Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.[CH3:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15]C)(=[O:8])=[O:7]>C(Cl)Cl.O>[CH3:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])(=[O:7])=[O:8]
Reactant: COc1ccccc1S(C)(=O)=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1ccccc1O
Reaction time: 0.17 h
Yield: 63.9 %

Procedure:
m-Chloroperbenzoic acid (280 mg, 1.62 mmol) was added to a cold (0-4° C.) solution of 1-methoxy-2-methylsulfanyl-benzene (100 mg, 0.64 mmol) in DCM (3 mL) and stirring was continued for 1 hr. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with saturated brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 110 mg (91.6% Yield) of 1-methanesulfonyl-2-methoxy-benzene. Boron tribromide (370 mg, 1.47 mmol) was added to a cold solution (−70° C.) solution of 1-methanesulfonyl-2-methoxy-benzene (10 mg, 0.591 mmol) in DCM (2 mL) and stirring was continued for 10 minutes. After which the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with saturated brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 65 mg (64.35% Yield) of 2-methanesulfonyl-phenol. 2-Methylsulfonyl-phenol was converted to 4-(2-methanesulfonyl-phenoxy)-piperidine hydrochloride according to Step 1 of the General Scheme).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C[O:11][C:12]([C:14]1[C:27]2[O:26][CH2:25][C:21]3([CH2:24][S:23][CH2:22]3)[CH2:20][O:19][C:18]=2[C:17]([O:28][CH3:29])=[CH:16][CH:15]=1)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH2:8][C:12]([C:14]1[C:27]2[O:26][CH2:25][C:21]3([CH2:24][S:23][CH2:22]3)[CH2:20][O:19][C:18]=2[C:17]([O:28][CH3:29])=[CH:16][CH:15]=1)=[O:11]
Reactant: Cc1c(Cl)cncc1Cl
Reactant: COC(=O)c1ccc(OC)c2c1OCC1(CO2)CSC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c1OCC1(CO2)CSC1

Procedure:
Following the general procedure, condensation of 3,5-dichloro-4-methylpyridine (366 mg, 2.26 mmol) with compound 516 (516 mg, 1.74 mmol) in THF (10 mL) in the presence of LiHMDS (5.2 mL, 5.2 mmol) afforded compound 123 as a white solid material after purification by column chromatography (55-65% EtOAc in light petroleum). LC-MS: RT=4.23 min.; m/z 426.24, 428.25 (M+H)+, 424.23 (M−H)−. 1H NMR (CDCl3): δ 8.51 (2H, s), 7.57 (1H, d, J 9.2), 6.71 (1H, d, J 9.2), 4.64 (2H, s), 4.46 (2H, s), 4.33 (2H, s), 3.93 (3H, s), 3.20 (2H, d, J 9.9), 3.12 (2H, d, J 9.9).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:19]1[S:20][CH:21]=[CH:22][N:23]=1)CCC>CN(C=O)C.[Pd](Cl)Cl.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]>[S:20]1[CH:21]=[CH:22][N:23]=[C:19]1[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: N#Cc1ccc(Br)cc1C(F)(F)F
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2nccs2)cc1C(F)(F)F
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
A solution of 4-bromo-2-(trifluoromethyl)benzonitrile (0.5 g, 2 mmol) in DMF (5 mL) was purged with argon and 2-(tributylstannyl)thiazole (1.12 g/0.9 mL, 3 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (0.14 g, 0.2 mmol) added. The reaction mixture was purged with argon for 5 min and retained in microwave for 30 min at 100° C. The reaction mixture was diluted with ice cold water (10 mL) and extracted with ethyl acetate (200 mL). The organic solvent was dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to obtain crude product. The crude product was purified by silica gel chromatography (100-200 mesh; 8% ethyl acetate in hexane) to give 4-(thiazol-2-yl)-2-(trifluoromethyl)benzonitrile (0.42 g, 84% yield) as pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.42-8.39 (m, 2H), 8.27 (d, 1H), 8.08 (d, 1H), 8.03 (d, 1H). LC-MS m/z calculated for [M+H]+255.01. found 255.0.
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([C:12]1([N:30]([CH3:32])[CH3:31])[CH2:17][CH2:16][CH:15]([C:18]2[NH:19][C:20]3[C:25]([C:26]=2[CH3:27])=[CH:24][C:23]([O:28]C)=[CH:22][CH:21]=3)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)Cl>[CH2:5]([C:12]1([N:30]([CH3:32])[CH3:31])[CH2:13][CH2:14][CH:15]([C:18]2[NH:19][C:20]3[C:25]([C:26]=2[CH3:27])=[CH:24][C:23]([OH:28])=[CH:22][CH:21]=3)[CH2:16][CH2:17]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccc2[nH]c(C3CCC(Cc4ccccc4)(N(C)C)CC3)c(C)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1c(C2CCC(Cc3ccccc3)(N(C)C)CC2)[nH]c2ccc(O)cc12

Procedure:
A 1 M solution of BBr3 in methylene chloride (3.48 ml, 3.48 mmol) was added to a solution of 1-benzyl-4-(5-methoxy-3-methyl-1H-indol-2-yl)-N,N-dimethylcyclohexanamine (less polar diastereoisomer, 437 mg, 1.16 mmol) in dry methylene chloride (50 ml) at RT, while stirring and with exclusion of moisture. After 10 min a precipitate precipitated out. The mixture was stirred at RT for 24 h.—For working up, sat. NaHCO3 solution (20 ml) was added to the mixture and the mixture was stirred for 48 h. The organic phase was separated off and the aqueous phase was extracted with methylene chloride (3×10 ml). The combined organic phases were dried over Na2SO4 and then concentrated. 2-(4-Benzyl-4-(dimethylamino)cyclohexyl)-3-methyl-1H-indol-5-ol (less polar diastereoisomer) was obtained in this way in a yield of 291 mg (69%).
Reaction SMILES: [OH:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH3:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:15][C:16]1[C:21]([N:22]([CH3:37])[C:23](=[O:36])[CH2:24][N:25]2[C:29](=[O:30])[C:28]3=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]3[C:26]2=[O:35])=[CH:20][CH:19]=[C:18]([Cl:38])[C:17]=1[CH2:39]OS(C)(=O)=O.O>CN(C)C=O>[Cl:15][C:16]1[C:21]([N:22]([C:23](=[O:36])[CH2:24][N:25]2[C:26](=[O:35])[C:27]3=[CH:34][CH:33]=[CH:32][CH:31]=[C:28]3[C:29]2=[O:30])[CH3:37])=[CH:20][CH:19]=[C:18]([Cl:38])[C:17]=1[CH2:39][O:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH3:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc2c(O)cccc2n1C
Reactant: CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)c(COS(C)(=O)=O)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN4C(=O)c5ccccc5C4=O)c3Cl)cccc2n1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.5 %

Procedure:
To a suspension of 4-hydroxy-1,2-dimethyl-1H-benzimidazole (250 mg) in N,N-dimethylformamide (2.5 ml) was added sodium hydride (60% in oil, 102 mg) under ice-cooling, and the mixture was stirred for 15 minutes at ambient temperature. To the mixture was added 2,6-dichloro-1-methylsulfonyloxymethyl-3-[N-methyl-N-(phthalimidoacetyl)-amino]benzene (799 mg), and the mixture was stirred for 3 hours at ambient temperature. Water was dropwise added thereto, and the resulting precipitates were collected by filtration to give 4-[2,6-dichloro-3-[N-(phthalimidoacetyl)-N-methylamino]benzyloxy]-1,2-dimethyl-1H-benzimidazole (418 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:40])=[C:4]([NH:18][C:19]([NH:21][C:22]2[C:27]([I:28])=[C:26]([C:29]([NH:31][CH2:32][CH:33]([OH:36])[CH2:34][OH:35])=[O:30])[C:25]([I:37])=[C:24]([NH2:38])[C:23]=2[I:39])=[O:20])[C:5]([I:17])=[C:6]([C:9]([NH:11][CH2:12][CH:13]([OH:16])[CH2:14][OH:15])=[O:10])[C:7]=1[I:8]>C(OC(=O)C)(=O)C.N1C=CC=CC=1.CN(C=O)C>[NH2:38][C:24]1[C:23]([I:39])=[C:22]([NH:21][C:19]([NH:18][C:4]2[C:5]([I:17])=[C:6]([C:9]([NH:11][CH2:12][CH:13]([O:16][C:9](=[O:10])[CH3:6])[CH2:14][O:15][C:14](=[O:15])[CH3:13])=[O:10])[C:7]([I:8])=[C:2]([NH2:1])[C:3]=2[I:40])=[O:20])[C:27]([I:28])=[C:26]([C:29]([NH:31][CH2:32][CH:33]([O:36][C:34](=[O:35])[CH3:33])[CH2:34][O:35][C:29](=[O:30])[CH3:26])=[O:30])[C:25]=1[I:37]
Reactant: Nc1c(I)c(NC(=O)Nc2c(I)c(N)c(I)c(C(=O)NCC(O)CO)c2I)c(I)c(C(=O)NCC(O)CO)c1I
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCC(CNC(=O)c1c(I)c(N)c(I)c(NC(=O)Nc2c(I)c(N)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c2I)c1I)OC(C)=O
Temperature: 25 °C
Reaction time: 65 h

Procedure:
N,N'-bis[3-amino-2,4,6-triiodo-5-(2,3-dihydroxypropylaminocarbonyl)phenyl]urea (1.23 g, 1.0 mmol) was dissolved in a mixture of acetic anhydride (5 ml), pyridine (5.5 ml) and DMF (5 ml). The solution was stirred at room temperature for 65 h, and the solvents were evaporated. The residue was dissolved in CH2Cl2 (250 ml) and the solution was washed with water (2×50 ml) 0.1M aqueous HCl (50 ml), water (100 ml) and a saturated aqueous solution of NaHCO3. After drying (Na2SO4) and evaporation, NMR and HPLC analysis of the residue showed an essentially pure product. Yield: 1.0 g (71%).
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:12]([CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].[Cl:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>CN(C=O)C>[ClH:24].[Cl:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]([N:14]([CH2:13][C:12]2[N:8]([CH2:7][C:6]3[CH:20]=[CH:21][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:9]=[N:10][CH:11]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:33])[CH:28]=[CH:29][CH:30]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: CCCCCNCc1cncn1Cc1ccc(C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCN(Cc1cncn1Cc1ccc(C#N)cc1)C(=O)Nc1cccc(Cl)c1
Product: Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the amine 7 (prepared above) in 2 mL of dry DMF at 0° C. was added NaH (37 mg, 60% dispersion in mineral oil). The solution was warmed to room temperature for 10 minutes, then recooled to 0° C. 3-Chlorophenylisocyanate (0.084 mL) was added dropwise, and the cooling bath was removed. After three hours, the reaction was poured into EtOAc/hexane (2:1) and water, washed with sat. aq. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude urea 1 as a yellow foam. Half of this material was purified by silica gel chromatography (3-5% MeOH/CH2Cl2), taken up in CH2Cl2 and treated with 1 M HCl/ether solution, and concentrated in vacuo. The product hydrochloride 1 (75 mg) was isolated as a yellow solid.
Reaction SMILES: [CH: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][CH2:12][O:13][C:14]([CH2:16][S:17][CH2:18]C(OCCC1C=CC2C(=CC=CC=2)C=1)=O)=[O:15].COS(=O)(=O)OC.O.[F:42][P-:43]([F:48])([F:47])([F:46])([F:45])[F:44].[K+]>C(OCC)(=O)C>[F:42][P-:43]([F:48])([F:47])([F:46])([F:45])[F:44].[CH: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][CH2:12][O:13][C:14]([CH2:16][SH+:17][CH3:18])=[O:15]
Reactant: O=C(CSCC(=O)OCCc1ccc2ccccc2c1)OCCc1ccc2ccccc2c1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: O
Solvent: CCOC(C)=O
Product: C[SH+]CC(=O)OCCc1ccc2ccccc2c1

Procedure:
2-naphthylethoxycarbonylmethyl sulfide in an amount of 24.63 g and dimethyl sulfuric acid in an amount of 13.24 g were mixed and allowed to a reaction at 80° C. for 10 hours. The reacted-mixture was then dissolved into a mixed solution of distillated water in an amount of 300 ml and ethyl acetate in an amount of 100 ml and stirred. The aqueous layer resulted was taken out, mixed with potassium hexafluorophosphate in an amount of 18.41 g and ethyl acetate in an amount of 300 ml and then stirred. The ethyl acetate layer was then washed with 100 ml of distillated water twice and mixed with anhydrous magnesium sulfate to remove water remained in the ethyl acetate layer. After evaporating ethyl acetate from the ethyl acetate layer, the residue was allowed to dry at 40° C. under reduced pressure to obtain the objective compound. The yield was 36.4 g.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C([O-])([O-])=O.[K+].[K+].[C:18]([O:22][C:23]([N:25]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].CCOC(C)=O>CC#N>[C:18]([O:22][C:23]([N:25]1[CH2:31][CH2:30][CH2:29][N:28]([CH2:2][CH2:3][C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:5])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: O=C(CCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCCN(CCC(=O)c2ccccc2)CC1
Temperature: 70 °C
Reaction time: 17 h
Yield: 80 %

Procedure:
3-Chloropropiophenone (7.14 g, 24.4 mmol). K2CO3 (8.79 g, 1.50 equiv) and KI (1.41 mg, 0.2 equiv) were added to a solution of the purified 1-(tert-butyloxycarbonyl)homopiperazine (8.486 g, 42.4 mmol) in CH3CN (60 mL). The reaction mixture was stirred at 70° C. for 17 h and then AcOEt (200 mL) was added to the cooled mixture. The precipitated solid was removed by filtration and washed with AcOEt (50 mL). The combined filtrate was evaporated to afford an oil which was purified by column chromatography (SiO2, 0%-20% CH3CN/AcOEt) to give 1-(tert-Butyloxycarbonyl)-4-(3-phenyl-3-oxopropyl)homopiperazine: 11.27 g, 80% yield, pale yellow oil: 1H NMR (CDCl3, 300 MHz) δ 1.40-1.65 (m, 9H), 1.80-1.95 (m, 2H), 2.65-2.85 (m, 4H), 3.01 (t, 2H, J=6.9 Hz), 3.19 (t, 2H, J=6.9 Hz), 3.35-3.55 (m, 4H), 7.47 (t, 2H, J=7.7 Hz), 7.55-7.65 (m, 1H), 7.90-8.02 (m, 2H). The purity was determined by RPLC/MS (Method B). RPLC tR=5.53 min (95%), 220 nm; ESI/MS m/e 333.4 (M++H, C19H29N2O3).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)=[O:3].[CH3:21][O:22][C:23]1[CH:35]=[CH:34][C:26]([CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:25][CH:24]=1>>[CH:14]1([CH2:13][C:12]([NH:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:31]3[CH2:30][CH2:29][N:28]([CH2:27][C:26]4[CH:34]=[CH:35][C:23]([O:22][CH3:21])=[CH:24][CH:25]=4)[CH2:33][CH2:32]3)=[O:3])=[CH:6][CH:7]=2)=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1ccc(CN2CCNCC2)cc1
Reactant: O=C(CC1CCCCC1)Nc1ccc(OC(=O)Cl)cc1
Product: COc1ccc(CN2CCN(C(=O)Oc3ccc(NC(=O)CC4CCCCC4)cc3)CC2)cc1

Procedure:
The title compound was prepared from 4-(2-cyclohexyl-acetylamino)-phenyl chloroformate and 1-(4-methoxybenzyl)-piperazine, preparative HPLC (Method C) (49%, white crystals). HPLC-MS m/z=466.3 (M+1), Rt: 2.85 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:12][N:13]([O:16]C2CCCCO2)[CH:14]=[O:15])[C:5]([F:30])=[C:4]([N:31]([CH2:33][C:34]2[O:35][CH:36]=[CH:37][CH:38]=2)[CH3:32])[N:3]=1>C(O)(=O)C.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:12][N:13]([OH:16])[CH:14]=[O:15])[C:5]([F:30])=[C:4]([N:31]([CH2:33][C:34]2[O:35][CH:36]=[CH:37][CH:38]=2)[CH3:32])[N:3]=1
Reactant: CN(Cc1ccco1)c1nc(Cl)nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)c1F
Solvent: O
Solvent: CC(=O)O
Product: CN(Cc1ccco1)c1nc(Cl)nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c1F
Reaction time: 8 h
Yield: 59.3 %

Procedure:
[(2R)-3-(2-{2-Chloro-5-fluoro-6-[(2-furanylmethyl)(methyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (0.6318 g, 1.145 mmol) was dissolved in acetic acid (8 mL) and water (2 mL). This reaction mixture was left to stir overnight. The volatiles were evaporated, and the resulting residue was purified by RP-HPLC to provide [(2R)-3-(2-{2-chloro-5-fluoro-6-[(2-furanylmethyl)(methyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide as a beige solid (0.3182 g, 59%). LCMS: (M+H)+=469.2.
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C@@:7]2([CH3:27])[N:11]3[C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=[C:10]3[N:9]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=3)[C:8]2=[O:26])=[CH:4][CH:3]=1.Cl.[C:31]([O:35][C:36](=[O:40])[C@@H:37]([NH2:39])[CH3:38])([CH3:34])([CH3:33])[CH3:32].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[C:31]([O:35][C:36](=[O:40])[C@@H:37]([NH:39][C:15]([C:12]1[N:11]2[C@@:7]([CH2:6][C:5]3[CH:28]=[CH:29][C:2]([Br:1])=[CH:3][CH:4]=3)([CH3:27])[C:8](=[O:26])[N:9]([C:18]3[CH:19]=[C:20]([Cl:25])[CH:21]=[C:22]([Cl:24])[CH:23]=3)[C:10]2=[N:14][CH:13]=1)=[O:17])[CH3:38])([CH3:34])([CH3:33])[CH3:32]
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Reactant: C[C@@]1(Cc2ccc(Br)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)O)n21
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: C[C@H](NC(=O)c1cnc2n1[C@](C)(Cc1ccc(Br)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 80.3 %

Procedure:
To a solution of (R)-5-(4-bromo-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid (2.5 g, 5.0 mmol) in DMF (5 mL) was added (S)-2-amino-propionic acid tert-butyl ester hydrochloride (0.92 g, 5.0 mmol), HOBt (0.68 g, 5.0 mmol), EDC (0.97 g, 5.0 mmol) and DMAP (0.061 g, 0.50 mmol). The reaction mixture was heated at 80° C. for 12 h. The mixture was allowed to cool to room temperature and diluted with water (100 mL). The mixture was extracted with EtOAc (3×100 mL) and the combined organic layers were washed with water, brine and dried with MgSO4. The mixture was filtered and concentrated in vacuo to give 2.5 g 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 tert-butyl ester as a yellow solid, m/z 623.5 [M+1]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:26][CH2:27][Cl:28])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:25])[NH:13][C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:24])[CH2:22]Cl)[CH:17]=[CH:18][CH:19]=2)=[CH:7][CH:6]=1.[CH3:29][NH:30][CH3:31]>C1COCC1>[Cl:28][CH2:27][CH2:26][N:4]([CH2:3][CH2:2][Cl:1])[C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:25])[NH:13][C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:24])[CH2:22][N:30]([CH3:31])[CH3:29])[CH:17]=[CH:18][CH:19]=2)=[CH:9][CH:10]=1
Reactant: CNC
Reactant: O=C(CCl)Nc1cccc(NC(=O)Nc2ccc(N(CCCl)CCCl)cc2)c1
Solvent: C1CCOC1
Product: CN(C)CC(=O)Nc1cccc(NC(=O)Nc2ccc(N(CCCl)CCCl)cc2)c1
Temperature: 55 °C

Procedure:
To a solution of N-(3-(3-(4-(bis(2-chloroethyl)amino)phenyl)ureido)phenyl)-2-chloroacetamide (0.88 g, 2 mmol) in THF (50 mL) was added dropwise dimethylamine (2M solution in THF) (2 mL, 4.0 mmol). The reaction mixture was heated at 50-60° C. for overnight. After cooling the mixture, the solvent was removed by evaporation under reduced pressure. The residue obtained was triturated with saturated aqueous solution of NaHCO3. The solid product was collected by filtration, washed successively with water and hexane, and dried to yield N-(3-(3-(4-(bis(2-chloroethyl)amino)phenyl)ureido)phenyl)-2-(dimethyl-amino)acetamide (BO-2189), 0.56 g (62%), mp 62-64° C. The product was dissolved in ethanol and excess of HCl in ethylacetate was added. The solution was evaporated in vacuo to dryness and the residue was co-evaporated several times with EtOH to dryness to form BO-2189 hydrochloride. 1H NMR (DMSO-d6) δ: 2.88 (6H, s, CH3), 3.68-3.71 (8H, m, CH2), 4.13 (2H, s, CH2), 6.71-6.73 (2H, d, J=8.8 Hz, Ar—H), 7.16-7.30 (5H, m, Ar—H), 7.78 (1H, s, Ar—H), 8.95 (1H, brs, NH), 9.24 (1H, brs, NH), 9.99 (1H, brs, NH). 13C NMR (CDCl3, 125 MHz) δ: 41.09, 43.25, 52.73, 57.88, 108.84, 112.56, 113.17, 113.55, 120.03, 129.04, 138.31, 140.73, 152.86, 162.91. HRMS [ES+]: calcd for C21H27Cl2N5O2, 452.3774 [M+H]+. found 452.1620. HPLC 97.3%.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][CH2:14][CH2:13]3)=[N:9][C:10]=2I)[CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[NH:35][CH:34]=[CH:33]3)O1>C1(P([Pd-4](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)C=CC=CC=1>[CH:12]1([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]3=[C:10]([C:30]3[CH:31]=[C:32]4[C:36](=[CH:37][CH:38]=3)[NH:35][CH:34]=[CH:33]4)[N:9]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: CC1(C)OB(c2ccc3[nH]ccc3c2)OC1(C)C
Reactant: Nc1nccn2c(C3CCC3)nc(I)c12
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Nc1nccn2c(C3CCC3)nc(-c3ccc4[nH]ccc4c3)c12
Temperature: 80 °C

Procedure:
A dry mixture of 8-amino-3-cyclobutyl-1-iodoimidazo[3,4-a]pyrazine (30 mg, 0.096 mmol), cesium carbonate (38 mg, 0.117 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (26 mg, 0.107 mmol) was purged with Argon 3 times prior to the addition of tetrakistriphenylphosphino palladium (0) (6 mg, 0.005 mmol). The mixture was purged twice more and then treated with a degassed mixture of DME:water (5:1, 2 mL). The resulting solution was degassed twice more and then heated at 80° C. overnight. The resulting reaction mixture was concentrated in vacuo, the residue dissolved in 1:1 MeCN:MeOH (1.5 mL) and purified by mass directed preparative HPLC to afford 3-cyclobutyl-1-(1H-indol-5-yl)imidazo[1,5-a]pyrazin-8-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.82-1.92 (1H, m) 1.95-2.08 (1H, m) 2.32-2.41 (4H, m) 3.82-3.93 (1H, m) 5.91 (2H, br. s.) 6.45 (1H, d, J=3.03 Hz) 6.90 (1H, d, J=−5.05 Hz) 7.26 (1H, dd, J=8.34, 1.52 Hz) 7.34 (1H, d, J=5.05 Hz) 7.35-7.39 (1H, m) 7.45 (1H, d, J=8.34 Hz) 7.64-7.68 (1H, m) 11.20 (1H, br. s.); MS (ES+): m/z 304.15 [MH+]. HPLC: tR 6.18 min (XTerra C18 5 uM, 4.6×15 mm, A: MeCN & B:10 mmol NH4OAc in 0.05% HOAc/aq., method Polar15).
Reaction SMILES: C(O)=O.C(N(CC)CC)C.[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([C:30](=[O:33])[CH2:31][Cl:32])[C:22]2[O:27][CH2:26][C:25](=[O:28])[NH:24][C:23]=2[CH:29]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O>[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([C@@H:30]([OH:33])[CH2:31][Cl:32])[C:22]2[O:27][CH2:26][C:25](=[O:28])[NH:24][C:23]=2[CH:29]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1COc2c(cc(OCc3ccccc3)cc2C(=O)CCl)N1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O=CO
Product: O=C1COc2c(cc(OCc3ccccc3)cc2[C@@H](O)CCl)N1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
The method is carried out analogously to a process described in the literature (Org. Lett. 2002, 4, 4373-4376). 8 mL of a mixture of formic acid and triethylamine (molar ratio=5:2) are added dropwise at −15° C. to 13.15 g (39.6 mmol) 6-benzyloxy-8-(2-chloro-acetyl)-4H-benzo[1,4]oxazin-3-one and 25.5 mg (0.04 mmol) Cp*RhCl[(S,S)-TsDPEN] (Cp*=pentamethylcyclopentadienyl and TsDPEN=(1S,2S)—N-p-toluenesulfonyl-1,2-diphenylethylenediamine) in 40 mL dimethylformamide. The mixture is stirred for 5 hours at this temperature, then 25 mg catalyst are added and the mixture is stirred overnight at −15° C. The reaction mixture is combined with ice water and filtered. The filter residue is dissolved in dichloromethane, dried with sodium sulfate and freed from the solvent. The residue is chromatographed (dichloromethane/methanol gradient) and the product recrystallized from diethyl ether/diisopropylether. Yield: 10.08 g (76%); Rf value=0.28 (dichloromethane:methanol=50:1 on silica gel).
Reaction SMILES: CNCC[C@H]([O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=12)[C:6]1[S:10][CH:9]=[CH:8][CH:7]=1.CC[O:24]CC>>[S:10]1[CH:9]=[CH:8][CH:7]=[C:6]1[OH:24].[C:12]1([OH:11])[C:17]2[C:16](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CNCC[C@H](Oc1cccc2ccccc12)c1cccs1
Reactant: CCOCC
Product: Oc1cccc2ccccc12
Product: Oc1cccs1

Procedure:
Duloxetine is acid labile, and acid hydrolysis of its ether linkage results in a thienyl alcohol and 1-naphthol. 50% of a dosage is hydrolyzed to 1-naphthol within one hour at a pH of 1.0, which is achieved under fasting conditions. At a pH of 2.0, 10% of the dosage degrades to 1-Naphthol in one hour and at a pH of 4.0, 10% degradation would take up to 63 hours. The reaction scheme showing the conversion of duloxetine to 1-naphthol and its thienyl derivative is shown below.