Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.O.[CH3:33][O:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[C:39]([O:41][CH3:42])[CH:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10]([C:37]3[CH:36]=[C:35]([O:34][CH3:33])[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=3)[C:3]=12
Reactant: COc1cc(OC)cc(B(O)O)c1
Reactant: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(I)c2c(N)ncnc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: COc1cc(OC)cc(-c2nn(C(C)c3oc4ccccc4c(=O)c3-c3cccc(F)c3)c3ncnc(N)c23)c1
Temperature: 90 °C

Procedure:
To a solution of example 57c (100 mg, 0.190 mmol) in DME (1 ml), and water (0.5 ml), 3,5-dimethoxy phenyl boronic acid (0.209 mmol) and sodium carbonate (40 mg, 0.380 mmol) were added and the system was degassed for 5 min. 1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (27.8 mg, 0.038 mmol) was added under nitrogen atmosphere and the mixture was heated to 90° C. at a microwave reactor for 15 min. LC-MS analysis indicated the total consumption of example 57c, then ethyl acetate (2 ml) and water (0.5 ml) was added. The two phases were separated and the aqueous layer was extracted by ethyl acetate (1 ml). The combined organic layer was dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by preparative TLC using mixture of ethyl acetate: petroleum ether in 2:1 ratio as an eluent to afford the desired compound. Brown solid (23.4 mg, 23%). MP: 224-227° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): δ 8.24(s,1H), 8.21(dd, J=8.0,1.5 Hz, 1H), 7.69(m,1H), 7.48(d, J=8.4 Hz, 1H), 7.42(t, J=8.0 Hz, 1H), 7.32(m,1H), 7.04(m,3H), 6.79(d, J=2.3 Hz, 2H), 6.56(t, J=2.1 Hz, 1H), 6.11(q, J=7.2 Hz,1H), 5.58(s,2H), 3.85(s, 6H), 2.02(d, J=7.1 Hz, 3H). Mass: 537.8(M+).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)#[N:2].[BH4-].[Na+].S([O-])(O)(=O)=O.[K+]>O1CCCC1.O>[OH:9][CH2:8][C:7]1[CH:11]=[CH:12][C:4]([CH2:3][C:1]#[N:2])=[CH:5][CH:6]=1
Reactant: N#CCc1ccc(C(=O)O)cc1
Agent: O=S(=O)([O-])O
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: N#CCc1ccc(CO)cc1

Procedure:
5.17 g (32 mol) of CDl are added to a solution of 4.7 g (29 mol) of 4-cyanomethyl-benzoic acid in 250 mL of tetrahydrofuran and stirred until no more gas is given off. This reaction mixture is added dropwise to a solution of 3.29 g (87 mol) of sodium borohydride in 200 mL of water in such a way that the temperature does not exceed 30° C. The mixture is stirred for two hours and the reaction mixture is adjusted to pH 3-4 with potassium hydrogen sulphate solution. Then it is extracted with EtOAc, the organic phase is dried over magnesium sulphate and the solvent is separated off using the rotary evaporator.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.C(N(CC)CC)C.[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>CC1C=CC=CC=1>[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1cccnc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(Nc1cccnc1)c1ccc(F)cc1
Reaction time: 2 h
Yield: 80.6 %

Procedure:
To a stirred mixture of 28.2 parts of 3-pyridinamine, 59 parts of N,N-diethylethanamine and 450 parts of methylbenzene were added dropwise 39 parts of 4-fluorobenzoyl chloride (exothermic reaction, the temperature rose to 40° C.). Upon complete addition, stirring was continued for 2 hours at reflux temperature. After cooling, the precipitated product was filtered off and dissolved in trichloromethane. The organic layer was washed twice with water, dried, filtered and evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered off and dried, yielding 52.3 paris (80.6%) of 4-fluoro-N-(3-pyridinyl)benzamide; mp. 150.2° C. (int. 66).
Reaction SMILES: C(OCC([NH:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[C:14]=1[NH:25][C:26](=O)[CH2:27][O:28]CC1C=CC=CC=1)=O)C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO.N>C1(C)C(C)=CC=CC=1>[OH:28][CH2:27][C:26]1[NH:25][C:14]2[C:15]([O:23][CH3:24])=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=2[N:12]=1
Reactant: COc1cc(NC(=O)COCc2ccccc2)c(NC(=O)COCc2ccccc2)c(OC)c1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: Cc1ccccc1C
Solvent: CO
Solvent: O
Product: COc1cc2nc(CO)[nH]c2c(OC)c1OC
Reaction time: 3 h

Procedure:
1,2-Di(benzyloxyacetamido)-3,4,5-trimethoxybenzene (1.9 g) was dissolved in xylene (30 mL), p-toluenesulfonic acid monohydrate (2.0 g) was added to the solution, and the mixture was stirred for 3 hours under reflux. After cooling, methanol saturated with ammonia was added to the reaction mixture into a uniform solution. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (chloroform:methanol=15:1 to 10:1) to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:16]([N+:17]([O-])=O)=[CH:15][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[O:8][C:4]=2[CH:3]=1>C(O)C.[Pt]=O>[NH2:17][C:16]1[C:2]([CH3:1])=[CH:3][C:4]2[O:8][C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)=[N:6][C:5]=2[CH:15]=1
Reactant: Cc1cc2oc(-c3ccccn3)nc2cc1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CCO
Product: Cc1cc2oc(-c3ccccn3)nc2cc1N
Reaction time: 2 h
Yield: 87.8 %

Procedure:
A suspension of 6-methyl-5-nitro-2-(2-pyridinyl)benzoxazole (10.0 g, 0.044 mole) and platinum oxide (1.0 g) in 150 ml of ethanol is hydrogenated over a period of 2 hours. The catalyst is separated by filtration and the ethanol removed under vacuum yielding 8.7 g of the title compound.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.[N-:27]=[N+:28]=[N-:29].[Na+].C(O)(=O)C>CN(C)C=O>[N:27]([CH2:2][C:3]1([OH:1])[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]3=[O:25])=[CH:11][C:10]=2[F:26])[CH2:7][CH2:8]1)=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(CN=[N+]=[N-])CC3)c(F)c2)C(=O)O1
Yield: 72 %

Procedure:
The title compound was prepared by reacting (S)—N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.37 mmol) with sodium azide (2.06 mmol) and glacial acetic acid (7.1 mmol) in dimethylformamide (15 ml) at a temperature 40° C. for 14 hours and by purifying the compound by silica gel column chromatography in 72% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15]C)=[O:14])[CH:11]=2)[CH:6]=[CH:5][N:4]=1.[OH-].[Li+]>CO.Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: COC(=O)c1ccc2ccnc(OC)c2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1nccc2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.9 %

Procedure:
To a solution of methyl 1-methoxyisoquinoline-7-carboxylate (443 mg, 2.04 mmol) in methanol (10 mL) was added 2 N aqueous lithium hydroxide (20 mL). The reaction was stirred at room temperature for 24 hours. The reaction mixture was diluted with 1 N aqueous hydrochloric acid and ethyl acetate. The layers were separated and the aqueous was extracted two more times with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford the title compound (414 mg, 100%) as a solid. +ESI (M+H) 204.1; 1H NMR (400 MHz, DMSO-d6, δ): 13.24 (s, 1H), 8.76 (d, J=0.8 Hz, 1H), 8.18 (dd, J=8.6, 1.8 Hz, 1H), 8.11 (d, J=5.9 Hz, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.45 (d, J=5.9 Hz, 1H), 4.07 (s, 3H).
Reaction SMILES: [I:1]I.N[C:4]1[C:8]([CH:9]2[CH2:11][C:10]2([Br:13])[Br:12])=[CH:7][N:6]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])[N:5]=1.N(OC(C)(C)C)=O>ClCCl>[Br:12][C:10]1([Br:13])[CH2:11][CH:9]1[C:8]1[C:4]([I:1])=[N:5][N:6]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])[CH:7]=1
Reactant: II
Reactant: Nc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C1CC1(Br)Br
Agent: CC(C)(C)ON=O
Solvent: ClCCl
Product: FC(F)(F)c1cc(Cl)c(-n2cc(C3CC3(Br)Br)c(I)n2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Iodine (0.55 g) was added to a stirred solution of the title compound of Example 8 (0.40 g) in dichioromethane (10 ml), followed by the dropwise addition of t-butyl nitrite (0.21 g). The reaction mixture was stirred at room temperature for 2 hours, then partitioned between dichloromethane and aqueous sodium thiosulphate solution and the organic phase separated, dried and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using hexane and then dichloromethane as eluants, followed by reverse phase HPLC on C18 silica, using a mixture of acetonitrile:water:methanol (30:60:10) as eluant, to produce the title compound as an off-white foam. δ (CDCl3): 1.84 (t,1H), 2.26 (dd,1H), 2.67 (dd,1H), 7.20 (s,1H), 7.72 (s,2H). MS (thermospray): M/Z [M+H] 602.4; C13H6Br2Cl2F3IN2 +H requires 602.74.
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[CH:5]=[CH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[C-:16]#[N:17].[Na+]>C(O)C>[C:16]([CH2:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[CH:5]=[CH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])#[N:17]
Reactant: CCOC(=O)C=Cc1ccccc1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C=Cc1ccccc1CC#N

Procedure:
A solution of ethyl o-(bromomethyl)cinnamate (94.1 g., 0.35 mole), and sodium cyanide (20.6 g., 0.42 mole) in ethanol (450 ml.) is heated at reflux for 3 hours. About half of the ethanol is removed at reduced pressure. To the residue is added 500 ml. of water. The oily product is taken up in ether, washed with water, and dried over magnesium sulfate. Evaporation of the ether affords the title compound as an oil.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:12]=[CH:11][N:10]3[N:13]=[C:14]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[C:15]([C:16](=[O:18])[CH3:17])=[C:9]3[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.CO[CH:30](OC)[N:31]([CH3:33])[CH3:32]>>[CH:1]1([NH:6][C:7]2[CH:12]=[CH:11][N:10]3[N:13]=[C:14]([C:19]4[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)[C:15]([C:16](=[O:18])[CH:17]=[CH:30][N:31]([CH3:33])[CH3:32])=[C:9]3[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(-c2nn3ccc(NC4CCCC4)cc3c2C(C)=O)cc1
Reactant: COC(OC)N(C)C
Solvent: O
Product: COc1ccc(-c2nn3ccc(NC4CCCC4)cc3c2C(=O)C=CN(C)C)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of 1-[5-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3yl]ethanone (1.14 g, 3.26 mmol) in N,N-dimethylformamide dimethyl acetal (25 mL) was heated at reflux for 5 days. The mixture was allowed to cool to room temperature. Water was added and the resulting mixture was extracted with ethyl acetate. The organic phase was dried (magnesium sulfate), filtered and concentrated. The resulting residue was crystallized from ethyl acetate to give 1-[5-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (1.05 g, 80%) as a yellow solid. 1H NMR (CDCl3): δ 8.11 (d, 1H), 7.56 (m, 3H), 7.41 (d, 1H), 6.95 (d, 2H), 6.22 (dd, 1H), 5.07 (d, 1H), 4.11 (d, 1H), 3.95 (m, 1H), 3.84 (s, 3H), 3.0–2.3 (broad, 6H), 2.12 (m, 2H), 1.74–1.48 (m, 6H); MS m/z 405 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([CH:12]([C:18](=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:10][CH3:11]>>[CH2:8]([C:12](=[C:18]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:10][CH3:11]
Reactant: Nc1ccccc1
Reactant: CCCCC(C(=O)OCC)C(=O)C(=O)OCC
Product: CCCCC(C(=O)OCC)=C(Nc1ccccc1)C(=O)OCC
Temperature: 75 °C
Reaction time: 72 h
Yield: 45.2 %

Procedure:
A mixture of 1 g of aniline with 2.65 g of the product of Step A and 150 mg of SiliporiteRNK10 was stirred for 3 days at 75° C. and then the reaction mixture was cooled down and chromatographed on silica (eluant: hexane-ethyl acetate (9-1) to obtain 1.55 g of the expected product.
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][N:14]3[CH2:19][CH2:18][CH:17]([C:20]([C:32]4[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=4)([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)[OH:21])[CH2:16][CH2:15]3)=[CH:9][CH:8]=2)=[N:3]1.ClC1C=C(C=CC=1)C(OO)=[O:47]>C(Cl)Cl>[CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][N+:14]3([O-:47])[CH2:15][CH2:16][CH:17]([C:20]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=4)([C:32]4[CH:33]=[CH:34][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:36][CH:37]=4)[OH:21])[CH2:18][CH2:19]3)=[CH:11][CH:12]=2)=[N:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cn1nnc(-c2ccc(CN3CCC(C(O)(c4ccc(C(F)(F)F)cc4)c4ccc(C(F)(F)F)cc4)CC3)cc2)n1
Solvent: ClCCl
Product: Cn1nnc(-c2ccc(C[N+]3([O-])CCC(C(O)(c4ccc(C(F)(F)F)cc4)c4ccc(C(F)(F)F)cc4)CC3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
A solution of 1.1 grams (0.002 mole) of N-[4-(2-methyl-2H-tetrazol-5-yl)phenylmethyl]-4-[bis(4-trifluoromethylphenyl)hydroxymethyl]piperidine (Compound 31—prepared in Example 9) in 100 mL of methylene chloride was stirred, and 0.6 gram (excess) of 50-85% 3-chloroperoxybenzoic acid was added. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about one hour. After this time the reaction mixture was washed with an aqueous 10% solution of sodium hydroxide. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 1.0 gram of N-[4-(2-methyl-2H-tetrazol-5-yl)phenyl-methyl]-4-[bis(4-trifluoromethylphenyl)hydroxymethyl]piperidine N-oxide. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([C:12]([O:14]C)=[O:13])=[CH:5][N:6]=[CH:7]2.[OH-].[K+]>CO.O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([C:12]([OH:14])=[O:13])=[CH:5][N:6]=[CH:7]2
Reactant: COC(=O)c1cncc2cccc(Br)c12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cncc2cccc(Br)c12
Temperature: 70 °C

Procedure:
To a stirred solution of methyl 5-bromoisoquinolin-4-carboxylate (Intermediate-16) (10.1 g, 38.0 mmol) in MeOH (50 mL) was added, KOH (21.3 g, 380 mmol) dissolved in water (50 mL) and the reaction mixture was heated to 70° C. for 3 h. Then it was concentrated, diluted with water and washed with Et2O (100 mL×3). The aqueous layer was acidified with 2N HCl (pH=3) and the white solid obtained was filtered to yield the desired acid derivative 6.0 g (62.7%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15][CH3:16])[C:3]=1[C:4]#[N:5].[S:17](Cl)(=[O:20])(=[O:19])[NH2:18]>>[S:17]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15][CH3:16])[C:3]=1[C:4]#[N:5])(=[O:20])(=[O:19])[NH2:18]
Reactant: NS(=O)(=O)Cl
Reactant: CSCCCCOc1cccc(N)c1C#N
Product: CSCCCCOc1cccc(NS(N)(=O)=O)c1C#N
Yield: 66 %

Procedure:
Prepared as in Example 215a from 2-amino-6-(4-(methylthio)-butoxy)benzonitrile (Example 244b) and sulfamoyl chloride in 66% yield. MS 316 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([F:11])[C:9]#[CH:10])[N:3]=1.[CH3:12][Si:13]([CH2:16][N:17]=[N+:18]=[N-:19])([CH3:15])[CH3:14].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CC(O)(C)C.O.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([F:11])[C:9]2[N:19]=[N:18][N:17]([CH2:16][Si:13]([CH3:15])([CH3:14])[CH3:12])[CH:10]=2)[N:3]=1
Reactant: C[Si](C)(C)CN=[N+]=[N-]
Reactant: C#CC(F)c1cccc(Br)n1
Agent: O=C([O-])O
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: C[Si](C)(C)Cn1cc(C(F)c2cccc(Br)n2)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromo-6-(1-fluoroprop-2-yn-1-yl)pyridine (520 mg, 2.43 mmol) and trimethylsilylmethyl azide (377 mg, 2.92 mmol) were combined in t-BuOH (5.0 mL) and water (3.0 mL). CuSO4.5H2O (30 mg, 0.12 mmol) in water (1.0 mL) was added, followed by sodium ascorbate (96 mg, 0.49 mmol) in water (1.0 mL). The reaction was stirred at room temperature overnight, diluted with saturated NaHCO3, and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated to a brown residue that was purified by flash chromatography (0-30% EtOAc/hexanes) to afford the title compound as a colorless solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][C:11]([OH:35])=[C:12]([C:17]3[N:18]=[N:19][C:20]([N:23]([CH3:34])[CH:24]4[CH2:29][C:28]([CH3:31])([CH3:30])[NH:27][C:26]([CH3:33])([CH3:32])[CH2:25]4)=[CH:21][CH:22]=3)[CH:13]=2)[CH:8]=1)(=O)=O.[CH3:38][N:39](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[OH:35][C:11]1[CH:10]=[C:9]2[C:14]([CH:15]=[CH:16][C:7]([C:38]#[N:39])=[CH:8]2)=[CH:13][C:12]=1[C:17]1[N:18]=[N:19][C:20]([N:23]([CH3:34])[CH:24]2[CH2:25][C:26]([CH3:33])([CH3:32])[NH:27][C:28]([CH3:30])([CH3:31])[CH2:29]2)=[CH:21][CH:22]=1
Reactant: CN(c1ccc(-c2cc3ccc(OS(=O)(=O)C(F)(F)F)cc3cc2O)nn1)C1CC(C)(C)NC(C)(C)C1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CN(c1ccc(-c2cc3ccc(C#N)cc3cc2O)nn1)C1CC(C)(C)NC(C)(C)C1
Temperature: 120 °C
Yield: 50 %

Procedure:
A degassed mixture of 7-hydroxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-yl trifluoromethanesulfonate (21 mg, 0.033 mmol), zinc cyanide (5.00 mg, 0.043 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.8 mg, 1.6 μmol) in DMF (0.8 mL) was heated at 120° C. under microwave irradiation for 1 h. The reaction mixture was filtered through celite, washed with EtOAc and concentrated. The residue was loaded on a 1 g SCX column, washed with MeOH, and eluted with 2 M NH3 in MeOH. The product-containing fractions were concentrated. The crude product was purified via HPLC to give the title compound as a light yellow solid (6.9 mg, 50% yield). LCMS Rt=0.55 min [Method Q], MS (M+1)=416.3. 1H NMR (METHANOL-d4) δ 8.26 (s, 1H), 8.16 (d, J=9.6 Hz, 1H), 8.04 (s, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.32 (dd, J=8.6, 1.5 Hz, 1H), 7.27 (s, 1H), 7.22 (d, J=9.6 Hz, 1H), 5.05 (t, J=11.9 Hz, 1H), 2.94 (s, 3H), 1.61 (dd, J=13.1, 3.5 Hz, 2H), 1.49 (t, J=12.4 Hz, 2H), 1.30 (s, 6H), 1.14 (s, 6H).
Reaction SMILES: [CH2:1]([S:3]([CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)(=[O:5])=[O:4])[CH3:2].[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][C:18]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([CH2:6][S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])=[CH:15][CH:14]=2)=[CH:19][C:18]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CCS(=O)(=O)Cc1ccc(C(=O)O)cc1
Product: CCS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
50 mg of 4-(ethylsulfonylmethyl)benzoic acid was coupled with 67 mg of 4-chloro-3-(pyridin-2-yl)aniline via Procedure G. This product was recrystallized from methanol to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(ethylsulfonylmethyl)benzamide. MS (Q1) 415 (M)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C@@H:5]([CH3:30])[CH2:6][CH:7]([NH:22]C(OC(C)(C)C)=O)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:11][CH:10]=1)[CH3:2].Cl>C(Cl)Cl>[ClH:21].[CH2:1]([O:3][C:4](=[O:31])[C@@H:5]([CH3:30])[CH2:6][CH:7]([NH2:22])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:11][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)[C@@H](C)CC(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)[C@@H](C)CC(N)Cc1ccc(-c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Next, to a solution of (S)-4-tert-butoxycarbonylamino-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester (2.47 g, 5.54 mmol) in DCM (15 mL) is added 5 mL of HCl (4N in dioxane) and the mixture is stirred at room temperature for 2 hours. The solvent is removed under reduced pressure to afford the title compound; HPLC Retention time 1.48 minutes (condition A): MS 346.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][NH2:15])=[CH:6][C:5]=1[OH:16].[CH2:18]([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26]1[CH:34]=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14]/[N:15]=[CH:34]/[C:26]2[N:25]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:33]3[C:28]([CH:27]=2)=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:6][C:5]=1[OH:16]
Reactant: O=Cc1cc2ccccc2n1Cc1ccccc1
Reactant: COC(=O)c1ccc(OCCCON)cc1O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: COC(=O)c1ccc(OCCCO/N=C/c2cc3ccccc3n2Cc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
To a solution of 4-(3-aminooxy-propoxy)-2-hydroxy-benzoic acid methyl ester (0.17 g, 0.69 mmol) and 1-benzyl-1H-indole-2-carbaldehyde (0.16 g, 0.69 mmol) in methylene chloride (10 mL) was added anhydrous magnesium sulfate (0.04 g). The mixture was allowed to stir at ambient temperature overnight, then heated to reflux for 1 hour and allowed to cool back to ambient temperature. The mixture was filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography through silica gel using ethyl acetate/hexanes (0/100 gradient to 20/80) to give 4-[3-({[(1E)-(1-benzyl-1H-indol-2-yl)methylidene]amino}oxy)propoxy]-2-hydroxybenzoic acid methyl ester (0.11 g, 36%) as a white solid. 1H NMR (400 MHz, CDCl3); δ 10.94 (s, 1H), 8.16 (s, 1H), 7.70 (d, 1H), 7.63 (d, 1H), 7.28-7.17 (m, 5H), 7.11 (t, 1H), 7.00 (d, 2H), 6.78 (s, 1H), 6.41 (s, 1H), 6.39 (d, 1H), 5.72 (s, 2H), 4.21 (t, 2H), 3.98 (t, 2H), 3.89 (s, 3H), 2.03 (m, 2H).