Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([O:12][C:13](=[O:24])[CH2:14][C:15]1([OH:23])[CH:20]2[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]2)[CH2:16]1)(C)(C)C>ClCCl>[CH3:8][O:12][C:13](=[O:24])[CH2:14][C:15]1([OH:23])[CH:20]2[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]2)[CH2:16]1
Reactant: CC(C)(C)OC(=O)CC1(O)CN2CCC1CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CC1(O)CN2CCC1CC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.6 %

Procedure:
Trifluoroacetic acid (40 mL) was added dropwise over 15 minutes to a solution of 2-(3-hydroxy-1-azabicyclo[2.2.2]oct-3-yl)acetic acid t-butyl ester (15.7 g) in anhydrous dichloromethane (40 mL) at 0° C. The mixture was stirred for 24 hours at room temperature, then the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (90 mL) and cooled in an ice bath. Concentrated sulfuric acid (9 mL) was added dropwise over 10 minutes, then the reaction mixture was stirred at room temperature. After 3 hours, the solution was poured into 100 mL of ice water, basified to pH 10 with saturated aqueous sodium carbonate solution, and extracted with chloroform (4×100 mL). The extracts were dried (MgSO4), filtered, and evaporated in vacuo to give a solid. Recrystallization from ethyl acetate provided 6.3 g of the tan crystalline subtitle compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]3[C:14]4[CH:26]=[CH:25][CH:24]=[N:23][C:15]=4[NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:12]3=[N:11][N:10]=2)=[CH:5][CH:4]=1.[NH:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:29][CH2:28]1.C(N(CC)CC)C>CC(N(C)C)=O.O>[N:11]1[N:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][N:27]3[CH2:28][CH2:29][CH:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH2:31][CH2:32]3)=[CH:8][CH:7]=2)[N:13]2[C:12]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[NH:16][C:15]1[N:23]=[CH:24][CH:25]=[CH:26][C:14]2=1
Reactant: ClCc1ccc(-c2nnc3n2-c2cccnc2Nc2ccccc2-3)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(Cc2ccc(-c3nnc4n3-c3cccnc3Nc3ccccc3-4)cc2)CC1
Temperature: 25 °C

Procedure:
A solution of 3-(4-(chloromethyl)phenyl)-9H-benzo[f]pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepine (1.3 g, 3.62 mmol), tert-butyl piperidin-4-ylcarbamate (0.71 g, 3.80 mmol), triethylamine (1 mL) in dimethylacetamide (15 mL) was stirred at 75° C. for 20 hours. The mixture wass diluted with water (30 mL). The resulting suspension was stirred at room temperature. The solid was collected by filtration, washed thoroughly with water and dried under high vacuum. The tert-butyl (1-(4-(9H-benzo[f]pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepin-3-yl)benzyl)piperidin-4-yl)carbamate was obtained as a yellow solid (1.3 g, 69%). M.p.=145-147° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.76 (s, 1H), 8.18 (dd, J=4.4, 1.2 Hz, 1H), 7.93 (dd, J=8.0, 1.2 Hz, 1H), 7.41 (td, J=8.0, 1.6 Hz, 1H), 7.35-7.30 (m, 5H), 7.15-7.08 (m, 2H), 6.87 (dd, J=8.0, 4.8 Hz, 1H), 6.76 (d, J=8.4 Hz, 1H), 3.45 (s, 2H), 3.21-3.06 (m, 1H), 2.80-2.65 (m, 2H), 2.0-1.9 (m, 2H), 1.7-1.6 (m, 2H), 1.4-1.3 (m, 2H), 1.34 (s, 9H); LCMS [M+H]: 524.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11](C2C=C(Cl)C=CC=2Cl)[C@H](C)CCCS(NC)(=O)=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(S(Cl)(=O)=O)CCCC.C(N)C>>[C:5]1([S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: CNS(=O)(=O)CCC[C@@H](C)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Agent: CCCCCS(=O)(=O)Cl
Agent: CCN
Product: NS(=O)(=O)c1ccccc1
Yield: 37 %

Procedure:
4-chloro-N-[2,5-dichlorophenyl]-N-[4-ethylaminosulfonyl)-1(R)-methylbutyl]benzenesulfonamide was prepared analogous to 4-chloro-N-[2,5-dichlorophenyl]-N-[4-[(methylamino)sulfonyl]-1(R)-methylbutyl]benzenesulfonamide by reacting (4R)-4-[2,5-dichlorophenyl][4-chlorophenyl)sulfonyl]-amino]pentylsulfonyl chloride with ethylamine. Yield=37%; MS (ESI+), 513 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11](=O)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[CH2:7][CH2:6]1)=[O:4].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:6][CH2:7][CH:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)C1CCC(C(=O)c2ccccc2OC)CC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CCC(Cc2ccccc2OC)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.2 %

Procedure:
In a 100 mL flask with stir bar and 4-(2-methoxybenzoyl)cyclohexanecarboxylic acid methyl ester (900 mg; 3.26 mmol), trifluoroacetic acid (10 mL) was chilled to 0° C. and triethylsilane (2 g; 16.3 mmol) was added over 1 minute. Mixture was allowed to warm to room temperature. After 48 hours, mixture was concentrated in vacuo and reduced by half volume. The mixture was poured into a water (40 mL) solution and extracted with ethyl acetate (EtOAc) (4×10 mL). The combined organic layers were washed with NaHCO3 (40 mL), brine (40 mL) and dried over anhydrous Na2SO4. The organic layer was concentrated in vacuo to obtain the crude mixture, which was purified by of silica gel flash chromatography, using EtOAc/hexane (gradient system), to obtain 4-(2-methoxybenzyl)cyclohexanecarboxylic acid methyl ester (0.78 g, 91% yield).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Si:7]([O:14][C:15]1[C:24]([CH2:25][CH2:26][CH3:27])=[CH:23][C:18]([C:19](OC)=[O:20])=[CH:17][C:16]=1[CH2:28][CH2:29][CH3:30])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].C(OCC)(=O)C.Cl>C1COCC1>[Si:7]([O:14][C:15]1[C:16]([CH2:28][CH2:29][CH3:30])=[CH:17][C:18]([CH2:19][OH:20])=[CH:23][C:24]=1[CH2:25][CH2:26][CH3:27])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:8])[CH3:9]
Reactant: CCCc1cc(C(=O)OC)cc(CCC)c1O[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1cc(CO)cc(CCC)c1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
Lithium aluminum hydride (9 mL of a 1M solution in THF) was added cautiously to a solution of the product of Step D at 0° C., and the reaction mixture was stirred overnight. Ethyl acetate was added to the mixture, cooled to 0° C. and treated with cold 1N HCl. After separating the organic phase, the aqueous phase was extracted with a mixture of ethyl acetate-ether-dichloromethane. The combined organic extracts were dried and concentrated. The concentrated material was purified by flash column chromatography using 20% ethyl acetate in hexane to afford 4.2 g (92%) of the title compound.
Reaction SMILES: [C:1]1([P:7](=S)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)(=[O:23])C>>[C:1]1([P:7](=[O:23])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(C)=O
Reactant: S=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Through a mixture of triphenylphosphine sulfide (11.03 g) and ethyl acetate (200 ml) is bubbled chlorine gas (ca. 2.2 molar equivalents) at room temperature. The resulting mixture is neutralized with aqueous 6% sodium hydrogen carbonate (350 ml) and stirred at room temperature for 10 minutes. The reaction mixture is then worked up as in the case of Example 1 to give triphenylphosphine oxide (10 g). m.p. 154°-157° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].CS(O[CH2:26][CH2:27][CH:28]1[CH2:33][O:32][CH2:31][CH2:30][O:29]1)(=O)=O>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:26][CH2:27][CH:28]3[CH2:33][O:32][CH2:31][CH2:30][O:29]3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Reactant: CS(=O)(=O)OCCC1COCCO1
Product: CCOC(=O)N1CCC(c2cn(CCC3COCCO3)c3ccccc23)CC1
Temperature: 40 °C
Reaction time: 24 h
Yield: 101.3 %

Procedure:
This compound was prepared following the procedure described in example 13 (part B) starting with 0.47 g (1.2 mmol) of 4-(1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester and 0.62 g (2.9 mmol) of 2-[1,4]dioxan-2-yl-ethyl methansulfonate. The reaction mixture was stirred at 40° C. for 24 hours. After standard work-up and purification, 0.47 g (51% of yield) of 4-[1-(2-[1,4]dioxan-2-yl-ethyl)-1H-indol-3-yl]-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[S:10]([OH:13])(=O)=[O:11].C(N(CCCC)CCCC)CCC.[Cl:27]P(Cl)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl>[NH2:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[S:10]([Cl:27])(=[O:13])=[O:11]
Reactant: ClP(Cl)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Nc1c(I)cc(Br)cc1S(=O)(=O)O
Solvent: ClCCl
Solvent: CCCCN(CCCC)CCCC
Product: Nc1c(I)cc(Br)cc1S(=O)(=O)Cl
Reaction time: 18 h

Procedure:
To a solution containing 7.6 g (20 mmol) of 2-amino-5-bromo-3-iodobenzenesulphonic acid and 4.8 ml (20 mmol) of tributylamine in 20 ml of dichloromethane is added dropwise, at 0° C. under a nitrogen atmosphere, a solution of dichlorotriphenylphosphorane (9.7 g (37.5 mmol) in 45 ml of dichloromethane). The mixture is brought to room temperature, stirring is continued for 18 hours and the product is purified by chromatography on a column of silica gel, eluting with a dichloromethane/pentane mixture (2:8).
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[CH:9]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][C:17]1=[O:25]>>[CH:1]1([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[CH:9]=[C:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:16][C:17]2=[O:25])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1Cc2ccccc2N1
Reactant: COc1ccc(C=O)cc1C1CCCC1
Product: COc1ccc(C=C2C(=O)Nc3ccccc32)cc1C1CCCC1

Procedure:
3-Cyclopentyl-4-methoxybenzaldehyde was condensed with 2-oxindole to give 0.25 g of 3-(3-Cyclopentyl-4-methoxybenzylidene)-1,3-dihydro-indol-2-one as a yellow-orange solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11]([NH:13][C@H:14]([C:26]([O:28]C)=[O:27])[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH3:25])[CH:17]=1)=[O:12].[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11]([NH:13][C@H:14]([C:26]([OH:28])=[O:27])[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH3:25])[CH:17]=1)=[O:12]
Reactant: COC(=O)[C@H](Cc1cn(C)c2ccccc12)NC(=O)C=Cc1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1cc(C[C@H](NC(=O)C=Cc2ccc(F)cc2F)C(=O)O)c2ccccc21
Yield: 76.7 %

Procedure:
The same procedures as in Example 64 were carried out from the compound obtained in Example 25 (0.73 g), 1 mol/L of an aqueous sodium hydroxide solution (2.7 mL), and methanol (27 mL), to give the captioned compound (0.54 g, 77%) as crystals.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.Cl.[CH:23]12[NH:31][CH2:30][CH:27]([NH:28][CH2:29]1)[CH2:26][CH2:25][CH2:24]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:28]4[CH2:29][CH:23]5[NH:31][CH2:30][CH:27]4[CH2:26][CH2:25][CH2:24]5)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C1CC2CNC(C1)CN2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC4CCCC3CN4)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
A mixture of 0.71 g (2.5 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.54 g (2.7 mmol) of 6,8-diazabicyclo[3.2.2]nonane, dihydrochloride, 1.13 ml (7.5 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 15 ml of acetonitrile was heated under reflux for 1.5 hr. The reaction mixture was stirred overnight at room temperature and filtered to obtain 0.40 g of the title compound, mp 268°-271° dec.
Reaction SMILES: Cl.CN1[CH2:8][CH2:7][CH:6]([C:9]([C:11]2[C:16]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)=[CH:15][CH:14]=[CH:13][N:12]=2)=O)CC1.F.[B].C1N[C:33](=O)[NH:32][C:30](=O)[C:29]=1C(F)(F)F>>[Cl:25][C:21]1[CH:22]=[CH:23][C:24]2[C:9](=[C:6]3[CH2:7][CH2:8][CH2:29][CH2:30][N:32]3[CH3:33])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:16]3[CH2:17][CH2:18][C:19]=2[CH:20]=1
Reactant: CN1CCC(C(=O)c2ncccc2CCc2cccc(Cl)c2)CC1
Reactant: O=c1[nH]cc(C(F)(F)F)c(=O)[nH]1
Agent: Cl
Agent: F
Agent: [B]
Product: CN1CCCCC1=C1c2ccc(Cl)cc2CCc2cccnc21

Procedure:
To a solution of a product of Step D above (59 g, 0.15 mole) in 120 mL (120 g, 6.0 mole) of hydrofluoric acid at -35° C. is added boron trifluoridine (44.3 g, 0.66 mole) over 1 hour. Completeness of the reaction is determined by thin-layer chromatography. The reaction is quenched using ice, water and potassium hydroxide to a final pH of 10. The product is extracted into toulene and the toluene solution is washed with water and brine. The toluene solution is concentrated to a residue, which is dissolved in hot hexane. Insolubles are removed by filtration and the filtrate is concentrated to an off-white powder. Yield: 45.7 g (HPLC purity 96%), 92% of theory.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH2:12][N:11]([C:13](=[O:15])[CH3:14])[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:20]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[CH:31][C:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[N:33][CH:34]=2)O1.C(N1C2C=CC=CC=2C=CC2N=C(C3C=NC(OC)=CC=3)C(F)=CC=2C1)(=O)C>>[C:13]([N:11]1[C:10]2[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=2[CH:8]=[CH:7][C:6]2[CH:20]=[C:2]([C:29]3[CH:34]=[N:33][C:32]([N:35]4[CH2:36][CH2:37][O:38][CH2:39][CH2:40]4)=[CH:31][CH:30]=3)[N:3]=[CH:4][C:5]=2[CH2:12]1)(=[O:15])[CH3:14]
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Reactant: CC(=O)N1Cc2cnc(Cl)cc2C=Cc2ccccc21
Agent: COc1ccc(-c2nc3c(cc2F)CN(C(C)=O)c2ccccc2C=C3)cn1
Product: CC(=O)N1Cc2cnc(-c3ccc(N4CCOCC4)nc3)cc2C=Cc2ccccc21
Yield: 12.1 %

Procedure:
The title compound (3.5 mg, 12%) was prepared from 41D (20 mg, 0.07 mmol) and 5A (30.5 mg, 0.105 mmol) by a route analogous to that used for the preparation of 2B. HPLC Rt=2.153 min; LCMS Found: (M+H)+=413.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:38]2[S:42][C:41]([C:43]3([O:47]COC)[CH2:46][CH2:45][CH2:44]3)=[N:40][CH:39]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:20]=[C:19]4[C:14]([CH2:15][CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18]4)=[CH:13][CH:12]=3)[N:8]([S:28]([C:31]3[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[C:5]2=[N:6][CH:7]=1.Cl>CO>[Cl:1][C:2]1[C:3]([C:38]2[S:42][C:41]([C:43]3([OH:47])[CH2:46][CH2:45][CH2:44]3)=[N:40][CH:39]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:20]=[C:19]4[C:14]([CH2:15][CH2:16][NH:17][CH2:18]4)=[CH:13][CH:12]=3)[N:8]([S:28]([C:31]3[CH:32]=[CH:33][C:34]([CH3:35])=[CH:36][CH:37]=3)(=[O:29])=[O:30])[C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(-c3ccc5c(c3)CN(C(=O)OC(C)(C)C)CC5)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Agent: Cl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2c(-c3ccc4c(c3)CNCC4)cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc32)cc1
Temperature: 65 °C

Procedure:
A solution of Example 45A (0.09 g, 0.122 mmol) in methanol (0.7 mL) was treated with 10% aqueous HCl solution (0.165 mL), and the reaction was heated at 65° C. for 3 hours. The reaction was cooled to ambient temperature and concentrated. The concentrate was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The layers were separated, and the aqueous layer was extracted with additional ethyl acetate (2×). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to provide the title compound. ESI(+) m/z 591.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[C:7]#[N:8].O>CC(O)C.[Co]>[Cl:1][C:2]1[CH:9]=[C:6]([CH2:7][NH2:8])[CH:5]=[N:4][CH:3]=1
Reactant: N#Cc1cncc(Cl)c1
Agent: [Co]
Solvent: O
Solvent: CC(C)O
Product: NCc1cncc(Cl)c1
Temperature: 25 °C
Reaction time: 11 h
Yield: 80.6 %

Procedure:
A mixture of 5-chloro-nicotinonitrile (63.8 mg, 461 μmol), 2-propanol (9.2 mL; not dry), and CaSO4 (−325 mesh) (920 mg, 6.76 mmol) was treated with a suspension of Raney Cobalt 2700 in 2-propanol under air (2 mL) (prepared by diluting 2 mL of the commercial water slurry with 15 mL 2-propanol, centrifuging, decanting, and repeating with 2×15 mL 2-propanol, then resuspending with 2 mL 2-propanol). The flask was then sealed and evacuated until bubbles formed, and the evacuated flask was flushed with H2 gas via balloon pressure. After 11 h stirring at rt under balloon H2 pressure, a NMR spectrum of a worked-up reaction aliquot indicated 80% conversion to the title compound. The reaction was then filtered, the filter cake was washed with 2-propanol (3×10 mL), and the combined clear colorless filtrates were concentrated briefly under rotary evaporation at 50° C. The residue was taken up in DCM and concentrated again to afford the volatile crude title compound (53 mg, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][N:6]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]2[O:15][C:16]([CH:18]=O)=[CH:17][C:7]1=2.[Cl-].O[NH3+:26].C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:18]([C:16]1[O:15][C:8]2[CH:9]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[N:6]([CH2:5][C:4]3[CH:20]=[CH:21][C:22]([Cl:23])=[C:2]([Cl:1])[CH:3]=3)[C:7]=2[CH:17]=1)#[N:26]
Reactant: COC(=O)c1cc2oc(C=O)cc2n1Cc1ccc(Cl)c(Cl)c1
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc2oc(C#N)cc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 90 °C
Yield: 99.4 %

Procedure:
Methyl 4-(3,4-dichlorobenzyl)-2-formylfuro[3,2-b]pyrrole-5-carboxylate (0.7 g) was dissolved in pyridine (7 mL). To this was added hydroxyammonium chloride (0.23 g) and reaction heated at 90° C. for 30 min. Acetic anhydride (2.5 mL) was added dropwise and reaction heated at 90° C. for a further 2 hours. The reaction was quenched by pouring onto ice/water, and the resulting precipitate was filtered off and dried in vacuo to give a pale brown solid (0.69 g, 100%), NMR d(CDCl3) 3.85 (3H, s), 5.6 (2H, s), 6.85 (2H, d), 6.95 (1H, dd), 7.2 (1H, d), 7.4 (1H, d); M/z (−) 349 (M-H+), 347, 189.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2[C:12]3[CH:13]=[CH:14][S:15][C:16]=3[CH2:17][C:10]=2[C:9]([C:18]2[CH:19]=[C:20]([NH:24]C(=O)C)[CH:21]=[CH:22][CH:23]=2)=[N:8]1.[ClH:30]>CO>[ClH:30].[S:15]1[CH:14]=[CH:13][C:12]2[C:11]3[NH:7][N:8]=[C:9]([C:18]4[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=4)[C:10]=3[CH2:17][C:16]1=2
Reactant: CC(=O)Nc1cccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sccc2-3)c1
Agent: Cl
Solvent: CO
Product: Nc1cccc(-c2n[nH]c3c2Cc2sccc2-3)c1
Temperature: 100 °C
Yield: 82 %

Procedure:
N-{3-[4-(2-Trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl]-phenyl}-acetamide (0.21 g, 0.5 mmol) was dissolved in MeOH and treated with concentrated HCl (0.16 mL, 5 mmol). The reaction mixture was heated at 100° C. for 4 hr. The solution was cooled to room temperature and the resultant precipitate was filtered, washed with MeOH and concentrated under reduced pressure to provide the corresponding 3-(4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-phenylamine hydrochloride (0.12 g, 0.41 mmol) as yellow solid in 81% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]2[C:21]3[N:28]([CH2:29][CH2:30][NH:31]C(=O)OC(C)(C)C)[CH:27]=[CH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:31][CH2:30][CH2:29][N:28]1[C:21]2[C:20]([NH:19][C:4]3[CH:5]=[CH:6][C:7]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:18])[F:16])[CH:10]=4)=[C:2]([CH3:1])[CH:3]=3)=[N:25][CH:24]=[N:23][C:22]=2[CH:26]=[CH:27]1
Reactant: Cc1cc(Nc2ncnc3ccn(CCNC(=O)OC(C)(C)C)c23)ccc1Oc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2ncnc3ccn(CCN)c23)ccc1Oc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.4 %

Procedure:
tert-Butyl {2-[4-({3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}carbamate (494 mg) was dissolved in dichloromethane (6.4 mL), trifluoroacetic acid (4.8 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (50 mL), and washed with aqueous sodium hydrogen carbonate (30 mL). The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (442 mg) as a powder.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:14]=[C:13]([C:15]([NH:17][C:18]3[CH:22]=[C:21]([C:23]([NH:25][CH2:26][CH2:27][C:28](N)=[NH:29])=[O:24])[N:20]([CH3:31])[CH:19]=3)=[O:16])[N:12]([CH3:32])[CH:11]=2)=[O:8])=[CH:5][C:4]([NH:33][CH:34]=[O:35])=[CH:3]1.C1(=O)OC(=O)CC1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:31][N:20]1[CH:19]=[C:18]([NH:17][C:15]([C:13]2[N:12]([CH3:32])[CH:11]=[C:10]([NH:9][C:7]([C:6]3[N:2]([CH3:1])[CH:3]=[C:4]([NH:33][CH:34]=[O:35])[CH:5]=3)=[O:8])[CH:14]=2)=[O:16])[CH:22]=[C:21]1[C:23]([NH:25][CH2:26][CH2:27][C:28]#[N:29])=[O:24]
Reactant: Cn1cc(NC(=O)c2cc(NC(=O)c3cc(NC=O)cn3C)cn2C)cc1C(=O)NCCC(=N)N
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)O1
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(NC(=O)c2cc(NC(=O)c3cc(NC=O)cn3C)cn2C)cc1C(=O)NCCC#N
Temperature: 60 °C
Yield: 77749.9 %

Procedure:
To a solution of 1 g of distamycin A in 20 ml DMF were added 550 mg of succinic anhydride and 950 mg of K2CO3. The solution was heated at 60° C. for 3 hours then evaporated to dryness and the crude residue was purified by flash chromatography (methylene chloride/methanol: 9/1) to give 750 g of 3-[1-methyl-4[1-methyl-4[1-methyl-4-formamidopyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionitrile which was dissolved in 20 ml of methanol and added of 5 ml of HCl 2N. The solution was stirred at room temperature for 2 days, the solvent evaporated in vacuo and the solid residue suspended in 20 ml of ethyl acetate, yielding, after filtration 560 mg of the intermediate.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][NH:5][C:6]=1[Br:7].CC(C)=O.C(=O)([O-])[O-].[K+].[K+].Br[CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CCCCCC>[Br:7][C:6]1[C:2]([Br:1])=[C:3]([CH3:8])[N:4]([CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:5]=1
Reactant: Cc1n[nH]c(Br)c1Br
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CCOC(=O)C(C)n1nc(Br)c(Br)c1C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
A reaction mixture consisting of a solution of 13.7 g. (0.057 mole) 4,5 -dibromo-3-methylpyrazole in 200 ml. acetone and 15.7 g. (0.114 mole) anhydrous potassium carbonate was heated at the reflux temperature with continuous stirring for 15 minutes. After cooling, 10.4 g. (0.06 mole) ethyl 2-bromopropionate was added. This reaction mixture was then heated at the reflux temperature for 2.5 hours. It was cooled and filtered. The acetone was then removed by evaporation under reduced pressure, and the residue thus obtained was dissolved in hot hexane. After chilling in a refrigerator the crystals that had formed were collected on a filter. There was thus obtained 14.5 g. (75% yield) of ethyl 3,4 -dibromo-α, 5-dimethylpyrazole-1-acetate having a melting point at 61° to 62° C.