Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[N:7]2[C:8](=[O:20])[C:9]3[NH:10][CH:11]=[N:12][C:13]=3[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:6]2=[N:5][N:4]=1.[Br:21]N1C(=O)CCC1=O>C1COCC1.O>[Br:21][C:11]1[NH:10][C:9]2[C:8](=[O:20])[N:7]3[C:3]([S:2][CH3:1])=[N:4][N:5]=[C:6]3[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:13]=2[N:12]=1
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(SC)nnc12
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(SC)nnc12

Procedure:
A solution of 3-(methylthio)-9-pentyl-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (111 mg, 0.380 mmol), N-bromosuccinimide (81.1 mg, 0.456 mmol) in THF (3 ml) was stirred at 70° C. for 3 hours. The reaction was diluted with water and extracted with ethyl acetate three times, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by Prep LCMS to yield the desired product. LCMS calculated for: C12H16BrN6OS (M+H) 371.0. Found: 371.0, 373.0.
Reaction SMILES: [OH:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH3:12])[C:6]=2[CH:5]=[C:4]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH:3]=1.Cl[CH:19]1[C:28]2[C:23](=[CH:24][C:25]([F:30])=[CH:26][C:27]=2[F:29])[O:22][CH2:21][CH2:20]1>>[F:29][C:27]1[CH:26]=[C:25]([F:30])[CH:24]=[C:23]2[C:28]=1[CH:19]([O:1][C:2]1[C:10]3[N:9]=[C:8]([CH3:11])[N:7]([CH3:12])[C:6]=3[CH:5]=[C:4]([C:13]([N:15]([CH3:16])[CH3:17])=[O:14])[CH:3]=1)[CH2:20][CH2:21][O:22]2
Reactant: Cc1nc2c(O)cc(C(=O)N(C)C)cc2n1C
Reactant: Fc1cc(F)c2c(c1)OCCC2Cl
Product: Cc1nc2c(OC3CCOc4cc(F)cc(F)c43)cc(C(=O)N(C)C)cc2n1C
Yield: 49 %

Procedure:
The title compound was prepared as a white solid in 49% yield (0.12 g) from 4-hydroxy-N,N,1,2-tetramethyl-1H-benzimidazole-6-carboxamide (0.14 g, 0.61 mmol, WO 2004054984) and 4-chloro-5,7-difluorochromane (0.15 g, 0.73 mmol, STEP 2) by the same manner in STEP 1 of Example 1:
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:5]=[C:4]([C@H:19]2[C@H:24]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@@H:23]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@H:22]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C@@H:21]([CH2:49][O:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[O:20]2)[C:3]=1[OH:58].C([O-])([O-])=O.[K+].[K+].Br[CH2:66][CH2:67][CH2:68][OH:69]>CC(C)=O>[Br:1][C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:5]=[C:4]([C@H:19]2[C@H:24]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@@H:23]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@H:22]([O:41][CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[C@@H:21]([CH2:49][O:50][CH2:51][C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)[O:20]2)[C:3]=1[O:58][CH2:66][CH2:67][CH2:68][OH:69]
Reactant: OCCCBr
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(O)c(Br)c2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(OCCCO)c(Br)c2Cl)cc1
Temperature: 55 °C
Reaction time: 15 h
Yield: 103.5 %

Procedure:
To a suspension of crude compound 28 (1.33 g, 1.54 mmol) and K2CO3 (0.322 g, 2.31 mmol) in acetone (20 mL) was added 3-bromopropanol (0.30 mL, 2.31 mmol) at r.t. The mixture was stirred at 55° C. for 15 hours. The reaction mixture was cooled to r.t and filtered off to remove inorganic salts. The filtrate was concentrated in vacuo. The residue was purified using normal phase column chromatography to provide the title product 29 (1.47 g, 100%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:16]=[C:17]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:18]=[N:19][CH:20]=2)[CH2:13][C:12]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[N:11]1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:16]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([S:42]([CH3:41])(=[O:44])=[O:43])[CH2:23][CH2:22]3)[CH:18]=[N:19][CH:20]=2)[CH2:13][C:12]([C:27]([F:33])([F:32])[C:28]([F:29])([F:30])[F:31])=[N:11]1
Reactant: CS(=O)(=O)Cl
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cncc(N3CCNCC3)c2)c(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2cncc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.3 %

Procedure:
1-(2,4-Difluoro-phenyl)-5-[3-(piperazin-1-yl)-pyridin-5-yl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Example 170, triethylamine (42.3 uL, 0.30 mmol) and methanesulfonyl chloride (10.4 mg, 0.09 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 1 hour, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 15.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH:8]=[N:9][OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].ClN1C(=O)CCC1=O.[CH:21]([P:23](=[O:28])([O:26][CH3:27])[O:24][CH3:25])=[CH2:22].C(N(CC)CC)C>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]2[CH2:22][CH:21]([P:23](=[O:28])([O:26][CH3:27])[O:24][CH3:25])[O:10][N:9]=2)=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: C=CP(=O)(OC)OC
Reactant: O=[N+]([O-])c1ccc(C=NO)cc1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Product: COP(=O)(OC)C1CC(c2ccc([N+](=O)[O-])cc2)=NO1

Procedure:
Preparation is carried out in analogy to Example 1 from 19.6 g (0.118 mol) of 4-nitrobenzaldoxime, 17.4 g (0.13 mol) of N-chlorosuccinimide, 16.1 g (0.118 mol) of dimethyl vinylphosphonate and 18.7 ml (0.13 mol) of triethylamine. Crystallization of the crude product from tert.butyl methyl ether provides analytically pure compound of melting point 156° to 158° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH3:2].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH:5]=1)[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCOc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Temperature: 120 °C
Yield: 170.6 %

Procedure:
The two reactions were performed in parallel. Two microwave vials were set up in parallel. In a large 30 mL microwave vial, 3-(ethyloxy)phenol (2 times 1.25 g, 9.045 mmol) was dissolved in 6 mL of dimethylformamide. 1-Fluoro-4-nitrobenzene (2 times 1.28 g, 9.045 mmol) and potassium carbonate (2 times 3.75 g, 27.15 mmol) were added. The reaction mixture was heated under microwave irradiation during 1 hour at 120° C. The combined reaction mixtures were filtered. The filtrated solid was washed with dichloromethane. The volatiles were evaporated under vacuum. Some dichloromethane and brine were added to this crude. The compound was extracted with dichloromethane (2 times) and ethyl acetate (2 times). The combined organic phases were dried over sodium sulphate. This afforded the title compound (4 g).
Reaction SMILES: [CH:1]1([C:7]2[O:8][C:9]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:10][C:11]=2[CH:12]([O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=2)[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:34][NH:35][CH2:36][CH2:37][C:38]([O:40]CC)=[O:39]>>[CH:1]1([C:7]2[O:8][C:9]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=3)=[CH:10][C:11]=2[CH:12]([O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:35]([CH3:34])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:20])=[CH:17][CH:16]=2)[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC
Reactant: CC(Oc1ccc(C(=O)O)cc1)c1cc(-c2ccc(C(F)(F)F)cc2)oc1C1CCCCC1
Product: CC(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)c1cc(-c2ccc(C(F)(F)F)cc2)oc1C1CCCCC1
Yield: 84.3 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-(1-{2-cyclohexyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethoxy)benzoic acid (138 mg) as well as ethyl 3-(methylamino)propanoate (47 mg) to give the title compound (138 mg, 84%) as an amorphous compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[C:10](O)(=O)[CH3:11]>Cl>[Cl:1][C:2]1[N:7]=[C:6]([CH2:10][CH3:11])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: CC(=O)O
Reactant: Fc1cnc(Cl)nc1Cl
Agent: Cl
Product: CCc1nc(Cl)ncc1F
Temperature: 100 °C

Procedure:
The product of part (i) (3.2 g) was dissolved in acetic acid (25 ml) and diluted with 5N HCl (10 ml). After heating the mixture at 100° C. for 16 hours the mixture was cooled and partitioned between water (30 ml) and dichloromethane (45 ml). The dichloromethane layer was separated, dried and concentrated under reduced pressure to give an oil. The title compound was isolated by chromatography on silica gel using dichloromethane as the eluent. The product was characterised by 1H-NMR and mass spectrometry (yield=350 mg).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:26]=[CH:25][C:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[C:4]([F:27])[CH:3]=1.C(I)(I)[I:29].N(OC(C)(C)C)=O>O1CCCC1>[F:27][C:4]1[CH:3]=[C:2]([I:29])[CH:7]=[CH:6][C:5]=1[O:8][C:9]1[CH:26]=[CH:25][C:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:11]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Oc3ccc(N)cc3F)cc2CC1
Reactant: IC(I)I
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Oc3ccc(I)cc3F)cc2CC1

Procedure:
To a solution of 1,1-dimethylethyl 7-[(4-amino-2-fluorophenyl)oxy]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (E274, Step 2) (0.5 g, 1.34 mmol) and iodoform (1 g, 2.69 mmol) in tetrahydrofuran (10 ml) was added dropwise tert-butyl nitrite (0.32 ml, 2.69 mmol). The reaction was then heated at reflux for 1 hour, cooled and concentrated in vacuo and resulting residue was purified by column chromatography eluting with a mixture of ethyl acetate:pentane (1:10) to afford the title compound. MS (ES+) m/e 384 [M−COOtBu]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH:20]1([NH:25][C:26](=O)[O:27]C2C=CC=CC=2)[CH2:24][CH2:23][CH2:22][CH2:21]1.O>CN(C)C=O>[CH:20]1([NH:25][C:26]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([O:10][C:11]4[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=4)=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(NC1CCCC1)Oc1ccccc1
Reactant: Nc1cc(Oc2ccc3[nH]ccc3c2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CCCC3)c2)ccn1
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
4-(1H-5-Indolyloxy)-2-pyridinamine (2.50 g, 11.1 mmol, CAS No. 417722-11-3), which was described in WO 02/32872, was dissolved in N,N-dimethylformamide (30 ml); sodium hydride (0.530 g, 13.3 mmol) was added thereto at room temperature; and the reaction mixture was stirred for 30 minutes. Phenyl N-cyclopentylcarbamate (2.50 g, 12.2 mmol) was added thereto at room temperature while stirring; and the reaction mixture was stirred for 30 minutes. Water was added to the reaction mixture; and the precipitated crystals were filtered off, and washed with water. This crystals were dissolved in methanol, and purified by silica gel column chromatography (Fuji Silysia NH; hexane:ethyl acetate=1:1, ethyl acetate, ethyl acetate:methanol=98:2 in this order). The obtained crystals were suspended in hexane:ethanol=10:1, filtered off, washed with hexane, and dried under aeration to yield the title compound as colorless crystals (2.08 g, 6.18 mmol, 55.7%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH3:9].[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[CH3:9][C:3]1[C:4]([CH3:8])=[CH:5][C:6]([N+:10]([O-:12])=[O:11])=[CH:7][C:2]=1[NH2:1]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(N)c1C
Agent: O=S(=O)(O)O
Product: Cc1cc([N+](=O)[O-])cc(N)c1C
Temperature: 12 °C

Procedure:
363 g of 2,3-xylidine are run into 1.8 of pure sulphuric acid while the temperature is kept at 40° C. To this solution, cooled to 12° C., a sulphonitric mixture (132 ml of nitric acid (d=1.52) and 180 ml of pure sulphuric acid) is added dropwise over 1 hour, the temperature not exceeding 15° C. After 15 minutes the mixture is poured onto 6 kg of ice with stirring.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:32][CH:33]([CH3:35])[CH3:34])=[C:4](/[C:17](/[CH2:30][CH3:31])=[CH:18]/[CH:19]=[CH:20]/[C:21](/[CH3:29])=[C:22](/[F:28])\[C:23]([O:25]CC)=[O:24])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:13])([CH3:12])[CH:8]=[C:7]2[CH:14]([CH3:16])[CH3:15].[OH-].[Na+]>C(O)C.C1COCC1>[Cl:1][C:2]1[C:3]([O:32][CH:33]([CH3:34])[CH3:35])=[C:4]([C:17]([CH2:30][CH3:31])=[CH:18][CH:19]=[CH:20][C:21]([CH3:29])=[C:22]([F:28])[C:23]([OH:25])=[O:24])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:13])([CH3:12])[CH:8]=[C:7]2[CH:14]([CH3:15])[CH3:16]
Reactant: CCOC(=O)/C(F)=C(C)\C=C\C=C(/CC)c1cc2c(c(Cl)c1OC(C)C)OC(C)(C)C=C2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCC(=CC=CC(C)=C(F)C(=O)O)c1cc2c(c(Cl)c1OC(C)C)OC(C)(C)C=C2C(C)C

Procedure:
Following General Procedure G, a solution of ethyl 7-(8-chloro-7-isopropoxy-4-isopropyl-2,2-dimethyl-2H-chromen-6-yl)-2-fluoro-3-methyl-nona-2E,4E,6E-trienoate (Compound 169, 1.02 g, 2.01 mmol) in ethanol and THF was hydrolyzed with 1M NaOH. Purification by flash chromatography (silica gel, 30% to 50% ethyl acetate in hexanes) and recrystallization from acetonitrile gave rise to the title compound as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([CH2:9][O:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1cccc(Br)c1
Reactant: BrCc1ccccc1
Product: Brc1cccc(OCc2ccccc2)c1

Procedure:
The title compound was synthesized (4.8 g, quant.) following Description 41 from 3-bromophenol (3 g, 17.3 mmol) and benzylbromide (2.1 ml); Rt (HPLC): 6.42 min.
Reaction SMILES: B(Cl)(Cl)Cl.C([O:12][C@H:13]1[C@H:17]([O:18]CC2C=CC=CC=2)[C@@H:16]([CH2:26][O:27]CC2C=CC=CC=2)[S:15][CH:14]1[N:35]1[CH:42]=[CH:41][C:39]([NH2:40])=[N:38][C:36]1=[O:37])C1C=CC=CC=1>ClCCl>[CH:14]1([N:35]2[CH:42]=[CH:41][C:39]([NH2:40])=[N:38][C:36]2=[O:37])[S:15][C@H:16]([CH2:26][OH:27])[C@@H:17]([OH:18])[C@@H:13]1[OH:12]
Reactant: Nc1ccn(C2S[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)c(=O)n1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: Nc1ccn(C2S[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a solution of boron trichloride (1 M solution) in dry dichloromethane (7 mL, 7 mmol) cooled to −78° C., was added dropwise over a period of 30 min, a solution of compound 7 (265 mg, 0.5 mmol) in dry dichloromethane (10 mL). Stirring was continued overnight at −20° C. The solvent was removed in vacuo and the residue was coevaporated with dichloromethane (4×20 mL). The residue was neutralized with saturated NaHCO3 (25 mL) and washed with chloroform (15 mL). The aqueous layer was applied to a cation exchange (H+) column and eluted with water to remove salts and then eluted with 1N NH4OH to obtain the desired compound 8 (110 mg, 85%) MS z/e 260(M+H)+.
Reaction SMILES: [Na].[NH2:2][C:3]([NH2:5])=[O:4].C([C:8]1[C:9]([C:14](O)=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1)C>N>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:8][C:9]=1[C:14]([NH:2][C:3]([NH2:5])=[O:4])=[O:15]
Reactant: CCc1cccnc1C(=O)O
Reactant: NC(N)=O
Agent: N
Agent: [Na]
Product: NC(=O)NC(=O)c1ccccn1

Procedure:
A mixture of sodium (0.23 g, 10 mmol), urea (0.8 g, 13.3 mmol) and liquid ammonia (40 ml) was stirred until the blue colour was discharged, then ethyl 2-pyridinecarboxylic acid (2.85 g, 18.8 mmol) was added all at once. After 1 h the ammonia was evaporated and the residue triturated with water to give the above compound, mp 183°-185° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH3:12])[CH:6]=[CH:5][C:4]=1[O:13][C:14](=[O:30])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:17](Br)[CH:16]=1)#[N:2].[CH3:31][N:32](C)C=O>Cl.O>[C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH3:12])[CH:6]=[CH:5][C:4]=1[O:13][C:14](=[O:30])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:17]([C:31]#[N:32])[CH:16]=1)#[N:2]
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CCCC)cc2C#N)cc1Br
Reactant: CN(C)C=O
Agent: Cl
Solvent: O
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CCCC)cc2C#N)cc1C#N
Temperature: 25 °C

Procedure:
9.9 g (0.021 mol) of the (2'-cyano-4'-n-butylphenyl)-3-bromo-4-n-heptyloxybenzoate prepared in Step VI and 4 g of cuprous cyanide were added to 80 ml of N,N-dimethylformamide. The suspension was gently refluxed for four hours. The reaction mixture was cooled to room temperature, poured into a solution of 14.5 g ferric chloride hexahydrate dissolved in a mixed solution of 3.6 ml of concentrated hydrochloric acid and 22 ml of water, and was stirred with heating at 65° C. for 30 minutes in order to decompose any complexes. An organic layer was extracted from the suspension with toluene, was cleaned and was dehydrated. The toluene was distilled off. The residue was recrystallized in ethanol to yield 3.4 g of purified (2'-cyano-4'-n-butylphenyl)-3-cyano-4-n-heptyloxybenzoate. The yield was calculated to be 39.1%.
Reaction SMILES: [C:1]1([C:7]2[N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[B:31](OC(C)C)([O:36]C(C)C)[O:32]C(C)C.C(O)(=O)C>C1COCC1>[C:12]([N:11]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[B:31]([OH:36])[OH:32])=[N:8][N:9]=[N:10]1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: OB(O)c1ccccc1-c1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -25 °C
Reaction time: 3 h
Yield: 69.3 %

Procedure:
A solution of 5-phenyl-1-trityl-1H-tetrazole (70.0 g, 180.20 mmol, 1.00 equiv) in THF (dried) (560 mL) was placed in a flask that had been purged and maintained with an inert atmosphere of nitrogen. The mixture was cooled to −25° C. Butyllithium was added to quench the trace of water in the reaction mixture until the color of the mixture remained red for at least 5 minutes. Butyllithium (80.0 mL, 2.5 mol/L) was then added dropwise to the mixture over a period of about 40 minutes at a temperature below −25° C. The temperature of the mixture was raised to −5° C., and the mixture was stirred at −5° C. for 3 hours. The mixture was then cooled to −25° C. and triisopropyl borate (50.8 g, 270.11 mmol, 1.50 equiv) was added dropwise. The mixture was warmed to temperature in the range of 25-35° C. and stirred for 2 hours. The mixture was cooled again in the range of 0-5° C., and 3% aqueous acetic acid (470 mL) was slowly added over 30-40 minutes. The mixture was stirred for 30-40 minutes and then filtered. The crude product was washed with water (2×300 mL) and dried over reduced pressure. The crude product was then purified by re-crystallization from EtOAc (1 g/15 ml) to yield 54 g (69%) of the title compound as a white solid. ES m/z: [M+H]+ calcd for C26H21BN4O2 433.1. found 433.1.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH2:7][CH2:8][OH:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:17][S:18]([O:9][CH2:8][CH2:7][C:6]1[S:5][CH:4]=[N:3][C:2]=1[CH3:1])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ncsc1CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ncsc1CCOS(C)(=O)=O
Temperature: 25 °C
Yield: 66.9 %

Procedure:
2-(4-methylthiazol-5-yl)ethanol (5.01 g) was dissolved in dichloromethane (100 ml) and to the solution was added triethylamine (5.06 g), followed by adjusting the temperature of reactor to 0° C. To the obtained solution was added dropwise methanesulfonyl chloride (4.58 g), and the mixture was stirred for 21. hours while allowed to warm up to room temperature. The reaction solution was washed with water, concentrated under reduced pressure, and then purified by column-chromatography (hexane/ethyl acetate=1/3) to yield 5-(2-methylsulfonyloxyethyl)-4-methylthiazole (5.18 g, 67%) as a pale yellow liquid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11](=O)[CH2:12]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26](C(C)(C)C)[N:25]=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][C@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]1[N:23]=[C:24]2[CH:29]=[CH:28][C:27]([C:2]([CH3:7])([CH3:3])[CH3:1])=[CH:26][N:25]2[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1cccc(N)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)CBr
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)c1cn2cc(C(C)(C)C)ccc2n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 1 %

Procedure:
A mixture of tert-butyl {(1S)-1-[(benzyloxy)methyl]-3-bromo-2-oxopropyl}carbamate (3.72 g, 10.0 mmol) and 2-amino-6-tert-butylpyridine (1.5 g, 10.0 mmol) in toluene (50 mL) was stirred at room temperature for 14 hours and then refluxed for 5 hours. The reaction mixture was cooled and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with 30% EtOAc in petroleum ether. The residue was treated with cold conc. HCl (5 mL) at 0° C. followed by stirring at room temperature for 18 hours. The reaction mixture was basified with saturated aqueous Na2CO3 solution, extracted with EtOAc, dried over Na2SO4 and concentrated in vacuo to afford a residue which was purified further by preparative TLC eluting with 20% MeOH in EtOAc to afford the title compound (21 mg, 25%).
Reaction SMILES: [I:1][C:2]1[N:7]=[N:6][C:5]2[N:8]([CH3:17])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[C:3]=1O.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:3]1[C:2]([I:1])=[N:7][N:6]=[C:5]2[N:8]([CH3:17])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1nc(-c2ccccc2)c2c(O)c(I)nnc21
Product: Cn1nc(-c2ccccc2)c2c(Cl)c(I)nnc21
Temperature: 25 °C

Procedure:
5-Iodo-1-methyl-3-phenyl-pyrazolo[3,4-c]pyridazin-4-ol (160 mg, 0.45 mmol) in phosphorous oxychloride (0.6 mL) was heated to 120° C. for 10 min. The reaction mixture was cooled to room temperature and the suspension was filtered. The collected solid was dissolved in CH2Cl2 and washed with water. The organic phase was dried (phase separator cartridge) and concentrated in vacuo, to yield Compound IIIa (130 mg).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([CH3:6])=[O:5].[F:7][C:8]1[CH:17]=[CH:16][C:11]([CH:12]=[CH:13][CH:14]=O)=[CH:10][CH:9]=1.Cl>O.C(O)C>[F:7][C:8]1[CH:17]=[CH:16][C:11]([CH:12]=[CH:13][CH:14]=[CH:3][C:4](=[O:5])[CH3:6])=[CH:10][CH:9]=1
Reactant: O=CC=Cc1ccc(F)cc1
Reactant: CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)C=CC=Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.3 %

Procedure:
Sodium hydroxide (2 g) in water (35 ml) was added to a stirred mixture of acetone (9.7 g) and ethanol (20 ml) cooled in a water bath. 4-Fluorocinnamaldehyde (5 g) was added dropwise to the stirred solution such that the temperature did not exceed 25°. The mixture was stirred at room temperature for 5 min, diluted with water (250 ml), adjusted to pH 1 with 5 M hydrochloric acid and extracted with ethyl acetate (3×100 ml). The combined extracts were washed with brine (1×100 ml), dried (MgSO4) and evaporated to give an orange oil (6.1 g) which was used crude in the next stage.