Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24].[CH2:25]([N:27]([CH2:38][CH3:39])[CH2:28][CH2:29][O:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1)[CH3:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:35][C:34]3[CH:33]=[CH:32][C:31]([O:30][CH2:29][CH2:28][N:27]([CH2:38][CH3:39])[CH2:25][CH3:26])=[CH:37][CH:36]=3)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24]
Reactant: CCN(CC)CCOc1ccc(N)cc1
Reactant: CN1C(=O)N(c2cc(Cl)ccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(C)C(=O)N(c2cc(Cl)ccc2Cl)C3)cc1
Temperature: 180 °C
Yield: 5.6 %

Procedure:
A mixture of 200 mg (0.52 mmol) of 3-(2,5-dichlorophenyl)-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one and 218 mg (1.04 mmol) of 4-(2-(diethylamino)ethoxy)aniline was heated at 180° C. for 30 minutes and then cooled. The residue was subjected to column chromatography on silica gel eluted with dichloromethane/methanol/acetic acid/water in a ratio of 240:24:3:2. Product containing fractions were combined, evaporated and the residue re-evaporated with toluene. The residue was dissolved in dichloromethane (40 ml), washed with saturated aqueous sodium bicarbonate (40 ml), dried over magnesium sulfate, filtered and evaporated to give 15 mg (6%) of 3-(2,5-dichlorophenyl)-7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 138° C. [Mass spectrum (ESI) MH+ =514].
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:23]=[C:22]([OH:24])[N:21]([CH3:25])[N:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:19]2[CH:23]=[C:22]([O:24][CH2:27][C:28]([O:30][CH3:31])=[O:29])[N:21]([CH3:25])[N:20]=2)=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cc1O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1cc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)nn1C
Temperature: 40 °C
Reaction time: 4 h
Yield: 72.8 %

Procedure:
A mixture of 3-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}-1-methyl-1H-pyrazol-5-ol (0.65 g), methyl bromoacetate (0.38 g, 2.48 mmol), potassium carbonate (0.60 g, 4.3 mmol) in N,N-dimethylformamide (5 mL) was stirred at 40° C. for 4 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to purify the residue by silica gel column chromatography (hexane/ethyl acetate 80:20 to 20:80). Solvent was removed to obtain a solid (0.573 g, 73%). LC/MS; ESI(+) m/z: 415 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:9]2[CH:10]=[C:11](Br)[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])=[CH:13][C:8]=2[O:7][CH:6]=1.[C:26]([O-])([O-])=O.[Na+].[Na+].CB(O)O>COCCOC.O.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>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:9]2[CH:10]=[C:11]([CH3:26])[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])=[CH:13][C:8]=2[O:7][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)Cc1coc2cc(OCc3ccc(Cl)cc3Cl)c(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB(O)O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1coc2cc(OCc3ccc(Cl)cc3Cl)c(C)cc12
Temperature: 80 °C
Reaction time: 7 h

Procedure:
To the mixture of methyl(5-bromo-6-((2,4-dichlorobenzyl)oxy)-1-benzofuran-3-yl)acetate (166 mg), aqueous 2M Na2CO3 (0.561 mL) and methylboronic acid (44.7 mg) in DME (3.7 mL) was added Pd(Ph3P)4 (43.2 mg). The mixture was stirred at 80° C. for 7 h. To the mixture was added methylboronic acid (44.8 mg) again. The mixture was stirred at 80° C. under nitrogen atmosphere over weekend. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (45.0 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[BrH:36].[NH+]1C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([Br:36])=[C:12]2[CH2:18][CH2:19][N:20]1[C:21](=[O:30])[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]1=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Br
Reactant: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccc(OCc3ccccc3)cc12
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1CCc1c(Br)[nH]c2ccc(OCc3ccccc3)cc12
Temperature: 0 °C

Procedure:
To a solution of 2-[2-(5-benzyloxy-1H-indol-3-yl)ethyl]isoindole-1,3-dione (800 mg in a mixture of dry 25 mL tetrahydrofuran and 25 mL dry chloroform) at 0° C. was added pyridinium hydrobromide perbromide (666 mg) and the mixture stirred at 0° C. After 23 minutes the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate. The organic portion was washed with saturated sodium bicarbonate (3×) and 0.3M sodium bisulfate (3×) then dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (hexane:ethyl acetate, 7:2) followed by repurification by flash chromatography on silica gel (methylene chloride) gave the title compound (632 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:27][CH3:28])[C:5]2[C:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:29][C:30]1[CH:38]=[C:37]2[C:33]([CH:34]=[N:35][NH:36]2)=[CH:32][CH:31]=1.C[Si](Cl)(C)C>C(O)CCC>[NH:36]1[C:37]2[C:33](=[CH:32][CH:31]=[C:30]([NH:29][C:2]3[N:3]=[C:4]([NH:27][CH3:28])[C:5]4[C:10]([C:11]5[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=5)=[CH:9][NH:8][C:6]=4[N:7]=3)[CH:38]=2)[CH:34]=[N:35]1
Reactant: CNc1nc(Cl)nc2c1c(-c1cccnc1)cn2S(=O)(=O)c1ccc(C)cc1
Reactant: Nc1ccc2cn[nH]c2c1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CNc1nc(Nc2ccc3cn[nH]c3c2)nc2[nH]cc(-c3cccnc3)c12
Temperature: 115 °C
Yield: 46.3 %

Procedure:
To a mixture of 2-chloro-N-methyl-5-(pyridin-3-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.075 g, 0.182 mmol) in nBuOH (1 mL) was added 6-aminoindazole (0.048 g, 0.36 mmol) and TMSCl (0.06 mL, 0.46 mmol). After heating at 115° C. for 72 h, the mixture was purified by preparative HPLC to give N2-(1H-indazol-6-yl)-N4-methyl-5-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (0.03 g), MS (MH 357.2), λ=203.9, 246.3, 305.6.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[NH:5][N:4]=[C:3]1[S:8][C:9]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O.[C:22]1(=[O:29])[CH2:27][CH2:26][CH2:25][C:24](=[O:28])[CH2:23]1.C1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)CC)C.C[Si](C#N)(C)C>>[CH3:1][N:2]1[C:6](=[O:7])[NH:5][N:4]=[C:3]1[S:8][C:9]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:10]=1[C:11]([CH:23]1[C:24](=[O:28])[CH2:25][CH2:26][CH2:27][C:22]1=[O:29])=[O:13]
Reactant: Cn1c(Sc2cc(C(F)(F)F)ccc2C(=O)O)n[nH]c1=O
Reactant: O=C1CCCC(=O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C[Si](C)(C)C#N
Solvent: CCN(CC)CC
Product: Cn1c(Sc2cc(C(F)(F)F)ccc2C(=O)C2C(=O)CCCC2=O)n[nH]c1=O
Temperature: 20 °C
Reaction time: 48 h
Yield: 67.7 %

Procedure:
A mixture of 0.80 g (2.5 mmol) of 2-[(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-sulphanyl]-4-trifluoromethyl-benzoic acid, 0.28 g (2.5 mmol) of 1,3-cyclohexanedione and 0.63 g (3.1 mmol) of N,N′-dicyclohexylcarbodiimide is stirred at room temperature (approximately 20° C.) for 48 hours. 0.7 ml (5 mmol) of triethylamine and a drop of trimethylsilyl cyanide are then added, and the mixture is stirred for a further 24 hours. The mixture is then concentrated under water pump vacuum and the residue is stirred with 10% strength aqueous sodium carbonate solution. The mixture is then filtered and the filtrate is washed twice with diethyl ether, acidified with 2N hydrochloric acid and extracted with dichloromethane. The organic phase is dried over magnesium sulphate and the solvent is removed under reduced pressure, giving 0.7 g (68% of theory) of 2-[2-[(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-sulphanyl]-4-trifluoromethyl-benzoyl]-1,3-cyclohexanedione as an oil (log P=2.00).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15].N12CCN(CC1)CC2>C(OC)(C)(C)C>[C:14](=[O:15])([O:10][CH:5]1[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([CH3:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1)[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Agent: C1CN2CCN1CC2
Solvent: COC(C)(C)C
Product: CN1C(C)(C)CC(OC(=O)Oc2ccccc2)CC1(C)C
Reaction time: 2 h

Procedure:
Into a 500 ml 3-neck flask was added 17.1 grams (0.1 mole) 1,2,2,6,6-pentamethyl-4-piperidinol and 300 mls of methyl t-butyl ether (MtBE). The flask was equipped with a magnetic stirrer, thermometer, reflux condenser and dropping funnel containing 15.6 grams (0.1 mole) phenyl chloroformate. The phenyl chloroformate was slowly added to the 1,2,2,6,6-pentamethyl-4-piperidinol solution without any appreciable exotherm. Then 11.2 grams (0.1 mole) of 1,4-diazabicyclo(2.2.2)octane (DABCO) was added at room temperature. The temperature rose to 50° C. and a precipitate formed. The reaction was stirred for 2 hours, an additional 2 grams of DABCO and 1.25 grams of phenyl chloroformate was added, the reaction heated to reflux and refluxed 2 hours. The reaction mixture was cooled, transferred to a separatory funnel and washed with water to remove DABCO, DABCO hydrochloride and a small amount of 1,2,2,6,6-pentamethyl-4-piperidinol. The product was then extracted out of the MtBE layer with 100 mls of 5% HCl diluted with water to 400 mls. The MtBE layer which contained diphenyl carbonate was discarded. The acid layer was made basic with 100 ml of 10% NaOH. The product was extracted out of the aqueous layer with 200 ml MtBE. The MtBE extract was washed with 100 ml 5% NaHCO3, dried over anhydrous MgSO4, filtered and the MtBE stripped off on a rotating evaporator under reduced pressure. The residue was a white solid weighing 20.4 grams (70.1% crude yield) which had a melting point of 63°-67° C. Liquid chromatography indicated the product was essentially one component. The infrared spectrum contained a strong carbonyl peak at 1755 cm-1.
Reaction SMILES: [O:1]=[C:2]([CH3:8])[CH2:3][CH2:4][CH2:5][C:6]#[N:7].[Cl-].[Ce+3].[Cl-].[Cl-].[CH:13]1([Mg]Cl)[CH2:17][CH2:16][CH2:15][CH2:14]1.Cl>C1COCC1>[CH:13]1([C:2]([OH:1])([CH3:8])[CH2:3][CH2:4][CH2:5][C:6]#[N:7])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Cl[Mg]C1CCCC1
Reactant: CC(=O)CCCC#N
Agent: Cl
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(O)(CCCC#N)C1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
5-Oxohexanenitrile (11.1 g; 0.10 mmol) was added at 20° C. to a suspension of anhydrous cerium(III) chloride (30 g; 0.12 mol) in THF (250 ml). After 1 hour stirring at room temperature, cyclopentylmagnesium chloride (60 ml of 2.0 M solution in diethyl ether; 0.12 mol) was added dropwise at 5° C. and stirring continued for more 0.5 hour at the same temperature. 2 N HCl (60 ml) was added, and the reaction mixture was extracted with MTBE (2×200 ml). The combined organic phases were washed with 2 N HCl (100 ml), and brine (2×100 ml), dried (MgSO4), and concentrated in vacuo, to give 13 g of crude (83% GC pure; 60% yield) 5-cyclopentyl-5-hydroxyhexanenitrile. The 5-cyclopentyl-5-hydroxyhexanenitrile was used without further purification in the next step.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][CH:8]([NH:11][C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:9][OH:10])(C)(C)C.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]O)=[CH:22][CH:21]=1>>[CH2:15]([O:14][C:12](=[O:13])[NH:11][CH:8]1[CH2:7][C:6](=[O:5])[O:18][CH:9]1[O:10][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([Cl:19])=[CH:21][CH:22]=1)[CH:16]=[CH2:17]
Reactant: C=CCOC(=O)NC(CO)CC(=O)OC(C)(C)C
Reactant: OCc1ccc(Cl)cc1
Product: C=CCOC(=O)NC1CC(=O)OC1OCc1ccc(Cl)cc1

Procedure:
Prepared from 3-allyloxycarbonylamino-4-hydroxy-butyric acid tert-butyl ester as described for 40 using 4-chlorobenzylalcohol to afford the title compound as a white solid. Anti-diastereomer: HPLC (C18 column) 10.924 min; 1H-NMR (500 MHz, CDCl3) δ 2.41 (d, J=8.0 Hz, 1H), 3.02 (dd, J=18.1, 7.8 Hz, 1H), 4.25 (br, 1H), 4.56 (m, 2H), 4.58 (d, J=11.7 Hz, 1H), 4.79 (d, J=11.7 Hz, 1H), 4.99 (br, 1H), 5.22 (dd, J=10.4, 1.1 Hz, 1H), 5.28 (dd, J=17.2, 1.3 Hz, 1H), 5.44 (s, 1H), 5.86 (m, 1H), 7.25 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.4 Hz, 2H) ppm; LC-MS (ES+) m/e=326 (M+H); Syn-diastereomer: HPLC (C18 column) 10.780 min; 1H-NMR (500 MHz, CDCl3) δ 2.47 (dd, J=17.3, 10.5 Hz, 1H), 2.85 (dd, J=17.3, 8.4 Hz, 1H), 4.55 (m, 3H), 4.58 (d, J=11.7 Hz, 1H), 4.84 (d, J=11.7 Hz, 1H), 5.23 (dd, H=10.4, 1.1 Hz, 1H), 5.30 (d, J=16.6 Hz, 1H), 5.49 (d, J=5.0 Hz, 1H), 5.89 (ddt, J=17.1, 11.0, 5.4 Hz, 1H), 7.23 (d, J=8.3 Hz, 2H), 7.31 (d, J=8.3 Hz, 2H) ppm; LC-MS (ES+) m/e=326 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[C:12](=O)[CH2:13][CH2:14][C:6]=3[C:5]=2[CH:4]=1.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>CCO.O>[OH:18][N:17]=[C:12]1[C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[C:6]=2[CH2:14][CH2:13]1
Reactant: NO
Reactant: COc1ccc2[nH]c3c(c2c1)CCC3=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc2[nH]c3c(c2c1)CCC3=NO
Reaction time: 8 h
Yield: 28.6 %

Procedure:
A stirred solution of 1,2-cyclopentadione mono-4-methoxyphenylhydrazone (6.0 g) in 100 ml of 10% aqueous H2SO4 was heated on a steam bath for 4 hours and thereafter allowed to cool to room temperature and filtered to give 1,4-dihydro 7-methoxycyclopent[b]indol-3(2H)-one as a solid. To the indole (2.6 g) in 25 ml of 95% EtOH was added hydroxylamine hydrochloride (1.7 g) in 15 ml water followed by sodium acetate (2.1 g) in 15 ml water. The mixture was heated at reflux for 2.5 hours and allowed to stand overnight. The EtOH was removed in vacuo and the solid material which formed was collected and purified by flash chromatography to give 0.8 g of a mixture of oxime isomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[CH3:16][C:15]([NH:12][CH2:11][CH2:10][C:9]1[C:13]2[CH:14]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[NH:7][CH:8]=1)=[O:17]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Product: COc1ccc2[nH]cc(CCNC(C)=O)c2c1

Procedure:
reacting said essentially pure 5-methoxy-tryptamine from step c) with acetic anhydride to obtain crude melatonin and purifying said crude melatonin by chromatography on silica gel and first eluting with methylene chloride followed by eluting with methylene chloride and acetone to obtain a solution, concentrating said methylene chloride and acetone solution to obtain a solid and recrystallizing said solid whereby purified melatonin
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:12](=[O:17])N(OC)C)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][Mg]Br.CCOCC>C1COCC1>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:12](=[O:17])[CH3:19])[CH2:9][CH2:10][CH2:11]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)C1(NC(=O)OC(C)(C)C)CCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)C1(NC(=O)OC(C)(C)C)CCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63 %

Procedure:
To a solution of [1-(methoxy-methyl-carbamoyl)-cyclobutyl]-carbamic acid tert-butyl ester (11.5 g, 44.6 mmol) in THF (150 mL) at 0° C. was slowly added methylmagnesium bromide as a 3.0M solution in ether (37.2 mL, 111 mmol). The reaction was allowed to slowly warm to 25° C. and stirred for 24 h then quenched by the addition of saturated aqueous NH4Cl (100 mL). EtOAc (200 mL) was added and the layers were separated. The aqueous phase was extracted two more times with EtOAc. The organic layers were combined, washed with brine, dried (Na2SO4), decanted and concentrated to afford a solid. The solid was purified via normal phase flash chromatography on silica gel (10-50% EtOAc-heptane) to afford (1-acetyl-cyclobutyl)-carbamic acid tert-butyl ester as a white solid (6.02 g, 63%).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]1=[O:17].Br[C:19]1[N:23]([CH:24]2[CH2:26][CH2:25]2)[C:22]2[CH:27]([C:40]3[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=3)[N:28]([C:31]3[CH:36]=[C:35]([Cl:37])[C:34](=[O:38])[N:33]([CH3:39])[CH:32]=3)[C:29](=[O:30])[C:21]=2[CH:20]=1.C(Cl)Cl.CO.N>>[Cl:37][C:35]1[C:34](=[O:38])[N:33]([CH3:39])[CH:32]=[C:31]([N:28]2[C:29](=[O:30])[C:21]3[CH:20]=[C:19]([C:5]4[CH:6]=[CH:7][N:2]([CH3:1])[C:3](=[O:17])[CH:4]=4)[N:23]([CH:24]4[CH2:26][CH2:25]4)[C:22]=3[CH:27]2[C:40]2[CH:41]=[CH:42][C:43]([Cl:46])=[CH:44][CH:45]=2)[CH:36]=1
Reactant: Cn1cc(N2C(=O)c3cc(Br)n(C4CC4)c3C2c2ccc(Cl)cc2)cc(Cl)c1=O
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)cc1=O
Agent: N
Solvent: CO
Solvent: ClCCl
Product: Cn1ccc(-c2cc3c(n2C2CC2)C(c2ccc(Cl)cc2)N(c2cc(Cl)c(=O)n(C)c2)C3=O)cc1=O

Procedure:
The title compound was prepared in analogy to the procedure described in Example 240 but using 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (Step 242.1) and 2-bromo-5-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(4-chlorophenyl)-1-cyclopropyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (Step 250.1). tR: 0.83 min (LC-MS 6); ESI-MS: 521.2/523.2 [M+H]+ (LC-MS 6); TLC (CH2Cl2/MeOH/NH3 94:5:1): Rf=0.18; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.35-0.450 (m, 1 H) 0.74-0.84 (m, 2 H) 1.12-1.25 (m, 1 H) 3.06-3.18 (m, 1 H) 3.41 (s, 3 H) 3.37 (s, 3 H) 6.30 (s, 1 H) 6.47 (dd, J=7.04, 1.95 Hz, 1 H) 6.52-6.61 (m, 1 H) 6.71 (s, 1 H) 7.30 (m, J=8.21 Hz, 2 H) 7.38 (m, J=8.60 Hz, 2 H) 7.62 (d, J=7.04 Hz, 1 H) 7.80-7.95 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[C:25]3[C:20](=[C:21]([CH2:26][S:27][CH3:28])[CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.ClC1C=CC(C(C2C=CC(Cl)=CC=2)C2C3C(=C(CS(C)=[O:48])C=CC=3)NC=2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:17]2[C:25]3[C:20](=[C:21]([CH2:26][S:27]([CH3:28])=[O:48])[CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[C:9]2[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=2)=[CH:6][CH:7]=1
Reactant: CSCc1cccc2c(C(c3ccc(Cl)cc3)c3ccc(C#N)cc3)c[nH]c12
Reactant: CS(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)c[nH]c12
Product: CS(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)c3ccc(C#N)cc3)c[nH]c12

Procedure:
The title compound was prepared starting from 60 mg (0.15 mmol) of the compound from Example 281 in analogy to the synthesis of the compound from Example 296. 62 mg (99% of theory) of the target compound were obtained as mixture of diastereomers.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]#[N:10])[CH2:3][CH2:2]1.C[O-].[Na+].[CH2:14]1[O:18][C:17]2[CH:19]=[C:20]([CH:23]=O)[CH:21]=[CH:22][C:16]=2[O:15]1>CS(C)=O>[O:1]1[CH2:6][CH2:5][N:4]([CH:7]=[C:8]([CH2:23][C:20]2[CH:21]=[CH:22][C:16]3[O:15][CH2:14][O:18][C:17]=3[CH:19]=2)[C:9]#[N:10])[CH2:3][CH2:2]1
Reactant: N#CCCN1CCOCC1
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CC(=CN1CCOCC1)Cc1ccc2c(c1)OCO2

Procedure:
β-Morpholinopropionitrile (20 g.), dimethylsulphoxide (30 ml.), and sodium methoxide (1 g.) were heated together at 80° C and a solution of piperonaldehyde (19 g.) in dimethylsulphoxide was added. The mixture was reacted at 80° C for 15 min., and on work-up gave β-morpholino-α-piperonylacrylonitrile, Wt.=21 g. (61%) m.p. 85°-85.5° C (recrystallised from methanol).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]#[C:14][C:15]1[CH:16]=[N:17][C:18]([NH:21][C:22]2[C:27]([N+:28]([O-])=O)=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:31])=[N:19][CH:20]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[Cl:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[C:3]=1[C:13]#[C:14][C:15]1[CH:20]=[N:19][C:18]([NH:21][C:22]2[C:27]([NH2:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:31])=[N:17][CH:16]=1
Reactant: COc1cc(OC)c(Cl)c(C#Cc2cnc(Nc3c(C)cccc3[N+](=O)[O-])nc2)c1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(OC)c(Cl)c(C#Cc2cnc(Nc3c(C)cccc3N)nc2)c1Cl
Temperature: 85 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
A mixture of 5-((2,6-dichloro-3,5-dimethoxyphenyl)ethynyl)-N-(2-methyl-6-nitrophenyl)pyrimidin-2-amine (150 mg, 0.33 mmol), Iron (147 mg, 2.64 mmol) and ammonium chloride (214 mg, 3.96 mmol) in ethanol (20 mL) and water (2 mL) was stirred at 85° C. for 1 h. LCMS showed the reaction was completed. The reaction was cooled to RT, and the solid was filtered off. The filtrate was concentrated, and the residue was purified by Prep-HPLC to afford the title compound as a white solid (58 mg, 35%). MS (ES+) C21H18Cl2N4O2 requires: 429, 431. Found: 430, 432 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.90 (s, 1H), 8.55-8.44 (br, 2H), 6.97 (s, 1H), 6.89-6.86 (m, 1H), 6.57 (d, 1H, J=7.6 Hz), 6.44 (d, 1H, J=7.6 Hz), 4.75 (s, 2H), 3.94 (s, 6H), 2.01 (s, 3H).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.Cl[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([C:26]([N:28]2[C:36]3[C:31](=[CH:32][C:33]([F:37])=[CH:34][CH:35]=3)[CH2:30][CH2:29]2)=[O:27])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[F:37][C:33]1[CH:32]=[C:31]2[C:36](=[CH:35][CH:34]=1)[N:28]([C:26]([C:22]1[CH:21]=[C:20]([N:3]3[CH2:4][CH2:5][CH:6]([N:9]4[C:17]5[C:12](=[N:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]4=[O:18])[CH2:7][CH2:8]3)[CH:25]=[CH:24][N:23]=1)=[O:27])[CH2:29][CH2:30]2
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: O=C(c1cc(Cl)ccn1)N1CCc2cc(F)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ccn1)N1CCc2cc(F)ccc21
Temperature: 130 °C
Reaction time: 30 h

Procedure:
314 mg (1.08 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one dihydrochloride were added to 300 mg (1.08 mmol) (4-chloropyridin-2-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone and 373 mg (2.70 mmol) potassium carbonate in 5.0 mL N-methylpyrrolidone. The reaction mixture was stirred for 30 h at 130° C. Then the mixture was poured onto 100 mL water and extracted with EtOAc (3×100 mL). The combined organic phases were dried and evaporated down using the rotary evaporator. The residue was purified by preparative HPLC. The product fractions were combined and evaporated down i. vac. The residue was triturated with 30 mL diethyl ether. The precipitated solid was suction filtered and dried in the air.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][CH2:20][CH2:21][OH:22]>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:22][CH2:21][CH2:20][O:19][CH3:18])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCO
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Product: COCCOc1ccc2c(c1)CN(C(=O)OC(C)(C)C)C2

Procedure:
Prepared in analogy to Example A6(a) from 5-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and 2-methoxyethanol. White solid. MS (m/e): 237.9 ([M+H−Me2C═CH2]+, 100%)