Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[N:7]=[C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:29])[CH2:18][N:19]3[C:23]([CH3:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[N:20]3)[CH2:13][CH2:12]2)[S:9][CH:10]=1)(=[O:5])[CH3:4].[F:30][C:31]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:32]=1[CH:33]=O>CO.O>[F:30][C:31]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:32]=1/[CH:33]=[CH:4]/[C:3]([C:6]1[N:7]=[C:8]([CH:11]2[CH2:12][CH2:13][N:14]([C:17](=[O:29])[CH2:18][N:19]3[C:23]([CH3:24])=[CH:22][C:21]([C:25]([F:26])([F:28])[F:27])=[N:20]3)[CH2:15][CH2:16]2)[S:9][CH:10]=1)=[O:5]
Reactant: CC(=O)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Reactant: O=Cc1c(F)cccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)/C=C/c3c(F)cccc3F)cs2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At room temperature, a solution of sodium hydroxide (19 mg) in methanol (0.25 ml) and water (0.05 ml) was added to a solution of 1-[4-(4-acetyl-1,3-thiazol-2-yl)piperidin-1-yl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (190 mg) and 2,6-difluorobenzaldehyde (67 mg) in methanol (0.12 ml). The reaction mixture was stirred at room temperature overnight. After aqueous work-up, the mixture was extracted with ethyl acetate and the extracts were dried with sodium sulphate and concentrated under reduced pressure. The residue was purified chromatographically. This gave (2E)-3-(2,6-difluorophenyl)-1-[2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]prop-2-en-1-one (160 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][C@:4]12[C:10]([CH3:12])([CH3:11])[C@H:7]([CH2:8][CH2:9]1)[CH2:6][C@@H:5]2[NH:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([CH3:27])[C:20]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:15].[CH3:28]I.O>CN(C)C=O>[CH3:28][N:13]([C@H:5]1[CH2:6][C@@H:7]2[C:10]([CH3:11])([CH3:12])[C@@:4]1([CH3:3])[CH2:9][CH2:8]2)[C:14]([C:16]1[CH:17]=[N:18][N:19]([CH3:27])[C:20]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:15]
Reactant: Cn1ncc(C(=O)N[C@H]2C[C@H]3CC[C@]2(C)C3(C)C)c1-c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)c1cnn(C)c1-c1ccccc1)[C@H]1C[C@H]2CC[C@]1(C)C2(C)C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in mineral oil; 15 mg, 0.375 mmol) is added to a cooled (˜0° C.) solution of 1-methyl-5-phenyl-1H-pyrazole-4-carboxylic acid ((1R,2S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]hept-2-yl)-amide (of Example 91; 100 mg, 0.3 mmol) in dry dimethylformamide (10 mL) and the mixture is allowed to stir for 30 min. Methyl iodide (30 μL, 0.49 mmol) is added and the solution is stirred at room temperature until the reaction is complete, as judged by TLC. Water is added and the solution is extracted twice with ethyl acetate. The combined organic layers are washed with water and brine, dried (magnesium sulfate), filtered, evaporated, and purified by C-18 reversed phase HPLC with a gradient of 10-100% acetonitrile/water containing 0.1% TFA as a modifier to give 1-methyl-5-phenyl-1H-pyrazole-4-carboxylic acid methyl-((1R,2S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]hept-2-yl)-amide.
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=O.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>O.CN(C=O)C>[CH3:8][CH:2]([CH3:1])[CH2:3][CH2:4][C:5]([N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7]
Reactant: CC(C)CCC(=O)O
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CCC(=O)N1CCCCC1

Procedure:
4-Methylvaleric acid (238 g) and DMF (833 mL) were mixed. After an addition of piperidine (233 mL), HOBt.H2O (361 g) and WSC.HCl (452 g) to the mixture at ice temperature, the resulting mixture was stirred at RT overnight. To the reaction was added water (1000 mL) at ice temperature and the resulting mixture was extracted with toluene (500 mL×2). The organic layer was washed with aqueous 10 w/v % sodium carbonate (500 mL+300 mL) and water (500 mL×2). The organic layer was concentrated in vacuo to give the title compound (414.29 g) as a crude product.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH2:6][N:7]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:10]=3[C:11]=2[N:12]=1.[CH3:25][NH2:26]>CN(C)C=O>[Cl:17][C:15]1[CH:14]=[CH:13][C:10]2[C:11]3[N:12]=[C:2]([NH:26][CH3:25])[N:3]=[CH:4][C:5]=3[CH2:6][N:7]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9]=2[CH:16]=1
Reactant: Fc1ccccc1C1=NCc2cnc(Cl)nc2-c2ccc(Cl)cc21
Reactant: CN
Solvent: CN(C)C=O
Product: CNc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Temperature: 0 °C
Reaction time: 64 h

Procedure:
A solution of 1 g(0.00279 mol) of 2,9-dichloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine in 4 ml of N,N-dimethylformamide was cooled in an ice bath and saturated with methylamine. After 64 hr at room temperature, 50 ml of ice water was added and the reaction was filtered. The precipitated was partitioned between 50 ml ofdichloromethane and 50 ml of water, and the organic layer was washed with 25 ml of brine solution, dried and evaporated to dryness. The oil was crystallized from ether and then recrystallized from dichloromethane/ether and then from methanol to give the end product as white prisms, mp 172°-179°.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH:7]([CH3:12])[CH2:6]1)=[O:4].[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][C@H:8]([NH:20][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:7]([CH3:12])[CH2:6]1)=[O:4]
Reactant: NCc1ccccc1
Reactant: COC(=O)N1CCC(=O)C(C)C1
Product: COC(=O)N1CC[C@H](NCc2ccccc2)[C@H](C)C1

Procedure:
Racemic cis 4-benzylamino-3-methyl-piperidine-1-carboxylic acid methyl ester was prepared in the same manner from racemic 3-methyl-4-oxo-piperidine-1-carboxylic acid methyl ester. In this instance, benzylamine was used instead of (R)-1-phenylethylamine.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(OC1C(C)=CC2C(=CC=CC=2)C=1C1C=CC([Cl:51])=CC=1Cl)(=O)=O>>[C:1]([O:5][CH:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[Cl:51])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2ccccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: Cc1cc2ccccc2c(-c2ccc(Cl)cc2Cl)c1OS(=O)(=O)C(F)(F)F
Product: Cc1cc2ccccc2c(-c2ccc(Cl)cc2Cl)c1C(OC(C)(C)C)C(=O)O

Procedure:
tert-butoxy-[1-(2,4-dichloro-phenyl)-3-methyl-naphthalen-2-yl]-acetic acid (33) was prepared in a similar manner as compound 3K in Example 1, except starting from 1-(2,4-dichlorophenyl)-3-methylnaphthalen-2-yl trifluoromethanesulfonate instead of 3E. 1H-NMR: 400 MHz, (CD3CN) δ: 7.84 (d, 1H), 7.78 (s, 1H), 7.69 (d, 1H), 7.63 (d, 1H), 7.47-7.54 (m, 2H), 7.37 (app dt, 1H), 7.16 (d, 1H), 5.17 (s, 1H), 2.60 (s, 3H), 1.06 (s, 9H).
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([CH2:9][CH2:10][C:11]([OH:13])=O)[C:4]=1[CH3:14])=[O:2].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH3:14][C:4]1[C:5]([CH2:9][CH2:10][C:11]([N:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)=[O:13])=[C:6]([CH3:8])[NH:7][C:3]=1[CH:1]=[O:2]
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Reactant: CN1CCNCC1
Product: Cc1[nH]c(C=O)c(C)c1CCC(=O)N1CCN(C)CC1

Procedure:
3-(5-Formyl-2,4-dimethyl-1H-pyrrol-3-yl)propionic acid (1.37 g, 6.50 mmol) reacted with 1-methylpiperazine (719.6 mg, 7.15 mmol) to give 3,5-dimethyl-4-[3-(4-methyl-piperazin-1-yl)-3-oxo-propyl]-1H-pyrrole-2-carbaldehyde (1.30 g, 72%.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]1[CH2:9][N:8]([C@@H:10]([CH2:18][CH3:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:7](=[O:20])[CH2:6]1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([O:3][CH2:4][CH:5]1[CH2:9][N:8]([C@@H:10]([CH2:18][CH3:19])[C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[C:7](=[O:20])[CH2:6]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC[C@@H](C(=O)OC(C)(C)C)N1CC(CO)CC1=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H](C(=O)OC(C)(C)C)N1CC(COCc2ccccc2)CC1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 37.1 %

Procedure:
In a 100 ml 3 necked flask, fitted with magnetic stirrer and reflux condenser under inert atmosphere, 1.1 g (60%, 27.5 mmoles, 1.1 eq) of sodium hydride are suspended in 60 ml of DMF and the mixture cooled down to 0° C. 6.37 g (24.8 mmoles, 1 eq) of tert-butyl (2S)-2-[4-(hydroxymethyl)-2-oxo-1-pyrrolidinyl]butanoate 398 in 10 ml of DMF are added cautiously. After 10 min, 3.3 ml (4.75 g, 27.8 mmoles, 1 eq) of benzyl bromide in 10 ml of DMF are added, and stirring continued for 30 min at 0° C., followed by 3 hours at room temperature. The mixture is concentrated to dryness, the residue is suspended in brine/CH2Cl2, decanted and extracted with CH2Cl2. The combined organic phases are dried over MgSO4, concentrated to dryness and the residue is purified by Prep LC (1 kg SiO2, hexane/MTBE, 40:60->0:100) to give 3.2 g of a mixture of t-Bu and Benzyl esters in two fractions, 37% total yields. It is used as such for the next step 7.3.1.b. 1H NMR (250 MHz, (CDCl3): 0.85 (t, 3H), 1.44 (s, 9H), 1.55-1.95 (m, 2H), 2.10 (dd, 1H), 2.45 (dd, 1H), 2.55-2.70 (m, 1H), 3.45-3.55 (m, 1H), 4.40 (dd, 1H), 4.55 (s, 2H), 7.20-7.40 (m, 5H).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:25]([O:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][C:45]=1[O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH:41]=O)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:41][C:40]1[CH:43]=[CH:44][C:45]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])=[C:38]([O:37][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:39]=1
Reactant: CCCCCCCCCCCCOc1ccc(C=O)cc1OCCCCCCCCCCCC
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCCCCCCCOc1ccc(C=C(Br)Br)cc1OCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
To a well stirred solution of CBr4 (6.99 g, 21.1 mmol) in dry CH2Cl2 at 0° C. was added PPh3 (11.05 g, 42.1 mmol) and 3,4-bis-dodecyloxy-benzaldehyde (10.0 g, 21.1 mmol). The resulting mixture was stirred for 1 h at ambient temperature. The reaction mixture was solidified during the time. The solid was dissolved in CH2Cl2, washed with H2O, and dried over anhydrous MgSO4. The solvent was removed under reduced pressure to give an off-white solid. The product was further purified by column chromatography (silica gel, hexanes:dichloromethane=2:1 (v/v)) to give a yellowish white solid (11.37 g, 85.6%).
Reaction SMILES: [C:1]1([N:7]2[C:11]([S:12][CH3:13])=[N:10][C:9]([OH:14])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OO)(=[O:17])C>C(OCC)(=O)C.C(O)(=O)C>[C:1]1([N:7]2[C:11]([S:12]([CH3:13])=[O:17])=[N:10][C:9]([OH:14])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OO
Reactant: CSc1nc(O)nn1-c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CS(=O)c1nc(O)nn1-c1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
An amount of 41.4 g of 1-phenyl-5-methylmercapto-3-hydroxy-1,2,4-triazole is suspended at 50°C in 400 ml of ethyl acetate. An addition is then made dropwise, within 15 minutes, of 60 ml of a 60% solution of peroxyacetic acid in glacial acetic acid at 45°-50°C. After completion of the addition, the solution is stirred for 2 hours at 50°C, and the cooled to 20°C. The precipitated product is filtered off, washed with water, and dried in vacuo. The resulting product is 1-phenyl-5-methylsulphinyl-3-hydroxy-1,2,4-triazole in the form of white crystals, M.P. 180°-182°C.
Reaction SMILES: [K:1].C([O:9][C:10]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[CH:12][C:11]=1[N:23]1[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]1)C1C=CC=CC=1>O.[Pd]>[K:1].[OH:9][C:10]1[CH:15]=[C:14]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:13]=[CH:12][C:11]=1[N:23]1[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]1
Reactant: O=C1CN(c2ccc(Oc3ccccc3)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Pd]
Agent: [K]
Solvent: O
Product: O=C1CN(c2ccc(Oc3ccccc3)cc2O)S(=O)(=O)N1

Procedure:
A solution of 5-(2-benzyloxy-4-phenoxyphenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one potassium salt (0.30 g, 0.67 mmol) in water (10 mL) is hydrogenated at 1 atm over 10% Pd/C (0.05 g) for 24 h. The catalyst is filtered and the water removed by lyophilization to afford the product, 5-(2-hydroxy-4-phenoxyphenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one potassium salt, as an amorphous pale-grey solid: mp=205-210° C.; 1H NMR (DMSO-d6) δ 9.52 (br s, 1H), 7.47-7.41 (m, 3H), 7.19 (t, 1H), 7.08 (d, J=7.57 Hz, 2H), 6.51 (d, J=2.78 Hz, 1H), 6.46 (dd, J=8.59, 2.78 Hz, 1H), 4.06 (s, 2H); MS (M−H)−=319.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.[NH2:9][NH2:10]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:9][NH2:10])[N:3]=1
Reactant: NN
Reactant: Fc1cccc(Br)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NNc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-6-fluoropyridine (2-1) (1.0 g, 5.68 mmol) in THF (10 mL) was added hydrazine (0.91 g, 0.89 mL, 28.4 mmol). After stirring for 1 h room temperature, the mixture was heated at 65° C. for 1 h. The mixture was cooled, diluted with EtOAc (200 mL), washed with water (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude product (2-2) was used in the subsequent step without further purification. 1H NMR (300 MHz, CHCl3-d): δ 7.32 (app t, J=7.8 Hz, 1H), 6.82 (dd, J=7.8, 0.6 Hz, 1H), 6.67 (dd, J=7.8, 0.6 Hz, 1H), 5.93 (s, 1H), 3.80 (s, 2H).
Reaction SMILES: Cl[C:2]([CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])=[O:3].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:14][C:15]1[NH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2.Cl>ClCCl.C(OCC)(=O)C>[CH3:14][C:15]1[NH:16][C:17]2[C:22]([C:23]=1[C:2](=[O:3])[CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])=[CH:21][CH:20]=[CH:19][CH:18]=2
Reactant: COC(=O)CCC(=O)Cl
Reactant: Cc1cc2ccccc2[nH]1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)CCC(=O)c1c(C)[nH]c2ccccc12
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 3-(chloroformyl)propionate (3 ml) and aluminum chloride [6.50 g) in dichloromethane (40 ml) was stirred at 20° C. for 1 hour. A solution of 2-methylindole (3 g) in dichloromethane (20 ml) was added to the mixture at 20° C. and the resulting mixture was stirred at 20° C. for 1 hour. The reaction mixture was poured into a mixture of ethyl acetate and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. After evaporation of solvent, the residue was purified by column chromatography on silica gel (100 g) eluting with chloroform and with recrystallization from a mixture of ethyl acetate and hexane to give methyl 4-(2-methylindol-3-yl)-4-oxobutyrate (908 mg) as pale brown crystals.
Reaction SMILES: [N+:1]([C:4]1[C:12]([F:13])=[C:11]([F:14])[C:10]([F:15])=[C:9]([F:16])[C:5]=1[C:6](O)=[O:7])([O-:3])=[O:2].C(Cl)(=O)C([Cl:20])=O>CN(C)C=O.ClCCl>[N+:1]([C:4]1[C:12]([F:13])=[C:11]([F:14])[C:10]([F:15])=[C:9]([F:16])[C:5]=1[C:6]([Cl:20])=[O:7])([O-:3])=[O:2]
Reactant: O=C(O)c1c(F)c(F)c(F)c(F)c1[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1c(F)c(F)c(F)c(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6.7 g (28 mmoles) of 2-nitro-3,4,5,6-tetrafluorobenzoic acid [Tetrahedron, 23, 4719, (1967)], 3.8 g (30 mmoles) of oxalyl chloride and 50 ml of dichloromethane was treated with four drops of N,N-dimethylformamide and stirred at room temperature overnight. The solvent was removed and the residue was used as is without further purification.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.O>CS(C)=O>[CH2:9]([O:8][C:6](=[O:7])[C:5]1[CH:11]=[CH:12][C:2]([NH:22][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:3]([N+:13]([O-:15])=[O:14])[CH:4]=1)[CH3:10]
Reactant: CCOC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NC1CCCCC1
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.9 %

Procedure:
Ethyl 4-chloro-3-nitrobenzoate (20.00 g, 87 mmol) was dissolved in DMSO (50 mL) and cyclohexylamine (2.1 equiv. 21 mL, 183 mmol) was added and the mixture stirred at 600C for 5 h. After cooling to ambient temperature, the reaction mixture was added drop-wise with vigorous stirring to water (500 mL). After stirring for an additional 15 min, the precipitated solid was collected by filtration, washed with water and dried. The title compound (25.67 g, 100% yield) was obtained as a bright yellow solid.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:12](=[O:15])([O-])[O-].[K+].[K+]>CC(C)=O>[NH:2]1[CH2:3][CH2:9][C@H:10]([O:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:12]1=[O:15]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C(=NO)C(C)=O
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)/C(=N\O[C@H]1CCNC1=O)C(C)=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 135.5 %

Procedure:
3.2 g of ethyl 2-hydroxyimino-3-oxo-n-butyrate are dissolved in 25 ml of acetone, and 4.2 g of potassium carbonate and 7.6 g of (R)-3-(p-tosyloxy)-2-pyrrolidone are added thereto. After the mixture is stirred at room temperature for 15 hours, the mixture is concentrated under reduced pressure to dryness. 50 ml of ice-water are added to the residue, and the mixture is extracted with ethyl acetate. The extract is dried and concentrated under reduced pressure to dryness. 3.3 g of ethyl (Z)-2-[((3S)-2-pyrrolidon-3-yl)oxyimino]-3-oxo-n-butyrate are obtained.
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][CH:9]=[C:8]([CH3:11])[C:4]=2[N:5]=[CH:6][N:7]=1.C(N(CC)CC)C>CO.[OH-].[OH-].[Pd+2]>[CH3:11][C:8]1[C:4]2[N:5]=[CH:6][N:7]=[CH:2][C:3]=2[S:10][CH:9]=1
Reactant: Cc1csc2c(Cl)ncnc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1csc2cncnc12
Reaction time: 5 h
Yield: 85.1 %

Procedure:
4-chloro-7-methyl-thieno[3,2-d]pyrimidine (6.5 g, 35.2 mmol) was dissolved in methanol (200 mL), added with Pd(OH)2 (1.3 g) and triethylamine (4.9 mL, 35.2 mmoL), and stirred for 5 hours under hydrogen pressure conditions. The reaction mixture was filtered through a Celite pad under reduced pressure, and concentrated. The concentrated compound was purified using silica gel chromatography (ethyl acetate:hexane=1:1 (v/v=1/1)) to obtain the title compound (4.5 g, 85%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:14]2[CH:15]=[N:16][CH:17]=[N:18][CH:19]=2)=[N:8][NH:9][C:10]=1[CH:11]1[CH2:13][CH2:12]1)=[O:5])[CH3:2].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:14]2[CH:15]=[N:16][CH:17]=[N:18][CH:19]=2)=[N:8][N:9]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([C:21]([F:32])([F:31])[F:20])[CH:27]=2)[C:10]=1[CH:11]1[CH2:13][CH2:12]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2cncnc2)n[nH]c1C1CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: CCOC(=O)c1c(-c2cncnc2)nn(-c2cccc(C(F)(F)F)c2)c1C1CC1
Yield: 34 %

Procedure:
In analogy to the procedure described in Example 162C], 5-cyclopropyl-3-pyrimidin-5-yl-1H-pyrazole-4-carboxylic acid ethyl ester and 3-(trifluoromethyl)benzeneboronic acid gave the title compound as a yellow oil (34%). MS: 403.2 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7]([CH3:14])([CH3:13])[CH2:6][C:5]2=[O:15].C(=O)([O-])[O-].[K+].[K+].I[CH2:23][CH3:24]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:23][CH3:24])[O:8][C:7]([CH3:13])([CH3:14])[CH2:6][C:5]2=[O:15]
Reactant: CC1(C)CC(=O)c2cc(Br)c(O)cc2O1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1cc2c(cc1Br)C(=O)CC(C)(C)O2

Procedure:
As described in General Procedure A, 6-bromo-7-hydroxy-2,2-dimethyl-chroman-4-one (Compound 3, 2.0 g, 7.35 mmol) was treated with potassium carbonate (500 mg) and iodoethane (1.5 mL, 18.75 mmol) to give rise to the title compound as a white solid after purification by flash chromatography (silica gel, 5% ethyl acetate in hexanes).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:27])[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][C:12]([Cl:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[F:37][C:38]([S:41](O)(=[O:43])=[O:42])([F:40])[F:39]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:27])[N:8]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[C:9]2[C:14]([C:15]=1[O:16][S:41]([C:38]([F:40])([F:39])[F:37])(=[O:43])=[O:42])=[CH:13][C:12]([Cl:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: CCOC(=O)c1c(O)c2cc(Cl)ccc2n(Cc2ccc(OC)cc2)c1=O
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2cc(Cl)ccc2n(Cc2ccc(OC)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
A solution of 10 (63.0 mg, 0.16 mmol), DMAP (7.0 mg, 0.054 mmol), and diisopropylethylamine (19.0 mg, 0.15 mmol) in anhydrous CH2Cl2 was treated with trifluoromethylsulfonic acid (78.0 mg, 0.28 mmol). The reaction was stirred at room temperature for 30 min and concentrated. Chromatography (SiO2, 3:1 Hex/EtOAc) gave 11 (75.0 mg, 88%) as a amorphous solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([F:28])([F:27])[C:17]([F:26])([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[CH:5]=[CH:4][C:3]=1I.FC1C(F)=C(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C=CC=1[B:56]([OH:58])[OH:57]>>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([F:28])([F:27])[C:17]([F:26])([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[CH:5]=[CH:4][C:3]=1[B:56]([OH:58])[OH:57]
Reactant: Fc1c(I)ccc(OCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c1F
Reactant: OB(O)c1ccc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c1F
Product: OB(O)c1ccc(OCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c1F
Yield: 89 %

Procedure:
2,3-Difluoro-4-(7,7,8,8,9,9,10,10,10-nonafluoro-decyloxy)-phenylboronic acid (11B) was prepared from 2,3-difluoro-1-iodo-4-(7,7,8,8,9,9,10,10,10-nonafluoro-decyloxy)-benzene (10B) as described in the preparation 2,3-difluoro-4-(5,5,6,6,7,7,8,8,8-nonafluoro-octyloxy)-phenylboronic acid (11A), yielding 2,3-difluoro-4-(7,7,8,8,9,9,10,10,10-nonafluoro-decyloxy)-phenylboronic acid (11B) as a colorless oil (89%).
Reaction SMILES: I[C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([CH2:16][CH2:17][CH3:18])=[CH:10][CH:11]=3)[CH:6]=[CH:5][C:4]=2[CH:3]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=1)#[CH:20]>CN(C)C=O.C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:16]([C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[C:4](=[CH:3][C:2]([C:20]#[C:19][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=4)=[CH:15][CH:14]=3)[CH:5]=[CH:6][C:7]=2[CH:8]=1)[CH2:17][CH3:18]
Reactant: C#Cc1ccc(F)c(F)c1
Reactant: CCCc1ccc2c(ccc3cc(I)ccc32)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCc1ccc2c(ccc3cc(C#Cc4ccc(F)c(F)c4)ccc32)c1

Procedure:
2-iodo-7-propyl-phenanthrene in dimethylformamide and triethylamine was reacted with 4-ethynyl-1,2-difluorobenzene in the presence of tetrakis(triphenylphosphine)palladium (0), and the product was purified by silica gel column chromatography (hexane) and then recrystallized from ethanol to yield 2-propyl-7-(3,4-difluorophenylethynyl)phenanthrene.