Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@@H:2]([C:23]([O:25]CC1C=CC=CC=1)=[O:24])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([S:13]([C:16]2[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:5]=1.[OH-].[Na+]>C(O)C>[NH:1]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@@H:2]([C:23]([OH:25])=[O:24])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([S:13]([C:16]2[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)OCc3ccccc3)c3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)c3ccccc32)cc1
Temperature: 0 °C
Yield: 92.6 %

Procedure:
To an ice cooled solution of Boc-D-Trp(Tos)-OBzl (3.23 g) in ethanol (40 ml) was added 1N sodium hydroxide solution (6 ml) at room temperature. The solution was stirred for two hours, during this period two 2 ml portions of 1N sodium hydroxide solution were added. After evaporation of ethanol, and addition of water (50 ml), the solution was extracted once with ether. The aqueous layer was acidified with 1N hydrochloric acid and the resulting oily material was extracted with ethyl acetate, and the extract was washed with sodium chloride, and dried over magnesium sulfate. Evaporation gave Boc-D-Trp(Tos)-OH (2.5 g) as an amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4].[F:19][C:20]1[CH:21]=[C:22]([Mg]Br)[CH:23]=[CH:24][C:25]=1[F:26]>C1COCC1>[C:15]([O:14][C:12]([NH:6][C@H:5]([CH2:10][CH2:9][CH2:8][C:7]([C:23]1[CH:22]=[CH:21][C:20]([F:19])=[C:25]([F:26])[CH:24]=1)=[O:11])[C:3]([O:2][CH3:1])=[O:4])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: COC(=O)[C@H]1CCCC(=O)N1C(=O)OC(C)(C)C
Reactant: Fc1ccc([Mg]Br)cc1F
Solvent: C1CCOC1
Product: COC(=O)[C@@H](CCCC(=O)c1ccc(F)c(F)c1)NC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of (R)-6-oxopiperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (820 mg) in THF (12 mL), 3,4-difluorophenylmagnesium bromide (0.5 M solution in THF, 7.0 mL) was added in a nitrogen atmosphere at −78° C. over 20 minutes. The reaction solution was stirred at −78° C. to −10° C. for two hours, and then quenched with a saturated ammonium chloride solution at −10° C. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain methyl (R)-2-tert-butoxycarbonylamino-6-(3,4-difluorophenyl)-6-oxohexanoate (850 mg). A solution of 4 N hydrochloric acid in ethyl acetate (25 mL) was added to a solution of methyl (R)-2-tert-butoxycarbonylamino-6-(3,4-difluorophenyl)-6-oxohexanoate (2.45 g) in ethyl acetate (25 mL) at room temperature, and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was made basic with a saturated sodium bicarbonate solution. Then, chloroform was added to the residue, and the mixture was stirred at room temperature for two hours. The organic layer was separated, dried over magnesium sulfate, and then concentrated under reduced pressure. 10% palladium-carbon (150 mg) was added to a solution of the residue in methanol (30 mL), and the reaction solution was stirred in a hydrogen atmosphere at room temperature for two hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 1.25 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [OH-].[NH2:2][C:3]1[C:4]2[C:9]([N:10]=[C:11]3[C:16]=1[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[F:18][C:19]([F:28])([F:29])[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH:2][C:3]1[C:4]2[C:9]([N:10]=[C:11]3[C:16]=1[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: Nc1c2c(nc3ccccc13)CCCC2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C1CCCc2nc3ccccc3c(NCc3cccc(C(F)(F)F)c3)c21
Reaction time: 1 h
Yield: 42 %

Procedure:
In 150 ml of toluene and 700 of 30% potassisum hydroxide were combined 3.00 g of 9-amino-3,4-dihydroacridin-1(2H)-one and 0.72 g of tetrabutylammonium hydrogen sulfate. The reaction was mechanically stirred and heated with a steam bath. To it was added dropwise a solution of 13.5 g 3-trifluoromethylbenzyl bromide in 30 ml of toluene over 1 hour. After the addition, heating was continued 1 hour during which the reaction went to completion. The organic phase was separated, washed with ice-cold saturated NaCl solution, dried over anhydrous magnesium sulfate, filtered and evaporated to an oil. The oil was diluted with 10 ml of ethyl acetate and purified by preparative HPLC (ethyl acetate). The product-containing fractions were evaporated and recrystallized from DCM/hexane to yield 2.20 g of solid, mp 147°-149° C.
Reaction SMILES: Br[CH2:2][C:3]1([C:6]2[CH:11]=[CH:10][C:9]([I:12])=[CH:8][CH:7]=2)[CH2:5][CH2:4]1.[N-:13]=[N+:14]=[N-:15].[Na+].CCOC(C)=O>CN(C=O)C>[N:13]([CH2:2][C:3]1([C:6]2[CH:11]=[CH:10][C:9]([I:12])=[CH:8][CH:7]=2)[CH2:5][CH2:4]1)=[N+:14]=[N-:15]
Reactant: BrCC1(c2ccc(I)cc2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCC1(c2ccc(I)cc2)CC1
Yield: 80.1 %

Procedure:
Part A. 1-(1-Bromomethylcyclopropyl)-4-iodobenzene (2.0 g, 5.97 mmol) and NaN3 (1.0 g, 15.38 mmol, 2.6 eq) were stirred in DMF (10 mL) overnight. Analytical LC-MS showed completion of the reaction. EtOAc was added to the solution. The mixture was washed with H2O and brine, dried over MgSO4, and concentrated to give 1-(1-azidomethyl-cyclopropyl)-4-iodobenzene (1.43 g, yield: 80%). The azide (1.40 g, 4.68 mmol) and PPh3 (1.84 g, 7.02 mmol, 1.5 eq) were stirred in THF (10 mL) at RT for 40 min. H2O (2 mL) was added, and the solution was stirred at 50° C. for 6 h. LC-MS showed completion of the reaction. The mixture was extracted with Et2O (2×). The aqueous layer was basified with 50% NaOH, extracted with CH2Cl2 (2×), washed with H2O, brine, dried over MgSO4, and concentrated to give 1-(4-iodophenyl)cyclopropyl methylamine (0.98 g, yield: 75%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.[ClH:21]>>[ClH:21].[ClH:21].[CH3:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][NH:11]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)cn1
Agent: Cl
Product: Cc1ccc(OC[C@@H]2CCN2)cn1
Yield: 63 %

Procedure:
The compound from step 40a (0.123 g, 0.44 mmol) was treated with saturated ethanolic HCl (5 mL) for 18 hr. The volatiles were removed in vacuo, and the dihydiochloride was washed with Et2O (3×20 mL), evaporated to dryness and recrystallized (EtOHIEt2O) to yield the title compound (0.074 g, 63%) as a white solid. mp 141-144° C. MS (DCI/NH3) m/e: 179 (M+H)+. 1H NMR (D2O, 300 MHz) δ: 8.33 (d, J=2.9 Hz, 1H), 7.89 (dd, J=9.0, 2.8 Hz, 1H), 7.64 (d J=8.8 Hz, 1H), 5.01-4.93 (m, 1H), 4.48 (d, J=4.4 Hz, 2H), 4.21-4.04 (m, 2H), 2.70 (q, J=8.5 Hz, 2H), 2.62 (s, 3H). Anal. calc. for C10H16Cl2N2O.1.0H2O: C, 44.62; H, 6.74; N, 10.41. Found: C, 44.55; H, 7.02; N, 10.50. [α]D24 -7.89 ° (c=0.19 in MeOH).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1.[C:12]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]([C:18](O)=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=1>>[C:12]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]([C:18]([N:6]2[CH2:7][C:2](=[O:1])[CH2:3][CH2:4][CH:5]2[C:8]([O:10][CH3:11])=[O:9])=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: COC(=O)C1CCC(=O)CN1
Product: COC(=O)C1CCC(=O)CN1C(=O)c1ccccc1-c1ccccc1

Procedure:
Methyl 1-(biphenylcarbonyl)-5-oxopiperidine-2-carboxylate was prepared according to general procedure A using methyl 5-oxopiperidine-2-carboxylate and biphenyl-2-carboxylic acid. MS (ESI) 338 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH3:10][O:11][CH2:12]OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(Cl)Cl>CCN(CC)CC>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][O:11][CH3:12]
Reactant: COCOC
Reactant: Oc1ccc(Br)cc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COCOc1ccc(Br)cc1Br
Yield: 85.5 %

Procedure:
Into a 500-mL round bottom flask equipped with a soxlet and a condensor were placed 2,4-dibromophenol (32.0 g, 0.13 mole), dimethoxymethane (200 mL, 2.26 mole), p-toluenesulfonic acid monohydrate (2.24 g, 12.0 mmol) and CH2Cl2 (200 mL). The soxlet extractor was filled with 3 A and 4 A molecular sieves. The reaction mixture was heated to reflux for 24 h after which time the soxlet extractor was filled with freshly activated sieves. The reaction mixture was heated to reflux for another 24 h. After this period of time, Et3N (10 mL) was added. The reaction mixture was stirred for 5 mn, and concentrated to dryness. The residue was dissolved in CH2Cl2 (400 mL) and the resulting solution was washed with 5% NaOH (400 mL), H2O (400 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was purified by flash chromatography (hexanes/EtOAc; 6:1) to yield 2,4-Dibromo-1-methoxymethoxybenzene [9](32.9 g, 88%) as a light yellow oil; 1H NMR (CDCl3, 300 MHz) δ7.67 [s, ArH(3)], 7.33 [d, J=8.7 Hz, ArH(5)], 7.02 [d, J=8.7 Hz, ArH(6)], 5.21 [s, OCH2OCH3 ], and 3.49 [s, OCH3 ]; LRMS (EI) m/z 298 (M+, 3), 296 (M+, 5), 294 (M+, 3), and 45 (100)
Reaction SMILES: [NH2:1][C:2]([CH3:10])([CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]#[N:4].Cl[N:12](Cl)[C:13]([CH3:21])([CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]#[N:15].[OH-].[Na+]>O>[N:12]([C:13]([CH3:21])([CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]#[N:15])=[N:1][C:2]([CH3:10])([CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]#[N:4]
Reactant: CC(C)CCC(C)(N)C#N
Reactant: CC(C)CCC(C)(C#N)N(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)CCC(C)(C#N)N=NC(C)(C#N)CCC(C)C

Procedure:
30 g of 94% pure 2-amino-2,5-dimethylhexanenitrile is chlorinated in water at 1080 mv by the method of Example 2. To the resulting aqueous dispersion of 2-dichloroamino-2,5-dimethylhexanenitrile, following the method of Example 1, caustic soda, wetter, and a further 20 g of 2-amino-2,5-dimethylhexanenitrile are added and the suspension is filtered to yield 40.6 g of the title compound as a creamy white solid, mp 56°-58° C. (88%).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]3[C:9]=2[N:10]=[CH:11][N:12]3[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:24][O:25][C:26]1[N:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH3:24][O:25][C:26]1[N:31]=[CH:30][C:29]([NH:32][C:2]2[C:7]([C:8]3[N:16]=[C:15]([CH3:17])[N:14]=[C:13]4[C:9]=3[N:10]=[CH:11][N:12]4[CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:28][CH:27]=1
Reactant: Cc1nc(-c2cccnc2F)c2ncn(C3CCCCO3)c2n1
Reactant: COc1ccc(N)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Nc2ncccc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Reaction time: 1 h
Yield: 38.1 %

Procedure:
A solution of 6-(2-fluoropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (190 mg, 606 μmol) and 6-methoxypyridin-3-amine (94.1 mg, 758 μmol) (Aldrich, St. Louis, Mo.) in THF (2.0 mL) was cooled in an ice bath and treated with LiHMDS (3.0 mL, 3.0 mmol)(a 1.0 M in THF solution). A blood-red solution was obtained. The mixture was stirred for 1 h, and then quenched with water (0.1 mL). The mixture was extracted into EtOAc from saturated aqueous NaHCO3, concentrated and purified by flash chromatography on silica (25 to 50% EtOAc/hexane; yellow band from column) to give 6-methoxy-N-(3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)pyridin-3-amine (96.3 mg, 38.0% yield) as a yellow crystalline solid. 1H NMR (400 MHz, d6-DMSO) δ 12.50 (s, 1H); 9.72 (dd, J=7.82, 1.71 Hz, 1H); 8.87 (s, 1H); 8.53 (d, J=2.69 Hz, 1H); 8.32 (dd, J=4.65, 1.96 Hz, 1H); 8.18 (dd, J=8.93, 2.81 Hz, 1H); 7.01 (dd, J=7.82, 4.65 Hz, 1H); 6.85 (d, J=9.05 Hz, 1H); 5.80-5.89 (m, 1H); 3.97-4.12 (m, 1H); 3.85 (s, 3H); 3.67-3.82 (m, 1H); 2.89 (s, 3H); 2.27-2.38 (m, 1H); 1.93-2.12 (m, 2H); 1.72-1.88 (m, 1H); 1.55-1.70 (m, 2H). m/z (ESI, +ve) 418.1 (M+H)+.
Reaction SMILES: [C:1]([C:9]1C([N+]([O-])=O)=CC(C(OCC)=O)=CC=1O)(=O)[C:2]1C=CC=C[CH:3]=1.C(I)C.[OH:27][C:28]1[CH:29]=[C:30]([CH:36]=[C:37]([N+:48]([O-:50])=[O:49])[C:38]=1[C:39](=[O:47])[C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=1)[C:31]([O:33]CC)=[O:32].C(I)CCC.C(O)C>>[CH2:9]([O:27][C:28]1[CH:29]=[C:30]([CH:36]=[C:37]([N+:48]([O-:50])=[O:49])[C:38]=1[C:39](=[O:47])[C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=1)[C:31]([OH:33])=[O:32])[CH2:1][CH2:2][CH3:3]
Reactant: CCOC(=O)c1cc(O)c(C(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Reactant: CCOC(=O)c1cc(O)c(C(=O)c2ccccc2)c([N+](=O)[O-])c1
Solvent: CCI
Solvent: CCO
Solvent: CCCCI
Product: CCCCOc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccc(C)cc1

Procedure:
By replacing in Example 6, step B, ethyl 4-benzoyl3-hydroxy-5-nitrobenzoate and ethyl iodide with equimolar amounts of ethyl 3-hydroxy-4-(4'-methylbenzoyl)-5-nitrobenzoate and n-butyl iodide respectively and following the procedure described, 3-n-butoxy-4-(4'-methylbenzoyl)5-nitrobenzoic acid crystallizing with 0.5mole of ethanol is obtained with a melting point of 162.5°-163° C.
Reaction SMILES: C[C@H]1N[C@@H](C)CN(S(N)(=O)=O)C1.[F:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:21][S:22][C:23]1[N:28]=[C:27]([NH:29][S:30]([N:33]2[CH2:38][C@H:37]([CH3:39])[NH:36][C@H:35]([CH3:40])[CH2:34]2)(=[O:32])=[O:31])[CH:26]=[C:25]([O:41][C@H:42](C)CO)[N:24]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].ClC1C=C(OC)N=C(SCC2C=CC=C(F)C=2F)N=1.[Cl-].[NH4+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.CCOC(C)=O>[F:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:21][S:22][C:23]1[N:28]=[C:27]([NH:29][S:30]([N:33]2[CH2:38][C@H:37]([CH3:39])[NH:36][C@H:35]([CH3:40])[CH2:34]2)(=[O:31])=[O:32])[CH:26]=[C:25]([O:41][CH3:42])[N:24]=1
Reactant: C[C@@H]1CN(S(=O)(=O)Nc2cc(O[C@H](C)CO)nc(SCc3cccc(F)c3F)n2)C[C@H](C)N1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(NS(=O)(=O)N2C[C@@H](C)N[C@@H](C)C2)nc(SCc2cccc(F)c2F)n1
Temperature: 100 °C

Procedure:
A mixture of (3R,5S)-3,5-dimethylpiperazine-1-sulfonamide (the product of example 72, 0.26 g), tris(dibenzylideneacetone)-dipalladium (0) (61 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (32 mg), cesium carbonate (0.32 g) and 4-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-methoxypyrimidine (the product of example 35 step i, 0.20 g) in anhydrous dioxane (8 ml) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 15 min. Saturated aqueous ammonium chloride (5 ml) and EtOAc (5 ml) were added, followed by H2O. The layers were separated and the organic layer extracted with H2O (×3). The organic layer was discarded and the combined aqueous extracts exhaustively extracted with further EtOAc. These extracts were combined, washed with saturated aqueous sodium chloride, dried with sodium sulfate, filtered and evaporated. The resulting solid was washed with H2O to afford the title compound as a white solid. Yield: 0.111 g
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:12]([F:23])[CH:11]=2)=[C:8]([O:24]COC)[CH:7]=[C:6]([CH2:28][C:29]2[C:30]([NH2:36])=[N:31][C:32]([NH2:35])=[N:33][CH:34]=2)[CH:5]=1)[CH3:2].Cl.N>CO>[NH2:35][C:32]1[N:31]=[C:30]([NH2:36])[C:29]([CH2:28][C:6]2[CH:7]=[C:8]([OH:24])[C:9]([C:10]3[CH:15]=[CH:14][C:13]([CH2:16][N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[C:12]([F:23])[CH:11]=3)=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)=[CH:34][N:33]=1
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCOC)c1-c1ccc(CN2CCOCC2)c(F)c1
Agent: Cl
Agent: N
Solvent: CO
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(O)c1-c1ccc(CN2CCOCC2)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
A solution of 5-(6-ethoxy-3′-fluoro-2-methoxymethoxy-4′-morpholin-4-ylmethyl-biphenyl-4-ylmethyl)-pyrimidine-2,4-diamine (120 mg; 0.24 mmol) in 20 ml methanol is heated to 50° C., 2.7 ml 4.5 M hydrochloric acid in methanol are then added and the mixture is stirred for 1 hour at this temperature. The pale yellow solution is cooled to 0° C., adjusted to pH 10 with 25% aqueous ammonia solution and concentrated to a volume of 2 ml. 20 ml water are added to the residue and the mixture is extracted three times with 50 ml methylene chloride each time. The combined organic phases are dried over magnesium sulphate and concentrated. 57 mg (52%) 4-(2,4-diamino-pyrimidin-5-ylmethyl)-6-ethoxy-3′-fluoro-4′-morpholin-4-ylmethyl-biphenyl-2-ol are obtained as a colourless powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][C:6]1[S:12][CH:11]2[N:8]([C:9](=[O:16])[C@@H:10]2[C@H:13]([OH:15])[CH3:14])[C:7]=1[C:17]([O-:19])=[O:18].[K+].[C:24]([O:30][CH2:31]I)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][C:6]1[S:12][CH:11]2[N:8]([C:9](=[O:16])[C@@H:10]2[C@H:13]([OH:15])[CH3:14])[C:7]=1[C:17]([O:19][CH2:31][O:30][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[O:18]
Reactant: CC(C)(C)C(=O)OCI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Oc3cccc(F)c3)SC12
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(Oc3cccc(F)c3)SC12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 100 mg of potassium 3-(3-fluorophenoxy)-6(S)-{1-(R)-hydroxyethyl}-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate in 1 ml of dimethylformamide were added 98 μl of pivaloyloxymethyl iodide and the mixture was stirred at room temperature for 90 minutes. The mixture was partitioned between ethyl acetate and water, the organic layer was washed with water and brine, dried over magnesium sulphate and evaporated in vacuo to dryness. Chromatography over silica gel and elution with hexane-ethylacetate afforded 50 mg of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]([C:8]1[CH:20]=[CH:19][C:11]([C:12]([C:14]2[S:18][CH:17]=[N:16][CH:15]=2)=O)=[CH:10][CH:9]=1)#[N:7].C(OCC)(=O)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCC.CCOCC>[C:6]([C:8]1[CH:20]=[CH:19][C:11]([C:12]([C:14]2[S:18][CH:17]=[N:16][CH:15]=2)=[CH2:1])=[CH:10][CH:9]=1)#[N:7]
Reactant: [Li]CCCC
Reactant: N#Cc1ccc(C(=O)c2cncs2)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: C=C(c1ccc(C#N)cc1)c1cncs1
Reaction time: 1.5 h

Procedure:
714 mg of methyltriphenylphosphonium bromide are introduced into 6.7 ml of ether, and 0.973 ml of 1.6M n-butyllithium in hexane is added at 7°. The orange suspension is stirred at the same temperature for 1.5 hours and then reacted with a suspension, cooled to 7°, of 5-(4-cyanobenzoyl)-thiazole (Example 8a) in 3 ml of ether. After stirring for 3 hours at RT, the ether is replaced by ethyl acetate and the mixture is stirred for a further 2 hours under reflux. The solid material is filtered off with suction and the mother liquor is concentrated. The residue is taken up in methylene chloride and the organic phase is washed in succession with 7 ml of 2N hydrochloric acid and with water, dried over sodium sulfate and concentrated. The crude product is purified by column chromatography (SiO2 0.04-0.06 mesh, 0.1 bar, hexane/ethyl acetate 2:1 to 1:1) and crystallised from hexane; m.p. 71°-73°; 1H-NMR (CDCl3): δ(ppm)=5.5 (s,1H), 5.73 (s,1H) 7.54 and 7.71 (m,4H), 7.69 (s,1H), 8.78 (s,1H).
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:12]([N:19]1[C:24]2[N:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22](=O)[O:21]C1=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:6]([O:5][C:3]([C:2]1[C:1](=[O:9])[N:19]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:24]2[C:23]([C:22]=1[OH:21])=[CH:28][CH:27]=[CH:26][N:25]=2)=[O:4])[CH3:7]
Reactant: O=c1oc(=O)n(Cc2ccccc2)c2ncccc12
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)c1c(O)c2cccnc2n(Cc2ccccc2)c1=O

Procedure:
Diethyl malonate can then be reacted with the 1-benzyl-1H-pyrido[2,3-d][1,3]oxazine-2,4-dione (2) to yield the intermediate 1-benzyl-4-hydroxy-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (3) as shown in Scheme 3:
Reaction SMILES: [OH:1][CH:2](/[CH:12]=[CH:13]/[C:14]1[C:15]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[N:18][N:17]2[C:26]=1[CH:27]([CH3:29])[CH3:28])[CH2:3][C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].CO.[BH4-].[Na+]>O>[OH:11][CH:4]([CH2:3][CH:2]([OH:1])/[CH:12]=[CH:13]/[C:14]1[C:15]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[N:18][N:17]2[C:26]=1[CH:27]([CH3:29])[CH3:28])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CC(=O)CC(O)/C=C/c1c(-c2ccccc2)c2c3ccccc3cnn2c1C(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)CC(O)CC(O)/C=C/c1c(-c2ccccc2)c2c3ccccc3cnn2c1C(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A stirred solution of ethyl (E)-5-hydroxy-7-(3-isopropyl-1-phenylpyrrolo[2,1-a]phthalazin-2-yl) -3-oxohept-6-enoate [0.32 g; prepared as described in Reference Example 1(i)]in methanol (10 ml) under an atmosphere of argon was cooled to 0° C and treated with sodium borohydride (15.2 mg). The solution was stirred for 15 minutes and then it was poured into a mixture of ice and water (50 ml). The resulting mixture was extracted with diethyl ether (100 ml) and then with ethyl acetate (2×50 ml). The combined extracts were dried over magnesium sulphate, evaporated and subjected to flash chromatography on silica gel, using as eluant a mixture of petroleum ether (b.p. 40-60° C) and diethyl ether (1:1 v/v), to give ethyl (E)-3,5-dihydroxy-7-(3-isopropyl-1-phenylpyrrolo[2.1-a]phthalazin-2-yl)-hept -6-enoate (0.26 g) in the form of a yellow gum. [NMR (in a mixture of CDCl3 and D2O): 1.28 (3 H, t, J=7 Hz), 1.4-1.7 (2 H, m), 1.52 (6 H, d, J=7 Hz), 2.40-2.48 (2 H, m), 3.8 (1H, septet, J=7 Hz), 4.08-4.14 (3 H, m), 4.28-4.42 (1 H, m), 5.31 and 5.36 (1 H, two dd, J=16 Hz, 6 Hz), 6.63 and 6.65 (1 H, two dd, J=16 Hz, 1 Hz), 7.22-7.64 (9 H, m), 8.24 (1 H, s)].
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10]C)=[O:9])[C:5]([O:12][CH3:13])=[CH:4][CH:3]=1.O[Li].O>O1CCOCC1.O>[Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([O:12][CH3:13])=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(Br)ccc1OC
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Br)nc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
A mixture of methyl 6-bromo-3-methoxypicolinate (4 g, 18.4 mmol) and LiOH—H2O (1.6 g, 36.9 mmol) in dioxane/H2O (5/1, 40 mL) was stirred at RT overnight. After pH was adjusted to 7, the mixture was filtered to provide crude 6-bromo-3-methoxypicolinic acid (3.1 g, yield: 81%). 1H-NMR (CDCl3, 400 MHz) δ 10.71 (m, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 4.01 (s, 3H). MS (M+H)+: 232/234.