Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH3:17])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[C:12]([Cl:16])[CH:13]=[C:14]([CH3:15])[C:8]2=[N:7]1)[C:3]#[N:4].[O:18]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Cl:16][C:12]1[CH:13]=[C:14]([CH3:15])[C:8]2[C:9]([CH:11]=1)=[N:10][N:6]([CH2:5][C:2]([NH:1][C:29](=[O:30])[C:28]1[CH:27]=[CH:26][C:25]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:33][CH:32]=1)([C:3]#[N:4])[CH3:17])[N:7]=2
Reactant: Cc1cc(Cl)cc2nn(CC(C)(N)C#N)nc12
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Product: Cc1cc(Cl)cc2nn(CC(C)(C#N)NC(=O)c3ccc(Oc4ccccc4)cc3)nc12

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(6-chloro-4-methyl-2H-benzotriazol-2-yl)-2-methylpropionitrile (60 mg, described in Example 27) and 4-phenoxybenzoyl chloride (0.067 mL), the title compound was isolated as a white solid (90 mg, 84%). MS (ES): M/Z [M+H]=446. NMR: (400 MHz, DMSO-d6): 1.73 (s, 3H), 2.47 (s, 3H), 5.38 (d, J=13.3 Hz, 1H), 5.45 (d, J=13.3 Hz, 1H), 7.08 (t, J=8.25 Hz, 4H), 7.23 (t, 1H), 7.28 (s, 1H), 7.45 (t, 2H), 7.84 (d, J=8.79 Hz, 2H), 7.91 (m, 1H) and 8.68 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][O:39][CH2:40][CH2:41][NH2:42]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:42][CH2:41][CH2:40][O:39][CH3:38])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: COCCN
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: COCCNc1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and 2-methoxyethylamine according to conditions described in general procedure C. Mp: 87-88° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.60-1.63 (m, 6 H), 3.00-3.38 (m, 1 H), 6.20-6.40 (m, 1 H), 6.99 (d, J=12.4 Hz, 1 H), 7.09-7.18 (m, 2 H), 7.40 (d, J=7.7 Hz, 1 H), 7.46 (s, 1 H), 7.55-7.62 (m, 3 H), 7.82 (d, J=8.0 Hz, 1 H), 7.99 (d, J=8.0 Hz, 1 H), 8.23 (s, 1 H), 10.43 (s, 1 H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH:11]1([NH2:14])[CH2:13][CH2:12]1.O>CS(C)=O>[CH:11]1([NH:14][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:13][CH2:12]1
Reactant: NC1CC1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccccc1NC1CC1
Yield: 49.7 %

Procedure:
1-fluoro-2-nitrobenzene (1.85 mL, 175 mmol) and cyclopropanamine (2.43 mL, 35 mmol) were stirred in DMSO for 3 hours. Water was added (250 mL) and the mixture was extracted with ether (2×250 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to afford title compound 380 (3.1 g, 99%) as an orange oil. MS (m/z): 178.9 (M+H). 1H NMR (CDCl3) δ (ppm): 8.15 (dd, J=8.6, 1.6 Hz, 1H), 8.09 (s, 1H), 7.49-7.45 (m, 1H), 7.32 (dd, J=8.6, 1.4 Hz, 1H), 6.72-6.67 (m, 1H), 2.60-2.58 (m, 1H), 0.94-0.89 (m, 2H), 0.68-0.64 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:18]=[CH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:13]([CH:17]=1)[C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:23]([O:22][C:20](=[O:21])[CH:19]=[CH:18][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:17][C:13]=1[C:14]([NH:34][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:16])([CH3:25])([CH3:24])[CH3:26]
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(OCc2ccccc2)cc1C(=O)O
Reactant: NCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)C=Cc1ccc(OCc2ccccc2)cc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 39.7 %

Procedure:
To a solution of 5-benzyloxy-2-(2-tert-butoxycarbonyl-vinyl)-benzoic acid (1.45 g, 4.09 mmol) in CH2Cl2 (40 mL) was added benzylamine (0.613 g, 5.73 mmol), EDC (1.254 g, 6.54 mmol), and DMAP (1.00 g, 8.18 mmol). The resulting mixture was stirred at room temperature for 12 h, washed with aqueous NH4Cl (50 mL), and extracted with CH2Cl2 (2×50 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was then purified using silica gel chromatography (hexanes/EtOAc 8/2) to afford the title compound as an oil (720 mg, 40%). 1H NMR (400 MHz, CDCl3): δ 1.52 (s, 9H), 4.63 (d, 2H, J=5.5 Hz), 5.09 (s, 2H), 5.97 (br s, 1H), 6.22 (d, 1H, J=15.6 Hz), 7.01 (dd, 1H, J=2.7, 8.6 Hz), 7.10 (d, 1H, J=2.8 Hz), 7.28-7.42 (m, 10H), 7.55 (d, 1H, J=9.0 Hz), 7.88 (d, 1H, J=16.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:11](I)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:13][CH3:14])[CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[C:11]1[C:2]([Cl:1])=[CH:3][C:4]([O:13][CH3:14])=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=1
Reactant: COC(=O)c1cc(I)c(Cl)cc1OC
Reactant: OB(O)c1cc(Cl)ccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2cc(Cl)ccc2Cl)c(Cl)cc1OC
Yield: 84 %

Procedure:
A mixture of Methyl 4-chloro-5-iodo-2-methoxybenzoate (1.8 g, 5.51 mmol), (2,5-dichlorophenyl)boronic acid (2.1 g, 11.03 mmol), Pd(PPh3)4 (403 mg, 0.55 mmol), Na2CO3 (1.75 g, 16.54 mmol) in 1,4-dioxane (50 mL) and water (5 mL) was stirred at reflux under argon for 16 h. The mixture was filtered and filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=20:1) to afford the desired product (1.6 g, 85% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:43])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[C:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]3)=[CH:26][CH:25]=2)[N:14]=1.C(O)C.[H][H]>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3](=[O:43])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][C:13]1[C:18]([C:19]([F:21])([F:22])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])[CH2:31]3)=[CH:26][CH:25]=2)[N:14]=1
Reactant: [H][H]
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(C3CCCN(C(=O)OC(C)(C)C)C3)cc2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCCN(C(=O)OC(C)(C)C)C3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
tert-Butyl 3-(4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I25) (0.302 g, 0.508 mmol) was dissolved in EtOAc (12 mL) and absolute ethanol (8 mL) under an atmosphere of nitrogen. 10% Pd/C (0.250 g) in EtOAc (4 mL) was added to the solution and the atmosphere was changed to hydrogen gas (balloon). The reaction was sealed with a balloon and stirred at room temperature for 18 hours after which the catalyst was removed by filtration through Celite and the solvent was removed in vacuo. The resulting solid was again dissolved in EtOAc (12 mL) and absolute ethanol (8 mL) under an atmosphere of nitrogen and 10% Pd/C (0.250 g) in EtOAc (4 mL) was added to the solution and the atmosphere was changed to hydrogen gas (balloon). The reaction was sealed with a balloon and stirred at room temperature for 24 hours. The catalyst was removed by filtration through Celite, which was washed with EtOAc (7×10 mL) and the solvent was removed in vacuo to give a pale yellow viscous oil. The crude product was purified by silica gel chromatography (Biotage Isolera, 40 g Si Cartridge, 0-50% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I26) (0.249 g, 82% yield) as a pale yellow viscous oil; 1H NMR (400 MHz, d5-DMSO) δ 10.18 (s, 1H), 8.67 (s, 1H), 7.72-7.64 (m, 2H), 7.26-7.16 (m, 6H), 4.02-3.89 (m, 2H), 3.76 (s, 2H), 3.57 (s, 3H), 3.10-2.95 (m, 4H), 2.91-2.66 (m, 2H), 2.61-2.51 (m, 1H), 1.88 (d, J=11.8 Hz, 1H), 1.75-1.54 (m, 2H), 1.43 (m, 10H). LCMS Method C: rt 7.11 min; m/z 599.3 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)[N:22]=1)[CH2:6][C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:20]=[CH:19][C:15]2[O:16][CH2:17][O:18][C:14]=2[CH:13]=1)=[O:8])#[N:2].N>CO.[Ni]>[NH2:2][CH2:1][CH2:3][CH2:4][N:5]([C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)[N:22]=1)[CH2:6][C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:20]=[CH:19][C:15]2[O:16][CH2:17][O:18][C:14]=2[CH:13]=1)=[O:8]
Reactant: Cc1cc(N(CCC#N)CC(=O)NCCc2ccc3c(c2)OCO3)nc(-n2ccnc2)n1
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cc1cc(N(CCCN)CC(=O)NCCc2ccc3c(c2)OCO3)nc(-n2ccnc2)n1
Reaction time: 16 h

Procedure:
To 2-[(2-cyanoethyl)[2-(1H-imidazol-1-yl)-6-methyl-4-pyrimidinyl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide (2.5 g, 5.8 mmol) (a compound of formula (Yc3)) in MeOH (50 mL) was bubbled ammonia. Raney nickel (1.0 g of a 50% slurry) was added and the reaction was placed on a Parr hydrogenator at 50 psi. After shaking for 16 hours, the pressure was released and the reaction mixture was suction filtered through Celite. The solvent was removed in vacuo and the residue was chromatographed on silica gel (9:1 CH3CN/NH4OH) to afford 2-[(3-aminopropyl)[2-(1H-imidazol-1-yl)-6-methyl-4-pyrimidinyl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide, a compound of formula (Yc6); as a white solid; NMR (DMSO-d6, 90° C.) 8.4 (s, 1), 7.8 (s, 1), 7.0 (s, 1), 6.75 (d, 1), 6.7 (s, 1), 6.6 (d, 1), 5.9 (s, 2), 4.1 (s, 2), 3.6 (br, 2), 3.3 (m, 2), 2.75 (t, 2), 2.6 (t, 2), 2.3 (s, 3), 1.8 (m, 2) ppm.
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)[CH:6]([CH3:8])[CH3:7].[C:19]([CH2:21][NH:22][C:23](=[O:30])[C@@H:24]([OH:29])[CH2:25][CH:26]([CH3:28])[CH3:27])#[N:20].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.CC(C)=O.CCOC(C)=O>C(Cl)Cl.CCOC(C)=O>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([CH:5]([O:29][C@@H:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[C:23]([NH:22][CH2:21][C:19]#[N:20])=[O:30])[CH:6]([CH3:8])[CH3:7])=[CH:10][CH:11]=1
Reactant: CC(C)C[C@H](O)C(=O)NCC#N
Reactant: CC(C)C(OC(=N)C(Cl)(Cl)Cl)c1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(C)C[C@H](OC(c1ccc(Br)cc1)C(C)C)C(=O)NCC#N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of the 1-(4-bromophenyl)-2-methylpropyl 2,2,2-trichloroethanimidoate (2.6 mmol, 0.97 g) in CH2Cl2 (15 mL) was added (2S)-N-(cyanomethyl)-2-hydroxy-4-methylpentanamide from Step 1, Example 67 (3.9 mmol, 0.66 g) and then PPTS (0.26 mmol, 65 mg). The mixture was stirred at r.t. for 20 h. The mixture was diluted with EtOAc and washed with NaHCO3. The organic extract was dried (anhyd. MgSO4) and concentrated under reduced pressure to give an oil. Chromatography (10% Acetone/EtOAc) gave 2 diastereomers.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH2:4][P:5](C(OCC)OCC)(=[O:9])[O:6]CC>Cl>[NH2:1][CH2:2][CH:3]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH2:4][P:5]([OH:9])[OH:6]
Reactant: CCOC(OCC)P(=O)(CC(CN)C1CCCCC1)OCC
Agent: Cl
Product: NCC(CP(O)O)C1CCCCC1
Temperature: 25 °C

Procedure:
A solution of 1.4 g of ethyl 3-amino-2-cyclohexylpropyl(diethoxymethyl)phosphinate in 30 ml of 36% aqueous hydrochloric acid is heated to reflux for a period of 1 hour. The reaction mixture is then allowed to cool to room temperature, concentrated under reduced pressure and co-evaporated twice with 10 ml of water under reduced pressure. The crude product is then dissolved in 20 ml of water washed twice with 20 ml of diethyl ether and the aqueous layer is then separated and evaporated under reduced pressure. The crude product is dissolved in 50 ml of dry ethanol and 5 ml of propylene oxide is added dropwise. The precipitated solid is collected by filtration and dried to give 3-amino-2-cyclohexylpropylphosphonous acid m.p. 235°-240° C., 31P=28.2 ppm (D2O).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[C:10](Cl)=[CH:9][C:8]([CH3:12])=[N:7][C:6]=1[Cl:13])[CH3:2].[CH3:15][CH2:16][O-:17].[Na+]>CCO.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[C:10]([O:17][CH2:16][CH3:15])=[CH:9][C:8]([CH3:12])=[N:7][C:6]=1[Cl:13])[CH3:2]
Reactant: CC[O-]
Reactant: CCOC(=O)c1c(Cl)cc(C)nc1Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1c(OCC)cc(C)nc1Cl
Temperature: 60 °C

Procedure:
To a solution of 2,4-dichloro-6-methylnicotinic acid ethyl ester (2.49 mmol) in 6 mL EtOH was added NaOEt (2.61 mmol). The reaction mixture was heated to 60° C. overnight in a closed vessel. At RT, the mixture was diluted with EtOAc and washed with aq. NH4Cl solution. The organic layer was dried over MgSO4 and concentrated in vacuo. Purification by (KP-SIL™ from Biotage) using Hept/EtOAc (1/1) gives the desired product as beige solid;
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:18](Cl)(=[O:22])[C:19]([CH3:21])=[CH2:20]>C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:18](=[O:22])[C:19]([CH3:21])=[CH2:20])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: C=C(C)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 31 %

Procedure:
Into a reaction vessel fitted with a cooling pipe, a stirrer, a thermometer and a nitrogen feed pipe, 50 parts of 4-nitroaniline, 40 parts of triethylamine and 525 parts of chloroform were fed, and then cooled to 5° C. or below. While the reaction solution obtained was kept at 5° C. or below, a solution prepared by dissolving 41 parts of methacrylic acid chloride in 30 parts of chloroform was dropwise added thereto. After its addition made dropwise was completed, the reaction solution was heated to room temperature, and, as it was, the reaction was carried out for 4 hours. After the reaction was completed, the organic phase formed was washed with 200 parts of ion-exchanged water. This organic phase was then dried with sodium sulfate, and thereafter the solvent was evaporated off under reduced pressure. The residue obtained was purified by silica gel column chromatography to obtain 22 parts of an intermediate N-(4-nitrophenyl)methacrylamide (yield: 31%).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10].[CH2:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([O:1][N:2]2[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]2([CH3:11])[CH3:10])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CC1(C)CCCC(C)(C)N1O
Reactant: C1CCCCC1
Product: CC1(C)CCCC(C)(C)N1OC1CCCCC1

Procedure:
The title compound is prepared from the reaction of 1-oxyl-2,2,6,6-tetramethylpiperidine (TEMPO) and cyclohexane according to the procedure of Example 5.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N+:4]([O-:8])=[C:5]([SH:7])[CH:6]=1.[C:9]([O-:14])(=[O:13])[C:10]([CH3:12])=[CH2:11].[CH3:15]C(N=NC(C#N)(C)C)(C#N)C>C(Cl)Cl>[CH:1]1[CH:2]=[CH:3][N+:4]([O-:8])=[C:5]([SH:7])[CH:6]=1.[C:9]([O-:14])(=[O:13])[C:10]([CH3:12])=[CH2:11].[C:9]([O:14][CH3:15])(=[O:13])[C:10]([CH3:12])=[CH2:11]
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C=C(C)C(=O)[O-]
Agent: [O-][n+]1ccccc1S
Solvent: ClCCl
Product: C=C(C)C(=O)OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 6-ml flask was charged with 0.097 g of pyrithione methacrylate (0.5 mmole), 2.60 ml of methyl nethacrylate (24.5 mmole) and 0.083 g of AIBN (0.5 mmole). The flask was sealed and placed in an oven at 80° C. for 16 hours. After cooling to room temperature, the product was diluted with 15 ml of methylene chloride and filtered. The solution was concentrated via roto-evaporation and 2.18 g of the desired product was isolated as a white polymeric material for an 85.5% yield. The structure was confirmed by NMR and IR. Similar results were obtained by employing either acetyl peroxide, benzoyl peroxide, or lauryl peroxide as the radical initiator.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][CH2:36][NH:37][C:38](=[O:52])[CH2:39][C:40]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[F:53][C:54]1[CH:59]=[CH:58][C:57]([CH2:60][CH2:61][C:62](O)=[O:63])=[CH:56][CH:55]=1.C(N(CC)CC)C>O1CCCC1.C(OCC)C>[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][CH2:36][NH:37][C:38](=[O:52])[CH2:39][C:40]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:45][CH2:44][N:43]([C:62](=[O:63])[CH2:61][CH2:60][C:57]2[CH:58]=[CH:59][C:54]([F:53])=[CH:55][CH:56]=2)[CH2:42][CH2:41]1
Reactant: O=C(CC1(c2ccccc2)CCNCC1)NCCc1ccccc1F
Reactant: O=C(O)CCc1ccc(F)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(CC1(c2ccccc2)CCN(C(=O)CCc2ccc(F)cc2)CC1)NCCc1ccccc1F
Yield: 34 %

Procedure:
Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.311 g, 0.704 mmol) was added to a solution of N-[2-(2-fluoro-phenyl)-ethyl]-2-(4-phenyl-piperidin-4-yl)-acetamide (0.200 g, 0.587 mmol), 3-(4-Fluoro-phenyl)-propionic acid (0.118 g, 0.704 mmol) and triethylamine (0.245 mL, 1.76 mmol) in tetrahydrofuran (5 mL). After 1 hour the mixture was diluted with ethyl ether (20 mL) and washed with saturated aqueous sodium bicarbonate (20 mL) followed by water (2×10 mL). The organic layer was collected, concentrated under reduced pressure and crude product purified by column chromatography on silica gel to give 0.098 g (34%) of N-[2-(2-fluoro-phenyl)-ethyl]-2-{1-[3-(4-fluoro-phenyl)-propionyl]-4-phenyl-piperidin-4-yl}-acetamide. LRMS m/z 491.1 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:25])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[OH:24])=[N:14]1)[CH3:4].I[CH3:27]>C1COCC1>[CH2:3]([O:5][C:6](=[O:25])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:27])=[N:14]1)[CH3:4]
Reactant: CI
Reactant: CCOC(=O)CCCCCCn1ccc(-c2ccccc2O)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CCCCCCn1ccc(-c2ccccc2OC)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.7 %

Procedure:
Add sodium hydride (900 mg, 18 mmol, 60% suspension in mineral oil) to a suspension of 7-[3-(2-hydroxyphenyl)pyrazol-1-yl]heptanoic acid ethyl ester (4.73 g, 15 mmol) and iodomethane (1.1 mL, 18 mmol) in THF (70 mL) at 0° C. under nitrogen and warm the mixture to room temperature to stir for 12 hours. Remove the solvent under reduced pressure, dilute the residue with ethyl acetate (150 mL), wash with water (100 mL), and dry over sodium sulfate. Remove the solvent under reduced pressure and purify the residue by flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (9:1), to provide 7-[3-(2-Methoxyphenyl)pyrazol-1-yl]heptanoic acid ethyl ester (3.75 g, 76%).
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:3]1=2.C([Br:25])(=O)C>C1C=CC=CC=1>[Br:25][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:3]1=2
Reactant: COC(=O)Cc1ccc2c(c1)C(O)c1ccccc1CO2
Reactant: CC(=O)Br
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc2c(c1)C(Br)c1ccccc1CO2

Procedure:
A mixture of 5.7 g. of methyl 6,11-dihydro-11-hydroxydibenz[b,e]oxepin-2-acetate, 5 ml. of acetyl bromide and 60 ml. of dry benzene is refluxed for two hours. Evaporation in vacuo provides methyl 6,11-dihydro-11-bromodibenz[b,e]oxepin-2-acetate as a yellow oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]1[S:24][C:25](Br)=[CH:26][CH:27]=1)[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][S:30]([C:33]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[CH:35][C:34]=1[CH2:48][OH:49])(=[O:32])=[O:31].[F-].[Cs+].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.COCCOC>[CH2:1]([N:8]([CH2:22][C:23]1[S:24][C:25]([C:37]2[CH:36]=[CH:35][C:34]([CH2:48][OH:49])=[C:33]([S:30]([CH3:29])(=[O:32])=[O:31])[CH:38]=2)=[CH:26][CH:27]=1)[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1C(F)(F)F)N(Cc1ccccc1)Cc1ccc(Br)s1
Reactant: CC1(C)OB(c2ccc(CO)c(S(C)(=O)=O)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: CS(=O)(=O)c1cc(-c2ccc(CN(Cc3ccccc3)S(=O)(=O)c3ccccc3C(F)(F)F)s2)ccc1CO
Temperature: 80 °C
Yield: 39 %

Procedure:
A suspension of N-benzyl-N-(5-bromo-thiophen-2-ylmethyl)-2-trifluoromethyl-benzenesulfonamide (example 1, step 2, 170 mg), [2-methanesulfonyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanol (CAS [918328-16-2], 90 mg), cesium fluoride (88 mg) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct (12 mg) in a 1 M aqueous sodium carbonate solution (0.72 mL) and 1,2-dimethoxyethane (1.5 mL) was heated to 80° C. for 36 h. After cooling to r.t., the mixture was filtered. The filtrate was diluted with ethyl acetate and washed with water. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 1:0 to 0:1) to give N-benzyl-N-[5-(4-hydroxymethyl-3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide (67 mg) as an off-white solid. MS: 612.6 ([M+NH4]+)
Reaction SMILES: [F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[C:11]([O:13]CC)=O.O=S(Cl)[Cl:18]>C1(C)C=CC=CC=1.[OH-].[Na+]>[F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[C:11]([Cl:18])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1c(C(F)F)nn(C)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cn1nc(C(F)F)c(C(=O)Cl)c1F
Temperature: 80 °C

Procedure:
A solution of 22.3 g (100 mmol) of ethyl 5-fluoro-1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylate in 100 ml of toluene and 50 ml of 10% NaOH are stirred at AT for 3 hours. The aqueous phase is separated and adjusted to pH 5 with HCl. After extracting the product with chlorobenzene and azeotropically drying the organic phase, 23.8 g (200 mmol) of SOCl2 are added to the solution and the mixture is heated at 80° C. for 2 hours. After evaporating the reaction mixture, 20.1 g of the product are obtained as an oil with a purity (GC) of 98%.