Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].CON(C)[C:8]([C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2)=[O:9].O.[Cl-].[NH4+]>C1COCC1>[C:10]12([C:8](=[O:9])[CH:1]=[CH2:2])[CH2:17][CH:16]3[CH2:15][CH:14]([CH2:13][CH:12]([CH2:18]3)[CH2:11]1)[CH2:19]2
Reactant: C=C[Mg]Br
Reactant: CON(C)C(=O)C12CC3CC(CC(C3)C1)C2
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A THF solution (20.0 mL, 10.0 mmol) comprising 1 mol/L of vinylmagnesium bromide was slowly added dropwise to a THF (45 mL) solution comprising 2.23 g (5.00 mmol) of N-methoxy-N-methyladamantan-1-carboxamide that had been cooled in a bath containing ice and salt while keeping the THF solution at −10 to 0° C. Thereafter, the mixture was stirred at 0° C. for 1 hour, and stirred at room temperature overnight. The reaction mixture was slowly added dropwise, using a Pasteur pipette, to saturated ammonium chloride water that had been cooled in a bath containing ice and salt, while keeping it at −10 to −5° C. After the completion of the dropwise addition, the mixture was heated to 0° C. Since the mixture comprises two layers, the water layer was separated, and ethyl acetate extraction was performed three times. Subsequently, the primarily separated organic layer and the combined ethyl acetate layers were combined, and the organic layer was washed with saturated ammonium chloride water 5 times, and with brine once. Drying over sodium sulfate, filtration, condensation, and drying under reduced pressure at room temperature for 3 hours were performed, thereby giving the crude product of 1-(adamantan-1-yl)prop-2-en-1-on (containing 1.56 g of impurities such as 3-[methoxy(methyl)amino]-1-(adamantan-1-yl)propan-1-on, etc.) The crude product was used in the next reaction without purification. Under an Ar atmosphere, 1.43 g of 1,8-diazabicyclo[5.4.0]undeca-7-en (DBU) was added to an ice-cooled suspension comprising 1.18 g of the crude product of 1-(adamantan-1-yl)prop-2-en-1-on, 1.60 g of 1-(2-oxopropyl)pyridinium chloride, 1.18 g of molecular sieves 4A, and ethanol (24 mL), and the mixture was stirred at room temperature for 2 days. Under ice-cooling, 1N HClaq. was added to the reaction mixture, the pH was adjusted to 1, and ethyl acetate extraction was performed. The organic layer was separated, and washed with brine three times, followed by drying over sodium sulfate, filtration, condensation, and drying under reduced pressure at room temperature for 1 hour, thereby giving the crude product (936 mg) of 3-(adamantan-1-yl)phenol. This crude product and the crude product of 3-(adamantan-1-yl)phenol (456 mg) obtained from the crude product of 400 mg of 1-(adamantan-1-yl)propa-2-en-1-on under the same conditions were combined. Then this crude product was separated and purified by silica gel column chromatography, thereby giving 222 mg of 3-(adamantan-1-yl)phenol (yield: 9.7%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([CH3:21])[N:17]=[C:18]([CH:19]=[O:20])[C:13]=3[CH2:12][CH2:11][C:10]2=[O:22])=[CH:4][CH:3]=1.[BH4-].[Na+]>O1CCCC1.C(O)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([CH3:21])[N:17]=[C:18]([CH2:19][OH:20])[C:13]=3[CH2:12][CH2:11][C:10]2=[O:22])=[CH:4][CH:3]=1
Reactant: Cc1nc(C=O)c2c(n1)N(Cc1ccc(Br)cc1)C(=O)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cc1nc(CO)c2c(n1)N(Cc1ccc(Br)cc1)C(=O)CC2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 122.2 %

Procedure:
To a solution of 8-[(4-bromophenyl)methyl]-2-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-4-carbaldehyde (550 mg, 1.53 mmol) in tetrahydrofuran (5 mL) and isopropanol (2 mL) was added sodium borohydride (116 mg, 3.05 mmol). After 45 min, the mixture was cooled to 0° C. and CO2 was bubbled in for 5 min. The mixture was filtered and the filtrate was concentrated to give 677 mg of a yellow foam. Purification by flash chromatography (5% MeOH/CH2Cl2) gave 496 mg (90%) of product as an off-white solid, mp 159°-160° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:33]=[C:19]4[CH:20]=[CH:21][CH:22]=[C:23]([C:24]5[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=5)[C:27](O)=[O:28])[N:18]4[N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1.C(Cl)CCl.C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1>>[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH:40][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][CH:32]=[C:24]([C:23]3[N:18]4[N:17]=[C:16]([NH:15][C:12]5[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]6[CH2:2][CH2:3][CH2:4][CH2:5]6)=[CH:10][CH:11]=5)[N:33]=[C:19]4[CH:20]=[CH:21][CH:22]=3)[CH:25]=2)=[CH:37][CH:36]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(O)c1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(Cl)cc1)c1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-benzoic acid (50 mg, 0.113 mmol), 4-chlorobenzylamine (27.5 μL, 0.226 mmol), EDC (44 mg, 0.226 mmol) and di-isopropylethylamine (98.5 μL, 0.564 mmol) was added HOBt (31 mg, 0.226 mmol). The mixture was stirred overnight at room temperature, and the desired product purified by preparatory HPLC. RT: 4.63 min, MI: 567.31, Method: basic. 1H NMR (DMSO, 300 MHz): 9.43 (s, 1H), 9.22 (t, 1H), 8.58 (s, 1H), 8.19 (t, 1H), 8.03 (d, 1H), 7.63 (m, 6H), 7.36 (s, 3H), 7.24 (dd, 1H), 6.84 (d, 2H), 4.50 (d, 2H), 3.99 (t, 2H), 2.81 (t, 2H), 2.50 (d, 2H), 2.36 (s, 2H), 1.69 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[O:16][CH:17]([CH3:19])[CH3:18].[OH-].[Na+].Cl>>[Cl:1][C:2]1[C:11]([O:12][CH:13]([CH3:14])[CH3:15])=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:16][CH:17]([CH3:19])[CH3:18]
Reactant: COC(=O)c1cc(OC(C)C)c(Cl)c(OC(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)Oc1cc(C(=O)O)cc(OC(C)C)c1Cl
Temperature: 100 °C
Reaction time: 3 h
Yield: 68.8 %

Procedure:
Methyl 4-chloro-3,5-diisopropoxybenzoate (5) (93 mg, 0.32 mmol) was suspended in 2M sodium hydroxide (1.6 mL, 3.2 mmol) and stirred at 100° C. for 3 h. After cooling to RT the mixture was acidified by the addition of 1 M HCl. The resulting precipitate was collected by filtration and dried in vacuo to afford 4-chloro-3,5-diisopropoxybenzoic acid (6) (60 mg, 66% yield) as a white solid. This material was used in the subsequent reaction step without purification.
Reaction SMILES: [CH2:1]([C:8]1([OH:33])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([N:26](CC=C)CC=C)[CH:21]=2)=[O:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1[C@H](C[C@H](N)C(O)=O)[C@H]2O[C@H]2C(=O)C1.N[C@H](C(O)=O)CC1C=CC(O)=CC=1>>[NH2:26][C:22]1[CH:21]=[C:20]([NH:19][C:17]([NH:16][CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)([OH:33])[CH2:9][CH2:10]2)=[O:18])[CH:25]=[CH:24][N:23]=1
Reactant: C=CCN(CC=C)c1cc(NC(=O)NCCN2CCC(O)(Cc3ccccc3)CC2)ccn1
Agent: N[C@@H](C[C@H]1CCC(=O)[C@@H]2O[C@H]12)C(=O)O
Agent: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Product: Nc1cc(NC(=O)NCCN2CCC(O)(Cc3ccccc3)CC2)ccn1

Procedure:
The compound is prepared from 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-diallylamino-pyridin-4-yl)-urea (Example 445.) using the method described in Laguzza B. C., Ganem B., “A new protecting group for amines. Synthesis of Anticapsin from L-Tyrosine”, Tetrahedron Lett. (1981) 22, 1483-1486.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:38]2[CH2:50][CH2:49][N:41]3[C:42]4[CH2:43][CH2:44][CH2:45][CH2:46][C:47]=4[CH:48]=[C:40]3[C:39]2=[O:51])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[N:23][C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH:31]4[CH2:34][O:33][CH2:32]4)[CH2:27][C@@H:26]3[CH3:35])=[CH:21][N:20]=2)[C:15](=[O:36])[N:14]([CH3:37])[CH:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[OH:4][CH2:5][C:6]1[C:7]([N:38]2[CH2:50][CH2:49][N:41]3[C:42]4[CH2:43][CH2:44][CH2:45][CH2:46][C:47]=4[CH:48]=[C:40]3[C:39]2=[O:51])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[N:23][C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH:31]4[CH2:32][O:33][CH2:34]4)[CH2:27][C@@H:26]3[CH3:35])=[CH:21][N:20]=2)[C:15](=[O:36])[N:14]([CH3:37])[CH:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3cnc(N4CCN(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: C[C@H]1CN(C2COC2)CCN1c1cnc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CCCC6)C4=O)c3CO)cn(C)c2=O)cn1
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 21.9 %

Procedure:
A mixture of 228a (50 mg, 0.070 mmol) and lithium hydroxide (43 mg, 1.8 mmol) in i-propanol/THF (1:1, 4 mL) and water (1 mL) was stirred at 35° C. for 30 mins. The reaction mixture was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 228 (10 mg, 21%). MS-ESI: [M+H]+ 652.3. 1H NMR (500 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.48 (d, J=4.5 Hz, 1H), 8.39 (s, 1H), 8.34 (s, 1H), 7.84 (s, 1H), 7.48 (s, 1H), 7.34 (d, J=5.0 Hz, 1H), 6.58 (s, 1H), 4.94 (bs, 1H), 4.56-4.55 (m, 2H), 4.49-4.47 (m, 1H), 4.42-4.36 (m, overlap, 4H) 4.25-4.17 (m, 2H), 4.13-4.10 (m, 1H), 3.86-3.76 (m, 2H), 3.60 (s, 3H), 3.39-3.37 (m, 1H), 3.01-2.96 (m, 1H), 2.78-2.76 (m, 1H), 2.62-2.57 (m, overlap, 3H), 2.50-2.47 (m, 2H), 2.10-2.07 (m, 1H), 1.94-1.90 (m, 1H), 1.80-1.78 (m, 2H), 1.70-1.69 (m, 2H), 1.12 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH2:14][C:15](O)=[O:16])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:18][C:19]1[S:20][C:21]2[CH:27]=[C:26]([O:28][C:29]([F:32])([F:31])[F:30])[CH:25]=[CH:24][C:22]=2[N:23]=1.[OH:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:33][CH:34]1[CH2:39][CH2:38][N:37]([C:15](=[O:16])[CH2:14][NH:13][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([O:28][C:29]([F:31])([F:30])[F:32])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:4][C:5]=3[CH:10]=2)=[O:12])[CH2:36][CH2:35]1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)O)ccc21
Reactant: OC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)N3CCC(O)CC3)ccc21
Yield: 73.5 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]amide (65 mg) was prepared by following General Procedure F starting from {[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetic acid (75 mg), 4-hydroxypiperidine (18 mg), HBTU (73 mg), and DIEA (42 uL), with a modification of General Procedure F where DIEA was slowly added to the reaction mixture as the last reagent. LC/MS: m/z 549.7. 1H NMR (DMSO-d6, 400 MHz): δ 8.41 (t, 1H), 8.11 (s, 1H), 7.94 (s, 1H), 7.80 (d, 1H), 7.65 (bs, 1H), 7.51 (d, 1H), 7.37 (d, 1H), 4.15 (d, 2H), 3.98-3.89 (m, 2H), 3.78-3.69 (m, 2H), 3.68 (s, 3H), 3.20 (t, 1H), 3.04 (t, 1H), 1.84-1.67 (m, 2H), 1.45-1.20 (m, 2H), —NH proton signal was not observed.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH2:29][CH2:30][CH3:31])[C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27]C)=[O:26])=[CH:19][CH:18]=2)[CH:10]=1.[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH2:29][CH2:30][CH3:31])[C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:21][CH:22]=2)[CH:10]=1
Reactant: CCCN(Cc1cccc(-c2c(C)cccc2C)c1)c1ccc(CCC(=O)OC)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCN(Cc1cccc(-c2c(C)cccc2C)c1)c1ccc(CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 99.9 %

Procedure:
To a solution of methyl 3-{4-[[(2′,6′-dimethylbiphenyl-3-yl)methyl](propyl)amino]phenyl}propanoate (0.735 g, 1.77 mmol) in a mixture of methanol (8 mL) and tetrahydrofuran (8 mL) was added 2 M aqueous sodium hydroxide solution (2.5 mL), and the mixture was stirred at room temperature for 19 hr. Water was added to the reaction mixture, and the mixture was weakly acidified with 10% aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-70% ethyl acetate/hexane) to give the title compound (0.710 g, yield 99%) as a yellow oil.
Reaction SMILES: C([N:8]([CH2:21][CH:22]([OH:32])[CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31])[CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[NH2:19])=[CH:14][N:13]=1)C1C=CC=CC=1.[H][H]>O1CCOCC1.[Pd]>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][NH:8][CH2:21][CH:22]([OH:32])[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])=[N:13][CH:14]=1)(=[O:20])[NH2:19]
Reactant: [H][H]
Reactant: Cc1ccccc1OCC(O)CN(CCOc1ccc(C(N)=O)cn1)Cc1ccccc1
Agent: [Pd]
Solvent: C1COCCO1
Product: Cc1ccccc1OCC(O)CNCCOc1ccc(C(N)=O)cn1

Procedure:
A solution of 22.6 g of crude 1-{N-benzyl-N-[2-(5-carbamoyl-2-pyridyloxy)-ethyl]-amino}-3-(2-methyl-phenyloxy)-2-propanol in 230 ml of dioxane is hydrogenated in the presence of 2.3 g of a palladium-on-charcoal catalyst (5% strength) at 20°-30° C. and under atmospheric pressure, until an equimolar amount of hydrogen has been taken up. The catalyst is filtered off and the filtrate is evaporated under reduced pressure. The residue is recrystallised from ethyl methyl ketone and gives 1-[2-(5-carbamoyl-2-pyridyloxy)-ethylamino]-3-(2-methyl-phenyloxy)-2-propanol, melting point 139°-141° C.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][O:9]C(=O)C(C)=C)(=[O:5])[C:2]([CH3:4])=[CH2:3].S([O-])(OCCCCCCCCCCCC)(=O)=O.[Na+]>O>[CH3:4][C:2]([C:1]([O:6][CH2:7][CH2:8][OH:9])=[O:5])=[CH2:3]
Reactant: C=C(C)C(=O)OCCOC(=O)C(=C)C
Agent: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Product: C=C(C)C(=O)OCCO
Reaction time: 12 h

Procedure:
A 500 mL media bottle equipped with a stir bar was charged with 4.52 g (34.8 mmol) hydroxyethyl methacrylate(HEMA) monomer, 77.74 mg (0.428 mmol) ethylene glycol dimethacrylate (EGDM), 0.2123 g (0.634 mmol) sodium dodecyl sulfate (SDS) and 240 mL milli-Q H2O. The bottle was closed with a sparging cap and purged with N2 for 1 hr at room temperature while stirring. Then, 0.166 g potassium persulfate (K2S2O8) was dissolved into 21 mL of milli-Q H2O and added to the media bottle while stirring. The bottle was transferred to a 40° C. water bath and held there for 12 hours. The resulting suspension of hydrogel particles had an opalescent blue color. The particles were analyzed by dynamic light scattering and found to have an average radius of 36.5 nm as shown in FIG. 1. The particles were purified by tangential flow filtration and are stored in an aqueous suspension. No flocculation was observed over several months.
Reaction SMILES: [C:1]([C:9]1[CH:27]=[CH:26][C:12]2[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:14](=[O:16])[NH:15][C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl.Cl[CH2:32][CH2:33][N:34]([CH3:36])[CH3:35]>CS(C)=O.O>[C:1]([C:9]1[CH:27]=[CH:26][C:12]2[N:13]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[C:14](=[O:16])[N:15]([CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Cn2c(=O)[nH]c3cc(C(=O)c4ccccc4)ccc32)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(Cn2c(=O)n(CCN(C)C)c3cc(C(=O)c4ccccc4)ccc32)cc1
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
To a solution of 1.09 g of 5-benzoyl-1-(4-methoxybenzyl)-2H-benzimidazol-2-one in 10 ml of dimethylsulfoxide was added at room temperature 0.27 g of 60% dispersion of sodium hydride in mineral oil. After being stirred for 30 minutes, the reaction mixture was treated with 0.48 g of chloroethyldimethylamine hydrochloride at room temperature for 2 hours and at 55° C for 3 hours, diluted with water and extracted with ethyl acetate. The ethyl acetate layer was extracted with 10% hydrogen chloride. The aqueous layer was alkalized with 20% sodium hydroxide and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine in turn and dried over anhydrous sodium sulfate. After removal of the solvent in vacuo, the residue was chromatographed on silica gel using chloroform-methanol (15:1) to afford 1.14 g of 5-benzoyl-1,3-dihydro-3-(2-dimethylaminoethyl)-1-(4-methoxybenzyl)-2H-benzimidazol-2-one.
Reaction SMILES: [Cl:1][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)[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:3]=1.[NH3:24]>O1CCOCC1>[NH2:24][C:6]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:2]([Cl:1])[N:3]=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:5]=1
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1Cl
Reactant: N
Solvent: C1COCCO1
Product: COc1ccccc1Oc1c(N)nc(-c2ccncc2)nc1Cl
Reaction time: 18 h

Procedure:
4,6-Dichloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidine (2.9 g, Referential Example 1d)) was suspended in dioxane (30 ml) and ammonia (gaseous) was introduced until the solution was saturated. Stirring was continued for 7 days while the saturation of the reaction mixture with ammonia (gaseous) was repeated every 16 to 20 h. The solvent was evaporated, water was added to the residue and the precipitate was filtered off. After drying at HV/50° C. 4-amino-6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidine (2.7 g) was obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([F:15])[CH:13]=2)[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[N:7]=1)=O)C.[NH3:24]>CO>[F:15][C:12]1[CH:13]=[C:14]2[C:6]([C:4]([NH2:24])=[O:3])=[N:7][N:8]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:9]2=[N:10][CH:11]=1
Reactant: CCOC(=O)c1nn(Cc2ccccc2F)c2ncc(F)cc12
Reactant: N
Solvent: CO
Product: NC(=O)c1nn(Cc2ccccc2F)c2ncc(F)cc12

Procedure:
1.00 g (3.152 mmol) of the compound obtained in example 8A was stirred in 10 ml of a 7N solution of ammonia in methanol at RT for three days. Then it was concentrated by vacuum evaporation. 908 mg (99% of theor.) of the title compound was obtained.
Reaction SMILES: C([NH2:9])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[K+].C1C2C3=C4C(=CC=2)C=CC=C4C=CC3=CC=1.[N+:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([O-:36])=[O:35]>C(OCC)(=O)C.CS(C)=O>[N+:34]([C:37]1[CH:42]=[CH:41][C:40]([NH2:9])=[CH:39][CH:38]=1)([O-:36])=[O:35]
Reactant: NC(=O)c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Nc1ccc([N+](=O)[O-])cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A 100 ml three-neck reactor equipped with a condenser and a thermometer was filled with 7.32 g (60 mmol) of benzamide, 1.50 g of potassium carbonate, 3.96 g (60 mmol) of potassium hydroxide, 0.3034 g of pyrene, and 25 g of DMSO. Next, the resulting mixture was stirred under oxygen, and then heated to 90° C. Once the reaction temperature reached 90° C., a mixed solution of 2.48 g (20 mmol) of nitrobenzene and 5 g of DMSO was slowly added dropwise over a period of time of 5 to 10 minutes via a syringe. After reacting for 2 hours, a sample was taken out, and dissolved in 2.5 ml of ethyl acetate. Then, moisture of the resulting solution was removed with magnesium sulfate (H2SO4). A quantitative analysis of the product by GC has indicated that 4-nitrosoaniline and 4-nitroaniline were obtained in yields of 14 mole % and 1 mole %, respectively, based on nitrobenzene, and an intermediate N-(4-nitrophenyl)benzamide was also obtained. For the identification of a production of N-(4-nitrophenyl)benzamide, the reaction solution was treated with hexane, added with 5 g of water and 30 g of DMSO, and then left to react at a temperature of 80 to 90° C. for 8 hours. After that, a sample was taken out, and dissolved in 2.5 ml of ethyl acetate. Then, moisture in the resulting solution was removed with magnesium sulfate (H2SO4). A quantitative analysis of the resulting material has shown that 4-nitroaniline was obtained in an yield of 26 mole % based on nitrobenzene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[H-].[Na+].Cl[CH2:20][O:21][CH2:22]Cl.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:20][O:21][CH3:22])=[CH:10][CH:9]=2)[CH:15]=1
Reactant: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: ClCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
At 0° C., to a stirred solution of 4-(5-bromo-2-chlorobenzyl)phenol (6.85 g, 23 mmol) in dimethylformamide (100 mL) was added portionswise sodium hydride (60% in mineral oil, 1.01 g, 25.3 mmol), the mixture was stirred at 0° C. for further 30 minutes. Chloromethyl ether (2.02 g, 25.3 mmol) was slowly added in drops and when the addition finished, the mixture was stirred at room temperature for further 3 hours. Water (150 mL) was added, the mixture was extracted for two times with ethyl acetate, the combined organic phases were washed with saturated brine for one time and dried over anhydrous sodium sulfate. The solvent was evaporated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 20:1) to afford the target compound.
Reaction SMILES: Br[C:2]1[C:7]2=[N:8][N:9]3[C:18]4[CH:17]=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=4[C:12]([CH3:20])=[CH:11][C:10]3=[C:6]2[CH:5]=[C:4]([CH3:21])[CH:3]=1.CC1(C)C(C)(C)OB([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[C:33]4[CH:43]=[CH:42][CH:41]=[CH:40][C:34]4=[CH:35][CH:36]=3)[N:31]=2)O1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCOCC1.C1(C)C=CC=CC=1>[N:31]1[C:32]2[C:37](=[CH:36][CH:35]=[C:34]3[CH:40]=[CH:41][CH:42]=[CH:43][C:33]3=2)[CH:38]=[CH:39][C:30]=1[C:2]1[C:7]2=[N:8][N:9]3[C:18]4[CH:17]=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=4[C:12]([CH3:20])=[CH:11][C:10]3=[C:6]2[CH:5]=[C:4]([CH3:21])[CH:3]=1
Reactant: Cc1ccc2c(c1)c(C)cc1c3cc(C)cc(Br)c3nn21
Reactant: CC1(C)OB(c2ccc3ccc4ccccc4c3n2)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)c(C)cc1c3cc(C)cc(-c4ccc5ccc6ccccc6c5n4)c3nn21

Procedure:
A mixture of 17.0 g (50 mmol) of 10-bromo-3,5,8-trimethylindazolo[2,3-a]-quinoline (Example 86), 19.8 g (65 mmol) of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[h]quinoline, 225 mg (1 mmol) of palladium(II) acetate, 1.8 g (6 mmol) of tri-o-tolylphosphine, 10.6 g (100 mmol) of sodium carbonate, 200 ml of toluene, 50 ml of dioxane and 300 ml of water is heated under reflux for 16 h. After cooling, the organic phase is separated off, washed twice with 300 ml of water, dried over magnesium sulfate, the organic phase is evaporated to dryness in vacuo, and the residue is recrystallised from toluene/ethanol. The solid obtained in this way is freed from readily volatile and non-volatile secondary components by fractional sublimation (p about 1×10−5 mbar, T about 270° C.). Yield: 15.8 g (36 mmol), 72%, purity: about 99.5% (NMR).