Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(OCC(C)C)=O.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C@H:17]2[C@:21]3([N:25]([CH3:26])[C:24](=[O:27])[N:23]([C:28]4[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=4)[C:22]3=[O:36])[CH2:20][N:19]([CH2:37][C:38](O)=[O:39])[CH2:18]2)=[CH:13][CH:12]=1)#[N:10].C[N:42]1CCOCC1.N>C(Cl)Cl.O>[C:9]([C:11]1[CH:12]=[CH:13][C:14]([C@H:17]2[C@:21]3([N:25]([CH3:26])[C:24](=[O:27])[N:23]([C:28]4[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=4)[C:22]3=[O:36])[CH2:20][N:19]([CH2:37][C:38]([NH2:42])=[O:39])[CH2:18]2)=[CH:15][CH:16]=1)#[N:10]
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CN(CC(=O)O)C[C@H]2c1ccc(C#N)cc1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: ClCCl
Solvent: O
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CN(CC(N)=O)C[C@H]2c1ccc(C#N)cc1
Reaction time: 1 h
Yield: 55.3 %

Procedure:
Isobutyl chloroformate (27 μl, 0.21 mmol) was added to a cooled (5° C.) suspension of Example 64 (90 mg, 0.19 mmol) and N-methyl morpholine (23 μl, 0.2 mmol) in DCM (4 ml). After 1 h, ammonia (420 μl, 0.5 M in dioxane, 0.21 mmol) was added. After 1 h at 5° C. and 3 h at RT, water (2 ml) was added. The organic layer was separated and the aqueous layer extracted with DCM. The combined organic layers were concentrated in vacuo and the resulting material was purified by chromatography over silica gel (eluent: DCM/MeOH 95/5) to yield the above-titled compound as a solid (49.6 mg). 1H NMR (CDCl3): 7.64 (2H, d, J=8.2 Hz), 7.25–7.30 (3H, m), 6.84 (1H, br s), 6.65 (2H, d, J=1.5 Hz), 6.18 (1H, br s), 3.87 (1H, t), 3.4–3.5 (5H, m), 3.24 (3H, s), 3.15 (1H, d, J=10.9 Hz).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:20]=[CH:19][C:7]([O:8][CH:9]2[CH2:12][N:11]([CH2:13][CH2:14][CH2:15][C:16](O)=[O:17])[CH2:10]2)=[CH:6][CH:5]=1.S(Cl)([Cl:25])=O>>[F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:20]=[CH:19][C:7]([O:8][CH:9]2[CH2:12][N:11]([CH2:13][CH2:14][CH2:15][C:16]([Cl:25])=[O:17])[CH2:10]2)=[CH:6][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCN1CC(Oc2ccc(OC(F)(F)F)cc2)C1
Product: O=C(Cl)CCCN1CC(Oc2ccc(OC(F)(F)F)cc2)C1
Yield: 97 %

Procedure:
4-(3-(4-(trifluoromethoxy)phenoxy)azetidin-1-yl)butyric acid (412 mg, 1.29 mmol) was dissolved in thionyl chloride, raised the temperature to reflux for 3 h, spun dry, residuals were washed by an appropriate amount of ethyl ether, generated 421 mg target product, yield was 97%, directly put to the next reaction step.
Reaction SMILES: [CH:1](=[C:8]1[NH:12][C:11](=[O:13])[NH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])(=[O:18])[CH:16]=[CH2:17].[OH-].[K+].CN(C=O)C>C1(C)C=CC=CC=1>[CH:1](=[C:8]1[C:9](=[O:14])[N:10]([CH2:17][CH2:16][C:15]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18])[C:11](=[O:13])[NH:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=O)OCC(C)C
Reactant: O=C1NC(=O)C(=Cc2ccccc2)N1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)COC(=O)CCN1C(=O)NC(=Cc2ccccc2)C1=O
Temperature: 110 °C
Reaction time: 2 h
Yield: 81.1 %

Procedure:
20 g (0.106 mol) of benzalhydantoin, 14.9 g (0.117 mol) of isobutyl acrylate and 1.2 g (0.02 mol) of potassium hydroxide were added to 150 ml of DMF, and the mixture was stirred at 110° C. for 2 hours. After cooling, the reaction solution was added with 300 ml of toluene and crystallized. The crystals were filtered out and dried to obtain 27.2 g of isobutyl 4-benzylidene-2,5-dioxo-1-imidazolidinepropionate (yield: 81%).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](O)=O)[C:7]([CH3:16])=[CH:6]2)#[N:2].[OH:21][NH:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1)=[NH:24]>>[CH3:16][C:7]1[N:8]([CH2:12][C:13]2[O:21][N:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:32])[F:34])[CH:26]=3)[N:24]=2)[C:9]2[C:5]([CH:6]=1)=[C:4]([C:17]([F:19])([F:18])[F:20])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=2
Reactant: N=C(NO)c1cccc(C(F)(F)F)c1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=O)O
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1nc(-c2cccc(C(F)(F)F)c2)no1

Procedure:
Synthesized as described in Example 37 using [5-cyano-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl]acetic acid and N-hydroxy-3-(trifluoromethyl)benzenecarboximidamide: 1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 8.20 (d, J=7.8 Hz, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.60 (m, 3H), 6.69 (s, 1H), 5.60 (s, 2H), 2.65 (s, 3H); MS (ES) m/z 473 (M+Na).
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][C:7](/[CH:11]=[CH:12]/[C:13]([NH:15][CH:16]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:17]([F:20])([F:19])[F:18])=[O:14])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.CN1CC[O:35][CH2:34][CH2:33]1.C(OC(=O)C)(=O)C>ClCCl>[C:34]([NH:1][CH:2]1[C:10]2[C:5](=[CH:6][C:7](/[CH:11]=[CH:12]/[C:13]([NH:15][CH:16]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=3)[C:17]([F:18])([F:19])[F:20])=[O:14])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)(=[O:35])[CH3:33]
Reactant: CN1CCOCC1
Reactant: NC1CCc2cc(/C=C/C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)ccc21
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)NC1CCc2cc(/C=C/C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
150 mg of (2E)-3-(1-amino-2,3-dihydro-1H-inden-5-yl)-N-{2,2,2-trifluoro-1-[3-(trifluoromethyl)-phenyl]ethyl}acrylamide were dissolved in 5 ml of dichloromethane, admixed with 71 mg of N-methylmorpholine and 36 mg of acetic anhydride, and stirred at room temperature overnight. The reaction mixture was concentrated on a rotary evaporator to obtain 165 mg of (2E)-3-(1-acetamido-2,3-dihydro-1H-inden-5-yl)-N-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}acrylamide (100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH2:16])[CH2:12][CH2:13][CH2:14][CH3:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38])(OCC)=O>O.C(#N)C>[C:29]1(=[O:38])[N:16]([CH:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:12][CH2:13][CH2:14][CH3:15])[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]12
Reactant: CCCCC(N)c1ccc(OC)c(OC)c1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCCCC(c1ccc(OC)c(OC)c1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
To a stirred solution of 1-(3′,4′-dimethoxyphenyl)pentylamine (0.3 grams, 1.34 mmol) and sodium carbonate (0.15 grams, 1.45 mmol) in a mixture of water (10 milliliters) and acetonitrile (10 milliliters) was added N-carbethoxyphthalimide (0.29 grams, 1.34 mmol). The resulting solution was stirred for 3 hours at room temperature, the acetonitrile was evaporated and a two phase mixture resulted. The organic phase was extracted into methylene chloride, dried over magnesium sulfate and concentrated to afford 0.41 grams of crude product as an oil. The crude product was purified by flash chromatography (silica gel, 30% ethyl acetate/hexane) to afford 0.18 grams (38%) of the product as an oil: 1H NMR (CDCl3) δ7.88-7.63(m, 4H), 7.20-7.07(m, 2H),6.82-6.76(m, 1H), 5.34-5.18(m, 1H), 3.89(s, 3H), 3.85(s, 3H),2.66-2.43(m, 1H),2.40-2.17(m, 1H), 1.50-1.20(m, 2H), 0.96-0.81(m, 3H). 13C NMR (CDCl3) δ1.68.5, 148.8, 148.5, 133.8, 132.5, 131.9, 123.1, 120.6, 111.6, 110.8, 55.9, 55.8, 55.0, 30.9, 29.2, 22.3, 13.9.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][C:4]([NH:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][C:14]=2[C:15]#[N:16])=[CH:3]1.C(=O)([O-])[O-].[K+].[K+].O1CCCC1>CO>[NH2:16][C:15]1[C:14]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:8]=[C:4]2[CH2:5][CH2:6][CH2:7][C:2](=[O:1])[C:3]=12
Reactant: N#Cc1ccncc1NC1=CC(=O)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1c2c(nc3cnccc13)CCCC2=O
Yield: 90.9 %

Procedure:
A mixture consisting of 3-(1-oxo-2-cyclohexen-3-yl)amino-4-cyanopyridine (3.3 g), potassium carbonate (2.35 g), cuprous chloride (153 mg) and 80 ml of tetrahydrofuran was refluxed for 1 hour. To the mixture was added 25 ml of methanol and the inorganics were removed by filtration. The filtrate liquid was then passed through a packed column and eluted with ethyl acetate to give 3.0 g of solid, mp 237°-242° C. This was recrystallized from n-butyl acetate to give 1.85 g of crystals, mp 242.5°-245° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C@@H:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH2:13]Cl)[CH:3]=1.[I-:21].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C@@H:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH2:13][I:21])[CH:3]=1
Reactant: [I-]
Reactant: N#Cc1ccc(Cl)cc1O[C@H](CCCl)c1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Product: N#Cc1ccc(Cl)cc1O[C@H](CCI)c1ccccc1
Yield: 84 %

Procedure:
4-Chloro-2-{[(1R)-3-chloro-1-phenylpropyl]oxy}benzonitrile (220mg, 0.718 mmol) was dissolved in acetone (20 ml) which had previously been saturated with sodium iodide and the solution was heated under reflux for 18 h. The reaction mixture was cooled, filtered, evaporated and the residue partitioned between water and ethyl acetate. The organic layer was separated, washed twice with water and dried (magnesium sulphate). The solvent was evaporated to leave 0.24 g (84%) of the product as a yellow oil. This was used without purification for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:18]=[N:19][C:20]([C:23](=[O:26])[NH:24][CH3:25])=C[CH:22]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].COC(C1C=C(OC2C=[N:45]C(C(O)=O)=NC=2)C2CC(C)(C)OC=2C=1)=O.CN>>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[N:45][C:20]([C:23](=[O:26])[NH:24][CH3:25])=[N:19][CH:18]=2)[C:8]2[CH2:9][C:10]([CH3:12])([CH3:13])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(Oc2cnc(C(=O)O)nc2)c2c(c1)OC(C)(C)C2
Reactant: CNC(=O)c1ccc(Oc2cc(C(=O)OC)cc3c2CC(C)(C)O3)cn1
Agent: CN
Product: CNC(=O)c1ncc(Oc2cc(C(=O)OC)cc3c2CC(C)(C)O3)cn1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 166b, from 5-(6-methoxycarbonyl-2,2-dimethyl-2,3-dihydro-benzofuran-4-yloxy)-pyrimidine-2-carboxylic acid (171c) (72.3 mg, 0.21 mmol) and methyl amine (2 mL, 2.0 M solution in THF) to give a white solid (45 mg, 60% yield). 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 2 H) 7.88 (d, J=3.79 Hz, 1 H) 7.28 (d, J=10.11 Hz, 1 H) 7.19 (s, 1 H) 3.88 (s, 3 H) 3.08 (d, J=5.05 Hz, 3 H) 2.92 (s, 2 H) 1.49 (s, 6 H); LCMS for C18H19N3O5 m/z 358.20 (M+H+).
Reaction SMILES: Cl[CH2:2][CH:3]=[CH:4][CH2:5][C:6]([CH3:13])([CH3:12])[CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9].[NH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.[O-2].[Mg+2].C1COCC1>C(OCC)C>[CH3:12][C:6]([CH3:13])([CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:5][CH:4]=[CH:3][CH2:2][NH:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: NCCN1CCNCC1
Reactant: CC(C)(C)CC(C)(C)CC=CCCl
Agent: [Mg+2]
Agent: [O-2]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)CC(C)(C)CC=CCNCCN1CCNCC1

Procedure:
In a similar manner to Example 4, 10 g (4.95 mmol) of 1-chloro-5,5,7,7-tetramethyl-2-octene, 64 g (495 mmol) of 1-(2-aminoethyl)piperazine, 10 g (248 mmol) of magnesium oxide and 30 ml of THF are refluxed for 4 h. The mixture is diluted with 300 ml of diethyl ether and extracted once each with 5% strength aqueous NaOH and water, concentrated and dried at 40° C./1 mbar. Yield: quantitative.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][C:9](=[O:11])[CH2:8][C:7](=[O:12])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:13]1([CH3:25])[CH:18]=[CH:17][C:16]([S:19]([N:22]=[C:23]=[O:24])(=[O:21])=[O:20])=[CH:15][CH:14]=1>C1C=CC=CC=1>[C:1]([CH:5]1[CH2:6][C:7](=[O:12])[CH:8]([C:23](=[O:24])[NH:22][S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:25])=[CH:14][CH:15]=2)(=[O:20])=[O:21])[C:9](=[O:11])[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CC(=O)CC(=O)C1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)NC(=O)C2C(=O)CC(C(C)(C)C)CC2=O)cc1

Procedure:
Reaction of 5-tert.-butyl-1,3-cyclohexanedione with p-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5-tert.-BUTYL-2-(N-p-TOLUENESULFONYLCARBAMOYL)-1,3-CYCLOHEXANEDIONE, m.p. 161.5°-163° C. (corr.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34](O)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:17](=[O:18])[C:16]4[C:15]5[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=5)[NH:9][C:8]=4[C:7]([CH3:21])([CH3:22])[C:6]=3[CH:23]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
8-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A6, 30 mg, 0.099 mmol) was dissolved in THF (1 mL), added with 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (40 mg, 2 eq.), triphenylphosphine (52 mg, 2 eq.), and diisopropyl azodicarboxlyate (43 μL, 2 eq.) in order, and stirred at room temperature for 4 hr. The reaction solution was poured to water, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (37 mg, 76%).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[N:6]1[CH:11]=[CH:10][CH:9]=[N:8][C:7]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C>C1COCC1>[Br:1][CH2:2][C:3]([N:15]1[CH2:16][CH2:17][N:12]([C:7]2[N:6]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:13][CH2:14]1)=[O:4]
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CBr)N1CCN(c2ncccn2)CC1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
20.2 g bromacetylbromide was dropped to 16.5 g 1-pyrimidin-2-yl-piperazin and 10.2 g triethylamine in 250 mL THF. The reaction was stirred over night at RT and evaporated. The residue was extracted with DCM and water. The organic layer was evaporated and the residue was crystallized with petrolether and then purified by chromatography on silica gel (DCM/MeOH:95/5) to yield 36 mg of the desired compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1)(=[O:9])[CH3:8]>O1CCOCC1>[C:7]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([S:17]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:19])=[O:18])=[CH:15][CH:16]=1)(=[O:9])[CH3:8]
Reactant: C1CCNCC1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(S(=O)(=O)N2CCCCC2)cc1
Temperature: 80 °C
Yield: 52.14 %

Procedure:
Piperidine (0.0114 Mol) is added to a solution of 4-acetamidophenylsulfonyl chloride (1.34 g, 0.0057 mol) in dioxane (5 mL). The mixture is heated for 1 hour at 80° C., then part of the solvent is removed by evaporation at reduced pressure, and water is added until precipitation of the resulting sulfonamide. The product is collected by filtration as a white solid (52.14% yield) and used without further purification. m.p. 137° C.-139° C. 1H NMR (acetone-d6): δ 1.35-1.43 (m, 2H); 1.52-1.63 (m, 4H); 2.17 (s, 3H); 2.89-2.95 (m, 4H); 7.68-7.70 (d, 2H, J=7); 7.90-7.92 (d, 2H, J=7); 9.55 (bs, 1H). In a similar fashion, the following sulfonamides were prepared:
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[I:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.O>[ClH:1].[I:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:12][CH:11]=1
Reactant: BrCc1ccc(I)cc1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CNCc1ccc(I)cc1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 29 %

Procedure:
A suspension of ethyl glycinate hydrochloride (944 mg) in DMF (6.0 mL) was stirred for 5 min. p-Iodobenzyl bromide (2.00 g) was added. The heterogeneous system was warmed to 50° C. and stirred for 5 min, during which time, most solids dissolved. K2CO3 (2.80 g, granular) was added steadily over 5 min. After 2 h, the reaction was cooled to 23° C. Conc. aq. HCl (3.3 mL) was added, followed by H2O (7.0 mL). The heterogeneous mix was stirred for 15 min and filtered (the cake was washed with CH3CN (4×5 mL)). The net filtrate was concentrated until no CH3CN remained. The crude product solution was filtered through a 0.45 micron Teflon filter and loaded directly onto a Teledyne Isco ‘gold’ 100 gram column and flashed (Eluent: 0.05% w/v aq. HCl/CH3CN 95:5→0:100), giving DK (688 mg, 29% yield) as an HCl salt. 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 9.78 (s, 2H), 7.84 (d, J=7.8 Hz, 2H), 7.36 (d, J=7.8 Hz, 2H), 4.23 (q, J=7.0 Hz, 2H), 4.15 (s, 2H), 3.95 (s, 2H), 1.25 (t, J=7.0 Hz, 3H). LCMS-ESI+: calc'd for C11H15INO2: 320.0 (M+H+). Found: 319.9 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[N:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:12]([C:3]1[CH:4]=[CH:5][C:6]([O:11][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[N:23])=[C:7]([CH2:8][CH2:9][CH3:10])[C:2]=1[OH:1])(=[O:14])[CH3:13]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: N#CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCCCC#N)ccc(C(C)=O)c1O
Yield: 83 %

Procedure:
A mixture of 5.8 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 5.4 ml of 7-bromoheptanenitrile and 8.3 g of anhydrous potassium carbonate in 50 ml of dimethyl formamide was stirred and heated at 75° for 20 hours. The reaction mixture was filtered and the filtrate was concentrated on the oil pump. The residual oil was chromatographed on 200 g of silica gel using 5% ethyl acetate-toluene to give 7.5 g (83% yield) of 7-(4-acetyl-3-hydroxy-2-propylphenoxy)heptane nitrile. This was dissolved in 200 ml of ether-methanol (1:1) and cooled in an ice bath while a stream of hydrochloric acid gas was introduced for 10 minutes. The reaction mixture was kept at 3° for 1 hour and at room temperature for 16 hours. Water (40 ml) was added and most of the solvent was removed in vacuo. The residue was treated with sodium bicarbonate solution to basify and the product was extracted with ether. The crude product was dissolved in 140 ml of methanol, treated with 120 ml of 1N sodium hydroxide and the solution was heated on the steam bath for 10 minutes and left at room temperature for 66 hours. The methanol was removed in vacuo and the aqueous solution was extracted with ether. The basic aqueous layer was acidified and extracted with ether. The dried (over magnesium sulfate) extract was concentrated and chromatographed on 50 g of silica gel. Elution with acetic acid (5): ethyl acetate (25): toluene (70) and crystallization of the combined pure fractions from ether-hexane gave 2.20 g, mp 64°-66°, of 7-(4-acetyl-3-hydroxy-2-propylphenoxy)heptanoic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@@H:8]([C:17](=[O:22])N(OC)C)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])([CH3:4])([CH3:3])[CH3:2].[C:24]([NH:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][C:31]=1[CH3:36])(C)([CH3:26])[CH3:25]>>[C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[C:17](=[O:22])[CH2:36][C:31]1[C:30]([C:29](=[O:37])[NH:28][CH:24]([CH3:25])[CH3:26])=[CH:35][CH:34]=[CH:33][N:32]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ncccc1C(=O)NC(C)(C)C
Reactant: CON(C)C(=O)[C@@H](Cc1ccccc1F)NC(=O)OC(C)(C)C
Product: CC(C)NC(=O)c1cccnc1CC(=O)[C@@H](Cc1ccccc1F)NC(=O)OC(C)(C)C

Procedure:
Using general procedure 2 with [(R)-2-(2-fluoro-phenyl)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester (0.65 g, 2.0 mmol) and substituting N-isopropyl-2-methyl-nicotinamide for N-tert-butyl-2-methyl-nicotinamide gives the title compound.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]=[CH:13][C:12]2=[O:17])=[CH:7][CH:6]=1.[CH2:20]([N:27]([CH2:31][Si](C)(C)C)[CH2:28]OC)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:20]([N:27]1[CH2:31][CH:14]2[CH:13]([C:12](=[O:17])[N:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][C:2]([F:1])([F:18])[F:19])=[CH:6][CH:7]=3)[CH2:16][CH2:15]2)[CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C1C=CCCN1c1ccc(OCC(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1C2CN(Cc3ccccc3)CC2CCN1c1ccc(OCC(F)(F)F)cc1
Temperature: 45 °C
Reaction time: 30 h
Yield: 309.1 %

Procedure:
A mixture of 1-[4-(2,2,2-Trifluoro-ethoxy)-phenyl]-5,6-dihydro-1H-pyridin-2-one (0.27 g, 0.1 mmol), N-benzyl(methoxy)-N-((trimethylsilyl)methyl)methanamine (0.71 g, 0.3 mmol) and TFA (0.114 g, 0.1 mmol) in 20 mL of DCM was stirred at 45° C. for 30 h. The mixture was evaporated to dryness and the residue was purified by silica-gel column chromatography (eluting with petroleum ether/ethyl acetate=1:1) to obtain the title compound as colorless oil (0.125 g, 31%). LC-MS: 405.2 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].[Br:20][C:21]1[CH:22]=[C:23]([SH:27])[CH:24]=[CH:25][CH:26]=1>CC(C)=O>[Br:20][C:21]1[CH:22]=[C:23]([S:27][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:3]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: Sc1cccc(Br)c1
Reactant: Brc1cccc(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Brc1cccc(Sc2cccc(-c3ccccc3)n2)c1
Temperature: 90 °C

Procedure:
2-Bromo-6-phenyl-pyridine (13) (100 mg, 0.43 mmol), K2CO3 (117 mg, 0.85 mmol) in acetone (2 mL) was added 3-bromothiophenol and the reaction mixture was heated in a CEM Discover microwave for 1×30 minutes at 90° C., then 4×2 hours at 130° C., followed by 1×8 hours at 130° C. The crude product was partially purified by column chromatography eluting with 10% EtOAc in heptane to give the title compound. Yield: 100 mg, 68%; LC-MS tr 1.97 min; HPLC Purity: 55%; MS (ES+) m/z 342, 344 (M+H)
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CS(O)(=O)=O.[N-:16]=[N+]=[N-].[Na+].[OH-].[Na+]>C(Cl)Cl>[NH:16]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2][C:1]1=[O:10]
Reactant: O=C1CCc2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C1CCc2ccccc2N1
Temperature: 0 °C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
Step 1 A solution of 2,3-dihydro-1H-inden-1-one (1 g, 7.57 mmol) in DCM (10 mL) was treated with methanesulfonic acid (10 mL) and cooled to 0° C. Sodium azide (0.984 g, 15.13 mmol) was added and the mixture was stirred at 0° C. for 2 h, then at rt overnight. The mixture was made basic with 20% aqueous sodium hydroxide and extracted with DCM. The organic phase was washed with water, dried and concentrated. The residue was purified by column chromatography (eluting with hexane-EtOAc) to provide 3,4-dihydroquinolin-2(1H)-one as a white solid (655 mg, 60%). 1H NMR (400 MHz, methanol-d4) δ 7.08-7.19 (2H, m), 6.92-6.99 (1H, m), 6.85 (1H, d, J=7.9 Hz), 5.47 (1H, s), 2.92 (2H, t, J=7.6 Hz), 2.49-2.58 (2H, m). Mass spectrum m/z 148.1 (M+H)+. Also obtained was 3,4-dihydroisoquinolin-1(2H)-one as a colorless oil (162 mg, 15%). 1H NMR (400 MHz, methanol-d4) δ 7.93 (1H, dd, J=7.8, 1.0 Hz), 7.44-7.52 (1H, m), 7.35 (1H, td, J=7.6, 1.2 Hz), 7.29 (1H, d, J=7.7 Hz), 3.50 (2H, t, J=6.6 Hz), 2.98 (2H, t, J=6.7 Hz). Mass spectrum m/z 148.1 (M+H)+.