Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])[O:4]1.[Na+].[I-].[C-:21]#[N:22].[K+].[Na].C([O-])(O)=O.[Na+]>O.CS(C)=O>[C:21]([CH2:2][C@H:3]1[CH2:7][CH2:6][C@H:5]([CH2:8][CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])[O:4]1)#[N:22]
Reactant: COc1ccc(F)cc1CCC1CCC(CBr)O1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(F)cc1CC[C@H]1CC[C@H](CC#N)O1
Temperature: 70 °C
Yield: 81 %

Procedure:
To a vial under Ar(g) was added 2-(bromomethyl)-5-(2′-methoxy-5′-fluorophenethyl)tetrahydrofuran (0.67 g, 2.1 mmol), NaI (70 mg), potassium cyanide (0.35 g, 5.3 mmol), and dry DMSO (5 mL). The mixture thus obtained was heated to 70° C. under Ar for 12 h. After it was cooled to room temperature, the reaction mixture was poured into a separatory funnel containing sodium bicarcarbonate aqueous solution (sat. NaHCO3:H2O=1:1, 40 mL). The organic function was extracted with ethyl acetate (2×50 mL) and the combined organic layers were washed with brine (50 mL) and dried over sodium sulfate. The solvent then was removed in vacuo and crude product thus obtained was purified by flash column chromatography (15% EtOAc in hexane) to result in the title product (448 mg, 86%).
Reaction SMILES: [K].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.CN(C)P(N(C)C)(N(C)C)=O.Cl[CH2:25][C:26]([NH2:28])=[O:27]>CS(C)=O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH2:25][C:26](=[O:27])[NH2:28])=[O:11])=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: NC(=O)CCl
Agent: [K]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CS(C)=O
Product: NC(=O)COC(=O)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.8 %

Procedure:
The potassium salt of 4-hydroxyphenylacetic acid (9.5 g, 0.1 mol) was taken up in a mixture of dimethylsulfoxide (80 mL) and hexamethylphosphoramide (5.37 g, 0.1 mol). 2-Chloroacetamide (13.5 g, 0.3 mol) was added and the reaction mixture was first stirred at room temperature for 24 hours, then heated for 1 hour. The reaction mixture was evaporated, then cooled. The product which separated was taken up in ethyl acetate (150 mL), stirred, filtered and evaporated. The oily residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was separated, dried over anhydrous MgSO4, filtered and evaporated to give the desired ester, carbamoylmethyl 4-hydroxyphenylacetate, melting at 85°-87° C., in 48.8% yield.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH:20]([C:22](=[O:30])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][N:18]([C:31]([C:33]3([NH:36]C(=O)OC(C)(C)C)[CH2:35][CH2:34]3)=[O:32])[CH2:17]2)=[CH:12][CH:11]=1)[CH3:9]>ClCCl>[NH2:36][C:33]1([C:31]([N:18]2[CH2:17][CH:16]([C:13]3[CH:14]=[CH:15][C:10]([CH2:8][CH3:9])=[CH:11][CH:12]=3)[CH2:21][CH:20]([C:22]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:30])[CH2:19]2)=[O:32])[CH2:34][CH2:35]1
Reactant: CCc1ccc(C2CC(C(=O)Nc3ccccc3)CN(C(=O)C3(NC(=O)OC(C)(C)C)CC3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1ccc(C2CC(C(=O)Nc3ccccc3)CN(C(=O)C3(N)CC3)C2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Under argon and at RT, 190 μl (2.5 mmol, 15 eq.) of trifluoroacetic acid were added to a solution of 81 mg (0.16 mmol) of tert-butyl (1-{[3-(4-ethylphenyl)-5-(phenylcarbamoyl)piperidin-1-yl]carbonyl}cyclopropyl)carbamate in 2 ml of dichloromethane. The reaction mixture was stirred at RT for 20 h, then concentrated under reduced pressure and repeatedly coevaporated with toluene. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 29 mg (45% of theory)
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:17][C:18](=[O:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH2:1]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[O:15][CH2:17][C:18](=[O:20])[CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(Cl)cc1Cc1ccccc1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1ccc(Cl)cc1Cc1ccccc1

Procedure:
5 g of 2-benzyl-4-chlorophenol, 2.6 ml of chloroacetone, 1.38 g of potassium carbonate and 0.34 g of potassium iodide are dissolved in 50 ml of acetone and boiled under reflux for 20 h. After cooling, the precipitate is filtered, concentrated by evaporation, the residue dissolved in ethyl acetate, the solution washed three times with a 1 n sodium hydroxide solution, then with saturated sodium chloride solution, dried with magnesium sulphate and concentrated by evaporation under vacuum. After recrystallisation from diethylether, 1-(2-benzyl-4-chlorophenoxy)-propan-2-one is obtained as a white powder with a melting point of 65-6° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.CCCCCC.[Li]CCCC.[C:19]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[C:27]1([C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[OH:26])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)(c1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
A solution of 3-bromopyridine (10 g, 0.063 mol) in dry THF (200 mL)/hexane (50 mL) was cooled to −90° C. To this cooled solution was added n-BuLi (2.2 M, 32 mL, 0.063 mol) slowly and allowed to stir for 30 min under N2 atmosphere. A solution of benzophenone (11.5 g, 0.063 mol) in dry THF (50 mL) was added to this at the same temperature over a period of 30 min. The reaction mixture was warmed slowly to RT and allowed to stir another 3 h at RT. The reaction mixture was cooled, quenched with water (200 mL) and extracted with ethylacetate (2×100 mL). The organic layer was dried, concentrated under vacuum and crude purified by column chromatography over silica gel (30% ethyl acetate in petroleum ether) to give the title product (3.3 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=O)[CH3:18])[C:12]=2[OH:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:21][C:22]1[CH:31]=[C:30]([C:32]([NH:34][NH2:35])=[O:33])[CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25]>C(O)(C)C>[Br:21][C:22]1[CH:31]=[C:30]([C:32]([NH:34][N:35]=[C:17]([C:13]2[C:12]([OH:20])=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)[N:15]([CH3:16])[N:14]=2)[CH3:18])=[O:33])[CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1ccc(C(=O)NN)cc1Br
Reactant: CC(=O)c1nn(C)c(-c2ccc(C(C)(C)C)cc2)c1O
Solvent: CC(C)O
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(C(C)(C)C)cc3)c2O)cc1Br
Temperature: 0 °C
Yield: 86.3 %

Procedure:
1-[5-(4-tert-Butylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (0.554 mmol, 150.9 mg) synthesized in Synthetic Example 3, methyl 2-bromo-4-hydrazinocarbonylbenzoate (0.554 mmol, 150.8 mg) synthesized in Reference Synthetic Example 42 and p-tosylic acid monohydride (30 mol %, 28.6 mg) were dissolved in isopropyl alcohol (15 mL) and stirred under heating with reflux for 8 hours, and the reactor was cooled to 0° C. The reaction solution was filtered and dried by means of a vacuum pump to give the desired product as a white solid (252.3 mg, yield 86%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:13])=[C:8]([OH:12])[C:9]=2[CH3:11])[S:4][C:3]=1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].CCN(CC)CC.[N:28]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1>CC#N>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:13])=[C:8]([O:12][C:33]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:34])[C:9]=2[CH3:11])[S:4][C:3]=1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: O=C(Cl)N1CCCC1
Reactant: Cc1nc2sc(C(=O)OC(C)(C)C)c(N)c2c(C)c1O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nc2sc(C(=O)OC(C)(C)C)c(N)c2c(C)c1OC(=O)N1CCCC1
Reaction time: 3 h
Yield: 52 %

Procedure:
tert-Butyl 3-amino-5-hydroxy-4,6-dimethyl-thieno[2,3-b]pyridine-2-carboxylate, prepared in example 1C, Step C, (40 mg, 0.14 mmol) in CH3CN (1 mL) was combined with Et3N (52 mg, 0.52 mmol) and pyrrolidine-1-carbonyl chloride (51 mg, 0.39 mmol) at room temperature. After stirring for 3 h, the mixture was evaporated under reduced pressure, water was added and extracted with ethyl acetate (3 mL), washed with water (3 mL×3), brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC to provide tert-butyl 3-amino-4,6-dimethyl-5-(pyrrolidine-1-carbonyloxy)-thieno[2,3-b]pyridine-2-carboxylate (41 mg, 52%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([OH:13])([CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH2:5][CH3:6].[CH2:14](Br)[CH:15]=[CH2:16]>CN(C)C=O>[CH2:16]([O:13][C:4]([CH3:3])([CH2:5][CH3:6])[CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH:15]=[CH2:14]
Reactant: CCC(C)(O)CCC=C(C)C
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC(C)(CC)CCC=C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 786.7 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 6.8 g, 170 mmol) and dimethylformamide (100 mL) were added to a three necked 500 mL flask fitted with thermocouple, condenser and addition funnel. To the stirred reaction mixture was added dropwise 3,7-dimethyloct-6-en-3-ol (22 g, 139 mmol) at room temperature. The mixture was stirred for 1 hr, cooled to ice bath temperature then allyl bromide (97% pure by GC RPA, 19 g, 15 mmol) was added dropwise whilst maintaining cooling. After a further 3 hr stirring ice/water was added to the reaction mixture and then extracted with methyltert-butyl ether (3×30 mL). The combined organic phase was washed with dilute hydrochloric acid (100 mL), saturated brine (100 mL) and dried with magnesium sulphate. The solvent was removed in vacuo and the residue fractionally distilled to give 6-(allyloxy)-2,6-dimethyloct-2-ene (25.4 g, 92% pure by GC RPA, 118 mmol, chemical yield 70%).
Reaction SMILES: Br[CH:2]([CH3:18])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:4].C(=O)(O)[O-].[Na+].[CH:24]([NH2:27])([CH3:26])[CH3:25]>C(#N)C>[CH:24]([NH:27][CH:2]([CH3:18])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:4])([CH3:26])[CH3:25]
Reactant: CCCCCCCCCCCCOC(=O)C(C)Br
Reactant: CC(C)N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCCCCCCCCCCCOC(=O)C(C)NC(C)C
Temperature: 57.5 °C
Reaction time: 12 h
Yield: 75.2 %

Procedure:
To a stirred solution of 59 (10 g, 31.2 mmol) in acetonitrile (30 mL) was added sodium bicarbonate (2.62 g, 31.2 mmol) and followed by isopropyl amine (50% in water) (30 mL, 3 vol) at 25-30° C. The reaction mixture was stirred for 12 h at 55-60° C. and the reaction was monitored by TLC. The solid obtained in the reaction mixture was filtered under vacuum. The solvent was concentrated, diluted with ethyl acetate/water and stirred for 15 minutes at 25-30° C. The aqueous and organic layers were separated, and the aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine solution. The organic layer was dried over Na2SO4 and concentrated under vacuum to afford crude 62 (7 g, yield: 75.2%) as a liquid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[C:14](F)[C:11]([C:12]#[N:13])=[C:10]([F:17])[CH:9]=2)[CH:5]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][C@H:19]2[CH:24]([CH3:26])[CH3:25])[N:3]=1.C1(C)C=CC=CC=1.[CH3:34][CH2:35][O-:36].[Na+]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([F:17])[C:11]([C:12]#[N:13])=[C:14]([O:36][CH2:35][CH3:34])[CH:15]=2)[CH:5]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][C@H:19]2[CH:24]([CH3:26])[CH3:25])[N:3]=1
Reactant: CC[O-]
Reactant: CC(C)[C@@H]1COCCN1c1cc(-c2cc(F)c(C#N)c(F)c2)nc(N)n1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOc1cc(-c2cc(N3CCOC[C@H]3C(C)C)nc(N)n2)cc(F)c1C#N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
4-{2-Amino-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}-2,6-difluorobenzonitrile (405 mg, 1.12 mmol) was azeotroped with toluene (2×15 mL). The residue was dissolved in 5 mL of DMF as a yellow clear solution, to which was added NaOEt (1.45 mL of a stock solution with concentration of 0.87 mmol/mL, 1.25 mmol, 1.12 equiv) at room temperature in one portion. The resulting light orange clear solution was stirred at room temperature for 20 hours. LCMS showed conversion complete. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography using gradient elution of 1% EtOAc in CHCl3 to 100% EtOAc, providing the title compound (310 mg) as a white solid residue. LC-MS (ES) m/z=386 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19]Br)[NH:12][C:11]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)=[N:10]1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][C@H:27]1[C:32]([OH:34])=[O:33]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)[NH:12][C:13]([CH2:19][N:26]2[CH2:31][CH2:30][O:29][CH2:28][C@H:27]2[C:32]([OH:34])=[O:33])=[C:14]1[C:15]([O:17][CH3:18])=[O:16]
Reactant: O=C(O)[C@@H]1COCCN1
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Product: COC(=O)C1=C(CN2CCOC[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 83.1 %

Procedure:
Methyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1.65 g, 3.37 mmol) was reacted with (S)-morpholine-3-carboxylic acid (0.44 g, 3.37 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (1.51 g, 83%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[CH3:30][O:31][C:32](=[O:41])[C:33]1[CH:38]=[C:37]([OH:39])[CH:36]=[CH:35][C:34]=1[OH:40].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:30][O:31][C:32](=[O:41])[C:33]1[CH:38]=[C:37]([O:39][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:36]=[CH:35][C:34]=1[OH:40]
Reactant: ICCCCCCc1cccc(OCc2ccccc2)c1OCc1ccccc1
Reactant: COC(=O)c1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)ccc1O
Yield: 38.9 %

Procedure:
A mixture of 1.00 g of 1-(6-iodohexyl)-2,3-bis(phenylmethoxy)benzene, 0.34 g of 2,5-dihydroxybenzoic acid methyl ester and 1.0 g of potassium carbonate in 30 mL of acetone was stirred at reflux for 17 hours. Workup as in Example 16 and chromatography on 60 g of silica gel using 1% ethyl acetatetoluene gave 0.42 g (39% yield) of 2-hydroxy-5-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]benzoic acid methyl ester as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:18][N:6]2[C:7](=[O:17])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][N:12]=3)[N:10]=[C:5]2[NH:4][CH2:3]1.[H-].[Na+].[N:22]1[C:27]2[CH2:28][CH:29]([CH2:31]OS(C)(=O)=O)[CH2:30][C:26]=2[N:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[N:22]1[C:27]2[CH2:28][CH:29]([CH2:31][N:4]3[C:5]4=[N:10][C:9]([C:11]5[CH:16]=[CH:15][N:14]=[CH:13][N:12]=5)=[CH:8][C:7](=[O:17])[N:6]4[CH2:18][C:2]([CH3:19])([CH3:1])[CH2:3]3)[CH2:30][C:26]=2[N:25]=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)OCC1Cc2nccnc2C1
Reactant: CC1(C)CNc2nc(-c3ccncn3)cc(=O)n2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CN(CC2Cc3nccnc3C2)c2nc(-c3ccncn3)cc(=O)n2C1
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 10.6 %

Procedure:
A suspension of 0.5 g (1.94 mmol) of 7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in 10 ml of anhydrous dimethylformamide was treated with 155 mg (3.89 mmol) of sodium hydride (50% suspension in mineral oil) and the resulting mixture was stirred for 40 min at 50° C. 0.888 g (3.89 mmol) of methanesulfonic acid 6,7-dihydro-5H-cyclopentapyrazin-6-ylmethyl ester in 2 ml of anhydrous dimethylformamide was added and the reaction mixture stirred at room temperature for 18 h. The solution was treated with water and extracted with ethyl acetate. The organic phase was dried and evaporated to give crude product, which was purified by silica gel chromatography, eluting with dichloromethane/methanol in the proportions 100/1 to 95/5 to give 80 mg of pure product obtained in the form of free base which was transformed into the hydrochloride salt. Mp: 193-195° C.
Reaction SMILES: [BH4-].[Na+].[N:3]1[O:7][N:6]=[C:5]2[CH:8]=[C:9]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][C:17]4([CH2:24][C:23](=[O:25])[C:22]5[CH:26]=[C:27]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH:28]=[CH:29][C:21]=5[O:20]4)[CH2:16][CH2:15]3)[CH:10]=[CH:11][C:4]=12.C(=O)([O-])O.[Na+].[ClH:40]>C(O)C.C(OCC)(=O)C>[ClH:40].[N:3]1[O:7][N:6]=[C:5]2[CH:8]=[C:9]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][C:17]4([CH2:24][CH:23]([OH:25])[C:22]5[CH:26]=[C:27]([NH:30][S:31]([CH3:34])(=[O:32])=[O:33])[CH:28]=[CH:29][C:21]=5[O:20]4)[CH2:16][CH2:15]3)[CH:10]=[CH:11][C:4]=12
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(=O)CC1(CCN(CCc3ccc4nonc4c3)CC1)O2
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccc2c(c1)C(O)CC1(CCN(CCc3ccc4nonc4c3)CC1)O2
Reaction time: 16 h
Yield: 65 %

Procedure:
Sodium borohydride (7.5 mg, 0.2 mmol) was added to a stirred suspension of 3,4-dihydro-1'-[2-(benzofurazan-5-yl)ethyl]-6-methanesulfonamidospiro[(2H)-1-benzopyran-2,4'-piperidine]-4-one [prepared as described in Example 94, Step B](45.6 mg, 0.1 mmol) in ethanol (2 ml). The mixture was stirred for 16 hours, then poured into aqueous sodium hydrogen carbonate (saturated, 10 ml) and extracted with dichloromethane (3×10 ml). The combined organic fractions were dried (Na2SO4) and evaporated under reduced pressure to give a pale yellow oil. The residue was dissolved in ethyl acetate (2 ml) and ethanolic HCl (6N, 0.5 ml) was added. The mixture was cooled and the precipitate collected and dried in vacuo to give the hydrochloride as a white solid (32 mg, 65%), m.p. =242°-244° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([C:10]2[NH:14][CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1.C1OCCOCCOCCOCCOC1.Cl[S:42]([C:45]1[O:49][C:48]([C:50]([O:52][CH3:53])=[O:51])=[CH:47][CH:46]=1)(=[O:44])=[O:43]>O1CCCC1.O>[C:19]([O:18][C:17]([N:16]([CH2:15][C:12]1[C:11]([F:25])=[C:10]([C:9]2[C:4]([F:3])=[N:5][CH:6]=[CH:7][CH:8]=2)[N:14]([S:42]([C:45]2[O:49][C:48]([C:50]([O:52][CH3:53])=[O:51])=[CH:47][CH:46]=2)(=[O:43])=[O:44])[CH:13]=1)[CH3:24])=[O:23])([CH3:21])([CH3:22])[CH3:20]
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)o1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)o1
Reaction time: 0.25 h
Yield: 83 %

Procedure:
To a suspension of sodium hydride (60% in oil, 64.3 mg) in tetrahydrofuran (2 mL) was added a solution of tert-butyl {[5-(2-fluoropyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (400 mg) in tetrahydrofuran (1 mL) at room temperature and the mixture was stirred for 15 min. 15-Crown-5 (354 mg) and methyl 5-(chlorosulfonyl)-2-furoate were added dropwise and the mixture was further stirred at room temperature for 30 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→2:1) to give the title compound as a pale-yellow oil (yield 522 mg, 83%).
Reaction SMILES: CCO[CH2:4][CH3:5].[Mg].[CH3:7][Si:8]([Cl:11])([Cl:10])[Cl:9].[C:12]1(Cl)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[CH3:7][Si:8]([Cl:11])([Cl:10])[Cl:9].[Si:8]([Cl:11])([C:5]1[CH:4]=[CH:14][CH:13]=[CH:12][CH:17]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:7]
Reactant: Clc1ccccc1
Reactant: CCOCC
Agent: C[Si](Cl)(Cl)Cl
Agent: [Mg]
Solvent: O
Product: C[Si](Cl)(c1ccccc1)c1ccccc1

Procedure:
The ether and phenylCl are fed in a ratio of 4:1 and the magnesium is fed at a rate to sustain the reaction as monitored by the reactor temperature profile, jacket water temperature rise, and agitator motor amps. The MeSiCl3 feed is varied to obtain a coupling ratio between 0.25 and 0.90 moles of PhCl/mole of MeSiCl3 depending on the ratio of Ph2SiMeCl/PhMeSiCl2 desired. Toluene is fed in at a 3:1 ratio to the PhenylCl in ether.
Reaction SMILES: [H-].[Na+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11].Br[CH2:15][CH:16]([CH3:18])[CH3:17]>CN(C)C=O.C(OCC)(=O)C>[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][N:9]([CH2:17][C:16]([CH3:18])=[CH2:15])[S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: CS(=O)(=O)NCc1ccco1
Reactant: CC(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C(C)CN(Cc1ccco1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 94.9 %

Procedure:
Sodium hydride (60% mineral oil dispersion, 0.284 g, 7.1 mmol) was added in portions to a stirring solution of N-(furan-2-ylmethyl)methanesulfonamide (1.0 g, 5.7 mmol) in anhydrous N,N-dimethylformamide (12 mL), which was kept at 0° C. by an external ice bath. The ice bath was removed and the mixture was stirred for 50 mins at ambient temperature. 3-bromo-2-methylpropane (1.15 g, 8.6 mmol) was added in one portion, and the resulting mixture was stirred overnight at 65° C. before being diluted with ethyl acetate. The organic layer was successively washed with water and saturated aqueous sodium chloride solutions, dried (anhydrous sodium sulfate), filtered, and concentrated. The crude material was purified by silica gel column chromatography (0-50% ethyl acetate in hexanes) to give a clear liquid (1.24 g, 95%). 1H NMR (CDCl3, 300 MHz) δ 7.41-7.40 (m, 1H), 6.38-6.34 (m, 1H), 6.29-6.28 (m, 1H), 5.03-5.00 (m, 2H), 4.37 (s, 2H), 3.73 (s, 2H), 2.76 (s, 3H), 1.77 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13](=O)[CH3:14])[CH:10]=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:26][O:27][CH3:28].Cl.N1C=CC=CC=1>CCO>[CH3:28][O:27][N:26]=[C:13]([C:11]1[CH:10]=[CH:9][C:8]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:20][CH:21]=2)=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:12]=1)[CH3:14]
Reactant: CC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)c(-c2ccccc2)n1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=C(C)c1ccc(-c2ccc(C(F)(F)F)cc2)c(-c2ccccc2)n1

Procedure:
Following General Procedure P, 1-[6-phenyl-5-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-ethanone (Compound 77, 15 mg, 0.04 mmol), NH2OMe—HCl (15 mg, 0.18 mmol) and pyridine (14 mg, 0.18 mmol) in EtOH (2 ml) were reacted to give title compound as a white solid. (12 mg, 75%).