Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:11]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: N#Cc1cccc(CBr)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: N#Cc1cccc(Cc2ccccc2)c1
Temperature: 25 °C

Procedure:
A mixture of benzeneboronic acid (2.05 g, 16.8 mmol), 3-bromomethylbenzonitrile (3 g, 15.3 mmol), dichlorobis(triphenylphosphine)palladium(II) (1.07 g, 1.53 mmol), tri-o-tolylphosphine (0.465 g, 29 mmol) and sodium carbonate (3.08 g, 29 mmol) in aqueous acetonitrile (1:10, 220 mL) was refluxed under nitrogen for 2 hours, cooled to room temperature, concentrated under reduced pressure, taken up in dilute hydrochloric acid (2N, 150 mL) and extracted with diethyl ether (3×70 mL). The organic extracts were combined, washed with water (2×100 mL), saturated aqueous sodium bicarbonate (100 mL), brine (70 mL), and dried over magnesium sulfate, then adsorbed on silica and chromatographed on silica using a mobile phase of ethyl acetate/hexane. The major fraction was concentrated under reduced pressure to leave a colorless liquid. Yield 2.1 g (71 percent). 1H NMR (CDCl3) δ 7.49 (dt, J1=7.5 Hz, J2=1.2 Hz, 1H), 7.46 (br, 1H), 7.43 (dt, J1=7.8 Hz, J2=1.8 Hz, 1H), 7.39 (d, J=7.5 Hz, 1H), 7.33 (dt, J1=6.9 Hz, J2=2.1 Hz, 1H), 7.30 (dt, J1=7.2 Hz, J2=1.2 Hz, 1H), 7.25 (dt, J1=7.2 Hz, J2=1.5 Hz, 1H), 7.15 (dt, J1=6.9 Hz, J2=1.8 Hz, 2H), 4.01 (s, 2H); EI/MS 193 m/e (M+); CI/MS 194 m/e (M+1);
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[Br:11]Br.O>C(O)(=O)C>[Br:11][C:8]1[N:6]2[N:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: Fc1ccc2nccn2n1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Fc1ccc2ncc(Br)n2n1
Yield: 27.2 %

Procedure:
To an ambient temperature, stirred solution of 6-fluoro-imidazo[1,2-b]pyridazine (2.1 g, 15.3 mmol) in glacial acetic acid (20 mL) was slowly added bromine (2.5 g, 15.3 mmol). Upon completion of this addition the reaction solution was poured into water and extracted with ethyl acetate. The extract was dried (MgSO4) and flash chromatographed (silica gel, eluted with 30% (v/v) ethyl acetate/hexanes) to provide 0.9 g of 3-bromo-6-fluoro-imidazo[1,2-b]pyridazine. LRMS (ESI) m/z 215.9/217.9 [(M+H)]+, calc'd for C6H3BrFN3: 216.01.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]1[CH:15]=[C:14]([N:16]2[C:20]3[CH:21]=[N:22][C:23]([CH2:25][OH:26])=[CH:24][C:19]=3[N:18]=[CH:17]2)[S:13][C:12]=1[C:27]([NH2:29])=[O:28])[CH3:9].[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C>ClCCl>[CH3:30][S:31]([O:26][CH2:25][C:23]1[N:22]=[CH:21][C:20]2[N:16]([C:14]3[S:13][C:12]([C:27](=[O:28])[NH2:29])=[C:11]([O:10][CH:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[CH3:9])[CH:15]=3)[CH:17]=[N:18][C:19]=2[CH:24]=1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: CC(Oc1cc(-n2cnc3cc(CO)ncc32)sc1C(N)=O)c1ccccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Oc1cc(-n2cnc3cc(COS(C)(=O)=O)ncc32)sc1C(N)=O)c1ccccc1F

Procedure:
In a similar manner as described for example 49 (step 1), 2.9 g of 3-[-1-(2-fluorophenyl)ethoxy]-5-[6-(hydroxymethyl)-3H-imidazo[4,5-c]pyridin-3-yl]thiophene-2-carboxamide, 1.53 g of methanesulfonyl chloride, and 1.42 g of triethylamine in 70 ml dichloromethane give (3-{5-carbamoyl-4-[-1-(2-fluorophenyl)ethoxy]-2-thienyl}-3H-imidazo[4,5-c]pyridin-6-yl)methyl methanesulfonate as crude material that is used for step 2 without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1.[CH3:8][CH2:9][CH2:10][CH:11]=[O:12].C1CCCCC1>O.C(Cl)(Cl)=O.[Rh]>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH:11]=[O:12].[CH3:8][CH2:9][CH2:10][CH:11]=[O:12]
Reactant: CC1=CCCCC1
Agent: [Rh]
Agent: O=C(Cl)Cl
Solvent: O
Solvent: C1CCCCC1
Solvent: CCCC=O
Product: CC1CCCCC1C=O
Temperature: 145 °C
Reaction time: 2 h

Procedure:
100 g of limonenemonoaldehyde (4-methylcyclohex-3-ene-β-methylpropanal), 300 ml of cyclohexane and 0.1 g of dimeric rhodium carbonyl-chloride were introduced into a stainless steel autoclave of 700 ml capacity and were heated to 145° C. under water gas (CO/H2), while stirring. The pressure was kept between 200 and 220 bar by regularly forcing in more water gas. After 2 hours, the pressure remained constant. The autoclave was cooled and let down and the reaction mixture was separated into its components by thin film distillation. 75 g of limonenedialdehyde (4-methyl-3-formylcyclohexane-β-methylpropanal) were obtained at 150° C. under 0.05 mbar, corresponding to a selectivity of 75%.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([S:11]([N:14]3[CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15]3)(=[O:13])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:23][NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=1.[ClH:33].C(=O)([O-])[O-].[NH4+:38].[NH4+]>C(O)C>[ClH:33].[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([S:11]([N:14]3[CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15]3)(=[O:12])=[O:13])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:23][NH:24][C:25]1[CH:26]=[CH:27][C:28]([C:31](=[NH:38])[NH2:32])=[CH:29][CH:30]=1
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(S(=O)(=O)N3Cc4ccccc4C3)ccc21
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(S(=O)(=O)N3Cc4ccccc4C3)ccc21
Yield: 33 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-5-(isoindolin-2-yl-sulphonyl)-benzimidazole and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 33% of theory, Rf value: 0.32 (silica gel; dichloromethane/methanol=4:1) C24H24N6O2S (460.6) EKA mass spectrum: (M+H)+ =461
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Br:23][C:24]1[C:25](Cl)=[C:26]([C:32](=[O:39])[C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])[C:27]([CH3:31])=[N:28][C:29]=1[CH3:30]>CC#N.CCOCC>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:25]2[C:24]([Br:23])=[C:29]([CH3:30])[N:28]=[C:27]([CH3:31])[C:26]=2[C:32](=[O:39])[C:33]([O:35][CH:36]([CH3:37])[CH3:38])=[O:34])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(Cl)c1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CC#N
Product: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(N2CCC(Cc3ccccc3)CC2)c1Br
Temperature: 80 °C
Reaction time: 18 h
Yield: 68.6 %

Procedure:
To a solution of 4-benzylpiperidine (0.80 g, 4.56 mmol) and DIEA (2.4 mL, 13.7 mmol) in anhydrous CH3CN (30 mL) was added isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (1.7 g, 4.56 mmol) at rt. The resulting mixture was placed in a pre-heated oil bath (80° C.) and stirred for 18 h; cooled, diluted with ether, washed with water, brine, and dried (MgSO4). The crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient eluted (0-25% EtOAc/hexanes) using an Isolera chromatography station gave isopropyl 2-(4-(4-benzylpiperidin-1-yl)-5-bromo-2,6-dimethylpyridin-3-yl)-2-oxoacetate 1.48 g (68%). 1H NMR (500 MHz, DMSO-d6) δ 7.3-7.27 (m, 2H), 7.20-7.15 (m, 3H), 5.09-5.04 (m, 1H), 3.23 (br. s, 2H), 2.84 (br. s, 2H), 2.59 (s, 3H), 2.51-2.49 (m, 2H), 2.28 (s, 3H), 1.61 (br. s, 1), 1.55 (d, J=13.6 Hz, 2H), 1.30 (d, J=6.2 Hz, 6H), 1.14 (br. s, 2H). UPLC (M+H)=475.2.
Reaction SMILES: Cl.C(O[CH:5]=[CH:6][C:7](=[NH:11])OCC)C.Br.[CH2:13]([O:15][C:16]([C:18]([NH2:20])=[NH:19])=[O:17])C.[Na]>CO>[NH2:11][C:7]1[CH:6]=[CH:5][N:20]=[C:18]([C:16]([O:15][CH3:13])=[O:17])[N:19]=1
Reactant: CCOC=CC(=N)OCC
Reactant: CCOC(=O)C(=N)N
Agent: Br
Agent: Cl
Agent: [Na]
Solvent: CO
Product: COC(=O)c1nccc(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 39 %

Procedure:
To a solution of ethyl 3-ethoxyacrylimidate hydrochloride (4.0 g) and 1-ethoxycarbonylformamidine hydrobromide (4.4 g) in methanol (110 ml) was added dropwise a solution of sodium metal (1 g) in methanol (110 ml) at 0° C. The reaction mixture was stirred for an hour at 0° to 5° C. and for additional 4 hours at ambient temperature. The solution was evaporated to dryness and the residue was dissolved in a mixture of ethyl acetate and an aqueous solution of sodium chloride. The organic layer was separated out and the aqueous layer was extracted with ethyl acetate five times. All organic layers were combined, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was triturated with diethyl ether to give methyl 4-aminopyrimidine-2-carboxylate (1.33 g), which was recrystallized from ethyl acetate, mp. 140°-142.5° C.
Reaction SMILES: [CH3:1][N:2]([CH3:35])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[CH:13][C:14]3[CH:20]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:18]([C:27]4[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=4)=[N:17][C:15]=3[N:16]=2)[CH2:7][CH2:6]1.FC(F)(F)C(O)=O.[NH:43]1[CH2:48][CH2:47][CH:46]([C:49]2[NH:50][C:51]([C:54]3[CH:59]=[CH:58][N+:57]([O-:60])=[CH:56][CH:55]=3)=[N:52][N:53]=2)[CH2:45][CH2:44]1.CCN(CC)CC.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:1][N:2]([CH3:35])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[CH:13][C:14]3[CH:20]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:18]([C:27]4[CH:34]=[CH:33][C:30]([CH2:31][N:43]5[CH2:48][CH2:47][CH:46]([C:49]6[NH:50][C:51]([C:54]7[CH:59]=[CH:58][N+:57]([O-:60])=[CH:56][CH:55]=7)=[N:52][N:53]=6)[CH2:45][CH2:44]5)=[CH:29][CH:28]=4)=[N:17][C:15]=3[N:16]=2)[CH2:7][CH2:6]1
Reactant: [O-][n+]1ccc(-c2nnc(C3CCNCC3)[nH]2)cc1
Reactant: CN(C)CCN1CCN(c2ncc3cc(-c4ccccc4)c(-c4ccc(C=O)cc4)nc3n2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CN(C)CCN1CCN(c2ncc3cc(-c4ccccc4)c(-c4ccc(CN5CCC(c6nnc(-c7cc[n+]([O-])cc7)[nH]6)CC5)cc4)nc3n2)CC1
Reaction time: 12 h

Procedure:
To a solution of 4-(2-{{4-[2-dimethylamino)ethyl]piperazine-1-yl}-6-phenylpyrido[2,3-d]pyrimidin-7-yl)benzaldehyde (6-5) (100 mg, 0.214 mmol) in DMF (5 mL) was added 4-(5-piperidin-4-yl-4H-1,2,4-triazol-3-yl)pyridine 1-oxide trifluoroacetate (B) (92 mg, 0.257 mmol) followed by Et3N (80 μL, 0.51 mmol), AcOH (91 μL, 1.5 mmol) and sodium triacetoxyborohydride (59 mg, 0.28 mmol). The reaction mixture was allowed to stir for 12 hr then diluted with EtOAc and washed with NaHCO3 (sat.), dried with MgSO4, filtered, and concentrated under reduced pressure. The oily residue was purified by reverse phase HPLC (20% MeCN/80% H2O to 47% MeCN/53% H2O) to afford the title compound. LRMS m/z (M+H) Calcd.: 696.9, found 696.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([N+:16]([O-])=O)[CH:10]=2)[CH:4]=1>O1CCCC1.C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH:10]=2)[NH2:16])[CH:4]=1
Reactant: COc1ccnc(-c2ccc(C)c([N+](=O)[O-])c2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccnc(-c2ccc(C)c(N)c2)c1
Yield: 96.5 %

Procedure:
A suspension of 4-(4-methoxypyridin-2-yl)-2-nitrotoluene (300 mg) in tetrahydrofuran (3 ml) and ethanol (3 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 150 mg) under a hydrogen atmosphere for 3 hours. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give 5-(4-methoxypyridin-2-yl)-2-methylaniline (254 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)=[O:4].[CH2:16](O)[CH2:17][OH:18].C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]([C:3]1([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)[O:18][CH2:17][CH2:16][O:4]1)([CH3:15])[CH3:14]
Reactant: OCCO
Reactant: CC(C)(C)C(=O)c1ccc(C(=O)O)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(C)C1(c2ccc(C(=O)O)cc2)OCCO1

Procedure:
A mixture of 63.5 grams (0.31 mole) of 4-(2,2-dimethyl-1-oxopropyl)benzoic acid, 156 ml. of ethylene glycol, and 1 gram of toluenesulfonic acid in 600 ml of toluene is refluxed for 24 hours using a Dean-Stark trap to remove water. The mixture is then cooled and partially evaporated; and to the residue, 4.5 grams of solid potassium hydroxide are carefully added followed by 225 ml of water. The resulting mixture is refluxed for 11/2 hours, cooled, filtered and the layers separated. The aqueous layer is acidified with 2N hydrochloric acid, and the resulting precipitate is removed by filtration. The precipitate is washed with water, then water/ethanol (5/1), and then petroleum ether. The product is dried in vacuo to yield the title product (m.p. 213.5°-215.5° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][CH:41]=1)[CH2:5][NH:6][C:7]([O:9][CH2:10][C@@H:11]1[C@@H:15]([O:16]C2CCCCO2)[CH2:14][C@@H:13]([O:23]C2CCCCO2)[C@H:12]1[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[S:8].[NH3:42]>>[C:36]([CH2:35][CH2:34][CH2:33]/[CH:32]=[CH:31]\[CH2:30][C@H:12]1[C@@H:13]([OH:23])[CH2:14][C@@H:15]([OH:16])[C@@H:11]1[CH2:10][O:9][C:7](=[S:8])[NH:6][CH2:5][C:4]1[CH:39]=[CH:40][CH:41]=[C:2]([Cl:1])[CH:3]=1)(=[O:37])[NH2:42]
Reactant: O=C(O)CCC/C=C\C[C@H]1[C@H](COC(=S)NCc2cccc(Cl)c2)[C@@H](OC2CCCCO2)C[C@H]1OC1CCCCO1
Reactant: N
Product: NC(=O)CCC/C=C\C[C@@H]1[C@@H](COC(=S)NCc2cccc(Cl)c2)[C@H](O)C[C@@H]1O

Procedure:
According to the procedures described above in Examples 17 and 18 acid 7 was converted with use of ammonia to 10 mg of the above titled compound.
Reaction SMILES: [CH:1]1([C:4]2[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH3:13])[C:5]=2[CH:6]=[O:7])[CH2:3][CH2:2]1.Cl([O-])=[O:15].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.CC(=CC)C.O>[CH:1]1([C:4]2[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH3:13])[C:5]=2[C:6]([OH:15])=[O:7])[CH2:2][CH2:3]1
Reactant: CCc1cccc(C2CC2)c1C=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCc1cccc(C2CC2)c1C(=O)O
Temperature: 25 °C

Procedure:
2-Cyclopropyl-6-ethyl-benzaldehyde (CAS 945408-11-7) (500 mg, 2.9 mmol) was dissolved in 3.5 mL tert butanol and 1.7 mL 2-methyl-2-butene. At 0° C. a solution of sodium chlorite (80% purity, 422 mg, 3.8 mmol) and sodium dihydrogenphosphate (452 mg, 3.8 mmol) in 3 mL water was added slowly. The reaction mixture was stirred at room temperature over night. The solvents were evaporated off. The residue was taken up in 1N sodium hydroxide solution and was extracted with tert butyl methylether. The aqueous phase was adjusted at pH 1 with 25% HCl and extracted twice with tert butyl methylether. The combined organic phases were dried on sodium sulfate, filtered and evaporated. The crude product was used without any further purification, white solid (412 mg, 75%), MS: m/e=189.3 [(M−H)−].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Cl[CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1)=[O:12].C([O-])([O-])=O.[Cs+].[Cs+].CC#N>C(Cl)Cl>[F:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:11](=[O:12])[CH2:10][N:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]2)=[N:15][CH:16]=1
Reactant: O=C(CCl)Nc1ccc(F)cn1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: ClCCl
Product: O=C(Cn1cc([N+](=O)[O-])cn1)Nc1ccc(F)cn1
Temperature: 80 °C

Procedure:
A flask was charged with 4-nitro-1H-pyrazole (230 mg, 2.03 mmol), 2-chloro-N-(5-fluoropyridin-2-yl)acetamide (2.24 mmol), Cs2CO3 (729 g, 2.24 mmol) and MeCN (11.5 mL). The resulting reaction mixture was stirred at reflux (80° C.) for 2 h, then allowed to reach rt. The mixture was diluted with DCM, filtered, the filter cake was washed with DCM. The filtercake was redisolved in DCM and water, the org. layer was separated and the aq. layer was extracted with DCM (2×). The combined org. layers were washed with brine, dried (MgSO4), filtered and concentrated to yield N-(5-fluoropyridin-2-yl)-2-(4-nitro-1H-pyrazol-1-yl)acetamide as a crude which was used in the next step without further purification. LC-MS conditions A: tR=0.67 min, [M+H]+=266.32.
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:11]=2[C:20]2[C:28]3[C:23](=[C:24]([O:29]C)[N:25]=[CH:26][CH:27]=3)[N:22]([CH3:31])[CH:21]=2)[CH2:4][CH2:3]1.Cl.O1CCOCC1>>[F:32][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][C:11]=2[C:20]2[C:28]3[CH:27]=[CH:26][NH:25][C:24](=[O:29])[C:23]=3[N:22]([CH3:31])[CH:21]=2)[CH2:4][CH2:3]1
Reactant: COc1nccc2c(-c3cc(S(C)(=O)=O)ccc3OCC3CCC(F)(F)CC3)cn(C)c12
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2OCC2CCC(F)(F)CC2)c2cc[nH]c(=O)c21
Temperature: 70 °C
Yield: 80.5 %

Procedure:
The product from Example 41A (0.1 g, 0.215 mmol) and 4 M hydrogen chloride in dioxane (5 mL, 20.00 mmol) were combined and heated at 70° C. for 24 hours, cooled and concentrated. Purification by chromatography (silica gel, 0-4% MeOH in dichloromethane) afforded the title compound (0.078 g, 80%). 1H NMR (300 MHz, DMSO-d6) δ ppm 10.96 (d, J=5.43 Hz, 1H) 7.86 (d, J=2.37 Hz, 1H) 7.79 (dd, J=8.65, 2.54 Hz, 1H) 7.55 (s, 1H) 7.33 (d, J=8.48 Hz, 1H) 6.88-6.95 (m, 1H) 6.43 (d, J=6.10 Hz, 1H) 4.12 (s, 3H) 4.04 (d, J=6.10 Hz, 2H) 3.20 (s, 3H) 1.60-2.12 (m, 7H) 1.24-1.41 (m, 2H). MS (ESI+) m/z 451 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1([OH:14])[CH2:13][CH2:12][CH2:11][C:6]2(OCC[O:7]2)[CH2:5]1)[CH:2]=[CH2:3].S(=O)(=O)(O)O>O>[CH2:1]([C:4]1([OH:14])[CH2:13][CH2:12][CH2:11][C:6](=[O:7])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(O)CCCC2(C1)OCCO2
Agent: O=S(=O)(O)O
Solvent: O
Product: C=CCC1(O)CCCC(=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 7-allyl-1,4-dioxa-spiro[4.5]decan-7-ol (12.8 g) and 0.5 M sulfuric acid (13 mL) is stirred at room temperature for 1 h. Water is then added and the resulting mixture is extracted with diethyl ether. The combined extract is washed with water (3×), brine, and dried (MgSO4). The solvent is evaporated and the residue is triturated with diispropyl ether/heptane 1:1 to give the title compound. Yield: 2.7 g (27% of theory); TLC [silicagel, cyclohexane/ethyl acetate 1:1]: rf=0.55; Mass spectrum (ESI+): m/z=155 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([S:16]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][N:7]=1.[H][H]>C(O)C.C(N(CC)CC)C.[Pd]>[C:21]1([CH2:20][CH2:19][S:16]([N:13]2[CH2:12][CH2:11][CH:10]([CH2:9][NH:8][C:3]3[CH:2]=[N:7][CH:6]=[CH:5][N:4]=3)[CH2:15][CH2:14]2)(=[O:18])=[O:17])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: [H][H]
Reactant: O=S(=O)(CCc1ccccc1)N1CCC(CNc2nccnc2Cl)CC1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=S(=O)(CCc1ccccc1)N1CCC(CNc2cnccn2)CC1

Procedure:
EXAMPLE 90 was prepared from (3-chloro-pyrazin-2-yl)-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-ylmethyl]-amine by hydrogenation in ethanol-triethylamine over 5% palladium on carbon, 1 atm of hydrogen: MS (m+1)=361.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]3[N:15]([CH3:28])[C:16](=[O:27])[N:17]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[C:13]=3[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.Br[CH:30]([CH3:32])[CH3:31].CN(C)C=O.[H-].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:30]([CH3:32])[CH3:31])[C:9]2[C:14]3[N:15]([CH3:28])[C:16](=[O:27])[N:17]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[C:13]=3[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CC(C)Br
Reactant: COc1ccc(Cn2c(=O)n(C)c3c(Nc4ccc(Cl)cc4)cccc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)n(C)c3c(N(c4ccc(Cl)cc4)C(C)C)cccc32)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 61.6 %

Procedure:
To a mixture of 7-[(4-chlorophenyl)amino]-3-(4-methoxybenzyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (0.118 g, 0.30 mmol), 2-bromopropane (0.056 ml, 0.60 mmol), tetrabutylammonium iodide (small amounts) and N,N-dimethylformamide (2 ml) was added sodium hydride (16 mg, 0.60 mmol, 90% dry). The mixture was stirred at 60° C. for 6 h. The mixture was diluted with water (20 ml) and extracted with ethyl acetate (40 ml). The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was flash chromatographed with 20-33% ethyl acetate/hexanes to give 80.6 mg (62%) of the title compound as an oil.
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([O:11][CH3:12])[N:5]=[CH:4][CH:3]=1.Cl.[CH:14]1([NH:19][NH2:20])[CH2:18][CH2:17][CH2:16][CH2:15]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O.C(N(CC)CC)C>[CH:14]1([NH:19][NH:20][C:8](=[O:10])[C:7]2[C:2]([I:1])=[CH:3][CH:4]=[N:5][C:6]=2[O:11][CH3:12])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: NNC1CCCC1
Reactant: COc1nccc(I)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1nccc(I)c1C(=O)NNC1CCCC1
Yield: 27.6 %

Procedure:
A solution of 4-iodo-2-methoxynicotinic acid (1.95 g) obtained in Step C of Example 6, cyclopentylhydrazine hydrochloride (1.05 g), EDCI hydrochloride (0.58 g), HOBt (2.01 g) and triethylamine (1.06 g) in DMF (30 mL) was stirred at room temperature for 3 days. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (697 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](OS(C(F)(F)F)(=O)=O)=[CH:10]2)=[CH:5][CH:4]=1.C[Sn](C)(C)[C:23]1[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][C:26]2[O:32][CH2:33][O:34][C:25]=2[CH:24]=1>C1COCC1.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>[CH2:33]1[O:34][C:25]2[C:26](=[CH:27][C:28]([N+:29]([O-:31])=[O:30])=[C:23]([C:9]3[CH:10]=[C:11]4[C:6]([CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:12]4)=[CH:7][CH:8]=3)[CH:24]=2)[O:32]1
Reactant: C[Sn](C)(C)c1cc2c(cc1[N+](=O)[O-])OCO2
Reactant: COc1ccc2ccc(OS(=O)(=O)C(F)(F)F)cc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc2ccc(-c3cc4c(cc3[N+](=O)[O-])OCO4)cc2c1
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (120 mg) and cuprous bromide (20 mg) were added to a solution of 7-Methoxy-2-trifluoromethanesulfonyloxynaphthalene 47 (336 mg, 1.1 mmol) and trimethylnitroarylstannane 62 (300 mg, 0.92 mmol) in THF (30 mL) at room temperature and stirred for 0.5 h. The mixture was then refluxed under N2 overnight. After cooling, THF was evaporated in vacuo and ethyl acetate (30 mL) was added to the residue. The solution was washed with water. The organic layer was separated and passed through a Celite bed to remove suspended particles. The organic layer was then washed with brine, dried (anhydrous Na2SO4), and evaporated in vacuo. The residue was chromatographed using a 80:20 mixture of hexanes:ethyl acetate to give 48 (100 mg) in 34% yield; IR (KBr) 2915, 1627, 1509, 1481, 1425, 1333, 1262, 1218 cm−1; 1H NMR (CDCl3) δ3.92 (3H, s), 6.15 (2H, s), 6.88 (1H, s), 7.13-7.23 (3H, m), 7.48 (1H, s), 7.64 (1H, s), 7.74-7.81 (2H, m); 13C NMR δ55.81, 103.47, 105.90, 106.46, 111.60, 119.84, 124.13, 126.07, 128.50, 128.72, 129.75, 133.89, 134.97, 136.60, 143.42, 147.63, 151.45, 158.61; HRMS (EI) calcd for C18H13NO5 m/z: 323.0794; found: 323.0787.