]=[C:33]2[N:32]2[C:22](=[O:24])[CH2:21][N:20]([CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:25][C:26]2=[O:28])=[CH:38][CH:39]=1
Reactant: COc1ccc2cccc(N)c2c1
Reactant: O=C(O)CN(CC(=O)O)Cc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2cccc(N3C(=O)CN(Cc4ccccc4)CC3=O)c2c1
Yield: 82 %

Procedure:
126 mmol (2.2 equivalents) of carbonyldiimidazole are added to a suspension containing 58 mmol (1 equivalent) of N-benzyliminodiacetic acid in 200 ml of anhydrous tetrahydrofuran. The mixture is brought to reflux until the evolution of CO2 has ceased. A solution containing 58 mmol (1 equivalent) of 1-amino-7-methoxynaphthalene in 40 ml of anhydrous tetrahydrofuran is then added to the above mixture. The resulting mixture is brought to reflux for 20 hours, the solvent is evaporated off and the residue obtained is taken up with 300 ml of anhydrous ethanol. The precipitate formed is filtered off and then dissolved in 200 ml of dichloromethane. The insoluble matter is filtered off and the filtrate concentrated. The expected product is then obtained after taking up in isopropyl ether followed by filtration.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[C:11]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([NH:39][C:40](=[O:48])[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[NH2:47])=[N:37][CH:38]=1>>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:47][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[C:40]([NH:39][C:36]2[CH:35]=[CH:34][C:33]([Cl:32])=[CH:38][N:37]=2)=[O:48])=[O:14])=[C:11]([O:18][CH:19]2[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(OCc3ccccc3)ccc2C(=O)O)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(OCc3ccccc3)ccc2C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1

Procedure:
Using methods substantially equivalent to those described in Example 1-F, 4-benzyloxy-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoic acid (529 mg, 1.27 mmol) and N-(5-chloropyridin-2-yl)-2-aminobenzamide (297 mg, 1.20 mmol) afforded, after purification by chromatography (SiO2: EtOAc in hexanes), 493 mg (63%) of the title compound.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([O:16][CH2:17][CH2:18][CH2:19][OH:20])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].CC(C)=[O:23].OS(O)(=O)=O.O=[Cr](=O)=O.CC(O)C.C(OCC)(=O)C>CC(C)=O>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([O:16][CH2:17][CH2:18][C:19]([OH:23])=[O:20])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)=O
Reactant: CCCCC(OCCCO)c1ccc(CC(C)C)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCCCC(OCCC(=O)O)c1ccc(CC(C)C)cc1
Reaction time: 0.17 h

Procedure:
Chromium(VI) oxide was dissolved in an aqueous solution of sulfuric acid, and diluted with water to give a Jones reagent. To a solution of 3-[1-(4-isobutylphenyl)pentyloxy]propanol in acetone was added the obtained Jones reagent at room temperature until an orange-brown color persisted. After 10 minutes, 2-propanol was added to the reaction mixture. Ethyl acetate was added thereto, and the mixture was washed with water and brine, dried over magnesium sulfate and concentrated. Silica gel column chromatography of the concentrate afforded the object compound.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([N:17]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:6]([OH:16])/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)C.[BH4-].[Na+]>CO>[OH:3][CH2:4][CH:5]([N:17]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[C@H:6]([OH:16])/[CH:7]=[CH:8]/[C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C([C@H](O)/C=C/c1ccc(C)cc1)N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(/C=C/[C@@H](O)C(CO)N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Yield: 83 %

Procedure:
β-hydroxy-α-hydrazino ester (6B) (465 mg, 1.0 mmol) was added to 25 mL MeOH, then 3.0 eq of NaBH4 (114 mg, 3.0 mmol) was added every 15 min until the starting material was consumed as indicated by TLC. The reaction was quenched with saturated NH4Cl (aq.), extracted with EtOAc, and the combined extracts were washed with brine, dried over anhydrous Na2SO4, and the solvent was removed in vacuo. Purification by chromatography on silica gel to afford the desired product as a white solid (83%) (Kim et al., Tetrahedron 2010, 66, 3995).
Reaction SMILES: [Mg].[CH2:2](Br)[CH2:3][CH2:4][CH3:5].[F:7][C:8]([F:13])([F:12])[C:9](O)=[O:10].Cl>CCOCC>[F:7][C:8]([F:13])([F:12])[C:9](=[O:10])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCBr
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CCCCC(=O)C(F)(F)F
Reaction time: 1.5 h
Yield: 51.2 %

Procedure:
In a nitrogen atmosphere, 9.12 g (380 mM) of magnesium into 120 ml of ether, and 49.32 g (360 mM) of butyl bromide dissolved in 30 ml of ether was added thereto, followed by 1.5 hours of heat refluxing. After cooling by standing and with ice, 13.68 g (120 mM) of trifluoroacetic acid dissolved in 30 ml of ether was added. After being stirred for 7 hours under cooling with ice, the system was subjected to hydrolysis with addition of hydrochloric acid, followed by extraction with ether and drying of the resultant ether layer with anhydrous sodium sulfate. The dried product was distilled under normal pressure to obtain 9.46 g of 1,1,1-trifluoro-2-hexanone. Yield: 47%.
Reaction SMILES: [CH3:1][Si](C)(C)[N-][Si](C)(C)C.[K+].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH:25]=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.C(OCC)(=O)C>[CH2:24]([CH:21]1[CH2:22][CH2:23][N:18]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[CH2:19][CH2:20]1)[CH:25]=[CH2:1]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
A solution of methyltriphenylphosphonium bromide (5.3 g, 14.8 mmol) in THF (50 mL) was cooled to 0° C. under nitrogen. Potassium hexamethyl disilazide (27.7 mL, 0.5M toluene solution, 13.9 mmol) was added and the mixture was stirred for 30 min. A solution of (1-t-butoxycarbonylpiperidin-4-yl)acetaldehyde from Step A (2.25 g, 9.9 mmol) in THF (10 mL) was added and the mixture was warmed to rt. After 30 min, the reaction was complete by tlc analysis. The mixture was diluted with ethyl acetate (200 mL) and washed with water and brine (100 mL each). The organic phase was dried over sodium sulfate and concentrated to give an oil which was purified by FC (75 g silica, 10/1 hexane/ethyl acetate) to afford the title compound (1.61 g).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[F:20][C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[C:24](F)=[CH:23][C:22]=1[NH:31][C:32](=[O:34])[CH3:33]>O>[F:20][C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[C:24]([O:2][C:1]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[OH:4])=[CH:23][C:22]=1[NH:31][C:32](=[O:34])[CH3:33]
Reactant: CC(=O)Nc1cc(F)c([N+](=O)[O-])cc1F
Reactant: Oc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(Oc2ccccc2O)c([N+](=O)[O-])cc1F
Temperature: 60 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
1.1 g of catechol and 2.76 g of potassium carbonate were added to 20 ml of N,N-dimethylformamide, and the mixture was heated to 60° C. Into this mixture was added dropwise a solution comprising 2.16 g of N-(2,5-difluoro-4-nitrophenyl)acetamide and 10 ml of N,N-dimethylformamide at temperatures from 65 to 70° C. The temperature of the mixture was kept for 1 hour, then, the mixture was cooled to room temperature, poured into water, extracted with ethyl acetate, and the organic layer was washed with dilute hydrochloric acid, washed with water, dried over magnesium sulfate, concentrated, and the resulted crystal was washed with t-butyl methyl ether to obtain 2.56 g of N-[2-fluoro-5-(2-hydroxyphenoxy)-4-nitrophenyl]acetamide.
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][C@@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:14][CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1.CN.C(O)C>>[CH3:1][C:2]1[C:10]([O:11][C@@H:12]2[CH2:13][CH2:14][C@H:15]([NH2:18])[CH2:16][CH2:17]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1
Reactant: Cc1c(O[C@H]2CC[C@@H](N3C(=O)c4ccccc4C3=O)CC2)ccc2c1cnn2C1CCCCO1
Agent: CN
Solvent: CCO
Product: Cc1c(O[C@H]2CC[C@@H](N)CC2)ccc2c1cnn2C1CCCCO1

Procedure:
A mixture of 2-{cis-4-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexyl}-1H-isoindole-1,3(2H)-dione (95.5 mg, 0.208 mmol) and a 30% methylamine-ethanol solution (5.0 ml) was stirred with heating under reflux for 2 hours. The reaction solution was allowed to cool, and then was concentrated under reduced pressure to obtain a crude product. The crude product was purified by a silica gel column chromatography (eluent: chloroform/methanol/28% aqueous ammonia) to obtain cis-4-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexanamine (60.4 mg, 88%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])/[CH:4]=[C:5](\[CH3:9])/[CH:6](O)[CH3:7].[Cl:11]P(Cl)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:10])/[CH:4]=[C:5](\[CH3:9])/[CH:6]([Cl:11])[CH3:7]
Reactant: ClP(Cl)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)/C=C(\C)C(C)O
Solvent: ClCCl
Product: COC(=O)/C=C(\C)C(C)Cl
Temperature: 25 °C

Procedure:
To (E)-4-hydroxy-3-methyl-2-pentenoic acid methyl ester (1.00 g, 6.94 mmol) in methylene chloride cooled to -15° C. in a flame dried flask is added dichlorotriphenylphosphorane (2.47 g, 7.63 mmol). The reaction is warmed to ambient temperature, quenched by addition of ice (10 ml), extracted with methylene chloride (2×10 ml), washed with saline (10 ml), dried over sodium sulfate, concentrated in vacuo, and chromatographed on silica gel (230-400 mesh, 75 ml), eluting with hexane/ethyl acetate (95/5). The appropriate fractions are combined (Rf =0.55, TLC, hexane/ethyl acetate, 75/25) and concentrated in vacuo to give (E)-4-chloro-3-methyl-2-pentenoic acid methyl ester. 4-Amino-6-chloro-2-mercaptopyrimidine mesylate (0.30 g, 1.16 mmol) is dissolved in DMF (4 ml) and sodium hydride (0.06 g, 2.56 mmol) at ambient temperature followed by the addition of (E)-4-chloro-3-methyl-2-pentenoic acid methyl ester (0.19 g, 1.16 mmol). The reaction is stirred for 15 hours, quenched with excess water, extracted with ethyl acetate (3×15 ml). The extracts are combined, washed with saline (15 ml), dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel (230-400 mesh, 100 ml), eluting with hexane/ethyl acetate (85/15). The appropriate fractions are combined (Rf =0.18, TLC, hexane/ethyl acetate, 50/50) and concentrated in vacuo to give the title compound, mp 124-126° C.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([NH:8][NH:9][C:10]([S-:12])=[S:11])=O)(=[O:3])[CH3:2].[K+]>S(=O)(=O)(O)O>[C:1]([NH:4][CH2:5][C:6]1[S:11][C:10]([SH:12])=[N:9][N:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCC(=O)NNC(=S)[S-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)NCc1nnc(S)s1
Temperature: 0 °C
Yield: 69.1 %

Procedure:
Potassium 3-(N-acetylglycyl)dithiocarbazate (102.3 g) was added bit by bit to concd. sulfuric acid (1 liter) at 0° to 5° C. and the mixture was stirred for an hour at the same temperature. The reaction mixture was added dropwise on crushed ice (c.a. 10 kg) under stirring. Precipitating crystals were collected by filtration to give 5-acetamidomethyl-1,3,4-thiadiazole-2-thiol (54.5 g). m.p. 200° to 203° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)=[CH:10][C:3]=12.Br[C:33]1[C:34]([C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:47](=[O:51])[N:48]([CH3:50])[CH3:49])=[CH:42][CH:41]=2)=[N:35][N:36]([CH2:38][CH3:39])[CH:37]=1>>[CH2:38]([N:36]1[CH:37]=[C:33]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[N:8]([S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:24])=[O:25])[C:9]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)=[CH:13][CH:12]=4)=[CH:10][C:3]=23)[C:34]([C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:47](=[O:51])[N:48]([CH3:50])[CH3:49])=[CH:42][CH:41]=2)=[N:35]1)[CH3:39]
Reactant: CCn1cc(Br)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Reactant: O=S(=O)(c1ccccc1)n1c(-c2ccc(N3CCOCC3)cc2)cc2c(Br)ccnc21
Product: CCn1cc(-c2ccnc3c2cc(-c2ccc(N4CCOCC4)cc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc(NC(=O)N(C)C)cc2)n1

Procedure:
Following the procedure described for Intermediate 32 with 4-bromo-2-[4-(4-morpholinyl)phenyl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine. Using this product crude and following the procedure described in Intermediate 100 using N′-[4-(4-bromo-1-ethyl-1H-pyrazol-3-yl)phenyl]-N,N-dimethylurea provided the title product. ESMS [M+H]+: 676.4