Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][CH2:11][C:12]1[C:13]([F:29])=[C:14]([O:19][C:20]2[CH:21]=[C:22]([CH:25]=[C:26]([Cl:28])[CH:27]=2)[C:23]#[N:24])[C:15]([Cl:18])=[CH:16][CH:17]=1.[CH3:30][C:31]1[NH:35][C:34](=[O:36])[NH:33][C:32]=1[C:37](O)=[O:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][NH:10][C:37]([C:32]2[NH:33][C:34](=[O:36])[NH:35][C:31]=2[CH3:30])=[O:38])=[C:13]([F:29])[C:14]=1[O:19][C:20]1[CH:21]=[C:22]([C:23]#[N:24])[CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: Cc1[nH]c(=O)[nH]c1C(=O)O
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1[nH]c(=O)[nH]c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.7 %

Procedure:
DIPEA (0.20 mL, 1.16 mmol) was added to a mixture of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.15 g, 0.48 mmol), 5-methyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylic acid (0.080 g, 0.58 mmol) and HATU (0.24 g, 0.63 mmol) in DMF (3 mL). The yellow solution was stirred at RT under nitrogen for 24 h then ethyl acetate (50 mL) and saturated sodium bicarbonate solution (100 mL) was added. The organic layer was separated, washed with saturated sodium bicarbonate solution (50 mL), water (50 mL), brine (50 mL) and dried over MgSO4. The mixture was filtered and the solvent was removed under vacuum. The crude material was purified by Reverse Phase HPLC (MeCN/water+0.1% TFA) to give the title compound (0.20 g, 10%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.42 (br. s., 1H), 9.75 (br. s., 1H), 7.74-7.95 (m, 2H), 7.42-7.57 (m, 3H), 7.37 (t, 1H), 4.44 (d, 2H), 2.20 (s, 3H). LCMS m/z 437.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:41])[C:7]([CH2:18][NH:19][C:20](=[O:40])[NH:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30]C4C=CC([N+]([O-])=O)=CC=4)=O)[CH2:24][CH2:23]3)=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:51][S:52]([CH:55]1[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1)(=[O:54])=[O:53]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:41])[C:7]([CH2:18][NH:19][C:20]([NH:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]([N:58]4[CH2:59][CH2:60][CH:55]([S:52]([CH3:51])(=[O:54])=[O:53])[CH2:56][CH2:57]4)=[O:30])[CH2:24][CH2:23]3)=[O:40])=[CH:8][N:9]2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)NC1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: CS(=O)(=O)C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)C1CCN(C(=O)N2CCC(NC(=O)NCc3cn(-c4ccccc4)c4cc(Cl)ccc4c3=O)CC2)CC1
Temperature: 100 °C

Procedure:
In a 20 mL round-bottomed flask, 4-nitrophenyl 4-(3-((7-chloro-4-oxo-1-phenyl-1,4-dihydroquinolin-3-yl)methyl)ureido)piperidine-1-carboxylate (0.100 g, 0.174 mmol), N,N-diisopropylethylamine (112 mg, 152 μL, 0.868 mmol) and 4-(methylsulfonyl)-piperidine (28.3 mg, 0.174 mmol) were combined with DMF (5 mL). The reaction mixture was stirred at 100° C. over the weekend. The reaction mixture was concentrated. The crude product was purified by preparative reverse-phase HPLC, giving the product 1-(7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-3-[1-(4-methanesulfonyl-piperidine-1-carbonyl)-piperidin-4-yl]-urea. MS calcd. for C29H35ClN5O5S [(M+H)+] 600.2, obsd. 600.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[O:9])[CH:3]=1.[CH3:21][S:22][C:23]1[N:24]=[CH:25][C:26]2[CH2:31][NH:30][CH2:29][C:27]=2[N:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[F:18][C:17]([F:20])([F:19])[C:13]1[CH:12]=[C:11]([NH:10][C:8]([C:4]2[CH:3]=[C:2]([N:30]3[CH2:31][C:26]4[CH:25]=[N:24][C:23]([S:22][CH3:21])=[N:28][C:27]=4[CH2:29]3)[CH:7]=[CH:6][N:5]=2)=[O:9])[CH:16]=[CH:15][CH:14]=1
Reactant: CSc1ncc2c(n1)CNC2
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1cc(Br)ccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CSc1ncc2c(n1)CN(c1ccnc(C(=O)Nc3cccc(C(F)(F)F)c3)c1)C2
Temperature: 100 °C
Yield: 44.5 %

Procedure:
To a toluene (5 mL) solution of 4-Bromo-N-(3-(trifluoromethyl)phenyl)picolinamide (172 mg, 0.50 mmol) and 2-(Methylthio)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine (84 mg, 0.50 mmol) was added cesium carbonate (325 mg, 1.00 mmol). The mixture was purged with nitrogen and then (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (31 mg, 0.05 mmol) and palladium(II) acetate (11 mg, 0.05 mmol) were added. The reaction was capped and heated at 100° C. for 7 hours. The cooled mixture was filtered. The solid was rinsed twice with ethyl acetate then with chloroform:methanol (9:1). The combined filtrate was evaporated in vacuo. The solid was triturated with hexanes:ethyl acetate (1:1) followed by ethyl acetate:methanol (9:1) and gave the title compound (96 mg). The filtrate was chromatographed on silica gel (12 g) eluted with hexanes:ethyl acetate (1:1) and gave additional title compound (25 mg). The total amount of the title compound obtained was 120 mg (0.28 mmol, yield 56%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C@H:10]2[O:19][C@H:13]3[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@H:12]3[C@H:11]2[CH2:20][CH2:21][N:22]2[C:27](=[O:28])[C:26]3[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=3[N:24]=[N:23]2)=[CH:4][CH:3]=1.[N:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[N:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>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>[CH3:17][C:15]1([CH3:18])[O:14][C@@H:13]2[O:19][C@H:10](/[CH:9]=[CH:8]/[C:5]3[CH:6]=[CH:7][C:2]([C:37]4[CH:38]=[N:33][CH:34]=[N:35][CH:36]=4)=[CH:3][CH:4]=3)[C@H:11]([CH2:20][CH2:21][N:22]3[C:27](=[O:28])[C:26]4[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=4[N:24]=[N:23]3)[C@@H:12]2[O:16]1
Reactant: CC1(C)O[C@@H]2O[C@H](/C=C/c3ccc(Br)cc3)[C@H](CCn3nnc4ccccc4c3=O)[C@@H]2O1
Reactant: OB(O)c1cncnc1
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+]
Product: CC1(C)O[C@@H]2O[C@H](/C=C/c3ccc(-c4cncnc4)cc3)[C@H](CCn3nnc4ccccc4c3=O)[C@@H]2O1
Temperature: 120 °C

Procedure:
A mixture of the compound obtained from step j above (0.35 g), pyrimidin-5-ylboronic acid (0.174 g), tetrakistriphenylphosphinepalladium (0) (0.081 g), and potassium carbonate (0.291 g) was dried under high vacuum for 10 minutes and dry dimethylformamide (5 mL) was added at room temperature. The reaction mixture was heated at 120° C. for 2 hours, and then quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine solution and dried over anhydrous sodium sulphate. The solvent was evaporated under the reduced pressure to obtain a residue which was purified by column chromatography over silica gel using 40% ethyl acetate in hexane as eluant to afford the title compound (0.3 g).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[C:13]([O:17][C:18]([NH:20][C@@H:21]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:22]([OH:24])=O)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(C(C)C)CC)(C)C.C1[CH:42]=[CH:43][C:44]2N(O)N=[N:47][C:45]=2C=1.C(N)CCC>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH2:45]([NH:47][C:22](=[O:24])[C@@H:21]([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:14])([CH3:15])[CH3:16])[CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:44][CH2:43][CH3:42]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCN
Solvent: CN(C)C=O
Product: CCCCNC(=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 127.7 %

Procedure:
Solid EDC.HCl (518 mg, 3.3 mmol) was added to a solution of (S)-2-(tert-butoxycarbonylamino)-3-cyclohexylpropanoic acid (405 mg, 1.5 mmol), diisopropylethylamine (2.5 mL, 14 mmol), HOBt (130 mg, 1.0 mmol), DMAP (18 mg, 0.15 mmol), butylamine (0.30 mL, 3 mmol), and anhydrous DMF (25 mL). The resulting clear light yellow solution was stirred at rt for 12 h. The solvent was removed (50° C., 150 Torr) and the residue was taken up in ether (100 mL) and washed with satd aq NaHCO3 (3×10 mL). Hexanes (30 mL) was added to the ether extract and this was washed with water (5×5 mL) and brine (3×5 mL), dried (Na2SO4), decanted, stripped and the crude material was purified using 40 g SiO2 with an eluent of hexanes to 30% MeOH in EA. Combining appropriate fractions and removal of solvent gave (S)-tert-butyl 1-(butylamino)-3-cyclohexyl-1-oxopropan-2-ylcarbamate (417 mg, 85%) as a white solid. 1H NMR (CDCl3) δ 0.80-1.80 (m 20H), 1.50 (s, 9H), 3.20 (m, 2H), 4.01 (d, 1H), 5.01 (d, 1H), 6.50 (bs, 1H). MS ESI +ve m/z 321 (M+Na).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.N1C=CC=CC=1.[C:31](Cl)(=[O:35])[C:32]([CH3:34])=[CH2:33]>C(Cl)(Cl)Cl>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([C:31](=[O:35])[C:32]([CH3:34])=[CH2:33])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C=C(C)C(=O)Cl
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)N1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1

Procedure:
700 mg (2.024 mmol) of 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(1-piperazinyl)-4-oxo-3-quinoline carboxylic acid were added to a round 3-neck flask of 50 ml under a nitrogen atmosphere, and then stirred at room temperature for 10 minutes after 30 ml of chloroform and 0.491 ml (3 mmol) of pyridine were added thereto. While the temperature of the inside of the container was kept at −10° C., 0.197 ml (2.024 mmol) of methacryloylchloride was slowly dripped thereinto. After reaction for 3 hours, distilled water was added to the reactants, which were then extracted with dichloromethane, concentrated, and chromatographed (20 gm silica, 7% MeOH/CH2Cl2) to give 1-cyclopropyl-6-fluoro-1,4-dihydro-7-[4-(2-methyl-1-oxo-2-propenyl)-1-piperazinyl]-4-oxo-3-quinoline carboxylic acid.
Reaction SMILES: CS(O[CH2:6][CH:7]1[N:17]2[C:18]3[N:9]([C:10](=[O:20])[CH:11]=[CH:12][C:13]=3[N:14]=[CH:15][C:16]2=[O:19])[CH2:8]1)(=O)=O.N1C=CC=CC=1.[NH:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:29][CH2:28]1.CO>CC#N.C(Cl)Cl>[O:19]=[C:16]1[CH:15]=[N:14][C:13]2=[C:18]3[N:17]1[CH:7]([CH2:6][N:27]1[CH2:28][CH2:29][CH:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH2:31][CH2:32]1)[CH2:8][N:9]3[C:10](=[O:20])[CH:11]=[CH:12]2
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CS(=O)(=O)OCC1Cn2c(=O)ccc3ncc(=O)n1c32
Solvent: CO
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC1CCN(CC2Cn3c(=O)ccc4ncc(=O)n2c43)CC1
Yield: 58 %

Procedure:
Crude (3,8-dioxo-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylen-2-yl)methyl methanesulfonate (6.950 g, 23.38 mmol) was dissolved in dry CH3CN (200 ml) and the mixture was treated with pyridine (7.55 ml, 94.0 mmol) followed by 1,1-dimethylethyl 4-piperidinylcarbamate (10.30 g, 51.4 mmol). The mixture was stirred at reflux under argon for 3 h then at 50° C. over the weekend. The mixture was then stirred at 90° C. for 2 h, then the volatiles were removed under reduced pressure and the residue was partitioned between DCM (600 ml) and water (100 ml). The organic phase was separated and the aqueous phase was extracted with DCM (2×200 ml). The combined organic extracts were washed with water (2×100 ml) dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to give a dark tan solid; this was taken up in a minimum of 5% MeOH in DCM and applied chromatographed, eluting with 0-10% MeOH in DCM. Appropriate fractions were combined and evaporated under reduced pressure to give the title compound as an amorphous pale tan solid (5.444 g, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])=[CH:18][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]([F:17])[C:10]([F:16])=[C:11]([CH:15]=1)[C:12]([OH:14])=O)=[O:5].[Br:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1>CN(C=O)C>[F:17][C:9]1[CH:8]=[C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:18]=[C:19]([CH2:22][NH:23][C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])[CH:20]=[CH:21][C:2]=2[Cl:1])[CH:15]=[C:11]([C:12]([NH:35][C:34]2[CH:36]=[CH:37][C:31]([Br:30])=[CH:32][CH:33]=2)=[O:14])[C:10]=1[F:16]
Reactant: Nc1ccc(Br)cc1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cc(F)c(F)c(C(=O)O)c2)c1
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cc(F)c(F)c(C(=O)Nc3ccc(Br)cc3)c2)c1

Procedure:
Prepared analogously to example 2f with 5-{2-Chloro-5-[(tert-butylcarbonylamino)-methyl]-benzoylamino}-2,3-difluoro-benzoic acid (0.29 g; 0.68 mmol); 4-bromoaniline (0.117 g; 0.68 mmol); PPA (0.523 mL; 0.89 mmol; 50% solution in DMF) and TEA (0.237 mL; 1.71 mmol).
Reaction SMILES: [NH2:1][C:2]([CH3:16])([CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([C:9]([Br:15])=[N:10][CH:11]=[CH:12]2)=[N:7]1)[C:3]#[N:4].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[S:24])=[CH:21][CH:20]=1>>[Br:15][C:9]1[C:8]2=[N:7][N:6]([CH2:5][C:2]([NH:1][C:23](=[S:24])[C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:28])[F:29])=[CH:27][CH:26]=3)([C:3]#[N:4])[CH3:16])[CH:14]=[C:13]2[CH:12]=[CH:11][N:10]=1
Reactant: CC(N)(C#N)Cn1cc2ccnc(Br)c2n1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: CC(C#N)(Cn1cc2ccnc(Br)c2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(7-bromo-2H-pyrazolo[3,4-c]pyridin-2-yl)-2-methylpropionitrile (100 mg, described in Example 202) and 4-trifluoromethylthiobenzoyl chloride (93 mg), the title compound was isolated as a white solid (153 mg, 89%). Rf=0.25 (1:1 EA/heptane). MS (ES): M/Z [M+H]=484. 1H NMR: (400 MHz, DMSO-d6): 1.70 (s, 3H), 5.18 (d, J=13.5 Hz, 1H), 5.33 (d, J=13.5 Hz, 1H), 7.76 (d, J=5.8 Hz, 1H), 7.87-7.90 (m, 3H), 7.96 (d, J=8.4 Hz, 1H), 8.71 (s 1H) and 9.01 (d, J=1.1 Hz, 1H). 19F NMR (376 MHz, DMSO-d6): −42.0 (s, 3F).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([Cl:25])[CH:20]=3)[N:17]=[C:16]([C:26](O)=[O:27])[CH:15]=2)[CH:6]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:8]=1.ClC1C=C(C2N(C3C=NC=CC=3)N=C(C([N:50]3[CH2:55][CH2:54][NH:53][C:52](=[O:56])[CH2:51]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[Cl:25][C:21]1[CH:20]=[C:19]([N:18]2[C:14]([C:5]3[CH:6]=[C:7]([O:9][C:10]([F:12])([F:11])[F:13])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:15][C:16]([C:26]([N:50]3[CH2:55][CH2:54][NH:53][C:52](=[O:56])[CH2:51]3)=[O:27])=[N:17]2)[CH:24]=[CH:23][N:22]=1
Reactant: COc1cc(OC(F)(F)F)cc(-c2cc(C(=O)O)nn2-c2ccnc(Cl)c2)c1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3cccnc3)n2)CCN1
Agent: O=C1CNCCN1
Product: COc1cc(OC(F)(F)F)cc(-c2cc(C(=O)N3CCNC(=O)C3)nn2-c2ccnc(Cl)c2)c1

Procedure:
31 mg (0.08 mmol) of the compound of Example 57A is reacted analogously to the synthesis of the compound of Example 4 with 8 mg (0.08 mmol) of 2-oxopiperazine. 37 mg (99% of theory) of the title compound is obtained.
Reaction SMILES: [CH2:1]([P:3]([OH:5])[OH:4])[CH3:2].[C:6](#[N:10])[C:7]([CH3:9])=[CH2:8].CC(N=NC(C#N)(C)C)(C#N)C>C(O)C>[CH2:1]([P:3]([CH2:8][CH:7]([C:6]#[N:10])[CH3:9])(=[O:5])[OH:4])[CH3:2]
Reactant: C=C(C)C#N
Reactant: CCP(O)O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCO
Product: CCP(=O)(O)CC(C)C#N
Yield: 85 %

Procedure:
94 g (1 mol) of ethylphosphonous acid (produced as in Example 1) and 67 g (1 mol) of methacrylonitrile are introduced into a four-neck round-bottom flask equipped with stirrer, reflux condenser, thermometer and nitrogen inlet and heated. At about 100° C., 98.4 g of a 5% strength solution of AIBN in ethanol are added dropwise over 1 h. Thereafter, the solvent was distilled off in vacuo to leave 137 g of ethyl(2-cyano-2-methylethyl)phosphinic acid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]([CH3:8])[C:5](Br)=[O:6].[CH3:9][OH:10]>C(Cl)(Cl)Cl>[CH3:9][O:10][C:5](=[O:6])[CH:4]([CH3:8])[CH2:3][CH2:2][Br:1]
Reactant: CC(CCBr)C(=O)Br
Reactant: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)C(C)CCBr
Temperature: 25 °C
Reaction time: 16 h
Yield: 51 %

Procedure:
A solution of 4-bromo-2-methyl-butyryl bromide (6.2 g, 43.0 mmol, 1.0 eq) in CHCl3 (10 mL) was cooled at 0° C. MeOH (10 mL) was slowly added and the resulting mixture stirred at room temperature for 16 hours. The solvent was evaporated and the residue dissolved in CHCl3 and washed with water and brine. The organic layer was collected and dried with Na2SO4. Evaporation of the solvent gave 4-bromo-2-methyl-butyric acid methyl ester as thick oil (4.3 g, yield 51%).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH:9]([NH2:12])([CH3:11])[CH3:10]>C1(C)C=CC=CC=1>[Cl:8][C:7]1[C:2]([NH:12][CH:9]([CH3:11])[CH3:10])=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Clc1nccnc1Cl
Reactant: CC(C)N
Solvent: Cc1ccccc1
Product: CC(C)Nc1nccnc1Cl

Procedure:
A solution of 2,3-dichloropyrazine (2.0 g) and isopropylamine (2.3 g) in toluene (8 ml) is refluxed for 40 hr. The mixture is cooled and filtered to remove isopropylamine hydrochloride. The filtrate is concentrated in vacuo to a residue which is diluted with an aqueous sodium hydroxide solution (10%) and dichloromethane. The phases are separated. The dichloromethane phase is washed with saline, dried over sodium sulfate, and concentrated to give the title compound, NMR (CDCl3) 1.28, 4.21, 5.02, 7.54 and 7.94 δ.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10]Br.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1.C(N(CC)CC)C.CCOCC>O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: N#Cc1ccc(Br)c(CBr)c1
Reactant: c1ccc2c(c1)CCN2
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1ccc(Br)c(CN2CCc3ccccc32)c1

Procedure:
A mixture of 4-bromo-3-bromomethyl-benzonitrile (2.66 g, 9.7 mmol), indoline (1.14 mL, 10.2 mmol) and triethylamine (1.60 mL, 11.5 mmol) was heated at reflux for 18 h in dry tetrahydrofuran (50 mL). The flask was cooled and ether (100 mL) was added. Evaporation gave crude 4-bromo-3-(2,3-dihydro-indol-1-ylmethyl)-benzonitrile.
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C(C)(C)OB([C:51]2[NH:59][C:58]3[CH2:57][CH2:56][NH:55][C:54](=[O:60])[C:53]=3[CH:52]=2)O1.[C:62]([NH:66][C:67]1[N:76]([CH3:77])[C:75](=[O:78])[C:74]2[C:69](=[C:70](I)[CH:71]=[CH:72][CH:73]=2)[N:68]=1)([CH3:65])([CH3:64])[CH3:63]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:62]([NH:66][C:67]1[N:76]([CH3:77])[C:75](=[O:78])[C:74]2[C:69](=[C:70]([C:51]3[NH:59][C:58]4[CH2:57][CH2:56][NH:55][C:54](=[O:60])[C:53]=4[CH:52]=3)[CH:71]=[CH:72][CH:73]=2)[N:68]=1)([CH3:65])([CH3:64])[CH3:63]
Reactant: Cn1c(NC(C)(C)C)nc2c(I)cccc2c1=O
Reactant: CC1(C)OB(c2cc3c([nH]2)CCNC3=O)OC1(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cn1c(NC(C)(C)C)nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2c1=O
Temperature: 105 °C
Yield: 30.4 %

Procedure:
A mixture of Xphos (12 mg, 0.027 mmol), Pd2dba3 (12 mg, 0.013 mmol), K3PO4 (169 mg, 0.80 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (609) (139 mg, 0.53 mmol) and 2-(tert-butylamino)-8-iodo-3-methylquinazolin-4(3H)-one (701) (95 mg, 0.27 mmol) in dioxane (2 mL), water (0.4 mL) in a sealed glass tube was heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc.) at 105° C. for 30 min. It was partitioned between 15 mL of EtOAc and 2 mL of 0.5 N NaOH. The organic layer was separated and concentrated under reduced pressure. The crude material was purified on a silica gel column (eluted with a gradient of 1-10% MeOH in DCM) to afford 2-(tert-butylamino)-3-methyl-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinazolin-4(3H)-one (30 mg, 31% yield) as an off-white crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.00 (1H, br.), 7.94 (1H, dd, J=7.5, 1.5 Hz), 7.86 (1H, dd, J=7.8, 1.4 Hz), 7.18 (1H, t, J=7.6 Hz), 6.94 (2H, d, J=2.2 Hz), 5.98 (1H, s), 3.50 (3H, s), 3.44 (2H, m), 2.86 (2H, t, J=6.8 Hz), 1.56 (9H, s). m/z (ESI, +ve ion) 366.2 (M+H)+.
Reaction SMILES: C([Li])CCC.[CH:6]1([O:11][CH:12]2[NH:16][C:15](=[O:17])[CH2:14][CH2:13]2)[CH2:10][CH2:9][CH2:8][CH2:7]1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CCCCCC.O1CCCC1>[C:18]([N:16]1[CH:12]([O:11][CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:13][CH2:14][C:15]1=[O:17])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1CCC(OC2CCCC2)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1CCC(OC2CCCC2)N1C(=O)c1ccccc1
Yield: 70.2 %

Procedure:
11.8 cm3 of a 1.5M solution of butyllithium in hexane is added at -70° C. to a solution of 3 g of 5-cyclopentyloxy pyrrolidin-2-one in 140 cm3 of tetrahydrofuran. The mixture is maintained at this temperature for 20 minutes, then a solution of 2.49 g of benzoyl chloride in 20 cm3 of tetrahydrofuran is added. The whole is heated gently, then brought to dryness under reduced pressure. After chromatography on silica (eluent: hexane-ethyl acetate 7-3), 3.4 g of expected product is obtained.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([NH:7][C:8]1[C:9]2[N:10]([N:20]=[N:21][N:22]=2)[C:11]([CH3:19])=[CH:12][C:13]=1[NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])=O)[CH3:2].Cl.N1C=CC=CC=1>N1C=CC=CC=1>[CH2:1]([O:3][CH2:4][C:5]1[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:13]2[CH:12]=[C:11]([CH3:19])[N:10]3[N:20]=[N:21][N:22]=[C:9]3[C:8]=2[N:7]=1)[CH3:2]
Reactant: CCOCC(=O)Nc1c(NCC(C)C)cc(C)n2nnnc12
Agent: Cl
Solvent: c1ccncc1
Product: CCOCc1nc2c(cc(C)n3nnnc23)n1CC(C)C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
A solution of 2-ethoxy-N-{7-[(2-methylpropyl)amino]-5-methyltetraazolo[1,5-α]pyridin-8-yl}acetamide (10.9 g, 35.6 mmol) and pyridine hydrochloride (10 g) in pyridine (100 mL) was heated at reflux under a nitrogen atmosphere for five days. An analysis by high-performance liquid chromatography indicated the presence of 16% starting material, and an additional 10 g of pyridine hydrochloride was added. After a total of seven days, the reaction was complete, and the solvent was removed under reduced pressure. The resulting black oil was dissolved in ethyl acetate (500 mL), and the solution was washed with water (3×200 mL), dried over magnesium sulfate, filtered, and concentrated to 200 mL. Needles began to form in the solution, which was placed in a freezer for two hours. The crystals were then filtered and washed with cold ethyl acetate to yield 6.85 g of 8-(ethoxymethyl)-7-(2-methylpropyl)-5-methyl-7H-imidazo[4,5-c]tetraazolo[1,5-α]pyridine as light brown needles, m.p. 158-160° C.