Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O)(=O)(=O)C.[NH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[N:10]=[C:9]([SH:14])[N:8]=1.[H-].[Na+].[CH3:17][O:18][C:19]1[CH:20]=[N:21][C:22]([CH:27](Cl)[CH3:28])=[CH:23][C:24]=1[CH2:25][CH3:26]>CN(C)C=O.C(OCC)(=O)C>[NH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[N:10]=[C:9]([S:14][CH:27]([C:22]2[CH:23]=[C:24]([CH2:25][CH3:26])[C:19]([O:18][CH3:17])=[CH:20][N:21]=2)[CH3:28])[N:8]=1
Reactant: Nc1cc(Cl)nc(S)n1
Reactant: CCc1cc(C(C)Cl)ncc1OC
Agent: CS(=O)(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc(C(C)Sc2nc(N)cc(Cl)n2)ncc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.6 %

Procedure:
A solution of 4-amino-6-chloro-2-mercapto-pyrimidine mesylate salt (290 mg, 1.1 mmol) in 2 mL of N,N-dimethylformamide at 0° C. is treated with 92 mg (60% in oil, 2.3 mmol) of sodium hydride and warmed to room temperature for 1 h. A solution of 3-methoxy-4-ethyl-6-(1-chloroethyl)-pyridine (225 mg, 1.1 mmol) in 2×1 mL of N,N-dimethylformamide is added dropwise to the mixture and the reaction was stirred for 18 h. The reaction is diluted with 50 mL of ethyl acetate, was washed with 4×25 mL of 50% saturated sodium chloride and dried over potassium carbonate. The organics are concentrated in vacuo and the crude material is chromatographed over 20 g of silica gel (230-400 mesh), eluting with 50% ethyl acetate/hexanes to afford 256 mg of an oil which upon crystallization from ether gave 188 mg (53%) of Cpd #245 (Melting Pt. 136-137° C.).
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][C:10]1[S:11][C:12]2[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1>C(O)(=O)C.C(O)C.[Fe]>[C:1]1([CH3:22])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][C:10]1[S:11][C:12]2[C:18]([NH2:19])=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1
Reactant: Cc1cc(C)c(Nc2nc3cccc([N+](=O)[O-])c3s2)c(C)c1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(C)c(Nc2nc3cccc(N)c3s2)c(C)c1
Temperature: 25 °C
Yield: 55.7 %

Procedure:
To a solution of 1.8 g (5.7 mmol) of N2-mesityl-7-nitro-1,3-benzothiazol-2-amine in 7.2 mL of glacial acetic acid and 25 mL of ethanol was added 1.8 g (32 mmol) of iron powder. The resulting solution was heated at reflux for 18 h before being cooled to room temperature. The slurry was filtered and the filtrate was concentrated to a brown solid. The solid was slurried in water, collected by filtration and purified by flash chromatography eluting with a 33% hexanes/ethyl acetate mixture to give 0.9 g (55%) of the title compound as a tan powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][CH2:12][CH2:13][N:14]2[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[N:15]2)[N:4]=1>CCOC(C)=O.CCO.O=[Pt]=O>[NH2:19][C:17]1[CH:16]=[N:15][N:14]([CH2:13][CH2:12][NH:11][C:5]2[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[N:6]=2)[CH:18]=1
Reactant: COc1cc(OC)nc(NCCn2cc([N+](=O)[O-])cn2)n1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(OC)nc(NCCn2cc(N)cn2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 4,6-dimethoxy-N-(2-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrimidin-2-amine (3.39 g, 11.54 mmol) in EtOAc (8.0 mL, degassed) and EtOH (32 mL, degassed), PtO2 (1.23 g, 1.15 mmol) was added and the reaction mixture was stirred at rt under a H2-atmosphere for 3 h. The mixture was diluted with EtOH, filtered over celite and the filter cake was rinsed with EtOH. The filtrate was concentrated to obtain the title compound of a pale pink solid. LC-MS conditions A: tR=0.42 min, [M+H]+=265.13.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][S:2]2(=[O:9])=[O:8].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH2:19][CH2:20][OH:21].[I-].[K+]>C(#N)C>[OH:21][CH2:20][CH2:19][N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][S:2]2(=[O:9])=[O:8]
Reactant: OCCBr
Reactant: O=S1(=O)C[C@@H]2C[C@H]1CN2
Agent: O=P([O-])([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=S1(=O)C[C@@H]2C[C@H]1CN2CCO
Temperature: 120 °C
Yield: 71 %

Procedure:
A mixture of (1S,4S)-2-thia-5-azabicyclo[2.2.1]heptane 2,2-dioxide (65 mg, 0.442 mmol), potassium phosphate (375 mg, 1.766 mmol), 2-bromoethanol (221 mg, 1.766 mmol) and potassium iodide (147 mg, 0.883 mmol) in acetonitrile (2 mL) was heated up at 120° C. for 4 hours. The reaction mixture was concentrated under reduced pressure and purified in silica gel with 0-15% methanol/ethyl acetate to provide the title product (60 mg, 71% yield) as a white solid. LCMS: m/e 192.07 (M+H)+, 0.87 min (method 2)
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]2)[O:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].FC(F)(F)S(N(C1C=CC(Cl)=CN=1)S(C(F)(F)F)(=O)=O)(=O)=O.[CH2:44]([O:46][C:47]([C:49]1[CH:54]=[CH:53][C:52](B(O)O)=[CH:51][CH:50]=1)=[O:48])[CH3:45].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(#N)C>[O:3]1[C:4]2([CH2:9][CH2:8][C:7]([C:52]3[CH:53]=[CH:54][C:49]([C:47]([O:46][CH2:44][CH3:45])=[O:48])=[CH:50][CH:51]=3)=[CH:6][CH2:5]2)[O:11][CH2:1][CH2:2]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: O=S(=O)(N(c1ccc(Cl)cn1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Product: CCOC(=O)c1ccc(C2=CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a cooled (−78° C.) solution of 1,4-cyclohexanedione mono-ethylene ketal (1.00 g, 6.40 mmol) in anhydrous THF (30 mL) was added lithium bis(trimethylsilyl)amide (7.7 mL, 1.0 M in THF, 7.70 mmol) dropwise. After 10 min, a solution of 2-[N,N-bis(trifluoromethylsulfonyl)amino]5-chloropyridine (2.51 g, 6.40 mmol) in THF (10 mL) was added, and the resulting mixture was allowed to warm slowly to ambient temperature overnight, at which point it was quenched by pouring into sat. aq. NaHCO3. The mixture was extracted with EtOAc. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo. To a flask containing the unpurified enol triflate (1.36 g, 4.72 mmol) were added 4-ethoxycarbonylphenylboronic acid (1.10 g, 5.66 mmol) and trans-dichlorobis(triphenylphosphine) palladium (II) (331 mg, 0.472 mmol). Acetonitrile (24 mL) and sodium carbonate (11.8 mL, 1.0 M aqueous, 11.8 mmol) were added and the resulting mixture was degassed via nitrogen sparge. The reaction mixture was stirred at 70° C. for 3 h, then was allowed to cool to ambient temperature and was poured into water. The mixture was extracted with EtOAc, and the organic phase was concentrated in vacuo. Purification by chromatography on silica gel (0 to 30% EtOAc in hexanes, then 30 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 289.1 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 7.97 (d, J=8.5 Hz, 2H), 7.44 (d, J=8.5 Hz, 2H), 6.12-6.10 (m, 1H), 4.36 (q, J=7.0 Hz, 2H), 4.03 (s, 4H), 2.70-2.67 (m, 2H), 2.50-2.48 (m, 2H), 1.93 (t, J=6.5 Hz, 2H), 1.39 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]1([N:7]2[C:15]3[N:14]=[CH:13][NH:12][C:11]=3[C:10](=[O:16])[N:9]([CH2:17][P:18](=[O:21])([CH3:20])[CH3:19])[C:8]2=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:24][CH:25]1[CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+]>>[CH:25]1([CH2:24][N:12]2[C:11]3[C:10](=[O:16])[N:9]([CH2:17][P:18](=[O:21])([CH3:20])[CH3:19])[C:8](=[O:22])[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:15]=3[N:14]=[CH:13]2)[CH2:27][CH2:26]1
Reactant: CP(C)(=O)Cn1c(=O)c2[nH]cnc2n(-c2ccccc2)c1=O
Reactant: ClCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CP(C)(=O)Cn1c(=O)c2c(ncn2CC2CC2)n(-c2ccccc2)c1=O

Procedure:
3.9 g (0.0123 mol) of [1-(3-phenylxanthin-1-yl)methyl]dimethylphosphine oxide (Example 70) were stirred at 70° C. for 6 hours with 1.33 g (0.0147 mol) of chloromethylcyclopropane and 2 g of potassium carbonate. The solution was filtered and concentrated, and the residue which remained was chromatographed on silica gel (eluent: ethyl acetate/methanol 10:1).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[CH:6](=O)[C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[OH:9].B.[Na]>[OH-].[Na+]>[OH:9][C:8]1[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=1[CH2:6][NH:1][CH2:2][C:3]([OH:5])=[O:4]
Reactant: O=Cc1ccccc1O
Reactant: NCC(=O)O
Agent: B
Agent: [Na+]
Agent: [Na]
Product: O=C(O)CNCc1ccccc1O
Reaction time: 1 h

Procedure:
Nine grams of glycine were dissolved in 60 ml of a 2N sodium hydroxide aqueous solution. To the solution were then added 12 ml of salicylaldehyde and 1.3 g of sodium boron hydride in this order. After the mixture was stirred for 1 hour, 12 ml of salicylaldehyde and 1.3 g of sodium boron hydride were added thereto again. After the resulting mixture was stirred at room temperature for 1 hour, the insoluble matter was separated through filtration, and the filtrate was extracted with diethyl ether. The extract was adjusted to a pH of 4 with hydrochloric acid to obtain 17 g of N-(2 -hydroxybenzyl) glycine. Various N-(2-hydroxybenzyl) amino acids were obtained in the same manner.
Reaction SMILES: [Mg].Br[C:3]1[C:8]2[S:9][CH:10]=[C:11]([CH2:12][CH3:13])[C:7]=2[CH:6]=[CH:5][CH:4]=1.CI.[C:16](=[O:18])=[O:17].Cl>CCOCC>[C:16]([C:3]1[C:8]2[S:9][CH:10]=[C:11]([CH2:12][CH3:13])[C:7]=2[CH:6]=[CH:5][CH:4]=1)([OH:18])=[O:17]
Reactant: CCc1csc2c(Br)cccc12
Reactant: O=C=O
Agent: Cl
Agent: [Mg]
Solvent: CI
Solvent: CCOCC
Product: CCc1csc2c(C(=O)O)cccc12
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
Magnesium (2.67 g) was stirred in ether (15 ml) at room temperature. A solution of 7-bromo-3-ethylbenzo[b]thiophene (4.40 g) and methyl iodide (7.76 g) in ether (50 ml) were added dropwise over 30 min. Then, refluxing was conducted for 50 min and the reaction mixture was cooled in ice water bath. Using a separate reaction vessel, pulverized dry ice was stirred in ether, and the Grignard reagent prepared above was transferred to the vessel for about 5 min. To the reaction mixture was added 2N hydrochloric acid to acidify the solution, and the ether layer was separated. The solution was made alkaline with a 5% aqueous sodium hydroxide solution. The separated aqueous layer was acidified with 2N hydrochloric acid. After extraction with ether, the extract was dried over sodium sulfate and concentrated to give the objective compound (3.22 g) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14]([OH:16])=[O:15])[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:31]I.Cl>CN(C)C=O.C(OCC)(=O)C>[CH3:31][O:15][C:14](=[O:16])[CH:13]([N:12]1[C:11]2[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=2[N:9]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CI
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the solution of 1 g (2.47 mmol) [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid in 10 ml N,N-dimethylformamide, 129 mg (2.964 mmol) sodium hydride (55% dispersion in mineral oil) and 368 mg (2.594 mmol) methyl iodide were added. The reaction was stirred at room temperature for 2 h and then poured on 100 ml ethyl acetate and 100 ml 1M aqueous hydrochloric acid. The phases were separated and the organic layer washed two times with 100 ml water and 100 ml brine. The combined water layers were extracted with 100 ml ethyl acetate, dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 60:40). Colorless solid (92%). MS (Turbo Spray): m/z=419.1 [M+H].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[F:9][C:10]1[C:15](B(O)O)=[CH:14][CH:13]=[CH:12][N:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.O.C(=O)(O)[O-].[Na+].O.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>[F:9][C:10]1[C:15]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: Cc1cc(Br)ccn1
Reactant: OB(O)c1cccnc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: Cc1cc(-c2cccnc2F)ccn1
Temperature: 80 °C
Yield: 81.4 %

Procedure:
A mixture of 4-bromo-2-methylpyridine (25.0 g, 145 mmol), 2-fluoropyridin-3-ylboronic acid (22.5 g, 160 mmol), Pd(PPh3)2Cl2 (5.10 g, 7.27 mmol), and sodium carbonate (46.2 g, 436 mmol) in 1,2-dimethoxyethane:ethanol:water (7:2:0.75, 292.5 ml total volume) was heated to 80° C. for 4 h. After cooling to room temperature, the mixture was diluted with saturated aqueous sodium bicarbonate solution and water, then extracted with dichloromethane (3×). The combined organic extracts were then extracted with 2 N aqueous HCl solution (4×). The combined aqueous layers were washed with dichloromethane, then the pH was raised to 10 with 10 N NaOH. The resulting suspension was extracted with dichloromethane (3×). The combined extracts were concentrated in vacuo to give 2-fluoro-3-(2-methylpyridin-4-yl)pyridine (22.14 g, 118 mmol, 81% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]2)[CH2:8][CH2:7]1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCCC(CN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(OC2CCN(CC3CCCNC3)CC2)cc1Cl
Reaction time: 3 h
Yield: 84 %

Procedure:
1,1-Dimethylethyl 3-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-1-piperidinecarboxylate (1.63 g) was dissolved in dichloromethane (30 ml) and trifluoroacetic acid (10 ml) was added. The mixture was stirred for 3 h, then concentrated. The residue was neutralized with sodium hydroxide solution (2M) and extracted with ethyl acetate thrice. The extracts were dried, filtered and evaporated to give the title compound (1.06 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:17])=[CH:4][C:5]([F:16])=[C:6]([CH:15]=1)[CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11].[N:18]([O-])=O.[Na+].O.O.Cl[Sn]Cl>Cl>[Cl:17][C:3]1[C:2]([NH:1][NH2:18])=[CH:15][C:6]([CH2:7][NH:8][C:9](=[O:14])[C:10]([F:11])([F:12])[F:13])=[C:5]([F:16])[CH:4]=1
Reactant: O=N[O-]
Reactant: Nc1cc(CNC(=O)C(F)(F)F)c(F)cc1Cl
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc(CNC(=O)C(F)(F)F)c(F)cc1Cl
Yield: 50015.5 %

Procedure:
The title compound was prepared according to the procedure described in step-1 of Intermediate-61 by using N-(5-amino-4-chloro-2-fluorobenzyl)-2,2,2-trifluoroacetamide (2.0 g, 0.007 mmol), NaNO2 (0.612 g, 0.008 mmol), SnCl2.2H2O (4.10 g, 0.018 mmol), and conc. HCl (100 mL) to afford 1.0 g of the desired product.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([I:9])[C:6]([CH:10]([O:12]COC)[CH3:11])=[CH:5][N:4]=1>CO.C(=O)([O-])[O-].[Na+].[Na+]>[F:2][C:3]1[N:4]=[CH:5][C:6]([CH:10]([OH:12])[CH3:11])=[C:7]([I:9])[CH:8]=1
Reactant: COCOC(C)c1cnc(F)cc1I
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1cnc(F)cc1I
Reaction time: 8 h
Yield: 87.8 %

Procedure:
Add 1 N HCl (5 mL) to a solution of 2-fluoro-4-iodo-5-(1-methoxymethoxy-ethyl)-pyridine (1 g, 3.2 mmol) in methanol (10 mL). Stir the mixture overnight. Dilute the reaction mixture with sodium carbonate (2 N). Extract the product into chloroform. Dry the organic phase over sodium sulfate. Concentrate the solution in vacuo. Purify the crude by column chromatography (10% methanol in DCM) to afford the title compound as a white solid (0.75 g, 87%). MS (ES) m/z 268 [M+1]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1.[I-:14].[Na+].[Cl-].[Na+]>CC(C)=O>[I:14][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1
Reactant: [I-]
Reactant: ClCCCCCOC1CCCCO1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCCCCOC1CCCCO1
Yield: 87.9 %

Procedure:
A solution of 2-(5-chloropentyloxy)tetrahydro-2H-pyrane (10) (20.67 g, 0.1 mol) in dry acetone (50 mL) was added in drops to a magnetically stirred solution of sodium iodide (16.49 g, 0.11 mol) in dry acetone (150 mL). The reaction mixture was refluxed in a nitrogen atmosphere over night. After cooling the precipitated sodium chloride was filtered out and acetone was distilled out on a rotary evaporator. The residue which still contained some sodium chloride was dissolved in dry pentane (200 mL). Sodium chloride was filtered out and pentane distilled out on a rotary evaporator, yielding 26.2 g (88%) of a yellowish brown oil. NMR indicated a pure product.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:9]=[C:8]([C:10]2[C:18]3[C:13](=[N:14][C:15]([Cl:19])=[N:16][CH:17]=3)[NH:12][N:11]=2)[CH:7]=[CH:6][CH:5]=1.Cl[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C>[Br:3][C:4]1[N:9]=[C:8]([C:10]2[C:18]3[C:13](=[N:14][C:15]([Cl:19])=[N:16][CH:17]=3)[N:12]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[N:11]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1ncc2c(-c3cccc(Br)n3)n[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(-c2cccc(Br)n2)c2cnc(Cl)nc21
Reaction time: 0.33 h

Procedure:
To a mixture of NaH (1.3 mg, 37.6 mmol, 60%) in DMF (80 mL) was added slowly the solution of crude 3-(6-bromo-pyridin-2-yl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidine (from Example 30 supra) (5.83 g, 18.8 mmol) in DMF (40 mL) at 5° C. The ice-bath was removed and the mixture was stirred for 20 minutes. Then (2-(chloromethoxy)ethyl)trimethylsilane (4.06 g, 24.4 mmol) was added. This solution was stirred for 12 hours at room temperature. The solvent was removed under reduced pressure. The residue was partitioned between saturated aqueous NH4Cl and dichloromethane (3×20 mL). The combined organics was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 60 g, 200-300 mesh, eluting with ethyl acetate:petroleum ether, 1:10) to give 3-(6-bromo-pyridin-2-yl)-6-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidine as a white solid. (Yield 4.9 g, 84%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][C:6]=1[CH:7]=[O:8].[H-].[Na+].C1OCCOCCOCCOCCOC1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:27]=1>>[CH3:1][C:2]1[N:3]([S:32]([C:28]2[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=2)(=[O:34])=[O:33])[CH:4]=[CH:5][C:6]=1[CH:7]=[O:8]
Reactant: Cc1[nH]ccc1C=O
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: Cc1c(C=O)ccn1S(=O)(=O)c1cccnc1

Procedure:
By a similar operation as in Reference Example 146 and using 2-methyl-1H-pyrrole-3-carbaldehyde (1.10 g), sodium hydride (60% in oil, 1.20 g), 15-crown-5 (6.0 mL) and pyridin-3-ylsulfonyl chloride (3.22 g), the title compound was obtained as white crystals (yield 1.10 g, 44%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.Cl.O.[NH:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1.C(N(CC)CC)C>C(O)C>[Cl:9][C:4]1[N:3]=[C:2]([CH3:1])[N:7]=[C:6]([N:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)[CH:5]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: Cc1nc(Cl)cc(N2CCC(=O)CC2)n1
Yield: 87.4 %

Procedure:
A mixture of 2-methyl-4,6-dichloropyrimidine (12.2 g), 4-piperidinone monohydrate monohydrochloride (10.9 g) and triethylamine (42 ml) in ethanol (300 ml) was heated to reflux. The resulting solution was stirred at reflux for 18 hours. The solution was evaporated to dryness. The solid residue was partitioned between ethyl acetate (1 l) and water (50 ml). The ethyl acetate layer was washed with water (3×50 ml), saturated brine (50 ml), dried (Na2SO4) and evaporated to dryness. The solid residue was recrystallised from ethyl acetate/isohexane to give a cream solid. This was further purified by column chromatography on alumina (ICN alumina N32-63), using dichloromethane as eluent, to give 1-(6-chloro-2-methylpyrimidin-4-yl)piperidin-4-one (14.0 g) as an off-white solid.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C@@H:4](C2SC=CC=2)[C@H:3]1[NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OC(N/C(=C\[C:46]1[CH:50]=[CH:49][O:48][CH:47]=1)/C(OC)=O)=O)C1C=CC=CC=1>>[CH2:21]([O:20][C:19](=[O:28])[NH:18][C@H:3]1[C:2](=[O:1])[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C@@H:4]1[C:46]1[CH:50]=[CH:49][O:48][CH:47]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(N[C@H]1C(=O)Nc2ccccc2S[C@H]1c1cccs1)OCc1ccccc1
Reactant: COC(=O)/C(=C/c1ccoc1)NC(=O)OCc1ccccc1
Product: O=C(N[C@H]1C(=O)Nc2ccccc2S[C@@H]1c1ccoc1)OCc1ccccc1

Procedure:
A method similar to that used for the preparation of (99b) was used except that methyl (2Z)-2-{[(benzyloxy)carbonyl]amino}-3-(3-furyl)acrylate (102a) (530 mg) was used as starting material to afford the title compound as a white solid (235 mg). 1H NMR (300 MHz, d6-DMSO) δ 4.66 (t, 1H, J=4 Hz), 4.97 (s, 2H), 5.20 (d, 1H, J=6 Hz), 6.38 (d, 2H, J=7 Hz), 6.5 (s, 1H), 7.07-7.75 (m, 1H), 10.44 (s, 1H). LC/MS: 2.32 min.
Reaction SMILES: CO[C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[CH2:14]Br.[CH3:17][O:18][C:19](=[O:28])[C@@H:20]([NH2:27])[CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C(N(CC)CC)C.C(#N)C>O>[CH3:17][O:18][C:19](=[O:28])[C@@H:20]([N:27]1[CH2:14][C:5]2[C:4](=[CH:9][CH:8]=[CH:7][C:6]=2[C:10]([F:11])([F:12])[F:13])[C:3]1=[O:16])[CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COC(=O)[C@@H](N)CC1CCCC1
Reactant: COC(=O)c1cccc(C(F)(F)F)c1CBr
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CC1CCCC1)N1Cc2c(cccc2C(F)(F)F)C1=O
Temperature: 82 °C
Yield: 81.2 %

Procedure:
A mixture of 2-bromomethyl-3-trifluoromethyl-benzoic acid methyl ester (695 mg, 2.34 mmol), (S)-2-amino-3-cyclopentyl-propionic acid methyl ester (400 mg, 2.34 mmol), triethylamine (358 μL, 2.57 mmol), and acetonitrile (20 mL) was heated at 82° C. for 7 h. The crude reaction mixture was treated with water (5 mL) and then concentrated in vacuo to remove the acetonitrile. The remaining solution was then diluted with water (10 mL) and extracted with ethyl acetate (3×20 mL), the combined organics were then dried over magnesium sulfate, filtered to remove the drying agent and the filtrate concentrated in vacuo. The residue was then purified via automated flash chromatography (12 g silica gel column, 10-40% ethyl acetate/hexanes) to afford (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid methyl ester (675 mg, 81%) as a clear colorless oil: [α]25D=−16.0°, (c=0.15, methylene chloride); HR-ES(+) m/e calcd for C18H20NO3F3 [M+H]+ 356.1468, observed 356.1466; 1H NMR (300 MHz, DMSO-d6, ppm) δ 8.02 (t, J=8.00 Hz, 2H), 7.71-7.89 (m, 1H), 4.92 (dd, J=4.08, 10.41 Hz, 1H), 4.69 (s, 2H), 3.66 (s, 3H), 0.94-2.21 (m, 11H).
Reaction SMILES: [OH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][OH:12].C=O>O>[OH:12][CH2:11][N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[S:3][C:2]1=[O:1]
Reactant: Oc1nc2ccccc2s1
Reactant: CO
Agent: C=O
Solvent: O
Product: O=c1sc2ccccc2n1CO
Temperature: 0 °C
Yield: 94 %

Procedure:
To a stirred slurry containing 30.2 g (0.2 mol) of 2-hydroxybenzothiazole and 40 ml of methyl alcohol, 32 ml of 37% aqueous formaldehyde was added in one portion. The stirred mixture was heated at 78°-80° C. (reflux) for 30 minutes. At 80° C., 60 ml of hot water was added to the stirred solution. After cooling to 0° C., the product was collected by filtration, washed with 100 ml of heptane and air-dried at 25°-30° C. The product, 3-(hydroxymethyl)-2-benzothiazolinone, mp. 101°-3° C., was obtained in 94% yield. After recrystallization from isopropyl alcohol the melting point remained unchanged.