Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12].[CH3:16][O:17][CH2:18]Cl>CC(N(C)C)=O>[CH3:16][O:17][CH2:18][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12]
Reactant: COCCl
Reactant: O=Cc1cccc(O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COCOc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
11.2 g of potassium t-butoxide were added, whilst ice-cooling and stirring, to a solution of 12.0 g of 3-hydroxybenzaldehyde in 100 ml of dimethylacetamide, and, about ten minutes later, 8.05 g of methoxymethyl chloride were added dropwise to the resulting mixture. The reaction mixture was then stirred at room temperature for 1 hour, after which it was partitioned between ethyl acetate and water. The organic layer was concentrated by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 5:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 11.1 g (yield 68%) of 3-methoxymethoxybenzaldehyde as a colorless oil. 10 g of this colorless oil were dissolved in 100 ml of acetonitrile, and 18.3 g of (triphenylphosphoranyldene)acetaldehyde were added to the solution. The resulting mixture was then heated under reflux for 5 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was mixed with a mixture of ethyl acetate and hexane in a proportion of about 2:1 by volume. The mixture was stirred and the resulting precipitates were filtered off. The filtrate was concentrated by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 3:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 7.16 g (yield 62%) of 3-(3-methoxymethoxyphenyl)-2-propenal as a colorless oil.
Reaction SMILES: [CH2:1]([CH:3]1[C:7](=[O:8])[CH2:6][C:5]2([CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[O:4]1)[CH3:2].[SH:15][CH2:16][CH2:17]O.[OH-].[Na+]>ClCCl>[NH3:11].[CH2:1]([CH:3]1[C:7]2([O:8][CH2:17][CH2:16][S:15]2)[CH2:6][C:5]2([CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]2)[O:4]1)[CH3:2]
Reactant: OCCS
Reactant: CCC1OC2(CCN(C)CC2)CC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCC1OC2(CCN(C)CC2)CC12OCCS2
Product: N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution (32 ml) of 0.53 g 2-ethyl-8-methyl-1-oxa-8-azaspiro[4,5]decane-3-one in dichloromethane was cooled in ice, 384 μl 2-mercaptoethanol and 2.05 ml boron trifluoride/ether complex were added in that order in an argon atmosphere, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into 23 ml of 20% aqueous solution of caustic soda, stirring was continued for about 15 minutes, and the two separate layers were collected. The aqueous layer was extracted with chloroform, the extract was joined to the organic layer separated above, and the combined solution was washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The dried solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using, as eluent, a mixed solvent of chloroform/methanol/conc. ammonia (20:1:0.1 by volume), giving 460 mg of 14-ethyl-10-methyl-1,13-dioxa-4-thia-10-aza-dispiro[4,1,5,2]tetradecane as oil. It was then converted to maleate by treatment with maleic acid in isopropanol.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:21])[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[CH2:18]([O:17][C:15]1[C:14]([Cl:21])=[CH:13][C:9]2[CH:10]([CH3:12])[CH2:11][NH:5][CH2:6][CH2:7][C:8]=2[CH:16]=1)[CH:19]=[CH2:20]
Reactant: C=CCOc1cc2c(cc1Cl)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCOc1cc2c(cc1Cl)C(C)CNCC2
Temperature: 20 °C
Reaction time: 8 h
Yield: 114.4 %

Procedure:
A solution of N-trifluoroacetyl-7-allyloxy-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (23 mg, 0.066 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH (2 mL), and stirred overnight at 20° C. The product mixture was diluted with water (5 mL), extracted twice with EtOAc (5 mL), the combined organic phases were washed with brine (5 mL), dried with Na2SO4 and concentrated to give 19 mg of a white solid. 1H NMR (400 MHz, CD3OD) δ 7.12 (s, 1H), 6.81 (s, 1H), 6.03 (m, 1H), 5.43 (d, J=17 Hz, 1H), 5.24 (d, J=10 Hz, 1H), 4.57 (d, J=5 Hz, 2H), 3.1-2.9 (m, 5H), 2.81 (m, 1H), 2.63 (m, 1H), 1.30 (d, J=7 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[C:23]([CH3:32])([CH3:31])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>C(OCC)(=O)C>[C:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][C:23]([CH3:32])([CH3:31])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:3][CH:4]=1)#[N:10]
Reactant: N#CCc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CC#N)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
4-Hydroxyphenylacetonitrile (13.3 g, 100 mmol) and potassium carbonate (20.73 g, 150 mmol) were added to dimethylformamide (75 mL). Subsequently, tert-butyl 2-bromoisobutyrate (50.41 mL, 250 mmol) was added thereto, and the mixture was stirred for 24 hours at 80° C. The temperature of the reaction mixture was returned to room temperature, and ethyl acetate was added thereto. Washing was performed sequentially with water and brine, followed by drying over sodium sulfate. The resultant mixture was subjected to concentration under reduced pressure and purification by silica gel column chromatography (n-hexane/ethyl acetate=7/1), whereby the target compound was obtained (18.62 g, 67.62 mmol, 67.6%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[CH3:13][C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([NH:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]3[CH:30]=[C:31]([C:33](O)=[O:34])[S:32][C:25]=13)=[CH:18][CH:17]=2>>[CH3:13][C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([NH:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]3[CH:30]=[C:31]([C:33]([N:1]4[CH2:5][CH2:4][CH2:3][C@H:2]4[CH2:6][N:7]4[CH2:8][CH2:9][O:10][CH2:11][CH2:12]4)=[O:34])[S:32][C:25]=13)=[CH:18][CH:17]=2
Reactant: Cc1cc2cc(Nc3ccnc4cc(C(=O)O)sc34)ccc2[nH]1
Reactant: C1CN[C@H](CN2CCOCC2)C1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N5CCC[C@H]5CN5CCOCC5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from (S)-4-pyrrolidin-2-ylmethyl-morpholine and 7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridine-2-carboxylic acid by a procedure analogous to Example 21B. MS: 476.3 (MH+); HPLC Rf: 5.378 min.; HPLC purity: 92%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][C:9]1=[O:15].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH3:27][S:28]([O:14][CH2:13][C@@H:11]1[O:10][C:9](=[O:15])[N:8]([CH2:7][CH2:6][O:5][C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]=2[O:2][CH3:1])[CH2:12]1)(=[O:30])=[O:29]
Reactant: COc1ccccc1OCCN1C[C@H](CO)OC1=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1OCCN1C[C@H](COS(C)(=O)=O)OC1=O

Procedure:
Using dichloromethane solution of the compound of formula 2 prepared in Example 2 80.1 g (0.3 mol), triethylamine 45.5 g (0.45 mol) and methanesulfonyl chloride 37.8 g (0.33 mol), the procedures as described in Example 7 were carried out to obtain the targeted product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[C:4]([CH:26]=O)[CH:3]=1.CO.C[O-].[Na+].Cl>C(=O)(OC)OC.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[CH2:9][CH2:10][CH2:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:26][C:4]=2[CH:3]=1
Reactant: COC(=O)CCCCN(Cc1ccc(OC)cc1)c1ccc(Br)cc1C=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: COC(=O)OC
Product: COC(=O)C1=Cc2cc(Br)ccc2N(Cc2ccc(OC)cc2)CCC1
Temperature: 50 °C
Reaction time: 6 h
Yield: 73.5 %

Procedure:
To a solution of methyl 5-((4-bromo-2-formylphenyl)(4-methoxybenzyl)amino)pentanoate (45.7 g) in dimethyl carbonate (900 ml) was added a methanol solution of sodium methoxide (28%, 26.4 g) and then the mixture was stirred at 50° C. under nitrogen atmosphere for 6 hours. The resultant was cooled to 0° C., followed by addition of water, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was recrystallized from hexane-ethyl acetate to give methyl 8-bromo-1-(4-methoxybenzyl)-1,2,3,4-terahydro-1-benzoazocine-5-carboxylate (32.2 g) as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[S:20][C:19]2[C:18]([NH:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[NH:27][CH:26]=[CH:25]4)=[N:17][CH:16]=[N:15][C:14]=2[CH:13]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[S:20][C:19]3[C:18]([NH:21][C:22]4[CH:23]=[C:24]5[C:28](=[CH:29][CH:30]=4)[NH:27][CH:26]=[CH:25]5)=[N:17][CH:16]=[N:15][C:14]=3[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Brc1cc2ncnc(Nc3ccc4[nH]ccc4c3)c2s1
Reactant: OB(O)c1ccc(Cl)cc1
Product: Clc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from p-chlorobenzeneboronic acid and (6-bromo-thieno[3,2-d]pyrimidin-4-yl)-(1H-indol-5-yl)-amine by a procedure analogous to example 2. 1H NMR (400 MHz, DMSO) d 11.4 (s, 1H), 8.86 (s, 1H), 7.58 (m, 9H), 7.21 (d, 1H), 6.50 (s, 1H). M.P. 190-210° C.; LC-MS: 377 (MH+); HPLC RT: 5.32 minutes.
Reaction SMILES: C1C=CC(OCCOC2C=CC=CC=2N(CC(O)=O)CC(O)=O)=C(N(CC(O)=O)CC(O)=O)C=1.[CH:35]1[C:40]([F:41])=[CH:39][C:38]([O:42][CH2:43][CH2:44][O:45][C:46]2[CH:51]=[C:50](F)[CH:49]=[CH:48][C:47]=2[N:53]([CH2:58][C:59]([OH:61])=[O:60])[CH2:54][C:55]([OH:57])=[O:56])=[C:37]([N:62]([CH2:67][C:68]([OH:70])=[O:69])[CH2:63][C:64]([OH:66])=[O:65])[CH:36]=1.[N+](C1C=CC([F:80])=C(F)C=1O)([O-])=O.CC1C=CC(N(CC(O)=O)CC(O)=O)=C(OCCOC2C=C3[CH:109]=[C:110]([C:112]4[O:116][C:115]([C:117]([OH:119])=[O:118])=[CH:114][N:113]=4)[O:111]C3=CC=2N(CC(O)=O)CC(O)=O)C=1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C>>[CH:36]1[C:37]([N:62]([CH2:67][C:68]([OH:70])=[O:69])[CH2:63][C:64]([OH:66])=[O:65])=[C:38]([O:42][CH2:43][CH2:44][O:45][C:46]2[CH:51]=[C:50]3[CH:109]=[C:110]([C:112]4[O:116][C:115]([C:117]([OH:119])=[O:118])=[CH:114][N:113]=4)[O:111][C:49]3=[CH:48][C:47]=2[N:53]([CH2:58][C:59]([OH:61])=[O:60])[CH2:54][C:55]([OH:57])=[O:56])[C:39]([F:80])=[C:40]([F:41])[CH:35]=1
Reactant: O=C(O)CN(CC(=O)O)c1ccc(F)cc1OCCOc1cc(F)ccc1N(CC(=O)O)CC(=O)O
Reactant: Cc1ccc(N(CC(=O)O)CC(=O)O)c(OCCOc2cc3cc(-c4ncc(C(=O)O)o4)oc3cc2N(CC(=O)O)CC(=O)O)c1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1O
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: O=C(O)CN(CC(=O)O)c1ccccc1OCCOc1ccccc1N(CC(=O)O)CC(=O)O
Product: O=C(O)CN(CC(=O)O)c1cc2oc(-c3ncc(C(=O)O)o3)cc2cc1OCCOc1c(N(CC(=O)O)CC(=O)O)ccc(F)c1F

Procedure:
As discussed above, the synthesis of 5,5', 6,6'-tetrafluoro-BAPTA (Formula II) was carried out as originally described for both BAPTA and 5,5'-difluoro BAPTA starting from commercially available 2-nitro-5,6-difluorophenol. Fura-F was synthesized via the pathway originally described for the preparation of Fura-2. Unless otherwise noted commercially available reagents and dry solvents were used as received. Reactions were carried out under an atmosphere of argon and reaction temperatures refer to the bath. Flash column chromatography was performed with Merck Silica Gel 60 (40-63 μm). Proton sponge is 1,8-bis(dimethylamino)naphthalene.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[C:16](=O)([O:18]C1C=CC=CC=1)N.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][C:36]=1[C:37]([F:40])([F:39])[F:38])[NH:33][CH2:32][CH2:31]2>C(OCC)(=O)C>[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][C:36]=1[C:37]([F:40])([F:38])[F:39])[N:33]([C:16](=[O:18])[NH:1][C:2]1[CH:7]=[N:6][C:5]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1)[CH2:32][CH2:31]2
Reactant: COc1cc2c(cc1C(F)(F)F)NCC2
Reactant: Nc1ccc(OCc2ccncc2)nc1
Reactant: NC(=O)Oc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1ccc(OCc3ccncc3)nc1)CC2
Yield: 13 %

Procedure:
5-Amino-2-(pyridin-4-ylmethyloxy)pyridine (0.5 g, 2.5 mmol) was converted to the phenyl carbamate and treated with 5-methoxy-6-trifluoromethylindoline (0.54 g, 2.5 mmol) as in the method of Example 52. Chromatography using ethyl acetate as eluant followed by recrystallisation from ethyl acetate/petroleum ether (60-80°) afforded the title compound (0.13 g, 13%) as an off-white solid m.p. 187-189° C.
Reaction SMILES: [CH2:1]([S:11][C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Mg].II.[C:22](=[O:24])=[O:23].Cl>O1CCCC1.O>[CH2:1]([S:11][C:12]1[CH:17]=[CH:16][C:15]([C:22]([OH:24])=[O:23])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C=O
Reactant: CCCCCCCCCCSc1ccc(Br)cc1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCSc1ccc(C(=O)O)cc1
Temperature: -70 °C

Procedure:
A solution of 4-(decylthio)bromobenzene (32.9 g) in dry tetrahydrofuran (100 ml) was added over about 30 minutes to a stirred, refluxing suspension of magnesium turnings (2.64 g) and one crystal of iodine in dry tetrahydrofuran (100 ml). The mixture was then stirred at reflux for 2 hours after which it was cooled to -70° C. Carbon dioxide was passed through the stirred solution at -70° C. for about 2 hours. The solution was warmed to room temperature and was then poured into a mixture of ice and water (1.251). Hydrochloric acid was added to bring the pH to 1, the precipitate was collected and washed with water, dried and then crystallized from cyclohexane to yield 4-(decylthio)benzoic acid (20.29 g) in the form of white crystals, m.p. 108°-109° C. [Elemental analysis: C,69.2; H,8.9; S,11.1%; calculated: C,69.34; H,8.9; S,10.88%].
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[C:19]([O:23][C:24]([N:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:36][CH2:37][CH3:38])[CH:32]=2)[CH:27]1[C:39]([OH:41])=O)=[O:25])([CH3:22])([CH3:21])[CH3:20].[CH2:42]([O:44][CH2:45][C:46]([C:49]1[C:55]([F:56])=[CH:54][C:52]([NH2:53])=[CH:51][C:50]=1[F:57])([CH3:48])[CH3:47])[CH3:43].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O>[CH2:37]([O:36][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[CH:27]([C:39](=[O:41])[NH:53][C:52]1[CH:51]=[C:50]([F:57])[C:49]([C:46]([CH3:48])([CH3:47])[CH2:45][O:44][CH2:42][CH3:43])=[C:55]([F:56])[CH:54]=1)[N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:35][CH2:34]2)[CH3:38]
Reactant: CCOc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2C(=O)O
Reactant: CCOCC(C)(C)c1c(F)cc(N)cc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOCC(C)(C)c1c(F)cc(NC(=O)C2c3ccc(OCC)cc3CCN2C(=O)OC(C)(C)C)cc1F
Temperature: 60 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
T3P (4.62 mL, 7.85 mmol) was added to a solution of 2-(tert-butoxycarbonyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (841 mg, 2.62 mmol), 4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluoroaniline (600 mg, 2.62 mmol), DIEA (2.285 mL, 13.09 mmol) and DMAP (320 mg, 2.62 mmol) in ethyl acetate (5 mL), and the mixture was stirred at 60° C. overnight. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 3→50% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give tert-butyl 6-ethoxy-1-((4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (700 mg, 1.314 mmol, 50.2%) as white crystals.
Reaction SMILES: [C:1]12([NH:11][C:12]3[N:17]=[C:16](Cl)[CH:15]=[C:14]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[C:1]12([NH:11][C:12]3[N:17]=[C:16]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[CH:15]=[C:14]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: C1CNCCN1
Reactant: Clc1cc(N2CCCC2)nc(NC23CC4CC(CC(C4)C2)C3)n1
Product: c1c(N2CCCC2)nc(NC23CC4CC(CC(C4)C2)C3)nc1N1CCNCC1
Yield: 69.7 %

Procedure:
By reacting 2-(1-adamantylamino)-4-chloro-6-pyrrolidinopyrimidine with piperazine as described in Example 4, the title compound is obtained in a yield of 69.7%, m.p.: 160°-164° C.
Reaction SMILES: [Li][CH2:2]CCC.[CH2:6]([N:9]([CH2:23][CH2:24][CH3:25])[CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[C:20](=O)[CH3:21])[O:12][CH2:11]1)[CH2:7][CH3:8]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)C>[CH2:6]([N:9]([CH2:23][CH2:24][CH3:25])[CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[C:20]([CH3:2])=[CH2:21])[O:12][CH2:11]1)[CH2:7][CH3:8]
Reactant: CCCN(CCC)C1COc2cccc(C(C)=O)c2C1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Product: C=C(C)c1cccc2c1CC(N(CCC)CCC)CO2
Reaction time: 4 h

Procedure:
Methyltriphenylphosphoniumbromide (0.62 g, 1.74 mmol) was dissolved in dry ethyl ether (20 ml) under nitrogen at ambient temperature and n-BuLi (0.7 ml, 2.5M, 1.74 mmol) was added and the solution was stirred for 4 hours. 3-Dipropylamino-5-acetylchroman (Example 7; 0.40 g, 1.45 mmol) was dissolved in dry diethyl ether (2.0 ml) and this solution was added to the previously formed Wittig-reagent.
Reaction SMILES: C(N(CC)CC)C.[C:8]([Si](C)(C)C)#[N:9].[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([C:26]2[S:27][CH:28]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N+:32]=3[O-])[N:30]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH3:25])[CH3:15]>C(#N)C>[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([C:26]2[S:27][CH:28]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:8]#[N:9])[N:32]=3)[N:30]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH3:25])[CH3:15]
Reactant: C[Si](C)(C)C#N
Reactant: CCOc1ccc(-c2nc(-c3cccc[n+]3[O-])cs2)cc1OCC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOc1ccc(-c2nc(-c3cccc(C#N)n3)cs2)cc1OCC

Procedure:
21.3 ml of triethylamine and 30.7 ml of cyanotrimethylsilane were added to a suspension of 26.3 g of 2-[2-(3,4-diethoxyphenyl)-4-thiazolyl]pyridine-1-oxide in 500 ml of acetonitrile. The mixture was refluxed for 62 hours. The solvent in the reaction mixture was removed by distillation. To the residue was added an aqueous sodium carbonate solution. The mixture was subjected to extraction with methylene chloride. The methylene chloride layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by silica gel column chromatography (elutant: methylene chloride) and recrystallized from ethanol to obtain 22.2 g of 2-(3,4-diethoxyphenyl)-4-(6-cyano-2-pyridyl)thiazole.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:13]([O:17][C:18](ON=C(C1C=CC=CC=1)C#N)=[O:19])([CH3:16])([CH3:15])[CH3:14]>O1CCCC1>[C:13]([O:17][C:18]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: NCCCNCc1ccccc1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCNCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.4 %

Procedure:
A solution of N-(3-aminopropyl)benzylamine (38 g, 231.71 mmoles) in dry tetrahydrofuran (300 mL) was cooled to 5° C. in an ice-alcohol bath. To this cold stirred solution 2-[[(tert-butyoxycarbonyl)oxy]imino]-2-phenylacetonitrile (BOC-ON) (56.58 g, 230 mmoles) in dry tetrahydrofuran (300 mL) was added slowly during a 6 hour period. After the addition of BOC-ON, the reaction mixture was stirred at room temperature under argon for an additional 6 hours. The reaction mixture was evaporated to dryness and the residue was dissolved in ether (750 mL). The ether extract was washed with 5% sodium hydroxide solution (4×100 mL), dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was purified by flash column using a chromatograpay over a silica dichloromethane→methanol gradient. The pure fractions were pooled together and evaporated to give 49.5 g (81%) of product as oil: 1H nmr (deuteriochloroform): δ 1.42 (s, 9H, t-Boc), 1.65 (m, 2H, CH2CH2CH2), 2.70 (t, 2H, CH2 NHCH2), 3.20 (m, 2H, BocNHCH2), 3.78 (s, 2H, ArCH2), 5.32 (br s, 1H, BocNH), 7.30 (m, 5H, ArH).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([O:30]CC)=O)[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.[CH3:43][CH:44]([NH2:46])[CH3:45]>>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([NH:46][CH:44]([CH3:45])[CH3:43])=[O:30])[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Reactant: CC(C)N
Product: CC(C)NC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12

Procedure:
Starting materials: Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and propan-2-amine
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[CH:5]=[C:4]2[NH:11][C:12](=[O:22])[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:3]=12.C(N(CC)CC)C.[CH2:30]([C:33]1([S:36](Cl)(=[O:38])=[O:37])[CH2:35][CH2:34]1)[CH:31]=[CH2:32]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:30]([C:33]1([S:36]([N:11]2[C:4]3=[CH:5][C:6]4[O:10][CH:9]=[N:8][C:7]=4[C:2]([F:1])=[C:3]3[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:12]2=[O:22])(=[O:38])=[O:37])[CH2:35][CH2:34]1)[CH:31]=[CH2:32]
Reactant: O=c1[nH]c2cc3ocnc3c(F)c2n1-c1ccc(I)cc1F
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCC1(S(=O)(=O)n2c(=O)n(-c3ccc(I)cc3F)c3c(F)c4ncoc4cc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To a solution of 4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one (100 mg, 0.24 mmol) in DCM (5 mL) was added triethylamine (74 mg, 0.73 mmol) at 0° C. followed by 1-allylcyclopropane-1-sulfonyl chloride (66 mg, 0.36 mmol) and DMAP (15 mg). After stirring at room temperature for 1 h, the mixture was washed with saturated NaHCO3 (aq.). The aqueous layer was extracted with DCM (20 mL×2). The combined organic phase was washed by water (20 mL) and brine (20 mL) sequentially, dried over Na2SO4, filtered and concentrated to give a residue, which was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (120 mg, 89.0% yield). 1H NMR (400 MHz, CDCl3): δ 8.09 (s, 1H), 7.99 (s, 1H), 7.70-7.68 (d, 2H), 7.27 (m, 1H), 5.75-5.58 (m, 1H), 5.05 (m, 2H), 2.90-2.80 (m, 1H), 2.10-2.0 (m, 1H), 1.95-1.86 (m, 2H), 1.25-1.10 (m, 2H).