Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:25]([OH:27])=O)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:29]1CCOCC1.N>COCCOC>[CH2:1]([O:8][C:9]([NH:11][C:12]1([C:25](=[O:27])[NH2:29])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)(C(=O)O)CC1
Reactant: CN1CCOCC1
Agent: N
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
A solution 4-(benzyloxycarbonylamino)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (1A, 2.0 g, 1.0 equivalent) in DME (0.5 M) was treated with NMM (1.0 equivalent) and IBCF (1.0 equivalent) at −15° C. After 10 min, aqueous ammonia (1.5 equivalents) was added. The reaction mixture was stirred at room temperature for 1.5 hr. The reaction was complete as determined by LCMS analysis and then partitioned between ethyl acetate and water. The organics were subsequently washed with brine, then dried over Na2SO4, filter, and the volatiles removed under reduced pressure. The residue was purified by crystallization from diethyl ether to afford the tert-butyl 4-(benzyloxycarbonylamino)-4-carbamoylpiperidine-1-carboxylate (1B, 70%).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:11]=[CH:12][C:13](OC)=[O:14].Cl>CO>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:11]=[CH:12][C:13]([NH:2][OH:3])=[O:14]
Reactant: COC(=O)C=Cc1ccc(OC)c(OC)c1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C=CC(=O)NO)cc1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
A solution of hydroxylamine hydrochloride (5.09 g, 72 mmol) in methanol (26 ml) was added to a solution of 88% potassium hydroxide (6.99 g, 109 mmol) in methanol (15.3 ml), keeping the temperature below 40° C. The mixture was cooled to 0° C., filtered, and methyl 3,4-dimethoxycinnamate (8.0 g, 36 mmol) was added to the filtrate. After two hours, concentrated HCl (5 ml) was added to the cold solution. The resulting precipitate was filtered, washed with water and ether, and dried in vacuo, to give 6.74 g (84% yield) of the named compound, mp 183°-185° C.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([S:10]C#N)[CH:7]=[CH:6][C:5]=1[OH:13].[CH3:14][C:15]1[CH:16]=[C:17]([S:26]CC2SC(C3C=CC(C(F)(F)F)=CC=3)=NC=2C)[CH:18]=[CH:19][C:20]=1[O:21]CC(O)=O.Cl>O.CCOCC>[C:15]1([CH3:14])[C:20]([OH:21])=[CH:19][CH:18]=[C:17]([S:26][S:10][C:8]2[CH:9]=[C:4]([CH3:3])[C:5]([OH:13])=[CH:6][CH:7]=2)[CH:16]=1
Reactant: Cc1cc(SCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OCC(=O)O
Reactant: Cc1cc(SC#N)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(SSc2ccc(O)c(C)c2)ccc1O
Temperature: 95 °C

Procedure:
To a stirred solution of 33.0 g (825.6 mmol) NaOH in 200 ml water was added 44.0 g (266.3 mmol) of 2-methyl-4-thiocyanato-phenol at 85° C. [Wei, Zhi-Liang; Kozikowski, Alan P., A Short and Efficient Synthesis of the Pharmacological Research Tool GW501516 for the Peroxisome Proliferator-Activated Receptor delta, Journal of Organic Chemistry (2003), 68(23), 9116-9118]. The temperature was raised to 95° C. and the mixture stirred over night. After cooling (10° C.), ether and 90 ml of aqueous conc. HCl were added. The water phase was extracted with ether (two times). The organic phase was washed with brine, dried (Na2SO4) and evaporated. The residue was dissolved in 300 ml of DMSO and heated for 2 h at 95° C. Subsequently, the solution was poured onto ice water and extracted with three 1 l portions of TBME. The organic layers were washed with 700 ml of water, dried (Na2SO4) and evaporated to give 42.1 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C@H:14]([N+:15]([O-])=O)[CH2:13][C:12]([CH2:18][O:19][C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=2)[C:23]([O:25][CH3:26])=[O:24])=[C:11]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:10]1>[Zn].CO.C(O)(=O)C>[NH2:15][C@@H:14]1[CH2:13][C:12]([CH2:18][O:19][C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=2)[C:23]([O:25][CH3:26])=[O:24])=[C:11]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:10][C@H:9]1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: COC(=O)c1cccc(OCC2=C(c3cccnc3)C[C@@H](c3ccc(Cl)cc3Cl)[C@H]([N+](=O)[O-])C2)c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cccc(OCC2=C(c3cccnc3)C[C@@H](c3ccc(Cl)cc3Cl)[C@H](N)C2)c1
Yield: 76.1 %

Procedure:
To a solution of Example 9A (35 mg, 0.068 mmol) in mixture of methanol/acetic acid (0.5 mL/0.5 mL) Zn powder (45 mg, 0.68 mmol) was added at room temperature. The reaction mixture was stirred for thirty minutes, filtered, concentrated under reduced pressure and purified by high-pressure liquid chromotography (eluting with 0-70% acetonitrile/water and 0.1% trifluoroacetic acid) to provide the title compound (25 mg, 76%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.54-8.72 (m, 1H), 7.89-8.11 (m, 2H), 6.96-7.72 (m, 8H), 4.46-4.58 (m, 2H), 3.80-3.87 (m, 4H), 3.59-3.72 (m, 1H), 2.53-2.88 (m, 4H). MS (ESI) m/z 483 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH2:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@@H:29]1[CH2:33][CH2:34][NH2:35])[CH3:27]>>[CH2:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@@H:29]1[CH2:33][CH2:34][NH:35][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9])[CH3:27]
Reactant: CCN1CCC[C@@H]1CCN
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Product: CCN1CCC[C@@H]1CCNc1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCC1CC21

Procedure:
Prepared by proceeding in a similar manner to Example 58, starting from (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (Intermediate 67) and 2-((R)-1-ethylpyrrolidin-2-yl)ethylamine (Intermediate 141).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([CH:18]([CH3:20])[CH3:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21](I)[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:15][CH2:21][CH3:22])=[O:14])=[C:11]([CH:18]([CH3:20])[CH3:19])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: CC(C)c1cc(OCc2ccccc2)ccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCc2ccccc2)cc1C(C)C
Temperature: 25 °C

Procedure:
A mixture of N-methylformanilide (9.92 g) and phosphoryl chloride (11.3 g) was stirred at room temperature for 30 minutes, and benzyloxy-3-isopropylbenzene (16.6 g) was added to the mixture. After being stirred at room temperature overnight, ice was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford 4-benzyloxy-2-isopropylbenzaldehyde (19.4 g) as a crude product. An aqueous solution (200 mL) of sodium chlorite (33.2 g) was added dropwise to an ice-cooled suspension of the crude 4-benzyloxy-2-isopropylbenzaldehyde and potassium dihydrogenphosphate (50.0 g) in tert-butylalcohol (200 mL)/2-methyl-2-butene (100 mL) with stirring. The mixture was stirred at room temperature for 3 hrs. To the resulting mixture was added water, and the insoluble materials were removed by filtration. The filtrate was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford 4-benzyloxy-2-isopropylbenzoic acid (23.3 g) as a crude product. A suspension of the crude 4-benzyloxy-2-isopropylbenzoic acid, ethyl iodide (13.7 g) and potassium carbonate (15.2 g) in N,N-dimethylformamide (300 mL) was stirred at room temperature for30 minutes. The reaction mixture was partitioned between diethyl ether and water. The organic layer was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to afford ethyl 4-benzyloxy-2-isopropylbenzoate (16.8 g). A suspension of ethyl 4-benzyloxy-2-isopropylbenzoate and 10% palladium-carbon (0.1 g) in ethanol (100 mL) was stirred at room temperature for 30 minutes under an atmosphere of hydrogen. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to afford the title compound (1.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:13])[CH2:9][CH2:10][CH:11]=[O:12])=[CH:4][CH:3]=1.[CH2:14]([Mg]I)[CH2:15][CH3:16].S(=O)(=O)(O)O>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH2:9][CH2:10][CH:11]([OH:12])[CH2:14][CH2:15][CH3:16])=[CH2:13])=[CH:6][CH:7]=1
Reactant: C=C(CCC=O)c1ccc(Cl)cc1
Reactant: CCC[Mg]I
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: C=C(CCC(O)CCC)c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 77.5 %

Procedure:
A solution of 4-(4-chlorophenyl)pent-4-enal (2.0 g) in dry diethyl ether (25 ml) was added to a stirred solution of propylmagnesium iodide [from 1-iodopropane (2.72 g) and magnesium turnings (0.48 g)] in dry diethyl ether (50 ml) under an atmosphere of nitrogen (exotherm). After stirring for 1 hour the reaction mixture was poured into a mixture of ice and dilute sulphuric acid, then extracted with ether. The extracts were washed with water, dried over magnesium sulphate, and concentrated under reduced pressure to give 2-(4-chlorophenyl)-5-hydroxyoct-1-ene (1.9 g, 77%) as a yellow oil.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH:14]([C:16]([N:18]3[CH2:23][CH2:22][N:21]([CH2:24][C:25]([O:27]CC4C=CC=CC=4)=[O:26])[CH2:20][CH2:19]3)=[O:17])[O:13][C:12]2=[O:35])=[CH:7][CH:6]=1.O.C(O)(=O)C>CO.[Pd].C>[ClH:1].[ClH:1].[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH:14]([C:16]([N:18]3[CH2:19][CH2:20][N:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:22][CH2:23]3)=[O:17])[O:13][C:12]2=[O:35])=[CH:7][CH:6]=1
Reactant: NCc1ccc(N2CC(C(=O)N3CCN(CC(=O)OCc4ccccc4)CC3)OC2=O)cc1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: NCc1ccc(N2CC(C(=O)N3CCN(CC(=O)O)CC3)OC2=O)cc1

Procedure:
0.6 g of benzyl 2-{1-[3-(4-aminomethylphenyl)-2-oxo-5-oxazolidinylcarbonyl]-4-piperazinyl}acetate, dihydrochloride, is hydrogenated over Pd/charcoal, in a mixture of 30 ml of methanol, 5 ml of water and 5 ml of glacial acetic acid. The reaction mixture is filtered and the filtrate is concentrated in vacuo. Trituration of the crude product with ethyl acetate gives 2-{1-[3-(4-aminomethylphenyl)-2-oxo-5-oxazolidinylcarbonyl]-4-piperazinyl}acetic acid, dihydrochloride, m.p. 91° (decomposition).
Reaction SMILES: [CH:1]1([C:6]2[S:10][C:9]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])=[N:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[S:21]([Cl:25])(=O)(=[O:23])[OH:22]>[OH-].[Na+]>[CH:1]1([C:6]2[S:10][C:9]([NH:11][C:12]([C:13]3[CH:18]=[C:17]([S:21]([Cl:25])(=[O:23])=[O:22])[CH:16]=[CH:15][C:14]=3[F:19])=[O:20])=[N:8][N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=S(=O)(O)Cl
Reactant: O=C(Nc1nnc(C2CCCC2)s1)c1ccccc1F
Agent: [Na+]
Agent: [OH-]
Product: O=C(Nc1nnc(C2CCCC2)s1)c1cc(S(=O)(=O)Cl)ccc1F
Temperature: 200 °C

Procedure:
3-{[(5-cyclopentyl-1,3,4-thiadiazol-2-yl)amino]carbonyl}-4-fluorobenzenesulfonyl chloride was prepared from N-(5-cyclopentyl-1,3,4-thiadiazol-2-yl)-2-fluorobenzamide using a Biotage Initiator 8 microwave set to high absorbance as follows. Using conditions described, the reaction reached a pressure of 12 barr. The pressure was reduced to 3 barr after cooling and was vented prior to decapping the reaction vessel. To a 5 ml Biotage microwave reaction tube was added N-(5-cyclopentyl-1,3,4-thiadiazol-2-yl)-2-fluorobenzamide (0.305 g, 1.05 mmol) and a Teflon covered magnetic stir-bar. To this was added 2 ml of chlorosulfuric acid. The vessel was capped and heated to 200° C. for 3.25 min. After cooling to room temperature, the remaining pressure was vented into a 50 ml syringe and discharged into 30 ml 1M NaOH. Reaction was quenched by adding dropwise to 30 ml of crushed ice-water while stirring. The solid product was collected by vacuum filtration, washed with water (5 ml, 3×) and air-dried under vacuum, yielding 3-{[(5-cyclopentyl-1,3,4-thiadiazol-2-yl)amino]carbonyl}-4-fluorobenzenesulfonyl chloride as a off white solid (290 mg, 71%), Crude product was used to next step.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl.[CH3:18][C:19]1([C:25]([O:27][CH3:28])=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CS(C)=O>[CH3:18][C:19]1([C:25]([O:27][CH3:28])=[O:26])[CH2:24][CH2:23][N:22]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:21][CH2:20]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: COC(=O)C1(C)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C1(C)CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 60 °C
Yield: 94.2 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (2.0 g, 12.62 mmol) in DMSO (20 mL) was added sodium carbonate (6.70 g, 63.08 mmol) followed by methyl 4-methylpiperidine-4-carboxylate hydrochloride (2.44 g, 12.62 mmol). The reaction mixture was heated to 60° C. for 2 hours. The reaction mixture was poured onto water (100 mL) and the suspension filtered, washed with water (4×150 mL) and dried to leave the title compound as a yellow solid (3.32 g, 11.89 mmol, 94%); 1H NMR (CDCl3) δ 1.26 (s, 3H), 1.46-1.52 (m, 2H), 2.21-2.25 (m, 2H), 3.26-3.32 (m, 2H), 3.74 (s, 3H), 4.16-4.20 (m, 2H), 6.56 (d, 1H), 8.18 (d, 1H), 9.03 (s, 1H); MS m/e MH+ 280.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][S:10][C:5]2=[CH:4][C:3]=1[CH:11]=[O:12].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:13]1([C:2]2[N:7]=[C:6]3[CH:8]=[CH:9][S:10][C:5]3=[CH:4][C:3]=2[CH:11]=[O:12])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1cc2sccc2nc1Cl
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: O=Cc1cc2sccc2nc1-c1ccccc1
Temperature: 100 °C
Yield: 86.5 %

Procedure:
To a solution of 5-chlorothieno[3,2-b]pyridine-6-carbaldehyde (396 mg, 2.01 mmol) in DME/water (10 mL/2 mL) was added phenylboronic acid (306 mg, 2.51 mmol), K2CO3 (833 mg, 6.03 mmol) and Pd(PPh3)4 (116 mg, 0.1 mmol). The mixture was degassed before being heated in a sealed tube at 100° C. for 5 h. The reaction mixture was allowed to cool to room temperature, diluted with EtOAc (25 mL), washed with water (2×10 mL) and washed with brine (10 mL). The organic layer was separated, dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by column chromatography (SiO2, 0-40% EtOAc in heptane) to give the title compound (416 mg, 86%) as a white solid. δH (CDCl3) 10.15 (s, 1H), 8.88 (s, 1H), 8.97 (d, J 6 Hz, 1H), 7.69 (d, J 6 Hz, 1H), 7.50-7.65 (m, 5H). LCMS (ES+) 240.2 (M+H)+, RT 3.46 minutes (Method 2).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([CH:18]=2)[C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[CH:6][N:5]=[C:4]2[N:19]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:20]=[C:21](I)[C:3]=12.[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>C(#N)C.C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([CH:18]=2)[C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[CH:6][N:5]=[C:4]2[N:19]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:20]=[C:21]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[F:31])[C:3]=12
Reactant: CN(C)C(=O)c1cncc(-c2cnc3c(c(I)cn3COCC[Si](C)(C)C)c2Cl)c1
Reactant: OB(O)c1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1cncc(-c2cnc3c(c(-c4ccccc4F)cn3COCC[Si](C)(C)C)c2Cl)c1
Temperature: 110 °C

Procedure:
78 mg (0.14 mmol) of (5-[4-chloro-3-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-nicotinamide, 21 mg (0.15 mmol) of 2-fluoro-phenylboronic acid and 6 mg (7 μmol) of (1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichloromethane adduct were dissolved in a mixture of 2.6 mL of acetonitrile, 2.6 mL of toluene and 1.5 mL of a saturated aqueous solution of sodium bicarbonate. The resulting mixture was heated to 110° C. in a closed vial for 22 h. The resulting mixture was diluted with ethyl acetate, dried over sodium sulfate and evaporated. The resulting crude was purified by flash chromatography on silica gel using a gradient of 10% v/v methanol in ethyl acetate and hexanes to afford 56.6 mg (0.10 mmol) of 5-[4-chloro-3-(2-fluoro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-nicotinamide. 1H-NMR [500 MHz, d6-DMSO] δ: 8.73 (d, 1H), 8.67 (d, 1H), 8.41 (s, 1H), 7.99 (t, 1H), 7.97 (s, 1H), 7.49-7.41 (m, 2H), 7.30-7.25 (m, 2H), 5.74 (s, 2H), 3.62 (t, 2H), 3.01 (s, 3H), 2.97 (s, 3H), 0.86 (t, 2H), −0.06 (s, 9H); MS [MH+] m/z: 525.
Reaction SMILES: C1(CCC(Cl)=O)CCCCCC1.[C:13]([NH:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28](=[O:38])[CH2:29][CH2:30][CH:31]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[C:23]([O:39][C:40](=[O:50])[CH2:41][CH2:42][CH:43]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH:22]=1)=[O:20])([CH3:16])([CH3:15])[CH3:14]>>[CH:43]1([CH2:42][CH2:41][C:40]([O:39][C:23]2[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=2[O:27][C:28](=[O:38])[CH2:29][CH2:30][CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)[CH:19]([OH:20])[CH2:18][NH:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:50])[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: CC(C)(C)NCC(=O)c1ccc(OC(=O)CCC2CCCCCC2)c(OC(=O)CCC2CCCCCC2)c1
Agent: O=C(Cl)CCC1CCCCCC1
Product: CC(C)(C)NCC(O)c1ccc(OC(=O)CCC2CCCCCC2)c(OC(=O)CCC2CCCCCC2)c1

Procedure:
Following the procedure described above in Example 15A but using cycloheptanepropionyl chloride instead of cyclohexanecarbonyl chloride the acylation product obtained is 3,4-bis(cycloheptanepropionyloxy)phenyl tert-butylaminomethyl ketone; and when this product is catalytically hydrogenated, using the procedure described above in Example 15B, there is obtained 3,4-bis(cycloheptanepropionyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=O)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[CH:26]1([NH2:30])[CH2:29][CH2:28][CH2:27]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:18])([CH3:19])[C:15]([NH:30][CH:26]2[CH2:29][CH2:28][CH2:27]2)=[O:17])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: NC1CCC1
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NC3CCC3)c2c1N

Procedure:
Prepared as in Example Da from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example 47b) and cyclobutanamine as an off-white solid (71%). MS 400 (MH+).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[CH:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[N:31]([CH3:32])[N:30]=[N:29][N:28]=2)[CH:20](N)[C:19]3=[O:34])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH3:32][N:31]1[C:27]([S:26][CH2:25][C:24]2[CH2:23][S:22][CH:21]3[N:18]([C:19](=[O:34])[CH2:20]3)[C:17]=2[C:15]([O:14][CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:16])=[N:28][N:29]=[N:30]1
Reactant: Cn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)C2SC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: Cn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)CC2SC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of part a and 7-amino-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid diphenylmethyl ester are dissolved in 650 ml. of absolute tetrahydrofuran and the solution is cooled to 0°. At this temperature, a solution of 7.3 gms. of dicyclohexylcarbodiimide in 60 ml. of absolute tetrahydrofuran is added dropwise over a period of about 20 minutes. The mixture is stirred at 0° for two hours and an additional two hours at room temperature. The dicyclohexylurea which precipitates is removed by filtration. The filtrate is concentrated in vacuum. The residue is dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution, then with water and dried with magnesium sulfate. After filtration, the filtrate is left overnight in the refrigerator. The reaction product crystallizes. On filtration 12.2 gms. of 7β-[[[[[(4-methoxyphenyl)methoxy]carbonyl]amino]-2-thienyl)acetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]-methyl]-8 -oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester are obtained, m.p. 126° (dec.). The filtrate is evaporated to dryness. Treatment with ethyl acetate yields a second crop of 2.6 gms. A third crop of 2.6 gms. is obtained when the filtrate is evaporated, dissolved in a small amount of ethyl acetate, precipitated with petroleum ether and again treated with ethyl acetate.
Reaction SMILES: [C:1]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C(#N)C.CN(C=O)C.C(OCC)(=O)C>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][NH:15][CH:12]1[CH2:11][CH2:10][CH:9]([NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:14][CH2:13]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CCC(NCC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a suspension of trans-N-Boc-1,4-diaminocyclohexane (0.256 g, 1.19 mmol) and potassium carbonate (0.663 g, 4.80 mmol) in acetonitrile (15 mL) and DMF (5 mL) was added benzyl bromoacetate (0.21 mL, 1.33 mmol) under argon and the reaction was stirred at RT for 19 hr. The reaction was diluted with ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was carried forward without purification. ESI-MS m/z 363 (MH)+.
Reaction SMILES: [CH:1]1([C:4]2[C:9]([CH2:10]O)=[CH:8][N:7]=[C:6]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:5]=2)[CH2:3][CH2:2]1.S(Cl)([Cl:24])=O>ClCCl.CCOCC>[Cl:24][CH2:10][C:9]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Solvent: CCOCC
Solvent: ClCCl
Product: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
A mixture of 1.9 g (6.456 mmol) of [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-methanol and 0.515 ml (7.1 mmol) thionylchloride in 20 ml dichloromethane was stirred for 1 h at RT. The reaction mixture was taken up in ether and washed with sodium bicarbonate solution and water. The ether phase was concentrated under reduced pressure to give 1.97 g of pure 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine.