Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[NH:16][C:15]3[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12](=[O:21])[N:11]([CH2:22][CH2:23][CH3:24])[C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[CH3:25][O:26][CH2:27][CH2:28][NH2:29]>CCO>[CH3:25][O:26][CH2:27][CH2:28][NH:29][C:2]1[N:7]=[CH:6][C:5]([C:8]2[NH:16][C:15]3[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12](=[O:21])[N:11]([CH2:22][CH2:23][CH3:24])[C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCCn1c(=O)c2[nH]c(-c3ccc(Cl)nc3)cc2n(CCC)c1=O
Reactant: COCCN
Solvent: CCO
Product: CCCn1c(=O)c2[nH]c(-c3ccc(NCCOC)nc3)cc2n(CCC)c1=O
Temperature: 164 °C
Reaction time: 28 h
Yield: 56.7 %

Procedure:
8a (100 mg) was suspended in methoxyethylamine (1.5 g), in EtOH (4 mL) in a pressure tube and stirred at 164° C. for 28 hrs. After cooling to room temperature, the solvent was removed and the solid was purified by column (26 g silica gel, RT Scientific) (CH2Cl2:MeOH=100:0 to 97:3). The fractions were evaporated and washed with ether to give the product 9a (63 mg). The mother liquid was evaporated and afforded another 30 mg of the product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH:27]([CH2:31][C:32]([OH:34])=[O:33])[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>C(#N)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:28]2[CH2:29][CH2:30][N:25]([C:23]([O:22][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:24])[CH2:26][CH:27]2[CH2:31][C:32]([OH:34])=[O:33])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(CC(=O)O)C1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2cc(Br)ccc2[N+](=O)[O-])C(CC(=O)O)C1
Temperature: 70 °C

Procedure:
4-Bromo-2-fluoro-1-nitrobenzene (5.3 g, 24.1 mmol) was dissolved in acetonitrile (70 mL) and water (10 mL). To this mixture, potassium carbonate (10 g, 72.3 mmol) and 2-(4-(tert-butoxycarbonyl)piperazin-2-yl)acetic acid (7.1 g, 28.9 mmol) were added. The resulting mixture was heated at 70° C. for 2 days. The mixture thus obtained was concentrated and ethyl acetate was added. 1 N HCl was then added slowly to the reaction solution until pH=6. The water layer was separated and washed multiple times with ethyl acetate. The organic layers thus obtained were combined and concentrated. The crude material thus obtained was purified by silica gel chromatography eluting with a gradient of 0% to 10% of methanol in dichloromethane to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.28 (br s), 7.71-7.83 (m, 1 H), 7.56-7.66 (m, 1 H), 7.30-7.40 (m, 1 H), 3.56-3.82 (m, 3 H), 3.33-3.44 (m, 1 H), 2.99-3.24 (m, 2 H), 2.87 (m, 1 H), 2.32-2.47 (m, 1 H), 2.17-2.29 (m, 1 H), 1.32-1.51 (s, 9 H); MS (DCI+) m/z 444.1 (M+H)+.
Reaction SMILES: C([SiH](CC)CC)C.C([O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([CH:31]=[N:32][OH:33])=[C:23]2[CH3:34])=[CH:18][C:17]=1[F:35])C1C=CC=CC=1.[Cl-].[NH4+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.O1CCCC1.C(OCC)(=O)C.O.CC([O-])=O.CC([O-])=O.[Pd+2].C(OCC)(=O)C.C(N(CC)CC)C>[F:35][C:17]1[CH:18]=[C:19]([N:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([CH:31]=[N:32][OH:33])=[C:23]2[CH3:34])[CH:20]=[CH:21][C:16]=1[OH:15]
Reactant: Cc1c(C=NO)c2ccccc2n1-c1ccc(OCc2ccccc2)c(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(C=NO)c2ccccc2n1-c1ccc(O)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.3 %

Procedure:
To a stirred solution of dichloromethane (10 mL), Pd(OAc)2 (50 mg, 0.2 mmol), and triethylsilane (3 mL) was added triethylamine (1.5 mL), and the mixture was stirred at ambient temperature for 15 min. To the mixture was added 1-(4-benzyloxy-3-fluorophenyl)-2-methyl-1H-indole-3-carbaldehyde oxime (0.52 g, 1.4 mmol) in dichloromethane (15 mL), and stirring was continued for 4 hr. Ethyl acetate (25 mL) and ammonium chloride (25 mL of 10% solution) were added and the product extracted into ethyl acetate (2×25 mL). The combined organics were washed with water (3×25 mL) and brine (25 mL) and dried over MgSO4. After removing the solvent, a liquid was obtained, which was dissolved in anhydrous tetrahydrofuran (10 mL). To this stirring mixture was added tetrabutyl ammonium fluoride (3 mL). After stirring for 30 min., the mixture was taken up in ethyl acetate/water and shaken and the layers separated. The organic portion was washed with water and brine and dried over MgSO4. After evaporation of the solvent, the crude solid was purified by silica gel chromatography (25% ethyl acetate-hexanes) to give a pale yellow solid (0.22 g, 56%): mp 182-184° C.; 1H NMR (DMSO-d6): δ 2.31 (3H, s), 6.98-7.01 (1H, m), 7.07-7.17 (4H, m), 7.35 (1H, dd, J=11.7 Hz, J=2.4 Hz), 7.99-8.03 (1H, m), 8.40 (1H, s), 10.35 (1H, br s), 10.64 (1H, s); MS m/z (M+H)+ 285: Anal. for C16H13FN2O2 (0.3H2O): Calc'd: C, 66.34; H, 4.57 N, 9.30. Found: C, 66.38; H, 4.61; N, 9.85.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([N+:22]([O-])=O)[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([C:14]2([CH3:17])[CH2:16][CH2:15]2)=[O:13])[CH:6]=1>C(Cl)Cl.[Pd]>[NH2:22][C:20]1[CH:19]=[CH:18][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([C:14]3([CH3:17])[CH2:16][CH2:15]3)=[O:13])[CH:6]=2)=[C:2]([F:1])[CH:21]=1
Reactant: CC1(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])cc3F)ccn2)CC1
Agent: [Pd]
Solvent: ClCCl
Product: CC1(C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Yield: 69.1 %

Procedure:
Dissolve N-[4-(2-fluoro-4-nitro-phenoxy)-2-pyridyl]-1-methyl-cyclopropanecarboxamide (160 mg, 0.48 mmol) in DCM (30 mL), add Pd/C (10%, 55 mg), flush with H2. Stir the reaction at room temperature under H2 atmosphere for 2 hrs. Filter the reaction mixture; concentrate the filtrate under reduced pressure to give the crude product (100 mg) which is used without further purification. MS: (M+1): 302.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C@H:14]([C:16]2[N:17]=[N:18][N:19]([C@@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])[CH:20]=2)[OH:15])=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[C@@H:14]([OH:15])[C:16]4[N:17]=[N:18][N:19]([C@@H:21]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH3:22])[CH:20]=4)=[CH:6][CH:7]=3)=[CH:39][CH:38]=2)[CH2:35][CH2:36]1)=[O:33])[CH3:30]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1[C@@H](O)c1cn([C@H](C)c2ccccc2)nn1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4[C@@H](O)c4cn([C@H](C)c5ccccc5)nn4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using (R)-[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-((R)-1-phenyl-ethyl)-1H-[1,2,3]triazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@@H:23]([CH:25](C)[NH:26][C:27]([SH:29])=[S:28])[O:22][C:21]3=[O:31])=[CH:16][C:15]=2[F:32])[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:33]O>>[CH3:33][S:29][C:27](=[S:28])[NH:26][CH2:25][C@@H:23]1[O:22][C:21](=[O:31])[N:20]([C:17]2[CH:18]=[CH:19][C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[C:15]([F:32])[CH:16]=2)[CH2:24]1
Reactant: CC(NC(=S)S)[C@@H]1CN(c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)C(=O)O1
Reactant: CO
Product: CSC(=S)NC[C@H]1CN(c2ccc(N3CCNCC3)c(F)c2)C(=O)O1
Reaction time: 120 h

Procedure:
A suspension of 510 mg 4-{2-fluoro-4-[(5S)-5-(methyl-sulfanylthiocarbonylamino-methyl)2-oxo-oxazolidin-3-yl]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (1.05 mmol) in 1.25 M/methanol was stirred for 5 days. The solvent was evaporated and the residue digested in water. The water layer was neutralized at pH 7 with a saturated solution of sodium bicarbonate and evaporated to dryness. The residue was digested in CH2Cl2/MeOH. The salts were filtered and the solvent evaporated:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[CH:22][C:19]=1[C:20]#[N:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][CH:29]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH2:28][CH2:27]4)=[CH:22][C:19]=3[C:20]#[N:21])=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: N#Cc1cc(N2CCC(N3CCOCC3)CC2)ccc1N
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)cc2C#N)cnn1-c1ccc(Cl)cc1
Yield: 18.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.81 g) and 2-amino-5-(4-morpholinopiperidin-1-yl)benzonitrile (0.9 g), the title compound (0.29 g) was obtained, melting point: 212–213° C.
Reaction SMILES: O1CCCC1.[CH:6]1([CH2:9][OH:10])[CH2:8][CH2:7]1.[H-].[Na+].[Br:13][C:14]1[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]2[CH:18]=[N:19][NH:20][C:21](=[O:22])[C:16]=2[C:15]=1[CH2:32]Br>O>[Br:13][C:14]1[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]2[CH:18]=[N:19][NH:20][C:21](=[O:22])[C:16]=2[C:15]=1[CH2:32][O:10][CH2:9][CH:6]1[CH2:8][CH2:7]1
Reactant: C[Si](C)(C)CCOCn1c(Br)c(CBr)c2c(=O)[nH]ncc21
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1c(Br)c(COCC2CC2)c2c(=O)[nH]ncc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.2 %

Procedure:
To 10 ml of dehydrated tetrahydrofuran solution containing 0.92 g (13 mmol) of cyclopropylmethanol was added 0.25 g (6.2 mmol) of sodium hydride (60% dispersed material in mineral oil) under ice-cooling, the mixture was stirred at room temperature for 30 minutes, then, 10 ml of dehydrated tetrahydrofuran solution containing 0.56 g (1.3 mmol) of 2-bromo-3-bromomethyl-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 24-(f) was further added to the mixture, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=2:3 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 157 mg of the title compound as a pale yellowish solid. (Yield: 29%)
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:18])[C@@H:5]1[CH2:9][C@@H:8]([NH2:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[Cl:19][C:20]1[S:24][C:23]([C:25](O)=[O:26])=[CH:22][CH:21]=1>>[CH3:2][O:3][C:4]([C@@H:5]1[CH2:9][C@@H:8]([NH:10][C:25]([C:23]2[S:24][C:20]([Cl:19])=[CH:21][CH:22]=2)=[O:26])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])=[O:18]
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: COC(=O)[C@@H]1C[C@@H](N)CN1C(=O)OC(C)(C)C
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](NC(=O)c2ccc(Cl)s2)CN1C(=O)OC(C)(C)C

Procedure:
11.1 Using general procedure D N-Boc-trans-4-amino-L-proline methyl ester hydrochloride was coupled with 5-chlorothiophene-2-carboxylic acid to give (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester. White solid. MS 389.4 ([M+H]+)
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.ClCCl.[Cl-].[Al+3].[Cl-].[Cl-].[C:22](Cl)(=[O:26])[CH:23]([CH3:25])[CH3:24]>O>[CH:23]([C:22]([C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:14])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=2[CH:7]=1)=[O:26])([CH3:25])[CH3:24]
Reactant: CC(C)C(=O)Cl
Reactant: CC1(C)CCC(C)(C)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC(C)C(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The synthesis process is as set forth in the chemical reaction formula below. To 5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene (188 mg, 1.00 mmol) were added anhydrous dichloromethane (1 mL), aluminum chloride (140 mg, 1.05 mmol), and isobutyryl chloride (112 mg, 1.05 mmol) followed by stirring at room temperature for 3 hours. The reaction solution was poured into cold water and extracted by ethyl acetate. The organic layer was washed by water, a saturated sodium hydrogen carbonate aq. solution, and a saturated saline solution, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography using hexane/ethyl acetate (20/1) as an elution solvent. The yield was 97.4 mg (38%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH3:15][CH:16]([CH3:35])[CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]1[N:24]=[N:25][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:27][CH:28]=1)=[O:22]>>[CH3:15][CH:16]([CH3:35])[CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]1[N:24]=[N:25][C:26]([N:29]2[CH2:34][CH2:33][N:32]([C:7](=[O:8])[C:6]3[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[C:11]([F:14])([F:13])[F:12])[CH2:31][CH2:30]2)=[CH:27][CH:28]=1)=[O:22]
Reactant: O=C(Cl)c1cc(F)ccc1C(F)(F)F
Reactant: CC(C)CCCNC(=O)c1ccc(N2CCNCC2)nn1
Product: CC(C)CCCNC(=O)c1ccc(N2CCN(C(=O)c3cc(F)ccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 5-fluoro-2-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (4-methylpentyl)amide, the title compound was obtained as a white solid (10% yield). 1H NMR (300 MHz, CDCl3) δ 8.04, 7.86, 7.75-7.71, 7.26-7.22, 7.08-7.04, 6.98, 4.10-3.98, 3.90-3.70, 3.46-3.40, 3.36-3.33, 1.61-1.50, 1.28-1.20, 0.85. 13C NMR (75 MHz, CDCl3) δ 166.0, 162.9, 162.6, 159.9, 145.5, 136.8, 129.7, 127.6, 127.7, 127.2, 125.1, 123.3, 121.4, 116.8, 116.5, 114.9, 114.6, 113.9, 112.5, 46.3, 44.5, 44.3, 41.3, 39.7, 36.0, 27.8, 27.4, 22.5. MS (ES+) m/z 482.4 (M+1).
Reaction SMILES: C(O[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][C:16]=1[C:17]([O:19]C)=[O:18])C1C=CC=CC=1>CO.O1CCCC1.[Pd]>[NH2:25][C:22]1[CH:23]=[CH:24][C:15]2[C:10]3[C:9](=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:19][C:17](=[O:18])[C:16]=2[CH:21]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1-c1ccccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)c(=O)oc1ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
Methyl 2-(2-benzyloxyphenyl)-5-nitrobenzoate (Reference Compound No. 1-1-(1), 21.0 g, 57.8 mmol) was dissolved in a mixture of methanol (135 mL) and tetrahydrofuran (90 mL), then 5% palladium on charcoal (2.19 g) was added thereto, and then the reaction mixture was stirred under hydrogen atmosphere at room temperature overnight. After the unsoluble materials were filtered, the filtrate was removed under reduced pressure. A mixture of ethyl acetate and hexane was added to the obtained residue, and then the mixture was filtered to give the titled reference compound (8.92 g) as a pale yellow solid. (Yield 73%)
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[Cl:7][C:8]1[CH:15]=[C:14]([N:16]([C@H:25]2[CH2:29][C:28](=[O:30])[N:27]([CH2:31][CH:32]([OH:35])CO)[CH2:26]2)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11]>C1COCC1>[Cl:7][C:8]1[CH:15]=[C:14]([N:16]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[C@H:25]2[CH2:29][C:28](=[O:30])[N:27]([CH2:31][CH:32]=[O:35])[CH2:26]2)[CH:13]=[CH:12][C:9]=1[C:10]#[N:11]
Reactant: Cc1ccccc1CN(c1ccc(C#N)c(Cl)c1)[C@H]1CC(=O)N(CC(O)CO)C1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Product: Cc1ccccc1CN(c1ccc(C#N)c(Cl)c1)[C@H]1CC(=O)N(CC=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An aqueous solution of sodium periodate (0.25 M in H2O, 12.8 mg, 0.06 mmol) was added to a solution of 2-chloro-4-{[(3S)-1-(2,3-dihydroxypropyl)-5-oxo-3-pyrrolidinyl][(2-methylphenyl)methyl]amino}benzonitrile (25.0 mg, 0.06 mmol) in THF. After stirring at room temperature for 30 min, the reaction mixture was extracted three times with ethyl acetate (5 mL). The organics were dried over anhydrous MgSO4 and concentrated to give the titled compound as white foam. The crude material was immediately used in the next step.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH2:20])=[N:8][C:6]=2[N:7]=1.[CH2:21]([N:25]=[C:26]=[O:27])[CH2:22][CH2:23][CH3:24]>>[CH2:21]([NH:25][C:26]([NH:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH:20][C:26]([NH:25][CH2:21][CH2:22][CH2:23][CH3:24])=[O:27])=[N:8][C:6]=2[N:7]=1)=[O:27])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCN=C=O
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Product: CCCCNC(=O)Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(NC(=O)NCCCC)nc2n1
Temperature: 25 °C

Procedure:
A mixture of 0.5 g 2,7-Diamino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidine from Example 1 and 15 mL of n-butyl isocyanate is refluxed for 2 hours. The reaction mixture is allowed to cool to room temperature and the insoluble material filtered. The solid is recrystallized several times from ethanol to give the title compound; mp 200°-202° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:3]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:3]1
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CCC[C@@H](O)C1
Agent: O=[Cr](=O)([O-])Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CCC[C@H](N2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 2-[(3R)-3-hydroxycyclohexyl]isoindoline-1,3-dione (3, 1.4 g, 5.71 mmol) in dichloromethane (50 mL) at 0° C., was added pyridinium chlorochromate (3.69 g, 17.12 mmol). The mixture was allowed to stir at 25° C. for 5 hours while monitoring by TLC. The reaction mixture was made basic (pH 8) with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (2×150 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain 2-(3-oxocyclohexyl)isoindoline-1,3-dione (4) as a brown solid. Yield: 1.31 g, 94%; MS (ESI) m/z 244.15 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:23][C:24](=O)[CH2:25][C:26](=[O:38])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[CH:37]=[CH:36][N:35]=[N:34]2)[CH:28]=1)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]=1[NH:19][C:24](=[O:23])[CH2:25][C:26](=[O:38])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[CH:37]=[CH:36][N:35]=[N:34]2)[CH:28]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-n2ccnn2)c1

Procedure:
The title compound was prepared from (2-amino-5-chloro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J14) (311 mg, 1.0 mmol) 3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid ethyl ester (Example K1) (259 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow oil (340 mg, 65%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8]O)[CH:5]=[N:6][CH:7]=1.S(Cl)([Cl:12])=O.[OH-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][Cl:12])[CH:3]=1
Reactant: OCc1cncc(Br)c1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: ClCc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
At 0° C., to a solution of (5-bromopyridin-3-yl)methanol (3 g, 16.0 mmol) in DCM (15 mL) was added thionylchloride (7.59 g, 63.8 mmol) dropwise and the reaction mixture was stirred at room temperature overnight. The mixture was poured onto ice/water (20 mL), and basified with conc. NaOH solution (8 mL). The mixture was extracted with EtOAc (2×50 mL) and combined organic layers were dried over anhy. Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 40% EtOAc-heptane gradient to give the title compound (3.08 g, 93%) as a white solid. MS: 206.0, 207.9 (M+H+).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH:14]([P:16]([CH3:21])(=[O:20])[O:17]CC)[OH:15])=O)C1C=CC=CC=1.[ClH:22]>>[ClH:22].[NH2:11][CH2:12][CH2:13][CH:14]([P:16]([CH3:21])(=[O:17])[OH:20])[OH:15]
Reactant: CCOP(C)(=O)C(O)CCNC(=O)OCc1ccccc1
Agent: Cl
Product: CP(=O)(O)C(O)CCN
Temperature: 25 °C

Procedure:
A solution of 4.0 g of ethyl P-(3-benzyloxycarbonylamino-1-hydroxy-propyl)-P-methyl-phosphinate in 50 ml of 5.0M aqueous hydrochloric acid is heated to reflux for 20 hours under an inert gas atmosphere. Then, the reaction mixture is cooled to room temperature and washed twice with 100ml each of dichloromethane and once with diethyl ether. The aqueous layer is evaporated to dryness at 50° under reduced pressure. The oily residue is then co-evaporated 5 times with 50 ml each of water and of absolute ethanol. The remaining white solid is dried under reduced pressure at 80° and then re-crystallised to afford P-(3-amino-1-hydroxy-propyl)-P-methyl-phosphinic acid hydrochloride of m.p. 115°-116.5°. This can be converted into the free compound by dissolving in ethanol and treating with propylene oxide yielding, after filtration and drying, P-(3-amino- 1-hydroxy-propyl)-P-methyl-phosphinic acid of m.p. 125°-126.5°.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]([CH3:18])[C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([Br:39])=[C:24]([NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=2)[CH:25]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C.CN(C)C1C=CN=CC=1>[Br:39][C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[C:9]([N:8]([CH3:7])[CH3:18])[CH:10]=2)=[CH:25][C:24]=1[NH:26][C:27](=[O:38])[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1
Reactant: CN(C)c1cccc(C(=O)O)c1
Reactant: COc1ccc(C(=O)Nc2cc(N)ccc2Br)cc1OC
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2cc(NC(=O)c3cccc(N(C)C)c3)ccc2Br)cc1OC
Temperature: 7.5 °C
Reaction time: 4 h
Yield: 56.8 %

Procedure:
Oxalyl chloride (0.24 ml) was added dropwise to a stirred suspension of 3-dimethylaminobenzoic acid (0.36 g) in methylene chloride (15 ml) at 20° C. DMF (2 drops) was added and the reaction mixture was stirred for 4 hours. The solvent was evaporated to give a yellow solid which was dissolved in methylene chloride (20 ml) and added dropwise over 5 minutes to a stirred mixture of N-(5-amino-2-bromophenyl)-3,4-dimethoxybenzamide (0.7 g), triethylamine (0.8 ml), 4-dimethylaminopyridine (0.005 g) and methylene chloride (20 ml) which had been cooled to 5-10° C. The reaction mixture was stirred at ambient temperature for 18 hours. The organic phase was washed with a saturated sodium bicarbonate solution, dried (MgSO4) and evaporated. The residual oil was purified by column chromatography on silica gel using a 49:1 mixture of methylene chloride and methanol as eluent. The solid so obtained was crystallised from a mixture of ethyl acetate and methyl tert-butyl ether to give the title compound (0.564 g), m.p. 184° C.;