Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[SH:29].CS(C)=O>O>[CH2:1]([O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]2[S:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N:22]=2)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: Nc1ccccc1S
Reactant: CCCCCCCCCCCCOc1ccc(C=O)cc1
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCCCCCOc1ccc(-c2nc3ccccc3s2)cc1
Yield: 45.6 %

Procedure:
A solution of 4-dodecyloxybenzaldehyde (37.12 g, 0.128 mol), 2-aminobenzenethiol (16 g, 0.128 mol) and dimethylsulfoxide acid (200 cm3) was heated under reflux for 24 hours. The cooled solution was added to water and extracted into dichloromethane (3×50 cm3). The combined organic layers were dried (MgSO4), filtered and the filtrate evaporated down under reduced pressure. The solid residue was recrystallised from ethanol to give 23.1 g (45.7%) of the desired product.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[NH:17][C:16]3[CH2:15][CH2:14][NH:13][C:12](=[O:18])[C:11]=3[CH:10]=2)O1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.Br[C:55]1[CH:56]=[CH:57][CH:58]=[C:59]2[C:64]=1[N:63]=[C:62]([NH:65][C:66]([CH3:69])([CH3:68])[CH3:67])[N:61]=[CH:60]2>O1CCOCC1.O.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.[Pd].[Pd]>[C:66]([NH:65][C:62]1[N:61]=[CH:60][C:59]2[C:64](=[C:55]([C:9]3[NH:17][C:16]4[CH2:15][CH2:14][NH:13][C:12](=[O:18])[C:11]=4[CH:10]=3)[CH:56]=[CH:57][CH:58]=2)[N:63]=1)([CH3:69])([CH3:67])[CH3:68]
Reactant: CC1(C)OB(c2cc3c([nH]2)CCNC3=O)OC1(C)C
Reactant: CC(C)(C)Nc1ncc2cccc(Br)c2n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)Nc1ncc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1
Temperature: 110 °C
Yield: 55.2 %

Procedure:
8-Bromo-2-chloroquinazoline (D-L Chiral Chemicals, LLC, Princeton, N.J.) (200 mg, 0.82 mmol) was treated with DMF (2.0 mL) and 2-methylpropan-2-amine (Aldrich Chemical Company, 0.44 mL, 4.11 mmol) and stirred at RT overnight (17 h). The reaction mixture was treated with water, extracted with EtOAc (30 mL), washed with brine (2×), dried over MgSO4, filtered and concentrated. The crude residue was purified on the ISCO Combiflash RF (12 g Thomson SingleStep column, using a gradient of 0-50% EtOAc in hexanes) affording 8-bromo-N-(tert-butyl)quinazolin-2-amine (374a) (94 mg, 0.34 mmol, 41% yield) as a light yellow amorphous solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.87 (1H, s), 7.95 (1H, dd, J=7.5, 1.3 Hz), 7.58 (1H, dd, J=7.9, 1.3 Hz), 7.05 (1H, t, J=7.7 Hz), 5.43 (1H, br. s.), 1.54 (9H, s). m/z (ESI, +ve ion) 280.0/282.0 (M+H)+. A 5-mL glass microwave reaction vessel was charged with 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (609) (120 mg, 0.46 mmol), K2PO4 (182 mg, 0.86 mmol), Pd2dba3 (Strem Chemicals, 13.07 mg, 0.014 mmol), Xphos (Strem Chemicals, 13.61 mg, 0.03 mmol) and 8-bromo-N-(tert-butyl)quinazolin-2-amine (374a) (80 mg, 0.29 mmol) in dioxane (2.5 mL) and water (0.80 mL). The reaction was stirred and heated in a heating block at 110° C. for 1 h. The reaction mixture was treated with water, extracted with EtOAc (30 mL), washed with brine and concentrated. The crude residue was purified on the ISCO Combiflash RF (25 g Thomson SingleStep column, using a gradient of 0-20% MeOH) affording 2-(2-(tert-butylamino)quinazolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (53.9 mg, 0.16 mmol, 56% yield) as a light yellow amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.37 (1H, br. s.), 9.17 (1H, s), 8.10 (1H, d, J=6.8 Hz), 7.64 (1H, d, J=7.0 Hz), 7.35 (1H, s), 7.25 (1H, t, J=7.6 Hz), 7.05 (1H, br. s.), 6.98 (1H, br. s.), 3.40-3.47 (3H, m), 2.92 (2H, br. s.), 1.52 (9H, s). m/z (ESI, +ve ion) 336.0 (M+H)+.
Reaction SMILES: [C:1](=[N:9][OH:10])([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[C:36](Cl)=O>CC1CCCO1.O>[C:2]1([C:1]2[N:8]=[C:36]([C:32]3[S:31][CH:35]=[CH:34][CH:33]=3)[O:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=NO)c1ccccc1
Reactant: O=C(Cl)c1cccs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC1CCCO1
Solvent: O
Product: c1ccc(-c2noc(-c3cccs3)n2)cc1
Temperature: 70 °C
Yield: 95 %

Procedure:
A 39.45% solution of benzamide oxime in 2-methyltetrahydrofuran (33.34 g) was charged to a 100 mL flask, followed by water (9.0 g), 40% aqueous solution of tetrabutylammonium hydroxide (1.02 g), and 51% sodium hydroxide (3.52 g, 0.045 moles). To this mixture was added 2-thiophenecarbonyl chloride (13.83 g, 0.0936 moles) and 51% sodium hydroxide (7.33 g, 0.0935 moles) simultaneously over a 30 minute period while heating to about 70° C. The reaction was complete in less than 80 minutes. The aqueous salt phase was removed, water was added (30 g), and the 2-methyltetrahydrofuran partly removed by atmospheric distillation (13.5 mL). An additional amount (32 g) of hot water was added, and the remainder of the 2-methyltetrahydrofuran was distilled out, during which time the product, 3-phenyl-5-(2-thienyl)-1,2,4-oxadiazole, precipitated. The aqueous slurry of 3-phenyl-5-(2-thienyl)-1,2,4-oxadiazole was filtered, washed with water and dried overnight in a vacuum oven to yield 3-phenyl-5-(2-thienyl)-1,2,4-oxadiazole, 20.47 g, 99.1% pure, 95.0% yield.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[C:7]([S:25][CH3:26])=[N:8][N:9]3[C:14]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[O:23][CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:3][CH2:2]1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+].C(O[C:39]1(O[Si](C)(C)C)[CH2:41][CH2:40]1)C>CO.C(O)(=O)C>[CH:39]1([N:5]([CH2:4][CH:1]2[CH2:2][CH2:3]2)[C:6]2[C:7]([S:25][CH3:26])=[N:8][N:9]3[C:14]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[O:23][CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:41][CH2:40]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: COc1cc(C)cc(C)c1-c1cccc2c(NCC3CC3)c(SC)nn12
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(C)cc(C)c1-c1cccc2c(N(CC3CC3)C3CC3)c(SC)nn12
Temperature: 25 °C

Procedure:
After dissolving N-cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine (100 mg) in methanol (10 mL), ((1-ethoxycyclopropyl)oxy)trimethylsilane (60 μL), acetic acid (298 μL) and sodium cyanoborohydride (171 mg) were added and the mixture was heated to reflux for 6 hours. After cooling the reaction mixture to room temperature, saturated aqueous sodium hydrogencarbonate was added, extraction was performed with ethyl acetate, and the organic layer washed with brine. After drying the obtained organic layer over anhydrous magnesium sulfate and filtering it, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (74 mg) was obtained from the n-hexane:ethyl acetate (10:1) fraction as a yellow oil.
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][N:6]([CH3:29])[C:7](=[O:28])[C:8]1[CH:13]=[C:12]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]=[C:15]2Cl)[C:11]([F:26])=[CH:10][C:9]=1[Cl:27].[C:30](OCC)(=[O:32])C.CCCCCC>CO>[CH3:4][O:5][N:6]([CH3:29])[C:7](=[O:28])[C:8]1[CH:13]=[C:12]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]=[C:15]2[O:32][CH3:30])[C:11]([F:26])=[CH:10][C:9]=1[Cl:27]
Reactant: CCOC(C)=O
Reactant: CON(C)C(=O)c1cc(-n2c(Cl)nc(C(F)(F)F)cc2=O)c(F)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Product: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(C(=O)N(C)OC)c(Cl)cc1F
Reaction time: 0.17 h

Procedure:
A solution of 0.54 g of sodium methylate in 5 ml of methanol is added dropwise to a suspension of 4.14 g of N-methoxy-N-methyl-2-chloro-5-[2-chloro-4-oxo-6-trifluoromethyl-3(4H)-pyrimidinyl]-4-fluorobenzamide in 25 ml of methanol and the reaction mixture is stirred for 10 minutes. The mixture is then treated with 30 ml of ethyl acetate as well as 50 ml of n-hexane, filtered and the filtrate is evaporated. The resulting colourless, viscous crude product crystallizes from diethyl ether/n-hexane. There is obtained N-methoxy-N-methyl-2-chloro-4-fluoro-5-[2-methoxy-4-oxo-6-trifluoromethyl-3(4H)-pyrimidinyl]-benzamide, m.p. 119° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.Cl.[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][NH:24][CH2:23]2.C(N=C=NCCCN(C)C)C>ClCCl>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][N:24]([C:14](=[O:16])[CH2:13][N:10]1[CH2:11][CH2:12][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9]1=[O:17])[CH2:23]2
Reactant: Fc1ccc2c(c1)CNC2
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccc(F)cc2)C1=O)N1Cc2ccc(F)cc2C1
Reaction time: 18 h

Procedure:
To a suspension of 2-(3-(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (0.053 g, 0.223 mmol; Example 216A) and 5-fluoroisoindoline hydrogen chloride (0.043 g, 0.246 mmol) in dichloromethane (0.4 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.059 mL, 0.335 mmol) and the reaction stirred for 18 hours. The reaction was loaded onto a GraceResolv™ 12 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 100% ethyl acetate/hexanes (Flow=20 mL/minute) over 30 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.34-7.16 (m, 4H), 7.08-6.93 (m, 3H), 4.82 (dd, J=8.6, 16.1, 4H), 4.27 (d, J=16.2, 1H), 4.15 (d, J=16.2, 1H), 3.79-3.59 (m, 3H), 2.67-2.51 (m, 1H), 2.18 (ddd, J=8.5, 12.9, 16.1, 1H); MS (ESI+) m/z 357.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([F:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=1.Cl>C(O)(C)C>[F:21][C:5]1[C:6]([NH:8][C:9]2[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[N:7][C:2]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:32][CH:33]=2)=[N:3][CH:4]=1
Reactant: CC(C)NC(=O)c1ccccc1Nc1nc(Cl)ncc1F
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: Cl
Solvent: CC(C)O
Product: CCOC(=O)c1ccc(Nc2ncc(F)c(Nc3ccccc3C(=O)NC(C)C)n2)cc1
Temperature: 95 °C
Yield: 77.4 %

Procedure:
To the solution of 2-[(2-chloro-5-fluoro-4-pyrimidinyl)amino]-N-(1-methylethyl)benzamide (1.0 g, 3.25 mmol) in isopropanol (30 mL) was added ethyl 4-aminobenzoate (0.59 g, 3.57 mmol, 1.1 eq) followed 0.2 mL of 12N HCl. The reaction mixture was sealed in vessel and heated in a 95° C. oil bath for 16 h. The reaction was cooled to room temperature then white solid was precipitated. The white solid was collected by filtration and washed with cooled isopropyl alcohol (3×5 mL) to give the titled compound (1.1 g, 77% yield). MS: M(C23H23FN5O3)=437.47, (M+H)+=438
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][CH:21]=1)[O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1)C=C.CN(C)[C:24]1[CH:29]=CC=C[CH:25]=1>C(OCC)(=O)C>[CH2:29]([C:21]1[CH:20]=[CH:19][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17][CH:18]=2)=[CH:6][C:5]=1[OH:4])[CH:24]=[CH2:25]
Reactant: C=CCOc1cccc(Oc2ccc(C(=O)OC)cc2)c1
Reactant: CN(C)c1ccccc1
Solvent: CCOC(C)=O
Product: C=CCc1ccc(Oc2ccc(C(=O)OC)cc2)cc1O
Yield: 92 %

Procedure:
A solution of methyl 4-(3-allyloxyphenoxy)benzoate in N,N-dimethylaniline was heated at 190° C. for 19 hours, cooled, diluted with ethyl acetate, washed with aqueous hydrochloric acid, dried, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with hexane/ethyl ether to give a 40:60 mixture of the title compounds as an oil in 92% yield. NMR.
Reaction SMILES: CO[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:13].[CH2:14]([Mg]Br)C>C(OCC)C>[CH3:14][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[OH:13]
Reactant: COc1cccc2c1CCCC2=O
Reactant: CC[Mg]Br
Solvent: CCOCC
Product: Cc1cccc2c(O)cccc12
Temperature: 0 °C

Procedure:
5-Methoxy-1-tetralone (5) (4 g, 22.6 mmol) was dissolved in 50 mL anhydrous diethyl ether, stirred, and cooled down on ice to 0° C. Ethylmagnesium bromide (19 mL, 56.8 mmol) was added dropwise to the solution, producing copious precipitation. The mixture was then heated to reflux and stirred for 10 h. After cooling, cold water was added slowly to the reaction mixture, which was then extracted with diethyl ether three times. The organic layer was evaporated to afford crude product 6. Without purification, zinc chloride (15 g, 114 mmol) was added to a solution of 6 in benzene (35 mL), then concentrated hydrochloride acid (12 mL) was added to the solution at room temperature. The reaction mixture was heated to reflux for 5 h, cooled, extracted with diethyl ether three times, and the organic layer was evaporated to afford crude product. Purification by column chromatography gave 7 (2 g). To a solution of 7 (2 g) in triglyme (15 mL) was added 10% Pd/C (2 g) and the mixture was heated to reflux for 3 days. After cooling, diethyl ether was added to the mixture and it was filtered on Celite, then washed with diethyl ether to provide compound 8.50% yield; 1H NMR δ1.37 (3H, t, J=7.8 Hz, CH3CH2—), 3.10 (2H, q, J=7.8 Hz, CH3CH2—), 4.01 (3H, s, OCH3), 6.82 (1H, d, J=7.8 Hz, H-2), 7.36-7.44 (3H, m, H-3, 6, 7), 7.64 (1H, d, J=8.7 Hz, H-4), 815 (1H, d, J=8.4 Hz, H-8).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][C:10]1[C:15]([Cl:16])=[C:14]([Cl:17])[CH:13]=[CH:12][C:11]=1[CH2:18][CH2:19][NH2:20].Cl>CO.CCOCC>[OH:7][CH2:8][CH2:9][C:10]1[C:15]([Cl:16])=[C:14]([Cl:17])[CH:13]=[CH:12][C:11]=1[CH2:18][CH2:19][NH2:20]
Reactant: NCCc1ccc(Cl)c(Cl)c1CCOC1CCCCO1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: NCCc1ccc(Cl)c(Cl)c1CCO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
81 g of the product obtained above according to (b) are dissolved in 38 ml of methanol. 80 ml of a saturated solution of hydrogen chloride in ether are added, the temperature being kept between 20° and 25° C. The mixture is stirred for 30 minutes at room temperature and then concentrated to dryness. The residue is dissolved in 250 ml of water, washed twice with ethyl ether, rendered alkaline with a solution of NaOH and extracted with CH2Cl2. After drying over MgSO4, the extract is concentrated to dryness, the residue is taken up in 800 ml of isopropyl ether, an insoluble material is filtered off on Celite, the filtrate is concentrated under vacuum to about 300 ml and seeded with crystals of amino alcohol and the mixture is stirred overnight. The crystals are filtered off and rinsed with isopropyl ether and then with n-pentane to give 30.2 g of the expected product. M.p.=90°-91° C.
Reaction SMILES: [O:1]=[O+][O-].C=[C:5]1[CH2:24][CH:8]2[C:9](=[O:23])[N:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[CH2:11][CH:7]2[CH2:6]1>C(Cl)Cl>[F:20][C:19]([F:21])([F:22])[O:18][C:15]1[CH:16]=[CH:17][C:12]([N:10]2[CH2:11][CH:7]3[CH2:6][C:5](=[O:1])[CH2:24][CH:8]3[C:9]2=[O:23])=[CH:13][CH:14]=1
Reactant: O=[O+][O-]
Reactant: C=C1CC2CN(c3ccc(OC(F)(F)F)cc3)C(=O)C2C1
Solvent: ClCCl
Product: O=C1CC2CN(c3ccc(OC(F)(F)F)cc3)C(=O)C2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A slow stream of ozone was bubbled into a solution of 5-Methylene-2-(4-trifluoromethoxy-phenyl)-hexahydro-cyclopenta[c]pyrrol-1-one (0.1 g, 0.34 mmol) in 30 mL of methylene chloride at −78° C. The stream of ozone was maintained until a slight blue color persisted. After removal of excess ozone with a stream of nitrogen, 2 mL of dimethyl sulfide was added at −78° C. The mixture was then allowed to warm to room temperature, and stirred for overnight. The solvent was removed, and the crude product was purified by prep-TLC (MeOH: dichloromethane=1:50) to yield the title compound (50 mg, 50%). 1H NMR (300 MHz, CDCl3): δ 7.69-7.65 (m, 2H), 7.26-7.22 (m, 2H), 4.20 (t, 1H, J=8.4 Hz), 3.69-3.66 (m, 1H), 3.45-3.38 (m, 1H), 3.22-3.16 (m, 1H), 2.88-2.56 (m, 3H), 2.25-2.18 (m, 1H); LC-MS: 300.1 [M+1]+.
Reaction SMILES: [CH2:1]([N:7]=[C:8]=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:10][C:11]1[N:16]=[N:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])=[O:24])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>>[CH2:1]([NH:7][C:8]([NH:10][C:11]1[N:16]=[N:15][C:14]([N:17]2[CH2:18][CH2:19][N:20]([C:23](=[O:24])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])[CH2:21][CH2:22]2)=[CH:13][CH:12]=1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN=C=O
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Product: CCCCCCNC(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 5, making variations only as required to use hexylisocyanate in place of (2-isocyanatocyclopropyl)benzene to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (50% yield). 1H NMR (300 MHz, CD3OD) δ 7.83, 7.76, 7.69, 7.52, 7.44, 7.39, 3.87-4.00, 3.66, 3.50, 3.25-3.43, 1.53-1.67, 1.28-1.48, 0.84-0.98. MS (ES+) m/z 479 (M+1).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9]1[CH:47]=[CH:46][C:12]([C:13]([O:28][CH2:29][C@H:30]2[O:34][C@@H:33]([N:35]3[CH:42]=[C:41]([CH3:43])[C:39](=[O:40])[NH:38][C:36]3=[O:37])[C@H:32]([OH:44])[C@@H:31]2[OH:45])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1.[Si:48](Cl)([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49]>C1COCC1.[N+]([O-])([O-])=O.[Ag+]>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([O:28][CH2:29][C@H:30]2[O:34][C@@H:33]([N:35]3[CH:42]=[C:41]([CH3:43])[C:39](=[O:40])[NH:38][C:36]3=[O:37])[C@H:32]([O:44][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[C@@H:31]2[OH:45])([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:12]2[CH:46]=[CH:47][C:9]([O:8][CH3:7])=[CH:10][CH:11]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 84.8 %

Procedure:
Anhydrous pyridine (9.9 mL) was added to a solution of 5′-O-(4,4′-dimethoxitrityl)-5-methyluridine (6.9 g) and AgNO3 (2.51 g) in dry THF (123 mL) and stirred at room temperature for 20 min under an argon atmosphere. Followed by addition of tert-butyldimethylsilyl chloride (2.51 g) in dry THF (6 mL) and stirred at the same temperature for 2-3 h. The solids were filtered off and the filtrate was concentrated to a crude residue which was applied to a column of silica gel eluted with hexane-ethyl acetate (3:1) to give a pure title compound (7.04 g) as an amorphous solid.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[C:7]([NH2:11])([CH3:10])([CH3:9])[CH3:8]>>[C:7]([NH:11][CH2:2][CH2:3][CH2:4][C:5]#[CH:6])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)N
Reactant: C#CCCCI
Product: C#CCCCNC(C)(C)C

Procedure:
A solution of 5-iodo-pent-1-yne (1.0 g, 5.2 mmol) in tert-BuNH2 (2.0 g. 27 mmol) was heated to reflux for 4 h, evaporated, diluted with Et2O, filtered, and concentrated to afford the title compound. 1H NMR (CDCl3) δ 2.67 (t, 2H), 2.27 (td, 2H), 1.96 (t, 1H), 1.70 (quint., 2H), 1.11 (s, 9H).
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[N:27][CH:26]=1>>[CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:25]([C:20]2([OH:23])[CH2:21][CH2:22][N:17]([CH2:16][C:13]34[CH2:15][CH:6]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=53)[C:5]3[C:14]4=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:18][CH2:19]2)=[CH:26][N:27]=1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: Brc1cncc2ccccc12
Product: OC1(c2cncc3ccccc23)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Yield: 53 %

Procedure:
Using a procedure similar to that described in example 1 except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and employing 4-bromo-isoquinoline, the title compound was formed in 53% yield as a white solid, mp 256°-259° C. (dec). free base: 1H NMR (CDCl3, 250 MHz) 9.10 (s, 1H), 8.82 (d, J=7.5 Hz, 1H), 8.50 (s, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.67 (m, 1H), 7.58 (m, 1H), 7.26 (m, 4H), 6.94 (m, 4H), 4.29 (s, 1H), 3.53 (s, 2H), 2.91 (m, 4H), 2.64 (d, J=1.3 Hz, 2H), 2.28 (m, 4H) MS (CI, CH4) m/z 433 (M+1,100), 461 (M+29,14), 415 (26), 123 (12) hydrochloride salt:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].Br[CH2:19][C:20]1[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([CH3:31])[C:21]=1[O:22][CH2:23][C:24]#[N:25]>>[Cl:30][C:28]1[CH:27]=[C:26]([CH2:31][O:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[C:21]([O:22][CH2:23][C:24]#[N:25])=[C:20]([CH3:19])[CH:29]=1
Reactant: OCCCCOCc1ccc2ccccc2n1
Reactant: Cc1cc(Cl)cc(CBr)c1OCC#N
Product: Cc1cc(Cl)cc(COCCCCOCc2ccc3ccccc3n2)c1OCC#N

Procedure:
MS (ESI) 424 (M+H)+. Prepared from 4-(quinolin-2-ylmethoxy)-butan-1-ol (EXAMPLE-34b) and (2-bromomethyl-4-chloro-6-methyl-phenoxy)-acetonitrile.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[C:13](=[O:30])[N:14]([CH3:29])[C:15]([CH2:24][C:25]([O:27][CH3:28])=[O:26])=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[O:41]1CCCC1>>[CH2:1]([N:8]1[C:12]2[C:13](=[O:30])[N:14]([CH3:29])[C:15]([CH:24]([OH:41])[C:25]([O:27][CH3:28])=[O:26])=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(-c2ccc(Cl)cc2)c2ccn(Cc3ccccc3)c2c(=O)n1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COC(=O)C(O)c1c(-c2ccc(Cl)cc2)c2ccn(Cc3ccccc3)c2c(=O)n1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
A solution of methyl 2-(1-benzyl-4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (2.3 g, 5.46 mmol) in Tetrahydrofuran (THF) (30 mL) was treated with LiHMDS (8.45 mL, 8.45 mmol) at −78° C. and then stirred for 1 hour. A solution of (2R,8aS)-(+)-(Camphorsulfonyl)oxaziridine (2.421 g, 10.56 mmol) in Tetrahydrofuran (THF) (20 mL) was added, the mixture was warmed to 0° C. and then stirred for 20 minutes. The mixture was quenched with HCl (1M) and then extracted with Ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4 and concentrated. The residue was purified on silica gel (0-100% ethyl acetate/hexanes) to afford methyl 2-(1-benzyl-4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-hydroxyacetate (3.3 g, 4.53 mmol, 82% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.28 (s, 9H) 7.01-7.07 (m, 1H) 5.93-5.99 (m, 1H) 5.85-5.92 (m, 1H) 5.77-5.84 (m, 1H) 5.20-5.27 (m, 1H) 3.79 (s, 3H) 3.58 (s, 3H); LCMS (m/z) ES+=437 (M+1).