Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:11][CH3:12])[CH3:10])[C:5]([N+:13]([O-:15])=[O:14])=[C:4]([CH3:16])[N:3]=1.[CH3:17][O-:18].[Na+]>CO>[CH3:17][O:18][C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:11][CH3:12])[CH3:10])[C:5]([N+:13]([O-:15])=[O:14])=[C:4]([CH3:16])[N:3]=1
Reactant: CCC(C)Nc1nc(Cl)nc(C)c1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCC(C)Nc1nc(OC)nc(C)c1[N+](=O)[O-]
Reaction time: 8 h
Yield: 73.1 %

Procedure:
17.1 g of 2-chloro-4-sec. butylamino-5-nitro-6-methyl-pyrimidine (0.07 mole) are dissolved in 200 ml of methanol. To this solution is added a solution of 8.1 g of sodium methylate (0.15 mole) in 100 ml of methanol and the mixture is boiled overnight at 100° C bath temperature. After it has been cooled, the solution is evaporated and the resultant red substance is treated with ether and then filtered over Hyflo. The filter residue is washed 5 times with ether and the combined ethereal extracts are then evaporated to yield 12.3 g of 2-methoxy-4-sec. butylamino-5nitro-6-methylpyrimidine which boils at 110° C at 0.001 Torr (=73% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH2:9])[N:5]=[C:4]([OH:10])[N:3]=1.[F:11][C:12]([F:26])([F:25])[C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[CH:16]=O>C(O)(=O)C.CCO>[F:11][C:12]([F:25])([F:26])[C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:20]=1)[CH:16]=[N:9][NH:8][C:6]1[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([OH:10])[N:5]=1
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NNc1nc(O)nc(Cl)n1
Solvent: CCO
Solvent: CC(=O)O
Product: Oc1nc(Cl)nc(NN=Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: 25 °C
Yield: 68.1 %

Procedure:
To a solution of 4-chloro-6-hydrazino-[1,3,5]triazin-2-ol (0.13 g, 0.0008 mol) and 3,5-bis(trifluoromethyl)benz aldehyde (0.39 g, 0.0016 mol) in abs. EtOH (10 mL), was added 1 drop of acetic acid. The reaction mixture was refluxed for 5 hours. The reaction mixture was cooling to room temperature and concentrated to remove solvent. The resulting residue was solidified by EtOAc to give red solid 0.21 g, in 72% yield, mp: 258.3° C. 1H NMR (DMSO-d6) δ 11.15 (s, 1H), 8.97 (s, 1H), 8.54 (s, 1H), 7.59 (s, 1H), 7.30 (s, 2H). 13C NMR (DMSO-d6) δ 179.0, 160.2, 149.8, 148.8, 128.3, 127.6, 125.4, 124.7.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[C:11](OCC)(=[O:13])[CH3:12]>CN(C)C=O.[Cl-].[Na+].O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:12][CH:11]=[O:13]
Reactant: Oc1cccc(F)c1
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=CCOc1cccc(F)c1
Temperature: 60 °C
Yield: 78.1 %

Procedure:
2.00 g (17.8 mmol) of m-fluorophenol was dissolved in 50 ml of dimethylformamide, 785 mg (19.6 mmol, 60% by weight, mineral) of sodium hydride and 3.21 ml (21.3 mmol) of bromoacetaldehydediethylacetal were successively added thereto, and the mixture was heated to 60° C. After completion of the reaction, brine was added thereto and the mixture was extractedwith ethyl acetate. Theorganiclayerwaswashedwith brine, dried over magnesium sulfate and then evaporated, to give a crude product. The crude product was subjected to 105 g of Cromatorex NH silica gel (ethyl acetate:hexane=1:40), to give 3.17 g (13.9 mmol, 78.1%) of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:9]=[C:8](O)[C:7]([C:11]#[N:12])=[CH:6][N:5]=1)[CH3:2].[Cl-].[Cl:14]C=[N+](C)C>O1CCOCC1>[CH2:1]([S:3][C:4]1[N:9]=[C:8]([Cl:14])[C:7]([C:11]#[N:12])=[CH:6][N:5]=1)[CH3:2]
Reactant: C[N+](C)=CCl
Reactant: CCSc1ncc(C#N)c(O)n1
Agent: [Cl-]
Solvent: C1COCCO1
Product: CCSc1ncc(C#N)c(Cl)n1
Temperature: 100 °C
Yield: 60.3 %

Procedure:
To a solution of 2-ethylthio-4-hydroxy-5-cyanopyrimidine (196 mg, 1.08 mmol) in 1,4-dioxane (5 mL) was added (chloro-methylene)dimethylammonium chloride (550 mg, 4.32 mmol). The mixture was heated at 100° C. for 4 h, cooled, and the solvent was removed under reduced pressure. The crude material was purified by flash chromatography using 1:20 acetone:hexane system to yield 130 mg of the title compound. Mass spectrum 199.3 (EI, M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[CH3:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:16]2[CH2:17][CH2:18][CH:13]([CH3:12])[CH2:14][CH2:15]2)[CH:3]=1
Reactant: CC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Solvent: O
Product: CC1CCN(c2cc(Br)ccc2[N+](=O)[O-])CC1
Temperature: 40 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a round bottom flask containing 4-bromo-2-fluoro-1-nitro-benzene (640 mg, 2.92 mmol) was added 4-methyl piperidine (4 mL) and the reaction was stirred at 40° C. overnight. At this time the dark solution was poured into water (25 mL) and extracted with DCM (2×25 mL). The combined organic layers were washed with water (2×25 mL), dried (Na2SO4) and concentrated in vacuo to afford 556 mg (64%) of 1-(5-bromo-2-nitro-phenyl)-4-methyl-piperidine as an orange oil which was used without further purification.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[CH:11][NH:12][CH:13]=[C:9]2[C:8](=[O:14])[N:7]([CH3:15])[C:6]1=[O:16])[CH:2]([CH3:4])[CH3:3].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([N:5]1[C:10]2=[CH:11][N:12]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)=[CH:23][CH:24]=3)[CH:13]=[C:9]2[C:8](=[O:14])[N:7]([CH3:15])[C:6]1=[O:16])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c[nH]cc21
Reactant: BrCc1ccc(-c2ccccn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cn(Cc3ccc(-c4ccccn4)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 1-isobutyl-3-methyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (100 mg, 0.45 mmol), 2-(4-(bromomethyl)phenyl)pyridine (160 mg, 0.65 mmol) and potassium carbonate (120 mg, 0.87 mmol) in anhydrous DMF is stirred at room temperature overnight. After routine workup, the obtained crude product is purified by a semi-preparative HPLC to give pure product as white solids. MS (ESI) m/z 389.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15]3=[N:17][C@H:18]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][N:14]3[C:13](=[O:27])[NH:12][C:11]=2[N:10]=[C:9]1[CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:39][O:40][C:41](=[O:44])[CH2:42]Br>CN(C)C=O>[CH2:1]([N:8]1[C:16]2[C:15]3=[N:17][C@H:18]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][N:14]3[C:13](=[O:27])[N:12]([CH2:42][C:41]([O:40][CH3:39])=[O:44])[C:11]=2[N:10]=[C:9]1[CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: O=C1Nc2nc(C3CCCC3)n(Cc3ccccc3)c2C2=N[C@H](Cc3ccccc3)CN12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2c1nc(C1CCCC1)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.4 %

Procedure:
Compound 66 (1.87 g, 4.21 mmol) obtained in Example 66 was dissolved in 1,4-dioxane (30 mL), to the solution was added 2 mol/L aqueous sodium hydroxide (15 mL), and the mixture was stirred with heating at 70° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and then the residue was neutralized by addition of concentrated hydrochloric acid. The deposited crystals were collected by filtration, washed with water and dried to obtain (R)-1,8-dibenzyl-2-cyclopentyl-7,8-dihydro-1H-imidazo[2,1-i]purin-5(4H)-one (Compound 77a, 1.61 g, 90%). Compound 77a (500 mg, 1.08 mmol) was dissolved in N,N-dimethylformamide (5 mL), to the solution were added potassium carbonate (192 mg, 1.41 mmol, 1.2 equivalents) and bromoacetic acid methyl ester (140 μL, 1.41 mmol, 1.2 equivalents), and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, water was added to the concentrate, the mixture was extracted with chloroform, and the extract was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=90:10) to obtain (R)-1,8-dibenzyl-2-cyclopentyl-7,8-dihydro-4-methoxycarbonylmethyl-1H-imidazo[2,1-i]purin-5(4H)-one (Compound 77b, 400 mg, 69%). From Compound 77b (850 mg, 1.71 mmol), (R)-8-benzyl-2-cyclopentyl-7,8-dihydro-4-methoxycarbonylmethyl-1H-imidazo[2,1-i]purin-5(4H)-one (Compound 77c, 220 mg, 29%) was obtained in a manner similar to the method by which Compound 40 was obtained from Adduct 40a in Example 40. Compound 77c (200 mg, 0.49 mmol) was dissolved in a mixed solvent of tetrahydrofuran (1 mL) and water (1 mL), to the solution was added lithium hydroxide hydrate (0.04 g, 0.98 mmol), and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was adjusted to pH 3 with 1 mol/L hydrochloric acid, and the resulting solid was washed with ethanol and collected by filtration to obtain the title compound (180 mg, 93%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]=[CH:14][C:15]1[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=1)[CH2:21][N:20]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH2:18]3)[CH:7]=[CH:6]2)#[N:2].[N+](=[CH2:34])=[N-]>C1COCC1.C(OCC)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]1[CH2:34][CH:14]1[C:15]1[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=1)[CH2:21][N:20]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH2:18]3)[CH:7]=[CH:6]2)#[N:2]
Reactant: C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C=Cc3ccc4cc(C#N)ccc4c3)ccc2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2cc(C3CC3c3ccc4cc(C#N)ccc4c3)ccc2C1

Procedure:
A solution of Example 42I (207 mg, 0.5 mmol) and Pd(OAc)2 (5 mg) in THF (100 mL), at 0° C. was treated with a 0° C. 2M solution of diazomethane in diethyl ether (20 mL), warmed to room temperature over 10 minutes, treated with Pd(OAc)2 (5 mg) and 2M diazomethane in diethyl ether (20 mL), and treated two more times with Pd(OAc)2 and 2M diazomethane after 10 minute stirring intervals. After the final addition, the mixture was stirred for 1 hour, filtered through diatomaceous earth (Celite®) and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]=[CH:9][N:8]([CH2:11][CH3:12])[C:4]=2[N:5]=[N:6][CH:7]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH2:11]([N:8]1[C:4]2[N:5]=[N:6][CH:7]=[C:2]([C:17]3[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=3)[C:3]=2[N:10]=[CH:9]1)[CH3:12]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCn1cnc2c(Cl)cnnc21
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
Product: CCn1cnc2c(-c3ccc(F)cc3)cnnc21
Yield: 55 %

Procedure:
To a room temperature solution of 4-chloro-7-ethyl-7H-imidazo[4,5-c]pyridazine (Preparation 8, 9.6 g, 52.4 mmol) in dioxane (300 mL) was added 4-fluorobenzene boronic acid (8.8 g, 63 mmol) and an aqueous solution of Na2CO3 (1M, 260 mL, 262 mmol). The reaction mixture was degassed and purged with nitrogen gas 3 times. Tetrakis(triphenylphosphine)palladium(0) (1.2 g, 1.0 mmol) was then added and the mixture was heated to reflux for 4 hours. The organic solvent was removed in vacuo and the resulting aqueous mixture filtered. The filter cake was dried under vacuum to afford the title compound as a yellow solid in 55% yield, 7 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([N:13]1[C@H:17]([CH3:18])[C@H:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:15][C:14]1=[O:25])=[O:12].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O([CH2:44][CH3:45])S(C(F)(F)F)(=O)=O>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C@H:10]([CH2:44][CH3:45])[C:11]([N:13]1[C@H:17]([CH3:18])[C@H:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:15][C:14]1=[O:25])=[O:12]
Reactant: CCOS(=O)(=O)C(F)(F)F
Reactant: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)CCc1ccc(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@@H](Cc1ccc(F)cc1F)C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Temperature: -78 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
A flask was charged with 54 g (156 mmol) of (4R,5S)-3-[3-(2,4-difluoro-phenyl)-propionyl]-4-methyl-5-phenyl-oxazolidin-2-one and 300 mL of dry THF, and the solution was cooled to −78° C. To this solution was added 172 mL (172 mmol) of 1 M NaHMDS in THF, and the mixture was stirred cold for 1 hour. Then 30.6 g (172 mmol) of ethyl triflate was added dropwise to the enolate solution, and the reaction mixture was warmed to −40° C. to −30° C. and stirred for 1.5 hour. The reaction mixture was quenched by the addition of aqueous brine. The THF was removed under reduced pressure and the residue was partitioned between EtOAc and water. The organics were collected, and EtOAc was removed under reduced pressure. The resulting crude oil was purified by column chromatography (3:1 hexanes/EtOAc eluent) to get 29.5 g of an impure oil that was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[CH:8]=[CH:9][C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[N:12][C:11]=3[C:4]=2[N:3]=1.S(=O)(=O)(O)O.O[Li].O.[N+:25]([O-])([OH:27])=[O:26]>C(#N)C>[CH3:16][C:13]1[CH:14]=[CH:15][C:10]2[C:11](=[C:4]3[C:5](=[CH:8][C:9]=2[N+:25]([O-:27])=[O:26])[CH:6]=[CH:7][C:2]([CH3:1])=[N:3]3)[N:12]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc2ccc3ccc(C)nc3c2n1
Agent: O=S(=O)(O)O
Agent: [Li]O
Solvent: O
Solvent: CC#N
Product: Cc1ccc2cc([N+](=O)[O-])c3ccc(C)nc3c2n1
Temperature: 0 °C
Reaction time: 192 h
Yield: 34 %

Procedure:
Neocuproine hydrochloride, hemihydrate (25.0 g, 99 mmol) was dissolved in 100 mL of concentrated nitric acid. 200 mL of concentrated sulfuric acid was added, and the reaction was heated at reflux for 2.5 hours, and then allowed to stand at room temperature for 8 days. The reaction mixture was then gradually added to a mixture of about 3 Kg of ice and 351 g (8.8 mole) of LiOH·H2O, while stirring with a glass rod. During the neutralization procedure, ice was added as necessary so that unmelted ice was always present during the neutralization, and the neutralization reaction was also simultaneously cooled by an acetone/ice bath. After the addition was completed, the pH of the reaction mixture was 12. The aqueous mixture was extracted two times with methylene chloride, first with 1000 mL, and then with 400 mL. The methylene chloride fractions were combined, and extracted once with 500 mL of distilled H2O. The methylene chloride phase was concentrated to a residue, and triturated with 500 mL of acetonitrile. The solid was filtered, washed with acetonitrile, and dried under vacuum to give 10.3 g of cream yellow solid, which was dissolved in 100 mL of refluxing acetonitrile, allowed to crystallize at room temperature, and was filtered to give 8.5 g (34%) of cream-yellow crystals, mp 184°-186° C. FDMS (m/e) 253M. Anal. calcd for C14H11N3O2 ·0.25 H2O: C, 65.23; H, 4.50; N, 16.30. Found: C, 65.57; H, 4.45; N, 16.27. The NMR and IR spectra were consistent with the assigned structure and the product was homogeneous by TLC.
Reaction SMILES: Br[CH2:2][CH2:3][S:4]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)(=[O:6])=[O:5].[CH3:15][C:16]1[N:20]=[CH:19][NH:18][N:17]=1>>[CH3:15][C:16]1[N:20]=[CH:19][N:18]([CH2:2][CH2:3][S:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[N:17]=1
Reactant: N#Cc1ccc(S(=O)(=O)CCBr)cc1
Reactant: Cc1nc[nH]n1
Product: Cc1ncn(CCS(=O)(=O)c2ccc(C#N)cc2)n1

Procedure:
To a stirred suspension of 10 g of thiosemicarbazide in 100 mL of pyridine was slowly added 7.8 ml of acetyl chloride at 0° C. The temperature was maintained throughout the addition (0-4° C.). The reaction mixture was allowed to warm to room temperature and stirred for 16 h. Evaporation gave 1-acetyl thiosemicarbazide. The crude 1-acetyl thiosemicarbazide was dissolved in 70 mL of MeOH and 12 g of sodium methoxide, and was refluxed for 10 h. The solvent was removed and the residue was dissolved in H2O, then acidified to pH 2 by the addition of 1N HCl. The resulting solid was filtered and washed with H2O to give 3-methyl-1,2,4-triazole-5-thiol. 1 g of 3-methyl-1,2,4-triazole-5-thiol was added to a solution of 61 mg of sodium nitrite in 3 ml of nitric acid and 6 mL of H2O at 0° C. The reaction-mixture was stirred for 1 h at 0° C., and basified with saturated sodium carbonate and concentrated. The residue was dissolved with MeOH and filtered. The filtrate was evaporated to give 3-methyl-1,2,4-triazole. 230 mg of 4-(2-bromoethylsulfonyl)benzonitrile was used in Procedure P with 3-methyl-1,2,4-triazole to yield 4-(2-(3-methyl-1H-1,2,4-triazole-1-yl)ethylsulfonyl)benzonitrile. 310 mg of 4-(2-(3-methyl-1H-1,2,4-triazole-1-yl)ethylsulfonyl)benzonitrile was reacted via Procedure T to give 4-(2-(3-methyl-1H-1,2,4-triazole-1-yl)ethylsulfonyl)benzoic acid.
Reaction SMILES: [OH:1][C@@:2]1([CH2:17][OH:18])[C:11]2[C:6](=[C:7]([O:13][CH:14]([F:16])[F:15])[CH:8]=[C:9]([Cl:12])[CH:10]=2)[O:5][CH2:4][CH2:3]1.O.C(=O)([O-])[OH:21].[Na+]>CC(C)=O.[Pt]>[OH:1][C@@:2]1([C:17]([OH:21])=[O:18])[C:11]2[C:6](=[C:7]([O:13][CH:14]([F:15])[F:16])[CH:8]=[C:9]([Cl:12])[CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: OC[C@@]1(O)CCOc2c(OC(F)F)cc(Cl)cc21
Reactant: O=C([O-])O
Agent: [Pt]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)[C@@]1(O)CCOc2c(OC(F)F)cc(Cl)cc21
Temperature: 75 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
To a solution of (S)- or (R)-4-hydroxy4-hydroxymethyl-6-chloro-8-difluoromethoxychromane (3.2 g, 11.4 mmol, from step (vii) above) in acetone (25 mL) was added non-ionized water (110 mL), then sodium hydrogencarbonate (2.13 g, 22.2 mmol) and Pt/C 5%, 58% water (2.13 g). A stream of air was bubbled through the solution with stirring at 75° C. (oil-bath) overnight. The solution was filtered through Celite and the filter-cake was washed with water. The acetone-water solution was acidified (HCl, 2M) to pH 2, saturated with NaCl and extracted with EtOAc (3×). The combined ethyl acetate phases were washed with water (2×) and with brine, then dried (Na2SO4) and concentrated. The residue was dissolved in ether. The ether solution was washed with water (3×) and concentrated, yielding 2.4 g (71%) of the sub-title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:12][CH:13]([O:19][CH:20]([CH3:22])[CH3:21])[C:14]([O:16]CC)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>>[CH:20]([O:19][CH:13]([CH2:12][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([CH2:3][CH2:2][O:1][C:30]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([CH3:32])=[CH:24][CH:25]=2)=[O:31])[CH:5]=1)[C:14]([OH:16])=[O:15])([CH3:21])[CH3:22]
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CCO)c1)OC(C)C
Reactant: Cc1ccc(N=C=O)cc1
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CCOC(=O)Nc1ccc(C)cc1

Procedure:
Using ethyl 3-[3-(2-hydroxyethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and p-tolylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:7]([NH:14][C:15](=O)[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:25])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N:27]([Si](C)(C)C)=[N+:28]=[N-:29].C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[CH2:7]([N:14]1[C:15]([C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:25])=[N:29][N:28]=[N:27]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cccc([N+](=O)[O-])c1C(=O)NCc1ccccc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cccc([N+](=O)[O-])c1-c1nnnn1Cc1ccccc1
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
Phosphorous pentachloride (0.42 g, 2 mmol) was added to a solution of N-benzyl-2-methyl-6-nitrobenzamide (Intermediate 19, 0.54 g) in DCM (10 mL). The mixture was stirred under nitrogen for 30 minutes and then azidotrimethylsilane (0.48 g) was added and the mixture was stirred for a further 72 hours. The mixture was diluted with DCM (50 mL) and water (50 mL). Solid sodium bicarbonate was then added to the mixture until there was no further gaseous evolution. The organic solution was washed with saturated aqueous sodium bicarbonate, then with 1N hydrochloric acid, dried with magnesium sulfate and filtered. The solvent was evaporated to give an orange solid which was recrystallised from ethyl acetate to give the title compound as a white solid (0.42 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[CH:9]=[CH:8][C:7]([N:10]=O)=[CH:6][CH:5]=1)[CH3:2].[C:14]1([C:20]2[CH:24]=[C:23]([NH2:25])[N:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(=O)C>[CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[CH:9]=[C:8]2[C:7]([N:10]=[C:24]3[C:20]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)=[N:21][N:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[C:23]3=[N:25]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: Nc1cc(-c2ccccc2)nn1-c1ccccn1
Reactant: CCN(CC)c1ccc(N=O)cc1
Solvent: CC(=O)O
Product: CCN(CC)c1ccc2nc3c(-c4ccccc4)nn(-c4ccccn4)c3nc2c1
Yield: 33 %

Procedure:
1.78 g N,N-diethyl-p-nitrosoaniline and 2.67 g 3-phenyl-1-(2-pyridyl)-5-aminopyrazole were refluxed for 2 hrs in acetic acid. The mixture was concentrated to half volume. Water was added to get a precipitate, then filtered. The solid was purified by chromatograph column on silica gel. After removing the solvent, 1.3 g pure 7-diethylamino-3-phenyl-1-(2-pyridyl)-1H-pyrazolo[3,4-b]quinoxaline (DEPPPQ) was obtained as brown-red solid.