Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:11].F[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([NH:1][CH2:2][C@H:3]2[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[N:13]=[C:14]([CH3:24])[S:15][C:16]=2[C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[O:11])=[N:27][CH:28]=1
Reactant: Fc1ccc(Cl)cn1
Reactant: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CN)c(-c2ccc(F)cc2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CNc2ccc(Cl)cn2)c(-c2ccc(F)cc2)s1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A mixture of rac-cis-(2-(aminomethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone, 2-fluoro-5-chloropyridine, and K2CO3 in DMAC was stirred at 120° C. for 16 h. The reaction was cooled and concentrated in vacuo. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 458.95 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1)[CH3:2].[Cl:11]([O-:15])(=[O:14])(=[O:13])=[O:12].CS[C:18]1[S:22][CH:21]=[CH:20][S+:19]=1>O1CCCC1>[Cl:11]([O-:15])(=[O:14])(=[O:13])=[O:12].[S:19]1[CH:20]=[CH:21][S:22][C:18]1=[N+:6]1[CH2:7][CH2:8][CH2:9][CH:5]1[C:4]([O:3][CH2:1][CH3:2])=[O:10]
Reactant: CSc1scc[s+]1
Reactant: CCOC(=O)[C@@H]1CCCN1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC[N+]1=c1sccs1
Temperature: 25 °C
Yield: 76 %

Procedure:
To 30 ml of tetrahydrofuran, 1.4 g of proline ethyl ester was dissolved, and 2.0 g of 2-methylthio-1,3-dithiolium perchlorate was gradually added under stirring at room temperature. The mixture was stirred at room temperature for 1 hour, and the precipitated crystals were collected by filtration and recrystallized from methanol-ethyl ether, whereby 2.1 g (yield: 76%) of 1-(1,3-dithiol-2-ylidene)-2-ethoxycarbonylpyrrolidinium perchlorate (Compound No. 41) was obtained as crystals having a melting point of from 113° to 114° C.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.CCCCCC.[C:19]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[CH3:20].[C:27]([Si:31]([CH3:34])([CH3:33])Cl)([CH3:30])([CH3:29])[CH3:28]>O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C>[C:23]([O:22][C:19]([O:21][Si:31]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:34])[CH3:33])=[CH2:20])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: C=C(OC(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 92 %

Procedure:
To a stirred solution of 58.2 g diisopropylamine (575 mmol) in 500 ml tetrahydrofuran were added at 0° C. 344 ml 1.6M BuLi in hexane (550 mmol) over 20 min. After stirring for 15 min the solution was cooled to −70° C. and 58.1 g tert-butyl acetate (500 mmol; Fluka) were added at −70° C. over 15 min and stirring continued for 15 min. After the addition of 75 ml HMPA (Fluka) a solution of 81.6 g tert-butyldimethylchlorosilane (525 mmol; Fluka) in 100 ml tetrahydrofuran was added at −70° C. over 15 min and the reaction mixture was warmed to RT over ˜1 h. The reaction mixture was concentrated by rotary evaporation (40° C./≧10 mbar) and the honey-oily residue was partitioned between 1000 ml hexane and 1000 ml deionized water. The organic layer was washed with 10% brine (2×500 ml) and dried (Na2SO4) affording after removal of the solvent by rotary evaporation (40° C./≧10 mbar) 116.1 g bright yellow oil. Purification by vacuum distillation gave 106.0 g (92.0%) product as a colorless oil, b.p. 53-54° C./2.0 mbar. 1H-NMR:
Reaction SMILES: OC[C@@]12[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)C=CC4)CCC1CCCC2.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[OH:35][CH2:36][C@@:37]12[C@@H:54]3[C@H:45]([C@H:46]4[C@@:50]([CH2:52][CH2:53]3)([CH3:51])[CH2:49][CH2:48][CH2:47]4)[CH2:44][CH2:43][C:42]1=[CH:41][C:40](=[O:55])[CH2:39][CH2:38]2.O1CCOCC1>C(Cl)Cl>[OH:35][CH2:36][C@@:37]12[C@@H:54]3[C@H:45]([C@H:46]4[C@@:50]([CH2:52][CH2:53]3)([CH3:51])[CH2:49][CH2:48][CH2:47]4)[CH2:44][CH2:43][C:42]1=[CH:41][C:40](=[O:55])[CH:39]=[CH:38]2
Reactant: C[C@@]12CCC[C@H]1[C@@H]1CCC3=CC(=O)CC[C@]3(CO)[C@H]1CC2
Agent: C[C@@]12C=CC[C@H]1[C@@H]1CCC3CCCC[C@]3(CO)[C@H]1CC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@]12CCC[C@H]1[C@@H]1CCC3=CC(=O)C=C[C@]3(CO)[C@H]1CC2

Procedure:
The 1,4 and 6-methylated derivatives for the 4-androstene-3, 19-diones of the present invention are best prepared by introducing the desired methyl group into the 19-hydroxy-androstene and oxidizing the 19-alcohol to the aldehyde. The 1α-methyl-19-hydroxy-4-androsten-3-ones which can be oxidized to the aldehydes are prepared in two steps. The reaction of dichlorodicyanobenzoquinone with a 19-hydroxy-4-androsten-3-one in refluxing dioxane or methylenechloride for 24-72 hours to produce the corresponding 19-hydroxy-1,4-androstadien-3-one. However, two restrictions in this sequence are necessary. First, the 19-hydroxy group must be protected as an ester or an ether in order to avoid aromatization. Secondly, the 1-position must possess an axial hydrogen atom suitable for elimination. Thus, the 1α-methyl androstene is not reactive although the 1β-methyl androstane is. Following this procedure 17β,19-dihydroxy-7α-methyl-4-androsten-3-one dipropionate is converted to 17β,19-dihydroxy-7α-methyl-1,4-androstadien-3-one dipropionate. Similarly, 19-hydroxy-6α-methyl-4-androstene-3,17-dione acetate forms 19-hydroxy-6α-methyl-1,4-androstadiene-3,17-dione acetate and 1β-methyl-19-tetrahydropyranyloxy-4-androstene-3,17-dione forms 1-methyl-19-tetrahydropyranyloxy-1,4-androstadiene-3,17-dione.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23]>>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]([NH:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1)=[O:23]
Reactant: CCOC(=S)c1cnc(C)nc1N
Reactant: O=C=Nc1ccccc1Cl
Product: CCOC(=S)c1cnc(C)nc1NC(=O)Nc1ccccc1Cl
Temperature: 102.5 °C
Reaction time: 14 h
Yield: 94.8 %

Procedure:
To a suspension of ethyl 4-amino-2-methylthiopyrimidine-5-carboxylate (1215 g, 5.7 moles) in 2600 mL xylenes heated at 100-105° C. was added (956.5 g, 6.23 moles 2-chlorophenylisocyanate so as to maintain the temperature at 100° C. The temperature of the reaction mixture was raised to 120° C. and stirred for 14 hours. Heating was stopped and slow cooling to 110° C. was begun. When crystallization began, slow addition of 5256 mL ethyl acetate completed the crystallization. The mixture was cooled to 20° C. and filtered. The cake was washed with ethyl acetate and was placed in a vacuum oven and dried for 10-12 hours at 60° to 80° C. to give 1895 g (90.7%)of ethyl 4-{[(2-chlorophenyl)amino]carbonylamino}-2-methylthiopyrimidine-5-carboxylate, m.p.172.3-172.6° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Li+].CC([N-]C(C)C)C.I[CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1>C1COCC1>[C:2]1([CH2:1][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:24][CH2:23]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCC(CI)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCc2nccc3ccccc23)CC1
Temperature: -78 °C
Reaction time: 1.75 h
Yield: 66 %

Procedure:
The procedure described in Example 7a was followed using 1-methyl isoquinoline (0.50 g, 3.49 mmol), 1M LDA (4.2 mL, 4.2 mmol), and 4-iodomethyl-1-piperidinecarboxylic acid, 1-(1,1-dimethylethyl) ester (1.2 g, 3.84 mmol) in dry THF (45 mL) except that after addition of the reagents, the mixture was stirred at −78° C. for 1.75 hours. Purification by chromatography (30% EtOAc/toluene) gave the title compound (0.784 g, 66%) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:17])[C:7]3[C:12]([S:13][C:14]=2[CH:15]=1)=[CH:11][C:10](Br)=[CH:9][CH:8]=3.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][N:6]1[C:7]2[CH:8]=[CH:9][C:10]([C:19]3[CH:20]=[CH:21][C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:18]=3)=[CH:11][C:12]=2[S:13][C:14]2[C:5]1=[CH:4][CH:3]=[C:2]([C:20]1[CH:19]=[CH:18][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=1)[CH:15]=2
Reactant: CN1c2ccc(Br)cc2Sc2cc(Br)ccc21
Reactant: OB(O)c1ccc2ccccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CN1c2ccc(-c3ccc4ccccc4c3)cc2Sc2cc(-c3ccc4ccccc4c3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
9.30 g (25.1 mmol) of 3,7-dibromo-10-methylphenothiazine, 9.50 g (55.2 mmol) of 2-naphthylboronic acid, 0.407 g (0.50 mmol) of bis(triphenylphosphine)palladium dichloride and 3.80 g (27.5 mmol) of potassium carbonate were heated to boiling under reflux under nitrogen for 5 hours in 204 ml of dimethoxyethane and 101 ml of water. The reaction mixture was cooled to room temperature, stirred further overnight and then filtered. The residue was washed with 470 ml of ethanol and hot water, and then dried at 70° C. under reduced pressure. The solid was dissolved in 200 ml of methylene chloride and filtered through silica gel. After the solvent had been removed under reduced pressure, 9.6 g of greenish-yellow solid were obtained (melting point 276-281° C.) and were recrystallized from 500 ml of toluene. 7.10 g (81% of theory) of analytically pure, shiny yellow microcrystals having a melting point of 285-289° C. were obtained, whose solution in chloroform fluoresced at λ=402 nm.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([NH:14][C:15]3[CH:16]=[C:17]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=3)=[N:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[N-:26]=[N+:27]=[N-:28].[Na+].[Cl-].[NH4+].O>CN(C=O)C>[NH:26]1[C:1]([C:3]2[CH:8]=[CH:7][C:6]([C:9]3[O:13][C:12]([NH:14][C:15]4[CH:16]=[C:17]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=4)=[N:11][CH:10]=3)=[CH:5][CH:4]=2)=[N:2][N:28]=[N:27]1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)Nc1cccc(Nc2ncc(-c3ccc(C#N)cc3)o2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)Nc1cccc(Nc2ncc(-c3ccc(-c4nnn[nH]4)cc3)o2)c1
Temperature: 120 °C
Yield: 89.3 %

Procedure:
N-(3-((5-(4-cyanophenyl)oxazol-2-yl)amino)phenyl)methanesulfonamide 7 (0.12 g, 0.338 mmol) was dissolved in anhydrous DMF (10 mL), Sodium azide (0.088 g, 1.35 mmol) and ammonium chloride (0.072 g, 1.35 mmol) were added to above solution. Resulting suspension was heated at 120° C. for overnight (14 hours). Reaction was cooled down and water was added. Resulting (precipitated) solid was filtered, washed with water, methanol, and water. This was further purified by dissolving into DMSO and re-precipitated with addition of water. Resulting solid was filtered, washed with water, methanol and dried under high vacuum to yield N-(3-((5-(4-(1H-tetrazol-5-yl)phenyl)oxazol-2-yl)amino)phenyl)methanesulfonamide 41 (0.12 g, 90%) as a white solid. MS (ES) m/z 398 (M+H+).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:27]([O:31][C:32](=[O:45])[NH:33][CH2:34][CH2:35][CH:36]([NH2:44])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:45])[NH:33][CH2:34][CH2:35][CH:36]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=1)[NH:44][C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CN1CCN(c2nccn3c(-c4ccnc(S(C)(=O)=O)n4)cnc23)CC1
Reactant: CC(C)(C)OC(=O)NCCC(N)c1cccc(Cl)c1
Product: CN1CCN(c2nccn3c(-c4ccnc(NC(CCNC(=O)OC(C)(C)C)c5cccc(Cl)c5)n4)cnc23)CC1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
The mixture of 3-(2-methanesulfonyl-pyrimidin-4-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine (from Example 46 supra) (100 mg, 0.27 mmol) and [3-amino-3-(3-chloro-phenyl)-propyl]-carbamic acid tert-butyl ester (from Example 62 supra) (307 mg, 1.08 mmol) was heated at 140° C. with stirring for 2 hours. The oil was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 20:1) to afford crude (3-(3-chloro-phenyl)-3-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-propyl)-carbamic acid tert-butyl ester. (Yield 123 mg). LC-MS: [M+H]+ 578.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[N:12]([CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[NH:11][C:10]2=[O:27])[CH:5]=[CH:6][C:7]=1[Cl:8].[Li+].[CH3:29][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:27])[N:11]([CH3:29])[N:12]([CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[C:13]=2[C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1NN(Cc2cccnc2)C(c2ccncc2)C1c1ccc(Cl)c(Cl)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1c(=O)c(-c2ccc(Cl)c(Cl)c2)c(-c2ccncc2)n1Cc1cccnc1
Temperature: 0 °C

Procedure:
In a 100 mL round bottom flask, was added 70 mg 4-(3,4-Dichloro-phenyl)-5-pyridin-4-yl-1-pyridin-3-ylmethyl-pyrazolidin-3-one and 10 mL THF, stirred at 0° C. under nitrogen. 0.26 mL 1 M LHMDS in THF was added drop wise. After stirred at 0° C. for 30 min. 0.017 mL iodomethane was added drop wise. The resulted mixture was stirred from 0° C. to rt for 2 hour, quenched with 20 mL sat. NH4Cl, extracted with dichloromethane 3×25 mL. The crude MS showed the desired 4-(3,4-Dichloro-phenyl)-2-methyl-5-pyridin-4-yl-1-pyridin-3-ylmethyl-pyrazolidin-3-one was there, MS (ES+): 413 (M+H)+. The organic phase was dried over anhydrous Na2SO4. After purification by flash chromatography, the 4-(3,4-Dichloro-phenyl)-5-pyridin-4-yl-1-pyridin-3-ylmethyl-pyrazolidin-3-one was oxidized on column and obtained the 4-(3,4-Dichloro-phenyl)-2-methyl-5-pyridin-4-yl-1-pyridin-3-ylmethyl-1,2-dihydro-pyrazol-3-one 12 mg as light yellow solid. MS (ES+): 411 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=O)[CH:3]=1.O>ClCCl>[CH:4]1([CH:8]=[O:10])[CH2:3][CH2:5][CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH2:8][CH2:2][CH2:7][CH2:6][CH2:5]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: O=CC1CCCCCCCCCCCC1
Yield: 60 %

Procedure:
To a stirred mixture of 3 g of zinc dust, 50 ml of anhydrous tetrahydrofuran and 2.66 g of dibromomethane, was added dropwise a solution of 2.13 g of anhydrous titanium tetrachloride in 5 ml of dichloromethane. After 15 minutes, to the resulting solution was added dropwise a solution of 2 g of cyclotridecanone in 8 ml of anhydrous tetrahydrofuran. The mixture was allowed to react at room temperature for 12 hours. The reaction mixture was diluted with 50 ml of pentane, admixed with 100 ml of 1-M hydrochloric acid, and intermixed by shaking. The organic layer was washed successively with water, dilute aqueous sodium hydrogencarbonate solution, and saturated aqueous sodium chloride solution, then dried, and concentrated to yield methylenecyclotridecane. To a solution of this substance in 40 ml of anhydrous dichloromethane, after having been cooled to -15° C., was added dropwise with stirring a solution of 2.64 g of m-chloroperbenzoic acid in 40 ml of anhydrous dichloromethane. After 3 hours of reaction, the organic layer was washed successively with 10-% sodium sulfite solution, 7-% sodium hydrogencarbonate solution, and saturated sodium chloride solution, then dried and concentrated under reduced pressure. The residue was purified by the silica gel chromatography [developed with a petroleum ether-ethyl acetate (20:1) mixture] to yield 2.04 g (95% yield based on the ketone compound) of an epoxide. To a solution of the epoxide in anhydrous dichloromethane, after having been cooled to -18° C., was added dropwise a borontrifluoride-ether complex. After completion of the addition, water was added to the reaction mixture. The organic layer was separated, then concentrated, and purified by the silica gel chromatography to yield only cyclotridecanecarbaldehyde in a yield of 60-70%.
Reaction SMILES: Br[O-].[Na+].[OH-].[Na+].BrBr.[CH3:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:12]=[CH:11][C:10]=1[C:24](=[O:26])C.S(=O)(O)[O-:28].[Na+]>O.O1CCOCC1>[CH3:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[CH:12]=[CH:11][C:10]=1[C:24]([OH:26])=[O:28]
Reactant: CC(=O)c1ccc(OCCN2CCOCC2)cc1C
Reactant: O=S([O-])O
Agent: BrBr
Agent: [Na+]
Agent: [O-]Br
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(OCCN2CCOCC2)ccc1C(=O)O
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A solution of sodium hypobromite, prepared at 0° C. by dissolving sodium hydroxide (45.71 g, 1.14 mole) in water (200 mL) and bromine (16.3 mL, 0.30 mole) over 5 minutes. This solution is then added dropwise over 30 minutes to a solution of 1-[2-methyl-4-(2-morpholin-4-yl-ethoxy)-phenyl]-ethanone (19.2 g, 0.073 mole) in dioxane (140 mL), then warmed to 40° C. and stirred for 30 minutes. Sodium bisulfite is added to destroy the excess sodium hypobromite and then diluted with water (800 mL) and stirred overnight at ambient temperature. The volume is reduced in-vacuo by about 300 mL and then acidified with 3 N hydrochloric acid to pH 6. This is then extracted repeatedly with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and evaporated to give a white solid, 4.09 g (21%), MS (ESI): m/z 266.2 (M+H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=2[CH3:15])[C:6](=[S:16])[N:5]([CH3:17])[N:4]=1.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22]>C(#N)C.C(N(CC)CC)C.C(Cl)(Cl)Cl.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.Cl[Pd]Cl.[Cu]I>[F:1][C:2]([F:19])([F:18])[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])=[CH:10][C:9]=2[CH3:15])[C:6](=[S:16])[N:5]([CH3:17])[N:4]=1
Reactant: Cc1cc(I)ccc1-n1c(C(F)(F)F)nn(C)c1=S
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc(C#C[Si](C)(C)C)ccc1-n1c(C(F)(F)F)nn(C)c1=S
Yield: 101.8 %

Procedure:
To a stirred mixture of 5.00 g (0.0125 mole) of 3-trifluoromethyl-4,5-dihydro-4-(4-iodo-2-methylphenyl)-1-methyl-1,2,4-triazol-5(1H)-thione and 2.46 g (0.0250 mole) of trimethylsilylacetylene in 20 ml of acetonitrile and 100 ml of triethylamine was added 0.0880 g (0.000125 mole) of bis(triphenylphosphine)palladium (II) chloride and 0.048 g (0.00025 mole) of copper (I) iodide. The reaction mixture was heated at reflux for approximately 18 hours. The solvents were removed from the reaction mixture by evaporation under reduced pressure, leaving a residue. This residue was dissolved in chloroform, and the organic solution was washed in succession with an aqueous, saturated sodium chloride solution and an aqueous, 20% ammonium chloride solution. The washed organic phase was evaporated under reduced pressure, leaving a dark oil. This oil was purified by column chromatography on silica gel, eluting with chloroform, to yield 4.7 g of 3-trifluoromethyl-4,5-dihydro-1-methyl-4-(2-methyl-4-trimethylsilylethynylphenyl)-1,2,4-triazol-5(1H)-thione as a solid, mp 90°-93° C., Compound 113 of Table 1. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1.Br[CH2:16][CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.O>[CH2:19]([O:18][CH2:17][CH2:16][O:3][CH:4]1[CH2:5][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCCOCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(OCCOCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (2.03 g, 60% in oil) was added portionwise to a ice-cooled solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (8 g) in DMF (20 ml). The mixture was stirred at 0° C. for 20 minutes and benzyl 2-bromoethyl ether (8.03 ml) was added. The mixture was heated at 80° C. for 18 hours. After cooling, the mixture was diluted in water and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. Evaporation of the solvent and chromatography on silica gel (eluting with 20% to 50% ethyl acetate in petroleum ether gave tert-butyl 3-(2-benzyloxyethoxy)azetidine-1-carboxylate (9.15 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:15])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][N:7]=1
Reactant: [H][H]
Reactant: COC(=O)COc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CO
Product: COC(=O)COc1ccc(N)cn1
Yield: 81.3 %

Procedure:
To a solution of (5-nitropyridin-2-yloxy)acetic acid methyl ester (0.23 g, 1.08 mmol) in methanol (30 mL) was added palladium on activated carbon (10 wt. %, 0.20 g) and the solution was blanketed with hydrogen at atmospheric pressure. After 4 h the solids were removed by filtration and the volatiles were removed to yield 0.16 g (82%) of (5-amino-pyridin-2-yloxy)-acetic acid methyl ester as an oil that was used without further purification.
Reaction SMILES: [K+].[C:2]([C:4]1[N:5]=[C:6]([C:17]([O-:19])=O)[N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=1)#[N:3].CCN(C(C)C)C(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[F:53][CH:54]1[CH2:59][CH2:58][CH2:57][N:56]([C:60]2[CH:65]=[C:64]([N:66]3[CH2:71][CH2:70][N:69]([CH3:72])[CH2:68][CH2:67]3)[CH:63]=[CH:62][C:61]=2[NH2:73])[CH2:55]1>C(Cl)Cl>[F:53][CH:54]1[CH2:59][CH2:58][CH2:57][N:56]([C:60]2[CH:65]=[C:64]([N:66]3[CH2:67][CH2:68][N:69]([CH3:72])[CH2:70][CH2:71]3)[CH:63]=[CH:62][C:61]=2[NH:73][C:17]([C:6]2[N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:15])[CH3:16])[CH:8]=[C:4]([C:2]#[N:3])[N:5]=2)=[O:19])[CH2:55]1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CN1CCN(c2ccc(N)c(N3CCCC(F)C3)c2)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(N3CCCC(F)C3)c2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
A suspension of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 3, step (d), 48 mg, 0.16 mmol) in CH2Cl2 (5 mL) was treated with DIEA (68 μL, 0.39 mmol) and PyBroP (0.11 g, 0.24 mmol). The reaction stirred at room temperature for 10 min. A solution of 2-(3-fluoro-piperidin-1-yl)-4-(4-methyl-piperazin-1-yl)-phenylamine (as prepared in the previous step, 46 mg, 0.16 mmol) in CH2Cl2 (4 mL) was added, and the reaction was stirred at room temperature for 19.5 h. The reaction was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3 and water. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the title compound (62 mg, 70%) as an off-white solid, which was used directly in the next reaction. LC-MS (ESI, m/z): Calcd. for C27H40FN7O2Si, 542.3 (M+H), found 542.4.