Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]12[CH2:11][CH:7]3[CH2:8][CH:9]([CH2:10]1)[C:5]([NH2:12])([CH2:6]3)[CH2:4]2.Cl[CH2:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]#[N:23])=[O:16].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOC(C)=O>[CH3:1][O:2][C:3]12[CH2:11][CH:7]3[CH2:8][CH:9]([CH2:10]1)[C:5]([NH:12][CH2:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]#[N:23])=[O:16])([CH2:6]3)[CH2:4]2
Reactant: COC12CC3CC(C1)C(N)(C3)C2
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC12CC3CC(C1)C(NCC(=O)N1CCC[C@H]1C#N)(C3)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.6 %

Procedure:
To a stirred solution of the amino compound obtained by step V (0.16 g, 0.95 mmol) in DMSO (4.0 mL) was added (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.17 g, 0.96 mmol) and K2CO3 (0.4 g, 2.9 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. The reaction mixture was diluted with EtOAc and washed with water ad brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-{[(1-methoxytricyclo[3.3.1.03,7]non-3-yl)amino]acetyl}pyrrolidine-2-carbonitrile (0.12 g) in 41% yield. m/z (M+1) 304; 1H NMR (CDCl3) 300 MHz δ 4.82-4.75 (m, 1H), 3.75-3.40-m, 4H), 3.27 (s, 3-H), 2.47-2.40 (m, 1H), 2.35-1.68 (13H), 1.57-1.41 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[F:7][C:8]1[CH:20]=[C:19](F)[C:18]([F:22])=[CH:17][C:9]=1[C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[O:11].O>CS(C)=O.CCOC(C)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:2]([O:4][C:19]1[C:18]([F:22])=[CH:17][C:9]([C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[O:11])=[C:8]([F:7])[CH:20]=1)([CH3:5])([CH3:3])[CH3:1]
Reactant: CC(C)(C)[O-]
Reactant: CS(=O)(=O)NC(=O)c1cc(F)c(F)cc1F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)Oc1cc(F)c(C(=O)NS(C)(=O)=O)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.7 %

Procedure:
Potassium tert-butoxide (1.46 g, 13.0 mmol) was added to a solution of 2,4,5-trifluoro-N-(methylsulfonyl)benzamide (Preparation 27, 1.5 g, 5.924 mmol) in DMSO (10 mL) and stirred at room temperature. After 3 hours, potassium tert-butoxide (140 mg, 1.3 mmol) was further added and stirred for 18 hours more. The reaction mixture was diluted with EtOAc and 10% aqueous citric acid solution. The pH of the water layer was acidic. The organic layer was washed with more 10% aqueous citric acid and brine, then dried over magnesium sulfate, filtered and concentrated in vacuo to yield the title compound as a cream solid (1.76 g, 100%):
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:18]=[CH:19]/[CH:20]=[CH:21]/[C:22]([NH:24][CH2:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][CH:31]([C:34]3[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[NH:36][CH:35]=3)[CH2:30][CH2:29]2)=[O:23])[CH:6]=[C:7]([O:16][CH3:17])[C:8]=1[O:9]COCCOC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[OH:9][C:8]1[C:7]([O:16][CH3:17])=[CH:6][C:5](/[CH:18]=[CH:19]/[CH:20]=[CH:21]/[C:22]([NH:24][CH2:25][CH2:26][CH2:27][N:28]2[CH2:29][CH2:30][CH:31]([C:34]3[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[NH:36][CH:35]=3)[CH2:32][CH2:33]2)=[O:23])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COCCOCOc1c(OC)cc(/C=C/C=C/C(=O)NCCCN2CCC(c3c[nH]c4ccccc34)CC2)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(/C=C/C=C/C(=O)NCCCN2CCC(c3c[nH]c4ccccc34)CC2)cc(OC)c1O
Temperature: 25 °C
Yield: 36 %

Procedure:
A mixture of 1-[3-[5-[3,5-dimethoxy-4-{(2-methoxyethoxy)methoxy}phenyl]-(2E,4E)-2,4-pentadienoylamino]propyl]-4-(3-indolyl)piperidine (1.67 g) and p-toluenesulfonic acid monohydrate (0.64 g) in methanol (33 ml) was refluxed for 30 minutes under an inert atmosphere. Upon cooling to ambient temperature, the mixture was added dropwise to an aqueous sodium carbonate solution. The resulting powder was subjected to column chromatography on silica gel and eluted with a mixture of chloroform and methanol (10:1 V/V). The fractions containing the object compound were combined and concentrated under reduced pressure. The obtained residue was recrystallized from a mixture of ethanol and water (7:3 V/V) to give 1-[3-{5-(4-hydroxy-3,5-dimethoxyphenyl)-(2E,4E)-2,4-pentadienoylamino}propyl]-4-(3-indolyl)piperidine (0.51 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][CH:8]=[C:7]2Cl)(=[O:3])[NH2:2].[OH:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2.C(N(C(C)C)CC)(C)C.CN1CCCC1=O>CS(C)=O>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][CH:8]=[C:7]2[O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2)(=[O:3])[NH2:2]
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: COc1cc2nccc(Cl)c2cc1C(N)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CN1CCCC1=O
Product: COc1cc2nccc(Oc3ccc4[nH]ccc4c3)c2cc1C(N)=O
Temperature: 150 °C
Reaction time: 5 h
Yield: 45.8 %

Procedure:
After mixing 6-carbamoyl-4-chloro-7-methoxyquinoline (2.0 g, 8.4509 mmol), 5-hydroxyindole (1.68 g), diisopropylethylamine (2.2 ml) and N-methylpyrrolidone (2.2 ml), the mixture was heated and stirred at 150° C. for 5 hours. After cooling, the partly solidified reaction mixture was dissolved in dimethylsulfoxide and then adsorbed onto NH silica gel and purified by NH silica gel column chromatography (ethyl acetate-methanol system). The obtained crystals were suspended in ethanol, the suspension was diluted with diethyl ether and hexane, and the crystals were filtered out, washed with diethyl ether:hexane=1:5 and dried by aspiration to obtain the title compound (1.291 g, 3.8698 mmol, 45.79%) as light yellow crystals.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[N:28]1([C:33]([C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[NH2:37])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:28]1([C:33]([C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[NH:37][C:2]2[C:7]([C:8]([F:10])([F:9])[F:11])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=3)[N:3]=2)=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Reactant: Nc1ccccc1C(=O)N1CCCC1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)N3CCCC3)n2)cc1)OCC

Procedure:
The title product was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate and the commercially available 2-(pyrrolidin-1-ylcarbonyl)aniline. MS (ES+): m/z 578.34 (100) [MH+]; HPLC: tR=1.02 min (UPLC, purity).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH3:8].[C:9]([O:13][C:14](=[O:37])[NH:15][C:16]([C:18]1[S:19][C:20]([S:35][CH3:36])=[C:21]([S:23]([C:26]2[CH:31]=[CH:30][C:29](O)=[C:28](B)[C:27]=2O)(=[O:25])=[O:24])[CH:22]=1)=[NH:17])([CH3:12])([CH3:11])[CH3:10].C(O)C.C1(C)C=CC=CC=1>C([O-])([O-])=O.[Na+].[Na+].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.CCOC(C)=O>[C:9]([O:13][C:14](=[O:37])[NH:15][C:16](=[NH:17])[C:18]1[S:19][C:20]([S:35][CH3:36])=[C:21]([S:23]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]([C:2]3[CH:7]=[CH:6][N:5]=[CH:4][C:3]=3[CH3:8])[CH:31]=2)(=[O:25])=[O:24])[CH:22]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: Cc1cnccc1Br
Reactant: Bc1c(O)ccc(S(=O)(=O)c2cc(C(=N)NC(=O)OC(C)(C)C)sc2SC)c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2ccncc2C)c1
Yield: 410 %

Procedure:
4-Bromo-3-methyl-pyridine (100 mg, 0.219 mmol, Example 138: step b), {[4-(3-Boranyl-dihydroxy-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (266 mg, 0.58 mmol, Example 140: step a) and Pd(PPh3)4 (134 mg, 0.12 mmol) were combined in aqueous Na2CO3 (2M, 2 mL), ethanol (2 mL) and toluene (4 mL) and heated to 80° C. overnight. The reaction mixture was dissolved into EtOAc and washed with brine. The organic layers were dried (MgSO4) and the solvent was removed in vacuo. Purification by flash column chromatography (10% DCM/MeOH) afforded the title compound (120 mg, 410%). ESI-MS (m/z): Calcd. for C23H25N3O4S3: 504.1 (M+1); found: 503.7.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[CH:16](N)=[NH:17]>C(O)C>[F:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:17][CH:16]=[N:1]2)=[CH:7][CH:8]=1
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: N=CN
Solvent: CCO
Solvent: CC(=O)O
Product: O=c1[nH]cnc2cc(F)ccc12
Yield: 82.4 %

Procedure:
25.0 g (0.156 mol) of 2-amino-4-fluorobenzoic acid and 33.0 g (0.317 mol) of formamidine acetate were suspended in 250 ml of ethanol. The reaction mixture was subsequently stirred under reflux for 16 h. Conventional work-up gave 21.1 g (Y=82%) of 7-fluoro-3H-quinazolin-4-one.
Reaction SMILES: [CH3:1][C@H:2]1[O:18][C:16](=[O:17])[CH2:15][C@@H:14]([O:19][C:20]([CH3:22])=[O:21])[C@H:13]([O:23][CH3:24])[C@@H:12]([O:25][C@@H:26]2[O:31][C@H:30]([CH3:32])[C@@H:29]([O:33][C@@H:34]3[O:39][C@@H:38]([CH3:40])[C@H:37]([O:41][C:42]([CH2:44][CH:45]([CH3:47])[CH3:46])=[O:43])[C@@:36]([OH:49])([CH3:48])[CH2:35]3)[C@H:28]([N:50]([CH3:52])[CH3:51])[C@H:27]2[OH:53])[C@@H:11]([CH2:54][CH:55]=[O:56])[CH2:10][C@@H:9]([CH3:57])[C@@H:8]([OH:58])[CH:7]=[CH:6][CH:5]=[CH:4][CH2:3]1.C(Cl)Cl>CS(C)=O.C(N(CC)CC)C>[CH3:1][C@H:2]1[O:18][C:16](=[O:17])[CH2:15][C@@H:14]([O:19][C:20]([CH3:22])=[O:21])[C@H:13]([O:23][CH3:24])[C@@H:12]([O:25][CH:26]2[O:31][CH:30]([CH3:32])[CH:29]([O:33][CH:34]3[O:39][CH:38]([CH3:40])[CH:37]([O:41][C:42]([CH2:44][CH:45]([CH3:46])[CH3:47])=[O:43])[C:36]([OH:49])([CH3:48])[CH2:35]3)[CH:28]([N:50]([CH3:52])[CH3:51])[CH:27]2[OH:53])[C@@H:11]([CH2:54][CH:55]=[O:56])[CH2:10][C@@H:9]([CH3:57])[C:8](=[O:58])[CH:7]=[CH:6][CH:5]=[CH:4][CH2:3]1
Reactant: CO[C@@H]1[C@@H](O[C@@H]2O[C@H](C)[C@@H](O[C@H]3C[C@@](C)(O)[C@@H](OC(=O)CC(C)C)[C@H](C)O3)[C@H](N(C)C)[C@H]2O)[C@@H](CC=O)C[C@@H](C)[C@@H](O)C=CC=CC[C@@H](C)OC(=O)C[C@H]1OC(C)=O
Agent: CO[C@@H]1[C@@H](OC2OC(C)C(OC3CC(C)(O)C(OC(=O)CC(C)C)C(C)O3)C(N(C)C)C2O)[C@@H](CC=O)C[C@@H](C)C(=O)/C=C/C=C/C[C@@H](C)OC(=O)C[C@H]1OC(C)=O
Agent: CO[C@@H]1[C@@H](O[C@@H]2O[C@H](C)[C@@H](O[C@H]3C[C@@](C)(O)[C@@H](OC(=O)CC(C)C)[C@H](C)O3)[C@H](N(C)C)[C@H]2O)[C@@H](CC=O)C[C@@H](C)[C@@H](O)/C=C/C=C/C[C@@H](C)OC(=O)C[C@H]1OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CO[C@@H]1[C@@H](OC2OC(C)C(OC3CC(C)(O)C(OC(=O)CC(C)C)C(C)O3)C(N(C)C)C2O)[C@@H](CC=O)C[C@@H](C)C(=O)C=CC=CC[C@@H](C)OC(=O)C[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
10.0 g (12.1 mmol) of leucomycin A3, also known as josamycin, are dissolved in 30 ml of DMSO and 15 ml of triethylamine. To the solution thereby obtained, 5.6 g of sulfur trioxide/pyridine complex (36.3 mmol), dissolved in 40 ml of DMSO, are added at room temperature and under a nitrogen atmosphere. The reaction medium is stirred at room temperature for 3 hours. Approximately 200 g of ice are added and the mixture is filtered: the product thereby obtained is taken up with methylene chloride and the organic phase is washed three times with water; the organic phase is dried over sodium sulfate, filtered and evaporated to dryness. The residue thereby obtained is purified by flash chromatography on a silica column; eluant: CH2Cl2 /MeOH/NH4OH (300:5:0.25). 3.6 g of carbomycin B are obtained.
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].[Na].[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][C:15]([CH3:17])=[O:16]>CCOCC.CCOC(C)=O>[CH2:20]([O:19][C:13](=[O:18])[CH:14]([C:15](=[O:16])[CH3:17])[CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][N+:1]([O-:3])=[O:2])[CH3:21]
Reactant: O=[N+]([O-])C=Cc1ccccc1
Reactant: CCOC(=O)CC(C)=O
Agent: [Na]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(C)=O)C(C[N+](=O)[O-])c1ccccc1
Reaction time: 1 h
Yield: 106.8 %

Procedure:
To a solution of (2-nitro-vinyl)-benzene (2.135 g, 14.3 mmol) in ether (30 mL) at 0° C. was added ethyl acetoacetate sodium salt (2.29 g, 14.3 mmol) portionwise in half minute; after addition, the mixture was stirred at that temperature for 1 hour; then it was diluted with EtOAc, washed with diluted hydrochloride aqueous solution and saturated sodium chloride aqueous solution respectively, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, oil-pumped to dryness to give a brown oil, the crude titled product (4.266 g); 1H NMR (200 MHz, CDCl3): δ (ppm)=7.4-7.2 (m, 5H), 4.73 (d, 1H, J=5.9 Hz), 4.2-3.9 (m, 4H), 2.30 (s, 3H), 1.01 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([N:16]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:25])[CH2:12][C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:39][OH:40]>O1CCCC1>[OH:40][NH:39][C:13](=[O:14])[CH2:12][CH:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[N:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:25]
Reactant: COc1ccc(C(CC(=O)O)N2Cc3ccccc3C2=O)cc1OC
Reactant: NO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc(C(CC(=O)NO)N2Cc3ccccc3C2=O)cc1OC
Yield: 78.3 %

Procedure:
N-Hydroxy-3-(3,4-dimethoxyphenyl)-3-(1-oxoisoindolinyl)propionamide was prepared by the procedure of Example 1 from 3-(3,4-dimethoxyphenyl)-3-(1-oxoisoindolinyl)propanoic acid (5.00 g, 14.7 mmol), carbonyldiimidazole (2.49 g, 15.4 mmol) and hydroxylamine hydrochloride (1.30 g, 19.1 mmol) in tetrahydrofuran (15 mL) to afford N-hydroxy-3-(3,4-dimethoxyphenyl)-3-(1-oxoisoindolinyl)propionamide as a white solid (4.1 g, 79% yield): mp, 188.5-189.5° C.; 1H NMR (DMSO-d6) δ2.82-2.87 (m, 2H, CH2), 3.71 (s, 3H, CH3), 3.74 (s, 3H, CH3), 4.15 (d, J=17.5 Hz, NCHH), 4.63 (d, J=17.5 Hz, 1H, NCHH), 5.74 (t, J=7.7 Hz, 1H, NCR), 6.85-6.93 (m, 3H, Ar), 7.45-7.69 (m, 4H, Ar), 8.83 (br s, 1H, OH), 10.60 (1H, NH); 13C NMR (DMSO-d6) δ35.11, 46.26, 51.25, 55.50, 111.09, 111.76, 119.19, 122.79, 123.43, 127.84, 131.29, 131.91, 132.27, 141.68, 148.27, 148.69, 166.03, 166.84; Anal Calcd for C19H20N2O5: C, 64.04; H, 5.66; N, 7.86. Found: C, 64.08; H, 5.55; N, 7.86.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[N:6][CH:7]=1.C(O[CH:23](OCC)[CH2:24][O:25][C:26]1[CH:27]=[CH:28][C:29](F)=[N:30][CH:31]=1)C.[NH:36]1[CH2:39][CH2:38][CH2:37]1>>[N:36]1([CH2:23][CH2:24][O:25][C:26]2[CH:27]=[CH:28][C:29]([O:19][C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[N:12]=[CH:11][N:10]=[C:9]4[NH:8][C:5]3[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=3)=[N:30][CH:31]=2)[CH2:39][CH2:38][CH2:37]1
Reactant: Cc1cnc(Nc2ncnc3ccc(O)cc23)cn1
Reactant: C1CNC1
Reactant: CCOC(COc1ccc(F)nc1)OCC
Product: Cc1cnc(Nc2ncnc3ccc(Oc4ccc(OCCN5CCC5)cn4)cc23)cn1

Procedure:
Using 4-[(5-methylpyrazin-2-yl)amino]quinazolin-6-ol, 5-(2,2-diethoxyethoxy)-2-fluoropyridine and azetidine, and in the same manner as in Example 31 or according to a method similar to it or according to a combination thereof with an ordinary method, the entitled compound (22 mg) was obtained as a pale yellow solid.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[S:11][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:14]=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.O1CCCC1>[CH2:18]([O:17][C:15]([C:12]1[S:11][C:10]([C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:14][CH:13]=1)=[O:16])[CH3:19]
Reactant: CCOC(=O)c1cnc(Br)s1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(C#Cc2ccccc2)s1
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
A solution of phenylacetylene (6.15 ml, 55.9 mmol), ethyl 2-bromothiazole-5-carboxylate (7.59 ml, 50.8 mmol), bis(triphenylphosphine)palladium(II) chloride (1.07 g, 1.52 mmol), copper (I) iodide (581 mg, 3.05 mmol), triethylamine (100 ml, 717 mmol) and tetrahydrofuran (225 mL) was stirred at 25° C. for 16 h. The reaction was worked up by concentrating to remove the THF and taken up in 400 mL of CHCl3. The CHCl3 was washed with 2×75 mL of 3.7% aq. HCl, 75 mL of brine, and dried (Na2SO4). The material was purified by silica gel chromatography using a gradient elution going from 4.5% to 8.5% EtOAc in hexanes over 30 minutes to give the titled compound, 2-phenylethynyl-thiazole-5-carboxylic acid ethyl ester (9.5 g, 73% yield), as a solid, which was used without further purification in the next step.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[C:10]3[CH:17]=[C:16]([C@@H:18]4[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:21]([OH:22])[C@H:19]4[OH:20])[CH:15]=[CH:14][C:11]=3[S:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:30]([O:32][CH2:33][CH3:34])=[O:31].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CC1C=C(C)C=C(C)N=1>[C:1]1([CH2:7][CH2:8][C:9]2[C:10]3[CH:17]=[C:16]([C@@H:18]4[O:26][C@H:25]([CH2:27][O:28][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C@@H:23]([OH:24])[C@H:21]([OH:22])[C@H:19]4[OH:20])[CH:15]=[CH:14][C:11]=3[S:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)Cl
Reactant: OC[C@H]1O[C@@H](c2ccc3scc(CCc4ccccc4)c3c2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1cc(C)nc(C)c1
Product: CCOC(=O)OC[C@H]1O[C@@H](c2ccc3scc(CCc4ccccc4)c3c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of 1-[3-(2-phenylethyl)benzo[b]-thiophen-5-yl]-1-deoxy-β-D-glucopyranose (0.19 g) in 2,4,6-trimethylpyridine (2 mL) was added ethyl chloroform ate (1.1 mL) at 0° C., and the mixture was stirred at room temperature for 7 hours. The reaction mixture was poured into 10% citric acid aqueous solution, and the mixture was extracted with ethyl acetate. The organic layer washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1) to give the title compound (0.16 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]=[CH:14][CH:15]=[C:16]([SH:17])[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:24][O:25][C:26]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)=[O:27]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]=[CH:14][CH:15]=[C:16]([S:17][C:32](=[O:33])[C:31]3[CH:30]=[CH:29][C:28]([C:26]([O:25][CH3:24])=[O:27])=[CH:36][CH:35]=3)[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)c1cnc2c(S)cccn2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cnc2c(SC(=O)c3ccc(C(=O)OC)cc3)cccn2c1=O
Yield: 87 %

Procedure:
To a mixture of 30 g of 3-ethoxycarbonyl-9-mercapto-4H-pyrido[1,2-a]pyrimidin-4-one II-1, 2.49 g of powdery potassium carbonate and 500 ml of acetone is added 23.8 g of 4-methoxycarbonylbenzoyl chloride with stirring, and the resultant mixture is stirred at room temperature for 1 hour. The reaction mixture is concentrated to dryness in vacuo and the residue is distributed in water-chlofororm. The chloroform layer is washed with saturated brine, dried over sodium sulfate and concentrated in vacuo. The residue is recrystallized from ethyl acetate to give 43 g of the titled compound Ie-66.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=O)[NH:8][CH:7]=[N:6]2.O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:9]1[C:10]2=[C:2]([CH3:1])[CH:3]=[CH:4][N:5]2[N:6]=[CH:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccn2nc[nH]c(=O)c12
Product: Cc1ccn2ncnc(Cl)c12
Temperature: 100 °C
Yield: 82 %

Procedure:
A suspension of of 5-methyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (2.57 gm, 17.2 mmole) in POCl3 (28 mL) was heated at 100° C. for 40 min. The excess reagent was removed under vacuum and the residue was dissolved in DCM (300 mL). This was washed with water, dried (Na2SO4), and the solvent removed. Flash chromatography on silica gel using DCM as eluent afforded the product as a yellow solid (2.38 gm, 82%). 1HNMR (CDCl3): δ 2.63 (s, 3H), 6.74 (d, 1H, J=2 Hz), 7.74 (d, 1H, J=2 Hz), 8.05 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][C:11]([OH:15])([CH3:14])[C:12]#[CH:13].O1CCCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:13]#[C:12][C:11]([OH:15])([CH3:14])[CH3:10])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(Br)cc1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(O)C#Cc1ccc(C#N)cc1
Yield: 105.3 %

Procedure:
50 g (274.7 mmol) 4-bromobenzonitrile, 46.2 g (550 mmol) 3-methyl-1-butyne-3-ol, 0.97 g (1.38 mmol) bis(triphenylphosphine) dichloropalladium, 0.26 g (1.38 mmol) copper iodide and 2 g (7.6 mmol) triphenyl phosphine were added in a nitrogen stream, and 100 ml tetrahydrofuran (THF) and 20 ml triethylamine were added thereto, and the mixture was reacted at 80 ° C. for 15 hours. The reaction solution was concentrated and partitioned by adding 300 ml ethyl acetate and 300 ml water, and the organic layer was washed twice with 100 ml water and dried over magnesium sulfate anhydride. The solvent was distilled away, and about 250 ml heptane was added to the residual paste and stirred for a while, and the precipitated crystals were filtered to give 53.6 g crystals.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1([F:19])[O:17][C:8]2=[CH:9][C:10]3[N:14]=[C:13]([SH:15])[NH:12][C:11]=3[CH:16]=[C:7]2[O:6][CH:5]1[F:18].Cl.Cl[CH2:22][C:23]1[C:28]([CH3:29])=[C:27]([O:30][CH3:31])[C:26]([CH3:32])=[CH:25][N:24]=1>C(O)C>[F:19][C:4]1([F:3])[O:17][C:8]2=[CH:9][C:10]3[N:14]=[C:13]([S:15][CH2:22][C:23]4[C:28]([CH3:29])=[C:27]([O:30][CH3:31])[C:26]([CH3:32])=[CH:25][N:24]=4)[NH:12][C:11]=3[CH:16]=[C:7]2[O:6][CH:5]1[F:18]
Reactant: COc1c(C)cnc(CCl)c1C
Reactant: FC1Oc2cc3[nH]c(S)nc3cc2OC1(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1c(C)cnc(CSc2nc3cc4c(cc3[nH]2)OC(F)C(F)(F)O4)c1C
Temperature: 40 °C
Reaction time: 5 h
Yield: 75.7 %

Procedure:
6.1 ml of 2M sodium hydroxide solution are added dropwise to a mixture of 1.6 g of 6,6,7-trifluoro-6,7-dihydro-1H-[1,4]-dioxino[2,3-f]benzimidazole-2-thiol and 1.4 g of 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride in 40 ml of ethanol at room temperature and the mixture is stirred at 40° C. for 5 h. The solvent is distilled off in vacuo, water is added, the mixture is extracted with methylene chloride, the organic solution is concentrated and the residue is recrystallized from ethanol and water. 1.9 g (77%) of the title compound of m.p. 138°-140° C. are obtained.