Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.[OH:5][C@@H:6]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[CH:13])[C:7]1=[O:14].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:11]([N:8]1[CH2:9][CH2:10][C@@H:6]([O:5][CH2:1][O:2][CH3:3])[C:7]1=[O:14])[C:12]#[CH:13]
Reactant: COCCl
Reactant: C#CCN1CC[C@@H](O)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C#CCN1CC[C@@H](OCOC)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.0 g of chloromethyl methyl ether in 15 ml of methylene chloride is added dropwise to a solution of 1.5 g of (R)-3-hydroxy-1-(2-propynyl)-2-pyrrolidinone, prepared by the procedure of Example 1, U.S. Pat. No. 5,089,518, and 1.5 g of ethyldiisopropylamine in 15 ml of methylene chloride which is stirred in an ice bath. The reaction is allowed to warm to room temperature and stirred overnight. The solution was washed with water, aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The methylene chloride solution is concentrated at reduced pressure and purified by column chromatography (silica gel: mehylene chloride) to give the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:4]=1.[NH:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:33]=[C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)[NH:31][N:30]=2)[CH2:25][CH2:24]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([CH2:13][N:23]3[CH2:24][CH2:25][CH:26]([C:29]4[CH:33]=[C:32]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=5)[NH:31][N:30]=4)[CH2:27][CH2:28]3)=[CH:15][CH:16]=2)=[C:5]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:4]=1
Reactant: c1ccc(-c2cc(C3CCNCC3)n[nH]2)nc1
Reactant: COc1cc(-c2ccccc2)c(-c2ccc(C=O)cc2)nn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1cc(-c2ccccc2)c(-c2ccc(CN3CCC(c4cc(-c5ccccn5)[nH]n4)CC3)cc2)nn1
Reaction time: 0.25 h

Procedure:
4-(6-Methoxy-4-phenylpyridazin-3-yl)benzaldehyde (2-2; 80 mg, 0.27 mmol) was dissolved in dry dimethylformamide (2 mL) and 2-(3-piperidin-4-yl-1H-pyazol-5-yl)pyridine (1-4; 99 mg, 0.43 mmol) and acetic acid (0.14 mL, 2.3 mmol) were added. After stirring for 15 min., sodium triacetoxyborohydride (116 mg, 0.54 mmol) was added and the reaction mixture was stirred at ambient temperature for 12 hours. This reaction mixture was partially evaporated and the residue chromatographed on a silica gel column eluting with a 0-5% methanol/ethyl acetate sat'd with NH4OH. 3-methoxy-5-phenyl-6-(4-{[4-(5-pyridin-2-yl-1H-pyrazol-3-yl)piperidin-1-yl]methyl}phenyl)pyridazine (2-3) was obtained as a nearly pure viscous oil. NMR (CDCl3): δ8.60 (1H, d, J=5 Hz), 7.69-7.72 (2H, m), 7.23-7.35 (6H, m), 7.17 (2H, br d, J=7 Hz), 6.98 (1H, s), 6.61 (1H, s), 4.22 (3H, s), 3.52 (2H, s), 2.95 (2H, d, J=12 Hz), 2.72 (1H, m), 2.10 (2H, br t, J=1 Hz), 1.97 (2H, br d, J=12 Hz), 1.81 (2H, br q, J=11).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[CH3:12][N:4]([CH2:3][CH:2]=[O:1])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:8])[CH3:9]
Reactant: CN(CCO)C(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CN(CC=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 124.9 %

Procedure:
To an ice-cooled solution of tert-butyl 2-hydroxyethyl(methyl)carbamate (300 mg, 1.71 mmol)) in dry CH2Cl2 (8.5 mL) under argon was added portion wise Dess-Martin periodinane (762 mg, 1.8 mmol). Once finished the addition, the reaction mixture was stirred at room temperature for 3 h. The mixture was poured into saturated solutions of NaHCO3 (50 mL) and Na2S2O3 (50 mL) and more CH2Cl2 (100 mL). It was well-stirred at room temperature for 30 minutes. The organic phase was separated and washed with sat. aq. NaHCO3 (1×20 mL). It was dried over magnesium sulphate and concentrated to afford the title compound (370 mg, 98%) as colourless oil together with a yellow solid, which was used in the next step without further purification.
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:10]1[C:14]2[N:15]=[C:16]([Cl:24])[CH:17]=[C:18]([C:19]([O:21]CC)=[O:20])[C:13]=2[CH:12]=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:3]([N:10]1[C:14]2[N:15]=[C:16]([Cl:24])[CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:13]=2[CH:12]=[N:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1cc(Cl)nc2c1cnn2Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)nc2c1cnn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
A molar solution of sodium hydroxide (116 mL/0.116 mol) is added to a solution of ethyl 1-benzyl-6-chloro-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (30.5 g/96.8 mmol) in 195 mL of THF. The mixture is stirred at ambient temperature for 2 hours and then run into a saturated aqueous solution of NaHCO3. The aqueous phase is washed with ethyl acetate and then acidified with a solution of KHSO4 (1 M) and extracted with EtOAc. The organic phase is dried over sodium sulphate and then concentrated to dryness. The product is taken up with diisopropyl ether, filtered, and then dried under vacuum to give 27.3 g of a pale yellow powder (yield: 98%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10]1[N:11]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)[C:12]2[C:13]([N:18]=1)=[N:14][CH:15]=[CH:16][CH:17]=2)[CH3:9])(C)(C)C.FC1C=C(N2C3C(=NC=CC=3)N=C2C(NC(=O)C)C)C=C(F)C=1>Cl>[F:26][C:21]1[CH:20]=[C:19]([N:11]2[C:12]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[N:18]=[C:10]2[CH:8]([NH2:7])[CH3:9])[CH:24]=[C:23]([F:25])[CH:22]=1
Reactant: CC(NC(=O)OC(C)(C)C)c1nc2ncccc2n1-c1cc(F)cc(F)c1
Agent: CC(=O)NC(C)c1nc2ncccc2n1-c1cc(F)cc(F)c1
Agent: Cl
Product: CC(N)c1nc2ncccc2n1-c1cc(F)cc(F)c1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
A crude mixture of {{1-[1-(3,5-difluorophenyl)-1H-imidazo[4,5-b]pyridin-2-yl]-ethyl}-carbamic acid tert-butyl ester and N-{1-[1-(3,5-difluorophenyl)-1H-imidazo[4,5-b]pyridin-2-yl]-ethyl}-acetamide (300 mg) was suspended in methanolic HCl (3 mL). The reaction mixture was stirred at 70° C. for 12 h. After completion of the reaction, the solvent was removed under vacuum. The residue was suspended in water and basified using satd sodium bicarbonate solution and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated in vacuo to provide 1-[1-(3,5-difluorophenyl)-1H-imidazo[4,5-b]pyridin-2-yl]-ethylamine: LC-MS (ESI) m/z 275.1 [M+H]+. The crude product was used without further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=O)[C:13]([NH2:15])=[O:14])(=[O:3])[CH3:2].Cl.[NH2:18][OH:19].C([O-])(=O)C.[K+].CO>O>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[N:18][OH:19])[C:13]([NH2:15])=[O:14])(=[O:3])[CH3:2]
Reactant: NO
Reactant: CC(=O)OCc1ccccc1C(=O)C(N)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(=O)OCc1ccccc1C(=NO)C(N)=O
Reaction time: 18 h
Yield: 70.8 %

Procedure:
A mixture of 2-(2-acetoxymethylphenyl)-2-oxoacetamide (1.56 g), 95% hydroxylamine hydrochloride (0.62 g), potassium acetate (1.34 g) and methanol (14 ml) was heated under reflux with stirring for 18 hours. After the mixture was cooled by allowing it to stand, water (about 150 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate three times. The combined ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave the crude product (1.55 g). The crude product was purified by column chromatography on silica gel (ethyl acetate:hexane=2:1) to give the title compound (1.18 g, yield: 70.9%) as a mixture of the E- and Z-isomers (E:Z=65:35 determined by 1H-NMR analysis).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8](C(=O)C(F)(F)F)[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][S:28]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:30])=[O:29])=[CH:23][CH:22]=1.O[Li].O>CO>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[C:3]=1[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][S:28]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:30])=[O:29])=[CH:23][CH:22]=1
Reactant: CC(C)(C)CS(=O)(=O)Cc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CC(C)(C)CS(=O)(=O)Cc1ccc(CNc2c(Cl)ccc3c2CCNCC3)cc1
Reaction time: 8 h
Yield: 94.2 %

Procedure:
Dissolve 7-chloro-6-[4-(2,2-dimethyl-propanesulfonylmethyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (605 mg, 1.14 mmol) in methanol (8 mL) and add LiOH H2O (478 mg, 11.4 mmol). Stir the reaction mixture overnight. Partition the mixture between water and chloroform. Extract the aqueous phase three times with chloroform and chloroform/iso-propanol (3:1). Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (40 g) eluting with DCM/(chloroform:methanol:concentrated NH4OH 80:18:2) (1:0 over 5 min, 19:1 over 5 min, 9:1; 50 mL/min) to obtain 7-chloro-6-[4-(2,2-dimethyl-propanesulfonylmethyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (467 mg, 94%). MS (APCI+) m/z: 435 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C.C(OCC)C>O1CCCC1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][C@H:2]2[CH2:6][CH2:5][CH2:4][C@H:3]2[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1N
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.9 %

Procedure:
To a solution of cis-ethyl 2-aminocyclopentanecarboxylate (1.57 g, 10 mmol) in 50 mL tetrahydrofuran was added 4-chlorobenzenesulfonyl chloride (3.17 g, 15 mmol) and triethylamine (2.1 mL, 15 mmol). The reaction was stirred at room temperature for 4 h, then diluted into 100 mL diethyl ether and washed with 100 mL water. The organic layer was concentrated and purified by flash chromatography on a 120 g silica gel column with 10 to 40% ethyl acetate in hexane, 20 min gradient, to yield cis-ethyl 2-(4-chlorophenylsulfonamido)cyclopentanecarboxylate (3.05 g, 92%). 1H NMR (400 MHz, CDCl3) δ ppm 7.76-7.80 (2H, m), 7.43-7.47 (2H, m), 5.57 (1 H, d, J=8.56 Hz), 3.91-4.10 (2H, m), 3.70-3.81 (1H, m), 2.74 (1H, dt, J=8.31, 6.55 Hz), 1.64-1.98 (5H, m), 1.44-1.58 (1H, m), 1.18 (3H, t, J=7.05 Hz). LC/MS R.T.=2.00 min; [M+H]+=332.07; [M+Na]+=354.04.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH:3]([O:6][CH2:7][C:8]([O:10]C(C)(C)C)=O)[CH:4]=[CH2:5].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:30][NH:31][O:32][CH3:33].N1C=CN=C1>C(OC)(C)(C)C.O.C(O)=O>[CH3:33][O:32][N:31]([CH3:30])[C:8](=[O:10])[CH2:7][O:6][CH:3]([CH:4]=[CH2:5])[C:2]([F:1])([F:15])[F:16]
Reactant: C=CC(OCC(=O)OC(C)(C)C)C(F)(F)F
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[nH]cn1
Solvent: O=CO
Solvent: COC(C)(C)C
Solvent: O
Product: C=CC(OCC(=O)N(C)OC)C(F)(F)F
Temperature: 57.5 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
To a reactor containing tert-butyl 2-(1,1,1-trifluorobut-3-en-2-yloxy)acetate (1.150 kg, 4.788 mol) was added formic acid (6.2 kg) at rt. The reaction mixture was heated to 55-60° C. for 4-5 h. The formic acid was evaporated under vacuum (T=40-45° C.) and chased with toluene (2×3.0 L). To the residue was added CH2Cl2 (2.0 L) and further concentrated under vacuum. To the resulting residue was added CH2Cl2 (4.6 L) and the solution was cooled to 0° C., followed by N,N-carbonyldiimidazole (1.05 kg, 6.49 mol) in five portions. The mixture was stirred for 30 mins, and N,O-dimethylhydroxylamine hydrochloride (0.67 kg, 6.72 mol) was added in portions while maintaining temperature below 10° C. The reaction mixture was warmed to rt and stirred over 14 h. The reaction mixture was cooled to 3.2° C. and imidazole (100.7 g, 1.48 mol) was charged in two portions. The reaction mixture was warmed to rt and water (1.4 kg) was added, followed by methyl tert-butyl ether (14.0 L). The organic phase was washed with 2.0 N aq. HCl (1.0 L and 0.7 L), followed by sat. aq. NaHCO3 (1.2 L) and sat. aq. NaCl (1.20 L). The organics were concentrated to afford the title compound as an oil (0.95 kg, 87.2%). 1H NMR (500 MHz, CDCl3) δ ppm 5.85-5.76 (m, 1H), 5.62 (d, J=17.2 Hz, 1H), 5.56 (d, J=10.4 Hz, 1H), 4.49-4.34 (m, 3H), 3.68 (s, 3H), 3.67 (s, 1H), 3.18 (s, 3H), 3.08 (s, 1H); 13C NMR (126 MHz, cdcl3) δ ppm 169.9*, 163.4*, 128.61, 123.87 (d, J=282.0 Hz), 123.82, 78.54 (q, J=31.3 Hz), 66.12, 61.52, 60.56, 36.20, 32.24. Note: this compound is a 3:1 mixture of amide bond rotamers. *Carbonyl chemical shifts estimated indirectly through 1H-13C HMBC (heteronuclear multiple-bond correlation).
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1.O>N1C=CC=CC=1>[C:1]([NH:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCC(=O)Nc1ccc(C(=O)O)cc1
Reaction time: 3 h
Yield: 86.2 %

Procedure:
n-Dodecanoyl chloride (8.74 g; 40 mmoles) is added dropwise to a solution of p-aminobenzoic acid (5.5 g; 40 mmoles) dissolved in pyridine (100 ml). The mixture is stirred for 3 hours and poured into water (3 L). The precipitate which forms is filtered and dried in vacuo to give N-(n-dodecanoyl)-p-aminobenzoic acid (11.01 g).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[S:7][C:6]([N:8]=[C:9]=[O:10])=[N:5][N:4]=1.[CH3:11][NH:12][CH2:13][CH:14]=[O:15]>C1C=CC=CC=1>[CH3:11][N:12]([CH2:13][CH:14]=[O:15])[C:9]([NH:8][C:6]1[S:7][C:3]([CH2:2][Cl:1])=[N:4][N:5]=1)=[O:10]
Reactant: O=C=Nc1nnc(CCl)s1
Reactant: CNCC=O
Solvent: c1ccccc1
Product: CN(CC=O)C(=O)Nc1nnc(CCl)s1

Procedure:
A mixture of 5-chloromethyl-1,3,4-thiadiazol-2-yl isocyanate dimer (9.5 grams), the dimethyl acetal of 2-methylaminoacetaldehyde (5.8 grams) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. This product is recrystallized to yield the desired product the dimethyl acetal of 2-[1-methyl-3-(5-chloromethyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19](O)=[O:20])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:28][NH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([N:32]5[CH2:33][CH2:34][CH:30]([NH:29][CH3:28])[CH2:31]5)=[O:20])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CNC1CCNC1
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Product: CNC1CCN(C(=O)c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)C1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (30 mg) was coupled to N-methylpyrrolidin-3-amine via General Procedure B. The product was purified via reverse phase HPLC to give 16.7 mg of 253. MS (Q1) 463.8 (M)+.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1>CC#N.O.[OH-].[Na+]>[CH:14]1[C:2]2[C:1](=[C:14]3[C:5](=[CH:4][CH:3]=2)[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12](=[O:16])[C:13]3=[O:15])[CH:3]=[CH:2][CH:1]=1
Reactant: O=C1C(=O)c2ccccc2-c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: O=C1C(=O)c2c(ccc3ccccc23)-c2ccccc21

Procedure:
In a typical preparation, 50 mg of Rh(III) starting material was dissolved in 32 mL of MeCN/water, 3:1,0.1 M in NaOH. To this mixture was added 1 equiv or more of, for example, 9,10-phenanthrenequinone to produce non-hindered control DNA photocleaving compounds, or 5,6-chrysenequinone (chrysi) or benzophenanzineduimine (phzi) to produce hindered intercalating compounds. During constant stirring, the reaction was allowed to progress for approximately 18 h at room temperature. After neutralization with dilute hydrochloric acid and addition of 500 mL of water, the reaction mixture was loaded onto a Sephadex SP-C25 ion exchange column equilibrated in 0.05 M MgCl2. The product was purified by elution with a gradient of 0.05-0.5 M MgCl2, and the orange product bands were collected. The fractions were concentrated on a Waters Sep-Pak 5 g C18 cartridge and washed with copious amounts of water. The metal complex was eluted from the cartridge with a minimum volume of 0.1% TFA in MeCN/water, 1:1, and lyophilized to dryness.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[N:11]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[N:10]=[C:9]3[Br:21])=[N:2]1.[C:22]1([C:28](Cl)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>N1C=CC=CC=1.C(OCC)(=O)C>[Br:21][C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([C:3]3[N:4]=[CH:5][N:1]([C:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:2]=3)[CH:7]=2)[N:11]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[N:10]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Brc1nn(C2CCCCO2)c2ccc(-c3nc[nH]n3)cc12
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Brc1nn(C2CCCCO2)c2ccc(-c3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc12
Temperature: 50 °C
Yield: 93 %

Procedure:
2-(5-(1H-1,2,4-Triazol-3-yl)-3-bromo-1H-indazolyl)perhydro-2H-pyran (15.05 g, 43.22 mmol), triphenylmethyl chloride (19.54 g, 70.09 mmol), and triethylamine (9.9 mL, 71.02 mmol) was taken up in pyridine (115 mL) and heated at 50° C. overnight. The reaction was quenched with methanol (10 mL), cooled to room temperature, and condensed. The brown oil was dissolved in ethyl acetate and washed with sodium bicarbonate (saturated aqueous). Upon sonication in a ultrasonic bath a white to yellow precipitate formed that was filtered and washed with 10% ethyl acetate in hexanes. The precipitate was dried in a vacuum oven overnight (23.80 g, 93% yield): ES-MS (m/z) 590 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7](Br)[CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4].[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1>>[Cl:1][C:2]1[CH:8]=[C:7]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([O:12][CH3:11])[CH:18]=2)[CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4]
Reactant: Nc1c(Cl)cc(Br)cc1Cl
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2cc(Cl)c(N)c(Cl)c2)c1
Yield: 102.6 %

Procedure:
The title compound (0.550 g) was prepared from 2,6-dichloro-4-bromoaniline (0.5 g, 2.0 mmol) and 3-methoxyphenylboronic acid (0.409 g, 2.69 mmol) as a white solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.58 (s, 2H), 7.29 (t, J 7.8, 1H), 7.18-7.10 (m, 2H), 6.85 (dd, J 2, 8.1, 1H), 5.63 (s, 2H), 3.81 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([OH:25])[CH2:18][C@@H:19]([CH3:24])[CH2:20][CH2:21][CH2:22][CH3:23])[C@H:13]([OH:26])[CH2:12][C:11]=1[O:27][CH2:28][CH2:29][CH2:30][CH3:31].P([O-])([O-])([O-])=O.Cl.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>CC(C)=O>[CH2:28]([O:27][C:11]1[CH2:12][C@@H:13]([OH:26])[C@H:14](/[CH:15]=[CH:16]/[C@@H:17]([OH:25])[CH2:18][C@@H:19]([CH3:24])[CH2:20][CH2:21][CH2:22][CH3:23])[C:10]=1[S:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:32])=[O:2])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCOC1=C(SCCCCCC(=O)OC)[C@@H](/C=C/[C@@H](O)C[C@@H](C)CCCC)[C@H](O)C1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)=O
Product: CCCCOC1=C(SCCCCCC(=O)O)[C@@H](/C=C/[C@@H](O)C[C@@H](C)CCCC)[C@H](O)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 13.9 %

Procedure:
Methyl(11R,12S,13E,15S,17S)-9-butyloxy-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoate (51 mg, 0.11 mmol) was dissolved in acetone (1 ml). To this solution was added a pH 8 phosphate buffer (10 ml). Further esterase (from porcine liver made by Sigma Co., 114 μl) was added and the mixture was stirred at room temperature for five hours. Further in a state with methyl ester remaining, the reaction solution was ice cooled, was made pH 4 by dilute hydrochloric acid, and was saturated by ammonium sulfate. The mixture was extracted by ethyl acetate, the extract was dried, then was concentrated under reduced pressure. The concentrate was purified by thin layer chromatography (developing solvent: ethyl acetate, Rf=0.2) to obtain (11R,12S,13E,15S,17S)-9-butyloxy-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoic acid (7 mg, 14%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3=[N:17][CH:18]=[CH:19][N:9]23)=[CH:4][CH:3]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.C1CCCCC1>[CH2:20]([C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2=[N:17][CH:18]=[CH:19][N:9]12)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: Brc1ccc(C2c3ccccc3-c3nccn32)cc1
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: Brc1ccc(C2(Cc3ccccc3)c3ccccc3-c3nccn32)cc1
Temperature: -40 °C

Procedure:
To a solution of 5-(4-bromophenyl)-5H-imidazo[2,1-a]isoindole (5 g) in THF (100 mL) at −78° C. was added LAD solution (21.42 mL, 1.5 M in cyclohexane). After stirring for 15 minutes benzylbromide was added and the reaction mixture was stirred at −40° C. After 20 minutes more benzylbromide (3 mL) was added and continued to stir at −40° C. for 40 minutes. The reaction was then quenched with aqueous saturated NH4Cl and partitioned between aqueous saturated NH4Cl and EtOAc. Aqueous layer was extracted with EtOAc (2×). Combined organic layers were dried over Na2SO4 and concentrated. The resulting yellow solid was recrystallized from hot EtOAc to yield title compound as a white solid. HRMS. Found, 401.0647; calcd for (M+H)+, 401.0648. 1HNMR (500 MHz, CDCl3): δ 7.62 (d, J=7.1 Hz, 1H), 7.50 (d, J=8.6 Hz, 2H), 7.36 (dd, J=7.1, 0.9 Hz, 1H), 7.33-7.27 (m, 2H), 7.24 (s, 1H), 7.15 (d, J=8.3 Hz, 2H), 7.03 (t, J=7.8 Hz, 1H), 6.95 (t, J=7.8 Hz, 2H), 6.91 (s, 1H), 6.56 (d, J=7.6 Hz, 2H), 3.78 (s, 2H).