Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[N:10]=[C:9]([S:11][CH3:12])[NH:8][N:7]=1.[C:13]([CH2:21][C:22](=O)[CH3:23])(=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)CCC>[CH3:23][C:22]1[CH:21]=[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:7]2[N:8]=[C:9]([S:11][CH3:12])[N:10]=[C:6]2[N:5]=1
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: CSc1nc(N)n[nH]1
Solvent: CC(=O)O
Solvent: CCCCCl
Product: CSc1nc2nc(C)cc(-c3ccccc3)n2n1
Yield: 27.2 %

Procedure:
To 50 ml of stirring glacial acetic acid, 2.5 g (19.2 mmol) of 3-amino-5-methylthio-1,2,4-triazole and 3.1 g (19.1 mmol) of benzoylacetone was added followed by heating at reflux for 2 h. The solvent was evaporated in vacuo and excess water added to the residue followed by extraction with 200 ml of ethyl acetate. The extract was washed with water, saturated sodium bicarbonate, brine, dried over magnesium sulfate and evaporated in vacuo to give an oil. Addition of n-butyl chloride resulted in crystallization of a solid which was filtered and washed with n-butyl chloride to give 1.33 g of the pure title compound, m.p. 121°-123° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:21][O:20][C:18]1[CH:19]=[C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:15]=[CH:16][N:17]=1
Reactant: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ncn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cc(C2CCNCC2)ncn1
Yield: 31.4 %

Procedure:
1.16 g 4-(6-Methoxy-pyrimidin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester were stirred in 2 mL 4 mol/L HCl solution in dioxane for 40 min. The mixture was diluted with dioxane and basified with sodiumcarbonate. The suspension was filtered and the filtrate was concentrated to give 0.24 g of the desired product.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:28])=[C:16]([NH:21][C:22](=[O:27])[C:23](=[O:26])[CH2:24][CH3:25])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[BH4-].[Na+].O>CO>[OH:26][CH:23]([CH2:24][CH3:25])[C:22]([NH:21][C:16]1[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]2[O:12][CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=3)[C:14]=2[C:15]=1[CH3:28])=[O:27]
Reactant: CCC(=O)C(=O)Nc1c(C)c(C)c2c(c1C)C(c1ccc(C(C)C)cc1)CO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCC(O)C(=O)Nc1c(C)c(C)c2c(c1C)C(c1ccc(C(C)C)cc1)CO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
To a solution of N-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-oxobutanamide obtained in Example 17 (237 mg, 0.62 mmol) in methanol (5 mL) was added sodium borohydride (24 mg, 0.62 mmol) at 0° C. and the resulting mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain 170 mg (yield: 72%) of the title compound. Melting point: 146-147° C.
Reaction SMILES: [CH2:1]([C:3]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1)([CH:9]=[CH2:10])[CH2:4][C:5]([O:7]C)=[O:6])[CH3:2].[OH-].[Na+]>C(O)(C)C>[CH2:9]([C:3]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1)([CH:1]=[CH2:2])[CH2:4][C:5]([OH:7])=[O:6])[CH3:10]
Reactant: C=CC(CC)(CC(=O)OC)c1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: C=CC(CC)(CC(=O)O)c1cccc([N+](=O)[O-])c1

Procedure:
A solution of methyl 3-ethyl-3-(3-nitrophenyl)-4-pentenoate (Preparation 59, assume 7.25 mmol) in isopropyl alcohol (9 ml) and 2M aqueous sodium hydroxide solution (4.4 ml, 8.75 mmol) was heated under reflux for 11 h, then the reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The phases were separated and the organic extract was dried (MgSO4), filtered and concentrated in vacuo to give the title compound as an oil which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>CCOCC>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[C:18]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=2)[C:6]([CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[N:7]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOCC
Product: CN1CCC(c2nn(C(=O)c3ccccc3)c3cc(F)ccc23)CC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 50.9 %

Procedure:
A mixture of 3.1 g of 6-fluoro-3-(1-methyl-4-piperidinyl)-1H-indazole and 8 ml of benzoyl chloride was heated at 100° C. in a steam bath for 8 hrs. After cooling, ether was added and the solid was collected. The solid was treated with ammonium hydroxide solution to give an oil. The oil was dissolved in 300 ml of ether, stirred and 1.2 g of fumaric acid was added. After four hrs at ambient temperature, the fumarate salt was collected. Recrystallization from ethanol-ether yielded 3.0 g (50.9%) of product, mp 180°-182° C.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].[CH3:15][S:16][C:17]1[N:22]=[C:21]([O:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([NH2:34])=[CH:26][CH:25]=2)[CH:20]=[CH:19][N:18]=1>>[C:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH:34][C:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:24]([O:23][C:21]2[CH:20]=[CH:19][N:18]=[C:17]([S:16][CH3:15])[N:22]=2)=[CH:25][CH:26]=1)=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CSc1nccc(Oc2ccc(N)c3ccccc23)n1
Reactant: CC(C)(C)Oc1cccc(C(=O)O)c1
Product: CSc1nccc(Oc2ccc(NC(=O)c3cccc(OC(C)(C)C)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-tert-butoxy-benzoic acid and 4-(2-methylsulfanyl-pyrimidin-4-yloxy)-naphthalen-1-ylamine according to conditions described in general procedure G. (0.130 g) (46%). Mp: 135-136° C. 1H NMR (300 MHz, DMSOd6) 10.49 (s, 1H), 8.56 (d, J=4.2 Hz, 1H), 8.04 (d, J=6.3 Hz, 1H), 7.83 (brd, 2H), 7.68-7.47 (m, 6H), 7.25 (d, J=5.7 Hz, 1H), 6.93 (d, J=4.5 Hz, 1H), 2.27 (s, 3H), 1.36 (s, 9H). MS: 460 (M+1).
Reaction SMILES: [N:1]([N:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][S:6](=[O:12])(=[O:11])[CH2:5][C:4]1([CH3:14])[CH3:13])=O>C(O)(=O)C.O.[Zn]>[NH2:1][N:3]1[C:4]([CH3:13])([CH3:14])[CH2:5][S:6](=[O:12])(=[O:11])[CH2:7][C:8]1([CH3:10])[CH3:9]
Reactant: CC1(C)CS(=O)(=O)CC(C)(C)N1N=O
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)CS(=O)(=O)CC(C)(C)N1N
Temperature: 50 °C
Reaction time: 3 h

Procedure:
22.0 g (0.1 mole) of 1-nitroso-2,2,6,6-tetramethyl-1-aza-4-thiacyclohexane-4,4-dioxide is suspended in a mixture of 150 ml of glacial acetic acid and 100 ml of water. Within 3 hours, 40 g of zinc dust is introduced in small portions, the temperature being maintained between 30° and 35°C. The reaction mixture is subsequently fully stirred for 5 hours at 50°C; the zinc sediment is filtered off hot, and the cooled filtrate rendered alkaline with sodium hydroxide solution. It is extracted with ether, the ether solution dried over sodium sulphate, and the solvent evaporated off. Crystallisation of the residue from ligroin yields 1-amino-2,2,6,6-tetramethyl-1-aza-4-thiacyclohexane-4,4-dioxide (10), M.P. 122°C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:28][CH2:29][CH:30]([C:32]1[CH:33]=[C:34]2[C:38](=[C:39]([C:41]([NH2:43])=[O:42])[CH:40]=1)[NH:37][CH:36]=[CH:35]2)[OH:31]>>[C:25]([NH:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([N:5]3[CH2:6][CH2:7][CH:2]([NH:28][CH2:29][CH:30]([C:32]4[CH:33]=[C:34]5[C:38](=[C:39]([C:41]([NH2:43])=[O:42])[CH:40]=4)[NH:37][CH:36]=[CH:35]5)[OH:31])[CH2:3][CH2:4]3)=[CH:9][CH:10]=2)(=[O:16])=[O:17])=[CH:19][CH:20]=1)(=[O:27])[CH3:26]
Reactant: NCC(O)c1cc(C(N)=O)c2[nH]ccc2c1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NCC(O)c4cc(C(N)=O)c5[nH]ccc5c4)CC3)cc2)cc1

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and 5-(2-amino-1-hydroxy-ethyl)-1H-indole-7-carboxamide according to the procedure of Example 255 as a pale grey solid; 1H NMR (300 MHz, DMSO-d6) δ 1.60–1.80 (m, 2 H), 2.00–2.15 (m, 2 H), 2.06 (s, 3 H), 2.50–2.70 (m, 2 H), 3.10–3.20 (m, 3 H), 3.60–3.75 (m, 2 H), 4.95–5.05 (m, 1 H), 6.13 (brs, 1 H), 6.49 (t, J=2.7 Hz, 1 H), 6.81 (d, J=9.0 Hz, 2 H), 6.88 (d, J=9.0 Hz, 2 H), 7.35 (t, J=2.7 Hz, 1 H), 7.42 (brs, 1 H), 7.59 (d, J=9.0 Hz, 2 H), 7.69 (d, J=9.0 Hz, 2 H), 7.77 (s, 1 H), 8.11 (s, 1 H), 9.72 (s, 1 H), 10.40 (s, 1 H); MS (ES) m/z: 591.1 (MH+); HRMS Calcd. for C30H35N6O5S (MH+): 591.2390. Found: 591.2392.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:25](O)=[O:26])=[N:23][CH:24]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:25]([C:22]3[CH:21]=[CH:20][C:19]([F:18])=[CH:24][N:23]=3)=[O:26])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Reactant: O=C(O)c1ccc(F)cn1
Product: C[C@]1(c2cc(NC(=O)c3ccc(F)cn3)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 5-fluoro-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=365.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[O:5][C:4](=O)[CH:3]=1.Cl.[NH2:18][OH:19].NC1C=CC=CN=1>>[OH:19][N:18]1[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:7][C:2]([CH3:1])=[CH:3][C:4]1=[O:5]
Reactant: NO
Reactant: Cc1cc(Cc2ccc(Cl)cc2)oc(=O)c1
Agent: Cl
Agent: Nc1ccccn1
Product: Cc1cc(Cc2ccc(Cl)cc2)n(O)c(=O)c1
Yield: 62 %

Procedure:
5 g of 4-methyl-6-(4-chlorobenzyl)-2-pyrone, 2.5 g of hydroxylamine hydrochloride and 10 g of 2-aminopyridine were heated for 16 hours to 60°C. After the usual working up, there were obtained 3.3 g (62 %) of 1-hyroxy-4-methyl-6-(4-chlorobenzyl)-2-pyridone melting at 142° C (Calc.: 5.6% N, found 5.9 % N).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](O)=[O:6].C[N:15]1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[OH-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([NH2:15])=[O:6]
Reactant: CN1CCOCC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a solution of 3-fluoro-4-nitrobenzoic acid, J. Am. Chem. Soc. 66, 1631-1632 (1944), (2.0 g, 10.81 mmol) in tetrahydrofuran (100 mL) at 0° C. was added 4-methyl morpholine (1.78 mL, 16.21 mmol), 1-hydroxybenzotriazole (2.18 g, 16.21 mmol), followed by 1-(3 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.10 g, 16.21 mmol). The reaction was stirred for 1 hour at 0° C., then concentrated ammonium hydroxide was added (2.19 mL, 16.21 mmol). The reaction was allowed to warm slowly to room temperature and stirred overnight. The reaction was then diluted with ethyl acetate and washed with 5% citric acid (50 mL), saturated sodium bicarbonate (50 mL), and saturated sodium chloride (50 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield a pale yellow powder. The powder was collected and washed with ether, followed by drying under reduced pressure to yield 3-fluoro-4-nitro-benzamide 1.22 g (69%). MS(APCI) m/z 183.0 (M−H). Anal. Calcd. for C7H5N2O3F1: C, 45.66; H, 2.74; N, 15.21. Found: C, 46.03; H, 2.75; N, 15.02.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[NH2:23]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[NH:23][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cnccn2)n1
Reactant: COc1ccc(N)cc1OC
Product: COc1ccc(Nc2cc(C(F)(F)F)nc(-c3cnccn3)n2)cc1OC

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.192 mmol), 3,4-dimethoxyaniline (44 mg, 0.288 mmol) similar to Example 76 and isolated as a yellow solid (52 mg, 72%). 1H NMR (CDCl3): 9.74 (d, J=1.2 Hz, 1H), 8.78 (dd, J=1.2, 2.4 Hz, 1H), 8.72 (d, J=2.4 Hz, 1H), 7.36 (s, 1H), 6.96–6.90 (m, 3H), 6.88 (s, 1H), 3.94 (s, 3H), 3.91 (s, 3H).
Reaction SMILES: [NH2-].[Na+].N.[C:4]([C:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=1)#[C:5][CH3:6].[K]>CCOCC>[CH:6]#[C:5][CH:4]=[C:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CC#CC1=CCCCC1
Agent: N
Agent: [K]
Agent: [NH2-]
Solvent: CCOCC
Product: C#CC=C1CCCCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 0.7 mol of sodium amide in about 700 mL of liquid ammonia was added 1-(1-propynyl)cyclohexene (0.50 mol) dropwise over 15 min with efficient stirring. A fine, white suspension of the potassium alkynylide was formed gradually. After 2 h, 200 mL of Et2O was added over a few minutes. The flask was then placed in a water bath at 40° C. When the stream of ammonia vapor had become faint, introduction of nitrogen (~500 mL/min) was started. An additional volume of 100 mL of Et2O was added. The flask was placed in an ice-water bath and ice water (~300 mL) was added to the reaction mixture over about half an hour with vigorous stirring. After dissolution of all solid material, the layers were separated and the aqueous layer was extracted twice with small portions of Et2O. The combined organic solutions was dried over MgSO4. Propynylidenecyclohexane (b.p. 55° C./10 mm Hg) was obtained in excellent yield by concentrating the ethereal solution in a water-pump vacuum (bath temperature not higher than 35° C.) and subsequently distilling the remaining liquid thorough a 30-cm Vigreaux column.
Reaction SMILES: [NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[N+:5]([O-])[CH:6]=[C:7]([CH2:13][O:14][CH3:15])[N:8]=2)[N:3]=1.NC1N=C(N)C2C(=[N+]([O-])C=C(COC)N=2)N=1.[OH-].[Na+]>>[NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[NH:8][CH:7]([CH2:13][O:14][CH3:15])[CH2:6][NH:5][C:4]=2[N:3]=1
Reactant: COCc1c[n+]([O-])c2nc(N)[nH]c(=O)c2n1
Agent: COCc1c[n+]([O-])c2nc(N)nc(N)c2n1
Agent: [Na+]
Agent: [OH-]
Product: COCC1CNc2nc(N)[nH]c(=O)c2N1

Procedure:
2-Amino-6-methoxymethyl-4(3H)-pteridinone-8-oxide. 2,4-Diamino-6-methoxymethylpteridine-8-oxide (E. C. Taylor and T. Kobayashi, J. Org. Chem., 2817, 38, (1973)) was treated with sodium hydroxide in a manner analogous to that described in Example 1 to give the title compound as a solid mp >250°. UV: (0.1N HCl) λmax 262(22600), 290 sh (4900), 388 (6100) nm; NMR: δ (TFA) 3.69 (s, OCH3); 4.89 (s, OCH2); 8.95 (s, H-7). IR: (KBr) 1725, 1700, 1650, 1605, 1490, 1480, 1390, 1360, 1325, 1235, 1155, 1110, 1065d, 1015d, 970 cm-1. Anal. calcd: C, 43.05; H, 4.06; N, 31.38. Found: C, 42.79; H, 4.14; N, 31.21.
Reaction SMILES: BrC1C=CC(F)=C(C2NC(=O)C3C(=NC=CN=3)N=2)C=1.CNC1C=CN=CC=1.[CH2:28]([N:32]([C:51]1[CH:56]=[CH:55][N:54]=[CH:53][CH:52]=1)[C:33]1[C:42]2[C:37](=[N:38][CH:39]=[CH:40][N:41]=2)[N:36]=[C:35]([C:43]2[CH:48]=[C:47]([Br:49])[CH:46]=[CH:45][C:44]=2[F:50])[N:34]=1)CCC>>[Br:49][C:47]1[CH:46]=[CH:45][C:44]([F:50])=[C:43]([C:35]2[N:34]=[C:33]([N:32]([CH3:28])[C:51]3[CH:52]=[CH:53][N:54]=[CH:55][CH:56]=3)[C:42]3[C:37](=[N:38][CH:39]=[CH:40][N:41]=3)[N:36]=2)[CH:48]=1
Reactant: CCCCN(c1ccncc1)c1nc(-c2cc(Br)ccc2F)nc2nccnc12
Agent: CNc1ccncc1
Agent: O=c1[nH]c(-c2cc(Br)ccc2F)nc2nccnc12
Product: CN(c1ccncc1)c1nc(-c2cc(Br)ccc2F)nc2nccnc12

Procedure:
The title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 4-(methylamino)pyridine following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.C(OCC)(=O)C.O.[CH3:19][N:20](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:8]1[C:9]2[C:4](=[CH:3][C:2]([C:19]#[N:20])=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc2cnccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc2cnccc2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
Next, to a solution of 6-bromoisoquinoline (382 mg, 1.84 mmol) in N,N-dimethylformamide (3.8 mL) were added zinc cyanide (431 mg, 3.67 mmol) and tetrakis(triphenylphosphine)palladium(0) (42 mg, 0.0367 mmol) under nitrogen atmosphere, and the mixture was stirred at 100° C. for 1 hour. Tetrakis(triphenylphosphine)palladium(0) (42 mg, 0.0367 mmol) was further added, and the mixture was stirred for 2.5 hours at 100° C. The reaction mixture was allowed to room temperature, ethyl acetate and water were added for extraction, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (hexane:ethyl acetate), and isoquinoline-6-carbonitrile (234 mg, 83%) was obtained as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:8]=1[Cl:34])[CH3:6])=[O:4].[C:35]([NH:38][C:39]1[N:44]=[CH:43][C:42]([CH2:45][CH2:46][C:47](O)=[O:48])=[CH:41][CH:40]=1)(=[O:37])[CH3:36].ClC1C(COC2C3N=C(OC)N(CC4C=CC=CN=4)C=3C=CC=2)=C(Cl)C=CC=1N(C)C(=O)CNC(=O)CCC1C=CC(C(NCCOC)=O)=CC=1>>[C:35]([NH:38][C:39]1[N:44]=[CH:43][C:42]([CH2:45][CH2:46][C:47]([NH:1][CH2:2][C:3]([N:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([CH2:14][O:15][C:16]3[C:24]4[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=5)[C:20]=4[CH:19]=[CH:18][CH:17]=3)[C:8]=2[Cl:34])[CH3:6])=[O:4])=[O:48])=[CH:41][CH:40]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)Nc1ccc(CCC(=O)O)cn1
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1Cc1ccccn1
Agent: COCCNC(=O)c1ccc(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)cc1
Product: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CCc4ccc(NC(C)=O)nc4)c3Cl)cccc2n1Cc1ccccn1

Procedure:
Compound 32 is prepared 2-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide and 3-(6-acetamidopyridin-3-yl)propanoic acid as described for compound 1. MS (APCI) 690 (M+), 1H NMR 2.18 (s, 3H), 2.49 (t, 2H, J=7.4 Hz), 2.89 (t, 2H, J=7.4 Hz), 3.32 (s, 3H), 3.4-3.55 (m, 1H), 3.7-3.82 (m, 1H), 4.21 (s, 3H), 5.28 (s, 2H), 5.66 (s, 2H), 6.45-6.52 (m, 1H), 6.81 (t, 2H, J=8.2 Hz), 6.92 (d, 1H, J=7.86 Hz), 7.01-7.06 (m, 1H), 7.17-7.19 (m 1H), 7.4-7.6 (m, 4H), 7.9-7.95 (m, 1H), 8.06-8.09 (m, 2H), 8.55-8.59 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CN(C=O)C>O>[Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:12])([CH3:14])[CH2:13][N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C[C@](C)(O)Cn2cc([N+](=O)[O-])nc2Cl)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
A mixture of (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (7.00 g, 32.2 mmol) and tert-butyl piperazine-1-carboxylate (6.29 g, 33.8 mmol) and DMF (70 ml) was stirred at 70° C. for 8 hours. The reaction mixture was allowed to return to room temperature, then diluted with water, and then the solution was extracted with ethyl acetate twice. The organic phases were combined, washed with water three times, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. To the residue, diethyl ether was added. The precipitates were filtered off, and dried at room temperature under reduced pressure to afford tert-butyl (S)-4-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]piperazin-1-carboxylate (10.25 g, yield 79%) as a light yellow powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][C:10]=3[N:9]=[CH:8]2)[CH2:3][CH2:2]1.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:16][C:14]1[CH:13]=[CH:12][C:11]2[N:7]([CH:4]3[CH2:3][CH2:2][N:1]([CH2:18][C:19]4[CH:20]=[CH:21][C:22]([C:25]([OH:34])([C:26]([F:27])([F:28])[F:29])[C:30]([F:31])([F:32])[F:33])=[CH:23][CH:24]=4)[CH2:6][CH2:5]3)[CH:8]=[N:9][C:10]=2[CH:15]=1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Reactant: Nc1ccc2c(c1)ncn2C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Nc1ccc2c(c1)ncn2C1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1

Procedure:
1-(Piperidin-4-yl)-1H-benzo[d]imidazol-5-amine, 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (4.82 mmol, 1.624 g) and potassium carbonate (9.64 mmol, 1.332 g) were combined and stirred in acetonitrile (25 mL) at room temperature for 3 days. The reaction mixture was concentrated under vacuum, taken up in dichloromethane, washed with water and concentrated under vacuum. The resulting residue was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 6% methanol/dichloromethane) to afford the title compound (594 mg). MS (ESI) m/z 473.0 [M+H]+