Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[N:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[N:6]=[N:5][N:4]=1.S(Cl)([Cl:22])=O>C1(C)C=CC=CC=1>[Cl:22][CH2:2][C:3]1[N:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[N:6]=[N:5][N:4]=1
Reactant: O=S(Cl)Cl
Reactant: N#Cc1ccc(-n2nnnc2CO)cc1C(F)(F)F
Solvent: Cc1ccccc1
Product: N#Cc1ccc(-n2nnnc2CCl)cc1C(F)(F)F
Reaction time: 2 h
Yield: 71.8 %

Procedure:
To a solution of 4-[5-(hydroxymethyl)-1H-tetrazol-1-yl]-2-(trifluoromethyl)benzonitrile (Intermediate 23, 30.0 g) in toluene (500 mL) was added thionyl chloride (14.5 g, 0.122 mol) at room temperature. The reaction was heated to reflux and stirred for 2 hours. The reaction mixture was concentrated under vacuum and diluted with DCM. The resulting solution was washed with ice-water, followed by aqueous NaHCO3. The organic was separated and washed with brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by triturating with ether (500 mL) and dried under vacuum to yield 4-[5-(chloromethyl)-1H-tetrazol-1-yl]-2-(trifluoromethyl)benzonitrile (23 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1.Cl.[O:18]([NH2:20])[CH3:19]>N1C=CC=CC=1>[CH3:19][O:18][N:20]=[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: CON
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: CON=C(Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of 2-(4-chlorophenyl)-1-phenyl-1-ethanone (2, 1.93 g, 8.37 mmol) in 25 ml pyridine (dried over molecular sieves) under nitrogen was added at room temperature methoxylamine hydrochloride (873 mg, 10.5 mmol). The resulting slightly cloudy, pale orange mixture was stirred at room temperature overnight. The pyridine was removed in vacuo with heating. The residual solids were stirred with ether (60 ml), isolated by filtration, and discarded. The filtrate was dried over sodium sulfate, and concentrated in vacuo to give a mixture of the oxime geometrical isomers as 2.00 g of a clear, pale yellow syrup (92% yield). 1H NMR showed the isomers to be formed in a 5:3 ratio: Rf 0.64, 0.50; IR (CDCl3) 3068 (w), 2940 (m), 2819 (w), 1602 (w), 1493 (s), 1442 (m); 1H NMR (CDCl3) 7.63 (m, 2H), 7.37-7.11 (m, 11.5 H), 4.12 (s, 2H), 4.05 (s, 3H), 3.91 (s, 1.6H), 3.82 (s, 1.2H); low resolution mass spec. 259 (M+, 8), 227 (100), 192 (28), 165 (18), 134 (12), 125 (62), 119 (37).
Reaction SMILES: [CH2:1]([C:3]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:16]1[CH:21]=[CH:20][C:19](C(OC)=O)=[CH:18][CH:17]=1)[CH3:2].[OH-:26].[K+].[CH3:28][OH:29].C1COCC1.O>>[C:28]([C:18]1[CH:17]=[C:16]([N:7]2[CH:6]=[N:5][C:4]3[C:8]2=[N:9][C:10]([C:12]([F:15])([F:13])[F:14])=[N:11][C:3]=3[CH2:1][CH3:2])[CH:21]=[CH:20][CH:19]=1)([OH:29])=[O:26]
Reactant: CCc1nc(C(F)(F)F)nc2c1ncn2-c1ccc(C(=O)OC)cc1
Reactant: [OH-]
Reactant: CO
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc(C(F)(F)F)nc2c1ncn2-c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 22 %

Procedure:
6-Ethyl-9-(4-methoxycarbonylphenyl)-2-trifluoromethylpurine (500 mg, 1.43 mmol) in 10 mL of MeOH/THF/H2O (1/2/1) was treated with KOH (800 mg, 14.3 mmol) and stirred for 14 hours at room temperature. The reaction mixture was concentrated under vacuum and the residue acidified to pH 4 by the addition of 30% TFA in dichloromethane and extracted with 10% MeOH in dichloromethane. The combined organic extracts were dried (Na2SO4), concentrated under vacuum and crystallized from MeOH to afford 9-(3-carboxyphenyl)-6-ethyl-2-trifluoromethylpurine (110 mg, 22% yield).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(CC)CC.[Cl:28][CH2:29][CH2:30][CH2:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][S:32]([CH2:31][CH2:30][CH2:29][Cl:28])(=[O:34])=[O:33])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2N)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2NS(=O)(=O)CCCCl)CC1
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
To a solution of N-boc-4-(2-amino-phenyl)-piperazine (555 mg, 2.0 mmol) and Et3N (837 uL, 6 mmol) in 20 mL of CH2Cl2 was added 3-chloropropanesulfonyl chloride (255 uL, 2.1 mmol). After stirring for about 30 minutes, the mixture was quenched with saturated aqueous sodium bicarbonate, diluted with EtOAc, washed with 1 M HCl, water and brine, and then dried (Na2SO4), filtered and concentrated. Purification by silica gel chromatography (35 g SiO2, 10 to 30% EtOAc/hexanes, over 30 min at 35 mL/min) afforded about 781 mg (1.87 mmol, 93%) of N-boc-4-[2-(3-chloro-propane-1-sulfonylamino)-phenyl]-piperazine as a white solid. LRMS (ESI+): 418.1 [M+1]
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][CH2:15][CH:14]([C:18]([NH2:20])=[O:19])[CH2:13]1)=[N:7][N:6]=[CH:5]2.[CH:21]1([NH:24][C:25](=[O:42])[C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:27]=2)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCO.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:21]1([NH:24][C:25]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8]([N:12]3[CH2:17][CH2:16][CH2:15][CH:14]([C:18]([NH2:20])=[O:19])[CH2:13]3)=[N:7][N:6]=[CH:5]4)[CH:27]=2)=[O:42])[CH2:22][CH2:23]1
Reactant: NC(=O)C1CCCN(c2nncc3cc(Br)ccc23)C1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CCCC(C(N)=O)C3)nncc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
A mixture of 1-(6-bromophthalazin-1-yl)piperidine-3-carboxamide (0.12g, 0.4 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide (0.1 g, 0.4 mmol), and tetrakis(triphenylphosphine)palladium (0.02 g, 0.02 mmol) in 5 mL DME/EtOH (4:1) was treated with 2 M potassium carbonate (0.5 mL, 1 mmol). The mixture resulted was warmed up to 90° C. and stirred for 1 h under nitrogen. The mixture was cooled down to room temperature, and the crude product was purified via flash chromatography (silica gel) eluting with a gradient of 4% 2 M ammonia in MeOH/DCM to 6% 2 M ammonia in MeOH/DCM to give (0.11 g) title compound as a pale yellow solid. Found MS (ES+): 430(M+H)+.
Reaction SMILES: [CH3:1][NH2:2].[CH:3]([C:6]1[C:7]([O:14][CH2:15][CH2:16][CH3:17])=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O)([CH3:5])[CH3:4].[BH4-].[Na+]>CO>[CH:3]([C:6]1[C:7]([O:14][CH2:15][CH2:16][CH3:17])=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][CH2:1][NH2:2])([CH3:5])[CH3:4]
Reactant: CN
Reactant: CCCOc1c(C=O)cccc1C(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCOc1c(CCN)cccc1C(C)C
Reaction time: 72 h
Yield: 95 %

Procedure:
A solution of methylamine (30 mL of a 2.0 M solution in MeOH, 60 mmol) was added to 3-isopropyl-2-propoxybenzaldehyde (1.49 g, 7.22 mmol) and the mixture was stirred for 72 h. The solution was concentrated under reduced pressure. The resulting dark yellow oil was dissolved in EtOH (30 mL) and treated with NaBH4 (0.273 g, 7.22 mmol). After 18 h, the reaction mixture was concentrated under reduced pressure and dissolved in 1 N NaOH (30 mL). The mixture was extracted with Et2O (3×75 mL). The combined organics were dried (Na2SO4) and concentrated to yield the title compound (1.52 g, 95%) as an orange oil: 1H NMR (300 MHz, DMSO-d6) δ 7.21-7.14 (m, 2H), 7.04 (t, J=7.5 Hz, 1H), 3.70 (t, J=6.3 Hz, 2H), 3.63 (s, 2H), 3.32-3.23 (m, 1H), 2.28 (s, 3H), 1.78 (br s, 1H), 1.76-1.71 (m, 2H), 1.16 (d, J=6.9 Hz, 6H), 1.03 (t, J=7.3 Hz, 3H).
Reaction SMILES: C([O:3][C:4](=[O:47])[CH:5]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39](=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH2:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:9][CH:8]=1)C.[OH-].[Na+]>C1COCC1.CCO>[C:39]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[NH:32][CH:5]([CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH2:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[O:23][C:24]=2[CH3:25])=[CH:9][CH:8]=1)[C:4]([OH:47])=[O:3])(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccccc12)Nc1ccccc1C(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC(Nc2ccccc2C(=O)c2ccccc2)C(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.8 %

Procedure:
0.213 g (0.341 mmol) of 2-(2-Benzoyl-phenylamino)-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yl}-propionic acid ethyl ester was dissolved in 1.6 ml of THF/EtOH=1/1 and treated with 0.568 ml of 3N NaOH(5 eq). The reaction flask was stirred for 20 h at ambient temperature. The mixture was then poured onto crashed ice/NH4Cl, extracted twice with AcOEt, washed with brine, dried over sodium sulfate, and evaporated to dryness. Twofold crystallization from hexane/AcOEt yielded 0.199 g of the title product as yellow crystals of mp. 125° (dec.).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[C:12]=2[O:19][CH3:20])[NH:5][C:6](=[O:10])[C:7]=1[N:8]=O.C(N(CC)CC)C.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[C:12]=2[O:19][CH3:20])[NH:5][C:6](=[O:10])[C:7]=1[NH2:8]
Reactant: COc1c(Cl)cc(Cl)cc1-c1nc(N)c(N=O)c(=O)[nH]1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Product: COc1c(Cl)cc(Cl)cc1-c1nc(N)c(N)c(=O)[nH]1
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
4-Amino-2-(3,5-dichloro-2-methoxyphenyl)-5-nitrosopyrimid-6-one (6.8 g.) was suspended in a solution of triethylamine (10 ml.) in water (100 ml.). Sodium dithionite (7.5 g.) was added, in portions, to the mixture with stirring, and stirring was continued for a further 30 minutes. A further quantity (2 g.) of sodium dithionite was added, and stirring was continued for a further 30 minutes, after which the mixture was allowed to stand overnight. The solid was filtered off and washed with water to give crude 4,5-diamino-2-(3,5-dichloro-2-methoxyphenyl)pyrimid-6-one (6 g.), m.p. 145°-150° C. (with decomposition), pure enough for use in the next stage of the preparation.
Reaction SMILES: [C:1]([O:5][C:6](/[C:8](=[CH:35]\[C:36](\[CH3:51])=[CH:37]\[CH:38]([CH3:50])[CH2:39][CH:40]([CH3:49])[CH2:41][CH:42]([CH3:48])[CH2:43][CH:44]([CH3:47])[CH2:45][CH3:46])/[CH2:9][CH:10]([CH3:34])[C:11]([O:13]C1C(=O)OC(C(OC(C)(C)C)=O)C1C(OC(C)(C)C)=O)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(#N)C.[OH-].[Na+]>O>[C:1]([O:5][C:6](/[C:8](=[CH:35]\[C:36](\[CH3:51])=[CH:37]\[CH:38]([CH3:50])[CH2:39][CH:40]([CH3:49])[CH2:41][CH:42]([CH3:48])[CH2:43][CH:44]([CH3:47])[CH2:45][CH3:46])/[CH2:9][CH:10]([CH3:34])[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(C)CC(C)CC(C)CC(C)/C=C(C)/C=C(/CC(C)C(=O)OC1C(=O)OC(C(=O)OC(C)(C)C)C1C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CCC(C)CC(C)CC(C)CC(C)/C=C(C)/C=C(/CC(C)C(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 104.9 %

Procedure:
(Step 2) To di-tert-butyl 4-{(4Z,6E)-4-(tert-butoxycarbonyl)-2,6,8,10,12,14-hexamethylhexadec-4,6-dienoyloxy}-5-oxotetrahydrofuran-2,3-dicarboxylate (500 mg, 0.694 mmol) obtained in Step 1, acetonitrile (35 mL) and an aqueous sodium hydroxide solution (0.25 mol/L, 28 mL, 6.94 mmol) were added, and the resulting mixture was stirred at room temperature for 6.5 hours. To the reaction mixture, water was added, and then, Dowex 50 (registered trademark) (Muromachi Technos, 50WX8, 50-100 mesh, H+ form) was added thereto to neutralize the mixture, and the insoluble matter was removed by filtration. After the filtrate was extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over sodium sulfate, and then, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=5/95 to 60/40), whereby Compound 8 (318 mg, quant.) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([NH:14][NH2:15])=[N:12][N:11]([CH2:16][C:17]3[C:18]([CH3:27])=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[C:10](=[O:28])[C:9]=2[C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)=[CH:4][CH:3]=1.[CH2:37]([O:44][C@@H:45]([CH3:49])[C:46](O)=[O:47])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CCOC(C)=O.C1COCC1>[CH2:37]([O:44][C@@H:45]([CH3:49])[C:46]([NH:15][NH:14][C:13]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:9]([C:29]2[CH:30]=[CH:31][C:32]([C:33]#[N:34])=[CH:35][CH:36]=2)[C:10](=[O:28])[N:11]([CH2:16][C:17]2[C:18]([CH3:27])=[N:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=2)[N:12]=1)=[O:47])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: C[C@H](OCc1ccccc1)C(=O)O
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc(NN)c(-c2ccc(Cl)cc2)c(-c2ccc(C#N)cc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1nc(C(F)(F)F)ccc1Cn1nc(NNC(=O)[C@H](C)OCc2ccccc2)c(-c2ccc(Cl)cc2)c(-c2ccc(C#N)cc2)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.1 %

Procedure:
To a round bottom flask was added 4-(5-(4-chlorophenyl)-6-hydrazinyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-oxo-2,3-dihydropyridazin-4-yl)benzonitrile (70 mg, 0.1367 mmol), prepared as described in Example 2B, (S)-2-(benzyloxy)propanoic acid (25 mg, 0.1367 mmol), EDAC (30 mg, 0.15 mmol), HOBT (20.3 mg, 0.15 0 mmol), THF (5 ml) and diisopropyl ethyl amine (19.4 mg, 0.15 mmol). The reaction was stirred at rt for 5 hr. After this time, the reaction was diluted with EtOAc (40 ml). The resulting solution was extracted with water (2×20 ml), and saturated NaCl (20 ml). The organic layer was dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (4 g silica gel) eluting with a gradient of 0%-60% EtOAc/Hex to give product (S)-2-(benzyloxy)-N′-(4-(4-chlorophenyl)-5-(4-cyanophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-1,6-dihydropyridazin-3-yl)propanehydrazide as a beige solid (70 mg, 76% yield).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][N:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:11][CH:10]=2)[CH:3]=1.[F:28][C:29]([F:33])([F:32])[CH2:30][OH:31].C([O-])([O-])=O.[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>C(Cl)Cl>[N:21]1[C:22]2[C:27](=[N:26][CH:25]=[CH:24][N:23]=2)[C:18]([NH:17][CH2:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][C:4]3[CH:3]=[C:2]([O:31][CH2:30][C:29]([F:33])([F:32])[F:28])[CH:7]=[CH:6][N:5]=3)=[CH:10][CH:11]=2)=[N:19][CH:20]=1
Reactant: Ic1ccnc(Oc2ccc(CCNc3ncnc4nccnc34)cc2)c1
Reactant: OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: ClCCl
Product: FC(F)(F)COc1ccnc(Oc2ccc(CCNc3ncnc4nccnc34)cc2)c1
Reaction time: 72 h
Yield: 26.1 %

Procedure:
To a solution of N-(2-{4-[(4-iodopyridin-2-yl)oxy]phenyl}ethyl)pteridin-4-amine (300 mg, 0.64 mmol) and 2,2,2-trifluoroethanol (5 mL, 1.27 mmol) in a 45 mL Parr Bomb was added Cs2CO3 (412 mg, 1.27 mmol), 1,10-phenanthroline (22 mg, 0.127 mmol), and Cut (12 mg, 0.064 mmol). The reaction was held at 110° C. for 72 h, diluted with CH2Cl2, and washed with H2O. The organic layer was concentrated in vacuo and the residue was purified by preparative HPLC to afford pteridin-4-yl-(2-{4-[4-(2,2,2-trifluoroethoxy)-pyridin-2-yloxy]-phenyl}-ethyl)-amine (74 mg, 26%) as a yellow solid: mp 166° C.; EIMS m/z 442 ([M]+).
Reaction SMILES: Cl[CH:2]1[C:11]2[C:6](=[C:7]([O:12][C:13]3[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[N:14]=3)[CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:3]1.[C:23]1([O-:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[CH3:22][O:21][C:15]1[CH:16]=[C:17]([O:19][CH3:20])[N:18]=[C:13]([O:12][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:6]=2[C:4](=[O:5])[O:3][CH:2]3[O:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:14]=1
Reactant: [O-]c1ccccc1
Reactant: COc1cc(OC)nc(Oc2cccc3c2C(=O)OC3Cl)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: COc1cc(OC)nc(Oc2cccc3c2C(=O)OC3Oc2ccccc2)n1
Reaction time: 19 h

Procedure:
A mixture of 1.4 g of 3-chloro-7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-phthalide (see Example 85) and 0.63 g of potassium phenolate is heated at reflux temperature in the presence of a spatula tip of 18-crown-6 in 15 ml of acetonitrile. After 19 hours, the reaction mixture is filtered through Celite® and concentrated by evaporation, and the crude product is purified by column chromatography (eluant 25% ethyl acetate/n-hexane) to yield 7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-3-phenoxy-phthalide in the form of white crystals, m.p. 155°-157° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Cl[C:6]([CH3:18])([CH3:17])[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[CH3:16])=[O:8]>ClCCl.CCCCCCC>[CH3:17][CH:6]1[CH2:18][C:14]2[C:9](=[C:10]([CH3:16])[CH:11]=[C:12]([CH3:15])[CH:13]=2)[C:7]1=[O:8]
Reactant: Cc1ccc(C(=O)C(C)(C)Cl)c(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCCCCCC
Product: Cc1cc(C)c2c(c1)CC(C)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Aluminium chloride (38 g, 0.29 mole) was suspended in 200 ml of anhydrous dichloromethane. 2-Chloro-2,2′,4′-trimethylpropiophenone (30.0 g, 0.14 mole) in 30 ml of heptane was slowly added to this suspension. During the addition (30 min) the temperature was kept at room temperature. After the addition was completed, the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was poured onto 400 g of ice water, and the organic layer was separated. The organic layer was successively washed twice with a 5 wt % aqueous hydrochloric acid solution (150 ml) and once with a 2 wt % aqueous sodium bicarbonate solution (150 ml). After drying over anhydrous magnesium sulfate the solution was concentrated under reduced pressure. The yield of crude 2,5,7-trimethyl-1-indanone was 22.9 g or 92%. A sample was crystallized from pentane to give crystalline material.
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].[OH:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12](N(OC)C)=[O:13])[CH2:8][CH2:7]1.CCOC(C)=O>C1COCC1>[OH:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12](=[O:13])[CH2:2][CH3:1])[CH2:8][CH2:7]1
Reactant: CC[Mg+]
Reactant: CON(C)C(=O)C1CCC(O)CC1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(=O)C1CCC(O)CC1
Reaction time: 8 h
Yield: 72 %

Procedure:
EtMgBr (1 M, 3.0 eq, 20 mL) was added to a solution of 4-hydroxy-N-methoxy-N-methylcyclohexanecarboxamide (1.0 g, 1.0 eq) in dry THF at 0° C. Once addition was complete, the mixture was stirred overnight. The reaction mixture was washed with saturated NH4Cl (aq), and extracted by EtOAc. The extract was dried, concentrated, and purified by column chromatography with petroleum ether:EtOAc=1:1 to give the desired product (0.6 g, 72% yield). 1H NMR (400 MHz, CDCl3) δ 3.50-3.64 (m, 1H), 2.47 (q, J=7.2 Hz, 2H), 2.28-2.37 (m, 1H), 2.00-2.10 (m, 2H), 1.88-1.94 (m, 2H), 1.70-1.80 (m, 1H), 1.21-1.49 (m, 4H), 1.05 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][S:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:4][CH:3]=1.Cl.[CH2:29]([O:31][C:32](=[O:35])[CH2:33][NH2:34])[CH3:30]>>[CH2:29]([O:31][C:32](=[O:35])[CH2:33][NH:34][C:21](=[O:23])[C:20]1[CH:19]=[CH:18][C:17]([S:14](=[O:16])(=[O:15])[NH:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[CH:26]=[CH:27][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:25][CH:24]=1)[CH3:30]
Reactant: CCOC(=O)CN
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(F)cc2)cc1
Agent: Cl
Product: CCOC(=O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared from 4-[2-(4-fluoro-phenoxy)-phenylsulfamoyl]-benzoic acid and glycine ethyl ester hydrochloride according to the method described in Example 1.1/d.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][N:7]([CH2:9][CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[C:6](=[O:23])[N:5]1[C:24]1[CH:29]=[CH:28][N:27]2[N:30]=[CH:31][C:32]([C:33]3[CH:38]=[CH:37][C:36]([C:39]4[N:43]=[CH:42][N:41](COCC[Si](C)(C)C)[N:40]=4)=[CH:35][CH:34]=3)=[C:26]2[N:25]=1)([CH3:3])[CH3:2].CCO.C([O-])(O)=O.[Na+].[ClH:60]>CCOCC>[ClH:60].[NH:41]1[CH:42]=[N:43][C:39]([C:36]2[CH:35]=[CH:34][C:33]([C:32]3[CH:31]=[N:30][N:27]4[CH:28]=[CH:29][C:24]([N:5]5[C@@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][N:7]([CH2:9][CH:10]6[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]6)[C:6]5=[O:23])=[N:25][C:26]=34)=[CH:38][CH:37]=2)=[N:40]1
Reactant: CC(C)[C@H]1CN(CC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3)c2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CC(C)[C@H]1CN(CC2CCNCC2)C(=O)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)cc3)c2n1

Procedure:
A mixture of (S)-tert-butyl 4-((4-isopropyl-2-oxo-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-1-yl)methyl)piperidine-1-carboxylate (99 mg, 0.14 mmol) and EtOH/6N aqueous HCl (1:2, 2 mL total) was heated at reflux for 2 hours. After cooling, the reaction mixture was neutralized by slow addition of saturated aqueous NaHCO3 solution. The mixture was extracted with 10% THF in dichloromethane. The combined extracts were washed with brine, dried and concentrated. The residue was purified by column chromatography (20% 7N ammonia in MeOH/dichloromethane) to give the free base, which was converted to HCl salt (38 mg, 53%) by treatment with 2N HCl in ether. LCMS (APCI+) m/z 486.8 [M+H]+.
Reaction SMILES: NC(C)C[C:4]1[C:9]([NH2:10])=[CH:8][CH:7]=[CH:6][N:5]=1.C([O-])([O-])=O.[K+].[K+].[CH:18]([Cl:21])(Cl)Cl>>[CH2:4]([N:5]1[C:4]2[N:5]=[CH:6][CH:7]=[CH:8][C:9]=2[N:10]=[C:6]1[CH2:18][Cl:21])[CH2:9][CH3:8]
Reactant: CC(N)Cc1ncccc1N
Reactant: ClC(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCn1c(CCl)nc2cccnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-aminopropyl-3-aminopyridine (172) (5.3 g, 35 mmol) is dissolved in 100 mL CHCl3 at room temperature. Ethyl chloromethylimidate hydrochloride (14 g, 89 mmol) is added followed by K2CO3 (25 g, 180 mmol). The suspension was stirred vigorously at room temperature for 3 hours. The reaction mixture is filtered through Celite and the solvent removed in vacuo. The residue is passed through a short plug of silica gel eluting with ethyl acetate to afford 3.7 g of 1-propyl-2-chloromethyl-7-azabenzimidazole (183). 1-propyl-2-(4-methoxybenzylamino)methyl-7-azabenzimidazole.