Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[N:3]=1.[CH3:13][NH:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C.O>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=[C:6]([N:14]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH3:13])[N:7]=1
Reactant: CNC1CCCCC1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cc(N(C)C2CCCCC2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A cooled (0° C.) solution of methyl 2,4-dichloropyrimidine-6-carboxylate (Apollo, OR2558, 25.00 g; 120 mmol) in THF (500 mL) was treated with a solution of n-methylcyclohexylamine (Aldrich, 15.7 ml; 121 mmol) and triethylamine (18.4 ml; 133 mmol) in THF (250 mL). The reaction mixture was stirred for 16 hours at RT. Water (250 mL) was poured into the reaction mixture which was extracted with EtOAc. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated to obtain the crude product, which was purified by recrystallisation from MTBE. The title product was obtained as a beige solid (25.7 g, 75%).
Reaction SMILES: [C:1]([C:9]1[C:10]([NH:16][C:17](=[O:20])[CH2:18][I:19])=[CH:11][N:12]([CH3:15])[C:13]=1[CH3:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21]C1C=CC=CC=1C(CC(=O)C)=O>>[Cl:21][C:7]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:1]([C:9]1[C:10]([NH:16][C:17](=[O:20])[CH2:18][I:19])=[CH:11][N:12]([CH3:15])[C:13]=1[CH3:14])=[O:8]
Reactant: Cc1c(C(=O)c2ccccc2)c(NC(=O)CI)cn1C
Reactant: CC(=O)CC(=O)c1ccccc1Cl
Product: Cc1c(C(=O)c2ccccc2Cl)c(NC(=O)CI)cn1C

Procedure:
This compound was prepared by following the procedures described in example (A), steps (a), (b), and (c) but starting from (2-chlorobenzoyl)acetone instead of benzoylacetone. M.p. 155°-57° C.
Reaction SMILES: [SH:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].Br[CH2:8][C:9]([C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=1)=[O:10]>>[OH:6][CH:3]([CH2:4][OH:5])[CH2:2][S:1][CH2:8][C:9]([C:11]1[CH:12]=[C:13]([O:21][CH3:22])[C:14]([O:19][CH3:20])=[C:15]([O:17][CH3:18])[CH:16]=1)=[O:10]
Reactant: OCC(O)CS
Reactant: COc1cc(C(=O)CBr)cc(OC)c1OC
Product: COc1cc(C(=O)CSCC(O)CO)cc(OC)c1OC
Yield: 94.8 %

Procedure:
Substantially the same procedure as in Reference Example 13 was repeated using 1-mercapto-2,3-propanediol (12.25 g) and 2-bromo-3',4',5'-trimethoxyacetophenone (Compound XIa, 16.39 g) obtained in Reference Example 1 to give 2-(2,3-dihydroxypropylthio)-3',4',5'-trimethoxyacetophenone (Compound IX-13, 17.00 g).
Reaction SMILES: [CH:1]([N:4]1[C:9]([CH3:10])=[CH:8][C:7](=[O:11])[CH2:6][S:5]1(=[O:13])=[O:12])([CH3:3])[CH3:2].[NH3:14]>CO>[NH2:14][C:9]([CH3:10])=[CH:8][C:7](=[O:11])[CH2:6][S:5]([NH:4][CH:1]([CH3:3])[CH3:2])(=[O:13])=[O:12]
Reactant: CC1=CC(=O)CS(=O)(=O)N1C(C)C
Reactant: N
Solvent: CO
Product: CC(N)=CC(=O)CS(=O)(=O)NC(C)C

Procedure:
A suspension of 10 g of 2-isopropyl-3-methyl-1,2-thiazin-5(6H)-one 1,1-dioxide in 100 ml of methanol was reacted with ammonia in accordance with the procedure described in Example 1. The solution obtained was concentrated to dryness under reduced pressure and the solid residue was recrystallized from isopropanol. There were obtained 10.1 g of 4-amino-N-isopropyl-2-oxo-3-pentenesulfonamide in the form of colorless crystals, m.p. 119°-121°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[CH:7]=1>[Pd]>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[C:5]([NH2:15])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1Nc1ccncn1
Agent: [Pd]
Product: Nc1ccc(F)cc1Nc1ccncn1
Reaction time: 3.5 h
Yield: 92.4 %

Procedure:
(5-Fluoro-2-nitrophenyl)pyrimidin-4-ylamine (0.31 g, 1.32 mmol) in IMS was hydrogenated at RT and pressure for 3.5 h using Pd—C (30 mg) as a catalyst. The catalyst was removed by filtration through Celite. The filtrate was concentrated in vacuo to give the title compound as an orange solid, (0.249 g, 92%). LCMS (Method J): RT=0.56 min, [M+H]+=205.16
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:5]([O:26][CH3:27])=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[CH:12][C:13]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[C:14]([CH:20]=2)CNC(=O)C)[CH:7]=1.[O:32]=[C:33]1[C:38](B(O)O)=[CH:37][CH:36]=[CH:35][NH:34]1>>[C:28]([C:4]1[C:5]([O:26][CH3:27])=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:20]=[CH:14][C:13]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:12][C:11]=2[CH2:35][NH:34][C:33](=[O:32])[CH3:38])[CH:7]=[C:2]([C:38]2[C:33](=[O:32])[NH:34][CH:35]=[CH:36][CH:37]=2)[CH:3]=1)([CH3:29])([CH3:30])[CH3:31]
Reactant: O=c1[nH]cccc1B(O)O
Reactant: COc1c(/C=C/c2ccc(NS(C)(=O)=O)c(CNC(C)=O)c2)cc(Br)cc1C(C)(C)C
Product: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2CNC(C)=O)cc(-c2ccc[nH]c2=O)cc1C(C)(C)C

Procedure:
step 3—Palladium-catalyzed coupling of 212 and B-(1,2-dihydro-2-oxo-3-pyridinyl)-boronic acid (213, CASRN 951655-49-5) was carried out in accord with the procedure in step 4 of example 38 to afford the title compound. The product was purified on a SiO2 preparative TLC plate developed with 5% MeOH/DCM to afford 17.5 mg of I-160
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:15](Cl)(=[O:17])[CH3:16]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:15](=[O:17])[CH3:16])=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: Nc1ccc(F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(F)cc1
Reaction time: 0.25 h
Yield: 91.4 %

Procedure:
To a chilled (ice-bath) solution of 4-fluorophenylamine (2.9 mL, 30 mmol) and anhydrous pyridine (3.7 mL, 45 mmol) in methylene chloride (50 mL) was slowly added a solution of acetyl chloride (2.4 mL, 33 mmol) in methylene chloride (10 mL). After 15 minutes, the mixture was concentrated in vacuo and the residue was diluted with cold water. The resulting precipitate was filtered, washed with water and dried to afford 4.2 g of N-(4-fluorophenyl)acetamide as an off white solid. MS m/z 154 (MH+).
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([OH:5])=[O:4].[C:10]1([C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N+]=[N-])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([O:5][CH:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:4]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: CCCCC(Br)C(=O)O
Product: CCCCC(Br)C(=O)OC(c1ccccc1)c1ccccc1
Yield: 90 %

Procedure:
α-Bromohexanoic acid (1.95g) in light petroleum spirit (25ml, b.p. 40°-60°) was treated with a stock solution of diphenyldiazomethane in petroleum spirit (b.p. 40°-60°) (ca. 3.8 mmole/10ml) dropwise with stirring until a faint violet colour persisted. The mixture was stirred for 2 hours at room temperature, whereupon the solvent was removed in vacuo. The resulting oil in ethyl acetate was washed with a saturated aqueous solution of sodium bicarbonate then with water and dried. Removal of the solvent gave the title ester (3.0g, 90%), λmax (EtOH) 252, 258, 263.5, 267.5 and 276 nm (ε 1650, 1600, 1350, 1150 and 850).
Reaction SMILES: C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.[Al+3:13].C(OCCOCCO)CCC.COC1C=CC(O)=CC=1.[C:34]([OH:38])(=[O:37])[CH:35]=[CH2:36]>C(O)(C)C>[C:34]([O-:38])(=[O:37])[CH:35]=[CH2:36].[C:34]([O-:38])(=[O:37])[CH:35]=[CH2:36].[C:34]([O-:38])(=[O:37])[CH:35]=[CH2:36].[Al+3:13]
Reactant: C=CC(=O)O
Agent: CC(C)[O-]
Agent: COc1ccc(O)cc1
Agent: [Al+3]
Solvent: CCCCOCCOCCO
Solvent: CC(C)O
Product: C=CC(=O)[O-]
Temperature: 53 °C

Procedure:
Into the flask described hereinabove there were placed 102.1 g of aluminium triisopropanolate, 120.1 g of diethylene glycol monobutyl ether, and 0.7 g of 4-methoxyphenol. To this mixture there were added in drops using a dropping funnel 108 grams of acrylic acid. The acid was added during 15 minutes at room temperature (25° C.). Owing to the reaction heat, the temperature increased to 53° C. The mixture was cooled to 39° C. using a water bath. The product remained liquid and stable so that it could be further treated as follows, namely it was heated to 60° C. during 30 minutes and the co-product isopropanol was expelled during 2 hours using a continuous vacuum up to 243 mbar.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[NH:6][C:7]2[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[C:11]([C:18]([O:20][CH3:21])=[O:19])=[CH:10][C:8]=2[N:9]=1.IC.[C:24](=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[CH3:24][N:9]1[C:8]2[CH:10]=[C:11]([C:18]([O:20][CH3:21])=[O:19])[C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][C:7]=2[N:6]=[C:5]1[CH3:4]
Reactant: O=C([O-])O
Reactant: COC(=O)c1cc2nc(C)[nH]c2cc1C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Solvent: CC(=O)O
Product: COC(=O)c1cc2nc(C)n(C)c2cc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
Sodium methoxide (1.96 g, 36.3 mmol) is added to a solution of dimethyl 2-methyl-5,6-benzimidazoledicarboxylate (8.50 g, 34.2 mmol) in methanol. The reaction mixture is stirred 0.5 hour at room temperature, treated with iodomethane (2.15 mL, 34.5 mmol) stirred overnight, acidified to pH 6 with acetic acid, treated with sodium bicarbonate to pH 8 and extracted with chloroform. The extracts are combined, dried (MgSO4) and concentrated in vacuo to yield the title product as a pink solid (6.25 g, 69.7%). A small portion is recrystallized from ethyl acetate to afford the title product as pink crystals, mp 147°-148° C.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[CH3:21][O:22][C:23](=[O:35])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32](=[O:34])[CH3:33])=[CH:27][CH:26]=1>C(Cl)(Cl)(Cl)Cl>[C:32]([O:31][C:28]1[CH:29]=[CH:30][C:25]([CH:24]([Br:8])[C:23]([O:22][CH3:21])=[O:35])=[CH:26][CH:27]=1)(=[O:34])[CH3:33]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccc(OC(C)=O)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccc(OC(C)=O)cc1
Yield: 0.1 %

Procedure:
9.5 g of NBS and 0.7 g of AIBN are added to a solution of 10 g of methyl(4-acetoxyphenyl)acetate in 100 mL of carbon tetrachloride in a 500 mL flask equipped with a magnetic stirrer and a condenser. After 16 hours under reflux, the mixture is filtered, the solid is washed with dichloromethane then the filtrate is concentrated. The residue is purified over a silica column with pure dichloromethane to yield 13 mg of expected product (oil, Yd=95%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[N:13][CH:12]=[C:11]([CH2:15]O)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].CN(C=O)C.S(Cl)(Cl)=O.[CH3:26][C:27]1[NH:28][CH:29]=[CH:30][N:31]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[N:13][CH:12]=[C:11]([CH2:15][N:28]3[CH:29]=[CH:30][N:31]=[C:27]3[CH3:26])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1ncc[nH]1
Reactant: OCc1cnnc(-c2ccc(F)c(Cl)c2)c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nccn1Cc1cnnc(-c2ccc(F)c(Cl)c2)c1
Temperature: 25 °C
Yield: 24.5 %

Procedure:
[6-(3-Chloro-4-fluoro-phenyl)-pyridazin-4-yl]-methanol (13 mg, 0.054 mmol) was dissolved in MeCl2 (1 ml) under argon and a drop of DMF was added. The mixture was cooled with an icebath, thionylchloride (0.02 ml, 0.27 mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature. After 30 minutes the reaction mixture was concentrated in vacuo. The residue was dissolved in ethanol and treated with 2-methyl-imidazole (22.3 mg, 0.27 mmol). The reaction mixture was refluxed for 12 hours then cooled to room temperature and concentrated. Ethyl acetate and a saturated NaHCO3 solution were added. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed over silica gel (CH2Cl2—MeOH 19:1) to provide 3-(3-chloro-4-fluoro-phenyl)-5-(2-methyl-imidazol-1-yl-methyl)-pyridazine (4 mg, 24%) as a light brown oil, MS: m/e=303.2 (M+H+).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:11]=[C:12]([Cl:18])[C:13]([OH:17])=[C:14]([I:16])[CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][CH2:30]O)=[N:25][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([O:9][C:10]1[CH:11]=[C:12]([Cl:18])[C:13]([O:17][CH2:30][CH2:29][CH2:28][O:27][C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:33])([F:19])[F:32])=[CH:26][N:25]=2)=[C:14]([I:16])[CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCCOc1ccc(C(F)(F)F)cn1
Reactant: O=C(Oc1cc(Cl)c(O)c(I)c1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(Oc1cc(Cl)c(OCCCOc2ccc(C(F)(F)F)cn2)c(I)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an atmosphere of protective gas, 3.5 g of 5-benzoyloxy-3-chloro-2-hydroxy-1-iodobenzene, 2.07 g of 3-(5-trifluoromethylpyrid-2-yloxy)propan-1-ol and 2.57 g of triphenylphosphine were dissolved in 100 ml of dry tetrahydrofuran (THF). With ice-bath cooling, 1.71 g of diethyl azodicarboxylate were added dropwise. After about 30 minutes, the ice-bath was removed, and the mixture was stirred at room temperature for 15 hours. The mixture was then concentrated under reduced pressure and the residue was taken up in a mixture of ethyl acetate and water. After shaking, the organic phase was isolated, dried and concentrated under reduced pressure. The crude product was purified chromatographically. Yield: 3.12 g (58%)
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[C:10]([OH:19])([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:3].Cl.[OH2:21]>>[CH3:3][N+:2]([O-:21])([CH2:4][CH:5]1[C:10]([OH:19])([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([O:17][CH3:18])[CH:16]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:1]
Reactant: COc1cccc(C2(O)CCCCC2CN(C)C)c1
Reactant: O
Agent: Cl
Product: COc1cccc(C2(O)CCCCC2C[N+](C)(C)[O-])c1

Procedure:
Tramadol N-oxide was prepared as set forth hereinafter. Tramadol hydrochloride (0.5 mol) was converted its free base in basified water (pH>9) and then extracted with ether. The solid was then heated under a high vacuum to remove as much water as possible to yield 131.5 g of material. The material was dissolved in methanol (500 mL) and 65 g of 30% H2O2 was added. The solution was stirred for 3 hours and then an additional 65 g of the 30% H2O2 was added. The reaction was stirred for 2.5 days at room temperature. Approximately 10 mg of PtO2 (use of Pt/C is suggested for its ease of removal) on carbon was then added to the reaction mixture, and very gentle foaming took place. An additional 10 mg of PtO2 was added and the reaction mixture was stirred overnight and then filtered thru filter aid. The filtrate was concentrated under vacuum while being heated to a temperature <40° C. The residue was taken up in methylene chloride. Since the methylene chloride solution contained some colloidial platinum, the solution was diluted with ethyl acetate to 1 L and filtered through a nylon filter membrane (0.45μ pore size) to yield a clear colorless filtrate. The filtrate was concentrated to 600 mL, and then ethyl acetate was added continuously to maintain a volume of 800 mL while the solution was heated until a vapor temperature of 74° C. was reached. The solution was then cooled to room temperature. The solid was collected by filtration, washed with ethyl acetate and dried in vacuo to yield 126.6 g of the tramadol N-oxide (mp. 159.5°-160° C.).
Reaction SMILES: N1C=CC=CC=1.[C:7]([C:11]1[C:12](=[O:22])[C:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]=2[C:19](=O)[CH:20]=1)([CH3:10])([CH3:9])[CH3:8].[NH2:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>ClC(Cl)C.O1CCCC1.O.[Ti](Cl)(Cl)(Cl)Cl>[C:7]([C:11]1[CH:20]=[C:19]([NH:23][C:24]2[S:25][CH:26]=[CH:27][N:28]=2)[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[C:12]=1[OH:22])([CH3:10])([CH3:9])[CH3:8]
Reactant: Nc1nccs1
Reactant: CC(C)(C)C1=CC(=O)C2=C(CCCC2)C1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(Nc2nccs2)c2c(c1O)CCCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 12.4 %

Procedure:
Pyridine (3.71 ml) was dissolved in 137 ml of dichloroethane, followed by addition of 1.26 ml of titanium tetrachloride. The mixture was heated under reflux for 15 minutes. Then, 5.00 g of 2-tert-butyl-5,6,7,8-tetrahydro-1,4-naphthoquinone and 2.29 g of 2-aminothiazole were added, and the mixture was heated under reflux for 2 hours. The reaction mixture was cooled to room temperature and filtered through Celite pad. The insoluble matter was washed with ethyl acetate. The filtrate was concentrated, and the crude product thus obtained was dissolved in 49 ml of tetrahydrofuran. To the solution was added a solution of 38.9 g of sodium hydrosulfite in 145 ml of water, and the mixture was stirred at room temperature for 15 minutes and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. The thus-obtained crude product was purified by silica gel column chromatography (diethyl ether-hexane =2:3) and washed with isopropyl ether to give 0.86 g of the desired compound as a colorless solid.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:17][CH:16]([NH2:18])[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Br[C:20]1[CH:21]=[CH:22][C:23]([C:26]([NH:28][CH3:29])=[O:27])=[N:24][CH:25]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(O[K])(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:15][CH:16]([NH:18][C:20]4[CH:21]=[CH:22][C:23]([C:26]([NH:28][CH3:29])=[O:27])=[N:24][CH:25]=4)[CH2:17]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CNC(=O)c1ccc(Br)cn1
Reactant: NC1CN(C(=O)N2CCCN(C3CCC3)CC2)C1
Agent: [Pd]
Agent: CC(C)(C)O[K]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CNC(=O)c1ccc(NC2CN(C(=O)N3CCCN(C4CCC4)CC3)C2)cn1
Temperature: 100 °C
Yield: 77.3 %

Procedure:
To a solution of 1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-amine (22 mg, 87 μmol) in degassed toluene (2 ml) was added 5-bromo-N-methylpyridine-2-carboxamide (19 mg, 87 μmol), racemic BINAP (8 mg, 13 μmol), tBuOK (12 mg, 0.10 mmol), followed by Pd2(dba)3 (8 mg, 9 μmol). The reaction was heated at 100° C. for 16 hours, concentrated and purified by FCC (DCM/MeOH/NH3 gradient, 98:2:1 to 95:5:1) giving the title compound as colourless oil (26 mg, 78%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11].[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[CH:32]=O>C1(C)C=CC=CC=1>[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[CH2:32][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:11])=[O:12]
Reactant: NCCCCCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: O=Cc1ccc2ccccc2c1
Agent: Cl
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCCCCCNCc1ccc2ccccc2c1
Yield: 18.1 %

Procedure:
A mixture of N-(6-Aminohexyl)-2-nitrobenzenesulfonamide hydrochloride (0.67 g, 2.0 mmol) and 2-naphthaldehyde(0.32 g, 2.1 mmol) in 75 mL of toluene was refluxed using a Dean Stark trap for 20 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethanol (40 mL) and sodium borohyride (0.020 g, 6.0 mmol) was added. After the reaction was complete (6 h), the solvent was evaporated and residue taken up in 30 mL of saturated sodium chloride solution and extracted with ethyl acetate(3×40 mL), washed with saturated sodium chloride solution, dried over sodium sulfate and concetrated to afford an oil. The oil was flash chromatographed over silica gel to afford the titled compound (0.16 g, 37%) which was converted into hydrochloride salt (mp 169° C.).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[S:33][C:34]5[CH2:35][N:36]([CH3:41])[CH2:37][CH2:38][C:39]=5[N:40]=4)[C:28](=[O:42])[N:27]([CH3:43])[CH:26]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:19][OH:20])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[S:33][C:34]5[CH2:35][N:36]([CH3:41])[CH2:37][CH2:38][C:39]=5[N:40]=4)[C:28](=[O:42])[N:27]([CH3:43])[CH:26]=3)[CH:22]=[CH:23][N:24]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCc2nc(Nc3cc(-c4ccnc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4C=O)cn(C)c3=O)sc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCc2nc(Nc3cc(-c4ccnc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)cn(C)c3=O)sc2C1
Temperature: 30 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
To a mixture of 115d (100 mg, 0.15 mmol) in methanol (6 mL) was added NaBH4 (18 mg, 0.45 mmol). The mixture was stirred at 30° C. for 1 h and then quenched with water (10 mL). It was extracted with dichloromethane (3×30 mL) and the combined organic layer was concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 115 (35 mg, 36%) as a white solid. MS-ESI: [M+H]+ 602.2. 1H NMR (500 MHz, CDCl3) δ 8.68 (d, J=5.0 Hz, 1H), 8.42 (d, J=2.5 Hz, 1H), 8.35 (d, J=2.5 Hz, 1H), 8.30 (s, 1H), 7.77 (d, J=2.0 Hz, 1H), 7.58-7.53 (m, 3H), 4.49-4.45 (m, 2H), 4.10 (bs, 1H), 3.73 (s, 3H), 3.58 (s, 2H), 2.83-2.79 (m, 4H), 2.52 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[N:15]1[CH:27]([CH2:28][CH:29]([OH:32])CO)[C:26]2[C:17](=[CH:18][C:19]([CH2:33][C:34]3[CH:35]=[N:36][C:37]([Cl:40])=[CH:38][CH:39]=3)=[C:20]3[C:25]=2[N:24]=[CH:23][CH:22]=[CH:21]3)[C:16]1=[O:41])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I([O-])(=O)(=O)=O.[Na+]>C(#N)C.O.ClCCl>[Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[N:15]1[CH:27]([CH2:28][CH:29]=[O:32])[C:26]2[C:17](=[CH:18][C:19]([CH2:33][C:34]3[CH:35]=[N:36][C:37]([Cl:40])=[CH:38][CH:39]=3)=[C:20]3[C:25]=2[N:24]=[CH:23][CH:22]=[CH:21]3)[C:16]1=[O:41])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCCC[C@@H]1N1C(=O)c2cc(Cc3ccc(Cl)nc3)c3cccnc3c2C1CC(O)CO
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCCC[C@@H]1N1C(=O)c2cc(Cc3ccc(Cl)nc3)c3cccnc3c2C1CC=O
Reaction time: 1.5 h

Procedure:
To a solution of 8-[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl]-5-[(6-chloropyridin-3-yl)methyl]-9-(2,3-dihydroxypropyl)-8,9-dihydro-7H-pyrrolo[3,4-h]quinolin-7-one (Example 21, 0.050 g, 0.084 mmol) in a mixture of 0.8 mL of acetonitrile and 0.6 mL of water at 0° C. was added sodium periodate (0.018 g, 0.084 mmol). After 1.5 hr, the mixture was diluted with dichloromethane, filtered through Celite, and poured into saturated aqueous sodium bicarbonate. The mixture was extracted 3× with dichloromethane and the combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo to provide {8-[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy)cyclohexyl]-5-[(6-chloropyridin-3-yl)methyl]-7-oxo-8,9-dihydro-7H-pyrrolo[3,4-h]quinolin-9-yl}acetaldehyde that gave a mass ion (ES+) of 564.5 for [M+H]+.