Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C@@H:5]2[C:6]([CH:8]=[CH:9][C@H:3]1[CH2:4]2)=[O:7].[CH3:11][C:12]([C:20]1[CH:21]=[C:22]([OH:27])[CH:23]=[C:24]([CH:26]=1)[OH:25])([CH3:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[OH:25][C:24]1[C:23]2[C@@H:9]3[CH2:8][C:6](=[O:7])[CH2:5][CH2:4][C@H:3]3[C:2]([CH3:1])([CH3:10])[O:27][C:22]=2[CH:21]=[C:20]([C:12]([CH3:11])([CH3:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:26]=1
Reactant: CCCCCCC(C)(C)c1cc(O)cc(O)c1
Reactant: CC1(C)[C@H]2C=CC(=O)[C@@H]1C2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCC(C)(C)c1cc(O)c2c(c1)OC(C)(C)[C@@H]1CCC(=O)C[C@@H]21

Procedure:
The process according to claim 7 wherein (+)-apoverbenone is reacted with about an equimolar quantity of 5-(1,1-dimethylheptyl)resorcinol in dichloromethane in the presence of about an equimolar quantity of aluminum chloride at a temperature of from about -10° C. to about 30° C. for a period of time of from about 48 to about 96 hours to form (-)-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]-pyran-9-one.
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][C:10]([Cl:27])([Cl:26])[CH2:11][O:12][C:13]([C:15]1[N:20]2[C:21](=[O:24])[CH:22]([NH2:23])[C@H:19]2[S:18][CH2:17][C:16]=1[CH3:25])=[O:14].Cl[C:29]1[C:34]([O:35][C:36](=[O:53])[CH:37]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:38](OC2C=CC=CC=2)=[O:39])=[C:33](Cl)[C:32](Cl)=[C:31](Cl)[C:30]=1Cl>C(Cl)Cl>[Cl:27][C:10]([Cl:9])([Cl:26])[CH2:11][O:12][C:13]([C:15]1[N:20]2[C:21](=[O:24])[CH:22]([NH:23][C:38](=[O:39])[CH:37]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:36]([O:35][C:34]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:53])[C@H:19]2[S:18][CH2:17][C:16]=1[CH3:25])=[O:14]
Reactant: O=C(Oc1ccccc1)C(C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl)c1ccccc1
Reactant: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(N)[C@H]2SC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)C(C(=O)Oc3ccccc3)c3ccccc3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
2.8 ml. (0.02 moles) of triethylamine are added to a suspension of 3.8 g. (0.01 mole) of 7-amino-3-methyl-ceph-3-em-4-carboxylic acid trichloroethyl ester hydrochloride in 30 ml. of methylene chloride. The separated triethylamine hydrochloride is filtered off, the filtrate is cooled to 0° C., and 5.02 g (0.01 mole) of phenylmalonic acid phenylester pentachlorophenyl ester are added. The obtained clear solution is stirred at the same temperature for 30 minutes, thereafter it is washed with 2 n aqueous hydrochloride acid and the solvent is evaporated. The residue is treated with absolute ethanol. 4.7 g. (80%) of 7-(α-phenoxycarbonyl-phenylacetamido)-3-methyl-ceph-3-em-4-carboxylic acid trichloroethyl ester are obtained. The white, crystalline substance melts at 120°-125° C.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:24].[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1>C1COCC1>[CH3:25][N:26]1[CH2:27][CH2:28][N:29]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:24])=[CH:34][CH:33]=2)[CH2:30][CH2:31]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CC(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(N3CCN(C)CC3)cc2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 53 %

Procedure:
A small screw cap test tube was charged with N-[3-(3-Hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-acetamide (as prepared in Example 40, 100 mg, 0.310 mmol) and THF (2 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (65.27 mg, 0.341 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was purified over silica (5% MeOH/CHCl3) providing the title compound in 53% yield (81 mg, 0.163 mmol).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.CCN(CC)CC.[CH2:17]([NH2:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>C(O)CCC>[Cl:9][C:3]1[N:4]=[CH:5][N:6]=[C:7]([NH:22][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:2]=1[NH2:1]
Reactant: CC(C)(C)CN
Reactant: Nc1c(Cl)ncnc1Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CC(C)(C)CNc1ncnc(Cl)c1N
Reaction time: 12 h

Procedure:
A solution of 5-amino-4,6-dichloropyrimidine (1 mmol) in nBuOH was treated with Et3N (1.2 mmol) and neopentylamine (1.05 mmol) at 80° C. After 12 h, the cooled reaction mixture was evaporated under vacuum and the residue was chromatographed to give 6-chloro-5-amino-4-(neopentylamino)-pyrimidine as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C(=O)(O)[O-:20].[Na+].O.ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][C:10]2=[O:20])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2=CCCc3ccccc32)c1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1cccc(C2C(=O)CCc3ccccc32)c1
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a 2-phase mixture of 25.1 g (0.106 mol) of 1-(3-methoxyphenyl)-3,4-dihydronaphthalene, 20 g (0.238 mol) of sodium bicarbonate, 200 ml of water, and 400 ml of methylene chloride at 5° C. was added 24.4 g of 80-85% m-chloroperbenzoic acid portion-wise over 15 minutes. The internal temperature rose to 10° C. After the addition was complete, the mixture was stirred at 0°-5° C. for 2 hr. The layers were separated and the aqueous layer was extracted with 100 ml of methylene chloride. The combined organic layers were extracted with 200 ml of 10% sodium carbonate and then with 100 ml of water, dried over MgSO4 and evaporated to an oil. IR, NMR, and thin layer chromatography indicated the presence of a mixture of epoxide and 1,2-diol monoester. The crude mixture was stirred 3 hours at room temperature in 1M solution of sodium hydroxide in 5:1 ethanol-water. After adjusting the pH to 8 with HCl, the bulk of the solvent was evaporated. The residue was taken up in 500 ml of ether, which was then washed with 50 ml of water, dried over MgSO4, and evaporated. The oily residue was dissolved in 300 ml of dry toluene containing 0.050 g of p-toluenesulfonic acid and refluxed 3 hour in a Dean-Stark apparatus. The solution was washed with 50 ml of 5% sodium bicarbonate and with 50 ml of water, dried over MgSO4 and evaporated to give 25.1 g of the title compound, which was characterized as its 2,4-dinitrophenyl hydrazone derivative, m.p. 161°-161.5° C. (ethanol).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15]Br)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH3:23][O:24][N:25]=[C:26]1[C:30]2[CH:31]=[CH:32][C:33]([OH:35])=[CH:34][C:29]=2[O:28][CH2:27]1>CN(C)C=O>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:35][C:33]1[CH:32]=[CH:31][C:30]2[C:26](=[N:25][O:24][CH3:23])[CH2:27][O:28][C:29]=2[CH:34]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CON=C1COc2cc(O)ccc21
Reactant: CON=C(C(=O)OC)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CON=C(C(=O)OC)c1ccccc1COc1ccc2c(c1)OCC2=NOC
Temperature: 0 °C

Procedure:
3.4 g of (E) methyl methoxyimino-(2-bromomethylphenyl)acetate was added to 9.0 g of potassium carbonate and 1.8 g of 3-methoxyimino-6-hydroxy-2,3-dihydrobenzofuran in 30 ml of N,N-dimethylformamide, and they were reacted at room temperature for 6 hours. After the completion of the reaction, the reaction liquid was poured in ice/water. After the extraction with ethyl acetate, the extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by the silica gel chromatography (hexane:ethyl acetate) to obtain 3.0 g of the title compound. (having a m.p. of 108-110° C. and 1H-NMR data shown in the following table).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([OH:37])[CH:34]=2)[CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:37][CH2:39][CH2:40][CH2:41][N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)[CH:34]=2)[CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1cc(C(=O)N2Cc3ccc(O)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: ClCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)c1cc(C(=O)N2Cc3ccc(OCCCN4CCOCC4)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 90 °C
Yield: 72.6 %

Procedure:
A mixture of (2,4-bis-benzyloxy-5-isopropyl-phenyl)-(5-hydroxy-1,3-dihydro-isoindol-2-yl)-methanone (100 mg, 0.2 mmol), 4-(3-chloropropyl)morpholine (82 mg, 0.5 mmol) and K2CO3 (104 mg, 0.75 mmol) in DMF (5 ml) was heated at 90° C. for 16 hours. The reaction mixture was diluted with EtOAc and filtered. The filtrate was reduced in vacuo and purified by flash column chromatography, eluting with 0-100% P.E./EtOAc then 0-10% MeOH/EtOAc to give the title compound as a colourless gel (90.1 mg). MS: [M+H]+ 621.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][N:34]=2)[CH:29]=[CH:28][C:27]=1[C:36](O)=[O:37]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:36]([C:27]4[CH:28]=[CH:29][C:30]5[C:35](=[N:34][CH:33]=[CH:32][CH:31]=5)[N:26]=4)=[O:37])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(O)c1ccc2cccnc2n1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccc5cccnc5n4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 1,8-naphthyridine-2-carboxylic acid as starting compounds. The crude product is purified by chromatography (silica gel and DCM/diethyl ether/methanol=49:49:3) to yield the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH3:12][NH:13][CH3:14].CO>>[CH3:12][N:13]([CH3:14])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: CNC
Reactant: COC(=O)c1ccc(Cl)nc1
Solvent: CO
Product: COC(=O)c1ccc(N(C)C)nc1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
A solution of methyl 6-chloronicotinate (4.0 g, 23 mmol) in dimethylamine/MeOH (2 M, 80 mL, 160 mmol) in a pressure vessel was stirred at 95° C. for 2 h, cooled to rt and concentrated. The residue was dissolved in EtOAc (250 mL), washed with water (2×150 mL), dried over Na2SO4, and concentrated to afford the title compound as a tan solid (4.1 g, 98%). MS (ESI), (M+H)+ 181.24; 1H NMR (CDCl3) δ 8.79 (s, 1H), 7.99 (d, 1H, J=9.2), 6.45 (d, 1H, J=9.2), 3.85 (s, 3H), 3.15 (s, 6H).
Reaction SMILES: [CH3:1][N:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[S:3]([C:6](=O)[C:7]1C=[CH:11][C:10]([NH:13]C)=[C:9]([N+:15]([O-])=O)[CH:8]=1)(=[O:5])=[O:4].O.NN.[CH4:28]>C(O)(C)C>[NH2:13][C:10]1[CH:11]=[C:6]([S:3]([N:2]([CH3:1])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)(=[O:4])=[O:5])[CH:7]=[CH:8][C:9]=1[NH:15][CH3:28]
Reactant: CNc1ccc(C(=O)S(=O)(=O)N(C)c2ccccc2)cc1[N+](=O)[O-]
Reactant: C
Agent: NN
Solvent: CC(C)O
Solvent: O
Product: CNc1ccc(S(=O)(=O)N(C)c2ccccc2)cc1N
Reaction time: 8 h

Procedure:
N-Methyl-4-(methylamino)-3-nitro-N-phenylbenzoyl sulfonamide (9 g, 0.028 mol) was dissolved in isopropanol (90 ml). To this solution, hydrazine hydrate (11 ml), activated charcoal (2 g), and FeCl3.6H2O (0.5 g in 10 ml ethanol) were added. The reaction mixture was boiled for 8 h. The charcoal was removed by filtration. The filtrate was evaporated to dryness. The yield of 3-amino-N-methyl-4-(methylamino)-N-phenylbenzene sulfonamide was 8.1 g (99%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[CH3:12][C@H:13]1[O:18][C@@H:17]([CH3:19])[CH2:16][NH:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:19][C@H:17]1[O:18][C@@H:13]([CH3:12])[CH2:14][N:15]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=2)[CH2:16]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])c(N)c2)C[C@H](C)O1
Temperature: 110 °C
Reaction time: 48 h
Yield: 68.2 %

Procedure:
A mixture of 5-chloro-2-nitrophenylamine (1.3 g, 7.0 mmol), cis-2,6-dimethylmorpholine (2.5 g, 20 mmol), and K2CO3 (3.0 g, 22 mmol) in DMF (20 mL) was stirred at 110° C. for 48 h. The reaction mixture was cooled to room temperature, poured into water (300 mL). The resulting crude yellow solid was collected by vacuum filtration, air dried, and purified by flash chromatography (silica gel, 4×7.5 cm, eluted with 95/5 CHCl3/ether) to yield the product as a yellow solid (1.2 g, 68%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][OH:8].[H-].[Na+].[I:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][C:16]([C:22]#[N:23])=[CH:15]2>CN(C=O)C>[I:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][C:16]([C:22]#[N:23])=[C:15]2[O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: N#Cc1cnc2ccc(I)cc2c1
Reactant: COCCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCCOc1c(C#N)cnc2ccc(I)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.6 %

Procedure:
To the solution of diethylene glycol monomethyl ether (0.75 mL, 6.4 mmol) in DMF (10 mL) was added sodium hydride (0.26 g, 6.4 mmol). After stirring at room temperature for 30 min, 6-iodo-quinoline-3-carbonitrile (example 14c) (1.0 g, 3.18 mmol) was added to the mixture. After further stirring at room temperature for 30 min, ice water was slowly added to the reaction. The reaction was extracted with methylene chloride. The combined organic layers were successively washed with a saturated aqueous sodium bicarbonate solution and water, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 0%-45% ethyl acetate in hexanes in 30 min) afforded 6-iodo-4-[2-(2-methoxy-ethoxy)-ethoxy]-quinoline-3-carbonitrile (0.59 g, 46%) as a light yellow solid. LC-MS m/e 399 (MH+).
Reaction SMILES: CO.[C:3]([NH:10][C:11]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[N:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:28]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:28][N:12]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C:11]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[N:10][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)C(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A solution of anhydrous methanol (0.04 ml, 1.0 mmol), N-,N′-,N″-tri-Boc-guanidine (1.80 g, 5.0 mmol), and triphenylphoshine (393 mg, 1.5 mmol) in anhydrous THF (50 ml) is cooled to −5° C. under an atmosphere of argon. Diethylazodicarboxylate (DEAD, 0.22 ml, 1.5 mmol) is added dropwise at a rate such that the reaction mixture is completely colorless before addition of the next drop. After the addition is completed, the reaction mixture is refluxed for 15 h. The solution is then cooled to room temperature, and hexanes (50 ml) is added. A precipitate of excess N-,N′-,N″-tri-Boc-guanidine forms which is collected by filtration on a Buechner-funnel and washed with a mixture of THF/hexanes 1:1. The filtrate is concentrated under reduced pressure and the product (colorless oil, 182 mg, 49%) isolated by flash chromatography on silica gel (eluent: dichloromethane-ethyl ether 98:2): 1H NMR (360 MHz, DMSO-d6) δ 10.17 (s, 1H), 2.94 (s, 3H), 1.43-1.36 (27H); FAB-MS m/e (relative intensity).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:22]([F:25])([F:24])[F:23])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH2:17][CH2:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[N:26]([O-])=[O:27].[Na+]>Cl.O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:22]([F:24])([F:23])[F:25])[CH:11]=[CH:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([N:26]=[O:27])[CH2:17][CH2:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: Fc1c(Cl)cc(C(/C=C/c2ccc3c(c2)CCN3)C(F)(F)F)cc1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=NN1CCc2cc(C=CC(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)indoline (0.2 g, 0.5 mmol) in concentrated HCl (5.0 ml) at 5° C., was added slowly NaNO2 in water and the reaction was allowed to stir at RT for 2 h. The reaction mixture was diluted with DCM, and the DCM layer washed with water and brine solution. The separated DCM layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude product as a pale yellow solid that was used in the next step without further purification (0.2 g): 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J=8.4 Hz, 1H), 7.39 (m, 4H), 6.61 (d, J=16.0 Hz, 1H), 6.35 (dd, J=16.0, 8.4 Hz, 1H), 4.07 (m, 3H), 3.23 (t, J=8.4 Hz, 2H); ESIMS m/z 418.82 ([M+H]+); IR (thin film) 1488, 1112, 860 cm−1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.C(O)C.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1.P(=O)(O)(O)O>C(Cl)Cl>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:20][CH2:19][C:18]2[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[N:3]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: COc1ccc(CN)cc1
Agent: O=P(O)(O)O
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(CNc2nc(Cl)cc(Cl)n2)cc1
Reaction time: 18 h

Procedure:
A 27.5 g portion of 2,4,6-trichloropyrimidine was suspended in a mixed solvent of 200 ml ethanol and 200 ml methylene chloride, to which, under ice-cooling, was subsequently added dropwise 30 ml of 4-methoxybenzylamine. After 19 hours of stirring at the same temperature, 10 ml of 4-methoxybenzylamine was further added dropwise and the mixture was stirred for 18 hours. The reaction solution was mixed with 200 ml of 0.5 N phosphoric acid aqueous solution and extracted with chloroform, and then the organic layer was washed with saturated brine. After drying with anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure, and the thus obtained residue was applied to a silica gel chromatography and developed with a chloroform-hexane (3:1) mixed solvent to obtain 13.3 g of 4,6-dichloro-2-(4-methoxybenzyl)aminopyrimidine and further developed with a chloroform-ethyl acetate (1:3) mixed solvent to obtain 24.2 g of 2,6-dichloro-4-(4-methoxybenzyl)aminopyrimidine. 2,6-Dichloro-4-(4-methoxybenzyl)aminopyrimidine
Reaction SMILES: C(N(CC)CC)C.[N-:8]=[N+:9]=[N-:10].[Na+].[N+]([C:15]1[CH:33]=[CH:32][CH:31]=[C:17]2[C:18]([N:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[C:21](=[O:22])[C:16]=12)=[O:19])([O-])=O>CS(C)=O>[N:8]([C:31]1[CH:32]=[CH:33][CH:15]=[C:16]2[C:21]([N:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[C:18](=[O:19])[C:17]=12)=[O:22])=[N+:9]=[N-:10]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)CCCCCN1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=Nc1cccc2c1C(=O)N(CCCCCC(=O)O)C2=O
Temperature: 50 °C
Reaction time: 18 h
Yield: 93.7 %

Procedure:
2.58 ml (0.018 mol) of triethylamine, followed by 1.3 g (0.0198 mol) of sodium azide, are added to a mixture of 5.7 g (0.018 mol) of 6-(3-nitrophthalimidyl)-caproic acid in 35 ml of dimethylsulphoxide. The reaction mixture is heated for 6 hours at 50° C. and is then concentrated in vacuo, diluted with 100 ml of water and acidified with 4 ml of concentrated hydrochloric acid. The resulting suspension of the reaction product is stirred for 18 hours and filtered with suction, and the filter residue is washed with 20 ml of water and dried for 24 hours at 60° C./0.100. mm Hg, over phosphorus pentoxide. 5.1 g (94% of theory) of 6-(3-azidophthalimidyl)-caproic acid are obtained; melting point 87°-90° C. (with decomposition). IR spectrum (CH2Cl2): 1780 and 1725 cm-1 (CO--N--CO); 2130 cm-1 (N3).
Reaction SMILES: [I-:1].[Na+].CS(O[CH2:8][CH2:9][CH2:10][C:11]([CH3:16])([N+:13]([O-:15])=[O:14])[CH3:12])(=O)=O.[Al].O>CC(C)=O>[CH3:12][C:11]([N+:13]([O-:15])=[O:14])([CH3:16])[CH2:10][CH2:9][CH2:8][I:1]
Reactant: [I-]
Reactant: CC(C)(CCCOS(C)(=O)=O)[N+](=O)[O-]
Agent: [Al]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(CCCI)[N+](=O)[O-]
Reaction time: 17 h
Yield: 97.1 %

Procedure:
A solution of sodium iodide (17.41 g, 3.9 equiv, 116.6 mmol) in acetone (100 mL, 0.3 M) was added a flask which contained 4-methyl-4-nitropentyl methanesulfonate (6.73 g, 29.9 mmol). The flask was sealed with a septum and covered with aluminum foil and allowed to stir for 17 h. Water (20 ml) was added to the suspension and the acetone was removed by rotovap at reduced pressure. The aqueous solution was extracted with ethyl acetate (150 mL) and washed with 5% aqueous sodium thiosulfate solution (40 ml) and brine (40 ml). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to give a yellow oil (7.46 g, yield 92.0%). 1H NMR (CDCl3, 400 MHz): δ 1.60 (s, 6H), 1.78-1.82 (m, 2H), 2.01-2.04 (m, 2H), 3.14-3.18 (t, 2H). LRMS (ESI+) for C6H12INO2 (257.0); Found: 258 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][CH:37]([C:40]([NH2:42])=[O:41])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([N:34]3[CH2:35][CH2:36][CH:37]([C:40]([NH2:42])=[O:41])[CH2:38][CH2:39]3)(=[O:32])=[O:33])=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: NC(=O)C1CCN(S(=O)(=O)c2ccccc2Br)CC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: NC(=O)C1CCN(S(=O)(=O)c2ccccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)CC1

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and 1-((2-bromophenyl)sulfonyl)piperidine-4-carboxamide. MS (ESI): mass calcd. for C22H22FN5O3S, 455.14; m/z found, 455.9 [M+H]+. 1H NMR (500 MHz, DMSO-δ6) δ 8.51 (d, J=1.4, 2H), 8.02 (dd, J=8.0, 1.3, 1H), 7.78-7.71 (m, 1H), 7.69-7.63 (m, 1H), 7.61-7.54 (m, 1H), 7.45 (dd, J=7.6, 1.4, 1H), 7.32 (dd, J=11.8, 1.7, 1H), 7.26 (dd, J=7.9, 1.8, 1H), 7.17 (s, 1H), 6.88 (s, 2H), 6.73 (s, 1H), 3.26-3.19 (m, 2H), 2.47-2.38 (m, 2H), 2.13-2.02 (m, 1H), 1.59 (dd, J=13.9, 3.8, 2H), 1.31-1.17 (m, 2H).