Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12]C(C)C)=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:3]=1.B(Cl)(Cl)Cl>>[Cl:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:3]=1
Reactant: CC(C)Oc1c(Cl)cc(-c2cccnc2)c2cccnc12
Agent: ClB(Cl)Cl
Product: Oc1c(Cl)cc(-c2cccnc2)c2cccnc12
Yield: 94.6 %

Procedure:
Cleavage of the isopropyl ether 22 (20 mg, 0.07 mmol) with boron trichloride following the method outlined in Example 8, gave 7-chloro-5-(pyridin-3-yl)-quinolin-8-ol (PBT 1057) as a pale straw-coloured solid (17 mg, 94%). 1H NMR (CD3OD, 400 MHz): δ 9.16 (m, 2 H), 9.04 (d, J=5.8, 1 H), 8.93 (dd, J=1.2 and 8.6, 1 H), 8.84 (m, 1 H), 8.30 (dd, J=5.8 and 8.1, 1 H), 8.09 (s, 1 H), 8.08 (dd, J=5.1 and 8.6, 1 H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C[Si]([C:11]#[C:12][C:13]1[NH:17][C:16]([C@@H:18]2[CH2:23][C@@H:22]3[C@@H:20]([CH2:21]3)[N:19]2[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:15][CH:14]=1)(C)C>CO>[C:12]([C:13]1[NH:17][C:16]([C@@H:18]2[CH2:23][C@@H:22]3[C@@H:20]([CH2:21]3)[N:19]2[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:15][CH:14]=1)#[CH:11]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(C#C[Si](C)(C)C)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cnc([C@@H]2C[C@H]3C[C@H]3N2C(=O)OC(C)(C)C)[nH]1
Temperature: 50 °C
Yield: 97.3 %

Procedure:
Potassium carbonate (194 mg, 1.40 mmol) was added to a solution of (1R,3S,5R)-tert-butyl 3-(5-((trimethylsilyl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (970 mg, 2.81 mmol) in MeOH (30 mL) and the reaction was stirred under nitrogen and then heated at 50° C. (bath temp) for 4 h. The reaction was concentrated to ˜5 mL of volume, diluted with DCM (˜40 mL) and washed with ½ sat brine (˜20 mL). The organics were dried (MgSO4) filtered and concentrated to a tan solid. This material was purified by BIOTAGE® Horizon (40 g SiO2, loaded with DCM, 35-45% EtOAc/hexanes) to yield (1R,3S,5R)-tert-butyl 3-(5-ethynyl-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (747 mg) as a light yellow solid. LC-MS retention time 2.866 min; m/z 272.12 (MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and Solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, MeOD) δ ppm 7.18 (br. s., 1 H), 4.59 (br. s., 1 H), 3.36-3.64 (m, 2 H), 2.46 (dd, J=13.2, 8.9 Hz, 1 H), 2.18-2.31 (m, 1 H), 1.64-1.74 (m, 1 H), 1.18-1.45 (m, 9 H), 0.83 (dt, J=8.5, 5.8 Hz, 1 H), 0.56 (br. s., 1 H).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11]([NH:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[O:12])[CH3:10])=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:14]([NH:13][C:11](=[O:12])[C@H:9]([CH3:10])[NH2:8])[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)CNC(=O)[C@H](C)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CNC(=O)[C@H](C)N

Procedure:
N2-(tert-Butoxycarbonyl)-N1-isobutyl-L-alaninamide (300 mg, 1.23 mmol) is stirred with 2 mL of TFA in 4 mL of dichloromethane for 1 h. The mixture is concentrated and neutralized with 2 mL of 1 N NaHCO3 and 2 mL of 1 N Na2CO3, and extracted into 50 mL of ethyl ether containing 2 mL of methanol. The organic phase was washed with brine and dried with Na2SO4. Concentration afforded the title compound as a colorless film (90 mg, 0.62 mmol, 51%). 1H NMR (CD3OD) δ 4.9 (s, 3H, includes water), 3.52 (q, J=7 Hz, 1H), 3.07-2.96 (m, 2H), 1.78 (m, 1H), 1.31 (d, J=7 Hz, 3H), 0.90 (m, 6H)
Reaction SMILES: [CH2:1](Cl)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][NH:12][CH2:13][CH2:14][OH:15].O>C(O)C>[CH3:11][N:12]([CH2:13][CH2:14][OH:15])[CH2:1]/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ClCC=Cc1ccccc1
Reactant: CNCCO
Solvent: O
Solvent: CCO
Product: CN(C/C=C/c1ccccc1)CCO

Procedure:
12.5 Grams of cinnamyl chloride and 21 g of 2-methylaminoethanol were dissolved in 100 ml of ethanol, and the solution was refluxed for 5 hours. The solvent was removed by evaporation, to the residue thus obtained was added water and washed with n-hexane. To the water layer was added 3N-sodium hydroxide aqueous solution to adjust its pH to 10-11, and extracted with ether. The ether extract was washed with water and dried with anhydrous sodium sulfate, and the solvent was removed by evaporation. The residue was purified by means of a silica gel column chromatography (eluent: chloroform:methanol=25:1) to yield 15 g of 2-[N-methyl-N-(3-phenyl-2(E)-propenyl)amino]ethanol.
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:22]([OH:24])=[O:23])[CH2:20][SH:21])(=[O:17])[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][CH3:16].[O:25]1[C:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:26]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:1]([NH:18][C@H:19]([C:22]([OH:24])=[O:23])[CH2:20][S:21][CH2:26][CH:27]([OH:25])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])(=[O:17])[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][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)N[C@@H](CS)C(=O)O
Reactant: CCCCCCCCCCCCCCCCC1=CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCC(O)CSC[C@H](NC(=O)CCCCCCCCCCCCCCC)C(=O)O

Procedure:
5.6 g of N-palmitoylcysteine, 5 g of 1,2-epoxy-octadecene and 5.35 g of potassium carbonate in 100 ml ethanol are heated in an atmosphere of nitrogen at 80° for 15 hours. After evaporation, HCl is added so as to obtain a pH of about 3 and the mixture is extracted with chloroform. The chloroform extract is washed with water and is then dried with sodium sulfate. After evaporation there is obtained a colorless residue which is recrystallized from ethyl acetate. There are obtained colorless crystals of the N-palmitoyl-S-[2(R,S)-hydroxyoctadecyl]-(L)-cysteine of melting point 96°-98° [α]D20 =+16° (c=0.78, chloroform).
Reaction SMILES: [CH3:1][Si:2]([CH3:30])([CH3:29])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[CH:9]=[C:8]1[Sn](CCCC)(CCCC)CCCC.[CH:31]1([C:35]2[N:39]3[CH:40]=[CH:41][N:42]=[C:43]([NH2:44])[C:38]3=[C:37](I)[N:36]=2)[CH2:34][CH2:33][CH2:32]1>C(O)C.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>[CH:31]1([C:35]2[N:39]3[CH:40]=[CH:41][N:42]=[C:43]([NH2:44])[C:38]3=[C:37]([C:8]3[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:29])[CH3:30])[C:11]4=[N:12][CH:13]=[CH:14][CH:15]=[C:10]4[CH:9]=3)[N:36]=2)[CH2:32][CH2:33][CH2:34]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2cccnc2n1COCC[Si](C)(C)C
Reactant: Nc1nccn2c(C3CCC3)nc(I)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Product: C[Si](C)(C)CCOCn1c(-c2nc(C3CCC3)n3ccnc(N)c23)cc2cccnc21
Temperature: 25 °C
Yield: 24.9 %

Procedure:
A mixture of N-(2-trimethylsilyl-1-ethoxymethyl)-2-(tributylstannyl)-1H-pyrrolo[2,3-b]pyridine (110 mg, 0.20 mmol), 3-cyclobutyl-1-iodoimidazo[1,5-a]pyrazin-8-amine (50 mg, 0.1592 mmol) and bis(triphenylphosphine)palladium(II) chloride (10 mg, 0.02 mmol) in ethanol (2 mL) was heated at reflux for 48 h. The mixture was then cooled to rt, filtered through a pad of Celite and concentrated in vacuo. The residue thus obtained was chromatographed over silica gel eluting with hex:EtOAc to afford 17.2 mg of the title compound. 11-1NMR (400 MHz CDCl3) δ 0.22 (s, 9H), 0.70 (t, 2H), 1.87-2.19 (m, 2H), 2.49-2.64 (m, 4H), 3.37 (t, 2H), 3.81-3.86 (m, 1H), 5.51 (bs, 2H), 6.07 (s, 2H), 6.67 (s, 1H), 7.10-7.16 (m, 3H), 7.93 (dd, J=1.6, 8.0 Hz, 1H) and 8.41 (dd, J=1.6, 4.8 Hz, 1H). MS (ES+): m/z: 435.21 [MH+].
Reaction SMILES: C([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[N:7][C:6]=1[NH2:12])C.[OH-].[Na+]>C(O)C>[NH2:12][C:6]1[N:7]=[C:8]([NH2:11])[CH:9]=[CH:10][C:5]=1[C:4]([OH:13])=[O:3]
Reactant: CCOC(=O)c1ccc(N)nc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(C(=O)O)c(N)n1
Temperature: 25 °C
Yield: 100.6 %

Procedure:
2,6-Diamino-nicotinic acid ethyl ester (2.0 g) described in Manufacturing Example 10-2-3 was dissolved in ethanol (15 mL), and a 1N aqueous solution of sodium hydroxide (15 mL) was added thereto, after which the solution was refluxed for 2 hours. The reaction mixture was cooled to room temperature, and the ethanol solvent was evaporated under a reduced pressure. The reaction mixture was neutralized with 1N hydrochloric acid at 0° C. The precipitated solids were filtered off to obtain the titled compound (1.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[N:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)=[C:19]=[O:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:19]([NH:18][C:21]2[CH:26]=[CH:25][C:24]([S:27][C:28]([F:30])([F:29])[F:31])=[CH:23][CH:22]=2)=[O:20])[CH2:7]1
Reactant: O=C=Nc1ccc(SC(F)(F)F)cc1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Nc1ccc(SC(F)(F)F)cc1

Procedure:
Example 34 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 1-isocyanato-4-[(trifluoromethyl)thio]benzene (21.9 μl) to give the title compound (0.0122 g). LC-MS (System A): Rt 2.70 mins, Mass Spectrum m/z 494 [MH+].
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:12][CH2:13][NH2:14])=[CH:8][CH2:9]2)=[CH:5][C:4]=1[O:15][CH3:16].[C:17](Cl)(=[O:21])[CH2:18][CH2:19][CH3:20]>>[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:12][CH2:13][NH:14][C:17](=[O:21])[CH2:18][CH2:19][CH3:20])=[CH:8][CH2:9]2)=[CH:5][C:4]=1[O:15][CH3:16]
Reactant: COc1cc2c(cc1F)CC=C2CCN
Reactant: CCCC(=O)Cl
Agent: Cl
Product: CCCC(=O)NCCC1=CCc2cc(F)c(OC)cc21

Procedure:
Starting with 2-(6-fluoro-5-methoxy-1H-inden-3-yl)ethylamine hydrochloride and butyryl chloride, the title compound was synthesized in otherwise the same manner as Example 8 (yield 80%).
Reaction SMILES: [C:1]([C:5]1[N:6]([CH3:33])[C:7](=[O:32])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([O:21][CH2:22][CH2:23][CH2:24][CH2:25]C1C=CC=CC=1)=[CH:10][CH:9]=2)([CH3:4])([CH3:3])[CH3:2].[C:34]1([CH2:40]CCCCI)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[C:1]([C:5]1[N:6]([CH3:33])[C:7](=[O:32])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:40][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[CH:10][CH:9]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(C(C)(C)C)c(-c2ccccc2)c2cc(OCCCCc3ccccc3)ccc2c1=O
Reactant: ICCCCCc1ccccc1
Product: Cn1c(C(C)(C)C)c(-c2ccccc2)c2cc(OCCCCCc3ccccc3)ccc2c1=O

Procedure:
Following the procedure for 3-tert-butyl-2-methyl-4-phenyl-6-(4-phenylbutoxy)isoquinolin-1(2H)-one, using 5-phenyl-1-iodopentane in place of 4-phenyl-1-iodobutane, the titled compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:21])[CH2:9][N:10]2[C:15](=[O:16])[CH:14]=[CH:13][CH:12]=[C:11]2[C:17]([O:19]C)=[O:18])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:21])[CH2:9][N:10]2[C:15](=[O:16])[CH:14]=[CH:13][CH:12]=[C:11]2[C:17]([OH:19])=[O:18])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(=O)n1CC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(Cn1c(C(=O)O)cccc1=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 79.7 %

Procedure:
To a suspension of methyl 1-[2-(4-chlorophenyl)-2-oxoethyl]-6-oxo-1,6-dihydropyridine-2-carboxylate (130 mg, 0.43 mmol) in MeOH (5 mL) and water (2.5 mL) was added a aqueous solution of NaOH (1 M) (0.8 mL, 0.8 mmol). The resulting dark orange solution was stirred at room temperature until completion (45 minutes, monitored by LCMS). The mixture was then acidified with an aqueous solution of HCl (1 M) and the resulting suspension was concentrated in vacuo to remove the MeOH. The precipitate formed was collected by filtration and washed with water to yield the acid derivative 1-[2-(4-chlorophenyl)-2-oxoethyl]-6-oxo-1,6-dihydropyridine-2-carboxylic acid as a yellow solid (100 mg, 80%). 1H NMR (400 MHz, d6-DMSO): 5.84 (s, 2H), 6.73 (dd, 1H, J 9.2, 1.2 Hz), 7.01 (dd, 1H, J 6.8, 1.0 Hz), 7.57 (dd, 1H, J 9.2, 6.9 Hz), 7.66 (d, 2H, J 8.6 Hz), 8.07 (d, 2H, J 8.5 Hz).
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([N:15]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:5]1)#[N:2].N.[H][H]>CO.[Ni]>[NH2:2][CH2:1][CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:14])[CH2:5]1
Reactant: CC1(C)O[C@H](CC#N)C[C@H](CC(=O)N(Cc2ccccc2)Cc2ccccc2)O1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC1(C)O[C@H](CCN)C[C@H](CC(=O)N(Cc2ccccc2)Cc2ccccc2)O1
Temperature: 20 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
A solution of (4R-cis)-6-(cyanomethyl)-2,2-dimethyl-N,N-bis(phenylmethyl)-1,3-dioxane-4-acetamide (10.0 g, 0.025 mol) in methanol (150 mL) containing anhydrous ammonia (2.25 g) is reacted with hydrogen gas in a Parr shaker at 30° C. in a presence of a slurry of Raney nickel A-7000 (3.7 g). After 3 hours, uptake of hydrogen has ceased, the mixture is cooled to 20° C., the atmosphere is vented and exchanged for nitrogen, the slurry is filtered through celite, and concentrated at reduced pressure to give 9.4 g of (4R-cis)-6-(2-aminoethyl)-2,2 -dimethyl-N,N-bis(phenylmethyl)-1,3-dioxane-4-acetamide as an oil;
Reaction SMILES: [CH3:1][C:2]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][CH3:14])=[O:12])[CH:6]=1)([CH3:4])[CH3:3].[CH:15]([CH:17]=[O:18])=[O:16].[OH-].[Na+]>C(O)C>[CH3:4][C:2]([C:5]1[O:9][N:8]=[C:7]([N:10]2[CH:15]([OH:16])[CH:17]([OH:18])[N:13]([CH3:14])[C:11]2=[O:12])[CH:6]=1)([CH3:1])[CH3:3]
Reactant: O=CC=O
Reactant: CNC(=O)Nc1cc(C(C)(C)C)on1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1C(=O)N(c2cc(C(C)(C)C)on2)C(O)C1O
Reaction time: 8 h

Procedure:
To a solution of 2.0 grams (0.010 mole) of 1-[5-(1,1-dimethylethyl)-3-isoxazolyl]-3-methylurea in 50 milliliters of 95 percent ethanol was added 7.3 grams of a 40 percent aqueous glyoxal solution which had been previously adjusted to pH 7 with dilute sodium hydroxide solution. After standing at room temperature overnight, the solution was topped on a rotary evaporator to give an oily residue which was extracted with two 20 milliliter portions of chloroform. The extract was washed with saturated sodium chloride solution, filtered through silicone-treated paper, and concentrated on a rotary evaporator to give 2.0 grams of oily residue. Crystallization from ether gave 0.4 grams of white crystals of 3-[5-(1,1-dimethylethyl)-3-isoxazolyl]-4,5-dihydroxy-1-methyl-2-imidazolidinone, M.P. 153°-157° C., which had consistent mass, infrared and NMR spectra.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]([CH3:27])([S:23]([CH3:26])(=[O:25])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:11](=[O:28])[CH:10]=1)C1C=CC=CC=1.C1CCCCC=1>C(O)C.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]([CH3:27])([S:23]([CH3:26])(=[O:25])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:11](=[O:28])[CH:10]=1
Reactant: CCOC(=O)C(C)(CCn1ccc(OCc2ccccc2)cc1=O)S(C)(=O)=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CCOC(=O)C(C)(CCn1ccc(O)cc1=O)S(C)(=O)=O
Temperature: 85 °C

Procedure:
Ethyl 4-[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoate (2.4 g, 5.9 mmol) which may be prepared by the same method disclosed in Example 51, step A, was dissolved in ethanol (100 ml) and cooled with a dry ice/acetone bath. To the cooled solution was added Pearlman's catalyst (2.0 g) and cyclohexene (9.0 ml, 88.4 mmol) then heated to 85° C. for 3 hours. The reaction mixture was cooled to RT and filtered through celite (approx 2 inches) to remove catalyst. The celite was washed with an additional 100 ml of ethanol. The filtrate was then concentrated under reduced pressure and the residue was dried under vacuum to afford a light gray solid. (1.75 g, 94%). MS (LC/MS) m/z 318.1 (M+1) 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (t, J=7.02 Hz, 3H) 1.56 (s, 3H) 2.02-2.26 (m, 1H) 2.33-2.48 (m, 1H) 3.14 (s, 3H) 3.67-3.84 (m, 1H) 3.84-4.02 (m, 1H) 4.13 (dd, J=7.02, 4.49 Hz, 2H) 5.55 (d, J=2.54 Hz, 1H) 5.85 (dd, J=7.42, 2.54 Hz, 1H) 7.48 (d, J=7.42 Hz, 1H)
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:32]2[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=2)[CH:6]([C:22]([O:24]CC2C=CC=CC=2)=[O:23])[C:7](=[O:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2].[H][H]>[Pd].O1CCCC1>[C:1]([C:4]1[CH:5]([C:32]2[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=2)[CH:6]([C:22]([OH:24])=[O:23])[C:7](=[O:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)C(C(=O)OCc2ccccc2)C1c1ccc(C#N)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)C(C(=O)O)C1c1ccc(C#N)cc1
Reaction time: 0.25 h

Procedure:
A stirred suspension of benzyl 5-acetyl-4-(4-cyanophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyridine-3-carboxylate (7.5 g, 14 mmol) (Example 6A) and 10%. palladium on charcoal (255 mg) in tetrahydrofuran (975 ml) is treated with hydrogen gas at room temperature under atmospheric pressure. After 15 minutes, the reaction is stopped and the solution is filtered and concentrated. The residue is immediately used in the next step without further purification and characterisation.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=1)=[O:6])#[N:2].[Br:16][C:17]1[C:18](I)=[N:19][C:20]([I:23])=[N:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[Br:16][C:17]1[C:18]([C:10]2[CH:11]=[CH:12][C:7]([C:5]([NH:4][CH2:3][C:1]#[N:2])=[O:6])=[CH:8][CH:9]=2)=[N:19][C:20]([I:23])=[N:21][CH:22]=1
Reactant: N#CCNC(=O)c1ccc(B(O)O)cc1
Reactant: Brc1cnc(I)nc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: N#CCNC(=O)c1ccc(-c2nc(I)ncc2Br)cc1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 50.2 %

Procedure:
To a mixture of 4-(cyanomethylcarbamoyl)phenylboronic acid (see example 3) (185 mg, 0.9 mmol) and 5-bromo-2,4-diiodopyrimidine (410 mg,1.0 mmol) in 1,4-dioxane (10 mL), was added 2M aqueous potassium carbonate (100 μL). The resulting mixture was stirred under nitrogen for 5 minutes then tetrakis(triphenylphophine)palladium(0) (52 mg, 0.045 mmol) was added under a nitrogen atmosphere. The mixture was heated at 80° C. overnight. The cooled reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were washed with water then brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product as a brown solid. The crude material was purified by flash chromatography, eluting with 50% ethyl acetate/petroleum spirit to give 4-(5-bromo-2-iodopyrimidin-4-yl)-N-(cyanomethyl)benzamide (200 mg, 35% over 2 steps). LC-ESI-MS (method B): rt 6.2 min.; m/z 443.0/445.0 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([O:13]CC)=O.[CH3:16][NH2:17]>CO>[CH3:16][NH:17][C:11]([C:3]1[N:2]([CH3:1])[C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:13]
Reactant: CN
Reactant: CCOC(=O)c1cc2ccccc2n1C
Solvent: CO
Product: CNC(=O)c1cc2ccccc2n1C
Temperature: 25 °C

Procedure:
A suspension of ethyl 1-methyl-1H-indole-2-carboxylate (27.10 g, 133.34 mmole) in 40% aqueous CH3NH2 (300 mL) and MeOH (30 mL) was stirred at RT. A solid tended to gradually creep up the walls of the flask, and was washed down periodically with MeOH. The flask was tightly stoppered to keep the material inside the flask. As the reaction proceeded, the solid dissolved, but eventually the product began to precipitate. The reaction was stirred at RT for 5 days, then was concentrated to remove approximately 200 mL of the solvent. The remaining residue was diluted with H2O (300 mL), and the solid was collected by suction filtration and washed with H2O. Drying at 50-60° C. in high vacuum left the title compound (23.45 g, 93%) as a faintly yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.63 (d, J=8.0 Hz, 1H), 7.27-7.43 (m, 2H), 7.10-7.20 (m, 1H), 6.80 (s, 1H), 6.10-6.30 (m, 1H), 4.06 (s, 3H), 3.01 (d, J=4.9 Hz, 3H).
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](Cl)=[O:10].[F:16][C:17]([F:30])([F:29])[O:18][C:19]1[CH:28]=[CH:27][C:22]([O:23][CH2:24][CH2:25][NH2:26])=[CH:21][CH:20]=1>C(N(CC)CC)C>[F:16][C:17]([F:29])([F:30])[O:18][C:19]1[CH:28]=[CH:27][C:22]([O:23][CH2:24][CH2:25][NH:26][C:9](=[O:10])[C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[Cl:6])=[CH:21][CH:20]=1
Reactant: NCCOc1ccc(OC(F)(F)F)cc1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCCOc1ccc(OC(F)(F)F)cc1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A tetrahydrofuran (5 ml) solution of 2-chlorobenzoyl chloride (0.88 g) was added dropwise under ice-cooling and stirring to a tetrahydrofuran (20 ml) solution of 2-(4-trifluoromethoxyphenoxy)ethylamine (1.10 g) and triethylamine (0.51 g) and the mixture was further stirred at room temperature for one hour.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OS(O)(=O)=O.[N+:22]([O-])([OH:24])=[O:23]>>[C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[C:14]([N+:22]([O-:24])=[O:23])[CH:15]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(O)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(S(=O)(=O)c2ccccc2)ccc1O
Yield: 112.3 %

Procedure:
Using the procedure of J. Org. Chem. 59(15) 1994, 4301, 4-benzenesulfonyl-phenol (5.348 g, 22.8 mmol) was added to 3.07 mL of conc. H2SO4 with stirring. Concentrated HNO3 (1.28 g) was added dropwise via addition funnel, and the reaction mixture was stirred under nitrogen for 4 hours. The reaction mixture was then poured over ice, and the resulting suspension was extracted four times with 50 mL of methylene chloride. The combined organic layers were dried (Na2SO4) and concentrated in vacuo to yield an oil which slowly solidified. The solid was washed with 1:1 EtOAc:hexanes to yield 4-benzenesulfonyl-2-nitro-phenol (6.37 g, quantitative) as a crude solid. MS: 235 (M+H)+.