Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].N1C=CC=CC=1.[C:19](Cl)(=[O:21])[CH3:20]>C(Cl)Cl.O>[C:19]([NH:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1ccc(N)cc1O
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1ccc(NC(C)=O)cc1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 10 g (59.9 mmol) of methyl 4-aminosalicylate in 100 ml of CH2Cl2 is added 6.8 ml (83.9 mmol) of pyridine in one portion at room temperature. The solution is cooled to 0° C. and 4.7 ml (65.9 mmol) of acetyl chloride is added dropwise. After addition is complete the reaction mixture is let stand 30 minutes at room temperature. The reaction mixture is diluted with water and extracted with CH2Cl2. The combined organic extracts are dried over MgSO4, filtered and concentrated to provide methyl 4-acetylaminosalicylate which is used directly in the next step.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]3[N:10]=[C:11]([N+:13]([O-])=O)[CH:12]=[C:6]3[CH2:5]2)[CH2:3][CH2:2]1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[CH:1]1([N:4]2[CH2:9][CH2:8][N:7]3[N:10]=[C:11]([NH2:13])[CH:12]=[C:6]3[CH2:5]2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cc2n(n1)CCN(C1CC1)C2
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cc2n(n1)CCN(C1CC1)C2
Yield: 78.3 %

Procedure:
A mixture of 128a (2.68 g, 12.9 mmol), Fe (3.6 g, 64.4 mmol) and NH4Cl (4.1 g, 77.4 mmol) in ethanol (30 mL) and water (5 mL) was heated at reflux for 2 h. After the completion of the reaction, the mixture was filtered and the solid was washed with ethanol (150 mL). The filtrate was evaporated in vacuo and the residue was extracted with methanol/methylene chloride (1/7). The combined extracts were dried over Na2SO4 and evaporated. The residue was purified on reverse phase Combi-flash to give 128b (1.8 g, 75%). MS: [M+H]+ 179.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[CH3:7][C:8]([C:12]1[N:16]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:15]2[CH:24]=[CH:25][C:26]([S:28]([N:31]3[CH:35]=[CH:34][C:33]([CH:36]=[O:37])=[CH:32]3)(=[O:30])=[O:29])=[CH:27][C:14]=2[N:13]=1)([CH3:11])[CH2:9][CH3:10]>CN(C=O)C>[CH3:11][C:8]([C:12]1[N:16]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:15]2[CH:24]=[CH:25][C:26]([S:28]([N:31]3[CH:35]=[CH:34][C:33]([C:36]([OH:1])=[O:37])=[CH:32]3)(=[O:30])=[O:29])=[CH:27][C:14]=2[N:13]=1)([CH3:7])[CH2:9][CH3:10]
Reactant: CCC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C=O)c3)ccc2n1CC1CCOCC1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)O)c3)ccc2n1CC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Oxone (148 mg, 0.24 mmol) was added to a solution of 1-{[2-(1,1-dimethylpropyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrrole-3-carbaldehyde (89 mg, 0.20 mmol) in DMF (8 mL). The resulting mixture was stirred overnight at room temperature and used directly for step A. MS (ESI) (M+H)+=460.06.
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=[C:12]([CH3:25])[CH:11]=2)[N:4]=1.Br[C:28]1[CH:29]=[N:30][N:31]([CH2:33][C:34](=[O:36])[CH3:35])[CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:26][CH:2]([F:1])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[C:14]([C:28]3[CH:29]=[N:30][N:31]([CH2:33][C:34](=[O:36])[CH3:35])[CH:32]=3)[CH:13]=[C:12]([CH3:25])[CH:11]=2)[N:4]=1
Reactant: Cc1cc(Nc2nccc(C(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CC(=O)Cn1cc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Cn1cc(-c2cc(C)cc(Nc3nccc(C(F)F)n3)c2)cn1
Temperature: 90 °C

Procedure:
4-(Difluoromethyl)-N-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine (400 mg, 1.11 mmol) and 1-(4-bromo-1H-pyrazol-1-yl)propan-2-one (225 mg, 1.11 mmol) were dissolved in dioxane (4 mL) and degassed with nitrogen for 5 minutes. PdCl2(dppf)-CH2Cl2 (90 mg, 0.11 mmol) and sodium carbonate (2.0 M in water, 1.107 ml, 2.215 mmol) were added, the reaction was sealed and heated to 90° C. for 12 hours. The reaction was cooled to ambient temperature, diluted with water (10 mL) and product extracted with ethyl acetate (2×20 mL). The extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by column chromatography on silica (5-50% ethyl acetate/hexanes) to afford 1-(4-(3-((4-(difluoromethyl)pyrimidin-2-yl)amino)-5-methylphenyl)-1H-pyrazol-1-yl)propan-2-one. MS ESI calcd. for C18H18F2N5O [M+H]+ 358. found 358.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([O:9][CH3:10])=[O:8].[CH3:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C.C(O)(=O)C>[CH3:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][NH:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([O:9][CH3:10])=[O:8]
Reactant: Cc1cccc(C=O)c1
Reactant: COC(=O)[C@@H]1CCC[C@@H]1N
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CCC[C@@H]1NCc1cccc(C)c1
Reaction time: 0.17 h
Yield: 79.8 %

Procedure:
To a stirred solution of methyl (1R,2S)-2-aminocyclopentanecarboxylate (240 mg, 1.68 mmol) in methanol (10 mL) under a nitrogen atmosphere, 3-methyl-benzaldehyde (202 mg, 1.68 mmol) was added. The mixture was stirred for 10 min, and then acetic acid (0.4 mL) was added followed by sodium cyanoborohydride (265 mg, 4.2 mmol). The resulting mixture was stirred at 25° C. for 16 h, and then poured into a mixture of saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous brine solution, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to afford the desired product, methyl (1R,2S)-2-[(3-methylbenzyl)amino]cyclopentanecarboxylate (330 mg, 1.34 mmol, 80%), as a clear oil. 1H NMR (400 MHz, CDCl3) δ: 1.62 (1H, m), 1.71 (1H, m), 1.91 (3H, m), 2.05 (1H, m), 2.37 (3H, s), 2.99 (1H, m), 3.34 (1H, m), 3.72 (3H, s), 3.77 (1H, d, J=12.8 Hz), 3.82 (1H, d, J=12.8 Hz), 7.24-7.07 (4H, m).
Reaction SMILES: [Li][CH2:2]CCC.CCCCCC.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[O:25][C@@H:24]([CH:26]=O)[C:23]([CH3:29])([CH3:28])[CH2:22][O:21]2)=[CH:16][CH:15]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:29][C:23]1([CH3:28])[CH2:22][O:21][CH:20]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=2)[O:25][C@H:24]1[CH:26]=[CH2:2]
Reactant: COc1ccc(C2OCC(C)(C)[C@H](C=O)O2)cc1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C[C@@H]1OC(c2ccc(OC)cc2)OCC1(C)C
Yield: 81 %

Procedure:
Following the general procedure for the methylenation by Wittig-olefination of Description 8, a phosphorous ylide generated from 73.4 g (205.5 mmol) of methyltriphenylphosphonium bromide and 125.7 mL of 1.6 M n-BuLi in hexane (201.1 mmol) in 440 mL of anhydrous tetrahydrofuran (THF), was reacted with 25.0 g (100.0 mmol) of (4R)-2-(4-methoxyphenyl)-5,5-dimethyl-1,3-dioxan-4-carbaldehyde (8b). Aqueous work-up followed by purification using column chromatography with mixtures of diethyl ether (Et2O), ethyl acetate (EtOAc), and hexanes (Hxn) as eluent (Et2O/Hxn=1:25→EtOAc/Hxn=1:9) provided 20.0 g (81% yield) of the title compound (8c) as a yellow liquid. Rf=0.42 (MTBE/Hxn=1:9). 1H NMR (400 MHz, CHCl3): δ=0.81 (s, 3H), 1.15 (s, 3H), 3.65 (d, J=10.8 Hz, 1H), 3.76 (d, J=11.2 Hz, 1H), 3.81 (s, 3H), 4.03 (d, J=6.4 Hz, 1H), 5.23-527 (m, 1H), 5.29-5.35 (m, 1H), 5.50 (s, 1H), 5.86 (ddd, J=17.2, 10.8, 6.4 Hz, 1H), 6.87-6.92 (m, 2H), 7.43-7.48 (m, 2H) ppm. MS (ESI) m/z: 249.1 (M+H)+. The analytical data was consistent with the proposed structure and with the data given in the literature for the compound (Blakemore, et al., J. Org. Chem. 2005, 70, 5449-5460; and Shiina, et al., Bull Chem. Soc. Jpn. 2001, 74, 113-122).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[Br:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([Br:26])=[CH:28][CH:29]=2)[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(Br)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (130 mg, 0.53 mmol) and triethylamine (110 μL, 0.79 mmol) in methylene chloride (25 mL) was added dropwise 4bromobenzoyl chloride (122 mg, 0.56 mmol) in methylene chloride (5 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with dilute aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:4) as the eluent. Yield: 120 mg (51%) of the title compound as white crystals: mp 200-201° C.; [α]21D -32° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 427 and 429 (3, M+).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[N:19]=[CH:18][N:17]=[C:16]3[N:20]([C:23]4[CH:28]=[CH:27][C:26](I)=[CH:25][C:24]=4[CH3:30])[N:21]=[CH:22][C:15]=23)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:31][S:32]([CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)(=[O:34])=[O:33].N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[N:19]=[CH:18][N:17]=[C:16]3[N:20]([C:23]4[CH:28]=[CH:27][C:26]([N:40]5[CH2:39][CH2:38][N:37]([CH2:36][CH2:35][S:32]([CH3:31])(=[O:33])=[O:34])[CH2:42][CH2:41]5)=[CH:25][C:24]=4[CH3:30])[N:21]=[CH:22][C:15]=23)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: Cc1cc(I)ccc1-n1ncc2c(OC3CCN(C(=O)OC(C)C)CC3)ncnc21
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: Cc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1-n1ncc2c(OC3CCN(C(=O)OC(C)C)CC3)ncnc21
Yield: 5.7 %

Procedure:
A solution of 4-[1-(4-iodo-2-methyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (78 mg, 0.15 mmol), 1-(2-methanesulfonyl-ethyl)-piperazine (0.75 mmol, 5.0 eq), CuI (0.15 mmol, 1 eq), L-proline (0.27 mmol, 1.8 eq), and potassium carbonate (0.15 mmole, 1 eq) in DMSO (2 mL) was heated at 120° C. for 1 hour under microwave conditions. The crude was purified through prep-LCMS 5–95% to provide Compound A223 as a brown sticky oil (5 mg, 6%). Exact mass calculated for C28H39N7O5S 585.3, found LCMS (ESI) m/z 586.6 (M+H+, 90%).
Reaction SMILES: Cl[C:2](OCC)=O.[NH2:7][CH2:8][C:9]1([C:20]2([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:19]2[C:11](=[CH:12][C:13]3[S:17][CH:16]=[CH:15][C:14]=3[CH:18]=2)[CH2:10]1.C(N(CC)CC)C>ClCCl>[CH3:2][NH:7][CH2:8][C:9]1([C:20]2([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:19]2[C:11](=[CH:12][C:13]3[S:17][CH:16]=[CH:15][C:14]=3[CH:18]=2)[CH2:10]1
Reactant: NCC1(C2(O)CCCC2)Cc2cc3sccc3cc21
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNCC1(C2(O)CCCC2)Cc2cc3sccc3cc21

Procedure:
A solution of 0.29 ml of ethyl chloroformate in 40 ml of dichloromethane is introduced, at 0° C., to a mixture of 1 g of the product of Example 21, 1.2 ml of triethylamine and 60 ml of dichloromethane. After returning to room temperature, the reaction mixture is washed with 0.1N hydrochloric acid and then with a saturated sodium hydrogen carbonate solution, dried and then evaporated. The resulting residue is dissolved in 20 ml of tetrahydrofuran. The solution is added to a mixture of 1.3 g of AlLiH4 in 60 ml of tetrahydrofuran. The reaction mixture is refluxed for 3 hours and then hydrolysed with 0.65 ml of water, 0.45 ml of 20% sodium hydroxide solution and 2.1 ml of water. After filtration and concentration, the residue is purified by chromatography over silica gel (dichloromethane/ethanol/NH4OH: 95/5/0.5) and recrystallised from isopropyl ether to yield the expected product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][CH3:11])=[CH:5][CH:4]=1.Cl[S:13]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)(=[O:15])=[O:14]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([CH3:11])[S:13]([C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=2)(=[O:15])=[O:14])=[CH:5][CH:4]=1
Reactant: CNCc1ccc(OC)cc1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(CN(C)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-27 from 1-(4-methoxyphenyl)-N-methylmethanamine and methyl 4-(chlorosulfonyl)-benzoate (Example 5-10c). MS (M−H, 335.1); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 2.51 (s, 3H), 3.71 (s, 3H), 4.05 (s, 2H), 6.88 (d, 2H), 7.18 (d, 2H), 7.91 (d, 2H); 8.13 (d, 2H). Elemental analysis: (found): C, 57.47%; H, 4.77%; and N, 4.31%. (theoretical): C, 57.30%; H, 5.11%; and N, 4.18%.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10][O:11][CH3:12])=[C:8]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=3)[N:14]=2)[CH:7]=[N:6]1)[CH:2]([CH3:4])[CH3:3].[NH:26]1[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]1>>[CH2:1]([N:5]1[C:9]([CH2:10][O:11][CH3:12])=[C:8]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:25]=[CH:24][C:21]([CH2:22][N:26]4[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]4)=[CH:20][CH:19]=3)[N:14]=2)[CH:7]=[N:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: COCc1c(-c2nc(-c3ccc(C=O)cc3)no2)cnn1CC(C)C
Reactant: O=C(O)C1CNC1
Product: COCc1c(-c2nc(-c3ccc(CN4CC(C(=O)O)C4)cc3)no2)cnn1CC(C)C

Procedure:
The title compound was prepared following the procedure described for Example 64 (step 2), but starting from 4-{5-[1-isobutyl-5-(methoxymethyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazol-3-yl}benzaldehyde, obtained from step 1, (170.2 mg; 0.50 mmol) and using 3-azetidine carboxylic acid (101.1 mg; 1.0 mmol) to give Example 76 as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.14-8.11 (3 H, m), 7.56 (2 H, d, J=8.0 Hz), 4.99 (2 H, s), 4.17 (2 H, s), 4.13-4.09 (2 H, m), 4.05 (2 H, d, J=7.6 Hz), 3.97 (2 H, t, J=9.3 Hz), 3.43-3.38 (4 H, m), 2.41-2.32 (1 H, m), 0.95 (6 H, d, J=6.7 Hz). LC/MS: 426 (M+H)+. HPLC (Method A) Rt=2.32 min (Purity: 99.3%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[CH3:11][C@H:12]1[NH:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1>[CH3:11][C@H:12]1[N:17]([C:2]2[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:13]1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc([N+](=O)[O-])nc1
Temperature: 100 °C
Yield: 49.6 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1,4-dioxane (60 mL), 5-bromo-2-nitropyridine (2.0 g, 10.0 mmol), (R)-tert-butyl 3-methylpiperazine-1-carboxylate (2.0 g, 10.0 mmol), and cesium carbonate (6.5 g, 20 mmol). See FIG. 9. After bubbling nitrogen through the resulting mixture for 30 minutes, XantPhos (579 mg, 1.0 mmol) and tris(di-benzylideneacetone)dipalladium(0) (915 mg, 1.0 mmol) were added, and the reaction mixture was heated at 100° C. for 15 h. After this time the reaction was cooled to room temperature and filtered. The filtrate was partitioned between ethyl acetate (100 mL) and water (100 mL). The aqueous layer was separated and extracted with ethyl acetate (150 mL×3). The combined organic layer was washed with brine (50 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified on flash column eluting with 30:1 DCM/MeOH to afford 109a (1.6 g, 44%) as a yellow solid. MS: [M+H]+ 323. 1H NMR (500 MHz, DMSO) δ 8.21 (d, J=3.5, 1H), 8.18 (d, J=9.0, 1H), 7.43-7.45 (m, 1H), 4.33 (s, 1H), 3.92-3.99 (m, 1H), 3.80 (d, J=12.5, 2H), 3.06-3.23 (m, 3H), 1.43 (s, 9H), 1.09 (d, J=6.5, 3H).
Reaction SMILES: N.[Cl:2][C:3]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:4]=1[O:5][CH:6]([CH3:10])[C:7]([NH2:9])=O.C[N:17]1CCO[CH2:19][CH2:18]1.Cl.NCCN>C(O)C.C(Cl)(Cl)Cl>[Cl:2][C:3]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:4]=1[O:5][CH:6]([C:7]1[NH:17][CH2:18][CH2:19][N:9]=1)[CH3:10]
Reactant: CN1CCOCC1
Reactant: CC(Oc1c(Cl)cccc1Cl)C(N)=O
Agent: Cl
Agent: N
Solvent: NCCN
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CC(Oc1c(Cl)cccc1Cl)C1=NCCN1

Procedure:
Another process is also based on (+)-2-(2,6-dichlorophenoxy)-propionic acid ethylester which is reacted with an ethanolic solution of ammonia at room temperature and is converted in to (-)-2-(2,6dichlorophenoxy)-propionic acid amide which is difficultly soluble in ethanol. This amide is dehydrated at from 0° to 30° C. with a titanium tetrachloride/tetrahydrofuran complex and 4-methyl-morpholine in chloroform into (+)-2-(2,6-dichlorophenoxy)-propionic acid nitrile. By introducing hydrogen chloride at 0° C., the nitrile is then converted with ethanol in chloroform into (+)-2-(2,6-dichlorophenoxy)-propionimido acid ethylester hydrochloride, this compound is dissolved in ethanol and is cyclised by adding 1,2-diaminoethane to produce (+)-2-[1-(2,6-dichlorophenoxy)-ethyl]-1,3-diazacyclopent-2-ene. Analogously to the previous process, (+)-2-[1-(2,6-dichlorophenoxy)-ethyl]-1,3-diazacyclopent-2-ene hydrochloride is produced from the (+) base thus obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:24]#[N:25])=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][CH2:6][C:7]([NH:10]C(=O)OCC1C=CC=CC=1)([CH3:9])[CH3:8].O=[C:27]([CH3:34])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>>[NH2:25][C:24]1[C:3]2[C:2](=[CH:23][CH:22]=[CH:21][C:4]=2[O:5][CH2:6][C:7]([NH2:10])([CH3:8])[CH3:9])[N:1]=[C:27]([CH3:34])[C:28]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)(COc1cccc(N)c1C#N)NC(=O)OCc1ccccc1
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)N)c2c1N

Procedure:
Prepared as in Example 2a from benzyl 1-(3-amino-2-cyanophenoxy)-2-methylpropan-2-ylcarbamate (Example 24c) and ethyl 3-oxobutanoate as a yellow-brown solid (91%). 1H NMR (400 MHz, DMSO-d6) δ 1.15 (s, 6H), 1.31 (t, J=4 Hz, 3H), 2.54 (s, 3H), 3.87 (s, 2H), 4.31 (q, J=4 Hz, 2H), 6.85 (d, J=4 Hz, 1H), 7.21 (d, J=4 Hz, 1H), 7.49 (t, J=8 Hz, 1H), 8.38 (brs, 2H). MS 318 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:14][CH3:15])(=[O:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10].F[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25].Cl>C1(C)C=CC=CC=1.CN(C)C=O>[F:23][C:21]1[CH:20]=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[C:17]([CH:8]([C:7]([O:14][CH3:15])=[O:13])[C:9]([O:11][CH3:12])=[O:10])[CH:22]=1
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 83518.1 %

Procedure:
In a flask made of glass equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel and having an inner volume of 500 ml were charged 55.3 g (0.40 mol) of potassium carbonate, 200 ml of N,N-dimethylformamide, 54.0 g (0.40 mol) of dimethyl malonate with a purity of 98% and 32.5 g (0.20 mmol) of 2,4-difluoronitrobenzene with a purity of 98% under argon atmosphere, and under stirring, the mixture was reacted at 70° C. for 3 hours. After completion of the reaction, the mixture was cooled to room temperature, 160 ml of toluene was added to the mixture, and 50 ml (0.60 mol) of 12 mol/l hydrochloric acid was gradually added dropwise to the mixture while stirring. Then, the organic layer was separated, and washed successively with 50 ml of water and 50 ml of a saturated saline solution in this order, and dried over anhydrous magnesium sulfate. After filtration, this organic layer was analyzed (absolute quantitative method) by high performance liquid chromatography, it was found that 45.3 g (reaction yield: 84%) of dimethyl 2-(5-fluoro-2-nitrophenyl)malonate was formed.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[S:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].Cl.CN(C)CCCN=C=NCC.[F:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]2[C:34]=1[CH2:35][CH2:36][NH:37]2>CN(C=O)C.N1C=CC=CC=1>[F:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]2[C:34]=1[CH2:35][CH2:36][N:37]2[C:16](=[O:18])[CH2:15][C:3]1[N:2]([CH3:1])[C:7](=[S:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=1
Reactant: Fc1cccc2c1CCN2
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=S
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1c(CC(=O)N2CCc3c(F)cccc32)nc(N2CCOCC2)cc1=S

Procedure:
The product is prepared by following the procedure described in example 4e (step 4e) using 250 mg of sodium (1-methyl-4-morpholin-4-yl-6-thioxo-1,6-dihydropyrimidin-2-yl)acetate in 6 ml of DMF and 6 ml of pyridine are added 512 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 141 mg of 4-fluoro-2,3-dihydro-1H-indole.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[C:5]([C:17]#[N:18])=[C:4]([SH:19])[N:3]=1.Br.Br[CH2:22][CH2:23][NH2:24].C([O-])(O)=O.[Na+]>CN(C=O)C.Cl>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)[C:5]([C:17]#[N:18])=[C:4]([S:19][CH2:22][CH2:23][NH2:24])[N:3]=1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1ccc(O)cc1
Reactant: NCCBr
Agent: Br
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(SCCN)c(C#N)c1-c1ccc(O)cc1

Procedure:
268 mg (1 mmol) of 2-amino-4-(4-hydroxyphenyl)-6-sulfanyl-3,5-pyridinedicarbonitrile, 105 mg (1 mmol) of 2-bromoethylamine hydrobromide and 168 mg (2 mmol) of NaHCO3 are stirred in 1 ml of DMF for 1 hour. The entire mixture is diluted with a few milliliters of 1N HCl. The crystals are filtered off with suction and dried under reduced pressure.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][C:28]1([CH3:40])[O:32][C@H:31]([CH2:33][N:34]2[CH:38]=[CH:37][C:36]([NH2:39])=[N:35]2)[CH2:30][O:29]1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[CH:13]=[N:12]2)[C:8]([NH:39][C:36]2[CH:37]=[CH:38][N:34]([CH2:33][C@@H:31]3[CH2:30][O:29][C:28]([CH3:40])([CH3:27])[O:32]3)[N:35]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2c(F)cccc2F)cc1=O
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC3CCCC3)n3ncc(Oc4c(F)cccc4F)cc3=O)n2)O1

Procedure:
Using the method described in Example 49, 3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 47) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded 3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-propionamide as a white solid as a mixture of diastereoisomers (4.56 g, 90%).