Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:24][C:25]1[CH:26]=[C:27]([NH:35][C:36](=[O:38])[CH3:37])[CH:28]=[CH:29][C:30]=1[C:31](=[O:34])[CH2:32]Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:36]([NH:35][C:27]1[CH:28]=[CH:29][C:30]([C:31](=[O:34])[CH2:32][N:14]2[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:12][CH2:13]2)=[C:25]([O:24][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:26]=1)(=[O:38])[CH3:37]
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CC(=O)Nc1ccc(C(=O)CBr)c(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C(=O)CN2CCN(C(=O)OCc3ccccc3)CC2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.2 %

Procedure:
1-(Benzyloxycarbonyl)piperazine (117 μL, 134 mg, 0.607 mmol) was added to a mixture of N-[3-benzyloxy-4-(2-bromo-acetyl)phenyl]-acetamide (200 mg, 0.552 mmol) and potassium carbonate (115 mg, 0.828 mmol) in DMF (5 mL), and stirred at room temperature for 18 hours. The solvent was removed in vacuo, and taken up in brine (25 mL). The aqueous was extracted with DCM (3×25 mL) and the combined organics dried (MgSO4). The solvents were removed in vacuo, and the product was purified by preparative HPLC to give pure 4′-acetamido-2′-benzyloxy-2-[4-(benzyloxycarbonyl)piperazin-1-yl]acetophenone (114 mg, 41%, 50% rec.) as an off-white solid; δH (CDCl3) 8.23 (1H, br s), 7.81 (1H, d, J=8.6 Hz), 7.77-7.76 (1H, m), 7.53-7.51 (2H, m), 7.42-7.28 (8H, m), 7.08 (1H, dd, J=8.6, 1.8 Hz), 5.20 (2H, s), 5.12 (2H, s), 4.00 (2H, s), 3.59-3.48 (4H, m), 2.65-2.60 (4H, m), 2.14 (3H, s); LCMS retention time 2.07 min, M+H+ 502.5, along with recovered N-(4-acetyl-3-benzyloxy-phenyl)-acetamide (35 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3I)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:19][CH:20]([OH:23])[C:21]#[CH:22]>C(NCC)C.C(Cl)CCl.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:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:22]#[C:21][CH:20]([OH:23])[CH3:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(I)ncn2-c2cccc(Cl)c2C1=O
Reactant: C#CC(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: ClCCCl
Product: CC(O)C#Cc1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2

Procedure:
7.47 g (20 mmol) of 7-chloro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to boiling under reflux for 4 hours with 1.75 g (25 mmol) of 3-butyn-2-ol, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 10 mg of copper(I) iodide in 50 ml of diethylamine and 20 ml of ethylene chloride. After removal of the solvent by evaporation the residue was taken up in methylene chloride and the thus-obtained suspension was suction filtered. The material obtained was washed with methylene chloride and, after recrystallization from ethyl acetate, there was obtained 7-chloro-4,5-dihydro-3-(3-hydroxy-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 251°-252°.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([C:19]1[CH:24]=[CH:23][C:22]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH2:31][CH2:32][C:33]3[CH:40]=[CH:39][C:36]([CH2:37][OH:38])=[CH:35][CH:34]=3)[CH2:27][CH2:26]2)=[CH:21][CH:20]=1)[CH2:17][CH3:18]>C(Cl)Cl>[CH2:16]([C:19]1[CH:24]=[CH:23][C:22]([C@H:25]2[CH2:26][CH2:27][C@H:28]([CH2:31][CH2:32][C:33]3[CH:40]=[CH:39][C:36]([CH:37]=[O:38])=[CH:35][CH:34]=3)[CH2:29][CH2:30]2)=[CH:21][CH:20]=1)[CH2:17][CH3:18]
Reactant: CCCc1ccc([C@H]2CC[C@H](CCc3ccc(CO)cc3)CC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCc1ccc([C@H]2CC[C@H](CCc3ccc(C=O)cc3)CC2)cc1

Procedure:
Dicyclohexylcarbodiimide in an amount of 12.9 g was suspended in 200 ml of methylene chloride and stirred. To the suspension was added dropwise a solution prepared by dissolving 10.1 g of the 4-(2-(trans-4-(4-n-propylphenyl)cyclohexyl)ethyl)benzyl alcohol mentioned above in 200 ml of methylene chloride, and stirred at room temperature for 2 hours. Crude reaction solution thus obtained was purified by a column chromatography over a silica gel, and then the solvent was distilled off under a reduced pressure to obtain 2.8 g of 4-(2-(trans-4-(4-n-propylphenyl)cyclohexyl)ethyl)benzaldehyde.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([NH2:18])[CH3:17]>>[CH2:16]([NH:18][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:17]
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: CCN
Product: CCNC(=O)c1ccccc1-c1ccccc1
Yield: 94 %

Procedure:
2-Phenylbenzoic acid was converted to the acid chloride by the procedure of example b. The acid chloride was reacted with 70% aq ethylamine using General Method El to afford 10.59 g of N-ethyl-2-phenylbenzamide in 94% yield. m.p. 77-79° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10](Cl)=[O:11])[CH2:7]1.[OH-].[NH4+:17]>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10]([NH2:17])=[O:11])[CH2:7]1
Reactant: [NH4+]
Reactant: O=C(Cl)N1CC(Oc2cccc(Br)c2)C1
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)N1CC(Oc2cccc(Br)c2)C1
Reaction time: 48 h
Yield: 68.2 %

Procedure:
A solution of 5.8 g (0.02 mole) of 3-(3-bromophenoxy)-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was stirred at ambient temperature while 4 ml (0.06 mole) of 57% ammonium hydroxide was slowly added. After stirring for 48 hr, the reaction mixture was diluted with 100 ml of water and the resulting solid collected by filtration (5 g). Recrystallization from isopropanol yielded 3.7 g (59%) of fine beige crystals, m.p. 188°-189° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[N:8]=[C:7]2[CH:19]=O)([O-:3])=[O:2].[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:29]=[C:30]([NH2:35])[C:31]([NH2:34])=[CH:32][CH:33]=2)[CH2:23][CH2:22]1.S(=O)(O)[O-].[Na+]>C1COCC1.Cl.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[N:8]=[C:7]2[C:19]1[NH:35][C:30]2[CH:29]=[C:28]([CH2:27][N:24]3[CH2:23][CH2:22][O:21][CH2:26][CH2:25]3)[CH:33]=[CH:32][C:31]=2[N:34]=1)([O-:3])=[O:2]
Reactant: O=Cc1nn(C2CCCCO2)c2ccc([N+](=O)[O-])cc12
Reactant: Nc1ccc(CN2CCOCC2)cc1N
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)c(-c1nc3ccc(CN4CCOCC4)cc3[nH]1)nn2C1CCCCO1
Temperature: 25 °C
Yield: 50 %

Procedure:
5-Nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (85 mg, 0.309 mmol) and 4-(morpholinomethyl)benzene-1,2-diamine (64 mg, 0.309 mmol) were dissolved in dry THF (8 mL) and 2N HCl (1 drop) was added. The solution was heated at a gentle reflux for 30 min and then 1N sodium bisulfite (1 mL) was added. After overnight at reflux, the solution was cooled to room temperature, and diluted with ethyl acetate (40 mL). The mixture was washed with water and brine, dried over Na2SO4, and concentrated. Purification by flash chromatography (20% ethyl acetate/hexane) afforded the title compound as a pale yellow solid in a 50% yield. 1H NMR: (400 MHz, CD3OD): δ 9.42 (d, 1H, J=2.0 Hz), 8.32 (dd, 1H, J=2.0 and 8.8 Hz), 7.92-7.87 (m, 1H), 7.67 (m, 2H), 7.32 (d, 1H, J=8.4 Hz), 5.97 (dd, 1H, J=2.8 and 8.8 Hz), 3.99 (m, 1H), 3.88-3.82 (m, 1H), 3.72 (m, 6H), 2.57 (m, 5H), 2.19 (m, 2H), 1.88 (m, 1H), 1.73 (m, 2H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[C:14]([CH:16]=[CH2:17])[C:13]([O:18][C@H:19]2[CH2:23][CH2:22][CH2:21][C@@H:20]2[C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)=[CH:12][C:11]=1[F:30])(=[O:9])=[O:8].C([SiH](CC)CC)C>ClCCl.FC(F)(F)C(O)=O>[CH2:16]([C:14]1[C:13]([O:18][C@H:19]2[CH2:23][CH2:22][CH2:21][C@@H:20]2[C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)=[CH:12][C:11]([F:30])=[C:10]([S:7]([NH:6][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][N:32]=2)(=[O:8])=[O:9])[CH:15]=1)[CH3:17]
Reactant: C=Cc1cc(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ccncn2)c(F)cc1O[C@H]1CCC[C@@H]1c1ccnn1C
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(S(=O)(=O)Nc2ccncn2)c(F)cc1O[C@H]1CCC[C@@H]1c1ccnn1C
Reaction time: 1 h

Procedure:
To a solution of the N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)-5-vinylbenzenesulfonamide (29 mg, 0.05 mmol) prepared in Example 61c and triethylsilane (0.10 mL) in dichloromethane (4.0 mL), trifluoroacetic acid (0.5 mL) was added at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was concentrated to yield a mixture of the title compound and a vinyl derivative.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.O1CCOCC1.O.[F-].[Cs+].[C:34]1(B2OC(C)(C)C(C)(C)O2)[CH2:38][CH2:37][CH2:36][CH:35]=1>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>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([C:34]4[CH2:38][CH2:37][CH2:36][CH:35]=4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(C3=CCCC3)ccc12
Yield: 4.1 %

Procedure:
2,6-Dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (300 mg, 0.74 mmol, 1.00 eq) in 1,4-Dioxane (6 mL, 69.44 mmol, 20 V)/Water (2 mL, 111.02 mmol, 6.67 V) was taken in a microwave vial and to this were added Cesium fluoride (338.80 mg, 2.23 mmol, 3.00 eq) and 2-Cyclopent-1-enyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (172.97 mg, 0.89 mmol, 1.20 eq). The reaction mixture was purged with nitrogen for 15 min and bis(triphenyl phosphine)palladium (II) dichloride (25.16 mg, 0.04 mmol, 0.05 eq) was added and heated under microwave at 130 OC for 1 h. The reaction mixture was concentrated and the crude obtained was purified by flash column chromatography to afford the title compound (12 mg, 0.03 mmol, 3.9%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.85 (t, J=5.64 Hz, 1H), 7.95-7.98 (m, 3H), 7.75 (d, J=9.0 Hz, 1H), 6.88 (s, 1H), 3.26-3.29 (m, 2H), 2.85-2.89 (m, 2H), 2.60 (s, 2H), 1.96-2.04 (m, 4H), 1.81-1.86 (m, 3H), 1.74-1.77 (m, 2H), 1.23-1.33 (m, 2H). m/z: 405 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:15]([CH3:17])[OH:16])[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([O:16][CH:15]([CH3:17])[C:8]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]1)(=[O:20])[CH3:19]
Reactant: CC(O)C1(c2cccc(Cl)c2)CCN(C)CC1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC(C)C1(c2cccc(Cl)c2)CCN(C)CC1

Procedure:
A mixture of 1.00 g of 4-(3′-chlorophenyl)-α,1-dimethyl-4-piperidinemethanol (Example 1) and 5 mL of acetic anhydride was heated under reflux for 90 minutes. Removal of the excess acetic anhydride and short-path distillation of the residue (170° C. bath temperature, 1 micron) gave 1.05 g of the title compound as an oil. 1H NMR (CDCl3): δ 7.1-7.4 (m, 4H); 4.9 (quartet, J=7 Hz,1H); 2.8 (m,2H); 2.2 (s,3H); 2.0 (s,3H); 1.9-2.4 (m,6H); and 0.9 (d,J=7 Hz,3H).
Reaction SMILES: O=[C:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH:11]([CH3:13])[CH2:10][CH2:9][CH:8]1[CH:14]([CH3:16])[CH3:15])=[O:6].N.[BH3-]C#[N:26].[Na+].C([O-])(O)=O.[Na+]>C(OCC)(=O)C.C(O)(=O)C>[NH2:26][CH:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH:11]([CH3:13])[CH2:10][CH2:9][CH:8]1[CH:14]([CH3:16])[CH3:15])=[O:6]
Reactant: [BH3-]C#N
Reactant: CC1CCC(C(C)C)C(C(=O)NCC(=O)c2ccccc2)C1
Agent: N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC1CCC(C(C)C)C(C(=O)NCC(N)c2ccccc2)C1
Reaction time: 1.33 h
Yield: 93.4 %

Procedure:
A 25 mL microwave reaction vessel equipped with a stir bar was charged with 2-isopropyl-5-methyl-cyclohexanecarboxylic acid (2-oxo-2-phenyl-ethyl)-amide (80 mg) and ammonia (1.5 mL, 7 M in methanol). A drop of acetic acid and NaCNBH3 (20 mg) were added to the reaction mixture and subjected to microwave at 80° C. for 80 min. The residue was taken up in ethyl acetate (30 mL) and saturated NaHCO3 (aq.) (30 mL). The heterogeneous mixture was transferred to a separatory funnel where the aqueous phase was separated and re-extracted with ethyl acetate (2×10 mL). The organic phases were combined and washed with sat NaHCO3 (3×10 mL), H2O (10 mL), brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a solid (75 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][C:6]([CH3:9])([CH3:8])[CH3:7]>CO.C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:10])[CH2:4][CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: COC(=O)C=CC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)CCC(C)(C)C
Reaction time: 12 h
Yield: 80.8 %

Procedure:
4,4-Dimethyl-pent-2-enoic acid methyl ester (8.52 g, 60.0 mmol) was dissolved in MeOH (30 mL) and ethyl acetate (30 mL). Palladium on carbon (10 wt %) (˜50 mg) was added to the reaction and was placed under a H2 balloon (1 atm). The reaction was allowed to stir for 12 hours, flushed with nitrogen and filtered over a pad of celite. Evaporated to provide 4,4-dimethyl-pentanoic acid methyl ester (7.0 g, 48.5 mmol, 81%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 0.89 (s, 9H), 1.53-1.57 (m, 2H), 2.26-2.30 (m, 2H), 3.67 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH3:15])[C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([CH3:14])[N:13]=1)[C:7]([NH:9][OH:10])=[NH:8])[CH3:2].[CH:16](N(C)C1C=C(C=C(C)N=1)C(O)=O)(C)C>>[OH:10][NH:9][C:7](=[NH:8])[C:6]1[CH:11]=[C:12]([CH3:14])[N:13]=[C:4]([N:3]([CH:1]([CH3:16])[CH3:2])[CH3:15])[CH:5]=1
Reactant: CCN(C)c1cc(C(=N)NO)cc(C)n1
Reactant: Cc1cc(C(=O)O)cc(N(C)C(C)C)n1
Product: Cc1cc(C(=N)NO)cc(N(C)C(C)C)n1

Procedure:
The title compound is prepared in analogy to 2-(ethyl-methyl-amino)-N-hydroxy-6-methyl-isonicotinamidine from 2-(isopropyl-methyl-amino)-6-methyl-isonicotinic acid; LC-MS: tR=0.50 min, [M+1]+=223.13.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.[K+].[Br-]>>[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:7]([C:6]2[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)=[NH:8])=[CH:15][CH:14]=1
Reactant: CSc1ccc(C#N)cc1
Reactant: COc1ccc(N)cc1
Agent: [Br-]
Agent: [K+]
Product: COc1ccc(NC(=N)c2ccc(SC)cc2)cc1
Yield: 76.84 %

Procedure:
The title compound was prepared from 4-methylthiobenzonitrile (12.11 g, 81 mmol) and 4-methoxyaniline (10 g, 81 mmol) by following the procedure described in preparation 10 (17 g, yield 76.84%, mp 166-168° C., purity 97.25% by HPLC). 1H-NMR (CDCl3):δ 2.51 (s, 3H), 3.80 (s, 3H), 4.80 (bs, 2H, D2O exchangeable), 6.91 (s, 4H), 7.26-7.29 (m, 2H), 7.78-7.8 (d, 2H). IR (KBr) cm−1: 3461, 3320, 2949, 2922, 2829, 1615. MS m/z:273.1 (M+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH3:12])[C:5]2[N:6]=[CH:7][N:8]=[CH:9][C:10]=2[N:11]=1.O[C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[CH3:12][N:4]1[C:5]2[N:6]=[CH:7][N:8]=[CH:9][C:10]=2[N:11]=[C:3]1[CH2:2][O:1][C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1
Reactant: Cn1c(CO)nc2cncnc21
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cncnc21

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 0.37 g of 2-hydroxymethyl-3-methylimidazo[5,4-d]pyrimidine (prepared as described in Preparation 50), 2.51 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4 dione, 1.34 ml of tributylphosphine, 1.36 g of 1,1'-(azodicarbonyl)dipiperidine and 50 ml of benzene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in a ratio of 2:1 by volume, and then in ratios ranging from 1:1 to 1:2 by volume, and subsequently a 6:1 by volume mixture of ethyl acetate and ethanol as the eluent. The desired fractions were collected and concentrated by evaporation under reduced pressure. The concentrate was further purified by preparative reverse-phase high speed liquid chromatography through YMC-Pack ODS-A (a product of YMC Inc.) using a 100:100:1:1 by volume mixture of acetonitrile, water, acetic acid and triethylamine as the eluent, to give 0.24 g of the title compound, melting at 55-65° C. (softening).
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5](=[O:31])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:3].CC(C)([O-])C.[K+].[N:38]1([CH2:43][C:44](=O)[CH2:45][CH2:46][CH2:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=2)[CH:42]=[CH:41][N:40]=[CH:39]1>O1CCCC1>[N:38]1([CH2:43][C:44]([CH2:45][CH2:46][CH2:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=2)=[CH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:31])[CH:42]=[CH:41][N:40]=[CH:39]1
Reactant: CCOC(=O)CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(CCCC(=O)Cn2ccnc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CCCCCC=C(CCCc1ccc(OC)cc1)Cn1ccnc1
Reaction time: 1 h

Procedure:
A stirred suspension containing (7-ethoxy-7-oxoheptyl) triphenylphosphonium bromide (12 g, 0.024 mol) in dry tetrahydrofuran (40 ml) at room temperature under a nitrogen atmosphere was treated with potassium t-butoxide (2.70 g, 0.024 mol). The resulting orange mixture was stirred for 1 hour, treated with a solution of 1-(1H-imidazol-1-yl)-5-(4-methoxyphenyl)-2-pentanone (5.0 g, 0.019 mol) in dry tetrahydrofuran (20 ml) and then stirred for an additional 14 hours. The solvent was evaporated off under reduced pressure and the residue was dissolved in ethyl acetate (300 ml), washed with water (3×150 ml) and extracted into hydrochloric acid (4×150 ml of 5M). The acid extracts were combined, washed with ethyl acetate, basified using sodium carbonate, and extracted with ethyl acetate (4×250 ml). The organic extracts were combined, washed with water then brine, dried over sodium sulfate and the solvent was evaporated off under reduced pressure to yield a crude product. The crude product was purified by column chromatography (silica gel, 40% ethyl acetate in hexane to 100% ethyl acetate) to yield an isomeric mixture of E- and Z-ethyl 8-[(1H-imidazol-1-yl)methyl]-11-(4-methoxyphenyl)-7-undecenoate as a pale-yellow oil having the following structural characteristics:
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[O:8][CH2:9][CH2:10][CH2:11][NH2:12])[C:2]([NH2:4])=[NH:3].[NH2:16][C:17]1[C:21](OC)=[N:20][S:19](=[O:24])[N:18]=1>CO>[NH2:16][C:17]1[C:21]([NH:12][CH2:11][CH2:10][CH2:9][O:8][C:7]2[CH:13]=[CH:14][CH:15]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[CH:6]=2)=[N:20][S:19](=[O:24])[N:18]=1
Reactant: N=C(N)Nc1cccc(OCCCN)c1
Reactant: COC1=NS(=O)N=C1N
Solvent: CO
Product: N=C(N)Nc1cccc(OCCCNC2=NS(=O)N=C2N)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of crude 3-(3-guanidinophenoxy)propylamine [prepared in Step D] in 10 ml of methanol was added 3-amino-4-methoxy-1,2,5-thiadiazole 1-oxide (0.59 g; 4.0 mmoles) and the mixture was stirred at ambient temperature for 17 hours and then heated at 50° for 2.5 hours. The reaction mixture was filtered, evaporated under reduced pressure and the residue was chromatographed by flash chromatography on 75 g of silica gel (230-400 mesh) using methanol-methylene chloride. The appropriate fractions were combined and evaporated under reduced pressure to yield 0.25 g of the title compound as an oil; TLC [silica gel/CH2Cl2 :CH3OH (4:1)] gave Rf=0.21.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([O:29][CH2:30][CH2:31][O:32][CH3:33])[C:11]3[CH2:17][N:16]([C:18]([C:20]4[CH:21]=[N:22][N:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=45)=[O:19])[CH2:15][CH2:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[CH3:34][Sn](C)(C)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:33][O:32][CH2:31][CH2:30][O:29][C:10]1[C:11]2[CH2:17][N:16]([C:18]([C:20]3[CH:21]=[N:22][N:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=34)=[O:19])[CH2:15][CH2:14][C:12]=2[N:13]=[C:8]([C:5]2[CH:6]=[N:7][C:2]([CH3:34])=[CH:3][CH:4]=2)[N:9]=1
Reactant: C[Sn](C)(C)C
Reactant: COCCOc1nc(-c2ccc(Cl)nc2)nc2c1CN(C(=O)c1cnn3ccccc13)CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COCCOc1nc(-c2ccc(C)nc2)nc2c1CN(C(=O)c1cnn3ccccc13)CC2
Temperature: 150 °C
Yield: 48.5 %

Procedure:
To a solution of 30 mg (0.065 mmol) O-2 in 1 mL DMF in a microwave vial was added approximately 20 uL (˜0.15 mmol) tetramethyltin and 8 mg (˜10 mol %) tetrakistriphenylphosphinepalladium(0). The reaction was heated by microwave irradiation for 20 minutes at 150° C. After cooling, the reaction was purified by reverse phase HPLC (CH3CN/H2O with TFA as modifier), and the fractions containing the product were partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to provide R-1 as a white solid (14 mg, 49% yield). HRMS m/z (M+H) 445.1977 found, 445.1983 required.
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:11])=[C:4](F)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[NH2:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15]>>[Cl:1][C:2]1[C:3]([I:11])=[C:4]([NH:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: N#Cc1ncc(Cl)c(I)c1F
Reactant: CCC(N)CC
Product: CCC(CC)Nc1c(C#N)ncc(Cl)c1I
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 5-chloro-3-fluoro-4-iodopicolinonitrile (46 mg, 0.16 mmol) in 3-aminopentane (1 mL) was heated to 80° C. for 1 h. The reaction mixture was allowed to cool to RT, concentrated in vacuo, and then diluted with EtOAc and water. The organic layer was washed with water and filtered through a silica gel plug to provide the title compound as a white powder (55 mg, 100%) which was characterized by LCMS (m/z=350.1 [M+H]+) and 1H NMR.