Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:9]=2)[CH:5]=[C:4]([CH:19]=O)[CH:3]=1.[CH3:21][O:22][C:23](=[O:38])[CH:24]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])P(OC)(OC)=O.CN(C)C(=N)N(C)C>O1CCCC1>[CH3:21][O:22][C:23](=[O:38])[C:24]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])=[CH:19][C:4]1[CH:3]=[C:2]([CH3:1])[C:10]2[C:6](=[CH:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:16])([CH3:17])[CH3:18])[N:9]=2)[CH:5]=1
Reactant: Cc1cc(C=O)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: COC(=O)C(C(=O)OC(C)(C)C)P(=O)(OC)OC
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C(=Cc1cc(C)c2nn(COCC[Si](C)(C)C)cc2c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2-H-indazole-5-carbaldehyde (8.5 g, 29.3 mmol) and methyl-2-(tert-butoxycarbonyl)-2-(dimethoxyphosphoryl)acetate (10 g, 32.2 mmol, 1.1 equiv) in tetrahydrofuran (30 mL) at 0° C. was added tetramethylguanidine (5.9 mL, 49.8 mmol, 1.7 equiv). After 10 min, the ice bath was removed and the reaction stirred at room temperature overnight. The solvent was evaporated and the residue purified by flash chromatography on silica gel to afford 11.2 g (83%). 1H-NMR (CD3OD, 300 MHz) δ −0.05 (s, 9H), 0.84-0.96 (m, 2H), 1.14 (bs, 9H), 2.56 (s, 3H), 3.58-3.70 (m, 2H), 3.82 (s, 3H), 5.73 (s, 2H), 7.41 (s, 1H), 7.45 (s, 1H), 7.84 (s, 1H), 8.41 (s, 1H). Mass spec.: 462.5 (MH)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.[F:28][C:29]1[C:34](B(O)O)=[CH:33][C:32]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([S:45][CH3:46])=[CH:41][CH:40]=2)=[CH:31][N:30]=1.C([O-])(=O)C.[K+]>CCO.O>[F:28][C:29]1[C:34]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[N:3]=2)=[CH:33][C:32]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([S:45][CH3:46])=[CH:41][CH:40]=2)=[CH:31][N:30]=1
Reactant: CSc1ccc(Cc2cnc(F)c(B(O)O)c2)cc1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(Cl)n2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cc4ccc(SC)cc4)cnc3F)n2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 79.5 %

Procedure:
4-Chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (2.37 g, 6.15 mmol), 2-fluoro-5-(4-(methylthio)benzyl)pyridin-3-ylboronic acid (1.89 g, 6.83 mmol), Am-Phos (224 mg, 0.316 mmol), and potassium acetate (2.72 g, 27.7 mmol) were suspended in EtOH (30 mL) and water (7.5 mL). Nitrogen was bubbled through the suspension for about 20 seconds, and then the flask was fitted with a reflux condenser and put in a preheated oil bath (80° C.-88° C.) and the reaction was stirred under nitrogen for 2 hours and 45 minutes. Then, the reaction was cooled to room temperature, treated with water (90 mL) and extracted with DCM. The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated. The residue was washed with hexanes, but the hexanes rinsings still contained product. So, these rinsings were combined with the residue and concentrated. The material was purified on a silica gel filter (600 mL fritted filter funnel with about 3 inches of silica gel; 5:1 DCM/hexanes to DCM to 40:1 DCM/MeOH to 30:1 DCM/MeOH) to give 4-(2-fluoro-5-(4-(methylthio)benzyl)pyridin-3-yl)-N,N-bis (4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (2.843 g). 1H NMR (CDCl3, 400 MHz) δ 8.32 (dd, J=9.00 Hz, 2.35 Hz, 1H), 8.14 (dd, J=1.56 Hz, 1H), 7.24-7.18 (m, 6H), 7.13-7.09 (m, 2H), 6.90-6.83 (m, 4H), 4.81 (s, 2H), 4.78 (s, 2H), 3.99 (s, 2H), 3.82 (s, 3H), 3.80 (s, 3H), 2.53 (s, 3H), 2.46 (s, 3H). m/z (ESI, pos. ion) 582 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.[C:12](=[O:15])([O-])[O-].[K+].[K+].C=O.[CH:20]1(Br)[CH2:24][CH2:23][CH2:22][CH2:21]1>CN(C=O)C.O.C(OCC)(=O)C>[CH:20]1([O:1][C:2]2[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=2[CH2:12][OH:15])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cn1nc(C(F)(F)F)cc1O
Reactant: O=C([O-])[O-]
Reactant: BrC1CCCC1
Agent: C=O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(C(F)(F)F)c(CO)c1OC1CCCC1
Temperature: 25 °C
Yield: 67 %

Procedure:
In 100 ml of DMF were suspended 16.6 g (0.10 mole) of the 5-hydroxy-1-methyl-3-trifluoromethylpyrazole synthesized in Reference Example 1 and 20.9 g (0.15 mole) of potassium carbonate. In this suspension being stirred at room temperature was placed 4.5 g (0.15 mole) of paraformaldehyde, followed by stirring at the same temperature for 1 hour. Then, 41.8 g (0.30 mole) of potassium carbonate was added. Thereto was dropwise added 44.7 g (0.30 mole) of cyclopentyl bromide. The reaction mixture was heated to 60° C., followed by stirring for 12 hours to give rise to a reaction. After the reaction, 200 ml of ethyl acetate and 200 ml of water were added. The organic layer, which appeared by phase separation, was separated. The aqueous layer was subjected to re-extraction with 50 ml of ethyl acetate. The two organic layers were combined and washed with 50 ml of water, 30 ml of a saturated aqueous ammonium chloride solution and 30 ml of a saturated aqueous sodium chloride solution in this order. The resulting organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 41.9 g (purity: 42.2%, yield: 67.0%) of a crude solution of title compound. The crude solution was subjected to vacuum distillation to obtain a title compound as a light yellow transparent solution.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:22]([F:25])([F:24])[F:23])[N:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[CH:8]=[CH:7][C:6]=12.[Li][C:27](C)(C)C.CI.O>CCOCC>[CH3:27][C:2]1[N:3]=[C:4]([C:22]([F:25])([F:24])[F:23])[N:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[CH:8]=[CH:7][C:6]=12
Reactant: FC(F)(F)Oc1ccc(-c2ccc3c(Br)nc(C(F)(F)F)n3c2)cc1
Reactant: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CI
Solvent: O
Product: Cc1nc(C(F)(F)F)n2cc(-c3ccc(OC(F)(F)F)cc3)ccc12
Temperature: -78 °C

Procedure:
1-bromo-6-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)imidazo[1,5-a]pyridine (50.0 mg, 0.118 mmol) was dissolved in ether (2 mL) in a 50 mL round bottomed flask under a nitrogen atmosphere. The solution was cooled down to −78° C. and treated with t-BuLi (1.7 M pentane solution, 0.15 mL, 0.255 mmol, 2.2 equiv.) for 5 min. To the mixture was added a solution of MeI (65.8 mg, 0.464 mmol, 4.0 equiv.) in ether (1 mL). The reaction was allowed to warm up to room temperature for 30 min. To the mixture was added H2O (30 mL) and the whole was extracted with EtOAc (30 mL×3). Combined organic layers were washed with brine (30 mL) and dried with Na2SO4. The solvent was removed under a reduced pressure to give a crude mixture. The crude mixture was purified by a preparative TLC (SiO2=1 plate, ether/hexane=1:3 Rf=0.4) to give 1-methyl-6-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)imidazo[1,5-a]pyridine as light yellow crystals.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([OH:17])(=[O:16])[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.O1COCO[CH2:19]1.C([O-])(O)=O.[Na+]>O.C(O)(=O)C>[C:11]([C:10]1[CH:14]=[C:15]2[C:7](=[CH:8][CH:9]=1)[C:6](=[O:17])[O:16][CH2:19]2)([OH:13])=[O:12]
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: C1OCOCO1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c(c1)COC2=O
Temperature: 131.5 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To 892 g of fuming sulfuric acid, containing 25-27% of SO3, 100 g (0.6 m) of terephthalic acid are added at 20-23° C., under stirring, then 46 g (0.5 m) of 1,3,5-trioxane are added portionwise thereto at about 15° C. At the end of the addition, the mixture is heated 2 hours at 130-133° C. whereby a dark, clear solution is obtained. When the reaction is complete, as shown by a HPLC control, the mixture is cooled to 20-22° C. and 210 g of glacial acetic acid are slowly added thereto, without exceeding the temperature of 23-25° C. The mass is cooled to −5-0° C. and 1800 ml of cold deionized water are added thereto. During this operation the temperature rises to 43-45° C. At the end of the addition, the mixture is kept 1 hour under stirring at 23-25° C., then it is filtered, the solid is washed with deionized water abundantly and suspended, still wet, in 1200 ml of deionized water at room temperature. To the suspension thus obtained, about 1550 g of a 7% solution of NaHCO3 are added to a constant pH of 7,6-7,8. The mixture is filtered on Celite®, washing with deionized water. The pH of the filtrate is brought to about 1 by slow addition of about 120 ml of 35% hydrochloric acid at 22-25° C. The suspension is kept 1 hour under stirring at 22-25° C., then it is filtered and washed with deionized water abundantly. The product is dried in vacuo at about 50° C. to give 81 g of 5-carboxyphthalide with a titer (HPLC)>94% and purity (HPLC)>95%.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1[C:17]2[NH:16][CH2:15][CH2:14][CH2:13][C:12]=2[CH:11]=[C:10]([C:18]2[CH:19]=[C:20]([O:24][CH:25]3[CH2:30][CH2:29][N:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]3)[CH:21]=[N:22][CH:23]=2)[CH:9]=1.[NH2:34][C:35]([NH2:37])=[O:36]>C(Cl)Cl>[N:8]1[C:17]2[NH:16][CH2:15][CH2:14][CH2:13][C:12]=2[CH:11]=[C:10]([C:18]2[CH:19]=[C:20]([O:24][CH:25]3[CH2:30][CH2:29][N:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]3)[CH:21]=[N:22][CH:23]=2)[CH:9]=1.[C:31]([N:28]1[CH2:29][CH2:30][CH:25]([O:24][C:20]2[CH:19]=[C:18]([C:10]3[CH:11]=[C:12]4[C:17](=[N:8][CH:9]=3)[N:34]([C:35]([NH2:37])=[O:36])[CH2:15][CH2:14][CH2:13]4)[CH:23]=[N:22][CH:21]=2)[CH2:26][CH2:27]1)(=[O:33])[CH3:32]
Reactant: NC(N)=O
Agent: CC(=O)N1CCC(Oc2cncc(-c3cnc4c(c3)CCCN4)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N1CCC(Oc2cncc(-c3cnc4c(c3)CCCN4C(N)=O)c2)CC1

Procedure:
1-{4-[5-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-yloxy]-piperidin-1-yl}-ethanone is synthesized according to the procedure for Step 2 of Example 27 using 20% trifluoroacetic acid in DCM as the reagent. 1-{4-[5-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-yloxy]-piperidin-1-yl}-ethanone (200 mg, 0.57 mmol) is converted to 34 mg of the titled product according to the procedure of Urea Formation Method I.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C([Mg]Cl)(C)C.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C.CCOCC>[CH2:17]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Temperature: -40 °C
Reaction time: 1 h

Procedure:
To an ether solution (7.5 ml) containing tetraisopropoxytitanium (0.284 g, 1.0 mmol) and diethyl malonate (0.145 g, 0.5 mmol) was added dropwise at −50° C. 1.53 ml of 1.31M ether solution containing isopropylmagnesium chloride (2 mmol). Upon stirring at −40° C. for 1 hour, the reaction liquid turned from yellow into brown. The reaction liquid was stirred together with benzaldehyde (0.080 g, 0.75 mmol) at 0° C. for 1 hour. With 1N hydrochloric acid added, the reaction liquid was stirred at room temperature for 15 minutes. After treatment and purification as in Referential Example 1, there was obtained diethyl benzylmalonate in deallylated form (yields: 97%).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[C:12]([C:20](O)=[O:21])=[CH:11]2)[C:4]=1[CH3:23].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.Cl.[F:51][CH2:52][CH2:53][NH2:54]>C(Cl)Cl>[CH3:24][N:2]([CH3:1])[C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[C:12]([C:20]([NH:54][CH2:53][CH2:52][F:51])=[O:21])=[CH:11]2)[C:4]=1[CH3:23]
Reactant: NCCF
Reactant: Cc1cnc2c(C(=O)O)cn(Cc3ncnc(N(C)C)c3C)c2c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cnc2c(C(=O)NCCF)cn(Cc3ncnc(N(C)C)c3C)c2c1
Temperature: 25 °C
Yield: 14.1 %

Procedure:
See FIG. 23(d). 1-((6-(dimethylamino)-5-methylpyrimidin-4-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (75 mg, 0.23 mmol) was taken in a thermal reactor. DCM (5 mL) was added to get a suspension. Triethyl amine (0.064 mL, 0.46 mmol) was added followed by the addition of 1-Propanephosphonic acid cyclic anhydride (0.274 mL, 0.46 mmol). 2-fluoroethanamine hydrochloride (22.94 mg, 0.23 mmol) was added and stirred at RT for ON. After the completion of the reaction, reaction mixture was concentrated and dissolved in DCM:MeOH. This crude compound was subjected for reverse phase purification. The final compound obtained 1-((6-(dimethylamino)-5-methylpyrimidin-4-yl)methyl)-N-(2-fluoroethyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (12.00 mg, 14.05%) as a white solid. ES+MS m/z: 371 (M+). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.27 (s, 3 H ) 2.40 (s, 3 H ) 2.95 (s, 6 H ) 3.66 (d, J=5.46 Hz, 1 H ) 3.75 (d, J=5.27 Hz, 1 H ) 4.49 (t, J=4.99 Hz, 1 H ) 4.65 (t, J=4.99 Hz, 1 H ) 5.54 (s, 2 H ) 7.75 (s, 1 H ) 8.13 (s, 1 H ) 8.22 (s, 1 H ) 8.34 (s, 1 H ) 8.88 (t, J=5.84 Hz, 1 H).
Reaction SMILES: [CH:1]1([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[Li]CCCC.[CH3:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C([CH:34](Br)[CH2:35][O:36][CH2:37]C(Br)CC1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[C:10]1([S:7]([C:1]2([CH2:34][CH2:35][O:36][CH2:37][C:23]3[CH:22]=[CH:21][CH:26]=[CH:25][CH:24]=3)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]2)(=[O:8])=[O:9])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=S(=O)(c1ccccc1)C1C=CCCC1
Reactant: CCCCCC
Reactant: BrC(COCC(Br)Cc1ccccc1)Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)C1(CCOCc2ccccc2)C=CCCC1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
Cyclohex-2-enesulfonyl-benzene (7) (10 g, 45 mmol) is dissolved in 450 ml of dry THF and cooled down to −20° C. Then 1.6 M BuLi in Hexane (30.9 ml, 49.5 mmol) is added and stirred for 15 min. After addition of benzyl 2-bromoethylether (8.5 ml, 54 mmol) the mixture is stirred for 1 h at 0° C. Then the mixture is evaporated to dryness. The residue is treated with ice/1M HCl and extracted twice with ether. The combined organic layers are dried over Na2SO4 and evaporated under educed pressure. The product is used in the next step without further purification.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[N:14]=[C:13](Cl)[C:12]([C:16](=O)[CH2:17][CH:18]2[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]2)=[C:11]([Cl:26])[N:10]=1.Cl.[CH3:28][O:29][C:30]1[CH:38]=[CH:37][C:33]([CH2:34][NH:35][NH2:36])=[CH:32][CH:31]=1.Cl>ClCCl>[Cl:26][C:11]1[N:10]=[C:9]([NH2:8])[N:14]=[C:13]2[N:35]([CH2:34][C:33]3[CH:37]=[CH:38][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)[N:36]=[C:16]([CH2:17][CH:18]3[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]3)[C:12]=12
Reactant: CC1(C)OCC(CC(=O)c2c(Cl)nc(N)nc2Cl)O1
Reactant: COc1ccc(CNN)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2nc(CC3COC(C)(C)O3)c3c(Cl)nc(N)nc32)cc1
Yield: 78.2 %

Procedure:
A solution of triethylamine (29.1 ml) in dichloromethane (100 ml) was added to a mixture composed of 1-(2-amino-4,6-dichloropyrimidin-5-yl)-2-(2,2-dimethyl-[1,3]dioxolan-4-yl)ethan-1-one (16 g), (4-methoxybenzyl)-hydrazine hydrochloride (14.1 g) and dichloromethane (400 ml) under cooling in an ice bath over 15 minutes. After stirring under cooling in an ice bath for 1.5 hours, a 0.2 N hydrochloric acid solution (1000 ml) was added to the reaction mixture, followed by extraction with dichloromethane (400 ml). The organic layer was washed with brine (500 ml) and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-chloroform) to obtain the title compound (16.5 g, 78%) as a solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][N:20]([CH2:25][CH2:26][OH:27])[C:21]3=[O:24])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[OH:27][CH2:26][CH2:25][N:20]1[CH:19]=[CH:18][C:17]2[C:22](=[CH:23][C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:15][CH:16]=2)[C:21]1=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3ccn(CCO)c(=O)c3c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1c2cc(N3CCNCC3)ccc2ccn1CCO
Yield: 97.7 %

Procedure:
A solution of compound 7 (6 g, 16.1 mmol) in methylene chloride (20 mL) and trifluoroacetic acid (20 mL) was stirred at r.t for 1 h. Then the mixture was concentrated in vacuo to give the compound 8 (4.3 g, 98%)
Reaction SMILES: COC([CH:5]1[CH2:10][C:9]([C:17]#[N:18])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:7][C:6]1=[O:19])=O>OS(O)(=O)=O.C(O)(=O)C.O>[C:17]([C:9]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:8][CH2:7][C:6](=[O:19])[CH2:5][CH2:10]1)#[N:18]
Reactant: COC(=O)C1CC(C#N)(c2ccccc2)CCC1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: N#CC1(c2ccccc2)CCC(=O)CC1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
5-Cyano-2-oxo-5-phenylcyclohexanecarboxylic acid methyl ester (7.71 g, 0.03 mol) was dissolved in 10 per cent strength H2SO4 and concentrated acetic acid (240 ml). The reaction mixture was stirred at 100° C. for 24 h. The course of the reaction was monitored by TLC. For working up, the mixture was diluted with water (400 ml), while cooling with ice, and extracted with ethyl acetate (3×100 ml). The organic phase was then washed thoroughly with water (6×100 ml), saturated sodium bicarbonate solution (10×100 ml) and saturated sodium chloride solution (1×100 ml). After drying with Na2SO4, the solvent was distilled off on a rotary evaporator. It was possible to isolate the desired product in a yield of 5.46 g (92%) with a melting point of 106-107° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.[H-].[Na+]>CN(C)C=O>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:14][CH:13]=1
Reactant: N#Cc1cccnc1Cl
Reactant: COc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ncccc2C#N)cc1

Procedure:
2-Chloro-3-cyanopyridine is reacted with 4-methoxyphenol in the presence of sodium hydride in dimethylformamide to give 2-(4-methoxyphenoxy)-3-cyanopyridine, which is subjected to Grignard reaction with 2-bromothiophene in a mixed solvent of ether and benzene, followed by treatment with hydrochloric acid to give 2-(4-methoxyphenoxy)-3-(2-thenoyl)pyridine. The thus obtained compound is subjected to demethylation reaction with the use of aluminium chloride and 1-butanethiol in dichloromethane to give 2-(4-hydroxyphenoxy)-3-(2-thenoyl)pyridine.
Reaction SMILES: CO.[OH-].[Li+].[C:5]([O:9][C:10]([NH:12][C:13]([CH3:29])([CH3:28])[CH2:14][C:15]1[N:19]([CH2:20][CH2:21][CH3:22])[N:18]=[C:17]([C:23]([O:25]CC)=[O:24])[CH:16]=1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>C(O)(=O)C.O>[C:5]([O:9][C:10]([NH:12][C:13]([CH3:28])([CH3:29])[CH2:14][C:15]1[N:19]([CH2:20][CH2:21][CH3:22])[N:18]=[C:17]([C:23]([OH:25])=[O:24])[CH:16]=1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CCCn1nc(C(=O)OCC)cc1CC(C)(C)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CCCn1nc(C(=O)O)cc1CC(C)(C)NC(=O)OC(C)(C)C
Reaction time: 5.5 h
Yield: 89.5 %

Procedure:
Methanol (39.9 mL), lithium hydroxide (5.06 g, 121 mmol), and water (13.3 mL) were added to ethyl 5-{2-[(tert-butoxycarbonyl)amino]-2-methylpropyl}-1-propyl-1H-pyrazole-3-carboxylate (10.65 g, 30.1 mmol) in a 500 mL round bottom flask. The mixture was stirred vigorously for 5.5 hours. Acetic acid (8.0 mL) and water (200 mL) were added. A white solid formed and more acetic acid (61 mL) was added. The solid was isolated by filtration, washed with water, and dried. A second crop of solid was isolated from the filtrate. The crops were combined to yield 8.77 g of 5-{2-[(tert-butoxycarbonyl)amino]-2-methylpropyl}-1-propyl-1H-pyrazole-3-carboxylic acid as a white solid, mp 151-152° C. MS (APCI) m/k 326 (M+H)+; Anal. calcd for C16H27N3O4: C, 59.06; H, 8.36; N, 12.91. Found: C, 58.93; H, 8.59; N, 12.94.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][O:8][C:9]([CH:11](P(OCC)(OCC)=O)[N:12]=[CH:13][S:14][CH2:15][C:16](=O)[CH3:17])=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[CH3:17][C:16]1[CH2:15][S:14][CH:13]=[N:12][C:11]=1[C:9]([O:8][CH2:7][C:6]1[CH:27]=[CH:28][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:10]
Reactant: CCOP(=O)(OCC)C(N=CSCC(C)=O)C(=O)OCc1ccc(OC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(COC(=O)C2=C(C)CSC=N2)cc1
Yield: 92.3 %

Procedure:
A solution of 2-oxo-propyl N-(p-methoxybenzyloxycarbonyl-diethylphosphonomethyl)thioformimidate (59 mg.) in acetone (0.5 ml.) is stirred with powdered potassium carbonate (25 mg.) for 21 hours at room temperature and under a nitrogen atmosphere. The resulting mixture is diluted with methylene chloride and filtered. Evaporation of the filtrate in vacuo yields an oil which is dissolved in carbon tetrachloride (4 ml.), washed with water (2 × 2 ml.) and saturated brine (4 ml.), dried over magnesium sulfate, and evaporated in vacuo to yield p-methoxybenzyl 5-methyl-6H-1,3-thiazine-4-carboxylate (35 mg.) as a yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([NH2:9])=[O:8].C(=O)([O-])O.[Na+].[CH:15](I)([CH3:17])[CH3:16]>C(#N)C.ClCCl>[CH3:16][CH:15]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([NH2:9])=[O:8])[CH3:17]
Reactant: NC(=O)C1COCCN1
Reactant: CC(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)N1CCOCC1C(N)=O
Temperature: 150 °C
Yield: 97 %

Procedure:
To a solution of 1.1 g (6.3 mmol) of morpholine-3-carboxamide (a synthesis of which is described in WO-2005/026 156, Hennequin L. F. A. et al.) in acetonitrile (16 ml) are successively added 1.86 g (22.2 mmol) of sodium hydrogen carbonate powder and 0.7 ml (7.0 mmol) of isopropyl iodide, and the mixture is then heated at 150° C. by microwave for 30 minutes. The reaction mixture is cooled to room temperature, diluted with dichloromethane (30 ml) and filtered through Celite. The filtrate is concentrated under reduced pressure and 1.1 g of compound are obtained in the form of a beige-coloured powder, which is used without further purification in the following step. Yield: 97%. MH+: 173.2 (tr: 0.72 min., condition 1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[CH:7]=[N+]=[N-])([CH3:4])([CH3:3])[CH3:2].[Sn](Cl)Cl.[CH3:14][O:15][C:16](=[O:27])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[C:20]([Cl:26])[CH:19]=1>C(Cl)Cl.[Cl-].[Na+].O>[C:1]([O:5][C:6](=[O:10])[CH2:7][C:24]([C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C:16]([O:15][CH3:14])=[O:27])=[CH:19][C:20]=1[Cl:26])=[O:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C=[N+]=[N-]
Reactant: COC(=O)Cc1ccc(C=O)c(Cl)c1
Agent: Cl[Sn]Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)Cc1ccc(C(=O)CC(=O)OC(C)(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A flame-dried flask is charged with tert-butyl-diazoacetate (0.62 mL, 4.48 mmol) and anhydrous tin(II) chloride (168 mg, 0.88 mmol) in dry DCM (10 mL). (3-Chloro-4-formyl-phenyl)-acetic acid methyl ester 14 (500 mg, 2.35 mmol) is dissolved in DCM (5 mL) and added dropwise to the reaction mixture. After stirring for 6 h at room temperature the reaction mixture is poured into brine (50 mL) and extracted with ether (3×50 mL). The combined organic layers are dried (MgSO4), filtered, concentrated and purified on reverse phase HPLC (H2O/MeCN gradient) to afford 3-(2-Chloro-4-methoxycarbonylmethyl-phenyl)-3-oxo-propionic acid tert-butyl ester 56 as a white solid: MS calculated for C16H19Cl2NaO5 (M+Na+) 349.1, found 349.1.