Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[CH2:2][C:3]1[C:4]([CH3:24])=[N:5][C:6]2[N:7]([N:17]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:19]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16].[O:25](C(OC(C)(C)C)=O)[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=O.CCN(CC)CC>C1COCC1>[C:29]([O:28][C:26]([CH2:2][C:3]1[C:4]([CH3:24])=[N:5][C:6]2[N:7]([N:17]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:19]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])=[O:25])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COC(=O)c1nc2nc(C)c(CN)c(-c3ccc(Cl)cc3Cl)n2n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1nc2nc(C)c(CC(=O)OC(C)(C)C)c(-c3ccc(Cl)cc3Cl)n2n1
Reaction time: 2 h
Yield: 20.6 %

Procedure:
To a stirred solution of methyl 6-(aminomethyl)-7-(2,4-dichlorophenyl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylate (Example 27, 50 mg, 0.14 mmol) in THF (3 mL) was added (BOC)2O (75 μL, 0.34 mmol) and Et3N (100 μl, 0.70 mmol). After 2 h, the reaction was concentrated under reduced pressure and diluted with EtOAc. The organic layer was washed with satd aq NH4Cl and brine prior to drying over anhydrous MgSO4. Filtration, concentration under reduced pressure and purification by silica gel chromatography (50% EtOAc in hexanes) afforded methyl 6-((tert-butoxycarbonyl)methyl)-7-(2,4-dichlorophenyl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylate (13 mg, 20%) as a white solid.
Reaction SMILES: [C:1]1([N:7]2[CH2:16][CH2:15][C:10]3(OCC[O:11]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)(=O)C.O.Cl>[C:1]1([N:7]2[CH2:8][CH2:9][C:10](=[O:11])[CH2:15][CH2:16]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(N2CCC3(CC2)OCCO3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCN(c2ccccc2)CC1
Temperature: 50 °C

Procedure:
8-Phenyl-1,4-dioxa-8-azaspiro[4.5]decane (18.1 g, 82.5 mmol) was dissolved in a mixture of acetic acid (150 mL), water (150 mL), and conc. hydrochloric acid (38 mL) and the resulting solution was heated to 50° C. for 18 hrs. The reaction mixture was cooled in an ice-water bath, and sodium hydroxide pellets were added in portions until the mixture was neutralized. This mixture was extracted with dichloromethane (3×300 mL) and the combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo to give a dark oil. Chromatography on silica gel, eluting with hexane--10% ethyl acetate gave the product as a pale yellow oil.
Reaction SMILES: BrC[Mg].[CH2:4]([N:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]2[CH:36]=[CH:35][C:18]([O:19][C:20]3[N:24]([CH2:25]C(OCC)=O)[C:23]4[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=4[N:21]=3)=[CH:17][CH:16]=2)[C:7]1=[O:37])[CH3:5].[Cl-].[Cl-].[Ca+2]>C1COCC1>[CH2:4]([N:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]2[CH:16]=[CH:17][C:18]([O:19][C:20]3[N:24]([CH2:25][C:18]([OH:19])([CH3:35])[CH3:17])[C:23]4[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=4[N:21]=3)=[CH:35][CH:36]=2)[C:7]1=[O:37])[CH3:5]
Reactant: CCOC(=O)Cn1c(Oc2ccc(-n3c(=O)n(CC)c4cccnc43)cc2)nc2ccccc21
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Mg]CBr
Solvent: C1CCOC1
Product: CCn1c(=O)n(-c2ccc(Oc3nc4ccccc4n3CC(C)(C)O)cc2)c2ncccc21
Yield: 121.9 %

Procedure:
Bromomethylmagnesium (3M in ether, 1.924 mL) was added to a solution of ethyl {2-[4-(1-ethyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)phenoxy]-1H-benzimidazol-1-yl}acetate (220 mg) in THF (40 mL) at 0° C. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 0%-50% EtOAc in hexane) to give 1-ethyl-3-(4-{[1-(2-hydroxy-2-methylpropyl)-1H-benzimidazol-2-yl]oxy}phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (130 mg) as white crystals.
Reaction SMILES: [K+].[C:2]([N:5]1[C:14]2[N:13]=[CH:12][C:11]([C:15]3[CH:23]=[N:22][CH:21]=[C:20]([F:24])[C:16]=3[C:17]([O-:19])=[O:18])=[CH:10][C:9]=2[CH2:8][CH2:7][CH2:6]1)(=[O:4])[NH2:3].IC.[C:27](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:27][O:18][C:17](=[O:19])[C:16]1[C:20]([F:24])=[CH:21][N:22]=[CH:23][C:15]=1[C:11]1[CH:12]=[N:13][C:14]2[N:5]([C:2](=[O:4])[NH2:3])[CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=1
Reactant: NC(=O)N1CCCc2cc(-c3cncc(F)c3C(=O)[O-])cnc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1c(F)cncc1-c1cnc2c(c1)CCCN2C(N)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.3 %

Procedure:
To a vial is added 3-(8-carbamoyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-5-fluoro-isonicotinic acid potassium salt (100 mg, 0.28 mmol) in 2 ml of DMF, followed by the addition of iodomethane (48 mg, 0.34 mmol) and potassium carbonate (47 mg, 0.34 mmol). The reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is concentrated in vacuo. The residue is diluted with EtOAc, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. Purification by the flash column chromatography affords 28 mg of the titled product.
Reaction SMILES: [C:1]([C:5]1[C:14]([CH3:15])=[CH:13][C:8]2[NH:9][C:10]([SH:12])=[N:11][C:7]=2[CH:6]=1)([O:3][CH3:4])=[O:2].[OH-].[Na+].Cl.[CH3:19][O:20][C:21]1[C:22]([CH2:29]Cl)=[N:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>O.CO>[C:1]([C:5]1[C:14]([CH3:15])=[CH:13][C:8]2[NH:9][C:10]([S:12][CH2:29][C:22]3[C:21]([O:20][CH3:19])=[C:26]([O:27][CH3:28])[CH:25]=[CH:24][N:23]=3)=[N:11][C:7]=2[CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1cc2nc(S)[nH]c2cc1C
Reactant: COc1ccnc(CCl)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc2nc(SCc3nccc(OC)c3OC)[nH]c2cc1C
Reaction time: 1 h
Yield: 92 %

Procedure:
5-Carbomethoxy-6-methyl-2-mercapto-1H-benzimidazole (0.67 g, 0.003 mol) and NaOH (0.12g, 0.003 mol) in H2O (0.6 ml) were dissolved in CH3OH (15 ml). 3,4-dimethoxy-2-chloromethylpyridine hydrochloride, (=0.0036 mol) as a crude material in CH3OH (10 ml) and NaOH (0.144 g, 0.0036 mol) in H2O (0.72 ml) were added. The mixture was heated to reflux and the reflux was continued for 1 hour. CH3OH was evaporated off and the crude material was purified by chromatography on a silica column using CH2Cl2 --CH3OH (98-2) as eluent, giving (1.03 g, 92%) of the pure title compound.
Reaction SMILES: [Si]([O:18][CH:19]([C:21]1[N:25]=[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[O:23][N:22]=1)[CH3:20])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.F.C([O-])(O)=O.[Na+]>C1COCC1.N1C=CC=CC=1>[OH:18][CH:19]([C:21]1[N:25]=[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[O:23][N:22]=1)[CH3:20]
Reactant: CCOC(=O)c1nc(C(C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)no1
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)c1nc(C(C)O)no1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Ethyl 3-(1-((tert-butyldiphenylsilyl)oxy)ethyl)-1,2,4-oxadiazole-5-carboxylate (5.90 mmol, 2.5 g) was dissolved in THF and cooled to 0° C. with an ice bath. 70% Hydrogen fluoride in pyridine (1.5 ml) was added slowly. After addition, the reaction mixture was stirred at ambient temperature for overnight. The reaction mixture was basified by aqueous NaHCO3 solution and extracted with DCM. The organic layers were washed with water, dried, filtered and evaporated. The product was purified by flash-chromatography. Yield 897 mg. 1H-NMR (400 MHz; CDCl3): δ 1.46 (t, 3H), 1.66 (d, 3H), 4.53 (q, 2H), 5.11 (q, 1H).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([OH:18])=O)[CH:14]=2)[CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[C:20]([N:24]1[CH:32]=[C:31]2[C:26]([C:27](=[O:38])[NH:28][C:29]3([CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[CH2:30]2)=[N:25]1)([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CN(C)C=O>[C:20]([N:24]1[CH:32]=[C:31]2[C:26]([C:27](=[O:38])[NH:28][C:29]3([CH2:37][CH2:36][N:35]([C:16]([C:13]4[CH:14]=[C:15]5[C:10]([CH:9]=[CH:8][N:7]=[C:6]5[NH:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:11][CH:12]=4)=[O:18])[CH2:34][CH2:33]3)[CH2:30]2)=[N:25]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)Nc1nccc2ccc(C(=O)O)cc12
Reactant: CC(C)(C)n1cc2c(n1)C(=O)NC1(CCNCC1)C2
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)Nc1nccc2ccc(C(=O)N3CCC4(CC3)Cc3cn(C(C)(C)C)nc3C(=O)N4)cc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 12.4 %

Procedure:
To a suspension of 1-(tert-butylamino)isoquinoline-7-carboxylic acid (24.7 mg, 0.101 mmol) and 2′-tert-butyl-4′,6′-dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridine]-7′(2′H)-one hydrochloride salt (33.9 mg, 0.101 mmol) in N,N-dimethylformamide (1 mL) was added triethylamine (0.07 mL, 0.50 mmol). The reaction mixture was stirred at room temperature for 10 minutes. Then 1-propanephosphonic acid cyclic anhydride (0.07 mL, 0.12 mmol, 50% solution in ethyl acetate) was added and the reaction mixture was stirred at room temperature overnight. N,N-dimethylformamide was removed under reduced pressure and the residue was purified by reversed-phase HPLC to give 2′-(tert-butyl)-1-(1-(tert-butylamino)isoquinoline-7-carbonyl)-4′,6′-dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridin]-7′(2′H)-one (6.1 mg, 24%). +ESI (m+H) 489.3; HPLC retention time 2.94 minutes (Method B).
Reaction SMILES: [C:1]1([N:7]=[N+:8]=[N-:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([Sn:14]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]#[CH:16])[CH2:11][CH2:12][CH3:13].C(N(CC)CC)C>C1COCC1.[Cu]I>[C:1]1([N:7]2[CH:16]=[C:15]([Sn:14]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=Nc1ccccc1
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC[Sn](CCCC)(CCCC)c1cn(-c2ccccc2)nn1

Procedure:
Phenylazide can be obtained from Pfaltz & Bauer, Inc., or can be synthesized by the method described in J. Biochem., 179, 397-405 (1979). A solution of tributylethynyl stannane (Sigma Aldrich; 400 mg, 1.27 mmol) in THF (4 ml) is treated with phenylazide (169 mg, 1.27 mmol), copper (I) iodide (90 mg, 0.47 mmol), and triethylamine (256 mg, 2.54 mmol) at room temperature over 48 h. The reaction is then filtered through celite to remove copper (I) iodide and chromatographed on silica in a gradient of 5-20% ethyl acetate in petrol. The second fraction is collected and concentrated in vacuo to give the 1-phenyl-4-(tributylstannyl)-1H[1,2,3]triazole as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][N:11]=[C:10]2S)=[CH:5][CH:4]=1.C(O)C.[OH-].[NH4+]>[Ni].C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:12][N:11]=[CH:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-n2c(-c3ccccc3)cnc2S)cc1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(-n2cncc2-c2ccccc2)cc1
Yield: 61 %

Procedure:
A mixture of 12 parts of 1-(4-methoxyphenyl)-5-phenyl-1H-imidazole-2-thiol, 10 parts of Raney-nickel catalyst, 160 parts of ethanol, 180 parts of ethyl acetate and 36 parts of ammonium hydroxide is stirred and refluxed overnight. The solution is decanted and the residual Raney-nickel is boiled again in a mixture of 160 parts of ethanol and 180 parts of ethyl acetate. The solvent is decanted. The combined ethanol/ethyl acetate phases are evaporated. The residue is crystallized from a mixture of 2-propanol and water. The product is filtered off and dried, yielding 6.5 parts (61%) of 1-(4-methoxyphenyl)-5-phenyl-1H-imidazole; mp. 105.7° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.Cl[CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[CH3:1][O:2][C:3]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:6]2[CH2:7][CH2:8][N:9]([CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1[N+](=O)[O-])CCNCC2
Reactant: CC(=O)NCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cc2c(cc1[N+](=O)[O-])CCN(CCNC(C)=O)CC2
Yield: 14.8 %

Procedure:
Into a 1-neck round-bottom flask was added 7-methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.5 g, 2.20 mmol), N-(2-chloro-ethyl)-acetamide (0.45 mL, 4.41 mmol), potassium iodide (92 mg, 0.55 mmol), and potassium carbonate (900 mg, 7 mmol), in N-methylpyrrolidinone (5 mL), and the reaction was heated at 90 overnight. The reaction mixture was next partitioned between water and ethyl acetate, and the layers separated. The aqueous phase was extracted twice with ethyl acetate and the combined organic extracts were washed with water, dried (MgSO4), filtered, and concentrated, and the product was isolated by flash chromatography on SiO2 (MeOH/dichloromethane 0-20%) to give N-[2-(7-Methoxy-8-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethyl]-acetamide (100 mg, 15%). 1H-NMR (CDCl3) δ 7.67 (s, 1H), 6.84 (s, 1H), 6.11 (br s, 1H), 3.94 (s, 3H), 3.38 (m, 2H), 2.95 (m, 2H), 2.89 (m, 2H), 2.66 (m, 6H), 2.01 (s, 3H); LC/MS (ESI+): 308.02 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=[CH:11][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C([O-])([O-])=O.[Na+].[Na+].Br[C:31]1[CH:36]=[CH:35][N:34]([CH2:37][CH2:38][CH:39]2[CH2:41][CH2:40]2)[C:33](=[O:42])[C:32]=1[C:43]#[N:44]>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:14]=[C:13]([C:31]2[CH:36]=[CH:35][N:34]([CH2:37][CH2:38][CH:39]3[CH2:41][CH2:40]3)[C:33](=[O:42])[C:32]=2[C:43]#[N:44])[CH:12]=[CH:11][C:3]=1[O:4][CH:5]1[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: CC1(C)OB(c2ccc(OC3CCOCC3)c(Cl)c2)OC1(C)C
Reactant: N#Cc1c(Br)ccn(CCC2CC2)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: N#Cc1c(-c2ccc(OC3CCOCC3)c(Cl)c2)ccn(CCC2CC2)c1=O
Yield: 15.9 %

Procedure:
To a solution of intermediate 18 (0.57 g, 1.7 mmol) in 1,4-dioxane (2 ml) and a saturated solution of Na2CO3 (2 ml) was added intermediate 9 (0.45 g, 1.7 mmol). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.19 mg, 0.17 mmol). The reaction was then microwaved in a sealed tube at 150° C. for 10 minutes. The resulting cooled reaction mixture was then diluted with EtOAc and filtered through a pad of diatomaceous earth. The filtrate was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude reaction mixture was then purified by column chromatography (silica gel; DCM to DCM/EtOAc up to 30% as eluent). The desired fractions were collected and evaporated in vacuo to yield compound 4 (0.108 g, 17%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[N:11]1[C:15]2[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:14]=2[N:13]=[CH:12]1)(=[O:3])[CH3:2].[Br:22]N1C(=O)CCC1=O>O1CCCC1.C(Cl)(Cl)Cl>[C:1]([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[N:11]1[C:15]2[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:14]=2[N:13]=[C:12]1[Br:22])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CCCC[C@H]1n1cnc2cc(Cl)c(Cl)cc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1CCCC[C@H]1n1c(Br)nc2cc(Cl)c(Cl)cc21
Reaction time: 0.17 h

Procedure:
(±)-Trans-2-(5,6-dichloro-1H-benzimidazol-1-yl)cyclohexyl acetate (part b of this example, 6.62 g, 20.2 mmol) in tetrahydrofuran (120 ml) was refluxed while N-bromosuccinimide (7.20 g, 40.5 mmol) was added in one portion. Reflux was continued for 10 minutes. The solution was cooled and diluted with chloroform (200 ml). The chloroform solution was extracted with aqueous sodium bicarbonate, then water, and dried (sodium sulfate). Evaporation of volatiles in vacuo left white crystals, after trituration from ethyl acetate-hexanes (5.77 g, 70%), m.p. 167-169° C.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3][CH2:2]1.Cl.[NH2:13][OH:14].CC([O-])=O.[Na+]>CCO.O>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[N:13][OH:14])[CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C1CCOc2ccccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C1CCOc2ccccc21
Temperature: 25 °C

Procedure:
To a mixture of 4-chromanone (10.00 g, 67.50 mmol) and hydroxylamine hydrochloride (7.04 g, 101 mmol) in EtOH (100 ml) was added a solution of NaOAc (16.61 g, 202.5 mmol) in H2O (30 mL). The reaction was heated to reflux for 2 h. The mixture was cooled to RT and concentrated in vacuo. The residue was diluted with H2O and acidified with 1N HCl. The aqueous was extracted with EtOAc until tlc analysis showed no evidence of title compound in the aqueous layer. The combined organics were dried with MgSO4 and concentrated in vacuo to furnish the crude title compound which was used without further purification. MS (APCI pos) 164 (M+H).
Reaction SMILES: CS([O:5][CH2:6][C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=O)=O.[Br:19][C:20]1[CH:25]=[CH:24][C:23](O)=[C:22]([O:27][CH3:28])[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([O:5][CH2:6][C@@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:22]([O:27][CH3:28])[CH:21]=1
Reactant: COc1cc(Br)ccc1O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Br)ccc1OC[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 22 h

Procedure:
To a solution of (S)-tert-butyl 2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (279 mg, 1.00 mmol) and 4-bromo-2-methoxyphenol (325 mg, 1.57 mmol) in N,N-dimethylformamide (5.55 mL) was added cesium carbonate (651 mg, 2.00 mmol). The mixture was heated to 100° C. After 22 h, the mixture was allowed to cool to 23° C. and diluted with water (30 mL). The mixture was extracted with ethyl acetate (3×30 mL). The combined organics were dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo. Purification by column chromatography (silica gel, 0-50% ethyl acetate in dichloromethane) afforded the title compound as an amber oil. MS (ES+) 408.2 (M+Na)+. 1H NMR (400 MHz, CDCl3): δ 7.07-6.79 (m, 3H), 4.25-4.10 (m, 2H), 4.01-3.73 (m, 1H), 3.84 (s, 3H), 3.48-3.26 (m, 2H), 2.16-1.80 (m, 4H), 1.48 (s, 9H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]([CH3:15])[C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[NH2:14].[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[Cl:26])[C:20](Cl)=[O:21]>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[Cl:26])[C:20]([NH:14][C@@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][C@H:8]1[N:7]([CH2:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[CH3:15])=[O:21]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CN(Cc1ccco1)[C@@H]1CCCC[C@H]1N
Product: CN(Cc1ccco1)[C@@H]1CCCC[C@H]1NC(=O)c1ccc(Cl)c(Cl)c1
Yield: 50 %

Procedure:
This titled benzamide was prepared according to the general acid chloride method described above on a 0.01 mol scale by reacting the trans-2-[N-(2-furylmethyl)methylamino]cyclohexylamine, prepared as described in part (a) above with 3,4-dichlorobenzoyl chloride. The reaction product mixture was extracted with methylene dichloride to extract the benzamide product therefrom. The crude product was chromatographed on 380 g. of silica gel using a 1 percent methanol-in-chloroform eluant. Fraction 1 (1000 m.) and fractions 2 to 17 (25 ml. each) gave no material. Fractions 18 to 54 (25 ml. each) gave a solid which was crystallized from ether giving colorless needles, 1.91 g., (50% yield) of the named benzamide product, melting point 149°-150° C. The Ultraviolet, Infrared, and Nuclear Magnetic Resonance spectral analyses were consistent for the named benzamide.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1.[CH3:19][O:20][CH2:21][CH2:22][OH:23]>[Na]>[NH2:1][C:2]1[N:10]=[C:9]([O:23][CH2:22][CH2:21][O:20][CH3:19])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1
Reactant: COCCO
Reactant: Nc1ncnc2c1ncn2Cc1ccc(F)cc1
Agent: [Na]
Product: COCCOc1nc(N)c2ncn(Cc3ccc(F)cc3)c2n1
Temperature: 20 °C
Yield: 95 %

Procedure:
6-Amino-9-(4-fluorobenzyl)purine (100 mg, 0.36 mmol) was dissolved in 30 ml of sodium 2-mehoxyethoxide in 2-methoxyethanol and the solution was heated at 20° C. for 3 hours. The reaction mixture was concentrated in vacuo to dryness and to the residue was added water. The mixture was extracted with chloroform and the organic layer was washed with water, dried on sodium sulfate and concentrated in vacuo to dryness. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (109 mg, yield 95%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[CH2:22]([NH:25][C:26](=[O:33])[CH2:27][C:28]1[N:29]=[CH:30][NH:31][CH:32]=1)[CH:23]=[CH2:24]>>[CH2:22]([NH:25][C:26](=[O:33])[CH2:27][C:28]1[N:29]=[CH:30][N:31]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])[CH:32]=1)[CH:23]=[CH2:24]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: C=CCNC(=O)Cc1c[nH]cn1
Product: C=CCNC(=O)Cc1cn(-c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2[N+](=O)[O-])cn1
Yield: 52 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with N-allyl-2-(1H-imidazol-4-yl)-acetamide according to the GPA affording 28 mg (52%) of a yellowish powder. Rt=2.36 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:12])[C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[O:13][CH3:14].C(O)(=[O:17])C>C(OC(=O)C)(=O)C.O.[O-2].[O-2].[O-2].[Cr+6]>[Cl:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]2[C:6](=[O:12])[O:11][C:7](=[O:17])[NH:8][C:9]=2[CH:10]=1
Reactant: CC(=O)O
Reactant: COc1cc2c(cc1Cl)NC(=O)C2=O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1cc2c(=O)oc(=O)[nH]c2cc1Cl

Procedure:
Chromium trioxide (4.7 g) was added in small portions to a stirred suspension of 6-chloro-5-methoxyisatin (5.9 g) in glacial acetic acid (22 ml) and acetic anhydride (22 ml) at 80°. Some spontaneous ignition of the chromium trioxide was observed where this reagent became exposed to the air in the stirring vortex. The mixture was cooled and diluted with water (100 ml). The solid product was recrystallised from industrial methylated spirit to give the novel compound 7-chloro-6-methoxy-1H-3,1-benzoxazine-2,4-dione containing some unreacted starting material.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[CH3:14].B([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)(O)O.C(=O)([O-])[O-].[Na+].[Na+].Cl>COCCOC.O>[CH3:14][C:3]1[CH:4]=[C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)[CH:6]=[CH:7][C:2]=1[C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Cc1nnc(-c2ccc(Br)c(C)c2)o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1nnc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)o1
Yield: 80.7 %

Procedure:
A stirred solution of 2-(4-bromo-3-methylphenyl)-5-methyl-1,3,4-oxadiazole (EP 0533268 A1) (0.21 g, 0.0008 mole) in a mixture of DME (10 ml) and water (30 ml) under argon was treated with 4-boronobenzoic acid (0.14 g, 0.0008 mole), sodium carbonate (0.39 g, 0.0037 mole) and tetrakis (triphenylphosphine)palladium (0) (16 mg), then heated under reflux for 4 hours. The mixture was acidified with 1M hydrochloric acid and extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated in vacuo to leave the title compound as a white solid (0.19 g, 78%).