Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:38]=[C:5]2[N:6]=[CH:7][C:8]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:11]([C:20]4[CH:37]=[CH:36][C:23]([CH2:24][N:25]5[CH2:30][CH2:29][CH:28]([C:31]([O:33]CC)=[O:32])[CH2:27][CH2:26]5)=[CH:22][CH:21]=4)=[N:10][C:9]=3[N:4]2[N:3]=1.O.[Li+].[OH-]>C1COCC1>[CH3:1][C:2]1[CH:38]=[C:5]2[N:6]=[CH:7][C:8]3[CH:13]=[C:12]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:11]([C:20]4[CH:37]=[CH:36][C:23]([CH2:24][N:25]5[CH2:30][CH2:29][CH:28]([C:31]([OH:33])=[O:32])[CH2:27][CH2:26]5)=[CH:22][CH:21]=4)=[N:10][C:9]=3[N:4]2[N:3]=1
Reactant: CCOC(=O)C1CCN(Cc2ccc(-c3nc4c(cnc5cc(C)nn54)cc3-c3ccccc3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2ncc3cc(-c4ccccc4)c(-c4ccc(CN5CCC(C(=O)O)CC5)cc4)nc3n2n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Compound (13-1) (1.78 g, 3.52 mmol, 1.0 eq) was dissolved in THF (35 mL) and then added H2O (35 mL) and LiOH (178 mg, 10% w/w). The reaction was stirred at room temperature for 20 hours. After that time, the THF was removed in vacuo, and the remaining solvent was diluted with additional water and the pH adjusted to 7 with dilute HCl (5% aq). The mixture was extracted with CHCl3/MeOH (4:1, ×5). The combined organic phases were dried with brine and Na2SO4, and then concentrated onto Celite in vacuo. The material was purified by silica gel chromatography by eluting with a gradient of CHCl3 to CHCl3/MeOH (1:1) to give Compound (14-1).
Reaction SMILES: [O:1]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:13].C([O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24]C(=O)C)=[CH:20][CH:19]=1)(=O)C.[Cl-].[Cl-].[Cl-].[Al+3]>C(=S)=S>[OH:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=1[C:2](=[O:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:1])=[O:12]
Reactant: CC(=O)Oc1ccc(OC(C)=O)cc1
Reactant: O=C1CCCCCCCCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C(O)CCCCCCCCC(=O)c1cc(O)ccc1O
Reaction time: 72 h
Yield: 2.6 %

Procedure:
To a 500 mL flask, equipped with mechanical stirrer and under inert atmosphere, was added the previously made Oxacycloundecane-2,11-dione (37.95 g, 206 mmol), 1,4-diacetoxy-benzene (20 g, 103 mmol), and 200 mL carbon disulfide. Aluminum (III) trichloride (68.7 g, 515 mmol) was added and the reaction stirred for 72 hours. Carbon disulfide was decanted away, and ice was carefully added until most of mixture was dissolved. The insoluble material was collected by suction filtration and washed with 2×100 mL of water. The solid was then dissolved in 50 mL of 1 M aqueous sodium hydroxide and stirred for 1 hour. The solution was acidified with 1 M aqueous hydrochloric acid until pH=2. The crude product precipitate was collected by filtration and was re dissolved in acetonitrile (50 mL) and methylene chloride (15 mL) and allowed to precipitate slowly over a week. The resulting brown powder was collected by filtration and recrystallized from 10:3 acetic acid:water. The product (0.8 g, 3%) was isolated by filtration. Found: C, 65.55, H, 7.69%; C16H22O5 requires C, 65.29; H, 7.53% 1H NMR (d6-DMSO): δ 12.0, s, 1H (COOH); δ 11.4, s, 1H (aryl-hydroxyl); δ 9.2, s, 1H (aryl-hydroxyl); δ 7.2 d, 1H (aryl H); δ 7.0, dd, 1H, (arylH); δ 6.8, d, 1H (aryl H's), 3.0, t, 2H(CH2 α to carbonyl); δ 2.2, t, 2H (CH2 β to COOH); δ 1.6, multiplet, 2H (CH2 β to carbonyl), δ 1.5, multiplet, 2H (CH2 β to COOH), δ 1.3, multiplet, 8H (rest of CH2's).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:18])=[C:8]([CH:17]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)([O-:3])=[O:2].Cl.[NH2:20][OH:21].Cl>[OH-].[K+]>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:18])=[C:8]([CH:17]=1)[C:9](=[N:20][OH:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1O
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc(O)c(C(=NO)c2ccccc2)c1
Reaction time: 5 h

Procedure:
Into an autoclave, were charged 30 g of 2-chloro-5-nitrobenzophenone, 300 ml of water, and 9.70 g of potassium hydroxide. The mixture was allowed to react at 150° to 160° C. with stirring for 5 hours. Upon cooling to room temperature, there was obtained a clear liquid, reddish orange in color. The liquid was further cooled below 0° C. and strongly acidified with cold concentrated hydrochloric acid. The precipitated solids were collected by filtration, washed with water, and recrystallized from ethanol to yield 15.7 g (56.1%) of 5-nitro-2-hydroxy-benzophenone having a melting point of 122°-123° C. To 150 ml of 40-% aqueous potassium hydroxide solution, was added 25.0 g of 5-nitro-2-hydroxybenzophenone followed by 50 g of hydroxylamine hydrochloride. After 5 hours, the resulting clear liquid was cooled and acidified with concentrated hydrochloric acid to form a precipitate. The precipitate was washed with water and a small volume of 50-% aqueous methanol, then dried in air, and recrystallized from benzene and petroleum ether to yield 5-nitro-2-hydroxybenzophenone oxime.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][C:16]([S@:19]([NH2:21])=[O:20])([CH3:18])[CH3:17].O>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[C:11](/[CH:12]=[N:21]/[S@@:19]([C:16]([CH3:18])([CH3:17])[CH3:15])=[O:20])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: Cc1cccc2cc(C=O)c(Cl)nc12
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc2cc(/C=N/[S@](=O)C(C)(C)C)c(Cl)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.7 %

Procedure:
To a solution of 2-chloro-8-methylquinoline-3-carboxaldehyde (2.05 g, 10 mmol) in dry THF (20 mL) under nitrogen was added titanium isopropoxide (5.68 g, 20 mmol) and the mixture stirred at r.t. for 10 minutes. (R)-(+)-2-Methyl-2-propanesulfinamide (1.21 g, 10 mmol) was added to the reaction which was stirred at r.t. for 72 h. Water (20 mL) was added and the mixture was extracted with DCM (150 mL). The organic layer was separated, dried (MgSO4), filtered and the solvent removed in vacuo to afford the title compound (2.4 g, 72%) as a pale yellow solid. δH (CDCl3) 9.12 (s, 1H), 8.79 (s, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.67 (d, J=6.8 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H), 2.79 (s, 3H), 1.32 (s, 9H). LCMS (ES+) 309, 311 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[C:13]([Cl:33])=[CH:14][C:15]([F:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=3)[CH:17]=1)[N:5]=2.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:33][C:13]1[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:34](=[O:37])[CH2:35][CH3:36])=[N:10][C:9]3=[CH:8][CH:7]=2)=[CH:17][C:16]([NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=2)=[C:15]([F:32])[CH:14]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(N)sc4n3)c(Cl)cc2F)c1
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCC(=O)Nc1nc2ccc(Oc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4)c(F)cc3Cl)nc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-chloro-2-fluorophenyl}-3-(1-cyano-1-methylethyl)benzamide produced in Example C52(v) in pyridine (1.0 mL) was added propionyl chloride (29 μL, 0.332 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (10 mL), washed with 5% aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=70/30→0/100), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/hexane to give the title compound (46.7 mg, 52%) as a colorless powder.
Reaction SMILES: [CH2:1]([N:10]1[C:15](=[O:16])[C:14]([CH2:17]OS(C)(=O)=O)=[CH:13][C:12]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([CH3:30])[CH:24]=2)=[N:11]1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:31][NH:32][CH3:33]>>[CH2:1]([N:10]1[C:15](=[O:16])[C:14]([CH2:17][N:32]([CH3:33])[CH3:31])=[CH:13][C:12]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([CH3:30])[CH:24]=2)=[N:11]1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cc(-c2cc(COS(C)(=O)=O)c(=O)n(CC=Cc3ccccc3)n2)ccc1F
Reactant: CNC
Product: Cc1cc(-c2cc(CN(C)C)c(=O)n(CC=Cc3ccccc3)n2)ccc1F
Yield: 90.9 %

Procedure:
Following the procedure of Example 7, 2-cinnamyl-6-(4-fluoro-3-methylphenyl)-4-methanesulonyloxymethyl-2H-pyridazin-3-one and dimethylamine were reacted to yield the title compound as a yellow oil (yield: 90.9%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][N:10]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:11]2=[O:14])=[CH:6][C:5]=1F.O.[C:26]([O:30][C:31]([N:33]1[CH:38]2[CH2:39][CH2:40][CH:34]1[CH2:35][CH:36]([OH:41])[CH2:37]2)=[O:32])([CH3:29])([CH3:28])[CH3:27]>CC(N(C)C)=O>[C:26]([O:30][C:31]([N:33]1[CH:38]2[CH2:39][CH2:40][CH:34]1[CH2:35][CH:36]([O:41][C:5]1[CH:6]=[C:7]3[C:12](=[CH:13][C:4]=1[Cl:3])[C:11](=[O:14])[N:10]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH:9]=[CH:8]3)[CH2:37]2)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(O)C2
Reactant: COc1ccc(Cn2ccc3cc(F)c(Cl)cc3c2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc(Cn2ccc3cc(OC4CC5CCC(C4)N5C(=O)OC(C)(C)C)c(Cl)cc3c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
528 mg of sodium hydride (60%) were suspended in 8 mL of dimethyl acetamide and 1.00 g of 3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (70), dissolved in 4 mL of dimethyl acetamide, were added dropwise. After 1 h, 1.40 g of 7-Chloro-6-fluoro-2-(4-methoxy-benzyl)-2H-isoquinolin-1-one (62), dissolved in another 8 mL of dimethyl acetamide, were added. The reaction mixture was stirred at room temperature until the reaction was complete. 30 mL of water were added, the resulting suspension extracted three times with a mixture of dichloromethane and 2-propanol (3:1) and the combined organic layers were evaporated. Water was added and the crude product was subjected to lyophilization to remove remainders of dimethyl acetamide. The obtained crude product was purified by silica gel chromatography to yield 1.85 g of the title compound as a mixture of diastereoisomers (71). Rt=1.95 min, 2.03 min (Method C). Detected mass: 525.0 (M+H+).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=O.Cl.[NH2:27][OH:28].C[O-].[Na+].CO.Cl>O1CCOCC1>[OH:28][NH:27][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:2]
Reactant: NO
Reactant: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc(F)cc3)CC2)s1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(NO)c1cnc(N2CCN(S(=O)(=O)c3ccc(F)cc3)CC2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound (12m) (125 mg, 0.320 mmol) in 1,4-dioxane (2 mL) were added hydroxylamine hydrochloride (225 mg, 3.20 mmol) and a freshly prepared solution of sodium methoxide in methanol (110 mg, 4.80 mmol of sodium dissolved in 1 mL of methanol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 2 h (progress of the reaction was monitored by TLC analysis). The reaction mixture was acidified to pH˜6 with 1M HCl and the formed precipitates were filtered off. The filtrate was diluted with ethylacetate (5 mL) and water (2 mL) and the organic layer was separated. The aqueous layer was washed with ethylacetate (5 mL) and the combined organic layers were dried on sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 13m. HPLC: (Rt=3.89 min).
Reaction SMILES: O=[C:2]([CH3:11])[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=O.[NH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1>>[CH3:11][CH:2]1[CH2:3][CH:4]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[N:12]1[C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1
Reactant: CC(=O)CC1CCCCC1=O
Reactant: Nc1ccc(C(=O)O)cc1
Product: CC1CC2CCCCC2N1c1ccc(C(=O)O)cc1
Yield: 65 %

Procedure:
Following the general methods as outlined under Intermediate 7, starting from 2-(2-oxopropyl)cyclohexanone and 4-aminobenzoic acid, the title compound was isolated in 65% yield (98% purity by HPLC). MS(ESI+): 256.4; MS(ESI−): 254.4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2([CH:15]([F:17])[F:16])[NH:13][C:12](=O)[CH2:11][O:10][CH2:9]2)[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2([CH:15]([F:17])[F:16])[NH:13][C:12](=[S:28])[CH2:11][O:10][CH2:9]2)[CH:7]=1
Reactant: O=C1COCC(c2cc(Br)ccc2F)(C(F)F)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(Br)cc1C1(C(F)F)COCC(=S)N1

Procedure:
A mixture of 7.34 g (22.65 mmol) 5-(5-bromo-2-fluoro-phenyl)-5-difluoromethyl-morpholin-3-one and 5.19 g (12.46 mmol) Lawesson's reagent in 73 ml of THF was refluxed for 1 h. The mixture was concentrated and crystallized from DCM/hexane and recrystallized from EtOH to yield the desired product as colorless crystals.
Reaction SMILES: C(O)C.[Na].[Cl:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13](=[NH:15])[NH2:14])[CH:9]=[CH:10][CH:11]=1.[CH2:16]([N:23]1[CH2:29][CH2:28][C:27](=O)[CH:26]([C:31](OCC)=[O:32])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[CH2:16]([N:23]1[CH2:24][CH2:25][C:26]2[C:31](=[O:32])[NH:15][C:13]([CH2:12][C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([Cl:5])[CH:7]=3)=[N:14][C:27]=2[CH2:28][CH2:29]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CCC1=O
Reactant: N=C(N)Cc1cccc(Cl)c1
Agent: [Na]
Solvent: O
Solvent: CCO
Product: O=c1[nH]c(Cc2cccc(Cl)c2)nc2c1CCN(Cc1ccccc1)CC2
Yield: 33 %

Procedure:
Ethanol (30 ml) was cooled in an ice bath then sodium (160 mg, 6.70 mmol) was added, with vigorous stirring. Once the sodium was dissolved, 2-(3-chlorophenyl)ethanimidamide (474 mg, 2.81 mmol) and ethyl 1-benzyl-5-oxoazepane-4-carboxylate (876 mg, 2.81 mmol) was added. The reaction mixture was refluxed, under nitrogen, for 17 h. Water (2 ml) was added to quench the reaction then the reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate (20 ml) and water (20 ml). The organic phase was dried over magnesium sulphate and concentrated in vacuo. Trituration of the residue with diethyl ether afforded the title compound as a solid in 33% yield, 361 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:27].C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:31]1[CH2:32][CH2:33][N:28]([CH:26]=[O:27])[CH2:29][CH2:30]1)=[O:5])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=CN1CCNCC1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N2CCN(C=O)CC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from 2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2yl)ethyl]aminocarbonyl}benzoic acid, 4-formylpiperazine, pentafluorophenyl-N,N′,N′-tetramethyluroniumhexafluorophosphate (PFTU), and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.01 minutes; C22H21Cl2N5O3 (474.35); mass spectrum: (M−H)−=473/475/477 (chlorine isotope).
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][N:15]=3)[S:13][C:6]=12.[CH3:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][NH2:36].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][C:17]([CH2:18][NH:36][CH2:35][CH2:34][O:33][CH2:32][CH2:31][O:30][CH3:29])=[CH:20][CH:21]=3)[S:13][C:6]=12
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Reactant: COCCOCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COCCOCCNCc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.2 %

Procedure:
A suspension of carbaldehyde 325 (0.50 g, 1.3 mmol), amine 326 (0.30 g, 2.5 mmol) and acetic acid (0.14 ml, 2.5 mmol) in dichloromethane (20 ml) was stirred for 1 h at room temperature. Then sodium triacetoxyborohydride (0.80 g, 3.8 mmol) was added and stirred at r.t. for 16 h. A further amount of sodium triacetoxyborohydride (1.0 g) was then added, and stirring continued for 2 h. The reaction mixture was partitioned between dichloromethane and 1N NaOH. The yellow suspension was removed by filtration and rinsed with dichloromethane and 1N NaOH. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified via Biotage (linear gradient 0-20%, methanol/dichloromethane; Snap 100 g column) to yield 327 (280 mg, 0.562 mmol, 44%) as a yellow solid. LRMS (M+H): 499.4
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[S:8].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=1)=O>C(O)C>[Br:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]2[N:6]([CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:16])[C:7](=[N:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[S:8][CH:18]=2)=[CH:22][CH:23]=1
Reactant: CN(C)CCCNC(=S)Nc1ccccc1
Reactant: O=C(CBr)c1ccc(Br)cc1
Solvent: CCO
Product: CN(C)CCCn1c(-c2ccc(Br)cc2)csc1=Nc1ccccc1
Yield: 59.1 %

Procedure:
A mixture of N-[3-(dimethylamino)propyl]-N′-phenylthiourea (800 mg) obtained in Reference Example 3 as described below and 2-bromo-4′-bromoacetophenone (1.09 g) in ethanol (30 ml) was heated with reflux under nitrogen atmosphere. Nine hours thereafter, the reaction mixture was concentrated under reduced pressure, and to the residue was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was washed with a saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol (50:1)), and crystallized from isopropyl alcohol to give the title compound (830 mg)
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][NH2:18]>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([NH:18][CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[C:14]([O:13][CH3:12])[CH:15]=3)=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: COc1cccc(CN)c1
Product: COc1cccc(CNc2cccn3nc(Cl)nc23)c1

Procedure:
(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(3-methoxy-benzyl)-amine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (2.00 g, 8.60 mmol), and 3-methoxy-benzylamine (1.26 mL, 9.72 mmol) in a manner analogous to Example 2d. Product was isolated as an off-white solid, (1.90 g. 77%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.08 (d, J=6.4 Hz, 1H), 7.24 (m, 2H), 6.96 (s, 3H), 6.79 (d, J=8.0 Hz, 1H), 6.41 (d, J=8.0 Hz, 1H), 4.44 (d, J=5.9 Hz, 2H), 3.71 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][C@@H:5]([OH:20])[C:6]1[C:16](=[O:17])[C:15]2[C:14]([OH:18])=[CH:13][CH:12]=[C:11]([OH:19])[C:10]=2[C:8](=[O:9])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37](O)(=[O:46])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>CN(C)C1C=CN=CC=1.ClCCl>[C:37]([O:20][CH:5]([C:6]1[C:16](=[O:17])[C:15]2[C:10]([C:8](=[O:9])[CH:7]=1)=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=2[OH:18])[CH2:4][CH:3]=[C:2]([CH3:21])[CH3:1])(=[O:46])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reactant: CCCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCC(=O)OC(CC=C(C)C)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
288 mg (1 mmole) of shikonin, 226 mg (1.1 mmole) of dicyclohexylcarbodiimide and 30 mg (0.25 mmole) of 4-dimethylaminopyridine were dissolved in 3 ml of dry dichloromethane. To the resulting solution was added 158 mg (1 mmole) of n-nonanoic acid at 0° C. under nitrogen gas, and the mixture was stirred for 30 minutes and then at room temperature for further 3 hours. The resulting product was separated and purified according to the procedures as described in Example 1 to obtain 231 mg (Yield: 54%) of the title compound having the following structure as a red oil.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=O)=O.[CH3:6][C:7]1[CH:12]=[CH:11][C:10](S)=[CH:9][CH:8]=1.N1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:1][Cl:5]
Reactant: Cc1ccc(S)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccccc1SCl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
A solution of 27.2 g of sulfuryl chloride in 50 ml of dry carbon tetrachloride was added dropwise to a cold (ice-salt bath) solution of 25 g of 4-methylbenzenethiol in 50 ml of carbon tetrachloride containing a few drops of pyridine. The solution was stirred for 0.5 hour at ice-salt bath temperature, allowed to warm to room temperature, then heated under gentle reflux for 0.5 hour. The solution was filtered through a layer of anhydrous sodium sulfate and the filtrate concentrated under reduced pressure. The red liquid residue was distilled to give 24.1 g of 2-methylbenzenesulfenyl chloride, b.p. 67°-69° at 2 mm, nD25 1.6015.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=O)[N:8]([CH3:11])[C:6](=O)[C:5]2=[CH:12][CH:13]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:11][N:8]1[CH2:9][C:4]2[C:5](=[CH:12][CH:13]=[C:2]([NH2:1])[CH:3]=2)[CH2:6]1
Reactant: CN1C(=O)c2ccc(N)cc2C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1Cc2ccc(N)cc2C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72 %

Procedure:
2.643 g 4-Amino-N-methylphthalimide was suspended in 50 ml THF and added to 1.328 g lithium aluminum hydride in 50 ml THF at room temperature. The mixture was refluxed for 3 hrs, then stirred a further 3 days at room temperature. Excess LAH was destroyed by addition of water and the mixture filtered over celite. An aqueous phase was separated and extracted with CH2Cl2. The combined organic phases were dried and evaporated. The residue was stirred with HCl in MeOH and the evaporated to yield 1.6 g of the title compound as the hydrochlorid salt.