Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[C:13]([CH3:14])=[N:12][N:11]([C:15]3[N:20]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[CH:18]=[CH:17][N:16]=3)[C:10]2=[O:27])=[CH:4][CH:3]=1.[C:28](=O)([O-])[O-].[K+].[K+].IC.O>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:13]([CH3:14])=[N:12][N:11]([C:15]3[N:20]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[CH:18]=[CH:17][N:16]=3)[C:10]=2[O:27][CH3:28])=[CH:4][CH:3]=1
Reactant: CC1=NN(c2nccc(-c3ccccn3)n2)C(=O)C1Sc1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(Sc2ccc(Cl)cc2)c(C)nn1-c1nccc(-c2ccccn2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 2 %

Procedure:
To a solution of 4-(4-chloro-phenylsulfanyl)-5-methyl-2(4-pyridin-2yl-pyrimidin-2-yl)-2,4-dihydro-pyrazol-3-one (0.344 g, 0.869 mmol) in acetone (10 mL) was added potassium carbonate (ca. 3 g) and iodomethane (0.130 g, 0.912 mmol). The suspension was heated to reflux and stirred for 2 hours. The suspension was allowed to cool to room temperature, and water (100 mL) was added. The mixture was extracted with diethyl ether (50 mL), and the organic phase was washed with brine (50 mL), dried (magnesium sulfate), filtered and concentrated to afford a white solid. Flash chromatography over silica (methylene chloride/2M ammonia in methanol, two columns) provided 0.007 g (2%) of the product as a white solid. 1H NMR analysis was consistent with the assigned structure.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:12]([C:17]([N:19]2[CH2:23][C@H:22]([OH:24])[CH2:21][C@H:20]2[CH2:25][NH:26][C:27]([C:29]2[CH:30]=[CH:31][CH:32]=[C:33]3[C:38]=2[N:37]=[CH:36][CH:35]=[CH:34]3)=[O:28])=[O:18])=[CH:13][CH:14]=[CH:15][CH:16]=1.CCN(CC)CC>C(Cl)Cl>[C:11]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:12]([C:17]([N:19]2[CH2:23][C:22](=[O:24])[CH2:21][C@H:20]2[CH2:25][NH:26][C:27]([C:29]2[CH:30]=[CH:31][CH:32]=[C:33]3[C:38]=2[N:37]=[CH:36][CH:35]=[CH:34]3)=[O:28])=[O:18])=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(NC[C@@H]1C[C@@H](O)CN1C(=O)c1ccccc1-c1ccccc1)c1cccc2cccnc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1C[C@@H](CNC(=O)c2cccc3cccnc23)N(C(=O)c2ccccc2-c2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 52.7 %

Procedure:
To a solution of oxalyl chloride (39 μL, 0.45 mmol) in DCM (7 mL) at −78° C., was added a solution of DMSO (64 μL, 0.90 mmol) in DCM (4 mL). After stirring at −78° C. for 15 min, a solution of N-(((2S,4R)-1-(biphenylcarbonyl)-4-hydroxypyrrolidin-2-yl)methyl)quinoline-8-carboxamide (0.135 g, 0.30 mmol) in DCM (4 mL) was added. The resulting mixture was stirred at −78° C. for 1 h, treated with Et3N (0.25 mL, 1.8 mmol) dropwise and then allowed to warm to rt gradually over 1.5 h. The mixture was then concentrated in vacuo to a beige solid and purified by column chromatography on silica gel (70% MeOH in EtOAc) to provide (S)—N-((1-(biphenylcarbonyl)-4-oxopyrrolidin-2-yl)methyl)quinoline-8-carboxamide as a white solid (0.071 g, 53% yield). MS (ESI) 450.12 (M+H).
Reaction SMILES: [CH:1]([S:3]([CH3:6])(=[O:5])=[O:4])=[CH2:2].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[NH2:36][C:37]1[C:46]2[N:47]=[CH:48][N:49]([CH2:50][C:51]([CH3:54])([OH:53])[CH3:52])[C:45]=2[C:44]2[CH:43]=[CH:42][C:41](Br)=[CH:40][C:39]=2[N:38]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[NH2:36][C:37]1[C:46]2[N:47]=[CH:48][N:49]([CH2:50][C:51]([CH3:54])([OH:53])[CH3:52])[C:45]=2[C:44]2[CH:43]=[CH:42][C:41]([CH:2]=[CH:1][S:3]([CH3:6])(=[O:5])=[O:4])=[CH:40][C:39]=2[N:38]=1
Reactant: C=CS(C)(=O)=O
Reactant: CC(C)(O)Cn1cnc2c(N)nc3cc(Br)ccc3c21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(O)Cn1cnc2c(N)nc3cc(C=CS(C)(=O)=O)ccc3c21
Temperature: 120 °C
Yield: 44.1 %

Procedure:
A thick walled glass tube, equipped with a stir bar, was charged with palladium (II) acetate (15 mg, 0.07 mmol), acetonitrile (50 mL), methyl vinyl sulfone (268 mg, 2.52 mmol), triethylamine (1.00 mL, 7.17 mmol), tri-o-tolylphosphine (45 mg, 0.21 mmol) and 1-(4-amino-7-bromo-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (800 mg, 2.39 mmol). The reaction mixture was purged with nitrogen and the tube was sealed and heated at 120° C. in an oil bath. The reaction was maintained at 120° C. for 12 hours, cooled to ambient temperature, and then concentrated under reduced pressure to yield a dark brown oil. The oil was partitioned between chloroform (75 mL) and a solution comprised of a 1:1 combination of 10% aqueous potassium carbonate and 10% sodium hydroxide. A precipitate formed. The mixture was filtered and the recovered solid was purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with 20% methanol in dichloromethane. The filtrate was also concentrated and the residue purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a 0-8% gradient of methanol in dichloromethane). The two lots of purified product were combined to provide 380 mg of 1-{4-amino-7-[2-(methylsulfonyl)ethenyl]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol as a pale yellow solid. MS (APCI) m/z 361 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[C:21]([CH2:22][OH:23])=[C:20]([CH2:24][N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)[C:19]2[CH:18]=[C:17]3[O:32][CH2:33][CH2:34][O:35][C:16]3=[CH:15][C:14]=2[N:13]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[C:21]([CH:22]=[O:23])=[C:20]([CH2:24][N:25]2[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)[C:19]2[CH:18]=[C:17]3[O:32][CH2:33][CH2:34][O:35][C:16]3=[CH:15][C:14]=2[N:13]=1
Reactant: CN1CCN(Cc2c(CO)c(Cl)nc3cc4c(cc23)OCCO4)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1CCN(Cc2c(C=O)c(Cl)nc3cc4c(cc23)OCCO4)CC1
Temperature: -78 °C
Reaction time: 0.05 h

Procedure:
A 3-necked 4-L round-bottom flask is equipped with a mechanical stirrer and a 250-mL addition funnel. Under nitrogen, the flask is charged with methylene chloride (800 mL), followed by addition of oxalyl chloride (28.8 mL, 330 mmol). The solution is cooled to −78° C. and dimethyl sulfoxide (46.7 mL, 660 mmol) is added over 6 min. The temperature of the solution increases to −58° C. during the addition and is cooled back to about −70 ° C. After stirring for 3 min, [7-chloro-9-(4-methylpiperazin-1-ylmethyl)-2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-8-yl]-methanol (100 g, 275 mmol), as prepared above, is added as a solution in 140 mL of methylene chloride over 10 min. The yellow slurry is stirred for 45 min, then anhydrous triethylamine (153 mL, 1.10 mol) is added over 4 min. Stirring is continued for 10 min at −78 ° C., then the cooling bath is removed. The reaction mixture iF allowed to warm to −5 ° C. and poured into 2 L of water. The organic layer is separated and the aqueous layer is extracted with methylene chloride (3×1.5 L). The combined organic layers are washed with brine (2 L), dried over anhydrous sodium sulfate and concentrated in vacuo yielding 7-chloro-9-(4-methylpiperazin-1-ylmethyl)-2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-8-carbaldehyde as a dark solid. This crude product is used for the next step without further purification. Recrystallization from CH2Cl2-MeOH (5:1) provided an analytical sample as a light yellow solid:140-142° C. (dec.). 1H NMR (CDCl3, 200 MHz) d 2.30 (s, 3H), 2.45, 2.59 (m, 8H), 3.98 (s, 2H). 4.41(s, 4H), 7.46 (s, 1H), 7.53 (s, 1H), 10.4 (s, 1H). Elemental analysis: Calculated for C18H20CIN3O3: C 59.75, H 5.57, N 11.61. Found: C 59.78, H 5.62, N 11.64.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6](O)=[CH:7][CH:8]=1.[C:12]([O-:15])([O-])=O.[K+].[K+].[Br:18][CH2:19][CH2:20][CH2:21]CBr.O>CC#N>[F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=1[O:15][CH2:12][CH2:21][CH2:20][CH2:19][Br:18]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: BrCCCCBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: FC(F)(F)c1ccccc1OCCCCBr
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of α,α,α-trifluoro-p-cresol (2.22 g, 13.7 mmol), K2CO3 (1.99 g, 14.4 mmol) and 1,4-dibromobutane (14.5 g, 68.5 mmol) in CH3CN (50 mL) was stirred at ref lux under N2 for 24 h. The reaction was allowed to cool to 25° C. and then added to water (100 mL). The resulting biphasic mixture was extracted with CHCl3 3×50 mL). The extract was washed with water (1×50 mL), saturated NaHCO3 (2×50 mL) and water (1×50 mL), filtered through cotton and the solvent removed in vacuo to give an orange liquid. The excess 1,4-dibromobutane was removed by vacuum distillation (5 Torr, 72-78° C.). The still pot residue, which contained the product was subjected to chromatography on silica gel (2.5×30 cm) with CHCl3 elution, yielded a colorless liquid; (2.75 g, 68%); 1H NMR (CDCl3) 1.89-2.17 (m, 4 H), 3.50 (t, J=6.3 Hz, 2 H), 4.09 (t, J=5.7 Hz, 2 H), 6.92-7.05 (m, 2 H), 7.48 (t, J=7.8 Hz, 1 H), 7.56 (d, J=7.8 Hz, 1 H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[NH:13][C:14]([CH:17]=[C:18]3[C:26]4[C:25]([Cl:27])=[N:24][CH:23]=[N:22][C:21]=4[NH:20][C:19]3=[O:28])=[CH:15][CH:16]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:29]([C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34])#[CH:30]>>[ClH:27].[N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[NH:13][C:14]([CH:17]=[C:18]3[C:26]4[C:25]([NH:34][C:33]5[CH:35]=[CH:36][CH:37]=[C:31]([C:29]#[CH:30])[CH:32]=5)=[N:24][CH:23]=[N:22][C:21]=4[NH:20][C:19]3=[O:28])=[CH:15][CH:16]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C1Nc2ncnc(Cl)c2C1=Cc1ccc(C(=O)NCCN2CCOCC2)[nH]1
Reactant: C#Cc1cccc(N)c1
Product: C#Cc1cccc(Nc2ncnc3c2C(=Cc2ccc(C(=O)NCCN4CCOCC4)[nH]2)C(=O)N3)c1
Product: Cl
Yield: 20 %

Procedure:
The title compound (20% yield) was prepared from 5-(4-chloro-6-oxo-6,7-dihydro-pyrrolo[2,3-d]pyrimidin-5-ylidenemethyl)-1H-pyrrole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide and 3-ethynylaniline according to the procedure described for Example 12. MS 484.3 [M++1].
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:8]([O:10]C(C)(C)C)=[O:9])[CH2:3][CH2:4][C:5](=O)[OH:6].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.[NH2:56][C:57]1[C:58]([OH:68])=[C:59]([S:64]([OH:67])(=[O:66])=[O:65])[CH:60]=[C:61]([Cl:63])[CH:62]=1>CN(C=O)C.C(O)(C(F)(F)F)=O.N1C=CC=CC=1>[NH2:1][C@@H:2]([CH2:3][CH2:4][C:5](=[O:6])[NH:56][C:57]1[CH:62]=[C:61]([Cl:63])[CH:60]=[C:59]([S:64]([OH:67])(=[O:66])=[O:65])[C:58]=1[OH:68])[C:8]([OH:10])=[O:9]
Reactant: Nc1cc(Cl)cc(S(=O)(=O)O)c1O
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CCC(=O)Nc1cc(Cl)cc(S(=O)(=O)O)c1O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
101 mg (0.33 mmol) of Boc-Glu-OtBu, 130 mg (0.33 mmol) of HATU, 45 mg (0.33 mmol) of HOAt and 77 mg (0.33 mmol) of 3-amino-5-chloro-2-hydroxybenzenesulfonic acid were suspended in 2.0 ml of DMF, to which 0.5 ml of pyridine was added and stirred at room temperature overnight. After distilling the solvent away, purification step A was used to obtain an intermediate. This crude product was dissolved in 2.0 ml of TFA and stirred at room temperature for 90 minutes. After distilling the solvent away, purification step A was used to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][C:13]#[N:14])=[CH:7][CH:6]=1.[H][H]>[Ni].CO>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][CH2:13][NH2:14])=[CH:9][CH:10]=1
Reactant: COCOc1ccc(C(CC#N)c2cccnc2)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: COCOc1ccc(C(CCN)c2cccnc2)cc1
Yield: 89.4 %

Procedure:
An appropriate amount of Raney nickel was suspended in 15 ml of saturated ammonical methanol solution, 0.54 g of 3-(4-methoxymethyloxyphenyl)-3-(3-pyridyl)propionitrile was added to the suspension and the mixture was stirred for 18 hours under 15 atmospheric pressure in an atmosphere of hydrogen. The resulting reaction mixture was filtered and the filtrate was concentrated under a reduced pressure. The thus prepared residue was subjected to silica gel column chromatography to obtain 0.49 g of 3-(4-methoxymethyloxyphenyl)-3-(3-pyridyl)propylamine from ammonia water-methanol-chloroform (1:10:100 v/v) eluate fraction.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:27][O:28][CH2:29]Cl>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:27][O:28][CH3:29])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCOc1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 70 °C
Yield: 54 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (30 mg, 0.11 mmol), potassium carbonate (31 mg, 0.23 mmol) and chloromethyl methyl ether (26 μL, 0.34 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 70° C. for 2 hour. The reaction was cooled, diluted with dichloromethane, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography using 20–30% hexanes/ethyl acetate afforded 1 g mg (54%) of 3-(2-Pyridyl)-5-(3-cyano-5-(methoxymethoxy)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.86 (d, 1H), 8.24 (d, 1H), 8.22 (s, 1H), 8.15 (s, 1H), 7.91 (t, 1H), 7.56 (s, 1H), 7.49 (m, 1H), 5.31 (s, 2H), 3.52 (s, 3H).
Reaction SMILES: [C:1]1([S:7][C@H:8]2[NH:11][C:10](=[O:12])[C@H:9]2[NH:13]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[NH2:13][C@H:9]1[C@@H:8]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:11][C:10]1=[O:12]
Reactant: O=C1N[C@H](Sc2ccccc2)[C@@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: N[C@@H]1C(=O)N[C@@H]1Sc1ccccc1

Procedure:
To a solution of 1.5 g of (3R,4R)-4-phenylthio-3-tritylamino-2-oxoazetidine in 20 ml of acetone is added 0.72 g of p-toluenesulfonic acid monohydrate under ice-cooling. Following the procedure to Reference Example 45B, there is obtained 1.25 g of tosyl salt of (3R,4R)-3-amino-4-phenylthio-2-oxoazetidine.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C@@H:19]3[O:23][CH2:22][C@@H:21](Br)[CH2:20]3)=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25]([O-:28])(=[S:27])[CH3:26].[K+].C1OCCOCCOCCOCCOCCOC1.C(#N)C>C(OCC)(=O)C.CCCCCC>[C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C@@H:19]3[O:23][CH2:22][C@H:21]([S:27][C:25](=[O:28])[CH3:26])[CH2:20]3)=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OCc1ccccc1)N1CCN(C(=O)[C@H]2C[C@H](Br)CO2)CC1
Reactant: CC([O-])=S
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)S[C@H]1CO[C@@H](C(=O)N2CCN(C(=O)OCc3ccccc3)CC2)C1
Yield: 82.4 %

Procedure:
The title compound is prepared by the procedure of Example 139 using 1.14 g of product from Example 151, 0.393 g of potassium thioacetate, 0.1517 g of 18-crown-6 and 10 ml of acetonitrile to give 0.928 g of the desired product after chromatography (silica gel: 10-60% ethyl acetate/hexane).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][O:8][C:9]2[C:18](C)=[CH:17][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:11][C:10]=2C)[CH2:4][O:3]1.[OH:22][C:23]1C=CC(C#N)=C(OC)C=1>>[CH3:21][C:2]1([CH3:1])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[C:17]([O:22][CH3:23])[CH:18]=2)[CH2:4][O:3]1
Reactant: COc1cc(O)ccc1C#N
Reactant: Cc1cc(C(=N)NO)cc(C)c1OCC1COC(C)(C)O1
Product: COc1cc(OC[C@@H]2COC(C)(C)O2)ccc1C(=N)NO

Procedure:
The title compound is obtained as a beige oil (2.46 g) in analogy to rac-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-N-hydroxy-3,5-dimethyl-benzamidine starting from 4-hydroxy-2-methoxy-benzonitrile and L-alpha-beta-isopropyliden glycerol; LC-MS: tR=0.62 min, [M+H]+=296.97.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([C:10]([F:13])([F:12])[F:11])=[CH:4][N:3]=1.[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[C:17]([O:22][CH3:23])[CH:16]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]2[N:7]=[C:6]([NH:8][CH3:9])[C:5]([C:10]([F:13])([F:12])[F:11])=[CH:4][N:3]=2)=[C:17]([O:22][CH3:23])[CH:16]=1
Reactant: COc1cc(Br)ccc1N
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: CNc1nc(Nc2ccc(Br)cc2OC)ncc1C(F)(F)F
Temperature: 100 °C
Yield: 914 %

Procedure:
A mixture of 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (0.5 g, 2.36 mmol), 4-bromo-2-methoxyaniline (0.72 g, 0.38 mmol) and p-toluene sulphonic acid (0.49 g, 2.6 mmol) in dioxane (10 mL) was heated at 100° C. for 2 h. The mixture was cooled, filtered and the solid washed with dioxane. The solid was dried in a vacuum oven to give crude N2-(4-bromo-2-methoxyphenyl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (1.31 g) which was used in the next step without any further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[C:5]([CH:12]([CH3:14])[CH3:13])[CH:4]=1.S(O[C:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1)(C(F)(F)F)(=O)=O>>[CH:23]1([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH:12]([CH3:14])[CH3:13])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[C:23]1([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH:12]([CH3:14])[CH3:13])[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1
Reactant: O=S(=O)(OC1=CCCCC1)C(F)(F)F
Reactant: COc1ccc(B(O)O)c(C(C)C)c1
Product: COc1ccc(C2=CCCCC2)c(C(C)C)c1
Product: COc1ccc(C2CCCCC2)c(C(C)C)c1

Procedure:
Cyclohexyl-4-methoxy-2-isopropyl-benzene was prepared in two steps by a Suzuki coupling of 4-methoxy-2-isopropyl-phenylboronic acid and cyclohexenol triflate following the procedures of Carmen et. al., Synlett 2005, No. 10, pp 1601-1605, to obtain 1-cyclohex-1-enyl-2-isopropyl-4-methoxy-benzene, which was subsequently hydrogenated (Pd/C, H2, MeOH) to form 1-cyclohexyl-4-methoxy-2-isopropyl-benzene.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([CH3:13])=[C:7]([CH3:12])[CH:8]=2)[N:3]=1.[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]2[CH:11]=[N:10][C:9]3[C:4](=[CH:5][C:6]([CH3:13])=[C:7]([CH3:12])[CH:8]=3)[N:3]=2)=[CH:17][CH:16]=1
Reactant: Nc1ccc(Br)cc1
Reactant: Cc1cc2ncc(Cl)nc2cc1C
Product: Cc1cc2ncc(Nc3ccc(Br)cc3)nc2cc1C
Yield: 7.3 %

Procedure:
A preferred method of synthesis of 2-(4-bromophenylamino)-6,7-quinoxaline (Compound 30) is as follows: 200 mg of 2-chloro-6,7-dimethyl quinoxaline (synthesized according to the protocol at Section 5.13, step 2) and 0.8 g of p-bromoaniline were heated at 100° for 3.5 hours. Chromatography gave 25 mg (37% yield) of a light yellow solid, having a melting point of 235° C.
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH:4](=[C:11]1[NH:15][C:14](=[O:16])[C:13]([N:17]=[O:18])=[C:12]1[OH:19])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CO>[CH:4](=[C:11]1[NH:15][C:14](=[O:16])[C:13]([N:17]=[O:18])=[C:12]1[O:19][CH3:3])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C=[N+]=[N-]
Reactant: O=NC1=C(O)C(=Cc2ccccc2)NC1=O
Solvent: CO
Product: COC1=C(N=O)C(=O)NC1=Cc1ccccc1
Yield: 90 %

Procedure:
An excess of an ethereal diazomethane solution was added to a suspension of 5-benzylidene-4-hydroxy-3-nitroso-1,5-dihydro-pyrrol-2-one (prepared by the method of H. Poschenrieder et al (Arch. Pharm. Pharm. Med. Chem. 1998, vol. 331, pp. 389-394) and Stachel et al (J. Heterocycl. Chem. 1980, vol. 17, pp. 1195-1199 and Liebigs Ann. Chem. 1985, pp. 1692-1696)) in methanol. After the vigorous evolution of nitrogen has subsided, the reaction solution is concentrated in vacuo and the residue thus obtained is recrystallized from methanol. Red crystals of 5-benzylidene-4-methoxy-3-nitroso-1,5-dihydropyrrol-2-one with a melting point of 172° C. were obtained in a yield of 90%.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1([C:15](OCC)=[O:16])[CH2:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C.O1CCCC1>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1([CH2:15][OH:16])[CH2:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(CCOCc2ccccc2)CCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCC1(CCOCc2ccccc2)CCC1
Reaction time: 2 h
Yield: 95.2 %

Procedure:
To a solution of 2.0 g (7.63 mmol) of ethyl 1-[2-(benzyloxy)ethyl]cyclobutanecarboxylate in 20 mL of diethyl ether at 0° C. was added a 1.0 M solution of 15.9 mL (15.9 mmol) of lithium aluminum hydride in tetrahydrofuran and the contents stirred for 2 h. The reaction was quenched with 20 ml of 20% sodium hydroxide solution. After filtration, the organic phase was isolated, dried with magnesium sulfate, and concentrated under vacuum to afford 1.6 g (95%) of {1-[2-(benzyloxy)ethyl]cyclobutyl}methanol as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.41-7.30 (m, 5H), 4.54 (s, 2H), 3.55 (t, J=6 Hz, 2H), 2.03-1.83 (m, 8H).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].C(N(C(C)C)CC)(C)C.[C:16]([Si:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:19])([CH3:18])[CH3:17].N#N>ClCCl>[C:16]([Si:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])([CH3:19])([CH3:17])[CH3:18]
Reactant: OCCCCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](OCCCCO)(c1ccccc1)c1ccccc1
Yield: 172.5 %

Procedure:
To a solution of 1,4-butanediol (5 g, 55 mol) in dichloromethane (10 mL) containing diisopropylethylamine (10 mL) was added tert-butylchlorodiphenylsilane (5 mL, 18 mmol) dropwise under N2 atmosphere at 18° C. over 2 h. The resultant solution was stirred at room temperature for 4 hours and concentrated under reduced pressure. Purification by column chromatography with hexane/ethyl acetate (1/1) gave 4-(tert-butyl-diphenyl-silanyloxy)-butan-1-ol (10.2 g, 85% yield) as colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.62-7.71 (4H, m); 7.32-7.43 (6H, m), 3.63-3.69 (4H, m), 1.83 (1H, br s), 1.59-1.71 (4H, m), 1.03 (9H, s).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]3[CH:8]([CH2:9][CH2:10][CH2:11][CH2:12]3)[CH2:7][N:6]3[CH2:15][CH2:16][N:17](C(OCC4C=CC=CC=4)=O)[CH2:18][C:4]([C:5]=23)=[CH:3][CH:2]=1.FC(F)(F)S(O)(=O)=O.C1(OC)C=CC=CC=1.[OH-].[Na+].C(Cl)[Cl:48]>O>[ClH:48].[CH:1]1[C:14]2[CH:13]3[CH:8]([CH2:9][CH2:10][CH2:11][CH2:12]3)[CH2:7][N:6]3[CH2:15][CH2:16][NH:17][CH2:18][C:4]([C:5]=23)=[CH:3][CH:2]=1
Reactant: O=C(OCc1ccccc1)N1CCN2CC3CCCCC3c3cccc(c32)C1
Reactant: ClCCl
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: COc1ccccc1
Solvent: O
Product: Cl
Product: c1cc2c3c(c1)C1CCCCC1CN3CCNC2
Reaction time: 2 h
Yield: 52 %

Procedure:
The compound from Example 5 (0.200 g, 0.53 mmol) was dissolved in methylene chloride (0.5 mL). Trifluoromethane sulfonic acid (0.0.329 mL, 3.72 mmol) and anisole (0.115 mL, 1.06 mmol) were added at 0° C. After 2 hours, another portion of trifluoromethane sulfonic acid (2 eq.) was added. After a total of 4 hours, the reaction was completed. 1N NaOH was added to quench the reaction (pH=9-10). The contents of the flask were transferred to a separatory funnel with methylene chloride and water, and extracted with methylene chloride (3×). The combined organic extracts were dried with magnesium sulfate, filtered and concentrated to give a brown oil, crude desired product. Further purification (10% ammonia in 2M solution of methanol/ethyl acetate) yielded 0.067 g of desired product (52%). The free amine product (0.0605 g, 0.249 mmol) was then dissolved in diethyl ether, and a 2M solution of hydrogen chloride (0.137 mL, 0.274 mmol) was added. After 40 minutes, the yellow precipitate was filtered off to give the desired product.