Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Cl)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.[K].O>CN(C)C=O>[C:1]1([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:25]2[C:24](=[O:26])[C:23]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]3[C:21]2=[O:31])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: ClCCCCCCCCOc1cccc2ccccc12
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCCCCCCOc1cccc2ccccc12

Procedure:
A solution of 1-(1-naphthyloxy)-8-chlorooctane (9.5 g) and potassium phthalimide (8.4 g) in dimethylformamide (50 ml) was heated at 140° for 3 hours. The solution was poured into water and extracted with dichloromethane; the extract was washed, dried and evaporated and the residue was crystallized from acetone hexane to afford the intermediate N-8-(1-naphthyloxy)octylphthalimide mp 63°-64°.
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH:7]=[C:8]([C:14](=O)[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([O:19][CH3:20])[CH:4]=1)#[N:2].[CH3:21][S:22][C:23]1[N:28]=[C:27]([NH2:29])[CH:26]=[C:25]([NH2:30])[N:24]=1>C(O)(C)C>[NH2:29][C:27]1[C:26]2[CH:7]([C:6]3[CH:17]=[CH:18][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[O:19][CH3:20])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:14]([CH3:15])[NH:30][C:25]=2[N:24]=[C:23]([S:22][CH3:21])[N:28]=1
Reactant: CSc1nc(N)cc(N)n1
Reactant: CCOC(=O)C(=Cc1ccc(C#N)cc1OC)C(C)=O
Solvent: CC(C)O
Product: CCOC(=O)C1=C(C)Nc2nc(SC)nc(N)c2C1c1ccc(C#N)cc1OC

Procedure:
740 mg (2.70 mmol) of ethyl 2-(4-cyano-2-methoxybenzylidene)-3-oxobutanoate and 422 mg (2.70 mmol) of 2-(methylthio)pyrimidine-4,6-diamine are dissolved in 5 ml of isopropanol and heated under reflux under argon for 12 h. The mixture is filtered and the remaining solid is washed with isopropanol. 395 mg (35% of theory) of the title compound are obtained as a white solid.
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]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.[C:24]([O:28][C:29](=[O:36])[N:30]([CH2:34][CH3:35])[CH2:31][CH2:32]O)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29](=[O:36])[N:30]([CH2:31][CH2:32][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]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:21])([CH3:22])[C:6]=2[CH:23]=1)[CH2:34][CH3:35])([CH3:26])([CH3:27])[CH3:25]
Reactant: CCN(CCO)C(=O)OC(C)(C)C
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CCN(CCOc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O)C(=O)OC(C)(C)C

Procedure:
Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and ethyl-(2-hydroxy-ethyl)-carbamic acid tert-butyl ester.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[C:8]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][CH:10]=[C:11]([CH3:12])[C:4]=2[N:3]=1.[Cl:18][C:19]1[CH:25]=[C:24]([CH3:26])[C:22]([NH2:23])=[C:21]([O:27][CH3:28])[CH:20]=1.CN1CCCC1=O>O>[Cl:18][C:19]1[CH:25]=[C:24]([CH3:26])[C:22]([NH:23][C:2]2[N:6]([CH3:7])[C:5]3[C:8]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][CH:10]=[C:11]([CH3:12])[C:4]=3[N:3]=2)=[C:21]([O:27][CH3:28])[CH:20]=1
Reactant: CCC(CC)c1ccc(C)c2nc(Cl)n(C)c12
Reactant: COc1cc(Cl)cc(C)c1N
Solvent: CN1CCCC1=O
Solvent: O
Product: CCC(CC)c1ccc(C)c2nc(Nc3c(C)cc(Cl)cc3OC)n(C)c12
Temperature: 120 °C
Reaction time: 48 h
Yield: 34.4 %

Procedure:
A mixture of 2-chloro-7-(1-ethylpropyl)-1,4-dimethyl-1H-benzimidazole (100 mg, 0.399 mmol), 4-chloro-2-methoxy-6-methylaniline (205 mg, 1.20 mmol) and 1-methyl-2-pyrrolidone (0.2 mL) was stirred at 120° C. for 2 days under nitrogen atmosphere. The mixture was diluted with water and extracted with ethyl acetate, washed with brine. The organic layer was dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=10:1-1:1) and crystallized from iso-propanol to afford the title compound as colorless crystals (53 mg, 34%).
Reaction SMILES: C1(C)C=CC=CC=1.I[C:9]1[O:10][C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:12]([CH3:14])[N:13]=1.[CH2:20]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)C>[C:21]1([CH2:20][N:27]([CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:9]2[O:10][C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:12]([CH3:14])[N:13]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1oc(I)nc1C
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1oc(N(Cc2ccccc2)Cc2ccccc2)nc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
A reaction vessel fitted with a calcium sulfate drying tube was charged with 5 ml of toluene, 0.56 g (2 mmol) of ethyl 2-iodo-4-methyl-5-oxazolecarboxylate and 2 ml (10 mmol) of dibenzylamine. The reaction mixture was stirred overnight at room temperature. The reaction mixture was then heated at reflux for 4 hours, cooled, and then diluted with ethyl ether. The mixture was washed with water, then with 5% hydrochloric acid, and then with water. The ether solution was dried with sodium sulfate and then concentrated under reduced pressure to yield 0.4 g of a yellow glass. This glass was dissolved in hot hexane and then with the vessel cooling in a dry ice bath, a white solid material was deposited. The solid material was filtered off giving 0.35 g of product (m.p.=75°-77° C.) identified in Table I.
Reaction SMILES: Cl.[F:2][C:3]1[NH:4][CH:5]=[CH:6][N:7]=1.Br[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[F:2][C:3]1[N:4]([CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][N:7]=1
Reactant: CCOC(=O)CCCBr
Reactant: Fc1ncc[nH]1
Agent: Cl
Product: CCOC(=O)CCCn1ccnc1F

Procedure:
Using the technique for the starting material of Example 74, 2-fluoroimidazole hydrochloride was alkylated with ethyl 4-bromobutyrate to give ethyl 4-(2-fluoroimidazol-1-yl)butyrate, having the following n.m.r. in CDCl3 : 1.3 (t, 3H); 1.9-2.5 (m, 4H); 3.9 (t, 2H); 4.1 (q, 2H); 6.5 (d, 1H); 6.6 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][P:4](F)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C[Si](C)(C)[O-:12].[K+:15]>CCOCC>[CH2:1]([O:3][P:4]([O-:12])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[K+:15]
Reactant: CCOP(=O)(F)OCC
Reactant: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCOP(=O)([O-])OCC
Yield: 54.5 %

Procedure:
The procedure of Example 1 was followed except that diethylfluorophosphate (0.9 mL, 6.4 mmol) was added by syringe to a slurry of potassium trimethylsilanolate (0.82 g, 6.4 mmol) in dry ether (25 mL) and a 5 h reaction time was used. Potassium diethylphosphate (0.67 g, 54% yield) was isolated as a tan solid: 1H NMR (D2O, DSS) δ 1.2 (t, J=6.9 Hz, CH3, 6H), 3.9 (q, J=6.9 Hz, CH2, 4H).
Reaction SMILES: [Cl-].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:3]=1.CC(C)([O-])C.[K+].[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([NH:44][CH2:45][CH2:46][CH2:47][CH2:48][CH:49]([CH2:56][CH:57]=O)[CH2:50][CH2:51][C:52]([O:54][CH3:55])=[O:53])(=[O:43])=[O:42])=[CH:37][CH:36]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([S:41]([NH:44][CH2:45][CH2:46][CH2:47][CH2:48][CH:49]([CH2:56][CH:57]=[CH:8][C:4]2[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=2)[CH2:50][CH2:51][C:52]([O:54][CH3:55])=[O:53])(=[O:43])=[O:42])=[CH:39][CH:40]=1
Reactant: c1ccc([P+](Cc2cccnc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)CCC(CC=O)CCCCNS(=O)(=O)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CCC(CC=Cc1cccnc1)CCCCNS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 0.545 g of 3-pyridylmethyltriphenylphosphonium chloride in 6 ml tetrahydrofuran is added slowly 1.6 ml of 1.61M potassium t-butoxide in tetrahydrofuran and the mixture is stirred at room temperature for 1 h. A solution of 0.454 g of methyl 8-(p-chlorophenylsulfonamido)-4-(formylmethyl)-octanoate in 1 ml tetrahydrofuran is added slowly and then stirred for 18 h at room temperature. The reaction mixture is poured into saturated ammonium chloride and extracted with ethyl acetate (3×15 ml). The combined organic extracts are dried, filtered and evaporated to give a dark residue which is purified by flash chromatography to obtain, as a light amber oil, methyl 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)-2-propenyl]-octanoate. The product is a mixture of cis and trans isomers, the major component being the cis isomer. The above product is dissolved in 5 ml methylene chloride in a crystallizing dish and the solution is irradiated for 5 h under UV light. The organic layer is diluted with methylene chloride and washed with aqueous sodium thiosulfate. The organic phase is dried, filtered and evaporated. The residue is purified by preparative thin layer chromatography to obtain a clear oil identified as about a 1:1 mixture of cis and trans isomers.
Reaction SMILES: [NH2:1][N:2]1[C@H:6]([CH2:7][O:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4][C:3]1=O.[CH:29]([NH2:31])=O>CN(C=O)C.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[C:9]([O:8][CH2:7][C@H:6]1[N:2]2[N:1]=[CH:29][N:31]=[C:3]2[CH2:4][CH2:5]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NN1C(=O)CC[C@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NC=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1ccc(C(OC[C@@H]2CCc3ncnn32)(c2ccccc2)c2ccccc2)cc1
Temperature: 160 °C
Yield: 48.8 %

Procedure:
To a stirred solution of 0.540 g (1.45 mmol) of (5S)-1-amino-5-[(trityloxy)methyl]pyrrolidin-2-one from step A in 5 mL of anhydrous DMF was added 0.327 g (7.25 mmol) of formamide followed by 0.050 g (036 mmol) of zinc(II)chloride. The resulting mixture was heated to 160° C. for 48 h, cooled to ambient temperature and diluted with 25 mL of ethyl acetate. The solution was washed sequentially with an aqueous sodium bicarbonate solution, water and then brine and the organic layer dried over magnesium sulfate. The mixture was then filtered, evaporated to dryness in vacuo and purified by silica gel chromatography eluting with a 0-100% ethyl acetatae in hexanes gradient to afford the title compound (0.27 g, 49%). LC-MS: m/z (ES) 382 (MH)+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[CH:29]=[CH:28][C:27]([C:30]4[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=4)[C:33](O)=[O:34])=[CH:26][C:20]=3[C:21]=2[C:22](=[O:25])[NH:23][CH3:24])=[CH:13][CH:12]=1.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>CN(C=O)C.CO>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[CH:29]=[CH:28][C:27]([C:30]4[CH:38]=[CH:37][CH:36]=[C:32]([C:33]([N:2]5[CH2:3][C:4]6[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=6)[CH2:1]5)=[O:34])[CH:31]=4)=[CH:26][C:20]=3[C:21]=2[C:22]([NH:23][CH3:24])=[O:25])=[CH:13][CH:12]=1
Reactant: c1ccc2c(c1)CNC2
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)O)c3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)N4Cc5ccccc5C4)c3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
Isoindoline (20 μL, 0.18 mmol) was added to a stirred suspension of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (20 mg, 0.051 mmol), HATU (25 mg, 0.066 mmol), and DIPEA (50 μL, 0.29 mmol) in DMF (0.5 mL). The reaction was stirred at r.t. overnight. The reaction was then diluted with MeOH and an off-white ppt. formed. The ppt. was collected by filtration, triturated with MeOH, and air dried to afford the title compound (17 mg, 68% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 8.50 (q, J=4.58 Hz, 1H) 7.99-8.05 (m, 2H) 7.90-7.95 (m, 2H) 7.85 (dt, J=6.10, 2.44 Hz, 1H) 7.77-7.81 (m, 1H) 7.73-7.77 (m, 1H) 7.58-7.64 (m, 2H) 7.36-7.45 (m, 3H) 7.30-7.34 (m, 1H) 7.29 (s, 2H) 4.91 (s, 2H) 4.84 (s, 2H) 2.86 (d, J=4.88 Hz, 3H). LC/MS was performed on a Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A=10% CH3CN/90% H2O/0.1% TFA, solvent B=90% CH3CN/10% H2O/0.1% TFA, start % B=0, final % B=100, gradient time=3 min, stop time=4 min, flow rate=4 ml/min, column: Sunfire C18 5 μm 4.6×50 mm; HPLC Rt=2.48 min, (ES+) m/z (MH+)=491. Analytical HPLC method: solvent A=5% CH3CN/95% H2O/0.1% TFA, solvent B=95% CH3CN/5% H2O/0.1% TFA, start % B=10, final % B=100, gradient time=15 min, stop time=18 min, flow rate=1 ml/min. Column: Waters Sunfire C-18, 3.5 μm 4.6×150 mm, Rt=13.81 min, purity=100%; column: Waters Xbridge Phenyl 3.5 μm 4.6×150 mm, Rt=13.81 min, purity=100%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[CH:9]=[C:10]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[N+:12]([O-:14])[CH:13]=1>>[N:1]1([C:8]2[CH:9]=[C:10]([O:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:11]=[N+:12]([O-:14])[CH:13]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: [O-][n+]1cc(Br)cc(Oc2ccccc2)c1
Product: [O-][n+]1cc(Oc2ccccc2)cc(N2CCNCC2)c1
Temperature: 150 °C

Procedure:
An intimate mixture of 43 g of piperazine with 26.6 g of 5-bromo-3-phenoxypyridine N-oxide [Agr. Biol. Chem., 34, 68 (1970)] is heated at 150° C. for five hours. The oil is concentrated at reduced pressure to remove excess piperazine. The mixture is dissolved in 1500 ml of dichloromethane, washed with excess 25% sodium hydroxide solution, dried over anhydrous MgSO4, filtered and concentrated to yield 5-piperazinyl-3-phenoxypyridine N-oxide as an oil. The oil is dissolved in 200 ml of toluene-methanol, (95-5) and chromatographed over 400 g, silica gel in toluene-methanol, (95-5). 5-Bromo-3-phenoxy-pyridine N-oxide is eluted first. Elution with toluene-methanol (50:50) yields 5-piperazinyl-3-phenoxypyridine N-oxide; mp 107°-115° C. after drying at 0.1 mm pressure for 16 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.C([O:11][C:12]([C:14]1[N:15]=[C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:28](=[O:39])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]([F:38])([F:37])[F:36])[CH2:24][CH2:23]3)=[N:18][N:17]2[CH:40]=1)=O)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:12]([C:14]2[N:15]=[C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:23][CH2:24][N:25]([C:28](=[O:39])[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[C:35]([F:36])([F:38])[F:37])[CH2:26][CH2:27]4)=[N:18][N:17]3[CH:40]=2)=[O:11])=[N:6][CH:7]=1
Reactant: CCOC(=O)c1cn2nc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)ccc2n1
Reactant: Nc1ccc(Cl)cn1
Product: O=C(Nc1ccc(Cl)cn1)c1cn2nc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)ccc2n1
Yield: 24 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to 5-chloropyridin-2-ylamine in place of isoamylamine to react with 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]imidazo[1,2-b]pyridazine-2-carboxylic acid ethyl ester, the title compound was obtained as a white solid in 24% yield (0.028 g). m.p. 265-268° C. 1H NMR (300 MHz, CDCl3) δ 9.78 (s, 1H), 8.35 (d, J=7.6 Hz, 1H), 8.27-8.25 (2H), 7.81-7.52 (m, 5H), 7.42-7.31 (m, 1H), 6.92 (d, J=7.6 Hz, 1H), 6.9 (d, J=7.6 Hz, 1H), 4.08-3.97 (m, 1H), 3.95-3.83 (m, 1H), 3.72-3.55 (m, 2H), 3.53-3.43 (m, 2H), 3.37-3.27 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 167.6, 160.7, 154.9, 149.7, 146.7, 137.8, 137.3, 135.8, 134.2, 132.4, 129.5, 127.2, 127.2, 126.9, 126.8, 126.7, 126.5, 125.4, 118.9, 114.5, 112.3, 46.2, 46.18, 45.6, 41.2. MS (ES+) m/z 530.1 (M+1).
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:5]2[C:6](=[O:12])[CH2:7][CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.[F-].[K+].[CH2:17]([Sn](CCCC)(CCCC)C=C)[CH2:18]CC.CCOC(C)=O>CN(C=O)C.[Cu]I.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>[CH:17]([C:2]1[CH:14]=[CH:13][C:5]2[C:6](=[O:12])[CH2:7][CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1)=[CH2:18]
Reactant: O=C1CCC(=O)c2ccc(I)cc2N1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=Cc1ccc2c(c1)NC(=O)CCC2=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 39.8 %

Procedure:
To a degassed solution of 8-iodo-3,4-dihydro-1H-1-benzazepine-2,5-dione (0.3 g, 1.0 mmol) in DMF (5 mL) was added CuI (19 mg, 0.1 mmol), KF (116 mg, 2.0 mmol), tributylethenylstannane (0.58 mL, 2.0 mmol), and Pd(PPh3)4 (116 mg, 0.1 mmol). The reaction mixture was allowed to stir at 100° C. for 4 h. After being allowed to cool to rt, EtOAc (50 mL) and a 1M aqueous KF solution (25 mL) were added and the mixture was allowed to stir for an additional 40 min. The mixture was filtered over Celite® and the organic solution was separated, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was treated with n-pentane and filtered. The resulting solid was purified by column chromatography to provide 8-vinyl-3,4-dihydro-1H-1-benzazepine-2,5-dione (80 mg, 40%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:34]=[CH:33][C:17]([O:18][CH2:19][CH2:20][CH2:21][C:22]([P:25](=[O:32])([O:29]CC)[O:26]CC)([F:24])[F:23])=[CH:16][C:15]=3[CH3:35])=[CH:7][C:6]=2[C:5]2[CH:36]=[CH:37][C:38]([CH3:40])=[CH:39][C:4]=2[N:3]=1.C(O)(C(F)(F)F)=O>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:34]=[CH:33][C:17]([O:18][CH2:19][CH2:20][CH2:21][C:22]([P:25](=[O:26])([OH:29])[OH:32])([F:23])[F:24])=[CH:16][C:15]=3[CH3:35])=[CH:7][C:6]=2[C:5]2[CH:36]=[CH:37][C:38]([CH3:40])=[CH:39][C:4]=2[N:3]=1
Reactant: CCOP(=O)(OCC)C(F)(F)CCCOc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCCCC(F)(F)P(=O)(O)O)cc3C)cc12

Procedure:
4-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluorobutylphosphonic acid (5) was prepared according to the procedure described in Example 1—Step 3, but using diethyl 4-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluorobutylphosphonate from step 2. TFA was added to the 1H NMR sample to solubilize the compound for analysis. The 1H NMR (Dimethylsulfoxide-d6) obtained for 4-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluorobutylphosphonic acid (5) was: δ 9.71 (br, 1H), 9.33 (br, 1H), 9.00 (s, 1H), 8.85 (s, 1H), 8.54 (d, 1H, J=8.4 Hz), 7.53 (s, 1H), 7.42 (d, 1H, J=8.3 Hz), 7.08 (d, 1H, J=8.4 Hz), 6.76 (s, 1H), 6.70 (d, 1H, J=8.3 Hz), 3.97 (t, 2H, J=6.2 Hz), 3.15 (t, 2H, J=8.5 Hz), 2.98 (t, 2H, J=8.5 Hz), 2.50 (s, 3H), 2.28 (s, 3H), 2.21-2.06 (m, 2H), 1.97-1.87 (m, 2H). LRMS [M+H]=516.2
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10]([OH:17])[C:11]2[N:12]([CH3:16])[CH:13]=[N:14][CH:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CC#N>C(Cl)Cl.O=[Mn]=O>[F:1][C:2]1[CH:9]=[C:8]([C:10]([C:11]2[N:12]([CH3:16])[CH:13]=[N:14][CH:15]=2)=[O:17])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cn1cncc1C(O)c1ccc(C#N)c(F)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: CC#N
Product: Cn1cncc1C(=O)c1ccc(C#N)c(F)c1

Procedure:
2-Fluoro-4-[hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-benzonitrile (0.655 g, 2.83 mmol) and MnO2 (1.23 g, 14.2 mmol) were stirred in CH2Cl2 (50 mL) and CH3CN (5 mL) for 3 h. The solution was filtered and concentrated to yield the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5]NC(=N)N.[NH2:13][C@H:14](C(O)=O)CC(=O)O.N[C@H](C(O)=O)CCC(=O)O.N[C@H](C(O)=O)[C@@H](C)O.NCC(O)=O.N[C@H](C(O)=O)C.N[C@H](C(O)=O)C(C)C.N[C@H](C(O)=O)CC(C)C.N[C@H](C(O)=O)CC1C=CC=CC=1.N[C@H](C(O)=O)CC1C=CC(O)=CC=1.N[C@H](C(O)=O)CS.N[C@H](C(O)=O)CCSC.N[C@H](C(O)=O)CC1C2C(=CC=CC=2)NC=1.N>>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][CH2:14][NH2:13]
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: CC(C)C[C@H](N)C(=O)O
Agent: CC(C)[C@H](N)C(=O)O
Agent: CSCC[C@H](N)C(=O)O
Product: NCCCC[C@H](N)C(=O)O

Procedure:
10 (9); His: 8 (5); Arg: 11 (4); Asp: 22 (28); Glu: 15 (12); Thr: 33 (19); Ser: 33 (32); Pro: 13 (9); Gly: 37 (35); Ala' 17 (41); Val: 16 (31); Leu (7 (16); Ileu: 15 (10); Phe: 6 (4); Tyr: 21 (13); Cys (1/2): 2 (0) Met: 3 (5); Trp: not detmd. (1); NH3 : 27 (25). Total number of amino acids: 269 (273), excl. Trp.
Reaction SMILES: [C:1]12([CH2:11][NH2:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Cl:13][C:14]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17]>>[Cl:13][C:14]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([NH:12][CH2:11][C:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2)=[O:17]
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cccc([N+](=O)[O-])c1Cl
Yield: 80.5 %

Procedure:
Prepared according to the method of Example 14 from 1-adamantanemethylamine (1.0 g) and 2-chloro-3-nitrobenzoic acid (1.22 g) to give the title compound as a yellow solid (1.7 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:32][CH3:33])[C:17]4[CH2:22][CH2:21][CH:20]([C:23]5[CH:28]=[C:27]([F:29])[C:26]([F:30])=[C:25]([F:31])[CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:34][CH3:35])[CH:6]=1>C(=O)=O.CO>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:32][CH3:33])[C:17]4[CH2:22][CH2:21][C@H:20]([C:23]5[CH:28]=[C:27]([F:29])[C:26]([F:30])=[C:25]([F:31])[CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:34][CH3:35])[CH:6]=1
Reactant: CNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CCC2c1cc(F)c(F)c(F)c1
Agent: O=C=O
Solvent: CO
Product: CNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CC[C@@H]2c1cc(F)c(F)c(F)c1

Procedure:
A racemic mixture of N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (59.8 mg, 0.119 mmol from Example 103) was purified using chiral SFC to afford 19.5 mg of peak A (Example 103A) and 34.8 mg of peak B (Example 103B). SFC Method: Chiralpak OJ-H (4.6×250 mm, 5 μM), 20% methanol (0.1% diethylamine) in CO2, 35° C., flow rate 2.0 mL/min for 16 min, absorbance 268 nm, injection 5 μL of 2 mg/mL solution in methanol (multiple stacked injections), tR (peak A)=9.7 min, tR (peak B) 11.9 min. The absolute stereochemistry of individual enantiomers (Examples 103A and 103B) was not determined LC-MS and 1H NMR analytical data for the separated enantiomers was identical to the racemate (Example 103).