Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:18][CH:19]([N:26]=[C:27]=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCCCCC.CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:27]([NH:26][CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH3:18])=[O:28])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Reactant: CC(N=C=O)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(NC(=O)N1CCN(c2ccnc3cc(Cl)ccc23)CC1)c1ccccc1

Procedure:
7-Chloro-4-(piperazin-1-yl)quinoline (62 mg, 0.25 mmol) and α-methylbenzyl isocyanate (42 μL, 0.30 mmol) in THF (10 mL) are reacted according to method C yielding the title product as a colorless solid after column chromatography with hexane-EtOAc.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][O:11][C:12]1[C:20]2[N:19]([CH3:21])[C:18](=[O:22])[N:17]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1)C)(C)(C)C.[ClH:31]>C(O)C>[ClH:31].[CH2:23]([N:17]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([O:11][CH2:10][CH2:9][NH:7][CH3:6])[C:20]=2[N:19]([CH3:21])[C:18]1=[O:22])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CN(CCOc1cccc2c1n(C)c(=O)n2Cc1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: CNCCOc1cccc2c1n(C)c(=O)n2Cc1ccccc1

Procedure:
[2-(1-Benzyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-ethyl]-methyl-carbamic acid tert-butyl ester (92 mg, 0.223 mmol) was dissolved in 1 mL ethanol and combined with 0.5 mL of 2N ethanolic HCl, and the resulting solution was refluxed 30 minutes. On cooling, a white precipitate was observed. The solid was filtered and dried for 18 hours under vacuum to give 47 mg of 1-benzyl-3-methyl-4-(2-methylamino-ethoxy)-1,3-dihydro-benzoimidazol-2-one hydrochloride. MP: 203.8-205.1° C. MS: 312 (M+H)+.
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][N:13]=[C:14]2[CH3:17])=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+]>CO>[CH3:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][NH:13][CH:14]2[CH3:17])=[CH:9][CH:8]=1
Reactant: COc1ccc2c(c1)C(C)=NCC2
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)C(C)NCC2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.4 %

Procedure:
Sodium cyanoborohydride (0.43 g) was added to a solution of 7-methoxy-1-methyl-3,4-dihydro-isoquinoline (2.67 g) in methanol (41 mL). The mixture was stirred at rt for 20 min. Aqueous sodium bicarbonate (saturated, 10 mL) was added to quench the excess hydride reagent. The methanol was evaporated under vacuum and the aqueous solution was diluted with sodium bicarbonate (saturated, 30 mL) and extracted with dichloromethane (2×30 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to afford 7-methoxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline (2.55 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH:13]([F:15])[F:14])=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH2:27][CH2:26][NH:25][N:24]=2)=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([O:12][CH:13]([F:15])[F:14])=[C:4]([NH:9][C:10]([N:25]2[CH2:26][CH2:27][C:23]([C:20]3[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=3)=[N:24]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1OC(F)F
Reactant: Clc1ccc(C2=NNCC2)cc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Cl)c(Cl)c1OC(F)F)N1CCC(c2ccc(Cl)cc2)=N1
Temperature: 80 °C
Reaction time: 2 h
Yield: 39.1 %

Procedure:
12.7 g (0.05 mol) of 3-chloro-4-monochlorodifluoromethoxy-phenyl isocyanate in 20 ml of toluene were added, at 60° C., to a solution of 9 g (0.05 mol) of 3-(4-chlorophenyl)-2-pyrazoline in 60 ml of toluene. The batch was stirred for 2 hours at 80° C. On cooling to room temperature, the product precipitated and was filtered off. 8.5 g (39% of theory) of 1-[(3-chloro-4-monochlorodifluoromethoxy-phenyl)-carbamoyl]-3-(4-chlorophenyl)-2-pyrazoline with a melting point of 161° C. were obtained.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1>>[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][CH2:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH2:5][CH2:13][C:12]2[CH:15]=[CH:16][C:9]([Cl:8])=[CH:10][CH:11]=2)=[CH:11][CH:10]=1
Reactant: CC(=O)CC(C)=O
Reactant: ClCc1ccc(Cl)cc1
Product: O=C(CCc1ccc(Cl)cc1)CC(=O)CCc1ccc(Cl)cc1

Procedure:
Using 2,4-pentanedione (20.0 g, 0.2 mol) and 4-chlorobenzyl chloride (74.7 g), the reaction was carried out in the same manner as described in Example 17, (1), and the residual orange red semisolid (69 g) was recrystallized from methanol to give the title compound as s white prisms which was an ca 3:17 mixture of Keto/Enol as seen by the methylene singlet at δ3.51 ppm and the methine singlet at δ5.37 ppm in the 1HNMR spectrum; yield: 24.7 g; mp 74.6°-76.1° C.
Reaction SMILES: [I-].[K+].C(Br)C.[Cl:6][C:7]1[C:11](N(CC)C(=O)C)=[CH:10][N:9]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:8]=1.Cl[C:25]1[C:29](NC(=O)C)=CN(C2C=NC=CC=2)[N:26]=1.Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:6][C:7]1([NH:26][CH2:25][CH3:29])[CH:11]=[CH:10][N:9]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[NH:8]1
Reactant: CC(=O)Nc1cn(-c2cccnc2)nc1Cl
Reactant: CCN(C(C)=O)c1cn(-c2cccnc2)nc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: O
Solvent: CCBr
Product: CCNC1(Cl)C=CN(c2cccnc2)N1
Reaction time: 24 h

Procedure:
3-Chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-amine (1d) may be prepared through the reaction pathway sequence disclosed in Scheme 5. In step d1, N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)acetamide (1c) may be alkylated with ethyl bromide (EtBr) in the presence of a base, such as sodium hydride (NaH), sodium tert-butoxide (NaOt-Bu), potassium tert-butoxide (KOt-Bu), or potassium tert-amyloxide in a polar aprotic solvent, such as tetrahydrofuran, at temperatures from about 20° C. to about 40° C., over a period of time of about 60 hours to about 168 hours, to yield N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (1c′). It has been discovered that use of an additive, such as potassium iodide (KI) or tetrabutylammonium iodide (TBAI) decreases the time necessary for the reaction to complete to about 24 hours. It was also discovered that heating the reaction at about 50° C. to about 70° C. in a sealed reactor (to prevent loss of ethyl bromide) decreases the reaction time to about 24 hours. In step d2, N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (1c′) may be treated with hydrochloric acid in water at temperatures from about 70° C. to about 90° C., to yield 3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazolamine (1d). The reaction pathway sequence disclosed in Scheme 5 may also be performed without the isolation of N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (1c′).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].Cl[CH2:13][C:14]1[CH:27]=[CH:26][C:17]([CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[CH:16][CH:15]=1.[I-].[K+]>C1COCC1>[O:4]=[C:3]([CH3:5])[CH:2]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[CH:26][CH:27]=1)[C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: ClCc1ccc(COC2CCCCO2)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(COC2CCCCO2)cc1)C(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl acetoacetate (11.7 ml) was added to a stirred suspension of sodium hydride (60% disp. in oil, 3.8 g) in THF (200 ml) at 0° C. under nitrogen. After 1 h, a solution of 2-(4-(chloromethyl)benzyloxy)tetrahydro-2H-pyran (22.2 g) in THF (50 ml) was added, the mixture warmed to rt, then potassium iodide (16 g) added and heated under reflux for 48 h. The mixture was partitioned between water and ether, the organics separated, washed with water, dried and evaporated under reduced pressure. The residue was purified by column chromatography eluting with 20% EtOAc in isohexane to afford the subtitle compound, 15.66 g.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22]C)=[O:21])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:9][CH:10]=1)[CH3:3].[OH-].[Na+]>CO>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([OH:22])=[O:21])=[CH:18][CH:19]=2)=[O:13])[CH:8]=[CH:9][CH:10]=1)[CH3:1]
Reactant: COC(=O)c1ccc(C(=O)Nc2cccc(CN(C)C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)Cc1cccc(NC(=O)c2ccc(C(=O)O)cc2)c1
Yield: 93.3 %

Procedure:
A solution of ester (IX; R=Z=H) (5.30 g, 17 mmol) in MeOH (10 mL) was treated with one equivalent of NaOH (17.0 nil of 1.0 N aqueous solution), and the mixture was heated until the MeOH had boiled off, and for 1 h under reflux, then cooled and filtered. Exact neutralisation (with17.0 mL of 1.0 N aqueous HCl) followed by refrigeration yielded 4-[3-(N,N-dimethylaminomethyl) phenyl]carbamoylbenzene-carboxylic acid (X;R=Z=H) (4.73 g, 93%), mp (MeOH/EtOAc) 209°-210 ° C. 1H NMR (CD3SOCD3) 10.41 (s, 1 H, NH), 8.07 (d, J=7.0 Hz, 2 H, H-2', 6'), 8.02 (d, J=7.0 Hz, 2 H, H-3',5'), 7.82 (s, 1 H, H-2), 7.72(d, J=8.05 Hz, 1 H, H-4), 7.33 (U, J= 7.8 Hz, 1 H, H-5), 7.09 (d, J=7.6 H z, 1 H, H -6 ), 3.61 (s, 2 H, CH2), 2.32 (s, 6 H, N(CH3)2).Anal. (C17H18N2O3) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CCCCCC.CC(N=NC(C#N)(C)C)(C#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][Br:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Cl)ccc1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(Br)c(CBr)c1
Temperature: 25 °C
Yield: 79.8 %

Procedure:
20.5 g (100 mmol) of 2-bromo-5-chlorotoluene was dissolved in 200 ml of carbon tetrachloride, 0.2 g (1 mmol) of AIBN and 19.6 g (110 mmol) of N-bromosuccinimide were added thereto, the resulting mixture was refluxed for 2 hours and cooled to room temperature. The reaction mixture was washed with 50 ml of water twice and with 50 ml of a brine solution, dried over anhydrous MgSO4, and distilled under a reduced pressure to obtain an oil containing a small amount of the starting material. The oil was dissolved in 20 ml of hexane, and recrystallized at room temperature to obtain 22.7 g (yield 80%) of 2-bromo-1-bromomethyl-5-chlorobenzene.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([N:12]2[CH2:18][C:17]3[CH:19]=[CH:20][C:21]([O:23][CH2:24][CH2:25][CH2:26][OH:27])=[CH:22][C:16]=3[S:15](=[O:29])(=[O:28])[CH2:14][CH2:13]2)[CH:3]=1.[C:30](=[O:37])([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[NH2:31].CC(C)([O-])C.[Na+]>O1CCOCC1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:27][CH2:26][CH2:25][CH2:24][O:23][C:21]1[CH:20]=[CH:19][C:17]2[CH2:18][N:12]([C:4]3[CH:3]=[C:2]([NH:31][C:30](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]=3)[CH2:13][CH2:14][S:15](=[O:29])(=[O:28])[C:16]=2[CH:22]=1
Reactant: CC(C)(C)OC(N)=O
Reactant: O=S1(=O)CCN(c2cc(Cl)c3ccccc3n2)Cc2ccc(OCCCO)cc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1cc(N2CCS(=O)(=O)c3cc(OCCCO)ccc3C2)nc2ccccc12
Temperature: 120 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A mixture solution of 3-{[4-(4-chloroquinolin-2-yl)-1,1-dioxido-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl]oxy}propan-1-ol (300.0 mg, 0.70 mmol), tert-butyl carbamate (175.0 mg, 1.5 mmol), 1,1′-bis(diphenylphosphino)ferrocene (70.0 mg, 0.113 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (70.0 mg, 0.075 mmol) and sodium tert-butoxide (232.0 mg, 2.25 mmol) in 1,4-dioxane (2.0 mL) was heated with stirring at 120° C. for 2 hours under microwave irridiation. After being cooled to room temperature, the reaction mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL×2), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 359.1 mg of the crude product as yellow oil which was used for next step without further purification. MS obsd. (ESI+) [(M+H)+] 514.
Reaction SMILES: [Br:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][C@@:7]2([CH3:32])[N:11]3[C:12]([C:15]([NH:17][C@@H:18]([CH3:22])[C:19]([OH:21])=O)=[O:16])=[CH:13][N:14]=[C:10]3[N:9]([C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)[C:8]2=[O:31])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH:42]1[C:46]([C@@H:47]2[CH2:52][CH2:51][CH2:50][NH:49][CH2:48]2)=[N:45][N:44]=[N:43]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Br:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][C@@:7]2([CH3:32])[N:11]3[C:12]([C:15]([NH:17][C@@H:18]([CH3:22])[C:19](=[O:21])[N:49]4[CH2:50][CH2:51][CH2:52][C@@H:47]([C:46]5[NH:45][N:44]=[N:43][N:42]=5)[CH2:48]4)=[O:16])=[CH:13][N:14]=[C:10]3[N:9]([C:23]3[CH:24]=[C:25]([Cl:30])[CH:26]=[C:27]([Cl:29])[CH:28]=3)[C:8]2=[O:31])=[CH:4][CH:3]=1
Reactant: C[C@H](NC(=O)c1cnc2n1[C@](C)(Cc1ccc(Br)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)O
Reactant: C1CNC[C@H](c2nnn[nH]2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)c1cnc2n1[C@](C)(Cc1ccc(Br)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)N1CCC[C@@H](c2nnn[nH]2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 16.2 %

Procedure:
To a cold (0° C.) solution of (S)-2-{[(R)-5-(4-bromo-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-propionic acid (0.050 g, 0.088 mmol) in DMF (1 mL) was added (R)-3-(1H-tetrazol-5-yl)-piperidine trifluoro-acetic acid salt (0.047 g, 0.18 mmol), HATU (0.040 g, 0.11 mmol) and Et3N (0.026 mL, 0.18 mmol). The reaction was allowed to stir for 10 minutes and HOAt (0.024 g, 0.18 mmol) was added and the mixture allowed to warm to room temperature overnight. The crude reaction mixture was purified by reverse-phase HPLC to give 10 mg of the title compound as a white solid, m/z 701.4 [M]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[C:6]([NH:8][C:9]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:26][C:10]=1[C:11]([NH:13][C:14]1[CH:15]=[N:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:18][CH:19]=1)=[O:12])=[O:7].[SH:39][C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=1)[C:43]([OH:45])=[O:44].C(N(CC)CC)C>CN(C)C=O.O>[C:20]1([C:17]2[N:18]=[CH:19][C:14]([NH:13][C:11]([C:10]3[CH:26]=[C:27]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[CH:28]=[CH:29][C:9]=3[NH:8][C:6]([C:5]3[CH:4]=[C:3]([CH:38]=[CH:37][CH:36]=3)[CH2:2][S:39][C:40]3[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=3)[C:43]([OH:45])=[O:44])=[O:7])=[O:12])=[CH:15][N:16]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)c1cccc(S)c1
Reactant: O=C(Nc1ccc(N2CCCCC2)cc1C(=O)Nc1cnc(-c2ccccc2)nc1)c1cccc(CBr)c1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(O)c1cccc(SCc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3C(=O)Nc3cnc(-c4ccccc4)nc3)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.7 %

Procedure:
To a solution of 2-(3-(bromomethyl)benzamido)-N-(2-phenylpyrimidin-5-yl)-5-(piperidin-1-yl)benzamide (120 mg, 0.23 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL) was added 3-mercaptobenzoic acid (42.12 mg, 0.27 mmol, 1.20 equiv) and triethylamine (46.08 mg, 0.46 mmol, 2.00 equiv) and the resulting solution was stirred for 3 h at room temperature. The mixture was diluted with 70 mL of water, extracted with 3×50 mL of ethyl acetate and the organic layers combined, dried over sodium sulfate, and concentrated under vacuum. The crude product (100 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA to afford 24.7 mg (17%) of a light yellow solid. 1H-NMR (300 MHz, DMSO, ppm): δ 10.94 (m, 2H), 9.23 (d, J=9.3 Hz, 2H), 8.36 (m, 2H), 8.12 (d, J=9 Hz, 1H), 7.95 (s, 1H), 7.85 (s, 1H), 7.73 (m, 2H), 7.45 (m, 9H) 4.39 (s, 2H), 3.33 (s, 4H), 1.72 (s, 6H). MS (ES, m/z): 644 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]([CH2:26][CH2:27][CH3:28])[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([NH2:25])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]=[CH:19][C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)=[CH:13][CH:12]=1)[CH2:2][CH3:3].[BH4-].[Na+]>CO>[CH2:26]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([NH2:25])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][NH:18][CH2:19][C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)=[CH:15][CH:16]=1)[CH2:27][CH3:28]
Reactant: CCCN(CCC)CCCCC(N)Cc1ccc(CN=Cc2ncc[nH]2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCN(CCC)CCCCC(N)Cc1ccc(CNCc2ncc[nH]2)cc1

Procedure:
560 mg (1.46 mmol, 1.0 equivalent) of {(4-dipropylaminobutyl)-[4-(1H-imidazol-2-ylmethylidene)aminomethylbenzyl]methyl}amine (43) and 12 ml of methanol were charged in a 50 ml recovery flask under a nitrogen stream. The mixture was then stirred. 113 mg (2.92 mol, 2.0 equivalents) of sodium borohydride was added to the mixture at 0° C. The mixture was then stirred at 0° C. for one hour and at 20° C. for one hour.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1.[CH2:18]([O:20][C:21](=[O:50])[C@@H:22]([NH:26][C:27](=[O:49])[CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]1)[CH:23]([CH3:25])[CH3:24])[CH3:19]>>[CH3:25][CH:23]([CH3:24])[C@H:22]([NH:26][C:27](=[O:49])[CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:37][CH2:38][N:39]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][C:13](=[O:17])[NH:14]3)=[CH:9][CH:8]=2)[CH2:40][CH2:41]1)[C:21]([O:20][CH2:18][CH3:19])=[O:50]
Reactant: O=C1CCc2ccc(OCCCCBr)cc2N1
Reactant: CCOC(=O)[C@@H](NC(=O)COc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1)C(C)C
Product: CCOC(=O)[C@@H](NC(=O)COc1ccccc1N1CCN(CCCCOc2ccc3c(c2)NC(=O)CC3)CC1)C(C)C

Procedure:
(S)-Ethyl 3-methyl-2-(2-(2-(4-(4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)butyl)piperazin-1-yl)phenoxy)acetamido)butanoate (14b) (Scheme 2) was synthesized from the compounds 3 and 13b by following the protocol described for the compound 14a (Example 15). Colorless oil, 0.27 g (58%). 1H NMR (400 MHz, CDCl3): δ 0.83 (d, J=7.0 Hz, 3H); 0.90 (d, J=7.0 Hz, 3H); 1.24 (t, J=7.2 Hz, 3H); 1.60-1.69 (m, 2H); 1.74-1.79 (m, 2H); 2.13 (quintet, J=6.4 Hz, 1H); 2.43 (t, J=7.2 Hz, 2H); 2.55 (t, J=7.2 Hz, 2H); 2.65 (broad s, 4H); 2.82 (t, J=7.2 Hz, 2H); 3.01-3.13 (m, 4H); 3.90 (t, J=6.0 Hz, 2H); 4.05 (q, J=7.2 Hz, 2H); 4.53-4.56 (m, 1H); 4.60 (two s, 2H); 6.39 (d, J=2.4 Hz, 1H); 6.45-6.47 (m, 1H); 6.84-6.87 (m, 1H); 6.92-6.95 (m, 3H); 7.56 (d, J=9.2 Hz, 1H); 9.46 (broad s, 2H). MS (ESI): m/z=581.30 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:15])[N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:5]=[CH:6][C:7]=1Cl.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][C:25]#[N:26].CC(C)([O-])C.[K+]>O1CCCC1>[Cl:1][C:2]1[C:3](=[O:15])[N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:5]=[CH:6][C:7]=1[CH:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]([F:16])([F:27])[F:28])[C:25]#[N:26]
Reactant: N#CCc1ccccc1C(F)(F)F
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC(c1ccccc1C(F)(F)F)c1cnn(C2CCCCO2)c(=O)c1Cl
Temperature: 80 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
A solution of 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20, 1.0 g, 4.01 mmol) in tetrahydrofuran (16.7 mL, 0.24M) was treated with (2-trifluoromethyl-phenyl)-acetonitrile (743 mg, 4.01 mmol) followed by potassium tert-butoxide (676 mg, 6.02 mmol). The reaction was heated at 80° C. for 2 h. After this time, the reaction was cooled to 25° C. where it stirred overnight. The reaction mixture was then partitioned between water (100 mL) and methylene chloride (3×75 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel column chromatography (AnaLogix, 40 g, 20-40% ethyl acetate/hexanes) afforded [5-chloro-6-oxo-1-(tetrahydro-pyran-2-yl)-1,6-dihydro-pyridazin-4-yl]-(2-trifluoromethyl-phenyl)-acetonitrile (0.73 g, 45%) as a yellow solid; ES+-HRMS m/e calcd for C18H15N3O2F3Cl [M+H+] 398.0878, found 398.0878.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:8]([CH2:11][C:12]([CH3:17])([N+:14]([O-:16])=[O:15])[CH3:13])=[CH:9][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[S:18]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19]1>>[CH3:13][C:12]([N+:14]([O-:16])=[O:15])([CH3:17])[CH2:11][C:8]1[N:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:20]3[CH:21]=[CH:22][S:18][CH:19]=3)[C:3]2=[N:10][CH:9]=1
Reactant: CC(C)(Cc1cnc2c(Br)cccn12)[N+](=O)[O-]
Reactant: OB(O)c1ccsc1
Product: CC(C)(Cc1cnc2c(-c3ccsc3)cccn12)[N+](=O)[O-]
Yield: 75.3 %

Procedure:
8-Bromo-3-(2-methyl-2-nitropropyl)imidazo[1,2-a]pyridine (1.0 g, 3.35 mmol) and thiophene-3-boronic acid (0.64 g, 5.0 mmol) are coupled as described in Amine 14 to give 760 mg of 3-(2-methyl-2-nitropropyl)-8-(3-thienyl)imidazo[1,2-a]pyridine (75%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([S:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([NH:20][C@@H:21]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:22][CH2:23][C:24]([N:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][C@H:27]2[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:25])=[O:19])[NH2:17])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CN1CCOCC1.[CH2:52]1[O:72][C:71]2[CH:70]=[CH:69][C:56]([CH2:57][O:58][C:59](ON3C(=O)CCC3=O)=[O:60])=[CH:55][C:54]=2[O:53]1>C(Cl)Cl>[CH2:52]1[O:72][C:71]2[CH:70]=[CH:69][C:56]([CH2:57][O:58][C:59]([NH:17][C@H:16]([C:18]([NH:20][C@@H:21]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:22][CH2:23][C:24]([N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:28][C@H:27]3[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:25])=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12][NH:11][S:10][C:5]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][N:6]=3)=[O:60])=[CH:55][C:54]=2[O:53]1
Reactant: O=C(OCc1ccc2c(c1)OCO2)ON1C(=O)CCC1=O
Reactant: CCOC(=O)[C@@H](CCC(=O)N1c2ccccc2C[C@H]1C(=O)OCC)NC(=O)[C@@H](N)CCCCNSc1ncccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@@H](CCC(=O)N1c2ccccc2C[C@H]1C(=O)OCC)NC(=O)[C@H](CCCCNSc1ncccc1[N+](=O)[O-])NC(=O)OCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.8 %

Procedure:
An aliquot (1.0 g) of the resulting ester was dissolved in 30 ml of methylene chloride, and 0.21 g of N-methylmorpholine and 1.07 g of N-(3,4-methylenedioxybenzyloxycarbonyloxy)succinimide were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was washed successively with saturated aqueous sodium bicarbonate solution, 5% aqueous potassium hydrogensulfate solution, and water, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was recrystallized from ethanol/methanol to give 1.1 g of ethyl 1-[N2 -(3,4-methylenedioxybenzyloxycarbonyl)-N6 -(3-nitro-2-pyridinesulfenyl)-L-lysyl-O1 -ethyl-gamma-D-glutamyl]indoline-2(S)-carboxylate. mp. 130°-135° C. [α]D27 : -23.2° (dimethylformamide).