Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]12[CH2:9][C@@H:5]([C:6]1([CH3:8])[CH3:7])[CH2:4][C@@H:3](/[CH:10]=[CH:11]\[CH:12]([CH:14]1OCC[O:15]1)[CH3:13])[C@H:2]2[CH3:19].Cl>C1COCC1>[CH3:13]/[C:12](=[CH:11]\[CH2:10][C@H:3]1[CH2:4][C@H:5]2[CH2:9][C@H:1]([C:6]2([CH3:8])[CH3:7])[C@@H:2]1[CH3:19])/[CH:14]=[O:15]
Reactant: CC(/C=C\[C@@H]1C[C@H]2C[C@@H]([C@@H]1C)C2(C)C)C1OCCO1
Agent: Cl
Solvent: C1CCOC1
Product: C/C(C=O)=C\C[C@H]1C[C@H]2C[C@@H]([C@@H]1C)C2(C)C
Temperature: 25 °C
Reaction time: 96 h
Yield: 69.5 %

Procedure:
A mixture of 18.1 g (68.6 mmol) of the dioxolane of Example 8, 250 ml of THF and 120 ml of 4N HCl is stirred for 4 days at room temperature (monitoring by gas chromatography) and is then poured into 250 ml of ice-cold water. After extraction with 3×200 ml of ethyl ether, drying (MgSO4) and evaporation of the solvents there are obtained 19 g of crude oil which is purified by flash chromatography on silica (eluent: petroleum ether+1% ethyl ether) to give 10.5 g of (E)-2-methyl-4-[(1S,2R,3S,5S)-3-pinanyl]-2-butenal (yield=70%).
Reaction SMILES: [OH2:1].[ClH:2].[NH2:3][C@H:4]([C:13]([NH:15][C@@H:16]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:22])[CH2:17][CH2:18][S:19][CH3:20])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.OO>C(O)(=O)C>[OH2:12].[ClH:2].[NH2:3][C@H:4]([C:13]([NH:15][C@@H:16]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:22])[CH2:17][CH2:18][S:19](=[O:1])[CH3:20])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[OH2:12].[OH2:12].[NH2:3][C@H:4]([C:13]([NH:15][C@@H:16]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:22])[CH2:17][CH2:18][S:19](=[O:1])[CH3:20])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[ClH:2]
Reactant: CSCC[C@@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)NCCCc1ccccc1
Agent: Cl
Agent: OO
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)CC[C@@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)NCCCc1ccccc1
Yield: 244.2 %

Procedure:
A solution of L-tyrosyl-N-(3-phenylpropyl)-D-methioninamide monohydrochloride monohydrate (219 mg.) and aqueous hydrogen peroxide (3%, 640 μl) in acetic acid (5 ml.) was stirred at room temperature for two and one quarter hours, then concentrated under vacuum. The residue was reevaporated under vacuum once from ethyl acetate and three times from ether. A solution of the residue in water was filtered and lyophilized, affording as an amorphous white solid L-tyrosyl-N-(3-phenylpropyl)-D-methioninamide S-oxide monohydrochloride sesquihydrate (225 mg.), whose free base is the compound of Formula II wherein Q is Met(O), R1, R2 and R5 are each hydrogen and R4 is (CH2)nY wherein n is 3 and Y is phenyl.
Reaction SMILES: O1CCC(C2N=C3C=CC=C(N)N3N=2)[CH2:2]1.[Br:16][C:17]1[N:31]=[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]([NH:25][C@@H:26]3[CH2:30][CH2:29][O:28][CH2:27]3)[N:19]2[N:18]=1.[H-].[Na+].IC>COCCOC.C(OCC)(=O)C>[Br:16][C:17]1[N:31]=[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]([N:25]([CH3:2])[C@@H:26]3[CH2:30][CH2:29][O:28][CH2:27]3)[N:19]2[N:18]=1
Reactant: Nc1cccc2nc(C3CCOC3)nn12
Reactant: Brc1nc2cccc(N[C@@H]3CCOC3)n2n1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CN(c1cccc2nc(Br)nn12)[C@@H]1CCOC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 71.2 %

Procedure:
(R)-2-Bromo-N-methyl-N-(tetrahydrofuran-3-yl-[1,2,4]triazolo[1,5-a]pyridin-5-amine. (R)-2-Bromo-N-(tetrahydrofuran-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-amine (500.0 mg, 1.766 mmol) was suspended in 1,2-dimethoxyethane (8.83 mL) and cooled to 0° C. The reaction was purged with nitrogen followed by the addition of sodium hydride (89.0 mg, 3.53 mmol, 95%). The mixture was allowed to stir for 10 min. Iodomethane (330.0 μL, 5.30 mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature and stir for 16 h. Ethyl acetate was added to the reaction and allowed to stir for 1 min followed by an extraction with ethyl acetate and water. The organics were washed with brine and dried with magnesium sulfate. Organic volatiles were removed under reduced pressure and purified using silica gel chromatography on an Emrys Biotage SP1 (10-100% ethyl acetate in hexanes) over 1.2 L. The desired fractions were combined and organic volatiles removed under reduced pressure to afford (R)-2-bromo-N-methyl-N-(tetrahydrofuran-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-amine (373.8 mg, 1.258 mmol, 71.2% yield). MS (ESI) m/z 297.1 [M]+, 299.1 [M+2]+.
Reaction SMILES: [C:1](=[S:3])=[S:2].[OH-].[K+:5].[CH2:6]([OH:10])[CH2:7][CH2:8][CH3:9]>>[C:1](=[S:3])([O:10][CH2:6][CH2:7][CH2:8][CH3:9])[S-:2].[K+:5]
Reactant: CCCCO
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Product: CCCCOC(=S)[S-]
Reaction time: 2 h

Procedure:
380 g of carbon disulfide were added at 20°-30° C to a mixture of 280 g of potassium hydroxide pellets and 2.5 liters of n-butanol and after stirring the mixture for 2 hours, it was vacuum filtered The precipitate was washed with butanol and then ether to obtain 640 l g of potassium O-n-butyl dithiocarbonate melting at ≈ 260° C (dec). A mixture of 190 g of the latter product, 1 liter of benzene and 500 ml of methyl iodide was refluxed for 10 hours and then was filtered. The filtrate was evaporated to dryness and the residue was rectified to obtain 156 g of methyl O-n-butyl dithiocarbonate with a boiling point of 74° C at 0.5 mm Hg.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[Li]C(C)(C)C.[CH3:19][N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1>>[OH:26][C:23]1([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][N:8]3[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=2)[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]1
Reactant: CC(C)n1ccc2ccc(Br)cc21
Reactant: CN1CCC(=O)CC1
Agent: [Li]C(C)(C)C
Product: CC(C)n1ccc2ccc(C3(O)CCN(C)CC3)cc21
Temperature: -20 °C
Reaction time: 0.12 h
Yield: 44.1 %

Procedure:
1.5 ml of a solution of 6-bromo-1-isoproylindole (240 mg, 1 mmol) was cooled to −78 ° C., 1.7M tBuLi (1.47 ml, 2.5 mmol) was added and the mixture stirred for 7 mins. N-Methyl-4-piperidone (340.8 mg, 3 mmol) was then added and the mixture stirred for a further 10 mins. The reaction mixture was then warmed up to −20° C. and quenched with water and dichloromethane. The organic layer was washed with water, dried over anhydrous Na2SO4, concentrated in vacuo and the residue purified by column chromatography on silica gel, eluting with 2% 2M ammonia/methanol in dichloromethane to give the title product (120 mg, 44%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([C:10]3([C:13]([NH:15][C:16]4[N:21]=[C:20]([C:22]5[CH:23]=[N:24][C:25]([O:28]C)=[CH:26][CH:27]=5)[CH:19]=[C:18]([CH3:30])[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Si](I)(C)(C)C>CO>[O:1]1[C:5]2[CH:6]=[C:7]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([CH3:30])[CH:19]=[C:20]([C:22]5[CH:27]=[CH:26][C:25](=[O:28])[NH:24][CH:23]=5)[N:21]=4)=[O:14])[CH2:12][CH2:11]3)[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2cc(C)cc(NC(=O)C3(c4ccc5c(c4)OCC5)CC3)n2)cn1
Agent: C[Si](C)(C)I
Solvent: CO
Product: Cc1cc(NC(=O)C2(c3ccc4c(c3)OCC4)CC2)nc(-c2ccc(=O)[nH]c2)c1
Temperature: 55 °C
Reaction time: 7 h
Yield: 42.1 %

Procedure:
To a slurry of 1-(2,3-dihydrobenzofuran-6-yl)-N-(6′-methoxy-4-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (20 mg, 0.049 mmol) in acetonitrilee (1.5 mL) was added TMS-I (28.4 μL, 0.19 mmol) and the mixture was stirred at 55° C. for 7 h. The reaction was diluted with methanol (1.0 mL) and stirred at room temperature for 2 h. The resulting mixture was concentrated under vacuum, and taken into ethyl acetate (10 mL). The organic solution was washed with sodium bisulphate (2×2 ml), water (2×3 mL), dried over sodium sulphate and concentrated under vacuum. The solid was stirred with methanol (1.0 mL) at 40° C. for 10 min and collected by filtration, washed with methanol (1.0 mL) and dried under vacuum to yield the product (8.0 mg, 41%). ESI-MS m/z calc. 387.4. found 388.2 (M+1)+. Retention time 1.44 minutes.
Reaction SMILES: [S:1]([NH:5][C:6](=[NH:11])[CH2:7][CH2:8][S:9][CH3:10])(=[O:4])(=[O:3])[NH2:2].[H-].[Na+].C1(O[C:21]#[N:22])C=CC=CC=1>O1CCCC1.C(OCC)C>[NH2:22][C:21]1[NH:2][S:1](=[O:3])(=[O:4])[N:5]=[C:6]([CH2:7][CH2:8][S:9][CH3:10])[N:11]=1
Reactant: N#COc1ccccc1
Reactant: CSCCC(=N)NS(N)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CSCCC1=NS(=O)(=O)NC(N)=N1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a solution of N-sulfamyl-3-(methylthio)propionamidine (4.9 gm, 25 mmol) in dry tetrahydrofuran (75 ml) under nitrogen there was added 60% sodium hydride in mineral oil (1.0 gm, 25 mmol). This mixture was warmed at 60° C. for 1/2 hour as a copious precipitate formed. To this suspension, a solution of phenylcyanate (3.0 gm, 25 mmol) in dry THF was added dropwise giving a homogeneous solution. After 1/2 hour, additional 60% sodium hydride in mineral oil (1.0 gm, 25 mmol) was added and the resultant solution warmed at 50° C. for 20 hours. The reaction mixture was diluted with diethyl ether and the precipitate collected by filtration. This precipitate was dissolved in water, acidified with dilute HCl, filtered and the aqueous solution extracted with 3% methanol/chloroform and then the water removed under vacuum. The residue was extracted with acetonitrile, filtered, and the extract evaporated to give crude product (2.0 gm). This material was chromatographed on silica gel and eluted with 5- 10% methanol/chloroform. Upon concentration of the appropriate fractions, the product crystallized, (1.4 gm), m.p. 243°-246° C.
Reaction SMILES: [H-].[Na+].C1COCC1.[N:8]1([CH2:14][CH2:15][CH2:16][OH:17])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[CH2:18]([C:20]1[N:21]=[N+:22]([O-:31])[C:23]2[CH:29]=[CH:28][C:27](F)=[CH:26][C:24]=2[N:25]=1)[CH3:19]>O>[CH2:18]([C:20]1[N:21]=[N+:22]([O-:31])[C:23]2[CH:29]=[CH:28][C:27]([O:17][CH2:16][CH2:15][CH2:14][N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:26][C:24]=2[N:25]=1)[CH3:19]
Reactant: CCc1nc2cc(F)ccc2[n+]([O-])n1
Reactant: OCCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc2cc(OCCCN3CCOCC3)ccc2[n+]([O-])n1
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 52.1 %

Procedure:
NaH (60% dispersion in oil, 310 mg, 7.75 mmol) was added to dry THF (10 mL) and stirred at 20° C. for 20 min prior to the addition of 3-(4-morpholinyl)propanol (676 mg, 4.66 mmol). The mixture was stirred for 30 min, fluoride 28 (300 mg, 1.55 mmol) added and the resulting solution stirred at 20° C. for 2.5 h under N2. Water was added and the solution extracted with DCM (4×30 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by column chromatography, eluting with a gradient (0-5%) MeOH/DCM to give 1-oxide 31 (257 mg, 52%) as a pale yellow solid, mp 108-111° C.; 1H NMR δ 8.33 (d, J=9.3 Hz, 1 H, H-8), 7.21-7.26 (m, 2 H, H-7 and H-5), 4.22 (t, J=6.4 Hz, 2 H, CH2), 3.73 (t, J=4.6 Hz, 4 H, 2×CH2O), 3.00 (q, J=7.6 Hz, 2 H, CH2), 2.55 (t, J=7.0 Hz, 2 H, CH2), 2.48 (t, J=4.6 Hz, 4 H, 2×CH2N), 2.06 (m, 2 H, CH2), 1.43 (t, J=7.6 Hz, 3 H, CH3); 13C NMR δ 168.7, 164.6, 150.3, 128.4, 123.1, 121.6, 106.3, 67.3 (2), 66.9, 55.1, 53.7 (2), 30.7, 26.0, 12.2. Anal. Calcd for C16H22N4O3: C, 60.4; H, 7.0; N, 17.6. Found: C, 60.4; H, 7.0; N, 17.4%.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C@@H:5]1[CH2:9][S:8][C:7]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=3[NH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:6]1.O1CCCC1.[BH4-].[Li+].O>O1CCCC1>[Cl:19][C:15]1[CH:16]=[C:17]2[C:12](=[C:13]([NH:20][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:14]=1)[NH:11][C:10]([C:7]1[S:8][CH2:9][C@@H:5]([CH2:4][CH2:3][OH:2])[N:6]=1)=[CH:18]2
Reactant: COC(=O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCC[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Reaction time: 1 h
Yield: 100.1 %

Procedure:
The compound (550 mg, 1.4 mmol) prepared in Example 26 was dissolved in tetrahydrofuran (50 ml). 1 M lithium borohydride tetrahydrofuran solution (2.11 ml, 2.11 mmol) was added thereto, and the mixture was stirred for 1 h while raising the reaction temperature from −60° C. to 0° C. After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and separated by column chromatography to give the title compound (510 mg, Yield 100%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[O:8])=[N:4][CH:3]=1.[CH2:20]([Mg]Br)[CH3:21]>C1COCC1.O.CCOC(C)=O>[Br:1][C:2]1[S:6][C:5]([C:7]([C@H:9]2[CH2:10][CH2:11][C@H:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14]2)([OH:8])[CH2:20][CH3:21])=[N:4][CH:3]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](C(=O)c2ncc(Br)s2)CC1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)[C@H]1CC[C@H](C(O)(CC)c2ncc(Br)s2)CC1
Reaction time: 1 h

Procedure:
A solution of ethyl trans-4-[(5-bromo-1,3-thiazol-2-yl)carbonyl]cyclohexanecarboxylate (500 mg, 1.444 mmol) in THF (6 mL) was cooled to −60° C. Ethylmagnesium bromide (3.0 M in THF, 481 μl, 1.444 mmol) was added dropwise and the resulting mixture was stirred for 1 hour. The mixture was diluted with water and EtOAc and the layers were separated. The organic layer was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (5-80% EtOAc/Hexanes) to afford racemic-trans-ethyl 4-[1-(5-bromo-1,3-thiazol-2-yl)-1-hydroxypropyl]cyclohexanecarboxylate as a yellow solid. The racemic mixture was purified by super critical fluid chromatography (Chiral Technology AD-H 2.1×25 cm, 5 uM, 30%/70% Methanol/CO2 with a 14 minute run time) to afford enantiomer 1 and enantiomer 2 as clear oils. Enantiomer 1 (retention time=7.24 min): MS ESI calc'd. for C12H22BrNO3S [M+H]+ 376, 378. found 376, 378. 1H NMR (500 MHz, DMSO-d6) δ 7.75 (s, 1H), 5.62 (s, 1H), 3.99 (q, J=7.0, 2H), 2.20-0.80 (m, 15H), 0.68 (t, J=6.9, 3H). Enantiomer 2 (retention time=10.18 min): MS ESI calcd for C17H26BrNO3S [M+H]+ 376, 378. found 376, 378. 1H NMR (500 MHz, DMSO-d6) δ 7.75 (s, 1H), 5.62 (s, 1H), 3.99 (q, J=7.0, 2H), 2.20-0.8 (m, 15H), 0.68 (t, J=6.9, 3H).
Reaction SMILES: [C:1](O)(=O)C.O.[CH:6](=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>C=O>[CH2:1]=[C:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:6]=[O:14]
Reactant: CC(=O)O
Reactant: CCCCCCCC=O
Agent: C=O
Solvent: O
Product: C=C(C=O)CCCCCC
Temperature: 50 °C

Procedure:
A 5-liter flask fitted with an overhead stirrer and condenser was charged with di-N-butyl amine (61 g, 0.47 mol) and acetic acid (56 g, 0.9 mol). Roughly 900 ml of 37% formaldehyde solution in water (351 g formaldehyde, 11.7 mol) was then added and the resulting solution was heated to 50° C. with stirring. After this temperature was reached octanal (1000 g, 7.0 mol) was fed in over about 2 h. A slight exotherm was noticed during the feed. Monitoring by GC showed the consumption of octanal and the production of 2-methylene octanal, finally reaching roughly 95% conversion after the addition was complete. The reaction mixture was allowed to cool to room temperature, poured into a separatory funnel, and washed once with 5% HCl solution. The organic layer was then washed once with saturated sodium bicarbonate, then taken directly on to the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].[Br:23][C:24]1[CH:25]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1.O>C1COCC1>[Br:23][C:24]1[CH:25]=[C:26]([S:30]([N:11]2[C:10](=[O:13])[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:12]2)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1n(S(=O)(=O)c2cccc(Br)c2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
360 mg (1.17 mmol) of the compound from Example 5A were dissolved in 10 ml of THF and, at 0° C., 94 mg (2.34 mmol) of sodium hydride (60% strength dispersion in mineral oil) were added. After 20 min, 299 mg (1.17 mmol) of 3-bromobenzenesulfonyl chloride were added, and the mixture was stirred at 0° C. for 1 h. For work-up, 10 ml of water were added and the mixture was extracted twice with in each case 15 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 8:1, then 1:1). This gave 181 mg (27% of theory) of the target compound.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:21]=[C:20]([C:22]#[N:23])[N:19]([CH3:24])[N:18]=3)=[CH:13][CH:12]=2)[CH2:6]1)=[N+:2]=[N-:3].[CH:25]12CC(C=C1)C=[CH:26]2>O1CCOCC1>[CH3:24][N:19]1[C:20]([C:22]#[N:23])=[CH:21][C:17]([C:14]2[CH:15]=[CH:16][C:11]([N:7]3[CH2:6][C@H:5]([CH2:4][N:1]4[CH:26]=[CH:25][N:3]=[N:2]4)[O:9][C:8]3=[O:10])=[CH:12][CH:13]=2)=[N:18]1
Reactant: Cn1nc(-c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2)cc1C#N
Reactant: C1=CC2C=CC1C2
Solvent: C1COCCO1
Product: Cn1nc(-c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2)cc1C#N
Temperature: 90 °C
Yield: 50.8 %

Procedure:
3-{4-[(5R)-5-(Azidomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-1-methyl-1H-pyrazole-5-carbonitrile (Intermediate 14, 00 mg, 0.62 mmol), bicyclo[2.2.1]hepta-2,5-diene (0.70 ml, 6.50 mmol) and dioxane (5 ml) were combined and warmed to 90° C. for 8 hours. The mixture was evaporated and purified by chromatography on silica gel eluting with ethyl acetate to give the title compound as an off-white solid (110 mg).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)=[O:4].[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[CH2:20][NH:21][CH3:22]>O1CCOCC1>[Br:11][C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][N:21]([CH2:20][C:14]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[Cl:12])[CH3:22])[CH:10]=[CH:9][CH:8]=1
Reactant: CNCc1ccc(Cl)cc1Cl
Reactant: O=C(CBr)c1cccc(Br)c1
Solvent: C1COCCO1
Product: CN(CC(=O)c1cccc(Br)c1)Cc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 1 L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-bromo-1-(3-bromophenyl)ethanone (55 g, 199.28 mmol, 1.00 equiv) in 1,4-dioxane (300 mL), TEA (40 g, 396.04 mmol, 1.99 equiv), and (2,4-dichlorophenyl)-N-methylmethanamine (38 g, 201.06 mmol, 1.01 equiv). The resulting solution was stirred for 2 h at 25° C. in an oil bath. The solids were filtered out and the filtrate was used without any further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:26])[C:11]3[C:16]([C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][C:14]([O:24]C)=[CH:13][CH:12]=3)[CH:5]=[CH:6][C:7]=1[CH3:8].FC1C=C(C2C3C(=CC=C(OC)C=3)C(=O)C=2C2C=NC=CC=2)C=C(F)C=1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:26])[C:11]3[C:16]([C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][C:14]([OH:24])=[CH:13][CH:12]=3)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COc1ccc2c(c1)C(c1ccccc1)=C(c1ccc(C)c(F)c1)C2=O
Agent: COc1ccc2c(c1)C(c1cc(F)cc(F)c1)=C(c1cccnc1)C2=O
Product: Cc1ccc(C2=C(c3ccccc3)c3cc(O)ccc3C2=O)cc1F
Yield: 88 %

Procedure:
The procedure of Step 5 of Example 128 was repeated except for using 2-(3-fluoro-4-methylphenyl)-5-methoxy-3-phenyl-1H-inden-1-one obtained in Step 1 as a starting material instead of 3-(3,5-difluorophenyl)-5-methoxy-2-(pyridin-3-yl)-1H-inden-1-one to obtain the title compound (88%).
Reaction SMILES: [C:1]([O:4][CH:5](P(OCC)(OCC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[Li+].[Cl-].CN(C)C(N(C)C)=N.[CH3:29][Si:30]([CH3:61])([CH3:60])[CH2:31][CH2:32][O:33][CH2:34][N:35]([CH2:52][O:53][CH2:54][CH2:55][Si:56]([CH3:59])([CH3:58])[CH3:57])[C:36]1[N:41]2[N:42]=[CH:43][CH:44]=[C:40]2[N:39]=[C:38]([CH:45]2[CH2:50][CH2:49][C:48](=O)[CH2:47][CH2:46]2)[CH:37]=1>C1COCC1.C(Cl)Cl>[C:1]([O:4][C:5](=[C:48]1[CH2:49][CH2:50][CH:45]([C:38]2[CH:37]=[C:36]([N:35]([CH2:52][O:53][CH2:54][CH2:55][Si:56]([CH3:59])([CH3:58])[CH3:57])[CH2:34][O:33][CH2:32][CH2:31][Si:30]([CH3:61])([CH3:29])[CH3:60])[N:41]3[N:42]=[CH:43][CH:44]=[C:40]3[N:39]=2)[CH2:46][CH2:47]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(OC(C)=O)P(=O)(OCC)OCC
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(=O)CC2)nc2ccnn12
Agent: CN(C)C(=N)N(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)C(OC(C)=O)=C1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a 100 mL roundbottom flask was charged ethyl 2-acetoxy-2-(diethoxyphosphoryl)acetate (1121 mmol, 3.16 g), LiCl (11.21 mmol, 475 mg), and THF (25 mL). The flask was then flushed with argon, sealed, and cooled to −78° C. in a dry ice/IPA bath. Added dropwise to this solution was a solution of 1,1,3,3-tetramethylguanidine (11.21 mmol. 1.41 g) in THF (5 mL). The resulting solution was allowed to stir at −78° C. for 30 minutes. At 30 minutes, 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone (5.09 mmol, 2.50 g) was added in THF (3 mL). The reaction was then allowed to slowly warm to room temperature and then stirred for 48 hours. After 48 hours, the reaction was diluted with DCM (100 mL) and washed with H2O (50 mL). The organic layer was collected, dried over Na2SO4, and reduced in vacuo. The resulting residue was purified via flash chromatography to yield the title compound.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH:16]=[CH:15]3)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)CCC>CN(C)C=O.[Cu](I)I.[CH2-]C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd+]>[NH:17]1[C:18]2[C:14](=[CH:13][C:12]([NH:11][C:8]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:3]=[C:2]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=5)[S:10][C:9]=34)=[CH:20][CH:19]=2)[CH:15]=[CH:16]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Brc1cc2nccc(Nc3ccc4[nH]ccc4c3)c2s1
Agent: Cl[Pd+]
Agent: I[Cu]I
Agent: [CH2-]c1ccccc1
Solvent: CN(C)C=O
Product: c1ccc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4)c3s2)nc1
Temperature: 90 °C
Yield: 30.5 %

Procedure:
In a sealed tube (2-bromo-thieno[3,2-b]pyridin-7-yl)-(1H-indol-5-yl)-amine (150 mg, 0.29 mmol) and 2-(tributylstannyl)pyridine (118 mg, 1.1 mmol) were combined in 3 mL of dimethylformamide along with copper iodide (3 mg, 0.015 mmol). Nitrogen was bubbled through the solution and trans-benzyl(chloro)bis-(triphenylphosphine)palladium(II) (33 mg, 0.044 mmol) was added, the tube was sealed and heated to 90° C. After 14 hours the solution was cooled and concentrated to dryness. Chromatography on 15 g of silica gel with CH2Cl2/MeOH (5-20%) afforded 30.3 mg (28%) of,the title compound. LC-MS: 343 (MH+); HPLC RT: 3.94 minutes.