Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[N:8]=[CH:7][N:6]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:15][CH2:16][CH:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]2)[N:8]=[CH:7][N:6]=1
Reactant: COc1ccc(Br)c(Nc2ncnc3cccc(OCC4CCN(C(=O)OC(C)(C)C)CC4)c23)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Br)c(Nc2ncnc3cccc(OCC4CCNCC4)c23)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.1 %

Procedure:
A mixture of 4-(2-bromo-5-methoxyanilino)-5-[N-(tert-butoxycarbonyl)piperidin-4-ylmethoxy]quinazoline (0.108 g), trifluoroacetic acid (1 ml) and methylene chloride (1 ml) was stirred at ambient temperature for 1.5 hours. The mixture was evaporated and the residue was triturated under diethyl ether. The resultant solid was isolated and dried under vacuum. The solid was dissolved in methylene chloride and few drops of a saturated methanolic ammonia solution was added. The solution was poured onto a chromatography column filled with silica and eluted with a 97:3 mixture of methylene chloride and a saturated methanolic ammonia solution. There was thus obtained the title compound (0.082 g); NMR Spectrum: (CDCl3) 1.2–1.4 (m, 2H), 1.9 (d, 2H), 2.3 (m, 1H), 2.65 (t, 2H), 3.12 (d, 2H), 3.84 (s, 3H), 4.2 (d, 2H), 6.61 (m, 1H), 6.93 (d, 1H), 7.5 (d, 2H), 7.68 (m, 1H), 8.22 (d, 1H), 8.68 (s, 1H); Mass Spectrum: M+H+ 443 and 445.
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3]([O:5]CC)=[O:4].C[O-].[Na+].Br[CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.[OH-].[Na+]>O.CO>[CH:17]1([CH2:16][CH:2]([C:3]([OH:5])=[O:4])[C:1]([OH:9])=[O:8])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: BrCC1CCCC1
Reactant: CCOC(=O)CC(=O)OCC
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(CC1CCCC1)C(=O)O
Reaction time: 3 h
Yield: 58.7 %

Procedure:
A solution of diethyl malonate (36.91 g, 230.4 mmol), anhydrous methanol (400 mL), and NaOMe (25% in methanol, 49.79 g, 230.4 mmol) is stirred at reflux for one hour under nitrogen. Bromomethyl-cyclopentane (31.31 g, 192.0 mmol) is added to the mixture, and stirred for an additional 3 hours. A solution of NaOH (23.04 g, 576.0 mmol) in water (400 mL) is added, and the mixture is stirred for an additional 1 hour at reflux. The mixture is cooled, diluted with water, and extracted with ether. The ether layer is discarded, and the aqueous layer is acidified with 1N HCl to pH=1. The aqueous layer is extracted with EtOAc. The EtOAc layers are combined, dried over Na2SO4, and concentrated. This gives 2-cyclopentylmethyl-malonic acid (21.0 g, 59% yield) as a white solid.
Reaction SMILES: [CH:1]1([C:8]2[N:13]3[N:14]=[CH:15][N:16]=[C:12]3[N:11]=[C:10](O)[C:9]=2[C:18]2[C:23]([F:24])=[CH:22][C:21]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)=[CH:20][C:19]=2[F:39])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:42])=O.C(N(CC)C1C=CC=CC=1)C>>[Cl:42][C:10]1[C:9]([C:18]2[C:19]([F:39])=[CH:20][C:21]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)=[CH:22][C:23]=2[F:24])=[C:8]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)[N:13]2[N:14]=[CH:15][N:16]=[C:12]2[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(COCCCOc2cc(F)c(-c3c(O)nc4ncnn4c3C3CCCCCC3)c(F)c2)cc1
Solvent: CCN(CC)c1ccccc1
Product: COc1ccc(COCCCOc2cc(F)c(-c3c(Cl)nc4ncnn4c3C3CCCCCC3)c(F)c2)cc1

Procedure:
To the above 7-cycloheptyl-6-(2,6-difluoro-4-{3-[(4-methoxybenzyl)oxy]propoxy}phenyl)[1,2,4]triazolo[1,5-a]pyrimidin-5-ol (820 mg) is added 5 mL of phosphorous oxychloride and 2 mL of N,N-diethylaniline, and the mixture is heated at reflux for 1 h. The excess phosphorous oxychloride is removed in vaccuo, and the resulting residue is partitioned between methylene chloride and 1 N hydrochloric acid. The organic layer is washed with saturated sodium chloride, dried over magnesium sulfate, and concentrated to a residue. The residue is chromatographed over silica gel, eluting with a gradient of hexanes to 20% ethyl acetate in hexanes. Concentration provides 5-chloro-7-cycloheptyl-6-(2,6-difluoro-4-{3-[(4-methoxybenzyl)oxy]propoxy}phenyl)[1,2,4]triazolo[1,5-a]pyrimidine as a yellow oil (180 mg). MS: m/z 557.2 (M+H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](N1C=CN=C1)=[O:11])[CH2:2]2.[CH:17]1([CH:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[OH:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:17]1([CH:23]([O:24][C:10](=[O:11])[O:9][C@@H:3]2[CH:4]3[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]3)[CH2:2]2)[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: OC(c1cccc(F)c1)C1CCCCC1
Reactant: O=C(O[C@H]1CN2CCC1CC2)n1ccnc1
Product: O=C(OC(c1cccc(F)c1)C1CCCCC1)O[C@H]1CN2CCC1CC2

Procedure:
The desired product was prepared by reacting imidazole-1-carboxylic acid (R)-1-aza-bicyclo[2.2.2]oct-3-yl ester with cyclohexyl-(3-fluoro-phenyl)-methanol.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C(N=C=NCCCN(C)C)C.[CH3:24][S:25]([NH2:28])(=[O:27])=[O:26].C(N(CC)CC)C.Cl>CN(C)C1C=CN=CC=1.ClCCl>[F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH:28][S:25]([CH3:24])(=[O:27])=[O:26])=[O:5]
Reactant: O=C(O)c1cc(F)c(F)cc1F
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC(=O)c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.2 %

Procedure:
2,4,5-Trifluorobenzoic acid (15 g, 85.2 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide (24.45 g, 128 mmol) and 4-dimethylaminopyridine (15.6 g, 128 mmol) were stirred in dichloromethane at room temperature for 15 minutes under an atmosphere of nitrogen. Methanesulfonamide (12.15 g, 128 mmol) and triethylamine (23.8 g, 254 mmol) were added and the reaction stirred at room temperature overnight. A 1M aqueous solution of hydrogen chloride was added and the mixture was extracted with ethyl acetate. The organic phase was washed sequentially with brine, dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo. The resulting residue was recrystallised from a mixture of ethyl acetate and heptane to afford the title compound (7.8 g, 36%).
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH:12]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)[CH2:13][CH2:14]S(C)(=O)=O)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:29][C:30]1[CH:53]=[CH:52][C:33]([CH2:34][N:35]2[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[N:37]=[C:36]2[C:44]([CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[O:45])=[CH:32][CH:31]=1>>[CH3:1][N:2]([CH2:11][CH:12]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)[CH2:13][CH2:14][N:49]1[CH2:50][CH2:51][CH:46]([C:44]([C:36]2[N:35]([CH2:34][C:33]3[CH:32]=[CH:31][C:30]([F:29])=[CH:53][CH:52]=3)[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[N:37]=2)=[O:45])[CH2:47][CH2:48]1)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(c1nc2ccccc2n1Cc1ccc(F)cc1)C1CCNCC1
Reactant: COc1ccc(C(CCS(C)(=O)=O)CN(C)C(=O)c2ccccc2)cc1OC
Product: COc1ccc(C(CCN2CCC(C(=O)c3nc4ccccc4n3Cc3ccc(F)cc3)CC2)CN(C)C(=O)c2ccccc2)cc1OC

Procedure:
Prepare by the method of Example 1.7 using N-methyl-N-(2-(3,4-dimethoxyphenyl)-4-methanesulfonylbutyl)benzamide and 4-(1-(4-fluorobenzyl)-1H-benzimidazole-2-carbonyl)piperidine to give the title compound.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]([NH:8][C:9]1[S:10][C:11]([S:15](Cl)(=[O:17])=[O:16])=[C:12]([CH3:14])[N:13]=1)(=[O:7])[CH3:6].C(N(CC)CC)C>O1CCOCC1>[OH:2][CH2:1][CH2:3][NH:4][S:15]([C:11]1[S:10][C:9]([NH:8][C:5](=[O:7])[CH3:6])=[N:13][C:12]=1[CH3:14])(=[O:16])=[O:17]
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: NCCO
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)Nc1nc(C)c(S(=O)(=O)NCCO)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 60.8 %

Procedure:
To a stirred solution of ethanolamine (1.08 g, 17.7 mmol) in dioxane (20 ml) was added at 0° C. (ice water bath) commercially available 2-acetamido-4-methylthiazole-5-sulfonyl chloride (1.5 g, 5.89 mmol) and triethylamine (0.9 ml, 6 mmol). The light yellow suspension was stirred at room temperature for 17 h, and evaporated. The crude product was further purified by flash chromatography on silica gel (ethyl acetate/MeOH) and subsequent crystallization (dichloromethane/MeOH/hexane) to yield 2-acetamido-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-ethyl)-amide (1.0 g, 61%) as a white solid. MS (ISP) 278.0 [(M−H)−]; mp 211° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH:16]([CH3:18])[CH3:17])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:27])[CH:6]=[C:7]([S:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[O:8]2.C(OC([N:35](C(OC(C)(C)C)=O)[CH2:36][C:37](O)=[O:38])=O)(C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1.[ClH:62]>ClCCl.C(OCC)(=O)C>[ClH:62].[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH:16]([CH3:18])[CH3:17])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:27])[CH:6]=[C:7]([S:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][C:37](=[O:38])[CH2:36][NH2:35])=[CH:24][CH:25]=1)[O:8]2
Reactant: COc1c(OC(C)C)cc2oc(Sc3ccc(O)cc3)cc(=O)c2c1OC
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1c(OC(C)C)cc2oc(Sc3ccc(OC(=O)CN)cc3)cc(=O)c2c1OC
Reaction time: 1 h

Procedure:
300 ml in dichloromethane of 9.11 g of 5,6-dimethoxy-2-(4-hydroxyphenylthio)-7-isopropoxychromone obtained in Example 22, 4.52 g of N-t-butoxycarbonyl(Boc)glycine, and 5.32 g of dicyclohexylcarbodiimide (DCC) was stirred over 3.5 hours at room temperature. The solution thus reacted was gravitationally filtered. The solvent was distilled out from the filtrate, so that 10.95 g of N-t-butoxycarbonyl(Boc)glycine ester was obtained. 5.27 g of N-t-butoxycarbonyl(Boc)glycine ester thus prepared was dissolved in 100 ml of ethyl acetate. Then, hydrochloric acid gas was introduced and bubbled in the solution for 10 min., followed by stirring for 1 hour. Subsequently, 200 ml ether was added and the resulting crystals were collected by filtration and then dried, whereby 3.53 g of 5,6-dimethoxy-2-(4-glycyloxyphenylthio)-7-isopropoxychromone hydrochloride with the following physicochemical properties was obtained.
Reaction SMILES: [Br:1][CH:2]([C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11]CC2C=CC(OC)=CC=2)=[CH:7][C:6]=1O[Si](C(C)(C)C)(C)C)=[O:4].S(=O)(=O)(O)O>C(O)C>[Br:1][C:2]1[C:3](=[O:4])[C:5]2[C:6](=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=2)[O:33][C:29]=1[CH:30]([CH3:31])[CH3:32]
Reactant: COc1ccc(COc2ccc(C(=O)C(Br)C(=O)C(C)C)c(O[Si](C)(C)C(C)(C)C)c2)cc1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CC(C)c1oc2cc(O)ccc2c(=O)c1Br
Temperature: 50 °C
Reaction time: 16 h

Procedure:
2-Bromo-1-[2-(tert-butyl-dimethyl-silanyloxy)-4-(4-methoxy-benzyloxy)-phenyl]-4-methyl-pentane-1,3-dione (6.77 g, 12.65 mmol) is dissolved in absolute ethanol (350 ml) at 50° C. Concentrated sulfuric acid (16 ml) is added dropwise. The mixture is stirred at 50° C. for 16 hours, after which time further 0.5 ml of concentrated sulfuric acid are added. The stirring is continued for a further 4 hours at 50° C. The reaction mixture is cooled to room temperature, and most of the ethanol is removed under reduced pressure. Water (400 ml) is added to the residue, and the colourless solid formed is recovered by filtration and dried in a desiccator. This material is not pure enough for subsequent use, so it is partitioned between water and ethyl acetate and extracted with ethyl acetate (3×100 ml). The ethyl acetate extracts are combined, washed with saturated brine (100 ml), dried (MgSO4), treated with activated charcoal (300 mg), filtered and concentrated, until crystallization commences. After standing at 4° C. for 16 h, the crystals are recovered by filtration, washed with n-hexane and dried.
Reaction SMILES: OO.[N:3]1([CH2:9][CH2:10][NH:11][C:12]2[N:13]=[N+:14]([O-:25])[C:15]3[CH:24]=[C:23]4[C:19]([CH2:20][CH2:21][CH2:22]4)=[CH:18][C:16]=3[N:17]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.C([O-])([O-])=[O:27].[Na+].[Na+]>C(O)(C(F)(F)F)=O.O>[N:3]1([CH2:9][CH2:10][NH:11][C:12]2[N:13]=[N+:14]([O-:25])[C:15]3[CH:24]=[C:23]4[C:19]([CH2:20][CH2:21][CH2:22]4)=[CH:18][C:16]=3[N+:17]=2[O-:27])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: O=C([O-])[O-]
Reactant: [O-][n+]1nc(NCCN2CCOCC2)nc2cc3c(cc21)CCC3
Agent: OO
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: [O-][n+]1nc(NCCN2CCOCC2)[n+]([O-])c2cc3c(cc21)CCC3
Temperature: 20 °C
Reaction time: 26 h
Yield: 36 %

Procedure:
H2O2 (70%, 0.50 mL, ca. 10.0 mmol) was added to a stirred solution of 1-oxide 44 (3.00 g, 9.52 mmol) in a mixture of TFA (30 mL) and water (2 mL) at 20° C. Ten more aliquots of 70% H2O2 (0.5 mL) were added in 30 min intervals and the reaction mixture was stirred at 20° C. for 26 h. Water (100 mL) was added and the mixture made basic with Na2CO3. The mixture was extracted with DCM (4×200 mL) and the combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give 1,4-dioxide 45 (1.13 g, 36%) as a red solid: 1H NMR δ 8.13 (s, 1H, H-9), 8.10 (s, 1H, H-5), 7.38 (br s, 1H, NH), 3.73 (t, J=4.5 Hz, 4H, CH2O), 3.67 (m, 2H, CH2N), 3.03-3.15 (m, 4H, H-6, H-8), 2.68 (t, J=6.0 Hz, 2H, CH2N), 2.53 (t, J=4.5 Hz, 4H, CH2N), 2.17-2.25 (m, 2H, H-7); 13C NMR δ 155.7, 149.4, 145.9, 137.9, 129.7, 115.8, 111.6, 65.9 (2), 56.8, 53.4 (2), 37.7, 33.4, 32.4, 25.6. The hydrochloride salt was crystallised as a red solid: mp (MeOH/DCM) 184-185° C. Anal. calcd for C16H21N5O3.¾HCl: C, 53.5; H, 6.2; N, 19.5. Found: C, 53.9; H, 6.3; N, 19.6%.
Reaction SMILES: [CH2:1]1[C:6]2[S:7][C:8]3[N:12]([C:5]=2[CH2:4][CH2:3][NH:2]1)[C:11]1[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=1[N:9]=3.N1C=CC=CC=1.[C:23](Cl)(=[O:27])[CH2:24][CH2:25][CH3:26].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[C:23]([N:2]1[CH2:3][CH2:4][C:5]2[N:12]3[C:11]4[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=4[N:9]=[C:8]3[S:7][C:6]=2[CH2:1]1)(=[O:27])[CH2:24][CH2:25][CH3:26]
Reactant: c1ccc2c(c1)nc1sc3c(n12)CCNC3
Reactant: CCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCC(=O)N1CCc2c(sc3nc4ccccc4n23)C1
Reaction time: 24 h

Procedure:
1,2,3,4-Tetrahydropyrido[4',3':4,5]thiazolo[3,2-a]benzimidazole (2.29 g., 0.01 mole) in 100 ml. of pyridine at 0° is treated with 1.06 g. (0.01 mole) butyryl chloride. After 24 hours at 5°, the mixture is stripped to a slurry, shaken with sodium bicarbonate and chloroform. Drying and evaporation of the organic solvents gives a solid which is recrystallized from methanol to give pure 2-butyryl-1,2,3,4-tetrahydropyrido[4',3':4,5]thiazolo[3,2-a]benzimidazole.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH2:17]O)=[CH:14][C:13]=2[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH2:17][N:24]3[C:20](=[O:30])[C:21]4[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:23]3=[O:25])=[CH:14][C:13]=2[CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cc2cc(OCc3ccccc3)ccc2o1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1Cc1cc2cc(OCc3ccccc3)ccc2o1
Temperature: 25 °C
Reaction time: 9 h
Yield: 74.9 %

Procedure:
To a tetrahydrofuran (10 mL) solution of (5-benzyloxy-benzofuran-2-yl)-methanol (561 mg, 2.21 mmol) described in Production Example 7-1-4 were added phthalimide (358 mg, 2.43 mmol), triphenylphosphine (696 mg, 2.65 mmol) and diethylazodicarboxylate (1.21 mL, 2.65 mmol) at 0° C., which was stirred at room temperature for 9 hours. Water was added to the reaction solution at room temperature followed by extraction with ethyl acetate. The organic layer was washed with sat. NaCl followed by drying over anhydrous magnesium sulfate and filtering. The filtrate was concentrated under a reduced pressure and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=7:3) to obtain the title compound (635 mg, 75%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[C:16]([Br:18])[S:17][C:11]=2[N:10]=[C:9]1[CH:19](Br)[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][NH2:27]>C(O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[C:16]([Br:18])[S:17][C:11]=2[N:10]=[C:9]1[CH:19]([NH:27][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCN
Reactant: CCC(Br)c1nc2sc(Br)cc2c(=O)n1Cc1ccccc1
Solvent: CCO
Product: CCC(NCCN(C)C)c1nc2sc(Br)cc2c(=O)n1Cc1ccccc1

Procedure:
A solution of 3-benzyl-6-bromo-2-(1-bromopropyl)thieno[2,3-d]pyrimidin-4(3H)-one (2-6, 35 mg, 0.079 mmol, 1 equiv) and N,N-dimethylethylenediamine (21 mg, 0.237 mmol, 3 equiv) in ethanol (5 mL) was heated at reflux for 18 h. The reaction was concentrated, and the residue was partitioned between EtOAc and brine. The organic layer was dried (MgSO4) and concentrated to provide 3-benzyl-6-bromo-2-(1-{[2-(dimethylamino)ethyl]amino}propyl)thieno[2,3-d]pyrimidin-4(3H)-one (2-8) as a yellow gum. MS(M+1)=449.9.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:32]([C@@H:34]([O:36]C(=O)C)[CH3:35])=[O:33]>>[OH:36][C@@H:34]([CH3:35])[C:32]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH2:27][CH:28]4[CH2:29][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:33]
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccccc4OCC4CC4)ncnc23)CC1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Product: C[C@H](O)C(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A161) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21](I)[S:22][C:13]=12.[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:26]=[C:25]1B(O)O>COCCOC.C(=O)(O)[O-].[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>[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:26]=[C:25]1[C:21]1[S:22][C:13]2[C:14](=[N:15][CH:16]=[C:17]([C:18]#[N:19])[C:12]=2[NH:11][C:3]2[CH:4]=[C:5]([O:9][CH3:10])[C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH:20]=1
Reactant: COc1cc(Nc2c(C#N)cnc3cc(I)sc23)c(Cl)cc1Cl
Reactant: OB(O)c1cc2ccccc2o1
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: COCCOC
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4cc5ccccc5o4)sc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 32.7 %

Procedure:
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile (500 mg, 1.05 mmol), 2-benzofuranboronic acid (340 mg, 2.10 mmol) and 65 mg of tetrakis(triphenylphosphine)palladium(0) in 70 mL of ethylene glycol dimethyl ether and 40 mL of saturated aqueous sodium bicarbonate is heated at reflux for 2.5 hours. An additional 50 mg of tetrakis(triphenylphosphine)palladium(0) is added and the reaction is heated at reflux for 1 hour. The reaction mixture is cooled to room temperature and partitioned between water and ethyl acetate. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 2:1 hexane:ethyl acetate. The fractions containing product are combined and concentrated in vacuo. The residue is washed with diethyl ether to provide 160 mg of 2-(1-benzofuran-2-yl)-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile as yellow crystals, mp 281–282° C.; 1H NMR (DMSO-d6) δ 3.87 (s, 3H), 7.29–7.45 (m, 3H), 7.61 (s, 1H), 5.69–7.73 (m, 2H), 7.81 (s, 1H), 8.02 (s, 1H), 8.65 (s, 1H), 9.82 (s, 1H); MS 464.2, 465.9 (M−H)−.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=2)[C:9]([O:11]C)=O)[CH:5]=[N:4][CH:3]=[N:2]1.[C:16]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH3:17].[Li]>>[C:20]([O:19][C:16](=[O:18])[CH2:17][C:9](=[O:11])[C:8]1[CH:13]=[CH:14][CH:15]=[C:6]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH:7]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)c1cccc(-n2cncn2)c1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2cncn2)c1

Procedure:
Prepared from methyl 3-[1,2,4]triazol-1-yl-benzoate [CAS-No. 167626-27-9] by treatment with lithium tert.-butyl acetate according to general procedure H (method b). Obtained as an orange liquid (2.41 g).
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=[O:20])[CH3:19].C(O)C>O1CCCC1>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([CH2:19][C:3]([O:7][CH2:8][CH3:9])=[O:10])=[O:20]
Reactant: CC(=O)c1ccccc1Cl
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccccc1Cl
Temperature: 0 °C

Procedure:
Sodium hydride (8.7 grams) and 21.4 grams of diethyl carbonate are suspended in 100 ml of tetrahydrofuran, 14 grams of o-chloroacetophenone is gradually dropped thereinto by keeping the inner temperature at 40° to 50° C., then a small amount of ethanol is added thereto and heated to reflux for four hours. After cooling, 20 ml of ethanol is added thereto, the mixture is poured into ice water, and extracted with ether. Ether extracts are combined, washed with water, dried with anhydrous magnesium sulfate, and ether is evaporated therefrom. The resulting oil is purified by distillation in vacuo to give 8.8 grams of colorless, oily product, b.p. 120° to 125° C./1 mmg Hg.
Reaction SMILES: [C:1]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl.[CH3:17][Si:18]([CH3:44])([CH3:43])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>COCCOC>[CH3:44][Si:18]([CH3:17])([CH3:43])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]1[CH:35]=[CH:36][C:37]([C:38]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])=[O:39])=[CH:41][CH:42]=1
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(C(=O)OC(C)(C)C)C(=O)c1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1

Procedure:
A solution of 14 g. of tert-butyl ethyl malonate in 5 ml. of 1,2-dimethoxyethane is added to a suspension of 2.0 g. of sodium hydride in 1,2-dimethoxyethane under argon. A solution of 8.4 g. of 4-[14-(trimethylsilyl)tetradecylamino]benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then added. The reaction mixture is refluxed for 5 hours, cooled, poured on ice and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried with anhydrous sodium sulfate and evaporated to dryness. The residue is then recrystallized to yield the title compound.