Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[N:9]1[C:13]2[CH:14]=[C:15](I)[CH:16]=[CH:17][C:12]=2[N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:10]1=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[CH3:34][N:35](C=O)C>[C-]#N.[Zn+2].[C-]#N>[C:1]([O:5][C:6]([CH:8]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[N:9]1[C:13]2[CH:14]=[C:15]([C:34]#[N:35])[CH:16]=[CH:17][C:12]=2[N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:10]1=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)C(c1ccccc1)n1c(=O)n(C(=O)OC(C)(C)C)c2ccc(I)cc21
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CC(C)(C)OC(=O)C(c1ccccc1)n1c(=O)n(C(=O)OC(C)(C)C)c2ccc(C#N)cc21
Reaction time: 0.33 h

Procedure:
1.74 (3.16 mmol) of tert-butyl 3-(tert-butoxycarbonylphenylmethyl)-5-iodo-2-oxo-2,3-dihydrobenzimidazole-1-carboxylate (XIIb) were dissolved in 20 ml of dry DMF and stirred under a stream of nitrogen for 20 min. 482 mg (4.11 mmol) of zinc(II) cyanide and 292 mmol (0.25 mmol) of Pd[P(Ph)3]4 were added, and the reaction solution was stirred at 80° C. for 1.5 h. The cooled reaction solution was mixed with 70 ml of water and extracted with ethyl acetate (3×). The combined organic phases were washed with saturated NaCl solution and dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (mobile phase gradient 10-30% ethyl acetate in cyclohexane). Yield: 1.08 g (76%) of white solid
Reaction SMILES: C([O:8][C:9](=[O:37])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[CH2:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[O:27][CH:28]([CH3:36])[C:29](=[O:35])[N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)C1C=CC=CC=1.[OH-].[Na+]>CO>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:9]([OH:37])=[O:8])=[C:13]([CH2:19][C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=2[O:27][CH:28]([CH3:36])[C:29](=[O:35])[N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:14]=1
Reactant: CC(Oc1ccc(Cl)cc1Cc1cc(Cl)ccc1OCC(=O)OCc1ccccc1)C(=O)N1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(Oc1ccc(Cl)cc1Cc1cc(Cl)ccc1OCC(=O)O)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution comprising {4-chloro-2-[5-chloro-2-(1-methyl-2-oxo-2-pyrrolidin-1-yl-ethoxy)-benzyl]-phenoxy}-acetic acid benzyl ester (63 mg, 0.116 mmol) in MeOH (1 mL) is treated with 2 M NaOH (145 μL) and allowed to stir at RT overnight. The resulting suspension is filtered, dissolved in water (1 mL) and the pH of the solution is adjusted to pH 1 using 2 M HCl. A precipitate forms which is filtered and dried in a vacuum oven to afford the titled product; MH+=452.
Reaction SMILES: C(O)(=O)[C@@:2]1([CH2:12][CH2:11][C@H:7]([C:8](O)=O)[C:4]1([CH3:6])C)C.[CH2:15]([N:18]1[CH2:23][C@@H:22]([CH3:24])[NH:21][CH2:20][C@@H:19]1[CH3:25])[CH:16]=[CH2:17].C(=O)C1C=CC=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(O)(=O)C>[CH2:15]([N:18]1[CH2:23][C@@H:22]([CH3:24])[N:21]([CH2:8][C:7]2[CH:4]=[CH:6][CH:2]=[CH:12][CH:11]=2)[CH2:20][C@@H:19]1[CH3:25])[CH:16]=[CH2:17]
Reactant: C=CCN1C[C@@H](C)NC[C@@H]1C
Reactant: CC1(C)[C@@H](C(=O)O)CC[C@@]1(C)C(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=Cc1ccccc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C=CCN1C[C@@H](C)N(Cc2ccccc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of the (+)-(1R,3S)-camphoric acid salt of (+)-(2S,5R)-1-allyl-2,5-dimethylpiperazine from Preparation 1 (78.2 g) and benzaldehyde (26.5 g) in tetrahydrofuran (500 ml) containing glacial acetic acid (2 ml) was added sodium triacetoxyborohydride (93.3 g) portionwise over 10 minutes. The resulting mixture was stirred at room temperature for 4 hours. The reaction was partitioned between ethyl acetate (1500 ml) and aqueous sodium hydroxide (750 ml of 2N solution). The layers were separated and the organic phase was washed with 10% sodium metabisulphite solution (200 ml) and saturated brine solution. The organic layer was dried (MgSO4) and evaporated to dryness in vacuo to give the title compound, 52.1 g.
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:16][C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[C:22](C)[CH:21]=3)[CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:7][CH:6]=1)C.[OH-].[Na+].[CH2:31]1COCC1.CO>>[CH3:15][CH:13]([CH3:14])[CH2:12][CH:11]([C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:3])=[O:28])=[CH:6][CH:7]=1)[NH:16][C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:31]
Reactant: CCOC(=O)c1ccc(C(CC(C)C)Nc2cnc3cc(C)ccc3c2)cc1
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc2cc(NC(CC(C)C)c3ccc(C(=O)O)cc3)cnc12
Yield: 100 %

Procedure:
A mixture of 4-[3-Methyl-1-(7-methyl-quinoline-3-ylamino)-butyl]-benzoic acid ethyl ester (48 mg, 0.13 mM) and 1N aqueous NaOH solution (0.318 mL, 0.318 mM) in THF-MeOH (1:1, 1.5 mL) was heated to 50° for 5 h. The reaction was cooled, concentrated to remove organic solvent. The aqueous solution was diluted with DCM (5 mL), acidified by 1N HCl solution to pH=3-4. The organic solution was separated and the aqueous solution was extracted with DCM (3×5 mL). The combined organic solution were dried (Na2SO4) and concentrated to give a yellow solid product (44 mg, −100%). 1H NMR (400 MHz, CD3OD) δ ppm 0.97 (d, J=6.44 Hz, 3H) 1.02 (d, J=6.44 Hz, 3H) 1.54-1.67 (m, 1H) 1.73-1.91 (m, 2H) 2.43 (s, 3H) 4.57-4.65 (m, 1H) 7.14 (d, J=2.54 Hz, 1H) 7.28 (dd, J=8.49, 1.27 Hz, 1H) 7.46-7.58 (m, 4H) 7.97 (d, 2H) 8.44 (d, J=2.34 Hz, 1H), two protons (COOH and NH) were exchanged. LC-MS: m/z 349.1 (M+1). This material will be used for the next step reaction without further work-up.
Reaction SMILES: [CH2:1]=CC.[CH2:4]([OH:8])[CH:5]([CH3:7])[CH3:6]>C(O)CCC>[CH:4](=[O:8])[CH2:5][CH2:6][CH3:1].[CH2:4]([OH:8])[CH:5]([CH3:7])[CH3:6]
Reactant: C=CC
Solvent: CC(C)CO
Solvent: CCCCO
Product: CCCC=O
Yield: 56.6 %

Procedure:
Three more runs were made with the same catalyst in the presence of alkylamines. Details of these runs are tabulated in Table I and II. Triethyl- and tributylamine were used in these reactions. The level of catalytic activity based on the apparent conversion of propylene was maintained well through these runs, and showed an increase in catalytic activity in the presence of amines. In the last run, 20 g. of propylene was reacted in 50% conversion to yield 30.9% isobutanol, 56.6% n-butanal, 1.6% isobutanol, 3.8% n-butanol and 7.2% unknown products.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:19][C:20]([CH3:27])=[C:21]([C:23]([O:25]C)=[O:24])[N:22]=3)=[CH:14][CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:19][C:20]([CH3:27])=[C:21]([C:23]([OH:25])=[O:24])[N:22]=3)=[CH:14][CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)OC)c(C)o3)cc2)nc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)O)c(C)o3)cc2)nc1Cl
Yield: 79.3 %

Procedure:
The same operation as in Example (91d) was performed using methyl 2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}phenyl)-5-methyl-1,3-oxazole-4-carboxylate obtained in Example (97e) (0.14 g, 0.36 mmol), 2 N lithium hydroxide (2 mL, 4 mmol), methanol (3 mL) and tetrahydrofuran (5 mL), to obtain 107 mg of the title compound as a light pink solid (79%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[N:4]=[CH:3]1.[CH3:11][N:12]=[C:13]=[S:14]>C(#N)C>[CH3:1][N:2]1[C:6]2[CH2:7][N:8]([C:13](=[S:14])[NH:12][CH3:11])[CH2:9][CH2:10][C:5]=2[N:4]=[CH:3]1
Reactant: Cn1cnc2c1CNCC2
Reactant: CN=C=S
Solvent: CC#N
Product: CNC(=S)N1CCc2ncn(C)c2C1

Procedure:
A solution of 1 g of 3-methyl-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine and 1 g of methyl isothiocyanate in 10 ml of acetonitrile is refluxed for 4 h. The solution is cooled and filtered: 0.9 g of 3-methyl-5-(N-methyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine, m.p. 235°, are collected.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:24]([O-:26])=[O:25])=[C:4]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])[C:5]([C:10]2[N:14]=[C:13]([CH3:15])[O:12][N:11]=2)=[CH:6][C:7]=1[O:8]C.C(OCC)(=O)C.[Cl-].[Al+3].[Cl-].[Cl-].Cl>N1C=CC=CC=1>[OH:1][C:2]1[C:3]([N+:24]([O-:26])=[O:25])=[C:4]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])[C:5]([C:10]2[N:14]=[C:13]([CH3:15])[O:12][N:11]=2)=[CH:6][C:7]=1[OH:8]
Reactant: COc1cc(-c2noc(C)n2)c(C(=O)c2ccccc2)c([N+](=O)[O-])c1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cc(O)c(O)c([N+](=O)[O-])c2C(=O)c2ccccc2)no1
Temperature: 25 °C
Yield: 87.5 %

Procedure:
To a mixture of [3-hydroxy-4-methoxy-6-(5-methyl-[1,2,4]oxadiazol-3-yl)-2-nitrophenyl]phenylmethanone (reference example 22-1) (377 mg) and ethyl acetate (10.6 mL) were added aluminum chloride (361 mg) and pyridine (0.387 mL). The mixture was refluxed for 2.5 hours. After cooling to room temperature, 1 mol/L hydrochloric acid was added to the mixture. The separated organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was triturated with hexane:methylene chloride=4:1 to give the title compound (317 mg) as an amorphous.
Reaction SMILES: C(Br)C.[Mg].II.[CH2:7]([O:9][C:10](=[O:17])[CH:11]([CH2:15][CH3:16])[C:12]([OH:14])=O)[CH3:8].[CH2:18]([O:25][CH2:26][CH2:27]C(Cl)=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>O1CCCC1.C1(C)C=CC=CC=1>[CH2:7]([O:9][C:10](=[O:17])[CH:11]([CH2:15][CH3:16])[C:12](=[O:14])[CH2:27][CH2:26][O:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:8]
Reactant: CCOC(=O)C(CC)C(=O)O
Reactant: O=C(Cl)CCOCc1ccccc1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCBr
Product: CCOC(=O)C(CC)C(=O)CCOCc1ccccc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
Ethyl bromide (5 ml) is added dropwise into a 2 l five-necked flask equipped with a mechanical stirrer, a condenser, a dropping funnel, a thermometer and an Argon inlet tube charged with magnesium turnings (26.6 g), anhydrous tetrahydrofuran (100 ml) and iodine (a few crystals). After 1 or 2 minutes, once the reaction begins, the mixture is stirred and diluted with anhydrous tetrahydrofuran (510 ml). Ethyl bromide (86.6 ml) is gradually added, over a period of 45 minutes keeping the temperature at about 30°-35° C. When the ethyl bromide has been added stirring is continued for an additional 30 minutes and the mixture is cooled to about -10° C. Then a solution of ethyl malonic acid monoethyl ester (87.7 g) in anhydrous tetrahydrofuran (80 ml) is slowly added dropwise (60 minutes) into the above mixture. When the addition is complete, the mixture is stirred for one hour at room temperature and for an additional hour at about 75° C. The mixture is then cooled to 15° C. and a solution of 3-benzyloxypropionyl chloride (108.8 g) in anydrous tetrahydrofuran (50 ml) is added drop by drop over a period of 15 minutes. After stirring at room temperature for two hours, the reaction mixture is allowed to stand at room temperature overnight and gradually poured into a 3-l beaker, equipped with a mechanical stirrer and a thermometer, containing 8% HCl (295 ml) and toluene (295 ml), keeping the temperature at about 10°-15° C. After stirring for a few minutes, the aqueous phase is separated and extracted with toluene (three 150-ml portions). The toluene extracts are combined, washed with a 15% phosphate buffer pH 6.5 (two 250-ml portions), dried over Na2SO4 and concentrated to dryness yielding 5-benzyloxy-3-oxo-2-ethyl-pentanoic acid ethyl ester (146.8 g). The ethylmalonic acid monoethyl ester used in this step has been prepared as follows:
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[O:11][C:12]([CH3:35])=[C:13]([CH2:15][N:16]([CH2:33][CH3:34])[C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:14]=2)[CH:5]=1.[Li+].[OH-].Cl.CCOCC>C1COCC1.O>[CH2:33]([N:16]([CH2:15][C:13]1[N:14]=[C:10]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:36])=[O:2])[O:11][C:12]=1[CH3:35])[C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:24]([F:25])([F:26])[F:27])[C:28]([F:30])([F:31])[F:29])=[CH:19][CH:18]=1)[CH3:34]
Reactant: CCN(Cc1nc(-c2cccc(C(=O)OC)c2)oc1C)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCN(Cc1nc(-c2cccc(C(=O)O)c2)oc1C)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
A solution of 92 mg (0.18 mmol) of 3-[4-({ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzoic acid methyl ester (example 30.2) in 1 mL of THF was treated with 1 mL of 1M aqueous LiOH and stirred at RT for 1 h. The mixture was acidified to pH 4-5 with aqueous HCl and distributed between Et2O and H2O. The combined organic phases were dried over Na2SO4 and evaporated to yield 79 mg (88%) of 3-[4-({ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzoic acid, light yellow solid, MS: 503 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:40])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([N:24]2[CH2:33][C:32]3[CH:31]=[N:30][N:29]([CH3:34])[C:28]=3[NH:27][C:26]3[CH:35]=[CH:36][CH:37]=[CH:38][C:25]2=3)=[O:23])=[CH:18][C:17]=1[CH3:39])(C)(C)C>ClCCl>[CH3:39][C:17]1[CH:18]=[C:19]([C:22]([N:24]2[CH2:33][C:32]3[CH:31]=[N:30][N:29]([CH3:34])[C:28]=3[NH:27][C:26]3[CH:35]=[CH:36][CH:37]=[CH:38][C:25]2=3)=[O:23])[CH:20]=[CH:21][C:16]=1[CH2:15][CH2:14][C:13]([OH:40])=[O:12]
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 90 %

Procedure:
Trifluoroacetic acid (5 ml) was added to a solution of 3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionic acid tert-butyl ester from Example E45.3 (413 mg, 0.92 mmol) in dichloromethane (10 ml) and the mixture was stirred for 45 min at room temperature. Solvents were removed in vacuo and azeotroped with dichloromethane. The residue was crystallised with MeOH/Et2O to yield the title compound (322 mg, 90%).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[O:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:25]([O:27][CH2:28]Cl)[CH3:26]>C(#N)C>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:18])([CH3:1])[O:3][B:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([O:15][CH2:28][O:27][CH2:25][CH3:26])=[O:14])=[CH:11][CH:10]=2)[O:5]1
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Reactant: CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOCOC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 65 °C
Yield: 84 %

Procedure:
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (0.50 g, 2.02 mmol) was dissolved in 20 mls of dry acetonitrile. To this solution was added powdered potassium carbonate (0.42 g, 3.02 mmol) followed by chloromethyl ethyl ether (0.24 mls, 2.42 mmol). This mixture was warmed to 65° C. for 2 hours, then allowed to cool to room temperature, filtered and the filtrate concentrated to give ethoxymethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate as a solid (84%). This material was taken onto the next step without further purification.
Reaction SMILES: CCCCCC.[H-].[K+].[NH:9]1[CH:13]=[CH:12][CH:11]=[N:10]1.[C:14]([O:18][C:19](=[O:38])[NH:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([S:28]([C:31]2[CH:36]=[CH:35][C:34](N)=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH2:24][CH2:23]1)([CH3:17])([CH3:16])[CH3:15]>CN(C=O)C.O>[C:14]([O:18][C:19](=[O:38])[NH:20][CH2:21][CH:22]1[CH2:23][CH2:24][N:25]([S:28]([C:31]2[CH:36]=[CH:35][C:34]([N:9]3[CH:13]=[CH:12][CH:11]=[N:10]3)=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH2:26][CH2:27]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)NCC1CCN(S(=O)(=O)c2ccc(N)cc2)CC1
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NCC1CCN(S(=O)(=O)c2ccc(-n3cccn3)cc2)CC1
Temperature: 70 °C
Yield: 30.7 %

Procedure:
To a stirred mixture of hexane washed potassium hydride (0.08 g, 2 mmol) in 5 mL of DMF was added pyrazole (0.136 g, 2 mmol) in one portion. Stirring was continued until gas evolution ceased. A solution of [1-(4-aminobenzenesulfonyl)-piperidin-4-ylmethyl]-carbamic acid t-butyl ester (0.745 g, 2 mmol) in 5 mL DMF was added and the solution was heated at 70° C. overnight. The reaction mixture was poured into water and the solids formed collected and dried (high vac). The crude product was purified by flash chromatography (silica Merck 60, CH2Cl2—CH3OH, 19:1) to give 0.258 g of the product as a white solid.
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=[C:4]([CH2:12]O)[CH:3]=1.C(N(CC)CC)C.S(Cl)([Cl:23])=O>ClCCl>[Cl:23][CH2:12][C:4]1[CH:3]=[C:2]([F:1])[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(F)c2c(c1)OCCO2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Fc1cc(CCl)cc2c1OCCO2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.8 %

Procedure:
To a solution of (8-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)methanol (0.84 g, 4.55 mmol) and triethylamine (960 μl, 4.84 mmol) in dichloromethane (20 mL) was slowly added thionyl chloride (400 μl, 5.47 mmol) at 0° C. The solution was stirred at 0° C. for 15 min then at rt for 3 h. Dichloromethane (80 mL) was added and the solution was washed with water (40 mL), saturated aqueous sodium bicarbonate (40 mL) then brine (40 mL) and dried over sodium sulfate. Filtration and concentration gave 7-(chloromethyl)-5-fluoro-2,3-dihydro-1,4-benzodioxine (0.92 g, quantitative yield) as a brown oil. The chloride was used in the next step without further purification.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH:14]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:13]=[C:12]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[N+:29]([O-])=O)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CO>CC(O)=O.[Fe]>[NH2:29][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][C:23]=1[C:12]1[CH2:11][CH2:10][CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[CH:14]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:13]=1
Reactant: CC(C)(C)OC(=O)NC1C=C(c2ccncc2[N+](=O)[O-])CCC1O[Si](C)(C)C(C)(C)C
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1C=C(c2ccncc2N)CCC1O[Si](C)(C)C(C)(C)C
Reaction time: 20 h
Yield: 94 %

Procedure:
To a solution of (+/−)-tert-butyl 6-(tert-butyldimethylsilyloxy)-3-(3-nitropyridin-4-yl)cyclohex-2-enylcarbamate (1.0 equiv.) in AcOH (0.18 M) was added Fe (6.0 equiv.) and the reaction was stirred for 20 h. Worked up by diluting the reaction with methanol, filtered, and concentrated the filtrate. To the crude was added ethyl acetate and saturated NaHCO3, the organics were dried with sodium sulfate and concentrated to give (+/−)-tert-butyl 3-(3-aminopyridin-4-yl)-6-(tert-butyldimethylsilyloxy)cyclohex-2-enylcarbamate as a yellow oil in 94% yield. LCMS (m/z): 420.3 (MH+), LC Rt=3.88 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=1.[Li+].CC([N-]C(C)C)C.Cl[CH:23]([C:32]1[CH:37]=[CH:36][N:35]=[C:34]([S:38][CH3:39])[N:33]=1)[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[C:27]#[N:28]>C1COCC1>[CH3:39][S:38][C:34]1[N:33]=[C:32]([CH:23]([C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[C:27]#[N:28])[CH:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:37]=[CH:36][N:35]=1
Reactant: c1cncc(Cc2cccnc2)c1
Reactant: CSc1nccc(C(Cl)c2cccc(C#N)c2)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1nccc(C(c2cccc(C#N)c2)C(c2cccnc2)c2cccnc2)n1
Reaction time: 1 h

Procedure:
To the solution of 3-(pyridin-3-ylmethyl)pyridine (1.24 g, 7.26 mmol) in THF (32 mL) at −78° C. was added LDA (4.4 mL, 1.8 M) and stirred for 1 h. 3-{chloro[2-(methylthio)pyrimidin-4-yl]methyl}benzonitrile (2.0 g, 7.25 mmol) in THF (5 mL) was added. The mixture was stirred at 0° C. for 2 h. The reaction was quenched with ice and extracted with CH2Cl2. The combined organic layer was dried, filtered, and concentrated to give a solid. The solid was purified by silica gel chromatography (3% MeOH in CH2Cl2) to give (±)-3-{1-[2-(methylthio)pyrimidin-4-yl]-2,2-dipyridin-3-ylethyl}benzonitrile. LRMS m/z (M+H) Calcd: 410.5, found: 410.1. Step D
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2([C:22]([O:24][CH3:25])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[C:26](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:25][O:24][C:22]([C:16]1([N:15]([S:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:7][CH:8]=2)(=[O:14])=[O:13])[CH3:26])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:23]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC2(C(=O)OC)CCCCC2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C2(C(=O)OC)CCCCC2)cc1
Temperature: 25 °C

Procedure:
A mixture of methyl 1-({[4-(2-butynyloxy)phenyl]sulfonyl}-amino)cyclohexanecarboxylate (4.5 g.,12.3 mmol), anhydrous potassium carbonate (20.0 g, excess) and methyl iodide (2 g, 14.08 mmol) was refluxed in acetone for sixteen hours. The reaction mixture was then cooled to room temperature and filtered. The acetone layer was concentrated and extracted with chloroform. The chloroform layer was washed well with water, dried over anhydrous MgSO4, filtered and concentrated to provide methyl1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]cyclohexanecarboxylate as a yellow oil. Yield: 4.6 g (quantitative) Electrospray Mass Spec 380 (M+H)+.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[C:9]([C:13]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[O:14])([CH3:12])([CH3:11])[CH3:10]>CS(C)=O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2([C:9]([CH3:12])([CH3:10])[CH3:11])[O:14][CH2:4]2)=[CH:16][CH:17]=1
Reactant: CC(C)(C)C(=O)c1ccc(Cl)cc1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)C1(c2ccc(Cl)cc2)CO1
Temperature: 50 °C
Yield: 95 %

Procedure:
A solution of dimethyl oxosulphonium methylide was prepared under nitrogen from sodium hydride (0.03 mol) and powdered trimethyl oxosulphonium iodide (0.03 mol) in dry dimethyl sulphoxide (40 ml). A solution of 4-chlorophenyl tertiary butyl ketone (0.025 mol) in dry dimethyl sulphoxide (10 ml) was added dropwise at room temperature and the solution heated at 50° C. for 2.5 hours. After cooling to room temperature the solution was extracted with ether (150 ml), washed with water and dried over anhydrous sodium sulphate. Removal of the solvent gave 1-(4-chlorophenyl)-1-t-butyl-ethylene oxide (95%) as a colourless liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[N:20]1([C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][N:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:26]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)=[N:27][CH:28]=1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: O=C(O)c1ccc(N2CCOCC2)nc1
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc(N2CCOCC2)nc1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 6-morpholin-4-yl-nicotinic acid. MS: 450.5 (M+H).