Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([OH:20])[C:5]=1[O:21][CH3:22])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=1>C(#N)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([O:20][CH2:30][C:31]2[CH:32]=[CH:33][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:35][CH:36]=2)[C:5]=1[O:21][CH3:22])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: CCOc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1ccc(-c2ccc3c(c2)COC3=O)c(OCc2ccc(S(C)(=O)=O)cc2)c1OC
Temperature: 80 °C
Yield: 16 %

Procedure:
To a stirring solution of 5-(4-ethoxy-2-hydroxy-3-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.266 mmol) in acetonitrile (7 mL) was added potassium carbonate (110 mg, 0.80 mmol) and 1-(bromomethyl)-4-(methylsulfonyl)benzene (99 mg, 0.399 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 0-40% ethyl acetate in pet ether) afforded title compound as a solid (20 mg, 16%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16](Br)[CH:17]=2)[O:9][N:8]=1.[N:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[N:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([C:23]3[CH:24]=[N:19][CH:20]=[N:21][CH:22]=3)[CH:17]=2)[O:9][N:8]=1
Reactant: Brc1cncc(-c2nc(-c3ccccn3)no2)c1
Reactant: OB(O)c1cncnc1
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: COCCOC
Product: c1ccc(-c2noc(-c3cncc(-c4cncnc4)c3)n2)nc1
Yield: 7.6 %

Procedure:
In a similar fashion, 3-(2-pyridyl)-5-(5-bromo-pyrid-3-yl)-1,2,4-oxadiazole (42 mg, 0.1385 mmole), 5-pyrimidylboronic acid (26.6 mg,0.208 mmole) and Pd(PPh3)4 (23.99 mg, 0.021 mmole) in a solution of 2M sodium carbonate (1.5 mL) and ethylene glycol dimethyl ether (1.5 mL) was heated overnight at 105° C. Standard workup afforded 3.2 mg (8%) of 3-(2-pyridyl)-5-[5-(5-pyrimidyl)-pyrid-3-yl ]-1,2,4-oxadiazole (3.2 mg, 7.6%).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13]([O-:17])(=[O:16])(=[O:15])=[O:14].CS[C:20]1[S:24][CH:23]=[CH:22][S+:21]=1>>[Cl:13]([O-:17])(=[O:16])(=[O:15])=[O:14].[S:21]1[CH:22]=[CH:23][S:24][C:20]1=[N+:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1
Reactant: CSc1scc[s+]1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: c1ccc(N2CC[N+](=c3sccs3)CC2)cc1
Yield: 74 %

Procedure:
2.0 g of N-phenylpiperazine and 2.5 g of 2-methylthio-1,3-dithiolium perchlorate were treated in the same manner as in Example 26, and the product was recrystallized from acetone-ethyl ether, whereby 2.7 g (yield: 74.3%) of 1-(1,3-dithiol-2-ylidene)-4-phenylpiperazinium perchlorate (Compound No. 32) was obtained as crystals having a melting point of from 197° to 199° C.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]([C:7]1[CH:16]=[CH:15][C:10]2[S:11][C:12]([CH3:14])=[CH:13][C:9]=2[CH:8]=1)=[O:6].C([O-])(=O)C.[Na+]>C(Cl)(Cl)Cl>[CH3:3][O:4][C:5]([C:7]1[CH:16]=[CH:15][C:10]2[S:11][C:12]([CH3:14])=[C:13]([Br:1])[C:9]=2[CH:8]=1)=[O:6]
Reactant: COC(=O)c1ccc2sc(C)cc2c1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc2sc(C)c(Br)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.3 %

Procedure:
Bromine (2.08 g) was added dropwise to a stirred mixture of 2-methylbenzo[b]thiophene-5-carboxylic acid methyl ester (2.40 g) and anhydrous sodium acetate (2.40 g) in chloroform (50 ml). The mixture was stirred for 2 hours at room temperature and then washed with water, sodium bicarbonate solution and dried (NaSO4). Evaporation of the chloroform gave a solid which was crystallised from methanol/water to give 3-bromo-2-methylbenzo[b]thiophene-5-carboxylic acid methyl ester (2.00 g), m.p. 84°-85°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Br[CH2:10][CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:10][CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]
Reactant: CCOC(CBr)OCC
Reactant: Sc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(CSc1ccccc1Cl)OCC
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution of 2-chlorobenzenethiol (5.0 g, 34.5 mmol) in acetone (35 mL) was added 2-bromo-1,1-diethoxyethane (7.15 g, 36.3 mmol) followed by potassium carbonate (9.55 g, 69.1 mmol). The mixture was heated at reflux for 3 h. then cooled to rt, filtered and the filtrate evaporated under reduced pressure to yield the crude product. This material was purified by chromatography over silica gel eluting with ethyl acetate in hexanes (0→2%) to afford pure 1-chloro-2-(2,2-diethoxyethylsulfanyl)benzene (7.3, 80%). 1H NMR (400 MHz, CDCl3) δ=1.20 (t, J=7.07 Hz, 6H), 3.15 (d, J=5.56 Hz, 2H), 3.51-3.61 (m, 2H), 3.63-3.74 (m, 2H), 4.69 (t, J=5.56 Hz, 1H), 7.12 (td, J=7.58, 1.52 Hz, 1H), 7.20 (td, J=7.58, 1.52 Hz, 1H), 7.36 (dd, J=7.83, 1.52 Hz, 1H), 7.39 (dd, J=8.08, 1.52 Hz, 1H); MS (ES+): m/z 187.17 [M-74].
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13]([N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[S:16]([N:19]2[CH2:22][CH2:21][CH2:20]2)(=[O:18])=[O:17])[CH:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:32][C@@H:33]([CH2:35][OH:36])[CH3:34]>>[CH2:1]([S:8][C:9]1[N:14]=[C:13]([N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[S:16]([N:19]2[CH2:22][CH2:21][CH2:20]2)(=[O:18])=[O:17])[CH:12]=[C:11]([NH:32][C@H:33]([CH3:34])[CH2:35][OH:36])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCN(c1cc(Cl)nc(SCc2ccccc2)n1)S(=O)(=O)N1CCC1
Reactant: C[C@@H](N)CO
Product: C[C@H](CO)Nc1cc(N(COCC[Si](C)(C)C)S(=O)(=O)N2CCC2)nc(SCc2ccccc2)n1

Procedure:
The subtitle compound was prepared as a yellow oil by the method of Example 32 step ii) by reacting the subtitle product of step ii) (12.2 g) with (R)-alaninol (18 ml). Yield: 11.3 g.
Reaction SMILES: [Cl:1][C:2]([Cl:11])=[CH:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[Cl:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH:21]=[C:22]([Cl:24])[Cl:23])[CH:16]=[C:15]([Cl:25])[C:14]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH:21]=[C:22]([Cl:24])[Cl:23])[CH:16]=[C:15]([Cl:25])[C:14]=1[O:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][CH:3]=[C:2]([Cl:11])[Cl:1]
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: OCCCCOCC=C(Cl)Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ClC(Cl)=CCOCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Yield: 48.5 %

Procedure:
To a mixture of 0.30 g of 4-(3,3-dichloro-2-propenyloxy)butanol, 0.43 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 0.39 g of triphenylphosphine and 15 ml of tetrahydrofuran was slowly added dropwise 0.30 g of diisopropyl azodicarboxylate with stirring under ice cooling. After stirring at room temperature for 24 hours, the reaction mixture was concentrated. The residue was subjected to silica gel chromatography, which afforded 0.34 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-(3,3-dichloro-2-propenyloxy)butyloxy)benzene (yield, 73%), nD24.5 1.5519.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][CH:9]([N:12]3[CH2:17][CH2:16][CH2:15][C@H:14]([NH:18][S:19]([C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[C:27]([Cl:32])[CH:28]=5)[CH:23]=4)(=[O:21])=[O:20])[C:13]3=[O:33])[CH2:8][CH2:7]2)[CH2:5]CC[CH2:2]1.Br[CH2:35][C:36]([O:38][CH3:39])=[O:37].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:39][O:38][C:36](=[O:37])[CH2:35][N:18]([S:19]([C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([Cl:32])[CH:28]=2)[CH:23]=1)(=[O:21])=[O:20])[C@H:14]1[CH2:15][CH2:16][CH2:17][N:12]([CH:9]2[CH2:10][CH2:11][N:6]([CH:1]([CH3:2])[CH3:5])[CH2:7][CH2:8]2)[C:13]1=[O:33]
Reactant: COC(=O)CBr
Reactant: O=C1[C@@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCCN1C1CCN(C2CCCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CN([C@H]1CCCN(C2CCN(C(C)C)CC2)C1=O)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a mixture of the product obtained from Example 1, step d (69 mg, 0.13 mmol) in DMF (2.0 mL) at 0° C. were added methyl bromoacetate (0.05 mL) and potassium carbonate (50 mg). After stirring at 0° C. for 2 hr, the solid was filtered out, and the solvent was removed. HPLC purification (50% to 100% acetonitrile/water) gave the desired product as a solid. LC-MS found: (M+1)+=594.30.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:30][CH:29]=3)=[CH:24][N:23]=2)=[CH:18][CH:17]=1)[C:3]([NH:5][C@@H:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH3:7])=[O:4].[C:42]([C:46]1[S:50][C:49]([C:51](O)=[O:52])=[CH:48][CH:47]=1)([CH3:45])([CH3:44])[CH3:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[C:42]([C:46]1[S:50][C:49]([C:51]([NH:1][C@@H:2]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:30][CH:29]=4)=[CH:24][N:23]=3)=[CH:18][CH:17]=2)[C:3]([NH:5][C@@H:6]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH3:7])=[O:4])=[O:52])=[CH:48][CH:47]=1)([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)c1ccc(C(=O)O)s1
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](N)C(=O)N[C@H](C)C(=O)OC(C)(C)C)cc3)nc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)s4)C(=O)N[C@H](C)C(=O)OC(C)(C)C)cc3)nc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
Prepared using General Procedure 7. To a stirred solution of tert-butyl ((S)-2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate (418 mg, 0.75 mmol), 5-(tert-butyl)thiophene-2-carboxylic acid (137 mg, 0.75 mmol) in DMF (8 mL) was added TEA (208 μl, 1.49 mmol). The mixture was cooled to 0° C. and HATU (298 mg, 0.78 mmol) was added in 2 portions over 5 mins. The mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with EA (150 mL) and washed with saturated aqueous NaHCO3 (100 mL), 1N HCl (100 mL), and brine (100 mL). The organic layer was dried over MgSO4 then concentrated. The crude product was purified by chromatography 0-30% ACN in DCM to afford 382 mg (69%) of tert-butyl ((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate as a white solid. LCMS-ESI (m/z) calculated for C42H54N4O5S: 726.4; no m/z observed, tR=3.47 min (Method 11).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([CH2:12][CH2:13][C:14](Cl)=[O:15])([O:10][CH3:11])=[O:9].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:14](=[O:15])[CH2:13][CH2:12][C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)CCC(=O)Cl
Reactant: Brc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CCC(=O)c1ccc(Br)cc1

Procedure:
In a manner similar to Example 2, Step (a), bromobenzene (10.0 mL, 0.0950 mol) was allowed to react with 3-carbomethoxypropionyl chloride (12.9 mL, 0.105 mol) in the presence of aluminum chloride (26.9 g, 0.202 mol) in dichloromethane to give, after chromatography on silica gel (435 g, 230-400 mesh), eluting with hexanes-acetone (9:1, 10×400 mL; 8:1, 7×400 mL), 21.2 g of 4-(4-bromo-phenyl)-4-oxo-butyric acid, methyl ester as an off-white solid; mp 49-51° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:34])=[C:21]([NH:25][S:26]([C:29]3[CH:33]=[CH:32][O:31][CH:30]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH2:35]([N:37]([CH2:41][CH3:42])[CH2:38][CH2:39][NH2:40])[CH3:36]>O1CCOCC1>[CH2:35]([N:37]([CH2:41][CH3:42])[CH2:38][CH2:39][NH:40][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:34])=[C:21]([NH:25][S:26]([C:29]3[CH:33]=[CH:32][O:31][CH:30]=3)(=[O:27])=[O:28])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1)[CH3:36]
Reactant: CCN(CC)CCN
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1ccoc1
Solvent: C1COCCO1
Product: CCN(CC)CCNc1nccc(-c2sc(C3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3ccoc3)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in example 300 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide (110 mg, 0.211 mmol), N,N-diethyl-1,2-ethanediamine (123 mg, 1.056 mmol) in 1,4-dioxane (2 mL), the title compound was obtained as a yellow foam (30 mg, 22.47%). 1H NMR (400 MHz, DMSO-d6) ppm 1.01 (t, J=6.44 Hz, 6H), 1.65-1.83 (m, 2H), 2.01 (dd, J=12.76, 1.89 Hz, 2H), 2.58-2.73 (m, 6H), 3.27-3.41 (m, 5H), 3.42-3.58 (m, 2H), 3.93 (dt, J=9.54, 2.18 Hz, 2H), 5.78-6.17 (m, 1H), 6.60 (d, J=1.26 Hz, 1H), 6.97-7.28 (m, 3H), 7.43 (td, J=7.77, 1.64 Hz, 1H), 7.75 (s, 1H), 7.96-8.30 (m, 2H); MS (ESI): 601.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N+:3]=1[O-:12].CC(C)([O-])C.[K+].[F:19][C:20]([F:26])([CH:23]([F:25])[F:24])[CH2:21][OH:22]>O>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:22][CH2:21][C:20]([F:26])([F:19])[CH:23]([F:25])[F:24])[CH:5]=[CH:4][N+:3]=1[O-:12]
Reactant: Cc1c([N+](=O)[O-])cc[n+]([O-])c1C
Reactant: OCC(F)(F)C(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: Cc1c(OCC(F)(F)C(F)F)cc[n+]([O-])c1C

Procedure:
In 2,2,3,3-tetrafluoropropanol (10 ml) was dissolved 2,3-dimethyl-4-nitropyridine-1-oxide (2 g). To the solution was added potassium t-butoxide (1.6 g) little by little at room temperature. The mixture was then heated at 80°-90° C. for 22 hours. The reaction solution was diluted with water, which was subjected to extraction with chloroform. The extract was dried on magnesium sulfate, and then concentrated. The concentrate was chromatographed on a column of silica gel (70 g). Elution was conducted with methanol-chloroform (1:10), and then subjected to recrystallization from ethyl acetate-hexane to yield 2.6 g of 2,3-dimethyl-4-(2,2,3,3-tetrafluoropropoxy)pyridine-1-oxide as colorless needles, m.p. 138°-139° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[N:25][C:24]=1[CH2:29][C:30](O)=[O:31]>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[C:30](=[O:31])[CH2:29][C:24]3[N:25]=[CH:26][CH:27]=[CH:28][N:23]=3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Reactant: O=C(O)Cc1ncccn1
Agent: Cl
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCCN3C(=O)Cc3ncccn3)c21

Procedure:
Prepared as in Example 15 from (R)-2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 15a) and 2-(pyrimidin-2-yl)acetic acid (Example 31a) (36% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.25 (m, 1H), 1.47-1.67 (m, 4H), 1.76 (m, 1H), 3.16 (t, 1H, J=12.6 Hz), 2.77-4.20 (m, 3H), 4.27-4.72 (m, 2H), 5.13 (m, 1H), 6.57 (d, 1H, J=8.2 Hz), 6.78 (br d, 1H, J=7.6 Hz), 7.35 (t, 1H, J=5.0 Hz), 7.40 (br t, 1H, J=8.2 Hz), 7.71 (br s, 1H), 7.91 (br s, 1H), 8.71 (m, 2H), 10.90 (br s, 1H). MS 431 (MH+).
Reaction SMILES: [CH3:1][C@H:2]([CH2:7][S:8][CH3:9])[C@@H:3]([OH:6])[CH2:4][OH:5].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1.CCOCC>[C:10]([O:5][CH2:4][C@H:3]([OH:6])[C@@H:2]([CH3:1])[CH2:7][S:8][CH3:9])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CSC[C@@H](C)[C@@H](O)CO
Solvent: CCOCC
Solvent: c1ccncc1
Product: CSC[C@H](C)[C@@H](O)COC(=O)c1ccccc1
Reaction time: 0.08 h

Procedure:
To a stirred, ice-cooled solution of (B) (3.7g.,0.025m.) in dried pyridine (30 ml.) was added dropwise over ca. 5 minutes under a nitrogen atmosphere a solution of benzoyl chloride (3.0 ml., 0.026m.) in dry ether (5 ml.). The mixture was stirred for an additional 5 minutes, the ice-bath removed, and the mixture allowed to stir at ambient temperatures. After ca.1.5 hr., tlc analysis indicated that the reaction was complete and the mixture was transferred to a separatory funnel with ether (300 ml.). The mixture was washed IX with water (100 ml.), 4 X with saturated copper sulfate solution, lX with saturated sodium chloride solution and dried over sodium sulfate. Concentration of the filtered solution followed by chromatography on silica gel (200g.; 1% methanol/methylene chloride as eluant) yielded 5.4g (C) as an oil. N.m.r. was consistent with the structure [α]D =30 9.1 (c=0.75, CDCl3).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:24]([Cl:25])=[CH:23][C:9]2[N:10]=[C:11]([NH:13][C:14]3[CH:19]=[C:18]([CH2:20][NH2:21])[CH:17]=[CH:16][C:15]=3[Cl:22])[NH:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[C:26](Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:24]([Cl:25])=[CH:23][C:9]2[N:10]=[C:11]([NH:13][C:14]3[CH:19]=[C:18]([CH2:20][NH:21][C:26]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:31])[CH:17]=[CH:16][C:15]=3[Cl:22])[NH:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2[nH]c(Nc3cc(CN)ccc3Cl)nc2cc1Cl
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2[nH]c(Nc3cc(CNC(=O)C(C)(C)C)ccc3Cl)nc2cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of Ethyl-2-[5-(aminomethyl)-2-chlorophenylamino]-6-chloro-benzimidazole-5-carboxylate (1.00 g, 2.4 mmol), pivaloyl chloride (0.296 ml, 2.4 mmol), 1.5 ml TEA and 50 ml THF were stirred for 18 h at rt. The mixture was concentrated, diluted with EtOAc, washed 2× with H2O, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give the sub-title compound. Yield 0.92 g (83%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:18]=[N:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:5]2=[N:6][C:7]=1[O:8][CH2:9][C:10]1[N:11]([CH3:15])[N:12]=[CH:13][N:14]=1.[CH3:25][Sn](C)(C)C>CN(C)C(=O)C.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.Cl[Pd]Cl>[CH3:25][C:2]1[CH:3]=[C:4]2[CH:18]=[N:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:5]2=[N:6][C:7]=1[O:8][CH2:9][C:10]1[N:11]([CH3:15])[N:12]=[CH:13][N:14]=1
Reactant: Cn1ncnc1COc1nc2c(cnn2-c2ccccc2)cc1Br
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd]Cl
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC(=O)N(C)C
Product: Cc1cc2cnn(-c3ccccc3)c2nc1OCc1ncnn1C
Temperature: 90 °C
Yield: 28.4 %

Procedure:
To a de-gassed solution of 5-bromo-6-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-1-phenyl-1H-pyrazolo[3,4-b]pyridine (84 mg, 0.22 mmol) in N,N-dimethylacetamide (2 ml) was added tetramethyltin (60 μl, 0.43 mmol) followed by dichlorobis(tri-ortho-tolylphosphine)palladium(II) (8.6 mg, 0.01 mmol). The reaction mixture was heated at 90° C. in a sealed tube for 20 h. The mixture was allowed to cool, quenched with saturated aqueous ammonium chloride solution and the product extracted into diethyl ether (×3). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by preparative thin layer chromatography, eluting with 55% ethyl acetate-hexane, afforded the title compound as a white solid (20 mg, 29%), m.p. 145-146° C. δH (400 MHz; CDCl3) 2.32 (3H, s), 3.96 (3H, s), 5.66 (2H, s), 7.31 (1H, t, J=7), 7.50-7.54 (2H, m), 7.82 (1H, s), 7.91 (1H, s), 8.02 (1H, s), 8.19-8.22 (2H, m); m/z (ES+) 321 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[O:13])=[C:5]([CH3:14])[CH:4]=1.[Br:15]Br>CO>[Br:15][CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH3:14])[C:10]1=[O:13]
Reactant: BrBr
Reactant: COc1cc(C)c2c(c1)C(=O)CCC2
Solvent: CO
Product: COc1cc(C)c2c(c1)C(=O)C(Br)CC2
Reaction time: 2 h

Procedure:
To the cold (−10° C.) solution of 7-methoxy-5-methyl-3,4-dihydro-2H-naphthalen-1-one (8.3 g, 0.04 mol) in methanol (20 mL), the solution of bromine (2.3 mL, 0.04 mol) in methanol (10 mL) was added dropwise and the mixture was stirred for 2 h while allowing the temperature to rise to room temperature. Methanol was evaporated in vacuo and the mixture was diluted with ethyl acetate and washed with aqueous sodium thiosulphate solution followed by saturated sodium bicarbonate, brine and dried. Evaporation of the solvent gave 2-bromo-7-methoxy-5-methyl-3,4-dihydro-2H-naphthalen-1-one as an off-white solid, 10 g, which was used as such in step 2. MS m/z 271 (M+2).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11][C:12]([OH:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.CI>[CH2:1]([O:8][C:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11][C:12]([O:15][CH3:20])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(O)ccc1OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1nc(OC)ccc1OCc1ccccc1
Yield: 48.3 %

Procedure:
Methyl 3-benzyloxy-6-hydroxy-picolinate (0.55 g) was dissolved in 55 ml of acetone and 20 ml of methyl iodide. Potassium carbonate (1.4 g) was added to the solution, and the mixture was refluxed for 3 hr. After cooling, the reaction solution was neutralized with 1 N hydrochloric acid, and was concentrated under the reduced pressure. Methylene chloride and water were then added to the concentrate to conduct extraction. The organic layer was dried over magnesium sulfate, and the dried organic layer was then concentrated under the reduced pressure. The residue was purified by column chromatography (chloroform-methanol) to give 0.28 g (yield 49%) of the title compound.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CS(C)=O.C(#N)C>[CH2:16]([C:12]1([CH2:12][CH2:13][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CS(C)=O
Product: CCCCCCCC1(CCCCCCC)c2ccccc2-c2ccccc21
Reaction time: 0.08 h

Procedure:
0.2 mol of fluorene is dissolved in 300 ml of DMSO at 80° C. 0.01 mol of phase transfer catalyst (aliquot) is added to the solution which is stirred for a further 5 minutes. For the alkylation, 0.5 mol of 50% sodium hydroxide solution and 0.5 mol of heptyl bromide are required. The addition is effected in three stages, and commences with the addition of one third of the amount of sodium hydroxide solution used. The solution changes color to deep red and slowly becomes yellow by addition of heptyl bromide. When the solution has become yellow, the second third of sodium hydroxide solution is added, etc. The end of the reaction is checked by means of TLC on RP18 in acetonitrile.