Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11](NCC3C=CC=CN=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>>[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:31][CH2:30][C:29]3[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=3)[N:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Reactant: NCc1ccc(F)cc1
Agent: Cl
Product: Cc1nc(NCc2ccc(F)cc2)nc(NC2CCCCC2)c1C

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using (4-fluorobenzyl)amine instead of (pyridin-2-ylmethyl)amine. The product was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03-1.10 (m, 1H), 1.20-1.34 (m, 2H), 1.59 (s, 1H), 1.68 (t, J=12.22 Hz, 4H), 1.87 (s, 3H), 2.23 (s, 3H), 3.86 (d, J=8.87 Hz, 1H), 4.52 (d, J=5.37 Hz, 2H), 7.14 (t, J=8.60 Hz, 2H), 7.33-7.38 (m, 2H), 7.57 (d, J=7.52 Hz, 1H), 8.10 (s, 1H), 12.78 (bs, 1H); MS (ESI) m/z 329.2 (M+1)+.
Reaction SMILES: C([O:3][P:4]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:35])[NH:15][C:16]2[CH:21]=[C:20]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[CH:19]=[CH:18][C:17]=2[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:10][CH:9]=1)([CH3:6])=[O:5])C.[OH-].[Na+].Cl>O1CCOCC1.CCOC(C)=O>[C:31]([O:30][C:28]([NH:27][C:17]1[CH:18]=[CH:19][C:20]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)=[CH:21][C:16]=1[NH:15][C:14]([C:11]1[CH:10]=[CH:9][C:8]([CH2:7][P:4]([CH3:6])(=[O:3])[OH:5])=[CH:13][CH:12]=1)=[O:35])=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: CCOP(C)(=O)Cc1ccc(C(=O)Nc2cc(-c3cccs3)ccc2NC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CP(C)(=O)O)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution [4-(2-tert-butoxycarbonylamino-5-thiophen-2-yl-phenylcarbamoyl)-benzyl]-methyl-phosphinic acid ethyl ester (377 mg, 0.733 mmol) in dioxane (2 mL) was added NaOH (1 mL, 5.00 mmol, 5M) and the solution was heated to 60° C. After 18 h, the reaction was diluted with EtOAc, acidified with 1N HCl. The organic layer was dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The material was used without further purification. 1H NMR (DMSO-d6) δ 9.94 (s, 1H), 8.74 (br s, 1H), 7.91 (d, J=8.2 Hz, 2H), 7.79 (d, J=2.0 Hz, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.50 (dd, J=5.0, 1.2 Hz, 1H), 7.48 (dd, J=8.5, 2.0 Hz, 1H), 7.44-7.39 (m, 3H), 7.10 (dd, J=5.3, 3.5 Hz, 1H), 3.13 (d, J=17.9 Hz, 2H), 1.43 (s, 9H), 1.21 (d, J=13.8 Hz, 3H). MS: cal'd 387 (MH+; -Boc), exp 387 (MH+; -Boc).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@@H:9]([OH:15])[CH2:10][CH2:11][O:12]2)=[CH:7][CH:6]=1)=[O:4].N1C=CN=C1.[CH3:21][C:22]([Si:25](Cl)([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C=O)C>[Si:25]([O:15][C@@H:9]1[C:8]2[C:13](=[CH:14][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)[O:12][CH2:11][CH2:10]1)([C:22]([CH3:24])([CH3:23])[CH3:21])([CH3:27])[CH3:26]
Reactant: COC(=O)c1ccc2c(c1)OCC[C@@H]2O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)OCC[C@@H]2O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of (S)-methyl-4-hydroxyl-3,4-dihydro-2H-chromene-7-carboxylate (10.2 g, 49.0 mmol), imidazole (3.70 g, 53.9 mmol), and TBSCl (8.12 g, 53.9 mmol) in DMF (100 mL) was stirred for 24 h at RT. The reaction mixture was quenched with H2O and extracted with ether (3×). The organic extracts were dried over MgSO4, and concentrated to give a brown oil. 1H NMR (400 MHz, CDCl3): δ 0.74 (s, 15H), 1.81 (m, 1H), 1.91 (m, 1H), 3.87 (s, 3H), 4.02 (m, 1H), 4.11 (m, 1H), 4.67 (t, 5.2 Hz, 1H), 7.09 (s, 1H), 7.11 (d, 7.6 Hz, 1H), 7.23 (d, 7.6 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][CH2:20][NH2:21]>>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:10](=[O:11])[C:3]([NH:21][CH2:20][CH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=1)=[O:2]
Reactant: NCCc1ccccn1
Reactant: COc1cccc(CN)c1OC
Product: COc1cccc(CNC(=O)C(=O)NCCc2ccccn2)c1OC

Procedure:
Prepared in a similar manner to example 125 using 2,3-dimethoxybenzylamine, ethyl oxalyl chloride, and 2-(pyridin-2-yl)ethylamine; m/e=343 [M+1].
Reaction SMILES: Br[C:2]1[C:6]([C:7]#[N:8])=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:4][C:3]=1[C:15]([O:17][CH3:18])=[O:16].B(O)(O)[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.CCO.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>[C:7]([C:6]1[C:2]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[C:3]([C:15]([O:17][CH3:18])=[O:16])[S:4][C:5]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)#[N:8]
Reactant: COC(=O)c1sc(N2CCOCC2)c(C#N)c1Br
Reactant: Cc1ccc(B(O)O)cc1
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: CCO
Solvent: COCCOC
Product: COC(=O)c1sc(N2CCOCC2)c(C#N)c1-c1ccc(C)cc1
Reaction time: 0.17 h
Yield: 73 %

Procedure:
A mixture of methyl 3-bromo-4-cyano-5-morpholin-4-ylthiophene-2-carboxylate (0.040 g, 0.12 mmol), p-tolylboronic acid (0.020 g, 0.14 mmol), tetrakis(triphenylphosphine)palladium(0) (0.004 g, 0.004), 2M aqueous K2CO3 solution (0.120 mL, 0.24 mmol) in 1,2-dimethoxyethane/EtOH (8/2) (2 mL) was subjected to MWI at 110° C. for 10 min. The reaction mixture was concentrated; the residue was diluted with water and extracted with DCM. The organic solutions were combined, washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography and triturated with cold MeOH to give methyl 4-cyano-3-(4-methylphenyl)-5-morpholin-4-ylthiophene-2-carboxylate (0.030 g, 83%). LCMS: (AA) ES+ 343.1. 1H NMR (400 MHz, CDCl3) δ: 7.24-7.27 (m, 4H), 3.87-3.89 (m, 4H), 3.69 (s, 3H), 3.60-3.62 (m, 4H) and 2.39 (s, 3H).
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[S:9]1[C:13]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[N:15]=2)=[CH:12][C:11]2[CH:24]=[CH:25][CH:26]=[CH:27][C:10]1=2>C(#N)C>[CH3:23][S:20]([C:16]1[N:15]=[C:14]([C:13]2[S:9][C:10]3[CH:27]=[CH:26][CH:25]=[CH:24][C:11]=3[C:12]=2[N+:7]([O-:8])=[O:6])[CH:19]=[CH:18][N:17]=1)(=[O:21])=[O:22]
Reactant: CS(=O)(=O)c1nccc(-c2cc3ccccc3s2)n1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: CS(=O)(=O)c1nccc(-c2sc3ccccc3c2[N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 60.7 %

Procedure:
Nitronium tetrafluoroborate (3.4 mL, 0.5 M in sulfolane, 1.72 mmol) was slowly added at 0° C. to a suspension of 4-(benzo[b]thiophen-2-yl)-2-(methylsulfonyl)pyrimidine (0.50 g, 1.72 mmol) in acetonitrile (10 mL). The resulting mixture was stirred at rt for 14 h and concentrated in vacuo. The product was purified by flash chromatography eluting with ethyl acetate/hexane (1:3) to afford the title compound (0.35 g, 57%). MS (M+H)+ 336.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[C:8]1[CH:9]=[N+:10]([O-:17])[CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15].[CH2:18]([NH:20]CC)[CH3:19]>C1COCC1>[CH2:18]([NH:20][C:8]1[CH:9]=[N+:10]([O-:17])[CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[CH3:19]
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1Cl
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCNc1c[n+]([O-])ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Anhydrous K2CO3 (19 g, 144.5 mmol) is suspended in a solution of 3-Chloro-4-nitro-pyridine-1-oxide (10 g, 57.8 mmol) in anhydrous acetonitrle (100 mL). Excess diethyl amine (2.0 M) in THF is added to the above suspension under cold conditions (ice-bath). After complete addition of diethyl amine, the reaction mixture is allowed to warm to room temperature and left stirring overnight. The reaction mixture is filtered to remove K2CO3 and the filtrate evaporated under reduced pressure to remove volatile solvents. The organic residue is subjected to chromatography, eluting with 30% EtOAc-hexanes to afford 3-Ethylamino-4-nitro-pyridine-1-oxide as an orange solid. 1H NMR (300 MHz, CDCl3) δ 8.0 1 (d, J=7.5 Hz, 1H), 7.91(s, 1H), 7.8 (brs, NH), 7.44 (d, J=7.2 Hz, 1H), 3.30 (t, J=7.2 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H), m/z 184 [M+1]
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:37]I>ClCCl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][I:37])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCc1ccccc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ICCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 5-phenyl-pentane-1-ol (1.0 gm, 6.089 mmol) in dichloromethane (20 ml), triphenyl phosphine (2.35 gm, 8.52 mmol), imidazole (0.58 gm, 8.52 mmol) and elemental iodine (2.16 gm, 8.52 mmol) was stirred at room temperature for 12 h and solvent was removed under reduced pressure. The crude mixture was taken up in ethyl acetate (30 ml), washed with water (20 ml) and then with brine (30 ml). The layers were separated, the organic layer was dried over anhydrous sodium sulfate and solvent was removed under reduced pressure. The crude product was purified on column chromatography using hexane as an eluent to yield an oily liquid, 750 mg. 1H NMR (CDCl3): δ 1.30-1.70 (m, 4H), 1.80 (m, 2H), 2.6 (t, 2H, J=7.2 Hz), 3.10 (t, 2H, J=7.8 Hz), 7.00-7.34 (m, 5H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[CH:5]=1.N([C:16]1[NH:17][CH2:18][CH2:19][N:20]=1)[N+]([O-])=O>C1(C)C(C)=CC=CC=1>[Cl:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[CH:3]([OH:11])[CH2:2][NH:1][C:16]1[NH:20][CH2:19][CH2:18][N:17]=1
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: O=[N+]([O-])NC1=NCCN1
Solvent: Cc1ccccc1C
Product: OC(CNC1=NCCN1)c1cccc(Cl)c1

Procedure:
A mixture of 9.5 parts of α-(aminomethyl)-m-chlorobenzyl alcohol, 7.15 parts of 2-(nitramino)-2-imidazoline and 40 parts of xylene is stirred in an oil-bath at 150°-160°C. while a great part of the xylene is distilled off. The resulting residue is diluted with a few parts of acetone and the product is allowed to crystallize. It is filtered off and crystallized from 4-methyl-2-pentanone, yielding m-chloro-α-(2-imidazolin-2-ylaminomethy)benzyl alcohol; m.p. 108.5°C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([CH3:9])[C:7]=1[NH2:8].[C:11](OC)(OC)(OC)[O:12][CH3:13].[OH-].[Na+]>C(O)(=O)C>[CH3:11][O:12][C:13]1[NH:1][C:2]2[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([CH3:9])[C:7]=2[N:8]=1
Reactant: COC(OC)(OC)OC
Reactant: Cc1cc(O)cc(N)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1nc2c(C)cc(O)cc2[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.60 g (4.34 mmol) 3,4-diamino-5-methylphenol were placed in 2 mL acetic acid. 4.0 mL (0.03 mol) tetramethyl orthocarbonate were added and the mixture was stirred for 4 h at RT. The reaction mixture was purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with a 1M aqueous NaOH solution and extracted with ethyl acetate. The organic phase was dried and evaporated down i.vac.
Reaction SMILES: [CH3:1][C:2](=[N:7][OH:8])[C:3]([CH3:6])=[N:4][OH:5].[CH3:9][S:10](Cl)(=[O:12])=[O:11].C(N(CC)CC)C>O1CCOCC1>[CH3:9][S:10]([O:5][N:4]=[C:3]([CH3:6])[C:2]([CH3:1])=[N:7][O:8][S:10]([CH3:9])(=[O:12])=[O:11])(=[O:12])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=NO)C(C)=NO
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=NOS(C)(=O)=O)C(C)=NOS(C)(=O)=O
Yield: 77.3 %

Procedure:
To 300 ml of 1,4 dioxane in a round-bottom flask was added 11.6 g (0.1 mole) of dimethylglyoxime. When the solid had completely dissolved, 22.9 g (0.2 mole) of methanesulfonyl chloride was added. The mixture was stirred and 20.2 g (0.2 mole) triethylamine was added dropwise. The reaction mixture was stirred for 51/2 hours during which time a precipitate was formed. The dioxane was removed by evaporation under reduced pressure. The residue was stirred in ice water, then filtered. The solid product was dissolved in dichloromethane and dried over anhydrous sodium sulfate. The slurry was filtered and the solvent was removed in a rotary evaporator. The solid residue was stirred in cold ethanol, then filtered and dried in a vacuum oven, giving 21.05 g (77% yield) of di-(methanesulfonyl)-dimethylglyoxime with mp 169-172° C.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9](=[O:14])[CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:4]1.[H-].[Na+].[NH2:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22](F)[C:19]=1[C:20]#[N:21]>C1COCC1>[NH2:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([O:1][CH2:2][C@H:3]2[CH2:8][CH2:7][CH2:6][N:5]([C:9](=[O:14])[CH2:10][CH:11]([CH3:12])[CH3:13])[CH2:4]2)[C:19]=1[C:20]#[N:21]
Reactant: CC(C)CC(=O)N1CCC[C@H](CO)C1
Reactant: N#Cc1c(N)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)CC(=O)N1CCC[C@H](COc2cccc(N)c2C#N)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
A solution of (S)-1-(3-(hydroxymethyl)piperidin-1-yl)-3-methylbutan-1-one (Example 5d) (42 g, 210.75 mmol, 1.2 eq.) in anhydrous THF (300 mL) was added dropwise at 0° C. to a suspension of NaH (60% in mineral oil, 8.43 g, 273.97 mmol, 1.63 eq.) in anhydrous THF (600 mL). The mixture was warmed up to about 25° C. and stirred for 1 h while keeping the temperature below 25° C. A solution of 2-amino-6-fluorobenzonitrile (22.95 g, 168.6 mmol, 1 eq.) in THF (300 mL) was added dropwise. The reaction was heated slowly to reflux and stirred overnight. The mixture was cooled down to room temperature, concentrated to about 400 mL of residual material. Saturated ammonium chloride (200 mL) was added. After stirring vigorously for 15 minutes, EtOAc (800 mL) was added and stirring continued for additional 30 minutes. The organic phase was washed subsequently with water, brine and dried over Na2SO4. The solvent was removed under vacuum and the residue was chromatographed on silica gel (Hex/EtOAc to provide the desired product (44.6 g, 141.40 mmol, 83.87%). 1H NMR (400 MHz, DMSO-d6, 20° C.) δ 0.79-0.92 (3×d, J=6.4 Hz/each, 6H), 1.19-1.46 (m, 2H), 1.51-2.01 (m, 4H), 2.03-2.25 (m, 2H), 2.57 (dd, J=10.4, 12.8 Hz, 0.3H), 2.75-2.88 (m, 0.6H), 2.92-3.10 (m, 1H), 3.65-4.08 (m, 3.6H), 4.27-4.40 (dm, 0.3H), 5.98 & 6.00 (s & s, 2H), 6.18 (pseudo t, J=8.4 & 9.2 Hz, 1H), 6.32 (pseudo d, J=8.4 Hz, 1H), 7.11-7.21 (m, 1H). MS 316 (MH+)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][C:18]=3[CH:19]3[CH2:21][CH2:20]3)[C:9]2=[O:22])[CH:5]=[CH:4][N:3]=1.[CH:23]1(B(O)O)[CH2:25][CH2:24]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.C1(C)C(C)=CC=CC=1>[CH:19]1([C:18]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:10]2[CH2:11][CH2:12][N:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH:23]4[CH2:25][CH2:24]4)[CH:7]=3)[C:9]2=[O:22])[CH2:21][CH2:20]1
Reactant: O=C1N(c2ccnc(Cl)c2)CCN1c1cnccc1C1CC1
Reactant: OB(O)C1CC1
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: Cc1ccccc1C
Product: O=C1N(c2ccnc(C3CC3)c2)CCN1c1cnccc1C1CC1
Yield: 33.4 %

Procedure:
1-(2-chloropyridin-4-yl)-3-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-39a: 220 mg, 0.7 mmol) was reacted with cyclopropyl boronic acid (72 mg, 0.84 mmol), Pd(PPh3)4 (41 mg, 0.035 mmol), potassium carbonate (194 g, 1.4 mmol) and xylene (10 mL) in seal tube at 125° C. for 14 hours. Purification by column chromatography on silica gel (1% methanol in chloroform) afforded 75 mg of the product (33.48% yield).
Reaction SMILES: [OH:1][CH:2]1[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]([C:10]2([CH3:18])[CH:12]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[O:11]2)[CH:3]1[O:19][CH3:20].O1CCCC1.[H-].[Na+].[O:28]1[CH2:33][CH2:32][N:31]([C:34](Cl)=[O:35])[CH2:30][CH2:29]1>C(OCC)C>[CH3:20][O:19][CH:3]1[CH:2]([O:1][C:34]([N:31]2[CH2:32][CH2:33][O:28][CH2:29][CH2:30]2)=[O:35])[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]1[C:10]1([CH3:18])[CH:12]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[O:11]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: COC1C(O)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC1C(OC(=O)N2CCOCC2)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Yield: 53.9 %

Procedure:
To a solution of 6-hydroxy-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]octane (14.1 mg) in freshly distilled tetrahydrofuran (0.5 ml) was added sodium hydride (2.0 mg, 60% oil dispersion) in one portion at 5° C. The mixture was stirred for half an hour at the same temperature and then morpholinocarbonyl chloride (6.8 mg) was added thereto. The reaction mixture was stirred for 2 hours at ambient temperature and diluted with diethyl ether (2 ml). The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (elution by diethyl ether/n-hexane=2/1) to yield 5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)-oxiranyl ]-6-(morpholinocarbonyloxy)-1-oxaspiro[2,5]octane (9.7 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[C:4](=[O:16])[C:3]=1[CH:17]=[N:18]O.P(Cl)(Cl)(Cl)=O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[C:4](=[O:16])[C:3]=1[C:17]#[N:18]
Reactant: O=c1c(C=NO)c(Cl)ccn1-c1c(F)cccc1F
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: N#Cc1c(Cl)ccn(-c2c(F)cccc2F)c1=O
Temperature: 100 °C
Yield: 80.1 %

Procedure:
To a solution of 4-chloro-1-(2,6-difluorophenyl)-3-((hydroxyimino)methyl)pyridin-2(1H)-one obtained in Step D (800 mg) in acetonitrile (7.0 mL) was added phosphorus oxychloride (0.341 mL) at room temperature. The reaction mixture was heated at 100° C. for 1 hr, cooled to room temperature, and poured into ice water. The resulting solid was collected by filtration, and dried under reduced pressure to give the title compound (600 mg).
Reaction SMILES: CN(C)C=O.[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[C:18]1[CH:22]=[C:21]([CH2:23]Br)[O:20][N:19]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[CH2:25]([O:27][C:28](=[O:42])[CH:29]([NH:35][C:36]([O:38][CH2:39][CH:40]=[CH2:41])=[O:37])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)C>[CH2:33]([O:32][C:30](=[O:31])[C:29]([NH:35][C:36]([O:38][CH2:39][CH:40]=[CH2:41])=[O:37])([CH2:23][C:21]1[O:20][N:19]=[C:18]([CH:14]2[CH2:15][CH2:16][CH2:17][N:13]2[C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])[CH:22]=1)[C:28]([O:27][CH2:25][CH3:26])=[O:42])[CH3:34]
Reactant: C=CCOC(=O)NC(C(=O)OCC)C(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CCCC1c1cc(CBr)on1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=CCOC(=O)NC(Cc1cc(C2CCCN2C(=O)OC(C)(C)C)no1)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.2 %

Procedure:
A dimethyl formamide (260 mL) solution of 2-(5-Bromomethyl-isoxazol-3-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (7.29 g, 56 mmol) and 2-allyloxycarbonylamino-malonic acid diethyl ester (8.25 g, 32 mmol) was cooled to 0° C. and cesium carbonate (25.41 g, 78 mmol) was added. The reaction was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was then poured into diethyl ether (2 L) and washed with water (5×200 mL) and brine. The organic portion was dried over magnesium sulfate and concentrated in vacuo. The crude residue was chromatographed on silica gel eluting with ethyl acetate:hexane (3:7) to afford the title compound as a clear colorless oil (10.95 g; 83%). MS (Cl) m/z 260.1 (M-99).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1B(O)O>>[CH3:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:17]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccncc1B(O)O
Reactant: Brc1ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nn12
Product: Cc1ccncc1-c1ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nn12

Procedure:
[7-(4-Methyl-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(4-morpholin-4-yl-phenyl)-amine was prepared from (7-bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-(4-morpholin-4-yl-phenyl)-amine and 4-methylpyridine-3-boronic acid in an analogous manner to Example 1031b. Product isolated as a yellow solid (55 mg, 48%). m.p.=191-193° C.; LCMS (m/e) 387 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.76-8.69 (m, 2H), 8.59-8.52 (m, 1H), 7.37 (d, 2H, J=7.40 Hz), 7.31-7.26 (m, 1H), 6.88-6.84 (m, 1H), 6.84-6.75 (m, 3H), 6.67 (s, 1H), 3.89-3.81 (m, 4H), 3.12-3.04 (m, 4H), 2.31 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[CH:7][C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[C:10]([CH2:16]Br)[CH:9]=3.[C:18]([O-:21])(=[O:20])[CH3:19].[K+]>C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[CH:7][C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[C:10]([CH2:16][O:21][C:18](=[O:20])[CH3:19])[CH:9]=3
Reactant: BrCc1ccc2c(ccc3ccc(Br)cc32)c1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CCOCC
Product: CC(=O)OCc1ccc2c(ccc3ccc(Br)cc32)c1
Temperature: 80 °C
Yield: 96.5 %

Procedure:
A mixture of 3-bromo-7-(bromomethyl)-phenanthrene (2.249 g, 6.425 mmol) and potassium acetate (1.26 g, 12.8 mmol) in 60 ml of DMf was heated at 80° C. for 7 hours. After cooling to RT, the reaction mixture was diluted with ethyl ether, washed with water and brine, dried (MgSO4) and evaporated to give 2.042 g (97%) of the title compound as a white solid which was used in the following reaction without purification.
Reaction SMILES: O.NN.[N:4]1[C:13]2[CH:12]([CH2:14][CH2:15][CH2:16][NH:17][C:18]3[C:23]([N+:24]([O-])=O)=[CH:22][C:21]([CH2:27][C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[CH:20][N:19]=3)[CH2:11][CH2:10][CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1>CO.[Ni]>[NH2:24][C:23]1[C:18]([NH:17][CH2:16][CH2:15][CH2:14][CH:12]2[C:13]3[N:4]=[CH:5][CH:6]=[CH:7][C:8]=3[CH2:9][CH2:10][CH2:11]2)=[N:19][CH:20]=[C:21]([CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH:22]=1
Reactant: O=[N+]([O-])c1cc(Cc2cccnc2)cnc1NCCCC1CCCc2cccnc21
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1cc(Cc2cccnc2)cnc1NCCCC1CCCc2cccnc21
Reaction time: 0.42 h

Procedure:
Hydrazine hydrate (7 ml) in methanol (25 ml) was added with stirring over 25 minutes to a cooled (5°-10° C.) solution of 2-[3-(5,6,7,8-tetrahydroquinol-8-yl)propylamino-3-nitro-5-(pyrid-3-ylmethyl)pyridine (6.1 g) in methanol (300 ml) containing Raney Nickel (ca. 12 g). The solution was stirred for a further hour at 5° C., the catalyst was removed by filtration and the filtrate was concentrated to dryness in vacuo giving the title compound as an orange oil (theoretical yield assumed) which was used unpurified in the next reaction.