Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N+:4]([CH3:13])([CH3:12])[CH2:5][CH2:6][CH2:7][S:8]([O-:11])(=[O:10])=[O:9].[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([F:50])[C:23]=1[CH2:24][S:25][C:26]1[N:27]([C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)[C:28]([C:31]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([O:41][CH3:42])[CH:35]=2)([CH3:33])[CH3:32])=[CH:29][N:30]=1)[C:18](O)=[O:19].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([F:50])[C:23]=1[CH2:24][S:25][C:26]1[N:27]([C:43]2[CH:44]=[CH:45][C:46]([F:49])=[CH:47][CH:48]=2)[C:28]([C:31]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([O:41][CH3:42])[CH:35]=2)([CH3:33])[CH3:32])=[CH:29][N:30]=1)[C:18]([NH:1][CH2:2][CH2:3][N+:4]([CH3:12])([CH3:13])[CH2:5][CH2:6][CH2:7][S:8]([O-:11])(=[O:9])=[O:10])=[O:19]
Reactant: C[N+](C)(CCN)CCCS(=O)(=O)[O-]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(C(=O)O)cc3Cl)n2-c2ccc(F)cc2)ccc1Cl
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: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(C(=O)NCC[N+](C)(C)CCCS(=O)(=O)[O-])cc3Cl)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 0.33 h
Yield: 63.3 %

Procedure:
A solution of tert-butyl 2-(dimethylamino)ethylcarbamate (1.8 g, 7.98 mmol) and 1,3-sultone (1.07 g, 8.77 mmol) in toluene was heated 4 h at 60° C. to form a white solid. After cooling to room temperature, the solids were collected by filtration and rinsed with hexanes (2×30 mL). The solids were dissolved in DCM (5 mL) and charged dropwise with TFA (5 mL). After 30 min, the reaction mixture was concentrated under reduced pressure to yield 3-((2-aminoethyl)-dimethylammonio)propane-1-sulfonate as a white solid (2.15 g). This quartarnary amine (82 mg, 0.266 mmol) was added to a solution of 3-chloro-4-((5-(2-(4-chloro-3-methoxyphenyl)-propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-5-fluorobenzoic acid (100 mg, 0.1776 mmol) in DMF (1 mL) followed by DIPEA (137 mg, 1.06 mmol) and HATU (74.2 mg, 0.195 mmol). After 20 min, the reaction was determined to be complete by LC-MS. The product mixture was concentrated and purified by HPLC (MeCN/H2O, 10-99%) to yield the title compound as a white solid (85 mg). 1H NMR (400 MHz, MeOD) δ 8.96 (t, J=5.3 Hz, 1H), 7.88 (s, 1H), 7.79 (s, 1H), 7.60 (dd, J=10.0, 1.6 Hz, 1H), 7.28-7.18 (m, 1H), 6.98 (d, J=8.6 Hz, 1H), 6.95 (d, J=8.6 Hz, 1H) 6.57-6.52 (m, 2H), 6.51-6.45 (m, 2H), 4.18 (s, 2H), 3.89 (t, J=5.5 Hz, 2H), 3.75 (s, 3H), 3.68-3.56 (m, 4H), 3.23 (s, 6H), 2.87 (t, J=6.7 Hz, 2H), 2.25 (dt, J=14.2, 7.1 Hz, 2H), 1.60 (s, 6H). LC-MS: 655.3 [M]+.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[S:11][C:12]([C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:26]=[C:25]([CH:27]4[CH2:29][CH2:28]4)[NH:24][N:23]=3)[C:18]([Br:30])=[CH:17][N:16]=2)=[CH:13][CH:14]=1)=[O:9])(=[O:3])[CH3:2].[C:31](OC(=O)C)(=[O:33])[CH3:32]>C1COCC1.O>[C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[S:11][C:12]([C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:26]=[C:25]([CH:27]4[CH2:29][CH2:28]4)[N:24]([C:31](=[O:33])[CH3:32])[N:23]=3)[C:18]([Br:30])=[CH:17][N:16]=2)=[CH:13][CH:14]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCNC(=O)c1ccc(-c2ncc(Br)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)NCCNC(=O)c1ccc(-c2ncc(Br)c(Nc3cc(C4CC4)n(C(C)=O)n3)n2)s1
Yield: 98.6 %

Procedure:
To N-(2-acetamidoethyl)-5-(5-bromo-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophene-2-carboxamide (273.8 mg, 0.56 mmol, 1.0 equiv.), acetic anhydride (114.2 mg, 1.1 mmol, 2.0 equiv.) in THF/H2O (10 ml/1 mL) was stirred at 23° C. for 2 hour. Then the mixture was extracted with THF (6×40 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated give N-(2-acetamidoethyl)-5-(4-(1-acetyl-5-cyclopropyl-1H-pyrazol-3-ylamino)-5-bromopyrimidin-2-yl)thiophene-2-carboxamide (294.0 mg, 98.5%) as pale yellow solid. LC-MS (m/z)=533.1 [M+H]+;
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH2:17]Br)[C:14](=[O:19])[O:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][P:21]([O:25]CC)[O:22][CH2:23][CH3:24]>>[CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH2:17][P:21]([O:22][CH2:23][CH3:24])([CH3:20])=[O:25])[C:14](=[O:19])[O:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OCN(C(=O)OCc2ccccc2)[C@H]1CCBr
Reactant: CCOP(C)OCC
Product: CCOP(C)(=O)CC[C@H]1C(=O)OCN1C(=O)OCc1ccccc1
Temperature: 120 °C
Yield: 81.1 %

Procedure:
5.30 g (16.1 mmol) of (4S)-3-benzyloxycarbonyl-4-(2-bromomethyl)-1,3-oxazolidin-5-one (from Example 5) are mixed with 4.40 g (32.3 mmol) of diethyl methanephosphonite and the mixture is heated under argon for 6 hours at 120° C. The excess diethyl methanephosphonite is distilled off in high vacuum and the residue is purified by chromatography on silica gel (mobile phase: dichloromethane/acetonitrile). 4.64 g (81.1% of theory) of (4S)-3-benzyloxycarbonyl-4-{2-[ethoxy(methyl)phosphinyl]ethyl}-1,3-oxazolidin-5-one are obtained as a colorless oil. Analytical data:
Reaction SMILES: Br[C:2]1[C:3]([F:22])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:18]4[CH2:20][CH2:19]4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:21]=1.[C:23]([C@:25]1([OH:32])[CH2:29][CH2:28][N:27]([CH3:30])[C:26]1=[O:31])#[CH:24]>>[CH:18]1([C:12]2[N:8]3[CH2:9][CH2:10][O:11][C:5]4[CH:4]=[C:3]([F:22])[C:2]([C:24]#[C:23][C@:25]5([OH:32])[CH2:29][CH2:28][N:27]([CH3:30])[C:26]5=[O:31])=[CH:21][C:6]=4[C:7]3=[N:14][C:13]=2[C:15]([NH2:17])=[O:16])[CH2:20][CH2:19]1
Reactant: NC(=O)c1nc2n(c1C1CC1)CCOc1cc(F)c(Br)cc1-2
Reactant: C#C[C@]1(O)CCN(C)C1=O
Product: CN1CC[C@@](O)(C#Cc2cc3c(cc2F)OCCn2c-3nc(C(N)=O)c2C2CC2)C1=O
Yield: 31 %

Procedure:
10-bromo-3-cyclopropyl-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford 14.2 mg (31%) of 3-cyclopropyl-9-fluoro-10-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide. M+1=425.0.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].C([SiH2][O:24][C:25](C)(C)[C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][C:36]=1[Cl:37])[CH2:29][NH:30][C:31](=[O:33])[CH3:32])(C)(C)C.CCOC(C)=O>C1COCC1>[Cl:37][C:36]1[CH:35]=[CH:34][C:28]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])=[CH:27][C:26]=1[CH2:25][OH:24]
Reactant: CC(=O)NCc1ccc(Cl)c(C(C)(C)O[SiH2]C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)NCc1ccc(Cl)c(CO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
TBAF (1M in THF, 12.0 mL, 12.0 mmol) was added to a sol. of N-[3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzyl]-acetamide (2.05 g, 6.00 mmol) in THF (60 mL) at 0° C. The mixture was stirred for 2 h while warming up to rt. EtOAc (100 mL) was added, and the mixture was washed with aq. sat. NH4Cl (1×) and water (4×). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC(CH2Cl2/MeOH 90:10) yielded the title compound (750 mg, 59%). LC-MS: tR=0.63 min; ES+: 237.09.
Reaction SMILES: Cl.[F:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.Cl[C:19]1[N:20]=[C:21]2[CH:29]=[CH:28][N:27]=[CH:26][C:22]2=[N:23][C:24]=1[Cl:25].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:25][C:24]1[N:23]=[C:22]2[CH:26]=[N:27][CH:28]=[CH:29][C:21]2=[N:20][C:19]=1[N:9]1[CH2:8][CH2:7][CH:6]([O:5][C:4]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=2[F:2])[CH2:11][CH2:10]1
Reactant: Clc1nc2ccncc2nc1Cl
Reactant: COc1ccc(OC2CCNCC2)c(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(OC2CCN(c3nc4ccncc4nc3Cl)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.2 %

Procedure:
A mixture of 4-(2-fluoro-4-methoxyphenoxy)piperidine hydrochloride (144 mg, 0.550 mmol), 2,3-dichloropyrido[3,4-b]pyrazine (100 mg, 0.500 mmol) and DIPEA (260 μL, 1.500 mmol) in DCM (1.0 mL) was stirred at room temperature for 30 min. The mixture was then partitioned between EtOAc and saturated aqueous NH4Cl. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was dissolved in EtOAc and filtered through a silica pad. The filtrate was concentrated to afford the crude title compound (200.7 mg, 100%) as a yellow oil, which was used without further purification. ESI-MS m/z [M+F]+ 389.2.
Reaction SMILES: O.O.[C:3]([OH:8])(=O)[C:4](O)=[O:5].[C:9]1([CH3:17])[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([NH2:16])[CH:10]=1.C(O)C.Cl>O>[OH:5][C:4]1[C:3]([OH:8])=[N:16][C:11]2[C:12](=[CH:13][CH:14]=[C:9]([CH3:17])[CH:10]=2)[N:15]=1
Reactant: Cc1ccc(N)c(N)c1
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc2nc(O)c(O)nc2c1
Temperature: 25 °C
Yield: 97 %

Procedure:
A mixture of oxalic acid dihydrate (20 g), 3,4-toluenediamine (20 g), ethanol (60 ml), conc. hydrochloric acid (20 ml) and water (50 ml) was refluxed for 5 hours. After cooling to room temperature, the precipitate was removed by filtration, washed with water and dried to yield 27.1g of 2,3-dihydroxy-6-methylquinoxaline, mp> 300° C. Phosgene was bubbled through a mixture of 27.1 g of the 2,3-dihydroxy compound in 200 ml of p-xylene and 5 ml of DMF at 120° C. The solution was degassed with nitrogen, clarified and the solvent flash evaporated to yield 26.2 g of 2,3-dichloro-6-methylquinoxaline, mp 112°-115° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][C:11]([N+:12]([O-:14])=[O:13])=[C:2]([O:1][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:3]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
REFERENCE: J. Med Chem. 1997, 40, 105-111. To an acetone solution (500 mL) of methyl 3-hydroxy-4-nitrobenzoate (25.0 g, 126.8 mmol) was added cesium carbonate (61.9 g, 190.2 mmol) followed by benzyl bromide (15.0 mL, 126.8 mmol). The reaction was heated to reflux and monitored by TLC. The reaction was judged complete in approximately 7 h. The reaction was then cooled to room temperature and concentrated under reduced pressure to approximately 20 mL. The residue was diluted with ethyl acetate (700 mL) and washed in succession with 1N hydrochloric acid, 1N sodium hydroxide, 1N hydrochloric acid and finally with saturated aqueous sodium chloride. The organic layer was then dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield 3-benzyloxy-4-nitro-benzoic acid methyl ester as a solid. 1H NMR (CDCl3) 7.83(m,2H), 7.70(dd, 1H), 7.50-7.30(m,5H), 5.28(s,2H), 3.96(s,3H).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[CH:24]=[C:23]([CH3:34])[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:25]2[CH:24]=[C:23]([CH3:34])[N:22]=[C:21]([C:17]3[CH:16]=[C:15]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:10]=4)[CH:20]=[CH:19][CH:18]=3)[N:26]=2)=[CH:28][CH:29]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-c2cccc(-c3cccc(S(N)(=O)=O)c3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 63 %

Procedure:
To a cooled and stirred solution of 3′-[4-(4-chloro-phenyl)-6-methyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (0.16 g) in dichloromethane (3 mL) was added TFA (3 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried to yield the title compound as an off-white solid (0.083, 63%). MS (ISP) 436.1 [(M+H)+]; mp 221° C.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH2:9][C:8](=[O:12])[N:7]([CH2:13][CH2:14][CH2:15][CH3:16])[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4].C(N(C(C)C)CC)(C)C.[N:27]([CH2:30][C:31]([O:33]CC)=[O:32])=[C:28]=[O:29]>ClCCl>[CH2:13]([N:7]1[C:8]([OH:12])=[C:9]([C:28]([NH:27][CH2:30][C:31]([OH:33])=[O:32])=[O:29])[C:10](=[O:11])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1=[O:17])[CH2:14][CH2:15][CH3:16]
Reactant: CCOC(=O)CN=C=O
Reactant: CCCCN1C(=O)CC(=O)N(CCCC)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCn1c(O)c(C(=O)NCC(=O)O)c(=O)n(CCCC)c1=O
Reaction time: 24 h
Yield: 64 %

Procedure:
A mixture of 1,3-dibutyl-2,4,6(1H,3H,5H)-pyrimidinetrione (1.3 g mg, 5.5 mmoles) and diisopropylethylamine (1.9 mL, 11.0 mmoles) in dichloromethane (20 mL) was treated with ethyl isocyanatoacetate (673 uL, 6.0 mmoles) and stirred for 24 hours. The mixture was washed with 1 molar hydrochloric acid (×2), dried and evaporated. The residue was taken up in ethanol (5 mL) and treated with 6 molar sodium hydroxide (3 mL) and stirred for 2 hours. The mixture was acidified with 1 molar hydrochloric acid and stirred for 30 minutes to give a solid which was recrystallized from acetic acid-water to afford the title compound (1.2 g, 64%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.10 (br. s., 1 H), 10.11 (t, J=6.19 Hz, 1 H), 4.13 (d, J=5.81 Hz, 2 H), 3.81 (t, 4 H), 1.43-1.63 (m, 4 H), 1.14-1.41 (m, 4 H), 0.89 (t, J=7.33 Hz, 6 H).
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([NH2:9])[NH:6][N:5]=1)([CH3:3])[CH3:2].[C:10]([C:12]([C:22](=O)[CH3:23])=[CH:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)#[N:11].C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([CH:13]2[N:6]3[N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:8]=[C:7]3[NH:9][C:22]([CH3:23])=[C:12]2[C:10]#[N:11])=[CH:15][CH:16]=1)#[N:19]
Reactant: CC(=O)C(C#N)=Cc1ccc(C#N)cc1
Reactant: CC(C)c1n[nH]c(N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1=C(C#N)C(c2ccc(C#N)cc2)n2nc(C(C)C)nc2N1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
Under an atmosphere of argon, 3-isopropyl-1H-1,2,4-triazole-5-amine (241 mg, 1.9 mmol) and 4-(2-cyano-3-oxobut-1-en-1-yl)benzonitrile (300 mg, 1.5 mmol, 0.8 eq.) were dissolved in DMF (3 ml), and solid sodium bicarbonate (803 mg, 9.6 mmol, 5 eq.) was added. The mixture was stirred at 55° C. overnight. The mixture was then filtered and the DMF was distilled off from the filtrate under reduced pressure. The residue was suspended in methanol (2 ml), and the solid was then filtered off and dried under high vacuum (34 mg, 7% of theory). The filtrate was acidified with 1 N hydrochloric acid and purified by preparative HPLC (Kromasil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA), which gave a second product fraction (67 mg, 13% of theory) as a solid.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1.[CH3:24][O:25][CH2:26][CH2:27][NH2:28].[CH2:29](O)C>>[CH3:24][O:25][CH:26]([CH3:29])[CH2:27][NH:28][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1
Reactant: CCCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Reactant: CCO
Reactant: COCCN
Product: CCCOc1ccccc1-c1nc2nc(NCC(C)OC)ncc2c(=O)[nH]1

Procedure:
In a similar manner to Example 13, reaction of 7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.41 g) and methoxyethylamine (1.04 g) in ethanol (15 ml) for 48 hours yielded the title compound, 0.38 g, m.p. 193°-4° C. (recrystallised twice from methanol).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[CH:15]=[C:14]([C:16]3[CH:17]=[N:18][NH:19][CH:20]=3)[S:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:22][CH2:23][N:24]([CH:28](C)C)C(C)C.CN.CN(C([O:40]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.O>[CH3:1][C:2]1([CH3:21])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[CH:15]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:22][C:23]([NH:24][CH3:28])=[O:40])[CH:20]=3)[S:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC1(C)CCCN(C(=O)c2csc(-c3cn[nH]c3)c2)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)Cn1cc(-c2cc(C(=O)N3CCCC(C)(C)CC3)cs2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.3 %

Procedure:
(4,4-Dimethyl-azepan-1-yl)-[5-(1H-pyrazol-4-yl)-thiophen-3-yl]-methanone (0.052 g, 0.14 mmol) was dissolved in THF (1 mL) and DIPEA (32 μL, 0.19 mmol) and methylamine (2 M in THF, 94 μL, 0.19 mmol) were added followed by HATU (0.066 g, 0.17 mmol). The reaction mixture was stirred at room temperature for 2 hours and then diluted with water and extracted with DCM (×3). The organic solution was dried over sodium sulfate, filtered and the solvent evaporated. The residue was purified by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid) over 20 minutes. The fractions containing the desired product were freeze-dried to give the title compound as a white solid (0.029 g). LCMS m/z 375.29 [M+H]+ R.T.=8.49 min (Analytical Method 2).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[S:5][CH:6]=1.C[CH2:15][O:16]CC.C([Li])CCC.CN(C=O)C>CCCCCC>[CH2:9]([O:8][CH:7]([O:11][CH2:12][CH3:13])[C:4]1[S:5][CH:6]=[C:2]([CH:15]=[O:16])[CH:3]=1)[CH3:10]
Reactant: CCOCC
Reactant: CCOC(OCC)c1cc(Br)cs1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOC(OCC)c1cc(C=O)cs1
Temperature: -78 °C
Reaction time: 1 h
Yield: 39.7 %

Procedure:
A solution of 4-bromo-2-(diethoxymethyl)thiophene (500 mg, 0.002 mol) in ether (5 mL, 0.05 mol) was cooled at −78° C. To this solution, 2.5 M n-butyllithium in hexane (0.83 mL) was added dropwise. The reaction was stirred at −78° C. for 1 hour. To the reaction was added DMF (0.4 g, 0.006 mol) at −78° C. and the mixture was stirred for 30 minutes. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by flash column chromatography to yield the 5-(diethoxymethyl)thiophene-3-carbaldehyde as an oil (170 mg, 42.0%). By 1H NMR two different regioisomers of aldehydes were formed and were not separated; (note: NMR shifts are for the major isomer only) 1H NMR (400 MHz, CDCl3): 9.85 (s, 1H), 8.05, (s, 1H), 7.45, (s, 1H), 5.7 (s, 1H), 3.65 (m, 4H), 1.25 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12]([OH:14])=O)=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2([OH:41])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[CH:31][CH:30]=1.C(Cl)Cl>CCOC(C)=O>[OH:41][C:35]1([C:32]2[CH:31]=[CH:30][C:29]([CH2:28][NH:27][C:12]([C:11]3[C:2]([CH3:1])=[N:3][C:4]4[C:9]([CH:10]=3)=[CH:8][CH:7]=[CH:6][N:5]=4)=[O:14])=[CH:34][CH:33]=2)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: Cc1nc2ncccc2cc1C(=O)O
Reactant: NCc1ccc(C2(O)CCCCC2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1nc2ncccc2cc1C(=O)NCc1ccc(C2(O)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 17.5 %

Procedure:
144 mg (0.76 mmol) 2-methyl-1,8-naphthyridine-3-carboxylic acid and 136 mg (0.84 mmol) CDI were refluxed in 5 ml EtOAc for 2 h. The solution was cooled to r.t. and 157 mg (0.76 mmol) 1-(4-(aminomethyl)phenyl)cyclohexanol followed by 5 ml CH2Cl2 was added. The mixture was stirred for 2 days at r.t. Concentrated to dryness and purified by flash chromatography (SiO2, CH2Cl2/MeOH 20:1→10:1) to afford 50 mg (13%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH:13]=[CH2:14])[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].[C:15]1([Si:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[SH:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC(N=NC(C#N)(C)C)(C#N)C.N#N>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH2:13][CH2:14][S:22][Si:21]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6]
Reactant: C=Cc1ccc(C(=O)N(C)C)cc1C
Reactant: S[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: N#N
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)N(C)C)ccc1CCS[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 69 %

Procedure:
A mixture of 3,N,N-trimethyl-4-vinyl-benzamide (706 mg, 3.73 mmol), triphenylsilanethiol (1.76 g, 6.00 mmol) and AIBN (185 mg, 1.13 mmol) in toluene (16 ml) was heated with stirring at 88° C. for two hours in a sealed test tube in an N2 atmosphere. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to give 3,N,N-trimethyl-4-(2-triphenylsilanylsulfanyl-ethyl)-benzamide (1.24 g, 69%).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])C>O1CCOCC1>[N:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:12][CH2:13][CH:8]([C:6]([OH:7])=[O:5])[CH2:9][CH2:10]1
Reactant: CCOC(=O)C1CCN(c2ccccn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)C1CCN(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 89.3 %

Procedure:
Sodium hydroxide solution (5M, 24.8 ml, 0.12 mol) was added drop wise to a solution of 3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester (5.8 g, 24 mmol) (see reference Farmaco, 1993, 48(10), 1439) in 1,4-dioxane (100 mL). The mixture was stirred at room temperature for 72 hours and then evaporated under reduced pressure. The residue was purified by ion exchange chromatography on Dowex® 50 WX8 resin using methanol:0.88 ammonia:water as eluant (gradient from 0:0:100 to 0:5:95 to 5:5:90). The material obtained was triturated with diethyl ether to give the title compound (4.42 g); LCMS: m/z ES+ 288 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([NH2:15])=[CH:13][C:12]([C:16]([CH3:19])([CH3:18])[CH3:17])=[N:11]2)=[CH:6][CH:5]=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14]([NH:15][C:22]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:23])=[CH:13][C:12]([C:16]([CH3:17])([CH3:19])[CH3:18])=[N:11]2)=[CH:8][CH:9]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COC(=O)c1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
To a solution of 4-(5-amino-3-tert-butyl-pyrazol-1-yl)-benzoic acid methyl ester (5.3 g, 19.4 mmol) in anhydrous THF (200 mL) was slowly added phenyl chloroformate (6.81 mL, 54.3 mmol), followed by sodium carbonate (2.1 g, 19.4 mmol). The mixture was stirred at room temperature overnight. Ethyl acetate (500 mL) was added, followed by saturated sodium carbonate (300 mL). The organic layer was washed with saturated sodium carbonate (3×) and brine (1×), dried over MgSO4, and concentrated at reduced pressure. The residue was washed with ether to give 4.3 g (56%) of the desired product. 1H-NMR (DMSO-d6) δ 10.19 (s, 1H), 8.10 (d, J=9.0 Hz, 2H), 7.73 (d, J=9.0 Hz, 2H), 7.38-7.11 (m, 5H), 6.41 (s, 1H), 3.87 (s, 3H), 1.27 (s, 1H); MS LC-MS [M+H]+=394.1, RT=3.53 min.