Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])(=[O:19])=[O:18].[CH2:27]([O:34][C:35]([NH:37][C:38]1[CH:43]=[CH:42][N:41]([CH2:44][C:45](O)=[O:46])[C:40](=[O:48])[N:39]=1)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:45](=[O:46])[CH2:44][N:41]2[CH:42]=[CH:43][C:38]([NH:37][C:35]([O:34][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:36])=[N:39][C:40]2=[O:48])[CH2:22][C:21]1=[O:26])(=[O:19])=[O:18]
Reactant: O=C(O)Cn1ccc(NC(=O)OCc2ccccc2)nc1=O
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2ccccc2s1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccn(CC(=O)N2CCN(S(=O)(=O)c3nc4ccccc4s3)C(=O)C2)c(=O)n1)OCc1ccccc1

Procedure:
The title compound was synthesized by the reaction of 1-(benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [4-N-(benzyloxycarbonyl)-cytosin-1-yl]-acetic acid as per the procedure of Example 52. 1H NMR (500 MHz; DMSO-d6) δ 10.79 (brs, 1H), 8.34 (m, 1H), 8.26 (m, 1H), 7.91 (d, 0.6H), 7.85 (d, 0.4H), 7.45˜7.30 (m, 5H), 7.10 (t, 1H), 5.18 (s, 2H), 4.82 (s, 1.2H), 4.72 (s, 0.8H), 4.45 (s, 0.8H), 4.28 (s, 1.2H), 4.22 (t, 1.2H), 4.07 (t, 0.8H), 3.99 (t, 1.2H), 3.86 (t, 0.8H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].[CH3:17][C:18]1([CH2:22]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:21][O:20][CH2:19]1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:17][C:18]2([CH3:22])[CH2:21][O:20][CH2:19]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: Cc1ccc(S(=O)(=O)OCC2(C)COC2)cc1
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(COc2ccc(Br)cc2C=O)COC1
Temperature: 140 °C
Yield: 50.1 %

Procedure:
To a mixture of 5-bromo-2-hydroxy-benzaldehyde (14 g, 70 mmol), KI (5 g) and K2CO3 (19 g, 140 mmol) in DMF (100 mL) was added toluene-4-sulfonic acid 3-methyl-oxetan-3-ylmethyl ester (18 g, 70 mmol). The mixture was heated at 140° C. for 2 h, and then cooled to room temperature, partitioned between water and ethyl acetate. The organic layer was washed with water for 3 times, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to give the title compound (10 g).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)C.O1CCCC1.[Pd]>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([N:10]2[CH2:9][CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(N2CC=C(c3ccccc3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc(N2CCC(c3ccccc3)CC2)cc1
Yield: 98.2 %

Procedure:
To a solution of 4-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)nitrobenzene (6.4 g) in ethyl alcohol (192 ml) and tetrahydrofuran (192 ml) was added 10% palladium on carbon (0.64 g), and hydrogen gas at atmosphere pressure for 6 hours. The reaction mixture was filtered through celite and evaporated under reduced pressure to give 1-(4-aminophenyl)-4-phenylpiperidine (5.66 g).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:10]([C:14]1[N:15]([CH2:28][CH2:29][CH2:30]Cl)[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[C:18]([NH2:26])[C:17]=2[N:27]=1)[CH2:11][CH2:12][CH3:13]>CN(C)C=O>[CH2:10]([C:14]1[N:15]([CH2:28][CH2:29][CH2:30][S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[C:18]([NH2:26])[C:17]=2[N:27]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCl
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCSc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, benzenethiol (0.68 g, 6.21 mmol), sodium hydride (0.25 g, 60% dispersion, 6.21 mmol), and anhydrous dimethyl formamide (28 mL) under a nitrogen atmosphere. After the reaction mixture had stirred at ambient temperature for 30 minutes, 2-butyl-1-(3-chloropropyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.64 g, 5.18 mmol) was added and the resulting cloudy solution was heated to 80° C. and maintained at 80° C. for 2.5 hours at which time the starting material was completely consumed. The hot solution was poured into rapidly stirred water (200 mL). The resulting mixture was extracted with chloroform (2×). The combined organic layers were washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford a light yellow oil. The material was purified by chromatography over silica gel (95/5 dichloromethane/methanol) to provide 2-butyl-1-[3-(phenylthio)propyl]-1H-imidazo[4,5-c]quinolin-4-amine (1.38 g, 3.53 mmol) as a white solid.
Reaction SMILES: [CH2:1]1[CH2:8][C:7]2[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:6]=2[C:4](=[O:5])[CH2:3][CH2:2]1.[Br:14]Br.O>C(O)(=O)C>[Br:14][CH:3]1[CH2:2][CH2:1][CH2:8][C:7]2[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:6]=2[C:4]1=[O:5]
Reactant: BrBr
Reactant: O=C1CCCCc2ccc(F)cc21
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2cc(F)ccc2CCCC1Br
Yield: 100.2 %

Procedure:
To a stirred solution of 8-fluoro-1-benzosuberone (20.00 g, 112.2 mmol) in glacial acetic acid (125 ml) was added bromine (5.8 ml, 112.6 mmol) dropwise. Once the addition was complete, the solution was poured into water (400 ml) and extracted with EtOAc (500 ml). The extract was separated and washed with water (500 ml). The organic layer was dried over MgSO4, filtered and evaporated to yield 100% (28.9 g) of the desired product as a viscous oil: 1H-NMR (CDCl3) δ 2.00 (2H, m), 2.33 (2H, m), 2.84 (1H, m), 3.00 (1H, m), 4.83 (1H, m), 7.13 (2H, m), 7.29 (1H, dd).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.Cl[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.O>CN(C=O)C>[CH2:3]([O:10][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Clc1ccncc1
Reactant: OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(COc2ccncc2)cc1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
A flask is charged with NaH (60% dispersion in mineral oil, 0.72 g, 18.0 mmol) then suspended in DMF (30 mL) and cooled to 5° C. To this mixture is added benzyl alcohol (1.04 mL, 10.0 mmol) drop-wise. The mixture is stirred for 15 minutes then 4-chloropyridine-HCl (1.00 g, 6.67 mmol) is added in three portions over 5 min. The resulting mixture is stirred at 5° C. for 10 min then warmed to 60° C. and stirred for 1.5 h. The mixture is then cooled to 23° C., treated with water, and extracted with EtOAc. The combined organics are dried with MgSO4, filtered, and concentrated in vacuo. Purification of the crude by flash chromatography (SiO2, 5% EtOAc in hexanes to 50% EtOAc in hexanes) gives the title intermediate (1.10 g, 89%).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[N:11]=[C:10]([C:12]([OH:14])=[O:13])[CH:9]=[CH:8][CH:7]=1.[CH3:15]O>C(Cl)(Cl)Cl>[Cl:5][C:6]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][CH:7]=1
Reactant: CO
Reactant: O=C(O)c1cccc(Cl)n1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(Cl)n1
Yield: 100 %

Procedure:
Add thionyl chloride (3.7 mL, 50.8 mmol) to a solution of 6-chloropicolinic acid (4.0 g, 25.4 mmol) in methanol (85 mL) at 0° C. Stir the resultant solution for 15 minutes at 0° C., 0.5 hours at room temperature, and 6 hours at 50° C. Concentrate the reaction in vacuo and dilute with CHCl3 (150 mL). Wash the organic solution with saturated aqueous sodium bicarbonate (3×100 mL), and brine (1×100 mL) and dry with sodium sulfate. Filtration and concentration afford methyl 6-chloropicolinate 4.38 g (100%) as a white solid.
Reaction SMILES: [O:1]1[CH2:7][CH2:6][C:5]([C:8](O)=[O:9])=[CH:4][C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]1=2.S(Cl)([Cl:17])=O>O1CCCC1>[O:1]1[CH2:7][CH2:6][C:5]([C:8]([Cl:17])=[O:9])=[CH:4][C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]1=2
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1=Cc2ccccc2OCC1
Solvent: C1CCOC1
Product: O=C(Cl)C1=Cc2ccccc2OCC1
Reaction time: 2 h

Procedure:
2,3-Dihydro-benzo[b]oxepine-4-carboxylicacid (2.3 mmol) was dissolved in 15 ml tetrahydrofuran. 0.7 ml of thionylchloride were added dropwise and the solution was stirred for two hours. The reaction was quenched by methanol. Methanol and thionylchloride were removed in vacuo yielding 340 mg of 2,3-Dihydro-benzo[b]oxepine-4-carbonylchloride. This was used for step E without further purification.
Reaction SMILES: [CH:1]1[C:6]2[S:7][CH2:8][CH2:9][CH2:10][O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.CN(C)CCN(C)C.C([Li])CCC.[C:25]([O:28]CC)(=[O:27])C>CCCCCC.Cl>[CH:1]1[C:6]2[S:7][CH2:8][CH2:9][CH2:10][O:11][C:5]=2[C:4]([C:25]([OH:28])=[O:27])=[CH:3][CH:2]=1
Reactant: CCOC(C)=O
Reactant: c1ccc2c(c1)OCCCS2
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: O=C(O)c1cccc2c1OCCCS2
Temperature: 0 °C
Yield: 81 %

Procedure:
To 7,8-dihydro-6H-5-oxa-9-thia-benzocycloheptene (16.2 g, 97 mmol) in 250 mL of dry hexane was added tetramethylethylene diamine (16 mL, 106 mmol). The solution was cooled to 0° C. and n-butyllitium (1.6 M solution in hexane, 73 mL, 116.8 mmol) was slowly added with stirring. A tan-colored precipitate slowly started to form and some gas evolution occured. The suspension was stirred at rt for 18 h, after which CO2 gas was bubbled though it for 20 min. An exothermic reaction occured. The mixture was diluted with 300 mL ethyl acetate and 4 N HCl. After all solids dissolved, the organic layer was washed with 1 N HCl. The acid was extracted into the water layer using sat. NaHCO3. The aqueous layer was washed with ethyl acetate and treated with 10 N HCl to pH 1. Extraction with ethyl acetate (2×250 mL), drying over Na2SO4 and concentration yielded the compound as a tan solid (16.5 g, 81%). MS [M−H]− 209.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][C@H:4]([OH:7])[C@@H:3]1[OH:8].[CH3:9][C:10]1([CH3:35])[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]2[CH:15]=[C:14]([C:22]3[N:27]=[C:26]([N:28]4[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]4)[CH:25]=[CH:24][CH:23]=3)[CH:13]=[CH:12][C:11]1=2.Cl>>[CH3:9][C:10]1([CH3:35])[CH2:19][CH2:18][C:17]([CH3:20])([CH3:21])[C:16]2[CH:15]=[C:14]([C:22]3[N:27]=[C:26]([N:28]4[CH2:33][CH2:32][CH:31]([NH:1][C@@H:2]5[CH2:6][CH2:5][C@H:4]([OH:7])[C@@H:3]5[OH:8])[CH2:30][CH2:29]4)[CH:25]=[CH:24][CH:23]=3)[CH:13]=[CH:12][C:11]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCC(=O)CC4)n3)ccc21
Reactant: N[C@@H]1CC[C@H](O)[C@@H]1O
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCC(N[C@@H]5CC[C@H](O)[C@@H]5O)CC4)n3)ccc21

Procedure:
The preparation is carried out analogously to FS1007 starting from 31 mg (0.199 mmol) of (1S,2R,3R)-3-aminocyclopentane-1,2-diol and 80 mg (0.199 mmol) of 6′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2,3,5,6-tetrahydro-1,2′-bipyridinyl-4-one. The product is in the form of the hydrochloride.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:32])[C:13]([N:14]3[CH2:19][C@H:18]([C:20]([F:23])([F:22])[F:21])[CH2:17][C@H:16]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:33][C:34]1[CH:39]=[C:38]([C:40]([OH:43])([CH3:42])[CH3:41])[CH:37]=[C:36]([F:44])[C:35]=1[C:45]1[N:50]=[C:49]([C:51](O)=[O:52])[CH:48]=[CH:47][C:46]=1[F:54].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:32][C:51]([C:49]3[CH:48]=[CH:47][C:46]([F:54])=[C:45]([C:35]4[C:34]([F:33])=[CH:39][C:38]([C:40]([OH:43])([CH3:42])[CH3:41])=[CH:37][C:36]=4[F:44])[N:50]=3)=[O:52])[C:13]([N:14]3[CH2:19][C@H:18]([C:20]([F:22])([F:21])[F:23])[CH2:17][C@H:16]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(C)(O)c1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@@H](NC(=O)OC(C)(C)C)C[C@@H](C(F)(F)F)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1ccc(F)c(-c3c(F)cc(C(C)(C)O)cc3F)n1)c2N1C[C@@H](NC(=O)OC(C)(C)C)C[C@@H](C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-amino-4-[(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (0.010 g, 0.022 mmol), 6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxylic acid (0.0082 g, 0.026 mmol), HATU (0.022 g, 0.057 mmol) in DMF (0.06 mL) and DIPEA (0.011 mL, 0.065 mmol) was stirred at room temperature for 1 h. The mixture was quenched with 1N NaOH solution and extracted with EtOAc. The organics were combined, dried over Na2SO4 and concentrated to give the sub-title compound as a brown solid. LCMS calc. for C36H40F6N5O6 (M+H)+ m/z=752.3. found: 752.0.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
To a pale yellow solution of N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (55 mg, 104 μmol) in dichloromethane (3 mL) was added TFA (1.48 g, 1000 μL, 13.0 mmol25), the reaction mixture turned orange and was stirred at 25° C. overnight then concentrated. The residue was re-dissolved in 5 mL of a solution of (dichloromethane/MeOH/ammonium hydroxide; 60:10:1) and stirred at 25° C. for 3 h, then evaporated to a light yellow solid, dissolved in dichloromethane (added few drops MeOH and heating) and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane. The pure product suspended in dichloromethane and cyclohexane added to complete solid formation, solid was separated by decantation and dried under high vacuum to give N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (26 mg, 64.9 μmol, 62.7%) as a white solid. MS (M+H)+=401.1 (100% purity); 1H NMR (DMSO-d6) δ: 9.12 (s, 1H), 8.36 (s, 1H), 8.21 (d, J=2.3 Hz, 1H), 7.88 (s, 1H), 7.72 (d, J=9.1 Hz, 1H), 7.35 (dd, J=9.1, 2.3 Hz, 1H), 7.17 (t, J=74.4 Hz, 1H), 1.50 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:14][CH:15]=2)=[O:9])[CH:7]=1.C[Sn](C)(C)[C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1>C1(C)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>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[NH:16][C:13]1[N:12]=[CH:11][C:10]([C:8]([C:6]2[CH:7]=[C:2]([C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)[CH:3]=[CH:4][C:5]=2[O:25][CH3:26])=[O:9])=[CH:15][CH:14]=1
Reactant: COc1ccc(Br)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)nc1
Reactant: C[Sn](C)(C)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1C
Product: COc1ccc(-c2ccncc2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)nc1
Yield: 31.9 %

Procedure:
(5-Bromo-2-methoxy-phenyl)-[6-(2,4-difluoro-phenylamino)-pyridin-3-yl]-methanone (100 mg; 0.24 mmol), 4-trimethylstannylpyridine (115 mg; 0.47 mml) and PdCl2(PPh3)2 (50 mg; 0.07 mmol) are dissolved in xylene (2 ml) and refluxed under argon for 20 min. The reaction mixture is purified via chromatography (SiO2; acetone/hexanes 3/7) and yields the title compound as a colorless foam (32 mg; 32%).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[O:10]1[CH:14]=[CH:13][CH2:12][CH2:11]1>CN(C)C=O>[O:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: C1=COCC1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: CN(C)C=O
Product: O=c1[nH]c(=O)n(C2CCCO2)cc1F
Yield: 60 %

Procedure:
In 20 ml of dimethylformamide were dissolved 1.3 g of 5-fluorouracil. To this solution were added 1.4 g of 2,3-dihydrofuran and the mixture was reacted in an autoclave for 5 hours at 170° C. After completion of the reaction, the reaction liquid was treated in the same manner as described in Example 1 whereby 0.35 g of the starting 5-fluorouracil was recovered as a substance insoluble in chloroform and 1.20 g of 1-(2-tetrahydrofuryl)-5-fluorouracil were obtained. The yield of the end product was 82% based on the consumed 5-fluorouracil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:13]1[O:15][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([NH:27][C:28]([CH:30]1[NH:34][CH:33]2[CH2:35][CH2:36][CH2:37][CH:32]2[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@H:13]([OH:15])[CH2:14][N:34]1[CH:30]([C:28]([NH:27][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:29])[CH2:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH:33]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H]1CO1)OCc1ccccc1
Reactant: CC(C)(C)NC(=O)C1CC2CCCC2N1
Solvent: CCO
Product: CC(C)(C)NC(=O)C1CC2CCCC2N1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Yield: 92.7 %

Procedure:
A solution of 2.98 g of 3(S)-(benzyloxyformamido)-1,2(S)-epoxy-4-phenylbutane and 2.1 g of N-tert.butyl-octahydro-cyclopenta[b]pyrrole-2-carboxamide in 50 ml of ethanol was heated at reflux for 10 hours and the solvent was then removedby evaporation. Chromatography on silica gel using System H for the elutionthen gave 4.7 g of 1-[3(S)-(benzyloxyformamido)-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-octahydro-cyclopenta[b]pyrrole-2-carboxamide as a mixture of four diastereomers: MS: m/e 508 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][CH:10]([N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:18])[CH:8]=2)[O:3]1.Cl.[CH2:21]([N:23]([CH2:26][CH2:27][CH2:28]Cl)[CH2:24][CH3:25])[CH3:22]>CN(C=O)C.CC(=O)OCC>[CH2:21]([N:23]([CH2:24][CH3:25])[CH2:26][CH2:27][CH2:28][O:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[O:3][C:2]([CH3:19])([CH3:1])[CH2:11][CH:10]2[N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])[CH3:22]
Reactant: CCN(CC)CCCCl
Reactant: CN(C1CC(C)(C)Oc2ccc(O)cc21)S(C)(=O)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC)CCCOc1ccc2c(c1)C(N(C)S(C)(=O)=O)CC(C)(C)O2
Temperature: 100 °C
Yield: 48.2 %

Procedure:
0.7g (2.5 mmol) of N-[2,2-dimethyl-6-hydroxychroman-4-yl]-N-methylmethanesulfonamide (Example 15b) was stirred at RT for 1 h with 1.6 g (5.2 mmol) of phosphazene base [tert-butylimino-tri(pyrrolidino)phosphorane] in 2.5 ml of DMF. 0.48 g (2.6 mmol) of diethylaminopropyl chloride hydrochloride was then added and the mixture was heated to 100° C. for 8 h. After stripping off the solvent in vacuo, the residue was taken up in EA and the mixture was washed with water. After drying over magnesium sulfate and chromatography through a short silica gel column, 0.48 g of N-[6-(3-diethylaminopropoxy)-2,2-dimethylchroman-4-yl]-N-methylmethanesulfonamide was obtained as a glassy solid.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:58]1([CH2:63][CH2:64][NH2:65])[CH2:62][CH2:61][CH2:60][CH2:59]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:65][CH2:64][CH2:63][N:58]5[CH2:62][CH2:61][CH2:60][CH2:59]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCN1CCCC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NCCN2CCCC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 2-(pyrrolidin-1-yl)ethanamine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (m, 1 H) 1.38 (m, 2 H) 1.65 (t, J=13.1 Hz, 3 H) 1.79-1.92 (m, 6 H) 2.03 (m, 2 H) 3.08 (m, 2 H) 3.33 (s, 3 H) 3.35 (d, J=5.8 Hz, 2 H) 3.61 (m, 4 H) 3.96 (s, 3 H) 4.12 (t, J=13.0 Hz, 2 H) 4.40-4.58 (m, 1 H) 7.53 (d, J=8.6 Hz, 1 H) 7.56 (s, 1 H) 8.22 (s, 1 H) 8.24 (d, J=1.3 Hz, 1 H) 8.29 (d, J=7.8 Hz, 1 H) 8.7 (dd, J=10.1, 1.3 Hz, 1 H). [M+H] calc'd for C28H37F2N7O3 558; found 558.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][C:11]1[C:12]2[CH:19]=[CH:18][NH:17][C:13]=2[N:14]=[CH:15][N:16]=1)=[O:4].N[C:21]1C=C(C)SC=1C(OC)=O>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH3:21])=[CH:8][C:9]=1[NH:10][C:11]1[C:12]2[CH:19]=[CH:18][NH:17][C:13]=2[N:14]=[CH:15][N:16]=1)=[O:4]
Reactant: COC(=O)c1sc(C)cc1N
Reactant: COC(=O)c1sccc1Nc1ncnc2[nH]ccc12
Product: COC(=O)c1sc(C)cc1Nc1ncnc2[nH]ccc12
Yield: 45 %

Procedure:
The title compound was prepared in an analogous manner as 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methyl ester using methyl 3-amino-5-methylthiophene-2-carboxylate instead of methyl 3-amino-2-thiophenecarboxylate and obtained in 45% yield (HPLC: 99%, RT: 6.89 min). 1H NMR (DMSO-d6) 12.40 (br s, 1H), 10.58 (br s, 1H), 8.44 (s, 1H), 7.96 (br s, 1H), 7.47 (dd, J=3.1, 2.6 Hz, 1H), 6.63 (dd, J=3.3, 1.5 Hz, 1H), 3.82 (s, 3H), 2.55 (s, 3H); MS (m/z) 289 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([CH:16]=1)[CH2:14][CH2:13][S:12]2.[Br:17]N1C(=O)CCC1=O>CN(C)C=O.O>[Br:17][C:16]1[N:15]2[C:11]([S:12][CH2:13][CH2:14]2)=[N:10][C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ccc(-c2cn3c(n2)SCC3)c(Cl)c1
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(-c2nc3n(c2Br)CCS3)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The 6-(2,4-dichlorophenyl)-2,3-dihydroimidazo[2,1-b]thiazole (0.6 g) prepared above and N-bromosuccinimide (0.45 g) were dissolved in dimethylformamide (5 ml). The mixture was heated to reflux and stirred for 18 h at room temperature. The mixture was diluted with water (60 ml) and allowed to crystallize. The liquid was decanted and the residue was dissolved in methylene chloride and dried with magnesium sulfate. The organic residue was chromatographed on silica gel with hexanes/ethyl acetate (3:1) as eluent to give the desired product as a solid (m.p. 200°-202° C.); NMR (CDCl3, 200 MHz) δ: 7.4-7.2 (3H), 4.2 (m, 2H), 3.9 (m, 2H).