Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[N:7]([C:15]1[S:16][C:17]([CH:21](O)[C:22]2[C:30]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[N:24]([Si](C(C)C)(C(C)C)C(C)C)[CH:23]=2)=[C:18]([Cl:20])[N:19]=1)[CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[C:1]([O:5][C:6](=[O:42])[N:7]([C:15]1[S:16][C:17]([CH2:21][C:22]2[C:30]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)=[C:18]([Cl:20])[N:19]=1)[CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2sc(N(Cc3ccncc3)C(=O)OC(C)(C)C)nc2Cl)c2cccnc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(Cc1ccncc1)c1nc(Cl)c(Cc2c[nH]c3ncccc23)s1
Temperature: 40 °C
Reaction time: 2 h
Yield: 48.5 %

Procedure:
A mixture of {4-chloro-5-[hydroxy-(1-triisopropylsilanyl-1H-pyrrolo[2, 3-1)]pyridin-3-yl)-methyl]-thiazol-2-yl}-pyridin-4-ylmethyl-carbamic acid tert-butyl ester (519, 0.397 g, 0.57 mmol), triethylsilane (1.0 mL, 6.3 mmol), and trifluoroacetic acid (0.5 mL, 6 mmol) in acetonitrile (10 mL) was stirred at 40° C. for 2 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with sodium bicarbonate, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with methanol in dichloromethane to provide the desired compound as a yellow solid (520, 126 mg, 49%). MS (ESI) [M+H+]+=456.2.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1.[CH2:20]([NH2:23])[CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:17][C:16]([F:19])([F:18])[S:13]([C:10]1[CH:11]=[CH:12][C:6]2[CH2:5][O:4][CH:3]([CH2:2][NH:23][CH2:20][CH2:21][CH3:22])[O:8][C:7]=2[CH:9]=1)(=[O:15])=[O:14]
Reactant: O=S(=O)(c1ccc2c(c1)OC(CBr)OC2)C(F)(F)F
Reactant: CCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCNCC1OCc2ccc(S(=O)(=O)C(F)(F)F)cc2O1
Yield: 58.5 %

Procedure:
2-(bromomethyl)-7-[(trifluoromethyl)sulfonyl]-4H-1,3-benzodioxine (1.0 g, 2.77 mmol), propan-1-amine (2.27 ml, 27.7 mmol), potassiumcarbonate (0.57 g, 4.15 mmol) and ACN were heated at 60° C. for 16 h. The volatiles were evaporated and the crude product was purified by flash column chromatography using EtOAc/MeOH (10:1) as eluent, to afford the title product (0.55 g, 58%). The amine (0.30 g) was converted into the hydrochloric acid salt and crystallized from EtOH/DEE. M.p. 201° C. MS m/z (rel. intensity, 70 eV) 339 (M+, 5), 310 (22), 239 (18), 222 (8), 72 (bp).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[C:27]5[CH:28]=[CH:29][CH:30]=[C:21]([C:22]=45)[S:20]3(=[O:32])=[O:31])[CH2:14][CH:15]=2)=[CH:2]1.[H-].[Na+].[CH3:35]I>CN(C)C=O.O1CCOCC1.O>[CH3:35][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[C:27]5[CH:28]=[CH:29][CH:30]=[C:21]([C:22]=45)[S:20]3(=[O:32])=[O:31])[CH2:12][CH:11]=2)=[CH:2]1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CC=C(c2c[nH]c3ccccc23)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(C2=CCN(CCCN3c4cccc5cccc(c45)S3(=O)=O)CC2)c2ccccc21
Temperature: 20 °C
Reaction time: 2 h
Yield: 29.1 %

Procedure:
A mixture of 2-{3-[4-(3-indolyl)-1,2,3,6-tetrahydro-1-pyridyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (11 g) in dimethylformamide (150 cc) is added over 30 minutes to sodium hydride (1.3 g) in a 50% dispersion in vaseline oil, under a current of argon, maintaining the temperature at about 20° C. The reaction medium is stirred for 2 hours at a temperature of about 20° C., then a solution of methyl iodide (3.9 g) in dioxane (50 cc) is added over 15 minutes. Stirring is maintained for 15 hours at a temperature of about 20° C. The reaction mixture is redissolved in distilled water (250 cc) and the organic phase is extracted with dichloromethane (4×100 cc) and then washed with distilled water (400 cc), dried over anhydrous magnesium sulphate, filtered and concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue obtained is purified by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with dichloromethane as eluant, and recrystallized from boiling methyl ethyl ketone (70 cc). 2-{3-[4-(1-Methyl-3-indolyl)-1,2,3,6-tetrahydro-1-pyridyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (3.3 g) is obtained, m.p. 161° C.
Reaction SMILES: C[O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[C:5]([C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11])=[O:6].[Cl-].[NH+]1C=CC=CC=1>>[OH:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[C:5]([C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11])=[O:6]
Reactant: COc1ccccc1C(=O)c1cccc(C#N)c1
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Product: N#Cc1cccc(C(=O)c2ccccc2O)c1
Temperature: 180 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
A mixture of 16 g (0.0675 mol) of 3-(2-methoxybenzoyl)benzonitrile and 50 g (0.43 mol) of pyridinium chloride is heated at 180° C. for 12 hours and the reaction mixture is then cooled to 140° C. and hydrolyzed with an ice/concentrated hydrochloric acid mixture. After stirring for 15 minutes, the expected product is extracted with ethyl acetate. The organic phase obtained is washed with water and then brine (saturated aqueous solution of NaCl) until the pH is neutral, dried over magnesium sulfate and then evaporated under reduced pressure. The resulting oil is purified on silica using a toluene/ethyl acetate mixture as the eluent. After evaporation of the solvents from the eluate, 8.5 g of a yellow solid are obtained (yield: 60%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH:25]([C:28]([O:30]CC)=[O:29])[CH2:24][CH2:23]4)=[O:21])=[CH:14][C:13]=3[C:33]([F:36])([F:35])[F:34])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[Na+].CCO>O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:23][CH2:24][CH:25]([C:28]([OH:30])=[O:29])[CH2:26][CH2:27]4)=[O:21])=[CH:14][C:13]=3[C:33]([F:35])([F:34])[F:36])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1CCN(C(=O)/C=C/c2ccc(Sc3ccc4c(c3)OCCO4)c(C(F)(F)F)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1CCN(C(=O)/C=C/c2ccc(Sc3ccc4c(c3)OCCO4)c(C(F)(F)F)c2)CC1

Procedure:
The title compound was prepared by hydrolysis of the compound of Example 252 under basic conditions (aq. NaOH/EtOH), giving a white solid, mp 88° C. (dec.). 1H NMR (DMSO-d6, 300 MHz) δ 1.40 (m, 2H), 1.98 (m, 2H), 2.95 (m, 1H), 3.15 (m, 1H), 3.45 (m, 1H), 4.20 (m, 2H), 4.35 (m, 4H), 7.00 (m, 4H), 7.20 (m, 2H), 7.90 (m, 1H), 8.20 (m, 1H), 12.30 (s, 1H). MS (APCI) m/z 494 (M+H)+. Anal. calcd. for C24H22F3NO5S.0.1 H2O: C, 58.20; H, 4.52; N, 2.83. Found: C, 58.14; H, 4.69; N, 2.76.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Br:7][C:8]1[CH:9]=[N:10]C(C(O)=O)=[N:12][CH:13]=1.CN(C)C=O>ClCCl.CN(C)C=O.CO>[Br:7][C:8]1[CH:13]=[N:12][C:1]([C:2]([Cl:4])=[O:3])=[N:10][CH:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ncc(Br)cn1
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(Cl)c1ncc(Br)cn1
Yield: 99.4 %

Procedure:
Oxalyl chloride (47.4 g, 369 mmol) was added to a suspension of 5-Bromo-pyrimidine-2-carboxylic acid (50 g, 250 mmol) in dichloromethane (821 ml) at room temperature followed by 1-2 drop of dimethylformamide. The reaction mixture was stirred under nitrogen for 2 hours LCMS in methanol indicated the presence of the methyl ester and some acid. Dimethylformamide (0.2 ml) was added to the reaction mixture. The acid dissolved after 30 minutes. LCMS showed corresponding methyl ester and no starting material peak was observed. The solvent was removed and dried in vacuo to afford the crude 5-Bromo-pyrimidine-2-carbonyl chloride (55 g, 100%).
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=O.[NH3:24]>CO>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]=1[CH2:11][O:10][C:8]1[CH:9]=[C:5]([C:3]([NH2:24])=[O:2])[NH:6][N:7]=1
Reactant: N
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)n[nH]1
Solvent: CO
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(N)=O)[nH]n1
Yield: 16 %

Procedure:
As described for example 6, 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.32 mmol) was converted, using ammonia in methanol instead of ethanolamine, to the title compound (15 mg, 16%), which was obtained as a white solid. MS: m/e=299.4 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])C.C=C(C)C.C(O)CCCCC.[C:21]1(O)[C:30]2[C:25](=CC=C[CH:29]=2)[CH:24]=[CH:23][CH:22]=1.C(OCCCCCC)(C)(C)C>>[C:6]([O:5][C:1]1[C:3]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:30]=[CH:29][CH:4]=1)([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(C)(C)C
Reactant: Oc1cccc2ccccc12
Agent: C=C(C)C
Agent: CCCCCCOC(C)(C)C
Solvent: CCCCCCO
Product: CC(C)(C)Oc1cccc2ccccc12
Yield: 67 %

Procedure:
The influence on the acid-catalyzed formation of t-butyl ether from isobutene with n-hexanol and 1-naphthol was examined in a competitive reaction. The formation of dimers and oligomers of isobutene as side-products was to be suppressed, and selectivity for one of the two alcohols was to be achieved. While the formation of almost 25% of isobutene dimers, based on the ethers formed, occurs in methyl-free Sn-containing Si glass (3% Sn, 97% Si), no dimer formation can be detected in the product with methyl-containing Sn--Si glass (30% Me--Si, 3% Sn, 67% Si). With methyl-free Al-containing Si glass (3% Al, 97% Si), the formation of isobutene dimers predominates, and the yield is around 67% naphthol t-butyl ether and 37% n-hexyl t-butyl ether. With methyl-containing Al-Si glass (10% Me--Si, 3% Al, 87% Si), only 30% isobutene dimers form, relatively to the ether formation, and the yield of ethers increases to 57% n-hexyl t-butyl ether and 43% naphthol t-butyl ether. This suppression of dimer formation and change of the ether selectivity with increasing methyl content of the glasses is continued in Zr-containing glasses.
Reaction SMILES: Cl[C:2]1[S:6][C:5]([S:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)(=[O:9])=[O:8])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[NH:19]1[CH2:24][CH2:23][CH:22]([C:25]([OH:27])=[O:26])[CH2:21][CH2:20]1.CN1C(=O)CCC1>O>[N+:16]([C:3]1[CH:4]=[C:5]([S:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)(=[O:9])=[O:8])[S:6][C:2]=1[N:19]1[CH2:24][CH2:23][CH:22]([C:25]([OH:27])=[O:26])[CH2:21][CH2:20]1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)N2CCCCC2)sc1Cl
Reactant: O=C(O)C1CCNCC1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(O)C1CCN(c2sc(S(=O)(=O)N3CCCCC3)cc2[N+](=O)[O-])CC1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
The mixture of 310 mg of 1-(5-chloro-4-nitrothiophene-2-sulfonyl)piperidine, 250 mg of piperidine-4-carboxylic acid and 3 ml of NMP is stirred at 85° C. for 1 h, cooled, diluted with 15 ml of water and stirred. The precipitate is filtered off with suction, washed with water and recrystallized from isopropanol/water (4:1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.Cl([O-])(=O)(=O)=O.[Li+].Cl[C:17](=[O:30])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27].O>[N+](C)([O-])=O.[O-]S(C(F)(F)F)(=O)=O.[Sc+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=1[C:17](=[O:30])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]
Reactant: COc1ccc(C)cc1
Reactant: COC(=O)CCCCCCCCC(=O)Cl
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C[N+](=O)[O-]
Solvent: O
Product: COC(=O)CCCCCCCCC(=O)c1cc(C)ccc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
4-Methylanisole (732 mg) was dissolved in nitromethane (30 ml) to prepare a solution. Anhydrous lithium perchlorate (3.8 g), methyl 10-chloro-10-oxodecanoate (2 ml), and scandium triflate (300 mg) were added to the solution, and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give methyl 10-(2-methoxy-5-methylphenyl)-10-oxo-decanoate (1.6 g, yield 83%).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].C(N(CC)CC)C.[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1>C(Cl)Cl.O>[CH2:1]([NH:3][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12]([F:11])=[CH:13][CH:14]=1)[CH3:2]
Reactant: CCN
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCNC(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of ethylamine (69.4 mL, 139 mmol) and triethylamine (21.10 mL, 151 mmol) in DCM (150 mL) was added p-fluorobenzoyl chloride (15.13 mL, 126 mmol) at 0° C. The reaction was stirred at 0° C. for 1 hr and then warmed slowly to room temperature. The reaction mixture was diluted with water. The layers were separated and the organic layer was washed with brine, dried over MgSO4, filtered, and the organic phase stripped to dryness via rotary evaporation. The organic extract was dried in vacuo to provide the title compound as a tan solid (21 g, 100% yield).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[C:7](=[S:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:14]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[C:10]2[O:9][C:8]([CH3:11])([CH3:12])[C:7](=[S:13])[C:6]=2[C:5]([Cl:14])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC1(C)Oc2c(N)cccc2C1=S
Solvent: CN(C)C=O
Product: CC1(C)Oc2c(N)ccc(Cl)c2C1=S

Procedure:
By the method of Example 3, Step C, 2.51 g (0.013 mole) of 7-amino-2,3-dihydro-2,2-dimethylbenzofuran-3-thione is reacted with 1.74 g (0.013 mole) of N-chlorosuccinimide in 35 mL of N,N-dimethylformamide, yielding 7-amino-4-chloro-2,3-dihydro-2,2-dimethylbenzofuran-3-thione.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:25]([CH:36]([CH3:38])[CH3:37])=[CH:24][C:10]=1[C:11]([N:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH:22]=O)[CH:19]=2)[CH2:14]1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:27]=[C:26]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:25]([CH:36]([CH3:38])[CH3:37])=[CH:24][C:10]=1[C:11]([N:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:22][N:43]3[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]3)[CH:19]=2)[CH2:14]1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1cc(C(=O)N2Cc3ccc(C=O)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)c1cc(C(=O)N2Cc3ccc(CN4CCN(C)CC4)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 5 h
Yield: 86.1 %

Procedure:
To a solution of 2-(2,4-bis-benzyloxy-5-isopropyl-benzoyl)-2,3-dihydro-1H-isoindole-5-carbaldehyde (0.316 g, 0.63 mmol) and n-methyl piperazine (63 mg, 0.63 mmol) in CH2Cl2 (10 ml) was added AcOH (38 mgs 0.63 mmol) and NaBH(OAc)3 (0.28 g, 1.33 mmol), then stirred at ambient for 5 hours. The reaction was quenched with water, layers separated and aqueous washed CH2Cl2. The organics were combined, washed with brine, dried (MgSO4), filtered and evaporated to give 0.32 g of (2,4-bis-benzyloxy-5-isopropyl-phenyl)-[5-(4-methyl-piperazin-1-ylmethyl)-1,3-dihydro-isoindol-2-yl]-methanone. MS: [M+H]+ 588.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:13]=[C:12]([O:14][CH:15]([F:17])[F:16])[N:11]([CH3:18])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(Cl)Cl.F[B-](F)(F)F.[O:27]=[N+:28]=[O:29]>C(OCC)(=O)C>[F:1][C:2]1[C:3]([C:9]2[C:13]([N+:28]([O-:29])=[O:27])=[C:12]([O:14][CH:15]([F:16])[F:17])[N:11]([CH3:18])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cn1nc(-c2ncc(Cl)cc2F)cc1OC(F)F
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cn1nc(-c2ncc(Cl)cc2F)c([N+](=O)[O-])c1OC(F)F
Reaction time: 8 h
Yield: 93.6 %

Procedure:
4.0 g of 3-(3-fluoro-5chloro-2-pyridyl)-5-difluoromethoxy-1-methyl-[1H]-pyrazole (Example HIS) are initially introduced into 30 ml of methylene chloride. 3.83 g of nitronium tetrafluoroborate are added, while stirring and cooling in an ice-bath, and the mixture is subsequently stirred overnight at 22° C. The following day, it is poured onto water, and ethyl acetate is added. After extraction by shaking and separation of the phases, the organic phase is washed with dilute bicarbonate solution and brine, dried over sodium sulfate, filtered and concentrated in vacuo. 4.35 g of the desired title compound are obtained as a brown solid of melting point 108-109° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19]S(C)(=O)=O)[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[N:11][C:10]([CH3:13])=[N:9]1.[N-:25]=[N+:26]=[N-:27].[Na+].O>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][CH:17]([CH2:19][N:25]=[N+:26]=[N-:27])[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[N:11][C:10]([CH3:13])=[N:9]1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ncn(-c2ccc(N3C[C@H](CS(C)(=O)=O)OC3=O)cc2F)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncn(-c2ccc(N3CC(CN=[N+]=[N-])OC3=O)cc2F)n1
Yield: 79.3 %

Procedure:
(5R)-3-[3-Fluoro-4-(3-methyl-1,2,4-triazol-1-yl)phenyl]-5-[(methanesulfonyl)methyl]-oxazolidin-2-one (Intermediate 24a) (5.432 g, 14.7 mmol), sodium azide (1.092 g, 16.6 mmol), and 18-crown-6 (0.069 g, 0.26 mmol) in dimethylformamide (15 mL) were heated to 90° C. for 3.75 hours. The reaction mixture was poured into water (200 ml) and extracted with dichloromethane (3×100 ml). The combined organic layers were washed once with brine, dried over MgSO4 and concentrated under vacuum. Chromatography on silica gel with 5% methanol in dichloromethane gave the title compound (3.7 g) as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=[O:19])[CH2:9]1.ClC1C=CC=C(C(OO)=[O:28])C=1.C(=O)([O-])O.[Na+].N([O-])=O.[Na+]>C1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N+:15]([O-:28])=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=[O:19])[CH2:9]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccnc2c1C(=O)CC(c1ccccc1Cl)C2
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: Cc1cc[n+]([O-])c2c1C(=O)CC(c1ccccc1Cl)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
In benzene (4 ml) was dissolved 7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (272 mg), and to the solution was added m-chloroperbenzoic acid (267 mg). The mixture was stirred at room temperature for 1 hour, and to the mixture were added ethyl acetate (70 ml), saturated sodium hydrogen carbonate solution (30 ml) and sodium nitrite (100 mg). The mixture was shaken, and the separated upper layer was washed with water and concentrated under reduced pressure. The residue was washed with ethyl acetate and dried to give 7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one-1-oxide (205 mg) as pale yellow crystals.
Reaction SMILES: C(O)(=O)C.N1C=[CH:9][CH:8]=[CH:7][CH:6]=1.[ClH:11].Cl.[NH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[C:25](=[O:26])[C:24]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[CH:23][NH:22]2)=[N:19][CH:20]=1.COC1CCC(OC)O1>O>[ClH:11].[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:24]2[C:25](=[O:26])[N:21]([C:18]3[CH:17]=[CH:16][C:15]([CH2:14][N:13]4[CH:9]=[CH:8][CH:7]=[CH:6]4)=[CH:20][N:19]=3)[NH:22][CH:23]=2)[CH:28]=1
Reactant: c1ccncc1
Reactant: NCc1ccc(-n2[nH]cc(-c3cccnc3)c2=O)nc1
Agent: COC1CCC(OC)O1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=c1c(-c2cccnc2)c[nH]n1-c1ccc(Cn2cccc2)cn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
565 mg (9.4 mmol) of acetic acid are initially charged in 0.3 ml of water. 744 mg (9.4 mmol) of pyridine are added slowly. 191 mg (0.6 mmol) of the compound from Example 13 and 74 mg (0.6 mmol) of 2,5-dimethoxytetrahydrofuran are then added, and the mixture is stirred at 100° C. for 16 h. The mixture is then concentrated on a rotary evaporator, 3 ml of acetonitrile and 3 ml of 1 N hydrochloric acid are added and the mixture is stirred at RT for 30 min. The solid formed is filtered off, washed once with water and dried under high vacuum.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:17]([NH2:20])[CH2:18][CH3:19]>C(Cl)Cl>[CH2:17]([NH:20][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:18][CH3:19]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of benzoyl chloride (116 μL, 1 mmol) in 1 mL of dry CH2Cl2 was treated successively at 0° C. with triethylamine (167 μL, 1.2 mmol) and n-propylamine (124 μL, 1.5 mmol). The reaction was stirred at room temperature for two hours. The resulting reaction mixture was diluted with CH2Cl2 washed with 2M HCl, followed by saturated NaHCO3, then brine. The resulting solution was then dried over MgSO4. The residue was purified using SiO2 with CH2Cl2/Petroluem ether 95:5 to CH2Cl2 100%. A white solid was obtained (166 mg, quantitative yield). NMR 1H (ppm, CDCl3): 7.74 (d, J3=8.1 Hz, 2H), 7.41 (t. t., J3=7.2 Hz, J4=1.3 Hz, 1H), 7.33 (t. t., J3=7.6 Hz, J4=1.6 Hz, 2H), 5.23 (br. s., 1H), 3.36-3.30 (m, 2H), 1.57 (sext., J3=7.2 Hz, 2H), 0.90 (t, J3=7.4 Hz, 3H).
Reaction SMILES: B([C:4]1[C:12]2[S:11][C:10]([NH:13][C:14](=[O:18])[NH:15][CH2:16][CH3:17])=[N:9][C:8]=2[CH:7]=[C:6]([C:19]2[CH:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][C:28]([CH2:34][CH3:35])([C:31]([OH:33])=[O:32])[CH2:27][CH2:26]3)=[N:23][CH:24]=2)[CH:5]=1)(O)O.C(N(CC)CC)C.[NH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:34]([C:28]1([C:31]([OH:33])=[O:32])[CH2:29][CH2:30][N:25]([C:22]2[N:21]=[CH:20][C:19]([C:6]3[CH:5]=[C:4]([N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)[C:12]4[S:11][C:10]([NH:13][C:14](=[O:18])[NH:15][CH2:16][CH3:17])=[N:9][C:8]=4[CH:7]=3)=[CH:24][N:23]=2)[CH2:26][CH2:27]1)[CH3:35]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(CC)(C(=O)O)CC4)nc3)cc(B(O)O)c2s1
Reactant: C1COCCN1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(CC)(C(=O)O)CC4)nc3)cc(N3CCOCC3)c2s1
Temperature: 25 °C

Procedure:
1-[5-[7-borono-2-(ethylcarbamoylamino)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-ethyl-piperidine-4-carboxylic acid (100 mg) was placed in DCM 5 ml and copper acetate 47 mg, triethylamine 122 mg, 4A molecular sieves (powdered) and morpholine 17 mg were added and the mixture stirred at rt over the weekend. LCMS showed that some desired product had formed and a close running 7-H impurity. The mixture was filtered and the solvent removed in vacuo to give a dark gum which was purified by preparative HPLC using a phenyl hexyl column eluting with 65-75% ACN to give Compound 114 as an off white solid (8 mg). 1H NMR (CDCl3) δ 8.52 (s, 2H), 7.38 (s, 1H), 6.84 (s, 1H), 4.50-4.42 (m, 2H), 3.89-3.85 (m, 4H), 3.35-3.29 (m, 4H), 3.21-3.17 (m, 4H), 2.22-2.14 (m, 2H), 1.61-1.54 (m, 2H), 1.45-1.35 (m, 2H), 1.19 (t, J=7.2 Hz, 3H), 0.86 (t, J=7.5 Hz, 3H). MS: 540.13 [M+H]+.