Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH:25]1([CH2:30]Cl)[CH2:29][CH2:28][CH2:27][CH2:26]1.[Na+].[I-].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.[Na+].[I-].O>[CH:25]1([CH2:30][N:13]2[C:12]3[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Reactant: ClCC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc2c1c1c(n2CC2CCCC2)CCCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (820 g, 3.37 mmol), a catalytic amount of NaI (ca. 10 mg) and K2CO3 (930 mg, 6.74 mmol) in 6 mL of DMF was treated with cyclopentylmethyl chloride (JOC, 1964, 29, 421-423; 400 mg, 3.37 mmol). After stirring overnight at ambient temperature, an additional 800 mg of cyclopentylmethyl chloride and 1 g of NaI were added, and the resulting mixture was heated at 80° C. overnight. An additional 800 mg of cyclopentylmethyl chloride and 2.2 g of Cs2CO3 were added, and the reaction mixture was heated at 80° C. for 24 h. An additional 1.6 g of cyclopentylmethyl chloride was added, and the reaction mixture was heated at 80° C. for 3 d The mixture was poured into H2O (30 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by radial chromatography on silica gel (elution with gradient of 10% to 40% EtOAc/hexanes) to afford 775 mg (2.38 mmol; 71%) of 9-[(cyclopentyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a brown foam. MS (ES) m/e 326 (M+1), 384 (M+AcO−).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:16]=1[O:17][C:18]1[CH:19]=[C:20]([CH2:24]O)[CH:21]=[CH:22][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:14][C:15]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:16]=1[O:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: Cc1cccc(C)c1Oc1cccc(CO)c1
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(OCc2cccc(Oc3c(C)cccc3C)c2)cc1
Temperature: 0 °C
Yield: 49.7 %

Procedure:
To a solution of methyl 3-(4-hydroxyphenyl)propanoate (0.25 g, 1.39 mmol), [3-(2,6-dimethylphenoxy)phenyl]methanol (0.41 g, 1.81 mmol) and triphenylphosphine (0.47 g, 1.81 mmol) in tetrahydrofuran (5 mL) was added dropwise diethyl azodicarboxylate toluene solution (40%, 0.82 mL) with stirring at 0° C., and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane/ethyl acetate=4/1) to give the title compound (0.27 g, yield 50%) as a yellow oil.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].I[C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH2:14][CH2:15][CH:16]2[O:21][Si](C)(C)C.Cl>CN1CCN(C)C1=O>[C:3]([CH:5]([C:12]1[C:13]2[CH2:14][CH2:15][CH:16]([OH:21])[C:17]=2[CH:18]=[CH:19][CH:20]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4]
Reactant: C[Si](C)(C)OC1CCc2c(I)cccc21
Reactant: CCOC(=O)CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Product: CCOC(=O)C(C#N)c1cccc2c1CCC2O
Reaction time: 4 h

Procedure:
6 ml of 1,3-dimethyl-2-imidazolidone and 0.99 g of sodium hydride at 50% are cooled to +15° C., 2.2 ml of ethyl cyanacetate in 10 ml of 1,3-dimethyl-2-imidazolidone is added over 5 minutes, with agitation for 40 minutes. 4.39 g of cuprous iodide, 3.62 g of 4-iodo-1-trimethylsilyloxy indane and 4 ml of 1,3-dimethyl-2-imidazolidone are added. The mixture is taken to 100° C. for 4 hours. After cooling, it is poured into 100 ml of 2N hydrochloric acid, filtered on celite, and rinsed with water; the filtrate is extracted with isopropyl ether, washed with a saturated solution of sodium bicarbonate and with water, dried and brought to dryness. The residue is chromatographed on silica in a hexane-ethyl acetate mixture (1-1) and 1.22 g of expected product is obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])=[N:8]3.C(N(CC)CC)C.C([O:29][C:30](=O)[C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33])C>C(#N)C>[CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:30](=[O:29])[C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33])=[N:8]3
Reactant: Cc1nc2cccc3nc(SCCCCCN)c1n23
Reactant: CCOC(=O)C(F)(F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc2cccc3nc(SCCCCCNC(=O)C(F)(F)C(F)(F)F)c1n23
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 275 mg (1.00 mmol) of 3-methyl-2-[5-(amino)pentan-1-ylthio]-1,4,7b-triazacyclopent[cd]indene in 30 ml of acetonitrile were added 0.19 ml (1.36 mmol) of triethylamine and 231 mg (1.20 mmol) of pentafluoropropionic acid ethyl ester. The mixture was stirred for 15 hours at room temperature, and the the solvent was distilled off. To the residue was added ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to afford 245 mg (58.1%, a pale brown solid) of the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26](=[O:31])[CH2:27][CH2:28][CH2:29]Cl)[CH:20]=3)=[CH:14][CH:13]=2)=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.O>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:25]4[CH2:29][CH2:28][CH2:27][C:26]4=[O:31])[CH:20]=3)=[CH:14][CH:13]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(CCCCl)Nc1cc(Oc2ccc(NC(=O)Nc3ccc(F)cc3)cc2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)cc1)Nc1ccc(Oc2ccnc(N3CCCC3=O)c2)cc1
Yield: 40.9 %

Procedure:
N-(4-Fluorophenyl)-N′-(4-{[2-(4-chlorobutyrylamino)-4-pyridyl]oxy}phenyl)urea (56 mg), potassium carbonate (46 mg) and dimethylformamide (2 ml) were stirred at 150° C. for 15 minutes. Water and ethyl acetate were added for extraction, and the extract was passed through a glass filter coated with silica gel. The silica gel was washed with ethyl acetate, and the organic layer was distilled off under reduced pressure. Ethyl acetate and hexane were added to the residue, and the precipitated solid was filtered out to obtain 21 mg of a faint brown powder.
Reaction SMILES: Cl.Cl.[CH:3]1([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][CH2:22][N:23]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:15][CH2:14]2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1.O.NN>C(O)C>[CH:3]1([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH2:17][CH2:18]2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCN1CCN(C2CCCc3ccccc32)CC1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCCN1CCN(C2CCCc3ccccc32)CC1

Procedure:
Batch size: 52 g (106 mmol) 2-{4-[4-(1,2,3,4-tetrahydronaphthalin-1-yl)-piperazin-1-yl]-butyl}-isoindolin-1,3-dione-dihydrochloride and 14.6 ml (300 mmol) hydrazine-hydrate in 500 ml ethanol.
Reaction SMILES: C([N:8]1[CH2:15][C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]2([CH2:13][CH2:12][CH2:11]2)[CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH2:13]1[C:10]2([C@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:15][NH:8][CH2:9]2)[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(Cc2ccccc2)CC12CCC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1CNCC12CCC2
Reaction time: 4 h

Procedure:
A stirred solution of (S)-tert-butyl (6-benzyl-6-azaspiro[3.4]octan-8-yl)carbamate (enantiopure Intermediate 13, 0.364 g, 1.149 mmol) in Ethanol (21.3 mL) with Pd/C (10% b/w) (0.291 g, 2.73 mmol), was charged with hydrogen gas @ 50 psi in a pressure bottle and agitated for 4 hrs. +/−MS analysis after 3 hrs 15 min indicated that essentially no starting material remained (m/e 227.2, M+H for desired product). The catalyst was removed by filtration, and the filtrate was concentrated under vacuum to yield 0.247 g of the desired product as a tan oil. +/−MS: m/e 227.2 (M+H). 1H NMR (400 MHz, CHLOROFORM-d) δ 4.66 (br. s., 1H), 3.96 (br. s., 1H), 3.24 (dd, J=11.3, 6.1 Hz, 1H), 3.05 (d, J=11.0 Hz, 1H), 2.89 (d, J=11.2 Hz, 1H), 2.72 (dd, J=11.6, 3.4 Hz, 1H), 2.13 (dd, J=9.6, 3.4 Hz, 3H), 2.04-1.71 (m, 5H), 1.46 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:17][CH2:16][C:15](=[O:18])[NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([CH2:32][CH2:33][C:34]2[NH:43][C:37]3=[N:38][CH:39]=[C:40](I)[CH:41]=[C:36]3[N:35]=2)[CH:27]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd](Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:11]1([S:8]([C:5]2[CH:6]=[CH:7][C:2]([C:40]3[CH:41]=[C:36]4[N:35]=[C:34]([CH2:33][CH2:32][C:28]5[CH:27]=[C:26]([O:25][CH3:24])[CH:31]=[CH:30][N:29]=5)[NH:43][C:37]4=[N:38][CH:39]=3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][CH2:13][CH2:12]1
Reactant: O=C1CCN(S(=O)(=O)c2ccc(Br)cc2)CCN1
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccnc(CCc2nc3cc(-c4ccc(S(=O)(=O)N5CCNC(=O)CC5)cc4)cnc3[nH]2)c1
Temperature: 90 °C
Yield: 25.3 %

Procedure:
A mixture of 0.50 g of 1-(4-bromo-benzene-sulfonyl)-1,4diazepan-5-one, 0.42 g of bis-(pinacolato)-diboron, 0.025 g of 1,1′-bis-(diphenylphosphino)-ferrocene, 0.033 g of 1,1′-bis(diphenylphosphino)-ferrocene]palladium-dichloride (complex with CH2Cl2), 0.442 g of potassium acetate in 6 ml of degassed dioxane are heated to 90° C. in a sealed tube under N2 for 17 hours. To the resulting mixture 5 ml of degassed dioxane, 0.371 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (starting material A1), 0.113 g of tetrakis(triphenylphosphine)-palladium(0) and a solution of 0.27 g of potassium carbonate and 0.083 g of lithium chloride in 5 ml of degassed water are added under N2. The tube is sealed again, the mixture is heated to 115° under N2 for 7 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 20-12:1+1% NH4OH). Concentration of the chromatographically pure fractions and crystallization of the residue from acetonitril gives 0.125 g of the title compound as a solid of m.p. 230-232° C. The mass spectrum shows the molecular peak MH+ at 507.3 Da.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[C:19]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH:18]=[C:17]([F:28])[CH:16]=2)=[O:13])[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C1([O:35][C:36](=O)[NH2:37])C=CC=CC=1.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>CS(C)=O.C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:13])[NH:14][C:15]2[CH:20]=[C:19]([CH:18]=[C:17]([F:28])[CH:16]=2)[O:21][CH:22]2[CH2:23][CH2:24][N:25]([C:36]([NH2:37])=[O:35])[CH2:26][CH2:27]2)[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1cc(F)cc(OC2CCNCC2)c1
Reactant: NC(=O)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1cc(F)cc(OC2CCN(C(N)=O)CC2)c1
Temperature: 85 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
Nitrogen gas is bubbled trough a solution of 1-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-3-{3-fluoro-5-(piperidin-4-yloxy)-phenyl}-urea (390.6 mg, 1.0 mmol) and carbamic acid phenyl ester (140.6 mg, 1.0 mmol) in DMSO (2 mL) for 5 minutes. Next, N,N-diisopropylethylamine (350 μL, 2.0 mmol) is added. After stirred at 85° C. overnight, the reaction mixture is distributed between ethyl acetate (15 mL) and saturated sodium bicarbonate (50 mL). The aqueous phase is isolated and extracted with ethyl acetate (2×15 mL). The combined organic phases are dried over sodium sulfate and concentrated. The residue is purified on a silica gel chromatography with hexanes and ethyl acetate to give a white solid (250 mg, 58% yield, ES+(m/z) 433.3 [M+H]).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.Cl.[N:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[N:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([N:12]2[CH2:13][CH:14]3[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]3)[CH2:11]2)=[O:29])=[CH:23][CH:22]=1
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Reactant: O=C(O)Cc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)Cc1ccncc1)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27.1 %

Procedure:
Triethylamine 1.75 ml (12.6 mill) was added to a methylene chloride 20 ml solution of (1S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 0.95 g (5.0 mill) and 4-pyridylacetic acid hydrochloride 0.96 g (5.5 mill) and stirred at 0° C. for 30 min. WSC 1.35 g (7.04 mill) was added thereto, then temperature of the reaction mixture was gradually changed to room temperature and stirred for 24 hours. The reaction mixture was washed with saturated aqueous sodium chloride solution and dried by anhydrous sodium sulfate. After the drying agent was removed by filtration, the filtrate was concentrated in vacuo to obtain crude (1S)-3-(4-pyridylacetyl)-1,8,8trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 30 ml solution of lithium aluminum hydride 0.39 g (10.3 mill) and refluxed under heating for 3 hours. The reaction mixture was cooled, then water was added thereto and the insoluble material was removed by filtration. The filtrate was concentrated in vacuo. The thus obtained residue was purified by means of silica gel column chromatography (Wako gel, C200, chloroform acetone=10:1) to obtain the product as orange colored oily material. Yield: 0.35 g (Yield 27.1%)
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[NH2:8][C:9]([NH2:11])=[NH2+:10].[CH3:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15](=[O:32])[N:16]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH:17]2[CH2:22][C:23](OCC)=[O:24]>O>[CH2:28]([N:16]1[C:15](=[O:32])[C:14]2[C:18](=[CH:19][CH:20]=[CH:21][C:13]=2[CH3:12])[CH:17]1[CH2:22][C:23]([NH:10][C:9]([NH2:11])=[NH:8])=[O:24])[CH:29]([CH3:31])[CH3:30]
Reactant: NC(N)=[NH2+]
Reactant: CCOC(=O)CC1c2cccc(C)c2C(=O)N1CC(C)C
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: Cc1cccc2c1C(=O)N(CC(C)C)C2CC(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 20 h
Yield: 55.8 %

Procedure:
N-[2-(2-Isobutyl-4-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-acetyl]-guanidine is prepared as described in Example 1, starting with 0.68 of potassium tert-butoxide, 0.58 g of guanidinium chloride and 0.36 g of ethyl (4-methyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate. The reaction mixture is stirred at a temperature in the region of 20° C. for 20 hours, followed by addition of 20 cm3 of water. The aqueous phase is extracted with 3 times 100 cm3 of ethyl acetate. The organic extracts are combined and then concentrated to dryness under reduced pressure (0.5 kPa) at a temperature in the region of 40° C. The residue is taken up in dichloromethane and then concentrated again under the same conditions. The residue is taken up in water, triturated and filtered, and then taken up in dichloromethane, triturated and filtered. The solid is then dried in a desiccator. 0.21 g of N-[2-(2-Isobutyl-4-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-acetyl]-guanidine is thus obtained in the form of a white powder melting at 270-272° C. (decomposition). 1NMR (300 MHz, d6-(CD3)2SO, δ in ppm): 0.76 (d, J=7 Hz: 3H); 0.91 (d, J=7 Hz: 3H); 2.03 (mt: 1H); 2.42 (dd, J=15.5 and 6.5 Hz: 1H); 2.60 (dd, J=15.5 and 6.5 Hz: 1H); 2.62 (s: 3H); 3.00 (dd, J=14 and 5.5 Hz: 1H); 3.56 (dd, J=14 and 10 Hz: 1H); 4.98 (t, J=6.5 Hz: 1H); from 6.40 to 7.10 (broad multiplet: 2H); 7.21 (broad d, J=7.5 Hz: 1H); 7.36 (broad d, J=7.5 Hz: 1H); 7.42 (t, J=7.5 Hz: 1H); from 7.50 to 8.30 (broad multiplet: 2H).
Reaction SMILES: [CH3:1][N:2]1[CH:9]=[CH:8][C:6](=[O:7])[N:5]([CH3:10])[C:3]1=[O:4].S(=O)(=O)(O)O.[F:16][C:17](I)([F:19])[F:18].OO>S([O-])([O-])(=O)=O.[Fe+2].CS(C)=O>[CH3:1][N:2]1[CH:9]=[C:8]([C:17]([F:19])([F:18])[F:16])[C:6](=[O:7])[N:5]([CH3:10])[C:3]1=[O:4]
Reactant: FC(F)(F)I
Reactant: Cn1ccc(=O)n(C)c1=O
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: CS(C)=O
Product: Cn1cc(C(F)(F)F)c(=O)n(C)c1=O
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 78 %

Procedure:
0.14 g (1.0 mmol) of 1,3-dimethyluracil was weighed and placed in a 50 ml two-neck flask equipped with a magnetic rotor and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 2.0 ml of a 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 ml of a 3.0 mol/l dimethyl sulfoxide solution of trifluoromethyl iodide, 0.2 ml of a 30% hydrogen peroxide aqueous solution and 0.3 ml of a 1.0 mol/l aqueous solution of iron (II) sulfate. The mixture was stirred at 40 to 50° C. for 20 minutes and then the resulting solution was cooled to room temperature. Formation of 1,3-dimethyl-5-trifluoromethyluracil (19F-NMR yield: 78%) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard. 1,3-Dimethyl-5-trifluoromethyluracil was obtained as a white solid (0.12 g, yield: 44%) by preparative thin-layer chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:4]=1[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][C:12]2[CH2:13][NH:14][CH2:15][CH2:16][C:17]=2[N:18]=1)=[NH:8].[C:25](Cl)(=[O:27])[CH3:26].C(N(CC)CC)C>C1COCC1>[C:25]([N:14]1[CH2:15][CH2:16][C:17]2[N:18]=[C:10]([NH:9][C:7]([NH:6][CH2:5][C:4]3[C:19]([O:23][CH3:24])=[CH:20][CH:21]=[CH:22][C:3]=3[O:2][CH3:1])=[NH:8])[S:11][C:12]=2[CH2:13]1)(=[O:27])[CH3:26]
Reactant: COc1cccc(OC)c1CNC(=N)Nc1nc2c(s1)CNCC2
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc(OC)c1CNC(=N)Nc1nc2c(s1)CN(C(C)=O)CC2

Procedure:
Acetylation of 110 mg N-(2,6-dimethoxybenzyl)-N′-(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-yl)guanidine (0.26 mmol, Example 221.3) under standard conditions with acetylchloride and triethylamine in 15 ml THF followed by purification, yielded 16 mg of the desired product as a white solid; ESI-MS [M+H+]=390.15.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-])=O)=[C:6]([CH:11]=1)[NH:7][CH:8]([CH3:10])[CH3:9].[Cl-].[NH4+].C1C[O:20][CH2:19]C1>C(O)C.O.[Fe]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:12][C:19](=[O:20])[N:7]([CH:8]([CH3:10])[CH3:9])[C:6]=2[CH:11]=1
Reactant: C1CCOC1
Reactant: CC(C)Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)n1c(=O)[nH]c2ccc(Cl)cc21
Temperature: 80 °C
Reaction time: 10 h
Yield: 40 %

Procedure:
A mixture of 5-chloro-N-isopropyl-2-nitroaniline (Step 1 of Example 12, 0.76 g, 3.54 mmol), iron (0.99 g, 17.7 mmol) and ammonium chloride (0.38 g, 7.08 mmol) was suspended in ethanol (27 mL) and H2O (9 mL). Then, the mixture was heated at 80° C. for 3 h. After cooling, the insoluble materials was filtered off on a pad of Celite, and the filtrate was evaporated under reduced pressure. To the residue was added N,N′-carbonyldiimidazole (CDI, 0.57 g, 3.50 mmol) and THF (10 mL) and then stirred at 100° C. for 10 h. After cooling, the volatile materials were removed under reduced pressure and the residue was partitioned between ethylacetate and H2O. After extraction with ethylacetate (3 times), the combined organic phase was washed with brine, dried over MgSO4 and concentrated. The residue was chromatographed on a column of silica gel eluting with hexane/ethyl acetate (2:1) to give 0.30 g (40%) of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:3]=1.[K+].[CH:25]([C:28]1[CH:29]=[CH:30][C:31]([S:34]([NH-:37])(=[O:36])=[O:35])=[N:32][CH:33]=1)([CH3:27])[CH3:26]>>[Cl:17][C:6]1[N:5]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:3]=[C:2]([NH:37][S:34]([C:31]2[CH:30]=[CH:29][C:28]([CH:25]([CH3:27])[CH3:26])=[CH:33][N:32]=2)(=[O:36])=[O:35])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16]
Reactant: CC(C)c1ccc(S([NH-])(=O)=O)nc1
Reactant: COc1ccccc1Oc1c(Cl)nc(N2CCOCC2)nc1Cl
Agent: [K+]
Product: COc1ccccc1Oc1c(Cl)nc(N2CCOCC2)nc1NS(=O)(=O)c1ccc(C(C)C)cn1

Procedure:
4,6-Dichloro-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidine is treated with 5-isopropyl-pyridine-2-sulfonamide potassium salt to form 5-isopropyl-pyridine-2-sulfonic acid 6-chloro-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl-amide. This compound is then added to a solution of sodium in ethylene glycol. After heating, 5-isopropyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl-amide is obtained and then added to a solution of pyridine-2-carbonyl azide in dioxane to form pyridin-2-yl-carbamic acid 2-[6-(5-isopropyl-pyridine-2-sulfonylamino)-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yloxy]-ethyl ester (see EP 0713875A1).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].I[C:10]1[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=1.[CH3:18][NH:19][CH:20]=[O:21].CCCCCCCCCCCC>C(OCC)(=O)C.[Cu]I.C1(C)C=CC=CC=1>[CH3:16][C:14]1[CH:15]=[C:10]([N:19]([CH3:18])[CH:20]=[O:21])[CH:11]=[C:12]([CH3:17])[CH:13]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: CNC=O
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCCCCCCCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(N(C)C=O)c1
Temperature: 110 °C
Reaction time: 24 h
Yield: 54 %

Procedure:
A Schlenk tube was charged with CuI (9.6 mg, 0.050 mmol, 5.0 mol %), 3,1′-dimethyl-4,5-dihydro-3H,1′H-[,2′]biimidazolyl-2-one (18 mg, 0.10 mmol, 10 mol %), K3PO4 (430 mg, 2.03 mmol), evacuated, backfilled with Ar. 5-Iodo-m-xylene (145 μL, 1.00 mmol), N-methylformamide (72 μL, 1.23 mmol), and toluene (1.0 mL) were added under Ar. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 110° C. for 24 h. The suspension was allowed to reach room temperature. Dodecane (internal GC standard, 230 μL) and ethyl acetate (2 mL) were added. A 0.1 mL sample of the supernatant solution was diluted with ethyl acetate (1 mL) and analyzed by GC to provide 54% yield of N-(3,5-dimethylphenyl)-N-methylformamide.