Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][O:7][CH:8]([F:10])[F:9])[C:3]([OH:5])=[O:4].C(=O)(O)[O-].[Na+].[C:16](OC(=O)C)(=[O:18])[CH3:17].Cl>O.O1CCOCC1>[C:16]([NH:1][C@H:2]([CH2:6][O:7][CH:8]([F:10])[F:9])[C:3]([OH:5])=[O:4])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@H](COC(F)F)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N[C@H](COC(F)F)C(=O)O
Yield: 67 %

Procedure:
(2R)-2-Amino-3-(difluoromethoxy)propanoic acid (680 mg, 4.39 mmol) was mixed with sodium bicarbonate (738 mg. 8.78 mmol) and acetic anhydride (491 mg, 4.82 mmol) in water (10 mL) and dioxane (10 mL) at 0° C. to room temperature overnight. The reaction mixture was acidified with 1N HCl to pH 2, concentrated and extracted with ethyl acetate, and concentrated again to give (2R)-2-(Acetylamino)-3-(difluoromethoxy)propanoic acid (580 mg, 82.3%) as a colorless sticky oil. 1H NMR (300 MHz, CDCl3): (ppm) 6.40 (d, 1H), 6.24 (wt, 1H), 4.88 (m, 1H), 4.36 (dd, 1H), 4.22 (dd, 1H), 2.12 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:28][CH3:29])[C:16]2[C:17]([CH2:26][CH3:27])=[C:18]([CH:22]=[C:23]([Cl:25])[CH:24]=2)[C:19]([OH:21])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:63][CH2:64][C:65]1[C:66](=[O:73])[NH:67][C:68]([CH3:72])=[CH:69][C:70]=1[CH3:71]>CN(C=O)C>[Cl:25][C:23]1[CH:22]=[C:18]([C:19](=[O:21])[NH:63][CH2:64][C:65]2[C:66](=[O:73])[NH:67][C:68]([CH3:72])=[CH:69][C:70]=2[CH3:71])[C:17]([CH2:26][CH3:27])=[C:16]([N:15]([CH2:28][CH3:29])[CH:12]2[CH2:13][CH2:14][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:11]2)[CH:24]=1
Reactant: CCc1c(C(=O)O)cc(Cl)cc1N(CC)C1CCC(NC(=O)OC(C)(C)C)CC1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1c(C(=O)NCc2c(C)cc(C)[nH]c2=O)cc(Cl)cc1N(CC)C1CCC(NC(=O)OC(C)(C)C)CC1
Reaction time: 0.17 h
Yield: 54.7 %

Procedure:
A stirred solution of 3-[(4-{[(tert-butoxy)carbonyl]amino}cyclohexyl)(ethyl)amino]-5-chloro-2-ethylbenzoic acid (139 mg, 0.33 mmol) in anhydrous DMF (2.0 ml) at 0° C. under nitrogen, was treated with HATU (149 mg, 0.39 mmol) and DIPEA (114 μl, 0.65 mmol). The resulting solution was stirred for 10 minutes and then treated with 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 61 mg, 0.36 mmol). The resulting suspension was stirred at 0° C. for 1 hour and then stirred at room temperature for 98.5 hours. The reaction mixture was treated with HATU (37 mg, 0.1 mmol), stirred for 1 hour and then 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 11 mg, 0.07 mmol). The reaction mixture was stirred at room temperature for a further 23 hours and then partitioned between water (20 ml) and CH2Cl2 (20 ml). The layers were separated and the aqueous phase was extracted with CH2Cl2 (3×10 ml). The combined organics were washed with a saturated solution of NaHCO3 (aq) (40 ml), water (20 ml), brine (2×20 ml), dried (MgSO4), filtered and concentrated in-vacuo. The crude residue was purified by flash column chromatography (10 g SNAP cartridge, Isolera, 0-13% MeOH/CH2Cl2) and triturated from ether/heptane (2.0 ml) with sonication and the liquor decanted. The remaining solid was dried under high vacuum to give the title compound (101 mg, 52%) as a beige solid. LC-MS 93%, 4.54 min (7 minute LC-MS method), m/z=559.2, 561.2. 1H NMR shows a mixture of cis/trans isomers.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([CH3:19])([N+:16]([O-])=O)[CH3:15])=[CH:9][CH:8]=1)[CH3:2].[H][H]>C(O)C.[Pt]=O>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([NH2:16])([CH3:15])[CH3:19])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)COc1ccc(CC(C)(C)[N+](=O)[O-])cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CCOC(=O)COc1ccc(CC(C)(C)N)cc1
Yield: 28 %

Procedure:
A solution of ethyl(4-[2-methyl-2-nitropropyl]phenoxy)ethanoate (3.6 g, 12.8 mmol) in ethanol (35 mL) was charged with platinum oxide (0.72 g) and hydrogenated on a Parr shaker using 60 psi of hydrogen for 72 h at room temperature. The catalyst was filtered and the solution concentrated in vacuo. The resulting residue was purified by flash chromatography over silica gel eluting with 5% MeOH/CHCl3/NH3 to provide 0.9 g (28%) of a clear oil. MS (FD+): m/z 251.
Reaction SMILES: Br[CH:2](Br)[C:3]([C:5]([F:8])([F:7])[F:6])=[O:4].C([O-])(=O)C.[Na+].[NH:15]([C:17]1[C:22]([F:23])=[CH:21][C:20]([Cl:24])=[CH:19][N:18]=1)[NH2:16]>O>[Cl:24][C:20]1[CH:21]=[C:22]([F:23])[C:17]([NH:15][N:16]=[CH:2][C:3](=[O:4])[C:5]([F:8])([F:7])[F:6])=[N:18][CH:19]=1
Reactant: O=C(C(Br)Br)C(F)(F)F
Reactant: NNc1ncc(Cl)cc1F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=C(C=NNc1ncc(Cl)cc1F)C(F)(F)F
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
6.75 g 1,1-dibromo-3,3,3-trifluoroacetone were stirred for 30 min. at 80° C. in a solution of 9.0 g sodium acetate in 250 ml water. Then the solution was cooled at 0° C. and 4.0 g 2-hydrazino-3-fluoro-5-chloropyridin were added. Stirring was continued for 3.5 hrs. Then the reaction mixture was extracted with ethyl acetate, the extracts were washed with water and dried. After evaporation, the remaining residue was purified on silcagel (hexane-ethyl acetate 8:2) to give the title compound as brownish residue which was directly used for the next step. MS: (M−H )=268.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][C:12]([NH:14][OH:15])=[O:13])=[CH:4][CH:3]=1.[OH:16]O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][CH2:10][CH2:11][C:12]([NH:14][OH:15])=[O:13])=[O:16])=[CH:6][CH:7]=1
Reactant: OO
Reactant: O=C(CCCSc1ccc(F)cc1)NO
Solvent: CC(=O)O
Product: O=C(CCCS(=O)c1ccc(F)cc1)NO
Reaction time: 1 h

Procedure:
10.5 g (0.046 mol) of 4-(p-fluorophenylthio)-butyrohydroxamic acid dissolved in 45 ml of acetic acid are oxidised with 4.6 ml of hydrogen peroxide of 110 volumes strength. After 1 hour at 50° C, the mixture is left to stand overnight and is then evaporated to dryness in vacuo. The residue is taken up in ethyl acetate and filtered off.
Reaction SMILES: Br[CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([OH:5])=[O:4].[N-:20]=[N+:21]=[N-:22].[Na+].O>CN(C)C=O>[N:20]([CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([OH:5])=[O:4])=[N+:21]=[N-:22]
Reactant: CCCCCCCCCCCCCCC(Br)C(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCC(N=[N+]=[N-])C(=O)O
Temperature: 80 °C
Reaction time: 12 h
Yield: 82.3 %

Procedure:
To the solution of 2-bromohexadecanoic acid (1.00 g) in N,N-dimethylformamide (DMF, 15 ml) was added sodium azide (0.86 g), and the mixture was stirred at 80° C. for 12 hours. To the reaction mixture, after having been cooled to room temperature, was then added water. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was separated, washed twice with brine, dried over anhydrous sodium sulfate. The solvent was removed by distillation to give 2-azidohexadecanoic acid (0.73 g). To the solution of 2-azidohexadecanoic acid in DMF were added N-hydroxysuccinimide (74 mg) and N,N'-dicyclohexylcarbodiimide (146 mg), and the mixture was stirred for 12 hours. Precipitates produced was removed by filtration, and the filtrate was concentrated to give the active ester of 2-azidohexadecanoic acid. To the active ester in DMF were further added 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (246 mg) and triethylamine (0.72 ml), and the mixture was stirred for 12 hours. The solvent was removed by distillation, and the residue was subjected to chromatography on a silica gel column with an eluent system of chloroform-methanol (6:1) to give SPK229 in the yield of 185 mg.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:22]=1.[CH3:23][NH:24][C:25](=[O:42])[C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][C:27]=1[CH3:41]>>[CH3:41][C:27]1[CH:28]=[C:29]([C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([CH:10]4[CH2:15][CH2:14][N:13]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]4)=[N:7][C:6]=3[CH:22]=2)[CH:30]=[CH:31][C:26]=1[C:25](=[O:42])[NH:24][CH3:23]
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1C
Reactant: CC(C)OC(=O)N1CCC(c2nc3cc(Br)ccc3o2)CC1
Product: CNC(=O)c1ccc(-c2ccc3oc(C4CCN(C(=O)OC(C)C)CC4)nc3c2)cc1C
Yield: 10.1 %

Procedure:
Following the General Procedure-3, the titled compound (30 mg) was prepared from Intermediate 13 (250 mg, 0.68 mmol) and N,2-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (187 mg, 0.68 mmol) as an off-white solid. M.P.: 151-154° C. MS (m/z): 436.5 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=C[C:5](O)=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:7]=1.[N:37]1C=CC=C(C(=O)C)C=1.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:6]2[CH:5]=[N:37][CH:3]=[CH:2][CH:7]=2)[CH:17]=[CH:16]3)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)c1cccnc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cccnc4)ccc3c1)n2C1CCCCC1
Yield: 17 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-pyridin-3-yl-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (19 mg, 17% yield). MS: 449.21 (M+H+) HPLC Procedure A, retention time=7.96 min.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH2:10][CH2:11][CH2:12][CH3:13])[C:5](=[O:9])[O:6][CH2:7][CH3:8].S(Cl)([Cl:16])=O>C(Cl)Cl>[CH2:7]([O:6][C:5](=[O:9])[N:4]([CH2:3][CH2:2][Cl:16])[CH2:10][CH2:11][CH2:12][CH3:13])[CH3:8]
Reactant: CCCCN(CCO)C(=O)OCC
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCN(CCCl)C(=O)OCC

Procedure:
52 g of ethyl (2-hydroxyethyl)-n-butylcarbamate are placed in 125 ml of methylene chloride and treated dropwise with 41.6 g of thionyl chloride during 45 minutes at 20°-25° C. Then the mixture is allowed to react for an additional 1 hour at room temperature. After removing the solvent, the residue is distilled to yield pure ethyl(2-chloroethyl)-n-butylcarbamate; b.p. 91° C./0.07 Torr.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CS([C:20]1[N:25]=[CH:24][C:23]2=[CH:26][CH:27]=[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])[N:22]2[N:21]=1)=O>>[CH3:36][O:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:28]1[N:22]2[C:23]([CH:24]=[N:25][C:20]([NH:16][C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[CH:11]=3)=[N:21]2)=[CH:26][CH:27]=1
Reactant: Nc1cccc(OCCN2CCOCC2)c1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Product: COc1ccccc1-c1ccc2cnc(Nc3cccc(OCCN4CCOCC4)c3)nn12

Procedure:
Prepared by following a procedure analagous to Example 251c by using 3-(2-Morpholin-4-yl-ethoxy)-phenylamine and 2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine. 1H-NMR (DMSO) δ 9.9 (br s, 1H), 9.46 (s, 1H), 8.97 (s, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.5 (t, 1H), 7.4 (brs, 1H), 7.35 (d, J=7.8 Hz, 1H), 7.23 (d, J=8.3 Hz, 1H), 7.15 (m, 2H), 6.9 (s, 2H), 6.6 (d, J=7.8 Hz, 1H), 4.4-3.3 (m, 12H), 3.8 (s, 3H); LC/MS (ESI+): 446 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH2:10]1[CH2:14][O:13][CH2:12][CH2:11]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:12]([OH:13])[C:11]2[CH:10]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: C1CCOC1
Product: O=Cc1ccc(C(O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 27 %

Procedure:
To a stirred solution of terepathaldehyde (0.5 g, 3.7 mmol) in anhydrous THF (8 ml) at 0° C. was added 2M THF solution of 4-fluorophenyl magnesium bromide (1.86 ml; 3.72 mmol) drop wise and the mixture was allowed to warm up to room temperature and stirred for 4 h. The mixture was then quenched with NH4Cl solution and diluted with to 100 ml with EtOAc. The organic layer was washed with H2O, dried over MgSO4, filtered and the filtrate evaporated to dryness. The residue was purified by FCC (SiO2) to give the desired product (0.23 g; 27%) as creamy paste. 1H-NMR (CDCl3) 2.57 (s, 1H); 5.86 (s, 1H); 7.0 (tr, 2H, J=8.58 Hz); 7.28-7.33 (m, 2H); 7.51 (d, 2H, J=7.98 Hz); 7.81 (d, 2H, J=8.1 Hz); 9.95 (s, 1H).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([C:7]#[CH:8])=[CH:3][CH:2]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][CH:20]([CH2:23][OH:24])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1CCCC1>[C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([C:7]#[C:8][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][CH:20]([CH2:23][OH:24])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[CH:3][CH:2]=1
Reactant: OCC1CCC(c2ccc(Br)cc2)CC1
Reactant: C#Cc1ccc(C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNC1
Product: Cc1ccc(C#Cc2ccc(C3CCC(CO)CC3)cc2)cc1
Temperature: 80 °C

Procedure:
25.0 g of p-tolylacetylene and 12.71 g of tetrakis(triphenylphosphine)palladium(0) (9.2% of Pd) were introduced into 500 ml of pyrrolidine, and 65.36 g of [4-(4-bromophenyl)cyclohexyl]methanol were added quickly. The mixture was then warmed at 80° C. for 2.5 hours with stirring, cooled and subjected to conventional work-up, giving [4-(4-p-tolylethynylphenyl)cyclohexyl]methanol as a crystalline solid.
Reaction SMILES: Cl.NC1C=C(OC2C=CC(NC3N=CC=CC=3[C:19]([NH:21]C3C=CC(F)=CC=3F)=[O:20])=CC=2F)C=CN=1.Cl.N1[C:40]2=[N:41][CH:42]=[CH:43][C:44]([O:45][C:46]3[CH:51]=[CH:50][C:49]([NH:52][C:53]4[C:58]([C:59]([NH:61][C:62]5[CH:67]=[CH:66][C:65]([F:68])=[CH:64][C:63]=5[F:69])=[O:60])=[CH:57][N:56]=[CH:55][CH:54]=4)=[CH:48][C:47]=3[F:70])=[C:39]2C=C1>>[F:69][C:63]1[CH:64]=[C:65]([F:68])[CH:66]=[CH:67][C:62]=1[NH:61][C:59]([C:58]1[CH:57]=[N:56][CH:55]=[CH:54][C:53]=1[NH:52][C:49]1[CH:50]=[CH:51][C:46]([O:45][C:44]2[CH:43]=[CH:42][N:41]=[C:40]([C:19]([NH2:21])=[O:20])[CH:39]=2)=[C:47]([F:70])[CH:48]=1)=[O:60]
Reactant: Nc1cc(Oc2ccc(Nc3ncccc3C(=O)Nc3ccc(F)cc3F)cc2F)ccn1
Reactant: O=C(Nc1ccc(F)cc1F)c1cnccc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Agent: Cl
Product: NC(=O)c1cc(Oc2ccc(Nc3ccncc3C(=O)Nc3ccc(F)cc3F)cc2F)ccn1
Yield: 12 %

Procedure:
4-(4-Amino-2-fluorophenoxy)picolinamide (0.12 g, 0.50 mmol, Compound C of Example 3) was converted to the desired compound (0.030 g, 12%) in a manner similar to the preparation of 4-(4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenylamino)-N-(2,4-di-fluorophenyl)nicotinamide (Step D of Example 1).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH3:44])[C:4]([NH:6][C@@H:7]([C:40]([CH3:43])([CH3:42])[CH3:41])[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([NH:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH3:29])[N:24]=[CH:23][N:22]=[C:21]2[NH:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[C:33]([Cl:38])[C:32]=1[F:39])=[O:16])=[O:9])=[O:5].C([O-])(O)=O.[Na+].O.[C:51](Cl)(=[O:54])[CH:52]=[CH2:53]>C1COCC1>[ClH:38].[C:51]([NH:2][C@@H:3]([CH3:44])[C:4]([NH:6][C@@H:7]([C:40]([CH3:43])([CH3:42])[CH3:41])[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([NH:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH3:29])[N:24]=[CH:23][N:22]=[C:21]2[NH:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[C:33]([Cl:38])[C:32]=1[F:39])=[O:16])=[O:9])=[O:5])(=[O:54])[CH:52]=[CH2:53]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3F)c2cc1NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H](C)N)C(C)(C)C
Reactant: C=CC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3F)ncnc2cc1OC)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
The compound (30 mg, 0.046 mmol) obtained in Example 12 and NaHCO3 (11.6 mg, 0.14 mmol) were dissolved in THF (0.8 mL): H2O (0.2 mL), and acryloyl chloride (0.004 mL, 0.046 mmol) was added thereto at 0° C. The mixture was stirred at 0° C. for 30 min, and an aqueous solution of NaHCO3 was added thereto, followed by washing several times with chloroform. The organic layer was dried over sodium sulfate, filtered and distilled under reduced pressure, and purified by column chromatography to obtain the title compound (15 mg, 8%).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].C(N(CC)CC)C.[N:21]1([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C1COCC1>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([N:30]2[CH2:31][CH2:32][CH:27]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:28][CH2:29]2)=[O:3])=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCC(N2CCCCC2)CC1
Reaction time: 2 h

Procedure:
To a solution of 4-nitrophenyl chloroformate (31) (5.15 g, 25.6 mmol) in 150 mL of dry THF at −78° C. was added triethylamine (10.7 mL, 76.2 mmol), followed by a solution of 4-piperidinopiperidine (30) (4.51 g, 25.6 mmol) in 40 mL of THF. This solution was stirred for two hours, after which the solvent was removed, and the residue was taken up in AcOEt, filtered and evaporated. The crude yellow solid was passed through a pad of neutral alumina using AcOEt as an eluent to yield, after evaporation, 6.73 g (79%) of a white solid: IR (CHCl3, cm−1) 3046, 2937, 2859, 1704, 1620, 1513, 1466, 1242, 1197; 1H NMR (300 MHz, CDCl3) δ1.20-1.80 (m, 8H), 1.90 (d, J=12.7 Hz, 2H), 2.20-2.70 (m, 5H), 2.87 (t, J=12 Hz, 1H), 3.01 (t, J=12 Hz, 1H), 4.30 (br s, 2H), 7.29 (d, J=9 Hz, 2H), 8.26 (d, J=9 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 24.6, 26.3, 27.5, 28.2, 40.1, 44.4, 50.1, 62.0, 122.2, 124.9, 144.8, 151.9, 156.3; HRMS (EI) m/z calcd for C17H23N3O4 (M+) 333.1676, found 333.1688; LRMS (EI) m/z 333 (M+), 195, 167, 124, 110, 96, 55.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1)([O-:11])=[O:10].C(O)(=O)C>N1C=CC=CC=1>[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH:1][C:2]2[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=2)(=[O:20])=[O:19])=[CH:16][CH:17]=1)([O-:11])=[O:10]
Reactant: Nc1cccc(O)c1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2cccc(O)c2)cc1
Yield: 56.6 %

Procedure:
A mixture of 3-aminophenol (33 g, 0.3 mole) and p-nitrobenzenesulfonyl chloride (66 g, 0.3 mole) in pyridine (350 ml) was heated at 80° on a steam bath for 4 hours. The reaction mixture was poured on ice and acidified with acetic acid. The precipitated product was filtered and recrystallized from isopropanol and gave 50 g (49%) of product which was used in Part B.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.S(Cl)([Cl:25])=O>CN(C=O)C>[Cl:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(O)ncnc2cc1OCCCN1CCCC1
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1

Procedure:
A mixture of 4-hydroxy-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (1.7 g, 5 mmol) and thionyl chloride (25 ml) containing DMF (0.2 ml) was heated at reflux for 3 hours. Excess thionyl chloride was removed by evaporation and by azeotroping with toluene (×2). The residue was suspended in ether and 10% aqueous solution of sodiurn hydrogen carbonate was added to the mixture. The organic layer was separated, dried (MgSO4) and the solvent removed by evaporation to give 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (1.94 g, quantitative).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24]Cl)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[SH:26][CH2:27][CH2:28][CH2:29][OH:30]>>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][S:26][CH2:27][CH2:28][CH2:29][OH:30])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5]
Reactant: OCCCS
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(OCCCl)ccc1Cl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(OCCSCCCO)ccc1Cl

Procedure:
Prepared according to the method of Example 10 using 2-chloro-5-(2-chloroethoxy)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 11a, 0.34 g) and 3-mercaptopropan-1-ol (0.25 ml) to give the title compound (0.4 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28]>C1COCC1>[F:26][C:24]1[CH:23]=[CH:22][C:21]([N+:27]([O-:29])=[O:28])=[C:20]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:25]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: Nc1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1Nc1ccc(F)cc1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 93.5 %

Procedure:
4-Fluorophenylamine (1.47 g, 13.19 mmol) was dissolved in THF (20 mL) and cooled to −70° C., under an atmosphere of nitrogen. A solution of 1M LiHMDS in THF (25.14 mL, 25.14 mmol) was added dropwise and the mixture stirred at −70° C., under an atmosphere of nitrogen for 15 minutes. A solution of 2,4-difluoronitrobenzene (2.0 g, 12.57 mmol) in THF (10 mL) was added dropwise to the mixture, at −70° C. and the resultant purple solution stirred at −70° C. for 30 min. The reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted into EtOAc (3×50 mL). The combined organic fractions were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, gradient 0-100% DCM in cyclohexane) to afford the title compound as an orange solid (2.94 g, 100%). 1H NMR (CDCl3, 400 MHz): δ 9.53 (1H, s), 8.27 (1H, dd, J=9.48, 5.98 Hz), 7.29-7.22 (2H, m), 7.20-7.11 (2H, m), 6.64 (1H, dd, J=11.26, 2.65 Hz), 6.48 (1H, ddd, J=9.47, 7.12, 2.65 Hz)