Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH:8]([CH3:12])[C:9](Cl)=[O:10])[N:3]=1.[O:13]1[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]1>>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH:8]([CH3:12])[C:9]([CH:15]2[C:16](=[O:19])[CH2:17][CH2:18][O:13][CH2:14]2)=[O:10])[N:3]=1
Reactant: O=C1CCOCC1
Reactant: Cc1cc(C)n(C(C)C(=O)Cl)n1
Product: Cc1cc(C)n(C(C)C(=O)C2COCCC2=O)n1

Procedure:
3-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)propanoyl)dihydro-2H-pyran-4 (3H)-one was synthesised from 2-(3,5-dimethyl-1H-pyrazol-1-yl)propanoyl chloride (0.5 g, 2.97 mmol) and tetrahydro-4H-pyran-4-one (0.549 mL, 5.95 mmol) by the general procedure for the preparation of diketones. MS (ES+) m/z 251.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH:19]=[CH:18]2.[OH:26]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH:19]=[CH:18]2)=[O:26]
Reactant: OO
Reactant: O=c1ccc2cc(OCCCCSc3cc(Cl)ccc3Cl)ccc2[nH]1
Product: O=c1ccc2cc(OCCCCS(=O)c3cc(Cl)ccc3Cl)ccc2[nH]1

Procedure:
Prepared analogous to Example 123 from 6-[4-(2,5-dichloro-phenyl-mercapto)-butoxy]-carbostyril and hydrogen peroxide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21]>CC(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:21][CH:20]=[CH2:19])=[CH:6][C:5]=1[OH:11]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C(=O)OC)c(O)c1
Temperature: 25 °C
Yield: 72.3 %

Procedure:
To a solution of 2,4-dihydroxy-benzoic acid methyl ester (12.254 g, 72.8 mmol) in acetone (120 mL) was added potassium carbonate (30.72 g, 222.3 mmol) and allyl bromide (7 mL, 80.9 mmol). The reaction mixture was heated at reflux for 5 hours, and then cooled to room temperature. It was partitioned between ethyl acetate and brine and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate/hexanes (4/96) to afford 4-allyloxy-2-hydroxy-benzoic acid methyl ester (10.952 g, 77%) as a yellow oil. 1H NMR (300 MHz, CDCl3); δ 10.95 (s, 1H), 7.72 (d, 2H), 6.45 (m, 2H), 6.02 (m, 1H), 5.35 (m, 2H), 4.55 (d, 2H), 3.90 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[C:11](Cl)[NH:10][C:9]=2[CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Cl:28])[C:21]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[C:11]([N:25]3[CH2:26][CH2:27][N:22]([C:21]4[C:20]([Cl:28])=[CH:19][N:18]=[CH:17][C:16]=4[Cl:15])[CH2:23][CH2:24]3)[NH:10][C:9]=2[CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1cncc(Cl)c1N1CCNCC1
Reactant: CC(C)(C)c1ccc2nc(Cl)[nH]c2c1
Product: CC(C)(C)c1ccc2nc(N3CCN(c4c(Cl)cncc4Cl)CC3)[nH]c2c1

Procedure:
The 6-tert-butyl-2-chloro-1H-benzoimidazole (209 mg, 1 mmol, Example 17b) and 1-(3,5-dichloropyridin-4-yl)piperazine (464 mg, 2 mmol, Maybridge) reacted under the conditions of Example 1d to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 404 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2([CH3:25])[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[CH2:8][CH2:7]1.[ClH:30]>C(O)C>[ClH:1].[ClH:30].[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]2([CH3:25])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1
Agent: Cl
Solvent: CCO
Product: CC1(N2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CCNCC1
Reaction time: 8 h

Procedure:
1,1-Dimethylethyl 4-(3,4-dichlorophenoxy)-4′-methyl-[1,4′-bipiperidine]-1′-carboxylate (100 mg) was dissolved in ethanol (5 ml). Hydrogen chloride (2 ml of 4M in dioxan) was added and the solution was stirred overnight. Further hydrogen chloride solution (2 ml) was added and the mixture was stirred for a further 2 h. The solvents were evaporated to give the title compound (95 mg; MS [M+H]+ (APCI+) 343/345).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](Cl)=[O:12])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.C(O[AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+]>COCCOC.CCOC(C)=O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccc2nccnc2c1
Agent: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Agent: [Li+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: O=Cc1ccc2nccnc2c1
Reaction time: 5 h
Yield: 73 %

Procedure:
In a 1 l 3-neck flask under argon was placed Quinoxaline-6-carbonyl chloride in 600 ml of DME. To this solution was added lithium tri-tert-butoxyaluminohydride (1 eq.) at −78° C. over 1.5 h. The reaction was kept at that temperature for 5 h. Then ice was added, and the reaction was diluted with AcOEt and filtrated over celite. The two layers were separated and the organic phase was washed with NaHCO3 sat. Quinoxaline-6-carbaldehyde was obtained upon evaporating the solvent in 73% yield as yellowish solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: Cc1cc2c(NCc3ccccc3)nc(Cl)nc2s1
Product: Cc1cc2c(NCc3ccccc3)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)C.[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:39]=[CH:38][C:29]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])=[CH:28][CH:27]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:39]=[CH:38][C:29]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:4]3[C:5](=[O:16])[C:6](=[O:15])[C:7]=3[NH:8][C:9]3[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=3)=[CH:28][CH:27]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: CCOc1c(Nc2ccncc2)c(=O)c1=O
Reactant: NCCCCCCOc1ccc(OCCN2CCOCC2)cc1
Product: O=c1c(NCCCCCCOc2ccc(OCCN3CCOCC3)cc2)c(Nc2ccncc2)c1=O
Yield: 64 %

Procedure:
The title compound was prepared according to the procedure described in example 1B starting from 3-ethoxy-4-(pyridin-4-yl-amino)-3-cyclobutene-1,2-dione prepared according to example 7A and 6-[4-(2-morpholin-4-yl-ethoxy)-phenoxy]-hexylamine.
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1)=O.P(Cl)(Cl)(Cl)=O>>[CH:1]1[N:6]2[C:7]3[C:12]([CH:13]=[CH:14][C:5]2=[CH:4][N:3]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: O=CNCc1ccc2ccccc2n1
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc2c(c1)ccc1cncn12

Procedure:
Treatment of 1.86 g. of 2-formamidomethylquinoline with 15 ml. of phosphorous oxychloride as in Preparation AIII-a gave imidazo[1,5-a]quinoline, which is used without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])C)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[O:17](Br)[Na].C(O)(=O)C.C1(C2C=CC=CC=2)C=CC=CC=1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([OH:16])=[O:17])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: [Na]OBr
Reactant: CC(=O)c1ccc(-c2ccc(F)cc2)cc1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(-c2ccc(F)cc2)cc1
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
NaOH (7 g) was dissolved in water (25 mL) and cooled in an ice bath. Bromine (7.8 g) was added dropwise to give a solution of NaOBr. 1-(4′-Fluoro-biphenyl-4-yl)-ethanone (0.01 mol) was dissolved in dioxane (35 mL) and warmed to 50° C. in a water bath. The NaOBr solution was added slowly to the stirred solution of the biphenyl acetate and stirring continued at 50° C. for a further 20 minutes. The solution was allowed to cool and a solution of sodium metabisulphite (8 g in 40 mL water) was added followed by water (170 mL). 50 mL of the liquid was evaporated under reduced pressure with heating. The remainder was acidified with HCl (5 mL) and a white precipitate formed upon cooling. The precipitate was filtered and recrystallised from acetic acid to give the title compound. δC (CDCl3, 62.9 MHz): 115.9, 126.8, 129.2, 129.6, 129.8 (d, J 2.9), 135.5 (d, J 2.9), 143.2, 162.4 (d, J 245.1) and 167.2.
Reaction SMILES: [CH2:1]([N:8]([CH3:16])[CH:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[CH2:19]1[C:28]2[C:23](=[CH:24][N:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][NH:20]1.[BH3-]C#N.[Na+]>CO>[CH2:1]([N:8]([CH3:16])[CH:9]1[CH2:14][CH2:13][CH:12]([N:25]2[CH2:26][CH2:27][C:28]3[C:23](=[CH:22][CH:21]=[N:20][CH:19]=3)[CH2:24]2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)C1CCC(=O)CC1
Reactant: c1cc2c(cn1)CCNC2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN(Cc1ccccc1)C1CCC(N2CCc3cnccc3C2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 38 %

Procedure:
4-(Benzyl(methyl)amino)cyclohexanone (680 mg, 3.133 mmol, 1.0 eq.) and 1,2,3,4-tetrahydro-2,6-naphthyridine dihydrochloride (713 mg, 3.44 mmol, 1.1 eq.) were dissolved in MeOH (20 ml) and the mixture was stirred for 5 hours at RT. Then the solution was cooled to 0° C., NaCNBH3 (393 mg, 3.26 mmol, 2.0 eq.) was added and the mixture was stirred for 16 hours at RT. The reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography (Alox, 1.2% MeOH in DCM). Yield: 38% (400 mg, 1.194 mmol)
Reaction SMILES: [C:1]([N:4]1[C:8]2([CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH2:7][CH2:6][CH:5]1[C:14]([O:16]CC)=[O:15])(=[O:3])[CH3:2].O.[OH-].[Li+].Cl>C1COCC1.O.CO>[C:1]([N:4]1[C:8]2([CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH2:7][CH2:6][CH:5]1[C:14]([OH:16])=[O:15])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C1CCC2(CCOCC2)N1C(C)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N1C(C(=O)O)CCC12CCOCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.2 %

Procedure:
To a solution of ethyl 1-acetyl-8-oxa-1-azaspiro[4.5]decane-2-carboxylate (170) (93 mg, 0.34 mmol) in THF/water/methanol (1.1 mL/0.6 mL/0.6 mL) was added lithium hydroxide monohydrate (29 mg, 0.69 mmol) and the reaction stirred at room temperature for 3 h. The reaction is treated with 1N HCl (0.7 mL) and partitioned between EtOAc and 0.1 N HCl, the aqueous layer was extracted twice with EtOAc, the combined organic layers were dried over MgSO4 and concentrated in vacuo to afford the title compound as a white solid (79 mg, 95% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C1COCCN1
Reactant: Clc1cc(Cl)cc(I)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: Clc1cc(Cl)cc(N2CCOCC2)c1
Temperature: 80 °C

Procedure:
To a solution of 3,5-dichloroiodobenzene (272 mg, 1 mmol) in anhydrous THF (3 mL) was added morpholine (200 μL, 2 mmol), catalytic (+/−) BINAP (6 mol %), catalytic Pd2(dba)3 (3 mol %) and sodium tert-butoxide (192 mg, 2 mmol). The mixture was sparged with N2 for 5 minutes, then the vial was sealed and heated at 80° C. for 18 h. The reaction mixture was directly purified via flash chromatography on silica gel, eluting with a 0-50% gradient of ethyl acetate/heptane to obtain 4-(3,5-dichlorophenyl)-morpholine as a white solid. 1H NMR (CDCl3, 400 MHz) δ 6.84 (t, J=1.71 Hz, 1H), 6.75 (d, J=1.77 Hz, 2H), 3.81-3.87 (m, 4H), 3.13-3.19 (m, 4H). MS (m/z) 232.2 (M+1).
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].[Cl:7][C:8]1[CH:13]=[C:12]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[CH:10][C:9]=1[CH3:18].[OH-].[Na+]>O>[CH3:18][C:9]1[CH:10]=[CH:11][C:12]([S:14]([OH:16])=[O:15])=[CH:13][C:8]=1[Cl:7]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(S(=O)O)cc1Cl
Temperature: 52.5 °C

Procedure:
2350 ml of water and 420 g (3.3 mol) of sodium sulfite (=15.1% strength Na2SO3 solution) are introduced into a stirrer apparatus equipped with 2 dropping funnels and a pH electrode, and the mixture is heated to 50-55° C. In the course of about 2 h, 677 g (3 mol) of 2-chloro-p-toluenesulfonyl chloride are run in and simultaneously 690 g of NaOH (35% strength) are added dropwise so that a pH of 8-10 is maintained. The temperature is allowed to rise to 65° C. The reaction is completed when the pH remains constant at 8-10. The sodium sulfinate is in solution at 60-65° C., and crystallizes out from about 55° C.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C@@H:30]1[CH2:35][CH2:34][CH2:33][C@H:32]([C:36]#[N:37])[CH2:31]1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOC(C)=O>[C:36]([C@H:32]1[CH2:33][CH2:34][CH2:35][C@H:30]([O:8][C:1](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:31]1)#[N:37]
Reactant: O=C(O)c1ccccc1
Reactant: N#C[C@H]1CCC[C@@H](O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#C[C@H]1CCC[C@H](OC(=O)c2ccccc2)C1
Reaction time: 12 h
Yield: 14.4 %

Procedure:
To a solution of benzoic acid (1.1 g, 8.8 mmol) and PS-triphenylphosphine (6.7 g, 15.5 mmol) in anhydrous THF (40 mL) was added cis-3-hydroxy-cyclohexanecarbonitrile (1.1 g, 8.8 mmol) in anhydrous THF (20 mL). The reaction mixture was cooled while diethyl azodicarboxylate (DEAD) (1.9 mL, 12.3 mmol) was added by syringe over 3 min. The reaction was shaken for 12 h. The mixture was filtered and the resin was washed with ether. The filtrate was concentrated in vacuo to afford an oily solid. Silica gel column chromatography using 95:5 hexanes:EtOAc as an eluent afforded 0.29 g (14%) of benzoic acid trans-3-cyano-cyclohexyl ester as a white solid.
Reaction SMILES: O.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[C:16]([C:20]1[CH:25]=[CH:24][C:23](/[C:26](/[C:45]2[CH:50]=[CH:49][C:48]([O:51][CH:52]([F:54])[F:53])=[C:47]([O:55]CC3C=CC(OC)=CC=3)[N:46]=2)=[CH:27]\[C@@H:28]2[N:32](CC3C=CC(OC)=CC=3OC)[C:31](=[O:44])[CH2:30][CH2:29]2)=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>C(Cl)(Cl)Cl>[C:16]([C:20]1[CH:21]=[CH:22][C:23](/[C:26](/[C:45]2[NH:46][C:47](=[O:55])[C:48]([O:51][CH:52]([F:53])[F:54])=[CH:49][CH:50]=2)=[CH:27]\[C@H:28]2[CH2:29][CH2:30][C:31](=[O:44])[NH:32]2)=[CH:24][CH:25]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: COc1ccc(COc2nc(/C(=C/[C@H]3CCC(=O)N3Cc3ccc(OC)cc3OC)c3ccc(C(C)(C)C)cc3)ccc2OC(F)F)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)c1ccc(/C(=C\[C@H]2CCC(=O)N2)c2ccc(OC(F)F)c(=O)[nH]2)cc1
Temperature: 65 °C
Reaction time: 16 h
Yield: 31.4 %

Procedure:
Water (0.4 mL) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.72 g) were added to a solution of (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-{5-(difluoromethoxy)-6-[(4-methoxybenzyl)oxy]-pyridin-2-yl}ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (511 mg) in chloroform (8 mL), and the mixture was stirred at 65° C. for 16 hours. Water was added to the reaction solution. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:0→1:1→chloroform:methanol=1:0→95:5→9:1) to give the title compound as a colorless oil (96 mg).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Cl:11][C:12]1[CH:13]=[C:14]([CH3:30])[C:15]2[N:16]([C:18]([CH2:27][CH2:28][OH:29])=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:20]=2)[CH:17]=1.C(Cl)(=O)C(Cl)=O.CS(C)=O.C(N(CC)C(C)C)(C)C>C(Cl)Cl.O>[Cl:11][C:12]1[CH:13]=[C:14]([CH3:30])[C:15]2[N:16]([C:18]([CH2:27][CH:28]=[O:29])=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:20]=2)[CH:17]=1
Reactant: Cc1cc(Cl)cn2c(CCO)c(-c3ccccc3)nc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cc(Cl)cn2c(CC=O)c(-c3ccccc3)nc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 27.7 %

Procedure:
A dry round bottom flask was charged with anhydrous CH2Cl2 (4 mL) and anhydrous DMSO (116 μL, 1.63 mmol) and cooled to −78° C. Oxalyl chloride (85 μL, 0.97 mmol) was added and the resulting clear solution was stirred at −78° C. for 1 h. 2-(6-Chloro-8-methyl-2-phenyl-imidazo[1,2-a]pyridin-3-yl)-ethanol 43b (233 mg, 0.81 mmol) was suspended in CH2Cl2 (2 mL) and added via syringe to the oxalyl chloride/DMSO mixture. After the resulting yellow/opaque solution had stirred at −78° C. for 1 h, N,N-diisopropylethylamine (Hunigs base) (705 mL, 4.06 mmol) was added. The solution was warmed to 0° C. and stirred for 2 h. Water (20 mL) was added and the crude reaction was washed with CH2Cl2 (2×30 mL). The organic washes were combined, dried (Na2SO4), filtered and concentrated. The crude product was purified by silica gel column chromatography with 30–80% EtOAc/hexanes to yield the title compound (64 mg, 28%) as an orange oil. 1H NMR (400 mHz, CDCl3) δ 9.74 (d, J=1.47 Hz, 1H), 7.77 (s, 1H), 7.63 (d, J=7.70 Hz, 2H), 7.46–7.35 (m, 4H), 7.00 (d, J=0.73 Hz, 1H), 4.09 (s, 2H), 2.63 (s, 3H); DEPT (100 mHz, CDCl3) CH3: 17.1, CH2: 39.6, CH: 196.0, 128.9, 128.8, 128.4, 125.1, 119.0. Mass spectrum (m/e) 285 (M+1)+.
Reaction SMILES: C[C@@H]1[O:7][C@@H](O[C@@H:9]2[C:14]3=C(O)[C:16]4C(=O)C5C(=CC=CC=5OC)C(=O)[C:17]=4[C:18](O)=[C:13]3[CH2:12][C@@:11](O)(C(CO)=O)[CH2:10]2)C[C@H](N)[C@@H]1O.Cl.C[C@@H]1O[C@@H](O[C@@H]2C3=C(O)C4C(=O)C5C(=CC=CC=5OC)C(=O)C=4[C:58]([OH:59])=[C:53]3[CH2:52][C@@:51]([OH:77])([C:73]([CH2:75][OH:76])=[O:74])C2)C[C@H](N)[C@@H]1O.C#CCCCCCC#C.[OH2:89]>CS(C)=O>[CH:14]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:18][C:17]#[CH:16].[O:89]=[C:75]1[O:76][C@H:52]([C@H:53]([CH2:58][OH:59])[OH:7])[C:51]([OH:77])=[C:73]1[OH:74]
Reactant: O
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1
Agent: C#CCCCCCC#C
Agent: Cl
Solvent: CS(C)=O
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O

Procedure:
100 mg of product 1 are dissolved in 1.1 ml of distilled water; a solution of 200 μl of 1,8-Nonadiyne in 11.23 ml of DMSO are prepared separately, whereas 23.2 mg of doxorubicin hydrochloride are dissolved in 0.5 ml of distilled water. The solution of hyaluronic acid is mixed with that of doxorubicin and with 0.2 ml of that of 1,8-Nonadiyne; 0.1 ml of an aqueous solution obtained with 50 mg of CuSO4.5H2O in 1 ml of H2O and 0.1 ml of an aqueous solution of 20 mg of ascorbic acid are then added. The mixture is stirred vortically for a few minutes. The rapidly formed gel (see FIG. 31) incorporates the doxorubicin hydrochloride inside.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][C:4]([NH:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.[Cl:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1>C1C=CC=CC=1>[Cl:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([N:7]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]2[CH:5]=[CH:6][C:1]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:2][CH:3]=2)=[O:37])=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)CCCNc1ccc(-c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccccc1
Product: CCOC(=O)CCCN(C(=O)c1ccc(Cl)cc1)c1ccc(-c2ccccc2)cc1
Yield: 63.1 %

Procedure:
Analogously to Example 47b), 10.0 g of ethyl 4-(biphenyl-4-yl)aminobutyrate and 4.6 g of ethyldiisopropylamine in 70 ml of benzene are reacted with 6.2 g of p-chlorobenzoyl chloride to obtain 9.4 g (62.9% of theory) of ethyl 4-[p-chloro-N-(biphenyl-4-yl)benzamido]butyrate as a viscous non-distillable oil. Saponification of this ester, analogously to Example 47c), yields 7.0 g (79.7% of theory) of 4-[p-chloro-N-(biphenyl-4-yl)-benzamido]butyric acid, MP 192° to 194°.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:18][CH2:19][CH3:20])=[C:6]([CH:12]2[CH2:16][NH:15][C:14](=[O:17])[CH2:13]2)[C:7](F)=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2].[C-:21]#[N:22].[Na+].O>CS(C)=O>[C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([C:21]#[N:22])=[C:6]([CH:12]2[CH2:13][C:14](=[O:17])[NH:15][CH2:16]2)[C:5]=1[O:18][CH2:19][CH3:20])(=[O:3])[CH3:2]
Reactant: CCOc1c(C(C)=O)cc(Cl)c(F)c1C1CNC(=O)C1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOc1c(C(C)=O)cc(Cl)c(C#N)c1C1CNC(=O)C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
A racemic mixture of 4-(3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (0.20 g, 0.67 mmol) (from Example 345, Step 5) and sodium cyanide (0.057 g, 1.2 mmol) in dimethyl sulfoxide (1.5 mL) was stirred at 80° C. for 3 h. The reaction mixture was poured into water (35 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to give a crude residue. The crude material was purified by flash column chromatography using ether (containing 10% methanol) in hexanes (0%-100%) to give the desired product (0.15 g, 71%) as a mixture of enantiomers. LCMS for C15H16ClN2O3 (M+H)+: m/z=307.1; Found: 307.0. The mixture of enantiomers was separated by chiral HPLC to give the individual enantiomers as peak 1 and peak 2 (RT=5.00 min and 10.4 min; Phenomenex Lux Cellulose C-2, 21.2×250 mm, 5 micron particle size, eluting with 60% ethanol in hexanes at 18 mL/min).
Reaction SMILES: I[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[NH:12]1[CH:16]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:9][C:8]([F:11])([F:10])[C:4]1[N:3]=[C:2]([N:12]2[CH:16]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:14]=[N:13]2)[CH:7]=[N:6][CH:5]=1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: FC(F)(F)c1cncc(I)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)c1cnn(-c2cncc(C(F)(F)F)n2)c1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
Under N2, 2-iodo-6-(trifluoromethyl)pyrazine (CAS 141492-94-6) (0.137 g, 500 μmol, Eq: 1.00), ethyl 1H-pyrazole-4-carboxylate (CAS 37622-90-5) (70.1 mg, 500 μmol, Eq: 1.00) and potassium carbonate (138 mg, 1.00 mmol, Eq: 2) were combined in DMSO (2.4 ml). The orange solution was stirred at 120° C. over 1 hour. Control with TLC: the reaction was finished. At RT, the RM was partitioned between water and EtOAc; extracted; the organic layer was washed with water and brine; dried over MgSO4; filtered; concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20 g, 5% to 25% EtOAc in heptane).