Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1([S:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH3:18])[C:12]=2[N:19]([C:27]2[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=2[F:34])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=C.CC1C=CC=C(C)N=1.[O:43]1CCOCC1>O.O=[Os](=O)(=O)=O>[F:34][C:28]1[CH:29]=[C:30]([I:33])[CH:31]=[CH:32][C:27]=1[N:19]([C:12]1[N:13]([CH3:18])[C:14](=[O:17])[CH:15]=[CH:16][C:11]=1[NH:10][S:7]([C:4]1([CH2:1][CH:2]=[O:43])[CH2:5][CH2:6]1)(=[O:9])=[O:8])[C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25]
Reactant: C1COCCO1
Reactant: C=CCC1(S(=O)(=O)Nc2ccc(=O)n(C)c2N(C(=O)OC(C)(C)C)c2ccc(I)cc2F)CC1
Agent: O=[Os](=O)(=O)=O
Solvent: Cc1cccc(C)n1
Solvent: O
Product: Cn1c(N(C(=O)OC(C)(C)C)c2ccc(I)cc2F)c(NS(=O)(=O)C2(CC=O)CC2)ccc1=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
To a solution of tert-butyl (3-{[(1-allylcyclopropyl)sulfonyl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-2-yl)(2-fluoro-4-iodophenyl)carbamate (140 mg, 0.232 mmol) in dioxane (2.30 ml) under a nitrogen atmosphere was added H2O (0.51 ml). Then NaIO4 (4 eq, 198 mg, 0.928 mmol) and 2,6-dimethyl pyridin (2 eq, 0.054 ml, 0.464 mmol) were added and the mixture was cooled to 0° C. At this temperature OsO4 (4% in H2O, 0.05 eq, 71 μl, 0.012 mmol) was added. The mixture was allowed to come to room temperature and then stirred for 18 hours. The mixture was diluted with H2O (4 ml) to form a fine suspension. After stirring for 30 min the precipitate was filtered off to afford the title compound (140 mg, 88%) in sufficient purity for the next transformation (88% UV) as a mixture of the aldehyde and a cyclised 1,2-thiazolidin-3-ol 1,1-dioxide form.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([CH3:21])[N:20]=1)=O)C1C=CC=CC=1>CCO.[Pd]>[CH3:21][C:19]1[N:20]=[C:16]([C@@H:12]2[CH2:13][CH2:14][CH2:15][NH:11]2)[NH:17][CH:18]=1
Reactant: Cc1c[nH]c([C@@H]2CCCN2C(=O)OCc2ccccc2)n1
Agent: [Pd]
Solvent: CCO
Product: Cc1c[nH]c([C@@H]2CCCN2)n1

Procedure:
A solution of 100 mg (S)-2-(4-Methyl-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid benzyl ester in 5 ml EtOH was stirred in the presence of 15 mg Pd/C (10%) under an atmosphere of hydrogen (1 bar) for 2 h. The reaction mixture was filtered over a plug of Celite and washed with EtOH. Evaporation of the solvent gave the product as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:15][CH:14]=1)[NH:6][C:7]2=[O:12].[C:26]([N:30]=[C:31]=[O:32])([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl>[C:26]([NH:30][C:31]([N:23]1[CH2:24][CH2:25][N:20]([CH2:19][C:16]2[CH:15]=[CH:14][C:13]([C:5]3[NH:6][C:7](=[O:12])[C:8]4[C:3]([CH:4]=3)=[C:2]([CH3:1])[CH:11]=[CH:10][CH:9]=4)=[CH:18][CH:17]=2)[CH2:21][CH2:22]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)N=C=O
Reactant: Cc1cccc2c(=O)[nH]c(-c3ccc(CN4CCNCC4)cc3)cc12
Solvent: ClCCl
Product: Cc1cccc2c(=O)[nH]c(-c3ccc(CN4CCN(C(=O)NC(C)(C)C)CC4)cc3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
To a stirred solution of 5-methyl-3-(4-piperazin-1-ylmethyl-phenyl)-2H-isoquinolin-1-one (40 mg, 0.12 mmol) in CH2Cl2 (0.5 mL) was added tert-butyl isocyanate (0.014 mL, 0.12 mmol) and the reaction mixture stirred at RT for 1 h after which time the solvent was removed in vacuo and the crude residue purified by reverse phase preparative HPLC-MS to afford 4-[4-(5-methyl-1-oxo-1,2-dihydro-isoquinolin-3-yl)-benzyl]-piperazine-1-carboxylic acid tert-butylamide as a white solid (28 mg, 54%).
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9](O)=O)=[CH:5][CH:4]=1)#[N:2].[NH2:14][C:15]1[C:20]([NH:21][CH3:22])=[CH:19][CH:18]=[C:17]([CH3:23])[N:16]=1>O1CCCC1>[CH3:22][N:21]1[C:20]2[C:15](=[N:16][C:17]([CH3:23])=[CH:18][CH:19]=2)[N:14]=[C:9]1[CH2:8][O:7][C:6]1[CH:12]=[CH:13][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: CNc1ccc(C)nc1N
Reactant: N#Cc1ccc(OCC(=O)O)cc1
Solvent: C1CCOC1
Product: Cc1ccc2c(n1)nc(COc1ccc(C#N)cc1)n2C
Reaction time: 0.25 h

Procedure:
11.4 g (63 mMol) of 4-cyano-phenoxyacetic acid were dissolved in 200 ml of absolute tetrahydrofuran and mixed at room temperature with 10.2 g (63 mMol) of N,N'-carbonyldiimidazole. After 15 minutes at 60° C., 5.70 g (41.5 mMol) of 2-amino-3-methylamino-6-methyl-pyridine were added. After 2 hours at 60° C. the solvent was distilled off and the crystalline residue was mixed with water, washed with water and dried. After crystallisation from ethanol 9.95 g (91% of theory) were obtained in the form of white crystals. C16H14N4O (278.32) Mass spectrum: M+ =278
Reaction SMILES: N1CCCC1=O.[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[C:20]2[CH:21]=[C:22]([N:25]=C=O)[CH:23]=[CH:24][C:19]=2[N:18]([CH3:28])[C:17](=[O:29])[C:16]([CH3:31])([CH3:30])[N:15]=1.ClC1C=CC=CC=1C1C2C=C(NC(N3CCCC3)=O)C=CC=2N(C)C(=O)C(C)(C)N=1>C(OCC)(=O)C.CCOCC>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]2[N:18]([CH3:28])[C:17](=[O:29])[C:16]([CH3:31])([CH3:30])[N:15]=[C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[Cl:7])[C:20]=2[CH:21]=1
Reactant: CN1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2cc(N=C=O)ccc21
Agent: CN1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2cc(NC(=O)N3CCCC3)ccc21
Agent: O=C1CCCN1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CN1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2cc(N)ccc21

Procedure:
From 5.1 g (0.015 mol) of 7-amino-5-(o-chlorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one and pyrrolidone there is obtained, in analogy to the details in Example 4, via [5-(o-chlorophenyl)-2,3-dihydro-1,3,3-trimethyl-2-oxo-1H-1,4-benzodiazepin-7-yl]isocyanate, N-[5-(o-chlorophenyl)-2,3-dihydro-1,3,3-trimethyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-1 -pyrrolidinecarboxamide of melting point 248°-150° (ethyl acetate/ether).
Reaction SMILES: C(OC([N:8]1[C@@H:13]([C@@H:14]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@@H:15]([NH:25][C:26](=[O:28])[CH3:27])[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C@H:10]([O:37][CH2:38][CH2:39][CH2:40][CH:41]2[CH2:45][CH2:44][CH2:43][CH2:42]2)[CH2:9]1)=O)(C)(C)C.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]>ClCCl>[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49].[CH2:30]([O:29][C@H:14]([C@H:13]1[CH2:12][O:11][C@H:10]([O:37][CH2:38][CH2:39][CH2:40][CH:41]2[CH2:42][CH2:43][CH2:44][CH2:45]2)[CH2:9][NH:8]1)[C@@H:15]([NH:25][C:26](=[O:28])[CH3:27])[CH2:16][C:17]1[CH:18]=[C:19]([F:24])[CH:20]=[C:21]([F:23])[CH:22]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](OCc1ccccc1)[C@H]1CO[C@H](OCCCC2CCCC2)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](OCc1ccccc1)[C@H]1CO[C@H](OCCCC2CCCC2)CN1
Reaction time: 0.33 h

Procedure:
Dissolve (2S,5R)-5-[(1S,2S)-2-Acetylamino-1-benzyloxy-3-(3,5-difluorophenyl)-propyl]-2-(3-cyclopentylpropoxy)-morpholine-4-carboxylic acid tert-butyl ester (67 mg, 0.106 mmol) in neat trifluoroacetic acid under nitrogen. After 20 min, dilute the reaction mixture with dichloromethane and concentrate it on the rotary evaporator four times, then dilute with benzene and concentrate again. Dry the residue under vacuum to give the title compound.
Reaction SMILES: Cl[C:2]1[C:3]([CH:8]2[CH2:11][N:10]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.O1CCOCC1>[C:22]1([C:2]2[C:3]([CH:8]3[CH2:11][N:10]([C:12]4[CH:21]=[CH:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[N:13]=4)[CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1nccnc1C1CN(c2ccc3ccccc3n2)C1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: c1ccc(-c2nccnc2C2CN(c3ccc4ccccc4n3)C2)cc1
Temperature: 100 °C
Yield: 87.8 %

Procedure:
A glass microwave reaction vessel was charged with 2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinoline (0.085 g, 0.286 mmol), phenylboronic acid (0.070 g, 0.573 mmol, Aldrich), potassium phosphate (0.152 g, 0.716 mmol, Alfa Aesar), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (0.020 g, 0.029 mmol, Aldrich), water (0.400 mL) and dioxane (1.6 mL). The mixture was purged with Argon gas and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 30 min. LCMS showed the product. The mixture was diluted with EtOAc and washed with Na2CO3 and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude was purified by silica gel chromatography (12 g, 10%-100% EtOAc-Hexane). The product was obtained as a white solid (85 mg, 88%).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:8]3[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:7]=3[S:6][C:5]=12.C(O)(=O)C.[BH4-].[Na+].[OH-].[NH4+].[CH3:22][C:23](=O)[CH3:24]>>[CH3:22][CH:23]([NH:13][C:10]1[CH:11]=[CH:12][C:7]2[S:6][C:5]3=[N:1][CH2:2][CH2:3][N:4]3[C:8]=2[CH:9]=1)[CH3:24]
Reactant: Nc1ccc2sc3nccn3c2c1
Reactant: CC(C)=O
Agent: [BH4-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)Nc1ccc2c(c1)N1CCN=C1S2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54 %

Procedure:
To a stirred mixture of 4 parts of imidazo[2,1-b]benzothiazol-6-amine and 30 parts of acetic acid are added 1.6 parts of 2-propanone. After stirring for 10 minutes at room temperature, 0.6 parts of sodium borohydride are added portionwise at 20° C. (cooling is necessary). Upon completion, stirring is continued for 10 minutes. The reaction mixture is poured onto water and the whole is alkalized to pH 7-8 with ammonium hydroxide. The product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume), saturated with ammonia, as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 2.5 parts (54%) of 2,3-dihydro-N-(1-methylethyl)imidazo[2,1-b]benzothiazol-6-amine; mp. 128.2° C.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH:14]2[NH:18][N:17]=[CH:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].O>C(Cl)(Cl)Cl>[CH2:23]([O:22][C:20]([N:18]1[CH:14]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:15][CH:16]=[N:17]1)=[O:21])[CH3:24]
Reactant: CCOC(=O)Cl
Reactant: C1=NNC(c2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1N=CCC1c1ccccc1
Yield: 61.9 %

Procedure:
Triethylamine (2.1 g) was added to a solution of 2.92 g 5-phenyl-2-pyrazoline in 50 ml chloroform, and the mixture was stirred with ice cooling. To the resulting solution, was added dropwise 2.17 g ethyl chloroformate, and the mixture was stirred for one hour. After addition of 50 ml water, the mixture was extracted with 50 ml chloroform, the extract was dried, the dried solution was concentrated, and the residue was purified by silica gel chromatography (chloroform/methanol=100/1), giving 2.7 g (yield: 62%) of pure product as oil. NMR (DMSO-d6): 1.21 (3H, t, J=6 Hz), 2.6-3.7 (2H, m), 4.18 (2H, q, J=6 Hz), 5.22 (1H, dd, J=6, 12 Hz), 6.92 (1H, t, J=2 Hz), 7.1-7.5 (5H, m).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=O)[CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1
Reactant: CC1(C)CC(=O)Nc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CCNc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (35 g, 0.2 mol) in THF (100 mL) was added dropwise to a suspension of LiAlH4 (18 g, 0.47 mol) in THF (200 mL) at 0° C. After addition, the mixture was stirred at room temperature for 30 min and then slowly heated to reflux for 1 h. The mixture was then cooled to 0° C. Water (18 mL) and NaOH solution (10%, 100 mL) were carefully added to quench the reaction. The solid was filtered off and the filtrate was concentrated to give 4,4-dimethyl-1,2,3,4-tetrahydro-quinoline.
Reaction SMILES: [OH-].[K+].[O:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[O:10]=[C:11]([CH3:21])[CH2:12]P(=O)(OCC)OCC>C(O)C.O>[O:3]1[CH2:8][CH2:7][C:6](=[CH:12][C:11]([CH3:21])=[O:10])[CH2:5][CH2:4]1
Reactant: O=C1CCOCC1
Reactant: CCOP(=O)(CC(C)=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)C=C1CCOCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.9 %

Procedure:
A solution of potassium hydroxide (4.66 g, 83.1 mmol) in ethanol (181 mL) and water (45 mL) was cooled to approximately 0° C. Tetrahydro-4H-pyran-4-one (7.56 g, 75.5 mmol) and diethyl (2-oxopropyl)phosphonate (16.1 g, 83.1 mmol) were sequentially added. The reaction was allowed to warm to room temperature and stirred for five hours. The reaction mixture was washed with brine and the organic layer was separated. The aqueous layer was extracted three times with tert-butyl methyl ether. The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in a mixture of 20% ethyl acetate in hexane and chloroform, dried again over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by automated flash chromatography (eluting with 35% to 45% ethyl acetate in hexane). The resulting colorless oil was dried under a stream of nitrogen to provide 8.03 g of 1-tetrahydro-4H-pyran-4-ylideneacetone.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[Cl:16][C:17]1[C:26]([I:27])=[CH:25][C:20]2[NH:21][C:22](=[S:24])[NH:23][C:19]=2[CH:18]=1>C1COCC1>[Cl:16][C:17]1[C:26]([I:27])=[CH:25][C:20]2[N:21]=[C:22]([S:24][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[NH:23][C:19]=2[CH:18]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: S=c1[nH]c2cc(Cl)c(I)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CSc1nc2cc(I)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Cs2CO3 (2.3 g, 7.08 mmol), followed by tert-butyl bromoacetate (0.52 mL, 3.54 mmol), was added to a solution of 5-chloro-6-iodo-1,3-dihydro-2H-benzimidazole-2-thione (Intermediate 7, 1.1 g, 3.54 mmol) in THF (20 mL) at 0° C. The reaction was stirred at rt for 0.5 h. Volatiles were removed and the residue was partitioned between EtOAc and water. Concentration afforded the desired product as a white power. LC-MS: calculated for C13H14ClIN2O2S 423.95, observed m/e 424.8 (M+H)+.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][O:21][CH2:20]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl.O1CCOCC1.[OH-].[Na+]>CO>[NH2:27][C:8]1[N:7]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][O:21][CH2:20]1
Reactant: CCCCNc1nc(N)c2nc(OC)n(CCCCC3CCCOC3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCCCNc1nc(N)c2[nH]c(=O)n(CCCCC3CCCOC3)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 51.3 %

Procedure:
To a solution of N2-butyl-8-(methoxy)-9-[4-(tetrahydro-2H-pyran-3-yl)butyl]-9H-purine-2,6-diamine (172 mg) in methanol (15.2 ml) at room temperature was added 4.0M hydrogen chloride in 1,4-dioxane (2.86 ml, 11.42 mmol) to give a colourless solution. The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was neutralised with 2M NaOH and concentrated in vacuo to give a white solid. This solid was triturated in water and filtered under vacuum to give an off-white solid (85 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][C:11](=O)[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.[N:21]1([C:26]2[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=2)[CH:25]=[CH:24][N:23]=[CH:22]1>C(O)C.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Zn+2]>[N:21]1([C:26]2[CH:27]=[CH:28][C:29]([N:32]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=4)=[CH:9][CH:10]=[C:11]3[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:30][CH:31]=2)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: CCOC(=O)CCC(=O)CCC(=O)c1ccc(Br)cc1
Reactant: Nc1ccc(-n2ccnc2)cn1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Zn+2]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(-c2ccc(Br)cc2)n1-c1ccc(-n2ccnc2)cn1
Yield: 7.2 %

Procedure:
To a solution of ethyl 7-(4-bromophenyl)-4,7-dioxoheptanoate (5B) (2.56 g, 7.5 mmol) and 5-(1H-imidazol-1-yl)pyridin-2-amine (1.20 g, 7.5 mmol) in 15 mL of ethanol was added Zn(OTf)2 (8.18 g, 22.5 mmol). The resultant mixture was heated at 120° C. for 4 h under microwave irradiation and then concentrated to dryness. The resultant residue was dissolved in EA, washed with water and brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (PE:EA=6:1) to afford ethyl 3-(1-(5-(1H-imidazol-1-yl)pyridin-2-yl)-5-(4-bromophenyl)-1H-pyrrol-2-yl)propanoate as a brown oil (250 mg, 7.1%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:4][C:3]=1[S:24]([NH2:27])(=[O:26])=[O:25].[OH2:28]>N1CCOCC1>[N:10]1([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[CH2:14][N:13]4[CH:21]=[CH:22][CH:23]=[C:12]4[CH2:11]3)=[O:9])=[CH:4][C:3]=2[S:24]([NH2:27])(=[O:26])=[O:25])[CH2:11][CH2:12][O:28][CH2:5][CH2:8]1
Reactant: O
Reactant: NS(=O)(=O)c1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1Cl
Solvent: C1COCCN1
Product: NS(=O)(=O)c1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1N1CCOCC1
Temperature: 25 °C

Procedure:
A solution of 1 g of 2-chloro-5-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)benzenesulfonamide of Step A in 20 mL of morpholine was heated for 20 hours under reflux. The reaction solution was allowed to cool to room temperature and poured into 50 mL of water with stirring. The precipitate was collected and washed with an additional 50 mL of water and dried to provide the title compound (0.8 g), m.p. 242-245° C. dec
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[N:3]=1.[NH2:17][C:18]1[S:19][CH:20]=[CH:21][N:22]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(OCC)(=O)C.O1CCOCC1>[Si:10]([O:9][CH2:8][C:4]1[N:3]=[C:2]([NH:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH:7]=[CH:6][CH:5]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: Nc1nccs1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(Br)n1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)OCc1cccc(Nc2nccs2)n1
Temperature: 100 °C
Reaction time: 4.5 h

Procedure:
A mixture of 7.85 g of 2-bromo-6-(((tert-butyl(dimethyl)silyl)oxy)methyl)pyridine, 3.12 g of 2-aminothiazole, 1.50 g of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene, 1.35 g of tris(dibenzylideneacetone)dipalladium(0)-chloroform complex, 13.8 g of potassium phosphate and 80 ml of 1,4-dioxane was stirred at 100° C. for 4.5 hours, cooled to room temperature and diluted with ethyl acetate. An insoluble matter was filtered off using Celite and the resulting ethyl acetate solution was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated. The residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=10/1 to 1/1) to give the title compound.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C:9]1([CH3:22])[CH3:21].C(N(CC)CC)C>C(Cl)Cl>[CH2:14]([N:11]1[CH2:12][CH2:13][CH:8]([NH:7][C:2]([O:4][CH2:5][CH3:6])=[O:3])[C:9]([CH3:22])([CH3:21])[CH2:10]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)Cl
Reactant: CC1(C)CN(Cc2ccccc2)CCC1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NC1CCN(Cc2ccccc2)CC1(C)C
Reaction time: 1 h

Procedure:
Ethyl chloroformate (2 ml) was added to a stirred solution of 4-amino-1-benzyl-3,3-dimethylpiperidine (1.6 g, 7.33 mmol) and triethylamine (2 ml) in methylene chloride (25 ml) at ambient temperature, stirring was continued for 1 hr concentrated to dryness, triturated with water, extracted with ethyl acetate, dried (Na2SO4) and concentrated to give 1-benzyl-4-carbethoxyamino-3,3-dimethyl piperidine as oil. Yield 1.3 g (62%), C17H26N2O2, m/z 291 (M+1), PMR (CDCl3): 0.98 (s, 3H), 1.2 (t, 6H), 1.78 (m, 2H), 2.42 (m, 2H), 2.82 (m, 2H), 3.6 (d, 2H), 3.9 (m, 1H), 4.1 (q, 2H), 4.8 (bs, 1H), 7.54 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][O:8][CH2:9][CH:10]([O:23][N:24]2C(=O)C3=CC=CC=C3C2=O)[CH2:11][CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.CNN>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][CH2:9][CH:10]([O:23][NH2:24])[CH2:11][CH2:12][O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[CH:35][CH:36]=1
Reactant: COc1ccc(COCCC(COCc2ccc(OC)cc2)ON2C(=O)c3ccccc3C2=O)cc1
Agent: CNN
Solvent: ClCCl
Product: COc1ccc(COCCC(COCc2ccc(OC)cc2)ON)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 68 %

Procedure:
To a solution of N-[1,4-bis(4-methoxybenzyloxy)but-2-oxy]phthalimide (10.3 g, 21 mmol) in dichloromethane (80 ml) was added methylhydrazine (1.49 ml, 28 mmol) and the solution was stirred at room temperature. After 20 minutes, further methylhydrazine (0.22 ml) was added. After a further 20 minutes the solution was filtered and the filtrate was extracted with aqueous sodium carbonate (3%). The organic layer was dried (magnesium sulphate) and the solvent removed. The residue was purified by column chromatography on silica gel eluting with hexane-ethyl acetate (1:1) to afford 1,4-bis(4-methoxybenzyloxy)but-2-oxyamine as a clear colourless oil (5.16 g, 68%). IR: υmax (film) 2860, 1615, 1515 and 1250 cm-1 ; 1H NMR: δH (CDCl3) 1.80 (2H, m, 3-H), 3.54 (4H, m, 1-H and 4-H), 3.80 (6H, s, 2×CH3), 3.86 (1H, m, 2-H), 4.42 (2H, s, ArCH2), 4.48 (2H, s, ArCH2), 5.37 (2H, s, D2O exchangeable, NH2), 6.87 (4H, m, Ar-H) and 7.25 (4H, m, Ar-H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(O)(C)C.[OH-].[Na+]>[Ni].O>[NH2:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: Nc1cc2ccccc2cc1C(=O)O
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Nc1cc2c(cc1C(=O)O)CCCC2
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a mixture of activated Raney Nickel (200 g of 50% slurry in water on aluminum; 700 mmol, 13 equiv) and 3-amino-2-naphthoic acid (1-1) (10 g, 53 mmol, 1 equiv) in 1:1 isopropanol:water (400 mL) at 90° C. was added 1% aqueous NaOH solution (200 mL) over 1 h. The reaction mixture was stirred for 16 h at 90° C. and additional Raney Nickel (50 g, 180 mmol, 3.4 equiv) was added and the resulting mixture was heated at 90° C. for 24 h. The mixture was filtered and the filtrate was concentrated to 200 mL of water and brought to pH=3 with the addition of 1N aqueous hydrochloric acid solution to precipitate the product. The off-white precipitate was filtered, and purified by reverse phase liquid chromatography (H2O/CH3CN gradient w/0.1% TFA present) to yield 3-amino-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (1-2) as a white solid. LRMS m/z (M+H) 192.2 found, 192.1 required.