Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][CH:7]=1)=[O:4].[NH:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[C:10]([C:9]1[CH:13]=[CH:14][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:15]2[CH2:16][CH2:17][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:19][CH2:20]2)=[CH:7][CH:8]=1)(=[O:11])[NH2:12]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: NC(=O)c1ccc(NC(=O)CCl)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CCN(CC(=O)Nc2ccc(C(N)=O)cc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 4-(2-chloroacetamido)benzamide (0.57 g; 2.68 mmol), tert-butyl piperidin-4-ylcarbamate (0.55 g; 2.68 mmol) and DBU (0.40 mL; 2.68 mmol) in ACN (30 mL) is stirred at r.t. over night. Then the solvent is evaporated and the residue is dissolved in DCM. The solution is washed once with water, then with brine. The organic layer is dried and the solvent is evaporated. The residue is suspended in ether, filtered off with suction and dried to yield tert-butyl 1-(2-(4-carbamoylphenylamino)-2-oxoethyl)piperidin-4-ylcarbamate.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH:9]1([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([OH:21])[CH:15]=2)[CH2:11][CH2:10]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C(CCC)=CC(CCC)=CC=1CCC)(C)(C)C.Cl[C:54]1[C:55]2[CH:64]=[N:63][N:62]([C:65]3[CH:70]=[CH:69][CH:68]=[C:67]([F:71])[CH:66]=3)[C:56]=2[N:57]([CH3:61])[C:58](=[O:60])[CH:59]=1>C1COCC1.C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:9]1([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([O:21][C:54]3[C:55]4[CH:64]=[N:63][N:62]([C:65]5[CH:70]=[CH:69][CH:68]=[C:67]([F:71])[CH:66]=5)[C:56]=4[N:57]([CH3:61])[C:58](=[O:60])[CH:59]=3)[CH:15]=2)[CH2:10][CH2:11]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1O
Reactant: Cn1c(=O)cc(Cl)c2cnn(-c3cccc(F)c3)c21
Agent: [Pd]
Agent: CCCc1cc(CCC)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(CCC)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)NC2CC2)cc1Oc1cc(=O)n(C)c2c1cnn2-c1cccc(F)c1
Temperature: 110 °C

Procedure:
In sealed a glass tube, a mixture of potassium phosphate tribasic (251 mg, 1.18 mmol), tris(dibenzylideneacetone)dipalladium (0) (14 mg, 0.015 mmol), N-cyclopropyl-3-hydroxy-4-methylbenzamide (136 mg, 0.71 mmol), 2-di-t-butylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl (14 mg, 0.032 mmol) and 4-chloro-1-(3-fluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (164 mg, 0.59 mmol) in THF (0.5 mL) and toluene (1.30 mL) was heated at 110° C. in an oil bath for 18 h. The reaction mixture was cooled to RT, quenched with saturated ammonium chloride, and extracted twice with EtOAc. The combined EtOAc layers were washed with brine, dried and concentrated. The resulting crude material was purified on an ISCO (12 g column) eluting with a solvent gradient of 50-90% EtOAc in hexanes, to afford the title compound as a tan amorphous solid. MS (ESI, pos.ion) m/z: 433.0 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=2)[CH:7]=1.[C:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)#[N:21]>>[C:20]([C:22]1[CH:27]=[C:26]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=3)[CH:7]=2)[CH:25]=[CH:24][CH:23]=1)#[N:21]
Reactant: O=C(Nc1nc2ccc(Br)cn2n1)c1cccnc1
Reactant: N#Cc1cccc(B(O)O)c1
Product: N#Cc1cccc(-c2ccc3nc(NC(=O)c4cccnc4)nn3c2)c1
Yield: 7.3 %

Procedure:
The title compound was prepared following procedure described for intermediate A1 step a), but starting from N-(6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B6), 75 mg; 0.24 mmol; 1.0 eq.) and 3-cyanophenylboronic acid (69 mg; 0.47 mmol; 2.0 eq.). Purification by flash chromatography on silica (MeOH/DCM, gradient from 0:100 to 10:90) gave the title compound as a brown powder (6 mg, 7%). HPLC, Rt: 2.09 min. (purity 92.5%). LC/MS, M+(ESI): 341.4.
Reaction SMILES: [Na].[CH:2]1([OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[OH:8].Cl[CH:11]([CH3:15])[C:12](O)=[O:13].S(=O)(=O)(O)O>C(O)C.O>[CH3:15][CH:11]1[O:9][CH:2]2[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7]2)[O:8][C:12]1=[O:13]
Reactant: CC(Cl)C(=O)O
Reactant: OC1CCCCC1O
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CC1OC2CCCCC2OC1=O
Reaction time: 5 h

Procedure:
25.3 gm (1.1 mol) of sodium were dissolved in 500 ml of ethanol under dry nitrogen. 116 gm (1 mol) of 1,2-cyclohexane-diol were added to the solution at room temperature. Then, the ethanol was completely removed under vacuum. 163 gm (1.2 mol) of the ethyl ester of 2-chloropropionic acid were added to the mono-sodium salt of 1,2-cyclohexane-diol so obtained, at 50° C., and the mixture was allowed to stand for 5 hours at 80° C. to react further. Then, the reaction mixture was decomposed with water and acidified with sulfuric acid. The organic phase was separated and the aqueous phase was extracted twice with ether. After combining the organic phases, these were washed neutral with water and sodium bicarbonate solution, dried over sodium sulfate and reduced under vacuum. The crude product obtained was distilled under high vacuum. 76 gm of 4-methyl-2,5-dioxabicyclo-[4,4,0]-decan-3-one were obtained with the following analytical data:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C@@H:5]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:6][C@H:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH:13]=1)[CH:8]([CH3:10])[CH3:9])[OH:4].ClCCl.C(N(CC)CC)C.[C:44](Cl)(=[O:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>O>[C:44]([NH:1][CH2:2][C@@H:3]([C@@H:5]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:6][C@H:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH:13]=1)[CH:8]([CH3:10])[CH3:9])[OH:4])(=[O:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN)C(C)C)ccc1OC
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CNC(=O)c2ccccc2)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The solution of 0.025 g of tert-butyl {1(S)-(2-amino-1(S)-hydroxyethyl)-3(S)-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentyl}carbamate (Example 36b) and 0.8 ml of dichloromethane is admixed successively with 0.006 ml of triethylamine and 0.007 ml of benzoyl chloride and stirred at room temperature over 1 hour. The reaction solution is admixed with water and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed successively with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a colourless oil. Rf=0.74 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=5.01 (gradient I).
Reaction SMILES: [O:1]1[CH2:22][CH:2]1[CH2:3][O:4][C:5]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=[O:8].[C:23]([NH2:27])([CH3:26])([CH3:25])[CH3:24]>CO>[C:23]([NH:27][CH2:22][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=[O:8])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)N
Reactant: Cc1ccc(C(=O)c2c(C)cc(C)cc2OCC2CO2)cc1
Solvent: CO
Product: Cc1ccc(C(=O)c2c(C)cc(C)cc2OCC(O)CNC(C)(C)C)cc1

Procedure:
A mixture of 2-(2,3-epoxypropoxy)-4,4',6-trimethylbenzophenone (10 g.), t-butylamine (10 ml.) and dry methanol (50 ml.) was heated at reflux overnight. The mixture was evaporated in vacuo, and the residue was recrystallized from cyclohexane to give DL-1-t-butylamino-3-(3,5-dimethyl-2-p-toluoylphenoxy)-2-hydroxypropane (7 g.), m.p. 116°-118° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([NH:13][CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[N:10][N:9]=2)=[C:4]([NH:27][CH:28]([CH3:30])[CH3:29])[CH:3]=1.[NH2:31][C:32]1[CH:40]=[CH:39][C:35]2[N:36]=[CH:37][S:38][C:34]=2[CH:33]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[S:38]1[C:34]2[CH:33]=[C:32]([NH:31][C:2]3[N:7]=[CH:6][C:5]([C:8]4[O:12][C:11]([NH:13][CH:14]5[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]5)=[N:10][N:9]=4)=[C:4]([NH:27][CH:28]([CH3:30])[CH3:29])[CH:3]=3)[CH:40]=[CH:39][C:35]=2[N:36]=[CH:37]1
Reactant: CC(C)Nc1cc(Cl)ncc1-c1nnc(NC2CCN(C(=O)OC(C)(C)C)CC2)o1
Reactant: Nc1ccc2ncsc2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1-c1nnc(NC2CCN(C(=O)OC(C)(C)C)CC2)o1
Temperature: 110 °C

Procedure:
To a solution of tert-butyl 4-((5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)piperidine-1-carboxylate (45) (400 mg, 0.9 mmol) in dioxane (10 mL): H2O (2 mL), 6-amino benzothiazole (1.3 mmol, 1.5 equiv.), xanthphos (0.4 mmol, 0.5 equiv.) and Na2CO3 (2.7 mmol, 3 equiv.) were added and degassed for 10 min. To the reaction mixture Pd2(dba)3 (0.4 mmol, 0.5 equiv.) was added and degassed again for 10 min. It was then heated at 110° C. for overnight. The reaction mass was cooled and filtered through small pad of celite. The filtrate obtained was concentrated to provide crude material. The crude material was purified by column chromatography through silica gel and MeOH: DCM as eluent. The material obtained was further purified by prep. HPLC to afford tert-butyl 4-((5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)piperidine-1-carboxylate. 1H NMR: 400 MHz, CD3OD: δ 1.34 (d, J=6.00 Hz, 6H), 1.48 (s, 9H), 1.58-1.60 (m, 2H), 1.96-2.06 (m, 4H), 3.29-3.34 (2H, merged with the water peak), 3.61-3.64 (m, 1H), 3.78-3.82 (m, 1H), 4.00-4.04 (m, 2H), 6.16 (s, 1H), 7.53-7.58 (m, 2H), 7.97 (d, J=8.80 Hz, 1H), 8.37 (s, 1H), 8.43 (d, J=2.00 Hz, 1H), 9.08 (s, 1H). LC/MS: Purospher@star RP-18, 4×55 mm, 3 μm; Solvent A=10% ACN: 90% H2O: 20 mM NH4OAc; Solvent B=90% ACN: 10% H2O: 20 mM NH4COOAc; gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 2.028 mM; LCMS (ES-API), m/z 551.2 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 7.276 mM; Purity: 98.8%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([N:9]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=2[O:31][CH3:32])[CH2:10][C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:8])[NH:5][CH:6]=1.N12CCCN=C1CCCCC2>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:7](=[O:8])[N:9]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH3:32])[CH:10]=[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)[N:5]2[CH:6]=1
Reactant: COc1ccc(CN(CC#Cc2ccc([N+](=O)[O-])cc2)C(=O)c2cc(Br)c[nH]2)c(OC)c1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(Cn2cc(Cc3ccc([N+](=O)[O-])cc3)n3cc(Br)cc3c2=O)c(OC)c1

Procedure:
To a solution of EXAMPLE 23C (10 g, 20 mmol in dry dichloromethane (150 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.22 g, 8 mmol). The mixture was heated under reflux for 6 hours. After cooling, the reaction mixture was diluted with dichloromethane, and then washed with 0.5 N aqueous HCl (300 mL) and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (1% methanol in CH2Cl2) to afford the title compound. LC-MS (ESI): m/z 500, 498 (M+H), RT: 2.29 min; 1H NMR (400 MHz, dimethylsulfoxide-d6): δ 3.74 (s, 3H), 3.75 (s, 3H), 4.21 (s, 2H), 4.87 (s, 2H), 6.47 (dd, J=6, 2.4 Hz, 1H), 6.56 (d, J=2.4 Hz, 1H), 6.69 (s, 1H), 6.99 (d, J=1.6 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 7.50 (d, J=2.0 Hz, 1H), 7.60 (d, J=8.8 Hz, 2H), 8.20 (d, J=8.4 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH2:13]=[O:14]>>[CH:13]([C:7]1[CH:6]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:4]=[CH:3][C:2]=1[OH:1])=[O:14]
Reactant: C=O
Reactant: COC(=O)Cc1ccc(O)cc1
Product: COC(=O)Cc1ccc(O)c(C=O)c1
Yield: 99.8 %

Procedure:
Proceeding as in Reference 8, but substituting methyl 4-hydroxyphenylacetate (42.9 g, 0.258 mol) and paraformaldehyde (77.5 g, 2.58 mole), gave methyl 3-formyl-4-hydroxy-phenyl-acetate (50.0 g, ˜100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:29])[C:13]2[CH:18]=[C:17]([OH:19])[CH:16]=[C:15]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Br)=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:29])[C:13]2[CH:14]=[C:15]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)[CH:16]=[C:17]([O:19][CH2:37][C:34]3[CH:35]=[CH:36][C:31]([Br:30])=[CH:32][CH:33]=3)[CH:18]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: BrCc1ccc(Br)cc1
Reactant: CCOC(=O)N1CCN(C(=O)c2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Product: CCOC(=O)N1CCN(C(=O)c2cc(OCc3ccc(Br)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 79.7 %

Procedure:
Using 0.75 g (1.89 mmol) of 4-[3-(4-cyano phenoxy)-5-hydroxy benzoyl]-piperazine-1-carboxylic acid ethyl ester and 1-bromo-4-bromomethyl-benzene (0.472 g, 1.89 mmol) and following the procedure of Example 42(b) afforded 0.85 g of the required product. Percentage purity (LCMS): 75.2%, (M+1)=563.1+1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([B:12]1[O:16]C(C)(C)C(C)(C)[O:13]1)[CH:6]=[CH:5]2.Cl>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([B:12]([OH:16])[OH:13])[CH:6]=[CH:5]2
Reactant: CC1(C)OB(c2ccc3cc(Cl)ccc3c2)OC1(C)C
Agent: Cl
Solvent: CC(C)=O
Product: OB(O)c1ccc2cc(Cl)ccc2c1
Temperature: 50 °C

Procedure:
2-(6-Chloro-2-naphthyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (340 mg, 1.18 mmol) was suspended in a mixture of 20 mL of acetone and 5 mL of aqueous 2N hydrochloric acid and heated at 50° C. for 16 h. The product was purified by reverse phase HPLC to provide the title compound as a white powder. 1H NMP (500 MHz, DMSO) δ: 8.38 (s, 1H); 8.23 (s, 2H); 8.01 (d, J=2.1 Hz, 1H); 7.95 (d, J=8.7 Hz, 1H); 7.91 (d, 8.2 Hz, 1H); 7.84 (d, J=8.2 Hz, 1H); 7.50 (dd, J=2.3, 8.7 Hz, 1H).
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][C:27]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23])=O.P(Cl)(Cl)(Cl)(Cl)Cl.[N-:40]=[N+:41]=[N-:42].[Na+]>CN(C=O)C>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:13]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-:24])=[O:23])[N:42]=[N:41][N:40]=2)[CH:25]=[CH:26][C:27]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc(C(=O)Nc2ccccc2[N+](=O)[O-])ccc1-c1ccccn1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc(-c2nnnn2-c2ccccc2[N+](=O)[O-])ccc1-c1ccccn1
Temperature: 25 °C

Procedure:
To toluene (1 mL) was added 3-methoxy-4-(pyridin-2-yl)-2′-nitrobenzanilide (97 mg, 0.28 mmol) and phosphorous pentachloride (56 mg, 0.27 mmol), and the mixture heated at reflux for 1 h. The resulting solution was cooled to rt and added to a solution of NaN3 (35 mg, 0.54 mmol) in DMF (2 mL). The mixture was heated at 90° C. for 1 h, cooled to rt, partitioned between EtOAc and water, and the organic layer concentrated. The crude product was purified by flash column chromatography on silica gel eluting with EtOAc:hexanes (0:1 to 1:1) to afford 2-{2-methoxy-4-[1-(2-nitrophenyl)-1H-tetraazol-5-yl]phenyl}pyridine as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:28])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:13]=2[S:26]C)=[CH:4][CH:3]=1.ClN1C(=O)CCC1=O>C(Cl)Cl>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:11](=[O:28])[C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:13]=3[S:26]2)=[CH:4][CH:3]=1
Reactant: CCCCCOc1c(OC)ccc(C(=O)NCCc2ccc(O)cc2)c1SC
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CCCCCOc1c(OC)ccc2c(=O)n(CCc3ccc(O)cc3)sc12
Temperature: 0 °C
Reaction time: 5 h
Yield: 41.8 %

Procedure:
N-[2-(4-Hydroxyphenyl)ethyl]-4-methoxy-2-methylthio-3-pentyloxybenzamide (85 mg, 0.21 mmol) obtained in Example 2-50, molecular sieve 4A (200 mg) and methylene chloride (1 ml) were mixed, and this mixture was cooled to 0° C. N-Chlorosuccinimide (29.4 mg, 0.22 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was filtered, ethyl acetate (20 ml) was added to the filtrate, and the mixture was washed twice with saturated brine (5 ml). The mixture was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified twice by column chromatography on silicagel (hene/ethyl acetate=1/1) to give apale-yellow oil. To allow reaction of the residual raw materials, this oil, molecular sieve 4A (200 mg) and methylene chloride (1 ml) were mixed, and cooled to 0° C. N-Chlorosuccinimide (17.4 mg, 0.13 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours, followed by filtration. Ethyl acetate (20 ml) was added to the filtrate, and the filtrate was washed once with saturated brine (5 ml) and dried over anhydrous magnesium sulfate. Th drying agent was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by thin layer chromatography (chloroform/methanol=20/1) to give 2-[2-(4-hydroxyphenyl)ethyl]-6-methoxy-7-pentyloxybenzo[d]isothiazol-3-one (34 mg, 42%) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[C:12](Cl)(=O)C(Cl)=O.CN(C)C=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O:7][CH3:12])=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1Br
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(C)c(Br)c1

Procedure:
To a solution of 2.0 g (9.3 mmol) of 3-bromo-4-methylbenzoic acid in 25 mL of dichloromethane was added 5.6 mL (11.2 mmol) of oxalyl chloride and 100 μL of N,N-dimethylformamide. The resultant mixture was stirred at ambient temperature for 2 hours, concentrated in vacuo, and the residue suspended in methanol. The solution was concentrated in vacuo and the residue purified by flash column chromatography (biotage) using 5% ethyl acetate/hexanes as eluent to provide the title compound. 1H NMR (500 MHz, CDCl3) δ 8.23 (s, 1H), 7.90 (d, 1H, J=8 Hz), 7.33 (d, 1H, J=8 Hz), 3.94 (s, 3H), 2.48 (s, 3H). HPLC/MS (ESI) m/z (M+H)=231.0 (3.63 min).
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].[OH-].[Mg+2:6].[OH-]>>[N+:1]([O-:4])([O-:3])=[O:2].[Mg+2:6].[N+:1]([O-:4])([O-:3])=[O:2]
Reactant: O=[N+]([O-])O
Agent: [Mg+2]
Agent: [OH-]
Product: O=[N+]([O-])[O-]

Procedure:
contacting said humidified gaseous stream containing nitric acid in a second wet scrubbing unit with a second aqueous medium containing magnesium hydroxide which reacts with nitric acid to form magnesium nitrate;
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=O>N1C=CC=CC=1>[CH3:11][C:8]1[CH:9]=[CH:10][C:2]2[N:1]=[C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: CCCCCCCCOC(=O)Cl
Reactant: Cc1ccc(N)c(C(=O)O)c1
Solvent: c1ccncc1
Product: CCCCCCCCOc1nc2ccc(C)cc2c(=O)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 24.9 %

Procedure:
A solution of 2-amino-5-methylbenzoic acid (302 mg, 2 mmol) in pyridine (10 ml) was cooled to 0° C. and treated dropwise with octyl chloroformate (1.15 ml, 6 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 4 h. The pyridine was removed under vacuum and the residue dissolved in ethyl acetate (50 ml). This solution was washed with 1M HCl (10 ml) and brine (5 ml), dried (MgSO4) and the solvent removed in vacuo to afford a pale orange oily solid. Recrystallisation from hexane afforded the desired product as an off-white solid (144 mg, 25%); δH (400 MHz, DMSO-d6) 0.68 (3H, t, J 7, CH2CH3), 1.26-1.40 (10H, m, 5×CH2), 1.73 (2H, tt, J, J′7, OCH2CH2), 2.35 (3H, s, CH3), 4.35 (2H, t, J 7, OCH2), 7.34 (1H, d, J 8, Ph), 7.65 (1H, d, J 8, Ph), 7.83 (1H, s, Ph); m/z (ES+) 290 (MH+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Li]CCCC.[B:17](OC)([O:20]C)[O:18]C.Cl>C1COCC1>[C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][C:2]([B:17]([OH:20])[OH:18])=[CH:3][C:4]=2[CH:9]=1)#[N:11]
Reactant: N#Cc1ccc2occc2c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1ccc2oc(B(O)O)cc2c1
Reaction time: 0.5 h

Procedure:
To benzofuran-5-carbonitrile (500 mg, 3.49 mmol) in THF (9.98 mL) at −78° C. was added n-BuLi 1.6M in hexanes (2.401 mL, 3.84 mmol) dropwise. The mixture was stirred for 30 min at this temperature, and then trimethyl borate (0.858 mL, 7.68 mmol) was added dropwise. The mixture was stirred for 20 min, and then HCl (2M, 11.52 mL, 23.05 mmol) was added. The bath was removed, and then stirred for 30 min. To the mixture was added more water and extracted with EtOAc three times, dried over magnesium sulfate, filtered, concentrated. crude 7a (623 mg, 87%) was then dried and used as is for next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:29])[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:21]([C:22](O)=[O:23])=[CH:20][C:19]([C:25]([F:28])([F:27])[F:26])=[N:18]2)[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:46][O:47][C:48]1[CH:53]=[CH:52][C:51]([NH2:54])=[C:50]([NH2:55])[CH:49]=1>CN(C=O)C>[NH2:54][C:51]1[CH:52]=[CH:53][C:48]([O:47][CH3:46])=[CH:49][C:50]=1[NH:55][C:22]([C:21]1[N:17]([CH:14]2[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][N:8]([CH3:29])[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:12][CH2:13]2)[N:18]=[C:19]([C:25]([F:27])([F:28])[F:26])[CH:20]=1)=[O:23]
Reactant: COc1ccc(N)c(N)c1
Reactant: CN(CCN1CCC(n2nc(C(F)(F)F)cc2C(=O)O)CC1)C(=O)OC(C)(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccc(N)c(NC(=O)c2cc(C(F)(F)F)nn2C2CCN(CCN(C)C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.5 %

Procedure:
To a stirred solution of 96 (160 mg, 0.381 mmol) in DMF (1.903 mL) was added EDC (88 mg, 0.457 mmol), HOBT (69.9 mg, 0.457 mmol) followed by 4-Methoxy-o-phenylenediamine dihydrochloride (73.1 mg, 0.419 mmol). The mixture was stirred for 16 h at room temperature. After the usual work-up, the residue was purified via Biotage (5% to 15% MeOH/CH2Cl2; 12M column) to afford 106 (172 mg, 84% yield) as yellow oil. LRMS (ESI): calc. 540.6; found 541.4 (MH)+.