Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[C:27]=1[OH:28])[CH:23]=O)[CH3:18].[NH2:32][C:33]([NH2:35])=[O:34].Cl>C(O)C>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:23]2[C:8]([C:9]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=3)=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:35][C:33](=[O:34])[NH:32]2)[CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[C:27]=1[OH:28])[CH3:18]
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: NC(N)=O
Reactant: Cc1ccc(CC(=O)c2ccccc2)cc1
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccc(C)cc2)cc([N+](=O)[O-])c1O
Yield: 14.3 %

Procedure:
To a solution of 1-phenyl-2-p-tolylethanone (70 mg, 0.33 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (65 mg, 0.33 mmol) and urea (60 mg, 1.0 mmol) in 20 mL of ethanol was added 0.2 mL of concentrated HCl, the mixture was stirred at reflux for 2 days. After the solvent was removed under reduced pressure, the residue was purified by reverse-phase preparatory HPLC (26-53% acetonitrile+0.1% trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 15 min.) to give Compound 14 (21 mg, yield 14.9%). 1H NMR (DMSO-d6 400 MHz TMS): δ 10.30 (s, 1H), 8.67 (s, 1H), 7.52 (s, 1H), 7.44 (s, 1H), 7.26-7.19 (m, 6H), 6.85-6.70 (m, 4H), 5.16 (s, 1H), 4.05 (s, 2H), 2.12 (s, 3H), 1.33 (t, J=6.4 Hz, 3H); MS (ESI): m/z 446.0 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:13](Br)[CH:14]=[CH2:15].C([O-])([O-])=O.[K+].[K+].[CH3:23][C:24]([CH3:26])=O>>[CH2:13]([O:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH2:26][CH:24]=[CH2:23])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1)[CH:14]=[CH2:15]
Reactant: CC(C)=O
Reactant: Oc1cccc2c(O)cccc12
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCOc1cccc2c(OCC=C)cccc12
Temperature: 25 °C

Procedure:
Into a 1,000 ml two-necked flask equipped with a refluxing condenser, 20.0 g of 1,5-dihydroxynaphthalene (Sigma-Aldrich), 27.0 ml of allyl bromide (Sigma-Aldrich), 103.61 g of K2CO3, and 500 ml of acetone were charged and mixed at room temperature. Then, the reaction temperature was set to 80° C., and the homogeneous mixture thus obtained was refluxed overnight. After finishing the reaction, the reaction mixture was cooled to room temperature and was filtered using Celite. The solvent was evaporated to obtain a coarse product. A target product was extracted from the coarse product using ethyl acetate, washed three times using water, and dried using MgSO4. MgSO4 was filtered off, and solvents were removed by using an evaporator to obtain an intermediate product (11), 1,5-bis(allyloxy)naphthalene. The reaction scheme of the 1st step and the NMR data of the intermediate product (11) thus obtained are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][CH2:31][O:32]C3CCCCO3)[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:39])=[O:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOC(C)=O.O>CO>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][CH2:31][OH:32])[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:39])=[O:18]
Reactant: Cc1ccc(-c2cn(CCOC3CCCCO3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(-c2cn(CCO)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A solution of compound 101 (350 mg, 0.63 mmol) in methanol (4.0 mL) was added toluene-4-sulfonic acid (60 mg, 0.32 mmol) and the mixture was stirred for 7 h at RT. The reaction mixture was poured into a mixture of EtOAc/water. The organic phase was washed with NaOH (aq., 2 M), water, brine and then dried (MgSO4), filtered and concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 25:75 as the eluent to afford the title compound as yellow foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH2:20](O)[CH3:21]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:20][CH3:21])=[O:13])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCCC(=O)O)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCCc1ccc(OC)cc1

Procedure:
After 4-(4-methoxyphenyl)butanoic acid (200 g) and then concentrated sulfuric acid (4 ml) were added to ethanol (400 ml), the resulting mixture was heated under reflux for 1 hour. About one-half of the solvent was distilled off under reduced pressure, and the residual reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate (1 L). The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain ethyl 4-(4-methoxyphenyl)butanoate quantitatively.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[NH:4][C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[Br:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:25])=[C:16]([CH:24]=1)[O:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:25])=[C:16]([CH:24]=1)[O:17][CH:18]1[CH2:19][CH2:20][N:21]([C:2]2[C:3](=[O:10])[NH:4][C:5](=[O:9])[N:6]([CH3:8])[N:7]=2)[CH2:22][CH2:23]1.[Cl:25][C:15]1[CH:14]=[CH:13][CH:12]=[CH:24][C:16]=1[O:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: Cn1nc(Br)c(=O)[nH]c1=O
Reactant: Clc1ccc(Br)cc1OC1CCNCC1
Product: Clc1ccccc1OC1CCNCC1
Product: Cn1nc(N2CCC(Oc3cc(Br)ccc3Cl)CC2)c(=O)[nH]c1=O

Procedure:
The compound 92 (yellow powder) is prepared from the triazine 2e and from 4-(5-bromo-2-chlorophenoxy)piperidine (obtained as under the preparative conditions of intermediate 8a) according to the synthesis method 1 in toluene.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([C@@H:15]3[CH2:20][CH2:19][O:18][CH2:17][C@H:16]3[NH2:21])=O)[CH2:8]2)=[CH:4][CH:3]=1.O1CCCC1.C(O)(=O)C>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][C@@H:15]3[CH2:20][CH2:19][O:18][CH2:17][C@H:16]3[NH2:21])[CH2:8]2)=[CH:22][CH:23]=1
Reactant: N[C@@H]1COCC[C@H]1C(=O)N1CCC[C@@H](Cc2ccc(F)cc2)C1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: N[C@@H]1COCC[C@H]1CN1CCC[C@@H](Cc2ccc(F)cc2)C1
Reaction time: 20 h
Yield: 89.6 %

Procedure:
[(S)-3-(4-Fluoro-benzyl)-piperidin-1-yl]-[(3S,4R)-3-aminotetrahydro-pyran-4-yl]-methanone (367 mg, 1.14 mmol) was treated with borane-tetrahydrofuran complex in tetrahydrofuran (1.0 M; 46 mL, 46 mmol) and stirred for 20 h. The mixture was treated slowly with 20% acetic acid in methanol (25 mL), and the resulting mixture was stirred at room temperature for 3 h. The solvents were removed, and the residue was dissolved in water, made basic (pH 11) with 50% sodium hydroxide, and extracted with dichloromethane. The combined organic phases were dried (Na2SO4) and concentrated to provide a gum (313 mg). A portion of this material (175 mg) was purified by flash column chromatography (5% methanol/dichloromethane, containing 0.5% ammonium hydroxide) to provide the product (103 mg, 52%) as an oil which solidified on standing.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH2:9][C:10]1[N:11]([CH3:23])[C:12]([C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:13][CH:14]=1)[NH2:5].N1C=CC=CC=1.[C:30]([O:33][CH2:34][CH2:35][S:36](Cl)(=[O:38])=[O:37])(=[O:32])[CH3:31]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][S:36]([CH2:35][CH2:34][O:33][C:30](=[O:32])[CH3:31])(=[O:38])=[O:37])[CH:6]=[CH:7][C:8]=1[CH2:9][C:10]1[N:11]([CH3:23])[C:12]([C:15](=[O:22])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:13][CH:14]=1
Reactant: CC(=O)OCCS(=O)(=O)Cl
Reactant: Cn1c(Cc2ccc(N)cc2F)ccc1C(=O)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCCS(=O)(=O)Nc1ccc(Cc2ccc(C(=O)c3ccccc3)n2C)c(F)c1
Yield: 57.7 %

Procedure:
3-Fluoro-4-[5-benzoyl-1-methyl-1H-pyrrol-2-ylmethyl]aniline (0.75 g, 2.43 mmol) [prepared as described in Example 1, but substituting ethyl 1,4-dimethylpyrrole-2-acetate with methyl 1-methylpyrrole-2-acetate in Step (a)], and pyridine (0.39 ml, 4.88 mmol) were dissolved in methylene chloride (8 ml). 2-Acetoxyethanesulfonyl chloride (681 mg, 3.65 mmol) was added to the solution and after 15 min, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated to dryness. Purification of the residue by flash chromatography (hexane-ethyl acetate, 3:2) gave N-{3-fluoro-4-[5-benzoyl-1-methyl-1H-pyrrol-2-ylmethyl]phenyl}-2-(acetoxy)ethanesulfonamide, (643 mg, 58%) as a solid. ##STR58##
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10](O)=[O:11])=[O:7])[CH:2]([CH3:4])[CH3:3].[Cl:20]CCl.S(Cl)(Cl)=O>CN(C)C=O>[CH2:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:10]([Cl:20])=[O:11])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COC(=O)NC(Cc1ccccc1)C(=O)O
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)COC(=O)NC(Cc1ccccc1)C(=O)Cl

Procedure:
A solution of 2-isobutoxycarbonylamino-3-phenyl-propionic acid (5 gm), dichloromethane (25 mL) and dimethylformamide (0.5 mL) was cooled to 0-5° C. To the resulting solution, thionyl chloride (1.5 mL) was added at same temperature. The solvent was distilled out completely to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([N:13]1[CH2:29][CH2:28][C:16]3([N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][NH:18][C:17]3=[O:27])[CH2:15][CH2:14]1)[CH2:7]2.[CH2:30](Br)[CH:31]=[CH2:32]>>[ClH:1].[CH2:32]([N:18]1[C:17](=[O:27])[C:16]2([CH2:28][CH2:29][N:13]([CH:6]3[CH2:5][CH2:4][C:3]4[C:8](=[C:9]([Cl:12])[CH:10]=[CH:11][C:2]=4[Cl:1])[CH2:7]3)[CH2:14][CH2:15]2)[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19]1)[CH:31]=[CH2:30]
Reactant: C=CCBr
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCc3c(Cl)ccc(Cl)c3C1)CC2
Product: C=CCN1CN(c2ccccc2)C2(CCN(C3CCc4c(Cl)ccc(Cl)c4C3)CC2)C1=O
Product: Cl

Procedure:
The title compound, m.p.>250° C. and MS: m/e=470.4, 472.4 (M+H+) was prepared in accordance with the general method of example 4 from 8-(5,8-dichloro-1,2,3,4-tetrahydro-2-naphthyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one and allyl bromide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[C:10](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(Cl)c(O)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COc1cc(C)ccc1Cl
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
2-Chloro-5-methylphenol (5.00 g, 35.0 mmol, 1.00 equiv) and potassium carbonate (29.0 g, 2.10 mol, 6 equiv) were combined in DMF and stirred 15 minutes. Dimethyl sulfate (9.95 mL, 1.05 mol, 3.00 equiv) was added and the mixture was heated to 70° C. After 1 hour, the reaction was cooled to room temperature and stirred an additional 18 hours. The mixture was diluted with 200 mL H2O and extracted with Et2O. The organic phase was washed three times with H2O and once with brine, then dried over MgSO4 and concentrated en vacuo. 5.48 g (100%) of the product was obtained as a red liquid. 1H NMR (400 MHz, CDCl3) 7.25 (d, 1H), 6.77 (s, 1H), 6.73 (d, 1H), 3.91 (s, 3H), 2.56 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:28]=[CH:27][C:7]([CH:8]=[C:9]2[C:13]3[O:14][C:15]4[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][C:16]=4[C:17](=[O:18])[C:12]=3[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O.O.O.Cl[Sn]Cl>C(O)(=O)C.Cl>[NH2:1][C:4]1[CH:28]=[CH:27][C:7]([CH:8]=[C:9]2[C:13]3[O:14][C:15]4[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][C:16]=4[C:17](=[O:18])[C:12]=3[CH2:11][CH2:10]2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc2oc3c(c(=O)c2c1)CCC3=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc2oc3c(c(=O)c2c1)CCC3=Cc1ccc(N)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 82.9 %

Procedure:
3-(4-nitro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylic acid, methyl ester (3.8 g), was reacted with SnCl2.2H2O (11.5 g) in acetic acid (130 ml) and 37% HCl (26.5 ml) under stirring at 60° C. for 3 hours: after cooling the precipitate was filtered and washed with 2N HCl and water finely dispersed in 2N NaOH. The precipitate was filtered and washed with water until neutral to give 3-(4-amino-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylic acid, methyl ester m.p. 265°-268° C. (2.9 g), which was treated with 37% HCl (60 ml) in acetic acid (120 ml) under stirring at 100° C. for 4 hours. After cooling the precipitate was filtered and then suspended under stirring in water containing Na2HPO4 : the precipitate was filtered and washed with water to give 2.1 g of 3-(4-amino-benzylidene)-1,2,3,9tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylic acid, m.p. 360° C. dec., NMR (DMSO d6) δppm: 2.90 (m) (4H, C-1 and C-2 protons), 3.30 (bs) (2H, NH2), 6.64 (d) (2H, C-3 and C-5 phenyl protons), 7.01 (bs) (1H=CH--), 7.31 (d) (2H, C-2 and C-6 phenyl protons, 7.69 (d) (1H, C-5 proton), 8.19 (dd) (1H, C-6 proton), 8.59 (d) (1H, C-8 proton).
Reaction SMILES: [OH:1][CH:2]1[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:3]1[NH:12][C:13]([CH3:15])=[O:14].C([O:18][C:19](=O)[CH:20]([CH3:22])[OH:21])C>P([O-])([O-])([O-])=O>[C:19]([O:11][CH2:10][C@H:8]1[O:9][CH:2]([OH:1])[C@@H:3]([NH:12][C:13](=[O:14])[CH3:15])[C@@H:4]([OH:5])[C@@H:6]1[OH:7])(=[O:18])[CH:20]([CH3:22])[OH:21]
Reactant: CCOC(=O)C(C)O
Reactant: CC(=O)N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: O=P([O-])([O-])[O-]
Product: CC(=O)N[C@@H]1C(O)O[C@H](COC(=O)C(C)O)[C@@H](O)[C@@H]1O
Temperature: 50 °C
Reaction time: 72 h
Yield: 50 %

Procedure:
ManNAc (200 mg) and 50 mg of subtilisin mutant 8399 were added to a mixture of lactic acid ethyl ester (4 mL) and 400 mL of 0.5 N phosphate buffer (pH 7.5). The reaction mixture was shaken under 50° C. for three days. The solvent was then evaporated and methanol was added to the residue. After the insoluble materials were filtered off, the filtrate was concentrated. The residue was chromatographed on silica gel with ethyl acetate/methanol (5/1) to give 6-O-Lactyl N-acetylmannosamine in 50 percent yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])[N:5]=[C:4]([NH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[N:3]=1.C[Si](C)(C)[O:28][NH2:29]>O1CCOCC1>[ClH:1].[Cl:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([Cl:15])[C:9]=1[CH2:8][C:6]1[N:7]=[C:2]([NH:29][OH:28])[N:3]=[C:4]([NH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[N:5]=1
Reactant: C[Si](C)(C)ON
Reactant: N#Cc1ccc(Nc2nc(Cl)nc(Cc3c(Cl)cccc3Cl)n2)cc1
Solvent: C1COCCO1
Product: Cl
Product: N#Cc1ccc(Nc2nc(Cc3c(Cl)cccc3Cl)nc(NO)n2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 54.6 %

Procedure:
Intermediate (27) (0.0128 mol), 1,4-dioxane (50 ml), and O-(trimethylsilyl)hydroxyl-amine, (0.134 mol) were combined under argon. The reaction mixture was stirred at RT for 20 hours. The reaction mixture was concentrated and DCM (50 ml), NaOH (1 N; 50 ml), and HCl (1N; 100 ml) were added. The solution was stirred for one hour. The precipitate was filtered off and recrystallized from methanol. The precipitate was filtered off and dried, yielding 2.96 g (59.8%) of 4-[[4-[(2,6-dichlorophenyl)methyl]-6-(hydroxyamino)-1,3,5-triazin-2-yl] amino]benzonitrile monohydrochloride.monohydrate (compound 21).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([NH2:13])=[CH:11][C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:9][N:8]=2)[CH2:3][CH2:2]1.Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=2)[N:24]=[C:23]([C:32]2[CH:33]=[N:34][CH:35]=[C:36]([F:38])[CH:37]=2)[C:22]=1[CH3:39].Cl.O1CCOCC1.CN1C(=O)CCC1>>[N:4]1([C:7]2[C:12]([NH:13][C:21]3[C:30]4[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=4)[N:24]=[C:23]([C:32]4[CH:33]=[N:34][CH:35]=[C:36]([F:38])[CH:37]=4)[C:22]=3[CH3:39])=[CH:11][C:10]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:9][N:8]=2)[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: Cc1c(-c2cncc(F)c2)nc2cc(F)ccc2c1Cl
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2cncc(F)c2)nc2cc(F)ccc2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Temperature: 150 °C

Procedure:
Prepared according to Procedure K, method 2 using 2,5-dimorpholinopyridin-3-amine (43 mg, 0.16 mmol; described herein), 4-chloro-7-fluoro-2-(5-fluoropyridin-3-yl)-3-methylquinoline (47 mg, 0.16 mmol; described herein), 4.0M hydrochloric acid in 1,4-dioxane (4 μL, 0.1 equiv, 16 μmol), and NMP (190 μL, 1.9 mmol). The reaction was heated in a microwave at 150° C. for 4 h. Purification afforded N-(2,5-di-4-morpholinyl-3-pyridinyl)-7-fluoro-2-(5-fluoro-3-pyridinyl)-3-methyl-4-quinolinamine as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.69 (1H, m), 8.60 (1H, d, J=2.7 Hz), 7.84 (1H, m), 7.76 (2H, m), 7.64 (1H, d, J=2.7 Hz), 7.33 (1H, m), 6.81 (1H, s), 6.21 (1H, d, J=2.7 Hz), 3.89-3.97 (4H, m), 3.72-3.79 (4H, m), 3.24 (4H, m), 2.89-2.98 (4H, m), 2.33 (3H, s). Mass Spectrum (ESI) m/e=519.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]3[CH:12]=[N:13][N:14]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[C:15]=3[CH:16]=[CH:17][CH:18]=2)=[O:9])=[C:4]([Cl:28])[CH:3]=1.[H-].[Na+].[CH3:31][O:32][CH2:33]Cl>CN(C=O)C.O.C(OCC)C>[Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]([CH2:31][O:32][CH3:33])[C:8]([C:10]2[C:11]3[CH:12]=[N:13][N:14]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[C:15]=3[CH:16]=[CH:17][CH:18]=2)=[O:9])=[C:4]([Cl:28])[CH:3]=1
Reactant: COCCl
Reactant: O=C(NCc1ccc(Br)cc1Cl)c1cccc2c1cnn2-c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COCN(Cc1ccc(Br)cc1Cl)C(=O)c1cccc2c1cnn2-c1ccc(F)cc1
Reaction time: 0.17 h

Procedure:
To a room temperature solution of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid 4-bromo-2-chloro-benzylamide (1.5 g, 3.3 mmol) in DMF (30 mL) was added a 60% dispersion of sodium hydride in mineral oil (145 mg, 3.60 mmol). After stirring for 10 minutes, chloromethyl methyl ether (0.28 mL, 3.6 mmol) was added. After 16 hours, the mixture was then diluted with water (30 mL) and extracted with ethyl acetate (3×20 mL). The extract was washed with saturated aqueous ammonium chloride (30 mL) followed by brine (30 mL) and dried over sodium sulfate. The residue was purified by silica gel chromatography eluting with a gradient of 0-70% ethyl acetate in hexanes. The fractions containing product were condensed in vacuo to provide a colorless oil. The oil was dissolved in diethyl ether (25 mL), causing the starting material to solidify from solution. Filtration gave the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([O:30]C(=O)C(C)(C)C)[CH:24]=[CH:23][C:22]=3[CH2:21]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]([N:43]1[CH2:48][CH2:47][CH:46]([CH3:49])[CH2:45][CH2:44]1)=O>>[CH3:19][O:18][C:16]1[CH:15]=[CH:14][C:13]([CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23][C:22]=3[CH2:21]2)=[C:12]([NH:11][CH2:10][CH2:9][CH2:8][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:40][CH2:41][N:43]3[CH2:48][CH2:47][CH:46]([CH3:49])[CH2:45][CH2:44]3)=[CH:38][CH:37]=2)[CH:17]=1
Reactant: CC1CCN(C(=O)CCl)CC1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCC(=O)c2ccc(O)cc2)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCCc2ccc(OCCN3CCC(C)CC3)cc2)c1
Yield: 60.2 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)propylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and 2-chloro-1-(4-methylpiperidin-1-yl)ethanone (21 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (19 mg) was obtained.
Reaction SMILES: Cl.[CH2:2]([C:5]1[N:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)[CH2:3][CH3:4].N1[CH:18]=[CH:17]C=CC=1.CN(C=[O:23])C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:12][C:7]1[CH:6]=[C:5]([CH2:2][CH2:3][CH3:4])[N:10]=[CH:9][C:8]=1[NH:11][C:17](=[O:23])[CH3:18]
Reactant: CN(C)C=O
Reactant: c1ccncc1
Reactant: CCCc1cc(N)c(N)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCc1cc(N)c(NC(C)=O)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 6-propyl-pyridine-3,4-diamine hydrochloride (prepared from ethyl butyrylacetate as described in Example 28, steps 1-9) (187 mg, 1.00 mmol) in CH2Cl2 (4 mL) at 0° C. under N2 is added pyridine (0.24 mL, 3.00 mmol) followed by DMF (2 mL) (for solubility). Next, AC20 (0.104 mL, 1.1 mmol) is added. The reaction mixture is stirred for 3 h while slowly warming to rt. It is then poured into saturated aq NaHCO3 and extracted thrice with CH2Cl2. The combined extracts are dried over K2CO3 and concentrated to 114 mg of crude N-(4-amino-6-propyl-pyridin-3-yl)-acetamide, which was used without further purification. 1H NMR (CDCl3, 300 MHz) δ 8.73 (br, 1H), 8.00 (s, 1H), 8.43 (s, 1H), 4.63 (br, 2H), 2.54 (m, 2H), 2.13 (s, 3H), 1.63 (sextet, J=7.2 Hz, 2H), 0.89 (t, J=7.2 Hz, 3H) ppm. Electrospray MS: m/z 194 [M+1].
Reaction SMILES: O[Li:2].O.C[O:5][C:6]([C:8]1[CH:9]=[C:10]([CH:43]=[CH:44][CH:45]=1)[CH2:11][CH2:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)=[CH:26][CH:25]=2)[N:14]=1)=[O:7]>C1COCC1.O.CO>[C:39]([O:38][C:36]([N:33]1[CH2:34][CH2:35][N:30]([C:27]2[CH:26]=[CH:25][C:24]([NH:23][C:15]3[N:14]=[C:13]([CH2:12][CH2:11][C:10]4[CH:9]=[C:8]([CH:45]=[CH:44][CH:43]=4)[C:6]([O-:7])=[O:5])[C:18]([C:19]([F:20])([F:21])[F:22])=[CH:17][N:16]=3)=[CH:29][CH:28]=2)[CH2:31][CH2:32]1)=[O:37])([CH3:42])([CH3:40])[CH3:41].[Li+:2]
Reactant: COC(=O)c1cccc(CCc2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)c1
Reactant: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4cccc(C(=O)[O-])c4)n3)cc2)CC1
Product: [Li+]
Temperature: 25 °C
Reaction time: 17 h
Yield: 91 %

Procedure:
LiOH.H2O (0.025 g, 0.60 mmol) was added to tert-butyl 4-(4-((4-(3-(methoxycarbonyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I33) (0.117 g, 0.200 mmol) in THF (7 mL), water (1.5 mL) and methanol (1 mL). The resulting mixture was allowed to stir at room temperature for 17 hours, the volatiles were removed in vacuo and the residue was diluted with EtOAc (100 mL) and sat. aq. NaHCO3 (80 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×80 mL), the organic layers were combined, washed with brine (70 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give the title compound (I34) (0.105 g, 91% yield) as a pale yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.00 (s, 1H), 8.60 (s, 1H), 7.85-7.74 (m, 2H), 7.56-7.48 (m, 2H), 7.47-7.35 (m, 2H), 6.93 (d, J=9.1 Hz, 2H), 3.50-3.41 (m, 4H), 3.17-2.98 (m, 8H), 1.42 (s, 9H). LCMS Method C: rt 6.30 min; m/z 572.3 [M+H]+.