Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:23])[C:4](=[O:22])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[CH2:7]2)[N:6]=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)#[N:25]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:23])[C:4](=[O:22])[C@:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:28]4[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=4)[C:24]#[N:25])[CH:14]=3)[O:9][C@H:8]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[CH2:7]2)[N:6]=1.[NH2:1][C:2]1[N:3]([CH3:23])[C:4](=[O:22])[C@:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:28]4[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=4)[C:24]#[N:25])[CH:14]=3)[O:9][C@@H:8]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(c3cccs3)Oc3ccc(Br)cc32)N=C1N
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)[C@@]2(C[C@@H](c3cccs3)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Product: CN1C(=O)[C@@]2(C[C@H](c3cccs3)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Yield: 1 %
Yield: 1 %

Procedure:
Pd(PPh3)2Cl2 (20 mg) in a 10 mL of flask under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-(thiophen-2-yl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (46 mg, 0.117 mmol) in 1,4-dioxane (5 mL), Cs2CO3 (2 N, 0.5 mL) and 4-cyanophenylboronic acid (34.5 mg, 0.23 mmol). The mixture was refluxed under Ar for 2 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC followed by preparative HPLC to give pure 3-((2S,4S)-2′-amino-1′-methyl-5′-oxo-2-(thiophen-2-yl)-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (Compound 8a, 1.35 mg, 1%), 1H-NMR (CDCl3): 442-069-3B: 2.30 (d, 1H), 2.49 (d, 1H), 3.01 (d, 3H), 5.81 (dd, 1H), 6.95 (t, 1H), 7.00 (m, 2H), 7.05 (s, 1H), 7.30 (d, 1H), 7.40 (d, 1H), 7.49 (d, 1H), 7.51 (t, 1H), 7.61 (t, 2H), and 3-((2R,4S)-2′-Amino-1′-methyl-5′-oxo-2-(thiophen-2-yl)-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)-benzonitrile (Compound 8b, 1.10 mg, 1%). 1H-NMR (CDCl3): 2.40 (d, 1H), 2.63 (t, 1H), 3.31 (s, 3H), 6.12 (d, 1H), 6.95 (t, 1H), 7.00 (d, 1H), 7.05 (m, 2H), 7.30 (d, 1H), 7.48 (m, 2H), 7.54 (d, 1H), 7.68 (t, 2H).
Reaction SMILES: ClC1C=C2C(=CC=1)[N:7](S(C1C=CC=CC=1)(=O)=O)C(C(OCC)=O)=C2S(N1CCOC(COC2C=CC=CC=2)C1)(=O)=O.[I:42][C:43]1[CH:44]=[C:45]2[C:49](=[CH:50][CH:51]=1)[N:48](S(C1C=CC=CC=1)(=O)=O)[C:47]([C:61](OCC)=[O:62])=[C:46]2[S:66]([N:69]1[CH2:74][CH2:73][O:72][CH:71]([CH2:75][O:76][C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[CH2:70]1)(=[O:68])=[O:67]>>[I:42][C:43]1[CH:44]=[C:45]2[C:49](=[CH:50][CH:51]=1)[NH:48][C:47]([C:61]([NH2:7])=[O:62])=[C:46]2[S:66]([N:69]1[CH2:74][CH2:73][O:72][C@@H:71]([CH2:75][O:76][C:77]2[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=2)[CH2:70]1)(=[O:68])=[O:67]
Reactant: CCOC(=O)c1c(S(=O)(=O)N2CCOC(COc3ccccc3)C2)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)c1c(S(=O)(=O)N2CCOC(COc3ccccc3)C2)c2cc(I)ccc2n1S(=O)(=O)c1ccccc1
Product: NC(=O)c1[nH]c2ccc(I)cc2c1S(=O)(=O)N1CCO[C@@H](COc2ccccc2)C1

Procedure:
Using the same procedures described for Example 23, replacing the product from Step A of Example 22, ethyl(±)-5-chloro-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1-(phenylsulfonyl)-1H-indole-2-carboxylate, with ethyl(±)-5-iodo-3-{[2-(phenoxymethyl)morpholin-1-yl]sulfonyl}-1-(phenylsulfonyl)-1H-indole-2-carboxylate, the second-eluting enantiomer of ethyl 5-iodo-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1-(phenylsulfonyl)-1H-indole-2-carboxylate was converted to the titled compound after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. ESI+MS: 542.82 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14])[N:9]=[C:10](I)[C:3]=12.[F:23][C:24]1[CH:29]=[C:28]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]=[CH:26][C:25]=1B(O)O.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>C(OCC)(=O)C.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.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14])[N:9]=[C:10]([C:25]3[CH:26]=[CH:27][C:28]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:29][C:24]=3[F:23])[C:3]=12
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1F
Reactant: C[C@H](Cn1nc(I)c2c(N)ncnc21)NC(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)NC(=O)OC(C)(C)C
Temperature: 140 °C
Yield: 130.5 %

Procedure:
To a microwave tube was added tert-butyl N-[(1R)-2-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)-1-methyl-ethyl]carbamate (1.7 g, 4.1 mmol), (2-fluoro-4-phenoxy-phenyl)boronic acid (1.4 g, 6.1 mmol), K2CO3 (1.27 g, 9.2 mmol), and tetrakis(triphenylphosphine)palladium(0) (213 mg, 0.18 mmol) and 1,4-dioxane (12 mL) and water (3 mL). The mixture was capped and heated under microwave conditions for 140° C. for 10 minutes. The reaction was cooled and diluted with ethyl acetate (50 mL) and washed with water (50 mL) and brine. The organic layer was dried (MgSO4), filtered and evaporated to obtain 2.56 g of crude tert-butyl N-[(1R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-methyl-ethyl]carbamate. This was used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.Cl.[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=[O:36].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35]([N:37]1[CH2:38][CH2:39][N:40]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][C:16]([C:22]5[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=5)=[CH:17][CH:18]=4)[CH:13]=3)=[O:11])=[CH:5][CH:4]=2)[CH2:41][CH2:42]1)=[O:36]
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Reactant: O=C(c1ccco1)N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN4CCN(C(=O)c5ccco5)CC4)cc2)CC3)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.5 %

Procedure:
In DMF (3 ml) was dissolved N-[4—(chloromethyl)-phenyl]-7—(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (150 mg), and to the solution were added 1—(2-furoyl)piperazine hydrochloride (109 mg) and potassium carbonate (268 mg). The mixture was stirred at room temperature for 18 hours, and to the mixture was added water (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified with ethyl acetate-diisopropylether to give N-[4-[1—(2-furoyl)-4-piperazinylmethyl]phenyl]-7—(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (Compound 44) (112 mg) as colorless amorphous.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4](SC2C=CC=CC=2)[N:3]=1.[OH-:29].[Na+]>C(O)C>[NH2:1][C:2]1[NH:3][C:4](=[O:29])[C:5]([C:20]#[N:21])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:7]=1[C:8]#[N:9]
Reactant: N#Cc1c(N)nc(Sc2ccccc2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1c(N)[nH]c(=O)c(C#N)c1-c1ccc(OCCO)cc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
500 mg (1.29 mmol) of the compound from Example 99A are initially charged in 6.4 ml of ethanol. After addition of 2.57 g (28.96 mmol) of sodium hydroxide, the mixture is stirred at 80° C. for 30 min, and a clear solution is formed. After cooling to RT, the solvent is removed on a rotary evaporator. The residue is taken up in 3 ml of water and acidified with 1 N hydrochloric acid until a yellowish precipitate is formed. The suspension is stirred at RT for 3 h. The precipitate is filtered off, washed with about 5 ml of water and a little ethanol and then recrystallized from about 10 ml of ethanol. The product obtained in this manner is used without further purification in the subsequent reactions.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[S:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1.[C:14]([OH:18])(=O)[CH2:15][CH3:16].[CH:19]1[C:28]2[C:23](=[C:24](CC(O)=O)[CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][N:20]=1>>[CH:19]1[C:28]2[C:23](=[C:24]([CH:15]([CH3:16])[C:14]([NH:9][CH2:8][C:7]3[CH:10]=[CH:11][C:4]([S:3][C:2]([F:12])([F:1])[F:13])=[CH:5][CH:6]=3)=[O:18])[CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][N:20]=1
Reactant: O=C(O)Cc1cccc2cnccc12
Reactant: NCc1ccc(SC(F)(F)F)cc1
Reactant: CCC(=O)O
Product: CC(C(=O)NCc1ccc(SC(F)(F)F)cc1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 4-[(trifluoromethyl)thio]benzylamine and 2-5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 391 (M+H)+; MS (ESI−) m/z 389 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.57 (d, J 7.1, 3H), 4.33 (d, J 6.1, 2H), 4.65 (q, J 7.1, 1H), 7.33 (d, J 8.1, 1H), 7.65 (m, 2H), 7.76 (m, 1H), 7.98 (m, 2H), 8.19 (d, J 7.1, 1H), 8.42 (d, J 7.8, 1H), 8.61 (br s, 1H), 8.62 (d, J 6.8, 1H), 8.73 (d, J 6.8, 1H), 8.96 (t, J 5.8, 1H), 9.86 (s, 1H); Anal. Calcd for C20H17F3N2OS+2.1 HCl: C, 51.44; H, 4.12. Found: C, 51.35; H, 3.91.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:8][N:9]1[C:17]2[C:12](=[C:13]([O:18][CH2:19][CH:20]3[O:22][CH2:21]3)[CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]1[C:23]([O:25]C)=[O:24]>CO.CN(C=O)C>[Cl:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:8][N:9]1[C:17]2[C:12](=[C:13]([O:18][CH2:19][CH:20]([OH:22])[CH2:21][N:2]([CH3:3])[CH3:1])[CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]1[C:23]([OH:25])=[O:24]
Reactant: COC(=O)c1cc2c(OCC3CO3)cccc2n1Cc1ccc(Cl)c(Cl)c1
Reactant: CNC
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)CC(O)COc1cccc2c1cc(C(=O)O)n2Cc1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
Dimethylamine in methanol (2.0 M, 2.14 ml) was added to a stirred solution of methyl N-(3,4-dichlorobenzyl)-4-(2,3-epoxypropyloxy)indole-2-carboxylate (87 mg) in DMF (5 ml) under an atmosphere of argon. The reaction was heated at 80° C. for 16 hours. The reaction was concentrated in vacuo and the residue partitioned between ethyl acetate and water. Combined organic extracts were washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated in vacuo. The residue was dissolved in THF (3 ml) and methanol (1.5 ml) and NaOH (2M, 3 ml) added and the reaction stirred for 16 hours. The reaction was then concentrated in vacuo and the residue dissolved in water. The solution was acidified by dropwise addition of acetic acid, resulting in the precipitation of a white solid which was filtered, washed with water and dried in vacuo to give the desired end product as a white solid (50 mg, 54%, 2 steps); NMR d (CD3SOCD3) 2.85 (s, 6H), 3.22-3.40 (m, 2H), 4.01-4.14 (m, 1H), 5.81 (s, 2H), 6.01 (d, 1H), 6.60 (d, 1H), 6.88 (dd, 1H), 7.13 (d, 1H), 7.21 (t, 1H), 7.28 (d, 1H), 7.44 (s, 1H), 7.53 (d, 1H); M/z (−) 435 (M−H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([C:16](O)=O)=[N:14][CH:15]=1.[OH-].[Na+]>O>[S:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:16]1[C:13]1[CH:12]=[CH:11][C:10]([CH3:9])=[CH:15][N:14]=1
Reactant: Nc1ccccc1S
Reactant: Cc1ccc(C(=O)O)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(-c2nc3ccccc3s2)nc1
Yield: 88.4 %

Procedure:
22.5 g (0.18 mol) of o-aminothiophenol, 25 g (0.18 mol) of 5-methylpicolic acid and 100 g of polyphosphoric acid were admixed and stirred in nitrogen gas streams at 170°-200° C. and the mixture was poured in 1 l of water. The mixture was adjusted to pH 5 with an aqueous solution of sodium hydroxide and the resulting crystals were recovered by filtration, whereupon 40 g of 2-(benzothiazol-2-yl)-5methylpyridine was obtained as crude crystals. This crude product was recrystallized from ligroine. By the above procedure was obtained 36 g of the same compound as colorless flakes melting at 169.5°-170.0° C.
Reaction SMILES: OCCCC[N:6]1[C:10]2[CH:11]=[C:12]([CH3:16])[C:13]([CH3:15])=[CH:14][C:9]=2[N:8]=[CH:7]1.[NH+]1C=[CH:21][CH:20]=[CH:19][CH:18]=1.C(CC[O:27][P:28](=[O:31])([O-:30])[O-:29])#N.[NH+]1C=CC=CC=1>>[CH3:16][C:12]1[C:13]([CH3:15])=[CH:14][C:9]2[N:8]=[C:7]([CH2:18][CH2:19][CH2:20][CH2:21][O:29][P:28](=[O:27])([OH:31])[OH:30])[NH:6][C:10]=2[CH:11]=1
Reactant: c1cc[nH+]cc1
Reactant: N#CCCOP(=O)([O-])[O-]
Reactant: Cc1cc2ncn(CCCCO)c2cc1C
Product: Cc1cc2nc(CCCCOP(=O)(O)O)[nH]c2cc1C

Procedure:
Using 0.2 g of the crude 1-(4-hydroxybutyl)-5,6-dimethylbenzimidazole and 2 ml of 2-cyanoethylphosphoric acid pyridinium salt solution (1 mmol/ml) as the starting substances, according to the same processes as in Example 1, 0.3 g of crude 4-(5,6-dimethylbenzimidazolyl)butylphosphoric acid was obtained.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]([C:35]#[N:36])[CH2:10][C:11]([CH3:34])=[CH:12][CH2:13][C:14]1[C:15]([O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])=[C:16]2[C:20](=[C:21]([CH3:25])[C:22]=1[O:23][CH3:24])[CH2:19][O:18][C:17]2=[O:26])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH3:37][Si]([N-][Si](C)(C)C)(C)C.[Na+].IC>C1COCC1>[CH2:1]([O:3][P:4]([C:9]([C:35]#[N:36])([CH3:37])[CH2:10][C:11]([CH3:34])=[CH:12][CH2:13][C:14]1[C:15]([O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:32])[CH3:33])=[C:16]2[C:20](=[C:21]([CH3:25])[C:22]=1[O:23][CH3:24])[CH2:19][O:18][C:17]2=[O:26])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(OCC)C(C#N)CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(C)(C#N)CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2
Reaction time: 0.33 h
Yield: 14.2 %

Procedure:
To a solution of {(1-cyano-5-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-3-methyl-pent-3-enyl}-phosphonic acid diethyl ester (45 mg, 0.084 mmol) in THF (0.5 mL) was added sodium bis(trimethysilyl)amide (1.0 M, 1.13 mL, 1.15 mmol). After stirring for 20 minutes, iodomethane (52 μL, 0.84 mmol) was added dropwise and the resulting mixture was allowed to stir at room temperature for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to dryness. The residue was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to afford 6.6 mg (23%) of the desired product. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 1.16 (dd, J=7, 8 Hz, 2H), 1.31 (t, 6H), 1.38 (d, 3H), 1.92 (s,3H), 2.17 (s, 3H), 2.23 (m, 1H), 2.65 (m, 1H), 3.30-3.42 (m, 2H), 3.73 (s, 3H), 4.14-4.27 (m, 6H), 5.08 (s, 2H), 5.28 (t, J=7.2 Hz, 1H) ppm; 31P (121.4 MHz, CDCl3) δ 22.26 ppm; MS (m/z) 574 [M+Na]+.
Reaction SMILES: Br[C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.Cl.[N:11]1([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([F:28])([F:27])[F:26])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[F:28][C:25]([F:26])([F:27])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]([N:11]1[CH2:12][CH2:13][N:14]([C:2]2[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=2)[CH2:15][CH2:16]1)=[O:18].[CH3:12][N:11]([CH3:16])[CH:17]=[O:18]
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: O=c1[nH]cc(Br)c(=O)[nH]1
Agent: Cl
Product: CN(C)C=O
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2c[nH]c(=O)[nH]c2=O)CC1
Yield: 47 %

Procedure:
The compound 6 (solid) is prepared from 5-bromo-1H-pyrimidine-2,4-dione and from the intermediate 6a according to the synthesis method 1 in dimethylformamide (yield: 47%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CC1C=CC(S(O[CH2:29][C:30]2([O:36][CH3:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)(=O)=O)=CC=1>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[N:7]=[C:6]([N:8]([CH2:29][C:30]2([O:36][CH3:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:4][CH:3]=1
Reactant: COC1(COS(=O)(=O)c2ccc(C)cc2)CCOCC1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC1(CN(C(=O)OC(C)(C)C)c2cccc(Br)n2)CCOCC1
Yield: 45.9 %

Procedure:
To a solution of tert-butyl 6-bromo-pyridin-2-ylcarbamate (136 mg, 0.50 mmol) in DMF (2 ml) under nitrogen was added NaH (60%, 40 mg, 1.0 mmol) under stirring. The resultant mixture was stirred at room temperature for one hour. A solution of (4-methoxytetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate (Intermediate 0, 152 mg, 0.506 mmol) in DMF (1.5 ml) was then added. The resulting mixture was then stirred at 85° C. for about 18 hours. The mixture was diluted with 30 ml of ethyl acetate, washed with water (20 ml×3) and dried with sodium sulfate. After concentration the residue was purified by silica gel chromatography using a 12 g column, eluting with 5-20% ethyl acetate in hexane to give the desired title compound as a viscous oil (92 mg, 46% yield), which solidified upon standing overnight. LCMS (m/z): 403.1 [M+H]+; Rt=1.026 min.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][N:17]=1)[C:11]([O:13][CH3:14])=[O:12].[Cl:18][C:19]1[CH:20]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:22]=[C:23]([Cl:25])[CH:24]=1.CO>O.C(Cl)Cl.Cl[Pd]Cl>[Cl:18][C:19]1[CH:20]=[C:21]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][N:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:22]=[C:23]([Cl:25])[CH:24]=1
Reactant: CC1(C)OB(c2cc(Cl)cc(Cl)c2)OC1(C)C
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccnc(-c2cc(Cl)cc(Cl)c2)c1
Temperature: 100 °C
Yield: 74.2 %

Procedure:
Potassium carbonate (2.416 g, 17.48 mmol), methyl 2-chloroisonicotinate (5 g, 29.14 mmol), 2-(3,5-dichlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10.34 g, 37.88 mmol), PdCl2 (dppf) (0.633 g, 0.87 mmol), and MeOH (45.7 mL) were split in three 20 mL microwave-vials and heated to 100° C. in a single node microwave reactor for 20 min. The reaction mixture was diluted with water and DCM, the aqueous layer extracted with DCM and the combined organic layers were evaporated. Purified by automated flash chromatography using 5% EtOAc in heptane ->30% EtOAc over 15 CV at 280 nm. Methyl 2-(3,5-dichlorophenyl)isonicotinate (6.1 g, 74%) was isolated as a white powder. 1H NMR (400 MHz, cdcl3) δ 4.01 (s, 3H), 7.44 (t, 1H), 7.84 (dd, 1H), 7.96 (d, 2H), 8.23-8.28 (m, 1H), 8.85 (dd, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([Br:12])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:18]([O:20]CC)=[CH2:19])CCC>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:12][C:4]1[CH:3]=[C:2]([C:18](=[O:20])[CH3:19])[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)c1cc(Br)cc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(Br)cc(C(C)(C)C)c1
Temperature: 95 °C
Reaction time: 3 h

Procedure:
To a solution of 1,3-dibromo-5-(tert-butyl)benzene (664 mg, 2.22 mmol) in toluene (15 mL) were added tri-n-butyl-1-ethoxyvinyl tin (965 mg, 2.66 mmol) and Pd(PPh3)2Cl2 (150 mg 0.22 mmol) under N2. The mixture was stirred at 95° C. for 3 h, evaporated, diluted with 1,4-dioxane and 2N HCl, stirred rapidly at 25° C. for 1 h and then extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by CC to afford compound P49a (310 mg, 55%).
Reaction SMILES: C([N:3]([CH2:6]C)CC)C.O=[P:9](Cl)(Cl)Cl.CC1(C)CN1.[CH3:18][O:19][CH2:20][CH2:21][CH2:22][NH2:23]>C1COCC1>[CH3:18][O:19][CH2:20][CH2:21][CH2:22][NH:23][P:9]1[CH2:6][NH:3]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCCCN
Reactant: CCN(CC)CC
Agent: CC1(C)CN1
Solvent: C1CCOC1
Product: COCCCNP1CN1
Temperature: -40 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
0.08 moles of triethylamine, 0.025 moles of POCl3 and 150 milliliters of dried tetrahydrofuran were combined in a 250 milliliter round bottom flask, under a nitrogen atmosphere to avoid moisture contamination, to form a first solution which was then cooled to -40° C. A second solution was then prepared containing 0.05 moles of 2,2-dimethylaziridine in 20 milliliters of THF and the second solution was added dropwise to the cooled first solution over a period of about 2 hours. The resulting slurry was then warmed over a period of about 1 hour to 0° C. then cooled again to -30° C. and then had added thereto, by dropwise addition, a solution containing 0.026 moles of 3-methoxypropyl amine in 20 milliliters of THF. The solution was then allowed to stand overnight with constant stirring at ambient temperature, the resulting slurry was filtered, the filtrate was concentrated by rotary evaporation, and thereafter vacuum distilled at 130° C./0.42 millimeters Hg to produce a 60% yield of 3-methoxypropylamino phosphoraziridine. NMR characterization indicated that the product was 95% pure.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=O)[C:8]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[Br:24]C1C=C2C(=CC=1OC)C(C)(C)C(=O)CC2>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:13]2[C:14]=1[C:6]1[CH2:7][C:8]3[CH:20]=[C:19]([Br:24])[C:18]([O:21][CH3:22])=[CH:17][C:9]=3[C:10]([CH3:15])([CH3:16])[C:11]=1[NH:12]2
Reactant: COc1cc2c(cc1Br)CCC(=O)C2(C)C
Reactant: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(Br)ccc3c1C2=O
Product: COc1cc2c(cc1Br)Cc1c([nH]c3cccc(Br)c13)C2(C)C

Procedure:
Under the same conditions as the method for synthesizing Compound A4, the title compound was prepared (as a mixture) from Compound E1.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].C[O:15][C:16](=O)[CH2:17]Br.[NH2:20][NH2:21]>C(#N)C.C(O)C>[NH2:20][NH:21][C:16](=[O:15])[CH2:17][N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1
Reactant: COC(=O)CBr
Reactant: NN
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Product: NNC(=O)CN1CCC(O)CC1
Temperature: 85 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
To a solution of 4-hydroxypiperidine (1.1 g, 0.011 mol) and potassium carbonate (1.52 g, 0.011 mol) in acetonitrile (˜20 mL) was added methylbromoacetate (0.93 mL, 0.01 mol) and the mixture was stirred in a nitrogen atmosphere overnight. The solvent was removed and the material was taken up in methanol. Gaseous hydrochloric acid was bubbled into solution. The methanol was removed and the material was taken up in tetrahydrofuran and sonicated. A solid was collected using a fritted funnel. The solid was taken up in ethyl acetate. Sodium carbonate was added to the solution and allowed to stir for one hour. The sodium carbonate was removed by filtration and the organic layer was concentrated. A solution of the crude material was made using anhydrous ethanol (˜1 mL) and hydrazine (0.167 mL, 5.34 mmol). This was placed in a sealed tube and was heated to 85° C. for 3 hours. The solvent was removed to yield the title compound (0.875 g, 50% yield). 1H NMR (DMSO-d6) δ 8.8 (s, 1H), 4.6 (s, 1H), 4.2 (s, 2H), 2.8 (s, 2H), 2.6 (m, 2H), 2.0 (m, 2H), 1.6 (m, 2H), 1.4 (m, 2H).