Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](C(=O)C)=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.ClC1C=C(C(OO)=[O:27])C=CC=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:27])=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1
Reactant: CC(=O)c1ccc(F)cc1OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Oc1ccc(F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 93 %

Procedure:
A mixture of 11 parts of 1-[4-fluoro-2-(phenylmethoxy)phenyl]ethanone, 8.48 parts of 3-chlorobenzenecarboperoxoic acid and 260 parts of dichloromethane was stirred for 5 days at room temperature. The precipitate was filtered off and the filtrate was stirred in a saturate thiosulfate solution for 15 minutes. The organic layer was separated and stirred in a saturate hydrogen carbonate solution for 15 minutes. The organic layer was separated, washed with water, dried, filtered and evaporated. The solid residue was stirred in 240 parts of methanol. 5.3 Parts of sodium methoxide were added portionwise. After complete addition, the whole was stirred for 1 hour at room temperature. After evaporation in vacuo at 50° C., the residue was stirred in water and acidified with a hydrochloric acid solution 3N. Trichloromethane was added, the organic layer was separated, washed twice with water, dried, filtered and evaporated, yielding 10 parts (93%) of 4-fluoro-2-(phenylmethoxy)phenol as a residue (intermediate 77).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@:9]([OH:15])([C@H:12](O)[CH3:13])[CH2:10]O.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@:9]([OH:15])([C@H:12]([S:17]([CH3:16])(=[O:19])=[O:18])[CH3:13])[CH2:10][S:17]([CH3:16])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](O)[C@](O)(CO)c1cc(F)ccc1F
Product: C[C@H]([C@](O)(CS(C)(=O)=O)c1cc(F)ccc1F)S(C)(=O)=O
Yield: 218.6 %

Procedure:
In the same manner as that described in Example 7(iii) above. 4.80 g (10.1 mmol) of (2R,3R)-2-(2,5-difluorophenyl)-1,2,3-butanetriol [prepared as described in Step 8(ii) above] were reacted with 7.75 g (67.8 mmol) of methanesulfonyl chloride and the resulting product was purified by chromatography on a silica gel (110 g) column using a 1:2 to 1:1 mixture of ethyl acetate and hexane as the eluant to afford 7.56 g (yield 92%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[C@H:10]1[CH2:14][C@H:13](Br)[CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:23])[C@H:10]1[CH2:14][C@@H:13]([N:24]=[N+:25]=[N-:26])[CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Br)C[C@@H]1C(=O)OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](N=[N+]=[N-])C[C@@H]1C(=O)OCc1ccccc1

Procedure:
The bromo benzyl ester 35 (4.67 g, 12.1 mmol) and NaN3 (4.7 g, 72.3 mmol) were suspended in 175 mL DMF. This mixture was subjected to the procedure for the synthesis of 20 ethyl ester, to give 3.73 g (89% crude yield) of a colorless oil which was used directly in subsequent reactions. 1H NMR (CDCl3) δ1.33/1.45 (2s, 9H), 2.18 (m, 1H), 2.48 (m, 1H), 3.48 (m, 1H), 3.71 (m, 1H), 4.14 (m, 1H), 4.35/4.49 (2dd, J=8.7/3.0 Hz, 1H), 5.16 (m, 2H), 7.34 (s, 5H). FAB MS; MH+ calc. for C17H23N4O4 =347.1719, found 347.1726.
Reaction SMILES: C1(C)C=C[C:4]([S:7](NC2C=CC(C)=CC=2/C=C/C(OC)=S)(=O)=O)=CC=1.Cl[C:26]1[CH:34]=[C:33]2[C:29]([C:30]([CH2:44][C:45]([OH:47])=[O:46])=[C:31]([C:35]([C:37]3[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][N:38]=3)=[O:36])[NH:32]2)=[CH:28][CH:27]=1>>[CH3:43][C:41]1[CH:40]=[CH:39][N:38]=[C:37]([C:35]([C:31]2[NH:32][C:33]3[C:29]([C:30]=2[CH2:44][C:45]([OH:47])=[O:46])=[CH:28][C:27]([S:7][CH3:4])=[CH:26][CH:34]=3)=[O:36])[CH:42]=1
Reactant: Cc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2CC(=O)O)c1
Reactant: COC(=S)/C=C/c1cc(C)ccc1NS(=O)(=O)c1ccc(C)cc1
Product: CSc1ccc2[nH]c(C(=O)c3cc(C)ccn3)c(CC(=O)O)c2c1

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-2-p-toluenesulfonylamino-5-methylthiocinnamate (step 2) and 2-bromoacetyl-4-methylpyridine hydrobromide (Preparation is described in step 2 of Example 31).
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][NH:10][CH2:11][CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1.S1CCCS[CH2:19]1.Cl>C(COC)OC>[CH:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[C:4]([CH2:9][N:10]2[CH2:19][C:17]3[CH:16]=[CH:15][S:14][C:13]=3[CH2:12][CH2:11]2)[CH:5]=1.[ClH:1]
Reactant: Clc1ccccc1CNCCc1cccs1
Reactant: C1CSCSC1
Agent: Cl
Solvent: COCCOC
Product: Clc1ccccc1CN1CCc2sccc2C1
Temperature: 10 °C
Yield: 62.7 %

Procedure:
N-[(2-chlorophenyl-methyl)]-2-(2-thienyl)ethylamine HCl (14.4 g) is suspended into 50 ml of dimethoxyethane. 1,3-Dithiane (9 g) and 0.12 ml of 37% hydrochloride acid are added. The reaction mixture is refluxed for 24 hours. Thereafter, the mixture is cooled to 10° C. and the crystalline precipitate is filtered and washed twice with 5 ml of dimethoxyethane. The product is dried at 60° C. under vacuum to yield 9.4 g (62.7%) of ticlopidine hydrochloride having the same physico-chemical characteristics as reported in Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([B:11]([OH:13])[OH:12])[CH:5]=[C:6]([C:8]([OH:10])=[O:9])[CH:7]=1.[C:14](Cl)(Cl)=[S:15]>Cl>[N:1]([C:2]1[CH:3]=[C:4]([B:11]([OH:13])[OH:12])[CH:5]=[C:6]([C:8]([OH:10])=[O:9])[CH:7]=1)=[C:14]=[S:15]
Reactant: S=C(Cl)Cl
Reactant: Nc1cc(B(O)O)cc(C(=O)O)c1
Agent: Cl
Product: O=C(O)c1cc(N=C=S)cc(B(O)O)c1
Temperature: 25 °C

Procedure:
To a solution of 3-amino-5-carboxyphenylboronic acid (150 mg, 0.08 mmol) in 3N HCl (3 ml) was added thiophosgene (92 mg, 0.08 mmol) in 3N HCl (3 ml) and the reaction mixture was stirred at room temperature. A white solid was formed after 20 minutes. This was recrystallized from hexane/ethyl acetate. M.P. >350° C. Anal. Calcd. for C8H6NO4BS.3H2O. C, 42.06; H, 2.91; N, 6.13. Found: C, 42.51; H, 2.87; N, 5.68.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Cl[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[O:15][CH3:16]>>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([NH:3][CH2:2][CH2:1][NH2:4])=[C:7]([O:15][CH3:16])[CH:8]=1)([O-:14])=[O:13]
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: NCCN
Product: COc1cc([N+](=O)[O-])ccc1NCCN

Procedure:
Ethylene diamine is reacted with 2-chloro-5-nitroanisole to form 4-nitro-2-methoxy-N-(β-aminoethyl)aniline which is isolated in the form of its monohydrochloride. This monohydrochloride is reacted with potassium isocyanate to form 4-nitro-2-methoxy-N-(β-ureidoethyl) aniline which is reduced by a sodium hydrosulfite solution to 4-amino-2-methoxy-N-(β-ureidoethyl) aniline.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11](O)[CH2:12][OH:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:7]2[O:13][CH2:12][CH2:11][O:8]2)[CH:9]=1
Reactant: OCCO
Reactant: Cc1ccc(Br)cc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(Br)cc1C1OCCO1
Temperature: 130 °C
Reaction time: 21 h

Procedure:
To a solution of INT 30 (17.3 g, 87 mmol) in toluene (505 mL) was added ethane-1,2-diol (24.3 mL, 436 mmol) followed by p-toluenesulfonic acid monohydrate (0.83 g, 4.36 mmol). The reaction mixture was stirred at 130° C. for 21 hours. The mixture was washed with saturated aqueous NaHCO3 (2×) and brine (2×). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by Kugelrohr distillation to give INT 31.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12]1[NH:13][CH2:14][CH2:15][N:16]=1.[CH2:17]([Sn](CCCC)(CCCC)CCCC)[CH:18]=[CH2:19].[F-].[Cs+].O1CCOCC1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.CN(C=O)C>[CH2:19]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12]1[NH:13][CH2:14][CH2:15][N:16]=1)[CH:18]=[CH2:17]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: Clc1cccc2c1CCOC2C1=NCCN1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: C=CCc1cccc2c1CCOC2C1=NCCN1
Temperature: 160 °C

Procedure:
To a mixture of 2-(5-chloroisochroman-1-yl)-4,5-dihydro-1H-imidazole (50 mg), allyltributyltin (69.9 mg), CsF (70.6 mg) and bis(tri-t-butylphosphine)palladium (3.24 mg) were added dioxane (2 ml) and DMF (0.5 ml). The reaction mixture was degassed with N2 and heated in a microwave oven for 30 min at 160° C. The title compound was purified by applying methods F and G. (Yield 5.8 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=O.C(O)(=O)[CH2:19][C:20]([OH:22])=[O:21].N1CCCCC1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1/[CH:12]=[CH:19]/[C:20]([OH:22])=[O:21]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccccc1Sc1ccc(Cl)cc1Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)/C=C/c1ccccc1Sc1ccc(Cl)cc1Cl
Temperature: 110 °C
Yield: 90.6 %

Procedure:
A mixture of the aldehyde (1.50 g, 5.3 mmol) from Example 1A, malonic acid (1.21 g, 11.6 mmol), piperidine (78.6 μL, 0.80 mmol) in 8.0 mL of anhydrous pyridine was heated at 110° C. for 2 hours. Gas evolution ceased during this period. Pyridine was then removed under vacuum. Water and 3N aq. HCl were then added with stirring. The desired cinnamic acid was then collected through filtration, washed with cold water and dried in a vacuum oven overnight to give 1.56 g (4.8 mmol, 91%) of white solid.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([C@H:8]1[CH2:13][CH2:12][C@H:11]([CH:14]([CH2:18][C:19]2[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=2)[C:15](O)=[O:16])[CH2:10][CH2:9]1)[CH2:6][CH3:7].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl>[F:25][C:23]1[CH:24]=[C:19]2[C:20](=[C:21]([F:27])[C:22]=1[F:26])[C:15](=[O:16])[CH:14]([C@H:11]1[CH2:10][CH2:9][C@H:8]([CH2:5][CH2:6][CH3:7])[CH2:13][CH2:12]1)[CH2:18]2
Reactant: CCC[C@H]1CC[C@H](C(Cc2cc(F)c(F)c(F)c2)C(=O)O)CC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCC[C@H]1CC[C@H](C2Cc3cc(F)c(F)c(F)c3C2=O)CC1
Reaction time: 2 h

Procedure:
Dichloromethane (25 ml) and thionyl chloride (20 ml) were added to 2-(trans-4-propylcyclohexyl)-3-(3,4,5-trifluorophenyl)propionic acid crude product (12.3 g), and refluxed while heating for 4 hours. The dichloromethane was distilled off at normal pressure and the thionyl chloride was distilled off under reduced pressure followed by the addition of dichloromethane (50 ml) to the residue to prepare a dichloromethane solution of 2-(trans-4-propylcyclohexyl)-3-(3,4,5-trifluorophenyl)propionic acid chloride. This was then dropped in to a dichloromethane suspension (20 ml) of aluminum chloride (8 g) at room temperature over the course of 30 minutes. Moreover, after stirring for 2 hours, the reaction solution was poured into 10% hydrochloric acid while cooling with ice. The organic layer was concentrated after drying with anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain 5,6,7-trifluoro-2-(trans-4-propylcyclohexyl)-1-indanone crude product (8.8 g, purity: 73%). This was then recrystallized from ethanol to obtain 5,6,7-trifluoro-2-(trans-4-propylcyclohexyl)-1-indanone (5 g, purity: 99%). This compound had a molecular weight of 310 as determined by mass analysis.
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][C:7]2(OCC[O:8]2)[CH2:6][CH2:5]1)[CH3:2].Cl>O1CCOCC1.O>[CH2:1]([O:3][C:4]1([C:14]([OH:16])=[O:15])[CH2:5][CH2:6][C:7](=[O:8])[CH2:12][CH2:13]1)[CH3:2]
Reactant: CCOC1(C(=O)O)CCC2(CC1)OCCO2
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CCOC1(C(=O)O)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
To a solution of the 8-ethoxy-1,4-dioxaspiro[4.5]decane-8-carboxylic acid in 1,4-dioxane (20 mL) was added HCl (6N) (7.53 mL, 45.2 mmol) and the mixture was stirred at rt for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3×40 mL). The organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 1-ethoxy-4-oxocyclohexanecarboxylic acid (0.777 g, 4.17 mmol, 65% yield over 2 steps) as a red oil. 1H NMR (500 MHz, CHLOROFORM-d) δ=3.59 (q, J=7.0 Hz, 2H), 2.66-2.55 (m, 2H), 2.42-2.33 (m, 4H), 2.24-2.15 (m, 2H), 1.31 (t, J=6.9 Hz, 3H).
Reaction SMILES: [C:1]([O:9][CH2:10][C@H:11]([C:36]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[C:38]([C:46]([F:49])([F:48])[F:47])[CH:37]=1)[O:12][C@H:13]1[CH2:21][CH2:20][C@H:19]2[C@@H:15]([CH2:16][N:17]([C:22]([NH:24][C:25](=[O:28])[CH2:26]Cl)=[O:23])[CH2:18]2)[C@@H:14]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH3:35])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[C:1]([O:9][CH2:10][C@H:11]([C:36]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[C:38]([C:46]([F:49])([F:48])[F:47])[CH:37]=1)[O:12][C@H:13]1[CH2:21][CH2:20][C@H:19]2[C@@H:15]([CH2:16][N:17]([C:22]3[O:23][CH2:26][C:25](=[O:28])[N:24]=3)[CH2:18]2)[C@@H:14]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH3:35])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1[C@H]1[C@@H]2CN(C(=O)NC(=O)CCl)C[C@H]2CC[C@@H]1O[C@H](COC(=O)c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccccc1[C@H]1[C@@H]2CN(C3=NC(=O)CO3)C[C@H]2CC[C@@H]1O[C@H](COC(=O)c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
A solution of the intermediate from Step C (8.84 g, 12.43 mmol) in THF (600 mL) and DBU (3.75 mL, 24.86 mmol) was heated at 50° C. for 2.5 hr. The volatiles were removed, and the crude material was purified by column chromatography [(6% methanol/EtOAc)/EtOAC 0 to 66% for 2900 mL, then 66% to 80% for 1200 mL] to give the title compound. M++1: 613.60.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([OH:26])[C:11]2[C:16]([C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:27](Cl)Cl>O>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([O:26][CH3:27])[C:11]2[C:16]([C:17]=1[O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(O)c2ccccc2c1OCc1ccccc1
Reactant: ClCCl
Solvent: O
Product: CCCCOC(=O)c1nc(OC)c2ccccc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 20 %

Procedure:
A mixture of 4-benzyloxy-1-hydroxy-isoquinoline-3-carboxylic acid butyl ester (1 eq.), Me3OBF4 (6 eq), KHCO3 (14 eq) and CH2Cl2 (10 ml/mmol 4-benzyloxy-1-hydroxy-isoquinoline-3-carboxylic acid butyl ester) was stirred at ambient temperature for 24 h. Then water (10 ml/mmol) was added and the mixture was extracted with CH2Cl2 (40 ml/mmol). The organic phase was separated, dried over MgSO4 and evaporated in vacuo to give a yellowish solid. The crude product was purified by flash column chromatography on silica gel using hexanes:EtOAc=85:15 as the eluent. Evaporation of the first fraction gave the title compound as a colorless oil in 20% yield; 1H NMR (CDCl3): δ=8.21 to 8.25 (m, 1H), 8.05 to 8.09 (m, 1H), 7.33 to 7.73 (m, 7H), 5.13 (s, 2H), 4.38 (t, 2H), 4.16 (s, 3H), 1.69 (m, 2H), 1.37 (m, 2H), 0.94 (t, 3H).
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:33])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:32])[NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14]>C1COCC1>[CH2:24]([NH:23][C:22]([C:19]1[CH:20]=[CH:21][C:16]([S:13]([NH:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]([OH:33])=[O:4])(=[O:14])=[O:15])=[CH:17][CH:18]=1)=[O:32])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)c1ccccc1NS(=O)(=O)c1ccc(C(=O)NCCc2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(NCCc1ccccc1)c1ccc(S(=O)(=O)Nc2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1 N aqueous lithium hydroxide (0.78 mL) is added to a solution of the title B compound, 2-(4-phenethylcarbamoyl-benzenesulfonylamino)-benzoic acid methyl ester (113.8 mg, 0.259 mmol) in 4 mL of THF. The reaction is stirred overnight at RT. The solvent is evaporated under a stream of nitrogen, and the residue is partitioned between water (6 mL) and EtOAc. The aqueous layer is washed with EtOAc (1 mL) and then acidified by adding it to a stirred solution of 1 N aqueous HCl (25 mL) to form a white solid. The solid is collected by filtration, washed with water, and dried under vacuum to give 2-(4-phenethylcarbamoyl-benzenesulfonylamino)-benzoic acid: m.p. 242-244° C.; ESI-MS 439.04 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14](N)=[CH:15][C:16]=3[C:17]=2[N:18]=1)=[O:5])[CH3:2].N(OCCC(C)C)=O.[CH3:28][S:29]SC>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([S:29][CH3:28])=[CH:15][C:16]=3[C:17]=2[N:18]=1)=[O:5])[CH3:2]
Reactant: CSSC
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(N)cc3c2n1
Agent: CC(C)CCON=O
Product: CCOC(=O)c1ncc2[nH]c3ccc(SC)cc3c2n1

Procedure:
400 mg of 8-amino-5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester (Example 11) is heated in 4.8 ml of dimethyl disulfide under argon to 60° C. The mixture is then combined with 2.8 ml of isoamyl nitrite and heated for one hour to 80° C. After evaporation, the mixture is chromatographed over silica gel with methylene chloride/ethanol=10:1 as the eluent. Recrystallization of the corresponding fractions yields 130 mg of 8-methylthio-5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester, mp 265°-266° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([CH2:16]O)[C@@H:14]([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:13]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@@H:12]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[I:60]I.[O-]S([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[C@H:15]([CH2:16][I:60])[C@@H:14]([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:13]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@@H:12]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: II
Reactant: CC(C)(C)OC(=O)N[C@H]1[C@H](COCc2ccccc2)[C@@H](CO)N(C(=O)OCc2ccccc2)[C@H]1c1ccccc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H]1[C@H](COCc2ccccc2)[C@@H](CI)N(C(=O)OCc2ccccc2)[C@H]1c1ccccc1
Temperature: 25 °C
Yield: 211.4 %

Procedure:
To a stirred mixture of (2S*,3S*,4S*,5S*)-1-benzyloxycarbonyl-4-benzyloxymethyl-3-[N-(t-butoxycarbonyl)amino]-5-hydroxymethyl-2-phenylpyrrolidine (9.00 g, 16.5 mmol), Ph3P (10.8 g, 41.3 mmol) and Im (2.81 g, 41.3 mmol) in dry PhMe (240 ml) was added I2 (8.38 g, 33.0 mmol) in one portion at room temperature. After stirring and heating at a gentle reflux for an hour, the dark brown mixture was allowed to cool to room temperature, and then sat. Na2SO3 aq. solution (70 ml) was added until the dark color due to the excess I2 was discharged. The layers were separated, and the organic layer was washed with sat. NaCl aq. solution (×1), dried (MgSO4), and concentrated in vacuo to give a deep red oil (22.9 g). This was chromatographed over SiO2 (Merck Kieselgel 60, 230 g). Elution with n-hexane-AcOEt (30:1→10:1→6:1) gave the title compound (9.95 g, 92%) as a white solid. A portion of it (105 mg) was recrystallized from isopropyl ether (IPE) to afford an analytical sample of the title compound as white powders (mp 107.5-108.5 C.); IRmax (nujol): 3440(s), 1705(vs), 1500(s), 1165(s), 780(m), 770(m), 755(m), 740(m), 707(s), 695(s) cm-1 ; 1H-NMR δ: 7.60-7.15(m, 14H), 7.09(br.s, 2H), 5.19(d, J=8.8 Hz, 1H), 5.03(br.s, 2H), 2H), 4.44(ddd, J=9.0, 9.0, 9.0 Hz, 1H), 4.15-3.97(m, 1H), 3.97-3.75(m, 2H), 3.71(dd, J=9.7, 5.3 Hz, 1H), 3.64(dd, J=9.7, 5.3 Hz, 1H), 2.34-2.18(m, 1H), 1.36(br.s, 9H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.Br[CH2:13][C:14]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:15].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH:16]1([C:14]([C:13]2[O:11][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=3[C:8]=2[CH3:9])=[O:15])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC(=O)c1cc(F)ccc1O
Reactant: O=C(CBr)C1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)C2CCCCC2)oc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
To a mixture of 5′-fluoro-2′-hydroxyacetophenone (5.00 g), 2-bromo-1-cyclohexylethanone (7.98 g) synthesized above and N,N-dimethylformamide (50 mL) was added potassium carbonate (13.4 g), and the mixture was stirred at room temperature overnight. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% ethyl acetate/hexane) to give the title object compound (5.38 g, 64%) as a pale-yellow solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH2:23]([CH2:25][NH2:26])[OH:24]>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:26][CH2:25][CH2:23][OH:24])=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: NCCO
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: OCCNCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
According to the method in example 6, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and ethanolamine were converted to yield 2-{4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butylamino}-ethanol as white solid, MS: 421(MH+, 1Br).
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C:9]1[NH:13][C:12](=[C:14]2[C:27]3[C:26]4[C:21](=[C:22]([N+:28]([O-])=O)[CH:23]=[CH:24][CH:25]=4)[NH:20][C:19]=3[C:18](=[O:31])[NH:17][CH2:16][CH2:15]2)[C:11](=[O:32])[N:10]=1>CO.[Pd]>[NH2:28][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:21]=1[NH:20][C:19]1[C:18](=[O:31])[NH:17][CH2:16][CH2:15][C:14](=[C:12]3[C:11](=[O:32])[N:10]=[C:9]([NH2:8])[NH:13]3)[C:27]2=1
Reactant: NC1=NC(=O)C(=C2CCNC(=O)c3[nH]c4c([N+](=O)[O-])cccc4c32)N1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: NC1=NC(=O)C(=C2CCNC(=O)c3[nH]c4c(N)cccc4c32)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(2-amino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-9-nitro-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one TFA salt (4 mg, 8.8 μmol) in MeOH (3 mL) is added 10% Pd/C (10 mg). The mixture is stirred at room temperature under hydrogen atmosphere overnight and then the catalyst is removed by filtration. The solution is concentrated and the residue purified by HPLC (C18 column, eluted with CH3CN/H2O with 0.05% TFA) to give 9-amino-5-(2-amino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one; 1H NMR (MeOD-d4) δ 3.48-3.53 (m, 4H), 7.358 (d, 1H, J=6.0 Hz), 7.362 (d, 1H, J=3.2 Hz), 7.63 (dd, 1H, J1=3.2 Hz, J2=6.0 Hz); m/z [M++1] 311.1.