Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=2[F:18])=[O:9])[CH:7]=1.[CH2:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:21]#[CH:22].C1CCCCC1.C(NCC)C>[Cu](I)I.ClC1C=CC2C3N=C(NC4C=CC(C(O)=O)=C(OC)C=4)N=CC=3CN=C(C3C(OC)=CC=CC=3F)C=2C=1.CC(OC)(C)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:22]#[C:21][CH2:20][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[C:6]([C:8](=[O:9])[C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=2[F:18])[CH:7]=1
Reactant: COc1cccc(F)c1C(=O)c1cc(Cl)ccc1I
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: I[Cu]I
Agent: COc1cc(Nc2ncc3c(n2)-c2ccc(Cl)cc2C(c2c(F)cccc2OC)=NC3)ccc1C(=O)O
Solvent: C1CCCCC1
Solvent: COC(C)(C)C
Solvent: O
Product: COc1cccc(F)c1C(=O)c1cc(Cl)ccc1C#CCNC(=O)OC(C)(C)C
Temperature: 30.5 °C
Yield: 99.7 %

Procedure:
Into a reactor was added 3 (15.0 kg, 38.4 mol), 7 (7.2 kg, 46.4 mol) and cyclohexane (230 L). The suspension was degassed three times for at least 3 min each time using a vacuum-nitrogen cycle. Diethylamine (8.6 kg, 119 mol) was added and the reaction mixture was heated to 28 to 33° C. Dichlorobis(triphenylphosphine)palladium (II) (0.134 kg, 0.192 mol) and copper (II) iodide (0.037 kg, 0.192 mol) were added and the mixture was stirred at 28 to 33° C. for at least 15 h until ≧99.0% conversion was obtained by HPLC analysis. Water (68 L) followed by MTBE (92 L) were added. The reaction mixture was heated to 45 to 50° C. and stirred for a minimum of 30 min and until all solids fully dissolved. The phases were separated at 45 to 50° C. and the organic phase was washed with water (2×68 L) at 45 to 50° C. The resulting organic phase was filtered and the reactor was rinsed with MTBE (32 L) at 45 to 50° C. The rinse was then transferred to the second reactor containing the filtrate via the filter membrane. The combined filtrate was concentrated under vacuum using a jacket temperature of 45 to 50° C. until 225 kg remained in the reactor. The mixture was cooled to 35 to 40° C. and a slurry of seed crystals (10 g of 8 in 500 mL cyclohexane) was added. The reaction mixture was stirred for 60 min at 35 to 40° C. and concentrated under vacuum using a jacket temperature of 45 to 50° C. until 144 kg remained in the reactor. The mixture was cooled to 18 to 23° C. over a minimum of 2 h and stirred for an additional 2 h at 18 to 23° C. The resulting suspension was filtered and washed with cyclohexane (2×53 L). The wet cake was dried under vacuum at 40 to 45° C. to provide 16.0 kg (80% yield) of 8. 1H NMR (300 MHz, CDCl3) δ 7.72 (s, 1H), 7.41 (m, 3H), 6.77 (m, 2H), 4.43 (s, 1H), 3.88 (d, J=5.3 Hz, 2H), 3.74 (s, 3H), 1.46 (s, 9H); MS (ESI) m/z 318.4 (M+H+-Boc, 23%), 362.4 (M+H+-t-butyl cation, 20%).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:28])[CH2:13][CH2:12]1>O.[OH-].[Na+]>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]2[OH:28])[CH2:13][CH2:12]1
Reactant: COc1ccccc1N1CCN(CC2CCc3ccccc3C2=O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccccc1N1CCN(CC2CCc3ccccc3C2O)CC1

Procedure:
3,4-Dihydro-2-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]-1(2H)-naphthalenone, dihydrochloride, hemihydrate (2.14 g) is dissolved in 40 ml of water and neutralized with 11.5 ml of 1N sodium hydroxide solution. The suspension is extracted with 200 ml methylene chloride and the organic extract is dried over anhydrous sodium sulfate, filtered and the solvent removed. The free base is then dissolved in 20 ml of methanol and cooled in an ice bath. While stirring, a solution of 0.5 ml of concentrated hydrochloric acid in 2.8 ml of water is added. The reaction vessel is removed from the ice bath and treated dropwise over a period of 10 minutes with a solution of 430 mg of sodium borohydride in 2.5 ml of water. The resulting suspension is stirred at room temperature for 90 minutes, followed by treatment with 30 ml of ice-water and stirring for an additional 5 to 10 minutes. The suspension is extracted with two 50 ml portions of methylene chloride. The organic phase is dried over anhydrous sodium sulfate, filtered and the solvent removed. The crude product is triturated with 40 ml of ether and the resulting precipitate filtered and washed with ether to yield 1.54 g of the title compound, melting point 151°-152° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH2:10][O:11][CH3:12].[B:13](OC(C)C)([O:18]C(C)C)[O:14]C(C)C.C([Li])CCC>C1(C)C=CC=CC=1.C1COCC1>[CH3:12][O:11][CH2:10][CH2:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:13]([OH:18])[OH:14]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COCCOc1ccccc1I
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COCCOc1ccccc1B(O)O
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 49.4 %

Procedure:
To a solution of the compound of step 1 (2.20 g, 7.91 mmol) in toluene (20 ml) and THF (4 ml) was added triisopropyl borate (2.19 ml, 9.49 mmol), and the mixture was cooled to −78° C. n-Butyllithium (3.79 ml, 9.49 mmol, 2.5 M in hexane) was added dropwise and the reaction mixture was stirred at −78° C. for 1.5 h. The cooling bath was removed and the reaction mixture was allowed to warm to −20° C. Then 2 N hydrochloric acid (7 ml) was added. When the mixture had reached room temperature, water and EA were added. The organic layer was separated, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by silica gel chromatography (EA/HEP 1:4). 766 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]([OH:6])=O.C1N(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)C1.[OH:35][C:36]([CH2:38][CH2:39][CH2:40][CH2:41][C@H:42]1[C@@H:50]2[C@@H:45]([NH:46][C:47]([NH:49]2)=[O:48])[CH2:44][S:43]1)=[O:37].N[C@@H](C(O)=O)C>CN(C=O)C.C(N(CC)CC)C>[CH3:1][NH:2][CH2:3][C:4]([CH:38]([CH2:39][CH2:40][CH2:41][C@H:42]1[C@@H:50]2[C@@H:45]([NH:46][C:47]([NH:49]2)=[O:48])[CH2:44][S:43]1)[C:36](=[O:35])[OH:37])=[O:6]
Reactant: CNCC(=O)O
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: C[C@@H](N)C(=O)O
Agent: O=C(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNCC(=O)C(CCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)C(=O)O

Procedure:
The N-methyl glycine-linked DOTA-biotin conjugate was prepared by an analogous method to that used to prepare D-alanine-linked DOTA-biotin conjugates. N-methyl-glycine (trivial name sarcosine, available from Sigma Chemical Co.) was condensed with biotin-NHS ester in DMF and triethylamine to obtain N-methyl glycyl-biotin. N-methyl-glycyl biotin was then activated with EDCI and NHS. The resultant NHS ester was not isolated and was condensed in situ with DOTA-aniline and excess pyridine. The reaction solution was heated at 60° C. for 10 minutes and then evaporated. The residue was purified by preparative HPLC to give [(N-methyl-N-biotinyl)-N-glycyl]-aminobenzyl-DOTA.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([C:13]1[CH:49]=[CH:48][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[N:27](C(OC(C)(C)C)=O)[CH:26]=[C:25]3[C:38](=[NH:47])[NH:39]C(OC(C)(C)C)=O)=[O:18])=[CH:15][CH:14]=1)([CH3:12])[CH3:11])=O)(C)(C)C>C(Cl)Cl>[NH2:8][CH2:9][C:10]([C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][CH:26]=[C:25]3[C:38](=[NH:39])[NH2:47])=[O:18])=[CH:48][CH:49]=1)([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)NCC(C)(C)c1ccc(C(=O)NCCc2ccc3c(c2)c(C(=N)NC(=O)OC(C)(C)C)cn3C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Product: CC(C)(CN)c1ccc(C(=O)NCCc2ccc3[nH]cc(C(=N)N)c3c2)cc1
Reaction time: 6 h

Procedure:
To a solution of 4-(2-[tert-Butoxycarbonylamino]-1,1-dimethylethyl)-N-(2-[1-tert-butoxycarbonyl-3-tert-butoxycarbonylcarbamimidoylindol-5-yl]ethyl)benzamide (0.092 g, 0.14 mmol, reference example 1aaal) in CH2Cl2 (8 mL) is added distilled water (0.1 mL) and trifluoroacetic acid (2 mL). After stirring six hours, the reaction mixture is concentrated and then placed under high vacuum to give a quantitative yield of the title compound as a white solid (m.p. 67-70° C). 1H NMR (D2O): δ 1.29 (6H, s), 2.91 (2H, t, J=7 Hz), 3.12 (2H, s), 3.53 (2H, t, J=7 Hz), 7.14 (1H, d, J=8 Hz), 7.36-7.46 (5H, m), 7.54 (1H, s), 7.93 (1H, s). MS (FAB) m/z 378 (M+H)+. Anal. calcd. for C22H27N5O.3C2HO2F3: C, 46.7; H, 4.2; N, 9.7. Found: C, 46.8; H, 4.5; N, 9.8.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([CH2:11][CH2:12][C:13]3[N:14]=[C:15]4[CH:20]=[C:19]([C:21]([O:23]C)=[O:22])[CH:18]=[CH:17][N:16]4[C:25]=3[CH3:26])[CH:8]=[CH:7][C:5]=2[N:6]=1.O.Cl>CO.[OH-].[Na+]>[NH2:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([CH2:11][CH2:12][C:13]3[N:14]=[C:15]4[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[CH:17][N:16]4[C:25]=3[CH3:26])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: COC(=O)c1ccn2c(C)c(CCc3ccc4nc(N)oc4c3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(CCc2ccc3nc(N)oc3c2)nc2cc(C(=O)O)ccn12
Temperature: 25 °C
Reaction time: 20 h
Yield: 31.3 %

Procedure:
A mixture of 2-amino-6-[2-(7-methoxycarbonyl-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (0.8 g) in methanol (8 ml) and 1N sodium hydroxide (6.8 ml) was stirred for 20 hours at ambient temperature. To the reaction mixture was added a water and the mixture was adjusted to pH 5 with 4N-hydrochloric acid. The isolated precipitate was collected by filtration and dried to give 2-amino-6-[2-(7-carboxy-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (0.24 g).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([NH2:14])=[O:13])=[N:7]2.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:33])([CH3:32])[CH2:23][C:24]([OH:31])([C:27]([F:30])([F:29])[F:28])[CH:25]=O)=[C:18]([O:34][CH3:35])[CH:17]=1>C(O)(=O)C.C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:32])([CH3:33])[CH2:23][C:24]([OH:31])([C:27]([F:30])([F:29])[F:28])[CH:25]=[N:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([C:12]([NH2:14])=[O:13])=[N:7]3)=[C:18]([O:34][CH3:35])[CH:17]=1
Reactant: NC(=O)c1ccc2c(N)cccc2n1
Reactant: COc1cc(Cl)ccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1cc(Cl)ccc1C(C)(C)CC(O)(C=Nc1cccc2nc(C(N)=O)ccc12)C(F)(F)F

Procedure:
Analogously to Example 37, 160 mg (0.87 mmol) of 5-aminoquinoline-2-carboxylic acid amide is reacted with 341 mg (1.05 mmol) of 4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal in 0.96 ml of concentrated acetic acid and 20 ml of toluene. After purification on silica gel with hexane-ethyl acetate (0-100%), 340 mg (79% of theory) of the product is obtained.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:26])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]3[CH2:25][O:24]3)=[CH:17][CH:16]=2)([CH3:14])[CH3:13])=[CH:8][CH:7]=1.FC(F)(F)S([O-])(=O)=O.[Bi+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.C(=O)(O)[O-].[Na+].[C:57]([OH:61])([CH3:60])([CH3:59])[CH3:58]>>[C:57]([O:61][CH2:25][CH:23]([OH:24])[CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]([C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH:3]([OH:26])[CH2:2][Cl:1])=[CH:11][CH:10]=2)([CH3:14])[CH3:13])=[CH:16][CH:17]=1)([CH3:60])([CH3:59])[CH3:58]
Reactant: CC(C)(c1ccc(OCC(O)CCl)cc1)c1ccc(OCC2CO2)cc1
Reactant: CC(C)(C)O
Agent: O=C([O-])O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Bi+3]
Product: CC(C)(C)OCC(O)COc1ccc(C(C)(C)c2ccc(OCC(O)CCl)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 28 %

Procedure:
To a solution of racemic 1-chloro-3-(4-(2-(4-(oxiran-2-ylmethoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol (300 mg, 0.8 mmol, 1 equiv) in t-Butanol (5 mL) was added solid Bismuth (III) trifluoromethanesulfonate (10 mg, 0.015 mmol, 1/50 equiv) in one portion and the mixture was stirred at room temperature for 12 h. Sodium bicarbonate was added (0.5 mL), the organic solvent was evaporated under reduced pressure, and the residue was extracted with dichloromethane (3×10 mL). The organic layer was washed with deionized water (2×10 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 40% to 80% ethyl acetate in hexane) to provide 1-(tert-butoxy)-3-(4-(2-(4-(3-chloro-2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol (100 mg, 28%) as a foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:9]=O)=[N:5][CH:6]=[CH:7][N:8]=1.[F:11][C:12]1[CH:24]=[CH:23][CH:22]=[CH:21][C:13]=1[O:14][CH2:15][CH:16]1[CH2:20][CH2:19][NH:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C(O)(=O)C.C(OCC)(=O)C>[F:11][C:12]1[CH:24]=[CH:23][CH:22]=[CH:21][C:13]=1[O:14][CH2:15][CH:16]1[CH2:20][CH2:19][N:18]([CH2:9][C:4]2[C:3]([O:2][CH3:1])=[N:8][CH:7]=[CH:6][N:5]=2)[CH2:17]1
Reactant: Fc1ccccc1OCC1CCNC1
Reactant: COc1nccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1nccnc1CN1CCC(COc2ccccc2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
After dissolving 148 mg of 3-methoxypyrazine-2-carboxaldehyde and 200 mg of 3-(2-fluorophenoxymethyl)pyrrolidine in 5 ml of dichloromethane, 0.07 ml of acetic acid and 297 mg of sodium triacetoxyborohydride were added and the mixture was stirred overnight at room temperature. Aqueous sodium carbonate solution was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (245 mg, 77% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C@H:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])=[C:20]([C:32](=O)[CH3:33])[CH:19]=1)[NH:6][C:7](=[O:16])[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])[CH3:2].[NH2:36][OH:37].Cl.CC([O-])=O.[Na+]>CCCCO>[CH2:1]([O:3][C:4](=[O:35])[C@H:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])=[C:20]([C:32](=[N:36][OH:37])[CH3:33])[CH:19]=1)[NH:6][C:7](=[O:16])[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])[CH3:2]
Reactant: NO
Reactant: CCOC(=O)[C@H](Cc1ccc(-c2ccccc2OC)c(C(C)=O)c1)NC(=O)c1c(Cl)cccc1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: CCOC(=O)[C@H](Cc1ccc(-c2ccccc2OC)c(C(C)=NO)c1)NC(=O)c1c(Cl)cccc1Cl

Procedure:
To a solution of N-(2,6-dichlorobenzoyl)-3-acetyl-4-(2-methoxyphenyl)-L-phenylalanine ethyl ester (0.15 g) in n-BuOH (5 mL) were added NH2OH HCl salt (23 mg) and NaOAc (40 mg). The mixture was refluxed for 6 hour, then evaporated. The residue was diluted with CH2Cl2, washed with 1N HCl, dried and evaporated. The residue was purified by preparative TLC (silica gel; eluent: EtOAc/hexane 1:1) to give N-(2,6-dichlorobenzoyl)-3-[1-(hydroxyimino)ethyl]-4-(2-methoxyphenyl)-L-phenylalanine ethyl ester. ESMS: m/z 490 (MH+).
Reaction SMILES: C[Al](C)C.[CH:5]1([CH2:8][NH:9][CH2:10][CH2:11][CH3:12])[CH2:7][CH2:6]1.C(O[C:16]([C:18]1[N:22]2[C:23]3[CH:24]=[C:25]([F:39])[CH:26]=[CH:27][C:28]=3[N:29]([C:30]3[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:31]=3[CH3:38])[C:21]2=[N:20][C:19]=1[CH3:40])=[O:17])C.[OH-].[Na+]>C1C=CC=CC=1>[CH:5]1([CH2:8][N:9]([CH2:10][CH2:11][CH3:12])[C:16]([C:18]2[N:22]3[C:23]4[CH:24]=[C:25]([F:39])[CH:26]=[CH:27][C:28]=4[N:29]([C:30]4[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:31]=4[CH3:38])[C:21]3=[N:20][C:19]=2[CH3:40])=[O:17])[CH2:7][CH2:6]1
Reactant: CCOC(=O)c1c(C)nc2n(-c3c(C)cc(C)cc3C)c3ccc(F)cc3n12
Reactant: CCCNCC1CC1
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CCCN(CC1CC1)C(=O)c1c(C)nc2n(-c3c(C)cc(C)cc3C)c3ccc(F)cc3n12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.8 %

Procedure:
A solution of trimethylaluminum (2.0 M in heptane, 1.4 mL, 2.8 mmol) was added to a solution of N-cyclopropylmethyl-N-propylamine (0.40 mL, 2.8 mmol) in benzene (3 mL) at 0° C. The mixture was warmed up to room temperature and stirred at this temperature for 1.5 hours, and then added to a stirred solution of 5-fluoro-2-methyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[a]indene-3-carboxylic acid ethyl ester (0.13 g, 0.35 mmol) in benzene (2.0 mL). The mixture was refluxed for 12 hours. Upon cooling at 0° C., 1 N sodium hydroxide (15 mL) was added dropwise to the above mixture. The mixture was extracted with dicholoromethane (30 mL), and the organic layer was dried over anhydrous sodium sulfate. Solvents were removed in vacuo and the residue was subjected to chromatography using ethyl acetate/hexanes (3:7) as eluent to afford the title compound as an off-white solid (0.156 g, 100% yield). 1H NMR (CDCl3, 300 MHz) δ 7.60 (dd, J=8.7, 2.5 Hz, 1H), 6.99 (s, 2H), 6.92 (td, J=9.0, 2.5 Hz, 1H), 6.75 (dd, J=8.8, 4.4 Hz, 1H), 3.66 (t, J=7.1 Hz, 2H), 3.46 (d, J=6.9 Hz, 2H), 2.35 (s, 3H), 2.32 (s, 3H), 1.92 (s, 6H), 1.71-1.63 (m, 2H), 1.11-1.05 (m, 1H), 0.88 (t, J=7.2 Hz, 3H), 0.57-0.53 (m, 2H), 0.19-0.16 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 163.6, 159.4, 156.3, 148.9, 143.3, 139.4, 137.0, 131.6, 129.7, 128.7, 124.8 (d, J=13 Hz), 114.2, 110.6 (d, J=25 Hz), 101.2 (d, J=29 Hz), 51.3, 48.6, 21.1, 21.0, 17.8, 15.7, 11.3, 10.1, 3.8. LC/MS: tR=1.95 min, 447.22 (MH+).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[NH:23]1[CH:30]=[CH:29][C:27]([NH2:28])=[N:26][C:24]1=[O:25].OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[NH2:28][C:27]1[CH:29]=[CH:30][N:23]([C:19]2[CH:20]=[CH:21][C:16]([N:14]3[CH:15]=[C:11]([CH2:10][NH:9][C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)=[O:8])[N:12]=[CH:13]3)=[CH:17][CH:18]=2)[C:24](=[O:25])[N:26]=1
Reactant: O=C(NCc1cn(-c2ccc(I)cc2)cn1)c1ccc(Cl)s1
Reactant: Nc1cc[nH]c(=O)n1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Nc1ccn(-c2ccc(-n3cnc(CNC(=O)c4ccc(Cl)s4)c3)cc2)c(=O)n1
Temperature: 130 °C
Yield: 15.6 %

Procedure:
A mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 1-6 (66 mg, 0.15 mmol), cytosine (46 mg, 0.41 mmol), 8-hydroxyquinoline (10 mg, 0.069 mmol) and K2CO3 (50 mg, 0.36 mmol) in DMSO (1 mL) was degassed with Ar before being charged with CuI (15 mg, 0.079 mmol). The mixture in a sealed tube was heated at 130° C. overnight. The mixture was then purified by HPLC to give the titled compound (10 mg). MS 427.1 and 429.1 (M+H, Cl pattern).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([F:10])[F:9])=[C:4](F)[CH:3]=1.[C-:12]#[N:13].[K+].O.CCCCCC>CN1C(=O)CCC1.C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([F:10])[F:9])=[C:4]([CH:3]=1)[C:12]#[N:13]
Reactant: [C-]#N
Reactant: Fc1cc(Br)ccc1C(F)F
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCCCCC
Product: N#Cc1cc(Br)ccc1C(F)F

Procedure:
A mixture of 4-bromo-1-(difluoromethyl)-2-fluorobenzene (5.0 g, 22 mmol) and KCN (4.34 g, 67 mmol) was heated at 150° C. in NMP (50 mL) for 16 h. After trituration with a mixture of water, hexane, EtOAc and DCM, the organic layer was concentrated and purified by silica gel flash chromatography using hexanes:DCM (4:1 to 4:1.5 v/v) as mobile phase to yield the title compound: 1H NMR (500 MHz, CD2Cl2) δ 7.97 (s, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.67 (d, J=8.5 Hz, 1H), 6.95 (t, J=54.5 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=O)[CH2:4][CH2:3]1.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][C:17]1=[O:25]>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=[C:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:16][C:17]2=[O:25])[CH2:4][CH2:3]1
Reactant: O=C1Cc2ccccc2N1
Reactant: CN1CCN(c2ccccc2C=O)CC1
Solvent: CCO
Product: CN1CCN(c2ccccc2C=C2C(=O)Nc3ccccc32)CC1
Yield: 116.9 %

Procedure:
Under nitrogen in a dry round bottom flask fitted with a condensor and magnetic stir bar were placed 2-(4methyl-1-piperazinyl)-benzaldehyde (0.152 g, 0.75 g, 0.75 mmol), oxindole (0.104 g, 0.78 mmol) pyrrolidine (62 μL) and ethanol (7.0 mL). The mixture was heated to reflux for 16 hours, cooled and evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water and the organic layer was washed with saturated aqueous sodium chloride (NaCl), dried over magnesium sulfate (MgSO4)1, filtered and absorbed onto 437 mg of silica gel. Elution with ethyl acetate (EtOAc) (125 mL), 1% methanol (CH3OH) in EtOAc (100 mL), 2% CH3OH in EtOAc (100 mL) and 4% CH3OH+1% triethylamine (Et3N) In EtOAc (50 mL) gave 280 mg of a yellow solid. Recrystallization from hot CH3OH gave the title product, m.p. 226-2280° C.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:14](=[O:24])[NH:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.Cl.[CH3:26][N:27]1[CH2:33][C:32]2[CH:34]=[C:35](/[CH:38]=[CH:39]/[C:40](O)=O)C=N[C:31]=2[NH:30][C:29](=O)[CH2:28]1.CNCC1N(C)C2C(C=1)=CC=CC=2.CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:13])[N:30]([CH3:31])[CH2:29][C:28]2[N:27]([CH3:26])[C:33]3[C:39]([CH:40]=2)=[CH:38][CH:35]=[CH:34][CH:32]=3)=[CH:5][C:4]=1[C:14]([NH:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:24]
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Reactant: Nc1ncc(C=CC(=O)O)cc1C(=O)NCCN1CCOCC1
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CNCc1cc2ccccc2n1C
Agent: Cl
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc(N)c(C(=O)NCCN2CCOCC2)c1
Yield: 23 %

Procedure:
According to the procedure of Example 1, except substituting 3-[6-amino-5-(2-morpholin-4-yl-ethylcarbamoyl)pyridin-3-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and methyl-(1-methyl-1H-indol-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (170 mg, 23%) was prepared as a pale yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 10.87-10.61 (m, 1H), 9.69-9.66 (m, 1H), 9.40-9.28 (m, 1H), 8.70-8.31 (m, 3H), 7.95-7.39 (m, 4H), 7.15-6.97 (m, 2H), 6.40-6.08 (m, 1H), 5.27-4.85 (m, 2H), 3.94-3.55 (m, 12H), 3.20-2.96 (m, 6H); MS (ESI) m/e 477 (M+H)+.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.[NH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][C:14]=1[I:22].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[NH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:3][CH:4]2[CH:9]3[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]3)[CH2:5]2)=[O:18])=[CH:15][C:14]=1[I:22]
Reactant: NC1CN2CCC1CC2
Reactant: Nc1ccc(C(=O)O)cc1I
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Nc1ccc(C(=O)NC2CN3CCC2CC3)cc1I
Yield: 90.2 %

Procedure:
A solution of 2.04 g (10.3 mmol) of 3-aminoquinuclidine dihydrochloride, 2.70 g (10.3 mmol) of 4-amino-3-iodobenzoic acid, 1.39 g (10.3 mmol) of HOBt, 2.16 g (11.3 mmol) of EDC and 6.63 g (51.3 mmol) of N,N-diisopropylethylamine in 150 ml of DMF was stirred at room temperature for 16 h. 300 ml of water were added, and the aqueous phase was extracted three times with 300 ml of ethyl acetate each time. The combined organic phases were dried over sodium sulfate and the solvent was distilled off in vacuo. The residue was purified on a flash column (mobile phase: dichloromethane/methanol/triethylamine 90:10:0.2). 3.45 g (87%) of the desired title compound were obtained.