Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[Na+].Br[C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1.C1(C)C=CC=CC=1.[CH3:22][NH:23][CH2:24][CH3:25]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].C(OCC)(=O)C>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([N:23]([CH2:24][CH3:25])[CH3:22])=[N:9][CH:10]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CCNC
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCN(C)c1ccc(Br)cn1
Temperature: 70 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
To a mixture of 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene (293 mg, 0.51 mmol), tris(dibenzylideneacetone)dipalladium (0)-chloroform adduct (174 mg, 0.17 mmol), sodium t-butoxide (974 mg, 10.0 mmol), 2,5-dibromopyridine (2.0 g, 8.44 mmol) and anhydrous toluene (30 ml) was added N-methylethylamine (1.09 ml, 12.7 mmol). The mixture was heated to 70° C., and the mixture was stirred for 3 hrs. The reaction mixture was cooled to room temperature, ethyl acetate was added, and the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19) to give 5-bromo-N-ethyl-N-methylpyridin-2-amine (1.21 g, yield 66%) as a yellow oil.
Reaction SMILES: B.O1CCCC1.[CH2:7]([O:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][C:15]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[C:14]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:13]=1)[CH2:8][CH2:9][CH3:10].CO>O1CCCC1>[CH2:7]([O:11][C:12]1[C:17]([CH2:18][NH2:19])=[CH:16][C:15]([C:20]2[CH:21]=[CH:22][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][CH:25]=2)=[C:14]([C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[N:13]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCOc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)cc1C#N
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)cc1CN
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Borane-tetrahydrofuran (1.0M in tetrahydrofuran, 1.5 mL, 0.0016 mole) was added by syringe to a solution of 2-butoxy-6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyridine-3-carbonitrile (Example 14) (0.68 g, 0.0016 mole) in tetrahydrofuran (100 mL). After stirring at room temperature for 1 hour the solution was heated to reflux for 20 hours. Additional borane-tetrahydrofuran (2.4 mL) was added in three portions over the next 3 hours to the hot solution and stirred for 1 hour before cooling to room temperature. Methanol (20 mL) was added and the solution was concentrated to an oily solid. The product was purified by silica gel chromatography (Example 29) (128 mg, 0.3 mMol) in dimethylformamide after hydroxymethyl-5-[4-(methylsulfonyl)phenyl]pyridine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])[C:3]=1[CH3:21]>C(N)CN>[NH2:14][CH2:15][CH2:16][NH:17][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])[C:3]=1[CH3:21]
Reactant: CC(=O)NCCNc1nc(-c2ccccc2)nc(Cl)c1C
Solvent: NCCN
Product: CC(=O)NCCNc1nc(-c2ccccc2)nc(NCCN)c1C
Temperature: 25 °C
Yield: 169.8 %

Procedure:
N-{2-[(6-Chloro-5-methyl-2-phenylpyrimidin-4-yl)amino]ethyl}acetamide (2.0 g) was dissolved in ethylenediamine (40 ml) and heated with stirring to reflux for 21 hrs. After cooling to ambient temperature the solution was evaporated onto silica gel (50 g). Purification via flash chromatography on silica gel eluting with a mixture of ethyl acetate, methanol and ammonium hydroxide (80:20:5 v/v/v) furnished the title compound (1.83 g).
Reaction SMILES: Cl[C:2]1[C:11]([NH:12][C:13](=O)[CH2:14][O:15][CH3:16])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1(C)C(C)=CC=CC=1>[CH3:16][O:15][CH2:14][C:13]1[S:27][C:2]2[C:11]([N:12]=1)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COCC(=O)Nc1cc(C(=O)OC)cnc1Cl
Solvent: Cc1ccccc1C
Product: COCc1nc2cc(C(=O)OC)cnc2s1

Procedure:
A mixture of 0.53 g (2.05 mMol) of methyl 6-chloro-5-methoxyacetamido-nicotinate and 0.42 g (1.0 mMol) of Lawessons reagent was refluxed for 16 hours in 25 ml of xylene. After the solvent had been removed in vacuo the crude product obtained was purified by flash chromatography (silica gel; methylene chloride/ethanol=100:1) and evaporated down again in vacuo. Yield: 0.33 g (67% of theory) of yellow amorphous solid, Rf value: 0.52 (silica gel; ethyl acetate/petroleum ether=1:4)
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]1([CH3:24])[CH:14]=[CH:13][C:12]([S:15]([CH2:18][C:19]([CH3:23])=[CH:20][CH2:21][OH:22])(=[O:17])=[O:16])=[CH:11][CH:10]=1.Br[CH2:26][CH:27]=[C:28]([CH3:40])[CH:29]=[CH:30][C:31]1[C:36]([CH3:38])([CH3:37])[CH2:35][CH2:34][CH2:33][C:32]=1[CH3:39]>O1CCCC1>[OH:22][CH2:21][CH:20]=[C:19]([CH3:23])[CH:18]([S:15]([C:12]1[CH:11]=[CH:10][C:9]([CH3:24])=[CH:14][CH:13]=1)(=[O:16])=[O:17])[CH2:26][CH:27]=[C:28]([CH3:40])[CH:29]=[CH:30][C:31]1[C:36]([CH3:38])([CH3:37])[CH2:35][CH2:34][CH2:33][C:32]=1[CH3:39]
Reactant: CC(=CCO)CS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C=CC1=C(C)CCCC1(C)C)=CCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C=CC1=C(C)CCCC1(C)C)=CCC(C(C)=CCO)S(=O)(=O)c1ccc(C)cc1
Temperature: -70 °C
Reaction time: 0.75 h
Yield: 70 %

Procedure:
The lithium diisopropylamide solution was then added over a 75 minute period to a -70°C. solution of 5.0 g. of 1-p-toluenesulfonyl-2-methyl-4-hydroxy-but-2-ene and 7.0 g. of 1-bromo-3-methyl-5-(2,6,6-trimethylcyclohexen-1-yl)-penta-2,4-diene in 50 ml. of tetrahydrofuran. After the addition, the reaction mixture was stirred for an additional 45 minutes at -70°C. and was then warmed to 0°C. and was poured onto 400 ml. of ice water. The mixture was extracted with three 300 ml. portions of diethyl ether, and the combined extracts were washed with two 400 ml. portions of brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent at reduced pressure gave a yellow oil which was immediately chromatographed on 300 g. of silica gel eluting with 5 to 30% diethyl ether in benzene followed by ethyl acetate. From the chromotography there was obtained 6.43 g. of pure 1-hydroxy-3,7-dimethyl-4-p-toluenesulfonyl-9 -(2,6,6-trimethylcyclohexen-1-yl)-nona-2,6,8-triene (70% yield) and 1.21 g. of recovered hydroxysulfone starting material. The product had UV in isopropanol at λmax = 228-9 mμ ( ε= 25,740); 260-2 mμ ( ε = 17,070) and 274-5 mμ ( ε = 15,010).
Reaction SMILES: C([N:4]1[C:12]2[CH:7]([N:8](C(=O)C)[CH:9]([Cl:17])[N:10](C(=O)C)[C:11]=2Cl)[N:6]([C@@H:21]2[O:27][C@H:26]([CH2:28][OH:29])[C@@H:24]([OH:25])[C@H:22]2[OH:23])[CH2:5]1)(=O)C.[C:30]1([CH:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:37][NH2:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>COCCOC>[C:39]1([CH:36]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:37][NH:38][C:11]2[C:12]3[N:4]=[CH:5][N:6]([C:7]=3[N:8]=[C:9]([Cl:17])[N:10]=2)[C@@H:21]2[O:27][C@H:26]([CH2:28][OH:29])[C@@H:24]([OH:25])[C@H:22]2[OH:23])[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CC(=O)N1CN([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)C2C1=C(Cl)N(C(C)=O)C(Cl)N2C(C)=O
Reactant: NCC(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2.75 g of triacetyl-2,6-dichloro-9-(β-D-ribofuranosyl)purine (M. J. Robins and B. Uznanski Can. J. Chem., 59, 2601 (1981), J. F. Gerster and R. K. Robins, J. Org. Chem., 31, 3528 (1966)), 1.34 g of 2,2-diphenylethylamine and 0.748 g of triethylamine is stirred at room temperature, under a nitrogen atmosphere for four hours in 50 ml of 1,2-dimethoxyethane (distilled over NaH). The precipitate of Et3N+HCl is filtered and the solvent is evaporated from the filtrate to dryness. The residue is dissolved in 50 ml of methanol saturated with ammonia and stirred at room temperature for three hours. The mixture is evaporated to dryness and the residue is purified by medium pressure liquid chromatography on silica gel using 5% methanol in chloroform as the eluent. Evaporation of the solvent from the pure fractions affords a solid material which is crystallized from a mixture of chloroform-2-propanol (10:1) and hexane yielding N6 -(2,2-diphenylethyl)-2-chloroadenosine, mp 120°- 123° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[N:12]=[C:11]([NH:13]C=O)[S:10][N:9]=1)[C:5]([OH:7])=[O:6].[OH-].[Na+].Cl.[Cl-].[Na+]>>[CH3:1][O:2][N:3]=[C:4]([C:8]1[N:12]=[C:11]([NH2:13])[S:10][N:9]=1)[C:5]([OH:7])=[O:6]
Reactant: CON=C(C(=O)O)c1nsc(NC=O)n1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Product: CON=C(C(=O)O)c1nsc(N)n1
Yield: 73.2 %

Procedure:
A solution of 2-methoxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) (1.4 g) in 1N aqueous solution of sodium hydroxide (19.1 ml) was heated at 50° to 55° C. for an hour. To the solution was added conc.hydrochloric acid (1.9 ml) under cooling in an ice-bath. The mixture was saturated with sodium chloride and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was triturated with diethyl ether to give the title compound (0.9 g), mp. 180° to 182° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[C:13]([CH3:19])=[CH:14][C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:20][OH:21]>>[CH:20]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[C:13]([CH3:19])=[CH:14][C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][CH2:9]2)=[CH:4][CH:3]=1)=[O:21]
Reactant: CO
Reactant: Cc1cc(C)c2c(c1C)OCC2c1ccc(Br)cc1
Product: Cc1cc(C)c2c(c1C)OCC2c1ccc(C=O)cc1
Yield: 73 %

Procedure:
Using 3-(4-bromophenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran obtained in Reference Example 236, the title compound was synthesized in the same manner as in Reference Example 245. Yield 73%. Melting point: 87-88° C. (methanol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].F[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:27][C:28]3[C:33]([N:34]=2)=[CH:32][CH:31]=[C:30]([C:35]2([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:37][CH2:36]2)[N:29]=3)=[CH:22][CH:21]=1>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[S:27][C:28]4[C:33]([N:34]=3)=[CH:32][CH:31]=[C:30]([C:35]3([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH2:36][CH2:37]3)[N:29]=4)=[CH:24][CH:25]=2)[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](Oc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)cc2)C[C@H]1C(=O)O
Temperature: 95 °C

Procedure:
A solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (162.1 mg, 0.701 mmol) in DMF (4.0 mL) was slowly added to a suspension of sodium hydride (60% w/w in mineral oil) (58 mg, 1.45 mmol) in DMF (4.0 mL), and the resulting mixture was heated at 95° C. for 5 min. 2-(4-Fluorophenyl)-5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine (75.3 mg, 0.217 mmol) was then added, and the resulting solution was heated at 95° C. for 18 h. The reaction mixture was subsequently cooled to 25° C. and diluted with EtOAc (5 mL). Excess NaH was quenched with water (5 mL), and the resulting mixture was diluted with 0.1N aq. HCl (40 mL) and extracted with EtOAc. The combined extracts were sequentially washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to provide (2S,4R)-1-(tert-butoxycarbonyl)-4-(4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenoxy)pyrrolidine-2-carboxylic acid as a yellow solid. MS (ESI) m/z: Calculated: 557.2; Observed: 557.8 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[F:10][C:11]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:12]=1[C:13](Cl)=[O:14]>>[OH:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[NH:1][C:13](=[O:14])[C:12]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:11]=1[F:10]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1F
Reactant: Cc1ccc(N)c(O)c1
Product: Cc1ccc(NC(=O)c2cc([N+](=O)[O-])ccc2F)c(O)c1

Procedure:
Prepared by the method of Example 15a), from 2-amino-5-methylphenol (605 mg, 4.9 mmol) and 2-fluoro-5-nitrobenzoyl chloride (1.00 g, 5.0 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([O:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH:37]=[N:38][O:39][CH3:40])=[CH:31][CH:30]=2)[CH:22]=1)(=O)C.O.[OH-].[Li+]>C1COCC1.CO.O>[CH3:40][O:39][N:38]=[CH:37][CH2:36][O:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][C:23]2[CH:22]=[C:21]([C@H:6]3[C@H:5]([OH:4])[C@@H:10]([OH:11])[C@H:9]([OH:15])[C@@H:8]([O:19][CH3:20])[O:7]3)[CH:26]=[CH:25][C:24]=2[Cl:27])=[CH:30][CH:31]=1
Reactant: CON=CCOc1ccc(Cc2cc([C@@H]3O[C@H](OC)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CON=CCOc1ccc(Cc2cc([C@@H]3O[C@H](OC)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of (2S,3S,4R,5S,6S)-2-(4-chloro-3-(4-(2-(methoxyimino)ethoxy)benzyl)phenyl)-6-methoxytetrahydro-2H-pyran-3,4,5-triyl triacetate (140 mg, 0.242 mmol) in THF (0.8 mL), methanol (1.2 mL) and water (0.4 mL) was added lithium hydroxide monohydrate (20.4 mg, 0.485 mmol) at 0° C. The reaction was stirred at r.t. for 1 h. Volatiles were evaporated in vacuo and the residue obtained was purified by column chromatography (silica gel, 1:9 MeOH:DCM) to provide the title compound (70 mg, 64.2%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[N+](C1C=CC([O:32][C:33]([N:35]2[CH:39]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[C:42]([Cl:47])[CH:41]=3)[CH2:38][O:37][C:36]2=[O:48])=O)=CC=1)([O-])=O>C1COCC1>[C:11]1([C:8]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:33]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][C:43]([F:46])=[C:42]([Cl:47])[CH:41]=4)[CH2:38][O:37][C:36]3=[O:48])=[O:32])[CH2:6][CH2:7]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: NCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Reactant: O=C1OCC(c2ccc(F)c(Cl)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: O=C(NCCCN1CCC(c2ccccc2)(c2ccccc2)CC1)N1C(=O)OCC1c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-amino-propyl-4,4-diphenyl piperidine (0.04 g, 0.1 mmol) in 5 mL of THF was added 4-(3-chloro-4-fluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid-4-nitro-phenyl ester (0.04 g, 0.12 mmol) and the resulting yellow solution was stirred under argon atmosphere for 3 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 50% hexane/EtOAC followed by 5% MeOH in EtOAC as the eluting systems (Rf=0.45, 1:3 MeOH/EtOAC) to obtain 4-(3-Chloro-4-fluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid [3-(4,4-diphenyl-piperidin-1-yl)-propyl]-amide as white foam (wt=0.03 g). It was converted into its hydrochloride salt. M.P. 112-115° C.; Anal. Calcd. for C30H32N3O 3Cl2F.0.5 CHCl3: C, 57.95; H, 5.18; N, 6.65. Found: C, 58.06; H, 5.74; N, 6.30.
Reaction SMILES: [CH2:1]([O:4][CH:5]([CH2:14][O:15][CH2:16][C:17]#[CH:18])[CH2:6][N:7]1[C:11](=[O:12])[NH:10][NH:9][C:8]1=[O:13])[C:2]#[CH:3]>C(Cl)Cl>[CH2:1]([O:4][CH:5]([CH2:14][O:15][CH2:16][C:17]#[CH:18])[CH2:6][N:7]1[C:8](=[O:13])[N:9]=[N:10][C:11]1=[O:12])[C:2]#[CH:3]
Reactant: C#CCOCC(Cn1c(=O)[nH][nH]c1=O)OCC#C
Solvent: ClCCl
Product: C#CCOCC(CN1C(=O)N=NC1=O)OCC#C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.8 %

Procedure:
To 4-(2,3-bis(prop-2-ynyloxy)propyl)-1,2,4-triazolidine-3,5-dione (I-13d: 50 mg, 0.199 mmol) in CH2Cl2 (1.99 mL) was added SiO2-HNO3 (150 mg). The mixture was stirred at room temperature for 15 minutes, then filtered, concentrated in vacuo and dried giving 4-(2,3-bis(prop-2-ynyloxy)propyl)-3H-1,2,4-triazole-3,5(4H)-dione (I-13e: 50 mg, quantitative) as a red oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1([F:46])[CH2:11][CH:10]1[C:12]([NH:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20](C1CCCCO1)[N:19]=[C:18]2[C:30]1[NH:34][C:33]2[CH:35]=[C:36]([CH2:39][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[CH:37]=[CH:38][C:32]=2[N:31]=1)=[O:13]>C(Cl)Cl>[F:46][C:9]1([F:8])[CH2:11][CH:10]1[C:12]([NH:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[C:18]2[C:30]1[NH:31][C:32]2[CH:38]=[CH:37][C:36]([CH2:39][N:40]3[CH2:41][CH2:42][O:43][CH2:44][CH2:45]3)=[CH:35][C:33]=2[N:34]=1)=[O:13]
Reactant: O=C(Nc1ccc2c(c1)c(-c1nc3ccc(CN4CCOCC4)cc3[nH]1)nn2C1CCCCO1)C1CC1(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc2[nH]nc(-c3nc4cc(CN5CCOCC5)ccc4[nH]3)c2c1)C1CC1(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
TFA (0.15 mL, 1.86 mmol) was added to solution of 2,2-difluoro-N-(3-(6-(morpholinomethyl)-1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropane carboxamide (10 mg, 0.018 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred overnight at room temperature, and then the solvent was removed by vacuum. Purification by flash column chromatography (5% CH3OH/CH2Cl2) afforded the title compound (4 mg) as a solid. 1H NMR: (400 MHz, CD3OD): δ 8.49 (d, 1H, J=1.6 Hz), 7.69 (dd, 1H, J=1.6 and 8.8 Hz), 7.63-7.58 (m, 3H), 7.28 (m, 1H), 3.71 (m, 4H), 3.67 (m, 2H), 2.79-2.70 (m, 1H), 2.52 (m, 4H), 2.36-2.32 (m, 1H), 2.15-2.06 (m, 1H); ESI-MS [M+H]+: 453.2.
Reaction SMILES: [C:1]([C:4]1[CH:13]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[F:22])[C:12]2[C:11](=[O:23])[NH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:5]=1[CH3:24])(=[O:3])[CH3:2].ClCCl.F[B-](F)(F)F.[CH2:33]([O+](CC)CC)[CH3:34].CO>O>[C:1]([C:4]1[CH:13]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[F:22])[C:12]2[C:7](=[CH:8][CH:9]=[N:10][C:11]=2[O:23][CH2:33][CH3:34])[NH:6][C:5]=1[CH3:24])(=[O:3])[CH3:2]
Reactant: CC[O+](CC)CC
Reactant: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1ccc(C#N)cc1F
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CCOc1nccc2c1C(c1ccc(C#N)cc1F)C(C(C)=O)=C(C)N2
Reaction time: 2 h

Procedure:
18 mg (0.056 mmol) of 4-(3-acetyl-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridin-4-yl)-3-fluorobenzonitrile are dissolved under an argon atmosphere in 5 ml abs. dichloromethane, and 21.2 mg (0.111 mmol) of triethyloxonium tetrafluoroborate are added. After a reaction time of two hours at room temperature (reaction checked by HPLC), the mixture is mixed with 5 ml of methanol and 0.5 ml of water and again stirred for 2 h. It is then diluted with 10 ml of water and extracted three times with dichloromethane. The combined organic phases are dried with sodium sulfate, and the solvent is removed in a rotary evaporator. The residue is purified by column chromatography (silica gel, mobile phase: cyclohexane/ethyl acetate 3:7). 7 mg (35.4% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[O:6][C:7]1[CH:15]=[CH:14][C:10]([CH:11]=[N:12][OH:13])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].ClN1C(=O)CCC1=O.[C:26]([O:30][CH2:31][CH3:32])(=[O:29])[C:27]#[CH:28].C(N(CC)CC)C>CN(C=O)C.CCOCC>[CH2:31]([O:30][C:26]([C:27]1[O:13][N:12]=[C:11]([C:10]2[CH:14]=[CH:15][C:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:17])[CH3:16])=[CH:8][CH:9]=2)[CH:28]=1)=[O:29])[CH3:32]
Reactant: C#CC(=O)OCC
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C=NO)cc1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2ccc(O[Si](C)(C)C(C)(C)C)cc2)no1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 2 %

Procedure:
4-(tert-Butyl-dimethyl-silanyloxy)-benzaldehyde oxime (which may be prepared according to the procedure described in Kao, Y. T. R. et al. US 20110212975 page 17; ˜20 g, ˜80 mmol) was dissolved in DMF (50 mL) and the solution was cooled to 0° C. N-Chlorosuccinimide (12.8 g, 96 mmol) was added in portions. The reaction mixture was stirred at 0° C. for 30 min, allowed to warm to room temperature and stirred at room temperature for 1.5 h. The reaction mixture was poured into ice-water (100 mL) and the resulting suspension was extracted with EtOAc (100 mL). The organic extract was dried over Na2SO4, filtered, and evaporated. Et2O (120 mL) was added to the residue, and then a solution of ethyl propiolate (16 mL, 158 mmol) and triethylamine (12 mL) in Et2O (120 mL) was added dropwise. The mixture was stirred at room temperature for 48 h. The reaction mixture was filtered and the filtrate was evaporated to give a brown oil which was purified by filtration through a silica gel plug (eluting with 12% EtOAc/hexanes) followed by silica gel chromatography. Final purification was accomplished using preparatory supercritical fluid chromatography (100 bar CO2 modified with 10% MeOH, flow rate of 2 mL/min at 30° C.) to give 3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-isoxazole-5-carboxylic acid ethyl ester (600 mg, 2%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH2:14])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:16]([C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[C:21]([CH:28]([CH3:30])[CH3:29])[C:20]=1[S:31](Cl)(=[O:33])=[O:32])([CH3:18])[CH3:17]>>[CH:16]([C:19]1[CH:24]=[C:23]([CH:25]([CH3:26])[CH3:27])[CH:22]=[C:21]([CH:28]([CH3:30])[CH3:29])[C:20]=1[S:31]([NH:14][C@H:10]1[CH2:11][CH2:12][CH2:13][C@@H:8]([NH:7][C:6](=[O:15])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:9]1)(=[O:33])=[O:32])([CH3:17])[CH3:18]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC[C@H](N)C1
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)N[C@H]2CCC[C@@H](NC(=O)OC(C)(C)C)C2)c(C(C)C)c1

Procedure:
Compound 7b was prepared following procedures similar to those described previously in Example 1, step A, substituting 7a for i-2d and 2,4,6-triisopropylbenzenesulfonyl chloride for i-5f, respectively. m/z (ES) 503 (MH+Na)+
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[CH:15]=[N:14][C:13](SC)=[N:12][C:11]=3[N:18]=2)[CH:4]=[N:3]1.C(Cl)[Cl:20]>C(#N)C>[Cl:20][C:13]1[N:14]=[CH:15][C:10]2[CH:9]=[CH:8][C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)=[N:18][C:11]=2[N:12]=1
Reactant: CSc1ncc2ccc(-c3cnn(C)c3)nc2n1
Reactant: ClCCl
Solvent: CC#N
Product: Cn1cc(-c2ccc3cnc(Cl)nc3n2)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
7-(1-Methyl-1H-pyrazol-4-yl)-2-(methylthio)pyrido[2,3-d]pyrimidine (Preparation 56, 13 mg, 0.05 mmol), was dissolved in acetonitrile and stirred at 0° C. for 15 minutes followed by the addition of SO2C2 in DCM. After 20 minutes the solution was quenched with NaHCO3 solution at 0° C., the organic solvents were removed in vacuo, and the solids were filtered, washed with water and dried to afford the title compound (7.5 mg, 60%).