Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:7])[CH2:6][CH2:5][CH2:4]1.Cl[C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH:10]=1>CN(C=O)C>[CH:3]1([O:7][C:9]2[N:14]=[CH:13][N:12]=[C:11]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[CH:10]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)ncn2)CC1
Reactant: OC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(OC3CCC3)ncn2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 469 mg, 11.7 mmol) in DMF (15 mL) was added cyclobutanol (0.92 ml, 11.7 mmol) at 0° C. After stirring at 0° C. for 30 min, a solution of tert-butyl 4-(6-chloropyrimidin-4-yl)piperazine-1-carboxylate (700 mg, 2.34 mmol) in DMF (0.5 mL) was slowly added, and the mixture was stirred at rt for 12 h. Then, the mixture was poured onto water, and the aqueous layer was extracted with EtOAc (twice). The combined organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/EtOAc (5:1-3:1) to give 687 mg (88% yield) of the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:37])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([N+:14]([O-])=O)=[CH:12][C:11]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]([CH3:33])[CH:25]=4)[C:21]([CH3:34])=[CH:20][N:19]=3)=[C:10]([O:35][CH3:36])[CH:9]=2)[CH2:4]1.[NH4+].[Cl-].C(Cl)Cl.CO>C(O)C.O.[Fe]>[CH3:37][N:2]([CH3:1])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([O:35][CH3:36])[C:11]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]([CH3:33])[CH:25]=4)[C:21]([CH3:34])=[CH:20][N:19]=3)=[CH:12][C:13]=2[NH2:14])[CH2:4]1
Reactant: COc1cc(N2CC[C@@H](N(C)C)C2)c([N+](=O)[O-])cc1Nc1ncc(C)c(-c2cn(C)c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: COc1cc(N2CC[C@@H](N(C)C)C2)c(N)cc1Nc1ncc(C)c(-c2cn(C)c3ccccc23)n1
Reaction time: 0.25 h
Yield: 83.8 %

Procedure:
A mixture of N-{4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl}-5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 84, 325 mg, 0.65 mmol), iron (217 mg, 3.89 mmol) and NH4Cl (24.26 mg, 0.45 mmol) in ethanol (16 mL) and water (5.33 mL) was heated at reflux for 3 h. The mixture was then cooled and concentrated in vacuo to give a thick slurry. CH2Cl2 (100 mL) and CH3OH (10 mL) were then added and the mixture was stirred for 0.25 h and then filtered. The filter cake was washed with further CH2Cl2 and CH3OH and the combined organics were dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 1-8% methanolic ammonia in CH2Cl2 gave the title compound (257 mg, 84%) as a yellow dry film; 1H NMR: 1.76 (1H, td), 2.03 (1H, dt), 2.18 (6H, s), 2.37 (3H, s), 2.79-2.87 (1H, m), 2.88-2.97 (2H, m), 3.08-3.14 (1H, m), 3.18 (1H, dd), 3.73 (3H, s), 3.90 (3H, s), 4.19 (2H, s), 6.70 (1H, s), 7.13 (1H, t), 7.25 (1H, t), 7.44 (1H, s), 7.51 (1H, d), 7.65 (1H, s), 8.04 (1H, s), 8.19 (1H, s), 8.46 (1H, d); m/z: ES+ MH+ 472.35.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C:9]([CH3:14])([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])[CH3:3].C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.CN(C(ON1C2=NC=CC=C2N=N1)=[N+](C)C)C.[CH3:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH3:55])[C:50]=1[O:56][C:57]1[N:62]=[CH:61][C:60]([NH2:63])=[CH:59][CH:58]=1>CN(C)C=O>[CH3:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH3:55])[C:50]=1[O:56][C:57]1[N:62]=[CH:61][C:60]([NH:63][C:11](=[O:13])[C:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:10])[CH3:14])=[CH:59][CH:58]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: Cc1cccc(C)c1Oc1ccc(N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1Oc1ccc(NC(=O)C(C)(C)NC(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.4 %

Procedure:
In a 8 mL vial N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-methylalanine (204 mg, 1.003 mmol) and N-ethyl-N-(1-methylethyl)-2-propanamine (0.219 mL, 1.253 mmol) were dissolved in N,N-Dimethylformamide (4 mL) to give a pale yellow solution. N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (381 mg, 1.003 mmol) was added. The reaction mixture became bright yellow and was stirred at room temperature for 15 minutes. 6-[(2,6-dimethylphenyl)oxy]-3-pyridinamine (Intermediate 42, 223.8 mg) was added and the reaction mixture was warmed at 60° C. After 4 hours, the reaction was complete. The solvent was evaporated under vacuum using the Genevac affording a dark brown oil which was purified by silica gel chromatography (Biotage system, 25 g SNAP column) using as eluents a gradient Cyclohexane/EtOAc from 3:1 to 1:1 in 10 CV; then 1:1 for 5 CV. The collected fractions afforded the title compound as a pale yellow solid (202.1 mg).
Reaction SMILES: [C:1]1(C)[CH:6]=CC(S(O)(=O)=O)=C[CH:2]=1.[C@@H:12]1([N:21]2[CH:28]=[CH:27][C:25](=[O:26])[NH:24][C:22]2=[O:23])[O:20][C@H:17]([CH2:18][OH:19])[C@@H:15]([OH:16])[C@H:13]1[OH:14]>CC(C)=O>[OH:19][CH2:18][CH:17]1[CH:15]2[O:16][C:1]([CH3:6])([CH3:2])[O:14][CH:13]2[CH:12]([N:21]2[CH:28]=[CH:27][C:25](=[O:26])[NH:24][C:22]2=[O:23])[O:20]1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC1(C)OC2C(CO)OC(n3ccc(=O)[nH]c3=O)C2O1
Reaction time: 4 h
Yield: 84 %

Procedure:
Para-toluene sulfonic acid (2.33 g, 12.3 mmoles, 3 eq.) was added to Uridine (1 g, 4.1 mmoles) in 180 mL of anhydrous acetone. After 4 hours at room temperature, acetone was evaporated and the residual crude product was dissolved in 200 mL of ethyl acetate. The organic phase was washed three times with 20 mL of a hydrogenocarbonate 10% solution, then dried over sodium sulfate. The solvent was removed under vacuum. 0.979 g of white powder was isolated (Yield: 83%). The characterization data were consistent with the chemical structure and formula.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B1OC(C)(C)C(C)(C)O1.Br[C:19]1[CH:24]=[CH:23][N:22]=[C:21]2[NH:25][CH:26]=[CH:27][C:20]=12.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:19]1[CH:24]=[CH:23][N:22]=[C:21]2[NH:25][CH:26]=[CH:27][C:20]=12
Reactant: Brc1ccnc2[nH]ccc12
Reactant: CNc1ccccc1B1OC(C)(C)C(C)(C)O1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CNc1ccccc1-c1ccnc2[nH]ccc12
Temperature: 80 °C

Procedure:
A 1000 mL round bottom flask containing N-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (18.88 g, 81 mmol) was charged with 4-bromo-1H-pyrrolo[2,3-b]pyridine (11.40 g, 57.9 mmol), potassium phosphate (36.8 g, 174 mmol) and phenylallylchloro[1,3-bis(diisopropylphenyl)-2-imidazol-2-ylidene]palladium (II) (1.873 g, 2.89 mmol) under argon. To this was added a mixture of dioxane (400 mL) and water (100 mL) that had been degassed with argon for 30 minutes. The mixture was purged with nitrogen again, and heated at 80° C. overnight under nitrogen. The reaction mixture was cooled to ambient temperature and partitioned between ethyl acetate (750 mL) and 50% brine (1000 mL). The organic layers were dried over sodium sulfate, filtered and concentrated. The crude residue was dissolved in a minimum of methylene chloride, diluted with an equal volume of heptane and was purified on a Teledyne CombiFlash RF chromatography system on a silica gel Gold Rf cartridge (330 g) eluted with a 5-30% 3:1 ethyl acetate/ethanol in heptane to give the title compound. MS (ESI+) m/z 224 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]3[S:19][C:20]([C:30]([OH:32])=[O:31])=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C:13]=23)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[CH3:38]O>>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]3[S:19][C:20]([C:30]([O:32][CH3:38])=[O:31])=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C:13]=23)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: COc1cccc(-c2c(C(=O)O)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1sc2nc(C)cc(NS(=O)(=O)c3cccc(Cl)c3)c2c1-c1cccc(OC)c1
Temperature: 70 °C
Reaction time: 48 h

Procedure:
A mixture of 4-{[(3-chlorophenyl)sulfonyl]amino}-6-methyl-3-[3-(methyloxy)phenyl]-thieno[2,3-b]pyridine-2-carboxylic acid (90 mg, 0.184 mmol) (Example 35) and concentrated sulfuric acid (0.069 mL, 1.288 mmol) in MeOH (5 mL) was heated at 70° C. under nitrogen for 20 h and then left stand at RT for 2 days. The reaction mixture was then concentrated and purified by chromatography on silica gel, eluting with a gradient of 30-50% ethyl acetate in cyclohexane, to give the title compound (46 mg). LCMS (A) m/z: 503 [M+1]+, Rt 1.41 min (acidic), Rt 0.96 min (basic).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[C:6]([CH3:20])[N:5]=[CH:4][N:3]=1.[NH2:21][CH2:22][C:23]1[O:27][C:26]([C:28]([O:30][CH3:31])=[O:29])=[CH:25][CH:24]=1>>[CH3:20][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:21][CH2:22][C:23]2[O:27][C:26]([C:28]([O:30][CH3:31])=[O:29])=[CH:25][CH:24]=2)[C:7]=1[C:8]#[C:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1
Reactant: Cc1ncnc(Cl)c1C#Cc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccc(CN)o1
Product: COC(=O)c1ccc(CNc2ncnc(C)c2C#Cc2ccc(C(F)(F)F)cc2)o1

Procedure:
The method described in Example 23 was repeated except that 4-chloro-6-methyl-5-{[4-(trifluoromethyl)phenyl]ethynyl}pyrimidine was used in place of 4-chloro-2,6-dimethyl-5-{[4-(trifluoromethyl)phenyl]ethynyl}pyrimidine and methyl 5-aminomethyl-2-furancarboxylate was used in place of ethyl (4-aminomethyl)benzoate to obtain a target substance. The target substance was subjected to e.g., proton nuclear magnetic resonance spectrometry (1H-NMR) and mass spectrometry (MS) and confirmed as the titled compound. Furthermore, MS measurement result is shown.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:15]2[C@@H:10]([CH2:11][CH2:12][N:13](C(=O)C(F)(F)F)[CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+]>CO.O.[NH4+].[OH-]>[C:1]([O:5][C:6]([N:8]1[C@@H:15]2[C@@H:10]([CH2:11][CH2:12][NH:13][CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CCN(C(=O)C(F)(F)F)C[C@@H]21
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H]2CCNC[C@@H]21
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.3 %

Procedure:
To the crude product of Example 3H (˜28.2 mmol) in 140 mL CH3OH and 30 mL H2O was added 4.7 g K2CO3 (33.8 mmol). The mixture stirred at ambient temperature for 16 h then was diluted with a 100 mL of a solution of 1% NH4OH: 9% CH3OH: 90% CH2Cl2 and filtered through Celite® diatomaceous earth and silica gel. The filtrate was concentrated under reduced pressure and purified via column chromatography (SiO2, 1% NH4OH: 9% CH3OH: 90% CH2Cl2) to give 3.3 g of the title compound (15.6 mmol, 55% yield). MS (DCl/NH3) m/z 213 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[C:10]([CH2:18][CH2:19][CH3:20])([CH2:15][CH2:16][CH3:17])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[Pd+2].[OH-]>[CH2:18]([C:10]1([CH2:15][CH2:16][CH3:17])[CH:11]([OH:14])[CH2:12][CH2:13][NH:8][CH2:9]1)[CH2:19][CH3:20]
Reactant: [H][H]
Reactant: CCCC1(CCC)CN(Cc2ccccc2)CCC1O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCC1(CCC)CNCCC1O

Procedure:
A mixture of 1-benzyl-3,3-di-n-propyl-4-hydroxypiperidine (0.9 g, 3.27 mmole) and 20% palladium hydroxide (0.2 g) in methanol (20 ml) was stirred at ambient temperature in hydrogen atmosphere (1 atm.) for 8 hr. Catalyst was filtered off, washed with methanol, filtrate was concentrated to dryness to give 3,3-di-n-propyl-4-hydroxypiperidine as oil. Yield 0.5 g (84%), C12H23NO, m/z 186 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:43])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]([CH2:38][CH2:39][N:40]([CH3:42])[CH3:41])[C:10]2[C:15]([C:16]=1[CH:17]([C:28]1[CH:33]=[CH:32][C:31]([O:34]COC)=[CH:30][CH:29]=1)[C:18]1[CH:23]=[CH:22][C:21]([O:24]COC)=[CH:20][CH:19]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7].Cl.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(O)C>[CH3:43][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]([CH2:38][CH2:39][N:40]([CH3:42])[CH3:41])[C:10]2[C:15]([C:16]=1[CH:17]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7]
Reactant: COCOc1ccc(C(c2ccc(OCOC)cc2)c2c(C(=O)NCCN(C)C)n(CCN(C)C)c3ccccc23)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(C)CCNC(=O)c1c(C(c2ccc(O)cc2)c2ccc(O)cc2)c2ccccc2n1CCN(C)C
Temperature: 25 °C
Yield: 75.9 %

Procedure:
Compound 49 (2.48 g, 4.21 mmol) obtained in Example 49 was dissolved in ethanol (50 ml), and 15 ml of 2N hydrochloric acid was added thereto, followed by heating under reflux for 2 hours. After cooling the reaction solution, a saturated aqueous solution of sodium bicarbonate was added thereto for neutralization. A little amount of ethyl acetate was added to the mixture followed by stirring at room temperature. The resulting crystals were collected by filtration, washed with water, and dried under reduced pressure to give 1.6 g (yield: 81%) of the title compound.
Reaction SMILES: [I-].[K+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17]Cl)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8]=2[CH:25]=1.[CH:26]1([NH2:29])[CH2:28][CH2:27]1>O1CCCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][NH:29][CH:26]4[CH2:28][CH2:27]4)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8]=2[CH:25]=1
Reactant: ClCc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1)=NC2
Reactant: NC1CC1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CNC3CC3)n1-2

Procedure:
In the manner given in Example 1, potassium iodide and 8-bromo-1-(chloromethyl)-6-phenyl-4H-s-triazolo-[4,3-a][1,4]benzodiazepine in tetrahydrofuran is treated with cyclopropylamine to give 8-bromo-1-[(cyclopropylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [CH2:1]=[O:2].[CH:3]1([CH:9]=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[OH-].[Na+]>CO>[CH:9]([C:3]1([CH2:1][OH:2])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)=[O:10]
Reactant: O=CC1CCCCC1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=CC1(CO)CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
Methanol is added to a suspension of 37% formaldehyde solution (69 ml.) and cyclohexanecarboxaldehyde (100 g.; 0.89 mole) to afford a homogeneous solution. The mixture is cooled to 0° C. and a sodium hydroxide solution (1 N; 67 ml.) is added with stirring over the course of 15 minutes. The mixture is allowed to warm to room temperature and is stirred at 25° C. overnight. The solution is then concentrated, diluted with water and extracted with ether. The ether extract is dried, evaporated in vacuo and the residual colorless liquid is distilled to afford 51% of 1-formyl-1-hydroxymethylcyclohexane (65 g.), b.p. 120°-125° C./0.90 mm.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][O:9]2)=[CH:4][CH:3]=1.[H-].[CH2:22]([Al+]CC(C)C)[CH:23](C)[CH3:24].C1(C)C=CC=CC=1.[Cl-].[NH4+].Cl.C([Si](C)(C)C)C=C>O1CCCC1.ClCCCl.[I-].[Zn+2].[I-].CO>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:24][CH:23]=[CH2:22])[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][O:9]2)=[CH:4][CH:3]=1
Reactant: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1=O
Reactant: CC(C)C[Al+]CC(C)C
Agent: C=CC[Si](C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: ClCCCl
Solvent: C1CCOC1
Product: C=CCC1c2ccc(O)cc2OCC1(C)c1ccc(O)cc1
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 44 %

Procedure:
The (+)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-one resolved as Peak 1 in Example 22 (2.0 g, 7.40 mmol) was dissolved in anhydrous tetrahydrofuran (30 ml) and then cooled to −78° C. To this solution, a solution of diisobutylaluminum hydride in toluene (1N, 22.94 ml, 22.94 mmol) was slowly added dropwise, and the resulting mixture was stirred for 35 minutes at −78° C. Methanol (1 ml) was added to the reaction mixture at −78° C., which was then warmed to 0° C. and saturated aqueous ammonium chloride (5 ml) and concentrated hydrochloric acid (7 ml) were added to the mixture followed by stirring for 30 minutes. The reaction mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, zinc iodide (2.55 g, 7.98 mmol) was added to a suspension of the residue and allyltrimethylsilane (5.3 ml, 33.2 mmol) in 1,2-dichloroethane (80 ml) followed by stirring for 12 hours at room temperature. Saturated aqueous ammonium chloride (15 ml), methanol (10 ml) and concentrated hydrochloric acid (10 ml) were added to the reaction mixture, followed by stirring for 30 minutes. The reaction mixture was extracted twice with dichloromethane. The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/4) to give optically active 7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-(2-propenyl)chroman (cis-configuration, 859 mg, Yield 44%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[CH2:9]([C:16]([C:18]([F:21])([F:20])[F:19])=O)[C:10]([C:12]([F:15])([F:14])[F:13])=O>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]2[C:4](=[N:8][C:10]([C:12]([F:13])([F:14])[F:15])=[CH:9][C:16]=2[C:18]([F:19])([F:21])[F:20])[N:3]=1
Reactant: O=C(CC(=O)C(F)(F)F)C(F)(F)F
Reactant: Nc1cccc(N)n1
Product: Nc1ccc2c(C(F)(F)F)cc(C(F)(F)F)nc2n1

Procedure:
A process as claimed in claim 1 wherein 2,6-diaminopyridine is reacted with 1,1,1,5,5,5-hexafluoroacetylacetone to provide 2-amino-5,7-di(trifluoromethyl)-1,8-naphthyridine.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[C:12](=[O:13])[N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[C:10]2[CH:22]=[CH:23][S:24][C:9]=2[C:8]=1Cl)=[O:6])([CH3:3])[CH3:2].C(OC(C1C(=O)N(CC2C=CC=C(F)C=2)C2C=CSC=2C=1[N:49]1[CH2:54][CH2:53][N:52]([C:55]([C:57]2[S:58][CH:59]=[CH:60][CH:61]=2)=[O:56])[CH2:51][CH2:50]1)=O)C>>[CH:1]([O:4][C:5]([C:7]1[C:12](=[O:13])[N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[C:10]2[CH:22]=[CH:23][S:24][C:9]=2[C:8]=1[N:49]1[CH2:54][CH2:53][N:52]([C:55]([C:57]2[S:58][CH:59]=[CH:60][CH:61]=2)=[O:56])[CH2:51][CH2:50]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2sccc2n(Cc2cccc(F)c2)c1=O
Reactant: CC(C)OC(=O)c1c(Cl)c2sccc2n(Cc2cccc(F)c2)c1=O
Product: CC(C)OC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2sccc2n(Cc2cccc(F)c2)c1=O

Procedure:
This compound was prepared from 7-chloro-4-(3-fluoro-benzyl)-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid isopropyl ester (18) by applying the same procedure as described for 4-(3-fluoro-benzyl)-5-oxo-7-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (9). Yield (57%). 1H-NMR (DMSO-d6) δ 1.29 (d, J=6.4 Hz, 6H), 3.37 (m, 4H), 3.81 (m, 4H), 5.10 (m, 1H), 5.38 (s, 2H), 7.04-7.16 (m, 4H), 7.32 (d, J=5.6 Hz, 1H), 7.37 (m, 1H), 7.47 (dd, J=1.2, 3.6 Hz, 1H), 7.79 (dd, J=1.2, 5.2 Hz, 1H), 8.02 (d, J=5.6 Hz, 1H); EIMS m/z 540 (M+1).
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][SH:4].[CH3:6][C@H:7]1[C:25](=[O:26])[O:24][C@H:9]2[CH2:10][C@:11]3([CH3:23])[O:13][C@H:12]3[C@@H:14]3[O:16][C@@H:15]3[C:17]3[C:21](=[O:22])[O:20][C@@H:19]([C@H:8]12)[CH:18]=3.CN(C1C=CC=CN=1)C>CC(C)=O>[OH:16][CH:14]1[CH:15]([S:4][CH2:3][CH:2]([CH3:5])[CH3:1])[C:17]2=[CH:18][CH:19]([O:20][C:21]2=[O:22])[CH:8]2[CH:9]([O:24][C:25](=[O:26])[CH:7]2[CH3:6])[CH2:10][C:11]2([CH3:23])[CH:12]1[O:13]2
Reactant: CC(C)CS
Reactant: C[C@H]1C(=O)O[C@H]2C[C@]3(C)O[C@H]3[C@@H]3O[C@@H]3C3=C[C@@H](OC3=O)[C@@H]21
Agent: CN(C)c1ccccn1
Solvent: CC(C)=O
Product: CC(C)CSC1C2=CC(OC2=O)C2C(CC3(C)OC3C1O)OC(=O)C2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
2-methyl-1-propanethiol (500 μmol; 54 μl) is added to a solution of dihydromikanolide (100 μmol; 30 mg) and dimethylaminopyridine (10 μmol; 1.2 mg) in acetone (1 ml). The reaction mass is stirred for two hours at ambient temperature then the solvent is evaporated off under reduced pressure. The residue is taken up in ether then the precipitate formed is filtered, washed with ether and dried under vacuum. 25 mg of product is obtained in the form of a white powder.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[N:5]([CH3:8])[CH:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([O:16][CH3:17])[CH:10]=2)[P:3]1(=[O:25])[O:18]C1C=CC=CC=1.C(#N)C.[OH2:29]>>[CH3:8][N:5]([CH:4]([P:3](=[O:25])([OH:18])[OH:29])[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([O:16][CH3:17])[CH:10]=1)[C:6]([NH:2][CH3:1])=[O:7]
Reactant: COc1cc(C2N(C)C(=O)N(C)P2(=O)Oc2ccccc2)ccc1O
Reactant: O
Solvent: CC#N
Product: CNC(=O)N(C)C(c1ccc(O)c(OC)c1)P(=O)(O)O

Procedure:
A solution of 10.0g of 1,4-dimethyl-3-(4-hydroxy-3-methoxyphenyl)-2-phenoxy-1,4,2-diazaphospholidin-5-one-2-oxide in 90g of acetonitrile and 10g of water was warmed at reflux for 0.5 hr, and then most of the solvent was allowed to evaporate. The residue was recrystallized twice from ethanol to give 4.6g of white solid: mp 183°-184° (dec); 31P nmr (CD3SOCD3) -18.6 ppm (d, J = 24Hz); 1H nmr δ10.0 (broad, 3, OH), 5.7 (d, 1, J = 24Hz, CH), 3.8 (s, 3, OCH3), 2.9 (s, 3, NCH3), 2.7 (s, 3, NCH3); 6.7-7.3 (m, 4, aryl and HN).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[N:5]=[N:4][N:3]=1.[CH2:13]([N:15](CC)[CH2:16][CH3:17])[CH3:14].ClC(OCC(C)C)=O.C(NCC)C>CN(C)C=O>[CH2:13]([N:15]([CH2:16][CH3:17])[C:10](=[O:12])[CH2:9][CH2:8][CH2:7][N:6]1[C:2]([CH3:1])=[N:3][N:4]=[N:5]1)[CH3:14]
Reactant: Cc1nnnn1CCCC(=O)O
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)CCCn1nnnc1C
Yield: 62.2 %

Procedure:
4-(5-Methyl-1,2,3,4-tetrazol-1-yl)butyric acid (1.7 g) is dissolved in dimethylformamide (50 ml) and triethylamine (1.1 g) is added to the solution. Isobutyl chloroformate (1.5 g) is added dropwise to the mixture with stirring and ice-cooling and the mixture is stirred at room temperature for 30 minutes. Diethylamine (0.9 g) is added dropwise to the mixture with stirring at room temperature. The mixture is stirred for 3 hours. Dimethylformamide is distilled off and the residue is purified by silica gel column chromatography (silica gel made of Merck & Co.). The column is eluted with chloroform-methanol (50:1) to obtain N,N-diethyl-4-(5-methyl-1,2,3,4-tetrazol-1-yl)butyric acid amide (1.4 g), b.p. 190°-200° C. (bath temperature)/0.04 mmHg, nD25 =1.4908.