Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5]C(=O)OC(C)(C)C)[CH2:2]1.CC1C=CC(S(O[C:24]2[C:33]3[CH2:32][CH2:31][CH2:30][C:29]4([CH2:37][CH2:36][CH2:35][CH2:34]4)[C:28]=3[N:27]=[C:26]([NH2:38])[N:25]=2)(=O)=O)=CC=1>>[NH2:5][CH:3]1[CH2:2][N:1]([C:24]2[C:33]3[CH2:32][CH2:31][CH2:30][C:29]4([CH2:37][CH2:36][CH2:35][CH2:34]4)[C:28]=3[N:27]=[C:26]([NH2:38])[N:25]=2)[CH2:4]1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCC32CCCC2)cc1
Product: Nc1nc(N2CC(N)C2)c2c(n1)C1(CCCC1)CCC2

Procedure:
The title compound was prepared according to the procedures of Examples 1G and 1H, substituting tert-butyl azetidin-3-ylcarbamate for the product from Example 1D. 1H NMR (300 MHz, CDCl3) δ 4.49 (br, 2H), 3.33 (m, 4H), 2.38-2.52 (m, 3H), 2.02-2.22 (m, 4H), 1.79-1.93 (m, 2H), 1.53-1.68 (m, 6H). MS (DCI+) m/z 274 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([OH:20])[C:5]=1[O:21][CH3:22])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=1>C(#N)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([O:20][CH2:30][C:31]2[CH:32]=[CH:33][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:35][CH:36]=2)[C:5]=1[O:21][CH3:22])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: CCOc1ccc(-c2cccc3c2CCC3=O)c(O)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1ccc(-c2cccc3c2CCC3=O)c(OCc2ccc(S(C)(=O)=O)cc2)c1OC
Temperature: 80 °C
Yield: 24 %

Procedure:
To a stirring solution of 4-(4-ethoxy-2-hydroxy-3-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.268 mmol) in acetonitrile (7 mL) was added potassium carbonate (111 mg, 0.80 mmol) and 1-(bromomethyl)-4-(methylsulfonyl)benzene (100 mg, 0.402 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 0-30% ethyl acetate in pet ether) afforded title compound as a solid (30 mg, 24%).
Reaction SMILES: N[C:2](N)=[O:3].[CH3:5][C:6]([SiH2:11]Cl)([CH2:9][CH3:10])[CH2:7][CH3:8]>CO>[CH3:5][C:6]([SiH2:11][O:3][CH3:2])([CH2:9][CH3:10])[CH2:7][CH3:8]
Reactant: CCC(C)(CC)[SiH2]Cl
Reactant: NC(N)=O
Solvent: CO
Product: CCC(C)(CC)[SiH2]OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 300 ml 3-necked flask equipped with a magnetic stirrer, a Dimroth condenser and a 50 ml dropping funnel were charged 50 ml of methanol and 4.5 g of urea. To this was added dropwise 7.3 g of 3-methyl-3-(chlorosilyl)pentane obtained above over 15 minutes. After completion of the addition, the resulting mixture was stirred at room temperature for 1 hour while monitoring the reaction by gas chromatography. After evaporation of methanol, the residue was extracted with 60 ml of hexane. The extraction was repeated 3 times. Then, hexane was distilled off and the residue was used for the following reaction.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:20])=[C:9]([CH3:19])[C:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12](=[O:17])[C:11]=2[CH:18]=1)=[O:5]>C1COCC1.CCCCCC>[OH:17][CH:12]1[C:11]2[CH:18]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:21])([CH3:1])[CH3:22])[C:8]([CH3:20])=[C:9]([CH3:19])[C:10]=2[O:14][C:13]1([CH3:16])[CH3:15]
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2O
Yield: 92 %

Procedure:
Using 3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamide obtained in Reference Example 65, the title compound was synthesized in the same manner as in Example 234. Yield: 92%. Melting point: 184-185° C. (THF-hexane).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[C:17]([CH3:28])[CH:16]=1.C(N(CC)CC)C.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:48]1([CH2:51][C:52](O)=[O:53])[CH2:50][CH2:49]1>CN(C)C=O>[CH:48]1([CH2:51][C:52]([N:25]2[CH2:26][CH2:27][CH:22]([O:21][C:18]3[CH:19]=[CH:20][C:15]([NH:14][C:7]4[C:6]5[C:11](=[CH:12][CH:13]=[C:4]([O:3][CH3:2])[CH:5]=5)[N:10]=[CH:9][N:8]=4)=[CH:16][C:17]=3[CH3:28])[CH2:23][CH2:24]2)=[O:53])[CH2:50][CH2:49]1
Reactant: O=C(O)CC1CC1
Reactant: COc1ccc2ncnc(Nc3ccc(OC4CCNCC4)c(C)c3)c2c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2ncnc(Nc3ccc(OC4CCN(C(=O)CC5CC5)CC4)c(C)c3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
To a suspension of (6-Methoxy-quinazolin-4-yl)-[3-methyl-4-(piperidin-4-yloxy)-phenyl]-amine hydrochloride (108mg, 0.251 mmol) in N,N-dimethylformamide (1.0 mL) was added triethylamine (143 μL, 1.03 mmol) and the preformed acyl imidazolide (0.343 mmol). The acyl imidazolide is prepared by mixing CDI (56 mg, 0.343 mmol), DMF (1 mL) and cyclopropylacetic acid (34 mg, 0.343 mmol) and stirring for one hour at ambient temperature. After addition of the acyl imidzolide, the reaction was stirred at room temperature overnight. The reaction was then filtered through a 0.45 μm PTFE membrane filter and purified by preparatory HPLC. 71.4 mg of 2-Cyclopropyl-1-{4-[4-(6-methoxy-quinazolin-4-ylamino)-2-methyl-phenoxy]-piperidin-1-yl}-ethanone was isolated. 1H NMR (300 MHz DMSO d6), δ 9.505 (s, 1H), 8.435 (s, 1H) 7.904 (d, J=9.0, 2.7 Hz, 1H), 7.708 (d, J=9.0 Hz, 1H), 7.552 (dd, J=2.7 Hz, 1H), 7.576-7.511 (m, 2H), 7.480 (dd, J=9.0, 2.7 Hz, 1H), 7.062 (d, J=9.0 Hz, 1H), 4.647-4.600 (m, 1H), 3.951 (s, 3H), 3.951-3.730 (m, 1H), (m, 1H), 3.729-3.645 (m, 1H), 3.442-3.369 (m, 3H), 2.300 (d, J=6.9 Hz, 2H), 2.223 (s, 1H), 1.985-1.882 (m, 2H), 1.692-1.576 (m, 2H) 0.980 (m, 1H), 0.499-0.439 (m, 2H), 0.162-0.113 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][N:5]([CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:6](=[O:17])[CH2:7][N:8]1[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]1=[O:10].[OH-].[Na+]>CO>[C:22]([NH:21][CH2:20][CH2:19][CH2:18][N:5]([C:6](=[O:17])[CH2:7][N:8]1[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]1=[O:10])[CH2:4][C:3]([OH:29])=[O:2])([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]
Reactant: COC(=O)CN(CCCNC(=O)OC(C)(C)C)C(=O)Cn1cc(C)c(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cn(CC(=O)N(CCCNC(=O)OC(C)(C)C)CC(=O)O)c(=O)[nH]c1=O

Procedure:
N-(N'-BOC-3'-aminopropyl)-N-[(1-thyminyl)acetyl]glycine methyl ester (3.02 g, 0.00732 mol) was dissolved in methanol (25 mL) and stirred for 1.5 h with 2M sodium hydroxide (25 mL). Methanol was removed by evaporation in vacuo, and the pH adjusted to 2 with 4M hydrochloric acid at 0° C. The product was isolated as white crystals by filtration, washed with water (3×10 mL), and dried over sicapent, in vacuo. Yield: 2.19 g (75%). Anal. for C17H26N4O7, H2O, found (calc.) C: 49.95 (49.03) H: 6.47 (6.29) N: 13.43 (13.45). The compound showed satisfactory 1H and 13C-NMR spectra.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10].[O:18]1[C:22]([C:23]2[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[CH:21][N:20]=[CH:19]1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:29]([C:26]2[CH:27]=[CH:28][C:23]([C:22]3[O:18][CH:19]=[N:20][CH:21]=3)=[CH:24][CH:25]=2)(=[O:30])=[O:31])=[C:3]([C:9]([C:11]2[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Reactant: Cc1ncccc1C(=O)c1cc(Cl)ccc1N
Product: Cc1ncccc1C(=O)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(-c2cnco2)cc1

Procedure:
The title compound was prepared according to the general procedure using (2-amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone and 4-oxazol-5-yl-benzenesulfonyl chloride and purified by HPLC. MS: m/z 454 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[CH2:33]([O:32][C:30]([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][N:12]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=[CH:11]1)=[O:31])[CH3:34]
Reactant: CCOC(=O)CCCCCCCBr
Reactant: COc1ccc(-c2nc[nH]c2-c2ccc(OC)cc2)cc1
Product: CCOC(=O)CCCCCCCn1cnc(-c2ccc(OC)cc2)c1-c1ccc(OC)cc1
Yield: 83.6 %

Procedure:
4,5-Bis(4-methoxyphenyl)imidazole (1.8 g) (J. Med. Chem., 1974, 17, 1182-8) and ethyl 8-bromooctanoate (3.2 g) were reacted in a method similar to Example 9. Column chromatography on silica gel eluted with a dichloro-methane:ethanol gradient gave 1-(7-ethoxycarbonyl-heptyl)-4,5-bis(4-methoxyphenyl)imidazole (2.42 g, 83%) as an oil. Found: C, 72.30; H, 7.72; N, 6.21%; C27H34N2O4 requires: C, 71.97; H, 7.61; N, 6.22%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:47]=[CH:46][C:45]([S:48]([N:51]2[CH2:56][CH2:55][N:54]([CH2:57][CH3:58])[CH2:53][CH2:52]2)(=[O:50])=[O:49])=[CH:44][CH:43]=1>>[CH2:57]([N:54]1[CH2:53][CH2:52][N:51]([S:48]([C:45]2[CH:46]=[CH:47][C:42]([N:27]3[C:17]4[N:18]=[C:19]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[N:20]=[C:15]([C:12]5[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]6[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=6)[CH2:30][C:31]6[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=6)=[N:14][CH:13]=5)[C:16]=4[CH2:29][CH2:28]3)=[CH:43][CH:44]=2)(=[O:49])=[O:50])[CH2:56][CH2:55]1)[CH3:58]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: CCN1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Product: CCN1CCN(S(=O)(=O)c2ccc(N3CCc4c(-c5cnc(N(Cc6ccc(OC)cc6)Cc6ccc(OC)cc6)nc5)nc(N5CCOCC5)nc43)cc2)CC1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and 1-(4-bromo-benzenesulfonyl)-4-ethyl-piperazine (prepared from 4-bromo-benzenesulfonyl chloride and N-ethylpiperazine in acetonitrile, 68 mg) instead of 4-bromobenzoic acid methyl ester in Example 1-D-08, in the same manner as Example 1-D-08, a crude product of (5-{7-[4-(4-ethyl-piperazine-1-sulfonyl)-phenyl]-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-yl)-bis-(4-methoxy-benzyl)-amine was obtained, and then the PMB groups were removed according to the above Deprotection method 1, to obtain the desired compound (D-96) as an ivory powder (70 mg, 69%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:33]([OH:35])=O)=[C:22]([CH3:32])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]=23)[CH2:3][CH2:2]1.[NH2:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:39][CH2:38]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:33]([NH:36][C@H:37]4[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[CH2:39][CH2:38]4)=[O:35])=[C:22]([CH3:32])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[C:16]=23)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)cc1F
Product: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)cc1F

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c8) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6](=[O:20])[C:7]([CH3:19])=[C:8]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[O:9]2)=[CH:4][CH:3]=1.Br[C:22]1[S:23][CH:24]=[CH:25][N:26]=1.N12CCCN=C1CCCCC2>CN1CCCC1=O>[OH:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6](=[O:20])[C:7]([CH3:19])=[C:8]([CH:13]3[CH2:18][CH2:17][N:16]([C:22]4[S:23][CH:24]=[CH:25][N:26]=4)[CH2:15][CH2:14]3)[O:9]2)=[CH:4][CH:3]=1
Reactant: Brc1nccs1
Reactant: Cc1c(C2CCNCC2)oc2c(C)c(O)ccc2c1=O
Solvent: CN1CCCC1=O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1c(C2CCN(c3nccs3)CC2)oc2c(C)c(O)ccc2c1=O
Temperature: 140 °C
Reaction time: 12 h
Yield: 26.9 %

Procedure:
A solution of 7-hydroxy-3,8-dimethyl-2-(piperidin-4-yl)-4H-chromen-4-one (68 mg, 0.25 mmol) obtained in Example 7-2, 2-bromothiazole (45 μL, 0.28 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (56 μL, 0.38 mmol) in N-methylpyrrolidone (0.2 mL) was heated with stirring at 140° C. for 12 hours. The reaction solution was allowed to cool and then purified by silica gel column chromatography (chloroform/methanol=100/0→95/5) to obtain 24 mg of the title compound (yield: 27%).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C@@:15]([OH:42])([CH2:36][N:37]1[CH:41]=[N:40][CH:39]=[N:38]1)[C@H:16]([N:18]1[C:23](=[O:24])[C:22]2[S:25][C:26]([C:28]3[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=3)=[CH:27][C:21]=2[N:20]=[CH:19]1)[CH3:17].Cl.[NH2:44][OH:45]>O.C1COCC1>[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C@@:15]([OH:42])([CH2:36][N:37]1[CH:41]=[N:40][CH:39]=[N:38]1)[C@H:16]([N:18]1[C:23](=[O:24])[C:22]2[S:25][C:26]([C:28]3[CH:35]=[CH:34][C:31]([CH:32]=[N:33][NH:44][OH:45])=[CH:30][CH:29]=3)=[CH:27][C:21]=2[N:20]=[CH:19]1)[CH3:17]
Reactant: NO
Reactant: C[C@@H](n1cnc2cc(-c3ccc(C#N)cc3)sc2c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](n1cnc2cc(-c3ccc(C=NNO)cc3)sc2c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 61.1 %

Procedure:
To a solution of Na2CO3 (0.84 g, 7.92 mmol) in a mixture of H2O (8 mL) and THF (30 mL) was added (1R,2R)-4-[3-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-6-yl]benzonitrile (0.5 g, 0.99 mmol, obtained in example 32) and hydroxylamine hydrochloride (0.35 g, 1.95 mmol). The mixture was stirred at reflux overnight, concentrated and the aqueous residue was extracted with CHCl3. The organic phase was separated, dried over Na2SO4, filtered and the filtrate concentrated to a solid which was purified by flash chromatography to give the title compound as a pale yellow solid (325 mg, 61%): mp 246°-247° C.; 1H NMR (300 MHz, MeOH-d4) δ (MeOH) 8.60 (s, 1H, N=CH--N), 8.18 (s, 1H, triazole), 7.86 (d, J=8.5, 2H, arom), 7.78 (d, J=8.5, 2H, arom), 7.71 (s, 1H, triazole), 7.66 (s, 1H, thiophene), 7.43 (dt, Jt =6.5, Jd =9, 1H, arom), 7.06 (ddd, Jd =2.5, Jd =8.5, Jd =14, 1H, arom), 6.89 (dt, Jd =2.5, Jt =8.5, 1H, arom), 6.09 (q, J=7.3, 1H, MeCH), 5.09 (d, J=14.2, 1H, CH(H)), 4.19 (d, J=14.2, 1H, CH(H)), 1.32 (d, J=7.3, 3H, CHMe); MS 314 (N-ethylheterocycle, C15H14N4O2S), 224 (Tr--CH2COHAr, C10H8F2N3O); [α]D =+74.9° (c 1, MeOH). Analysis calculated for C25H21F2N7O3S: C 55.86; H 3.94; N 18.24; S 5.96. Found: C 55.10; H 3.84; N 17.72; S 5.69.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:17])[C:5]2[S:10][C:9](=[O:11])[N:8]([CH2:12]/[CH:13]=[CH:14]/[CH2:15]Cl)[C:6]=2[N:7]=1.[P:18]([O:25]CC)([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]>CC#N>[NH2:1][C:2]1[NH:3][C:4](=[O:17])[C:5]2[S:10][C:9](=[O:11])[N:8]([CH2:12]/[CH:13]=[CH:14]/[CH2:15][P:18]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[O:25])[C:6]=2[N:7]=1
Reactant: CCOP(OCC)OCC
Reactant: Nc1nc2c(sc(=O)n2C/C=C/CCl)c(=O)[nH]1
Solvent: CC#N
Product: CCOP(=O)(C/C=C/Cn1c(=O)sc2c(=O)[nH]c(N)nc21)OCC

Procedure:
A mixture of 5-Amino-3-[(E)-4-chloro-2-buten-1-yl]thiazolo[4,5-d]pyrimidine-2,7(3H, 6H)-dione (0.75 g, 2.75 mmol), anhydrous CH3CN (75 mL) and triethyl phosphite (10 mL) was stirred and heated at reflux for 6 days while adding additional quantities of triethyl phosphite (2×5 mL) at 2 day intervals. The mixture was evaporated and the residue was dissolved in CH2Cl2 (50 mL). The solution was applied to a silica gel column (5.5×20 cm) and the column was flash eluted with progressively increasing concentrations of MeOH in CH2Cl2 (%MeOH, vol in L): (0, 1), (1, 1), (2, 1), (3, 3), (5, 2), (10, 1). The eluate containing the product was evaporated and the solid residue was dried in vacuum for 16 h. The light yellow solid was stirred with 2-PrOH (10 mL) to obtain a white solid. The solid was collected and dried in vacuum at 85° C. for 3 days; 0.38 g (1.02 mmol, 37%), mp 191-192° C. Ir (KBr): ν3420, 3300 and 3190 (NH, NH2), 1690 (C=O), and 1666 broad (C=O, C=N, C=C) cm1. Uv, λmax (nm) (ε×10-3): pH 1, 302 (9.6), 250 (8.71), 220 (29.5); MeOH, 302 (9.00), 250 (8.55), 220 (29.0); pH 11, 292 (7.61), 248 (7.77), 224 (10.1). 1H nmr (DMSO-d6): δ1.17 (t, 6H, 2 CH3), 2.63 (dd, 2H, PCH2), 3.93 (q, 4H, OCH2), 4.34 (br s, 2H, NCH2), 5.43-5.49 (m, 1H, CH), 5.67-5.73 (m, 1H, CH), 6.95 (br s, 2H, NH2), and 11.14 (br s, 1H, NH). Anal. Calc'd for C13H19N4O5PS (374.35): C, 41.71; H, 5.11; N, 14.97; P, 8.27. Found: C, 41.68; H, 4.93; N, 15.01; P, 8.11.
Reaction SMILES: [Na].Cl[C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][S:6][N:7]=1.[CH2:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][S:6][N:7]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Clc1nsnc1-c1cccnc1
Reactant: OCc1ccccc1
Agent: [Na]
Product: c1ccc(COc2nsnc2-c2cccnc2)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of sodium (490 mg, 2.5 mmol) in benzyl alcohol (15 ml) was added 3-(4-chloro-1,2,5-thiadiazol-3-yl)-pyridine (490 mg, 2.5 mmol). The mixture was stirred at 50° C. for 2 h and evaporated. The residue was dissolved in water and extracted with ether. The combined organic phases were dried and evaporated to give the wanted compound.
Reaction SMILES: [CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)=[O:4].[NH:16]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]2[CH:23]=[CH:24][CH:25]=[CH:26][C:17]1=2.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][O:2][C:3](=[O:4])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[CH:9][C:10]([C:11]([N:16]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]3[CH:23]=[CH:24][CH:25]=[CH:26][C:17]2=3)=[O:13])=[CH:14][CH:15]=1
Reactant: COC(=O)/C=C/c1ccc(C(=O)O)cc1
Reactant: c1ccc2c(c1)CCCCN2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc(C(=O)N2CCCCc3ccccc32)cc1
Yield: 48 %

Procedure:
WSCD (1.17 g, 6.16 mmol) was added to a solution of 4-((E)-2-methoxycarbonyl-vinyl)-benzoic acid from Example E65.1 (740 mg, 3.59 mmol), 2,3,4,5-tetrahydro-1H-benzo[b]azepine (445 mg, 3.02 mmol) and DMAP (370 mg, 3.02 mmol) in dichloromethane (40 ml) and triethylamine (0.7 ml, 5.02 mmol). The mixture was heated at reflux for 42 h then solvents were concentrated in vacuo. The residue was dissolved in EtOAc, washed with 1M KHSO4 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 30% EtOAc:70% pet. ether) to yield the title compound (484 mg, 48%).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][O:21][CH2:20]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl.O1CCOCC1.[OH-].[Na+]>CO>[NH2:27][C:8]1[N:7]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][O:21][CH2:20]1
Reactant: CCCCNc1nc(N)c2nc(OC)n(CCCCC3CCCOC3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CCCCNc1nc(N)c2[nH]c(=O)n(CCCCC3CCCOC3)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 51.3 %

Procedure:
To a solution of N2-butyl-8-(methoxy)-9-[4-(tetrahydro-2H-pyran-3-yl)butyl]-9H-purine-2,6-diamine (172 mg) in methanol (15.2 ml) at room temperature was added 4.0M hydrogen chloride in 1,4-dioxane (2.86 ml, 11.42 mmol) to give a colourless solution. The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was neutralised with 2M NaOH and concentrated in vacuo to give a white solid. This solid was triturated in water and filtered under vacuum to give an off-white solid (85 mg).
Reaction SMILES: [Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)C=CC=CC=1.[O:28]=[C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH:39]=O)=[CH:31][NH:30]1.O>C1COCC1>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH:9]=[CH:39][C:32]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:29](=[O:28])[NH:30][CH:31]=2)[CH:11]=1
Reactant: O=Cc1c[nH]c(=O)c2ccccc12
Reactant: c1ccc([P+](Cc2cccnc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]cc(C=Cc2cccnc2)c2ccccc12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Under an N2 atmosphere,147 g (377 mmol) of triphenyl-(pyridin-3-yl-methyl)-phosphonium chloride in 2.2 l of THF are mixed with 44.1 g (393 mmol) of potassium-tert-butylate and stirred for 30 min. The suspension is heated to 50° C. and a mixture of 50.0 g (289 mmol) of 1-oxo-1,2-dihydro-isoquinoline-4-carbaldehyde and 2.2 l of THF is added dropwise and finally stirred for 10 h at 60° C. To the cooled reaction mixture is added 700 ml of water and then the THF is evaporated off on a RE. The residue is taken up in 5 l of water and 8 l of EtOAc, the water phase is separated and extracted 3 more times with EtOAc. The organic phases are washed with water and with brine, combined, dried (Na2SO4) and left to stand over night. A solid separates from the mixture and is filtered off and washed with EtOAc [→(E) 4-[2-(pyridin-3-yl)-vinyl]-2H-isoquinolin-1-one]. The filtrate is extracted twice with 1 N HCl and then discarded. The acidic aqueous phases are immediately rendered basic with sat. Na2CO3 solution and extracted 3 times with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2, EtOAc/ethanol 19:1→9:1) yields first of all (Z) 4-[2-(pyridin-3-yl)-vinyl]-2H-isoquinolin-1-one, followed by an (E/Z) mixture of 4-[2-(pyridin-3-yl)-vinyl]-2H-isoquinolin-1-one. (E) 4-[2-(pyridin-3-yl)-vinyl]-2H-isoquinolin-1-one: m.p. 222-224° C.; 1H NMR (DMSO-d6) δ11.57 (sb, HN), 8.80 (s, 1H), 8.44 (d, 1H), 8.26 (d, 1H), 8.12 (m, 2H, m), 7.79 (t, 1H), 7.68 (d, J=16.3 Hz, 1H), 7.56 (m, 2H), 7.39 (dd, 1H), 7.07 (d, J=16.3 Hz 1H). (Z) 4-[2-(pyridin-3-yl)-vinyl]-2H-isoquinolin-1-one: 1H NMR (DMSO-d6) δ11.24 (sb, HN), 8.39 (s, 1H), 8.32 (d, 1H), 8.25 (d, 1H), 7.71 (t, 1H), 7.65 (d, 1H), 7.54 (m, 2H), 7.21 (dd, 1H), 6.90 (s, 1H), 6.81 (s, 2HOlef.).