Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:7]([OH:9])=O)(=[O:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH:36]1[CH2:40][CH2:39][CH2:38][C@H:37]1[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>C(Cl)Cl.CN(C=O)C>[C:1]([O:4][CH2:5][C@H:6]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:7]([N:36]1[CH2:40][CH2:39][CH2:38][C@H:37]1[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)OC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
(S)-3-Acetoxy-2-(benzyloxycarbonylamino)-propanoic acid (1.5 g, 5.33 mmol) was dissolved in CH2Cl2 (15 mL). N-Methylmorpholine (NMM) (0.64 mL, 5.87 mmol) and isobutyl chloroformate (IBCF) (0.72 mL, 6.12 mmol) were added at −15° C. and stirred for 30 minutes under inert atmosphere. A mixture of (S)-tert-butyl pyrrolidine-2-carboxylate (1) (998 mg, 5.87 mmol) and NMM (0.64 mL, 5.87 mmol) in DMF (5 mL) were added drop wise to the reaction mixture and stirring was continued for another 3 h at RT. The reaction mixture was diluted with DCM (200 mL), washed with water (50 mL), citric acid solution (10 mL) and brine (10 mL). The separated organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained crude residue was purified by silica gel column chromatography eluting with 30% EtOAc/Hexane to afford compound 2 (1.6 g, 69.5%).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]=[CH:9][C:8]2=[O:13])=[CH:4][CH:3]=1.C[O:17][C:18]1O[C:21]([C:23]([O:25][CH3:26])=[O:24])=[N:20][CH:19]=1.Cl>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][C:10]3[C:21]([C:23]([O:25][CH3:26])=[O:24])=[N:20][CH:19]=[C:18]([OH:17])[C:9]=3[C:8]2=[O:13])=[CH:14][CH:15]=1
Reactant: O=C1C=CCCN1Cc1ccc(F)cc1
Reactant: COC(=O)c1ncc(OC)o1
Agent: Cl
Solvent: CO
Product: COC(=O)c1ncc(O)c2c1CCN(Cc1ccc(F)cc1)C2=O
Temperature: 120 °C
Reaction time: 24 h

Procedure:
In a sealed tube, 1-(4-fluorobenzyl)-5,6-dihydropyridin-2-(1H)-one (3.84 g, 18.7 mmol), and methyl 5-methoxy-1,3-oxazole-2-carboxylate prepared in Step 5 (2.94 g, 18.7 mmol), were combined. The reaction mixture was heated at 120° C. After 24 hours, the resultant mixture was cooled and methanol saturated with HCl (2 mL) was added. The product mixture stirred at room temperature for 40 minutes, then was concentrated under vacuum. The residual crude material was diluted with DMSO (6.0 mL) and filtered to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.Br.Br[CH2:26][C:27]([C:29]1[S:33][N:32]=[N:31][C:30]=1[CH3:34])=[O:28]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:26]=1[C:27]([C:29]1[S:33][N:32]=[N:31][C:30]=1[CH3:34])=[O:28]
Reactant: Cc1nnsc1C(=O)CBr
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Agent: Br
Product: COC(=O)Cc1c(C(=O)c2snnc2C)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 5-bromoacetyl-4-methyl-1,2,3-thiadiazole (Preparation is described in Example 228).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[N:27]1([C:33]2[CH:42]=[N:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:30]2[CH2:31][CH2:32][N:27]([C:33]3[CH:42]=[N:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)[CH2:28][CH2:29]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: c1ccc2nc(N3CCNCC3)cnc2c1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3cnc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-piperazin-1-yl-quinoxaline
Reaction SMILES: [CH2:1](S)[CH3:2].[H-].[Na+].[NH2:6][C:7]1[N:12]=[C:11]([NH2:13])[C:10]([CH2:14][C:15]2[CH:20]=[C:19]([O:21]C)[C:18]([C:23]([CH3:25])=[CH2:24])=[C:17]([O:26][CH3:27])[CH:16]=2)=[CH:9][N:8]=1>CN(C)C=O>[NH2:6][C:7]1[N:12]=[C:11]([NH2:13])[C:10]([CH2:14][C:15]2[CH:16]=[C:17]([O:26][CH3:27])[C:18]([C:23]([CH3:25])=[CH2:24])=[C:19]([O:21][CH2:1][CH3:2])[CH:20]=2)=[CH:9][N:8]=1
Reactant: C=C(C)c1c(OC)cc(Cc2cnc(N)nc2N)cc1OC
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)c1c(OC)cc(Cc2cnc(N)nc2N)cc1OCC

Procedure:
A solution of 16.1 ml. of ethylmercaptan in 130 ml. of dimethylformamide was added dropwise while stirring and gassing with nitrogen to a suspension of 10.4 g. of sodium hydride (50%) in 130 ml. of dimethylformamide. After the evolution of gas had ceased, the mixture was stirred at room temperature for an additional 15 minutes and treated with a solution of 13 g. of 2,4-diamino-5-(4-isopropenyl-3,5-dimethoxybenzyl)-pyrimidine in 260 ml. of dimethylformamide. The mixture was stirred at 120° C. for 6 hours. The solvent was removed under a high vacuum. The solid residue was dissolved in water, filtered and the filtrate was adjusted to pH 4 with 1-N hydrochloric acid. The acid solution was then adjusted to pH 8 with ammonia and the solid crude product was isolated in a yield of 98%. Recrystallization from methanol yielded pure 2,4-diamino-5-(3-hydroxy-4-isopropenyl-5-methoxybenzyl)-pyrimidine, having a melting point of 218°-219° C.
Reaction SMILES: C(N1C(C=O)=CN=C1C1CC1)(C)(C)C.N([C:18]1[CH:19]=[C:20]([CH:41]=[CH:42][C:43]=1C)[C:21]([NH:23]C1C=C(C(C)(C)C)C=C(NS(C)(=O)=O)C=1OC)=[O:22])=[N+]=[N-]>>[C:21]([NH2:23])(=[O:22])[C:20]1[CH:41]=[CH:42][CH:43]=[CH:18][CH:19]=1
Reactant: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: CC(C)(C)n1c(C=O)cnc1C1CC1
Product: NC(=O)c1ccccc1

Procedure:
Example 82 benzamide was prepared from 3-tert-butyl-2-cyclopropyl-3H-imidazole-4-carbaldehyde and 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide in the same manner as Example 39. ESI MS m/z 620 [C32H41N7O4S+H]+.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[NH:13][C:12]1=[O:20].[OH-].[Na+]>>[O:20]=[C:12]1[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:21])=[O:2])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[NH:13]1
Reactant: COC(=O)CCCCCCCn1c(=O)[nH]c2ccccc21
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCCCn1c(=O)[nH]c2ccccc21

Procedure:
The product is produced as described in example 22 from 10 g. of 8-(2-oxo-benzimidazolin-1-yl)-caprylic acid methyl ester and 1.44 g. of NaOH.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:18])[CH:14]=2)[CH:9]1[C:19](O)=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:24]=1[NH2:25].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1.O>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:18])[CH:14]=2)[CH:9]1[C:19](=[O:20])[NH:25][C:24]1[C:23]([F:22])=[CH:29][CH:28]=[CH:27][C:26]=1[F:30])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Nc1c(F)cccc1F
Reactant: CC(C)(C)OC(=O)N1CCc2cc(F)ccc2C1C(=O)O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCc2cc(F)ccc2C1C(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.9 %

Procedure:
To a solution of 6-fluoro-3,4-dihydro-1H-isoquinoline-1,2-dicarboxylic acid 2-tert-butyl ester (0.37 g, 1.25 mmol, Eq: 1.00) and 2,6-difluoroaniline (194 mg, 162 μl, 1.5 mmol, Eq: 1.2) in Pyridine (7 mL) at 0° C. was added phosphorus oxychloride (288 mg, 175 μl, 1.88 mmol, Eq: 1.5). The reaction was warmed to RT, stirred for 18 h, diluted with water and extracted with EtOAc. The combined organics were washed with 1 N HCl, water, brine, dried with Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography to afford 0.2181 g 1-(2,6-difluoro-phenylcarbamoyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester as white foam. 42.8% MS m/z 428.9 (M+H)
Reaction SMILES: C([O:4][CH2:5][C:6](=[O:30])[NH:7][C:8]1[S:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=3)[CH:14]=2)=[CH:11][N:12]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:4][CH2:5][C:6]([NH:7][C:8]1[S:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]3[N:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][N:21]=3)[CH:14]=2)=[CH:11][N:12]=1)=[O:30]
Reactant: CC(=O)OCC(=O)Nc1ncc(-c2cccc(Nc3nccc(C(F)(F)F)n3)c2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(CO)Nc1ncc(-c2cccc(Nc3nccc(C(F)(F)F)n3)c2)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.6 %

Procedure:
To a suspension of 2-oxo-2-{[5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]amino}ethyl acetate 1 (8.3 mg, 0.019 mmol) in MeOH (1 mL) at room temperature, under nitrogen, was added potassium carbonate (5.25 mg, 0.038 mmol). The mixture was stirred at room temperature for 18 hours. The mixture was filtered through celite and concentrated to dryness. The product was purified by column chromatography on silica gel (ethanol/ethyl acetatee) to afford 2-hydroxy-N-[5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]acetamide (2.3 mg, 30.7%) as a beige solid. APCI [M+H]+ m/z 396.0. 1H NMR (400 MHz, DMSO): δ 11.86 (s, 1H); 10.31 (s, 1H); 8.86 (d, J=4.9 Hz, 1H); 8.12 (s, 1H); 7.82 (s, 1H); 7.65 (d, J=8.0 Hz, 1H); 7.42-7.23 (m, 3H); 5.55 (t, J=6.3 Hz, 1H); 4.18 (d, J=6.0 Hz, 2H). rhSYK activity=+++
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[O:20][C:19]([CH:21]=O)=[CH:18][CH:17]=3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[CH3:35][S:36]([CH2:39][CH2:40][NH2:41])(=[O:38])=[O:37]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]4[O:20][C:19]([CH2:21][NH:41][CH2:40][CH2:39][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:18][CH:17]=4)[CH:14]=3)[N:9]=[CH:8][N:7]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Reactant: CS(=O)(=O)CCN
Product: CS(=O)(=O)CCNCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1

Procedure:
Prepared according to Procedure D from 5-(4-{3-chloro-4-(3-fluorobenzyloxy)-anilino}-6-quinazolinyl)-furan-2-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). 1H NMR 400 MHz (DMSO-d6) 9.60 (bs, 1H); 9.32 (bs, 1H); 8.82 (bs, 1H); 8.34 (d, 1H); 8.0 (s, 1H); 7.88 (d, 1H); 7.74 (d, 1H); 7.45 (m, 1H); 7.34-7.23 (m, 4H); 7.17 (m, 1H); 6.83 (d, 1H); 5.27 (s, 2H); 4.42 (s, 2H); 3.59 (m, 2H); 3.40 (m, 2H, obscured by waterpeak); 3.12 (s, 3H); MS m/z 581 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[O:8][C:9]3[C:10](=[C:12]([C:16]([OH:18])=O)[CH:13]=[CH:14][CH:15]=3)[N:11]=2)=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:43][C@H:44]1[CH:49]2[CH2:50][CH2:51][N:46]([CH2:47][CH2:48]2)[CH2:45]1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:46]12[CH2:51][CH2:50][CH:49]([CH2:48][CH2:47]1)[C@H:44]([NH:43][C:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:9]3[O:8][C:7]([C:5]4[S:6][C:2]([CH3:1])=[CH:3][CH:4]=4)=[N:11][C:10]=13)=[O:18])[CH2:45]2
Reactant: Cc1ccc(-c2nc3c(C(=O)O)cccc3o2)s1
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc3c(C(=O)N[C@@H]4CN5CCC4CC5)cccc3o2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 12.6 %

Procedure:
A mixture of 2-(5-methylthiophen-2-yl)benzoxazole-4-carboxylic acid (106 mg, 0.41 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (156 mg, 0.82 mmol), 1-hydroxybenzotriazole (110 mg, 0.82 mmol) and (S)-(−)-3-aminoquinuclidine dihydrochloride (101 mg, 0.51 mmol) in DMF (3 mL) was stirred at room temperature for 10 min, then triethylamine (0.23 mL, 1.64 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×50 mL). The combined organic layers were washed with brine (2×50 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) and recrystallization from acetonitrile to afford (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(5-methylthiophen-2-yl)benzoxazole-4-carboxamide (19 mg, 13%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.55 (d, J=7.4 Hz, 1H), 8.15 (dd, J=7.8, 0.9 Hz, 1H), 7.74 (d, J=3.7 Hz, 1H), 7.65 (dd, J=7.2, 1.0 Hz, 1H), 7.42 (t, J=7.9 Hz, 1H), 6.89 (dd, J=3.7, 1.0 Hz, 1H), 4.35-4.30 (m, 1H), 3.55-3.48 (m, 1H), 3.16-3.07 (m, 2H), 2.96-2.91 (m, 2H), 2.86-2.82 (m, 1H), 2.60 (s, 3H), 2.18-2.12 (m, 2H), 1.80-1.75 (m, 2H), 1.71-1.65 (m, 1H); MS (ESI+) m/z 368 (M+H); HPLC 98.0% (AUC), tR=12.40 min.
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6]Br.C(Br)=C.C(=O)=O.[C:14]1([C:20]2[CH:35]=[CH:34][C:23]3[C:24](=[O:33])[C:25]4[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=4[CH2:27][CH2:28][C:22]=3[CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[NH4+]>O1CCCC1>[C:14]1([C:20]2[CH:35]=[CH:34][C:23]3[C:24]([CH:5]=[CH2:6])([OH:33])[C:25]4[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=4[CH2:27][CH2:28][C:22]=3[CH:21]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: BrCCBr
Reactant: O=C1c2ccccc2CCc2cc(-c3ccccc3)ccc21
Agent: C=CBr
Agent: II
Agent: O=C=O
Solvent: C1CCOC1
Product: C=CC1(O)c2ccccc2CCc2cc(-c3ccccc3)ccc21
Temperature: 35 °C
Yield: 86 %

Procedure:
Magnesium turnings (0.45 g, 18.5 mmol) under tetrahydrofuran (5 mL) was activated with grain of iodine and with 1,2-dibromoethane (0.25 mL) and after the reaction was over, a solution of vinyl bromide (2.0 g, 18.5 mmol) in tetrahydrofuran (30 mL) was added (dry ice condenser, nitrogen atmosphere). The reaction start immediately and the remaining part of the vinyl bromide solution was added dropwise under stirring at such a rate as to maintain the mixture under reflux (30 min). The mixture was stirred at 65° C. for next 30 min, cooled to 35° C. and then over 30 min a solution of the above ketone (1.75 g, 6.15 mmol) in tetrahydrofuran (35 mL) was added dropwise. The mixture was stirred at 35° C. for 3 h and then poured on a mixture of crushed ice (100 g) and 25% solution of ammonium chloride (30 mL). The mixture was extracted with diethyl ether (50 mL, 2×20 mL), combined organic solutions were washed with brine, dried (MgSO4) and evaporated in vacuo. The residue (2.5 g) was purified by flash-chromatography on silica gel (Fluka 60, 80 g, hexane/benzene 6:4) to yield 1.65 g (86%) of 2-phenyl-5-vinyl-10,11 dihydro-5H-dibenzo[a,d]cyclohepten-5-ol.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[NH:34][C:33](=[O:35])[O:32][N:31]=3)=[CH:26][CH:25]=2)O1>>[CH2:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[NH:34][C:33](=[O:35])[O:32][N:31]=4)=[CH:26][CH:25]=3)=[CH:3][N:4]=2)[N:7]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CC1(C)OB(c2ccc(-c3noc(=O)[nH]3)cc2)OC1(C)C
Reactant: CCCCNc1ccc2ncc(Br)n2n1
Product: CCCCNc1ccc2ncc(-c3ccc(-c4noc(=O)[nH]4)cc3)n2n1
Yield: 25.3 %

Procedure:
Following the Suzuki coupling conditions described in example 5.6.45 from (3-bromo-imidazo[1,2-b]pyridazin-6-yl)-butyl-amine (213.1 mg, 0.8 mmol), and 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,2,4-oxadiazol-5(4H)-one (308.2 mg, 1.1 mmol) to provide 70.9 mg of 3-[4-(6-butylamino-imidazo[1,2-b]pyridazin-3-yl)-phenyl]-4H-[1,2,4]oxadiazol-5-one as white crystalline powder, mp. 253-254° C. (dec.). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.96 (t, J=7.33 Hz, 3H) 1.44 (sxt, J=7.38 Hz, 2H) 1.65 (quin, J=7.26 Hz, 2H) 3.26-3.35 (m, 2H) 6.75 (d, J=9.85 Hz, 1H) 7.15 (t, J=5.31 Hz, 1H) 7.77 (d, J=9.60 Hz, 1H) 7.88 (m, J=8.84 Hz, 2H) 8.05 (s, 1H) 8.44 (m, J=8.59 Hz, 2H). 13C NMR (100 MHz, DMSO-d6) δ ppm 13.73, 19.89, 30.15, 40.81, 112.82, 120.91, 125.38, 125.50, 126.11, 131.05, 133.01, 137.80, 153.62, 157.06, 159.94. LRMS (ESI) m/z 351.2 [(M+H)]+, calc'd for C18H18N6O2: 350.38.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10](=[O:13])[CH2:11]Br)[S:7][CH:6]=1)=[O:4].[NH2:14][C:15]([NH2:17])=O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[O:13][C:15]([NH2:17])=[N:14][CH:11]=2)[S:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1csc(C(=O)CBr)c1
Reactant: NC(N)=O
Solvent: CN(C)C=O
Product: COC(=O)c1csc(-c2cnc(N)o2)c1
Temperature: 140 °C
Yield: 100.9 %

Procedure:
5-(2-Bromo-acetyl)-thiophene-3-carboxylic acid methyl ester (0.261 g, 0.99 mmol) was dissolved in DMF (4 mL) and urea (0.131 g, 2.18 mmol) was added. The vessel was purged with nitrogen then sealed and heated by microwave irradiation at 140° C. for 10 minutes. The resultant mixture was diluted with water and extracted with ethyl acetate (×3). The organic phase was washed with lithium chloride (15% aqueous solution) then dried over sodium sulfate, filtered and evaporated to give crude 5-(2-amino-oxazol-5-yl)-thiophene-3-carboxylic acid methyl ester as an orange-brown solid (0.224 g).
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH:15][CH2:16][CH2:17][N:18]([CH2:23][CH2:24][OH:25])[C:19](=[O:22])[CH2:20][OH:21]>>[C:1]([O:15][CH2:16][CH2:17][N:18]([CH2:23][CH2:24][O:25][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:19](=[O:22])[CH2:20][O:21][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: O=C(CO)N(CCO)CCO
Product: CCCCCCCCCCCC(=O)OCCN(CCOC(=O)CCCCCCCCCCC)C(=O)COC(=O)CCCCCCCCCCC

Procedure:
This compound was prepared from 131 g (0.6 mole) of lauroyl chloride and 32.6 g (0.2 mole) of N,N-bis(hydroxyethyl)hydroxyacetamide by the procedure of Example 1. Its structure was established by infrared and nuclear magnetic resonance spectroscopy. It was a low-melting solid and had nD30 1.4597 and m.p. 29.6° C.
Reaction SMILES: CO[C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[N:12]2)=[C:7]([Br:16])[N:6]=1)=[O:4].[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[S:26]([N:29]([CH3:31])[CH3:30])(=[O:28])=[O:27].C(N(CC)CC)C.C(O)(=O)C>CCO.CN(C=O)C.O>[Br:16][C:7]1[N:6]=[C:5]([C:3]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[S:26]([N:29]([CH3:31])[CH3:30])(=[O:27])=[O:28])=[O:4])[C:14]([OH:15])=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[N:12]2
Reactant: COC(=O)c1nc(Br)c2cccnc2c1O
Reactant: CN(C)S(=O)(=O)c1cc(F)ccc1CN
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: CN(C)S(=O)(=O)c1cc(F)ccc1CNC(=O)c1nc(Br)c2cccnc2c1O
Temperature: 78 °C

Procedure:
A mixture of 5-bromo-8-hydroxy-1,6-naphthyridine-7-carboxylic acid methyl ester (1.00 g, 3.53 mmol, see Example 113), 2-(aminomethyl)-5-fluoro-N,N-dimethylbenzenesulfonamide (1.64 g, 7.07 mmol), and triethylamine (0.99 mL, 7.07 mmol) in EtOH (8 mL) and DMF (2 mL) was heated to 78° C. overnight. The mixture was cooled to 40° C. and glacial acetic acid (0.81 mL, 14.1 mmol) was added. The mixture was allowed to cool to room temperature and water was added dropwise while sonicating to facilitate the product precipitating out of solution. The solids were collected by vacuum filtration to afford the desired product as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[CH2:21]([OH:24])[C:22]#[CH:23]>O1CCCC1.CCOCC.Cl.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][S:8][C:5]1[CH:6]=[CH:7][C:2]([C:23]#[C:22][CH2:21][OH:24])=[CH:3][CH:4]=1
Reactant: CSc1ccc(Br)cc1
Reactant: C#CCO
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CSc1ccc(C#CCO)cc1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
To a degassed solution of 4-bromothioanisole (10.15 g, 50.0 mmol) in tetrahydrofuran (50 mL) were in the following order added: copper(I) iodide (286 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium (1.73 g, 1.5 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (9.05 mL, 60.0 mmol). The resulting mixture was degassed one more time and a solution of propargyl alcohol (3.5 mL, 60.0 mmol) in tetrahydrofuran (5 mL) was added over period of 10 min. The reaction mixture was slowly heated up to 50° C. and then stirred at this temperature over night (˜20 h). The mixture was diluted with ether (350 mL) and 5% hydrochloric acid (100 mL) was added. The mixture was filtered and the phases were separated. The aqueous phase was extracted with ether (2×60 mL) and collected ethereal solutions were washed with 1 M hydrochloric acid (30 mL) and saturated aqueous solution of sodium hydrogen carbonate (2×50 mL), dried with anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, chloroform) affording 3-(4-methylsulfanylphenyl)prop-2-yn-1-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH:21]=[CH2:22]>C(#N)C>[CH2:22]([O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Cl:1])[CH2:21][CH:20]=[CH2:19]
Reactant: C=CCCBr
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCCOc1ccc([N+](=O)[O-])cc1Cl

Procedure:
To an acetonitrile (40 mL) solution of 2-chloro-4-nitrophenol (2.60 g; 15.0 mmol) and potassium carbonate (2.74 g; 19.8 mmol), 4-bromo-1-butene (2.81 g; 20.4 mmol) was added, and the mixture was refluxed and then reacted overnight. After completion of the reaction, the solution was filtrated by Celite, and then the filtrate was concentrated under a reduced pressure. The residue was purified by flash column chromatography using methylene chloride, and then the effluent was concentrated to obtain 4-(3-butenyloxy)-3-chloronitrobenzene (1 h) (2.32 g, 68% of yield, a light yellow solid, melting point of from 39 to 40° C.) represented by the following formula.