Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[C:20]([C:24]1[CH:25]=[C:26]([NH2:43])[N:27]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][N:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)=[CH:31][CH:30]=2)[N:28]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[C:26]([NH:43][C:17](=[O:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:15][CH:14]=2)[N:27]([C:29]2[CH:30]=[CH:31][C:32]([CH2:35][N:36]3[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]3)=[CH:33][CH:34]=2)[N:28]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Reactant: CN1CCN(Cc2ccc(-n3nc(C(C)(C)C)cc3N)cc2)CC1
Product: CN1CCN(Cc2ccc(-n3nc(C(C)(C)C)cc3NC(=O)Cc3ccc(-n4cnc5cccnc54)cc3)cc2)CC1

Procedure:
The title compound is prepared as described in Example 28 but using 2-(4-imidazo[4,5-b]pyridine-3-yl-phenyl)-acetic acid and 5-tert-butyl-2-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl)-2H-pyrazol-3-ylamine. Title compound: ES-MS: 563.10 [M+H]+; tR=2.66 min (System 3).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[CH:8][N:9]=1)(=[O:3])[CH3:2].[CH:10]([C:13]1[O:18][C:17](=[O:19])[C:16]2[CH:20]=[CH:21][CH:22]=[C:23]([C:24]([F:27])([F:26])[F:25])[C:15]=2[N:14]=1)=[CH:11][CH3:12]>>[O:19]=[C:17]([C:16]1[CH:20]=[CH:21][CH:22]=[C:23]([C:24]([F:27])([F:26])[F:25])[C:15]=1[NH:14][C:13](=[O:18])[CH:10]=[CH:11][CH3:12])[CH2:2][C:1]([NH:4][C:5]1[S:6][CH:7]=[CH:8][N:9]=1)=[O:3]
Reactant: CC(=O)Nc1nccs1
Reactant: CC=Cc1nc2c(C(F)(F)F)cccc2c(=O)o1
Product: CC=CC(=O)Nc1c(C(=O)CC(=O)Nc2nccs2)cccc1C(F)(F)F
Yield: 70.6 %

Procedure:
Using the procedure of Step A of Example 1, 19.44 g of 2-acetylamino thiazole and 17.3g of 2-(1-propenyl)-8-trifluoromethyl-4H-3,1-benzoxazin-4-one [prepared by Step A of Example 12 of European patent No. 40,573 from crotonyl chloride and 2-amino-trifluoromethyl benzoic acid] were reacted to obtain 19.03g of β-oxo-2-[(1-oxo-2-butenyl)-amino]-N-(2-thiazolyl)-3-trifluoromethyl-benzene-proponamide melting at 206°-208° C.
Reaction SMILES: Cl[C:2]1[N:12]2[C:13]3[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=1.[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C(=O)(O)[O-].[Na+].O>[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([C:2]2[N:12]3[C:13]4[C:8]([CH2:9][CH2:10][CH2:11]3)=[CH:7][CH:6]=[CH:5][C:4]=4[N:3]=2)[CH2:17][CH2:16]1
Reactant: CN1CCNCC1
Reactant: Clc1nc2cccc3c2n1CCC3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN1CCN(c2nc3cccc4c3n2CCC4)CC1
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
A solution of 2-chloro-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline (4.30 g) in 20 ml of N-methylpiperazine (18.06 g) was heated under reflux, under nitrogen, with stirring. After 30 mins, the solution was diluted with sodium bicarbonate solution (100 ml) and water (200 ml). The aqueous solution was extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by high performance liquid chromatography (silica gel; methanol). The appropriate fractions were collected and evaporated. The residue was crystallized from ether-petroleum ether to give 4.0 g (70%) of product, mp 112°-113° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:5][CH:4]=1.Cl[C:16]1[N:17]([CH3:30])[C:18](=[O:29])[CH:19]=[C:20]([C:22]2[C:27]([F:28])=[CH:26][N:25]=[CH:24][N:23]=2)[N:21]=1.C(N(CC)CC)C.Cl>O1CCCC1>[F:28][C:27]1[C:22]([C:20]2[N:21]=[C:16]([N:11]3[CH2:12][CH2:13][O:14][C@@H:9]([C:6]4[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=4)[CH2:10]3)[N:17]([CH3:30])[C:18](=[O:29])[CH:19]=2)=[N:23][CH:24]=[N:25][CH:26]=1
Reactant: Cn1c(Cl)nc(-c2ncncc2F)cc1=O
Reactant: Fc1ccc([C@H]2CNCCO2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCO[C@@H](c3ccc(F)cc3)C2)nc(-c2ncncc2F)cc1=O
Reaction time: 8 h
Yield: 78 %

Procedure:
To a mixture of (S)-2-(4-fluorophenyl)-morpholine hydrochloride (0.19 g, 0.87 mmol; This compound was synthesized according to WO2007/011065) and 2-chloro-5′-fluoro-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (intermediate 1, 0.20 g, 0.83 mmol) in tetrahydrofuran (5 mL) was added triethylamine (0.35 mL, 2.5 mmol) at room temperature. The reaction mixture was stirred for 8 hours and poured into 1N hydrochloric acid. Extraction with chloroform was performed and the organic phase was dried over anhydrous sodium sulfate. The organic solvent was removed under reduced pressure and the residue was crystallized from ethanol to afford (S)-5′-fluoro-2-[2-(4-fluoro-phenyl)-morpholin-4-yl]-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (0.25 g, 0.65 mmol, 78%) as colorless crystalline.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:18][C@@H:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:16]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:15]1[C:35](=[O:37])[CH3:36])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>O1CCCC1>[CH2:7]([N:14]1[CH2:18][C@@H:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:16]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:15]1[CH:35]([OH:37])[CH3:36])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)C1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)CN1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)C1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)CN1Cc1ccccc1

Procedure:
1 M lithium aluminiumhydride in tetrahydrofuran (1.5 ml, 1.5 mmol) was added slowly to a solution of (3R,4R)-1-benzyl-3,4-dibenzyloxy-2-acetylpyrrolidine (390 mg, 0.94 mmol) in dry tetrahydrofuran (5 ml) at 0-5° C. Stirring was continued for 11/2 hour at room temperature. Water (1 ml) was slowly added. The mixture was filtered and the filtrate was evaporated to dryness in vacuo to give the title compound as an oil. Purification of the crude product on a silica gel column (Eluent: methylene chloride: ethyl acetate (9:1)) afforded (3R,4R)-1-benzyl-3,4-dibenzyloxy-2-(1-hydroxyethyl)pyrrolidine (90 mg, yield 23%) as an oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH:24]([C:28]([O:30][CH3:31])=[O:29])[CH2:23]1.C([O-])([O-])=O.[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.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]>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([N:22]3[CH2:27][CH2:26][CH2:25][CH:24]([C:28]([O:30][CH3:31])=[O:29])[CH2:23]3)[N:3]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: COC(=O)C1CCCNC1
Reactant: COc1ccc(Nc2nc(Cl)nc3scnc23)cc1OC
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
Product: COC(=O)C1CCCN(c2nc(Nc3ccc(OC)c(OC)c3)c3ncsc3n2)C1
Yield: 55.9 %

Procedure:
To a solution of (5-chloro-thiazolo[5,4-d]pyrimidin-7-yl)-(3,4-dimethoxy-phenyl)-amine (80 mg, 0.25 mmol) in 10 mL of dioxane, methyl piperidine-3-carboxylate (107 mg, 0.75 mmol), Cs2CO3 (163 mg, 0.50 mmol), X-Phos (47.6 mg, 0.1 mmol) were added. After degassed three times under nitrogen, Pd2(dba)3 (28 mg, 0.05 mmol) was added. The resulting mixture was degassed one more time, and stirred at reflux overnight. The excess of dioxane was removed under reduced pressure and the residue was purified by silica gel chromatography (200-300 mesh, petroleum ether:ethyl acetate=1:1) to give methyl 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxylate (60 mg, 56%) as an oil, which was solidified after standing overnight. 1H NMR (300 MHz, CDCl3): δ 8.41 (s, 1H), 7.77 (s, 1H), 7.64 (s, 1H), 7.08 (d, 1H, J=9.0 Hz), 6.88 (d, 1H, J=8.7 Hz), 4.92-4.87 (m, 1H), 4.68-4.64 (m, 1H), 3.93 (s, 3H), 3.91 (s, 3H), 3.71 (s, 3H), 3.30-3.22 (m, 1H), 3.10-3.09 (m, 1H), 2.60-2.59 (m, 1H), 2.11-2.06 (m, 1H), 1.85-1.60 (m, 3H). LC-MS: 430.1 [M+H]+, 452.1 [M+Na]+, tR=1.63 min.
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[N:4]([CH2:14][CH2:15][CH2:16][O:17][CH3:18])[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:20][O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>CN(C=O)C>[CH3:20][O:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:2]2[C:3](=[O:19])[N:4]([CH2:14][CH2:15][CH2:16][O:17][CH3:18])[C:5](=[O:13])[C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:24][CH:23]=1
Reactant: COCCCN1C(=O)C(Cl)=C(c2ccccc2)C1=O
Reactant: COc1ccc(N)cc1
Solvent: CN(C)C=O
Product: COCCCN1C(=O)C(Nc2ccc(OC)cc2)=C(c2ccccc2)C1=O
Temperature: 150 °C
Yield: 15 %

Procedure:
3-Chloro-1-(3-methoxypropyl)-4-phenyl-1H-pyrrole-2,5-dione (0.20 mmol, 56 mg) and 4-methoxyaniline (0.48 mmol, 59 mg) were dissolved in DMF (1 mL). The mixture was heated in a microwave reactor at 150° C. for five min. After cooling, the reaction mixture was purified by HPLC (95% 0.1M ammonium acetate buffer: 5% CH3CN→100% CH3CN) to give 11 mg (15%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 7.17 (bs, 1H), 7.14-7.05 (m, 3H), 7.01-6.95 (m, 2H), 6.63-6.52 (m, 4H), 3.71 (t, J=7.0 Hz, 2H), 3.70 (s, 3H), 3.45 (t, J=6.2 Hz, 2H), 3.34 (s, 3H), 1.94 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.O1CCCC1.[CH2:21]([Mg]Br)[CH:22]([CH3:24])[CH3:23].Cl>C/C(/[O-])=C\C(C)=O.C/C(/[O-])=C\C(C)=O.C/C(/[O-])=C\C(C)=O.[Fe+3].CN1CCCC1=O>[CH2:21]([C:2]1[C:11]2[C:6](=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1)[CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)C[Mg]Br
Reactant: Clc1ncnc2c1ccc1ccccc12
Agent: [Fe+3]
Agent: CC(=O)/C=C(\C)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CC(C)Cc1ncnc2c1ccc1ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 24 %

Procedure:
In a 100-mL three-neck flask were put 0.53 g (2.5 mmol) of 4-chlorobenzo[h]quinazoline, 52 mg (0.148 mmol) of tris(2,4-pentanedionato)iron(III) (abbreviation: Fe(acac)3), 25 mL of dehydrated tetrahydrofuran (THF), and 2.0 mL of 1-methyl-2-pyrrolidone (abbreviation: NMP), and the air in the flask was replaced with nitrogen. The flask was cooled with ice, 2.6 mL of isobutylmagnesium bromide solution (1 M in THF) (abbreviation: iBuMgBr) was added, and the mixture was stirred at room temperature for 16 hours. Then, 1 M hydrochloric acid was added, and an organic layer was subjected to extraction with ethyl acetate. The solution of the extract was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. After washing, anhydrous magnesium sulfate was added to the organic layer for drying. The resulting mixture was subjected to gravity filtration, and the filtrate was concentrated to give a residue. The residue was purified by silica gel column chromatography. As the developing solvent, first, dichloromethane was used; then, a 10:1 dichloromethane-ethyl acetate mixed solvent was used. The resulting fraction was concentrated to give 0.14 g of an orange oily substance in a yield of 24%. Synthesis Scheme (b-1) of Step 1 is shown below.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:15]C)=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][CH2:11][CH3:12])[S:7][C:6]=2[C:13]=1[Cl:14].Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[C:3]([OH:15])=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][CH2:11][CH3:12])[S:7][C:6]=2[C:13]=1[Cl:14]
Reactant: CCCc1cc2cc(OC)c(Cl)c(Cl)c2s1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCc1cc2cc(O)c(Cl)c(Cl)c2s1
Yield: 56.3 %

Procedure:
A mixture of 29 g of 6,7-dichoro-5-methoxy-2-n-propylbenzo[b]thiophene and 280 g of pyridine hydrochloride is heated at 190° for 5 hrs and allowed to cool. The reaction mixture is poured into 300 ml of water and extracted with three 33-ml portions of ether. The ether extracts are washed with 500 ml of 2N hydrochloric acid, water, dried over anhydrous magnesium sulfate-charcoal, filtered and evaporated to give an oil. Crystallization of the oil with hexane followed by recrystallization from hexane give 15.5 g of 6,7-dichloro-5-hydroxy-2-n-propylbenzo[b]thiophene, mp 50°-51°.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]3[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=3[C:12]3[CH2:13][N:14]([C@H:19]4[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]4[OH:25])[C:15](=[O:18])[C:16]=3[CH:17]=2)=[CH:4][CH:3]=1.[CH3:30][N:31](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[OH:25][C@H:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C@@H:19]1[N:14]1[CH2:13][C:12]2[C:11]3[CH:26]=[CH:27][CH:28]=[CH:29][C:10]=3[C:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([C:30]#[N:31])=[N:7][CH:6]=3)=[CH:17][C:16]=2[C:15]1=[O:18]
Reactant: O=C1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2CN1[C@H]1CCCC[C@@H]1O
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(Cc2cc3c(c4ccccc24)CN([C@H]2CCCC[C@@H]2O)C3=O)cn1
Temperature: 25 °C

Procedure:
To a solution of 5-[(6-chloropyridin-3-yl)methyl]-2-[(1S,2S)-2-hydroxycyclohexyl]-1,2-dihydro-3H-benzo[e]isoindol-3-one (0.022 g, 0.019 mmol) in 0.5 mL of N,N-dimethylformamide was added zinc cyanide (0.034 g, 0.29 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.039 g, 0.097 mmol). The mixture was irradiated in a microwave reactor at 160° C. for 30 min, cooled to ambient temperature, and purified via preparative reverse phase HPLC and preparative thin layer chromatography, eluting with 50% ethyl acetate in dichloromethane, to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 398.2 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 7.92 (d, J=8.1 Hz, 1H), 7.84 (d, J=8.3 Hz, 1H), 7.66 (s, 1H), 7.64-7.58 (m, 2H), 7.51 (d, J=8.1 Hz, 1H), 7.46-7.44 (m, 1H), 4.87-4.71 (m, 2H), 4.45 (s, 2H), 4.21-4.09 (m, 1H), 3.79-3.64 (m, 1H), 2.70-2.67 (m, 1H), 2.24-2.21 (m, 1H), 2.01-1.98 (m, 1H), 1.87-1.83 (m, 1H), 1.72-1.61 (m, 1H), 1.56-1.38 (m, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[CH3:6].NC(N)=O.[N+:19]([O-])([O-:21])=[O:20].[K+]>S(=O)(=O)(O)O>[CH3:1][O:2][CH2:3][CH2:4][N:5]([C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[C:11]([N+:19]([O-:21])=[O:20])[CH:12]=1)[CH3:6]
Reactant: O=[N+]([O-])[O-]
Reactant: COCCN(C)c1ccc(OC)cc1
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COCCN(C)c1ccc(OC)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.3 %

Procedure:
To a stirred solution of 600 mg (3.07 mmol) (2-methoxy-ethyl)-(4-methoxy-phenyl)-methyl-amine in 1.3 ml concentrated sulfuric acid at room temperature was added 222 mg (3.69 mmol) urea. After stirring for 1 h at room temperature, a solution of 342 mg (3.38 mmol) potassium nitrate in 0.6 ml concentrated sulfuric acid was added dropwise and stirring continued for a further 16 h. The mixture was then poured onto water amd extracted five times with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (1/9 ethyl acetate/hexane) afforded 260 mg (35%) (2-methoxy-ethyl)-(4-methoxy-3-nitro-phenyl)-methyl-amine as an orange oil. ES-MS m/e (%): 241 (M+H+, 100).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[C:10](=[O:28])[C:11]([C:13]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15][C:14]=1[NH:20]C(=O)OC(C)(C)C)=O.[F-].[Cs+].C[Si]([N:35]=[C:36]=[N:37][Si](C)(C)C)(C)C.Cl>C(#N)C.ClCCl>[NH2:35][C:36]1[N:37]=[C:11]([C:10]([N:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:1]2)=[O:28])[C:13]2[C:14](=[CH:15][CH:16]=[C:17]([I:19])[CH:18]=2)[N:20]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1C(=O)C(=O)N1Cc2ccccc2C1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: ClCCl
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(I)ccc2n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
24.50 g of tert-butyl {2-[2-(1,3-dihydroisoindol-2-yl)-2-oxoacetyl]-4-iodophenyl}carbamate are dissolved in 500 ml of acetonitrile under argon. 0.756 g of caesium fluoride is added, and 16.887 ml of bis(trimethylsilyl)-carbodiimide are added dropwise to the solution over 5 min. The mixture is stirred at room temperature for 15 min, and 400 ml of dichloromethane are added. After addition of 400 ml of hydrochloric acid (1N), the product precipitates out as a white solid. Yield: 14 g of (2-amino-6-iodoquinazolin-4-yl)-(1,3-dihydroisoindol-2-yl)methanone; LC-MS retention time: 1.655 min;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([N:25]2[CH:29]=[C:28]([CH2:30][CH2:31][N:32]3CC[O:35][CH2:34][CH2:33]3)[N:27]=[N:26]2)[CH:22]=[CH:21][C:20]=1[CH3:38])=[O:18].ClC1C=C(NC2C=CC(F)=CC=2F)C=CC=1C(C1C=C(N2C=C(CCOS(C3C=CC(C)=CC=3)(=O)=O)N=N2)C=CC=1C)=O.NCCO>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([N:25]2[CH:29]=[C:28]([CH2:30][CH2:31][NH:32][CH2:33][CH2:34][OH:35])[N:27]=[N:26]2)[CH:22]=[CH:21][C:20]=1[CH3:38])=[O:18]
Reactant: Cc1ccc(-n2cc(CCN3CCOCC3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: Cc1ccc(S(=O)(=O)OCCc2cn(-c3ccc(C)c(C(=O)c4ccc(Nc5ccc(F)cc5F)cc4Cl)c3)nn2)cc1
Solvent: NCCO
Product: Cc1ccc(-n2cc(CCNCCO)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 138, using compound 435 (0.24 mmol) and 2-amino-ethanol (0.5 mL). The crude product was purified by continuous gradient flash chromatography using MeOH/DCM 0:100 to 15:85 as the eluent to afford the title compound as yellow foam.
Reaction SMILES: CS(O)(=O)=O.C(OC([NH:13][C@H:14]([C:19]([OH:21])=[O:20])[C:15]([CH3:18])([CH3:17])[CH3:16])=O)(C)(C)C.C(N(CC)CC)C>C(Cl)Cl>[NH2:13][C@H:14]([C:19]([OH:21])=[O:20])[C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methanesulfonic acid (576 mg, 6 mmol) was added to a solution of (S)—N-(tert-butoxycarbonyl)-tert-leucine (1155 mg, 5 mmol) and methylene chloride (5 mL), and the mixture was stirred at 25° C. for 3 hours. When triethylamine (708 mg, 7 mmol) was added thereto, a solid was precipitated. The solid was sufficiently precipitated, and then the solution was stirred at 25° C. for 30 minutes and further stirred at 25° C. for 30 minutes. Thereafter, the solid was separated by filtration under reduced pressure. The solid was washed with methylene chloride (5 mL), and then was subjected to vacuum drying. Thereby, the titled compound was produced as a white solid (514 mg, yield of 75%).
Reaction SMILES: [CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][C:23]=1[CH3:32]>CO>[NH2:31][S:28]([C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:14]([C:10]2[CH:9]=[C:8]([N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH2:17][CH:18]3[CH2:20][CH2:19]3)[N:13]=[CH:12][N:11]=2)=[O:16])=[C:23]([CH3:32])[CH:24]=1)(=[O:29])=[O:30]
Reactant: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Reactant: Cc1cc(S(N)(=O)=O)ccc1N
Solvent: CO
Product: Cc1cc(S(N)(=O)=O)ccc1NC(=O)c1cc(N(CC2CC2)C2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-[cyclohexyl(cyclopropylmethyl)amino]pyrimidine-4-carboxylic acid (Intermediate 13) and 4-amino-3-methyl-benzenesulfonamide (Biofine), the title compound was obtained as an off-white solid after trituration in methanol.
Reaction SMILES: CC(C)([O-])C.[K+].[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([O-:9])=[O:8].Cl.Cl[CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][N:22]([CH3:26])[CH2:21]1>CN(C=O)C.[OH-].[Na+]>[CH3:26][N:22]1[CH2:23][CH2:24][CH2:25][CH:20]([CH2:19][O:16][C:13]2[CH:14]=[CH:15][C:10]([N+:7]([O-:9])=[O:8])=[CH:11][CH:12]=2)[CH2:21]1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CN1CCCC(CCl)C1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCCC(COc2ccc([N+](=O)[O-])cc2)C1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
1 M potassium t-butoxide (50.6 mL) was added dropwise to 4-nitrophenol Compound 35a (7.03 g, 50.6 mmol) in DMF (100 mL) at 0° C. After 20 mins, 3-chloromethyl-1-methylpiperidine hydrochloride Compound 35b (9.31 g, 50.6 mmol, neutralized prior to addition) in DMF (10 mL) was added to the reaction mixture. The reaction was then heated at 100° C. for 5 days. The cooled reaction was diluted with 1 N NaOH and washed with ethyl ether. The aqueous layer was then adjusted to pH 5 with NaH2PO4 and extracted with ethyl acetate. After drying over MgSO4, the organic layer was evaporated down to give 6.0 g of 1-methyl-3-(4-nitro-phenoxymethyl)-piperidine Compound 35c. Using the procedure of Example 1, Compound 35c was used in place of Compound 1n3 and carried forward to prepare 4-(1-methyl-piperidin-3-ylmethoxy)-phenylamine Compound 35d.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]1.[C:16]([O-])(=[O:18])[CH3:17].[Na+].C(C1C(=O)CC(C2C=CC(F)=CC=2)CC1=O)(=O)C>>[C:16]([CH:11]1[C:12](=[O:14])[CH2:13][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:9][C:10]1=[O:15])(=[O:18])[CH3:17]
Reactant: O=C1CC(=O)CC(c2ccccc2F)C1
Reactant: CC(=O)[O-]
Agent: CC(=O)C1C(=O)CC(c2ccc(F)cc2)CC1=O
Agent: [Na+]
Product: CC(=O)C1C(=O)CC(c2ccccc2F)CC1=O

Procedure:
The title compound was prepared from 5-(2-fluoro-phenyl)-cyclohexane-1,3-dione (770 mg, 3.74 mmol), example 1/b stage 2, and sodium acetate (307 mg, 3.74 mmol), following the procedure describing the synthesis of 2-acetyl-5-(4-fluoro-phenyl)-cyclohexane-1,3 dione (example 3/a stage 1).
Reaction SMILES: Cl[C:2]1[NH:7][C:6](=[O:8])[N:5]([CH:9]([CH3:11])[CH3:10])[C:4](=[O:12])[CH:3]=1.[CH3:13][C@H:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCCCCC>O1CCOCC1>[CH:9]([N:5]1[C:4](=[O:12])[CH:3]=[C:2]([NH:21][C@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:13])[NH:7][C:6]1=[O:8])([CH3:11])[CH3:10]
Reactant: C[C@H](N)c1ccccc1
Reactant: CC(C)n1c(=O)cc(Cl)[nH]c1=O
Solvent: CCCCCC
Solvent: C1COCCO1
Product: CC(C)n1c(=O)cc(N[C@@H](C)c2ccccc2)[nH]c1=O
Temperature: 80 °C
Reaction time: 24 h
Yield: 68.9 %

Procedure:
To a solution of 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (1.3, 1.0 g, 5.31 mmol) in 1,4-dioxane (20 mL) was added (S)-α-methylbenzylamine (Sigma-Aldrich, 1.43 g, 11.7 mmol, 2.2 equiv). The reaction mixture was stirred at 80° C. for 24 h. After cooling to ambient temperature, the mixture was concentrated under reduced pressure. The residual was taken up in EtOAc (70 mL) and washed with aqueous 1N HCl (2×50 mL) and brine (40 mL). The organic layer was dried with anhydrous Na2SO4 and then concentrated under reduced pressure to half the original volume to yield a precipitate. Hexane (20 mL) was added and the mixture was stirred at room temperature. The resulting solid was collected by filtration, washed with hexane (20 mL), and dried to yield 1.0 g (69%) of the title compound as a white solid. LC/MS: m/z (ES+) 274 (M+H)+.1H-NMR (400 MHz, d6-DMSO): δ 9.77 (s, 1H), 7.32 (m, 4H), 7.24 (m, 1H), 6.50 (d, J=6.8 Hz, 1H), 4.87 (m, 1H), 4.52 (m, 1H), 4.31 (d, J=6.8 Hz, 1H), 1.37 (m, 3H), 1.24 (m, 6H). 1H NMR (400 MHz, CD3OD) δ ppm 7.39-7.20 (m, 5H), 5.01 (m, 1H), 4.48 (m, 1H), 1.49 (d, J=6.7 Hz, 3H), 1.36 (m, 6H).