Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:5]=1[OH:16])([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:5]=1[OH:16]
Reactant: O=[N+]([O-])c1ccc(-c2ccccc2)cc1O
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(-c2ccccc2)cc1O

Procedure:
8.8 g (40 mmol) of 4-nitro-1,1′-biphenyl-3-ol from step B was dissolved in 120 mL of ethanol and hydrogenated in the presence of 0.8 g of a palladium-activated carbon catalyst (10%) at 25° C. After the required quantity of hydrogen had been absorbed, the catalyst was filtered off, and the solvent was distilled off in a rotary evaporator. This gave 7.3 g of 4° amino-1,1′-biphenyl-3-ol.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:29]([O:36][CH2:37][CH2:38][CH2:39]Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:39][CH2:38][CH2:37][O:36][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: BrCCCOCc1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCOCc2ccccc2)CC1
Yield: 98.4 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (6 g) as a starting compound, potassium carbonate (10.1 g) and 3-benzyloxypropyl bromide (4.45 g) were reacted and treated in the same manner as in Example 199 to give 7.1 g of 4-amino-N-((1-(3-benzyloxypropyl)piperidin-4-yl)methyl)-5-chloro-2-methoxybenzamide, m.p. 82°-83° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=1)=[O:10].[Cu](C#N)[C:20]#[N:21]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:20]#[N:21])=[CH:4][C:3]=1[C:9](=[O:10])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=1
Reactant: CCc1ccc(C(=O)c2cc(Br)ccc2N)cc1
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Product: CCc1ccc(C(=O)c2cc(C#N)ccc2N)cc1
Temperature: 180 °C
Yield: 87.4 %

Procedure:
A flask charged with (2-amino-5-bromo-phenyl)-(4-ethyl-phenyl)-methanone (0.10 g, 0.32 mmol), copper cyanide (0.0347 g, 0.41 mmol), and 1 mL of DMF was heated at 180° C. for 1 hour in a microwave reactor. The title compound was eluted from a 5 g SPE with 100% DCM to give 0.07 g (81%) of a white solid. 1H NMR (400 MHz, CDCl3) δ 7.84 (d, 1H), 7.58 (d, 2H), 7.50 (dd, 1H), 7.36 (d, 2H), 6.78 (d, 1H), 6.60 (br s, 2H), 2.78 (q, 2H), 1.30 (t, 3H). This was prepared according to example 41. 1H NMR (400 MHz, CD3OD) δ 8.60 (s, 1H), 7.90 (dd, 1H), 7.50 (m, 4H), 7.22 (d, 2H), 6.48 (s, 1H), 2.82 (q, 2H), 1.36 (t, 3H). Mass spectrum (ESI, m/z) calcd. for C21H16N4O 340.1, found 341.1 (M+H).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=2[O:2]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27])[C:20](O)=[O:21].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C(Cl)CCl>[CH2:1]1[O:2][C:3]2[C:8](=[CH:7][C:6]([C:20](=[O:21])[C:19]3[CH:23]=[CH:24][C:25]([N+:26]([O-:28])=[O:27])=[C:17]([O:16][CH3:15])[CH:18]=3)=[C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:4]=2)[O:9]1
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCCl
Product: COC(=O)Cc1cc2c(cc1C(=O)c1ccc([N+](=O)[O-])c(OC)c1)OCO2

Procedure:
The title compound was prepared from methyl 3,4-methylenedioxyphenylacetate (1.6 g, 8.0 mmol) in ClCH2CH2Cl (50 mL), 3-methoxy-4-nitrobenzoic acid (1.8 g, 9.3 mmol) and P2O5 (4 g) as a light yellow solid (1.2 g, 3.2 mmol, 40%). 1H NMR (CDCl3) 7.84 (d, J=8.2, 1H), 7.54 (d, J=1.4, 1H), 7.32 (dd, J=8.2, 1.4, 1H), 6.85 (s, 2H), 6.07 (s, 2H), 4.00 (s, 3H), 3.85 (s, 2H), 3.64 (s, 3H).
Reaction SMILES: [OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C([O-])([O-])=O.[K+].[K+].[CH2:36](I)[CH2:37][CH3:38]>CN(C=O)C.Cl>[OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([O:27][CH2:36][CH2:37][CH3:38])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: O=C(O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Reactant: CCCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOC(=O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.3 %

Procedure:
To a solution of 4-(((1R,2R)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (100 mg, 0.26 mmol) and K2CO3 (72 mg, 0.52 mmol) in DMF (2.5 mL), was added n-PrI (90 mg, 0.52 mmol) and then stirred at room temperature for 4 h. The reaction mixture was diluted with 1.5 N HCl (50 mL) and extracted with ethyl acetate (3×25 mL). The organic layer was washed with 10% aq. NaHCO3 (25 mL), brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by CombiFlash using 20% ethyl acetate in chloroform as an eluent to yield 82 mg (73%) of the title compound as an off white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([N:16]2[C:20](=[O:21])[C:19]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]3[C:17]2=[O:26])[CH2:12][C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[NH2:28][OH:29]>O1CCCC1>[OH:29][NH:28][C:13](=[O:14])[CH2:12][CH:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26]
Reactant: COc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1OC
Reactant: NO
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(C(CC(=O)NO)N2C(=O)c3ccccc3C2=O)cc1OC
Yield: 80.2 %

Procedure:
N-Hydroxy-3-(3,4-dimethoxyphenyl)-3-phthalimidopropionamide was prepared by the procedure of Example 1 from 3-(3,4-dimethoxyphenyl)-3-phthalimidopropanoic acid (1.82 g, 5.12 mmol), N,N′-carbonyldiimidazole (870 mg, 5.39 mmol) and hydroxylamine hydrochloride (391 mg, 5.63 mmol) in tetrahydrofuran (8 mL) to afford N-hydroxy-3-(3,4-dimethoxyphenyl)-3-phthalimidopropionamide as a white solid (1.52 g, 80% yield): mp, 186.5–188.0° C.; 1H NMR (DMSO-d6) δ 3.12 (d, J=7.8 Hz, 2H, CH2), 3.72 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 5.69 (t, J=7.8 Hz, 1H, NCH), 6.91–6.92 (m, 2H, Ar), 7.03 (br s, 1H, Ar), 7.85 (br s, 4H, Ar), 8.82 (s, 1H, OH), 10.62 (br s, 1H, NH); 13C NMR (DMSO-d6) δ 34.33, 50.25, 55.52, 111.27, 111.67, 119.65, 123.17, 131.26, 134.63, 148.41, 148.56, 166.07, 167.69. Anal. Calcd for C19H18N2O6: C, 61.62; H, 4.90; N, 7.56. Found: C, 61.29; H, 4.72; N, 7.47.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[CH2:9]([CH:11]1[O:13][CH2:12]1)Cl.[OH-].[K+]>>[OH:13][CH2:12][CH:11]1[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2][CH2:9]1
Reactant: ClCC1CO1
Reactant: Oc1ccccc1O
Agent: [K+]
Agent: [OH-]
Product: OCC1COc2ccccc2O1

Procedure:
0.5 mole of pyrocatechol were stirred vigorously with 1.5 moles of epichlorohydrin and 1 mole of 10% strength aqueous potassium hydroxide solution at 100° C. After the mixture had been cooled, it was extracted with ether, the ether extract was washed with dilute potassium hydroxide solution and water, dried and evaporated and the product was recrystallized from ethanol. Melting point: 87°-90° C.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[Cl:17])(=O)C>N>[Cl:17][C:8]1[C:7]2[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([OH:4])[CH:6]=2)[N:11]=[CH:10][N:9]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC(C)=O
Agent: N
Product: COc1cc2ncnc(Cl)c2cc1O
Temperature: 10 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
6-Acetoxy-4-chloro-7-methoxyquinazoline (10.0 g, 39.6 mmol), (WO 01/04102, Table VI examples), was added in portions to a stirred 7N methanolic ammonia solution (220 ml) and the mixture cooled to 10° C. in an ice/water bath. Initially the solid dissolved to give a yellow solution which then deposited a yellow precipitate. After stirring for one hour the precipitate was filtered off, washed with diethyl ether and dried thoroughly under high vacuum to give 4-chloro-6-hydroxy-7-methoxyquinazoline (5.65 g, 67.8%).
Reaction SMILES: [CH3:1][Si:2]([CH3:52])([O:7][C@@H:8]1[C@H:12]([O:13][Si:14]([CH3:20])([CH3:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C@@H:11]([CH2:21][O:22][Si:23]([CH3:29])([CH3:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[O:10][C@H:9]1[N:30]1[CH:38]=[N:37][C:36]2[C:31]1=[N:32][C:33]([C:40]1[CH:41]=[N:42][N:43](CC3C=CC=CC=3)[CH:44]=1)=[N:34][C:35]=2[NH2:39])[C:3]([CH3:6])([CH3:5])[CH3:4].I[C:54]1[C:55](C(C)C)=NN[CH:58]=1.IC1C=CC(CC2C=CNN=2)=CC=1>>[CH3:1][Si:2]([CH3:52])([O:7][C@@H:8]1[C@H:21]([O:22][Si:23]([CH3:28])([CH3:29])[C:24]([CH3:27])([CH3:25])[CH3:26])[C@@H:11]([CH2:12][O:13][Si:14]([CH3:20])([CH3:19])[C:15]([CH3:17])([CH3:18])[CH3:16])[O:10][C@H:9]1[N:30]1[CH:38]=[N:37][C:36]2[C:31]1=[N:32][C:33]([C:40]1[CH:41]=[N:42][N:43]([CH:54]([CH3:55])[CH3:58])[CH:44]=1)=[N:34][C:35]=2[NH2:39])[C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)c1n[nH]cc1I
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(N)nc(-c4cnn(Cc5ccccc5)c4)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: Ic1ccc(Cc2cc[nH]n2)cc1
Product: CC(C)n1cc(-c2nc(N)c3ncn([C@@H]4O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]4O[Si](C)(C)C(C)(C)C)c3n2)cn1

Procedure:
Compound 16 was prepared in the manner of compound 11 substituting 4-iodo-(1-methylethyl)pyrazole for 4-iodo-benzylpyrazole to afford compound 16: 1H NMR(CDCl3) 0.00 (s, 3H, CH3), 0.01 (s, 3H, CH3), 0.04 (s, 3H, CH3), 0.07 (s, 3H, CH3), 0.11 (s, 3H, CH3), 0.14 (s, 3 H, CH3), 0.78 (s, 9H, t-bu), 0.83 (s, 9H, t-bu), 0.91 (s, 9H, t-bu), 1.55(d, 6H, C(CH3)2), 3.8 (d, 1H), 4.05 (d, 1H), 4.08-4.15(m, 1H), 4.30-4.32 (m, 1H), 4.44-4.56 (m, 2H), 5.55(bs, 1H, D2O exchangeable), 6.05 (s, 1H), 8.05 (s, 1H), 8.10 (s, 1H), 8.2 (s, 1H)
Reaction SMILES: Br[C@H:2]([CH:16]([CH3:18])[CH3:17])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([CH3:14])[CH3:13])[C:7]=1[OH:15])=[O:4].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:16]([C@H:2]1[C:3](=[O:4])[NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([CH3:14])[CH3:13])[C:7]=2[O:15]1)([CH3:18])[CH3:17]
Reactant: CC(C)c1cccc(NC(=O)[C@H](Br)C(C)C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1cccc2c1O[C@@H](C(C)C)C(=O)N2
Yield: 80.1 %

Procedure:
A solution of (R)-2-(2-bromo-3-methylbutyryl)amino-6-isopropylphenol (18.5 g) in dimethylformamide (120 ml) was treated with powdered potassium carbonate (9.75 g) at room temperature for 3 hours. Dilution with water gave crystals, which were recrystallized from 2-propanol to yield (S)-2,8-diisopropyl-2H-1,4-benzoxazin-3(4H)-one as colorless prisms (11.0 g, 80.3%), mp 151°-152° C., [α]D23 -5.6° (c=1.0, MeOH).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([NH:9][CH:10]([P:19](=[O:26])([O:23]CC)[O:20]CC)[P:11](=[O:18])([O:15]CC)[O:12]CC)[CH:5]=2)[CH2:3][CH2:2]1>Cl>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([NH:9][CH:10]([P:11](=[O:12])([OH:18])[OH:15])[P:19](=[O:20])([OH:26])[OH:23])[CH:5]=2)[CH2:2][CH2:3]1
Reactant: CCOP(=O)(OCC)C(Nc1cc(C2CC2)on1)P(=O)(OCC)OCC
Agent: Cl
Product: O=P(O)(O)C(Nc1cc(C2CC2)on1)P(=O)(O)O
Yield: 93.6 %

Procedure:
A solution of 2.5 g of tetraethyl [(5-cyclopropyl-3-isoxazolyl)-amino]methylene-bis(phosphonate) in 25 ml of concentrated hydrochloric acid was heated under reflux for 3.5 hours. The reaction mixture was concentrated. Methanol and acetone were added to the concentrate to give 1.7 g of [(5-cyclopropyl-3-isoxazolyl)-amino]-methylene-bis(phosphonic acid) as a solid.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([OH:26])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:46]([N:49]1[CH2:54][CH2:53][N:52]([CH2:55][CH2:56][CH2:57]O)[CH2:51][CH2:50]1)(=[O:48])[CH3:47]>>[C:46]([N:49]1[CH2:54][CH2:53][N:52]([CH2:55][CH2:56][CH2:57][O:26][C:20]2[CH:19]=[C:18]3[C:23]([C:14]([Cl:13])=[N:15][CH:16]=[N:17]3)=[CH:22][C:21]=2[O:24][CH3:25])[CH2:51][CH2:50]1)(=[O:48])[CH3:47]
Reactant: COc1cc2c(Cl)ncnc2cc1O
Reactant: CC(=O)N1CCN(CCCO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
Diethyl azodicarboxylate (0.243 g, 1.396 mmol) was added dropwise to a solution of 4-chloro-7-hydroxy-6-methoxyquinazoline (0.245 g, 1.16 mmol), triphenylphosphine (0.396 g, 1.51 mmol) and 3-(4-acetylpiperazin-1-yl)propan-1-ol (0.238 g, 1.28 mmol), (prepared as described for the starting material in Example 1 or Example 7). After stirring at ambient temperature for 1 hour, the mixture was poured onto silica and eluted with increasingly polar mixtures of methylene chloride and methanol to give 7-(3-(4-acetylpiperazin-1-yl)propoxy)-4-chloro-6-methoxyquinazoline (0.29 g, 66%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9]C.[BrH:20]>>[BrH:20].[N+:11]([C:7]1[CH:6]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:4]=[C:3]([OH:2])[C:8]=1[OH:9])([O-:13])=[O:12]
Reactant: COc1cc(-c2ccccn2)cc([N+](=O)[O-])c1OC
Agent: Br
Product: O=[N+]([O-])c1cc(-c2ccccn2)cc(O)c1O
Reaction time: 18 h

Procedure:
1.5 g of 2-(3,4-dimethoxy-5-nitrophenyl)pyridine are dissolved in 30 ml of 48 percent aqueous hydrobromic acid. The reaction mixture is stirred at 100° for 16 hours and at 23° for 18 hours. The precipitate which thereby forms is filtered and recrystallized from methanol/ether. There is obtained 3-nitro-5-(2-pyridyl)pyrocatechol hydrobromide of m.p. 239°-240°.
Reaction SMILES: C(OC(N1CCN(C2N=CC(C3C=CC(F)=CC=3)=CN=2)CC1)=O)(C)(C)C.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:45]=[CH:44][C:43](Br)=[CH:42][N:41]=2)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].[Cl:47][C:48]1[CH:53]=[CH:52][C:51](B(O)O)=[CH:50][CH:49]=1>>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:45]=[CH:44][C:43]([C:51]3[CH:52]=[CH:53][C:48]([Cl:47])=[CH:49][CH:50]=3)=[CH:42][N:41]=2)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cn2)CC1
Agent: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3ccc(Cl)cc3)cn2)CC1
Yield: 99.1 %

Procedure:
Prepared according to the method for the preparation of 4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-carboxylic acid tert-butyl ester, from 4-(5-bromo-pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (0.536 g) and 4-chlorophenylboronic acid (0.269 g), to yield the title compound as a beige solid (0.580 g, 99%).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30]>C(Cl)Cl>[NH2:13][C:9]1[C:8]([N+:14]([O-:16])=[O:15])=[C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([NH:1][C:27]([NH:26][C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[C:21]([C:29]([F:31])([F:30])[F:32])[CH:22]=3)=[O:28])=[CH:3][CH:4]=2)[CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Oc2ccnc(N)c2[N+](=O)[O-])cc1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: ClCCl
Product: Nc1nccc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 20 h
Yield: 74.4 %

Procedure:
Method H3 (in DCM). 4-(4-Aminophenoxy)-3-nitropyridin-2-amine (170 mg, 0.69 mmol) was dissolved in dry DCM (5 mL) and cooled to 0° C. 4-Chloro-3-trifluoromethyl-phenyl isocyanate (153 mg, 0.69 mg) was dissolved in dry DCM (3 mL) and was added dropwise to the cooled solution. The reaction mixture was allowed to warm at room temperature and was stirred for 20 hours under argon. The resulting precipitate was recovered by filtration, washed with more DCM and dried, to afford the title compound (240 mg, 74%). 1H-NMR (δ, ppm, DMSO-d6): 5.98 (d, 1H, HPy,5, J=5.0 Hz), 7.14-7.18 (m, 4H, NH2,Py+Harom,Ph,3+5), 7.57 (d, 2H, Harom,Ph,2+6), 7.64 (broad s, 2H, Harom′), 8.00 (d, 1H, HPy,6), 8.13 (s, 1H, Harom′), 9.00 (s, 1H, NHurea,1), 9.21 (s, 1H, NHurea,3); LC-MS (m/z): 468 (M+H, 100).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH:6]1([C:12]2[CH2:16][C:15](=O)[N:14]([CH3:18])[N:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-]>>[Cl:3][C:15]1[N:14]([CH3:18])[N:13]=[C:12]([CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH:16]=1
Reactant: CN1N=C(C2CCCCC2)CC1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: [OH-]
Product: Cn1nc(C2CCCCC2)cc1Cl
Temperature: 0 °C

Procedure:
Phosphorus oxychloride (15.3 g, 0.1 mole) is added to 3-cyclohexyl-1-methyl-2-pyrazolin-5-one and the mixture stirred and heated at 120° to 135° C. for 8 hours. The cooled reaction mixture is then poured into ice-water, made alkaline with 1% aqueous hydroxide and extracted with methylene chloride. Removal of solvent under reduced pressure, then in vacuo at 70° C. affords an oil, 8 g, (93.8%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=5)[C:19]([C:33](O)=[O:34])=[CH:18][CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.CN.O1CCCC1.C[CH2:44][N:45](CC)CC.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28]([N:29]([CH3:30])[CH3:31])=[O:32])=[CH:24][CH:23]=5)[C:19]([C:33]([NH:45][CH3:44])=[O:34])=[CH:18][CH:17]=4)=[O:14])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: CN(C)C(=O)c1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2C(=O)O)cc1
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(C(=O)N(C)C)cc1
Reaction time: 3 h
Yield: 10.3 %

Procedure:
5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-4′-(dimethylcarbamoyl)biphenyl-2-carboxylic acid (47 mg, 0.10 mmol) and 75 μL of a 2.0 M solution of methylamine in tetrahydrofuran (0.15 mmol) were dissolved in DMF (1.0 mL) containing Et3N (28 μL, 0.20 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) was added to the mixture and the resulting solution was allowed to stir for 3 hours. The mixture was filtered and purified by reverse phase HPLC to yield 5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamido)-N2,N4′,N4′-trimethylbiphenyl-2,4′-dicarboxamide (5.0 mg, 10%). ESI-MS m/z calc. 485.5, found 486.5 (M+1)+; retention time 2.54 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][C:23]([CH3:25])=[CH2:24])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([OH:19])=O)=[CH:13][CH:12]=1)[CH2:9][CH3:10].Cl.CN(C)CCCN=C=NCC.CN(C1C=CC=CN=1)C.[CH2:47]([S:50]([NH2:53])(=[O:52])=[O:51])[CH2:48][CH3:49]>ClCCl.CN(C1C=CN=CC=1)C.CCO.C(Cl)Cl.O.CC#N>[CH2:47]([S:50]([NH:53][C:17]([C:14]1[N:15]=[N:16][C:11]([N:8]([CH2:7][C:6]2[CH:20]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[O:21][CH2:22][C:23]([CH3:25])=[CH2:24])[CH2:9][CH3:10])=[CH:12][CH:13]=1)=[O:19])(=[O:52])=[O:51])[CH2:48][CH3:49]
Reactant: C=C(C)COc1ccc(Br)cc1CN(CC)c1ccc(C(=O)O)nn1
Reactant: CCCS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC#N
Solvent: CCO
Product: C=C(C)COc1ccc(Br)cc1CN(CC)c1ccc(C(=O)NS(=O)(=O)CCC)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-[N-(5-Bromo-2-(2-methylprop-2-enyloxy)benzyl)-N-ethylamino]pyridazin-3-carboxylic acid (185 mg, 0.46 mmol) was dissolved in dichloromethane (20 ml), (1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDAC), dimethylaminopyridine, (DMAP) (111 mg, 0.91 mmol) and propanesulfonamide (68 mg, 0.55 mmol) were added. The mixture was stirred at ambient temperature under argon overnight, after which TLC (25% water/CH3CN) suggested the reaction was complete. The reaction mixture was loaded directly onto a MPLC column (silica) and the title compound obtained by elution with 5% EtOH/CH2Cl2 then 5% EtOH/0.5% AcOH/CH2Cl2, as a clear oil which solidified on triturating with hexane to give a colourless powder (110 mg, 47%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[C:9](=O)[CH2:8][CH:7]1[CH3:20])=[O:5])[CH3:2].Cl.[NH2:22][OH:23].C([O-])(=O)C.[Na+].O>C(O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[C:9](=[N:22][OH:23])[CH2:8][CH:7]1[CH3:20])=[O:5])[CH3:2]
Reactant: NO
Reactant: CCOC(=O)N1c2cc(O)c(OC)cc2C(=O)CC1C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)N1c2cc(O)c(OC)cc2C(=NO)CC1C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
7-Hydroxy-6-methoxy-2-methyl-4-oxo-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (5.10 g, 18.3 mmol) was dissolved in ethanol (100 mL), and hydroxylamine hydrochloride (3.81 g, 54.8 mmol) was added, followed by sodium acetate (3.74 g, 45.7 mmol). The mixture was heated at reflux for 2 h and then left to stand at room temperature overnight. Water (100 mL) was added, and the volatiles were removed in vacuo to give a yellow slurry. This slurry was filtered and washed with water to give the title compound as a fine powder (4.755 g, 89%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][C:31]=1B(O)O>>[CH3:28][O:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][C:31]=1[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: COc1ccncc1B(O)O
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: COc1ccncc1-c1nc(N2CCOCC2)c2sc(CN3CCN(S(C)(=O)=O)CC3)cc2n1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with 4-methoxy-3-pyridineboronic acid in General Procedure A. Purification on silica yielded 162. NMR (CDCl3): 2.67-2.69 (m, 4H, 2×CH2), 2.81 (s 3H, CH3), 3.29-3.31 (m, 4H, 2×CH2), 3.84-3.86 (m, 4H, 2×CH2), 3.88 (s, 2H, CH2), 3.92 (s, 3H, CH3), 4.00-4.02 (m, 4H, 2×CH2), 6.91 (d, H, ArH, J=5.81 Hz), 7.33 (s, H, ArH), 8.52 (d, H, ArH, J=5.83 Hz), 8.85 (s, H, ArH). MS: (ESI+): MH+=505.17
Reaction SMILES: [C:1]([CH2:3][C:4]1[O:8][C:7]([C:9]2[N:10]=[C:11]([N:14]=[C:15]([NH2:17])[NH2:16])[S:12][CH:13]=2)=[CH:6][CH:5]=1)#[N:2].Cl.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C.O>[NH2:2][CH2:1][CH2:3][C:4]1[O:8][C:7]([C:9]2[N:10]=[C:11]([N:14]=[C:15]([NH2:17])[NH2:16])[S:12][CH:13]=2)=[CH:6][CH:5]=1
Reactant: N#CCc1ccc(-c2csc(N=C(N)N)n2)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: NCCc1ccc(-c2csc(N=C(N)N)n2)o1
Temperature: 25 °C
Yield: 29 %

Procedure:
To this mixture was dropwise added a mixture of 4-(5-cyanomethylfuran-2-yl)-2-(diaminomethyleneamino)thiazole (16.0 g) in tetrahydrofuran (30 ml) for 30 minutes under ice-cooling and the mixture was stirred for an hour at ambient temperature. The reaction mixture was added to a mixture of ethyl acetate and water and the mixture was adjusted to pH 1 with 6N-hydrochloric acid. The separated aqueous layer was adjusted to pH 10 with 10% aqueous sodium hydroxide and the mixture was extraced with a mixture of tetrahydrofuran and ethyl acetate. The extract layer was washed with brine and dired over magnesium sulfate. The solvent was concentrated to give 4-[5-(2-aminoethyl)furan-2-yl]-2-(diaminomethyleneamino)thiazole (4.71 g).