Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:32]([O:39]CC)([O:36][CH2:37][CH3:38])[O:33][CH2:34][CH3:35]>C1(C)C(C)=CC=CC=1>[C:1]1([C:7]2[N:8]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][P:32]([O:36][CH2:37][CH3:38])(=[O:39])[O:33][CH2:34][CH3:35])[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOP(OCC)OCC
Reactant: BrCCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Solvent: Cc1ccccc1C
Product: CCOP(=O)(CCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1)OCC
Yield: 34.7 %

Procedure:
A mixture of 2,4,5-triphenyl-1-(7-bromoheptyl)-imidazole (0.95 g) and triethyl phosphite (1.66 g) in xylene (5 ml) was heated at reflux temperature for 20 hours. The mixture was evaporated to an oil and chromatographed on silica gel (ethyl acetate/ethanol) to give diethyl 7-(2,4,5-triphenylimidazol-1-yl)heptane-phosphonate (0.37 g, 35%) as a light brown oil.
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:10]([O-:13])(=[S:12])[CH3:11].[K+]>CN(C=O)C>[CH2:6]([O:5][C:3](=[O:4])[C:2]([S:12][C:10](=[O:13])[CH3:11])([CH3:9])[CH3:8])[CH3:7]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)SC(C)=O
Reaction time: 16 h
Yield: 72.3 %

Procedure:
To a solution of ethyl α-bromoisobutyrate (62 g, 0.32 mol) in DMF (500 mL) at room temperature is added potassium thioacetate (72 g, 0.63 mol). The reaction is stirred for 16 h and then concentrated under reduced pressure. The residue is diluted with a 2 M aq. HCl solution (500 mL) and extracted with EE (3×500 mL). The organic fractions are combined, washed with brine (300 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Purification by chromatography on silica eluting with heptanes/DCM provides 44 g of 2-acetylsulfanyl-2-methyl-propionic acid ethyl ester. Yield: 73%; ESI-MS: 191 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[S:15][CH:14]=[N:13][C:12]=3[CH:11]=[C:10]([CH3:17])[C:9]=2[C@H:18]([OH:21])[CH2:19][OH:20])=[CH:4][CH:3]=1.ClCCl.[CH3:25][C:26]([CH3:31])([CH3:30])[C:27](Cl)=[O:28]>N1C=CC=CC=1.C(OCC)(=O)C>[C:27]([O:20][CH2:19][C@H:18]([C:9]1[C:10]([CH3:17])=[CH:11][C:12]2[N:13]=[CH:14][S:15][C:16]=2[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[OH:21])(=[O:28])[C:26]([CH3:31])([CH3:30])[CH3:25]
Reactant: Cc1cc2ncsc2c(-c2ccc(Cl)cc2)c1[C@H](O)CO
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc2ncsc2c(-c2ccc(Cl)cc2)c1[C@H](O)COC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-1-(7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)ethane-1,2-diol (5H) (0.018 g, 0.056 mmol) in pyridine (0.5 mL)/dichloromethane (1 mL) was added trimethylacetyl chloride (0.010 mL, 0.081 mmol). Reaction mixture was stirred for 1 h at room temperature and additional trimethylacetyl chloride (0.020 ml 0.081 mmol) was added and left it overnight at room temperature. More trimethylacetyl chloride (0.030 ml, 0.242 mmol) was added to the mixture and stirred at room temperature for 30 min. Reaction mixture was diluted with ethyl acetate. Organic layer was washed with saturated sodium bicarbonate solution, dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 0 to 50% ethyl acetate/hexanes). LCMS-ESI+: calc'd for C21H22ClNO3S: 404.1 (M+H+). Found: 404.1 (M+H+).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([NH:22][CH2:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[N:16]=3)[C:12]([Cl:30])=[CH:11][N:10]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.CC1C=CC(S(O[CH2:51][C@@H:52]2[CH2:56][O:55][C:54]([CH3:58])([CH3:57])[O:53]2)(=O)=O)=CC=1>CN(C=O)C.O>[Cl:21][C:20]1[C:15]([C:13]2[C:12]([Cl:30])=[CH:11][N:10]=[C:9]([NH:8][C@H:5]3[CH2:6][CH2:7][C@H:2]([NH:1][CH2:51][C@@H:52]4[CH2:56][O:55][C:54]([CH3:58])([CH3:57])[O:53]4)[CH2:3][CH2:4]3)[CH:14]=2)=[N:16][C:17]([NH:22][CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:18][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Reactant: N[C@H]1CC[C@H](Nc2cc(-c3nc(NCC4CCOCC4)ccc3Cl)c(Cl)cn2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OC[C@@H](CN[C@H]2CC[C@H](Nc3cc(-c4nc(NCC5CCOCC5)ccc4Cl)c(Cl)cn3)CC2)O1
Temperature: 75 °C

Procedure:
To a stirred solution of N2′-(trans-4-aminocyclohexyl)-3,5′-dichloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine (68 mg, 0.151 mmol) in DMF (0.2 ml) was added DIPEA (80 μL, 0.458 mmol) followed by (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (42 mg, 0.147 mmol). The mixture was heated at 75° C. for 19 hours. The mixture was allowed to cool, then diluted with water and then extracted with EtOAc (×3). The organics were combined then washed with water (×2), saturated brine (×2), then dried (Na2SO4), filtered and evaporated under reduced pressure. The resulting residue was purified by reverse phase prep HPLC and lyaphllized to yield 3,5′-dichloro-N2′-(trans-4-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)aminocyclohexyl)-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine (4.4 mg), LCMS (m/z): 564.4/566.3 (bis-chloro isotopic signature for MH+) retention time=0.65 min as a TFA salt.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:25])[CH2:22][CH2:23][CH3:24]>C(Cl)Cl>[C:21]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:25])[CH2:22][CH2:23][CH3:24]
Reactant: CCCC(=O)Cl
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)NCCCSc1ccncc1
Yield: 91.1 %

Procedure:
To a solution of 700 mg (2.90 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 1.62 ml (11.6 mmol) of triethylamine in 30 ml of methylene chloride was added 0.36 ml (3.48 mmol) of butyryl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: methanol/ethyl acetate=1:1) to obtain 630 mg of the desired compound (91.1%, pale yellow oil).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1C.C(N(CC)CC)C.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>C1COCC1>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31](=[O:32])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(N)c(C)c1
Reactant: COc1ccccc1N=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(NC(=O)Nc2ccccc2OC)cc1
Reaction time: 23 h
Yield: 100.8 %

Procedure:
To a stirred solution of ethyl 4-amino-3-methylphenylacetate (1.32 g, 7.37 mmol) and triethylamine (205 ml, 1.47 mmol) in THF (20 ml) was added 2-methoxyphenyl isocyanate (980 ml, 7.37 mmol), and the resulting mixture was stirred for 23 h. The mixture was concentrated to a small volume in vacuo and hexane was added to the residue to give precipitate, which was collected to give ethyl 4-[N′-(2-methoxyphenyl)ureido]phenylacetate (2.44 g, quant.) as a white crystalline material. mp 107–109° C.; 1H-NMR (CDCl3) δ 1.26 (t, J=7.1 Hz, 3 H), 3.56 (s, 3 H), 3.79 (s, 3 H), 4.15 (q, J=7.1 Hz, 2 H), 6.82–6.85 (m, 1 H), 6.91–7.00 (m, 2 H), 7.08 (s, 1 H), 7.17 (d, J=8.5 Hz, 2 H), 7.27 (d, J=8.6 Hz, 2 H), 7.33 (s, 1 H), 8.07–8.10 (m, 1 H); MS (ESI) m/z 329 (M++H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:8]1[CH:9]=[C:10]2[C:19](=[C:20]3[C:25]=1[CH:24]=[CH:23][CH:22]=[N:21]3)[NH:18][S:17](=[O:27])(=[O:26])[C:16]1[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=1.C1CCN2C(=NCCC2)CC1.C1C[O:42][CH2:41]C1>>[O:26]=[S:17]1(=[O:27])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[C:19](=[C:20]3[C:25](=[C:8]([C:41]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:42])[CH:9]=2)[CH:24]=[CH:23][CH:22]=[N:21]3)[NH:18]1
Reactant: C1COCCN1
Reactant: C1CCOC1
Reactant: O=S1(=O)Nc2c(cc(Br)c3cccnc23)-c2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(c1cc2c(c3ncccc13)NS(=O)(=O)c1ccccc1-2)N1CCOCC1
Temperature: 150 °C
Yield: 6 %

Procedure:
Morpholine was added to a suspension of 12-bromo-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide 545 (100 mg, 0.28 mmol), Hermann's palladacycle (13 mg, 14 μmol), Mo(CO)6 (73 mg, 0.28 mmol), DBU (126 mg, 0.83 mmol) and THF (2 ml) in a microwave vessel. The vessel was sealed under air and the mixture was heated in the microwave at 150° C. for 15 min. After cooling, the mixture was concentrated in vacuo. The residue was diluted with MeOH (2 ml), filtered and the filtrate was purified by preparative HPLC (acidic conditions 1) to give the title compound (6 mg, 6%).
Reaction SMILES: [S:1]=[P:2]1(Cl)[NH:6][CH2:5][CH:4]([CH3:7])[O:3]1.C1(C)C=CC=CC=1.[CH3:16][CH2:17][O-:18].[Na+]>C(O)C>[S:1]=[P:2]1([O:18][CH2:17][CH3:16])[NH:6][CH2:5][CH:4]([CH3:7])[O:3]1
Reactant: CC[O-]
Reactant: CC1CNP(=S)(Cl)O1
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOP1(=S)NCC(C)O1
Reaction time: 2 h
Yield: 82.8 %

Procedure:
18 g (0.1 mol) of 2-thioxo-2-chloro-5-methyl-1,3,2-oxazaphospholane were initially introduced into 100 ml of toluene, and a solution of 0.1 mol of sodium ethylate in ethanol was added dropwise at an internal temperature of between 10° and 15° C. The reaction mixture was stirred for a further two hours, washed with water, dried and filtered and the filtrate was distilled. 15 g (83% of theory) of 2-thioxo-2-ethoxy-5-methyl-1,3,2-oxazaphospholane were obtained as a colorless liquid of boiling point 78° C./0.01 mbar and of refractive index nD23 : 1.5041.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].C(N(CC)CC)C.Cl[CH2:15][O:16][CH:17]1[CH:24]2[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:26][CH:18]1[CH2:19]3)[CH2:23]2>O1CCCC1>[CH:18]12[CH2:26][CH:22]3[CH2:21][CH:20]([CH2:25][CH:24]([CH2:23]3)[CH:17]1[O:16][CH2:15][O:5][C:1](=[O:6])[C:2]([CH3:4])=[CH2:3])[CH2:19]2
Reactant: ClCOC1C2CC3CC(C2)CC1C3
Reactant: C=C(C)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCOC1C2CC3CC(C2)CC1C3
Temperature: 25 °C

Procedure:
6.9 g of methacrylic acid was dissolved in 200 ml of tetrahydrofuran, and 8.0 g of triethylamine was added. Following stirring at room temperature, a solution containing 15 g of 2-adamantyl chloromethyl ether dissolved in 100 ml of tetrahydrofuran was added dropwise to the reaction solution. Following stirring for 12 hours at room temperature, the precipitated salt was removed by filtration. The solvent was removed from the remaining filtrate by evaporation, the residue was dissolved in 200 ml of ethyl acetate, and following washing with pure water (100 ml×3), the solvent was removed by evaporation. The residue was then allowed to stand under ice cooling, thereby yielding a white solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:11]=[C:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[NH:16][C:15]3[N:23]=[CH:24][CH:25]=[CH:26][C:14]=3[N:13]2[C:27]=1[C:28]1[CH:33]=[CH:32][C:31]([C:34]2([NH:38]C(=O)OC(C)(C)C)[CH2:37][CH2:36][CH2:35]2)=[CH:30][CH:29]=1.[ClH:46].O1CCOCC1>C(Cl)Cl>[ClH:46].[ClH:46].[ClH:46].[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:11]=[C:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[NH:16][C:15]3[N:23]=[CH:24][CH:25]=[CH:26][C:14]=3[N:13]2[C:27]=1[C:28]1[CH:29]=[CH:30][C:31]([C:34]2([NH2:38])[CH2:37][CH2:36][CH2:35]2)=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4nc5ccccc5s4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC1(c2ccc(-c3c(-c4nc5ccccc5s4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.4 %

Procedure:
tert-Butyl (1-{4-[2-(1,3-benzothiazol-2-yl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutyl)carbamate (24.8 mg, 0.0405 mmol) was dissolved in DCM (1 mL). 4M HCl/dioxane (1 mL) was added to the mixture and stirred at room temperature for 18 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (21.8 mg, 86.4%) as yellow solid. 1HNMR (DMSO-d6) 400 MHz δ: 8.85-8.65 (m, 3H), 8.16 (dd, J=4.8, 1.6 Hz, 1H), 8.11-8.07 (m, 1H), 7.97 (dd, J=7.8, 1.8 Hz, 1H), 7.83-7.78 (m, 1H), 7.65-7.55 (m, 4H), 7.51-7.46 (m, 1H), 7.45-7.39 (m, 2H), 7.37-7.32 (m, 1H), 7.21-7.15 (m, 1H), 6.98 (dd, J=8.0, 1.6 Hz, 1H), 6.79 (dd, J=8.0, 4.8 Hz, 1H), 2.66-2.54 (m, 4H), 2.28-2.15 (m, 1H), 1.92-1.77 (m, 1H); LCMS: 513 [M+H].
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH:5]([CH:7]([N:24]2[C:28](=[O:29])[C:27]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]3[C:25]2=[O:34])[C:8]([O:10][CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[O:4][NH:3]1.[N+](=[CH2:37])=[N-].CCOCC>C(Cl)Cl>[CH3:37][O:1][C:2]1[CH2:6][CH:5]([CH:7]([N:24]2[C:25](=[O:34])[C:26]3=[CH:33][CH:32]=[CH:31][CH:30]=[C:27]3[C:28]2=[O:29])[C:8]([O:10][CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])[O:4][N:3]=1
Reactant: C=[N+]=[N-]
Reactant: O=C1CC(C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)c3ccccc3C2=O)ON1
Solvent: CCOCC
Solvent: ClCCl
Product: COC1=NOC(C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)c3ccccc3C2=O)C1

Procedure:
To 90 mg. (0.2 mmole) of 3-oxo-α-phthalimido 5-isoxazolidine acetic acid, benzhydryl ester (IIa) in 5 ml of methylene chloride is added a 50% molar excess of a standard etheral diazomethane solution. A 5 μl. amount of βF3.Et2O is added and, after 30 minutes, the reaction is concentrated and the residue chromatographed on preparative TLC (AIX eluent) to yield (45 mg) of 3-methoxy-4,5-dihydro-α-phthalimido-5-isoxazole acetic acid, benzhydryl ester.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH:28]([CH3:32])[C:29](O)=[O:30])[CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[CH3:35][N:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1.C1C=NC=C(C2NC(C(F)(F)F)=CN=2)C=1>>[CH3:35][N:36]1[CH2:41][CH2:40][CH:39]([NH:42][C:29](=[O:30])[CH:28]([N:26]2[CH:27]=[C:23]([C:21]3[CH:20]=[N:19][N:18]4[C:14]([C:10]5[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:33])([F:34])[F:1])=[O:6])[CH:9]=5)=[CH:15][N:16]=[C:17]4[CH:22]=3)[CH:24]=[N:25]2)[CH3:32])[CH2:38][CH2:37]1
Reactant: CN1CCC(N)CC1
Reactant: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Agent: FC(F)(F)c1cnc(-c2cccnc2)[nH]1
Product: CC(C(=O)NC1CCN(C)CC1)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid and 1-methylpiperidin-4-amine (ABCR and Cat. No. MK534). LCMS (M+H)+: m/z=570.2.
Reaction SMILES: C[N+]1([O-])CCOCC1.[Si:9]([O:26][CH2:27][C:28]1[C:29]([N:44]2[CH2:49][C@H:48]([CH3:50])[O:47][C@H:46]([CH3:51])[CH2:45]2)=[C:30]([F:43])[C:31]([F:42])=[C:32]([CH:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[OH:35])[CH:33]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl.CC#N.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[Si:9]([O:26][CH2:27][C:28]1[C:29]([N:44]2[CH2:45][C@H:46]([CH3:51])[O:47][C@H:48]([CH3:50])[CH2:49]2)=[C:30]([F:43])[C:31]([F:42])=[C:32]([C:34]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[O:35])[CH:33]=1)([C:22]([CH3:24])([CH3:23])[CH3:25])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(O)c3ccccc3)c(F)c2F)C[C@H](C)O1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)c3ccccc3)c(F)c2F)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
NMO (428 mg, 0.0037 mmol) and TPAP (65 mg, 0.0002 mmol) were added to a stirred solution of {5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2,3-difluorophenyl}(phenyl)methanol (Intermediate 17, 1.1 g, 0.002 mmol) in CH2Cl2:CH3CN (1:1, 10 mL) 0° C. The mixture was allowed to warm to room temperature with stirring for 12 hours. The solvents were removed, and the residue was purified over a silica gel chromatography column using an ethyl acetate-pet. ether gradient, providing the title compound. Yield: 1 g, (92%)
Reaction SMILES: [ClH:1].Cl.Cl.[CH3:4][N:5]1[CH2:10][CH2:9]C[CH:7]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:6]1.[O:17]=[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]([C:27]([Cl:29])=[O:28])[CH2:19]1.C([N:32](CC)CC)C>>[ClH:29].[ClH:1].[CH3:4][N:5]1[CH2:10][CH2:9][N:32]([C:27]([CH:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18](=[O:17])[CH2:19]2)=[O:28])[CH:7]([CH2:11][N:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[CH2:6]1
Reactant: O=C1CC(C(=O)Cl)c2ccccc21
Reactant: CCN(CC)CC
Reactant: CN1CCCC(CN2CCCC2)C1
Agent: Cl
Product: CN1CCN(C(=O)C2CC(=O)c3ccccc32)C(CN2CCCC2)C1

Procedure:
The procedure described in Example 24 was repeated, but using 3.21 g of 1-methyl-3-(pyrrolidin-1-ylmethyl)piperidine trihydrochloride, 6.9 ml of triethylamine and 4.5 g of 3-oxoindan-1-carbonyl chloride, to afford 1.45 g of the title compound, melting at 252°-255° C. (dec.).
Reaction SMILES: Br[C:2]#[N:3].O.[Cl:5][C:6]1[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10](N)[C:9]([NH2:17])=[CH:8][CH:7]=1.C(#[N:20])C>CO>[Cl:5][C:6]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]2[NH:17][C:2]([NH2:3])=[N:20][C:8]=2[CH:7]=1
Reactant: CC#N
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1N
Reactant: N#CBr
Solvent: CO
Solvent: O
Product: Nc1nc2cc(Cl)c(C(F)(F)F)cc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
318 mg (3 mmol) BrCN are dissolved in 0.6 ml acetonitrile and treated with 6 ml water. To this solution, 575 mg (2.73 mmol) 5-chloro-6-trifluoromethyl-benzene-1,2-diamine, dissolved in 6 ml methanol, are added dropwise within 30 min. After 2 hrs of stirring at room temperature, the reaction mixture is concentrated and the water solution extracted 2× with ethyl acetate. The combined organic phases where re-extracted 1× with water. The combined water phases where made alkaline (pH=8) with saturated NaHCO3-solution and extracted 2× with ethyl acetate. The combined organic phases where dried, filtered and evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH2:20])=[O:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(O)(=[O:23])C.ClC1C=CC=C(C(OO)=O)C=1>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH2:20])=[O:19])[C:11]3=[N+:12]([O-:23])[CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: NC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Product: NC(=O)Cn1c(-c2ccc(Cl)cc2)nc2ccc[n+]([O-])c21
Temperature: 60 °C
Yield: 52 %

Procedure:
A mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetamide (1.84 g, 0.0064 mole), glacial acetic acid, and m-chloroperbenzoic acid (4.4 g, 0.0256 mole) was heated at 60° C. for a total of 4 hrs. The reaction mixture was diluted with water and the organic acid which precipitated was filtered. The aqueous filtrate was neutralized for peroxides with 10% sodium sulfate. The aqueous solution was evaporated to dryness and the residue was treated with methylene chloride/saturated sodium bicarbonate. The insoluble precipitate was filtered, washed with methylene chloride and water, and dried at 50° C. under high vacuum overnight to give 1.0 g (52%) of title compound, mp. 272°-75° C. with decomposition.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>C1C=CC=CC=1>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][NH:5][CH2:4][CH2:3][O:2][CH3:1])[CH3:19]
Reactant: COCCN
Reactant: CCOC(=O)CBr
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNCCOC
Yield: 75.3 %

Procedure:
To a stirred solution of 165.2 g of 2-methoxyethylamine and 202.4 g of triethylamine in 1 l of benzene was added dropwise a solution of 334.0 g of ethyl bromoacetate in 200 ml of benzene in one hour at room temperature. At the end of this period, the mixture was heated at reflux for 2 hours to complete the reaction. Upon chilling, the triethylamine hydrobromide was removed by filtration and washed with benzene. After removal of the solvent, the product was distilled in vacuo to yield 242.8 g (75.3 percent) of N-(2-methoxyethyl)glycine ethyl ester, B.P. 73°-75° C/4 mmHg.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[C:4]([O:17]C)[CH:3]=1.C[S-].[Na+].O>CN(C)C=O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[C:4]([OH:17])[CH:3]=1
Reactant: COc1cc(C)c(C)cc1C(=O)c1ccccc1
Agent: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(O)c(C(=O)c2ccccc2)cc1C
Temperature: 25 °C

Procedure:
(4,5-Dimethyl-2-methoxyphenyl)(phenyl)methanone (650 mg) was dissolved in dimethylformamide (10 ml) to prepare a solution. Sodium thiomethoxide (379 mg) was added to the solution, and the mixture was stirred while heating under reflux overnight. The reaction solution was cooled to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, was dried over sodium sulfate and was concentrated. The residue was subjected to separation and purification by column chromatography on silica gel using hexane/ethyl acetate as a solvent to give (4,5-dimethyl-2-hydroxy-phenyl)(phenyl)methanone. The (4,5-dimethyl-2-hydroxy-phenyl)(phenyl)methanone (40 mg) thus obtained and 4-chloro-6,7-dimethoxyquinoline (150 mg) were added to o-dichlorobenzene (0.2 ml), and the mixture was heated at 180° C. for two days. The reaction solution was concentrated and was subjected to separation and purification by column chromatography on silica gel using hexane-ethyl acetate. Subsequently, a hydrochloric acid-methanol mixed solution was added thereto, the solvent was removed by distillation, and the residue was suspended in ethyl acetate. The solid thus obtained was collected by filtration, was washed with ethyl acetate, and was then dried to give the title compound (9.2 mg, yield 11%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[C:10]([I:11])[C:3]=12.[H-].[Na+].[H][H].[CH:16](Br)([CH3:18])[CH3:17]>CN(C)C=O>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH:16]([CH3:18])[CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1nc[nH]c2ncc(I)c1-2
Reactant: [H][H]
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(I)c2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
4-Chloro-5-iodo-pyrrolo[2,3-d]-pyrimidine (5.0 g) was added under nitrogen to a mixture of sodium hydride (0.8 g of a 60% dispersion in mineral oil) in N,N-dimethylformamide (100 ml) at 0° C. and then the mixture was allowed to warm to ambient temperature. When hydrogen evolution had ceased a solution of isopropyl bromide (17 ml) in N,N-dimethylformamide (50 ml) was added dropwise. The mixture was stirred for 20 hours at ambient temperature and then quenched with water (150 ml). The mixture was extracted with ethyl acetate to give 4-chloro-5-iodo-7-isopropylpyrrolo[2,3-d]pyrimidine.