Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.NO.C([N:7](CC)C(C)C)(C)C.C(OC(=O)[NH:17][C:18](=S)[NH:19][C:20]1[C:25]([CH3:26])=[N:24][CH:23]=[C:22]([CH3:27])[N:21]=1)C>C(O)C.O>[CH3:27][C:22]1[N:21]2[N:7]=[C:18]([NH2:17])[N:19]=[C:20]2[C:25]([CH3:26])=[N:24][CH:23]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1nc(C)cnc1C
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: O
Product: Cc1ncc(C)n2nc(N)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.4 %

Procedure:
A mixture of hydroxylamine hydrochloride (13.68 g, 196.85 mmol) and N,N-diisopropylethylamine (20.6 ml, 118.11 mmol) in ethanol (200 ml) was stirred for 10 minutes at 25° C. To this mixture was then added ethyl-N-[(3,6-dimethylpyrazin-2-yl)carbamothioyl]carbamate (10 g, 39.37 mmol), and the resultant mixture was heated under reflux for 16 hours. The resultant mixture was diluted with water (100 ml), stirred for 10 min, and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated. The crude material thus obtained was triturated with hexane affording 5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine (2.4 g, 71.87%) as a white solid. MS: m/z=164 (M+H+)
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:27]=1)=[C:5]([CH3:20])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][C@@H:15]([CH3:19])[CH2:14]1)=[N:7]2.[CH3:34][N:35]=[C:36]=[O:37]>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:27]=1)=[C:5]([CH3:20])[C:6]([N:13]1[CH2:18][CH2:17][N:16]([C:36]([NH:35][CH3:34])=[O:37])[C@@H:15]([CH3:19])[CH2:14]1)=[N:7]2
Reactant: CN=C=O
Reactant: Cc1c(N2CCN[C@@H](C)C2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Product: CNC(=O)N1CCN(c2nc3cc(F)cc(F)c3c(Nc3cncc(N4CCOCC4)c3)c2C)C[C@@H]1C

Procedure:
Prepared according to Procedure N using (S)-5,7-difluoro-3-methyl-2-(3-methylpiperazin-1-yl)-N-(5-morpholinopyridin-3-yl)quinolin-4-amine (50.0 mg, 0.11 mmol) and methylisocyanate to give (S)-4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)-N,2-dimethylpiperazine-1-carboxamide. 1H NMR (CDCl3) δ ppm 7.94 (1H, d, J=2.5 Hz), 7.69 (1H, d, J=2.2 Hz), 7.30 (1H, ddd, J=10.0, 2.5, 1.2 Hz), 6.90 (1H, d, J=13.3 Hz), 6.81 (1H, ddd, J=13.8, 8.7, 2.5 Hz), 6.59 (1H, t, J=2.3 Hz), 4.49 (1H, q, J=4.9 Hz), 4.18-4.31 (1H, m), 3.78-3.91 (5H, m), 3.69-3.78 (1H, m), 3.60 (1H, dt, J=12.8, 1.7 Hz), 3.37 (1H, td, J=12.4, 3.1 Hz), 3.09-3.23 (5H, m), 2.96 (1H, td, J=12.4, 3.5 Hz), 2.87 (3H, d, J=4.7 Hz), 2.10 (3H, s), 1.31 (3H, d). Mass Spectrum (ESI) m/e=512.2 (M+1).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([N:7]=[N:8][C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[CH:5][CH:6]=1.IC.[C:18](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:18][O:15][C:12]1[CH:11]=[CH:10][C:9]([N:8]=[N:7][C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)=[CH:14][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(N=Nc2ccccc2)cc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(N=Nc2ccccc2)cc1

Procedure:
A mixture of 4-phenylazophenol (9.9 g; 50 mmol), iodomethane (7.1 g; 50 mmol), potassium carbonate (6.9 g; 50 mmol), and acetone (100 ml) was refluxed 48 h. After evaporating off the solvent, the residue was dissolved in water (25 ml), diethyl ether (50 ml) and THF (30 ml). The aqueous layer was extracted with ether (3×20 ml) and the combined organic solutions were washed with saturated NaCl solution (1×20 ml) and dried (MgSO4). After filtration and evaporation, the residue was recrystallized from 96% ethanol to give 8.7 g (82%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].S(OC)(O[CH3:18])(=O)=O.[OH-].[Na+].S(=O)(=O)(O)O>>[CH3:18][O:1][C:2]1[C:11]([OH:12])=[C:10]([OH:13])[CH:9]=[C:4]([CH:3]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(O)c(O)c(O)c1
Reactant: COS(=O)(=O)OC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1cc(O)c(O)c(OC)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.5 %

Procedure:
In 2.95 l of a 5% aqueous solution of borax was dissolved 36.8 g of methyl 3,4,5-trihydroxybenzoate, and the solution was stirred at room temperature for 5 hours. Then, 110.5 ml of dimethyl sulfate and a solution of sodium hydroxide were dropped into the solution and the reaction mixture was further stirred for 5 hours. After cooling, the mixture was made acidic by concentrated sulfuric acid and extracted with ethyl acetate. The solvent was removed from the extract to obtain 25.5 g of methyl 5-methoxy-3,4-dihydroxybenzoate (the yield was 64.5%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:24]O>C(Cl)(Cl)Cl.CN(C)C=O>[CH3:24][O:6][C:5](=[O:7])[C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:3][CH2:2][Br:1]
Reactant: CO
Reactant: O=C(O)C(CCBr)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)C(CCBr)(c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
4-Bromo-2,2-diphenylbutyric acid (5.0 g, 16 mmol), thionyl chloride (1.1 mL, 16 mmol), and N,N-dimethylformamide (0.02 mL, 0.20 mmol) in chloroform (16 mL) were mixed at room temperature under a stream of nitrogen. The reaction mixture was heated to reflux, stirred under reflux for 4 h, and cooled to 0° C. Methanol (50 mL) was added. The reaction mixture was warmed to room temperature and concentrated to dryness, yielding a brown oil. The crude material was purified on SiO2 (120 g) using 10% EtOAc/Hexanes as eluent to provide the title compound (3.9 g) as a clear oil that crystallized on standing. 1H NMR (DMSO-d6, 400 mHz) δ (ppm): 7.33-7.20 (m, 10H), 3.70 (s, 3H), 3.12-3.08 (m, 2H), 2.98-2.93 (m, 2H).
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH:12]1([CH2:17][CH2:18][OH:19])[CH2:16][CH:15]=[CH:14][CH2:13]1.N1C=CC=C[CH:21]=1>>[C:3]1([CH3:21])[C:4]([S:7]([O:19][CH2:18][CH2:17][CH:12]2[CH2:16][CH:15]=[CH:14][CH2:13]2)(=[O:8])=[O:9])=[CH:5][CH:6]=[CH:1][CH:2]=1
Reactant: OCCC1CC=CC1
Reactant: c1ccncc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccccc1S(=O)(=O)OCCC1CC=CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
A para-toluenesulfonylchloride (3.81 g, 20 mmol) was added to the pyridine (30 ml) solution of 2-(cyclopent-3-en-1-yl)ethyl alcohol (2.24 g, 20 mmol) and then the reaction mixture was stirred at room temperature for 2 hrs. After the removement of pyridine, the residue was extracted with dichloromethane, washed with 1N HCl, dried, filtered and separated by column chromatography to give a desirable product (3.24 g).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][O:4][CH2:3]1.C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[O:4]1[CH2:5][CH2:6][C@@H:2]([O:1][S:15]([CH3:14])(=[O:17])=[O:16])[CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: O[C@@H]1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]1CCOC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
A solution of 4.86 g (55.18 mmol) of (R)-(−)-3-hydroxytetrahydrofuran in 55 mL of anhydrous DCM (1M) was cooled to 0° C. with an ice bath. Then 8.5 mL (60.7 mmol, 1.1 eq.) of triethylamine and 4.8 mL (60.7 mmol, 1.1 eq.) of methanesulfonyl chloride were added successively. The reaction mixture was stirred for 2 hours at 0° C. and quenched with a saturated solution of sodium bicarbonate (70 mL). The aqueous layer was extracted with DCM (50 mL). Then the organic layers were washed with water (2×50 mL), brine (50 mL) and dried over sodium sulfate. After filtration and concentration in vacuo, a yellowish oil (7.93 g, 86.4%) was obtained corresponding to the methanesulfonic acid(R)-(tetrahydrofuran-3-yl)ester.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[C:30](=[O:31])[CH2:29][NH:28][CH2:27]4)=[CH:22][CH:21]=3)[N:16]=2)[CH:3]=1.C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.ClCCl>[CH3:34][N:28]1[CH2:29][C:30](=[O:31])[N:26]([C:23]2[CH:24]=[CH:25][C:20]([C:17]3[N:16]=[C:15]([C:4]4[CH:3]=[C:2]([CH3:1])[N:6]([CH2:7][C:8]5[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=5)[N:5]=4)[O:19][N:18]=3)=[CH:21][CH:22]=2)[CH2:27]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1ccc(Cn2nc(-c3nc(-c4ccc(N5CNCC5=O)cc4)no3)cc2C)cc1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1ccc(Cn2nc(-c3nc(-c4ccc(N5CN(C)CC5=O)cc4)no3)cc2C)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.3 %

Procedure:
A mixture of 3-(4-{5-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-1,2,4-oxadiazol-3-yl}-phenyl)imidazolidin-4-one (Example 141, 50 mg, 0.12 mmol) and aqueous formaldehyde solution (37%, 0.09 mL, 1.21 mmol) in acetic acid (0.5 mL) was stirred at rt for 15 min and then cooled to 0° C. Sodium triacetoxyborohydride (384 mg, 1.81 mmol) was added, and the mixture was stirred for 1 h at 0° C. and then at rt over night. Dichloromethane was added, and the mixture was extracted twice with saturated aqueous sodium bicarbonate solution, whereupon it was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to preparative HPLC (RP-18 column; acetonitrile/water gradient containing 0.1% trifluoroacetic acid). The product-containing fractions were combined, and the solvent was partly removed which resulted in precipitation of a solid. A neutral pH was established by adding saturated aqueous sodium bicarbonate solution, and the mixture was stirred for 30 min whereupon the solid was filtered off and dried under reduced pressure to yield the title compound (30 mg, 59%): 1H NMR (400 MHz, CDCl3) δ 8.22 (d, 2H), 7.69 (d, 2H), 7.12 (d, 2H), 7.08 (d, 2H), 6.80 (s, 1H), 5.41 (s, 2H), 4.61 (s, 2H), 3.48 (s, 2H), 2.58 (s, 3H), 2.33 (s, 3H), 2.27 (s, 3H); ES-MS m/z 429 (MH)+, HPLC RT (Method D) 2.31 min.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:53]/[O:54][CH2:55][C:56]([O:58][CH:59]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[O:57])/[C:27]([NH:29][CH:30]2[C:51](=[O:52])[N:32]3[C:33]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37]Cl)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:72][C:73]1[S:74][C:75]2[CH:80]=[CH:79][N:78]=[CH:77][C:76]=2[N:81]=1>>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:53]/[O:54][CH2:55][C:56]([O:58][CH:59]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[O:57])/[C:27]([NH:29][CH:30]2[C:51](=[O:52])[N:32]3[C:33]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37][S:72][C:73]4[S:74][C:75]5[CH:80]=[CH:79][N:78]=[CH:77][C:76]=5[N:81]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(NC(=O)/C(=N\OCC(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Reactant: Sc1nc2cnccc2s1
Product: COc1ccc(COC(=O)C2=C(CSc3nc4cnccc4s3)CS[C@@H]3C(NC(=O)/C(=N\OCC(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Yield: 78.3 %

Procedure:
Using 402 mg of p-methoxybenzyl 7-{(Z)-2-(2-tritylaminothiazol-4-yl)-2-diphenylmethoxycarbonylmethoxyiminoacetamido}-3-chloromethyl-3-cephem-4-carboxylate in place of p-methoxybenzyl 7-{(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido}-3-chloromethyl-3-cephem-4-carboxylate and 74 mg of 2-mercaptothiazolo[4,5-c]pyridine, the reaction and purification were carried out in the same manner as in Example 1(a) to obtain 356 mg of the title compound in a yield of 78%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:19]=[CH:18][C:12]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[CH:11][CH:10]=1.CN(C)C1C=CC=CC=1.[C:29](Cl)(=[O:32])[CH:30]=[CH2:31].Cl>O1CCCC1>[C:29]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[CH:18][CH:19]=1)(=[O:32])[CH:30]=[CH2:31]
Reactant: C=CC(=O)Cl
Reactant: O=C(O)C=Cc1ccc(OCCCCCCO)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)c1ccccc1
Product: C=CC(=O)OCCCCCCOc1ccc(C=CC(=O)O)cc1
Reaction time: 4 h
Yield: 53.3 %

Procedure:
The resulting 4-(6-hydroxyhexyloxy)cinnamic acid (6 g, 0.023 mole) and N,N-dimethylaniline (6.6 g, 0.054 mole) were dissolved in tetrahydrofuran (50 mL), and to this mixture was further added dropwise a solution prepared by dissolving acryloyl chloride (4.4 g, 0.049 mole) in tetrahydrofuran (20 mL). After this addition, the mixture was stirred for 4 hours. Then, the reaction solution was poured into 10% hydrochloric acid, and deposited crystal was filtrated off. The resulting coarse crystal was dissolved in ethyl acetate (100 mL), and an organic layer was washed with saturated saline solution and dried over magnesium sulfate. The organic solvent was distilled off under reduced pressure, and then the coarse crystal was re-crystallized (n-hexane-ethyl acetate) to obtain 4-(6-acryloyloxyhexyloxy)cinnamic acid (3.9 g, 54%) in the form of a colorless crystalline powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](F)=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH:19]([CH3:21])[CH3:20])[N:3]=1.[N-:22]=[N+]=[N-].[Na+].O>CN1C(=O)CCC1>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:22])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH:19]([CH3:21])[CH3:20])[N:3]=1
Reactant: CC(C)c1cc(-c2ccc(F)c3ccccc23)nc(N)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)c1cc(-c2ccc(N)c3ccccc23)nc(N)n1
Reaction time: 16 h
Yield: 53 %

Procedure:
2-Amino-4-(4-fluoronaphth-1-yl)-6-isopropyl-pyrimidine (0.288 g) was dissolved in N-methy pyrrolidinone (5 mL) and sodium azide (0.288 g) was added. The mixture was brought to a temperature of 160° C. under an inert atmosphere for 16 hours. After cooling the reaction mixture was poured into water (50 mL) and the reaction product was extracted with ethyl acetate (3×30 mL). The organic layer was dried over sodium sulfate and evaporated to dryness. The product was purified by column chromatography on silica gel, eluting with hexane/ethyl acetate, and recrystallized from tert-butyl methyl ether to give 2-amino-4-(4-aminonaphth-1-yl)-6-isopropyl-pyrimidine (0.151 g), m.p. 185-186° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[N:10]12[CH2:17][CH2:16][CH2:15][C:14]1([CH2:18][CH2:19][NH2:20])[CH2:13][CH2:12][CH2:11]2>>[N:10]12[CH2:17][CH2:16][CH2:15][C:14]1([CH2:18][CH2:19][NH:20][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH2:13][CH2:12][CH2:11]2
Reactant: NCCC12CCCN1CCC2
Reactant: N#Cc1ccc(F)cc1
Product: N#Cc1ccc(NCCC23CCCN2CCC3)cc1

Procedure:
The procedures described in Example 1 were repeated except that 4-fluorobenzonitrile (1.00 g, 8.26 mmol ) and 2-(1-azabicyclo[3.3.0]octan-5-yl)ethylamine (3.15 g, 20.4 mmol) were employed. In this case, the desired compound was obtained as a colorless liquid (2.02 g, 99.1%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][N:3]=1.O.[Cl-].[CH3:13][O:14]C1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][C@H:39]2[CH2:43][O:42][C:41]([NH2:44])=[N:40]2)=[CH:33][CH:32]=1>CO>[NH2:44][C:41]1[O:42][CH2:43][C@H:39]([CH2:38][CH2:37][C:34]2[CH:35]=[CH:36][C:31]([NH:30][C:8]([C:5]3[CH:6]=[N:7][C:2]([O:14][CH3:13])=[N:3][CH:4]=3)=[O:10])=[CH:32][CH:33]=2)[N:40]=1
Reactant: NC1=N[C@@H](CCc2ccc(N)cc2)CO1
Reactant: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Reactant: O=C(O)c1cnc(Cl)nc1
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: COc1ncc(C(=O)Nc2ccc(CC[C@H]3COC(N)=N3)cc2)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 18.2 %

Procedure:
2-Chloro-pyrimidine-5-carboxylic acid (23 mg) was dissolved in methanol (1 ml) and the solution cooled to 0° C. before addition of 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (45 mg). The reaction mixture was stirred for 5 minutes at 0° C. before dropwise addition of a solution of (S)-4-[2-(4-Amino-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine (30 mg) in methanol (1 ml). Stirring at 0° C. was continued for 1 hour before quenching by addition of a 1N solution of sodium hydroxide. The reaction mixture was then extracted three times with ethyl acetate and the combined organic layers washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give 2-methoxy-pyrimidine-5-carboxylic acid {4-[2-((S)-2-amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-amide (9 mg) as a yellow solid. MS (ISP): 342.2 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]([F:11])([F:10])[F:9])=[N:4][NH:5][C:6]=1[CH3:7].C([O-])([O-])=O.[K+].[K+].Cl[CH2:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[O:21].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([N:25]2[CH2:24][CH2:23][N:22]([C:20](=[O:21])[CH2:19][N:5]3[C:6]([CH3:7])=[C:2]([Br:1])[C:3]([C:8]([F:9])([F:11])[F:10])=[N:4]3)[CH2:27][CH2:26]2)=[CH:33][CH:32]=1
Reactant: Cc1[nH]nc(C(F)(F)F)c1Br
Reactant: O=C(CCl)N1CCN(c2ccc(Cl)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Cc1c(Br)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(Cl)cc2)CC1

Procedure:
Protocol T was followed using 4-Bromo-5-methyl-3-trifluoromethyl-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3) afforded the title compound as white solid. 1H NMR (400 MHz, CDCl3): 6.96–7.1 (m, 2H), 6.84–6.89 (m, 2H), 5.2(s, 2H), 3.6.2–3.8 (m, 4H), 3.0–3.16 (m, 4H), 2.32 (s, 3H). 13C NMR (400 MHz, CDCl3): 162, 146.4, 142.2, 118.5, 116.2, 52, 50.4, 46.2, 42.2, 15.2.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1.C(O[Li])(C)(C)C>[Cu]I.CN1C(=O)N(C)CCC1>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: Clc1cccc(Cl)c1
Agent: [Cu]I
Agent: [Li]OC(C)(C)C
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CN1CCCN(C)C1=O
Product: Clc1cccc(Cl)c1-c1ccccc1
Yield: 17.9 %

Procedure:
Copper(I) iodide (19 mg, 0.1 mmol), iodobenzene (204 mg, 1.0 mmol), 1,10-phenanthroline (18 mg, 0.1 mmol), 1,3-dichlorobenzene (220 mg, 1.5 mmol), tBuOLi (160 mg, 2.0 mmol), and DMPU (0.5 mL), 125° C., 12 hours. After column chromatography (hexanes) 40 mg (18%) of a colorless oil was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8](Cl)=[O:9].[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13].O>C(Cl)Cl>[CH2:12]([N:14]([CH2:15][CH3:16])[C:8]([C:7]1[CH:6]=[C:5]([Cl:11])[N:4]=[N:3][C:2]=1[Cl:1])=[O:9])[CH3:13]
Reactant: CCNCC
Reactant: O=C(Cl)c1cc(Cl)nnc1Cl
Solvent: ClCCl
Solvent: O
Product: CCN(CC)C(=O)c1cc(Cl)nnc1Cl

Procedure:
3,6-Dichloropyridazine-4-carbonyl chloride (2.5 g) was initially charged in DCM (25 ml) at RT. Thereafter, diethylamine (1.5 ml) predissolved in DCM (5 ml) was slowly added dropwise while stirring. After stirring at RT for 3 h, the mixture was admixed with water and extracted three times with DCM. The combined DCM phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by means of silica gel (70 g cartridge, n-heptane/EA gradient). 1.8 g of the title compound were obtained.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16](=[O:18])[CH3:17])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(NC(C)C)(C)C.[Li].[CH2:27]([O:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][CH:43]=[O:44])=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:34][C:35]1[CH:36]=[CH:37][C:38]([CH2:41][CH2:42][CH:43]([OH:44])[CH2:17][C:16](=[O:18])[CH2:15][CH2:14][C:11]2[CH:10]=[CH:9][C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:13][CH:12]=2)=[CH:39][CH:40]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=CCCc1ccc(OCc2ccccc2)cc1
Reactant: CCCCCCOc1ccc(CCC(C)=O)cc1
Agent: [Li]
Solvent: CC(C)NC(C)C
Product: CCCCCCOc1ccc(CCC(=O)CC(O)CCc2ccc(OCc3ccccc3)cc2)cc1

Procedure:
In a manner similar to Example 3, 2.48 g (10 mmol) of 4-(4-hexyloxyphenyl)-butan-2-one was treated with 15 mmol of lithium diisopropylamine, followed by 3 g (12 mmol) of 3-(4-benzyloxyphenyl)-propan-1-al to give, after purification (silica gel dry column, hexane: ethyl acetate, 2:1), 0.7 g of the title compound pound as a pale yellow oil. MS(EI): 488 (m+), 470 (m+ -H2O) Using the method described hereinabove, the following examples further illustrate the invention:
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.[CH2:25]([OH:28])[C:26]#[CH:27]>O1CCOCC1.ClCCl.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([C:27]#[C:26][CH2:25][OH:28])=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: C#CCO
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(C#CCO)ccc12
Temperature: 90 °C
Yield: 75.8 %

Procedure:
To a solution of 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (500 mg, 1.24 mmol, 1.00 eq) in degassed 1,4-dioxane (2.50 mL, 5.00 V), prop-2-yn-1-ol (0.09 mL, 1.49 mmol, 1.20 eq) Et3N (0.52 mL, 3.71 mmol, 3.00 eq), Bis(triphenylphosphine)palladium (II) dichloride (34.86 mg, 0.05 mmol, 0.04 eq) and copper (I) iodide (4.81 mg, 0.02 mmol, 0.02 eq) were added. The reaction mixture was heated at 90° C. for 1 h. The reaction mixture was diluted with dichloromethane and filtered through celite. The filtrate was concentrated and subjected to column chromatography to afford the title compound (0.38 g, 0.94 mmol, 75.7%) as a off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.87 (t, J=5.92 Hz, 1H), 8.09 (d, J=8.61 Hz, 1H), 8.01 (d, J=9.01 Hz, 1H), 7.86 (d, J=9.11 Hz, 1H), 7.68 (d, J=8.72 Hz, 1H), 5.53 (t, J=6.13 Hz, 1H), 4.39 (d, J=6.01 Hz, 2H), 3.27 (t, J=6.32 Hz, 2H), 1.98-2.04 (m, 2H), 1.74-1.86 (m, 5H), 1.24-1.33 (m, 2H). m/z: 393.2 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]2[CH:16]=[C:15]([CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[S:14][CH:13]=2)=[N:5]S(=O)[N:3]=1.[ClH:25]>CO>[ClH:25].[ClH:25].[ClH:25].[N:18]1([CH2:17][C:15]2[S:14][CH:13]=[C:12]([CH2:11][S:10][CH2:9][CH2:8][NH:7][C:6](=[NH:5])[C:2](=[NH:1])[NH2:3])[CH:16]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NC1=NS(=O)N=C1NCCSCc1csc(CN2CCCCC2)c1
Agent: Cl
Solvent: CO
Product: N=C(N)C(=N)NCCSCc1csc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
A suspension of 3-amino-4-{2-[(5-piperidinomethyl-3-thienyl)methylthio]ethylamino}-1,2,5-thiadiazole 1-oxide (6.1 g; 15.8 mmoles) [prepared according to published United Kingdom Patent Application No. 2,067,987] in 80 ml of methanol was treated with 10.5 ml of concentrated HCl. After stirring at ambient temperature for 3 hours, the solution was concentrated and the residue triturated with 50 ml of 1- propanol, filtered and dried to give 5.86 g (83%) of product. A sample was recrystallized from methanol-acetone to give the title compound, mp 201°-214° C. (dec.).