Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:15].N1C=CC=CC=1.[C:22]12([CH2:32][C:33](Cl)=[O:34])[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2>C(Cl)Cl.CCOC(C)=O>[C:22]12([CH2:32][C:33]([NH:1][N:2]3[N:11]=[C:10]([CH:12]([CH3:13])[CH3:14])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]3=[O:15])=[O:34])[CH2:29][CH:28]3[CH2:27][CH:26]([CH2:25][CH:24]([CH2:30]3)[CH2:23]1)[CH2:31]2
Reactant: CC(C)c1nn(N)c(=O)c2ccccc12
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)c1nn(NC(=O)CC23CC4CC(CC(C4)C2)C3)c(=O)c2ccccc12
Reaction time: 2 h
Yield: 87.9 %

Procedure:
A mixture of the product of Example 1B (45.4 mg, 0.223 mmol), pyridine (0.023 mL, 0.28 mmol), and (adamantan-1-yl)acetyl chloride (0.052 g, 0.24 mmol) in CH2Cl2 (0.8 mL) was stirred for 2 hours, diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), and filtered. The residue was chromatographed on SiO2 (eluted with 8% EtOAc/CH2Cl2) to give the title compound (0.0743 g, 0.196 mmol) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.35 (dd, 1H), 8.10 (d, 1H), 7.98 (td, 1H), 7.89 (ddd, 1H), 3.62 (quin, 1H), 2.03 (s, 2H), 1.95 (s, 3H), 1.76-1.52 (m, 12H), 1.26 (d, 6H); MS (ESI−) M/Z 378.1 (M−H)−.
Reaction SMILES: N([O-])=O.[Na+].[F:5][C:6]1[CH:12]=[C:11]([CH3:13])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:7]=1N.[BrH:17]>O.[Cu]Br>[Br:17][C:7]1[CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]([CH3:13])=[CH:12][C:6]=1[F:5]
Reactant: Br
Reactant: Cc1cc(F)c(N)cc1[N+](=O)[O-]
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(F)c(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 50 %

Procedure:
A solution of sodium nitrite (7.6 g, 110 mmol) in water (30 mL) was added dropwise over 15 min to a stirred suspension of 2-fluoro-4-methyl-5-nitroaniline (17 g, 100 mmol) in hydrobromic acid, (48%, 150 mL) and water (30 mL) at 0° C. The mixture was stirred at 0° C. for 15 min then added portionwise over 10 min to a stirred suspension of copper(I)bromide (16.5 g, 112 mmol) in hydrobromic acid (48%, 50 mL) and water (90 mL) at 0° C. The mixture was stirred at 0° C. for 30 min then warmed to room temperature and stirred for 3 h. The mixture was poured onto ice-water (500 mL) and extracted with ethyl acetate (3×). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution, dried (magnesium sulfate), concentrated in vacuo and purified by column chromatography [SiO2; heptane-ethyl acetate (19:1)] to give the product (11.8 g, 50%) as an off-white solid: IR νmax (nujol)/cm−1 2925, 2855, 1571, 1523, 1478, 1349, 1264, 1103, 895, 671 and 589; NMR δH (400 MHz, CDCl3) 8.27 (1H, d, J 6.5), 7.10 (1H, d, J 9.1), 2.60 (3H, s).
Reaction SMILES: [C:1]1([C:7]2([CH2:12][CH2:13][OH:14])[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([OH:28])[C:25]=1[O:26][CH3:27])[C:20](O)=[O:21].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CO.ClCCl>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([OH:28])[C:25]=1[O:26][CH3:27])[C:20]([N:9]1[CH2:10][CH2:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH2:12][CH2:13][OH:14])[CH2:8]1)=[O:21]
Reactant: OCCC1(c2ccccc2)CCNC1
Reactant: COc1cc(C(=O)O)cc(O)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)N2CCC(CCO)(c3ccccc3)C2)cc(O)c1OC
Reaction time: 18 h

Procedure:
Combine 3-phenyl-3-(2-hydroxyethyl)pyrrolidine (0.50 g, 2.7 mmol) (prepared by extraction from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) and dichloromethane (25 mL). Add 3,4-dimethoxy-5-hydroxybenzoic acid (0.55 g, 2.78 mmol), 1-hydroxybenzotriazole hydrate (0.4 g, 2.9 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.56 g, 2.9 mmol). After 18 hours, dilute the reaction mixture with dichloromethane and extract with saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give residue. Chromatograph the residue on silica gel eluting with methanol/dichloromethane/concentrated aqueous ammonia 1/10/0.1 to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15](I)[CH:14]=2)[C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[N:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:23]3[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=3)[CH:14]=2)[C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1
Reactant: NC(=O)c1cnc(Cl)cc1NCc1cccc(I)c1
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)c1cnc(Cl)cc1NCc1cccc(-c2ccncc2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 33.1 %

Procedure:
To a solution of 6-chloro-4-(3-iodobenzylamino)nicotinamide (200 mg, 0.50 mmol) in Dioxane (2 mL) was added pyridine-4-boronic acid (92 mg, 0.75 mmol) and Pd(PPh3)2Cl2 (56 mg, 0.08 mmol), followed by a solution of Na2CO3 (173 mg, 1.63 mmol) in H2O (1 mL). After stirring at 100° C. for 2 h, it was concentrated and purified by preparative HPLC to give 6-chloro-4-(3-(pyridine-4-yl)benzylamino)nicotinamide (56 mg).
Reaction SMILES: [NH2:1][NH2:2].C(O)(=O)C.[Cl:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH:15]([C:18](=O)[CH3:19])[C:16]#[N:17])=[C:10]([CH3:21])[CH:9]=1>C1(C)C=CC=CC=1>[NH2:17][C:16]1[NH:2][N:1]=[C:18]([CH3:19])[C:15]=1[C:11]1[C:12]([CH3:14])=[CH:13][C:8]([Cl:7])=[CH:9][C:10]=1[CH3:21]
Reactant: NN
Reactant: CC(=O)C(C#N)c1c(C)cc(Cl)cc1C
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)cc(C)c1-c1c(C)n[nH]c1N
Temperature: 130 °C
Reaction time: 0.17 h

Procedure:
Dissolve anhydrous hydrazine (0.91 g, 0.90 mL) in 20 mL toluene. Add glacial acetic acid (2.25 mL) and allow to stand at ambient temperature for 10 minutes until solution becomes cloudy white. Add a solution of 2-(4-chloro-2,6-dimethylphenyl)-3-oxobutanenitrile in 10 mL toluene, rinsing out the ketonitrile flask with an additional 5 mL toluene. Heat to reflux under N2 (130° C.) with Dean-Stark trap attached. Water will begin to accumulate after 10 minutes or so. After 2 hours, evaporate down and partition between 1.0 N NaOH (100 mL) and EtOAc (100 mL). Extract aqueous layer with EtOAc (2×100 mL), then pool the organic layers and dry over Na2SO4. Filter and evaporate to yellow oil (1.75 g). Use without further purification. LCMS=236.5 (M+); 234.5 (M−)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([OH:19])=O)[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[CH:4][CH:3]=1.Cl.Cl.[NH2:22][CH:23]1[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1>>[N:25]12[CH2:30][CH2:29][CH:28]([CH2:27][CH2:26]1)[CH:23]([NH:22][C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:10]3[O:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:12][C:11]=13)=[O:19])[CH2:24]2
Reactant: NC1CN2CCC1CC2
Reactant: O=C(O)c1cccc2oc(-c3ccc(F)cc3)nc12
Agent: Cl
Product: O=C(NC1CN2CCC1CC2)c1cccc2oc(-c3ccc(F)cc3)nc12
Yield: 8 %

Procedure:
N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-fluorophenyl)benzoxazole-4-carboxamide was prepared from 2-(4-fluorophenyl)benzoxazole-4-carboxylic acid and 3-aminoquinuclidine dihydrochloride using the method outlined in Step C of Example 14. This compound was obtained in 8% yield as a white solid: mp 208-209° C.; 1H NMR (500 MHz, CD3OD) δ 8.33 (m, 2H), 8.05 (m, 1H), 7.90 (dd, J=8.2, 0.9 Hz, 1H), 7.55 (m, 1H), 7.39 (m, 2H), 4.29 (m, 1H), 3.52 (m, 1H), 3.06 (m, 2H), 2.94 (m, 2H), 2.92 (m, 1H), 2.16 (m, 2H), 1.86 (m, 3H); MS (ESI) m/z 366 [M+H]+
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[CH3:14][N:15]([CH:17](OC)OC)[CH3:16]>C1COCC1>[CH3:14][N:15](/[CH:17]=[C:6]1/[CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3][C:2]/1=[O:1])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: COC(OC)N(C)C
Solvent: C1CCOC1
Product: CN(C)/C=C1/CN(C(=O)OC(C)(C)C)CC1=O
Temperature: 67.5 °C

Procedure:
A solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (53.4 kg, 288 mol) in THF (133 kg) was treated with DMF-DMA (103 kg, 864 mol) in THF (472 kg) and heated at 65-70° C. under nitrogen for 20 h. The solution was cooled, evaporated under reduced pressure and solvent switched under distillation to cyclohexane. The resulting slurry was then filtered, cake washed with cyclohexane, and then water. The solids were then dried under vacuum at 35-40° C. to give tert-butyl (3Z)-3-[(dimethylamino)methylene]-4-oxopyrrolidine-1-carboxylate.
Reaction SMILES: Br[CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([Br:13])=[CH:7][C:8]=2[Br:12])[C:3]1=[O:14].[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1>CN(C)C=O>[N:15]1([CH:2]2[CH2:11][CH2:10][C:9]3[C:4](=[CH:5][C:6]([Br:13])=[CH:7][C:8]=3[Br:12])[C:3]2=[O:14])[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: O=C1c2cc(Br)cc(Br)c2CCC1Br
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: O=C1c2cc(Br)cc(Br)c2CCC1n1ccnc1
Yield: 62.1 %

Procedure:
A solution of 2,5,7-tribromo-3,4-dihydro-1(2H)-naphthalenone (1 g), imidazole (0.7 g), and N,N-dimethylformamide (15 ml) was stirred at room temperature for 5 hours. The solvent was evaporated under reduced pressure and the residue, taken up with CH2Cl2 (20 ml), washed with H2O, was extracted with a solution of 8% HCl. The acid solution, neutralized with NaHCO3, extracted with CH2Cl2, dried and evaporated, gave 0.6 g of 2-(1-imidazolyl)-3,4-dihydro-5,7-dibromo-1(2H)-naphthalenone;
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13]C)=[CH:4][C:5]2[CH:9]=[C:8]([CH3:10])[S:7][C:6]=2[C:11]=1[Cl:12].Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[C:3]([OH:13])=[CH:4][C:5]2[CH:9]=[C:8]([CH3:10])[S:7][C:6]=2[C:11]=1[Cl:12]
Reactant: COc1cc2cc(C)sc2c(Cl)c1Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1cc2cc(O)c(Cl)c(Cl)c2s1
Reaction time: 3 h

Procedure:
A mixture of 4.8 g of 6,7-dichloro-5-methoxy-2-methylbenzo[b]thiophene and 40 g of pyridine hydrochloride is stirred at 190° for 3 hours. The cooled mixture is diluted with 500 ml of water. The solid is collected and air-dried. Recrystallization from ether-hexane mixture gives 6,7-dichloro-5-hydroxy 2-methylbenzo[b]thiophene as off-white crystals, mp 93°-95° C.
Reaction SMILES: [CH3:1][N:2]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH2:21][C:22]#[CH:23])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH2:3][C:4]([O:6]C(C)(C)C)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][N:2]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH2:21][C:22]#[CH:23])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: C#CCNc1ccc(S(=O)(=O)N(C)CC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C#CCNc1ccc(S(=O)(=O)N(C)CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 866.7 %

Procedure:
To a solution of 0.160 g (0.047 mmol) of 2-(methyl{[4-(prop-2-ynylamino)phenyl]sulfonyl}amino)acetic acid, tert-butyl ester in 1 mL of dichloromethane was added 1 mL of trifluoroacetic acid and the reaction was stirred at room temperature for 19 h. Concentration of the mixture in vacuo provides 0.115 g (86%) of 2-(methyl{[4-(prop-2-ynylamino)phenyl]sulfonyl}amino)acetic acid as a brown glass. Electrospray Mass Spec 281.1 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:29])[C@@H:13]([NH:21]C(OC(C)(C)C)=O)[CH2:14][CH2:15][C:16]2[N:17]=[N:18][NH:19][N:20]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:29])[C@@H:13]([NH2:21])[CH2:14][CH2:15][C:16]2[N:17]=[N:18][NH:19][N:20]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCc2nn[nH]n2)NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCc2nn[nH]n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 120 mg 4-[(S)-2-tert-butoxycarbonylamino-4-(2H-tetrazol-5-yl)-butyryl]-piperazine-1-carboxylic acid ethyl ester in 1.5 ml dichloromethane were added 0.4 ml TFA. After 2 h stirring at RT the solvents were removed and the residue was used without further purification. Yield: 130 mg.
Reaction SMILES: C(OC(=O)[N:7]([CH2:30][CH:31]1[CH2:33][CH2:32]1)[C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:29])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25](=[O:28])(=[O:27])[NH2:26])[CH:20]=2)=[CH:13][CH:12]=1)(C)(C)C.[ClH:35].C(OCC)(=O)C>>[ClH:35].[CH:31]1([CH2:30][NH:7][C@@H:8]2[CH2:10][C@H:9]2[C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:29])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25](=[O:27])(=[O:28])[NH2:26])[CH:20]=3)=[CH:15][CH:16]=2)[CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)N(CC1CC1)[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(S(N)(=O)=O)c2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1cccc(C(=O)Nc2ccc([C@@H]3C[C@H]3NCC3CC3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl(cyclopropylmethyl)(trans-2-{4-[(3-sulfamoylbenzoyl)amino]phenyl}cyclopropyl)carbamate (125.0 mg) was dissolved in 4N hydrochloric acid/ethyl acetate solution (1.25 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/diisopropyl ether to give the title compound (69.5 mg).
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:24][C:25]([CH3:27])=[CH2:26]>CS(C)=O>[OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:26][C:25]([CH3:27])=[CH2:24])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: C=C(C)CCl
Reactant: O=C(c1ccc(O)cc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=C(C)COc1ccc(C(=O)c2ccc(O)cc2)cc1
Temperature: 0 °C
Yield: 47 %

Procedure:
A solution of 14.6 grams (0.0682 mole) of 4,4'-dihydroxybenzophenone and 10.4 grams (0.0751 mole) of potassium carbonate in 250 mL of dimethyl sulfoxide was stirred under a nitrogen atmosphere for 20 minutes. To this was added during a 20 minute period via syringe 7.32 mL (0.0751 mole) of 3-chloro-2-methylpropene. Upon completion of addition the reaction mixture was heated at 60°-65° C. for 18 hours. The reaction mixture was poured into 600 mL of ice-water and then was extracted with four portions of diethyl ether. The combined ether extracts were washed with two 200 mL portions of aqueous 1N sodium hydroxide. The combined sodium hydroxide washes were made acidic with aqueous 20% hydrochloric acid. The resultant solid was dissolved in diethyl ether, and the solution was washed first with a saturated aqueous sodium chloride solution and then with water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield 8.6 grams of 4-hydroxy-4'-(2-methyl-2-propenoxy)benzophenone.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[CH:3]=1.CC(OC)(C)C.[Br:16]Br>O>[Br:16][C:6]1[CH:5]=[C:4]([CH3:9])[CH:3]=[C:2]([F:1])[C:7]=1[NH2:8]
Reactant: BrBr
Reactant: Cc1ccc(N)c(F)c1
Solvent: COC(C)(C)C
Solvent: O
Product: Cc1cc(F)c(N)c(Br)c1
Temperature: 18 °C
Reaction time: 0.5 h

Procedure:
6-fluoro-4-methylaniline 6 (15 kg) was added to a mixture of MTBE (92 L, 66.6 kg) calcium carbonate (12 kg) and water (135 kg), inerted and cooled to <5° C. Bromine (18.22 kg) was charged, keeping T<10° C. Age for 30 minutes at T<10° C. The batch was warmed to ˜18° C. and allowed to settle.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:19])=[O:18].CC([O-])(C)C.[K+]>C1(C)C=CC=CC=1>[CH2:1]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:24][CH2:23][CH2:22][CH2:21][CH2:20][C:17]([OH:19])=[O:18])[CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(Cc2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(O)CCCCC=Cc1cccc(Cc2ccccc2)c1

Procedure:
By using a similar procedure to that described in example 24 but with 1 g of 3-benzylbenzaldehyde, 5.5 g of (6-carboxy-hexyl)triphenylphosphonium iodide, 2.5 g of potassium ter-butylate and 40 cc of toluene as the starting material (1 hour; 50° C.), and after purification by flash chromatography on silica gel (30-60 Mm; eluent: 8:2:0.05 n-hexane/ethyl acetate/acetic acid), 7-(3-benzyl-phenyl)-6-heptenoic acid is obtained. (m.p.=68° C.)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1.[OH-:29].[Na+].CO>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:5]2[N:6]([C:8]([C:11]([NH2:12])=[O:29])=[CH:9][N:10]=2)[N:7]=1
Reactant: [OH-]
Reactant: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(C#N)cnc23)cc1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(C(N)=O)cnc23)cc1
Temperature: 100 °C

Procedure:
A mixture of 6-chloro-3-cyano-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-amine (25 mgs) from Example XXXI(1) step 1b, 6N NaOH (0.1 mL), MeOH (0.1 mL) and dioxane (1 mL) in a vial was heated to 100° C. for 16 h. The mixture was cooled to room temperature and concentrated in vacuo. Upon addition of 1M HCl a precipitate forms. The precipitate was collected by filtration and dried to provide 35 mgs of crude 6-chloro-8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazine-3-carboxamide.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:28])[N:4]([CH2:17][C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20](OC)=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.[Li+].[BH4-]>C1COCC1>[Br:1][C:2]1[C:3](=[O:28])[N:4]([CH2:17][C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[CH2:20][OH:21])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccccc1Cn1ccc(OCc2ccc(F)cc2)c(Br)c1=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1c(Br)c(OCc2ccc(F)cc2)ccn1Cc1ccccc1CO
Temperature: 40 °C
Reaction time: 6 h

Procedure:
To an ice-cold solution of 3-bromo-4-(4-fluorobenzyloxy)-1-(2-hydroxymethylbenzyl)-1H-pyridin-2-one (Example 72) (0.25 g, 0.56 mmol) in THF (1 mL) was added LiBH4 (2.0 M solution in THF, 0.56 mmol), and the reaction mixture was stirred at 40° C. for 6 hours. The reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the residue was dissolved in EtOAc. The organic solution was washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. 1H NMR (300 MHz, DMSO-d6) δ 7.82 (d, J=8 Hz, 1H), 7.54-7.49 (m, 2H), 7.41 (d, J=7 Hz, 1H), 7.29-7.21 (m, 4H), 6.81 (d, J=7 Hz, 1H), 6.53 (d, J=8 Hz, 1H), 5.30-5.25 (m, 3H), 5.18 (s, 2H), 4.60 (d, J=7 Hz, 2H). ESHRMS m/z 418.0437 (M+H C20H18BrFNO3 requires 418.0449)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([CH3:27])([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[F:35]>>[F:28][C:29]1[CH:30]=[C:31]([C:2]2[N:7]=[C:6]([C:8]3[N:12]4[CH:13]=[CH:14][C:15]([C:17]([CH3:27])([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:18])=[N:16][C:11]4=[N:10][CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:32]=[CH:33][C:34]=1[F:35]
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(Cl)n3)cnc2n1
Reactant: OB(O)c1ccc(F)c(F)c1
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(-c4ccc(F)c(F)c4)n3)cnc2n1

Procedure:
3-(2-Chloropyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)-imidazo-[1,2-α]pyrimidine (250 mg, 0.62 mmol) and 3,4-difluorobenzeneboronic acid (196 mg, 1.24 mmol) were reacted together as described in Example 61. Purification by column chromatography on silica using 2.5% MeOH/CH2Cl2 gave 3-[2-(3,4-difluorophenyl)pyrimidin-4-yl]-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine: m/z (ES+) 482 (M+H+).
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[C:10]2[C:11]3[C:12](=[N:23][N:24]([CH2:26][C:27]4[C:32]([CH3:33])=[C:31]([O:34][CH3:35])[C:30]([CH3:36])=[CH:29][N:28]=4)[N:25]=2)[CH:13]=[C:14]([CH2:19][C:20]([OH:22])=O)[C:15]=3[CH2:16][S:17][N:18]=1)=O)(C)(C)C.[Cl-].[NH4+].O.O[N:48]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>CN(C)C=O>[NH2:8][C:9]1[C:10]2[C:11]3[C:12](=[N:23][N:24]([CH2:26][C:27]4[C:32]([CH3:33])=[C:31]([O:34][CH3:35])[C:30]([CH3:36])=[CH:29][N:28]=4)[N:25]=2)[CH:13]=[C:14]([CH2:19][C:20]([NH2:48])=[O:22])[C:15]=3[CH2:16][S:17][N:18]=1
Reactant: On1nnc2ccccc21
Reactant: COc1c(C)cnc(Cn2nc3cc(CC(=O)O)c4c-3c(n2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C)cnc(Cn2nc3cc(CC(N)=O)c4c-3c(n2)C(N)=NSC4)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.9 %

Procedure:
A mixture composed of {4-[bis(tert-butoxycarbonyl)amino]-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-8-yl}acetic acid of Example 111 (24 mg), dimethylformamide (0.7 ml), ammonium chloride (13 mg), 1-hydroxybenzotriazole monohydrate (6 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (15 mg) and diisopropylethylamine (34 μl) was stirred at room temperature for three days. The solvent in the reaction mixture was evaporated by spraying, and a 0.2 N sodium hydroxide solution was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure. Dichloromethane (2 ml) and trifluoroacetic acid (0.5 ml) were added to the resulting residue, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure. A saturated sodium bicarbonate solution was placed into the resulting residue, followed by extraction with chloroform. The organic layer was dried over sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (chloroform-methanol) to obtain the title compound (16.1 mg, 70%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([CH3:17])[CH:4]=1.C([OH:22])(C)(C)C.C(Cl)Cl.CC(=CC)C.[O-]Cl=O.[Na+]>O.CCOCC>[CH3:1][O:2][C:3]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:9][C:6]([C:7]([OH:22])=[O:8])=[C:5]([CH3:17])[CH:4]=1
Reactant: CC(C)(C)O
Reactant: COCCCOc1cc(C=O)c(C)cc1OC
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: COCCCOc1cc(C(=O)O)c(C)cc1OC
Reaction time: 8 h

Procedure:
To a solution of 4-methoxy-5-(3-methoxy-propoxy)-2-methyl-benzaldehyde (1.25 g, 5.25 mmol) in a 3:1 mixture of tert-butanol/CH2Cl2 (60 mL) is added 2-methyl-2-butene (25.0 mL), followed by dropwise addition of a solution of NaClO2 (5.81 g, 51.4 mmol) and NaH2PO4 (4.07 g, 33.6 mmol) in water (45 mL) over 15 min at room temperature, and stirring is continued overnight. The reaction mixture is poured into ice/saturated aqueous NaHCO3 solution, the water phase is washed with AcOEt, then acidified and extracted with AcOEt. The combined organics are washed with brine, dried (Na2SO4) and concentrated to give a yellow solid. The crude product is stirred for 30 min in a 95:5 mixture of hexaneldiisopropyl ether (25 mL), the precipitate is filtered off, washed with a 95:5 mixture of hexane/diisopropyl ether and dried to give the title compound as yellowish solid. MS: 253.0 [M−H]+. tR (HPLC, Nucleosil C18HD column, 20-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 3.23 min. 1H-NMR (CDCl3): δ 1.96 (m, 2H), 2.51 (s, 3H), 3.27 (s, 3H), 3.48 (m, 2H), 3.84 (s, 3H), 4.00 (m, 2H), 6.89 (s, 1H), 7.41 (s, 1H) ppm.