Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[CH:2][CH3:3].[F:4][C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7]>>[F:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:2]([CH3:3])[CH3:1])[C:6]=1[NH2:7]
Reactant: C=CC
Reactant: Nc1ccccc1F
Product: CC(C)c1cccc(F)c1N

Procedure:
2-fluoro-6-isopropyl aniline was prepared by the method of Example 2 using an H-Y zeolite catalyst for the condensation of 2-aniline and propylene. In this reaction 2-fluoroaniline and propylene were fed to a reactor in a 1:5 mole ratio and LHSV of 0.25 based on 2-fluoroaniline. The reaction was conducted at 255° C. and 879 psig. The effluent product stream was analyzed by gas chromatography. Conversion of 2-fluoroaniline was 71.2%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][C:5]2([CH3:14])[CH3:13].[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>C(N(CC)CC)C.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>[CH3:15][Si:16]([C:19]#[C:20][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][C:5]2([CH3:14])[CH3:13])([CH3:18])[CH3:17]
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)CCC(=O)c2ccc(Br)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: CC1(C)CCC(=O)c2ccc(C#C[Si](C)(C)C)cc21
Reaction time: 24 h

Procedure:
To a solution (flushed for 15 minutes with a stream of argon) of 13.55 g (53.8 mmol) of 6-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H) in 280 ml of triethylamine was added 1.87 g (2.66 mmol) of bis(triphenylphosphine)palladium(II) chloride and 0.53 g (2.66 mmol) of cuprous iodide. The solution mixture was flushed with argon for 5 minutes and then 100 ml (938.7 mmol) of (trimethylsilyl)acetylene was added. The reaction mixture was sealed in a pressure tube and placed in a preheated oil bath (100° C.) for 24 hours. The reaction mixture was then filtered through Celite, washed with Et2O and the filtrate concentrated in vacuo to give crude 6-(trimethylsilyl)ethynyl-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one. To a solution of this crude TMS-acetylenic compound in 50 ml of methanol was added 2.8 g (20.3 mmol) of K2CO3. The mixture was stirred for 8 hours at ambient temperature and then filtered. The filtrate was concentrated in vacuo, diluted with Et2O (100 ml), washed with water (10 ml), 10% HCl (10 ml) and brine (10 ml), dried over MgSO4 and concentrated in vacuo. Purification by column chromatography (silica, 10% EtOAc-hexane) yielded the title compound as a white solid.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:18][C:19]([C:21]1[CH:40]=[CH:39][C:24]2[N:25]=[C:26]([NH:29][C@H:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:32][CH2:31]3)[O:27][CH2:28][C:23]=2[CH:22]=1)=[NH:20]>O1CCCC1>[C@H:30]1([NH:29][C:26]2[O:27][CH2:28][C:23]3[CH:22]=[C:21]([C:19]4[N:20]=[C:1]([CH3:2])[O:4][N:18]=4)[CH:40]=[CH:39][C:24]=3[N:25]=2)[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31]1
Reactant: CC(=O)O
Reactant: N=C(NO)c1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc3c(c2)COC(N[C@@H]2CCc4ccccc42)=N3)no1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 53.4 %

Procedure:
To a stirred solution of acetic acid (67 mg, 1.12 mmol) in tetrahydrofuran (7.5 ml) was added at room temperature 1,1′-carbonyl-diimidazole (193 mg, 1.19 mmol). The mixture was allowed to stir for 15 min at room temperature and afterwards for 90 min at 70° C. N-hydroxy-2-((R)-indan-1-ylamino)-4H-benzo[d][1,3]oxazine-6-carboxamidine (Example 130) (240 mg, 0.74 mmol) was added at room temperature. The mixture was allowed to stir for 1 h at room temperature, evaporated to dryness and diluted with acetic acid (10 ml). The reaction mixture was allowed to stir for 2 h at 100° C., evaporated, poured into saturated sodium hydrogen carbonate solution (20 ml) and extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with brine (1×20 ml), dried (magnesium sulfate) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel and crystallization (dichloromethane/hexane) to yield the title compound as white solid (137 mg, 53%). MS (ISP): m/e=347.1 (M+H+); m.p. 138° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=O)[CH3:11].S([CH2:23][N+:24]#[C-])(C1C=CC(C)=CC=1)(=O)=O.CC([O-])(C)C.[K+]>COCCOC.CC(O)(C)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:11])[C:23]#[N:24]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COc1ccc(C(C)=O)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: COCCOC
Product: COc1ccc(C(C)C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2′-chloro-4′-methoxyacetophenone (18.5 g, 0.10 mol) and tosylmethylisocyanide (TOSMIC, 21.5 g, 0.11 mol) in dry 1,2-dimethoxyethane (100 mL) was cooled to −10° C. A solution of t-BuOK (22.4 g, 0.20 mol) in dry t-BuOH (250 mL) was added slowly keeping the temperature below 5° C. The homogeneous orange solution was stirred for 2 h/0° C. and 1 h/25° C. The resulting suspension was evaporated to a slurry. Water (200 mL) was added and extracted with Et2O (3×150 mL). The organic phase was dried (Na2SO4) and the solvent was removed under reduced pressure leaving an orange oil. Yield: 19 g (97%). GCMS: >98%
Reaction SMILES: [CH:1]1([N:4]=[C:5]=[O:6])[CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH:15]=[O:16]>>[CH:1]1([NH:4][C:5](=[O:6])[N:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[F:7])[CH:15]=[O:16])[CH2:3][CH2:2]1
Reactant: O=C=NC1CC1
Reactant: O=CNc1ccccc1F
Product: O=CN(C(=O)NC1CC1)c1ccccc1F
Temperature: 100 °C
Reaction time: 48 h

Procedure:
An equimolar mixture of 1A and 1B in tetrohydrofuran was stirred for 2 days at 100° C. The solvent was evaporated, and the residue was recrystallized from ether to give 1, as a white solid, m.p.: 104°-105° C.
Reaction SMILES: Cl.[CH3:2][CH:3]1[C:8](=O)[CH:7]2[CH2:10][CH2:11][N:4]1[CH2:5][CH2:6]2.Cl.[NH2:13][OH:14].O.O.O.C([O-])(=O)C.[Na+]>CCO>[CH3:2][CH:3]1[C:8](=[N:13][OH:14])[CH:7]2[CH2:10][CH2:11][N:4]1[CH2:5][CH2:6]2
Reactant: NO
Reactant: CC1C(=O)C2CCN1CC2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1C(=NO)C2CCN1CC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.9 %

Procedure:
2-Methylquinuclidin-3-one hydrochloride from Step L (5.3 g, 30.2 mrol, 1 eq), hydroxylamine hydrochloride (2.5 g, 36.4 mmol, 1.2 eq) and sodium acetate trihydrate (12.4 g, 90.9 mmol, 3 eq) are suspended in 70 mL EtOH and stirred at room temperature. After 24 h, the mixture is concentrated in vacuo. The residue is suspended in CHCl3 and the solids are filtered. The solids are rinsed with excess CH3CN. The combined organic washes are concentrated in vacuo to give 4.65 g (100%) of 2-methyl-1-azabicyclo[2.2.2]octan-3-one oxime. MS (ESI) for C8H14N2O m/z 155.2 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:41])[C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([O:20][CH3:21])[C:14]=2[NH:22][C:23]([C:25]2[S:26][CH:27]=[C:28]([CH2:31][C:32]3[N:36]=[C:35](C(Cl)(Cl)Cl)[O:34][N:33]=3)[C:29]=2[Cl:30])=[O:24])=[N:9][CH:10]=1.O>CN(C=O)C>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:41])[C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([O:20][CH3:21])[C:14]=2[NH:22][C:23]([C:25]2[S:26][CH:27]=[C:28]([CH2:31][C:32]3[N:36]=[C:35]([N:2]([CH3:3])[CH3:1])[O:34][N:33]=3)[C:29]=2[Cl:30])=[O:24])=[N:9][CH:10]=1
Reactant: CNC
Reactant: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(Cc2noc(C(Cl)(Cl)Cl)n2)c1Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(Cc2noc(N(C)C)n2)c1Cl
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Dimethylamine (40% aqueous, 0.51 mL, 4.1 mmol) was dissolved in DMF (2 mL) under nitrogen, and N-(5-chloropyridin-2-yl)-2-[((4-((5-trichloromethyl-1,2,4-oxadiazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide (0.151 g, 0.23 mmol) was added. The reaction mixture was stirred for 40 minutes at ambient temperature, then poured into water (40 mL). The aqueous layer was extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with water (3×25 mL), brine (25 mL), dried over magnesium sulfate, concentrated in vacuo, and dried under vacuum. The crude product was purified by flash chromatography on silica gel, eluting with 75% ethyl acetate/hexanes to afford N-(5-chloropyridin-2-yl)-2-[((4-((5-(dimethylamino)-1,2,4-oxadiazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide; NMR (DMSO-d6) 10.9 (br, 1), 9.4 (br, 1), 8.4 (d, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.8 (s, 1), 7.4 (d, 1), 7.2 (d, 1), 3.9 (s, 3), 3.8 (s, 2), 3.0 (s, 6) ppm.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O>C(Cl)(Cl)Cl>[C:15]1([C:13]2[N:1]=[C:2]3[N:6]([CH:12]=2)[C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[S:3]3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Nc1nc2c(s1)CCCC2
Solvent: ClC(Cl)Cl
Product: c1ccc(-c2cn3c4c(sc3n2)CCCC4)cc1

Procedure:
0.1 m. Quantitites of 2-amino-4,5,6,7-tetrahydrobenzothiazole and α-bromoacetophenone in 100 ml. of chloroform are heated at reflux for 2 hours. After cooling, the solid is filtered off and slurried in 1 l. of water containing 40 g. of ammonium acetate. This suspension is heated to boiling over a 2-hour period and allowed to cool. The product is collected, washed with water and dried. The yield of product is 19.8 g. melting at 158°-160° C. and having the formula: ##STR14##
Reaction SMILES: N1C=CN=N1.[Na].[NH:7]1[CH:11]=[N:10][C:9]([SH:12])=[N:8]1.Br[CH2:14][CH2:15][O:16][CH2:17][CH3:18]>C(O)C>[CH2:15]([O:16][CH2:17][CH2:18][S:12][C:9]1[N:10]=[CH:11][NH:7][N:8]=1)[CH3:14]
Reactant: Sc1nc[nH]n1
Reactant: CCOCCBr
Agent: [Na]
Agent: c1c[nH]nn1
Solvent: CCO
Product: CCOCCSc1nc[nH]n1

Procedure:
The novel intermediate triazole compounds used in the above preparation were prepared as follows. To a solution of 11.8 g. sodium in 350 ml. absolute ethanol was added 52.5 g. 1,2,4-triazole-3-thiol. To the resulting solution was added 84 g. 1-bromo-2-ethoxyethane and the resulting solution refluxed for 3 hours. The cooled reaction mixture was filtered, the filtrate was evaporated under reduced pressure to remove solvent, and the residue was dissolved in ether. The resulting solution was filtered, the filtrate was evaporated to remove solvent and the residue distilled under reduced pressure to give 3-(2-ethoxyethylthio)-1,2,4-triazole, b.p. 337°-345° C./0.3-0.5 mm. Elemental analysis satisfactory.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:58])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12](=[O:26])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:15][C:14]=2[OH:25])[CH:9]=[CH:8][C:7]=1[O:27][CH2:28][C:29]1[CH:57]=[CH:56][C:32]2[C:33](=[O:55])[N:34](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[O:35][C:31]=2[CH:30]=1.C(C(C)=O)C(C)C.S(=O)(=O)(O)O.[OH-].[Na+]>O.CO>[CH3:1][O:2][C:3](=[O:58])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12](=[O:26])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:15][C:14]=2[OH:25])[CH:9]=[CH:8][C:7]=1[O:27][CH2:28][C:29]1[CH:57]=[CH:56][C:32]2[C:33]([OH:55])=[N:34][O:35][C:31]=2[CH:30]=1
Reactant: COC(=O)CCc1cc(C(=O)c2ccc(OC3CCCC3)cc2O)ccc1OCc1ccc2c(=O)n(C(c3ccccc3)(c3ccccc3)c3ccccc3)oc2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(=O)CC(C)C
Product: COC(=O)CCc1cc(C(=O)c2ccc(OC3CCCC3)cc2O)ccc1OCc1ccc2c(O)noc2c1
Reaction time: 1 h
Yield: 81 %

Procedure:
300 g of 3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-oxo-2-triphenylmethyl-2,3-dihydro-1,2-benzisoxazol-6-yl)methoxy]phenyl}propionic acid methyl ester was added to a mixture of 1200 mL of methyl isobutyl ketone and 600 mL of methanol. 43.5 mL of sulfuric acid was added dropwise under ice-cooling. This was stirred for 1 hour under water-cooled, and then stirred for 1 hour 30 minutes at room temperature. After adding 1200 mL of water and 200 mL of 20% sodium hydroxide aqueous solution, the result was stirred at room temperature for 30 minutes and solids were filtered to obtain 167 g of 3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-1,2-benzisoxazol-6-yl)methoxy]phenyl}propionic acid methyl ester in the form of a pale yellowish-white solid.
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].Br[C:10]1[CH:11]=[C:12]2[C:16](=[C:17]([Cl:19])[CH:18]=1)[C:15](=[O:20])[N:14]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:24][CH:23]=1)[CH2:13]2.C(Cl)(Cl)Cl.CO>C(NC(C)C)(C)C.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.[Cu]I>[Cl:19][C:17]1[CH:18]=[C:10]([C:3]#[C:2][CH2:1][N:4]2[CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:11]=[C:12]2[C:16]=1[C:15](=[O:20])[N:14]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:24][CH:23]=1)[CH2:13]2
Reactant: C#CCN1CCCC1
Reactant: O=C1c2c(Cl)cc(Br)cc2CN1Cc1ccc(Oc2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CO
Solvent: CC(C)NC(C)C
Solvent: ClC(Cl)Cl
Product: O=C1c2c(Cl)cc(C#CCN3CCCC3)cc2CN1Cc1ccc(Oc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
A mixture of 1-prop-2-ynyl-pyrrolidine (0.024 mL, 0.22 mmol), 5-bromo-7-chloro-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.086 g, 0.20 mmol), PdCl2(PPh3)2 (0.011 g, 0.015 mmol), and CuI (0.0028 g, 0.015 mmol) in diisopropyl amine (4 mL) was stirred at 100° C. for 2 h. Workup and silica gel column chromatography using 10:1 CHCl3-MeOH afforded 7-chloro-2-(4-phenoxy-benzyl)-5-(3-pyrolidin-1-yl-prop-1-ynyl)-2,3-dihydro-isoindol-1-one (0.061 g, 66%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.83 (m, 4H), 2.65 (m, 4H), 3.64 (s, 2H), 4.23 (s, 2H), 4.76 (s, 2H), 6.93-7.38 (m, 10H), 7.43 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:14]([N:27]1[CH2:30][CH:29](OS(C)(=O)=O)[CH2:28]1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:29]2[CH2:30][N:27]([CH:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Product: CC(C)(C)OC(=O)N1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1

Procedure:
The title compound is synthesized by condensation of piperazine-1-carboxylic acid tert-butyl ester and Methanesulfonic acid 1-benzhydryl-azetidin-3-yl ester (commercially available from Fluorochem Ltd) analogously to the preparation of Intermediate 149.2 as a white solid; ES-MS: M+=408.3; HPLC: AtRet=3.84 min.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH:15]=[CH2:16])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH:25]([C:27]1[N:28]=[CH:29][N:30]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:31]=1)=[O:26].C(N(CC)CC)C.O1CCCC1>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH2:15][CH2:16][C:25]([C:27]3[N:28]=[CH:29][N:30]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:31]=3)=[O:26])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CCOC(=O)Cn1cnc(C=O)c1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1cnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)c1
Yield: 76.8 %

Procedure:
A mixture of 4-[4-(cyclopropylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (0.77 g), ethyl (4-formyl-1H-imidazol-1-yl)acetate (0.45 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (60 mg), triethylamine (0.12 mL), tetrahydrofuran (4 mL) and ethanol (4 mL) was stirred with heating under reflux for 1 hr. The reaction mixture was concentrated, and the residue was subjected to basic silica gel column chromatography, and the title compound (0.90 g, yield 77%) was obtained as a yellow oil from a fraction eluted with ethyl acetate. MS: 531 (Me).
Reaction SMILES: [C:1]1([CH:7]2[S:12][CH2:11][CH2:10][CH2:9][S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li][CH2:14][CH2:15][CH2:16][CH3:17].[CH2:18]([Ge:20]([CH2:23][CH3:24])(Cl)Cl)[CH3:19]>C1COCC1.CCCCCC>[CH2:18]([Ge:20]([CH2:23][CH3:24])([C:17]1([C:16]2[CH:6]=[CH:1][CH:2]=[CH:14][CH:15]=2)[S:12][CH2:11][CH2:10][CH2:9][S:8]1)[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[S:8][CH2:9][CH2:10][CH2:11][S:12]1)[CH3:19]
Reactant: c1ccc(C2SCCCS2)cc1
Reactant: [Li]CCCC
Reactant: CC[Ge](Cl)(Cl)CC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC[Ge](CC)(C1(c2ccccc2)SCCCS1)C1(c2ccccc2)SCCCS1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.85 g (9.42 mmol) 2 phenyl-1,3-dithian was placed in a dry 50-ml three-necked flask under argon and dissolved in 28 ml anhydrous THF. 3.99 ml 2.36 M BuLi solution in hexane was added dropwise at 0° C. and the reaction solution stirred for 2 h at 0° C. 0.83 mg (3.93 mmol) diethyldichlorogermanium dissolved in 8 ml anhydrous THF was added slowly dropwise at 0° C. to the reaction mixture and then stirred for an additional 2 h at 0° C. To complete the reaction a further solution of 2-phenyl-2-lithium-1,3-dithian (2.36 mmol) was prepared as described above and added dropwise at 0° C. to the reaction solution, which was then stirred for 18 h at 6° C. The reaction was quenched by the addition of 20 ml water and the raw product extracted with diethyl ether (3×30 ml). The combined organic phases were dried with Na2SO4 and the solvent drawn off at the rotary evaporator. The residue was separated off by column chromatography (petroleum ether: ethyl acetate=20:1). 1.42 g (70% of the theoretical value) diethylbis(2-phenyl-1,3-dithian-2-yl)germanium was obtained as colorless solid. DC (petroleum ether: ethyl acetate=20:1): Rf=0.51
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][C:21](=[CH:23][C:24]#[N:25])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]3[N:37]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[CH:38]=[CH:39][C:32]=23)[CH:28]=[N:27]1.C(#N)C.N12CCCN=C1CCCCC2>>[Si:1]([O:18][CH:19]1[CH2:22][C:21]([CH2:23][C:24]#[N:25])([N:26]2[CH:30]=[C:29]([C:31]3[CH:36]=[CH:35][N:34]=[C:33]4[N:37]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[CH:38]=[CH:39][C:32]=34)[CH:28]=[N:27]2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ccnc21
Reactant: CC(C)(C)[Si](OC1CC(=CC#N)C1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)[Si](OC1CC(CC#N)(n2cc(-c3ccnc4c3ccn4COCC[Si](C)(C)C)cn2)C1)(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of (3-{[tert-butyl(diphenyl)silyl]oxy}cyclobutylidene)acetonitrile (4.0 g, 8.7 mmol, from Step 4 of Example 1a) and 4-(1H-pyrazol-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine (1.50 g, 4.77 mmol, US 20090181959) in acetonitrile (10 mL, 200 mmol) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.68 mL, 4.6 mmol). The reaction was stirred overnight. A further portion of 1,8-diazabicyclo[5.4.0]undec-7-ene (0.7 mL, 5 mmol) was added and the reaction was allowed to continue for an additional 72 hours. Acetonitrile was removed in vacuo. Flash chromatography on silica gel, eluting with 0%-30% EtOAc/Hexanes, was used to purify product, which was obtained as a mixture of diastereomers (2 g, 60%). 1H NMR (300 MHz, CDCl3) δ 8.33 (d, J=5.0 Hz, 1H major), 8.29 (d, J=5.0 Hz, 1H minor), 8.06 (s, 1H major), 8.03 (s, 1H major), 8.00 (s, 1H minor), 7.93 (s, 1H minor), 7.70-7.31 (m, 10H major and 10H minor), 7.19 (d, J=5.0 Hz, 1H major), 7.11 (d, J=5.0 Hz, 1H minor), 6.74 (d, J=3.6 Hz, 1H major), 6.63 (d, J=3.7 Hz, 1H minor), 5.71 (s, 2H major), 5.69 (s, 2H minor), 4.49-4.39 (m, 1H minor), 4.33 (tt, J=7.0, 7.0 Hz, 1H major), 3.67-3.45 (m, 2H major and 2H minor), 3.22 (s, 2H minor), 3.11-2.95 (m, 2H minor), 2.92-2.77 (m, 6H major), 2.65-2.50 (m, 2H minor), 1.08 (s, 9H minor), 1.03 (s, 9H major), 0.98-0.80 (m, 2H major and 2H minor), −0.06 (s, 9H major), −0.08 (s, 9H minor); LCMS (M+H)+: 662.1.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12]>>[OH:15][CH:10]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]#[N:9]
Reactant: CC(C)(C)C=O
Reactant: N#CCc1ccccc1
Product: CC(C)(C)C(O)C(C#N)c1ccccc1
Yield: 87 %

Procedure:
Reaction of phenylacetonitrile and pivalaldehyde on a 30 mmol scale according to the procedure in Example 1, and recrystallization from toluene/hexane gave 5.34 g of the desired anti-aldol product (87%), m.p.: 70.7-71.2° C. NMR (1H, 13C), IR, and Mass spectra were consistent with the assigned structure. Analysis: Calculated for C13H17NO: C, 76.81; H, 8.42; N, 6.89. Found: C, 76.80; H, 8.43; N, 6.83.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14]Br)[CH:9]=2)=[CH:6][N:7]=1.[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[C:29]([F:31])[CH:30]=1)[C@@H:27]([NH2:32])[CH2:26][CH2:25]2.C(N(C(C)C)CC)(C)C>C(#N)C>[NH2:1][C:2]1[C:3]([C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:32][CH:27]3[C:28]4[C:24](=[CH:23][C:22]([F:21])=[CH:30][C:29]=4[F:31])[CH2:25][CH2:26]3)[CH:9]=2)=[CH:6][N:7]=1
Reactant: N[C@H]1CCc2cc(F)cc(F)c21
Reactant: CCNC(=O)c1nc(-c2cccc(CBr)c2)cnc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCNC(=O)c1nc(-c2cccc(CNC3CCc4cc(F)cc(F)c43)c2)cnc1N
Reaction time: 8 h

Procedure:
The 3-Amino-6-[3-(bromomethyl)phenyl]-N-ethylpyrazine-2-carboxamide (100 mg, 1.0 eq) was dissolved in acetonitrile (5 mL) and treated with [(1S)-5,7-difluoro-2,3-dihydro-1H-inden-1-yl]amine (151 mg, 3.0 eq), diisopropylethylamine (62 mg, 1.6 eq) at ambient temperature. After being stirred for 8 h, the white suspension was concentrated in vacuo and purified by flash column chromatography to give the title compound as colorless oil, which was dissolved in ethyl acetate (10 mL) and treated 1M HCl in ether. The resulting precipitate was filtered, washed with ether (2×2mL), and dried to afford 42mg (12% yield) of 3-amino-6-(3-{[(5,7-difluoro-2,3-dihydro-1H-inden-1-yl)amino]methyl}phenyl)-N-ethylpyrazine-2-carboxamide hydrochloride as a yellow solid: 1H NMR (400 MHz, CD3OD): δ 8.71 (s, 1H), 8.22 (s, 1H), 8.13 (d, 1H), 7.57 (t, 1H), 7.51 (m, 1H), 7.06 (m, 1H), 6.98 (m, 1H), 5.08 (m, 1H), 4.38 (q, 2H), 3.45 (m, 2H), 3.39 (m, 1H), 3.05 (m, 1H), 2.84 (m, 1H), 2.53 (m, 1H); MS (FI) for C23H23NSOF2: 424.16 (MH+).