Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8]([OH:10])[CH:7]=[C:6]([CH2:11]Cl)[N:5]=1)([CH3:3])[CH3:2].C([O-])(=[O:15])C.[Na+].[OH-].[Na+].Cl>O>[CH:1]([C:4]1[N:9]=[C:8]([OH:10])[CH:7]=[C:6]([CH2:11][OH:15])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nc(O)cc(CCl)n1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)c1nc(O)cc(CO)n1
Reaction time: 72 h

Procedure:
9.33 gm of 2-isopropyl-4-hydroxy-6-chloromethyl-pyrimidine (0.0495 mole) and 13.60 gm of sodium acetate (having 3 molecules water of crystallization, 0.10 mole) were heated in 200 ml of water under reflux (atmospheric pressure). At the 5, 24 and 48 hours periods in the reaction, the reaction was interrupted and the pH of the reaction mixture was adjusted to 7 with 1N sodium hydroxide solution. After 72 hours overall duration, the reaction was discontinued. (Throughout this reaction period the pH was always between 5 and 8.) 50 ml of 1N hydrochloric acid were added. Over a 5 hour period, acetic acid and water were distilled off, with the lost water continuously being replaced. The distillation residue was brought to a pH of 5 and was evaporated until dry. The dry residue subsequently was extracted with methylene chloride in a Soxhlet extractor (separation of NaCl and sodium acetate). After distillation off of the methylene chloride, the 2-isopropyl-4-hydroxy-6-hydroxymethyl-pyrimidine was obtained. The yield of the product was 93.72 percent and the product has a purity of 97.9 percent. The melting point of the product was 186.2° to 186.5°C.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:11][C@H:10]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[C:14]([CH3:22])([CH3:21])[C:13]2=[O:23])[CH2:9]1)(C)(C)C.[ClH:25].O1CCOCC1>C(OCC)(=O)C>[ClH:25].[NH2:7][C@H:8]1[CH2:11][C@H:10]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[C:14]([CH3:21])([CH3:22])[C:13]2=[O:23])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](N2C(=O)C(C)(C)c3cccnc32)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC1(C)C(=O)N([C@H]2C[C@H](N)C2)c2ncccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
To the product from step 2 was added ethyl acetate (10 mL) followed by 4 M hydrogen chloride in 1,4-dioxane (3649 μl, 14.60 mmol). After stirring at room temperature for 3 hours, the precipitate was collected by filtration, washed with additional ethyl acetate, and dried to give 1-(trans-3-aminocyclobutyl)-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-2(3H)-one hydrochloride (680 mg, 2.54 mmol, 87% yield) as tan solid.
Reaction SMILES: [Al+3:1].[Cl-].[Cl-].[Cl-].[C:5]1([Mg]Br)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O(CCCC)CCCC>[C:5]1([Al:1]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Br[Mg]c1ccccc1
Reactant: [Al+3]
Agent: [Cl-]
Solvent: CCCCOCCCC
Product: c1ccc([Al](c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of AlCl3 (133 mg; 1.0 mmol) in Bu2O (4.0 mL) was added phenylmagnesium bromide (1.2 mL, 3.1 mmol, 2.6 M in Et2O) at ambient temperature. After stirring at ambient temperature overnight, the product mixture was purged with a strong stream of nitrogen gas to evaporate the THF and Et2O. Bu2O (5.0 mL) was added to the residue and the mixture was stirred overnight, then filtered and the filtrate was purged with a strong stream of nitrogen gas to provide Ph3Al as a solid.
Reaction SMILES: [CH3:1][S:2]([Cl:5])(=[O:4])=[O:3].[NH2:6][C:7]1[CH:35]=[CH:34][C:10]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.C(N(CC)CC)C>O1CCOCC1>[ClH:5].[C:28]1([CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:20][CH2:19][CH:16]2[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][C:10]3[CH:9]=[CH:8][C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:35][CH:34]=3)[CH2:14][CH2:15]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Nc1ccc(CCN2CCC(COC(c3ccccc3)c3ccccc3)CC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc(CCN2CCC(COC(c3ccccc3)c3ccccc3)CC2)cc1
Product: Cl
Yield: 34.9 %

Procedure:
Methanesulphonyl chloride (69 mg, 0.60 mmol) was added dropwise to a stirred solution of 1-(4-aminophenethyl)-4-(diphenylmethoxymethyl)piperidine (200 mg, 0.50 mmol) (see Example 21) and triethylamine (61 mg, 0.60 mmol) in dioxane (5 ml) and the mixture heated under reflux for 2 hours and evaporated. The residue was partitioned between ethyl acetate and 10% aqueous potassium carbonate solution. The layers were separated and the aqueous layer extracted into ethyl acetate. The combined organic layers were dried over magnesium sulphate and evaporated. The residue was purified by chromatography on silica using dichloromethane plus 0-4% methanol as eluant. Appropriate fractions were combined and evaporated. The residue was dissolved in ether and the solution treated with excess ethereal hydrogen chloride. The mixture was decanted and the residual oil was washed with ether and dried to give the title compound (90 mg) as a pale yellow foam which was characterised containing 0.25 equivalents of water.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:27])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=2[CH:26]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[C:35]([O:37][CH3:38])=[O:36].N1C=CC=CC=1.Cl>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:38][O:37][C:35](=[O:36])[C:34]1[CH:33]=[CH:32][C:31]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:27])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=4[CH:26]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[CH:30][C:29]=1[Cl:28]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)cc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc4oc(=O)n(C)c4c3)C(F)(F)F)c(Cl)c2)cc1Cl
Temperature: 25 °C
Yield: 27 %

Procedure:
5-[2-(2-Chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (90 mg, obtained in Example 172), 3-chloro-4-methoxycarbonylphenyl-boronic acid (144 mg, [CAS Reg. No. 603122-82-3]), copper(II)-acetate (122 mg) and pyridine (0.090 mL) were dissolved in CH2Cl2 (3 mL). The mixture was stirred over night at r.t. The reaction mixture was poured into ice/water and acified with 1M aqueous HCl. The aqueous layer was extracted three times with ethylacetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a colorless foam (35 mg, 27%). MS (m/e)=570.1 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]1[N:10]([CH3:17])[CH2:9][CH:8]([C@H:18]3[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20][CH2:19]3)[O:7][C:6]2=1.[O:25]=[C:26]1[NH:31][C:30]2[CH:32]=[C:33]([C:36](O)=[O:37])[CH:34]=[CH:35][C:29]=2[S:28][CH2:27]1>>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]1[N:10]([CH3:17])[CH2:9][CH:8]([C@H:18]3[CH2:23][CH2:22][C@H:21]([NH:24][C:36]([C:33]4[CH:34]=[CH:35][C:29]5[S:28][CH2:27][C:26](=[O:25])[NH:31][C:30]=5[CH:32]=4)=[O:37])[CH2:20][CH2:19]3)[O:7][C:6]2=1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Reactant: COc1ccc2ncc3c(c2n1)OC([C@H]1CC[C@H](N)CC1)CN3C
Product: COc1ccc2ncc3c(c2n1)OC([C@H]1CC[C@H](NC(=O)c2ccc4c(c2)NC(=O)CS4)CC1)CN3C

Procedure:
The titled compound is prepared as an off-white lyophilizated powder following Scheme 7 and in analogy to Example 47 using trans-4-(6-methoxy-1-methyl-2,3-dihydro-1H-4-oxa-1,5,9-triaza-phenanthren-3-yl)-cyclohexylamine and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][CH2:26][C:27]2[CH:28]=[C:29](/[C:33](/[CH2:47][CH3:48])=[CH:34]/[C:35]#[C:36][C:37]([C:43]([F:46])([F:45])[F:44])([OH:42])[C:38]([F:41])([F:40])[F:39])[CH:30]=[CH:31][CH:32]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][O:17][Si](C(C)(C)C)(C)C)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][CH2:26][C:27]2[CH:28]=[C:29](/[C:33](/[CH2:47][CH3:48])=[CH:34]/[C:35]#[C:36][C:37]([C:38]([F:39])([F:40])[F:41])([OH:42])[C:43]([F:45])([F:46])[F:44])[CH:30]=[CH:31][CH:32]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][OH:17]
Reactant: CC/C(=C\C#CC(O)(C(F)(F)F)C(F)(F)F)c1cccc(CCc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC/C(=C\C#CC(O)(C(F)(F)F)C(F)(F)F)c1cccc(CCc2ccc(CO)c(CO)c2)c1

Procedure:
In a manner analogous to example 2m, by reaction of 1 g (1.4 mmol) of (E)-6-(3-{2-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenyl]ethyl}-phenyl)-1,1,1-trifluoro-2-trifluoromethyloct-5-en-3-yn-2-ol with 3.3 ml (3.3 mmol) of a 1.0 M solution of tetrabutylammonium fluoride. A yellowish solid is obtained (m.p.=123° C.; m=570 mg; Y=84%).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2].NCN1CC[CH2:17][C:16]1=[O:20].NCN1CC[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:24]1=[O:32]>C(Cl)Cl>[O:32]=[C:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:12][CH2:11][N:10]1[CH2:9][NH:8][C:1]([NH:3][CH2:4][N:5]1[CH2:6][CH2:7][CH2:17][C:16]1=[O:20])=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCN1CCCC1=O
Reactant: NCN1CCCCCCCC1=O
Solvent: ClCCl
Product: O=C(NCN1CCCCCCCC1=O)NCN1CCCC1=O
Yield: 36.8 %

Procedure:
A solution of 8.1 g (0.05 mole) of 1,1'-carbonyldiimidazole in 20 ml of methylene chloride is added, with vigorous stirring, to a solution of 5.7 g (0.05 mole) of 1-aminomethyl-2-pyrrolidinone in 20 ml of methylene chloride cooled to -70° C., whereafter 8.5 g (0.05 mole) of 1-aminomethyloctahydro-2H-azonin-2-one in 20 ml of methylene chloride are also added. After the addition, the reaction mixture is heated under reflux for 2 hours. After evaporation of the solvent under reduced pressure, the residue obtained is purified by chromatography on silica (eluent: chloroform). 5.7 g (0.0184 mole) of 1-[(octahydro-2-oxo-1H-azonin-1-yl)methyl]-3-[(2-oxopyrrolidino)methyl]-urea are thus obtained.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[C:5]([O:13][CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)(C)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:9]2[C:4](=[C:5]([O:13][CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1cccc2c(Cl)nc(Cl)nc12
Reactant: Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COc1cccc2c(Nc3ccccc3)nc(Cl)nc12

Procedure:
A solution of 2,4-dichloro-8-methoxy-quinazoline (prepared as described in J. Chem. Soc. 1948, 1759) (0.6 g), N,N-diisopropyl-ethylamine (0.87 ml), and aniline (0.26 ml) in isopropanol (10 ml) is heated to reflux for 45 min. The cold reaction mixture is filtered and residue is crystallized from dichloromethane and hexanes to give 2-chloro-8-methoxy-4-phenylamino-quinazoline, m.p. 245-246° C.
Reaction SMILES: N[C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].N([O-])=O.[Na+].[ClH:20]>O.CC(C)=O>[Cl:20][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(N)c(OC)cc1OC
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1cc(Cl)c(OC)cc1OC
Temperature: 25 °C

Procedure:
A 0.65 g portion of methyl 5-amino-2,4-dimethoxybenzoate was dissolved in a mixture solvent of 1.5 ml of water and 10 ml of acetone, and 1.3 ml of concentrated hydrochloric acid was added thereto, followed by dropwise addition of 0.23 g of sodium nitrite dissolved in 1 ml of water under ice-cooling and subsequent stirring for a while. Next, 0.35 g of cuprous chloride was added and the mixture was warmed up to room temperature. After completion of the reaction, insoluble matter was filtered and the resulting residue was mixed with water, extracted with ethyl acetate and then washed with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=500:1-40:1) to give 0.56 g of methyl 5-chloro-2,4-dimethoxybenzoate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[I:18].[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1.O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][O:19]1)[N:13]=[C:12]2[I:18]
Reactant: C1=COCCC1
Reactant: Fc1cccc(F)c1-c1ccc2[nH]nc(I)c2c1
Solvent: O
Solvent: C1CCOC1
Product: Fc1cccc(F)c1-c1ccc2c(c1)c(I)nn2C1CCCCO1
Temperature: 70 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
To a solution of 5-(2,6-difluoro-phenyl)-3-iodo-1H-indazole (45.5 g, 127.76 mmol) and TSA (4.86 g, 25.55 mmol) in THF (383.2 mL) was added 3,4-dihydro-2H-pyran (23.8 mL, 255.53 mmol) at RT. The mixture was stirred at 70° C. for 8 h. The reaction mixture was cooled to RT. Water was added to the reaction mixture and extracted with EtOAc (2×500 mL). The organic layer was washed with brine and dried over Na2SO4. The organic layer was concentrated under reduced pressure. The crude product was purified by column using (100-200 mesh) silica with 0-5% EtOAc in hexane to provide 5-(2,6-difluoro-phenyl)-3-iodo-1-(tetrahydro-pyran-2-yl)-1H-indazole (42.95 g, 78.2% yield). MS (ESI, pos. ion) m/z: 441.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][CH:3]=1.N12CCN(CC1)CC2.[CH3:17][CH:18]([N:20]=[C:21]=[O:22])[CH3:19]>CN(C)C=O>[Cl:8][C:6]1[N:5]=[N:4][CH:3]=[C:2]([NH:1][C:21]([NH:20][CH:18]([CH3:19])[CH3:17])=[O:22])[CH:7]=1
Reactant: Nc1cnnc(Cl)c1
Reactant: CC(C)N=C=O
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Product: CC(C)NC(=O)Nc1cnnc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 0.8 gram of 4-amino-6-chloro-pyridazine in 30 ml of dimethylformamide is added 0.2 gram of 1,4-diazabicyclo[2.2.2]octane, followed by 0.6 gram of 1-methylethyl isocyanate. The reaction mixture is stirred at ambient temperature for 18 hours, then at 60° C. for six hours. The majority of the dimethylformamide is removed under reduced pressure, and the residue is slurried in water. The resultant solid is collected by filtration and dried to yield N-(6-chloro-4-pyridazinyl)-N'-(1-methylethyl)urea.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:16]3[CH:27]=[CH:26][CH:25]=[CH:24][C:17]=3[S:18][C:19]=2[C:20]([O:22]C)=[O:21])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(#N)C.Cl>CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:16]3[CH:27]=[CH:26][CH:25]=[CH:24][C:17]=3[S:18][C:19]=2[C:20]([OH:22])=[O:21])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sc2ccccc2c1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2c(C(=O)O)sc3ccccc23)cc1
Reaction time: 8 h
Yield: 100.2 %

Procedure:
To a solution of 88 (0.120 g; 0.31 mmol) in methanol (2 mL) was added aqueous sodium hydroxide (1 mL; 2 mmol; 2N). Acetonitrile (2 mL) was added to aid in solubility, and the resulting mixture was stirred overnight. The reaction mixture was acidified with aqueous hydrochloric acid (2N) and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, decanted, and concentrated under reduced pressure. Trituration of the crude product from hexanes and dichloromethane yielded the desired product as a pink solid (121 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[C:19]#[C:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[N-:27]=[N+:28]=[N-:29].[Na+]>CS(C)=O.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:14])([F:13])[F:15])[CH2:9][CH2:10][C:4]=2[C:3]=1[C:19]1[NH:27][N:28]=[N:29][C:20]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(N1CCc2ccc(Cl)c(C#Cc3ccccc3)c2CC1)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(N1CCc2ccc(Cl)c(-c3[nH]nnc3-c3ccccc3)c2CC1)C(F)(F)F
Yield: 39.3 %

Procedure:
Heat 7-chloro-6-phenylethynyl-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (100 mg, 0.26 mmol) and sodium azide (69 mg, 1.06 mmol) in anhydrous DMSO (5.3 mL) for 5.5 h. Cool the mixture, add brine and extract ten times with dichloromethane. Dry the combined organic extracts over Na2SO4, filter and evaporate onto silica gel. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 to 2:3 gradient) to obtain the desired intermediate (43 mg, 39%). MS (ES+) m/z: 421 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]([C:9]2[N:13]([CH3:14])[CH:12]=[N:11][CH:10]=2)[OH:8])=[CH:5][N:4]=[N:3]1>O1CCOCC1.[O-2].[O-2].[Mn+4]>[CH3:1][N:2]1[C:6]([C:7]([C:9]2[N:13]([CH3:14])[CH:12]=[N:11][CH:10]=2)=[O:8])=[CH:5][N:4]=[N:3]1
Reactant: Cn1cncc1C(O)c1cnnn1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: Cn1cncc1C(=O)c1cnnn1C
Temperature: 25 °C

Procedure:
A mixture of (1-methyl-1H-1,2,3-triazol-5-yl)(1-methyl-1H-imidazol-5-yl)methanol (1.90 g, 9.83 mmol, Intermediate 6: step a) and manganese dioxide (5.04 g, 49.3 mmol) in 1,4-dioxane (100 mL) was stirred in a 100° C. oil bath under argon for 2 hours. The mixture was allowed to cool to room temperature, then was filtered through a pad of Celite®, rinsing with DCM. The filtrate was concentrated, yielding the title compound as a brown powder.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][C:4]=1[O:18][CH3:19].Cl[Si](C)(C)C.BrCCBr.Br[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>[Zn].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.C1COCC1>[CH3:19][O:18][C:4]1[CH:5]=[C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:7]=[CH:8][C:3]=1[CH2:2][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1
Reactant: Brc1ccccn1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1CBr
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: COc1cc(-c2nc3ccccc3o2)ccc1Cc1ccccn1

Procedure:
A solution of 2-[4-(bromomethyl)-3-methoxyphenyl]-1,3-benzoxazole (320 mg, 1.0 mmol) and THF (10 mL) was treated with Zn powder (activated by grinding with mortar and pestle), a drop of chlorotrimethylsilane, and a drop of 1,2-dibromoethane. The mixture was heated at reflux for 1 h. The resultant organozinc reagent was filtered through a plug of Celite, and transferred to a flask containing 2-bromopyridine (360 mg, 2.0 mmol) and Pd(Ph3P)4 (115 mg, 0.1 mmol). The mixture was degassed with bubbling argon for 15 min, and heated at reflux for 12 h. The reaction was poured into H2O (40 mL) and extracted with CH2Cl2 (2×30 mL). The organic extracts were dried (MgSO4) and concentrated to afford a colorless solid. Purification of the solid by flash chromatography on silica gel (EtOAc:hexanes 3:1) afforded the desired 2-[3-methoxy-4-(pyridin-2-ylmethyl)phenyl]-1,3-benzoxazole as a yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.55 (d, 1H), 7.76–7.82 (m, 3H), 7.56–7.62 (d, 2H), 7.32–7.36 (m, 3H), 7.11–7.16 (m, 2H), 4.23 (s, 2H), 3.95 (s, 3H). MS (ESI) 317 (M+H)+.
Reaction SMILES: O[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(-c2cc3c(O)ncnc3o2)cc1
Product: O=[N+]([O-])c1ccc(-c2cc3c(Cl)ncnc3o2)cc1
Temperature: 0 °C

Procedure:
13.5 g of 4-hydroxy-6-(4-nitrophenyl)furo[2,3-d]pyrimidine are heated for 1.5 h under RF in ca. 200 ml of phosphorus oxychloride (Fluka, Buchs). Afterwards, the reaction mixture is left to stand in the open for 3 days, and then added to 4 kg of ice. The suspension is filtered by suction and washed with a lot of H2O. The product is sublimated at ca. 200° C. and at ca. 0.1 mbar. The sublimate consists of lemon-yellow non-crystalline needles: m.p.: from 245° C. (decomposition). 1H-NMR (300 MHz, DMSO): 8.91 (s, H—C(2)); 8.40, 8.31 (d, J=9.2, H—C(2′, 3′)); 8.09 (s, H—C(5)).
Reaction SMILES: [OH-].[Li+].[NH2:3][C:4]1[N:9]=[C:8]([NH:10][CH2:11][CH2:12][CH2:13][N:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[CH:16]=[C:15]2[C:27]([O:29]CC2C=CC=CC=2)=[O:28])[CH:7]=[CH:6][C:5]=1[N+:37]([O-:39])=[O:38].Cl>C1COCC1.O>[NH2:3][C:4]1[N:9]=[C:8]([NH:10][CH2:11][CH2:12][CH2:13][N:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[CH:16]=[C:15]2[C:27]([OH:29])=[O:28])[CH:7]=[CH:6][C:5]=1[N+:37]([O-:39])=[O:38]
Reactant: Nc1nc(NCCCn2cc(-c3ccc(Cl)cc3Cl)cc2C(=O)OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc(NCCCn2cc(-c3ccc(Cl)cc3Cl)cc2C(=O)O)ccc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 99 %

Procedure:
Solid lithium hydroxide (20 eq) was added to a stirred solution of 1-{3-[(6-amino-5-nitro(2-pyridyl))amino]propyl}-4-(2,4-dichlorophenyl)pyrrole-2-carboxylate (10) (1 eq) in THF and water at rt. The mixture was heated to 50° C. for 12 h until complete by LC/MS. The reaction was allowed to cool to room temperature and acidified with 1 M HCl (aq.). The acidic solution was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and concentrated to pure 1-{3-[(6-amino-5-nitro(2-pyridyl))amino]propyl}-4-(2,4-dichlorophenyl)pyrrole-2-carboxylic acid (11) as a sticky yellow solid (99% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:14])=[CH:3][CH2:4][CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[N+:11]([O-:13])=[O:12].[ClH:15].[N+:16]([O-:24])(OCCC(C)C)=O>>[Cl:15][C:2]([CH3:14])([CH3:1])[CH:3]([N:16]=[O:24])[CH2:4][CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[N+:11]([O-:13])=[O:12]
Reactant: Cl
Reactant: CC(C)=CCCn1ccnc1[N+](=O)[O-]
Reactant: CC(C)CCO[N+](=O)[O-]
Product: CC(C)(Cl)C(CCn1ccnc1[N+](=O)[O-])N=O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 81 %

Procedure:
4-Methyl-1-(2-nitro-1H-imidazol-1-yl)-3-pentene (8 g, 41 mmol) was dissolved in isoamyl nitrate (50 mL) at room temperature. The solution was cooled to 0° C. in an ice-salt bath and concentrated HCl (12 mL) was added dropwise. The reaction temperature was maintained between 3-5° C. during the HCl addition; the reaction was stirred in an ice-salt bath for 45 minutes after the addition of HCl. The product was filtered, washed with ethanol-ether (1:2) and dried in vacuum to give 8.6 g (81%) of the title product as a white solid; mp: 96-07° C. MS: (M+H)+=261, M+=2601H NMR (DMSO-d6) δ1.70 (s, 6H, gem-di-CH3), 2.94 (t, 2H, CH2CH=NOH), 4.65 [t, 2H, CH2-(2-nitroimidazole)], 7.16 and 7.52 (s, 2H, 2-nitroimidazolyl-H), 11.43 (s, 1H, CH2C=NOH).