Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][O:5][CH2:6]Cl.[Br:10][C:11]1[C:12]([NH:17][C:18]([C:20]2[O:39][C:23]3=[N:24][CH:25]=[C:26]([CH2:28][O:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=4)[CH:27]=[C:22]3[CH:21]=2)=[O:19])=[N:13][CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:10][C:11]1[C:12]([N:17]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:9])([CH3:8])[CH3:1])[C:18]([C:20]2[O:39][C:23]3=[N:24][CH:25]=[C:26]([CH2:28][O:29][CH2:30][C:31]4[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=4)[CH:27]=[C:22]3[CH:21]=2)=[O:19])=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1ccc(COCc2cnc3oc(C(=O)Nc4ncccc4Br)cc3c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(COCc2cnc3oc(C(=O)N(COCC[Si](C)(C)C)c4ncccc4Br)cc3c2)cc1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
2-Trimethylsilylethoxymethyl chloride (0.13 g, 0.81 mmol) was added to a solution of N-(3-bromopyridin-2-yl)-5-(((4-methoxybenzyl)oxy)methyl)furo[2,3-b]pyridine-2-carboxamide (0.29 g, 0.62 mmol) and cesium carbonate (0.61 g, 1.8 mmol) in DMF (6.2 mL) at 0° C. The reaction mixture was gradually warmed to 23° C. and stirred for 2 h, then partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 18% ethyl acetate in petroleum ether to give the title compound. MS: m/z=600.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([NH:19][C:20](=[O:23])[CH2:21][Cl:22])([CH2:14][O:15]COC)[CH2:9][O:10]COC)[CH:5]=[CH:4][CH:3]=1.B(F)(F)F.CCOCC>C(S)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH:19][C:20](=[O:23])[CH2:21][Cl:22])([CH2:14][OH:15])[CH2:9][OH:10])[CH:5]=[CH:4][CH:3]=1
Reactant: COCOCC(COCOC)(NC(=O)CCl)c1cccc(Br)n1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCS
Product: O=C(CCl)NC(CO)(CO)c1cccc(Br)n1
Reaction time: 0.17 h

Procedure:
To a solution of N-[1-(6-bromo-pyridin-2-yl)-2-methoxymethoxy-1-methoxymethoxymethyl-ethyl]-2-chloro-acetamide (9.0 g, 21.861 mmol) in ethanethiol (30 ml) and BF3.Et2O (9.3 g, 141.93 mmol) was added at 0° C. and stirred for 10 min. Stirring was continued for 3 h at rt. Reaction mixture was quenched with saturated NaHCO3 solution and the product formed was extracted with ethyl acetate. Organic layer was separated and washed with brine solution, followed by drying over anhydrous Na2SO4. Organic layer was concentrated under reduced pressure and purified by column chromatography using 2% methanol in chloroform to obtain title compound as a brown liquid. Yield=5.5 g (77%). TLC (10% methanol in chloroform) Rf=0.51; LCMS: RtH8=0.916, [M+1]=322.9 and 324.8; HPLC RtH9=5.931 min (89%); 1H NMR (400 MHz, CDCl3): δ 8.27 (s, 1H), 7.56 (t, 1H), 7.42-7.39 (m, 2H), 4.38 (s, 2H), 4.09-4.07 (m, 4H), 3.95 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.CC(C)([O-])C.[K+]>C1COCC1>[Br:13][C:14]1[CH:21]=[CH:20][C:17](/[CH:18]=[CH:12]/[C:5]2[N:4]=[CH:3][C:2]([Cl:1])=[CH:11][C:6]=2[C:7]([OH:9])=[O:8])=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: COC(=O)c1cc(Cl)cnc1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)cnc1/C=C/c1ccc(Br)cc1
Temperature: -5 °C
Reaction time: 0.17 h

Procedure:
A stirred solution of methyl 5-chloro-2-methylnicotinate (7.26 kg, 96.4 wt %, 37.7 mol) and 4-bromobenzaldehyde (6.98 kg, 37.7 mol, 1.0 equiv) in THF (112 L) was put under a nitrogen atmosphere, and then cooled to −5° C. A solution of potassium tert-butoxide (8.46 kg, 75.4 mol, 2.0 equiv) in THF (53 L) was then added via a 1 μm filter, whilst maintaining the internal temperature at <0° C. The resulting reaction mixture was warmed to 25° C., and then aged at this temperature until the reaction was complete (typically 1 h). The reaction was then quenched by addition of water (54 L), ensuring the batch temperature remained <30° C. The biphasic mixture was stirred for ˜10 min, and the lower aqueous layer was then removed. The remaining THF layer was diluted with ethyl acetate (54 L), and then washed with 2 M hydrochloric acid (27 L) followed by half-saturated brine (20 L). The resulting organic layer was solvent-switched to ethyl acetate (to a final volume of 27 L), and then to methanol (to give a final volume of ˜106 L). The temperature of the resulting slurry was adjusted to ˜20° C., and it was then filtered, washing the filter-cake with methanol (11 L). The resulting solid was dried under vacuum at 50° C. to afford the title compound.
Reaction SMILES: FC(F)(F)C([NH:5][C@H:6]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:7]([OH:10])([CH3:9])[CH3:8])=O.[OH-].[K+].O>CO>[NH2:5][C@H:6]([C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)[C:7]([CH3:9])([OH:10])[CH3:8]
Reactant: CC(C)(O)[C@H](NC(=O)C(F)(F)F)c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(O)[C@H](N)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 20 h
Yield: 87.1 %

Procedure:
5.6 g of 2,2,2-trifluoro-N—[(R)-1-(4-fluorophenyl)-2-hydroxy-2-methylpropyl]-acetamide and 2.27 g KOH are suspended in 60 ml of methanol. The reaction mixture is stirred for 20 hours at 60° C., then mixed with water and the product is extracted with dichloromethane. 3.2 g product are obtained in the form of an oil. Analytical HPLC-MS (method A): RT=0.79 min.
Reaction SMILES: [Na].Cl.[C:3]([NH2:9])(=[NH:8])[CH2:4][CH2:5][CH2:6][CH3:7].[Cl:10][C:11]1[CH:12]=[C:13]([N:17]=[C:18]=[O:19])[CH:14]=[CH:15][CH:16]=1>CC(C)=O>[Cl:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]([NH:8][C:3](=[NH:9])[CH2:4][CH2:5][CH2:6][CH3:7])=[O:19])[CH:14]=[CH:15][CH:16]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: CCCCC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: CCCCC(=N)NC(=O)Nc1cccc(Cl)c1

Procedure:
Following a procedure similar to that described in Example 1 but using 6.9 g. sodium in 300 ml. dry acetone, 41.1 g. valeramidine hydrochloride, and 46.2 g. 3-chlorophenyl isocyanate in 200 ml. dry acetone, there was obtained after recrystallization from acetone 27.1 g. of tjhe hydrochloride of 1-(3-chlorophenyl)-3-(pentanimidoyl)urea; m.p. 135°-137°C.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH2:17]1[CH:21]2[CH2:22][C:23](=[O:24])[CH:19]([CH2:20]2)[CH2:18]1.[Cl-].[NH4+]>C1COCC1.CCOC(C)=O>[OH:24][C:23]1([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=2)[CH2:22][CH:21]2[CH2:20][CH:19]1[CH2:18][CH2:17]2
Reactant: COC(=O)c1ccc(I)cc1
Reactant: O=C1CC2CCC1C2
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C2(O)CC3CCC2C3)cc1
Temperature: -47 °C
Reaction time: 1 h

Procedure:
A solution of methyl 4-iodobenzoate (23.1 g, 0.0882 mol) dissolved in anhydrous THF (200 mL) was cooled to −47° C. Isopropyl magnesium chloride (48 mL of a 2.0 M solution in THF, 0.097 mol) was slowly added to the solution. The reaction mixture was stirred at −47° C. for 1 h, then cannulated into a pre-cooled solution of norcamphor (11.6 g, 0.105 mol) in THF (100 mL) at −47° C. The reaction mixture was subsequently stirred at −40° C. overnight, and was then allowed to warm to −20° C. Saturated aqueous ammonium chloride was added. EtOAc was used to extract three times. The combined organic portion was washed with water and brine, dried (MgSO4), filtered, concentrated, and purified by flash chromatography on silica gel (gradient elution; 0%-30% EtOAc/hexanes as eluent) to afford the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=O)[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:18][OH:19].N1C=CC=CC=1>C(O)C>[CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[N:18][OH:19])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC2CCC(C1)N2Cc1ccccc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: ON=C1CC2CCC(C1)N2Cc1ccccc1

Procedure:
2,5-dimethoxytetrahydrofuran (95) is combined with acetone dicarboxylic acid (96) and benzyl amine HCl salt (97) in sodium acetate to give 8-benzyl-8-azabicyclo[3.2.1]octan-3-one 98. The ketone 98 in ethanol is added to hydroxylamine hydrochloride and pyridine, and heated under reflux conditions to afford 8-benzyl-8-azabicyclo[3.2.1]octan-3-one oxime 99. The oxime 99 in 1-pentanol is combined with sodium metal and heated under reflux to produce 8-benzyl-8-azabicyclo[3.2.1]octan-3-amine 100. The amine 100 in CH2Cl2 (13 mL) is treated with 1M Na2CO3 and isobutyryl chloride to yield amide 101. The amide 101 is dissolved in CHCl3 and pyridine followed by the addition of POCl3. To this was then added diisopropylethylamine and appropriately deuterated acetylhydrazine 110 to produce triazol 102. The triazole 102 in EtOH was treated with Pd(OH)2/C (140 mg) under an H2 atmosphere to yield amine 103. Amine 103 was combined with appropriately deuterated aldehyde 111 in CH2Cl2 (5 mL), Na2SO4 and NaCNBD3 to afford 107. A solution of 107 in HCl/MeOH was heated to reflux to afford the free amine 108. The amine 108 in CH2Cl2 was combined with saturated Na2CO3 and H2O followed by appropriately deuterated cyclohexanecarbonyl chloride 109 to produce a compound of Formula II.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:15](=[S:17])=S>C(O)C>[CH2:7]([O:6][C:5]([NH:4][CH2:3][CH2:2][NH:1][C:15]([NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[S:17])=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: S=C=S
Reactant: NCCNC(=O)OCc1ccccc1
Solvent: CCO
Product: O=C(NCCNC(=S)NCCNC(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
To a suspension of benzyl 2-aminoethylcarbamate LIX (3 g; 15.45 mmol) in anhydrous ethanol (20 mL) was added carbon disulfide (0.47 mL; 7.73 mmol). The mixture was heated under gently reflux for 22 h. After cooling to r.t., the product precipitated and was filtered, washed with anhydrous ethanol (3×) and air dried. Benzyl N-(2-{[(2-{[(benzyloxy)carbonyl]amino}ethyl)carbamothioyl]amino}ethyl)carbamate LX was obtained as white solid (2.97 g; 6.90 mmol; 89.3% yield). 1H NMR (DMSO-d6) 3.10-3.14 (m, 4H), 3.37-3.42 (m, 4H), 5.00 (s, 4H), 7.30-7.37 (m, 12H), 7.54 (brs, 2H); ESIMS found for C21H26N4O4S m/z 431.4 (M+H).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:25]=[CH:24][C:13]([O:14][CH:15]([CH3:23])[CH:16]([OH:22])[CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[C:28](Cl)(=[O:30])[CH3:29].C(N(CC)CC)C>C(Cl)Cl>[F:27][C:2]([F:26])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:25]=[CH:24][C:13]([O:14][CH:15]([CH3:23])[CH:16]([O:22][C:28](=[O:30])[CH3:29])[CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)=[N:7][CH:8]=1
Reactant: CC(=O)Cl
Reactant: COC(=O)CC(O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CC(OC(C)=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reaction time: 3 h

Procedure:
5 g of methyl 4-[4-(5-trifluoromethyl-2-pyridyloxy)phenoxy]-3-hydroxypentanoate were dissolved in 35 ml of methylene chloride at 0° C. 0.9 ml of acetyl chloride and then 0.94 ml of triethylamine were added dropwise under nitrogen. After 18.5 hours of standing at room temperature and three hours of reflux, an additional 0.9 ml of acetyl chloride and 0.94 ml of triethylamine were added. The mixture was washed with water dilute acid and brine. The product was purified using silica gel chromatography and identified as the above methyl-3-acetoxy ester.
Reaction SMILES: Cl.[CH2:2]([O:9][CH2:10][CH2:11][CH2:12][C:13]([NH2:15])=[NH:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:24](=[CH2:27])[C:25]#[N:26]>CCO>[NH2:26][C:25]1[CH:24]=[CH:27][N:15]=[C:13]([CH2:12][CH2:11][CH2:10][O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:14]=1
Reactant: N=C(N)CCCOCc1ccccc1
Reactant: C=C(Cl)C#N
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1ccnc(CCCOCc2ccccc2)n1
Yield: 63.1 %

Procedure:
To a mixture of 4-benzyloxybutanamidine hydrochloride (14.6 g.) and triethylamine (33 g.) in EtOH (80 ml.) was added 2-chloroacrylonitrile (11.3 g.) and the solution was heated under reflux for 2 hours and then evaporated to dryness. The residue was partitioned between 10% aqueous HOAc (100 ml.) and EtOAc (200 ml.) and the EtOAc was reextracted with 10% v/v aqueous HOAc (2×100 ml.). The combined aqueous layers were basified with concentrated aqueous NaOH and extracted with EtOAc (3×75 ml.) and the EtOAc solution was washed with brine and dried to give 4-amino-2-(3-benzyloxypropyl)pyrimidine (9.8 g.). This amino-derivative was heated under reflux with 2,2,2-trifluoroethylisothiocyanate (10 g.) in acetonitrile (20 ml.) for 23 hours and the mixture evaporated to dryness. The residue was chromatographed on silica gel using CH2Cl2 containing 1% v/v MeOH as eluant to give 2-(3-benzyloxypropyl)-4-[3-(2,2,2-trifluoroethyl)thioureido]pyrimidine (10 g.).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][SH:6].[H-].[Na+].Br[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.C(OCC)(=O)C>CS(C)=O>[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][S:6][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1
Reactant: CN(C)CCS
Reactant: O=Cc1ccc(Br)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CN(C)CCSc1ccc(C=O)cc1
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 73 %

Procedure:
2-dimethylaminoethanethiol hydrochloride (1.00 g, 7.06 mmol) was suspended in dry DMSO (20 ml) and sodium hydride (60% in mineral oil, 593 mg, 2.1 equivs) was added. The reaction mixture was left stirring for 40 mins to form Me2NCH2CH2SNa, before 4-bromobenzaldehyde (1.193 g, 1 eq) was added, and the reaction mixture was then warmed to 90° C. under nitrogen. After 1 hour at 90°-100° C. analysis by thin layer chromatography (tlc) indicated almost complete disappearance of the starting material. The reaction mixture was therefore cooled, ethyl acetate was added and the mixture washed with sodium carbonate solution and brine. The mixture was then extracted with HCl (2N), basified and re-extracted with dichloromethane, dried over magnesium sulphate and the solvent was removed in vacuo to give the title compound as a yellow oil (73%).
Reaction SMILES: CC(C)=O.[O-]S([O-])(=O)=O.[Mg+2].[CH2:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O[C:25]([CH3:29])([CH3:28])[C:26]#[N:27]>CN(C)C(=O)C>[CH2:11]([N:18]1[CH2:23][CH2:22][N:21]([C:25]([CH3:29])([CH3:28])[C:26]#[N:27])[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CC(C)(O)C#N
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C#N)N1CCN(Cc2ccccc2)CC1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
4.5 ml of acetone, 20 g of dry MgSO4, 10 g of N,N-dimethylacetamide, 10 g of 1-benzylpiperazine and 9.5 ml of 2-hydroxyisobutyronitrile are mixed together and heated at 45° C. for 48 hours with vigorous stirring. The reaction mixture is poured onto ice and left stirring for 30 minutes. The mixture is extracted with ether, the organic phase is washed several times with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. 13 g of the expected product are obtained.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8](S(Cl)(=O)=O)=[CH:9][CH:10]=2)[C:5](Cl)=[N:4][CH:3]=1.C1([OH:27])C2C(=CC=CC=2)C=CN=1.BrN1C(=O)CCC1=O>CC#N>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:27])[NH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc2c(Br)cnc(Cl)c2c1
Reactant: Oc1nccc2ccccc12
Agent: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: O=c1[nH]cc(Br)c2ccccc12

Procedure:
4-Bromo-1-chloro-7-isoquinolinesulphonyl chloride ##STR198## A suspension of isoquinolinol (10 g, 68.9 mmol) in MeCN (250 ml) at 50° C., was treated with N-bromosuccinimide (12.6 g, 70.8 mmol) whereupon almost complete solution occurred before a thick white precipitate was formed. After heating under reflux for 3 h, the reaction mixture was cooled in ice and the solid filtered, washed with MeCN, and dried to afford 4-bromo-1-(2H)-isoquinolone (7.6 g, 34.0 mmol).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][CH:9]([O:12][C:13]3[N:18]=[CH:17][C:16](Br)=[CH:15][N:14]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C:21]1=[O:26]>>[CH:1]1([N:6]2[CH2:11][CH2:10][CH:9]([O:12][C:13]3[N:18]=[CH:17][C:16]([N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][C:21]4=[O:26])=[CH:15][N:14]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCN1
Reactant: Brc1cnc(OC2CCN(C3CCCC3)CC2)nc1
Product: O=C1CCCCN1c1cnc(OC2CCN(C3CCCC3)CC2)nc1

Procedure:
According to the same method as in Example 17 but using 2-(1-cyclopentylpiperidin-4-yloxy)-5-bromopyrimidine and piperidin-2-one, the entitled compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10](Cl)=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[N:7][C:6]=12.[CH3:17][C:18]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:19]=1[NH2:20]>>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([NH:20][C:19]3[CH:21]=[C:22]([CH3:25])[CH:23]=[CH:24][C:18]=3[CH3:17])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[N:7][C:6]=12
Reactant: Cc1ccc(C)c(N)c1
Reactant: CCOC(=O)c1cnc2c(Br)cnn2c1Cl
Product: CCOC(=O)c1cnc2c(Br)cnn2c1Nc1cc(C)ccc1C
Yield: 67.7 %

Procedure:
In the same manner as in Example 1, step 4 and using ethyl 3-bromo-7-chloropyrazolo[1,5-a]pyrimidine-6-carboxylate (400 mg, 1.31 mmol) obtained in Example 22, step 1 and 2,5-dimethylaniline (0.19 mL, 1.57 mmol), the title compound (345 mg, 68%) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[C:31]3=[N:32][CH:33]=[N:34][C:35](Cl)=[C:30]3[CH:29]=[N:28]2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:14]([O:18][C:19]([N:21]1[CH2:22][CH2:23][CH:24]([N:27]2[C:31]3=[N:32][CH:33]=[N:34][C:35]([O:1][C:2]4[CH:7]=[CH:6][C:5]([S:8](=[O:10])(=[O:9])[N:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=4)=[C:30]3[CH:29]=[N:28]2)[CH2:25][CH2:26]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: CN(C)S(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 160 °C
Yield: 29.1 %

Procedure:
A mixture of 4-hydroxy-N,N-dimethyl-benzenesulfonamide (ChemService Inc., West Chester, Pa., USA; 18 mg, 0.089 mmol), 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 30 mg, 0.089 mmol), and potassium carbonate (27 mg, 0.196 mmol) in dimethylformamide (1 mL) was heated in a microwave oven at 160° C. for 10 min. Saturated sodium carbonate solution was added to the reaction mixture, and the mixture was then filtered through a pad of silica gel to remove the precipitate. The silica gel pad was washed with methanol and the solvents were evaporated from the filtrate. The residue was purified by HPLC to give 4-[4-(4-dimethylsulfamoyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (13 mg, 28%) as a white solid. Mass spectrum MH+=503.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:6]=[N:5][C:4]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][C:20]=1[O:30][CH3:31].[Br:32]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:32][C:6]1[C:7]([NH:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[N:8][C:3]([O:2][CH3:1])=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:27])([F:29])[F:28])=[CH:21][C:20]=2[O:30][CH3:31])[N:5]=1
Reactant: COc1ccc(CNc2cnc(-c3ccc(OC(F)(F)F)cc3OC)c(OC)n2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNc2nc(OC)c(-c3ccc(OC(F)(F)F)cc3OC)nc2Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
A solution of {6-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2yl}[(4-methoxyphenyl)methyl]amine (870 mg, 2.0 mmol) in chloroform (10 mL) is cooled to 0 C and N-bromosuccinimide (356 mg, 2.0 mmol) is added in portions. After the addition, the mixture is further stirred for 1 hour while being allowed to warm to room temperature. The mixture is washed with saturated aqueous sodium bicarbonate, aqueous sodium chloride, dried (magnesium sulfate), filtered, and evaporated to give {3-bromo-6-methoxy-5-[2methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2-yl} [(4-methoxyphenyl)methyl]amine (920 mg), a yellow solid.
Reaction SMILES: CO.C(O[CH2:7]/[CH:8]=[CH:9]/[CH2:10][O:11][CH:12]([CH3:14])[CH3:13])(C)C.[CH3:15][CH:16]([OH:18])[CH3:17]>>[CH:12]([O:11][CH2:10][CH2:9][C:8]([O:18][CH:16]([CH3:17])[CH3:15])=[CH2:7])([CH3:13])[CH3:14]
Reactant: CC(C)OC/C=C/COC(C)C
Reactant: CC(C)O
Solvent: CO
Product: C=C(CCOC(C)C)OC(C)C

Procedure:
A reaction was carried out using the catalyst and according to the procedure described in example 6, except that the methanol was replaced with an equivalent amount of 2-propanol (30 ml). 1.8 mmol of 1,3-diisopropoxy-3-butene and 9.7 mmol of cis + trans 1,4-diisopropoxy-2-butene were obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][N:11]1[C:19]2[N:18]=[CH:17][NH:16][C:15]=2[C:14](=[O:20])[NH:13][C:12]1=[S:21].[CH3:22][N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([CH:32]=O)=[CH:24]1>>[CH3:22][N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:32][NH:8][CH2:9][CH2:10][N:11]2[C:19]3[N:18]=[CH:17][NH:16][C:15]=3[C:14](=[O:20])[NH:13][C:12]2=[S:21])=[CH:24]1
Reactant: NCCn1c(=S)[nH]c(=O)c2[nH]cnc21
Reactant: Cn1cc(C=O)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(CNCCn2c(=S)[nH]c(=O)c3[nH]cnc32)c2ccccc21
Yield: 197.5 %

Procedure:
The title compound was prepared in accordance with the general method described in Example 26(c) by using 3-(2-aminoethyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one trifluoroacetate (98 mg, 0.3 mmol, obtained from Example 26(b)) and 1-methylindole-3-aldehyde (51 mg, 0.03 mmol) which yielded 0.021 g (20% yield) of the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)([OH:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.Br[CH2:21][CH2:22][CH2:23]Br>C(O)C>[Cl:19][C:15]1[CH:14]=[C:13]([C:11]2([OH:12])[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]3[CH2:21][CH2:22][CH2:23][N:2]=[C:3]23)[CH:18]=[CH:17][CH:16]=1
Reactant: BrCCCBr
Reactant: NC1=Nc2ccccc2C1(O)c1cccc(Cl)c1
Agent: Cl
Solvent: CCO
Product: OC1(c2cccc(Cl)c2)C2=NCCCN2c2ccccc21

Procedure:
2-Amino-3-(m-chlorophenyl)-3H-indol-3-ol hydrochloride (2.3 g) is converted to its oily base then heated under reflux in ethanol (10 ml) with 1,3-dibromopropane (1.55 g) for 20 hours. On cooling the title compound is obtained as its hydrobromide, m.p. 270°-273°C (decomp.).