Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11](I)=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[C:9]([N+:18]([O-:20])=[O:19])=[CH:10][C:11]([C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([F:22])[C:28]=2[F:29])=[C:12]([N:14]([CH3:16])[CH3:15])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1I
Reactant: OB(O)c1cccc(F)c1F
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1-c1cccc(F)c1F

Procedure:
The title compound was prepared from (5-dimethylamino-4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example C2) and 2,3-difluorophenylboronic acid according to the general procedure D. Obtained as a yellow solid (3.096 g).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]4[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=4)=[CH:15][C:10]=3[N:9]=[CH:8]2)[S:4][C:3]=1[C:22]([O:24][CH3:25])=[O:23].O[CH:27]([C:29]1[CH:30]=[C:31]([O:35][CH:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)[CH:32]=[CH:33][CH:34]=1)[CH3:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[CH3:25][O:24][C:22]([C:3]1[S:4][C:5]([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]4[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=4)=[CH:15][C:10]=3[N:9]=[CH:8]2)=[CH:6][C:2]=1[O:1][CH:27]([C:29]1[CH:30]=[C:31]([O:35][CH:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:46])([CH3:48])[CH3:47])=[O:43])[CH2:38][CH2:37]2)[CH:32]=[CH:33][CH:34]=1)[CH3:28])=[O:23]
Reactant: COC(=O)c1sc(-n2cnc3cc(-c4cnn(C)c4)ccc32)cc1O
Reactant: CC(O)c1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1sc(-n2cnc3cc(-c4cnn(C)c4)ccc32)cc1OC(C)c1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 249.1 %

Procedure:
Methyl 3-hydroxy-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxylate (0.300 g, 0.847 mmol), (+/−)-1,1-dimethylethyl 4-{[3-(1-hydroxyethyl)phenyl]oxy}-1-piperidinecarboxylate (0.285 mmol), and triphenylphosphine (0.667 g, 2.54 mmol) were dissolved in 25 mL of DCM with stirring. Diisopropyl azodicarboxylate was added slowly dropwise via syringe. The reaction was stirred overnight, and the mixture was adsorbed onto silica gel. Purification by flash chromatography afforded 0.467 g (84%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.17 (s, 1H), 7.94 (s, 1H), 7.90 (s, 1H), 7.56 (s, 2H), 7.48 (s, 1H), 7.26 (dd, J=8.1, 7.9 Hz, 1H), 7.08 (m, 1H), 7.01 (d, J=7.9 Hz, 1H), 6.87 (dd, J=8.1, 2.2 Hz, 1H), 5.69 (q, J=6.0 Hz, 1H), 4.50 (m, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.65-3.56 (m, 2H), 3.18-3.05 (m, 2H), 1.91-1.78 (m, 2H), 1.58 (d, J=6.2 Hz, 3H), 1.53-1.40 (m, 2H), 1.35 (s, 9H).
Reaction SMILES: [ClH:1].[NH2:2][C:3]([CH3:16])([CH3:15])[CH2:4][C:5]([N:7]([CH2:9][CH2:10][N+:11]([CH3:14])([CH3:13])[CH3:12])[CH3:8])=[O:6].C(O[Cl:22])(C)(C)C>CO>[Cl-:22].[Cl:1][N:2]([Cl:22])[C:3]([CH3:16])([CH3:15])[CH2:4][C:5]([N:7]([CH2:9][CH2:10][N+:11]([CH3:12])([CH3:14])[CH3:13])[CH3:8])=[O:6]
Reactant: CC(C)(C)OCl
Reactant: Cl
Reactant: CN(CC[N+](C)(C)C)C(=O)CC(C)(C)N
Solvent: CO
Product: CN(CC[N+](C)(C)C)C(=O)CC(C)(C)N(Cl)Cl
Product: [Cl-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.4 %

Procedure:
To a solution of 2-(3-amino-N,3-dimethylbutanamido)-N,N,N-trimethylethanaminium hydrochloride (511 mg, 2.0 mmol) in methanol (40 ml) was added tert-butylhypochlorite (0.77 g, 7.1 mmol). The mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated in vacuo, and purified by prep-HPLC to give 253 mg (39%) of 2-(3-(dichloroamino)-N,3-dimethylbutanamido)-N,N,N-trimethylethanaminium chloride. 1H NMR (D2O) δ 3.88 (t, J=5.4 Hz, 2 H), 3.53 (t, J=5.4, 2 H), 3.26 (s, 3 H), 3.21 (s, 9 H), 2.98 (s, 2 H), 1.51 (s, 6 H); calc. for C11H24C12N3O+: 284.13, Found: 284.1 (M+).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[C:6]([O:10][CH3:11])=[CH:5][N:4]=1.[CH3:12][NH2:13].C1CCCCC1.C(OCC)(=O)C>C(O)C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:13][CH3:12])[C:6]([O:10][CH3:11])=[CH:5][N:4]=1
Reactant: CN
Reactant: COc1cnc(SC)nc1Cl
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNc1nc(SC)ncc1OC

Procedure:
Prepared from 2-methylsulphenyl-4-chloro-5-methoxy-pyrimidine by reacting with methylamine in ethanol at 90° C., Rf value: 0.22 (silica gel; cyclohexane/ethyl acetate=2:1)
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[N:9]([CH3:18])[CH2:8][C:7]=12.CI.[CH3:21]N(C)C=O.[H-].[Na+]>O>[CH3:21][O:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[N:9]([CH3:18])[CH2:8][C:7]=12
Reactant: CN(C)C=O
Reactant: CN1Cc2c(CO)ncn2-c2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COCc1ncn2c1CN(C)C(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1.1 g (4.5 mmol) of 4,5-dihydro-3-(hydroxymethyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one, 0.3 ml (5.0 mmol) of methyl iodide and 10 ml of dry dimethylformamide is treated with 0.2 g (4.5 mmol) of sodium hydride (55 percent oil dispersion, washed with n-hexane) and the mixture is stirred at room temperature for about 16 hours. The mixture is poured into 70 ml of water and extracted three times with chloroform. The chloroform solution is washed once with water, dried over magnesium sulphate and evaporated. The crude product is chromatographed on silica gel while eluting with chloroform containing 5% of methanol. Recrystallization of the material obtained from ethyl acetate/hexane yields 4,5-dihydro-3-(methoxymethyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 115°-116°.
Reaction SMILES: [CH3:1][I:2].[CH2:3]([O:9][C:10]1[C:14]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:13][S:12][N:11]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>CC(C)=O>[I-:2].[CH2:3]([O:9][C:10]1[C:14]([C:15]2[CH:16]=[N+:17]([CH3:1])[CH:18]=[CH:19][CH:20]=2)=[N:13][S:12][N:11]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CI
Reactant: CCCCCCOc1nsnc1-c1cccnc1
Solvent: CC(C)=O
Product: CCCCCCOc1nsnc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (0.5 ml, 7.5 mmol) and 3-(3-hexyloxy-1,2,5-thiadiazol-4-yl)pyridine (658 mg, 2.5 mmol) in acetone (5 ml) was stirred at room temperature for 18 h. The title compound precipitated from the solution and was collected by filtration to yield 0.81 g (80%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.N1CC[CH2:23][C@H:19]1[C:20](O)=[O:21].[NH4+].[Cl-].C(OCC)(=[O:30])C>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:17]=[CH:16][C:13]([CH:14]([OH:15])[CH:20]([OH:21])[C:19](=[O:30])[CH3:23])=[CH:12][CH:11]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CCOC(C)=O
Reactant: O=Cc1ccc(-c2nc3ccccc3o2)cc1
Agent: [Cl-]
Agent: [NH4+]
Product: CC(=O)C(O)C(O)c1ccc(-c2nc3ccccc3o2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66 %

Procedure:
Flame dried 10 mL flask was filled with argon and charged with hydroxyacetone (1 ml) and anhydrous DMSO (2 ml). After solution is formed the 4-benzoxazol-2-yl-benzaldehyde (2.2 mmol) followed by L-Proline (1.1 mmol) were added. The resulted homogeneous reaction mixture was stirred at room temperature for 24 h. Then, half saturated NH4Cl solution (20 ml) and ethyl acetate (10 ml) was added with vigorous stirring, the layers were separated and the aqueous phase was extracted thoroughly with ethyl acetate (5×10 ml). The combined organic phases were dried (Na2SO4) and concentrated in vacuum. The residue was recrystallized from EtOH yielding 95 mg of pure product as white crystals; the mother liquor was purified by column chromatography (eluent-ethyl acetate/hexanes-6/3) yielding next 125 mg (total yield 66%) of the pure product.
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([C:15]([OH:17])=O)[C:8]2[O:13][CH2:12][CH2:11][O:10][C:9]=2[CH:14]=1)(=[O:4])(=[O:3])[NH2:2].O1CCOCC1.[N:24]1[CH:29]=[CH:28][CH:27]=[N:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.N>O.C(N(CC)CC)C>[CH2:12]1[CH2:11][O:10][C:9]2[C:8](=[C:7]([CH:6]=[C:5]([S:1](=[O:3])(=[O:4])[NH2:2])[CH:14]=2)[C:15]([N:33]2[CH2:34][CH2:35][N:30]([C:25]3[N:24]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH2:31][CH2:32]2)=[O:17])[O:13]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: NS(=O)(=O)c1cc2c(c(C(=O)O)c1)OCCO2
Agent: N
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: NS(=O)(=O)c1cc2c(c(C(=O)N3CCN(c4ncccn4)CC3)c1)OCCO2
Temperature: 10 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
146 g of 7-sulfamoyl-1,4-benzodioxane-5-carboxylic acid, 300 ml of dioxane and 57 g of triethylamine were introduced into a 1-liter 3-neck flask provided with an agitator, a thermometer and an introduction funnel. The mixture was heated to 40°-50° C. and 80 ml of water was added. The solution was cooled to a temperature of from 5°-10° C. and 61.5 g of ethyl chloroformiate was added. Agitation of the mixture was maintained for one hour at 10° C. and 93 g of 1-(2-pyrimidinyl)-piperazine was added without the temperature rising above 15° C. Agitation of the mixture was continued for one hour at ambient temperature and then, after the addition of 1,500 ml of water, the mixture was rendered alkaline to a pH of 10 with ammonia. The crystals produced after distillation under vacuum of the solvents and cooling were dried off, washed with water, dried in a drying oven at 50° C. and then purified by treatment with 120 ml of chloroform. After filtration and drying, 92 g of 1-(2,3-ethylenedioxy-5-sulfamoylbenzoyl)-4-(2-pyrimidinyl)-piperazine was produced (M.P.: 239° C.; yield: 40.2%). The structure was confirmed by nuclear magnetic resonance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[N:11][N:10]=[C:9]1[C:13]1[S:27][C:16]2[C:17]3[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:18]=3[O:19][CH2:20][CH2:21][C:15]=2[CH:14]=1.[CH3:28][N:29]=[C:30]=[O:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[N:11][N:10]=[C:9]1[C:13]1[S:27][C:16]2[C:17]3[CH:25]=[CH:24][C:23]([NH:26][C:30]([NH:29][CH3:28])=[O:31])=[CH:22][C:18]=3[O:19][CH2:20][CH2:21][C:15]=2[CH:14]=1
Reactant: CN=C=O
Reactant: Nc1ccc2c(c1)OCCc1cc(-c3nncn3-c3ccccc3Cl)sc1-2
Product: CNC(=O)Nc1ccc2c(c1)OCCc1cc(-c3nncn3-c3ccccc3Cl)sc1-2

Procedure:
Following the procedures of Example 76, 2-(4-(2-chlorophenyl)-4H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-amine was reacted with methyl isocyanate to give 112. MS: (ESI+) 452.1
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH2:18][OH:19])[CH2:9][NH:10]C(=O)OC(C)(C)C.ClS([N:24]=[C:25]=[O:26])(=O)=O.O.C(=O)(O)[O-].[Na+]>C(#N)C>[C:25](=[O:26])([O:19][CH2:18][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH2:9][NH2:10])[NH2:24]
Reactant: CC(C)(C)OC(=O)NCC(CO)c1ccccc1Cl
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: NCC(COC(N)=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 344 mg (1.20 mmol) of the compound of Example 14A in 86 ml of acetonitrile was cooled to −15° C., and 314 μl (3.61 mmol) of chlorosulphonyl isocyanate were added. After 5 min, 10 ml of water were added and stirring of the reaction mixture was continued at 60° C. overnight. After cooling to RT, 10 ml of a saturated aqueous sodium bicarbonate solution were added. The mixture was extracted four times with ethyl acetate. The combined organic phases were dried over sodium sulphate and freed from the solvent on a rotary evaporator. The residue (118 mg, about 85% pure, about 37% of theory) corresponded to the title compound and was reacted further without further purification.
Reaction SMILES: [CH:1]([C:4]1([OH:18])[CH2:9][CH2:8][CH:7]([NH:10]C(=O)OC(C)(C)C)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[ClH:19].O1CCOCC1>O1CCOCC1>[ClH:19].[NH2:10][CH:7]1[CH2:8][CH2:9][C:4]([CH:1]([CH3:3])[CH3:2])([OH:18])[CH2:5][CH2:6]1
Reactant: CC(C)C1(O)CCC(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)C1(O)CCC(N)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of tert-butyl (4-isopropyl-4-hydroxycyclohexyl)carbamate (Preparation Example 252) (0.179 g) and dioxane (1.5 mL), 26% hydrogen chloride-dioxane (0.9 mL) was added under ice cooling and stirred at room temperature for 18 hours. The precipitated solid was collected by filtration to give 4-amino-1-isopropylcyclohexanol hydrochloride (0.086 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH:12]([CH2:15][OH:16])[CH2:13]O)[O:8][CH2:7][CH:6]([CH2:17][CH2:18][CH3:19])[CH2:5]2.C([Li])CCC.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1COCC1.CCCCCC>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH:12]1[CH2:15][O:16][CH2:13]1)[O:8][CH2:7][CH:6]([CH2:17][CH2:18][CH3:19])[CH2:5]2
Reactant: CCCC1COc2cc(C(CO)CO)c(F)cc2C1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC1COc2cc(C3COC3)c(F)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3.80 g (13.7 mmol) of 2-(6-fluoro-3-propylchroman-7-yl)propane-1,3-diol are dissolved in 70 ml of THF, and 8.7 ml (13.7 mmol) of a 15 percent solution of n-butyllithium in hexane are added at 0° C. After 30 min, 2.7 g (14.2 mmol) of p-toluenesulfonyl chloride in 30 ml of THF are added, and the mixture is stirred at RT for 1 h and re-cooled to 0° C. After addition of a further 8.7 ml (13.7 mmol) of a 15% solution of n-butyllithium in hexane, the cooling is removed, and the batch is heated under reflux for 4 h. The batch is subsequently diluted with MTB ether and washed with water. The org. phase is dried over sodium sulfate and evaporated, and the crude product is purified by chromatography on silica gel with heptane/ethyl acetate (3:2). The product fractions (Rf=0.5) are evaporated, and the product is used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][C:3]=1[C:30]([O:37][CH2:38][CH3:39])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33].[CH:40]1([NH2:45])[CH2:44][CH2:43][CH2:42][CH2:41]1>>[CH:40]1([NH:45][C:2]2[N:7]3[N:8]=[C:9]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:10]([C:11]4[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]5[CH2:22][CH2:21][CH2:20][CH2:19]5)[N:12]=4)=[C:6]3[CH:5]=[CH:4][C:3]=2[C:30]([O:37][CH2:38][CH3:39])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])[CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: NC1CCCC1
Reactant: CCOC(OCC)(OCC)c1ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn2c1Cl
Product: CCOC(OCC)(OCC)c1ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn2c1NC1CCCC1
Temperature: 80 °C
Yield: 96.1 %

Procedure:
A mixture of 4-[7-chloro-2-(4-fluorophenyl)-6-(triethoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (2.37 g, 4.28 mmol) and cyclopentylamine (10 mL 100 mmol) was heated in a sealed tube at 80° C. for 16 hours. The reaction mixture was cooled to room temperature and excess cyclopentylamine was removed in vacuo. The crude solid was triturated in water. The solids were collected on a filter to provide N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-6-(triethoxymethyl)pyrazolo[1,5-a]pyridin-7-amine (2.48 g, 96%). Rf 0.42 (4:1 hexanes:ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.04 (d, 1H), 7.75 (d, 1H), 7.68-7.60 (m, 3H), 7.12 (t, 2H), 6.36-6.31 (m, 2H), 5.30 (m, 1H), 5.07 (d, 1H), 4.35 (m, 1H), 3.45 (q, 6H), 2.12-1.95 (m, 4H), 1.80-1.45 (m, 12H), 1.25 (t, 9H); MS m/z 603 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[NH:18][C:19]([C:22]5[CH:27]=[CH:26][C:25]([O:28]C)=[CH:24][CH:23]=5)=[N:20][N:21]=4)[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[NH:18][C:19]([C:22]5[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=5)=[N:20][N:21]=4)[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2nnc(-c3ccc4[nH]nc(-c5ccc(F)cc5)c4c3)[nH]2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-c2nnc(-c3ccc4[nH]nc(-c5ccc(F)cc5)c4c3)[nH]2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 18.6 %

Procedure:
To a round bottom flask containing 1-{5-[3-(4-fluorophenyl)(1H-indazol-5-yl)](4H-1,2,4-triazol-3-yl)]-4-methoxybenzene (100 mg, 0.26 mmol) was added anhydrous dichloromethane (2 ml). The flask, under a nitrogen atmosphere, was placed in an ice/salt bath. To the flask was added boron tribromide (1.3 ml, 1.3 mmol). The reaction was allowed to stir at 0° C. for one hour and at room temperature for an additional four hours. The reaction was quenched with water and the solvent was removed. The product was extracted from the reaction mixture with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered and concentrated. The product was purified by semipreparative HPLC (20-80% acetonitrile over 30 minutes) to yield the title compound (18 mg, 18.7% yield). 1H NMR (DMSO-d6) δ 13.5 (s, 1H), 9.95 (s, 1H), 8.65 (s, 1H), 8.1 (m, 3H), 7.95 (m, 2H), 7.78 (d, 1H), 7.4 (m, 2H), 6.85 (m, 2H), ES-MS m/z 372 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:7][N:6]([CH3:8])[C:5](=[O:9])[C:4]1([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2([OH:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.[C:36](=[O:39])([O-:38])[O-].[K+].[K+]>C(O)C>[C:5]([OH:35])(=[O:9])/[CH:4]=[CH:16]/[C:36]([OH:38])=[O:39].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2([OH:35])[CH2:30][CH2:31][N:32]([CH2:2][CH:3]3[CH2:7][N:6]([CH3:8])[C:5](=[O:9])[C:4]3([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:33][CH2:34]2)=[CH:25][CH:24]=1
Reactant: CN1CC(CCl)C(c2ccccc2)(c2ccccc2)C1=O
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN1CC(CN2CCC(O)(c3ccc(Cl)cc3)CC2)C(c2ccccc2)(c2ccccc2)C1=O
Product: O=C(O)/C=C/C(=O)O
Temperature: 200 °C
Reaction time: 48 h

Procedure:
To a steel bomb was added 17.0 g. (0.057 mole) of 4-chloromethyl-1-methyl-3,3-diphenyl-2-pyrrolidinone in 150 ml. of ethanol, 12.0 g. (0.057 mole) of 4-(p-chlorophenyl)-4-hydroxypiperidine and 21.2 g. (0.17 mole) of finely ground potassium carbonate. The mixture was heated with stirring to 200° C. for 48 hours. After concentrating the mixture in vacuo, the residue was partitioned between dilute hydrochloric acid solution and isopropyl ether. The ether was discarded, the acid solution was made basic with 50 percent sodium hydroxide solution and the base insoluble material was extracted with chloroform. The chloroform was dried, filtered and concentrated in vacuo. The residue was dissolved in a mixture of isopropyl ether and isopropanol and treated with an equivalent of fumaric acid. The fumarate salt was recrystallized twice from ethanol and once from isopropanol-methanol. The fumarate salt (2.0 g., 10%) melted at 213°-215° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][CH:4]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH2:29][N:30]2[CH:34]=[CH:33][N:32]=[C:31]2[CH3:35])[N:26]=[N:27][CH:28]=1>>[ClH:22].[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:23]2[CH:24]=[C:25]([CH2:29][N:30]3[CH:34]=[CH:33][N:32]=[C:31]3[CH3:35])[N:26]=[N:27][CH:28]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)c2ccccc12
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Product: COc1ccc(-c2cnnc(Cn3ccnc3C)c2)c2ccccc12
Product: Cl

Procedure:
The title compound, MS: m/e=331.3 (M+H+), was prepared from 2-(4-methoxy-naphthalen-1-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][O:4][CH2:3]1.C(NC(C)C)(C)C.[Li].[N:16]1([C:21]2[C:30]3[C:25](=[N:26][C:27](Cl)=[C:28]([Cl:31])[N:29]=3)[N:24]=[C:23]([Cl:33])[N:22]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1.O>O1CCCC1>[Cl:33][C:23]1[N:22]=[C:21]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:30]2[C:25](=[N:26][C:27]([O:1][C@@H:2]3[CH2:7][CH2:6][CH2:5][O:4][CH2:3]3)=[C:28]([Cl:31])[N:29]=2)[N:24]=1
Reactant: Clc1nc(N2CCCC2)c2nc(Cl)c(Cl)nc2n1
Reactant: O[C@@H]1CCCOC1
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: Clc1nc(N2CCCC2)c2nc(Cl)c(O[C@@H]3CCCOC3)nc2n1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
a)+b) 170 mg (1.67 mmol) (R)-3-hydroxytetrahydropyran are dissolved in 5 ml of tetrahydrofuran and under protective gas at −10° C. mixed with 821 μl (1.64 mmol) of a 2 molar solution of lithium diisopropylamine in tetrahydrofuran. The mixture is stirred for 30 minutes at −10° C., then for one hour at ambient temperature. The mixture is cooled to −10° C. again and combined with a suspension of 500 mg (1.64 mmol) 4-pyrrolidin-1-yl-2,6,7-trichloropteridine in 15 ml of tetrahydrofuran. The mixture is stirred for one hour at −10° C., slowly allowed to come up to ambient temperature and stirred for another four hours. The reaction mixture is combined with approx. 100 ml of water and extracted with dichloromethane. The organic phase is dried on sodium sulphate and the solvent is eliminated in vacuo. The residue is taken up in approx. 50 ml diethyl ether and stirred for one hour. The solid is suction filtered, washed with diethyl ether and dried. Yield 320 mg (53% of theory). The (R)-2,6-dichloro-7-(3-tetrahydropyranyloxy)-4-pyrrolidin-1-yl-pteridine thus obtained is dissolved in 13 ml dioxane and slowly added dropwise to a solution of 372 mg (4.3 mmol) piperazine in 12 ml dioxane at a temperature of 80° C. The mixture is stirred for approx. another 16 hours at 80° C., cooled to ambient temperature and the reaction mixture is combined with water. It is extracted with dichloromethane, the organic phase is dried on sodium sulphate and the solvent is eliminated in vacuo. The residue is purified by chromatography. The product obtained is stirred with diethyl ether, the solid substance is suction filtered, washed with diethyl ether and dried. Yield 170 mg (47% of theoretical)
Reaction SMILES: [NH3:1].O=[C:3]([CH3:11])[CH2:4][C:5]([O:7][CH2:8][CH2:9][OH:10])=[O:6]>C(O)C>[NH2:1]/[C:3](/[CH3:11])=[CH:4]\[C:5]([O:7][CH2:8][CH2:9][OH:10])=[O:6]
Reactant: N
Reactant: CC(=O)CC(=O)OCCO
Solvent: CCO
Product: C/C(N)=C/C(=O)OCCO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Anhydrous ammonia gas was bubbled through a solution of 2-hydroxyethyl 3-oxo-butyrate (25 g, 0.17 moles) (ref 5) and ethanol (250 mL) for 20 minutes. This solution was stirred for 16 hours at room temperature. The solvent was removed in vacuo and the resulting oil was chromatographed on silica gel (250 g) using ethyl acetate-hexane 60:40 as eluant. The enriched fractions were combined and the solvent removed in vacuo to give the product; H' NMR CDCl3 4.33 (t, 2H) 3.85 (t, 2H) 3.55 (s, 1H) 2.85 (broad singlet, 1H) 2.31 (s, 3H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN1CCN(C)C1=O>[C:16]1([S:22][C:8]2[CH:9]=[CH:2][CH:3]=[CH:4][C:5]=2[CH:6]=[O:7])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCN(C)C1=O
Product: O=Cc1ccccc1Sc1ccccc1
Temperature: 120 °C
Reaction time: 2.5 h

Procedure:
To a solution of 4-fluorobenzaldehyde (0.443 mL) in 1,3-dimethyl-2-imidazolidinone (6.4 mL) was added potassium carbonate (0.659 g). Then benzenethiol (0.326 mL) was added, and the resulting mixture was stirred at 120° C. for 2.5 hours. The reaction mixture was cooled to room temperature and then partitioned between diethyl ether (60 mL) and water (15 mL). The organic layer was washed successively with water (15 mL×2) and brine (15 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (0.826 g).