Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][O:10][CH2:11]OC.CO>C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][O:10][CH3:11])[CH:3]=1
Reactant: COCOC
Reactant: Oc1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClCCl
Product: COCOc1cccc(Cl)c1
Reaction time: 24 h
Yield: 12.5 %

Procedure:
To a solution of 3-chlorophenol (8 ml, 77 mmol, ABCR) in DCM (120 ml) was added dimethoxymethane (32 ml, 362 mmol, Aldrich) and then p-toluenesulphonic acid (0.164 g, 0.952 mmol, Alfa Aesar). The solution was heated to reflux under nitrogen using a Soxhlet apparatus containing 3A activated molecular sieves (approximately 20 g)* for 24 h. *The 3A molecular sieves were replaced after 6 h. Approximately a quarter of the reaction mixture was applied to a 70 g aminopropyl cartridge (prewashed with methanol). The cartridge was eluted with methanol (1-2 column volumes) and several fractions collected. Appropriate fractions were combined (TLC 50:50 DCM in cyclohexane) and the solvent removed in vacuo to give 1-chloro-3-{[(methyloxy)methyl]oxy}benzene as a colourless mobile oil (1.66 g). The remaining reaction mixture was applied evenly to 3×70 g aminopropyl cartridges (pre-washed with methanol). The cartridges were eluted with methanol (1-2 column volumes) and several fractions collected. Appropriate fractions were combined (TLC 50:50 DCM in cyclohexane) and the solvent removed in vacuo to leave a colourless mobile oil (first batch). The mixed fractions were combined and the solvent removed in vacuo to leave a colourless mobile oil. The residue from the mixed fractions was applied to a 70 g aminopropyl cartridge (pre-washed with methanol) and eluted with methanol. Appropriate fractions were combined (TLC 50:50 DCM in cyclohexane) and added to the first batch. The solvent was removed in vacuo to give another batch of 1-chloro-3-{[(methyloxy)methyl]oxy}benzene as a colourless mobile oil (5.27 g). To THF (20 ml) under nitrogen at 0° C. was added 1.6 M n-butyllithium in hexanes (18.1 ml, 29.0 mmol, Aldrich). To the solution at −60° C. was added a solution of 2,2,6,6-tetramethylpiperidine (4.90 ml, 29.0 mmol, Alfa Aesar) in THF (5 ml) and then a solution of 1-chloro-3-{[(methyloxy)methyl]oxy}benzene (5.01 g, 29.0 mmol) in THF (10 ml). The temperature was maintained below −50° C. during the addition. The solution was stirred at −60° C. to −70° C. for 1 h. To the solution was added a large excess of freshly ground solid carbon dioxide and the mixture allowed to warm to ambient temperature. The reaction mixture was diluted with water (100 ml) and diethyl ether (130 ml). The phases were separated and aqueous phase carefully acidified to pH1 using concentrated HCl. The suspension was extracted with dichloromethane (3×40 ml). The solvent was removed in vacuo to give the title compound as a white solid (4.36 g);
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]#[N:9])[CH:2]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:15]=O>>[CH3:10][O:11][C:12]1[CH:13]=[C:14](/[CH:15]=[C:7](/[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)\[C:8]#[N:9])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: N#CCc1cccnc1
Reactant: COc1ccc(C=O)cc1OC
Product: COc1ccc(/C=C(\C#N)c2cccnc2)cc1OC
Yield: 73.7 %

Procedure:
3-Pyridineacetonitrile (1.18 g) was condensed with 3,4-dimethoxybenzaldehyde (1.66 g) through Method B (production step 2), to thereby yield the target product (yield: 1.96 g, 74%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([N+:12]([O-])=O)=[C:8]([CH2:10][OH:11])[CH:9]=1)[CH3:2].O.NN>CCO.[Pd]>[NH2:12][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:9][C:8]=1[CH2:10][OH:11]
Reactant: CCOc1ccc([N+](=O)[O-])c(CO)c1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: CCOc1ccc(N)c(CO)c1
Temperature: 90 °C

Procedure:
To a solution of (5-ethoxy-2-nitro-phenyl)-methanol (592 mg, 3.0 mmol) in absolute EtOH (20 mL) at rt was added 150 mg of Pd/C (Aldrich, 10 wt. % on active carbon), followed by slow addition of hydrazine hydrate (1.5 mL). The resulting reaction mixture was refluxed at 90° C. for 1 h. It was then cooled to rt, filtered through Celite, and then concentrated in vacuo to afford crude (2-amino-5-ethoxy-phenyl)-methanol as a pale yellow oil: MS (ESI) 168 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]([O:23][CH2:24][CH3:25])([CH3:22])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)O)[CH3:2].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>ClCCl>[CH2:1]([O:3][C:4](=[O:26])[C:5]([O:23][CH2:24][CH3:25])([CH3:22])[CH2:6][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(OCC)C(O)c1ccc(OCc2ccccc2)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C(C)(Cc1ccc(OCc2ccccc2)cc1)OCC
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 101.9 %

Procedure:
3-(4-Benzyloxyphenyl)-2-ethoxy-3-hydroxy-2-methyl propanoic acid ethyl ester (0.358 g; 1 mmole) and triethylsilane (0.32 ml; 2 mmole) were dissolved in dry dichloromethane (4 ml) and cooled to 0° C. whereafter borontrifluoride etherate (0.284 g; 2 mmole) was added. The reaction mixture was then stirred at 0° C. for 2.5 hours and then quenched by addition of saturated sodium hydrogencarbonate (10 ml) and dichloromethane (10 ml). The aqueous layer was extracted three times with diethyl ether. The organic phases were combined and dried over sodium sulfate. Evaporation of the solvent gave 0.349 g (100% yield) of 3-(4-benzyloxyphenyl)-2-ethoxy-2-methyl propanoic acid ethyl ester.
Reaction SMILES: [CH:1]([N:4]([CH2:9][CH:10]([O:14]CC)[O:11][CH2:12]C)[C:5](=[O:8])[CH2:6][Cl:7])([CH3:3])[CH3:2].[C:17]1([CH3:27])[C:18](S(O)(=O)=O)=[CH:19]C=C[CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH:1]([N:4]([CH2:9][CH:10]1[O:11][CH2:12][CH:18]([CH3:19])[CH:17]([CH3:27])[CH2:22][O:14]1)[C:5](=[O:8])[CH2:6][Cl:7])([CH3:3])[CH3:2]
Reactant: CCOC(CN(C(=O)CCl)C(C)C)OCC
Reactant: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC1COC(CN(C(=O)CCl)C(C)C)OCC1C

Procedure:
N-Isopropyl-N-(2,2-diethoxyethyl)-α-chloroacetamide (10 grams), 2,3-dimethylbutandiol-1,4 (4.5 grams) and trace amounts of toluenesulfonic acid are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated until no more ethanol is given off. After this time sodium carbonate (1 gram) is added to the mixture with stirring and the resulting mixture is distilled to yield the desired product N-isopropyl-N-(5,6-dimethyl-1,3-dioxepan-2-ylmethyl)-α-chloroacetamide as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[F:16][C:17]([F:26])([F:25])[C:18]1[CH:19]=[CH:20][C:21](Br)=[N:22][CH:23]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:21]3[CH:20]=[CH:19][C:18]([C:17]([F:26])([F:25])[F:16])=[CH:23][N:22]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Product: FC(F)(F)c1ccc(NC2CCCc3c2[nH]c2ccc(Br)cc32)nc1

Procedure:
6-Bromo-N-[5-(trifluoromethyl)pyridin-2-yl]-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine (75 mg, 0.28 mmol) and 5-(trifluoromethyl)-2-bromopyridine (192 mg, 0.85 mmol) in a similar manner as described in Example 22 to give 6.5 mg (6%) of a off-white solid. 1H-NMR (DMSO-d6): δ 10.95 (s, 1H), 8.36 (s, 1H), 7.79 (d, 1H), 7.64 (dd, 1H), 7.57 (s, 1H), 7.23 (d, 1H), 7.13 (dd, 1H), 6.62 (d, 1H), 5.40-5.36 (m, 1H), 2.70-2.55 (m, 2H), 2.06-1.78 (m, 4H); MS m/z (M−1) 408, 410.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][C:21]([C:27]([O:29]C)=[O:28])=[CH:20][C:19]=3[CH:31]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][C:21]([C:27]([OH:29])=[O:28])=[CH:20][C:19]=3[CH:31]=2)=[CH:9][CH:10]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc(CCCOc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCOc1ccc(CCCOc2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Temperature: 60 °C
Reaction time: 18.5 h
Yield: 36.7 %

Procedure:
To methyl 7-[3-(4-propoxyphenyl)propoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (937 mg) dissolved in THF-methanol (15-7.5 ml) was added a 2 M aqueous solution (1.5 ml) of potassium carbonate, and the resulting mixture was stirred at 60° C. for 18.5 hours. The reaction mixture was treated with 1 N hydrochloric acid to bring the pH to 2. The resulting mixture was extracted with ethyl acetate, and the organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with anhydrous magnesium sulfate. After evaporation under reduced pressure to remove the solvent, the precipitated crystals were washed with hexane-ethyl acetate to obtain 7-[3-(4-propoxyphenyl)propoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (333 mg) as white crystals.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:7]1([N:13]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH:21]=[C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[CH2:19][CH2:18]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CO.[H][H]>[Pd].C(O)(=O)C>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:34]1([N:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:14][CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][CH:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=3)[CH2:21][CH2:22]2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: FC(F)(F)c1cccc(OC2=CCN(CCCN(c3ccccc3)c3ccccc3)CC2)c1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CC(=O)O
Solvent: CO
Product: FC(F)(F)c1cccc(OC2CCN(CCCN(c3ccccc3)c3ccccc3)CC2)c1
Yield: 65.6 %

Procedure:
A mixture of 7.7 g. (0.014 moles) of 3,6-dihydro-N,N-diphenyl-4-[3-(trifluoromethyl)phenoxy]-1(2H)-pyridinepropanamine ethanedioate (1:1) (preparation described in Example 16), 90 ml. of methanol, 10 ml. of acetic acid and 0.5 g. of 20% Pd/c is shaken under 50 psi. of hydrogen at room temperature for about 4 hours. The reaction mixture is then filtered, and the solvent is evaporated. The residue is initially recrystallized from aqueous isopropanol, then recrystallized from aqueous isopropanol, and again recrystallized from aqueous ethanol to give 5.0 g of N,N-diphenyl-4-[3-(trifluoromethyl)phenoxy]-1-piperidinepropanamine ethanedioate (1:1), mp 189°-190.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][NH2:14]>>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:13][NH2:14])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: NN
Product: NNC(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
4-Nitro benzoic acid can be reacted with hydrazine to give 4-nitrobenzoic acid hydrazide. This acid hydrazide can be reacted with 2,4-dichlorobenzaldehyde to yield the corresponding acid hydrazone adduct of 2,6-dichlorobenzoldehyde. Treatment of this material with acetic anhydride according to the method of J. Chem. Research Synopsis, 1995, 88-89 can lead to the corresponding N-acetylated 4,5-dihydrooxadiazole. Basic hydrolysis can yield the N-deacetylated product which can be reduced with tin dichloride or with iron powder and ammonium chloride to yield the corresponding aniline. This racemic aniline can be treated with 2,2-dichloroacetyl chloride and triethylamine to yield (±)-2,2-dichloro-N-[4-[5-(2,6-dichlorophenyl)-2-(4,5-dihydrooxadiazolyl)phenyl]acetamide.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:28][CH2:29][OH:30]>C(#N)C>[F:1][C:2]1[C:7]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:9])=[O:10])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:15]1[CH2:20][CH2:19][N:18]([CH2:28][CH2:29][OH:30])[CH2:17][CH2:16]1
Reactant: OCCI
Reactant: O=S(=O)(c1cccc(C2CCNCC2)c1F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=S(=O)(c1cccc(C2CCN(CCO)CC2)c1F)C(F)(F)F

Procedure:
Preparation according to Example 1: 4-{2-fluoro-3-[(trifluoromethyl)sulfonyl]phenyl}-piperidine (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and 2-iodoethanol (0.01 g). MS m/z (rel. intensity, 70 eV) 355 (M+, 1), 325 (15), 324 (bp), 191 (36), 133 (12).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[I:14])=[O:4].[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][O:15]1)[N:9]=[C:8]2[I:14])=[O:4]
Reactant: COC(=O)c1ccc2[nH]nc(I)c2c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)c(I)nn2C1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
In 50 mL R. B. flask, to a solution of 3-iodo-1H-indazole-5-carboxylic acid methyl ester (0.2 g, 0.66 mmol) in DCM (10 mL) was added 3,4-dihydropyran (0.117 g, 1.32 mmol) at 5° C. followed by the addition of PTSA (0.038 g, 0.264 mmol). The reaction was stirred for 2 h at RT, quenched with water (25 mL) and extracted with DCM (50 mL). The organic layer was separated and washed with water (2×25 mL) and dried over anhydrous Na2SO4, filtered and concentrated. The residue was triturated with n-pentane to give 3-iodo-1-(tetrahydro-pyran-2-yl)-1H-indazole-5-carboxylic acid methyl ester (0.15 g, 58%) as off white solid. MS (ESI, pos. ion) m/z: 302.7 (M-THP+1); 1H-NMR (300 MHz DMSO-d6): δ ppm 8.24 (t, 1 H, J=9 Hz), 8.13 (dd, 1 H, J=8.7, 1.5 Hz), 7.60 (d, 1 H, J=9 Hz), 5.73 (dd, 1 H, J=9.6, 2.7 Hz), 4.95 (m, 1H), 3.96-4.04 (m, 4H), 3.75-3.78 (m, 1H), 3.52-3.53 (m, 1H), 2.52-2.56 (m, 1H), 2.05-2.17 (m, 2H), 1.58-1.84 (m, 4H).
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][N:7]=1.[CH2:12]([O:14][P:15]([O:19]CC)[O:16][CH2:17][CH3:18])[CH3:13]>C1(C)C=CC=CC=1>[CH2:12]([O:14][P:15]([CH2:2][C:3]1[O:4][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][N:7]=1)(=[O:19])[O:16][CH2:17][CH3:18])[CH3:13]
Reactant: CC(C)(C)c1cnc(CCl)o1
Reactant: CCOP(OCC)OCC
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1ncc(C(C)(C)C)o1)OCC
Temperature: 25 °C
Yield: 97.7 %

Procedure:
A solution of 2-(chloromethyl)-5-t-butyloxazole (8.00 g, 46.1 mmol) in triethylphosphite (15.3 g, 92.0 mmol) was heated at 120° C. for 18 hours. After cooling the mixture to room temperature, toluene (30 mL) was added and the solution was concentrated in vacuo with a bath temperature of 70° C. This procedure was repeated three times and the resulting brown oil was dried in vacuo at 90° C. for 30 minutes to give (5-t-butyl-oxazol-2-ylmethyl)-phosphonic acid diethyl ester (12.4 g, 98%, C12H22NO4P, MS m/e 276 (M+H)+) as a red-orange liquid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].NCC[C:13]1[N:17]=[CH:16][NH:15][CH:14]=1.C=O>O1CCOCC1>[NH:15]1[CH:14]=[CH:13][N:17]=[C:16]1[CH:5]([NH:6][CH2:7][CH2:2][C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:3])[CH3:4]
Reactant: NCCc1c[nH]cn1
Reactant: CC(=O)c1cccnc1
Agent: C=O
Solvent: C1COCCO1
Product: CC(NCCC(=O)c1cccnc1)c1ncc[nH]1

Procedure:
3-acetylpyridine (6.5 mg), histamine (6 mg), and paraformaldehyde (2 mg) were reacted in dioxane (0.1 ml) at 150° C. for 2 hours.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[CH2:3]1.C(N(CC)CC)C.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:8][CH:4]2[CH2:5][CH2:6][CH2:7][C:2]([CH3:9])([CH3:1])[CH2:3]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)CCCC(O)C1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC2CCCC(C)(C)C2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
Under a nitrogen atmosphere, add 3,3-dimethylcyclohexanol (1 g, 9.75 mmol), DMAP (238 mg, 1.95 mmol), triethylamine (2.70 mL, 19.5 mmol), and p-toluenesulfonyl chloride (2.045 g, 10.72 mmol) to DCM (25 mL) at 0° C. Stir the mixture for 1 h at 0° C. and warm to room temperature overnight. Add saturated aqueous NaHCO3 (20 mL) and separate the layers. Extract the aqueous layer with DCM (3×20 mL). Wash the combined organic extracts with water and brine. Dry the organic phase over Na2SO4, filter, and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel (45 g, pre-packed cartridge) eluting with hexane/EtOAc (1:0 to 1:1 gradient over 60 min, 80 mL/min) to obtain the desired intermediate as a clear oil (1.93 g, 70%). MS (APCI+) m/z: 283 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7](Cl)=[O:8])([O-:3])=[O:2].[Br:16][C:17]1[CH:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1>CN(C=O)C>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:12]([N+:13]([O-:15])=[O:14])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[N:21][CH:22]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Br)cn1)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1

Procedure:
A mixture 3,4-dinitro-benzoyl chloride (1.78 g, 7.8 mmol) and 5-bromo-2-amino-pyridine (1.35 g, 7.8 mmol) in 20 mL DMF was stirred overnight. After evaporation of the solvent, the residue was purified by chromatography on silica gel (eluent gradient: dichloromethane/methanol 100:0->75:1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[N:12][C:11]([NH:14][NH2:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:16][CH2:17][C:18](Cl)=O>>[Cl:16][CH2:17][C:18]1[N:12]2[N:13]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH:9]=[CH:10][C:11]2=[N:14][N:15]=1
Reactant: NNc1ccc(-c2cccc(F)c2)nn1
Reactant: O=C(Cl)CCl
Product: Fc1cccc(-c2ccc3nnc(CCl)n3n2)c1

Procedure:
As for Example 2, 6-(3-fluorophenyl)-3-hydrazinopyridazine (prepared in a manner similar to that described in Example 1) is reacted with chloroacetyl chloride to give the product of the Example.
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][NH:3]1.C(N(CC)C(C)C)(C)C.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>ClCCl>[CH3:1][CH:2]1[CH2:4][N:3]1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CC1CN1
Reactant: CCOC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CN1CC1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold (−78° C.) solution of 2-methylaziridine (5.6 g, 99 mmol) and N,N-diisopropylethylamine (18.8 mL, 108 mmol) in dichloromethane (250 mL) under an atmosphere of nitrogen, ethyl bromoacetate (10 mL, 90 mmol) was added over a period of 1 h. The resultant mixture was allowed to slowly warm up and stirred at room temperature overnight. The resultant mixture was concentrated under vacuum, and the residue was suspended in chloroform. A stream of anhydrous ammonia gas was bubbled into the mixture with stirring for a period of 15 min. The resultant suspension was filtered, and the filtrate concentrated under vacuum. The residue was further treated with anhydrous diethyl ether and the milky solution filtered through a pad of Celite. The filtrate was concentrated under vacuum, and the residue subjected to distillation under reduced pressure (bp ˜60° C., 18 torr) to provide the title compound as colorless oil.
Reaction SMILES: [C-:1]#[N:2].[K+].[CH:4]1([O:9][C:10]2[CH:11]=[C:12]([C:18]3[CH:19]=[N:20][C:21](S(C)(=O)=O)=[N:22][CH:23]=3)[CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH2:8][CH2:7][CH2:6][CH2:5]1.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH:4]1([O:9][C:10]2[CH:11]=[C:12]([C:18]3[CH:19]=[N:20][C:21]([C:1]#[N:2])=[N:22][CH:23]=3)[CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: [C-]#N
Reactant: COc1ccc(-c2cnc(S(C)(=O)=O)nc2)cc1OC1CCCC1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cnc(C#N)nc2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.8 %

Procedure:
To a solution of potassium cyanide (205 mg) in dry DMF (10 ml) was added the compound of Example 12 (1.0 g) and the reaction mixture stirred at room temperature for 3 hr then at 50° C. for 2 h. The reaction mixture was poured into a saturated NaHCO3 solution (2.5 g Na2CO3 in 120 ml ice). The resulting yellow precipitate was filtered offand washed with water. Recrystallisation from EtOAc/hexane (1:2) gave the title compound (575 mg) as yellow needles (mp 121°-123° C.).Found C, 69.15; H, 5.73; N, 14.13. C17H17N3O2 requires C, 69.14; H, 5.80; N, 14.23%.
Reaction SMILES: [Br:1][C:2]1(Br)[CH2:4][C:3]1([CH3:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(O)(=O)C>CO.[Zn]>[Br:1][CH:2]1[CH2:4][C:3]1([CH3:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC1(c2ccccc2)CC1(Br)Br
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: CC1(c2ccccc2)CC1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.4 %

Procedure:
To a solution of 6.40 g (0.0221 mol) of 2,2-dibromo-1-methyl-1-phenylcyclopropane in 22 g of methanol was added 2.16 g (0.0360 mol) glacial acetic acid and 2.11 g (0.0323 mol) of zinc dust. After stirring at room temperature for 4 hours, the solvent was removed it vacuo. To the resulting residue hexanes and water were added. The resulting mixture was transferred to a separatory funnel and the phases were separated. The organic layer was dried over MgSO4 and filtered. The solvent was removed from the filtrate in vacuo to yield 3.24 g of 2-bromo-1-methyl-1-phenylcyclopropane as an oil which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[C@@H:15]3[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]3[C@@H:13]([NH:21][C:22](=[O:25])[CH2:23][CH3:24])[CH2:12]2)=[C:4]([NH:26][CH2:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:3]=1.[H-].[Na+].[Cl:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50][CH2:51][OH:52])=[CH:46][CH:45]=1>C1COCC1>[Cl:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50][CH2:51][O:52][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[C@H:11]3[C@@H:15]4[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]4[C@@H:13]([NH:21][C:22](=[O:25])[CH2:23][CH3:24])[CH2:12]3)=[C:4]([NH:26][CH2:27][CH:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:3]=2)=[CH:46][CH:45]=1
Reactant: OCCc1ccc(Cl)cc1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(OCCc4ccc(Cl)cc4)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 50 °C
Reaction time: 48 h

Procedure:
The title compound is prepared by adding N-{(3aR,4S,6R,6aS)-6-[2-Chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,2-dimethyl-tetrahydro-cyclopenta[1,3]dioxol-4-yl}-propionamide (example 235, step 1) to a premixed solution of sodium hydride (60% in oil) and 2-(4-chloro-phenyl)-ethanol (1 equivalent) in dry THF. The reaction is stirred at 50° C. for 48 hours, before quenching residual sodium hydride with excess aqueous ammonium chloride. The reaction mixture id then partitioned between ethyl acetate and water; the organic phase is washed consecutively with water and brine before drying over magnesium sulfate. Filtration and removal of the volatile components under reduced pressure yields the crude product; purification by column chromatography/crystallisation affords the title compound.