Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][CH:14]([C:42]1[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=1)[CH2:15][O:16][CH2:17][C:18]1[N:19]=[CH:20][N:21]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=1>ClCCl>[CH3:8][S:9]([O:13][CH:14]([C:42]1[CH:43]=[CH:44][C:45]([C:46]#[N:47])=[CH:48][CH:49]=1)[CH2:15][O:16][CH2:17][C:18]1[N:19]=[CH:20][N:21]([C:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:22]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(C(O)COCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC(COCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4 mmol of triethylamine and 2.00 mmol of methanesulphonyl chloride are added to a solution of 1.00 mmol of 4-[1-hydroxy-2-(1-trityl-1H-imidazol-4-ylmethoxy)ethyl]benzonitrile in 10 ml of dichloromethane at 0° C. The reaction mixture is stirred at 0° C. for 1 hour, diluted with dichloro-methane, washed with 1N HCl, dried with sodium sulphate and evaporated. The crude title compound is used without further purification in the next stage. Rf=0.43 (dichloromethane-methanol 95:5); Rt=4.46 (gradient I).
Reaction SMILES: I(O)(=O)(=O)=[O:2].[F:6][C:7]([F:36])([F:35])[CH2:8][CH2:9][C@H:10]([NH:13][C@@H:14]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)[C:15]([F:18])([F:17])[F:16])[CH2:11][OH:12]>C(#N)C.[O-2].[O-2].[O-2].[Cr+6]>[F:36][C:7]([F:6])([F:35])[CH2:8][CH2:9][C@H:10]([NH:13][C@@H:14]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)[C:15]([F:16])([F:17])[F:18])[C:11]([OH:2])=[O:12]
Reactant: CS(=O)(=O)c1ccc(-c2ccc([C@H](N[C@H](CO)CCC(F)(F)F)C(F)(F)F)cc2)cc1
Reactant: [O-][I+3]([O-])([O-])O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(-c2ccc([C@H](N[C@@H](CCC(F)(F)F)C(=O)O)C(F)(F)F)cc2)cc1
Temperature: 2.5 °C
Reaction time: 4 h

Procedure:
A stock oxidant suspension was prepared by stirring periodic acid (2.28 g) and chromium trioxide (4.6 mg) in wet acetonitrile (0.75% water) to create a suspension of total volume of 22.8 mL. The oxidant suspension (4.22 mL) was then added to a stirred solution of (2S)-5,5,5-trifluoro-2-({(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}amino)pentan-1-ol (0.35 g, 0.74 mmol) in wet acetonitrile (3.7 mL) dropwise while maintaining the temperature at 0-5° C. The reaction mixture was allowed to warm to ambient temperature after one hour and then stirred for an additional 4 hours. The reaction was quenched with aqueous sodium hydrogen phosphate (6 g/100 mL) and toluene was added and the mixture shaken vigorously. The organic phase was wased with 1:1 brine:water, then with aqueous sodium bisulfite (2.2 g/50 mL), then brine. The organic layer was then dried with sodium sulfate, filtered, and concentrated by rotary evaporation. The crude product was purified by silica gel chromatography using 5-10% methanol in methylene chloride as eluant to yield (2S)-5,5,5-trifluoro-2-({(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}amino)pentanoic acid.
Reaction SMILES: C([Sn]([N:14]=[N+:15]=[N-:16])(CCCC)CCCC)CCC.[CH2:17]([O:24][C:25]1[CH:26]=[C:27]([CH:39]=[C:40]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:41]=1)[C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][N:32]=1)=[O:29])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[CH2:43]([O:42][C:40]1[CH:39]=[C:27]([CH:26]=[C:25]([O:24][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:41]=1)[C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[NH:16][N:15]=[N:14][N:38]=2)=[CH:33][N:32]=1)=[O:29])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: N#Cc1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)nc1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(-c2nnn[nH]2)cn1)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1

Procedure:
Tributyltin azide (156 μL, 0.57 mmol) was added to a suspension of 3,5-bis(benzyloxy)-N-(5-cyanopyridin-2-yl)benzamide (180 mg, 0.41 mmol) in toluene (3 mL). The mixture was heated at reflux for 16 hours. The suspension was cooled and partitioned between ethyl acetate and hydrochloric acid (1M). The organic layer was concentrated in vacuo and the residue was purified by MPLC on silica MPLC (eluting with 1% methanol/DCM to 15% methanol/DCM). The tetrazole was obtained as a colourless solid (113 mg, 57%). 1H NMR δ (d6-DMSO): 5.19 (4H, s); 6.88 (1H, s); 7.26-7.48 (12H, m); 8.40 (1H, d); 8.46 (1H, dd); 9.04 (1H, s); 11.13 (1H, br s); m/z (LCMS; ESI+) 479 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][CH:5]=[CH:6][C:7]=1[CH3:8].Br[CH:11]([CH3:16])[CH2:12][O:13][CH2:14][CH3:15]>>[CH2:14]([O:13][CH2:12][CH:11]([NH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9])[CH3:16])[CH3:15]
Reactant: Cc1cccc(C)c1N
Reactant: CCOCC(C)Br
Product: CCOCC(C)Nc1c(C)cccc1C
Yield: 46.1 %

Procedure:
Manufacture of the starting material: A solution of 484 g (4 mole) of 2,6-xylidine and 334 g (2 mole) of 2-bromo-1-ethoxypropane is cooled to 10° C. The reaction vessel is then evacuated to 13 mm Hg and the mixture heated at 130°-135° C. for 16 hours. After cooling 1 liter of diethylether and 1 liter of water are added to the mixture which is than made alkaline with 200 ml of a 30% sodium hydroxide solution. The ethereal phase is separated, washed with water until neutral, dried with sodium sulfate and evaporated in vacuo. 191.2 g of pure N-[1-ethoxyprop-2-yl]-2,6-dimethylaniline are obtained, b.p. 58°-62°/0.05 Torr.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[N:12]=[C:13]1[S:17][CH2:16][C:15]2([CH2:21][CH2:20][CH2:19][CH2:18]2)[NH:14]1)[CH3:2].[CH2:22](Br)[CH:23]([CH3:25])[CH3:24]>>[CH2:22]([N:14]1[C:15]2([CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:16][S:17][C:13]1=[N:12][C:4]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[CH2:1][CH3:2])[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)CBr
Reactant: CCc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1
Product: CCc1cc([N+](=O)[O-])ccc1N=C1SCC2(CCCC2)N1CC(C)C

Procedure:
2-Ethylaniline was converted to 2-ethylacetanilide according to Method A2a, Step 1. The acetanilide was converted to 2-ethyl-4-nitroacetanilide according to Method A2a, Step 2. The acetanilide was deprotected according to Method A2a, Step 3 to give 2-ethyl-4-nitroaniline. The aniline was converted to 2-ethyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3. 1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 2-ethyl-4-nitrophenyl isothiocyanate according to Method C1a to give 2-(2-ethyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2-(2-ethyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: C[Si](C)(C)[O-].[Na+].[NH2:7]/[C:8](/[C:15]([F:18])([F:17])[F:16])=[CH:9]\[C:10]([O:12]CC)=O.[NH2:19][C:20]1[C:21]([O:34][CH3:35])=[C:22]([NH:28][C:29](=O)[O:30]CC)[C:23]([F:27])=[CH:24][C:25]=1[Cl:26].C1CCN2C(=NCCC2)CC1.[H-].[Na+]>CN(C=O)C>[NH2:19][C:20]1[C:21]([O:34][CH3:35])=[C:22]([N:28]2[C:10](=[O:12])[CH:9]=[C:8]([C:15]([F:16])([F:17])[F:18])[NH:7][C:29]2=[O:30])[C:23]([F:27])=[CH:24][C:25]=1[Cl:26]
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: CCOC(=O)Nc1c(F)cc(Cl)c(N)c1OC
Agent: C[Si](C)(C)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COc1c(N)c(Cl)cc(F)c1-n1c(=O)cc(C(F)(F)F)[nH]c1=O

Procedure:
This compound was prepared using 4.0 grams (0.036 mole) of sodium trimethylsilanolate, 6.6 grams (0.036 mole) of ethyl 3-amino4,4,4-trifluorocrotonate, 8.5 grams (0.032 mole) of ethyl N-(3-amino4-chloro-6-fluoro-2-methoxyphenyl)carbamate, and 2.2 grams (0.014 mole) of DBU in 75 mL of DMF. This preparation differs from well-known literature preparations for pyrimidinedione rings in that sodium trimethylsilanolate and DBU were used rather than sodium hydride. The yield of title compound was 1.7 grams. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:11][CH:10]=1.[H-].[Na+].[CH2:32](I)[CH3:33].O>CN(C)C=O>[Cl:1][C:2]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:15][O:16][CH2:32][CH3:33])=[NH:14])=[CH:17][CH:18]=1
Reactant: CCI
Reactant: N=C(NO)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCONC(=N)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
P1.2) A solution of 790 mg of 4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-N-hydroxy-benzamidine in 20 ml of dimethylformamide is added dropwise in the course of 15 minutes at 0-5° C. to 80 mg of sodium hydride 55% in 10 ml of dimethylformamide. After 3 hours' stirring at 0-5° C., 256 mg of ethyl iodide are added. After being stirred for 16 hours at room temperature the reaction mixture is poured into water and extracted with ethyl acetate. After concentration of the organic phases and purification over silica gel, 4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-N-ethoxy-benzamidine is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C1C=CC=CC=1>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([NH:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:7])=[CH:4][CH:3]=1
Reactant: NCCN1CCOCC1
Reactant: O=Cc1ccc(Cl)cc1
Solvent: c1ccccc1
Solvent: O
Product: O=C(NCCN1CCOCC1)c1ccc(Cl)cc1

Procedure:
26 G. of p-chlorobenzaldehyde and 24 g. of N-(2-aminoethyl)-morpholine are boiled in 150 ml. of benzene for 3 hours under reflux with water being separated. Then, the mixture is evaporated to dryness and the residue is distilled at 165° C./0.01 mmHg. 5 G. of the resulting 4-{2-[(p-chlorobenzylidene)-amino]-ethyl}-morpholine, 2.3 g. of sodium acetate and 3 ml. of 30% hydrogen peroxide are stirred in 60 ml. of methanol overnight at room temperature. Thereafter, the mixture is evaporated to dryness and the residue is taken up in 50 ml. of methylene chloride and 50 ml. of water. The phases are separated and the aqueous phase extracted with 50 ml. of methylene chloride. The methylene chloride extract is dried over sodium sulfate and evaporated. The residue is chromatographed over a silica gel column with a mixture of chloroform and ethanol. The pure fractions are combined and evaporated. The residue is recrystallized from isopropanol, and 0.7 g. of p-chloro-N-(2-morpholinoethyl)-benzamide is obtained, which is identical to the product obtained in Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.OO.C([O-])([O-])=[O:12].[K+].[K+]>C(Cl)Cl.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N+:6]([O-:12])[CH:7]=1
Reactant: Cc1ccc(Br)cn1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1ccc(Br)c[n+]1[O-]
Temperature: 50 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
A solution of 5-bromo-2-methyl-pyridine (1.47 g, 8.54 mmol) in CH2Cl2 (5 mL) was treated with a cold solution of 30% hydrogen peroxide (4.6 mL) in acetic acid (13.8 mL) at 0° C. The reaction mixture was stirred at 50° C. for 18 h and poured into ice water (5 mL). The resulting mixture was adjusted to pH=9 by addition of K2CO3. The mixture was stirred at rt for 15 min and diluted with CH2Cl2 (10 mL). The aqueous layer was extracted three times with CH2Cl2. The combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 5-bromo-2-methyl-pyridine N-oxide as a white solid (1.6 g, 99%) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:4]=1[CH2:5][NH:6][C:7]1[N:15]=[CH:14][N:13]=[C:12]2[C:8]=1[N:9]=[CH:10][N:11]2[C@H:16]1[C@@H:20]2[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]2[C@@H:18]([CH2:26][NH:27][CH:28]2[CH2:31][CH:30]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:29]2)[CH2:17]1.C(#N)C.[CH:48](I)([CH3:50])[CH3:49]>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:4]=1[CH2:5][NH:6][C:7]1[N:15]=[CH:14][N:13]=[C:12]2[C:8]=1[N:9]=[CH:10][N:11]2[C@H:16]1[C@@H:20]2[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]2[C@@H:18]([CH2:26][N:27]([CH:48]([CH3:50])[CH3:49])[CH:28]2[CH2:29][CH:30]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:31]2)[CH2:17]1
Reactant: CC(C)I
Reactant: CCOC(=O)CCC1CC(NC[C@H]2C[C@@H](n3cnc4c(NCc5ccc(OC)cc5OC)ncnc43)[C@@H]3OC(C)(C)O[C@H]23)C1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CCC1CC(N(C[C@H]2C[C@@H](n3cnc4c(NCc5ccc(OC)cc5OC)ncnc43)[C@@H]3OC(C)(C)O[C@H]23)C(C)C)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
Ethyl 3-(3-((((3aR,4R,6R,6aS)-6-(6-((2,4-dimethoxybenzyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)amino)cyclobutyl)propanoate (0.06 g, 0.1 mmol) was taken up in acetonitrile (2.6 mL, 50 mmol) and isopropyl iodide (0.098 mL, 0.98 mmol) and triethylamine (0.21 mL, 1.5 mmol) were added. The reaction was heated to 80° C. for 12 hours at which point the reaction appeared to stall. Another 15 equivalents triethylamine and another 15 equivalents isopropyl iodide were added and the reaction continued 8 hours more. Reaction appeared to have stalled again so another 15 equivalents each of isopropyl iodide and triethylamine were added. Upon consumption of the starting material the reaction was concentrated and saturated Na2CO3 (20 mls) and DCM (20 mls) was added. The residue was partitioned between the organic layer and the aqueous layer. The aqueous layer was extracted 3 times with DCM, then the combined organics were dried and purified by FC (DCM/7N NH3 in MeOH 97:3). Product was still contaminated with TEA-H+I−, so to a 30 ml solution of the product in DCM was added 20 mls saturated NaHCO3 and 10 mls 1N NaOH. The mixture was stirred for 15 minutes then the aqueous was extracted with DCM 3 times. The combined organics were dried with MgSO4 and solvent removed to yield pure ethyl 3-(3-((((3aR,4R,6R,6aS)-6-(6-((2,4-dimethoxybenzyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(isopropyl)amino)cyclobutyl)propanoate (0.045 g; 70%) as a brown foam/solid with no more amine salts present by NMR. MS (ESI+) for C35H50N6O6 z 651.3 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][N:26]=2)[C:21]([CH:28]=O)=[CH:20]1.N1CCCCC1>CO>[NH:19]1[C:27]2=[N:26][CH:25]=[CH:24][CH:23]=[C:22]2[C:21](/[CH:28]=[C:7]2\[O:8][C:4]3[C:3]([CH2:12][N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[CH:20]1
Reactant: O=C1COc2c1ccc(O)c2CN1CCOCC1
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1/C(=C/c2c[nH]c3ncccc23)Oc2c1ccc(O)c2CN1CCOCC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
A solution of 6-hydroxy-7-(morpholinomethyl)benzofuran-3(2H)-one (0.170 g, 0.684 mmol) obtained in Example A41, Step 1 in methanol (3 mL) was added with 7-aza-1H-indole-3-carboxaldehyde (0.100 g, 0.684 mmol) and piperidine (0.00582 g, 0.0684 mmol), and the mixture was stirred at 60° C. for 1 hour. The reaction mixture was cooled to room temperature, and then added with methanol (2 mL), and the precipitated solid was suspended in methanol and thereby washed. The solid was collected by filtration to obtain the objective (Z)-2-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-6-hydroxy-7-(morpholinomethyl)benzofuran-3(2H)-one (0.135 g, 52%).
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:12]([OH:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].Cl>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH2:12]([O:20][C:1]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)=[O:10])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCO
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCOC(=O)c1ccc(C=O)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
Next, a solution of the above terephthalaldehydic acid chloride (20 g) dissolved in toluene (100 ml) was dropwise added to a solution of 1-octanol (20 g) dissolved in pyridine (150 ml), followed by heating the mixture on a water bath at 60° C. with stirring, allowing to stand overnight, thereafter adding toluene (500 ml), adding 6N hydrochloric acid, separating the liquid layer, washing with an aqueous solution of 2N NaOH, washing with water, drying, distilling off toluene, and further distilling under reduced pressure to obtain p-octyloxycarbonylbenzaldehyde (166°~167° C./4 mmHg) (22 g).
Reaction SMILES: Cl[CH:2]1[CH2:8][C:7]([CH3:10])([CH3:9])[CH2:6][CH2:5][NH:4][C:3]1=[O:11].S([O-])([O-])(=O)=[O:13].[NH4+].[NH4+]>O>[CH3:10][C:7]1([CH3:9])[CH2:6][CH2:5][NH:4][CH:2]([C:3]([OH:11])=[O:13])[CH2:8]1
Reactant: CC1(C)CCNC(=O)C(Cl)C1
Reactant: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: O
Product: CC1(C)CCNC(C(=O)O)C1
Temperature: 110 °C
Yield: 70.7 %

Procedure:
A suspension of 9.6 g (0.054 moles) of 3-chloro-5,5-dimethyl-2-oxoperhydroazepine and 18.98 g (0.054 moles) of Ba(OH)2.8H2O in 250 ml of water, was heated in a Parr apparatus at 110° C. for 2 hours. Then, 7.22 g (0.054 moles) of ammonium sulphate were added. The precipitate was filtered off, and the solution was evaporated in vacuo to dryness. The residue was treated with hot 2-propanol and filtered to afford a white solid which was dissolved in water and passed over an ion-exchange column (Dovex 50). The residual salts were removed with 200 ml of water and the aminoacid was eluted with 2N ammonium hydroxide to yield 6.0 g of 4,4-dimethyl pipecolic acid. M.P. >300° C. (dec.).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C:5]2[S:10][CH:9]=[C:8]([CH:11]=[CH2:12])[C:6]=2[N:7]=1.[O:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][NH2:30])[CH2:24][CH2:23]1>>[O:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][NH:30][C:2]2[N:3]=[C:4]([NH:13][C@@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[C:5]3[S:10][CH:9]=[C:8]([CH:11]=[CH2:12])[C:6]=3[N:7]=2)[CH2:24][CH2:23]1
Reactant: NCCN1CCOCC1
Reactant: C=Cc1csc2c(N[C@H](C)c3ccccc3)nc(Cl)nc12
Product: C=Cc1csc2c(N[C@H](C)c3ccccc3)nc(NCCN3CCOCC3)nc12
Yield: 65.4 %

Procedure:
The target compound of Example 47 (34 mg, 65% yield) was prepared in the same manner as Step 3 of Example 44 using (R)-2-chloro-N-(1-phenylethyl)-7-vinylthieno[3,2-d]pyrimidin-4-amine (40 mg, 0.127 mmol) and 2-morpholinoethanamine (82 mg, 0.63 mmol).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:14]=1)[C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CCN(CC)CC.[F:34][C:35]([F:42])([F:41])[C:36](OCC)=[O:37]>CO>[CH:22]1([O:21][C:15]2[CH:14]=[C:13]([CH:4]([C:5]#[C:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:3][NH:2][C:36](=[O:37])[C:35]([F:42])([F:41])[F:34])[CH:18]=[CH:17][C:16]=2[O:19][CH3:20])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COc1ccc(C(C#Cc2ccccc2)CN)cc1OC1CCCC1
Reactant: CCOC(=O)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(C(C#Cc2ccccc2)CNC(=O)C(F)(F)F)cc1OC1CCCC1

Procedure:
A solution of (+/-)-4-amino-3-(3-cyclopentyloxy-4-methoxyphenyl)-1-phenyl-1-butyne hydrochloride (50 mg, 0.14 mmol) and Et3N (40 mg) in a mixture of MeOH (1 ml) and ethyl trifluoroacetate (0.5 ml) was refluxed overnight. The solvents were evaporated, the residue taken up in Et2O, washed with H2O, 0.01N HCl, dried, and the solvent evaporated. The residue was crystallized from a mixture of cyclohexane and Et2O, and gave the titled compound, 32 mg (55%). mp 143-145°. 1H NMR (400 MHz, CDCl3) δ 7.42 (m, 2 H), 7.32 (m, 3 H), 6.94 (m, 2 H), 6.84 (d, 1 H), 6.54 (broad s, 1 H), 4.78 (m, 1 H), 4.08 (t, 1 H), 3.82 (s, 3 H), 3.78 (m, 1 H), 3.58 (m, 1 H), 1.76-1.92 (m, 6 H), 1.60 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([NH:6][CH2:7][CH3:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:18][C:19]1[N:24]=[C:23](Cl)[C:22]([CH:26]=[O:27])=[C:21]([Cl:28])[N:20]=1>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([N:6]([C:23]2[N:24]=[C:19]([Cl:18])[N:20]=[C:21]([Cl:28])[C:22]=2[CH:26]=[O:27])[CH2:7][CH3:8])=[CH:4][CH:3]=1
Reactant: CCNc1ccc(Cl)cc1
Reactant: O=Cc1c(Cl)nc(Cl)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(c1ccc(Cl)cc1)c1nc(Cl)nc(Cl)c1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.3 %

Procedure:
Solutions of 15.56 g (0.1 mole) of 4-chloro-N-ethylaniline (III) and 11.13 g (0.11 mole) of triethylamine, in each case in 50 ml of tetrahydrofuran, were successively added dropwise to a solution of 21.14 g (0.1 mole) of 2,4,6-trichloropyrimidine-5-carbaldehyde (II) in 100 ml of tetrahydrofuran. The solution was then stirred for three hours at room temperature and the triethylammoniumchloride was filtered off. The filtrate was then evaporated in vacuo and stirred with 150 ml of methanol at 0° C. 23.9 g of colorless crystals were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4](Cl)[CH:3]=1.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.F[P-](F)(F)(F)(F)F.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Reactant: Oc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(Br)cc1Oc1ccccc1
Yield: 100.7 %

Procedure:
4-Bromo-2-chloro-benzoic acid (10 g, 42 mmol), phenol (4.19 g, 44 mmol), tetrakisacetonitrilecopper hexafluorophosphate (3.95 g, 10.6 mmol), and cesium carbonate (27.6 g, 85 mmol) were added to a 1 L 3-neck round bottom flask equipped with a mechanical stirrer, reflux condenser, and containing toluene (350 mL). The reaction was refluxed overnight under nitrogen with stirring. After cooling, ethyl acetate (200 mL) was added and the reaction was acidified with aqueous 2N HCI. The organic phase was separated, dried (MgSO4), and filtered. The filtrate was concentrated to afford 4-bromo-2-phenoxybenzoic acid (12.4 g) that was used in subsequent reactions without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.Cl.[NH2:12][OH:13].C(N(CC)CC)C>CO>[NH2:1][C:2]1[C:3](/[C:9](=[N:12]\[OH:13])/[NH2:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: NO
Reactant: N#Cc1nc(Br)cnc1N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: N/C(=N/O)c1nc(Br)cnc1N
Temperature: 0 °C
Reaction time: 48 h
Yield: 98.4 %

Procedure:
3-amino-6-bromo-pyrazine-2-carbonitrile (4.5958 g, 23.09 mmol) was dissolved in MeOH (91.92 mL), cooled to 0° C. and treated with hydroxylamine hydrochloride (1.605 g, 23.09 mmol) and triethylamine (2.336 g, 3.218 mL, 23.09 mmol). The reaction was allowed to warm to ambient temperature, stirred for 48 hours and then evaporated to dryness. Methanol (a minimum amount) was added, the mixture sonicated, filtered and washed with MeOH to give the product as a brown solid 5.27 g, 98% Yield). 1H NMR (400.0 MHz, DMSO) d 5.88 (s, 2H), 7.64 (br s, 2H), 8.14 (s, 1H) and 10.38 (s, 1H) ppm; MS (ES+) 233.75