Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[CH:5]=[C:6]([I:8])[CH:7]=1>C(O)C>[I:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([I:8])[CH:7]=1)[NH2:9]
Reactant: O=[N+]([O-])c1cc(I)cc(I)c1
Solvent: CCO
Product: Nc1cc(I)cc(I)c1
Yield: 61.9 %

Procedure:
A mixture of 61.5 g (0.164M) of 3,5-diiodonitrobenzene and 111.1 g (0.4924M) of stannous chloride in 900 mL of ethanol was heated to reflux 1.5 hrs under nitrogen. The reaction mixture was cooled and most of the solvent was removed in vacuo. The residue was partitioned between ethyl acetate and excess ice-cold 5N sodium hydroxide and ice. The organic phase was separated, washed with sat'd sodium chloride solution, and dried over anhyd. magnesium sulfate. Solvent removal afforded a crude oil which was purified on silica gel using 8:1:1 mixture of hexane:methylene chloride:ethyl acetate to give 35 g of 3,5-diiodoaniline as a light tan colored solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:10])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[C:11]([O-])([O-])=O.[Cs+].[Cs+].BrC[CH2:19][O:20][CH3:21]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:19][O:20][CH3:21])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1ccc(Br)cc1O
Reactant: COCCBr
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCOc1ccc(Br)cc1OC
Temperature: 100 °C

Procedure:
2.0 g (9.65 mmol) 4-bromoguaiacol and 1.89 g (5.8 mmol) Cs2CO3 are suspended in 20.0 ml dry DMF and 1.02 ml (10.6 mmol) 2-bromoethylmethylether are introduced at RT under an argon flux. The resulting pale brown suspension is heated to 100° C. for 15 h. After cooling, the reaction mixture is partitioned between EtOAc and water. The aqueous phase is re-extracted twice with EtOAc. The combined organic solution is washed with brine, dried over Na2SO4 and concentrated in vacuo to afford the title compound as a light yellow residue.
Reaction SMILES: [OH:1][CH:2]([C@@H:6]([NH:11][C:12]([C:14]1([NH:20][C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]2)=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[CH2:7][CH2:8][CH2:9][CH3:10])[C:3](O)=[O:4].ClC1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36][NH2:37].C1(CN)CCCC1>>[CH:35]1([CH2:36][NH:37][C:3](=[O:4])[C:2](=[O:1])[C@@H:6]([NH:11][C:12]([C:14]2([NH:20][C:21]([N:23]3[CH2:24][CH2:25][N:26]([C:29](=[O:31])[CH3:30])[CH2:27][CH2:28]3)=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:13])[CH2:7][CH2:8][CH2:9][CH3:10])[CH2:34][CH2:40][CH2:39][CH2:38]1
Reactant: CCCC[C@H](NC(=O)C1(NC(=O)N2CCN(C(C)=O)CC2)CCCCC1)C(O)C(=O)O
Reactant: NCc1cccc(Cl)c1
Agent: NCC1CCCC1
Product: CCCC[C@H](NC(=O)C1(NC(=O)N2CCN(C(C)=O)CC2)CCCCC1)C(=O)C(=O)NCC1CCCC1
Yield: 11 %

Procedure:
The same procedure as in Example 28 was repeated except that the (2RS,3S)-2-hydroxy-3-[1-[N-[N-(morpholine-4-carbonyl)amino]cyclohexanecarbonyl]amino]heptanoic acid was replaced by 881 mg of (2RS,3S)-2-hydroxy-3-[N-[1-[N-(4-acetylpiperazine-1-carbonyl)amino]cyclohexanecarbonyl]amino]heptanoic acid synthesized in Reference Example 28 and the 3-chlorobenzylamine was replaced by 496 mg of cyclopentylmethylamine, whereby 64 mg of the captioned N-[(S)-1-(N-cyclopentylmethylamino)-1,2-dioxo-3-heptyl]-1-[N-(4-acetylpiperazine-1-carbonyl) amino]cyclohexanecarboxamide was obtained in a yield of 11%.
Reaction SMILES: [F:1][C:2]1([CH2:26][NH2:27])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>ClCCl>[F:1][C:2]1([CH2:26][NH:27][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(F)(CN)CC3)c(F)c2)C(=O)O1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(F)(CNS(C)(=O)=O)CC3)c(F)c2)C(=O)O1
Yield: 75 %

Procedure:
The title compound was prepared by reacting (S)-N-{3-[4-(4-fluoro-4-aminomethylpiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.30 mmol) with methane sulfonyl chloride (1.40 mmol) and triethylamine (2.08 mmol) in dichloromethane (10 ml) at a temperature 25° C. for 2 hours followed by purifification of the compound using silica gel column chromatography in 75% yield.
Reaction SMILES: [C:1]([S:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][NH2:28])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[CH:38]=1)[C:33](O)=[O:34].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[CH:38]=1)[C:33]([NH:28][CH2:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[S:20][C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:34]
Reactant: NCc1ccccc1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cc(F)cc(N2CCOCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccccc1SC(c1ccccc1)(c1ccccc1)c1ccccc1)c1cc(F)cc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A suspension of 1-[2-(tritylsulfanyl)phenyl]methanamine (335 mg, 0.88 mmol), 3-fluoro-5-morpholin-4-yl-benzoic acid (WO2004/089929) (237 mg, 1.05 mmol) and DIPEA (0.38 mL, 2.19 mmol) in DMF (15 mL) was treated with HATU (400 mg, 1.05 mmol). The mixture was stirred at RT for 45 min, then partitioned between aqueous saturated NaHCO3 and EtOAc. The organic layer was separated, dried over MgSO4, filtered, and the filtrate was concentrated in vacuo to afford the title compound (quantitative) as an off-white solid. 1H NMR (300 MHz, CDCl3): δ 7.35-7.29 (6H, m), 7.27-7.19 (10H, m), 7.17 (2H, m), 7.10 (1H, t, J 1.7), 6.98-6.92 (1H, m), 6.73-6.64 (2H, m), 5.98 (1H, br t, J 6), 4.21 (2H, d, J 6), 3.84 (4H, t, J 4.8), 3.19 (4H, t, J 4.8).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[S:12](=[O:23])(=[O:22])[N:13]([CH3:21])[C:14]([C:17]([O:19]C)=O)=[C:15]([OH:16])[C:4]1=2)[CH3:2].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1(C)C(C)=CC=CC=1>[CH2:1]([N:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[S:12](=[O:23])(=[O:22])[N:13]([CH3:21])[C:14]([C:17]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:19])=[C:15]([OH:16])[C:4]1=2)[CH3:2]
Reactant: CCn1c2c(c3ccccc31)S(=O)(=O)N(C)C(C(=O)OC)=C2O
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1C
Product: CCn1c2c(c3ccccc31)S(=O)(=O)N(C)C(C(=O)Nc1ccccc1)=C2O
Yield: 56 %

Procedure:
5-Ethyl-2,5-dihydro-4-hydroxy-2-methyl-N-phenyl-1,2-thiazino-[5,6-b]indole-3-carboxamide-1,1-dioxide was prepared analogous to Example 15 from methyl 5-ethyl-2,5-dihydro-4-hydroxy-2-methyl-1,2-thiazino[5,6-b]indole-3-carboxylate-1,1-dioxide and aniline a yield of 56% of theory. M.p.: 268° C. (decomposition; from xylene).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([S:19]([CH2:22][CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)(=[O:21])=[O:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:31])([CH3:30])[C:6]=2[CH:32]=1.[C:33]([SiH2]OC(C)(C)[C@@H]1OC(C)(C)O[C@@H]1CO)(C)([CH3:35])[CH3:34].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1COCC1.O.C(OCC)(=O)C>[CH:33]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([S:19]([CH2:22][CH2:23][C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)(=[O:21])=[O:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:30])([CH3:31])[C:6]=2[CH:32]=1)([CH3:35])[CH3:34]
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(S(=O)(=O)CCc3ccccc3)ccc21
Reactant: CC1(C)O[C@@H](C(C)(C)O[SiH2]C(C)(C)C)[C@@H](CO)O1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc2c(c1)C(C)(C)c1[nH]c3cc(S(=O)(=O)CCc4ccccc4)ccc3c1C2=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
8-Hydroxy-6,6-dimethyl-3-(2-phenyl-ethanesulfonyl)-5,6-dihydro-benzo[b]carbazol-11-one (30 mg, 0.0673 mmol), [(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-yl]methanol (22.3 mg, 0.0808 mmol), and PPh3 (23 mg, 0.0875 mmol) were dissolved in THF (0.5 ml), added with DIAD (0.0169 ml, 0.0808 mmol), and the mixture was stirred at 50° C. overnight. After cooling, the reaction solution was filtered and concentrated under reduced pressure. The resulting residues were purified by silica gel column (ethyl acetate/hexane). The resulting residues were dissolved in THF (0.4 ml) and water (0.13 ml), added with camphor sulfonic acid (28.1 mg, 0.121 mmol), and then subjected to microwave irradiation at 80° C. for 15 min under nitrogen atmosphere. Ethyl acetate was added to the resultant. The organic layer was washed with saturated aqueous solution of sodium hydrocarbonate and saturated brine, and then concentrated under reduced pressure. The resulting residues were purified by thin layer chromatography (MeOH/DCM) to obtain Compound GT20-2 (10.5 mg) and Compound GT20-3 (2.4 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([CH:9]=[CH2:10])[N:6]=[CH:5][N:4]=1)=[CH2:2].CC1C=[C:16](C)[N:15]=[CH:14]N=1.Cl.[CH3:20][NH:21][CH3:22].C=O>O>[CH3:20][N:21]([CH2:2][CH2:1][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][N:15]([CH3:14])[CH3:16])[N:6]=[CH:5][N:4]=1)[CH3:22]
Reactant: C=Cc1cc(C=C)ncn1
Reactant: Cc1cc(C)ncn1
Reactant: CNC
Agent: C=O
Agent: Cl
Solvent: O
Product: CN(C)CCc1cc(CCN(C)C)ncn1

Procedure:
The compound 4,6-divinylpyrimidine is miscible with water and can be prepared according to the synthetic scheme illustrated in FIG. 1. As shown, in a two-step process, 4,6-dimethylpyrimidine is reacted with dimethylamine hydrochloride and formaldehyde to provide the corresponding 4,6-bis(dimethylaminoethyl)pyrimidine. This dimethylaminoethyl compound is methylated and deaminated in the presence of a base to provide the desired 4,6-divinylpyrimidine.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:13]=NN(C)C=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CC1C=CC(B2OC(C)(C)C(C)(C)O2)=C(C=1)C(OC)=O.[Cl:38][C:39]1[N:44]=C(Cl)C=[CH:41][N:40]=1>>[Cl:38][C:39]1[N:44]=[C:12]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])[CH:13]=[CH:41][N:40]=1
Reactant: COC(=O)c1cc(C)ccc1-c1cnn(C)c1
Reactant: Clc1ccnc(Cl)n1
Agent: COC(=O)c1cc(C)ccc1B1OC(C)(C)C(C)(C)O1
Product: COC(=O)c1cc(C)ccc1-c1ccnc(Cl)n1

Procedure:
The title compound was synthesized following the same general protocol as described for methyl 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoate in Example A1, using methyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate and 2,4-dichloropyrimidine. ESI-MS (m/z): 263 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[N:10]3[CH:12]=[CH:13][CH:14]=[C:9]3[C:8](=[O:15])[N:7]([CH2:16][C:17]([O:19]C)=[O:18])[C:6]=2[N:5]=[CH:4][CH:3]=1.[Li+].[OH-]>CO.O.C1COCC1>[CH3:1][C:2]1[C:11]2[N:10]3[CH:12]=[CH:13][CH:14]=[C:9]3[C:8](=[O:15])[N:7]([CH2:16][C:17]([OH:19])=[O:18])[C:6]=2[N:5]=[CH:4][CH:3]=1
Reactant: COC(=O)Cn1c(=O)c2cccn2c2c(C)ccnc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1ccnc2c1n1cccc1c(=O)n2CC(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.5 %

Procedure:
Methyl 2-(1-methyl-6-oxopyrido[2,3-e]pyrrolo[1,2-a]pyrazin-5(6H)-yl)acetate (517 mg, 1.91 mmol) was dissolved in 20 mL of MeOH/H2O/THF (1:1:4). LiOH (68.5 mg, 2.86 mmol) was added. The mixture was stirred at room temperature for 16 hours. The solvents were removed and residue was dissolved in water, washed with ether, then neutralized with 2N HCl to pH=3. 356 mg (73%) white solid was obtained after filtration and dried under vacuum. 1H NMR (400 MHz, DMSO) δ 12.90 (s, 1H), 8.27-8.17 (m, 2H), 7.29-7.19 (m, 2H), 6.80 (dd, J=2.9, 3.9 Hz, 1H), 5.02 (s, 2H), 2.85 (s, 3H). 13C NMR (101 MHz, DMSO, APT) δ 169.8, 154.5, 143.1, 141.4, 135.9, 123.9, 123.3, 122.8, 119.5, 113.3, 112.7, 41.6, 22.2. HRMS (m/z): calcd for C13H12N3O3 (M+H) 258.0879. found 258.0894.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]C(Cl)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:21]=[N+]=[N-].[Na+].C1(C)C=CC=CC=1.C[C:33](C)=[O:34]>O>[O:1]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:21]=[C:33]=[O:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCCCCCCCCCOc1ccccc1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)=O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C=NCCCCCCCCCCOc1ccccc1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
A solution of 11-phenoxyundecanoyl chloride (31.1 g, 104.8 mmoles) in acetone (30 ml) was dropped into a solution of sodium azide (9.53 g, 146.6 mmoles) in water (30 ml), cooled in an ice bath, keeping the solution temperature between 10 and 15° C. After one hour, the solution was transferred in a separatory funnel and the lower phase (the aqueous one) was eliminated. The higher phase was transferred into a flask containing 100 ml of toluene, previously warmed at 65° C. After 1.5 hours, the solution was evaporated to dryness, giving 13.37 g of crude product, which could be used as such in the subsequent reaction.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[NH:17][CH2:16][CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)=[CH:3][CH:2]=1.[H-].[Na+].CS([O:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])(=O)=O.[OH2:35]>CN(C)C=O>[C:28]([OH:33])(=[O:13])/[CH:27]=[CH:26]\[C:25]([OH:24])=[O:35].[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][CH2:25][N:17]1[C:9]2=[N:8][C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[CH:12][C:11](=[O:13])[N:10]2[CH2:14][CH2:15][CH2:16]1
Reactant: O=c1cc(-c2ccncc2)nc2n1CCCN2
Reactant: COc1ccccc1CCOS(C)(=O)=O
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1CCN1CCCn2c1nc(-c1ccncc1)cc2=O
Product: O=C(O)/C=C\C(=O)O
Temperature: 70 °C

Procedure:
A suspension of 0.25 g (1.09 mmol) of 2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in 3 ml of anhydrous dimethylformamide was treated with 57 mg (1.42 mmol) of sodium hydride (60% suspension in mineral oil) and the resulting mixture was heated at 70° C. for 30 min. 0.327 g (1.42 mmol) of 1-[2-(methylsulfonyloxy)ethyl]-2-methoxybenzene (prepared according to J. Med. Chem. 1983, 26(1), 42) was added and the reaction mixture was heated at 130° C. during 1 h. The cooled solution was treated with water and extracted with ethyl acetate. The organic phase was dried and evaporated to give crude product, which was purified by silica gel chromatography, eluting with dichloromethane/methanol in the proportions 100/0 to 95/5. The 0.338 g of pure product obtained in the form of free base was dissolved in hot ethanol and treated with 1 equivalent of (Z)-but-2-enedioïc acid. The cooled solution was filtered to afford 0.325 g (62%) of white solid. Mp: 157-160° C.
Reaction SMILES: C(Cl)CCl.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:21][N:22]2[CH2:25][CH:24]([OH:26])[CH2:23]2)=[C:10]([CH:20]=1)[CH2:11][NH:12][C:13](=[O:19])[C@@H:14]1[CH2:18][CH2:17][CH2:16][NH:15]1.[OH:27][C:28]1([C:41](O)=[O:42])[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[OH:27][C:28]1([C:41]([N:15]2[CH2:16][CH2:17][CH2:18][C@H:14]2[C:13]([NH:12][CH2:11][C:10]2[CH:20]=[C:6]([Cl:5])[CH:7]=[CH:8][C:9]=2[CH2:21][N:22]2[CH2:25][CH:24]([OH:26])[CH2:23]2)=[O:19])=[O:42])[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=2[C:35]2[C:40]1=[CH:39][CH:38]=[CH:37][CH:36]=2
Reactant: O=C(O)C1(O)c2ccccc2-c2ccccc21
Reactant: O=C(NCc1cc(Cl)ccc1CN1CC(O)C1)[C@@H]1CCCN1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(NCc1cc(Cl)ccc1CN1CC(O)C1)[C@@H]1CCCN1C(=O)C1(O)c2ccccc2-c2ccccc21

Procedure:
EDC (49.5, 0.26 mmol) was added to a stirred mixture of N-{5-chloro-2-[(3-hydroxyazetidin-1-yl)methyl]benzyl}-L-prolinamide (55.8 mg, 0.17 mmol), 9-hydroxy-9-H-fluoren-9-ylcarboxylic acid (40.9 mg, 0.18 mmol) and HOAT (11.7 mg, 0.086 mmol) in DMF (1.25 mL). After 16 h the mixture was concentrated and the residue was partitioned between EtOAc and 10% NaHCO3. The organic layer was washed with water and brine, dried (Na2SO4) and evaporated. The residue was purified by chromatography on silica (ammonia saturated CHCl3/MeOH, 98:2) to give the title compound as a glass: HRMS (FAB) calcd C30H31ClN3O4 (M+1) 554.1817, found 554.1855.
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(=O)([O-])[O-].[Na+].[Na+].Cl.[CH3:16][NH:17][OH:18]>CO>[CH3:16][N:17]([C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[OH:18]
Reactant: CCCCCC(=O)Cl
Reactant: CNO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCC(=O)N(C)O

Procedure:
Hexanoylchloride (g, 0.1 mole) is added dropwise with stirring and ice-cooling to a mixture of sodium carbonate (10.6 g, 0.1 mole) and N-methylhydroxylamine hydrochloride (8.35 g, 0.1 mole) in methanol (60 ml), the temperature being kept at less than 5° C. After stirring for a further 30 minutes the mixture is filtered and the solvent is removed using a rotary evaporator. The resultant residue is re-filtered and the residue distilled in vacuo to yield N-methyl-hexanohydroxamic acid as an oil, b.p. 87°-90°/0.1 mm.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4](C(O)CN)[CH:5]=[CH:6][CH:7]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:19]([OH:22])[CH2:20][NH2:21])[CH:16]=[CH:17][CH:18]=1.[C:23](O)(=O)/[CH:24]=[CH:25]/[C:26](O)=O>>[CH3:23][C:24]1[CH:3]=[CH:2][C:7]([CH2:6][CH:5]([NH:21][CH2:20][CH:19]([OH:22])[C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=2)[CH3:4])=[CH:26][CH:25]=1
Reactant: O=C(O)/C=C/C(=O)O
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: NCC(O)c1cccc(F)c1
Product: Cc1ccc(CC(C)NCC(O)c2cccc(F)c2)cc1

Procedure:
The title compound was prepared in the manner described in Example 3 replacing 2-(3-chlorophenyl)-2-hydroxyethanamine with 2-(3-fluorophenyl)-2-hydroxyethanamine. The chromatographed material was treated with methanolic fumaric acid and the derived salt recrystallised from ethyl acetate to give the title compound (fumarate), mp 58-83, as a 52-48 mixture of diastereoisomers.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([NH:12][CH2:13][C@:14]2([F:27])[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]2)[N:3]=1.[CH3:28][O:29][CH2:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.[OH-].[K+]>COCCOC.O.C(O)C>[F:27][C@@:14]1([CH2:13][NH:12][C:4]2[N:3]=[C:2]([C:34]3[CH:33]=[N:32][N:31]([CH2:30][O:29][CH3:28])[CH:35]=3)[CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][CH:8]=[N:9]3)[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@](F)(CNc2nc(Cl)cc3ncccc23)C1
Reactant: COCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: COCn1cc(-c2cc3ncccc3c(NC[C@]3(F)CCCN(C(=O)OC(C)(C)C)C3)n2)cn1
Temperature: 130 °C
Yield: 105 %

Procedure:
To 1,1-dimethylethyl (3R)-3-{[(7-chloro-1,6-naphthyridin-5-yl)amino]methyl}-3-fluoro-1-piperidinecarboxylate (650 mg, 1.646 mmol) in DME (5 ml), water (2.5 ml), ethanol (5.00 ml) was added 1-[(methyloxy)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.03 g 4.33 mmol), potassium hydroxide (3.95 ml, 3.95 mmol, 1M aqueous solution) and PEPPSI (112 mg, 0.165 mmol). The reaction was refluxed at 130° C. under nitrogen for 4 nights. LCMS showed main peak as product. The reaction mixture was filtered through celite and the solvent removed. The residue was dissolved in DCM and loaded onto a 25 g silica column and purified on the SP4 eluting with a 50-100% ethyl acetate in cyclohexane gradient. Appropriate fractions were combined and the solvent removed to give a yellow oil which was dried under high vacuum overnight to give the title compound as a yellow solid/film (813 mg).
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[C:5]([NH:8][C:9]([C@@H:11]2[CH2:13][C@H:12]2[CH3:14])=[O:10])[S:4][N:3]=1.[CH3:15][N:16]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][C:21]([Sn](C)(C)C)=[CH:22]2)=[N:17]1.[Cl-].[Li+]>O1CCOCC1>[CH3:20][CH2:19][CH2:18][CH:23]([CH3:24])[CH3:22].[Br:7][C:6]1[C:2]([C:21]2[CH:20]=[CH:19][C:18]3[C:23](=[CH:24][N:16]([CH3:15])[N:17]=3)[CH:22]=2)=[N:3][S:4][C:5]=1[NH:8][C:9]([C@@H:11]1[CH2:13][C@H:12]1[CH3:14])=[O:10]
Reactant: C[C@@H]1C[C@H]1C(=O)Nc1snc(Br)c1Br
Reactant: Cn1cc2cc([Sn](C)(C)C)ccc2n1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: CCCC(C)C
Product: C[C@@H]1C[C@H]1C(=O)Nc1snc(-c2ccc3nn(C)cc3c2)c1Br
Temperature: 105 °C
Yield: 43 %

Procedure:
Charge a round bottom flask with (1R,2R)-2-methyl-cyclopropanecarboxylic acid (3,4-dibromo-isothiazol-5-yl)-amide (2.55; g, 7.49; mmol), 2-methyl-5-trimethylstannanyl-2H-indazole (2.21; g, 7.49; mmol) and lithium chloride (0.95; g, 22.48; mmol) in 1,4-dioxane (19.2; mL). Purge with nitrogen for 20; min, add tetrakis(triphenylphosphine) palladium (1.31; g, 1.12; mmol) and heat at 105° C. for 48; h. Directly load reaction mixture onto a silica gel column and purify by gradient eluting from 0:100; to 100:0; ethyl acetate:iso-hexane to give the title compound (1.25; g, 43%). MS (m/z): 391, 393; (M+1).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:22])[CH:8]=2)[N:3]=1.[CH2:23]([CH2:25][NH2:26])[OH:24]>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:12]([CH3:13])[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:22])[CH:8]=3)[N:3]=[C:2]([NH:26][CH2:25][CH2:23][OH:24])[N:11]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccc(C)cc23)cc1
Reactant: NCCO
Product: COc1ccc(N(C)c2nc(NCCO)nc3ccc(C)cc23)cc1
Yield: 35 %

Procedure:
A solution of (2-chloro-6-methyl-quinazolin-4-yl)-(4-methoxyphenyl)-methyl-amine (50.3 mg, 0.16 mmol) in ethanolamine (1.5 mL) was heated to 140° C. in the microwave for 20 min. The reaction was then concentrated onto SiO2 and purified by gradient MPLC (SiO2, 0-100%, EtOAc/hexanes, 20 min). 19.1 mg (35%) of the title compound was isolated: 1H NMR (DMSO-d6) δ 7.33 (d, 1 H), 7.21 (dd, 1 H), 7.04-7.10 (m, 2H), 6.86-6.92 (m, 2H), 6.57-6.62 (m, 1H), 5.44 (br s, 1H), 3.82-3.94 (m, 2H), 3.83 (s, 3H), 3.62-3.67 (m, 2H), 3.48 (s, 3H), 2.01 (s, 3H). HRMS (ES) calcd for C19H23N4O2 [(M+H)] 339.1816, found 339.1854.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([F:12])[CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[Cl:21])[NH2:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:17][C:16]2[CH:18]=[CH:19][C:20]([Cl:21])=[C:14]([Cl:13])[CH:15]=2)=[O:11])=[C:4]([F:12])[CH:3]=1
Reactant: O=C(O)Cc1ccc(Br)cc1F
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(Br)cc1F)Nc1ccc(Cl)c(Cl)c1
Temperature: 20 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
To a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (144 mg, 0.617 mmol), 3,4-dichloroaniline (100 mg, 0.617 mmol) and HATU (704 mg, 1.852 mmol) in DCM (20 mL) was added Et3N (0.258 mL, 1.852 mmol) dropwise. Then the mixture was stirred at 20° C. under a N2 atmosphere for 3 h. After LCMS analysis showed the starting material had disappeared, the solvent was removed in vacuo. Then the crude product was dissolved in DCM and washed with H2O and brine. The organic layer was evaporated to dryness to give the crude product which was purified by silica column chromatography (PE/EA=100/1 to 8/1) to afford pure product 2-(4-bromo-2-fluorophenyl)-N-(3,4-dichlorophenyl)acetamide (190 mg, 0.419 mmol, 67.8% yield): 1H NMR: (400 MHz, CD3OD) δ 10.25 (br. s, 1H), 7.89 (s, 1H), 7.44 (s, 2H), 7.28-7.37 (m, 3H), 3.74 (s, 2H); ES-LCMS: m/z 377.9 (M+H).