Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C1COCC1.CO.C[O:11][C:12]([C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)[CH:17]=[CH:18][CH:19]=1)=[O:13]>CCOC(C)=O>[C:31]([O:30][C:28]([N:25]1[CH2:26][CH2:27][CH:22]([CH2:21][CH2:20][C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=2)[C:12]([OH:13])=[O:11])[CH2:23][CH2:24]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: COC(=O)c1cccc(CCC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCc2cccc(C(=O)O)c2)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
Aqueous 1 M sodium hydroxide solution (196 ml) was added to a THF (200 ml)/methanol (50 ml) mixed solution of tert-butyl 4-{2-[3-(methoxycarbonyl)phenyl]ethyl}-1-piperidinecarboxylate (45.4 g), followed by stirring at 60° C. for 2 hours. The organic solvent was evaporated under reduced pressure, and under ice cooling, 0.5 M hydrochloric acid (400 ml) was added to the residue. The reaction liquid was diluted with EtOAc, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 3-{2-[1-(tert-butoxycarbonyl)-4-piperidinyl]ethyl}benzoic acid (43.5 g) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([C:15]1[N:16]=[CH:17][N:18](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:19]=1)=[O:14])[CH:7]=[CH:6]2.C(O)=O.[CH2:42]1[CH2:46]OC[CH2:43]1>>[NH:18]1[CH:19]=[C:15]([C:13]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=2)([OH:14])[CH:42]([CH3:46])[CH3:43])[N:16]=[CH:17]1
Reactant: C1CCOC1
Reactant: COc1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Solvent: O=CO
Product: COc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
(6-Methoxynaphthalen-2-yl)-(1-trityl-1H-imidazol-4-yl)ketone (15.0 g) was dissolved in THF (80 ml). To the solution was added 90% formic acid (20 ml), and the mixture was stirred at 50° C. for 2 h. After removal of the solvents by evaporation, 1N-hydrochloric acid (60 ml) was added and the precipitate was filtered off. The filtrate was washed with ether, and neutralized with potassium carbonate. The resulting precipitate was collected by filtration, dried under reduced pressure to give the titled compound (7.54 g) as a colorless solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[S:8][C:9](Br)=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.N#N.[NH4+].[Cl-].C(O[CH2:20][CH3:21])C>>[CH2:20]([C:4]1[CH:3]=[CH:2][S:6][C:5]=1[C:7]1[S:8][C:9]([C:9]2[S:8][C:7]([C:5]3[S:6][CH:2]=[CH:3][C:4]=3[CH2:9][CH2:10][CH2:11][CH2:7][CH2:20][CH3:21])=[CH:11][CH:10]=2)=[CH:10][CH:11]=1)[CH2:21][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCOCC
Reactant: Brc1ccc(-c2ccc(Br)s2)s1
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Product: CCCCCCc1ccsc1-c1ccc(-c2ccc(-c3sccc3CCCCCC)s2)s1
Temperature: 20 °C

Procedure:
The Grignard reagent prepared above, added dropwise to a suspension of 5.0 g (15.4 mmoles) of 5,5′-dibromo-2,2′-bithiophene and 0.084 g (0.154 mmoles) of Ni(dppp)2Cl2 in 50 mL dry ethyl ether. Typically, the Grignard is added from a feeding funnel under an inert gas (e.g., N2). The resulting mixture was heated to reflux for about 20 hours. The resulting mixture is cooled to about room temperature (e.g., to about 20° C.) and combined with about 200 mL of 5% aqueous NH4Cl to which some ice is added, to effect hydrolysis. The aqueous phase is extracted with about 2×100 mL of CH2Cl2. The organic phases combined are back washed with about 200 mL water and dried over MgSO4. The solvent is evaporated to give a raw product, 3,3′″-dihexyl-[2,2′;5′,2″;5″,2′″]quaterthiophene, which can be purified using, for example, a silica-gel column using hexanes 100% as eluant to give 6.4 g of material, (yield=83.4%). Proton NMR can be used to determine the presence of the raw product: 1HNMR: 7.25 ppm, (2H, d), 7.20 ppm, (2H, d), 7.10 ppm, (2H, d), 7.00 ppm, (2H, d), 2.83 ppm, (4H, t), 2.7 ppm, (4H, m), 1.41 ppm, (12H, m), 1.00 ppm, (6H, m).
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1F)[C@H:4]([SH:9])[C:5]([O:7][CH3:8])=[O:6].C(OC(N[C@@H](C1C=CC=CC=1F)C(S)C(OC)=O)=O)(C)(C)C.Cl>C(OCC)(=O)C>[ClH:1].[NH2:2][C@@H:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@H:4]([SH:9])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)[C@@H](S)[C@@H](N)c1ccccc1F
Agent: COC(=O)C(S)[C@@H](NC(=O)OC(C)(C)C)c1ccccc1F
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](S)[C@@H](N)c1ccccc1
Reaction time: 3 h

Procedure:
Methyl (2S,3S) 3-amino-2-mercapto-3-(2-fluorophenyl)propionate hydrochloride may be prepared in a similar manner to that described in Example 1E, but starting with 8.2 g of methyl (2RS,3S)-3-tert-butoxycarbonylamino-2-mercapto-3-(2-fluorophenyl)propionate and 20 ml of a methanolic 5N solution of hydrochloric acid. Stirring is continued for 3 h at a temperature in the region of 20° C. and the reaction medium is then concentrated to dryness under reduced pressure at 30° C. The residue obtained is beaten in 20 ml of ethyl acetate. The solid obtained is separated out by filtration and air-dried. 2.3 g of methyl (2S,3S) 3-amino-2-mercapto-3-phenylpropionate hydrochloride are thus obtained in the form of a white solid melting at 172° C. After evaporation of the filtrate, 1.8 g of methyl (2RS,3S)-3-amino-2-mercapto-3-phenylpropionate hydrochloride are also isolated, in the form of a white solid which is used without further purification in the subsequent syntheses.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1.C(N=C=NCCCN(C)C)C.[CH3:30][S:31]([NH2:34])(=[O:33])=[O:32]>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH:34][S:31]([CH3:30])(=[O:33])=[O:32])=[O:15])=[CH:12][CH:11]=1
Reactant: CS(N)(=O)=O
Reactant: COc1ccccc1Sc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COc1ccccc1Sc1ccc(C(=O)NS(C)(=O)=O)cc1
Reaction time: 1 h
Yield: 30.9 %

Procedure:
4-(2-methoxyphenylthio)benzoic acid (126 mg, 0.48 mmol), 4-dimethylaminopyridine (12.2 mg, 0.10 mmol) and 1-ethyl-3-(dimethylaminopropyl)carbodiimide (195 mg, 0.97 mmol) were dissolved in anhydrous N,N-dimethylformamide (4 mL) and stirred for 60 minutes. To this solution was added methanesulphonamide (70 mg, 0.72 mmol) and the reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched by the addition of water (10 mL) and the mixture extracted with ethyl acetate (3×10 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 50 mg of a crude oil which was purified by preparative HPLC title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.Br[C:19]1[C:24]([O:25][CH2:26][C@@H:27]2[CH2:29][O:28]2)=[CH:23][CH:22]=[CH:21][N:20]=1.CC1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:25]1[C:24]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[O:28][CH:27]([CH2:29][N:1]2[CH2:2][CH:3]=[C:4]([C:7]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=4)[NH:9][CH:8]=3)[CH2:5][CH2:6]2)[CH2:26]1
Reactant: Brc1ncccc1OC[C@@H]1CO1
Reactant: N#Cc1ccc2[nH]cc(C3=CCNCC3)c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccc(P(c2ccc(C)cc2)c2ccc3ccccc3c2-c2c(P(c3ccc(C)cc3)c3ccc(C)cc3)ccc3ccccc23)cc1
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: N#Cc1ccc2[nH]cc(C3=CCN(CC4COc5cccnc5O4)CC3)c2c1
Temperature: 25 °C
Yield: 7.4 %

Procedure:
3-(1,2,3,6-Tetrahydro-4-pyridinyl)1H-indole-5-carbonitrile (1.62 g, 7.26 mmole) and 2-bromo-3-[(2S)oxiranylmethoxy]pyridine (0.84 g, 3.65 mmol) were combined in DMSO (40 mL). This solution was heated at 75–80° C. under nitrogen for 5 hours. After completion, the reaction was cooled to room temperature and partitioned between 250 mL each of ethyl acetate and saturated sodium bicarbonate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuum. The crude residue was column chromatographed on silica gel using first methylene chloride as eluant to remove impurities and then 3% methanol in methylene chloride to elute the product, which was a yellow foam (0.30 g, 18%). The intermediate (0.30 g, 0.66 mmole) was then cyclized in toluene (40 mL) in the presence of palladium (II) acetat (0.015 g, 0.067 mmole), (S)-(−)-2,2′-Bis(di-p-tolylphosphino)-1,1′-binaphthyl (0.032 g, 0.047 mmole), and potassium carbonate (0.13 g, 0.94 mmole). The heterogeneous mixture was heated at 100° C. for a period of 30 hours. After the mixture cooled to room temperature, the catalysts were removed by filtration and the filtrate was concentrated in vacuum. The resulting crude brown oil was then column chromatographed on silica gel with 3% methanol in methylene chloride to give the desired product as a brown oil (0.100 g, 42%). The oil was crystallized from ethanol with the addition of a solution of oxalic acid in hot ethanol to give 0.050 g of the (S)-enantiomer of the title compound as a white solid, m.p. 165° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].CC(O)C.C(=O)=O.[O:14]1[C:18]2([CH2:23][CH2:22][CH:21]([C:24](OCC)=[O:25])[CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1>C(OCC)C>[O:14]1[C:18]2([CH2:23][CH2:22][CH:21]([CH2:24][OH:25])[CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Agent: O=C=O
Agent: [Al+3]
Agent: [H-]
Solvent: CC(C)O
Solvent: CCOCC
Product: OCC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.8 %

Procedure:
A 12-L, four-necked flask equipped with a mechanical stirrer, dropping funnel, thermometer and a nitrogen-inlet tube was flushed with nitrogen and then charged with a 1.0 M LAH (2754 mL, 2754 mmol). The mixture was cooled (0-4° C. internal temperature, 2-propanol/dry ice bath) and a solution of ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (590 g, 2754 mmol) was added over 3.5 h via dropping funnel. The reaction mixture was then stirred for 3 h while allowing it to warm to room temperature then stirred for an additional 16 h at room temp. The reaction mixture was then cooled (0° C.) bath and diluted with ethyl ether (3 L). The reaction mixture was then carefully quenched by adding water (100 mL, over 1 h), followed by 15% aqueous NaOH (100 mL, over 40 min) and water (300 ml, over 30 min). After the mixture was stirred for 1 h, sodium sulfate was added and stirring continued for 10 min. The white precipitate was the filtered off and the cake was washed with ether and the filtrate concentrated to afford the title compound (440 g, 92% yield) as a light yellow liquid. Ref. J. Org. Chem. 1997, 62, 5284-5292.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].Cl.[OH2:5]>[Pd]>[CH2:2]([OH:5])[C@@H:1]([C@H:2]([C@@H:1]([C@@H:2]([CH2:1][OH:3])[OH:5])[OH:3])[OH:5])[OH:3]
Reactant: O
Reactant: CCO
Agent: [Pd]
Agent: Cl
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
0.18 g (0.3 mmol) of 1,5-dideoxy-2,3,6-Tri-O-benzyl-1,5-{[6-(trimethylsilyl)hexyl]imino}-D-glucitol 20 ml of a 4:1 mixture of ethanol and water and 0.1N hydrochloric acid (3 ml, 0.3 mmol) are hydrogenated at atmospheric pressure in presence of 60 mg of palladium 10% on charcoal to afford 0.065 g (66%) of expected 1,5-dideoxy-1,5-{5-(trimethylsilyl)hexyl]imino}-D-glucitol as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([CH2:19][CH2:20][CH2:21][N:15]4[CH2:14][C@@H:13]4[CH2:22][N:23](C(OC(C)(C)C)=O)[CH2:24][C@@H:12]34)[CH:18]=2)=[C:5]([C:32]([F:35])([F:34])[F:33])[CH:4]=1.FC(F)(F)C(O)=O.CCOCC.[ClH:48]>C(Cl)Cl.C(O)C>[ClH:48].[ClH:48].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([CH2:19][CH2:20][CH2:21][N:15]4[CH2:14][C@@H:13]4[CH2:22][NH:23][CH2:24][C@@H:12]34)[CH:18]=2)=[C:5]([C:32]([F:35])([F:33])[F:34])[CH:4]=1
Reactant: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN4CCC3)c(C(F)(F)F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Solvent: CCOCC
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNC[C@H]2CN4CCC3)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
To a solution of (±)-trans-tert-butyl 2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,8a,9,11,11a-hexahydro-4H-pyrido[3,2,1-ij]pyrrolo[3,4-c]quinoline-10(8H)-carboxylate (160 mg, 0.33 mmol) in 5 mL of methylene chloride was added 1 mL of trifluoroacetic acid. The mixture was allowed to stir at ambient temperature for 2 h and then was concentrated in vacuo. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA). Product-containing fractions were combined, concentrated and partitioned between chloroform and saturated aqueous sodium carbonate. The organics were washed with brine, dried (K2CO3) and concentrated in vacuo. The residue (30 mg, 0.077 mmol) was dissolved in ethanol and ether and there was added 2M HCl in ether (0.077 mL, 0.15 mmol). The solvent was decanted and the remaining solid was triturated twice with ether and was dried in vacuo to afford 20 mg (57%) of the title compound of EXAMPLE 7 as an off white powder. 1H NMR (d6-dmso): δ 9.40 (broad s, 2H), 7.29-7.18 (m, 3H), 6.71 (s, 1H), 6.58 (s, 1H), 3.82 (s, 3H), 3.57-3.49 (m, 1H), 3.40-3.18 (m, 5H), 2.93-2.80 (m, 3H), 2.70-2.62 (m, 2H), 2.16-2.06 (m, 1H), 1.95-1.88 (m, 1H), 1.85-1.78 (m, 1H). LRMS (ES)+: 389.2 (M+H)+.
Reaction SMILES: C(NC(=O)/C=C(\O[C:11](=[O:30])[C:12]1[CH:17]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[C:15]([Cl:22])=[CH:14][C:13]=1[NH:23][CH2:24][C:25]1[O:29][CH:28]=[CH:27][CH:26]=1)/C)(C)(C)C.[NH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>C(#N)C>[O:38]1[CH2:39][CH2:40][N:35]([CH2:34][CH2:33][NH:32][C:11](=[O:30])[C:12]2[CH:17]=[C:16]([S:18]([CH3:21])(=[O:19])=[O:20])[C:15]([Cl:22])=[CH:14][C:13]=2[NH:23][CH2:24][C:25]2[O:29][CH:28]=[CH:27][CH:26]=2)[CH2:36][CH2:37]1
Reactant: C/C(=C/C(=O)NC(C)(C)C)OC(=O)c1cc(S(C)(=O)=O)c(Cl)cc1NCc1ccco1
Reactant: NCCN1CCOCC1
Solvent: CC#N
Product: CS(=O)(=O)c1cc(C(=O)NCCN2CCOCC2)c(NCc2ccco2)cc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
N-tert-butyl-3-(2-furfurylamino-4-chloro-5-methylsulfonylbenzoyloxy)crotonamide (4.00 g.; 0.0085 mole) and N-(2-aminoethyl)morpholine (2.21 g.; 0.017 mole) are added to acetonitrile (100 ml.). The resulting solution is stirred at room temperature for 24 hours. The acetonitrile is removed under reduced pressure, and the residue is triturated with butyl chloride to give N-(2-morpholinoethyl)-2-furfurylamino-4-chloro-5-methylsulfonylbenzamide which after drying yields 2.7 g. (72%), m.p. 127°-130° C. Several recrystallizations from butyl chloride yields product with m.p. 132°-134° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([OH:11])[CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[N:6]=1)([CH3:3])[CH3:2].P(OCC)(OCC)OCC.[CH3:26][O:27][CH:28]=[C:29]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40]Br)[C:30]([O:32][CH3:33])=[O:31].S>CCCCCCCC.O.[Cu].[Cu].O>[CH3:26][O:27][CH:28]=[C:29]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][O:11][C:9]1[CH:8]=[C:7]([C:12]([F:14])([F:15])[F:13])[N:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[N:10]=1)[C:30]([O:32][CH3:33])=[O:31]
Reactant: CC(C)Oc1nc(O)cc(C(F)(F)F)n1
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Agent: [Cu]
Agent: CCOP(OCC)OCC
Agent: S
Solvent: CCCCCCCC
Solvent: O
Product: COC=C(C(=O)OC)c1ccccc1COc1cc(C(F)(F)F)nc(OC(C)C)n1
Temperature: 100 °C
Reaction time: 5 h
Yield: 57.7 %

Procedure:
2.22 g of 2-isopropoxy-6-trifluoromethyl-4-hydroxypyrimidine and 0.86 g of copper suboxide were suspended in 30 ml of octane. The suspension was refluxed until no water was recognized to form, while formed water was being taken into a quantitative water receiver. 1.86 g of triethyl phosphite was added, and, 30 minutes later, 3.65 g of methyl 3-methoxy-2-(2-bromomethylphenyl)acrylate was added at an instance. The reaction was carried out for 5 hours at reflux of octane. The solution was cooled down to 100° C. Hydrogen sulfide gas was blown into the solution at a rate of 15-30 ml/min for an hour. The resultant was stirred for 30 minutes. The formed precipitate was filtrated and washed with 9 ml of octane. The mixed solution of the obtained filtrate and washing was analyzed with high-performance liquid chromatography. The reaction yield was 72%. Octane was concentrated under reduced pressure. To the residue were added 10.3 ml of ethanol and 3.9 ml of water, and heated to 64° C. to dissolve. The resulting solution was left to cool over night. 2.8 ml of a mixed solution of ethanol/water (7/1) was added to it and cooled down to 5° C. to deposit crystals fully. The crystals were filtrated, washed with 1.4 ml of a mixed solution of ethanol/water (7/1) twice to give 2.46 g (yield 67%) of the target compound with melting point of 109˜110° C.
Reaction SMILES: O=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][C:4]#[N:5].S(O)(O)(=O)=O.[NH2:17][OH:18].[OH-].[Na+]>C(O)C>[C:6]1([C:2]2[CH:3]=[C:4]([NH2:5])[O:18][N:17]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#CCC(=O)c1ccccc1
Reactant: NO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(-c2ccccc2)no1
Temperature: 25 °C
Yield: 36 %

Procedure:
A mixture of 3-oxo-3-phenylpropanenitrile (5.00 g, 34.4 mmol), hydroxylamine sulfate (3.10 g, 18.9 mmol), ethanol (35 ml) and an aqueous solution (35 ml) of sodium hydroxide (1.66 g, 41.4 mmol) was stirred at 80° C. for 24 hours. After cooling to room temperature, the reaction mixture was adjusted to pH=11 by addition of an aqueous 8N sodium hydroxide solution and then extracted with chloroform. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the desired product (1.09 g, 19.8%) as a solid.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][CH2:31][NH2:32].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CS(C)=O>[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][CH2:31][NH:32][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: NCCCc1ccccc1Br
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Cl)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(NCCCc3ccccc3Br)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 20-mL sealed tube, was placed methyl 3-chloro-2-phenylquinoxaline-6-carboxylate (180 mg, 0.60 mmol, 1.00 equiv), toluene/DMSO (5/1 mL), 3-(2-bromophenyl)propan-1-amine (385 mg, 1.80 mmol, 2.99 equiv), and potassium carbonate (414 mg, 3.00 mmol, 4.98 equiv). The resulting solution was stirred overnight at 100° C. The mixture was concentrated under vacuum. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:50). This resulted in 240 mg (80%) of methyl 3-(3-(2-bromophenyl)propylamino)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18]([O:25][CH2:26][C:27]([CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[CH:28][CH2:29]Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:29][CH:28]=[C:27]([CH2:31][O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:26][O:25][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:4]([Cl:11])[N:3]=1
Reactant: ClCC=C(COCc1ccccc1)COCc1ccccc1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(Cl)c2ncn(CC=C(COCc3ccccc3)COCc3ccccc3)c2n1
Reaction time: 0.08 h
Yield: 18 %

Procedure:
A mixture of 1.61 g 2-amino-6-chloropurine (9.5 mmol) and 1.31 g finely ground anhydrous K2CO3 (9.5 mmol) in 50 ml of dry dimethylformamide (DMF) was kept at 100° C. for 5 min. and cooled. At 10° C. the crude 1-benzyloxy-2-benzyloxymethyl-4-chlorobut-2-ene in 25 ml of dry DMF was added with stirring during 4 h. After 2 days at room temperature the mixture was evaporated in vacuum, the residue was extracted with 2×25 ml of chloroform and the extract evaporated to dryness. Chromatography (silica gel, CHCl3 +MeOH 19+1) afforded 0.25 g (18%) of 4-(2-amino-6-chloropurin-9-yl)-1-benzyloxy-2-benzyloxymethyl-2-butene (TLC on silica gel, CHCl3 +MeOH 13+1 parts by volume Rf 0.62).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][CH2:30][O:31][C:24]=3[CH:23]=2)[C:10]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][CH2:30][O:31][C:24]=4[CH:23]=3)[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: Clc1nc(NCc2ccc3c(c2)OCCO3)c2c3c(sc2n1)CCCC3
Product: c1cn(-c2nc(NCc3ccc4c(c3)OCCO4)c3c4c(sc3n2)CCCC4)cn1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5,6,7,8-tetrahydro-4-(3,4-ethylendioxybenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5,6,7,8-tetrahydro4-(3,4-ethylendioxybenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: O1CCCCC1[NH:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]2[N:14](C3CCCCO3)[N:15]=[C:16]([C:17]([F:20])([F:19])[F:18])[C:9]=12.FC(F)(F)C(O)=O>CCO.O>[F:19][C:17]([F:18])([F:20])[C:16]1[C:9]2[C:10](=[N:11][CH:12]=[N:13][C:8]=2[NH2:7])[NH:14][N:15]=1
Reactant: FC(F)(F)c1nn(C2CCCCO2)c2ncnc(NC3CCCCO3)c12
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: Nc1ncnc2[nH]nc(C(F)(F)F)c12
Temperature: 80 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
To a solution of N,1-bis(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (intermediate G15, 88 mg, 0.237 mmol) in EtOH (5 mL), water (0.5 mL) was added. Then 2,2,2-trifluoroacetic acid (0.3 ml, 0.237 mmol) was added and the mixture was stirred at 80° C. overnight. Solvent was removed to give the title compound (45 mg, 93%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:24][CH2:25][C:26](=O)[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:45])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]1[S:45][C:26]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:25][N:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)OCCn2c1nc(C(=O)NCC(=O)Cc1ccc(F)cc1)c(OCc1ccccc1)c2=O
Solvent: Cc1ccccc1
Product: CC1(C)OCCn2c1nc(-c1ncc(Cc3ccc(F)cc3)s1)c(OCc1ccccc1)c2=O
Yield: 43 %

Procedure:
A solution of 3-(benzyloxy)-N-(3-(4-fluorophenyl)-2-oxopropyl)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide: (0.12 g, 0.25 mmol) and Lawesson's reagent (0.11 g, 0.275 mmol) in toluene (10 mL) was stirred 15 min at room temperature, 30 min at 60° C. and 2 h at 100° C. The mixture was cooled, concentrated and purified by preparative HPLC on a C18 column using water/MeOH containing 0.1% TFA as eluent to afford the title compound (0.05 g, 43% yield) as a yellow solid. 1HNMR (500 MHz, CDCl3) δ: 7.78 (1H, s), 7.54-7.51 (2H, m), 7.32-7.29 (3H, m), 7.19 (2H, dd, J=8.6, 5.2 Hz), 7.01 (2H, t, J=8.6 Hz), 5.35 (2H, s), 4.15 (2H, s), 4.06-4.00 (4H, m), 1.66 (6H, s). HRMS (M+H) calcd for C26H25N3O3FS: 478.1601. found: 478.1623.