Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(Cl)(O[C:11](=[O:17])[O:12][C:13](Cl)(Cl)Cl)Cl.O[CH2:20][C:21]1(C)[O:25][C:24]2=[N:26][C:27]([N+:29]([O-:31])=[O:30])=[CH:28][N:23]2[CH2:22]1.N1CCCCC1.Cl>C(Cl)Cl>[N:1]1([C:11]([O:12][CH2:13][C:21]2([CH3:20])[O:25][C:24]3=[N:26][C:27]([N+:29]([O-:31])=[O:30])=[CH:28][N:23]3[CH2:22]2)=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(CO)Cn2cc([N+](=O)[O-])nc2O1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC1(COC(=O)N2CCCCC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.9 %

Procedure:
Pyridine (0.37 ml, 4.5 mmol) and triphosgene (0.18 g, 0.6 mmol) were added to a suspension of 2-hydroxymethyl-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole prepared in Example 33 (0.3 g, 1.5 mmol) in methylene chloride (15 ml) with cooling on ice-bath followed by stirring at room temperature for 2 hours. The reaction mixture was cooled on ice-bath and added piperidine (0.16 ml, 1.7 mmol). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was cooled on ice-bath and added 10% hydrochloric acid, and the insoluble matters were removed by filtration. The filtrate was extracted with methylene chloride, and the organic phase was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=3/2) and recrystallized from methylene chloride-diisopropyl ether to afford 2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl piperidine-1-carboxylate (65 mg, yield 14%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.C(N(CC)CC)C.Cl.Cl.[NH2:38][O:39][CH2:40][CH2:41][N:42]([CH3:44])[CH3:43]>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:38][O:39][CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CCON
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reaction time: 0.5 h
Yield: 40.2 %

Procedure:
A solution of the carboxylic acid (6b, 553 mg, 2.00 mmol) of Example 9 or 16 in dehydrated methylene chloride (10 mL) was cooled to 0° C. under an argon atmosphere, followed by adding dropwise isobutyl chloroformate (289 μL, 2.20 mmol). Then, triethylamine (293 μL) was added, followed by stirring for 30 minutes. Thereby, a mixed acid anhydride was prepared in the reaction system. To this reaction mixture were gradually added 2-(aminooxy)-N,N-dimethylethanamine dihydrochloride (591 mg) described in Reference Example 18 and triethylamine (930 μL) while washing with dehydrated methylene chloride (7.0 mL), followed by stirring at the same temperature for 1 hour. This reaction mixture was filtered though Kiriyama filter paper. Subsequently, the residue was washed with methanol and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in methylene chloride and water, and the organic layer extracted with methylene chloride was dried over magnesium sulfate, followed by distilling off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (amino silica, chloroform/methanol=10/1) to afford 291.1 mg of the title compound as a colorless oil (yield 40%).
Reaction SMILES: [CH3:1][N:2]([C:6]1[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1)[C:3]#[C:4][CH3:5].[OH-].[K+].[I:17]I>CO.O>[CH3:1][N:2]([CH2:3][C:4]#[C:5][I:17])[C:6]1[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: II
Reactant: CC#CN(C)c1nc2ccccc2s1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(CC#CI)c1nc2ccccc2s1
Yield: 99.8 %

Procedure:
Compound (d) (2.02 g) was dissolved in a mixture of methanol (35 ml), water (10 ml) and 86% potassium hydroxide (1.4 g) and then iodine (2.66 g) was added in small portions with stirring under ice-cooling. The mixture was stirred at room temperature for 1.5 hours and then water was added thereto. The resultant crystals were filtered off, washed with water and dried to give 2-(N-methyl-3-iodo-2-propynylamino)benzothiazole (No.2) (3.27 g, yield 100%): mp. 100°-101° C. (decomp.) (acetone-hexane), Hydrochloride: mp. 156°-160° C. (decomp.), Nitrate: mp. 108°-109° C. (decomp.), Hydrobromide: mp. 158°-160° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:3]=1[C:4](Cl)=[N:5][C:6]1[C:11]([F:12])=[CH:10][N:9]=[CH:8][C:7]=1F.NC(N)=[S:24].N1C=CC=CC=1.CCN(CC)CC>C(O)(C)C>[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:3]=1[C:4]1[S:24][C:7]2[CH:8]=[N:9][CH:10]=[C:11]([F:12])[C:6]=2[N:5]=1
Reactant: NC(N)=S
Reactant: O=[N+]([O-])c1cccc(Cl)c1C(Cl)=Nc1c(F)cncc1F
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cccc(Cl)c1-c1nc2c(F)cncc2s1
Temperature: 25 °C
Yield: 49.6 %

Procedure:
A suspension of 2-chloro-N-(3,5-difluoropyridin-4-yl)-6-nitrobenzimidoyl chloride (5.53 g, 16.6 mmol), thiourea (5.05 g, 0.066 mol) and pyridine (6.7 mL, 83 mmol) in isopropanol (90 mL), under nitrogen, was heated under reflux for 6 hours. After this time, Et3N (14 mL, 100 mmol) was added over 5 minutes and the reaction mixture was heated under reflux for 18 hours. Upon cooling to room temperature, the volatiles were removed under reduced pressure and the resultant residue was partitioned between water and EtOAc. The aqueous phase was further extracted with EtOAc (×2) and the combined organic layers were dried (Na2SO4) and concentrated to dryness. The resultant residue was purified by column chromatography on silica gel eluting with 0-80% EtOAc in pentane followed by 0-50% EtOAc in DCM to afford the title compound as a yellow solid (2.55 g, 50% yield). LCMS (Method D): RT=3.29 min, m/z: 310 [M+H+].
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[CH2:50][CH2:49][CH2:48][C@H:2]1[C:3]([NH:5][C@H:6]([C:16]([N:18]1[CH2:47][CH2:46][CH2:45][CH2:44][C@H:19]1[C:20]([NH:22][C@H:23]([C:34]([O:36]CC1C=CC=CC=1)=[O:35])[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[NH:33])[NH:29][N+]([O-])=O)=[O:21])=[O:17])[CH2:7][O:8]CC1C=CC=CC=1)=[O:4]>[C].[Pd]>[NH:1]1[CH2:50][CH2:49][CH2:48][C@H:2]1[C:3]([NH:5][C@H:6]([C:16]([N:18]1[CH2:47][CH2:46][CH2:45][CH2:44][C@H:19]1[C:20]([NH:22][C@H:23]([C:34]([OH:36])=[O:35])[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[NH:29])[NH2:33])=[O:21])=[O:17])[CH2:7][OH:8])=[O:4].[CH3:23][C:34]([OH:36])=[O:35]
Reactant: N=C(NCCC[C@H](NC(=O)[C@@H]1CCCCN1C(=O)[C@H](COCc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)OCc1ccccc1)N[N+](=O)[O-]
Agent: [Pd]
Product: CC(=O)O
Product: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCCN1C(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1)C(=O)O

Procedure:
150 mg of Z-Pro-Ser(Bzl)-Pip-Arg(NO2)-OBzl was reduced in the presence of palladium-carbon in the same manner as in Example 12-(4). The resulting product was purified by high-performance liquid chromatography at 12 ml/min.(flow rate), 0 to 10% (B) 20 min. linear gradient (A) (mobile phase), subjected to Dowex 1×2 (acetate type) treatment and freeze-dried to obtain the desired compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[Li]CCCC.[C:17](=[O:19])=[O:18].O>C1COCC1.CCCCCC>[CH3:11][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([C:17]([OH:19])=[O:18])[CH:3]=1)[NH:9][CH:8]=[CH:7]2
Reactant: Cc1cc(Br)c2[nH]ccc2c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)c2[nH]ccc2c1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
1.68 g of 7-bromo-5-methyl-indole (8 mmol) were dissolved in 30 ml THF and 15 ml of a 1.6 molar solution of n-BuLi in hexane were added at −78° C. The reaction mixture was then allowed to warm to 0-5° C. and was stirred at this temperature for 30 min. Then it was cooled again to −78° C., dry ice was added and the mixture was allowed to warm to rt. After 15 min at rt it was poured into water and extracted twice with ether. The aqueous phase was then acidified with 1 N HCl solution and extracted several times with DCM. The combined DCM extracts were then washed with brine, dried with magnesium sulfate, filtered and the solvent was evaporated. The remaining residue was triturated with n-hexane. Final filtration yielded 0.78 g (56%) of 5-methyl-1H-indole-7-carboxylic acid as light brown solid. 1H NMR (DMSO-d, 300 MHz): δ 2.41 (s, 3H), 6.44 (m, 1H), 7.31 (m, 1H), 7.58 (s, 1H), 7.61 (s, 1H), 10.91 (br s, 1H), 12.92 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[OH:14].C(=O)([O-])[O-].[K+].[K+].Cl[C:23]([F:29])([F:28])C(OC)=O.O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[O:14][CH:23]([F:29])[F:28]
Reactant: COC(=O)C(F)(F)Cl
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(F)(F)F)cc1OC(F)F
Temperature: 65 °C
Yield: 73.2 %

Procedure:
To a solution of 500 mg (2.271 mmol) 2-hydroxy-4-trifluoromethyl-benzoic acid methyl ester (CAS: 345-28-8) in 5 ml N,N-dimethylformamide at room temperature, was added 470.8 mg (3.407 mmol) potassium carbonate, followed by dropwise addition of 293.4 ul (2.725 mmol) methyl chlorodifluoroacetate. The reaction mixture was heated at 65° C. oil bath for 22 hours. Water and ethyl acetate were added. The organic phase was washed 3 times with water. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to provide 449 mg of the title compound as a pink oil which was used in the next step without any further purification.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[CH:19]2[CH2:23][CH2:22][S:21][CH2:20]2)=[C:12]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([I:32])[CH:27]=2)[N:11]=1>>[ClH:9].[ClH:9].[NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][N:16]3[CH:19]3[CH2:23][CH2:22][S:21][CH2:20]3)=[C:12]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([I:32])[CH:27]=3)[N:11]=2)[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Clc1nc(NCc2cccc(I)c2)c2ncn(C3CCSC3)c2n1
Product: Cl
Product: NC1CCC(Nc2nc(NCc3cccc(I)c3)c3ncn(C4CCSC4)c3n2)CC1
Reaction time: 6 h
Yield: 81.9 %

Procedure:
The operation is carried out as in Stage 3 of Example 5 starting from 330 mg of trans-1,4-diaminocyclohexane and 137 mg of the product obtained in Stage 1 above, the reaction medium is taken to a temperature of approximately 140 to 145° C. for approximately 6 hours then left to return to ambient temperature and left overnight. After purification on silica eluting with methanol/ammonium hydroxide (NH4OH) in a proportion of 98/2 salification is carried out with 1.4 N hydrochloric acid in ethanol, followed by separating, washing and drying at a temperature of approximately 50° C. In this way 74 mg of expected product is obtained in the form of brown-pink crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][OH:12])=[CH:4][CH:3]=1.[OH-:13].[K+].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][OH:12])=[CH:6][CH:7]=1.[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O-:23])(=[O:22])=[O:13])=[CH:17][CH:16]=1
Reactant: [OH-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: OC/C=C\Cc1ccc(Cl)cc1
Agent: [K+]
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C

Procedure:
Dissolve 7.3 g (0.04 mole) of (Z)-4-(4-chlorophenyl)but-2-en-ol in 100 ml of anhydrous ether. Add 3.2 g (0.05 mole) of powdered 86% KOH. Stir and cool the mixture in ice bath while adding a solution of 8.4 g (0.044 mole) of p-toluenesulfonyl chloride in 50 ml of anhydrous ether. Slowly warm the reaction mixture to room temperature and stir at room temperature for 16 hours. Remove the solid by filtration. Wash the filtrate with saturated aqueous sodium bicarbonate, H2O. Dry, evaporate, and recrystallize from cyclohexane to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[S:11][C:10]2[NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5](=O)[C:4]=2[CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:18].C(O)C.O>N1C=CC=CC=1>[CH3:1][C:2]1[S:11][C:10]2[NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5](=[S:18])[C:4]=2[CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cc1cc2c(s1)Nc1ccccc1NC2=O
Solvent: c1ccncc1
Solvent: CCO
Solvent: O
Product: Cc1cc2c(s1)Nc1ccccc1NC2=S
Temperature: 25 °C
Yield: 71.7 %

Procedure:
Combine 2-methyl-4,9-dihydro-3-thia-4,9-diazabenzo[f]azulene-10-one (21 g, 0.09 mol) and phosphorus pentasulfide (53 g, 0.12 mol) in pyridine (350 mL) and stir at room temperature overnight, heat at reflux for 5 h. Cool to room temperature to allow precipitate to settle, collect solid by filtration, wash cake with cold ethanol/water and air-dry for a few minutes to obtain 29 g of crude material. Take up solid in a small amount of pyridine, add a like volume of ethanol/water, sonicate for a few minutes and collect again by filtration. Air-dry cake, then place in the vacuum oven at 40° C. for 48 h to obtain 15.9 g of the title compound as an orange solid, which was used directly on the next step without further purification: melting point: 259.0-259.5° C.; Mass spectrum (APCI): m/z=247.0 (M+1).
Reaction SMILES: BrC1C=CC(CCCO)=CC=1.[C:12]([C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([O:24][Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])[CH:18]=[CH:17]2)#[CH:13].C(OCC)(=O)C>C1COCC1.C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:29]([Si:25]([CH:26]([CH3:27])[CH3:28])([CH:32]([CH3:34])[CH3:33])[O:24][C:19]1[CH:18]=[CH:17][C:16]2[C:21](=[CH:22][CH:23]=[C:14]([C:12]#[C:13][Si:25]([CH3:32])([CH3:29])[CH3:26])[CH:15]=2)[CH:20]=1)([CH3:31])[CH3:30]
Reactant: C#Cc1ccc2cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: OCCCc1ccc(Br)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)[Si](Oc1ccc2cc(C#C[Si](C)(C)C)ccc2c1)(C(C)C)C(C)C
Temperature: 70 °C
Reaction time: 5 h

Procedure:
7.0 g (32.5 mmol) of 3-(4-bromophenyl)propan-1-ol are initially introduced in 70 ml of THF and 30 ml of diisopropylamine, and, after addition of 1.0 g (1.4 mmol) of bis(triphenylphosphine)palladium(II) chloride and 0.4 g (2.1 mmol) of copper(I) iodide, 16.4 g (50.5 mmol) of (6-ethynylnaphthalen-2-yloxy)triisopropylsilane in 30 ml of THF are added dropwise at 70° C. The batch is left to stir for 5 h at 70° C., 200 ml of ethyl acetate are added, and the mixture is washed three times with water. The combined aqueous phases are extracted with ethyl acetate, and the combined org. phases are dried over sodium sulfate and evaporated in vacuo. Chromatography of the crude product on silica gel with firstly toluene and then toluene/ethyl acetate (7:3) gives 2-triisopropylsilanyloxy-6-trimethylsilanylethynylnaphthalene as a brown oil, which is employed in the next step without further purification.
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH:12]=[CH2:13]>C(OCC)C>[Cl:8][C:9]1[CH:10]=[C:11]([CH:12]2[NH:5][C:6](=[O:7])[CH2:13]2)[CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: C=Cc1ccc(Cl)c(Cl)c1
Solvent: CCOCC
Product: O=C1CC(c2ccc(Cl)c(Cl)c2)N1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To chlorosulfonyl isocyanate (CSI) (2.46 ml) in diethyl ether (8 ml) was added dropwise with stirring 3,4-dichlorostyrene (4.89 g, 28.3 mmol). The reaction was heated to 35° C. for 90 min after which time a further 1 ml CSI was added. The reaction was left for 16 h at 35° C., then the oil bath temperature was increased to 70° C. and the ether distilled off. The reaction was stirred at 70° C. for 1 h then cooled and slurried in dichloromethane (50 ml), and added portionwise with stirring to water containing sodium bisulfite (10 g) and potassium carbonate (15 g), using an ice bath for cooling. After stirring for 30 min. the phases were separated and the organic phase dried (MgSO4) to give a yellow oil (4 g). Purification by column chromatography on silica gel eluting with 0-50% dichloromethane in hexane gave the title compound as a white solid, (2.6 g, 43%). δH (CDCl3) 2.85 (1H, dd), 3.45 (1H, m), 4.7 (1H, m), 6.35 (1H, bs), 7.25 (1H, m), 7.45 (2H, m).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH3:11]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(O)(C)C>[CH:8]1[CH:7]=[C:5]2[N:6]=[C:2]([S:1][S:1][C:2]3[S:3][C:4]4[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:11]=3)[S:3][C:4]2=[CH:10][CH:9]=1
Reactant: Sc1nc2ccccc2s1
Reactant: N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: c1ccc2sc(SSc3nc4ccccc4s3)nc2c1
Temperature: 70 °C

Procedure:
40 g (0.24 mol) of 2-mercaptobenzothiazole (MBT), 4 mg (0.02×10-3 mol) of copper (II) acetate, (Cu(OAc)2. H2O), 4.08 g (0.24 mol) of ammonia, and 120 g of isopropanol are placed in a glass autoclave equipped with a jacket for the circulation of a heating liquid, a thermometer, a pressure measuring device and a stirring device. The reaction mixture is heated to 70° C., stirred vigorously, and placed under an oxygen pressure of 4 bar. Absorption of oxygen is noted immediately and a precipitate, dibenzothiazyl disulfide (MBTS), is formed. After 6.5 hours the reaction is discontinued and the precipitate is filtered off, washed with isopropanol, and dried under a vacuum at 50° C. 37.8 g of a product are obtained in this manner. Upon elementary analysis, IR, NMR and MS, the product formed is found to correspond to dibenzothiazyl disulfide. The purity is found to be 100% upon chromatographic analysis (melting point 178° C.).
Reaction SMILES: [CH2:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH2:15])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:4][CH2:3][CH2:2]1.N1CCOCC1.[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[N:15][C:13]2[C:12]3[C:7]([N:6]=[C:5]4[C:14]=2[CH2:1][CH2:2][CH2:3][CH2:4]4)=[CH:8][CH:9]=[CH:10][CH:11]=3)=[CH:25][CH:24]=1
Reactant: Nc1c2c(nc3ccccc13)CCCC2
Reactant: O=Cc1ccc(F)cc1
Solvent: C1COCCN1
Solvent: Cc1ccccc1
Product: Fc1ccc(C=Nc2c3c(nc4ccccc24)CCCC3)cc1

Procedure:
1,2,3,4-Tetrahydro-9-acridinamine (4.0 g) was refluxed in 400 ml of toluene that contained 3.5 g of morpholine and 3.10 g of 4-fluorobenzaldehyde that had been freshly washed in K2CO3. The reaction mixture was refluxed over two (2) nights and then concentrated, purified by flash chromatography (20% EtOAc/CH2Cl2) and recrystallized from dichloromethane/pentane to give 2.20 g of analytically pure product, m.p. 161°-163° C.
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:7]([CH2:8]O)[O:6][C:4](=[O:5])[CH2:3]1.N1C(C)=CC=CC=1C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[N-:33]=[N+:34]=[N-:35].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[N:33]([CH2:8][C@H:7]1[O:6][C:4](=[O:5])[CH2:3][C@@H:2]1[CH3:1])=[N+:34]=[N-:35]
Reactant: C[C@H]1CC(=O)O[C@@H]1CO
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Product: C[C@H]1CC(=O)O[C@@H]1CN=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,3-dideoxy-3-C-methyl-D-erythro-pentono-1,4-lactone (490 mg, 3.76 mmol) in methylene chloride (10 mL) cooled in an ice-bath were added 2,6-lutidine (501 mL, 4.30 mmol) and trifluoromethanesulfonic anhydride (682 mL, 4.05 mmol). The reaction mixture was stirred at 0° C. for 30 minutes, diluted with methylene chloride, washed with water, 2N hydrochloric acid, saturated sodium hydrogencarbonate solution, saturated brine solution, dried (Na2SO4), and evaporated. The crude product was taken up in DMF (6 mL) and treated with sodium azide (856 mg, 13.2 mmol) at room temperature for 30 minutes. The mixture was diluted with ethyl acetate, washed with water, dried (Na2SO4), and evaporated. The pure title compound was obtained after flash silica gel chromatography eluting with 25% ethyl acetate in hexane; yield 358 mg (61%); 1H NMR (400 MHz, CDCl3): δ1.15 (d, 3H), 2.21 (dd, 1H), 2.42 (m, 1H), 2.74 (dd, 1H), 3.44 (dd, 1H), 3.60 (dd, 1H), 4.15 (m, 1H); mass spectrum: 128 (M+1-N2).
Reaction SMILES: [OH:1][CH:2]([C:30]1[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[CH:32][N:31]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:46])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[OH:1][CH:2]([C:30]1[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[CH:32][N+:31]=1[O-:46])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1
Reactant: COc1cccnc1C(O)c1ccc(NC(=O)C2=Cc3cc(-c4ccc(C)cc4)ccc3OCC2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc[n+]([O-])c1C(O)c1ccc(NC(=O)C2=Cc3cc(-c4ccc(C)cc4)ccc3OCC2)cc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 46.5 %

Procedure:
To a solution of N-[4-[hydroxy-(3-methoxypyridin-2-yl)methyl]phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (350mg) in tetrahydrofuran (30 ml) was added 3-chloroperbenzoic acid (70%, 0.26 g) at 0° C., and the mixture was stirred at room temperature for 64 hours. To the mixture was added sodium thiosulfate, and the mixture was stirred for a few minutes and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate→ethanol/ethyl acetate=1:4) recrystallized from tetrahydrofuran-hexane to give N-[4-[hydroxy(3-methoxy-1-oxidopyridin-2-yl)methyl]phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 170) (168mg) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[NH2:8].[CH3:13][O:14][C:15]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:16]=1[CH:17]=[CH:18][C:19](O)=O>>[CH3:13][O:14][C:15]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:16]=1/[CH:17]=[CH:18]/[C:19]1[NH:1][C:2]2[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=2[N:8]=1
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Reactant: COc1ccc(C=CC(=O)O)c(OC)c1
Product: COc1ccc(/C=C/c2nc3c([nH]2)c(=O)n(C)c(=O)n3C)c(OC)c1
Yield: 11 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 1.0 g (5.88 mmol) of 5,6-diamino-1,3-dimethyluracil and 1.35 g (6.48 mmol) of 2,4-dimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dimethylformamide to give 221 mg (yield 11%) of Compound 99 as pale yellow grains.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[OH:11].[NH2:12][C:13]1[N:18]=[C:17]([NH2:19])[C:16]([CH2:20]C2C=C(OC)C(O)=C(OC)C=2)=[CH:15][N:14]=1>>[NH2:12][C:13]1[N:18]=[C:17]([NH2:19])[C:16]([CH2:20][C:8]2[CH:7]=[CH:6][C:5]([O:9][CH3:10])=[C:4]([OH:11])[C:3]=2[O:2][CH3:1])=[CH:15][N:14]=1
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1O
Reactant: COc1cccc(OC)c1O
Product: COc1ccc(Cc2cnc(N)nc2N)c(OC)c1O

Procedure:
The procedure of Example 1 was repeated using 2,6-dimethoxyphenol in place of the 2,6-diethylphenol. A good yield of a mixture of 2,4-diamino-5-(3,5-dimethoxy-4-hydroxybenzyl)pyrimidine and 2,4-diamino-5-(2,4-dimethoxy-3-hydroxybenzyl)pyrimidine was obtained. These components of the mixture could be separated by fractional crystallisation. The latter melting at between 246° and 248° C. (free base).