Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:21]([O:28][C:29](Cl)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1.O.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:29]([O:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:30])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 116.5 %

Procedure:
Commercially available N-tert-butyloxycarbonyl-piperazine (0.5 g, 2.68 mmol) was dissolved in 5 mL of THF:water (1:1) and cooled in an ice bath. Triethylamine (0.748 mL, 5.4 mmol), followed by benzyloxycarbonyl chloride (0.575 mL, 3.21 mmol) in diethyl ether was slowly added to the reaction mixture. It was stirred at 0° C. for 1.5 hours. Solvents were removed and 50 mL of ethyl acetate was added to the residue. The ethyl acetate layer was washed with saturated NaHCO3 (20 mL×3), brine (20 mL×3), and dried over anhydrous sodium sulfate. N-tert-butyloxycarbonyl-N'-benzyloxycarbonyl-piperazine (1.0 g) was obtained after evaporated to dryness in quantitative yield. MS: M+NH4 =338. M+H+ =321.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[C:4]([Cl:10])[C:3]=1[Cl:11].O.NN.N(C1C=CC=CN=1)N.ClC1N=C(Cl)C(Cl)=C(NN)C=1Cl>C(O)C.S([O-])([O-])(=O)=O.[Cu+2].[Ag]=O>[Cl:11][C:3]1[C:4]([Cl:10])=[C:5]([Cl:9])[C:6]([Cl:8])=[N:7][CH:2]=1
Reactant: Clc1nc(Cl)c(Cl)c(Cl)c1Cl
Agent: O=[Ag]
Agent: [Cu+2]
Agent: NN
Solvent: O
Solvent: CCO
Product: Clc1cnc(Cl)c(Cl)c1Cl

Procedure:
Another method of preparing tetrachloropyridines is taught in Collins et al., J. Chem. Soc. (C) pages 167-174 (1971) wherein pentachloropyridine is reacted with hydrazine hydrate in ethanol and the resulting tetrachloro-4 and/or 2-hydrazinopyridine is oxidized with aqueous copper sulfate or silver oxide in ethanol. This reference also teaches pyrolyzing tetrachloro-4-hydrazinopyridine in sand at 160° C. to yield tetrachloropyridine. In addition, this reference teaches the preparation of 2,3,6-trichloropyridine from the reaction of tetrachloro-4-hydrazinopyridine with cuprous oxide in hot water.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([OH:9])=[CH:4][N:3]=1.[H-].[Na+].C1N=CN([C:17](N2C=NC=C2)=[O:18])C=1>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[O:9][C:17](=[O:18])[NH:8][C:6]=2[N:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ncc(O)c(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncc2oc(=O)[nH]c2n1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
2,4-Diamino-pyrimidin-5-ol (500 mg, 3.97 mmol) [prepared according to the method of Hull. J. Chem. Soc. 1956, 2033-2035] was suspended in DMF (10 mL). To this was added consecutively NaH (86.7 mg, 3.77 mmol) and CDI (707 mg, 4.36 mmol), and the reaction mixture was heated with vigorous stirring at 60° C. for 3 h. The mixture was cooled to ambient temperature, and then quenched with water (25 mL). The solvent and water were removed via rotary evaporation, and the residue was then triturated in water (5 mL). The solid was then collected by filtration and dried, affording 230 mg (38%): 1H NMR (400 MHz, d6-DMSO) δ 11.90 (br s, 1H), 7.72 (br s, 1H), 6.72 (s, 2H); Analysis calc'd for C5H4N4O2.0.2H2O: C, 38.56; H, 2.85; N, 35.98. Found: C, 39.01; H, 2.71; N, 35.58; [M+H]+ m/z 153.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5].Br[CH2:13][C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5])[O:10][CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: O=Cc1c(Cl)cc(O)cc1Cl
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1cc(Cl)c(C=O)c(Cl)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 382 mg (2.0 mmol) A1, 337 mg (2.2 mmol) methyl bromoacetate and 387 mg (2.8 mmol) potassium carbonate in 6 ml dry acetone were stirred for 2 h at 60° C. After filtration and removal of the solvent the residue was purified by column chromatography on SiGel (hexane/ethyl acetate 4:1). Yield: 508 mg (97%) A4, colorless solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3][CH2:2]1.Cl.[CH3:11][NH:12][O:13][CH3:14].CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(Cl)Cl>[CH3:14][O:13][N:12]([CH3:11])[C:7]([CH:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)=[O:9]
Reactant: CNOC
Reactant: O=C(O)C1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C1CCOCC1
Temperature: 29 °C
Reaction time: 24 h
Yield: 59.2 %

Procedure:
To a suspension of tetrahydro-2H-pyran-4-carboxylic acid (9.0 g, 69.2 mmol) in CH2Cl2 (300 mL) was added N,O-dimethylhydroxylamine hydrochloride (8.05 g, 83.0 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (20.0 g, 103.8 mmol) and triethylamine (17.5 g, 173.0 mmol) at 29° C. under N2. The reaction was stirred at 29° C. for 24 hrs. Then the mixture was filtered and the filtrate was washed with 1M HCl and saturated aqueous NaHCO3. The organic layer was concentrated in vacuo to give N-methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide (7.1 g, 59.7%) as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 4.02-3.98 (m, 2H), 3.69 (s, 3H), 3.47-3.41 (m, 2H), 3.17 (s, 3H), 2.90 (t, J=11.6 Hz, 3H), 1.90-1.82 (m, 2H), 1.81-1.62 (m, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3][CH2:2]1.Cl.[CH3:11][NH:12][O:13][CH3:14].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.Cl.CCOC(C)=O>[CH3:14][O:13][N:12]([CH3:11])[C:7]([CH:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)=[O:9]
Reactant: O=C(O)C1CCOCC1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CON(C)C(=O)C1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
To a solution of tetrahydro-2H-pyran-4-carboxylic acid 1 (4.0 g, 31 mmol) in DCM (65 mL) was added sequentially N,O-dimethylhydroxylamine hydrochloride (3.3 g, 34 mmol), 4-methylmorpholine (7.4 mL, 68 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (6.5 g, 34 mmol). The resulting mixture was stirred at RT for 18 h. At that time, the reaction was diluted with 1N HCl and EtOAc and stirred vigorously until both phases cleared. The phases were separated, and the aqueous layer was extracted with EtOAc. The organic portions were combined, washed with brine, dried over MgSO4, filtered, and concentrated. The crude residue was subjected to column chromatography (120 g silica, 80 ml/min, 0% to 100% EtOAc/hexanes) to give N-methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide 2 (4.3 g, 24.8 mmol, 81%). LCMS for 2 (conditions D): tR=1.12 min, m/e=174.3 (M+H, base).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:25]2[CH:30]=[CH:29][C:28](Br)=[CH:27][CH:26]=2)([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[N:42][NH:43][CH:44]=2)O1>>[CH3:24][O:23][CH2:22][CH2:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2([C:25]3[CH:26]=[CH:27][C:28]([C:40]4[CH:41]=[N:42][NH:43][CH:44]=4)=[CH:29][CH:30]=3)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:19][CH:18]=1
Reactant: COCCOc1ccc(C2(c3ccc(Br)cc3)CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: COCCOc1ccc(C2(c3ccc(-c4cn[nH]c4)cc3)CCNCC2)cc1

Procedure:
4-(4-Bromo-phenyl)-4-[4-(2-methoxy-ethoxy)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-pyrazole following the procedure set out in Example 1, substituting tetrakis triphenylphosphine palladium (0) as catalyst, the title compound was obtained. LC/MS: (PS-A2) Rt 3.27 [M+H]+ 478.
Reaction SMILES: [C:1](Cl)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17].C(O)(=O)CCCCCCCCCCCCCCC(C)C.S(Cl)(Cl)=O.[CH2:45]([NH2:53])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52].C(N(CC)CC)C>CCOCC.CN(C)C=O>[CH2:45]([NH:53][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]
Reactant: CC(C)CCCCCCCCCCCCCCC(=O)Cl
Reactant: CCCCCCCCN
Agent: CC(C)CCCCCCCCCCCCCCC(=O)O
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCCCCCNC(=O)CCCCCCCCCCCCCCC(C)C

Procedure:
Isostearoyl chloride, prepared from 20 g isostearic acid, 10.1 g thionyl chloride and 0.2 ml dimethyl formamide, according to the procedure of Example 1, is added to 11 g (0.09 mole) n-octylamine and 10 g. (0.10 mole) triethylamine in 100 ml ether. The reaction mixture is treated in accordance with the procedure of Example 2, yielding 22 g of an amber oil which exhibits infrared spectra values typical of a secondary amide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]([C:15]1[S:16][C:17](I)=[CH:18][C:19]=1[N:20]([C:28]([C@H:30]1[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]1)=[O:29])[CH:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1)=[O:14].C1(C)C=CC=CC=1.CO.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:18][C:19]=1[N:20]([C:28]([C@H:30]1[CH2:31][CH2:32][C@H:33]([CH3:36])[CH2:34][CH2:35]1)=[O:29])[CH:21]1[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]1)=[O:14]
Reactant: COC(=O)c1sc(I)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN(C)CC1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN(C)CC1
Temperature: 70 °C

Procedure:
To the mixture of 4-chlorophenylboronic acid (46.9 mg, 0.3 mmol) and 5-iodo-3-[(trans-4-methyl-cyclohexanecarbonyl)-(1-methyl-piperidin-4-yl)-amino]-thiophene-2-carboxylic acid methyl ester (50 mg, 0.099 mmol), from step 5, in 5:1 mixture of toluene/MeOH (2.0 mL) was added a solution of Pd(PPh3) 4 (12.0 mg, 0.01 mmol, 10 mol %) in toluene (1.0 mL) followed by aqueous 2M Na2CO3 solution (0.1 mL, 0.2 mmol). The resultant reaction mixture was heated at 70° C. for 16 h, cooled to room temperature, filtered off through MgSO4 and washed with EtOAc. Evaporation of the solvent and purification of the residue over preparative TLC (1 mm, 60A°) using DCM/CHCl3/MeOH/Et3N (100:90:16:1) as an eluent furnished 5-(4-chloro-phenyl)-3-[(trans-4-methyl-cyclohexanecarbonyl)-(1-methyl-piperidin-4-yl)-amino-]-thiopene-2-carboxylic acid methyl ester (35.0 mg, 71.5% yield). NMR 1H (CDCl3, 400 MHz): 7.53 (d, J=8.3, 2H), 7.4 (d, J=8.5, 2H), 7.0 (s, 1H), 4.67-4.58 (m, 1H), 3.84 (s, 3H), 2.82-2.64 (m, 1H), 2.2 (s, 3H), 2.14-1.35 (m), 0.763 (d, J=6.6, 3H), 0.76-0.56 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([O-:22])=[O:21].[K+].C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH3:1][C:2]1([CH3:23])[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([OH:22])=[O:21]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O

Procedure:
Reaction of potassium benzylpenicillin with α-chlorodiethylcarbonate in an aqueous solution of 70% dioxane in the presence of sodium bicarbonate. The 1-ethoxycarbonyloxyethyl ester of benzylpenicillin which is obtained is subjected to the reaction of removing the phenylacetic chain, via the iminochloride-iminoether, in order to obtain the 1-ethoxycarbonyloxyethyl ester of the 6-aminopenicillanic acid, which is isolated as the hydrochloride. By subsequent condensation of the latter intermediate with D-(-)-αphenylglycine, the compound according to formula I is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.C([BH3-])#N.[Na+].O.[OH-].[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6]2
Reactant: COc1ccc2[nH]ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCN2
Reaction time: 2 h

Procedure:
Part A: To 5-methoxyindole (5.0 g) in glacial acetic acid (90 mL, 15-17° C.) was added sodium cyanoborohydride (6.41 g, 3 eq.), and the mixture was stirred 2 h. Water (250 mL) was added to the mixture, which was then cooled in an ice bath and made strongly basic with sodium hydroxide pellets. The solution was extracted with ether, which was then washed with water and brine and dried over MgSO4. The ether solution was concentrated to give 5-methoxyindoline, which was reacted without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1)([O-])=O.[OH-].[Na+]>CCOC(C)=O>[C:9]1([N:7]2[CH:8]=[C:4]([NH2:1])[CH:5]=[N:6]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1cnn(-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Nc1cnn(-c2ccccc2)c1
Reaction time: 3 h
Yield: 46.8 %

Procedure:
A mixture of 4-nitro-1-phenyl-1H-pyrazole (440 mg, 2.32 mmol) and SnCl2 dihydrate (2.18 g, 9.66 mmol) in EtOAc (15 mL) was stirred at 80 C for 3 h. Aqueous 1N NaOH was added to bring pH to 12. The mixture was filtered through celite. The organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was purified by HPLC to give 1-phenyl-1H-pyrazol-4-amine as a solid (173 mg).
Reaction SMILES: [CH2:1]([N:5]([CH2:11][CH:12](OC)[O:13]C)[C:6](=[O:10])[O:7][CH2:8][CH3:9])[CH:2]=[CH:3][CH3:4].C(O)=O.[Cl-].[Na+]>O>[CH2:1]([N:5]([CH2:11][CH:12]=[O:13])[C:6](=[O:10])[O:7][CH2:8][CH3:9])[CH:2]=[CH:3][CH3:4]
Reactant: CC=CCN(CC(OC)OC)C(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: CC=CCN(CC=O)C(=O)OCC

Procedure:
111 g (0.48 mol) of ethyl N-(2-buten-1-yl)-N-(2,2-dimethoxyethyl)-carbamate are heated under reflux for three hours with 50 g of formic acid in 950 ml of water. The mixture is saturated with sodium chloride and extracted three times using 200 ml of methylene chloride each time. The organic phases are washed with sodium hydrogen carbonate solution until neutral, dried over magnesium sulphate and concentrated, and the residue is distilled.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]([C:9]([C:19]#[N:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](Cl)=[O:11])[CH3:8]>C(OCC)C>[C:19]([C:9]([CH2:7][CH3:8])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:11])#[N:20]
Reactant: CCC(C#N)(C(=O)Cl)c1ccccc1
Reactant: C1COCCN1
Solvent: CCOCC
Product: CCC(C#N)(C(=O)N1CCOCC1)c1ccccc1
Yield: 88.3 %

Procedure:
8.7 g (0.1 mole) of morpholine are dissolved in 20 ml of dry diethyl ether, and a solution of 10.5 g (0.05 mole) of 2-ethyl-2-phenyl-cyanoacetyl chloride in 20 ml of dry diethyl ether are added dropwise under cooling with ice (at a temperature below 10° C.). The reaction mixture is refluxed for 30 minutes, then cooled and washed with water. The organic phase is separated, washed in succession with 5% aqueous sodium carbonate solution, 2n aqueous hydrochloric acid and water, dried over magnesium sulfate, and evaporated. 11.4 g (89%) of 2-cyano-2-ethyl-2-phenylacetic acid morpholide are obtained; m.p.: 88°-90° C.
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2([CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][OH:15])[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4]1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH2:16]([O:15][CH2:14][CH2:13][CH:10]1[CH2:11][CH2:12][C:7]2([O:6][CH2:5][CH2:4][O:3]2)[CH2:8][CH2:9]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: OCCC1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(COCCC2CCC3(CC2)OCCO3)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83.2 %

Procedure:
To a precooled (0° C.) suspension of NaH (60% in mineral, 0.44 g, 11 mmol) in THF (20 mL) was added 2-(1,4-dioxaspiro[4.5]decan-8-yl)ethanol (1.86 g, 10 mmol) in THF (10 mL). The resulting solution was stirred at 0° C. for 10 min, and allowed to warm to RT, and stirred for 1 h. To the above mixture was added benzyl bromide (1.78 g, 15 mmol) and the resulting mixture was stirred at rt overnight. The reaction was quenched by addition of saturated aqueous NH4Cl solution, extracted with EtOAc, washed with brine, dried over Na2SO4. Purification by flash column chromatography (eluent: 20% EtOAc in hexanes to 30%) gave the product (2.3 g, 83%). LC/MC: 277.1 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)N(C2CC2)CCC3(C)C)=[CH:7][CH:6]=1)[CH3:2].C(O)(=O)C1C=CC=CC=1.[CH2:38]([O:40][C:41](=O)[C:42]1[CH:47]=CC(I)=CC=1)C>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:38][O:40][C:41]1([C:20]2[CH:15]=[CH:14][C:13]([C:12]#[C:11][C:8]3[CH:9]=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:28])=[CH:6][CH:7]=3)=[CH:22][CH:21]=2)[CH2:42][CH2:47]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCN3C2CC2)cc1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C(O)c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OC)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-methoxycyclopropyl)-benzene (Intermediate 61, 100.0 mg, 0.47 mmol) and ethyl-4-iodo benzoate (Reagent A, 141.0 mg, 0.51 mmol) in triethyl amine (6 mL) was treated with copper(I)iodide (30.0 mg, 0.16 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (109 mg, 0.16 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-5% EtOAc-hexanes) afforded 135.0 mg (90%) of the title compound as an orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:11][C:10](=[O:12])[CH2:9]2)=[CH:4][CH:3]=1.O.[Cl-].[NH4+].Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:9][C@H:10]([OH:12])[CH2:11]2)=[CH:6][CH:7]=1
Reactant: O=C1CC(c2ccc(Br)cc2)C1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: O[C@H]1C[C@@H](c2ccc(Br)cc2)C1
Reaction time: 1.5 h
Yield: 66.6 %

Procedure:
At −78° C., 1.0 M tri(tert-butoxy)lithiumaluminium hydride (24 mL, 24 mmol) was added to a THF (20 mL) solution of 3-(4-bromophenyl)cyclobutanone (4.53 g, 20.1 mmol), and stirred at the same temperature for 1.5 hours. Saturated ammonium chloride water and 1 N hydrochloric acid were added to the reaction liquid, extracted with ethyl acetate, dried with anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography (C-200, ethyl acetate:hexane=1:4 to 3:7) to obtain the entitled compound (3.04 g, 66%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][CH2:11][OH:12])[C:6]=2[C:13]=1[F:14].P([O-])([O-])([O-])=[O:16].[Na+].[Na+].[Na+].[O-]Cl=O.[Na+].[O-]Cl.[Na+].[O-]S([O-])=O.[Na+].[Na+].[OH-].[Na+]>O.CC#N>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]([OH:16])=[O:12])[C:6]=2[C:13]=1[F:14]
Reactant: O=P([O-])([O-])[O-]
Reactant: OCCn1cnc2ccc(F)c(F)c21
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC#N
Solvent: O
Product: O=C(O)Cn1cnc2ccc(F)c(F)c21
Temperature: 42 °C
Reaction time: 48 h

Procedure:
2-(6,7-difluoro-1H-benzimidazol-1-yl)ethanol (2.96 g, 15 mmol) is taken into 75 ml of MeCN and sodium phosphate buffer (56 ml, 0.67 M, pH 6.8) and the mixture is heated to 42° C. Tempo (165 mg, 1.05 mol) is added followed by the simultaneous dropwise addition of a solution of NaClO2 (3.38 g, 80% pure, 30 mmol in 15 ml water) and a solution of bleach (350 μL of 6% NaOCl in 7.5 mL water) over 1.5 hours. After 48 hrs, the same quantities of NaClO2 and bleach are added. After a further 24 hours, Tempo (165 mg, 1.05 mol) is added and the reaction is stirred for 72 hrs. The darkened reaction is allowed to cool to room temperature followed by the dropwise addition of 30 ml of a saturated solution of Na2SO3 (exothermic). The reaction becomes almost colourless. Using 2 N NaOH, the pH is raised to 9.2 and the reaction is extracted 4 times with ethyl acetate. The pH is then lowered to 3.8 with 2 N HCl and the solution allowed to stand for 48 hours. 1.98 grams of white crystalline material is recovered. The mother liquor is reduced to half the volume and allowed to stand. A further 260 mg is collected. (Combined yield 2.23 g, 70%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH2:23][CH3:24]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:22][CH2:23][CH3:24])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: OC1(c2cc(F)cc(F)c2)CCNC1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCC(O)(c2cc(F)cc(F)c2)C1

Procedure:
Preparation according to Example 24: Enantiomer E2 of 3-(3,5-difluorophenyl)-pyrrolidin-3-ol (0.53 g, 2.66 mmol), acetonitrile (3 mL), potassium carbonate (0.55 g, 3.99 mmol) and iodopropane (260 μl, 2.66 mmol). Purification by HPLC on Waters OBD C18, 5 μm (MeOH/33 mM NH3, 40:60 to 60:40). Yield: 0.295 g. [α]D=−22.7° (methanol). The amine was converted to the oxalic acid salt and recrystallized from methanol/diethyl ether: M.p. 118-119° C.; MS m/z (relative intensity, 70 eV) 241 (M+, 9), 213, (12), 212 (bp), 182 (32), 84 (36).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][S:11]([OH:14])(=O)=[O:12])=[N:2]1.P(Cl)(Cl)([Cl:17])=O>ClCCCl>[CH:8]1[CH:9]=[C:4]2[C:3]([CH2:10][S:11]([Cl:17])(=[O:14])=[O:12])=[N:2][O:1][C:5]2=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)Cc1noc2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: O=S(=O)(Cl)Cc1noc2ccccc12

Procedure:
1,2-Benzisoxazole-3-methanesulfonic acid (1) (1.00 g, 4.7 mmol) was mixed with 1,2-dichloroethane (10 mL) and phosphorous oxychloride (2.0 mL, 21 mmol). The mixture was heated to reflux until the reaction was complete, filtered through CELITE™ and evaporated to give 1,2-benzisoxazole-3-methanesulfonyl chloride (2). It was converted into zonisamide in analogy to the previous examples.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[CH3:10][N:11]([CH3:15])[C:12](Cl)=[O:13]>>[CH3:10][N:11]([CH3:15])[C:12](=[O:13])[O:1][NH:2][C:3]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:9]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)NO
Product: CN(C)C(=O)ONC(=O)OC(C)(C)C

Procedure:
[(tert-Butoxy)carbonyl]amino N,N-dimethylcarbamate is prepared from tert-butyl N-hydroxycarbamate and dimethyl carbamoyl chloride according to Scheme 1. (2.4 g, 78%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.82 (1H, br. s.), 3.02 (3H, s), 2.98 (3H, s), 1.49 (9H, s)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][C:11]([NH2:13])=[O:12].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:10][C:11]([NH2:13])=[O:12]
Reactant: Oc1cccc(F)c1
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: NC(=O)COc1cccc(F)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of 3-fluorophenol (5.61 g, 50.0 mmol), 2-bromoacetamide (7.59 g, 55.0 mmol) and K2CO3 (13.82 g, 100 mmol) in acetone (80 mL) was stirred at 70° C. overnight. The mixture was cooled to rt and filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a white solid. (7.89 g, 93%)